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

Abstract

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

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 000,584, filed March 27, 2020, which is incorporated herein by reference in its entirety.

[0002] The present invention relates to novel pyridopyrimidinone derivatives capable of modulating the activity of the aryl hydrocarbon receptor (AhR). The compounds of formula (I) of the present invention can be used (as a single agent or in combination with another active ingredient) to inhibit cancer cell proliferation, tumor cell metastasis and invasion, and to treat diseases associated with dysregulated immune responses related to AhR signaling. [Background technology]

[0003] The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and is well known as an important intracellular chemical sensor that responds to both natural and artificial environmental compounds. AhR is a member of the PER (periodic circadian protein)-ARNT (AhR nuclear translocator)-SIM (single-minded protein) transcription factor superfamily, and the PER-ARNT-SIM (PAS) domain of this transcription factor senses ligands (Burbach et al., PNAS September 1, 1992 89 (17) 8185-8189). Upon activation by various ligands, AhR translocates to the nucleus and dimerizes with its partner protein, ARNT. This heterodimeric complex directly or indirectly regulates the expression of AhR-associated genes by interacting with xenobiotic response elements (XREs). Kynurenine is a well-characterized endogenous ligand of AhR. Kynurenine is produced by TDO (Opitz et al., Nature, 2011 Oct 5;478(7368):197-203) or IDO (Mezrich, J Immunol. 2010 Sep 15;185(6):3190-8.). Recent studies have shown that high plasma kynurenine levels and a high serum Kyn / Trp ratio after PD-1 inhibition correlate with poor prognosis in patients with various types of cancer, including lung cancer, melanoma, and renal cell carcinoma (Haoxin Li et al., Nat Commun. 2019 Sep 25;10(1):4346).

[0004] Recently, it has become clear that the AhR regulates the functions of numerous cell types in both the innate and adoptive immune systems. Activated AhR suppresses the induction of cytokines that promote the polarization of pathogenic T cell subsets and reduces MHC class II expression. Furthermore, AhR activation by agonists and modulators suppresses the differentiation of helper Th17 cells and stabilizes regulatory T cells. Furthermore, activated AhR induces the production of AhR ligands through a positive feedforward loop involving indoleamine 2,3-dioxygenase 1 (IDO1) (Nguyen et al., PNAS, 2010, 107(46):19961-19966, Mascanfroni, ID et al. Nat. Med., 2015, 21:638-646). Furthermore, repopulating tumor cells (TRCs) upregulate PD-1 on CD8+ T cells via the Kyn-AhR pathway as an immune evasion mechanism (Yuying Liu et al, Cancer cell, 2018 Mar 12; 33(3):480-494.e7.).

[0005] Furthermore, several studies have revealed that AhR signaling plays an important role in various diseases, including autoimmune diseases, infectious diseases, and cancer. It has been suggested that AhR signaling may be related to autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and multiple sclerosis (MS) (Xiao-Song Wang et al., Inflammopharmacology, 2020 Feb; 28(1):63-81). Constitutive AhR activation reduces the antiviral response of type I interferon (IFN-I) (Yamada et al., Nat Immunol, 2016 Jun; 17(6):687-94). In addition, several viruses induce AhR activation to evade the host immune response. This evasion mechanism has been successfully exploited to inhibit Zika virus and SARS-COV-2 replication in mouse models (Federico Giovannoni et al., Cell Research, 2021 Dec., 31:1-2). AhR may also affect cancer cell proliferation, tissue invasion, metastasis, and angiogenesis (Jae Eun Cheong et al., Trends in Pharmacological Sciences, 2018 Mar; 39(3):307-325). Furthermore, various types of cancer are known to evade immune system recognition via the AhR pathway. Developing therapeutics targeting AhR may offer a promising path to overcoming immune-related diseases. Summary of the Invention [Problem to be solved by the invention]

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

[0007] Another object of the present invention is to provide a pharmaceutical composition for regulating the activity of AhR, which comprises the compound as a modulator of AhR.

[0008] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating a disease, disorder, or condition associated with AhR activity (e.g., cancer, autoimmune disease, etc.), which comprises the compound as an AhR modulator.

[0009] It is also an object of the present invention to provide a method for modulating the activity of AhR by administering the compounds as modulators of AhR.

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

[0011] It is a further object of the present invention to provide the use of prostaglandin analogues for modulating the activity of AhR or for the prevention or treatment of diseases, disorders or conditions associated with AhR. [Means for solving the problem]

[0012] The present invention provides novel compounds, or enantiomers, diastereomers or pharmaceutically acceptable salts thereof, which are effective as modulators or antagonists of AhR. The compounds have the formula (I): [ka] (In the formula, X 1 , X 2 and X 3 are each independently 2 , N or NR 3 and; Ar 1 and Ar 2 is a substituted or unsubstituted monocyclic or bicyclic C 6-10Aryl, substituted or unsubstituted monocyclic or bicyclic C 5-10 Heteroaryl and substituted or unsubstituted monocyclic or bicyclic C 3-10 heterocycloalkyl; D is H, halo, cyano, hydroxy, amino, substituted or unsubstituted, C 1-5 Alkyl, monocyclic or bicyclic C 3-10 Cycloalkyl, C 1-5 Alkylhydroxy, C 1-5 Alkenylhydroxy, C 1-5 Alkynylhydroxy, C 1-5 Alkylamines, C 1-5 Alkenylamines, C 1-5 Alkynylamines, monocyclic or bicyclic C 3-10 Heterocycloalkyl, or monocyclic or bicyclic C 3-10 is heteroaryl; E is absent (direct bond) or is amino, substituted or unsubstituted, C 1-5 Alkyl, monocyclic or bicyclic C 3-10 Cycloalkyl, C 1-5 Alkylhydroxy, C 1-5 Alkenylhydroxy, C 1-5 Alkynylhydroxy, C 1-5 Alkylamines, C 1-5 Alkenylamines, C 1-5 Alkynylamines, monocyclic or bicyclic C 3-10 Heterocycloalkyl, or monocyclic or bicyclic C 3-10 is heteroaryl; or D and E, together with the atoms to which they are attached, form a substituted or unsubstituted monocyclic or bicyclic C 3-10 forming a heterocycloalkyl ring; G is absent (direct bond) or is H, halo, cyano, hydroxy, amino, nitro, ether (-O-), thioether (-S-), sulfinyl (-SO-), sulfonyl (-SO2-), sulfonylamido (-SO2NR 4 -), aminosulfonyl (-NR 4SO2-), carbonyl (-(CO)-), amide (-(CO)NR 4 -), reverse amide (-NR 4 (CO)-), esters (-(CO)O-), substituted or unsubstituted monocyclic or bicyclic C 3-10 Cycloalkyl, substituted or unsubstituted monocyclic or bicyclic C 3-10 Heterocycloalkyl, substituted or unsubstituted monocyclic or bicyclic C 6-10 Aryl or substituted or unsubstituted monocyclic or bicyclic C 5-10 is heteroaryl; R 1 is absent or is selected from H, halo, cyano, hydroxy, amino, N(R 5 )2, OR 5 , substituted or unsubstituted, C 1-5 Alkyl, C 3-10 Cycloalkyl, C 1-5 Alkylhydroxy, C 1-5 Alkenylhydroxy, C 1-5 Alkynylhydroxy, C 1-5 Alkylamines, C 1-5 Alkenylamine or C 1-5 Alkynylamines, substituted or unsubstituted monocyclic or bicyclic C 3-10 Heterocycloalkyl or substituted or unsubstituted monocyclic or bicyclic C 5-10 is heteroaryl; R 2 is H, halo, cyano, hydroxy or C 1-3 is alkyl; R 3 is H, halo, cyano, hydroxyl or amino; R 4 is H, substituted or unsubstituted C 1-5 Alkyl, substituted or unsubstituted C 1-5 Alkoxy, or substituted or unsubstituted C 1-5 It is an alkyl carboxylic acid; R 5 is H, substituted or unsubstituted C 1-5 Alkyl, substituted or unsubstituted C 1-5Alkoxy, or substituted or unsubstituted C 1-5 alkyl carboxylic acid) It is shown as follows.

[0013] In some embodiments of these and such aspects described herein, the AhR modulator of formula (I) is a modulator of AhR or an antagonist of AhR.

[0014] In some embodiments, methods for modulating AhR activity are described. More specifically, methods for modulating constitutive AhR activity in a subject in need of such modulation are described. The method comprises administering to a subject having 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 and such embodiments described herein, the method further comprises selecting a subject having constitutive AhR activity.

[0015] The compounds of formula (I) of the present invention have been shown to have a beneficial pharmacological spectrum of action that has not been anticipated until now.Surprisingly, it has been found that the compounds of the present invention can effectively inhibit AhR, and therefore the compounds of the present invention can be used in humans and animals to treat or prevent diseases or conditions mediated by aryl hydrocarbon receptor (AhR), and preferably can be used to treat or prevent cancer, cancerous conditions, tumors, fibrotic diseases, conditions involving dysregulated immune response, or other disorders associated with abnormal signal transduction of AhR.

[0016] Examples of diseases associated with dysregulation of immune responses related to AhR signaling include sepsis (SIRS), multiple organ dysfunction syndrome (MODS, MOF), inflammatory kidney disease, chronic enteritis (IBD, Crohn's disease, UC), pancreatitis, peritonitis, inflammatory skin diseases, inflammatory eye diseases, and autoimmune diseases (rheumatic diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS)).

[0017] Examples of fibrotic disease include fibrotic diseases of internal organs such as lung, heart, kidney, bone marrow, etc., particularly liver fibrosis, skin fibrosis and eye fibrotic disease.In the present invention, "fibrotic disease" specifically includes liver fibrosis, liver cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic disorders associated with diabetes, myelofibrosis and fibrotic diseases similar thereto; and scleroderma, morphea, keloid, hypertrophic scar (hypertrophic scar after surgery), nevus, diabetic retinopathy, proliferative vitreoretinopathy and connective tissue disorders (for example, sarcoidosis).

[0018] In another aspect, a method for treating cancer or a cancerous condition by modulating the activity of AhR is described, comprising administering to a subject having cancer or a cancerous condition a therapeutically effective amount of a pharmaceutical composition comprising an AhR modulator, such as an AhR antagonist of formula (I) as described herein.

[0019] In some embodiments, methods are described for inhibiting tumor cell invasion in a subject having cancer, a cancerous condition, or a tumor, comprising administering to the subject having cancer or a tumor a therapeutically effective amount of a pharmaceutical composition comprising an AhR modulator, such as an AhR antagonist of Formula (I) as described herein.

[0020] In some embodiments of these and such aspects described herein, the method further comprises selecting a subject with cancer, a cancerous condition, or a tumor.

[0021] Cancers, cancerous conditions, or tumors particularly suitable for treatment with the AhR inhibitors of the present invention include liquid and solid tumors such as breast cancer, respiratory cancer, brain cancer, reproductive cancer, gastrointestinal cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer, and distant metastases thereof. These cancers, cancerous conditions, or tumors further include lymphomas, sarcomas, and leukemias.

[0022] Examples of breast cancer include, but are not limited to, triple-negative breast cancer, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.

[0023] Examples of respiratory cancers include, but are not limited to, small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.

[0024] Examples of brain tumors include, but are not limited to, brain stem and hypothalamic glioma, cerebellar and cerebral astrocytoma, glioblastoma, medulloblastoma, ependymoma, as well as neuroectodermal tumor and pineal tumor.

[0025] Tumors of the male reproductive organs include, but are not limited to, prostate cancer and testicular cancer.

[0026] Tumors of the female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as uterine sarcoma.

[0027] Examples of ovarian cancer include, but are not limited to, serous tumor, endometrial tumor, mucinous cystadenocarcinoma, granulosa cell tumor, Sertoli-Leydig cell tumor, and virilizing tumor.

[0028] Examples of cervical cancer include, but are not limited to, squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, small cell carcinoma, neuroendocrine tumor, ground cell carcinoma, and villous tubular adenocarcinoma.

[0029] Digestive tract tumors include, but are not limited to, anal cancer, colon cancer, colorectal cancer, esophageal cancer, gallbladder cancer, gastric cancer, pancreatic cancer, rectal cancer, small intestine cancer, and salivary gland cancer.

[0030] Examples of esophageal cancer include, but are not limited to, esophageal cell carcinoma and esophageal adenocarcinoma, as well as squamous cell carcinoma, leiomyosarcoma, malignant melanoma, rhabdomyosarcoma, and lymphoma.

[0031] Examples of gastric cancer include, but are not limited to, intestinal-type adenocarcinoma and diffuse gastric-type adenocarcinoma.

[0032] Examples of pancreatic cancer include, but are not limited to, intraductal adenocarcinoma, adenosquamous carcinoma, and pancreatic endocrine tumors.

[0033] Urinary tract tumors include, but are not limited to, bladder cancer, penile cancer, kidney cancer, renal pelvis cancer, ureter cancer, urethral cancer, and human papillary renal carcinoma.

[0034] Examples of kidney cancer include, but are not limited to, renal cell carcinoma, urothelial cell carcinoma, paraglomerular tumor (nephroma), angiomyolipoma, renal oncocytoma, Bellini duct carcinoma, clear cell sarcoma of the kidney, mesoblastic nephroma, and Wilms' tumor.

[0035] Examples of bladder cancer include, but are not limited to, transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma, and small cell carcinoma.

[0036] Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.

[0037] Examples of liver cancer include, but are not limited to, hepatocellular carcinoma (fibrolamellar or non-fibrolamellar), cholangiocarcinoma (intrahepatic cholangiocarcinoma), and mixed hepatocellular carcinoma and cholangiocarcinoma.

[0038] Skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-malignant melanoma skin cancer.

[0039] Head and neck cancers include, but are not limited to, squamous cell carcinoma of the head and neck, laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, salivary gland cancer, lip and oral cavity cancer, and squamous cell carcinoma.

[0040] Lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, and central nervous system lymphoma.

[0041] Sarcomas include, but are not limited to, soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.

[0042] Leukemias include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.

[0043] The terms "treat" or "treatment" as used throughout this specification are used in their ordinary sense to refer to the management or medical care of a subject for the purpose of addressing the condition of a disease or disorder, such as, for example, cancer, or to alleviate, inhibit, relieve or ameliorate the condition of a disease or disorder, such as cancer.

[0044] The compounds of the present invention can be used to treat and prevent (i.e., preventive treatment) tumor growth and metastasis, and in particular, can be used to treat and prevent the growth and metastasis of solid tumors of any indication and any stage, regardless of whether or not they have been previously treated for tumor growth.The tumors are breast cancer, squamous cell carcinoma, lung cancer, peritoneal cancer, hepatocellular carcinoma, gastric cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, colon cancer, colorectal cancer, endometrial cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, head and neck cancer, B-cell lymphoma, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), hairy cell leukemia or chronic myeloblastic leukemia.In some of these embodiments, the cancer is hepatocellular carcinoma.

[0045] Some embodiments of the method may further comprise the concurrent administration or treatment of one or more additional anti-cancer therapies, in some such embodiments, the additional anti-cancer therapies comprise surgery, radiation therapy, biological therapy, immunotherapy, chemotherapy, or any combination thereof.

[0046] Some embodiments of the method may further comprise administering or treating with one or more anti-cancer therapeutic agents, in some such embodiments, the anti-cancer therapeutic agent is a chemotherapeutic agent, an antiproliferative agent, an anti-angiogenic agent, a cytotoxic agent, an anti-hormonal agent, a prodrug, or a cytokine.

[0047] In another embodiment of the present invention, the compounds of the present invention represented by formula (I) may be used to increase the sensitivity of cells to radiation. That is, by treating cells with the compounds of the present invention before radiation therapy, the sensitivity of cells to DNA damage and cell death can be increased compared to cells not treated with the compounds of the present invention. In one aspect, cells are treated with at least one compound of the present invention represented by general formula (I).

[0048] Thus, the present invention provides a method for killing cells comprising administering to the cells one or more compounds of the present invention in combination with conventional radiation therapy.

[0049] The present invention further provides a method for sensitizing cells to cell death, comprising treating the cells with one or more compounds of the present invention represented by Formula (I) prior to treatment that induces or induces cell death. In one embodiment, after treating the cells with one or more compounds of the present invention represented by Formula (I), the cells are treated with at least one compound or at least one method, or a combination thereof, to induce DNA damage and inhibit normal cell function or kill the cells.

[0050] In another embodiment of the present invention, cells are killed by treating with at least one DNA damaging agent.That is, cells are treated with one or more compounds of the present invention represented by formula (I) to enhance the sensitivity of cells to cell death, and then cells are killed by treating with at least one DNA damaging agent.DNA damaging agents useful in the present invention include, but are not limited to, chemotherapeutic agents (such as cisplatin), ionizing radiation (X-rays, ultraviolet rays), carcinogens and mutagens.

[0051] In another embodiment, cell is killed by treating cell with at least one method that induces or induces DNA damage.Such method includes but is not limited to DNA damage caused by activating cell signaling pathway, DNA damage caused by suppressing cell signaling pathway, and DNA damage caused by inducing cell biochemical change.For example, by suppressing cell DNA repair pathway, DNA damage repair can be prevented, resulting in abnormal accumulation of DNA damage in cell.

[0052] In one embodiment of the present invention, the compound of the present invention represented by formula (I) is administered to a cell before inducing DNA damage in the cell by irradiation or other methods. In another embodiment of the present invention, the compound of the present invention represented by general formula (I) is administered to a cell simultaneously with inducing DNA damage in the cell by irradiation or other methods. In yet another embodiment of the present invention, the compound of the present invention represented by formula (I) is administered to a cell immediately after inducing DNA damage in the cell by irradiation or other methods.

[0053] In another embodiment, the cell is an in vitro cell. In another embodiment, the cell is an in vivo cell. The compounds of the present invention can be administered as the sole pharmaceutical agent or can be administered in combination with one or more other active pharmaceutical ingredients, and do not cause undesirable adverse effects when combined with one or more other active pharmaceutical ingredients.

[0054] The present invention also includes combinations of pharmaceuticals such as those described above. For example, pharmaceuticals that can be combined with the compounds of the present invention include: 131I-chTNT, abarelix, abiraterone, aclarubicin, adalimumab, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alendronate, alitretinoin, altretamine, amifostine, aminoglutethimide, hexaminolevulinic acid, amrubicin, amsacrine, anastrozole, ancestim, anetholedithiolthione, anethumab emtansine, angiotensin II, antithrombin Imbib III, aprepitant, arcitumomab, aruglavin, arsenic trioxide, asparaginase, atezolizumab, axitinib, azacitidine, basiliximab, belotecan, bendamustine, besilesomab, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, blinatumomab, bortezomib, buserelin, bosutinib, brentuximab Vedotin, busulfan, cabazitaxel, cabozantinib, calcitonin, calcium folinate, calcium levofolinate, capecitabine, capromab, carbamazepine, carboplatin, carboquone, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronate, clofarabine, cobimetinib, copanlisib, crisantaspase, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daratumumab, darbepoetin Alfa, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dianhydrogalactitol, dexrazoxane, dibrospidiumchloride, dianhydrogalactitol, diclofenac, dinutuximab, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, eculizumab, edrecolomab, elliptinium acetate, elotuzumab, eltrombopag, endostatin, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta, peptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, ethinyl estradiol, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folic acid Phosphate, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoterate meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, glucarpidase, glutoxim, GM-CSF, goserelin, granisetron, granulocyte colony-stimulating factor, histamine dihydrochloride, histamine dihydrochloride Strelin, hydroxycarbamide, I-125 seed source, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate, interferon α, interferon β, interferon γ, iobitridol, iobenguane ( 123I), iomeprol, ipilimumab, irinotecan, itraconazole, ixabepilone, ixazomib, lanreotide, lansoprazole, lapatinib, lasocholine, lenalidomide, lenvatinib, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, Methadone, methotrexate, methoxsalen, methyl aminolevulinate, methylprednisolone, methyltestosterone, metyrosine, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphine hydrochloride, morphine sulfate, nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, necitumumab, nedaplatin, nelarabine, neridronic acid, nezu Pitant / palonosetron, nivolumab, pentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nintedanib, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, olaparib, olaratumab, omacetaxine mepesuxinate, omeprazole, ondansetron, oprelvekin, orgotein, orilotimod, osimertinib, oxaliplatin, oxycodone, oxymetholone, ozogamicin, p53 gene therapy, paclitaxel, palbociclib, palifermin, paracetamol Zinc-103 seed source, palonosetron, pamidronic acid, panitumumab, panobinostat, pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxy-PEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon α-2b, pembrolizumab, pemetrexed, pentazocine, pentostatin, peplomycin, perflubutane, perfosfamide, pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, poliglusum,Polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib, regorafenib, risedronate, rhenium-186 etidronate, rituximab, rolapitant, romidepsin, romiplostim, romurtide, roniciclib, samarium (, 153 Sm) lexidronam, sargramostim, satumomab, secretin, siltuximab, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sonidegib, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin, talimogene laherparepvec, tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium ( 99m Tc) nofetumomab merpentane, 99m Tc-HYNIC-[Tyr 3]-Octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa, thioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trametinib, tramadol, trastuzumab, trastuzumab These include emtansine, treosulfan, tretinoin, trifluridine plus tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, valatinib, valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, and zorubicin.

[0055] The compounds of the invention may also be combined with other agents that target the immune system, such as immune checkpoint inhibitors, for example antagonists of the PD-1 / PD-L1 axis.

[0056] PD-1 and its ligands, PD-L1 and PD-L2, act as negative regulators of T cell activation. AhR suppresses immune cell function and enhances cancer cell proliferation and motility. PD-L1 is overexpressed in various cancers, and PD-1 overexpression often coincides with T cell infiltration into tumors. This results in attenuated T cell activation and evasion from immune surveillance, thereby reducing antitumor immune responses (Keir ME et al. (2008) Annu. Rev. Immunol. 26:677).

[0057] Simultaneous targeting of the PD-1 / PD-L1 axis and AhR can enhance antitumor immune responses compared to additive approaches and, unexpectedly, suppress tumor growth.

[0058] Thus, it has surprisingly been found that a composition comprising an antagonist against the PD-1 / PD-L1 axis and an AhR antagonist is effective in enhancing immune responses and treating cancer.

[0059] Furthermore, the compounds of the present invention can also be used as therapeutic agents for various other diseases in which AhR is involved.

[0060] Other examples of disorders associated with inflammation due to aberrant AhR signaling include vaccination against infectious diseases, cancer, viral infections, obesity and diet-induced obesity, steatosis, metabolic diseases, hepatic steatosis, uterine fibroids in women (uterine leiomyomas or uterine fibroids), chronic kidney injury, acute and chronic renal failure, diabetic nephropathy, inflammatory nephropathy, hypertensive nephropathy, heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular disorders, thromboembolic disorders, arteriosclerosis, sickle cell anemia, erectile dysfunction, benign prostatic hyperplasia, voiding disorders associated with benign prostatic hyperplasia, Huntington's disease, dementia, Alzheimer's disease, and Creutzfeldt-Jakob disease.

[0061] Additionally, in another aspect, there is provided a pharmaceutical composition comprising an AhR modulator, such as an AhR antagonist of formula (I), and a pharmaceutically acceptable excipient.

[0062] In some embodiments, a pharmaceutical composition is provided comprising an AhR modulator, such as an AhR antagonist of Formula (I), for use in modulating constitutive AhR activity in a subject in need thereof.

[0063] In some embodiments, there is provided a pharmaceutical composition comprising an AhR modulator, such as an AhR antagonist of Formula (I), for use in treating cancer or a cancerous condition by modulating the activity of AhR.

[0064] In some embodiments, a pharmaceutical composition is provided comprising an AhR modulator, such as an AhR antagonist of Formula (I), for use in inhibiting cancer cell proliferation, tissue invasion, metastasis, and angiogenesis in a subject having cancer, a cancerous condition, or a tumor.

[0065] In some embodiments of these aspects and aspects described herein, the use further comprises selecting a subject with cancer, cancerous condition or tumor.In some of these embodiments, the cancer is breast cancer, squamous cell carcinoma, lung cancer, peritoneal cancer, hepatocellular carcinoma, gastric cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, colon cancer, colorectal cancer, endometrial cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, head and neck cancer, B-cell lymphoma, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), hairy cell leukemia or chronic myeloblastic leukemia.In some of these embodiments, the cancer is hepatocellular carcinoma.

[0066] In some embodiments of these and other such aspects described herein, the use further comprises one or more additional anti-cancer therapies. In some such embodiments, the additional anti-cancer therapies comprise surgery, radiation therapy, biological therapy, immunotherapy, or chemotherapy.

[0067] In some embodiments of these and other such aspects described herein, the use further comprises one or more anti-cancer therapeutic agents. In some such embodiments, the anti-cancer therapeutic agent is a chemotherapeutic agent, an antiproliferative agent, an anti-angiogenic agent, a cytotoxic agent, an anti-hormonal agent, a prodrug, or a cytokine. [Effects of the Invention]

[0068] The novel compounds of the present invention represented by formula (I) can effectively modulate the activity of AhR and are therefore useful as therapeutic or prophylactic agents for various diseases, disorders or conditions associated with AhR activity, such as cancer, cancerous conditions, tumors, fibrosis, conditions involving dysregulated immune responses (including, for example, autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE), multiple sclerosis (MS)), or other disorders associated with abnormal signaling of AhR. DETAILED DESCRIPTION OF THE INVENTION

[0069] The present invention will now be described in further detail.

[0070] Unless otherwise specified, all technical terms used herein have the meanings commonly understood by those skilled in the art to which this invention belongs. Furthermore, although the present invention has been described with reference to specific methods and specific samples, similar and equivalent values ​​thereof are also included within the scope of this invention. Furthermore, unless otherwise specified, numerical values ​​described herein are to be construed as including the meaning of "about." All publications and other references mentioned herein are incorporated herein by reference in their entirety.

[0071] The definitions of groups used herein are explained in detail below. Unless otherwise specified, each group has the following definition and is used in the sense that it is commonly understood by a person skilled in the art.

[0072] As used herein, "halo," "halogen," or "halide" includes fluoro, chloro, bromo, or iodo.

[0073] As used herein, "alkyl" refers to an aliphatic hydrocarbon group, including straight-chain and branched hydrocarbon groups. For example, C 1-6Alkyl is an aliphatic hydrocarbon having 1 to 6 carbon atoms, and specifically 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 is C 1-6 refers to alkyl, C 1-4 Preferably it is alkyl, C 1-3 It is more preferably alkyl.

[0074] As used herein, "alkenyl" refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond, including straight-chain and branched hydrocarbon groups. Examples of "alkenyl" include, but are not limited to, vinyl, allyl, but-1-enyl, or but-2-enyl.

[0075] As used herein, "alkynyl" refers to an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond, including straight-chain and branched hydrocarbon groups. Examples of "alkynyl" include, but are not limited to, ethynyl, propargyl, but-1-ynyl, or but-2-ynyl.

[0076] As used herein, "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms, and the alkyl group is defined as above. "Halo" refers to F, Cl, Br, or I, and is used interchangeably with "halogen." Unless otherwise specified, haloalkyl refers to fluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl, or 2,2,2-trifluoromethyl.

[0077] As used herein, "alkoxy" refers to an -O-alkyl group or an alkyl-O- group, where the alkyl group is as defined above. Examples of "alkoxy" include methoxy, ethoxy, n-propoxy, n-butoxy, and t-butoxy.

[0078] As used herein, "alkoxyalkyl" refers to an alkyl-O-alkyl group, where alkyl is as defined above. Examples of "alkoxyalkyl" include, but are not limited to, methoxymethyl, ethoxymethyl, methoxyethyl, or isopropoxymethyl.

[0079] As used herein, "hydroxy" or "hydroxyl," used alone or in combination with another term, refers to --OH.

[0080] As used herein, "cyano" refers to -CN, and "cyanoalkyl" refers to alkyl substituted with -CN. The alkyl group is as defined above.

[0081] As used herein, "amino" refers to -NH2 and "nitro" refers to -NO2.

[0082] As used herein, "carboxy" refers to the group --C(O)--OH.

[0083] As used herein, "ester" refers to the group -C(O)-OR, where R is alkyl and C 1-10 may be alkyl, C 1-8 Alkyl, C 1-6 Alkyl or C 1-4 Preferably, it is alkyl. Such ester groups may be unsubstituted or substituted with one or more suitable substituents.

[0084] As used herein, "cycloalkyl" refers to a substituted or unsubstituted cyclic alkyl. For example, C 3-20 Cycloalkyl refers to a monovalent saturated hydrocarbon ring system of 3 to 20 carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Unless otherwise specified, cycloalkyl is preferably C 3-8 Cycloalkyl or C3-6 It may also be cycloalkyl.

[0085] As used herein, "aryl" refers to, for example, an aromatic ring system having 6 to 20 carbon atoms (C 6-20 ) refers to a monovalent aromatic hydrocarbon. Aryl can also include bicyclic groups containing an aromatic ring fused to a saturated or partially unsaturated ring. Examples of aryl groups include groups derived from benzene (phenyl), substituted phenyl, biphenyl, naphthyl, toluyl, naphthalenyl, anthracenyl, indenyl, indanyl, and the like. Unless otherwise specified, aryl refers to any of the C 6-12 C refers to aryl 6-10 It is preferably aryl.

[0086] As used herein, the term "heteroaryl" refers to a monovalent or divalent substituent derived from a heteromonocyclic or heteropolycyclic aromatic hydrocarbon having 1 to 10 carbon members and containing one or more (preferably 1 to 3) heteroatoms selected from N, O, and S. Examples of heteroaryl include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3 ... Examples of heteroaryls include, but are not limited to, 3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl, indolyl, and the like. Examples of bicyclic heteroaryls include, but are not limited to, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, quinolinyl, isoquinolinyl, purinyl, furopyridinyl, octahydropyranopyridine, benzodioxolyl, and the like. Unless otherwise specified, heteroaryl refers to a C 3-10 Heteroaryl, C 3-7 Heteroaryl is preferred, C 3-5 More preferably, it is heteroaryl.

[0087] As used herein, "heterocycloalkyl" refers to a 3- to 10-carbon-membered monocyclic alkyl, bicyclic alkyl, tricyclic alkyl, or alkyl having more rings containing one or more (e.g., 1 to 4) heteroatoms selected from N, O, and S. Furthermore, the heterocycloalkyl in the present invention may be a fused heterocycloalkyl or a bridged heterocycloalkyl. Examples of non-aromatic rings include azetidinyl, oxetanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, oxapiperazinyl, oxapiperidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydrofuryl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyranyl, dihydropyranyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, Examples of heterocycloalkyl include, but are not limited to, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, indolinyl, indolinylmethyl, thiomorpholinyl, azepanyl, diazepanyl, N-oxide, azaadamantanyl, diazamatanyl, and the like. Substitution by heterocycloalkyl may occur via a carbon atom or a heteroatom. Heterocycloalkyl groups may be substituted with one or more suitable groups via one or more of the aforementioned groups. Unless otherwise specified, heterocycloalkyl refers to a heterocycloalkyl ring having 3 to 10 carbon members, and C 3-7 Heterocycloalkyl is preferred, and heterocycloalkyl having 3 to 5 carbon atoms is more preferred.

[0088] Unless otherwise specified, "substituted" means a group selected from the group consisting of a halogen atom (e.g., F, Cl, Br, or I), a cyano group, a hydroxyl group, a thiol group, a nitro group, an amino group, an imino group, an azido group, an amidino group, a hydrazino group, a hydrazono group, an oxo group, a carbonyl group, a carbamyl group, an ester group, an ether group, a carboxyl group or a salt thereof, a sulfonic acid group or a salt thereof, a phosphoric acid group or a salt thereof, a C 1-6 Alkyl group, halo C 1-6 Alkyl group, hydroxy C 1-6 Alkyl group, C 2-6 Alkenyl group, haloC 2-6 Alkenyl group, C 2-6 Alkynyl group, haloC 2-6 Alkynyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, hydroxy C 1-6 Alkoxy group, C 1-20 Alkylthio group, C 1-6 Alkylsulfonyl group, C 1-6 Alkylcarbonyl group, C 1-6 Alkoxycarbonyl group, C 3-20 Carbocyclic groups (e.g., C 3-9 Cycloalkyl groups, haloC 3-9 Cycloalkyl groups, C 3-9 Cycloalkenyl group, haloC 3-9 Cycloalkenyl group, C 1-9 Heterocycloalkyl groups, haloC 1-9 Heterocycloalkyl groups, C 2-9 Heterocycloalkenyl group, haloC 2-9 heterocycloalkenyl group) and C 1-20 Heterocyclic groups (e.g., C 6-20 Aryl group, C 6-20 Aryloxy group, C 6-20 Arylthio group, C 2-20 Heteroaryl groups, C 2-20 Heteroaryloxy group, C 2-20 It means that at least one hydrogen atom is substituted with 1 to 3 substituents selected from the group consisting of heteroarylthio groups.

[0089] From the studies carried out and results obtained to date, the following compounds of formula (I), as well as their isomers, isomer mixtures, pharmaceutically acceptable salts and solvates, are believed to be of particular interest:

[0090] aryl hydrocarbon receptor The aryl hydrocarbon receptor ("AhR") is a ligand-dependent member of the basic helix-loop-helix transcription factor family and is known to be activated by a large number of structurally diverse synthetic and natural compounds, including polycyclic aromatic hydrocarbons, indoles, and flavonoids. In the unliganded state, AhR resides in a latent cytoplasmic compartment in association with two molecular chaperones, heat shock protein 90 ("hsp90"), the immunophilin-like protein XAP2, and the hsp90-interacting protein p23.

[0091] As used herein, "aryl hydrocarbon receptor" or "AhR" refers to an 848 amino acid long polypeptide, e.g., designated NP_001612, as well as naturally occurring allelic variants, naturally occurring splice variants, and processed forms thereof. AhR typically refers to human AhR. Additionally, "AhR" refers to truncated forms or fragments of the AhR polypeptide, e.g., truncated forms or fragments containing specific AhR domains. Such forms of AhR are referred to herein, e.g., as "AhR(122-224)."

[0092] AhR modulators The present inventors have discovered that the novel AhR modulator compounds described herein (e.g., small molecule compounds represented by Formula (I)) can modulate constitutive AhR activity by acting as AhR antagonists. Furthermore, the present inventors have discovered that the AhR modulator compounds can inhibit cancer cell proliferation, as well as tumor invasion, metastasis, and angiogenesis. Thus, the present invention describes novel modulators of AhR and novel modulators of constitutive AhR signaling for use in therapeutic compositions and methods for treating and inhibiting cancer proliferation and tumor cell invasion, as well as immune-related diseases such as autoimmune diseases.

[0093] AhR mediates various functional responses, including, but not limited to, de novo transcription of target genes and the AhR gene battery containing response elements such as DREs and XREs with the sequence 5'-TNGCGTG-3'. Other AhR signaling pathways have been reported, including binding to retinoblastoma proteins, estrogen receptors (ERs), or the transcription factor E2F1, as well as to the NFκB pathway subunits RelA and RelB. AhR also acts as a ubiquitin ligase. Therefore, AhR-mediated signal transduction encompasses multiple pathways, including constitutive and non-constitutive AhR signaling pathways, or constitutive and non-constitutive signaling activities (as these terms are defined herein).

[0094] As used herein, "constitutive AhR signaling" refers to one or more AhR-mediated or AhR-regulated signaling pathways activated or induced by one or more endogenous AhR ligands or one or more environmental factors (e.g., toxins or pollutants) that result in constitutive or long-term nuclear translocation of AhR, or that result in the activation or modulation of one or more AhR gene batteries involved in unregulated cell growth and proliferation, tumor cell invasion, or a combination thereof.

[0095] As used herein, "non-constitutive AhR signaling" refers to one or more AhR-mediated or AhR-induced signaling pathways that do not result in constitutive or long-term nuclear translocation of AhR, nor in activation or modulation of one or more AhR gene batteries involved in unregulated cell growth and proliferation, tumor cell invasion, or a combination thereof. In some embodiments, non-constitutive AhR signaling does not result in upregulation of expression of CYP1A1, CYP1B1, or a combination thereof.

[0096] Thus, as used herein, "AhR modulator" refers to an agent (e.g., a compound of Formula (I)) that modulates, induces, or promotes the qualitative or quantitative change, alteration, or regulation of one or more processes, mechanisms, effects, responses, functions, activities, or pathways mediated by the AhR receptor. Such changes mediated by AhR modulators (e.g., AhR antagonists described herein) may refer to the reduction, suppression, or conversion of the constitutive activity of the AhR. "Expression" refers to the cellular processes involved in the production of RNA and proteins (and, where appropriate, secreted proteins), including, but not limited to, transcription, translation, folding, modification, and processing. "Expression product" includes RNA transcribed from a gene and polypeptides obtained by translation of mRNA transcribed from a gene.

[0097] The term "modulation," as used in connection with AhR modulators, is used in the same sense as in the art, e.g., to refer to the induction or promotion of a qualitative or quantitative change, alteration, or regulation of one or more biological processes, mechanisms, effects, responses, functions, activities, pathways, or other phenomena of interest. Thus, as used herein, "modulation" refers to the qualitative or quantitative change, alteration, or regulation of one or more processes, mechanisms, effects, responses, functions, activities, or pathways mediated by the AhR receptor.

[0098] The term "agent," as used herein in connection with AhR modulators, refers to any compound or substance, including, but not limited to, small molecules, nucleic acids, polypeptides, peptides, drugs, ions, etc. An "agent" can be any chemical compound, substance, or moiety, including, but not limited to, synthetic or natural proteinaceous or non-proteinaceous substances. In some embodiments, the agent is a nucleic acid, nucleic acid analog, protein, antibody, peptide, aptamer, nucleic acid oligomer, amino acid, or sugar chain, including, but not limited to, a protein, oligonucleotide, ribozyme, DNAzyme, glycoprotein, siRNA, lipoprotein, aptamer, variants thereof, combinations thereof, etc. In certain embodiments, as described herein, the agent is a small molecule having a chemical moiety, such as, for example, a substituted or unsubstituted alkyl moiety, aromatic moiety, or heterocyclyl moiety. The compound may be a compound known to have a desired activity and / or property, e.g., a compound known to be capable of modulating the activity of AhR, and may be selected from a library containing various compounds, e.g., by using the screening methods described herein.

[0099] In some embodiments, the AhR modulator selectively binds to AhR. As used herein, "selectively binds" or "specifically binds" refers to an AhR antagonist described herein that selectively binds to AhR. -5 K below M (10000nM) D , e.g., 10 -6 M or less, 10 -7 M or less, 10 -8 M or less, 10 -9 M or less, 10 -10 M or less, 10 -11 M or less or 10 -12 K below M D For example, the antagonists described herein may bind to a target (e.g., AhR) at 10 -5 K below MD An antagonist is said to specifically bind to AhR if it binds to AhR at a specific site but not to other molecules or related homologs. Specific binding can be affected, for example, by the affinity and avidity of the antagonist and the concentration of the antagonist used. Those skilled in the art can determine the appropriate conditions for selective binding of the antagonists described herein using a suitable method, such as titrating AhR antagonists using a suitable cell-binding assay, as described herein.

[0100] In some embodiments of the compositions and methods described herein, the AhR modulator is an AhR antagonist having the chemical structure shown in formula (I), as described herein.

[0101] As used herein, AhR refers to an "AhR antagonist." An AhR antagonist refers to an AhR inhibitor that specifically binds to AhR but does not induce a biological response by itself, but can block or reduce the response mediated by an AhR agonist or an AhR ligand. That is, an AhR antagonist can bind to AhR but does not activate AhR, and by binding to AhR, it disrupts the interaction with AhR agonists, replaces AhR agonists, and / or suppresses the function of AhR agonists. Therefore, as described herein, an AhR antagonist binds to AhR but does not function as an inducer of AhR activity, i.e., it functions as a pure AhR inhibitor. In some embodiments, an AhR antagonist selectively binds to AhR.

[0102] In some embodiments of these aspects, the AhR antagonists described herein, such as, for example, compounds of Formula (I), block constitutive AhR effector functions that mediate established tumor growth and progression. In another embodiment, the small molecule AhR antagonists of Formula (I) described herein act as chemical inhibitors by inhibiting AhR-mediated CYP1A1 induction and mutagenesis upon exposure to environmental factors (ligands).

[0103] In some embodiments of these aspects, the AhR antagonists of Formula (I) described herein inhibit the induction of early malignant transformation mediated by constitutively active AhR. In some embodiments, the compounds of Formula (I) described herein inhibit the proliferation of cancer cells or tumor cells mediated by constitutive AhR signaling. In some embodiments, the compounds of Formula (I) described herein inhibit the induction of malignant transformation mediated by tumor invasion mediated by constitutive AhR signaling.

[0104] Accordingly, there is provided an AhR antagonist of formula (I) for use in the various embodiments described herein.

[0105] One aspect of the present invention relates to novel compounds capable of modulating the human aryl hydrocarbon receptor (AhR), which specifically bind to the AhR.

