RU2826628C1 - Aminopyrimidine derivatives and use thereof as aromatic hydrocarbon receptor modulators - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: group of inventions relates to a compound of formula (I) or its enantiomer, diastereomer, racemate, solvate, hydrate or pharmaceutically acceptable salt:

also relates to a compound selected from compounds 1–187 and 189–376, or an enantiomer, diastereomer, racemate, solvate, hydrate or pharmaceutically acceptable salt thereof, also relates to a pharmaceutical composition for preventing and/or treating a disease or condition mediated by an aromatic hydrocarbon receptor (AhR) and to a pharmaceutical composition for inhibiting proliferation, tissue invasion, metastasis and angiogenesis of malignant tumour cells in a subject with a malignant tumour or cancer condition, also relates to a method of modulating AhR activity in a subject, a method for preventing or treating a disease or condition mediated by an aromatic hydrocarbon receptor (AhR) in a subject, and a method for inhibiting proliferation, tissue invasion, metastasis and angiogenesis of cancer cells in a subject with a malignant tumour or cancer condition.

EFFECT: group of inventions provides the development of compounds which have selective inhibitory action on AhR.

24 cl, 2 tbl, 376 ex

Description

Field of technology

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No. 63/000,584, filed March 27, 2020, which is incorporated herein by reference in its entirety.

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

Prior art

The aromatic hydrocarbon receptor (AhR) is a ligand-activating transcription factor and is well known as an important intracellular chemosensor responding to both natural and synthetic environmental compounds. As is well known, AhR is a member of the circadian rhythm protein (PER)-AhR nuclear translocator (ARNT)-targeted homolog (SIM) superfamily of transcription factors, in which the PER-ARNT-SIM(PAS) domain responds to ligands (Burbach et al, PNAS September 1, 1992 89 (17) 8185-8189). AhR, activated by several binding ligands, translocates to the nucleus and dimerizes with its ARNT partner protein. This heterodimeric complex interacts with xenobiotic response elements (XREs), and it directly or indirectly controls the expression of AhR-related genes. One well-studied endogenous ligand is kynurenine, which is produced by tryptophan 2,3-dioxygenase (Opitz et al, Nature , Nature. 2011 Oct 5;478(7368):197-203) or IDO (Mezrich, J Immunol. 2010 Sep 15;185(6):3190-8.) or indoleamine 2,3-dioxygenase (Mezrich, J Immunol. 2010 Sep 15;185(6):3190-8.). Recent studies have found that high plasma kynurenine concentrations in various cancer patients and high plasma kynurenine/tryptophan ratio are correlated with poor prognosis after PD-1 (programmed cell death protein 1) blockade in several types of malignancies, including lung cancer, melanoma, and renal cell carcinoma (Haoxin Li et al, Nat Commun. 2019 Sep 25;10(1):4346).

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

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

Description of the invention

Technical task

Thus, the object of the present invention is to provide new compounds or their enantiomers, diastereoisomers, racemates, solvates, hydrates or pharmaceutically acceptable salts as AhR modulators.

The aim of the present invention is to provide a pharmaceutical composition for modulating AhR activity, containing the said compounds as AhR modulators.

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

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

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

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

Technical solution

BRIEF DESCRIPTION OF THE INVENTION

The present invention provides novel compounds or an enantiomer, diastereomer or pharmaceutically acceptable salt thereof that are effective as AhR modulators or antagonists. The compounds are represented by formula (I)

in which:

X ¹ , X ² and X ³ each independently represent CR ² , N or NR ³ ;

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

D is H, halo, cyano, hydroxy, amino, substituted or unsubstituted C _1-5 alkyl, mono- or bicyclic C _3-10 cycloalkyl, C _1-5 alkylhydroxy, C _1-5 alkenylhydroxy, C _1-5 alkynylhydroxy, C _1-5 alkylamine, C _1-5 alkenylamine, C _1-5 alkynylamine, mono- or bicyclic C _3-10 heterocycloalkyl, mono- or bicyclic C _3-10 heteroaryl,

E is absent (direct bond), is amino, substituted or unsubstituted C _1-5 alkyl, mono- or bicyclic C _3-10 cycloalkyl, C _1-5 alkylhydroxy, C _1-5 alkenylhydroxy, C _1-5 alkynylhydroxy, C _1-5 alkylamine, C _1-5 alkenylamine, C _1-5 alkynylamine, mono- or bicyclic C _3-10 heterocycloalkyl, mono- or bicyclic C _3-10 heteroaryl,

or D and E, together with the atoms to which they are attached, are combined to form a substituted or unsubstituted mono- or bicyclic C _3-10 heterocycloalkyl ring;

G is absent (direct bond), is H, halo, cyano, hydroxy, amino, nitro, ether (-O-), thioether (-S-), sulfinyl (-SO-), sulfonyl (-SO ₂ -), sulfonylamido (-SO ₂ NR ⁴ -), aminosulfonyl (-NR ⁴ SO ₂ -), carbonyl (-(CO)-), amido (-(CO)NR ⁴ -), reverse amido (-NR ⁴ (CO)-), ester (-(CO)O-), substituted or unsubstituted mono- or bicyclic C _3-10 -cycloalkyl, substituted or unsubstituted mono- or bicyclic C _3-10 -heterocycloalkyl, substituted or unsubstituted mono- or bicyclic C _6-10 -aryl and substituted or unsubstituted mono- or bicyclic C _5-10 -heteroaryl;

R ¹ is absent, 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 alkylamine, C _1-5 alkenylamine, C _1-5 alkynylamine, substituted or unsubstituted mono- or bicyclic C _3-10 heterocycloalkyl and substituted or unsubstituted mono- or bicyclic C _5-10 heteroaryl;

R ² is H, halo, cyano, hydroxy and C _1-3 -alkyl;

R ³ is H, halo, cyano, hydroxyl and amino; and

R ⁴ is H, substituted or unsubstituted C _1-5 -alkyl, substituted or unsubstituted C _1-5 -alkoxy and substituted or unsubstituted C _1-5 -alkylcarboxylic acid; and

R ⁵ is H, substituted or unsubstituted C _1-5 alkyl, substituted or unsubstituted C _1-5 alkoxy and substituted or unsubstituted C _1-5 alkylcarboxylic acid;

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

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

The compounds of formula (I) according to the present invention exhibit a valuable pharmacological spectrum of action that could not have been predicted. It was unexpectedly found that the compounds according to the present invention effectively inhibit AhR, and therefore it is possible that said compounds are used for the treatment or prevention of a disease or condition mediated by the aromatic hydrocarbon receptor (AhR), preferably a malignant tumor, cancerous conditions, tumor, fibrosing disorders or conditions with uncontrolled immune responses, or other disorders associated with aberrant AhR signaling in humans and animals.

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

Examples of said fibrosing disorders are fibrosing disorders of internal organs, such as the lungs, heart, kidneys, bone marrow and in particular the liver, as well as dermatological fibroses and fibrosing disorders of the eyes. In the context of the present invention, the term fibrosing disorders includes in particular the following terms: liver fibrosis, liver cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic injury due to diabetes, bone marrow fibrosis and similar fibrosing disorders, scleroderma, annular scleroderma, keloids, hypertrophic scars (including after surgical operations), nevus, diabetic retinopathy, proliferative vitreoretinopathy and connective tissue diseases (e.g. sarcoidosis).

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

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

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

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

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

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

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

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

Tumors of the female reproductive organs include, but are not limited to, cancer of the endometrium, cervix, ovary, vagina, and vulva, as well as uterine sarcoma.

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

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

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

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

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

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

Tumors of the urinary tract include, but are not limited to, malignant tumors of the bladder, penis, kidney, renal pelvis, ureter, urethra, and human papillary renal cell carcinoma.

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

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

Malignant tumors of the eye include, but are not limited to, intraocular melanoma and retinoblastoma.

Examples of malignant liver tumors include, but are not limited to, hepatocellular carcinoma (hepatocellular carcinoma with or without fibrolamellar type), cholangiocarcinoma (carcinoma of the intrahepatic bile ducts), and mixed hepatocellular cholangiocarcinoma.

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

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

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

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

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

The term "treatment" or "method of treatment" as used throughout this document is used in its general sense, such as the management or care of a subject with the aim of combating, alleviating, reducing, ameliorating, or improving a disease or disorder such as a malignancy.

The compounds of the present invention can be used in particular in therapy and prophylaxis, i.e. prevention of tumor growth and metastasis, especially in solid tumors of any signs and stages with or without prior treatment of tumor growth; the malignant tumor is breast cancer, squamous cell carcinoma, lung cancer, peritoneal cancer, hepatocellular carcinoma, gastric cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney cancer or renal cell carcinoma, 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 myeloid leukemia. In some such embodiments, the malignancy is hepatocellular carcinoma.

Some embodiments of these methods may further comprise administering or treating with one or more additional anti-tumor therapies. In some such embodiments, the additional anti-tumor therapies comprise surgery, radiation therapy, biotherapy, immunotherapy, chemotherapy, or any combination thereof.

Some embodiments of these methods may further comprise administering or treating with one or more antineoplastic drugs. In some such embodiments, the antineoplastic drug is a chemotherapeutic agent, a growth inhibitory agent, an antiangiogenesis agent, a cytotoxic agent, an antihormonal agent, a prodrug, or a cytokine.

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

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

The present invention also provides a method for making cells more sensitive to cell death, wherein the cell is treated with one or more compounds of formula (I) according to the present invention before treating the cell to cause or induce cell death. In one aspect, after the cell is treated with one or more compounds of formula (I) according to the present invention, the cell is treated with at least one compound or at least one method, or a combination thereof, to cause DNA damage in order to inhibit the function of a normal cell or to kill the cell.

In other embodiments of the present invention, the cell is killed by treating the cell with one or more DNA damaging agents, i.e., after treating the cell with one or more compounds of formula (I) according to the present invention to sensitize the cell to cell death, the cell is treated with at least one DNA damaging agent to kill the cell. DNA damaging agents useful in the present invention include, but are not limited to, chemotherapeutic agents (e.g., cisplatin), ionizing radiation (x-rays, ultraviolet radiation), carcinogens, and mutagenic agents.

In other embodiments of the invention, a cell is killed by treating the cell with at least one method to cause or induce DNA damage. Such methods include, but are not limited to, activating a cell signaling pathway that results in DNA damage when said pathway is activated, inhibiting a cell signaling pathway that results in DNA damage when said pathway is inhibited, and inducing a biochemical change in a cell, wherein the change results in DNA damage. As a non-limiting example, a DNA repair signaling pathway in a cell can be inhibited, thereby preventing repair of DNA damage and resulting in abnormal accumulation of DNA damage in the cell.

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

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

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

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

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

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

Thus, compositions containing a PD-1/-L1 axis antagonist and an AhR antagonist are remarkably effective in enhancing the immune response and in treating malignant tumors.

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

Examples of other inflammation-associated disorders with aberrant AhR signaling include vaccination against infection and malignancy, viral infections, obesity and diet-induced obesity, fat deposition, metabolic disorders, hepatic steatosis and uterine fibroids (uterine leiomyoma or uterine myoma) in women, chronic kidney disorders, acute and chronic renal failure, diabetic, inflammatory or hypertensive nephropathy, heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemic disease, vascular disorders, thromboembolic disorders, arteriosclerosis, sickle cell anemia, erectile dysfunction, benign prostatic hyperplasia, dysuria associated with benign prostatic hyperplasia, Huntington's disease, dementia, Alzheimer's disease and Creutzfeldt-Jakob disease.

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

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

In some aspects, pharmaceutical compositions comprising an AhR modulator, such as an AhR antagonist of formula (I), are provided for use in the treatment of a malignancy or cancerous condition by modulating AhR activity.

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

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

In some embodiments of these and any similar aspects described herein, the use further comprises one or more additional anti-tumor treatments. In some such embodiments, the additional anti-tumor treatment comprises surgery, radiation therapy, biotherapy, immunotherapy, or chemotherapy.

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

BENEFICIAL EFFECTS OF THE INVENTION

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

The best embodiment of the invention

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

Unless otherwise specified, all technical terms used herein have the same meaning as commonly understood by one skilled in the art to which the present invention pertains. Furthermore, although the invention is described in conjunction with specific methods and examples, their analogs or equivalents should be within the scope of the present invention. Furthermore, numerical values set forth herein are deemed to include the meaning "about" unless expressly indicated. All publications and other references mentioned herein are incorporated herein by reference in their entirety.

The definition of structural units used in this document is described in detail. Unless otherwise specified, each structural unit has the following definition and is used in the sense commonly understood by anyone skilled in the art.

In the context of this document, the term "halo", "halogen", "halide(s)" includes fluoro-, chloro-, bromine- and iodine-.

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

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

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

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

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

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

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

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

In the context of this document, "amino" means -NH ₂ ; and "nitro" means -NO ₂ .

In the context of this document, "carboxy" means the group -C(O)-OH.

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

In the context of the present document, the term "cycloalkyl" means a cyclic alkyl which may be substituted or unsubstituted, and for example, _C3-20 -cycloalkyl is a monovalent saturated hydrocarbon ring system having from 3 to 20 carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like, but are not limited thereto. Preferably, unless otherwise specified, cycloalkyl may be _C3-8 -cycloalkyl or _C3-6 -cycloalkyl.

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

As used herein, "heteroaryl" means a monovalent or divalent substituent derived from a monoheterocyclic or polyheterocyclic aromatic hydrocarbon having from 1 to 10 carbon ring members containing one or more, preferably one to three, heteroatoms selected from N, O or S. Examples of heteroaryl include, but are not limited to, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl, indolyl and the like. Examples of bicyclic heteroaryl include, but are not limited to, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzothiadiazolyl, quinolinyl, isoquinolinyl, furinyl, furopyridinyl, octahydropyranopyridine, benzodioxolyl and the like. Unless otherwise specified, heteroaryl is _C3-10 heteroaryl, preferably _C3-7 heteroaryl, more preferably _C3-5 heteroaryl.

In the context of the present document, "heterocycloalkyl" means a monocyclic, bicyclic, tricyclic or higher cyclic alkyl having from 3 to 10 carbon ring members containing one or more, for example from one to four heteroatoms selected from N, O or S. Furthermore, the heterocycle according to the present invention can also be a fused or bridged heterocycloalkyl. Examples of non-aromatic rings include azetidinyl, oxetanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, oxapiperazinyl, oxapiperidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydrofuryl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyranyl, dihydropyranyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, indolinyl, indolinylmethyl, thiomorpholinyl, azepanyl, diazepanyl, N-oxide, azaadamantanyl, diazamantanyl and the like, but are not limited thereto. The attachment of the heterocycloalkyl substituent may be via a carbon atom or a heteroatom. The heterocycloalkyl group may be optionally substituted with one or more suitable groups via one or more of the above-mentioned groups. Unless otherwise specified, heterocycloalkyl means a heterocycloalkyl having from 3 to 10 carbon ring members, preferably C _3-7 heterocycloalkyl, more preferably a heterocycloalkyl having from 3 to 5 carbon ring atoms.

Unless otherwise specified herein, the term "substituted" means that one or more hydrogen atoms are replaced by one to three substituents selected from the group consisting of a halogen atom (e.g., F, Cl, Br, or I), cyano, hydroxy, thiol, nitro, amino, imino, azido, amidino, hydrazino, hydrazo, oxo, carbonyl, carbamyl, ester, ether, carboxyl or a salt thereof, sulfonic acid or a salt thereof, phosphoric acid or a salt thereof, C _1-6 -alkyl, halo-C _1-6 -alkyl, hydroxy- _{C 1-6} -alkyl, C _2-6 -alkenyl, halo-C _2-6 -alkenyl, C _2-6 alkynyl group, halo-C _2-6 alkynyl group, C _1-6 alkoxy group, halo-C _1-6 alkoxy group, hydroxyC _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 group (e.g. C _3-9 cycloalkyl group, halo-C _3-9 cycloalkyl group, C _3-9 cycloalkenyl group, halo-C _3-9 cycloalkenyl group, C _1-9 heterocycloalkyl group, halo-C _1-9 heterocycloalkyl group, C _2-9 -heterocycloalkenyl group, halo- _C2-9 -heterocycloalkenyl group and _C1-20 -heterocyclic group (e.g. _C6-20 -aryl group, _C6-20 -aryloxy group, _C6-20- arylthio group, _C2-20- heteroaryl group, _C2-20 -heteroaryloxy group, _C2-20- heteroarylthio group).

Based on the studies carried out and the results obtained to date, it is believed that the following compounds of formula (I), including isomers, mixtures of isomers, as well as pharmaceutically acceptable salts and solvates thereof, are of particular interest.

Aromatic hydrocarbon receptor

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

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

AhR modulators

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

AhR mediates a variety of functional responses, including but not limited to de novo transcription of target genes or AhR battery genes having a 5′-TNGCGTG-3′ DRE (dioxin response element) or XRE (xenobiotic response element) response element. Alternative AhR signaling pathways have also been described, such as binding to retinoblastoma protein, estrogen receptor (ER), transcription factor E2F1, and NFκB pathway subunits RelA and RelB. AhR can also act as a ubiquitin ligase. Accordingly, signaling through AhR includes multiple pathways, including constitutive and non-constitutive AhR signaling pathways or signaling activities as those terms are defined herein.

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

As used herein, "non-constitutive AhR signaling" means one or more AhR-mediated or -induced signaling pathways that do not cause constitutive or sustained nuclear translocation of AhR, as well as activation or modulation of one or more AhR battery genes involved in unregulated cell growth, tumor cell invasiveness, or a combination thereof. In some embodiments, non-constitutive AhR signaling does not cause an increase in the expression of CYP1A1, CYP1B1, or a combination thereof.

Accordingly, as used herein, an "AhR modulator" means an agent, such as a compound of formula (I), that modulates or causes, or facilitates, a qualitative or quantitative change, alteration or modification in one or more processes, mechanisms, effects, responses, functions, activities or pathways mediated by the AhR receptor. Such changes mediated by an AhR modulator, such as an AhR antagonist described herein, may mean a decrease, inhibition or reversal of the constitutive activity of the AhR. The term "expression" means cellular processes involved in the production of RNA and proteins and, where appropriate, secretory proteins, including, where applicable, but not limited to, for example, transcription, translation, folding, modification and processing. "Expression products" include RNA transcribed from a gene and polypeptides produced by translation of mRNA transcribed from a gene.

The term "modulate" in relation to an AhR modulator is used in accordance with its application in the art, for example, to cause or facilitate a qualitative or quantitative change, rearrangement or modification in one or more biological processes, mechanisms, effects, responses, functions, activities, pathways or other phenomena of interest. Accordingly, in the context of this document, modulate means a qualitative or quantitative change, rearrangement or modification in one or more processes, mechanisms, effects, responses, functions, activities or pathways mediated by the AhR receptor.

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

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

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

In the context of the present document, an AhR inhibitor is an "AhR antagonist". An AhR antagonist means an AhR inhibitor that does not as such elicit a biological response upon specific binding to the AhR, but blocks or attenuates agonist-mediated or ligand-mediated responses, i.e., the AhR antagonist can bind to but does not activate the AhR, and the binding disrupts the interaction, displaces the AhR agonist and/or inhibits the function of the AhR agonist. Thus, in the context of the present document, an AhR antagonist does not function, such as an inducer of AhR activity upon binding to the AhR, i.e., they function as pure AhR inhibitors. In some embodiments, the AhR antagonist selectively binds to the AhR.

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

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

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

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

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

in which:

X ¹ , X ² and X ³ each independently represent CR ² , N or NR ³ ;

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

D is H, halo, cyano, hydroxy, amino, substituted or unsubstituted C _1-5 -alkyl, mono- or bicyclic C _3-10 -cycloalkyl, C _1-5 -alkylhydroxy, C _1-5 -alkenylhydroxy, C _1-5 -alkynylhydroxy, C _1-5 -alkylamine, C _1-5 -alkenylamine, C _1-5 -alkynylamine, mono- or bicyclic C _3-10 -heterocycloalkyl, mono- or bicyclic C _3-10 -heteroaryl,

E is absent (direct bond), is amino, substituted or unsubstituted C _1-5 -alkyl, mono- or bicyclic C _3-10 -cycloalkyl, C _1-5 -alkylhydroxy, C _1-5 -alkenylhydroxy, C _1-5 -alkynylhydroxy, C _1-5 -alkylamine, C _1-5 -alkenylamine, C _1-5 -alkynylamine, mono- or bicyclic C _3-10 -heterocycloalkyl, mono- or bicyclic C _3-10 -heteroaryl,

or D and E, together with the atoms to which they are attached, are combined to form a substituted or unsubstituted mono- or bicyclic C _3-10 heterocycloalkyl ring;

G is absent (direct bond), is H, halo, cyano, hydroxy, amino, nitro, ether (-O-), thioether (-S-), sulfinyl (-SO-), sulfonyl (-SO ₂ -), sulfonylamido (-SO ₂ NR ⁴ -), aminosulfonyl (-NR ⁴ SO ₂ -), carbonyl (-(CO)-), amido (-(CO)NR ⁴ -), reverse amido (-NR ⁴ (CO)-), ester (-(CO)O-), substituted or unsubstituted mono- or bicyclic C _3-10 -cycloalkyl, substituted or unsubstituted mono- or bicyclic C _3-10 -heterocycloalkyl, substituted or unsubstituted mono- or bicyclic C _6-10 -aryl and substituted or unsubstituted mono- or bicyclic C _5-10 -heteroaryl;

R ¹ is absent, is 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 alkylamine, C _1-5 alkenylamine, C _1-5 alkynylamine, substituted or unsubstituted mono- or bicyclic C _3-10 heterocycloalkyl and substituted or unsubstituted mono- or bicyclic C _5-10 heteroaryl;

R ² is H, halo, cyano, hydroxy and C _1-3 -alkyl;

R ³ is H, halo, cyano, hydroxyl and amino; and

R ⁴ is H, substituted or unsubstituted C _1-5 -alkyl, substituted or unsubstituted C _1-5 -alkoxy and substituted or unsubstituted C _1-5 -alkylcarboxylic acid; and

R ⁵ is H, substituted or unsubstituted C _1-5 -alkyl, substituted or unsubstituted C _1-5 -alkoxy and substituted or unsubstituted C _1-5 -alkylcarboxylic acid;

In a preferred embodiment of the invention, Ar ¹ may be a substituted or unsubstituted monocyclic C _5-7 heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S. More preferably, Ar ¹ may be a monocyclic C _5-6 heteroaryl containing one or two heteroatoms selected from the group consisting of N, O and S, which may be unsubstituted or substituted with C _1-3 alkyl. Much more preferably, Ar ¹ may be pyrazole or pyridine, which may be unsubstituted or substituted with methyl.

In a preferred embodiment of the invention, Ar ² may be a mono- or bicyclic C _6-10 -aryl containing one or more heteroatoms selected from the group consisting of N, O and S, which is unsubstituted or substituted by halo. More preferably, Ar ² may be phenyl, which may be unsubstituted or substituted by chloro.

In a preferred embodiment of the invention, D may be H or C _1-3 -alkyl.

In a preferred embodiment of the invention, E may be absent (direct bond), amino, substituted or unsubstituted C _1-4 -alkyl, mono- or bicyclic C _3-8 -cycloalkyl, C _1-4 -alkylhydroxy, C _1-4 -alkenylhydroxy, C _1-4 -alkynylhydroxy, C _1-4 -alkylamine, C _1-4 -alkenylamine, C _1-4 -alkynylamine, mono- or bicyclic C _3-8 -heterocycloalkyl, mono- or bicyclic C _3-8 -heteroaryl, wherein the mono- or bicyclic C _3-8 -heterocycloalkyl and mono- or bicyclic C _3-8 -heteroaryl contain one or more, preferably one or two, heteroatoms selected from the group consisting of N, O and S.

In a preferred embodiment of the invention, D and E, together with the atoms to which they are attached, may be combined to form a substituted or unsubstituted mono- or bicyclic C _3-10 -heterocycloalkyl ring, one or more heteroatoms being selected from the group consisting of N, O and S. More preferably, said mono- or bicyclic C _3-10 -heterocycloalkyl ring may be unsubstituted or substituted with pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine or octahydropyranopyridine.

In a preferred embodiment of the invention, G is absent (direct bond), H, halo, cyano, hydroxy, amino, nitro, ether (-O-), thioether (-S-), sulfinyl (-SO-), sulfonyl (-SO ₂ -), sulfonylamido (-SO ₂ NR ⁴ -), aminosulfonyl (-NR ⁴ SO ₂ -), carbonyl (-(CO)-), amido (-(CO)NR ⁴ -), reverse amido (-NR ⁴ (CO)-), ester (-(CO)O-), substituted or unsubstituted mono- or bicyclic C _3-8 -cycloalkyl, substituted or unsubstituted mono- or bicyclic C _3-8 -heterocycloalkyl, substituted or unsubstituted mono- or bicyclic C _6-10 -aryl, and substituted or unsubstituted mono- or bicyclic C _5-8 -heteroaryl, wherein the mono- or bicyclic C _3-8 -heterocycloalkyl and the mono- or bicyclic C _5-8- heteroaryl contain one or more, preferably one or two, heteroatoms selected from the group consisting of N, O and S.

In a preferred embodiment of the invention R ¹ is absent, 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 alkylamine, C _1-4 alkenylamine, C _1-4 alkynylamine, substituted or unsubstituted mono- or bicyclic C _3-8 heterocycloalkyl and substituted or unsubstituted mono- or bicyclic C _5-8 heteroaryl, phosphate, substituted or unsubstituted C _1-3 alkylphosphate, wherein the mono- or bicyclic C _3-8 heterocycloalkyl and mono- or bicyclic C _5-8 heteroaryl comprises one or more, preferably one or two, heteroatoms selected from the group consisting of N, O and S.

Furthermore, in a more specific embodiment of the invention, the compound of formula I may be one selected from the group consisting of compounds 1 to 276, as shown below:

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)propan-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)propan-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 -dimethylpropan-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. Methyl (R)-4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazine-2-carboxylate;

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. methyl (6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)prolinate;

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)piperidin-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. ethyl 2-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)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. methyl 2-(4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)piperidin-1-yl)acetate;

172. 1-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)ethyl 2,2,2-trifluoroacetate;

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)piperidin-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. methyl-(2R,4R)-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)pyrrolidine-2-carboxylate;

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)pyrrolidin-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. tert-butyl (S)-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-(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;

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.

Individual stereochemical isomers, enantiomers, diastereomers and pharmaceutically acceptable salts of the above compounds also form the scope of the present invention. Pharmaceutically acceptable salts can, for example, be prepared from suitable inorganic and organic acids and bases.

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

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 salt thus formed. Such salts include, but are not limited to, alkali metal (e.g., sodium, lithium, and potassium), alkaline earth metal (e.g., magnesium and calcium), ammonium, and N ⁺ ( _C1-4 -alkyl) ₄ salts.

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-hydroxyethanesulfonate, 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.

Furthermore, the compounds represented by formula I according to the present invention include not only their pharmaceutically acceptable salts, but also all solvates or hydrates and all possible stereoisomers which can be prepared from them, but are not limited thereto. All stereoisomers of the present compounds (e.g., those which may exist due to asymmetric carbon atoms on various substituents), including enantiomeric forms and diastereomeric forms, are considered within the scope of the present invention. Individual stereoisomers of the compounds according to the present invention may, for example, be substantially free of other isomers (e.g., as a pure or substantially pure optical isomer having the desired activity) or may be mixed, for example, as racemates, or with all the others or with other selected stereoisomers. The chiral centers of the compounds of the present invention may have the S or R configuration as defined in the IUPAC Recommendations of 1974. Racemic forms may be analyzed by physical methods such as fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. Individual optical isomers may be obtained from racemates by any suitable method, including, but not limited to, salt formation with an optically active acid followed by crystallization.

A solvate and a stereoisomer of a compound represented by formula I can be prepared from a compound represented by formula I using methods known in the art.

In addition, the compounds represented by formula I according to the present invention may be prepared in either a crystalline form or a non-crystalline form. When the compound is prepared in a crystalline form, it may be optionally hydrated or solvated. In the present invention, the compound of formula I may include not only a stoichiometric hydrate, but also include a compound containing various amounts of water. The solvate of the compound of formula I according to the present invention includes both stoichiometric solvates and non-stoichiometric solvates.

The compounds of the present invention can be synthesized by methods known in the art or by the methods illustrated in Examples 1-376 below.

Pharmaceutical compositions, methods and applications

In a specific embodiment of the invention, the pharmaceutical composition and method provided herein comprise a compound of formula (I).

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

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

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

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

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

Examples of carriers, excipients and diluents that may be contained in the composition may include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil. A diluent or excipient such as commonly used fillers, stabilizers, binders, disintegrants and surfactants may be used in processing to form a preparation. Solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like, and these solid preparations can be prepared by mixing the compound of the present invention with at least one auxiliary substance such as starch, microcrystalline cellulose, sucrose, lactose, low-substituted hydroxypropyl cellulose, hypromellose or the like. In addition to the simple auxiliary substance, a lubricant such as magnesium stearate and talc is also used. Liquid preparations for oral administration include suspension, internal liquid, emulsion, syrup and the like. In addition to the generally used simple diluents such as water and liquid paraffin, various auxiliary substances such as humectants, sweeteners, flavors, preservatives and the like may also be contained. The parenteral dosage forms include a sterilized aqueous solution, a non-aqueous solution, a suspension, an emulsion, a lyophilized composition, and a suppository. The non-aqueous solution or suspension may include propylene glycol, polyethylene glycol, a vegetable oil such as olive oil, an injectable ester such as ethyl oleate, etc. As a suppository base, witepsol, macrogol, tween 61, cocoa butter, lauric oil, glycerogelatin, etc. may be used. In order to prepare a dosage form for parenteral administration, the compound of formula I or a pharmaceutically acceptable salt thereof can be mixed in water together with sterilized and/or contained auxiliary substances such as preservatives, stabilizers, auxiliary agents such as a wettable powder or emulsification accelerators, salt for regulating osmotic pressure and/or buffers, etc., as well as other therapeutically useful substances to prepare a solution or suspension, which is then released in the form of an ampoule or a set of vials for administration.

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

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

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

In one embodiment of the invention, the fibrosing conditions are selected from the group consisting of fibrosing conditions of the internal organs, such as the lungs, heart, kidneys, bone marrow and, in particular, the liver, as well as dermatological fibroses and fibrosing conditions of the eyes. In the context of the present invention, the term fibrosing disorders includes, in particular, the following terms: liver fibrosis, liver cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic injury due to diabetes, bone marrow fibrosis and similar fibrosing disorders, scleroderma, annular scleroderma, keloids, hypertrophic scars (including those resulting from surgical operations), nevus, diabetic retinopathy, proliferative vitreoretinopathy and connective tissue diseases (for example, sarcoidosis).

In some embodiments, the malignant tumor, cancerous condition or tumor particularly suitable for treatment with the AhR antagonist of the present invention are liquid tissue tumors and solid tumors, such as breast cancer, squamous cell carcinoma, lung cancer, peritoneal cancer, hepatocellular carcinoma, gastric cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, renal cancer or renal cell carcinoma, 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 myeloid leukemia.

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

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

Examples of other disorders associated with inflammation with aberrant AhR signaling include vaccination against infections and malignancies, viral infections, obesity and diet-induced obesity, fat deposition, metabolic disorders, hepatic steatosis and uterine fibroids (uterine leiomyoma or uterine myoma) in women, chronic kidney disorders, acute and chronic renal failure, diabetic, inflammatory or hypertensive nephropathy, heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemic disease, vascular disorders, thromboembolic disorders, arteriosclerosis, sickle cell anemia, erectile dysfunction, benign prostatic hyperplasia, dysuria associated with benign prostatic hyperplasia, Huntington's disease, dementia, Alzheimer's disease and Creutzfeldt-Jakob disease.

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

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

In some aspects, pharmaceutical compositions comprising an AhR modulator, such as an AhR antagonist of formula (I), are intended for use in the treatment of a malignancy or cancerous condition by modulating AhR activity.

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

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

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

In some embodiments of the invention, compounds of chemical formula I are administered orally.

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

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

In some embodiments, the effective dose range of the compound is determined by measuring the concentration of the compound in the patient's blood at a given dosing regimen to establish a concentration-time profile, checking with an established correlation between the concentration-time profile and the effects of inhibiting or killing the cancer achieved in the test, and balancing the achievable therapeutic effects with possible toxicity to the patient, with further consideration of the health condition or physical tolerance of the patient. The frequency of dosing of the compound can be determined in a similar manner. Dosing can be continued until the patient is free of cancer.

In some embodiments, an effective amount for treating a tumor can be measured by its ability to stabilize disease progression and/or alleviate symptoms in a patient, and preferably to help eliminate disease progression, such as by reducing tumor size. In some embodiments, a maintenance dose can be administered after the patient has been cleared of cancer to ensure its complete elimination or destruction, or to prevent residual disease. The duration of administration of the maintenance dose can be determined based on clinical trial data.

In some embodiments, the compound may be administered in combination with one or more other cancer treatments that also target AhR or target molecules other than AhR. The compounds may be formulated either alone or together with other cancer treatments. The compounds may be administered either on the same schedule or on a schedule different from the other cancer treatments. The proportion of the compound related to the other cancer treatments may be determined in clinical trials. Combination of the compounds with other cancer treatments may further enhance the effectiveness of each other. For example, a compound of the present invention can be administered with an immune checkpoint inhibitor, such as a PD-1, PD-L1 or PD-L2 inhibitor (e.g., pembrolizumab, nivolumab or atezolizumab), or administered with CAR-T cell therapy (CAR-T therapy) (e.g., axicabtagene ciloleucel) to achieve an additive or synergistic antitumor effect.

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

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

It is contemplated that a suitable dose of a compound of the present invention may be in the range of 0.001-200 mg/kg per day, and preferably from about 0.01 mg/kg to 20 mg/kg body weight per day, in particular about 0.5-50 mg/kg, such as about 1-20 mg/kg. The compound may be administered, for example, at a dose of at least 0.25 mg/kg, such as at least 0.5 mg/kg, in particular at least 1 mg/kg, such as at least 1.5 mg/kg, in particular at least 2 mg/kg, such as at least 3 mg/kg, in particular at least 4 mg/kg, such as at least 5 mg/kg; and, for example, up to a maximum of 50 mg/kg, in particular up to a maximum of 30 mg/kg, for example, up to a maximum of 20 mg/kg, in particular up to a maximum of 15 mg/kg. The administration is usually repeated at appropriate intervals, for example twice daily, three times daily, once daily, once weekly, once every two weeks or once every three weeks, and for as long as the responsible physician considers appropriate, who may further increase or decrease the dosage as necessary.

General methods of synthesis

The compounds of formula (I) of the present invention can be prepared according to one or more of the schemes discussed below.

These methods can be used either directly or with obvious variations by trained chemists to prepare the key intermediates and specific compounds of this invention.

Suitable synthetic sequences are readily selected according to the specific structures of the present invention within the scope of the art known to those skilled in organic synthesis, such as the methods summarized in available chemical databases such as CAS Scifinder and Elesevier Reaxys. Based on these general methods, the implementation of the capabilities for producing a compound of the present invention is straightforward and can be practiced within the scope of common professional knowledge. Some general synthetic methods for preparing compounds of the present invention are shown below in Schemes 1-5 (General Procedure A~E).

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

Scheme 1. General methodology A.

a) 1. CH ₃ ONa, MeOH, 2. ammonia solution in MeOH; b) diethyl malonate, CH ₃ ONa, MeOH; c) POCl ₃ ; d) Ar ² -B(OH) ₂ or its pinacol ester, Pd(PPh ₃ ) ₄ , Na ₂ CO ₃ , tetrahydrofuran/H ₂ O (4/1) heating, microwave; e) RNH ₂ or (R) ₂ NH (primary or secondary amine), triethylamine, tetrahydrofuran, heating; f) hydrochloric acid in ethanol, 1 M ammonium acetate solution.

