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WO2019158070A1 - A2a和/或a2b受体拮抗剂 - Google Patents

A2a和/或a2b受体拮抗剂 Download PDF

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Publication number
WO2019158070A1
WO2019158070A1 PCT/CN2019/074927 CN2019074927W WO2019158070A1 WO 2019158070 A1 WO2019158070 A1 WO 2019158070A1 CN 2019074927 W CN2019074927 W CN 2019074927W WO 2019158070 A1 WO2019158070 A1 WO 2019158070A1
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group
cancer
optionally substituted
alkyl
compound
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French (fr)
Inventor
刘世峰
俞智勇
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Adlai Nortye Biopharma Co Ltd
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Adlai Nortye Biopharma Co Ltd
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Priority to CN201980004345.5A priority Critical patent/CN111989313A/zh
Publication of WO2019158070A1 publication Critical patent/WO2019158070A1/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
    • C07D253/06—1,2,4-Triazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
    • C07D253/06—1,2,4-Triazines
    • C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
    • C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention provides a novel class of heterocyclic compounds which are synthesized and useful as antagonists of adenosine receptors (A2A and/or A2B).
  • Adenosine is a signaling molecule used to limit inflammation and immune responses in vivo. It is greatly elevated in metabolic disorders and cell damage. Activated adenosine receptors are involved in the immune regulation of the body, in many different types of tumor microenvironments. Maintain a high level. The adenosine produced by the tumor can interact with the adenosine receptor on the surface of the invading immune cells.
  • Adenosine receptors There are four subtypes of adenosine receptors, A1, A2A, A2B and A3, all belonging to the G protein coupled receptor family, mainly with Gs and G ⁇ protein are coupled. Each receptor exhibits a different affinity for adenosine, A1R, A2AR and A3R are high-affinity receptors that can be activated by (250-700 nM) adenosine, while A2BR is a low-affinity receptor and requires a higher adenosine concentration ( 25 ⁇ M) activation. Adenosine receptors can also be classified according to their downstream signaling small molecule cAMP.
  • A2A and A2B receptors When A2A and A2B receptors are activated, receptor conformational changes result in the release of activated Gs protein, activation of adenylate cyclase, and accelerated conversion of ATP to cAMP. Increased cAMP concentrations, usually accompanied by strong immunosuppression, and activation of the A1 and A3 receptors inhibit cAMP production, thus activation of the A1 and A3 receptors is generally considered to activate immunity.
  • Adenosine A2A receptors are mainly expressed in the striatum, spleen, thymus, lymphocytes and platelets of the brain. Some expressions are also found in the heart, lungs and blood vessels, and are often expressed in some cells of the immune system, such as T cells. NK cells, macrophages and dendritic cells.
  • Early A2A receptor antagonists are mainly used for the treatment of neurological diseases such as Parkinson, Huntington, Alzheimer's, attention-related diseases and psychosis. Recent studies have found that A2A receptor antagonists can increase dendritic cell antigen presentation, T cell and natural killer cell activation and killing ability, inhibit regulatory T cells (T-regs), MDSC and TAM, and eliminate tumor immune tolerance.
  • A2A receptor antagonists may become one of the effective methods for treating tumors.
  • A2A receptor antagonists can be used alone or in combination with other anti-tumor drugs, especially in combination with immunological checkpoint inhibitors.
  • Adenosine A2B receptor is expressed in various tissues, vasculature, brain, small intestine, and tumor, and is also expressed in different cells, including mast cells, dendritic cells, neutrophils, macrophages, and Lymphocytes and the like as well as endothelial cells, nerve cells and glial cells.
  • the widespread expression of the A2B receptor makes it a target for a variety of disease research, including cardiovascular disease, lung disease, diabetes, and cancer. Studies have shown that A2B antagonists can prevent the growth of tumors (bladder cancer, breast cancer), and high expression of A2B in patients with triple-negative breast cancer can also lead to a reduction in therapeutic survival.
  • a compound for use in an A2A receptor antagonist is disclosed in International Patent Application Publication No. WO2011/095625, WO2001/92264, WO2003/048165, WO2004/09443, WO2002/055083, etc., International Patent Application Publication No. WO2005/040155, WO2016/164838, WO2016 /150901, WO20161/35048, WO2015/05206, WO2012/076974, WO2011/005871, Chinese Patent Application Publication No. CN102532137, and U.S. Patent Application Publication No. US20140142113, etc.
  • a compound of formula I a pharmaceutically acceptable salt, prodrug, isotope derivative, hydrate, isomer, solvate thereof, or metabolite thereof,
  • Cy 1 is selected from the group consisting of 5-12 membered aryl, 5-12 membered heteroaryl, C 3 -C 9 cycloalkyl, C 3 -C 9 heterocycloalkyl;
  • Cy 2 is selected from a 5-12 membered aryl group and a 5-12 membered heteroaryl group;
  • R 3 is selected from the group consisting of hydrogen, hydroxy, amino, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkane a carbonyloxy group, an optionally substituted C 3 -C 12 cycloalkyl group, an optionally substituted bis(C 1 -C 8 alkyl)amino group, an optionally substituted C 1 -C 8 alkylamino group, Optionally substituted C 1 -C 8 alkylcarbamoyl, optionally substituted 5-12 membered aryl, optionally substituted 5-12 membered heteroaryl; wherein said optionally substituted is substituted
  • the group is selected from the group consisting of halogen, cyano, sulfonate, C 1 -C 8 alkyl, 5-12 membered aryl, 5-12 membered heteroaryl, OR 6 , SR 6 , NR 6 R 7 , C(
  • R 4 and R 5 are selected from hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted 5-12 membered aryl, An optionally substituted 5-12 membered heteroaryl group, wherein the optionally substituted substituent is selected from the group consisting of halogen, cyano, sulfonate, OR 6 , SR 6 , NR 6 R 7 , C(O)R 6 , C(O)OR 6 , C(O)NR 6 R 7 , NC(O)NR 6 R 7 , or S(O) 2 R 6 substituted; or, R 4 and R 5 are bonded to a nitrogen atom Forming together a 3- to 9-membered cyclic structure optionally containing 1-2 additional heteroatoms selected from N, O or S; the cyclic structure may optionally be 1, 2 or 3 R 8 Substituted, the substituted sites are on the C or N atom, provided that the structure formed
  • Cy 1 is a 5-membered heteroaryl group which may be optionally substituted with a group selected from 0, 1, 2 or 3 R a .
  • Cy 1 is independently selected from the group consisting of phenyl, pyridyl, pyrazinyl, cyclopropyl, cyclopentyl, cyclohexyl, furyl, thiazolyl, piperidinyl, piperazinyl , oxazolyl, imidazolyl, thienyl; preferably phenyl, furyl, oxazolyl or pyridyl; Cy 2 is independently selected from phenyl, pyridyl, pyrazinyl, furyl, thiazolyl, piperidine a pyridyl group, a piperazinyl group, an oxazolyl group, an imidazolyl group, a thienyl group; preferably a phenyl group, a pyridyl group; wherein the Cy 1 and Cy 2 may be optionally 0, 1, 2 or 3 selected from C 1 - Substituted by
  • Cy 1 and Cy 2 may be independently selected from phenyl, pyridyl, pyrazinyl, cyclopropyl, cyclopentyl, cyclohexyl, furyl, thiazolyl, piperidine
  • the above substituent may be optionally substituted by 0, 1, 2 or 3 R a wherein R a has the formula I.
  • Another aspect of the invention provides a compound having the structure of Formula II, a pharmaceutically acceptable salt, prodrug, isotope derivative, hydrate, isomer, solvate thereof, or metabolite thereof:
  • W 1 and W 2 are each independently selected from CR b or N, R b has the definition of R a; R a, Cy 1 and R 2 having the formula I as defined, m is 1, 2 or 3.
  • Cy 1 is selected from a five-membered heteroaryl group, for example, furyl, thiazolyl, oxazolyl, imidazolyl, thienyl; Cy 2 is selected from the group consisting of phenyl, pyridyl, pyrazinyl, piperidinyl, piperazinyl, preferably phenyl, pyridyl; wherein said Cy 1 and Cy 2 may be optionally 0, 1, 2 or 3 One selected from C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio, halogen, cyano, sulfonate, nitro Substituted by a substituent.
  • Another aspect of the invention provides a compound having the structure of Formula III or Formula IV, a pharmaceutically acceptable salt, prodrug, isotope derivative, hydrate, isomer, solvate thereof, or metabolite thereof :
  • R a , Cy 1 and R 2 have the formula I, and m is 0, 1, 2 or 3.
  • R 3 is selected from hydrogen, hydroxy, amino, optionally substituted C 1 -C 8 alkyl, optionally Substituted C 3 -C 12 cycloalkyl or optionally substituted 5-12 membered aryl; preferably an optionally substituted C 1 -C 8 alkyl, optionally substituted C 3 -C 12 naphthenic Or optionally substituted 5-12 membered aryl, wherein said optionally substituted substituent is selected from the group consisting of C 1 -C 8 alkyl, C 1 -C 8 alkoxy, halogen, hydroxy, amino, Cyano, sulfonate, 5-12 membered aryl, 5-12 membered heteroaryl.
  • the compounds of the invention are selected from the following structures:
  • the compounds of the present invention can also be prepared in the form of a pharmaceutically acceptable salt formed using, for example, the following inorganic or organic acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, Lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzene Formic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid.
  • inorganic or organic acids hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, Lactic acid, pyruvic acid,
  • the pharmaceutically acceptable salts of the present invention can be prepared by conventional methods, for example, by dissolving the compound of the present invention in a water-miscible organic solvent such as acetone, methanol, ethanol and acetonitrile, and adding an excess of an organic acid or inorganic thereto. An aqueous acid solution is used to precipitate a salt from the resulting mixture, from which the solvent and the remaining free acid are removed, and then the precipitated salt is separated.
  • a water-miscible organic solvent such as acetone, methanol, ethanol and acetonitrile
  • the compound of the present invention or a pharmaceutically acceptable salt thereof may include hydrates and solvates thereof.
  • the invention also provides the use of a compound of the invention in the manufacture of a medicament for the prevention or treatment of a cancer, a tumor, an inflammatory disease, an autoimmune disease or an immune-mediated disease.
  • the present invention provides a pharmaceutical composition for preventing or treating cancer, a tumor, an inflammatory disease, an autoimmune disease, a neurodegenerative disease, a attention-related disease or an immune-mediated disease, which comprises the compound of the present invention as Active ingredient.
  • the present invention provides a method for preventing or treating cancer, a tumor, an inflammatory disease, an autoimmune disease, a neurodegenerative disease, a attention-related disease or an immune-mediated disease, which includes the need to The mammal is administered a compound of the invention.
  • the invention provides a method of inhibiting A2A and/or A2B receptors comprising exposing an A2A and/or A2B receptor to a compound of the invention.
  • cancer or tumor can include, but are not limited to, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neurocytoma, rectal cancer.
  • Colon cancer familial adenomatous polyposis, hereditary non-polyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal carcinoma, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid carcinoma, Papillary thyroid cancer, renal cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, endometrial cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary cancer, melanoma, brain tumor such as Glioblastoma, astrocytoma, meningiomas, medulloblastoma and peripheral neuroectodermal
  • a compound of the present invention, or a pharmaceutically acceptable salt thereof When a compound of the present invention, or a pharmaceutically acceptable salt thereof, is administered in combination with an additional anticancer or checkpoint inhibitor for the treatment of cancer or a tumor, the compound of the present invention or a pharmaceutically acceptable salt thereof provides an enhanced anticancer effect.
  • anticancer agents for treating cancer or tumors can include, but are not limited to, cell signaling inhibitors, chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, card Mistin, lomustine, streptozotocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, Indole, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trobeidine, dactinomycin, doxorubicin , epirubicin, daunorubicin, mitoxantrone, bleomycin, mitomycin C, ixabepilone, tamoxifen, flutamide,
  • inflammatory diseases may include, but are not limited to, arthritis, rheumatoid arthritis, spondylarthritis, gouty arthritis, osteoarthritis, juvenile arthritis , other arthritic conditions, lupus, systemic lupus erythematosus (SLE), skin-related diseases, psoriasis, eczema, dermatitis, allergic dermatitis, pain, lung disease, lung inflammation, adult respiratory distress syndrome (ARDS) , pulmonary sarcoidosis, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease (COPD), cardiovascular disease, atherosclerosis, myocardial infarction, congestive heart failure, myocardial ischemia-reperfusion injury, inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, asthma, Sjogren's syndrome, autoimmune thyroid disease, urticaria (rubella), multiple sclerosis,
  • a compound of the invention, or a pharmaceutically acceptable salt thereof provides enhanced when a compound of the invention, or a pharmaceutically acceptable salt thereof, is administered in combination with an additional therapeutic agent for the treatment of an inflammatory disease, an autoimmune disease, and an immune-mediated disease Therapeutic effect.
  • therapeutic agents for treating inflammatory diseases, autoimmune diseases, and immune-mediated diseases may include, but are not limited to, steroidal drugs (eg, prednisone, hydrogenated prednisone, methylhydroponone) Pine, cortisone, hydroxycortisone, betamethasone, dexamethasone, etc.), methotrexate, leflunomide, anti-TNF ⁇ agents (eg, etanercept, infliximab, Adali Monoclonal antibodies, etc., calcineurin inhibitors (eg, tacrolimus, pimecrolimus, etc.) and antihistamines (eg, diphenhydramine, hydroxyzine, loratadine, Ibas
  • At least one therapeutic agent selected from the group consisting of statins, ketotifen, cetirizine, levocetirizine, fexofenadine, etc. may be included in the pharmaceutical composition of the present invention.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof can be administered orally or parenterally as an active ingredient in an amount effective to be 0.1 to 2,000 mg/kg body weight/day in the case of a mammal including a human body (body weight: about 70 kg). It is preferably from 1 to 1,000 mg/kg body weight/day, and is administered in a single or four divided doses per day, or with/without following a predetermined time.
  • the dosage of the active ingredient can be adjusted based on a number of relevant factors, such as the condition of the subject to be treated, the type and severity of the disease, the rate of administration, and the opinion of the physician. In some cases, amounts less than the above dosages may be suitable. An amount greater than the above dosage can be used if it does not cause harmful side effects and the amount can be administered in divided doses per day.
  • the pharmaceutical composition of the present invention can be formulated into a dosage form for oral administration or parenteral administration (including intramuscular, intravenous and subcutaneous routes) according to any of the conventional methods, such as tablets, granules, powders, capsules, syrups. , emulsions, microemulsions, solutions or suspensions.
  • the pharmaceutical composition of the present invention for oral administration can be prepared by mixing the active ingredient with, for example, a carrier such as cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, hard.
  • a carrier such as cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, hard.
  • Examples of carriers for use in the injectable compositions of the present invention are water, saline solutions, dextrose solutions, glucose-like solutions, alcohols, glycols, ethers (e.g., polyethylene glycol 400), oils, Fatty acids, fatty acid esters, glycerides, surfactants, suspending agents and emulsifiers.
  • the compounds of the present invention can be prepared in a variety of ways known to those skilled in the art of organic synthesis, using the methods described below, as well as synthetic methods known in the art of organic synthetic chemistry or by variations thereof as appreciated by those skilled in the art.
  • the compounds of the invention are synthesized. Preferred methods include, but are not limited to, those described below.
  • the reaction is carried out in a solvent or solvent mixture suitable for the kit materials used and for the transitions achieved.
  • Those skilled in the art of organic synthesis will understand that the functionality present on the molecule is consistent with the proposed transition. This sometimes requires judgment to alter the order or starting materials of the synthetic steps to obtain the desired compounds of the invention.
  • the inventors have unexpectedly discovered a class of heterocyclic compounds having A2A and/or A2B inhibitory activity after long-term and intensive research, and thus can be used for the preparation of a pharmaceutical composition for treating diseases associated with A2A and/or A2B receptors. . Based on the above findings, the inventors completed the present invention.
  • the present invention describes cis- and trans- (or E- and Z-) geometric isomers of the compounds of the invention, and which can be separated into a mixture of isomers or as separate isomers.
  • the compounds of the invention can be isolated in optically active or racemic forms.
  • All methods for preparing the compounds of the invention and the intermediates prepared therein are considered part of the invention.
  • they can be separated by conventional methods, for example by chromatography or fractional crystallization.
  • the end products of the invention are obtained in free (neutral) or salt form depending on the process conditions. Free forms and salts of these end products are within the scope of the invention.
  • one form of the compound can be converted to another form.
  • the free base or acid can be converted to a salt; the salt can be converted to the free compound or another salt; the mixture of isomer compounds of the invention can be separated into the individual isomers.
  • the compounds of the invention may exist in a variety of tautomeric forms in which a hydrogen atom is transposed to other portions of the molecule and thereby the chemical bonds between the atoms of the molecule are rearranged. It should be understood that all tautomeric forms that may be present are included within the invention.