[0106] In some embodiments, the compound or an enantiomer, diastereomer, racemate, solvate, hydrate, or pharmaceutically acceptable salt thereof has the formula (I): [ka] (In the formula, X 1 , X 2 and X 3 are each independently 2 , N or NR 3 and; Ar 1 and Ar2 is a substituted or unsubstituted monocyclic or bicyclic C 6-10 Aryl, substituted or unsubstituted monocyclic or bicyclic C 5-10 Heteroaryl and substituted or unsubstituted monocyclic or bicyclic C 3-10 heterocycloalkyl; D is H, halo, cyano, hydroxy, amino, substituted or unsubstituted, C 1-5 Alkyl, monocyclic or bicyclic C 3-10 Cycloalkyl, C 1-5 Alkylhydroxy, C 1-5 Alkenylhydroxy, C 1-5 Alkynylhydroxy, C 1-5 Alkylamines, C 1-5 Alkenylamines, C 1-5 Alkynylamines, monocyclic or bicyclic C 3-10 Heterocycloalkyl, or monocyclic or bicyclic C 3-10 is heteroaryl; E is absent (direct bond) or is amino, substituted or unsubstituted, C 1-5 Alkyl, monocyclic or bicyclic C 3-10 Cycloalkyl, C 1-5 Alkylhydroxy, C 1-5 Alkenylhydroxy, C 1-5 Alkynylhydroxy, C 1-5 Alkylamines, C 1-5 Alkenylamines, C 1-5 Alkynylamines, monocyclic or bicyclic C 3-10 Heterocycloalkyl, or monocyclic or bicyclic C 3-10 is heteroaryl; or D and E, together with the atoms to which they are attached, form a substituted or unsubstituted monocyclic or bicyclic C 3-10 forming a heterocycloalkyl ring; G is absent (direct bond) or is H, halo, cyano, hydroxy, amino, nitro, ether (-O-), thioether (-S-), sulfinyl (-SO-), sulfonyl (-SO2-), sulfonylamido (-SO2NR4 -), aminosulfonyl (-NR 4 SO2-), carbonyl (-(CO)-), amide (-(CO)NR 4 -), reverse amide (-NR 4 (CO)-), esters (-(CO)O-), substituted or unsubstituted monocyclic or bicyclic C 3-10 Cycloalkyl, substituted or unsubstituted monocyclic or bicyclic C 3-10 Heterocycloalkyl, substituted or unsubstituted monocyclic or bicyclic C 6-10 Aryl or substituted or unsubstituted monocyclic or bicyclic C 5-10 is heteroaryl; R 1 is absent or is selected from H, halo, cyano, hydroxy, amino, N(R 5 )2, OR 5 , substituted or unsubstituted, C 1-5 Alkyl, C 3-10 Cycloalkyl, C 1-5 Alkylhydroxy, C 1-5 Alkenylhydroxy, C 1-5 Alkynylhydroxy, C 1-5 Alkylamines, C 1-5 Alkenylamine or C 1-5 Alkynylamines, substituted or unsubstituted monocyclic or bicyclic C 3-10 Heterocycloalkyl or substituted or unsubstituted monocyclic or bicyclic C 5-10 is heteroaryl; R 2 is H, halo, cyano, hydroxy or C 1-3 is alkyl; R 3 is H, halo, cyano, hydroxyl or amino; R 4 is H, substituted or unsubstituted C 1-5 Alkyl, substituted or unsubstituted C 1-5 Alkoxy, or substituted or unsubstituted C 1-5 It is an alkyl carboxylic acid; R 5 is H, substituted or unsubstituted C 1-5Alkyl, substituted or unsubstituted C 1-5 Alkoxy, or substituted or unsubstituted C 1-5 alkyl carboxylic acid) It has the structure shown below.

[0107] In one preferred embodiment, Ar 1 is a substituted or unsubstituted monocyclic C ring containing one or more heteroatoms selected from the group consisting of N, O and S. 5-7 It may be heteroaryl. More preferably, Ar 1 is a monocyclic C ring containing one or two heteroatoms selected from the group consisting of N, O and S 5-6 Heteroaryl, and the monocyclic C 5-6 Heteroaryl may be unsubstituted and may be C 1-3 It may be substituted with alkyl. More preferably, Ar 1 may be a methyl-substituted or unsubstituted pyrazole or pyridine.

[0108] In one preferred embodiment, Ar 2 is a monocyclic or bicyclic C ring containing one or more heteroatoms selected from the group consisting of N, O and S. 6-10 aryl, and the monocyclic or bicyclic C 6-10 Aryl may be unsubstituted or substituted with halo. More preferably, Ar 2 may be phenyl substituted or unsubstituted with chloro.

[0109] In a preferred embodiment, D may be H, and C 1-3 It may also be alkyl.

[0110] In a preferred embodiment, E may be absent (direct bond) or may be selected from the group consisting of amino, substituted or unsubstituted, C 1-4 Alkyl, monocyclic or bicyclic C 3-8 Cycloalkyl, C 1-4 Alkylhydroxy, C 1-4 Alkenylhydroxy, C1-4 Alkynylhydroxy, C 1-4 Alkylamines, C 1-4 Alkenylamines, C 1-4 Alkynylamines, monocyclic or bicyclic C 3-8 Heterocycloalkyl, or monocyclic or bicyclic C 3-8 heteroaryl; the monocyclic or bicyclic C 3-8 Heterocycloalkyl and the monocyclic or bicyclic C 3-8 The heteroaryl contains one or more (preferably one or two) heteroatoms selected from the group consisting of N, O and S.

[0111] In a preferred embodiment, D and E together with the atoms to which they are attached form a substituted or unsubstituted monocyclic or bicyclic C 3-10 A heterocycloalkyl ring may be formed, and this monocyclic or bicyclic C 3-10 The heterocycloalkyl ring contains one or more heteroatoms selected from the group consisting of N, O and S. More preferably, said monocyclic or bicyclic C 3-10 The heterocycloalkyl ring may be unsubstituted or substituted pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, or octahydropyranopyridine.

[0112] In a preferred embodiment, G is absent (direct bond) or is selected from the group consisting of H, halo, cyano, hydroxy, amino, nitro, ether (—O—), thioether (—S—), sulfinyl (—SO—), sulfonyl (—SO—), sulfonylamido (—SONR 4 -), aminosulfonyl (-NR 4 SO2-), carbonyl (-(CO)-), amide (-(CO)NR 4 -), reverse amide (-NR 4 (CO)-), esters (-(CO)O-), substituted or unsubstituted monocyclic or bicyclic C 3-8 Cycloalkyl, substituted or unsubstituted monocyclic or bicyclic C 3-8Heterocycloalkyl, substituted or unsubstituted monocyclic or bicyclic C 6-10 Aryl or substituted or unsubstituted monocyclic or bicyclic C 5-8 heteroaryl; the monocyclic or bicyclic C 3-8 Heterocycloalkyl and the monocyclic or bicyclic C 5-8 The heteroaryl contains one or more (preferably one or two) heteroatoms selected from the group consisting of N, O and S.

[0113] In one preferred embodiment, R 1 is absent or is selected from H, halo, cyano, hydroxy, amino, N(R 5 )2, OR 5 , substituted or unsubstituted, C 1-4 Alkyl, C 3-8 Cycloalkyl, C 1-4 Alkylhydroxy, C 1-4 Alkenylhydroxy, C 1-4 Alkynylhydroxy, C 1-4 Alkylamines, C 1-4 Alkenylamine or C 1-4 Alkynylamines, substituted or unsubstituted monocyclic or bicyclic C 3-8 Heterocycloalkyl, substituted or unsubstituted monocyclic or bicyclic C 5-8 Heteroaryl, phosphate, or substituted or unsubstituted C 1-3 alkyl phosphate, wherein the monocyclic or bicyclic C 3-8 Heterocycloalkyl and the monocyclic or bicyclic C 5-8 The heteroaryl contains one or more (preferably one or two) heteroatoms selected from the group consisting of N, O and S.

[0114] Furthermore, in one more specific embodiment, the compound of formula (I) is 1. (R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)butan-1-ol, 2. (S)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propan-1-ol, 3. (S)-2-((4-(4-chlorophenyl)-6-(pyridin-3-yl)pyrimidin-2-yl)amino)propan-1-ol, 4. 2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)-2-methylpropan-1-ol, 5. 2-((4-(4-chlorophenyl)-6-(pyridin-3-yl)pyrimidin-2-yl)amino)-2-methylpropan-1-ol, 6. 2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)ethan-1-ol, 7. 3-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propan-1-ol, 8. (S)-1-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propan-2-ol, 9. (R)-1-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propan-2-ol, 10. 3-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propane-1,2-diol, 11. (R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propan-1-ol, 12. 2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)-3-methylbutan-1-ol, 13. (S)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)-3-methylbutan-1-ol, 14. (R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)-3-methylbutan-1-ol, 15. 2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)butan-1-ol, 16. 2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propane-1,3-diol, 17. (R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)-1-phenylethan-1-ol, 18. (S)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)-1-phenylethan-1-ol, 19. 6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrimidin-4-amine, 20.N 1 -(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-N 3 ,N 3 -dimethylpropane-1,3-diamine, 21. 6-(4-chlorophenyl)-N-ethyl-2-(pyridin-3-yl)pyrimidin-4-amine, 22. 6-(4-chlorophenyl)-N-propyl-2-(pyridin-3-yl)pyrimidin-4-amine, 23. N-butyl-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-amine, 24. 1-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)butan-2-ol, 25. 6-(4-chlorophenyl)-N-(cyclopropylmethyl)-2-(pyridin-3-yl)pyrimidin-4-amine, 26. 6-(4-chlorophenyl)-N-cyclopentyl-2-(pyridin-3-yl)pyrimidin-4-amine, 27. 4-(4-chlorophenyl)-6-(4-methylpiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine, 28. N-(tert-butyl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-amine, 29. (1R,2R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol, 30. (1S,2R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol, 31. 6-(4-chlorophenyl)-N-(pyridin-2-ylmethyl)-2-(pyridin-3-yl)pyrimidin-4-amine, 32. 6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(pyridin-3-ylmethyl)pyrimidin-4-amine, 33. 6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(pyridin-4-ylmethyl)pyrimidin-4-amine, 34. trans-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexan-1-ol, 35. trans-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexan-1-ol, 36. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-2-yl)methanol, 37. 2-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-2-yl)ethan-1-ol, 38. (R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-ol, 39. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-ol, 40. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanol, 41. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-ol, 42. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol, 43. 2-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)ethan-1-ol, 44. 3-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)propan-1-ol, 45. 4-(4-chlorophenyl)-6-(4-methoxypiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine, 46. ​​4-(4-chlorophenyl)-6-(piperidin-1-yl)-2-(pyridin-3-yl)pyrimidine, 47. 4-(4-chlorophenyl)-6-(2-methylpiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine, 48. 4-(4-chlorophenyl)-6-(3-methylpiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine, 49. 4-(4-chlorophenyl)-6-(2,6-dimethylpiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine, 50. 4-(4-chlorophenyl)-6-(3,5-dimethylpiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine, 51. 4-(4-chlorophenyl)-6-(3,3-difluoropiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine, 52. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(3-(trifluoromethyl)piperidin-1-yl)pyrimidine, 53. 4-(4-chlorophenyl)-6-(3-ethylpiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine, 54. 6-(4-chlorophenyl)-N-(piperidin-4-yl)-2-(pyridin-3-yl)pyrimidin-4-amine, 55. 6-(4-chlorophenyl)-N-(piperidin-3-ylmethyl)-2-(pyridin-3-yl)pyrimidin-4-amine, 56. 6-(4-chlorophenyl)-N-(piperidin-4-ylmethyl)-2-(pyridin-3-yl)pyrimidin-4-amine, 57. 6-(4-chlorophenyl)-N-(1-methylpiperidin-4-yl)-2-(pyridin-3-yl)pyrimidin-4-amine, 58. 6-(4-chlorophenyl)-N-(2-(piperidin-4-yl)ethyl)-2-(pyridin-3-yl)pyrimidin-4-amine, 59. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-2-yl)methanamine, 60. (R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-amine, 61. (S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-amine, 62. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanamine, 63. (S)-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanamine, 64. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-amine, 65. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanamine, 66. (1R,2S)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol, 67. (1S,2S)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol, 68. trans-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol, 69. (1R,2R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexan-1-ol, 70. cis-4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-2,6-dimethylmorpholine, 71. 4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)morpholine, 72. 6-(4-chlorophenyl)-N-(morpholin-2-ylmethyl)-2-(pyridin-3-yl)pyrimidin-4-amine, 73. 4-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)morpholine, 74. 4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)thiomorpholine, 75. 6-(4-chlorophenyl)-N-(3-morpholinopropyl)-2-(pyridin-3-yl)pyrimidin-4-amine, 76. (R)-4-(4-chlorophenyl)-6-(2-methylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 77. (R)-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-methylpiperazin-1-yl)(phenyl)methanone, 78. (R)-4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazine-2-carboxylate methyl ester, 79. (R)-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-2-yl)methanol, 80. 4-(4-chlorophenyl)-6-(4-(2,3-dichlorophenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 81. 4-(4-chlorophenyl)-6-(4-(2,5-dimethoxybenzyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 82. 2-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)ethan-1-ol, 83. 4-(4-chlorophenyl)-6-(4-(2-methoxyphenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 84. 4-(4-chlorophenyl)-6-(4-(2-ethoxyphenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 85. 4-(4-chlorophenyl)-6-(4-(2-fluorophenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 86. (4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)(furan-2-yl)methanone, 87. 4-(4-chlorophenyl)-6-(4-phenethylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 88. 6-(4-chlorophenyl)-N-(2-(piperazin-1-yl)ethyl)-2-(pyridin-3-yl)pyrimidin-4-amine, 89. 4-(4-chlorophenyl)-6-(4-(pyridin-2-yl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 90. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidine, 91. 4-(2-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)ethyl)morpholine, 92. 4-(4-chlorophenyl)-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-(pyridin-3-yl)pyrimidine, 93. trans-4-(4-chlorophenyl)-6-(4-cinnamylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 94. 4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-2-one, 95. 4-(4-chlorophenyl)-6-(4-phenylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 96. 4-(4-chlorophenyl)-6-(4-propylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 97. 4-(4-(benzo[d][1,3]dioxol-5-ylmethyl)piperazin-1-yl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidine, 98. (S)-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-2-yl)methanol, 99. 4-(4-chlorophenyl)-6-(4-(4-fluorophenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 100. 6-(4-chlorophenyl)-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2-(pyridin-3-yl)pyrimidin-4-amine, 101. 6-(4-chlorophenyl)-N-(piperidin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-amine, 102. 4-(4-chlorophenyl)-6-(piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 103. trans-4-(4-chlorophenyl)-6-(2,5-dimethylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 104. cis-4-(4-chlorophenyl)-6-(3,5-dimethylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 105. 4-(4-chlorophenyl)-6-(4-methylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 106. 4-(4-chlorophenyl)-6-(4-ethylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 107. 4-(4-chlorophenyl)-6-(4-(methylsulfonyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 108. 1-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)ethan-1-one, 109. 4-(4-chlorophenyl)-6-(3-ethylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 110. Ethyl 4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazine-1-carboxylate, 111. 4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazine-2-carboxylic acid, 112. Methyl 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazine-2-carboxylate, 113. (S)-4-(4-chlorophenyl)-6-(2-phenylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 114. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(4-(o-tolyl)piperazin-1-yl)pyrimidine, 115. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(4-(p-tolyl)piperazin-1-yl)pyrimidine, 116. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(4-(m-tolyl)piperazin-1-yl)pyrimidine, 117. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)pyrimidine, 118. 4-(4-chlorophenyl)-6-(4-(2,3-dimethylphenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 119. 4-(4-chlorophenyl)-6-(4-(3,4-dichlorophenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 120. 4-(4-chlorophenyl)-6-(4-(4-methoxyphenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 121. 4-(4-chlorophenyl)-6-(4-(4-nitrophenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 122. 4-(4-chlorophenyl)-6-(3-(4-methylpiperazin-1-yl)pyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidine, 123. 4-(4-benzhydrylpiperazin-1-yl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidine, 124. 4-(4-chlorophenyl)-6-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 125. 1'-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)spiro[indene-1,4'-piperidine], 126. 6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(pyrrolidin-3-yl)pyrimidin-4-amine, 127. (R)-6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(pyrrolidin-3-yl)pyrimidin-4-amine, 128. (R)-6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(pyrrolidin-3-ylmethyl)pyrimidin-4-amine, 129. 6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(2-(pyrrolidin-1-yl)ethyl)pyrimidin-4-amine, 130. 6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(3-(pyrrolidin-1-yl)propyl)pyrimidin-4-amine, 131. 6-(4-chlorophenyl)-N-(2-(1-methylpyrrolidin-2-yl)ethyl)-2-(pyridin-3-yl)pyrimidin-4-amine, 132. N-(1-benzylpyrrolidin-3-yl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-amine, 133. (3R,4S)-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)pyrrolidin-3-ol, 134. (3S,4R)-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)pyrrolidin-3-ol, 135. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(pyrrolidin-1-yl)pyrimidine, 136. 4-(4-chlorophenyl)-6-(2-methylpyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidine, 137. (S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 138. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)methanol, 139. (R)-4-(4-chlorophenyl)-6-(3-fluoropyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidine, 140. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-amine, 141. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-N-methylpyrrolidin-3-amine, 142. (6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)prophosphate methyl ester 143. N-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)acetamide, 144. (2R,3R)-3-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)butan-2-ol, 145. 3-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)butan-2-ol, 146. 1-(4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)piperidin-1-yl)ethan-1-one, 147. (R)-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanol, 148. (S)-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanol, 149. 6-(4-chlorophenyl)-N-(2-(piperidin-1-yl)ethyl)-2-(pyridin-3-yl)pyrimidin-4-amine, 150. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidine-4-carbonitrile, 151. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(3-(trifluoromethyl)phenyl)piperidin-4-ol, 152. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyrimidine, 153. 4-(4-chlorophenyl)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-ol, 154. 1-(4-(((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)ethan-1-one, 155. 1-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-phenylpiperidin-4-yl)ethan-1-one, 156. 4-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)morpholine, 157. 4-(4-chlorophenyl)-6-(4-(3,5-dichlorophenyl)piperidin-1-yl)-2-(pyridin-3-yl)pyrimidine, 158. 6-(4-chlorophenyl)-N-((1-cyclohexylpiperidin-3-yl)methyl)-2-(pyridin-3-yl)pyrimidin-4-amine, 159. N-((1-benzylpiperidin-4-yl)methyl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-amine, 160. Ethyl 3-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)-3-oxopropanoate, 161. 2-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)ethyl acetate, 162. (1S,3R)-3-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol, 163. (S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-ol, 164. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-N,N-dimethylpyrrolidin-3-amine, 165. 2-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-2-yl)-N,N-dimethylethan-1-amine, 166. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-one, 167. 6-(4-chlorophenyl)-N-methyl-N-(piperidin-4-yl)-2-(pyridin-3-yl)pyrimidin-4-amine, 168. 6-(4-chlorophenyl)-N-(2-(1-methylpiperidin-2-yl)ethyl)-2-(pyridin-3-yl)pyrimidin-4-amine, 169. 6-(4-chlorophenyl)-N-(1-(1-methylpiperidin-4-yl)ethyl)-2-(pyridin-3-yl)pyrimidin-4-amine, 170. 6-(4-chlorophenyl)-N-((1-(2-methoxyethyl)piperidin-4-yl)methyl)-2-(pyridin-3-yl)pyrimidin-4-amine, 171. 2-(4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)piperidin-1-yl)methyl acetate 172. 2,2,2-trifluoroacetic acid 1-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)ethyl ester 173. 6-(4-chlorophenyl)-N-(1-methylpiperidin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-amine, 174. (1S,2R)-2-((6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol, 175. (R)-1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperidin-3-ol, 176. 1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperidin-4-ol, 177. (1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperidin-4-yl)methanol, 178. 2-(1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperidin-4-yl)ethan-1-ol, 179. 3-(1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperidin-4-yl)propan-1-ol, 180. 4-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-6-(4-methylpiperidin-1-yl)pyrimidine, 181. 4-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-6-(4-methylpiperazin-1-yl)pyrimidine, 182. 2-(4-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperazin-1-yl)ethan-1-ol, 183. (S)-1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 184. 1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperidine-4-carbonitrile, 185. (R)-(1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperidin-3-yl)methanol, 186. (R)-1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 187. (1S,3R)-3-((6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol, 188. (R)-2-((6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)butan-1-ol, 189. trans-4-((6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclohexan-1-ol, 190. 7-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)octahydro-2H-pyrano[2,3-c]pyridine 191. 7-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)octahydro-2H-pyrano[2,3-c]pyridin-4-ol, 192. (2R,3R)-3-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)pentan-2-ol, 193. 6-(4-chlorophenyl)-N-((1-methylpiperidin-4-yl)methyl)-2-(pyridin-3-yl)pyrimidin-4-amine, 194. (R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 195. (S)-6-(4-chlorophenyl)-N-(2-(methoxymethyl)pyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-amine, 196. (S)-4-(4-chlorophenyl)-6-(3-fluoropyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidine, 197. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidine, 198. 4-(4-chlorophenyl)-6-(3,3-difluoropyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidine, 199. 4-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)morpholine, 200. 5-(((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)methyl)pyrrolidin-2-one, 201. trans-6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(4-(pyrrolidin-1-yl)tetrahydrofuran-3-yl)pyrimidin-4-amine, 202. 6-(4-chlorophenyl)-N-((3S,4S)-4-methoxy-1-methylpyrrolidin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-amine, 203. (R)-6-(4-chlorophenyl)-N-(piperidin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-amine, 204. 6-(4-chlorophenyl)-N-(piperidin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-amine, 205. 6-(4-chlorophenyl)-N-((3R,4R)-3-fluoropiperidin-4-yl)-2-(pyridin-3-yl)pyrimidin-4-amine, 206. (S)-6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(pyrrolidin-3-ylmethyl)pyrimidin-4-amine, 207. (2R,4R)-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)pyrrolidine-2-carboxylate methyl 208. (2R,4S)-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)pyrrolidine-2-carboxylic acid, 209. trans-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)-1-isopropylpyrrolidin-3-ol, 210. (R)-4-(3-(chloromethyl)pyrrolidin-1-yl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidine, 211. (S)-4-(3-(chloromethyl)pyrrolidin-1-yl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidine, 212. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidine-3-carbonitrile, 213. (R)-1-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)butan-2-ol, 214. (1R,3S)-3-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol, 215. cis-(4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexyl)methanol, 216. cis-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexan-1-ol, 217. trans-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexan-1-ol, 218. 4-(4-chlorophenyl)-6-(4-(2-methoxyethyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 219. (3S,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-ol, 220. (3R,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-ol, 221. (3R,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-ol, 222. (3S,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-ol, 223. 1-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-2-hydroxyethan-1-one, 224. 2-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)propan-1-ol, 225. N-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)-2-methoxyacetamide, 226. (1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol, 227. (1-(2-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol, 228. (1-(6-(4-methoxyphenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol, 229. (1-(2-(pyridin-3-yl)-6-(p-tolyl)pyrimidin-4-yl)piperidin-4-yl)methanol, 230. (3R,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidine-3,4-diol, 231. (3R,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidine-3,4-diol, 232. 1-(3-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)tetrahydropyrimidin-1(2H)-yl)ethan-1-one, 233. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)piperidin-3-ol, 233. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)piperidin-3-ol, 234. (3R,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-fluoropyrrolidin-3-ol, 235. (3R,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-fluoropyrrolidin-3-ol, 236. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)pyrrolidin-3-ol, 237. N-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)-2-hydroxypropanamide, 238. N-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)-2-hydroxyacetamide, 239. 2-((4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)ethan-1-ol, 240. (S)-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)methanol, 241. N-((3R,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-hydroxypyrrolidin-3-yl)acetamide, 242. (3R,4R)-4-acetamido-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl acetate, 243. N-((3R,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-hydroxypyrrolidin-3-yl)acetamide, 244. N-((3S,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-hydroxypyrrolidin-3-yl)acetamide, 245. N-((3S,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-hydroxypyrrolidin-3-yl)acetamide 246. (1-(6-(4-chloro-3-fluorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol, 247. (3S,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)piperidin-3-ol, 248. (3S,4R)-4-(hydroxymethyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-3-ol, 249. ((3S,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-yl)methanol, 250. ((3S,4R)-3-fluoro-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol, 251. ((3R,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-yl)methanol, 252. ((3R,4S)-3-Fluoro-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol, 253. ((3R,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-yl)methanol, 254. ((3R,4R)-3-fluoro-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol, 255. (3S,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)pyrrolidin-3-ol, 256. (3S,4R)-4-(hydroxymethyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol, 257. (3R,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)pyrrolidin-3-ol, 258. (3R,4R)-4-(hydroxymethyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol, 259. (3R,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)piperidin-3-ol, 260. (3R,4R)-4-(hydroxymethyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-3-ol, 261. (3S,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)piperidin-3-ol, 262. (3S,4S)-4-(hydroxymethyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-3-ol, 263. (S)-1-(2-(4-methylpyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol, 264. (3R,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)piperidin-3-ol, 265. (3R,4S)-4-(hydroxymethyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-3-ol, 266. (3S,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)pyrrolidin-3-ol, 267. (3S,4S)-4-(hydroxymethyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol, 268. (1-(6-(4-morpholinophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol, 269. (S)-1-(2-(2-methylpyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol, 270. (S)-3-(4-(3-hydroxypyrrolidin-1-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)pyridin-2-ol, 271. 5-chloro-2-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)phenol, 272. (S)-tert-Butyl 4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-2-(hydroxymethyl)piperazine-1-carboxylate 273. 2-Chloro-5-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)phenol, 274. N-(4-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)phenyl)methanesulfonamide, 275. (1-(6-(4-(4-methylpiperazin-1-yl)phenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol, 276. (1-(6-(3-fluoro-4-morpholinophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol, 277. (1-(2-(pyridin-3-yl)-6-(2,4,6-trifluorophenyl)pyrimidin-4-yl)piperidin-4-yl)methanol, 278. (1-(2-(pyridin-3-yl)-6-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol, 279. (S)-(4-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)morpholin-2-yl)methanol, 280. (R)-(4-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)morpholin-2-yl)methanol, 281. ((3S,4S)-3-Fluoro-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol, 282. ((3S,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-yl)methanol, 283. (3S,4S)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidine-3,4-diol, 284. (3S,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidine-3,4-diol, 285. 3-(4-(4-(hydroxymethyl)piperidin-1-yl)-6-(4-morpholinophenyl)pyrimidin-2-yl)pyridin-2-ol, 286. (1-(2-(1-methyl-1H-pyrazol-4-yl)-6-(4-morpholinophenyl)pyrimidin-4-yl)piperidin-4-yl)methanol, 287. (1-(6-(3-fluoro-4-morpholinophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperidin-4-yl)methanol, 288. (1-(6-(1H-indazol-5-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol, 289. (1-(6-(6-morpholinopyridin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol, 290. 5-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)indolin-2-one, 291. 4-(4-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)phenyl)morpholin-3-one, 292. 4-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)benzoic acid, 293. 4-(1-(6-(1-methyl-1H-pyrazol-3-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol, 294. (1-(6-(5-fluoropyridin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol, 295. (S)-3-(4-(3-hydroxypyrrolidin-1-yl)-6-(6-morpholinopyridin-3-yl)pyrimidin-2-yl)pyridin-2-ol, 296. (S)-1-(6-(4-fluoro-3-nitrophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 297. (S)-1-(6-(4-morpholino-3-nitrophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 298. (S)-1-(6-(3-amino-4-morpholinophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 299. (S)-N-(5-(6-(3-hydroxypyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)-2-morpholinophenyl)acetamide, 300. (S)-1-(6-(6-fluoropyridin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 301. (S)-1-(6-(6-((2-(dimethylamino)ethyl)amino)pyridin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 302. (3S)-1-(6-(6-(2,6-dimethylmorpholino)pyridin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 303. 5-Chloro-2-(6-(4-((2-hydroxyethyl)sulfonyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)phenol, 304. (S)-3-(4-(4-chloro-2-hydroxyphenyl)-6-(3-hydroxypyrrolidin-1-yl)pyrimidin-2-yl)pyridin-2-ol, 305. (S)-1-(6-(4-aminophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 306. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(4-(vinylsulfonyl)piperazin-1-yl)pyrimidine, 307. (1-(6-(2,4-dichlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol, 308. (S)-(4-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperazin-2-yl)methanol, 309. (R)-(4-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperazin-2-yl)methanol, 310. (R)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidine-3-carboxylic acid, 311. (R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidine-3-carboxylic acid, 312. (R)-1-(2-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidine-3-carboxylic acid, 313. (R)-1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)pyrrolidine-3-carboxylic acid, 314. (R)-2-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)isoxazolidin-4-ol, 315. (S)-1-(6-(6-morpholinopyridin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 316. (S)-1-(6-(4-chloro-2-hydroxyphenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 317. (S)-3-(6-(3-hydroxypyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyridin-2-ol, 318. (1-(6-(6-fluoropyridin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol, 319. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)azetidin-3-ol, 320. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)azetidin-3-yl)methanol, 321. 4-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-6-(4-(methylsulfonyl)piperazin-1-yl)pyrimidine, 322. (S)-1-(6-(4-chlorophenyl)-2-(3-hydroxyphenyl)pyrimidin-4-yl)pyrrolidin-3-ol formate. 322. (S)-1-(6-(4-chlorophenyl)-2-(3-hydroxyphenyl)pyrimidin-4-yl)pyrrolidin-3-ol, 323. (S)-1-(6-(4-chlorophenyl)-2-(5-fluoropyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 324. (S)-1-(6-(4-chlorophenyl)-2-(pyridin-4-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 325. 4-(4-chlorophenyl)-2-(5-fluoropyridin-3-yl)-6-(4-(methylsulfonyl)piperazin-1-yl)pyrimidine, 326. 4-(4-chlorophenyl)-6-(4-(methylsulfonyl)piperidin-1-yl)-2-(pyridin-3-yl)pyrimidine, 327. (S)-1-(2-(5-fluoropyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol, 328. 4-(4-chlorophenyl)-6-(4-(cyclopropylsulfonyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 329. (S)-1-(6-(4-chlorophenyl)-2-(pyridazin-4-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 330. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)azepan-4-ol, 331. 2-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane, 332. (S)-1-(6-(4-chlorophenyl)-2-(2-methyl-2H-tetrazol-5-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 333. (S)-1-(2-(2-methyl-2H-tetrazol-5-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol , 334. 4-(4-chlorophenyl)-2-(2-methyl-2H-tetrazol-5-yl)-6-(4-(methylsulfonyl)piperazin-1-yl)pyrimidine, 335. 4-(4-chlorophenyl)-6-(4-((2-fluoroethyl)sulfonyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 336. (S)-1-(6-(4-chlorophenyl)-2-(isoxazol-4-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 337. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(methylsulfonyl)piperidin-4-yl)methanol, 338. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)azepan-3-ol, 339. 4-(4-chlorophenyl)-6-(4-((difluoromethyl)sulfonyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 340. (S)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol, 341. 4-(4-(methylsulfonyl)piperazin-1-yl)-2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidine, 342. (S)-1-(6-(4-chlorophenyl)-2-(5,6-difluoropyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 343. (3S,4R)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidine-3,4-diol, 344. (S)-1-(6-(4-chlorophenyl)-[2,5'-bipyrimidin]-4-yl)pyrrolidin-3-ol, 345. (S)-1-(6-(4-chlorophenyl)-2-(6-fluoropyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 346. (S)-1-(6-(4-chlorophenyl)-2-(2-fluoropyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 347. (S)-1-(6-(4-chlorophenyl)-2-(pyridin-2-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 348. 2-((4-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)ethanol, 349. 2-((4-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)ethan-1-ol, 350. (S)-1-(2-(isothiazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol, 351. (4-(methylsulfonyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol, 352. 1-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-3-hydroxypropan-1-one, 353. 2-((4-(2-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)ethanol, 354. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-(dimethylamino)piperidin-4-ol, 355. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-5-(dimethylamino)piperidin-3-ol, 356. (1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-4-(methylsulfonyl)piperidin-4-yl)methanol, 357. (1-(2-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)-4-(methylsulfonyl)piperidin-4-yl)methanol, 358. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-(dimethylamino)piperidin-4-yl)methanol, 359. 2-((4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-methylpiperazin-1-yl)sulfonyl)ethan-1-ol, 360. 2-((1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)amino)ethanol, 361. 1-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-4-hydroxybutan-1-one, 362. 3-((4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)propan-1-ol, 363. 1-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-3,4-dihydroxybutan-1-one, 364. 1-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-2,3-dihydroxybutan-1-one, 365. 4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-6-methylpiperazin-2-one, 366. (S)-3-(4-(3-hydroxypyrrolidin-1-yl)-6-(6-morpholinopyridin-3-yl)pyrimidin-2-yl)pyridin-2-ol, 367. (S)-4-(4-(6-(3-hydroxypyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)phenyl)morpholin-3-one, 368. 2-((4-(6-(4-chlorophenyl)-2-(isothiazol-4-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)ethanol, 369. 3-((4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)propane-1,2-diol, 369. 3-((4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)propane-1,2-diol, 370. 2-((4-(2-(isothiazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)ethanol, 371. (S)-2-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-2-yl)ethanol, 372. (S)-4-(5-(6-(3-hydroxypyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyridin-2-yl)morpholin-3-one, 373. (S)-3-(4-(3-fluoro-4-morpholinophenyl)-6-(3-hydroxypyrrolidin-1-yl)pyrimidin-2-yl)pyridin-2-ol, 373. (S)-3-(4-(3-fluoro-4-morpholinophenyl)-6-(3-hydroxypyrrolidin-1-yl)pyrimidin-2-yl)pyridin-2-ol, 374. (S)-1-(6-(4-((2-(dimethylamino)ethyl)amino)phenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 375. (S)-1-(6-(4-(2-(dimethylamino)ethoxy)phenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol, and 376.(S)-1-(6-(4-((2-hydroxyethyl)amino)phenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol It may also be a compound selected from the group consisting of:

[0115] Also included within the scope of this disclosure are single stereochemical isomers, enantiomers, diastereomers, and pharmaceutically acceptable salts of the above-exemplified compounds, which may be derived, for example, from suitable inorganic or organic acids or bases.

[0116] Acid addition salts can be prepared by reacting the purified compound, if possible in free base form, with a suitable organic or inorganic acid and isolating the salt formed. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid, etc., or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, etc.

[0117] Base addition salts can be prepared by reacting the purified compound in its acid form with a suitable organic or inorganic base and isolating the resulting salt. Such salts include alkali metal salts (e.g., sodium, lithium, and potassium), alkaline earth metal salts (e.g., magnesium and calcium), ammonium salts, and N + (C 1-4 Examples of suitable salts include, but are not limited to, alkyl)4 salts.

[0118] Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, gluconate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethane These include sulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate salts.

[0119] Furthermore, the compounds of the present invention represented by Formula (I) include, but are not limited to, not only pharmaceutically acceptable salts thereof, but also any solvates or hydrates and stereoisomers that can be prepared from the compounds. All stereoisomers of the compounds of the present invention, such as enantiomers and diastereomers (e.g., stereoisomers based on asymmetric carbon atoms on various substituents), are also within the scope of the present invention. Individual stereoisomers of the compounds of the present invention may be, for example, substantially free of other isomers (e.g., pure or substantially pure optical isomers having a specific activity), or may be present in a mixture, for example, as a racemate, in a mixture with any other stereoisomers, or in a mixture with other selected stereoisomers. Chiral centers in the compounds of the present invention may have the S or R configuration as defined by the IUPAC (1974) Recommendations. Racemates can be analyzed by physical methods such as fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. The individual optical isomers can be obtained from the racemate by a suitable method such as forming a salt with an optically active acid followed by crystallization, but the method for obtaining the individual optical isomers is not limited thereto.

[0120] Solvates and stereoisomers of compounds of formula (I) may be prepared from compounds of formula (I) using methods known in the art.

[0121] Furthermore, the compound of the present invention represented by formula (I) may be prepared in crystalline form or in amorphous form.When the compound of the present invention is prepared in crystalline form, the crystalline compound of the present invention may be hydrated or solvated.In the present invention, the compound of formula (I) may include not only stoichiometric hydrates but also compounds containing various amounts of water.The solvates of the compound of the present invention represented by formula (I) include stoichiometric solvates and non-stoichiometric solvates.

[0122] The compounds of the present invention may be synthesized by methods known in the art or as illustrated in Examples 1-376 below.

[0123] Pharmaceutical compositions, methods and uses In one particular embodiment, the pharmaceutical compositions and methods provided herein comprise a compound of formula (I).

[0124] The subject may be a mammal, including human cells or mammalian cells, such as a mammal (e.g., a human) suffering from a disease, disorder, or condition associated with AhR activity, as described above, or mammalian cells isolated from such a mammal.

[0125] The compound of the present invention as an active ingredient or the pharmaceutical composition of the present invention may be administered orally or parenterally. For example, parenteral administration may be performed by any of intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, intradermal administration, topical administration, intranasal administration, intrapulmonary administration, intrarectal administration, etc.

[0126] An effective amount may refer to a pharmaceutically effective amount and / or a therapeutically effective amount, and may be formulated depending on factors such as the type of preparation (formulation), the route of administration, the age, weight, sex and / or medical condition of the patient.

[0127] Pharmaceutically acceptable salts of the compounds of formula (I) include, but are not limited to, addition salts formed with inorganic acids such as hydrochloride, sulfate, phosphate, hydrobromide, hydroiodide, nitrate, pyrosulfate, metaphosphate, etc.; addition salts formed with organic acids such as citrate, oxalate, benzoate, acetate, trifluoroacetate, propionate, succinate, fumarate, lactate, maleate, tartrate, glutarate, sulfonate, etc.; and metal salts such as lithium, sodium, potassium, magnesium, calcium salts.

[0128] The pharmaceutical composition of the present invention can be formulated into an appropriate form with a commonly used pharmaceutically acceptable carrier. "Pharmaceutically acceptable" refers to being physiologically acceptable, and when administered to humans, it usually does not cause allergic reactions or similar reactions (such as gastrointestinal disorders or dizziness). Furthermore, the pharmaceutical composition of the present invention may be formulated into oral preparations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, or parenteral preparations such as transdermal preparations, suppositories, and sterile injections, according to conventional methods, before use.

[0129] Examples of carriers, additives, and diluents that can be added to the compositions of the present invention include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil. When preparing formulations, commonly used diluents and additives such as fillers, stabilizers, binders, disintegrants, and surfactants can be used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules, and the like. These solid formulations can be prepared by mixing the compounds of the present invention with at least one additive, such as starch, microcrystalline cellulose, sucrose, lactose, low-substituted hydroxypropyl cellulose, and hypromellose. In addition to simple additives, lubricants such as magnesium stearate and talc can also be used. Oral liquid preparations include suspensions, oral solutions, emulsions, syrups, etc. In addition to commonly used simple diluents such as water and liquid paraffin, various additives such as humectants, sweeteners, flavorings, and preservatives may be added. Parenteral preparations include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solutions or suspensions may contain propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases may include witepsol, macrogol, Tween 61, cocoa butter, lauric butter, and glycerogelatin. In preparing formulations for parenteral administration, a solution or suspension may be prepared by mixing the compound of formula (I) or a pharmaceutically acceptable salt thereof with auxiliary substances such as preservatives, stabilizers, adjuvants such as wetting agents and emulsifiers, salts and / or buffers for adjusting osmotic pressure, and other therapeutically useful substances in sterile water, and the resulting solution or suspension is then manufactured into a unit dosage form such as an ampule or vial.

[0130] Pharmaceutical compositions comprising as active ingredients the compounds of formula (I) disclosed herein may be administered by various routes to mammals, such as mice, livestock, and humans, for the purposes of modulating the activity of AhR or preventing or treating diseases, disorders, or conditions associated with AhR activity.

[0131] In some embodiments, the disease, disorder or condition associated with AhR activity may be cancer, a cancerous condition, a tumor, a fibrotic disease, an immune-related disease or other disease associated with AhR signaling.

[0132] In some embodiments, the disease associated with dysregulation of the immune response associated with AhR signaling is selected from the group consisting of sepsis (SIRS), multiple organ dysfunction syndrome (MODS, MOF), inflammatory kidney disease, chronic bowel inflammation (IBD, Crohn's disease, UC), pancreatitis, peritonitis, inflammatory skin diseases, inflammatory eye diseases, and autoimmune diseases (rheumatic diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and multiple sclerosis (MS)).

[0133] In some embodiments, the fibrotic disease is selected from the group consisting of fibrotic diseases of internal organs such as lung, heart, kidney, bone marrow (particularly liver fibrosis), skin fibrosis, and eye fibrotic disease.In the present invention, "fibrotic disease" specifically includes liver fibrosis, liver cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, renal interstitial fibrosis, fibrotic disorders associated with diabetes, myelofibrosis, and fibrotic diseases similar thereto; as well as scleroderma, morphea, keloid, hypertrophic scar (post-surgical hypertrophic scar), nevus, diabetic retinopathy, proliferative vitreoretinopathy, and connective tissue disorders (e.g., sarcoidosis).

[0134] In some embodiments, cancers, cancerous conditions, or tumors particularly suitable for treatment with the AhR antagonists of the invention are liquid tumors and solid tumors, such as breast cancer, squamous cell carcinoma, lung cancer, peritoneal cancer, hepatocellular carcinoma, gastric cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, colon cancer, colorectal cancer, endometrial cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, head and neck cancer, B-cell lymphoma, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), hairy cell leukemia, and chronic myeloblastic leukemia.

[0135] In some embodiments, the pharmaceutical compositions of the present invention can be used in combination with one or more additional anti-cancer therapies. In some such embodiments, the additional anti-cancer therapies include surgery, radiation therapy, biological therapy, immunotherapy, chemotherapy, or any combination thereof.

[0136] In some embodiments, the pharmaceutical compositions of the present invention can be used in combination with an anti-cancer therapeutic agent, which in some such embodiments is a chemotherapeutic agent, an anti-proliferative agent, an anti-angiogenic agent, a cytotoxic agent, an anti-hormonal agent, a prodrug, or a cytokine.

[0137] Other examples of disorders associated with inflammation due to aberrant AhR signaling include vaccination against infectious diseases, cancer, viral infections, obesity and diet-induced obesity, steatosis, metabolic diseases, hepatic steatosis, uterine fibroids in women (uterine leiomyomas or uterine fibroids), chronic kidney injury, acute and chronic renal failure, diabetic nephropathy, inflammatory nephropathy, hypertensive nephropathy, heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular disorders, thromboembolic disorders, arteriosclerosis, sickle cell anemia, erectile dysfunction, benign prostatic hyperplasia, voiding disorders associated with benign prostatic hyperplasia, Huntington's disease, dementia, Alzheimer's disease, and Creutzfeldt-Jakob disease.

[0138] Additionally, in another aspect, there is provided a pharmaceutical composition comprising an AhR modulator, such as an AhR antagonist of formula (I), and a pharmaceutically acceptable excipient.