* R ¹ denotes unprotected tert-butoxycarbonyl (BOC) forms of R-fragments.

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

Scheme 2. General methodology B.

a) 1. HCl, MeOH, 2. ammonia solution in MeOH; b) NaH, tetrahydrofuran, heating under reflux; c) CH ₃ ONa, MeOH, heating; d) POCl ₃ , heating; e) RNH ₂ , or (R) ₂ NH (primary or secondary amine), triethylamine, tetrahydrofuran, heating; f) hydrochloric acid in ethanol, 1 M ammonium acetate solution.

* R ¹ denotes unprotected BOC forms of R fragments.

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

Scheme 3. General methodology C.

a) Ar ² -B(OH) ₂ or its pinacol ester, Pd(PPh ₃ ) ₄ , Na ₂ CO ₃ , tetrahydrofuran/H2O(4/1), heating, microwave oven; b) RNH ₂ or (R) ₂ NH (primary or secondary amine), triethylamine, tetrahydrofuran, heating; c) Ar ¹ -B(OH) ₂ or its pinacol ester, Pd(PPh ₃ ) ₄ , Na ₂ CO ₃ , tetrahydrofuran/H2O (4/1), heating, microwave oven; d) hydrochloric acid in ethanol, 1 M ammonium acetate solution.

* R ¹ denotes unprotected BOC forms of R fragments.

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

Scheme 4. General methodology D.

a) 1. CH ₃ ONA, MeOH, 2. ammonia solution in MeOH; b) diethyl malonate, CH ₃ ONa, MeOH; c) POCl ₃ ; d) RNH ₂ or (R) ₂ NH (primary or secondary amine), triethylamine, tetrahydrofuran, heating; e) Ar ² -B(OH) ₂ or its pinacol ester, Pd(PPh ₃ ) ₄ , Na ₂ CO ₃ , tetrahydrofuran/H ₂ O (4/1) heating, microwave; f) hydrochloric acid in ethanol, 1 M ammonium acetate solution.

* R ¹ denotes unprotected BOC forms of R fragments.

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

Scheme 5. General methodology E.

a) RNH ₂ or (R) ₂ NH (primary or secondary amine), triethylamine, tetrahydrofuran, heat; b) Ar ² -B(OH) ₂ or its pinacol ester, Pd(PPh ₃ ) ₄ , Na ₂ CO ₃ , tetrahydrofuran/H ₂ O (4/1), heat, microwave; c) Ar ¹ -B(OH) ₂ or its pinacol ester, Pd(PPh ₃ ) ₄ , Na ₂ CO ₃ , tetrahydrofuran/H ₂ O (4/1), heat, microwave.

* R ¹ denotes unprotected BOC forms of R fragments.

Principle of the invention

Examples

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

All chemicals are commercially available. Unless otherwise stated, flash column chromatography refers to silica gel chromatography performed on a Teledyne Combiflash-RF200. ^1H NMR (δ, ppm) spectra were recorded on a 400 MHz or 600 MHz instrument. Positive ionization mode mass spectroscopy data are presented. Positive ionization mode mass spectroscopy data are presented. Preparative high-performance liquid chromatography (HPLC) was performed on an Agilent technologies G1361A and a Gilson Preparative HPLC .

Example 1. (R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)butan-1-ol

Scheme for obtaining the connection according to example 1:

Intermediate 1. Nicotinimidamide hydrochloride

To a suspension of 3-cyanopyridine (5 g, 48.03 mmol) in 50 mL MeOH was added sodium methoxide 30 wt% in MeOH (4 mL) and the mixture was stirred at room temperature (RT) for 24 h. After addition of _NH4Cl (16.5 g, 0.31 mol), the mixture was heated under reflux for 6 h and then cooled. The solvent was removed in vacuo and then EtOH (60 mL) was added and the mixture was heated to condensation for 30 min. After the reaction mixture was cooled to room temperature, the solids were filtered off and the filtrate was concentrated in vacuo. A suspension of the reaction mixture in 3 mL EtOH was filtered and the solid product was dried to give 4.9 g of the title compound.

¹ H NMR (400 MHz, hexadeuterodimethyl sulfoxide (DMSO-D6)) δ [ppm] = 9.43 (br.s., 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 mass spectrum (electrospray ionization (ESI), mass/charge (m/z)): 122.1 [M+H] ⁺ .

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), followed by a solution of 30 wt% sodium methoxide in MeOH (20 mL) at 0 °C. The resulting mixture was stirred for 24 h at room temperature. The solvents were removed in vacuo. The resulting residue was used without further purification.

MS (ESI, m/z): 190.0 [M+H] ⁺ .

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 material from the previous step) in POCl ₃ (10 mL) was added dimethylaminoaniline (4.77 g, 35.03 mmol) and the reaction mixture was heated at 120° for 4 h. The residue was cooled to room temperature, extracted with 500 mL of EtOAc and concentrated in vacuo. The crude product was purified by silica gel column chromatography to give 4.45 g of the title compound.

^1H 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 (ush, 1H); MS (ESI, m/z): 226.0 [M+H] ⁺ .

Intermediate 4. 4-chloro-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidine

To a mixture of 4,6-dichloro-2-pyridin-3-ylpyrimidine (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) in 50 mL of tetrahydrofuran/ _H2O (4/1) was added Pd( _PPh3 ) ₄ (203 mg, 0.18 mmol). The mixture was heated in a microwave oven at 80° for 20 min, cooled to room temperature and extracted three times with ethyl acetate (EtOAc) (50 mL). The organic layer was dried over anhydrous _MgSO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 1.02 g of the title compound.

^1H NMR (600 MHz, CDCl ₃ ) 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] ⁺ .

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), followed by (R)-2-aminobutan-1-ol (27 mg, 0.30 mmol) at room temperature. The reaction mixture was heated at 120 °C for 4 h in a sealed tube and cooled to room temperature. The residue was filtered, evaporated in vacuo and isolated by preparative HPLC to give 50 mg of the title compound.

¹ H NMR (400 MHz, CD ₃ OD) 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, 2H), 8.10-8.13 (m, 3H), 8.90 (d, 1H), 9.44 (d, 1H), 9.69 (d, 1H); MS (ESI, m/z): 355.1 [M+H] ⁺ .

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

Scheme for obtaining the connection of example 2 and 3:

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 20 mL of tetrahydrofuran/ _H2O (4/1) was added Pd( _PPh3 ) ₄ (253.7 mg, 0.22 mmol). The mixture was heated to 80° overnight, cooled to room temperature and extracted three times with EtOAc (150 mL) twice. 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 afford 510.0 mg of the title compound.

¹ H NMR (600 MHz, CDCl ₃ ) δ [ppm] = 7.52 (d, 2H), 7.67 (s, 1H), 8.05 (d, 2H); MS (ESI, m/z): 258.0 [M+H] ⁺ .

Intermediates 6 and 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) was added triethylamine (0.1 mL, 0.712 mmol), followed by (S)-2-aminopropan-1-ol (28.95 mg, 0.385 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered, evaporated in vacuo and isolated by flash chromatography (silica gel, hexane/ethyl acetate, gradient) to yield 54.0 mg and 30.1 mg of intermediates 6 and 7, respectively.

Intermediate product 6

^1H NMR (600 MHz, CDCl ₃ ) 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] ⁺ .

Intermediate product 7

¹ H NMR (600 MHz, CDCl ₃ ) 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] ⁺ .

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), sodium carbonate (90 mg, 0.849 mmol) in 10 mL of tetrahydrofuran/H ₂ O (4/1) was added Pd(PPh ₃ ) ₄ (80 mg, 0.069 mmol). The mixture was heated in a microwave at 130 °C for 15 min, cooled to room temperature and extracted three times with EtOAc (30 mL). The organic layer was washed with brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, hexane/ethyl acetate, gradient) to afford 32 mg of the title compound (Scheme 3, General Method C).

¹ H NMR (600 MHz, CD ₃ OD) 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] ⁺ .

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), sodium carbonate (35 mg, 0.336 mmol) in 5 mL of tetrahydrofuran/H ₂ O (4/1) was added Pd(PPh ₃ ) ₄ (34 mg, 0.029 mmol). The mixture was heated in a microwave at 130 °C for 15 min, cooled to room temperature and extracted three times with EtOAc (30 mL). The organic layer was washed with brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, hexane/ethyl acetate, gradient) to afford 17.6 mg of the title compound (Scheme 3, General Method C).

^1H NMR (600 MHz, CD ₃ OD) 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, 1H), 7.60 (s, 1H), 8. 17 (d, 2H), 8.58 (d, 1H), 8.67 (s, 1H), 9.34 (s, 1H); MS (ESI, m/z): 341.1 [M+H] ⁺ .

Example 4. 2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)-2-methylpropan-1-ol

Using 2-amino-2-methylpropan-1-ol, the title compound was prepared as described for Example 2 (Scheme 3, General Procedure C).

¹ H NMR (600 MHz, CD ₃ OD) 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] ⁺ .

Example 5. 2-((4-(4-chlorophenyl)-6-(pyridin-3-yl)pyrimidin-2-yl)amino)-2-methylpropan-1-ol

Using 2-amino-2-methylpropan-1-ol, the title compound was prepared as described for Example 3 (Scheme 3, General Procedure C).

^1H NMR (600 MHz, CDCl ₃ ) 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] ⁺ .

Example 6. 2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)ethan-1-ol

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

^1H NMR (600 MHz, CD ₃ OD) 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] ⁺ .

Example 7. 3-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propan-1-ol

Using 3-aminopropan-1-ol, the title compound was prepared as described for Example 1 (Scheme 1. General Procedure A.).

¹ H NMR (600 MHz, CD ₃ OD) 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] ⁺ .

Example 8. (S)-1-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propan-2-ol

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

^1H NMR (600 MHz, CDCl ₃ ) 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] ⁺ .

Example 9. (R)-1-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propan-2-ol

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

^1H NMR (600 MHz, CDCl ₃ ) 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] ⁺ .

Example 10. 3-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propane-1,2-diol

Using 3-aminopropane-1,2-diol, the title compound was prepared as described for Example 1 (Scheme 1. General Procedure A.).

MS (ESI, m/z): 357.1 [M+H] ⁺ .

Example 11. (R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propan-1-ol

Using (R)-2-aminopropan-1-ol and a preparative HPLC isolation method, the title compound was prepared as described for Example 1 (Scheme 1. General Procedure A.)

¹ H NMR (600 MHz, CD ₃ OD) 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] ⁺ .

Example 12. 2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)-3-methylbutan-1-ol

Using 2-amino-3-methylbutan-1-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (600 MHz, CD ₃ OD) 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, 1H), 7.54 (d, 2H), 8 .06 (br, 1H), 8.14 (d, 2H), 8.88 (br, 1H), 9.38 (d, 1H), 9.69 (br, 1H); MS (ESI, m/z): 369.2 [M+H] ⁺ .

Example 13. (S)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)-3-methylbutan-1-ol

Using (S)-2-amino-3-methylbutan-1-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (600 MHz, CD ₃ OD) 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, 1H), 7.54 (d, 2H), 8 .06 (br, 1H), 8.14 (d, 2H), 8.88 (br, 1H), 9.38 (d, 1H), 9.69 (br, 1H); MS (ESI, m/z): 369.2 [M+H] ⁺ .

Example 14. (R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)-3-methylbutan-1-ol

Using (R)-2-amino-3-methylbutan-1-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (600 MHz, CD ₃ OD) 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, 1H), 7.54 (d, 2H), 8 .06 (br, 1H), 8.14 (d, 2H), 8.88 (br, 1H), 9.38 (d, 1H), 9.69 (br, 1H); MS (ESI, m/z): 369.2 [M+H] ⁺ .

Example 15. 2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)butan-1-ol

Using 2-aminobutan-1-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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, 2H), 8.10-8.13 (m, 3H), 8.90 (d, 1H), 9.44 (d, 1H), 9.69 (d, 1H); MS (ESI, m/z): 355.1 [M+H] ⁺ .

Example 16. 2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propane-1,3-diol

Using 2-aminopropane-1,3-diol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (600 MHz, CD ₃ OD) 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] ⁺ .

Example 17. (R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)-1-phenylethan-1-ol

Using (R)-2-amino-1-phenylethan-1-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Procedure A.).

¹ H NMR (600 MHz, CD ₃ OD) 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] ⁺ .

Example 18. (S)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)-1-phenylethan-1-ol

Using (S)-2-amino-1-phenylethan-1-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (600 MHz, CD ₃ OD) 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] ⁺ .

Example 19. 6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrimidin-4-amine

Using (tetrahydro-2H-pyran-4-yl)methanamine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (600 MHz, CD ₃ OD) 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, 1H), 7.54 (d, 2H), 8 .06 (br, 1H), 8.14 (d, 2H), 8.87 (br, 1H), 9.36 (d, 1H), 9.73 (br, 1H); MS (ESI, m/z): 381.1 [M+H] ⁺ .

Example 20. N ¹ -(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-N ³ ,N ³ -dimethylpropane-1,3-diamine

Using N ¹ ,N ¹ -dimethylpropane-1,3-diamine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

^1H NMR (600 MHz, CD ₃ OD) 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] ⁺ .

Example 21. 6-(4-chlorophenyl)-N-ethyl-2-(pyridin-3-yl)pyrimidin-4-amine

Using ethanamine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

^1H NMR: (400 MHz, CD ₃ OD) 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] ⁺ .

Example 22. 6-(4-chlorophenyl)-N-propyl-2-(pyridin-3-yl)pyrimidin-4-amine

Using propan-1-amine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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 (US, 1H); MS (ESI, m/z): 325.1 [M+H] ⁺ .

Example 23. N-butyl-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-amine

Using butan-1-amine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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 (ush, 1H), 9.18 (d, 1H), 9.69 (ush, 1H); MS (ESI, m/z): 339.1 [M+H] ⁺ .

Example 24. 1-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)butan-2-ol

Using 1-aminobutan-2-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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 (ush, 1H), 9.18 (d, 1H), 9.69 (ush, 1H); MS (ESI, m/z): 355.1 [M+H] ⁺ .

Example 25. 6-(4-chlorophenyl)-N-(cyclopropylmethyl)-2-(pyridin-3-yl)pyrimidin-4-amine

Using cyclopropylmethanamine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 26. 6-(4-chlorophenyl)-N-cyclopentyl-2-(pyridin-3-yl)pyrimidin-4-amine

Using cyclopentaneamine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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 (ush, 1H), 6.93 (s, 1H), 7.54 (d, 2H), 8. 08 (br, 1H), 8.13 (d, 2H), 8.89 (br, 1H), 9.38 (d, 1H), 9.72 (br, 1H); MS (ESI, m/z): 351.1 [M+H] ⁺ .

Example 27 4-(4-chlorophenyl)-6-(4-methylpiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using 4-methylpiperidine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 28. N-(tert-butyl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-amine

Using 2-methylpropan-2-amine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

^1H NMR (600 MHz, CD ₃ OD) 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] ⁺ .

Example 29. (1R,2R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol

Using (1R,2R)-2-aminocyclopentan-1-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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, 1H), 6.97 (s, 1H), 7, 53 (d, 2H), 8.07 (br, 1H), 8.14 (d, 2H), 8.88 (br, 1H), 9.45 (d, 1H), 9.73 (br, 1H ); MS (ESI, m/z): 367.1 [M+H] ⁺ .

Example 30. (1S,2R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol

Using (1S,2R)-2-aminocyclopentan-1-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (600 MHz, CD ₃ OD) 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] ⁺ .

Example 31. 6-(4-chlorophenyl)-N-(pyridin-2-ylmethyl)-2-(pyridin-3-yl)pyrimidin-4-amine

Using pyridin-2-yl-methanamine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

^1H NMR (600 MHz, CD ₃ OD) 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] ⁺ .

Example 32. 6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(pyridin-3-ylmethyl)pyrimidin-4-amine

Using pyridin-3-yl-methanamine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

^1H NMR (600 MHz, CD ₃ OD) 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] ⁺ .

Example 33. 6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(pyridin-4-ylmethyl)pyrimidin-4-amine

Using pyridin-4-yl-methanamine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

^1H NMR (600 MHz, CD ₃ OD) 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] ⁺ .

Example 34. trans-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexan-1-ol

Using trans -4-aminocyclohexan-1-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (600 MHz, CD ₃ OD) 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 (ush, 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 (ush, 1H); MS (ESI, m/z): 381.1 [M+H] ⁺ .

Example 35. trans-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexan-1-ol

Using trans -2-aminocyclohexan-1-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (600 MHz, CD ₃ OD) 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] ⁺ .

Example 36. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-2-yl)methanol

Using piperidin-2-ylmethanol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

^1H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 37. 2-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-2-yl)ethan-1-ol

Using 2-(piperidin-2-yl)ethan-1-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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 (ush, 1H); MS (ESI, m/z): 395.2 [M+H] ⁺ .

Example 38. (R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-ol

Using (R)-piperidin-3-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 39. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-ol

Using piperidin-3-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 40. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanol

Using piperidin-3-ylmethanol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 41. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-ol

Using piperidin-4-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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, 1H), 7.50 (d, 2H), 8. 10 (br, 1H), 8.18 (d, 2H), 8.89 (br, 1H), 9.43 (d, 1H), 9.70 (br, 1H); MS (ESI, m/z): 367.1 [M+H] ⁺ .

Example 42. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol

Using piperidin-4-ylmethanol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

^1H NMR (400 MHz, CD ₃ OD) 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, 2H), 8.11 (br, 1H), 8 .17 (d, 2H), 8.90 (br, 1H), 9.43 (d, 1H), 9.69 (br, 1H); MS (ESI, m/z): 381.1 [M+H] ⁺ .

Example 43. 2-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)ethan-1-ol

Using 2-(piperidin-4-yl)ethan-1-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 44. 3-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)propan-1-ol

Using 3-(piperidin-4-yl)propan-1-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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 (ush, 1H); MS (ESI, m/z): 409.2 [M+H] ⁺ .

Example 45 4-(4-chlorophenyl)-6-(4-methoxypiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using 4-methoxypiperidine and a preparative HPLC isolation method, the title compound was prepared as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 46. 4-(4-chlorophenyl)-6-(piperidin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using piperidine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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 (US, 1H); MS (ESI, m/z): 351.1 [M+H] ⁺ .

Example 47 4-(4-chlorophenyl)-6-(2-methylpiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using 2-methylpiperidine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 48 4-(4-chlorophenyl)-6-(3-methylpiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using 3-methylpiperidine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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), 4.59 (br, 2H), 7.23 (s, 1H), 7.53 (d, 2H), 8.11 (br, 1H), 8.19 (d, 2H), 8.91 (br, 1H), 9.42 (d, 1H), 9, 70 (ush, 1H), 9.75 (ush, 1H); MS (ESI, m/z): 365.2 [M+H] ⁺ .

Example 49. 4-(4-chlorophenyl)-6-(2,6 - dimethylpiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using 2,6-dimethylpiperidine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

MS (ESI, m/z): 379.2 [M+H] ⁺ .

Example 50. 4-(4-chlorophenyl)-6-(3,5 - dimethylpiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using 3,5-dimethylpiperidine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

^1H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 51. 4-(4-chlorophenyl)-6-(3,3 - difluoropiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using 3,3-difluoropiperidine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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 (ush, 1H), 9.40 (d, 1H), 9.72 (ush, 1H); MS (ESI, m/z): 387.1 [M+H] ⁺ .

Example 52. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(3-(trifluoromethyl)piperidin-1-yl)pyrimidine

Using 3-(trifluoromethyl)piperidine and a preparative HPLC isolation method, the title compound was prepared as described for Example 1 (Scheme 1, General Procedure A.).

¹ H NMR (400 MHz, CD ₃ OD) 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 (br, 1H), 4.95 (br, 1H ), 7.28 (s, 1H), 7.52 (d, 2H), 8.07 (br, 1H), 8.23 (d, 2H), 8.88 (br, 1H), 9.37 (d, 1H), 9.70 (ush, 1H); MS (ESI, m/z): 419.1 [M+H] ⁺ .

Example 53. 4-(4-chlorophenyl)-6-(3-ethylpiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using 3-(trifluoromethyl)piperidine and a preparative HPLC isolation method, the title compound was prepared as described for Example 1 (Scheme 1, General Procedure A.).

MS (ESI, m/z): 379.2 [M+H] ⁺ .

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), followed by tert-butyl 4-aminopiperidine-1-carboxylate (20 mg, 0.10 mmol) at room temperature. The reaction mixture was heated in a sealed tube at 120° for 4 h and cooled to room temperature. The residue was filtered and evaporated in vacuo. To a solution of the reaction mixture in ethanol (1 mL) was added 1 M ethanolic hydrochloric acid (2 mL). The reaction mixture was stirred at 50° overnight, evaporated in vacuo and quenched with 1 M methanolic ammonium acetate (2 mL). The residue was filtered and purified by preparative HPLC to yield 7.6 mg of the title compound (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 55. 6-(4-chlorophenyl)-N-(piperidin-3-ylmethyl)-2-(pyridin-3-yl)pyrimidin-4-amine

Using tert-butyl 3-(aminomethyl)piperidine-1-carboxylate, the title compound was prepared as described for Example 54 (Scheme 1, General Procedure A.).

^1H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 56. 6-(4-chlorophenyl)-N-(piperidin-4-ylmethyl)-2-(pyridin-3-yl)pyrimidin-4-amine

Using tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, the title compound was prepared as described for Example 54 (Scheme 1, General Procedure A.).

^1H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 57. 6-(4-chlorophenyl)-N-(1-methylpiperidin-4-yl)-2-(pyridin-3-yl)pyrimidin-4-amine

Using 1-methylpiperidin-4-amine and a preparative HPLC isolation method, the title compound was prepared as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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, 1H), 6.97 (s, 1H), 7. 53 (d, 2H), 8.06 (d, 1H), 8.15 (d, 2H), 8.88 (d, 1H), 9.42 (d, 1H), 9.75 (d, 1H ); MS (ESI, m/z): 380.2 [M+H] ⁺ .

Example 58. 6-(4-chlorophenyl)-N-(2-(piperidin-4-yl)ethyl)-2-(pyridin-3-yl)pyrimidin-4-amine

Using tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate, the title compound was prepared as described for Example 54 (Scheme 1, General Procedure A.).

¹ H NMR (400 MHz, CD ₃ OD) 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, 1H), 7.54 (d, 2H), 8 .00 (br, 1H), 8.14 (d, 2H), 8.86 (br, 1H), 9.32 (d, 1H), 9.69 (br, 1H); MS (ESI, m/z): 394.2 [M+H] ⁺ .

Example 59. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-2-yl)methanamine

Using tert-butyl (piperidin-2-ylmethyl)carbamate, the title compound was prepared as described for Example 54 (Scheme 1, General Procedure A.).

¹ H NMR (400 MHz, CD ₃ OD) 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, 1H), 7.55 (d, 2H), 8 .07 (br, 1H), 8.27 (d, 2H), 8.89 (br, 1H), 9.47 (d, 1H), 9.81 (br, 1H); MS (ESI, m/z): 380.2 [M+H] ⁺ .

Example 60. (R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-amine

Using tert-butyl (R)-piperidin-3-ylcarbamate, the title compound was prepared as described for Example 54 (Scheme 1, General Procedure A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 61. (S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-amine

Using tert-butyl (S)-piperidin-3-yl carbamate, the title compound was prepared as described for Example 54 (Scheme 1, General Procedure A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 62. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanamine

Using tert-butyl (piperidin-3-ylmethyl)carbamate, the title compound was prepared as described for Example 54 (Scheme 1, General Procedure A.).

¹ H NMR (400 MHz, CD ₃ OD) 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 (br, 1H), 4.77 (br, 1H ), 7.30 (s, 1H), 7.53 (d, 2H), 8.09 (br, 1H), 8.23 (d, 2H), 8.90 (br, 1H), 9.46 (d, 1H), 9.79 (br, 1H); MS (ESI, m/z): 380.2 [M+H] ⁺ .

Example 63. (S)-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanamine

Using tert-butyl (R)-(piperidin-3-ylmethyl)carbamate, the title compound was prepared as described for Example 54 (Scheme 1, General Procedure A.).

¹ H NMR (400 MHz, CD ₃ OD) 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 (br, 1H), 4.77 (br, 1H ), 7.30 (s, 1H), 7.53 (d, 2H), 8.09 (br, 1H), 8.23 (d, 2H), 8.90 (br, 1H), 9.46 (d, 1H), 9.79 (br, 1H); MS (ESI, m/z): 380.2 [M+H] ⁺ .

Example 64. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-amine

Using tert-butylpiperidin-4-yl carbamate, the title compound was prepared as described for Example 54 (Scheme 1, General Procedure A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 65. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanamine

Using tert-butyl (piperidin-4-ylmethyl)carbamate, the title compound was prepared as described for Example 54 (Scheme 1, General Procedure A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 66. (1R,2S)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol

Using (1R,2S)-2-aminocyclopentan-1-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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, 1H), 6.96 (s, 1H), 7, 53 (d, 2H), 8.02 (br, 1H), 8.14 (d, 2H), 8.86 (br, 1H), 9.38 (d, 1H), 9.72 (br, 1H ); MS (ESI, m/z): 367.1 [M+H] ⁺ .

Example 67. (1S,2S)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol

Using (1S,2S)-2-aminocyclopentan-1-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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, 1H), 6.96 (s, 1H), 7, 53 (d, 2H), 8.02 (br, 1H), 8.14 (d, 2H), 8.86 (br, 1H), 9.38 (d, 1H), 9.72 (br, 1H ); MS (ESI, m/z): 367.1 [M+H] ⁺ .

Example 68. trance -2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol

Using trans -2-aminocyclopentan-1-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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, 1H), 6.96 (s, 1H), 7, 53 (d, 2H), 8.02 (br, 1H), 8.14 (d, 2H), 8.86 (br, 1H), 9.38 (d, 1H), 9.72 (br, 1H ); MS (ESI, m/z): 367.1 [M+H] ⁺ .

Example 69. (1R,2R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexan-1-ol

Using (1R,2R)-2-aminocyclohexan-1-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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 (ush, 1H), 6.95 (s, 1H), 7.52 (d, 2H), 8. 03 (br, 1H), 8.12 (d, 2H), 8.86 (br, 1H), 9.32 (d, 1H), 9.66 (br, 1H); MS (ESI, m/z): 381.1 [M+H] ⁺ .

Example 70. cis-4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-2,6 - dimethylmorpholine

Using cis-2,6-dimethylmorpholine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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 (ush, 1H); MS (ESI, m/z): 381.1 [M+H] ⁺ .

Example 71 4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)morpholine

Using morpholine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 72. 6-(4-chlorophenyl)-N-(morpholin-2-ylmethyl)-2-(pyridin-3-yl)pyrimidin-4-amine

Using tert-butyl 2-(aminomethyl)morpholine-4-carboxylate and a preparative HPLC isolation method, the title compound was obtained as described for Example 54 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 73. 4-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)morpholine

Using 4-(pyrrolidin-3-yl)morpholine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 74. 4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)thiomorpholine

Using thiomorpholine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 75. 6-(4-chlorophenyl)-N-(3-morpholinopropyl)-2-(pyridin-3-yl)pyrimidin-4-amine

Using 3-morpholinopropan-1-amine and a preparative HPLC isolation method, the title compound was prepared as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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, 1H), 7.53 (d, 2H), 8 .00 (br, 1H), 8.15 (d, 2H), 8.85 (br, 1H), 9.35 (d, 1H), 9.72 (br, 1H); MS (ESI, m/z): 410.2 [M+H] ⁺ .

Example 76 (R)-4-(4-chlorophenyl)-6-(2-methylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using tert-butyl (R)-3-methylpiperazine-1-carboxylate and a preparative HPLC isolation method, the title compound was obtained as described for Example 54 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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, 1H), 7.53 (d, 2H), 8 .00 (br, 1H), 8.15 (d, 2H), 8.85 (br, 1H), 9.35 (d, 1H), 9.72 (br, 1H); MS (ESI, m/z): 366.1 [M+H] ⁺ .

Example 77. (R)-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-methylpiperazin-1-yl)(phenyl)methanone

Using (R)-(3-methylpiperazin-1-yl)(phenyl)methanone and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Procedure A.).

MS (ESI, m/z): 470.2 [M+H] ⁺ .

Example 78 Methyl (R)-4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazine-2-carboxylate

Using 1-(tert-butyl)-2-methyl (R)-piperazine-1,2-dicarboxylate and a preparative HPLC isolation method, the title compound was obtained as described for Example 54 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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 (br, 1H), 7.43 (s, 1H), 7.56 (d, 2H), 7.74 (br, 1H), 8.29 (d, 2H), 8.74 (br, 1H), 9.06 (d, 1H), 9.67 (br , 1H); MS (ESI, m/z): 410.1 [M+H] ⁺ .

Example 79. (R)-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-2-yl)methanol

Using tert-butyl (R)-2-(hydroxymethyl)piperazine-1-carboxylate and a preparative HPLC isolation method, the title compound was prepared as described for Example 54 (Scheme 1, General Procedure A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 80 4-(4-chlorophenyl)-6-(4-(2,3 - dichlorophenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using 1-(2,3-dichlorophenyl)piperazine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 81 4-(4-chlorophenyl)-6-(4-(2,5 - dimethoxybenzyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using 1-(2,5-dimethoxybenzyl)piperazine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 82. 2-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)ethan-1-ol

Using 2-(piperazin-1-yl)ethan-1-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 83 4-(4-chlorophenyl)-6-(4-(2-methoxyphenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using 1-(2-methoxyphenyl)piperazine and a preparative HPLC isolation method, the title compound was prepared as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 84. 4-(4-chlorophenyl)-6-(4-(2-ethoxyphenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using 1-(2-ethoxyphenyl)piperazine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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, 1H), 7.55 (d, 2H), 8 .11 (br, 1H), 8.26 (d, 2H), 8.90 (br, 1H), 9.49 (d, 1H), 9.78 (br, 1H); MS (ESI, m/z): 472.2 [M+H] ⁺ .

Example 85 4-(4-chlorophenyl)-6-(4-(2-fluorophenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using 1-(2-fluorophenyl)piperazine and a preparative HPLC isolation method, the title compound was prepared as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 86. (4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)(furan-2-yl)methanone

Using furan-2-yl(piperazin-1-yl)methanone and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

^1H NMR (400 MHz, CD ₃ OD) 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 (ush, 1H); MS (ESI, m/z): 446.1 [M+H] ⁺ .

Example 87. 4-(4-chlorophenyl)-6-(4-phenethylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using 1-phenethylpiperazine and a preparative HPLC isolation method, the title compound was prepared as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 88. 6-(4-chlorophenyl)-N-(2-(piperazin-1-yl)ethyl)-2-(pyridin-3-yl)pyrimidin-4-amine

Using tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate and a preparative HPLC isolation method, the title compound was prepared as described for Example 54 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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 (ush, 1H); MS (ESI, m/z): 395.2 [M+H] ⁺ .

Example 89. 4-(4-chlorophenyl)-6-(4-(pyridin-2-yl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using 1-(pyridin-2-yl)piperazine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 90 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidine

Using 1-(pyridin-2-yl)piperazine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 91. 4-(2-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)ethyl)morpholine

Using 4-(2-(piperazin-1-yl)ethyl)morpholine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 92. 4-(4-chlorophenyl)-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using 1-methyl-4-(piperidin-4-yl)piperazine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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 (ush, 1H); MS (ESI, m/z): 449.2 [M+H] ⁺ .

Example 93. trans-4-(4-chlorophenyl)-6-(4-cinnamylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using trans-1-cinnamylpiperazine and a preparative HPLC isolation method, the title compound was prepared as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 94. 4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-2-one

Using piperazin-2-one and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 95. 4-(4-chlorophenyl)-6-(4-phenylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using 1-phenylpiperazine and a preparative HPLC isolation method, the title compound was prepared as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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 (ush, 1H); MS (ESI, m/z): 428.2 [M+H] ⁺ .

Example 96. 4-(4-chlorophenyl)-6-(4-propylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using 1-propylpiperazine and a preparative HPLC isolation method, the title compound was prepared as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 97. 4-(4-(benzo[d][1,3]dioxol-5-ylmethyl)piperazin-1-yl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidine

Using 1-(benzo[d][1,3]dioxol-5-ylmethyl)piperazine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

^1H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 98. (S)-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-2-yl)methanol

Using tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate, the title compound was prepared as described for Example 54 (Scheme 1, General Procedure A.).

¹ H NMR (400 MHz, CD ₃ OD) 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 (m, 1H), 7.50 (s, 1H), 7.56 ( d, 2H), 8.25-8.28 (m, 1H), 8.33 (d, 2H), 8.99 (d, 1H), 9.69 (d, 1H), 9.88 (s, 1H); MS (ESI, m/z): 382.1 [M+H] ⁺ .

Example 99 4-(4-chlorophenyl)-6-(4-(4-fluorophenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using 1-(4-fluorophenyl)piperazine and a preparative HPLC isolation method, the title compound was prepared as described for Example 1 (Scheme 1, General Procedure A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 100. 6-(4-chlorophenyl)-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2-(pyridin-3-yl)pyrimidin-4-amine

Using 1,2,2,6,6-pentamethylpiperidin-4-amine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 101. 6-(4-chlorophenyl)-N-(piperidin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-amine

Using tert-butyl 3-aminopiperidine-1-carboxylate and a preparative HPLC isolation method, the title compound was obtained as described for Example 54 (Scheme 1, General Method A.).

^1H NMR (400 MHz, CD ₃ OD) 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, 1H), 4.55 (br, 1H), 7. 03 (s, 1H), 7.53 (d, 2H), 8.10 (br, 1H), 8.16 (d, 2H), 8.91 (br, 1H), 9.49 (d, 1H ), 9.83 (br, 1H); MS (ESI, m/z): 366.1 [M+H] ⁺ .

Example 102 4-(4-chlorophenyl)-6-(piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using tert-butylpiperazine-1-carboxylate and a preparative HPLC isolation method, the title compound was obtained as described for Example 54 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 103. Trans-4-(4-chlorophenyl)-6-(2,5 - dimethylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using tert-butyl trans-2,5-dimethylpiperazine-1-carboxylate and a preparative HPLC isolation method, the title compound was obtained as described for Example 54 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 104. Cis-4-(4-chlorophenyl)-6-(3,5 - dimethylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using tert-butyl cis-2,6-dimethylpiperazine-1-carboxylate and a preparative HPLC isolation method, the title compound was obtained as described for Example 54 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 105 4-(4-chlorophenyl)-6-(4-methylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using 1-methylpiperazine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 106. 4-(4-chlorophenyl)-6-(4-ethylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using 1-ethylpiperazine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 107. 4-(4-chlorophenyl)-6-(4-(methylsulfonyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using 1-(methylsulfonyl)piperazine and a preparative HPLC isolation method, the title compound was prepared as described for Example 1 (Scheme 1, General Procedure A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 108. 1-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)ethan-1-one

Using 1-(piperazin-1-yl)ethan-1-one and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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, 1H), 8.25 (d, 2H), 8 .83 (d, 1H), 9.34 (d, 1H), 9.71 (s, 1H); MS (ESI, m/z): 394.1 [M+H] ⁺ .

