WO2021194326A1 - Aminopyrimidine derivatives and their use as aryl hydrocarbon receptor modulators - Google Patents

Aminopyrimidine derivatives and their use as aryl hydrocarbon receptor modulators Download PDF

Info

Publication number
WO2021194326A1
WO2021194326A1 PCT/KR2021/003883 KR2021003883W WO2021194326A1 WO 2021194326 A1 WO2021194326 A1 WO 2021194326A1 KR 2021003883 W KR2021003883 W KR 2021003883W WO 2021194326 A1 WO2021194326 A1 WO 2021194326A1
Authority
WO
WIPO (PCT)
Prior art keywords
pyridin
pyrimidin
chlorophenyl
piperidin
pyrimidine
Prior art date
Application number
PCT/KR2021/003883
Other languages
French (fr)
Inventor
Jung-Sang Park
Daewon CHA
Wonhyung LEE
Min Sung Joo
Taeyoung Yoon
Hyounmie Doh
Hyun Jung Sung
Bo Ryeong LEE
Seunghyun SONG
Yoonjung Kim
Ji Hoon Choi
Hyeon Seok Jung
Original Assignee
Dong-A St Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dong-A St Co., Ltd. filed Critical Dong-A St Co., Ltd.
Priority to BR112022019387A priority Critical patent/BR112022019387A2/en
Priority to JP2022558169A priority patent/JP2023520988A/en
Priority to US17/906,742 priority patent/US20230150970A1/en
Priority to KR1020227037504A priority patent/KR20230005844A/en
Priority to CN202180024853.7A priority patent/CN115397818A/en
Priority to AU2021242143A priority patent/AU2021242143B2/en
Priority to EP21776706.0A priority patent/EP4126839A4/en
Priority to MX2022011826A priority patent/MX2022011826A/en
Priority to CA3176957A priority patent/CA3176957A1/en
Publication of WO2021194326A1 publication Critical patent/WO2021194326A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to novel pyridopyrimidinone derivatives that can modulate the activities of aryl hydrocarbon receptor (AhR).
  • the compounds of formula (I) of the present invention can also be used for inhibiting the growth of cancer cells, tumor cell metastasis and invasion and for the treatment of diseases related with dysregulated immune responses associated with AhR signaling (a sole agent or in combination with other active ingredients).
  • Aryl hydrocarbon receptor is a ligand-activated transcription factor and is well-known as an important intracellular chemosensor responsive to both natural and man-made environmental compounds.
  • the AhR is a member of the periodic circadian protein (PER) - AhR nuclear translocator (ARNT) - single-minded protein (SIM) superfamily of transcription factors in which the PER-ARNT-SIM(PAS) domain senses ligands.(Burbach et al, PNAS September 1, 1992 89 (17) 8185-8189)
  • the AhR activated by several binding ligands translocates to the nucleus and dimerizes with its partner protein, the ARNT.
  • This heterodimeric complex interacts with the xenobiotic response elements (XREs) and it control the expression of AhR related genes directly or indirectly.
  • XREs xenobiotic response elements
  • One of the endogenous ligands to be well-characterized is kynurenine, generated by TDO (Opitz et al, Nature , 2011 Oct 5;478(7368):197-203) or IDO (Mezrich, J Immunol. 2010 Sep 15;185(6):3190-8.).
  • AhR AhR regulates the functions of a plethora of cells of both the innate and adaptive immune system. Activated AhR attenuates the induction of cytokines that promote the polarization of pathogenic T cell subsets and reduces MHC class II expression. In addition, AhR activation by agonist or modulator, inhibits the differentiation of helper Th17 cell and stabilizes regulatory T cell. Invigorated AhR also induces the generation of its ligands via a positive feedforward loop involving indolamine 2,3-dioxygenase 1 (IDO1). (Nguyen et al., PNAS , 2010, 107(46):19961-19966, Mascanfroni, I. D. et al.
  • TRCs Tumor-repopulating cells
  • AhR signaling plays important roles in diverse disease such as autoimmunity, infection, and cancer.
  • AhR signaling may be related to autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS).
  • RA rheumatoid arthritis
  • SLE systemic lupus erythematosus
  • MS multiple sclerosis
  • the AhR activation is induced by multiple viruses to evade the host immune response, a strategy exploited in mouse models to limit the replication of Zika virus, SARS-COV-2 infection.
  • the AhR may affect 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).
  • many cancer types can escape from immune recognition via an AhR pathway.
  • Developing AhR-targeted therapeutics could be the potential opportunities to overcome immune related diseases.
  • the present invention provides novel compounds, or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof are effective as modulators or antagonists of AhR.
  • the compounds are represented by formula (I)
  • X 1 , X 2 and X 3 are each independently CR 2 , N or NR 3 ;
  • Ar 1 and Ar 2 are each 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 -Song Wang et al, 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), 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,
  • 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 3-10 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
  • 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 alkyl carboxylic acid;
  • 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 alkyl carboxylic acid;
  • the AhR modulator of Formula (I) is an AhR modulator or AhR antagonist.
  • described herein are methods of modulating AhR activity, more specifically constitutive AhR activity in a subject in need thereof. Such methods comprise administering to a subject having constitutive AhR activity a therapeutically effective amount of an AhR modulator, such as an AhR antagonist of Formula (I), described herein. In some embodiments of these aspects and all such aspects described herein, the methods further comprise the step of selecting the subject having constitutive AhR activity.
  • an AhR modulator such as an AhR antagonist of Formula (I)
  • Compounds of formula (I) of the present invention demonstrate a valuable pharmacological spectrum of action, which could not have been predicted.
  • Compounds of the present invention have surprisingly been found to effectively inhibit AhR and it is possible therefore that said compounds be used for the treatment or prophylaxis of a disease or condition mediated by aryl hydrocarbon receptor (AhR), preferably cancer,, cancerous consitions, tumor, fibrotic disorders, or conditions with dysregulated immune responses or other disorders associated with aberrant AhR signaling, in humans and animals.
  • AhR aryl hydrocarbon receptor
  • Examples of said diseases related with dysregulated immune response associated with AhR signaling are sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory disorders of the kidney, chronic intestinal inflammations (IBD, Crohn's disease, UC), 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.
  • SIRS sepsis
  • MODS multiple organ failure
  • IBD chronic intestinal inflammations
  • UC Crohn's disease
  • 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.
  • fibrotic disorders are fibrotic disorders of the internal organs, for example the lung, the heart, the kidney, the bone marrow and in particular the liver, and also dermatological fibroses and fibrotic eye disorders.
  • the term fibrotic disorders includes in particular the following terms: hepatic fibrosis, cirrhosis of the liver, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage resulting from diabetes, bone marrow fibrosis and similar fibrotic disorders, scleroderma, morphea, keloids, hypertrophic scarring (also following surgical procedures), naevi, diabetic retinopathy, proliferative vitroretinopathy and disorders of the connective tissue (for example sarcoidosis).
  • described herein are methods of treating a cancer or a cancerous condition by modulating AhR activity.
  • Such methods comprise administering to a subject having a cancer 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.
  • described herein are methods of inhibiting tumor cell invasiveness in a subject having a cancer, a cancerous condition, or a tumor.
  • Such methods comprise administering to a subject having a cancer or a 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.
  • the methods further comprise the step of selecting the subject having a cancer, a cancerous condition, or a tumor.
  • Said cancer, cancerous condition, or tumor particularly suitable for treatment with an AHR inhibitor of the present invention are liquid and solid tumours, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases.
  • Those disorders also include lymphomas, sarcomas, and leukaemias.
  • breast cancers 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.
  • cancers 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.
  • brain cancers include, but are not limited to, brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, glioblastoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumour.
  • Tumours of the male reproductive organs include, but are not limited to, prostate and testicular cancer.
  • Tumours of the female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
  • ovarian cancer examples include, but are not limited to serous tumour, endometrioid tumour, mucinous cystadenocarcinoma, granulosa cell tumour, Sertoli-Leydig cell tumour and arrhenoblastoma.
  • cervical cancer examples include, but are not limited to squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, small cell carcinoma, neuroendocrine tumour, glassy cell carcinoma and villoglandular adenocarcinoma.
  • Tumours of the digestive tract include, but are not limited to, anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
  • esophageal cancer examples include, but are not limited to esophageal cell carcinomas and adenocarcinomas, as well as squamous cell carcinomas, leiomyosarcoma, malignant melanoma, rhabdomyosarcoma and lymphoma.
  • gastric cancer examples include, but are not limited to intestinal type and diffuse type gastric adenocarcinoma.
  • pancreatic cancer examples include, but are not limited to ductal adenocarcinoma, adenosquamous carcinomas and pancreatic endocrine tumours.
  • Tumours of the urinary tract include, but are not limited to, bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers.
  • kidney cancer examples include, but are not limited to renal cell carcinoma, urothelial cell carcinoma, juxtaglomerular cell tumour (reninoma), angiomyolipoma, renal oncocytoma, Bellini duct carcinoma, clear-cell sarcoma of the kidney, mesoblastic nephroma and Wilms' tumour.
  • bladder cancer examples include, but are not limited to transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma and small cell carcinoma.
  • Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.
  • liver cancers include, but are not limited to, hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
  • Skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
  • Head-and-neck cancers include, but are not limited to, squamous cell cancer of the head and neck, laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, salivary gland cancer, lip and oral cavity cancer and squamous cell.
  • Lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.
  • Sarcomas include, but are not limited to, sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
  • Leukemias include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
  • treating or “treatment” as stated throughout this document is used conventionally, for example the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or disorder, such as a carcinoma.
  • the compounds or of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of tumour growth and metastases, especially in solid tumours of all indications and stages with or without pre-treatment of the tumour growththe cancer is a breast cancer, squamous cell cancer, lung cancer, a cancer of the peritoneum, a hepatocellular cancer, a gastric cancer, a pancreatic cancer, a glioblastoma, a cervical cancer, an ovarian cancer, a liver cancer, a bladder cancer, a hepatoma, a colon cancer, a colorectal cancer, an endometrial or uterine carcinoma, a salivary gland carcinoma, a kidney or renal cancer, a prostate cancer, a vulval cancer, a thyroid cancer, a head and neck cancer, a B-cell lymphoma, a chronic lymphocytic leukemia (CLL); an acute lymphoblastic leukemia (ALL), a Hairy cell leukemia
  • Some embodiments of these methods can further comprise administration or treatment with one or more additional anti-cancer therapies.
  • the additional anti-cancer therapy comprises surgery, radiation therapy, biotherapy, immunotherapy, chemotherapy, or any combination thereof.
  • the anti-cancer therapeutic agent is a chemotherapeutic agent, a growth inhibitor agent, an anti-angiogenesis agent, a cytotoxic agent, an anti-hormonal agent, a prodrug, or a cytokine.
  • the compounds of formula (I) of the present invention may be used to sensitize a cell to radiation, i.e. treatment of a cell with a compound of the present invention prior to radiation treatment of the cell renders the cell more susceptible to DNA damage and cell death than the cell would be in the absence of any treatment with a compound of the present invention.
  • the cell is treated with at least one compound of general formula (I) of the present invention.
  • the present invention also provides a method of killing a cell, wherein a cell is administered one or more compounds of the present invention in combination with conventional radiation therapy.
  • the present invention also provides a method of rendering a cell more susceptible to cell death, wherein the cell is treated with one or more compounds of formula (I) of the present invention prior to the treatment of the cell to cause or induce cell death.
  • the cell is treated with at least one compound, or at least one method, or a combination thereof, in order to cause DNA damage for the purpose of inhibiting the function of the normal cell or killing the cell.
  • a cell is killed by treating the cell with at least one DNA damaging agent, i.e. after treating a cell with one or more compounds of formula (I) of 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), carcinogenic agents, and mutagenic agents.
  • a cell is killed by treating the cell with at least one method to cause or induce DNA damage.
  • methods include, but are not limited to, activation of a cell signalling pathway that results in DNA damage when the pathway is activated, inhibiting of a cell signalling pathway that results in DNA damage when the pathway is inhibited, and inducing a biochemical change in a cell, wherein the change results in DNA damage.
  • a DNA repair pathway in a cell can be inhibited, thereby preventing the repair of DNA damage and resulting in an abnormal accumulation of DNA damage in a cell.
  • a compound of formula (I) of the present invention is administered to a cell prior to the radiation or other induction of DNA damage in the cell.
  • a compound of general formula (I) of the present invention is administered to a cell concomitantly with the radiation or other induction of DNA damage in the cell.
  • a compound of formula (I) of the present invention is administered to a cell immediately after radiation or other induction of DNA damage in the cell has begun.
  • the cell is in vitro. In another embodiment, the cell is in vivo.
  • the compounds of the present invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutically active ingredients where the combination causes no unacceptable adverse effects.
  • the compounds of the present invention can be combined with: 131 1-chTNT, abarelix, abiraterone, aclarubicin, adalimumab, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, hexyl aminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, anetumab ravtansine, angiotensin II, antithrombin III, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, atezolizumab, axitinib,
  • the compounds of the invention can further be combined with other reagents targeting the immune system, such as immune checkpoint inhibitors, e.g. aPD-1/-L1 axis antagonists.
  • immune checkpoint inhibitors e.g. aPD-1/-L1 axis antagonists.
  • PD-1 along with its ligands PD-L1 and PD-L2, function as negative regulators of T cell activation.
  • AHR suppresses immune cell function while increasing cancer cell proliferation and motility.
  • PD-L1 is overexpressed in many cancers and overexpression of PD-1 often occurs concomitantly in tumor infiltrating T cells. Thus results in attenuation of T cell activation and evasion of immune surveillance, which contributes to impaired antitumor immune responses. (Keir M E et al. (2008) Annu. Rev. Immunol. 26:677).
  • compositions comprising a PD-1/-L1 axis antagonist and an AHR antagonist are surprisingly effective in enhancing an immune response and in the treatment of cancer.
  • inventive compounds can also be used as a therapeutic in a variety of other disorders wherein AHR is involved.
  • Examples of other disorders associated with aberrant AhR signaling inflammation are vaccination for infection & cancer, viral infections, obesity and diet-induced obesity, adiposity, metabolic disorders, hepatic steatosis and uterine fibroids (uterine leiomyoma or uterine myoma) in women, chronic renal disorders, acute and chronic renal insufficiency, diabetic, inflammatory or hypertensive nephropaties, cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischemias, vascular disorders, thromboembolic disorders, arteriosclerosis, sickle cell anemia, erectile dysfunction, benign prostate hyperplasia, dysuria associated with benign prostate hyperplasia, Huntington, dementia, Alzheimer, and Creutzfeld-Jakob.
  • compositions comprising an AhR modulator, such as an AhR antagonist of Formula (I), and pharmaceutically acceptable excipients.
  • compositions comprising an AhR modulator, such as an AhR antagonist of Formula (I), are provided for use in for modulating constitutive AhR activity in a subject in need thereof.
  • AhR modulator such as an AhR antagonist of Formula (I)
  • compositions comprising an AhR modulator, such as an AhR antagonist of Formula (I), are provided for use in treating a cancer or a cancerous condition by modulating AhR activity.
  • an AhR modulator such as an AhR antagonist of Formula (I)
  • compositions comprising an AhR modulator, such as an AhR antagonist of Formula (I), are provided for use in inhibiting proliferation, tissue invasion, metastasis and angiogenesis of cancer cells in a subject having a cancer, a cancerous condition, or a tumor.
  • an AhR modulator such as an AhR antagonist of Formula (I)
  • the use further comprises the step of selecting the subject having a cancer, a cancerous condition, or a tumor.
  • the cancer is a breast cancer, squamous cell cancer, lung cancer, a cancer of the peritoneum, a hepatocellular cancer, a gastric cancer, a pancreatic cancer, a glioblastoma, a cervical cancer, an ovarian cancer, a liver cancer, a bladder cancer, a hepatoma, a colon cancer, a colorectal cancer, an endometrial or uterine carcinoma, a salivary gland carcinoma, a kidney or renal cancer, a prostate cancer, a vulval cancer, a thyroid cancer, a head and neck cancer, a B-cell lymphoma, a chronic lymphocytic leukemia (CLL); an acute lymphoblastic leukemia (ALL), a Hairy cell leukemia, or a chronic myeloblastic le
  • ALL acute lymphoblastic leukemia
  • the use further comprises one or more additional anti-cancer therapies.
  • the additional anti-cancer therapy comprises surgery, radiation therapy, biotherapy, immunotherapy, or chemotherapy.
  • the use further comprises one or more anti-cancer therapeutic agents.
  • the anti-cancer therapeutic agent is a chemotherapeutic agent, a growth inhibitor agent, an anti-angiogenesis agent, a cytotoxic agent, an anti-hormonal agent, a prodrug, or a cytokine.
  • novel compounds of Formula (I) effectively modulate AhR activity, and therefore they are useful as a therapeutic or prophylactic drug for various disease, disorder, or condition associated with AhR activity such as cancer, cancerous condition, tumor, fibrotic disease, conditions with dysregulated immune responses including autoimmune disease such as rheumatoid arthiritis, systemic lupus erythematosus (SLE), multiple sclerosis (MS), or other disorders associated with aberrant AhR signaling etc.
  • autoimmune disease such as rheumatoid arthiritis, systemic lupus erythematosus (SLE), multiple sclerosis (MS), or other disorders associated with aberrant AhR signaling etc.
  • halo halogen
  • halide (s) includes fluoro, chloro, bromo and iodo.
  • alkyl refers to an aliphatic hydrocarbon radical, and includes both linear and branched hydrocarbon radicals.
  • C 1-6 alkyl is an aliphatic hydrocarbon having 1 to 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.
  • the alkyl refers to C 1-6 alkyl, preferably C 1-4 alkyl, more preferably C 1-3 alkyl.
  • alkenyl refers to an aliphatic hydrocarbon radical comprising at least one carbon-carbon double bond, and includes both linear and branched hydrocarbon radicals.
  • alkenyl is vinyl, allyl, but-1-enyl or but-2-enyl.
  • alkynyl refers to an aliphatic hydrocarbon radical comprising at least one carbon-carbon triple bond, and includes both linear and branched hydrocarbon radicals.
  • the unlimited example of the “alkynyl” is ethynyl, propargyl, but-1-ynyl or but-2-ynyl.
  • haloalkyl refers to an alkyl group substituted with one or more halogen atom, and the alkyl group is defined as above.
  • halo refers to F, Cl, Br, or I, and the term is compatibly used with the term “halogen”.
  • the haloalkyl refers tofluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl or 2,2,2-trifluoromethyl.
  • alkoxy refers to-O-alkyl or alkyl-O- group, and the alkyl group is defined as shown above. For example, it includes methoxy, ethoxy, n-propoxy, n-butoxy and t-butoxy.
  • alkoxyalkyl refers to alkyl-O-alkyl group, and the alkyl group is defined as above.
  • the unlimited example is methoxymethyl, ethoxymethyl, methoxyethyl or isopropoxymethyl.
  • hydroxy or “hydroxyl” alone or in combination with other terms means -OH.
  • cyano refers to ⁇ CN
  • cyanoalkyl refers to alkyl substituted with ⁇ CN, wherein the alkyl group is as defined above.
  • amino refers to ⁇ NH 2 ; and “nitro” refers to -NO 2 .
  • ester refers to a group of ⁇ C(O) ⁇ OR, where R is alkyl may be C 1-10 , preferably C 1-8 , C 1-6 or C 1-4 alkyl. Such ester groups may or may not be substituted with one or more suitable substituents.
  • cycloalkyl refers to a cyclic alkyl which may be substituted or unsubstituted, and for example, the C 3-20 cycloalkyl represents a monovalent saturated hydrocarbon ring system having 3 to 20 carbon atoms.
  • the cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • the cycloalkyl may be C 3-8 cycloalkyl, or C 3-6 cycloalkyl.
  • aryl refers to a monovalent aromatic hydrocarbon having, for example, 6 to 20 carbon atoms (C 6-20 ) that is derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • the aryl may include a bicyclic radical containing an aromatic ring fused to a saturated or partially unsaturated ring.
  • Exemplary aryl groups may include radicals derived from benzene (phenyl), substituted phenyl, biphenyl, naphthyl, toluyl, naphthalenyl, anthracenyl, indenyl, indanyl, and the like.
  • the aryl refers to C 6-12 aryl, preferably C 6-10 aryl.
  • heteroaryl refers to a monovalent or divalent substituent derived from a monoheterocyclic or polyheterocyclic aromatic hydrocarbon having 1 to 10 carbon ring members containing one or more, preferably one to three, heteroatoms selected among N, O, and S.
  • heteroaryl examples 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.
  • the bicyclic heteroaryl examples includeindolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, quinolinyl, isoquinolinyl,
  • heterocycloalkyl refers to monocyclic, bicyclic, tricyclic or higher cyclic alkyl having 3 to 10 carbon ring members containing one or more, for example, one to four, heteroatoms selected among N, O, and S.
  • the heterocycle according to the present invention may also be a fused or bridged heterocycloalkyl.
  • 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, dihydro
  • heterocycloalkyl refers to heterocycloalkyl having 3 to 10 carbon ring members, preferably C 3-7 heterocycloalkyl, more preferably heterocycloalkyl having 3 to 5 carbon ring atoms.
  • substituted means that at least one hydrogen atom is substituted by one to three substituents selected from the group consisting of a halogen atom (e.g., F, Cl, Br, or I), a cyano group, a hydroxyl group, a thiol group, a nitro group, an amino group, an imino group,an azido group, an amidino group, a hydrazino group, a hydrazono group, an oxo group, a carbonyl group, a carbamyl group, an ester group, an ether group, a carboxyl group or a salt thereof, a sulfonic acid group or a salt thereof, phosphoric acid or a salt thereof, a C 1-6 alkyl group, a halo C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, a C 2-6 alkenyl group, a halo C 2-6 al
  • the Aryl Hydrocarbon Receptor (“AhR”) is a ligand-dependent member of the family of basic-helix-loop-helix transcription factors that has been found to be activated by numerous structurally diverse synthetic and naturally occurring compounds, such as polycyclic aromatic hydrocarbons, indoles, and flavonoids.
  • the AhR In the absence of bound ligand, the 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”), an immunophilin-like protein, XAP2, and the hsp90 interacting protein, p23.
  • aryl hydrocarbon receptor or “AhR” as used herein refers to the 848 amino acid polypeptide, as described by, e.g., NP_001612, together with any naturally occurring allelic, splice variants, and processed forms thereof.
  • AhR refers to human AhR.
  • AhR is also used to refer to truncated forms or fragments of the AhR polypeptide, comprising, for example, specific AhR domains. Reference to any such forms of the AhR can be identified in the application, e.g., by “AhR (122-224).”
  • novel AhR modulator compounds described herein such as the small molecules of Formula (I), modulate constitutive AhR activity, by functioning as AhR antagonists. Further, they have discovered that such AhR modulator compounds can inhibit cancer cell growth, as well as tumor invasion, metastasis and angiogenesis. Accordingly, described herein are novel modulators of the AhR and constitutive AhR signaling for use in therapeutic compositions for, and methods of, treating and inhibiting cancer growth and tumor cell invasion, and immune related diseases such as autoimmune diseases.
  • the AhR mediates a variety of functional responses, including, but not limited to de novo transcription of target genes or AhR battery genes having the DRE or XRE responsive element 5′-TNGCGTG-3′.
  • Alternative pathways of AhR signaling have also been described, such as binding to retinoblastoma protein, estrogen receptor (ER), the transcription factor E2F1 and to the NF ⁇ B pathway subunits RelA and RelB.
  • the AhR can also act as a ubiquitin ligase. Accordingly, signaling via the AhR comprises multiple pathways, including constitutive and non-constitutive AhR signaling pathways or signaling activity, as those terms are defined herein.
  • Constitutive AhR signaling refers to one or more signaling pathways mediated or regulated by the AhR that are activated or driven by one or more endogenous AhR ligands, or one or more environmental ligands, such as toxins or pollutants, that cause constitutive or long-term translocation of the AhR to 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.
  • non-constitutive AhR signaling refers to one or more signaling pathways mediated or induced by the AhR that does not cause constitutive or long-term translocation of the AhR to the nucleus, nor 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 upregulation of expression of CYP1A1, CYP1B1, or a combination thereof.
  • an “AhR modulator,” as the term is used herein refers to 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 antagonist of the AhR described herein can refer to a decrease in, inhibition of, or diversion of, constitutive activity of the AhR.
  • expression refers to the cellular processes involved in producing RNA and proteins and as appropriate, secreting proteins, including where applicable, but not limited to, for example, transcription, translation, folding, modification and processing.
  • “Expression products” include RNA transcribed from a gene and polypeptides obtained by translation of mRNA transcribed from a gene.
  • modulate in reference to an Ahr modulator is used consistently with its use in the art, e.g., meaning to cause or facilitate a qualitative or quantitative change, alteration, or modification in one or more biological processes, mechanisms, effects, responses, functions, activities, pathways, or other phenomena of interest. Accordingly, as used herein, modulate refers to 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.
  • agent as used herein in reference to an AhR modulator means any compound or substance such as, but not limited to, a small molecule, nucleic acid, polypeptide, peptide, drug, ion, etc.
  • An “agent” can be any chemical, entity, or moiety, including, without limitation, synthetic and naturally-occurring proteinaceous and non-proteinaceous entities.
  • an agent is a nucleic acid, a nucleic acid analogue, a protein, an antibody, a peptide, an aptamer, an oligomer of nucleic acids, an amino acid, or a carbohydrate, and includes, without limitation, proteins, oligonucleotides, ribozymes, DNAzymes, glycoproteins, siRNAs, lipoproteins, aptamers, and modifications and combinations thereof etc.
  • agents are small molecules having a chemical moiety.
  • chemical moieties include unsubstituted or substituted alkyl, aromatic, or heterocyclyl moieties.
  • Compounds can be known to have a desired activity and/or property, e.g., modulate AhR activity, or can be selected from a library of diverse compounds, using, for example, the screening methods described herein.
  • an AhR modulator selectively binds to the AhR.
  • “selectively binds” or “specifically binds” refers to the ability of an AhR antagonist, described herein to bind to a target, such as the AhR, with a K D 10 -5 M (10000 nM) or less, e.g., 10 -6 M or less, 10 -7 M or less, 10 -8 M or less, 10 -9 M or less, 10 -10 M or less, 10 -11 M or less, or 10 -12 M or less.
  • an antagonist described herein binds to the AhR with a K D of 10 -5 M or lower, but not to other molecules, or a related homologue, then the agent is said to specifically bind the AhR.
  • Specific binding can be influenced by, for example, the affinity and avidity of the antagonist and the concentration of the antagonist used.
  • the person of ordinary skill in the art can determine appropriate conditions under which the antagonists described herein selectively bind using any suitable methods, such as titration of an AhR antagonist in a suitable cell binding assay, such as those described herein.
  • AhR modulators are AhR antagonists having the chemical structures of Formula (I), described herein.
  • the AhR is an “AhR antagonist.”
  • An AhR antagonist refers to an AhR inhibitor that does not provoke a biological response itself upon specifically binding to the AhR, but blocks or dampens agonist-mediated or ligand-mediated responses, i.e., an AhR antagonist can bind but does not activate the AhR, and the binding disrupts the interaction, displaces an AhR agonist, and/or inhibits the function of an AhR agonist.
  • an AhR antagonist does not function as an inducer of AhR activity when bound to the AhR, i.e., they function as pure AhR inhibitors.
  • an AhR antagonist selectively binds to the AhR.
  • the AhR antagonists described herein such as the compounds of Formula (I) block constitutive AhR effector functions that mediate growth and progression of established tumors.
  • the small molecule AhR antagonists of Formula (I), described herein act as chemopreventatives by blocking AhR-mediated CYP1A1 induction and mutagen production on exposure to environmental ligands.
  • the AhR antagonists of Formula (I), described herein inhibit the early contributions of constitutively active AhR in driving malignant transformation.
  • the compunds of Formula (I) described herein inhibit constitutive AhR signaling-mediated cancer or tumor cell growth.
  • the compounds of Formula (I), described herein inhibit constitutive AhR signaling-mediated tumor invasion in driving malignant transformation.
  • An aspect of the present invention relates to novel compounds that can modulate human aryl hydrocarbon receptor (AhR). These compounds bind specifically to AhR.
  • AhR human aryl hydrocarbon receptor
  • the compound has the structure of formula (I), or an enantiomer, diastereomer, racemate, solvate, hydrate, or pharmaceutically acceptable salt thereof:
  • X 1 , X 2 and X 3 are each independently CR 2 , N or NR 3 ;
  • Ar 1 and Ar 2 are each 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), 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,
  • 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 3-10 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
  • 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 alkyl carboxylic acid;
  • 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 alkyl carboxylic acid;
  • the Ar 1 may be substituted or unsubstituted monocyclic C 5-7 heteroaryl comprising one or more hetero atoms selected from the group consisting of N, O and S. More preferably, the Ar 1 may be monocyclic C 5-6 heteroaryl comprising one or two hetero atoms selected from the group consisting of N, O and S, which may be unsubstituted or substituted with C 1-3 alkyl. Far more preferably, the Ar 1 may be pyrazole or pyridine which may be unsubstituted or substituted with methyl.
  • the Ar 2 may be mono- or bicyclic C 6-10 aryl comprising one or more hetero atoms selected from the group consisting of N, O and S, which is unsubstituted or substituted with halo. More preferably, the Ar 2 may be phenyl which may be unsubstituted or substituted with chloro.
  • the D may be H or C 1-3 alkyl.
  • the E may 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 comprises one or more, preferably one or two heteroatoms selected from the group consisting of N, O and S.
  • the D and E together with the atoms to which they are attached, may be combined to form substituted or unsubstituted mono- or bicyclic C 3-10 heterocycloalkyl ring one or more hetero atoms 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 pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, or octahydropyranopyridine.
  • 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
  • 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 alkyl phosphate, 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.
  • the compound of the Formula I may be one selected from the group consisting of Compounds 1 to 276, as shown below:
  • Acid addition salts can be prepared by reacting the purified compound in its free-based form, if possible, with a suitable organic or inorganic acid and isolating the salt thus formed.
  • suitable organic or inorganic acid examples include, without limitations, salts of an 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.
  • suitable organic or inorganic base include, without limitations, alkali metal (e.g., sodium, lithium, and potassium), alkaline earth metal (e.g., magnesium and calcium), ammonium and N + (C 1-4 alkyl) 4 salts.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, gluconate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, ox
  • the compounds represented by Formula I according to the present invention include, but are not limited thereto, not only pharmaceutically acceptable salts thereof, but also all solvates or hydrates and all possible stereoisomers that can be prepared therefrom. All stereoisomers of the present compounds (e.g., those which may exist due to asymmetric carbons on various substituents), including enantiomeric forms and diastereomeric forms, are contemplated within the scope of this invention. Individual stereoisomers of the compounds of the present invention may, for example, be substantially free of other isomers (e.g., as a pure or substantially pure optical isomer having a specified activity), or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
  • the chiral centers of the compounds of the present invention may have the S or R configuration as defined by the IUPAC 1974 Recommendations.
  • the racemic forms can be analyzed by physical methods, such as fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography.
  • the individual optical isomers can be obtained from the racemates by any suitable method, including without limitation, salt formation with an optically active acid followed by crystallization.
  • the solvate and stereoisomer of the compound represented by Formula I may be prepared from the compound represented by Formula I using methods known in the art.
  • the compounds represented by Formula I according to the present invention may be prepared either in a crystalline form or in a non-crystalline form, When the compound is prepared in a crystalline form, it may be optionally hydrated or solvated.
  • the compound of Formula I may not only include 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 may be synthesized by methods known in the art or by methods illustrated in Examples 1-376 below.
  • the pharmaceutical composition and the method provided herein comprises the compound of Formula (I).
  • the subject may be a mammal including human or a mammalian cell; for example, a mammal (e.g., human) suffering from the disease, disorder, or condition associated with AhR activity as described above or a mammalian cell isolated therefrom.
  • a mammal e.g., human
  • AhR activity as described above or a mammalian cell isolated therefrom.
  • the compound as an active ingredient or the pharmaceutical composition may be administered orally or parenterally.
  • the parenteral administration may be performed by any one of intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, endothelial administration, topical administration, intranasal administration, intrapulmonary administration, intrarectal administration, and the like.
  • the effective amount may refer to pharmaceutically and/or therapeutically effective amount, and may be prescribed depending on factors such as a type of preparation (formulation), administration route, the patient’s age, body weight, gender, and/or pathologic conditions, and the like.
  • a pharmaceutically acceptable salt of the compound of Formula (I) may include addition salts formed by inorganic acids such as hydrochloride, sulfate, phosphate, hydrobromide, hydroiodide, nitrate, pyrosulfate, or metaphosphate, addition salts formed by 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 is not limited thereto.
  • inorganic acids such as hydrochloride, sulfate, phosphate, hydrobromide, hydroiodide, nitrate, pyrosulfate, or metaphosphate
  • organic acids such as citrate, oxalate, benzoate, acetate, trifluoroacetate, propionate, succinate, fumarate
  • the pharmaceutical composition according to the present invention can be formulated into a suitable form together with a commonly used pharmaceutically acceptable carrier.
  • pharmaceutically acceptable refers to being physiologically acceptable, and not usually causing an allergic reaction or a similar reaction such as gastrointestinal disorders and dizziness when administered to humans.
  • the pharmaceutical composition of the present invention may be used after being formulated into an oral preparation, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, etc., and a parental preparation, such as epidermal formulations, suppositories, or sterile injection solutions, in accordance with a conventional method.
  • Examples of carriers, excipients and diluents that can be included in the composition may include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, arabic gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil, but are not limited thereto.
  • a diluting agent or an excipient such as commonly-used fillers, stabilizing agents, binding agents, disintegrating agents, and surfactants can be used.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and these solid preparations may be prepared by mixing the compound of the present invention with at least one excipient, for example, starch, microcrystalline cellulose, sucrose, lactose, low-substituted hydroxypropyl cellulose, hypromellose or the like.
  • a lubricant such as magnesium stearate and talc are also used.
  • Liquid preparations for oral administration include a suspension, a liquid for internal use, an emulsion, a syrup, etc.
  • various excipients such as a humectant, a sweetener, an aromatic, a preservative, etc. may also be contained.
  • Formulations for parenteral administration include a sterilized aqueous solution, a non-aqueous solution, a suspension, an emulsion, a lyophilized formulation and a suppository.
  • the non-aqueous solution or suspension may contain propylene glycol, polyethylene glycol, a vegetable oil such as olive oil, an injectable ester such as ethyl oleate, etc.
  • a base of the suppository witepsol, macrogol, tween 61, cocoa butter, laurin butter, glycerogelatin, etc. may be used.
  • the compound of Formula I or a pharmaceutically acceptable salt thereof may be mixed in water together with sterilized and/or contain adjuvants such as preservatives, stabilizers, auxiliary agents such as wettable powder or emulsifying accelerators, salt for controlling osmotic pressure and/or buffers and the like, and other therapeutically useful substances, to prepare a solution or suspension, which is then manufactured in the form of an ampoule or vial unit administration.
  • adjuvants such as preservatives, stabilizers, auxiliary agents such as wettable powder or emulsifying accelerators, salt for controlling osmotic pressure and/or buffers and the like, and other therapeutically useful substances
  • the pharmaceutical composition including the compound of Formula I disclosed herein as an active ingredient may be administered to mammals such as mice, livestock, and humans by various routes for the modulation of AhR activity, or the prevention or treatment of a disease, disorder, or condition associated with AhR activity.
  • the disease, disorder, or condition associated with AhR activity may be a cancer, cancerous condition, tumor, fibrotic dieases, immune related disease or other disease related with AhR signaling.
  • the diseases related with dysregulated immune response associated with AhR signaling are selected from the group consisting of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory disorders of the kidney, chronic intestinal inflammations (IBD, Crohn's disease, 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).
  • SIRS sepsis
  • MODS multiple organ failure
  • IBD chronic intestinal inflammations
  • UC Crohn's disease
  • pancreatitis peritonitis
  • inflammatory skin disorders and inflammatory eye disorders inflammatory skin disorders and inflammatory eye disorders
  • autoimmune diseases such as rheumatoid diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and multiple
  • the fibrotic disorders are selected from the group consisting of fibrotic disorders of the internal organs, for example the lung, the heart, the kidney, the bone marrow and in particular the liver, and also dermatological fibroses and fibrotic eye disorders.
  • the term fibrotic disorders includes in particular the following terms: hepatic fibrosis, cirrhosis of the liver, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage resulting from diabetes, bone marrow fibrosis and similar fibrotic disorders, scleroderma, morphea, keloids, hypertrophic scarring (also following surgical procedures), naevi, diabetic retinopathy, proliferative vitroretinopathy and disorders of the connective tissue (for example sarcoidosis).
  • cancerous condition, or tumor particularly suitable for treatment with an AHR antagonist of the present invention are liquid and solid tumours, such as a breast cancer, squamous cell cancer, lung cancer, a cancer of the peritoneum, a hepatocellular cancer, a gastric cancer, a pancreatic cancer, a glioblastoma, a cervical cancer, an ovarian cancer, a liver cancer, a bladder cancer, a hepatoma, a colon cancer, a colorectal cancer, an endometrial or uterine carcinoma, a salivary gland carcinoma, a kidney or renal cancer, a prostate cancer, a vulval cancer, a thyroid cancer, a head and neck cancer, a B-cell lymphoma, a chronic lymphocytic leukemia (CLL); an acute lymphoblastic leukemia (ALL), a Hairy cell leukemia, or a chronic myeloblastic leukemia.
  • CLL chronic lymphocytic leukemia
  • ALL acute lymph
  • the pharmaceutical composition of the preset invention can be used together with one or more additional anti-cancer therapies.
  • the additional anti-cancer therapy comprises surgery, radiation therapy, biotherapy, immunotherapy, chemotherapy, or any combination thereof.
  • the pharmaceutical composition of the preset invention can be used together with anti-cancer therapeutic agents.
  • the anti-cancer therapeutic agent is a chemotherapeutic agent, a growth inhibitor agent, an anti-angiogenesis agent, a cytotoxic agent, an anti-hormonal agent, a prodrug, or a cytokine.
  • Examples of other disorders associated with aberrant AhR signaling inflammation are vaccination for infection & cancer, viral infections, obesity and diet-induced obesity, adiposity, metabolic disorders, hepatic steatosis and uterine fibroids (uterine leiomyoma or uterine myoma) in women, chronic renal disorders, acute and chronic renal insufficiency, diabetic, inflammatory or hypertensive nephropaties, cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischemias, vascular disorders, thromboembolic disorders, arteriosclerosis, sickle cell anemia, erectile dysfunction, benign prostate hyperplasia, dysuria associated with benign prostate hyperplasia, Huntington, dementia, Alzheimer, and Creutzfeld-Jakob.
  • compositions comprising an AhR modulator, such as an AhR antagonist of Formula (I), and pharmaceutically acceptable excipients.
  • compositions comprising an AhR modulator, such as an AhR antagonist of Formula (I), are provided for use in for modulating constitutive AhR activity in a subject in need thereof.
  • AhR modulator such as an AhR antagonist of Formula (I)
  • compositions comprising an AhR modulator, such as an AhR antagonist of Formula (I), are provided for use in treating a cancer or a cancerous condition by modulating AhR activity.
  • an AhR modulator such as an AhR antagonist of Formula (I)
  • compositions comprising an AhR modulator, such as an AhR antagonist of Formula (I), are provided for use in inhibiting proliferation, tissue invasion, metastasis and angiogenesis of cancer cells in a subject having a cancer, a cancerous condition, or a tumor.
  • an AhR modulator such as an AhR antagonist of Formula (I)
  • the pharmaceutical composition of the present invention may be for use in inhibiting proliferation, tissue invasion, metastasis and angiogenesis of cancer cells in a subject having a cancer, a cancerous condition, or a tumor.
  • compositions described herein are administrable to a subject in a variety of by multiple administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular, rectal, enfometrial or cerebrovascular injection), intranasal, buccal, topical or transdermal administration routes.
  • parenteral e.g., intravenous, subcutaneous, intramuscular, rectal, enfometrial or cerebrovascular injection
  • intranasal e.g., buccal, topical or transdermal administration routes.
  • the 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, e.g., in a patient suffering from cancer or an infection (e.g., a viral, bacterial, or parasitic infection).
  • the method includes administering to the patient a therapeutically effective amount of one or a combination of the compounds described herein.
  • the patient has an increased count of white blood cells, T and/or B lymphocytes, macrophases, dendritic cells, neutrophils, natural killer (NK) cells, and/or platelets after the administering step.
  • the compound decreases IL-21 level in the patient.
  • the patient may have cancer, or may be immune-compromised.
  • Treatment refers to a method of alleviating or abrogating a biological disorder and/or at least one of its attendant symptoms.
  • to “alleviate” a disease, disorder or condition means reducing the severity and/or occurrence frequency of the symptoms of the disease, disorder, or condition.
  • references herein to “treatment” include references to curative, palliative and prophylactic treatment.
  • Treatment of cancer encompasses inhibiting cancer growth (including causing partial or complete cancer regression), inhibiting cancer progression or metastasis, preventing cancer recurrence or residual disease, and/or prolonging the patient's survival.
  • “A therapeutically effective amount” is an amount of the medication that can achieve the desired curative, palliative, or prophylactic effect for the treated condition.
  • the effective dose range of a compound is determined by measuring the patient's blood concentration of the compound under a specified dosing regimen to establish a concentration-time profile, consulting with an established correlation between the concentration-time profiles and effects on cancer inhibition or eradication obtained during a trial, and balancing the therapeutic effects achievable with possible toxicity to the patient, with further consideration of the health condition or physical durability of the patient.
  • the dosing frequency of the compound may be determined similarly. The dosing may be continued until the patiunlessent is free from the cancer.
  • an effective amount for tumor therapy may be measured by its ability to stabilize disease progression and/or ameliorate symptoms in a patient, and preferably to reverse disease progression, e.g., by reducing tumor size.
  • a maintenance dosing may be provided after the patient is free of cancer to ensure its complete elimination or eradication, or prevention of residual disease. The duration of the maintenance dosing can be determined based on clinical trial data.
  • a compound may be administered in combination with one or more other cancer therapeutic agents that also target AhR or target molecules other than AhR.
  • Compounds can be formulated either separately from, or together with, the other cancer therapeutic agents.
  • Compounds can be administered either at the same schedule as, or at a different schedule from, the other cancer therapeutic agents.
  • the proportion of a compound relative to other cancer therapeutic agents may be determined by clinical trials. Combining the compounds with the other cancer therapeutic agents may further enhance the efficacy of one another.
  • a compound of the present invention can be administered with an immune checkpoint inhibitor, such as an inhibitor of PD-1, PD-L1 or PD-L2 (e.g., pembrolizumab, nivolumab, or atezolizumab), or administered with CAR-T therapy (e.g., axicabtagene ciloleucel), to achieve additive or synergistic anti-cancer effect.
  • an immune checkpoint inhibitor such as an inhibitor of PD-1, PD-L1 or PD-L2 (e.g., pembrolizumab, nivolumab, or atezolizumab)
  • CAR-T therapy e.g., axicabtagene ciloleucel
  • Dosage regimens may be adjusted to provide the optimum desired response.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the patients/subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the embodied composition. Further, the dosage regimen with the compositions of this invention may be based on a variety of factors, including the type of disease, the age, weight, sex, medical condition of the patient, the severity of the condition, the route of administration, and the particular antibody employed. Thus, the dosage regimen can vary widely, but can be determined routinely using standard methods. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and/or laboratory values.
  • 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 about 20 mg/kg body weight per day, such as about 0.5-50 mg/kg, e.g., about 1-20 mg/kg.
  • the compound may for example be administered in a dosage of at least 0.25 mg/kg, e.g., at least 0.5 mg/kg, such as at least 1 mg/kg, e.g., at least 1.5 mg/kg, such as at least 2 mg/kg, e.g., at least 3 mg/kg, such as at least 4 mg/kg, e.g., at least 5 mg/kg; and e.g., up to at most 50 mg/kg, such as up to at the most 30 mg/kg, e.g., up to at the most 20 mg/kg, such as up to at the most 15 mg/kg.
  • at least 0.25 mg/kg e.g., at least 0.5 mg/kg, such as at least 1 mg/kg, e.g., at least 1.5 mg/kg, such as at least 2 mg/kg, e.g., at least 3 mg/kg, such as at least 4 mg/kg, e.g., at least 5 mg/kg; and e.g., up to
  • Administration will normally be repeated at suitable intervals, e.g., twice a day, thrice a day, once a day, once every week, once every two weeks, or once every three weeks, and for as long as deemed appropriate by the responsible doctor, who may optionally increase or decrease the dosage as necessary.
  • the compounds of Formlua (I) of the presnet invention can be prepared in accordance with one or more of schemes discussed below.
  • Suitable synthetic sequences are readily selected per specific structures of this invention, but within the art known to individuals practicing organic synthesis, such as methods summarized in available chemistry data bases, as in CAS Scifinder and Elesevier Reaxys. Based on these general methods, the enablement for making the compounds of this invention is straightforward and can be practiced within a common professional knowledge. Some general synthetic methods to prepare the compounds of this invention are illustrated below in Schemes 1-5(general procedure A ⁇ E).
  • R 1 s mean boc-deprotected forms of R moieties.
  • R 1 s mean boc-deprotected forms of R moieties.
  • R 1 s mean boc-deprotected forms of R moieties.
  • R 1 s mean boc-deprotected forms of R moieties.
  • R 1 s mean boc-deprotected forms of R moieties.
  • Flash column chromatography means silica gel chromatography unless specified otherwise, which was performed on Teledyne Combiflash-RF200 System. 1 H NMR spectra ( ⁇ , ppm) are recorded on 400 MHz or 600 MHz instrument. Mass spectroscopy data for a positive ionization method are provided. Preparative HPLC was performed on Agilent technologies G1361A and Gilson Preparative HPLC System.
  • Example 50 4-(4-chlorophenyl)-6-(3,5 -di methylpiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine
  • Example 51 4-(4-chlorophenyl)-6-(3,3 -di fluoropiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine
  • Example 70 cis-4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-2,6 -di methylmorpholine
  • Example 80 4-(4-chlorophenyl)-6-(4-(2,3 -di chlorophenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine
  • Example 81 4-(4-chlorophenyl)-6-(4-(2,5 -di methoxybenzyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine
  • Example 84 4-(4-chlorophenyl)-6-(4-(2-ethoxyphenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The present invention relates to novel compounds effective as modulators Aryl hydrocarbon receptor (AhR), pharmaceutical composition comprising the compounds for the modulation of AhR, or prevention or treatment of a disease, disorder, or condition associated with AhR activity, as an active ingredient, and thus, can be useful as a medication for the prevention or treatment of a disease, disorder, or condition associated with AhR activity, in particular, cancer, cancerous condition, tumor, fibrotic disease, condition with dysregulated immune responses, etc.