  • substituent when a substituent is referred to as "optionally substituted,” the substituent is selected, for example, from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, halo, hydroxy, Alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amine groups (of which 2 amino substituents are selected From alkyl, aryl or arylalkyl), alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkylamino, thio, alkyl Thio group, arylthio group, arylalkylthio group, arylthiocarbonyl group, arylalkylthiocarbonyl group, alkyl
  • alkyl or "alkylene” as used herein is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • C1-C6 alkyl means an alkyl group having from 1 to 6 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (eg, n-propyl and isopropyl), butyl (eg, n-butyl, isobutyl, t-butyl), and A pentyl group (eg, n-pentyl, isopentyl, neopentyl).
  • alkenyl denotes a straight or branched chain hydrocarbon radical containing one or more double bonds and generally having from 2 to 20 carbon atoms in length.
  • C2-C8 alkenyl contains two to eight carbon atoms.
  • Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.
  • alkynyl denotes a straight or branched chain hydrocarbon radical containing one or more triple bonds and generally having a length of from 2 to 20 carbon atoms.
  • C2-C8 alkynyl contains two to eight carbon atoms.
  • Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.
  • alkoxy refers to -O-alkyl.
  • C1-6 alkoxy (or alkyloxy) is intended to include C1, C2, C3, C4, C5 and C6 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (eg, n-propoxy and isopropoxy) and t-butoxy.
  • alkylthio or “thioalkoxy” denotes a thio-bridged alkyl group as defined above having the indicated number of carbon atoms; for example, methyl-S- and ethyl-S-.
  • aryl alone or as part of a larger moiety such as “aralkyl”, “aralkyloxy” or “aryloxyalkyl”, refers to a single ring having a total of from 5 to 12 ring members.
  • “aryl” refers to an aromatic ring system including, but not limited to, phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthalene. base.
  • aralkyl or "arylalkyl” refers to an alkyl residue attached to an aryl ring. Non-limiting examples include benzyl, phenethyl and the like.
  • the fused aryl group may be attached to another group at a suitable position of the cycloalkyl ring or the aromatic ring.
  • An arrow line drawn from the ring system indicates that the bond can be attached to any suitable ring atom.
  • cycloalkyl refers to a monocyclic or bicyclic cyclic alkyl group.
  • Monocyclic cyclic alkyl refers to a C3-C8 cyclic alkyl group including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and norbornyl.
  • Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl”.
  • the bicyclic cyclic alkyl group includes a bridged ring, a spiro ring or a cycloalkyl group of a fusion ring.
  • cycloalkenyl refers to a monocyclic or bicyclic cyclic alkenyl group.
  • Monocyclic cyclic alkenyl refers to C3-C8 cyclic alkenyl groups including, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and norbornyl.
  • Branched cycloalkenyl groups such as 1-methylcyclopropenyl and 2-methylcyclopropenyl are included in the definition of "cycloalkenyl”.
  • the bicyclic cyclic alkenyl group includes a bridged ring, a spiro ring or a cyclic alkenyl group of a fused ring.
  • Halo or halogen includes fluoro, chloro, bromo and iodo.
  • Haloalkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoro Propyl and heptachloropropyl.
  • haloalkyl group examples include "fluoroalkyl group" which is intended to include a branched and straight-chain saturated aliphatic hydrocarbon group having a specified number of carbon atoms and substituted with one or more fluorine atoms.
  • Haloalkoxy or "haloalkyloxy” denotes an alkyl bridge as defined above attached via an oxygen bridge having the indicated number of carbon atoms.
  • C1-C6 haloalkoxy is intended to include C1, C2, C3, C4, C5 and C6 haloalkoxy.
  • Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy.
  • haloalkylthio or “thiohaloalkoxy” denotes a thio bridged haloalkyl group as defined above having the indicated number of carbon atoms; for example, trifluoromethyl-S- and pentafluoroethyl -S-.
  • aryl refers to a monocyclic or bicyclic (and above bicyclic) aryl group which is all carbon atoms.
  • a monocyclic aromatic group means a phenyl group
  • a bicyclic or bicyclic or higher aromatic group means a naphthyl group, a fluorenyl group or the like
  • the aryl bicyclic ring may also be a benzene ring in which a cycloalkyl group is fused or a ring is fused.
  • Alkenyl, or a cycloalkynyl group Alkenyl, or a cycloalkynyl group.
  • arylhetero means a stable 3-, 4-, 5-, 6-, or 7-membered aromatic monocyclic ring or An aromatic bicyclic ring or a 7-, 8-, 9-, 10-, 11-, 12-, 13- or 14-membered aromatic polycyclic heterocyclic ring which is completely unsaturated, partially unsaturated, and which contains a carbon atom.
  • 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; and include any of the following polycyclic groups, wherein any of the heterocycles defined above is fused to a benzene ring.
  • the nitrogen and sulfur heteroatoms can be optionally oxidized.
  • the nitrogen atom is substituted or unsubstituted (i.e., N or NR, wherein R is H or, if defined, another substituent).
  • the heterocycle can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. If the resulting compound is stable, the heterocyclic groups described herein can be substituted on a carbon or nitrogen atom.
  • the nitrogen in the heterocycle can optionally be quaternized.
  • the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to each other.
  • the total number of S and O atoms in the heterocycle is no more than one.
  • heterocycle it is intended to include heteroaryl.
  • aromatic heterocycles include, but are not limited to, acridinyl, azetidinyl, anthracycline, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothienyl, benzoxan Azolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, carbazolyl, 4aH-carbazolyl, porphyrinyl, chromanyl, chromenyl, porphyrinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuran[2, 3-b]tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazo
  • heterocycloalkyl refers to a monocyclic heterocycloalkyl system, or a bicyclic heterocycloalkyl system, as well as a spiroheterocycle or a bridged heterocycloalkyl.
  • Monocyclic heterocycloalkyl refers to a cyclic alkyl system of 3-8 members and containing at least one saturated or unsaturated but not aromatic selected from O, N, S, P.
  • the bicyclic heterocycloalkyl system refers to a heterocycloalkyl group fused to a phenyl group, or a cycloalkyl group, or a cycloalkenyl group, or a heterocycloalkyl group, or a heteroaryl group.
  • bridged cycloalkyl refers to a polycyclic compound that shares two or more carbon atoms. It can be divided into bicyclic bridge cyclic hydrocarbons and polycyclic bridge cyclic hydrocarbons. The former consists of two alicyclic rings sharing two or more carbon atoms; the latter is a bridged cyclic hydrocarbon composed of three or more rings.
  • spirocycloalkyl refers to a polycyclic hydrocarbon that shares a carbon atom (called a spiro atom) between the individual rings.
  • bridged heteroalkyl refers to a polycyclic compound that shares two or more carbon atoms, the ring having at least one atom selected from the group consisting of O, N, and S. It can be divided into a bicyclic bridged ring heterocyclic ring and a polycyclic bridged heterocyclic ring.
  • heterospiro refers to a polycyclic hydrocarbon that shares a carbon atom (called a spiro atom) between the monocyclic rings, and the ring contains at least one atom selected from the group consisting of O, N, and S.
  • substituted means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that the normal valence is maintained and the substitution results in a stable compound.
  • nitrogen atom for example, an amine
  • these nitrogen atoms can be converted into N-oxides by treatment with an oxidizing agent such as mCPBA and/or hydrogen peroxide to obtain other compounds of the present invention.
  • an oxidizing agent such as mCPBA and/or hydrogen peroxide
  • the nitrogen atoms shown and claimed are considered to cover both the nitrogen and its N-oxides shown to obtain the derivatives of the invention.
  • any variable occurs more than once in any composition or formula of a compound, its definition at each occurrence is independent of its definition in each of the other cases.
  • the group may be optionally substituted with up to three R groups, and each occurrence of R is independently selected from R. definition.
  • substituents and/or variables are only permitted if the combination described above produces a stable compound.
  • solvate means a physical association of a compound of the invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In some cases, such as when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid, the solvate will be capable of being separated.
  • the solvent molecules in the solvate may be present in a regular arrangement and/or a disordered arrangement.
  • Solvates may comprise stoichiometric or non-stoichiometric solvent molecules.
  • “Solvate” encompasses both the solution phase and the separable solvate. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.
  • patient refers to an organism that is treated by the methods of the invention.
  • organisms preferably include, but are not limited to, mammals (e.g., rodents, baboons, monkeys, horses, cows, pigs, dogs, cats, etc.) and most preferably humans.
  • an effective amount means the amount of a drug or agent (ie, a compound of the invention) that will elicit, for example, a biological or medical response of a tissue, system, animal or human sought by a researcher or clinician.
  • a therapeutically effective amount means an amount which results in an improved treatment, cure, prevention or alleviation of a disease, disorder or side effect, or a reduction in disease, as compared to a corresponding subject not receiving the above amount. Or the speed of progression of the condition.
  • An effective amount can be administered in one or more administrations, administrations or dosages and is not intended to be limited by the particular formulation or route of administration. The term also includes an effective amount within its scope that enhances normal physiological function.
  • treating includes any effect that results in an amelioration of a condition, disease, disorder, etc., such as reducing, reducing, regulating, ameliorating or eliminating, or ameliorating the symptoms thereof.
  • composition refers to a combination of an active agent with an inert or active carrier, such that the composition is especially suitable for in vivo or ex vivo diagnosis or treatment.
  • bases include, but are not limited to, alkali metal (e.g., sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides, ammonia, and the like.
  • Salts of the Compounds of the Invention For therapeutic use, the salts of the compounds of the invention are expected to be pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable acids and bases can also be used, for example, in the preparation or purification of pharmaceutical compounds.
  • pharmaceutically acceptable is used herein to mean those compounds, substances, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity or irritation. Sex, allergic reactions and/or other problems or complications, and commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier means a pharmaceutical substance, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (eg, lubricant, talc, magnesium stearate, Calcium stearate or zinc stearate or stearic acid) or a solvent encapsulating material which involves carrying or transporting a subject compound from one organ or part of the body to another organ or part of the body.
  • manufacturing aid eg, lubricant, talc, magnesium stearate, Calcium stearate or zinc stearate or stearic acid
  • solvent encapsulating material which involves carrying or transporting a subject compound from one organ or part of the body to another organ or part of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient.
  • composition means a composition comprising a compound of the invention and at least one other pharmaceutically acceptable carrier.
  • “Pharmaceutically acceptable carrier” refers to a medium that is generally accepted in the art for delivery of a biologically active agent to an animal, particularly a mammal, including (ie) an adjuvant, excipient or vehicle, such as a diluent, preservative , fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterials, antifungals, lubricants and dispersing agents, depending on The mode of administration and the nature of the dosage form.
  • an adjuvant, excipient or vehicle such as a diluent, preservative , fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterials, antifungals, lubricants and dispersing agents, depending on The mode of
  • acceptable refers to a prescription component or active ingredient that does not have an unduly detrimental effect on the health of a general therapeutic target.
  • cancer refers to abnormal growth of an uncontrollable cell and is capable of metastasis (propagation) under certain conditions.
  • This type of cancer includes, but is not limited to, solid tumors (eg, bladder, intestine, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (eg thyroid), prostate) , skin (melanoma) or hematoma (eg non-leukocytic leukemia).
  • administered in combination refers to the administration of several selected therapeutic agents to a patient, administered at the same or different times, in the same or different modes of administration.
  • the term “enhancement” or “enhancement”, as used herein, means that the desired result can be increased or prolonged in potency or duration.
  • the term “enhanced” in terms of enhancing the therapeutic effect of a drug means the ability of the drug to increase or extend the potency or duration in the system.
  • potency value refers to the ability to maximize the effectiveness of another therapeutic agent in an ideal system.
  • immune disease refers to a disease or condition that produces an adverse or deleterious response to an endogenous or exogenous antigen. The result is usually a dysfunction of the cell, or it can destroy and cause dysfunction, or destroy an organ or tissue that may produce an immune symptom.
  • kit is synonymous with “product packaging.”
  • subject or “patient” includes mammals and non-mammals.
  • Mammals include, but are not limited to, mammals: humans, non-human primates such as orangutans, baboons and monkeys; agricultural animals such as cattle, horses, goats, sheep, pigs; livestock such as rabbits, dogs; experimental animals including rodents, Such as rats, mice and guinea pigs.
  • Non-mammals include, but are not limited to, birds, fish, and the like.
  • the selected mammal is a human.
  • treatment include alleviating, inhibiting, or ameliorating the symptoms or condition of a disease; inhibiting the production of complications; ameliorating or preventing a potential metabolic syndrome; inhibiting the production of a disease or condition, Such as controlling the development of a disease or condition; reducing a disease or symptom; making a disease or symptom diminished; reducing a complication caused by the disease or symptom, or preventing or treating a symptom caused by the disease or symptom.
  • a compound or pharmaceutical composition after administration, can ameliorate a disease, condition, or condition, particularly if the severity is improved, delays the onset, slows progression, or reduces the duration of the condition. Whether administered fixedly or temporarily, continuously or intermittently, it may be attributable to or related to the administration.
  • Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transdermal, vaginal, oral canal. , nasal administration and topical administration.
  • parenteral administration includes intramuscular, subcutaneous, intravenous, intramedullary, ventricular, intraperitoneal, intralymphatic, and intranasal injections.
  • the modes of administration of the compounds described herein are topical rather than systemic.
  • the drug depot is administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection.
  • the drug is administered by a targeted drug delivery system.
  • liposomes encapsulated by organ-specific antibodies In this particular embodiment, the liposomes are selectively directed to a particular organ and absorbed.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of the invention formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents, and optionally one One or more of the other therapeutic agents described above.
  • the compounds of the invention may be administered by any suitable means for any of the above uses, for example, orally, such as tablets, pills, powders, granules, elixirs, elixirs, suspensions (including nanosuspensions, microsuspensions, spray dried Dispersion), syrup and emulsion; sublingual; buccal; parenteral, such as by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion techniques (eg, in sterile injectable aqueous or nonaqueous solutions or suspensions) Nasal, including nasal administration, such as by inhalation spray; topical, such as in the form of a cream or ointment; or transrectal, such as in the form of a suppository. They can be administered alone, but are usually administered using a pharmaceutical carrier selected based on the chosen route of administration and standard pharmaceutical practice.
  • Pharmaceutical carriers are formulated according to a number of factors within the scope of those skilled in the art. These factors include, but are not limited to, the type and nature of the active agent being formulated; the subject to which the active agent-containing composition is to be administered; the intended route of administration of the composition; and the targeted therapeutic indication.
  • Pharmaceutically acceptable carriers include aqueous and non-aqueous liquid vehicles and various solid and semi-solid dosage forms.
  • the above carriers may include a number of different ingredients and additives in addition to the active ingredients, which are included in the formulation for various reasons well known to those skilled in the art, such as stabilizing active agents, binders and the like.
  • suitable pharmaceutical carriers and carriers can be found in a number of readily available sources, for example, Allen LV Jr. et al. Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition (2012) , Pharmaceutical Press.
  • the dosage regimen of the compounds of the invention will vary depending on known factors, such as the pharmacodynamic properties of the particular agent and its mode of administration and route; the species, age, sex, health, medical condition and weight of the recipient The nature and extent of the symptoms; the type of treatment at the same time; the frequency of treatment; the route of administration, the kidney and liver function of the patient, and the desired effect.
  • the daily oral dose of each active ingredient should be from about 0.001 mg/day to about 10-5000 mg/day, preferably from about 0.01 mg/day to about 1000 mg/day, and most preferably The ground is from about 0.1 mg/day to about 250 mg/day.
  • the most preferred intravenous dose during a constant rate infusion should be from about 0.01 mg/kg/min to about 10 mg/kg/min.
  • the compounds of the invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses of two, three or four times daily.
  • the compounds are usually administered in a suitable pharmaceutical diluent, excipient or carrier, as appropriate in accordance with the intended mode of administration (for example, oral administration of tablets, capsules, elixirs and syrups) and in accordance with conventional pharmaceutical practice. Administration is carried out in the form of a mixture of the medium and the drug carriers.
  • Dosage forms suitable for administration may contain from about 1 mg to about 2000 mg of active ingredient per dosage unit.
  • the active ingredient will generally be present in an amount of from about 0.1% to about 95% by weight, based on the total weight of the composition.
  • a typical capsule for oral administration contains at least one compound of the invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture was passed through a 60 mesh screen and packaged into size 1 gelatin capsules.
  • a typical injectable preparation can be prepared by sterilizing at least one compound of the invention (250 mg) in a vial, lyophilizing and sealing in a sterile manner. For use, the contents of the bottle were mixed with 2 mL of physiological saline to produce an injectable preparation.
  • the scope of the invention includes (individually or in combination with a pharmaceutical carrier) a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of the invention as an active ingredient.
  • a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of the invention as an active ingredient.