[0139] In some embodiments, a pharmaceutical composition is provided comprising an AhR modulator, such as an AhR antagonist of Formula (I), for use in modulating constitutive AhR activity in a subject in need thereof.

[0140] In some embodiments, there is provided a pharmaceutical composition comprising an AhR modulator, such as an AhR antagonist of Formula (I), for use in treating cancer or a cancerous condition by modulating the activity of AhR.

[0141] In some embodiments, a pharmaceutical composition is provided comprising an AhR modulator, such as an AhR antagonist of Formula (I), for use in inhibiting cancer cell proliferation, tissue invasion, metastasis, and angiogenesis in a subject having cancer, a cancerous condition, or a tumor.

[0142] In some embodiments, the pharmaceutical compositions of the present invention may be for use in inhibiting cancer cell proliferation, tissue invasion, metastasis and angiogenesis in a subject with cancer, a cancerous condition or a tumor.

[0143] The pharmaceutical formulations described herein can be administered to a subject via a variety of routes of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular, rectal, endometrial, intracerebrovascular), intranasal, buccal, topical, or transdermal routes of administration.

[0144] In some embodiments, the compound of Formula (I) is administered orally.

[0145] Another aspect of the present invention relates to a method of stimulating the immune system in a patient in need thereof, e.g., a patient suffering from cancer or an infectious disease (e.g., a viral, bacterial, or parasitic infection). The method comprises administering to the patient a therapeutically effective amount of one compound described herein or a therapeutically effective amount of a combination of compounds described herein. In some embodiments, the patient following this administration step has an increased number of leukocytes, T and / or B lymphocytes, macrophages, dendritic cells, neutrophils, natural killer (NK) cells, and / or platelets. In some embodiments, the compound of the present invention reduces the patient's IL-21 level. The patient may be a patient suffering from cancer or an immunocompromised patient.

[0146] "Treate," "treating," or "treatment" refers to a method of alleviating or preventing a biological disorder and / or at least one symptom associated therewith. As used herein, "alleviating" a disease, disorder, or condition means reducing the severity and / or frequency of the symptoms of the disease, disorder, or condition. Furthermore, as used herein, "treatment" includes treatment for the purpose of cure, palliative, or prophylaxis. Cancer treatment includes inhibiting cancer growth (including inhibiting cancer growth to induce partial or complete regression of the cancer), inhibiting cancer progression or metastasis, preventing cancer recurrence or residual disease, and / or prolonging patient survival. A "therapeutically effective amount" is the amount of a pharmaceutical agent capable of producing the desired therapeutic, palliative, or prophylactic effect for the condition being treated.

[0147] In some embodiments, the effective dosage range of the compound is determined by carrying out a predetermined administration regimen and measuring the concentration of the compound in the patient's blood to establish the relationship between the concentration and time of the compound; then establishing and examining the correlation between the concentration and time of the compound and the cancer suppressive or eradicating effect observed during the clinical trial; and further taking into account the patient's health condition or physical endurance, balancing the obtainable therapeutic effect with the toxicity to the patient. The frequency of administration of the compound may also be determined in a similar manner. The administration of the compound may be continued until the patient's cancer is eradicated.

[0148] In some embodiments, an effective amount for treating a tumor may be determined based on the effect of slowing disease progression and / or alleviating symptoms in a patient, and preferably based on the effect of reversing disease progression, such as by reducing tumor volume. In some embodiments, maintenance administration after the patient's cancer disappears may completely eliminate or eradicate the cancer or prevent the recurrence of residual disease. The duration of maintenance administration may be determined based on clinical trial data.

[0149] In some embodiments, the compounds of the present invention may be administered in combination with one or more additional cancer therapeutic agents that target AhR or target molecules other than AhR. The compounds of the present invention and the additional cancer therapeutic agents may be formulated as separate formulations, or a formulation containing the compounds of the present invention and the additional cancer therapeutic agents may be prepared. The compounds of the present invention and the additional cancer therapeutic agents may be administered using the same dosing regimen, or they may be administered using different dosing regimens. The ratio of the compounds of the present invention to the additional cancer therapeutic agents may be determined based on the results of clinical trials. Combining the compounds of the present invention with the additional cancer therapeutic agents may improve the efficacy of the compounds of the present invention and the additional cancer therapeutic agents. For example, the compounds of the present invention may be administered in combination with immune checkpoint inhibitors, such as PD-1, PD-L1, or PD-L2 inhibitors (e.g., pembrolizumab, nivolumab, or atezolizumab), or in combination with CAR-T therapy (e.g., axicabtageneciloreucel), thereby achieving additive or synergistic effects against cancer.

[0150] Dosage regimens may be adjusted to obtain the optimum desired response. As used herein, unit dosage form refers to a physically distinct unit suitable for administering a unit dose to a patient or subject to be treated, each unit dosage form containing a predetermined amount of active compound calculated to produce the desired therapeutic effect, and the required pharmaceutical carrier.

[0151] It should be noted that dosages may vary depending on the type and severity of the condition being alleviated and may include single or multiple administrations. Furthermore, it should be noted that specific dosing regimens for a particular subject should be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the compositions of the invention. Furthermore, the dosage ranges set forth herein are exemplary and are not intended to limit the scope or practice of the compositions specifically described herein. Furthermore, dosage regimens for use with the compositions of the invention may depend on a variety of factors, including the type of disease; the patient's age, weight, sex, and condition; the severity of the condition; the route of administration; and the particular antibody used. Thus, dosage regimens may vary widely but can be routinely determined using standard methods. For example, dosages may be adjusted in response to pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxicity and / or laboratory values.

[0152] A suitable dosage of the compound of the present invention may be in the range of 0.001 to 200 mg / kg body weight per day, preferably about 0.01 mg / kg to about 20 mg / kg body weight per day, for example, about 0.5 to 50 mg / kg, for example, about 1 to 20 mg / kg. The compound of the present invention may be administered at a dose of, for example, at least 0.25 mg / kg, for example, at least 0.5 mg / kg, for example, at least 1 mg / kg, for example, at least 1.5 mg / kg, for example, at least 2 mg / kg, for example, at least 3 mg / kg, for example, at least 4 mg / kg, for example, at least 5 mg / kg; for example, at a dose of not more than 50 mg / kg, for example, not more than 30 mg / kg, for example, not more than 20 mg / kg, for example, not more than 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, for a period determined to be appropriate by the attending physician, and the dose may be increased or decreased as necessary at the discretion of the attending physician.

[0153] Basic compositing method The compounds of the present invention of formula (I) can be prepared according to one or more of the schemes illustrated below.

[0154] The following methods can be used directly or with easy modification by the skilled chemist to prepare key intermediates and specific compounds of the present invention.

[0155] Suitable synthetic sequences can be easily selected according to the specific structures of the present invention within the scope of techniques known to those skilled in the art of organic synthesis, such as methods compiled in available chemical databases such as CAS Scifinder and Elsevier Reaxys. The compounds of the present invention can be easily prepared based on such general methods, and the preparation methods for the compounds of the present invention are within the scope of general expertise. General synthetic methods for preparing the compounds of the present invention are shown in Schemes 1 to 5 (General Procedures A to E) below.

[0156] The basic method for producing the compounds of the present invention is shown in Scheme 1. [ka] a) 1. CHONa, MeOH, 2. Ammonia in MeOH; b) Diethyl malonate, CHONa, MeOH; c) POCl3; d) Ar 2 -B(OH)2 or its pinacol ester, Pd(PPh3)4, Na2CO3, THF / H2O (4 / 1), heating, microwave; e) RNH2 or (R)2NH (primary or secondary amine), TEA, THF, heating; f) ethanolic solution of hydrochloric acid, 1M ammonium acetate solution *R 1 means R deprotected from boc.

[0157] Another basic method for preparing the compounds of the present invention is shown in Scheme 2. [ka] a) 1. HCl, MeOH, 2. Ammonia in MeOH; b) NaH, THF, reflux; c) CH3ONa, MeOH, heating; d) POCl3, heating; e) RNH2 or (R)2NH (primary or secondary amine), TEA, THF, heating; f) Hydrochloric acid in ethanol, 1M ammonium acetate solution *R 1 means R deprotected from boc.

[0158] Another basic method for preparing the compounds of the present invention is shown in Scheme 3. [ka] a) Ar 2 -B(OH)2 or its pinacol ester, Pd(PPh3)4, Na2CO3, THF / H2O (4 / 1), heating, microwave; b) RNH2 or (R)2NH (primary or secondary amine), TEA, THF, heating; c) Ar 1 -B(OH)2 or its pinacol ester, Pd(PPh3)4, Na2CO3, THF / H2O (4 / 1), heating, microwave; d) Ethanol solution of hydrochloric acid, 1M ammonium acetate solution *R 1 means R deprotected from boc.

[0159] Another basic method for preparing the compounds of the present invention is shown in Scheme 4. [ka] a) 1. CHONa, MeOH, 2. Ammonia in MeOH; b) Diethyl malonate, CHONa, MeOH; c) POCl3; d) RNH2 or (R)2NH (primary or secondary amine), TEA, THF, heating; e) Ar 2 -B(OH)2 or its pinacol ester, Pd(PPh3)4, Na2CO3, THF / H2O (4 / 1), heating, microwave; f) Ethanol solution of hydrochloric acid, 1M ammonium acetate solution *R 1 means R deprotected from boc.

[0160] Another basic method for preparing the compounds of the present invention is shown in Scheme 5. [ka] a) RNH2 or (R)2NH (primary or secondary amine), TEA, THF, heating; b) Ar 2 -B(OH)2 or its pinacol ester, Pd(PPh3)4, Na2CO3, THF / H2O (4 / 1), heating, microwave; c) Ar 1 -B(OH)2 or its pinacol ester, Pd(PPh3)4, Na2CO3, THF / H2O (4 / 1), heating, microwave *R 1 means R deprotected from boc. [Example]

[0161] Embodiments of the present invention are described in the following examples, which are intended for illustrative purposes and are not intended to limit the scope of the invention. Common abbreviations known to those skilled in the synthetic arts are used throughout the examples.

[0162] All chemical reagents were commercially available. Flash column chromatography refers to silica gel chromatography unless otherwise stated and was performed using a Teledyne Combiflash-RF200 system. 1 H NMR spectra (δ, ppm) were recorded using a 400 MHz or 600 MHz instrument. Mass spectrometry data were also provided using positive ionization. Preparative HPLC was performed using an Agilent Technologies G1361A preparative HPLC system or a Gilson preparative HPLC system.

[0163] Example 1. (R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)butan-1-ol Scheme for preparing the compound of Example 1 [ka]

[0164] Intermediate 1. Nicotinimidamide Hydrochloride To a suspension of 3-cyanopyridine (5 g, 48.03 mmol) in MeOH (50 mL) was added a solution of 30 wt% sodium methoxide in MeOH (4 mL), and the mixture was stirred at room temperature for 24 hours. After adding NH4Cl (16.5 g, 0.31 mol), the mixture was heated to reflux for 6 hours and then cooled. The solvent was removed under reduced pressure, and EtOH (60 mL) was added. The mixture was heated to reflux for 30 minutes. After cooling to room temperature, the solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The suspension of the reaction mixture in EtOH (3 mL) was filtered, and the solid product was dried to give 4.9 g of the title compound. 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 9.43 (bs, 4H), 8.98 (d, J = 1.6 Hz, 1H), 8.74 (dd, J = 4.8 Hz, J = 1.2 Hz, 1H), 8.20-8.23 (m, 1H), 7.64-7.67 (m, 1H); MS (ESI, m / z): 122.1 [M+H] +

[0165] Intermediate 2. 2-Pyridin-3-yl-pyrimidine-4,6-diol To a solution of 3-pyridylamidine hydrochloride (4.8 g, 30.46 mmol) in MeOH (120 mL) was added diethyl malonate (4.63 mL, 30.46 mmol) at 0° C., followed by the addition of a 30 wt % solution of sodium methoxide in MeOH (20 mL). The resulting mixture was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure. The resulting residue was used without further purification. MS (ESI, m / z): 190.0 [M+H] +

[0166] Intermediate 3. 4,6-Dichloro-2-pyridin-3-yl-pyrimidine To a solution of 2-pyridin-3-yl-pyrimidine-4,6-diol (5.0 g of the crude product obtained in the previous step) in POCl (10 mL) was added dimethylaminoaniline (4.77 g, 35.03 mmol), and the reaction mixture was heated at 120 °C for 4 hours. The residue was cooled to room temperature, extracted with 500 mL of EtOAc, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 4.45 g of the title compound. 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 7.36 (s, 1H), 7.49 (dd, J = 4.8 Hz, J = 1.6 Hz, 1H), 8.80-8.72 (m, 2H), 9.64 (br, 1H); MS (ESI, m / z): 226.0 [M+H] +

[0167] Intermediate 4. 4-Chloro-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidine 4,6-Dichloro-2-pyridin-3-yl-pyrimidine (1.03 g, 4.6 mmol), (4-chlorophenyl)boronic acid (0.66 g, 4.2 mmol), and sodium carbonate (1.01 g, 9.5 mmol) were dissolved in tetrahydrofuran / HO (4 / 1) (50 mL), and Pd(PPh) (203 mg, 0.18 mmol) was added to the resulting mixture. The mixture was heated at 80 °C for 20 min in a microwave oven, cooled to room temperature, and extracted three times with EtOAc (50 mL). The organic layer was dried over anhydrous MgSO and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 1.02 g of the title compound. 1 H NMR (600 MHz, CDCl3) δ [ppm] = 7.52 (d, 2H), 7.74 (s, 1H), 7.79 (dd, 1H), 8.06 (d, 2H), 9.02 (d, 1H), 9.12 (d, 1H), 10.16 (s, 1H); MS (ESI, m / z): 302.0 [M+H] +

[0168] Example 1. (R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)butan-1-ol To a solution of 4-chloro-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidine (45 mg, 0.15 mmol) in tetrahydrofuran (6 mL) was added triethylamine (0.3 mL, 2.15 mmol) at room temperature, followed by (R)-2-aminobutan-1-ol (27 mg, 0.30 mmol). The reaction was heated in a sealed tube at 120° C. for 4 hours and cooled to room temperature. The residue was filtered, concentrated under reduced pressure, and separated by preparative HPLC to give 50 mg of the title compound. 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.05 (t, 3H), 1.59-1.64 (m, 1H), 1.83-1.86 (m, 1H), 3.70 (d, 2H), 4.39 (br, 1H), 6.96 (s, 1H), 7.50 (d, MS (ESI, m / z): 355.1 [M+H] +

[0169] Examples 2 and 3. (S)-2-((4-(4-chlorophenyl)-6-(pyridin-3-yl)pyrimidin-2-yl)amino)propan-1-ol and (S)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propan-1-ol Schemes for preparing the compounds of Example 2 and Example 3 [ka]

[0170] Intermediate 5. 2,4-Dichloro-6-(4-chlorophenyl)pyrimidine To a solution of 2,4,6-trichloropyrimidine (813.5 mg, 4.43 mmol), (4-chlorophenyl)boronic acid (329.2 mg, 2.11 mmol), and sodium carbonate (314.6 mg, 2.97 mmol) in tetrahydrofuran / HO (4 / 1) (20 mL) was added Pd(PPh) (253.7 mg, 0.22 mmol). The mixture was heated at 80 °C overnight, cooled to room temperature, and extracted three times with EtOAc (150 mL). The organic layer was washed with brine, dried over anhydrous MgSO, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, hexane / ethyl acetate, gradient) to give 510.0 mg of the title compound. 1 H NMR (600 MHz, CDCl3) δ [ppm] = 7.52 (d, 2H), 7.67 (s, 1H), 8.05 (d, 2H); MS (ESI, m / z): 258.0 [M+H] +

[0171] Intermediate 6 and Intermediate 7. (S)-2-((2-chloro-6-(4-chlorophenyl)pyrimidin-4-yl)amino)propan-1-ol and (S)-2-((4-chloro-6-(4-chlorophenyl)pyrimidin-2-yl)amino)propan-1-ol To a solution of 2,4-dichloro-6-(4-chlorophenyl)pyrimidine (Intermediate 5, 76.2 mg, 0.294 mmol) in tetrahydrofuran (6 mL), triethylamine (0.1 mL, 0.712 mmol) was added at room temperature, followed by (S)-2-aminopropan-1-ol (28.95 mg, 0.385 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was filtered, concentrated under reduced pressure, and separated by flash chromatography (silica gel, hexane / ethyl acetate, gradient) to give 54.0 mg of Intermediate 6 and 30.1 mg of Intermediate 7.

[0172] Intermediate 6 1H NMR (600 MHz, CDCl3) δ [ppm] = 1.28 (d, 3H), 3.61-3.65 (m, 1H), 3.78-3.81 (m, 1H), 4.15 (br, 1H), 5.48 (br, 1H), 6.59 (s, 1H), 7.41 (d, 2H), 7.86 (d, 2H); MS (ESI, m / z): 298.0 [M+H] +

[0173] Intermediate 7 1 H NMR (600 MHz, CDCl3) δ [ppm] = 1.28 (d, 3H), 3.61-3.66 (m, 1H), 3.79-3.83 (m, 1H), 4.27 (br, 1H), 5.58 (br, 1H), 6.93 (s, 1H), 7.42 (d, 2H), 7.88 (d, 2H); MS (ESI, m / z): 298.0 [M+H] +

[0174] Example 2. (S)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propan-1-ol To a solution of (S)-2-((2-chloro-6-(4-chlorophenyl)pyrimidin-4-yl)amino)propan-1-ol (60 mg, 0.201 mmol), 3-pyridylboronic acid (80 mg, 0.651 mmol), and sodium carbonate (90 mg, 0.849 mmol) in tetrahydrofuran / HO (4 / 1) (10 mL) was added Pd(PPh) (80 mg, 0.069 mmol). The mixture was heated at 130 °C for 15 min in a microwave oven, cooled to room temperature, and extracted three times with EtOAc (30 mL). The organic layer was washed with brine, dried over anhydrous MgSO, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, hexane / ethyl acetate, gradient) to give 32 mg of the title compound (Scheme 3, General Procedure C). 1H NMR (600 MHz, CD3OD) δ [ppm] = 1.25 (d, 3H), 3.56-3.59 (m, 1H), 3.63-3.66 (m, 1H), 4.35 (br, 1H), 6.73 (s, 1H), 7.36 (d, 2H), 7.45-7.49 (m, 1H), 7.98 (d, 2H), 8.56 (br, 1H), 8.71 (d, 1H), 9.48 (br, 1H); MS (ESI, m / z): 341.1 [M+H] +

[0175] Example 3. (S)-2-((4-(4-chlorophenyl)-6-(pyridin-3-yl)pyrimidin-2-yl)amino)propan-1-ol To a solution of (S)-2-((4-chloro-6-(4-chlorophenyl)pyrimidin-2-yl)amino)propan-1-ol (25 mg, 0.084 mmol), 3-pyridylboronic acid (31 mg, 0.252 mmol), and sodium carbonate (35 mg, 0.336 mmol) in tetrahydrofuran / HO (4 / 1) (5 mL) was added Pd(PPh) (34 mg, 0.029 mmol). The mixture was heated at 130 °C for 15 min in a microwave oven, cooled to room temperature, and extracted three times with EtOAc (30 mL). The organic layer was washed with brine, dried over anhydrous MgSO, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, hexane / ethyl acetate, gradient) to give 17.6 mg of the title compound (Scheme 3, General Procedure C). 1 H NMR (600 MHz, CD3OD) δ [ppm] = 1.34 (d, 3H), 3.64-3.66 (m, 1H), 3.73-3.76 (m, 1H), 4.33-4.36 (m, 1H), 7.49 (d, 2H), 7.57-7.59 (m, MS (ESI, m / z): 341.1 [M+H] +

[0176] Example 4. 2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)-2-methylpropan-1-ol The title compound was obtained in the same manner as in Example 2, except that 2-amino-2-methylpropan-1-ol was used (Scheme 3, General Procedure C). 1 H NMR (600 MHz, CD3OD) δ [ppm] = 1.53 (s, 6H), 3.91 (s, 2H), 7.01 (s, 1H), 7.53 (d, 2H), 8.11 (d, 2H), 8.05-8.15 (m, 1H), 8.90 (br, 1H), 9.33 (d, 1H), 9.68 (br, 1H); MS (ESI, m / z): 355.1 [M+H] +

[0177] Example 5. 2-((4-(4-chlorophenyl)-6-(pyridin-3-yl)pyrimidin-2-yl)amino)-2-methylpropan-1-ol The title compound was obtained in the same manner as in Example 3 except for using 2-amino-2-methylpropan-1-ol (Scheme 3, General Procedure C). 1 H NMR (600 MHz, CDCl3) δ [ppm] = 1.55 (s, 6H), 3.84 (s, 2H), 7.12 (d, 1H), 7.40 (s, 1H), 7.44-7.48 (m, 1H), 7.54 (d, 2H), 7.98 (d, 2H), 8.03 (d, 1H), 8.82 (br, 1H); MS (ESI, m / z): 355.1 [M+H] +

[0178] Example 6. 2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)ethan-1-ol The title compound was obtained in the same manner as in Example 1 except for using 2-aminoethan-1-ol (Scheme 1, General Procedure A). 1 H NMR (600 MHz, CD3OD) δ [ppm] = 3.80 (t, 2H), 4.10 (t, 2H), 6.84 (s, 1H), 7.45 (d, 2H), 7.50-7.52 (m, 1H), 8.07 (d, 2H), 8.59 (d, 1H), 8.79 (d, 1H), 9.52 (s, 1H); MS (ESI, m / z): 327.1 [M+H] +

[0179] Example 7. 3-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propan-1-ol The title compound was obtained in the same manner as in Example 1 except for using 3-aminopropan-1-ol (Scheme 1, General Procedure A). 1 H NMR (600 MHz, CD3OD) δ [ppm] = 1.91-1.94 (m, 2H), 3.72 (t, 2H), 4.10 (t, 2H), 6.89 (s, 1H), 7.82 (d, 2H), 7.56-7.58 (m, 1H), 8.15 (d, 2H), 8.63 (d, 1H), 8.87 (d, 1H), 9.58 (s, 1H); MS (ESI, m / z): 341.1 [M+H] +

[0180] Example 8. (S)-1-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propan-2-ol The title compound was obtained in the same manner as in Example 1 except for using (S)-1-aminopropan-2-ol (Scheme 1, General Procedure A). 1 H NMR (600 MHz, CDCl3) δ [ppm] = 1.31 (d, 3H), 3.41 (br, 1H), 3.70 (br, 1H), 4.12-4.15 (m, 1H), 5.63 (br, 1H), 6.65 (s, 1H), 7.43 (d, 2H), 7.39-7.45 (m, 1H), 8.00 (d, 2H), 8.66 (br, 1H), 8.72 (d, 1H), 9.64 (br, 1H); MS (ESI, m / z): 341.1 [M+H] +

[0181] Example 9. (R)-1-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propan-2-ol The title compound was obtained in the same manner as in Example 1 except for using (R)-1-aminopropan-2-ol (Scheme 1, General Procedure A). 1H NMR (600 MHz, CDCl3) δ [ppm] = 1.31 (d, 3H), 3.41 (br, 1H), 3.70 (br, 1H), 4.12-4.15 (m, 1H), 5.63 (br, 1H), 6.65 (s, 1H), 7.43 (d, 2H), 7.39-7.45 (m, 1H), 8.00 (d, 2H), 8.66 (br, 1H), 8.72 (d, 1H), 9.64 (br, 1H); MS (ESI, m / z): 341.1 [M+H] +

[0182] Example 10. 3-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propane-1,2-diol The title compound was obtained in the same manner as in Example 1 except for using 3-aminopropane-1,2-diol (Scheme 1, General Procedure A). MS (ESI, m / z): 357.1 [M+H] +

[0183] Example 11. (R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propan-1-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that (R)-2-aminopropan-1-ol was used (Scheme 1, General Procedure A). 1 H NMR (600 MHz, CD3OD) δ [ppm] = 1.31 (d, 3H), 3.61-3.64 (m, 1H), 3.67-3.70 (m, 1H), 4.50 (br, 1H), 6.95 (s, 1H), 7.52 (d, 2H), 8.01-8.19 (m, 1H), 8.12 (d, 2H), 8.85 (br, 1H), 9.38 (d, 1H), 9.71 (br, 1H); MS (ESI, m / z): 341.1 [M+H] +

[0184] Example 12. 2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)-3-methylbutan-1-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 2-amino-3-methylbutan-1-ol was used (Scheme 1, General Procedure A). 1 H NMR (600 MHz, CD3OD) δ [ppm] = 1.06 (d, 3H), 1.09 (d, 3H), 2.10 (br, 1H), 3.73-3.76 (m, 1H), 3.80-3.83 (m, 1H), 4.41 (br, 1H), 7.02 (s, MS (ESI, m / z): 369.2 [M+H] +

[0185] Example 13 (S)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)-3-methylbutan-1-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that (S)-2-amino-3-methylbutan-1-ol was used (Scheme 1, General Procedure A). 1 H NMR (600 MHz, CD3OD) δ [ppm] = 1.06 (d, 3H), 1.09 (d, 3H), 2.10 (br, 1H), 3.73-3.76 (m, 1H), 3.80-3.83 (m, 1H), 4.41 (br, 1H), 7.02 (s, MS (ESI, m / z): 369.2 [M+H] +

[0186] Example 14 (R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)-3-methylbutan-1-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that (R)-2-amino-3-methylbutan-1-ol was used (Scheme 1, General Procedure A). 1H NMR (600 MHz, CD3OD) δ [ppm] = 1.06 (d, 3H), 1.09 (d, 3H), 2.10 (br, 1H), 3.73-3.76 (m, 1H), 3.80-3.83 (m, 1H), 4.41 (br, 1H), 7.02 (s, MS (ESI, m / z): 369.2 [M+H] +

[0187] Example 15. 2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)butan-1-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that 2-aminobutan-1-ol was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.05 (t, 3H), 1.59-1.64 (m, 1H), 1.83-1.86 (m, 1H), 3.70 (d, 2H), 4.39 (br, 1H), 6.96 (s, 1H), 7.50 (d, MS (ESI, m / z): 355.1 [M+H] +

[0188] Example 16. 2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propane-1,3-diol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that 2-aminopropane-1,3-diol was used (Scheme 1, General Procedure A). 1H NMR (600 MHz, CD3OD) δ [ppm] = 3.81 (d, 4H), 4.54 (br, 1H), 7.02 (s, 1H), 7.51 (d, 2H), 8.06 (br, 1H), 8.13 (d, 2H), 8.87 (br, 1H), 9.43 (d, 1H), 9.70 (br, 1H); MS (ESI, m / z): 357.1 [M+H] +

[0189] Example 17 (R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)-1-phenylethan-1-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that (R)-2-amino-1-phenylethan-1-ol was used (Scheme 1, General Procedure A). 1 H NMR (600 MHz, CD3OD) δ [ppm] = 3.77 (br, 1H), 3.91 (br, 1H), 4.95 (br, 1H), 6.95 (s, 1H), 7.25 (t, 1H), 7.35 (t, 2H), 7.47 (d, 2H), 7.53 (d, 2H), 8.00 (br, 1H), 8.13 (d, 2H), 8.86 (br, 1H), 9.28 (d, 1H), 9.68 (br, 1H); MS (ESI, m / z): 403.1 [M+H] +

[0190] Example 18 (S)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)-1-phenylethan-1-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that (S)-2-amino-1-phenylethan-1-ol was used (Scheme 1, General Procedure A). 1H NMR (600 MHz, CD3OD) δ [ppm] = 3.77 (br, 1H), 3.91 (br, 1H), 4.95 (br, 1H), 6.95 (s, 1H), 7.25 (t, 1H), 7.35 (t, 2H), 7.47 (d, 2H), 7.53 (d, 2H), 8.00 (br, 1H), 8.13 (d, 2H), 8.86 (br, 1H), 9.28 (d, 1H), 9.68 (br, 1H); MS (ESI, m / z): 403.1 [M+H] +

[0191] Example 19. 6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrimidin-4-amine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that (tetrahydro-2H-pyran-4-yl)methanamine was used (Scheme 1, General Procedure A). 1 H NMR (600 MHz, CD3OD) δ [ppm] = 1.38-1.45 (m, 2H), 1.77 (d, 2H), 1.95-2.02 (m, 1H), 3.44 (t, 2H), 3.54 (br, 2H), 3.98 (d, 2H), 6.95 (s, MS (ESI, m / z): 381.1 [M+H] +

[0192] Example 20.N 1 -(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-N 3 ,N 3 -Dimethylpropane-1,3-diamine N 1 ,N 1 The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that -dimethylpropane-1,3-diamine was used (Scheme 1, General Procedure A). 1H NMR (600 MHz, CD3OD) δ [ppm] = 2.14-2.21 (m, 2H), 2.93 (s, 6H), 3.04-3.06 (m, 1H), 3.23-3.26 (m, 1H), 3.74 (br, 2H), 7.02 (s, 1H), 7.56 (d, 2H), 8.08 (br, 1H), 8.19 (d, 2H), 8.90 (br, 1H), 9.44 (d, 1H), 9.77 (br, 1H); MS (ESI, m / z): 368.2 [M+H] +

[0193] Example 21. 6-(4-chlorophenyl)-N-ethyl-2-(pyridin-3-yl)pyrimidin-4-amine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that ethanamine was used (Scheme 1, General Procedure A). 1 H NMR: (400 MHz, CD3OD) δ [ppm] = 1.32 (t, 3H), 3.60 (br, 2H), 6.91 (s, 1H), 7.53 (d, 2H), 7.97 (br, 1H), 8.14 (d, 2H), 8.85 (br, 1H), 9.27 (d, 1H), 9.71 (br, 1H); MS (ESI, m / z): 311.1 [M+H] +

[0194] Example 22. 6-(4-chlorophenyl)-N-propyl-2-(pyridin-3-yl)pyrimidin-4-amine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that propan-1-amine was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.05 (t, 3H), 1.74 (q, 2H), 3.56 (br, 2H), 6.93 (s, 1H), 7.53 (d, 2H), 8.01 (br, 1H), 8.13 (d, 2H), 8.84 (br, 1H), 9.32 (d, 1H), 9.69 (br, 1H); MS (ESI, m / z): 325.1 [M+H] +

[0195] Example 23. N-butyl-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-amine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that butan-1-amine was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.01 (t, 3H), 1.45-1.54 (m, 2H), 1.66-1.73 (m, 2H), 3.58 (br, 2H), 6.89 (s, 1H), 7.52 (d, 2H), 7.90 (br, 1H), 8.12 (d, 2H), 8.84 (br, 1H), 9.18 (d, 1H), 9.69 (br, 1H); MS (ESI, m / z): 339.1 [M+H] +

[0196] Example 24. 1-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)butan-2-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that 1-aminobutan-2-ol was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.01 (t, 3H), 1.45-1.54 (m, 2H), 1.66-1.73 (m, 2H), 3.58 (br, 2H), 6.89 (s, 1H), 7.52 (d, 2H), 7.90 (br, 1H), 8.12 (d, 2H), 8.84 (br, 1H), 9.18 (d, 1H), 9.69 (br, 1H); MS (ESI, m / z): 355.1 [M+H] +

[0197] Example 25. 6-(4-chlorophenyl)-N-(cyclopropylmethyl)-2-(pyridin-3-yl)pyrimidin-4-amine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that cyclopropylmethanamine was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 0.32-0.36 (m, 2H), 0.57-0.61 (m, 2H), 1.14-1.26 (m, 1H), 3.46 (br, 2H), 6.93 (s, 1H), 7.53 (d, 2H), 8.05 (br, 1H), 8.13 (d, 2H), 8.97 (br, 1H), 9.29 (d, 1H), 9.82 (br, 1H); MS (ESI, m / z): 337.1 [M+H] +

[0198] Example 26. 6-(4-chlorophenyl)-N-cyclopentyl-2-(pyridin-3-yl)pyrimidin-4-amine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that cyclopentanamine was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.59-1.69 (m, 2H), 1.70-1.77 (m, 2H), 1.79-1.89 (m, 2H), 2.12-2.20 (m, 2H), 4.59 (br, 1H), 6.93 (s, MS (ESI, m / z): 351.1 [M+H] +

[0199] Example 27. 4-(4-chlorophenyl)-6-(4-methylpiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 4-methylpiperidine was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 1.02 (d, 3H), 1.18-1.31 (m, 2H), 1.74-1.92 (m, 3H), 3.09 (t, 2H), 3.33-3.38 (m, 2H), 7.23 (s, 1H), 7.53 (d, 2H), 8.09 (br, 1H), 8.20 (d, 2H), 8.94 (br, 1H), 9.38 (d, 1H), 9.76 (br, 1H); MS (ESI, m / z): 365.2 [M+H] +

[0200] Example 28. N-(tert-butyl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-amine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that 2-methylpropan-2-amine was used (Scheme 1, General Procedure A). 1 H NMR (600 MHz, CD3OD) δ [ppm] = 4.64 (s, 9H), 7.63 (d, 2H), 7.66 (br, 1H), 8.10 (s, 1H), 8.36 (d, 2H), 8.75 (br, 1H), 8.94 (d, 1H), 9.67 (br, 1H); MS (ESI, m / z): 339.1 [M+H] +

[0201] Example 29 (1R,2R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that (1R,2R)-2-aminocyclopentan-1-ol was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 1.61-1.75 (m, 2H), 1.79-1.96 (m, 2H), 1.98-2.07 (m, 1H), 2.27-2.35 (m, 1H), 4.16 (br, 1H), 4.44 (br, MS (ESI, m / z): 367.1 [M+H] +

[0202] Example 30 (1S,2R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that (1S,2R)-2-aminocyclopentan-1-ol was used (Scheme 1, General Procedure A). 1 H NMR (600 MHz, CD3OD) δ [ppm] = 1.67-1.82 (m, 3H), 1.91-1.97 (m, 1H), 2.00-2.07 (m, 1H), 2.13 (br, 1H), 4.37 (br, 1H), 4.49 (br, 1H), 7.04 (s, 1H), 7.53 (d, 2H), 7.70 (br, 3H), 8.86 (br, 1H), 9.35 (d, 1H), 9.67 (br, 1H); MS (ESI, m / z): 367.1 [M+H] +

[0203] Example 31. 6-(4-chlorophenyl)-N-(pyridin-2-ylmethyl)-2-(pyridin-3-yl)pyrimidin-4-amine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that pyridin-2-ylmethanamine was used (Scheme 1, General Procedure A). 1H NMR (600 MHz, CD3OD) δ [ppm] = 5.16 (s, 2H), 7.24 (s, 1H), 7.54 (d, 2H), 7.88 (t, 1H), 8.07-8.11 (m, 2H), 8.20 (d, 2H), 8.49 (t, 1H), 8.76 (d, 1H), 8.88 (d, 1H), 9.32 (d, 1H), 9.57 (s, 1H); MS (ESI, m / z): 374.1 [M+H] +

[0204] Example 32. 6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(pyridin-3-ylmethyl)pyrimidin-4-amine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that pyridin-3-ylmethanamine was used (Scheme 1, General Procedure A). 1 H NMR (600 MHz, CD3OD) δ [ppm] = 5.04 (s, 2H), 7.15 (s, 1H), 7.53 (d, 2H), 8.06 (br, 1H), 8.14 (br, 1H), 8.19 (d, 2H), 8.67 (d, 1H), 8.79 (br, 1H), 8.97 (br, 2H), 9.43 (d, 1H), 9.71 (s, 1H); MS (ESI, m / z): 374.1 [M+H] +

[0205] Example 33. 6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(pyridin-4-ylmethyl)pyrimidin-4-amine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that pyridin-4-ylmethanamine was used (Scheme 1, General Procedure A). 1 H NMR (600 MHz, CD3OD) δ [ppm] = 5.12 (s, 2H), 7.23 (s, 1H), 7.55 (d, 2H), 8.09 (br, 1H), 8.13 (d, 2H), 8.21 (d, 2H), 8.79 (d, 2H), 8.88 (br, 1H), 9.34 (d, 1H), 9.59 (s, 1H); MS (ESI, m / z): 374.1 [M+H]+

[0206] Example 34. trans-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexan-1-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that trans-4-aminocyclohexan-1-ol was used (Scheme 1, General Procedure A). 1 H NMR (600 MHz, CD3OD) δ [ppm] = 1.39-1.46 (m, 2H), 1.48-1.54 (m, 2H), 2.02-2.07 (m, 2H), 2.14-2.19 (m, 2H), 3.62-3.67 (m, 1H), 4.14 (br, 1H), 6.90 (s, 1H), 7.53 (d, 2H), 7.99 (br, 1H), 8.13 (d, 2H), 8.83 (br, 1H), 9.28 (d, 1H), 9.66 (br, 1H); MS (ESI, m / z): 381.1 [M+H] +

[0207] Example 35. trans-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexan-1-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that trans-2-aminocyclohexan-1-ol was used (Scheme 1, General Procedure A). 1 H NMR (600 MHz, CD3OD) δ [ppm] = 1.34-1.52 (m, 4H), 1.77-1.84 (m, 2H), 2.08-2.16 (m, 2H), 3.55 (br, 1H), 4.19 (br, 1H), 6.95 (s, 1H), 7.53 (d, 2H), 8.08 (br, 1H), 8.12 (d, 2H), 8.89 (br, 1H), 9.37 (d, 1H), 9.67 (br, 1H); MS (ESI, m / z): 381.1 [M+H] +

[0208] Example 36 (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-2-yl)methanol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that piperidin-2-ylmethanol was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.54-1.66 (m, 1H), 1.67-1.81 (m, 3H), 1.84-1.92 (m, 1H), 1.98-2.05 (m, 1H), 3.11-3.21 (m, 1H), 3.79-3.91 (m, 2H), 4.21-4.40 (m, 1H), 4.70 (br, 1H), 7.26 (s, 1H), 7.53 (d, 2H), 8.12 (br, 1H), 8.19 (d, 2H), 8.92 (br, 1H), 9.45 (d, 1H), 9.73 (br, 1H); MS (ESI, m / z): 381.1 [M+H] +

[0209] Example 37. 2-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-2-yl)ethan-1-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 2-(piperidin-2-yl)ethan-1-ol was used (Scheme 1. General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.29-1.35 (m, 2H), 1.53-1.65 (m, 1H), 1.70-1.76 (m, 1H), 1.78-1.90 (m, 4H), 1.90-1.97 (m, 1H), 2.07-2.16 (m, 1H), 3.10-3.20 (m, 1H), 3.57-3.69 (m, 2H), 7.31 (s, 1H), 7.54 (d, 2H), 8.03 (br, 1H), 8.20 (d, 2H), 8.87 (br, 1H), 9.37 (d, 1H), 9.71 (br, 1H); MS (ESI, m / z): 395.2 [M+H] +

[0210] Example 38 (R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that (R)-piperidin-3-ol was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.56-1.73 (m, 2H), 1.90-1.99 (m, 1H), 2.02-2.09 (m, 1H), 4.47 (dd, 1H), 3.63 (br, 1H), 3.77-3.82 (m, 1H), 4.04 (br, 1H), 4.29 (br, 1H), 7.21 (s, 1H), 7.50 (d, 2H), 8.13 (br, 1H), 8.17 (d, 2H), 8.95 (br, 1H), 9.43 (d, 1H), 9.73 (br, 1H); MS (ESI, m / z): 367.1 [M+H] +

[0211] Example 39. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that piperidin-3-ol was used (Scheme 1. General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.56-1.73 (m, 2H), 1.90-1.99 (m, 1H), 2.02-2.09 (m, 1H), 4.47 (dd, 1H), 3.63 (br, 1H), 3.77-3.82 (m, 1H), 4.04 (br, 1H), 4.29 (br, 1H), 7.21 (s, 1H), 7.50 (d, 2H), 8.13 (br, 1H), 8.17 (d, 2H), 8.95 (br, 1H), 9.43 (d, 1H), 9.73 (br, 1H); MS (ESI, m / z): 367.1 [M+H] +

[0212] Example 40 (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that piperidin-3-ylmethanol was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.35-1.46 (m, 1H), 1.56-1.68 (m, 1H), 1.78-1.95 (m, 4H), 3.02 (dd, 1H), 3.23 (dd, 1H), 3.63 (br, 1H), 3.38-3.46 (m, 1H), 3.47-3.61 (m, 2H), 7.24 (s, 1H), 7.52 (d, 2H), 8.10 (dd, 1H), 8.19 (d, 2H), 8.89 (br, 1H), 9.45 (d, 1H), 9.71 (br, 1H); MS (ESI, m / z): 381.1 [M+H] +

[0213] Example 41. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that piperidin-4-ol was used (Scheme 1. General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.54-1.62 (m, 2H), 1.96-2.03 (m, 2H), 3.46-3.53 (m, 2H), 3.93-3.99 (m, 2H), 4.36 (br, 2H), 7.23 (s, MS (ESI, m / z): 367.1 [M+H] +

[0214] Example 42 (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that piperidin-4-ylmethanol was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 1.24-1.34 (m, 2H), 1.82-1.94 (m, 3H), 3.08 (t, 2H), 3.47 (d, 2H), 4.77 (br, 2H), 7.21 (s, 1H), 7.50 (d, MS (ESI, m / z): 381.1 [M+H] +

[0215] Example 43. 2-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)ethan-1-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 2-(piperidin-4-yl)ethan-1-ol was used (Scheme 1. General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.22-1.32 (m, 2H), 1.51-1.56 (m, 2H), 1.81-1.93 (m, 3H), 3.07 (t, 2H), 3.67 (t, 2H), 4.72 (br, 2H), 7.20 (s, 1H), 7.51 (d, 2H), 8.10 (br, 1H), 8.17 (d, 2H), 8.89 (br, 1H), 9.41 (d, 1H), 9.68 (br, 1H); MS (ESI, m / z): 395.2 [M+H] +