Description

AMINOPYRIMIDINE DERIVATIVES AND THEIR USE AS ARYL HYDROCARBON RECEPTOR MODULATORS
CROSS-REFERENCE TO RELATED APPLICATIONS
The present application claims priority from U.S. Provisional Application No. 63/000,584, filed Mar. 27, 2020, which are incorporated herein by reference in their entirety.
The present invention relates to novel pyridopyrimidinone derivatives that can modulate the activities of aryl hydrocarbon receptor (AhR). The compounds of formula (I) of the present invention can also be used for inhibiting the growth of cancer cells, tumor cell metastasis and invasion and for the treatment of diseases related with dysregulated immune responses associated with AhR signaling (a sole agent or in combination with other active ingredients).
Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and is well-known as an important intracellular chemosensor responsive to both natural and man-made environmental compounds. As is well known, the AhR is a member of the periodic circadian protein (PER) - AhR nuclear translocator (ARNT) - single-minded protein (SIM) superfamily of transcription factors in which the PER-ARNT-SIM(PAS) domain senses ligands.(Burbach et al, PNAS　September 1, 1992　89　(17)　8185-8189) The AhR, activated by several binding ligands translocates to the nucleus and dimerizes with its partner protein, the ARNT. This heterodimeric complex interacts with the xenobiotic response elements (XREs) and it control the expression of AhR related genes directly or indirectly. One of the endogenous ligands to be well-characterized is kynurenine, generated by TDO (Opitz et al, Nature, 2011 Oct 5;478(7368):197-203) or IDO (Mezrich, J Immunol. 2010 Sep 15;185(6):3190-8.). Recent studies found that high concentrations of kynurenine in the plasma of diverse cancer patients and a high serum Kyn/Trp ratio correlates with poor prognosis after PD-1 blockade in several cancer types, including lung cancer, melanoma, and renal cell carcinomas.(Haoxin Li et al, Nat Commun. 2019 Sep 25;10(1):4346)
It has been well-known lately that AhR regulates the functions of a plethora of cells of both the innate and adaptive immune system. Activated AhR attenuates the induction of cytokines that promote the polarization of pathogenic T cell subsets and reduces MHC class II expression. In addition, AhR activation by agonist or modulator, inhibits the differentiation of helper Th17 cell and stabilizes regulatory T cell. Invigorated AhR also induces the generation of its ligands via a positive feedforward loop involving indolamine 2,3-dioxygenase 1 (IDO1). (Nguyen et al., PNAS, 2010, 107(46):19961-19966, Mascanfroni, I. D. et al. Nat. Med., 2015, 21:638-646) As an immune escape mechanism, Tumor-repopulating cells (TRCs) drive PD-1 upregulation in CD8+ T cells through a Kyn-AhR pathway. (Yuying Liu et al, Cancer cell, 2018 Mar 12;33(3):480-494.e7.).
Moreover, several studies have shown that AhR signaling plays important roles in diverse disease such as autoimmunity, infection, and cancer. AhR signaling may be related to 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 AhR activation reduces the type I IFN (IFN-I) antiviral response (Yamada et al, Nat immunol, 2016 Jun;17(6):687-94). The AhR activation is induced by multiple viruses to evade the host immune response, a strategy exploited in mouse models to limit the replication of Zika virus, SARS-COV-2 infection. (Federico Giovannoni et al, Cell Research, 2021 Dec., 31:1-2) The AhR may affect 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 cancer types can escape from immune recognition via an AhR pathway. Developing AhR-targeted therapeutics could be the potential opportunities to overcome immune related diseases.
Therefore, it is an object of the present invention to provide novel compounds, or an enantiomer, diastereomer, racemate, solvate, hydrate or pharmaceutically acceptable salt thereof as modulators of AhR.
It is an object of the present invention to provide a pharmaceutical composition for the modulation of AhR activity, comprising the compounds as modulators of AhR.
It is an object of the present invention to provide a pharmaceutical composition for the prevention or treatment of disease, disorder, or condition associated with AhR activity such as a cancer or an autoimmune disease, comprising the compounds as modulators of AhR.
It is an object of the present invention to provide a method for modulating AhR activity by administering the compounds as modulators of AhR.
It is an object of the present invention to provide a method for preventing or treating prostaglandin related diseases by administering the compounds as modulators of AhR.
It is an object of the present invention to provide a use of the prostaglandin anlalog for the modulation of AhR acitivity, or the prevention or treatment of disease, disorder, or condition associated with AhR.
SUMMARY OF THE INVENTION
The present invention provides novel compounds, or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof are effective as modulators or antagonists of AhR. The compounds are represented by formula (I)
Figure PCTKR2021003883-appb-I000001
wherein:
X1, X2 and X3 are each independently CR2, N or NR3;
Ar1 and Ar2 are each independently selected from substituted or unsubstituted mono- or bicyclic C6-10 aryl, substituted or unsubstituted mono- or bicyclic C5-10 heteroaryl and substituted or unsubstituted mono- or bicyclic C3-10 heterocycloalkyl;
D is H, halo, cyano, hydroxy, amino, substituted or unsubstituted C1-5 alkyl, mono- or bicyclic C3-10 cycloalkyl, C1-5 alkylhydroxy, C1-5 -Song Wang et al, alkenylhydroxy, C1-5 alkynylhydroxy, C1-5 alkylamine, C1-5 alkenylamine, C1-5 alkynylamine, mono- or bicyclic C3-10 heterocycloalkyl, mono- or bicyclic C3-10 heteroaryl,
E is absent(direct bond), amino, substituted or unsubstituted C1-5 alkyl, mono- or bicyclic C3-10 cycloalkyl, C1-5 alkylhydroxy, C1-5 alkenylhydroxy, C1-5 alkynylhydroxy, C1-5 alkylamine, C1-5 alkenylamine, C1-5 alkynylamine, mono- or bicyclic C3-10 heterocycloalkyl, mono- or bicyclic C3-10 heteroaryl,
or D and E, together with the atoms to which they are attached, are combined to form substituted or unsubstituted mono- or bicyclic C3-10 heterocycloalkyl ring;
G is absent(direct bond), H, halo, cyano, hydroxy, amino, nitro, ether(-O-), thioether(-S-), sulfinyl(-SO-), sulfonyl(-SO2-), sulfonylamido(-SO2NR4-), aminosulfonyl(-NR4SO2-), carbonyl(-(CO)-), amido(-(CO)NR4-), reverse amido(-NR4(CO)-), ester(-(CO)O-), substituted or unsubstituted mono- or bicyclic C3-10 cycloalkyl, substituted or unsubstituted mono- or bicyclic C3-10 heterocycloalkyl, substituted or unsubstituted mono- or bicyclic C6-10 aryl and substituted or unsubstituted mono- or bicyclic C5-10 heteroaryl;
R1 is absent, H, halo, cyano, hydroxy, amino, N(R5)2, OR5, substituted or unsubstituted C1-5 alkyl, C3-10 cycloalkyl, C1-5 alkylhydroxy, C1-5 alkenylhydroxy, C1-5 alkynylhydroxy, C1-5 alkylamine, C1-5 alkenylamine, C1-5 alkynylamine, substituted or unsubstituted mono- or bicyclic C3-10 heterocycloalkyl and substituted or unsubstituted mono- or bicyclic C5-10 heteroaryl;
R2 is H, halo, cyano, hydroxy and C1-3 alkyl;
R3 is H, halo, cyano, hydroxyl and amino; and
R4 is H, substituted or unsubstituted C1-5 alkyl, substituted or unsubstituted C1-5 alkoxy and substituted or unsubstituted C1-5 alkyl carboxylic acid; and
R5 is H, substituted or unsubstituted C1-5 alkyl, substituted or unsubstituted C1-5 alkoxy and substituted or unsubstituted C1-5 alkyl carboxylic acid;
In some embodiments of these aspects and all such aspects described herein, the AhR modulator of Formula (I) is an AhR modulator or AhR antagonist.
In some aspects, described herein are methods of modulating AhR activity, more specifically constitutive AhR activity in a subject in need thereof. Such methods comprise administering to a subject having constitutive AhR activity a therapeutically effective amount of an AhR modulator, such as an AhR antagonist of Formula (I), described herein. In some embodiments of these aspects and all such aspects described herein, the methods further comprise the step of selecting the subject having constitutive AhR activity.
Compounds of formula (I) of the present invention demonstrate a valuable pharmacological spectrum of action, which could not have been predicted. Compounds of the present invention have surprisingly been found to effectively inhibit AhR and it is possible therefore that said compounds be used for the treatment or prophylaxis of a disease or condition mediated by aryl hydrocarbon receptor (AhR), preferably cancer,, cancerous consitions, tumor, fibrotic disorders, or conditions with dysregulated immune responses or other disorders associated with aberrant AhR signaling, in humans and animals.
Examples of said diseases related with dysregulated immune response associated with AhR signaling are sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory disorders of the kidney, chronic intestinal inflammations (IBD, Crohn's disease, UC), 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 fibrotic disorders are fibrotic disorders of the internal organs, for example the lung, the heart, the kidney, the bone marrow and in particular the liver, and also dermatological fibroses and fibrotic eye disorders. In the context of the present invention, the term fibrotic disorders includes in particular the following terms: hepatic fibrosis, cirrhosis of the liver, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage resulting from diabetes, bone marrow fibrosis and similar fibrotic disorders, scleroderma, morphea, keloids, hypertrophic scarring (also following surgical procedures), naevi, diabetic retinopathy, proliferative vitroretinopathy and disorders of the connective tissue (for example sarcoidosis).
In other aspects, described herein are methods of treating a cancer or a cancerous condition by modulating AhR activity. Such methods comprise administering to a subject having a cancer 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 of inhibiting tumor cell invasiveness in a subject having a cancer, a cancerous condition, or a tumor. Such methods comprise administering to a subject having a cancer or a 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 all such aspects described herein, the methods further comprise the step of selecting the subject having a cancer, a cancerous condition, or a tumor.
Said cancer, cancerous condition, or tumor particularly suitable for treatment with an AHR inhibitor of the present invention are liquid and solid tumours, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include lymphomas, sarcomas, and leukaemias.
Examples of breast cancers 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 cancers 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 brain cancers include, but are not limited to, brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, glioblastoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumour.
Tumours of the male reproductive organs include, but are not limited to, prostate and testicular cancer.
Tumours of the female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
Examples of ovarian cancer include, but are not limited to serous tumour, endometrioid tumour, mucinous cystadenocarcinoma, granulosa cell tumour, Sertoli-Leydig cell tumour and arrhenoblastoma.
Examples of cervical cancer include, but are not limited to squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, small cell carcinoma, neuroendocrine tumour, glassy cell carcinoma and villoglandular adenocarcinoma.
Tumours of the digestive tract include, but are not limited to, anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
Examples of esophageal cancer include, but are not limited to esophageal cell carcinomas and adenocarcinomas, as well as squamous cell carcinomas, leiomyosarcoma, malignant melanoma, rhabdomyosarcoma and lymphoma.
Examples of gastric cancer include, but are not limited to intestinal type and diffuse type gastric adenocarcinoma.
Examples of pancreatic cancer include, but are not limited to ductal adenocarcinoma, adenosquamous carcinomas and pancreatic endocrine tumours.
Tumours of the urinary tract include, but are not limited to, bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers.
Examples of kidney cancer include, but are not limited to renal cell carcinoma, urothelial cell carcinoma, juxtaglomerular cell tumour (reninoma), angiomyolipoma, renal oncocytoma, Bellini duct carcinoma, clear-cell sarcoma of the kidney, mesoblastic nephroma and Wilms' tumour.
Examples of bladder cancer include, but are not limited to transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma and small cell carcinoma.
Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.
Examples of liver cancers include, but are not limited to, hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
Skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
Head-and-neck cancers include, but are not limited to, squamous cell cancer of the head and neck, laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, salivary gland cancer, lip and oral cavity cancer and squamous cell.
Lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.
Sarcomas include, but are not limited to, sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
Leukemias include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
The term "treating" or "treatment" as stated throughout this document is used conventionally, for example the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or disorder, such as a carcinoma.
The compounds or of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of tumour growth and metastases, especially in solid tumours of all indications and stages with or without pre-treatment of the tumour growththe cancer is a breast cancer, squamous cell cancer, lung cancer, a cancer of the peritoneum, a hepatocellular cancer, a gastric cancer, a pancreatic cancer, a glioblastoma, a cervical cancer, an ovarian cancer, a liver cancer, a bladder cancer, a hepatoma, a colon cancer, a colorectal cancer, an endometrial or uterine carcinoma, a salivary gland carcinoma, a kidney or renal cancer, a prostate cancer, a vulval cancer, a thyroid cancer, a head and neck cancer, a B-cell lymphoma, a chronic lymphocytic leukemia (CLL); an acute lymphoblastic leukemia (ALL), a Hairy cell leukemia, or a chronic myeloblastic leukemia. In some such embodiments, the cancer is a hepatocellular cancer.
Some embodiments of these methods can further comprise administration or treatment with one or more additional anti-cancer therapies. In some such embodiments, the additional anti-cancer therapy comprises surgery, radiation therapy, biotherapy, immunotherapy, chemotherapy, or any combination thereof.
Some embodiments of these methods can further comprise administration or treatment with one or more anti-cancer therapeutic agents. In some such embodiments, the anti-cancer therapeutic agent is a chemotherapeutic agent, a growth inhibitor agent, an anti-angiogenesis agent, a cytotoxic agent, an anti-hormonal agent, a prodrug, or a cytokine.
In a further embodiment of the present invention, the compounds of formula (I) of the present invention may be used to sensitize a cell to radiation, i.e. treatment of a cell with a compound of the present invention prior to radiation treatment of the cell renders the cell more susceptible to DNA damage and cell death than the cell would be in the absence of any treatment with a compound of the present invention. In one aspect, the cell is treated with at least one compound of general formula (I) of the present invention.
Thus, the present invention also provides a method of killing a cell, wherein a cell is administered one or more compounds of the present invention in combination with conventional radiation therapy.
The present invention also provides a method of rendering a cell more susceptible to cell death, wherein the cell is treated with one or more compounds of formula (I) of the present invention prior to the treatment of the cell to cause or induce cell death. In one aspect, after the cell is treated with one or more compounds of formula (I) of the present invention, the cell is treated with at least one compound, or at least one method, or a combination thereof, in order to cause DNA damage for the purpose of inhibiting the function of the normal cell or killing the cell.
In other embodiments of the present invention, a cell is killed by treating the cell with at least one DNA damaging agent, i.e. after treating a cell with one or more compounds of formula (I) of 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), carcinogenic agents, and mutagenic agents.
In other embodiments, 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, activation of a cell signalling pathway that results in DNA damage when the pathway is activated, inhibiting of a cell signalling pathway that results in DNA damage when the pathway is inhibited, and inducing a biochemical change in a cell, wherein the change results in DNA damage. By way of a non-limiting example, a DNA repair pathway in a cell can be inhibited, thereby preventing the repair of DNA damage and resulting in an abnormal accumulation of DNA damage in a cell.
In one aspect of the invention, a compound of formula (I) of the present invention is administered to a cell prior to the radiation or other induction of DNA damage in the cell. In another aspect of the invention, a compound of general formula (I) of the present invention is administered to a cell concomitantly with the radiation or other induction of DNA damage in the cell. In yet another aspect of the invention, a compound of formula (I) of the present invention is administered to a cell immediately after radiation 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 the sole pharmaceutical agent or in combination with one or more other pharmaceutically active ingredients where the combination causes no unacceptable adverse effects.
The present invention also covers such pharmaceutical combinations. For example, the compounds of the present invention can be combined with: 131 1-chTNT, abarelix, abiraterone, aclarubicin, adalimumab, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, hexyl aminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, anetumab ravtansine, angiotensin II, antithrombin III, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, atezolizumab, axitinib, azacitidine, basiliximab, belotecan, bendamustine, besilesomab, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, blinatumomab, bortezomib, buserelin, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib, calcitonine, 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 , crisantaspase, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daratumumab, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dianhydrogalactitol, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, dinutuximab, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, eculizumab, edrecolomab, elliptinium acetate, elotuzumab, eltrombopag, endostatin, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, ethinylestradiol, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, Glucarpidase, glutoxim, GM-CSF, goserelin, granisetron, granulocyte colony stimulating factor, histamine dihydrochloride, histrelin, hydroxycarbamide, 1-125 seeds, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate, interferon alfa, interferon beta, interferon gamma, iobitridol, iobenguane (1231), iomeprol, ipilimumab, irinotecan, Itraconazole, ixabepilone, ixazomib, lanreotide, lansoprazole, lapatinib, lasocholine, lenalidomide, lenvatinib, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone, methyltestosterone, metirosine, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphine hydrochloride, morphine sulfate, nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, necitumumab, nedaplatin, nelarabine, neridronic acid, netupitant/palonosetron, nivolumab, pentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nintedanib, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, olaparib, olaratumab, omacetaxine mepesuccinate, omeprazole, ondansetron, oprelvekin, orgotein, orilotimod, osimertinib, oxaliplatin, oxycodone, oxymetholone, ozogamicine, p53 gene therapy, paclitaxel, palbociclib, palifermin, palladium-103 seed, palonosetron, pamidronic acid, panitumumab, panobinostat, pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alfa-2b, pembrolizumab, pemetrexed, pentazocine, pentostatin, peplomycin, Perflubutane, perfosfamide, Pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib , regorafenib, risedronic acid, rhenium-186 etidronate, rituximab, rolapitant, romidepsin, romiplostim, romurtide, roniciclib , samarium (153Sm) lexidronam, sargramostim, satumomab, secretin, siltuximab, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sonidegib, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin, talimogene laherparepvec, tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium (99mTc) nofetumomab merpentan, 99mTc-HYNIC-[Tyr3]-octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa, tioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trametinib, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, valatinib , valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin.
The compounds of the invention can further be combined with other reagents targeting the immune system, such as immune checkpoint inhibitors, e.g. aPD-1/-L1 axis antagonists.
PD-1 , along with its ligands PD-L1 and PD-L2, function as negative regulators of T cell activation. AHR suppresses immune cell function while increasing cancer cell proliferation and motility. PD-L1 is overexpressed in many cancers and overexpression of PD-1 often occurs concomitantly in tumor infiltrating T cells. Thus results in attenuation of T cell activation and evasion of immune surveillance, which contributes to impaired antitumor immune responses. (Keir M E et al. (2008) Annu. Rev. Immunol. 26:677).
Simultaneously targeting both the PD-1/-L1 axis and AHR enhances antitumor immune responses more than in an additive manner, leading to a reduction of tumor growth that is unexpected.
Thus, compositions comprising a PD-1/-L1 axis antagonist and an AHR antagonist are surprisingly effective in enhancing an immune response and in the treatment of cancer.
In addition, the inventive compounds can also be used as a therapeutic in a variety of other disorders wherein AHR is involved.
Examples of other disorders associated with aberrant AhR signaling inflammation are vaccination for infection & cancer, viral infections, obesity and diet-induced obesity, adiposity, metabolic disorders, hepatic steatosis and uterine fibroids (uterine leiomyoma or uterine myoma) in women, chronic renal disorders, acute and chronic renal insufficiency, diabetic, inflammatory or hypertensive nephropaties, cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischemias, vascular disorders, thromboembolic disorders, arteriosclerosis, sickle cell anemia, erectile dysfunction, benign prostate hyperplasia, dysuria associated with benign prostate hyperplasia, Huntington, dementia, Alzheimer, and Creutzfeld-Jakob.
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 for 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 treating a cancer or a 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 proliferation, tissue invasion, metastasis and angiogenesis of cancer cells in a subject having a cancer, a cancerous condition, or a tumor.
In some embodiments of these aspects and all such aspects described herein, the use further comprises the step of selecting the subject having a cancer, a cancerous condition, or a tumor. In some such embodiments, the cancer is a breast cancer, squamous cell cancer, lung cancer, a cancer of the peritoneum, a hepatocellular cancer, a gastric cancer, a pancreatic cancer, a glioblastoma, a cervical cancer, an ovarian cancer, a liver cancer, a bladder cancer, a hepatoma, a colon cancer, a colorectal cancer, an endometrial or uterine carcinoma, a salivary gland carcinoma, a kidney or renal cancer, a prostate cancer, a vulval cancer, a thyroid cancer, a head and neck cancer, a B-cell lymphoma, a chronic lymphocytic leukemia (CLL); an acute lymphoblastic leukemia (ALL), a Hairy cell leukemia, or a chronic myeloblastic leukemia. In some such embodiments, the cancer is a hepatocellular cancer.
In some embodiments of these aspects and all such aspects described herein, the use further comprises one or more additional anti-cancer therapies. In some such embodiments, the additional anti-cancer therapy comprises surgery, radiation therapy, biotherapy, immunotherapy, or chemotherapy.
In some embodiments of these aspects and all such aspects described herein, the use further comprises one or more anti-cancer therapeutic agents. In some such embodiments, the anti-cancer therapeutic agent is a chemotherapeutic agent, a growth inhibitor agent, an anti-angiogenesis agent, a cytotoxic agent, an anti-hormonal agent, a prodrug, or a cytokine.
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 disease, disorder, or condition associated with AhR activity such as cancer, cancerous condition, tumor, fibrotic disease, conditions with dysregulated immune responses including autoimmune disease such as rheumatoid arthiritis, systemic lupus erythematosus (SLE), multiple sclerosis (MS), or other disorders associated with aberrant AhR signaling etc.
Hereinafter, the present invention will be described in more detail.
Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Also, although the invention has been described in conjunction with specific methods and samples, their analogs or equivalents should be within the scope of the present invention. Furthermore, the numerical values set forth herein are considered to include the meaning of “about” unless explicitly stated. All publications and other references mentioned herein are hereby incorporated by reference in their entirety.
The definition of residues used herein is described in detail. Unless otherwise indicated, each residue has the following definition and is used in the sense as commonly understood by one of ordinary skill in the art.
As used herein, the term “halo” “halogen”, “halide (s)” includes fluoro, chloro, bromo and iodo.
As used herein, the “alkyl” refers to an aliphatic hydrocarbon radical, and includes both linear and branched hydrocarbon radicals. For example, C1-6 alkyl is an aliphatic hydrocarbon having 1 to 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 defined, the alkyl refers to C1-6 alkyl, preferably C1-4 alkyl, more preferably C1-3 alkyl.
As used herein, the “alkenyl” refers to an aliphatic hydrocarbon radical comprising at least one carbon-carbon double bond, and includes both linear and branched hydrocarbon radicals. The unlimited example of the “alkenyl” is vinyl, allyl, but-1-enyl or but-2-enyl.
As used herein, the “alkynyl” refers to an aliphatic hydrocarbon radical comprising at least one carbon-carbon triple bond, and includes both linear and branched hydrocarbon radicals. The unlimited example of the “alkynyl” is ethynyl, propargyl, but-1-ynyl or but-2-ynyl.
As used herein, the “haloalkyl” refers to an alkyl group substituted with one or more halogen atom, and the alkyl group is defined as above. The “halo” refers to F, Cl, Br, or I, and the term is compatibly used with the term “halogen”. Unless otherwise defined, the haloalkyl refers tofluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl or 2,2,2-trifluoromethyl.
As used herein, the term "alkoxy" refers to-O-alkyl or alkyl-O- group, and the alkyl group is defined as shown above. For example, it includes methoxy, ethoxy, n-propoxy, n-butoxy and t-butoxy.
As used herein, the “alkoxyalkyl” refers to alkyl-O-alkyl group, and the alkyl group is defined as above. The unlimited example is methoxymethyl, ethoxymethyl, methoxyethyl or isopropoxymethyl.
As used herein, the term “hydroxy” or “hydroxyl” alone or in combination with other terms means -OH.
As used herein, “cyano” refers to ―CN, “cyanoalkyl” refers to alkyl substituted with ―CN, wherein the alkyl group is as defined above.
As used herein, “amino” refers to ―NH2; and "nitro" refers to -NO2.
As used herein, “carboxy” refers to-C(O)-OH group.
As used herein, “ester” refers to a group of ―C(O)―OR, where R is alkyl may be C1-10, preferably C1-8, C1-6 or C1-4 alkyl. Such ester groups may or may not be substituted with one or more suitable substituents.
As used herein,the term "cycloalkyl" refers to a cyclic alkyl which may be substituted or unsubstituted, and for example, the C3-20 cycloalkyl represents a monovalent saturated hydrocarbon ring system having 3 to 20 carbon atoms. Examples of the cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Preferably, unless otherwise defined, the cycloalkyl may be C3-8 cycloalkyl, or C3-6 cycloalkyl.
As used herein, the term "aryl" refers to a monovalent aromatic hydrocarbon having, for example, 6 to 20 carbon atoms (C6-20) that is derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. The aryl may include a bicyclic radical containing an aromatic ring fused to a saturated or partially unsaturated ring.Exemplary aryl groups may include radicals derived from benzene (phenyl), substituted phenyl, biphenyl, naphthyl, toluyl, naphthalenyl, anthracenyl, indenyl, indanyl, and the like. Unless otherwise defined, the aryl refers to C6-12 aryl, preferably C6-10 aryl.
As used herein, the “heteroaryl” refers to a monovalent or divalent substituent derived from a monoheterocyclic or polyheterocyclic aromatic hydrocarbon having 1 to 10 carbon ring members containing one or more, preferably one to three, heteroatoms selected among N, O, and S. Examples of the 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 the bicyclic heteroaryl includeindolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, quinolinyl, isoquinolinyl, furinyl, furopyridinyl, octahydropyranopyridine, benzodioxolyl and similar groups thereof, but are not limited thereto. Unless otherwise defined, the heteroaryl is C3-10 heteroaryl, preferably C3-7 heteroaryl, more preferably C3-5 heteroaryl.
As used herein, the “heterocycloalkyl” refers to monocyclic, bicyclic, tricyclic or higher cyclic alkyl having 3 to 10 carbon ring members containing one or more, for example, one to four, heteroatoms selected among N, O, and S. In addition, the heterocycle according to the present invention may also be a fused or bridged heterocycloalkyl. Examples of non-aromatic rings include azetidinyl, oxetanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, oxapiperazinyl, oxapiperidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, 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. Attachment of a heterocycloalkyl substituent can occur via a carbon atom or a heteroatom. A heterocycloalkyl group may be optionally substituted with one or more suitable groups via one or more aforementioned groups. Unless otherwise defined, heterocycloalkyl refers to heterocycloalkyl having 3 to 10 carbon ring members, preferably C3-7 heterocycloalkyl, more preferably heterocycloalkyl having 3 to 5 carbon ring atoms.
Unless otherwise specified herein, the term "substituted” means that at least one hydrogen atom is substituted by one to three substituents selected from the group consisting of a halogen atom (e.g., F, Cl, Br, or I), a cyano group, a hydroxyl group, a thiol group, a nitro group, an amino group, an imino group,an azido group, an amidino group, a hydrazino group, a hydrazono group, an oxo group, a carbonyl group, a carbamyl group, an ester group, an ether group, a carboxyl group or a salt thereof, a sulfonic acid group or a salt thereof, phosphoric acid or a salt thereof, a C1-6 alkyl group, a halo C1-6 alkyl group, a hydroxy C1-6 alkyl group, a C2-6 alkenyl group, a halo C2-6 alkenyl group, a C2-6 alkynyl group, a halo C2-6 alkynyl group, a C1-6 alkoxy group, a halo C1-6 alkoxy group, a hydroxy C1-6 alkoxy group, a C1-20 alkylthio group, a C1-6 alkylsulfonyl group, a C1-6 alkylcarbonyl group, a C1-6 alkoxycarbonyl group, a C3-20 carbocyclic group (e.g., a C3-9 cycloalkyl group, a halo C3-9 cycloalkyl group, a C3-9 cycloalkenyl group, a halo C3-9 cycloalkenyl group, a C1-9 heterocycloalkyl group, a halo C1-9 heterocycloalkyl group, a C2-9 heterocycloalkenyl group, a halo C2-9 heterocycloalkenyl group) and a C1-20 heterocyclic group (e.g., a C6-20 aryl group, a C6-20 aryloxy group, a C6-20 arylthio group, a C2-20 heteroaryl group, a C2-20 heteroaryloxygroup, a C2-20 heteroarylthio group).
Based on the studies conducted and the results obtained so far, it is believed that the following compounds of Formula (I), including isomers, mixtures of isomer as well as pharmaceutically acceptable salts and solvates thereof, are particularly interesting.
Aryl Hydrocarbon Receptor
The Aryl Hydrocarbon Receptor (“AhR”) is a ligand-dependent member of the family of basic-helix-loop-helix transcription factors that has been found to be activated by numerous structurally diverse synthetic and naturally occurring compounds, such as polycyclic aromatic hydrocarbons, indoles, and flavonoids. In the absence of bound ligand, the 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”), an immunophilin-like protein, XAP2, and the hsp90 interacting protein, p23.
The term “aryl hydrocarbon receptor” or “AhR” as used herein refers to the 848 amino acid polypeptide, as described by, e.g., NP_001612, together with any naturally occurring allelic, splice variants, and processed forms thereof. Typically, AhR refers to human AhR. The term AhR is also used to refer to truncated forms or fragments of the AhR polypeptide, comprising, for example, specific AhR domains. Reference to any such forms of the AhR can be identified in the application, e.g., by “AhR (122-224).”
AhR Modulators
The inventors of the present invention have discovered that the novel AhR modulator compounds described herein, such as the small molecules of Formula (I), modulate constitutive AhR activity, by functioning as AhR antagonists. Further, they have discovered that such AhR modulator compounds can inhibit cancer cell growth, as well as tumor invasion, metastasis and angiogenesis. Accordingly, described herein are novel modulators of the AhR and constitutive AhR signaling for use in therapeutic compositions for, and methods of, treating and inhibiting cancer growth and tumor cell invasion, and immune related diseases such as autoimmune diseases.
The AhR mediates a variety of functional responses, including, but not limited to de novo transcription of target genes or AhR battery genes having the DRE or XRE responsive element 5′-TNGCGTG-3′. Alternative pathways of AhR signaling have also been described, such as binding to retinoblastoma protein, estrogen receptor (ER), the transcription factor E2F1 and to the NFκB pathway subunits RelA and RelB. The AhR can also act as a ubiquitin ligase. Accordingly, signaling via the AhR comprises multiple pathways, including constitutive and non-constitutive AhR signaling pathways or signaling activity, as those terms are defined herein.
As used herein, “constitutive AhR signaling” refers to one or more signaling pathways mediated or regulated by the AhR that are activated or driven by one or more endogenous AhR ligands, or one or more environmental ligands, such as toxins or pollutants, that cause constitutive or long-term translocation of the AhR to 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” refers to one or more signaling pathways mediated or induced by the AhR that does not cause constitutive or long-term translocation of the AhR to the nucleus, nor 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 upregulation of expression of CYP1A1, CYP1B1, or a combination thereof.
Accordingly, an “AhR modulator,” as the term is used herein refers to 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 antagonist of the AhR described herein, can refer to a decrease in, inhibition of, or diversion of, constitutive activity of the AhR. The term “expression,” refers to the cellular processes involved in producing RNA and proteins and as appropriate, secreting proteins, including where applicable, but not limited to, for example, transcription, translation, folding, modification and processing. “Expression products” include RNA transcribed from a gene and polypeptides obtained by translation of mRNA transcribed from a gene.
The term “modulate” in reference to an Ahr modulator is used consistently with its use in the art, e.g., meaning to cause or facilitate a qualitative or quantitative change, alteration, or modification in one or more biological processes, mechanisms, effects, responses, functions, activities, pathways, or other phenomena of interest. Accordingly, as used herein, modulate refers to 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.
The term “agent” as used herein in reference to an AhR modulator means any compound or substance such as, but not limited to, a small molecule, nucleic acid, polypeptide, peptide, drug, ion, etc. An “agent” can be any chemical, entity, or moiety, including, without limitation, synthetic and naturally-occurring proteinaceous and non-proteinaceous entities. In some embodiments, an agent is a nucleic acid, a nucleic acid analogue, a protein, an antibody, a peptide, an aptamer, an oligomer of nucleic acids, an amino acid, or a carbohydrate, and includes, without limitation, proteins, oligonucleotides, ribozymes, DNAzymes, glycoproteins, siRNAs, lipoproteins, aptamers, and modifications and combinations thereof etc. In certain embodiments, as described herein, agents are small molecules having a chemical moiety. For example, chemical moieties include unsubstituted or substituted alkyl, aromatic, or heterocyclyl moieties. Compounds can be known to have a desired activity and/or property, e.g., modulate AhR activity, or can be selected from a library of diverse 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” refers to the ability of an AhR antagonist, described herein to bind to a target, such as the AhR, with a KD　10-5　M (10000 nM) or less, e.g., 10-6　M or less, 10-7　M or less, 10-8　M or less, 10-9　M or less, 10-10　M or less, 10-11　M or less, or 10-12　M or less. For example, if an antagonist described herein binds to the AhR with a KD　of 10-5　M or lower, but not to other molecules, or a related homologue, then the agent is said to specifically bind the AhR. Specific binding can be influenced by, for example, the affinity and avidity of the antagonist and the concentration of the antagonist used. The person of ordinary skill in the art can determine appropriate conditions under which the antagonists described herein selectively bind using any suitable methods, such as titration of an AhR antagonist in a suitable cell binding assay, such as those described herein.
In some aspects of the compositions and methods described herein, AhR modulators are AhR antagonists having the chemical structures of Formula (I), described herein.
As used herein, the AhR is an “AhR antagonist.” An AhR antagonist refers to an AhR inhibitor that does not provoke a biological response itself upon specifically binding to the AhR, but blocks or dampens agonist-mediated or ligand-mediated responses, i.e., an AhR antagonist can bind but does not activate the AhR, and the binding disrupts the interaction, displaces an AhR agonist, and/or inhibits the function of an AhR agonist. Thus, as used herein, an AhR antagonist does not function as an inducer of AhR activity when bound to the AhR, i.e., they function as pure AhR inhibitors. In some embodiments, an 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 growth and progression of established tumors. In other embodiments, the small molecule AhR antagonists of Formula (I), described herein act as chemopreventatives by blocking AhR-mediated CYP1A1 induction and mutagen production on exposure to environmental ligands.
In some embodiments of these aspects, the AhR antagonists of Formula (I), described herein inhibit the early contributions of constitutively active AhR in driving malignant transformation. In some embodiments, the compunds of Formula (I) described herein inhibit constitutive AhR signaling-mediated cancer or tumor cell growth. In some embodiments, the compounds of Formula (I), described herein inhibit constitutive AhR signaling-mediated tumor invasion in driving malignant transformation.
Accordingly, provided for use in the various aspects described herein are AhR antagonist of Formula (I):
An aspect of the present inventionrelates to novel compounds that can modulate human aryl hydrocarbon receptor (AhR). These compounds bind specifically to AhR.
In some embodiments, the compound has the structure of formula (I), or an enantiomer, diastereomer, racemate, solvate, hydrate, or pharmaceutically acceptable salt thereof:
Figure PCTKR2021003883-appb-I000002
wherein:
X1, X2 and X3 are each independently CR2, N or NR3;
Ar1 and Ar2 are each independently selected from substituted or unsubstituted mono- or bicyclic C6-10 aryl, substituted or unsubstituted mono- or bicyclic C5-10 heteroaryl and substituted or unsubstituted mono- or bicyclic C3-10 heterocycloalkyl;
D is H, halo, cyano, hydroxy, amino, substituted or unsubstituted C1-5 alkyl, mono- or bicyclic C3-10 cycloalkyl, C1-5 alkylhydroxy, C1-5 alkenylhydroxy, C1-5 alkynylhydroxy, C1-5 alkylamine, C1-5 alkenylamine, C1-5 alkynylamine, mono- or bicyclic C3-10 heterocycloalkyl, mono- or bicyclic C3-10 heteroaryl,
E is absent(direct bond), amino, substituted or unsubstituted C1-5 alkyl, mono- or bicyclic C3-10 cycloalkyl, C1-5 alkylhydroxy, C1-5 alkenylhydroxy, C1-5 alkynylhydroxy, C1-5 alkylamine, C1-5 alkenylamine, C1-5 alkynylamine, mono- or bicyclic C3-10 heterocycloalkyl, mono- or bicyclic C3-10 heteroaryl,
or D and E, together with the atoms to which they are attached, are combined to form substituted or unsubstituted mono- or bicyclic C3-10 heterocycloalkyl ring;
G is absent(direct bond), H, halo, cyano, hydroxy, amino, nitro, ether(-O-), thioether(-S-), sulfinyl(-SO-), sulfonyl(-SO2-), sulfonylamido(-SO2NR4-), aminosulfonyl(-NR4SO2-), carbonyl(-(CO)-), amido(-(CO)NR4-), reverse amido(-NR4(CO)-), ester(-(CO)O-), substituted or unsubstituted mono- or bicyclic C3-10 cycloalkyl, substituted or unsubstituted mono- or bicyclic C3-10 heterocycloalkyl, substituted or unsubstituted mono- or bicyclic C6-10 aryl and substituted or unsubstituted mono- or bicyclic C5-10 heteroaryl;
R1 is absent, H, halo, cyano, hydroxy, amino, N(R5)2, OR5, substituted or unsubstituted C1-5 alkyl, C3-10 cycloalkyl, C1-5 alkylhydroxy, C1-5 alkenylhydroxy, C1-5 alkynylhydroxy, C1-5 alkylamine, C1-5 alkenylamine, C1-5 alkynylamine, substituted or unsubstituted mono- or bicyclic C3-10 heterocycloalkyl and substituted or unsubstituted mono- or bicyclic C5-10 heteroaryl;
R2 is H, halo, cyano, hydroxy and C1-3 alkyl;
R3 is H, halo, cyano, hydroxyl and amino; and
R4 is H, substituted or unsubstituted C1-5 alkyl, substituted or unsubstituted C1-5 alkoxy and substituted or unsubstituted C1-5 alkyl carboxylic acid; and
R5 is H, substituted or unsubstituted C1-5 alkyl, substituted or unsubstituted C1-5 alkoxy and substituted or unsubstituted C1-5 alkyl carboxylic acid;
In a preferred embodiment, the Ar1 may be substituted or unsubstituted monocyclic C5-7 heteroaryl comprising one or more hetero atoms selected from the group consisting of N, O and S. More preferably, the Ar1 may be monocyclic C5-6 heteroaryl comprising one or two hetero atoms selected from the group consisting of N, O and S, which may be unsubstituted or substituted with C1-3 alkyl. Far more preferably, the Ar1 may be pyrazole or pyridine which may be unsubstituted or substituted with methyl.
In a preferred embodiment, the Ar2 may be mono- or bicyclic C6-10 aryl comprising one or more hetero atoms selected from the group consisting of N, O and S, which is unsubstituted or substituted with halo. More preferably, the Ar2 may be phenyl which may be unsubstituted or substituted with chloro.
In a preferred embodiment, the D may be H or C1-3 alkyl.
In a preferred embodiment, the E may absent(direct bond), amino, substituted or unsubstituted C1-4 alkyl, mono- or bicyclic C3-8 cycloalkyl, C1-4 alkylhydroxy, C1-4 alkenylhydroxy, C1-4 alkynylhydroxy, C1-4 alkylamine, C1-4 alkenylamine, C1-4 alkynylamine, mono- or bicyclic C3-8 heterocycloalkyl, mono- or bicyclic C3-8 heteroaryl, wherein the mono- or bicyclic C3-8 heterocycloalkyl and mono- or bicyclic C3-8 heteroaryl comprises one or more, preferably one or two heteroatoms selected from the group consisting of N, O and S.
In a preferred embodiment, the D and E, together with the atoms to which they are attached, may be combined to form substituted or unsubstituted mono- or bicyclic C3-10 heterocycloalkyl ring one or more hetero atoms selected from the group consisting of N, O and S. More preferably, said mono- or bicyclic C3-10 heterocycloalkyl ring may be unsubstituted or substituted pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, or octahydropyranopyridine.
In a preferred embodiment, G is absent(direct bond), H, halo, cyano, hydroxy, amino, nitro, ether(-O-), thioether(-S-), sulfinyl(-SO-), sulfonyl(-SO2-), sulfonylamido(-SO2NR4-), aminosulfonyl(-NR4SO2-), carbonyl(-(CO)-), amido(-(CO)NR4-), reverse amido(-NR4(CO)-), ester(-(CO)O-), substituted or unsubstituted mono- or bicyclic C3-8 cycloalkyl, substituted or unsubstituted mono- or bicyclic C3-8 heterocycloalkyl, substituted or unsubstituted mono- or bicyclic C6-10 aryl and substituted or unsubstituted mono- or bicyclic C5-8 heteroaryl, wherein the mono- or bicyclic C3-8 heterocycloalkyl and mono- or bicyclic C5-8 heteroaryl comprises one or more, preferably one or two heteroatoms selected from the group consisting of N, O and S.
