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WO2017181849A1 - Inhibiteur de l'indoléamine 2,3-dioxygénase, procédé pour sa préparation et application - Google Patents

Inhibiteur de l'indoléamine 2,3-dioxygénase, procédé pour sa préparation et application Download PDF

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Publication number
WO2017181849A1
WO2017181849A1 PCT/CN2017/079585 CN2017079585W WO2017181849A1 WO 2017181849 A1 WO2017181849 A1 WO 2017181849A1 CN 2017079585 W CN2017079585 W CN 2017079585W WO 2017181849 A1 WO2017181849 A1 WO 2017181849A1
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group
cancer
alkyl
membered
amino
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English (en)
Chinese (zh)
Inventor
吴盛华
李凯龙
包如迪
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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Priority claimed from CN201610573473.XA external-priority patent/CN107304191B/zh
Application filed by Jiangsu Hansoh Pharmaceutical Group Co Ltd, Shanghai Hansoh Biomedical Co Ltd filed Critical Jiangsu Hansoh Pharmaceutical Group Co Ltd
Priority to CA3019450A priority Critical patent/CA3019450A1/fr
Priority to CN201780010654.4A priority patent/CN108966651A/zh
Priority to US16/093,821 priority patent/US20190040025A1/en
Priority to JP2018552745A priority patent/JP2019513743A/ja
Publication of WO2017181849A1 publication Critical patent/WO2017181849A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/08—1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles

Definitions

  • the invention belongs to the field of drug development, and particularly relates to a guanamine 2,3-dioxygenase inhibitor and a preparation method and application thereof.
  • IDO Indoleamine 2,3-dioxygenase
  • Tryptophan is one of the eight essential amino acids. In vivo, tryptophan can be used to synthesize proteins. Tryptophan can also be used as a precursor substrate to synthesize serotonin and melatonin through the methoxypurine metabolic pathway (N- Acetyl-5-methoxytryptamine). Serotonin and melatonin are neurotransmitters and neuroendocrine hormones that are involved in the regulation of various neurological and physiological processes in the body. In addition, tryptophan can also produce metabolites such as kynurenine through the kynurenine metabolic pathway.
  • the first step in the kynurenine metabolic pathway is the tryptophan L-color ammonia catalyzed by indoleamine 2,3-dioxygenase or tryptophan 2,3-dioxygenase (TDO).
  • TDO tryptophan 2,3-dioxygenase
  • Canine uridine and 3-hydroxyanthranilic acid are involved in the regulation of lymphocyte activity leading to inhibition of the immune system.
  • indoleamine 2,3-dioxygenase In addition to placental tissue, indoleamine 2,3-dioxygenase is not expressed in most tissue cells under normal health conditions. In the region of inflammation, inflammatory cytokines such as interferon gamma can induce an increase in the expression of indoleamine 2,3-dioxygenase. The results of various experiments prove that the high expression of indoleamine 2,3-dioxygenase in tissue cells can lead to inhibition of the immune system of the tissue microenvironment, or immune suppression or immune checkpoint. . High expression of placental tissue indoleamine 2,3-dioxygenase prevents immune rejection of the fetus.
  • indoleamine 2,3-dioxygenase in the inflammatory region prevents excessive immune responses and prevents excessive damage to cellular tissues.
  • One of the mechanisms leading to inhibition of immunity is that high expression of indoleamine 2,3-dioxygenase causes local L-tryptophan depletion, which is sensed by surrounding lymphocytes through mechanisms such as GCN2, causing CD8+ cytotoxic T cells. Cell cycle arrest or apoptosis occurs.
  • Another mechanism that leads to inhibition of immunity is the high expression of indoleamine 2,3-dioxygenase, which causes an increase in kynurenine. After kynurenine formation, it leaves the cell and enters the extracellular matrix, and then enters the nearby lymph.
  • the cells regulate CD8+ T cells and regulatory Treg cells by binding to AHR transcription factors, and the activity of CD8+ cytotoxic T cells is inhibited, while the number of regulatory Treg cells is increased and activated, resulting in inhibition of immunity.
  • indoleamine 2,3-dioxygenase is abnormally highly expressed, including hematological tumors and solid tumors such as colorectal cancer, liver cancer, lung cancer, pancreatic cancer, and throat cancer.
  • the abnormally high expression of indoleamine 2,3-dioxygenase was positively correlated with poor tumor prognosis.
  • Tumor cell escape immune monitoring is a key step in the further development of cancer and cancer.
  • the abnormally high expression of indoleamine 2,3-dioxygenase in tumors may be the escape of tumor cells.
  • indoleamine 2,3-dioxygenase Inhibitors as an immune checkpoint inhibitor, have attracted a lot of interest in the medical community.
  • IDO indoleamine 2,3-dioxygenase
  • IDO-1 indoleamine 2,3-dioxygenase
  • IDO-2 indoleamine 2,3-dioxygenase
  • the main inhibitory of the above immunity is IDO-1.
  • the role of IDO-2 in immune suppression is not yet very clear.
  • TDO Tryptophan 2,3-dioxygenase
  • IDO Tryptophan 2,3-dioxygenase
  • the purpose of cancer treatment Because normal liver cells express TDO, it is unclear whether TDO inhibitors affect liver function and normal tryptophan metabolism, but there is no abnormality in the mouse model of TDO knockout, indicating that TDO inhibitors may not affect liver function and normality. The metabolism of tryptophan.
  • IDO/TDO bispecific inhibitors have also attracted interest in the pharmaceutical industry. IDO/TDO bispecific inhibitors will be suitable for IDO positive, TDO positive, IDO/TDO double positive. Patient.
  • Canine uridine can be converted to canine urinary quinolinic acid under the catalysis of kynurenine aminotransferase.
  • Canine urinary quinolinic acid is an NMDA antagonist, which is common in the central nervous system of patients with schizophrenia.
  • Quinolinic acid is neurotoxic and can cause neuronal apoptosis and neurodegeneration.
  • Indoleamine 2,3-dioxygenase is not only involved in the metabolism of tryptophan, but also involved in the metabolism of tryptamine.
  • the serotonin can be converted to 5-- under the catalysis of indoleamine 2,3-dioxygenase.
  • Hydroxamic acid, a decrease in serotonin may be one of the factors leading to depression.
  • Patent WO2016041489A1 discloses a series of sulfonimido compounds which have good inhibitory activity against indoleamine 2,3-dioxygenase (IDO), but the best compound 6 disclosed in this patent is relative to INCB-24360.