Example 109. 4-(4-chlorophenyl)-6-(3-ethylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using tert-butyl 2-ethylpiperazine-1-carboxylate and a preparative HPLC isolation method, the title compound was obtained as described for Example 54 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 110. Ethyl 4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazine-1-carboxylate

Using ethyl piperazine-1-carboxylate and a preparative HPLC isolation method, the title compound was prepared as described for Example 1 (Scheme 1, General Procedure A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 111. 4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazine-2-carboxylic acid

Using 1-(tert-butoxycarbonyl)piperazine-2-carboxylic acid and a preparative HPLC isolation method, the title compound was prepared as described for Example 54 (Scheme 1, General Method A.).

MS (ESI, m/z): 396.1 [M+H] ⁺ .

Example 112 Methyl 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazine-2-carboxylate

Using 1-(tert-butyl) 3-methylpiperazine-1,3-dicarboxylate and a preparative HPLC isolation method, the title compound was obtained as described for Example 54 (Scheme 1, General Procedure A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 113. (S)-4-(4-chlorophenyl)-6-(2-phenylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using tert-butyl (S)-3-phenylpiperazine-1-carboxylate and a preparative HPLC isolation method, the title compound was obtained as described for Example 54 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 114. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(4-(o-tolyl)piperazin-1-yl)pyrimidine

Using 1-( o -tolyl)piperazine and a preparative HPLC isolation method, the title compound was prepared as described for Example 1 (Scheme 1, General Procedure A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 115. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(4-(p-tolyl)piperazin-1-yl)pyrimidine

Using 1-( p -tolyl)piperazine and a preparative HPLC isolation method, the title compound was prepared as described for Example 1 (Scheme 1, General Procedure A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 116. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(4-(m-tolyl)piperazin-1-yl)pyrimidine

Using 1-( m -tolyl)piperazine and a preparative HPLC isolation method, the title compound was prepared as described for Example 1 (Scheme 1, General Procedure A.).

¹ H NMR (400 MHz, CD ₃ OD) 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 (s, 1H), 7.54 (d, 2H), 8.12-8.15 (m, 1H), 8.26 (d, 2H), 8.91 (d, 1H), 9.52 (d, 1H), 9.77 (s, 1H); MS (ESI, m/z): 442.2 [M+H] ⁺ .

Example 117 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)pyrimidine

Using 1-(3-(trifluoromethyl)phenyl)piperazine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Procedure A.).

^1H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 118 4-(4-chlorophenyl)-6-(4-(2,3 - dimethylphenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using 1-(2,3-dimethylphenyl)piperazine and a preparative HPLC isolation method, the title compound was prepared as described for Example 1 (Scheme 1, General Procedure A.).

¹ H NMR (400 MHz, CD ₃ OD) δ [ppm] = 2.29 (s, 3H), 2.33 (s, 3H), 3.03 (br, 4H), 4.08 ( ush, 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] ⁺ .

Example 119 4-(4-chlorophenyl)-6-(4-(3,4- dichlorophenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using 1-(3,4-dichlorophenyl)piperazine and a preparative HPLC isolation method, the title compound was prepared as described for Example 1 (Scheme 1, General Procedure A.).

^1H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 120 4-(4-chlorophenyl)-6-(4-(4-methoxyphenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using 1-(4-methoxyphenyl)piperazine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

^1H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 121 4-(4-chlorophenyl)-6-(4-(4-nitrophenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using 1-(4-nitrophenyl)piperazine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

^1H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 122. 4-(4-chlorophenyl)-6-(3-(4-methylpiperazin-1-yl)pyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using 1-methyl-4-(pyrrolidin-3-yl)piperazine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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 (br, 1H), 6.99 (s, 1H), 7.54 (d, 2H), 8.10-8.13 (m, 1H), 8.23 (d, 2H), 8.91 (d, 1H), 9.49 (d, 1H), 9 .77 (s, 1H); MS (ESI, m/z): 435.2 [M+H] ⁺ .

Example 123. 4-(4-benzhydrylpiperazin-1-yl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidine

Using 1-benzhydrylpiperazine and a preparative HPLC isolation method, the title compound was prepared as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 124 4-(4-chlorophenyl)-6-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using 1-((4-chlorophenyl)(phenyl)methyl)piperazine and a preparative HPLC isolation method, the title compound was prepared as described for Example 1 (Scheme 1. General Procedure A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 125. 1'-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)spiro[indene-1,4'-piperidine]

Using spiro[indene-1,4'-piperidine] and a preparative HPLC isolation method, the title compound was prepared as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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, 2H), 7.37 (s, 1H), 7 .55 (d, 2H), 8.09-8.13 (m, 1H), 8.25 (d, 2H), 8.90 (d, 1H), 9.49 (d, 1H), 9. 76 (s, 1H); MS (ESI, m/z): 451.2 [M+H] ⁺ .

Example 126. 6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(pyrrolidin-3-yl)pyrimidin-4-amine

Using tert-butyl 3-aminopyrrolidine-1-carboxylate and a preparative HPLC isolation method, the title compound was obtained as described for Example 54 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 127. (R)-6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(pyrrolidin-3-yl)pyrimidin-4-amine

Using tert-butyl (R)-3-aminopyrrolidine-1-carboxylate and a preparative HPLC isolation method, the title compound was obtained as described for Example 54 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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), 4.05-4.12 (m, 1H), 7.06 (s, 1H), 7.53 (d, 2H), 8.02-8.06 (m, 1H), 8.18 (d, 2H), 8.88 (d, 1H), 9.41 (d, 1H), 9.75 (s, 1H); MS (ESI, m/z): 352.1 [M+H] ⁺ .

Example 128. (R)-6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(pyrrolidin-3-ylmethyl)pyrimidin-4-amine

Using tert-butyl (S)-3-(aminomethyl)pyrrolidine-1-carboxylate and a preparative HPLC isolation method, the title compound was prepared as described for Example 54 (Scheme 1, General Procedure A.).

¹ H NMR (400 MHz, CD ₃ OD) 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 (ush, 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] ⁺ .

Example 129. 6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(2-(pyrrolidin-1-yl)ethyl)pyrimidin-4-amine

Using 2-(pyrrolidin-1-yl)ethan-1-amine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) δ [ppm] = 3.19 (br, 4H), 3.40 (d, 2H), 3.53 (d, 2H), 3.76 ( ush, 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] ⁺ .

Example 130. 6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(3-(pyrrolidin-1-yl)propyl)pyrimidin-4-amine

Using 3-(pyrrolidin-1-yl)propan-1-amine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 131. 6-(4-chlorophenyl)-N-(2-(1-methylpyrrolidin-2-yl)ethyl)-2-(pyridin-3-yl)pyrimidin-4-amine

Using 2-(1-methylpyrrolidin-2-yl)ethan-1-amine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 132 N-(1-benzylpyrrolidin-3-yl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-amine

Using 1-benzylpyrrolidin-3-amine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 133. (3R,4S)-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)pyrrolidin-3-ol

Using tert-butyl (3S,4R)-3-amino-4-hydroxypyrrolidine-1-carboxylate and a preparative HPLC isolation method, the title compound was obtained as described for Example 54 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) δ [ppm] = 1.06 (br, 2H), 2.18 (br, 1H), 3.80 (br, 1H), 4.17 ( ush, 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] ⁺ .

Example 134. (3S,4R)-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)pyrrolidin-3-ol

Using tert-butyl (3R,4S)-3-amino-4-hydroxypyrrolidine-1-carboxylate and a preparative HPLC isolation method, the title compound was obtained as described for Example 54 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) δ [ppm] = 1.06 (br, 2H), 2.18 (br, 1H), 3.80 (br, 1H), 4.17 ( ush, 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] ⁺ .

Example 135. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(pyrrolidin-1-yl)pyrimidine

Using pyrrolidine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 136 4-(4-chlorophenyl)-6-(2-methylpyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using 2-methylpyrrolidine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 137. (S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol

Using (S)-pyrrolidin-3-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) δ [ppm] = 2.17 (br, 2H), 3.70 (br, 2H), 3.86 (br, 2H), 4.59 ( ush, 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] ⁺ .

Example 138. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)methanol

Using pyrrolidin-3-ylmethanol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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, 1H), 7.52 (d, 2H), 8 .04-8.08 (m, 1H), 8.18 (d, 2H), 8.88 (d, 1H), 9.39 (d, 1H), 9.68 (s, 1H); MS (ESI, m/z): 367.1 [M+H] ⁺ .

Example 139. (R)-4-(4-chlorophenyl)-6-(3-fluoropyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using (R)-3-fluoropyrrolidine and a preparative HPLC isolation method, the title compound was prepared as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 140. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-amine

Using tert-butylpyrrolidin-3-ylcarbamate and a preparative HPLC isolation method, the title compound was obtained as described for Example 54 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) δ [ppm] = 2.31 (br, 1H), 2.57 (br, 1H), 3.87 (br, 2H), 4.06 ( ush, 2H), 4.14 (ush, 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] ⁺ .

Example 141. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-N-methylpyrrolidin-3-amine

Using tert-butylmethyl (pyrrolidin-3-yl)carbamate and a preparative HPLC isolation method, the title compound was obtained as described for Example 54 (Scheme 1, General Procedure A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 142 Methyl (6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)prolinate

Using methyl prolinate and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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, 2H), 8.05-8.08 (m, 1H), 8.23 ( d, 2H), 8.88 (d, 1H), 9.32 (d, 1H), 9.59 (s, 1H); MS (ESI, m/z): 395.1 [M+H] ⁺ .

Example 143. N-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)acetamide

Using N-(pyrrolidin-3-yl)acetamide and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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 (br, 1H), 6.97 (s, 1H), 7.53 (d, 2H), 8.13-8.16 (m, 1H), 8.21 (d, 2H), 8.92 (d, 1H), 9.50 (d, 1H), 9 .73 (s, 1H); MS (ESI, m/z): 394.1 [M+H] ⁺ .

Example 144 (2R,3R)-3-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)butan-2-ol

Using (2R,3R)-3-aminobutan-2-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (600 MHz, CD ₃ OD) δ [ppm] = 1.23 (d, 3H), 1.30 (d, 3H), 3.94 (br, 1H), 4.51 ( ush, 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] ⁺ .

Example 145. 3-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)butan-2-ol

Using 3-aminobutan-2-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (600 MHz, CD ₃ OD) 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] ⁺ .

Example 146. 1-(4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)piperidin-1-yl)ethan-1-one

Using 1-(4-aminopiperidin-1-yl)ethan-1-one and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (600 MHz, CD ₃ OD) 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] ⁺ .

Example 147. (R)-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanol

Using (R)-piperidin-3-ylmethanol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (600 MHz, CD ₃ OD) 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] ⁺ .

Example 148. (S)-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanol

Using (S)-piperidin-3-ylmethanol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (600 MHz, CD ₃ OD) 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] ⁺ .

Example 149. 6-(4-chlorophenyl)-N-(2-(piperidin-1-yl)ethyl)-2-(pyridin-3-yl)pyrimidin-4-amine

Using 2-(piperidin-1-yl)ethan-1-amine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

^1H NMR (600 MHz, CD ₃ OD) 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, 2H), 7.08 (s, 1H), 7 .57 (d, 2H), 8.10-8.12 (m, 1H), 8.21 (d, 2H), 8.92 (d, 1H), 9.48 (d, 1H), 9. 80 (s, 1H); MS (ESI, m/z): 394.2 [M+H] ⁺ .

Example 150. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidine-4-carbonitrile

Using piperidine-4-carbonitrile and a preparative HPLC isolation method, the title compound was prepared as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (600 MHz, CD ₃ OD) 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 (ush, 2H), 7.32 (s, 1H), 7.54 (d, 2H), 8. 11-8.13 (m, 1H), 8.25 (d, 2H), 8.90 (d, 1H), 9.50 (d, 1H), 9.75 (s, 1H); MS (ESI, m/z): 376.1 [M+H] ⁺ .

Example 151. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(3-(trifluoromethyl)phenyl)piperidin-4-ol

Using 4-(3-(trifluoromethyl)phenyl)piperidin-4-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (600 MHz, CD ₃ OD) 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, 2H), 7.76 (d, 1H), 7 .88 (s, 1H), 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): 511.1 [M+H] ⁺ .

Example 152. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyrimidine

Using 4-(pyrrolidin-1-yl)piperidine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (600 MHz, CD ₃ OD) 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 (ush, 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] ⁺ .

Example 153. 4-(4-chlorophenyl)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-ol

Using 4-(4-chlorophenyl)piperidin-4-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (600 MHz, CD ₃ OD) 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] ⁺ .

Example 154. 1-(4-(((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)ethan-1-one

Using 1-(4-(aminomethyl)piperidin-1-yl)ethan-1-one and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (600 MHz, CD ₃ OD) 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, 2H), 8.14-8.16 (m, 1H), 8.22 (d, 2H), 8.92 (d, 1H), 9.50 (d, 1H), 9.73 (s, 1H); MS (ESI, m/z): 422.2 [M+H] ⁺ .

Example 155. 1-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-phenylpiperidin-4-yl)ethan-1-one

Using 1-(4-phenylpiperidin-4-yl)ethan-1-one and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (600 MHz, CD ₃ OD) 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, 1H), 7.42 (d, 4H), 7 .51 (d, 2H), 8.10-8.12 (m, 1H), 8.20 (d, 2H), 8.90 (d, 1H), 9.46 (d, 1H), 9.71 ( s, 1H); MS (ESI, m/z): 469.2 [M+H] ⁺ .

Example 156. 4-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)morpholine

Using 4-(piperidin-4-yl)morpholine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (600 MHz, CD ₃ OD) 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] ⁺ .

Example 157. 4-(4-chlorophenyl)-6-(4-(3,5 - dichlorophenyl)piperidin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using 4-(3,5-dichlorophenyl)piperidine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

^1H NMR (600 MHz, CD ₃ OD) 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, 1H), 7.35 (s, 1H), 7 .55 (d, 2H), 8.15-8.18 (m, 1H), 8.25 (d, 2H), 8.93 (d, 1H), 9.54 (d, 1H), 9. 76 (s, 1H); MS (ESI, m/z): 495.1 [M+H] ⁺ .

Example 158. 6-(4-chlorophenyl)-N-((1-cyclohexylpiperidin-3-yl)methyl)-2-(pyridin-3-yl)pyrimidin-4-amine

Using (1-cyclohexylpiperidin-3-yl)methanamine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (600 MHz, CD ₃ OD) 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] ⁺ .

Example 159 N-((1-benzylpiperidin-4-yl)methyl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-amine

Using (1-benzylpiperidin-4-yl)methanamine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (600 MHz, CD ₃ OD) 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] ⁺ .

Example 160. Ethyl 3-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)-3-oxopropanoate

Using ethyl 3-oxo-3-(piperidin-4-yl)propanoate and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (600 MHz, CD ₃ OD) 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] ⁺ .

Example 161. Ethyl 2-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)acetate

Using ethyl 2-(piperidin-4-yl)acetate and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (600 MHz, CD ₃ OD) 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), 4.78 (br, 2H), 7.27 (s , 1H), 7.55 (d, 2H), 8.16-8.18 (m, 1H), 8.22 (d, 2H), 8.94 (d, 1H), 9.51 (d, 1H), 9.74 (s, 1H); MS (ESI, m/z): 437.2 [M+H] ⁺ .

Example 162. (1S,3R)-3-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol

Using (1S,3R)-3-aminocyclopentan-1-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

^1H NMR (600 MHz, CD ₃ OD) 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 (ush, 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] ⁺ .

Example 163. (S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-ol

Using (S)-piperidin-3-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (600 MHz, CD ₃ OD) 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 (kv, 1H), 3.65 (ush, 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] ⁺ .

Example 164. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-N, N- dimethylpyrrolidin-3-amine

Using N,N-dimethylpyrrolidin-3-amine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (600 MHz, CD ₃ OD) 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 (s, 1H), 7.54 (d, 2H), 8.15-8.18 (m, 1H), 8.27 (d, 2H), 8.94 (d, 1H), 9.57 (d, 1H), 9.81 (s, 1H); MS (ESI, m/z): 380.2 [M+H] ⁺ .

Example 165. 2-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-2-yl)-N, N- dimethylethan-1-amine

Using N,N-dimethyl-2-(pyrrolidin-2-yl)ethan-1-amine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (600 MHz, CD ₃ OD) 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 (s, 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] ⁺ .

Example 166. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-one

Using piperidin-4-one and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (600 MHz, CD ₃ OD) 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] ⁺ .

Example 167. 6-(4-chlorophenyl)-N-methyl-N-(piperidin-4-yl)-2-(pyridin-3-yl)pyrimidin-4-amine

Using tert-butyl 4-(methylamino)piperidine-1-carboxylate and a preparative HPLC isolation method, the title compound was obtained as described for Example 54 (Scheme 1, General Procedure A.).

¹ H NMR (600 MHz, CD ₃ OD) 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, 1H), 7.55 (d, 2H), 8 .16-8.18 (m, 1H), 8.27 (d, 2H), 8.94 (d, 1H), 9.59 (d, 1H), 9.85 (s, 1H); MS (ESI, m/z): 380.2 [M+H] ⁺ .

Example 168. 6-(4-chlorophenyl)-N-(2-(1-methylpiperidin-2-yl)ethyl)-2-(pyridin-3-yl)pyrimidin-4-amine

Using 2-(1-methylpiperidin-2-yl)ethan-1-amine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (600 MHz, CD ₃ OD) 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] ⁺ .

Example 169. 6-(4-chlorophenyl)-N-(1-(1-methylpiperidin-4-yl)ethyl)-2-(pyridin-3-yl)pyrimidin-4-amine

Using 1-(1-methylpiperidin-4-yl)ethan-1-amine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

^1H NMR (600 MHz, CD ₃ OD) 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] ⁺ .

Example 170. 6-(4-chlorophenyl)-N-((1-(2-methoxyethyl)piperidin-4-yl)methyl)-2-(pyridin-3-yl)pyrimidin-4-amine

Using (1-(2-methoxyethyl)piperidin-4-yl)methanamine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (600 MHz, CD ₃ OD) 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] ⁺ .

Example 171. Methyl 2-(4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)piperidin-1-yl)acetate

Using methyl 2-(4-aminopiperidin-1-yl)acetate and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (600 MHz, CD ₃ OD) 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] ⁺ .

Example 172. 1-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)ethyl 2,2,2-trifluoroacetate

Using 1-(piperidin-4-yl)ethyl 2,2,2-trifluoroacetate and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (600 MHz, CD ₃ OD) 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, 2H), 8.02-8.05 (m, 1H), 8.21 (d, 2H), 8.86 (d, 1H), 9.37 (d, 1H), 9.69 (s, 1H); MS (ESI, m/z): 491.1 [M+H] ⁺ .

Example 173. 6-(4-chlorophenyl)-N-(1-methylpiperidin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-amine

Using 1-methylpiperidin-3-amine and a preparative HPLC isolation method, the title compound was prepared as described for Example 1 (Scheme 1, General Method A.).

^1H NMR (600 MHz, CD ₃ OD) 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] ⁺ .

Example 174. (1S,2R)-2-((6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol

Scheme for obtaining the compound of example 174:

Intermediate 8. methyl 1-methyl-1H-pyrazole-4-carbiimidate

A suspension of 1-methyl-1H-pyrazole-4-carbonitrile (3.0 g, 28.04 mmol) in methanolic hydrogen chloride solution (4 M HCl gas in MeOH, 30 ml) was stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (dichloromethane/MeOH = 20/1; v/v) to give 1.7 g of the title compound.

MS (ESI, m/z): 140.1 [M+H] ⁺ .

Intermediate 9. 1-methyl-1H-pyrazole-4-carboximidamide

A solution of methyl 1-methyl-1H-pyrazole-4-carbiimidate (2.7 g, 19.4 mmol) in 30 mL of methanolic ammonia solution (7.0 M NH ₃ in MeOH) was stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was purified by reverse phase column chromatography (H ₂ O/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] ⁺ .

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 the above reaction mixture was added a solution of dimethyl carbonate (0.7 g, 7.76 mmol) in tetrahydrofuran (5 mL) over 5 min. The reaction mixture was heated at 70 °C for 2 h. The reaction mixture was cooled to room temperature and quenched with saturated aqueous ammonium chloride. The mixture was acidified to pH = 6.0 and the residue was extracted with dichloromethane (20 mL x 3), dried over anhydrous sodium sulfate. The solids were filtered off and the filtrate was concentrated in vacuo. 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.

^1H 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, 1H), 7.89 (d, J = 8.2 Hz, 2H), 8.06 (d, J = 8.1 Hz, 1H), 12.48 (s, 1H); MS (ESI, m/z): 213.1 [M+H] ⁺ .

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 nitrogen for 16 h. 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 in vacuo to give 1.1 g of the title compound as a white solid.

^1H 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] ⁺ .

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 10 mL of phosphorus oxychloride was heated under reflux for 13 h. The mixture was concentrated in vacuo. The residue was poured into water and extracted with EtOAc (20 mL x 2), washed with brine, dried and concentrated in vacuo. The residue was purified by column chromatography (dichloromethane/MeOH = 10/1; v/v) to give 950 mg of the title compound.

¹ H NMR (400 MHz, DMSO-D6) δ [ppm] = 3.94 (s, 3H), 7.93 (d, J = 8.3 Hz, 2H), 8.14 (d, J = 5.5 Hz, 2H), 8.53 (d, J = 8.2 Hz, 2H), 8.56 (s, 1H); MS (ESI, m/z): 305.1 [M+H] ⁺ .

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), followed by (1S,2R)-2-aminocyclopentan-1-ol (20 mg, 0.20 mmol) at room temperature. The reaction mixture was heated at 120 °C for 4 h in a sealed tube and cooled to room temperature. The residue was filtered, evaporated in vacuo and isolated by preparative HPLC to give 15 mg of the title compound.

¹ H NMR (400 MHz, CD ₃ OD) δ [ppm] = 1.95 (br, 1H), 2.05 (br, 1H), 3.41 (br, 3H), 3.49 ( ush, 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] ⁺ .

Example 175. (R)-1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperidin-3-ol

Using (R)-piperidin-3-ol, the title compound was prepared as described for Example 174 (Scheme 2, General Procedure B).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 176. 1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperidin-4-ol

Using piperidin-4-ol, the title compound was prepared as described for Example 174 (Scheme 2, General Procedure B).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 177. (1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperidin-4-yl)methanol

Using piperidin-4-ylmethanol, the title compound was prepared as described for Example 174 (Scheme 2, General Procedure B).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 178. 2-(1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperidin-4-yl)ethan-1-ol

Using 2-(piperidin-4-yl)ethan-1-ol, the title compound was prepared as described for Example 174 (Scheme 2, General Procedure B).

¹ H NMR (400 MHz, CD ₃ OD) δ [ppm] = 1.28-1.37 (m, 4H), 1.55 (sq, 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] ⁺ .

Example 179. 3-(1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperidin-4-yl)propan-1-ol

Using 3-(piperidin-4-yl)propan-1-ol, the title compound was prepared as described for Example 174 (Scheme 2, General Procedure B.).

¹ H NMR (400 MHz, CD ₃ OD) 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 (ush, 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] ⁺ .

Example 180 4-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-6-(4-methylpiperidin-1-yl)pyrimidine

Using 4-methylpiperidine, the title compound was prepared as described for Example 174 (Scheme 2, General Procedure B).

¹ H NMR (400 MHz, CD ₃ OD) 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, 2H), 7.07 (s, 1H), 7 .64 (d, 2H), 7.87 (d, 2H), 8.31 (s, 1H), 8.58 (s, 1H); MS (ESI, m/z): 368.2 [M+H] ⁺ .

Example 181 4-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-6-(4-methylpiperazin-1-yl)pyrimidine

Using 1-methylpiperazine, the title compound was prepared as described for Example 174 (Scheme 2, General Procedure B).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 182. 2-(4-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperazin-1-yl)ethan-1-ol

Using 2-(piperazin-1-yl)ethan-1-ol, the title compound was prepared as described for Example 174 (Scheme 2, General Procedure B).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 183. (S)-1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)pyrrolidin-3-ol

Using (S)-pyrrolidin-3-ol, the title compound was prepared as described for Example 174 (Scheme 2, General Procedure B).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 184. 1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperidine-4-carbonitrile

Using piperidine-4-carbonitrile, the title compound was prepared as described for Example 174 (Scheme 2, General Procedure B).

¹ H NMR (400 MHz, CD ₃ OD) 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 (ush, 2H), 7.12 (s, 1H), 7. 63 (d, 2H), 7.91 (d, 2H), 8.31 (s, 1H), 8.56 (s, 1H); MS (ESI, m/z): 379.1 [M+H] ⁺ .

Example 185. (R)-(1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperidin-3-yl)methanol

Using (R)-piperidin-3-ylmethanol, the title compound was prepared as described for Example 174 (Scheme 2, General Procedure B).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 186. (R)-1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)pyrrolidin-3-ol

Using (R)-pyrrolidin-3-ol, the title compound was prepared as described for Example 174 (Scheme 2, General Procedure B).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 187. (1S,3R)-3-((6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol

Using (1S,3R)-3-aminocyclopentan-1-ol, the title compound was prepared as described for Example 174 (Scheme 2, General Procedure B).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 188. (R)-2-((6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)butan-1-ol

Using (R)-2-aminobutan-1-ol, the title compound was prepared as described for Example 174 (Scheme 2, General Procedure B).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 189. Trans-4-((6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclohexan-1-ol

Using trans-4-aminocyclohexan-1-ol, the title compound was prepared as described for Example 174 (Scheme 2, General Procedure B.).

¹ H NMR (400 MHz, CD ₃ OD) 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, 1H), 7.65 (d, 2H), 7 .89 (d, 2H), 8.31 (s, 1H), 8.56 (s, 1H); MS (ESI, m/z): 384.2 [M+H] ⁺ .

Example 190. 7-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)octahydro-2H-pyrano[2,3-c]pyridine

Using octahydro-2H-pyrano[2,3-c]pyridine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 191. 7-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)octahydro-2H-pyrano[2,3-c]pyridin-4-ol

Using octahydro-2H-pyrano[2,3-c]pyridin-4-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 192. (2R,3R)-3-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)pentan-2-ol

Using (2R,3R)-3-aminopentan-2-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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), 4.36 (br, 1H), 7.02 (s, 1H), 7.54 (d, 2H), 7.98-8.02 (m, 1H), 8.14 (d, 2H), 8.84 (d, 1H), 9.34 (d, 1H ), 9.67 (s, 1H); MS (ESI, m/z): 369.1 [M+H] ⁺ .

Example 193. 6-(4-chlorophenyl)-N-((1-methylpiperidin-4-yl)methyl)-2-(pyridin-3-yl)pyrimidin-4-amine

Using (1-methylpiperidin-4-yl)methanamine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 194. (R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol

Using (R)-pyrrolidin-3-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR: (400 MHz, CD ₃ OD) δ [ppm] = 2.17 (br, 2H), 3.70 (br, 2H), 3.86 (br, 2H), 4.59 (ush, 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] ⁺ .

Example 195. (S)-6-(4-chlorophenyl)-N-(2-(methoxymethyl)pyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-amine

Using (S)-2-(methoxymethyl)pyrrolidin-1-amine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR: (400 MHz, CD ₃ OD) 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 (ush, 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] ⁺ .

Example 196. (S)-4-(4-chlorophenyl)-6-(3-fluoropyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using (S)-3-fluoropyrrolidine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR: (400 MHz, CD ₃ OD) δ [ppm] = 2.24 (br, 2H), 3.79 (br, 2H), 3.87 (br, 2H), 4.17 (ush, 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] ⁺ .

Example 197. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidine

Using 2-(trifluoromethyl)pyrrolidine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR: (400 MHz, CD ₃ OD) δ [ppm] = 2.26 (br, 2H), 2.32 (br, 2H), 3.74 (br, 2H), 3.89 (ush, 1H), 7.20 (s, 1H), 7.56 (d, 2H), 8.02-8.06 (m, 1H), 8.28 (d, 2H), 8.87 ( d, 1H), 9.40 (d, 1H), 9.74 (s, 1H); MS (ESI, m/z): 405.1 [M+H] ⁺ .

Example 198. 4-(4-chlorophenyl)-6-(3,3 - difluoropyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using 3,3-difluoropyrrolidine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR: (400 MHz, CD ₃ OD) 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] ⁺ .

Example 199. 4-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)morpholine

Using 4-(pyrrolidin-3-yl)morpholine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR: (400 MHz, CD ₃ OD) 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] ⁺ .

Example 200. 5-(((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)methyl)pyrrolidin-2-one

Using 5-(aminomethyl)pyrrolidin-2-one and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR: (400 MHz, CD ₃ OD) δ [ppm] = 2.00 (br, 2H), 2.32-2.38 (m, 2H), 3.73 (br, 2H) , 4.04 (ush, 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] ⁺ .

Example 201. Trans-6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(4-(pyrrolidin-1-yl)tetrahydrofuran-3-yl)pyrimidin-4-amine

Using trans-4-(pyrrolidin-1-yl)tetrahydrofuran-3-amine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR: (400 MHz, CD ₃ OD) 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, 1H), 7.06 (s, 1H), 7.55 (d, 2H ), 8.00-8.03 (m, 1H), 8.18 (d, 2H), 8.88 (d, 1H), 9.36 (d, 1H), 9.73 (s, 1H); MS (ESI, m/z): 422.2 [M+H] ⁺ .

Example 202. 6-(4-chlorophenyl)-N-((3S,4S)-4-methoxy-1-methylpyrrolidin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-amine

Using (3S,4S)-4-methoxy-1-methylpyrrolidin-3-amine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

¹ H NMR: (400 MHz, CD ₃ OD) 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] ⁺ .

Example 203. (R)-6-(4-chlorophenyl)-N-(piperidin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-amine

Using tert-butyl (R)-3-aminopiperidine-1-carboxylate and a preparative HPLC isolation method, the title compound was prepared as described for Example 54 (Scheme 1, General Method A.).

^1H NMR: (400 MHz, CD ₃ OD) 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] ⁺ .

Example 204. 6-(4-chlorophenyl)-N-(piperidin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-amine

Using tert-butyl 3-aminopiperidine-1-carboxylate and a preparative HPLC isolation method, the title compound was obtained as described for Example 54 (Scheme 1, General Method A.).

^1H NMR: (400 MHz, CD ₃ OD) 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] ⁺ .

Example 205. 6-(4-chlorophenyl)-N-((3R,4R)-3-fluoropiperidin-4-yl)-2-(pyridin-3-yl)pyrimidin-4-amine

Using tert-butyl (3R,4R)-4-amino-3-fluoropiperidine-1-carboxylate and a preparative HPLC isolation method, the title compound was obtained as described for Example 54 (Scheme 1, General Method A.).

¹ H NMR: (400 MHz, CD ₃ OD) δ [ppm] = 1.60 (br, 1H), 1.92 (br, 1H), 2.03 (br, 1H), 3.79 (ush, 5H), 7.08 (s, 1H), 7.55 (d, 2H), 8.08-8.11 (m, 1H), 8.20 (d, 2H), 8.90 ( d, 1H), 9.41 (d, 1H), 9.70 (s, 1H); MS (ESI, m/z): 384.1 [M+H] ⁺ .

Example 206. (S)-6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(pyrrolidin-3-ylmethyl)pyrimidin-4-amine

Using tert-butyl (R)-3-(aminomethyl)pyrrolidine-1-carboxylate and a preparative HPLC isolation method, the title compound was obtained as described for Example 54 (Scheme 1, General Method A.).

^1H NMR: (400 MHz, CD ₃ OD) 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] ⁺ .

Example 207 Methyl (2R,4R)-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)pyrrolidine-2-carboxylate

Using 1-(tert-butyl)-2-methyl-(2R,4R)-4-aminopyrrolidine-1,2-dicarboxylate and a preparative HPLC isolation method, the title compound was obtained as described for Example 54 (Scheme 1. General Method A.).

MS (ESI, m/z): 410.1 [M+H] ⁺ .

Example 208. (2R,4S)-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)pyrrolidine-2-carboxylic acid

Using (2R,4S)-4-amino-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid and a preparative HPLC isolation method, the title compound was prepared as described for Example 54 (Scheme 1, General Method A.).

¹ H NMR: (400 MHz, CD ₃ OD) δ [ppm] = 1.61 (br, 2H), 2.04 (br, 2H), 2.20 (t, 1H), 3.35 (ush, 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] ⁺ .

Example 209 Trans-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)-1-isopropylpyrrolidin-3-ol

Using trans-4-amino-1-isopropylpyrrolidin-3-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

^1H NMR: (400 MHz, CD ₃ OD) 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), 3.84 (br, 1H), 7.06 (s, 1H) , 7.55 (d, 2H), 7.95-7.80 (m, 1H), 8.19 (d, 2H), 8.85 (d, 1H), 9.36 (d, 1H), 9.75 (s, 1H); MS (ESI, m/z): 410.2 [M+H] ⁺ .

Example 210. (R)-4-(3-(chloromethyl)pyrrolidin-1-yl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidine

Using (R)-3-(chloromethyl)pyrrolidine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Procedure A.).

¹ H NMR: (400 MHz, CD ₃ OD) 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, 1H), 7.50 (d, 2H), 8.08- 8.11 (m, 1H), 8.18 (d, 2H), 8.89 (d, 1H), 9.43 (d, 1H), 9.67 (s, 1H); MS (ESI, m/z): 385.1 [M+H] ⁺ .

Example 211. (S)-4-(3-(chloromethyl)pyrrolidin-1-yl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidine

Using (S)-3-(chloromethyl)pyrrolidine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Procedure A.).

¹ H NMR: (400 MHz, CD ₃ OD) 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, 1H), 7.50 (d, 2H), 8.08- 8.11 (m, 1H), 8.18 (d, 2H), 8.89 (d, 1H), 9.43 (d, 1H), 9.67 (s, 1H); MS (ESI, m/z): 385.1 [M+H] ⁺ .

Example 212. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidine-3-carbonitrile

Using pyrrolidine-3-carbonitrile and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

¹ H NMR: (400 MHz, CD ₃ OD) 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] ⁺ .

Example 213. (R)-1-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)butan-2-ol

Using (R)-1-aminobutan-2-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

^1H NMR: (400 MHz, CD ₃ OD) 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] ⁺ .

Example 214. (1R,3S)-3-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol

Using (1R,3S)-3-aminocyclopentan-1-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

^1H NMR: (400 MHz, CD ₃ OD) 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 (br, 1H), 6.94 (s, 1H), 7.53 (d, 2H), 8.06-8.10 (m, 1H), 8.12 (d, 2H), 8.89 (d, 1H), 9.41 (d, 1H ), 9.69 (s, 1H); MS (ESI, m/z): 367.1 [M+H] ⁺ .

Example 215. Cis-(4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexyl)methanol

Using cis-4-aminocyclohexan-1-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

^1H NMR: (400 MHz, CD ₃ OD) 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] ⁺ .

Example 216. Cis-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexan-1-ol

Using cis-(4-aminocyclohexyl)methanol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

^1H NMR: (400 MHz, CD ₃ OD) 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] ⁺ .

Example 217. trans-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexan-1-ol

Using trans-(4-aminocyclohexyl)methanol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

^1H NMR: (400 MHz, CD ₃ OD) 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] ⁺ .

Example 218. 4-(4-chlorophenyl)-6-(4-(2-methoxyethyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using 1-(2-methoxyethyl)piperazine and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

^1H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 219. (3S,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-ol

Using (3S,4R)-3-fluoropiperidin-4-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

^1H NMR (400 MHz, CD ₃ OD) 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, 1H), 3.82-3.68 (m, 1H), 2.18-2.05 (m, 1H), 1.74-1.60 (m, 1H ); MS (ESI, m/z): 385.1 [M+H] ⁺ .

Example 220. (3R,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-ol

Using (3R,4S)-3-fluoropiperidin-4-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

^1H NMR (400 MHz, CD ₃ OD) 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, 1H), 3.82-3.68 (m, 1H), 2.18-2.05 (m, 1H), 1.74-1.60 (m, 1H ); MS (ESI, m/z): 385.1 [M+H] ⁺ .