In a preferred embodiment, R1 is absent, H, halo, cyano, hydroxy, amino, N(R5)2, OR5, substituted or unsubstituted C1-4 alkyl, C3-8 cycloalkyl, C1-4 alkylhydroxy, C1-4 alkenylhydroxy, C1-4 alkynylhydroxy, C1-4 alkylamine, C1-4 alkenylamine, C1-4 alkynylamine, substituted or unsubstituted mono- or bicyclic C3-8 heterocycloalkyl and substituted or unsubstituted mono- or bicyclic C5-8 heteroaryl, phosphate, substituted or unsubstituted C1-3 alkyl phosphate, wherein the mono- or bicyclic C3-8 heterocycloalkyl and mono- or bicyclic C5-8 heteroaryl comprises one or more, preferably one or two heteroatoms selected from the group consisting of N, O and S.
Further, in a more specific embodiment, the compound of the 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)propane-1,2-diol
11. (R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propan-1-ol
12. 2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)-3-methylbutan-1-ol
13. (S)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)-3-methylbutan-1-ol
14. (R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)-3-methylbutan-1-ol
15. 2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)butan-1-ol
16. 2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propane-1,3-diol
17. (R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)-1-phenylethan-1-ol
18. (S)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)-1-phenylethan-1-ol
19. 6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrimidin-4-amine
20. N1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-N3,N3-dimethylpropane-1,3-diamine
21. 6-(4-chlorophenyl)-N-ethyl-2-(pyridin-3-yl)pyrimidin-4-amine
22. 6-(4-chlorophenyl)-N-propyl-2-(pyridin-3-yl)pyrimidin-4-amine
23. N-butyl-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-amine
24. 1-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)butan-2-ol
25. 6-(4-chlorophenyl)-N-(cyclopropylmethyl)-2-(pyridin-3-yl)pyrimidin-4-amine
26. 6-(4-chlorophenyl)-N-cyclopentyl-2-(pyridin-3-yl)pyrimidin-4-amine
27. 4-(4-chlorophenyl)-6-(4-methylpiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine
28. N-(tert-butyl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-amine
29. (1R,2R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol
30. (1S,2R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol
31. 6-(4-chlorophenyl)-N-(pyridin-2-ylmethyl)-2-(pyridin-3-yl)pyrimidin-4-amine
32. 6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(pyridin-3-ylmethyl)pyrimidin-4-amine
33. 6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(pyridin-4-ylmethyl)pyrimidin-4-amine
34. trans-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexan-1-ol
35. trans-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexan-1-ol
36. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-2-yl)methanol
37. 2-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-2-yl)ethan-1-ol
38. (R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-ol
39. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-ol
40. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanol
41. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-ol
42. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol
43. 2-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)ethan-1-ol
44. 3-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)propan-1-ol
45. 4-(4-chlorophenyl)-6-(4-methoxypiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine
46. 4-(4-chlorophenyl)-6-(piperidin-1-yl)-2-(pyridin-3-yl)pyrimidine
47. 4-(4-chlorophenyl)-6-(2-methylpiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine
48. 4-(4-chlorophenyl)-6-(3-methylpiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine
49. 4-(4-chlorophenyl)-6-(2,6-dimethylpiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine
50. 4-(4-chlorophenyl)-6-(3,5-dimethylpiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine
51. 4-(4-chlorophenyl)-6-(3,3-difluoropiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine
52. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(3-(trifluoromethyl)piperidin-1-yl)pyrimidine
53. 4-(4-chlorophenyl)-6-(3-ethylpiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine
54. 6-(4-chlorophenyl)-N-(piperidin-4-yl)-2-(pyridin-3-yl)pyrimidin-4-amine
55. 6-(4-chlorophenyl)-N-(piperidin-3-ylmethyl)-2-(pyridin-3-yl)pyrimidin-4-amine
56. 6-(4-chlorophenyl)-N-(piperidin-4-ylmethyl)-2-(pyridin-3-yl)pyrimidin-4-amine
57. 6-(4-chlorophenyl)-N-(1-methylpiperidin-4-yl)-2-(pyridin-3-yl)pyrimidin-4-amine
58. 6-(4-chlorophenyl)-N-(2-(piperidin-4-yl)ethyl)-2-(pyridin-3-yl)pyrimidin-4-amine
59. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-2-yl)methanamine
60. (R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-amine
61. (S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-amine
62. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanamine
63. (S)-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanamine
64. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-amine
65. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanamine
66. (1R,2S)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol
67. (1S,2S)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol
68. trans-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol
69. (1R,2R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexan-1-ol
70. cis-4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-2,6-dimethylmorpholine
71. 4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)morpholine
72. 6-(4-chlorophenyl)-N-(morpholin-2-ylmethyl)-2-(pyridin-3-yl)pyrimidin-4-amine
73. 4-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)morpholine
74. 4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)thiomorpholine
75. 6-(4-chlorophenyl)-N-(3-morpholinopropyl)-2-(pyridin-3-yl)pyrimidin-4-amine
76. (R)-4-(4-chlorophenyl)-6-(2-methylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine
77. (R)-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-methylpiperazin-1-yl)(phenyl)methanone
78. 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)piperidine-4-carbonitrile
151. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(3-(trifluoromethyl)phenyl)piperidin-4-ol
152. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyrimidine
153. 4-(4-chlorophenyl)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-ol
154. 1-(4-(((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)ethan-1-one
155. 1-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-phenylpiperidin-4-yl)ethan-1-one
156. 4-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)morpholine
157. 4-(4-chlorophenyl)-6-(4-(3,5-dichlorophenyl)piperidin-1-yl)-2-(pyridin-3-yl)pyrimidine
158. 6-(4-chlorophenyl)-N-((1-cyclohexylpiperidin-3-yl)methyl)-2-(pyridin-3-yl)pyrimidin-4-amine
159. N-((1-benzylpiperidin-4-yl)methyl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-amine
160. ethyl 3-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)-3-oxopropanoate
161. 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)piperidine-4-carbonitrile
185. (R)-(1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperidin-3-yl)methanol
186. (R)-1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)pyrrolidin-3-ol
187. (1S,3R)-3-((6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol
188. (R)-2-((6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)butan-1-ol
189. Trans-4-((6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclohexan-1-ol
190. 7-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)octahydro-2H-pyrano[2,3-c]pyridine
191. 7-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)octahydro-2H-pyrano[2,3-c]pyridin-4-ol
192. (2R,3R)-3-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)pentan-2-ol
193. 6-(4-chlorophenyl)-N-((1-methylpiperidin-4-yl)methyl)-2-(pyridin-3-yl)pyrimidin-4-amine
194. (R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol
195. (S)-6-(4-chlorophenyl)-N-(2-(methoxymethyl)pyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-amine
196. (S)-4-(4-chlorophenyl)-6-(3-fluoropyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidine
197. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidine
198. 4-(4-chlorophenyl)-6-(3,3-difluoropyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidine
199. 4-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)morpholine
200. 5-(((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)methyl)pyrrolidin-2-one
201. Trans-6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(4-(pyrrolidin-1-yl)tetrahydrofuran-3-yl)pyrimidin-4-amine
202. 6-(4-chlorophenyl)-N-((3S,4S)-4-methoxy-1-methylpyrrolidin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-amine
203. (R)-6-(4-chlorophenyl)-N-(piperidin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-amine
204. 6-(4-chlorophenyl)-N-(piperidin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-amine
205. 6-(4-chlorophenyl)-N-((3R,4R)-3-fluoropiperidin-4-yl)-2-(pyridin-3-yl)pyrimidin-4-amine
206. (S)-6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(pyrrolidin-3-ylmethyl)pyrimidin-4-amine
207. 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)pyrrolidine-3-carbonitrile
213. (R)-1-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)butan-2-ol
214. (1R,3S)-3-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol
215. Cis-(4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexyl)methanol
216. Cis-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexan-1-ol
217. Trans-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexan-1-ol
218. 4-(4-chlorophenyl)-6-(4-(2-methoxyethyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine
219. (3S,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-ol
220. (3R,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-ol
221. (3R,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-ol
222. (3S,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-ol
223. 1-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-2-hydroxyethan-1-one
224. 2-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)propan-1-ol
225. N-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)-2-methoxyacetamide
226. (1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol
227. (1-(2-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol
228. (1-(6-(4-methoxyphenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol
229. (1-(2-(pyridin-3-yl)-6-(p-tolyl)pyrimidin-4-yl)piperidin-4-yl)methanol
230. (3R,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidine-3,4-diol
231. (3R,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidine-3,4-diol
232. 1-(3-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)tetrahydropyrimidin-1(2H)-yl)ethan-1-one
233. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)piperidin-3-ol
233. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)piperidin-3-ol
234. (3R,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-fluoropyrrolidin-3-ol
235. (3R,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-fluoropyrrolidin-3-ol
236. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)pyrrolidin-3-ol
237. N-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)-2-hydroxypropanamide
238. N-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)-2-hydroxyacetamide
239. 2-((4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)ethan-1-ol
240. (S)-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)methanol
241. N-((3R,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-hydroxypyrrolidin-3-yl)acetamide
242. (3R,4R)-4-acetamido-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl acetate
243. N-((3R,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-hydroxypyrrolidin-3-yl)acetamide
244. N-((3S,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-hydroxypyrrolidin-3-yl)acetamide
245. N-((3S,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-hydroxypyrrolidin-3-yl)acetamide
246. (1-(6-(4-chloro-3-fluorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol
247. (3S,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)piperidin-3-ol
248. (3S,4R)-4-(hydroxymethyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-3-ol
249. ((3S,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-yl)methanol
250. ((3S,4R)-3-fluoro-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol
251. ((3R,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-yl)methanol
252. ((3R,4S)-3-fluoro-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol
253. ((3R,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-yl)methanol
254. ((3R,4R)-3-fluoro-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol
255. (3S,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)pyrrolidin-3-ol
256. (3S,4R)-4-(hydroxymethyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol
257. (3R,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)pyrrolidin-3-ol
258. (3R,4R)-4-(hydroxymethyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol
259. (3R,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)piperidin-3-ol
260. (3R,4R)-4-(hydroxymethyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-3-ol
261. (3S,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)piperidin-3-ol
262. (3S,4S)-4-(hydroxymethyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-3-ol
263. (S)-1-(2-(4-methylpyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol
264. (3R,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)piperidin-3-ol
265. (3R,4S)-4-(hydroxymethyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-3-ol
266. (3S,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(hydroxymethyl)pyrrolidin-3-ol
267. (3S,4S)-4-(hydroxymethyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol
268. (1-(6-(4-morpholinophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol
269. (S)-1-(2-(2-methylpyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol
270. (S)-3-(4-(3-hydroxypyrrolidin-1-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)pyridin-2-ol
271. 5-chloro-2-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)phenol
272. 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-(6-(4-chlorophenyl)-2-(2-methyl-2H-tetrazol-5-yl)pyrimidin-4-yl)pyrrolidin-3-ol
334. 4-(4-chlorophenyl)-2-(2-methyl-2H-tetrazol-5-yl)-6-(4-(methylsulfonyl)piperazin-1-yl)pyrimidine
335. 4-(4-chlorophenyl)-6-(4-((2-fluoroethyl)sulfonyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine
336. (S)-1-(6-(4-chlorophenyl)-2-(isoxazol-4-yl)pyrimidin-4-yl)pyrrolidin-3-ol
337. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(methylsulfonyl)piperidin-4-yl)methanol
338. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)azepan-3-ol
339. 4-(4-chlorophenyl)-6-(4-((difluoromethyl)sulfonyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine
340. (S)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol
341. 4-(4-(methylsulfonyl)piperazin-1-yl)-2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidine
342. (S)-1-(6-(4-chlorophenyl)-2-(5,6-difluoropyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol
343. (3S,4R)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidine-3,4-diol
344. (S)-1-(6-(4-chlorophenyl)-[2,5'-bipyrimidin]-4-yl)pyrrolidin-3-ol
345. (S)-1-(6-(4-chlorophenyl)-2-(6-fluoropyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol
346. (S)-1-(6-(4-chlorophenyl)-2-(2-fluoropyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol
347. (S)-1-(6-(4-chlorophenyl)-2-(pyridin-2-yl)pyrimidin-4-yl)pyrrolidin-3-ol
348. 2-((4-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)ethanol
349. 2-((4-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)ethan-1-ol
350. (S)-1-(2-(isothiazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol
351. (4-(methylsulfonyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol
352. 1-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-3-hydroxypropan-1-one
353. 2-((4-(2-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)ethanol
354. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-(dimethylamino)piperidin-4-ol
355. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-5-(dimethylamino)piperidin-3-ol
356. (1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-4-(methylsulfonyl)piperidin-4-yl)methanol
357. (1-(2-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)-4-(methylsulfonyl)piperidin-4-yl)methanol
358. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-(dimethylamino)piperidin-4-yl)methanol
359. 2-((4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-methylpiperazin-1-yl)sulfonyl)ethan-1-ol
360. 2-((1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)amino)ethanol
361. 1-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-4-hydroxybutan-1-one
362. 3-((4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)propan-1-ol
363. 1-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-3,4-dihydroxybutan-1-one
364. 1-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-2,3-dihydroxybutan-1-one
365. 4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-6-methylpiperazin-2-one
366. (S)-3-(4-(3-hydroxypyrrolidin-1-yl)-6-(6-morpholinopyridin-3-yl)pyrimidin-2-yl)pyridin-2-ol
367. (S)-4-(4-(6-(3-hydroxypyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)phenyl)morpholin-3-one
368. 2-((4-(6-(4-chlorophenyl)-2-(isothiazol-4-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)ethanol
369. 3-((4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)propane-1,2-diol
369. 3-((4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)propane-1,2-diol
370. 2-((4-(2-(isothiazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)ethanol
371. (S)-2-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-2-yl)ethanol
372. (S)-4-(5-(6-(3-hydroxypyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyridin-2-yl)morpholin-3-one
373. (S)-3-(4-(3-fluoro-4-morpholinophenyl)-6-(3-hydroxypyrrolidin-1-yl)pyrimidin-2-yl)pyridin-2-ol
373. (S)-3-(4-(3-fluoro-4-morpholinophenyl)-6-(3-hydroxypyrrolidin-1-yl)pyrimidin-2-yl)pyridin-2-ol
374. (S)-1-(6-(4-((2-(dimethylamino)ethyl)amino)phenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol
375. (S)-1-(6-(4-(2-(dimethylamino)ethoxy)phenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol, and
376. (S)-1-(6-(4-((2-hydroxyethyl)amino)phenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol.
Single stereochemical isomers, enantiomers, diastereomers, and pharmaceutically acceptable salts of the above exemplified compounds are also within the scope of the present disclosure. Pharmaceutically acceptable salts may be, for example, derived from suitable inorganic and organic acids and bases.
Acid addition salts can be prepared by reacting the purified compound in its free-based form, if possible, with a suitable organic or inorganic acid and isolating the salt thus formed. Examples of pharmaceutically acceptable acid addition salts include, without limitations, salts of an 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, without limitations, alkali metal (e.g., sodium, lithium, and potassium), alkaline earth metal (e.g., magnesium and calcium), ammonium and N+(C1-4alkyl)4　salts.
Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, gluconate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate salts.
In addition, the compounds represented by Formula I according to the present invention include, but are not limited thereto, not only pharmaceutically acceptable salts thereof, but also all solvates or hydrates and all possible stereoisomers that can be prepared therefrom. All stereoisomers of the present compounds (e.g., those which may exist due to asymmetric carbons on various substituents), including enantiomeric forms and diastereomeric forms, are contemplated within the scope of this invention. Individual stereoisomers of the compounds of the present invention may, for example, be substantially free of other isomers (e.g., as a pure or substantially pure optical isomer having a specified activity), or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the compounds of the present invention may have the S or R configuration as defined by the IUPAC 1974 Recommendations. The racemic forms can be analyzed by physical methods, such as fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography. The individual optical isomers can be obtained from the racemates by any suitable method, including without limitation, salt formation with an optically active acid followed by crystallization.
The solvate and stereoisomer of the compound represented by Formula I may be prepared from the compound represented by Formula I using methods known in the art.
Furthermore, the compounds represented by Formula I according to the present invention may be prepared either in a crystalline form or in 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 not only include 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 inventionmay be synthesized by methods known in the art or by methods illustrated in Examples 1-376 below.
Pharmaceutical compositions, Methods and Use
In a specific embodiment, the pharmaceutical composition and the method provided herein comprises the compound of Formula (I).
The subject may be a mammal including human or a mammalian cell; for example, a mammal (e.g., human) suffering from the 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 may be administered orally or parenterally. For example, the parenteral administration may be performed by any one of intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, endothelial administration, topical administration, intranasal administration, intrapulmonary administration, intrarectal administration, and the like.
The effective amount may refer to pharmaceutically and/or therapeutically effective amount, and may be prescribed depending on factors such as a type of preparation (formulation), administration route, the patient’s age, body weight, gender, and/or pathologic conditions, and the like.
A pharmaceutically acceptable salt of the compound of Formula (I) may include addition salts formed by inorganic acids such as hydrochloride, sulfate, phosphate, hydrobromide, hydroiodide, nitrate, pyrosulfate, or metaphosphate, addition salts formed by 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 is not limited thereto.
The pharmaceutical composition according to the present invention can be formulated into a suitable form together with a commonly used pharmaceutically acceptable carrier. The “pharmaceutically acceptable” refers to being physiologically acceptable, and not usually causing an allergic reaction or a similar reaction such as gastrointestinal disorders and dizziness when administered to humans. Further, the pharmaceutical composition of the present invention may be used after being formulated into an oral preparation, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, etc., and a parental preparation, such as epidermal formulations, suppositories, or sterile injection solutions, in accordance with a conventional method.
Examples of carriers, excipients and diluents that can be included in the composition, may include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, arabic gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil, but are not limited thereto. When formulated into a preparation, a diluting agent or an excipient, such as commonly-used fillers, stabilizing agents, binding agents, disintegrating agents, and surfactants can be used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and these solid preparations may be prepared by mixing the compound of the present invention with at least one excipient, for example, starch, microcrystalline cellulose, sucrose, lactose, low-substituted hydroxypropyl cellulose, hypromellose or the like. In addition to the simple excipient, a lubricant such as magnesium stearate and talc are also used. Liquid preparations for oral administration include a suspension, a liquid for internal use, an emulsion, a syrup, etc. In addition to a commonly used simple diluent such as water and liquid paraffin, various excipients such as a humectant, a sweetener, an aromatic, a preservative, etc. may also be contained. Formulations for parenteral administration include a sterilized aqueous solution, a non-aqueous solution, a suspension, an emulsion, a lyophilized formulation and a suppository. The non-aqueous solution or suspension may contain propylene glycol, polyethylene glycol, a vegetable oil such as olive oil, an injectable ester such as ethyl oleate, etc. As a base of the suppository, witepsol, macrogol, tween 61, cocoa butter, laurin butter, glycerogelatin, etc. may be used. In order to formulate the formulation for parenteral administration, the compound of Formula I or a pharmaceutically acceptable salt thereof may be mixed in water together with sterilized and/or contain adjuvants such as preservatives, stabilizers, auxiliary agents such as wettable powder or emulsifying accelerators, salt for controlling osmotic pressure and/or buffers and the like, and other therapeutically useful substances, to prepare a solution or suspension, which is then manufactured in the form of an ampoule or vial unit administration.
The pharmaceutical composition including the compound of Formula I disclosed herein as an active ingredient may be administered to mammals such as mice, livestock, and humans by various routes for the modulation of AhR activity, or the prevention or treatment of a disease, disorder, or condition associated with AhR activity.
In some embodiment, the disease, disorder, or condition associated with AhR activity. may be a cancer, cancerous condition, tumor, fibrotic dieases, immune related disease or other disease related with AhR signaling.
In some embodiment, the diseases related with dysregulated immune response associated with AhR signaling are selected from the group consisting of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory disorders of the kidney, chronic intestinal inflammations (IBD, Crohn's disease, 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 some embodiment, the fibrotic disorders are selected from the group consisting of fibrotic disorders of the internal organs, for example the lung, the heart, the kidney, the bone marrow and in particular the liver, and also dermatological fibroses and fibrotic eye disorders. In the context of the present invention, the term fibrotic disorders includes in particular the following terms: hepatic fibrosis, cirrhosis of the liver, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage resulting from diabetes, bone marrow fibrosis and similar fibrotic disorders, scleroderma, morphea, keloids, hypertrophic scarring (also following surgical procedures), naevi, diabetic retinopathy, proliferative vitroretinopathy and disorders of the connective tissue (for example sarcoidosis).
In some embodiments of the cancer, cancerous condition, or tumor particularly suitable for treatment with an AHR antagonist of the present invention are liquid and solid tumours, such as a breast cancer, squamous cell cancer, lung cancer, a cancer of the peritoneum, a hepatocellular cancer, a gastric cancer, a pancreatic cancer, a glioblastoma, a cervical cancer, an ovarian cancer, a liver cancer, a bladder cancer, a hepatoma, a colon cancer, a colorectal cancer, an endometrial or uterine carcinoma, a salivary gland carcinoma, a kidney or renal cancer, a prostate cancer, a vulval cancer, a thyroid cancer, a head and neck cancer, a B-cell lymphoma, a chronic lymphocytic leukemia (CLL); an acute lymphoblastic leukemia (ALL), a Hairy cell leukemia, or a chronic myeloblastic leukemia.
In some embodiments, the pharmaceutical composition of the preset invention can be used together with one or more additional anti-cancer therapies. In some such embodiments, the additional anti-cancer therapy comprises surgery, radiation therapy, biotherapy, immunotherapy, chemotherapy, or any combination thereof.
In some embodiments, the pharmaceutical composition of the preset invention can be used together with anti-cancer therapeutic agents. In some such embodiments, the anti-cancer therapeutic agent is a chemotherapeutic agent, a growth inhibitor agent, an anti-angiogenesis agent, a cytotoxic agent, an anti-hormonal agent, a prodrug, or a cytokine.
Examples of other disorders associated with aberrant AhR signaling inflammation are vaccination for infection & cancer, viral infections, obesity and diet-induced obesity, adiposity, metabolic disorders, hepatic steatosis and uterine fibroids (uterine leiomyoma or uterine myoma) in women, chronic renal disorders, acute and chronic renal insufficiency, diabetic, inflammatory or hypertensive nephropaties, cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischemias, vascular disorders, thromboembolic disorders, arteriosclerosis, sickle cell anemia, erectile dysfunction, benign prostate hyperplasia, dysuria associated with benign prostate hyperplasia, Huntington, dementia, Alzheimer, and Creutzfeld-Jakob.
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 for 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 treating a cancer or a 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 proliferation, tissue invasion, metastasis and angiogenesis of cancer cells in a subject having a cancer, a cancerous condition, or a tumor.
In some embodiment, the pharmaceutical composition of the present invention may be for use in inhibiting proliferation, tissue invasion, metastasis and angiogenesis of cancer cells in a subject having a cancer, a cancerous condition, or a tumor.
Pharmaceutical formulations described herein are administrable to a subject in a variety of by multiple administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular, rectal, enfometrial or cerebrovascular injection), intranasal, buccal, topical or transdermal administration routes.
In some embodiments, the　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, e.g., in a patient suffering from cancer or an infection (e.g., a viral, bacterial, or parasitic infection). The method includes administering to the patient a therapeutically effective amount of one or a combination of the compounds described herein. In some embodiments, the patient has an increased count of white blood cells, T and/or B lymphocytes, macrophases, dendritic cells, neutrophils, natural killer (NK) cells, and/or platelets after the administering step. In some embodiments, the compound decreases IL-21 level in the patient. The patient may have cancer, or may be immune-compromised.
“Treat”, “treating” and “treatment” refer to a method of alleviating or abrogating a biological disorder and/or at least one of its attendant symptoms. As used herein, to “alleviate” a disease, disorder or condition means reducing the severity and/or occurrence frequency of the symptoms of the disease, disorder, or condition. Further, references herein to “treatment” include references to curative, palliative and prophylactic treatment. Treatment of cancer encompasses inhibiting cancer growth (including causing partial or complete cancer regression), inhibiting cancer progression or metastasis, preventing cancer recurrence or residual disease, and/or prolonging the patient's survival. “A therapeutically effective amount” is an amount of the medication that can achieve the desired curative, palliative, or prophylactic effect for the treated condition.
In some embodiments, the effective dose range of a compound is determined by measuring the patient's blood concentration of the compound under a specified dosing regimen to establish a concentration-time profile, consulting with an established correlation between the concentration-time profiles and effects on cancer inhibition or eradication obtained during a trial, and balancing the therapeutic effects achievable with possible toxicity to the patient, with further consideration of the health condition or physical durability of the patient. The dosing frequency of the compound may be determined similarly. The dosing may be continued until the patiunlessent is free from the cancer.
In some embodiments, an effective amount for tumor therapy may be measured by its ability to stabilize disease progression and/or ameliorate symptoms in a patient, and preferably to reverse disease progression, e.g., by reducing tumor size. In some embodiments, a maintenance dosing may be provided after the patient is free of cancer to ensure its complete elimination or eradication, or prevention of residual disease. The duration of the maintenance dosing can be determined based on clinical trial data.
In some embodiments, a compound may be administered in combination with one or more other cancer therapeutic agents that also target AhR or target molecules other than AhR. Compounds can be formulated either separately from, or together with, the other cancer therapeutic agents. Compounds can be administered either at the same schedule as, or at a different schedule from, the other cancer therapeutic agents. The proportion of a compound relative to other cancer therapeutic agents may be determined by clinical trials. Combining the compounds with the other cancer therapeutic agents may further enhance the efficacy of one another. For example, a compound of the present invention can be administered with an immune checkpoint inhibitor, such as an inhibitor of PD-1, PD-L1 or PD-L2 (e.g., pembrolizumab, nivolumab, or atezolizumab), or administered with CAR-T therapy (e.g., axicabtagene ciloleucel), to achieve additive or synergistic anti-cancer effect.
Dosage regimens may be adjusted to provide the optimum desired response. Dosage unit form, as used herein, refers to physically discrete units suited as unitary dosages for the patients/subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the embodied composition. Further, the dosage regimen with the compositions of this invention may be based on a variety of factors, including the type of disease, the age, weight, sex, medical condition of the patient, the severity of the condition, the route of administration, and the particular antibody employed. Thus, the dosage regimen can vary widely, but can be determined routinely using standard methods. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and/or laboratory values.
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 about 20 mg/kg body weight per day, such as about 0.5-50 mg/kg, e.g., about 1-20 mg/kg. The compound may for example be administered in a dosage of at least 0.25 mg/kg, e.g., at least 0.5 mg/kg, such as at least 1 mg/kg, e.g., at least 1.5 mg/kg, such as at least 2 mg/kg, e.g., at least 3 mg/kg, such as at least 4 mg/kg, e.g., at least 5 mg/kg; and e.g., up to at most 50 mg/kg, such as up to at the most 30 mg/kg, e.g., up to at the most 20 mg/kg, such as up to at the most 15 mg/kg. Administration will normally be repeated at suitable intervals, e.g., twice a day, thrice a day, once a day, once every week, once every two weeks, or once every three weeks, and for as long as deemed appropriate by the responsible doctor, who may optionally increase or decrease the dosage as necessary.
General Synthetic Methods
The compounds of Formlua (I) of the presnet invention can be prepared in accordance with one or more of schemes discussed below.
These methods can be used either directly or with obvious variations to trained chemists to prepare key intermediates and certain compounds of this invention.
Suitable synthetic sequences are readily selected per specific structures of this invention, but within the art known to individuals practicing organic synthesis, such as methods summarized in available chemistry data bases, as in CAS Scifinder and Elesevier Reaxys. Based on these general methods, the enablement for making the compounds of this invention is straightforward and can be practiced within a common professional knowledge. Some general synthetic methods to prepare the compounds of this invention are illustrated below in Schemes 1-5(general procedure A~E).
One general approach to the compounds of this invention is illustrated in general Scheme 1.
Figure PCTKR2021003883-appb-I000003
Scheme 1. General procedure A.
a) 1. CH3ONa, MeOH, 2. ammonia solution in MeOH; b) Diethyl malonate, CH3ONa, MeOH; c) POCl3; d) Ar2-B(OH)2 or its pinacol ester, Pd(PPh3)4, Na2CO3, THF/H2O (4/1) heat, microwave; e) RNH2 or (R)2NH(primary or secondary amine), TEA, THF, heat; f) Hydrochloric acid in ethanol, Ammonium acetate 1M solution.
* R1s mean boc-deprotected forms of R moieties.
Another general approach to the compounds of this invention is illustrated in general Scheme 2.
Figure PCTKR2021003883-appb-I000004
Scheme 2. General procedure B.
a) 1. HCl, MeOH, 2. ammonia solution in MeOH; b) NaH, THF, reflux; c) CH3ONa, MeOH heat; d) POCl3, heat; e) RNH2 or (R)2NH(primary or secondary amine), TEA, THF, heat; f) Hydrochloric acid in ethanol, Ammonium acetate 1M solution.
* R1s mean boc-deprotected forms of R moieties.
Another general approach to the compounds of this invention is illustrated in general Scheme 3.
Figure PCTKR2021003883-appb-I000005
Scheme 3. General procedure C.
a) Ar2-B(OH)2 or its pinacol ester, Pd(PPh3)4, Na2CO3, THF/H2O(4/1) heat, microwave; b) RNH2 or (R)2NH(primary or secondary amine), TEA, THF, heat; c) Ar1-B(OH)2 or its pinacol ester, Pd(PPh3)4, Na2CO3, THF/H2O(4/1) heat, microwave; d) Hydrochloric acid in ethanol, Ammonium acetate 1M solution.
* R1s mean boc-deprotected forms of R moieties.
Another general approach to the compounds of this invention is illustrated in general Scheme 4.
Figure PCTKR2021003883-appb-I000006
Scheme 4. General procedure D.
a) 1. CH3ONa, MeOH, 2. ammonia solution in MeOH; b) Diethyl malonate, CH3ONa, MeOH; c) POCl3; d) RNH2 or (R)2NH(primary or secondary amine), TEA, THF, heat; e) Ar2-B(OH)2 or its pinacol ester, Pd(PPh3)4, Na2CO3, THF/H2O (4/1) heat, microwave; f) Hydrochloric acid in ethanol, Ammonium acetate 1M solution.
* R1s mean boc-deprotected forms of R moieties.
Another general approach to the compounds of this invention is illustrated in general Scheme 5.
Figure PCTKR2021003883-appb-I000007
Scheme 5. General procedure E.
a) RNH2 or (R)2NH(primary or secondary amine), TEA, THF, heat; b) Ar2-B(OH)2 or its pinacol ester, Pd(PPh3)4, Na2CO3, THF/H2O (4/1) heat, microwave; c) Ar1-B(OH)2 or its pinacol ester, Pd(PPh3)4, Na2CO3, THF/H2O (4/1) heat, microwave.
* R1s mean boc-deprotected forms of R moieties.
 Examples
Embodiments of the present invention are described in the following examples, which are meant to illustrate and not limit the scope of this invention. Common abbreviations well known to those with ordinary skills in the synthetic art used throughout.
All chemical reagents were commercially available. Flash column chromatography means silica gel chromatography unless specified otherwise, which was performed on Teledyne Combiflash-RF200 System. 1H NMR spectra (δ, ppm) are recorded on 400 MHz or 600 MHz instrument. Mass spectroscopy data for a positive ionization method are provided. Preparative HPLC was performed on Agilent technologies G1361A and Gilson Preparative HPLC　System.
Example 1. (R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)butan-1-ol
Scheme for the preparation of the Compound of Example 1:
Figure PCTKR2021003883-appb-I000008
Intermediate 1. Nicotinimidamide hydrochloride
To a suspension of 3-Cyanopyridine (5 g, 48.03 mmol) in 50 mL of MeOH was added Sodium methoxide 30 wt % in MeOH (4 mL) and the mixture was stirred at room temperature for 24 hr. After adding NH4C1 (16.5 g, 0.31 mol), the mixture was heated at 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 reflux for 30min. After the reaction mixture was cooled to room temperature, solids were filtered off and the filtrate was concentrated in vacuo. The suspension of reaction mixture in 3 mL of EtOH was filtered and the solid product was dried to afford 4.9 g of the title compound.
1H NMR (400 MHz, DMSO-d6) δ [ppm] = 9.43 (bs, 4H), 8.98 (d, J = 1.6 Hz, 1H), 8.74 (dd, J = 4.8 Hz, J = 1.2 Hz, 1H), 8.20-8.23 (m, 1H), 7.64-7.67 (m, 1H); MS (ESI, m/z): 122.1 [M+H]+
Intermediate 2. 2-Pyridin-3-yl-pyrimidine-4,6-diol
; To a solution of 3-pyridyl amidine 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 sodium methoxide 30 wt % 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 (crude 5.0 g of previous step) in POCl3 (10 mL) was added dimethylamino aniline (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 silicagel 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 (br, 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-yl-pyrimidine (1.03 g, 4.6 mmol), (4-chlorophenyl)boronic acid (0.66 g, 4.2 mmol) and sodium carbonate (1.01 g, 9.5 mmol) in 50 mL of tetrahydrofuran/H2O (4/1) was added Pd(PPh3)4 (203 mg, 0.18 mmol). The mixture is heated under microwave at 80 ℃ for 20 minutes, 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 silicagel column chromatography to give 1.02 g of the title compound.
1H NMR (600 MHz, CDCl3) δ [ppm] = 7.52 (d, 2H), 7.74 (s, 1H), 7.79 (dd, 1H), 8.06 (d, 2H), 9.02 (d, 1H), 9.12 (d, 1H), 10.16 (s, 1H); MS (ESI, m/z): 302.0 [M+H]+
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 in sealed tube was heated at 120 0C for 4 h. 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.
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.05 (t, 3H), 1.59-1.64 (m, 1H), 1.83-1.86 (m, 1H), 3.70 (d, 2H), 4.39 (br, 1H), 6.96 (s, 1H), 7.50 (d, 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 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 the preparation of the Compound of Example 2 and 3:
Figure PCTKR2021003883-appb-I000009
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 is heated to 80 ℃ for overnight, cooled to room temperature and extracted three times with EtOAc (150 mL) two times. The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography(silica gel, hexane/ethyl acetate, gradient) to give 510.0 mg of the title compound.
1H NMR (600 MHz, CDCl3) δ [ppm] = 7.52 (d, 2H), 7.67 (s, 1H), 8.05 (d, 2H); MS (ESI, m/z): 258.0 [M+H]+
Intermediate 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 RT for overnight. The reaction mixture was filtered, evaporated in vacuo and isolated by flash chromatography(silica gel, hexane/ethyl acetate, gradient) to give 54.0 mg and 30.1 mg of the intermediate 6 and 7 respectively.
intermediate 6
1H NMR (600 MHz, CDCl3) δ [ppm] = 1.28 (d, 3H), 3.61-3.65 (m, 1H), 3.78-3.81 (m, 1H), 4.15 (br, 1H), 5.48 (br, 1H), 6.59 (s, 1H), 7.41 (d, 2H), 7.86 (d, 2H); MS (ESI, m/z): 298.0 [M+H]+
intermediate 7
1H NMR (600 MHz, CDCl3) δ [ppm] = 1.28 (d, 3H), 3.61-3.66 (m, 1H), 3.79-3.83 (m, 1H), 4.27 (br, 1H), 5.58 (br, 1H), 6.93 (s, 1H), 7.42 (d, 2H), 7.88 (d, 2H); MS (ESI, m/z): 298.0 [M+H]+
Example 2. (S)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propan-1-ol
To a solution (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/H2O (4/1) was added Pd(PPh3)4 (80 mg, 0.069 mmol). The mixture is heated under microwave at 130 ℃ for 15 minutes, cooled to room temperature and extracted three times with EtOAc (30 mL). The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography(silica gel, hexane/ethyl acetate, gradient) to give 32 mg of the title compound (Scheme 3. General procedure C.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 1.25 (d, 3H), 3.56-3.59 (m, 1H), 3.63-3.66 (m, 1H), 4.35 (br, 1H), 6.73 (s, 1H), 7.36 (d, 2H), 7.45-7.49 (m, 1H), 7.98 (d, 2H), 8.56 (br, 1H), 8.71 (d, 1H), 9.48 (br, 1H); MS (ESI, m/z): 341.1 [M+H]+
Example 3. (S)-2-((4-(4-chlorophenyl)-6-(pyridin-3-yl)pyrimidin-2-yl)amino)propan-1-ol
To a solution (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/H2O (4/1) was added Pd(PPh3)4 (34 mg, 0.029 mmol). The mixture is heated under microwave at 130 ℃ for 15 minutes, cooled to room temperature and extracted three times with EtOAc (30 mL). The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, hexane/ethyl acetate, gradient) to give 17.6 mg of the title compound (Scheme 3. General procedure C.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 1.34 (d, 3H), 3.64-3.66 (m, 1H), 3.73-3.76 (m, 1H), 4.33-4.36 (m, 1H), 7.49 (d, 2H), 7.57-7.59 (m, 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 obtained as described for the example 2 (Scheme 3. General procedure C.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 1.53 (s, 6H), 3.91 (s, 2H), 7.01 (s, 1H), 7.53 (d, 2H), 8.11 (d, 2H), 8.05-8.15 (m, 1H), 8.90 (br, 1H), 9.33 (d, 1H), 9.68 (br, 1H); MS (ESI, m/z): 355.1 [M+H]+
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 obtained as described for the example 3 (Scheme 3. General procedure C.).
1H NMR (600 MHz, CDCl3) δ [ppm] = 1.55 (s, 6H), 3.84 (s, 2H), 7.12 (d, 1H), 7.40 (s, 1H), 7.44-7.48 (m, 1H), 7.54 (d, 2H), 7.98 (d, 2H), 8.03 (d, 1H), 8.82 (br, 1H); MS (ESI, m/z): 355.1 [M+H]+
Example 6. 2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)ethan-1-ol
Using 2-aminoethan-1-ol, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 3.80 (t, 2H), 4.10 (t, 2H), 6.84 (s, 1H), 7.45 (d, 2H), 7.50-7.52 (m, 1H), 8.07 (d, 2H), 8.59 (d, 1H), 8.79 (d, 1H), 9.52 (s, 1H); MS (ESI, m/z): 327.1 [M+H]+
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 obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 1.91-1.94 (m, 2H), 3.72 (t, 2H), 4.10 (t, 2H), 6.89 (s, 1H), 7.82 (d, 2H), 7.56-7.58 (m, 1H), 8.15 (d, 2H), 8.63 (d, 1H), 8.87 (d, 1H), 9.58 (s, 1H); MS (ESI, m/z): 341.1 [M+H]+