[0216] Example 44. 3-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)propan-1-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 3-(piperidin-4-yl)propan-1-ol was used (Scheme 1. General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 1.18-1.29 (m, 2H), 1.34-1.39 (m, 2H), 1.58-1.73 (m, 3H), 1.93 (d, 2H), 3.07 (t, 2H), 3.57 (t, 2H), 4.75 (br, 2H), 7.22 (s, 1H), 7.52 (d, 2H), 8.11 (br, 1H), 8.18 (d, 2H), 8.90 (br, 1H), 9.42 (d, 1H), 9.70 (br, 1H); MS (ESI, m / z): 409.2 [M+H] +

[0217] Example 45. 4-(4-chlorophenyl)-6-(4-methoxypiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that 4-methoxypiperidine was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.60-1.68 (m, 2H), 1.98-2.05 (m, 2H), 3.42 (s, 3H), 3.57-3.65 (m, 3H), 4.21 (br, 2H), 7.22 (s, 1H), 7.50 (d, 2H), 8.09 (br, 1H), 8.18 (d, 2H), 8.89 (br, 1H), 9.41 (d, 1H), 9.69 (br, 1H); MS (ESI, m / z): 381.1 [M+H] +

[0218] Example 46. 4-(4-chlorophenyl)-6-(piperidin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that piperidine was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 1.71 (br, 4H), 1.78 (br, 2H), 3.90 (br, 4H), 7.21 (s, 1H), 7.53 (d, 2H), 8.03 (br, 1H), 8.19 (d, 2H), 8.88 (br, 1H), 9.33 (d, 1H), 9.69 (br, 1H); MS (ESI, m / z): 351.1 [M+H] +

[0219] Example 47. 4-(4-chlorophenyl)-6-(2-methylpiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 2-methylpiperidine was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.33 (d, 3H), 1.53-1.63 (m, 1H), 1.70-1.91 (m, 5H), 3.14-3.21 (m, 1H), 4.60 (br, 1H), 5.06 (br, 1H), 7.20 (s, 1H), 7.53 (d, 2H), 8.13 (br, 1H), 8.19 (d, 2H), 8.96 (br, 1H), 9.39 (d, 1H), 9.75 (br, 1H); MS (ESI, m / z): 365.2 [M+H] +

[0220] Example 48. 4-(4-chlorophenyl)-6-(3-methylpiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that 3-methylpiperidine was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 1.04 (d, 3H), 1.28-1.35 (m, 1H), 1.56-1.76 (m, 2H), 1.83-1.96 (m, 2H), 2.81 (dd, 1H), 3.12 (dd, 1H), MS (ESI, m / z): 365.2 [M+H] +

[0221] Example 49. 4-(4-chlorophenyl)-6-(2,6-dimethylpiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that 2,6-dimethylpiperidine was used (Scheme 1, General Procedure A). MS (ESI, m / z): 379.2 [M+H] +

[0222] Example 50. 4-(4-chlorophenyl)-6-(3,5-dimethylpiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that 3,5-dimethylpiperidine was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 0.94 (q, 1H), 1.03 (d, 6H), 1.59-1.73 (m, 3H), 1.91 (d, 1H), 2.51 (t, 2H), 4.68 (br, 1H), 7.21 (s, 1H), 7.51 (d, 2H), 8.11 (br, 1H), 8.18 (d, 2H), 8.94 (br, 1H), 9.39 (d, 1H), 9.73 (br, 1H); MS (ESI, m / z): 379.2 [M+H] +

[0223] Example 51. 4-(4-chlorophenyl)-6-(3,3-difluoropiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that 3,3-difluoropiperidine was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.87-1.93 (m, 2H), 2.14-2.24 (m, 2H), 3.92 (br, 2H), 4.23 (t, 2H), 7.32 (s, 1H), 7.51 (d, 2H), 8.06 (br, 1H), 8.23 ​​(d, 2H), 8.87 (br, 1H), 9.40 (d, 1H), 9.72 (br, 1H); MS (ESI, m / z): 387.1 [M+H] +

[0224] Example 52. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(3-(trifluoromethyl)piperidin-1-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 3-(trifluoromethyl)piperidine was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.59-1.82 (m, 2H), 1.94-1.97 (m, 1H), 2.12-2.15 (m, 1H), 2.44-2.56 (m, 1H), 3.19-3.27 (m, 2H), 4.48 MS (ESI, m / z): 419.1 [M+H] +

[0225] Example 53. 4-(4-chlorophenyl)-6-(3-ethylpiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 3-(trifluoromethyl)piperidine was used (Scheme 1, General Procedure A). MS (ESI, m / z): 379.2 [M+H] +

[0226] Example 54. 6-(4-chlorophenyl)-N-(piperidin-4-yl)-2-(pyridin-3-yl)pyrimidin-4-amine To a solution of 4-chloro-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidine (15 mg, 0.05 mmol) in tetrahydrofuran (2 mL) was added triethylamine (0.06 mL, 0.43 mmol) at room temperature, followed by tert-butyl 4-aminopiperidine-1-carboxylate (20 mg, 0.10 mmol). The reaction mixture was heated in a sealed tube at 120° C. for 4 hours and then cooled to room temperature. The residue was filtered and concentrated under reduced pressure. To a solution of the reaction mixture in ethanol (1 mL) was added 1 M hydrochloric acid in ethanol (2 mL). The reaction mixture was stirred overnight at 50° C., concentrated under reduced pressure, and quenched with 1 M ammonium acetate in methanol (2 mL). The residue was filtered and purified by preparative HPLC to give 7.6 mg of the title compound (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.81-1.92 (m, 2H), 2.37 (d, 2H), 3.26 (d, 2H), 3.52 (d, 2H), 4.47 (br, 1H), 7.00 (s, 1H), 7.54 (d, 2H), 8.07 (br, 1H), 8.16 (d, 2H), 8.88 (br, 1H), 9.43 (d, 1H), 9.76 (br, 1H); MS (ESI, m / z): 366.1 [M+H] +

[0227] Example 55. 6-(4-chlorophenyl)-N-(piperidin-3-ylmethyl)-2-(pyridin-3-yl)pyrimidin-4-amine The title compound was obtained in the same manner as in Example 54, except for using tert-butyl 3-(aminomethyl)piperidine-1-carboxylate (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 1.39-1.48 (m, 1H), 1.70-1.82 (m, 1H), 2.02 (t, 2H), 2.26 (br, 1H), 2.83 (t, 1H), 2.94 (t, 1H), 3.37 (d, 1H), 3.50 (d, 1H), 3.62 (br, 2H), 6.99 (s, 1H), 7.53 (d, 2H), 8.06 (br, 1H), 8.16 (d, 2H), 8.88 (br, 1H), 9.41 (d, 1H), 9.75 (br, 1H); MS (ESI, m / z): 380.2 [M+H] +

[0228] Example 56. 6-(4-chlorophenyl)-N-(piperidin-4-ylmethyl)-2-(pyridin-3-yl)pyrimidin-4-amine The title compound was obtained in the same manner as in Example 54, except for using tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.29-1.40 (m, 1H), 1.45-1.55 (m, 1H), 2.01 (t, 4H), 2.91 (d, 2H), 2.98-3.14 (m, 2H), 3.45 (d, 1H), 7.26 (s, 1H), 7.52 (d, 2H), 8.10 (br, 1H), 8.21 (d, 2H), 8.89 (br, 1H), 9.42 (d, 1H), 9.72 (br, 1H); MS (ESI, m / z): 380.2 [M+H] +

[0229] Example 57. 6-(4-chlorophenyl)-N-(1-methylpiperidin-4-yl)-2-(pyridin-3-yl)pyrimidin-4-amine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that 1-methylpiperidin-4-amine was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 1.83-2.04 (m, 2H), 2.18-2.29 (m, 2H), 2.89 (s, 3H), 3.10-3.24 (m, 2H), 3.42-3.54 (m, 2H), 3.63 (br, MS (ESI, m / z): 380.2 [M+H] +

[0230] Example 58. 6-(4-chlorophenyl)-N-(2-(piperidin-4-yl)ethyl)-2-(pyridin-3-yl)pyrimidin-4-amine The title compound was obtained in the same manner as in Example 54, except for using tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.42-1.52 (m, 2H), 1.70-1.86 (m, 3H), 2.07 (d, 2H), 2.98 (t, 2H), 3.40 (d, 2H), 3.68 (br, 2H), 6.94 (s, MS (ESI, m / z): 394.2 [M+H] +

[0231] Example 59 (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-2-yl)methanamine The title compound was obtained in the same manner as in Example 54 except for using tert-butyl (piperidin-2-ylmethyl)carbamate (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 1.63 (br, 2H), 1.76-1.91 (m, 5H), 3.24-3.33 (m, 2H), 3.61 (t, 2H), 4.47 (br, 1H), 5.50 (br, 1H), 7.37 (s, MS (ESI, m / z): 380.2 [M+H] +

[0232] Example 60 (R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-amine The title compound was obtained in the same manner as in Example 54 except for using tert-butyl (R)-piperidin-3-ylcarbamate (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.72-1.88 (m, 2H), 1.93-1.99 (m, 1H), 2.19-2.26 (m, 1H), 3.40-3.46 (m, 1H), 3.51-3.57 (m, 1H), 3.62-3.67 (m, 1H), 4.18 (d, 1H), 4.71 (d, 1H), 7.33 (s, 1H), 7.51 (d, 2H), 8.05 (br, 1H), 8.25 (d, 2H), 8.89 (br, 1H), 9.42 (d, 1H), 9.80 (br, 1H); MS (ESI, m / z): 366.1 [M+H] +

[0233] Example 61 (S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-amine The title compound was obtained in the same manner as in Example 54 except for using tert-butyl (S)-piperidin-3-ylcarbamate (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 1.72-1.88 (m, 2H), 1.93-1.99 (m, 1H), 2.19-2.26 (m, 1H), 3.40-3.46 (m, 1H), 3.51-3.57 (m, 1H), 3.62-3.67 (m, 1H), 4.18 (d, 1H), 4.71 (d, 1H), 7.33 (s, 1H), 7.51 (d, 2H), 8.05 (br, 1H), 8.25 (d, 2H), 8.89 (br, 1H), 9.42 (d, 1H), 9.80 (br, 1H); MS (ESI, m / z): 366.1 [M+H] +

[0234] Example 62 (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanamine The title compound was obtained in the same manner as in Example 54 except for using tert-butyl (piperidin-3-ylmethyl)carbamate (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.44-1.53 ​​(m, 1H), 1.61-1.71 (m, 1H), 1.91-2.07 (m, 3H), 2.92-3.09 (m, 3H), 3.15-3.24 (m, 1H), 4.57 MS (ESI, m / z): 380.2 [M+H] +

[0235] Example 63 (S)-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanamine The title compound was obtained in the same manner as in Example 54 except for using tert-butyl (R)-(piperidin-3-ylmethyl)carbamate (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 1.44-1.53 ​​(m, 1H), 1.61-1.71 (m, 1H), 1.91-2.07 (m, 3H), 2.92-3.09 (m, 3H), 3.15-3.24 (m, 1H), 4.57 MS (ESI, m / z): 380.2 [M+H] +

[0236] Example 64. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-amine The title compound was obtained in the same manner as in Example 54 except for using tert-butyl piperidin-4-ylcarbamate (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.60-1.71 (m, 2H), 2.18 (d, 2H), 3.18 (t, 2H), 3.47-3.56 (m, 1H), 4.83-4.94 (m, 2H), 7.33 (s, 1H), 7.54 (d, 2H), 7.98 (br, 1H), 8.25 (d, 2H), 8.84 (br, 1H), 9.32 (d, 1H), 9.73 (br, 1H); MS (ESI, m / z): 366.1 [M+H] +

[0237] Example 65 (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanamine The title compound was obtained in the same manner as in Example 54 except for using tert-butyl (piperidin-4-ylmethyl)carbamate (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 1.31-1.42 (m, 2H), 1.98 (d, 2H), 2.01-2.10 (m, 1H), 2.91 (d, 2H), 3.13 (t, 2H), 4.81-4.95 (m, 2H), 7.29 (s, 1H), 7.54 (d, 2H), 8.00 (br, 1H), 8.23 ​​(d, 2H), 8.85 (br, 1H), 9.34 (d, 1H), 9.71 (br, 1H); MS (ESI, m / z): 380.2 [M+H] +

[0238] Example 66 (1R,2S)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that (1R,2S)-2-aminocyclopentan-1-ol was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.59-1.74 (m, 2H), 1.79-1.94 (m, 2H), 1.98-2.07 (m, 1H), 2.27-2.35 (m, 1H), 4.16 (br, 1H), 4.43 (br, MS (ESI, m / z): 367.1 [M+H] +

[0239] Example 67 (1S,2S)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that (1S,2S)-2-aminocyclopentan-1-ol was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 1.59-1.74 (m, 2H), 1.79-1.94 (m, 2H), 1.98-2.07 (m, 1H), 2.27-2.35 (m, 1H), 4.16 (br, 1H), 4.43 (br, MS (ESI, m / z): 367.1 [M+H] +

[0240] Example 68. trans-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that trans-2-aminocyclopentan-1-ol was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.59-1.74 (m, 2H), 1.79-1.94 (m, 2H), 1.98-2.07 (m, 1H), 2.27-2.35 (m, 1H), 4.16 (br, 1H), 4.43 (br, MS (ESI, m / z): 367.1 [M+H] +

[0241] Example 69 (1R,2R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexan-1-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that (1R,2R)-2-aminocyclohexan-1-ol was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 1.28-1.51 (m, 4H), 1.76-1.84 (m, 2H), 2.08-2.16 (m, 2H), 3.52-3.57 (m, 1H), 4.16 (br, 1H), 6.95 (s, MS (ESI, m / z): 381.1 [M+H] +

[0242] Example 70. cis-4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-2,6-dimethylmorpholine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that cis-2,6-dimethylmorpholine was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.29 (d, 6H), 2.69 (t, 2H), 3.67-3.74 (m, 2H), 4.56 (br, 2H), 7.23 (s, 1H), 7.51 (d, 2H), 8.05 (br, 1H), 8.22 (d, 2H), 8.88 (br, 1H), 9.38 (d, 1H), 9.72 (br, 1H); MS (ESI, m / z): 381.1 [M+H] +

[0243] Example 71. 4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)morpholine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that morpholine was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 3.81-3.88 (m, 8H), 7.22 (s, 1H), 7.51 (d, 2H), 8.12 (br, 1H), 8.21 (d, 2H), 8.88 (br, 1H), 9.41 (d, 1H), 9.83 (br, 1H); MS (ESI, m / z): 353.1 [M+H]+

[0244] Example 72. 6-(4-chlorophenyl)-N-(morpholin-2-ylmethyl)-2-(pyridin-3-yl)pyrimidin-4-amine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 54, except that tert-butyl 2-(aminomethyl)morpholine-4-carboxylate was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 3.88-4.18 (m, 9H), 7.07 (s, 1H), 7.60 (d, 2H), 8.15 (br, 1H), 8.33 (d, 2H), 8.89 (br, 1H), 9.41 (d, 1H), 9.73 (br, 1H); MS (ESI, m / z): 382.9 [M+H] +

[0245] Example 73. 4-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)morpholine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 4-(pyrrolidin-3-yl)morpholine was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 2.43 (br, 1H), 2.68 (br, 1H), 3.50 (br, 4H), 3.69 (br, 1H), 3.86-4.40 (m, 8H), 7.05 (s, 1H), 7.53 (d, 2H), 8.14 (br, 1H), 8.25 (d, 2H), 8.92 (br, 1H), 9.52 (d, 1H), 9.79 (br, 1H); MS (ESI, m / z): 422.2 [M+H] +

[0246] Example 74. 4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)thiomorpholine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that thiomorpholine was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 2.74-7.76 (m, 4H), 4.24 (br, 4H), 7.25 (s, 1H), 7.52 (d, 2H), 8.12 (br, 1H), 8.22 (d, 2H), 8.91 (br, 1H), 9.45 (d, 1H), 9.73 (br, 1H); MS (ESI, m / z): 422.2 [M+H] +

[0247] Example 75. 6-(4-chlorophenyl)-N-(3-morpholinopropyl)-2-(pyridin-3-yl)pyrimidin-4-amine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 3-morpholinopropan-1-amine was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 2.15-2.22 (m, 2H), 3.15 (br, 2H), 3.32-3.35 (m, 2H), 3.51 (br, 2H), 3.72 (br, 4H), 4.03 (br, 2H), 6.98 (s, MS (ESI, m / z): 410.2 [M+H] +

[0248] Example 76. (R)-4-(4-chlorophenyl)-6-(2-methylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 54, except that (R)-tert-butyl 3-methylpiperazine-1-carboxylate was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 2.15-2.22 (m, 2H), 3.15 (br, 2H), 3.32-3.35 (m, 2H), 3.51 (br, 2H), 3.72 (br, 4H), 4.03 (br, 2H), 6.98 (s, MS (ESI, m / z): 366.1 [M+H] +

[0249] Example 77. (R)-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-methylpiperazin-1-yl)(phenyl)methanone The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that (R)-(3-methylpiperazin-1-yl)(phenyl)methanone was used (Scheme 1, General Procedure A). MS (ESI, m / z): 470.2 [M+H] +

[0250] Example 78. (R)-4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazine-2-carboxylate methyl The title compound was obtained by separation by preparative HPLC in the same manner as in Example 54, except that 1-(tert-butyl)2-methyl (R)-piperazine-1,2-dicarboxylate was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.60 (br, 1H), 2.03 (br, 1H), 3.64 (s, 3H), 3.77 (br, 1H), 4.01 (br, 1H), 4.46 (br, 1H), 4.55 (br, 1H), 5.35 MS (ESI, m / z): 410.1 [M+H] +

[0251] Example 79. (R)-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-2-yl)methanol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 54, except that (R)-tert-butyl 2-(hydroxymethyl)piperazine-1-carboxylate was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 3.27-3.35 (m, 2H), 3.42-3.58 (m, 4H), 3.80-3.85 (m, 2H), 3.94-3.98 (m, 2H), 4.82-4.85 (m, 1H), 7.44 (s, 1H), 7.56 (d, 2H), 8.03 (br, 1H), 8.30 (d, 2H), 8.87 (br, 1H), 9.40 (d, 1H), 9.77 (br, 1H); MS (ESI, m / z): 410.1 [M+H] +

[0252] Example 80. 4-(4-chlorophenyl)-6-(4-(2,3-dichlorophenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 1-(2,3-dichlorophenyl)piperazine was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 3.21 (br, 4H), 4.10 (br, 4H), 7.13-7.17 (m, 1H), 7.28 (d, 2H), 7.34 (s, 1H), 7.55 (d, 2H), 8.12 (br, 1H), 8.26 (d, 2H), 8.91 (br, 1H), 9.50 (d, 1H), 9.77 (br, 1H); MS (ESI, m / z): 496.1 [M+H] +

[0253] Example 81. 4-(4-chlorophenyl)-6-(4-(2,5-dimethoxybenzyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 1-(2,5-dimethoxybenzyl)piperazine was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 3.54 (br, 8H), 3.80 (s, 3H), 3.90 (s, 3H), 4.43 (s, 2H), 7.09 (s, 3H), 7.42 (s, 1H), 7.55 (d, 2H), 8.14 (br, 1H), 8.28 (d, 2H), 8.92 (br, 1H), 9.54 (d, 1H), 9.81 (br, 1H); MS (ESI, m / z): 502.2 [M+H] +

[0254] Example 82. 2-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)ethan-1-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 2-(piperazin-1-yl)ethan-1-ol was used (Scheme 1. General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 3.38 (t, 2H), 3.52 (br, 8H), 3.96 (t, 2H), 7.42 (s, 1H), 7.55 (d, 2H), 8.00 (br, 1H), 8.28 (d, 2H), 8.86 (br, 1H), 9.37 (d, 1H), 9.76 (br, 1H); MS (ESI, m / z): 396.2 [M+H] +

[0255] Example 83. 4-(4-chlorophenyl)-6-(4-(2-methoxyphenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 1-(2-methoxyphenyl)piperazine was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 3.50 (br, 4H), 3.98 (s, 3H), 4.22 (br, 4H), 7.04 (dd, 1H), 7.15 (d, 1H), 7.26-7.32 (m, 2H), 7.37 (s, 1H), 7.53 (d, 2H), 8.12 (br, 1H), 8.26 (d, 2H), 8.91 (br, 1H), 9.50 (d, 1H), 9.77 (br, 1H); MS (ESI, m / z): 458.2 [M+H] +

[0256] Example 84. 4-(4-chlorophenyl)-6-(4-(2-ethoxyphenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that 1-(2-ethoxyphenyl)piperazine was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.48 (t, 3H), 3.47 (br, 4H), 4.17-4.22 (m, 6H), 7.01 (dd, 1H), 7.10 (d, 1H), 7.19-7.25 (m, 2H), 7.38 (s, MS (ESI, m / z): 472.2 [M+H] +

[0257] Example 85. 4-(4-chlorophenyl)-6-(4-(2-fluorophenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that 1-(2-fluorophenyl)piperazine was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 3.22 (br, 4H), 4.07 (br, 4H), 6.99-7.13 (m, 4H), 7.31 (s, 1H), 7.52 (d, 2H), 8.12 (br, 1H), 8.23 ​​(d, 2H), 8.90 (br, 1H), 9.46 (d, 1H), 9.75 (br, 1H); MS (ESI, m / z): 446.2 [M+H] +

[0258] Example 86 (4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)(furan-2-yl)methanone The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that furan-2-yl(piperazin-1-yl)methanone was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 4.02 (br, 8H), 6.64 (dd, 1H), 7.14 (d, 1H), 7.29 (s, 1H), 7.53 (d, 2H), 7.74 (d, 1H), 8.06 (dd, 1H), 8.25 (d, 2H), 8.87 (br, 1H), 9.43 (d, 1H), 9.74 (br, 1H); MS (ESI, m / z): 446.1 [M+H] +

[0259] Example 87. 4-(4-chlorophenyl)-6-(4-phenethylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that 1-phenethylpiperazine was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 3.14-3.18 (m, 2H), 3.45-3.50 (m, 2H), 3.61 (br, 8H), 7.26-7.38 (m, 5H), 7.44 (s, 1H), 7.54 (d, 2H), 8.16 (br, 1H), 8.28 (d, 2H), 8.94 (br, 1H), 9.54 (d, 1H), 9.81 (br, 1H); MS (ESI, m / z): 456.2 [M+H] +

[0260] Example 88. 6-(4-chlorophenyl)-N-(2-(piperazin-1-yl)ethyl)-2-(pyridin-3-yl)pyrimidin-4-amine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 54, except that tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 2.70 (t, 2H), 2.75 (br, 4H), 3.08 (t, 2H), 4.18 (br, 4H), 7.37 (s, 1H), 7.52 (d, 2H), 8.11 (br, 1H), 8.25 (d, 2H), 8.91 (br, 1H), 9.48 (d, 1H), 9.78 (br, 1H); MS (ESI, m / z): 395.2 [M+H] +

[0261] Example 89. 4-(4-chlorophenyl)-6-(4-(pyridin-2-yl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 1-(pyridin-2-yl)piperazine was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 3.98 (br, 4H), 4.20 (br, 4H), 7.06 (t, 1H), 7.30 (s, 1H), 7.44 (d, 1H), 7.54 (d, 2H), 8.04 (d, 1H), 8.08-8.16 (m, 2H), 8.27 (d, 2H), 8.93 (br, 1H), 9.53 (d, 1H), 9.80 (br, 1H); MS (ESI, m / z): 429.2 [M+H] +

[0262] Example 90. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 1-(pyridin-2-yl)piperazine was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 4.04 (br, 8H), 6.72 (t, 1H), 7.36 (s, 1H), 7.55 (d, 2H), 8.04 (d, 1H), 8.19 (br, 1H), 8.28 (d, 2H), 8.43 (d, 2H), 8.93 (br, 1H), 9.59 (d, 1H), 9.81 (br, 1H); MS (ESI, m / z): 429.2 [M+H] +

[0263] Example 91. 4-(2-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)ethyl)morpholine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 4-(2-(piperazin-1-yl)ethyl)morpholine was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 3.27 (br, 4H), 3.35 (br, 4H), 3.41 (t, 2H), 3.55 (t, 2H), 3.95 (br, 4H), 4.18 (br, 4H), 7.39 (s, 1H), 7.54 (d, 2H), 8.16 (br, 1H), 8.26 (d, 2H), 8.93 (br, 1H), 9.54 (d, 1H), 9.79 (br, 1H); MS (ESI, m / z): 429.2 [M+H] +

[0264] Example 92. 4-(4-chlorophenyl)-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 1-methyl-4-(piperidin-4-yl)piperazine was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.69-1.79 (m, 2H), 2.53 (d, 2H), 2.93 (s, 3H), 3.14 (t, 2H), 3.44 (br, 4H), 3.52 (br, 4H), 3.63 (br, 2H), 4.29 (br, 1H), 7.34 (s, 1H), 7.54 (d, 2H), 8.14 (br, 1H), 8.24 (d, 2H), 8.92 (br, 1H), 9.51 (d, 1H), 9.76 (br, 1H); MS (ESI, m / z): 449.2 [M+H] +

[0265] Example 93. trans-4-(4-chlorophenyl)-6-(4-cinnamylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that trans-1-cinnamylpiperazine was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 3.58 (br, 8H), 4.04 (d, 2H), 6.35-6.43 (m, 1H), 6.96 (d, 1H), 7.32-7.40 (m, 3H), 7.44 (s, 1H), 7.50-7.55 (m, 4H), 8.16 (br, 1H), 8.28 (d, 2H), 8.93 (br, 1H), 9.56 (d, 1H), 9.82 (br, 1H); MS (ESI, m / z): 468.2 [M+H] +

[0266] Example 94. 4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-2-one The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that piperazin-2-one was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 3.53 (t, 2H), 4.10 (br, 2H), 4.46 (s, 2H), 7.29 (s, 1H), 7.54 (d, 2H), 8.11 (br, 1H), 8.28 (d, 2H), 8.89 (br, 1H), 9.49 (d, 1H), 9.77 (br, 1H); MS (ESI, m / z): 366.1 [M+H] +

[0267] Example 95. 4-(4-chlorophenyl)-6-(4-phenylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that 1-phenylpiperazine was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 3.43 (t, 4H), 4.13 (br, 4H), 7.02 (t, 1H), 7.14 (d, 2H), 7.34 (t, 3H), 7.53 (d, 2H), 8.14-8.17 (m, 1H), 8.25 (d, 2H), 8.92 (br, 1H), 9.54 (d, 1H), 9.77 (br, 1H); MS (ESI, m / z): 428.2 [M+H] +

[0268] Example 96. 4-(4-chlorophenyl)-6-(4-propylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that 1-propylpiperazine was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.06 (t, 3H), 1.80-1.90 (m, 2H), 3.17-3.21 (m, 2H), 3.54 (br, 8H), 7.43 (s, 1H), 7.55 (d, 2H), 8.03 (t, 1H), 8.28 (d, 2H), 8.87 (br, 1H), 9.41 (d, 1H), 9.77 (br, 1H); MS (ESI, m / z): 394.2 [M+H] +

[0269] Example 97. 4-(4-(benzo[d][1,3]dioxol-5-ylmethyl)piperazin-1-yl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 1-(benzo[d][1,3]dioxol-5-ylmethyl)piperazine was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 3.44 (br, 8H), 4.34 (s, 2H), 6.04 (s, 2H), 6.94 (d, 1H), 7.03 (d, 1H), 7.05 (s, 1H), 7.42 (s, 1H), 7.54 (d, 2H), 8.11-8.14 (m, 1H), 8.28 (d, 2H), 8.92 (br, 1H), 9.51 (d, 1H), 9.80 (br, 1H); MS (ESI, m / z): 486.2 [M+H] +

[0270] Example 98. (S)-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-2-yl)methanol The title compound was obtained in the same manner as in Example 54, except for using tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 3.55 (br, 1H), 3.45-3.59 (m, 4H), 3.62-3.67 (m, 1H), 3.72-3.77 (m, 1H), 3.82-3.87 (m, 1H), 3.95-4.00 MS (ESI, m / z): 382.1 [M+H] +

[0271] Example 99. 4-(4-chlorophenyl)-6-(4-(4-fluorophenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 1-(4-fluorophenyl)piperazine was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 4.09 (br, 8H), 7.02-7.07 (m, 2H), 7.10-7.13 (m, 2H), 7.32 (s, 1H), 7.52 (d, 2H), 8.14-8.17 (m, 1H), 8.23 (d, 2H), 8.92 (d, 1H), 9.53 (d, 1H), 9.76 (s, 1H); MS (ESI, m / z): 446.2 [M+H] +

[0272] Example 100. 6-(4-chlorophenyl)-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2-(pyridin-3-yl)pyrimidin-4-amine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 1,2,2,6,6-pentamethylpiperidin-4-amine was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.55 (s, 6H), 1.68 (s, 6H), 1.86 (t, 1H), 2.43 (d, 4H), 2.92 (s, 3H), 7.00 (s, 1H), 7.54 (d, 2H), 8.06-8.09 (m, 1H), 8.16 (d, 2H), 8.89 (d, 1H), 9.41 (d, 1H), 9.73 (s, 1H); MS (ESI, m / z): 436.2 [M+H] +

[0273] Example 101. 6-(4-chlorophenyl)-N-(piperidin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-amine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 54, except that tert-butyl 3-aminopiperidine-1-carboxylate was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 1.74-1.83 (m, 1H), 1.92-2.03 (m, 1H), 2.12-2.23 (m, 2H), 2.96-3.11 (m, 2H), 3.40 (d, 1H), 3.71 (d, MS (ESI, m / z): 366.1 [M+H] +

[0274] Example 102. 4-(4-chlorophenyl)-6-(piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 54, except that tert-butyl piperazine-1-carboxylate was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 3.41 (br, 4H), 4.19 (br, 4H), 7.41 (s, 1H), 7.55 (d, 2H), 8.04 (t, 1H), 8.28 (d, 2H), 8.87 (d, 1H), 9.41 (d, 1H), 9.77 (s, 1H); MS (ESI, m / z): 352.1 [M+H] +

[0275] Example 103. trans-4-(4-chlorophenyl)-6-(2,5-dimethylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 54, except that tert-butyl trans-2,5-dimethylpiperazine-1-carboxylate was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 1.47 (d, 3H), 1.48 (d, 3H), 3.62-3.73 (m, 3H), 3.91 (br, 1H), 4.67 (d, 1H), 5.17 (br, 1H), 7.35 (s, 1H), 7.56 (d, 2H), 8.02-8.05 (m, 1H), 8.28 (d, 2H), 8.87 (d, 1H), 9.41 (d, 1H), 9.76 (s, 1H); MS (ESI, m / z): 380.2 [M+H] +

[0276] Example 104. cis-4-(4-chlorophenyl)-6-(3,5-dimethylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 54, except that tert-butyl cis-2,6-dimethylpiperazine-1-carboxylate was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.48 (d, 6H), 3.03-3.09 (m, 2H), 3.46-3.51 (m, 2H), 5.04 (br, 2H), 7.47 (s, 1H), 7.55 (d, 2H), 8.08-8.12 (m, 1H), 8.30 (d, 2H), 8.91 (d, 1H), 9.50 (d, 1H), 9.81 (s, 1H); MS (ESI, m / z): 380.2 [M+H] +

[0277] Example 105. 4-(4-chlorophenyl)-6-(4-methylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that 1-methylpiperazine was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 3.00 (s, 3H), 3.49 (br, 4H), 3.55 (br, 4H), 7.43 (s, 1H), 7.56 (d, 2H), 7.97-8.00 (m, 1H), 8.29 (d, 2H), 8.86 (d, 1H), 9.36 (d, 1H), 9.76 (s, 1H); MS (ESI, m / z): 366.1 [M+H] +

[0278] Example 106. 4-(4-chlorophenyl)-6-(4-ethylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that 1-ethylpiperazine was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.43 (t, 3H), 3.27 (q, 2H), 3.54 (br, 4H), 3.56 (br, 4H), 7.43 (s, 1H), 7.56 (d, 2H), 7.97-8.01 (m, 1H), 8.29 (d, 2H), 8.86 (d, 1H), 9.36 (d, 1H), 9.76 (s, 1H); MS (ESI, m / z): 380.2 [M+H] +

[0279] Example 107. 4-(4-chlorophenyl)-6-(4-(methylsulfonyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that 1-(methylsulfonyl)piperazine was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 2.90 (s, 3H), 3.40 (br, 4H), 4.06 (br, 4H), 7.35 (s, 1H), 7.55 (d, 2H), 8.02 (br, 1H), 8.27 (d, 2H), 8.85 (br, 1H), 9.38 (d, 1H), 9.76 (br, 1H); MS (ESI, m / z): 430.1 [M+H] +

[0280] Example 108. 1-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)ethan-1-one The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 1-(piperazin-1-yl)ethan-1-one was used (Scheme 1. General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 2.19 (s, 3H), 3.73-3.78 (m, 4H), 3.93 (br, 2H), 3.99 (br, 2H), 7.28 (s, 1H), 7.54 (d, 2H), 7.96-7.99 (m, MS (ESI, m / z): 394.1 [M+H] +

[0281] Example 109. 4-(4-chlorophenyl)-6-(3-ethylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 54, except that tert-butyl 2-ethylpiperazine-1-carboxylate was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.19 (t, 3H), 1.73-1.90 (m, 3H), 3.25-3.35 (m, 4H), 3.49-3.59 (m, 2H), 7.45 (s, 1H), 7.56 (d, 2H), 8.07-8.10 (m, 1H), 8.30 (d, 2H), 8.90 (d, 1H), 9.46 (d, 1H), 9.78 (s, 1H); MS (ESI, m / z): 380.2 [M+H] +

[0282] Example 110. Ethyl 4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazine-1-carboxylate The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that ethyl piperazine-1-carboxylate was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 1.31 (t, 3H), 3.66 (br, 4H), 3.94 (br, 4H), 4.19 (q, 2H), 7.29 (s, 1H), 7.53 (d, 2H), 8.02-8.06 (m, 1H), 8.24 (d, 2H), 8.86 (d, 1H), 9.41 (d, 1H), 9.73 (s, 1H); MS (ESI, m / z): 424.2 [M+H] +

[0283] Example 111. 4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazine-2-carboxylic acid The title compound was obtained by separation by preparative HPLC in the same manner as in Example 54, except that 1-(tert-butoxycarbonyl)piperazine-2-carboxylic acid was used (Scheme 1, General Procedure A). MS (ESI, m / z): 396.1 [M+H] +

[0284] Example 112. Methyl 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazine-2-carboxylate The title compound was obtained by separation by preparative HPLC in the same manner as in Example 54, except that 1-(tert-butyl)3-methyl piperazine-1,3-dicarboxylate was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.49 (s, 3H), 3.47-3.57 (m, 3H), 3.63 (br, 1H), 3.83 (br, 1H), 4.07 (br, 1H), 4.10 (br, 1H), 7.43 (s, 1H), 7.55 (d, 2H), 7.80-7.84 (m, 1H), 8.28 (d, 2H), 8.77 (d, 1H), 9.16 (d, 1H), 9.68 (s, 1H); MS (ESI, m / z): 410.1 [M+H] +

[0285] Example 113 (S)-4-(4-chlorophenyl)-6-(2-phenylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 54, except that (S)-tert-butyl 3-phenylpiperazine-1-carboxylate was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 3.47-3.55 (m, 2H), 3.58-3.71 (m, 2H), 4.55-4.60 (m, 2H), 5.09-5.12 (m, 1H), 7.47 (s, 1H), 7.53-7.63 (m, 7H), 7.79-7.82 (m, 1H), 8.29 (d, 2H), 8.76 (d, 1H), 9.15 (d, 1H), 9.67 (s, 1H); MS (ESI, m / z): 428.2 [M+H] +

[0286] Example 114. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(4-(o-tolyl)piperazin-1-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that 1-(o-tolyl)piperazine was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 2.40 (s, 3H), 3.06 (t, 4H), 4.07 (br, 4H), 7.01 (t, 1H), 7.08 (d, 1H), 7.31 (s, 1H), 7.53 (d, 2H), 7.59 (d, 1H), 8.11-8.14 (m, 1H), 8.24 (d, 2H), 8.42 (t, 1H), 8.91 (d, 1H), 9.50 (d, 1H), 9.75 (s, 1H); MS (ESI, m / z): 442.2 [M+H] +

[0287] Example 115. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(4-(p-tolyl)piperazin-1-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that 1-(p-tolyl)piperazine was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 2.31 (s, 3H), 3.44 (t, 4H), 4.17 (br, 4H), 7.14 (d, 2H), 7.20 (d, 2H), 7.37 (s, 1H), 7.54 (d, 2H), 8.11-8.14 (m, 1H), 8.26 (d, 2H), 8.91 (d, 1H), 9.52 (d, 1H), 9.78 (s, 1H); MS (ESI, m / z): 442.2 [M+H] +

[0288] Example 116. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(4-(m-tolyl)piperazin-1-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that 1-(m-tolyl)piperazine was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 2.34 (s, 3H), 3.43 (t, 4H), 4.13 (br, 4H), 6.87 (d, 1H), 6.98 (d, 1H), 7.01 (s, 1H), 7.22 (t, 1H), 7.35 MS (ESI, m / z): 442.2 [M+H] +

[0289] Example 117. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that 1-(3-(trifluoromethyl)phenyl)piperazine was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 3.42 (t, 4H), 4.08 (br, 4H), 7.13 (d, 1H), 7.25 (s, 1H), 7.26 (d, 1H), 7.31 (s, 1H), 7.44 (t, 1H), 7.53 (d, 2H), 8.10-8.14 (m, 1H), 8.24 (d, 2H), 8.90 (d, 1H), 9.50 (d, 1H), 9.75 (s, 1H); MS (ESI, m / z): 496.1 [M+H] +

[0290] Example 118. 4-(4-chlorophenyl)-6-(4-(2,3-dimethylphenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 1-(2,3-dimethylphenyl)piperazine was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 2.29 (s, 3H), 2.33 (s, 3H), 3.03 (br, 4H), 4.08 (br, 4H), 6.94 (t, 2H), 7.06 (t, 1H), 7.32 (s, 1H), 7.54 (d, 2H), 8.10-8.13 (m, 1H), 8.25 (d, 2H), 8.90 (d, 1H), 9.49 (d, 1H), 9.75 (s, 1H); MS (ESI, m / z): 456.2 [M+H] +

[0291] Example 119. 4-(4-chlorophenyl)-6-(4-(3,4-dichlorophenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 1-(3,4-dichlorophenyl)piperazine was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 3.39 (t, 4H), 4.09 (br, 4H), 6.96 (d, 1H), 6.99 (d, 1H), 7.35 (d, 2H), 7.55 (d, 2H), 8.10-8.14 (m, 1H), 8.27 (d, 2H), 8.90 (d, 1H), 9.51 (d, 1H), 9.77 (s, 1H); MS (ESI, m / z): 496.1 [M+H] +

[0292] Example 120. 4-(4-chlorophenyl)-6-(4-(4-methoxyphenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 1-(4-methoxyphenyl)piperazine was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 3.57 (t, 4H), 3.83 (s, 3H), 4.27 (br, 4H), 7.04 (d, 2H), 7.39 (d, 2H), 7.44 (s, 1H), 7.57 (d, 2H), 8.13-8.16 (m, 1H), 8.30 (d, 2H), 8.93 (d, 1H), 9.54 (d, 1H), 9.81 (s, 1H); MS (ESI, m / z): 458.2 [M+H] +

[0293] Example 121. 4-(4-chlorophenyl)-6-(4-(4-nitrophenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that 1-(4-nitrophenyl)piperazine was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 3.73 (t, 4H), 4.13 (br, 4H), 7.05 (d, 2H), 7.32 (s, 1H), 7.56 (d, 2H), 8.03-8.07 (m, 1H), 8.17 (d, 2H), 8.28 (d, 2H), 8.87 (d, 1H), 9.42 (d, 1H), 9.76 (s, 1H); MS (ESI, m / z): 473.1 [M+H] +

[0294] Example 122. 4-(4-chlorophenyl)-6-(3-(4-methylpiperazin-1-yl)pyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 1-methyl-4-(pyrrolidin-3-yl)piperazine was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 2.02 (br, 2H), 2.41 (br, 2H), 2.93 (s, 3H), 2.97 (br, 2H), 3.28 (br, 2H), 3.38 (br, 4H), 3.62 (br, 2H), 4.16 MS (ESI, m / z): 435.2 [M+H] +

[0295] Example 123. 4-(4-Benzhydrylpiperazin-1-yl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that 1-benzhydrylpiperazine was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 3.35 (br, 4H), 4.22 (br, 4H), 5.41 (s, 1H), 7.31 (t, 2H), 7.37 (s, 1H), 7.43-7.55 (m, 8H), 7.69 (d, 2H), 8.00-8.04 (m, 1H), 8.26 (d, 2H), 8.86 (d, 1H), 9.40 (d, 1H), 9.74 (s, 1H); MS (ESI, m / z): 518.2 [M+H] +

[0296] Example 124. 4-(4-chlorophenyl)-6-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that 1-((4-chlorophenyl)(phenyl)methyl)piperazine was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 3.29 (br, 4H), 4.21 (br, 4H), 5.36 (s, 1H), 7.30-7.34 (m, 1H), 7.36 (s, 1H), 7.42-7.54 (m, 7H), 7.67-7.71 (m, 3H), 8.07-8.11 (m, 1H), 8.25 (d, 2H), 8.90 (br, 1H), 9.47 (d, 1H), 9.76 (s, 1H); MS (ESI, m / z): 552.2 [M+H] +

[0297] Example 125. 1'-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)spiro[indene-1,4'-piperidine] The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that spiro[indene-1,4'-piperidine] was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 2.17-2.24 (m, 4H), 3.53-3.59 (m, 4H), 6.89 (d, 1H), 7.12 (d, 1H), 7.17 (t, 1H), 7.23 (t, 1H), 7.35 (d, MS (ESI, m / z): 451.2 [M+H] +