Example 221. (3R,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-ol

Using (3R,4R)-3-fluoropiperidin-4-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

^1H NMR (400 MHz, CD ₃ OD) 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, 1H), 3.82-3.68 (m, 1H), 2.18-2.05 (m, 1H), 1.74-1.60 (m, 1H ); MS (ESI, m/z): 385.1 [M+H] ⁺ .

Example 222. (3S,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-ol

Using (3S,4S)-3-fluoropiperidin-4-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

^1H NMR (400 MHz, CD ₃ OD) 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, 1H), 3.82-3.68 (m, 1H), 2.18-2.05 (m, 1H), 1.74-1.60 (m, 1H ); MS (ESI, m/z): 385.1 [M+H] ⁺ .

Example 223. 1-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-2-hydroxyethan-1-one

Using 2-hydroxy-1-(piperazin-1-yl)ethan-1-one and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

^1H NMR (400 MHz, CD ₃ OD) 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 (dd, 1H), 7.54 (d, 2H ), 7.31 (s, 1H), 4.32 (s, 2H), 4.04-3.91 (m, 4H), 3.84-3.74 (m, 2H), 3.68-3, 60 (m, 2H); MS (ESI, m/z): 410.1 [M+H] ⁺ .

Example 224. 2-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)propan-1-ol

Using 2-(piperazin-1-yl)propan-1-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

^1H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 225. N-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)-2-methoxyacetamide

Using 2-methoxy-N-(piperidin-4-yl)acetamide and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

^1H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 226. (1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol

The diagram for obtaining the connection of example 226:

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 dimethylformamide (50 mL) was added diisopropylethylamine (DIPEA) (4.63 mL, 26.54 mmol) followed by piperidin-4-ylmethanol (2.01 g, 13.27 mmol) at room temperature. The reaction mixture was heated at 70 °C overnight and cooled to room temperature. The reaction mixture was quenched with water and extracted three times with dichloromethane. The organic layer was washed with brine, dried over anhydrous MgSO ₄ 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.

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), sodium carbonate (300 mg, 2.831 mmol) in 30 mL of tetrahydrofuran/H ₂ O (4/1) was added Pd(PPh ₃ ) ₄ (60 mg, 0.052 mmol). The mixture was heated in a microwave at 80 °C for 120 min, cooled to room temperature and extracted three times with EtOAc (30 mL). The organic layer was washed with brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, hexane/ethyl acetate, gradient) to afford 219 mg of the title compound (Scheme 4, General Method D).

^1H 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, 2H), 1.80 (d, 2H), 1.77-1.67 (m, 1H), 1.16 (dd, J = 12.5, 4.2 Hz, 2H); MS (ESI, m/z): 415.2 [M+H] ⁺ .

Example 227. (1-(2-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol

Using (4-(trifluoromethoxy)phenyl)boronic acid and a preparative HPLC isolation method, the title compound was prepared as described for Example 226 (Scheme 4, General Method D.).

^1H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 228. (1-(6-(4-methoxyphenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol

Using (4-methoxyphenyl)boronic acid and a preparative HPLC isolation method, the title compound was obtained as described for Example 226 (Scheme 4, General Method D.).

^1H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 229. (1-(2-(pyridin-3-yl)-6-(p-tolyl)pyrimidin-4-yl)piperidin-4-yl)methanol

Using p-tolylboronic acid and a preparative HPLC isolation method, the title compound was prepared as described for Example 226 (Scheme 4, General Method D.).

^1H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 230. (3R,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidine-3,4 - diol

Using (3R,4R)-pyrrolidine-3,4-diol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

^1H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 231. (3R,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidine-3,4 - diol

Using (3R,4S)-pyrrolidine-3,4-diol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

^1H NMR (400 MHz, CD ₃ OD) 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 (d.kv, J = 18.0, 10.8, 8.5 Hz, 1H), 1.70-1.41 (m, 1H); MS (ESI, m/z): 367.1 [M+H] ⁺ .

Example 232. 1-(3-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)tetrahydropyrimidin-1(2H)-yl)ethan-1-one

Using 1-(tetrahydropyrimidin-1(2H)-yl)ethan-1-one and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

^1H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 233. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)piperidin-3-ol

Using 4-(hydroxymethyl)piperidin-3-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

^1H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 233. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)piperidin-3-ol

Using 4-(hydroxymethyl)piperidin-3-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

^1H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 234. (3R,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-fluoropyrrolidin-3-ol

Using (3R,4R)-4-fluoropyrrolidin-3-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

^1H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 235. (3R,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-fluoropyrrolidin-3-ol

Using (3R,4S)-4-fluoropyrrolidin-3-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

^1H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 236. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)pyrrolidin-3-ol

Using 4-(hydroxymethyl)pyrrolidin-3-ol and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

^1H NMR (400 MHz, CD ₃ OD) 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, 1H), 2.31-1.99 (m, 2H), 1.99-1.73 (m, 1H), 1.73-1.37 (m, 1H ); MS (ESI, m/z): 383.1 [M+H] ⁺ .

Example 237. N-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)-2-hydroxypropanamide

Using 2-hydroxy-N-(piperidin-4-yl)propanamide and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1. General Method A.).

^1H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 238. N-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)-2-hydroxyacetamide

Using 2-hydroxy-N-(piperidin-4-yl)acetamide and a preparative HPLC isolation method, the title compound was obtained as described for Example 1 (Scheme 1, General Method A.).

^1H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 239. 2-((4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)ethan-1-ol

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

^1H 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] ⁺ .

Example 240. (S)-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)methanol

Using (S)-pyrrolidin-3-ylmethanol, the title compound was prepared as described for Example 1 (Scheme 1, General Procedure A.).

^1H NMR (400 MHz, CDCl ₃ ) 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] ⁺ .

Example 241. N-((3R,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-hydroxypyrrolidin-3-yl)acetamide

Using N-((3R,4R)-4-hydroxypyrrolidin-3-yl)acetamide, the title compound was prepared as described for Example 1 (Scheme 1. General Procedure A.).

^1H NMR (600 MHz, CD ₃ OD) 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] ⁺ .

Example 242

Using (3R,4R)-4-acetamidopyrrolidin-3-yl acetate, the title compound was prepared as described for Example 1 (Scheme 1. General Procedure A.).

^1H NMR (600 MHz, CD ₃ OD) 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, 1H), 7.48 (d, J = 8.5 Hz, 2H), 6.81 (s, 1H), 5.29 (s, 1H), 4.51 (s, 1H), 4.19-3.38 (m, 4H), 2.11 (s , 3H), 1.98 (s, 3H); MS (ESI, m/z): 452.1 [M+H] ⁺ .

Example 243. N-((3R,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-hydroxypyrrolidin-3-yl)acetamide

Using N-((3R,4S)-4-hydroxypyrrolidin-3-yl)acetamide, the title compound was prepared as described for Example 1 (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 = 37.3 Hz, 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] ⁺ .

Example 244. N-((3S,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-hydroxypyrrolidin-3-yl)acetamide

Using N-((3S,4R)-4-hydroxypyrrolidin-3-yl)acetamide, the title compound was prepared as described for Example 1 (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 = 37.3 Hz, 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] ⁺ .

Example 245. N-((3S,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-hydroxypyrrolidin-3-yl)acetamide

Using N-((3S,4S)-4-hydroxypyrrolidin-3-yl)acetamide, the title compound was prepared as described for Example 1 (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 = 37.3 Hz, 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] ⁺ .

Example 246. (1-(6-(4-chloro-3-fluorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol

Using (4-chloro-3-fluorophenyl)boronic acid, the title compound was prepared as described for Example 226 (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] ⁺ .

Example 247. (3S,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)piperidin-3-ol

Using (3S,4R)-4-(hydroxymethyl)piperidin-3-ol, the title compound was prepared as described for Example 1 (Scheme 1. General Procedure A.).

^1H 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), 3.53-3.42 (m, 1H), 3.16-3.07 (m, 1H), 3.03-2.90 (m, 1H), 2.48-2.40 (m, 1H ), 1.82-1.69 (m, 1H), 1.59-1.48 (m, 2H); MS (ESI, m/z): 397.1 [M+H] ⁺ .

Example 248. (3S,4R)-4-(hydroxymethyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-3-ol

The diagram for obtaining the connection of example 248:

Intermediate 14. 4-chloro-2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidine

To a mixture of 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) in 50 mL of tetrahydrofuran/ _H2O (4/1) was added Pd( _PPh3 ) ₄ (203 mg, 0.18 mmol). The mixture was heated in a microwave oven at 65° for 20 min, cooled to room temperature and extracted three times with EtOAc (50 mL). The organic layer was dried over anhydrous _MgSO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 1.02 g of the title compound.

^1H NMR (600 MHz, CDCl ₃ ) 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] ⁺ .

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), followed by (3S,4R)-4-(hydroxymethyl)piperidin-3-ol (39 mg, 0.30 mmol) at room temperature. The reaction mixture was heated at 120 °C for 4 h in a sealed tube and cooled to room temperature. The residue was filtered, evaporated in vacuo and isolated by preparative HPLC to afford 50 mg of the title compound (Scheme 1, General Procedure A.).

^1H 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] ⁺ .

Example 249. ((3S,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-yl)methanol

Using ((3S,4R)-3-fluoropiperidin-4-yl)methanol, the title compound was prepared as described for Example 1 (Scheme 1, General Procedure A.).

¹ H 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, 1H), 2.01-1.82 (m, 1H), 1.66 (d, J = 13.3 Hz, 1H), 1.48-1.33 (m, 1H); MS (ESI, m/z): 399.1 [M+H] ⁺ .

Example 250. ((3S,4R)-3-fluoro-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol

Using ((3S,4R)-3-fluoropiperidin-4-yl)methanol, the title compound was prepared as described for Example 248 (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] ⁺ .

Example 251. ((3R,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-yl)methanol

Using ((3R,4S)-3-fluoropiperidin-4-yl)methanol, the title compound was prepared as described for Example 1 (Scheme 1. General Procedure A.).

^1H 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] ⁺ .

Example 252. ((3R,4S)-3-fluoro-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol

Using ((3R,4S)-3-fluoropiperidin-4-yl)methanol, the title compound was prepared as described for Example 248 (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] ⁺ .

Example 253. ((3R,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-yl)methanol

Using ((3R,4R)-3-fluoropiperidin-4-yl)methanol, the title compound was prepared as described for Example 1 (Scheme 1. General Procedure A.).

^1H 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] ⁺ .

Example 254. ((3R,4R)-3-fluoro-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol

Using ((3R,4R)-3-fluoropiperidin-4-yl)methanol, the title compound was prepared as described for Example 248 (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] ⁺ .

Example 255. (3S,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)pyrrolidin-3-ol

Using (3S,4R)-4-(hydroxymethyl)pyrrolidin-3-ol, the title compound was prepared as described for Example 1 (Scheme 1. General Procedure A.).

¹ H 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 = 24.3 Hz, 1H), 3.99-3.83 (m, 1H), 3.78-3.61 (m, 2H), 3.57-3.50 (m, 1H), 3.48-3.24 (m, 1H); MS (ESI, m/z): 383.1 [M+H] ⁺ .

Example 256. (3S,4R)-4-(hydroxymethyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol

Using (3S,4R)-4-(hydroxymethyl)pyrrolidin-3-ol, the title compound was prepared as described for Example 248 (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), 3.92-3.83 (m, 1H), 3.81-3.69 (m, 1H), 3.63 (d, J = 12.1 Hz, 1H), 3.55-3.45 ( m, 1H), 3.46-3.35 (m, 1H), 2.40-2.22 (m, 1H); MS (ESI, m/z): 417.2 [M+H] ⁺ .

Example 257. (3R,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)pyrrolidin-3-ol

Using (3R,4R)-4-(hydroxymethyl)pyrrolidin-3-ol, the title compound was prepared as described for Example 1 (Scheme 1. General Procedure A.).

¹ H 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 = 24.3 Hz, 1H), 3.99-3.83 (m, 1H), 3.78-3.61 (m, 2H), 3.57-3.50 (m, 1H), 3.48-3.24 (m, 1H); MS (ESI, m/z): 383.1 [M+H] ⁺ .

Example 258. (3R,4R)-4-(hydroxymethyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol

Using (3R,4R)-4-(hydroxymethyl)pyrrolidin-3-ol, the title compound was prepared as described for Example 248 (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), 3.92-3.83 (m, 1H), 3.81-3.69 (m, 1H), 3.63 (d, J = 12.1 Hz, 1H), 3.55-3.45 ( m, 1H), 3.46-3.35 (m, 1H), 2.40-2.22 (m, 1H); MS (ESI, m/z): 417.2 [M+H] ⁺ .

Example 259. (3R,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)piperidin-3-ol

Using (3R,4R)-4-(hydroxymethyl)piperidin-3-ol, the title compound was prepared as described for Example 1 (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] ⁺ .

Example 260. (3R,4R)-4-(hydroxymethyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-3-ol

Using (3R,4R)-4-(hydroxymethyl)piperidin-3-ol, the title compound was prepared as described for Example 248 (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] ⁺ .

Example 261. (3S,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)piperidin-3-ol

Using (3S,4S)-4-(hydroxymethyl)piperidin-3-ol, the title compound was prepared as described for Example 1 (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] ⁺ .

Example 262. (3S,4S)-4-(hydroxymethyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-3-ol

Using (3S,4S)-4-(hydroxymethyl)piperidin-3-ol, the title compound was prepared as described for Example 248 (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] ⁺ .

Example 263. (S)-1-(2-(4-methylpyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol

The diagram for obtaining the connection of example 263:

Intermediate 15. 2,4-dichloro-6-(4-(trifluoromethyl)phenyl)pyrimidine

To a solution of 2,4,6-trichloropyrimidine (5 g, 27.5 mmol) in 1,4-dioxane (50 mL) and H ₂ O (5 mL) were added (4-(trifluoromethyl)phenyl)boronic acid (3.61 g, 19.25 mmol), Na ₂ CO ₃ (3.79 g, 35.75 mmol), palladium acetate (617.5 mg, 2.75 mmol) and PPh ₃ (721.3 mg, 2.75 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was heated and stirred at 90 °C under N ₂ for 16 h. The mixture was cooled to room temperature and the residue was extracted with EtOAc (20 mL x 3), washed with brine. The combined organic layer was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated in vacuo. 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.

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 acetonitrile (ACN) (20 mL) were added (S)-pyrrolidin-3-ol (716 mg, 82.2 mmol) and diisopropylethylamine (2.66 g, 205.5 mmol) at room temperature. The reaction mixture was heated at 65 °C for 5 h. The mixture was concentrated in vacuo. 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, 2H), 3.39-3.72 (m, 4H), 4.43 (d, J = 27.3 Hz, 1H), 7.11 (d, J = 7.3 Hz, 1H), 7.87 (d, J = 8.0 Hz, 2H), 8.32 (d, J = 7.0 Hz, 2H); MS (ESI, m/z): 344.2 [M+H] ⁺ .

Example 263. (S)-1-(2-(4-methylpyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol

To (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), sodium carbonate (20.8 mg, 0.20 mmol) in 10 mL of 1,4-dioxane/H ₂ O (4/1) was added Pd(PPh ₃ ) ₄ (11.4 mg, 0.01 mmol). The mixture was heated in a microwave at 150 °C for 120 min, cooled to room temperature and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, dichloromethane/MeOH, gradient) to afford 30 mg of the title compound (Scheme 3, General Method C).

¹ H 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] ⁺ .

Example 264. (3R,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)piperidin-3-ol

Using (3R,4S)-4-(hydroxymethyl)piperidin-3-ol, the title compound was prepared as described for Example 1 (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] ⁺ .

Example 265. (3R,4S)-4-(hydroxymethyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-3-ol

Using (3R,4S)-4-(hydroxymethyl)piperidin-3-ol, the title compound was prepared as described for Example 248 (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] ⁺ .

Example 266. (3S,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)pyrrolidin-3-ol

Using (3S,4S)-4-(hydroxymethyl)pyrrolidin-3-ol, the title compound was prepared as described for Example 1 (Scheme 1. General Procedure A.).

¹ H 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 = 24.3 Hz, 1H), 3.99-3.83 (m, 1H), 3.78-3.61 (m, 2H), 3.57-3.50 (m, 1H), 3.48-3.24 (m, 1H); MS (ESI, m/z): 383.1 [M+H] ⁺ .

Example 267. (3S,4S)-4-(hydroxymethyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol

Using (3S,4S)-4-(hydroxymethyl)pyrrolidin-3-ol, the title compound was prepared as described for Example 248 (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), 3.92-3.83 (m, 1H), 3.81-3.69 (m, 1H), 3.63 (d, J = 12.1 Hz, 1H), 3.55-3.45 ( m, 1H), 3.46-3.35 (m, 1H), 2.40-2.22 (m, 1H); MS (ESI, m/z): 417.2 [M+H] ⁺ .

Example 268. (1-(6-(4-morpholinophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol

Using (4-morpholinophenyl)boronic acid, the title compound was prepared as described for Example 226 (Scheme 4, General Procedure D.).

^1H NMR (600 MHz, CDCl ₃ ) 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] ⁺ .

Example 269. (S)-1-(2-(2-methylpyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol

Using (2-methylpyridin-3-yl)boronic acid, the title compound was prepared as described for Example 263 (Scheme 3, General Procedure C).

^1H NMR (600 MHz, CDCl ₃ ) 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, 2H), 7.25-7.22 (m, 1H), 6.66 (s, 1H), 4.69 (s, 1H), 3.83-3.68 (m, 4H), 2.92 (s, 3H), 2.28-2.10 (m, 2H); MS (ESI, m/z): 401.2 [M+H] ⁺ .

Example 270. (S)-3-(4-(3-hydroxypyrrolidin-1-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)pyridin-2-ol

Using (2-hydroxypyridin-3-yl)boronic acid, the title compound was prepared as described for Example 263 (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] ⁺ .

Example 271. 5-chloro-2-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)phenol

Using (4-chloro-2-hydroxyphenyl)boronic acid, the title compound was prepared as described for Example 226 (Scheme 4, General Procedure D.).

^1H NMR (600 MHz, CD ₃ OD) 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, J = 6.2 Hz, 2H), 3.09 (t, J = 13.0 Hz, 2H), 1.98-1.90 (m, 2H), 1.90-1.82 (m, 1H), 1.38-1.22 (m, 4H ); MS (ESI, m/z): 397.1 [M+H] ⁺ .

Example 272. Tert-butyl (S)-4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-2-(hydroxymethyl)piperazine-1-carboxylate

Using tert-butyl (S)-2-(hydroxymethyl)piperazine-1-carboxylate, the title compound was prepared as described for Example 1 (Scheme 1. General Procedure A.).

^1H 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] ⁺ .

Example 273. 2-chloro-5-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)phenol

Using (4-chloro-3-hydroxyphenyl)boronic acid, the title compound was prepared as described for Example 226 (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] ⁺ .

Example 274. N-(4-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)phenyl)methanesulfonamide

Using [4-(methanesulfonamido)phenyl]boronic acid, the title compound was prepared as described for Example 226 (Scheme 4, General Procedure D.).

^1H 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] ⁺ .

Example 275. (1-(6-(4-(4-methylpiperazin-1-yl)phenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol

Using [4-(4-methylpiperazin-1-yl)phenyl]boronic acid, the title compound was prepared as described for Example 226 (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] ⁺ .

Example 276. (1-(6-(3-fluoro-4-morpholinophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol

Using (3-fluoro-4-morpholino-phenyl)boronic acid, the title compound was prepared as described for Example 226 (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] ⁺ .

Example 277. (1-(2-(pyridin-3-yl)-6-(2,4,6-trifluorophenyl)pyrimidin-4-yl)piperidin-4-yl)methanol

Using (2,4,6-trifluorophenyl)boronic acid, the title compound was prepared as described for Example 226 (Scheme 4, General Procedure D.).

^1H 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] ⁺ .

Example 278. (1-(2-(pyridin-3-yl)-6-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol

Using (4-tetrahydropyran-2-yloxyphenyl)boronic acid, the title compound was prepared as described for Example 226 (Scheme 4, General Procedure D.).

¹ H 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] ⁺ .

Example 279. (S)-(4-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)morpholin-2-yl)methanol

Using (S)-morpholin-2-ylmethanol, the title compound was prepared as described for Example 248 (Scheme 1, General Procedure A.).

^1H 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] ⁺ .

Example 280. (R)-(4-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)morpholin-2-yl)methanol

Using (R)-morpholin-2-ylmethanol, the title compound was prepared as described for Example 248 (Scheme 1, General Procedure A.).

^1H 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] ⁺ .

Example 281. ((3S,4S)-3-fluoro-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol

Using ((3S,4S)-3-fluoropiperidin-4-yl)methanol, the title compound was prepared as described for Example 248 (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 = 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] ⁺ .

Example 282. ((3S,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-yl)methanol

Using ((3S,4S)-3-fluoropiperidin-4-yl)methanol, the title compound was prepared as described for Example 1 (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] ⁺ .

Example 283. (3S,4S)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidine-3,4 - diol

Using (3S,4S)-pyrrolidine-3,4-diol, the title compound was prepared as described for Example 248 (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 = 2.7 Hz, 2H), 3.71 (dd, J = 11.5, 4.2 Hz, 1H), 3.48 (d, J = 11.3 Hz, 1H); MS (ESI, m/z): 403.1 [M+H] ⁺ .

Example 284. (3S,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidine-3,4 - diol

Using (3S,4S)-pyrrolidine-3,4-diol, the title compound was prepared as described for Example 1 (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 = 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] ⁺ .

Example 285. (1-(2-(1-methyl-1H-pyrazol-4-yl)-6-(4-morpholinophenyl)pyrimidin-4-yl)piperidin-4-yl)methanol

The diagram for obtaining the connection of example 285:

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), piperidin-4-ylmethanol (310 mg, 3.60 mmol) in 15 mL of tetrahydrofuran was added diisopropylethylamine (2.46 mL, 14.16 mmol). The reaction mixture was stirred for 60 min at room temperature and extracted three times with dichloromethane (30 mL). The organic layer was washed with brine, dried over anhydrous MgSO ₄ 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.

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), sodium carbonate (543 mg, 5.13 mmol) in 15 mL of tetrahydrofuran/H ₂ O (4/1) was added Pd(PPh ₃ ) ₄ (296 mg, 0.26 mmol). The mixture was heated in a microwave oven at 80 °C for 120 min, cooled to room temperature and extracted three times with ethyl acetate (30 mL). The organic layer was washed with brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, hexane/ethyl acetate, gradient) to afford 200 mg of the title compound.

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), sodium carbonate (144 mg, 1.36 mmol) in 15 mL of 1,4-dioxane/H ₂ O (4/1) was added Pd(PPh ₃ ) ₄ (78 mg, 0.08 mmol). The mixture was heated in a microwave oven at 150 °C for 120 min, cooled to room temperature and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, dichloromethane/MeOH, gradient) to afford 120 mg of the title compound (Scheme 5, General Method E).

^1H 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] ⁺ .

Example 286. (1-(2-(1-methyl-1H-pyrazol-4-yl)-6-(4-morpholinophenyl)pyrimidin-4-yl)piperidin-4-yl)methanol

Using (1-methyl-1H-pyrazol-4-yl)boronic acid, the title compound was prepared as described for Example 285 (Scheme 5, General Method 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] ⁺ .

Example 287. (1-(6-(3-fluoro-4-morpholinophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperidin-4-yl)methanol

The diagram for obtaining the connection of example 287:

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), sodium carbonate (243 mg, 2.29 mmol) in 12 mL of 1,4-dioxane/H ₂ O (4/1) was added Pd(PPh ₃ ) ₄ (132 mg, 0.11 mmol). The mixture was heated under reflux at 150° for 20 h, cooled to room temperature and extracted three times with dichloromethane (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, dichloromethane/MeOH, gradient) to give 40 mg of the title compound.

Example 287. (1-(6-(3-fluoro-4-morpholinophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperidin-4-yl)methanol

To (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), sodium carbonate (20.8 mg, 0.20 mmol) in 10 mL 1,4-dioxane/H ₂ O (4/1) was added Pd(PPh ₃ ) ₄ (11.4 mg, 0.01 mmol). The mixture was heated in a microwave oven at 150° for 120 min, cooled to room temperature and extracted with dichloromethane. 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, dichloromethane/MeOH, gradient) to afford 30 mg of the title compound (Scheme 5, General Method 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] ⁺ .

Example 288. (1-(6-(1H-indazol-5-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol

Using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole, the title compound was prepared as described for Example 226 (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, J = 12.0 Hz, 2H), 1.86-1.67 (m, 3H), 1.30-1.26 (m, 5.7 Hz, 1H), 1.21-1, 12 (m, 2H); MS (ESI, m/z): 387.2 [M+H] ⁺ .

Example 289. (1-(6-(6-morpholinopyridin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol

Using 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]morpholine, the title compound was prepared as described for Example 226 (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, J = 12.2 Hz, 2H), 1.86-1.67 (m, 3H), 1.30-1.26 (m, 5.7 Hz, 1H), 1.20-1, 10 (m, 2H); MS (ESI, m/z): 433.2 [M+H] ⁺ .

Example 290. 5-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)indolin-2-one

Using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one, the title compound was prepared as described for Example 226 (Scheme 4, General Procedure D.).

^1H NMR (600 MHz, DMSO-D6) δ [ppm] = 10.63 (s, 1H), 9.57 (s, 1H), 8.78-8.61 (m, 2H), 8.24-8.20 (m, 2H), 7.26-7.24 (m, 1H), 7.25 (s, 1H), 6.94 (d, J = 10.4 Hz, 1H) , 4.72 (s, 1H), 4.53 (t, J = 5.3 Hz, 1H), 3.59 (s, 2H), 3.30 (t, J = 12.4 Hz, 2H) , 2.98 (t, J = 12.4 Hz, 2H), 1.84-1.65 (m, 3H), 1.30-1.26 (m, 5.7 Hz, 1H), 1.20-1.10 (m, 2H); MS (ESI, m/z): 402.2 [M+H] ⁺ .

Example 291. 4-(4-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)phenyl)morpholin-3-one

Using 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]morpholin-3-one, the title compound was prepared as described for Example 226 (Scheme 4, General Procedure D.).

^1H NMR (600 MHz, DMSO-D6) δ [ppm] = 9.58-9.56 (m, 1H), 8.74-8.68 (m, 2H), 8.35 (d , J = 9.0 Hz, 2H), 7.57 (d, J = 9.0 Hz, 2H), 7.55-7.53 (m, 1H), 7.35 (s, 1H), 7 .16-7.08 (m, 1H), 4.67 (s, 1H), 4.25 (s, 2H), 4.02-4.00 (m, 2H), 3.83-3.81 (m , 2H), 3.30 (t, J = 6.0 Hz, 2H), 3.00 (t, J = 12.6 Hz, 2H), 1.82-1.70 (m, 3H), 1.30-1.26 (m, 5.7 Hz, 1H), 1.20-1.12 (m, 2H); MS (ESI, m/z): 446.2 [M+H] ⁺ .

Example 292. 4-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)benzoic acid

Using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid, the title compound was prepared as described for Example 226 (Scheme 4, General Procedure D.).

^1H NMR (600 MHz, DMSO-D6) δ [ppm] = 13.16 (s, 1H), 9.59 (s, 1H), 8.78-8.68 (m, 2H), 8.44 (d, J = 8.4 Hz, 2H), 8.07 (d, J = 8.4 Hz, 2H), 7.55 (dd, J = 7.7, 4.8 Hz, 1H ), 7.43 (s, 1H), 4.75 (s, 1H), 4.54 (t, J = 5.3 Hz, 1H), 3.30 (t, J = 5.7 Hz, 2H ), 3.01 (t, J = 12.4 Hz, 2H), 1.84-1.70 (m, 3H), 1.30-1.26 (m, 5.7 Hz, 1H), 1.22-1.12 (m, 2H); MS (ESI, m/z): 391.2 [M+H] ⁺ .

Example 293. 4-(1-(6-(1-methyl-1H-pyrazol-3-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol

Using 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole, the title compound was prepared as described for Example 226 (Scheme 4, General Procedure D.).

^1H NMR (600 MHz, DMSO-D6) δ [ppm] = 9.55-9.53 (m, 1H), 8.68-8.84 (m, 2H), 8.49 (s , 1H), 8.21 (s, 1H), 7.55-7.47 (m, 1H), 7.05 (s, 1H), 4.64 (s, 1H), 4.53 (t, J = 5.3 Hz, 1H), 3.90 (s, 3H), 3.30 (t, J = 8.5 Hz, 2H), 2.95 (t, J = 12.0 Hz, 2H) , 1.85-1.66 (m, 3H), 1.32-1.26 (m, 1H), 1.18-1.10 (m, 2H); MS (ESI, m/z): 427.2 [M+H] ⁺ .

Example 294. (1-(6-(5-fluoropyridin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol

Using 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, the title compound was prepared as described for Example 226 (Scheme 4, General Procedure D.).

^1H NMR (600 MHz, DMSO-D6) δ [ppm] = 9.60 (s, 1H), 9.39 (s, 1H), 8.77-8.71 (m, 3H), 8.62-8.59 (m, 1H), 7.56-7.52 (m, 1H), 7.51 (s, 1H), 4.72 (s, 1H), 4.53 (t, J = 5.3 Hz, 1H), 3.30 (t, J = 8.5 Hz, 2H), 3.02 (t, J = 12.0 Hz, 2H), 1.75-1.40 ( m, 3H), 1.32-1.26 (m, 1H), 1.20-1.10 (m, 2H); MS (ESI, m/z): 366.2 [M+H] ⁺ .

Example 295. (S)-3-(4-(3-hydroxypyrrolidin-1-yl)-6-(6-morpholinopyridin-3-yl)pyrimidin-2-yl)pyridin-2-ol

The diagram for obtaining the connection of example 295:

Intermediate 20. (S)-1-(2,6-dichloropyrimidin-4-yl)pyrrolidin-3-ol

To a solution of 2,4,6-trichloropyrimidine (1 g, 5.45 mmol) in _CH3CN (20 mL) were added diisopropylethylamine (3.25 g, 27.26 mmol) and (S)-3-hydroxypyrrolidine hydrochloride (712 mg, 8.18 mmol) at room temperature. The reaction mixture was stirred at 65 °C for 16 h. Thin layer chromatography (TLC) showed that the reaction was complete. The reaction mixture was cooled to room temperature and quenched with water (30 mL). The mixture was extracted with dichloromethane (40 mL x 3). The combined organic layers were washed with brine (30 mL). The organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 5/1; v/v) to give 800 mg of the title compound.

¹ H NMR (400 MHz, DMSO-D6) δ [ppm] = 2.07-2.23 (m, 2H), 3.31-3.69 (m, 4H), 3.78-3.81 (m, 1H), 4.66 (d, J = 25.1 Hz, 1H), 6.25 (s, 1H); MS (ESI, m/z): 233.0 [M+H] ⁺ .

Intermediate 21. (S)-1-(2-chloro-6-(6-morpholinopyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol

To (S)-1-(2,6-dichloropyrimidin-4-yl)pyrrolidin-3-ol (300 mg, 1.28 mmol), 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (533 mg, 2.56 mmol), sodium carbonate (272 mg, 2.56 mmol) in 20 mL of tetrahydrofuran/H ₂ O (4/1) was added Pd(PPh ₃ ) ₄ (148 mg, 0.13 mmol). The mixture was heated in a microwave at 80 °C for 120 min, cooled to room temperature and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, dichloromethane/MeOH, gradient) to afford 140 mg of the title compound.

Example 295. (S)-3-(4-(3-hydroxypyrrolidin-1-yl)-6-(6-morpholinopyridin-3-yl)pyrimidin-2-yl)pyridin-2-ol

To (S)-1-(2-chloro-6-(6-morpholinopyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol (130 mg, 0.36 mmol), (2-hydroxypyridin-3-yl)boronic acid (100 mg, 0.72 mmol), sodium carbonate (76 mg, 0.72 mmol) in 10 mL of 1,4-dioxane/H ₂ O (4/1) was added Pd(PPh ₃ ) ₄ (20.8 mg, 0.036 mmol). The mixture was heated in a microwave at 150 °C for 120 min, cooled to room temperature and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, dichloromethane/MeOH, gradient) to afford 13 mg of the title compound (Scheme 5, General Method E).

^1H NMR (400 MHz, DMSO-D6) δ [ppm] = 12.00 (s, 1H), 9.15 (d, J = 2.2 Hz, 1H), 8.81 (dd, J = 7.2, 2.2 Hz, 1H), 8.47 (dd, J = 8.9, 2.3 Hz, 1H), 7.76 (s, 1H), 7.62-7.51 (m, 1H), 6.89 (d, J = 8.9 Hz, 1H), 6.43 (t, J = 7.2 Hz, 1H), 5.01 (s, 1H), 4.50 -4.35 (m, 1H), 3.74-3.68 (m, 4H), 3.66-3.58 (m, 2H), 3.58-3.52 (m, 4H), 3.50-3.40 (m, 2H), 2.10-1.85 (m, 2H); MS (ESI, m/z): 421.2 [M+H] ⁺ .

Example 296. (S)-1-(6-(4-fluoro-3-nitrophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol

Example 297. (S)-1-(6-(4-morpholino-3-nitrophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol

Example 298. (S)-1-(6-(3-amino-4-morpholinophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol

Example 299. (S)-N-(5-(6-(3-hydroxypyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)-2-morpholinophenyl)acetamide

The diagram for obtaining the connection of example 299:

Intermediate 22. (S)-1-(6-chloro-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol

To a solution of 4,6-dichloro-2-(3-pyridyl)pyrimidine (800 mg, 3.54 mmol), (3S)-pyrrolidin-3-ol (310 mg, 3.60 mmol) in 15 mL of tetrahydrofuran was added diisopropylethylamine (2.46 mL, 14.16 mmol). The reaction mixture was heated at 60° for 60 min, cooled to room temperature and extracted three times with dichloromethane (30 mL). The organic layer was washed with brine, dried over anhydrous MgSO ₄ 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.

¹ H NMR (600 MHz, DMSO-D6) δ [ppm] = 9.38 (dd, J = 6.1, 1.7 Hz, 1H), 8.67 (dd, J = 4.7, 1.7 Hz, 1H), 8.55-8.48 (m, 1H), 7.52-7.46 (m, 1H), 6.58 (d, J = 8.9 Hz, 1H), 5.07 (dd, J = 52.4, 3.6 Hz, 1H), 4.39 (d, J = 29.2 Hz, 1H), 3.70-3.57 (m, 2H), 3.50-3.41 (m, 2H), 2.04-1.87 (m, 2H); MS (ESI, m/z): 277.1 [M+H] ⁺ .

Example 296. (S)-1-(6-(4-fluoro-3-nitrophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol

To a solution of (S)-1-(6-chloro-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol (250 mg, 0.90 mmol), 2-(4-fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (290 mg, 1.08 mmol), sodium carbonate (287 mg, 2.71 mmol) in 15 mL of tetrahydrofuran/H ₂ O (4/1) was added Pd(PPh ₃ ) ₄ (104 mg, 0.09 mmol). The mixture was heated in a microwave oven at 80° for 120 min, cooled to room temperature and extracted three times with dichloromethane (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, dichloromethane/MeOH, gradient) to afford 120 mg of the title compound (Scheme 4, General Method D.).