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 obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CDCl3) δ [ppm] = 1.31 (d, 3H), 3.41 (br, 1H), 3.70 (br, 1H), 4.12-4.15 (m, 1H), 5.63 (br, 1H), 6.65 (s, 1H), 7.43 (d, 2H), 7.39-7.45 (m, 1H), 8.00 (d, 2H), 8.66 (br, 1H), 8.72 (d, 1H), 9.64 (br, 1H); MS (ESI, m/z): 341.1 [M+H]+
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 obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CDCl3) δ [ppm] = 1.31 (d, 3H), 3.41 (br, 1H), 3.70 (br, 1H), 4.12-4.15 (m, 1H), 5.63 (br, 1H), 6.65 (s, 1H), 7.43 (d, 2H), 7.39-7.45 (m, 1H), 8.00 (d, 2H), 8.66 (br, 1H), 8.72 (d, 1H), 9.64 (br, 1H); MS (ESI, m/z): 341.1 [M+H]+
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 obtained as described for the 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.)
1H NMR (600 MHz, CD3OD) δ [ppm] = 1.31 (d, 3H), 3.61-3.64 (m, 1H), 3.67-3.70 (m, 1H), 4.50 (br, 1H), 6.95 (s, 1H), 7.52 (d, 2H), 8.01-8.19 (m, 1H), 8.12 (d, 2H), 8.85 (br, 1H), 9.38 (d, 1H), 9.71 (br, 1H); MS (ESI, m/z): 341.1 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 1.06 (d, 3H), 1.09 (d, 3H), 2.10 (br, 1H), 3.73-3.76 (m, 1H), 3.80-3.83 (m, 1H), 4.41 (br, 1H), 7.02 (s, 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 1.06 (d, 3H), 1.09 (d, 3H), 2.10 (br, 1H), 3.73-3.76 (m, 1H), 3.80-3.83 (m, 1H), 4.41 (br, 1H), 7.02 (s, 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 1.06 (d, 3H), 1.09 (d, 3H), 2.10 (br, 1H), 3.73-3.76 (m, 1H), 3.80-3.83 (m, 1H), 4.41 (br, 1H), 7.02 (s, 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.05 (t, 3H), 1.59-1.64 (m, 1H), 1.83-1.86 (m, 1H), 3.70 (d, 2H), 4.39 (br, 1H), 6.96 (s, 1H), 7.50 (d, 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 3.81 (d, 4H), 4.54 (br, 1H), 7.02 (s, 1H), 7.51 (d, 2H), 8.06 (br, 1H), 8.13 (d, 2H), 8.87 (br, 1H), 9.43 (d, 1H), 9.70 (br, 1H); MS (ESI, m/z): 357.1 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 3.77 (br, 1H), 3.91 (br, 1H), 4.95 (br, 1H), 6.95 (s, 1H), 7.25 (t, 1H), 7.35 (t, 2H), 7.47 (d, 2H), 7.53 (d, 2H), 8.00 (br, 1H), 8.13 (d, 2H), 8.86 (br, 1H), 9.28 (d, 1H), 9.68 (br, 1H); MS (ESI, m/z): 403.1 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 3.77 (br, 1H), 3.91 (br, 1H), 4.95 (br, 1H), 6.95 (s, 1H), 7.25 (t, 1H), 7.35 (t, 2H), 7.47 (d, 2H), 7.53 (d, 2H), 8.00 (br, 1H), 8.13 (d, 2H), 8.86 (br, 1H), 9.28 (d, 1H), 9.68 (br, 1H); MS (ESI, m/z): 403.1 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 1.38-1.45 (m, 2H), 1.77 (d, 2H), 1.95-2.02 (m, 1H), 3.44 (t, 2H), 3.54 (br, 2H), 3.98 (d, 2H), 6.95 (s, 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. N1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-N3,N3-dimethylpropane-1,3-diamine
Using N1,N1-dimethylpropane-1,3-diamine and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 2.14-2.21 (m, 2H), 2.93 (s, 6H), 3.04-3.06 (m, 1H), 3.23-3.26 (m, 1H), 3.74 (br, 2H), 7.02 (s, 1H), 7.56 (d, 2H), 8.08 (br, 1H), 8.19 (d, 2H), 8.90 (br, 1H), 9.44 (d, 1H), 9.77 (br, 1H); MS (ESI, m/z): 368.2 [M+H]+
Example 21. 6-(4-chlorophenyl)-N-ethyl-2-(pyridin-3-yl)pyrimidin-4-amine
Using ethanamine and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR: (400 MHz, CD3OD) δ [ppm] = 1.32 (t, 3H), 3.60 (br, 2H), 6.91 (s, 1H), 7.53 (d, 2H), 7.97 (br, 1H), 8.14 (d, 2H), 8.85 (br, 1H), 9.27 (d, 1H), 9.71 (br, 1H); MS (ESI, m/z): 311.1 [M+H]+
Example 22. 6-(4-chlorophenyl)-N-propyl-2-(pyridin-3-yl)pyrimidin-4-amine
Using propan-1-amine and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.05 (t, 3H), 1.74 (q, 2H), 3.56 (br, 2H), 6.93 (s, 1H), 7.53 (d, 2H), 8.01 (br, 1H), 8.13 (d, 2H), 8.84 (br, 1H), 9.32 (d, 1H), 9.69 (br, 1H); MS (ESI, m/z): 325.1 [M+H]+
Example 23. N-butyl-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-amine
Using butan-1-amine and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.01 (t, 3H), 1.45-1.54 (m, 2H), 1.66-1.73 (m, 2H), 3.58 (br, 2H), 6.89 (s, 1H), 7.52 (d, 2H), 7.90 (br, 1H), 8.12 (d, 2H), 8.84 (br, 1H), 9.18 (d, 1H), 9.69 (br, 1H); MS (ESI, m/z): 339.1 [M+H]+
Example 24. 1-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)butan-2-ol
Using 1-aminobutan-2-ol and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.01 (t, 3H), 1.45-1.54 (m, 2H), 1.66-1.73 (m, 2H), 3.58 (br, 2H), 6.89 (s, 1H), 7.52 (d, 2H), 7.90 (br, 1H), 8.12 (d, 2H), 8.84 (br, 1H), 9.18 (d, 1H), 9.69 (br, 1H); MS (ESI, m/z): 355.1 [M+H]+
Example 25. 6-(4-chlorophenyl)-N-(cyclopropylmethyl)-2-(pyridin-3-yl)pyrimidin-4-amine
Using cyclopropylmethanamine and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 0.32-0.36 (m, 2H), 0.57-0.61 (m, 2H), 1.14-1.26 (m, 1H), 3.46 (br, 2H), 6.93 (s, 1H), 7.53 (d, 2H), 8.05 (br, 1H), 8.13 (d, 2H), 8.97 (br, 1H), 9.29 (d, 1H), 9.82 (br, 1H); MS (ESI, m/z): 337.1 [M+H]+
Example 26. 6-(4-chlorophenyl)-N-cyclopentyl-2-(pyridin-3-yl)pyrimidin-4-amine
Using cyclopentanamine and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.59-1.69 (m, 2H), 1.70-1.77 (m, 2H), 1.79-1.89 (m, 2H), 2.12-2.20 (m, 2H), 4.59 (br, 1H), 6.93 (s, 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.02 (d, 3H), 1.18-1.31 (m, 2H), 1.74-1.92 (m, 3H), 3.09 (t, 2H), 3.33-3.38 (m, 2H), 7.23 (s, 1H), 7.53 (d, 2H), 8.09 (br, 1H), 8.20 (d, 2H), 8.94 (br, 1H), 9.38 (d, 1H), 9.76 (br, 1H); MS (ESI, m/z): 365.2 [M+H]+
Example 28. N-(tert-butyl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-amine
Using 2-methylpropan-2-amine and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 4.64 (s, 9H), 7.63 (d, 2H), 7.66 (br, 1H), 8.10 (s, 1H), 8.36 (d, 2H), 8.75 (br, 1H), 8.94 (d, 1H), 9.67 (br, 1H); MS (ESI, m/z): 339.1 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.61-1.75 (m, 2H), 1.79-1.96 (m, 2H), 1.98-2.07 (m, 1H), 2.27-2.35 (m, 1H), 4.16 (br, 1H), 4.44 (br, 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 1.67-1.82 (m, 3H), 1.91-1.97 (m, 1H), 2.00-2.07 (m, 1H), 2.13 (br, 1H), 4.37 (br, 1H), 4.49 (br, 1H), 7.04 (s, 1H), 7.53 (d, 2H), 7.70 (br, 3H), 8.86 (br, 1H), 9.35 (d, 1H), 9.67 (br, 1H); MS (ESI, m/z): 367.1 [M+H]+
Example 31. 6-(4-chlorophenyl)-N-(pyridin-2-ylmethyl)-2-(pyridin-3-yl)pyrimidin-4-amine
Using pyridin-2-ylmethanamine and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 5.16 (s, 2H), 7.24 (s, 1H), 7.54 (d, 2H), 7.88 (t, 1H), 8.07-8.11 (m, 2H), 8.20 (d, 2H), 8.49 (t, 1H), 8.76 (d, 1H), 8.88 (d, 1H), 9.32 (d, 1H), 9.57 (s, 1H); MS (ESI, m/z): 374.1 [M+H]+
Example 32. 6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(pyridin-3-ylmethyl)pyrimidin-4-amine
Using pyridin-3-ylmethanamine and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 5.04 (s, 2H), 7.15 (s, 1H), 7.53 (d, 2H), 8.06 (br, 1H), 8.14 (br, 1H), 8.19 (d, 2H), 8.67 (d, 1H), 8.79 (br, 1H), 8.97 (br, 2H), 9.43 (d, 1H), 9.71 (s, 1H); MS (ESI, m/z): 374.1 [M+H]+
Example 33. 6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(pyridin-4-ylmethyl)pyrimidin-4-amine
Using pyridin-4-ylmethanamine and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 5.12 (s, 2H), 7.23 (s, 1H), 7.55 (d, 2H), 8.09 (br, 1H), 8.13 (d, 2H), 8.21 (d, 2H), 8.79 (d, 2H), 8.88 (br, 1H), 9.34 (d, 1H), 9.59 (s, 1H); MS (ESI, m/z): 374.1 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 1.39-1.46 (m, 2H), 1.48-1.54 (m, 2H), 2.02-2.07 (m, 2H), 2.14-2.19 (m, 2H), 3.62-3.67 (m, 1H), 4.14 (br, 1H), 6.90 (s, 1H), 7.53 (d, 2H), 7.99 (br, 1H), 8.13 (d, 2H), 8.83 (br, 1H), 9.28 (d, 1H), 9.66 (br, 1H); MS (ESI, m/z): 381.1 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 1.34-1.52 (m, 4H), 1.77-1.84 (m, 2H), 2.08-2.16 (m, 2H), 3.55 (br, 1H), 4.19 (br, 1H), 6.95 (s, 1H), 7.53 (d, 2H), 8.08 (br, 1H), 8.12 (d, 2H), 8.89 (br, 1H), 9.37 (d, 1H), 9.67 (br, 1H); MS (ESI, m/z): 381.1 [M+H]+
Example 36. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-2-yl)methanol
Using piperidin-2-ylmethanol and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.54-1.66 (m, 1H), 1.67-1.81 (m, 3H), 1.84-1.92 (m, 1H), 1.98-2.05 (m, 1H), 3.11-3.21 (m, 1H), 3.79-3.91 (m, 2H), 4.21-4.40 (m, 1H), 4.70 (br, 1H), 7.26 (s, 1H), 7.53 (d, 2H), 8.12 (br, 1H), 8.19 (d, 2H), 8.92 (br, 1H), 9.45 (d, 1H), 9.73 (br, 1H); MS (ESI, m/z): 381.1 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.29-1.35 (m, 2H), 1.53-1.65 (m, 1H), 1.70-1.76 (m, 1H), 1.78-1.90 (m, 4H), 1.90-1.97 (m, 1H), 2.07-2.16 (m, 1H), 3.10-3.20 (m, 1H), 3.57-3.69 (m, 2H), 7.31 (s, 1H), 7.54 (d, 2H), 8.03 (br, 1H), 8.20 (d, 2H), 8.87 (br, 1H), 9.37 (d, 1H), 9.71 (br, 1H); MS (ESI, m/z): 395.2 [M+H]+
Example 38. (R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-ol
Using (R)-piperidin-3-ol and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.56-1.73 (m, 2H), 1.90-1.99 (m, 1H), 2.02-2.09 (m, 1H), 4.47 (dd, 1H), 3.63 (br, 1H), 3.77-3.82 (m, 1H), 4.04 (br, 1H), 4.29 (br, 1H), 7.21 (s, 1H), 7.50 (d, 2H), 8.13 (br, 1H), 8.17 (d, 2H), 8.95 (br, 1H), 9.43 (d, 1H), 9.73 (br, 1H); MS (ESI, m/z): 367.1 [M+H]+
Example 39. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-ol
Using piperidin-3-ol and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.56-1.73 (m, 2H), 1.90-1.99 (m, 1H), 2.02-2.09 (m, 1H), 4.47 (dd, 1H), 3.63 (br, 1H), 3.77-3.82 (m, 1H), 4.04 (br, 1H), 4.29 (br, 1H), 7.21 (s, 1H), 7.50 (d, 2H), 8.13 (br, 1H), 8.17 (d, 2H), 8.95 (br, 1H), 9.43 (d, 1H), 9.73 (br, 1H); MS (ESI, m/z): 367.1 [M+H]+
Example 40. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanol
Using piperidin-3-ylmethanol and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.35-1.46 (m, 1H), 1.56-1.68 (m, 1H), 1.78-1.95 (m, 4H), 3.02 (dd, 1H), 3.23 (dd, 1H), 3.63 (br, 1H), 3.38-3.46 (m, 1H), 3.47-3.61 (m, 2H), 7.24 (s, 1H), 7.52 (d, 2H), 8.10 (dd, 1H), 8.19 (d, 2H), 8.89 (br, 1H), 9.45 (d, 1H), 9.71 (br, 1H); MS (ESI, m/z): 381.1 [M+H]+
Example 41. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-ol
Using piperidin-4-ol and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.54-1.62 (m, 2H), 1.96-2.03 (m, 2H), 3.46-3.53 (m, 2H), 3.93-3.99 (m, 2H), 4.36 (br, 2H), 7.23 (s, 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.24-1.34 (m, 2H), 1.82-1.94 (m, 3H), 3.08 (t, 2H), 3.47 (d, 2H), 4.77 (br, 2H), 7.21 (s, 1H), 7.50 (d, 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.22-1.32 (m, 2H), 1.51-1.56 (m, 2H), 1.81-1.93 (m, 3H), 3.07 (t, 2H), 3.67 (t, 2H), 4.72 (br, 2H), 7.20 (s, 1H), 7.51 (d, 2H), 8.10 (br, 1H), 8.17 (d, 2H), 8.89 (br, 1H), 9.41 (d, 1H), 9.68 (br, 1H); MS (ESI, m/z): 395.2 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.18-1.29 (m, 2H), 1.34-1.39 (m, 2H), 1.58-1.73 (m, 3H), 1.93 (d, 2H), 3.07 (t, 2H), 3.57 (t, 2H), 4.75 (br, 2H), 7.22 (s, 1H), 7.52 (d, 2H), 8.11 (br, 1H), 8.18 (d, 2H), 8.90 (br, 1H), 9.42 (d, 1H), 9.70 (br, 1H); MS (ESI, m/z): 409.2 [M+H]+
Example 45. 4-(4-chlorophenyl)-6-(4-methoxypiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine
Using 4-methoxypiperidine and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.60-1.68 (m, 2H), 1.98-2.05 (m, 2H), 3.42 (s, 3H), 3.57-3.65 (m, 3H), 4.21 (br, 2H), 7.22 (s, 1H), 7.50 (d, 2H), 8.09 (br, 1H), 8.18 (d, 2H), 8.89 (br, 1H), 9.41 (d, 1H), 9.69 (br, 1H); MS (ESI, m/z): 381.1 [M+H]+
Example 46. 4-(4-chlorophenyl)-6-(piperidin-1-yl)-2-(pyridin-3-yl)pyrimidine
Using piperidine and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.71 (br, 4H), 1.78 (br, 2H), 3.90 (br, 4H), 7.21 (s, 1H), 7.53 (d, 2H), 8.03 (br, 1H), 8.19 (d, 2H), 8.88 (br, 1H), 9.33 (d, 1H), 9.69 (br, 1H); MS (ESI, m/z): 351.1 [M+H]+
Example 47. 4-(4-chlorophenyl)-6-(2-methylpiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine
Using 2-methylpiperidine and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.33 (d, 3H), 1.53-1.63 (m, 1H), 1.70-1.91 (m, 5H), 3.14-3.21 (m, 1H), 4.60 (br, 1H), 5.06 (br, 1H), 7.20 (s, 1H), 7.53 (d, 2H), 8.13 (br, 1H), 8.19 (d, 2H), 8.96 (br, 1H), 9.39 (d, 1H), 9.75 (br, 1H); MS (ESI, m/z): 365.2 [M+H]+
Example 48. 4-(4-chlorophenyl)-6-(3-methylpiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine
Using 3-methylpiperidine and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.04 (d, 3H), 1.28-1.35 (m, 1H), 1.56-1.76 (m, 2H), 1.83-1.96 (m, 2H), 2.81 (dd, 1H), 3.12 (dd, 1H), 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 (br, 1H), 9.75 (br, 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 0.94 (q, 1H), 1.03 (d, 6H), 1.59-1.73 (m, 3H), 1.91 (d, 1H), 2.51 (t, 2H), 4.68 (br, 1H), 7.21 (s, 1H), 7.51 (d, 2H), 8.11 (br, 1H), 8.18 (d, 2H), 8.94 (br, 1H), 9.39 (d, 1H), 9.73 (br, 1H); MS (ESI, m/z): 379.2 [M+H]+
Example 51. 4-(4-chlorophenyl)-6-(3,3-difluoropiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine
Using 3,3-difluoropiperidine and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.87-1.93 (m, 2H), 2.14-2.24 (m, 2H), 3.92 (br, 2H), 4.23 (t, 2H), 7.32 (s, 1H), 7.51 (d, 2H), 8.06 (br, 1H), 8.23 (d, 2H), 8.87 (br, 1H), 9.40 (d, 1H), 9.72 (br, 1H); MS (ESI, m/z): 387.1 [M+H]+
Example 52. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(3-(trifluoromethyl)piperidin-1-yl)pyrimidine
Using 3-(trifluoromethyl)piperidine and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.59-1.82 (m, 2H), 1.94-1.97 (m, 1H), 2.12-2.15 (m, 1H), 2.44-2.56 (m, 1H), 3.19-3.27 (m, 2H), 4.48 (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 (br, 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 separation method of PREP. HPLC, the title compound was obtained as described for the 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 in sealed tube was heated at 120 ℃ for 4 h. and cooled to room temperature. The residue was filtered, evaporated in vacuo. To a solution of the reaction mixture in ethanol(1 mL) was added 1M hydrochloric acid ethanol solution (2 mL). The reaction mixture was stirred at 50 ℃ for overnight, evaporated in vacuo and quenched with 1M ammonium acetate methanol solution (2mL). The residue was filtered and purified by Preparative HPLC to give 7.6 mg of the title compound (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.81-1.92 (m, 2H), 2.37 (d, 2H), 3.26 (d, 2H), 3.52 (d, 2H), 4.47 (br, 1H), 7.00 (s, 1H), 7.54 (d, 2H), 8.07 (br, 1H), 8.16 (d, 2H), 8.88 (br, 1H), 9.43 (d, 1H), 9.76 (br, 1H); MS (ESI, m/z): 366.1 [M+H]+
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 obtained as described for the example 54 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.39-1.48 (m, 1H), 1.70-1.82 (m, 1H), 2.02 (t, 2H), 2.26 (br, 1H), 2.83 (t, 1H), 2.94 (t, 1H), 3.37 (d, 1H), 3.50 (d, 1H), 3.62 (br, 2H), 6.99 (s, 1H), 7.53 (d, 2H), 8.06 (br, 1H), 8.16 (d, 2H), 8.88 (br, 1H), 9.41 (d, 1H), 9.75 (br, 1H); MS (ESI, m/z): 380.2 [M+H]+
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 obtained as described for the example 54 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.29-1.40 (m, 1H), 1.45-1.55 (m, 1H), 2.01 (t, 4H), 2.91 (d, 2H), 2.98-3.14 (m, 2H), 3.45 (d, 1H), 7.26 (s, 1H), 7.52 (d, 2H), 8.10 (br, 1H), 8.21 (d, 2H), 8.89 (br, 1H), 9.42 (d, 1H), 9.72 (br, 1H); MS (ESI, m/z): 380.2 [M+H]+
Example 57. 6-(4-chlorophenyl)-N-(1-methylpiperidin-4-yl)-2-(pyridin-3-yl)pyrimidin-4-amine
Using 1-methylpiperidin-4-amine and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.83-2.04 (m, 2H), 2.18-2.29 (m, 2H), 2.89 (s, 3H), 3.10-3.24 (m, 2H), 3.42-3.54 (m, 2H), 3.63 (br, 1H), 6.97 (s, 1H), 7.53 (d, 2H), 8.06 (br, 1H), 8.15 (d, 2H), 8.88 (br, 1H), 9.42 (d, 1H), 9.75 (br, 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 obtained as described for the example 54 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.42-1.52 (m, 2H), 1.70-1.86 (m, 3H), 2.07 (d, 2H), 2.98 (t, 2H), 3.40 (d, 2H), 3.68 (br, 2H), 6.94 (s, 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 obtained as described for the example 54 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.63 (br, 2H), 1.76-1.91 (m, 5H), 3.24-3.33 (m, 2H), 3.61 (t, 2H), 4.47 (br, 1H), 5.50 (br, 1H), 7.37 (s, 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 obtained as described for the example 54 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.72-1.88 (m, 2H), 1.93-1.99 (m, 1H), 2.19-2.26 (m, 1H), 3.40-3.46 (m, 1H), 3.51-3.57 (m, 1H), 3.62-3.67 (m, 1H), 4.18 (d, 1H), 4.71 (d, 1H), 7.33 (s, 1H), 7.51 (d, 2H), 8.05 (br, 1H), 8.25 (d, 2H), 8.89 (br, 1H), 9.42 (d, 1H), 9.80 (br, 1H); MS (ESI, m/z): 366.1 [M+H]+
Example 61. (S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-amine
Using tert-butyl (S)-piperidin-3-ylcarbamate, the title compound was obtained as described for the example 54 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.72-1.88 (m, 2H), 1.93-1.99 (m, 1H), 2.19-2.26 (m, 1H), 3.40-3.46 (m, 1H), 3.51-3.57 (m, 1H), 3.62-3.67 (m, 1H), 4.18 (d, 1H), 4.71 (d, 1H), 7.33 (s, 1H), 7.51 (d, 2H), 8.05 (br, 1H), 8.25 (d, 2H), 8.89 (br, 1H), 9.42 (d, 1H), 9.80 (br, 1H); MS (ESI, m/z): 366.1 [M+H]+
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 obtained as described for the example 54 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.44-1.53 (m, 1H), 1.61-1.71 (m, 1H), 1.91-2.07 (m, 3H), 2.92-3.09 (m, 3H), 3.15-3.24 (m, 1H), 4.57 (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 obtained as described for the example 54 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.44-1.53 (m, 1H), 1.61-1.71 (m, 1H), 1.91-2.07 (m, 3H), 2.92-3.09 (m, 3H), 3.15-3.24 (m, 1H), 4.57 (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-butyl piperidin-4-ylcarbamate, the title compound was obtained as described for the example 54 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.60-1.71 (m, 2H), 2.18 (d, 2H), 3.18 (t, 2H), 3.47-3.56 (m, 1H), 4.83-4.94 (m, 2H), 7.33 (s, 1H), 7.54 (d, 2H), 7.98 (br, 1H), 8.25 (d, 2H), 8.84 (br, 1H), 9.32 (d, 1H), 9.73 (br, 1H); MS (ESI, m/z): 366.1 [M+H]+
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 obtained as described for the example 54 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.31-1.42 (m, 2H), 1.98 (d, 2H), 2.01-2.10 (m, 1H), 2.91 (d, 2H), 3.13 (t, 2H), 4.81-4.95 (m, 2H), 7.29 (s, 1H), 7.54 (d, 2H), 8.00 (br, 1H), 8.23 (d, 2H), 8.85 (br, 1H), 9.34 (d, 1H), 9.71 (br, 1H); MS (ESI, m/z): 380.2 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.59-1.74 (m, 2H), 1.79-1.94 (m, 2H), 1.98-2.07 (m, 1H), 2.27-2.35 (m, 1H), 4.16 (br, 1H), 4.43 (br, 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.59-1.74 (m, 2H), 1.79-1.94 (m, 2H), 1.98-2.07 (m, 1H), 2.27-2.35 (m, 1H), 4.16 (br, 1H), 4.43 (br, 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. trans -2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol
Using trans-2-aminocyclopentan-1-ol and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.59-1.74 (m, 2H), 1.79-1.94 (m, 2H), 1.98-2.07 (m, 1H), 2.27-2.35 (m, 1H), 4.16 (br, 1H), 4.43 (br, 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.28-1.51 (m, 4H), 1.76-1.84 (m, 2H), 2.08-2.16 (m, 2H), 3.52-3.57 (m, 1H), 4.16 (br, 1H), 6.95 (s, 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.29 (d, 6H), 2.69 (t, 2H), 3.67-3.74 (m, 2H), 4.56 (br, 2H), 7.23 (s, 1H), 7.51 (d, 2H), 8.05 (br, 1H), 8.22 (d, 2H), 8.88 (br, 1H), 9.38 (d, 1H), 9.72 (br, 1H); MS (ESI, m/z): 381.1 [M+H]+
Example 71. 4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)morpholine
Using morpholine and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 3.81-3.88 (m, 8H), 7.22 (s, 1H), 7.51 (d, 2H), 8.12 (br, 1H), 8.21 (d, 2H), 8.88 (br, 1H), 9.41 (d, 1H), 9.83 (br, 1H); MS (ESI, m/z): 353.1 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 54 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 3.88-4.18 (m, 9H), 7.07 (s, 1H), 7.60 (d, 2H), 8.15 (br, 1H), 8.33 (d, 2H), 8.89 (br, 1H), 9.41 (d, 1H), 9.73 (br, 1H); MS (ESI, m/z): 382.9 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 2.43 (br, 1H), 2.68 (br, 1H), 3.50 (br, 4H), 3.69 (br, 1H), 3.86-4.40 (m, 8H), 7.05 (s, 1H), 7.53 (d, 2H), 8.14 (br, 1H), 8.25 (d, 2H), 8.92 (br, 1H), 9.52 (d, 1H), 9.79 (br, 1H); MS (ESI, m/z): 422.2 [M+H]+
Example 74. 4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)thiomorpholine
Using thiomorpholine and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 2.74-7.76 (m, 4H), 4.24 (br, 4H), 7.25 (s, 1H), 7.52 (d, 2H), 8.12 (br, 1H), 8.22 (d, 2H), 8.91 (br, 1H), 9.45 (d, 1H), 9.73 (br, 1H); MS (ESI, m/z): 422.2 [M+H]+
Example 75. 6-(4-chlorophenyl)-N-(3-morpholinopropyl)-2-(pyridin-3-yl)pyrimidin-4-amine
Using 3-morpholinopropan-1-amine and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 2.15-2.22 (m, 2H), 3.15 (br, 2H), 3.32-3.35 (m, 2H), 3.51 (br, 2H), 3.72 (br, 4H), 4.03 (br, 2H), 6.98 (s, 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 54 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 2.15-2.22 (m, 2H), 3.15 (br, 2H), 3.32-3.35 (m, 2H), 3.51 (br, 2H), 3.72 (br, 4H), 4.03 (br, 2H), 6.98 (s, 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 separation method of PREP. HPLC, the title compound was obtained as described for the 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 54 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.60 (br, 1H), 2.03 (br, 1H), 3.64 (s, 3H), 3.77 (br, 1H), 4.01 (br, 1H), 4.46 (br, 1H), 4.55 (br, 1H), 5.35 (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 separation method of PREP. HPLC, the title compound was obtained as described for the example 54 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 3.27-3.35 (m, 2H), 3.42-3.58 (m, 4H), 3.80-3.85 (m, 2H), 3.94-3.98 (m, 2H), 4.82-4.85 (m, 1H), 7.44 (s, 1H), 7.56 (d, 2H), 8.03 (br, 1H), 8.30 (d, 2H), 8.87 (br, 1H), 9.40 (d, 1H), 9.77 (br, 1H); MS (ESI, m/z): 410.1 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 3.21 (br, 4H), 4.10 (br, 4H), 7.13-7.17 (m, 1H), 7.28 (d, 2H), 7.34 (s, 1H), 7.55 (d, 2H), 8.12 (br, 1H), 8.26 (d, 2H), 8.91 (br, 1H), 9.50 (d, 1H), 9.77 (br, 1H); MS (ESI, m/z): 496.1 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 3.54 (br, 8H), 3.80 (s, 3H), 3.90 (s, 3H), 4.43 (s, 2H), 7.09 (s, 3H), 7.42 (s, 1H), 7.55 (d, 2H), 8.14 (br, 1H), 8.28 (d, 2H), 8.92 (br, 1H), 9.54 (d, 1H), 9.81 (br, 1H); MS (ESI, m/z): 502.2 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 3.38 (t, 2H), 3.52 (br, 8H), 3.96 (t, 2H), 7.42 (s, 1H), 7.55 (d, 2H), 8.00 (br, 1H), 8.28 (d, 2H), 8.86 (br, 1H), 9.37 (d, 1H), 9.76 (br, 1H); MS (ESI, m/z): 396.2 [M+H]+
Example 83. 4-(4-chlorophenyl)-6-(4-(2-methoxyphenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine
Using 1-(2-methoxyphenyl)piperazine and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 3.50 (br, 4H), 3.98 (s, 3H), 4.22 (br, 4H), 7.04 (dd, 1H), 7.15 (d, 1H), 7.26-7.32 (m, 2H), 7.37 (s, 1H), 7.53 (d, 2H), 8.12 (br, 1H), 8.26 (d, 2H), 8.91 (br, 1H), 9.50 (d, 1H), 9.77 (br, 1H); MS (ESI, m/z): 458.2 [M+H]+
Example 84. 4-(4-chlorophenyl)-6-(4-(2-ethoxyphenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine
Using 1-(2-ethoxyphenyl)piperazine and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.48 (t, 3H), 3.47 (br, 4H), 4.17-4.22 (m, 6H), 7.01 (dd, 1H), 7.10 (d, 1H), 7.19-7.25 (m, 2H), 7.38 (s, 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 3.22 (br, 4H), 4.07 (br, 4H), 6.99-7.13 (m, 4H), 7.31 (s, 1H), 7.52 (d, 2H), 8.12 (br, 1H), 8.23 (d, 2H), 8.90 (br, 1H), 9.46 (d, 1H), 9.75 (br, 1H); MS (ESI, m/z): 446.2 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 4.02 (br, 8H), 6.64 (dd, 1H), 7.14 (d, 1H), 7.29 (s, 1H), 7.53 (d, 2H), 7.74 (d, 1H), 8.06 (dd, 1H), 8.25 (d, 2H), 8.87 (br, 1H), 9.43 (d, 1H), 9.74 (br, 1H); MS (ESI, m/z): 446.1 [M+H]+
Example 87. 4-(4-chlorophenyl)-6-(4-phenethylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine
Using 1-phenethylpiperazine and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 3.14-3.18 (m, 2H), 3.45-3.50 (m, 2H), 3.61 (br, 8H), 7.26-7.38 (m, 5H), 7.44 (s, 1H), 7.54 (d, 2H), 8.16 (br, 1H), 8.28 (d, 2H), 8.94 (br, 1H), 9.54 (d, 1H), 9.81 (br, 1H); MS (ESI, m/z): 456.2 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 54 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 2.70 (t, 2H), 2.75 (br, 4H), 3.08 (t, 2H), 4.18 (br, 4H), 7.37 (s, 1H), 7.52 (d, 2H), 8.11 (br, 1H), 8.25 (d, 2H), 8.91 (br, 1H), 9.48 (d, 1H), 9.78 (br, 1H); MS (ESI, m/z): 395.2 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 3.98 (br, 4H), 4.20 (br, 4H), 7.06 (t, 1H), 7.30 (s, 1H), 7.44 (d, 1H), 7.54 (d, 2H), 8.04 (d, 1H), 8.08-8.16 (m, 2H), 8.27 (d, 2H), 8.93 (br, 1H), 9.53 (d, 1H), 9.80 (br, 1H); MS (ESI, m/z): 429.2 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 4.04 (br, 8H), 6.72 (t, 1H), 7.36 (s, 1H), 7.55 (d, 2H), 8.04 (d, 1H), 8.19 (br, 1H), 8.28 (d, 2H), 8.43 (d, 2H), 8.93 (br, 1H), 9.59 (d, 1H), 9.81 (br, 1H); MS (ESI, m/z): 429.2 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 3.27 (br, 4H), 3.35 (br, 4H), 3.41 (t, 2H), 3.55 (t, 2H), 3.95 (br, 4H), 4.18 (br, 4H), 7.39 (s, 1H), 7.54 (d, 2H), 8.16 (br, 1H), 8.26 (d, 2H), 8.93 (br, 1H), 9.54 (d, 1H), 9.79 (br, 1H); MS (ESI, m/z): 429.2 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.69-1.79 (m, 2H), 2.53 (d, 2H), 2.93 (s, 3H), 3.14 (t, 2H), 3.44 (br, 4H), 3.52 (br, 4H), 3.63 (br, 2H), 4.29 (br, 1H), 7.34 (s, 1H), 7.54 (d, 2H), 8.14 (br, 1H), 8.24 (d, 2H), 8.92 (br, 1H), 9.51 (d, 1H), 9.76 (br, 1H); MS (ESI, m/z): 449.2 [M+H]+
Example 93. trans-4-(4-chlorophenyl)-6-(4-cinnamylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine
Using trans-1-cinnamylpiperazine and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 3.58 (br, 8H), 4.04 (d, 2H), 6.35-6.43 (m, 1H), 6.96 (d, 1H), 7.32-7.40 (m, 3H), 7.44 (s, 1H), 7.50-7.55 (m, 4H), 8.16 (br, 1H), 8.28 (d, 2H), 8.93 (br, 1H), 9.56 (d, 1H), 9.82 (br, 1H); MS (ESI, m/z): 468.2 [M+H]+
Example 94. 4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-2-one
Using piperazin-2-one and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 3.53 (t, 2H), 4.10 (br, 2H), 4.46 (s, 2H), 7.29 (s, 1H), 7.54 (d, 2H), 8.11 (br, 1H), 8.28 (d, 2H), 8.89 (br, 1H), 9.49 (d, 1H), 9.77 (br, 1H); MS (ESI, m/z): 366.1 [M+H]+
Example 95. 4-(4-chlorophenyl)-6-(4-phenylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine
Using 1-phenylpiperazine and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 3.43 (t, 4H), 4.13 (br, 4H), 7.02 (t, 1H), 7.14 (d, 2H), 7.34 (t, 3H), 7.53 (d, 2H), 8.14-8.17 (m, 1H), 8.25 (d, 2H), 8.92 (br, 1H), 9.54 (d, 1H), 9.77 (br, 1H); MS (ESI, m/z): 428.2 [M+H]+
Example 96. 4-(4-chlorophenyl)-6-(4-propylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine
Using 1-propylpiperazine and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.06 (t, 3H), 1.80-1.90 (m, 2H), 3.17-3.21 (m, 2H), 3.54 (br, 8H), 7.43 (s, 1H), 7.55 (d, 2H), 8.03 (t, 1H), 8.28 (d, 2H), 8.87 (br, 1H), 9.41 (d, 1H), 9.77 (br, 1H); MS (ESI, m/z): 394.2 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 3.44 (br, 8H), 4.34 (s, 2H), 6.04 (s, 2H), 6.94 (d, 1H), 7.03 (d, 1H), 7.05 (s, 1H), 7.42 (s, 1H), 7.54 (d, 2H), 8.11-8.14 (m, 1H), 8.28 (d, 2H), 8.92 (br, 1H), 9.51 (d, 1H), 9.80 (br, 1H); MS (ESI, m/z): 486.2 [M+H]+
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 obtained as described for the example 54 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 3.55 (br, 1H), 3.45-3.59 (m, 4H), 3.62-3.67 (m, 1H), 3.72-3.77 (m, 1H), 3.82-3.87 (m, 1H), 3.95-4.00 (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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 4.09 (br, 8H), 7.02-7.07 (m, 2H), 7.10-7.13 (m, 2H), 7.32 (s, 1H), 7.52 (d, 2H), 8.14-8.17 (m, 1H), 8.23 (d, 2H), 8.92 (d, 1H), 9.53 (d, 1H), 9.76 (s, 1H); MS (ESI, m/z): 446.2 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.55 (s, 6H), 1.68 (s, 6H), 1.86 (t, 1H), 2.43 (d, 4H), 2.92 (s, 3H), 7.00 (s, 1H), 7.54 (d, 2H), 8.06-8.09 (m, 1H), 8.16 (d, 2H), 8.89 (d, 1H), 9.41 (d, 1H), 9.73 (s, 1H); MS (ESI, m/z): 436.2 [M+H]+
Example 101. 6-(4-chlorophenyl)-N-(piperidin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-amine
Using tert-butyl 3-aminopiperidine-1-carboxylate and separation method of PREP. HPLC, the title compound was obtained as described for the example 54 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.74-1.83 (m, 1H), 1.92-2.03 (m, 1H), 2.12-2.23 (m, 2H), 2.96-3.11 (m, 2H), 3.40 (d, 1H), 3.71 (d, 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-butyl piperazine-1-carboxylate and separation method of PREP. HPLC, the title compound was obtained as described for the example 54 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 3.41 (br, 4H), 4.19 (br, 4H), 7.41 (s, 1H), 7.55 (d, 2H), 8.04 (t, 1H), 8.28 (d, 2H), 8.87 (d, 1H), 9.41 (d, 1H), 9.77 (s, 1H); MS (ESI, m/z): 352.1 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 54 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.47 (d, 3H), 1.48 (d, 3H), 3.62-3.73 (m, 3H), 3.91 (br, 1H), 4.67 (d, 1H), 5.17 (br, 1H), 7.35 (s, 1H), 7.56 (d, 2H), 8.02-8.05 (m, 1H), 8.28 (d, 2H), 8.87 (d, 1H), 9.41 (d, 1H), 9.76 (s, 1H); MS (ESI, m/z): 380.2 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 54 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.48 (d, 6H), 3.03-3.09 (m, 2H), 3.46-3.51 (m, 2H), 5.04 (br, 2H), 7.47 (s, 1H), 7.55 (d, 2H), 8.08-8.12 (m, 1H), 8.30 (d, 2H), 8.91 (d, 1H), 9.50 (d, 1H), 9.81 (s, 1H); MS (ESI, m/z): 380.2 [M+H]+
Example 105. 4-(4-chlorophenyl)-6-(4-methylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine
Using 1-methylpiperazine and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 3.00 (s, 3H), 3.49 (br, 4H), 3.55 (br, 4H), 7.43 (s, 1H), 7.56 (d, 2H), 7.97-8.00 (m, 1H), 8.29 (d, 2H), 8.86 (d, 1H), 9.36 (d, 1H), 9.76 (s, 1H); MS (ESI, m/z): 366.1 [M+H]+
Example 106. 4-(4-chlorophenyl)-6-(4-ethylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine
Using 1-ethylpiperazine and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.43 (t, 3H), 3.27 (q, 2H), 3.54 (br, 4H), 3.56 (br, 4H), 7.43 (s, 1H), 7.56 (d, 2H), 7.97-8.01 (m, 1H), 8.29 (d, 2H), 8.86 (d, 1H), 9.36 (d, 1H), 9.76 (s, 1H); MS (ESI, m/z): 380.2 [M+H]+
Example 107. 4-(4-chlorophenyl)-6-(4-(methylsulfonyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine
Using 1-(methylsulfonyl)piperazine and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 2.90 (s, 3H), 3.40 (br, 4H), 4.06 (br, 4H), 7.35 (s, 1H), 7.55 (d, 2H), 8.02 (br, 1H), 8.27 (d, 2H), 8.85 (br, 1H), 9.38 (d, 1H), 9.76 (br, 1H); MS (ESI, m/z): 430.1 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 2.19 (s, 3H), 3.73-3.78 (m, 4H), 3.93 (br, 2H), 3.99 (br, 2H), 7.28 (s, 1H), 7.54 (d, 2H), 7.96-7.99 (m, 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 54 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.19 (t, 3H), 1.73-1.90 (m, 3H), 3.25-3.35 (m, 4H), 3.49-3.59 (m, 2H), 7.45 (s, 1H), 7.56 (d, 2H), 8.07-8.10 (m, 1H), 8.30 (d, 2H), 8.90 (d, 1H), 9.46 (d, 1H), 9.78 (s, 1H); MS (ESI, m/z): 380.2 [M+H]+
Example 110. ethyl 4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazine-1-carboxylate
Using ethyl piperazine-1-carboxylate and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.31 (t, 3H), 3.66 (br, 4H), 3.94 (br, 4H), 4.19 (q, 2H), 7.29 (s, 1H), 7.53 (d, 2H), 8.02-8.06 (m, 1H), 8.24 (d, 2H), 8.86 (d, 1H), 9.41 (d, 1H), 9.73 (s, 1H); MS (ESI, m/z): 424.2 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 54 (Scheme 1. General procedure 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-methyl piperazine-1,3-dicarboxylate and separation method of PREP. HPLC, the title compound was obtained as described for the example 54 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.49 (s, 3H), 3.47-3.57 (m, 3H), 3.63 (br, 1H), 3.83 (br, 1H), 4.07 (br, 1H), 4.10 (br, 1H), 7.43 (s, 1H), 7.55 (d, 2H), 7.80-7.84 (m, 1H), 8.28 (d, 2H), 8.77 (d, 1H), 9.16 (d, 1H), 9.68 (s, 1H); MS (ESI, m/z): 410.1 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 54 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 3.47-3.55 (m, 2H), 3.58-3.71 (m, 2H), 4.55-4.60 (m, 2H), 5.09-5.12 (m, 1H), 7.47 (s, 1H), 7.53-7.63 (m, 7H), 7.79-7.82 (m, 1H), 8.29 (d, 2H), 8.76 (d, 1H), 9.15 (d, 1H), 9.67 (s, 1H); MS (ESI, m/z): 428.2 [M+H]+
Example 114. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(4-(o-tolyl)piperazin-1-yl)pyrimidine
Using 1-(o-tolyl)piperazine and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 2.40 (s, 3H), 3.06 (t, 4H), 4.07 (br, 4H), 7.01 (t, 1H), 7.08 (d, 1H), 7.31 (s, 1H), 7.53 (d, 2H), 7.59 (d, 1H), 8.11-8.14 (m, 1H), 8.24 (d, 2H), 8.42 (t, 1H), 8.91 (d, 1H), 9.50 (d, 1H), 9.75 (s, 1H); MS (ESI, m/z): 442.2 [M+H]+
Example 115. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(4-(p-tolyl)piperazin-1-yl)pyrimidine
Using 1-(p-tolyl)piperazine and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 2.31 (s, 3H), 3.44 (t, 4H), 4.17 (br, 4H), 7.14 (d, 2H), 7.20 (d, 2H), 7.37 (s, 1H), 7.54 (d, 2H), 8.11-8.14 (m, 1H), 8.26 (d, 2H), 8.91 (d, 1H), 9.52 (d, 1H), 9.78 (s, 1H); MS (ESI, m/z): 442.2 [M+H]+
Example 116. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(4-(m-tolyl)piperazin-1-yl)pyrimidine
Using 1-(m-tolyl)piperazine and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 2.34 (s, 3H), 3.43 (t, 4H), 4.13 (br, 4H), 6.87 (d, 1H), 6.98 (d, 1H), 7.01 (s, 1H), 7.22 (t, 1H), 7.35 (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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 3.42 (t, 4H), 4.08 (br, 4H), 7.13 (d, 1H), 7.25 (s, 1H), 7.26 (d, 1H), 7.31 (s, 1H), 7.44 (t, 1H), 7.53 (d, 2H), 8.10-8.14 (m, 1H), 8.24 (d, 2H), 8.90 (d, 1H), 9.50 (d, 1H), 9.75 (s, 1H); MS (ESI, m/z): 496.1 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 2.29 (s, 3H), 2.33 (s, 3H), 3.03 (br, 4H), 4.08 (br, 4H), 6.94 (t, 2H), 7.06 (t, 1H), 7.32 (s, 1H), 7.54 (d, 2H), 8.10-8.13 (m, 1H), 8.25 (d, 2H), 8.90 (d, 1H), 9.49 (d, 1H), 9.75 (s, 1H); MS (ESI, m/z): 456.2 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 3.39 (t, 4H), 4.09 (br, 4H), 6.96 (d, 1H), 6.99 (d, 1H), 7.35 (d, 2H), 7.55 (d, 2H), 8.10-8.14 (m, 1H), 8.27 (d, 2H), 8.90 (d, 1H), 9.51 (d, 1H), 9.77 (s, 1H); MS (ESI, m/z): 496.1 [M+H]+
Example 120. 4-(4-chlorophenyl)-6-(4-(4-methoxyphenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine
Using 1-(4-methoxyphenyl)piperazine and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 3.57 (t, 4H), 3.83 (s, 3H), 4.27 (br, 4H), 7.04 (d, 2H), 7.39 (d, 2H), 7.44 (s, 1H), 7.57 (d, 2H), 8.13-8.16 (m, 1H), 8.30 (d, 2H), 8.93 (d, 1H), 9.54 (d, 1H), 9.81 (s, 1H); MS (ESI, m/z): 458.2 [M+H]+
Example 121. 4-(4-chlorophenyl)-6-(4-(4-nitrophenyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine
Using 1-(4-nitrophenyl)piperazine and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 3.73 (t, 4H), 4.13 (br, 4H), 7.05 (d, 2H), 7.32 (s, 1H), 7.56 (d, 2H), 8.03-8.07 (m, 1H), 8.17 (d, 2H), 8.28 (d, 2H), 8.87 (d, 1H), 9.42 (d, 1H), 9.76 (s, 1H); MS (ESI, m/z): 473.1 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 2.02 (br, 2H), 2.41 (br, 2H), 2.93 (s, 3H), 2.97 (br, 2H), 3.28 (br, 2H), 3.38 (br, 4H), 3.62 (br, 2H), 4.16 (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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 3.35 (br, 4H), 4.22 (br, 4H), 5.41 (s, 1H), 7.31 (t, 2H), 7.37 (s, 1H), 7.43-7.55 (m, 8H), 7.69 (d, 2H), 8.00-8.04 (m, 1H), 8.26 (d, 2H), 8.86 (d, 1H), 9.40 (d, 1H), 9.74 (s, 1H); MS (ESI, m/z): 518.2 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 3.29 (br, 4H), 4.21 (br, 4H), 5.36 (s, 1H), 7.30-7.34 (m, 1H), 7.36 (s, 1H), 7.42-7.54 (m, 7H), 7.67-7.71 (m, 3H), 8.07-8.11 (m, 1H), 8.25 (d, 2H), 8.90 (br, 1H), 9.47 (d, 1H), 9.76 (s, 1H); MS (ESI, m/z): 552.2 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 2.17-2.24 (m, 4H), 3.53-3.59 (m, 4H), 6.89 (d, 1H), 7.12 (d, 1H), 7.17 (t, 1H), 7.23 (t, 1H), 7.35 (d, 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 54 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 2.16 (br, 1H), 2.50 (br, 1H), 3.18-3.23 (m, 1H), 3.38-3.46 (m, 1H), 3.52-3.59 (m, 1H), 3.70-3.75 (m, 1H), 4.04-4.11 (m, 1H), 7.00 (s, 1H), 7.53 (d, 2H), 7.70-7.74 (m, 1H), 8.16 (d, 2H), 8.72 (d, 1H), 9.06 (d, 1H), 9.63 (s, 1H); MS (ESI, m/z): 352.1 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 54 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 2.11-2.24 (m, 1H), 2.46-2.56 (m, 1H), 3.37-3.46 (m, 1H), 3.48-3.61 (m, 2H), 3.71-3.81 (m, 1H), 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 54 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.85-1.94 (m, 1H), 2.22-2.32 (m, 1H), 2.79-2.87 (m, 1H), 3.00-3.15 (m, 2H), 3.40-3.46 (m, 1H), 3.47-3.57 (m, 1H), 3.73 (br, 2H), 7.00 (s, 1H), 7.53 (d, 2H), 8.05-8.08 (m, 1H), 8.16 (d, 2H), 8.88 (d, 1H), 9.43 (d, 1H), 9.75 (s, 1H); MS (ESI, m/z): 366.1 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 3.19 (br, 4H), 3.40 (d, 2H), 3.53 (d, 2H), 3.76 (br, 4H), 7.06 (s, 1H), 7.54 (d, 2H), 8.02-8.05 (m, 1H), 8.18 (d, 2H), 8.88 (d, 1H), 9.41 (d, 1H), 9.76 (s, 1H); MS (ESI, m/z): 380.2 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 2.00-2.18 (br, 6H), 3.03-3.13 (br, 6H), 3.69 (br, 2H), 6.98 (s, 1H), 7.52 (d, 2H), 7.95-7.98 (m, 1H), 8.15 (d, 2H), 8.84 (d, 1H), 9.31 (d, 1H), 9.71 (s, 1H); MS (ESI, m/z): 394.2 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.89-2.00 (m, 2H), 2.02-2.18 (m, 2H), 2.35-2.43 (m, 1H), 2.93 (s, 3H), 3.03-3.07 (m, 2H), 3.11-3.20 (m, 1H), 3.34-3.44 (m, 1H), 3.72 (br, 2H), 6.96 (s, 1H), 7.52 (d, 2H), 7.87-7.90 (m, 1H), 8.15 (d, 2H), 8.80 (d, 1H), 9.21 (d, 1H), 9.67 (s, 1H); MS (ESI, m/z): 394.2 [M+H]+
Example 132. N-(1-benzylpyrrolidin-3-yl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-amine
Using 1-benzylpyrrolidin-3-amine and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 2.21 (br, 1H), 2.62 (br, 1H), 3.39-4.17 (br, 5H), 4.48 (s, 2H), 7.03 (s, 1H), 7.47-7.49 (m, 3H), 7.52-7.56 (m, 4H), 8.10-8.14 (m, 1H), 8.16 (d, 2H), 8.87 (d, 1H), 9.36 (d, 1H), 9.73 (s, 1H); MS (ESI, m/z): 442.2 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 54 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.06 (br, 2H), 2.18 (br, 1H), 3.80 (br, 1H), 4.17 (br, 2H), 7.09 (s, 1H), 7.53 (d, 2H), 7.65-7.70 (m, 1H), 8.17 (d, 2H), 8.69 (d, 1H), 9.01 (d, 1H), 9.62 (s, 1H); MS (ESI, m/z): 368.1 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 54 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.06 (br, 2H), 2.18 (br, 1H), 3.80 (br, 1H), 4.17 (br, 2H), 7.09 (s, 1H), 7.53 (d, 2H), 7.65-7.70 (m, 1H), 8.17 (d, 2H), 8.69 (d, 1H), 9.01 (d, 1H), 9.62 (s, 1H); MS (ESI, m/z): 368.1 [M+H]+
Example 135. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(pyrrolidin-1-yl)pyrimidine
Using pyrrolidine and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 2.09 (br, 4H), 3.59 (br, 2H), 3.82 (br, 2H), 6.95 (s, 1H), 7.54 (d, 2H), 8.05-8.08 (m, 1H), 8.20 (d, 2H), 8.88 (d, 1H), 9.40 (d, 1H), 9.69 (s, 1H); MS (ESI, m/z): 337.1 [M+H]+
Example 136. 4-(4-chlorophenyl)-6-(2-methylpyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidine
Using 2-methylpyrrolidine and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.36 (br, 3H), 1.87 (br, 1H), 2.20 (br, 3H), 3.70 (br, 2H), 4.63 (br, 1H), 6.91 (s, 1H), 7.53 (d, 2H), 8.04-8.07 (m, 1H), 8.18 (d, 2H), 8.88 (d, 1H), 9.37 (d, 1H), 9.67 (s, 1H); MS (ESI, m/z): 351.1 [M+H]+
Example 137. (S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol
Using (S)-pyrrolidin-3-ol and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 2.17 (br, 2H), 3.70 (br, 2H), 3.86 (br, 2H), 4.59 (br, 1H), 6.95 (s, 1H), 7.52 (d, 2H), 8.07-8.11 (m, 1H), 8.19 (d, 2H), 8.89 (d, 1H), 9.43 (d, 1H), 9.69 (s, 1H); MS (ESI, m/z): 353.1 [M+H]+
Example 138. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)methanol
Using pyrrolidin-3-ylmethanol and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.92 (br, 1H), 2.21 (br, 1H), 2.60 (br, 1H), 3.52-3.59 (m, 2H), 3.60-3.71 (m, 3H), 3.97 (br, 1H), 6.91 (s, 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 2.25 (br, 1H), 2.45 (br, 1H), 3.71 (br, 1H), 3.79 (br, 2H), 3.88 (br, 1H), 4.17 (br, 1H), 7.00 (s, 1H), 7.53 (d, 2H), 8.07-8.10 (m, 1H), 8.23 (d, 2H), 8.88 (d, 1H), 9.46 (d, 1H), 9.72 (s, 1H); MS (ESI, m/z): 355.1 [M+H]+
Example 140. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-amine
Using tert-butyl pyrrolidin-3-ylcarbamate and separation method of PREP. HPLC, the title compound was obtained as described for the example 54 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 2.31 (br, 1H), 2.57 (br, 1H), 3.87 (br, 2H), 4.06 (br, 2H), 4.14 (br, 1H), 7.04 (s, 1H), 7.54 (d, 2H), 8.06-8.09 (m, 1H), 8.25 (d, 2H), 8.89 (d, 1H), 9.45 (d, 1H), 9.75 (s, 1H); MS (ESI, m/z): 352.1 [M+H]+
Example 141. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-N-methylpyrrolidin-3-amine
Using tert-butyl methyl(pyrrolidin-3-yl)carbamate and separation method of PREP. HPLC, the title compound was obtained as described for the example 54 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 2.38 (br, 1H), 2.59 (br, 1H), 2.85 (s, 3H), 3.80 (br, 1H), 3.89 (br, 1H), 4.05 (br, 3H), 7.04 (s, 1H), 7.53 (d, 2H), 8.08-8.12 (m, 1H), 8.25 (d, 2H), 8.90 (d, 1H), 9.47 (d, 1H), 9.76 (s, 1H); MS (ESI, m/z): 366.1 [M+H]+
Example 142. methyl (6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)prolinate
Using methyl prolinate and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 2.13-2.29 (m, 3H), 2.39-2.49 (m, 1H), 3.63-3.80 (m, 5H), 4.76-4.79 (m, 1H), 7.06 (s, 1H), 7.52 (d, 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.98 (s, 3H), 2.13 (br, 1H), 2.37 (br, 1H), 3.46 (br, 1H), 3.72 (br, 1H), 3.89 (br, 1H), 4.02 (br, 1H), 4.52 (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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 1.23 (d, 3H), 1.30 (d, 3H), 3.94 (br, 1H), 4.51 (br, 1H), 7.01 (s, 1H), 7.55 (d, 2H), 8.07-8.10 (m, 1H), 8.15 (d, 2H), 8.89 (d, 1H), 9.44 (d, 1H), 9.71 (s, 1H); MS (ESI, m/z): 355.1 [M+H]+
Example 145. 3-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)butan-2-ol
Using 3-aminobutan-2-ol and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 1.27 (d, 3H), 1.31 (d, 3H), 3.90-3.94 (m, 1H), 4.46 (br, 1H), 7.00 (s, 1H), 7.55 (d, 2H), 8.13-8.20 (m, 3H), 8.92 (d, 1H), 9.48 (d, 1H), 9.71 (s, 1H); MS (ESI, m/z): 355.1 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 1.49-1.65 (m, 4H), 2.05-2.22 (m, 4H), 2.17 (s, 3H), 4.49 (br, 1H), 6.99 (s, 1H), 7.57 (d, 2H), 8.14-8.19 (m, 3H), 8.93 (d, 1H), 9.52 (d, 1H), 9.77 (s, 1H); MS (ESI, m/z): 408.2 [M+H]+
Example 147. (R)-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanol
Using (R)-piperidin-3-ylmethanol and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 1.39-1.45 (m, 1H), 1.59-1.66 (m, 1H), 1.79-1.84 (m, 1H), 1.86-1.92 (m, 2H), 3.03 (t, 1H), 3.24 (t, 1H), 3.35 (d, 1H), 3.50 (dd, 1H), 3.60 (dd, 1H), 4.58 (br, 1H), 7.27 (s, 1H), 7.54 (d, 2H), 8.13-8.15 (m, 1H), 8.21 (d, 2H), 8.92 (d, 1H), 9.50 (d, 1H), 9.73 (s, 1H); MS (ESI, m/z): 381.1 [M+H]+
Example 148. (S)-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanol
Using (S)-piperidin-3-ylmethanol and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 1.39-1.45 (m, 1H), 1.59-1.66 (m, 1H), 1.79-1.84 (m, 1H), 1.86-1.92 (m, 2H), 3.03 (t, 1H), 3.24 (t, 1H), 3.35 (d, 1H), 3.50 (dd, 1H), 3.60 (dd, 1H), 4.58 (br, 1H), 7.27 (s, 1H), 7.54 (d, 2H), 8.13-8.15 (m, 1H), 8.21 (d, 2H), 8.92 (d, 1H), 9.50 (d, 1H), 9.73 (s, 1H); MS (ESI, m/z): 381.1 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 1.51-1.57 (m, 1H), 1.75-1.86 (m, 3H), 1.97 (d, 2H), 3.05 (t, 2H), 3.48 (t, 2H), 3.72 (d, 2H), 4.05 (br, 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 1.89-1.95 (m, 2H), 2.08-2.13 (m, 2H), 3.16-3.20 (m, 1H), 3.76-3.80 (m, 2H), 4.24 (br, 2H), 7.32 (s, 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 1.92 (d, 2H), 2.14-2.19 (m, 2H), 3.59 (br, 2H), 4.70 (br, 2H), 7.33 (s, 1H), 7.53 (d, 2H),7.53-7.59 (m, 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 1.71-1.78 (m, 2H), 2.03 (br, 2H), 2.18 (br, 2H), 2.34 (d, 2H), 3.13 (t, 2H), 3.22 (br, 2H), 3.31 (br, 2H), 3.52-3.56 (m, 1H), 3.70 (br, 2H), 7.36 (s, 1H), 7.54 (d, 2H),8.16-8.18 (m, 1H), 8.25 (d, 2H), 8.94 (d, 1H), 9.55 (d, 1H), 9.78 (s, 1H); MS (ESI, m/z): 420.2 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 1.90 (d, 2H), 2.08-2.13 (m, 2H), 3.58 (br, 2H), 4.66 (br, 2H), 7.32 (s, 1H), 7.33 (d, 2H), 7.51 (d, 2H), 7.53 (d, 2H), 8.13-8.15 (m, 1H), 8.22 (d, 2H), 8.92 (d, 1H), 9.50 (d, 1H), 9.74 (s, 1H); MS (ESI, m/z): 477.1 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 1.22-1.39 (m, 3H), 1.91 (d, 2H), 1.96 (s, 3H), 3.08-3.13 (m, 4H), 4.79 (br, 2H), 7.28 (s, 1H), 7.54 (d, 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 1.99 (s, 3H), 2.14-2.19 (m, 2H), 2.58 (d, 2H), 3.60 (t, 2H), 4.27 (br, 2H), 7.24 (s, 1H), 7.30-7.34 (m, 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 1.75-1.82 (m, 2H), 2.35 (d, 2H), 3.14 (t, 2H), 3.24 (t, 2H), 3.55 (d, 2H), 3.60-3.66 (m, 2H), 3.80 (t, 2H), 4.10 (d, 2H), 5.00 (br, 2H), 7.37 (s, 1H), 7.54 (d, 2H), 8.17-8.19 (m, 1H), 8.26 (d, 2H), 8.94 (d, 1H), 9.56 (d, 1H), 9.79 (s, 1H); MS (ESI, m/z): 436.2 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 1.72-1.79 (m, 2H), 2.04 (d, 2H), 2.98-3.04 (m, 1H), 3.20 (t, 2H), 4.95 (br, 2H), 7.27 (s, 2H), 7.29 (s, 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 1.35-1.41 (m, 2H), 1.46-1.53 (m, 2H), 1.61-1.72 (m, 3H), 1.93 (d, 2H), 2.08 (d, 3H), 2.15 (d, 2H), 3.07 (t, 2H), 3.14-3.19 (m, 1H), 3.54 (d, 2H), 3.59 (br, 1H), 4.87-4.91 (m, 2H), 6.99 (s, 1H), 7.53 (d, 2H), 8.14-8.16 (m, 3H), 8.93 (d, 1H), 9.51 (d, 1H), 9.76 (s, 1H); MS (ESI, m/z): 462.2 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 1.56-1.63 (m, 2H), 2.07 (br, 2H), 2.14 (d, 2H), 3.05 (t, 2H), 3.56 (d, 2H), 3.59 (br, 1H), 4.30 (s, 2H), 7.00 (s, 1H), 7.49 (s, 5H), 7.54 (d, 2H), 8.13-8.15 (m, 3H), 8.94 (d, 1H), 9.51 (d, 1H), 9.77 (s, 1H); MS (ESI, m/z): 470.2 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 1.24 (t, 3H), 1.60-1.71 (m, 4H), 2.18-2.24 (m, 1H), 3.20-3.29 (m, 2H), 3.70 (s, 2H), 4.69 (br, 4H), 7.26 (s, 1H), 7.53 (d, 2H), 8.06-8.08 (m, 1H), 8.22 (d, 2H), 8.88 (d, 1H), 9.42 (d, 1H), 9.71 (s, 1H); MS (ESI, m/z): 465.2 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 1.28 (t, 3H), 1.95 (d, 2H), 2.15-2.23 (m, 1H), 2.35 (d, 2H), 3.13 (t, 2H), 3.80 (br, 2H), 4.17 (q, 2H), 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 1.61-1.67 (m, 1H), 1.79-1.95 (m, 4H), 2.15-2.22 (m, 1H), 2.42-2.49 (m, 1H), 4.34-4.39 (m, 1H), 4.60 (br, 1H), 6.92 (s, 1H), 7.50 (d, 2H), 8.08-8.14 (m, 3H), 8.91 (d, 1H), 9.44 (d, 1H), 9.69 (s, 1H); MS (ESI, m/z): 367.1 [M+H]+
