CN112062717A - Indoleamine 2, 3-dioxygenase inhibitor - Google Patents
Indoleamine 2, 3-dioxygenase inhibitor Download PDFInfo
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Abstract
The invention provides a novel compound capable of inhibiting activity of indoleamine 2, 3-dioxygenase (IDO), a pharmaceutical composition containing the compound, a preparation method of the compound and application of the compound in preparing a medicament for treating proliferative diseases, infectious diseases, immune-related diseases and/or inflammatory diseases.
Description
Technical Field
The present invention relates to compounds that modulate or inhibit indoleamine 2, 3-dioxygenase (IDO) activity, pharmaceutical compositions containing such compounds, and methods of using the compounds of the invention in the treatment of proliferative disorders, such as cancer, infectious diseases, immune-related disorders, and/or inflammatory disorders.
Background
Tryptophan is an essential amino acid in the human body, and part of tryptophan obtained from the diet is used for synthesizing protein and neurotransmitter 5-hydroxytryptamine, and the rest is mainly metabolized through the kynurenine pathway to form nicotinamide adenine dinucleotide (NAD +) through a series of steps. Indoleamine 2, 3-dioxygenase (IDO) is a heme-containing monomeric oxidoreductase that catalyzes the degradation of tryptophan to N-formyl-kynurenine, the first step of the kynurenine metabolic pathway for tryptophan, and is also the rate-limiting enzyme of the entire reaction pathway. IDO1 is expressed in many tissues and cells of humans and animals, particularly in the small intestine, reproductive tract, placenta, dendritic cells, macrophages, and tumor cells. Low expression under normal conditions, significantly increased expression during inflammation and infection, and IFN-gamma can induce its expression. In addition to IFN- γ, other cytokines such as IFN- α, IFN- β, IL-10, IL-6, IL-4, IL-1 and TGF- β may also regulate the expression of IDO 1.
The IDO pathway is one of the endogenous mechanisms of the body to induce peripheral immune tolerance. Mouse experiments prove that after IDO is knocked out or the functional activity of the IDO is inhibited, the immune tolerance of a mother body to a fetus, the immune tolerance of intestinal mucosa, the tolerance of an organism to apoptotic cells and other acquired peripheral tolerance can be damaged. Thus, blocking or deleting IDO activity can lead to exacerbation of inflammation and aggravation of disease progression during GVHD models, autoimmune diseases, or infections. Notably, IDO-/-mice do not develop spontaneous autoimmune disease or lymphoproliferative disorders. This result suggests that while the IDO pathway plays an important role in the body's immune tolerance to foreign antigens, it does not appear to play a role in maintaining the body's immune tolerance to self-antigens.
When the expression level of IDO1 in the tissue cells is increased, a large amount of tryptophan is metabolized through a kynurenine pathway, the content of tryptophan is reduced, the lack of tryptophan causes a large amount of aggregation of the unloaded tRNA, and the stress response kinase GCN2 directly inhibits the activation and proliferation of T cells after receiving signals of the unloaded tRNA; and metabolites such as kynurenine, kynurenine quinolinic acid, 3-hydroxykynurenine, 3-hydroxyaminobenzoic acid and the like generated in the kynurenine pathway have a certain inhibition effect on the immune system. For example, the metabolite kynurenine, when bound to the aromatic hydrocarbon receptor AhR, not only directly inhibits the survival of T cells, but also inhibits the function of effector T cells by promoting the differentiation of regulatory T cells (Tregs). Thus, upregulation of IDO expression may shift the local microenvironment from an immune-activated state to an immune-tolerant state.
IDO expression was detected in both primary and metastatic tumors of different tumor types. The expression of IDO is in positive correlation with the reduction of the survival time of patients, serious disease stages, tumor metastasis, reduction of tumor infiltrating lymphocytes and Foxp3+ Tregs cytosis. IDO overexpression has been shown to be an independent prognostic factor in decreasing survival in patients with melanoma, pancreatic, colorectal and endometrial cancers, among others.
From a pharmacological perspective, IDO is a good target for the development of small molecule inhibitors for the treatment of various immune-related disorders, including cancer. Among the numerous pharmaceutical companies targeting IDO, Incyte is leading in the development of IDO inhibitors for cancer therapy. Incyte started a program in 2004 aimed at finding small molecule IDO1 inhibitors, focusing on the hydroxytryptamine family, in which the tryptophan competitive inhibitor Epacadostat (INCB024360, WO2010005958) was developed as a lead clinical agent. Epacadostat has entered the phase II/III trial for melanoma, non-small cell lung cancer and various solid tumors. BMS986205(WO2016073770) is an IDO inhibitor issued by Flexus Inc. to Bristol-Myers Squibb for clinical development. The compound is used as an irreversible inhibitor with high activity, and has more excellent cell activity and pharmacokinetic performance compared with Epacadostat. BMS986205 in combination with Nivolumab has entered phase I/II clinical study (NCT02658890) in melanoma patients, phase II clinical study (NCT03519256) in BCG non-responsive bladder cancer patients, and phase III trial study (NCT03661320) in muscle-invasive bladder cancer.
Given the role played by IDO in a diverse range of diseases, there is still a need to find effective IDO inhibitors and their related compositions and uses.
Disclosure of Invention
The present invention aims to provide novel compounds as indoleamine 2, 3-dioxygenase (IDO) inhibitors, pharmaceutical compositions containing said compounds and the use of said compounds for the preparation of a medicament for the treatment and/or prophylaxis of diseases, disorders or conditions which are mediated in whole or in part by indoleamine 2, 3-dioxygenase (IDO).
The present invention provides a compound represented by the formula (I)
Or a stereoisomer, tautomer, or pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotopically labeled derivative thereof, wherein:
x is a bond, -C (O) NH-or-NHC (O) -;
cy is C6-10Aryl or heteroaryl of (a), which is optionally substituted by halogen.
According to some embodiments of the compounds of formula (I) of the present invention, Cy is phenyl or quinolinyl, optionally substituted with halogen.
According to some embodiments of the compounds of formula (I) according to the present invention, Cy is quinolin-4-yl, optionally substituted with halogen.
According to some embodiments of the compounds of formula (I) according to the present invention, Cy is phenyl or quinolin-4-yl, optionally substituted with F or Cl.
According to some embodiments of the compounds of formula (I) according to the present invention, Cy is fluorophenyl, chlorophenyl, fluoroquinolyl, preferably fluoroquinolin-4-yl.
According to some embodiments of the compounds of formula (I) according to the present invention, Cy is phenyl, 4-fluorophenyl, 4-chlorophenyl, 6-fluoroquinolin-4 yl.
In some embodiments of the compounds of formula (I) of the present invention, there are provided compounds having the structure:
in some embodiments of the compounds of formula (I) of the present invention, there are provided compounds having the structure:
the present invention provides a compound represented by the formula (II)
Or a stereoisomer, tautomer or pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotopically labeled derivative thereof, wherein
X is a bond or optionally substituted by C1-6An alkyl-substituted methylene group;
y is a bond, -C (O) NH-or-NHC (O) -;
cy is C6-10Aryl or heteroaryl of (a), which is optionally substituted by halogen.
According to some embodiments of the compounds of formula (II) of the present invention, Cy is phenyl or quinolinyl, optionally substituted with halogen.
According to some embodiments of the compounds of formula (II) of the present invention, Cy is quinolin-4-yl or quinolin-2-yl, optionally substituted with halogen.
According to some embodiments of the compounds of formula (II) of the present invention, Cy is phenyl, quinolin-4-yl, or quinolin-2-yl, optionally substituted with F or Cl.
According to some embodiments of the compounds of formula (II) of the present invention, Cy is phenyl, 6-fluoroquinolin-4 yl or 6-fluoroquinolin-2 yl.
According to some embodiments of the compounds of formula (II) of the present invention, X is methylene substituted with methyl.
In some embodiments of the compounds of formula (II) of the present invention, there are provided compounds having the structure:
in some embodiments of the compounds of formula (II) of the present invention, there are provided compounds having the structure:
another aspect of the invention relates to a pharmaceutical composition comprising a compound of formula (I) as described above, together with one or more pharmaceutically acceptable carriers, diluents or excipients.
Another aspect of the invention relates to a pharmaceutical composition comprising a compound of formula (II) as described above, together with one or more pharmaceutically acceptable carriers, diluents or excipients.
According to some embodiments of the invention, the above pharmaceutical composition further comprises one or more additional therapeutic agents.
According to some embodiments of the invention, the additional therapeutic agent is selected from chemotherapeutic agents, signal transduction inhibitors, anti-infective agents, immune modulators and/or inflammation modulators.
According to some embodiments of the invention, the additional therapeutic agent is an immune checkpoint inhibitor. The immune checkpoint inhibitor is preferably a PD-1 antibody and/or a PD-L1 antibody. The PD-1 antibody includes but is not limited to OPDIVO (nivolumab) or KEYTRUDA (pertuzumab). The PD-L1 antibodies include, but are not limited to, Tecntriq, Imfinzi or Bavencio.
The invention also relates to the application of the compound or the pharmaceutical composition in preparing a medicament for inhibiting the activity of indoleamine 2, 3-dioxygenase.
The invention also relates to the use of the above-mentioned compounds or pharmaceutical compositions in the manufacture of a medicament for the treatment and/or prevention of a disease, disorder or condition mediated in whole or in part by indoleamine 2, 3-dioxygenase (IDO). According to some embodiments of the invention, the disease, disorder or condition is a proliferative disease, an infectious disease, an immune-related disease and/or an inflammatory disease. Such proliferative diseases include, but are not limited to, cancer. The infectious disease includes, but is not limited to, viral infection. The use further comprises a combination or combination of the compound or pharmaceutical composition with a chemotherapeutic agent, radiation therapy, transplantation therapy, vaccine, cytokine therapy, signal transduction inhibitor, anti-infective agent, immune modulator and/or inflammation modulator.
The invention also relates to the use of the above compounds or pharmaceutical compositions for the treatment and/or prevention of a variety of diseases, disorders, or conditions mediated in whole or in part by indoleamine 2, 3-dioxygenase (IDO). According to some embodiments of the invention, the disease, disorder or condition is a proliferative disease, including but not limited to cancer, an infectious disease, including but not limited to a viral infection, an immune-related disease and/or an inflammatory disease. The use further comprises administering to a patient with the disease, disorder, or condition a chemotherapeutic agent, radiation therapy, transplantation therapy, vaccine, cytokine therapy, signal transduction inhibitors, anti-infective agents, immunomodulators and/or inflammation modulators.
Immunoregulatory abnormalities are closely associated with tumor evasion by the host immune system, leading to tumor growth and development. Traditional treatment methods, including chemotherapy and radiation therapy, are generally intolerable to patients and become less effective as tumors evolve to survive these treatments. Immunotherapy has the benefit of reduced toxicity by exploiting the patient's autoimmune system to identify and eliminate tumor cells. Since upregulation of the immunomodulatory enzyme indoleamine 2, 3-dioxygenase comprises a mechanism for promoting growth through tumor control, agents that inhibit enzymatic activity (e.g., small molecule compounds) present a promising approach for prophylaxis and/or treatment. A large number of experimental data indicate a role for IDO inhibition in diseases or disorders such as immunosuppression, tumor tolerance and/or rejection, chronic infection, HIV infection, and autoimmunity. Inhibition of IDO may also be an important therapeutic strategy for patients with neurological or neuropsychiatric diseases or disorders, such as depression. The compounds, compositions and methods of the invention provide a novel class of IDO modulators and uses thereof.
Unless otherwise indicated, when the use of the compounds of the present invention is described herein, it is understood that the compounds may be in the form of compositions (e.g., pharmaceutical compositions).
As described below, although the compounds of the present invention are believed to achieve their activity by inhibiting IDO, the practice of the present invention does not require an accurate understanding of the underlying mechanism of action of the compounds. The compounds of the invention may alternatively achieve their activity by inhibiting tryptophan-2, 3-dioxygenase (TDO) activity. The compounds of the present invention may also achieve their activity by inhibiting the function of both IDO and TDO. Although the compounds of the present invention are generally referred to herein as IDO inhibitors, it is understood that the term "IDO inhibitor" includes compounds that act by inhibiting IDO or TDO alone, and/or compounds that act by inhibiting both IDO and TDO.
In some embodiments of the invention, the invention relates to a method of treating or preventing cancer in a subject (e.g., a human) comprising administering to the subject a therapeutically effective amount of at least one IDO inhibitor described herein. The present invention relates to methods of treating or preventing cancer in a subject comprising administering to the subject an effective amount of an IDO inhibitor that reverses or prevents the progress of IDO-mediated immunosuppression. In some embodiments, IDO-mediated immunosuppression is mediated by Antigen Presenting Cells (APCs).
Examples of cancers that may be treated using the compounds and/or compositions described herein include, but are not limited to: prostate cancer, colorectal cancer, pancreatic cancer, cervical cancer, gastric cancer, endometrial cancer, brain cancer, liver cancer, bladder cancer, ovarian cancer, testicular cancer, head cancer, neck cancer, skin cancer (including melanoma and basal carcinoma), mesothelial intimal cancer, white blood cell cancer (including lymphoma and leukemia), esophageal cancer, breast cancer, muscle cancer, connective tissue cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), adrenal cancer, thyroid cancer, kidney cancer, bone cancer, glioblastoma, mesothelioma, renal cell carcinoma, sarcoma, choriocarcinoma, cutaneous basal cell carcinoma, and testicular seminoma. In some embodiments of the invention, the cancer is melanoma, colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, leukemia, brain tumors, lymphoma, sarcoma, ovarian cancer, or kaposi's sarcoma.
