WO2023202652A1 - Pharmaceutical combination and use thereof - Google Patents

Pharmaceutical combination and use thereof Download PDF

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Publication number
WO2023202652A1
WO2023202652A1 PCT/CN2023/089400 CN2023089400W WO2023202652A1 WO 2023202652 A1 WO2023202652 A1 WO 2023202652A1 CN 2023089400 W CN2023089400 W CN 2023089400W WO 2023202652 A1 WO2023202652 A1 WO 2023202652A1
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alkyl
cancer
aryl
deuterium
cycloalkyl
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PCT/CN2023/089400
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French (fr)
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WO2023202652A9 (en
Inventor
Jing XIONG
Yanping Wang
Wei LONG
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Jacobio Pharmaceuticals Co., Ltd.
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Publication of WO2023202652A1 publication Critical patent/WO2023202652A1/en
Publication of WO2023202652A9 publication Critical patent/WO2023202652A9/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

  • the present invention relates a pharmaceutical combination comprising a glutamine antagonist, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, and an isotopic substitution thereof, and an additional therapeutic agent; pharmaceutical compositions thereof; commercial packages thereof; and uses of such pharmaceutical combinations and pharmaceutical compositions for the treatment of cancer and cancer occurrence-related diseases.
  • WO 2017/023774 discloses isopropyl (S) -2- ( (S) -2-acetamido-3- (lH-indol-3-yl) propanamido) -6-diazo-5-oxohexanoate and other prodrugs of DON.
  • DON and DON prodrugs can be used to treat a variety of diseases, disorders, and conditions including, but not limited to, cancer, cognitive deficits, and metabolic reprogramming disorders. See WO 2017/023793, WO 2017/023791, WO 2017/023787, and WO2020/150639.
  • the combination of the present invention may show improved efficacy compared to either single agent alone in the treatment of diseases, e.g. cancer.
  • the present invention provides for a pharmaceutical combination comprising:
  • an additional therapeutic agent selected from a immune checkpoint inhibitor, an activator of a costimulatory molecule, a chemotherapeutic agent, a radiotherapeutic agent, a immunotherapeutic agent, a targeted anti-cancer therapy, an anticancer agent, an oncolytic drug, a cytotoxic agent, or any of the therapeutic agents disclosed herein.
  • the additional therapeutic agent can be chosen from: a PD-1 inhibitor, a PD-L1 inhibitor, a LAG-3 inhibitor, a CTL4 inhibitor, a TIM-3 inhibitor, a CD47 inhibitor, a CDK4/6 inhibitor, an Aurora A kinase inhibitor, chemotherapeutic drug (Taxol, Cisplatin, Carboplatin, 5-Fu, topotecan, cyclophosphamide, and so on) , radiotherapy, HDAC inhibitor, a SHP2 inhibtor, a KRASG12C inhibitor, a BET inhibitor, a EGFR inhibitor, a VEGFR inhibitor, a GITR agonist, a SERD, a Plk3 inhibitor, a CXCR2 inhibitor, a CSF-1/1R binding agent, a c-MET inhibitor, a TGF- ⁇ inhibitor, an A2aR antagonist, an IDO inhibitor, a STING inhibitor, a Galectin inhibitor, a MEK
  • the pharmaceutical combination comprises:
  • an immune checkpoint inhibitor e.g., a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor, a LAG3 inhibitor, a TIM3 inhibitor, or a CD47 inhibitor.
  • the pharmaceutical combination comprises: (i) a glutamine antagonist, or a pharmaceutically acceptable salt thereof; and (ii) a PD-1 inhibitor or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical combination comprises: (i) a glutamine antagonist, or a pharmaceutically acceptable salt thereof; and (ii) a PD-L1 inhibitor or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical combination comprises: (i) a glutamine antagonist, or a pharmaceutically acceptable salt thereof; and (ii) a CTLA-4 inhibitor or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical combination comprises: (i) a glutamine antagonist, or a pharmaceutically acceptable salt thereof; and (ii) a LAG3 inhibitor or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical combination comprises: (i) a glutamine antagonist, or a pharmaceutically acceptable salt thereof; and (ii) a TIM3 inhibitor or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical combination comprises: (i) a glutamine antagonist, or a pharmaceutically acceptable salt thereof; and (ii) a CD47 inhibitor or a pharmaceutically acceptable salt thereof.
  • a glutamine antagonist or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof are in the same formulation.
  • a glutamine antagonist or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof, are in the separate formulation.
  • the pharmaceutical combination of the invention is for simultaneous or sequential (in any order) administration.
  • the present disclosure is directed to a method of treating (e.g., inhibiting, reducing, ameliorating, or preventing) a disorder or disease, e.g., a hyperproliferative condition or disorder (e.g., a cancer) , cognitive deficits, and metabolic reprogramming disorders etc. in a subject.
  • the method includes administering to the subject a therapeutically effective amount of pharmaceutical combination comprising a glutamine antagonist and an additional therapeutic agent disclosed herein.
  • the additional therapeutic agent is chosen from: a PD-1/PD-L1 inhibitor, a LAG-3 inhibitor, a CTL4 inhibitor, a TIM-3 inhibitor, a CD47 inhibitor, a CDK4/6 inhibitor, an Aurora A kinase inhibitor, chemotherapeutic drug (Taxol, Cisplatin, Carboplatin, 5-Fu, topotecan, cyclophosphamide, and so on) , radiotherapy, HDAC inhibitor, a SHP2 inhibtor, a KRASG12C inhibitor, a BET inhibitor, a EGFR inhibitor, a VEGFR inhibitor, a GITR agonist, a SERD, a Plk3 inhibitor, a CXCR2 inhibitor, a CSF-1/1R binding agent, a c-MET inhibitor, a TGF- ⁇ inhibitor, an A2aR antagonist, an IDO inhibitor, a STING inhibitor, a Galectin inhibitor, a MEK inhibitor, an IL
  • the present disclosure is directed to a method of treating (e.g., inhibiting, reducing, ameliorating, or preventing) a disorder or disease, e.g., a hyperproliferative condition or disorder (e.g., a cancer) , in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a glutamine antagonist or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor e.g., a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor, a LAG3 inhibitor, a TIM3 inhibitor, or a cd47 inhibitor, or a pharmaceutically acceptable salt thereof.
  • an immune checkpoint inhibitor e.g., a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor, a LAG3 inhibitor, a TIM3 inhibitor, or a cd47 inhibitor, or a pharmaceutically acceptable salt thereof.
  • the invention provides the pharmaceutical combination of the invention defined herein for use in the treating (e.g., inhibiting, reducing, ameliorating, or preventing) a disorder, e.g., a hyperproliferative condition or disorder (e.g., a cancer) .
  • a disorder e.g., a hyperproliferative condition or disorder (e.g., a cancer) .
  • the invention provides for the pharmaceutical combination of the invention for use in the manufacture of a medicament for treating (e.g., inhibiting, reducing, ameliorating, or preventing) a disorder, e.g., a hyperproliferative condition or disorder (e.g., a cancer) .
  • a disorder e.g., a hyperproliferative condition or disorder (e.g., a cancer)
  • composition comprising the combination of the invention.
  • the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients as detailed herein.
  • the cancer is a solid tumor. In another embodiment, the cancer is a hematological cancer. In another embodiment, the cancer is any one or more of the cancers of Table 1.
  • Exemplary hematological cancers include, but are not limited to, the cancers listed in Table 2.
  • the hematological cancer is acute lymphocytic leukemia, chronic lymphocytic leukemia (including B-cell chronic lymphocytic leukemia) , or acute myeloid leukemia.
  • the cancer is any one or more of the cancers of a breast cancer (e.g., a triple negative breast cancer) , a colorectal cancer (e.g., a microsatellite stable colorectal cancer (MSS CRC) ) , acute lymphoblastic leukemia, acute myelogenous leukemia, advanced soft tissue sarcoma, brain cancer, metastatic or aggressive breast cancer, bronchogenic carcinoma, choriocarcinoma, chronic myelocytic leukemia, colon carcinoma, Ewing's sarcoma, gastrointestinal tract carcinoma, glioma, glioblastoma multiforme, hepatocellular carcinoma, Hodgkin's disease, intracranial ependymoblastoma, large bowel cancer, leukemia, liver cancer, lung cancer, Lewis lung carcinoma, lymphoma, lymphangioma, lymphangiosarcoma, malignant fibrous histiocytoma, a mammary tumor,
  • the cancer is selected from the group consisting of squamous cell carcinoma of the head and neck, adenocarcinoma squamous cell carcinoma of the esophagus, adenocarcinoma of the stomach, adenocarcinoma of the colon, hepatocellular carcinoma, cholangiocarcinoma of the biliary system, adenocarcinoma of gall bladder, adenocarcinoma of the pancreas, ductal carcinoma in situ of the breast, adenocarcinoma of the breast, adenocarcinoma of the lungs, squamous cell carcinoma of the lungs, transitional cell carcinoma of the bladder, squamous cell carcinoma of the bladder, squamous cell carcinoma of the cervix, adenocarcinoma of the cervix, endometrial carcinoma, penile squamous cell carcinoma, and squamous cell carcinoma of the skin.
  • a precancerous tumor is selected from the group consisting of leukoplakia of the head and neck, Barrett's esophagus, metaplasia of the stomach, adenoma of the colon, chronic hepatitis, bile duct hyperplasia, pancreatic intraepithelial neoplasia, atypical adenomatous hyperplasia of the lungs, dysplasia of the bladder, cervical initraepithelial neoplasia, penile intraepithelial neoplasia, and actinic keratosis of the skin.
  • the cancer is selected from the group consisting of hepatocellular carcinoma, glioblastoma, lung cancer, breast cancer, head and neck cancer, prostate cancer, melanoma, and colorectal cancer.
  • the cancer is selected from the group consisting of colorectal cancer, breast cancer, lymphoma, melanoma, kidney cancer, and lung cancer.
  • the cancer has become resistant to conventional cancer treatments.
  • conventional cancer treatments refers to any cancer drugs, biologies, or radiotherapy, or combination of cancer drugs and/or biologies and/or radiotherapy that have been tested and/or approved for therapeutic use in humans by the U.S. Food and Drug Administration, European Medicines Agency, or similar regulatory agency.
  • the glutamine antagonist comprises a compound disclosed in International Application No. PCT/CN2021/123674 hereby incorporated by reference in its entirety.
  • the glutamine antagonist a compound having the structure of formula I, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, and an isotopic substitution thereof:
  • Z is OR 1 or SR 1 ;
  • R 1 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, -C 3-8 cycloalkyl, -C 0-6 alkylene-C 3-8 heterocyclyl, -C 0-6 alkylene-NH-C 0-6 alkylene C 6-10 aryl, -C 0-6 alkylene-NH-C 0-6 alkylene-5-12 membered heteroaryl, -C 0-6 alkylene-C 6-10 aryl and -C 0-6 alkylene-5-12 membered heteroaryl; and each of which can be optional substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-8 cycloalkyl, -NH 2 , -NH (C 1-6 al
  • W is oxygen, CO or a bond
  • n is selected from 1, 2, 3, 4, 5, 6, 7 or 8;
  • p and q are each independently selected from 0, 1 or 2 provided that the sum of p and q is 2;
  • R X1 and R X3 together with the carbon atom and the oxygen atom to which they are attached respectively form a 5-12 membered heterocyclyl, wherein said 5-12 membered heterocyclyl can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-8 cycloalkyl, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , carboxyl; and each of the heterocyclyl independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S;
  • R 5 and R 5 ’ are each independently selected from the group consisting of hydrogen, deuterium, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-8 cycloalkyl, C 5-12 aryl, 5-12 membered heteroaryl, 5-12 membered heterocyclyl, and wherein said -C 1-6 alkyl, said -C 1-6 alkoxy, said -C 3-8 cycloalkyl, said C 5-12 aryl, said 5-12 membered heteroaryl, said 5-12 membered heterocyclyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-8 cycloalkyl, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , carboxyl
  • each of R 6 is independently selected from the group consisting of hydrogen, deuterium, -C 1-6 alkyl, -C 3-8 cycloalkyl, 5-12 membered heterocyclyl ring, -C 1-6 alkenyl, and -C 3-8 cycloalkenyl, and wherein said -C 1-6 alkyl, said -C 3-8 cycloalkyl, said 5-12 membered heterocyclyl ring, said -C 1-6 alkenyl, and said -C 3-8 cycloalkenyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-8 cycloalkyl, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , carboxyl;
  • each of R 7 is independent selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, C 3-8 cycloalkyl, 5-12 membered heterocyclyl ring, C 1-6 alkenyl, C 3-8 cycloalkenyl, C 5-12 aryl, and 5-12 membered heteroaryl, and wherein said C 1-6 alkyl, said C 3-8 cycloalkyl, said 5-12 membered heterocyclyl ring, said C 1-6 alkenyl, said C 3-8 cycloalkenyl, said C 5-12 aryl, and said 5-12 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-8 cycloalkyl, -NH 2 , -NH (C 1-6 alkyl)
  • R 8 and R 9 are each independently selected from the group consisting of C 1-6 alkyl, C 3-8 cycloalkyl, monosaccharide, acylated monosaccharide, C 5-12 aryl, and 5-12 membered heteroaryl, and wherein said C 1-6 alkyl, said C 3-8 cycloalkyl, said monosaccharide, said acylated monosaccharide, said C 5-12 aryl, and said 5-12 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-8 cycloalkyl, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , carboxyl;
  • G is C 5-12 aryl, or 5-12 membered heteroaryl, wherein C 5-12 aryl, and 5-12 membered heteroaryl can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-8 cycloalkyl, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , carboxyl;
  • R 2 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, and C 1-6 alkoxy, and wherein said C 1-6 alkyl, and said C 1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-8 cycloalkyl, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , carboxyl;
  • R 3 and R 3 ’ are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, and C 1-6 alkoxy, and wherein said C 1-6 alkyl, and said C 1-6 alkoxy can be optional substituted with one or more substituents, which are independently from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-8 cycloalkyl, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , carboxyl;
  • Y is a bond, oxygen, or - (CR Y1 R Y2 ) n -;
  • n is selected from 1, 2, 3, 4, 5, 6, 7 or 8;
  • R Y1 and R Y2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, and C 1-6 alkoxy, and wherein said C 1-6 alkyl, and said C 1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-8 cycloalkyl, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , carboxyl;
  • R 4 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, and C 1-6 alkoxy, and wherein said C 1-6 alkyl, and said C 1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-8 cycloalkyl, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , carboxyl;
  • R 10 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, and C 1-6 alkoxy, and wherein said C 1-6 alkyl, and said C 1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-8 cycloalkyl, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , carboxyl.
  • R 1 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, C 1-3 alkoxy, -C 3-8 cycloalkyl, -C 0-3 alkylene-C 3-8 heterocyclyl, -C 0-3 alkylene-NH-C 0-3 alkylene C 6-10 aryl, -C 0-3 alkylene-NH-C 0-3 alkylene-5-12membered heteroaryl, -C 0-3 alkylene-C 6-10 aryl and -C 0-3 alkylene-5-12 membered heteroaryl; and each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN,
  • R 1 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, C 1-3 alkoxy, -C 3-8 cycloalkyl, -C 0-3 alkylene-C 3-8 heterocyclyl, -C 0-3 alkylene-NH-C 0-3 alkylene C 6-10 aryl, -C 0-3 alkylene-NH-C 0-3 alkylene-5-12 membered heteroaryl, -C 0-3 alkylene-C 6-10 aryl and -C 0-3 alkylene-5-12 membered heteroaryl; each of the heteroaryl and heterocyclyl contains 1 or 2 heteroatoms selected from N or O; and wherein each of which can be optional substituted with one or more substituents, which are independently selected from
  • R 1 is selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, and each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 alkyl, -C 1-3 alkoxy, -C 3-6 cycloalkyl, -NH 2 , -NH (C 1-6 alkyl) , -NH-C 3-6 cycloalkyl, -N (C 1-3 alkyl) 2 , carboxyl, -CO-C 1-3 al
  • R 1 is selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, and each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C 3 cycloalkyl, -C 4 cycloalkyl, -C 5 cycloalkyl, -C 6 cycloalkyl, -NH 2 , -NH
  • R 1 is seleted from hydrogen, deuterium, isopropyl, methyl, ethyl, -tert-butyl, -CF 3 , -CH 2 CF 3 , -CH(CH 3 ) CF 3 , -CH (CH 3 ) CH 2 CF 3 , - (CH 2 ) 2 CF 3 , - (CH 2 ) 2 CF 3 , - (CH 2 ) 2 -CH (CH 3 ) 2 , -C (CH 3 ) 2 CF 3 , -C (CH 3 ) 2 CH 2 CF 3 , -CN, -CH 2 CN, -CH (CH 3 ) CN, -CH 2 CH 2 CN, -CH (CH 3 ) CH 2 CN, -C (CH 3 ) 2 CN, -C
  • W is oxygen, CO or a bond
  • n is selected from 1, 2 or 3;
  • p and q are each independently selected from 0, 1 or 2 provided that the sum of p and q is 2;
  • R X1 and R X3 together with the carbon atom and the oxygen atom to which they are attached respectively form a 5-10 membered heterocyclyl, wherein said 5-10 membered heterocyclyl can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-8 cycloalkyl, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , carboxyl; and each of the heterocyclyl independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S;
  • R 5 and R 5 ’ are each independently selected from the group consisting of hydrogen, deuterium, -C 1-3 alkyl, -C 1-3 alkoxy, -C 3-6 cycloalkyl, C 5-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, and wherein said -C 1-3 alkyl, -C 1-3 alkoxy, said -C 3-6 cycloalkyl, said C 5-10 aryl, said 5-10 membered heteroaryl, said 5-10 membered heterocyclyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-8 cycloalkyl, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , carboxyl;
  • each of R 6 is independently selected from the group consisting of hydrogen, deuterium, -C 1-3 alkyl, -C 3-6 cycloalkyl, 5-10 membered heterocyclyl ring, -C 1-3 alkenyl, and -C 3-6 cycloalkenyl, and wherein said -C 1-3 alkyl, said -C 3-6 cycloalkyl, said 5-10 membered heterocyclyl ring, said -C 1-3 alkenyl, and said -C 3-6 cycloalkenyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-8 cycloalkyl, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , carboxyl;or R
  • each of R 7 is independent selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, C 3-6 cycloalkyl, 5-10 membered heterocyclyl ring, C 1-3 alkenyl, C 3-6 cycloalkenyl, C 5-10 aryl, and 5-10 membered heteroaryl, and wherein said C 1-3 alkyl, said C 3-6 cycloalkyl, said 5-10 membered heterocyclyl ring, said C 1-3 alkenyl, said C 3-6 cycloalkenyl, said C 5-10 aryl, and said 5-10 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-8 cycloalkyl, -NH 2 , -NH (C 1-6 alkyl)
  • R 8 and R 9 are each independently selected from the group consisting of C 1-3 alkyl, C 3-6 cycloalkyl, monosaccharide, acylated monosaccharide, C 5-10 aryl, and 5-10 membered heteroaryl, and wherein said C 1-3 alkyl, said C 3-6 cycloalkyl, said monosaccharide, said acylated monosaccharide, said C 5-10 aryl, and said 5-10 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-8 cycloalkyl, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , carboxyl; or
  • G is C 5-10 aryl, or 5-10 membered heteroaryl, wherein C 5-10 aryl, and 5-10 membered heteroaryl can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-8 cycloalkyl, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , carboxyl.
  • substituents which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-8 cycloalkyl, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , carboxyl.
  • W is oxygen or a bond
  • n is selected from 1, 2 or 3;
  • p and q are each independently selected from 0, 1 or 2 provided that the sum of p and q is 2;
  • R X1 and R X2 together with the carbon atom to which they are attached form C 4-6 carbocyclic ring, C 4-6 membered heterocyclyl, and each of the heterocyclyl independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S; each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -NH 2 , -CN, -OH, -NO 2 , oxo, carboxyl, C 1-3 alkoxy, C 1-3 alkyl;
  • R X1 and R X3 together with the carbon atom and the oxygen atom to which they are attached respectively form a 5-10 membered heterocyclyl, wherein said 5-10 membered heterocyclyl can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 alkyl, -C 1-3 alkoxy, -C 3-6 cycloalkyl, -NH 2 , -NH (C 1-3 alkyl) , -N (C 1-3 alkyl) 2 , carboxyl; and each of the heterocyclyl independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S;
  • R 5 and R 5 ’ are each independently selected from the group consisting of hydrogen, deuterium, -C 1-3 alkyl, -C 1-3 alkoxy, -C 3-6 cycloalkyl, C 5-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, and wherein said -C 1-3 alkyl, -C 1-3 alkoxy, said -C 3-6 cycloalkyl, said C 5-10 aryl, said 5-10 membered heteroaryl, said 5-10 membered heterocyclyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 alkyl, -C 1-3 alkoxy, -C 3-6 cycloalkyl, -NH 2 , -NH (C 1-3 alkyl) , -N (C 1-3 alkyl) 2 ,
  • each of R 6 is independently selected from the group consisting of hydrogen, deuterium, -C 1-3 alkyl, -C 3-6 cycloalkyl, 5-10 membered heterocyclyl ring, -C 1-3 alkenyl, and -C 3-6 cycloalkenyl, and wherein said -C 1-3 alkyl, said -C 3-6 cycloalkyl, said 5-10 membered heterocyclyl ring, said -C 1-3 alkenyl, and said -C 3-6 cycloalkenyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 alkyl, -C 1-3 alkoxy, -C 3-6 cycloalkyl, -NH 2 , -NH (C 1-3 alkyl) , -N (C 1-3 alkyl) 2 , carboxy
  • each of R 7 is independent selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, C 3-6 cycloalkyl, 5-10 membered heterocyclyl ring, C 1-3 alkenyl, C 3-6 cycloalkenyl, C 5-10 aryl, and 5-10 membered heteroaryl, and wherein said C 1-3 alkyl, said C 3-6 cycloalkyl, said 5-10 membered heterocyclyl ring, said C 1-3 alkenyl, said C 3-6 cycloalkenyl, said C 5-10 aryl, and said 5-10 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 alkyl, -C 1-3 alkoxy, -C 3-6 cycloalkyl, -NH 2 , -NH (C 1-3
  • R 8 and R 9 are each independently selected from the group consisting of C 1-3 alkyl, C 3-6 cycloalkyl, monosaccharide, acylated monosaccharide, C 5-10 aryl, and 5-10 membered heteroaryl, and wherein said C 1-3 alkyl, said C 3-6 cycloalkyl, said monosaccharide, said acylated monosaccharide, said C 5-10 aryl, and said 5-10 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 alkyl, -C 1-3 alkoxy, -C 3-6 cycloalkyl, -NH 2 , -NH (C 1-3 alkyl) , -N (C 1-3 alkyl) 2 , carboxyl; or
  • G is C 5-10 aryl, or 5-10 membered heteroaryl, wherein C 5-10 aryl, and 5-10 membered heteroaryl can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 alkyl, -C 1-3 alkoxy, -C 3-6 cycloalkyl, -NH 2 , -NH (C 1-3 alkyl) , -N (C 1-3 alkyl) 2 , carboxyl.
  • substituents which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 alkyl, -C 1-3 alkoxy, -C 3-6 cycloalkyl, -NH 2 , -NH (C 1-3 alkyl) , -N (C 1-3 alkyl) 2
  • W is oxygen or a bond
  • n is selected from 1, 2 or 3;
  • p and q are each independently selected from 0, 1 or 2 provided that the sum of p and q is 2;
  • R X1 and R X3 together with the carbon atom and the oxygen atom to which they are attached respectively form 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, 7 membered heterocyclyl, 8 membered heterocyclyl, 9 membered heterocyclyl, 10 membered heterocyclyl, wherein said 4 membered heterocyclyl, said 5 membered heterocyclyl, said 6 membered heterocyclyl, said 7 membered heterocyclyl, said 8 membered heterocyclyl, said 9 membered heterocyclyl, said 10 membered heterocyclyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 alkyl, -C 1-3 alkoxy, -C 3-6 cycloalkyl, -NH 2 , -NH(C 1-3 al
  • R 5 and R 5 ’ are each independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C 3 cycloalkyl, -C 4 cycloalkyl, -C 5 cycloalkyl, -C 6 cycloalkyl, C 5 aryl, C 6 aryl, C 7 aryl, C 8 aryl, C 9 aryl, C 10 aryl, 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl, 10 membered heteroaryl, 5 membered heterocyclyl, 6 membered heterocyclyl, 7 membered heterocyclyl, 8 membered heterocyclyl, 9 membered heteroaryl, 10 membered heteroaryl, 5 membered heterocyclyl, 6 membered heterocycl
  • each of R 6 is independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, -C 3 cycloalkyl, -C 4 cycloalkyl, -C 5 cycloalkyl, -C 6 cycloalkyl, 5 membered heterocyclyl ring, 6 membered heterocyclyl ring, 7 membered heterocyclyl ring, 8 membered heterocyclyl ring, 9 membered heterocyclyl ring, 10 membered heterocyclyl ring, vinyl, allyl, -C 3 cycloalkenyl, -C 4 cycloalkenyl, -C 5 cycloalkenyl, -C 6 cycloalkenyl, and wherein said methyl, said ethyl, said propyl, said isopropyl, said -C 3 cycloalkyl, said -C 4 cycloalkyl, said
  • each of R 7 is independent selected from the group consisting of hydrogen, deuterium, halogen, methyl, ethyl, propyl, isopropyl, C 3 cycloalkyl, C 4 cycloalkyl, C 5 cycloalkyl, C 6 cycloalkyl, 5-10 membered heterocyclyl ring, 5 membered heterocyclyl ring, 6 membered heterocyclyl ring, 7 membered heterocyclyl ring, 8 membered heterocyclyl ring, 9 membered heterocyclyl ring, 10 membered heterocyclyl ring, vinyl, allyl, C 3 cycloalkenyl, C 4 cycloalkenyl, C 5 cycloalkenyl, C 6 cycloalkenyl, C 5 aryl, C 6 aryl, C 7 aryl, C 8 aryl, C 9 aryl, C 10 aryl, 5 membered heteroaryl, 6 membered heteroaryl,
  • R 8 and R 9 are each independently selected from the group consisting of C 1-3 alkyl, C 3-6 cycloalkyl, monosaccharide, acylated monosaccharide, C 5-10 aryl, and 5-10 membered heteroaryl, and wherein said C 1-3 alkyl, said C 3-6 cycloalkyl, said monosaccharide, said acylated monosaccharide, said C 5-10 aryl, and said 5-10 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 alkyl, -C 1-3 alkoxy, -C 3-6 cycloalkyl, -NH 2 , -NH (C 1-3 alkyl) , -N (C 1-3 alkyl) 2 , or carboxyl; or
  • G is C 5 aryl, C 6 aryl, C 7 aryl, C 8 aryl, C 9 aryl, C 10 aryl, 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl, or 10 membered heteroaryl, wherein said C 5 aryl, said C 6 aryl, said C 7 aryl, said C 8 aryl, said C 9 aryl, said C 10 aryl, said 5 membered heteroaryl, said 6 membered heteroaryl, said 7 membered heteroaryl, said 8 membered heteroaryl, said 9 membered heteroaryl, or said 10 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 alkyl, -C 1-3 alkoxy, -
  • W is oxygen or a bond
  • n is selected from 1, 2 or 3;
  • p and q are each independently selected from 0, 1 or 2 provided that the sum of p and q is 2;
  • R X1 and R X2 together with the carbon atom to which they are attached form 3-membered carbocyclic ring, 4-membered carbocyclic ring, 5-membered carbocyclic ring, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, and each of the heterocyclyl independently optionally contains 1 or 2 heteroatoms selected from N or O; each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, -F, -Cl, -Br, -I, -NH 2 , -CN, -OH, -NO 2 , oxo, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy;
  • R X1 and R X3 together with the carbon atom and the oxygen atom to which they are attached respectively form 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, 7 membered heterocyclyl, 8 membered heterocyclyl, 9 membered heterocyclyl, 10 membered heterocyclyl, wherein said 4 membered heterocyclyl, said 5 membered heterocyclyl, said 6 membered heterocyclyl, said 7 membered heterocyclyl, said 8 membered heterocyclyl, said 9 membered heterocyclyl, said 10 membered heterocyclyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C 3 cycloal
  • R 5 and R 5 ’ are each independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C 3 cycloalkyl, -C 4 cycloalkyl, -C 5 cycloalkyl, -C 6 cycloalkyl, C 5 aryl, C 6 aryl, C 7 aryl, C 8 aryl, C 9 aryl, C 10 aryl, 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl, 10 membered heteroaryl, 5 membered heterocyclyl, 6 membered heterocyclyl, 7 membered heterocyclyl, 8 membered heterocyclyl, 9 membered heteroaryl, 10 membered heteroaryl, 5 membered heterocyclyl, 6 membered heterocycl
  • each of R 6 is independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, -C 3 cycloalkyl, -C 4 cycloalkyl, -C 5 cycloalkyl, -C 6 cycloalkyl, 5 membered heterocyclyl ring, 6 membered heterocyclyl ring, 7 membered heterocyclyl ring, 8 membered heterocyclyl ring, 9 membered heterocyclyl ring, 10 membered heterocyclyl ring, vinyl, allyl, -C 3 cycloalkenyl, -C 4 cycloalkenyl, -C 5 cycloalkenyl, -C 6 cycloalkenyl, and wherein said methyl, said ethyl, said propyl, said isopropyl, said -C 3 cycloalkyl, said -C 4 cycloalkyl, said
  • each of R 7 is independent selected from the group consisting of hydrogen, deuterium, halogen, methyl, ethyl, propyl, isopropyl, C 3 cycloalkyl, C 4 cycloalkyl, C 5 cycloalkyl, C 6 cycloalkyl, 5-10 membered heterocyclyl ring, 5 membered heterocyclyl ring, 6 membered heterocyclyl ring, 7 membered heterocyclyl ring, 8 membered heterocyclyl ring, 9 membered heterocyclyl ring, 10 membered heterocyclyl ring, vinyl, allyl, C 3 cycloalkenyl, C 4 cycloalkenyl, C 5 cycloalkenyl, C 6 cycloalkenyl, C 5 aryl, C 6 aryl, C 7 aryl, C 8 aryl, C 9 aryl, C 10 aryl, 5 membered heteroaryl, 6 membered heteroaryl,
  • R 8 and R 9 are each independently selected from the group consisting of C 1-3 alkyl, C 3-6 cycloalkyl, monosaccharide, acylated monosaccharide, C 5-10 aryl, and 5-10 membered heteroaryl, and wherein said C 1-3 alkyl, said C 3-6 cycloalkyl, said monosaccharide, said acylated monosaccharide, said C 5-10 aryl, and said 5-10 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C 3 cycloalkyl, -C 4 cycloalkyl, -C 5 cycloalkyl, -C 6 cycloalkyl, -
  • G is C 5 aryl, C 6 aryl, C 7 aryl, C 8 aryl, C 9 aryl, C 10 aryl, 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl, or 10 membered heteroaryl, wherein said C 5 aryl, said C 6 aryl, said C 7 aryl, said C 8 aryl, said C 9 aryl, said C 10 aryl, said 5 membered heteroaryl, said 6 membered heteroaryl, said 7 membered heteroaryl, said 8 membered heteroaryl, said 9 membered heteroaryl, or said 10 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, me
  • W is a bond
  • n 1 or 2;
  • R X1 and R X2 together with the carbon atom to which they are attached form 3-membered carbocyclic ring, 4-membered carbocyclic ring, 5-membered carbocyclic ring, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, and each of the heterocyclyl independently optionally contains 1 or 2 heteroatoms selected from N or O; each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy; or
  • R X1 and R X3 together with the carbon atom and the oxygen atom to which they are attached respectively form 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, 7 membered heterocyclyl, 8 membered heterocyclyl, 9 membered heterocyclyl, 10 membered heterocyclyl, wherein said 4 membered heterocyclyl, said 5 membered heterocyclyl, said 6 membered heterocyclyl, said 7 membered heterocyclyl, said 8 membered heterocyclyl, said 9 membered heterocyclyl, said 10 membered heterocyclyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C 3 cycloal
  • W is a bond
  • n 1 or 2;
  • R 2 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-8 cycloalkyl, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , and carboxyl.
  • R 2 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 alkyl, -C 1-3 alkoxy, -C 3-6 cycloalkyl, -NH 2 , -NH (C 1-3 alkyl) , -N (C 1-3 alkyl) 2 , and carboxyl.
  • R 2 is selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, and said isopropoxy, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 alkyl, -C 1-3 alkoxy, -C 3-6 cycloalkyl, -NH 2 , -NH (C 1-3 al
  • R 2 is selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, and said isopropoxy, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C 3 cycloal
  • R 3 and R 3 ’ are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-8 cycloalkyl, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , and carboxyl.
  • R 3 and R 3 ’ are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 alkyl, -C 1-3 alkoxy, -C 3-6 cycloalkyl, -NH 2 , -NH (C 1-3 alkyl) , -N (C 1-3 alkyl) 2 , and carboxyl.
  • R 3 and R 3 ’ are each independently selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, and said isopropoxy, can be optional substituted with one or more substituents, which are independently from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 alkyl, -C 1-3 alkoxy, -C 3-6 cycloalkyl, -NH 2 , -
  • R 3 and R 3 ’ are each independently selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, and said isopropoxy, can be optional substituted with one or more substituents, which are independently from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -
  • Y is a bond, or - (CR Y1 R Y2 ) n -;
  • n is selected from 1, 2, or 3;
  • R Y1 and R Y2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-8 cycloalkyl, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , and carboxyl.
  • Y is a bond, or - (CR Y1 R Y2 ) n -;
  • n is selected from 1, 2, or 3;
  • R Y1 and R Y2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 alkyl, -C 1-3 alkoxy, -C 3-6 cycloalkyl, -NH 2 , -NH (C 1-3 alkyl) , -N (C 1-3 alkyl) 2, and carboxyl.
  • substituents which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 alkyl, -C 1-3 alkoxy, -C 3-6 cycloalkyl, -NH 2 ,
  • Y is a bond, or - (CR Y1 R Y2 ) n -;
  • n is selected from 1, 2, or 3;
  • R Y1 and R Y2 are each independently selected from the group consisting of F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, and said isopropoxy, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 alkyl, -C 1-3 alkoxy, -C 3-6 cycloalkyl, -NH 2 , -NH (C 1-3 alkyl) , -N (C 1-3 alkyl) 2, and carboxyl.
  • substituents which are independently selected from the group consisting of deuterium, F, Cl, Br, I,
  • Y is a bond, or - (CR Y1 R Y2 ) n -;
  • n is selected from 1, 2, or 3;
  • R Y1 and R Y2 are each independently selected from the group consisting of F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, and said isopropoxy, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C 3 cycloalkyl, -C 4 cycloalkyl, -C 5 cycloalkyl, -C 6 cycloalkyl, -NH 2 , -NHCH 3 ,
  • R 4 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-8 cycloalkyl, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , and carboxyl.
  • R 4 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 alkyl, -C 1-3 alkoxy, -C 3-6 cycloalkyl, -NH 2 , -NH (C 1-3 alkyl) , -N (C 1-3 alkyl) 2 , and carboxyl.
  • R 4 is selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, and said isopropoxy, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 alkyl, -C 1-3 alkoxy, -C 3-6 cycloalkyl, -NH 2 , -NH (C 1-3 al
  • R 4 is selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, and said isopropoxy, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C 3 cycloal
  • R 10 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-8 cycloalkyl, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , and carboxyl.
  • R 10 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 alkyl, -C 1-3 alkoxy, -C 3-6 cycloalkyl, -NH 2 , -NH (C 1-3 alkyl) , -N (C 1-3 alkyl) 2 , and carboxyl.
  • R 10 is selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, and said isopropoxy, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 alkyl, -C 1-3 alkoxy, -C 3-6 cycloalkyl, -NH 2 , -NH (C 1-3 al
  • R 10 is selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, and said isopropoxy, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C 3 cycloal
  • the glutamine antagonist is a compound of Formula I-C, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, and an isotopic substitution thereof:
  • the glutamine antagonist is a compound of Formula II, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, and an isotopic substitution thereof:
  • the glutamine antagonist is a compound of Formula III, or the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof:
  • R 1 , R X1 , R X2 , R X3 , and m are the same as defined herein.
  • the glutamine antagonist is a compound of Formula IV, or the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof :
  • the glutamine antagonist is a compound of Formula V, or the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof:
  • the glutamine antagonist is a compound of Formula VI, or the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof:
  • the glutamine antagonist is a compound of Formula VII, or the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof:
  • the glutamine antagonist is a compound of Formula VIII or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an isotopic substitution thereof:
  • R 1 , R X1 , R X2 , R X3 , and m are the same as defined herein
  • the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention wherein one or more hydrogen is optionally substitued with deuterium.
  • the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention wherein one or more hydrogen in R 1 or R X3 is substitued with deuterium, preferably, all hydrogens on one or more methyl groups, methylene groups, or methane groups are substituted with deuterium.
  • R 1 is selected from the group consisting of hydrogen, deuterium, hydrogen, deuterium, C 1-3 alkyl, C 1-3 alkoxy, and each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 alkyl, -C 1-3 alkoxy;
  • R X1 and R X2 are each independently selected from the group consisting of hydrogen, deuterium, CN, OH,
  • R X3 is independently selected from the group consisting of hydrogen, deuterium, C 1-3 alkyl, C 1-3 alkoxy, each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 alkyl, -C 1-3 alkoxy, -C 3-6 cycloalkyl, -NH 2 , -NH (C 1-3 alkyl) , -N (C 1-3 alkyl) 2 , carboxy, -S-C 1-3 alkyl.
  • R 1 is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy; and each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy;
  • R X1 and R X2 are each independently selected from the group consisting of hydrogen, deuterium, CN, CF 3 ,
  • oxo carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy;
  • R X3 is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, tert-butyl, each of which can be substituted with deuterium.
  • R 1 is seleted from hydrogen, deuterium, isopropyl, methyl, ethyl, -tert-butyl, isopentyl, -CD 3 , -CH 2 CD 3 , -CD 2 CD 3 , -CD (CD 3 ) 2 , -CH (CD 3 ) 2 ,
  • R X1 and R X2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, CN,
  • R X3 is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, tert-butyl, -CD 3 , -CH 2 CD 3 , -CD 2 CD 3 .
  • R 1 is selected from -CD 3 , -CH 2 CD 3 , -CD 2 CD 3 , -CD (CD 3 ) 2 , -CH(CD 3 ) 2
  • the deuterated R X3 is selected from -CD 3 , -CH 2 CD 3 , -CD 2 CD 3 , -CD 2 CD 3
  • the glutamine antagonist is a compound selected from the compounds in the following table (table 3) , or the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof:
  • the glutamine antagobist is selected from a compound in Table 3, or a pharmaceutically acceptable salt thereof.
  • the glutamine antagonist is selected from compound 1, compound 2, compound 3, compound 4, compound 5, or compound 6, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, and an isotopic substitution thereof.
  • the glutamine antagonist is compound 1, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, and an isotopic substitution thereof.
  • the glutamine antagonist is compound 2, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, and an isotopic substitution thereof.
  • the glutamine antagonist is compound 3, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, and an isotopic substitution thereof.
  • the glutamine antagonist is compound 4, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, and an isotopic substitution thereof.
  • the glutamine antagonist is compound 5, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, and an isotopic substitution thereof.
  • the glutamine antagonist is compound 6, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, and an isotopic substitution thereof.
  • Immune checkpoint inhibitors are therapies that blockade immune system inhibitor checkpoints.
  • Immune checkpoints can be stimulatory or inhibitory. Blockade of inhibitory immune checkpoint activates immune system function and can be used for cancer immunotherapy. Pardoll, Nature Reviews. Cancer 72: 252-64 (2012) . Tumor cells turn off activated T cells when they attach to specific T-cell receptors. Immune checkpoint inhibitors prevent tumor cells from attaching to T cells, which results in T cells remaining activated. In effect, the coordinated action by cellular and soluble components combats pathogens and injuries by cancers.
  • the modulation of immune system pathways may involve changing the expression or the functional activity of at least one component of the pathway to then modulate the response by the immune system.
  • immune checkpoint inhibitors include PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, LAG3 inhibitors, TIM3 inhibitors, cd47 inhibitors, and B7-H1 inhibitors.
  • the immune checkpoint inhibitor is selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor, a LAG3 inhibitor, a TIM3 inhibitor, and a cd47 inhibitor.
  • the immune checkpoint inhibitor is a programmed cell death (PD-1) inhibitor.
  • PD-1 is a T-cell coinhibitory receptor that plays a pivotal role in the ability of tumor cells to evade the host's immune system. Blockage of interactions between PD-1 and PD-L1, a ligand of PD-1, enhances immune function and mediates antitumor activity.
  • PD-1 inhibitors include antibodies that specifically bind to PD-1.
  • Particular anti-PD-1 antibodies include, but are not limited to nivolumab, pembrolizumab, STI-A1014, and pidilzumab.
  • the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, pidilizumab, STI-A1110, PDR001, MEDI-0680, Balstilimab (AGEN2034) , Tislelizumab (BGB-A317) , AB122, TSR-042, PF-06801591, cemiplimab, SYM021, JNJ-63723283, HLX10, LZM009, and MGA012.
  • the immune checkpoint inhibitor is a PD-L1 (also known as B7-H1 or CD274) inhibitor.
  • PD-L1 inhibitors include antibodies that specifically bind to PD-L1.
  • Particular anti-PD-Ll antibodies include, but are not limited to, avelumab, atezolizumab, durvalumab, STI-A1014 and BMS-936559.
  • the immune checkpoint inhibitor is a CTLA-4 inhibitor.
  • CTLA-4 also known as cytotoxic T-lymphocyte antigen 4
  • CTLA-4 is a protein receptor that downregulates the immune system.
  • CTLA-4 is characterized as a "brake” that binds costimulatory molecules on antigen-presenting cells, which prevents interaction with CD28 on T cells and also generates an overtly inhibitory signal that constrains T cell activation.
  • CTLA-4 inhibitors include antibodies that specifically bind to CTLA-4.
  • Particular anti-CTLA-4 antibodies include, but are not limited to, ipilimumab and tremelimumab.
  • the immune checkpoint inhibitor is a LAG3 inhibitor.
  • LAG3, Lymphocyte Activation Gene 3 is a negative co-simulatory receptor that modulates T cell homeostatis, proliferation, and activation.
  • LAG3 has been reported to participate in regulatory T cells (Tregs) suppressive function. A large proportion of LAG3 molecules are retained in the cell close to the microtubule-organizing center, and only induced following antigen specific T cell activation.
  • Tregs regulatory T cells
  • Examples of LAG3 inhibitors include antibodies that specifically bind to LAG3.
  • Particular anti-LAG3 antibodies include, but are not limited to, GSK2831781.
  • the immune checkpoint inhibitor is a TIM3 inhibitor.
  • TIM3, T-cell immunoglobulin and mucin domain 3 is an immune checkpoint receptor that functions to limit the duration and magnitude of T H 1 and T C 1 T-cell responses.
  • the TIM3 pathway is considered a target for anticancer immunotherapy due to its expression on dysfunctional CD8 + T cells and Tregs, which are two reported immune cell populations that constitute immunosuppression in tumor tissue.
  • Anderson, Cancer Immunology Research 2: 393-98 (2014) .
  • Examples of TIM3 inhibitors include antibodies that specifically bind to TIM3.
  • the immune checkpoint inhibitor is a cd47 inhibitor. See Unanue, E.R., PNAS 110: 10886-87 (2013) .
  • an Aurora A kinase inhibitor is selected from VX-689, VIC-1911, LY3295668, or a pharmaceutically acceptable salt thereof.
  • a SHP2 inhibitor selecte from compounds described in WO2015/107493, WO2015/107494, WO2015/107495, WO2016/203406, WO2016/203404, WO2016/203405, WO2017/216708, WO2018/013597, WO2018/136264, WO2018/13265, WO2019/051084, WO2019/075265, WO2019/118909, WO2019/199792, WO2017/211303, WO2018/172984, WO2017/156397, WO2018/057884, WO2018/081091, WO2019/067843, WO2019/165073, WO2019/183367, WO2017210134, WO2019213318, WO2020033828, WO2019051469, WO2019158019, WO2019182960, WO2021061515, WO2020022323, WO2019167000, WO2021033153, WO2020061101, WO2020061103, WO20
  • the SHP2 inhibitor comprises or consists of RMC-4630, RMC-4550, RLY-1971, BBP-398, ERAS-601, RG001 , GH-21 , SH3809 , ET0038 , ICP-189 , BT-102 , PF-07284892 , SNG-201 , (3S, 4S) -8- (6-amino-5- ( (2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (TN0155) , or a pharmaceutically acceptable salt thereof; 6- (4-amino-4-methylpiperidin-l-yl) -3 - (2, 3 -dichlorophenyl) pyrazin -2-amine (SHP099) or a pharmaceutically acceptable salt thereof, and any one of pharmaceutical combination thereof.
  • a “KRASG12C inhibitor” is a compound selected from the compounds detailed in WO2013/155223, WO2014/143659, WO2014/152588, WO2014/160200, WO2015/054572, WO2016/044772, WO2016/049524, WO2016164675, WO2016168540, W02017/058805, WO2017015562, WO2017058728, WO2017058768, WO2017058792, W02017058805, W02017058807, W02017058902, WO2017058915, WO2017087528, W02017100546, WO2017/201161, WO2018/064510, WO2018/068017, WO2018/119183, WO2018/217651, W02018/140512, W02018/140513, W02018/140514, WO2018/140598, WO2018/140599, W02018/140600, WO2018/143315,
  • the KRASG12C inhibitor is selected from AMG 510, MRTX849, RMC-6291, GH-35 , LY-3537982 , BEBT-607 , BPI-421286, D-1553, YL-15293, JDQ-443, 1 - (4- (6-chloro-8-fluoro-7- (3-hydroxy-5 -vinylphenyl) quinazolin-4-yl) piperazin-1 -yl) prop-2-en-l -one-methane (1/2) ; (S) -l- (4- (6-chloro-8-fluoro-7- (2-fluoro-6-hydroxyphenyl) quinazolin-4-yl) piperazin-l-yl) prop-2-en-l-one ; 2- ( (S) -l-acryloyl-4- (2- ( ( (S) -l-methylpyrrolidin-2 -yl) methoxy) -7- (naphthal
  • antibody is meant to include intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments, so long as they exhibit the desired biological activity.
  • antibody is meant to include soluble receptors that do not possess the Fc portion of the antibody.
  • the antibodies are humanized monoclonal antibodies and fragments thereof made by means of recombinant genetic engineering.
  • Another class of immune checkpoint inhibitors include polypeptides that bind to and block PD-1 receptors on T-cells without triggering inhibitor signal transduction.
  • Such peptides include B7-DC polypeptides, B7-H1 polypeptides, B7-1 polypeptides and B7-2 polypeptides, and soluble fragments thereof, as disclosed in U.S. Pat. 8,114,845.
  • immune checkpoint inhibitors include compounds with peptide moieties that inhibit PD-1 signaling. Examples of such compounds are disclosed in U.S. Pat. 8,907,053 and have the structure:
  • the compound comprises at least 5 amino acids useful as therapeutic agents capable of inhibiting the PD-1 signaling pathway.
  • IDO indoleamine 2, 3 dioxygenase
  • the IDO enzyme inhibits immune responses by depleting amino acids that are necessary for anabolic functions in T cells or through the synthesis of particular natural ligands for cytosolic receptors that are able to alter lymphocyte functions.
  • Particular IDO blocking agents include, but are not limited to levo-l-methyl typtophan (L-1MT) and 1 -methyl-tryptophan (1MT) .
  • the immune checkpoint inhibitor is nivolumab, pembrolizumab, pidilizumab, STI-A1110, avelumab, atezolizumab, durvalumab, STI-A1014, ipilimumab, tremelimumab, GSK2831781, BMS-936559 or MED14736.
  • compositions or commercial package comprising the pharmaceutical combination of the invention, and at least one pharmaceutically acceptable carrier.
  • the present application provides a use of the pharmaceutical combination defined herein and/or the pharmaceutical composition or the commercial package of the present invention for the manufacture of a medicament.