Example 163. (S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-ol
Using (S)-piperidin-3-ol and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 1.59-1.66 (m, 1H), 1.67-1.72 (m, 1H), 1.93-1.99 (m, 1H), 2.04-2.08 (m, 1H), 3.51 (q, 1H), 3.65 (br, 1H), 3.80-3.82 (m, 1H), 4.06 (br, 1H), 4.30 (br, 1H), 7.26 (s, 1H), 7.53 (d, 2H), 8.14-8.16 (m, 1H), 8.20 (d, 2H), 8.92 (d, 1H), 9.50 (d, 1H), 9.73 (s, 1H); MS (ESI, m/z): 367.1 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 2.40 (br, 1H), 2.68 (br, 1H), 3.05 (s, 6H), 3.72 (br, 1H), 3.94 (br, 1H), 4.13 (br, 2H), 4.33 (br, 1H), 7.08 (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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 2.08-2.15 (m, 2H), 2.39-2.45 (m, 2H), 2.88 (s, 6H), 3.08-3.13 (m, 2H), 3.26-3.31 (m, 2H), 3.50-3.59 (m, 2H), 3.92-3.96 (m, 1H), 7.31 (s, 1H), 7.56 (d, 2H), 8.20-8.22 (m, 1H), 8.26 (d, 2H), 8.95 (d, 1H), 9.58 (d, 1H), 9.80 (s, 1H); MS (ESI, m/z): 408.2 [M+H]+
Example 166. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-one
Using piperidin-4-one and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 1.85-1.90 (m, 4H), 3.93 (br, 2H), 3.99 (br, 2H), 7.31 (s, 1H), 7.54 (d, 2H), 8.12-8.14 (m, 1H), 8.23 (d, 2H), 8.91 (d, 1H), 9.49 (d, 1H), 9.74 (s, 1H); MS (ESI, m/z): 365.1 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 54 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 2.05 (d, 2H), 2.14-2.21 (m, 2H), 3.17 (s, 3H), 3.34-3.36 (m, 2H), 3.59 (d, 2H), 5.26 (br, 1H), 7.23 (s, 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 1.90-1.96 (m, 4H), 2.30 (d, 1H), 2.41-2.46 (m, 1H), 2.92 (s, 3H), 3.05-3.10 (m, 1H), 3.52-3.57 (m, 2H), 3.73 (br, 2H), 3.77 (br, 2H), 7.01 (s, 1H), 7.54 (d, 2H), 8.13-8.15 (m, 1H), 8.17 (d, 2H), 8.93 (d, 1H), 9.49 (d, 1H), 9.76 (s, 1H); MS (ESI, m/z): 408.2 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 1.32 (d, 3H), 1.39-1.45 (m, 2H), 1.62-1.67 (m, 1H), 1.94 (br, 2H), 2.11-2.18 (m, 1H), 3.85 (s, 3H), 2.97-3.13 (m, 2H), 3.48-3.63 (m, 2H), 7.29 (s, 1H), 7.54 (d, 2H), 7.94-7.97 (m, 1H), 8.23 (d, 2H), 8.83 (d, 1H), 9.30 (d, 1H), 9.70 (s, 1H); MS (ESI, m/z): 408.2 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 1.65 (br, 2H), 2.12 (br, 2H), 3.02 (br, 2H), 3.40 (s, 3H), 3.48 (br, 1H), 3.60 (br, 1H), 3.64-3.72 (m, 2H), 4.51 (br, 1H), 4.90-4.97 (m, 4H), 6.97 (s, 1H), 7.54 (d, 2H), 7.94-7.98 (m, 1H), 8.16 (d, 2H), 8.83 (d, 1H), 9.29 (d, 1H), 9.70 (s, 1H); MS (ESI, m/z): 438.2 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 1.97 (br, 4H), 2.43 (br, 4H), 3.89 (s, 3H), 4.23 (s, 2H), 4.47 (br, 1H), 6.97 (s, 1H), 7.54 (d, 2H), 7.81-7.84 (m, 1H), 8.16 (d, 2H), 8.77 (d, 1H), 9.16 (d, 1H), 9.66 (s, 1H); MS (ESI, m/z): 438.2 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 1.20 (d, 3H), 1.29-1.44 (m, 4H), 1.66 (br, 1H), 3.05 (br, 4H), 3.53-3.59 (m, 1H), 7.26 (s, 1H), 7.54 (d, 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 1.61-1.71 (m, 1H), 1.94-2.07 (m, 2H), 2.14-2.26 (m, 2H), 2.79 (t, 1H), 2.96 (s, 3H), 3.57-3.62 (m, 1H), 3.88-3.93 (m, 1H), 4.62 (br, 1H), 7.00 (s, 1H), 7.55 (d, 2H), 7.97-8.00 (m, 1H), 8.17 (d, 2H), 8.86 (d, 1H), 9.38 (d, 1H), 9.79 (s, 1H); MS (ESI, m/z): 380.2 [M+H]+
Example 174. (1S,2R)-2-((6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol
Scheme for the preparation of the Compound of Example 174:
Figure PCTKR2021003883-appb-I000010
Intermediate 8. methyl 1-methyl-1H-pyrazole-4-carbimidate
A suspension of 1-methyl-1H-pyrazole-4-carbonitrile (3.0 g, 28.04 mmol) in Hydrogen chloride-methanol solution (4 M HCl gas in MeOH, 30 mL) was stirred at room temperature for 16 hr. The solvent was removed in vacuo and the residue was purified via silica gel column chromatography (DCM / MeOH = 20 / 1; V / V) to afford 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-carbimidate (2.7 g, 19.4 mmol) in 30 mL of ammonia-MeOH solution (7.0 M NH3 in MeOH) was stirred at room temperature for 16 hr. The solvent was removed in vacuo and the residue was purified via reverse phase column chromatography (H2O / MeOH = 10 / 1; V / V) to afford 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. A solution of dimethyl carbonate (0.7 g, 7.76 mmol) in tetrahydrofuran (5 mL) was added to the above reaction mixture during 5 minutes. The reaction mixture was heated at 70 °C for 2 hr. The reaction mixture was cooled to room temperature and quenched by saturated ammonium chloride aqueous solution. 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 was filtered off and the filtrate was concentrated in vacuo. The residue was purified via silica gel column chromatography (Petroleum ether / EtOAc = 20 / 1; V / V) to afford 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 hr. 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 at reflux for 13 hr. 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 via column chromatography (DCM / MeOH = 10 / 1; V / V) to afford 950 mg of the title compound.
1H 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 in sealed tube was heated at 120 0C for 4 h. 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.
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.95 (br, 1H), 2.05 (br, 1H), 3.41 (br, 3H), 3.49 (br, 3H), 4.03 (s, 3H), 6.98 (s, 1H), 7.67 (d, 2H), 7.90 (d, 2H), 8.33 (s, 1H), 8.59 (s, 1H); MS (ESI, m/z): 370.1 [M+H]+
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 obtained as described for the example 174 (Scheme 2. General procedure B.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.69 (br, 2H), 1.77 (br, 2H), 1.99 (br, 1H), 2.03 (d, 2H), 3.89 (br, 1H), 3.93 (br, 2H), 4.01 (s, 3H), 7.08 (s, 1H), 7.64 (d, 2H), 7.88 (d, 2H), 8.32 (s, 1H), 8.58 (s, 1H); MS (ESI, m/z): 370.1 [M+H]+
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 obtained as described for the example 174 (Scheme 2. General procedure B.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.63-1.72 (m, 2H), 2.01-2.06 (m, 2H), 3.78 (br, 2H), 4.01 (s, 3H), 4.01-4.07 (m, 1H), 4.36 (br, 2H), 7.10 (s, 1H), 7.63 (d, 2H), 7.89 (d, 2H), 8.31 (s, 1H), 8.57 (s, 1H); MS (ESI, m/z): 370.1 [M+H]+
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 obtained as described for the example 174 (Scheme 2. General procedure B.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.30-1.40 (m, 4H), 1.89-2.04 (m, 4H), 3.21-3.28 (m, 1H), 3.48 (d, 2H), 4.01 (s, 3H), 7.08 (s, 1H), 7.64 (d, 2H), 7.88 (d, 2H), 8.30 (s, 1H), 8.56 (s, 1H); MS (ESI, m/z): 384.2 [M+H]+
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 obtained as described for the example 174 (Scheme 2. General procedure B.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.28-1.37 (m, 4H), 1.55 (q, 2H), 1.91-2.00 (m, 4H), 3.25 (br, 1H), 3.67 (t, 2H), 4.01 (s, 3H), 7.08 (s, 1H), 7.64 (d, 2H), 7.87 (d, 2H), 8.31 (s, 1H), 8.58 (s, 1H); MS (ESI, m/z): 398.2 [M+H]+
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 obtained as described for the example 174 (Scheme 2. General procedure B.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.23-1.41 (m, 4H), 1.57-1.65 (m, 2H), 1.69-1.80 (m, 1H), 1.98 (d, 2H), 3.21 (t, 2H), 3.57 (t, 2H), 4.00 (s, 3H), 4.83 (br, 2H), 7.05 (s, 1H), 7.63 (d, 2H), 7.88 (d, 2H), 8.29 (s, 1H), 8.55 (s, 1H); MS (ESI, m/z): 412.2 [M+H]+
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 obtained as described for the example 174 (Scheme 2. General procedure B.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.03 (d, 3H), 1.23-1.34 (m, 2H), 1.82-1.89 (m, 1H), 1.92 (d, 2H), 3.24 (br, 2H), 4.01 (s, 3H), 4.83 (br, 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 obtained as described for the example 174 (Scheme 2. General procedure B.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 3.00 (t, 3H), 3.59 (br, 8H), 4.01 (s, 3H), 7.22 (s, 1H), 7.63 (d, 2H), 7.95 (d, 2H), 8.33 (s, 1H), 8.59 (s, 1H); MS (ESI, m/z): 369.2 [M+H]+
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 obtained as described for the example 174 (Scheme 2. General procedure B.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 3.39 (t, 2H), 3.60 (br, 4H), 3.96 (t, 2H), 4.01 (s, 3H), 4.34 (br, 4H), 7.22 (s, 1H), 7.63 (d, 2H), 7.96 (d, 2H), 8.33 (s, 1H), 8.59 (s, 1H); MS (ESI, m/z): 399.2 [M+H]+
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 obtained as described for the example 174 (Scheme 2. General procedure B.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 2.10-2.30 (m, 3H), 3.82 (br, 2H), 4.01 (s, 3H), 4.03 (br, 1H), 4.63 (d, 1H), 6.83 (s, 1H), 7.65 (d, 2H), 7.90 (d, 2H), 8.30 (s, 1H), 8.55 (s, 1H); MS (ESI, m/z): 356.1 [M+H]+
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 obtained as described for the example 174 (Scheme 2. General procedure B.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.93-2.01 (m, 2H), 2.11-2.18 (m, 2H), 3.19-3.25 (m, 1H), 3.84-3.90 (m, 2H), 4.01 (s, 3H), 4.31 (br, 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 obtained as described for the example 174 (Scheme 2. General procedure B.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.44-1.52 (m, 1H), 1.62-1.71 (m, 1H), 1.87 (br, 1H), 1.93 (d, 2H), 3.18 (br, 1H), 3.39 (t, 1H), 3.48-3.52 (m, 1H), 3.58-3.62 (m, 1H), 4.01 (s, 3H), 4.59 (br, 2H), 7.08 (s, 1H), 7.63 (d, 2H), 7.88 (d, 2H), 8.31 (s, 1H), 8.57 (s, 1H); MS (ESI, m/z): 384.2 [M+H]+
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 obtained as described for the example 174 (Scheme 2. General procedure B.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 2.10-2.30 (m, 3H), 3.82 (br, 2H), 4.01 (s, 3H), 4.03 (br, 1H), 4.63 (d, 1H), 6.83 (s, 1H), 7.65 (d, 2H), 7.90 (d, 2H), 8.30 (s, 1H), 8.55 (s, 1H); MS (ESI, m/z): 356.1 [M+H]+
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 obtained as described for the example 174 (Scheme 2. General procedure B.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.83-1.94 (m, 1H), 3.43 (br, 6H), 4.02 (s, 3H), 4.37 (br, 1H), 6.97 (s, 1H), 7.65 (d, 2H), 7.88 (d, 2H), 8.32 (s, 1H), 8.58 (s, 1H); MS (ESI, m/z): 370.1 [M+H]+
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 obtained as described for the example 174 (Scheme 2. General procedure B.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.03 (t, 3H), 1.59-1.68 (m, 2H), 1.78-1.86 (m, 1H), 3.69-3.73 (m, 2H), 4.02 (s, 3H), 6.97 (s, 1H), 7.65 (d, 2H), 7.89 (d, 2H), 8.32 (s, 1H), 8.56 (s, 1H); MS (ESI, m/z): 358.1 [M+H]+
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 obtained as described for the example 174 (Scheme 2. General procedure B.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.46-1.52 (m, 2H), 2.01-2.05 (m, 2H), 2.13 (br, 1H), 3.43 (br, 4H), 3.63 (br, 1H), 4.02 (s, 3H), 6.97 (s, 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.29-1.35 (m, 2H), 1.54 (d, 1H), 1.72-1.80 (m, 2H), 1.85 (d, 1H), 1.95 (d, 1H), 2.10-2.20 (m, 1H), 2.98-3.08 (m, 2H), 3.20 (d, 1H), 3.53 (t, 2H), 3.92 (d, 1H), 7.17 (s, 1H), 7.46 (d, 2H), 8.06-8.09 (m, 1H), 8.11 (d, 2H), 8.87 (d, 1H), 9.37 (d, 1H), 9.63 (s, 1H); MS (ESI, m/z): 407.2 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.56-1.60 (m, 1H), 1.66-1.74 (m, 1H), 1.77-1.83 (m, 1H), 1.88-1.92 (m, 1H), 1.94-2.04 (m, 1H), 2.14-2.21 (m, 1H), 2.99-3.11 (m, 1H), 3.18-3.27 (m, 1H), 3.51 (t, 1H), 3.61-3.73 (m, 1H), 3.78-3.86 (m, 1H), 3.88-4.00 (m, 2H), 7.23 (s, 1H), 7.50 (d, 2H), 8.12-8.19 (m, 3H), 8.91 (d, 1H), 9.47 (d, 1H), 9.69 (s, 1H); MS (ESI, m/z): 423.2 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.02 (t, 3H), 1.21 (d, 3H), 1.58-1.68 (m, 2H), 1.79-1.85 (m, 1H), 2.01-2.05 (m, 1H), 4.00 (br, 1H), 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 1.53-1.66 (m, 2H), 1.94-2.08 (m, 2H), 2.13 (d, 2H), 2.86 (s, 3H), 3.01 (t, 1H), 3.13 (t, 1H), 3.57 (br, 2H), 3.81-3.93 (m, 1H), 7.00 (s, 1H), 7.54 (d, 2H), 8.12-8.16 (m, 1H), 8.24 (d, 2H), 8.92 (d, 1H), 9.49 (d, 1H), 9.76 (s, 1H); MS (ESI, m/z): 394.2 [M+H]+
Example 194. (R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol
Using (R)-pyrrolidin-3-ol) and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR: (400 MHz, CD3OD) δ [ppm] = 2.17 (br, 2H), 3.70 (br, 2H), 3.86 (br, 2H), 4.59 (br, 1H), 6.95 (s, 1H), 7.52 (d, 2H), 8.07-8.11 (m, 1H), 8.19 (d, 2H), 8.89 (d, 1H), 9.43 (d, 1H), 9.69 (s, 1H); MS (ESI, m/z): 353.1 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR: (400 MHz, CD3OD) δ [ppm] = 1.60 (br, 1H), 1.80-1.87 (m, 1H), 1.89-1.97 (m, 1H), 2.02-2.10 (m, 1H), 2.17-2.21 (m, 1H), 2.82-2.89 (m, 1H), 3.07 (br, 1H), 3.24 (s, 3H), 3.44 (t, 2H), 7.42 (s, 1H), 7.56 (d, 2H), 8.08-8.12 (m, 1H), 8.21 (d, 2H), 8.89 (d, 1H), 9.45 (d, 1H), 9.71 (s, 1H); MS (ESI, m/z): 396.2 [M+H]+
Example 196. (S)-4-(4-chlorophenyl)-6-(3-fluoropyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidine
Using (S)-3-fluoropyrrolidine and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR: (400 MHz, CD3OD) δ [ppm] = 2.24 (br, 2H), 3.79 (br, 2H), 3.87 (br, 2H), 4.17 (br, 1H), 6.98 (s, 1H), 7.53 (d, 2H), 8.03-8.06 (m, 1H), 8.23 (d, 2H), 8.86 (d, 1H), 9.40 (d, 1H), 9.71 (s, 1H); MS (ESI, m/z): 355.1 [M+H]+
Example 197. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidine
Using 2-(trifluoromethyl)pyrrolidine and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR: (400 MHz, CD3OD) δ [ppm] = 2.26 (br, 2H), 2.32 (br, 2H), 3.74 (br, 2H), 3.89 (br, 1H), 7.20 (s, 1H), 7.56 (d, 2H), 8.02-8.06 (m, 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR: (400 MHz, CD3OD) δ [ppm] = 2.58-2.68 (m, 2H), 3.95 (br, 2H), 4.11 (br, 2H), 7.06 (s, 1H), 7.55 (d, 2H), 8.04-8.07 (m, 1H), 8.28 (d, 2H), 8.87 (d, 1H), 9.44 (d, 1H), 9.75 (s, 1H); MS (ESI, m/z): 373.1 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR: (400 MHz, CD3OD) δ [ppm] = 2.44 (br, 1H), 2.68 (br, 1H), 3.52 (br, 4H), 3.70 (br, 2H), 3.99 (br, 5H), 4.14 (br, 2H), 7.06 (s, 1H), 7.54 (d, 2H), 8.16-8.19 (m, 1H), 8.25 (d, 2H), 8.94 (d, 1H), 9.57 (d, 1H), 9.80 (s, 1H); MS (ESI, m/z): 422.2 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR: (400 MHz, CD3OD) δ [ppm] = 2.00 (br, 2H), 2.32-2.38 (m, 2H), 3.73 (br, 2H), 4.04 (br, 1H), 7.01 (s, 1H), 7.54 (d, 2H), 8.07-8.10 (m, 1H), 8.17 (d, 2H), 8.88 (d, 1H), 9.46 (d, 1H), 9.73 (s, 1H); MS (ESI, m/z): 380.1 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR: (400 MHz, CD3OD) δ [ppm] = 2.09 (br, 8H), 3.74-3.78 (m, 1H), 3.96-3.99 (m, 1H), 4.19-4.21 (m, 2H), 4.43-4.47 (m, 1H), 5.31 (br, 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR: (400 MHz, CD3OD) δ [ppm] = 1.59 (br, 1H), 1.90 (br, 1H), 2.02 (br, 1H), 3.06 (s, 3H), 3.55 (s, 3H), 3.72 (br, 1H), 3.84 (br, 2H), 7.10 (s, 1H), 7.53 (d, 2H), 8.18 (d, 2H), 8.19-8.27 (m, 1H), 8.95 (d, 1H), 9.55 (d, 1H), 9.78 (s, 1H); MS (ESI, m/z): 396.2 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 54 (Scheme 1. General procedure A.).
1H NMR: (400 MHz, CD3OD) δ [ppm] = 1.77-1.83 (m, 1H), 1.95-2.04 (m, 1H), 2.10-2.15 (m, 1H), 2.17-2.23 (m, 1H), 2.96-3.01 (m, 1H), 3.04-3.11 (m, 1H), 3.37-3.43 (m, 1H), 3.69-3.73 (m, 1H), 4.56 (br, 1H), 7.03 (s, 1H), 7.54 (d, 2H), 8.02-8.06 (m, 1H), 8.17 (d, 2H), 8.88 (d, 1H), 9.44 (d, 1H), 9.82 (s, 1H); MS (ESI, m/z): 366.1 [M+H]+
Example 204. 6-(4-chlorophenyl)-N-(piperidin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-amine
Using tert-butyl 3-aminopiperidine-1-carboxylate and separation method of PREP. HPLC, the title compound was obtained as described for the example 54 (Scheme 1. General procedure A.).
1H NMR: (400 MHz, CD3OD) δ [ppm] = 1.77-1.83 (m, 1H), 1.95-2.04 (m, 1H), 2.10-2.15 (m, 1H), 2.17-2.23 (m, 1H), 2.96-3.01 (m, 1H), 3.04-3.11 (m, 1H), 3.37-3.43 (m, 1H), 3.69-3.73 (m, 1H), 4.56 (br, 1H), 7.03 (s, 1H), 7.54 (d, 2H), 8.02-8.06 (m, 1H), 8.17 (d, 2H), 8.88 (d, 1H), 9.44 (d, 1H), 9.82 (s, 1H); MS (ESI, m/z): 366.1 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 54 (Scheme 1. General procedure A.).
1H NMR: (400 MHz, CD3OD) δ [ppm] = 1.60 (br, 1H), 1.92 (br, 1H), 2.03 (br, 1H), 3.79 (br, 5H), 7.08 (s, 1H), 7.55 (d, 2H), 8.08-8.11 (m, 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 54 (Scheme 1. General procedure A.).
1H NMR: (400 MHz, CD3OD) δ [ppm] = 1.85-1.95 (m, 2H), 2.24-2.32 (m, 1H), 2.80-2.87 (m, 1H), 3.10-3.15 (m, 1H), 3.41-3.48 (m, 1H), 3.50-3.55 (m, 1H), 3.75 (br, 2H), 7.01 (s, 1H), 7.54 (d, 2H), 8.09-8.13 (m, 1H), 8.17 (d, 2H), 8.91 (d, 1H), 9.48 (d, 1H), 9.77 (s, 1H); MS (ESI, m/z): 366.1 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 54 (Scheme 1. General procedure 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 54 (Scheme 1. General procedure A.).
1H NMR: (400 MHz, CD3OD) δ [ppm] = 1.61 (br, 2H), 2.04 (br, 2H), 2.20 (t, 1H), 3.35 (br, 1H), 7.01 (s, 1H), 7.55 (d, 2H), 7.78-7.81 (m, 1H), 8.18 (d, 2H), 8.76 (d, 1H), 9.12 (d, 1H), 9.66 (s, 1H); MS (ESI, m/z): 396.1 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR: (400 MHz, CD3OD) δ [ppm] = 1.43 (t, 6H), 1.61 (br, 1H), 1.90 (br, 1H), 2.02 (br, 1H), 2.19 (t, 1H), 3.55 (br, 1H), 3.72 (br, 1H), 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR: (400 MHz, CD3OD) δ [ppm] = 1.98 (br, 1H), 2.28 (br, 1H), 2.79 (br, 1H), 3.54 (br, 1H), 3.68-3.78 (m, 4H), 4.02 (br, 1H), 6.88 (s, 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR: (400 MHz, CD3OD) δ [ppm] = 1.98 (br, 1H), 2.28 (br, 1H), 2.79 (br, 1H), 3.54 (br, 1H), 3.68-3.78 (m, 4H), 4.02 (br, 1H), 6.88 (s, 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR: (400 MHz, CD3OD) δ [ppm] = 2.44 (br, 1H), 2.53 (br, 1H), 3.57 (br, 1H), 3.84 (br, 2H), 4.06 (br, 2H), 7.06 (s, 1H), 7.55 (d, 2H), 8.08-8.12 (m, 1H), 8.27 (d, 2H), 8.89 (d, 1H), 9.49 (d, 1H), 9.76 (s, 1H); MS (ESI, m/z): 362.1 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR: (400 MHz, CD3OD) δ [ppm] = 1.05 (t, 3H), 1.48-1.59 (m, 1H), 1.61-1.70 (m, 1H), 3.55 (br, 1H), 3.72 (br, 1H), 3.76 (br, 1H), 6.99 (s, 1H), 7.51 (d, 2H), 8.09-8.13 (m, 3H), 8.90 (d, 1H), 9.44 (d, 1H), 9.69 (s, 1H); MS (ESI, m/z): 355.1 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR: (400 MHz, CD3OD) δ [ppm] = 1.60-1.66 (m, 1H), 1.81-1.95 (m, 4H), 2.17-2.23 (m, 1H), 2.43-2.50 (m, 1H), 4.34-4.38 (m, 1H), 4.62 (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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR: (400 MHz, CD3OD) δ [ppm] = 1.76-1.83 (m, 4H), 1.84-1.87 (m, 4H), 2.02 (br, 1H), 3.92 (br, 1H), 4.24 (br, 1H), 6.96 (s, 1H), 7.53 (d, 2H), 8.01-8.05 (m, 1H), 8.12 (d, 2H), 8.86 (d, 1H), 9.34 (d, 1H), 9.67 (s, 1H); MS (ESI, m/z): 381.1 [M+H]+
Example 216. Cis-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexan-1-ol
Using Cis-(4-aminocyclohexyl)methanol and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR: (400 MHz, CD3OD) δ [ppm] = 1.70-1.84 (m, 4H), 1.85-1.95 (m, 4H), 1.98-2.05 (m, 1H), 3.71-3.74 (m, 1H), 3.84-8.37 (m, 1H), 4.46 (br, 1H), 7.04 (s, 1H), 7.55 (d, 2H), 8.09-8.15 (m, 3H), 8.90 (d, 1H), 9.43 (d, 1H), 9.69 (s, 1H); MS (ESI, m/z): 395.2 [M+H]+
Example 217. Trans-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexan-1-ol
Using Trans-(4-aminocyclohexyl)methanol and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR: (400 MHz, CD3OD) δ [ppm] = 1.70-1.84 (m, 4H), 1.85-1.95 (m, 4H), 1.98-2.05 (m, 1H), 3.71-3.74 (m, 1H), 3.84-8.37 (m, 1H), 4.46 (br, 1H), 7.04 (s, 1H), 7.55 (d, 2H), 8.09-8.15 (m, 3H), 8.90 (d, 1H), 9.43 (d, 1H), 9.69 (s, 1H); MS (ESI, m/z): 395.2 [M+H]+
Example 218. 4-(4-chlorophenyl)-6-(4-(2-methoxyethyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine
Using 1-(2-methoxyethyl)piperazine and separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 9.83 (d, J = 2.0, 0.8 Hz, 1H), 9.59 (dd, J = 8.2, 2.0, 1.5 Hz, 1H), 8.95 (d, J = 5.7, 1.5, 0.7 Hz, 1H), 8.28 (d, 2H), 8.19 (dd, J = 8.2, 5.7, 0.7 Hz, 1H), 7.54 (d, 2H), 7.44 (s, 1H), 3.82-3.77 (m, 4H), 3.77-3.50 (m, 4H), 3.49-3.43 (m, 7H); MS (ESI, m/z): 410.2 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 9.74 (d, J = 1.7, 0.8 Hz, 1H), 9.52 (dd, J = 8.2, 1.9, 1.5 Hz, 1H), 8.92 (dd, J = 5.7, 1.5, 0.8 Hz, 1H), 8.21 (dd, 2H), 8.19-8.14 (m, 1H), 7.51 (d, 2H), 7.30 (s, 1H), 4.56-4.47 (m, 1H), 4.47-4.33 (m, 1H), 4.17-4.06 (m, 1H), 4.04-3.94 (m, 1H), 3.94-3.82 (m, 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 9.74 (d, J = 1.7, 0.8 Hz, 1H), 9.52 (dd, J = 8.2, 1.9, 1.5 Hz, 1H), 8.92 (dd, J = 5.7, 1.5, 0.8 Hz, 1H), 8.21 (dd, 2H), 8.19-8.14 (m, 1H), 7.51 (d, 2H), 7.30 (s, 1H), 4.56-4.47 (m, 1H), 4.47-4.33 (m, 1H), 4.17-4.06 (m, 1H), 4.04-3.94 (m, 1H), 3.94-3.82 (m, 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 9.74 (d, J = 1.7, 0.8 Hz, 1H), 9.52 (dd, J = 8.2, 1.9, 1.5 Hz, 1H), 8.92 (dd, J = 5.7, 1.5, 0.8 Hz, 1H), 8.21 (dd, 2H), 8.19-8.14 (m, 1H), 7.51 (d, 2H), 7.30 (s, 1H), 4.56-4.47 (m, 1H), 4.47-4.33 (m, 1H), 4.17-4.06 (m, 1H), 4.04-3.94 (m, 1H), 3.94-3.82 (m, 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 9.74 (d, J = 1.7, 0.8 Hz, 1H), 9.52 (dd, J = 8.2, 1.9, 1.5 Hz, 1H), 8.92 (dd, J = 5.7, 1.5, 0.8 Hz, 1H), 8.21 (dd, 2H), 8.19-8.14 (m, 1H), 7.51 (d, 2H), 7.30 (s, 1H), 4.56-4.47 (m, 1H), 4.47-4.33 (m, 1H), 4.17-4.06 (m, 1H), 4.04-3.94 (m, 1H), 3.94-3.82 (m, 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 9.73 (d, J = 1.3 Hz, 1H), 9.39 (dd, J = 8.1, 1.8 Hz, 1H), 8.85 (dd, J = 5.5, 1.5 Hz, 1H), 8.26 (d, 2H), 8.02 (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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 9.83 (s, 1H), 9.59 (d, 1H), 8.95 (dd, J = 5.6, 1.5, 0.7 Hz, 1H), 8.29 (d, 2H), 8.19 (dd, J = 8.2, 5.7, 0.8 Hz, 1H), 7.54 (d, 2H), 7.45 (s, 1H), 3.96 (d, J = 3.7 Hz, 1H), 3.92-3.79 (m, 2H), 3.80-3.70 (m, 2H), 3.60-3.50 (m, 2H), 3.45-3.35 (m, 1H), 2.04-1.74 (m, 3H), 1.42 (d, J = 6.8 Hz, 3H); MS (ESI, m/z): 410.2 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 9.75 (s, 1H), 9.52 (dd, J = 8.2, 1.7 Hz, 1H), 8.92 (d, J = 5.6, 1.5, 0.7 Hz, 1H), 8.23 (d, 2H), 8.15 (dd, J = 8.2, 5.7, 0.7 Hz, 1H), 7.53 (d, 2H), 7.31 (s, 1H), 4.85-4.66 (m, 2H), 4.21-4.05 (m, 1H), 3.90 (s, 2H), 3.40 (s, 3H), 3.28-3.15 (m, 2H), 2.04 (d, J = 12.8, 3.7 Hz, 2H), 1.70-1.53 (m, 2H); MS (ESI, m/z): 438.2 [M+H]+
Example 226. (1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol
Scheme for the preparation of the Compound of Example 226:
Figure PCTKR2021003883-appb-I000011
Intermediate 13. (1-(6-chloro-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol
To a solution of 4,6-dichloro-2-(pyridin-3-yl)pyrimidine (3.0 g, 13.3 mmol) in DMF (50 mL) was added diisopropylethylamine (4.63 mL, 26.54 mmol) followed by piperidin-4-ylmethanol (2.01 g, 13.27 mmol) at room temperature. The reaction mixture was heated at 70 °C for overnight and cooled to room temperature. The reaction mixture was quenched with water and extracted three times with DCM. The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, hexane/ethyl acetate, gradient) to give 1.0 g of the title compound.
Example 226. (1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol
To a solution (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/H2O (4/1) was added Pd(PPh3)4 (60 mg, 0.052 mmol). The mixture is heated under microwave at 80 ℃ for 120 minutes, cooled to room temperature and extracted three times with EtOAc (30 mL). The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, hexane/ethyl acetate, gradient) to give 219 mg of the title compound. (Scheme 4. General procedure 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 226 (Scheme 4. General procedure D.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 9.60 (s, 1H), 8.96 (d, J = 8.2 Hz, 1H), 8.67 (d, J = 4.9 Hz, 1H), 8.33 (dd, J = 8.9, 3.5 Hz, 2H), 7.68-7.62 (m, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.21 (s, 1H), 3.51-3.44 (m, 2H), 3.27-3.03 (m, 4H), 2.19 (t, J = 7.6 Hz, 0H), 1.99-1.79 (m, 3H), 1.41-1.22 (m, 2H); MS (ESI, m/z): 431.2 [M+H]+
Example 228. (1-(6-(4-methoxyphenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol
Using (4-methoxyphenyl)boronic acid and separation method of PREP. HPLC, the title compound was obtained as described for the example 226 (Scheme 4. General procedure D.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 9.64 (s, 1H), 9.25 (d, J = 8.1 Hz, 1H), 8.85 (dd, 1H), 8.15 (d, 2H), 8.01-7.96 (m, 1H), 7.21 (s, 1H), 7.10 (dd, J = 8.9, 3.1 Hz, 2H), 4.33 (d, J = 6.5 Hz, 2H), 3.89 (s, 3H), 3.20-3.07 (m, 4H), 2.33-2.15 (m, 1H), 2.01-1.90 (m, 2H), 1.50-1.35 (m, 2H); MS (ESI, m/z): 377.2 [M+H]+
Example 229. (1-(2-(pyridin-3-yl)-6-(p-tolyl)pyrimidin-4-yl)piperidin-4-yl)methanol
Using p-tolylboronic acid and separation method of PREP. HPLC, the title compound was obtained as described for the example 226 (Scheme 4. General procedure D.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 9.66 (s, 1H), 9.31 (d, J = 8.2, 1.8 Hz, 1H), 8.87 (dd, J = 5.5, 1.5, 0.5 Hz, 1H), 8.07 (d, 2H), 8.05-8.00 (m, 1H), 7.37 (d, 2H), 7.25 (s, 1H), 4.89-4.72 (m, 2H), 4.33 (d, J = 6.6 Hz, 2H), 3.23-3.06 (m, 2H), 2.44 (s, 3H), 2.31-2.14 (m, 1H), 1.96 (d, J = 13.4 Hz, 2H), 1.51-1.34 (m, 2H); MS (ESI, m/z): 361.2 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 9.68 (d, J = 2.1 Hz, 1H), 9.40 (dt, J = 8.2, 1.8 Hz, 1H), 8.87 (d, J = 5.5 Hz, 1H), 8.24-8.16 (m, 2H), 8.06 (dd, J = 8.2, 5.6 Hz, 1H), 7.51 (dd, J = 8.9, 2.2 Hz, 2H), 6.94 (d, J = 8.4 Hz, 1H), 4.36-4.22 (m, 1H), 3.95-3.88 (m, 1H), 3.88-3.79 (m, 1H), 2.10-1.97 (m, 1H), 1.90 (dq, J = 18.0, 10.8, 8.5 Hz, 1H), 1.70-1.41 (m, 1H); MS (ESI, m/z): 367.1 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 9.68 (d, J = 2.1 Hz, 1H), 9.40 (dt, J = 8.2, 1.8 Hz, 1H), 8.87 (d, J = 5.5 Hz, 1H), 8.24-8.16 (m, 2H), 8.06 (dd, J = 8.2, 5.6 Hz, 1H), 7.51 (dd, J = 8.9, 2.2 Hz, 2H), 6.94 (d, J = 8.4 Hz, 1H), 4.36-4.22 (m, 1H), 3.95-3.88 (m, 1H), 3.88-3.79 (m, 1H), 2.10-1.97 (m, 1H), 1.90 (dq, J = 18.0, 10.8, 8.5 Hz, 1H), 1.70-1.41 (m, 1H); MS (ESI, m/z): 367.1 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 9.71 (d, J = 6.8 Hz, 1H), 9.38 (d, J = 7.8 Hz, 1H), 8.80 (d, J = 5.0 Hz, 1H), 8.19 (d, J = 8.5 Hz, 2H), 8.06-8.01 (m, 1H), 7.54 (d, J = 8.6 Hz, 2H), 7.03 (s, 1H), 4.04-3.52 (m, 4H), 2.09-1.76 (m, 2H), 1.68-1.48 (m, 2H), 1.29 (s, 3H); MS (ESI, m/z): 394.1 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 9.67 (s, 1H), 9.40 (dd, J = 8.2, 4.3, 2.5 Hz, 1H), 8.88 (d, 1H), 8.15 (d, 2H), 8.12-8.04 (m, 1H), 7.50 (d, 2H), 7.23 (s, 1H), 3.93-3.78 (m, 1H), 3.78-3.61 (m, 1H), 3.61-3.46 (m, 1H), 3.35 (d, 2H), 3.13-2.98 (m, 1H), 1.97-1.82 (m, 1H), 1.81-1.37 (m, 3H); MS (ESI, m/z): 397.1 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 9.67 (s, 1H), 9.40 (dd, J = 8.2, 4.3, 2.5 Hz, 1H), 8.88 (d, 1H), 8.15 (d, 2H), 8.12-8.04 (m, 1H), 7.50 (d, 2H), 7.23 (s, 1H), 3.93-3.78 (m, 1H), 3.78-3.61 (m, 1H), 3.61-3.46 (m, 1H), 3.35 (d, 2H), 3.13-2.98 (m, 1H), 1.97-1.82 (m, 1H), 1.81-1.37 (m, 3H); MS (ESI, m/z): 397.1 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 9.66 (s, 1H), 9.40 (d, J = 8.2, 1.7 Hz, 1H), 8.87 (dd, J = 5.7, 1.5 Hz, 1H), 8.17 (d, 2H), 8.07 (dd, 1H), 7.48 (d, 2H), 6.91 (s, 1H), 5.14 (dd, J = 50.2, 15.3 Hz, 1H), 4.57-4.46 (m, 1H), 4.24-3.88 (m, 1H), 3.86-3.70 (m, 1H), 2.13-1.69 (m, 2H); MS (ESI, m/z): 371.1 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 9.66 (s, 1H), 9.40 (d, J = 8.2, 1.7 Hz, 1H), 8.87 (dd, J = 5.7, 1.5 Hz, 1H), 8.17 (d, 2H), 8.07 (dd, 1H), 7.48 (d, 2H), 6.91 (s, 1H), 5.14 (dd, J = 50.2, 15.3 Hz, 1H), 4.57-4.46 (m, 1H), 4.24-3.88 (m, 1H), 3.86-3.70 (m, 1H), 2.13-1.69 (m, 2H); MS (ESI, m/z): 371.1 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 9.65 (s, 1H), 9.39 (d, J = 8.3, 1.7 Hz, 1H), 8.87 (dd, J = 5.6, 1.6 Hz, 1H), 8.15 (d, J = 8.6, 2.4 Hz, 2H), 8.07 (dd, J = 9.1, 5.7, 3.6 Hz, 1H), 7.48 (dd, J = 8.7, 2.3 Hz, 2H), 6.87 (s, 1H), 4.06-3.77 (m, 1H), 3.77-3.62 (m, 1H), 3.62-3.39 (m, 1H), 2.68-2.38 (m, 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 9.76 (d, J = 449.8 Hz, 1H), 9.53 (d, J = 1746.2 Hz, 1H), 8.92 (d, J = 5.5 Hz, 1H), 8.24 (d, 2H), 8.15 (dd, J = 8.2, 5.7 Hz, 1H), 7.55 (dd, J = 8.5, 1.6 Hz, 2H), 7.33 (s, 1H), 4.17-3.99 (m, 2H), 3.30-3.20 (m, 4H), 2.11-1.97 (m, 2H), 1.71-1.54 (m, 2H), 1.35 (d, J = 6.8 Hz, 3H); MS (ESI, m/z): 438.2 [M+H]+
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 separation method of PREP. HPLC, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CD3OD) δ [ppm] = 9.76 (s, 1H), 9.53 (d, 1H), 8.92 (d, J = 5.6 Hz, 1H), 8.25 (d, 2H), 8.15 (dd, J = 8.2, 5.6 Hz, 1H), 7.55 (d, J = 8.6 Hz, 2H), 7.34 (s, 1H), 4.86-4.65 (m, 2H), 4.20-4.07 (m, 1H), 3.99 (s, 2H), 3.29-3.18 (m, 2H), 2.05 (d, J = 12.8 Hz, 2H), 1.71-1.53 (m, 2H); MS (ESI, m/z): 424.2 [M+H]+
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 obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, DMSO-d 6) 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 obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CDCl3) δ [ppm] = 9.68 (s, 1H), 8.75 (dd, J = 8.0, 1.9 Hz, 1H), 8.68-8.62 (m, 1H), 8.05 (d, 2H), 7.43 (d, 2H), 7.37 (dd, J = 7.9, 4.8, 0.8 Hz, 1H), 6.55 (s, 1H), 4.10-3.85 (m, 1H), 3.85-3.64 (m, 3H), 3.62-3.40 (m, 2H), 2.72-2.51 (m, 1H), 2.26-2.07 (m, 1H), 1.99-1.76 (m, 1H); MS (ESI, m/z): 367.1 [M+H]+
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 obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 9.60 (s, 1H), 8.86 (d, J = 7.9 Hz, 1H), 8.66-8.63 (m, 1H), 8.20 (d, 2H), 7.56 (s, 1H), 7.51 (d, 2H), 6.88 (s, 1H), 4.35 (d, J = 28.7 Hz, 2H), 4.14-3.74 (m, 3H), 3.50 (s, 1H), 1.97 (s, 3H); MS (ESI, m/z): 410.1 [M+H]+
Example 242. (3R,4R)-4-acetamido-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl acetate
Using (3R,4R)-4-acetamidopyrrolidin-3-yl acetate, the title compound was obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 9.52 (s, 1H), 8.79 (d, J = 7.9 Hz, 1H), 8.60 (s, 1H), 8.15 (d, J = 8.5 Hz, 2H), 7.51 (dd, J = 7.4, 5.0 Hz, 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 obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, DMSO-d 6) 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 obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, DMSO-d 6) 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 obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, DMSO-d 6) 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 obtained as described for the example 226 (Scheme 4. General procedure D.).
1H NMR (600 MHz, DMSO-d 6) 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 obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, DMSO-d 6) 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
Scheme for the preparation of the Compound of Example 248:
Figure PCTKR2021003883-appb-I000012
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 is heated under microwave at 65 ℃ for 20 minutes, 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 silicagel column chromatography to give 1.02 g of the title compound.
1H NMR (600 MHz, CDCl3) δ [ppm] = 7.52 (d, 2H), 7.74 (s, 1H), 7.79 (dd, 1H), 8.06 (d, 2H), 9.02 (d, 1H), 9.12 (d, 1H), 10.16 (s, 1H); MS (ESI, m/z): 336.1 [M+H]+
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 in sealed tube was heated at 120 0C for 4 h. 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 (Scheme 1. General procedure A.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 248 (Scheme 1. General procedure A.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, DMSO-d 6) 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 obtained as described for the example 248 (Scheme 1. General procedure A.).
1H NMR (600 MHz, DMSO-d 6) 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 obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, DMSO-d 6) 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 obtained as described for the example 248 (Scheme 1. General procedure A.).
1H NMR (600 MHz, DMSO-d 6) 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 obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 248 (Scheme 1. General procedure A.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 248 (Scheme 1. General procedure A.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 248 (Scheme 1. General procedure A.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 248 (Scheme 1. General procedure A.).
1H NMR (400 MHz, DMSO-d 6) 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
Scheme for the preparation of the Compound of Example 263:
Figure PCTKR2021003883-appb-I000013
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 H2O (5 mL) was added (4-(trifluoromethyl)phenyl)boronic acid (3.61 g, 19.25 mmol), Na2CO3 (3.79 g, 35.75 mmol), Palladium acetate (617.5 mg, 2.75 mmol) and PPh3 (721.3 mg, 2.75 mmol) at room temperature under Nitrogen. The reaction mixture was heated and stirred at 90 °C under N2 for 16 hr. 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 via silica gel column chromatography (Petroleum ether / EtOAc = 20 / 1; V / V) to afford 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 ACN (20 mL) was added (S)-pyrrolidin-3-ol (716 mg, 82.2 mmol) and DIPEA (2.66 g, 205.5 mmol) at room temperature. The reaction mixture was heated at 65 °C for 5 h. The mixture was concentrated in vacuo. The residue was purified via silica gel column chromatography (Petroleum ether / EtOAc = 2 / 1; V / V) to afford 573 mg of the title compound.
1H NMR (400 MHz, DMSO-d 6) δ [ppm] = 1.83-2.14 (m, 2 H), 3.39-3.72 (m, 4 H), 4.43 (d, J = 27.3 Hz, 1 H), 7.11 (d, J = 7.3 Hz, 1 H), 7.87 (d, J =8.0 Hz, 2 H), 8.32 (d, J = 7.0 Hz, 2 H); MS (ESI, m/z): 344.2 [M+H]+
Example 263. (S)-1-(2-(4-methylpyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol
To a (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/H2O (4/1) was added Pd(PPh3)4 (11.4 mg, 0.01 mmol). The mixture is heated under microwave at 150 ℃ for 120 minutes, cooled to room temperature and extracted with DCM. The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, DCM/MeOH, gradient) to give 30 mg of the title compound. (Scheme 3. General procedure C.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 248 (Scheme 1. General procedure A.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 248 (Scheme 1. General procedure A.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 226 (Scheme 4. General procedure D.).
1H NMR (600 MHz, CDCl3) δ [ppm] = 9.69 (s, 1H), 8.76 (dd, J = 7.9, 1.9 Hz, 1H), 8.65 (dd, J = 4.7, 1.7 Hz, 1H), 8.07 (d, J = 8.9 Hz, 2H), 7.37 (dd, J = 7.9, 4.8, 0.9 Hz, 1H), 6.98 (d, J = 8.9 Hz, 2H), 6.81 (s, 1H), 4.74-4.58 (m, 2H), 3.92-3.83 (m, 4H), 3.55 (d, J = 6.2 Hz, 2H), 3.30-3.22 (m, 4H), 3.00 (t, J = 12.8, 2.6 Hz, 2H), 1.90 (d, J = 13.9 Hz, 2H), 1.88-1.81 (m, 1H), 1.39-1.26 (m, 2H); MS (ESI, m/z): 432.2 [M+H]+
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 obtained as described for the example 263 (Scheme 3. General procedure C.).
1H NMR (600 MHz, CDCl3) δ [ppm] = 8.54 (dd, J = 4.8, 1.8 Hz, 1H), 8.31 (dd, J = 7.7, 1.8 Hz, 1H), 8.18 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.0 Hz, 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 obtained as described for the example 263 (Scheme 3. General procedure C.).
1H NMR (600 MHz, DMSO-d 6) 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 obtained as described for the example 226 (Scheme 4. General procedure D.).
1H NMR (600 MHz, CD3OD) δ [ppm] = 9.41 (s, 1H), 8.91 (d, 1H), 8.85 (s, 1H), 7.94-7.86 (m, 2H), 7.19 (s, 1H), 6.94-6.89 (m, 2H), 3.47 (d, 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 obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, DMSO-d 6) 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-hydroxy-phenyl)boronic acid, the title compound was obtained as described for the example 226 (Scheme 4. General procedure D.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 226 (Scheme 4. General procedure D.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 226 (Scheme 4. General procedure D.).
1H NMR (600 MHz, DMSO-d 6) 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 obtained as described for the example 226 (Scheme 4. General procedure D.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 226 (Scheme 4. General procedure D.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 226 (Scheme 4. General procedure D.).
1H NMR (600 MHz, DMSO-d 6) 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 obtained as described for the example 248 (Scheme 1. General procedure A.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 248 (Scheme 1. General procedure A.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 248 (Scheme 1. General procedure A.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 248 (Scheme 1. General procedure A.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, DMSO-d 6) 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
Scheme for the preparation of the Compound of Example 285:
Figure PCTKR2021003883-appb-I000014
Intermediate 17. (1-(2,6-dichloropyrimidin-4-yl)piperidin-4-yl)methanol
To a solution 2,4,6-trichloropyrimidine (600 mg, 2.56 mmol), piperidin-4-ylmethanol (310 mg, 3.60 mmol) in 15 mL of tetrahydrofuran was added DIPEA (2.46 ml, 14.16 mmol). The reaction mixture was stirred for 60 minutes at room temperature and extracted three times with DCM (30 mL). The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, hexane/ethyl acetate, gradient) to give 500 mg of the title compound.
Intermediate 18. (1-(2-chloro-6-(4-morpholinophenyl)pyrimidin-4-yl)piperidin-4-yl)methanol
To a solution (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/H2O (4/1) was added Pd(PPh3)4 (296 mg, 0.26 mmol). The mixture is heated under microwave at 80 ℃ for 120 minutes, cooled to room temperature and extracted three times with EtOAc (30 mL). The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, hexane/ethyl acetate, gradient) to give 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 (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/H2O (4/1) was added Pd(PPh3)4 (78 mg, 0.08 mmol). The mixture is heated under microwave at 150 ℃ for 120 minutes, cooled to room temperature and extracted with DCM. The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, DCM/MeOH, gradient) to give 120 mg of the title compound. (Scheme 5. General procedure E.).
1H NMR (600 MHz, DMSO-d 6) 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 obtained as described for the example 285 (Scheme 5. General procedure E.).
1H NMR (600 MHz, DMSO-d 6) 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
Scheme for the preparation of the Compound of Example 287:
Figure PCTKR2021003883-appb-I000015
Intermediate 19. (1-(2-chloro-6-(3-fluoro-4-morpholinophenyl)pyrimidin-4-yl)piperidin-4-yl)methanol
To a solution (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/H2O (4/1) was added Pd(PPh3)4 (132 mg, 0.11 mmol). The mixture is refluxed at 150 ℃ for 20 hours, cooled to room temperature and extracted three times with DCM (30 mL). The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, DCM/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 a (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 of 1,4-dioxane/H2O (4/1) was added Pd(PPh3)4 (11.4 mg, 0.01 mmol). The mixture is heated under microwave at 150 ℃ for 120 minutes, cooled to room temperature and extracted with DCM. The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, DCM/MeOH, gradient) to give 30 mg of the title compound (Scheme 5. General procedure E.).
1H NMR (600 MHz, DMSO-d 6) 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 obtained as described for the example 226 (Scheme 4. General procedure D.).
1H NMR (600 MHz, DMSO-d 6) 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 obtained as described for the example 226 (Scheme 4. General procedure D.).
1H NMR (600 MHz, DMSO-d 6) 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 obtained as described for the example 226 (Scheme 4. General procedure D.).
1H NMR (600 MHz, DMSO-d 6) 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 obtained as described for the example 226 (Scheme 4. General procedure D.).
1H NMR (600 MHz, DMSO-d 6) 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 obtained as described for the example 226 (Scheme 4. General procedure D.).
1H NMR (600 MHz, DMSO-d 6) 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 obtained as described for the example 226 (Scheme 4. General procedure D.).
1H NMR (600 MHz, DMSO-d 6) 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 obtained as described for the example 226 (Scheme 4. General procedure D.).
1H NMR (600 MHz, DMSO-d 6) 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
Scheme for the preparation of the Compound of Example 295:
Figure PCTKR2021003883-appb-I000016
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 DIPEA (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 oC for 16 h. TLC showed the reaction was complete. The reaction mixture cooled to room temperature and quenched by 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 via silica gel column chromatography (Petroleum ether / EtOAc = 5 / 1; V / V) to give 800 mg of the title compound.
1H NMR (400 MHz, DMSO-d 6) 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 a (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 THF/H2O (4/1) was added Pd(PPh3)4 (148 mg, 0.13 mmol). The mixture is heated under microwave at 80 ℃ for 120 minutes, cooled to room temperature and extracted with DCM. The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, DCM/MeOH, gradient) to give 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 a (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/H2O (4/1) was added Pd(PPh3)4 (20.8 mg, 0.036 mmol). The mixture is heated under microwave at 150 ℃ for 120 minutes, cooled to room temperature and extracted with DCM. The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, DCM/MeOH, gradient) to give 13 mg of the title compound (Scheme 5. General procedure 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
Scheme for the preparation of the Compound of Example 299:
Figure PCTKR2021003883-appb-I000017
Intermediate 22. (S)-1-(6-chloro-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol
To a solution 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 DIPEA (2.46 ml, 14.16 mmol). The reaction mixture was heated at 60 ℃ for 60 minutes, cooled to room temperature and extracted three times with DCM (30 mL). The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, hexane/ethyl acetate, gradient) to give 500 mg of the title compound.
1H NMR (600 MHz, DMSO-d 6) 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 (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 THF/H2O (4/1) was added Pd(PPh3)4 (104 mg, 0.09 mmol). The mixture is heated under microwave at 80 ℃ for 120 minutes, cooled to room temperature and extracted three times with DCM (30 mL). The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, DCM/MeOH, gradient) to give 120 mg of the title compound (Scheme 4. General procedure D.).
1H NMR (600 MHz, DMSO-d 6) 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 (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), K2CO3 (43 mg, 0.31 mmol) in 8 mL of acetonitrile was added KI (4.4 mg, 0.026 mmol). The mixture is heated under microwave at 120 ℃ for 60 minutes, cooled to room temperature and extracted three times with DCM (30 mL). The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, DCM/MeOH, gradient) to give 104 mg of the title compound.
1H NMR (600 MHz, DMSO-d 6) 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 (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% wet) and bubbled with H2 gas. The mixture is stirred for overnight at room temperature under H2 gas using balloon. The mixture was filtered through Celite 545 pad and filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, DCM/MeOH, gradient) to give 54 mg of the title compound.
1H NMR (600 MHz, DMSO-d 6) 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 (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 THF was added TEA (24 mg, 0.24 mmol). And then acetyl chloride (10 mg, 0.13 mmol) was added to the mixture at 0 ℃. The reaction mixture was stirred for overnight at room temperature, quenched with water and extracted with DCM (10 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, DCM/MeOH, gradient) to give 11 mg of the title compound.
1H NMR (600 MHz, DMSO-d 6) 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
Scheme for the preparation of the Compound of Example 301:
Figure PCTKR2021003883-appb-I000018
Intermediate 23. (S)-1-(2-chloro-6-(6-fluoropyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol
To a solution (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/H2O (4/1) was added Pd(PPh3)4 (296 mg, 0.26 mmol). The mixture is heated under microwave at 80 ℃ for 120 minutes, cooled to room temperature and extracted three times with EtOAc (30 mL). The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, hexane/ethyl acetate, gradient) to give 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 (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/H2O (4/1) was added Pd(PPh3)4 (78 mg, 0.08 mmol). The mixture is heated under microwave at 150 ℃ for 120 minutes, cooled to room temperature and extracted three times with EtOAc (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, DCM/MeOH, gradient) to give 120 mg of the title compound (Scheme 4. General procedure D.).
1H NMR (600 MHz, DMSO-d 6) 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 (S)-1-(6-(6-fluoropyridin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol (50 mg, 0.15 mmol), N1,N1-dimethylethane-1,2-diamine hydrochloride (17 mg, 0.18 mmol), K2CO3 (25 mg, 0.18 mmol) in 8 mL of acetonitrile was added KI (2.5 mg, 0.015 mmol). The mixture is heated under microwave at 120 ℃ for 60 minutes, cooled to room temperature and extracted three times with EtOAc (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, DCM/MeOH, gradient) to give 25 mg of the title compound.