  • the compounds of the invention may be used alone, in combination with other compounds of the invention or in combination with one or more other therapeutic agents, such as anti-cancer agents or other pharmaceutically active substances.
  • the compound of the present invention (which may be used in a suitable hydrated form) and/or the pharmaceutical composition of the present invention is formulated into a pharmaceutical dosage form by conventional methods known to those skilled in the art, regardless of the selected route of administration.
  • the actual dosage level of the active ingredient in the pharmaceutical compositions of the present invention can be varied to achieve an amount of active ingredient that is effective to achieve a desired therapeutic response, composition, and mode of administration for a particular patient without toxicity to the patient.
  • the selected dosage level will depend on a variety of factors, including the activity of the particular compound of the invention or its ester, salt or amide employed; the route of administration; the time of administration; the excretion rate of the particular compound employed; the rate and extent of absorption. Duration of treatment; other drugs, compounds and/or substances used in combination with the particular compound used; factors known in the medical arts, such as age, sex, weight, condition, general health and prior medical history of the patient being treated.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe an effective amount of the desired pharmaceutical composition.
  • a physician or veterinarian can begin the contest of the compounds of the invention used in the pharmaceutical compositions below the desired level and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a compound of the invention will be the amount of the compound which is the lowest dose effective to produce a therapeutic effect.
  • Such effective dosage will generally depend on the above factors.
  • oral, intravenous, intraventricular, and subcutaneous doses of a compound of the invention for a patient range from about 0.01 to about 50 mg/kg body weight per day.
  • an effective daily dose of the active compound may be administered separately in two, three, four, five, six or more sub-doses at appropriate intervals throughout the day, optionally in unit dosage form. In certain aspects of the invention, the administration is once a day.
  • the compound of the present invention can be administered alone, it is preferred to administer the compound in the form of a pharmaceutical preparation (composition).
  • Kits/product packages are also described herein for use in the treatment of the above indications. These kits may be comprised of a conveyor, a pack or a container, which may be divided into a plurality of compartments to accommodate one or more containers, such as vials, test tubes, and the like, each containing a container A single component of the method. Suitable containers include bottles, vials, syringes and test tubes. The container is made of materials such as glass or plastic that are acceptable.
  • the container may contain one or more of the compounds described herein, and the compound may exist as a pharmaceutical component or as a mixture with other ingredients described herein.
  • the container may have a sterile outlet (for example, the container may be an IV bag or bottle, and the stopper may be pierced by a hypodermic needle).
  • kits may carry a compound, as well as instructions, labels or instructions for use as described herein.
  • a typical kit may include one or more containers that are adapted to commercial promotion and user demand for compound use, each container containing one or more materials (eg, reagents, or concentrated mother liquor, and / Or equipment). These materials include, but are not limited to, buffers, diluents, filters, needles, syringes, conveyors, bags, containers, bottles and/or test tubes, with a list of contents and/or instructions for use, as well as instructions for the internal packaging. The entire set of instructions must be included.
  • materials eg, reagents, or concentrated mother liquor, and / Or equipment.
  • materials include, but are not limited to, buffers, diluents, filters, needles, syringes, conveyors, bags, containers, bottles and/or test tubes, with a list of contents and/or instructions for use, as well as instructions for the internal packaging. The entire set of instructions must be included.
  • the label can be displayed on or closely related to the container.
  • the presence of a label on a container means that the label letter, number or other feature is pasted, molded, or engraved on the container; the label may also be present in a container or shipping box containing a plurality of containers, such as in a product insert.
  • a label can be used to indicate a particular therapeutic use of the contents.
  • the label may also indicate a usage statement for the content, such as described in the above method.
  • Preparative HPLC typically uses an acidic method (gradient of acetonitrile and water, each containing 0.1% formic acid) with Thermo U3000 AFC-3000; column: Globalsil C-18 12 nm, 250 x 20 mm, 10 ⁇ m, or equivalent; flow rate: 20 mL/min, separation .
  • the compound INT-2, INT-3, INT-4, and INT-5 can be prepared by referring to the preparation method of the compound INT-1.
  • the specific spectrum information is as follows:
  • the compounds INT-8, INT-9, INT-10, INT-11, INT-13 can be prepared, and the structure and spectrum information are as follows:
  • the reaction solution was adjusted to pH 4-5 with a hydrochloric acid solution (1 mol/L), and diluted with ethyl acetate (100 mL). The organic layer was washed with water and brine (100 mL).
  • the compounds 17h, 43, 44, 58 and 64 can be prepared.
  • the specific spectrum information is as follows:
  • Chlorosulfonate isocyanate (15.5 mg, 0.11 mmol) was added to a solution of compound 1h in dichloromethane (3 mL). The reaction solution was stirred at 0 °C for 2 hours, and the reaction of the starting material was confirmed by LC-MS.
  • reaction solution was diluted with dichloromethane (30 mL) and brine (30 mL
  • organic layer was dried over anhydrous sodium sulfate (MgSO4)ielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielie
  • Iron powder (41 mg, 0.73 mmol) was added to a mixed solution of the compound 19 (50 mg, 0.12 mmol) in acetic acid (0.2 mL) and methanol (0.8 mL), and the reaction mixture was stirred at 50 °C for 2 hours, LC- The MS detects the completion of the reaction.
  • the reaction mixture was diluted with EtOAc (EtOAc) (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH
  • the A2A receptor binding assay affinity test procedure is referenced in the literature: British Journal of Pharmacology (1997) 121, 353-360; wherein the A2A receptor (expressed by HEK cells) is derived from Perkin Elmer (product number: RBHA2AM400UA); the competitive isotope label is: 3 H] SCH58261.
  • the specific test was completed by the Department of Biology of Shanghai Ruizhi Chemical Research Co., Ltd.
  • A2B Receptor Binding Experimental Affinity Test Procedure Reference: ACS Medicinal Chemistry Letters (2011) 2, 213–218; wherein the A2B receptor (expressed by HEK cells) was constructed by the Department of Biology of Shanghai WuXi PharmaTech Research and Development Co., Ltd. as part of the CRO service. Commercial supply; competitive isotope label: [ 3 H]DPCPX. The specific test was completed by the Department of Biology of Shanghai WuXi PharmaTech Research and Development Co., Ltd.
  • the A2A cell line was derived from PerkinElmer (product number: ES-011-C); the A2B cell line was derived from PerkinElmer (product number: ES-013-C).