  • AUC Exposure to exposure
  • T 1/2 is short, which is not conducive to clinical development
  • Compound 13 Compound 6 prodrug
  • T 1/2 is not as effective as INCB- 24360, therefore, further development of compounds with a suitable T 1/2 for clinical administration, while having a high exposure (AUC) has attracted many scientists around the world to work hard for this.
  • the inventors discovered N'-hydroxy-N-phenylformamidine derivatives after a series of studies, which have high inhibitory activity against indoleamine 2,3-dioxygenase (IDO), while tryptophan 2 , 3-dioxygenase (TDO) has no inhibitory activity and has a very good exposure (AUC) in the PK animal model, while having a T 1/2 that is well suited for clinical applications.
  • IDO indoleamine 2,3-dioxygenase
  • TDO tryptophan 2 , 3-dioxygenase
  • Such compounds are effective in inhibiting the activity of IDO and can also be used to inhibit immunosuppression in patients. It can be widely used to treat or prevent cancer or tumors, viral infections, depression, neurodegenerative diseases, trauma, age-related cataracts, organ transplant rejection or autoimmune diseases, and is expected to be developed into a new generation of immunosuppressive agents.
  • the present invention provides a (Z)-N'-hydroxy-N-phenylformamidine derivative having the structure of the following formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
  • Z type and E type preferably Z type
  • X is selected from C 1-8 alkyl or C 3-8 cycloalkyl, optionally further selected from one or more selected from the group consisting of hydrazine, halogen, hydroxy, thiol, cyano, nitro, azide, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halogen substituted C 1-8 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclic ring Alkoxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 Nonheteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 8 , -C 0-8 -OR 5 , -C 0-8 -C(O) OR 5 , -C 0-8 -
  • R 1 is selected from the following structures:
  • Y is selected from -S(O) 2 - or -C(O)-C(O)-;
  • Z is selected from a bond, O, S or -NR 7 -;
  • R 2 is selected from hydrogen, deuterium, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5- 10 aryl, 5-10 membered heteroaryl or C 0-8 alkylcarbonyl,
  • R 3 is selected from the group consisting of hydrogen, hydrazine, hydroxy, amino, C 1-8 alkyl, C 2-8 alkenyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, C 5-10 aryl, 5-10 membered heteroaryl, C 1-8 alkoxy, C 3-8 cycloalkoxy, 3-8 membered heterocyclyloxy, C 5-10 aryloxy, 5-10 membered heteroaryl Alkoxy group, -C 0-8 -S(O) r R 4 , -C 0-8 -C(O)OR 5 , -C 0-8 -OC(O)R 6 , -C 0-8 - NR 7 R 8 , -C 0-8 -C(O)NR 7 R 8 , -N(R 7 )-C(O)R 6 or -N(R 7 )-C(O)OR 5 ,
  • R 4 is selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, C 2-8 alkenyl, C 3-8 cycloalkyl, halogen substituted C 1-8 alkyl, phenyl, p-methylphenyl, amino , a mono C 1-8 alkylamino group, a di C 1-8 alkylamino group or a C 1-8 alkanoylamino group;
  • R 5 is selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, C 3-8 cycloalkyl, halogen substituted C 1-8 alkyl or hydroxy substituted C 1-8 alkyl;
  • R 6 is selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, halogen substituted C 1-8 alkyl, halogen Substituting a C 1-8 alkoxy group, a hydroxy-substituted C 1-8 alkyl group or a hydroxy-substituted C 1-8 alkoxy group;
  • R 7 , R 8 , R 9 and R 10 are each independently selected from the group consisting of hydrogen, hydrazine, hydroxy, C 1-8 alkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 2-8 chain Alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl or C 1-8 alkanoyl, or And R 7 and R 8 , R 9 and R 10 and the nitrogen atom to be bonded form a 3-8 membered heterocycloalkyl group,
  • substituents selected from halo, hydroxy, mercapto, cyano, nitro, acetamido, azido, a sulfonyl group, mesyl group, C 1-8 alkyl, trifluoromethyl, C 2 8 -alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, C 1-8 alkoxy, C 1-8 alkoxycarbonyl, C 1-8 Alkylcarbonyl, C 1-8 alkylcarbonyloxy, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, amino, mono C 1-8 alkylamino or di C Substituted by a substituent of a 1
  • r is 0 to 2.
  • the (Z)-N'-hydroxy-N-phenylformamidine derivative, a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of the compound of the formula (II):
  • X is selected from C 1-6 alkyl or C 3-8 cycloalkyl, optionally further selected from one or more selected from the group consisting of hydrazine, halogen, hydroxy, thiol, cyano, nitro, azide, C 1-8 Substituted by a substituent of an alkyl group, a halogen-substituted C 1-8 alkyl group or a C 3-8 cycloalkyl group; R 7 , R 9 and R 10 are each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, and C 1-8 alkyl.
  • the (Z)-N'-hydroxy-N-phenylformamidine derivative, a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of Formula (IIA) or (IIB) ) Compound:
  • X is selected from ethyl, cyclobutyl, cyclohexyl, optionally further selected from one or more selected from the group consisting of hydrazine, halogen, hydroxy, decyl, cyano, nitro, trifluoromethyl, C 1-8 alkyl or C Substituted by a substituent of a 3-8 cycloalkyl group;
  • R 7 , R 9 and R 10 are each independently selected from the group consisting of hydrogen, hydrazine, hydroxy, C 1-8 alkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 5-10 aryl group, C 1-8 alkyl substituted C 5-10 aryl group, 5-10 membered heteroaryl group, C 1-8 alkanoyl group or -C 0-8 -C(O)OR 5 , or R 9 , R 10 form a 5-6 heterocycloalkyl group with the attached nitrogen atom.
  • the (Z)-N'-hydroxy-N-phenylformamidine derivative, a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of the following compounds:
  • the (Z)-N'-hydroxy-N-phenylformamidine derivative, a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of the compound of the formula (III):
  • Z is selected from a bond or -NR 7 -;
  • R 2 is selected from the group consisting of hydrogen, hydrazine, and C 1-8 alkyl
  • R 3 is selected from the group consisting of hydrazine, hydroxy, amino, C 1-8 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, C 5-10 aryl, 5-10 membered heteroaryl, C 1 -8 alkoxy, C 3-8 cycloalkoxy, 3-8 membered heterocyclyloxy, C 5-10 aryloxy, 5-10 membered heteroaryloxy, -C 0-8 - S(O) r R 4 , -C 0-8 -C(O)OR 5 or -C 0-8 -OC(O)R 6 ;
  • R 4 is selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, C 2-8 alkenyl, C 3-8 cycloalkyl, halogen substituted C 1-8 alkyl, phenyl, p-methylphenyl, amino , a mono C 1-8 alkylamino group, a di C 1-8 alkylamino group or a C 1-8 alkanoylamino group;
  • R 5 is selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, C 3-8 cycloalkyl, halogen substituted C 1-8 alkyl or hydroxy substituted C 1-8 alkyl;
  • R 6 is selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, halogen substituted C 1-8 alkyl, halogen Substituting a C 1-8 alkoxy group, a hydroxy-substituted C 1-8 alkyl group or a hydroxy-substituted C 1-8 alkoxy group;
  • r is 0 to 2.