[0298] Example 126. 6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(pyrrolidin-3-yl)pyrimidin-4-amine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 54, except that tert-butyl 3-aminopyrrolidine-1-carboxylate was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 2.16 (br, 1H), 2.50 (br, 1H), 3.18-3.23 (m, 1H), 3.38-3.46 (m, 1H), 3.52-3.59 (m, 1H), 3.70-3.75 (m, 1H), 4.04-4.11 (m, 1H), 7.00 (s, 1H), 7.53 (d, 2H), 7.70-7.74 (m, 1H), 8.16 (d, 2H), 8.72 (d, 1H), 9.06 (d, 1H), 9.63 (s, 1H); MS (ESI, m / z): 352.1 [M+H] +

[0299] Example 127 (R)-6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(pyrrolidin-3-yl)pyrimidin-4-amine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 54, except that (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 2.11-2.24 (m, 1H), 2.46-2.56 (m, 1H), 3.37-3.46 (m, 1H), 3.48-3.61 (m, 2H), 3.71-3.81 (m, 1H), MS (ESI, m / z): 352.1 [M+H] +

[0300] Example 128 (R)-6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(pyrrolidin-3-ylmethyl)pyrimidin-4-amine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 54, except that (S)-tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.85-1.94 (m, 1H), 2.22-2.32 (m, 1H), 2.79-2.87 (m, 1H), 3.00-3.15 (m, 2H), 3.40-3.46 (m, 1H), 3.47-3.57 (m, 1H), 3.73 (br, 2H), 7.00 (s, 1H), 7.53 (d, 2H), 8.05-8.08 (m, 1H), 8.16 (d, 2H), 8.88 (d, 1H), 9.43 (d, 1H), 9.75 (s, 1H); MS (ESI, m / z): 366.1 [M+H] +

[0301] Example 129. 6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(2-(pyrrolidin-1-yl)ethyl)pyrimidin-4-amine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 2-(pyrrolidin-1-yl)ethan-1-amine was used (Scheme 1. General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 3.19 (br, 4H), 3.40 (d, 2H), 3.53 (d, 2H), 3.76 (br, 4H), 7.06 (s, 1H), 7.54 (d, 2H), 8.02-8.05 (m, 1H), 8.18 (d, 2H), 8.88 (d, 1H), 9.41 (d, 1H), 9.76 (s, 1H); MS (ESI, m / z): 380.2 [M+H] +

[0302] Example 130. 6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(3-(pyrrolidin-1-yl)propyl)pyrimidin-4-amine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 3-(pyrrolidin-1-yl)propan-1-amine was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 2.00-2.18 (br, 6H), 3.03-3.13 (br, 6H), 3.69 (br, 2H), 6.98 (s, 1H), 7.52 (d, 2H), 7.95-7.98 (m, 1H), 8.15 (d, 2H), 8.84 (d, 1H), 9.31 (d, 1H), 9.71 (s, 1H); MS (ESI, m / z): 394.2 [M+H] +

[0303] Example 131. 6-(4-chlorophenyl)-N-(2-(1-methylpyrrolidin-2-yl)ethyl)-2-(pyridin-3-yl)pyrimidin-4-amine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 2-(1-methylpyrrolidin-2-yl)ethan-1-amine was used (Scheme 1. General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 1.89-2.00 (m, 2H), 2.02-2.18 (m, 2H), 2.35-2.43 (m, 1H), 2.93 (s, 3H), 3.03-3.07 (m, 2H), 3.11-3.20 (m, 1H), 3.34-3.44 (m, 1H), 3.72 (br, 2H), 6.96 (s, 1H), 7.52 (d, 2H), 7.87-7.90 (m, 1H), 8.15 (d, 2H), 8.80 (d, 1H), 9.21 (d, 1H), 9.67 (s, 1H); MS (ESI, m / z): 394.2 [M+H] +

[0304] Example 132. N-(1-benzylpyrrolidin-3-yl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-amine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 1-benzylpyrrolidin-3-amine was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 2.21 (br, 1H), 2.62 (br, 1H), 3.39-4.17 (br, 5H), 4.48 (s, 2H), 7.03 (s, 1H), 7.47-7.49 (m, 3H), 7.52-7.56 (m, 4H), 8.10-8.14 (m, 1H), 8.16 (d, 2H), 8.87 (d, 1H), 9.36 (d, 1H), 9.73 (s, 1H); MS (ESI, m / z): 442.2 [M+H] +

[0305] Example 133 (3R,4S)-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)pyrrolidin-3-ol The title compound was obtained by preparative HPLC separation in the same manner as in Example 54, except that tert-butyl (3S,4R)-3-amino-4-hydroxypyrrolidine-1-carboxylate was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 1.06 (br, 2H), 2.18 (br, 1H), 3.80 (br, 1H), 4.17 (br, 2H), 7.09 (s, 1H), 7.53 (d, 2H), 7.65-7.70 (m, 1H), 8.17 (d, 2H), 8.69 (d, 1H), 9.01 (d, 1H), 9.62 (s, 1H); MS (ESI, m / z): 368.1 [M+H] +

[0306] Example 134 (3S,4R)-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)pyrrolidin-3-ol The title compound was obtained by preparative HPLC separation in the same manner as in Example 54, except that tert-butyl (3R,4S)-3-amino-4-hydroxypyrrolidine-1-carboxylate was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.06 (br, 2H), 2.18 (br, 1H), 3.80 (br, 1H), 4.17 (br, 2H), 7.09 (s, 1H), 7.53 (d, 2H), 7.65-7.70 (m, 1H), 8.17 (d, 2H), 8.69 (d, 1H), 9.01 (d, 1H), 9.62 (s, 1H); MS (ESI, m / z): 368.1 [M+H] +

[0307] Example 135. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(pyrrolidin-1-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that pyrrolidine was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 2.09 (br, 4H), 3.59 (br, 2H), 3.82 (br, 2H), 6.95 (s, 1H), 7.54 (d, 2H), 8.05-8.08 (m, 1H), 8.20 (d, 2H), 8.88 (d, 1H), 9.40 (d, 1H), 9.69 (s, 1H); MS (ESI, m / z): 337.1 [M+H] +

[0308] Example 136. 4-(4-chlorophenyl)-6-(2-methylpyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that 2-methylpyrrolidine was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.36 (br, 3H), 1.87 (br, 1H), 2.20 (br, 3H), 3.70 (br, 2H), 4.63 (br, 1H), 6.91 (s, 1H), 7.53 (d, 2H), 8.04-8.07 (m, 1H), 8.18 (d, 2H), 8.88 (d, 1H), 9.37 (d, 1H), 9.67 (s, 1H); MS (ESI, m / z): 351.1 [M+H] +

[0309] Example 137 (S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that (S)-pyrrolidin-3-ol was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 2.17 (br, 2H), 3.70 (br, 2H), 3.86 (br, 2H), 4.59 (br, 1H), 6.95 (s, 1H), 7.52 (d, 2H), 8.07-8.11 (m, 1H), 8.19 (d, 2H), 8.89 (d, 1H), 9.43 (d, 1H), 9.69 (s, 1H); MS (ESI, m / z): 353.1 [M+H] +

[0310] Example 138 (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)methanol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that pyrrolidin-3-ylmethanol was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.92 (br, 1H), 2.21 (br, 1H), 2.60 (br, 1H), 3.52-3.59 (m, 2H), 3.60-3.71 (m, 3H), 3.97 (br, 1H), 6.91 (s, MS (ESI, m / z): 367.1 [M+H] +

[0311] Example 139. (R)-4-(4-chlorophenyl)-6-(3-fluoropyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that (R)-3-fluoropyrrolidine was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 2.25 (br, 1H), 2.45 (br, 1H), 3.71 (br, 1H), 3.79 (br, 2H), 3.88 (br, 1H), 4.17 (br, 1H), 7.00 (s, 1H), 7.53 (d, 2H), 8.07-8.10 (m, 1H), 8.23 ​​(d, 2H), 8.88 (d, 1H), 9.46 (d, 1H), 9.72 (s, 1H); MS (ESI, m / z): 355.1 [M+H] +

[0312] Example 140. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-amine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 54, except that tert-butyl pyrrolidin-3-ylcarbamate was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 2.31 (br, 1H), 2.57 (br, 1H), 3.87 (br, 2H), 4.06 (br, 2H), 4.14 (br, 1H), 7.04 (s, 1H), 7.54 (d, 2H), 8.06-8.09 (m, 1H), 8.25 (d, 2H), 8.89 (d, 1H), 9.45 (d, 1H), 9.75 (s, 1H); MS (ESI, m / z): 352.1 [M+H] +

[0313] Example 141. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-N-methylpyrrolidin-3-amine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 54, except that tert-butyl methyl(pyrrolidin-3-yl)carbamate was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 2.38 (br, 1H), 2.59 (br, 1H), 2.85 (s, 3H), 3.80 (br, 1H), 3.89 (br, 1H), 4.05 (br, 3H), 7.04 (s, 1H), 7.53 (d, 2H), 8.08-8.12 (m, 1H), 8.25 (d, 2H), 8.90 (d, 1H), 9.47 (d, 1H), 9.76 (s, 1H); MS (ESI, m / z): 366.1 [M+H] +

[0314] Example 142. (6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)prophosphate methyl ester The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that methyl prophosphate was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 2.13-2.29 (m, 3H), 2.39-2.49 (m, 1H), 3.63-3.80 (m, 5H), 4.76-4.79 (m, 1H), 7.06 (s, 1H), 7.52 (d, MS (ESI, m / z): 395.1 [M+H] +

[0315] Example 143. N-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)acetamide The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that N-(pyrrolidin-3-yl)acetamide was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 1.98 (s, 3H), 2.13 (br, 1H), 2.37 (br, 1H), 3.46 (br, 1H), 3.72 (br, 1H), 3.89 (br, 1H), 4.02 (br, 1H), 4.52 MS (ESI, m / z): 394.1 [M+H] +

[0316] Example 144 (2R,3R)-3-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)butan-2-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that (2R,3R)-3-aminobutan-2-ol was used (Scheme 1, General Procedure A). 1 H NMR (600 MHz, CD3OD) δ [ppm] = 1.23 (d, 3H), 1.30 (d, 3H), 3.94 (br, 1H), 4.51 (br, 1H), 7.01 (s, 1H), 7.55 (d, 2H), 8.07-8.10 (m, 1H), 8.15 (d, 2H), 8.89 (d, 1H), 9.44 (d, 1H), 9.71 (s, 1H); MS (ESI, m / z): 355.1 [M+H] +

[0317] Example 145. 3-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)butan-2-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that 3-aminobutan-2-ol was used (Scheme 1, General Procedure A). 1H NMR (600 MHz, CD3OD) δ [ppm] = 1.27 (d, 3H), 1.31 (d, 3H), 3.90-3.94 (m, 1H), 4.46 (br, 1H), 7.00 (s, 1H), 7.55 (d, 2H), 8.13-8.20 (m, 3H), 8.92 (d, 1H), 9.48 (d, 1H), 9.71 (s, 1H); MS (ESI, m / z): 355.1 [M+H] +

[0318] Example 146. 1-(4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)piperidin-1-yl)ethan-1-one The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 1-(4-aminopiperidin-1-yl)ethan-1-one was used (Scheme 1. General Procedure A). 1 H NMR (600 MHz, CD3OD) δ [ppm] = 1.49-1.65 (m, 4H), 2.05-2.22 (m, 4H), 2.17 (s, 3H), 4.49 (br, 1H), 6.99 (s, 1H), 7.57 (d, 2H), 8.14-8.19 (m, 3H), 8.93 (d, 1H), 9.52 (d, 1H), 9.77 (s, 1H); MS (ESI, m / z): 408.2 [M+H] +

[0319] Example 147. (R)-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that (R)-piperidin-3-ylmethanol was used (Scheme 1, General Procedure A). 1H NMR (600 MHz, CD3OD) δ [ppm] = 1.39-1.45 (m, 1H), 1.59-1.66 (m, 1H), 1.79-1.84 (m, 1H), 1.86-1.92 (m, 2H), 3.03 (t, 1H), 3.24 (t, 1H), 3.35 (d, 1H), 3.50 (dd, 1H), 3.60 (dd, 1H), 4.58 (br, 1H), 7.27 (s, 1H), 7.54 (d, 2H), 8.13-8.15 (m, 1H), 8.21 (d, 2H), 8.92 (d, 1H), 9.50 (d, 1H), 9.73 (s, 1H); MS (ESI, m / z): 381.1 [M+H] +

[0320] Example 148 (S)-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that (S)-piperidin-3-ylmethanol was used (Scheme 1, General Procedure A). 1 H NMR (600 MHz, CD3OD) δ [ppm] = 1.39-1.45 (m, 1H), 1.59-1.66 (m, 1H), 1.79-1.84 (m, 1H), 1.86-1.92 (m, 2H), 3.03 (t, 1H), 3.24 (t, 1H), 3.35 (d, 1H), 3.50 (dd, 1H), 3.60 (dd, 1H), 4.58 (br, 1H), 7.27 (s, 1H), 7.54 (d, 2H), 8.13-8.15 (m, 1H), 8.21 (d, 2H), 8.92 (d, 1H), 9.50 (d, 1H), 9.73 (s, 1H); MS (ESI, m / z): 381.1 [M+H] +

[0321] Example 149. 6-(4-chlorophenyl)-N-(2-(piperidin-1-yl)ethyl)-2-(pyridin-3-yl)pyrimidin-4-amine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 2-(piperidin-1-yl)ethan-1-amine was used (Scheme 1. General Procedure A). 1 H NMR (600 MHz, CD3OD) δ [ppm] = 1.51-1.57 (m, 1H), 1.75-1.86 (m, 3H), 1.97 (d, 2H), 3.05 (t, 2H), 3.48 (t, 2H), 3.72 (d, 2H), 4.05 (br, MS (ESI, m / z): 394.2 [M+H] +

[0322] Example 150. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidine-4-carbonitrile The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that piperidine-4-carbonitrile was used (Scheme 1, General Procedure A). 1 H NMR (600 MHz, CD3OD) δ [ppm] = 1.89-1.95 (m, 2H), 2.08-2.13 (m, 2H), 3.16-3.20 (m, 1H), 3.76-3.80 (m, 2H), 4.24 (br, 2H), 7.32 (s, MS (ESI, m / z): 376.1 [M+H] +

[0323] Example 151. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(3-(trifluoromethyl)phenyl)piperidin-4-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 4-(3-(trifluoromethyl)phenyl)piperidin-4-ol was used (Scheme 1, General Procedure A). 1H NMR (600 MHz, CD3OD) δ [ppm] = 1.92 (d, 2H), 2.14-2.19 (m, 2H), 3.59 (br, 2H), 4.70 (br, 2H), 7.33 (s, 1H), 7.53 (d, 2H),7.53-7.59 (m, MS (ESI, m / z): 511.1 [M+H] +

[0324] Example 152. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 4-(pyrrolidin-1-yl)piperidine was used (Scheme 1, General Procedure A). 1 H NMR (600 MHz, CD3OD) δ [ppm] = 1.71-1.78 (m, 2H), 2.03 (br, 2H), 2.18 (br, 2H), 2.34 (d, 2H), 3.13 (t, 2H), 3.22 (br, 2H), 3.31 (br, 2H), 3.52-3.56 (m, 1H), 3.70 (br, 2H), 7.36 (s, 1H), 7.54 (d, 2H),8.16-8.18 (m, 1H), 8.25 (d, 2H), 8.94 (d, 1H), 9.55 (d, 1H), 9.78 (s, 1H); MS (ESI, m / z): 420.2 [M+H] +

[0325] Example 153. 4-(4-chlorophenyl)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 4-(4-chlorophenyl)piperidin-4-ol was used (Scheme 1, General Procedure A). 1H NMR (600 MHz, CD3OD) δ [ppm] = 1.90 (d, 2H), 2.08-2.13 (m, 2H), 3.58 (br, 2H), 4.66 (br, 2H), 7.32 (s, 1H), 7.33 (d, 2H), 7.51 (d, 2H), 7.53 (d, 2H), 8.13-8.15 (m, 1H), 8.22 (d, 2H), 8.92 (d, 1H), 9.50 (d, 1H), 9.74 (s, 1H); MS (ESI, m / z): 477.1 [M+H] +

[0326] Example 154. 1-(4-(((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)ethan-1-one The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 1-(4-(aminomethyl)piperidin-1-yl)ethan-1-one was used (Scheme 1. General Procedure A). 1 H NMR (600 MHz, CD3OD) δ [ppm] = 1.22-1.39 (m, 3H), 1.91 (d, 2H), 1.96 (s, 3H), 3.08-3.13 (m, 4H), 4.79 (br, 2H), 7.28 (s, 1H), 7.54 (d, MS (ESI, m / z): 422.2 [M+H] +

[0327] Example 155. 1-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-phenylpiperidin-4-yl)ethan-1-one The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 1-(4-phenylpiperidin-4-yl)ethan-1-one was used (Scheme 1. General Procedure A). 1H NMR (600 MHz, CD3OD) δ [ppm] = 1.99 (s, 3H), 2.14-2.19 (m, 2H), 2.58 (d, 2H), 3.60 (t, 2H), 4.27 (br, 2H), 7.24 (s, 1H), 7.30-7.34 (m, MS (ESI, m / z): 469.2 [M+H] +

[0328] Example 156. 4-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)morpholine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 4-(piperidin-4-yl)morpholine was used (Scheme 1, General Procedure A). 1 H NMR (600 MHz, CD3OD) δ [ppm] = 1.75-1.82 (m, 2H), 2.35 (d, 2H), 3.14 (t, 2H), 3.24 (t, 2H), 3.55 (d, 2H), 3.60-3.66 (m, 2H), 3.80 (t, 2H), 4.10 (d, 2H), 5.00 (br, 2H), 7.37 (s, 1H), 7.54 (d, 2H), 8.17-8.19 (m, 1H), 8.26 (d, 2H), 8.94 (d, 1H), 9.56 (d, 1H), 9.79 (s, 1H); MS (ESI, m / z): 436.2 [M+H] +

[0329] Example 157. 4-(4-chlorophenyl)-6-(4-(3,5-dichlorophenyl)piperidin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 4-(3,5-dichlorophenyl)piperidine was used (Scheme 1, General Procedure A). 1H NMR (600 MHz, CD3OD) δ [ppm] = 1.72-1.79 (m, 2H), 2.04 (d, 2H), 2.98-3.04 (m, 1H), 3.20 (t, 2H), 4.95 (br, 2H), 7.27 (s, 2H), 7.29 (s, MS (ESI, m / z): 495.1 [M+H] +

[0330] Example 158. 6-(4-chlorophenyl)-N-((1-cyclohexylpiperidin-3-yl)methyl)-2-(pyridin-3-yl)pyrimidin-4-amine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that (1-cyclohexylpiperidin-3-yl)methanamine was used (Scheme 1, General Procedure A). 1 H NMR (600 MHz, CD3OD) δ [ppm] = 1.35-1.41 (m, 2H), 1.46-1.53 ​​(m, 2H), 1.61-1.72 (m, 3H), 1.93 (d, 2H), 2.08 (d, 3H), 2.15 (d, 2H), 3.07 (t, 2H), 3.14-3.19 (m, 1H), 3.54 (d, 2H), 3.59 (br, 1H), 4.87-4.91 (m, 2H), 6.99 (s, 1H), 7.53 (d, 2H), 8.14-8.16 (m, 3H), 8.93 (d, 1H), 9.51 (d, 1H), 9.76 (s, 1H); MS (ESI, m / z): 462.2 [M+H] +

[0331] Example 159. N-((1-benzylpiperidin-4-yl)methyl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-amine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that (1-benzylpiperidin-4-yl)methanamine was used (Scheme 1, General Procedure A). 1H NMR (600 MHz, CD3OD) δ [ppm] = 1.56-1.63 (m, 2H), 2.07 (br, 2H), 2.14 (d, 2H), 3.05 (t, 2H), 3.56 (d, 2H), 3.59 (br, 1H), 4.30 (s, 2H), 7.00 (s, 1H), 7.49 (s, 5H), 7.54 (d, 2H), 8.13-8.15 (m, 3H), 8.94 (d, 1H), 9.51 (d, 1H), 9.77 (s, 1H); MS (ESI, m / z): 470.2 [M+H] +

[0332] Example 160. Ethyl 3-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)-3-oxopropanoate The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that ethyl 3-oxo-3-(piperidin-4-yl)propanoate was used (Scheme 1, General Procedure A). 1 H NMR (600 MHz, CD3OD) δ [ppm] = 1.24 (t, 3H), 1.60-1.71 (m, 4H), 2.18-2.24 (m, 1H), 3.20-3.29 (m, 2H), 3.70 (s, 2H), 4.69 (br, 4H), 7.26 (s, 1H), 7.53 (d, 2H), 8.06-8.08 (m, 1H), 8.22 (d, 2H), 8.88 (d, 1H), 9.42 (d, 1H), 9.71 (s, 1H); MS (ESI, m / z): 465.2 [M+H] +

[0333] Example 161. 2-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)ethyl acetate The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that ethyl 2-(piperidin-4-yl)acetate was used (Scheme 1, General Procedure A). 1H NMR (600 MHz, CD3OD) δ [ppm] = 1.28 (t, 3H), 1.95 (d, 2H), 2.15-2.23 (m, 1H), 2.35 (d, 2H), 3.13 (t, 2H), 3.80 (br, 2H), 4.17 (q, 2H), MS (ESI, m / z): 437.2 [M+H] +

[0334] Example 162 (1S,3R)-3-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that (1S,3R)-3-aminocyclopentan-1-ol was used (Scheme 1, General Procedure A). 1 H NMR (600 MHz, CD3OD) δ [ppm] = 1.61-1.67 (m, 1H), 1.79-1.95 (m, 4H), 2.15-2.22 (m, 1H), 2.42-2.49 (m, 1H), 4.34-4.39 (m, 1H), 4.60 (br, 1H), 6.92 (s, 1H), 7.50 (d, 2H), 8.08-8.14 (m, 3H), 8.91 (d, 1H), 9.44 (d, 1H), 9.69 (s, 1H); MS (ESI, m / z): 367.1 [M+H] +

[0335] Example 163 (S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that (S)-piperidin-3-ol was used (Scheme 1. General Procedure A). 1H NMR (600 MHz, CD3OD) δ [ppm] = 1.59-1.66 (m, 1H), 1.67-1.72 (m, 1H), 1.93-1.99 (m, 1H), 2.04-2.08 (m, 1H), 3.51 (q, 1H), 3.65 (br, 1H), 3.80-3.82 (m, 1H), 4.06 (br, 1H), 4.30 (br, 1H), 7.26 (s, 1H), 7.53 (d, 2H), 8.14-8.16 (m, 1H), 8.20 (d, 2H), 8.92 (d, 1H), 9.50 (d, 1H), 9.73 (s, 1H); MS (ESI, m / z): 367.1 [M+H] +

[0336] Example 164. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-N,N-dimethylpyrrolidin-3-amine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that N,N-dimethylpyrrolidin-3-amine was used (Scheme 1, General Procedure A). 1 H NMR (600 MHz, CD3OD) δ [ppm] = 2.40 (br, 1H), 2.68 (br, 1H), 3.05 (s, 6H), 3.72 (br, 1H), 3.94 (br, 1H), 4.13 (br, 2H), 4.33 (br, 1H), 7.08 MS (ESI, m / z): 380.2 [M+H] +

[0337] Example 165. 2-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-2-yl)-N,N-dimethylethan-1-amine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that N,N-dimethyl-2-(pyrrolidin-2-yl)ethan-1-amine was used (Scheme 1, General Procedure A). 1H NMR (600 MHz, CD3OD) δ [ppm] = 2.08-2.15 (m, 2H), 2.39-2.45 (m, 2H), 2.88 (s, 6H), 3.08-3.13 (m, 2H), 3.26-3.31 (m, 2H), 3.50-3.59 (m, 2H), 3.92-3.96 (m, 1H), 7.31 (s, 1H), 7.56 (d, 2H), 8.20-8.22 (m, 1H), 8.26 (d, 2H), 8.95 (d, 1H), 9.58 (d, 1H), 9.80 (s, 1H); MS (ESI, m / z): 408.2 [M+H] +

[0338] Example 166. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-one The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that piperidin-4-one was used (Scheme 1. General Procedure A). 1 H NMR (600 MHz, CD3OD) δ [ppm] = 1.85-1.90 (m, 4H), 3.93 (br, 2H), 3.99 (br, 2H), 7.31 (s, 1H), 7.54 (d, 2H), 8.12-8.14 (m, 1H), 8.23 ​​(d, 2H), 8.91 (d, 1H), 9.49 (d, 1H), 9.74 (s, 1H); MS (ESI, m / z): 365.1 [M+H] +

[0339] Example 167. 6-(4-chlorophenyl)-N-methyl-N-(piperidin-4-yl)-2-(pyridin-3-yl)pyrimidin-4-amine The title compound was obtained by preparative HPLC separation in the same manner as in Example 54, except that tert-butyl 4-(methylamino)piperidine-1-carboxylate was used (Scheme 1, General Procedure A). 1H NMR (600 MHz, CD3OD) δ [ppm] = 2.05 (d, 2H), 2.14-2.21 (m, 2H), 3.17 (s, 3H), 3.34-3.36 (m, 2H), 3.59 (d, 2H), 5.26 (br, 1H), 7.23 (s, MS (ESI, m / z): 380.2 [M+H] +

[0340] Example 168. 6-(4-chlorophenyl)-N-(2-(1-methylpiperidin-2-yl)ethyl)-2-(pyridin-3-yl)pyrimidin-4-amine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 2-(1-methylpiperidin-2-yl)ethan-1-amine was used (Scheme 1. General Procedure A). 1 H NMR (600 MHz, CD3OD) δ [ppm] = 1.90-1.96 (m, 4H), 2.30 (d, 1H), 2.41-2.46 (m, 1H), 2.92 (s, 3H), 3.05-3.10 (m, 1H), 3.52-3.57 (m, 2H), 3.73 (br, 2H), 3.77 (br, 2H), 7.01 (s, 1H), 7.54 (d, 2H), 8.13-8.15 (m, 1H), 8.17 (d, 2H), 8.93 (d, 1H), 9.49 (d, 1H), 9.76 (s, 1H); MS (ESI, m / z): 408.2 [M+H] +

[0341] Example 169. 6-(4-chlorophenyl)-N-(1-(1-methylpiperidin-4-yl)ethyl)-2-(pyridin-3-yl)pyrimidin-4-amine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 1-(1-methylpiperidin-4-yl)ethan-1-amine was used (Scheme 1. General Procedure A). 1H NMR (600 MHz, CD3OD) δ [ppm] = 1.32 (d, 3H), 1.39-1.45 (m, 2H), 1.62-1.67 (m, 1H), 1.94 (br, 2H), 2.11-2.18 (m, 1H), 3.85 (s, 3H), 2.97-3.13 (m, 2H), 3.48-3.63 (m, 2H), 7.29 (s, 1H), 7.54 (d, 2H), 7.94-7.97 (m, 1H), 8.23 ​​(d, 2H), 8.83 (d, 1H), 9.30 (d, 1H), 9.70 (s, 1H); MS (ESI, m / z): 408.2 [M+H] +

[0342] Example 170. 6-(4-chlorophenyl)-N-((1-(2-methoxyethyl)piperidin-4-yl)methyl)-2-(pyridin-3-yl)pyrimidin-4-amine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that (1-(2-methoxyethyl)piperidin-4-yl)methanamine was used (Scheme 1, General Procedure A). 1 H NMR (600 MHz, CD3OD) δ [ppm] = 1.65 (br, 2H), 2.12 (br, 2H), 3.02 (br, 2H), 3.40 (s, 3H), 3.48 (br, 1H), 3.60 (br, 1H), 3.64-3.72 (m, 2H), 4.51 (br, 1H), 4.90-4.97 (m, 4H), 6.97 (s, 1H), 7.54 (d, 2H), 7.94-7.98 (m, 1H), 8.16 (d, 2H), 8.83 (d, 1H), 9.29 (d, 1H), 9.70 (s, 1H); MS (ESI, m / z): 438.2 [M+H] +

[0343] Example 171. Methyl 2-(4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)piperidin-1-yl)acetate The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that methyl 2-(4-aminopiperidin-1-yl)acetate was used (Scheme 1, General Procedure A). 1H NMR (600 MHz, CD3OD) δ [ppm] = 1.97 (br, 4H), 2.43 (br, 4H), 3.89 (s, 3H), 4.23 (s, 2H), 4.47 (br, 1H), 6.97 (s, 1H), 7.54 (d, 2H), 7.81-7.84 (m, 1H), 8.16 (d, 2H), 8.77 (d, 1H), 9.16 (d, 1H), 9.66 (s, 1H); MS (ESI, m / z): 438.2 [M+H] +

[0344] Example 172. 1-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)ethyl 2,2,2-trifluoroacetate The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 1-(piperidin-4-yl)ethyl 2,2,2-trifluoroacetate was used (Scheme 1, General Procedure A). 1 H NMR (600 MHz, CD3OD) δ [ppm] = 1.20 (d, 3H), 1.29-1.44 (m, 4H), 1.66 (br, 1H), 3.05 (br, 4H), 3.53-3.59 (m, 1H), 7.26 (s, 1H), 7.54 (d, MS (ESI, m / z): 491.1 [M+H] +

[0345] Example 173. 6-(4-chlorophenyl)-N-(1-methylpiperidin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-amine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 1-methylpiperidin-3-amine was used (Scheme 1, General Procedure A). 1H NMR (600 MHz, CD3OD) δ [ppm] = 1.61-1.71 (m, 1H), 1.94-2.07 (m, 2H), 2.14-2.26 (m, 2H), 2.79 (t, 1H), 2.96 (s, 3H), 3.57-3.62 (m, 1H), 3.88-3.93 (m, 1H), 4.62 (br, 1H), 7.00 (s, 1H), 7.55 (d, 2H), 7.97-8.00 (m, 1H), 8.17 (d, 2H), 8.86 (d, 1H), 9.38 (d, 1H), 9.79 (s, 1H); MS (ESI, m / z): 380.2 [M+H] +

[0346] Example 174 (1S,2R)-2-((6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol Scheme for preparing the compound of Example 174 [ka]

[0347] Intermediate 8. Methyl 1-methyl-1H-pyrazole-4-carbimidate 1-Methyl-1H-pyrazole-4-carbonitrile (3.0 g, 28.04 mmol) was suspended in a hydrogen chloride-methanol solution (4 M HCl gas in MeOH (30 mL)), and the resulting suspension was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1; V / V) to give 1.7 g of the title compound. MS (ESI, m / z): 140.1 [M+H] +

[0348] Intermediate 9. 1-Methyl-1H-pyrazole-4-carboximidamide Methyl 1-methyl-1H-pyrazole-4-carbimidate (2.7 g, 19.4 mmol) was dissolved in ammonia-MeOH solution (30 mL) (7.0 M NH in MeOH), and the resulting solution was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, and the residue was purified by reverse-phase column chromatography (HO / MeOH = 10 / 1; V / V) to give 1.8 g of the title compound as a white solid. MS (ESI, m / z): 125.1 [M+H] +

[0349] Intermediate 10. Methyl 3-(4-chlorophenyl)-3-oxopropanoate To a solution of 1-(4-chlorophenyl)ethan-1-one (2.4 g, 15.5 mmol) in tetrahydrofuran (25 mL) was added sodium hydride (60%, 0.62 g, 15.5 mmol) at room temperature. To this reaction solution, a solution of dimethyl carbonate (0.7 g, 7.76 mmol) in tetrahydrofuran (5 mL) was added over 5 minutes. The reaction solution was heated at 70 °C for 2 hours. The reaction solution was cooled to room temperature and quenched with saturated aqueous ammonium chloride. The reaction solution was acidified to pH 6.0, and the residue was extracted with dichloromethane (20 mL × 3) and dried over anhydrous sodium sulfate. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 20 / 1; V / V) to give 2.3 g of the title compound as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 3.77 (s, 1H), 3.83 (s, 3H), 4.03 (s, 1H), 5.73 (s, 1H), 7.68 (d, J = 8.3 Hz, 2H), 7.76 (d, J = 8.2 Hz, MS (ESI, m / z): 213.1 [M+H] +

[0350] Intermediate 11. 6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ol To a solution of methyl 3-(4-chlorophenyl)-3-oxopropanoate (1.7 g, 8.13 mmol) in MeOH (20 mL) was added 1-methyl-1H-pyrazole-4-carboximidamide (1.0 g, 8.13 mmol) and sodium methoxide (527 mg, 9.576 mmol) at room temperature. The reaction mixture was heated at 80° C. under a nitrogen atmosphere for 16 hours. The residue was cooled to room temperature and acidified to pH 6.0. A white solid was formed. The solid was collected by filtration and dried under reduced pressure to give 1.1 g of the title compound as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 3.93 (s, 3H), 6.85 (s, 1H), 7.85 (d, J = 8.3 Hz, 2H), 8.29 (s, 1H), 8.59 (s, 1H), 8.36 (d, J = 8.1 Hz, 2H), 12.70 (s, 1H); MS (ESI, m / z): 287.1 [M+H] +

[0351] Intermediate 12. 4-Chloro-6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine A solution of 6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ol (1.0 g, 3.43 mmol) in phosphorus oxychloride (10 mL) was heated to reflux for 13 hours. The mixture was concentrated under reduced pressure. The residue was poured into water, extracted with EtOAc (20 mL x 2), washed with brine, dried, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 10 / 1; V / V) to give 950 mg of the title compound. 1 MS (ESI, m / z): 305.1 [M+H] +

[0352] Example 174 (1S,2R)-2-((6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol To a solution of 4-chloro-6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine (28 mg, 0.09 mmol) in tetrahydrofuran (4 mL) was added triethylamine (0.2 mL, 1.43 mmol) at room temperature, followed by (1S,2R)-2-aminocyclopentan-1-ol (20 mg, 0.20 mmol). The reaction was heated in a sealed tube at 120° C. for 4 hours and cooled to room temperature. The residue was filtered, concentrated under reduced pressure, and separated by preparative HPLC to give 15 mg of the title compound. 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.95 (br, 1H), 2.05 (br, 1H), 3.41 (br, 3H), 3.49 (br, 3H), 4.03 (s, 3H), 6.98 (s, 1H), 7.67 (d, 2H), 7.90 (d, 2H), 8.33 (s, 1H), 8.59 (s, 1H); MS (ESI, m / z): 370.1 [M+H] +

[0353] Example 175 (R)-1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperidin-3-ol The title compound was obtained in the same manner as in Example 174 except for using (R)-piperidin-3-ol (Scheme 2, General Procedure B). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.69 (br, 2H), 1.77 (br, 2H), 1.99 (br, 1H), 2.03 (d, 2H), 3.89 (br, 1H), 3.93 (br, 2H), 4.01 (s, 3H), 7.08 (s, 1H), 7.64 (d, 2H), 7.88 (d, 2H), 8.32 (s, 1H), 8.58 (s, 1H); MS (ESI, m / z): 370.1 [M+H] +

[0354] Example 176. 1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperidin-4-ol The title compound was obtained in the same manner as in Example 174, except that piperidin-4-ol was used (Scheme 2, General Procedure B). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.63-1.72 (m, 2H), 2.01-2.06 (m, 2H), 3.78 (br, 2H), 4.01 (s, 3H), 4.01-4.07 (m, 1H), 4.36 (br, 2H), 7.10 (s, 1H), 7.63 (d, 2H), 7.89 (d, 2H), 8.31 (s, 1H), 8.57 (s, 1H); MS (ESI, m / z): 370.1 [M+H] +

[0355] Example 177. (1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperidin-4-yl)methanol The title compound was obtained in the same manner as in Example 174, except that piperidin-4-ylmethanol was used (Scheme 2, General Procedure B). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.30-1.40 (m, 4H), 1.89-2.04 (m, 4H), 3.21-3.28 (m, 1H), 3.48 (d, 2H), 4.01 (s, 3H), 7.08 (s, 1H), 7.64 (d, 2H), 7.88 (d, 2H), 8.30 (s, 1H), 8.56 (s, 1H); MS (ESI, m / z): 384.2 [M+H] +

[0356] Example 178. 2-(1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperidin-4-yl)ethan-1-ol The title compound was obtained in the same manner as in Example 174, except that 2-(piperidin-4-yl)ethan-1-ol was used (Scheme 2, General Procedure B). 1H NMR (400 MHz, CD3OD) δ [ppm] = 1.28-1.37 (m, 4H), 1.55 (q, 2H), 1.91-2.00 (m, 4H), 3.25 (br, 1H), 3.67 (t, 2H), 4.01 (s, 3H), 7.08 (s, 1H), 7.64 (d, 2H), 7.87 (d, 2H), 8.31 (s, 1H), 8.58 (s, 1H); MS (ESI, m / z): 398.2 [M+H] +

[0357] Example 179. 3-(1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperidin-4-yl)propan-1-ol The title compound was obtained in the same manner as in Example 174, except that 3-(piperidin-4-yl)propan-1-ol was used (Scheme 2, General Procedure B). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.23-1.41 (m, 4H), 1.57-1.65 (m, 2H), 1.69-1.80 (m, 1H), 1.98 (d, 2H), 3.21 (t, 2H), 3.57 (t, 2H), 4.00 (s, 3H), 4.83 (br, 2H), 7.05 (s, 1H), 7.63 (d, 2H), 7.88 (d, 2H), 8.29 (s, 1H), 8.55 (s, 1H); MS (ESI, m / z): 412.2 [M+H] +

[0358] Example 180. 4-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-6-(4-methylpiperidin-1-yl)pyrimidine The title compound was obtained in the same manner as in Example 174, except that 4-methylpiperidine was used (Scheme 2, General Procedure B). 1H NMR (400 MHz, CD3OD) δ [ppm] = 1.03 (d, 3H), 1.23-1.34 (m, 2H), 1.82-1.89 (m, 1H), 1.92 (d, 2H), 3.24 (br, 2H), 4.01 (s, 3H), 4.83 (br, MS (ESI, m / z): 368.2 [M+H] +

[0359] Example 181. 4-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-6-(4-methylpiperazin-1-yl)pyrimidine The title compound was obtained in the same manner as in Example 174 except for using 1-methylpiperazine (Scheme 2, General Procedure B). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 3.00 (t, 3H), 3.59 (br, 8H), 4.01 (s, 3H), 7.22 (s, 1H), 7.63 (d, 2H), 7.95 (d, 2H), 8.33 (s, 1H), 8.59 (s, 1H); MS (ESI, m / z): 369.2 [M+H] +

[0360] Example 182. 2-(4-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperazin-1-yl)ethan-1-ol The title compound was obtained in the same manner as in Example 174 except for using 2-(piperazin-1-yl)ethan-1-ol (Scheme 2, General Procedure B). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 3.39 (t, 2H), 3.60 (br, 4H), 3.96 (t, 2H), 4.01 (s, 3H), 4.34 (br, 4H), 7.22 (s, 1H), 7.63 (d, 2H), 7.96 (d, 2H), 8.33 (s, 1H), 8.59 (s, 1H); MS (ESI, m / z): 399.2 [M+H] +

[0361] Example 183 (S)-1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)pyrrolidin-3-ol The title compound was obtained in the same manner as in Example 174 except for using (S)-pyrrolidin-3-ol (Scheme 2, General Procedure B). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 2.10-2.30 (m, 3H), 3.82 (br, 2H), 4.01 (s, 3H), 4.03 (br, 1H), 4.63 (d, 1H), 6.83 (s, 1H), 7.65 (d, 2H), 7.90 (d, 2H), 8.30 (s, 1H), 8.55 (s, 1H); MS (ESI, m / z): 356.1 [M+H] +

[0362] Example 184. 1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperidine-4-carbonitrile The title compound was obtained in the same manner as in Example 174, except that piperidine-4-carbonitrile was used (Scheme 2, General Procedure B). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.93-2.01 (m, 2H), 2.11-2.18 (m, 2H), 3.19-3.25 (m, 1H), 3.84-3.90 (m, 2H), 4.01 (s, 3H), 4.31 (br, MS (ESI, m / z): 379.1 [M+H] +

[0363] Example 185. (R)-(1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperidin-3-yl)methanol The title compound was obtained in the same manner as in Example 174 except for using (R)-piperidin-3-ylmethanol (Scheme 2, General Procedure B). 1H NMR (400 MHz, CD3OD) δ [ppm] = 1.44-1.52 (m, 1H), 1.62-1.71 (m, 1H), 1.87 (br, 1H), 1.93 (d, 2H), 3.18 (br, 1H), 3.39 (t, 1H), 3.48-3.52 (m, 1H), 3.58-3.62 (m, 1H), 4.01 (s, 3H), 4.59 (br, 2H), 7.08 (s, 1H), 7.63 (d, 2H), 7.88 (d, 2H), 8.31 (s, 1H), 8.57 (s, 1H); MS (ESI, m / z): 384.2 [M+H] +

[0364] Example 186. (R)-1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)pyrrolidin-3-ol The title compound was obtained in the same manner as in Example 174 except for using (R)-pyrrolidin-3-ol (Scheme 2, General Procedure B). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 2.10-2.30 (m, 3H), 3.82 (br, 2H), 4.01 (s, 3H), 4.03 (br, 1H), 4.63 (d, 1H), 6.83 (s, 1H), 7.65 (d, 2H), 7.90 (d, 2H), 8.30 (s, 1H), 8.55 (s, 1H); MS (ESI, m / z): 356.1 [M+H] +

[0365] Example 187 (1S,3R)-3-((6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol The title compound was obtained in the same manner as in Example 174 except for using (1S,3R)-3-aminocyclopentan-1-ol (Scheme 2, General Procedure B). 1H NMR (400 MHz, CD3OD) δ [ppm] = 1.83-1.94 (m, 1H), 3.43 (br, 6H), 4.02 (s, 3H), 4.37 (br, 1H), 6.97 (s, 1H), 7.65 (d, 2H), 7.88 (d, 2H), 8.32 (s, 1H), 8.58 (s, 1H); MS (ESI, m / z): 370.1 [M+H] +