  • the experimental procedure is referred to ACS Medicinal Chemistry Letters (2011) 2, 213–218; the specific test is completed by Beijing Kanglong Chemical New Drug Technology Co., Ltd., the steps are as follows:
  • the tracer working solution and the Ulight-anti-cAMP working solution were added to the cell culture plate at 5 uL/well, and the cell plate fluorescence values (excitation light wavelength: 320 nm, emission light wavelength: 665 nm and 615 nm) were read with Envision.
  • the corresponding inhibition rate in each well was obtained according to the following formula, and the S-type dose-inhibition rate curve was plotted using a nonlinear regression model and the IC 50 value was calculated.

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Abstract

一种作为A2A和/或A2B受体拮抗剂的杂环化合物，具体地，提供了一种如下式I所示的化合物，其中，各基团的定义如说明书中所述。化合物具有A2A和/或A2B抑制活性，可以用于预防或治疗与A2A和/或A2B活性或表达量相关的疾病。(I)

Description

A2A和/或A2B受体拮抗剂 技术领域
本发明提供了一类新型杂环化合物，其合成及作为腺苷受体(A2A和/或A2B)拮抗剂的应用。
背景技术
检查点抑制剂在免疫治疗领域取得一些突破性进展，大量的临床研究表明，PD-1/PDL-1抗体对多种肿瘤(小细胞肺癌、黑色素瘤、头颈癌、肾癌等)具有一定的临床效果，但单药应答率普遍偏低，一般在20-40％。实体肿瘤不仅包括肿瘤细胞成分，肿瘤组织当中还有相当多的其他非肿瘤细胞成分，这些细胞成分构成了所谓肿瘤微环境，在肿瘤的浸润、增殖和转移中发挥重要的作用。研究表明PD-1/PDL-1抗体与其他免疫调节小分子(消除肿瘤微环境的免疫耐受)联合用药是解决应答率低的一个有效手段之一。
正常情况下人体可以依赖完整的免疫机制来有效地控制细胞，T淋巴细胞、NK细胞和巨噬细胞都对肿瘤细胞有杀伤作用，但是当癌变细胞本身或上述免疫细胞功能发生改变，可能逃脱机体免疫系统的清除，恶性增生形成肿瘤。腺苷是一种体内用于限制炎症和免疫应答的信号分子，在代谢障碍及细胞损伤时会大幅升高，激活的腺苷受体参与机体的免疫调节，在许多不同类型的肿瘤微环境中维持较高水平。肿瘤产生的腺苷能与入侵免疫细胞表面上的腺苷受体相互作用，腺苷受体有四种亚型，A1、A2A、A2B和A3，都属于G蛋白偶联受体家族，主要与Gs和Gα蛋白偶联。每个受体对腺苷表现不同的亲和力，A1R、A2AR和A3R是高亲和力受体，可以被(250-700nM)腺苷激活，而A2BR是低亲和力受体，需要较高的腺苷浓度(25μM)激活。腺苷受体也可以根据其引起下游信号小分子cAMP来分类，当A2A和A2B受体激活，受体构象变化导致释放激活Gs蛋白，活化腺苷环化酶，加速ATP转化为cAMP。增加的cAMP浓度，通常伴随着强烈的免疫抑制，而激活A1和A3受体会抑制cAMP的产生，因而激活A1和A3受体一般会认为激活免疫。
腺苷A2A受体主要表达于大脑的纹状体、脾脏、胸腺、淋巴细胞和血小板，在心脏、肺和血管中也发现一定的表达，常表达于免疫系统中的一些细胞，如T细胞、NK细胞、巨噬细胞和树突状细胞。A2A受体拮抗剂早期主要用于神经系统疾病的治疗，例如帕金森、亨廷顿、阿尔茨海默、注意力相关疾病和精神病等。近期研究发现发现，A2A受体拮抗剂能提高树突细胞抗原呈递、T细胞以及自然杀伤细胞的活化和杀伤能力，抑制调节性T细胞(T-regs)、MDSC和TAM，消除肿瘤免疫耐受，促进抗肿瘤免疫应答的发生，进而导致肿瘤的消退，因而A2A受体拮抗剂有可能成为治疗肿瘤的有效方法之一。A2A受体拮抗剂既可以单独用药又可以与其他抗肿瘤药物联合使用，特别是与免疫检查点抑制剂联合用药是目前的临床研究热点。
腺苷A2B受体表达于多种组织，脉管系统、脑、小肠以及肿瘤等，在不同的细胞中也表达，包括免疫系统中的肥大细胞、树突细胞、中性白细胞、巨噬细胞和淋巴细胞等以及内皮细胞、神经细胞和胶质细胞。A2B受体的广泛表达使之成为多种疾病研究的靶点，心血管疾病、肺部疾病、糖尿病以及癌症等。研究表明A2B拮抗剂可以阻止肿瘤(膀胱癌、乳腺癌)的生长，三阴乳腺癌肿瘤病人的A2B高表达也可以导致治疗生存率降低。
国际专利申请公开号WO2011/095625、WO2001/92264、WO2003/048165、WO2004/09443、WO2002/055083等公开了化合物用于A2A受体拮抗剂，国际专利申请公开号WO2005/040155、WO2016/164838、WO2016/150901、WO20161/35048、WO2015/05206、WO2012/076974、WO2011/005871、中国专利申请公开号CN102532137以及美国专利申请公开号US20140142113等公开了化合物用于A2B受体拮抗剂，但同时抑制A2A和A2B受体的拮抗剂目前报道较少。经过长期而深入的研究，我们意外地发现了一类具有A2A和/或A2B受体抑制活性的杂环化合物。
发明内容
本发明的第一个方面，提供了式I所示的化合物、其药学上可接受的盐、前药、同位素衍生物、水合物、异构体、溶剂化物、或其代谢产物，
Figure PCTCN2019074927-appb-000001
其中，
Cy 1选自5-12元芳基、5-12元杂芳基、C 3-C 9环烷基、C 3-C 9杂环烷基；
Cy 2选自5-12元芳基、5-12元杂芳基；
其中，Cy 1和Cy 2分别独立地可以被选自0、1、2或3个R a的基团所取代，其中R a选自氢、C 1-C 8烷基、C 2-C 8烯基、C 2-C 8炔基、C 3-C 9环烷基、C 1-C 8卤代烷基、C 1-C 8烷基硫基、卤素、氰基、磺酸基、硝基、OR 6、SR 6、NR 6R 7、C(＝O)R 6、C(＝O)OR 6、C(＝O)NR 6R 7、NR 6C(＝O)R 7、或S(O) 2R 6；各个R 6和R 7各自独立地为氢、C 1-C 8烷基、5-12元芳基、5-12元杂芳基，或者R 6和R 7与其相邻的氮原子共同环合成为3-6元环，该环中还可以任选地含有1-2个选自N、O、S的杂原子；
R 1和R 2分别独立地选自氢、C 1-C 8烷基、C 2-C 8烯基、C 2-C 8炔基、C 1-C 8烷氧基、-(CH 2) n5-12元芳基、C 1-C 8卤代烷基、C 3-C 9环烷基、-C(＝O)R 3、-SOR 3、-SO 2R 3、-C(＝O)OR 3、氰基、-(CH 2) nNR 4R 5、-C(＝O)(CH 2) nNR 4R 5，n为0、1、2、3、4或5；或者，R 1和R 2与其相邻的N原子共同环合成为3-9元饱和或不饱和环，该环中还可以任选地含有1-2个选自N、O、S的杂原子；
其中，R 3选自氢、羟基、氨基、任选被取代的C 1-C 8烷基、任选被取代的C 1-C 8烷氧基、任选被取代的C 1-C 8烷基羰基氧基、任选被取代的C 3-C 12环烷基、任选被取代的二(C 1-C 8烷基)氨基、任选被取代的C 1-C 8烷基氨基、任选被取代的C 1-C 8烷基氨基甲酰基、任选被取代的5-12元芳基、任选被取代的5-12元杂芳基；其中所述任选被取代的取代基选自卤素、氰基、磺酸基、C 1-C 8烷基、5-12元芳基、5-12元杂芳基、OR 6、SR 6、NR 6R 7、C(O)R 6、C(O)OR 6、C(O)NR 6R 7、NC(O)NR 6R 7、或S(O) 2R 6，或者当上述芳基、杂芳基、环烷基的取代基的个数为 2或更多时，相邻的两个取代基可以形成5-8元环，该环中可以含有2-4个杂原子；
其中，R 4和R 5选自氢、任选被取代的C 1-C 8烷基、任选被取代的C 3-C 12环烷基、任选被取代的5-12元芳基、任选被取代的5-12元杂芳基，其中所述任选被取代的取代基选自卤素、氰基、磺酸基、OR 6、SR 6、NR 6R 7、C(O)R 6、C(O)OR 6、C(O)NR 6R 7、NC(O)NR 6R 7、或S(O) 2R 6所取代；或者，R 4和R 5与其相连的氮原子共同形成任选地含有1-2个额外的选自N、O或S的杂原子的3-至9-元环状结构；该环状结构可以任选地被1、2或3个R 8所取代，取代的位点在C或N原子上，前提条件是所形成的结构是合理的稳定结构；R 8各自独立地选自氢、卤素、C 1-C 8烷基、C 3-C 9环烷基、C(O)R 9、S(O) 2R 9、3-9元杂环烷基、5-12元芳基、5-12元杂芳基、或＝O；并且R 8还可以任意的被选自卤素、-O(CH 2) pO(CH 2) qOR 10的基团所取代；其中，R 9、R 10分别独立地为氢、C 1-C 8烷基或者C 3-C 9环烷基；
附加条件为，当R 1和R 2同时为氢时，Cy 1为5元杂芳基，其可以任意地被选自0、1、2或3个R a的基团所取代。
在本发明的另一个技术方案中，Cy 1独立地选自苯基、吡啶基、吡嗪基、环丙基、环戊基、环己基、呋喃基、噻唑基、哌啶基、哌嗪基、噁唑基、咪唑基、噻吩基；优选为苯基、呋喃基、噁唑基或吡啶基；Cy 2独立地选自苯基、吡啶基、吡嗪基、呋喃基、噻唑基、哌啶基、哌嗪基、噁唑基、咪唑基、噻吩基；优选为苯基、吡啶基；其中所述的Cy 1和Cy 2可以任意地被0、1、2或3个选自C 1-C 8烷基、C 1-C 8卤代烷基、C 1-C 8烷氧基、C 1-C 8烷基硫基、卤素、氰基、磺酸基、硝基的取代基所取代。
在本发明的另一个技术方案中，其中Cy 1和Cy 2可以独立地选自苯基、吡啶基、吡嗪基、环丙基、环戊基、环己基、呋喃基、噻唑基、哌啶基、哌嗪基，噁唑基、咪唑基、噻吩基，上述取代基可以任意地被0、1、2或3个R a所取代，其中，R a具有如式I定义。
本发明的另一方面提供了一种具有式II结构的化合物，、其药学上可接受的盐、前药、同位素衍生物、水合物、异构体、溶剂化物、或其代谢产物：
Figure PCTCN2019074927-appb-000002
其中，W 1和W 2分别独立地选自CR b或N，R b具有R a的定义；R a、Cy 1和R 2具有如式I所定义，m为0、1、2或3。
在本发明的另一个技术方案中，当R 1和R 2同时为氢时，Cy 1选自五元杂芳基，例如：呋喃基、噻唑基、噁唑基、咪唑基、噻吩基；Cy 2选自苯基、吡啶基、吡嗪基、哌啶基、哌嗪基，优选为苯基、吡啶基；其中，所述的Cy 1和Cy 2可以任意地被0、1、2或3个选自C 1-C 8烷基、C 1-C 8卤代烷基、C 1-C 8烷氧基、C 1-C 8烷基硫基、卤素、氰基、磺酸基、硝基的取代基所取代。
本发明的另一方面提供了一种具有式III或式IV结构的化合物，、其药学上可接受的盐、前药、同位素衍生物、水合物、异构体、溶剂化物、或其代谢产物：
Figure PCTCN2019074927-appb-000003
其中，R a、Cy 1和R 2具有如式I所定义，m为0、1、2或3。
在本发明的一个优选技术方案中，R 2选自-C(＝O)R 3、-SOR 3、-SO 2R 3、-C(＝O)(CH 2) nNR 4R 5；其中，R 3、R 4、R 5具有式I所定义；n选自1、2或3。
在本发明的另一个优选技术方案中，R 2选自-C(＝O)R 3或-C(＝O)(CH 2) nNR 4R 5，其中R 3、R 4、R 5具有式I所定义；n选自1、2或3。
在本发明的另一个优选技术方案中，R 2选自-C(＝O)R 3；R 3选自氢、羟基、 氨基、任选被取代的C 1-C 8烷基、任选被取代的C 3-C 12环烷基或任选被取代的5-12元芳基；优选为任选被取代的C 1-C 8烷基、任选被取代的C 3-C 12环烷基或任选被取代的5-12元芳基，其中所述的任选被取代的取代基选自C 1-C 8烷基、C 1-C 8烷氧基、卤素、羟基、氨基、氰基、磺酸基，5-12元芳基、5-12元杂芳基。
在本发明的另一个优选技术方案中，R 2选自-C(＝O)(CH 2) nNR 4R 5；n为1、2或3；R 4、R 5具有式I所定义。
在本发明的另一个优选技术方案中，R 2选自-C(＝O)(CH 2) nNR 4R 5；n为1、2或3；R 4和R 5与其相连的氮原子共同形成任选地含有1-2个额外的选自N、O或S的杂原子的3-至9-元环状结构；该环状结构可以任选地被1、2或3个R 8所取代，取代的位点在C或N原子上，前提条件是所形成的结构是合理的稳定结构；R 8各自独立地选自氢、卤素、C 1-C 8烷基、C 3-C 9环烷基、C(O)R 9、S(O) 2R 9、3-9元杂环烷基、5-12元芳基、5-12元杂芳基、或＝O；并且R 8还可以任意的被选自卤素和-O(CH 2) pO(CH 2) qOR 10的取代基所取代，其中，p和q分别独立地为0、1、2、3；其中，R 9、R 10分别独立地为氢、C 1-C 8烷基或者C 3-C 9环烷基。
在本发明的另一个优选技术方案中，R 2为-C(＝O)(CH 2) nNR 4R 5；n为1、2或3，R 4和R 5与其相连的氮原子共同形成
Figure PCTCN2019074927-appb-000004
其中
Figure PCTCN2019074927-appb-000005
表示与(CH 2) n相连接的键，R 11选自氢、C 1-C 8烷基、C 3-C 9环烷基、C(O)R 9、S(O) 2R 9、3-9元杂环烷基、5-12元芳基、5-12元杂芳基；并且R 8还可以任意的被选自卤素和-O(CH 2) pO(CH 2) qOR 10的基团所取代，其中，p和q分别独立地为0、1、2、3；R 9、R 10分别独立地为氢、C 1-C 8烷基或者C 3-C 9环烷基。
优选的，本发明的化合物选自以下结构：
Figure PCTCN2019074927-appb-000006
Figure PCTCN2019074927-appb-000007
Figure PCTCN2019074927-appb-000008
Figure PCTCN2019074927-appb-000009
Figure PCTCN2019074927-appb-000010
Figure PCTCN2019074927-appb-000011
Figure PCTCN2019074927-appb-000012
Figure PCTCN2019074927-appb-000013
Figure PCTCN2019074927-appb-000014
Figure PCTCN2019074927-appb-000015
Figure PCTCN2019074927-appb-000016
Figure PCTCN2019074927-appb-000017
Figure PCTCN2019074927-appb-000018
本发明的化合物也可制备成可药用盐的形式，所述可药用盐使用例如以下的无机酸或有机酸而形成：盐酸、氢溴酸、硫酸、磷酸、硝酸、乙酸、乙醇酸、乳酸、丙酮酸、丙二酸、琥珀酸、戊二酸、富马酸、苹果酸、扁桃酸、酒石酸、柠檬酸、抗坏血酸、棕榈酸、马来酸、羟基马来酸、苯甲酸、羟基苯甲酸、苯乙酸、肉桂酸、水杨酸、甲磺酸、苯磺酸或甲苯磺酸。
本发明的可药用盐可通过常规方法制备，例如通过将本发明的化合物溶解于与水可混溶的有机溶剂(例如丙酮、甲醇、乙醇和乙腈)，向其中添加过量的有机酸或无机酸水溶液，以使得盐从所得混合物中沉淀，从中除去溶剂和剩余的游离酸，然后分离所沉淀的盐。
本发明化合物或其可药用盐可包括其水合物和溶剂化物。
本发明还提供了本发明化合物在制备用于预防或治疗癌症、肿瘤、炎症性疾病、自身免疫性疾病或免疫介导性疾病的药物中的用途。
此外，本发明提供了用于预防或治疗癌症、肿瘤、炎症性疾病、自身免疫性疾病、神经退行性疾病、注意力相关疾病或免疫介导性疾病的药物组合物，其包含本发明化合物作为活性成分。
此外，本发明提供了一种用于预防或治疗癌症、肿瘤、炎症性疾病、自身免疫性疾病、神经退行性疾病、注意力相关疾病或免疫介导性疾病的方法，其包括向有此需要的哺乳动物施用本发明化合物。
此外，本发明提供了一种抑制A2A和/或A2B受体的方法，其包括使A2A和/或A2B受体暴露于本发明化合物。
癌症或肿瘤的代表性实例可包括但不限于，皮肤癌、膀胱癌、卵巢癌、乳腺癌、胃癌、胰腺癌、前列腺癌、结肠癌、肺癌、骨癌、脑癌、神经细胞瘤、直肠癌、结肠癌、家族性腺瘤性息肉性癌、遗传性非息肉性结直肠癌、食管癌、唇癌、喉癌、下咽癌、舌癌、唾液腺癌、胃癌、腺癌、甲状腺髓样癌、乳头状甲状腺癌、肾癌、肾实质癌、卵巢癌、宫颈癌、子宫体癌、子宫内膜癌、绒毛膜癌、胰腺癌、前列腺癌、睾丸癌、泌尿癌、黑素瘤、脑肿瘤诸如成胶质细胞瘤、星形细胞瘤、脑膜瘤、成神经管细胞瘤和外周神经外胚层肿瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、伯基特淋巴瘤、急性淋巴性白血病(ALL)、慢性淋巴性白血病(CLL)、急性骨髓性白血病(AML)、慢性粒细胞白血病(CML)、成人T细胞白血病淋巴瘤、弥漫性大B细胞淋巴瘤(DLBCL)、肝细胞癌、胆囊癌、支气管癌、小细胞肺癌、非小细胞肺癌、多发性骨髓瘤、基底细胞瘤、畸胎瘤、成视网膜细胞瘤、脉络膜黑素瘤、精原细胞瘤、横纹肌肉瘤、颅咽管瘤、骨肉瘤、软骨肉瘤、肌肉瘤、脂肪肉瘤、纤维肉瘤、尤因肉瘤或浆细胞瘤。
当将本发明化合物或其可药用盐与另外的用于治疗癌症或肿瘤的抗癌剂或检查点抑制剂组合施用时，本发明化合物或其可药用盐可提供增强的抗癌作用。