  • the (Z)-N'-hydroxy-N-phenylformamidine derivative, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, the compound of the formula (III) has the following two Way of expression:
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is a compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
  • Z is selected from a bond or -NR 7 -;.
  • R 2 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl;
  • R 3 is selected from the group consisting of hydroxyl, amino, C 1-8 alkyl or -C 0-8 -S(O) r R 4 ;
  • R 4 is selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, C 2-8 alkenyl, C 3-8 cycloalkyl, halogen substituted C 1-8 alkyl, phenyl, p-methylphenyl, amino , a mono C 1-8 alkylamino group, a di C 1-8 alkylamino group or a C 1-8 alkanoylamino group;
  • r is 0 to 2.
  • the (Z)-N'-hydroxy-N-phenylformamidine derivative, a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of the following compounds:
  • the present invention also relates to an intermediate for preparing a compound of the formula (III), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which is a compound represented by the formula (IV), a stereoisomer thereof Or a pharmaceutically acceptable salt thereof:
  • the invention further relates to a process for the preparation of a compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which comprises the following steps:
  • X, R 2 and R 3 are as defined in the formula (III). According to another aspect of the present invention, there is provided a process for the preparation of the above-mentioned N'-hydroxy-N-phenylformamidine derivative, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the following steps:
  • X, R 1 are as defined for the compound of formula (I).
  • Another aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the above formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a compound of the above formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above for use in the preparation of a medicament for inhibiting indoleamine 2 The activity of 3-dioxygenase is either used to inhibit immunosuppression in patients.
  • the use refers to a therapeutically effective amount of the aforementioned compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition and an anti-CTLA-4 antibody, Combination of anti-PD-1 antibody, anti-PD-L1 antibody, antiviral agent, chemotherapeutic agent, immunosuppressant, radiation, anti-tumor vaccine, anti-viral vaccine, cytokine therapy or tyrosine kinase inhibitor; preferably,
  • the cytokine is preferably IL-2, IL-3, IL-4 or IL-5
  • the chemotherapeutic agent is preferably a cytotoxic agent
  • the anti-PD-1 antibody is preferably a Keytruda antibody.
  • Another aspect of the invention provides a method of modulating guanamine 2,3-dioxygenase activity, comprising administering a therapeutically effective amount of a compound of the above formula (I), a stereoisomer thereof, or a pharmaceutically acceptable
  • the salt, or the aforementioned pharmaceutical composition is contacted with the indoleamine 2,3-dioxygenase; preferably, the modulation is preferably an inhibitory effect.
  • Another aspect of the invention provides a method of inhibiting immunosuppression in a patient, the method comprising treating An effective amount of a compound of the above formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, is administered to a patient.
  • Another aspect of the invention relates to a method of treating cancer comprising administering to a patient a therapeutically effective amount of a compound of the formula (I) of the invention or a tautomer, a mesogen thereof, a foreign body A form of a rot, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • the method exhibits outstanding efficacy and fewer side effects, wherein the cancer or tumor is selected from the group consisting of lung cancer, bone cancer, stomach cancer, pancreatic cancer, skin cancer, head and neck cancer, uterine cancer, ovarian cancer, testicular cancer, uterine cancer, fallopian tubes Cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, rectal cancer, colon cancer, anal cancer, breast cancer, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer , urethral cancer, penile cancer, prostate cancer, pancreatic cancer, brain cancer, testicular cancer, lymphoma, transitional cell carcinoma, bladder cancer, kidney or ureteral cancer, renal cell carcinoma, renal pelvic cancer, Hodgkin's disease, non-Hodge Gold lymphoma, soft tissue sarcoma, solid tumor of children, lymphocytic lymphoma, central nervous system (CNS) tumor, primary central nervous system lymph
  • Figure 1 is a detection spectrum of the compound of Example 15, the abscissa is the retention time (unit: min); the ordinate is the response value (unit: mV);
  • Figure 2 is the optical isomer 1 detection spectrum, the abscissa is the retention time (unit: min); the ordinate is the response value (unit: mV);
  • Figure 3 is a photodetection spectrum of optical isomer 2, the abscissa is the retention time (unit: min); the ordinate is the response value (unit: mV).
  • C 1-8 alkyl means a straight-chain alkyl group having 1 to 8 carbon atoms and a branched alkyl group, the alkyl group means a saturated aliphatic hydrocarbon group, and C 0-8 means no carbon atom or C.
  • a 1-8 alkyl group preferably a linear alkyl group having 1 to 6 carbon atoms, more preferably a linear alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-Butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1, 1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl , 3-methylpentyl, 4-methylpentyl, 2,3-d
  • Cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and "C 3-8 cycloalkyl” refers to a cycloalkyl group of 3 to 8 carbon atoms, "5-10 membered ring.”
  • Alkyl means a cycloalkyl group comprising from 5 to 10 carbon atoms, for example, a non-limiting example of a monocyclic cycloalkyl group comprising a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclopentenyl group, a cyclohexyl group, Cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc., preferably cyclopropyl, cyclobutyl and cyclohexyl; polycyclic
  • Heterocyclyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer 0, 1, 2 a hetero atom, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • the "5-10 membered heterocyclic group” means a ring group containing 5 to 10 ring atoms
  • the "3-8 membered heterocyclic group” means a ring group containing 3 to 8 ring atoms, preferably a 5-6 membered heterocyclic group. .
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like, preferably morphinyl.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • Aryl means an all-carbon monocyclic or fused polycyclic (ie, a ring that shares a pair of adjacent carbon atoms) groups having a polycyclic ring of a conjugated ⁇ -electron system (ie, having a ring adjacent to a carbon atom) a group
  • C 5-10 aryl means an all-carbon aryl group having 5 to 10 carbons
  • 5-10 membered aryl group means an all-carbon aryl group having 5 to 10 carbons, such as phenyl and Naphthyl.
  • Heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms including nitrogen, oxygen and a hetero atom of S(O) r (where r is an integer 0, 1, 2), 5-
  • a 7-membered heteroaryl group means a heteroaromatic system having 5 to 7 ring atoms
  • a 5-10 membered heteroaryl group means a heteroaromatic system having 5 to 10 ring atoms, such as furyl, thienyl, pyridyl, Pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like.
  • Alkenyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, and a C 2-8 alkenyl group means a straight or branched olefin containing from 2 to 8 carbons base.
  • alkenyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond
  • a C 2-8 alkenyl group means a straight or branched olefin containing from 2 to 8 carbons base.
  • vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like are examples of the alkenyl group.
  • Alkynyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond
  • C2-8 alkynyl refers to a straight or branched alkynyl group containing from 2 to 8 carbons.
  • ethynyl 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.
  • Alkoxy means -O-(alkyl) wherein alkyl is as defined above.
  • the C 1-8 alkoxy group means an alkyloxy group having 1-8 carbons, and the non-limiting examples include a methoxy group, an ethoxy group, a propoxy group, a butoxy group and the like.
  • Halo-substituted C 1-8 alkyl means a hydrogen on the alkyl group optionally substituted with 1-8 carbon alkyl groups substituted by fluorine, chlorine, bromine or iodine atoms, such as difluoromethyl, dichloromethyl Base, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, and the like.
  • the hydrogen on the "halo-substituted C 1-8 alkoxy" alkyl group is optionally a 1-8 carbon alkoxy group substituted with a fluorine, chlorine, bromine or iodine atom.
  • a fluorine chlorine, bromine or iodine atom.
  • Halogen means fluoro, chloro, bromo or iodo.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond such as an olefin.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • Stepoisomerization includes three types of geometric isomerism (cis-trans isomerization), optical isomerism, and conformational isomerism.
  • the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS).
  • NMR chemical shift ( ⁇ ) is given in parts per million (ppm).
  • the NMR was measured using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ) internally labeled as tetramethylsilane (TMS).
  • LC-MS was determined by LC-MS using an Agilent 1200 Infinity Series mass spectrometer.
  • the HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).
  • the thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification for TLC is 0.15mm ⁇ 0.20mm, and the specification for separation and purification of thin layer chromatography is 0.4mm ⁇ 0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.
  • An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the solution in the examples means an aqueous solution unless otherwise specified.
  • the temperature of the reaction is room temperature.
  • the room temperature is an optimum reaction temperature of 20 ° C to 30 ° C.
  • TLC thin layer chromatography
  • LC-MS liquid chromatography-mass spectrometry
  • Column chromatography eluent system includes: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: dichloromethane and ethyl acetate system, D: ethyl acetate and methanol, solvent
  • A dichloromethane and methanol system
  • B n-hexane and ethyl acetate system
  • C dichloromethane and ethyl acetate system
  • D ethyl acetate and methanol
  • solvent The volume ratio is adjusted depending on the polarity of the compound, and may be adjusted by adding a small amount of ammonia water and acetic acid.
  • Step 1 4-amino-N'-hydroxy-1,2,5-oxadiazole-3-carbonoxaxan 1b
  • Propyl dicyanohydrin (20 g, 303 mmol) was dissolved in 350 ml of water, heated at 45 ° C for 5 minutes, sodium nitrite (23 g, 333.3 mmol) was added under ice bath, and 6N HCl (3.4 ml) was added when the temperature was raised to 10 ° C.
  • the temperature was raised to 16 ° C, the temperature was stirred at 16-18 ° C for 1.5 hours, cooled to 13 ° C, 50% aqueous hydroxylamine solution (61.7 g, 909 mmol) was added in one portion, and the temperature was sharply increased to 27 ° C, and stirred at this temperature. After one hour, it was refluxed for another 2 hours, cooled to room temperature and stirred overnight.
  • the compound 4-amino-N'-hydroxy-1,2,5-oxadiazol-3-carboindole (8.4 g, 59 mmol) was dissolved in 100 ml of water and glacial acetic acid (60 ml), and 6N HCl ( 29 ml), heating to complete dissolution, then adding NaCl (10.36 g, 59.5 mmol), and then adding an aqueous solution (14 ml) of sodium nitrite (3.99 g, 5.78 mmol) in an ice bath, and stirring at a temperature of 0 ° C for 1.5 hours.
  • Step 3 4-Amino-N'-hydroxy-N-(2-methoxyethyl)-1,2,5-oxadiazole-3-carbonoxaxanthene 1d
  • Step 4 N'-hydroxy-4-((2-methoxyethyl)amino)-1,2,5-oxadiazole-3-carbonoxaxan 1e
  • Step 5 N-hydroxy-4-((2-methoxyethyl)amino)-1,2,5-oxadiazol-3-carbamimidyl chloride 1f
  • Step 6 N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-4-((2-methoxyethyl)amino)-1,2,5-oxadiazol-3-carb miscellaneous Xanthene 1g
  • Step 7 4-(3-Bromo-4-fluorophenyl)-3-(4-((2-methoxyethyl)amino)-1,2,5-oxadiazol-3-yl)- 1,2,4-Evil Diazol-5(4H)-one 1h
  • Step 8 4-(3-Bromo-4-fluorophenyl)-3-(4-((2-hydroxyethyl)amino)-1,2,5-oxadiazol-3-yl)-1, 2,4-Evil 2 Oxazol-5(4H)-one 1i
  • Step 9 2-((4-(4-(3-Bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)- 1,2,5-Evil 2 Zyrid-3-yl)amino)ethyl methanesulfonate 1j
  • Step 10 3-(4-((2-azidoethyl)amino)-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1 , 2,4-Evil 2 Oxazol-5(4H)-one 1k
  • Step 11 3-(4-((2-Aminoethyl)amino)-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1 , 2,4- evil Diazol-5(4H)-one hydroiodinated 1l
  • Step 1 N 1 -(2-((4-(4-(3-Bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazole-3) -base)-1,2,5-evil Diazol-3-yl)amino)ethyl)oxyaldehyde amide 1m.
  • Step two (Z) -N 1 - ( 2 - ((4- (N- (3- bromo-4-fluorophenyl) -N'- hydroxyamino azomethine group) -1,2,5 evil Diazole -3-yl)amino)ethyl)oxyaldehyde amide 1.
  • N 1 -(2-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-carboyl) in a 100 mL vial Zyridin-3-yl)-1,2,5-oxadiazol-3-yl)amino)ethyl)oxyaldehyde amide (105 mg, 0.23 mmol) dissolved in tetrahydrofuran / methanol (5 mL / 5 mL), sodium hydroxide (46 mg, 1.15 mmol) was dissolved in water (2 mL) and added to the above solution and allowed to react at room temperature for 2 hours. The reaction was completed with EtOAc (3 mL).