1H NMR (600 MHz, DMSO-d 6) 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 obtained as described for the example 301.
1H NMR (600 MHz, DMSO-d 6) 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
Scheme for the preparation of the Compound of Example 303:
Figure PCTKR2021003883-appb-I000019
Example 303. 5-chloro-2-(6-(4-((2-hydroxyethyl)sulfonyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)phenol
To a 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 THF/H2O (4/1) was added Pd(PPh3)4 (9 mg, 0.008 mmol). The mixture is heated under microwave at 80 ℃ for 120 minutes, cooled to room temperature and extracted with DCM. The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, DCM/MeOH, gradient) to give 17 mg of the title compound (Scheme 4. General procedure D.).
1H NMR (600 MHz, DMSO-d 6) 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 the preparation of the Compound of Example 304:
Figure PCTKR2021003883-appb-I000020
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 THF/H2O (4/1) was added Pd(PPh3)4 (296 mg, 0.26 mmol). The mixture is heated under microwave at 80 ℃ for 120 minutes, cooled to room temperature and extracted with DCM. The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, DCM/MeOH, gradient) to give 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 a (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/H2O (4/1) was added Pd(PPh3)4 (17.7 mg, 0.015 mmol). The mixture is heated under microwave at 150 ℃ for 120 minutes, cooled to room temperature and extracted with DCM. The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, DCM/MeOH, gradient) to give 1.8 mg of the title compound (Scheme 5. General procedure E.).
1H NMR (600 MHz, DMSO-d 6) 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 obtained as described for the example 296 (Scheme 4. General procedure D.).
1H NMR (600 MHz, DMSO-d 6) 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 obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, CDCl3) 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 obtained as described for the example 226 (Scheme 4. General procedure D.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 248 (Scheme 1. General procedure A.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 248 (Scheme 1. General procedure A.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 248 (Scheme 1. General procedure A.).
1H NMR (600 MHz, DMSO-d 6) 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 (br, 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 obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (600 MHz, DMSO-d 6) 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 obtained as described for the example 357 (Scheme 2. General procedure B.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 174 (Scheme 2. General procedure B.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the 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 obtained as described for the 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 obtained as described for the 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 obtained as described for the example 296 (Scheme 4. General procedure D.).
1H 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 obtained as described for the example 226 (Scheme 4. General procedure D.).
1H NMR (600 MHz, DMSO-d 6) 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 obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, DMSO-d 6) 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
Scheme for the preparation of the Compound of Example 321:
Figure PCTKR2021003883-appb-I000021
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) was added 1-(methylsulfonyl)piperazine (286 mg, 1.74 mmol) and DIPEA (448 mg, 3.48 mmol) at room temperature. The reaction mixture was heated at 65 °C for 3 hr. TLC showed the starting　material consumed completely. After the reaction mixture was cooled to room temperature, the mixture was concentrated in vacuo. The residue was extracted with DCM (30 mL x 2), washed with water (30 mL), dried and concentrated in vacuo. The residue was purified via column chromatography (Petroleum ether / EtOAc = 1 / 1; V / V) to afford 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 H2O (0.5 mL) was added (1-methyl-1H-pyrazol-4-yl)boronic acid (49 mg, 0.39 mmol), Pd(dppf)Cl2 (15 mg, 0.021 mmol) and Cs2CO3 (250 mg, 0.77 mmol) at room temperature under Nitrogen. The reaction mixture was heated at 90 °C via microwave irradiation for 1.5 hr under nitrogen. LCMS showed the starting　material consumed completely. After the reaction mixture was cooled to room temperature, the mixture was concentrated in vacuo. The residue was extracted with EtOAc (30 mL x 2), washed with water (30 mL), dried and concentrated in vacuo. The residue was purified via column chromatography (Petroleum ether / EtOAc = 2 / 3; V / V) to afford 60 mg of the title compound (Scheme 3. General procedure C.).
1H NMR (400 MHz, CDCl3) 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
Scheme for the preparation of the Compound of Example 322:
Figure PCTKR2021003883-appb-I000022
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) was added (S)-pyrrolidin-3-ol (243.0 mg, 2.79 mmol), DIPEA (451.0 mg, 3.495 mmol) at room temperature. The reaction mixture was heated and stirred at 65 oC for 3 hr. TLC showed the starting material was consumed completely. The solvent was removed in vacuo and the residue was purified via column chromatography (Petroleum ether / EtOAc = 1 / 1; V / V) to afford 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) was added (3-hydroxyphenyl)boronic acid (67 mg, 0.485 mmol), Pd(dppf)Cl2 (23.7 mg, 0.0324 mmol) and Cs2CO3 (316.7 mg, 0.972 mmol) at room temperature under Nitrogen. The reaction mixture was heated at 85 °C via microwave irradiation for 45 min under Nitrogen atmosphere. The reaction mixture was concentrated in vacuo. The residue was purified via reverse phase column chromatography eluted with CH3CN: H2O (0.1 % Formic acid) to afford 60.8 mg of the title compound (Scheme 3. General procedure C.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 322 (Scheme 3. General procedure C.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 322 (Scheme 3. General procedure C.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 321 (Scheme 3. General procedure C.).
1H NMR (400 MHz, DMSO-d 6) 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 the preparation of the Compound of Example 326:
Figure PCTKR2021003883-appb-I000023
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 ACN (5 mL) was added 4-(methylsulfonyl)piperidine (284 mg, 1.74 mmol) and DIPEA (448.9 mg, 3.48 mmol) at room temperature. The reaction mixture was heated at 65 °C for 6 hr. The mixture was concentrated in vacuo. The residue was purified via silica gel column chromatography (Petroleum ether / EtOAc = 2 / 1; V / V) to afford 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 H2O (0.8 mL) was added pyridin-3-ylboronic acid (119.8 mg, 0.97 mmol), Cs2CO3 (635.3 mg, 1.95 mmol) and Pd(dppf)Cl2 (53 mg, 0.065 mmol) at room temperature under Nitrogen. The reaction mixture was heated and stirred at 85 °C via microwave irradiation for 45 minutes under N2 atmosphere. 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 via silica gel column chromatography (DCM / MeOH = 20 / 1; V / V) to afford 110 mg of the title compound (Scheme 3. General procedure C.).
1H NMR (400 MHz, DMSO-d 6) δ [ppm] = 1.55-1.72 (m, 2 H), 2.17 (d, J = 10.9 Hz, 2H), 2.97 (s, 3 H), 3.10 (t, J = 12.1 Hz, 2 H), 3.39-3.59 (m, 1 H), 4.74-5.02 (m, 2 H), 7.55 (ddd, J =7.9, 4.8, 0.7 Hz, 1 H), 7.58-7.67 (m, 2 H), 8.32-8.44 (m, 2 H), 8.67-8.79 (m, 2 H), 9.59 (d, J = 1.4 Hz, 1 H); 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 obtained as described for the example 263 (Scheme 3. General procedure C.).
1H NMR (400 MHz, DMSO-d 6) 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
Scheme for the preparation of the Compound of Example 328:
Figure PCTKR2021003883-appb-I000024
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) added tert-butyl piperazine-1-carboxylate (2.1 g, 11.63 mmol) and DIPEA (3 g, 23.25 mmol) at room temperature. The reaction mixture was heated at 65 °C for 4 hr under nitrogen. LCMS showed the starting　material consumed completely. After the reaction mixture was cooled to room temperature, the mixture was extracted with DCM (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 via silica gel column chromatography (Petroleum ether / EtOAc = 4 / 1; V / V) to afford 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 H2O (4 mL) was added pyridin-3-ylboronic acid (543 mg, 4.41 mmol), Pd(dppf)Cl2 (172 mg, 0.235 mmol) and CsCO3 (2.8 g, 8.82 mmol) at room temperature under Nitrogen. The reaction mixture was stirred at 100 °C via microwave irradiation for 3 hr under nitrogen atmosphere. LCMS showed the starting　material consumed completely. After the reaction mixture was cooled to room temperature, the mixture was extracted with EtOAc (50 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 via silica gel column chromatography (Petroleum ether / EtOAc = 65 / 35; V / V) to afford 720 mg of the title compound.
1H NMR (400 MHz, CDCl3) 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
To 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 gas in MeOH, 12 mL) was stirred at room temperature for 2hr. TLC showed the starting　material consumed completely. The reaction mixture was concentrated in vacuo to afford 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 DCM (3 mL) 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 16hr. LCMS showed the starting　material consumed completely. The reaction mixture was extracted with DCM (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 prep-HPLC to afford 16 mg of the title compound.
1H NMR (400 MHz, CDCl3) 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
Scheme for the preparation of the Compound of Example 329:
Figure PCTKR2021003883-appb-I000025
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) was added 4-(tributylstannyl)pyridazine (167 mg , 0.4516 mmol), Pd(PPh3)4 (37 mg, 0.0322 mmol) at room temperature under Nitrogen. The reaction mixture was stirred via microwave irradiation at 130 °C for 0.5 hr under Nitrogen atmosphere. TLC showed the starting　material consumed completely. 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 prep-HPLC to afford 19.5 mg of the title compound.
1H NMR (400 MHz, CDCl3) 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 obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CDCl3) 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
Scheme for the preparation of the Compound of Example 332:
Figure PCTKR2021003883-appb-I000026
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 NMP (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. The reaction mixture was heated and stirred at 160 °C via 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 x 2). The combined organic layer was washed with brine, dried over Na2SO4 filtered and concentrated in vacuo. The residue was purified via silica gel column chromatography (Petroleum ether / EtOAc = 1 / 1; V / V) to afford 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 THF (15 mL) was added TMSN3 (230 mg, 3.0 mmol) and TBAF (130.8 mg, 0.5 mmol) at room temperature. The reaction mixture was heated at 96 °C in a sealed tube for 16 hr. 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 Na2SO4. Filtered and concentrated in vacuo to afford 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) was added CH3I (49 mg, 0.35 mmol) and K2CO3 (35.4 mg, 0.26 mmol) at room temperature. The reaction mixture was stirred at room temperature for 13 hr. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified via column chromatography (DCM / MeOH = 10 / 1; V / V) to afford 5.6 mg of the title compound.
1H NMR (400 MHz, DMSO-d 6) 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
Scheme for the preparation of the Compound of Example 333:
Figure PCTKR2021003883-appb-I000027
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 NMP (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. The reaction mixture was heated and stirred at 160 °C via 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 x 2). The combined organic layer was washed with brine, dried over Na2SO4. Filtered and concentrated in vacuo. The residue was purified via silica gel column chromatography (Petroleum ether / EtOAc = 1 / 1; V / V) to afford 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 THF (15 mL) was added TMSN3 (941.6 mg, 8.174 mmol) and TBAF (355.6 mg, 1.36 mmol) at room temperature. The reaction mixture was heated at 96 °C in a sealed tube for 16 hr. 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 Na2SO4. Filtered and concentrated in vacuo to afford 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) was added CH3I (84.7 mg, 0.597 mmol) and K2CO3 (109.8 mg, 0.796 mmol) at room temperature. The reaction mixture was stirred at room temperature for 13 hr. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified via column chromatography (DCM / MeOH = 10 / 1; V / V) to afford 28.8 mg of the title compound.
1H NMR (400 MHz, DMSO-d 6) 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 the preparation of the Compound of Example 334:
Figure PCTKR2021003883-appb-I000028
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 NMP (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. The reaction mixture was heated and stirred at 160 °C via 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 x 2). The combined organic layer was washed with brine, dried over Na2SO4. Filtered and concentrated in vacuo. The residue was purified via silica gel column chromatography (Petroleum ether / EtOAc = 1 / 1; V / V) to afford 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 THF (15 mL) was added TMSN3 (450.8 mg, 3.98 mmol) and TBAF (174.4 mg, 0.67 mmol) at room temperature. The reaction mixture was heated at 96 °C in a sealed tube for 16 hr. 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 Na2SO4, filtered and concentrated in vacuo. The residue was purified via silica gel column chromatography (Petroleum ether / EtOAc = 1 / 100; V / V) to afford 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) was added CH3I (76.1 mg, 0.536 mmol) and K2CO3 (98.5 mg, 0.714 mmol) at room temperature. The reaction mixture was stirred at room temperature for 13 hr. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified via reverse phase column chromatography eluted with CH3CN: H2O (0.1 % Formic acid) to afford 21.0 mg of the title compound.
1H NMR (400 MHz, DMSO-d 6) 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
Scheme for the preparation of the Compound of Example 335:
Figure PCTKR2021003883-appb-I000029
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 DCM (3 mL) was added DAST (52 mg , 0.32 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 5hr under nitrogen. LCMS showed the starting　material consumed completely. The mixture was quenched by H2O at 0 oC, extracted with EtOAc (25 mL x 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 prep-TLC (DCM / EtOAc / MeOH = 20 / 1 / 1;V / V / V) to afford 12 mg of the title compound.
1H NMR (400 MHz, CDCl3) 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 the preparation of the Compound of Example 336:
Figure PCTKR2021003883-appb-I000030
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) was added 1,1,1,2,2,2-hexabutyldistannane (450.6 mg, 0.777 mmol) and Pd(PPh3)4 (75.1 mg, 0.065 mmol) at room temperature under Nitrogen. The reaction mixture was stirred at 120 °C via microwave irradiation for 2 hr under nitrogen atmosphere. LCMS showed the starting　material consumed completely. The mixture was filtered and concentrated in vacuo. The residue was purified via silica gel column chromatography (DCM / MeOH = 10 / 1; V / V) to afford 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) was added 4-iodoisoxazole (67.3 mg, 0.345 mmol), CuI (15 mg, 0.08 mmol) and Pd(PPh3)4 (46.2 mg, 0.04 mmol) at room temperature under Nitrogen. The reaction mixture was stirred at 130 °C via microwave irradiation for 2 hr under nitrogen atmosphere. LCMS showed the starting　material consumed completely. The mixture was filtered and concentrated in vacuo. The residue was purified via Prep-HPLC to afford 25 mg of the title compound.
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CDCl3) 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 obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CDCl3) 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 obtained as described for the example 248 (Scheme 2. General procedure B.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 248 (Scheme 2. General procedure B.).
1H NMR (400 MHz, DMSO-d 6) δ [ppm] = 2.93 (s, 3H), 3.23-3. 13 (m, 4H), 4.03 (s, 4H), 7.52-7.61 (m, 2H), 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 obtained as described for the example 336.
1H NMR (400 MHz, CDCl3) 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 obtained as described for the example 248 (Scheme 2. General procedure B.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 336.
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 336.
*1H NMR (400 MHz, CDCl3) 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 obtained as described for the example 336.
*1H NMR (400 MHz, CDCl3) 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 obtained as described for the example 329.
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 174 (Scheme 2. General procedure B.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 248 (Scheme 1. General procedure A.).
1H NMR (400 MHz, DMSO-d 6) δ [ppm] = 3.25 (t, J = 6.1Hz, 2H), 3.33-3.36 (m, 4H), 3.73-3.79 (m, 2H), 3.96-4.04 (m, 4H), 5.04 (t, J =5.4Hz, 1H), 7.52-7.58 (m, 2H), 7.91 (d, J = 8.3Hz, 2H), 8.55 (d, J =8.2Hz, 2H), 8.70-8.78 (m, 2H), 9.61 (d, J =1.6Hz, 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
Scheme for the preparation of the Compound of Example 350:
Figure PCTKR2021003883-appb-I000031
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) was added Hexabutylditin (1.01 g, 1.75 mmol) and Pd(PPh3)Cl2 (102 mg, 0.15 mmol) at room temperature under nitrogen. The reaction mixture was stirred at 150 °C via microwave irradiation for 7 h under nitrogen atmosphere. LCMS showed the starting material was consumed and produced the desired compound. The reaction mixture was cooled to room temperature and filtrated through a pad of celite. The filtrate was concentrated in vacuo. The residue was purified via silica gel chromatography eluted to afford 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(PPh3)4 (58 mg, 0.05 mmol), CuI (19 mg, 0.1 mmol) at room temperature under Nitrogen. The reaction mixture was stirred at 130 °C via microwave irradiation for 3 h under Nitrogen atmosphere. LCMS showed the starting material was consumed and produced the desired compound. The reaction mixture was concentrated in vacuo. The residue was diluted with water (20 ml), extracted with EtOAc (20 mL x 3), the combined organic layers were washed with brine, dried and concentrated in vacuo. The residue was purified via prep-HPLC to afford 14.3 mg of the title compound.
1H NMR (400 MHz, DMSO-d 6) δ [ppm] = 1.90-2.16 (m, 2H), 3.44-3.84 (m, 4H), 4.46 (d, J = 22.2Hz, 1H), 5.07 (s, 1H), 7.05 (s, 1H), 7.88 (d, J = 8.2Hz, 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 obtained as described for the example 248 (Scheme 1. General procedure A.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, DMSO-d 6) δ [ppm] = 2.57 (t, J = 6.5Hz, 2H), 3.61-3.71 (m, 6H), 3.81-3.98 (m, 4H), 4.57 (t, J = 5.2Hz, 1H), 7.40 (s, 1H), 7.52-7.58 (m, 1H), 7.61 (d, J = 8.6Hz, 2H), 8.14 (s, 1H), 8.37 (d, J = 8.6Hz, 2H), 8.67-8.77 (m, 2H), 9.60 (d, J = 1.7Hz, 1H). MS (ESI, m/z): 424.2 [M+H]+
Example 353. 2-((4-(2-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)ethanol
Scheme for the preparation of the Compound of Example 353:
Figure PCTKR2021003883-appb-I000032
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 ACN (20 mL) was added tert-butyl piperazine-1-carboxylate (1.9 g, 10.3 mmol) and DIPEA (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 x 3), washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel column chromatography (Petroleum ether / EtOAc =5 / 1; V / V) to afford 780mg of the title compound.
Intermediate 39. tert-butyl4-(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 H2O (0.8 mL) was added (1-methyl-1H-pyrazol-4-yl)boronic acid (479 mg, 3.8 mmol), Cs2CO3 (2.39 g, 7.35 mmol) and Pd(dppf)Cl2 (163 mg, 0.2 mmol) at room temperature under Nitrogen. The reaction mixture was heated and stirred at 85 °C for 5 hr. 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 via silica gel column chromatography (Petroleum ether / EtOAc = 5 / 1; V / V) to afford 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
To a solution of tert-butyl4-(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 of 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 DCM (10 Ml) was added TEA (570.7 mg, 5.65 mmol) at 0oC. 2-chloroethanesulfonyl chloride (221.7 mg, 1.36 mmol) was dropwised to the above reaction mixture at 0oC. 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 via silica gel column chromatography (Petroleum ether / EtOAc = 1 / 1; V / V) to afford 120 mg of the title compound.
MS (ESI, m/z): 479.2 [M+H]+
Example 353. 2-((4-(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 THF 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 x 3), dried and concentrated in vacuo. The obtained solid was slurried 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-d 6) 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 obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CDCl3) 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 obtained as described for the example 174 (Scheme 2. General procedure B.).
1H NMR (400 MHz, DMSO-d 6) 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-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)-4-(methylsulfonyl)piperidin-4-yl)methanol
Scheme for the preparation of the Compound of Example 357:
Figure PCTKR2021003883-appb-I000033
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) 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 hr. 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
To 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 at reflux for 13 hr. 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 via column chromatography (DCM / MeOH = 10 / 1; V / V) to afford 950 mg of the title compound.
MS (ESI, m/z): 339.2 [M+H]+
Example 357. (1-(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 ACN (5 mL) was added (4-(methylsulfonyl)piperidin-4-yl)methanol hydrochloride (32 mg, 0.14 mmol) and DIPEA (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 x 3). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified via Prep-HPLC to afford 8.2 mg of the title compound (Scheme 2. General procedure B.).
1H NMR (400 MHz, DMSO-d 6) 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 obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, DMSO-d 6) 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 = 8.6Hz, 2H), 8.67-8.74 (m, 2H), 9.57(d, J = 1.5Hz, 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 obtained as described for the example 1 (Scheme 2. General procedure B.).
1H NMR (400 MHz, DMSO-d 6) δ [ppm] = 1.27 (d, J = 6.6Hz, 3H), 2.95-3.06(m, 1H), 3.13-3.21(m, 1H), 3.22-3.29 (m, 3H), 3.50 (d, J =12.0Hz, 1H), 3.68 (d, J =11.6Hz, 1H), 3.78 (t, J =5.4Hz, 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 =8.6Hz, 2H), 8.37 (d, J = 8.6Hz, 2H), 8.68-8.78 (m, 2H), 9.60 (d, J =1.9Hz, 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
Scheme for the preparation of the Compound of Example 360:
Figure PCTKR2021003883-appb-I000034
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 ACN (5 mL) was added DIPEA (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 oC for 16 hr. The mixture was concentrated in vacuo. 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 obtained crude product was purified via column chromatography (Petroleum ether / EtOAc = 2 / 1; V / V) to afford 330 mg of the title compound (Scheme 1. General procedure 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 THF (15 mL) was added 2-aminoethanol (83 mg, 1.36 mmol) and 2 drops of CH3COOH. The reaction mixture was stirred at r.t. for 16 hr. 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 r.t. for 3 hr. 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 obtained crude product was purified via Prep-HPLC to afford 204.3 mg of the title compound.
1H NMR (400 MHz, DMSO-d 6) 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 the preparation of the Compound of Example 361:
Figure PCTKR2021003883-appb-I000035
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 (450mg, 0.57 mmol) in 10 mL of DCM was added TEA (585.8 mg, 1.39 mmol) at 0oC. Ethyl 4-chloro-4-oxobutanoate (585.8mg, 5.8 mmol) was added dropwised to the above reaction mixture at 0oC. The reaction mixture was stirred at room temperature for 3 hr. The residue was extracted with dichloromethane (20 mL x 3), washed with brine, dried and concentrated in vacuo. The residue was purified via silica gel column chromatography (Petroleum ether / EtOAc = 2 / 1; V / V) to afford 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 diethel ether (10 mL) was added LiBH4 (17.6 mg, 0.81 mmol) and MeOH (26 mg, 0.81 mmol) at 0 oC. The reaction mixture was stirred at room temperature for 2 hr. Methanol was added dropwise to the above reaction mixture until no bubbles are generated. The solvent was removed in vacuo and the residue was purified via Prep-HPLC to afford 15.9 mg of the title compound.
1H NMR (400 MHz, DMSO-d 6) 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 the preparation of the Compound of Example 362:
Figure PCTKR2021003883-appb-I000036
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 DCM was added TEA (172.71 mg, 1.71 mmol) at 0 ℃. Methyl 3-(chlorosulfonyl)propanoate (127 mg, 0.68 mmol) was dropwised 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 via silica gel column chromatography (Petroleum ether / EtOAc = 2 / 1; V / V) to afford 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) was added LiBH4 (6.2 mg, 0.29 mmol) and MeOH (9.28 mg, 0.29 mmol) at 0oC. The reaction mixture was stirred at room temperature for 2 h. Methanol was added dropwise to the above reaction mixture at 0oC until no bubbles are generated. The solvent was removed in vacuo and the residue was purified via Prep-HPLC to afford 30.6 mg of the title compound.
1H NMR (400 MHz, DMSO-d 6) 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 the preparation of the Compound of Example 363 and 364:
Figure PCTKR2021003883-appb-I000037
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 DMF (10 mL) was added but-3-enoic acid (147 mg, 0.17 mmol), HATU (864 mg, 2.28 mmol), DIPEA (440 mg,3.41 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hr. LCMS showed the starting material was consumed and produced the desired 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 via silica gel column chromatography (Petroleum ether / EtOAc = 1 / 1; V / V) to afford 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 DCM (15 mL) and H2O (2 mL) was added NMO (83.8 mg, 0.72 mmol) and K2OsO4 (17.5 mg, 0.048 mmol) at room temperature. The reaction mixture was heated and stirred at 35 °C for 16 hr. LCMS showed the starting material was consumed and produced the desired compound. The reaction mixture was filtrated, 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 obtained crude product was purified via prep-HPLC to afford 8.2 mg of the example 363 as a white solid and 8.3 mg of the example 364 as a white solid.
Example 363: 1H NMR (400 MHz, CDCl3) 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 = 7.9Hz, 1H), 9.70 (s, 1H); MS (ESI, m/z): 454.2 [M+H]+
Example 364: 1H NMR (400 MHz, DMSO-d 6) δ [ppm] = 1.08 (d, J = 6.3Hz, 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 = 8.6Hz, 2H), 8.37 (d, J = 8.6 Hz, 2H), 8.68-8.77 (m, 2H), 9.60 (d, J = 1.6Hz, 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 obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, DMSO-d 6) 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 = 17.8Hz, 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 = 8.6Hz, 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 the preparation of the Compound of Example 366:
Figure PCTKR2021003883-appb-I000038
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 H2O (1 mL) was added (2-methoxypyridin-3-yl)boronic acid (110 mg, 0.72 mmol), Cs2CO3 (350 mg, 1.08 mmol) and Pd(dppf)Cl2 (58.5 mg, 0.07 mmol) at room temperature under nitrogen. The reaction mixture was stirred at 110 °C via microwave irradiation for 3 h under nitrogen atmosphere. LCMS showed the starting material was consumed and produced the desired compound. The reaction mixture was concentrated in vacuo. The residue was purified via silica gel column chromatography (DCM / MeOH= 10 / 1; V / V) to afford 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
To a suspension of (S)-1-(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 H2O, 4 mL) was stirred 100 °C for 10 h in a sealed tube. LCMS showed the starting material was consumed and produced the desired compound. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified via prep-HPLC to afford 13.2 mg of the example 363 as a white solid and 8.3 mg of the title compound.
1H NMR (400 MHz, DMSO-d 6) 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 the preparation of the Compound of Example 367:
Figure PCTKR2021003883-appb-I000039
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), Cs2CO3 (250 mg, 0.77 mmol) and 1'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (41 mg, 0.05 mmol) under Nitrogen at room temperature. The mixture was degassed and purged with N2 three times. The reaction mixture was heated at 90 °C under Nitrogen for 16 h. LCMS showed the reaction was complete. The mixture was filtered. The filtrate was concentrated in vacuo. The residue was purified by prep-TLC (EtOAc / MeOH = 20 / 1, V / V) to give 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 H2O (0.5 mL) were added pyridin-3-ylboronic acid (65 mg, 0.55 mmol), Cs2CO3 (173 mg, 0.54 mmol) and Pd(dppf)Cl2 (22 mg, 0.03 mmol) at 10 o C. The reaction mixture was degassed and purged with N2 three times. The reaction was stirred at 100 oC for 16 h. LCMS showed the reaction was complete. The reaction was cooled to room temperature and quenched by water (10 mL). The residue was extracted with EtOAc (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 prep-HPLC to give 8.7 mg of the title compound.
1H NMR (400 MHz, DMSO-d 6) 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 the preparation of the Compound of Example 368:
Figure PCTKR2021003883-appb-I000040
Intermediate 50. tert-butyl4-(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) was added Hexabutylditin (319 mg, 0.55mmol), Pd(PPh3)4 (86.7 mg, 0.075 mmol) at room temperature under Nitrogen. The reaction mixture was heated and stirred at 130 °C for 3.5 hr under Nitrogen. TLC showed the starting　material consumed completely. The mixture was concentrated in vacuo and the residue was purified via silica gel column chromatography (DCM / MeOH = 10 / 1; V / V) to afford 1.1 g of the title compound.
1H NMR (400 MHz, CDCl3) 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-butyl4-(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) was added 4-bromoisothiazole (91.1 mg, 0.555 mmol), Pd(PPh3)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 N2 for 2 hr. LCMS showed the starting　material was consumed completely. After the reaction mixture was cooled to room temperature. The mixture was concentrated in vacuo and the residue was purified via silica gel column chromatography (Petroleum ether / EtOAc = 5 / 1; V / V) to afford 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
To 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 Hydrogen chloride-Methanol solution (4 M HCl gas 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 dichloromethan was added TEA (318 mg, 3.15 mmol) at 0 oC. 2-chloroethanesulfonyl chloride (123 mg, 0.76 mmol) was added dropwise to the above reaction mixture at 0 oC. The reaction mixture was stirred at room temperature for 16 h. TLC showed the starting　material consumed completely. The mixture was concentrated in vacuo and the residue was purified via silica gel column chromatography (DCM / MeOH = 10 / 1; V / V) to afford 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 THF 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 the starting　material was consumed completely. The mixture was cooled to room temperature. The mixture was concentrated in vacuo and the residue was purified via Prep-HPLC to afford 19.3 mg of the title compound.
1H NMR (400 MHz, DMSO-d 6) δ [ppm] = 3.25 (t, J = 6.1 Hz, 2H), 3.32-3.28 (m, 4H), 3.76 (dd, J = 11.2, 5.6Hz, 2H), 3.96 (s, 4H), 5.03 (t, J = 5.3Hz, 1H), 7.39 (s, 1H), 7.60(d, J = 8.5Hz, 2H), 8.35(d, J = 8.6Hz, 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
Scheme for the preparation of the Compound of Example 369:
Figure PCTKR2021003883-appb-I000041
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 DCM (10 mL) was added TEA (719 mg, 7.12 mmol) at room temperature. Prop-2-ene-1-sulfonyl chloride (400 mg, 2.85 mmol) was dropwised to the above reaction mixture at 0 oC. The reaction mixture was stirred at room temperature for 16 h. LCMS showed the starting material was consumed and produced the desired compound. The reaction mixture concentrated in vacuo. The residue was purified via silica gel column chromatography (Petroleum ether / EtOAc = 1 / 1; V / V) to afford 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 DCM (30 mL) and H2O (3 mL) was added NMO (672 mg, 5.74 mmol) and K2OsO4 (140 mg, 0.38 mmol) at room temperature. The reaction mixture was heated and stirred at 45 °C for 16hr. 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 obtained crude product was purified via prep-HPLC to afford 30.5 mg of the title compound.
1H NMR (400 MHz, DMSO-d 6) 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
Scheme for the preparation of the Compound of Example 370:
Figure PCTKR2021003883-appb-I000042
Intermediate 55. tert-butyl4-(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, 2.65mmol), Pd(PPh3)4 (255 mg, 0.221 mmol) at room temperature under Nitrogen. The reaction mixture was heated and stirred at 130 °C for 5 hr under Nitrogen. The residue was cooled to room temperature and KF aq was added to the reaction mixture stirring for another 30 min. The mixture was concentrated in vacuo and the residue was purified via silica gel column chromatography (Petroleum ether / EtOAc = 5 / 1; V / V) to afford 1.4 g of the title compound.
1H NMR (400 MHz, CDCl3) 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-butyl4-(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) was added 4-bromoisothiazole (91.56 mg , 0.56 mmol), Pd(PPh3)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 via microwave irradiation for 3 hr under nitrogen atmosphere. LCMS showed the starting　material consumed completely. After the reaction mixture was cooled to room temperature and 5 mL of Sat. KF aq. was added to the reaction mixture stirring for another 30 min. The mixture was concentrated in vacuo and the residue was purified via silica gel column chromatography (DCM / MeOH = 10 / 1; V / V) to afford 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
To 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 Hydrogen chloride-Methanol solution (4 M HCl gas 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 dichloromethan was added TEA (111 mg, 1.1 mmol) at 0oC. 2-chloroethanesulfonyl chloride (43.8 mg, 0.27 mmol) was added dropwise to the above reaction mixture at 0oC. The reaction mixture was stirred at room temperature for 16 h. TLC showed the starting　material consumed completely. The mixture was concentrated in vacuo and the residue was purified via silica gel column chromatography (DCM / MeOH = 10 / 1; V / V) to afford 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 THF 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 the starting　material consumed completely. The mixture was cooled to room temperature. The mixture was concentrated in vacuo and the residue was purified via silica gel column chromatography (DCM / MeOH = 10 / 1; V / V) to afford 80 mg of the title compound.
1H NMR (400 MHz, DMSO-d 6) δ [ppm] = 3.25 (t, J = 6.1 Hz, 2H), 3.34 (s, 4H), 3.76 (q, 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 obtained as described for the example 1 (Scheme 1. General procedure A.).
1H NMR (400 MHz, CDCl3) 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 obtained as described for the example 296 (Scheme 4. General procedure D.).
1H NMR (400 MHz, DMSO-d 6) 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 the preparation of the Compound of Example 373:
Figure PCTKR2021003883-appb-I000043
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 H2O (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), Cs2CO3 (1.39 g, 4.2 mmol) and Pd(dppf)Cl2 (174 mg, 0.21mmol) at room temperature. The mixture was degassed and purged with under Nitrogen three times. The reaction mixture was heated and stirred at 90 °C for 16 h under Nitrogen atmosphere. LCMS showed 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 via 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 H2O (0.5 mL) were added (2-methoxypyridin-3-yl)boronic acid (72 mg, 0.48 mmol), Cs2CO3 (206 mg, 0.63 mmol) and Pd(dppf)Cl2 (25 mg, 0.031mmol) at room temperature. The mixture was degassed and purged with under Nitrogen three times. The reaction mixture was heated and stirred at 90 °C for 16 h under Nitrogen atmosphere. LCMS showed the reaction was complete. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo. The residue was purified via 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
To a solution of (S)-1-(6-(3-fluoro-4-morpholinophenyl)-2-(2-methoxypyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol was dissolved in a solution of HBr in H2O (5 mL, 48 %). The reaction mixture was heated and stirred at 100 oC for 16 hr. LCMS showed the reaction was complete. The reaction mixture was concentrated in vacuo. The residue was purified via column chromatography (DCM / MeOH = 10 / 1; V / V) to afford 41.8 mg of the title compound (Scheme 5. General procedure E.).
1H NMR (400 MHz, DMSO-d 6) 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 N1,N1-dimethyl-N2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethane-1,2-diamine and separation method of PREP. HPLC, the title compound was obtained as described for the example 296 (Scheme 4. General procedure D.).
1H NMR (400 MHz, DMSO-d 6) 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 separation method of PREP. HPLC, the title compound was obtained as described for the example 296 (Scheme 4. General procedure D.).
1H NMR (400 MHz, DMSO-d 6) 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 the preparation of the Compound of Example 376:
Figure PCTKR2021003883-appb-I000044
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 H2O (1 mL) was 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), Cs2CO3 (883 mg, 2.72 mmol) and Pd(dppf)Cl2 (147 mg, 0.18 mmol) at room temperature under nitrogen. The reaction mixture was stirred at 110 °C via microwave irradiation for 2.5 h under Nitrogen atmosphere. LCMS showed the starting material was consumed and produced the desired compound. The reaction mixture was concentrated in vacuo. The residue was purified via reverse phase column chromatography (MeOH / H2O= 1 / 1; V / V) to afford 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
To 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 4N hydrochloric acid methanol solution (10 mL) was stirred at room temperature for 2 hr. LC-MS showed the starting material was consumed and produced the desired 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 THF (10 mL) was added LiAlH4 (56 mg, 1.48 mmol) at 0 oC. The reaction mixture was stirred at room temperature for 1 hr. LCMS showed the starting material was consumed and produced the desired compound. The mixture was quenched with H2O. The aqueous layer was extracted with EtOAc (10 mL x 2). The combined organic layer was washed with brine, dried over Na2SO4. The mixture was filtered and concentrated in vacuo. The residue was purified via prep-HPLC to afford 13.8 mg of the title compound as a white solid.
1H NMR (400 MHz, DMSO-d 6) 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 XRE-luciferase reporter assay (in vitro assay 1, 2, 3)
AhR activation leads the induction of target gene expression such as CYP1A1 and CYP1B1 by AhR binding to AhR-responsive DNA elements also known as xenobiotics responsive elements (XREs). The assay for measuring AhR activity herein is the luciferase assay using cell lines transfected with luciferase reporter plasmid containing XREs at the upstream of the reporter gene. Cells transfected with XRE-luciferase reporter (XRE-Luc), plasmid drive luciferase activity reflecting activation and inhibition of AhR in the cells. In addition to transfection with XRE-reporter vector, cells were co-transfected with Nano-luciferase reporter gene construct (Nano-Luc), containing constitutively active promoter as internal control. Kynurenine (an endogenous AhR agonist), was used to stimulate cells to test antagonistic properties of the compounds. The half-maximal inhibitory concentration (IC50), or half-maximal effective concentration (EC50), value was calculated using nonlinear regression (four parameters), with Prism8.0 software (GraphPad).
In vitro assay 1 : Antagonism in human cell line
HepG2 (human hepatoma cell line) cell line with a XRE- luciferase reporter either transiently or stably (Invivogen) were plated in complete medium and incubated at 37℃ in a CO2 incubator. After 24 hours, cells were treated with kynurenine (50* or 200 μM) alone (negative control) or with test compounds for 6 hours. Luciferase activity was measured with a commercial kit such as the Promega Luciferase kit or Invivogen Luciferase kit. Relative luciferase activity (Firefly/Nano-Luc) was used to calculate IC50 values. The relative luciferase activity was further normalized with kynurenine alone group as the maximum control and the vehicle group as the minimum control. The AhR antagonistic potency of the example compounds is listed in Table 1 below. (IC50 values are grouped as A, B, C and D, whereby A: IC50 < 0.01 μM; B: 0.01 < IC50 < 0.1 μM; C: 0.1 < IC50 < 1.0 μM; D: IC50 > 1.0 μM)
In vitro assay 2 : Antagonism in mouse cell line
Hepa1c1c7 (murine liver cancer cell line) cells co-transfected with XRE-Luc and Nano-Luc plasmids were plated in complete medium and incubated overnight at 37℃ in a CO2 incubator. Following incubation, cells were treated with AhR activating ligands such as kynurenic acid, kynurenine(#) with or without test compounds for 6 hours. Firefly luciferase and Nano-luciferase activity was measured using Nano-glo Luciferase kit (Promega) and relative luciferase activity (Firefly/Nano-Luc) was used to calculate IC50 values. The relative luciferase activity was further normalized with agonists alone group as the maximum control and the vehicle group as the minimum control. The AhR antagonistic potency of the example compounds is listed in Table 1 below. (IC50 Values are grouped as A, B, C and D, whereby A: IC50 < 0.01 μM; B: 0.01 < IC50 < 0.1 μM; C: 0.1 < IC50 < 1.0 μM; D: IC50 > 1.0 μM)
In vitro assay 3 : Agonism in human cell line
HepG2 (human hepatoma cell line) cells co-transfected with XRE-Luc and Nano-Luc plasmids were plated in tryptophan free medium containing 1% of dialyzed fetal bovine serum and incubated overnight at 37℃ in a CO2 incubator. After 24 hours, cells were treated for 6 hours with test compounds or not. Firefly luciferase and Nano-luciferase activity was measured using Nano-glo Luciferase kit (Promega) and relative luciferase activity (Firefly/Nano-Luc) was used to calculate EC50 values. As a positive control, cells were incubated with TCDD.
(EC50 Values are grouped as A, B, C and D, whereby A: EC50 < 0.1 μM; B: 0.1 < EC50 < 1.0 μM; C: 1.0 < EC50 < 10 μM; D: EC50 > 10 μM)
Figure PCTKR2021003883-appb-T000001
Figure PCTKR2021003883-appb-I000045
Figure PCTKR2021003883-appb-I000046
Figure PCTKR2021003883-appb-I000047
Figure PCTKR2021003883-appb-I000048
Figure PCTKR2021003883-appb-I000049
Figure PCTKR2021003883-appb-I000050
Figure PCTKR2021003883-appb-I000051
Figure PCTKR2021003883-appb-I000052
Figure PCTKR2021003883-appb-I000053
In vitro assay 4 : Endogenous AhR activity assay
HepG2 cells were seeded in 12-well plate (3×105 cells/well). A day after seeding, the cells were treated with TCDD (10 nM) alone or with compounds (123 nM) for 4 hours. Total RNA was extracted using Trizol (Thermo Fisher Scientific). cDNA synthesis and quantitative RT-PCR (qRT-PCR) assays were performed using PrimeScript™ RT Master Mix (TAKARA) and TB Green™ Premix Ex Taq™ II (TAKARA) in accordance with manufacturer’s instruction. For the measurement of endogenous AhR activity, relative mRNA levels of CYP1A1 and CYP1B1 were quantitated relative to B-actin mRNA by the comparative Ct (ΔΔCt) method. The percent inhibitions were calculated according to:
Figure PCTKR2021003883-appb-I000054
The endogenous AhR antagonistic potency of the example compounds is listed in Table 2 below.
Figure PCTKR2021003883-appb-T000002