  • the medicament prepared can be used for the treatment or prevention of cancer or cancer metastasis.
  • the cancer is selected from a breast cancer (e.g., a triple negative breast cancer) , a colorectal cancer (e.g., a microsatellite stable colorectal cancer (MSS CRC) ) , acute lymphoblastic leukemia, acute myelogenous leukemia, advanced soft tissue sarcoma, brain cancer, metastatic or aggressive breast cancer, bronchogenic carcinoma, choriocarcinoma, chronic myelocytic leukemia, colon carcinoma, Ewing's sarcoma, gastrointestinal tract carcinoma, glioma, glioblastoma multiforme, hepatocellular carcinoma, Hodgkin's disease, intracranial ependymoblastoma, large bowel cancer, leukemia, liver cancer, lung cancer, Lewis lung carcinoma, lymphoma, lymphangioma, lymphangiosarcoma, malignant fibrous histiocytoma, a mammary tumor, melanom
  • a breast cancer
  • the cancer is selected from hepatocellular carcinoma, glioblastoma, lung cancer, breast cancer, head and neck cancer, prostate cancer, melanoma, lymphoma, kidney cancer, and colorectal cancer.
  • the present application provides a use of the pharmaceutical combination of defined herein or the pharmaceutical composition or the commercial package of the present invention, wherein a medicament prepared can be used for the treatment or prevention of cancer or cancer metastasis.
  • the cancer is selected from a breast cancer (e.g., a triple negative breast cancer) , a colorectal cancer (e.g., a microsatellite stable colorectal cancer (MSS CRC) ) , acute lymphoblastic leukemia, acute myelogenous leukemia, advanced soft tissue sarcoma, brain cancer, metastatic or aggressive breast cancer, bronchogenic carcinoma, choriocarcinoma, chronic myelocytic leukemia, colon carcinoma, Ewing's sarcoma, gastrointestinal tract carcinoma, glioma, glioblastoma multiforme, hepatocellular carcinoma, Hodgkin's disease, intracranial ependymoblastoma, large bowel cancer, leukemia, liver cancer, lung cancer, Lewis lung carcinoma, lymphoma, lymphangioma, lymphangiosarcoma, malignant fibrous histiocytoma, a mammary tumor, melanoma,
  • the cancer is selected from hepatocellular carcinoma, glioblastoma, lung cancer, breast cancer, head and neck cancer, prostate cancer, melanoma, lymphoma, kidney cancer, and colorectal cancer.
  • the pharmaceutical combination of defined herein or the pharmaceutical composition or the commercial package of the present invention for use in the treatment of cancer or the prevention of cancer metastasis.
  • the cancer is selected from a breast cancer (e.g., a triple negative breast cancer) , a colorectal cancer (e.g., a microsatellite stable colorectal cancer (MSS CRC) ) , acute lymphoblastic leukemia, acute myelogenous leukemia, advanced soft tissue sarcoma, brain cancer, metastatic or aggressive breast cancer, bronchogenic carcinoma, choriocarcinoma, chronic myelocytic leukemia, colon carcinoma, Ewing's sarcoma, gastrointestinal tract carcinoma, glioma, glioblastoma multiforme, hepatocellular carcinoma, Hodgkin's disease, intracranial ependymoblastoma, large bowel cancer, leukemia, liver cancer, lung cancer, Lewis lung carcinoma, lymphoma, lymphangioma, lymphangiosarcoma, malignant fibrous histiocytoma, a mammary tumor, melanoma,
  • the cancer is selected from hepatocellular carcinoma, glioblastoma, lung cancer, breast cancer, head and neck cancer, prostate cancer, melanoma, lymphoma, kidney cancer, and colorectal cancer.
  • the present invention relates to a method of treating cancer is selected from a breast cancer (e.g., a triple negative breast cancer) , a colorectal cancer (e.g., a microsatellite stable colorectal cancer (MSS CRC) ) , acute lymphoblastic leukemia, acute myelogenous leukemia, advanced soft tissue sarcoma, brain cancer, metastatic or aggressive breast cancer, bronchogenic carcinoma, choriocarcinoma, chronic myelocytic leukemia, colon carcinoma, Ewing's sarcoma, gastrointestinal tract carcinoma, glioma, glioblastoma multiforme, hepatocellular carcinoma, Hodgkin's disease, intracranial ependymoblastoma, large bowel cancer, leukemia, liver cancer, lung cancer, Lewis lung carcinoma, lymphoma, lymphangioma, lymphangiosarcoma, malignant fibrous histiocytoma, a mammary tumor,
  • the glutamine antagonist is administered to the patient according to an intermittent dosing schedule. In some embodiments, the glutamine antagonist is subcutaneously administered to the patient according to an intermittent dosing schedule. In some embodiments, the glutamine antagonist is intravenously administered to the patient according to an intermittent dosing schedule.
  • the glutamine antagonist is administered prior to the immune checkpoint inhibitor, e.g., 0.5, 1, 2, 3, 4, 5, 10, 12, or 18 hours, 1, 2, 3, 4, 5, or 6 days, or 1, 2, 3, or 4 weeks prior to the administration of the immune checkpoint inhibitor.
  • the glutamine antagonist is administered after the immune checkpoint inhibitor, e.g., 0.5, 1, 2, 3, 4, 5, 10, 12, or 18 hours, 1, 2, 3, 4, 5, or 6 days, or 1, 2, 3, or 4 weeks after the administration of the immune checkpoint inhibitor.
  • the glutamine antagonist, and the immune checkpoint inhibitor are administered concurrently but on different schedules, e.g, the glutamine antagonist is administered daily while the immune checkpoint inhibitor is administered once a week, once every two weeks, once every three weeks, or once every four weeks. In other embodiments, the glutamine antagonist is administered once a day while the immune checkpoint inhibitor is administered once a week, once every two weeks, once every three weeks, or once every four weeks.
  • the therapeutic methods provided herein comprise administering a glutamine antagonist to a cancer patient in an amount which is effective to achieve its intended purpose. While individual needs vary, determination of optimal ranges of effective amounts of each component is within the skill of the art.
  • the glutamine antagonist is administered in an amount from about 0.05 mg/kg to about 500 mg/kg, about 0.05 mg/kg to about 100 mg/kg, about 0.05 mg/kg to about 50 mg/kg, or about 0.05 mg/kg to about 10 mg/kg.
  • the dosage of a composition can be at any dosage including, but not limited to, about 0.05 mg/week to about 25 mg/week. Particular doses include 0.05, 1, 2, 5, 10, 20, 50, and 100 mg/kg once weekly. In one embodiment, the glutamine antagonist is administered once a week.
  • dosages are exemplary, but there can be individual instances in which higher or lower dosages are merited, and such are within the scope of this disclosure.
  • the physician determines the actual dosing regimen that is most suitable for an individual patient, which can vary with the age, weight, and response of the particular patient. In one embodiment, about 0.1 mg/kg to about 2 mg/kg of DON is administered to the subject.
  • the unit oral dose of the glutamine antagonist may comprise from about 0.01 to about 1000 mg, e.g., about 0.01 to about 100 mg of the glutamine antagonist.
  • the unit oral dose of the glutamine antagonist is 0.05 mg, 1 mg, 3 mg, 5 mg, 7 mg, 9 mg, 10 mg 12 mg, 14 mg, 15 mg, 17 mg, 20 mg, 22 mg, 25 mg, 27 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg.
  • the unit dose may be administered one or more times daily, e.g., as one or more tablets or capsules.
  • the unit does may also be administered by IV or subcutaneously to the subject. In practice, the physician determines the actual dosing regimen that is most suitable for an individual patient, which can vary with the age, weight, and response of the particular patient.
  • the glutamine antagonist in addition to administering the glutamine antagonist as a raw chemical, it may be administered as part of a pharmaceutical preparation or composition.
  • the pharmaceutical preparation or composition can include one or more pharmaceutically acceptable carriers, excipients, and/or auxiliaries.
  • the one or more carriers, excipients, and auxiliaries facilitate processing of the glutamine antagonist into a preparation or composition which can be used pharmaceutically.
  • the preparations particularly those preparations which can be administered orally, subcutaneously, intravenously, or topically, and which can be used for one type of administration, such as tablets, dragees, slow release lozenges and capsules, mouth rinses and mouth washes, gels, liquid suspensions, hair rinses, hair gels, and shampoos, and also preparations which can be administered rectally, such as suppositories, as well as suitable solutions for administration by intravenous infusion, subcutaneous injection, topically or orally, contain from about 0.01 to 99 percent, in one embodiment from about 0.25 to 75 percent of active compound (s) , together with the one or more carriers, excipients, and/or auxiliaries.
  • compositions of provided herein may be administered to any subject which may experience the beneficial effects of the glutamine antagonist.
  • mammals e.g., humans, although the methods and compositions provided herein are not intended to be so limited.
  • Other subjects include veterinary animals (cows, sheep, pigs, horses, dogs, cats and the like) .
  • the subject is a human cancer patient.
  • compositions provided herein are manufactured by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes.
  • pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as saccharides, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone.
  • fillers such as saccharides, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose,
  • disintegrating agents may be added such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
  • Auxiliaries can be suitable flow-regulating agents and lubricants. Suitable auxiliaries include, for example, silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol.
  • Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juices.
  • concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
  • suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate, are used.
  • Dye stuffs or pigments may be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
  • Other pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol.
  • the push-fit capsules can contain the active compounds in the form of granules which may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds are in one embodiment dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin.
  • stabilizers may be added.
  • Possible pharmaceutical preparations which can be used rectally include, for example, suppositories, which consist of a combination of one or more of the active compounds with a suppository base.
  • Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffin hydrocarbons.
  • gelatin rectal capsules which consist of a combination of the active compounds with a base.
  • Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.
  • Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts and alkaline solutions.
  • suspensions of the active compounds as appropriate oily injection suspensions may be administered.
  • Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension including, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran.
  • the suspension may also contain stabilizers.
  • solvates of the glutamine antagonist typically do not significantly alter the physiological activity or toxicity of a compound, and as such may function as pharmacological equivalents.
  • solvate as used herein is a combination, physical association and/or solvation of the glutamine antagonist with a solvent molecule such as, e.g ., a disolvate, monosolvate or hemisolvate, where the ratio of solvent molecule to the glutamine antagonist is about 2: 1, about 1 : 1 or about 1 : 2, respectively.
  • This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding.
  • the solvate can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid.
  • solvate encompasses both solution-phase and isolatable solvates.
  • the glutamine antagonist can be present as solvated forms with a pharmaceutically acceptable solvent, such as water, methanol, ethanol, and the like, and it is intended that the disclosure includes both solvated and unsolvated forms of the glutamine antagonist.
  • a pharmaceutically acceptable solvent such as water, methanol, ethanol, and the like
  • solvate is a hydrate.
  • a "hydrate” relates to a particular subgroup of solvates where the solvent molecule is water.
  • Solvates typically can function as pharmacological equivalents. Preparation of solvates is known in the art. See, for example, M.
  • a typical, non-limiting, process of preparing a solvate involves dissolvingthe glutamine antagonist in a desired solvent (organic, water, or a mixture thereof) at temperatures above 20°C to about 25°C, then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods, e.g ., filtration.
  • Analytical techniques such as infrared spectroscopy can be used to confirm the presence of the solvent in a crystal of the solvate.
  • Therapeutically effective amounts of the glutamine antagonist, and the immune checkpoint inhibitor formulated in accordance with standard pharmaceutical practices, are administered to a human patient in need thereof. Whether such a treatment is indicated depends on the individual case and is subject to medical assessment (diagnosis) that takes into consideration signs, symptoms, and/or malfunctions that are present, the risks of developing particular signs, symptoms and/or malfunctions, and other factors.
  • the glutamine antagonist, and the immune checkpoint inhibitor can be administered by any suitable route, for example by oral, buccal, inhalation, sublingual, rectal, vaginal, intracistemal or intrathecal through lumbar puncture, transurethral, nasal, percutaneous, i.e., transdermal, or parenteral (including intravenous, intramuscular, subcutaneous, intracoronary, intradermal, intramammary, intraperitoneal, intraarticular, intrathecal, retrobulbar, intrapulmonary injection and/or surgical implantation at a particular site) administration.
  • Parenteral administration can be accomplished using a needle and syringe or using a high pressure technique.
  • the glutamine antagonist is administered subcutaneously to the subject.
  • the glutamine antagonist is administered intraveneously to the subject.
  • compositions include those wherein the glutamine antagonist, and the immune checkpoint inhibitor are administered in an effective amount to achieve its intended purpose.
  • the exact formulation, route of administration, and dosage is determined by an individual physician in view of the diagnosed condition or disease. Dosage amount and interval can be adjusted individually to provide levels of the glutamine antagonist, and the immune checkpoint inhibitor that is sufficient to maintain therapeutic effects.
  • Toxicity and therapeutic efficacy of the glutamine antagonist, and the immune checkpoint inhibitor can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the maximum tolerated dose (MTD) of a compound, which defines as the highest dose that causes no toxicity in a patient.
  • MTD maximum tolerated dose
  • the dose ratio between the maximum tolerated dose and therapeutic effects (e.g. inhibiting of tumor growth) is the therapeutic index.
  • the dosage can vary within this range depending upon the dosage form employed, and the route of administration utilized. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • a therapeutically effective amount of the glutamine antagonist, and the immune checkpoint inhibitor required for use in therapy varies with the nature of the condition being treated, the length of time that activity is desired, and the age and the condition of the subject, and ultimately is determined by the attendant physician.
  • dosage amounts and intervals can be adjusted individually to provide plasma levels of the glutamine antagonist, and immune checkpoint inhibitor that are sufficient to maintain the desired therapeutic effects.
  • the desired dose conveniently can be administered in a single dose, or as multiple doses administered at appropriate intervals, for example as one, two, three, four or more subdoses per day. Multiple doses often are desired, or required.
  • the glutamine antagonist, and immune checkpoint inhibitor can be administered at a frequency of: one dose per day; four doses delivered as one dose per day at four-day intervals (q4d x 4) ; four doses delivered as one dose per day at three-day intervals (q3d x 4) ; one dose delivered per day at five-day intervals (qd x 5) ; one dose per week for three weeks (qwk3) ; five daily doses, with two days rest, and another five daily doses (5/2/5) ; or, any dose regimen determined to be appropriate for the circumstance.
  • the immune checkpoint inhibitor is administered in therapeutically effective amounts.
  • the immune checkpoint inhibitor is a monoclonal antibody, 1-20 mg/kg is administered as an intravenous infusion every 2-4 weeks.
  • 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg and 2000 mg of the antibody may be administered.
  • the immune checkpoint inhibitor when the immune checkpoint inhibitor is the anti-PD-1 antibody nivolumab, 3 mg/kg may be administered by intravenous infusion over 60 minutes every two weeks.
  • the immune checkpoint inhibitor is the anti-PD-1 antibody pembrolizumab, mg/kg may be administered by intravenous infusion over 30 minutes every two or three weeks.
  • the immune checkpoint inhibitor is the anti-PD-Ll antibody avelumab, 10 mg/kg may be administered by intravenous infusion as frequently as every 2 weeks.
  • the immune checkpoint inhibitor is the anti-PD-Ll antibody MPDL3280A
  • 20 mg/kg may be administered by intravenous infusion every 3 weeks.
  • the immune checkpoint inhibitor is the anti-CTLA-4 antibody ipilumumab
  • 3 mg/kg may be administered by intravenous infusion over 90 minutes every 3 weeks.
  • the immune checkpoint inhibitor is the anti-CTLA-4 antibody tremelimumab
  • 15 mg/kg may be administered by intravenous infusion every 12 weeks.
  • the immune checkpoint inhibitor is the anti-LAG3 antibody GSK2831781, 1.5 to 5 mg/kg may be administered by intravenous infusion over 120 minutes every 2-4 weeks.
  • the immune checkpoint inhibitor is an anti-TIM3 antibody, 1-5 mg/kg may be administered by intravenous infusion over 30-90 minutes every 2-4 weeks.
  • an inhibitor of indoleamine 2, 3 -di oxygenase (IDO) pathway is inhibitor indoximod in combination with temozolomide, 18.5 mg/kg/dose BID with an escalation to 27.7 mg/kg/dose BID of indoximod with 200 mg/m 2 every 5 days of temozolomide.
  • the immune checkpoint inhibitor is an antibody and 1-20 mg/kg is administered by intravenous infusion every 2-4 weeks. In another embodiment, 50-2000 mg of the antibody is administered by intravenous infusion every 2-4 weeks.
  • the glutamine antagonist is administered prior to administration of the antibody. In another embodiment, the glutamine antagonist is administered 3-7 days prior to the day of administration of the antibody. In another embodiment, the glutamine antagonist is also administered the day the antibody is administered and on consecutive days thereafter until disease progression or untilthe glutamine antagonist administration is no longer beneficial.
  • the cancer patient receives 2 mg/kg pembrolizumab administered by intravenous infusion every three weeks and about 0.1 to 100 mg of the glutamine antagonist administered for 1-7 days prior to pembrolizumab administration, optionally, on the day of pembrolizumab administration, and, optionally, thereafter until disease progression or until there is no therapeutic benefit.
  • the cancer patient receives 3 mg/kg nivolumab administered by intravenous infusion every 2 weeks and about 0.1 to 100 mg of the glutamine antagonist administered for 1-7 days prior to nivolumab administration, optionally, on the day of nivolumab administration, and, optionally, thereafter until disease progression or until there is no therapeutic benefit.
  • the cancer patient receives 3 mg/kg nivolumab administered by intravenous infusion every 2 weeks and about 0.1 to 100 mg of the glutamine antagonist administered for 1-7 days prior to nivolumab administration, optionally, on the day of nivolumab administration, and, optionally, thereafter until disease progression or until there is no therapeutic benefit.
  • the treatment of the cancer patient with a glutamine antagonist, and an immune checkpoint inhibitor induces anti proliferative response faster than when the immune checkpoint inhibitor is administered alone.
  • halogen means fluoro, chloro, bromo or iodo.
  • the preferred halogen groups include F, Cl and Br.
  • haloC 1-6 alkyl means fluoro, chloro, bromo or iodo.
  • the preferred halogen groups include F, Cl and Br.
  • haloC 1-6 alkyl means fluoro, chloro, bromo or iodo.
  • the preferred halogen groups include F, Cl and Br.
  • haloC 1-6 alkyl , “haloC 2-6 alkenyl” , “haloC 2-6 alkynyl” and “haloC 1-6 alkoxy” mean a C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 alkoxy in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by halogen atoms, especially fluorine or chlorine atoms.
  • fluoroC 1-6 alkyl, fluoroC 2-6 alkenyl, fluoroC 2-6 alkynyl and fluoroC 1-6 alkoxy groups in particular fluoroC 1-3 alkyl, for example, CF 3 , CHF 2 , CH 2 F, CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 and fluoroC 1-3 alkoxy groups, for example, OCF 3 , OCHF 2 , OCH 2 F, OCH 2 CH 2 F, OCH 2 CHF 2 or OCH 2 CF 3 , and most especially CF 3 , OCF 3 and OCHF 2 .
  • fluoroC 1-3 alkyl for example, CF 3 , CHF 2 , CH 2 F, CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 and fluoroC 1-3 alkoxy groups, for example, OCF 3 , OCHF 2 , OCH 2 F, OCH 2 CH 2 F, OCH 2 CHF 2 or OCH
  • alkyl includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties.
  • alkyl radicals include methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclobutyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl.
  • C 1-8 as in C 1-8 alkyl is defined to identify the group as having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms in a linear or branched arrangement.
  • Alkylene means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above.
  • methylene i.e., -CH 2 -
  • ethylene i.e., -CH 2 -CH 2 -or –CH (CH 3 ) -
  • propylene i.e., -CH 2 -CH 2 -CH 2 -, -CH (-CH 2 -CH 3 ) -or –CH 2 -CH (CH 3 ) -
  • Alkenyl and alkynyl groups include straight, branched chain or cyclic alkenes and alkynes.
  • C 2-8 alkenyl and “C 2-8 alkynyl” means an alkenyl or alkynyl radicals having 2, 3, 4, 5, 6, 7 or 8 carbon atoms in a linear or brached arrangement.
  • Alkenyl group include, but are not limited to, for example, ethenyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, hepetenyl, octenyl and the like.
  • Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl and the like.
  • Alkoxy radicals are oxygen ethers formed from the previously described straight, branched chain or cyclic alkyl groups.
  • aryl refers to an unsubstituted or substituted mono-or polycyclic ring system containing carbon ring atoms.
  • the preferred aryls are mono cyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls. The most preferred aryl is phenyl.
  • heterocyclic ring or “heterocyclyl” , as used herein, unless otherwise indicated, refers to unsubstituted and substituted mono-or polycyclic non-aromatic ring system containing one or more heteroatoms.
  • Preferred heteroatoms include N, O, and S, including N-oxides, sulfur oxides, and dioxides.
  • the ring is three to eight membered and is either fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, preferably one, two or three, are included within the present definition.
  • heterocyclic groups include, but are not limited to azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepinyl, azepinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone and oxadiazolyl.
  • heteroaryl represents an aromatic ring system containing carbon (s) and at least one heteroatom.
  • Heteroaryl may be monocyclic or polycyclic, substituted or unsubstituted.
  • a monocyclic heteroaryl group may have 1 to 4 heteroatoms in the ring, while a polycyclic heteroaryl may contain 1 to 10 hetero atoms.
  • a polycyclic heteroaryl ring may contain fused, spiro or bridged ring junction, for example, bycyclic heteroaryl is a polycyclic heteroaryl.
  • Bicyclic heteroaryl rings may contain from 8 to 12 member atoms.
  • Monocyclic heteroaryl rings may contain from 5 to 8 member atoms (cabons and heteroatoms) .
  • heteroaryl groups include, but are not limited to thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl adeninyl, quinolinyl or isoquinolinyl.
  • cycloalkyl refers to a substituted or unsubstituted monocyclic, bicyclic or polycyclic non-aromatic saturated ring, which optionally includes an alkylene linker through which the cycloalkyl may be attached.
  • Examplary "cycloalkyl” groups includes but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and so on.
  • alkyl or aryl or either of their prefix roots appear in a name of a substituent (e.g., aralky or dialkylamino) it shall be interpreted as including those limitations given above for “alkyl” and “aryl” .
  • Designated numbers of carbon atoms e.g., C l - 6 ) shall refer independently to the number of carbon atoms in an alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
  • substituted refers to a group mentioned above in which one or more (preferably 1-6, more preferably 1-3) hydrogen atoms are each independently replaced with the same or different substituent (s) .
  • the substituent (s) is independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluromethoxy, ethoxy, propyloxy, iso-propyloxy, n-butyloxy, isobutyloxy, t-butyloxy, -SCH 3 , -SC 2 H 5 , formaldehyde group, -C (OCH 3 ) , cyano, nitro, CF 3 , -OCF 3 , amino, dimethylamino, methyl thio, sulfonyl and acetyl.
  • Particularly preferred substituent (s) is -F, -Cl or -Br.
  • Compounds described herein such as certain compounds of Formula I, I-A, I-B, I-C, II, III, IV, V, VI, VII, or VIII, may contain asymmetrically substituted carbon atoms (or chiral centers) in the R or S configuration.
  • the present invention includes racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and absolute stereoisomers.
  • enriched R-or S-designated isomer can be substantially free (e.g., with less than 5%, less than 1%, or non-detectable, as determined by chiral HPLC) of the other isomer for the respective chiral center.
  • the enriched R-or S-isomers can be prepared by methods exemplified in this application, such as by using a chiral auxiliary such as R-or S-tert-butylsulfinamide in the synthetic process.
  • chiral HPLC purifications of a stereoisomeric mixture such as a racemic mixture.
  • General methods for separating stereoisomers (such as enantiomers and/or diastereomers) using HPLC are known in the art.
  • Isotopes can be radioactive or non-radioactive isotopes.
  • Isotopes of atoms such as hydrogen, carbon, phosphorous, sulfur, fluorine, chlorine, and iodine include, but are not limited to 2H, 3H, 13C, 14C, 15N, 18O, 32P, 35S, 18F, 36Cl, and 125I.
  • Compounds that contain other isotopes of these and/or other atoms are within the scope of this invention.
  • one or more hydrogen atoms of any of the compounds described herein can be substituted with deuterium to provide the corresponding deterium-labeled or -enriched compounds.
  • any asymmetric carbon atom may be present in the (R) -, (S) -or (R, S) -configuration, preferably in the (R) -or (S) -configuration.
  • the compounds may thus be present as mixtures of isomers or preferably as pure isomers, preferably as pure diastereomers or pure enantiomers.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from pharmaceutical combinations of the specified ingredients in the specified amounts. Accordingly, pharmaceutical compositions containing the compounds of the present invention as the active ingredient as well as methods of preparing the instant compounds are also part of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents and such solvates are also intended to be encompassed within the scope of this invention.
  • the compounds of the present invention may also be present in the form of pharmaceutically acceptable salts.
  • the salts of the compounds of this invention refer to non-toxic “pharmaceutically acceptable salts” .
  • the pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts.
  • the pharmaceutically acceptable acidic/anionic salt generally takes a form in which the basic nitrogen is protonated with an inorganic or organic acid.
  • organic or inorganic acids include hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, saccharinic or trifluoroacetic.
  • Pharmaceutically acceptable basic/cationic salts include, and are not limited to aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, sodium and zinc.
  • the present invention includes within its scope the prodrugs of the compounds of this invention.
  • such prodrugs will be functional derivatives of the compounds that are readily converted in vivo into the required compound.
  • the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the subject.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs” , ed. H. Bundgaard, Elsevier, 1985.
  • the present invention includes compounds described can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers.
  • the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.
  • the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, except where specifically stated otherwise.
  • the present invention includes any possible solvates and polymorphic forms.
  • a type of a solvent that forms the solvate is not particularly limited so long as the solvent is pharmacologically acceptable.
  • water, ethanol, propanol, acetone or the like can be used.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
  • the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases.
  • the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous) .
  • the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient.
  • the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion, or as a water-in-oil liquid emulsion.
  • the pharmaceutical combination of the invention may also be administered by controlled release means and/or delivery devices.
  • compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
  • the pharmaceutical carrier employed can be, for example, a solid, liquid, or gas.
  • solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • liquid carriers are sugar syrup, peanut oil, olive oil, and water.
  • gaseous carriers include carbon dioxide and nitrogen.
  • oral liquid preparations such as suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets.
  • oral solid preparations such as powders, capsules and tablets.
  • tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed.
  • tablets may be coated by standard aqueous or nonaqueous techniques.
  • a tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • Each tablet preferably contains from about 0.05mg to about 5g of the active ingredient and each cachet or capsule preferably containing from about 0.05mg to about 5g of the active ingredient.
  • a formulation intended for the oral administration to humans may contain from about 0.5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
  • Unit dosage forms will generally contain between from about lmg to about 2g of the active ingredient, typically 25mg, 50mg, l00mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg, or l000mg.
  • compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water.
  • a suitable surfactant can be included such as, for example, hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
  • compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions.
  • the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions.
  • the final injectable form must be sterile and must be effectively fluid for easy syringability.
  • the pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol) , vegetable oils, and suitable mixtures thereof.
  • compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing The pharmaceutical combination of the invention, or a pharmaceutically acceptable salt thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 5wt%to about 10wt%of the compound, to produce a cream or ointment having a desired consistency.
  • compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier (s) followed by chilling and shaping in molds.
  • the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient.
  • dosage levels on the order of from about 0.01mg/kg to about 150mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5mg to about 7g per patient per day.
  • inflammation, cancer, psoriasis, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system (CNS) may be effectively treated by the administration of from about 0.01 to 50mg of the compound per kilogram of body weight per day, or alternatively about 0.5mg to about 3.5g per patient per day.
  • subject or “patient” as used herein is intended to include animals, which are capable of suffering from or afflicted with a cancer or any disorder involving, directly or indirectly, a cancer.
  • subjects include mammals, e.g., humans, apes, monkeys, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals.
  • the subject is a human, e.g., a human suffering from, at risk of suffering from, or potentially capable of suffering from cancers.
  • treating comprises a treatment relieving, reducing or alleviating at least one symptom in a subject or effecting a delay of progression of a disease.
  • treatment can be the diminishment of one or several symptoms of a disorder or complete eradication of a disorder, such as cancer.
  • the term “treat” also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease.
  • glutamine antagonist refers to a glutamine analog that interfers with a glutamine metabolic pathway, e.g., the inhibition or blocking of a metabolic pathway downstream of glutamine in which glutamine acts as a precursor of one or more non-glutamine compounds.
  • glutamine metabolic pathway e.g., the inhibition or blocking of a metabolic pathway downstream of glutamine in which glutamine acts as a precursor of one or more non-glutamine compounds.
  • Examples of such metabolic pathways are well known (see, e.g., Hensley et al, "Glutamine and cancer: cell biology, physiology, and clinical opportunities” J Clin Invest. 2013; 123 (9) : 3678-3684; DeBerardinis et al, "Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer” Oncogene.
  • glutamine antagonist also includes glutamine analogs that inhibit glutamine uptake by cells, thereby reducing its biological activity. Diseases or conditions wherein excess and/or aberrant glutamine.
  • a “therapeutically effective amount” when used in connection with a compound is an amount effective for treating or preventing a disease in a subject as described herein.
  • pharmaceutical combination therapy refers to the administration of two or more therapeutic agents to treat a condition or disorder described in the present disclosure (e.g., cancer) .
  • Such administration encompasses co -administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients.
  • Such administration encompasses coadministration in multiple, or in separate containers (e.g., capsules, powders, and liquids) for each active ingredient. Powders and/or liquids may be reconstituted or diluted to a desired dose prior to administration.
  • such administration also encompasses use of each type of therapeutic agent in a sequential manner, either at approximately the same time or at different times. In either case, the treatment regimen will provide beneficial effects of the drug pharmaceutical combination in treating the conditions or disorders described herein.
  • the combination therapy can provide “synergy” and prove “synergistic” , i.e., the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately.
  • a synergistic effect can be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined, unit dosage formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen.
  • a synergistic effect can be attained when the compounds are administered or delivered sequentially, e.g., by different injections in separate syringes.
  • an effective dosage of each active ingredient is administered sequentially, i.e., serially
  • effective dosages of two or more active ingredients are administered together.
  • pharmaceutical combination refers to either a fixed pharmaceutical combination in one dosage unit form, or non-fixed pharmaceutical combination or a kit of parts for the combined administration where two or more therapeutic agents may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the pharmaceutical combination partners show a cooperative, e.g. synergistic effect.
  • synergistic effect refers to action of two or more therapeutic agents such as, for example, a glutamine antagonist, and the immune checkpoint inhibitor, producing an effect, for example, slowing the symptomatic progression of a proliferative disease, particularly cancer, or symptoms thereof, which is greater than the simple addition of the effects of each drug administered by themselves.
  • a synergistic effect can be calculated, for example, using suitable methods such as the Sigmoid-Emax equation (Holford, N. H. G. and Scheiner, L. B., Clin. Pharmacokinet. 6: 429-453 (1981) ) , the equation of Loewe additivity (Loewe, S. and Muischnek, H., Arch. Exp.
  • Each equation referred to above can be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug pharmaceutical combination.
  • the corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and pharmaceutical combination index curve, respectively.
  • the pharmaceutical combination of the invention, a glutamine antagonist and an immune checkpoint inhibitor is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
  • Isotopically labeled compounds have one or more atoms replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into the glutamine antagonist and the immune checkpoint inhibitor include isotopes of hydrogen, carbon, nitrogen, oxygen, and chlorine, for example, 2 H, 3 H, n C, 13 C, 14 C, 15 N, 35 S, 36 C1.
  • the invention includes isotopically labeled a glutamine antagonist and a immune checkpoint inhibitor, for example into which radioactive isotopes, such as 3 H and 14 C, or non-radio active isotopes, such as 2 H and 13 C, are present.
  • Isotopically labelled the glutamine antagonist and the immune checkpoint inhibitor are useful in metabolic studies (with 14 C) , reaction kinetic studies (with, for example 2 H or 3 H) , detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using appropriate isotopically-labeled reagents.
  • Fig. 1 shows anti-tumor effect of the test compound alone and in combination with Anti-PD-1 mAb in MC38 Model
  • FIG. 2 shows survival curve for different treatment groups in MC38 Model
  • Fig. 3 shows body weight change of different treatment groups in MC38 Model
  • Fig. 4 shows anti-tumor effect of the test compound alone and in combination with Anti-PD-L1 mAb in H22 Model
  • Fig. 5 shows the tumor volume of Individual Mice in H22 Model
  • Fig. 6 shows survival curve for different treatment groups in H22 Model
  • Fig. 7 shows body weight change of different treatment groups in H22 Model
  • Step a To a solution of 7-Fluoroindole (308 mg, 2.279 mmol) and Ytterbium (III) triflate hydrate (219 mg, 343.119 ⁇ mol) in Chloroform (3 mL) was added (2S) -Methylglycidate (121 mg, 1.185 mmol) under N 2 . The mixture was heated to 85°C and stirred for 3 h. The reaction mixture was cooled to RT. The reaction mixture was quenched with Na 2 CO 3 (aq) (10 mL) , and adjusted the pH to 5-6 with 2M HCl. The aqueous layer was separated and extracted with DCM (2 ⁇ 10 mL) .
  • Step b To a solution of methyl (2S) -3- (7-fluoro-1H-indol-3-yl) -2-hydroxy-propanoate (136 mg, 573.292 ⁇ mol) in water (1 mL) was added LiOH (2M solution in water, 1 mL) . The mixture was stirred for overnight at RT-60°C, Citric acid (solid) was added, diluted with water (5 mL) and extracted with EA (2 ⁇ 10 mL) .
  • Step a To a solution of Indole (302 mg, 2.578 mmol) in DMF (3 mL) was added NaH (217 mg, 9.043 mmol) at ice-water bath for 1h .
  • (2S) -Methylglycidate (685 mg, 6.710 mmol) was added and the mixture was stirred over night at RT.
  • the reaction mixture was quenched with H 2 O, and adjusted the pH to 3-4 with citric acid.
  • the aqueous layers were extracted with EA. The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step a To a solution of Methyl (S) - (-) -lactate (1099 mg, 10.5567 mmol) , Iodoethane (3726 mg, 23.8900 mmol) in Diethyl ether (10 mL) was added Ag 2 O (4772 mg, 20.5925 mmol) under N 2. The reaction mixture was stirred over night at RT by light-avoiding. The reaction mixture was monitored by TLC. The reaction mixture was filtered and concentrated under reduced pressure. The residue was dissolved by THF (3 mL) , MeOH (3 mL) , H 2 O (3 mL) and then the reaction mixture was added LiOH (246 mg, 10.2721 mmol) .
  • reaction mixture was stirred for 3h at RT.
  • the reaction mixture was monitored by TLC and adjusted the pH to 2 with 1N HCl.
  • the reaction mixture was concentrated under reduced pressure to 5 mL.
  • the aqueous layers were extracted with EA (3 ⁇ 10 mL) .
  • the combined organic layers were washed with saturated solution of NaCl (3 ⁇ 10 mL) and dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to afford (S) -2-ethoxypropanoic acid (772 mg, 6.5351 mmol) .
  • Step a To a solution of 2-hydroxy-4- (methylthio) butanoic acid (0.68 g, 4.5274 mmol) , CH 3 I (3.35 g, 23.6019 mmol) in Diethyl ether (10 mL) was added Ag 2 O (4.41 g, 19.0303 mmol) . The reaction mixture was stirred over night at RT. The reaction mixture was monitored by LC-MS. The reaction mixture was filtered and concentrated under reduced pressure. The residue was dissolved by MeOH (6 mL) , H 2 O (2 mL) and then the reaction mixture was added NaOH (318 mg, 7.9506 mmol) . The reaction mixture was stirred for 3h at RT.
  • reaction mixture was monitored by TLC and adjusted the pH to 3 with 1M HCl.
  • the reaction mixture was concentrated under reduced pressure to 5 mL.
  • the aqueous layers were extracted with EA (3 ⁇ 10 mL) .
  • the combined organic layers were washed with saturated solution of NaCl (3 ⁇ 10 mL) and dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to afford 2-methoxy-4- (methylthio) butanoic acid (128 mg, 779.4318 ⁇ mol) .
  • Step a To a solution of 2-hydroxy-3- (1H-indol-3-yl) propanoic acid (152 mg, 740.706 ⁇ mol) in THF (10 mL) was added NaH (55 mg, 2.292 mmol) . The reaction mixture was stirred for 20 min at RT and then CH 3 I (370 mg, 2.607 mmol) was added. The reaction mixture was monitored by LC-MS. CH 3 I (358 mg, 2.522 mmol) was added again. The reaction mixture was monitored by LC-MS. The reaction mixture was stirred for 3h at 40°C. The reaction mixture was added H 2 O (5 mL) and extracted with EA (10 mL) .
  • Step a To a solution of methyl (S) -2-hydroxy-3- (1H-indol-3-yl) propanoate (2 g, 9.123 mmol) in DCM (20 mL) was added Imidazole (2061 mg, 30.274 mmol) and TBDMS-Cl (2980 mg, 19.772 mmol) . The mixture was stirred for overnight at RT. The reaction mixture was quenched with Water (10 mL) and extracted with DCM (10 mL). The reaction mixture was separated and organic extracts were collected. The aqueous solution was extracted with DCM (2 ⁇ 10 mL) . The residue was purified by wet column chromatography with EA/Hex (0-20%) .
  • Step b To a -78°C solution of methyl (S) -2- ( (tert-butyldimethylsilyl) oxy) -3- (1H-indol-3-yl) propanoate (3.099g, 9.292 mmol) in THF (30 mL) was added LiHMDS (10.5 mL, 10.491 mmol) . The mixture was stirred for 30min at -78°C. Then Carbobenzyloxy chloride (4623 mg, 27.100 mmol) was dropped into the mixture at -78°C. The reaction mixture was stirred for 1h at this temperature. Quenched the reaction with sat.
  • Step c To a solution of benzyl (S) -3- (2- ( (tert-butyldimethylsilyl) oxy) -3-methoxy-3-oxopropyl) -1H-indole-1-carboxylate (4.345 g, 9.292 mmol) in THF (30 mL) was added Tetrabutylammonium fluoride (5 mL) . The mixture was stirred for overnight at RT. The reaction mixture was concentrated under reduced pressure. The residue was purified by FLASH with EA/Hex (0-60%) . The product’s solution was concentrated under reduced pressure.
  • Step d To a solution of benzyl 3- [ (2S) -2-hydroxy-3-methoxy-3-oxo-propyl] indole-1-carboxylate (103 mg, 291.481 ⁇ mol) , and 4A molecular sieve in CH 3 I (1mL) was added Silver oxide (216 mg, 932.098 ⁇ mol) . The mixture was stirred for overnight at RT. The reaction mixture was concentrated under reduced pressure. The reaction mixture was diluted with EA (5mL) and filtered, the filtrate was concentrated to afford benzyl (S) -3- (2, 3-dimethoxy-3-oxopropyl) -1H-indole-1-carboxylate (107.088 mg, 100.000%yield) . MS: m/z 368(M+H) + .
  • Step e To a solution of benzyl (S) -3- (2, 3-dimethoxy-3-oxopropyl) -1H-indole-1-carboxylate (0.107g, 291.240 ⁇ mol) in THF (5 mL) and MeOH (5mL) was added NaOH (3mL, 3M/L) . The mixture was stirred for 1h at RT. The reaction mixture was adjusted the pH to 3 with 1M HCl. The aqueous solution was extracted with EA (2 ⁇ 10 mL) . The combined organic extracts were washed with brine (3 ⁇ 10 mL) , dried over anhydrous Na 2 SO 4 . The organic phase was concentrated under reduced pressure and (S) -3- (1H-indol-3-yl) -2-methoxypropanoic acid (71 mg) was obtained. MS: m/z 220 (M+H) + .
  • Each C57BL/6 mouse was inoculated subcutaneously in the right flank region with MC38 cells (1 x 10 6 ) for tumor development.
  • the treatments were started when the mean tumor size reached approximately 75 mm 3 .
  • the experimental animals were divided using stratified randomization with 7 mice per group based upon their tumor volumes. The treatment was started from the day of randomization, Group 1 was treated with Vehicle s. c. QD, Group 2 was treated with anti-PD-1 10 mg/kg i. p. BIW, Group 3 was treated with Compound 2 1.2 mg/kg s.c. Q2D, Group 4 was treated with Compound 2 1.2 mg/kg s. c. Q2D and anti-PD-1 10 mg/kg i. p. BIW.
  • TGI tumor growth inhibition
  • Compound 2 in combination with anti-PD-1 mAb further enhanced tumor growth inhibition and showed improved survival compared to single agent treatment in MC38 model.
  • EXAMPLE B Efficacy of Compound 2 in Combination with Anti-PD-L1 mAb in H22 Syngeneic Model
  • Each BALB/c mouse was inoculated subcutaneously in the right flank region with H22 cells (1 x 10 6 ) for tumor development. The treatments were started when the mean tumor size reached 146 mm 3 .
  • the experimental animals were divided using stratified randomization with 8 mice per group based upon their tumor volumes. The treatment was started from the day of randomization.
  • Group 1 was treated with Vehicle s. c. QD
  • Group 2 was treated with anti-PD-L1 5 mg/kg i.p. BIW
  • Group 3 was treated with Compound 2 1.2 mg/kg s.c. 5 days on/2 days off
  • Group 4 was treated with Compound 2 1.2 mg/kg s.c. 5 days on/2 days off and anti-PD-L1 5 mg/kg i.p. BIW.
  • the in vivo efficacy was examined according to tumor growth inhibition (TGI) and the safety was evaluated according to weight change and survival in mice.
  • TGI tumor growth inhibition
  • Treatments were ended at day 20 and survival curves from different groups were analyzed. Median survival of the groups was 20 days, 24 days, 42 days and undefined, respectively. The result showed that combination of Compound 2 and anti-PD-L1 further improved mouse survival compared to single agent treatment.
  • the tumor growth curves of individual mice are shown in Fig. 5.
  • the survival curves are shown in Fig. 6.
  • Compound 2 in combination with anti-PD-L1 mAb further enhanced tumor growth inhibition and showed improved survival compared to single agent treatment in H22 model.
  • the compounds of the present invention are preferably formulated as pharmaceutical compositions administered by a variety of routes. Most preferably, such compositions are for oral administration.
  • Such pharmaceutical compositions and processes for preparing the same are well known in the art. See, e.g., REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (A. Gennaro, et al, eds., 19 th ed., Mack Publishing Co., 1995) .
  • the combinations are generally effective over a wide dosage range.
  • dosages per day normally fall within the range of about 1 mg to about 200 mg total daily dose, preferably 0.2 mg to 50 mg total daily dose, more preferably 0.2 mg to 20 mg total daily dose. In some instances dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed.
  • the above dosage range is not intended to limit the scope of the invention in any way. It will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.