¹ H NMR (600 MHz, DMSO-D6) δ [ppm] = 9.56 (s, 1H), 9.00 (s, 1H), 8.78-8.60 (m, 3H), 7.73 (t, J = 9.8 Hz, 1H), 7.54-7.51 (m, 1H), 7.14 (d, J = 11.1 Hz, 1H), 5.09 (dd, J = 57.8, 3.5 Hz, 1H), 4.48-4.32 (m, 1H), 3.83-3.54 (m, 4H), 2.11-1.90 (m, 2H); MS (ESI, m/z): 382.1 [M+H] ⁺ .

Example 297. (S)-1-(6-(4-morpholino-3-nitrophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol

To a solution of (S)-1-(6-(4-fluoro-3-nitrophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol (100 mg, 0.26 mmol), morpholine (115 mg, 1.31 mmol), K ₂ CO ₃ (43 mg, 0.31 mmol) in 8 mL of acetonitrile was added KI (4.4 mg, 0.026 mmol). The mixture was heated in a microwave oven at 120° for 60 min, cooled to room temperature and extracted three times with dichloromethane (30 mL). The organic layer was washed with brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, dichloromethane/MeOH, gradient) to give 104 mg of the title compound.

¹ H NMR (600 MHz, DMSO-D6) δ [ppm] = 9.56 (s, 1H), 8.77-8.59 (m, 3H), 8.50-8.48 (m, 1H), 7.54-7.50 (m, 1H), 7.39 (d, J = 8.7 Hz, 1H), 7.02 (d, J = 11.7 Hz, 1H), 5.07 (d, J = 57.0 Hz, 1H), 4.43 (d, J = 36.5 Hz, 1H), 3.89-3.51 (m, 8H), 3.13-3.02 (m, 4H), 1.96 (dd, J = 27.3, 19.6 Hz, 2H); MS (ESI, m/z): 449.2 [M+H] ⁺ .

Example 298. (S)-1-(6-(3-amino-4-morpholinophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol

To a solution of (S)-1-(6-(4-morpholino-3-nitrophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol (100 mg, 0.22 mmol) in MeOH 8 mL was added Pd/C (10 mg, 5% humidity) and bubbled with H ₂ gas. The mixture was stirred overnight at room temperature under H ₂ gas atmosphere using a balloon. The mixture was filtered through a pad of Celite 545 and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, dichloromethane/MeOH, gradient) to give 54 mg of the title compound.

^1H NMR (600 MHz, DMSO-D6) δ [ppm] = 9.57 (s, 1H), 8.74-8.64 (m, 2H), 7.65 (d, J = 2 ,1 Hz, 1H), 7.53-7.49 (m, 1H), 7.42 (dd, J = 8.3, 1.7 Hz, 1H), 6.99 (dd, J = 31, 4, 8.2 Hz, 1H), 6.78-6.66 (m, 1H), 5.05 (dd, J = 52.4, 3.5 Hz, 1H), 4.93 (s, 2H ), 4.42 (d, J = 34.5 Hz, 1H), 3.88-3.48 (m, 8H), 2.86-2.81 (m, 4H), 2.11-1.89 (m, 2H); MS (ESI, m/z): 419.2 [M+H] ⁺ .

Example 299. (S)-N-(5-(6-(3-hydroxypyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)-2-morpholinophenyl)acetamide

To a solution of (S)-1-(6-(3-amino-4-morpholinophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol (50 mg, 0.12 mmol) in 8 mL of tetrahydrofuran was added triethylamine (24 mg, 0.24 mmol). Then, acetyl chloride (10 mg, 0.13 mmol) was added to the mixture at 0°. The reaction mixture was stirred overnight at room temperature, quenched with water and extracted with dichloromethane (10 mL). The organic layer was washed with brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, dichloromethane/MeOH, gradient) to give 11 mg of the title compound.

¹ H NMR (600 MHz, DMSO-D6) δ [ppm] = 9.55 (s, 1H), 9.04 (s, 1H), 8.70-8.62 (m, 2H), 7.95 (s, 1H), 7.56-7.48 (m, 1H), 7.20 (d, J = 8.3 Hz, 1H), 6.84-6.76 (m, 1H), 5.06 (dd, J = 52.4, 3.5 Hz, 1H), 4.43 (d, J = 33.7 Hz, 1H), 3.89-3.42 (m, 8H), 2.90-2.82 (m, 4H), 2.13 (s, 3H), 2.00-1.88 (m, 2H); MS (ESI, m/z): 461.2 [M+H] ⁺ .

Example 300. (S)-1-(6-(6-fluoropyridin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol

Example 301. (S)-1-(6-(6-((2-(dimethylamino)ethyl)amino)pyridin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol

Schematic diagram for obtaining the connection of example 301:

Intermediate 23. (S)-1-(2-chloro-6-(6-fluoropyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol

To a solution of (S)-1-(2,6-dichloropyrimidin-4-yl)pyrrolidin-3-ol (600 mg, 2.56 mmol), 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (570 mg, 2.56 mmol), sodium carbonate (543 mg, 5.13 mmol) in 15 mL of tetrahydrofuran/H ₂ O (4/1) was added Pd(PPh ₃ ) ₄ (296 mg, 0.26 mmol). The mixture was heated in a microwave at 80 °C for 120 min, cooled to room temperature and extracted three times with EtOAc (30 mL). The organic layer was washed with brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, hexane/ethyl acetate, gradient) to afford 200 mg of the title compound.

Example 300. (S)-1-(6-(6-fluoropyridin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol

To a solution of (S)-1-(2-chloro-6-(6-fluoropyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol (200 mg, 0.68 mmol), 3-pyridylboronic acid (85 mg, 0.70 mmol), sodium carbonate (144 mg, 1.36 mmol) in 15 mL of 1,4-dioxane/H ₂ O (4/1) was added Pd(PPh ₃ ) ₄ (78 mg, 0.08 mmol). The mixture was heated in a microwave at 150 °C for 120 min, cooled to room temperature and extracted three times with EtOAc (30 mL). The organic layer was washed with brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, dichloromethane/MeOH, gradient) to afford 120 mg of the title compound (Scheme 4, General Method D.).

^1H 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): 338.1 [M+H] ⁺ .

Example 301. (S)-1-(6-(6-((2-(dimethylamino)ethyl)amino)pyridin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol

To a solution of (S)-1-(6-(6-fluoropyridin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol (50 mg, 0.15 mmol), N ¹ ,N ¹ -dimethylethane-1,2-diamine hydrochloride (17 mg, 0.18 mmol), K ₂ CO ₃ (25 mg, 0.18 mmol) in 8 mL of acetonitrile was added KI (2.5 mg, 0.015 mmol). The mixture was heated in a microwave oven at 120 °C for 60 min, cooled to room temperature and extracted three times with EtOAc (30 mL). The organic layer was washed with brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, dichloromethane/MeOH, gradient) to afford 25 mg of the title compound.

^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): 406.2 [M+H] ⁺ .

Example 302. (3S)-1-(6-(6-(2,6 - dimethylmorpholino)pyridin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol

Using 2,6-dimethylmorpholine, the title compound was prepared as described for Example 301.

^1H NMR (600 MHz, DMSO-D6) δ [ppm] = 9.54 (s, 1H), 9.03 (d, J = 2.4 Hz, 1H), 8.70 (d, J = 8.0 Hz, 1H), 8.65 (dd, J = 4.7, 1.7 Hz, 1H), 8.38 (d, J = 7.5 Hz, 1H), 7.54- 7.46 (m, 1H), 6.94 (d, J = 9.0 Hz, 1H), 6.90-6.82 (m, 1H), 5.05 (d, J = 58.9 Hz , 1H), 4.42 (d, J = 34.0 Hz, 1H), 4.27 (d, J = 11.3 Hz, 2H), 3.83-3.34 (m, 8H), 2.04-1.88 (m, 2H), 1.15 (d, J = 6.2 Hz, 6H); MS (ESI, m/z): 433.2 [M+H] ⁺ .

Example 303. 5-chloro-2-(6-(4-((2-hydroxyethyl)sulfonyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)phenol

Schematic diagram for obtaining the connection of example 303:

Example 303. 5-chloro-2-(6-(4-((2-hydroxyethyl)sulfonyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)phenol

To 2-((4-(6-chloro-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)ethan-1-ol (30 mg, 0.076 mmol), (4-chloro-2-hydroxyphenyl)boronic acid (17 mg, 0.1 mmol), sodium carbonate (25 mg, 0.24 mmol) in 10 mL of tetrahydrofuran/H ₂ O (4/1) was added Pd(PPh ₃ ) ₄ (9 mg, 0.008 mmol). The mixture was heated in a microwave at 80° for 120 min, cooled to room temperature and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, dichloromethane/MeOH, gradient) to afford 17 mg of the title compound (Scheme 4, General Method D.).

¹ H NMR (600 MHz, DMSO-D6) δ [ppm] = 9.35 (d, J = 1.9 Hz, 1H), 8.74 (dd, J = 4.7, 1.5 Hz, 1H), 8.53-8.46 (m, 1H), 8.27-8.20 (m, 1H), 7.62-7.55 (m, 1H), 7.47 (s, 1H), 7.03-6.96 (m, 2H), 5.04 (t, J = 5.4 Hz, 1H), 4.05-3.90 (m, 4H), 3.74-3.70 (m, 2H), 3.31-3.28 (m, 4H), 3.22 (t, J = 6.1 Hz, 2H); MS (ESI, m/z): 476.1 [M+H] ⁺ .

Example 304. (S)-3-(4-(4-chloro-2-hydroxyphenyl)-6-(3-hydroxypyrrolidin-1-yl)pyrimidin-2-yl)pyridin-2-ol

Scheme for obtaining the compound of example 304:

Intermediate 24. (S)-1-(2-chloro-6-(4-chloro-2-hydroxyphenyl)pyrimidin-4-yl)pyrrolidin-3-ol

To a (S)-1-(2,6-dichloropyrimidin-4-yl)pyrrolidin-3-ol (600 mg, 2.56 mmol), (4-chloro-2-hydroxyphenyl)boronic acid (442 mg, 2.56 mmol), sodium carbonate (815 mg, 7.69 mmol) in 20 mL of tetrahydrofuran/H ₂ O (4/1) was added Pd(PPh ₃ ) ₄ (296 mg, 0.26 mmol). The mixture was heated in a microwave oven at 80° for 120 min, cooled to room temperature and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, dichloromethane/MeOH, gradient) to afford 50 mg of the title compound.

Example 304. (S)-3-(4-(4-chloro-2-hydroxyphenyl)-6-(3-hydroxypyrrolidin-1-yl)pyrimidin-2-yl)pyridin-2-ol

To (S)-1-(2-chloro-6-(4-chloro-2-hydroxyphenyl)pyrimidin-4-yl)pyrrolidin-3-ol (50 mg, 0.15 mmol), (2-hydroxypyridin-3-yl)boronic acid (42.6 mg, 0.31 mmol), sodium carbonate (48.7 mg, 0.46 mmol) in 10 mL of dioxane/H ₂ O (4/1) was added Pd(PPh ₃ ) ₄ (17.7 mg, 0.015 mmol). The mixture was heated in a microwave at 150 °C for 120 min, cooled to room temperature and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, dichloromethane/MeOH, gradient) to afford 1.8 mg of the title compound (Scheme 5, General Method E.).

^1H NMR (600 MHz, DMSO-D6) δ [ppm] = 13.01 (s, 1H), 8.89 (s, 1H), 8.01 (d, J = 6.8 Hz, 2H), 7.21-6.98 (m, 3H), 6.70 (s, 1H), 5.32-5.14 (m, 1H), 4.49 (d, J = 34.7 Hz , 1H), 3.85-3.57 (m, 4H), 2.13-1.95 (m, 2H); MS (ESI, m/z): 385.1 [M+H] ⁺ .

Example 305. (S)-1-(6-(4-aminophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol

Using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, the title compound was prepared as described for Example 296 (Scheme 4, General Procedure D.).

^1H NMR (600 MHz, DMSO-D6) δ [ppm] = 9.57 (s, 1H), 8.75-8.70 (m, 1H), 8.67 (dd, J = 4 .7, 1.7 Hz, 1H), 8.01 (d, J = 8.6 Hz, 2H), 7.54-7.50 (m, 1H), 6.73 (s, 1H), 6 .66 (d, J = 8.6 Hz, 2H), 5.62 (s, 2H), 5.12-4.98 (m, 1H), 4.42 (s, 1H), 3.384-3, 50 (m, 4H), 2.11-1.87 (m, 2H); MS (ESI, m/z): 385.1 [M+H] ⁺ .

Example 306. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(4-(vinylsulfonyl)piperazin-1-yl)pyrimidine

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

^1H NMR (600 MHz, CDCl ₃ ) δ [ppm] = 9.66 (s, 1H), 8.73 (dd, J = 8.0, 2.0 Hz, 1H), 8.69 (dd, J = 4.8, 1.8 Hz, 1H), 8.06 (d, 2H), 7.47 (d, 2H), 7.40 (dd, J = 7.9, 4.8 Hz, 1H), 6.84 (s, 1H), 6.44 (dd, J = 16.6, 9.9 Hz, 1H), 6.31 (d, J = 16.6 Hz, 1H), 6.09 (d, J = 9.9 Hz, 1H), 3.96 (t, J = 5.0 Hz, 4H), 3.31 (t, J = 5.1 Hz, 4H); MS (ESI, m/z): 442.1 [M+H] ⁺ .

Example 307. (1-(6-(2,4 - dichlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol

Using (2,4-dichlorophenyl)boronic acid, the title compound was prepared as described for Example 226 (Scheme 4, General Procedure D.).

^1H NMR (400 MHz, DMSO-D6) δ [ppm] = 9.46 (dd, J = 2.2, 0.9 Hz, 1H), 8.69-8.65 (m, 1H ), 8.61 (dt, J = 8.0, 1.9 Hz, 1H), 7.77 (d, J = 2.1 Hz, 1H), 7.71 (d, J = 8.3 Hz , 1H), 7.57 (dd, J = 8.3, 2.1 Hz, 1H), 7.51 (dd, J = 8.0, 4.8, 0.9 Hz, 1H), 7, 03 (s, 1H), 4.65-4.31 (m, 2H), 3.28 (d, J = 5.8 Hz, 2H), 3.04-2.94 (m, 2H), 1.85-1.65 (m, 3H), 1.20-1.04 (m, 2H); MS (ESI, m/z): 415.1 [M+H] ⁺ .

Example 308. (S)-(4-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperazin-2-yl)methanol

Using (S)-piperazin-2-ylmethanol, the title compound was prepared as described for Example 248 (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 (dt, J = 7.9 , 1.9 Hz, 1H), 8.70 (dd, J = 4.8, 1.7 Hz, 1H), 8.55-8.48 (m, 2H), 7.93-7.85 ( m, 2H), 7.55 (dd, J = 7.9, 4.8, 0.9 Hz, 1H), 7.43 (s, 1H), 4.90-4.76 (m, 1H) , 4.59-4.54 (m, 2H), 3.56-3.38 (m, 1H), 3.12-2.96 (m, 2H), 2.83-2.68 (m, 3H); MS (ESI, m/z): 416.2 [M+H] ⁺ .

Example 309. (R)-(4-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperazin-2-yl)methanol

Using (R)-piperazin-2-ylmethanol, the title compound was prepared as described for Example 248 (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 (dt, J = 7.9 , 1.9 Hz, 1H), 8.70 (dd, J = 4.8, 1.7 Hz, 1H), 8.55-8.48 (m, 2H), 7.93-7.85 ( m, 2H), 7.55 (dd, J = 7.9, 4.8, 0.9 Hz, 1H), 7.43 (s, 1H), 4.90-4.76 (m, 1H) , 4.59-4.54 (m, 2H), 3.56-3.38 (m, 1H), 3.12-2.96 (m, 2H), 2.83-2.68 (m, 3H); MS (ESI, m/z): 416.2 [M+H] ⁺ .

Example 310. (R)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidine-3-carboxylic acid

Using (R)-pyrrolidine-3-carboxylic acid, the title compound was prepared as described for Example 248 (Scheme 1, General Procedure A.).

^1H NMR (600 MHz, DMSO-D6) δ [ppm] = 2.10-2.39 (m, 2H), 3.61-4.08 (m, 4H), 7.10-7 .20 (m, 1H), 7.55-7.57 (m, 1H), 7.89-7.91 (m, 2H), 8.54 (ush, 2H), 8.70-8.71 (m, 1H), 8.74-8.76 (m, 1H), 9.61 (s, 1H); MS (ESI, m/z): 415.2 [M+H] ⁺ .

Example 311. (R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidine-3-carboxylic acid

Using (R)-pyrrolidine-3-carboxylic acid, the title compound was prepared as described for Example 1 (Scheme 1, General Procedure A.).

^1H NMR (600 MHz, DMSO-D6) δ [ppm] = 2.10-2.30 (m, 2H), 3.34 (br, 2H), 3.50-3.95 (m , 2H), 7.02-7.10 (m, 1H), 7.53-7.55 (m, 1H), 7.59 (d, 2H), 8.35 (br, 2H), 8. 69-8.70 (m, 1H), 8.73 (d, 1H), 9.58 (s, 1H); MS (ESI, m/z): 381.1 [M+H] ⁺ .

Example 312. (R)-1-(2-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidine-3-carboxylic acid

Using (R)-pyrrolidine-3-carboxylic acid, the title compound was prepared as described for Example 357 (Scheme 2, General Procedure B.).

^1H NMR (400 MHz, DMSO-D6) δ [ppm] = 1.23 (br, 4H), 3.35 (s, 3H), 3.91 (s, 2H), 6.87 ( br, 1H), 7.86 (d, 2H), 8.03 (s, 1H), 8.34 (s, 1H), 8.44 (br, 2H); MS (ESI, m/z): 418.2 [M+H] ⁺ .

Example 313. (R)-1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)pyrrolidine-3-carboxylic acid

Using (R)-pyrrolidine-3-carboxylic acid, the title compound was prepared as described for Example 174 (Scheme 2, General Procedure B).

^1H NMR (400 MHz, DMSO-D6) δ [ppm] = 1.20-1.23 (m, 4H), 3.35 (s, 3H), 3.90 (s, 2H), 6.87 (br, 1H), 7.56 (d, 2H), 8.01 (s, 1H), 8.27 (br, 2H), 8.33 (s, 1H); MS (ESI, m/z): 384.1 [M+H] ⁺ .

Example 314. (R)-2-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)isoxazolidin-4-ol

Using (R)-isoxazolidin-4-ol, the title compound was prepared as described for Example 248 (Scheme 1, General Procedure A.).

^1H NMR (600 MHz, DMSO-D6) δ [ppm] = 3.94-4.01 (m, 1H), 4.02-4.11 (m, 1H), 4.76 (br , 1H), 5.45 (m, 1H), 7.58-7.59 (m, 2H), 7.91 (d, 2H), 8.51 (d, 2H), 8.73-8, 77 (m, 2H), 9.61 (br, 1H); MS (ESI, m/z): 389.2 [M+H] ⁺ .

Example 315. (S)-1-(6-(6-morpholinopyridin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol

Using (6-morpholinopyridin-3-yl)boronic acid, the title compound was prepared as described for Example 296 (Scheme 4, General Procedure D.).

^1H NMR (600 MHz, DMSO-D6) δ [ppm] = 1.94-2.09 (m, 2H), 3.57-3.59 (m, 4H), 3.69-3 .73 (m, 4H), 4.42-4.74 (m, 2H), 5.02-5.12 (m, 2H), 6.90-6.96 (d, 2H), 7.51 -7.54 (m, 1H), 8.42 (d, 1H), 8.67 (d, 1H), 8.73 (d, 1H), 9.07 (br, 1H), 9.56 ( s, 1H); MS (ESI, m/z): 405.2 [M+H] ⁺ .

Example 316. (S)-1-(6-(4-chloro-2-hydroxyphenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol

Using (4-chloro-2-hydroxyphenyl)boronic acid, the title compound was prepared as described for Example 296 (Scheme 4, General Procedure D.).

^1H NMR (600 MHz, DMSO-D6) δ [ppm] = 1.94-2.03 (m, 2H), 3.60-3.77 (m, 2H), 4.43-4 .49 (m, 2H), 6.98-7.03 (m, 2H), 7.08 (d, 1H), 7.59-7.61 (m, 1H), 8.20-8.23 (m, 1H), 8.49-8.50 (m, 1H), 8.74-8.75 (m, 1H), 9.36 (br, 1H); MS (ESI, m/z): 369.1 [M+H] ⁺ .

Example 317. (S)-3-(6-(3-hydroxypyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyridin-2-ol

Using (2-hydroxypyridin-3-yl)boronic acid, the title compound was prepared as described for Example 296 (Scheme 4, General Procedure D.).

¹ H NMR (600 MHz, DMSO-D6) δ [ppm] = 9.63 (d, J = 5.6 Hz, 1H), 9.17 (s, 1H), 8.88 (d, J = 8.5 Hz, 2H), 8.74 (dd, J = 4.9, 1.7 Hz, 1H), 7.64 (dd, J = 7.9, 5.0 Hz, 1H), 7.37 (dd, J = 8.9, 2.5 Hz, 1H), 7.13 (d, J = 14.7 Hz, 1H), 4.46 (d, J = 35.8 Hz, 1H), 3.77-3.55 (m, 3H), 2.02-1.93 (m, 2H), 1.48-1.41 (m, 1H); MS (ESI, m/z): 336.1 [M+H] ⁺ .

Example 318. (1-(6-(6-fluoropyridin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol

Using (6-fluoropyridin-3-yl)boronic acid, the title compound was prepared as described for Example 226 (Scheme 4, General Procedure D.).

^1H NMR (600 MHz, DMSO-D6) δ [ppm] = 9.68 (d, J = 2.2 Hz, 1H), 9.20 (d, J = 2.5 Hz, 1H) , 9.07 (d, J = 8.0 Hz, 1H), 8.89 (td, J = 8.2, 2.6 Hz, 1H), 8.84 (dd, J = 5.1, 1 .7 Hz, 1H), 7.82 (dd, J = 8.2, 5.2 Hz, 1H), 7.51 (s, 1H), 7.38 (dd, J = 8.6, 2, 8 Hz, 1H), 4.83-4.66 (m, 2H), 4.31 (d, J = 6.6 Hz, 2H), 3.13-2.96 (m, 2H), 2.22-2.12 (m, 1H), 1.85-1.79 (m, 2H), 1.33-1.24 (m, 2H ); MS (ESI, m/z): 366.2 [M+H] ⁺

Example 319. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)azetidin-3-ol

Using azetidin-3-ol hydrochloride, the title compound was prepared as described for Example 1 (Scheme 1. General Procedure A.).

¹ H NMR (400 MHz, DMSO-D6) δ [ppm] = 3.94 (dd, J = 9.8, 4.3 Hz, 2H), 4.40-4.42 (m, 2H), 4.64-4.69 (m, 1H), 5.84 (d, J = 6.4 Hz, 1H), 6.97 (s, 1H), 7.58-7.50 (m, 1H), 7.66-7.58 (m, 2H), 8.38-8.27 (m, 2H), 8.76-8.65 (m, 2H), 9.57 (d, J = 1.3 Hz, 1H); MS (ESI, m/z): 339.3 [M+H] ⁺ .

Example 320. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)azetidin-3-yl)methanol

Using azetidin-3-ylmethanol hydrochloride, the title compound was prepared as described for Example 1 (Scheme 1, General Procedure A.).

^1H NMR (400 MHz, DMSO-D6) δ [ppm] = 2.83-2.96 (m, 1H), 3.63 (d, J = 6.0 Hz, 2H), 3, 94 (dd, J = 8.6, 5.5 Hz, 2H), 4.21 (t, J = 8.6 Hz, 2H), 4.87 (s, 1H), 6.94 (s, 1H ), 7.50-7.57 (m, 1H), 7.57-7.65 (m, 2H), 8.28-8.36 (m, 2H), 8.70 (m, 2H), 9.563 (s, 1H); MS (ESI, m/z): 353.2 [M+H] ⁺ .

Example 321. 4-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-6-(4-(methylsulfonyl)piperazin-1-yl)pyrimidine

Schematic diagram for obtaining the connection of example 321:

Intermediate 25. (S)-1-(2-chloro-6-(4-chlorophenyl)pyrimidin-4-yl)pyrrolidin-3-ol

To a solution of 2,4-dichloro-6-(4-chlorophenyl)pyrimidine (300 mg, 1.16 mmol) in acetonitrile (5 ml) were added 1-(methylsulfonyl)piperazine (286 mg, 1.74 mmol) and diisopropylethylamine (448 mg, 3.48 mmol) at room temperature. The reaction mixture was heated at 65 °C for 3 h. TLC showed that the starting material was completely consumed. After cooling the reaction mixture to room temperature, the mixture was concentrated in vacuo. The residue was extracted with dichloromethane (30 ml x 2), washed with water (30 ml), dried and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/EtOAc = 1/1; v/v) to give 160 mg of the title compound.

MS (ESI, m/z): 387.2 [M+H] ⁺ .

Example 321. 4-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-6-(4-(methylsulfonyl)piperazin-1-yl)pyrimidine

To a solution of 2-chloro-4-(4-chlorophenyl)-6-(4-(methylsulfonyl)piperazin-1-yl)pyrimidine (100 mg, 0.26 mmol) in 1,4-dioxane (2.5 mL) and H ₂ O (0.5 mL) were added (1-methyl-1H-pyrazol-4-yl)boronic acid (49 mg, 0.39 mmol), Pd(dppf)Cl ₂ (15 mg, 0.021 mmol) and Cs ₂ CO ₃ (250 mg, 0.77 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was heated at 90 °C with microwave irradiation for 1.5 h under nitrogen atmosphere. Liquid chromatography-mass spectrometry showed that the starting material was completely consumed. After cooling the reaction mixture to room temperature, the mixture was concentrated in vacuo. The residue was extracted with EtOAc (30 mL × 2), washed with water (30 mL), dried and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/EtOAc = 2/3; v/v) to afford 60 mg of the title compound (Scheme 3, General Procedure C).

¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm] = 2.82 (s, 3H), 3.32-3.41 (m, 4H), 3.87-3.95 (m, 4H), 3.97 (s, 3H), 6.69 (s, 1H), 7.45 (d, J = 8.5 Hz, 2H), 8.01 (d, J = 8.5 Hz, 2H), 8.12 (s, 1H), 8.17 (s, 1H); MS (ESI, m/z): 433.4 [M+H] ⁺ .

Example 322. (S)-1-(6-(4-chlorophenyl)-2-(3-hydroxyphenyl)pyrimidin-4-yl)pyrrolidin-3-ol formate

Schematic diagram for obtaining the connection of example 322:

Intermediate 26. (S)-1-(2-chloro-6-(4-chlorophenyl)pyrimidin-4-yl)pyrrolidin-3-ol

To a solution of 2,4-dichloro-6-(4-chlorophenyl)pyrimidine (600 mg, 2.33 mmol) in _CH3CN (30 mL) were added (S)-pyrrolidin-3-ol (243.0 mg, 2.79 mmol), diisopropylethylamine (451.0 mg, 3.495 mmol) at room temperature. The reaction mixture was heated and stirred at 65°C for 3 h. TLC showed that the starting material was completely consumed. The solvent was removed in vacuo and the residue was purified by column chromatography (petroleum ether/EtOAc = 1/1; v/v) to give 490 mg of the title compound.

MS (ESI, m/z): 310.1 [M+H] ⁺ .

Example 322. (S)-1-(6-(4-chlorophenyl)-2-(3-hydroxyphenyl)pyrimidin-4-yl)pyrrolidin-3-ol

To a solution of (S)-1-(2-chloro-6-(4-chlorophenyl)pyrimidin-4-yl)pyrrolidin-3-ol (100 mg, 0.324 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) were added (3-hydroxyphenyl)boronic acid (67 mg, 0.485 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (Pd(dppf)Cl ₂ ) (23.7 mg, 0.0324 mmol) and Cs ₂ CO ₃ (316.7 mg, 0.972 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was heated at 85 °C by microwave irradiation for 45 min under nitrogen atmosphere. The reaction mixture was concentrated in vacuo. The residue was purified by reverse phase column chromatography eluting with _CH3CN : _H2O (0.1% formic acid) to give 60.8 mg of the title compound (Scheme 3, General Method C).

^1H NMR (400 MHz, DMSO-D6) δ [ppm] = 2.19 -1.85 (m, 2H), 3.94-3.53 (m, 4H), 4.44 (s , 1H), 5.07 (m, 1H), 6.91-6.82 (m, 1H), 6.95 (s, 1H), 7.28 (t, J = 8.0 Hz, 1H) , 7.60 (d, J = 8.6 Hz, 2H), 7.92 (dd, J = 4.0, 2.2 Hz, 2H), 8.18 (s, 0.28H), 8, 30 (d, J = 8.6 Hz, 2H), 9.50 (s, 1H); MS (ESI, m/z): 368.3 [M+H] ⁺ .

Example 323. (S)-1-(6-(4-chlorophenyl)-2-(5-fluoropyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol

Using (5-fluoropyridin-3-yl)boronic acid, the title compound was prepared as described for Example 322 (Scheme 3, General Procedure C).

^1H NMR (400 MHz, DMSO-D6) δ [ppm] = 2.23-1.80 (m, 2H), 3.91-3.40 (m, 4H), 4.56-4 .35 (m, 1H), 5.06 (s, 1H), 7.05 (s, 1H), 7.59 (d, J = 8.6 Hz, 2H), 8.35 (d, J = 8.4 Hz, 2H), 8.52 (d, J = 9.8 Hz, 1H), 8.71 (d, J = 2.9 Hz, 1H), 9.46 (s, 1H); MS (ESI, m/z): 371.3 [M+H] ⁺ .

Example 324. (S)-1-(6-(4-chlorophenyl)-2-(pyridin-4-yl)pyrimidin-4-yl)pyrrolidin-3-ol

Using pyridin-4-ylboronic acid, the title compound was prepared as described for Example 322 (Scheme 3, General Procedure C).

^1H NMR (400 MHz, DMSO-D6) δ [ppm] = 2.20-1.81 (m, 2H), 3.90-3.47 (m, 4H), 4.47 (d , J = 19.1 Hz, 1H), 5.08 (s, 1H), 7.07 (s, 1H), 7.60 (d, J = 8.6 Hz, 2H), 8.17 (s , 1H), 8.41-8.27 (m, 4H), 8.75 (d, J = 5.7 Hz, 2H); MS (ESI, m/z): 353.2 [M+H] ⁺ .

Example 325. 4-(4-chlorophenyl)-2-(5-fluoropyridin-3-yl)-6-(4-(methylsulfonyl)piperazin-1-yl)pyrimidine

Using (5-fluoropyridin-3-yl)boronic acid, the title compound was prepared as described for Example 321 (Scheme 3, General Procedure C).

¹ H NMR (400 MHz, DMSO-D6) δ [ppm] = 2.92 (s, 3H), 3.20-3.30 (m, 4H), 4.02 (s, 4H), 7.50 (s, 1H), 7.61 (d, J = 8.6 Hz, 2H), 8.40 (d, J = 8.7 Hz, 2H), 8.52-8.60 (m, 1H), 8.73 (d, J = 2.8 Hz, 1H), 9.41-9.54 (m, 1H); MS (ESI, m/z): 448.4 [M+H] ⁺ .

Example 326. 4-(4-chlorophenyl)-6-(4-(methylsulfonyl)piperidin-1-yl)-2-(pyridin-3-yl)pyrimidine

Scheme for obtaining the compound of example 326:

Intermediate 27. 2-chloro-4-(4-chlorophenyl)-6-(4-(methylsulfonyl)piperazin-1-yl)pyrimidine

To a solution of 2,4-dichloro-6-(4-chlorophenyl)pyrimidine (300 mg, 1.16 mmol) in acetonitrile (5 ml) were added 4-(methylsulfonyl)piperidine (284 mg, 1.74 mmol) and diisopropylethylamine (448.9 mg, 3.48 mmol) at room temperature. The reaction mixture was heated at 65°C for 6 h. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 2/1; v/v) to give 250 mg of the title compound.

MS (ESI, m/z): 386.1 [M+H] ⁺ .

Example 326. 4-(4-chlorophenyl)-6-(4-(methylsulfonyl)piperidin-1-yl)-2-(pyridin-3-yl)pyrimidine

To a solution of 2-chloro-4-(4-chlorophenyl)-6-(4-(methylsulfonyl)piperazin-1-yl)pyrimidine (250 mg, 0.65 mmol) in 1,4-dioxane (4 mL) and H ₂ O (0.8 mL) were added pyridin-3-ylboronic acid (119.8 mg, 0.97 mmol), Cs ₂ CO ₃ (635.3 mg, 1.95 mmol) and Pd(dppf)Cl ₂ (53 mg, 0.065 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was heated and stirred at 85 °C with microwave irradiation for 45 min under N ₂ atmosphere. The mixture was cooled to room temperature and the residue was extracted with EtOAc (20 mL × 3), washed with brine. The combined organic layer was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane/MeOH = 20/1; v/v) to afford 110 mg of the title compound (Scheme 3, General Method C).

¹ H NMR (400 MHz, DMSO-D6) δ [ppm] = 1.55-1.72 (m, 2H), 2.17 (d, J = 10.9 Hz, 2H), 2.97 (s, 3H), 3.10 (t, J = 12.1 Hz, 2H), 3.39-3.59 (m, 1H), 4.74-5.02 (m, 2H), 7.55 (ddd, J = 7.9, 4.8, 0.7 Hz, 1H), 7.58-7.67 (m, 2H), 8.32-8.44 (m, 2H), 8.67-8.79 (m, 2H), 9.59 (d, J = 1.4 Hz, 1H); MS (ESI, m/z): 429.3 [M+H] ⁺ .

Example 327. (S)-1-(2-(5-fluoropyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol

Using (5-fluoropyridin-3-yl)boronic acid, the title compound was prepared as described for Example 263 (Scheme 3, General Procedure C.).

¹ H NMR (400 MHz, DMSO-D6) δ [ppm] = 2.15-1.92 (m, 2H), 3.70 (m, 4H), 4.47 (d, J = 23.6 Hz, 1H), 5.10 (d, J = 36.4 Hz, 1H), 7.14 (d, J = 7.5 Hz, 1H), 7.89 (d, J = 8.3 Hz, 2H), 8.53 (d, J = 8.1 Hz, 3H), 8.73 (d, J = 2.9 Hz, 1H), 9.48 (s, 1H); MS (ESI, m/z): 405.4 [M+H] ⁺ .

Example 328. 4-(4-chlorophenyl)-6-(4-(cyclopropylsulfonyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine

Schematic diagram for obtaining the connection of example 328:

Intermediate 28. tert-butyl 4-(2-chloro-6-(4-chlorophenyl)pyrimidin-4-yl)piperazine-1-carboxylate

To a solution of 2,4-dichloro-6-(4-chlorophenyl)pyrimidine (2 g, 7.75 mmol) in acetonitrile (20 mL) were added tert-butyl piperazine-1-carboxylate (2.1 g, 11.63 mmol) and diisopropylethylamine (3 g, 23.25 mmol) at room temperature. The reaction mixture was heated at 65 °C for 4 h under nitrogen atmosphere. Liquid chromatography-mass spectrometry showed that the starting material was completely consumed. After cooling the reaction mixture to room temperature, the mixture was extracted with dichloromethane (60 mL x 2), washed with water (65 mL), dried over anhydrous sodium sulfate. The solid was filtered off, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 4/1; v/v) to give 1.8 g of the title compound.

MS (ESI, m/z): 409.4 [M+H] ⁺ .