[0366] Example 188 (R)-2-((6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)butan-1-ol The title compound was obtained in the same manner as in Example 174 except for using (R)-2-aminobutan-1-ol (Scheme 2, General Procedure B). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.03 (t, 3H), 1.59-1.68 (m, 2H), 1.78-1.86 (m, 1H), 3.69-3.73 (m, 2H), 4.02 (s, 3H), 6.97 (s, 1H), 7.65 (d, 2H), 7.89 (d, 2H), 8.32 (s, 1H), 8.56 (s, 1H); MS (ESI, m / z): 358.1 [M+H] +

[0367] Example 189. trans-4-((6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclohexan-1-ol The title compound was obtained in the same manner as in Example 174 except for using trans-4-aminocyclohexan-1-ol (Scheme 2, General Procedure B). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.46-1.52 (m, 2H), 2.01-2.05 (m, 2H), 2.13 (br, 1H), 3.43 (br, 4H), 3.63 (br, 1H), 4.02 (s, 3H), 6.97 (s, MS (ESI, m / z): 384.2 [M+H] +

[0368] Example 190. 7-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)octahydro-2H-pyrano[2,3-c]pyridine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that octahydro-2H-pyrano[2,3-c]pyridine was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.29-1.35 (m, 2H), 1.54 (d, 1H), 1.72-1.80 (m, 2H), 1.85 (d, 1H), 1.95 (d, 1H), 2.10-2.20 (m, 1H), 2.98-3.08 (m, 2H), 3.20 (d, 1H), 3.53 (t, 2H), 3.92 (d, 1H), 7.17 (s, 1H), 7.46 (d, 2H), 8.06-8.09 (m, 1H), 8.11 (d, 2H), 8.87 (d, 1H), 9.37 (d, 1H), 9.63 (s, 1H); MS (ESI, m / z): 407.2 [M+H] +

[0369] Example 191. 7-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)octahydro-2H-pyrano[2,3-c]pyridin-4-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that octahydro-2H-pyrano[2,3-c]pyridin-4-ol was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 1.56-1.60 (m, 1H), 1.66-1.74 (m, 1H), 1.77-1.83 (m, 1H), 1.88-1.92 (m, 1H), 1.94-2.04 (m, 1H), 2.14-2.21 (m, 1H), 2.99-3.11 (m, 1H), 3.18-3.27 (m, 1H), 3.51 (t, 1H), 3.61-3.73 (m, 1H), 3.78-3.86 (m, 1H), 3.88-4.00 (m, 2H), 7.23 (s, 1H), 7.50 (d, 2H), 8.12-8.19 (m, 3H), 8.91 (d, 1H), 9.47 (d, 1H), 9.69 (s, 1H); MS (ESI, m / z): 423.2 [M+H] +

[0370] Example 192 (2R,3R)-3-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)pentan-2-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that (2R,3R)-3-aminopentan-2-ol was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.02 (t, 3H), 1.21 (d, 3H), 1.58-1.68 (m, 2H), 1.79-1.85 (m, 1H), 2.01-2.05 (m, 1H), 4.00 (br, 1H), MS (ESI, m / z): 369.1 [M+H] +

[0371] Example 193. 6-(4-chlorophenyl)-N-((1-methylpiperidin-4-yl)methyl)-2-(pyridin-3-yl)pyrimidin-4-amine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that (1-methylpiperidin-4-yl)methanamine was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 1.53-1.66 (m, 2H), 1.94-2.08 (m, 2H), 2.13 (d, 2H), 2.86 (s, 3H), 3.01 (t, 1H), 3.13 (t, 1H), 3.57 (br, 2H), 3.81-3.93 (m, 1H), 7.00 (s, 1H), 7.54 (d, 2H), 8.12-8.16 (m, 1H), 8.24 (d, 2H), 8.92 (d, 1H), 9.49 (d, 1H), 9.76 (s, 1H); MS (ESI, m / z): 394.2 [M+H] +

[0372] Example 194 (R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that (R)-pyrrolidin-3-ol was used (Scheme 1, General Procedure A). 1 H NMR: (400 MHz, CD3OD) δ [ppm] = 2.17 (br, 2H), 3.70 (br, 2H), 3.86 (br, 2H), 4.59 (br, 1H), 6.95 (s, 1H), 7.52 (d, 2H), 8.07-8.11 (m, MS (ESI, m / z): 353.1 [M+H] +

[0373] Example 195. (S)-6-(4-chlorophenyl)-N-(2-(methoxymethyl)pyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-amine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that (S)-2-(methoxymethyl)pyrrolidin-1-amine was used (Scheme 1, General Procedure A). 1H NMR: (400 MHz, CD3OD) δ [ppm] = 1.60 (br, 1H), 1.80-1.87 (m, 1H), 1.89-1.97 (m, 1H), 2.02-2.10 (m, 1H), 2.17-2.21 (m, 1H), 2.82-2.89 (m, 1H), 3.07 (br, 1H), 3.24 (s, 3H), 3.44 (t, 2H), 7.42 (s, 1H), 7.56 (d, 2H), 8.08-8.12 (m, 1H), 8.21 (d, 2H), 8.89 (d, 1H), 9.45 (d, 1H), 9.71 (s, 1H); MS (ESI, m / z): 396.2 [M+H] +

[0374] Example 196. (S)-4-(4-chlorophenyl)-6-(3-fluoropyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that (S)-3-fluoropyrrolidine was used (Scheme 1, General Procedure A). 1 H NMR: (400 MHz, CD3OD) δ [ppm] = 2.24 (br, 2H), 3.79 (br, 2H), 3.87 (br, 2H), 4.17 (br, 1H), 6.98 (s, 1H), 7.53 (d, 2H), 8.03-8.06 (m, 1H), 8.23 ​​(d, 2H), 8.86 (d, 1H), 9.40 (d, 1H), 9.71 (s, 1H); MS (ESI, m / z): 355.1 [M+H] +

[0375] Example 197. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 2-(trifluoromethyl)pyrrolidine was used (Scheme 1, General Procedure A). 1H NMR: (400 MHz, CD3OD) δ [ppm] = 2.26 (br, 2H), 2.32 (br, 2H), 3.74 (br, 2H), 3.89 (br, 1H), 7.20 (s, 1H), 7.56 (d, 2H), 8.02-8.06 (m, MS (ESI, m / z): 405.1 [M+H] +

[0376] Example 198. 4-(4-chlorophenyl)-6-(3,3-difluoropyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that 3,3-difluoropyrrolidine was used (Scheme 1, General Procedure A). 1 H NMR: (400 MHz, CD3OD) δ [ppm] = 2.58-2.68 (m, 2H), 3.95 (br, 2H), 4.11 (br, 2H), 7.06 (s, 1H), 7.55 (d, 2H), 8.04-8.07 (m, 1H), 8.28 (d, 2H), 8.87 (d, 1H), 9.44 (d, 1H), 9.75 (s, 1H); MS (ESI, m / z): 373.1 [M+H] +

[0377] Example 199. 4-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)morpholine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 4-(pyrrolidin-3-yl)morpholine was used (Scheme 1, General Procedure A). 1H NMR: (400 MHz, CD3OD) δ [ppm] = 2.44 (br, 1H), 2.68 (br, 1H), 3.52 (br, 4H), 3.70 (br, 2H), 3.99 (br, 5H), 4.14 (br, 2H), 7.06 (s, 1H), 7.54 (d, 2H), 8.16-8.19 (m, 1H), 8.25 (d, 2H), 8.94 (d, 1H), 9.57 (d, 1H), 9.80 (s, 1H); MS (ESI, m / z): 422.2 [M+H] +

[0378] Example 200. 5-(((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)methyl)pyrrolidin-2-one The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 5-(aminomethyl)pyrrolidin-2-one was used (Scheme 1, General Procedure A). 1 H NMR: (400 MHz, CD3OD) δ [ppm] = 2.00 (br, 2H), 2.32-2.38 (m, 2H), 3.73 (br, 2H), 4.04 (br, 1H), 7.01 (s, 1H), 7.54 (d, 2H), 8.07-8.10 (m, 1H), 8.17 (d, 2H), 8.88 (d, 1H), 9.46 (d, 1H), 9.73 (s, 1H); MS (ESI, m / z): 380.1 [M+H] +

[0379] Example 201. trans-6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(4-(pyrrolidin-1-yl)tetrahydrofuran-3-yl)pyrimidin-4-amine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that trans-4-(pyrrolidin-1-yl)tetrahydrofuran-3-amine was used (Scheme 1, General Procedure A). 1H NMR: (400 MHz, CD3OD) δ [ppm] = 2.09 (br, 8H), 3.74-3.78 (m, 1H), 3.96-3.99 (m, 1H), 4.19-4.21 (m, 2H), 4.43-4.47 (m, 1H), 5.31 (br, MS (ESI, m / z): 422.2 [M+H] +

[0380] Example 202. 6-(4-chlorophenyl)-N-((3S,4S)-4-methoxy-1-methylpyrrolidin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-amine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that (3S,4S)-4-methoxy-1-methylpyrrolidin-3-amine was used (Scheme 1, General Procedure A). 1 H NMR: (400 MHz, CD3OD) δ [ppm] = 1.59 (br, 1H), 1.90 (br, 1H), 2.02 (br, 1H), 3.06 (s, 3H), 3.55 (s, 3H), 3.72 (br, 1H), 3.84 (br, 2H), 7.10 (s, 1H), 7.53 (d, 2H), 8.18 (d, 2H), 8.19-8.27 (m, 1H), 8.95 (d, 1H), 9.55 (d, 1H), 9.78 (s, 1H); MS (ESI, m / z): 396.2 [M+H] +

[0381] Example 203 (R)-6-(4-chlorophenyl)-N-(piperidin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-amine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 54, except that (R)-tert-butyl 3-aminopiperidine-1-carboxylate was used (Scheme 1, General Procedure A). 1H NMR: (400 MHz, CD3OD) δ [ppm] = 1.77-1.83 (m, 1H), 1.95-2.04 (m, 1H), 2.10-2.15 (m, 1H), 2.17-2.23 (m, 1H), 2.96-3.01 (m, 1H), 3.04-3.11 (m, 1H), 3.37-3.43 (m, 1H), 3.69-3.73 (m, 1H), 4.56 (br, 1H), 7.03 (s, 1H), 7.54 (d, 2H), 8.02-8.06 (m, 1H), 8.17 (d, 2H), 8.88 (d, 1H), 9.44 (d, 1H), 9.82 (s, 1H); MS (ESI, m / z): 366.1 [M+H] +

[0382] Example 204. 6-(4-chlorophenyl)-N-(piperidin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-amine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 54, except that tert-butyl 3-aminopiperidine-1-carboxylate was used (Scheme 1, General Procedure A). 1 H NMR: (400 MHz, CD3OD) δ [ppm] = 1.77-1.83 (m, 1H), 1.95-2.04 (m, 1H), 2.10-2.15 (m, 1H), 2.17-2.23 (m, 1H), 2.96-3.01 (m, 1H), 3.04-3.11 (m, 1H), 3.37-3.43 (m, 1H), 3.69-3.73 (m, 1H), 4.56 (br, 1H), 7.03 (s, 1H), 7.54 (d, 2H), 8.02-8.06 (m, 1H), 8.17 (d, 2H), 8.88 (d, 1H), 9.44 (d, 1H), 9.82 (s, 1H); MS (ESI, m / z): 366.1 [M+H] +

[0383] Example 205. 6-(4-chlorophenyl)-N-((3R,4R)-3-fluoropiperidin-4-yl)-2-(pyridin-3-yl)pyrimidin-4-amine The title compound was obtained by preparative HPLC separation in the same manner as in Example 54, except that tert-butyl (3R,4R)-4-amino-3-fluoropiperidine-1-carboxylate was used (Scheme 1, General Procedure A). 1 H NMR: (400 MHz, CD3OD) δ [ppm] = 1.60 (br, 1H), 1.92 (br, 1H), 2.03 (br, 1H), 3.79 (br, 5H), 7.08 (s, 1H), 7.55 (d, 2H), 8.08-8.11 (m, MS (ESI, m / z): 384.1 [M+H] +

[0384] Example 206 (S)-6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(pyrrolidin-3-ylmethyl)pyrimidin-4-amine The title compound was obtained by preparative HPLC separation in the same manner as in Example 54, except that (R)-tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate was used (Scheme 1, General Procedure A). 1 H NMR: (400 MHz, CD3OD) δ [ppm] = 1.85-1.95 (m, 2H), 2.24-2.32 (m, 1H), 2.80-2.87 (m, 1H), 3.10-3.15 (m, 1H), 3.41-3.48 (m, 1H), 3.50-3.55 (m, 1H), 3.75 (br, 2H), 7.01 (s, 1H), 7.54 (d, 2H), 8.09-8.13 (m, 1H), 8.17 (d, 2H), 8.91 (d, 1H), 9.48 (d, 1H), 9.77 (s, 1H); MS (ESI, m / z): 366.1 [M+H] +

[0385] Example 207. (2R,4R)-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)pyrrolidine-2-carboxylate methyl The title compound was obtained by preparative HPLC separation in the same manner as in Example 54, except that 1-(tert-butyl)2-methyl (2R,4R)-4-aminopyrrolidine-1,2-dicarboxylate was used (Scheme 1, General Procedure A). MS (ESI, m / z): 410.1 [M+H] +

[0386] Example 208 (2R,4S)-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)pyrrolidine-2-carboxylic acid The title compound was obtained by preparative HPLC separation in the same manner as in Example 54, except that (2R,4S)-4-amino-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid was used (Scheme 1, General Procedure A). 1 H NMR: (400 MHz, CD3OD) δ [ppm] = 1.61 (br, 2H), 2.04 (br, 2H), 2.20 (t, 1H), 3.35 (br, 1H), 7.01 (s, 1H), 7.55 (d, 2H), 7.78-7.81 (m, 1H), 8.18 (d, 2H), 8.76 (d, 1H), 9.12 (d, 1H), 9.66 (s, 1H); MS (ESI, m / z): 396.1 [M+H] +

[0387] Example 209. trans-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)-1-isopropylpyrrolidin-3-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that trans-4-amino-1-isopropylpyrrolidin-3-ol was used (Scheme 1, General Procedure A). 1H NMR: (400 MHz, CD3OD) δ [ppm] = 1.43 (t, 6H), 1.61 (br, 1H), 1.90 (br, 1H), 2.02 (br, 1H), 2.19 (t, 1H), 3.55 (br, 1H), 3.72 (br, 1H), MS (ESI, m / z): 410.2 [M+H] +

[0388] Example 210. (R)-4-(3-(chloromethyl)pyrrolidin-1-yl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that (R)-3-(chloromethyl)pyrrolidine was used (Scheme 1, General Procedure A). 1 H NMR: (400 MHz, CD3OD) δ [ppm] = 1.98 (br, 1H), 2.28 (br, 1H), 2.79 (br, 1H), 3.54 (br, 1H), 3.68-3.78 (m, 4H), 4.02 (br, 1H), 6.88 (s, MS (ESI, m / z): 385.1 [M+H] +

[0389] Example 211. (S)-4-(3-(chloromethyl)pyrrolidin-1-yl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that (S)-3-(chloromethyl)pyrrolidine was used (Scheme 1, General Procedure A). 1H NMR: (400 MHz, CD3OD) δ [ppm] = 1.98 (br, 1H), 2.28 (br, 1H), 2.79 (br, 1H), 3.54 (br, 1H), 3.68-3.78 (m, 4H), 4.02 (br, 1H), 6.88 (s, MS (ESI, m / z): 385.1 [M+H] +

[0390] Example 212. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidine-3-carbonitrile The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that pyrrolidine-3-carbonitrile was used (Scheme 1, General Procedure A). 1 H NMR: (400 MHz, CD3OD) δ [ppm] = 2.44 (br, 1H), 2.53 (br, 1H), 3.57 (br, 1H), 3.84 (br, 2H), 4.06 (br, 2H), 7.06 (s, 1H), 7.55 (d, 2H), 8.08-8.12 (m, 1H), 8.27 (d, 2H), 8.89 (d, 1H), 9.49 (d, 1H), 9.76 (s, 1H); MS (ESI, m / z): 362.1 [M+H] +

[0391] Example 213 (R)-1-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)butan-2-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that (R)-1-aminobutan-2-ol was used (Scheme 1, General Procedure A). 1H NMR: (400 MHz, CD3OD) δ [ppm] = 1.05 (t, 3H), 1.48-1.59 (m, 1H), 1.61-1.70 (m, 1H), 3.55 (br, 1H), 3.72 (br, 1H), 3.76 (br, 1H), 6.99 (s, 1H), 7.51 (d, 2H), 8.09-8.13 (m, 3H), 8.90 (d, 1H), 9.44 (d, 1H), 9.69 (s, 1H); MS (ESI, m / z): 355.1 [M+H] +

[0392] Example 214 (1R,3S)-3-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that (1R,3S)-3-aminocyclopentan-1-ol was used (Scheme 1, General Procedure A). 1 H NMR: (400 MHz, CD3OD) δ [ppm] = 1.60-1.66 (m, 1H), 1.81-1.95 (m, 4H), 2.17-2.23 (m, 1H), 2.43-2.50 (m, 1H), 4.34-4.38 (m, 1H), 4.62 MS (ESI, m / z): 367.1 [M+H] +

[0393] Example 215. cis-(4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexyl)methanol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that cis-4-aminocyclohexan-1-ol was used (Scheme 1, General Procedure A). 1H NMR: (400 MHz, CD3OD) δ [ppm] = 1.76-1.83 (m, 4H), 1.84-1.87 (m, 4H), 2.02 (br, 1H), 3.92 (br, 1H), 4.24 (br, 1H), 6.96 (s, 1H), 7.53 (d, 2H), 8.01-8.05 (m, 1H), 8.12 (d, 2H), 8.86 (d, 1H), 9.34 (d, 1H), 9.67 (s, 1H); MS (ESI, m / z): 381.1 [M+H] +

[0394] Example 216. cis-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexan-1-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that cis-(4-aminocyclohexyl)methanol was used (Scheme 1, General Procedure A). 1 H NMR: (400 MHz, CD3OD) δ [ppm] = 1.70-1.84 (m, 4H), 1.85-1.95 (m, 4H), 1.98-2.05 (m, 1H), 3.71-3.74 (m, 1H), 3.84-8.37 (m, 1H), 4.46 (br, 1H), 7.04 (s, 1H), 7.55 (d, 2H), 8.09-8.15 (m, 3H), 8.90 (d, 1H), 9.43 (d, 1H), 9.69 (s, 1H); MS (ESI, m / z): 395.2 [M+H] +

[0395] Example 217. trans-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexan-1-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that trans-(4-aminocyclohexyl)methanol was used (Scheme 1, General Procedure A). 1H NMR: (400 MHz, CD3OD) δ [ppm] = 1.70-1.84 (m, 4H), 1.85-1.95 (m, 4H), 1.98-2.05 (m, 1H), 3.71-3.74 (m, 1H), 3.84-8.37 (m, 1H), 4.46 (br, 1H), 7.04 (s, 1H), 7.55 (d, 2H), 8.09-8.15 (m, 3H), 8.90 (d, 1H), 9.43 (d, 1H), 9.69 (s, 1H); MS (ESI, m / z): 395.2 [M+H] +

[0396] Example 218. 4-(4-chlorophenyl)-6-(4-(2-methoxyethyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 1-(2-methoxyethyl)piperazine was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 9.83 (d, J = 2.0, 0.8 Hz, 1H), 9.59 (dd, J = 8.2, 2.0, 1.5 Hz, 1H), 8.95 (d, J = 5.7, 1.5, 0.7 Hz, 1H), 8.28 (d, 2H), 8.19 (dd, J = 8.2, 5.7, 0.7 Hz, 1H), 7.54 (d, 2H), 7.44 (s, 1H), 3.82-3.77 (m, 4H), 3.77-3.50 (m, 4H), 3.49-3.43 (m, 7H); MS (ESI, m / z): 410.2 [M+H] +

[0397] Example 219 (3S,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that (3S,4R)-3-fluoropiperidin-4-ol was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 9.74 (d, J = 1.7, 0.8 Hz, 1H), 9.52 (dd, J = 8.2, 1.9, 1.5 Hz, 1H), 8.92 (dd, J = 5.7, 1.5, 0.8 Hz, 1H), 8.21 (dd, 2H), 8.19-8.14 (m, 1H), 7.51 (d, 2H), 7.30 (s, 1H), 4.56-4.47 (m, 1H), 4.47-4.33 (m, 1H), 4.17-4.06 (m, 1H), 4.04-3.94 (m, 1H), 3.94-3.82 (m, MS (ESI, m / z): 385.1 [M+H] +

[0398] Example 220 (3R,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that (3R,4S)-3-fluoropiperidin-4-ol was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 9.74 (d, J = 1.7, 0.8 Hz, 1H), 9.52 (dd, J = 8.2, 1.9, 1.5 Hz, 1H), 8.92 (dd, J = 5.7, 1.5, 0.8 Hz, 1H), 8.21 (dd, 2H), 8.19-8.14 (m, 1H), 7.51 (d, 2H), 7.30 (s, 1H), 4.56-4.47 (m, 1H), 4.47-4.33 (m, 1H), 4.17-4.06 (m, 1H), 4.04-3.94 (m, 1H), 3.94-3.82 (m, MS (ESI, m / z): 385.1 [M+H] +

[0399] Example 221 (3R,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that (3R,4R)-3-fluoropiperidin-4-ol was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 9.74 (d, J = 1.7, 0.8 Hz, 1H), 9.52 (dd, J = 8.2, 1.9, 1.5 Hz, 1H), 8.92 (dd, J = 5.7, 1.5, 0.8 Hz, 1H), 8.21 (dd, 2H), 8.19-8.14 (m, 1H), 7.51 (d, 2H), 7.30 (s, 1H), 4.56-4.47 (m, 1H), 4.47-4.33 (m, 1H), 4.17-4.06 (m, 1H), 4.04-3.94 (m, 1H), 3.94-3.82 (m, MS (ESI, m / z): 385.1 [M+H] +

[0400] Example 222 (3S,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that (3S,4S)-3-fluoropiperidin-4-ol was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 9.74 (d, J = 1.7, 0.8 Hz, 1H), 9.52 (dd, J = 8.2, 1.9, 1.5 Hz, 1H), 8.92 (dd, J = 5.7, 1.5, 0.8 Hz, 1H), 8.21 (dd, 2H), 8.19-8.14 (m, 1H), 7.51 (d, 2H), 7.30 (s, 1H), 4.56-4.47 (m, 1H), 4.47-4.33 (m, 1H), 4.17-4.06 (m, 1H), 4.04-3.94 (m, 1H), 3.94-3.82 (m, MS (ESI, m / z): 385.1 [M+H] +

[0401] Example 223. 1-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-2-hydroxyethan-1-one The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 2-hydroxy-1-(piperazin-1-yl)ethan-1-one was used (Scheme 1. General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 9.73 (d, J = 1.3 Hz, 1H), 9.39 (dd, J = 8.1, 1.8 Hz, 1H), 8.85 (dd, J = 5.5, 1.5 Hz, 1H), 8.26 (d, 2H), 8.02 MS (ESI, m / z): 410.1 [M+H] +

[0402] Example 224. 2-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)propan-1-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 2-(piperazin-1-yl)propan-1-ol was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 9.83 (s, 1H), 9.59 (d, 1H), 8.95 (dd, J = 5.6, 1.5, 0.7 Hz, 1H), 8.29 (d, 2H), 8.19 (dd, J = 8.2, 5.7, 0.8 Hz, 1H), 7.54 (d, 2H), 7.45 (s, 1H), 3.96 (d, J = 3.7 Hz, 1H), 3.92-3.79 (m, 2H), 3.80-3.70 (m, 2H), 3.60-3.50 (m, 2H), 3.45-3.35 (m, 1H), 2.04-1.74 (m, 3H), 1.42 (d, J = 6.8 Hz, 3H); MS (ESI, m / z): 410.2 [M+H] +

[0403] Example 225. N-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)-2-methoxyacetamide The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 2-methoxy-N-(piperidin-4-yl)acetamide was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 9.75 (s, 1H), 9.52 (dd, J = 8.2, 1.7 Hz, 1H), 8.92 (d, J = 5.6, 1.5, 0.7 Hz, 1H), 8.23 ​​(d, 2H), 8.15 (dd, J = 8.2, 5.7, 0.7 Hz, 1H), 7.53 (d, 2H), 7.31 (s, 1H), 4.85-4.66 (m, 2H), 4.21-4.05 (m, 1H), 3.90 (s, 2H), 3.40 (s, 3H), 3.28-3.15 (m, 2H), 2.04 (d, J = 12.8, 3.7 Hz, 2H), 1.70-1.53 ​​(m, 2H); MS (ESI, m / z): 438.2 [M+H] +

[0404] Example 226 (1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol Scheme for preparing the compound of Example 226 [ka]

[0405] Intermediate 13. (1-(6-chloro-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol To a solution of 4,6-dichloro-2-(pyridin-3-yl)pyrimidine (3.0 g, 13.3 mmol) in DMF (50 mL) was added diisopropylethylamine (4.63 mL, 26.54 mmol) at room temperature, followed by piperidin-4-ylmethanol (2.01 g, 13.27 mmol). The reaction was heated at 70 °C overnight and cooled to room temperature. The reaction was quenched with water and extracted three times with DCM. The organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, hexane / ethyl acetate, gradient) to give 1.0 g of the title compound.

[0406] Example 226 (1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol To a solution of (1-(6-chloro-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol (300 mg, 0.984 mmol), (4-(trifluoromethyl)phenyl)boronic acid (300 mg, 1.580 mmol), and sodium carbonate (300 mg, 2.831 mmol) in tetrahydrofuran / HO (4 / 1) (30 mL) was added Pd(PPh) (60 mg, 0.052 mmol). The mixture was heated at 80 °C for 120 min in a microwave oven, cooled to room temperature, and extracted three times with EtOAc (30 mL). The organic layer was washed with brine, dried over anhydrous MgSO, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, hexane / ethyl acetate, gradient) to give 219 mg of the title compound (Scheme 4, General Procedure D). 1 H NMR (600 MHz, DMSO-d6) δ [ppm] = 9.57 (s, 1H), 8.72 (d, J = 8.0, 2.0 Hz, 1H), 8.69 (dd, J = 4.8, 1.7 Hz, 1H), 8.52 (d, J = 8.1 Hz, 2H), 7.88 (d, J = 8.2 Hz, 2H), 7.54 (dd, J = 7.9, 4.8 Hz, 1H), 7.45 (s, 1H), 4.88-4.58 (m, 2H), 4.53 (t, J = 5.2 Hz, 1H), 3.29 (t, J = 5.7 Hz, 2H), 3.01 (t, J = 12.9 Hz, MS (ESI, m / z): 415.2 [M+H] +

[0407] Example 227 (1-(2-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 226, except that (4-(trifluoromethoxy)phenyl)boronic acid was used (Scheme 4, General Procedure D). 1H NMR (400 MHz, CD3OD) δ [ppm] = 9.60 (s, 1H), 8.96 (d, J = 8.2 Hz, 1H), 8.67 (d, J = 4.9 Hz, 1H), 8.33 (dd, J = 8.9, 3.5 Hz, 2H), 7.68-7.62 (m, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.21 (s, 1H), 3.51-3.44 (m, 2H), 3.27-3.03 (m, 4H), 2.19 (t, J = 7.6 Hz, 0H), 1.99-1.79 (m, 3H), 1.41-1.22 (m, 2H); MS (ESI, m / z): 431.2 [M+H] +

[0408] Example 228 (1-(6-(4-Methoxyphenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol The title compound was obtained by preparative HPLC separation in the same manner as in Example 226, except that (4-methoxyphenyl)boronic acid was used (Scheme 4, General Procedure D). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 9.64 (s, 1H), 9.25 (d, J = 8.1 Hz, 1H), 8.85 (dd, 1H), 8.15 (d, 2H), 8.01-7.96 (m, 1H), 7.21 (s, 1H), 7.10 (dd, J = 8.9, 3.1 Hz, 2H), 4.33 (d, J = 6.5 Hz, 2H), 3.89 (s, 3H), 3.20-3.07 (m, 4H), 2.33-2.15 (m, 1H), 2.01-1.90 (m, 2H), 1.50-1.35 (m, 2H); MS (ESI, m / z): 377.2 [M+H] +

[0409] Example 229 (1-(2-(pyridin-3-yl)-6-(p-tolyl)pyrimidin-4-yl)piperidin-4-yl)methanol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 226, except that p-tolylboronic acid was used (Scheme 4, General Procedure D). 1H NMR (400 MHz, CD3OD) δ [ppm] = 9.66 (s, 1H), 9.31 (d, J = 8.2, 1.8 Hz, 1H), 8.87 (dd, J = 5.5, 1.5, 0.5 Hz, 1H), 8.07 (d, 2H), 8.05-8.00 (m, 1H), 7.37 (d, 2H), 7.25 (s, 1H), 4.89-4.72 (m, 2H), 4.33 (d, J = 6.6 Hz, 2H), 3.23-3.06 (m, 2H), 2.44 (s, 3H), 2.31-2.14 (m, 1H), 1.96 (d, J = 13.4 Hz, 2H), 1.51-1.34 (m, 2H); MS (ESI, m / z): 361.2 [M+H] +

[0410] Example 230 (3R,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidine-3,4-diol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1 except that (3R,4R)-pyrrolidine-3,4-diol was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 9.68 (d, J = 2.1 Hz, 1H), 9.40 (dt, J = 8.2, 1.8 Hz, 1H), 8.87 (d, J = 5.5 Hz, 1H), 8.24-8.16 (m, 2H), 8.06 (dd, J = 8.2, 5.6 Hz, 1H), 7.51 (dd, J = 8.9, 2.2 Hz, 2H), 6.94 (d, J = 8.4 Hz, 1H), 4.36-4.22 (m, 1H), 3.95-3.88 (m, 1H), 3.88-3.79 (m, 1H), 2.10-1.97 (m, 1H), 1.90 (dq, J = 18.0, 10.8, 8.5 Hz, 1H), 1.70-1.41 (m, 1H); MS (ESI, m / z): 367.1 [M+H] +

[0411] Example 231 (3R,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidine-3,4-diol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that (3R,4S)-pyrrolidine-3,4-diol was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 9.68 (d, J = 2.1 Hz, 1H), 9.40 (dt, J = 8.2, 1.8 Hz, 1H), 8.87 (d, J = 5.5 Hz, 1H), 8.24-8.16 (m, 2H), 8.06 (dd, J = 8.2, 5.6 Hz, 1H), 7.51 (dd, J = 8.9, 2.2 Hz, 2H), 6.94 (d, J = 8.4 Hz, 1H), 4.36-4.22 (m, 1H), 3.95-3.88 (m, 1H), 3.88-3.79 (m, 1H), 2.10-1.97 (m, 1H), 1.90 (dq, J = 18.0, 10.8, 8.5 Hz, 1H), 1.70-1.41 (m, 1H); MS (ESI, m / z): 367.1 [M+H] +

[0412] Example 232. 1-(3-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)tetrahydropyrimidin-1(2H)-yl)ethan-1-one The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 1-(tetrahydropyrimidin-1(2H)-yl)ethan-1-one was used (Scheme 1. General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 9.71 (d, J = 6.8 Hz, 1H), 9.38 (d, J = 7.8 Hz, 1H), 8.80 (d, J = 5.0 Hz, 1H), 8.19 (d, J = 8.5 Hz, 2H), 8.06-8.01 (m, 1H), 7.54 (d, J = 8.6 Hz, 2H), 7.03 (s, 1H), 4.04-3.52 (m, 4H), 2.09-1.76 (m, 2H), 1.68-1.48 (m, 2H), 1.29 (s, 3H); MS (ESI, m / z): 394.1 [M+H] +

[0413] Example 233. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)piperidin-3-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 4-(hydroxymethyl)piperidin-3-ol was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 9.67 (s, 1H), 9.40 (dd, J = 8.2, 4.3, 2.5 Hz, 1H), 8.88 (d, 1H), 8.15 (d, 2H), 8.12-8.04 (m, 1H), 7.50 (d, 2H), 7.23 (s, 1H), 3.93-3.78 (m, 1H), 3.78-3.61 (m, 1H), 3.61-3.46 (m, 1H), 3.35 (d, 2H), 3.13-2.98 (m, 1H), 1.97-1.82 (m, 1H), 1.81-1.37 (m, 3H); MS (ESI, m / z): 397.1 [M+H] +

[0414] Example 233. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)piperidin-3-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 4-(hydroxymethyl)piperidin-3-ol was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 9.67 (s, 1H), 9.40 (dd, J = 8.2, 4.3, 2.5 Hz, 1H), 8.88 (d, 1H), 8.15 (d, 2H), 8.12-8.04 (m, 1H), 7.50 (d, 2H), 7.23 (s, 1H), 3.93-3.78 (m, 1H), 3.78-3.61 (m, 1H), 3.61-3.46 (m, 1H), 3.35 (d, 2H), 3.13-2.98 (m, 1H), 1.97-1.82 (m, 1H), 1.81-1.37 (m, 3H); MS (ESI, m / z): 397.1 [M+H] +

[0415] Example 234 (3R,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-fluoropyrrolidin-3-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that (3R,4R)-4-fluoropyrrolidin-3-ol was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 9.66 (s, 1H), 9.40 (d, J = 8.2, 1.7 Hz, 1H), 8.87 (dd, J = 5.7, 1.5 Hz, 1H), 8.17 (d, 2H), 8.07 (dd, 1H), 7.48 (d, 2H), 6.91 (s, 1H), 5.14 (dd, J = 50.2, 15.3 Hz, 1H), 4.57-4.46 (m, 1H), 4.24-3.88 (m, 1H), 3.86-3.70 (m, 1H), 2.13-1.69 (m, 2H); MS (ESI, m / z): 371.1 [M+H] +

[0416] Example 235 (3R,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-fluoropyrrolidin-3-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that (3R,4S)-4-fluoropyrrolidin-3-ol was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 9.66 (s, 1H), 9.40 (d, J = 8.2, 1.7 Hz, 1H), 8.87 (dd, J = 5.7, 1.5 Hz, 1H), 8.17 (d, 2H), 8.07 (dd, 1H), 7.48 (d, 2H), 6.91 (s, 1H), 5.14 (dd, J = 50.2, 15.3 Hz, 1H), 4.57-4.46 (m, 1H), 4.24-3.88 (m, 1H), 3.86-3.70 (m, 1H), 2.13-1.69 (m, 2H); MS (ESI, m / z): 371.1 [M+H] +

[0417] Example 236. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)pyrrolidin-3-ol The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 4-(hydroxymethyl)pyrrolidin-3-ol was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 9.65 (s, 1H), 9.39 (d, J = 8.3, 1.7 Hz, 1H), 8.87 (dd, J = 5.6, 1.6 Hz, 1H), 8.15 (d, J = 8.6, 2.4 Hz, 2H), 8.07 (dd, J = 9.1, 5.7, 3.6 Hz, 1H), 7.48 (dd, J = 8.7, 2.3 Hz, 2H), 6.87 (s, 1H), 4.06-3.77 (m, 1H), 3.77-3.62 (m, 1H), 3.62-3.39 (m, 1H), 2.68-2.38 (m, MS (ESI, m / z): 383.1 [M+H] +

[0418] Example 237. N-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)-2-hydroxypropanamide The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 2-hydroxy-N-(piperidin-4-yl)propanamide was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, CD3OD) δ [ppm] = 9.76 (d, J = 449.8 Hz, 1H), 9.53 (d, J = 1746.2 Hz, 1H), 8.92 (d, J = 5.5 Hz, 1H), 8.24 (d, 2H), 8.15 (dd, J = 8.2, 5.7 Hz, 1H), 7.55 (dd, J = 8.5, 1.6 Hz, 2H), 7.33 (s, 1H), 4.17-3.99 (m, 2H), 3.30-3.20 (m, 4H), 2.11-1.97 (m, 2H), 1.71-1.54 (m, 2H), 1.35 (d, J = 6.8 Hz, 3H); MS (ESI, m / z): 438.2 [M+H] +

[0419] Example 238. N-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)-2-hydroxyacetamide The title compound was obtained by separation by preparative HPLC in the same manner as in Example 1, except that 2-hydroxy-N-(piperidin-4-yl)acetamide was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CD3OD) δ [ppm] = 9.76 (s, 1H), 9.53 (d, 1H), 8.92 (d, J = 5.6 Hz, 1H), 8.25 (d, 2H), 8.15 (dd, J = 8.2, 5.6 Hz, 1H), 7.55 (d, J = 8.6 Hz, 2H), 7.34 (s, 1H), 4.86-4.65 (m, 2H), 4.20-4.07 (m, 1H), 3.99 (s, 2H), 3.29-3.18 (m, 2H), 2.05 (d, J = 12.8 Hz, 2H), 1.71-1.53 ​​(m, 2H); MS (ESI, m / z): 424.2 [M+H] +

[0420] Example 239. 2-((4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)ethan-1-ol The title compound was obtained in the same manner as in Example 1 except for using 2-(piperazin-1-ylsulfonyl)ethan-1-ol (Scheme 1, General Procedure A). 1 H NMR (600 MHz, DMSO-d6) δ [ppm] = 9.59 (s, 1H), 8.75 (dd, J = 8.0, 2.0 Hz, 1H), 8.70 (d, J = 4.7 Hz, 1H), 8.37 (d, J = 8.3 Hz, 2H), 7.61 (d, J = 8.3 Hz, 2H), 7.55 (dd, J = 8.0, 4.8 Hz, 1H), 7.45 (s, 1H), 5.04 (s, 1H), 3.97 (s, 4H), 3.75 (t, J = 6.1 Hz, 2H), 3.31 (d, J = 5.1 Hz, 4H), 3.23 (t, J = 6.1 Hz, 2H); MS (ESI, m / z): 460.1 [M+H] +

[0421] Example 240. (S)-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)methanol The title compound was obtained in the same manner as in Example 1 except for using (S)-pyrrolidin-3-ylmethanol (Scheme 1, General Procedure A). 1 H NMR (400 MHz, CDCl3) δ [ppm] = 9.68 (s, 1H), 8.75 (dd, J = 8.0, 1.9 Hz, 1H), 8.68-8.62 (m, 1H), 8.05 (d, 2H), 7.43 (d, 2H), 7.37 (dd, J = 7.9, 4.8, 0.8 Hz, 1H), 6.55 (s, 1H), 4.10-3.85 (m, 1H), 3.85-3.64 (m, 3H), 3.62-3.40 (m, 2H), 2.72-2.51 (m, 1H), 2.26-2.07 (m, 1H), 1.99-1.76 (m, 1H); MS (ESI, m / z): 367.1 [M+H] +

[0422] Example 241. N-((3R,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-hydroxypyrrolidin-3-yl)acetamide The title compound was obtained in the same manner as in Example 1 except for using N-((3R,4R)-4-hydroxypyrrolidin-3-yl)acetamide (Scheme 1, General Procedure A). 1 H NMR (600 MHz, CD3OD) δ [ppm] = 9.60 (s, 1H), 8.86 (d, J = 7.9 Hz, 1H), 8.66-8.63 (m, 1H), 8.20 (d, 2H), 7.56 (s, 1H), 7.51 (d, 2H), 6.88 (s, 1H), 4.35 (d, J = 28.7 Hz, 2H), 4.14-3.74 (m, 3H), 3.50 (s, 1H), 1.97 (s, 3H); MS (ESI, m / z): 410.1 [M+H] +

[0423] Example 242. Acetic acid (3R,4R)-4-acetamido-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl The title compound was obtained in the same manner as in Example 1 except for using (3R,4R)-4-acetamidopyrrolidin-3-yl acetate (Scheme 1, General Procedure A). 1 H NMR (600 MHz, CD3OD) δ [ppm] = 9.52 (s, 1H), 8.79 (d, J = 7.9 Hz, 1H), 8.60 (s, 1H), 8.15 (d, J = 8.5 Hz, 2H), 7.51 (dd, J = 7.4, 5.0 Hz, MS (ESI, m / z): 452.1 [M+H] +

[0424] Example 243. N-((3R,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-hydroxypyrrolidin-3-yl)acetamide The title compound was obtained in the same manner as in Example 1 except for using N-((3R,4S)-4-hydroxypyrrolidin-3-yl)acetamide (Scheme 1, General Procedure A). 1H NMR (600 MHz, DMSO-d6) δ [ppm] = 9.60 (s, 1H), 8.74 (d, J = 7.8 Hz, 1H), 8.69 (d, J = 4.7 Hz, 1H), 8.36 (d, 2H), 8.13 (dd, J = 26.2, 7.0 Hz, 1H), 7.59 (dd, J = 8.7, 2.8 Hz, 2H), 7.54 (t, J = 6.7 Hz, 1H), 7.07 (d, J = 6.2 Hz, 1H), 5.48 (dd, J = 55.9, 3.7 Hz, 1H), 4.16 (d, J = 37.3Hz, 2H), 3.93-3.66 (m, 3H), 3.47 (d, J = 11.1 Hz, 1H), 1.81 (d, J = 2.7 Hz, 3H); MS (ESI, m / z): 410.1 [M+H] +

[0425] Example 244. N-((3S,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-hydroxypyrrolidin-3-yl)acetamide The title compound was obtained in the same manner as in Example 1 except for using N-((3S,4R)-4-hydroxypyrrolidin-3-yl)acetamide (Scheme 1, General Procedure A). 1 H NMR (600 MHz, DMSO-d6) δ [ppm] = 9.60 (s, 1H), 8.74 (d, J = 7.8 Hz, 1H), 8.69 (d, J = 4.7 Hz, 1H), 8.36 (d, 2H), 8.13 (dd, J = 26.2, 7.0 Hz, 1H), 7.59 (dd, J = 8.7, 2.8 Hz, 2H), 7.54 (t, J = 6.7 Hz, 1H), 7.07 (d, J = 6.2 Hz, 1H), 5.48 (dd, J = 55.9, 3.7 Hz, 1H), 4.16 (d, J = 37.3Hz, 2H), 3.93-3.66 (m, 3H), 3.47 (d, J = 11.1 Hz, 1H), 1.81 (d, J = 2.7 Hz, 3H); MS (ESI, m / z): 410.1 [M+H] +