Abstract

Provided herein is a pharmaceutical combination comprising a Glutamine antagonist, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, and an isotopic substitution thereof, and an additional therapeutic agent; pharmaceutical compositions thereof; commercial packages thereof; and uses of such pharmaceutical combinations and pharmaceutical compositions for the treatment or prevention of diseases, for example, the treatment of cancers.

Description

PHARMACEUTICAL COMBINATION AND USE THEREOF Technical Field
The present invention relates a pharmaceutical combination comprising a glutamine antagonist, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, and an isotopic substitution thereof, and an additional therapeutic agent; pharmaceutical compositions thereof; commercial packages thereof; and uses of such pharmaceutical combinations and pharmaceutical compositions for the treatment of cancer and cancer occurrence-related diseases.
Background Art
WO 2017/023774 discloses isopropyl (S) -2- ( (S) -2-acetamido-3- (lH-indol-3-yl) propanamido) -6-diazo-5-oxohexanoate and other prodrugs of DON. DON and DON prodrugs can be used to treat a variety of diseases, disorders, and conditions including, but not limited to, cancer, cognitive deficits, and metabolic reprogramming disorders. See WO 2017/023793, WO 2017/023791, WO 2017/023787, and WO2020/150639.
The combination of the present invention, may show improved efficacy compared to either single agent alone in the treatment of diseases, e.g. cancer.
Summary of Invention
The present invention provides for a pharmaceutical combination comprising:
(i) a glutamine antagonist, or a pharmaceutical acceptable salt thereof; and
(ii) an additional therapeutic agent selected from a immune checkpoint inhibitor, an activator of a costimulatory molecule, a chemotherapeutic agent, a radiotherapeutic agent, a immunotherapeutic agent, a targeted anti-cancer therapy, an anticancer agent, an oncolytic drug, a cytotoxic agent, or any of the therapeutic agents disclosed herein.
In some embodiments, the additional therapeutic agent can be chosen from: a PD-1 inhibitor, a PD-L1 inhibitor, a LAG-3 inhibitor, a CTL4 inhibitor, a TIM-3 inhibitor, a CD47 inhibitor, a CDK4/6 inhibitor, an Aurora A kinase inhibitor, chemotherapeutic drug (Taxol, Cisplatin, Carboplatin, 5-Fu, topotecan, cyclophosphamide, and so on) , radiotherapy, HDAC inhibitor, a SHP2 inhibtor, a KRASG12C inhibitor, a BET inhibitor, a EGFR inhibitor, a VEGFR inhibitor, a GITR agonist, a SERD, a Plk3 inhibitor, a CXCR2 inhibitor, a CSF-1/1R binding agent, a c-MET inhibitor, a TGF-β inhibitor, an A2aR antagonist, an IDO inhibitor, a STING inhibitor, a Galectin inhibitor, a MEK inhibitor, an IL-15/IL-15RA complex, an IL-1β inhibitor, an MDM2 inhibitor, or a pharmaceutically acceptable salt thereof; or any pharmaceutical combination thereof. Preferably, a PD-1 inhibitor, a PD-L1 inhibitor, a CTL4 inhibitor, a LAG-3 inhibitor, a TIM-3 inhibitor, a CD47 inhibitor.
In some embodiments, the pharmaceutical combination comprises:
(i) a glutamine antagonist, or a pharmaceutical acceptable salt thereof; and
(ii) an immune checkpoint inhibitor, e.g., a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor, a LAG3 inhibitor, a TIM3 inhibitor, or a CD47 inhibitor.
In some embodiments, the pharmaceutical combination comprises: (i) a glutamine antagonist, or a pharmaceutically acceptable salt thereof; and (ii) a PD-1 inhibitor or a pharmaceutically acceptable salt thereof.
In some embodiments, the pharmaceutical combination comprises: (i) a glutamine antagonist, or a pharmaceutically acceptable salt thereof; and (ii) a PD-L1 inhibitor or a pharmaceutically acceptable salt thereof.
In some embodiments, the pharmaceutical combination comprises: (i) a glutamine antagonist, or a pharmaceutically acceptable salt thereof; and (ii) a CTLA-4 inhibitor or a pharmaceutically acceptable salt thereof.
In some embodiments, the pharmaceutical combination comprises: (i) a glutamine antagonist, or a pharmaceutically acceptable salt thereof; and (ii) a LAG3 inhibitor or a pharmaceutically acceptable salt thereof.
In some embodiments, the pharmaceutical combination comprises: (i) a glutamine antagonist, or a pharmaceutically acceptable salt thereof; and (ii) a TIM3 inhibitor or a pharmaceutically acceptable salt thereof.
In some embodiments, the pharmaceutical combination comprises: (i) a glutamine antagonist, or a pharmaceutically acceptable salt thereof; and (ii) a CD47 inhibitor or a pharmaceutically acceptable salt thereof.
In another embodiment of the pharmaceutical combination of the invention, a glutamine antagonist or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof, are in the same formulation.
In another embodiment of the pharmaceutical combination of the invention, a glutamine antagonist or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof, are in the separate formulation.
In another embodiment, the pharmaceutical combination of the invention is for simultaneous or sequential (in any order) administration.
In a further embodiment, the present disclosure is directed to a method of treating (e.g., inhibiting, reducing, ameliorating, or preventing) a disorder or disease, e.g., a hyperproliferative condition or disorder (e.g., a cancer) ,  cognitive deficits, and metabolic reprogramming disorders etc. in a subject. The method includes administering to the subject a therapeutically effective amount of pharmaceutical combination comprising a glutamine antagonist and an additional therapeutic agent disclosed herein. In some embodiments, the additional therapeutic agent is chosen from: a PD-1/PD-L1 inhibitor, a LAG-3 inhibitor, a CTL4 inhibitor, a TIM-3 inhibitor, a CD47 inhibitor, a CDK4/6 inhibitor, an Aurora A kinase inhibitor, chemotherapeutic drug (Taxol, Cisplatin, Carboplatin, 5-Fu, topotecan, cyclophosphamide, and so on) , radiotherapy, HDAC inhibitor, a SHP2 inhibtor, a KRASG12C inhibitor, a BET inhibitor, a EGFR inhibitor, a VEGFR inhibitor, a GITR agonist, a SERD, a Plk3 inhibitor, a CXCR2 inhibitor, a CSF-1/1R binding agent, a c-MET inhibitor, a TGF-β inhibitor, an A2aR antagonist, an IDO inhibitor, a STING inhibitor, a Galectin inhibitor, a MEK inhibitor, an IL-15/IL-15RA complex, an IL-1βinhibitor, an MDM2 inhibitor, or a pharmaceutically acceptable salt thereof; or any pharmaceutical combination thereof.
In a further embodiment, the present disclosure is directed to a method of treating (e.g., inhibiting, reducing, ameliorating, or preventing) a disorder or disease, e.g., a hyperproliferative condition or disorder (e.g., a cancer) , in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a glutamine antagonist or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor e.g., a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor, a LAG3 inhibitor, a TIM3 inhibitor, or a cd47 inhibitor, or a pharmaceutically acceptable salt thereof.
In a further embodiment, the invention provides the pharmaceutical combination of the invention defined herein for use in the treating (e.g., inhibiting, reducing, ameliorating, or preventing) a disorder, e.g., a hyperproliferative condition or disorder (e.g., a cancer) .
In a further embodiment, the invention provides for the pharmaceutical combination of the invention for use in the manufacture of a medicament for treating (e.g., inhibiting, reducing, ameliorating, or preventing) a disorder, e.g., a hyperproliferative condition or disorder (e.g., a cancer) .
In another embodiment, there is a pharmaceutical composition comprising the combination of the invention.
In a further embodiment, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients as detailed herein.
In one embodiment of method and use defined herein, the cancer is a solid tumor. In another embodiment, the cancer is a hematological cancer. In another embodiment, the cancer is any one or more of the cancers of Table 1.
Table 1