Intermediate 29. tert-Butyl 4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazine-1-carboxylate

To a solution of tert-butyl 4-(2-chloro-6-(4-chlorophenyl)pyrimidin-4-yl)piperazine-1-carboxylate (1.2 g, 2.94 mmol) in 1,4-dioxane (20 mL) and H ₂ O (4 mL) were added pyridin-3-ylboronic acid (543 mg, 4.41 mmol), Pd(dppf)Cl ₂ (172 mg, 0.235 mmol) and CsCO ₃ (2.8 g, 8.82 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 100 °C with microwave irradiation for 3 h under nitrogen atmosphere. Liquid chromatography-mass spectrometry showed that the starting material was completely consumed. After cooling the reaction mixture to room temperature, the mixture was extracted with EtOAc (50 ml × 2), washed with water (65 ml), dried over anhydrous sodium sulfate. The solid was filtered off and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 65/35; v/v) to give 720 mg of the title compound.

^1H NMR (400 MHz, CDCl ₃ ) δ [ppm] = 1.51 (s, 9H), 3.56-3.66 (m, 4H), 3.78-3.91 (m, 4H), 6.85 (s, 1H), 7.48 (d, J = 8.4 Hz, 3H), 8.07 (d, J = 8.5 Hz, 2H), 8.70 (s, 1H), 8.85 (d, J = 7.5 Hz, 1H), 9.70 (s, 1H); MS (ESI, m/z): 452.2 [M+H] ⁺ .

Example 102 4-(4-chlorophenyl)-6-(piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine

A solution of tert-butyl 4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazine-1-carboxylate (720 mg, 1.6 mmol) in MeOH-HCl (4 N HCl (g) in MeOH, 12 mL) was stirred at room temperature for 2 h. TLC showed that the starting material was completely consumed. The reaction mixture was concentrated in vacuo to give 700 mg of the title compound.

MS (ESI, m/z): 352.1 [M+H] ⁺ .

Example 328. 4-(4-chlorophenyl)-6-(4-(cyclopropylsulfonyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine

To a solution of 4-(4-chlorophenyl)-6-(piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine (100 mg, 0.285 mmol) in dichloromethane (3 mL) were added cyclopropanesulfonyl chloride (60 mg, 0.427 mmol) and _Et3N (144 mg, 1.425 mmol) at room temperature. The mixture was stirred at room temperature for 16 h. Liquid chromatography-mass spectrometry showed that the starting material was completely consumed. The reaction mixture was extracted with dichloromethane (30 mL x 2), washed with water (35 mL), dried over anhydrous sodium sulfate. The solid was filtered off and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC to give 16 mg of the title compound.

¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm] = 0.96-1.10 (m, 2H), 1.16-1.32 (m, 2H), 2.21-2, 36 (m, 1H), 3.49 (s, 4H), 3.98 (s, 4H), 6.92 (s, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.75 (s, 1H), 8.06 (d, J = 8.5 Hz, 2H), 8.83 (s, 1H), 9.15 (d, J = 7.1 Hz, 1H), 9.75 (s, 1H); MS (ESI, m/z): 456.4 [M+H] ⁺ .

Example 329. (S)-1-(6-(4-chlorophenyl)-2-(pyridazin-4-yl)pyrimidin-4-yl)pyrrolidin-3-ol

Schematic diagram for obtaining the connection of example 329:

Example 329. (S)-1-(6-(4-chlorophenyl)-2-(pyridazin-4-yl)pyrimidin-4-yl)pyrrolidin-3-ol

To a solution of (S)-1-(6-(4-chlorophenyl)-2-(pyridazin-4-yl)pyrimidin-4-yl)pyrrolidin-3-ol (100 mg, 0.3226 mmol) in 1,4-dioxane (3 mL) were added 4-(tributylstannyl)pyridazine (167 mg, 0.4516 mmol), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh ₃ ) ₄ ) (37 mg, 0.0322 mmol) at room temperature under nitrogen. The reaction mixture was stirred by microwave irradiation at 130 °C for 0.5 h under nitrogen. TLC showed that the starting material was completely consumed. The mixture was cooled to room temperature and extracted with EtOAc (30 mL x 2), washed with water (35 mL), dried over anhydrous sodium sulfate. The solid was filtered off and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC to give 19.5 mg of the title compound.

^1H NMR (400 MHz, CDCl ₃ ) δ [ppm] = 2.23 (s, 2H), 3.54-4.18 (m, 4H), 4.73 (s, 1H), 6 .64 (s, 1H), 7.48 (d, J = 8.6 Hz, 2H), 8.05 (d, J = 8.6 Hz, 2H), 8.42 (dd, J = 5, 3, 2.1 Hz, 1H), 9.28 (dd, J = 5.3, 1.1 Hz, 1H), 10.15 (s, 1H); MS (ESI, m/z): 354 [M+H] ⁺ .

Example 330. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)azepan-4-ol

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

^1H NMR (400 MHz, DMSO-D6) δ [ppm] = 1.56 (s, 1H), 1.63-1.79 (m, 3H), 1.93-2.06 (m , 2H), 3.56-4.08 (m, 5H), 4.57 (s, 1H), 7.17 (s, 1H), 7.55 (dd, J = 7.8, 4.8 Hz, 1H), 7.57-7.69 (m, 2H), 8.34 (d, J = 8.6 Hz, 2H), 8.61-8.79 (m, 2H), 9.58 (s, 1H); MS (ESI, m/z): 381.4 [M+H] ⁺ .

Example 331. 2-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane

Using 2-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane, the title compound was prepared as described for Example 1 (Scheme 1. General Procedure A.).

¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm] = 2.00-2.17 (m, 2H), 2.93 (s, 3H), 3.40-3.96 (m, 4H), 4.71 (s, 1H), 5.42 (s, 1H), 6.59 (s, 1H), 7.43 (dd, J = 7.8, 4.9 Hz, 1H), 7.48 (d, J = 8.6 Hz, 2H), 8.08 (d, J = 8.6 Hz, 2H), 8.71 (d, J = 3.2 Hz, 1H), 8. 79 (dt, J = 8.0, 1.7 Hz, 1H), 9.69 (s, 1H); MS (ESI, m/z): 442.40 [M+H] ⁺ .

Example 332. (S)-1-(6-(4-chlorophenyl)-2-(2-methyl-2H-tetrazol-5-yl)pyrimidin-4-yl)pyrrolidin-3-ol

Schematic diagram for obtaining the connection of example 332:

Intermediate 30. (S)-4-(4-chlorophenyl)-6-(3-hydroxypyrrolidin-1-yl)pyrimidine-2-carbonitrile

To a solution of (S)-1-(2-chloro-6-(4-chlorophenyl)pyrimidin-4-yl)pyrrolidin-3-ol (500 mg, 1.62 mmol) in N-methyl-2-pyrrolidone (6 mL) was added Zn(CN) ₂ (285 mg, 2.42 mmol), Pd( _PPh3 ) ₄ (279.6 mg, 0.24 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was heated and stirred at 160 °C with microwave irradiation for 1 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature and diluted with water. The aqueous layer was extracted with EtOAc (10 mL _× 2). The combined organic layer was washed with brine, dried over _Na2SO4 , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 1/1; v/v) to give 300 mg of the title compound.

MS (ESI, m/z): 301.2 [M+H] ⁺ .

Intermediate 31. (S)-1-(6-(4-chlorophenyl)-2-(2H-tetrazol-5-yl)pyrimidin-4-yl)pyrrolidin-3-ol

To a solution of (S)-4-(4-chlorophenyl)-6-(3-hydroxypyrrolidin-1-yl)pyrimidine-2-carbonitrile (300 mg, 1.0 mmol) in tetrahydrofuran (15 mL) was added trimethylsilyl azide (TMSN ₃ ) (230 mg, 3.0 mmol) and tetrabutylammonium fluoride (130.8 mg, 0.5 mmol) at room temperature. The reaction mixture was heated at 96 °C in a sealed tube for 16 h. The reaction mixture was cooled to room temperature and diluted with water. The aqueous layer was extracted with EtOAc (15 mL x 2). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ . Filtered and concentrated in vacuo to give 80 mg of the title compound.

MS (ESI, m/z): 344.3 [M+H] ⁺ .

Example 332. (S)-1-(6-(4-chlorophenyl)-2-(2-methyl-2H-tetrazol-5-yl)pyrimidin-4-yl)pyrrolidin-3-ol

To a solution of (S)-1-(6-(4-chlorophenyl)-2-(2H-tetrazol-5-yl)pyrimidin-4-yl)pyrrolidin-3-ol (80 mg, 0.23 mmol) in acetone (40 mL) were added CH ₃ I (49 mg, 0.35 mmol) and K ₂ CO ₃ (35.4 mg, 0.26 mmol) at room temperature. The reaction mixture was stirred at room temperature for 13 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (dichloromethane/MeOH = 10/1; v/v) to give 5.6 mg of the title compound.

¹ H NMR (400 MHz, DMSO-D6) δ [ppm] = 2.00 (m, 7.3 Hz, 2H), 3.87-3.45 (m, 4H), 4.47 (m, 4H), 5.11 (m, 1H), 7.17 (d, J = 7.6 Hz, 1H), 7.62 (d, J = 8.4 Hz, 2H), 8.28 (d, J = 6.5 Hz, 2H); MS (ESI, m/z): 358.0 [M+H] ⁺ .

Example 333. (S)-1-(6-(4-chlorophenyl)-2-(2-methyl-2H-tetrazol-5-yl)pyrimidin-4-yl)pyrrolidin-3-ol

Schematic diagram for obtaining the connection of example 333:

Intermediate 32. (S)-4-(3-hydroxypyrrolidin-1-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidine-2-carbonitrile

To a solution of (S)-1-(2-chloro-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol (300 mg, 0.836 mmol) in N-methyl-2-pyrrolidone (6 mL) was added Zn(CN) ₂ (147.22 mg, 1.254 mmol), Pd( _Ph3 ) ₄ (144.5 mg, 0.125 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was heated and stirred at 160 °C with microwave irradiation for 1 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature and diluted with water. The aqueous layer was extracted with EtOAc (10 mL × 2). _The combined organic layer was washed with brine, dried over _Na2SO4 , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 1/1; v/v) to give 411.1 mg of the title compound.

MS (ESI, m/z): 335.1 [M+H] ⁺ .

Intermediate 33. (S)-1-(2-(2H-tetrazol-5-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol

To a solution of (S)-4-(3-hydroxypyrrolidin-1-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidine-2-carbonitrile (910 mg, 2.72 mmol) in tetrahydrofuran (15 mL) was added TMSN ₃ (941.6 mg, 8.174 mmol) and tetrabutylammonium fluoride (TBAF) (355.6 mg, 1.36 mmol) at room temperature. The reaction mixture was heated at 96 °C in a sealed tube for 16 h. The reaction mixture was cooled to room temperature and diluted with water. The aqueous layer was extracted with EtOAc (15 mL x 2). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ . Filtered and concentrated in vacuo to give 990 mg of the title compound.

MS (ESI, m/z): 378.2 [M+H] ⁺ .

Example 333. (S)-1-(2-(2-methyl-2H-tetrazol-5-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol

To a solution of (S)-1-(2-(2H-tetrazol-5-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol (150 mg, 0.3998 mmol) in acetone (20 mL) were added CH ₃ I (84.7 mg, 0.597 mmol) and K ₂ CO ₃ (109.8 mg, 0.796 mmol) at room temperature. The reaction mixture was stirred at room temperature for 13 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (dichloromethane/MeOH = 10/1; v/v) to give 28.8 mg of the title compound.

¹ H NMR (400 MHz, DMSO-D6) δ [ppm] = 2.18-1.89 (m, 2H), 3.88-3.45 (m, 4H), 4.460 (s, 3H), 4.507 (s, 1H), 5.13 (d, J = 36.2 Hz, 1H), 7.26 (d, J = 7.3 Hz, 1H), 7.92 (d, J = 8.2 Hz, 2H), 8.45 (d, J = 6.8 Hz, 2H); MS (ESI, m/z): 392.2 [M+H] ⁺ .

Example 334. 4-(4-chlorophenyl)-2-(2-methyl-2H-tetrazol-5-yl)-6-(4-(methylsulfonyl)piperazin-1-yl)pyrimidine

Scheme for obtaining the compound of example 334:

Intermediate 34. 4-(4-chlorophenyl)-6-(4-(methylsulfonyl)piperazin-1-yl)pyrimidine-2-carbonitrile

To a solution of 2-chloro-4-(4-chlorophenyl)-6-(4-(methylsulfonyl)piperazin-1-yl)pyrimidine (300 mg, 0.813 mmol) in N-methyl-2-pyrrolidone (6 mL) was added Zn(CN) ₂ (143.23 mg, 1.22 mmol), Pd( _Ph3 ) ₄ (141.0 mg, 0.122 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was heated and stirred at 160 °C with microwave irradiation for 1 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature and diluted with water. The aqueous layer was extracted with EtOAc (10 mL × 2). _The combined organic layer was washed with brine, dried over _Na2SO4 , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 1/1; v/v) to give 431.1 mg of the title compound.

MS (ESI, m/z): 378.1 [M+H] ⁺ .

Intermediate 35. 4-(4-chlorophenyl)-6-(4-(methylsulfonyl)piperazin-1-yl)-2-(2H-tetrazol-5-yl)pyrimidine

To a solution of 4-(4-chlorophenyl)-6-(4-(methylsulfonyl)piperazin-1-yl)pyrimidine-2-carbonitrile (500 mg, 1.33 mmol) in tetrahydrofuran (15 mL) was added TMSN ₃ (450.8 mg, 3.98 mmol) and tetrabutylammonium fluoride (174.4 mg, 0.67 mmol) at room temperature. The reaction mixture was heated at 96 °C in a sealed tube for 16 h. The reaction mixture was cooled to room temperature and diluted with water. The aqueous layer was extracted with EtOAc (15 mL × 2). The combined organic layer was washed with brine, dried over NA ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 1/100; v/v) to give 250 mg of the title compound.

MS (ESI, m/z): 421.0 [M+H] ⁺ .

Example 334. 4-(4-chlorophenyl)-2-(2-methyl-2H-tetrazol-5-yl)-6-(4-(methylsulfonyl)piperazin-1-yl)pyrimidine

To a solution of 4-(4-chlorophenyl)-6-(4-(methylsulfonyl)piperazin-1-yl)-2-(2H-tetrazol-5-yl)pyrimidine (150 mg, 0.357 mmol) in acetone (20 mL) were added CH ₃ I (76.1 mg, 0.536 mmol) and K ₂ CO ₃ (98.5 mg, 0.714 mmol) at room temperature. The reaction mixture was stirred at room temperature for 13 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by reverse phase column chromatography eluting with CH ₃ CH:H ₂ O (0.1% formic acid) to give 21.0 mg of the title compound.

¹ H NMR (400 MHz, DMSO-D6) δ [ppm] = 2.93 (s, 3H), 3.30-3.21 (m, 4H), 4.40-3.92 (m, 4H), 4.44 (s, 3H), 7.62 (t, J = 1.9 Hz, 2H), 7.64 (d, J = 1.9 Hz, 1H), 8.34-8.28 (m, 2H); MS (ESI, m/z): 435.0 [M+H] ⁺ .

Example 335. 4-(4-chlorophenyl)-6-(4-((2-fluoroethyl)sulfonyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine

The diagram for obtaining the connection of example 335:

Example 335. 4-(4-chlorophenyl)-6-(4-((2-fluoroethyl)sulfonyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine

To a solution of 2-((4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)ethanol (74 mg, 0.16 mmol) in dichloromethane (3 mL) was added diethylaminosulfur trifluoride (DAST) (52 mg, 0.32 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 5 h under nitrogen. Liquid chromatography-mass spectrometry showed that the starting material was completely consumed. The mixture was quenched with H ₂ O at 0 °C, extracted with EtOAc (25 mL × 2), washed with water (30 mL), dried over anhydrous sodium sulfate. The solid was filtered off and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (dichloromethane/ethyl acetate/MeOH = 20/1/1; v/v/v) to give 12 mg of the title compound.

¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm] = 3.35 (t, J = 5.2 Hz, 1H), 3.42 (t, J = 5.2 Hz, 1H), 3.45-3.52 (m, 4H), 3.92-3.99 (m, 4H), 4.78 (t, J = 5.2 Hz, 1H), 4.90 (t, J = 5.2 Hz, 1H), 6.86 (s, 1H), 7.43-7.47 (m, 1H), 7.49 (d, J = 8.6 Hz, 2H), 8.07 (d, J = 8.6 Hz, 2H), 8.71 (d, J = 3.6 Hz, 1H), 8.80 (d, J = 8.0 Hz, 1H), 9.69 (s, 1H); MS (ESI, m/z): 462.0 [M+H] ⁺ .

Example 336. (S)-1-(6-(4-chlorophenyl)-2-(isoxazol-4-yl)pyrimidin-4-yl)pyrrolidin-3-ol

Scheme for obtaining the compound of example 336:

Intermediate 36. (S)-1-(6-(4-chlorophenyl)-2-(tributylstannyl)pyrimidin-4-yl)pyrrolidin-3-ol

To a solution of (S)-1-(2-chloro-6-(4-chlorophenyl)pyrimidin-4-yl)pyrrolidin-3-ol (200 mg, 0.647 mmol) in 1,4-dioxane (10 mL) were added 1,1,1,2,2,2-hexabutylditin (450.6 mg, 0.777 mmol) and Pd(PPh ₃ ) ₄ (75.1 mg, 0.065 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 120 °C with microwave irradiation for 2 h under nitrogen atmosphere. Liquid chromatography-mass spectrometry showed that the starting material was completely consumed. The mixture was filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane/MeOH = 10/1; v/v) to give 231 mg of the title compound.

MS (ESI, m/z): 566.2 [M+H] ⁺ .

Example 336. (S)-1-(6-(4-chlorophenyl)-2-(isoxazol-4-yl)pyrimidin-4-yl)pyrrolidin-3-ol

To a solution of (S)-1-(6-(4-chlorophenyl)-2-(tributylstannyl)pyrimidin-4-yl)pyrrolidin-3-ol (150 mg, 0.265 mmol) in 1,4-dioxane (2 mL) were added 4-iodoisoxazole (67.3 mg, 0.345 mmol), CuI (15 mg, 0.08 mmol) and Pd(PPh ₃ ) ₄ (46.2 mg, 0.04 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 130 °C using microwave irradiation for 2 h under nitrogen atmosphere. Liquid chromatography-mass spectrometry showed that the starting material was completely consumed. The mixture was filtered and concentrated in vacuo. The residue was purified using preparative high performance liquid chromatography to give 25 mg of the title compound.

^1H NMR (400 MHz, DMSO-D6) δ [ppm] = 2.03 (m, J = 34.2 Hz, 2H), 3.44-3.94 (m, 4H), 4, 41-4.47 (m, 1H), 5.02-5.10 (m, 1H), 6.94 (s, 1H), 7.57 (d, J = 8.6 Hz, 2H), 8 .30 (d, J = 8.5 Hz, 2H), 9.13 (s, 1H), 9.58 (s, 1H); MS (ESI, m/z): 343.0 [M+H] ⁺ .

Example 337. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(methylsulfonyl)piperidin-4-yl)methanol

Using (4-(methylsulfonyl)piperidin-4-yl)methanol hydrochloride, the title compound was prepared as described for Example 1 (Scheme 1, General Procedure A.).

^1H NMR (400 MHz, DMSO-D6) δ [ppm] = 1.89 (d, J = 13.8 Hz, 2H), 1.95-2.09 (m, 2H), 2, 98 (s, 3H), 3.40 (dd, J = 17.8, 6.8 Hz, 2H), 3.96 (d, J = 5.1 Hz, 2H), 4.55 (s, 2H ), 5.56 (t, J = 5.1 Hz, 1H), 7.41 (s, 1H), 7.52-7.58 (m, 1H), 7.58-7.64 (m, 2H), 8.34-8.41 (m, 2H) 8.70 (dd, J = 4.8, 1.7 Hz, 1H), 8.72-8.77 (m, 1H), 9.59 (d, J = 1.5 Hz, 1H); MS (ESI, m/z): 459.0 [M+H] ⁺ .

Example 338. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)azepan-3-ol

Using azepan-3-ol, the title compound was prepared as described for Example 1 (Scheme 1. General Procedure A.).

¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm] = 1.41-1.56 (m, 1H), 1.57-1.69 (m, 1H), 1.74-1, 84 (m, 1H), 1.84-1.95 (m, 3H), 3.50 (s, 1H), 3.79 (dd, J = 14.7, 3.8 Hz, 1H), 3 .86-3.97 (m, 1H), 4.21 (s, 1H), 4.43 (s, 1H), 6.85 (s, 1H), 7.37-7.55 (m, 3H ), 8.04-8.11 (m, 2H), 8.70 (d, J = 3.8 Hz, 1H), 8.77 (s, 1H), 9.70 (s, 1H); MS (ESI, m/z): 381.2 [M+H] ⁺ .

Example 339. 4-(4-chlorophenyl)-6-(4-((difluoromethyl)sulfonyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine

Using 1-((difluoromethyl)sulfonyl)piperazine, the title compound was prepared as described for Example 1 (Scheme 1, General Procedure A.).

^1H NMR (400 MHz, CDCl ₃ ) δ [ppm] = 3.70 (t, J = 4.9 Hz, 4H), 3.97 (s, 4H), 6.28 (t, J = 53.7 Hz, 1H), 6.88 (s, 1H), 7.49 (d, J = 8.6 Hz, 3H), 8.07 (d, J = 8.7 Hz, 2H), 8.72-8.73 (m, 1H), 8.83-8.85 (m, 1H), 9.69 (s, 1H); MS (ESI, m/z): 466.0 [M+H] ⁺ .

Example 340. (S)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol

Using (S)-pyrrolidin-3-ol, the title compound was prepared as described for Example 248 (Scheme 2, General Procedure B).

^1H NMR (400 MHz, DMSO-D6) δ [ppm] = 2.17-1.87 (m, 2H), 3.90-3.43 (m, 4H), 4.47 (d , J = 21.3 Hz, 1H), 5.09 (d, J = 36.9 Hz, 1H), 7.11 (s, 1H), 7.54-7.57 (m, 1H), 7 .89 (d, J = 8.3 Hz, 2H), 8.51 (d, J = 8.1 Hz, 2H), 8.69-8.71 (m, 2H), 9.61 (s, 1H); MS (ESI, m/z): 387.2 [M+H] ⁺ .

Example 341. 4-(4-(methylsulfonyl)piperazin-1-yl)-2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidine

Using 1-(methylsulfonyl)piperazine, the title compound was prepared as described for Example 248 (Scheme 2, General Procedure B).

¹ H NMR (400 MHz, DMSO-D6) δ [ppm] = 2.93 (s, 3H), 3.23-3.13 (m, 4H), 4.03 (s, 4H), 7.52-7.61 (m, 2H), 7.91 (d, J = 8.3 Hz, 2H), 8.55 (d, J = 8.2 Hz, 2H), 8.72 (dd, J = 4.8, 1.7 Hz, 1H), 8.74-8.79 (m, 1H), 9.62 (d, J = 1.6 Hz, 1H); MS (ESI, m/z): 464.0 [M+H] ⁺ .

Example 342. (S)-1-(6-(4-chlorophenyl)-2-(5,6-difluoropyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol

Using 5-bromo-2,3-difluoropyridine, the title compound was prepared as described for Example 336.

^1H NMR (400 MHz, CDCl ₃ ) δ [ppm] = 2.20 (s, 2H), 3.78 (s, 4H), 4.72 (s, 1H), 6.63 (s , 1H), 7.47 (d, J = 7.8 Hz, 2H), 8.05 (d, J = 8.1 Hz, 2H), 8.57-8.72 (m, 1H), 9 .09 (s, 1H); MS (ESI, m/z): 389.2 [M+H] ⁺ .

Example 343. (3S,4R)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidine-3,4-diol

Using (3S,4R)-pyrrolidine-3,4-diol hydrochloride, the title compound was prepared as described for Example 248 (Scheme 2, General Procedure B.).

^1H NMR (400 MHz, DMSO-D6) δ [ppm] = 3.43 (dd, J = 10.2, 5.4 Hz, 1H), 3.63 (dd, J = 11.9 , 4.1 Hz, 1H), 3.74 (dd, J = 10.3, 5.9 Hz, 1H), 3.84 (dd, J = 11.7, 5.0 Hz, 1H), 4 .14-4.22 (m, 1H), 4.26 (m, 1H), 5.04 (d, J = 4.6 Hz, 1H), 5.11 (d, J = 5.3 Hz, 1H), 7.11 (s, 1H), 7.56 (dd, J = 7.6, 4.7 Hz, 1H), 7.89 (d, J = 8.3 Hz, 2H), 8.52 (d, J = 8.2 Hz, 2H), 8.70 (dd, J = 4.7, 1.5 Hz, 1H ), 8.75 (dt, J = 8.0, 1.9 Hz, 1H), 9.60 (d, J = 1.5 Hz, 1H); MS (ESI, m/z): 403.4 [M+H] ⁺ .

Example 344. (S)-1-(6-(4-chlorophenyl)-[2,5'-bipyrimidin]-4-yl)pyrrolidin-3-ol

Using 5-bromopyrimidine, the title compound was prepared as described for Example 336.

^1H NMR (400 MHz, DMSO-D6) δ [ppm] = 1.84-2.20 (m, 2H), 3.41-3.91 (m, 4H), 4.47 (d , J = 20.7 Hz, 1H), 5.09 (d, J = 36.4 Hz, 1H), 7.06 (d, J = 6.6 Hz, 1H), 7.59 (d, J = 8.4 Hz, 2H), 8.35 (d, J = 8.1 Hz, 2H), 9.32 (s, 1H), 9.68 (s, 2H); MS (ESI, m/z): 354.2 [M+H] ⁺ .

Example 345. (S)-1-(6-(4-chlorophenyl)-2-(6-fluoropyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol

Using 5-bromo-2-fluoropyridine, the title compound was prepared as described for Example 336.

^*1H NMR (400 MHz, CDCl ₃ ) δ [ppm] = 2.22 (s, 2H), 3.42-4.20 (m, 4H), 4.73 (s, 1H), 6.64 (s, 1H), 6.96-7.07 (m, 1H), 7.44 (s, 2H), 8.06 (d, J = 6.4 Hz, 2H), 8.89 (t, J = 7.2 Hz, 1H), 9.29 (s, 1H); MS (ESI, m/z): 371.4 [M+H] ⁺ .

Example 346. (S)-1-(6-(4-chlorophenyl)-2-(2-fluoropyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol

Using 3-bromo-2-fluoropyridine, the title compound was prepared as described for Example 336.

* ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm] = 2.17 (s, 2H), 3.72 (s, 4H), 4.65 (s, 1H), 6.57 ( s, 1H), 7.23-7.34 (m, 1H), 7.43 (d, J = 8.6 Hz, 2H), 8.02 (d, J = 8.6 Hz, 2H), 8.24-8.30 (m, 1H), 8.57-8.67 (m, 1H); MS (ESI, m/z): 371.4 [M+H] ⁺ .

Example 347. (S)-1-(6-(4-chlorophenyl)-2-(pyridin-2-yl)pyrimidin-4-yl)pyrrolidin-3-ol

Using 2-(tributylstannyl)pyridine, the title compound was prepared as described for Example 329.

^1H NMR (400 MHz, DMSO-D6) δ [ppm] = 1.84-2.17 (m, 2H), 3.42-3.95 (m, 4H), 4.44 (s , 1H), 5.06 (d, J = 35.4 Hz, 1H), 7.04 (s, 1H), 7.51 (s, 1H), 7.60 (d, J = 8.5 Hz , 2H), 7.96 (s, 1H), 8.31 (d, J = 7.8 Hz, 2H), 8.43 (d, J = 7.1 Hz, 1H), 8.74 (d , J = 3.3 Hz, 1H); MS (ESI, m/z): 353.2 [M+H] ⁺ .

Example 348. 2-((4-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)ethanol

Using 2-(piperazin-1-ylsulfonyl)ethan-1-ol, the title compound was prepared as described for Example 174 (Scheme 2, General Procedure B.).

^1H NMR (400 MHz, DMSO-D6) δ [ppm] = 3.24 (t, J = 6.1 Hz, 2H), 3.30 (d, J = 3.8 Hz, 4H) , 3.76 (m, 2H), 3.90-3.904 (m, 7H), 5.03 (t, J = 5.4 Hz, 1H), 7.23 (s, 1H), 7.58 ( d, J = 8.6 Hz, 2H), 8.05 (s, 1H), 8.30 (d, J = 8.6 Hz, 2H), 8.37 (s, 1H); MS (ESI, m/z): 463.4 [M+H] ⁺ .

Example 349. 2-((4-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)ethan-1-ol

Using 2-(piperazin-1-ylsulfonyl)ethan-1-ol, the title compound was prepared as described for Example 248 (Scheme 1, General Procedure A.).

¹ H NMR (400 MHz, DMSO-D6) δ [ppm] = 3.25 (t, J = 6.1 Hz, 2H), 3.33-3.36 (m, 4H), 3.73-3.79 (m, 2H), 3.96-4.04 (m, 4H), 5.04 (t, J =5.4 Hz, 1H), 7.52-7.58 (m, 2H), 7.91 (d, J = 8.3 Hz, 2H), 8.55 (d, J =8.2 Hz, 2H), 8.70-8.78 (m, 2H), 9.61 (d, J =1.6 Hz, 1H); MS (ESI, m/z): 494.4[M+H] ⁺ .

Example 350. (S)-1-(2-(isothiazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol

Schematic diagram for obtaining the connection of example 350:

Intermediate 37. (S)-1-(6-(4-chlorophenyl)-2-(tributylstannyl)pyrimidin-4-yl)pyrrolidin-3-ol

To a solution of (S)-1-(2-chloro-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol (500 mg, 1.46 mmol) in 1,4-dioxane (5 mL) were added hexabutylditin (1.01 g, 1.75 mmol) and Pd( _PPh3 ) _Cl2 (102 mg, 0.15 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 150 °C using microwave irradiation for 7 h under nitrogen atmosphere. Liquid chromatography-mass spectrometry showed that the starting material was consumed, giving the title compound. The reaction mixture was cooled to room temperature and filtered through a pad of celite. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography, eluting to give 200 mg of the title compound.

MS (ESI, m/z): 600.3 [M+H] ⁺ .

Example 350. (S)-1-(2-(isothiazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol

To a solution of (S)-1-(2-(tributylstannyl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol (200 mg, 0.33 mmol) in 1,4-dioxane (6 mL) was added 4-bromoisothiazole (71 mg, 0.43 mmol), Pd(PPh ₃ ) ₄ (58 mg, 0.05 mmol), CuI (19 mg, 0.1 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 130 °C with microwave irradiation for 3 h under nitrogen atmosphere. Liquid chromatography-mass spectrometry showed that the starting material was consumed, giving the title compound. The reaction mixture was concentrated in vacuo. The residue was diluted with water (20 mL), extracted with EtOAc (20 mL × 3), the combined organic layers were washed with brine, dried and concentrated in vacuo. The residue was purified by preparative high-performance liquid chromatography to give 14.3 mg of the title compound.

^1H NMR (400 MHz, DMSO-D6) δ [ppm] = 1.90-2.16 (m, 2H), 3.44-3.84 (m, 4H), 4.46 (d , J = 22.2 Hz, 1H), 5.07 (s, 1H), 7.05 (s, 1H), 7.88 (d, J = 8.2 Hz, 2H), 8.48 (d, J = 8.0Hz, 2H), 9.26 (s, 1H), 9.68 (s, 1H); MS (ESI, m/z): 393.3[M+H] ⁺ .

Example 351. (4-(methylsulfonyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol

Using (4-(methylsulfonyl)piperidin-4-yl)methanol hydrochloride, the title compound was prepared as described for Example 248 (Scheme 1, General Procedure A.).

¹ H NMR (400 MHz, DMSO-D6) δ [ppm] = 1.90 (d, J = 13.8 Hz, 2H), 1.98-2.11 (m, 2H), 2.98 (s, 3H), 3.43 (t, J = 11.3 Hz, 2H), 3.97 (d, J = 4.9 Hz, 2H), 4.56 (s, 2H), 5.57 (t, J = 5.0 Hz, 1H), 7.49 (s, 1H), 7.56 (dd, J = 7.7, 4.9 Hz, 1H), 7.90 (d, J = 8.1 Hz, 2H), 8.54 (d, J = 8.0 Hz, 2H), 8.72 (d, J = 4.5 Hz, 1H), 8.75 (d, J = 7.9 Hz, 1H), 9.61 (s, 1H); MS (ESI, m/z): 493.2 [M+H] ⁺ .

Example 352. 1-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-3-hydroxypropan-1-one

Using 3-hydroxy-1-(piperazin-1-yl)propan-1-one hydrochloride, the title compound was prepared as described for Example 1 (Scheme 1, General Procedure A.).

¹ H NMR (400 MHz, DMSO-D6) δ [ppm] = 2.57 (t, J = 6.5 Hz, 2H), 3.61-3.71 (m, 6H), 3.81-3.98 (m, 4H), 4.57 (t, J = 5.2 Hz, 1H), 7.40 (s, 1H), 7.52-7.58 (m, 1H), 7.61 (d, J = 8.6 Hz, 2H), 8.14 (s, 1H), 8.37 (d, J = 8.6 Hz, 2H), 8.67-8.77 (m, 2H), 9.60 (d, J = 1.7 Hz, 1H). MS (ESI, m/z): 424.2 [M+H] ⁺ .

Example 353. 2-((4-(2-(2-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)ethanol

Scheme for obtaining compound example 353:

Intermediate 38. Tert-butyl 4-(2-chloro-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperazine-1-carboxylate

To a solution of 2,4-dichloro-6-(4-(trifluoromethyl)phenyl)pyrimidine (2 g, 6.85 mmol) in acetonitrile (20 mL) were added tert-butyl piperazine-1-carboxylate (1.9 g, 10.3 mmol) and diisopropylethylamine (2.65 g, 20.1 mmol) at room temperature. The reaction mixture was heated at 85 °C for 16 h. The mixture was concentrated in vacuo and the residue was extracted with EtOAc (20 mL × 3), washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 5/1; v/v) to give 780 mg of the title compound.

Intermediate 39. tert-Butyl 4-(2-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperazine-1-carboxylate

To a solution of tert-butyl 4-(2-chloro-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperazine-1-carboxylate (1 g, 2.45 mmol) in 1,4-dioxane (4 mL) and H ₂ O (0.8 mL) were added (1-methyl-1H-pyrazol-4-yl)boronic acid (479 mg, 3.8 mmol), Cs ₂ CO ₃ (2.39 g, 7.35 mmol) and Pd(dppf)Cl ₂ (163 mg, 0.2 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was heated and stirred at 85 °C for 5 h. The mixture was concentrated in vacuo and the residue was extracted with EtOAc (20 mL x 3), washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 5/1; v/v) to give 400 mg of the title compound.

MS (ESI, m/z): 489.2 [M+H] ⁺ .

Intermediate 40. 2-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidine hydrochloride

A solution of tert-butyl 4-(2-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperazine-1-carboxylate (400.0 mg, 0.88 mmol) in 10 mL MeOH-HCl (4 N HCl (gas) in MeOH) was stirred at room temperature for 2 h. The mixture was concentrated in vacuo to give 400 mg of the title compound.

Intermediate 41. 2-(1-methyl-1H-pyrazol-4-yl)-4-(4-(trifluoromethyl)phenyl)-6-(4-(vinylsulfonyl)piperazin-1-yl)pyrimidine

To a solution of 2-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidine hydrochloride (400 mg, 1.13 mmol) in dichloromethane (10 mL) was added triethylamine (570.7 mg, 5.65 mmol) at 0 °C. 2-Chloroethanesulfonyl chloride (221.7 mg, 1.36 mmol) was added dropwise to the above reaction mixture at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The mixture was extracted with dichloromethane (20 mL x 3), washed with brine, dried and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 1/1; v/v) to give 120 mg of the title compound.