Claims (27)

  1. A compound of Formula (I), or an enantiomer, diastereomer, racemate, solvate, hydrate, or pharmaceutically acceptable salt thereof:
    [Formula (I)]
    Figure PCTKR2021003883-appb-I000055
    wherein:
    X1, X2 and X3 are each independently CR2, N or NR3;
    Ar1 and Ar2 are each independently selected from substituted or unsubstituted mono- or bicyclic C6-10 aryl, substituted or unsubstituted mono- or bicyclic C5-10 heteroaryl and substituted or unsubstituted mono- or bicyclic C3-10 heterocycloalkyl;
    D is H, halo, cyano, hydroxy, amino, substituted or unsubstituted C1-5 alkyl, mono- or bicyclic C3-10 cycloalkyl, C1-5 alkylhydroxy, C1-5 alkenylhydroxy, C1-5 alkynylhydroxy, C1-5 alkylamine, C1-5 alkenylamine, C1-5 alkynylamine, mono- or bicyclic C3-10 heterocycloalkyl, mono- or bicyclic C3-10 heteroaryl,
    E is absent(direct bond), amino, substituted or unsubstituted C1-5 alkyl, mono- or bicyclic C3-10 cycloalkyl, C1-5 alkylhydroxy, C1-5 alkenylhydroxy, C1-5 alkynylhydroxy, C1-5 alkylamine, C1-5 alkenylamine, C1-5 alkynylamine, mono- or bicyclic C3-10 heterocycloalkyl, mono- or bicyclic C3-10 heteroaryl,
    or D and E, together with the atoms to which they are attached, are combined to form substituted or unsubstituted mono- or bicyclic C3-10 heterocycloalkyl ring;
    G is absent(direct bond), H, halo, cyano, hydroxy, amino, nitro, ether(-O-), thioether(-S-), sulfinyl(-SO-), sulfonyl(-SO2-), sulfonylamido(-SO2NR4-), aminosulfonyl(-NR4SO2-), carbonyl(-(CO)-), amido(-(CO)NR4-), reverse amido(-NR4(CO)-), ester(-(CO)O-), substituted or unsubstituted mono- or bicyclic C3-10 cycloalkyl, substituted or unsubstituted mono- or bicyclic C3-10 heterocycloalkyl, substituted or unsubstituted mono- or bicyclic C6-10 aryl and substituted or unsubstituted mono- or bicyclic C5-10 heteroaryl;
    R1 is absent, H, halo, cyano, hydroxy, amino, N(R5)2, OR5, substituted or unsubstituted C1-5 alkyl, C3-10 cycloalkyl, C1-5 alkylhydroxy, C1-5 alkenylhydroxy, C1-5 alkynylhydroxy, C1-5 alkylamine, C1-5 alkenylamine, C1-5 alkynylamine, substituted or unsubstituted mono- or bicyclic C3-10 heterocycloalkyl and substituted or unsubstituted mono- or bicyclic C5-10 heteroaryl;
    R2 is H, halo, cyano, hydroxy and C1-3 alkyl;
    R3 is H, halo, cyano, hydroxyl and amino; and
    R4 is H, substituted or unsubstituted C1-5 alkyl, substituted or unsubstituted C1-5 alkoxy and substituted or unsubstituted C1-5 alkyl carboxylic acid; and
    R5 is H, substituted or unsubstituted C1-5 alkyl, substituted or unsubstituted C1-5 alkoxy and substituted or unsubstituted C1-5 alkyl carboxylic acid.
  2. The compound, or an enantiomer, diastereomer, racemate, solvate, hydrate, or pharmaceutically acceptable salt thereof according to claim 1,
    wherein the Ar1 is substituted or unsubstituted monocyclic C5-7 heteroaryl comprising one or more hetero atoms selected from the group consisting of N, O and S.
  3. The compound, or an enantiomer, diastereomer, racemate, solvate, hydrate, or pharmaceutically acceptable salt thereof according to claim 1, the Ar1 is monocyclic C5-6 heteroaryl comprising one or two hetero atoms selected from the group consisting of N, O and S, which is unsubstituted or substituted with C1-3 alkyl.
  4. The compound, or an enantiomer, diastereomer, racemate, solvate, hydrate, or pharmaceutically acceptable salt thereof according to claim 1, the Ar1 is pyrazole or pyridine which is unsubstituted or substituted with methyl.
  5. The compound, or an enantiomer, diastereomer, racemate, solvate, hydrate, or pharmaceutically acceptable salt thereof according to claim 1, the Ar2 is mono- or bicyclic C6-10 aryl comprising one or more hetero atoms selected from the group consisting of N, O and S, which is unsubstituted or substituted with halo.
  6. The compound, or an enantiomer, diastereomer, racemate, solvate, hydrate, or pharmaceutically acceptable salt thereof according to claim 1, the Ar2 is phenyl which is unsubstituted or substituted with chloro.
  7. The compound, or an enantiomer, diastereomer, racemate, solvate, hydrate, or pharmaceutically acceptable salt thereof according to claim 1, the D is H or C1-3 alkyl.
  8. The compound, or an enantiomer, diastereomer, racemate, solvate, hydrate, or pharmaceutically acceptable salt thereof according to claim 1, the E is absent(direct bond), amino, substituted or unsubstituted C1-4 alkyl, mono- or bicyclic C3-8 cycloalkyl, C1-4 alkylhydroxy, C1-4 alkenylhydroxy, C1-4 alkynylhydroxy, C1-4 alkylamine, C1-4 alkenylamine, C1-4 alkynylamine, mono- or bicyclic C3-8 heterocycloalkyl, mono- or bicyclic C3-8 heteroaryl, wherein the mono- or bicyclic C3-8 heterocycloalkyl and mono- or bicyclic C3-8 heteroaryl comprises one or more heteroatoms selected from the group consisting of N, O and S.
  9. The compound, or an enantiomer, diastereomer, racemate, solvate, hydrate, or pharmaceutically acceptable salt thereof according to claim 1, the D and E, together with the atoms to which they are attached, is combined to form substituted or unsubstituted mono- or bicyclic C3-10 heterocycloalkyl ring one or more hetero atoms selected from the group consisting of N, O and S.
  10. The compound, or an enantiomer, diastereomer, racemate, solvate, hydrate, or pharmaceutically acceptable salt thereof according to claim 9, the mono- or bicyclic C3-10 heterocycloalkyl ring is unsubstituted or substituted pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, or octahydropyranopyridine.
  11. The compound, or an enantiomer, diastereomer, racemate, solvate, hydrate, or pharmaceutically acceptable salt thereof according to claim 1, the G is absent(direct bond), H, halo, cyano, hydroxy, amino, nitro, ether(-O-), thioether(-S-), sulfinyl(-SO-), sulfonyl(-SO2-), sulfonylamido(-SO2NR4-), aminosulfonyl(-NR4SO2-), carbonyl(-(CO)-), amido(-(CO)NR4-), reverse amido(-NR4(CO)-), ester(-(CO)O-), substituted or unsubstituted mono- or bicyclic C3-8 cycloalkyl, substituted or unsubstituted mono- or bicyclic C3-8 heterocycloalkyl, substituted or unsubstituted mono- or bicyclic C6-10 aryl and substituted or unsubstituted mono- or bicyclic C5-8 heteroaryl, wherein the mono- or bicyclic C3-8 heterocycloalkyl and mono- or bicyclic C5-8 heteroaryl comprises one or more heteroatoms selected from the group consisting of N, O and S.
  12. The compound, or an enantiomer, diastereomer, racemate, solvate, hydrate, or pharmaceutically acceptable salt thereof according to claim 1, R1 is absent, H, halo, cyano, hydroxy, amino, N(R5)2, OR5, substituted or unsubstituted C1-4 alkyl, C3-8 cycloalkyl, C1-4 alkylhydroxy, C1-4 alkenylhydroxy, C1-4 alkynylhydroxy, C1-4 alkylamine, C1-4 alkenylamine, C1-4 alkynylamine, substituted or unsubstituted mono- or bicyclic C3-8 heterocycloalkyl and substituted or unsubstituted mono- or bicyclic C5-8 heteroaryl, phosphate, substituted or unsubstituted C1-3 alkyl phosphate, wherein the mono- or bicyclic C3-8 heterocycloalkyl and mono- or bicyclic C5-8 heteroaryl comprises one or more heteroatoms selected from the group consisting of N, O and S.
  13. The compound according to claim 1, which is selected from any one of the compounds 1 to 376, or The compound, 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)propane-1,2-diol
    11. (R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propan-1-ol
    12. 2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)-3-methylbutan-1-ol
    13. (S)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)-3-methylbutan-1-ol
    14. (R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)-3-methylbutan-1-ol
    15. 2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)butan-1-ol
    16. 2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propane-1,3-diol
    17. (R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)-1-phenylethan-1-ol
    18. (S)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)-1-phenylethan-1-ol
    19. 6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrimidin-4-amine
    20. N1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-N3,N3-dimethylpropane-1,3-diamine
    21. 6-(4-chlorophenyl)-N-ethyl-2-(pyridin-3-yl)pyrimidin-4-amine
    22. 6-(4-chlorophenyl)-N-propyl-2-(pyridin-3-yl)pyrimidin-4-amine
    23. N-butyl-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-amine
    24. 1-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)butan-2-ol
    25. 6-(4-chlorophenyl)-N-(cyclopropylmethyl)-2-(pyridin-3-yl)pyrimidin-4-amine
    26. 6-(4-chlorophenyl)-N-cyclopentyl-2-(pyridin-3-yl)pyrimidin-4-amine
    27. 4-(4-chlorophenyl)-6-(4-methylpiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine
    28. N-(tert-butyl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-amine
    29. (1R,2R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol
    30. (1S,2R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol
    31. 6-(4-chlorophenyl)-N-(pyridin-2-ylmethyl)-2-(pyridin-3-yl)pyrimidin-4-amine
    32. 6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(pyridin-3-ylmethyl)pyrimidin-4-amine
    33. 6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(pyridin-4-ylmethyl)pyrimidin-4-amine
    34. trans-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexan-1-ol
    35. trans-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexan-1-ol
    36. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-2-yl)methanol
    37. 2-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-2-yl)ethan-1-ol
    38. (R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-ol
    39. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-ol
    40. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanol
    41. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-ol
    42. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol
    43. 2-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)ethan-1-ol
    44. 3-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)propan-1-ol
    45. 4-(4-chlorophenyl)-6-(4-methoxypiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine
    46. 4-(4-chlorophenyl)-6-(piperidin-1-yl)-2-(pyridin-3-yl)pyrimidine
    47. 4-(4-chlorophenyl)-6-(2-methylpiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine
    48. 4-(4-chlorophenyl)-6-(3-methylpiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine
    49. 4-(4-chlorophenyl)-6-(2,6-dimethylpiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine
    50. 4-(4-chlorophenyl)-6-(3,5-dimethylpiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine
    51. 4-(4-chlorophenyl)-6-(3,3-difluoropiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine
    52. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(3-(trifluoromethyl)piperidin-1-yl)pyrimidine
    53. 4-(4-chlorophenyl)-6-(3-ethylpiperidin-1-yl)-2-(pyridin-3-yl)pyrimidine
    54. 6-(4-chlorophenyl)-N-(piperidin-4-yl)-2-(pyridin-3-yl)pyrimidin-4-amine
    55. 6-(4-chlorophenyl)-N-(piperidin-3-ylmethyl)-2-(pyridin-3-yl)pyrimidin-4-amine
    56. 6-(4-chlorophenyl)-N-(piperidin-4-ylmethyl)-2-(pyridin-3-yl)pyrimidin-4-amine
    57. 6-(4-chlorophenyl)-N-(1-methylpiperidin-4-yl)-2-(pyridin-3-yl)pyrimidin-4-amine
    58. 6-(4-chlorophenyl)-N-(2-(piperidin-4-yl)ethyl)-2-(pyridin-3-yl)pyrimidin-4-amine
    59. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-2-yl)methanamine
    60. (R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-amine
    61. (S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-amine
    62. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanamine
    63. (S)-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanamine
    64. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-amine
    65. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanamine
    66. (1R,2S)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol
    67. (1S,2S)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol
    68. trans-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol
    69. (1R,2R)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexan-1-ol
    70. cis-4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-2,6-dimethylmorpholine
    71. 4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)morpholine
    72. 6-(4-chlorophenyl)-N-(morpholin-2-ylmethyl)-2-(pyridin-3-yl)pyrimidin-4-amine
    73. 4-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)morpholine
    74. 4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)thiomorpholine
    75. 6-(4-chlorophenyl)-N-(3-morpholinopropyl)-2-(pyridin-3-yl)pyrimidin-4-amine
    76. (R)-4-(4-chlorophenyl)-6-(2-methylpiperazin-1-yl)-2-(pyridin-3-yl)pyrimidine
    77. (R)-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-methylpiperazin-1-yl)(phenyl)methanone
    78. 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)piperidine-4-carbonitrile
    151. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(3-(trifluoromethyl)phenyl)piperidin-4-ol
    152. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyrimidine
    153. 4-(4-chlorophenyl)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-ol
    154. 1-(4-(((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)ethan-1-one
    155. 1-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-phenylpiperidin-4-yl)ethan-1-one
    156. 4-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)morpholine
    157. 4-(4-chlorophenyl)-6-(4-(3,5-dichlorophenyl)piperidin-1-yl)-2-(pyridin-3-yl)pyrimidine
    158. 6-(4-chlorophenyl)-N-((1-cyclohexylpiperidin-3-yl)methyl)-2-(pyridin-3-yl)pyrimidin-4-amine
    159. N-((1-benzylpiperidin-4-yl)methyl)-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-amine
    160. ethyl 3-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)-3-oxopropanoate
    161. 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)piperidine-4-carbonitrile
    185. (R)-(1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperidin-3-yl)methanol
    186. (R)-1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)pyrrolidin-3-ol
    187. (1S,3R)-3-((6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol
    188. (R)-2-((6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)butan-1-ol
    189. Trans-4-((6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclohexan-1-ol
    190. 7-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)octahydro-2H-pyrano[2,3-c]pyridine
    191. 7-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)octahydro-2H-pyrano[2,3-c]pyridin-4-ol
    192. (2R,3R)-3-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)pentan-2-ol
    193. 6-(4-chlorophenyl)-N-((1-methylpiperidin-4-yl)methyl)-2-(pyridin-3-yl)pyrimidin-4-amine
    194. (R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol
    195. (S)-6-(4-chlorophenyl)-N-(2-(methoxymethyl)pyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-amine
    196. (S)-4-(4-chlorophenyl)-6-(3-fluoropyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidine
    197. 4-(4-chlorophenyl)-2-(pyridin-3-yl)-6-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidine
    198. 4-(4-chlorophenyl)-6-(3,3-difluoropyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidine
    199. 4-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)morpholine
    200. 5-(((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)methyl)pyrrolidin-2-one
    201. Trans-6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(4-(pyrrolidin-1-yl)tetrahydrofuran-3-yl)pyrimidin-4-amine
    202. 6-(4-chlorophenyl)-N-((3S,4S)-4-methoxy-1-methylpyrrolidin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-amine
    203. (R)-6-(4-chlorophenyl)-N-(piperidin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-amine
    204. 6-(4-chlorophenyl)-N-(piperidin-3-yl)-2-(pyridin-3-yl)pyrimidin-4-amine
    205. 6-(4-chlorophenyl)-N-((3R,4R)-3-fluoropiperidin-4-yl)-2-(pyridin-3-yl)pyrimidin-4-amine
    206. (S)-6-(4-chlorophenyl)-2-(pyridin-3-yl)-N-(pyrrolidin-3-ylmethyl)pyrimidin-4-amine
    207. 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)pyrrolidine-3-carbonitrile
    213. (R)-1-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)butan-2-ol
    214. (1R,3S)-3-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentan-1-ol
    215. Cis-(4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexyl)methanol
    216. Cis-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexan-1-ol
    217. Trans-4-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexan-1-ol
    218. 4-(4-chlorophenyl)-6-(4-(2-methoxyethyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine
    219. (3S,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-ol
    220. (3R,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-ol
    221. (3R,4R)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-ol
    222. (3S,4S)-1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-fluoropiperidin-4-ol
    223. 1-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-2-hydroxyethan-1-one
    224. 2-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)propan-1-ol
    225. N-(1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)-2-methoxyacetamide
    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-(6-(4-chlorophenyl)-2-(2-methyl-2H-tetrazol-5-yl)pyrimidin-4-yl)pyrrolidin-3-ol
    334. 4-(4-chlorophenyl)-2-(2-methyl-2H-tetrazol-5-yl)-6-(4-(methylsulfonyl)piperazin-1-yl)pyrimidine
    335. 4-(4-chlorophenyl)-6-(4-((2-fluoroethyl)sulfonyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine
    336. (S)-1-(6-(4-chlorophenyl)-2-(isoxazol-4-yl)pyrimidin-4-yl)pyrrolidin-3-ol
    337. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-4-(methylsulfonyl)piperidin-4-yl)methanol
    338. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)azepan-3-ol
    339. 4-(4-chlorophenyl)-6-(4-((difluoromethyl)sulfonyl)piperazin-1-yl)-2-(pyridin-3-yl)pyrimidine
    340. (S)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol
    341. 4-(4-(methylsulfonyl)piperazin-1-yl)-2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidine
    342. (S)-1-(6-(4-chlorophenyl)-2-(5,6-difluoropyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol
    343. (3S,4R)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidine-3,4-diol
    344. (S)-1-(6-(4-chlorophenyl)-[2,5'-bipyrimidin]-4-yl)pyrrolidin-3-ol
    345. (S)-1-(6-(4-chlorophenyl)-2-(6-fluoropyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol
    346. (S)-1-(6-(4-chlorophenyl)-2-(2-fluoropyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol
    347. (S)-1-(6-(4-chlorophenyl)-2-(pyridin-2-yl)pyrimidin-4-yl)pyrrolidin-3-ol
    348. 2-((4-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)ethanol
    349. 2-((4-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)ethan-1-ol
    350. (S)-1-(2-(isothiazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)pyrrolidin-3-ol
    351. (4-(methylsulfonyl)-1-(2-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methanol
    352. 1-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-3-hydroxypropan-1-one
    353. 2-((4-(2-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)ethanol
    354. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-(dimethylamino)piperidin-4-ol
    355. 1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-5-(dimethylamino)piperidin-3-ol
    356. (1-(6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-4-(methylsulfonyl)piperidin-4-yl)methanol
    357. (1-(2-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)-4-(methylsulfonyl)piperidin-4-yl)methanol
    358. (1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-(dimethylamino)piperidin-4-yl)methanol
    359. 2-((4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-3-methylpiperazin-1-yl)sulfonyl)ethan-1-ol
    360. 2-((1-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)amino)ethanol
    361. 1-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-4-hydroxybutan-1-one
    362. 3-((4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)propan-1-ol
    363. 1-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-3,4-dihydroxybutan-1-one
    364. 1-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-2,3-dihydroxybutan-1-one
    365. 4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)-6-methylpiperazin-2-one
    366. (S)-3-(4-(3-hydroxypyrrolidin-1-yl)-6-(6-morpholinopyridin-3-yl)pyrimidin-2-yl)pyridin-2-ol
    367. (S)-4-(4-(6-(3-hydroxypyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)phenyl)morpholin-3-one
    368. 2-((4-(6-(4-chlorophenyl)-2-(isothiazol-4-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)ethanol
    369. 3-((4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)propane-1,2-diol
    369. 3-((4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)propane-1,2-diol
    370. 2-((4-(2-(isothiazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)ethanol
    371. (S)-2-(4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-2-yl)ethanol
    372. (S)-4-(5-(6-(3-hydroxypyrrolidin-1-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyridin-2-yl)morpholin-3-one
    373. (S)-3-(4-(3-fluoro-4-morpholinophenyl)-6-(3-hydroxypyrrolidin-1-yl)pyrimidin-2-yl)pyridin-2-ol
    373. (S)-3-(4-(3-fluoro-4-morpholinophenyl)-6-(3-hydroxypyrrolidin-1-yl)pyrimidin-2-yl)pyridin-2-ol
    374. (S)-1-(6-(4-((2-(dimethylamino)ethyl)amino)phenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol
    375. (S)-1-(6-(4-(2-(dimethylamino)ethoxy)phenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol, and
    376. (S)-1-(6-(4-((2-hydroxyethyl)amino)phenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol.
  14. A pharmaceutical composition comprising the 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 according to claim 14 for use in the prevention and/or treatment of a disease or condition mediated by aryl hydrocarbon receptor (AhR).
  16. The pharmaceutical composition according to claim 15, wherein the disease or condition mediated by aryl hydrocarbon receptor (AhR) is cancer, cancerous consitions, tumor, fibrotic disorders, or conditions with dysregulated immune responses or other disorders associated with aberrant AhR signaling.
  17. The pharmaceutical composition according to claim 14, for use in inhibiting proliferation, tissue invasion, metastasis and angiogenesis of cancer cells in a subject having a cancer, a cancerous condition, or a tumor.
  18. The pharmaceutical composition according to claim 17, wherein the cancer is selected from a group consisting of a breast cancer, squamous cell cancer, lung cancer, a cancer of the peritoneum, a hepatocellular cancer, a gastric cancer, a pancreatic cancer, a glioblastoma, a cervical cancer, an ovarian cancer, a liver cancer, a bladder cancer, a hepatoma, a colon cancer, a colorectal cancer, an endometrial or uterine carcinoma, a salivary gland carcinoma, a kidney or renal cancer, a prostate cancer, a vulval cancer, a thyroid cancer, a head and neck cancer, a B-cell lymphoma, a chronic lymphocytic leukemia (CLL); an acute lymphoblastic leukemia (ALL), a Hairy cell leukemia, and a chronic myeloblastic leukemia.
  19. The pharmaceutical composition according to claim 16, wherein the fibrotic disorder is selected from a group consisting of hepatic fibrosis, cirrhosis of the liver, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage resulting from diabetes, bone marrow fibrosis, scleroderma, morphea, keloids, hypertrophic scarring, naevi, diabetic retinopathy, proliferative vitroretinopathy and sarcoidosis.
  20. The pharmaceutical composition according to claim 16, wherein the condition with dysregulated immune responses is selected from a group consisting of sepsis, multiple organ failure, inflammatory disorders of the kidney, chronic intestinal inflammations, pancreatitis, peritonitis, inflammatory skin disorders and inflammatory eye disorders, rheumatoid diseases, systemic lupus erythematosus and multiple sclerosis.
  21. A method of modulating AhR activity in a subject comprising administering a therapeutically effective amount of the compound of formula (I) according to claim 1.
  22. A method of preventing or treating a disease or condition mediated by aryl hydrocarbon receptor (AhR) in a subject comprising administering a therapeutically effective amount of the compound of formula (I) according to claim 1.
  23. The method according to claim 22, wherein the disease or condition mediated by aryl hydrocarbon receptor (AhR) is cancer, cancerous consitions, tumor, fibrotic disorders, or conditions with dysregulated immune responses or other disorders associated with aberrant AhR signaling.
  24. The method according to claim 23, wherein the cancer is selected from a group consisting of a breast cancer, squamous cell cancer, lung cancer, a cancer of the peritoneum, a hepatocellular cancer, a gastric cancer, a pancreatic cancer, a glioblastoma, a cervical cancer, an ovarian cancer, a liver cancer, a bladder cancer, a hepatoma, a colon cancer, a colorectal cancer, an endometrial or uterine carcinoma, a salivary gland carcinoma, a kidney or renal cancer, a prostate cancer, a vulval cancer, a thyroid cancer, a head and neck cancer, a B-cell lymphoma, a chronic lymphocytic leukemia (CLL); an acute lymphoblastic leukemia (ALL), a Hairy cell leukemia, and a chronic myeloblastic leukemia.
  25. The method according to claim 23, wherein the fibrotic disorder is selected from a group consisting of hepatic fibrosis, cirrhosis of the liver, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage resulting from diabetes, bone marrow fibrosis, scleroderma, morphea, keloids, hypertrophic scarring, naevi, diabetic retinopathy, proliferative vitroretinopathy and sarcoidosis.
  26. The method according to claim 23, wherein the condition with dysregulated immune responses is selected from a group consisting of sepsis, multiple organ failure, inflammatory disorders of the kidney, chronic intestinal inflammations, pancreatitis, peritonitis, inflammatory skin disorders and inflammatory eye disorders, rheumatoid diseases, systemic lupus erythematosus and multiple sclerosis.
  27. A method of inhibiting proliferation, tissue invasion, metastasis and angiogenesis of cancer cells in a subject having a cancer, a cancerous condition, or a tumor comprising administering a therapeutically effective amount of the compound of formula (I) according to claim 1.
PCT/KR2021/003883 2020-03-27 2021-03-29 Aminopyrimidine derivatives and their use as aryl hydrocarbon receptor modulators WO2021194326A1 (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
BR112022019387A BR112022019387A2 (en) 2020-03-27 2021-03-29 AMINOPYRIMIDINE DERIVATIVES AND THEIR USE AS ARYL HYDROCARBON RECEPTOR MODULATORS
JP2022558169A JP2023520988A (en) 2020-03-27 2021-03-29 Aminopyrimidine derivatives and their use as aryl hydrocarbon receptor modulators
US17/906,742 US20230150970A1 (en) 2020-03-27 2021-03-29 Aminopyrimidine derivatives and their use as aryl hydrocarbon receptor modulators
KR1020227037504A KR20230005844A (en) 2020-03-27 2021-03-29 Aminopyrimidine derivatives and their use as aryl hydrocarbon receptor modulators
CN202180024853.7A CN115397818A (en) 2020-03-27 2021-03-29 Aminopyrimidine derivatives and their use as modulators of arene receptors
AU2021242143A AU2021242143B2 (en) 2020-03-27 2021-03-29 Aminopyrimidine derivatives and their use as Aryl hydrocarbon receptor modulators
EP21776706.0A EP4126839A4 (en) 2020-03-27 2021-03-29 Aminopyrimidine derivatives and their use as aryl hydrocarbon receptor modulators
MX2022011826A MX2022011826A (en) 2020-03-27 2021-03-29 Aminopyrimidine derivatives and their use as aryl hydrocarbon receptor modulators.
CA3176957A CA3176957A1 (en) 2020-03-27 2021-03-29 Aminopyrimidine derivatives and their use as aryl hydrocarbon receptor modulators