用于治疗癌症或肿瘤的抗癌剂的代表性实例可包括但不限于细胞信号转导抑制剂、苯丁酸氮芥、美法仑、环磷酰胺、异环磷酰胺、白消安、卡莫司汀、洛莫司汀、链脲佐菌素、顺铂、卡铂、奥沙利铂、达卡巴嗪、替莫唑胺、丙卡巴肼、甲氨蝶呤、氟尿嘧啶、阿糖胞苷、吉西他滨、巯基嘌呤、氟达拉滨、长春碱、长春新碱、长春瑞滨、紫杉醇、多西紫杉醇、拓扑替康、伊立替康、依托泊苷、曲贝替定、更生霉素、多柔比星、表柔比星、道诺霉素、米托蒽醌、博来霉素、丝裂霉素C、伊沙匹隆、他莫昔芬、氟他胺、戈那瑞林类似物、甲地孕酮、强的松、 地塞米松、甲泼尼龙、沙利度胺、干扰素α、亚叶酸钙、西罗莫司、西罗莫司脂化物、依维莫司、阿法替尼、alisertib、amuvatinib、阿帕替尼、阿西替尼、硼替佐米、波舒替尼、布立尼布、卡博替尼、西地尼布、crenolanib、克卓替尼、达拉菲尼、达可替尼、达努塞替、达沙替尼、多维替尼、厄洛替尼、foretinib、ganetespib、吉非替尼、依鲁替尼、埃克替尼、伊马替尼、iniparib、拉帕替尼、lenvatinib、linifanib、linsitinib、马赛替尼、momelotinib、莫替沙尼、来那替尼、尼罗替尼、niraparib、oprozomib、olaparib、帕唑帕尼、pictilisib、普纳替尼、quizartinib、瑞格菲尼、rigosertib、rucaparib、鲁索利替尼、塞卡替尼、saridegib、索拉非尼、舒尼替尼、替拉替尼、tivantinib、替沃扎尼、托法替尼、曲美替尼、凡德他尼、维利帕尼、威罗菲尼、维莫德吉、volasertib、阿仑单抗、贝伐单抗、贝伦妥单抗维多汀、卡妥索单抗、西妥昔单抗、地诺单抗、吉妥珠单抗、伊匹单抗、尼妥珠单抗、奥法木单抗、帕尼单抗、利妥昔单抗、托西莫单抗、曲妥珠单抗；检查点抑制剂，包括但不局限于抗PD-1抗体、抗PD-L1抗体、LAG3抗体、TIM-3抗体以及抗CTLA-4抗体或它们的任意组合。
炎症性疾病、自身免疫性疾病和免疫介导性疾病的代表性实例可包括但不限于，关节炎、类风湿性关节炎、脊柱关节炎、痛风性关节炎、骨关节炎、幼年型关节炎、其他关节炎性病症、狼疮、系统性红斑狼疮(SLE)、皮肤相关疾病、银屑病、湿疹、皮炎、过敏性皮肤炎、疼痛、肺病、肺部炎症、成人呼吸窘迫综合征(ARDS)、肺结节病、慢性肺部炎症性疾病、慢性阻塞性肺病(COPD)、心血管疾病、动脉粥样硬化、心肌梗塞、充血性心力衰竭、心肌缺血再灌注损伤、炎性肠病、克罗恩病、溃疡性结肠炎、肠易激综合征、哮喘、干燥综合征、自身免疫甲状腺疾病、荨麻疹(风疹)、多发性硬化、硬皮症、器官移植排斥、异种移植、特发性血小板减少性紫癜(ITP)、帕金森病、阿尔兹海默病、糖尿病相关疾病、炎症、盆腔炎性疾病、过敏性鼻炎、过敏性支气管炎、过敏性鼻窦炎、白血病、淋巴瘤、B细胞淋巴瘤、T细胞淋巴瘤、骨髓瘤、急性淋巴性白血病(ALL)、慢性淋巴性白血病(CLL)、急性髓性白血病(AML)、慢性髓性白血病(CML)、毛细胞白血病、何杰金氏病、非何杰金淋巴瘤、多发性骨髓瘤、骨髓增生异常综合征(MDS)、骨髓增生性肿瘤(MPN)、弥漫性大B细胞淋巴瘤和滤泡性淋巴瘤。
当将本发明化合物或其可药用盐与另外的用于治疗炎症性疾病、自身免疫性疾病和免疫介导性疾病的治疗剂组合施用时，本发明化合物或其可药用盐可提供增强的治疗作用。
用于治疗炎症性疾病、自身免疫性疾病和免疫介导性疾病的治疗剂的代表性实例可包括但不限于，甾体药物(例如，强的松、氢化波尼松、甲基氢化波尼松、可的松、羟基可的松、倍他米松、地塞米松等)、甲氨蝶呤、来氟米特、抗TNFα剂(例如，依那西普、英夫利昔单抗、阿达利单抗等)、钙调神经磷酸酶抑制剂(例如，他克莫司、吡美莫司等)和抗组胺药(例如，苯海拉明、羟嗪、氯雷他定、依巴斯汀、酮替芬、西替利嗪、左西替利嗪、非索非那定等)，并且选自其中的至少一种治疗剂可包含于本发明药物组合物中。
本发明的化合物或其可药用盐可作为活性成分通过口服或肠胃外施用，其有效量的范围为在哺乳动物包括人(体重约70kg)的情况下0.1至2,000mg/kg体重/天、优选1至1,000mg/kg体重/天，并且每天以单次或4次分次剂量，或者遵循/不遵循预定时间施用。活性成分的剂量可根据多个相关因素(例如待治疗对象的情况、疾病类型和严重性、施用速率和医生意见)进行调整。在某些情况下，小于以上剂量的量可能是合适的。如果不引起有害的副作用则可使用大于以上剂量的量并且该量可以每天以分次剂量施用。
可根据常规方法中的任何一种将本发明药物组合物配制成用于口服施用或肠胃外施用(包括肌内、静脉内和皮下途径)的剂型，例如片剂、颗粒、粉末、胶囊、糖浆、乳剂、微乳剂、溶液或混悬液。
用于口服施用的本发明药物组合物可通过将活性成分与例如以下的载体混合来制备：纤维素、硅酸钙、玉米淀粉、乳糖、蔗糖、右旋糖、磷酸钙、硬脂酸、硬脂酸镁、硬脂酸钙、明胶、滑石、表面活性剂、助悬剂、乳化剂和稀释剂。在本发明的注射组合物中采用的载体的实例是水、盐溶液、葡萄糖溶液、葡萄糖样溶液(glucose-like solution)、醇、二醇、醚(例如，聚乙二醇400)、油、脂肪酸、脂肪酸酯、甘油酯、表面活性剂、助悬剂和乳化剂。
本发明描述示例性实施方案的过程中，本发明的其它特征将变得显而易见，给出所述实施方案用于说明本发明而不意欲成为其限制，以下实施例使用本发明 所公开的方法制备、分离和表征。
可以用有机合成领域的技术人员已知的多种方式来制备本发明的化合物，可使用下述方法以及有机合成化学领域中已知的合成方法或通过本领域技术人员所了解的其变化形式来合成本发明化合物。优选方法包括但不限于下文所述的这些。在适用于所使用试剂盒材料和适用于所实现转变的溶剂或溶剂混合物中实施反应。有机合成领域的技术人员将理解，分子上存在的官能性与所提出的转变一致。这有时需要加以判断改变合成步骤的顺序或原料以获得期望的本发明化合物。
具体实施方式
本发明人经过长期而深入的研究，意外地发现了一类具有A2A和/或A2B抑制活性的杂环化合物，因此可以用于制备治疗与A2A和/或A2B受体相关的疾病的药物组合物。基于上述发现，发明人完成了本发明。
术语
如果无另外说明，用于本发明申请，包括说明书和权利要求书中的术语，定义如下。必须注意，在说明书和所附的权利要求书中，如果文中无另外清楚指示，单数形式“一个”包括复数意义。如果无另外说明，使用质谱、核磁、HPLC、蛋白化学、生物化学、重组DNA技术和药理的常规方法。在本申请中，如果无另外说明，使用“或”或“和”指“和/或”。
在说明书和权利要求书中，给定化学式或名称应涵盖所有立体和光学异构体及其中存在上述异构体的外消旋物。除非另外指明，否则所有手性(对映异构体和非对映异构体)和外消旋形式均在本发明范围内。所述化合物中还可存在C＝C双键、C＝N双键、环系统等的许多几何异构体，且所有上述稳定异构体均涵盖于本发明内。本发明描述了本发明化合物的顺式-和反式-(或E-和Z-)几何异构体，且其可分离成异构体的混合物或分开的异构体形式。本发明化合物可以光学活性或外消旋形式加以分离。用于制备本发明化合物和其中制备的中间体的所有方法均视为本发明的部分。在制备对映异构体或非对映异构体产物时，其可通过常规 方法(例如通过色谱或分段结晶)进行分离。取决于方法条件，以游离(中性)或盐形式获得本发明的终产物。这些终产物的游离形式和盐均在本发明的范围内。如果需要的话，则可将化合物的一种形式转化成另一种形式。可将游离碱或酸转化成盐；可将盐转化成游离化合物或另一种盐；可将本发明异构体化合物的混合物分离成单独的异构体。本发明化合物、其游离形式和盐可以多种互变异构体形式存在，其中氢原子转置到分子的其它部分上且由此分子的原子之间的化学键发生重排。应当理解的是，可存在的所有互变异构体形式均包括在本发明内。
除非另有定义，否则当取代基被标注为“任选取代的”时，所述取代基选自例如以下取代基，诸如烷基、环烷基、芳基、杂环基、卤素、羟基、烷氧基、氧代、烷酰基、芳基氧基、烷酰基氧基、氨基、烷基氨基、芳基氨基、芳基烷基氨基、二取代的胺基团(其中2个氨基取代基选自烷基、芳基或芳基烷基)、烷酰基氨基、芳酰基氨基、芳烷酰基氨基、取代的烷酰基氨基、取代的芳基氨基、取代的芳烷酰基氨基、硫基、烷基硫基、芳基硫基、芳基烷基硫基、芳基硫羰基、芳基烷基硫羰基、烷基磺酰基、芳基磺酰基、芳基烷基磺酰基、磺酰氨基例如-SO 2NH 2、取代的磺酰氨基、硝基、氰基、羧基、氨基甲酰基例如-CONH 2、取代的氨基甲酰基例如-CONH烷基、-CONH芳基、-CONH芳基烷基或在氮上具有两个选自烷基、芳基或芳基烷基的取代基的情况、烷氧基羰基、芳基、取代的芳基、胍基、杂环基，例如吲哚基、咪唑基、呋喃基、噻吩基、噻唑基、吡咯烷基、吡啶基、嘧啶基、吡咯烷基、哌啶基、吗啉基、哌嗪基、高哌嗪基等和取代的杂环基。
本文使用的术语“烷基”或“亚烷基”意欲包括具有指定碳原子数的支链和直链饱和脂族烃基团。例如，“C1-C6烷基”表示具有1个至6个碳原子的烷基。烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(例如正丙基和异丙基)、丁基(例如正丁基、异丁基、叔丁基)和戊基(例如正戊基、异戊基、新戊基)。
术语“烯基”表示含一个或多个双键且通常长度为2至20个碳原子的直链或支链的烃基。例如，“C2-C8烯基”含有两个至八个碳原子。烯基包括但不限于例如乙烯基、丙烯基、丁烯基、1-甲基-2-丁烯-1-基、庚烯基、辛烯基等。
术语“炔基”表示含一个或多个三键且通常长度为2至20个碳原子的直链或支链的烃基。例如，“C2-C8炔基”含有两个至八个碳原子。代表性炔基包括但不限于例如乙炔基、1-丙炔基、1-丁炔基、庚炔基、辛炔基等。
术语“烷氧基”或“烷基氧基”是指-O-烷基。“C1-6烷氧基”(或烷基氧基)意欲包括C1、C2、C3、C4、C5和C6烷氧基。烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(例如正丙氧基和异丙氧基)和叔丁氧基。类似地，“烷基硫基”或“硫代烷氧基”表示具有指定数量碳原子的经硫桥连接的如上文所定义的烷基；例如甲基-S-和乙基-S-。
术语“羰基”是指由碳和氧两种原子通过双键连接而成的有机官能团(C＝O)。
术语“芳基”，单独或作为较大部分诸如“芳烷基”、“芳烷氧基”或“芳基氧基烷基”的部分，是指具有总计5至12个环成员的单环、二环或三环的环系统，其中所述系统中的至少一个环为芳族的且其中所述系统中的每个环含有3至7个环成员。在本发明的某些实施方案中，“芳基”是指芳族环系统，其包括但不限于苯基、联苯基、茚满基、1-萘基、2-萘基和四氢萘基。术语“芳烷基”或“芳基烷基”是指连接至芳基环的烷基残基。非限制性实例包括苄基、苯乙基等。稠合的芳基可在环烷基环或芳族环的合适位置上连接至另一基团。例从环系统中画出的箭头线表明键可连接至任意合适的环原子。
术语“环烷基”是指单环或二环的环状烷基。单环的环状烷基指C3-C8的环状烷基，包括但不限于环丙基、环丁基、环戊基、环己基和降莰烷基。支化环烷基诸如1-甲基环丙基和2-甲基环丙基包括在“环烷基”的定义中。二环的环状烷基包括桥环、螺环或融合环的环烷基。
术语“环烯基”是指单环或二环的环状烯基。单环的环状烯基指C3-C8的环状烯基，包括但不限于环丙烯基、环丁烯基、环戊烯基、环己烯基和降莰烯基。支化环烯基诸如1-甲基环丙烯基和2-甲基环丙烯基包括在“环烯基”的定义中。二环的环状烯基包括桥环、螺环或融合环的环状烯基。
“卤代”或“卤素”包括氟、氯、溴和碘。“卤代烷基”意欲包括具有指定碳原子数且取代有1个或多个卤素的支链和直链饱和脂族烃基团。卤代烷基的实例包括但不限于氟甲基、二氟甲基、三氟甲基、三氯甲基、五氟乙基、五氯乙基、2,2,2-三氟乙基、七氟丙基和七氯丙基。卤代烷基的实例还包括意欲包括具有指定碳原子数且取代有1个或多个氟原子的支链和直链饱和脂族烃基团的“氟烷基”。
“卤代烷氧基”或“卤代烷基氧基”表示具有指定数量碳原子的经氧桥连接的如上文所定义的卤代烷基。例如，“C1-C6卤代烷氧基”意欲包括C1、C2、C3、 C4、C5和C6卤代烷氧基。卤代烷氧基的实例包括但不限于三氟甲氧基、2,2,2-三氟乙氧基和五氟乙氧基。类似地，“卤代烷基硫基”或“硫代卤代烷氧基”表示具有指定数量碳原子的经硫桥连接的如上文所定义的卤代烷基；例如三氟甲基-S-和五氟乙基-S-。
术语“芳基”指的是单环或二环(及二环以上)的全为碳原子的芳香基。单环的芳香基指的是苯基，二环及二环以上的芳香基指萘基、蒽基等，同时此芳基二环也可为苯环融合了一个环烷基、或融合一个环烯基、或融合一个环炔基。
术语“芳杂基”、“芳杂环”、“芳杂环基”或“芳杂环基团”意指稳定的3元、4元、5元、6元、或7元芳香单环或芳香二环或7元、8元、9元、10元、11元、12元、13元或14元芳香多环杂环，其为完全不饱和的、部分不饱和的，且其含有碳原子和1个、2个、3个或4个独立地选自N、O和S的杂原子；且包括任何以下多环基团，其中上文所定义的任意杂环与苯环稠合。氮和硫杂原子可任选地被氧化。氮原子为取代的或未取代的(即N或NR，其中R为H或如果被定义，则为另一取代基)。杂环可在得到稳定结构的任何杂原子或碳原子处连接至其侧基。如果所得化合物是稳定的，则本文所述的杂环基可在碳或氮原子上被取代。杂环中的氮可任选地被季铵化。优选地，当杂环中S和O原子的总数超过1时，则这些杂原子彼此不相邻。优选地，杂环中S和O原子的总数不大于1。当使用术语“杂环”时，其意欲包括杂芳基。芳杂环的实施例包括但不限于吖啶基、氮杂环丁基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并硫代呋喃基、苯并噻吩基、苯并噁唑基、苯并噁唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异噁唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、色满基、色烯基、噌啉基、十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、咪唑并吡啶基、假吲哚基(indolenyl)、二氢吲哚基、吲嗪基、吲哚基、3H-吲哚基、靛红酰基(isatinoyl)、异苯并呋喃基、异色满基、异吲唑基、异二氢吲哚基、异吲哚基、异喹啉基、异噻唑基、异噻唑并吡啶基、异噁唑基、异噁唑并吡啶基、亚甲基二氧基苯基、吗啉基、二氮杂萘基、八氢异喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑烷基、噁唑基、噁唑并吡啶基、噁唑烷基、萘嵌间二氮杂苯基、羟吲哚基、嘧啶基、菲啶基、菲咯啉 基、吩嗪基、吩噻嗪基、吩噁噻基、吩噁嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、喋啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑并吡啶基、吡唑基、哒嗪基、吡啶并噁唑基、吡啶并咪唑基、吡啶并噻唑基、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2-吡咯烷酮基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四唑基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、噻吩基、噻唑并吡啶基、噻吩并噻唑基、噻吩并噁唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基和呫吨基、喹啉基、异喹啉基、酞嗪基、喹唑啉基、吲哚基、异吲哚基、二氢吲哚基、1H-吲唑基、苯并咪唑基、1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基、5,6,7,8-四氢-喹啉基、2,3-二氢-苯并呋喃基、色满基、1,2,3,4-四氢-喹喔啉基和1,2,3,4-四氢-喹唑啉基。本发明还包括含有例如上述杂环的稠环和螺环化合物。
本文使用的术语“杂环烷基”指的是一个单环杂环烷基体系，或为一个二环杂环烷基体系，同时还包括螺杂环或桥杂环烷基。单环的杂环烷基指的是3-8元、且至少含一个选自O、N、S、P的饱和或不饱和但不为芳香性的环状烷基体系。二环杂环烷基体系指的是一个杂环烷基融合到一个苯基、或一个环烷基、或一个环烯基、或一个杂环烷基、或一个杂芳基。
本文使用的术语“桥环烷基”指的是共用两个或两个以上碳原子的多环化合物。可分为二环桥环烃及多环桥环烃。前者由两个脂环共用两个以上碳原子所构成；后者是由三个以上的环组成的桥环烃。
本文使用的术语“螺环烷基”指的是单环之间共用一个碳原子(称螺原子)的多环烃。
本文使用的术语“桥环杂基”指的是共用两个或两个以上碳原子的多环化合物，该环中至少含一个选自O、N、S原子。可分为二环桥环杂环及多环桥杂环。
本文使用的术语“杂螺环基”指的是单环之间共用一个碳原子(称螺原子)的多环烃，该环中至少含一个选自O、N、S原子。
本文中所用的术语“取代”意指至少一个氢原子被非氢基团替代，条件是维持正常化合价且所述取代得到稳定的化合物。本文所用的环双键为在两个相邻环原 子之间形成的双键(例如C＝C、C＝N或N＝N)。
在本发明化合物上存在氮原子(例如胺)的情形下，可通过使用氧化剂(例如mCPBA和/或过氧化氢)进行处理来将这些氮原子转化成N-氧化物以获得本发明的其它化合物。因此，所显示和要求保护的氮原子视为均涵盖所显示氮及其N-氧化物以获得本发明衍生物。
当任何变量在化合物的任何组成或式中出现一次以上时，其每次出现时的定义均独立于其在其它每种情况下出现时的定义。因此，例如如果显示基团取代有0、1、2或3个R，则所述基团可任选地取代有至多三个R基团，且在每次出现时R独立地选自R的定义。此外，取代基和/或变量的组合仅在上述组合可产生稳定的化合物时才容许存在。
术语“溶剂化物”意指本发明化合物与一个或多个溶剂分子(无论有机的还是无机的)的物理缔合。该物理缔合包括氢键。在某些情形中，例如当一个或多个溶剂分子纳入结晶固体的晶格中时，溶剂化物将能够被分离。溶剂化物中的溶剂分子可按规则排列和/或无序排列存在。溶剂化物可包含化学计量或非化学计量的溶剂分子。“溶剂合物”涵盖溶液相和可分离的溶剂化物。示例性溶剂化物包括但不限于水合物、乙醇合物、甲醇合物和异丙醇合物。溶剂化方法是本领域公知的。
本文使用的术语“患者”是指通过本发明的方法进行治疗的有机体。这类有机体优选包括但不限于哺乳动物(例如鼠类、猿/猴、马、牛、猪、犬、猫等)且最优选是指人类。