The present invention relates to methods of treating a subject receiving a bone marrow transplant or peripheral blood stem cell transplant by administering a therapeutically effective amount of an IDO inhibitor of the present invention sufficient to increase delayed-type hypersensitivity to a tumor antigen, delay the time to recurrence of a malignant tumor after transplant, increase the time to survival without recurrence after transplant, and/or increase long term survival after transplant.
In some embodiments of the invention, the invention relates to methods of treating or preventing an infectious disorder (e.g., a viral infection) in a subject (e.g., a human), comprising administering to the subject a therapeutically effective amount of at least one IDO inhibitor (e.g., the novel IDO inhibitors of the invention). In some embodiments, the infectious disease is a viral infection (e.g., a chronic viral infection), a bacterial infection, or a parasitic infection. In some embodiments, the viral infection is human immunodeficiency virus or cytomegalovirus. In certain embodiments, the bacterial infection is a mycobacterial infection (e.g., Mycobacterium leprae (Mycobacterium leprae) or Mycobacterium tuberculosis (Mycobacterium tuberculosis)). In certain embodiments, the parasitic infection is an infection by Leishmania donovani (Leishmania donovani), Leishmania tropicalis (Leishmania tropica), Leishmania major (Leishmania major), Leishmania aethiopica (Leishmania aethiopica), Leishmania mexicana (Leishmania mexicana), Plasmodium falciparum (Plasmodium falciparum), Plasmodium vivax (Plasmodium ovax), Plasmodium ovale (Plasmodium ovale), or Plasmodium malariae (Plasmodium malarial). In a further embodiment, the infectious disease is a fungal infection.
In some embodiments of the invention, the invention relates to methods of treating or preventing immune and inflammation-related diseases, disorders, or conditions in a subject (e.g., a human) comprising administering to the subject a therapeutically effective amount of at least one IDO inhibitor (e.g., preferably the novel IDO inhibitors of the present invention).
Immune and inflammation-related diseases, disorders or conditions described herein include, but are not limited to, arthritis (e.g., rheumatoid arthritis), renal failure, lupus, asthma, psoriasis, colitis, pancreatitis, allergy, fibrosis, surgical complications (e.g., where inflammatory cytokines prevent healing), anemia, and fibromyalgia. Other diseases and conditions that may be associated with chronic inflammation include Alzheimer's disease, congestive heart failure, stroke, aortic valve stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infections, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), allergic contact dermatitis and other eczemas, systemic sclerosis, transplantation, and multiple sclerosis. Inhibition of IDO function is also expected to play a role in immune tolerance and prevention of intrauterine fetal rejection, among other immune-related disorders.
Candidate indications for IDO inhibitors described herein also include other diseases, disorders, and conditions that may be treated or prevented, in whole or in part, by modulating IDO activity.
The invention further relates to the use of an IDO inhibitor as described herein in combination with one or more other therapeutic agents. One or more other therapeutic agents may have some IDO modulating activity and/or they may act through different mechanisms of action. In some embodiments, such therapeutic agents include radiation therapy (e.g., local or systemic radiation therapy) and/or other treatment modalities of a non-pharmacological nature. When a combination therapy is used, the IDO inhibitor and one of the other therapeutic agents may be in the form of a single composition or multiple compositions, and the mode of treatment may be administered simultaneously, sequentially or by some other regimen. For example, the present invention relates to a treatment regimen in which chemotherapy is performed after radiation therapy. The combination therapy may have additive or synergistic effects.
In some embodiments of the invention, the use of an IDO inhibitor as described herein in combination with bone marrow transplantation, peripheral blood stem cell transplantation or other types of transplantation therapies is also encompassed.
In some embodiments, IDO inhibitors of the present invention may be combined with immunosuppressive agents to reduce the number of immune effector cells.
In some embodiments, the invention relates to the use of an IDO inhibitor as described herein in combination with an immune checkpoint inhibitor. Blocking immune checkpoints, resulting in the expansion of antigen-specific T cell responses, has proven to be a promising approach in the treatment of human cancer. Blocked are some immune checkpoints (ligands and receptors) that are selectively upregulated in the tumor microenvironment, including PD-1 (programmed cell death protein 1), PD-L1(PD-1 ligand), BTLA (B and T lymphocyte attenuating agents), CTLA4 (cytotoxic T lymphocyte-associated antigen 4), TIM3(T cell membrane protein 3), LAG3 (lymphocyte activation gene 3), A2aR (adenosine A2a receptor A2aR), and killer inhibitory receptors. In some embodiments, the immune checkpoint inhibitor is a PD-1 antibody, including but not limited to OPDIVO (nivolumab), KEYTRUDA (pertuzumab); WO 2012/145493). In some embodiments, the immune checkpoint inhibitor is a PD-L1 antibody, including but not limited to Tecentriq, Imfinzi, or Bavencio.
In some embodiments, the present invention provides methods of treating cancer in a subject comprising administering to the subject a therapeutically effective amount of at least one IDO inhibitor and at least one chemotherapeutic agent.
Chemotherapeutic agents of the invention include, but are not limited to, alkylating agents (e.g., nitrogen mustards (e.g., chlorambucil, cyclophosphamide, ifosfamide, dichloromethyldiethylamine, melphalan, and uracil mustard), aziridines (e.g., thiotepa), resveratrol esters (e.g., busulfan), nucleoside analogs (e.g., gemcitabine), nitrosoureas (e.g., carmustine, lomustine, and streptozotocin), topoisomerase 1 inhibitors (e.g., irinotecan), platinum complexes (e.g., cisplatin and carboplatin), bioreductive alkylating agents (e.g., mitomycin, procarbazine, dacarbazine, and altretamine)); DNA strand breaking agents (e.g., bleomycin); topoisomerase II inhibitors (e.g., amsacrine, dactinomycin, daunorubicin, idarubicin, mitoxantrone, doxorubicin, etoposide, and teniposide); DNA minor groove binders (e.g., plicamycin); antimetabolites (e.g., folic acid antagonists (e.g., methotrexate and trimetrexate), pyrimidine antagonists (e.g., fluorouracil, fluorodeoxyuridine, CB3717, azacitidine, cytarabine, floxuridine), purine antagonists (e.g., mercaptopurine, 6-thioguanine, fludarabine, pentostatin), asparaginase, and ribonucleotide reductase inhibitors (e.g., hydroxyurea)); tubulin interacting agents (e.g., vincristine, estramustine, vinblastine, docetaxel, epothilone derivatives and paclitaxel); hormonal agents (e.g., estrogens, conjugated estrogens, ethinyl estradiol, diethylstilbestrol, chlorethene (chlorendinisen), idenestrol, progestins (e.g., hydroxyprogesterone caproate, medroxyprogesterone, and megestrol) and androgens (e.g., testosterone propionate, fluoxymesterone, and methyltestosterone)); adrenocortical steroids (e.g., prednisone, dexamethasone, methylprednisolone, and prednisolone); luteinizing hormone releasing agents or gonadotropin releasing hormone antagonists (e.g., leuprolide acetate and goserelin acetate); and anti-hormonal antigens (e.g., tamoxifen, anti-androgens (such as flutamide), and anti-adrenal agents (such as mitotane and aminoglutethimide)). The invention also relates to the use of IDO inhibitors in combination with other agents known in the art (e.g., arsenic trioxide) and other chemotherapeutic agents developed in the future.
Some embodiments of the present invention relate to methods for treating cancer, administering a therapeutically effective amount of a combination of an IDO inhibitor of the present invention and at least one chemotherapeutic agent results in higher survival rates for the cancer than observed by either administration alone. A further embodiment of the invention relates to a method for treating cancer, administering a therapeutically effective amount of a combination of an IDO inhibitor of the present invention and at least one chemotherapeutic agent more reduces tumor size and/or slows tumor growth more than observed by either administration alone.
In a further embodiment, the present invention relates to a method of treating or preventing cancer in a subject comprising administering to the subject a therapeutically effective amount of at least one IDO inhibitor of the present invention and at least one Signal Transduction Inhibitor (STI).
Signal Transduction Inhibitors (STI) of the present invention include, but are not limited to, bcr/abl kinase inhibitors, Epidermal Growth Factor (EGF) receptor inhibitors, her-2/neu receptor inhibitors and Farnesyl Transferase Inhibitors (FTIs).
The present invention also relates to a method of increasing tumor cell rejection in a subject comprising administering an IDO inhibitor of the present invention in combination with at least one chemotherapeutic agent and/or radiation therapy, wherein the resulting tumor cell rejection is greater than the tumor cell rejection obtained by administration of either an IDO inhibitor, chemotherapeutic agent or radiation therapy alone.
In a further embodiment, the present invention provides a method of treating cancer in a subject comprising administering to the subject a therapeutically effective amount of at least one IDO inhibitor of the present invention and at least one immunomodulatory agent other than an IDO inhibitor.
Immunomodulators of the present invention include, but are not limited to, CD40L, B7, B7RP1, anti-CD 40, anti-CD 38, anti-ICOS, 4-IBB ligand, dendritic cell carcinoma vaccine, IL2, IL12, ELC/CCL19, SLC/CCL21, MCP-1, IL-4, IL-18, TNF, IL-15, MDC, IFN- α/- β, M-CSF, IL-3, GM-CSF, IL-13, and anti-IL-10.
The present invention relates to methods of treating or preventing an infectious disease (e.g., a viral infection) in a subject (e.g., a human), comprising administering to the subject a therapeutically effective amount of at least one IDO inhibitor of the present invention and a therapeutically effective amount of an anti-infective agent.
The anti-infective agents of the present invention include, but are not limited to, antiviral agents, antiparasitic agents, and antibacterial agents. Antiviral agents of the present invention include those that target various viral life-cycle stages and have different mechanisms of action, including but not limited to: inhibitors of viral uncoating (e.g., amantadine and rimantadine); reverse transcriptase inhibitors (e.g., acyclovir (acyclovir), zidovudine, and lamivudine (lamivudine)); agents targeting integrase; an agent that blocks the linkage of a transcription factor to viral DNA; agents that affect translation (e.g., antisense molecules) (e.g., fomivirsen); agents that modulate translation/ribonuclease function; a protease inhibitor; viral assembly modulators (e.g., rifampin); antiretrovirals such as nucleoside analog reverse transcriptase inhibitors (e.g., Azidothymidine (AZT), ddl, ddC, 3TC, d 4T); non-nucleoside reverse transcriptase inhibitors (e.g., efavirenz (efavirenz), nevirapine (nevirapine)); nucleotide analog reverse transcriptase inhibitors; and agents that prevent release of viral particles (e.g., zanamivir (zanamivir) and oseltamivir (oseltamivir)). The treatment and/or prevention of certain viral infections (e.g., HIV) often requires a panel of antiviral agents ("cocktail"). Antiparasitic agents of the present invention include, but are not limited to, thiabendazole, pyrantel pamoate, mebendazole, praziquantel, niclosamide, dithiol, hydroxylamine nitroquine, metraflox, ivermectin, albendazole, eflornithine, melarsanol, pentamidine, metronidazole, nifurolimus, and nitroimidazole, as well as other agents useful in the art for treating parasitic conditions. Antibacterial agents of the present invention include, but are not limited to, antibacterial agents that target bacterial cell walls (e.g., cephalosporins and penicillins) or cell membranes (e.g., polymyxins) or interfere with essential bacterial enzymes (e.g., sulfonamides, rifamycins, and quinolines), antibacterial agents that target protein synthesis (e.g., tetracyclines and macrolides), antibacterial agents (e.g., aminoglycosides), and antibacterial agents that one of skill in the art can select for use in a particular bacterial infection.
In some embodiments of the invention, the additional therapeutic agent is a cytokine, including, for example, granulocyte-macrophage colony-stimulating factor (GM-CSF) or flt 3-ligand. The invention also relates to the use of an IDO inhibitor of the present invention for the treatment or prevention of a viral infection (e.g., a chronic viral infection), alone or as a component of a combination therapy. Such viruses include, but are not limited to, Hepatitis C Virus (HCV), Human Papilloma Virus (HPV), Cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella zoster virus, coxsackie virus and Human Immunodeficiency Virus (HIV).
The present invention relates to methods of treating or preventing immune and inflammation-related diseases, disorders, and conditions in a subject (e.g., a human) comprising administering to the subject a therapeutically effective amount of at least one IDO inhibitor of the present invention and a therapeutically effective amount of an inflammation modulator.
The inflammation modulators of the present invention include, but are not limited to, nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen and other propionic acid derivatives (alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid, and thioprofen), acetic acid derivatives (indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozicacid, fentiazac, fenticlate, flurofenac (furofenac), ibufenac, isofenac, oxpinac, sulindac, thiopinac, tolmetin, zidometacin, and zomepirac), fenamic acid derivatives (flufenamic acid, meclofenamic acid, mefenamic acid, flunixic acid, and tolfenamic acid), biphenylcarboxylic acid derivatives (diflunisal and flufenisal), oxicams (oxicams) (isoxicam, piroxicam, sudoxicam and tenoxicam), salicylates (acetylsalicylic acid, sulfasalazine) and dihydropyrazolones (apazone, benperone, feprazone, mofebuzone, oxybuprazone, phenylbutazone) and cyclooxygenase-2 (COX-2) inhibitors.
In additional embodiments, treatment of an infectious disease is achieved by co-administering a vaccine with a therapeutically effective amount of an IDO inhibitor of the present invention. In some embodiments, the vaccine is an antiviral vaccine, including, for example, an anti-HIV vaccine. In some embodiments, the vaccine is effective against tuberculosis or malaria. In some embodiments, the vaccine is a tumor vaccine (e.g., a vaccine effective against melanoma). The tumor vaccine may comprise genetically modified tumor cells or genetically modified cell lines, including genetically modified tumor cells or genetically modified cell lines that have been transfected to express granulocyte-macrophage colony stimulating factor (GM-CSF). In particular embodiments, the vaccine comprises one or more immunogenic peptides and/or dendritic cells.