Exemplary hematological cancers include, but are not limited to, the cancers listed in Table 2. In another embodiment, the hematological cancer is acute lymphocytic leukemia, chronic lymphocytic leukemia (including B-cell chronic lymphocytic leukemia) , or acute myeloid leukemia.
Table 2
In another embodiment, the cancer is any one or more of the cancers of a breast cancer (e.g., a triple negative breast cancer) , a colorectal cancer (e.g., a microsatellite stable colorectal cancer (MSS CRC) ) , acute lymphoblastic leukemia, acute myelogenous leukemia, advanced soft tissue sarcoma, brain cancer, metastatic or aggressive breast cancer, bronchogenic carcinoma, choriocarcinoma, chronic myelocytic leukemia, colon carcinoma, Ewing's sarcoma, gastrointestinal tract carcinoma, glioma, glioblastoma multiforme, hepatocellular carcinoma, Hodgkin's disease, intracranial ependymoblastoma, large bowel cancer, leukemia, liver cancer, lung cancer, Lewis lung carcinoma, lymphoma, lymphangioma, lymphangiosarcoma, malignant fibrous histiocytoma, a mammary tumor, melanoma, mesothelioma, neuroblastoma, osteosarcoma, ovarian cancer, pancreatic cancer, a pontine tumor, premenopausal breast cancer, prostate cancer, rhabdomyosarcoma, reticulum cell sarcoma, sarcoma, small cell lung cancer, a solid tumor, stomach cancer, testicular cancer, uterine carcinoma, skin cancer, a gastric cancer, a gastroesophageal cancer, lung cancer, cervical cancer, head and neck cancer, esophageal cancer, non-small cell lung cancer, non-Hodgkin lymphoma, or any of combination thereof. In some embodiments, the skin cancer is a melanoma (e.g., a refractory melanoma) .
In another embodiment, the cancer is selected from the group consisting of squamous cell carcinoma of the head and neck, adenocarcinoma squamous cell carcinoma of the esophagus, adenocarcinoma of the stomach, adenocarcinoma of the colon, hepatocellular carcinoma, cholangiocarcinoma of the biliary system, adenocarcinoma of gall bladder, adenocarcinoma of the pancreas, ductal carcinoma in situ of the breast, adenocarcinoma of the breast, adenocarcinoma of the lungs, squamous cell carcinoma of the lungs, transitional cell carcinoma of the bladder, squamous cell carcinoma of the bladder, squamous cell carcinoma of the cervix, adenocarcinoma of the cervix, endometrial carcinoma, penile squamous cell carcinoma, and squamous cell carcinoma of the skin.
In another embodiment, a precancerous tumor is selected from the group consisting of leukoplakia of the head and neck, Barrett's esophagus, metaplasia of the stomach, adenoma of the colon, chronic hepatitis, bile duct hyperplasia, pancreatic intraepithelial neoplasia, atypical adenomatous hyperplasia of the lungs, dysplasia of the bladder, cervical initraepithelial neoplasia, penile intraepithelial neoplasia, and actinic keratosis of the skin.
In another embodiment, the cancer is selected from the group consisting of hepatocellular carcinoma, glioblastoma, lung cancer, breast cancer, head and neck cancer, prostate cancer, melanoma, and colorectal cancer.
In another embodiment, the cancer is selected from the group consisting of colorectal cancer, breast cancer, lymphoma, melanoma, kidney cancer, and lung cancer.
In another embodiment, the cancer has become resistant to conventional cancer treatments. The term "conventional cancer treatments" as used herein refers to any cancer drugs, biologies, or radiotherapy, or combination of cancer drugs and/or biologies and/or radiotherapy that have been tested and/or approved for therapeutic use in humans by the U.S. Food and Drug Administration, European Medicines Agency, or similar regulatory agency.
In some embodiments of the pharmaceutical combination of the invention, the glutamine antagonist comprises a compound disclosed in International Application No. PCT/CN2021/123674 hereby incorporated by reference in its entirety.
In some embodiments, the glutamine antagonist a compound having the structure of formula I, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, and an isotopic substitution thereof:
Wherein,
Z is OR1 or SR1; R1 is selected from the group consisting of hydrogen, deuterium, halogen, C1-6 alkyl, C1-6alkoxy, -C3-8cycloalkyl, -C0-6alkylene-C3-8heterocyclyl, -C0-6alkylene-NH-C0-6alkylene C6-10aryl, -C0-6alkylene-NH-C0-6alkylene-5-12 membered heteroaryl, -C0-6alkylene-C6-10aryl and -C0-6alkylene-5-12 membered heteroaryl; and each of which can be optional substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8cycloalkyl, -NH2, -NH (C1-6alkyl) , -N (C1-6alkyl) 2, -NH-C3-8cycloalkyl, carboxyl, -CO-C1-6alkyl; each of the heteroaryl and heterocyclyl contains 1, 2 or 3 heteroatoms selected from N, O or S;
X is selected from the group consisting of hydrogen, deuterium, C1-6alkyl, -C (=O) -G, -C (=O) -W- (CRX1RX2) m-O-RX3, -C (=O) -W- (CRX1RX2) m-S-RX3, C (=O) -W- (CRX1RX2) m-SO-RX3, C (=O) -W- (CRX1RX2) m-SO2-RX3, -C (=O) -W- (CRX1RX2) m-G, -C (=O) -W- (CRX1RX2) m-NR5R5’, -P (=O) (OR6) p (NHR7) q, -C (=O) -W- (CRX1RX2) m-G-O-C (=O) -R8, -C (=O) -W- (CRX1RX2) m-G-O-R8, -C (=O) -O- (CRX1RX2) m-O-C (=O) -R9, -C (=O) -O-R7, -C (=O) -W- (CRX1RX2) m-G-O-C (=O) -G, and -C (=O) -W- (CRX1RX2) m-G-NR5R5’;
W is oxygen, CO or a bond;
m is selected from 1, 2, 3, 4, 5, 6, 7 or 8;
p and q are each independently selected from 0, 1 or 2 provided that the sum of p and q is 2;
RX1 and RX2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, NH2, C1-6 alkyl, C1-6alkoxy, C4-10 cycloalkyl, -C (=O) -C1-6alkyl, C5-12aryl, –C1-6 alkylene-C5-12aryl, -5-12 membered heteroaryl, and –C1-6 alkylene-5-12 membered heteroaryl, and wherein said C1-6 alkyl, said C1-6alkoxy, said C4-10 cycloalkyl, said C5-12aryl, said–C1-6 alkylene-C5-12aryl, said -5-12 membered heteroaryl, and said–C1-6 alkylene-5-12 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-6alkyl) 2, -S-C1-6alkyl, carboxyl; and each of the heteroaryl independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S;
or RX1 and RX2 together with the carbon atom to which they are attached form C3-10carbocyclic ring, C3-10 membered heterocyclyl, and each of the heterocyclyl independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S; each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -NH2, -CN, -OH, -NO2, carbonyl, =O, oxo, carboxyl, C1-6alkoxy, C1-6alkyl;
RX3 is independently selected from the group consisting of hydrogen, deuterium, C1-6 alkyl, C1-6 alkoxy, C3-8 cycloalkyl, -C (=O) -C1-6 alkyl, and -C1-6alkylenen-C5-12 aryl, wherein said C1-6 alkyl, said C1-6 alkoxy, said C3-8 cycloalkyl, said -C (=O) -C1-6 alkyl, and said -C1-6alkylenen-C5-12 aryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-6alkyl) 2, carboxyl, 4-8 membered heterocyclyl, -C6-12aryl, -C (=O) -C1-6alkyl, -NH-C (=O) -C1-6alkyl, -C (=O) -NH2, -C (=O) -NH-C1-6alkyl, and -C (=O) -N (C1-6 alkyl) 2;
or RX1 and RX3 together with the carbon atom and the oxygen atom to which they are attached respectively form a 5-12 membered heterocyclyl, wherein said 5-12 membered heterocyclyl can be  optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-6alkyl) 2, carboxyl; and each of the heterocyclyl independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S;
R5 and R5’ are each independently selected from the group consisting of hydrogen, deuterium, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, C5-12 aryl, 5-12 membered heteroaryl, 5-12 membered heterocyclyl, and wherein said -C1-6 alkyl, said -C1-6 alkoxy, said -C3-8 cycloalkyl, said C5-12 aryl, said 5-12 membered heteroaryl, said 5-12 membered heterocyclyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-6alkyl) 2, carboxyl;
each of R6 is independently selected from the group consisting of hydrogen, deuterium, -C1-6 alkyl, -C3-8 cycloalkyl, 5-12 membered heterocyclyl ring, -C1-6 alkenyl, and -C3-8 cycloalkenyl, and wherein said -C1-6 alkyl, said -C3-8 cycloalkyl, said 5-12 membered heterocyclyl ring, said -C1-6 alkenyl, and said -C3-8 cycloalkenyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-6alkyl) 2, carboxyl;
or R6 together with the oxygen atom to which it is attached forms a purine or pyrimidine nucleoside;
each of R7 is independent selected from the group consisting of hydrogen, deuterium, halogen, C1-6 alkyl, C3-8 cycloalkyl, 5-12 membered heterocyclyl ring, C1-6 alkenyl, C3-8 cycloalkenyl, C5-12 aryl, and 5-12 membered heteroaryl, and wherein said C1-6 alkyl, said C3-8 cycloalkyl, said 5-12 membered heterocyclyl ring, said C1-6 alkenyl, said C3-8 cycloalkenyl, said C5-12 aryl, and said 5-12 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-6alkyl) 2, carboxyl;
R8 and R9 are each independently selected from the group consisting of C1-6 alkyl, C3-8 cycloalkyl, monosaccharide, acylated monosaccharide, C5-12 aryl, and 5-12 membered heteroaryl, and wherein said C1-6 alkyl, said C3-8 cycloalkyl, said monosaccharide, said acylated monosaccharide, said C5-12 aryl, and said 5-12 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-6alkyl) 2, carboxyl;
G is C5-12 aryl, or 5-12 membered heteroaryl, wherein C5-12 aryl, and 5-12 membered heteroaryl can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-6alkyl) 2, carboxyl;
R2 is selected from the group consisting of hydrogen, deuterium, halogen, C1-6 alkyl, and C1-6 alkoxy, and wherein said C1-6 alkyl, and said C1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-6alkyl) 2, carboxyl;
R3 and R3’ are each independently selected from the group consisting of hydrogen, deuterium, halogen, C1-6 alkyl, and C1-6 alkoxy, and wherein said C1-6 alkyl, and said C1-6 alkoxy can be optional substituted with one or more substituents, which are independently from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-6alkyl) 2, carboxyl;
Y is a bond, oxygen, or - (CRY1RY2) n-;
n is selected from 1, 2, 3, 4, 5, 6, 7 or 8;
RY1 and RY2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, C1-6 alkyl, and C1-6 alkoxy, and wherein said C1-6 alkyl, and said C1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-6alkyl) 2, carboxyl;
R4 is selected from the group consisting of hydrogen, deuterium, halogen, C1-6 alkyl, and C1-6 alkoxy, and wherein said C1-6 alkyl, and said C1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6alkyl, -C1-6alkoxy, -C3-8cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-6alkyl) 2, carboxyl;
R10 is selected from the group consisting of hydrogen, deuterium, halogen, C1-6 alkyl, and C1-6 alkoxy, and wherein said C1-6 alkyl, and said C1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6alkyl, -C1-6alkoxy, -C3-8cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-6alkyl) 2, carboxyl.
In some embodiments of the compound of Formula I, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereofe of the present invention, wherein the compound is of formula I-A:
In some embodiments of the compound of Formula I, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereofe of the present invention, wherein the compound is of formula I-B:
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R1 is selected from the group consisting of hydrogen, deuterium, halogen, C1-3 alkyl, C1-3 alkoxy, -C3-8cycloalkyl, -C0-3alkylene-C3-8heterocyclyl, -C0-3alkylene-NH-C0-3alkylene C6-10aryl, -C0-3alkylene-NH-C0-3alkylene-5-12membered heteroaryl, -C0-3alkylene-C6-10aryl and -C0-3alkylene-5-12 membered heteroaryl; and each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH (C1-6 alkyl) , -NH-C3-8 cycloalkyl, -N (C1-6alkyl) 2, carboxyl, -CO-C1-6alkyl; each of the heteroaryl and heterocyclyl contains 1 or 2 heteroatoms selected from N, O or S.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R1 is selected from the group consisting of hydrogen, deuterium, halogen, C1-3 alkyl, C1-3 alkoxy, -C3-8cycloalkyl, -C0-3alkylene-C3-8heterocyclyl, -C0-3alkylene-NH-C0-3alkylene C6-10aryl, -C0-3alkylene-NH-C0-3alkylene-5-12 membered heteroaryl, -C0-3alkylene-C6-10aryl and -C0-3alkylene-5-12 membered heteroaryl; each of the heteroaryl and heterocyclyl contains 1 or 2 heteroatoms selected from N or O; and wherein each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH (C1-6 alkyl) , -NH-C3-6 cycloalkyl, -N (C1-3alkyl) 2, carboxyl, -CO-C1-3alkyl; each of the heteroaryl and heterocyclyl contains 1 or 2 heteroatoms selected from N or O.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R1 is selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy,  and each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH (C1-6 alkyl) , -NH-C3-6 cycloalkyl, -N (C1-3alkyl) 2, carboxyl, -CO-C1-3alkyl.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R1 is selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy,  and each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH (CH3) 2, -N (CH3) 2, -N (CH2CH3) 2, -N (CH2CH2CH3) 2, -N (CH (CH3) 2) 2, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-cyclohexyl, carboxyl and -CO-tert-butyl.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R1 is seleted from hydrogen, deuterium, isopropyl, methyl, ethyl, -tert-butyl, -CF3, -CH2CF3, -CH(CH3) CF3, -CH (CH3) CH2CF3, - (CH2) 2CF3, - (CH2) 2-CH (CH3) 2, -C (CH3) 2CF3, -C (CH3) 2CH2CF3, -CN, -CH2CN, -CH (CH3) CN, -CH2CH2CN, -CH (CH3) CH2CN, -C (CH3) 2CN, -C (CH3) 2CH2CN, -CH2OH, -CH2-O-CH3, -CH2-O-CH2CH3, -CH2-O-CH (CH3) 2, 
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof,  the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein
X is selected from the group consisting of hydrogen, deuterium, C1-6 alkyl, -C (=O) -G, -C (=O) -W- (CRX1RX2) m-O-RX3, -C (=O) -W- (CRX1RX2) m-S-RX3, C (=O) -W- (CRX1RX2) m-SO-RX3, C (=O) -W- (CRX1RX2) m-SO2-RX3, -C (=O) -W- (CRX1RX2) m-G, -C (=O) -W- (CRX1RX2) m-NR5R5’, -P (=O) (OR6) p (NHR7) q, -C (=O) -W- (CRX1RX2) m-G-O-C (=O) -R8, -C (=O) -W- (CRX1RX2) m-G-O-R8, -C (=O) -O- (CRX1RX2) m-O-C (=O) -R9, -C (=O) -O-R7, -C (=O) -W- (CRX1RX2) m-G-O-C (=O) -G, and -C (=O) -W- (CRX1RX2) m-G-NR5R5’;
W is oxygen, CO or a bond;
m is selected from 1, 2 or 3;
p and q are each independently selected from 0, 1 or 2 provided that the sum of p and q is 2;
RX1 and RX2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, C1-4alkyl, C1-3alkoxy, C4-8 cycloalkyl, -C (=O) -C1-3alkyl, C5-10aryl, -C1-3 alkylene-C5-10aryl, 5-10 membered heteroaryl, and -C1-3 alkylene-5-10 membered heteroaryl, and wherein said C1-3 alkyl, said C1-3alkoxy, said C4-8 cycloalkyl, said C5-10aryl, said -C1-3 alkylene-C5-10aryl, said 5-10 membered heteroaryl, and said -C1-3 alkylene-5-10 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-6alkyl) 2, -S-C1-6alkyl or carboxyl; and each of the heteroaryl independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S;
or RX1 and RX2 together with the carbon atom to which they are attached form C4-8carbocyclic ring, C4-8 membered heterocyclyl, and each of the heterocyclyl independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S; each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -NH2, -CN, -OH, -NO2, carbonyl, =O, oxo, carboxyl, C1-6alkoxy, C1-6alkyl;
RX3 is independently selected from the group consisting of hydrogen, deuterium, C1-3 alkyl, C1-3 alkoxy, C3-6 cycloalkyl, -C (=O) -C1-3 alkyl, and -C1-3alkylenen-C5-10 aryl, wherein said C1-3 alkyl, said C1-3 alkoxy, said C3-6 cycloalkyl, said -C (=O) -C1-3 alkyl, and said -C1-3alkylenen-C5-10 aryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-6alkyl) 2, carboxyl, 4-8 membered heterocyclyl, -C6-12aryl, -C (=O) -C1-6alkyl, -NH-C (=O) -C1-6alkyl, -C (=O) -NH2, -C (=O) -NH-C1-6alkyl, and -C (=O) -N (C1-6 alkyl) 2;
or RX1 and RX3 together with the carbon atom and the oxygen atom to which they are attached respectively form a 5-10 membered heterocyclyl, wherein said 5-10 membered heterocyclyl can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-6alkyl) 2, carboxyl; and each of the heterocyclyl independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S;
R5 and R5’ are each independently selected from the group consisting of hydrogen, deuterium, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, C5-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, and wherein said -C1-3 alkyl, -C1-3 alkoxy, said -C3-6 cycloalkyl, said C5-10 aryl, said 5-10 membered heteroaryl, said 5-10 membered heterocyclyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-6alkyl) 2, carboxyl;
each of R6 is independently selected from the group consisting of hydrogen, deuterium, -C1-3 alkyl, -C3-6 cycloalkyl, 5-10 membered heterocyclyl ring, -C1-3alkenyl, and -C3-6 cycloalkenyl, and wherein said -C1-3 alkyl, said -C3-6 cycloalkyl, said 5-10 membered heterocyclyl ring, said -C1-3alkenyl, and said -C3-6 cycloalkenyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-6alkyl) 2, carboxyl;or R6 together with the oxygen atom to which it is attached forms a purine or pyrimidine nucleoside;
each of R7 is independent selected from the group consisting of hydrogen, deuterium, halogen, C1-3 alkyl, C3-6 cycloalkyl, 5-10 membered heterocyclyl ring, C1-3 alkenyl, C3-6 cycloalkenyl, C5-10 aryl, and 5-10 membered heteroaryl, and wherein said C1-3 alkyl, said C3-6 cycloalkyl, said 5-10 membered heterocyclyl ring, said C1-3 alkenyl, said C3-6 cycloalkenyl, said C5-10 aryl, and said 5-10 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH (C1-6  alkyl) , -N (C1-6alkyl) 2, carboxyl;
R8 and R9 are each independently selected from the group consisting of C1-3 alkyl, C3-6 cycloalkyl, monosaccharide, acylated monosaccharide, C5-10 aryl, and 5-10 membered heteroaryl, and wherein said C1-3 alkyl, said C3-6 cycloalkyl, said monosaccharide, said acylated monosaccharide, said C5-10 aryl, and said 5-10 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-6alkyl) 2, carboxyl; or
G is C5-10 aryl, or 5-10 membered heteroaryl, wherein C5-10 aryl, and 5-10 membered heteroaryl can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-6alkyl) 2, carboxyl.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein
X is selected from the group consisting of hydrogen, deuterium, C1-3 alkyl, –C (=O) -G, -C (=O) -W- (CRX1RX2) m-O-RX3, -C (=O) -W- (CRX1RX2) m-S-RX3, C (=O) -W- (CRX1RX2) m-SO-RX3, C (=O) -W- (CRX1RX2) m-SO2-RX3, -C (=O) -W- (CRX1RX2) m-G, -C (=O) -W- (CRX1RX2) m-NR5R5’, -P (=O) (OR6) p (NHR7) q, -C (=O) -W- (CRX1RX2) m-G-O-C (=O) -R8, -C (=O) -W- (CRX1RX2) m-G-O-R8, -C (=O) -O- (CRX1RX2) m-O-C (=O) -R9, -C (=O) -O-R7, -C (=O) -W- (CRX1RX2) m-G-O-C (=O) -G, and -C (=O) -W- (CRX1RX2) m-G-NR5R5’;
W is oxygen or a bond;
m is selected from 1, 2 or 3;
p and q are each independently selected from 0, 1 or 2 provided that the sum of p and q is 2;
RX1 and RX2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, C1-4 alkyl, C1-3alkoxy, C4-8 cycloalkyl, -C (=O) -C1-3alkyl, C5-10aryl, -C1-3 alkylene-C5-10aryl, 5-10 membered heteroaryl, and –C1-3 alkylene-5-10 membered heteroaryl, and wherein said C1-3 alkyl, said C1-3alkoxy, said C4-8cycloalkyl, said C5-10aryl, said–C1-3 alkylene-C5-10aryl, said 5-10 membered heteroaryl, and said–C1-3 alkylene-5-10 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-3alkyl) 2, -S-C1-3alkyl carboxyl; and each of the heteroaryl independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S;
or RX1 and RX2 together with the carbon atom to which they are attached form C4-6carbocyclic ring, C4-6 membered heterocyclyl, and each of the heterocyclyl independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S; each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -NH2, -CN, -OH, -NO2, oxo, carboxyl, C1-3alkoxy, C1-3alkyl;
RX3 is independently selected from the group consisting of hydrogen, deuterium, C1-3 alkyl, C1-3 alkoxy, C3-6 cycloalkyl, -C (=O) -C1-3 alkyl, and -C1-3alkylenen-C5-10 aryl, wherein said C1-3 alkyl, said C1-3 alkoxy, said C3-6 cycloalkyl, said -C (=O) -C1-3 alkyl, and said -C1-3alkylenen-C5-10 aryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH (C1-3 alkyl) , -N (C1-3alkyl) 2, -S-C1-3alkyl carboxyl, 4-6 membered heterocyclyl, -C6-10aryl, -C (=O) -C1-3alkyl, -NH-C (=O) -C1-3alkyl, -C (=O) -NH2, -C (=O) -NH-C1-3alkyl, -C (=O) -N (C1-3alkyl) 2;
or RX1 and RX3 together with the carbon atom and the oxygen atom to which they are attached respectively form a 5-10 membered heterocyclyl, wherein said 5-10 membered heterocyclyl can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH (C1-3 alkyl) , -N (C1-3alkyl) 2, carboxyl; and each of the heterocyclyl independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S;
R5 and R5’ are each independently selected from the group consisting of hydrogen, deuterium, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, C5-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, and wherein said -C1-3 alkyl, -C1-3 alkoxy, said -C3-6 cycloalkyl, said C5-10 aryl, said 5-10 membered heteroaryl, said 5-10 membered heterocyclyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH (C1-3 alkyl) , -N (C1-3alkyl) 2, carboxyl;
each of R6 is independently selected from the group consisting of hydrogen, deuterium, -C1-3 alkyl, -C3-6 cycloalkyl, 5-10 membered heterocyclyl ring, -C1-3alkenyl, and -C3-6 cycloalkenyl, and wherein said -C1-3  alkyl, said -C3-6 cycloalkyl, said 5-10 membered heterocyclyl ring, said -C1-3alkenyl, and said -C3-6 cycloalkenyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH (C1-3 alkyl) , -N (C1-3alkyl) 2, carboxyl;
or R6 together with the oxygen atom to which it is attached forms a purine or pyrimidine nucleoside;
each of R7 is independent selected from the group consisting of hydrogen, deuterium, halogen, C1-3 alkyl, C3-6 cycloalkyl, 5-10 membered heterocyclyl ring, C1-3 alkenyl, C3-6 cycloalkenyl, C5-10 aryl, and 5-10 membered heteroaryl, and wherein said C1-3 alkyl, said C3-6 cycloalkyl, said 5-10 membered heterocyclyl ring, said C1-3 alkenyl, said C3-6 cycloalkenyl, said C5-10 aryl, and said 5-10 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH (C1-3 alkyl) , -N (C1-3alkyl) 2, carboxyl;
R8 and R9 are each independently selected from the group consisting of C1-3 alkyl, C3-6 cycloalkyl, monosaccharide, acylated monosaccharide, C5-10 aryl, and 5-10 membered heteroaryl, and wherein said C1-3 alkyl, said C3-6 cycloalkyl, said monosaccharide, said acylated monosaccharide, said C5-10 aryl, and said 5-10 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH (C1-3 alkyl) , -N (C1-3alkyl) 2, carboxyl; or
G is C5-10 aryl, or 5-10 membered heteroaryl, wherein C5-10 aryl, and 5-10 membered heteroaryl can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH (C1-3 alkyl) , -N (C1-3alkyl) 2, carboxyl.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein
X is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, -C (=O) -G, -C (=O) -W- (CRX1RX2) m-O-RX3, -C (=O) -W- (CRX1RX2) m-S-RX3, C (=O) -W- (CRX1RX2) m-SO-RX3, C (=O) -W- (CRX1RX2) m-SO2-RX3, -C (=O) -W- (CRX1RX2) m-G, -C (=O) -W- (CRX1RX2) m-NR5R5’, -P (=O) (OR6) p (NHR7) q, -C (=O) -W- (CRX1RX2) m-G-O-C (=O) -R8, -C (=O) -W- (CRX1RX2) m-G-O-R8, -C (=O) -O- (CRX1RX2) m-O-C (=O) -R9, -C (=O) -O-R7, -C (=O) -W- (CRX1RX2) m-G-O-C (=O) -G, and -C (=O) -W- (CRX1RX2) m-G-NR5R5’;
W is oxygen or a bond;
m is selected from 1, 2 or 3;
p and q are each independently selected from 0, 1 or 2 provided that the sum of p and q is 2;
RX1 and RX2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, butyl, sec-butyl, iso-butyl, tert-butyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, -C (=O) -CH3, -C (=O) -CH2CH3, -C (=O) -CH2CH2CH3, -C (=O) -CH (CH3) 2, C5 aryl, C6aryl, C7 aryl, C8 aryl, C9 aryl, C10 aryl, -CH2-C5 aryl, -CH2-C6aryl, -CH2-C7 aryl, -CH2-C8 aryl, -CH2-C9 aryl, -CH2-C10 aryl, - (CH2) 2-C5 aryl, - (CH2) 2-C6aryl, - (CH2) 2-C7 aryl, - (CH2) 2-C8 aryl, - (CH2) 2-C9 aryl, - (CH2) 2-C10 aryl, - (CH2) 3-C5 aryl, - (CH2) 3-C6aryl, - (CH2) 3-C7 aryl, - (CH2) 3-C8 aryl, - (CH2) 3-C9 aryl, - (CH2) 3-C10 aryl, 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl, 10 membered heteroaryl, -CH2-5 membered heteroaryl, -CH2-6 membered heteroaryl, -CH2-7 membered heteroaryl, -CH2-8 membered heteroaryl, -CH2-9 membered heteroaryl, -CH2-10 membered heteroaryl, - (CH2) 2-5 membered heteroaryl, - (CH2) 2-6 membered heteroaryl, - (CH2) 2-7 membered heteroaryl, - (CH2) 2-8 membered heteroaryl, - (CH2) 2-9 membered heteroaryl, - (CH2) 2-10 membered heteroaryl, - (CH2) 3-5 membered heteroaryl, - (CH2) 3-6 membered heteroaryl, - (CH2) 3-7 membered heteroaryl, - (CH2) 3-8 membered heteroaryl, - (CH2) 3-9 membered heteroaryl, and - (CH2) 3-10 membered heteroaryl, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, said isopropoxy, said C5 aryl, said C6aryl, said C7 aryl, said C8 aryl, said C9 aryl, said C10 aryl, said -CH2-C5 aryl, said -CH2-C6aryl, said -CH2-C7 aryl, said -CH2-C8 aryl, said -CH2-C9 aryl, said -CH2-C10 aryl, said - (CH2) 2-C5 aryl, said - (CH2) 2-C6aryl, said - (CH2) 2-C7 aryl, said - (CH2) 2-C8 aryl, said - (CH2) 2-C9 aryl, said - (CH2) 2-C10 aryl, said - (CH2) 3-C5 aryl, said - (CH2) 3-C6aryl, said - (CH2) 3-C7 aryl, said - (CH2) 3-C8 aryl, said - (CH2) 3-C9 aryl, said - (CH2) 3-C10 aryl, said 5 membered heteroaryl, said 6 membered heteroaryl, said 7 membered heteroaryl, said 8 membered heteroaryl, said 9 membered heteroaryl, said 10 membered heteroaryl, said -CH2-5 membered heteroaryl, said -CH2-6 membered heteroaryl, said -CH2-7 membered heteroaryl, said -CH2-8 membered heteroaryl, said -CH2-9 membered heteroaryl, said -CH2-10 membered heteroaryl, said - (CH2) 2-5 membered heteroaryl, said - (CH2) 2-6 membered heteroaryl, said - (CH2) 2-7 membered heteroaryl, said - (CH2) 2-8 membered heteroaryl, said - (CH2) 2-9 membered heteroaryl, said - (CH2) 2-10 membered  heteroaryl, said - (CH2) 3-5 membered heteroaryl, said - (CH2) 3-6 membered heteroaryl, said - (CH2) 3-7 membered heteroaryl, said - (CH2) 3-8 membered heteroaryl, said - (CH2) 3-9 membered heteroaryl, and said - (CH2) 3-10 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-3alkyl) 2, -S-C1-3alkyl, carboxyl; and each of the heteroaryl independently optionally contains 1 or 2 heteroatoms selected from N, O or S; or RX1 and RX2 together with the carbon atom to which they are attached form 3-membered carbocyclic ring, 4-membered carbocyclic ring, 5-membered carbocyclic ring, or 6-membered carbocyclic ring, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, and each of the heterocyclyl independently optionally contains 1 or 2 heteroatoms selected from N or O; each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, -F, -Cl, -Br, -I, -NH2, -CN, -OH, -NO2, oxo, carboxyl, C1-3alkoxy, C1-3alkyl;
RX3 is independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, -C (=O) -CH3, -C (=O) -CH2CH3, -C (=O) -CH2CH2CH3, -C (=O) -CH (CH3) 2, -CH2-C5 aryl, - (CH2) 2-C5 aryl, - (CH2) 3-C5 aryl, -CH2-C6 aryl, - (CH2) 2-C6 aryl, - (CH2) 3-C6 aryl, -CH2-C7 aryl, - (CH2) 2-C7 aryl, - (CH2) 3-C7 aryl, -CH2-C8 aryl, - (CH2) 2-C8 aryl, - (CH2) 3-C8 aryl, -CH2-C9 aryl, - (CH2) 2-C9 aryl, - (CH2) 3-C9 aryl, -CH2-C10 aryl, - (CH2) 2-C10 aryl, - (CH2) 3-C10 aryl, wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, said isopropoxy, said C3 cycloalkyl, said C4 cycloalkyl, said C5 cycloalkyl, said C6 cycloalkyl, said -C (=O) -CH3, said -C (=O) -CH2CH3, said -C (=O) -CH2CH2CH3, said -C (=O) -CH (CH3) 2, said -CH2-C5 aryl, said - (CH2) 2-C5 aryl, said - (CH2) 3-C5 aryl, said -CH2-C6 aryl, said - (CH2) 2-C6 aryl, said - (CH2) 3-C6 aryl, said -CH2-C7 aryl, said - (CH2) 2-C7 aryl, said - (CH2) 3-C7 aryl, said -CH2-C8 aryl, said - (CH2) 2-C8 aryl, said - (CH2) 3-C8 aryl, said -CH2-C9 aryl, said - (CH2) 2-C9 aryl, said - (CH2) 3-C9 aryl, said -CH2-C10 aryl, said - (CH2) 2-C10 aryl, and said - (CH2) 3-C10 aryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH (C1-3 alkyl) , -N (C1-3alkyl) 2, carboxyl, 4-6 membered heterocyclyl, -C6-10aryl, -C (=O) -C1-3alkyl, -NH-C (=O) -C1-3alkyl, -C (=O) -NH2, -C (=O) -NH-C1-3alkyl, and -C (=O) -N (C1-3alkyl) 2;
or RX1 and RX3 together with the carbon atom and the oxygen atom to which they are attached respectively form 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, 7 membered heterocyclyl, 8 membered heterocyclyl, 9 membered heterocyclyl, 10 membered heterocyclyl, wherein said 4 membered heterocyclyl, said 5 membered heterocyclyl, said 6 membered heterocyclyl, said 7 membered heterocyclyl, said 8 membered heterocyclyl, said 9 membered heterocyclyl, said 10 membered heterocyclyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH(C1-3 alkyl) , -N (C1-3alkyl) 2, carboxyl; and each of the heterocyclyl independently optionally contains 1 or 2 heteroatoms selected from N, O or S;
R5 and R5’ are each independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, C5 aryl, C6 aryl, C7 aryl, C8 aryl, C9 aryl, C10 aryl, 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl, 10 membered heteroaryl, 5 membered heterocyclyl, 6 membered heterocyclyl, 7 membered heterocyclyl, 8 membered heterocyclyl, 9 membered heterocyclyl, 10 membered heterocyclyl, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, said isopropoxy, said -C3 cycloalkyl, said -C4 cycloalkyl, said -C5 cycloalkyl, said -C6 cycloalkyl, said C5 aryl, said C6 aryl, said C7 aryl, said C8 aryl, said C9 aryl, said C10 aryl, said 5 membered heteroaryl, said 6 membered heteroaryl, said 7 membered heteroaryl, said 8 membered heteroaryl, said 9 membered heteroaryl, said 10 membered heteroaryl, said 5 membered heterocyclyl, said 6 membered heterocyclyl, said 7 membered heterocyclyl, said 8 membered heterocyclyl, said 9 membered heterocyclyl, said 10 membered heterocyclyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH (C1-3 alkyl) , -N (C1-3alkyl) 2, carboxyl;
each of R6 is independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, 5 membered heterocyclyl ring, 6 membered heterocyclyl ring, 7 membered heterocyclyl ring, 8 membered heterocyclyl ring, 9 membered heterocyclyl ring, 10 membered heterocyclyl ring, vinyl, allyl, -C3 cycloalkenyl, -C4  cycloalkenyl, -C5 cycloalkenyl, -C6 cycloalkenyl, and wherein said methyl, said ethyl, said propyl, said isopropyl, said -C3 cycloalkyl, said -C4 cycloalkyl, said -C5 cycloalkyl, said -C6 cycloalkyl, said 5 membered heterocyclyl ring, said 6 membered heterocyclyl ring, said 7 membered heterocyclyl ring, said 8 membered heterocyclyl ring, said 9 membered heterocyclyl ring, said 10 membered heterocyclyl ring, said vinyl, said allyl, said -C3 cycloalkenyl, said -C4 cycloalkenyl, said -C5 cycloalkenyl, said -C6 cycloalkenyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH (C1-3 alkyl) , -N (C1-3alkyl) 2, carboxyl;
or R6 together with the oxygen atom to which it is attached forms a purine or pyrimidine nucleoside;
each of R7 is independent selected from the group consisting of hydrogen, deuterium, halogen, methyl, ethyl, propyl, isopropyl, C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, 5-10 membered heterocyclyl ring, 5 membered heterocyclyl ring, 6 membered heterocyclyl ring, 7 membered heterocyclyl ring, 8 membered heterocyclyl ring, 9 membered heterocyclyl ring, 10 membered heterocyclyl ring, vinyl, allyl, C3 cycloalkenyl, C4 cycloalkenyl, C5 cycloalkenyl, C6 cycloalkenyl, C5 aryl, C6 aryl, C7 aryl, C8 aryl, C9 aryl, C10 aryl, 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl, 10 membered heteroaryl, and wherein said methyl, said ethyl, said propyl, said isopropyl, said C3 cycloalkyl, said C4 cycloalkyl, said C5 cycloalkyl, said C6 cycloalkyl, said 5-10 membered heterocyclyl ring, said 5 membered heterocyclyl ring, said 6 membered heterocyclyl ring, said 7 membered heterocyclyl ring, said 8 membered heterocyclyl ring, said 9 membered heterocyclyl ring, said 10 membered heterocyclyl ring, said vinyl, said allyl, said C3 cycloalkenyl, said C4 cycloalkenyl, said C5 cycloalkenyl, said C6 cycloalkenyl, said C5 aryl, said C6 aryl, said C7 aryl, said C8 aryl, said C9 aryl, said C10 aryl, said 5 membered heteroaryl, said 6 membered heteroaryl, said 7 membered heteroaryl, said 8 membered heteroaryl, said 9 membered heteroaryl, said 10 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH (C1-3 alkyl) , -N (C1-3alkyl) 2, carboxyl;
R8 and R9 are each independently selected from the group consisting of C1-3 alkyl, C3-6 cycloalkyl, monosaccharide, acylated monosaccharide, C5-10 aryl, and 5-10 membered heteroaryl, and wherein said C1-3 alkyl, said C3-6 cycloalkyl, said monosaccharide, said acylated monosaccharide, said C5-10 aryl, and said 5-10 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3alkyl, -C1-3alkoxy, -C3-6cycloalkyl, -NH2, -NH (C1-3alkyl) , -N (C1-3alkyl) 2, or carboxyl; or
G is C5 aryl, C6 aryl, C7 aryl, C8 aryl, C9 aryl, C10 aryl, 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl, or 10 membered heteroaryl, wherein said C5 aryl, said C6 aryl, said C7 aryl, said C8 aryl, said C9 aryl, said C10 aryl, said 5 membered heteroaryl, said 6 membered heteroaryl, said 7 membered heteroaryl, said 8 membered heteroaryl, said 9 membered heteroaryl, or said 10 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3alkyl, -C1-3alkoxy, -C3-6cycloalkyl, -NH2, -NH (C1-3alkyl) , -N (C1-3alkyl) 2, carboxyl.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein
X is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, –C (=O) -G, -C (=O) -W- (CRX1RX2) m-O-RX3, -C (=O) -W- (CRX1RX2) m-S-RX3, C (=O) -W- (CRX1RX2) m-SO-RX3, C (=O) -W- (CRX1RX2) m-SO2-RX3, –C (=O) -W- (CRX1RX2) m-G, –C (=O) -W- (CRX1RX2) m-NR5R5’, -P (=O) (OR6) p (NHR7) q, –C (=O) -W- (CRX1RX2) m-G-O-C (=O) -R8, –C (=O) -W- (CRX1RX2) m-G-O-R8, –C (=O) -O- (CRX1RX2) m-O-C (=O) -R9, -C (=O) -O-R7, –C (=O) -W- (CRX1RX2) m-G-O-C (=O) -G, and –C (=O) -W- (CRX1RX2) m-G-NR5R5’;
W is oxygen or a bond;
m is selected from 1, 2 or 3;
p and q are each independently selected from 0, 1 or 2 provided that the sum of p and q is 2;
RX1 and RX2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, butyl, sec-butyl, iso-butyl, tert-butyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, -C (=O) -CH3, -C (=O) -CH2CH3, -C (=O) -CH2CH2CH3, -C (=O) -CH (CH3) 2, C5 aryl, C6aryl, C7 aryl, C8 aryl, C9 aryl, C10 aryl, -CH2-C5 aryl, -CH2-C6aryl, -CH2-C7 aryl, -CH2-C8 aryl, -CH2-C9 aryl, -CH2-C10 aryl, - (CH2) 2-C5 aryl, - (CH2) 2-C6aryl, - (CH2) 2-C7 aryl, - (CH2) 2-C8 aryl, - (CH2) 2-C9 aryl, - (CH2) 2-C10 aryl, - (CH2) 3-C5 aryl, - (CH2) 3-C6aryl, - (CH2) 3-C7 aryl, - (CH2) 3-C8 aryl, - (CH2) 3-C9 aryl, - (CH2) 3-C10 aryl, 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl, 10 membered heteroaryl, -CH2-5  membered heteroaryl, -CH2-6 membered heteroaryl, -CH2-7 membered heteroaryl, -CH2-8 membered heteroaryl, -CH2-9 membered heteroaryl, -CH2-10 membered heteroaryl, - (CH2) 2-5 membered heteroaryl, - (CH2) 2-6 membered heteroaryl, - (CH2) 2-7 membered heteroaryl, - (CH2) 2-8 membered heteroaryl, - (CH2) 2-9 membered heteroaryl, - (CH2) 2-10 membered heteroaryl, - (CH2) 3-5 membered heteroaryl, - (CH2) 3-6 membered heteroaryl, - (CH2) 3-7 membered heteroaryl, - (CH2) 3-8 membered heteroaryl, - (CH2) 3-9 membered heteroaryl, and - (CH2) 3-10 membered heteroaryl, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, said isopropoxy, said C5 aryl, said C6aryl, said C7 aryl, said C8 aryl, said C9 aryl, said C10 aryl, said -CH2-C5 aryl, said -CH2-C6aryl, said -CH2-C7 aryl, said -CH2-C8 aryl, said -CH2-C9 aryl, said -CH2-C10 aryl, said - (CH2) 2-C5 aryl, said - (CH2) 2-C6aryl, said - (CH2) 2-C7 aryl, said - (CH2) 2-C8 aryl, said - (CH2) 2-C9 aryl, said - (CH2) 2-C10 aryl, said - (CH2) 3-C5 aryl, said - (CH2) 3-C6aryl, said - (CH2) 3-C7 aryl, said - (CH2) 3-C8 aryl, said - (CH2) 3-C9 aryl, said - (CH2) 3-C10 aryl, said 5 membered heteroaryl, said 6 membered heteroaryl, said 7 membered heteroaryl, said 8 membered heteroaryl, said 9 membered heteroaryl, said 10 membered heteroaryl, said -CH2-5 membered heteroaryl, said -CH2-6 membered heteroaryl, said -CH2-7 membered heteroaryl, said -CH2-8 membered heteroaryl, said -CH2-9 membered heteroaryl, said -CH2-10 membered heteroaryl, said - (CH2) 2-5 membered heteroaryl, said - (CH2) 2-6 membered heteroaryl, said - (CH2) 2-7 membered heteroaryl, said - (CH2) 2-8 membered heteroaryl, said - (CH2) 2-9 membered heteroaryl, said - (CH2) 2-10 membered heteroaryl, said - (CH2) 3-5 membered heteroaryl, said - (CH2) 3-6 membered heteroaryl, said - (CH2) 3-7 membered heteroaryl, said - (CH2) 3-8 membered heteroaryl, said - (CH2) 3-9 membered heteroaryl, and said - (CH2) 3-10 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH (CH3) 2, -N (CH3) 2, -N (CH2CH3) 2, -N(CH2CH2CH3) 2, -N (CH (CH3) 2) 2, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-cyclohexyl, -S-methyl and carboxyl; and each of the heteroaryl independently optionally contains 1 or 2 heteroatoms selected from N, O or S;
or RX1 and RX2 together with the carbon atom to which they are attached form 3-membered carbocyclic ring, 4-membered carbocyclic ring, 5-membered carbocyclic ring, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, and each of the heterocyclyl independently optionally contains 1 or 2 heteroatoms selected from N or O; each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, -F, -Cl, -Br, -I, -NH2, -CN, -OH, -NO2, oxo, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy;
RX3 is independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, -C (=O) -CH3, -C (=O) -CH2CH3, -C (=O) -CH2CH2CH3, -C (=O) -CH (CH3) 2, -CH2-C5 aryl, - (CH2) 2-C5 aryl, - (CH2) 3-C5 aryl, -CH2-C6 aryl, - (CH2) 2-C6 aryl, - (CH2) 3-C6 aryl, -CH2-C7 aryl, - (CH2) 2-C7 aryl, - (CH2) 3-C7 aryl, -CH2-C8 aryl, - (CH2) 2-C8 aryl, - (CH2) 3-C8 aryl, -CH2-C9 aryl, - (CH2) 2-C9 aryl, - (CH2) 3-C9 aryl, -CH2-C10 aryl, - (CH2) 2-C10 aryl, - (CH2) 3-C10 aryl, wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, said isopropoxy, said C3 cycloalkyl, said C4 cycloalkyl, said C5 cycloalkyl, said C6 cycloalkyl, said -C (=O) -CH3, said -C (=O) -CH2CH3, said -C (=O) -CH2CH2CH3, said -C (=O) -CH (CH3) 2, said -CH2-C5 aryl, said - (CH2) 2-C5 aryl, said - (CH2) 3-C5 aryl, said -CH2-C6 aryl, said - (CH2) 2-C6 aryl, said - (CH2) 3-C6 aryl, said -CH2-C7 aryl, said - (CH2) 2-C7 aryl, said - (CH2) 3-C7 aryl, said -CH2-C8 aryl, said - (CH2) 2-C8 aryl, said - (CH2) 3-C8 aryl, said -CH2-C9 aryl, said - (CH2) 2-C9 aryl, said - (CH2) 3-C9 aryl, said -CH2-C10 aryl, said - (CH2) 2-C10 aryl, and said - (CH2) 3-C10 aryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, -C6aryl, -C (=O) -CH3, -NH-C (=O) -CH3, -C (=O) -NH2, -C (=O) -NH-CH3, -C (=O) -N (CH3) 2, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH (CH3) 2, -N (CH3) 2, -N (CH2CH3) 2, -N (CH2CH2CH3) 2, -N (CH (CH3) 2) 2, and carboxyl;
or RX1 and RX3 together with the carbon atom and the oxygen atom to which they are attached respectively form 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, 7 membered heterocyclyl, 8 membered heterocyclyl, 9 membered heterocyclyl, 10 membered heterocyclyl, wherein said 4 membered heterocyclyl, said 5 membered heterocyclyl, said 6 membered heterocyclyl, said 7 membered heterocyclyl, said 8 membered heterocyclyl, said 9 membered heterocyclyl, said 10 membered heterocyclyl, can be optional substituted with one or more substituents, which are independently selected from the group  consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH (CH3) 2, -N (CH3) 2, -N (CH2CH3) 2, -N (CH2CH2CH3) 2, -N (CH (CH3) 2) 2, and carboxyl; and each of the heterocyclyl independently optionally contains 1 or 2 heteroatoms selected from N, O or S;
R5 and R5’ are each independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, C5 aryl, C6 aryl, C7 aryl, C8 aryl, C9 aryl, C10 aryl, 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl, 10 membered heteroaryl, 5 membered heterocyclyl, 6 membered heterocyclyl, 7 membered heterocyclyl, 8 membered heterocyclyl, 9 membered heterocyclyl, 10 membered heterocyclyl, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, said isopropoxy, said -C3 cycloalkyl, said -C4 cycloalkyl, said -C5 cycloalkyl, said -C6 cycloalkyl, said C5 aryl, said C6 aryl, said C7 aryl, said C8 aryl, said C9 aryl, said C10 aryl, said 5 membered heteroaryl, said 6 membered heteroaryl, said 7 membered heteroaryl, said 8 membered heteroaryl, said 9 membered heteroaryl, said 10 membered heteroaryl, said 5 membered heterocyclyl, said 6 membered heterocyclyl, said 7 membered heterocyclyl, said 8 membered heterocyclyl, said 9 membered heterocyclyl, said 10 membered heterocyclyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH (CH3) 2, -N (CH3) 2, -N (CH2CH3) 2, -N (CH2CH2CH3) 2, -N (CH (CH3) 2) 2, and carboxyl;
each of R6 is independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, 5 membered heterocyclyl ring, 6 membered heterocyclyl ring, 7 membered heterocyclyl ring, 8 membered heterocyclyl ring, 9 membered heterocyclyl ring, 10 membered heterocyclyl ring, vinyl, allyl, -C3 cycloalkenyl, -C4 cycloalkenyl, -C5 cycloalkenyl, -C6 cycloalkenyl, and wherein said methyl, said ethyl, said propyl, said isopropyl, said -C3 cycloalkyl, said -C4 cycloalkyl, said -C5 cycloalkyl, said -C6 cycloalkyl, said 5 membered heterocyclyl ring, said 6 membered heterocyclyl ring, said 7 membered heterocyclyl ring, said 8 membered heterocyclyl ring, said 9 membered heterocyclyl ring, said 10 membered heterocyclyl ring, said vinyl, said allyl, said -C3 cycloalkenyl, said -C4 cycloalkenyl, said -C5 cycloalkenyl, said -C6 cycloalkenyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH (CH3) 2, -N (CH3) 2, -N (CH2CH3) 2, -N (CH2CH2CH3) 2, -N (CH (CH3) 2) 2, and carboxyl;
or R6 together with the oxygen atom to which it is attached forms a purine or pyrimidine nucleoside;
each of R7 is independent selected from the group consisting of hydrogen, deuterium, halogen, methyl, ethyl, propyl, isopropyl, C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, 5-10 membered heterocyclyl ring, 5 membered heterocyclyl ring, 6 membered heterocyclyl ring, 7 membered heterocyclyl ring, 8 membered heterocyclyl ring, 9 membered heterocyclyl ring, 10 membered heterocyclyl ring, vinyl, allyl, C3 cycloalkenyl, C4 cycloalkenyl, C5 cycloalkenyl, C6 cycloalkenyl, C5 aryl, C6 aryl, C7 aryl, C8 aryl, C9 aryl, C10 aryl, 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl, 10 membered heteroaryl, and wherein said methyl, said ethyl, said propyl, said isopropyl, said C3 cycloalkyl, said C4 cycloalkyl, said C5 cycloalkyl, said C6 cycloalkyl, said 5-10 membered heterocyclyl ring, said 5 membered heterocyclyl ring, said 6 membered heterocyclyl ring, said 7 membered heterocyclyl ring, said 8 membered heterocyclyl ring, said 9 membered heterocyclyl ring, said 10 membered heterocyclyl ring, said vinyl, said allyl, said C3 cycloalkenyl, said C4 cycloalkenyl, said C5 cycloalkenyl, said C6 cycloalkenyl, said C5 aryl, said C6 aryl, said C7 aryl, said C8 aryl, said C9 aryl, said C10 aryl, said 5 membered heteroaryl, said 6 membered heteroaryl, said 7 membered heteroaryl, said 8 membered heteroaryl, said 9 membered heteroaryl, said 10 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH (CH3) 2, -N (CH3) 2, -N (CH2CH3) 2, -N (CH2CH2CH3) 2, -N (CH (CH3) 2) 2, and carboxyl;
R8 and R9 are each independently selected from the group consisting of C1-3 alkyl, C3-6 cycloalkyl, monosaccharide, acylated monosaccharide, C5-10 aryl, and 5-10 membered heteroaryl, and wherein said C1-3 alkyl, said C3-6 cycloalkyl, said monosaccharide, said acylated monosaccharide, said C5-10 aryl, and said 5-10 membered heteroaryl, can be optional substituted with one or more substituents, which are  independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH (CH3) 2, -N (CH3) 2, -N (CH2CH3) 2, -N (CH2CH2CH3) 2, -N (CH (CH3) 2) 2, and carboxyl; or
G is C5 aryl, C6 aryl, C7 aryl, C8 aryl, C9 aryl, C10 aryl, 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl, or 10 membered heteroaryl, wherein said C5 aryl, said C6 aryl, said C7 aryl, said C8 aryl, said C9 aryl, said C10 aryl, said 5 membered heteroaryl, said 6 membered heteroaryl, said 7 membered heteroaryl, said 8 membered heteroaryl, said 9 membered heteroaryl, or said 10 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH (CH3) 2, -N (CH3) 2, -N(CH2CH3) 2, -N (CH2CH2CH3) 2, -N (CH (CH3) 2) 2, and carboxyl.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein
X is -C (=O) -W- (CRX1RX2) m-O-RX3;
W is a bond;
m is 1 or 2;
RX1 and RX2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, butyl, sec-butyl, iso-butyl, tert-butyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, -C (=O) -CH3, -C (=O) -CH2CH3, -C (=O) -CH2CH2CH3, -C (=O) -CH (CH3) 2, C5 aryl, C6aryl, C7 aryl, C8 aryl, C9 aryl, C10 aryl, -CH2-C5 aryl, -CH2-C6aryl, -CH2-C7 aryl, -CH2-C8 aryl, -CH2-C9 aryl, -CH2-C10 aryl, - (CH2) 2-C5 aryl, - (CH2) 2-C6aryl, - (CH2) 2-C7 aryl, - (CH2) 2-C8 aryl, - (CH2) 2-C9 aryl, - (CH2) 2-C10 aryl, - (CH2) 3-C5 aryl, - (CH2) 3-C6aryl, - (CH2) 3-C7 aryl, - (CH2) 3-C8 aryl, - (CH2) 3-C9 aryl, - (CH2) 3-C10 aryl, 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl, 10 membered heteroaryl, -CH2-5 membered heteroaryl, -CH2-6 membered heteroaryl, -CH2-7 membered heteroaryl, -CH2-8 membered heteroaryl, -CH2-9 membered heteroaryl, -CH2-10 membered heteroaryl, - (CH2) 2-5 membered heteroaryl, - (CH2) 2-6 membered heteroaryl, - (CH2) 2-7 membered heteroaryl, - (CH2) 2-8 membered heteroaryl, - (CH2) 2-9 membered heteroaryl, - (CH2) 2-10 membered heteroaryl, - (CH2) 3-5 membered heteroaryl, - (CH2) 3-6 membered heteroaryl, - (CH2) 3-7 membered heteroaryl, - (CH2) 3-8 membered heteroaryl, - (CH2) 3-9 membered heteroaryl, and - (CH2) 3-10 membered heteroaryl, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, said isopropoxy, said C5 aryl, said C6aryl, said C7 aryl, said C8 aryl, said C9 aryl, said C10 aryl, said -CH2-C5 aryl, said -CH2-C6aryl, said -CH2-C7 aryl, said -CH2-C8 aryl, said -CH2-C9 aryl, said -CH2-C10 aryl, said - (CH2) 2-C5 aryl, said - (CH2) 2-C6aryl, said - (CH2) 2-C7 aryl, said - (CH2) 2-C8 aryl, said - (CH2) 2-C9 aryl, said - (CH2) 2-C10 aryl, said - (CH2) 3-C5 aryl, said - (CH2) 3-C6aryl, said - (CH2) 3-C7 aryl, said - (CH2) 3-C8 aryl, said - (CH2) 3-C9 aryl, said - (CH2) 3-C10 aryl, said 5 membered heteroaryl, said 6 membered heteroaryl, said 7 membered heteroaryl, said 8 membered heteroaryl, said 9 membered heteroaryl, said 10 membered heteroaryl, said -CH2-5 membered heteroaryl, said -CH2-6 membered heteroaryl, said -CH2-7 membered heteroaryl, said -CH2-8 membered heteroaryl, said -CH2-9 membered heteroaryl, said -CH2-10 membered heteroaryl, said - (CH2) 2-5 membered heteroaryl, said - (CH2) 2-6 membered heteroaryl, said - (CH2) 2-7 membered heteroaryl, said - (CH2) 2-8 membered heteroaryl, said - (CH2) 2-9 membered heteroaryl, said - (CH2) 2-10 membered heteroaryl, said - (CH2) 3-5 membered heteroaryl, said - (CH2) 3-6 membered heteroaryl, said - (CH2) 3-7 membered heteroaryl, said - (CH2) 3-8 membered heteroaryl, said - (CH2) 3-9 membered heteroaryl, and said - (CH2) 3-10 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH (CH3) 2, -N (CH3) 2, -N (CH2CH3) 2, -N (CH2CH2CH3) 2, -N (CH (CH3) 2) 2, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-cyclohexyl, -S-methyl and carboxyl; and each of the heteroaryl independently optionally contains 1 or 2 heteroatoms selected from N, O or S;
or RX1 and RX2 together with the carbon atom to which they are attached form 3-membered carbocyclic ring, 4-membered carbocyclic ring, 5-membered carbocyclic ring, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, and each of the heterocyclyl independently optionally contains 1 or 2 heteroatoms selected from N or O; each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy; or
RX3 is independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, -C (=O) -CH3, -C (=O) -CH2CH3, -C (=O) -CH2CH2CH3, -C (=O) -CH (CH3) 2, -CH2-C5 aryl, - (CH2) 2-C5 aryl, - (CH2) 3-C5 aryl, -CH2-C6 aryl, - (CH2) 2-C6 aryl, - (CH2) 3-C6 aryl, -CH2-C7 aryl, - (CH2) 2- C7 aryl, - (CH2) 3-C7 aryl, -CH2-C8 aryl, - (CH2) 2-C8 aryl, - (CH2) 3-C8 aryl, -CH2-C9 aryl, - (CH2) 2-C9 aryl, - (CH2) 3-C9 aryl, -CH2-C10 aryl, - (CH2) 2-C10 aryl, - (CH2) 3-C10 aryl, wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, said isopropoxy, said C3 cycloalkyl, said C4 cycloalkyl, said C5 cycloalkyl, said C6 cycloalkyl, said -C (=O) -CH3, said -C (=O) -CH2CH3, said -C (=O) -CH2CH2CH3, said -C (=O) -CH (CH3) 2, said -CH2-C5 aryl, said - (CH2) 2-C5 aryl, said - (CH2) 3-C5 aryl, said -CH2-C6 aryl, said - (CH2) 2-C6 aryl, said - (CH2) 3-C6 aryl, said -CH2-C7 aryl, said - (CH2) 2-C7 aryl, said - (CH2) 3-C7 aryl, said -CH2-C8 aryl, said - (CH2) 2-C8 aryl, said - (CH2) 3-C8 aryl, said -CH2-C9 aryl, said - (CH2) 2-C9 aryl, said - (CH2) 3-C9 aryl, said -CH2-C10 aryl, said - (CH2) 2-C10 aryl, and said - (CH2) 3-C10 aryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, -C6aryl, -C (=O) -CH3, -NH-C (=O) -CH3, -C (=O) -NH2, -C (=O) -NH-CH3, -C (=O) -N (CH3) 2, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH (CH3) 2, -N (CH3) 2, -N (CH2CH3) 2, -N (CH2CH2CH3) 2, -N (CH (CH3) 2) 2, and carboxyl;
or RX1 and RX3 together with the carbon atom and the oxygen atom to which they are attached respectively form 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, 7 membered heterocyclyl, 8 membered heterocyclyl, 9 membered heterocyclyl, 10 membered heterocyclyl, wherein said 4 membered heterocyclyl, said 5 membered heterocyclyl, said 6 membered heterocyclyl, said 7 membered heterocyclyl, said 8 membered heterocyclyl, said 9 membered heterocyclyl, said 10 membered heterocyclyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH (CH3) 2, -N (CH3) 2, -N (CH2CH3) 2, -N (CH2CH2CH3) 2, -N (CH (CH3) 2) 2, and carboxyl; and each of the heterocyclyl independently optionally contains 1 or 2 heteroatoms selected from N, O or S.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein
X is -C (=O) -W- (CRX1RX2) m-O-RX3;
W is a bond;
m is 1 or 2;
RX1 and RX2 are each independently selected from the group consisting of hydrogen, deuterium, CN, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, butyl, sec-butyl, iso-butyl, tert-butyl, cyclobutyl, cyclopentyl, -C (=O) -CH3,  and each of which is independently optionally subsitituted with deuterium, -F, -Cl, -Br, -I, -NH2, -CN, -OH, oxo, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -NHmethyl, -NHethyl, -NHpropyl, -NHcyclopropyl, -NHisopropyl, -N (CH3) 2, -NH-cyclobutyl, -NH-cyclopentyl, -NH-cyclohexyl, or -S-methyl;
or RX1 and RX2 together with the carbon atom to which they are attached form 
RX3 is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, tert-butyl, -CD3, -C (=O) -CH2-CN, -C (=O) -C (CH3) 3, -C (=O) -CH3, -C (=O) -CH2CH3, -C (=O) -NH-CH3, -C (=O) -CH2-N (CH3) 2, -CH2-C (=O) -CH3, -CH2-C (=O) -NHCH3, -CH2-C (=O) -N (CH3) 2, -CH2-NH2, -CH2-NH-CH3, -CH2CH2-OH, -CH2CH2-CN, -CH2-CN, -CH2CH2-C (=O) -NH2, -CH2CH2-C (=O) -NH-CH3, -CH2CH2-NH-C (=O) -CH3, 
or RX1 and RX3 together with the carbon atom and the oxygen atom to which they are attached respectively form
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein
X is -C (=O) -CRX1RX2-O-RX3;
RX1 and RX2 are each independently selected from the group consisting of hydrogen, deuterium, CN, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, butyl, sec-butyl, iso-butyl, tert-butyl, cyclobutyl, cyclopentyl, -C (=O) -CH3, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, 
RX3 is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, tert-butyl, -CD3, -C (=O) -CH2-CN, -C (=O) -C (CH3) 3, -C (=O) -CH3, -C (=O) -CH2CH3, 
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention,  wherein R2 is selected from the group consisting of hydrogen, deuterium, halogen, C1-3 alkyl, and C1-3 alkoxy, and wherein said C1-3 alkyl, and said C1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-6alkyl) 2, and carboxyl.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R2 is selected from the group consisting of hydrogen, deuterium, halogen, C1-3 alkyl, and C1-3 alkoxy, and wherein said C1-3 alkyl, and said C1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH (C1-3 alkyl) , -N (C1-3alkyl) 2, and carboxyl.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R2 is selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, and said isopropoxy, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH (C1-3 alkyl) , -N (C1-3alkyl) 2, and carboxyl.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R2 is selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, and said isopropoxy, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH (CH3) 2, -N (CH3) 2, -N(CH2CH3) 2, -N (CH2CH2CH3) 2, -N (CH (CH3) 2) 2, and carboxyl. Preferably, R2 is selected from hydrogen or deuterium.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R3 and R3’ are each independently selected from the group consisting of hydrogen, deuterium, halogen, C1-3 alkyl, and C1-3 alkoxy, and wherein said C1-3 alkyl, and said C1-3 alkoxy can be optional substituted with one or more substituents, which are independently from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-6alkyl) 2, and carboxyl.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R3 and R3’ are each independently selected from the group consisting of hydrogen, deuterium, halogen, C1-3 alkyl, and C1-3 alkoxy, and wherein said C1-3 alkyl, and said C1-3 alkoxy can be optional substituted with one or more substituents, which are independently from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH (C1-3 alkyl) , -N (C1-3alkyl) 2, and carboxyl.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R3 and R3’ are each independently selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, and said isopropoxy, can be optional substituted with one or more substituents, which are independently from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH (C1-3 alkyl) , -N (C1-3alkyl) 2, and carboxyl.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R3 and R3’ are each independently selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, and said isopropoxy, can be optional substituted with one or more substituents, which are independently from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH (CH3) 2, -N (CH3) 2, -N (CH2CH3) 2, -N (CH2CH2CH3) 2, -N (CH (CH3) 2) 2, and carboxyl. Preferably, R3 and R3’ are each independently selected from hydrogen or deuterium.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention,  wherein
Y is a bond, or - (CRY1RY2) n-;
n is selected from 1, 2, or 3;
RY1 and RY2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, C1-3 alkyl, and C1-3 alkoxy, and wherein said C1-3 alkyl, and said C1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-6alkyl) 2, and carboxyl.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein
Y is a bond, or - (CRY1RY2) n-;
n is selected from 1, 2, or 3;
RY1 and RY2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, C1-3 alkyl, and C1-3 alkoxy, and wherein said C1-3 alkyl, and said C1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH (C1-3 alkyl) , -N (C1-3alkyl) 2, and carboxyl.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein
Y is a bond, or - (CRY1RY2) n-;
n is selected from 1, 2, or 3;
RY1 and RY2 are each independently selected from the group consisting of F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, and said isopropoxy, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH (C1-3 alkyl) , -N (C1-3alkyl) 2, and carboxyl.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein
Y is a bond, or - (CRY1RY2) n-;
n is selected from 1, 2, or 3;
RY1 and RY2 are each independently selected from the group consisting of F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, and said isopropoxy, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH (CH3) 2, -N (CH3) 2, -N (CH2CH3) 2, -N (CH2CH2CH3) 2, and -N (CH (CH3) 2) 2, and carboxyl.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein Y is -CH2-.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R4 is selected from the group consisting of hydrogen, deuterium, halogen, C1-3 alkyl, and C1-3 alkoxy, and wherein said C1-3 alkyl, and said C1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-6alkyl) 2, and carboxyl.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R4 is selected from the group consisting of hydrogen, deuterium, halogen, C1-3 alkyl, and C1-3 alkoxy, and wherein said C1-3 alkyl, and said C1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3alkoxy, -C3-6 cycloalkyl, -NH2, -NH (C1-3 alkyl) , -N (C1-3alkyl) 2, and carboxyl.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R4 is selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, and said isopropoxy, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo,  -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH (C1-3 alkyl) , -N (C1-3alkyl) 2, and carboxyl.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R4 is selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, and said isopropoxy, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH (CH3) 2, -N (CH3) 2, -N (CH2CH3) 2, -N (CH2CH2CH3) 2, and -N (CH (CH3) 2) 2, and carboxyl. Preferably, R4 is selected from hydrogen or deuterium.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R10 is selected from the group consisting of hydrogen, deuterium, halogen, C1-3 alkyl, and C1-3 alkoxy, and wherein said C1-3 alkyl, and said C1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-6alkyl) 2, and carboxyl.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R10 is selected from the group consisting of hydrogen, deuterium, halogen, C1-3 alkyl, and C1-3 alkoxy, and wherein said C1-3 alkyl, and said C1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH (C1-3 alkyl) , -N (C1-3alkyl) 2, and carboxyl.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R10 is selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, and said isopropoxy, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH (C1-3 alkyl) , -N (C1-3alkyl) 2, and carboxyl.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R10 is selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, and said isopropoxy, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH (CH3) 2, -N (CH3) 2, -N (CH2CH3) 2, -N (CH2CH2CH3) 2, and -N (CH (CH3) 2) 2, and carboxyl. Preferably, R10 is hydrogen or deuterium.
In some embodiments, the glutamine antagonist is a compound of Formula I-C, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, and an isotopic substitution thereof:
wherein Q is O, S, SO, or SO2; Z, RX1, RX2, RX3, and m are the same as defined herein.
In some embodiments, the glutamine antagonist is a compound of Formula II, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, and an isotopic substitution thereof:
wherein Z, RX1, RX2, RX3, and m are the same as defined herein.
In some embodiments, the glutamine antagonist is a compound of Formula III, or the pharmaceutically  acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof: 
wherein R1, RX1, RX2, RX3, and m are the same as defined herein.
In some embodiments, the glutamine antagonist is a compound of Formula IV, or the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof :
In some embodiments, the glutamine antagonist is a compound of Formula V, or the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof:
In some embodiments, the glutamine antagonist is a compound of Formula VI, or the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof:
In some embodiments, the glutamine antagonist is a compound of Formula VII, or the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof:
In some embodiments, the glutamine antagonist is a compound of Formula VIII or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an isotopic substitution thereof:
wherein R1, RX1, RX2, RX3, and m are the same as defined herein
In some embodiments of the compound of Formula I, I-A, I-B, I-C, II, III, IV, V, VI, VII, or VIII, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein one or more hydrogen is optionally substitued with deuterium.
In some embodiments of the compound of Formula I, I-A, I-B, I-C, II, III, IV, V, VI, VII, or VIII, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein one or more hydrogen in R1 or RX3 is substitued with deuterium, preferably, all hydrogens on one or more methyl groups, methylene groups, or methane groups are  substituted with deuterium.
In some embodiments of the compound of Formula I, I-A, I-B, I-C, II, III, IV, V, VI, VII, or VIII, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R1 is selected from the group consisting of hydrogen, deuterium, hydrogen, deuterium, C1-3 alkyl, C1-3 alkoxy, and each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy;
RX1 and RX2 are each independently selected from the group consisting of hydrogen, deuterium, CN, OH,
C1-4alkyl, C1-3alkoxy, each of which can be optional substituted with one or more substituents, which are
independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3
alkoxy, -C3-6 cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-3alkyl) 2, -S-C1-3alkyl; or
RX3 is independently selected from the group consisting of hydrogen, deuterium, C1-3 alkyl, C1-3 alkoxy, each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH (C1-3 alkyl) , -N (C1-3alkyl) 2, carboxy, -S-C1-3alkyl.
In some embodiments of the compound of Formula I, I-A, I-B, I-C, II, III, IV, V, VI, VII, or VIII, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R1 is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy; and each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy;
RX1 and RX2 are each independently selected from the group consisting of hydrogen, deuterium, CN, CF3,
methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, butyl, sec-butyl, iso-butyl, tert-butyl,
and each of which is independently optionally subsitituted with deuterium, -F, -Cl, -Br, -I, -NH2, -CN, -OH,
oxo, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy; or
RX3 is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, tert-butyl, each of which can be substituted with deuterium.
In some embodiments of the compound of Formula I, I-A, I-B, I-C, II, III, IV, V, VI, VII, or VIII, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R1 is seleted from hydrogen, deuterium, isopropyl, methyl, ethyl, -tert-butyl, isopentyl, -CD3, -CH2CD3, -CD2CD3, -CD (CD3) 2, -CH (CD3) 2, 
RX1 and RX2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, CN,
OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, butyl, sec-butyl, iso-butyl, tert-butyl, or
RX3 is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, tert-butyl, -CD3, -CH2CD3, -CD2CD3.
In some embodiments of the compound of Formula I, I-A, I-B, I-C, II, III, IV, V, VI, VII, or VIII, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R1 is selected from -CD3, -CH2CD3, -CD2CD3, -CD (CD3) 2, -CH(CD3) 2, the deuterated RX3 is selected from -CD3, -CH2CD3, -CD2CD3
In some embodiments, the glutamine antagonist is a compound selected from the compounds in the following table (table 3) , or the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof:
Table 3




