本文使用的术语“有效量”意指将会引起例如研究人员或临床医师所寻求的组织、系统、动物或人的生物学或医学响应的药物或药剂(即本发明化合物)的量。此外，术语“治疗有效量”意指这样的量：与未接受上述量的相应受试者相比，所述量导致改善的治疗、治愈、预防或减轻疾病、病症或副作用，或降低在疾病或病症的进展速度。有效量可以一个或多个给药、施用或剂量给予且不意欲被特定的制剂或给药途径限制。该术语还包括在其范围内的增强正常生理机能的有效量。
本文使用的术语“治疗”包括导致改善病症、疾病、障碍等的任何效果，例如减轻、减少、调节、改善或消除，或改善其症状。
本文使用的术语“药物组合物”是指活性剂与惰性或活性的载体的组合，使得所述组合物尤其适用于体内或离体诊断或治疗。碱的实例包括但不限于碱金属(例如钠)氢氧化物、碱土金属(例如镁)氢氧化物、氨等。对于治疗用途，本发明化合物的盐对于治疗用途，本发明化合物的盐预期为是药用的。然而，非药用的酸和碱的盐也可用于例如药用化合物的制备或纯化中。
术语“药用”在本文中用于指如下那些化合物、物质、组合物和/或剂型：在合理医学判断的范围内，其适于与人类和动物的组织接触使用而无过高毒性、刺激性、过敏反应和/或其它问题或并发症，并与合理的益处/风险比相称。
本文使用的短语“药用载体”意指药用物质、组合物或媒介物，诸如液体或固体填充剂、稀释剂、赋形剂、制造助剂(例如润滑剂、滑石、硬脂酸镁、硬脂酸钙或硬脂酸锌或硬脂酸)或溶剂包囊物质，其涉及将主题化合物从一个器官或身体的部分携带或运送至另一个器官或身体的部分。每种载体在与制剂的其它成分相容和对患者无害的意义上必须是“可接受的”。
术语“药物组合物”意指包含本发明化合物与至少一种其它药用载体的组合物。“药用载体”是指本领域中通常接受用于将生物活性剂递送至动物(具体为哺乳动物)的介质，包括(即)佐剂、赋形剂或媒介物，诸如稀释剂、防腐剂、填充剂、流动调控剂、崩解剂、润湿剂、乳化剂、悬浮剂、增甜剂、矫味剂、芳香剂、抗细菌剂、抗真菌剂、润滑剂和分散剂，这取决于给药模式和剂型的性质。
特定药学及医学术语
术语“可接受的”，如本文所用，指一个处方组分或活性成分对一般治疗目标的健康没有过分的有害影响。
术语“癌症”，如本文所用，指一种不能控制的细胞的异常生长，并且在某种条件下能够转移(传播)。这种类型的癌症包括但不限于，实体肿瘤(如膀胱、肠、脑、胸、子宫、心脏、肾、肺、淋巴组织(淋巴瘤)、卵巢、胰腺或其它内分泌器官(如甲状腺)、前列腺、皮肤(黑色素瘤)或血液瘤(如非白血性白血病)。
术语“联合给药”或其类似术语，如本文所用，指将几种所选的治疗药物给一个病人用药，以相同或不同的给药方式在相同或不同的时间给药。
术语“增强”或“能增强”，如本文所用，指预期的结果能够在效价或是持续时 间方面都有增加或延长。因此，在增强药物的治疗效果方面，术语“能增强”指药物在系统中有提高或延长效价或持续时间的能力。本文所用的“增效值”，指在理想的系统中，能够最大限度地的增强另外一个治疗药物的能力。
术语“免疫性疾病”指对内源性或外源性抗原产生的不良或有害反应的疾病或症状。结果通常会造成细胞的功能障碍、或因此而破坏并造成机能障碍、或破坏可能产生免疫症状的器官或组织。
术语“试剂盒”与“产品包装”是同义词。
术语“受试者”或“病人”包括哺乳动物和非哺乳动物。哺乳动物包括但不限于，哺乳类：人、非人灵长类如猩猩、猿及猴类；农业动物如牛、马、山羊、绵羊、猪；家畜如兔、狗；实验动物包括啮齿类，如大鼠、小鼠及豚鼠等。非哺乳类动物包括但不限于，鸟、鱼等。在一优选例中，所选哺乳动物是人。
术语“治疗”、“治疗过程”或“疗法”如本文所用，包括缓和、抑制或改善疾病的症状或状况；抑制并发症的产生；改善或预防潜在代谢综合症；抑制疾病或症状的产生，如控制疾病或情况的发展；减轻疾病或症状；使疾病或症状减退；减轻由疾病或症状引起的并发症，或预防或治疗由疾病或症状引起的征兆。
如本文所用，某一化合物或药物组合物，给药后，可以使某一疾病、症状或情况得到改善，尤指其严重度得到改善，延迟发病，减缓病情进展，或减少病情持续时间。无论固定给药或临时给药、持续给药或断续给药，可以归因于或与给药有关的情况。
给药途径
适合的给药途径包括但不限于，口服、静脉注射、直肠、气雾剂、非肠道给药、眼部给药、肺部给药、经皮给药、阴道给药、耳道给药、鼻腔给药及局部给药。此外，仅作举例说明，肠道外给药，包括肌肉注射、皮下注射、静脉注射、髓内注射、心室注射、腹膜内注射、淋巴管内注射、及鼻内注射。
在一方面，此处描述的化合物给药方式是局部的而不是全身性的给药方式。在特定的具体实施例中，长效制剂通过植入给药(例如皮下或肌肉)或通过肌肉注射。此外，在另一具体化实施例中，药物通过靶向药物给药系统来给药。例如，由器官特异性抗体包裹的脂质体。在这种具体实施例中，所述脂质体被选择性的 导向特定器官并吸收。
药物组合物和剂量
本发明还提供药用组合物，其包含治疗有效量的与一种或多种药用载体(添加剂)和/或稀释剂一起配制的一种或多种本发明的化合物，和任选的一种或多种上述其它治疗剂。可通过任意合适方式给予本发明化合物以用于任意上述用途，例如口服，诸如片剂、丸剂、粉剂、颗粒剂、酏剂、酊剂、悬浮液(包括纳米悬浮液、微悬浮液、喷雾干燥的分散液)、糖浆和乳液；经舌下；含服；经肠胃外，诸如通过皮下、静脉内、肌内或胸骨内注射或输注技术(例如以无菌可注射水性或非水性溶液或悬浮液形式)；经鼻，包括向鼻膜给药，诸如通过吸入喷雾；局部，诸如以乳膏剂或软膏剂形式；或经直肠，诸如以栓剂形式。它们可单独给药，但通常使用基于所选给药途径和标准药学实践选择的药物载体给药。
根据本领域技术人员认识范围内的诸多因素来调配药用载体。这些因素包括，但不限于：所调配活性剂的类型和性质；含有活性剂的组合物所要给药的受试者；组合物的预期给药途径；及所靶向的治疗适应症。药用载体包括水性和非水性液体介质及各种固体和半固体剂型。
上述载体可包括除活性剂外的诸多不同成分和添加剂，上述其它成分出于本领域技术人员公知的各种原因包括于制剂中，例如稳定活性剂、粘合剂等。关于合适的药用载体和载体选择中所涉及的因素的描述可参见多个容易获得的来源，例如Allen L.V.Jr.et al.Remington:The Science and Practice of Pharmacy(2Volumes),22nd Edition(2012),Pharmaceutical Press。
当然，本发明化合物的剂量方案取决于已知因素而有所变化，诸如具体药剂的药效学特性及其给药模式和途径；接受者的物种、年龄、性别、健康状况、医学病状和重量；症状的性质和程度；同时治疗的种类；治疗频率；给药途径、患者的肾和肝功能及期望效应。根据一般指导，当用于指定效应时，各活性成分的日口服剂量应为约0.001mg/天至约10-5000mg/天，优选地为约0.01mg/天至约1000mg/天，且最优选地为约0.1mg/天至约250mg/天。在恒速输注期间，静脉内最优选剂量应为约0.01mg/kg/分钟至约10mg/kg/分钟。本发明化合物可以单一日剂量给药，或可以每日两次、三次或四次的分开剂量给药总日剂量。
所述化合物通常以与根据预期给药形式(例如口服片剂、胶囊剂、酏剂和糖浆剂)适当地选择且与常规药学实践相符合的合适药物稀释剂、赋形剂或载体(在本文中统称为药物载体)的混合物形式进行给药。
适于给药的剂型(药物组合物)可含有约1毫克至约2000毫克活性成分/剂量单位。在这些医药组合物中，以组合物的总重量计，活性成分通常将以约0.1-95重量％的量存在。
用于口服给药的典型胶囊剂含有至少一种本发明化合物(250mg)、乳糖(75mg)和硬脂酸镁(15mg)。使该混合物穿过60目网筛，并包装成1号明胶胶囊。
典型的可注射制剂可如下制备：以无菌方式将至少一种本发明化合物(250mg)置于瓶中、以无菌方式冻干并密封。为进行使用，将瓶内容物与2mL生理盐水混合，以产生可注射制剂。
本发明范围包括(单独或与药物载体组合)包含治疗有效量的至少一种本发明化合物作为活性成分的药物组合物。任选地，本发明化合物可单独使用、与本发明其它化合物组合使用或与一种或多种其它治疗剂(例如抗癌剂或其它药学活性物质)组合使用。
不考虑所选择的给药路径，通过本领域技术人员已知的常规方法来将本发的化合物(其可以合适的水合形式使用)和/或本发明的药物组合物配制成药用剂量形式。
可改变活性成分在本发明的药物组合物中的实际剂量水平，从而获得对于实现特定患者的期望的治疗响应、组成和给药模式有效的而对患者无毒的活性成分量。
选定的剂量水平会取决于多种因素，包括所用的本发明的特定化合物或其酯、盐或酰胺的活性；给药路径；给药时间；所用的特定化合物的排泄速率；吸收速率和程度；治疗的持续时间；与所用的特定化合物组合使用的其它药物、化合物和/或物质；所治疗的患者的年龄、性别、重量、状况、一般健康和先前的医学史等医学领域公知的因素。
具有本领域普通技术的医生或兽医可容易地确定并开出有效量的所需药物组合物。例如，为了达到所期望的治疗效果，医师或兽医可在低于所需的水平开始药物组合物中所用的本发明化合物的较量，并逐步增加剂量直至实现所期望的 效果。通常，合适日剂量的本发明化合物将是有效产生治疗效果的最低剂量的化合物的量。此种有效剂量通常取决于上述因素。通常，口服、静脉内、脑室内和皮下剂量的用于患者的本发明化合物的范围为约0.01至约50mg/kg体重/天。如果需要的话，有效日剂量的活性化合物可以两个、三个、四个、五个、六个或更多个亚剂量在一天当中的适当的间隔分别给药，任选地呈单位剂型形式。在本发明的某些方面中，服药为每天一次给药。
虽然本发明化合物可单独给药，但优选以药物制剂(组合物)形式给予化合物。
试剂盒/产品包装
为了用于上述适应症的治疗，试剂盒/产品包装也在此进行描述。这些试剂盒可以由输送器、药包或容器盒组成，容器盒可被划分成多格，以容纳一种或多种容器，如管形瓶、试管及类似物等，每个容器中包含所述方法中的单独一种成分。合适的容器包括瓶子，管形瓶，注射器和试管等。容器由可接受的玻璃或塑料等材料制作而成。
举例来讲，容器可装有一种或多种在此所述的化合物，化合物可能以药物组分形式存在，也可能与在本文中所述的其它成分组成混合物体存在。容器可有一个无菌输出口(例如容器可为静脉输液包或瓶，瓶塞可被皮下注射器针头刺破)。这样的试剂盒可带有一种化合物，及本文中所述的使用方法的说明、标签或操作说明。
一个典型的试剂盒可包括一种或多种容器，为适应商业推广和使用者对化合物使用的需求，每个容器装有一种或多种材料(如试剂，也可以是浓缩的母液，和/或器械)。这些材料包括但不局限于缓冲液，稀释液，滤器，针头，注射器，输送器，包，容器，瓶和/或试管，附有内容清单和/或使用说明书，内置包装也附有说明书。整套的说明都要包括在内。
标签可显示在容器上或与容器紧密相关。标签出现在容器上即指标签字母、数字或其它特征被粘贴、铸模、刻在容器上；标签也可出现在装有多种容器的容器盒或运输盒内，如在产品插页中。一个标签可用来提示内容物的某种特定治疗用途。标签也可标示内容物使用说明，诸如在上述方法中描述的。
在本说明书中被描述的所有特征(包括任何所述的权利要求、摘要和图),和/或任何方法或过程中涉及的所有步骤，均有可能以任意一种组合存在，除非某些特征或步骤在同一组合中是相互排斥的。
本发明提到的上述特征，或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。除非另外说明，否则所有的百分数、比率、比例、或份数按重量计。
本发明中的重量体积百分比中的单位是本领域技术人员所熟知的，例如是指在100毫升的溶液中溶质的重量。除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
在本发明的优选例中，提供但不局限于以下化合物：
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
具体实施例
当未包括制备途径时，相关中间体是市售的(例如来自Sigma Aldrich,Alfa)
通用过程
使用市售试剂而不需进一步纯化。室温是指20-27℃。1H-NMR谱在Bruker仪器上于500MHz记录。化学位移值以百万分率表示，即δ值。以下简写用于NMR信号的多重性：s＝单峰，brs＝宽峰，d＝二重峰，t＝三重峰，m＝多重峰。耦 合常数以J值列出，以Hz测量。NMR和质谱结果根据背景峰校正。色谱是指使用100筛目硅胶进行并在氮气压力(快速色谱)条件下完成的柱色谱。用于监测反应的TLC指使用特定流动相和来自Merck的硅胶F254作为固定相进行的TLC。
LC-MS实验在以下条件下测量：
仪器：Thermo U3000,ALLtech ELSD,MSQ，UV检测器结合ELSD和MSD(流出比为4：1)。柱：Waters X-Bridge C-18,3.5μm，4.6x50mm；柱温：30℃。梯度【时间(min)/溶剂B在A中(％)】：0.00/5.0，0.70/95，1.40/95，1.41/5，1.50/5。(溶剂A＝0.01％三氟乙酸在水中；溶剂B＝0.01％三氟乙酸在乙腈中)。UV检测：214/254/280/300nm；DAD检测：200-400nm；流速：4mL/min；MS：ESI，100-1500m/z
制备型HPLC通常使用酸性方法(乙腈和水的梯度，各含有0.1％甲酸)用Thermo U3000AFC-3000；柱：Globalsil C-18 12nm,250x 20mm,10μm,或相当；流速：20mL/min，进行分离。
中间体的合成
化合物INT-1的制备：
Figure PCTCN2019074927-appb-000019
在氮气保护下，将联硼酸频那醇酯(19.9g,78.4mmol)，4,4’-二叔丁基联吡啶(848mg,3.14mmol)和化合物INT-1a(1.04g,1.57mmol)加入至圆底烧瓶中；并用氮气反复置换3次后用注射器加入正庚烷(130mL)。得到的体系在50度的条件下反应10分钟，随后通过注射器加入2-氯-6-甲基吡啶(10g,78.4mmol)；得到的体系在相同的温度下继续反应6小时薄层层析检测原料反应完毕。反应体系过滤，滤液浓缩后得到的粗品用硅胶柱层析纯化(石油醚/乙酸乙酯＝20：1)得到白色固体化合物INT-1(19g，收率：95％)。 1H NMR(CDCl 3,500MHz):δ7.49(s,1H),7.42(s,1H)；2.55(s,3H),1.35(s,12H).
化合物INT-3b的制备：
Figure PCTCN2019074927-appb-000020
将化合物INT-3a(1.0g,7.1mmol)溶于二氯甲烷(20mL)中，在氮气保护和冰浴条件下加入二乙胺基三氟化硫(2.5g,15.5mmol)。反应液逐渐升温至室温，并在室温搅拌2小时，薄层层析检测原料反应完全。反应液倒入冰水中淬灭，并用饱和碳酸氢钠溶液调至弱碱性(pH＝8)。水相用二氯甲烷反萃(20mL x 2)，合并有机层依次用水，饱和食盐水洗涤，无水硫酸钠干燥，滤液浓缩后得到黄色油状化合物INT-3b(750mg,收率:65％)。
参照化合物INT-1的制备方法，可制备得到化合物INT-2、INT-3、INT-4、INT-5，具体谱图信息如下表：
Figure PCTCN2019074927-appb-000021
化合物INT-6的制备：
Figure PCTCN2019074927-appb-000022
将硫代氨基脲(33g,0.36mol)和碘甲烷(24.8mL,0.40mol)加入甲醇中(200mL)，反应液在室温下搅拌过夜。反应液浓缩得到淡黄色固体化合物INT-6(84g,收率:99％)。
化合物INT-7的制备：
Figure PCTCN2019074927-appb-000023
将化合物INT-7a(2.0g,13mmol)，二甲羟胺盐酸盐(3.8g,38.9mmol)，1-羟基苯并三唑(3.5g,26mmol)，N,N-二异丙基乙胺(5.0g,38.9mmol)和1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(5.0g,26mmol)依次加入至二氯甲烷(40mL)中。反应液在室温下搅拌1小时，薄层层析检测原料反应完全。反应结束后，反应液依次用水，10％碳酸钠溶液和饱和食盐水洗(各50mL)。有机层用无水硫酸钠干燥，滤液浓缩后得到黄色油状化合物INT-7b(2.3g,收率:90％)。
在0度条件下，将甲基溴化镁溶液(3mol/L 2-甲基四氢呋喃，5.8mL)慢慢加入至含有化合物INT-7b(2.3g,11.7mmol)的四氢呋喃溶液中(40mL)。反应体系搅拌逐渐升至室温，并在室温反应1小时，薄层层析检测原料反应完全。反应结束后，反应液冷却至0度后缓慢加入氯化铵溶液(1M,50mL)，水相用乙醚萃取(100mL x 2)。将有机层合并，用饱和食盐水洗涤，无水硫酸钠干燥，滤液浓缩后得到黄色油状化合物INT-7(1.62g,收率:91％)。LC-MS纯度:95％
参照化合物INT-7的制备方法，可制备得到化合物INT-8,INT-9,INT-10, INT-11,INT-13，结构及谱图信息见下表：
Figure PCTCN2019074927-appb-000024
化合物INT-12的制备：
Figure PCTCN2019074927-appb-000025
将草酰氯(496mg,3.9mmol)和1滴N,N’-二甲基甲酰胺依次加入含有化合物INT-12a(150mg,0.98mmol)的二氯甲烷(2mL)溶液中。反应液在室温条件下搅拌1小时，薄层层析检测原料反应完全。反应液浓缩旋干得到淡黄色固体化合物INT-12(168mg,收率:99％)
化合物INT-13g的制备：
Figure PCTCN2019074927-appb-000026
化合物INT-13a(4.0g,21mmol)和二氯亚砜(3.95mL,54mmol)的甲醇混合溶液在室温条件下搅拌过夜，薄层层析检测原料反应完全。反应液浓缩旋干，粗品用乙酸乙酯(150mL)溶解；有机层用水和饱和食盐水洗涤(各150mL)，无水硫酸钠干燥，滤液浓缩后得到淡黄色固体化合物INT-13b(4.0g,收率:93％)。