In some embodiments, the present invention relates to methods of combining an IDO inhibitor of the present invention with one or more antimicrobial agents.
In certain embodiments, the infection is treated by administering an IDO inhibitor of the present invention in combination with at least one additional therapeutic agent, and the symptoms of the infection observed after administration of the IDO inhibitor and the additional therapeutic agent are improved as compared to the same symptoms of the infection observed after administration of one of the IDO inhibitors and the additional therapeutic agent alone. In some embodiments, the observed symptom of infection may be a reduction in viral load, CD4+An increase in the number of T cells, a decrease in opportunistic infections, an increase in survival time, eradication of chronic infections or a combination thereof.
The present invention also provides pharmaceutically acceptable compositions comprising a therapeutically effective amount of one or more compounds of formula (I) or formula (II) or stereoisomers, tautomers or pharmaceutically acceptable salts thereof, formulated with one or more pharmaceutically acceptable carriers, diluents and/or excipients, and optionally one or more of the other therapeutic agents described above. Pharmaceutical compositions can be used in the methods of the invention, e.g., pharmaceutical compositions can be administered to a subject ex vivo or in vivo in order to practice the therapeutic and prophylactic methods and uses described herein. The pharmaceutical compositions of the present invention may be formulated to be compatible with the intended method or route of administration. Furthermore, the pharmaceutical compositions of the invention may be used in combination with other therapeutic agents or compounds as described herein for the treatment or prevention of diseases, disorders, and conditions as encompassed by the invention.
The compounds of the invention can be administered by any suitable method for any of the uses described herein, such as orally, e.g., tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions; sublingual administration; taking orally; parenterally, e.g., by subcutaneous, intravenous, intramuscular, or intrasternal injection, or infusion techniques (e.g., as sterile injectable aqueous or nonaqueous solutions or suspensions); nasally, including administration to the nasal mucosa, e.g., by inhalation spray; topically, e.g., in the form of a cream or ointment; or rectally, e.g., in the form of suppositories. They may be administered alone, but will generally be administered with a pharmaceutical carrier selected according to the chosen route of administration and standard pharmaceutical practice.
The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable carrier" refers to vehicles generally accepted in the art for delivering biologically active agents to animals, particularly mammals, and includes, depending on the mode of administration and nature of the dosage form, for example, adjuvants, excipients, or vehicles such as diluents, preservatives, fillers, flow control agents, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antimicrobials, antifungals, lubricants, and dispersants. Pharmaceutically acceptable carriers are formulated by one of ordinary skill in the art based on a number of factors within the purview of one skilled in the art. Which include but are not limited to: the type and nature of the active agent formulated, the subject to which the composition containing the agent is to be administered, the intended route of administration of the composition, and the targeted therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous media as well as a variety of solid and semi-solid dosage forms. Such carriers include many different ingredients and additives in addition to the active agent, and such additional ingredients included in the formulation for a variety of reasons (e.g., to stabilize the active agent, binders, etc.) are well known to those of ordinary skill in the art.
The dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration, the species, age, sex, health, medical condition and weight of the recipient, the nature and extent of the symptoms, the type of concurrent therapy, the frequency of therapy, the route of administration, the function of the patient's kidney and liver, and the desired effect.
As a general guideline, when used for the indicated effect, the daily oral dosage of each active ingredient is in the range of between about 0.001 to about 5000mg per day, preferably between about 0.01 to about 1000mg per day, most preferably between about 0.1 to about 250mg per day, with the most preferred dosage being in the range of about 0.01 to about 10 mg/kg/minute intravenously during constant rate infusion. The compounds of the invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses of 2,3 or 4 times daily.
Definition of
The term "IDO inhibitor" includes agents that are capable of inhibiting the activity of indoleamine 2, 3-dioxygenase (IDO) and thereby reversing IDO-mediated immunosuppression. IDO inhibitors may inhibit IDO1 and/or IDO2(INDOL 1). The IDO inhibitor may be a reversible or irreversible IDO inhibitor. A "reversible IDO inhibitor" is a compound that reversibly inhibits IDO enzyme activity at a catalytic site or a non-catalytic site, and an "irreversible IDO inhibitor" includes compounds that irreversibly destroy IDO enzyme activity by forming a covalent bond with an enzyme. The term "IDO inhibitor" also includes compounds capable of inhibiting tryptophan-2, 3-dioxygenase (TDO) activity. The term "IDO inhibitor" of the present invention is to be understood to include compounds that act by inhibiting IDO or TDO alone, and/or by inhibiting both IDO and TDO.
The term "alkyl" or "alkylene" refers to branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. "C1-6The "alkyl group" of (a) represents an alkyl group having 1 to 6 carbon atoms. "C1-4The "alkyl group" of (a) represents an alkyl group having 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to: methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl) and hexyl (e.g., n-hexyl, 2-methylpentyl). Examples of alkylene groups include, but are not limited to, methylene (-CH)2-) ethylene (-CH2CH2-)。
The term "aryl" refers to an unsaturated, usually aromatic, hydrocarbon group which may be a single ring or multiple rings fused together. C6-10Examples of aryl groups of (a) include, but are not limited to, phenyl, naphthyl.
The term "heteroaryl" refers to a stable monocyclic or polycyclic aromatic hydrocarbon containing at least 1 heteroatom ring member (e.g., sulfur, oxygen, or nitrogen). C6-10Examples of heteroaryl groups of (a) include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, indolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzimidazolyl.
The term "halogen" includes fluorine, chlorine, bromine and iodine.
The term "alkoxy" refers to-O-alkyl. The term "alkoxycarbonyl" refers to a carbonyl group substituted with an alkoxy group, i.e., -C (O) -O-alkyl. "C1-6Examples of "alkoxycarbonyl" include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl.
The term "arylcarbonyl" refers to a carbonyl substituted with an aryl, i.e., -C (O) -aryl. "C6-10Examples of arylcarbonyl "include, but are not limited to, benzoyl.
The term "tautomer" refers to two isomers which are rapidly converted to each other by a change in functional groups to form a mixture in dynamic equilibrium, and these two isomers are referred to as tautomers.
The term "stereoisomers" refers to isomers of the same molecular formula and structure, but which occur as a result of different positions of atoms or groups in the molecule in space. Stereoisomers include configurational isomers and conformational isomers, which in turn include cis-trans isomers and enantiomers, diastereomers. The term "enantiomer" also known as "chiral isomer" or "mirror image isomer", refers to mirror images of each other, but do not coincide. The term "racemate" refers to a mixture of equal amounts of enantiomers.
The term "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. The salt has safety and effectiveness when used in a mammal body, and has due biological activity. Examples of pharmaceutically acceptable salts include, but are not limited to: inorganic or organic acid salts of basic groups (e.g., amines), and basic or organic salts of acidic groups (e.g., carboxylic acids). Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids (e.g., hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids), and salts prepared from organic acids (e.g., acetic, propionic, palmitic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfamic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic and isethionic acids, and the like).
The term "prodrug" refers to a compound that is convertible in vivo by metabolic means (e.g., by hydrolysis) to the disclosed compound or active ingredient. Prodrugs can be prepared by techniques known to those skilled in the art.
The term "solvate" refers to a complex of variable stoichiometry formed by a solute and a solvent. Such solvents for the purposes of the present invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water. Water is a solvate of a solvent molecule commonly referred to as a "hydrate". Hydrates include compositions containing a stoichiometric amount of water, as well as compositions containing variable amounts of water.
The term "isotopically labeled derivative" refers to a compound described herein, wherein one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (i.e., naturally occurring).
The term "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs or does not occur. For example, "aryl optionally substituted with halogen" means that halogen may or may not be present, including the case where aryl is substituted with halogen and the case where aryl is not substituted with halogen.
The term "patient" refers to an organism treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murines, monkeys, horses, cows, pigs, dogs, cats, etc.), and most preferably humans.
The term "effective amount" refers to the amount of a drug or agent (i.e., a compound of the invention) that elicits the biological or medical response in a tissue, system, animal or human that is being sought, for example, by a researcher or clinician.
The term "therapeutically effective amount" refers to an amount that results in an improved treatment, cure, prevention, or amelioration of a disease, disorder, or side effect, or a reduction in the rate of progression of a disease or disorder, as compared to a corresponding subject that does not receive such an amount. An effective amount may be administered in 1 or more administrations, applications or doses, and is not intended to be limited to a specific prescription or route of administration. The term also includes within its scope an amount effective to enhance normal physiological function.
Detailed Description
The compounds of the present invention may be prepared by a variety of synthetic methods known to those skilled in the art, including embodiments formed by combinations of the methods illustrated in the following schemes, and other chemical synthetic methods, from starting materials known in the chemical literature or commercially available, and equivalents thereof known to those skilled in the art. Preferred embodiments include, but are not limited to, examples of the present invention. Solvents, temperatures, pressures, and other reaction conditions can be readily selected by one of ordinary skill in the art. The reaction is carried out in a solvent or solvent mixture suitable for the reagents and materials used and for the conversion to take place. It will be appreciated by those skilled in the art of organic synthesis that the functional groups present on the molecule should conform to the proposed transformations. This often requires judgment to modify the order of the synthetic steps or to otherwise select a particular process scheme to obtain the desired compounds of the invention. The following schemes and examples are illustrative and are provided for the purpose of example only, and the invention should not be construed as being limited to these examples, nor is it meant to be limiting as to the possible techniques available to one skilled in the art for preparing the compounds disclosed herein, with the understanding that the invention includes any and all variations that are obvious with respect to the embodiments disclosed herein. In addition, the various steps in the synthesis may be performed in alternating order or in an order that results in the desired compound. Furthermore, the representation of reactions as discrete steps in the following schemes does not preclude their performance in series, or by nesting multiple steps in the same reaction vessel or by performing multiple steps without purifying or characterizing intermediates. In addition, many of the compounds prepared by the following methods may be further modified using conventional chemistry known to those skilled in the art. All documents cited in this application are fully incorporated herein by reference.
Preparation examples
As shown in scheme 1, the synthesis of the compounds of the present invention can be carried out starting from compound A-1 by a known free radical reaction ((a) Eur.J.Med.chem.2015,93, 511-522 (b) RSC adv.2015,5, 28892-28895), i.e.the carboxylic acid is in a silver salt (e.g.AgNO-3),K2S2O7And salts of divalent copper (e.g. CuSO)4Or copper acetate) to form the coupling product a-2 by coupling with an aromatic compound (e.g., quinoline optionally substituted with a halogen). A-2 can pass throughHydrolysis to carboxylic acid A-3 followed by amidation to form Weinreb amide A-4(WO 2016054971A 1); a-4 reacts with an alkyl nucleophile (e.g., methyl Grignard) to produce methyl ketone A-5, which is then converted to an alkylether A-6 by a Wittig reagent; it is a precursor of aldehyde, which can be converted first to aldehyde A-7 and then oxidized to carboxylic acid A-8; a-8 as a common intermediate can be reacted with various amines to form amides, such as amide A-9 of the present invention is the product of carboxylic acid A-8 and an aromatic amine compound (c) in the presence of a coupling reagent such as HATU (2- (7-oxabenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate)/DIEA (N, N-diisopropylethylamine). Chiral isomers can be obtained by chiral chromatographic resolution, and the compounds of examples 1 and 2 can be synthesized by the method.
In scheme 1, R1And R2Each independently selected from C1-4Alkyl or C6-10Aryl of (a); a, D, G and J are each independently selected from C, O, N or S; b, E, F and I are each independently selected from a covalent bond, C, O, N, or S; k and Q are each independently selected from hydrogen or halogen (e.g., F, Cl or Br); ar is optionally substituted C6-10Aryl (e.g. optionally substituted by halogen, preferably 4-chlorophenyl).