  • Step 1 methyl 2-((2-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazole) -3- 1,1,2,5-oxadiazol-3-yl)amino)ethyl)amino)-2-carbonyl acetate 2b.
  • Step 2 (Z)-N 1 -(2-((4-(N-(3-Bromo-4-fluorophenyl)-N'-hydroxycarbamoyl))-1,2,5- Diazole -3-yl)amino)ethyl)-N 2 -methyloxyaldehyde amide 2.
  • Step 1 N 1 -(2-((4-(4-(3-Bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazole-3) -base)-1,2,5- Oxadiazol-3-yl) amino) ethyl) -N 2 - oxo ethyl aldehyde amide 3b.
  • Step 2 (Z)-N 1 -(2-((4-(N-(3-Bromo-4-fluorophenyl)-N'-hydroxycarbamoyl))-1,2,5- Diazole -3-yl)amino)ethyl)-N 2 -ethyloxyaldehydeamide 3.
  • N 1 -(2-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-carboyl) in a 100 mL vial Zyrid-3-yl)-1,2,5-oxadiazol-3-yl)amino)ethyl)-N 2 -ethyloxyaldehyde amide (190 mg, 0.39 mmol) dissolved in tetrahydrofuran / methanol (8 mL / 8 mL)
  • Sodium hydroxide (62.7 mg, 1.57 mmol) was dissolved in water (4 mL) and added to the above solution, and allowed to react at room temperature for 2 hours.
  • Step 1 N 1 -benzyl-N 2 -(2-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2, 4-oxadiazole-3- 1,1,2,5-oxadiazol-3-yl)amino)ethyl)oxyaldehyde amide 4b.
  • Step 2 ((Z)-N 1 -benzyl-N 2 -(2-((4-(N-(3-bromo-4-fluorophenyl)-N'-hydroxycarbamimidyl) 1,1,2,5-oxadiazol-3-yl)amino)ethyl)oxyaldehyde amide 4
  • Step 1 N-(2-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-) Base)-1,2,5-evil Diazol-3-yl)amino)ethyl)-2-morpholino-2-carbonylacetamide 5b.
  • Step 2 (Z)-N-(2-((4-(N-(3-bromo-4-fluorophenyl)-N'-hydroxyaminoimino))-1,2,5-Ethylene Azole 3-yl)amino)ethyl)-2-morpholino-2-carbonylacetamide 5.
  • Step 1 Ethyl 2-((2-(4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazole) -3- 1,1,2,5-oxadiazol-3-yl)amino)ethyl)amino)-2-carbonyl acetate 6b.
  • Step 2 (Z)-2-((2-((4-(N-(3-bromo-4-fluorophenyl)-N'-hydroxycarbamoyl))-1,2,5- Diazole -3-yl)amino)ethyl)amino)-2-carbonylacetic acid 6c.
  • Step 3 2-((2-(4-(4-(3-Bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazole-3) -base)-1,2,5-evil Azoxa-3-yl)amino)ethyl)amino)-2-carbonylacetic acid 6d.
  • Step 4 N 1 -(2-((4-(4-(3-Bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazole-3) -base)-1,2,5- Oxadiazol-3-yl)amino)ethyl)-N 2 -methoxyoxyaldehyde amide 6e.
  • Step 5 (Z)-N 1 -(2-((4-(N-(3-Bromo-4-fluorophenyl)-N'-hydroxycarbamoyl))-1,2,5- Diazole 3-yl)amino)ethyl)-N 2 -methoxyoxyaldehyde amide 6.
  • N 1 -(2-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxo) in a 50 mL vial Zyrid-3-yl)-1,2,5-oxadiazol-3-yl)amino)ethyl)-N 2 -methoxyoxyaldehyde amide (30 mg, 0.06 mmol) dissolved in ethanol (5 mL)
  • Sodium hydroxide 0.3 ml, 0.6 mmol
  • Step 1 methyl 2-((2-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazole) -3- 1,1,2,5-oxadiazol-3-yl)amino)ethyl)amino)-2-carbonyl acetate 7b.
  • Step two (Z) -N 1 - ( 2 - ((4- (N- (3- bromo-4-fluorophenyl) -N'- hydroxyamino azomethine group) -1,2,5 evil Diazole -3-yl)amino)ethyl)-N 2 -cyclopropyl oxy aldehyde amide 7.
  • Step 1 Ethyl 2-((2-(4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazole) -3- -1,2,5-oxadiazol-3-yl)amino)ethyl)amino)-2-carbonyl acetate 8b.
  • Step 2 N 1 -(2-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazole-3) -base)-1,2,5- Oxadiazol-3-yl)amino)ethyl)-N 2 -hydroxyoxyaldehyde amide 8c
  • Step 3 (Z)-N 1 -(2-((4-(N-(3-Bromo-4-fluorophenyl)-N'-hydroxycarbamoyl))-1,2,5- Diazole -3-yl)amino)ethyl)-N 2 -hydroxyoxyaldehyde amide amide 8.
  • Step 1 N 1 -(2-((4-(4-(3-Bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazole-3) -base)-1,2,5-evil Diazol-3-yl)amino)propyl)oxyaldehyde amide 9b.
  • Step 2 (Z)-N 1 -(2-((4-(N-(3-Bromo-4-fluorophenyl)-N'-hydroxycarbamoyl))-1,2,5- Diazole -3-yl)amino)propyl)oxyaldehydeamide 9
  • N 1 -(2-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxo) in a 50 mL vial Zyrid-3-yl)-1,2,5-oxadiazol-3-yl)amino)propyl)oxyaldehyde amide (36 mg, 0.07 mmol) was dissolved in ethanol (5 mL). 0.4 mmol), reacted overnight at room temperature. LC-MS monitored the conversion of the starting material completely.
  • Step 1 4-amino-N'-hydroxy-N-(4-hydroxycyclohexyl)-1,2,5-oxadiazole-3-carbonoxaxanthene 10b
  • Step 2 N'-hydroxy-4-((4-hydroxycyclohexyl)amino)-1,2,5-oxadiazole-3-carbonoxaxanthene 10c
  • Step 4 N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-4-((4-hydroxycyclohexyl)amino)-1,2,5-oxadiazol-3-carbon Xanthene 10e
  • Step 5 4-(3-Bromo-4-fluorophenyl)-3-(4-((4-hydroxycyclohexyl)amino)-1,2,5-oxadiazol-3-yl)-1, 2,4- evil Diazol-5(4H)-one 10f
  • Step 6 4-((4-(4-(3-Bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)- 1,2,5-Evil 2 Zyrid-3-yl)amino)cyclohexyl methanesulfonate 10g
  • Step 7 3-(4-((4-Azidocyclohexyl)amino)-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1 , 2,4- evil Diazol-5(4H)-one 10h
  • Step 8 3-(4-((4-Aminocyclohexyl)amino)-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1, 2,4- evil Diazol-5(4H)-one 10i
  • Step 9 tert-butyl (N-(4-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxole) Diazole-3- 1,1,2,5-oxadiazol-3-yl)amino)cyclohexyl)sulfamoyl)carbamate 10j
  • intermediate solution A was added, stirred for 5 minutes, then triethylamine was added. (0.25 ml, 1.78 mmol), stirred at 0 ° C for 30 minutes. Then, ethyl acetate (50 ml) was added, and brine was evaporated.