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202063000584P 2020-03-27 2020-03-27
US63/000,584 2020-03-27

Publications (1)

Publication Number Publication Date
WO2021194326A1 true WO2021194326A1 (en) 2021-09-30

Family

ID=77892076

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2021/003883 WO2021194326A1 (en) 2020-03-27 2021-03-29 Aminopyrimidine derivatives and their use as aryl hydrocarbon receptor modulators

Country Status (10)

Country Link
US (1) US20230150970A1 (en)
EP (1) EP4126839A4 (en)
JP (1) JP2023520988A (en)
KR (1) KR20230005844A (en)
CN (1) CN115397818A (en)
AU (1) AU2021242143B2 (en)
BR (1) BR112022019387A2 (en)
CA (1) CA3176957A1 (en)
MX (1) MX2022011826A (en)
WO (1) WO2021194326A1 (en)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003006439A1 (en) * 2001-07-13 2003-01-23 Astrazeneca Uk Limited Preparation of aminopyrimidine compounds
EP1395568B1 (en) * 2001-05-23 2006-11-02 F. Hoffmann-La Roche Ag 4-aminopyrimidine derivatives
WO2018136700A1 (en) * 2017-01-20 2018-07-26 Arcus Biosciences, Inc. Azolopyrimidine for the treatment of cancer-related disorders
WO2018195397A2 (en) * 2017-04-21 2018-10-25 Kyn Therapeutics Indole ahr inhibitors and uses thereof
WO2019196720A1 (en) * 2018-04-08 2019-10-17 中国科学院上海药物研究所 Arginine methyltransferase inhibitor, pharmaceutical composition thereof and use thereof

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3922735A1 (en) * 1989-07-11 1991-01-24 Hoechst Ag AMINOPYRIMIDINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, THE AGENTS CONTAINING THEY AND THEIR USE AS FUNGICIDES
JP4105948B2 (en) * 2000-09-15 2008-06-25 バーテックス ファーマシューティカルズ インコーポレイテッド Pyrazole compounds useful as protein kinase inhibitors
JO2660B1 (en) * 2006-01-20 2012-06-17 نوفارتيس ايه جي PI-3 Kinase inhibitors and methods of their use
WO2010096619A1 (en) * 2009-02-23 2010-08-26 Wyeth Llc Process, purification and crystallization of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea
ES2365960B1 (en) * 2010-03-31 2012-06-04 Palobiofarma, S.L NEW ANTAGONISTS OF ADENOSINE RECEPTORS.
KR101328978B1 (en) * 2010-10-26 2013-11-13 삼성디스플레이 주식회사 Organic light emitting device
KR101556317B1 (en) * 2013-10-29 2015-10-01 한국과학기술연구원 2,4,6-Trisubstituted pyrimidine compounds for ROS kinase inhibitors
EP3134388B1 (en) * 2014-04-22 2019-01-09 Universität Basel Novel manufacturing process for triazine, pyrimidine and pyridine derivatives
US11008280B2 (en) * 2016-04-26 2021-05-18 Duk San Neolux Co., Ltd. Compound for organic electric element, organic electric element using same, and electronic device comprising same organic electronic element
CN109863140B (en) * 2016-05-25 2023-02-21 拜耳医药股份有限公司 3-oxo-2, 6-diphenyl-2, 3-dihydropyridazine-4-carboxamide
JOP20190193A1 (en) * 2017-02-09 2019-08-08 Bayer Pharma AG 2-heteroaryl-3-oxo-2,3-dihydropyridazine-4-carboxamides for the treatment of cancer

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1395568B1 (en) * 2001-05-23 2006-11-02 F. Hoffmann-La Roche Ag 4-aminopyrimidine derivatives
WO2003006439A1 (en) * 2001-07-13 2003-01-23 Astrazeneca Uk Limited Preparation of aminopyrimidine compounds
WO2018136700A1 (en) * 2017-01-20 2018-07-26 Arcus Biosciences, Inc. Azolopyrimidine for the treatment of cancer-related disorders
WO2018195397A2 (en) * 2017-04-21 2018-10-25 Kyn Therapeutics Indole ahr inhibitors and uses thereof
WO2019196720A1 (en) * 2018-04-08 2019-10-17 中国科学院上海药物研究所 Arginine methyltransferase inhibitor, pharmaceutical composition thereof and use thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP4126839A4 *

Also Published As

Publication number Publication date
EP4126839A1 (en) 2023-02-08
EP4126839A4 (en) 2024-04-17
CA3176957A1 (en) 2021-09-30
US20230150970A1 (en) 2023-05-18
BR112022019387A2 (en) 2022-11-16
MX2022011826A (en) 2022-10-18
KR20230005844A (en) 2023-01-10
CN115397818A (en) 2022-11-25
JP2023520988A (en) 2023-05-23
AU2021242143B2 (en) 2024-07-18
AU2021242143A1 (en) 2022-10-20

Similar Documents

Publication Publication Date Title
AU2021257373B2 (en) Pyridopyrimidinone derivatives and their use as Aryl hydrocarbon receptor modulators
WO2018230934A1 (en) N2,n4-diphenylpyrimidine-2,4-diamine derivative, method for preparing same, and pharmaceutical composition containing same as active ingredient for prevention or treatment of cancer
AU2016317806B2 (en) Heteroaryl compounds and their use as therapeutic drugs
WO2022055181A1 (en) Compounds for suppressing egfr mutant cancer and pharmaceutical use thereof
WO2023017446A1 (en) Novel plk1 degradation inducing compound
EP3166945A2 (en) Novel triazolopyrimidinone or triazolopyridinone derivatives, and use thereof
WO2016006974A2 (en) Novel triazolopyrimidinone or triazolopyridinone derivatives, and use thereof
AU2021242143B2 (en) Aminopyrimidine derivatives and their use as Aryl hydrocarbon receptor modulators
EP4392415A1 (en) Substituted aminopyridine compounds as egfr inhibitors
WO2022225238A1 (en) Heteroaryl derivative compound and use thereof
WO2022025640A1 (en) Compound for inhibiting or disintegrating androgen receptor, and pharmaceutical use thereof
WO2022019597A1 (en) Compound for androgen receptor degradation, and pharmaceutical use thereof
RU2826628C1 (en) Aminopyrimidine derivatives and use thereof as aromatic hydrocarbon receptor modulators
WO2024162746A1 (en) Indole compound decomposing ikzf2, and use thereof
WO2023177233A1 (en) Novel compound and use thereof for inhibiting checkpoint kinase 2
WO2024172632A1 (en) Azolylpyridine pyridazinone amide as sos1 inhibitor
WO2023211256A1 (en) Novel pim kinase inhibitors and uses thereof
WO2024172631A1 (en) Pharmaceutical composition for treatment of cancer, comprising sos1 inhibitor and anticancer drug
WO2020106059A1 (en) Novel tricyclic compound as irak4 inhibitor
WO2022235091A1 (en) Novel heterocyclic compound and use thereof
WO2023113457A1 (en) Novel compound for degrading target protein or polypeptide by using polyubiquitination
WO2023121413A1 (en) Novel bicyclic heterocyclyl compound and use thereof
WO2023027516A1 (en) 5-membered heteroaryl-containing aminopyridine compounds as egfr inhibitors
WO2024177362A1 (en) Macrocyclic aminopyridine compounds as egfr inhibitors
WO2023229380A1 (en) Heterocyclic compound as diacylglycerol kinase inhibitor and use thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21776706

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2022558169

Country of ref document: JP

Kind code of ref document: A

Ref document number: 3176957

Country of ref document: CA

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112022019387

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 2021242143

Country of ref document: AU

Date of ref document: 20210329

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2021776706

Country of ref document: EP

Effective date: 20221027

ENP Entry into the national phase

Ref document number: 112022019387

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20220926