The invention is further illustrated by the following examples, which may be synthesized and isolated as free bases or as salts.
In some embodiments of the pharmaceutical combination of the invention, the glutamine antagobist is selected from a compound in Table 3, or a pharmaceutically acceptable salt thereof.
In some embodiments of the pharmaceutical combination defined herein, wherein the glutamine antagonist is selected from compound 1, compound 2, compound 3, compound 4, compound 5, or compound 6, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, and an isotopic substitution thereof.
In some embodiments of the pharmaceutical combination defined herein, wherein the glutamine antagonist is compound 1, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, and an isotopic substitution thereof.
In some embodiments of the pharmaceutical combination defined herein, wherein the glutamine antagonist is compound 2, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, and an isotopic substitution thereof.
In some embodiments of the pharmaceutical combination defined herein, wherein the glutamine antagonist is compound 3, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, and an isotopic substitution thereof.
In some embodiments of the pharmaceutical combination defined herein, wherein the glutamine antagonist is compound 4, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, and an isotopic substitution thereof.
In some embodiments of the pharmaceutical combination defined herein, wherein the glutamine antagonist is compound 5, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, and an isotopic substitution thereof.
In some embodiments of the pharmaceutical combination defined herein, wherein the glutamine antagonist is compound 6, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, and an isotopic substitution thereof.
Immune checkpoint inhibitors are therapies that blockade immune system inhibitor checkpoints. Immune checkpoints can be stimulatory or inhibitory. Blockade of inhibitory immune checkpoint activates immune system function and can be used for cancer immunotherapy. Pardoll, Nature Reviews. Cancer 72: 252-64 (2012) . Tumor cells turn off activated T cells when they attach to specific T-cell receptors. Immune checkpoint inhibitors prevent tumor cells from attaching to T cells, which results in T cells remaining activated. In effect, the coordinated action by cellular and soluble components combats pathogens and injuries by cancers. The modulation of immune system pathways may involve changing the expression or the functional activity of at least one component of the pathway to then modulate the response by the immune system. U.S. 2015/0250853. Examples of immune checkpoint inhibitors include PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, LAG3 inhibitors, TIM3 inhibitors, cd47 inhibitors, and B7-H1 inhibitors. Thus, in one embodiment, the immune checkpoint inhibitor is selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor, a LAG3 inhibitor, a TIM3 inhibitor, and a cd47 inhibitor.
In another embodiment, the immune checkpoint inhibitor is a programmed cell death (PD-1) inhibitor. PD-1 is a T-cell coinhibitory receptor that plays a pivotal role in the ability of tumor cells to evade the host's immune system. Blockage of interactions between PD-1 and PD-L1, a ligand of PD-1, enhances immune function and mediates antitumor activity. Examples of PD-1 inhibitors include antibodies that specifically bind to PD-1. Particular anti-PD-1 antibodies include, but are not limited to nivolumab, pembrolizumab, STI-A1014, and pidilzumab. For a general discussion of the availability, methods of production, mechanism of action, and clinical studies of anti-PD-1 antibodies, see U.S. 2013/0309250, U.S. 6,808,710, U.S. 7,595,048, U.S. 8,008,449, U.S. 8,728,474, U.S. 8,779,105, U.S. 8,952,136, U.S. 8,900,587, U.S. 9,073,994, U.S. 9,084,776, and Naido et al., British Journal of Cancer 777: 2214-19 (2014) . In some embodiments, the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, pidilizumab, STI-A1110, PDR001, MEDI-0680, Balstilimab (AGEN2034) , Tislelizumab (BGB-A317) , AB122, TSR-042, PF-06801591, cemiplimab, SYM021, JNJ-63723283, HLX10, LZM009, and MGA012.
In another embodiment, the immune checkpoint inhibitor is a PD-L1 (also known as B7-H1 or CD274) inhibitor. Examples of PD-L1 inhibitors include antibodies that specifically bind to PD-L1. Particular anti-PD-Ll antibodies include, but are not limited to, avelumab, atezolizumab, durvalumab, STI-A1014 and BMS-936559. For a general discussion of the availability, methods of production, mechanism of action, and clinical studies, see U.S. 8,217,149, U.S. 2014/0341917, U.S. 2013/0071403, WO 2015036499, and Naido et al., British Journal of Cancer 777: 2214-19 (2014) .
In another embodiment, the immune checkpoint inhibitor is a CTLA-4 inhibitor.
CTLA-4, also known as cytotoxic T-lymphocyte antigen 4, is a protein receptor that downregulates the immune system. CTLA-4 is characterized as a "brake" that binds costimulatory molecules on antigen-presenting cells, which prevents interaction with CD28 on T cells and also generates an overtly inhibitory signal that constrains T cell activation. Examples of CTLA-4 inhibitors include antibodies that specifically bind to CTLA-4. Particular anti-CTLA-4 antibodies include, but are not limited to, ipilimumab and tremelimumab. For a general discussion of the availability, methods of production, mechanism of action, and clinical studies, see U.S. 6,984,720, U.S. 6,207,156, and Naido et al., British Journal of Cancer 777: 2214-19 (2014) .
In another embodiment, the immune checkpoint inhibitor is a LAG3 inhibitor.
LAG3, Lymphocyte Activation Gene 3, is a negative co-simulatory receptor that modulates T cell homeostatis, proliferation, and activation. In addition, LAG3 has been reported to participate in regulatory T cells (Tregs) suppressive function. A large proportion of LAG3 molecules are retained in the cell close to the microtubule-organizing center, and only induced following antigen specific T cell activation. U.S. 2014/0286935. Examples of LAG3 inhibitors include antibodies that specifically bind to LAG3. Particular anti-LAG3 antibodies include, but are not limited to, GSK2831781. For a general discussion of the availability, methods of production, mechanism of action, and studies, see, U.S. 2011/0150892, U.S. 2014/0093511, U.S. 20150259420, and Huang et ah, Immunity 21 : 503-13 (2004) .
In another embodiment, the immune checkpoint inhibitor is a TIM3 inhibitor.
TIM3, T-cell immunoglobulin and mucin domain 3, is an immune checkpoint receptor that functions to limit the duration and magnitude of TH1 and TC1 T-cell responses. The TIM3 pathway is considered a target for anticancer immunotherapy due to its expression on dysfunctional CD8+T cells and Tregs, which are two reported immune cell populations that constitute immunosuppression in tumor tissue. Anderson, Cancer Immunology Research 2: 393-98 (2014) . Examples of TIM3 inhibitors include antibodies that specifically bind to TIM3. For a general discussion of the availability, methods of production, mechanism of action, and studies of TIM3 inhibitors, see U.S. 20150225457, U.S. 20130022623, U.S. 8,522,156, Ngiow et al., Cancer Res 71: 6567-71 (2011) , Ngiow, et al., Cancer Res 77: 3540-51 (2011) , and Anderson , Cancer Immunology Res 2: 393-98 (2014) .
In another embodiment, the immune checkpoint inhibitor is a cd47 inhibitor. See Unanue, E.R., PNAS 110: 10886-87 (2013) .
In another embodiments of the pharmaceutical combination of the invention, an Aurora A kinase inhibitor is selected from VX-689, VIC-1911, LY3295668, or a pharmaceutically acceptable salt thereof.
In some embodiments, a SHP2 inhibitor selecte from compounds described in WO2015/107493, WO2015/107494, WO2015/107495, WO2016/203406, WO2016/203404, WO2016/203405, WO2017/216708, WO2018/013597, WO2018/136264, WO2018/13265, WO2019/051084, WO2019/075265, WO2019/118909, WO2019/199792, WO2017/211303, WO2018/172984, WO2017/156397, WO2018/057884, WO2018/081091, WO2019/067843, WO2019/165073, WO2019/183367, WO2017210134, WO2019213318, WO2020033828, WO2019051469, WO2019158019, WO2019182960, WO2021061515, WO2020022323, WO2019167000, WO2021033153, WO2020061101, WO2020061103, WO2020072656, WO2020073945, WO2020073949, WO2020081848, WO2020201991, WO2021043077, WO2020094018, WO2021018287, WO2020094104, CN111704611A, WO2020108590, WO2020259679, WO2020156242, WO2020156243, WO2021147879, WO2020177653, WO2020181283, WO2020210384, CN111825700A, WO2020249079, WO2021028362, WO2021073439, WO2021088945, WO2021115286, WO2021143823, WO2021143680, WO2021143701, WO2021148010 &CN113248449A, each of which is incorporated herein by reference in its entirety.
In some embodiments of the disclosure, the SHP2 inhibitor comprises or consists of RMC-4630, RMC-4550, RLY-1971, BBP-398, ERAS-601, RG001 , GH-21 , SH3809 , ET0038 , ICP-189 , BT-102 , PF-07284892 , SNG-201 , (3S, 4S) -8- (6-amino-5- ( (2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (TN0155) , or a pharmaceutically acceptable salt thereof; 6- (4-amino-4-methylpiperidin-l-yl) -3 - (2, 3 -dichlorophenyl) pyrazin -2-amine (SHP099) or a pharmaceutically acceptable salt thereof, and any one of pharmaceutical combination thereof. Preferably RMC-4630, or TNO-155.
In some embodiments, A “KRASG12C inhibitor” is a compound selected from the compounds detailed in WO2013/155223, WO2014/143659, WO2014/152588, WO2014/160200, WO2015/054572, WO2016/044772, WO2016/049524, WO2016164675, WO2016168540, W02017/058805, WO2017015562, WO2017058728, WO2017058768, WO2017058792, W02017058805, W02017058807, W02017058902, WO2017058915, WO2017087528, W02017100546, WO2017/201161, WO2018/064510, WO2018/068017, WO2018/119183, WO2018/217651, W02018/140512, W02018/140513, W02018/140514, WO2018/140598, WO2018/140599, W02018/140600, WO2018/143315, WO2018/206539, WO2018/218070, W02018/218071, WO2019/051291, WO2019/099524, WO2019/110751, W02019/141250, W02019/150305, WO2019/155399, WO2019/213516, WO2019/213526, WO2019/217307 and WO2019/217691. In some embodiments of the disclosure, the KRASG12C inhibitor is selected from AMG 510, MRTX849, RMC-6291, GH-35 , LY-3537982 , BEBT-607 , BPI-421286, D-1553, YL-15293, JDQ-443, 1 - (4- (6-chloro-8-fluoro-7- (3-hydroxy-5 -vinylphenyl) quinazolin-4-yl) piperazin-1 -yl) prop-2-en-l -one-methane (1/2) ; (S) -l- (4- (6-chloro-8-fluoro-7- (2-fluoro-6-hydroxyphenyl) quinazolin-4-yl) piperazin-l-yl) prop-2-en-l-one ; 2- ( (S) -l-acryloyl-4- (2- ( ( (S) -l-methylpyrrolidin-2 -yl) methoxy) -7- (naphthalen-l-yl) -5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile, and any one of pharmaceutical combination thereof.
The term "antibody" is meant to include intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments, so long as they exhibit the desired biological activity. In another embodiment, "antibody" is meant to include soluble receptors that do not possess the Fc portion of the antibody. In one embodiment, the antibodies are humanized monoclonal antibodies and fragments thereof made by means of recombinant genetic engineering.
Another class of immune checkpoint inhibitors include polypeptides that bind to and block PD-1 receptors on T-cells without triggering inhibitor signal transduction. Such peptides include B7-DC polypeptides, B7-H1 polypeptides, B7-1 polypeptides and B7-2 polypeptides, and soluble fragments thereof, as disclosed in U.S. Pat. 8,114,845.
Another class of immune checkpoint inhibitors include compounds with peptide moieties that inhibit PD-1 signaling. Examples of such compounds are disclosed in U.S. Pat. 8,907,053 and have the structure:
or a pharmaceutically acceptable salt thereof, wherein the compound comprises at least 5 amino acids useful as therapeutic agents capable of inhibiting the PD-1 signaling pathway.
Another class of immune checkpoint inhibitors include inhibitors of certain metabolic enzymes, such as indoleamine 2, 3 dioxygenase (IDO) , which is expressed by infiltrating myeloid cells and tumor cells. The IDO enzyme inhibits immune responses by depleting amino acids that are necessary for anabolic functions in T cells or through the synthesis of particular natural ligands for cytosolic receptors that are able to alter lymphocyte functions. Pardoll, Nature Reviews. Cancer 72: 252-64 (2012) ; Lob, Cancer Immunol Immunother 55: 153-57 (2009) . Particular IDO blocking agents include, but are not limited to levo-l-methyl typtophan (L-1MT) and 1 -methyl-tryptophan (1MT) . Qian et al, Cancer Res 69: 5498-504 (2009) ; and Lob el al, Cancer Immunol Immunother 55: 153-7 (2009) .
In one embodiment, the immune checkpoint inhibitor is nivolumab, pembrolizumab, pidilizumab, STI-A1110, avelumab, atezolizumab, durvalumab, STI-A1014, ipilimumab, tremelimumab, GSK2831781, BMS-936559 or MED14736.
In another embodiment there is provided a pharmaceutical composition or commercial package (e.g. a kit-of-parts) comprising the pharmaceutical combination of the invention, and at least one pharmaceutically acceptable carrier.
In another aspect, the present application provides a use of the pharmaceutical combination defined herein and/or the pharmaceutical composition or the commercial package of the present invention for the manufacture of a medicament.
In some embodiments, the medicament prepared can be used for the treatment or prevention of cancer or cancer metastasis.
In some embodiments, wherein the cancer is selected from a breast cancer (e.g., a triple negative breast cancer) , a colorectal cancer (e.g., a microsatellite stable colorectal cancer (MSS CRC) ) , acute lymphoblastic leukemia, acute myelogenous leukemia, advanced soft tissue sarcoma, brain cancer, metastatic or aggressive breast cancer, bronchogenic carcinoma, choriocarcinoma, chronic myelocytic leukemia, colon carcinoma, Ewing's sarcoma, gastrointestinal tract carcinoma, glioma, glioblastoma multiforme, hepatocellular carcinoma, Hodgkin's disease, intracranial ependymoblastoma, large bowel cancer, leukemia, liver cancer, lung cancer, Lewis lung carcinoma, lymphoma, lymphangioma, lymphangiosarcoma, malignant fibrous histiocytoma, a mammary tumor, melanoma, mesothelioma, neuroblastoma, osteosarcoma, ovarian cancer, pancreatic cancer, a pontine tumor, premenopausal breast cancer, prostate cancer, rhabdomyosarcoma, reticulum cell sarcoma, sarcoma, small cell lung cancer, a solid tumor, stomach cancer, testicular cancer, uterine carcinoma, skin cancer, a gastric cancer, a gastroesophageal cancer, lung cancer, cervical cancer, head and neck cancer, esophageal cancer, non-small cell lung cancer, non-Hodgkin lymphoma, or any of combination thereof. In some embodiments, the skin cancer is a melanoma (e.g., a refractory melanoma) .
In some embodiments, wherein the cancer is selected from hepatocellular carcinoma, glioblastoma, lung cancer, breast cancer, head and neck cancer, prostate cancer, melanoma, lymphoma, kidney cancer, and colorectal cancer.
In another aspect, the present application provides a use of the pharmaceutical combination of defined herein or the pharmaceutical composition or the commercial package of the present invention, wherein a medicament prepared can be used for the treatment or prevention of cancer or cancer metastasis.
In some embodiments, the cancer is selected from a breast cancer (e.g., a triple negative breast cancer) , a colorectal cancer (e.g., a microsatellite stable colorectal cancer (MSS CRC) ) , acute lymphoblastic leukemia, acute myelogenous leukemia, advanced soft tissue sarcoma, brain cancer, metastatic or aggressive breast cancer, bronchogenic carcinoma, choriocarcinoma, chronic myelocytic leukemia, colon carcinoma, Ewing's sarcoma, gastrointestinal tract carcinoma, glioma, glioblastoma multiforme, hepatocellular carcinoma, Hodgkin's disease, intracranial ependymoblastoma, large bowel cancer, leukemia, liver cancer, lung cancer, Lewis lung carcinoma, lymphoma, lymphangioma, lymphangiosarcoma, malignant fibrous histiocytoma, a mammary tumor, melanoma, mesothelioma, neuroblastoma, osteosarcoma, ovarian cancer, pancreatic cancer, a pontine tumor, premenopausal breast cancer, prostate cancer, rhabdomyosarcoma, reticulum cell sarcoma, sarcoma, small cell lung cancer, a solid tumor, stomach cancer, testicular cancer, uterine carcinoma, skin cancer, a gastric cancer, a gastroesophageal cancer, lung cancer, cervical cancer, head and neck cancer, esophageal cancer, non-small cell lung cancer,  non-Hodgkin lymphoma, or any of combination thereof. In some embodiments, the skin cancer is a melanoma (e.g., a refractory melanoma) .
In some embodiments, the cancer is selected from hepatocellular carcinoma, glioblastoma, lung cancer, breast cancer, head and neck cancer, prostate cancer, melanoma, lymphoma, kidney cancer, and colorectal cancer.
The pharmaceutical combination of defined herein or the pharmaceutical composition or the commercial package of the present invention, for use in the treatment of cancer or the prevention of cancer metastasis.
In some embodiments, the cancer is selected from a breast cancer (e.g., a triple negative breast cancer) , a colorectal cancer (e.g., a microsatellite stable colorectal cancer (MSS CRC) ) , acute lymphoblastic leukemia, acute myelogenous leukemia, advanced soft tissue sarcoma, brain cancer, metastatic or aggressive breast cancer, bronchogenic carcinoma, choriocarcinoma, chronic myelocytic leukemia, colon carcinoma, Ewing's sarcoma, gastrointestinal tract carcinoma, glioma, glioblastoma multiforme, hepatocellular carcinoma, Hodgkin's disease, intracranial ependymoblastoma, large bowel cancer, leukemia, liver cancer, lung cancer, Lewis lung carcinoma, lymphoma, lymphangioma, lymphangiosarcoma, malignant fibrous histiocytoma, a mammary tumor, melanoma, mesothelioma, neuroblastoma, osteosarcoma, ovarian cancer, pancreatic cancer, a pontine tumor, premenopausal breast cancer, prostate cancer, rhabdomyosarcoma, reticulum cell sarcoma, sarcoma, small cell lung cancer, a solid tumor, stomach cancer, testicular cancer, uterine carcinoma, skin cancer, a gastric cancer, a gastroesophageal cancer, lung cancer, cervical cancer, head and neck cancer, esophageal cancer, non-small cell lung cancer, non-Hodgkin lymphoma, or any of combination thereof. In some embodiments, the skin cancer is a melanoma (e.g., a refractory melanoma) .
In some embodiments, the cancer is selected from hepatocellular carcinoma, glioblastoma, lung cancer, breast cancer, head and neck cancer, prostate cancer, melanoma, lymphoma, kidney cancer, and colorectal cancer.
The pharmaceutical combination of defined herein and/or a pharmaceutical composition or the commercial package of the present invention, which is used in therapy.
The pharmaceutical combination of defined herein and/or a pharmaceutical composition or the commercial package of the present invention which is used as a medicament.
The present invention relates to a method of treating cancer is selected from a breast cancer (e.g., a triple negative breast cancer) , a colorectal cancer (e.g., a microsatellite stable colorectal cancer (MSS CRC) ) , acute lymphoblastic leukemia, acute myelogenous leukemia, advanced soft tissue sarcoma, brain cancer, metastatic or aggressive breast cancer, bronchogenic carcinoma, choriocarcinoma, chronic myelocytic leukemia, colon carcinoma, Ewing's sarcoma, gastrointestinal tract carcinoma, glioma, glioblastoma multiforme, hepatocellular carcinoma, Hodgkin's disease, intracranial ependymoblastoma, large bowel cancer, leukemia, liver cancer, lung cancer, Lewis lung carcinoma, lymphoma, lymphangioma, lymphangiosarcoma, malignant fibrous histiocytoma, a mammary tumor, melanoma, mesothelioma, neuroblastoma, osteosarcoma, ovarian cancer, pancreatic cancer, a pontine tumor, premenopausal breast cancer, prostate cancer, rhabdomyosarcoma, reticulum cell sarcoma, sarcoma, small cell lung cancer, a solid tumor, stomach cancer, testicular cancer, uterine carcinoma, skin cancer, a gastric cancer, a gastroesophageal cancer, lung cancer, cervical cancer, head and neck cancer, esophageal cancer, non-small cell lung cancer, non-Hodgkin lymphoma, or any of combination thereof, in a mammal comprising administering to a mammal in need of such treatment an effective amount of the pharmaceutical combination of defined herein, and/or a pharmaceutical composition of the present invention.
In some embodiments, the glutamine antagonist is administered to the patient according to an intermittent dosing schedule. In some embodiments, the glutamine antagonist is subcutaneously administered to the patient according to an intermittent dosing schedule. In some embodiments, the glutamine antagonist is intravenously administered to the patient according to an intermittent dosing schedule.
In some embodiments, the glutamine antagonist is administered prior to the immune checkpoint inhibitor, e.g., 0.5, 1, 2, 3, 4, 5, 10, 12, or 18 hours, 1, 2, 3, 4, 5, or 6 days, or 1, 2, 3, or 4 weeks prior to the administration of the immune checkpoint inhibitor.
In some embodiments, the glutamine antagonist is administered after the immune checkpoint inhibitor, e.g., 0.5, 1, 2, 3, 4, 5, 10, 12, or 18 hours, 1, 2, 3, 4, 5, or 6 days, or 1, 2, 3, or 4 weeks after the administration of the immune checkpoint inhibitor.
In some embodiments, the glutamine antagonist, and the immune checkpoint inhibitor are administered concurrently but on different schedules, e.g, the glutamine antagonist is administered daily while the immune checkpoint inhibitor is administered once a week, once every two weeks, once every three weeks, or once every four weeks. In other embodiments, the glutamine antagonist is administered once a day while the immune checkpoint inhibitor is administered once a week, once every two weeks, once every three weeks, or once every four weeks.
The therapeutic methods provided herein comprise administering a glutamine antagonist to a cancer patient in an amount which is effective to achieve its intended purpose. While individual needs vary, determination of optimal ranges of effective amounts of each component is within the skill of the art. Typically, the glutamine antagonist is administered in an amount from about 0.05 mg/kg to about 500 mg/kg, about 0.05 mg/kg to about  100 mg/kg, about 0.05 mg/kg to about 50 mg/kg, or about 0.05 mg/kg to about 10 mg/kg. The dosage of a composition can be at any dosage including, but not limited to, about 0.05 mg/week to about 25 mg/week. Particular doses include 0.05, 1, 2, 5, 10, 20, 50, and 100 mg/kg once weekly. In one embodiment, the glutamine antagonist is administered once a week. These dosages are exemplary, but there can be individual instances in which higher or lower dosages are merited, and such are within the scope of this disclosure. In practice, the physician determines the actual dosing regimen that is most suitable for an individual patient, which can vary with the age, weight, and response of the particular patient. In one embodiment, about 0.1 mg/kg to about 2 mg/kg of DON is administered to the subject.
The unit oral dose of the glutamine antagonist may comprise from about 0.01 to about 1000 mg, e.g., about 0.01 to about 100 mg of the glutamine antagonist. In one embodiment, the unit oral dose of the glutamine antagonist is 0.05 mg, 1 mg, 3 mg, 5 mg, 7 mg, 9 mg, 10 mg 12 mg, 14 mg, 15 mg, 17 mg, 20 mg, 22 mg, 25 mg, 27 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg. The unit dose may be administered one or more times daily, e.g., as one or more tablets or capsules. The unit does may also be administered by IV or subcutaneously to the subject. In practice, the physician determines the actual dosing regimen that is most suitable for an individual patient, which can vary with the age, weight, and response of the particular patient.
In addition to administering the glutamine antagonist as a raw chemical, it may be administered as part of a pharmaceutical preparation or composition. In some embodiments, the pharmaceutical preparation or composition can include one or more pharmaceutically acceptable carriers, excipients, and/or auxiliaries. In some embodiments, the one or more carriers, excipients, and auxiliaries facilitate processing of the glutamine antagonist into a preparation or composition which can be used pharmaceutically. The preparations, particularly those preparations which can be administered orally, subcutaneously, intravenously, or topically, and which can be used for one type of administration, such as tablets, dragees, slow release lozenges and capsules, mouth rinses and mouth washes, gels, liquid suspensions, hair rinses, hair gels, and shampoos, and also preparations which can be administered rectally, such as suppositories, as well as suitable solutions for administration by intravenous infusion, subcutaneous injection, topically or orally, contain from about 0.01 to 99 percent, in one embodiment from about 0.25 to 75 percent of active compound (s) , together with the one or more carriers, excipients, and/or auxiliaries.
The pharmaceutical compositions of provided herein may be administered to any subject which may experience the beneficial effects of the glutamine antagonist. Foremost among such subjects are mammals, e.g., humans, although the methods and compositions provided herein are not intended to be so limited. Other subjects include veterinary animals (cows, sheep, pigs, horses, dogs, cats and the like) . In one embodiment, the subject is a human cancer patient.
The pharmaceutical preparations provided herein are manufactured by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
Suitable excipients are, in particular, fillers such as saccharides, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, disintegrating agents may be added such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Auxiliaries can be suitable flow-regulating agents and lubricants. Suitable auxiliaries include, for example, silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol. Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juices. For this purpose, concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate, are used. Dye stuffs or pigments may be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
Other pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The push-fit capsules can contain the active compounds in the form of granules which may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are in one embodiment dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin. In addition, stabilizers may be added.
Possible pharmaceutical preparations which can be used rectally include, for example, suppositories, which consist of a combination of one or more of the active compounds with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffin hydrocarbons. In addition, it is also possible to use gelatin rectal capsules which consist of a combination of the active compounds with a base. Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.
Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts and alkaline solutions. In addition, suspensions of the active compounds as appropriate oily injection suspensions may be administered. Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension including, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran. Optionally, the suspension may also contain stabilizers.
The present disclosure encompasses the use of solvates of the glutamine antagonist. Solvates typically do not significantly alter the physiological activity or toxicity of a compound, and as such may function as pharmacological equivalents. The term "solvate" as used herein is a combination, physical association and/or solvation of the glutamine antagonist with a solvent molecule such as, e.g ., a disolvate, monosolvate or hemisolvate, where the ratio of solvent molecule to the glutamine antagonist is about 2: 1, about 1 : 1 or about 1 : 2, respectively. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Thus, "solvate" encompasses both solution-phase and isolatable solvates. the glutamine antagonist can be present as solvated forms with a pharmaceutically acceptable solvent, such as water, methanol, ethanol, and the like, and it is intended that the disclosure includes both solvated and unsolvated forms of the glutamine antagonist. One type of solvate is a hydrate. A "hydrate" relates to a particular subgroup of solvates where the solvent molecule is water. Solvates typically can function as pharmacological equivalents. Preparation of solvates is known in the art. See, for example, M. Caira et al, J. Pharmaceut. Sci., 93 (3) : 601-611 (2004) , which describes the preparation of solvates of fluconazole with ethyl acetate and with water. Similar preparation of solvates, hemisolvates, hydrates, and the like are described by E. C. van Tonder et al., AAPS Pharm. Sci. Tech., 5 (1) : Article 12 (2004) , and A. L. Bingham et al ., Chem. Commun. 603-604 (2001) . A typical, non-limiting, process of preparing a solvate involves dissolvingthe glutamine antagonist in a desired solvent (organic, water, or a mixture thereof) at temperatures above 20℃ to about 25℃, then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods, e.g ., filtration. Analytical techniques such as infrared spectroscopy can be used to confirm the presence of the solvent in a crystal of the solvate.
Therapeutically effective amounts of the glutamine antagonist, and the immune checkpoint inhibitor formulated in accordance with standard pharmaceutical practices, are administered to a human patient in need thereof. Whether such a treatment is indicated depends on the individual case and is subject to medical assessment (diagnosis) that takes into consideration signs, symptoms, and/or malfunctions that are present, the risks of developing particular signs, symptoms and/or malfunctions, and other factors.
The glutamine antagonist, and the immune checkpoint inhibitor can be administered by any suitable route, for example by oral, buccal, inhalation, sublingual, rectal, vaginal, intracistemal or intrathecal through lumbar puncture, transurethral, nasal, percutaneous, i.e., transdermal, or parenteral (including intravenous, intramuscular, subcutaneous, intracoronary, intradermal, intramammary, intraperitoneal, intraarticular, intrathecal, retrobulbar, intrapulmonary injection and/or surgical implantation at a particular site) administration. Parenteral administration can be accomplished using a needle and syringe or using a high pressure technique. In one embodiment, the glutamine antagonist is administered subcutaneously to the subject. In one embodiment, the glutamine antagonist is administered intraveneously to the subject.
Pharmaceutical compositions include those wherein the glutamine antagonist, and the immune checkpoint inhibitor are administered in an effective amount to achieve its intended purpose. The exact formulation, route of administration, and dosage is determined by an individual physician in view of the diagnosed condition or disease. Dosage amount and interval can be adjusted individually to provide levels of the glutamine antagonist, and the immune checkpoint inhibitor that is sufficient to maintain therapeutic effects.
Toxicity and therapeutic efficacy of the glutamine antagonist, and the immune checkpoint inhibitor can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the maximum tolerated dose (MTD) of a compound, which defines as the highest dose that causes no toxicity in a patient. The dose ratio between the maximum tolerated dose and therapeutic effects (e.g. inhibiting of tumor growth) is the therapeutic index. The dosage can vary within this range depending upon the dosage form employed, and the route of administration utilized. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
A therapeutically effective amount of the glutamine antagonist, and the immune checkpoint inhibitor required for use in therapy varies with the nature of the condition being treated, the length of time that activity is desired, and the age and the condition of the subject, and ultimately is determined by the attendant physician. For example, dosage amounts and intervals can be adjusted individually to provide plasma levels of the glutamine antagonist, and immune checkpoint inhibitor that are sufficient to maintain the desired therapeutic effects. The desired dose conveniently can be administered in a single dose, or as multiple doses administered at appropriate intervals, for example as one, two, three, four or more subdoses per day. Multiple doses often are desired, or required. For example, the glutamine antagonist, and immune checkpoint inhibitor can be administered at a frequency of: one dose per day; four doses delivered as one dose per day at four-day intervals (q4d x 4) ; four doses delivered as one dose per day at three-day intervals (q3d x 4) ; one dose delivered per day at five-day intervals (qd x 5) ; one dose per week for three weeks (qwk3) ; five daily doses, with two days rest, and another five daily doses (5/2/5) ; or, any dose regimen determined to be appropriate for the circumstance.
The immune checkpoint inhibitor is administered in therapeutically effective amounts. When the immune checkpoint inhibitor is a monoclonal antibody, 1-20 mg/kg is administered as an intravenous infusion every 2-4 weeks. For example, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg and 2000 mg of the antibody may be administered.
For example, when the immune checkpoint inhibitor is the anti-PD-1 antibody nivolumab, 3 mg/kg may be administered by intravenous infusion over 60 minutes every two weeks. When the immune checkpoint inhibitor is the anti-PD-1 antibody pembrolizumab, mg/kg may be administered by intravenous infusion over 30 minutes every two or three weeks. When the immune checkpoint inhibitor is the anti-PD-Ll antibody avelumab, 10 mg/kg may be administered by intravenous infusion as frequently as every 2 weeks. Disis et al ., J Clin Oncol. 33 (2015) (suppl; abstr 5509) . When the immune checkpoint inhibitor is the anti-PD-Ll antibody MPDL3280A, 20 mg/kg may be administered by intravenous infusion every 3 weeks. Herbst et al., Nature 575: 563-80 (2014) . When the immune checkpoint inhibitor is the anti-CTLA-4 antibody ipilumumab, 3 mg/kg may be administered by intravenous infusion over 90 minutes every 3 weeks. When the immune checkpoint inhibitor is the anti-CTLA-4 antibody tremelimumab, 15 mg/kg may be administered by intravenous infusion every 12 weeks. Naido et al., British Journal of Cancer 777: 2214-19 (2014) ; Drugs R D , 70: 123-32 (2010) . When the immune checkpoint inhibitor is the anti-LAG3 antibody GSK2831781, 1.5 to 5 mg/kg may be administered by intravenous infusion over 120 minutes every 2-4 weeks. When the immune checkpoint inhibitor is an anti-TIM3 antibody, 1-5 mg/kg may be administered by intravenous infusion over 30-90 minutes every 2-4 weeks. When an inhibitor of indoleamine 2, 3 -di oxygenase (IDO) pathway is inhibitor indoximod in combination with temozolomide, 18.5 mg/kg/dose BID with an escalation to 27.7 mg/kg/dose BID of indoximod with 200 mg/m2 every 5 days of temozolomide.
In one embodiment, the immune checkpoint inhibitor is an antibody and 1-20 mg/kg is administered by intravenous infusion every 2-4 weeks. In another embodiment, 50-2000 mg of the antibody is administered by intravenous infusion every 2-4 weeks. In another embodiment, the glutamine antagonist is administered prior to administration of the antibody. In another embodiment, the glutamine antagonist is administered 3-7 days prior to the day of administration of the antibody. In another embodiment, the glutamine antagonist is also administered the day the antibody is administered and on consecutive days thereafter until disease progression or untilthe glutamine antagonist administration is no longer beneficial.
In one embodiment, the cancer patient receives 2 mg/kg pembrolizumab administered by intravenous infusion every three weeks and about 0.1 to 100 mg of the glutamine antagonist administered for 1-7 days prior to pembrolizumab administration, optionally, on the day of pembrolizumab administration, and, optionally, thereafter until disease progression or until there is no therapeutic benefit.
In another embodiment, the cancer patient receives 3 mg/kg nivolumab administered by intravenous infusion every 2 weeks and about 0.1 to 100 mg of the glutamine antagonist administered for 1-7 days prior to nivolumab administration, optionally, on the day of nivolumab administration, and, optionally, thereafter until disease progression or until there is no therapeutic benefit.
In another embodiment, the cancer patient receives 3 mg/kg nivolumab administered by intravenous infusion every 2 weeks and about 0.1 to 100 mg of the glutamine antagonist administered for 1-7 days prior to nivolumab administration, optionally, on the day of nivolumab administration, and, optionally, thereafter until disease progression or until there is no therapeutic benefit.
In another embodiment, the treatment of the cancer patient with a glutamine antagonist, and an immune checkpoint inhibitor induces anti proliferative response faster than when the immune checkpoint inhibitor is administered alone.
Definitions:
The term “halogen” , as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo. The preferred halogen groups include F, Cl and Br. The terms "haloC1-6alkyl" , "haloC2-6alkenyl" , "haloC2-6alkynyl" and "haloC1-6alkoxy" mean a C1-6alkyl, C2-6alkenyl, C2-6alkynyl or C1-6alkoxy in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by halogen atoms, especially fluorine or chlorine atoms. In some embodiment, preferred are fluoroC1-6alkyl, fluoroC2-6alkenyl, fluoroC2-6alkynyl and fluoroC1-6alkoxy groups, in particular fluoroC1-3alkyl, for example, CF3, CHF2, CH2F, CH2CH2F, CH2CHF2, CH2CF3 and fluoroC1-3alkoxy groups, for example, OCF3, OCHF2, OCH2F, OCH2CH2F, OCH2CHF2 or OCH2CF3, and most especially CF3, OCF3 and OCHF2.
As used herein, unless otherwise indicated, alkyl includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclobutyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl. Similary, C1-8, as in C1-8alkyl is defined to identify the group as having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms in a linear or branched arrangement.
Alkylene means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above. For example, methylene (i.e., -CH2-) , ethylene (i.e., -CH2-CH2-or –CH (CH3) -) and propylene (i.e., -CH2-CH2-CH2-, -CH (-CH2-CH3) -or –CH2-CH (CH3) -) .
Alkenyl and alkynyl groups include straight, branched chain or cyclic alkenes and alkynes. Likewise, “C2-8alkenyl" and “C2-8alkynyl" means an alkenyl or alkynyl radicals having 2, 3, 4, 5, 6, 7 or 8 carbon atoms in a linear or brached arrangement. Alkenyl group include, but are not limited to, for example, ethenyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, hepetenyl, octenyl and the like. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl and the like.
Alkoxy radicals are oxygen ethers formed from the previously described straight, branched chain or cyclic alkyl groups.
The term “aryl” , as used herein, unless otherwise indicated, refers to an unsubstituted or substituted mono-or polycyclic ring system containing carbon ring atoms. The preferred aryls are mono cyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls. The most preferred aryl is phenyl.
The term “heterocyclic ring” or “heterocyclyl” , as used herein, unless otherwise indicated, refers to unsubstituted and substituted mono-or polycyclic non-aromatic ring system containing one or more heteroatoms. Preferred heteroatoms include N, O, and S, including N-oxides, sulfur oxides, and dioxides. Preferably the ring is three to eight membered and is either fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, preferably one, two or three, are included within the present definition.
Examples of such heterocyclic groups include, but are not limited to azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepinyl, azepinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone and oxadiazolyl.
The term “heteroaryl” , as used herein, unless otherwise indicated, represents an aromatic ring system containing carbon (s) and at least one heteroatom. Heteroaryl may be monocyclic or polycyclic, substituted or unsubstituted. A monocyclic heteroaryl group may have 1 to 4 heteroatoms in the ring, while a polycyclic heteroaryl may contain 1 to 10 hetero atoms. A polycyclic heteroaryl ring may contain fused, spiro or bridged ring junction, for example, bycyclic heteroaryl is a polycyclic heteroaryl. Bicyclic heteroaryl rings may contain from 8 to 12 member atoms. Monocyclic heteroaryl rings may contain from 5 to 8 member atoms (cabons and heteroatoms) . Examples of heteroaryl groups include, but are not limited to thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl adeninyl, quinolinyl or isoquinolinyl.
The term “cycloalkyl” refers to a substituted or unsubstituted monocyclic, bicyclic or polycyclic non-aromatic saturated ring, which optionally includes an alkylene linker through which the cycloalkyl may be attached. Examplary "cycloalkyl" groups includes but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and so on.
The term “carbonyl” , “=O” , “-C=O” , “C=O” , “-CO” , “-C (O) ” and “” CO refers to the group
The term “oxo” refers to the radical =O.
Whenever the term “alkyl” or “aryl” or either of their prefix roots appear in a name of a substituent (e.g., aralky or dialkylamino) it shall be interpreted as including those limitations given above for “alkyl” and “aryl” . Designated numbers of carbon atoms (e.g., Cl-6) shall refer independently to the number of carbon atoms in an alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
wherein the term "substituted" refers to a group mentioned above in which one or more (preferably 1-6, more preferably 1-3) hydrogen atoms are each independently replaced with the same or different substituent (s) . Typical substituents include, but are not limited to, X, Cl-6alkyl, Cl-6alkoxy, C3-20 cycloalkyl, -OR13, SR13, =O, =S, -C (O) R13, -C (S) R13, =NR13, -C (O) OR13, -C (S) OR13, -NR13R14, -C (O) NR13R14, cyano, nitro, -S (O) 2R13, -OS (O2) OR13, -OS (O) 2R13, or -OP (O) (OR13) (OR14) ; wherein each X is independently a halogen (F, Cl, Br or I) , and R13 and R14 is independently selected from -H, C1-6 alkyl and C1-6 haloalkyl. In some embodiments, the substituent (s) is independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluromethoxy, ethoxy, propyloxy, iso-propyloxy, n-butyloxy, isobutyloxy, t-butyloxy, -SCH3 , -SC2H5 , formaldehyde group, -C (OCH3) , cyano, nitro, CF3 , -OCF3, amino, dimethylamino, methyl thio, sulfonyl and acetyl. Particularly preferred substituent (s) is -F, -Cl or -Br.
Compounds described herein, such as certain compounds of Formula I, I-A, I-B, I-C, II, III, IV, V, VI, VII, or VIII, may contain asymmetrically substituted carbon atoms (or chiral centers) in the R or S configuration. The present invention includes racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and absolute stereoisomers.
The compounds described herein, when specifically designated as the R-or S-isomer, either in a chemical name or in a drawing, should be understood as an enriched R-isomer or S-isomer, respectively. For example, in any of the embodiments described herein, such enriched R-or S-designated isomer can be substantially free (e.g., with less than 5%, less than 1%, or non-detectable, as determined by chiral HPLC) of the other isomer for the respective chiral center. The enriched R-or S-isomers can be prepared by methods exemplified in this application, such as by using a chiral auxiliary such as R-or S-tert-butylsulfinamide in the synthetic process. Other methods for prepaing the enriched R-or S-isomers herein include, but are not limited to, chiral HPLC purifications of a stereoisomeric mixture, such as a racemic mixture. General methods for separating stereoisomers (such as enantiomers and/or diastereomers) using HPLC are known in the art.
Compounds described herein can exist in isotope-labeled or -enriched form containing one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most abundantly found in nature. Isotopes can be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, phosphorous, sulfur, fluorine, chlorine, and iodine include, but are not limited to 2H, 3H, 13C, 14C, 15N, 18O, 32P, 35S, 18F, 36Cl, and 125I. Compounds that contain other isotopes of these and/or other atoms are within the scope of this invention. In some embodiments, one or more hydrogen atoms of any of the compounds described herein can be substituted with deuterium to provide the corresponding deterium-labeled or -enriched compounds.
Compounds described herein may have different isomeric forms. For example, any asymmetric carbon atom may be present in the (R) -, (S) -or (R, S) -configuration, preferably in the (R) -or (S) -configuration. Substituents at a double bond or especially a ring may be present m cis- (= Z-) or trans (= E-) form. The compounds may thus be present as mixtures of isomers or preferably as pure isomers, preferably as pure diastereomers or pure enantiomers.
Where the plural form (e.g. compounds, salts) is used, this includes the singular (e.g. a single compound, a single salt) . “A compound” does not exclude that (e.g. in a pharmaceutical formulation) more than one compound of the invention (or a salt thereof) is present, the "a" merely representing the indefinite article. “A” can thus preferably be read as “one or more” , less preferably alternatively as “one” .
The term “composition” , as used herein, is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from pharmaceutical combinations of the specified ingredients in the specified amounts. Accordingly, pharmaceutical compositions containing the compounds of the present invention as the active ingredient as well as methods of preparing the instant compounds are also part of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents and such solvates are also intended to be encompassed within the scope of this invention.
The compounds of the present invention may also be present in the form of pharmaceutically acceptable salts. For use in medicine, the salts of the compounds of this invention refer to non-toxic “pharmaceutically acceptable salts” . The pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts. The pharmaceutically acceptable acidic/anionic salt generally takes a form in which the basic nitrogen is protonated with an inorganic or organic acid. Representative organic or inorganic acids include hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, saccharinic or trifluoroacetic. Pharmaceutically acceptable basic/cationic salts include, and are not limited to aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, sodium and zinc.
The present invention includes within its scope the prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds that are readily converted in vivo into the required  compound. Thus, in the methods of treatment of the present invention, the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the subject. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs” , ed. H. Bundgaard, Elsevier, 1985.
It is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques know in the art as well as those methods set forth herein.
The present invention includes compounds described can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.
When a tautomer of the compounds of the invention exists, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, except where specifically stated otherwise.
When the compounds of the invention and pharmaceutically acceptable salts thereof exist in the form of solvates or polymorphic forms, the present invention includes any possible solvates and polymorphic forms. A type of a solvent that forms the solvate is not particularly limited so long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone or the like can be used.
The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous) . Thus, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion, or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the pharmaceutical combination of the invention, may also be administered by controlled release means and/or delivery devices. The compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen. In preparing the compositions for oral dosage form, any convenient pharmaceutical media may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets may be coated by standard aqueous or nonaqueous techniques.
A tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet  preferably contains from about 0.05mg to about 5g of the active ingredient and each cachet or capsule preferably containing from about 0.05mg to about 5g of the active ingredient. For example, a formulation intended for the oral administration to humans may contain from about 0.5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Unit dosage forms will generally contain between from about lmg to about 2g of the active ingredient, typically 25mg, 50mg, l00mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg, or l000mg.
Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol) , vegetable oils, and suitable mixtures thereof.
Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing The pharmaceutical combination of the invention, or a pharmaceutically acceptable salt thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 5wt%to about 10wt%of the compound, to produce a cream or ointment having a desired consistency.
Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier (s) followed by chilling and shaping in molds.
In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing The pharmaceutical combination of the invention, , or pharmaceutically acceptable salts thereof, may also be prepared in powder or liquid concentrate form.
Generally, dosage levels on the order of from about 0.01mg/kg to about 150mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5mg to about 7g per patient per day. For example, inflammation, cancer, psoriasis, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system (CNS) , may be effectively treated by the administration of from about 0.01 to 50mg of the compound per kilogram of body weight per day, or alternatively about 0.5mg to about 3.5g per patient per day.
It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug pharmaceutical combination and the severity of the particular disease undergoing therapy.
The term “subject” or “patient” as used herein is intended to include animals, which are capable of suffering from or afflicted with a cancer or any disorder involving, directly or indirectly, a cancer. Examples of subjects include mammals, e.g., humans, apes, monkeys, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In an embodiment, the subject is a human, e.g., a human suffering from, at risk of suffering from, or potentially capable of suffering from cancers.
The term “treating” or “treatment” as used herein comprises a treatment relieving, reducing or alleviating at least one symptom in a subject or effecting a delay of progression of a disease. For example, treatment can be the diminishment of one or several symptoms of a disorder or complete eradication of a disorder, such as cancer. Within the meaning of the present disclosure, the term “treat” also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease.
As used herein, the term "glutamine antagonist" refers to a glutamine analog that interfers with a glutamine metabolic pathway, e.g., the inhibition or blocking of a metabolic pathway downstream of glutamine in which glutamine acts as a precursor of one or more non-glutamine compounds. Examples of such metabolic pathways are well known (see, e.g., Hensley et al, "Glutamine and cancer: cell biology, physiology, and clinical opportunities" J Clin Invest. 2013; 123 (9) : 3678-3684; DeBerardinis et al, "Q's next: the diverse functions of  glutamine in metabolism, cell biology and cancer" Oncogene. 2009; 29 (3) : 313-324; and Medina et al, "Relevance of glutamine metabolism to tumor cell growth" Mol Cell Biochem. 1992; 113 (1) : 1 -15) . In some contexts, the term glutamine antagonist also includes glutamine analogs that inhibit glutamine uptake by cells, thereby reducing its biological activity. Diseases or conditions wherein excess and/or aberrant glutamine.
A “therapeutically effective amount” when used in connection with a compound is an amount effective for treating or preventing a disease in a subject as described herein.
The terms “comprising” and “including” are used herein in their open-ended and non-limiting sense unless otherwise noted.
The terms “a” and “an” and “the” and similar references in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt, or the like.
The term “pharmaceutical combination therapy” or “in pharmaceutical combination with” refers to the administration of two or more therapeutic agents to treat a condition or disorder described in the present disclosure (e.g., cancer) . Such administration encompasses co -administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients. Alternatively, such administration encompasses coadministration in multiple, or in separate containers (e.g., capsules, powders, and liquids) for each active ingredient. Powders and/or liquids may be reconstituted or diluted to a desired dose prior to administration. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner, either at approximately the same time or at different times. In either case, the treatment regimen will provide beneficial effects of the drug pharmaceutical combination in treating the conditions or disorders described herein.
The combination therapy can provide “synergy” and prove “synergistic” , i.e., the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately. A synergistic effect can be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined, unit dosage formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen. When delivered in alternation therapy, a synergistic effect can be attained when the compounds are administered or delivered sequentially, e.g., by different injections in separate syringes. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e., serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together.
The term “pharmaceutical combination” as used herein refers to either a fixed pharmaceutical combination in one dosage unit form, or non-fixed pharmaceutical combination or a kit of parts for the combined administration where two or more therapeutic agents may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the pharmaceutical combination partners show a cooperative, e.g. synergistic effect.
The term “synergistic effect” as used herein refers to action of two or more therapeutic agents such as, for example, a glutamine antagonist, and the immune checkpoint inhibitor, producing an effect, for example, slowing the symptomatic progression of a proliferative disease, particularly cancer, or symptoms thereof, which is greater than the simple addition of the effects of each drug administered by themselves. A synergistic effect can be calculated, for example, using suitable methods such as the Sigmoid-Emax equation (Holford, N. H. G. and Scheiner, L. B., Clin. Pharmacokinet. 6: 429-453 (1981) ) , the equation of Loewe additivity (Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol. 114: 313-326 (1926) ) and the median-effect equation (Chou, T. C. and Talalay, P., Adv. Enzyme Regul. 22: 27-55 (1984) ) . Each equation referred to above can be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug pharmaceutical combination. The corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and pharmaceutical combination index curve, respectively.
The pharmaceutical combination of the invention, a glutamine antagonist and an immune checkpoint inhibitor, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have one or more atoms replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the glutamine antagonist and the immune checkpoint inhibitor include isotopes of hydrogen, carbon, nitrogen, oxygen, and chlorine, for example, 2H, 3H, nC, 13C, 14C, 15N, 35S, 36C1. The invention includes isotopically labeled a glutamine antagonist and a immune checkpoint inhibitor, for example into which radioactive isotopes, such as3H and14C, or non-radio active isotopes, such as 2H and13C, are present. Isotopically labelled the glutamine antagonist and the immune checkpoint inhibitor are useful in metabolic studies (with 14C) , reaction kinetic studies (with, for example2H or3H) , detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques  known to those skilled in the art or by processes analogous to those described in the accompanying Examples using appropriate isotopically-labeled reagents.
These and other aspects will become apparent from the following written description of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 shows anti-tumor effect of the test compound alone and in combination with Anti-PD-1 mAb in MC38 Model
Fig. 2 shows survival curve for different treatment groups in MC38 Model
Fig. 3 shows body weight change of different treatment groups in MC38 Model
Fig. 4 shows anti-tumor effect of the test compound alone and in combination with Anti-PD-L1 mAb in H22 Model
Fig. 5 shows the tumor volume of Individual Mice in H22 Model
Fig. 6 shows survival curve for different treatment groups in H22 Model
Fig. 7 shows body weight change of different treatment groups in H22 Model
Example
The following abbreviations have been used in the examples:
Intermediate A1
Intermediate A1 was prepared referring to the compound 3 in WO2017023774 in Scheme 1 at page 82.
The following compounds were synthesized using the above procedure or modification procedure with the corresponding starting materials.
Intermediate B1
Step a: To a solution of 7-Fluoroindole (308 mg, 2.279 mmol) and Ytterbium (III) triflate hydrate (219 mg, 343.119 μmol) in Chloroform (3 mL) was added (2S) -Methylglycidate (121 mg, 1.185 mmol) under N2. The mixture was heated to 85℃ and stirred for 3 h. The reaction mixture was cooled to RT. The reaction mixture was quenched with Na2CO3 (aq) (10 mL) , and adjusted the pH to 5-6 with 2M HCl. The aqueous layer was separated and extracted with DCM (2×10 mL) . The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica chromatography eluting with EtOAc/Hexane (1: 2) to afford methyl (2S) -3- (7-fluoro-1H-indol-3-yl) -2-hydroxy-propanoate (136 mg, 573.292 μmol) . MS: m/z 238 (M+H) +.
Step b: To a solution of methyl (2S) -3- (7-fluoro-1H-indol-3-yl) -2-hydroxy-propanoate (136 mg, 573.292 μmol) in water (1 mL) was added LiOH (2M solution in water, 1 mL) . The mixture was stirred for overnight at RT-60℃, Citric acid (solid) was added, diluted with water (5 mL) and extracted with EA (2×10 mL) . The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford (2S) -3- (7-fluoro-1H-indol-3-yl) -2-hydroxy-propanoic acid (165 mg, 739.247 μmol) which was used in next step without any further purification. MS: m/z (224) +.
Intermediate B2
Step a: To a solution of Indole (302 mg, 2.578 mmol) in DMF (3 mL) was added NaH (217 mg, 9.043 mmol) at ice-water bath for 1h . (2S) -Methylglycidate (685 mg, 6.710 mmol) was added and the mixture was stirred over night at RT. The reaction mixture was quenched with H2O, and adjusted the pH to 3-4 with citric acid. The aqueous layers were extracted with EA. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by FLASH with H2O/MeCN (5%-95%) to afford (S) -2-hydroxy-3- (1H-indol-1-yl) propanoic acid (222 mg, 1.082 mmol) . MS: m/z 206 (M+H) +.
The following compounds were synthesized using the above procedure or modification procedure with the corresponding starting materials.