Synthesis scheme 1
Example 1
N- (4-chlorophenyl) -2- [3- (6-fluoroquinolin-4-yl) bicyclo [1.1.1] pentan-1-yl ] propanamide 1 (enantiomer, peak1)
Example 2
N- (4-chlorophenyl) -2- [3- (6-fluoroquinolin-4-yl) bicyclo [1.1.1] pentan-1-yl ] propanamide 2 (enantiomer, peak2)
Synthetic route
The first step is as follows:
reacting 3- (methoxycarbonyl) bicyclo [1.1.1]Pentane-1-carboxylic acid (CAS #83249-10-9,4.5g,26.6mmol,1.0equiv), 6-fluoroquinoline (1.9g,13.3mmol,0.5equiv), silver nitrate (903mg,5.3mmol,0.2equiv), copper acetate (241mg,1.3mmol,0.05equiv), potassium persulfate (7.2g,27mmol,1.0equiv) were added to a 250mL reaction flask in that order, followed by acetonitrile (70mL) and water (30mL), stirred well at room temperature, heated to 60 ℃ and stirred for 2.5 h. After the reaction was completed, the reaction mixture was cooled to room temperature, and after removing acetonitrile by rotary evaporation, a small amount of water was added for dilution, ethyl acetate was extracted three times, the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate for 15min, anhydrous sodium sulfate was removed by filtration, and the crude product after the filtrate was dried was purified by reverse phase chromatography (column type: Xbridge C18,19X150 mm; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 58 mL/min; gradient (B%): 5 → 52%, 5 min; 52%, 8 min; 52 → 63%, 10 min; 63%, 3.5 min; 63 → 67%, 3 min; 95%, 5 min; detection wavelength: 254/220nm) to obtain 370mg of Compound 1-1 as a brown solid (5%). MS (ESI, M/z) 272[ M + 1]]+;1H NMR(300MHz,CDCl3)8.83(d,J=4.5Hz,1H),8.19(dd,J=9.3,5.7Hz,1H),7.83(dd,J=10.1,2.8Hz,1H),7.52(ddd,J=9.2,8.0,2.8Hz,1H),7.22(d,J=4.4Hz,1H),3.79(s,3H),2.67(s,6H);19F-NMR(282MHz,CDCl3)-111.45。
The second step is that:
in a 25mL reaction flask, compound 1-1, tetrahydrofuran (2.4mL), methanol (0.8mL), water (0.8mL) and lithium hydroxide (131mg,5.4mmol,4equiv) were added in this order, followed by stirring at room temperature for 2 h. After completion of the reaction, hydrochloric acid (2mol/L, 2.7mL) was slowly dropped into the reaction flask at 0 ℃ to adjust the pH to 5, and finally extracted three times with dichloromethane. And combining organic phases, drying the organic phases for 15min by using anhydrous sodium sulfate, filtering to remove the anhydrous sodium sulfate, and spin-drying the filtrate to obtain a yellow foamy crude product 1-2. MS (ESI, m/z):258[M+1]+。
The third step:
in a 25mL reaction flask, compounds 1-2(350mg,1.4mmol,1equiv), N-dimethylformamide (3mL) and HATU (i.e., 2- (7-oxabenzotriazol) -N, N' -tetramethyluronium hexafluorophosphate, 1.2g,3.1mmol,2.3equiv) were added in sequence, stirred at room temperature for 15min, then N, N-diisopropylethylamine (967mg,7.5mmol,5.5equiv) and O, N-dimethylhydroxylamine hydrochloride (279mg,2.9mmol,2.1equiv) were added, and then stirred at room temperature overnight. After completion of the reaction, the crude product was purified by reverse phase chromatography (mobile phase A: water; mobile phase B: acetonitrile; gradient: 5 → 10%, 10 min; 20 → 60%, 20 min; 60 → 80%, 40 min; detection wavelength: 254nm) to give 390mg of compound 1-3 as a pale yellow solid. MS (ESI, M/z):301[ M +1 [)]+;1H NMR(400MHz,CDCl3)8.84(d,J=4.5Hz,1H),8.26(dd,J=9.3,5.6Hz,1H),7.88(dd,J=10.0,2.8Hz,1H),7.55(ddd,J=10.6,8.1,2.8Hz,1H),7.31(d,J=5.5Hz,1H)3.79(s,3H),3.29(s,3H),2.73(s,6H);19F-NMR(282MHz,CDCl3)-110.80。
The fourth step:
under nitrogen protection, a solution of compounds 1-3(360mg,1.2mmol,1.0equiv) in tetrahydrofuran (5mL) was added via syringe to a 25mL Schlenk tube, then cooled to 0 deg.C, and methyl magnesium bromide Grignard reagent (3.2M,0.8mL) was added dropwise to the reaction system. After stirring at room temperature for 2 hours, after the reaction was completed, 30mL of a saturated ammonium chloride solution was slowly added to the reaction solution to quench the reaction, the reaction solution was stirred and then extracted with ethyl acetate three times, the organic phases were combined, the organic phase was dried with anhydrous sodium sulfate for 15min, anhydrous sodium sulfate was removed by filtration, and the crude product after spin-drying of the filtrate was purified by column chromatography (ethyl acetate/petroleum ether, gradient: 0 → 50%) to obtain 220mg of compounds 1 to 4 as pale yellow solidsBody (75%). MS (ESI, M/z) 256[ M + 1]]+;1H NMR(400MHz,CH3OH-d4)8.78(d,J=4.5Hz,1H),8.13(dd,J=9.2,5.6Hz,1H),8.00(dd,J=10.1,2.8Hz,1H),7.64(td,J=8.8,2.8Hz,1H),7.40(d,J=4.4Hz,1H),2.66(s,6H),2.28(s,3H);19F-NMR(282MHz,CH3OH-d4)-113.26。
The fifth step:
(methoxymethyl) triphenylphosphonium bromide (4.9mmol,6equiv) was suspended in dry tetrahydrofuran (10mL) under nitrogen, and then the reaction flask was placed in an ice bath; potassium tert-butoxide (554mg,4.9mmol,6equiv) was added slowly. After the system was stirred for 30min under ice bath, compound 1-4(210mg,0.8mmol,1equiv) was added thereto. The reaction was stirred at room temperature for 3 h. After completion of the reaction, 50mL of a saturated aqueous ammonium chloride solution was added to the reaction system, stirred and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate for 15min, filtered to remove anhydrous sodium sulfate, and the crude product after spin-drying the filtrate was purified by column chromatography (ethyl acetate/petroleum ether, gradient: 0 → 25%) to give 200mg of compound 1-5 as a pale yellow solid (67%). MS (ESI, M/z):284[ M + 1]]+;1H NMR(400MHz,CDCl3)8.92-8.73(m,1H),8.33-8.17(m,1H),8.05-7.87(m,1H),7.61-7.44(m,1H),7.25(t,J=4.5Hz,1H),5.89(dq,J=4.4,1.5Hz,1H),3.59-3.65(m,3H),2.35-2.51(m,6H),1.58-1.67(m,3H);19F-NMR(282MHz,CDCl3)-111.85。
And a sixth step:
compound 1-5(190mg,0.7mmol,1equiv) was dissolved in 3mL of tetrahydrofuran, to which was added dilute hydrochloric acid (2mol/L, 2.4mL), followed by stirring at room temperature for 2 h. After completion of the reaction, a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction solution to adjust the pH to 7, followed by extraction with ethyl acetate three times. Combining the organic phase and the organic phaseDried over anhydrous sodium sulfate for 15min, filtered to remove anhydrous sodium sulfate, and the crude product after spin-drying the filtrate was purified by column chromatography (ethyl acetate/petroleum ether, gradient: 0 → 40%) to give 170mg of compounds 1-6 as pale yellow solids (94%). MS (ESI, M/z):270[ M + 1]]+;1H NMR(400MHz,CDCl3)9.81(d,J=1.8Hz,1H),8.82(d,J=4.5Hz,1H),8.27(d,J=8.3Hz,1H),7.87(dd,J=10.1,2.8Hz,1H),7.59–7.51(m,1H),7.25(d,J=4.5Hz,1H),2.78–2.68(m,1H),2.37-2.43(m,6H),1.23(d,J=7.1Hz,3H)。
The seventh step:
compounds 1 to 6(100mg,0.4mmol,1equiv) were dissolved in 2.2mL of tetrahydrofuran, to which was added in this order 2-methyl-2-butene (276mg,3.9mmol,11equiv), sodium dihydrogen phosphate (89mg,0.7mmol,2equiv), sodium chlorite (101mg,1.1mmol,3equiv), and finally water (1.2mL), and stirred at room temperature for 2 h. After the reaction was complete, the pH was adjusted to 4 with dilute hydrochloric acid, followed by extraction three times with ethyl acetate, the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate for 15min, the anhydrous sodium sulfate was removed by filtration, and the filtrate was spin-dried to give 160mg of compound 1-7 as a yellow crude product. MS (ESI, M/z):284[ M-1 ]]-。
Eighth step:
compounds 1-7(140mg,0.5mmol,1equiv), N-dimethylformamide (2mL) and HATU (i.e., 2- (7-benzotriazole oxide) -N, N' -tetramethylurea hexafluorophosphate, 280mg,0.7mmol,1.5equiv) were added sequentially in an 8mL reaction flask, and after stirring at room temperature for 15min, 4-chloroaniline (81mg,0.6mmol,1.3equiv) and N, N-diisopropylethylamine (190mg,1.5mmol,3.0equiv) were added sequentially thereto. Stirring overnight at room temperature, after completion of the reaction, purifying the reaction system by reverse phase chromatography (mobile phase A: water; mobile phase B: acetonitrile, gradient: 30 → 60%, 30 min; detection wavelength: UV 254nm) to obtain 100mg of compound 1-8, XYellow dope (racemate, 52%). MS (ESI, M/z):395[ M + 1]]+。
The ninth step:
n- (4-chlorophenyl) -2- [3- (6-fluoroquinolin-4-yl) bicyclo [1.1.1] pentan-1-yl ] propanamide 1 (enantiomer, peak1) and
n- (4-chlorophenyl) -2- [3- (6-fluoroquinolin-4-yl) bicyclo [1.1.1] pentan-1-yl ] propanamide 2 (enantiomer, peak2)
The racemate 1 to 8(100mg) was passed through a preparative chiral separation column (column: CHIRALPAK IG, 2X 25cm,5 μm; mobile phase A: n-hexane (10mM NH)3) The mobile phase B is isopropanol; the flow rate is 20 mL/min; gradient 20% B → 20% B,20 min; detection wavelength: 254 nm; the sample injection amount is 0.9 mL; the number of needles is 5 times) to split the front and the back peaks. The pre-peak gives compound 1 (enantiomer, peak 1); retention time: 6.8 min; 27mg of a white solid (27%). MS (ESI, M/z):395[ M + 1]]+;1H NMR(400MHz,DMSO-d6)10.04(s,1H),8.80(d,J=4.4Hz,1H),8.11(dd,J=9.2,5.8Hz,1H),7.92(dd,J=10.4,2.9Hz,1H),7.74–7.59(m,3H),7.40–7.33(m,2H),7.31(d,J=4.4Hz,1H),2.80(q,J=6.9Hz,1H),2.21-2.27(m,6H),1.16(d,J=6.8Hz,3H);19F-NMR (282MHz, DMSO-d6) -112.023. The latter peak gave compound 2 (enantiomer, peak 2); retention time: 10.3 min; 18mg (18%); a white solid. MS (ESI, M/z):395[ M + 1]]+;1H NMR(400MHz,DMSO-d6)10.04(s,1H),8.80(d,J=4.4Hz,1H),8.11(dd,J=9.2,5.8Hz,1H),7.92(dd,J=10.5,2.9Hz,1H),7.74–7.62(m,3H),7.37(d,J=8.8Hz,2H),7.32(d,J=4.4Hz,1H),2.79(q,J=6.7Hz,1H),2.21-2.27(m,6H),1.16(d,J=6.8Hz,3H);19F-NMR(282MHz,DMSO-d6)-112.025。
Other compounds of the invention can also be prepared synthetically by the methods described, as shown in scheme 2. Starting from the known compound A-1, the intermediate B-6 can be obtained by the method described below. Hydrolysis of B-6 gives the intermediate carboxylic acid B-7, which is a common intermediate that can be used to synthesize a wide variety of derivatives such as the amide B-8, and compounds such as B-9 and B-10, through a variety of reactions. The compounds of examples 3-5 can be synthesized by the methods shown in scheme 2. The compounds of examples 6-8 and 16-21 were synthesized using intermediate B-7 as a starting material.
In scheme 2, R1And R2Each independently selected from C1-4Alkyl or C6-10Aryl of (a); r3And R4Each independently selected from C optionally substituted with halogen6-10Aryl of (a); r5And R6Each independently selected from hydrogen or halogen; r7And R8Each independently selected from hydrogen, C1-6Alkoxycarbonyl of, C6-10An arylcarbonyl group; a is C6-10Aryl of (a); y is-NHC (O) -.
Synthesis scheme 2
Example 3
(±)3- [1- [ (4-chlorophenyl) carbamoyl ] ethyl ] -N-phenylbicyclo [1.1.1] pentane-1-carboxamide 3 (racemate)
Example 4
3- [1- [ (4-chlorophenyl) carbamoyl ] ethyl ] -N-phenylbicyclo [1.1.1] pentane-1-carboxamide 4 (enantiomer, peak1)
Example 5
3- [1- [ (4-chlorophenyl) carbamoyl ] ethyl ] -N-phenylbicyclo [1.1.1] pentane-1-carboxamide 5 (enantiomer, peak2)
Synthetic route
The first step is as follows:
oxalyl chloride (4.5g,35mmol,1.5equiv) and 0.03mL of N, N-dimethylformamide were added sequentially to a solution of 3- (methoxycarbonyl) bicyclo [1.1.1] pentane-1-carboxylic acid (CAS No.: 83249-10-9, 4g,24mmol,1equiv) in dichloromethane (15mL) with stirring at 0 ℃. The reaction was stirred at room temperature for 1 h. After completion of the reaction, spin-drying was conducted directly to obtain 4.4g of crude compound 3-1 (99%) as a yellow foamy solid.