  • Step 10 3-(4-((4-(sulfonylamino)cyclohexyl)amino)-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorobenzene Base)-1,2,4-oxadiazole-5(4H)-one 10k
  • reaction mixture was stirred at 0 ° C for 30 min, then concentrated in vacuo and evaporated to dryness crystals crystals -yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one 10k (120 mg, brown viscous).
  • Step 11 (Z)-N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-4-((4-(sulfamoylamino)cyclohexyl)amino)-1,2,5 - Oxadiazole-3-carbon oxonium 10
  • Step 2 4-Amino-N'-hydroxy-N-(3-hydroxycyclobutyl)-1,2,5-oxadiazol-3-carbonoxaxanthene 11d
  • the compound 3-aminocyclobutan-1-ol trifluoroacetate 11b (9 g, 48 mmol) was dissolved in ethyl acetate (25 ml), and then potassium carbonate (13.5 g, , a free 1b solution was obtained.
  • the compound 4-amino-N-hydroxy-1,2,5-oxadiazol-3-carbamimidoyl chloride (6.6 g, 40 mmol) was dissolved in ethyl acetate (25 mL). A solution of free 3-aminocyclobutan-1-ol trifluoroacetate 1b was added.
  • reaction solution was stirred at 0 ° C for 30 min, then triethylamine (16.7 ml, 120 mmol) was slowly added and stirred at 0 ° C for 30 min.
  • the reaction mixture was poured into water, and the organic phase was separated, washed with saturated brine, and evaporated.
  • Step 3 N'-hydroxy-4-((3-hydroxycyclobutyl)amino)-1,2,5-oxadiazole-3-carbonoxaxan 11e
  • Step 4 N-hydroxy-4-((3-hydroxycyclobutyl)amino)-1,2,5-oxadiazol-3-carbamimidoyl chloride 11f
  • Step 5 N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-4-((3-hydroxycyclobutyl)amino)-1,2,5-oxadiazol-3-carbon Xanthene 11g
  • Step 6 4-(3-Bromo-4-fluorophenyl)-3-(4-((3-hydroxycyclobutyl)amino)-1,2,5-oxadiazol-3-yl)-1 , 2,4- evil Diazol-5(4H)-one 11h
  • N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-((3-hydroxycyclobutyl)amino)-1,2,5-oxadiazol-3-carbooxy 11g (3.24g, crude) was dissolved in ethyl acetate (20ml). N,N-carbonyldiimidazole (1.36g, 8.4mmol) was slowly added at 0 ° C, stirred at 0 ° C for 2 hours, slowly rising The mixture was washed with saturated brine and dried over anhydrous sodium sulfate.
  • Step 7 3-((4-(4-(3-Bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)- 1,2,5-Evil 2 Zyrid-3-yl)amino)cyclobutyl methanesulfonate 11i
  • Step 8 3-(4-((3-Azidocyclobutyl)amino)-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)- 1,2,4-Evil Diazol-5(4H)-one 11j
  • Step 9 3-(4-((3-Aminocyclobutyl)amino)-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1 , 2,4- evil Diazol-5(4H)-one 11k
  • Step 10 tert-butyl (N-(3-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxole) Diazole-3- 1,1,2,5-oxadiazol-3-yl)amino)cyclobutyl)sulfamoyl)carbamate 11l
  • the intermediate solution A was added, stirred for 5 minutes, then added to the three Amine (0.20 ml, 1.44 mmol) was stirred at 0 °C for 30 min. Then, ethyl acetate (50 ml) was added, and brine was evaporated.
  • Step 11 3-(4-((3-(Aminosulfonylamino)cyclobutyl)amino)-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4- Fluorobenzene Base)-1,2,4-oxadiazole-5(4H)-one 11m
  • Step 12 (Z)-N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-4-((3-(sulfamoylamino)cyclobutyl)amino)-1,2, 5- Oxadiazole-3-carbon oxonium 11
  • Step 3 N-(((2-(4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazole-) 3-base)-1,2,5- Oxadiazol-3-yl)amino)ethyl)amino)(methyl)(carbonyl)-l6-sulfaninyl)-4-methylbenzenesulfonamide 13e
  • Step 4 (Z)-N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-4-((2-(S-methyl-N-(4-methylbenzenesulfonyl))sulfonate Imidyl Amino)ethyl)amino)-1,2,5-oxadiazole-3-carbonoxaxanthene 13.
  • Step 1 4-(3-Bromo-4-fluorophenyl)-3-(4-((2-(methylthio)ethyl)amino)-1,2,5-oxadiazol-3-yl )-1,2,4- Oxadiazole-5(4H)-one 14b.
  • Step 2 4-(3-Bromo-4-fluorophenyl)-3-(4-((2-(methylsulfinyl)ethyl)amino)-1,2,5-oxadiazole-3 - Base)-1,2,4-oxadiazole-5(4H)-one 14c.
  • Step 3 4-(3-Bromo-4-fluorophenyl)-3-(4-((2-(S-methylsulfonimido)ethyl)amino)-1,2,5-oxa 2 Azole -3-yl)-1,2,4-oxadiazole-5(4H)-one 14d.
  • Step 4 N-((2-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazole-3) -base)-1,2,5- Oxadiazol-3-yl)amino)ethyl)(methyl)(carbonyl)-6-sulfaninyl)methanesulfonamide 14e.
  • Step 5 (Z)-N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-4-((2-(S-methyl-N-(methylsulfonyl))) B Base) amino)-1,2,5-oxadiazole-3-carbonoxaxanthene 14.
  • Step 1 N-((2-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazole-3) -base)-1,2,5- Oxadiazol-3-yl)amino)ethyl)(methyl)(carbonyl)-l6-sulfaninyl)cyclopropanesulfonamide 15b.
  • Step 2 (Z)-N-(3-Bromo-4-fluorophenyl)-4-((2-(N-(cyclopropylsulfonyl)-S-methylsulfinimidyl)ethyl) Amino)-N'-hydroxy-1,2,5-oxadiazole-3-carbonoxaxanthene 15.