在氮气条件下，将化合物INT-13b(4.0g,19.5mmol),化合物INT-13c(1.43g,1.95mmol),化合物INT-13d(3.15g,23.4mmol)和碳酸钾(5.4g,39mmol)加入到二氧六环(80mL)和水(25mL)的混合溶液中。反应体系用氮气置换3次后，在80度条件下搅拌过夜，LC-MS检测原料反应完全。反应液用乙酸乙酯(200mL)稀释，并用水和饱和食盐水(各300mL)洗涤。有机层用无水硫酸钠干燥，滤液浓缩后得到粗品，用硅胶柱层析纯化得到黄色油状物INT-13e(2.23g，收率：75％)。 1H NMR(CDCl 3,500MHz):δ7.14(d,J＝3.5Hz,1H),6.53(dd,J＝17.5,11.5Hz,1H),6.37(d,J＝3.5Hz,1H),5.92(d,J＝17.5Hz,1H),5.37(d,J＝11.5Hz,1H),3.88(s,3H)。
在氢气(15psi)和室温条件下，化合物INT-13e(2.23g,14.7mmol)和10％钯炭(1.5g,1.5mmol)的甲醇溶液搅拌4小时。粗品核磁检测原料反应完全。滤液浓缩后得到淡黄色油状物INT-13f(2.0g，收率：88％)。 1H NMR(CDCl 3,500MHz):δ7.08(d,J＝3.5Hz,1H),6.11(d,J＝3.5Hz,1H),3.86(s,3H),2.71(q,J＝7.5Hz,2H),1.25(t,J＝7.5Hz,3H)。
在80度条件下，化合物INT-13f(2.4g,15.6mmol)和氢氧化钠(1.25g,31.2mmol)在乙醇(10mL)和水(10mL)的混合溶液搅拌2小时，薄层层析检测原料反应完全。反应液用盐酸溶液(1mol/L)调节pH至4-5，用乙酸乙酯(100mL)稀释。有机层用水，饱和食盐水洗涤(各100mL)，无水硫酸钠干燥，滤液浓缩后得到淡黄色固体化合物INT-13g(2.13g,收率:98％)。
实施例1：化合物1的制备
Figure PCTCN2019074927-appb-000027
将化合物1a(8.0g,57.9mmol)溶于二氧六环(180mL)和水(5mL)的混合溶液中，随即加入二氧化硒(7.07g,63.7mmol)；反应温度升到55度搅拌直至二氧化硒完全溶解。随后反应体系在回流温度下搅拌过夜，薄层层析检测原料反应完毕。反应液过滤，滤液浓缩后得到油状粗品，加入水中(120mL)，用乙酸乙酯萃取(100mLx 3)。将有机层合并，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩后得到淡黄色油状化合物1b(6.5g,收率:66％)。
将化合物1b(6.5g,38mmol)溶于乙醇中(100mL)，依次加入碳酸氢钠(8.0g,96mmol)和化合物INT-6(9.8g,42mmol)。反应液在回流温度下搅拌2小时，薄层层析检测原料反应完毕。反应液浓缩，得到粗品加入水中(100mL)，用乙酸乙酯萃取(100mL x 3)。将有机层合并，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩后得到粗品用柱层析纯化得到淡黄色固体化合物1c(8.2g,收率:97％)。MS:222.1[M+H] +
将化合物1c(2g,9.0mmol)溶于二氯甲烷中(120mL)，随后在冰浴条件下加入间氯过氧苯甲酸(4.6g,22.6mmol)。反应体系在搅拌条件下逐渐升温至室温后，再搅拌5小时，LC-MS检测原料反应完毕。反应液用饱和碳酸钠溶液洗涤(100mL x 2)，水相用二氯甲烷反萃(100mL x 2)。将有机层合并，用饱 和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩后得到淡黄色固体化合物1d(2.0g,收率:87％)。MS:254.1[M+H] +
将化合物1d(2.0g,8.0mmol)加入至含有氨水(25-28％w/w,10mL)和二氧六环(1mL)的封管中，搅拌加热至50度，反应2小时。LC-MS检测原料反应完毕。反应液倒入水中(20mL)，剧烈搅拌，过滤。滤饼依次用水，石油醚/乙酸乙酯(v/v＝5/1)洗涤，真空下干燥得到淡黄色固体化合物1e(1.32g,收率:87％)。MS:191.0[M+H] +
将化合物1e(950mg,5mmol)加入N’N’-二甲基甲酰胺(5mL)中，随后在室温搅拌下慢慢加入N-溴代丁二酰亚胺(1.33g,7.5mmol)。反应液在相同温度下继续搅拌2小时，薄层层析检测原料反应完毕。反应液加入饱和食盐水中(50mL)，水相用乙酸乙酯萃取(50mL x 3)。将有机层合并，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩后得到粗品用柱层析纯化得到淡黄色固体化合物1f(850mg,收率:64％)。 1H NMR(DMSO-d 6,500MHz)δ7.86-7.79(m,2H),7.53(s,2H),7.41-7.33(m,2H)；MS:268.8[M+H] +
在氮气保护下，将化合物1f(200mg,0.74mmol)，化合物INT-1(225mg,0.89mmol)，化合物1g(54mg,0.074mmol)和碳酸钾(306mg,2.22mmol)加入至二氧六环(3mL)和水(1mL)的混合溶液中。反应体系再用氮气反复置换3次后，在90度的条件下搅拌6小时，直至LC-MS检测原料反应完毕。反应液倒入水中(20mL)，水相用乙酸乙酯萃取(30mL x 2)。将有机层合并，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩后得到粗品用柱层析(石油醚/乙酸乙酯＝1：2)纯化得到淡黄色固体化合物1h(160mg,收率:68％)。 1H NMR(DMSO-d 6,500MHz):δ7.68(s,2H),7.51-7.43(m,2H),7.28-7.24(m,3H),7.14(s,1H),2.39(s,3H)；MS:315.9[M+H] +
在-10℃条件下，将化合物1h(80mg,0.25mmol)溶于二氯甲烷(3mL)和吡啶(0.5mL)的混合溶液中，随后加入化合物1i(208mg,2mmol)。反应液在 相同温度下反应15min，LC-MS检测原料反应完毕。反应液倒入水中(10mL)，水相用二氯甲烷萃取(10mL x 2)。将有机层合并，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩后得到粗品用制备薄层层析纯化得到淡黄色固体化合物1(40mg,收率:42％)。 1HNMR(500M Hz,DMSO-d6):δ11.70(s,1H),7.63-7.54(m,2H),7.39(s,1H),7.33(s,1H),7.30-7.25(m,2H),2.48(s,3H),2.20-2.15(m,1H),0.89(d,J＝6.0Hz,4H)；MS:383.9[M+H] +
参照化合物1的制备方法，可制备得到化合物2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,49,50,56,57,63,64。具体谱图信息如下表：
Figure PCTCN2019074927-appb-000028
Figure PCTCN2019074927-appb-000029
Figure PCTCN2019074927-appb-000030
Figure PCTCN2019074927-appb-000031
Figure PCTCN2019074927-appb-000032
Figure PCTCN2019074927-appb-000033
Figure PCTCN2019074927-appb-000034
Figure PCTCN2019074927-appb-000035
Figure PCTCN2019074927-appb-000036
参照化合物1h的制备方法，可制备得到化合物17h,43,44,58,64,具体谱图信息如下表：
Figure PCTCN2019074927-appb-000037
Figure PCTCN2019074927-appb-000038
实施例2：化合物45的制备
Figure PCTCN2019074927-appb-000039
将氯磺酸异氰酸酯(15.5mg,0.11mmol)在0度条件下加入到含有化合物1h的二氯甲烷(3mL)溶液中。反应液在0度条件下搅拌2小时，LC-MS检测原料反应完毕。反应液用二氯甲烷(30mL)稀释，并用饱和食盐水洗涤(30mL x2)。有机层用无水硫酸钠干燥，滤液浓缩后得到粗品，用制备高效液相色谱(5-95％乙腈，0.1％甲酸)分离得到淡黄色固体化合物45(8mg,收率:22％)。 1HNMR(500MHz,MeOH-d 4):δ7.65-7.58(m,2H),7.34(s,1H),7.31(s,1H),7.21-7.15(m,2H),2.46(s,3H)；MS 359.3[M+H] +
实施例3：化合物46的制备
Figure PCTCN2019074927-appb-000040
亚硝酸异戊酯(148mg,1.27mmol)和溴化亚酮(273mg,1.9mmol)加到含有化合物1h(200mg,0.63mmol)的乙腈溶液中(5mL)。反应液在回流条件下搅拌1小时，LC-MS检测原料反应完毕。反应液用乙酸乙酯稀释(30mL)，用水和饱和食盐水洗涤(各30mL)。有机层用无水硫酸钠干燥，滤液浓缩后得到粗品用柱层析纯化得到黄色固体化合物46a(30mg,收率:13％)。
在溶于化合物46a(30mg,0.079mmol)的乙腈溶液(3mL)中加入氰氨(6.6mg,0.16mmol)和碳酸钾(33mg,0.24mmol)。反应液在100度的封管中搅拌2小时，LC-MS检测原料反应完毕。反应液用四氢呋喃(30mL)稀释，用水和饱和食盐水洗涤(各30mL)。有机层用无水硫酸钠干燥，滤液浓缩后得到粗品，用制备高效液相色谱(5-95％乙腈，0.1％甲酸)纯化得到黄色固体化合物46(10mg,收率:37％)。 1HNMR(500MHz,DMSO-d 6):δ7.50-7.43(m,2H),7.30-7.20(m,3H),7.16-7.11(m,1H),7.10(s,1H),2.37(s,3H)；MS 341.4[M+H] +
实施例4：化合物47的制备
Figure PCTCN2019074927-appb-000041
钠氢(60％在煤油中，10.0mg,0.25mmol)加入至溶有化合物17h(50mg,0.17mmol)的N,N’-二甲基甲酰胺(2mL)的溶液中，在室温下搅拌10分钟后，缓慢滴加化合物47a(28mg,0.20mmol)。所得反应液在室温下搅拌过夜，LC-MS 检测原料反应完毕。反应液用二氯甲烷(20mL)稀释，用水和饱和食盐水洗涤(各20mL)。有机层用无水硫酸钠干燥，滤液浓缩后得到粗品，用制备高效液相色谱(5-95％乙腈，0.1％甲酸)纯化得到黄色固体化合物47(8mg,收率:12％)。1HNMR(500MHz,DMSO-d6):δ7.58-7.52(m,3H),7.43(t,J＝7.5Hz,2H),7.33(s,1H),7.30(s,1H),3.27-3.20(m,1H),2.44(s,3H),1.19(brs,2H),1.11-1.08(m,2H)；MS 402.5[M+H] +
实施例5：化合物48的制备
Figure PCTCN2019074927-appb-000042
铁粉(41mg,0.73mmol)加入到溶有化合物19(50mg,0.12mmol)的醋酸(0.2mL)和甲醇(0.8mL)的混合溶液中，反应液在50度条件下搅拌2小时，LC-MS检测原料反应完毕。反应液用乙酸乙酯(20mL)稀释，随后用硅藻土过滤，滤液浓缩后得到粗品，用高效液相色谱(5-95％乙腈，0.1％甲酸)纯化得到淡黄色固体化合物48(25mg,收率:54％)。 1HNMR(500MHz,DMSO-d 6):δ11.59(s,1H),7.41(s,1H),7.27(s,1H),7.00(t,J＝7.5Hz,1H),6.80(s,1H),6.66(d,J＝7.5Hz,1H),6.46(d,J＝7.5Hz,1H),5.34(s,2H),2.43(s,3H),2.16(brs,1H),0.88(brs,4H)；MS 381.4[M+H] +
实施例6：化合物51的制备
Figure PCTCN2019074927-appb-000043
在氮气保护下，三溴化硼(76mg,0.30mmol)在0度和搅拌条件下慢慢加入到溶有化合物26(50mg,0.15mmol)的二氯甲烷(3mL)溶液中。反应液在0度条件下继续搅拌1小时，LC-MS检测原料消失。反应液用水(10mL)淬灭，水相用二氯甲烷萃取(10mL x 2)。有机层浓缩后得到粗品，用高效液相色谱(5-95％乙腈，0.1％甲酸)纯化得到白色固体化合物51(6mg,收率:13％)。 1HNMR(500MHz,MeOH-d 4):δ7.38(s,1H),7.34(s,1H),7.23(t,J＝8.0Hz,1H),7.01(s,1H),6.98(d,J＝8.0Hz,1H),6.93(d,J＝8.0Hz,1H),2.46(s,3H),2.16-2.06(m,1H),1.08(d,J＝4.0Hz,2H),0.99(d,J＝4.0Hz,2H)；MS 382.4[M+H] +
实施例7：化合物52的制备
Figure PCTCN2019074927-appb-000044
亚硝酸异戊酯(62mg,0.50mmol)和溴化亚酮(96mg,0.67mmol)加到含有化合物17h(100mg,0.34mmol)的乙腈溶液中(5mL)。反应液在回流条件下搅拌1.5小时，LC-MS检测原料反应完毕。反应液用乙酸乙酯稀释(30mL)，用水和饱和食盐水洗涤(各30mL)。有机层用无水硫酸钠干燥，滤液浓缩后得到粗品用柱层析纯化(石油醚/乙酸乙酯＝3：1)得到黄色固体化合物52a(40mg,收率:33％)。
在100度条件下，溶有化合物52a(40mg,0.11mmol)，化合物52b(19.5mg,0.22mmol)和碳酸钾(46mg,0.33mmol)的1,4-二氧六环(3mL)的封管体系搅拌2小时，LC-MS检测原料反应完毕。反应液降至室温后，浓缩后得到粗品，用高效液相色谱(5-95％乙腈，0.1％甲酸)纯化得到黄色固体化合物52(10mg,收率:25％)。 1HNMR(500MHz,MeOH-d 4):δ7.55-7.47(m,3H),7.43-7.37(m,2H),7.22(s,1H),7.21(s,1H),3.95(brs,2H),3.41(brs,2H),2.92(s,6H),2.41(s,3H)；MS 369.4[M+H] +
参照化合物52的制备方法，化合物53,54,55可制备得到，具体谱图信息如下表：
Figure PCTCN2019074927-appb-000045
实施例8：化合物59,60的制备
Figure PCTCN2019074927-appb-000046
从化合物INT-11开始，参照化合物1c的合成，得到黄色固体化合物59a。MS272.3[M+H] +
将化合物1c(2.7g,9.9mmol)和亚硝酸钠(2.05g,29.7mmol)加入至醋酸(20mL)中，混合液在封管下70度搅拌3小时,LC-MS检测原料反应完毕。反 应液浓缩，所得粗品用乙酸乙酯(100mL)稀释，并用水和饱和食盐水洗涤(各100mL)。有机层用无水硫酸钠干燥，滤液浓缩后得到粗品用柱层析纯化得到黄色油状化合物59b(1.8g,收率:76％)。
从化合物59b开始，参照化合物1h的合成，得到黄色固体化合物59。1HNMR(500MHz,DMSO-d6):δ7.91(s,2H),7.71(s,1H),7.52(s,1H),7.50(s,1H),7.03(s,1H),2.48(s,3H)；MS333.3[M+H] +
从化合物59开始，参照化合物1的合成，得到黄色固体化合物60。 1HNMR(500MHz,DMSO-d 6):δ11.82(s,1H),7.74(d,J＝4.0Hz,1H),7.62(s,1H),7.58(s,1H),7.24(d,J＝4.0Hz,1H),2.52(s,3H),2.22-2.14(m,1H),0.95-0.88(m,4H)；MS401.3[M+H] +
实施例9：化合物61的制备
Figure PCTCN2019074927-appb-000047
化合物60(48mg,0.12mmol)加入到浓盐酸(2mL)和1,4-二氧六环(0.5mL)的混合溶液中，反应体系在40度条件下搅拌1小时，LC-MS检测原料反应完全。反应液用水(10mL)稀释，并用二氯甲烷萃取(20mL x 3)。有机层用水，饱和碳酸氢钠，饱和食盐水洗涤，无水硫酸钠干燥，滤液浓缩后得到粗品用制备薄层层析(石油醚/乙酸乙酯＝4：1)得到黄色固体化合物61(32mg,收率:69％)。 1HNMR(500MHz,DMSO-d 6):δ11.62(s,1H),7.58(s,1H),7.54(s,1H),6.98(d,J＝4.0Hz,1H),6.37(d,J＝4.0Hz,1H),2.52(s,3H),2.20-2.13(m,1H),0.89(d,J＝5.0Hz,4H)；MS390.3[M+H] +
实施例10：化合物62的制备
Figure PCTCN2019074927-appb-000048
化合物61(20mg,0.05mmol)和碳酸钾(200mg,1.45mmol)加入到甲醇(3mL)溶液中，反应体系在室温条件下搅拌1小时，LC-MS检测原料反应完全。反应液用水(10mL)稀释，并用乙酸乙酯萃取(10mL x 3)。有机层用水，0.1N盐酸，饱和食盐水洗涤，无水硫酸钠干燥，滤液浓缩后得到粗品用制备薄层层析得到黄色固体化合物62(6mg,收率:38％)。 1HNMR(500MHz,MeOH-d 4):δ7.42(s,1H),7.39(s,1H),7.15(s,1H),6.50(s,1H),2.55(s,3H)；MS322.3[M+H] +
测试实施例
A2A/A2B受体结合实验亲和力测试
A2A受体结合实验亲和力测试步骤参照文献：British Journal of Pharmacology(1997)121,353-360；其中A2A受体(由HEK细胞表达)来源于Perkin Elmer(产品编号：RBHA2AM400UA)；竞争同位素标记物为：[ 3H]SCH58261。具体测试由上海睿智化学研究有限公司生物部完成。