The second step is that:
cuprous iodide (5.3g,28mmol,1.2equiv) was added to a 250mL three-necked flask, nitrogen was replaced three times, and 50mL of tetrahydrofuran was added. Methyllithium (1.6M,29mL, 47mmol,2equiv) was added dropwise at 0 ℃ under nitrogen protection and reacted at 0 ℃ for 30min, then cooled to-78 ℃. Under the same temperature and nitrogen protection, a solution of compound 3-1(4.4g,23mmol,1equiv) in tetrahydrofuran (30mL) was added dropwise. And reacting for 1h at-78 ℃ under the protection of nitrogen. After the reaction was complete, it was quenched with 200mL of saturated ammonium chloride at 0 ℃ and then extracted three times with 200mL of ethyl acetate. The combined organic phases were washed once with 300mL of saturated brine, the organic phase was dried over anhydrous sodium sulfate for 15min, the anhydrous sodium sulfate was removed by filtration, the crude product was purified by column chromatography after the filtrate was dried by spinning (ethyl acetate/petroleum ether, 10 → 35%) to give 1.95g of compound 3-2 (50%) as a white solid.1H NMR(300MHz,DMSO-d6)3.62(s,3H),2.21(s,6H),2.10(s,3H)。
The third step:
(methoxymethyl) triphenylphosphonium chloride (5.4mmol,1.5equiv) was added to a 50mL Schlenk's tube, nitrogen was replaced three times, and 10mL tetrahydrofuran was added under nitrogen. 0 deg.CThen, potassium tert-butoxide (600mg,5.4mmol,1.5equiv) was added in portions, and after reaction at room temperature for 30min, the temperature was reduced to 0 ℃ and compound 3-2(600mg,3.6mmol,1equiv) was added to the above system. The reaction was carried out at room temperature for 1.5 h. After completion of the reaction, the reaction mixture was quenched with 100mL of saturated ammonium chloride solution, extracted three times with 100mL of ethyl acetate, the combined organic phases were washed once with 150mL of saturated brine, the organic phase was dried over anhydrous sodium sulfate for 15min, the anhydrous sodium sulfate was removed by filtration, and the crude product was purified by column chromatography after the filtrate was dried (ethyl acetate/petroleum ether, 0 → 15%) to obtain 460mg of compound 3-3 (66%) as a yellow oily liquid. MS (ESI, M/z) 197[ M + 1]]+;1H NMR(400MHz,CDCl3)5.80-5.76(m,1H),3.70-3.51(m,6H),2.19-2.03(m,6H),1.55-1.47(m, 3H); cis and trans isomeric mixtures.
The fourth step:
compound 3-3(450mg,1equiv) was added to a mixed solvent of 4.5mL of tetrahydrofuran and 4.5mL of hydrochloric acid (2mol/L) at room temperature, and stirred for 2 hours. After completion of the reaction, the reaction mixture was quenched with 50mL of saturated sodium bicarbonate solution, extracted three times with 50mL of ethyl acetate, the combined organic phases were washed once with 50mL of saturated brine, the organic phase was dried over anhydrous sodium sulfate for 15min, the anhydrous sodium sulfate was removed by filtration, and the crude product was purified by column chromatography after the filtrate was dried (ethyl acetate/petroleum ether, 5 → 25%) to obtain 220mg of compound 3-4 (53%) as a yellow oily liquid. MS (ESI, M/z):183[ M + 1]]+;1H NMR(300MHz,CDCl3)9.68(d,J=1.9Hz,1H),3.70(s,3H),2.51–2.59(m,1H),2.02–2.11(m,6H),1.08–1.10(m,3H)。
The fifth step:
the compound 3-4(220mg,1.2mmol,1equiv) was dissolved in 5mL of THF, and 2-methyl-2-butene (847mg,12.1mmol,10equiv), sodium dihydrogen phosphate (290mg,2.4mmol,2equiv), sodium chlorite (2: (R) ((R) ()) and sodium chlorite (0 ℃ C.) were added in this order at 0 ℃328mg,3.6mmol,3equiv) and 5mL of water. Stir at room temperature for 1 h. After the reaction is completed, 1mol/L hydrochloric acid is used for adjusting the pH value to about 6, 80mL ethyl acetate is used for extraction for three times, organic phases after combination are washed once by 80mL saturated salt solution, the organic phases are dried for 15min by anhydrous sodium sulfate, the anhydrous sodium sulfate is removed by filtration, and 230mg of crude products (96%) of the compounds 3-5 are obtained as yellow solids after the filtrate is dried by spinning. MS (ESI, M/z) 197[ M + 1]]+.
And a sixth step:
at room temperature, the compounds 3-5(230mg,1.2mmol,1equiv), HATU (i.e., 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate, 574mg,1.5mmol,1equiv) and N, N-dimethylformamide (2mL) were sequentially added to a 25mL reaction flask, and after stirring at room temperature for reaction for 15min, p-chloroaniline (192mg,1.5mmol,1equiv) and N, N-diisopropylethylamine (390mg,3.0mmol,2.6equiv) were added thereto, and the reaction was carried out at room temperature for 4 hours. After completion of the reaction, the reaction mixture was purified by reverse chromatography [ acetonitrile/water (10mmol/L ammonium bicarbonate, 20 → 80% ]]280mg of compound 3-6 (78%) were obtained as off-white solid. MS (ESI, M/z):308[ M +1 [)]+;1H NMR(400MHz,DMSO-d6)9.95(s,1H),7.66–7.56(m,2H),7.40–7.30(m,2H),3.58(s,3H),2.65(q,J=6.8Hz,1H),1.85-1.92(m,6H),1.03(d,J=6.9Hz,3H)。
The seventh step:
at room temperature, compound 3-6(130mg,0.4mmol,1equiv) was added to a mixed solvent of 1.5mL of methanol, 0.5mL of tetrahydrofuran and 0.5mL of water, and lithium hydroxide (41mg,1.7mmol,4equiv) was further added. Stirred at room temperature for 3 h. After the reaction is completed, the pH value of the reaction solution is adjusted to about 6 by using 1mol/L hydrochloric acid, the water phase is extracted for three times by using ethyl acetate, the organic phase is washed once by using 80mL of saturated salt water after combination, the organic phase is dried for 15min by using anhydrous sodium sulfate, the anhydrous sodium sulfate is removed by filtration, and the filtrate is dried by spinning to obtain 120mg crude product of compounds 3-7 (97%) as off-white solid. MS (ESI, M/z):293[ M + 1]]+。
Eighth step:
(±)3- [1- [ (4-chlorophenyl) carbamoyl ] ethyl ] -N-phenylbicyclo [1.1.1] pentane-1-carboxamide 3 (racemate)
The crude products of compounds 3 to 7(140mg,0.5mmol,1equiv), HATU (i.e., 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate, 236mg,0.6mmol,1.3equiv) and 1.5mL of N, N-dimethylformamide were sequentially added to a 8mL reaction flask, and after stirring at room temperature for 15min, aniline (58mg,0.6mmol,1.3equiv) and N, N-diisopropylethylamine (160mg,1.2mmol,2.6equiv) were sequentially added thereto, and reacted at room temperature overnight. After completion of the reaction, the reaction mixture was purified by reverse chromatography [ acetonitrile/water (10mmol/L ammonium bicarbonate), 35 → 95%]150mg of Compound 3 (85%) was obtained as an off-white solid. MS (ESI, M/z):369[ M + 1]]+;1H NMR(400MHz,DMSO-d6)9.98(s,1H),9.47(s,1H),7.69–7.59(m,4H),7.41–7.33(m,2H),7.28(t,J=7.9Hz,2H),7.07–6.98(m,1H),2.68(q,J=6.8Hz,1H),2.01–1.86(m,6H),1.06(d,J=6.8Hz,3H)。
The ninth step:
3- [1- [ (4-chlorophenyl) carbamoyl ] ethyl ] -N-phenylbicyclo [1.1.1] pentane-1-carboxamide 4 (enantiomer, peak1) and 3- [1- [ (4-chlorophenyl) carbamoyl ] ethyl ] -N-phenylbicyclo [1.1.1] pentane-1-carboxamide 5 (enantiomer, peak2)
Resolution of racemate 3(123mg,0.33mmol) using a chiral separation column (column model: CHIRALPAK ID,2 × 25cm (5 μm)) by chiral high performance liquid chromatography; mobile phase A is n-hexane (10mM ammonia), and mobile phase B is isopropanol; the flow rate is 22 mL/min; gradient 30% → 30% B; 8 min; detection wavelength: 254 nm; the front peak emergence time is 4.0 min; the time of peak emergence is 6.0 min; the total sample injection amount is 9 mL; the number of sampling needles is 18); the pre-peak (retention time 4.0min) was spin-dried to give compound 4 as a white solid (37mg, 30%). The latter peak (retention time 6.0min) was spin-dried to give compound 5 as a white solid (39mg, 32%).
4:MS(ESI,m/z)369[M+1]+;1H NMR(400MHz,DMSO-d6)9.98(s,1H),9.47(s,1H),7.69–7.59(m,4H),7.41–7.33(m,2H),7.28(t,J=7.9Hz,2H),7.07–6.98(m,1H),2.68(q,J=6.8Hz,1H),2.01–1.86(m,6H),1.06(d,J=6.8Hz,3H)。
5:MS(ESI,m/z)369[M+1]+;1H NMR(400MHz,DMSO-d6)9.99(s,1H),9.48(s,1H),7.72–7.58(m,4H),7.40–7.33(m,2H),7.32–7.24(m,2H),7.07–6.99(m,1H),2.68(q,J=6.8Hz,1H),2.03–1.84(m,6H),1.05(d,J=6.8Hz,3H)。
Example 6
(±) N- (3- [1- [ (4-chlorophenyl) carbamoyl ] ethyl ] bicyclo [1.1.1] pentane-1-yl) benzamide 6 (racemate)
Example 7
N- (3- [1(S) - [ (4-chlorophenyl) carbamoyl ] ethyl ] bicyclo [1.1.1] pentan-1-yl) benzamide 7(S isomer, peak1)
Example 8
N- (3- [1(R) - [ (4-chlorophenyl) carbamoyl ] ethyl ] bicyclo [1.1.1] pentan-1-yl) benzamide 8(R isomer, peak2)
Synthetic route
The first step is as follows:
at room temperature, compounds 3 to 7(500mg,1.7mmol,1equiv), diphenylphosphorylazide (562mg,2mmol,1.2equiv), tert-butanol (6mL) and triethylamine (224mg,2.2mmol,1.3equiv) were sequentially added to a 25mL reaction flask. After stirring for 4h at room temperature, the temperature is raised to 90 ℃ to continue the reaction for 4 h. After completion of the reaction, the reaction mixture was cooled to room temperature, 50mL of water was added to the reaction system, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and washed once with saturated brine, the organic phase was dried over anhydrous sodium sulfate for 15min, the anhydrous sodium sulfate was removed by filtration, and the filtrate was purified by column chromatography (ethyl acetate/petroleum ether, 20 → 70%) to give compound 6-1 about 480mg (77%) as a yellow solid. MS (ESI, M/z) 309[ M + 1-56%]+,350[M+1-15]+,365[M+1]+;1H NMR(300MHz,DMSO-d6)9.89(s,1H),7.69–7.53(m,2H),7.39–7.29(m,2H),2.68(q,J=6.8Hz,1H),1.86–1.66(m,6H),1.36(s,9H),1.18(s,1H),1.02(d,J=6.8Hz,3H)。
The second step is that:
at room temperature, a 8mL reaction flask was charged with compound 6-1(200mg,0.5mmol,1equiv) and dioxane solution of hydrochloric acid (4mol/L, 1mL) in that order. Stir at room temperature overnight. After completion of the reaction, 130mg of compound 6-2 (90%) as the hydrochloride salt was obtained as a pale yellow solid after spin-drying. MS (ESI, M/z):265[ M +1 [)]+。
The third step:
(±) N- (3- [1- [ (4-chlorophenyl) carbamoyl ] ethyl ] bicyclo [1.1.1] pentane-1-yl) benzamide 6 (racemate)
Benzoic acid (72mg,0.59mmol,1.2equiv), HATU (i.e., 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate, 243mg,0.64mmol,1.3equiv) and DMF (1.5mL) were added sequentially to an 8mL reaction flask, and after stirring at room temperature for 15 minutes, Compound 6-2(130mg, 0.49) was added sequentially theretommol,1equiv) and N, N-diisopropylethylamine (228mg,1.8mmol,3.6equiv), stirring at room temperature for a further 3 h. After completion of the reaction, the reaction mixture was purified by reverse phase chromatography [ acetonitrile/water (10mmol/L ammonium bicarbonate), 35 → 95%]To give 110mg of Compound 6 (racemate, 61%) as an off-white solid. MS (ESI, M/z):369[ M + 1]]+;1H NMR(300MHz,DMSO-d6)9.94(s,1H),8.92(s,1H),7.87–7.77(m,2H),7.69–7.59(m,2H),7.56–7.40(m,3H),7.39–7.32(m,2H),2.74(q,J=6.8Hz,1H),2.06–1.88(m,6H),1.07(d,J=6.8Hz,3H)。
The fourth step:
n- (3- [1(S) - [ (4-chlorophenyl) carbamoyl ] ethyl ] bicyclo [1.1.1] pentan-1-yl) benzamide 7(S isomer, peak1) and
n- (3- [1(R) - [ (4-chlorophenyl) carbamoyl ] ethyl ] bicyclo [1.1.1] pentan-1-yl) benzamide 8(R isomer, peak2)
Resolution of racemate 6(94mg,0.26mmol,1equiv) using chiral separation column [ column model: CHIRALPAK ID,2 × 25cm (5 μm) ], using chiral high performance liquid chromatography; mobile phase A is n-hexane (10mM ammonia), and mobile phase B is isopropanol; the flow rate is 20 mL/min; gradient B phase 30% → 30% B, 10 min; detection wavelength: 254 nm; the front peak emergence time is 4.4 min; the time of peak emergence is 7.4 min; the total sample injection amount is 28 mL; the number of sampling needles is 23. The pre-peak (retention time 4.4min) was spin-dried to give compound 7 as a white solid (30mg, 32%). The latter peak (retention time 6.0min) was spin-dried to give compound 8 as a white solid (29mg, 32%). Compound 7 was determined to be in the S configuration and compound 8 to be in the R configuration by single crystal X-ray diffraction (instrument model XtaLAB PRO 007HF (Mo), manufacturer Rigaku, test conditions: 180K).