  • Step 1 4-(3-Bromo-4-fluorophenyl)-3-(4-((2-(N,S-dimethylsulfonimido)ethyl)amino)-1,2,5 -evil Diazol-3-yl)-1,2,4-oxadiazole-5(4H)-one 16b
  • Step 2 (Z)-N-(3-Bromo-4-fluorophenyl)-4-((2-(N,S-dimethylsulfinamido)ethyl)amino)-N'-hydroxyl Base-1,2,5-oxadiazole-3-carbon oxonium 16
  • Step 1 4-(3-Bromo-4-fluorophenyl)-3-(4-((2-(N-methylethyl)sulfonyl)ethyl)amino)-1,2,5- evil Diazol-3-yl)-1,2,4-oxadiazol-5(4H)-one 17b
  • Step 2 (Z)-N-(3-Bromo-4-fluorophenyl)-4-((2-(N,S-dimethylsulfinamido)ethyl)amino)-N'-hydroxyl Base-1,2,5-oxadiazole-3-carbon oxonium 17
  • the preparation method is as follows:
  • the invention adopts a preparation device (K-Prep LAB100S type supercritical fluid chromatography preparation instrument of YMC Corporation of Japan) and a chiral column (AD-H 4.6*250, particle size 5um) of the game, and 2.3457g of the compound of Example 15 (detection spectrum) Figure 1) Performing chiral isomer separation, collecting 8.56 min and 9.69 min, respectively.
  • the sample solution was evaporated to remove the solvent to obtain 10.79 liters of optical isomer 10.79744 (ee% value: 99.322%, detection spectrum see Fig. 2) and 9.69 min optical isomer 20.9552 g (ee%) Value: 98.676%, the detection spectrum is shown in Figure 3).
  • the chiral purity detection analysis method is as follows:
  • optical rotation is determined as follows:
  • Optical rotation tester Perkin Elmer (PE) model Perkin Elmer 341, the results are as follows: blank:
  • IDO Human indoleamine 2,3-dioxygenase
  • the idoleamine 2,3-dioxygenase (IDO) enzymatic reaction was carried out in a 96-well plate with a reaction volume of 20 ⁇ L.
  • the reaction conditions were: 40 nM IDO enzyme, 0.2 mM L-tryptophan, 50 mM KPB. (pH 6.5) buffer, 20 mM L-ascorbate, 10 ⁇ M methylene blue, 0.2 mg/mL catalase, solvent ⁇ 1% different concentrations of dimethyl sulfoxide.
  • test compound stock solution was prepared as 10 mM with dimethyl sulfoxide.
  • the experiment was diluted with dimethyl sulfoxide to the highest concentration of the test, then subjected to a 1:3 gradient dilution, generally diluted to 8 to 10 concentration points, each A multi-well was set at the concentration point, and each test contained one reference compound.
  • Analysis of 490nm absorbance microplate reader reads the raw data, calculation points at different concentrations of the test compound to inhibit the activity of IDO, using GraphPad Prism software fitting the percent inhibition data analysis nonlinear compound obtained half inhibitory concentration 50 value IC.
  • Interferon gamma induces expression of IDO in Hela cells, a model used to test the inhibitory activity of compounds on indoleamine 2,3-dioxygenase (IDO).
  • the culture medium of Hela cells ATCC
  • the test compound storage solution was prepared as 10 mM with dimethyl sulfoxide.
  • the experiment was diluted with dimethyl sulfoxide to the highest concentration in the experiment.
  • the experiment was carried out with a medium serial dilution of 3 times, usually diluted to 8 to 10 concentration points. Multiple holes are provided for each concentration point.
  • the final concentration of DMSO was 0.5% and each experiment contained an internal reference compound.
  • the procedure was as follows: 20,000 HeLa cells (ATCC) were added to each well in a 96-well culture plate overnight, and interferon gamma (final concentration 50 ng/mL) and different concentrations of the test compound and internal reference were administered 24 hours later. The compound is added to the cultured cells. After 24:00, 140 ⁇ L of supernatant/well was transferred to a new 96-well plate, 10 ⁇ L of 6.1 N trichloroacetic acid was added to each well, and incubation was carried out at 50 ° C for 30 minutes to hydrolyze N-formyl-kynurenine into dogs. Urinine.
  • reaction mixture was centrifuged (centrifugation at 2500 rpm for 10 minutes) to remove the precipitate, and 100 ⁇ L of the supernatant was transferred to another new 96-well plate, and 100 ⁇ L of 2% (w/v) p-(dimethyl) was added to each well.
  • Amino)benzaldehyde (p-DMBA)/glacial acetic acid solution was read at 490 nm absorbance using a BioTek Synergy H1 plate reader (Molecular Devices).
  • test results demonstrate that the compounds of the examples of the present invention have good enzymatic and cytological IDO inhibitory activities.
  • the pharmacokinetic test of the test compound was carried out using SD rats (Shanghai Shrek).
  • ⁇ Mode of administration single oral administration.
  • Formulation formulation 3% dimethylacetamide and 20% hydroxypropyl- ⁇ -cyclodextrin.
  • ⁇ Sampling point 15 minutes, 0.5, 1, 2, 4, 6, 8, 24 hours before administration and 15 minutes after administration.
  • Mass Spectrometry Mass Spectrometer Setup Conditions: Cationic Electrospray Ionization (ESI) mode.
  • test results prove that the compound of the present invention is obviously superior to the reference compound (INCB-24360), and has better pharmacokinetics, and the maximum pharmacokinetic parameters (Cmax) and drug exposure (AUC) are relatively high.
  • the reference compound (INCB-24360) has been greatly improved.
  • the present invention employs a PAN02 tumor-bearing mouse model to test the anti-tumor effect of the compounds of the examples.
  • the PAN02 tumor-bearing mouse model is: the mouse pancreatic cancer cell line PAN02 was purchased from Guangzhou Jini Biotech Co., Ltd., and the culture solution used was DMEM containing 10% fetal calf serum.
  • the mouse strain for tumor-bearing is C57/BL6, purchased from Shanghai Slack Laboratory Animal Co., Ltd.
  • PAN02 cells in the logarithmic growth phase were collected, mixed with the growth factor-reducing BD Matrigel Matrigel to 50 million/ml, and each mouse was subcutaneously implanted with 100 ⁇ l of 5 million cells. Animals were randomized when the tumor grew to approximately 100 cubic millimeters, with 8 animals per group, starting dosing (D0).
  • Mode of administration intragastric administration, 2 times a day.