MS (ESI, m/z): 479.2 [M+H] ⁺ .

Example 353. 2-((4-(2-(2-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)ethanol

To a solution of 2-(1-methyl-1H-pyrazol-4-yl)-4-(4-(trifluoromethyl)phenyl)-6-(4-(vinylsulfonyl)piperazin-1-yl)pyrimidine (400 mg, 0.84 mmol) in 10 mL of tetrahydrofuran was added tetrabutylammonium hydroxide (1.08 mg, 1.67 mmol) at room temperature. The reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was cooled to room temperature and extracted with EtOAc (20 mL × 3), dried and concentrated in vacuo. The resulting solid was suspended in EtOAc (10 mL). A white solid was formed. The solid was collected by filtration and dried in vacuo to give 33.7 mg of the title compound.

^1H NMR (400 MHz, DMSO-D6) δ [ppm] = 2.00 (m, 2H), 3.24 (t, J = 6.1 Hz, 4H), 3.76 (m, 2H), 3.91 (s, 7H), 5.04 (t, J = 5.4 Hz, 1H), 7.31 (s, 1H), 7.88 (d, J = 8.3 Hz, 2H), 8.06 (s, 1H), 8.38 (s, 1H), 8.46 (d, J = 8.2 Hz, 2H); MS (ESI, m/z): 497.2 [M+H] ⁺ .

Example 354. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-(dimethylamino)piperidin-4-ol

Using 3-(dimethylamino)piperidin-4-ol, the title compound was prepared as described for Example 1 (Scheme 1. General Procedure A.).

¹ H NMR (400 MHz, DMSO-D6) δ [ppm] = 1.37-1.46 (m, 1H), 1.96-2.00 (m, 1H), 2.25-2.26 (m, 1H), 2.41 (s, 6H), 3.23-3.26 (m, 4H), 3.82-3.84 (m, 1H), 4.39-4.50 (m, 1H), 7.37 (s, 1H), 7.55 (dd, J = 7.9, 4.8 Hz, 1H), 7.59 (d, J = 8.6 Hz, 2H), 8.32-8.43 (m, 2H), 8.49-8.87 (m, 2H), 9.57 (d, J = 1.8 Hz, 1H); MS (ESI, m/z): 410.2 [M+H] ⁺ .

Example 355. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-5-(dimethylamino)piperidin-3-ol

Using 5-(dimethylamino)piperidin-3-ol, the title compound was prepared as described for Example 1 (Scheme 1, General Procedure A.).

^1H NMR (400 MHz, CDCl ₃ ) δ [ppm] = 1.79-1.86 (m, 1H), 2.15-2.22 (m, 1H), 2.48 (s, 6H), 2.96 (t, J = 11.1 Hz, 1H), 3.12-3.35 (m, 2H), 4.33 (s, 1H), 4.45-4.62 (m , 1H), 4.62-4.77 (m, 1H), 6.96 (s, 1H), 7.33-7.39 (m, 1H), 7.46 (d, J = 8.4 Hz, 2H), 8.07 (d, J = 8.4 Hz, 2H), 8.66-8.74 (m, 2H), 9.64 (s, 1H); MS (ESI, m/z): 410.2 [M+H] ⁺ .

Example 356. (1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-4-(methylsulfonyl)piperidin-4-yl)methanol

Using (4-(methylsulfonyl)piperidin-4-yl)methanol hydrochloride, the title compound was prepared as described for Example 174 (Scheme 2, General Procedure B.).

^1H NMR (400 MHz, DMSO-D6) δ [ppm] = 1.89-1.93 (m, 2H), 1.98-2.09 (m, 2H), 2.99 (s , 3H), 3.44-3.54 (m, 2H), 3.94 (s, 5H), 4.53 (s, 2H), 7.24 (s, 1H), 7.67 (d, J = 8.4 Hz, 2H), 8.11 (d, J = 7.8 Hz, 2H), 8.27 (s, 1H), 8.63 (s, 1H); MS (ESI, m/z): 462.0 [M+H] ⁺ .

Example 357. (1-(2-(2-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)-4-(methylsulfonyl)piperidin-4-yl)methanol

Scheme for obtaining the compound of example 357:

Intermediate 42. 2-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-ol

To a solution of methyl 3-oxo-3-(4-(trifluoromethyl)phenyl)propanoate (2.0 g, 8.13 mmol) in MeOH (20 mL) were 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 nitrogen for 16 h. The mixture was cooled to room temperature and acidified to pH = 6.0. A white solid was formed. The solid was collected by filtration and dried in vacuo to give 1.1 g of the title compound.

MS (ESI, m/z): 321.1 [M+H] ⁺ .

Intermediate 43. 4-chloro-2-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidine

A solution of 2-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-ol (1.1 g, 3.43 mmol) in 10 mL of phosphorus oxychloride was heated under reflux for 13 h. The mixture was concentrated in vacuo. The residue was poured into water and extracted with EtOAc (20 mL x 2), washed with brine, dried and concentrated in vacuo. The residue was purified by column chromatography (dichloromethane/MeOH = 10/1; v/v) to give 950 mg of the title compound.

MS (ESI, m/z): 339.2 [M+H] ⁺ .

Example 357. (1-(2-(2-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)-4-(methylsulfonyl)piperidin-4-yl)methanol

To a solution of 4-chloro-2-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidine (40 mg, 0.12 mmol) in acetonitrile (5 mL) were added (4-(methylsulfonyl)piperidin-4-yl)methanol hydrochloride (32 mg, 0.14 mmol) and diisopropylethylamine (46.4 mg, 0.36 mmol) at room temperature. The reaction mixture was heated and stirred at 75 °C for 6 h. The residue was cooled to room temperature and extracted with EtOAc (20 mL × 3). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative high performance liquid chromatography to afford 8.2 mg of the title compound (Scheme 2, General Method B).

^1H NMR (400 MHz, DMSO-D6) δ [ppm] = 1.85 (d, J = 13.7 Hz, 2H), 1.94-2.03 (m, 2H), 2, 97 (s, 3H), 3.36 (s, 2H), 3.91 (s, 3H), 3.95 (s, 2H), 4.50 (s, 2H), 5.55 (s, 1H ), 7.27 (s, 1H), 7.87 (d, J = 8.4 Hz, 2H), 8.05 (s, 1H), 8.37 (s, 1H), 8.46 (d , J = 8.2 Hz, 2H); MS (ESI, m/z): 496.2 [M+H] ⁺ .

Example 358. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-(dimethylamino)piperidin-4-yl)methanol

Using (3-(dimethylamino)piperidin-4-yl)methanol, the title compound was prepared as described for Example 1 (Scheme 1, General Procedure A.).

^1H NMR (400 MHz, DMSO-D6) δ [ppm] = 1.48-1.59 (m, 1H), 1.92-2.04 (m, 1H), 2.13-2 .30 (m, 2H), 2.34 (s, 6H), 3.05-3.24 (m, 1H), 3.37-3.49 (m, 2H), 3.61-3.78 (m, 2H), 4.15 (s, 1H), 4.46-5.00 (m, 1H), 7.38 (s, 1H), 7.55 (dd, J = 7.9, 4 .9Hz, 1H), 7.60 (d, J = 8.6Hz, 2H), 8.36 (d, J = 8.6 Hz, 2H), 8.67-8.74 (m, 2H), 9.57 (d, J = 1.5 Hz, 1H); MS (ESI, m/z): 424.2[M+H] ⁺ .

Example 359. 2-((4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-methylpiperazin-1-yl)sulfonyl)ethan-1-ol

Using 2-((3-methylpiperazin-1-yl)sulfonyl)ethan-1-ol, the title compound was prepared as described for Example 1 (Scheme 2, General Procedure B.).

^1H NMR (400 MHz, DMSO-D6) δ [ppm] = 1.27 (d, J = 6.6 Hz, 3H), 2.95-3.06 (m, 1H), 3, 13-3.21 (m, 1H), 3.22-3.29 (m, 3H), 3.50 (d, J =12.0 Hz, 1H), 3.68 (d, J =11, 6 Hz, 1H), 3.78 (t, J =5.4 Hz, 2H), 4.66 (s, 1H), 5.06 (s, 2H), 7.40 (s, 1H), 7 .56 (dd, J =7.9, 4.8Hz, 1H), 7.61 (d, J =8.6 Hz, 2H), 8.37 (d, J = 8.6 Hz, 2H), 8.68-8.78 (m, 2H), 9.60 (d, J = 1.9 Hz, 1H); MS (ESI, m/z): 474.2 [M+H] ⁺ .

Example 360. 2-((1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)amino)ethanol

Schematic diagram for obtaining the connection of example 360:

Intermediate 44. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-one

To a solution of 4-chloro-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidine (400.0 mg, 1.33 mmol) in acetonitrile (5 mL) were added diisopropylethylamine (515 mg, 4.0 mmol) and piperidin-4-one hydrochloride (270 mg, 1.99 mmol) at room temperature. The reaction mixture was heated and stirred at 75 °C for 16 h. The mixture was concentrated in vacuo. The residue was poured into water and extracted with ethyl acetate (20 mL × 2), washed with brine. The combined organic layer was dried and concentrated in vacuo. The obtained crude product was purified by column chromatography (petroleum ether/EtOAc = 2/1; v/v) to give 330 mg of the title compound (Scheme 1, General Method A.).

MS (ESI, m/z): 365.2 [M+H] ⁺ .

Example 360. 2-((1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)amino)ethanol

To a solution of 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-one (330.0 mg, 0.906 mmol) in tetrahydrofuran (15 mL) were added 2-aminoethanol (83 mg, 1.36 mmol) and 2 drops of CH ₃ COOH. The reaction mixture was stirred at room temperature for 16 h. And then NaBH(OAc) ₃ (576.0 mg, 2.72 mmol) was added to the above reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 3 h. The residue was poured into water and extracted with EtOAc (20 mL x 2), washed with brine. The combined organic layer was dried and concentrated in vacuo. The resulting crude product was purified by preparative high performance liquid chromatography to give 204.3 mg of the title compound.

^1H NMR (400 MHz, DMSO-D6) δ [ppm] = 1.64-1.72 (m, 2H), 2.25 (d, J = 10.8 Hz, 2H), 3, 05-3.11 (m, 4H), 3.45 (s, 1H), 3.72-3.75 (t, J = 4.9 Hz, 2H), 4.88 (s, 2H), 7 .54 (s, 1H), 7.62 (d, J = 8.5 Hz, 2H), 8.18 (dd, J = 7.8, 5.8 Hz, 1H), 8.41 (d, J = 8.5 Hz, 2H), 9.04 (d, J = 5.2 Hz, 1H), 9.30 (s, 2H), 9.44 (d, J = 8.1 Hz, 1H), 9.71 (s, 1H); MS (ESI, m/z): 410.2 [M+H] ⁺ .

Example 361. 1-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-4-hydroxybutan-1-one

Scheme for obtaining the compound of example 361:

Intermediate 45. ethyl 4-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-4-oxobutanoate

To a solution of 4-(4-chlorophenyl)-6-(piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine hydrochloride (450 mg, 0.57 mmol) in 10 mL of dichloromethane was added triethylamine (585.8 mg, 1.39 mmol) at 0 °C. Ethyl 4-chloro-4-oxobutanoate (585.8 mg, 5.8 mmol) was added dropwise to the above reaction mixture at 0 °C. The reaction mixture was stirred at room temperature for 3 h. The residue was extracted with dichloromethane (20 mL × 3), washed with brine, dried and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 2/1; v/v) to give 300 mg of the title compound.

MS (ESI, m/z): 480.2 [M+H] ⁺ .

Example 361. 1-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-4-hydroxybutan-1-one

To a suspension of ethyl 4-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-4-oxobutanoate (300 mg, 0.63 mmol) in diethyl ether (10 mL) were added LiBH ₄ (17.6 mg, 0.81 mmol) and MeOH (26 mg, 0.81 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. Methanol was added dropwise to the above reaction mixture until bubbles appeared. The solvent was removed in vacuo and the residue was purified by preparative high performance liquid chromatography to give 15.9 mg of the title compound.

¹ H NMR (400 MHz, DMSO-D6) δ [ppm] = 1.61-1.78 (m, 2H), 2.43 (t, J = 7.4 Hz, 2H), 3.44 (t, J = 6.1 Hz, 2H), 3.58-3.68 (m, 4H), 3.89 (d, J = 27.3 Hz, 4H), 4.49 (s, 1H), 7.40 (s, 1H), 7.55 (dd, J = 7.9, 4.8 Hz, 1H), 7.61 (d, J = 8.6 Hz, 2H), 8.37 (d, J = 8.6 Hz, 2H), 8.65-8.82 (m, 2H), 9.60 (d, J = 1.4 Hz, 1H); MS (ESI, m/z): 438.2 [M+H] ⁺ .

Example 362. 3-((4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)propan-1-ol

Scheme for obtaining the compound of example 362:

Intermediate 46. Methyl 3-((4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)propanoate

To a solution of 4-(4-chlorophenyl)-6-(piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine hydrochloride (200 mg, 0.57 mmol) in 10 mL of dichloromethane, triethylamine (172.71 mg, 1.71 mmol) was added at 0°. Methyl 3-(chlorosulfonyl)propanoate (127 mg, 0.68 mmol) was added dropwise to the above reaction mixture at 0°. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was extracted with dichloromethane (20 mL x 3), washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 2/1; v/v) to give 110 mg of the title compound.

MS (ESI, m/z): 501.2 [M+H] ⁺ .

Example 362. 3-((4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)propan-1-ol

To a suspension of 3-((4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)propanoate (110 mg, 0.22 mmol) in diethyl ether (10 mL) were added LiBH ₄ (6.2 mg, 0.29 mmol) and MeOH (9.28 mg, 0.29 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. Methanol was added dropwise to the above reaction mixture at 0 °C until bubbles formed. The solvent was removed in vacuo and the residue was purified by preparative high performance liquid chromatography to give 30.6 mg of the title compound.

¹ H NMR (400 MHz, DMSO-D6) δ [ppm] = 1.80-1.86 (m, 2H), 3.08-3.15 (m, 2H), 3.30-3.36 (m, 4H), 3.48 (t, J = 6.2 Hz, 2H), 3.99 (s, 4H), 7.47 (s, 1H), 7.59-7.67 (m, 3H), 8.38 (d, J = 8.6 Hz, 2H), 8.76 (dd, J = 4.9, 1.5 Hz, 1H), 8.85 (d, J = 8.0 Hz, 1H), 9.62 (d, J = 1.6 Hz, 1H); MS (ESI, m/z):474.0 [M+H] ⁺ .

Example 363. 1-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-3,4-dihydroxybutan-1-one

Example 364. 1-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-2,3-dihydroxybutan-1-one

Scheme for obtaining the connection of examples 363 and 364:

Intermediate 47. 1-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)but-3-en-1-one

To a solution of 4-(4-chlorophenyl)-6-(piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine (400 mg, 0.114 mmol) in dimethylformamide (10 mL) were added buta-3-enoic acid (147 mg, 0.17 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (864 mg, 2.28 mmol), diisopropylethylamine (440 mg, 3.41 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. Liquid chromatography-mass spectrometry showed that the starting material was consumed, giving the title compound. The reaction mixture was diluted with water (20 mL), extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine, dried and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 1/1; v/v) to give 420 mg of the title compound.

MS (ESI, m/z): 420.2 [M+H] ⁺ .

Example 363. 1-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-3,4-dihydroxybutan-1-one

Example 364. 1-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-2,3-dihydroxybutan-1-one

To a solution of 1-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)but-3-en-1-one (200 mg, 0.48 mmol) in dichloromethane (15 mL) and H ₂ O (2 mL) were added N-methylmorpholine N-oxide (NMO) (83.8 mg, 0.72 mmol) and K ₂ OsO ₄ (17.5 mg, 0.048 mmol) at room temperature. The reaction mixture was heated and stirred at 35 °C for 16 h. Liquid chromatography-mass spectrometry showed that the starting material was consumed, giving the title compound. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was diluted with water and extracted with EtOAc (20 mL x 2). The combined organic layer was dried and concentrated in vacuo. The resulting crude product was purified by preparative high-performance liquid chromatography to give 8.2 mg of Example 363 as a white solid and 8.3 mg of Example 364 as a white solid.

Example 363: ^1H NMR (400 MHz, CDCl ₃ ) δ [ppm] = 2.55-2.70 (m, 2H), 3.58-3.72 (m, 3H), 3.74 -3.91 (m, 5H), 3.91-4.04 (m, 2H), 4.18-4.25 (m, 1H), 6.86 (s, 1H), 7.43-7 .53 (m, 3H), 8.08 (d, J = 8.6 Hz, 2H), 8.72 (d, J = 3.9 Hz, 1H), 8.84 (d, J = 7, 9 Hz, 1H), 9.70 (s, 1H); MS (ESI, m/z): 454.2 [M+H] ⁺ .

Example 364: ¹ H NMR (400 MHz, DMSO-D6) δ [ppm] = 1.08 (d, J = 6.3 Hz, 3H), 3.58-3.78 (m, 4H), 3.81-4.00 (m, 5H), 4.23 (s, 1H), 4.68 (s, 1H), 4.86 (s, 1H), 7.41 (s, 1H), 7.55 (dd, J = 7.9, 4.8 Hz, 1H), 7.61 (d, J = 8.6 Hz, 2H), 8.37 (d, J = 8.6 Hz, 2H), 8.68-8.77 (m, 2H), 9.60 (d, J = 1.6 Hz, 1H); MS (ESI, m/z): 454.2 [M+H] ⁺ .

Example 365. 4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-6-methylpiperazin-2-one

Using 6-methylpiperazin-2-one, the title compound was prepared as described for Example 1 (Scheme 1, General Procedure A.).

^1H NMR (400 MHz, DMSO-D6) δ [ppm] = 1.20 (d, J = 6.4 Hz, 3H), 3.42-3.53 (m, 1H), 3, 61-3.70 (m, 1H), 4.17 (d, J = 17.8 Hz, 1H), 4.31-4.53 (m, 2H), 7.40 (s, 1H), 7 .55 (dd, J = 7.7, 4.9 Hz, 1H), 7.61 (d, J = 8.6 Hz, 2H), 8.26 (s, 1H), 8.40 (d, J = 8.6Hz, 2H), 8.71 (s, 1H), 8.73-8.81 (m, 1H), 9.60 (s, 1H); MS (ESI, m/z): 380.2 [M+H] ⁺ .

Example 366. (S)-3-(4-(3-hydroxypyrrolidin-1-yl)-6-(6-morpholinopyridin-3-yl)pyrimidin-2-yl)pyridin-2-ol

Scheme for obtaining the compound of example 366:

Intermediate 48. (S)-1-(2-(2-methoxypyridin-3-yl)-6-(6-morpholinopyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol

To a solution of (S)-1-(2-chloro-6-(6-morpholinopyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol (130 mg, 0.36 mmol) in 1,4-dioxane (5 mL) and H ₂ O (1 mL) were added (2-methoxypyridin-3-yl)boronic acid (110 mg, 0.72 mmol), Cs ₂ CO ₃ (350 mg, 1.08 mmol) and Pd(dppf)Cl ₂ (58.5 mg, 0.07 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 110 °C using microwave irradiation for 3 h under nitrogen atmosphere. Liquid chromatography-mass spectrometry showed that the starting material was consumed, giving the title compound. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane/MeOH=10/1; v/v) to give 80 mg of the title compound.

MS (ESI, m/z): 435.2 [M+H] ⁺ .

Example 366. (S)-3-(4-(3-hydroxypyrrolidin-1-yl)-6-(6-morpholinopyridin-3-yl)pyrimidin-2-yl)pyridin-2-ol

A suspension of (S)-1-(2-(2-(2-methoxypyridin-3-yl)-6-(6-morpholinopyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol (120 mg, 0.27 mmol) in HBr solution (40% HBr in H ₂ O, 4 mL) at 100 °C was stirred for 10 h in a sealed tube. Liquid chromatography-mass spectrometry showed that the starting material was consumed to give the title compound. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by preparative high performance liquid chromatography to give 13.2 mg of Example 363 as a white solid and 8.3 mg of the title compound.

¹ H NMR (400 MHz, DMSO-D6) δ [ppm] = 1.89-2.16 (m, 2H), 3.44-3.88 (m, 12H), 4.47 (d, J = 14.8 Hz, 1H), 5.14 (d, J = 28.6 Hz, 1H), 6.88-6.99 (m, 2H), 7.01 (d, J = 9.1 Hz, 1H), 8.18 (s, 1H), 8.14 (s, 1H), 8.26 (dd, J = 8.9, 2.1 Hz, 1H), 8.74 (s, 1H), 8.93 (d, J = 2.4 Hz, 1H); MS (ESI, m/z): 421.2 [M+H] ⁺ .

Example 367. (S)-4-(4-(6-(3-hydroxypyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)phenyl)morpholin-3-one

Scheme for obtaining the compound of example 367:

Intermediate 49. (S)-4-(4-(2-chloro-6-(3-hydroxypyrrolidin-1-yl)pyrimidin-4-yl)phenyl)morpholin-3-one

To a mixture of (S)-1-(2,6-dichloropyrimidin-4-yl)pyrrolidin-3-ol (60 mg, 0.26 mmol) in dioxane (3 mL) and water (0.5 mL) were added 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholin-3-one (93 mg, 0.31 mmol), Cs ₂ CO ₃ (250 mg, 0.77 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride dichloromethane complex (Pd(dppf)Cl ₂ .CH ₂ Cl ₂ ) (41 mg, 0.05 mmol) under nitrogen atmosphere at room temperature. The mixture was degassed and purged with N ₂ three times. The reaction mixture was heated at 90°C under nitrogen for 16 h. Liquid chromatography-mass spectrometry showed that the reaction was complete. The mixture was filtered. The filtrate was concentrated in vacuo. The residue was purified by preparative TLC (EtOAc/MeOH = 20/1, v/v) to afford 10 mg of the title compound.

MS (ESI, m/z): 475.0 [M+H] ⁺ .

Example 367. (S)-4-(4-(6-(3-hydroxypyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)phenyl)morpholin-3-one

To a mixture of ( S)-4-(4-(2-chloro-6-(3-hydroxypyrrolidin-1-yl)pyrimidin-4-yl)phenyl)morpholin-3-one (100 mg, 0.27 mmol) in dioxane (3 mL) and H ₂ O (0.5 mL) was added pyridin-3-ylboronic acid (65 mg, 0.55 mmol), Cs ₂ CO ₃ (173 mg, 0.54 mmol) and Pd(dppf)Cl ₂ (22 mg, 0.03 mmol) at 10 °C. The reaction mixture was degassed and purged with N ₂ three times. The reaction mixture was stirred at 100 °C for 16 h. Liquid chromatography-mass spectrometry showed that the reaction was complete. The reaction mixture was cooled to room temperature and quenched with water (10 mL). The residue was extracted with ethyl acetate (15 mL x 3). The organic layers were combined and washed with brine (10 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by preparative high-performance liquid chromatography to yield 8.7 mg of the title compound.

¹ H NMR (400 MHz, DMSO-D6) δ [ppm] = 1.94-2.13 (m, 2H), 3.41-3.77 (m, 4H), 3.81-3.83 (m, 2H), 4.00-4.02 (m, 2H), 4.25 (s, 2H), 4.44-4.48 (m, 1H), 5.08 (d, J = 35.2 Hz, 1H), 7.00 (s, 1H), 7.57-7.59 (m, 1H), 7.58 (d, J = 8.5 Hz, 2H), 8.32-8.34 (m, 2H), 8.67-8.70 (m, 1H), 8.75 (d, J = 7.9 Hz, 1H), 9.60 (s, 1H); MS (ESI, m/z): 418.2 [M+H] ⁺ .

Example 368. 2-((4-(6-(4-chlorophenyl)-2-(isothiazol-4-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)ethanol

Scheme for obtaining the compound of example 368:

Intermediate 50. Tert-butyl 4-(6-(4-chlorophenyl)-2-(tributylstannyl)pyrimidin-4-yl)piperazine-1-carboxylate

To a solution of tert-butyl 4-(2-chloro-6-(4-chlorophenyl)pyrimidin-4-yl)piperazine-1-carboxylate (204 mg, 0.5 mmol) in 1,4-dioxane (8 ml) were added hexabutylditin (319 mg, 0.55 mmol), Pd(PPh ₃ ) ₄ (86.7 mg, 0.075 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was heated and stirred at 130 °C for 3.5 h under nitrogen atmosphere. TLC showed that the starting material was completely consumed. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (dichloromethane/MeOH = 10/1; v/v) to give 1.1 g of the title compound.

¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm] = 0.87-0.94 (m, 9H), 1.11-1.15 (m, 4H), 1.29-1, 39 (m, 8H), 1.49 (s, 9H), 1.60-1.68 (m, 6H), 3.53-3.56 (m, 4H), 3.70-3.72 ( m, 4H), 6.69 (s, 1H), 7.41 (d, J = 8.6 Hz, 2H), 7.97 (d, J = 8.6 Hz, 2H); MS (ESI, m/z): 665.3 [M+H] ⁺ .

Intermediate 51. Tert-butyl 4-(6-(4-chlorophenyl)-2-(isothiazol-4-yl)pyrimidin-4-yl)piperazine-1-carboxylate

To a solution of tert-butyl 4-(6-(4-chlorophenyl)-2-(tributylstannyl)pyrimidin-4-yl)piperazine-1-carboxylate (550 mg, 0.832 mmol) in 1,4-dioxane (12 mL) were added 4-bromoisothiazole (91.1 mg, 0.555 mmol), Pd(PPh ₃ ) ₄ (144.5 mg, 0.125 mmol) and CuI (23.8 mg, 0.1255 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was heated and stirred at 120 °C under N ₂ for 2 h. Liquid chromatography-mass spectrometry showed that the starting material was completely consumed. Then the reaction mixture was cooled to room temperature. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 5/1; v/v) to give 270 mg of the title compound.

MS (ESI, m/z): 458.1 [M+H] ⁺ .

Intermediate 52. 4-(4-(4-chlorophenyl)-6-(piperazin-1-yl)pyrimidin-2-yl)isothiazole

A solution of tert-butyl 4-(6-(4-chlorophenyl)-2-(isothiazol-4-yl)pyrimidin-4-yl)piperazine-1-carboxylate (270 mg, 0.6 mmol) in a solution of hydrogen chloride in methanol (4 M HCl (g) in MeOH, 5 ml) was stirred at room temperature for 2 h. The mixture was concentrated in vacuo to give 250 mg of the title compound.

MS (ESI, m/z): 358.1 [M+H] ⁺ .

Intermediate 53. 4-(4-(4-chlorophenyl)-6-(4-(vinylsulfonyl)piperazin-1-yl)pyrimidin-2-yl)isothiazole

To a solution of 4-(4-(4-chlorophenyl)-6-(piperazin-1-yl)pyrimidin-2-yl)isothiazole (250 mg, 0.63 mmol) in 5 ml of dichloromethane was added triethylamine (318 mg, 3.15 mmol) at 0 °C. 2-Chloroethanesulfonyl chloride (123 mg, 0.76 mmol) was added dropwise to the above reaction mixture at 0 °C. The reaction mixture was stirred at room temperature for 16 h. TLC showed that the starting material was completely consumed. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (dichloromethane/MeOH = 10/1; v/v) to give 120 mg of the title compound.

MS (ESI, m/z): 448.1 [M+H] ⁺ .

Example 368. 2-((4-(6-(4-chlorophenyl)-2-(isothiazol-4-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)ethanol

To a solution of 4-(4-(4-chlorophenyl)-6-(4-(vinylsulfonyl)piperazin-1-yl)pyrimidin-2-yl)isothiazole (120 mg, 0.27 mmol) in 10 mL of tetrahydrofuran was added tetrabutylammonium hydroxide (310 mg, 0.30 mmol) at room temperature. The reaction mixture was stirred at 50 °C for 4 h. TLC showed that the starting material was completely consumed. The mixture was cooled to room temperature. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC to give 19.3 mg of the title compound.

^1H NMR (400 MHz, DMSO-D6) δ [ppm] = 3.25 (t, J = 6.1 Hz, 2H), 3.32-3.28 (m, 4H), 3, 76 (dd, J = 11.2, 5.6 Hz, 2H), 3.96 (s, 4H), 5.03 (t, J = 5.3 Hz, 1H), 7.39 (s, 1H ), 7.60 (d, J = 8.5 Hz, 2H), 8.35 (d, J = 8.6 Hz, 2H), 9.28 (s, 1H), 9.73 (s, 1H ); MS (ESI, m/z): 466.0 [M+H] ⁺ .

Example 369. 3-((4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)propane-1,2-diol

The diagram for obtaining the connection of example 369:

Intermediate 54. 4-(4-(allylsulfonyl)piperazin-1-yl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidine

To a solution of 4-(4-chlorophenyl)-6-(piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine hydrochloride (500 mg, 1.42 mmol) in dichloromethane (10 mL) was added triethylamine (719 mg, 7.12 mmol) at room temperature. Prop-2-ene-1-sulfonyl chloride (400 mg, 2.85 mmol) was added dropwise to the above reaction mixture at 0 °C. The reaction mixture was stirred at room temperature for 16 h. Liquid chromatography-mass spectrometry showed that the starting material was consumed, giving the title compound. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 1/1; v/v) to give 900 mg of the title compound.

MS (ESI, m/z): 456.2 [M+H] ⁺ .

Example 369. 3-((4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)propane-1,2-diol

To a solution of 4-(4-(allylsulfonyl)piperazin-1-yl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidine (870 mg, 1.91 mmol) in dichloromethane (30 mL) and H ₂ O (3 mL) were added NMO (672 mg, 5.74 mmol) and K ₂ OsO ₄ (140 mg, 0.38 mmol) at room temperature. The reaction mixture was heated and stirred at 45 °C for 16 h. The mixture was concentrated in vacuo, the residue was diluted with water and extracted with EtOAc (20 mL x 2), washed with brine. The combined organic layer was dried and concentrated in vacuo. The resulting crude product was purified by preparative high performance liquid chromatography to afford 30.5 mg of the title compound.

¹ H NMR (400 MHz, DMSO-D6) δ [ppm] = 3.07 (dd, J = 14.7, 8.3 Hz, 1H), 3.19-3.46 (m, 7H), 3.85-3.93 (m, 1H), 3.94-4.13 (m, 4H), 7.51 (s, 1H), 7.63 (d, J = 8.6 Hz, 2H), 7.90 (dd, J = 7.8, 5.3 Hz, 1H), 8.40 (d, J = 8.6 Hz, 2H), 8.89 (d, J = 5.1 Hz, 1H), 9.13 (d, J = 8.0 Hz, 1H), 9.68 (d, J = 1.8 Hz, 1H); MS (ESI, m/z): 490.2 [M+H] ⁺ .

Example 370. 2-((4-(2-(isothiazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)ethanol

Schematic diagram for obtaining the connection of example 370:

Hexabutylditin

Intermediate 55. Tert-butyl 4-(6-(4-chlorophenyl)-2-(tributylstannyl)pyrimidin-4-yl)piperazine-1-carboxylate

To a solution of tert-butyl 4-(2-chloro-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperazine-1-carboxylate (652 mg, 1.47 mmol) in 1,4-dioxane (10 mL) was added hexabutylditin (1.54 g, 2.65 mmol), Pd(PPh ₃ ) ₄ (255 mg, 0.221 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was heated and stirred at 130 °C for 5 h under nitrogen atmosphere. The residue was cooled to room temperature and aqueous KF was added to the reaction mixture, stirring for another 30 min. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 5/1; v/v) to give 1.4 g of the title compound.

^1H NMR (400 MHz, CDCl ₃ ) δ [ppm] = 0.94-0.84 (m, 9H), 1.15 (dd, J = 9.2, 6.9 Hz, 5H) , 1.43-1.31 (m, 7H), 1.50 (s, 9H), 1.74-1.58 (m, 6H), 3.61-3.49 (m, 4H), 3 .78-3.67 (m, 4H), 6.75 (s, 1H), 7.26 (s, 1H), 7.70 (d, J = 8.2 Hz, 2H), 8.13 ( d, J = 8.1 Hz, 2H); MS (ESI, m/z): 699.3 [M+H] ⁺ .

Intermediate 56. Tert-butyl 4-(2-(isothiazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperazine-1-carboxylate

To a solution of tert-butyl 4-(2-(tributylstannyl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperazine-1-carboxylate (467 mg, 0.67 mmol) in 1,4-dioxane (10 mL) were added 4-bromoisothiazole (91.56 mg, 0.56 mmol), Pd(PPh ₃ ) ₄ (116.2 mg, 0.1005 mmol) and CuI (19.2 mg, 0.1005 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 120 °C using microwave irradiation for 3 h under nitrogen atmosphere. Liquid chromatography-mass spectrometry showed that the starting material was completely consumed. The reaction mixture was then cooled to room temperature and 5 ml of saturated aqueous KF was added, stirring for another 30 min. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (dichloromethane/MeOH = 10/1; v/v) to yield 141 mg of the title compound.

MS (ESI, m/z): 492.2 [M+H] ⁺ .

Intermediate 57. 4-(4-(piperazin-1-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)isothiazole hydrochloride

A solution of tert-butyl 4-(2-(isothiazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperazine-1-carboxylate (141 mg, 0.28 mmol) in a solution of hydrogen chloride in methanol (4 M HCl (g) in MeOH, 5 mL) was stirred at room temperature for 2 h. The mixture was concentrated in vacuo to give 160 mg of the title compound.

MS (ESI, m/z): 392.2 [M+H] ⁺ .

Intermediate 58. 4-(4-(4-(trifluoromethyl)phenyl)-6-(4-(vinylsulfonyl)piperazin-1-yl)pyrimidin-2-yl)isothiazole

To a solution of 4-(4-(piperazin-1-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)isothiazole (110 mg, 0.22 mmol) in 10 ml of dichloromethane was added triethylamine (111 mg, 1.1 mmol) at 0 °C. 2-Chloroethanesulfonyl chloride (43.8 mg, 0.27 mmol) was added dropwise to the above reaction mixture at 0 °C. The reaction mixture was stirred at room temperature for 16 h. TLC showed that the starting material was completely consumed. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (dichloromethane/MeOH = 10/1; v/v) to give 80 mg of the title compound.

MS (ESI, m/z): 482.1 [M+H] ⁺ .

Example 370. 2-((4-(2-(isothiazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)ethanol

To a solution of 4-(4-(4-(trifluoromethyl)phenyl)-6-(4-(vinylsulfonyl)piperazin-1-yl)pyrimidin-2-yl)isothiazole (100 mg, 0.2 mmol) in 5 ml of tetrahydrofuran was added tetrabutylammonium hydroxide (208 mg, 0.2 mmol) at room temperature. The reaction mixture was stirred at 50°C for 16 h. TLC showed that the starting material was completely consumed. The mixture was cooled to room temperature. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (dichloromethane/MeOH = 10/1; v/v) to give 80 mg of the title compound.

^1H NMR (400 MHz, DMSO-D6) δ [ppm] = 3.25 (t, J = 6.1 Hz, 2H), 3.34 (s, 4H), 3.76 (sq, J = 6.0 Hz, 2H), 3.97 (s, 4H), 5.04 (t, J = 5.4 Hz, 1H), 7.47 (s, 1H), 7.90 (d, J = 8.3 Hz, 2H), 8.52 (d, J = 8.1 Hz, 2H), 9.30 (s, 1H), 9.75 (s, 1H); MS (ESI, m/z): 500.2 [M+H] ⁺ .