7:MS(ESI,m/z)369[M+1]+;1H NMR(400MHz,DMSO-d6)9.94(s,1H),8.92(s,1H),7.86–7.77(m,2H),7.63(d,J=8.8Hz,2H),7.55–7.29(m,5H),2.74(q,J=6.8Hz,1H),1.90-1.97(m,6H),1.07(d,J=6.8Hz,3H)。
8:MS(ESI,m/z)369[M+1]+;1H NMR(400MHz,DMSO-d6)9.94(s,1H),8.92(s,1H),7.88–7.77(m,2H),7.69–7.59(m,2H),7.54–7.48(m,1H),7.44(dd,J=8.2,6.6Hz,2H),7.39–7.33(m,2H),2.74(q,J=6.7Hz,1H),1.90-1.97(m,6H),1.07(d,J=6.8Hz,3H)。
Example 9
N- (4-chlorophenyl) -4- (6-fluoroquinolin-4-yl) cubane-1-carboxamide 9
Example 10
N- (4-chlorophenyl) -4- (6-fluoroquinolin-2-yl) cubane-1-carboxamide 10
Synthetic route
The first step is as follows:
1, 4-cubane dicarboxylic acid dimethyl ester (CAS number: 29412-62-2,2g,9mmol,1equiv) was placed in a 100mL single neck flask, followed by the addition of 50mL tetrahydrofuran solvent. Sodium hydroxide (364mg,9mmol,1equiv) was dissolved in 4.5mL of methanol to prepare a 2mol/L solution, the solution was slowly dropped into the above 100mL single-neck flask, stirred at room temperature overnight, followed by monitoring by TLC (MeOH/DCM ═ 1/20) to find the reaction was complete, 2mol/L diluted hydrochloric acid (4.6mL) was dropped into the reaction solution under stirring in an ice bath, the pH was adjusted to 5 to 6, and then extracted three times with a mixed solvent of 3:1(V/V) chloroform/isopropanol, the organic phases were combined, and the organic phases were spin-dried to obtain 1.7g (91%) of compound 9-1 as a white solid. MS (ESI, M/z):205[ M-1]-.1H NMR(300MHz,DMSO-d6)12.42(s,1H),4.24–4.01(m,6H),3.63(s,3H)。
The second step is that:
compound 9-1(1.7g,8mmol,1equiv) was added to a 250mL single neck flask, followed by the addition of N, N-dimethylformamide (40mL) and HATU (i.e., 2- (7-benzotriazole oxide) -N, N' -tetramethylurea hexafluorophosphate, 2.3g,6mmol,0.8equiv) in that order, followed by stirring at room temperature for 30min, followed by the addition of N, N-diisopropylethylamine (1.7g,13mmol,1.6equiv) and 4-chloroaniline (723mg,5.7mmol,0.7equiv) in that order, followed by stirring at room temperature for 6 h. After the reaction is completed, the reaction solution is poured into 200mL of water, extracted with 50mL of ethyl acetate for three times, the organic phases are combined, and the crude product is purified by column chromatography after being dried (ethyl acetate/petroleum ether, 5 → 50%]To give 1.4g (54%) of compound 9-2 as a pale yellow solid. MS (ESI, M/z) 316[ M + 1]]+;1H NMR(300MHz,DMSO-d6):9.79(s,1H),7.69(d,J=8.4Hz,2H),7.43–7.25(m,2H),4.32–4.10(m,6H),3.64(s,3H).
The third step:
9-2(1.4g,4.3mmol,1equiv) was placed in a 100mL single neck flask, and tetrahydrofuran (18mL), methanol (6mL), water (6mL) and lithium hydroxide (206mg,8.6mmol,2equiv) were added in this order, followed by stirring at room temperature for 3 h. After the reaction is completed, slowly dropwise adding a hydrochloric acid solution (1mol/L,8.6mL) into the reaction system under an ice bath condition, adjusting the pH to 5-6, supplementing a small amount of water, stirring for 30min, extracting for three times by using a mixed solvent of 3:1(V/V) chloroform/isopropanol, combining organic phases, and carrying out spin drying on the organic phases to obtain 1.2g (90%) of a compound 9-3 which is a white solid. (ESI, M/z):302[ M +1]+;1H-NMR(300MHz,DMSO-d6)12.38(s,1H),9.78(s,1H),7.69(d,J=8.5Hz,2H),7.36(d,J=8.5Hz,2H),4.26–4.10(m,6H)。
The fourth step:
n- (4-chlorophenyl) -4- (6-fluoroquinolin-4-yl) cubane-1-carboxamide 9 and
n- (4-chlorophenyl) -4- (6-fluoroquinolin-2-yl) cubane-1-carboxamide 10
The compounds 9-3(90mg,0.3mmol,1equiv), 6-fluoroquinoline (22mg,0.2mmol,0.5equiv), silver nitrate (7.6mg, 40. mu. mol,0.2equiv), potassium persulfate (76mg,0.3mmol,1equiv) and copper acetate (2.7mg, 10. mu. mol,0.1equiv) were added to an 8mL reaction flask in this order, and after stirring uniformly at room temperature, acetonitrile (0.5mL) and water (0.5mL) were added, and after heating to 80 ℃ and stirring were carried out for 4 hours. After completion of the reaction, the reaction solution was filtered, and the filtrate was purified by high performance liquid chromatography (column: Xbridge RP18,19X 150 mm; mobile phase A: water (10mm NH)4HCO3) The mobile phase B is acetonitrile; the flow rate is 25 ml/min; gradient of 40% B for 10 min; detection wavelength: 254/220nm), and separating the front and back peaks corresponding to the target molecular weight.
Front peak: the retention time is 8.7 min; 4.3mg (4%) of a white solid.1H-NMR confirmed that the peak corresponded to the compound 9: (ESI, M/z)403[ M +1]+;1H-NMR(300MHz,CDCl3)8.86(s,1H),8.23–8.14(m,1H),7.57-7.35(m,5H),7.30(s,1H),7.25-7.16(m,2H),4.59–4.40(m,6H).19F-NMR(282MHz,CDCl3)-111.54(s)。
And (3) post peak: the retention time is 9.4 min; 3.8mg (3%) of a white solid.1H-NMR confirmed that the peak corresponds to the compound 10: (ESI, M/z)403[ M +1]+;1H-NMR(300MHz,CDCl3)8.13(d,J=8.3Hz,2H),7.59(d,J=8.4Hz,2H),7.51–7.32(m,5H),7.21(s,1H),4.46(s,6H).19F-NMR(282MHz,CDCl3)-114.31(s)。
Example 11
N- (4-chlorophenyl) -2- (4- (6-fluoroquinolin-4-yl) cuban-1-yl) propanamide 11 (enantiomer, peak1)
Example 12
Synthesis of N- (4-chlorophenyl) -2- (4- (6-fluoroquinolin-4-yl) cuban-1-yl) propanamide 12 (enantiomer, peak2)
Synthetic route
The first step is as follows:
compound 9-1(1650mg,8.0mmol,1equiv), 6-fluoroquinoline (588.76mg,4.0mmol,0.5equiv), silver nitrate (203.9mg,1.2mmol,0.15equiv), potassium persulfate (2032mg,8.0mmol, 1eq) and copper acetate (72.7mg,0.4mmol,0.05equiv) were added sequentially to a 250mL one-neck flask, acetonitrile (45mL) and water (30mL) were added, stirred well at room temperature, then heated to 70 ℃ and stirred for 1.0 h. The reaction was monitored by LCMS and found to be complete. The reaction was quenched by dropwise addition of saturated aqueous sodium bicarbonate (70mL) to the reaction system with stirring in an ice bath, followed by extraction three times with dichloromethane, combining the organic phases, drying the organic phases over anhydrous sodium sulfate, filtering, and spin-drying the organic phases. After spin-drying, the crude product is purified by column chromatography [ ethyl acetate/petroleum ether, 0% → 40%]This gave 300mg (12%) of Compound 11-1 as a yellow solid. MS (ESI, M/z):308[ M +1 [)]+.1H NMR(400MHz,CD3OD)8.32(d,J=8.6Hz,1H),8.09(m,1H),7.64–7.55(m,2H),7.52(d,J=8.6Hz,1H),4.44–4.30(m,6H),3.77(s,3H).
The second step is that:
11-1(300mg,0.98mmol,1equiv) was placed in a 25mL single-neck flask, and tetrahydrofuran (2.4mL), methanol (0.8mL), water (0.8mL) and lithium hydroxide (93.5mg,3.9mmol,4equiv) were added in this order, followed by stirring at room temperature for 2.0 h. After the reaction is completed, under the ice-bath condition, a hydrochloric acid solution (2.0mol/L,2.0mL) is slowly dropped into the reaction system, and the pH is adjusted to 5-6. The mixture was then directly spin dried to give 300mg (crude) of the starting materialCompound 11-2, a yellow solid. MS (ESI, M/z):294[ M + 1]]+。
The third step:
compound 11-2(300mg,1.0mmol,1equiv) was added to a 25mL single neck flask, followed by N, N-dimethylformamide (3.0mL) and HATU (i.e., 2- (7-oxabenzotriazol) -N, N' -tetramethyluronium hexafluorophosphate, 583.4mg,1.5mmol,1.5equiv), followed by stirring at room temperature for 30min, followed by addition of dimethylamine hydrochloride (129.7mg,1.3mmol,1.3equiv) and N, N-diisopropylethylamine (462.7mg,3.6mmol,3.5equiv), followed by stirring at room temperature for 16 h. The reaction was monitored by LCMS and found to be complete. The reaction mixture was filtered and the filtrate was purified by reverse phase chromatography over the reaction mixture [ acetonitrile/water (0.5% mmol/L ammonium bicarbonate), 10 → 80%]300mg (87%) of compound 11-3 are obtained as a brown solid. MS (ESI, M/z) 337[ M + 1]]+.1H NMR(400MHz,CDCl3)8.84(d,J=4.4Hz,1H),8.16-8.20(m,1H),7.49-7.54(m,1H),7.30-7.16(m,2H),4.54–4.39(m,6H),3.81(s,3H),3.28(s,3H)。
The fourth step:
after compound 11-3(300mg,0.9mmol,1equiv) was added to a 50mL Schlenk tube and nitrogen was replaced three times, 4.0mL of dried tetrahydrofuran was added to dissolve it, and methyl magnesium bromide (3M, 0.6mL) was slowly added dropwise to the reaction system with stirring in an ice bath. After the dropwise addition, the temperature was raised to room temperature and stirred for 2.0 h. The reaction was monitored by LCMS and found to be complete. The reaction was slowly poured into a saturated aqueous ammonium chloride solution stirred in an ice bath, then extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the organic phase was spin dried. After spin-drying, the crude product is purified by column chromatography [ ethyl acetate/petroleum ether, 0% → 50%]220mg (85%) of compound 11-4 are obtained as a yellow solid. MS (ESI, M/z) 292[ M + 1]]+.1H NMR(400MHz,CDCl3)8.85(d,J=4.5Hz,1H),8.17-8.21(m,1H),7.50-7.55(m,1H),7.24-7.28(m,1H),7.20–7.14(m,1H),4.55–4.48(m,3H),4.46–4.25(m,3H),2.26(s,3H)。
The fifth step:
the compound (methoxymethyl) triphenyl phosphonium chloride (797.6mg,2.0mmol,3.0equiv) was added to a 50mL Schlenk's tube, nitrogen was replaced three times, and dried tetrahydrofuran (4.0mL) was added for dilution, and then a 1mol/L tetrahydrofuran solution of potassium t-butoxide (167.9mg,2.3mmol,3.3equiv) was slowly added dropwise with stirring in an ice bath, and after completion of the addition, stirring was performed for 30 minutes in an ice bath. Then, compound 11-4(200.0mg,0.7mmol,1.0equiv) was dissolved in 3.0mL of tetrahydrofuran solution and slowly dropped into the above system under stirring in an ice bath, and after dropping, the temperature was raised to room temperature and further stirred for 3.0 hours. The reaction was monitored by LCMS and found to be complete. The reaction was slowly poured into a saturated aqueous ammonium chloride solution stirred in an ice bath, then extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the organic phase was spin dried. After spin-drying, the crude product is purified by column chromatography [ ethyl acetate/petroleum ether, 0% → 50%]200mg (91%) of compound 11-5 are obtained as a pale yellow solid. MS (ESI, M/z) 320[ M + 1]]+。
And a sixth step:
compound 11-5(200mg,0.6mmol,1.0equiv) was charged into a 25mL one-necked flask, followed by the addition of tetrahydrofuran (3.0mL) and 2.0mol/L dilute hydrochloric acid (2.4mL) in that order, and after the addition was completed, the mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS and found to be complete. Adjusting the pH value to 7-8 by using a saturated sodium bicarbonate aqueous solution, extracting for three times by using ethyl acetate, combining organic phases, drying by using anhydrous sodium sulfate, filtering, and spin-drying the organic phases. The crude product is treated with column chromatography after being dried by spinningPurification [ ethyl acetate/petroleum ether, 0% → 50%]120mg (60%) of compound 11-6 are obtained as a pale yellow solid. MS (ESI, M/z) 306[ M + 1]]+;1H NMR(400MHz,CDCl3)9.81-9.82(m,1H),8.83-8.84(m,1H),8.27-8.30(m,1H),7.52-7.57(m,1H),7.31-7.34(m,1H),7.19-7.20(m,1H),4.39-4.41(m,3H),4.16-4.18(m,3H),2.91–2.83(m,1H),1.22(d,J=7.1Hz,3H).
The seventh step:
compounds 11-6(120.0mg,0.4mmol,1.0equiv) were added to a 50mL single-necked flask, followed by tetrahydrofuran (3.0mL), 2-methyl-2-butene (292.2mg,4.2mmol,10.6equiv), sodium dihydrogen phosphate (94.3mg,0.8mmol,2.0equiv), sodium chlorite (107mg,1.2mmol,3.0equiv) and water (1.4mL) in that order, and stirred at room temperature for 3 h. The reaction was monitored by LCMS and found to be complete. Extracting the reaction system with ethyl acetate once, adjusting the pH value of the water phase to 5-6 by using 2.0mol/L dilute hydrochloric acid under the condition of ice bath stirring, then extracting with ethyl acetate three times, combining the organic phases, drying with anhydrous sodium sulfate, filtering, and spin-drying the organic phases. 120mg (crude) of compound 11-7 are obtained as a yellow solid. MS (ESI, M/z):322[ M +1 [)]+.