Intermediate C1
Step a: To a solution of Methyl (S) - (-) -lactate (1099 mg, 10.5567 mmol) , Iodoethane (3726 mg, 23.8900 mmol) in Diethyl ether (10 mL) was added Ag2O (4772 mg, 20.5925 mmol) under N2. The reaction mixture was stirred over night at RT by light-avoiding. The reaction mixture was monitored by TLC. The reaction mixture was filtered and concentrated under reduced pressure. The residue was dissolved by THF (3 mL) , MeOH (3 mL) , H2O (3 mL) and then the reaction mixture was added LiOH (246 mg, 10.2721 mmol) . The reaction mixture was stirred for 3h at RT. The reaction mixture was monitored by TLC and adjusted the pH to 2 with 1N HCl. The reaction mixture was concentrated under reduced pressure to 5 mL. The aqueous layers were extracted with EA (3×10 mL) . The combined organic layers were washed with saturated solution of NaCl (3×10 mL) and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford (S) -2-ethoxypropanoic acid (772 mg, 6.5351 mmol) . MS: m/z 119 (M+H) +.
Intermediate C2
Step a: To a solution of 2-hydroxy-4- (methylthio) butanoic acid (0.68 g, 4.5274 mmol) , CH3I (3.35 g, 23.6019 mmol) in Diethyl ether (10 mL) was added Ag2O (4.41 g, 19.0303 mmol) . The reaction mixture was stirred over night at RT. The reaction mixture was monitored by LC-MS. The reaction mixture was filtered and concentrated under reduced pressure. The residue was dissolved by MeOH (6 mL) , H2O (2 mL) and then the reaction mixture was added NaOH (318 mg, 7.9506 mmol) . The reaction mixture was stirred for 3h at RT. The reaction mixture was monitored by TLC and adjusted the pH to 3 with 1M HCl. The reaction mixture was concentrated under reduced pressure to 5 mL. The aqueous layers were extracted with EA (3×10 mL) . The combined organic layers were washed with saturated solution of NaCl (3×10 mL) and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 2-methoxy-4- (methylthio) butanoic acid (128 mg, 779.4318 μmol) . MS: m/z 165 (M+H) +.
Intermediate C3
Step a: To a solution of 2-hydroxy-3- (1H-indol-3-yl) propanoic acid (152 mg, 740.706 μmol) in THF (10 mL) was added NaH (55 mg, 2.292 mmol) . The reaction mixture was stirred for 20 min at RT and then CH3I (370 mg, 2.607 mmol) was added. The reaction mixture was monitored by LC-MS. CH3I (358 mg, 2.522 mmol) was added again. The reaction mixture was monitored by LC-MS. The reaction mixture was stirred for 3h at 40℃. The  reaction mixture was added H2O (5 mL) and extracted with EA (10 mL) . The aqueous layers were combined and purified by FLASH with H2O/MeCN (0%-100%, 40min, C18) . The product layers were concentrated under reduced pressure to afford 2-methoxy-3- (1-methyl-1H-indol-3-yl) propanoic acid (119 mg, 510.155 μmol) . MS: m/z 234 (M+H) +.
The following compounds were synthesized using the above procedure or modification procedure with the corresponding starting materials.