Example 371. (S)-2-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-2-yl)ethanol

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

¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm] = 1.82-1.73 (m, 2H), 2.97-2.85 (m, 2H), 3.15-3, 02 (m, 2H), 3.22-3.16 (m, 1H), 3.96-3.84 (m, 2H), 4.45 (dd, J = 31.6, 11.1 Hz, 2H), 6.82 (s, 1H), 7.39 (dd, J = 7.9, 4.8 Hz, 1H), 7.49-7.45 (m, 2H), 8.09-8 .04 (m, 2H), 8.69 (dd, J = 4.8, 1.7 Hz, 1H), 8.74 (dt, J = 8.0, 1.9 Hz, 1H), 9.68 (d, J = 1.5 Hz, 1H); MS (ESI, m/z): 396.2 [M+H] ⁺ .

Example 372. (S)-4-(5-(6-(3-hydroxypyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyridin-2-yl)morpholin-3-one

Using (6-(3-oxomorpholino)pyridin-3-yl)boronic acid, the title compound was prepared as described for Example 296 (Scheme 4, General Procedure D.).

¹ H NMR (400 MHz, DMSO-D6) δ [ppm] = 1.84-2.21 (m, 2H), 3.62-3.73 (m, 4H), 4.04 (s, 4H), 4.32 (s, 2H), 4.47 (d, J = 21.9 Hz, 1H), 5.09 (d, J = 38.1 Hz, 1H), 7.07 (s, 1H), 7.54 (dd, J = 7.9, 4.8 Hz, 1H), 8.22 (d, J = 8.8 Hz, 1H), 8.72-8.63 (m, 2H), 8.75 (d, J = 7.9 Hz, 1H), 9.33 (d, J = 2.0 Hz, 1H), 9.60 (s, 1H); MS (ESI, m/z): 419.0 [M+H] ⁺ .

Example 373. (S)-3-(4-(3-fluoro-4-morpholinophenyl)-6-(3-hydroxypyrrolidin-1-yl)pyrimidin-2-yl)pyridin-2-ol

Scheme for obtaining the compound of example 373:

Intermediate 59. (S)-1-(2-chloro-6-(3-fluoro-4-morpholinophenyl)pyrimidin-4-yl)pyrrolidin-3-ol

To a solution of (S)-1-(2,6-dichloropyrimidin-4-yl)pyrrolidin-3-ol (500 mg, 2.1 mmol) in dioxane (10 mL) and H ₂ O (2 mL) were added 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine (789 mg, 2.56 mmol), Cs ₂ CO ₃ (1.39 g, 4.2 mmol) and Pd(dppf)Cl ₂ (174 mg, 0.21 mmol) at room temperature. The mixture was degassed and purged with nitrogen three times. The reaction mixture was heated and stirred at 90 °C for 16 h under nitrogen atmosphere. Liquid chromatography-mass spectrometry showed that the reaction was complete. The reaction mixture was cooled to room temperature. The mixture was filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 1/2; v/v) to give 220 mg of the title compound.

MS (ESI, m/z): 379.0 [M+H] ⁺ .

Intermediate 60. (S)-1-(6-(3-fluoro-4-morpholinophenyl)-2-(2-methoxypyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol

To a solution of (S)-1-(2-chloro-6-(3-fluoro-4-morpholinophenyl)pyrimidin-4-yl)pyrrolidin-3-ol (120 mg, 0.32 mmol) in dioxane (3 mL) and H ₂ O (0.5 mL) were added (2-methoxypyridin-3-yl)boronic acid (72 mg, 0.48 mmol), Cs ₂ CO ₃ (206 mg, 0.63 mmol) and Pd(dppf)Cl ₂ (25 mg, 0.031 mmol) at room temperature. The mixture was degassed and purged with nitrogen three times. The reaction mixture was heated and stirred at 90 °C for 16 h under nitrogen atmosphere. Liquid chromatography-mass spectrometry showed that the reaction was complete. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 1/2; v/v) to give 150 mg of the title compound.

MS (ESI, m/z): 452.1 [M+H] ⁺ .

Example 373. (S)-3-(4-(3-fluoro-4-morpholinophenyl)-6-(3-hydroxypyrrolidin-1-yl)pyrimidin-2-yl)pyridin-2-ol

( S)-1-(6-(3-fluoro-4-morpholinophenyl)-2-(2-methoxypyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol was dissolved in HBr solution in _H2O (5 mL, 48%). The reaction mixture was heated and stirred at 100°C for 16 h. Liquid chromatography-mass spectrometry showed that the reaction was complete. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (dichloromethane/MeOH = 10/1; v/v) to give 41.8 mg of the title compound (Scheme 5, General Method E).

¹ H NMR (400 MHz, DMSO-D6) δ [ppm] = 1.99-2.17 (m, 2H), 3.19-3.21 (m, 4H), 3.58-3.99 (m, 8H), 4.51 (d, J = 24.8 Hz, 1H), 5.26 (d, J = 34.2 Hz, 1H), 6.76-6.91 (m, 1H), 7.17 (d, J = 6.8 Hz, 1H), 7.28 (t, J = 8.7 Hz, 1H), 7.68-7.84 (m, 1H), 7.96 (d, J = 14.5 Hz, 1H), 8.07-8.25 (m, 1H), 8.78-8.99 (m, 1H); MS (ESI, m/z): 438.2 [M+H] ⁺ .

Example 374. (S)-1-(6-(4-((2-(dimethylamino)ethyl)amino)phenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol

Using N ¹ ,N ¹ -dimethyl-N ² -(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethane-1,2-diamine and a preparative HPLC isolation method, the title compound was obtained as described for Example 296 (Scheme 4, General Method D.).

^1H NMR (400 MHz, DMSO-D6) δ [ppm] = 1.89-2.13 (m, 2H), 2.20 (s, 6H), 2.47 (t, J = 6 .6 Hz, 2H), 3.18 (dd, J = 12.2, 6.3 Hz, 2H), 3.46-3.90 (m, 4H), 4.44 (s, 1H), 5.04 (s, 1H ), 5.95 (t, J = 5.3 Hz, 1H), 6.70 (d, J = 8.7 Hz, 2H), 6.75 (s, 1H), 7.52 (dd, J = 7.9, 4.8 Hz, 1H), 8 .07 (d, J = 8.6 Hz, 2H), 8.67 (d, J = 3.6 Hz, 1H), 8.72 (d, J = 7.9 Hz, 1H), 9.57 (s, 1H); MS (ESI, m/z): 405.0 [M+H] ⁺ .

Example 375. (S)-1-(6-(4-(2-(dimethylamino)ethoxy)phenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol

Using N,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethan-1-amine and a preparative HPLC isolation method, the title compound was obtained as described for Example 296 (Scheme 4, General Method D.).

¹ H NMR (400 MHz, DMSO-D6) δ [ppm] = 1.91-2.06 (m, 2H), 2.35 (s, 6H), 2.80-2.83 (m, 2H), 3.26-3.70 (m, 4H), 4.20 (t, J = 5.6 Hz, 2H), 4.44-4.47 (m, 1H), 5.08 (d, J = 32.8 Hz, 1H), 6.90 (s, 1H), 7.09 (d, J = 8.8 Hz, 2H), 7.54 (dd, J = 7.9, 4.8 Hz, 1H), 8.26 (d, J = 8.8 Hz, 2H), 8.68 (dd, J = 4.7, 1.5 Hz, 1H), 8.73 (d, J = 7.9 Hz, 1H), 9.59 (d, J = 1.2 Hz, 1H); MS (ESI, m/z): 406.2 [M+H] ⁺ .

Example 376. (S)-1-(6-(4-((2-hydroxyethyl)amino)phenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol

Scheme for obtaining the compound of example 376:

Intermediate 61. Ethyl (S)-N-(tert-butoxycarbonyl)-N-(4-(6-(3-hydroxypyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)phenyl)glycinate

To a solution of (S)-1-(6-chloro-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol (250 mg, 0.91 mmol) in 1,4-dioxane (5 mL) and H ₂ O (1 mL) were added ethyl N-(tert-butoxycarbonyl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)glycinate (513 mg, 1.27 mmol), Cs ₂ CO ₃ (883 mg, 2.72 mmol) and Pd(dppf)Cl ₂ (147 mg, 0.18 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 110 °C with microwave irradiation for 2.5 h under nitrogen atmosphere. Liquid chromatography/mass spectrometry showed that the starting material was consumed to give the title compound. The reaction mixture was concentrated in vacuo. The residue was purified by reverse phase column chromatography (MeOH/ _H2O =1/1; v/v) to give 440 mg of the title compound.

MS (ESI, m/z): 520.0 [M+H] ⁺ .

Intermediate 62. Methyl (S)-(4-(6-(3-hydroxypyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)phenyl)glycinate

A solution of (S)-ethyl 2-((tert-butoxycarbonyl)(4-(6-(3-hydroxypyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)phenyl)amino)acetate (240 mg, 0.46 mmol) in 4 N hydrochloric acid in methanol (10 mL) was stirred at room temperature for 2 h. Liquid chromatography-mass spectrometry showed that the starting material was consumed, giving the title compound. The reaction mixture was concentrated in vacuo and used in the next step without further purification.

MS (ESI, m/z): 405.8 [M+H] ⁺ .

Example 376. (S)-1-(6-(4-((2-hydroxyethyl)amino)phenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol

To a solution of methyl (S)-(4-(6-(3-hydroxypyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)phenyl)glycinate (200 mg, 0.49 mmol) in tetrahydrofuran (10 mL) was added LiAlH ₄ (56 mg, 1.48 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. Liquid chromatography-mass spectrometry showed that the starting material was consumed to give the title compound. The mixture was quenched with H ₂ O. The aqueous layer was extracted with EtOAc (10 mL × 2). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ . The mixture was filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give 13.8 mg of the title compound as a white solid.

^1H NMR (400 MHz, DMSO-D6) δ [ppm] = 1.88-2.14 (m, 2H), 3.18 (q, J = 5.8 Hz, 2H), 3, 48-3.95 (m, 6H), 4.44 (s, 1H), 4.74 (s, 1H), 5.04 (s, 1H), 6.09 (t, J = 5.5 Hz , 1H), 6.70 (d, J = 8.8 Hz, 2H), 6.74 (s, 1H), 7.52 (dd, J = 7.8, 4.8 Hz, 1H), 8 .06 (d, J = 8.7 Hz, 2H), 8.18 (s, 1H), 8.67 (d, J = 3.6 Hz, 1H), 8.72 (dt, J = 7.9, 1.8 Hz, 1H), 9.58 (s, 1H); MS (ESI, m/z): 378.0 [M+H] ⁺ .

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

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

In vitro analysis 1 : Antagonism in a human cell line

HepG2 cell line (human hepatoma cell line) with XRE-luciferase reporter either transiently or stationary (Invivogen) were placed in complete medium and incubated at 37° in a _CO2 incubator. After 24 hours, the cells were treated with kynurenine alone (50* or 200 μM) (negative control) or test compounds for 6 hours. Luciferase activity was measured using a commercially available kit such as Promega Luciferase kit or Invivogen Luciferase kit. Relative luciferase activity (Firefly/Nano-Luc) was used to calculate _IC50 values. Relative luciferase activity was further normalized using kynurenine alone group as maximum control and vehicle group as minimum control. AhR antagonist activity of example compounds is shown in Table 1 below. (IC ₅₀ values are grouped into A, B, C and D, where A: IC ₅₀ < 0.01 μM; B: 0.01 < IC ₅₀ < 0.1 μM; C: 0.1 < IC ₅₀ < 1.0 μM; D: IC ₅₀ > 1.0 μM).

In vitro analysis 2 :Antagonism in a mouse cell line

Hepa1c1c7 cells (mouse liver cancer cell line) co-transfected with XRE-Luc and Nano-Luc plasmids were placed in complete medium and incubated overnight at 37°C in a _CO2 incubator. After incubation, the cells were treated with AhR activating ligands such as kynurenic acid, kynurenine(#) in the presence or absence of test compounds for 6 h. Firefly luciferase and nanoluciferase activities were measured using Nano-glo Luciferase kit (Promega), and the relative luciferase activity (Firefly/Nano-Luc) was used to calculate _IC50 values. The relative luciferase activity was further normalized using the agonist-only group as the maximum control and the vehicle group as the minimum control. The AhR antagonist activity of the example compounds is shown in Table 1 below (IC ₅₀ values are grouped as A, B, C and D, with A: IC ₅₀ < 0.01 μM; B: 0.01 < IC ₅₀ < 0.1 μM; C: 0.1 < IC ₅₀ < 1.0 μM; D: IC ₅₀ > 1.0 μM).

In vitro analysis 3 :Agonism in a human cell line

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

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

Table 1 Results of quantitative analysis of XRE-luciferase activity Example Assay 1: Human AhR-Luc Antagonism (IC ₅₀ , nM) Assay 2: Mouse AhR-Luc Antagonism (IC ₅₀ , nM) Assay 3: Human AhR-Luc Agonism (EC ₅₀ , nM) Example 1 B* C# 12.63 (A) Example 2 C* - - Example 3 C* - - Example 4 C* - - Example 5 D* - - Example 6 C* - - Example 7 D* - - Example 8 C* - - Example 9 C* - - Example 10 C* - - Example 11 B* - - Example 12 C* - - Example 13 D* - - Example 14 D* - - Example 15 D* - - Example 16 D* - - Example 17 D* - - Example 18 D* - - Example 19 C* - - Example 20 D* - - Example 21 C* - - Example 22 C* - - Example 23 D* - - Example 24 C* - - Example 25 D* - - Example 26 D* - - Example 27 A* - - Example 28 D* - - Example 29 B* - - Example 30 B* - - Example 31 C* - - Example 32 C* - - Example 33 C* - - Example 34 B* - - Example 35 D* - - Example 36 B* - ^- Example 37 D* - ^- Example 38 A* - ^- Example 39 B* - ^- Example 40 B* - - Example 41 A* - - Example 42 A* - ^- Example 43 A* - ^- Example 44 A* - - Example 45 B* - - Example 46 C* - ^- Example 47 D* - - Example 48 D* - ^- Example 49 D* - - Example 50 D* - - Example 51 C* - ^- Example 52 C* - ^- Example 53 D* - ^- Example 54 D* - ^- Example 55 D* - - Example 56 C* - - Example 57 D* - ^- Example 58 D* - ^- Example 59 D* - - Example 60 D* - ^- Example 61 D* - ^- Example 62 D* - ^- Example 63 D* - - Example 64 C* - - Example 65 C* - - Example 66 D* - - Example 67 C* - - Example 68 B* - - Example 69 C* - - Example 70 D* - 757.7(B) Example 71 B* - - Example 72 D* - - Example 73 D* - - Example 74 C* - - Example 75 D* - - Example 76 D* - - Example 77 D* - - Example 78 D* - - Example 79 D* - - Example 80 D* - - Example 81 A* - - Example 82 A* - - Example 83 B* - - Example 84 D* - - Example 85 C* - - Example 86 B* - - Example 87 B* - - Example 88 D* - - Example 89 B* - - Example 90 B* - - Example 91 B* - - Example 92 B* C# >30,000 (D) Example 93 B* - - Example 94 B* C# >30,000 (D) Example 95 B* - - Example 96 A* - - Example 97 A* - - Example 98 D* - - Example 99 B* - - Example 100 D* - - Example 101 C* - - Example 102 C* - - Example 103 D* - - Example 104 D* - - Example 105 A* C# >30,000 (D) Example 106 B* - - Example 107 A B# >30,000 (D) Example 108 A* - - Example 109 D* - - Example 110 A* - - Example 111 D* - - Example 112 D* - - Example 113 D* - - Example 114 D* - - Example 115 D* - - Example 116 D* - - Example 117 C* - - Example 118 B* - 1580(C) Example 119 D* - - Example 120 A* - - Example 121 D* - - Example 122 B* - - Example 123 D* - - Example 124 D* - - Example 125 C* - - Example 126 D* - - Example 127 D* - - Example 128 D* - - Example 129 D* - - Example 130 D* - - Example 131 D* - - Example 132 C* - - Example 133 D* - - Example 134 D* - - Example 135 B* - - Example 136 C* - - Example 137 A A >30,000 (D) Example 138 A* - - Example 139 B* - - Example 140 D* - - Example 141 D* - - Example 142 C* - - Example 143 A* C# >30,000 (D) Example 144 B* - 55.94 (A) Example 145 C* - - Example 146 B* - - Example 147 A* - - Example 148 B* - - Example 149 D* - - Example 150 A* - - Example 151 D* - - Example 152 C* - - Example 153 D* - - Example 154 A* B# >30,000 (D) Example 155 D* - - Example 156 A* - - Example 157 D* - - Example 158 C* - - Example 159 C* - - Example 160 D* - - Example 161 D* - - Example 162 A* C# >30,000 (D) Example 163 B* - - Example 164 C* - - Example 165 D* - - Example 166 B* - - Example 167 D* - - Example 168 D* - - Example 169 D* - - Example 170 B* - >30,000 (D) Example 171 B* - - Example 172 A* - - Example 173 C* - - Example 174 C* - - Example 175 B* - - Example 176 D* - - Example 177 B* - - Example 178 C* - - Example 179 C* - - Example 180 D* - - Example 181 C* - - Example 182 C* - - Example 183 C* - - Example 184 C* - - Example 185 C* - - Example 186 D* - - Example 187 C* - - Example 188 C* - - Example 189 C* - - Example 190 B* - - Example 191 B* - - Example 192 C* - - Example 193 C* - - Example 194 A* - - Example 195 D* - - Example 196 B* - - Example 197 D* - - Example 198 B* - - Example 199 C* - - Example 200 D* - - Example 201 D* - - Example 202 D* - - Example 203 C* - - Example 204 D* - - Example 205 D* - - Example 206 D* - - Example 207 D* - - Example 208 D* - - Example 209 D* - - Example 210 B* - - Example 211 B* - - Example 212 B* - - Example 213 B* - - Example 214 B* - - Example 215 B* - - Example 216 B* - - Example 217 B* - - Example 218 A* - - Example 219 A* - - Example 220 B* - - Example 221 B* - - Example 222 A* - - Example 223 A* - - Example 224 A* - >30,000 (D) Example 225 A* - >30,000 (D) Example 226 A B# >30,000 (D) Example 227 B - - Example 228 B - - Example 229 B - >30,000 (D) Example 230 B* B# - Example 231 A B# >30,000 (D) Example 232 A* D# - Example 233 A* - - Example 234 A* - - Example 235 A* B# 3563(C) Example 236 A* C# 40.06 (A) Example 237 B - - Example 238 B - - Example 239 A A >30,000 (D) Example 240 A - - Example 241 B - - Example 242 B - - Example 243 A B# - Example 244 D - - Example 245 B - - Example 246 A - >30,000 (D) Example 247 B - - Example 248 B - - Example 249 B - - Example 250 A - - Example 251 A - - Example 252 A - - Example 253 A - - Example 254 A - - Example 255 B - - Example 256 A - - Example 257 A - - Example 258 A A - Example 259 A - - Example 260 A - >30,000 (D) Example 261 A - - Example 262 A - >30,000 (D) Example 263 A - - Example 264 B - - Example 265 A - - Example 266 A - - Example 267 A - - Example 268 A A# >30,000 (D) Example 269 A - - Example 270 A - - Example 271 A - - Example 272 B - - Example 273 B - >30,000 (D) Example 274 D - - Example 275 B - - Example 276 A - >30,000 (D) Example 277 C - - Example 278 B - >30,000 (D) Example 279 A - - Example 280 A B - Example 281 A - - Example 282 A C >30,000 (D) Example 283 A B >30,000 (D) Example 284 A - - Example 285 B - - Example 286 C - - Example 287 C - - Example 288 C - - Example 289 A - >30,000 (D) Example 290 D - - Example 291 D - - Example 292 D - - Example 293 D - - Example 294 C - - Example 295 D - - Example 296 D - - Example 297 D - - Example 298 B - - Example 299 D - - Example 300 C - - Example 301 C - - Example 302 D - - Example 303 A - - Example 304 A - - Example 305 D - - Example 306 B - - Example 307 B - - Example 308 C - - Example 309 B - - Example 310 C - - Example 311 C - - Example 312 - D - Example 313 D - - Example 314 A - >30,000 (D) Example 315 A - - Example 316 A - - Example 317 D - - Example 318 B - - Example 319 B - - Example 320 B - - Example 321 C - - Example 322 D - - Example 323 A B# >30,000 (D) Example 324 D - - Example 325 B - - Example 326 B - - Example 327 A B# 1724(C) Example 328 B - - Example 329 C - - Example 330 B - - Example 331 A - - Example 332 D - - Example 333 D - - Example 334 D - - Example 335 A - - Example 336 C - - Example 337 A - - Example 338 C - - Example 339 B - - Example 340 A - - Example 341 D - - Example 342 D - - Example 343 D - - Example 344 A - - Example 345 C - - Example 346 B - - Example 347 D - - Example 348 B - - Example 349 A - - Example 350 A - - Example 351 D - - Example 352 A B# >30,000 (D) Example 353 B - - Example 354 D - - Example 355 C - - Example 356 B - - Example 357 A - - Example 358 C - - Example 359 B - - Example 360 D - - Example 361 A - >30,000 (D) Example 362 A - - Example 363 A - - Example 364 A - - Example 365 C - - Example 366 D - - Example 367 D - - Example 368 B - - Example 369 B - - Example 370 B - - Example 371 C - - Example 372 C - - Example 373 B - - Example 374 D - - Example 375 D - - Example 376 C - -

In vitro analysis 4 :Analysis of endogenous AhR activity

HepG2 cells were seeded in a 12-well plate (3× ¹⁰⁵ cells/well). One day after seeding, cells were treated with tetrachlorodibenzo-p-dioxin alone (10 nM) or compounds (123 nM) for 4 h. Total RNA was extracted using Trizol (Thermo Fisher Scientific). cDNA synthesis and quantitative reverse transcription-PCR (real-time quantitative PCR) analysis were performed using PrimeScript™ RT Master Mix (TAKARA) and TB Green™ Premix Ex Taq™ II (TAKARA) according to the manufacturer's instructions. To measure endogenous AhR activity, the relative levels of CYP1A1 and CYP1B1 mRNA to β-actin mRNA were quantified using the comparative Ct (ΔΔCt) assay. The percentage of inhibition was calculated according to:

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

Table 2 Results of in vitro analysis of endogenous AhR activity. Connection ID CYP1A1 (% inhibition) CYP1B1 (% inhibition) Example 1 60.03 91.96 Example 27 68.37 90.33 Example 42 98.78 99.27 Example 43 97.13 99.97 Example 94 63.08 92.13 Example 105 59.20 88.37 Example 137 91.56 97.70 Example 146 41.75 77.22 Example 226 107.66 101.03 Example 228 107.33 101.04 Example 229 107.68 100.99 Example 231 105.66 100.71 Example 232 100.01 99.82 Example 235 105.90 100.84 Example 239 107.55 101.15 Example 243 89.74 Example 258 100.76 Example 268 101.81 Example 323 107.59 99.82 Example 327 105.83 100.68 Example 339 84.65 Example 349 97.59 Example 352 87.22

Claims (435)

1. A compound of formula (I) or an enantiomer, diastereomer, racemate, solvate, hydrate or pharmaceutically acceptable salt thereof: [Formula (I)] in which X ¹ , X ² and X ³ each independently represent CR ² or N; Ar ¹ is pyridine, unsubstituted or substituted by C _1-6 -alkyl, halogen or OH, pyrazole, unsubstituted or substituted by C _1-6 -alkyl, or isothiazole; Ar ² is phenyl, unsubstituted or substituted with substituents selected from the group consisting of halogen, hydroxyl group, nitro group, amino group, carboxyl group, amidino group, halo-C _1-6 -alkyl group, halo-C _1-6 -alkoxy group, C _1-6 -alkyl group, C _1-6 -alkoxy group, morpholinyl, morpholinone, piperazinyl, C _1-6 -alkylpiperazinyl and pyrazolyl; indoline, unsubstituted or substituted with oxo group, or pyridine substituted with substituents selected from the group consisting of OH, morpholine, dimethylmorpholine and morpholinone; D is H or C _1-3 -alkyl, E is absent (direct bond), is C _1-5 -alkyl, monocyclic C _3-10 -cycloalkyl, C _1-5 -alkylhydroxy, C _1-5 -alkylamine or monocyclic C _3-10 -heterocycloalkyl containing from 1 to 2 heteroatoms selected from N and O, unsubstituted or substituted with CH ₃ or OH, or D and E, together with the atoms to which they are attached, are combined to form a mono- or bicyclic C _3-10 heterocycloalkyl ring containing from 1 to 2 heteroatoms selected from N, O and S, unsubstituted or substituted by halogen, hydroxy, oxo, C _1-5 alkylhydroxy, C _1-5 alkyl, halo-C _1-5 alkyl, phenyl, -O-C=O-CH ₃ or butyloxycarbonyl; G is absent (direct bond), is H, halo, cyano, hydroxy, amino, ether (-O-), sulfinyl (-SO-), sulfonyl (-SO ₂ -), carbonyl (-(CO)-), amido (-(CO)NR ⁴ -), reverse amido (-NR ⁴ (CO)-), ester (-(CO)O-), unsubstituted mono- or bicyclic C _3-10 -cycloalkyl, mono- or bicyclic C _3-10 -heterocycloalkyl containing from 1 to 2 heteroatoms selected from N and O, unsubstituted or substituted with oxo, mono- or bicyclic C ₆ -aryl, unsubstituted or substituted with halogen, C _1-5 -alkyl, halo-C _1-5 -alkyl, NO ₂ , or unsubstituted mono- or bicyclic C _5-10 -heteroaryl containing from 1 to 2 heteroatoms selected from N and O; R ¹ is absent, is H, halo, cyano, hydroxy, amino, N(R ⁵ )2, OR ⁵ , CF ₃ , COCH ₃ , CH ₂ -O-CH ₃ , CH ₂ CH ₂ -O-CH ₃ , C _1-5 alkyl, halo-C _1-5 alkyl, C _3-10 cycloalkyl, C _1-5 alkylhydroxy, C _1-5 alkylamine, C _1-5 alkenylamine, C _1-5 alkynylamine, mono- or bicyclic C _3-10 heterocycloalkyl containing from 1 to 2 heteroatoms selected from N and O, or unsubstituted mono- or bicyclic C _5-10 heteroaryl containing from 1 to 2 heteroatoms selected from N and O; R ² is H; R ⁴ is H or C _1-5 -alkyl; and R ⁵ is C _1-5 -alkyl, provided that when Ar ¹ is pyridine substituted with substituents or pyrazole substituted with substituents, Ar ² is unsubstituted phenyl or unsubstituted indoline; and when Ar ² is phenyl substituted with substituents, indoline substituted with an oxo group, or pyridine substituted with substituents, Ar ¹ is unsubstituted pyridine, unsubstituted pyrazole or unsubstituted isothiazole, or the compound of formula (I) is selected from the following compounds: (R)-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-methylpiperazin-1-yl)(phenyl)methanone; 4-(4-chlorophenyl)-6-(4-(2,5-dimethoxybenzyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine; 4-(4-chlorophenyl)-6-(4-phenylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine; 4-(2-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)ethyl)morpholine; trans-4-(4-chlorophenyl)-6-(4-cinnamylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine; 4-(4-(benzo[c1][1,3]dioxol-5-ylmethyl)piperazin-1-yl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidine; 4-(4-benzhydrylpiperazin-1-yl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidine; 4-(4-chlorophenyl)-6-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine; N-(1-benzylpyrrolidin-3-yl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-amine; N-((1-benzylpiperidin-4-yl)methyl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-amine; ethyl 3-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)-3-oxopropanoate; 1-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)ethyl 2,2,2-trifluoroacetate; (R)-4-(3-(chloromethyl)pyrrolidin-1-yl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidine; 2-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)propan-1-ol; (1-(6-(1H-indazol-5-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol; 4-(1-(6-(1-methyl-1H-pyrazol-3-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol; (S)-1-(6-(6-((2-(dimethylamino)ethyl)amino)pyridin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol; 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(4-(vinylsulfonyl)piperazin-1-yl)pyrimidine. 2. A compound or its enantiomer, diastereomer, racemate, solvate, hydrate or pharmaceutically acceptable salt according to claim 1, wherein Ar ¹ is a monocyclic C _5-7 -heteroaryl containing from 1 to 4 heteroatoms selected from N, O and S, unsubstituted or substituted with substituents selected from the group consisting of halogen, C _1-6 -alkyl group and hydroxyl group. 3. The compound or its enantiomer, diastereomer, racemate, solvate, hydrate or pharmaceutically acceptable salt according to claim 1, wherein Ar ¹ is pyridine, unsubstituted or substituted by methyl, F or OH, pyrazole, unsubstituted or substituted by methyl, or isothiazole. 4. The compound or its enantiomer, diastereomer, racemate, solvate, hydrate or pharmaceutically acceptable salt according to claim 1, wherein Ar ¹ is pyridine which is unsubstituted or substituted by methyl, F or OH. 5. The compound or its enantiomer, diastereomer, racemate, solvate, hydrate or pharmaceutically acceptable salt according to claim 1, wherein Ar ² is phenyl substituted with substituents selected from the group consisting of halogen, hydroxyl group, nitro group, amino group, carboxyl group, halo-C _1-6 -alkyl group, C _1-6 -alkyl group, morpholinyl, morpholinone, piperazinyl, C _1-6 -alkylpiperazinyl, pyrazolyl, indoline substituted with an oxo group, or pyridine substituted with substituents selected from the group consisting of OH, morpholine, dimethylmorpholine and morpholinone. 6. The compound or its enantiomer, diastereomer, racemate, solvate, hydrate or pharmaceutically acceptable salt according to claim 1, wherein Ar ² is phenyl which is unsubstituted or substituted by chlorine. 7. A compound or enantiomer, diastereomer, racemate, solvate, hydrate or pharmaceutically acceptable salt thereof according to claim 1, wherein D is H or methyl. 8. The compound or its enantiomer, diastereomer, racemate, solvate, hydrate or pharmaceutically acceptable salt according to claim 1, wherein E is absent (direct bond), is C _1-4 -alkyl, monocyclic C _3-8 -cycloalkyl, C _1-4 -alkylhydroxy, C _1-4 -alkylamine or monocyclic C _3-8 -heterocycloalkyl containing from 1 to 2 heteroatoms selected from N and O, unsubstituted or substituted with CH ₃ or OH. 9. The compound or its enantiomer, diastereomer, racemate, solvate, hydrate or pharmaceutically acceptable salt according to claim 1, wherein D and E together with the atoms to which they are attached are combined to form a mono- or bicyclic C _3-10 -heterocycloalkyl ring containing 1 or 2 heteroatoms selected from N, O and S, unsubstituted or substituted by halogen, hydroxy, oxo, methylhydroxy, C _1-2 -alkyl, CF ₃ , phenyl, -O-C=O-CH ₃ or butyloxycarbonyl. 10. The compound or its enantiomer, diastereomer, racemate, solvate, hydrate or pharmaceutically acceptable salt according to claim 9, wherein the mono- or bicyclic C _3-10 -heterocycloalkyl ring is pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine or octahydropyranopyridine. 11. A compound selected from compounds 1-187 and 189-376, or an enantiomer, diastereomer, racemate, solvate, hydrate, or pharmaceutically acceptable salt thereof: 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)propan-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)propan-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 -dimethylpropan-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) (lR,2R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-l-ol; 30) (1S,2R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentane-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)cyclopentane-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) methyl (R)-4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazine-2-carboxylate; 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) methyl (6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)prolinate; 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)piperidin-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) ethyl 2-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)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) methyl 2-(4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)piperidin-1-yl)acetate; 172) 1-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)ethyl 2,2,2-trifluoroacetate; 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)piperidin-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; 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) methyl-(2R,4R)-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)pyrrolidine-2-carboxylate; 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)pyrrolidin-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-l-(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)pyrrolidone-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) tert-butyl (S)-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-(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. 12. A pharmaceutical composition for the prevention and/or treatment of a disease or condition mediated by an aromatic hydrocarbon receptor (AhR), comprising an effective amount of a compound of formula (I) according to claim 1 or a compound according to claim 11 or its enantiomer, diastereomer, racemate, solvate, hydrate or pharmaceutically acceptable salt and a pharmaceutically acceptable carrier. 13. The pharmaceutical composition of claim 12, wherein the disease or condition mediated by the aromatic hydrocarbon receptor (AhR) is a malignant tumor, cancerous conditions, fibrosing disorders or conditions with uncontrolled immune responses or other disorders associated with aberrant AhR signaling. 14. A pharmaceutical composition for inhibiting proliferation, tissue invasion, metastasis and angiogenesis of malignant tumor cells in a subject with a malignant tumor or cancerous condition, comprising an effective amount of a compound of formula (I) according to claim 1 or an enantiomer, diastereomer, racemate, solvate, hydrate or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 15. The pharmaceutical composition of claim 14, wherein the malignant tumor is selected from the group consisting of breast cancer, squamous cell cancer, lung cancer, peritoneal cancer, hepatocellular cancer, gastric cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney cancer or renal cell carcinoma, prostate cancer, vulvar cancer, thyroid cancer, malignant tumor of the head and neck, B-cell lymphoma, chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL), hairy cell leukemia and chronic myeloid leukemia. 16. The pharmaceutical composition of claim 13, wherein the fibrosing disorder is selected from the group consisting of liver fibrosis, liver cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic injury due to diabetes, bone marrow fibrosis, scleroderma, annular scleroderma, keloids, hypertrophic scars, nevus, diabetic retinopathy, proliferative vitreoretinopathy, and sarcoidosis. 17. The pharmaceutical composition of claim 13, wherein the condition with uncontrolled immune responses is selected from the group consisting of sepsis, multiple organ failure, inflammatory kidney disorders, chronic inflammatory bowel diseases, pancreatitis, peritonitis, inflammatory skin disorders and inflammatory eye disorders, rheumatoid diseases, systemic lupus erythematosus and multiple sclerosis. 18. A method for modulating AhR activity in a subject comprising administering a therapeutically effective amount of a compound of formula (I) according to claim 1 or a compound according to claim 11. 19. A method for preventing or treating a disease or condition mediated by an aromatic hydrocarbon receptor (AhR) in a subject, comprising administering a therapeutically effective amount of a compound of formula (I) according to claim 1 or a compound according to claim 11. 20. The method of claim 19, wherein the disease or condition mediated by the aromatic hydrocarbon receptor (AhR) is a malignancy, cancerous conditions, fibrosing disorders or conditions with unregulated immune responses or other disorders associated with aberrant AhR signaling that are associated with AhR activity. 21. The method 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 or uterine carcinoma, salivary gland carcinoma, kidney cancer or renal cell carcinoma, 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 myeloid leukemia. 22. The method of claim 20, wherein the fibrosing disorder is selected from the group consisting of liver fibrosis, liver cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic injury due to diabetes, bone marrow fibrosis, scleroderma, annular scleroderma, keloids, hypertrophic scars, nevus, diabetic retinopathy, proliferative vitreoretinopathy, and sarcoidosis. 23. The method of claim 20, wherein the condition with uncontrolled immune responses is selected from the group consisting of sepsis, multiple organ failure, inflammatory kidney disorders, chronic inflammatory bowel diseases, pancreatitis, peritonitis, inflammatory skin disorders and inflammatory eye disorders, rheumatoid diseases, systemic lupus erythematosus and multiple sclerosis. 24. A method for inhibiting proliferation, tissue invasion, metastasis and angiogenesis of cancer cells in a subject with a malignant tumor or cancerous condition, comprising administering a therapeutically effective amount of a compound of formula (I) according to claim 1 or a compound according to claim 11.