Eighth step:
compounds 11-7(120.0mg,0.36mmol,1.0equiv) were added to a 25mL single neck flask, followed by the addition of N, N-dimethylformamide (2mL) and HATU (i.e., 2- (7-oxabenzotriazol) -N, N' -tetramethyluronium hexafluorophosphate, 213mg,0.56mmol,1.5equiv) in that order, followed by stirring at room temperature for 30min, followed by the addition of N, N-diisopropylethylamine (144.79mg,1.1mmol,3.0equiv) and 4-chloroaniline (61.93mg,0.48mmol,1.3equiv) in that order, followed by stirring at room temperature for 16 h. The reaction was monitored by LCMS and found to be complete. The reaction solution was filtered, and the filtrate was purified by reverse chromatography over the reaction solution [ acetonitrile/water (0).5% mmol/L ammonium bicarbonate), 25 → 70%]86mg (53%) of compound 11-8 were obtained as a pale yellow solid. MS (ESI, M/z):431[ M + 1]]+.
The ninth step:
n- (4-chlorophenyl) -2- (4- (6-fluoroquinolin-4-yl) cuban-1-yl) propanamide 11 (enantiomer, peak1) and
n- (4-chlorophenyl) -2- (4- (6-fluoroquinolin-4-yl) cuban-1-yl) propanamide 12 (enantiomer, peak2)
Racemate 11-8(80mg) was passed through a preparative Chiral separation column (column: Chiral pak AD-H,2 × 25cm (5 μm); mobile phase A: n-hexane (10mM NH)3) The mobile phase B is ethanol; the flow rate is 20 mL/min; gradient 15% B → 15% B,15 min; detection wavelength: 220 nm; the sample injection amount is 0.6 mL; the number of needles is 6 times) to split the front and the back peaks. The pre-peak gives compound 11 (enantiomer, peak 1); retention time: 7.8 min; 22.2mg (28%); a white solid. MS (ESI, M/z):431[ M + 1]]+;1H NMR(400MHz,CD3OD)8.77-8.12(m,2H),7.65–7.59(m,3H),7.40(dd,J=9.8,2.8Hz,1H),7.36–7.29(m,3H),4.33-4.36(m,3H),4.17-4.19(m,3H),2.91(q,J=6.8Hz,1H),1.29(d,J=6.9Hz,3H);19F NMR(377MHz,CD3OD) -113.50. The latter peak gives compound 12 (enantiomer, peak 2); retention time: 11.5 min; 27mg (34%); a white solid. MS (ESI, M/z):431[ M + 1]]+;1H NMR(400MHz,CD3OD)8.77-8.12(m,2H),7.67–7.58(m,3H),7.40(dd,J=9.8,2.8Hz,1H),7.36–7.29(m,3H),4.33-4.36(m,3H),4.17-4.19(m,3H),2.91(q,J=6.8Hz,1H),1.29(d,J=6.8Hz,3H);19F NMR(377MHz,CD3OD)-113.50。
Example 13
(±)4- [1- [ (4-chlorophenyl) carbamoyl ] ethyl ] -N-phenyl cubane-1-carboxamide 13 (racemate)
Example 14
4- [1- [ (4-chlorophenyl) carbamoyl ] ethyl ] -N-phenylcubane-1-carboxamide 14 (enantiomer, peak1)
Example 15
Synthesis of 4- [1- [ (4-chlorophenyl) carbamoyl ] ethyl ] -N-phenylcubane-1-carboxamide 15 (enantiomer, peak2)
Synthetic route
The first step is as follows:
compound 9-1(1.3g,6.3mmol,1.0equiv) was dissolved in dichloromethane (15mL), 120uL of N, N-dimethylformamide was added, the temperature was reduced to 0 ℃ and oxalyl chloride (1.2g,9.5mmol,1.5equiv) was added dropwise thereto. The reaction was stirred at room temperature for 1.5 h. After completion of the reaction, it was directly spin-dried to give 1.2g of crude compound 13-1 (93%) as a yellow foamy solid.
The second step is that:
cuprous iodide (1.4g,7.6mmol,1.2equiv) was added to a 250mL three-necked flask, nitrogen was replaced three times, and 30mL of tetrahydrofuran was added. Methyl lithium (1.6M,7.9mL, 12.7mmol,2.0equiv) was added dropwise at 0 ℃ under nitrogen protection, reacted at 0 ℃ for 30min, and then cooled to-78 ℃. A solution of compound 13-1(1.2g,5.4mmol,1.0equiv) in tetrahydrofuran (20mL) was added dropwise at the same temperature under nitrogen. And reacting for 1h at-78 ℃ under the protection of nitrogen. After the reaction was complete, it was quenched with 50mL of saturated ammonium chloride at 0 ℃ and then extracted three times with ethyl acetate. After the combination, the organic phase was washed once with 200mL of saturated saline and the organic phase was washed withDried over anhydrous sodium sulfate for 15min, filtered to remove anhydrous sodium sulfate, and the crude product after rotary drying of the filtrate was purified by column chromatography (ethyl acetate/petroleum ether, 5 → 50%) to give 770mg of compound 13-2 (59.8%) as a pale yellow solid. MS (ESI, M/z):205[ M + 1]]+;1H NMR(400MHz,CDCl3)4.35–4.17(m,6H),3.74(s,3H),2.16(s,3H).
The third step:
(methoxymethyl) triphenylphosphonium chloride (903.0mg,2.9mmol,1.5equiv) was added to a 50mL Schlenk's tube, nitrogen was replaced three times, and 6.0mL tetrahydrofuran was added under nitrogen protection. Potassium tert-butoxide (330mg,2.97mmol,1.5equiv) was added in portions at 0 ℃ to react at room temperature for 30min, then the temperature was reduced to 0 ℃ and the compound 13-2(400mg,2.0mmol,1.0equiv) was added to the above system. The reaction was carried out at room temperature for 1.0 h. After completion of the reaction, the reaction mixture was quenched with 100mL of saturated ammonium chloride solution, extracted three times with ethyl acetate, the combined organic phases were washed once with 150mL of saturated brine, the organic phase was dried over anhydrous sodium sulfate for 15min, filtered to remove anhydrous sodium sulfate, and the crude product was purified by column chromatography after the filtrate was dried by spinning (ethyl acetate/petroleum ether, 0 → 20%) to obtain 328mg of compound 13-3 (72.1%) as a pale yellow oily liquid. MS (ESI, M/z):233[ M + 1]]+;1H NMR(300MHz,DMSO-d6)5.79-5.86(m,1H),4.01-4.11(m,4H),3.88-3.92(m,2H),3.46-3.63(m,6H),1.43-1.46(m,3H).
The fourth step:
compound 13-3(320mg,1.4mmol,1.0equiv) was added to a mixed solvent of 3.0mL of tetrahydrofuran and 3.0mL of hydrochloric acid (2mol/L) at room temperature, and stirred at room temperature for 3.0 h. After the reaction is completed, quenching the mixture by 50mL of saturated sodium bicarbonate solution, extracting the mixture by ethyl acetate for three times, combining the mixture, washing an organic phase by 50mL of saturated saline solution once, drying the organic phase by anhydrous sodium sulfate for 15min, filtering the mixture to remove the anhydrous sodium sulfate, filtering the filtrate, and obtaining the filtrateAfter spin-drying, the crude product was purified by column chromatography (ethyl acetate/petroleum ether, 5 → 40%) to give 115mg of compound 13-4 (38.3%) as a colorless oily liquid. MS (ESI, M/z) 219[ M + 1]]+;1H NMR(300MHz,DMSO-d6)9.65(d,J=1.1Hz,1H),4.21–4.02(m,3H),3.98–3.84(m,3H),3.62(s,3H),2.79(q,J=7.1Hz,1H),0.99(d,J=7.1Hz,3H).
The fifth step:
13-4(115.0mg,0.5mmol,1.0equiv) was dissolved in 2.0mL of THF, and 2-methyl-2-butene (392mg,5.6mmol,10.6equiv), sodium dihydrogen phosphate (126.4mg,1.1mmol,2.0equiv), sodium chlorite (143mg,1.6mmol,3.0equiv) and 2.0mL of water were added in this order at 0 ℃. The reaction was stirred at room temperature for 1 h. After the reaction is completed, 1mol/L hydrochloric acid is used for adjusting the pH value to about 6, ethyl acetate is used for extraction for three times, organic phases after combination are washed once by 80mL saturated salt solution, the organic phases are dried for 15min by anhydrous sodium sulfate, the anhydrous sodium sulfate is removed by filtration, and 144mg of crude product of the compound 13-5 is obtained after the filtrate is dried by spinning and is yellow oily liquid. MS (ESI, M/z):235[ M + 1]]+.
And a sixth step:
at room temperature, the compounds 13 to 5(144.0mg,0.6mmol,1.0equiv), HATU (i.e., 2- (7-benzotriazole oxide) -N, N' -tetramethylurea hexafluorophosphate, 303.9mg,0.8mmol,1.3equiv) and N, N-dimethylformamide (1.5mL) were sequentially added to a 25mL reaction flask, and after stirring at room temperature for reaction for 15min, p-chloroaniline (94.1mg,0.7mmol,1.2equiv) and N, N-diisopropylethylamine (206.6mg,1.6mmol,2.6equiv) were added thereto and reacted at room temperature for 16 h. After completion of the reaction, the reaction mixture was purified by reverse chromatography [ acetonitrile/water (0.5% mmol/L ammonium bicarbonate), 30 → 95%]110mg of compound 13-6 (52.1%) are obtained as a pale yellow solid. MS (ESI, M/z) 344[ M + 1]]+;1H NMR(300MHz,DMSO-d6)9.96(s,1H),7.67–7.57(m,2H),7.40–7.27(m,2H),4.08–3.98(m,3H),3.93–3.82(m,3H),3.62(s,3H),2.75(q,J=6.7Hz,1H),1.08(d,J=6.8Hz,3H).
The seventh step:
compound 13-6(170.0mg,0.5mmol,1.0equiv) was added to a mixed solvent of 1.8mL of methanol, 0.6mL of tetrahydrofuran and 0.6mL of water at room temperature, and lithium hydroxide (35.5mg,1.5mmol,3.0equiv) was further added. Stirred at 50 ℃ for 4.0 h. After the reaction is completed, the pH value of the reaction solution is adjusted to about 6 by using 1mol/L hydrochloric acid, the water phase is extracted for three times by using dichloromethane, the organic phases are combined and dried for 15min by using anhydrous sodium sulfate, the anhydrous sodium sulfate is removed by filtration, and the crude product of 200mg of the compound 13-7 is light yellow solid after the filtrate is dried by spinning. MS (ESI, M/z):330[ M + 1]]+。
Eighth step:
(±)4- [1- [ (4-chlorophenyl) carbamoyl ] ethyl ] -N-phenyl cubane-1-carboxamide 13 (racemate)
The crude product (200mg,0.6mmol,1.0equiv) from the previous step 13 to 7, HATU (i.e., 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate, 300.0mg,0.8mmol,1.3equiv) and 3.0mL of N, N-dimethylformamide were sequentially added to a 25mL single-neck flask, and after stirring at room temperature for 15min, aniline (67.8mg,0.7mmol,1.2equiv) and N, N-diisopropylethylamine (203.8mg,1.6mmol,2.6equiv) were sequentially added thereto and reacted at room temperature overnight. After completion of the reaction, the reaction mixture was purified by reverse chromatography [ acetonitrile/water (0.5% mmol/L ammonium bicarbonate), 30 → 95%]160mg of compound 13 (65.2%) are obtained as a white solid. MS (ESI, M/z):405[ M + 1]]+;1H NMR(300MHz,DMSO-d6)9.97(s,1H),9.51(s,1H),7.63-7.67(m,4H),7.27-7.36(m,4H),7.02-7.05(m,1H),4.10-4.13(m,3H),3.86-3.89(m,3H),2.78(q,J=6.8Hz,1H),1.10(d,J=6.7Hz,3H).
The ninth step:
4- [1- [ (4-chlorophenyl) carbamoyl ] ethyl ] -N-phenylcubane-1-carboxamide 14 (enantiomer, peak1) and 4- [1- [ (4-chlorophenyl) carbamoyl ] ethyl ] -N-phenylcubane-1-carboxamide 15 (enantiomer, peak2)
Resolution of racemate 13(100.0mg,0.2mmol,1.0equiv) using chiral separation column (column model: CHIRAL ART Cellulose-SB,2 × 25cm,5 μm) using chiral high performance liquid chromatography; mobile phase A is n-hexane (10mM ammonia), and mobile phase B is isopropanol; the flow rate is 25 mL/min; gradient 30% → 30% B; 12 min; detection wavelength: 254 nm; the front peak emergence time is 4.0 min; the time of peak emergence is 8.5 min; the total sample injection amount is 4.0 mL; the number of sampling needles is 8); the pre-peak (retention time 4.0min) was spin-dried to give compound 14 as a white solid (20mg, 20%). The latter peak (retention time 8.5min) was spin-dried to give compound 15 as a white solid (20mg, 20%).
14:MS(ESI,m/z)405[M+1]+;1H NMR(300MHz,DMSO-d6)9.97(s,1H),9.51(s,1H),7.63-7.67(m,4H),7.26-7.36(m,4H),7.01-7.06(m,1H),4.10-4.13(m,3H),3.86-3.89(m,3H),2.78(q,J=6.8Hz,1H),1.10(d,J=6.7Hz,3H).