Intermediate D1
Step a: To a solution of methyl (S) -2-hydroxy-3- (1H-indol-3-yl) propanoate (2 g, 9.123 mmol) in DCM (20 mL) was added Imidazole (2061 mg, 30.274 mmol) and TBDMS-Cl (2980 mg, 19.772 mmol) . The mixture was stirred for overnight at RT. The reaction mixture was quenched with Water (10 mL) and extracted with DCM (10 mL). The reaction mixture was separated and organic extracts were collected. The aqueous solution was extracted with DCM (2×10 mL) . The residue was purified by wet column chromatography with EA/Hex (0-20%) . The product’s solution was concentrated under reduced pressure. The methyl (S) -2- ( (tert-butyldimethylsilyl) oxy) -3- (1H-indol-3-yl) propanoate (3099 mg) was obtained. MS: m/z 334 (M+H) +.
Step b: To a -78℃ solution of methyl (S) -2- ( (tert-butyldimethylsilyl) oxy) -3- (1H-indol-3-yl) propanoate (3.099g, 9.292 mmol) in THF (30 mL) was added LiHMDS (10.5 mL, 10.491 mmol) . The mixture was stirred for 30min at -78℃. Then Carbobenzyloxy chloride (4623 mg, 27.100 mmol) was dropped into the mixture at -78℃. The reaction mixture was stirred for 1h at this temperature. Quenched the reaction with sat. NH4Cl, and the aqueous solution was extracted with EA (2×10 mL) . The combined organic extracts were washed with brine (3×10 mL), dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure. The benzyl (S) -3- (2- ( (tert-butyldimethylsilyl) oxy) -3-methoxy-3-oxopropyl) -1H-indole-1-carboxylate (4345 mg) was obtained. MS: m/z 468 (M+H) +.
Step c: To a solution of benzyl (S) -3- (2- ( (tert-butyldimethylsilyl) oxy) -3-methoxy-3-oxopropyl) -1H-indole-1-carboxylate (4.345 g, 9.292 mmol) in THF (30 mL) was added Tetrabutylammonium fluoride (5 mL) . The mixture was stirred for overnight at RT. The reaction mixture was concentrated under reduced pressure. The residue was purified by FLASH with EA/Hex (0-60%) . The product’s solution was concentrated under reduced pressure. The benzyl 3- [ (2S) -2-hydroxy-3-methoxy-3-oxo-propyl] indole-1-carboxylate (2.21 g) was obtained. MS: m/z 354 (M+H) +.
Step d: To a solution of benzyl 3- [ (2S) -2-hydroxy-3-methoxy-3-oxo-propyl] indole-1-carboxylate (103 mg, 291.481 μmol) , and 4A molecular sieve in CH3I (1mL) was added Silver oxide (216 mg, 932.098 μmol) . The mixture was stirred for overnight at RT. The reaction mixture was concentrated under reduced pressure. The reaction mixture was diluted with EA (5mL) and filtered, the filtrate was concentrated to afford benzyl (S) -3- (2, 3-dimethoxy-3-oxopropyl) -1H-indole-1-carboxylate (107.088 mg, 100.000%yield) . MS: m/z 368(M+H) +.
Step e: To a solution of benzyl (S) -3- (2, 3-dimethoxy-3-oxopropyl) -1H-indole-1-carboxylate (0.107g, 291.240  μmol) in THF (5 mL) and MeOH (5mL) was added NaOH (3mL, 3M/L) . The mixture was stirred for 1h at RT. The reaction mixture was adjusted the pH to 3 with 1M HCl. The aqueous solution was extracted with EA (2×10 mL) . The combined organic extracts were washed with brine (3×10 mL) , dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure and (S) -3- (1H-indol-3-yl) -2-methoxypropanoic acid (71 mg) was obtained. MS: m/z 220 (M+H) +.
The following compounds were synthesized using intermediate D1 and the above procedure or modification procedure with the corresponding starting materials.