  • Dosage 50 mg/10 mL/kg.
  • Formulation formulation 3% dimethylacetamide and 20% hydroxypropyl- ⁇ -cyclodextrin.
  • T/C 100 x ⁇ T / ⁇ C.
  • Tumor inhibition rate (%) 1 - T / C (%).
  • the compound inhibition rate of the compound of Example 15 in the PAN02 tumor-bearing mice was 74.8% at a dose of 50 mg/kg, which was significantly higher than the reference positive compound INCB 24360 (the tumor inhibition rate was 39.7%). ).
  • the present invention further employs a Colon26 tumor-bearing mouse model to test the anti-tumor effect of the example compounds.
  • the Colon26 tumor-bearing mouse model is: Mouse colon cancer cell line Colon26 was purchased from Guangzhou Ginuo Biotechnology Co., Ltd., and the culture solution used was RPMI1640 containing 10% fetal bovine serum for tumor-bearing mice. The strain is Balb/c and was purchased from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd. At the time of planting, Colon26 cells in the logarithmic growth phase were collected and mixed to 10 million/ml, and each mouse was subcutaneously planted with 100 ⁇ l of one million cells. Animals were randomized when the tumor grew to approximately 100 cubic millimeters, with 8 animals per group, starting dosing (D0).
  • Mode of administration intragastric administration, 2 times a day.
  • Dosage 50 mg/10 mL/kg.
  • Formulation formulation 3% dimethylacetamide and 20% hydroxypropyl- ⁇ -cyclodextrin.
  • T/C 100 x ⁇ T / ⁇ C.
  • Tumor inhibition rate (%) 1 - T / C (%).
  • the compound inhibition rate of the compound of Example 15 in Colon26 tumor-bearing mice was 94.6% at a dose of 25 mg/kg, which was significantly higher than the reference positive compound INCB 24360 (the tumor inhibition rate was 78.4%). ).
  • Example 15 The antitumor effect of Example 15 and its optical isomers 18-1 and 18-2 on the Colon26 tumor-bearing mouse model is shown in the following table:

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Abstract

La présente invention concerne un inhibiteur de l'indoléamine 2,3-dioxygénase présentant la structure de la formule (I), un procédé pour sa préparation et une application. L'inhibiteur d'IDO est un dérivé de N'-hydroxyl-N-phénylformamidine, présente une activité inhibitrice élevée sur l'IDO, inhibe efficacement l'activité de l'IDO et peut également être utilisé pour inhiber l'immunosuppression d'un patient. L'inhibiteur peut être largement utilisé pour traiter ou prévenir des cancers ou des tumeurs, des infections virales, une dépression, des maladies neurodégénératives, un traumatisme, des cataractes liées à l'âge, un rejet de greffe d'organe ou des maladies auto-immunes et dispose d'un potentiel de mise au point d'une nouvelle génération d'immunosuppresseurs.
PCT/CN2017/079585 2016-04-20 2017-04-06 Inhibiteur de l'indoléamine 2,3-dioxygénase, procédé pour sa préparation et application Ceased WO2017181849A1 (fr)

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CA3019450A CA3019450A1 (fr) 2016-04-20 2017-04-06 Inhibiteur de l'indoleamine 2,3-dioxygenase, procede pour sa preparation et application
CN201780010654.4A CN108966651A (zh) 2016-04-20 2017-04-06 吲哚胺2,3-双加氧酶抑制剂及其制备方法与应用
US16/093,821 US20190040025A1 (en) 2016-04-20 2017-04-06 Indoleamine 2,3-dioxygenase inhibitor, preparation method therefor, and application
JP2018552745A JP2019513743A (ja) 2016-04-20 2017-04-06 インドールアミン ２，３−ジオキシゲナーゼ阻害剤、その製造方法及び応用

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WO2019057104A1 (fr) * 2017-09-20 2019-03-28 上海翰森生物医药科技有限公司 Sel d'un inhibiteur de dioxygénase, son procédé de préparation et son utilisation
JP2020512399A (ja) * 2017-04-07 2020-04-23 シャンハイ ジョーユー ファーマテック エルティーディー． Ｉｄｏを抑制する化合物、その調製方法及びその使用
EP4052705A1 (fr) 2021-03-05 2022-09-07 Universität Basel Vizerektorat Forschung Compositions pour le traitement des maladies ou des pathologies associées à l'ebv
WO2022184930A2 (fr) 2021-03-05 2022-09-09 Universität Basel Compositions pour le traitement de maladies ou d'états associés à ebv

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WO2007075598A2 (fr) * 2005-12-20 2007-07-05 Incyte Corporation N-hydroxyamidinoheterocycles en tant que modulateurs d'indoleamine 2,3-dioxygenase
CN102164902A (zh) * 2008-07-08 2011-08-24 因塞特公司 作为吲哚胺2,3-双加氧酶的抑制剂的1,2,5-二唑
WO2014066834A1 (fr) * 2012-10-26 2014-05-01 The University Of Chicago Combinaison synergique d'inhibiteurs immunologiques pour le traitement du cancer
WO2015070007A1 (fr) * 2013-11-08 2015-05-14 Incyte Corporation Procédé pour la synthèse d'un inhibiteur de l'indoleamine 2,3-dioxygénase
WO2015119944A1 (fr) * 2014-02-04 2015-08-13 Incyte Corporation Combinaison d'un antagoniste de pd-1 et d'un inhibiteur de ido1 pour traiter le cancer
WO2016041489A1 (fr) * 2014-09-15 2016-03-24 中国科学院上海有机化学研究所 Inhibiteur de l'indoleamine-2,3-dioxygénase et son procédé de préparation
WO2016155545A1 (fr) * 2015-03-31 2016-10-06 江苏恒瑞医药股份有限公司 Dérivé de 1,2,5-oxadiazole contenant un groupe sulfamyle, son procédé de préparation et son utilisation dans des produits pharmaceutiques

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2020512399A (ja) * 2017-04-07 2020-04-23 シャンハイ ジョーユー ファーマテック エルティーディー． Ｉｄｏを抑制する化合物、その調製方法及びその使用
WO2019057104A1 (fr) * 2017-09-20 2019-03-28 上海翰森生物医药科技有限公司 Sel d'un inhibiteur de dioxygénase, son procédé de préparation et son utilisation
EP4052705A1 (fr) 2021-03-05 2022-09-07 Universität Basel Vizerektorat Forschung Compositions pour le traitement des maladies ou des pathologies associées à l'ebv
WO2022184930A2 (fr) 2021-03-05 2022-09-09 Universität Basel Compositions pour le traitement de maladies ou d'états associés à ebv

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