15:MS(ESI,m/z)405[M+1]+;1H NMR(400MHz,DMSO-d6)9.97(s,1H),9.51(s,1H),7.63-7.67(m,4H),7.26-7.36(m,4H),7.01-7.06(m,1H),4.10-4.13(m,3H),3.86-3.89(m,3H),2.78(q,J=6.7Hz,1H),1.10(d,J=6.8Hz,3H).
Example 16
(±) N- (3- [1- [ (4-chlorophenyl) carbamoyl ] ethyl ] bicyclo [1.1.1] pentane-1-yl) -4-fluorobenzamide 16 (racemate)
Example 18
N- (3- [1- [ (4-chlorophenyl) carbamoyl ] ethyl ] bicyclo [1.1.1] pentan-1-yl) -4-fluorobenzamide 18 (enantiomer, peak1)
Example 19
N- (3- [1- [ (4-chlorophenyl) carbamoyl ] ethyl ] bicyclo [1.1.1] pentan-1-yl) -4-fluorobenzamide 19 (enantiomer, peak2)
Synthetic route
The first step is as follows:
(±) N- (3- [1- [ (4-chlorophenyl) carbamoyl ] ethyl ] bicyclo [1.1.1] pentane-1-yl) -4-fluorobenzamide 16
The compound 6-2(100mg,0.4mmol,1equiv), N-diisopropylethylamine (195mg,1.5mmol,4equiv) and dichloromethane (2mL) were sequentially added to an 8mL reaction flask, followed by dropwise addition of 4-fluorobenzoyl chloride (84mg,0.5mmol,1.4equiv) with stirring in an ice bath; the reaction was stirred at room temperature for 1 h. The reaction was monitored by LCMS and found to be complete. The reaction solution was purified by reverse phase chromatography [ acetonitrile/water (10mmol/L ammonium bicarbonate, 40 → 95% ]]89mg of compound 16 (60.9%) are obtained as a white solid. MS (ESI, M/z) 387[ M + 1]]+;1H NMR(300MHz,DMSO-d6)9.94(s,1H),8.95(s,1H),7.93–7.85(m,2H),7.67–7.60(m,2H),7.39–7.23(m,4H),2.74(q,J=6.8Hz,1H),2.05–1.88(m,6H),1.07(d,J=6.8Hz,3H).19F NMR(282MHz,DMSO-d6)-109.53。
The second step is that:
n- (3- [1- [ (4-chlorophenyl) carbamoyl ] ethyl ] bicyclo [1.1.1] pentan-1-yl) -4-fluorobenzamide 18 (enantiomer, peak1) and
n- (3- [1- [ (4-chlorophenyl) carbamoyl ] ethyl ] bicyclo [1.1.1] pentan-1-yl) -4-fluorobenzamide 19 (enantiomer, peak2)
Resolution of racemate 16(89mg,0.23mmol,1.0equiv) using a chiral separation column (column model: CHIRALPAK ID,2 × 25cm,5 μm) using chiral high performance liquid chromatography; mobile phase A is n-hexane (10mM ammonia), and mobile phase B is isopropanol; the flow rate is 20 mL/min; gradient 20% → 20% B; 10 min; detection wavelength: 254 nm; the front peak emergence time is 4.7 min; the time of peak emergence is 7.5 min; the sample injection amount is 2.0 mL; the number of sampling needles is 10); the pre-peak (retention time 4.7min) was spin-dried to give compound 18 as a white solid (24mg, 27%). The latter peak (retention time 7.5min) was spin-dried to give compound 19 as a white solid (22mg, 25%).
18:MS(ESI,m/z)387[M+1]+;1H NMR(300MHz,DMSO-d6)9.93(s,1H),8.95(s,1H),7.93–7.84(m,2H),7.68–7.58(m,2H),7.40–7.32(m,2H),7.32–7.23(m,2H),2.74(q,J=6.8Hz,1H),2.03–1.89(m,6H),1.07(d,J=6.7Hz,3H).19F NMR(282MHz,DMSO-d6)-109.53.
19:MS(ESI,m/z)387[M+1]+;1H NMR(300MHz,DMSO-d6)9.93(s,1H),8.95(s,1H),7.94–7.84(m,2H),7.68–7.58(m,2H),7.40–7.32(m,2H),7.32–7.22(m,2H),2.74(q,J=6.7Hz,1H),2.03–1.88(m,6H),1.07(d,J=6.8Hz,3H).19F NMR(282MHz,DMSO-d6)-109.52.
Example 17
(±) N- (3- [1- [ (4-chlorophenyl) carbamoyl ] ethyl ] bicyclo [1.1.1] pentane-1-yl) -4-chlorobenzamide 17 (racemate)
Example 20
N- (3- [1- [ (4-chlorophenyl) carbamoyl ] ethyl ] bicyclo [1.1.1] pentan-1-yl) -4-chlorobenzamide 20 (enantiomer, peak1)
Example 21
N- (3- [1- [ (4-chlorophenyl) carbamoyl ] ethyl ] bicyclo [1.1.1] pentan-1-yl) -4-chlorobenzamide 21 (enantiomer, peak2)
The first step is as follows:
(±) N- (3- [1- [ (4-chlorophenyl) carbamoyl ] ethyl ] bicyclo [1.1.1] pentane-1-yl) -4-chlorobenzamide 17 (racemate)
4-chlorobenzoic acid (76.88mg,0.491mmol,1.30equiv), HATU (i.e., 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate, 186.70mg,0.491mmol,1.30equiv) and DMF (1.5mL) were added sequentially to an 8mL reaction flask, and after stirring at room temperature for 15 minutes, compound 6-2(100mg,0.4mmol,1equiv) and N, N-diisopropylethylamine (195mg,1.5mmol,4equiv) were added sequentially thereto, and stirring was continued at room temperature for 2 hours. After completion of the reaction, the reaction mixture was purified by reverse phase chromatography [ acetonitrile/water (10mmol/L ammonium bicarbonate, 40 → 95% ]]95mg of compound 17 (62.4%) are obtained as a white solid. MS (ESI, M/z):403[ M +1 [)]+;1H NMR(300MHz,DMSO-d6)9.94(s,1H),9.01(s,1H),7.88–7.80(m,2H),7.67–7.59(m,2H),7.56–7.48(m,2H),7.39–7.32(m,2H),2.74(q,J=6.8Hz,1H),2.03–1.88(m,6H),1.07(d,J=6.8Hz,3H).
The second step is that:
n- (3- [1- [ (4-chlorophenyl) carbamoyl ] ethyl ] bicyclo [1.1.1] pentan-1-yl) -4-chlorobenzamide 20 (enantiomer, peak1) and
n- (3- [1- [ (4-chlorophenyl) carbamoyl ] ethyl ] bicyclo [1.1.1] pentan-1-yl) -4-chlorobenzamide 21 (enantiomer, peak2)
Resolution of racemate 17(95mg,0.2mmol,1equiv) using a chiral separation column (column model: CHIRALPAK ID,2 × 25cm,5 μm) using chiral high performance liquid chromatography; mobile phase A is n-hexane (10mM ammonia), and mobile phase B is isopropanol; the flow rate is 20 mL/min; gradient 25% → 25% B; 12 min; detection wavelength: 254 nm; the front peak emergence time is 4.5 min; the time of peak emergence is 8.8 min; the sample injection amount is 1.6 mL; the number of sampling needles is 7); the pre-peak (retention time 4.5min) was spin-dried to give compound 20 as a white solid (26mg, 27%). The latter peak (retention time 8.8min) was spin-dried to give compound 21 as a white solid (21mg, 23%).
20:MS(ESI,m/z)403[M+1]+;1H NMR(300MHz,DMSO-d6)9.93(s,1H),9.00(s,1H),7.84(d,J=8.2Hz,2H),7.63(d,J=8.5Hz,2H),7.52(d,J=8.2Hz,2H),7.36(d,J=8.2Hz,2H),2.74(q,J=6.7Hz,1H),2.04–1.88(m,6H),1.07(d,J=6.7Hz,3H).
21:MS(ESI,m/z)403[M+1]+;1H NMR(400MHz,DMSO-d6)9.94(s,1H),9.01(s,1H),7.86–7.81(m,2H),7.66–7.60(m,2H),7.55–7.50(m,2H),7.39–7.33(m,2H),2.74(q,J=6.7Hz,1H),2.02–1.90(m,6H),1.07(d,J=6.8Hz,3H).
Biological examples
Evaluation of inhibitory Activity of Compounds on IDO1 on Hela cell level
Hela cells were cultured in EMEM complete medium (90% EMEM, 10% fetal bovine serum, 1% Pen/Strep).
The test compounds were diluted to 10mM stock in DMSO, followed by a 3-fold gradient dilution with DMSO for a total of 10 concentrations. Then 5 μ L of compound was added to 45 μ L of medium as an intermediate dilution.
HeLa cells were harvested from the cell culture medium and seeded into 96-well cell culture plates at 3000/well/100. mu.L. The diluted compound was added to the cells to give a final DMSO concentration of 0.1%. Then placed at 37 ℃ and 5% CO2Incubate in the incubator for 30 minutes. And after the incubation is finished, adding IFN-gamma into Hela cells, wherein the final concentration of the IFN-gamma is 10 ng/mL.
At 37 ℃ 5% CO2Incubations were continued for 48 hours in the incubator and 140. mu.L of supernatant per well was transferred to a new 96-well plate after incubation. Then 10. mu.L of 6.1N trichloroacetic acid was added to each well and mixed well, and the plate was sealed and mounted onIncubate at 50 ℃ for 30 minutes. After the incubation, the cells were centrifuged at 2500rpm for 10 minutes. At the end of centrifugation, 100. mu.L of supernatant per well was transferred to a new 96-well assay plate and mixed with 100. mu.L of 6% (w/v) p-dimethylaminobenzaldehyde. The formation of kynurenine can be determined by measuring the absorbance of the reaction product at 480 nm.
The percent activity at various concentrations of test compound was determined and IC50 values were evaluated using non-linear regression. The activity data for the compounds of the examples of the invention are shown in the table below.
Claims (23)
2. The compound of claim 1, wherein Cy is phenyl or quinolinyl, optionally substituted with halogen.
3. The compound of any one of claims 1-2, wherein Cy is phenyl or quinolin-4-yl, optionally substituted with F or Cl.
4. A compound according to any one of claims 1 to 3 wherein Cy is phenyl, 4-fluorophenyl, 4-chlorophenyl or 6-fluoroquinolin-4 yl.
7. a compound of formula (II):
or a stereoisomer, tautomer or pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotopically labeled derivative thereof, wherein
X is a bond or methylene optionally substituted with C1-6 alkyl;
y is a bond, -C (O) NH-or-NHC (O) -;
cy is C6-10 aryl or heteroaryl, optionally substituted with halogen.
8. The compound of claim 7, wherein Cy is phenyl or quinolinyl, optionally substituted with halogen.
9. The compound of any one of claims 7-8, wherein Cy is phenyl, quinolin-4-yl, or quinolin-2-yl, optionally substituted with F or Cl.
10. The compound of any one of claims 7-9, wherein Cy is phenyl, 6-fluoroquinolin-4 yl, or 6-fluoroquinolin-2 yl, and X is methylene substituted with methyl.
13. a pharmaceutical composition comprising a compound according to any one of claims 1 to 12 and a pharmaceutically acceptable carrier, diluent or excipient.
14. The pharmaceutical composition of claim 13, further comprising one or more additional therapeutic agents.
15. The pharmaceutical composition according to claim 14, the additional therapeutic agent being selected from chemotherapeutic agents, signal transduction inhibitors, anti-infective agents, immunomodulators and/or inflammation modulators.
16. The pharmaceutical composition according to claim 14, the further therapeutic agent being an immune checkpoint inhibitor, preferably a PD-1 antibody and/or a PD-L1 antibody.
17. The use of a compound according to any one of claims 1-12 in the manufacture of a medicament for inhibiting indoleamine 2, 3-dioxygenase activity.
18. Use of a compound according to any one of claims 1-12 in the manufacture of a medicament for the treatment and/or prevention of a disease, disorder or condition mediated in whole or in part by indoleamine 2, 3-dioxygenase.
19. The use of claim 18, wherein the disease, disorder or condition is a proliferative disease, an infectious disease, an immune-related disease and/or an inflammatory disease.
20. The use of claim 19, wherein the proliferative disease is cancer.
21. The use of claim 20, wherein the cancer is prostate cancer, colorectal cancer, pancreatic cancer, cervical cancer, gastric cancer, endometrial cancer, brain cancer, liver cancer, bladder cancer, ovarian cancer, testicular cancer, head cancer, neck cancer, skin cancer, mesothelial intimal cancer, leukocyte cancer, esophageal cancer, breast cancer, muscle cancer, connective tissue cancer, lung cancer, adrenal cancer, thyroid cancer, kidney cancer, bone cancer, glioblastoma, mesothelioma, renal cell carcinoma, sarcoma, choriocarcinoma, basal cell carcinoma of the skin, and testicular seminoma.
22. The use according to claim 20, wherein the cancer is melanoma, basal carcinoma, colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, leukemia, brain tumor, lymphoma, sarcoma, ovarian cancer or kaposi's sarcoma, preferably small cell lung cancer and non-small cell lung cancer.
23. The use of any one of claims 18-22, further comprising combining or co-using a compound of any one of claims 1-12 with a chemotherapeutic agent, radiation therapy, transplantation therapy, vaccine, cytokine therapy, signal transduction inhibitors, anti-infective agents, immunomodulators and/or inflammation modulators.
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