[0426] Example 245. N-((3S,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-hydroxypyrrolidin-3-yl)acetamide The title compound was obtained in the same manner as in Example 1 except for using N-((3S,4S)-4-hydroxypyrrolidin-3-yl)acetamide (Scheme 1, General Procedure A). 1 H NMR (600 MHz, DMSO-d6) δ [ppm] = 9.60 (s, 1H), 8.74 (d, J = 7.8 Hz, 1H), 8.69 (d, J = 4.7 Hz, 1H), 8.36 (d, 2H), 8.13 (dd, J = 26.2, 7.0 Hz, 1H), 7.59 (dd, J = 8.7, 2.8 Hz, 2H), 7.54 (t, J = 6.7 Hz, 1H), 7.07 (d, J = 6.2 Hz, 1H), 5.48 (dd, J = 55.9, 3.7 Hz, 1H), 4.16 (d, J = 37.3Hz, 2H), 3.93-3.66 (m, 3H), 3.47 (d, J = 11.1 Hz, 1H), 1.81 (d, J = 2.7 Hz, 3H); MS (ESI, m / z): 410.1 [M+H] +

[0427] Example 246 (1-(6-(4-chloro-3-fluorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol The title compound was obtained in the same manner as in Example 226, except that (4-chloro-3-fluorophenyl)boronic acid was used (Scheme 4, General Procedure D). 1H NMR (600 MHz, DMSO-d6) δ [ppm] = 9.58 (s, 1H), 8.77-8.68 (m, 2H), 8.39 (dd, J = 11.0, 2.0 Hz, 1H), 8.25 (dd, J = 8.4, 1.8 Hz, 1H), 7.75 (t, J = 14.9 Hz, 1H), 7.54 (dd, J = 7.8, 4.7 Hz, 1H), 7.43 (s, 1H), 4.75 (s, 1H), 4.56-4.45 (m, 1H), 3.30 (t, J = 5.7 Hz, 2H), 3.01 (t, J = 12.5 Hz, 2H), 1.84-1.68 (m, 3H), 1.33-1.26 (m, 1H), 1.22-1.12 (m, 2H); MS (ESI, m / z): 399.1[M+H] +

[0428] Example 247 (3S,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)piperidin-3-ol The title compound was obtained in the same manner as in Example 1 except for using (3S,4R)-4-(hydroxymethyl)piperidin-3-ol (Scheme 1, General Procedure A). 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 9.57 (dd, J = 2.1, 0.9 Hz, 1H), 8.71 (dd, J = 8.0, 2.0 Hz, 1H), 8.68 (dd, J = 4.8, 1.7 Hz, 1H), 8.33 (d, J = 8.7 Hz, 2H), 7.61-7.56 (m, 2H), 7.53 (dd, J = 7.9, 4.8, 0.9 Hz, 1H), 7.32 (s, 1H), 4.55 (d, J = 4.3 Hz, 1H), 4.43 (t, J = 5.2 Hz, 1H), 3.95 (s, 1H), MS (ESI, m / z): 397.1 [M+H] +

[0429] Example 248 (3S,4R)-4-(hydroxymethyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-3-ol Scheme for preparing the compound of Example 248 [ka]

[0430] Intermediate 14. 4-Chloro-2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidine 4,6-Dichloro-2-pyridin-3-yl-pyrimidine (1.03 g, 4.6 mmol), (4-(trifluoromethyl)phenyl)boronic acid (0.80 g, 4.2 mmol), and sodium carbonate (1.01 g, 9.5 mmol) were dissolved in tetrahydrofuran / HO (4 / 1) (50 mL), and Pd(PPh) (203 mg, 0.18 mmol) was added to the resulting mixture. The mixture was heated at 65 °C for 20 min in a microwave oven, cooled to room temperature, and extracted three times with EtOAc (50 mL). The organic layer was dried over anhydrous MgSO and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 1.02 g of the title compound. 1 H NMR (600 MHz, CDCl3) δ [ppm] = 7.52 (d, 2H), 7.74 (s, 1H), 7.79 (dd, 1H), 8.06 (d, 2H), 9.02 (d, 1H), 9.12 (d, 1H), 10.16 (s, 1H); MS (ESI, m / z): 336.1 [M+H] +

[0431] Example 248 (3S,4R)-4-(hydroxymethyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-3-ol To a solution of 4-chloro-2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidine (50 mg, 0.15 mmol) in tetrahydrofuran (6 mL) was added triethylamine (0.3 mL, 2.15 mmol) at room temperature, followed by (3S,4R)-4-(hydroxymethyl)piperidin-3-ol (39 mg, 0.30 mmol). The reaction was heated in a sealed tube at 120° C. for 4 hours and cooled to room temperature. The residue was filtered, concentrated under reduced pressure, and separated by preparative HPLC to give 50 mg of the title compound (Scheme 1, General Procedure A). 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 9.58 (s, 1H), 8.72 (dd, J = 8.0, 2.0 Hz, 1H), 8.69 (dd, J = 4.8, 1.7 Hz, 1H), 8.50 (d, J = 8.1 Hz, 2H), 7.88 (d, J = 8.2 Hz, 2H), 7.54 (dd, J = 8.0, 4.8, 0.9 Hz, 1H), 7.40 (s, 1H), 4.57 (d, J = 4.2 Hz, 1H), 4.44 (t, J = 5.2 Hz, 1H), 3.96 (s, 1H), 3.52-3.41 (m, 1H), 3.31-3.24 (m, 1H), 3.20-3.08 (m, 1H), 3.08-2.90 (m, 1H), 1.81-1.70 (m, 1H), 1.57-1.52 (m, 2H); MS (ESI, m / z): 431.2 [M+H] +

[0432] Example 249. ((3S,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-yl)methanol The title compound was obtained in the same manner as in Example 1 except for using ((3S,4R)-3-fluoropiperidin-4-yl)methanol (Scheme 1, General Procedure A). 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 9.57 (s, 1H), 8.75-8.66 (m, 2H), 8.36 (d, 2H), 7.59 (d, 2H), 7.54 (dd, J = 7.9, 4.9, 0.9 Hz, 1H), 7.41 (s, 1H), 5.00 (d, J = 47.8 Hz, 1H), 4.73 (t, J = 5.1 Hz, 1H), 3.51-3.32 (m, 1H), 3.33-3.21 (m, 1H), 3.21-3.09 (m, 1H), 3.09-2.96 (m, 1H), 2.53-2.38 (m, MS (ESI, m / z): 399.1 [M+H] +

[0433] Example 250. ((3S,4R)-3-Fluoro-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol The title compound was obtained in the same manner as in Example 248, except for using ((3S,4R)-3-fluoropiperidin-4-yl)methanol (Scheme 1, General Procedure A). 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 9.58 (s, 1H), 8.76-8.66 (m, 2H), 8.53 (d, 2H), 7.89 (d, 2H), 7.55 (dd, J = 7.9, 4.8, 0.9 Hz, 1H), 7.50 (s, 1H), 5.01 (d, J = 47.8 Hz, 1H), 4.73 (t, J = 5.1 Hz, 1H), 3.48-3.38 (m, 1H), 3.37-3.25 (m, 1H), 3.24-3.12 (m, 1H), 3.05 (t, J = 12.9 Hz, 1H), 2.48-2.42 (m, 1H), 2.04-1.79 (m, 1H), 1.67 (d, J = 13.3 Hz, 1H), 1.49-1.32 (m, 1H); MS (ESI, m / z): 433.2 [M+H] +

[0434] Example 251 ((3R,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-yl)methanol The title compound was obtained in the same manner as in Example 1 except for using ((3R,4S)-3-fluoropiperidin-4-yl)methanol (Scheme 1, General Procedure A). 1 H NMR (600 MHz, DMSO-d6) δ [ppm] = 9.58 (s, 1H), 8.73 (dd, J = 8.0, 1.9 Hz, 1H), 8.70 (s, 1H), 8.38 (d, 2H), 7.59 (d, 2H), 7.55 (dd, J = 7.9, 4.7 Hz, 1H), 7.46 (s, 1H), 4.86-4.72 (m, 1H), 4.68 (s, 1H), 4.60-4.35 (m, 1H), 3.60-3.55 (m, 1H), 3.53-3.46 (m, 1H), 3.25-3.18 (m, 1H), 2.00-1.84 (m, 3H), 1.45 (dd, J = 14.0, 10.3 Hz, 1H); MS (ESI, m / z): 399.1 [M+H] +

[0435] Example 252 ((3R,4S)-3-fluoro-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol The title compound was obtained in the same manner as in Example 248, except for using ((3R,4S)-3-fluoropiperidin-4-yl)methanol (Scheme 1, General Procedure A). 1H NMR (600 MHz, DMSO-d6) δ [ppm] = 9.60-9.57 (m, 1H), 8.73 (dd, J = 7.9, 2.0 Hz, 1H), 8.70 (dd, J = 4.7, 1.7 Hz, 1H), 8.55 (d, J = 8.2 Hz, 2H), 7.89 (d, J = 8.2 Hz, 2H), 7.58-7.52 (m, 2H), 4.89-4.72 (m, 1H), 4.68 (t, J = 5.3 Hz, 1H), 4.62-4.44 (m, 1H), 3.61-3.55 (m, 1H), 3.54-3.48 (m, 1H), 3.41-3.34 (m, 1H), 3.28-3.17 (m, 1H), 1.99-1.85 (m, 2H), 1.52-1.42 (m, 1H); MS (ESI, m / z): 433.2 [M+H] +

[0436] Example 253 ((3R,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-yl)methanol The title compound was obtained in the same manner as in Example 1 except for using ((3R,4R)-3-fluoropiperidin-4-yl)methanol (Scheme 1, General Procedure A). 1 H NMR (600 MHz, DMSO-d6) δ [ppm] = 9.58 (s, 1H), 8.73 (dd, J = 8.0, 1.9 Hz, 1H), 8.70 (s, 1H), 8.38 (d, 2H), 7.59 (d, 2H), 7.55 (dd, J = 7.9, 4.7 Hz, 1H), 7.46 (s, 1H), 4.86-4.72 (m, 1H), 4.68 (s, 1H), 4.60-4.35 (m, 1H), 3.60-3.55 (m, 1H), 3.53-3.46 (m, 1H), 3.25-3.18 (m, 1H), 2.00-1.84 (m, 3H), 1.45 (dd, J = 14.0, 10.3 Hz, 1H); MS (ESI, m / z): 399.1 [M+H] +

[0437] Example 254 ((3R,4R)-3-fluoro-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol The title compound was obtained in the same manner as in Example 248, except for using ((3R,4R)-3-fluoropiperidin-4-yl)methanol (Scheme 1, General Procedure A). 1 H NMR (600 MHz, DMSO-d6) δ [ppm] = 9.60-9.57 (m, 1H), 8.73 (dd, J = 7.9, 2.0 Hz, 1H), 8.70 (dd, J = 4.7, 1.7 Hz, 1H), 8.55 (d, J = 8.2 Hz, 2H), 7.89 (d, J = 8.2 Hz, 2H), 7.58-7.52 (m, 2H), 4.89-4.72 (m, 1H), 4.68 (t, J = 5.3 Hz, 1H), 4.62-4.44 (m, 1H), 3.61-3.55 (m, 1H), 3.54-3.48 (m, 1H), 3.41-3.34 (m, 1H), 3.28-3.17 (m, 1H), 1.99-1.85 (m, 2H), 1.52-1.42 (m, 1H); MS (ESI, m / z): 433.2 [M+H] +

[0438] Example 255 (3S,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)pyrrolidin-3-ol The title compound was obtained in the same manner as in Example 1 except for using (3S,4R)-4-(hydroxymethyl)pyrrolidin-3-ol (Scheme 1, General Procedure A). 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 9.58 (s, 1H), 8.72 (d, J = 8.0, 2.0 Hz, 1H), 8.68 (d, J = 4.7 Hz, 1H), 8.34 (d, J = 8.6, 1.6 Hz, 2H), 7.58 (d, J = 8.5, 1.7 Hz, 2H), 7.53 (dd, J = 7.9, 4.8, 0.8 Hz, 1H), 7.00 (d, J = 12.6 Hz, 1H), 5.02 (dd, J = 34.8, 4.2 Hz, 1H), 4.61-4.57 (m, 1H), 4.37 (d, J = MS (ESI, m / z): 383.1 [M+H] +

[0439] Example 256 (3S,4R)-4-(hydroxymethyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol The title compound was obtained in the same manner as in Example 248, except that (3S,4R)-4-(hydroxymethyl)pyrrolidin-3-ol was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 9.59 (s, 1H), 8.74 (dd, J = 8.0, 1.9 Hz, 1H), 8.69 (dd, J = 4.8, 1.7 Hz, 1H), 8.51 (d, J = 8.1 Hz, 2H), 7.88 (d, 2H), 7.54 (dd, J = 7.9, 4.8, 0.9 Hz, 1H), 7.10 (d, J = 13.8 Hz, 1H), 5.19 (dd, J = 36.7, 4.3 Hz, 1H), 4.85-4.73 (m, 1H), 4.23 (d, J = 22.9 Hz, 1H), MS (ESI, m / z): 417.2 [M+H] +

[0440] Example 257 (3R,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)pyrrolidin-3-ol The title compound was obtained in the same manner as in Example 1 except for using (3R,4R)-4-(hydroxymethyl)pyrrolidin-3-ol (Scheme 1, General Procedure A). 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 9.58 (s, 1H), 8.72 (d, J = 8.0, 2.0 Hz, 1H), 8.68 (d, J = 4.7 Hz, 1H), 8.34 (d, J = 8.6, 1.6 Hz, 2H), 7.58 (d, J = 8.5, 1.7 Hz, 2H), 7.53 (dd, J = 7.9, 4.8, 0.8 Hz, 1H), 7.00 (d, J = 12.6 Hz, 1H), 5.02 (dd, J = 34.8, 4.2 Hz, 1H), 4.61-4.57 (m, 1H), 4.37 (d, J = MS (ESI, m / z): 383.1 [M+H] +

[0441] Example 258 (3R,4R)-4-(hydroxymethyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol The title compound was obtained in the same manner as in Example 248, except that (3R,4R)-4-(hydroxymethyl)pyrrolidin-3-ol was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 9.59 (s, 1H), 8.74 (dd, J = 8.0, 1.9 Hz, 1H), 8.69 (dd, J = 4.8, 1.7 Hz, 1H), 8.51 (d, J = 8.1 Hz, 2H), 7.88 (d, 2H), 7.54 (dd, J = 7.9, 4.8, 0.9 Hz, 1H), 7.10 (d, J = 13.8 Hz, 1H), 5.19 (dd, J = 36.7, 4.3 Hz, 1H), 4.85-4.73 (m, 1H), 4.23 (d, J = 22.9 Hz, 1H), MS (ESI, m / z): 417.2 [M+H] +

[0442] Example 259 (3R,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)piperidin-3-ol The title compound was obtained in the same manner as in Example 1 except for using (3R,4R)-4-(hydroxymethyl)piperidin-3-ol (Scheme 1, General Procedure A). 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 9.57 (dd, J = 2.3, 0.8 Hz, 1H), 8.72 (dd, J = 7.9, 2.2, 1.7 Hz, 1H), 8.69 (dd, J = 4.8, 1.7 Hz, 1H), 8.35 (d, 2H), 7.58 (d, 2H), 7.54 (dd, J = 7.9, 4.8, 0.9 Hz, 1H), 7.35 (s, 1H), 5.01 (d, J = 5.0 Hz, 1H), 4.43 (t, J = 5.1 Hz, 1H), 3.67-3.58 (m, 1H), 3.44-3.37 (m, 1H), 3.35-3.22 (m, 1H), 2.98 (t, J = 12.8 Hz, 1H), 2.81-2.67 (m, 1H), 1.88-1.79 (m, 1H), 1.68-1.50 (m, 1H), 1.42-1.22 (m, 1H); MS (ESI, m / z): 397.1 [M+H] +

[0443] Example 260 (3R,4R)-4-(hydroxymethyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-3-ol The title compound was obtained in the same manner as in Example 248, except that (3R,4R)-4-(hydroxymethyl)piperidin-3-ol was used (Scheme 1, General Procedure A). 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 9.59 (s, 1H), 8.76-8.67 (m, 2H), 8.52 (d, 2H), 7.88 (d, 2H), 7.55 (dd, J = 7.9, 4.8, 0.9 Hz, 1H), 7.44 (s, 1H), 5.02 (d, J = 4.9 Hz, 1H), 4.44 (s, 1H), 3.69-3.58 (m, 1H), 3.48-3.23 (m, 1H), 3.01 (t, J = 12.8 Hz, 1H), 2.87-2.70 (m, 1H), 2.56-2.50 (m, 1H), 1.86 (dd, J = 13.6, 3.7 Hz, 1H), 1.66-1.51 (m, 1H), 1.30 (dd, J = 12.6, 4.3 Hz, 1H); MS (ESI, m / z): 431.2 [M+H] +

[0444] Example 261 (3S,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)piperidin-3-ol The title compound was obtained in the same manner as in Example 1 except for using (3S,4S)-4-(hydroxymethyl)piperidin-3-ol (Scheme 1, General Procedure A). 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 9.57 (dd, J = 2.3, 0.8 Hz, 1H), 8.72 (dd, J = 7.9, 2.2, 1.7 Hz, 1H), 8.69 (dd, J = 4.8, 1.7 Hz, 1H), 8.35 (d, 2H), 7.58 (d, 2H), 7.54 (dd, J = 7.9, 4.8, 0.9 Hz, 1H), 7.35 (s, 1H), 5.01 (d, J = 5.0 Hz, 1H), 4.43 (t, J = 5.1 Hz, 1H), 3.67-3.58 (m, 1H), 3.44-3.37 (m, 1H), 3.35-3.22 (m, 1H), 2.98 (t, J = 12.8 Hz, 1H), 2.81-2.67 (m, 1H), 1.88-1.79 (m, 1H), 1.68-1.50 (m, 1H), 1.42-1.22 (m, 1H); MS (ESI, m / z): 397.1 [M+H] +

[0445] Example 262 (3S,4S)-4-(hydroxymethyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-3-ol The title compound was obtained in the same manner as in Example 248, except for using (3S,4S)-4-(hydroxymethyl)piperidin-3-ol (Scheme 1, General Procedure A). 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 9.59 (s, 1H), 8.76-8.67 (m, 2H), 8.52 (d, 2H), 7.88 (d, 2H), 7.55 (dd, J = 7.9, 4.8, 0.9 Hz, 1H), 7.44 (s, 1H), 5.02 (d, J = 4.9 Hz, 1H), 4.44 (s, 1H), 3.69-3.58 (m, 1H), 3.48-3.23 (m, 1H), 3.01 (t, J = 12.8 Hz, 1H), 2.87-2.70 (m, 1H), 2.56-2.50 (m, 1H), 1.86 (dd, J = 13.6, 3.7 Hz, 1H), 1.66-1.51 (m, 1H), 1.30 (dd, J = 12.6, 4.3 Hz, 1H); MS (ESI, m / z): 431.2 [M+H] +

[0446] Example 263 (S)-1-(2-(4-methylpyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol Scheme for preparing the compound of Example 263 [ka]

[0447] Intermediate 15. 2,4-Dichloro-6-(4-(trifluoromethyl)phenyl)pyrimidine To a solution of 2,4,6-trichloropyrimidine (5 g, 27.5 mmol) in a mixed solvent of 1,4-dioxane (50 mL) and HO (5 mL), (4-(trifluoromethyl)phenyl)boronic acid (3.61 g, 19.25 mmol), NaCO (3.79 g, 35.75 mmol), palladium acetate (617.5 mg, 2.75 mmol), and PPh (721.3 mg, 2.75 mmol) were added at room temperature under a nitrogen atmosphere. The reaction mixture was heated and stirred at 90 °C for 16 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and the residue was extracted with EtOAc (20 mL × 3) and washed with brine. The combined organic layer was dried over anhydrous sodium sulfate. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 20 / 1; V / V) to give 3.2 g of the title compound.

[0448] Intermediate 16. (S)-1-(2-chloro-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol To a solution of 2,4-dichloro-6-(4-(trifluoromethyl)phenyl)pyrimidine (2 g, 68.5 mmol) in ACN (20 mL) were added (S)-pyrrolidin-3-ol (716 mg, 82.2 mmol) and DIPEA (2.66 g, 205.5 mmol) at room temperature. The reaction mixture was heated at 65° C. for 5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 2 / 1; V / V) to give 573 mg of the title compound. 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 1.83-2.14 (m, 2 H), 3.39-3.72 (m, 4 H), 4.43 (d, J = 27.3 Hz, 1 H), 7.11 (d, J = 7.3 Hz, 1 H), 7.87 (d, J =8.0 Hz, 2 H), 8.32 (d, J = 7.0 Hz, 2 H); MS (ESI, m / z): 344.2 [M+H] +

[0449] Example 263 (S)-1-(2-(4-methylpyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol To a solution of (S)-1-(2-chloro-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol (34 mg, 0.098 mmol), (4-methylpyridin-3-yl)boronic acid (27 mg, 0.20 mmol), and sodium carbonate (20.8 mg, 0.20 mmol) in 1,4-dioxane / HO (4 / 1) (10 mL) was added Pd(PPh) (11.4 mg, 0.01 mmol). The mixture was heated at 150 °C for 120 min in a microwave oven, cooled to room temperature, and extracted with DCM. The organic layer was washed with brine, dried over anhydrous MgSO, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, DCM / MeOH, gradient) to give 30 mg of the title compound (Scheme 3, General Procedure C). 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 9.06 (s, 1H), 8.48 (d, J = 5.0 Hz, 1H), 8.43 (d, J = 8.2 Hz, 2H), 7.88 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 5.1, 0.7 Hz, 1H), 7.11-7.05 (m, 1H), 5.08 (d, J = 39.2 Hz, 1H), 4.44 (d, J = 28.6 Hz, 1H), 3.83-3.41 (m, 3H), 2.64 (s, 3H), 2.13-1.85 (m, 2H); MS (ESI, m / z): 401.2 [M+H] +

[0450] Example 264 (3R,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)piperidin-3-ol The title compound was obtained in the same manner as in Example 1 except for using (3R,4S)-4-(hydroxymethyl)piperidin-3-ol (Scheme 1, General Procedure A). 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 9.57 (dd, J = 2.3, 0.8 Hz, 1H), 8.72 (dd, J = 7.9, 2.2, 1.7 Hz, 1H), 8.69 (dd, J = 4.8, 1.7 Hz, 1H), 8.35 (d, 2H), 7.58 (d, 2H), 7.54 (dd, J = 7.9, 4.8, 0.9 Hz, 1H), 7.35 (s, 1H), 5.01 (d, J = 5.0 Hz, 1H), 4.43 (t, J = 5.1 Hz, 1H), 3.67-3.58 (m, 1H), 3.44-3.37 (m, 1H), 3.35-3.22 (m, 1H), 2.98 (t, J = 12.8 Hz, 1H), 2.81-2.67 (m, 1H), 1.88-1.79 (m, 1H), 1.68-1.50 (m, 1H), 1.42-1.22 (m, 1H); MS (ESI, m / z): 397.1 [M+H] +

[0451] Example 265 (3R,4S)-4-(hydroxymethyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-3-ol The title compound was obtained in the same manner as in Example 248, except that (3R,4S)-4-(hydroxymethyl)piperidin-3-ol was used (Scheme 1, General Procedure A). 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 9.59 (s, 1H), 8.76-8.67 (m, 2H), 8.52 (d, 2H), 7.88 (d, 2H), 7.55 (dd, J = 7.9, 4.8, 0.9 Hz, 1H), 7.44 (s, 1H), 5.02 (d, J = 4.9 Hz, 1H), 4.44 (s, 1H), 3.69-3.58 (m, 1H), 3.48-3.23 (m, 1H), 3.01 (t, J = 12.8 Hz, 1H), 2.87-2.70 (m, 1H), 2.56-2.50 (m, 1H), 1.86 (dd, J = 13.6, 3.7 Hz, 1H), 1.66-1.51 (m, 1H), 1.30 (dd, J = 12.6, 4.3 Hz, 1H); MS (ESI, m / z): 431.2 [M+H] +

[0452] Example 266 (3S,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)pyrrolidin-3-ol The title compound was obtained in the same manner as in Example 1 except for using (3S,4S)-4-(hydroxymethyl)pyrrolidin-3-ol (Scheme 1, General Procedure A). 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 9.58 (s, 1H), 8.72 (d, J = 8.0, 2.0 Hz, 1H), 8.68 (d, J = 4.7 Hz, 1H), 8.34 (d, J = 8.6, 1.6 Hz, 2H), 7.58 (d, J = 8.5, 1.7 Hz, 2H), 7.53 (dd, J = 7.9, 4.8, 0.8 Hz, 1H), 7.00 (d, J = 12.6 Hz, 1H), 5.02 (dd, J = 34.8, 4.2 Hz, 1H), 4.61-4.57 (m, 1H), 4.37 (d, J = MS (ESI, m / z): 383.1 [M+H] +

[0453] Example 267 (3S,4S)-4-(hydroxymethyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol The title compound was obtained in the same manner as in Example 248, except for using (3S,4S)-4-(hydroxymethyl)pyrrolidin-3-ol (Scheme 1, General Procedure A). 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 9.59 (s, 1H), 8.74 (dd, J = 8.0, 1.9 Hz, 1H), 8.69 (dd, J = 4.8, 1.7 Hz, 1H), 8.51 (d, J = 8.1 Hz, 2H), 7.88 (d, 2H), 7.54 (dd, J = 7.9, 4.8, 0.9 Hz, 1H), 7.10 (d, J = 13.8 Hz, 1H), 5.19 (dd, J = 36.7, 4.3 Hz, 1H), 4.85-4.73 (m, 1H), 4.23 (d, J = 22.9 Hz, 1H), MS (ESI, m / z): 417.2 [M+H] +

[0454] Example 268 (1-(6-(4-morpholinophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol The title compound was obtained in the same manner as in Example 226, except that (4-morpholinophenyl)boronic acid was used (Scheme 4, General Procedure D). 1H NMR (600 MHz, CDCl3) δ [ppm] = 9.69 (s, 1H), 8.76 (dd, J = 7.9, 1.9 Hz, 1H), 8.65 (dd, J = 4.7, 1.7 Hz, 1H), 8.07 (d, J = 8.9 Hz, 2H), 7.37 (dd, J = 7.9, 4.8, 0.9 Hz, 1H), 6.98 (d, J = 8.9 Hz, 2H), 6.81 (s, 1H), 4.74-4.58 (m, 2H), 3.92-3.83 (m, 4H), 3.55 (d, J = 6.2 Hz, 2H), 3.30-3.22 (m, 4H), 3.00 (t, J = 12.8, 2.6 Hz, 2H), 1.90 (d, J = 13.9 Hz, 2H), 1.88-1.81 (m, 1H), 1.39-1.26 (m, 2H); MS (ESI, m / z): 432.2 [M+H] +

[0455] Example 269. (S)-1-(2-(2-methylpyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol The title compound was obtained in the same manner as in Example 263, except that (2-methylpyridin-3-yl)boronic acid was used (Scheme 3, General Procedure C). 1 H NMR (600 MHz, CDCl3) δ [ppm] = 8.54 (dd, J = 4.8, 1.8 Hz, 1H), 8.31 (dd, J = 7.7, 1.8 Hz, 1H), 8.18 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.0 Hz, MS (ESI, m / z): 401.2 [M+H] +

[0456] Example 270. (S)-3-(4-(3-hydroxypyrrolidin-1-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)pyridin-2-ol The title compound was obtained in the same manner as in Example 263, except that (2-hydroxypyridin-3-yl)boronic acid was used (Scheme 3, General Procedure C). 1 H NMR (600 MHz, DMSO-d6) δ [ppm] = 8.37 (d, J = 7.7 Hz, 2H), 7.93 (d, J = 7.8 Hz, 2H), 7.40 (dd, J = 9.1, 6.6, 2.2 Hz, 1H), 7.33 (dd, J = 6.4, 2.2, 0.8 Hz, 1H), 6.29 (d, J = 9.2, 1.0 Hz, 1H), 6.13 (t, J = 6.5, 1.1 Hz, 1H), 5.15 (d, J = 42.0 Hz, 1H), 4.47 (d, J = 26.1 Hz, 1H), 3.76-3.57 (m, 3H), 2.18-1.90 (m, 2H); MS (ESI, m / z): 403.1 [M+H] +

[0457] Example 271. 5-Chloro-2-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)phenol The title compound was obtained in the same manner as in Example 226, except that (4-chloro-2-hydroxyphenyl)boronic acid was used (Scheme 4, General Procedure D). 1 H NMR (600 MHz, CD3OD) δ [ppm] = 9.41 (s, 1H), 8.91 (d, 1H), 8.85 (s, 1H), 7.94-7.86 (m, 2H), 7.19 (s, 1H), 6.94-6.89 (m, 2H), 3.47 (d, MS (ESI, m / z): 397.1 [M+H] +

[0458] Example 272. (S)-4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-2-(hydroxymethyl)piperazine-1-carboxylate tert-butyl ester The title compound was obtained in the same manner as in Example 1 except for using tert-butyl (S)-2-(hydroxymethyl)piperazine-1-carboxylate (Scheme 1, General Procedure A). 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 9.58 (dd, J = 2.2, 0.9 Hz, 1H), 8.73 (dd, J = 8.0, 2.0 Hz, 1H), 8.69 (dd, J = 4.8, 1.7 Hz, 1H), 8.33 (d, J = 8.7 Hz, 2H), 7.60 (d, J = 8.8 Hz, 2H), 7.54 (dd, J = 7.9, 4.8, 0.9 Hz, 1H), 7.32 (s, 1H), 4.90 (s, 1H), 4.08 (s, 1H), 3.86 (d, J = 11.1 Hz, 1H), 3.49-3.26 (m, 5H), 3.25-3.05 (m, 1H), 1.42 (s, 9H); MS (ESI, m / z): 482.2 [M+H] +

[0459] Example 273. 2-Chloro-5-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)phenol The title compound was obtained in the same manner as in Example 226, except that (4-chloro-3-hydroxy-phenyl)boronic acid was used (Scheme 4, General Procedure D). 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 10.35 (s, 1H), 9.58 (d, J = 1.9 Hz, 1H), 8.72-8.64 (m, 2H), 8.03 (d, J = 2.1 Hz, 1H), 7.76-7.69 (m, 1H), 7.58-7.50 (m, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.27 (s, 1H), 4.70 (s, 1H), 4.52 (t, J = 5.3 Hz, 1H), 3.29 (dd, J = 11.1, 5.5 Hz, 2H), 3.00 (t, J = 11.9 Hz, 2H), 1.85-1.68 (m, 3H), 1.33-1.26 (m, 1H), 1.22-1.10 (m, 2H); MS (ESI, m / z): 397.1 [M+H] +

[0460] Example 274. N-(4-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)phenyl)methanesulfonamide The title compound was obtained in the same manner as in Example 226, except that [4-(methanesulfonamido)phenyl]boronic acid was used (Scheme 4, General Procedure D). 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 9.89 (s, 1H), 9.65 -9.58 (m, 2H), 8.78-8.64 (m, 2H), 8.24-8.22 (m, 1H), 8.03-7.90 (m, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.32-7.16 (m, 2H), 4.72 (s, 1H), 4.52 (t, J = 5.3 Hz, 1H), 3.30 (t, J = 5.7 Hz, 2H), 3.07 (s, 3H), 2.99-2.93 (m, 2H), 1.86-1.68 (m, 3H), 1.33-1.26 (m, 1H), 1.22-1.15 (m, 2H); MS (ESI, m / z): 440.2 [M+H] +

[0461] Example 275. (1-(6-(4-(4-methylpiperazin-1-yl)phenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol The title compound was obtained in the same manner as in Example 226, except that [4-(4-methylpiperazin-1-yl)phenyl]boronic acid was used (Scheme 4, General Procedure D). 1 H NMR (600 MHz, DMSO-d6) δ [ppm] = 9.55 (d, J = 1.6 Hz, 1H), 8.72-8.63 (m, 2H), 8.19 (d, J = 8.9 Hz, 2H), 7.53 (dd, J = 7.7, 4.9 Hz, 1H), 7.19 (s, 1H), 7.03 (d, J = 9.0 Hz, 2H), 4.70 (s, 1H), 4.52 (t, J = 5.3 Hz, 1H), 3.31-3.24 (m, 6H), 2.96 (t, J = 11.9 Hz, 2H), 2.47 (m, 4H), 2.24 (s, 3H), 1.84-1.68 (m, 3H), 1.30-1.26 (m, 1H), 1.18-1.11 (m, 2H); MS (ESI, m / z): 445.3 [M+H] +

[0462] Example 276 (1-(6-(3-fluoro-4-morpholinophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol The title compound was obtained in the same manner as in Example 226, except that (3-fluoro-4-morpholino-phenyl)boronic acid was used (Scheme 4, General Procedure D). 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 9.60-9.51 (m, 1H), 8.76-8.63 (m, 2H), 8.18-8.10 (m, 2H), 7.54-7.50 (m, 1H), 7.30 (s, 1H), 7.16-7.08 (m, 1H), 4.74 (s, 1H), 4.52 (t, J = 5.3 Hz, 1H), 3.87-3.65 (m, 4H), 3.32-3.26 (m, 2H), 3.16-3.03 (m, 4H), 2.98 (t, J = 11.7 Hz, 2H), 1.84-1.69 (m, 3H), 1.29 (m, 1H), 1.20-1.15 (m, 2H); MS (ESI, m / z): 450.2 [M+H]+

[0463] Example 277 (1-(2-(pyridin-3-yl)-6-(2,4,6-trifluorophenyl)pyrimidin-4-yl)piperidin-4-yl)methanol The title compound was obtained in the same manner as in Example 226, except that (2,4,6-trifluorophenyl)boronic acid was used (Scheme 4, General Procedure D). 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 9.53 (s, 1H), 8.79-8.61 (m, 2H), 8.24-8.15 (m, 1H), 7.83-7.66 (m, 1H), 7.54-7.48 (m, 1H), 7.14 (s, 1H), 4.63 (s, 1H), 4.52 (t, J = 5.3 Hz, 1H), 3.29 (t, J = 5.7 Hz, 2H), 3.02 (t, J = 12.1 Hz, 2H), 1.88-1.66 (m, 3H), 1.27 (m, 1H), 1.15 (m, 2H); MS (ESI, m / z): 401.2 [M+H] +

[0464] Example 278 (1-(2-(pyridin-3-yl)-6-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol The title compound was obtained in the same manner as in Example 226, except that 4-tetrahydropyran(2-yloxyphenyl)boronic acid was used (Scheme 4, General Procedure D). 1H NMR (600 MHz, DMSO-d6) δ [ppm] = 9.56 (d, J = 1.5 Hz, 1H), 8.75-8.66 (m, 2H), 8.26 (d, J = 5.9 Hz, 2H), 7.55-7.48 (m, 1H), 7.25 (s, 1H), 7.14 (d, J = 5.9 Hz, 2H), 5.60 (t, J = 3.2 Hz, 1H), 4.72 (s, 1H), 4.52 (t, J = 5.3 Hz, 1H), 3.84-3.71 (m, 1H), 3.63-3.53 (m, 1H), 3.30 (t, J = 13.4 Hz, 2H), 2.98 (t, J = 11.9 Hz, 2H), 1.91-1.53 ​​(m, 9H), 1.30-1.26 (m, 1H), 1.19-1.11 (m, 2H); MS (ESI, m / z): 447.2 [M+H] +

[0465] Example 279. (S)-(4-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)morpholin-2-yl)methanol The title compound was obtained in the same manner as in Example 248, except for using (S)-morpholin-2-ylmethanol (Scheme 1, General Procedure A). 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 9.60 (dd, J = 2.2, 0.9 Hz, 1H), 8.74 (dd, J = 7.9, 2.2, 1.7 Hz, 1H), 8.70 (dd, J = 4.8, 1.7 Hz, 1H), 8.53 (d, J = 8.0, 0.8 Hz, 2H), 7.89 (d, J = 8.2, 0.7 Hz, 2H), 7.55 (dd, J = 7.9, 4.8, 0.9 Hz, 1H), 7.46 (s, 1H), 4.88 (t, J = 5.6 Hz, 1H), 4.56-4.52 (m, 1H), 4.04-3.96 (m, 1H), 3.64-3.45 (m, 5H), 3.11 (t, J = 12.4 Hz, 1H), 2.88 (t, J = 11.2 Hz, 1H); MS (ESI, m / z): 417.2 [M+H] +

[0466] Example 280. (R)-(4-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)morpholin-2-yl)methanol The title compound was obtained in the same manner as in Example 248, except for using (R)-morpholin-2-ylmethanol (Scheme 1, General Procedure A). 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 9.60 (dd, J = 2.2, 0.9 Hz, 1H), 8.74 (dd, J = 7.9, 2.2, 1.7 Hz, 1H), 8.70 (dd, J = 4.8, 1.7 Hz, 1H), 8.53 (d, J = 8.0, 0.8 Hz, 2H), 7.89 (d, J = 8.2, 0.7 Hz, 2H), 7.55 (dd, J = 7.9, 4.8, 0.9 Hz, 1H), 7.46 (s, 1H), 4.88 (t, J = 5.6 Hz, 1H), 4.56-4.52 (m, 1H), 4.04-3.96 (m, 1H), 3.64-3.45 (m, 5H), 3.11 (t, J = 12.4 Hz, 1H), 2.88 (t, J = 11.2 Hz, 1H); MS (ESI, m / z): 417.2 [M+H] +

[0467] Example 281 ((3S,4S)-3-fluoro-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol The title compound was obtained in the same manner as in Example 248, except for using ((3S,4S)-3-fluoropiperidin-4-yl)methanol (Scheme 1, General Procedure A). 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 9.59 (dd, J = 2.2, 0.9 Hz, 1H), 8.73 (dd, J = 8.0, 2.0 Hz, 1H), 8.70 (dd, J = 4.8, 1.7 Hz, 1H), 8.55 (d, J = 7.9, 0.8 Hz, 2H), 7.89 (d, J = 8.8, 0.8 Hz, 2H), 7.59-7.52 (m, 2H), 4.87-4.72 (m, 1H), 4.68 (t, J = 5.3 Hz, 1H), 4.64-4.56 (m, 1H), 4.53-4.43 (m, 1H), 3.63-3.46 (m, 2H), 3.42-3.33 (m, 1H), 3.29-3.17 (m, 1H), 2.01-1.83 (m, 2H), 1.54-1.40 (m, 1H); MS (ESI, m / z): 433.2 [M+H] +

[0468] Example 282 ((3S,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-yl)methanol The title compound was obtained in the same manner as in Example 1 except for using ((3S,4S)-3-fluoropiperidin-4-yl)methanol (Scheme 1, General Procedure A). 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 9.57 (d, J = 1.5 Hz, 1H), 8.72 (dd, J = 7.9, 1.9 Hz, 1H), 8.69 (dd, J = 4.8, 1.7 Hz, 1H), 8.38 (d, J = 8.8 Hz, 2H), 7.59 (d, J = 8.7 Hz, 2H), 7.54 (dd, J = 8.0, 4.8, 0.9 Hz, 1H), 7.46 (s, 1H), 4.85-4.71 (m, 1H), 4.67 (t, J = 5.3 Hz, 1H), 4.63-4.54 (m, 1H), 4.53-4.40 (m, 1H), 3.64-3.54 (m, 1H), 3.54-3.45 (m, 1H), 3.40-3.28 (m, 1H), 3.28-3.15 (m, 1H), 1.99-1.83 (m, 2H), 1.53-1.37 (m, 1H); MS (ESI, m / z): 399.1 [M+H] +

[0469] Example 283 (3S,4S)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidine-3,4-diol The title compound was obtained in the same manner as in Example 248 except for using (3S,4S)-pyrrolidine-3,4-diol (Scheme 1, General Procedure A). 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 9.60 (d, J = 2.1 Hz, 1H), 8.74 (dd, J = 8.0, 2.0 Hz, 1H), 8.69 (dd, J = 4.8, 1.7 Hz, 1H), 8.51 (d, J = 8.1 Hz, 2H), 7.89 (d, J = 8.2 Hz, 2H), 7.55 (dd, J = 7.9, 4.8 Hz, 1H), 7.11 (s, 1H), 5.34-5.29 (m, 1H), 5.26-5.20 (m, 1H), 4.14 (s, 1H), 4.09 (s, 1H), 3.77 (d, J = MS (ESI, m / z): 403.1 [M+H] +

[0470] Example 284 (3S,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidine-3,4-diol The title compound was obtained in the same manner as in Example 1 except for using (3S,4S)-pyrrolidine-3,4-diol (Scheme 1, General Procedure A). 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 9.59 (dd, J = 2.2, 0.9 Hz, 1H), 8.73 (dd, J = 7.9, 1.9 Hz, 1H), 8.68 (dd, J = 4.8, 1.7 Hz, 1H), 8.34 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 8.6 Hz, 2H), 7.54 (dd, J = 8.0, 4.8, 0.9 Hz, 1H), 7.02 (s, 1H), 5.31 (d, J = 3.6 Hz, 1H), 5.22 (d, J = 3.3 Hz, 1H), 4.13 (s, 1H), 4.08 (s, 1H), 3.76 (d, J = 2.8 Hz, 2H), 3.69 (dd, J = 11.3, 4.2 Hz, 1H), 3.46 (d, J = 11.2 Hz, 1H); MS (ESI, m / z): 369.1 [M+H]+

[0471] Example 285 (1-(2-(1-methyl-1H-pyrazol-4-yl)-6-(4-morpholinophenyl)pyrimidin-4-yl)piperidin-4-yl)methanol Scheme for preparing the compound of Example 285 [ka]

[0472] Intermediate 17. (1-(2,6-dichloropyrimidin-4-yl)piperidin-4-yl)methanol To a solution of 2,4,6-trichloropyrimidine (600 mg, 2.56 mmol) and piperidin-4-ylmethanol (310 mg, 3.60 mmol) in tetrahydrofuran (15 mL) was added DIPEA (2.46 mL, 14.16 mmol). The reaction mixture was stirred at room temperature for 60 minutes and extracted three times with DCM (30 mL). The organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, hexane / ethyl acetate, gradient) to give 500 mg of the title compound.