EXAMPLE 1
Isopropyl (S) -6-diazo-2- ( (S) -3- (7-fluoro-1H-indol-3-yl) -2-hydroxypropanamido) -5-oxohexanoate (Compound 1)
To a solution of (2S) -3- (7-fluoro-1H-indol-3-yl) -2-hydroxy-propanoic acid (0.165 g, 739.247 μmol) and isopropyl (2S) -2-amino-6-diazo-5-oxo-hexanoate (123 mg, 576.834 μmol) in DCM (2 mL) was added N, N'-Diisopropylcarbodiimide (95 mg, 752.779 μmol) , 2, 4, 6-Collidine (115 mg, 949.008 μmol) and Ethyl cyanoglyoxylate-2-oxime (83 mg, 584.044 μmol) at 0℃. The mixture was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC, and concentrated under reduced pressure to afford isopropyl (2S) -6-diazo-2- [ [ (2S) -3- (7-fluoro-1H-indol-3-yl) -2-hydroxy-propanoyl] amino] -5-oxo-hexanoate (41.6 mg, 99.422 μmol) by lyophilization. MS: m/z 419 (M+H) +, 1H NMR (400 MHz, CDCl3) δ 8.47 –8.39 (m, 1H) , 7.47 (d, J = 7.9 Hz, 1H) , 7.21 –7.19 (m, 1H) , 7.16 (d, J = 7.8 Hz, 1H) , 7.05 (td, J = 7.9, 4.8 Hz, 1H) , 6.93 (dd, J = 10.8, 7.8 Hz, 1H), 5.09 (s, 1H) , 5.03 (dt, J = 12.5, 6.3 Hz, 1H) , 4.53 –4.45 (m, 1H) , 4.43 (s, 1H) , 3.29 (ddd, J = 21.3, 14.8, 5.4 Hz, 2H) , 2.73 –2.60 (m, 1H) , 2.43 –2.25 (m, 1H) , 2.18 –1.98 (m, 2H) , 1.97 –1.80 (m, 1H) , 1.30 –1.22 (m, 6H) . EXAMPLE 2
Isopropyl (S) -6-diazo-2- ( (S) -2-methoxypropanamido) -5-oxohexanoate (Compound 2)
To a solution of (S) -2-methoxypropanoic acid (267 mg, 2.565 mmol) and isopropyl (2S) -2-amino-6-diazo-5-oxo-hexanoate (0.152 g, 712.835 μmol) in DMF (5 mL) was added N,N'-Diisopropylcarbodiimide (327 mg, 2.591 mmol) , 2, 4, 6-Collidine (412 mg, 3.400 mmol) and Ethyl cyanoglyoxylate-2-oxime (375 mg, 2.639 mmol) at 0℃. The mixture was stirred at RT for 15 h. The reaction mixture was quenched with saturated NH4Cl (50 mL) and extracted with EA (20 mL×3) . The combined organic layers were washed with brine (50 mL×3) and concentrated under reduced pressure. The residue was purified by pre-HPLC (C18, MeCN/H2O=5-100%, 40min) and concentrated under reduced pressure to afford isopropyl (S) -6-diazo-2- ( (S) -2-methoxypropanamido) -5-oxohexanoate (60.2 mg, 201.1211 μmol, easily dissolved in water) . MS:m/z 300 (M+H) +, 1H NMR (400 MHz, CDCl3) δ 7.22 –7.08 (m, 1H) , 5.12 –5.01 (m, 1H) , 4.57 (td, J = 8.7, 4.8 Hz, 1H) , 3.77 (dt, J = 6.7, 5.7 Hz, 1H) , 3.45 (s, 3H) , 2.82 –2.58 (m, 1H) , 2.50 –2.22 (m, 2H) , 2.09 –1.85 (m, 1H) , 1.44 –1.35 (m, 3H) , 1.31 –1.26 (m, 6H) .
EXAMPLE 3
Methyl (S) -6-diazo-2- ( (S) -2-methoxypropanamido) -5-oxohexanoate (Compound 3)
To a solution of (S) -2-methoxypropanoic acid (2.06 g, 19.7879 mmol) and methyl (S) -2-amino-6-diazo-5-oxohexanoate (2308 mg, 12.4635 μmol) in DMF (5 mL) was added NMM (3.73 g, 36.8770 mmol) and HATU (6.26 g, 16.4637 mmol) at 0℃. The mixture was stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (C18, MeCN/H2O=0-100%, 40 min) and concentrated under reduced pressure to afford methyl (S) -6-diazo-2- ( (S) -2-methoxypropanamido) -5-oxohexanoate (2.87 g, 10.5799 mmol, easily dissolved in water) . MS:m/z 272 (M+H) +, 1H NMR (400 MHz, CD3OD) δ 5.82 (s, 1H) , 4.46 (dd, J = 8.9, 4.8 Hz, 1H) , 3.79 –3.74 (m, 1H), 3.72 (s, 3H) , 3.40 (s, 3H) , 2.43 (s, 2H) , 2.33 –2.15 (m, 1H) , 2.08 –1.90 (m, 1H) , 1.33 (d, J = 6.7 Hz, 3H) .
EXAMPLE 4
(S) -6-diazo-2- ( (S) -2-methoxypropanamido) -5-oxohexanoic acid (Compound 4)
To a solution of methyl (S) -6-diazo-2- ( (S) -2-methoxypropanamido) -5-oxohexanoate (0.96 g, 3.5389 mmol) in THF (10 mL) was added a solution of NaOH (176 mg, 4.4003 mmol) in water (5 mL) at 0℃. The mixture was stirred at RT for 40 min. The reaction mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (C18, MeCN/H2O=0-80%, 30 min) and concentrated under reduced pressure to afford (S) -6-diazo-2- ( (S) -2-methoxypropanamido) -5-oxohexanoic acid (866 mg, 3.3665 mmol, easily dissolved in water) . MS:m/z 258 (M+H) +, 1H NMR (400 MHz, CD3OD) δ 5.82 (s, 1H) , 4.27 (t, J = 5.8 Hz, 1H) , 3.72 (q, J = 6.6 Hz, 1H), 3.40 (s, 3H) , 2.46 –2.27 (m, 2H) , 2.28 –2.13 (m, 1H) , 2.06 –1.91 (m, 1H) , 1.33 (d, J = 6.7 Hz, 3H) .
EXAMPLE 5
Isopropyl (S) -2- ( (S) -2-acetoxy-3- (7-fluoro-1H-indol-3-yl) propanamido) -6-diazo-5-oxohexanoate (Compound 5)
To a solution of isopropyl (S) -6-diazo-2- ( (S) -3- (7-fluoro-1H-indol-3-yl) -2-hydroxypropanamido) -5-oxohexanoate (0.166 g, 396.7325 μmol) in DMF (3.5 mL) was added pyridine (189 mg, 2.3894 mmol) and acetic anhydride (104 mg, 1.0187 mmol) at RT. The mixture was stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (C18, MeCN/H2O=2-80%) and concentrated under reduced pressure to afford isopropyl (S) -2- ( (S) -2-acetoxy-3- (7-fluoro-1H-indol-3-yl) propanamido) -6-diazo-5-oxohexanoate (75.2 mg, 163.3196 μmol) . MS: m/z 461 (M+H) +, 1H NMR (400 MHz, CD3OD) δ 7.39 (d, J = 7.9 Hz, 1H) , 7.17 (s, 1H) , 6.96 (dd, J = 13.4, 6.4 Hz, 1H) , 6.88 –6.76 (m, 1H) , 5.24 (t, J = 5.4 Hz, 1H) , 4.96 (dt, J = 12.4, 6.3 Hz, 1H) , 4.27 (d, J = 8.7 Hz, 1H) , 3.28 (d, J = 5.6 Hz, 2H) , 2.26 –2.13 (m, 1H) , 2.10 (s, 3H) , 2.05 (d, J = 10.2 Hz, 2H) , 1.88 –1.75 (m, 1H) , 1.22 (t, J = 6.8 Hz, 6H) .
EXAMPLE 6
Ethyl (S) -6-diazo-2- ( (S) -2-methoxypropanamido) -5-oxohexanoate (Compound 6)
To a solution of (S) -6-diazo-2- ( (S) -2-methoxypropanamido) -5-oxohexanoic acid (104 mg, 404.2870 μmol) and EtOH (96 mg, 2.0839 mmol) in DMF (5 mL) was added NMM (117 mg, 1.1567 mmol) and HATU (237 mg, 623.3081 μmol) at 0℃. The mixture was stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (C18, MeCN/H2O=0-100%, 30 min) and concentrated under reduced pressure to afford ethyl (S) -6-diazo-2- ( (S) -2-methoxypropanamido) -5-oxohexanoate (0.0332 g, 116.3705 μmol, easily dissolved in water) . MS: m/z 286 (M+H) +, 1H NMR (400 MHz, CD3OD) δ 4.49 –4.35 (m, 1H), 4.23 –4.13 (m, 2H) , 3.83 –3.71 (m, 1H) , 3.44 –3.35 (m, 3H) , 2.43 (s, 2H) , 2.30 –2.15 (m, 1H) , 2.08 –1.93 (m, 1H) , 1.36 –1.31 (m, 3H) , 1.29 –1.24 (m, 3H) .
The following compounds were synthesized using the above procedure or modification procedure of the aboved schemes with the corresponding starting materials.
















































































EXAMPLE A: Efficacy of Compound 2 in Combination with Anti-PD-1 mAb in MC38 Syngeneic Model
Test Compound:
Compound 2; Physical description: Powder; Purity > 95%; Storage condition: 4 ℃.
InVivoMAb anti-mouse PD-1 (Anti-PD-1) ; Supplier: BioXcell; Physical description: Liquid; Purity > 95%; Storage condition: 4 ℃.
Each C57BL/6 mouse was inoculated subcutaneously in the right flank region with MC38 cells (1 x 106) for tumor development. The treatments were started when the mean tumor size reached approximately 75 mm3. The experimental animals were divided using stratified randomization with 7 mice per group based upon their tumor volumes. The treatment was started from the day of randomization, Group 1 was treated with Vehicle s. c. QD, Group 2 was treated with anti-PD-1 10 mg/kg i. p. BIW, Group 3 was treated with Compound 2 1.2 mg/kg s.c. Q2D, Group 4 was treated with Compound 2 1.2 mg/kg s. c. Q2D and anti-PD-1 10 mg/kg i. p. BIW. The in vivo efficacy was examined according to tumor growth inhibition (TGI) and the safety was evaluated according to weight change and survival in mice.
The result showed that Compound 2 alone had a significant anti-tumor effect in the MC38 syngeneic model, and combination with anti-PD-1 mAb further inhibited tumor growth and significantly prolonged the survival time. At day 22 post tumor implantation, the TGI were 57.2%, 76.2%and 89.7%, respectively (p =0.151, 0.019 and 0.008 compared to the vehicle group, respectively) . The tumor growth curves are shown in Fig. 1.
Treatments were ended at day 26 and survival curves from different groups were analyzed. Median survival of the groups was 26 days, 29 days, 33 days and 40 days, respectively. The result showed that combination of Compound 2 and anti-PD-1 further improved mouse survival compared to single agent treatment. The survival curves are shown in Fig. 2.
All the treatments were well-tolerated without any adverse effects observed in the MC38 tumor-bearing mice. The body weight curves are shown in Fig. 3.
In this study, Compound 2 in combination with anti-PD-1 mAb further enhanced tumor growth inhibition and showed improved survival compared to single agent treatment in MC38 model.
EXAMPLE B: Efficacy of Compound 2 in Combination with Anti-PD-L1 mAb in H22 Syngeneic Model
Test Compound:
Compound 2; Physical description: Powder; Purity > 95%; Storage condition: 4 ℃.
InVivoMAb anti-mouse PD-L1 (Anti-PD-L1) ; Supplier: BioXcell; Physical description: Liquid; Purity >95%; Storage condition: 4 ℃.
Each BALB/c mouse was inoculated subcutaneously in the right flank region with H22 cells (1 x 106) for tumor development. The treatments were started when the mean tumor size reached 146 mm3. The experimental animals were divided using stratified randomization with 8 mice per group based upon their tumor volumes.  The treatment was started from the day of randomization. Group 1 was treated with Vehicle s. c. QD, Group 2 was treated with anti-PD-L1 5 mg/kg i.p. BIW, Group 3 was treated with Compound 2 1.2 mg/kg s.c. 5 days on/2 days off, Group 4 was treated with Compound 2 1.2 mg/kg s.c. 5 days on/2 days off and anti-PD-L1 5 mg/kg i.p. BIW. The in vivo efficacy was examined according to tumor growth inhibition (TGI) and the safety was evaluated according to weight change and survival in mice.
The result showed that Compound 2 alone had a significant anti-tumor effect in the H22 syngeneic model, and combination with anti-PD-L1 mAb further inhibited tumor growth and significantly prolonged the survival time. At day 17 post tumor implantation, the TGI were 34.4%, 87.7%and 92.3%, respectively (p = 0.807, 0.022 and 0.018 compared to the vehicle group, respectively) . The tumor growth curves are shown in Fig. 4.
Treatments were ended at day 20 and survival curves from different groups were analyzed. Median survival of the groups was 20 days, 24 days, 42 days and undefined, respectively. The result showed that combination of Compound 2 and anti-PD-L1 further improved mouse survival compared to single agent treatment. The tumor growth curves of individual mice are shown in Fig. 5. The survival curves are shown in Fig. 6.
All the treatments were well-tolerated without any adverse effects observed in the H22 tumor-bearing mice. The body weight curves are shown in Fig. 7.
In this study, Compound 2 in combination with anti-PD-L1 mAb further enhanced tumor growth inhibition and showed improved survival compared to single agent treatment in H22 model.
The compounds of the present invention are preferably formulated as pharmaceutical compositions administered by a variety of routes. Most preferably, such compositions are for oral administration. Such pharmaceutical compositions and processes for preparing the same are well known in the art. See, e.g., REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (A. Gennaro, et al, eds., 19th ed., Mack Publishing Co., 1995) . The combinations are generally effective over a wide dosage range.
For example, dosages per day normally fall within the range of about 1 mg to about 200 mg total daily dose, preferably 0.2 mg to 50 mg total daily dose, more preferably 0.2 mg to 20 mg total daily dose. In some instances dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed. The above dosage range is not intended to limit the scope of the invention in any way. It will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.
It is understood that the Examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims.

Claims (35)

  1. a pharmaceutical combination comprising:
    (i) a glutamine antagonist, or a pharmaceutical acceptable salt thereof; and
    (ii) an immune checkpoint inhibitor.
  2. The pharmaceutical combination of claim 1, wherein the immune checkpoint inhibitor is selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor, a LAG3 inhibitor, or a TIM3 inhibitor.
  3. The pharmaceutical combination of claim 1 or 2, wherein the immune checkpoint inhibitor is a PD-1 inhibitor.
  4. The pharmaceutical combination of claim 3, wherein the PD-1 inhibitor is an anti-PD-1 antibody.
  5. The pharmaceutical combination of claim 4, wherein the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, pidilizumab, STI-A1110, PDR001, MEDI-0680, AGEN2034, BGB-A317, AB122, TSR-042, PF-06801591, cemiplimab, SYM021, JNJ-63723283, HLX10, LZM009, and MGA012.
  6. The pharmaceutical combination of claim 1 or 2, wherein the immune checkpoint inhibitor is a PD-L1 inhibitor.
  7. The pharmaceutical combination of claim 6, wherein the PD-L1 inhibitor is an anti-PD-Ll antibody.
  8. The pharmaceutical combination of claim 7, wherein the anti-PD-Ll antibody is selected from the group consisting of avelumab, atezolizumab, durvalumab, and STI-A1014.
  9. The pharmaceutical combination of claim 1 or 2, wherein the immune checkpoint inhibitor is a an anti-CTLA-4 inhibitor.
  10. The pharmaceutical combination of claim 9, wherein the anti-CTLA-4 inhibitor is an anti-CTLA-4 antibody.
  11. The pharmaceutical combination of claim 10, wherein the anti-CTLA-4 antibody is selected from the group consisting of ipilimumab and tremelimumab.
  12. The pharmaceutical combination of claim 1 or 2, wherein the immune checkpoint inhibitor is a LAG3 inhibitor.
  13. The pharmaceutical combination of claim 12, wherein the LAG3 inhibitor is an anti-LAG3 antibody.
  14. The pharmaceutical combination of claim 13, wherein the anti-LAG3 antibody is GSK2831781.
  15. The pharmaceutical combination of claim 1 or 2, wherein the immune checkpoint inhibitor is a TIM3 inhibitor.
  16. The pharmaceutical combination of claim 15, wherein the TIM3 inhibitor is an anti-TIM3 antibody.
  17. The pharmaceutical combination of any one of claims 1-16, wherein the glutamine antagonist is a compound of formula I, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an isotopic substitution thereof,
    wherein,
    Z is OR1 or SR1; R1 is selected from the group consisting of hydrogen, deuterium, halogen, C1-6 alkyl, C1-6alkoxy, -C3-8cycloalkyl, -C0-6alkylene-C3-8heterocyclyl, -C0-6alkylene-NH-C0-6alkylene C6-10aryl, -C0-6alkylene-NH-C0-6alkylene-5-12membered heteroaryl, -C0-6alkylene-C6-10aryl and -C0-6alkylene-5-12 membered heteroaryl; each of which can be optional substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-6alkyl) 2, carboxyl, -CO-C1-6alkyl; and each of the heteroaryl and heterocyclyl contains 1, 2 or 3 heteroatoms selected from N, O or S;
    X is selected from the group consisting of hydrogen, deuterium, C1-6alkyl, -C (=O) -G, -C (=O) -W- (CRX1RX2) m-O-RX3, -C (=O) -W- (CRX1RX2) m-S-RX3, C (=O) -W- (CRX1RX2) m-SO-RX3, C (=O) -W- (CRX1RX2) m-SO2-RX3, -C (=O) -W- (CRX1RX2) m-G, -C (=O) -W- (CRX1RX2) m-NR5R5’, -P (=O) (OR6) p (NHR7) q, -C (=O) -W- (CRX1RX2) m-G-O-C (=O) -R8, -C (=O) -W- (CRX1RX2) m-G-O-R8, -C (=O) -O- (CRX1RX2) m-O-C (=O) -R9, -C (=O) -O-R7, -C (=O) -W- (CRX1RX2) m-G-O-C (=O) -G, and -C (=O) -W- (CRX1RX2) m-G-NR5R5’;
    W is oxygen, CO or a bond;
    m is selected from 1, 2, 3, 4, 5, 6, 7 or 8;
    p and q are each independently selected from 0, 1 or 2 provided that the sum of p and q is 2;
    RX1 and RX2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, NH2, C1-6 alkyl, C1-6alkoxy, C4-10 cycloalkyl, -C (=O) -C1-6alkyl, C5-12aryl, -C1-6 alkylene-C5-12aryl, -5-12 membered heteroaryl, and –C1-6 alkylene-5-12 membered heteroaryl, and wherein said C1-6 alkyl, said C1-6alkoxy, said C4-10 cycloalkyl, said C5-12aryl, said–C1-6 alkylene-C5-12aryl, said -5-12 membered heteroaryl, and said–C1-6 alkylene-5-12 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-6alkyl) 2, -S-C1-6alkyl, carboxyl; and each of the heteroaryl independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S;
    or RX1 and RX2 together with the carbon atom to which they are attached form C3-10carbocyclic ring, C3-10 membered heterocyclyl, each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -NH2, -CN, -OH, -NO2, carbonyl, =O, oxo, carboxyl, C1-6alkoxy, C1-6alkyl; and each of the heterocyclyl independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S;
    RX3 is independently selected from the group consisting of hydrogen, deuterium, C1-6 alkyl, C1-6 alkoxy, C3-8 cycloalkyl, -C (=O) -C1-6 alkyl, and -C1-6alkylenen-C5-12 aryl, wherein said C1-6 alkyl, said C1-6 alkoxy, said C3-8 cycloalkyl, said -C (=O) -C1-6 alkyl, and said -C1-6alkylenen-C5-12 aryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-6alkyl) 2, carboxyl, 4-8 membered heterocyclyl, -C6-12aryl, -C (=O) -C1-6alkyl, -NH-C (=O) -C1-6alkyl, -C (=O) -NH2, -C (=O) -NH-C1-6alkyl, -C (=O) -N (C1-6 alkyl) 2;
    or RX1 and RX3 together with the carbon atom and the oxygen atom to which they are attached respectively form a 5-12 membered heterocyclyl, wherein said 5-12 membered heterocyclyl can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-6alkyl) 2, carboxyl; and each of the heterocyclyl independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S;
    R5 and R5’ are each independently selected from the group consisting of hydrogen, deuterium, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, C5-12 aryl, 5-12 membered heteroaryl, 5-12 membered heterocyclyl, and wherein said -C1-6 alkyl, said -C1-6 alkoxy, said -C3-8 cycloalkyl, said C5-12 aryl, said 5-12 membered heteroaryl, said 5-12 membered heterocyclyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-6alkyl) 2, carboxyl;
    each of R6 is independently selected from the group consisting of hydrogen, deuterium, -C1-6 alkyl, -C3-8 cycloalkyl, 5-12 membered heterocyclyl ring, -C1-6 alkenyl, and -C3-8 cycloalkenyl, and wherein said -C1-6 alkyl, said -C3-8 cycloalkyl, said 5-12 membered heterocyclyl ring, said -C1-6 alkenyl, and said -C3-8 cycloalkenyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-6alkyl) 2, carboxyl;
    or R6 together with the oxygen atom to which it is attached forms a purine or pyrimidine nucleoside;
    each of R7 is independent selected from the group consisting of hydrogen, deuterium, halogen, C1-6 alkyl, C3-8 cycloalkyl, 5-12 membered heterocyclyl ring, C1-6 alkenyl, C3-8 cycloalkenyl, C5-12 aryl, and 5-12 membered heteroaryl, and wherein said C1-6 alkyl, said C3-8 cycloalkyl, said 5-12 membered heterocyclyl ring, said C1-6 alkenyl, said C3-8 cycloalkenyl, said C5-12 aryl, and said 5-12 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-6alkyl) 2, carboxyl;
    R8 and R9 are each independently selected from the group consisting of C1-6 alkyl, C3-8 cycloalkyl, monosaccharide, acylated monosaccharide, C5-12 aryl, and 5-12 membered heteroaryl, and wherein said C1-6 alkyl, said C3-8 cycloalkyl, said monosaccharide, said acylated monosaccharide, said C5-12 aryl, and said 5-12 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-6alkyl) 2, carboxyl;
    G is C5-12 aryl, or 5-12 membered heteroaryl, wherein C5-12 aryl, and 5-12 membered heteroaryl can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH (C1-6  alkyl) , -N (C1-6alkyl) 2, carboxyl;
    R2 is selected from the group consisting of hydrogen, deuterium, halogen, C1-6 alkyl, and C1-6 alkoxy, and wherein said C1-6 alkyl, and said C1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-6alkyl) 2, carboxyl;
    R3 and R3’ are each independently selected from the group consisting of hydrogen, deuterium, halogen, C1-6 alkyl, and C1-6 alkoxy, and wherein said C1-6 alkyl, and said C1-6 alkoxy can be optional substituted with one or more substituents, which are independently from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-6alkyl) 2, carboxyl;
    Y is a bond, oxygen, or - (CRY1RY2) n-;
    n is selected from 1, 2, 3, 4, 5, 6, 7 or 8;
    RY1 and RY2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, C1-6 alkyl, and C1-6 alkoxy, and wherein said C1-6 alkyl, and said C1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N(C1-6alkyl) 2, carboxyl;
    R4 is selected from the group consisting of hydrogen, deuterium, halogen, C1-6 alkyl, and C1-6 alkoxy, and wherein said C1-6 alkyl, and said C1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-6alkyl) 2, carboxyl;
    R10 is selected from the group consisting of hydrogen, deuterium, halogen, C1-6 alkyl, and C1-6 alkoxy, and wherein said C1-6 alkyl, and said C1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-6alkyl) 2, carboxyl.
  18. The pharmaceutical combination of any one of claims 1-17, wherein the glutamine antagonist is a compound, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an isotopic substitution thereof, wherein
    the compound is of Formula I-A:
    the compound is of Formula I-B: 
    wherein X, Y, R1, R2, R3, R3’, R4, and R10 are the same as defined in claim 17;
    preferably, the compound is of formula I-C,
    wherein Q is O, S, SO, or SO2; Z, RX1, RX2, RX3, and m are the same as defined in claim 17;
    or the compound is of formula II, 
    wherein Z, RX1, RX2, RX3, and m are the same as defined in claim 17; or
    the compound is of formula III, 
    wherein Z, RX1, RX2, RX3, and m are the same as defined in claim 17; or
    the compound is of formula IV, 
    wherein R1, RX1, RX2 and RX3 are the same as defined in claim 17; or
    the compound is of formula V, 
    wherein R1, RX1, RX2 and RX3 are the same as defined in claim 17; or
    the compound is of formula VI, 
    wherein R1, RX1, RX2 and RX3 are the same as defined in claim 17; or
    the compound is of formula VII, 
    wherein R1, RX1, RX2 and RX3 are the same as defined in claim 17; or
    the compound is of formula VIII, 
    wherein R1, RX1, RX2, and RX3 are the same as defined in claim 17.
  19. The pharmaceutical combination of any one of claims 1-18, wherein
    one or more hydrogen in R1 or RX3 is substituted with deuterium, preferably, all hydrogens on one or more methyl groups, methylene groups, or methane groups are substituted with deuterium;
    R1 is selected from the group consisting of hydrogen, deuterium, hydrogen, deuterium, C1-3 alkyl, C1-3 alkoxy, and each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy;
    RX1 and RX2 are each independently selected from the group consisting of hydrogen, deuterium, CN, OH, C1-4alkyl, C1-3alkoxy, each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH (C1-6 alkyl) , -N (C1-3alkyl) 2, -S-C1-3alkyl; or
    RX3 is independently selected from the group consisting of hydrogen, deuterium, C1-3 alkyl, C1-3  alkoxy, each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH (C1-3 alkyl) , -N (C1-3alkyl) 2, carboxy, -S-C1-3alkyl;
    Preferably,
    R1 is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy; and each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy;
    RX1 and RX2 are each independently selected from the group consisting of hydrogen, deuterium, CN, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, butyl, sec-butyl, iso-butyl, tert-butyl, cyclobutyl, and each of which is independently optionally subsitituted with deuterium, -F, -Cl, -Br, -I, -NH2, -CN, -OH, oxo, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy; or
    RX3 is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, tert-butyl, each of which can be substituted with deuterium;
    More preferably,
    R1 is seleted from hydrogen, deuterium, isopropyl, methyl, ethyl, -tert-butyl, isopentyl, -CD3, -CH2CD3, -CD2CD3, -CD (CD3) 2, -CH (CD3) 2, 
    RX1 and RX2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, butyl, sec-butyl, iso-butyl, tert-butyl, or
    RX3 is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, tert-butyl, -CD3, -CH2CD3, -CD2CD3.
  20. The pharmaceutical combination of any one of claims 1-19, wherein the glutamine antagonist is a compound in table 3, or a pharmaceutically acceptable salt thereof.
  21. The pharmaceutical combination of any one of claims 1-20, wherein the glutamine antagonist is selected from:
    or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, and an isotopic substitution thereof.
  22. The pharmaceutical combination of any one of claims 1-21, wherein the glutamine antagonist and the immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof, are in the same formulation.
  23. The pharmaceutical combination of any one of claims 1-21, wherein the glutamine antagonist and the immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof, are in the separate formulation.
  24. The pharmaceutical combination of any one of claims 1-23, wherein the pharmaceutical combination of the invention is for simultaneous or sequential (in any order) administration.
  25. A pharmaceutical composition or commercial package (e.g. a kit-of-parts) comprising the pharmaceutical combination of any one of the preceding claims and at least one pharmaceutically acceptable carrier.
  26. A use of a pharmaceutical combination of any one of claims 1 to 24 and/or a pharmaceutical composition or the commercial package of claim 25 for the manufacture of a medicament.
  27. The use of pharmaceutical combination of any one of claims 1 to 24 or the pharmaceutical composition or the commercial package of claim 25, wherein a medicament prepared can be used for the treatment or prevention of cancer or cancer metastasis.
  28. The use of pharmaceutical combination or the pharmaceutical composition or the commercial package of claim 27, wherein the cancer is selected from a breast cancer (e.g., a triple negative breast cancer) , a colorectal cancer (e.g., a microsatellite stable colorectal cancer (MSS CRC) ) , acute lymphoblastic leukemia, acute myelogenous leukemia, advanced soft tissue sarcoma, brain cancer, metastatic or aggressive breast cancer, bronchogenic carcinoma, choriocarcinoma, chronic myelocytic leukemia, colon carcinoma, Ewing's sarcoma, gastrointestinal tract carcinoma, glioma, glioblastoma multiforme, hepatocellular carcinoma, Hodgkin's disease, intracranial ependymoblastoma, large bowel cancer, leukemia, liver cancer, lung cancer, Lewis lung carcinoma, lymphoma, lymphangioma, lymphangiosarcoma, malignant fibrous histiocytoma, a mammary tumor, melanoma, mesothelioma, neuroblastoma, osteosarcoma, ovarian cancer, pancreatic cancer, a pontine tumor, premenopausal breast cancer, prostate cancer, rhabdomyosarcoma, reticulum cell sarcoma, sarcoma, small cell lung cancer, a solid tumor, stomach cancer, testicular cancer, uterine carcinoma, skin cancer, a gastric cancer, a gastroesophageal cancer, lung cancer, cervical cancer, head and neck cancer, esophageal cancer, non-small cell lung cancer, non-Hodgkin lymphoma, or any of combination thereof; preferably, the skin cancer is a melanoma (e.g., a refractory melanoma) .
  29. The use of pharmaceutical combination or the pharmaceutical composition or the commercial package of claim 27 or 28, wherein the cancer is selected from hepatocellular carcinoma, glioblastoma, lung cancer, breast cancer, head and neck cancer, prostate cancer, melanoma, lymphoma, kidney cancer, and colorectal cancer.
  30. The pharmaceutical combination of any one of claims 1 to 24 or the pharmaceutical composition or the commercial package of claim 25, for use in the treatment of cancer or the prevention of cancer metastasis.
  31. The pharmaceutical combination or the pharmaceutical composition or the commercial package for use of claim 30, wherein the cancer is selected from a breast cancer (e.g., a triple negative breast cancer) , a colorectal cancer (e.g., a microsatellite stable colorectal cancer (MSS CRC) ) , acute lymphoblastic leukemia, acute myelogenous leukemia, advanced soft tissue sarcoma, brain cancer, metastatic or aggressive breast cancer, bronchogenic carcinoma, choriocarcinoma, chronic myelocytic leukemia, colon carcinoma, Ewing's sarcoma, gastrointestinal tract carcinoma, glioma, glioblastoma multiforme, hepatocellular carcinoma, Hodgkin's disease, intracranial ependymoblastoma, large bowel cancer, leukemia, liver cancer, lung cancer, Lewis lung carcinoma, lymphoma, lymphangioma, lymphangiosarcoma, malignant fibrous histiocytoma, a mammary tumor, melanoma, mesothelioma, neuroblastoma, osteosarcoma, ovarian cancer, pancreatic cancer, a pontine tumor, premenopausal breast cancer, prostate cancer, rhabdomyosarcoma, reticulum cell sarcoma, sarcoma, small cell lung cancer, a solid tumor, stomach cancer, testicular cancer, uterine carcinoma, skin cancer, a gastric cancer, a gastroesophageal cancer, lung cancer, cervical cancer, head and neck cancer, esophageal cancer, non-small cell lung cancer, non-Hodgkin lymphoma, or any of combination thereof; preferably, the skin cancer is a melanoma (e.g., a refractory melanoma) .
  32. The pharmaceutical combination or the pharmaceutical composition or the commercial package for use of claim 30 or claim 31, wherein the cancer is selected from hepatocellular carcinoma, glioblastoma, lung cancer, breast cancer, head and neck cancer, prostate cancer, melanoma, lymphoma, kidney cancer, and colorectal cancer.
  33. The pharmaceutical combination of any one of claims 1 to 24 and/or a pharmaceutical composition or the commercial package of claim 25, which is used in therapy.
  34. The pharmaceutical combination of any one of claims 1 to 24 and/or a pharmaceutical composition or the commercial package of claim 25 which is used as a medicament.
  35. A method of treating cancer is selected from a breast cancer (e.g., a triple negative breast cancer) , a colorectal cancer (e.g., a microsatellite stable colorectal cancer (MSS CRC) ) , acute lymphoblastic leukemia, acute myelogenous leukemia, advanced soft tissue sarcoma, brain cancer, metastatic or aggressive breast cancer, bronchogenic carcinoma, choriocarcinoma, chronic myelocytic leukemia, colon carcinoma, Ewing's sarcoma, gastrointestinal tract carcinoma, glioma, glioblastoma multiforme, hepatocellular carcinoma, Hodgkin's disease, intracranial ependymoblastoma, large bowel cancer, leukemia, liver cancer, lung cancer, Lewis lung carcinoma, lymphoma, lymphangioma, lymphangiosarcoma, malignant fibrous histiocytoma, a mammary tumor, melanoma, mesothelioma, neuroblastoma, osteosarcoma, ovarian cancer, pancreatic cancer, a pontine tumor, premenopausal breast  cancer, prostate cancer, rhabdomyosarcoma, reticulum cell sarcoma, sarcoma, small cell lung cancer, a solid tumor, stomach cancer, testicular cancer, uterine carcinoma, skin cancer, a gastric cancer, a gastroesophageal cancer, lung cancer, cervical cancer, head and neck cancer, esophageal cancer, non-small cell lung cancer, non-Hodgkin lymphoma, or any of combination thereof, in a mammal comprising administering to a mammal in need of such treatment an effective amount of the pharmaceutical combination of any one of claims 1 to 24, and/or a pharmaceutical composition of claim 25.
PCT/CN2023/089400 2022-04-21 2023-04-20 Pharmaceutical combination and use thereof WO2023202652A1 (en)

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Citations (6)

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WO2017062354A1 (en) * 2015-10-05 2017-04-13 Calithera Biosciences, Inc. Combination therapy with glutaminase inhibitors and immuno-oncology agents
WO2017201501A1 (en) * 2016-05-20 2017-11-23 Biohaven Pharmaceutical Holding Company Ltd. Use of riluzole, riluzole prodrugs or riluzole analogs with immunotherapies to treat cancers
CN108290827A (en) * 2015-07-31 2018-07-17 约翰霍普金斯大学 The prodrug of glutamine analogues
CN108348492A (en) * 2015-07-31 2018-07-31 约翰霍普金斯大学 Use the method for cancer and immunotherapy of the glutamine analogues including DON
WO2019089952A1 (en) * 2017-11-03 2019-05-09 Calithera Biosciences, Inc. Conjoint therapy with glutaminase inhibitors
WO2022022612A1 (en) * 2020-07-29 2022-02-03 Jacobio Pharmaceuticals Co., Ltd. Novel glutamine analogs

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CN108290827A (en) * 2015-07-31 2018-07-17 约翰霍普金斯大学 The prodrug of glutamine analogues
CN108348492A (en) * 2015-07-31 2018-07-31 约翰霍普金斯大学 Use the method for cancer and immunotherapy of the glutamine analogues including DON
WO2017062354A1 (en) * 2015-10-05 2017-04-13 Calithera Biosciences, Inc. Combination therapy with glutaminase inhibitors and immuno-oncology agents
WO2017201501A1 (en) * 2016-05-20 2017-11-23 Biohaven Pharmaceutical Holding Company Ltd. Use of riluzole, riluzole prodrugs or riluzole analogs with immunotherapies to treat cancers
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