[0473] Intermediate 18. (1-(2-chloro-6-(4-morpholinophenyl)pyrimidin-4-yl)piperidin-4-yl)methanol To a solution of (1-(2,6-dichloropyrimidin-4-yl)piperidin-4-yl)methanol (600 mg, 2.56 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine (570 mg, 2.56 mmol), and sodium carbonate (543 mg, 5.13 mmol) in tetrahydrofuran / HO (4 / 1) (15 mL) was added Pd(PPh) (296 mg, 0.26 mmol). The mixture was heated at 80 °C for 120 min in a microwave oven, cooled to room temperature, and extracted three times with EtOAc (30 mL). The organic layer was washed with brine, dried over anhydrous MgSO, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, hexane / ethyl acetate, gradient) to give 200 mg of the title compound.

[0474] Example 285. 3-(4-(4-(hydroxymethyl)piperidin-1-yl)-6-(4-morpholinophenyl)pyrimidin-2-yl)pyridin-2-ol To a solution of (1-(2-chloro-6-(4-morpholinophenyl)pyrimidin-4-yl)piperidin-4-yl)methanol (200 mg, 0.68 mmol), 3-pyridylboronic acid (85 mg, 0.70 mmol), and sodium carbonate (144 mg, 1.36 mmol) in 1,4-dioxane / HO (4 / 1) (15 mL) was added Pd(PPh) (78 mg, 0.08 mmol). The mixture was heated at 150 °C for 120 min in a microwave oven, cooled to room temperature, and extracted with DCM. The organic layer was washed with brine, dried over anhydrous MgSO, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, DCM / MeOH, gradient) to give 120 mg of the title compound (Scheme 5. General Procedure E). 1 H NMR (600 MHz, DMSO-d6) δ [ppm] = 9.57 (s, 1H), 9.13 (s, 1H), 8.87-8.82 (m, 1H), 8.72 (d, J = 7.3 Hz, 1H), 8.67 (dd, J = 4.7, 1.7 Hz, 1H), 7.54-7.50 (m, 1H), 7.36-7.30 (m, 1H), 7.09 (d, J = 15.3 Hz, 1H), 5.08 (dd, J = 60.5, 3.3 Hz, 1H), 4.43 (d, J = 35.5 Hz, 1H), 3.76-3.52 (m, 4H), 2.13-1.89 (m, 2H); MS (ESI, m / z): 448.2 [M+H] +

[0475] Example 286 (1-(2-(1-methyl-1H-pyrazol-4-yl)-6-(4-morpholinophenyl)pyrimidin-4-yl)piperidin-4-yl)methanol The title compound was obtained in the same manner as in Example 285, except that (1-methyl-1H-pyrazol-4-yl)boronic acid was used (Scheme 5, General Procedure E). 1H NMR (600 MHz, DMSO-d6) δ [ppm] = 9.94 (s, 1H), 9.62 (s, 1H), 9.02-8.91 (m, 2H), 8.85-8.84 (m, 1H), 8.45 (s, 1H), 7.77-7.71 (m, 1H), 6.98-6.88 (m, 1H), 6.79 (s, 1H), 4.46 (d, J = 36.0 Hz, 1H), 3.85-3.56 (m, 6H), 3.32-3.20 (m, 2H), 2.84 (s, 6H), 2.12-1.92 (m, 2H); MS (ESI, m / z): 435.2 [M+H] +

[0476] Example 287. (1-(6-(3-fluoro-4-morpholinophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperidin-4-yl)methanol Scheme for preparing the compound of Example 287 [ka]

[0477] Intermediate 19. (1-(2-chloro-6-(3-fluoro-4-morpholinophenyl)pyrimidin-4-yl)piperidin-4-yl)methanol To a solution of (1-(2,6-dichloropyrimidin-4-yl)piperidin-4-yl)methanol (300 mg, 1.14 mmol), 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine (527 mg, 1.72 mmol), and sodium carbonate (243 mg, 2.29 mmol) in 1,4-dioxane / HO (4 / 1) (12 mL) was added Pd(PPh) (132 mg, 0.11 mmol). The mixture was refluxed at 150 °C for 20 h, cooled to room temperature, and extracted three times with DCM (30 mL). The organic layer was washed with brine, dried over anhydrous MgSO, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, DCM / MeOH, gradient) to give 40 mg of the title compound.

[0478] Example 287. (1-(6-(3-fluoro-4-morpholinophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperidin-4-yl)methanol To a solution of (1-(2-chloro-6-(3-fluoro-4-morpholinophenyl)pyrimidin-4-yl)piperidin-4-yl)methanol (40 mg, 0.098 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (41 mg, 0.20 mmol), and sodium carbonate (20.8 mg, 0.20 mmol) in 1,4-dioxane / HO (4 / 1) (10 mL) was added Pd(PPh) (11.4 mg, 0.01 mmol). The mixture was heated at 150 °C for 120 min using a microwave, cooled to room temperature, and extracted with DCM. The organic layer was washed with brine, dried over anhydrous MgSO, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, DCM / MeOH, gradient) to give 30 mg of the title compound (Scheme 5. General Procedure E). 1 H NMR (600 MHz, DMSO-d6) δ [ppm] = 8.31 (s, 1H), 8.05-8.00 (m, 2H), 7.98 (d, J = 0.5 Hz, 1H), 7.10-7.02 (m, 2H), 4.63 (s, 1H), 4.49 (t, J = 5.3 Hz, 1H), 3.86 (s, 3H), 3.76-3.65 (m, 4H), 3.25 (t, J = 5.7 Hz, 2H), 3.12-3.01 (m, 4H), 2.86 (t, J = 11.9 Hz, 2H), 1.77-1.62 (m, 3H), 1.28-1.22 (m, 1H), 1.12-1.04 (m, 2H); MS (ESI, m / z): 453.2 [M+H] +

[0479] Example 288 (1-(6-(1H-indazol-5-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol The title compound was obtained in the same manner as in Example 226, except for using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (Scheme 4, General Procedure D). 1H NMR (600 MHz, DMSO-d6) δ [ppm] = 13.24 (s, 1H), 9.61 (d, J = 1.7 Hz, 1H), 8.80 (s, 1H), 8.78-8.60 (m, 2H), 8.35 (dd, J = 8.8, 1.5 Hz, 1H), 8.22 (s, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.55 (dd, J = 7.9, 4.8 Hz, 1H), 7.38 (s, 1H), 4.75 (s, 1H), 4.54 (t, J = 5.3 Hz, 1H), 3.30 (t, J = 5.7 Hz, 2H), 3.00 (t, MS (ESI, m / z): 387.2 [M+H] +

[0480] Example 289. (1-(6-(6-morpholinopyridin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol The title compound was obtained in the same manner as in Example 226, except for using 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]morpholine (Scheme 4, General Procedure D). 1H NMR (600 MHz, DMSO-d6) δ [ppm] = 9.55 (s, 1H), 9.10 (d, J = 2.3 Hz, 1H), 8.74-8.64 (m, 2H), 8.45 (dd, J = 9.0, 2.5 Hz, 1H), 7.55-7.47 (m, 1H), 7.25 (s, 1H), 6.95 (d, J = 9.0 Hz, 1H), 4.71 (s, 1H), 4.53 (t, J = 5.3 Hz, 1H), 3.78-3.65 (m, 4H), 3.65-3.52 (m, 4H), 3.29 (t, J = 5.7 Hz, 2H), 2.97 (t, MS (ESI, m / z): 433.2 [M+H] +

[0481] Example 290. 5-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)indolin-2-one The title compound was obtained in the same manner as in Example 226, except for using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (Scheme 4, General Procedure D). 1 H NMR (600 MHz, DMSO-d6) δ [ppm] = 10.63 (s, 1H), 9.57 (s, 1...

Claims

1. Formula (I) 【Chemistry 1】 (In the formula, X 1 and X 2 are each independently N; X 3 CR 2 and Ar 1 and Ar 2 is a substituted or unsubstituted monocyclic or bicyclic C 6-10 Aryl, unsubstituted monocyclic or bicyclic C 5-10 Heteroaryl and substituted or unsubstituted monocyclic or bicyclic C 3-10 heterocycloalkyl; D and E, together with the atoms to which they are attached, form a substituted or unsubstituted monocyclic or bicyclic ring system containing one or more heteroatoms selected from the group consisting of N, O and S. 3-10 forming a heterocycloalkyl ring; G is an ether (-O-), a thioether (-S-), a sulfinyl (-SO-), or a sulfonyl (-SO 2 -), sulfonylamide (-SO 2 NR 4 -), aminosulfonyl (-NR 4 SO 2 -), carbonyl (-(CO)-), amide (-(CO)NR 4 -), reverse amide (-NR 4 (CO)-), esters (-(CO)O-), substituted or unsubstituted monocyclic or bicyclic C 3-10 Cycloalkyl, substituted or unsubstituted monocyclic or bicyclic C 3-10 Heterocycloalkyl, substituted or unsubstituted monocyclic or bicyclic C 6-10 Aryl or substituted or unsubstituted monocyclic C 5-10 is heteroaryl; R 1 is halo, cyano, hydroxy, amino, N(R 5 ) 2 , OR 5 , substituted or unsubstituted, C 1-5 Alkyl, C 3-10 Cycloalkyl, C 1-5 Alkyl hydroxy, C 1-5 Alkenylhydroxy, C 1-5 Alkynylhydroxy, C 1-5 Alkylamines, C 1-5 Alkenylamine or C 1-5 Alkynylamines, substituted or unsubstituted monocyclic or bicyclic C 3-10 Heterocycloalkyl, substituted or unsubstituted monocyclic C 5-10 Heteroaryl, phosphate, or substituted or unsubstituted C 1-3 is an alkyl phosphate; R 2 is H, halo, cyano or hydroxy; R 4 is H, substituted or unsubstituted C 1-5 Alkyl, substituted or unsubstituted C 1-5 Alkoxy, or substituted or unsubstituted C 1-5 is an alkyl carboxylic acid; R 5 is H, substituted or unsubstituted C 1-5 Alkyl, substituted or unsubstituted C 1-5 Alkoxy, or substituted or unsubstituted C 1-5 It is an alkyl carboxylic acid. or an enantiomer, diastereomer, racemate, solvate, hydrate or pharma- ceutically acceptable salt thereof.

2. Ar 1 is an unsubstituted monocyclic ring C containing one or more heteroatoms selected from the group consisting of N, O and S; 5-7 2. The compound of claim 1, or an enantiomer, diastereomer, racemate, solvate, hydrate, or pharma- ceutically acceptable salt thereof, which is heteroaryl.

3. Ar 1 is a monocyclic ring C containing 1 or 2 heteroatoms selected from the group consisting of N, O and S; 5-6 2. The compound of claim 1, or an enantiomer, diastereomer, racemate, solvate, hydrate, or pharma- ceutically acceptable salt thereof, which is heteroaryl.

4. Ar 1 2. The compound of claim 1, or an enantiomer, diastereomer, racemate, solvate, hydrate or pharma- ceutically acceptable salt thereof, wherein is pyrazole or pyridine.

5. Ar 2 is a monocyclic or bicyclic C 6-10 aryl, wherein the monocyclic or bicyclic C 6-10 2. The compound of claim 1, or an enantiomer, diastereomer, racemate, solvate, hydrate or pharma- ceutically acceptable salt thereof, wherein aryl is unsubstituted or substituted with halo.

6. Ar 2 2. The compound of claim 1, wherein is chloro substituted or unsubstituted phenyl, or an enantiomer, diastereomer, racemate, solvate, hydrate or pharma- ceutically acceptable salt thereof.

7. The compound of claim 1, or an enantiomer, diastereomer, racemate, solvate, hydrate or pharma- ceutically acceptable salt thereof, wherein D and E together with the atoms to which they are bound form a substituted or unsubstituted pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine or octahydropyranopyridine.

8. G is an ether (-O-), a thioether (-S-), a sulfinyl (-SO-), a sulfonyl (-SO 2 -), sulfonylamide (-SO 2 NR 4 -), aminosulfonyl (-NR 4 SO 2 -), carbonyl (-(CO)-), amide (-(CO)NR 4 -), reverse amide (-NR 4 (CO)-), esters (-(CO)O-), substituted or unsubstituted monocyclic or bicyclic C 3-8 Cycloalkyl, substituted or unsubstituted monocyclic or bicyclic C 3-8 Heterocycloalkyl, substituted or unsubstituted monocyclic or bicyclic C 6-10 Aryl or substituted or unsubstituted monocyclic C 5-8 heteroaryl; said monocyclic or bicyclic C 3-8 Heterocycloalkyl and the monocyclic C 5-8 2. The compound of claim 1, or an enantiomer, diastereomer, racemate, solvate, hydrate, or pharma- ceutically acceptable salt thereof, wherein heteroaryl contains one or more heteroatoms selected from the group consisting of N, O, and S.

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

10. 1. (R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)butan-1-ol, 2. (S)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propan-1-ol, 3. (S)-2-((4-(4-chlorophenyl)-6-(pyridin-3-yl)pyrimidin-2-yl)amino)propan-1-ol, 4. 2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)-2-methylpropan-1-ol, 5. 2-((4-(4-chlorophenyl)-6-(pyridin-3-yl)pyrimidin-2-yl)amino)-2-methylpropan-1-ol, 6. 2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)ethan-1-ol, 7. 3-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propan-1-ol, 8. (S)-1-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propan-2-ol, 9. (R)-1-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propan-2-ol, 10. 3-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propane-1,2-diol, 11. (R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propan-1-ol, 12. 2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)-3-methylbutan-1-ol, 13. (S)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)-3-methylbutan-1-ol, 14. (R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)-3-methylbutan-1-ol, 15. 2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)butan-1-ol, 16. 2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propane-1,3-diol, 17. (R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)-1-phenylethan-1-ol, 18. (S)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)-1-phenylethan-1-ol, 19. 6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrimidin-4-amine, 20. N 1 -(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-N 3 ,N 3 -dimethylpropane-1,3-diamine, 21. 6-(4-chlorophenyl)-N-ethyl-2-(pyridin-3-yl)pyrimidin-4-amine, 22. 6-(4-chlorophenyl)-N-propyl-2-(pyridin-3-yl)pyrimidin-4-amine, 23. N-butyl-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-amine, 24. 1-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)butan-2-ol, 25. 6-(4-chlorophenyl)-N-(cyclopropylmethyl)-2-(pyridin-3-yl)pyrimidin-4-amine, 26. 6-(4-chlorophenyl)-N-cyclopentyl-2-(pyridin-3-yl)pyrimidin-4-amine, 27. 4-(4-chlorophenyl)-6-(4-methylpiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine, 28. N-(tert-butyl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-amine, 29. (1R,2R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol, 30. (1S,2R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol, 31. 6-(4-chlorophenyl)-N-(pyridin-2-ylmethyl)-2-(pyridin-3-yl)pyrimidin-4-amine, 32. 6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(pyridin-3-ylmethyl)pyrimidin-4-amine, 33. 6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(pyridin-4-ylmethyl)pyrimidin-4-amine, 34. trans-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexan-1-ol, 35. trans-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexan-1-ol, 36. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-2-yl)methanol, 37. 2-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-2-yl)ethan-1-ol, 38. (R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-ol, 39. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-ol, 40. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanol, 41. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-ol, 42. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol, 43. 2-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)ethan-1-ol, 44. 3-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)propan-1-ol, 45. 4-(4-chlorophenyl)-6-(4-methoxypiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine, 46. ​​4-(4-chlorophenyl)-6-(piperidin-1-yl)-2-(pyridin-3-yl)pyrimidine, 47. 4-(4-chlorophenyl)-6-(2-methylpiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine, 48. 4-(4-chlorophenyl)-6-(3-methylpiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine, 49. 4-(4-chlorophenyl)-6-(2,6-dimethylpiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine, 50. 4-(4-chlorophenyl)-6-(3,5-dimethylpiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine, 51. 4-(4-chlorophenyl)-6-(3,3-difluoropiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine, 52. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(3-(trifluoromethyl)piperidin-1-yl)pyrimidine, 53. 4-(4-chlorophenyl)-6-(3-ethylpiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine, 54. 6-(4-chlorophenyl)-N-(piperidin-4-yl)-2-(pyridin-3-yl)pyrimidin-4-amine, 55. 6-(4-chlorophenyl)-N-(piperidin-3-ylmethyl)-2-(pyridin-3-yl)pyrimidin-4-amine, 56. 6-(4-chlorophenyl)-N-(piperidin-4-ylmethyl)-2-(pyridin-3-yl)pyrimidin-4-amine, 57. 6-(4-chlorophenyl)-N-(1-methylpiperidin-4-yl)-2-(pyridin-3-yl)pyrimidin-4-amine, 58. 6-(4-chlorophenyl)-N-(2-(piperidin-4-yl)ethyl)-2-(pyridin-3-yl)pyrimidin-4-amine, 59. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-2-yl)methanamine, 60. (R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-amine, 61. (S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-amine, 62. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanamine, 63. (S)-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanamine, 64. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-amine, 65. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanamine, 66. (1R,2S)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol, 67. (1S,2S)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol, 68. trans-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol, 69. (1R,2R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexan-1-ol, 70. cis-4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-2,6-dimethylmorpholine, 71. 4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)morpholine, 72. 6-(4-chlorophenyl)-N-(morpholin-2-ylmethyl)-2-(pyridin-3-yl)pyrimidin-4-amine, 73. 4-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)morpholine, 74. 4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)thiomorpholine, 75. 6-(4-chlorophenyl)-N-(3-morpholinopropyl)-2-(pyridin-3-yl)pyrimidin-4-amine, 76. (R)-4-(4-chlorophenyl)-6-(2-methylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 77. (R)-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-methylpiperazin-1-yl)(phenyl)methanone, 78. (R)-4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazine-2-carboxylate methyl 79. (R)-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-2-yl)methanol, 80. 4-(4-chlorophenyl)-6-(4-(2,3-dichlorophenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 81. 4-(4-chlorophenyl)-6-(4-(2,5-dimethoxybenzyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 82. 2-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)ethan-1-ol, 83. 4-(4-chlorophenyl)-6-(4-(2-methoxyphenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 84. 4-(4-chlorophenyl)-6-(4-(2-ethoxyphenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 85. 4-(4-chlorophenyl)-6-(4-(2-fluorophenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 86. (4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)(furan-2-yl)methanone, 87. 4-(4-chlorophenyl)-6-(4-phenethylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 88. 6-(4-chlorophenyl)-N-(2-(piperazin-1-yl)ethyl)-2-(pyridin-3-yl)pyrimidin-4-amine, 89. 4-(4-chlorophenyl)-6-(4-(pyridin-2-yl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 90. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidine, 91. 4-(2-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)ethyl)morpholine, 92. 4-(4-chlorophenyl)-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-(pyridin-3-yl)pyrimidine, 93. trans-4-(4-chlorophenyl)-6-(4-cinnamylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 94. 4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-2-one, 95. 4-(4-chlorophenyl)-6-(4-phenylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 96. 4-(4-chlorophenyl)-6-(4-propylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 97. 4-(4-(benzo[d][1,3]dioxol-5-ylmethyl)piperazin-1-yl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidine, 98. (S)-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-2-yl)methanol, 99. 4-(4-chlorophenyl)-6-(4-(4-fluorophenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 100. 6-(4-chlorophenyl)-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2-(pyridin-3-yl)pyrimidin-4-amine, 101. 6-(4-chlorophenyl)-N-(piperidin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-amine, 102. 4-(4-chlorophenyl)-6-(piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 103. trans-4-(4-chlorophenyl)-6-(2,5-dimethylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 104. cis-4-(4-chlorophenyl)-6-(3,5-dimethylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 105. 4-(4-chlorophenyl)-6-(4-methylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 106. 4-(4-chlorophenyl)-6-(4-ethylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 107. 4-(4-chlorophenyl)-6-(4-(methylsulfonyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 108. 1-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)ethan-1-one, 109. 4-(4-chlorophenyl)-6-(3-ethylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 110. Ethyl 4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazine-1-carboxylate.

111. 4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazine-2-carboxylic acid, 112. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazine-2-carboxylate methyl 113. (S)-4-(4-chlorophenyl)-6-(2-phenylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 114. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(4-(o-tolyl)piperazin-1-yl)pyrimidine, 115. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(4-(p-tolyl)piperazin-1-yl)pyrimidine, 116. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(4-(m-tolyl)piperazin-1-yl)pyrimidine, 117. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)pyrimidine, 118. 4-(4-chlorophenyl)-6-(4-(2,3-dimethylphenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 119. 4-(4-chlorophenyl)-6-(4-(3,4-dichlorophenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 120. 4-(4-chlorophenyl)-6-(4-(4-methoxyphenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 121. 4-(4-chlorophenyl)-6-(4-(4-nitrophenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 122. 4-(4-chlorophenyl)-6-(3-(4-methylpiperazin-1-yl)pyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidine, 123. 4-(4-benzhydrylpiperazin-1-yl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidine, 124. 4-(4-chlorophenyl)-6-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 125. 1'-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)spiro[indene-1,4'-piperidine], 126. 6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(pyrrolidin-3-yl)pyrimidin-4-amine, 127. (R)-6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(pyrrolidin-3-yl)pyrimidin-4-amine, 128. (R)-6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(pyrrolidin-3-ylmethyl)pyrimidin-4-amine, 129. 6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(2-(pyrrolidin-1-yl)ethyl)pyrimidin-4-amine, 130. 6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(3-(pyrrolidin-1-yl)propyl)pyrimidin-4-amine, 131. 6-(4-chlorophenyl)-N-(2-(1-methylpyrrolidin-2-yl)ethyl)-2-(pyridin-3-yl)pyrimidin-4-amine, 132. N-(1-benzylpyrrolidin-3-yl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-amine, 133. (3R,4S)-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)pyrrolidin-3-ol, 134. (3S,4R)-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)pyrrolidin-3-ol, 135. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(pyrrolidin-1-yl)pyrimidine, 136. 4-(4-chlorophenyl)-6-(2-methylpyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidine, 137. (S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 138. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)methanol, 139. (R)-4-(4-chlorophenyl)-6-(3-fluoropyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidine, 140. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-amine, 141. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-N-methylpyrrolidin-3-amine, 142. (6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)proline methyl ester, 143. N-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)acetamide, 144. (2R,3R)-3-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)butan-2-ol, 145. 3-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)butan-2-ol, 146. 1-(4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)piperidin-1-yl)ethan-1-one, 147. (R)-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanol, 148. (S)-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanol, 149. 6-(4-chlorophenyl)-N-(2-(piperidin-1-yl)ethyl)-2-(pyridin-3-yl)pyrimidin-4-amine, 150. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidine-4-carbonitrile, 151. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(3-(trifluoromethyl)phenyl)piperidin-4-ol, 152. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyrimidine, 153. 4-(4-chlorophenyl)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-ol, 154. 1-(4-(((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)ethan-1-one, 155. 1-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-phenylpiperidin-4-yl)ethan-1-one, 156. 4-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)morpholine, 157. 4-(4-chlorophenyl)-6-(4-(3,5-dichlorophenyl)piperidin-1-yl)-2-(pyridin-3-yl)pyrimidine, 158. 6-(4-chlorophenyl)-N-((1-cyclohexylpiperidin-3-yl)methyl)-2-(pyridin-3-yl)pyrimidin-4-amine, 159. N-((1-benzylpiperidin-4-yl)methyl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-amine, 160. ethyl 3-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)-3-oxopropanoate, 161. 2-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)ethyl acetate, 162. (1S,3R)-3-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol, 163. (S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-ol, 164. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-N,N-dimethylpyrrolidin-3-amine, 165. 2-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-2-yl)-N,N-dimethylethan-1-amine, 166. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-one, 167. 6-(4-chlorophenyl)-N-methyl-N-(piperidin-4-yl)-2-(pyridin-3-yl)pyrimidin-4-amine, 168. 6-(4-chlorophenyl)-N-(2-(1-methylpiperidin-2-yl)ethyl)-2-(pyridin-3-yl)pyrimidin-4-amine, 169. 6-(4-chlorophenyl)-N-(1-(1-methylpiperidin-4-yl)ethyl)-2-(pyridin-3-yl)pyrimidin-4-amine, 170. 6-(4-chlorophenyl)-N-((1-(2-methoxyethyl)piperidin-4-yl)methyl)-2-(pyridin-3-yl)pyrimidin-4-amine, 171. 2-(4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)piperidin-1-yl)acetate methyl 172. 2,2,2-trifluoroacetate 1-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)ethyl 173. 6-(4-chlorophenyl)-N-(1-methylpiperidin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-amine, 174. (1S,2R)-2-((6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol, 175. (R)-1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperidin-3-ol, 176. 1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperidin-4-ol, 177. (1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperidin-4-yl)methanol, 178. 2-(1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperidin-4-yl)ethan-1-ol, 179. 3-(1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperidin-4-yl)propan-1-ol, 180. 4-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-6-(4-methylpiperidin-1-yl)pyrimidine, 181. 4-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-6-(4-methylpiperazin-1-yl)pyrimidine, 182. 2-(4-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperazin-1-yl)ethan-1-ol, 183. (S)-1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 184. 1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperidine-4-carbonitrile, 185. (R)-(1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperidin-3-yl)methanol, 186. (R)-1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 187. (1S,3R)-3-((6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol, 188. (R)-2-((6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)butan-1-ol, 189. trans-4-((6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclohexan-1-ol, 190. 7-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)octahydro-2H-pyrano[2,3-c]pyridine, 191. 7-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)octahydro-2H-pyrano[2,3-c]pyridin-4-ol, 192. (2R,3R)-3-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)pentan-2-ol, 193. 6-(4-chlorophenyl)-N-((1-methylpiperidin-4-yl)methyl)-2-(pyridin-3-yl)pyrimidin-4-amine, 194. (R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 195. (S)-6-(4-chlorophenyl)-N-(2-(methoxymethyl)pyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-amine, 196. (S)-4-(4-chlorophenyl)-6-(3-fluoropyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidine, 197. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidine, 198. 4-(4-chlorophenyl)-6-(3,3-difluoropyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidine, 199. 4-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)morpholine, 200. 5-(((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)methyl)pyrrolidin-2-one, 201. trans-6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(4-(pyrrolidin-1-yl)tetrahydrofuran-3-yl)pyrimidin-4-amine, 202. 6-(4-chlorophenyl)-N-((3S,4S)-4-methoxy-1-methylpyrrolidin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-amine, 203. (R)-6-(4-chlorophenyl)-N-(piperidin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-amine, 204. 6-(4-chlorophenyl)-N-(piperidin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-amine, 205. 6-(4-chlorophenyl)-N-((3R,4R)-3-fluoropiperidin-4-yl)-2-(pyridin-3-yl)pyrimidin-4-amine, 206. (S)-6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(pyrrolidin-3-ylmethyl)pyrimidin-4-amine, 207. (2R,4R)-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)pyrrolidine-2-carboxylate methyl 208. (2R,4S)-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)pyrrolidine-2-carboxylic acid, 209. trans-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)-1-isopropylpyrrolidin-3-ol, 210. (R)-4-(3-(chloromethyl)pyrrolidin-1-yl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidine, 211. (S)-4-(3-(chloromethyl)pyrrolidin-1-yl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidine, 212. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidine-3-carbonitrile, 213. (R)-1-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)butan-2-ol, 214. (1R,3S)-3-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol, 215. cis-(4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexyl)methanol, 216. cis-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexan-1-ol, 217. trans-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexan-1-ol, 218. 4-(4-chlorophenyl)-6-(4-(2-methoxyethyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 219. (3S,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-ol, 220. (3R,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-ol, 221. (3R,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-ol, 222. (3S,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-ol, 223. 1-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-2-hydroxyethan-1-one, 224. 2-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)propan-1-ol, 225. N-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)-2-methoxyacetamide, 226. (1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol, 227. (1-(2-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol, 228. (1-(6-(4-methoxyphenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol, 229. (1-(2-(pyridin-3-yl)-6-(p-tolyl)pyrimidin-4-yl)piperidin-4-yl)methanol, 230. (3R,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidine-3,4-diol, 231. (3R,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidine-3,4-diol, 232. 1-(3-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)tetrahydropyrimidin-1(2H)-yl)ethan-1-one, 233. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)piperidin-3-ol, 234. (3R,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-fluoropyrrolidin-3-ol, 235. (3R,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-fluoropyrrolidin-3-ol, 236. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)pyrrolidin-3-ol, 237. N-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)-2-hydroxypropanamide, 238. N-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)-2-hydroxyacetamide, 239. 2-((4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)ethan-1-ol, 240. (S)-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)methanol, 241. N-((3R,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-hydroxypyrrolidin-3-yl)acetamide, 242. (3R,4R)-4-acetamido-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl acetate, 243. N-((3R,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-hydroxypyrrolidin-3-yl)acetamide, 244. N-((3S,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-hydroxypyrrolidin-3-yl)acetamide, 245. N-((3S,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-hydroxypyrrolidin-3-yl)acetamide, 246. (1-(6-(4-chloro-3-fluorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol, 247. (3S,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)piperidin-3-ol, 248. (3S,4R)-4-(hydroxymethyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-3-ol, 249. ((3S,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-yl)methanol, 250. ((3S,4R)-3-fluoro-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol, 251. ((3R,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-yl)methanol, 252. ((3R,4S)-3-fluoro-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol, 253. ((3R,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-yl)methanol, 254. ((3R,4R)-3-fluoro-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol, 255. (3S,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)pyrrolidin-3-ol, 256. (3S,4R)-4-(hydroxymethyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol, 257. (3R,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)pyrrolidin-3-ol, 258. (3R,4R)-4-(hydroxymethyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol, 259. (3R,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)piperidin-3-ol, 260. (3R,4R)-4-(hydroxymethyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-3-ol, 261. (3S,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)piperidin-3-ol, 262. (3S,4S)-4-(hydroxymethyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-3-ol, 263. (S)-1-(2-(4-methylpyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol, 264. (3R,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)piperidin-3-ol, 265. (3R,4S)-4-(hydroxymethyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-3-ol, 266. (3S,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)pyrrolidin-3-ol, 267. (3S,4S)-4-(hydroxymethyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol, 268. (1-(6-(4-morpholinophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol, 269. (S)-1-(2-(2-methylpyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol, 270. (S)-3-(4-(3-hydroxypyrrolidin-1-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)pyridin-2-ol, 271. 5-chloro-2-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)phenol, 272. (S)-tert-Butyl 4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-2-(hydroxymethyl)piperazine-1-carboxylate, 273. 2-Chloro-5-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)phenol, 274. N-(4-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)phenyl)methanesulfonamide, 275. (1-(6-(4-(4-methylpiperazin-1-yl)phenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol, 276. (1-(6-(3-fluoro-4-morpholinophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol, 277. (1-(2-(pyridin-3-yl)-6-(2,4,6-trifluorophenyl)pyrimidin-4-yl)piperidin-4-yl)methanol, 278. (1-(2-(pyridin-3-yl)-6-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol, 279. (S)-(4-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)morpholin-2-yl)methanol, 280. (R)-(4-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)morpholin-2-yl)methanol, 281. ((3S,4S)-3-fluoro-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol, 282. ((3S,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-yl)methanol, 283. (3S,4S)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidine-3,4-diol, 284. (3S,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidine-3,4-diol, 285. 3-(4-(4-(hydroxymethyl)piperidin-1-yl)-6-(4-morpholinophenyl)pyrimidin-2-yl)pyridin-2-ol, 286. (1-(2-(1-methyl-1H-pyrazol-4-yl)-6-(4-morpholinophenyl)pyrimidin-4-yl)piperidin-4-yl)methanol, 287. (1-(6-(3-fluoro-4-morpholinophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperidin-4-yl)methanol, 288. (1-(6-(1H-indazol-5-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol, 289. (1-(6-(6-morpholinopyridin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol, 290. 5-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)indolin-2-one, 291. 4-(4-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)phenyl)morpholin-3-one, 292. 4-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)benzoic acid, 293. 4-(1-(6-(1-methyl-1H-pyrazol-3-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol, 294. (1-(6-(5-fluoropyridin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol, 295. (S)-3-(4-(3-hydroxypyrrolidin-1-yl)-6-(6-morpholinopyridin-3-yl)pyrimidin-2-yl)pyridin-2-ol, 296. (S)-1-(6-(4-fluoro-3-nitrophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 297. (S)-1-(6-(4-morpholino-3-nitrophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 298. (S)-1-(6-(3-amino-4-morpholinophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 299. (S)-N-(5-(6-(3-hydroxypyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)-2-morpholinophenyl)acetamide, 300. (S)-1-(6-(6-fluoropyridin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 301. (S)-1-(6-(6-((2-(dimethylamino)ethyl)amino)pyridin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 302. (3S)-1-(6-(6-(2,6-dimethylmorpholino)pyridin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 303. 5-chloro-2-(6-(4-((2-hydroxyethyl)sulfonyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)phenol, 304. (S)-3-(4-(4-chloro-2-hydroxyphenyl)-6-(3-hydroxypyrrolidin-1-yl)pyrimidin-2-yl)pyridin-2-ol, 305. (S)-1-(6-(4-aminophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 306. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(4-(vinylsulfonyl)piperazin-1-yl)pyrimidine, 307. (1-(6-(2,4-dichlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol, 308. (S)-(4-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperazin-2-yl)methanol, 309. (R)-(4-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperazin-2-yl)methanol, 310. (R)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidine-3-carboxylic acid, 311. (R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidine-3-carboxylic acid, 312. (R)-1-(2-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidine-3-carboxylic acid, 313. (R)-1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)pyrrolidine-3-carboxylic acid, 314. (R)-2-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)isoxazolidin-4-ol, 315. (S)-1-(6-(6-morpholinopyridin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 316. (S)-1-(6-(4-chloro-2-hydroxyphenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 317. (S)-3-(6-(3-hydroxypyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyridin-2-ol, 318. (1-(6-(6-fluoropyridin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol, 319. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)azetidin-3-ol, 320. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)azetidin-3-yl)methanol, 321. 4-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-6-(4-(methylsulfonyl)piperazin-1-yl)pyrimidine, 322. (S)-1-(6-(4-chlorophenyl)-2-(3-hydroxyphenyl)pyrimidin-4-yl)pyrrolidin-3-ol formate.

322. (S)-1-(6-(4-chlorophenyl)-2-(3-hydroxyphenyl)pyrimidin-4-yl)pyrrolidin-3-ol, 323. (S)-1-(6-(4-chlorophenyl)-2-(5-fluoropyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 324. (S)-1-(6-(4-chlorophenyl)-2-(pyridin-4-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 325. 4-(4-chlorophenyl)-2-(5-fluoropyridin-3-yl)-6-(4-(methylsulfonyl)piperazin-1-yl)pyrimidine, 326. 4-(4-chlorophenyl)-6-(4-(methylsulfonyl)piperidin-1-yl)-2-(pyridin-3-yl)pyrimidine, 327. (S)-1-(2-(5-fluoropyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol, 328. 4-(4-chlorophenyl)-6-(4-(cyclopropylsulfonyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 329. (S)-1-(6-(4-chlorophenyl)-2-(pyridazin-4-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 330. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)azepan-4-ol, 331. 2-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane, 332. (S)-1-(6-(4-chlorophenyl)-2-(2-methyl-2H-tetrazol-5-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 333. (S)-1-(2-(2-methyl-2H-tetrazol-5-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol, 334. 4-(4-chlorophenyl)-2-(2-methyl-2H-tetrazol-5-yl)-6-(4-(methylsulfonyl)piperazin-1-yl)pyrimidine, 335. 4-(4-chlorophenyl)-6-(4-((2-fluoroethyl)sulfonyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 336. (S)-1-(6-(4-chlorophenyl)-2-(isoxazol-4-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 337. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(methylsulfonyl)piperidin-4-yl)methanol, 338. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)azepan-3-ol, 339. 4-(4-chlorophenyl)-6-(4-((difluoromethyl)sulfonyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine, 340. (S)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol, 341. 4-(4-(methylsulfonyl)piperazin-1-yl)-2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidine, 342. (S)-1-(6-(4-chlorophenyl)-2-(5,6-difluoropyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 343. (3S,4R)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidine-3,4-diol, 344. (S)-1-(6-(4-chlorophenyl)-[2,5'-bipyrimidin]-4-yl)pyrrolidin-3-ol, 345. (S)-1-(6-(4-chlorophenyl)-2-(6-fluoropyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 346. (S)-1-(6-(4-chlorophenyl)-2-(2-fluoropyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 347. (S)-1-(6-(4-chlorophenyl)-2-(pyridin-2-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 348. 2-((4-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)ethanol, 349. 2-((4-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)ethan-1-ol, 350. (S)-1-(2-(isothiazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol, 351. (4-(methylsulfonyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol, 352. 1-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-3-hydroxypropan-1-one, 353. 2-((4-(2-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)ethanol, 354. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-(dimethylamino)piperidin-4-ol, 355. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-5-(dimethylamino)piperidin-3-ol, 356. (1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-4-(methylsulfonyl)piperidin-4-yl)methanol, 357. (1-(2-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)-4-(methylsulfonyl)piperidin-4-yl)methanol, 358. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-(dimethylamino)piperidin-4-yl)methanol, 359. 2-((4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-methylpiperazin-1-yl)sulfonyl)ethan-1-ol, 360. 2-((1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)amino)ethanol, 361. 1-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-4-hydroxybutan-1-one, 362. 3-((4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)propan-1-ol, 363. 1-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-3,4-dihydroxybutan-1-one, 364. 1-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-2,3-dihydroxybutan-1-one, 365. 4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-6-methylpiperazin-2-one, 366. (S)-3-(4-(3-hydroxypyrrolidin-1-yl)-6-(6-morpholinopyridin-3-yl)pyrimidin-2-yl)pyridin-2-ol, 367. (S)-4-(4-(6-(3-hydroxypyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)phenyl)morpholin-3-one, 368. 2-((4-(6-(4-chlorophenyl)-2-(isothiazol-4-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)ethanol, 369. 3-((4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)propane-1,2-diol, 370. 2-((4-(2-(isothiazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)ethanol, 371. (S)-2-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-2-yl)ethanol, 372. (S)-4-(5-(6-(3-hydroxypyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyridin-2-yl)morpholin-3-one, 373. (S)-3-(4-(3-fluoro-4-morpholinophenyl)-6-(3-hydroxypyrrolidin-1-yl)pyrimidin-2-yl)pyridin-2-ol, 374. (S)-1-(6-(4-((2-(dimethylamino)ethyl)amino)phenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol, 375. (S)-1-(6-(4-(2-(dimethylamino)ethoxy)phenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol, and 376. (S)-1-(6-(4-((2-hydroxyethyl)amino)phenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol Compounds selected from 1 to 376, enantiomers, diastereomers, racemates, solvates, hydrates or pharma- ceutically acceptable salts thereof.

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

12. 12. A pharmaceutical composition according to claim 11 for use in the prevention and / or treatment of a disease or condition mediated by the aryl hydrocarbon receptor (AhR).

13. The pharmaceutical composition of claim 12, wherein the disease or condition mediated by the aryl hydrocarbon receptor (AhR) is cancer, a cancerous condition, a tumor, a fibrotic disease, a condition involving dysregulated immune response, or other disorder associated with abnormal signaling of the AhR.

14. 12. The pharmaceutical composition of claim 11 for use in inhibiting cancer cell proliferation, tissue invasion, metastasis and angiogenesis in a subject having cancer, a cancerous condition or a tumor.

15. 15. The pharmaceutical composition of claim 14, wherein the cancer is selected from the group consisting of breast cancer, squamous cell carcinoma, lung cancer, peritoneal cancer, hepatocellular carcinoma, gastric cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, colon cancer, colorectal cancer, endometrial cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, head and neck cancer, B-cell lymphoma, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), hairy cell leukemia and chronic myeloblastic leukemia.

16. 14. The pharmaceutical composition of claim 13, wherein the fibrotic disease is selected from the group consisting of hepatic fibrosis, liver cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, renal interstitial fibrosis, fibrotic disorders associated with diabetes, myelofibrosis, scleroderma, mottled scleroderma, keloids, hypertrophic scars, nevi, diabetic retinopathy, proliferative vitreoretinopathy and sarcoidosis.

17. 14. The pharmaceutical composition of claim 13, wherein the condition involving dysregulated immune response is selected from the group consisting of sepsis, multiple organ failure, inflammatory kidney disease, chronic enteritis, pancreatitis, peritonitis, inflammatory skin disease, inflammatory eye disease, rheumatic disease, systemic lupus erythematosus and multiple sclerosis.

18. Use of a compound according to claim 1 or 10, or an enantiomer, diastereomer, racemate, solvate, hydrate or pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for modulating the activity of an aryl hydrocarbon receptor (AhR) in a subject.

19. Use of a compound according to claim 1 or 10, or an enantiomer, diastereomer, racemate, solvate, hydrate or pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for the prophylaxis or treatment of a disease or condition mediated by the aryl hydrocarbon receptor (AhR) in a subject.

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

21. 21. The use of claim 20, wherein the cancer is selected from the group consisting of breast cancer, squamous cell carcinoma, lung cancer, peritoneal cancer, hepatocellular carcinoma, gastric cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, colon cancer, colorectal cancer, endometrial cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, head and neck cancer, B-cell lymphoma, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), hairy cell leukemia and chronic myeloblastic leukemia.

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

23. 21. The use according to claim 20, wherein the condition involving dysregulated immune response is selected from the group consisting of sepsis, multiple organ failure, inflammatory kidney disease, chronic enteritis, pancreatitis, peritonitis, inflammatory skin disease, inflammatory eye disease, rheumatic disease, systemic lupus erythematosus and multiple sclerosis.

24. 13. Use of a compound according to claim 1 or 10, or an enantiomer, diastereomer, racemate, solvate, hydrate or pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting cancer cell proliferation, tissue invasion, metastasis and angiogenesis in a subject having cancer, a cancerous condition or a tumor.

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