A2B受体结合实验亲和力测试步骤参照文献：ACS Medicinal Chemistry Letters(2011)2,213–218；其中A2B受体(由HEK细胞表达)由上海药明康德新药研发有限公司生物部构建并作为CRO服务的一部分商业供应；竞争同位素标记物为：[ 3H]DPCPX。具体测试由上海药明康德新药研发有限公司生物部完成。
A2A/A2B受体拮抗功能实验测试:
A2A细胞系来源于PerkinElmer(产品编号：ES-011-C)；A2B细胞系来源于PerkinElmer(产品编号：ES-013-C)。实验步骤参照ACS Medicinal Chemistry Letters(2011)2,213–218；具体测试由北京康龙化成新药技术有限公司完成，步骤如下：
室温条件下，依次将10nL化合物的DMSO贮备液(10mM)、10μL A2A或A2B细胞悬液(30000个细胞/mL)转移至384孔板的测定孔中，在室温条件下孵育20分钟。将EC 80激活浓度下对应的5’-N-ethylcarboxamidoadenosine的量转移至各个测试孔中，在37℃，5％CO 2，95％湿度的条件下进一步孵育30分钟后，依次将Eu-cAMP示踪剂工作溶液和Ulight-anti-cAMP工作溶液以5uL/孔添加至细胞培养板，并用Envision读取细胞板荧光值(激发光波长：320nm，发射光波长：665nm和615nm)。按照下述公式得到每个孔中相对应的抑制率，使用非线性回归模型绘制S型剂量-抑制率曲线并计算得到IC 50值。
Figure PCTCN2019074927-appb-000049
实施例中所列化合物对于A2A/A2B受体结合亲和力以及拮抗功能活性结果：
Figure PCTCN2019074927-appb-000050
Figure PCTCN2019074927-appb-000051
Figure PCTCN2019074927-appb-000052

Claims (20)

  1. 一种具有式I结构的化合物、其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物、或其代谢产物，
    Figure PCTCN2019074927-appb-100001
    其中，
    Cy 1选自5-12元芳基、5-12元杂芳基、C 3-C 9环烷基、C 3-C 9杂环烷基；
    Cy 2选自5-12元芳基、5-12元杂芳基；
    其中，Cy 1和Cy 2分别独立地可以被选自0、1、2或3个R a的基团所取代，其中R a选自氢、C 1-C 8烷基、C 2-C 8烯基、C 2-C 8炔基、C 3-C 9环烷基、C 1-C 8卤代烷基、卤素、氰基、磺酸基、硝基、OR 6、SR 6、NR 6R 7、C(＝O)R 6、C(＝O)OR 6、C(＝O)NR 6R 7、NR 6C(＝O)R 7、或S(O) 2R 6；各个R 6和R 7各自独立地为氢、C 1-C 8烷基、5-12元芳基、5-12元杂芳基，或者R 6和R 7与其相邻的氮原子共同环合成为3-6元环，该环中还可以任选地含有1-2个选自N、O、S的杂原子；
    R 1和R 2分别独立地选自氢、C 1-C 8烷基、C 2-C 8烯基、C 2-C 8炔基、C 1-C 8烷氧基、-(CH 2) n5-12元芳基、C 1-C 8卤代烷基、C 3-C 9环烷基、-C(＝O)R 3、-SOR 3、-SO 2R 3、-C(＝O)OR 3、氰基、-(CH 2) nNR 4R 5、-C(＝O)(CH 2) nNR 4R 5，n为0、1、2、3、4或5；或者，R 1和R 2与其相邻的N原子共同环合成为3-9元饱和或不饱和环，该环中还可以任选地含有1-2个选自N、O、S的杂原子；
    其中，R 3选自氢、羟基、氨基、任选被取代的C 1-C 8烷基、任选被取代的C 1-C 8烷氧基、任选被取代的C 1-C 8烷基羰基氧基、任选被取代的C 3-C 12环烷基、任选被取代的二(C 1-C 8烷基)氨基、任选被取代的C 1-C 8烷基氨基、任选被取代的C 1-C 8烷基氨基甲酰基、任选被取代的5-12元芳基、任选被取代的5-12元杂芳基；其中所述任选被取代的取代基选自卤素、氰基、磺酸基、C 1-C 8烷基、5-12 元芳基、5-12元杂芳基、OR 6、SR 6、NR 6R 7、C(O)R 6、C(O)OR 6、C(O)NR 6R 7、NC(O)NR 6R 7、或S(O) 2R 6，或者当上述芳基、杂芳基、环烷基的取代基的个数为2或更多时，相邻的两个取代基可以形成5-8元环，该环中可以含有2-4个杂原子；
    其中，R 4和R 5选自氢、任选被取代的C 1-C 8烷基、任选被取代的C 3-C 12环烷基、任选被取代的5-12元芳基、任选被取代的5-12元杂芳基，其中所述任选被取代的取代基选自卤素、氰基、磺酸基、OR 6、SR 6、NR 6R 7、C(O)R 6、C(O)OR 6、C(O)NR 6R 7、NC(O)NR 6R 7、或S(O) 2R 6所取代；或者，R 4和R 5与其相连的氮原子共同形成任选地含有1-2个额外的选自N、O或S的杂原子的3-至9-元环状结构；该环状结构可以任选地被1、2或3个R 8所取代，取代的位点在C或N原子上，前提条件是所形成的结构是合理的稳定结构；R 8各自独立地选自氢、卤素、C 1-C 8烷基、C 3-C 9环烷基、C(O)R 9、S(O) 2R 9、3-9元杂环烷基、5-12元芳基、5-12元杂芳基、或＝O；并且R 8还可以任意的被选自卤素和-O(CH 2) pO(CH 2) qOR 10的基团所取代；其中，R 9、R 10分别独立地为氢、C 1-C 8烷基或者C 3-C 9环烷基；附加条件为，当R 1和R 2同时为氢时，Cy 1为5元杂芳基，其可以任意地被选自0、1、2或3个R a的基团所取代。
  2. 如权利要求1所述的化合物、其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物、或其代谢产物，其中所述化合物具有以下式II结构：
    Figure PCTCN2019074927-appb-100002
    其中，W 1和W 2分别独立地选自CR b或N，R b具有R a的定义；R a、Cy 1和R 2具有如权利要求1所定义，m为0、1、2或3。
  3. 如权利要求1或2所述的化合物、其药学上可接受的盐、前药、同位素衍生 物、异构体、溶剂化物、或其代谢产物，其中所述化合物具有以下式III或式IV结构：
    Figure PCTCN2019074927-appb-100003
    其中，R a、Cy 1和R 2具有如权利要求1或权利要求2所定义，m为0、1、2或3。
  4. 如权利要求1-3任一项所述的化合物、其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物、或其代谢产物，其中：R 2选自-C(＝O)R 3、-SOR 3、-SO 2R 3和-C(＝O)(CH 2) nNR 4R 5，n选自1、2或3；R 3、R 4、R 5如权利要求1-3任一项所定义。
  5. 如权利要求1-4任一项所述的化合物、其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物、或其代谢产物，其中：R 2选自-C(＝O)R 3，其中，R 3如权利要求1-4任一项所定义。
  6. 如权利要求1-5任一项所述的化合物、其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物、或其代谢产物，其中：R 3选自氢、羟基、氨基、任选被取代的C 1-C 8烷基、任选被取代的C 3-C 12环烷基或任选被取代的5-12元芳基，其中所述的任选被取代的取代基可以选自C 1-C 8烷基、C 1-C 8烷氧基、卤素、羟基、氨基、氰基、磺酸基、5-12元芳基或和5-12元杂芳基。
  7. 如权利要求1-6任一项所述的化合物、其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物、或其代谢产物，其中：R 3选自任选被取代的C 1-C 8烷基、任选被取代的C 3-C 12环烷基或任选被取代的5-12元芳基，其中所述的任选被取代的取代基可以选自C 1-C 8烷基、C 1-C 8烷氧基、卤素、羟基、氨基、氰基、磺酸基、5-12元芳基、或5-12元杂芳基。
  8. 如权利要求1-4任一项所述的化合物、其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物、或其代谢产物，其中：R 2选自-C(＝O)(CH 2) nNR 4R 5，n选自1、2或3；R 4、R 5如权利要求1-4任一项所定义。
  9. 如权利要求1-4任一项或权利要求8所述的化合物、其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物、或其代谢产物，其中：R 2选自-C(＝O)(CH 2) nNR 4R 5；n为1、2或3；R 4和R 5选自氢、任选被取代的C 1-C 8烷基、任选被取代的C 3-C 12环烷基、任选被取代的5-12元芳基、任选被取代的5-12元杂芳基，其中所述任选被取代的取代基选自卤素、氰基、磺酸基、OR 6、SR 6、NR 6R 7、C(O)R 6、C(O)OR 6、C(O)NR 6R 7、NC(O)NR 6R 7、或S(O) 2R 6所取代；或者，R 4和R 5与其相连的氮原子共同形成任选地含有1-2个额外的选自N、O或S的杂原子的3-至9-元环状结构；该环状结构可以任选地被1、2或3个R 8所取代，取代的位点在C或N原子上，前提条件是所形成的结构是合理的稳定结构；R 8各自独立地选自氢、卤素、C 1-C 8烷基、C 3-C 9环烷基、C(O)R 9、S(O) 2R 9、3-9元杂环烷基、5-12元芳基、5-12元杂芳基、或＝O；并且R 8还可以任意的被选自卤素、-O(CH 2) pO(CH 2) qOR 10的基团所取代；其中，R 9、R 10分别独立地为氢、C 1-C 8烷基或者C 3-C 9环烷基。
  10. 如权利要求1-4或权利要求8-9任一项所述的化合物、其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物、或其代谢产物，其中：R 2为-C(＝O)(CH 2) nNR 4R 5；n为1、2或3；R 4和R 5与其相连的氮原子共同形成任选地含有1-2个额外的选自N、O或S的杂原子的3-至9-元环状结构；该环状结构可以任选地被1、2或3个R 8所取代，取代的位点在C或N原子上，前提条件是所形成的结构是合理的稳定结构；R 8各自独立地选自氢、卤素、C 1-C 8烷基、C 3-C 9环烷基、C(O)R 9、S(O) 2R 9、3-9元杂环烷基、5-12元芳基、5-12元杂芳基、或＝O；并且R 8还可以任意的被选自卤素和-O(CH 2) pO(CH 2) qOR 10的基团所取代，其中，p和q分别独立地为0、1、2或3；其中，R 9、R 10分别独立地为氢、C 1-C 8烷基或者C 3-C 9环烷基。
  11. 如权利要求1-4或权利要求8-10任一项所述的化合物、其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物、或其代谢产物，其中，R 2为-C(＝O)(CH 2) nNR 4R 5；n为1、2或3，R 4和R 5与其相连的氮原子共同形成
    Figure PCTCN2019074927-appb-100004
    其中
    Figure PCTCN2019074927-appb-100005
    表示与(CH 2) n相连接的键，R 11选自氢、C 1-C 8烷基、C 3-C 9环烷基、C(O)R 9、S(O) 2R 9、3-9元杂环烷基、5-12元芳基、5-12元杂芳基； 并且R 8还可以任意的被选自卤素和-O(CH 2) pO(CH 2) qOR 10的基团所取代，其中，p和q分别独立地为0、1、2或3；R 9、R 10分别独立地为氢、C 1-C 8烷基或者C 3-C 9环烷基。
  12. 如权利要求1-11任一项所述的化合物、其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物、或其代谢产物，其中所述的Cy 1独立地选自苯基、吡啶基、吡嗪基、环丙基、环戊基、环己基、呋喃基、噻唑基、哌啶基、哌嗪基、噁唑基、咪唑基、噻吩基；优选为苯基、呋喃基、噁唑基或吡啶基；Cy 2独立地选自苯基、吡啶基、吡嗪基、呋喃基、噻唑基、哌啶基、哌嗪基、噁唑基、咪唑基、噻吩基；优选为苯基或吡啶基；其中所述的Cy 1和Cy 2可以任意地被0、1、2或3个选自C 1-C 8烷基、C 2-C 8烯基、C 2-C 8炔基、C 1-C 8卤代烷基、C 1-C 8烷氧基、C 1-C 8烷基硫基、卤素、氰基、磺酸基、硝基的取代基所取代。
  13. 如权利要求1所述的化合物、其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物、或其代谢产物，其中，当R 1和R 2同时为氢时，Cy 1选自五元杂芳基，例如：呋喃基、噻唑基、噁唑基、咪唑基、噻吩基；Cy 2选自苯基、吡啶基、吡嗪基、哌啶基、哌嗪基，优选为苯基或吡啶基；其中，所述的Cy 1和Cy 2可以任意地被0、1、2或3个选自C 1-C 8烷基、C 2-C 8烯基、C 2-C 8炔基、C 1-C 8卤代烷基、C 1-C 8烷氧基、C 1-C 8烷基硫基、卤素、氰基、磺酸基、硝基的取代基所取代。
  14. 如权利要求1所述的化合物，其选自：
    Figure PCTCN2019074927-appb-100006
    Figure PCTCN2019074927-appb-100007
    Figure PCTCN2019074927-appb-100008
    Figure PCTCN2019074927-appb-100009
    Figure PCTCN2019074927-appb-100010
    Figure PCTCN2019074927-appb-100011
    Figure PCTCN2019074927-appb-100012
    Figure PCTCN2019074927-appb-100013
    Figure PCTCN2019074927-appb-100014
    Figure PCTCN2019074927-appb-100015
    Figure PCTCN2019074927-appb-100016
    Figure PCTCN2019074927-appb-100017
    Figure PCTCN2019074927-appb-100018
  15. 一种药物组合物或者药物制剂，其包含权利要求1至14任意一项所述的化合物、其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物、或其代谢产物，以及药学上可接受的载体。
  16. 如权利要求15所述的药物组合物或者药物制剂，其进一步包含另外的治疗剂和/或检查点抑制剂，所述另外的治疗剂优选地选自苯丁酸氮芥、美法仑、环磷酰胺、异环磷酰胺、白消安、卡莫司汀、洛莫司汀、链脲佐菌素、顺铂、卡铂、奥沙利铂、达卡巴嗪、替莫唑胺、丙卡巴肼、甲氨蝶呤、氟尿嘧啶、阿糖胞苷、吉西他滨、巯基嘌呤、氟达拉滨、长春碱、长春新碱、长春瑞滨、紫杉醇、多西紫杉醇、拓扑替康、伊立替康、依托泊苷、曲贝替定、更生霉素、多柔比星、表柔比星、道诺霉素、米托蒽醌、博来霉素、丝裂霉素C、伊沙匹隆、他莫昔芬、氟他胺、戈那瑞林类似物、甲地孕酮、强的松、地塞米松、甲泼尼龙、沙利度胺、干扰素α、亚叶酸钙、西罗莫司、西罗莫司脂化物、依维莫司、阿法替尼、alisertib、amuvatinib、阿帕替尼、阿西替尼、硼替佐米、波舒替尼、布立尼布、卡博替尼、西地尼布、crenolanib、克卓替尼、达拉菲尼、达可替尼、达努塞替、达沙替尼、多维替尼、厄洛替尼、foretinib、ganetespib、吉非替尼、依鲁替尼、埃克替尼、伊马替尼、iniparib、拉帕替尼、lenvatinib、linifanib、linsitinib、马赛替尼、momelotinib、莫替沙尼、来那替尼、尼罗替尼、niraparib、oprozomib、olaparib、帕唑帕尼、pictilisib、普纳替尼、quizartinib、瑞格菲尼、rigosertib、rucaparib、鲁索利替尼、塞卡替尼、saridegib、索拉非尼、舒尼替尼、替拉替尼、tivantinib、替沃扎尼、托法替尼、曲美替尼、凡德他尼、维利帕尼、威罗菲尼、维莫德吉、volasertib、阿仑单抗、贝伐单抗、贝伦妥单抗维多汀、卡妥索单抗、西妥昔单抗、 地诺单抗、吉妥珠单抗、伊匹单抗、尼妥珠单抗、奥法木单抗、帕尼单抗、利妥昔单抗、托西莫单抗、曲妥珠单抗；所述的检查点抑制剂优选地选自抗PD-1抗体、抗PD-L1抗体、LAG3抗体、TIM-3抗体及抗CTLA-4抗体。
  17. 如权利要求1-14任一项所述的化合物、其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物、或其代谢产物或者如权利要求15-16任一项所述的药物组合物或药物制剂在制备用于通过对A2A受体和/或A2B受体的抑制来预防或治疗肿瘤、癌症、病毒感染、器官移植排斥、神经退行性疾病、注意力相关疾病或自身免疫性疾病的药物中的应用。
  18. 如权利要求17所述的用途，其中，所述肿瘤或癌症选自皮肤癌、膀胱癌、卵巢癌、乳腺癌、胃癌、胰腺癌、前列腺癌、结肠癌、肺癌、骨癌、脑癌、神经细胞瘤、直肠癌、结肠癌、家族性腺瘤性息肉性癌、遗传性非息肉性结直肠癌、食管癌、唇癌、喉癌、下咽癌、舌癌、唾液腺癌、胃癌、腺癌、甲状腺髓样癌、乳头状甲状腺癌、肾癌、肾实质癌、卵巢癌、宫颈癌、子宫体癌、子宫内膜癌、绒毛膜癌、胰腺癌、前列腺癌、睾丸癌、泌尿癌、黑素瘤、脑肿瘤诸如成胶质细胞瘤、星形细胞瘤、脑膜瘤、成神经管细胞瘤和外周神经外胚层肿瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、伯基特淋巴瘤、急性淋巴性白血病(ALL)、慢性淋巴性白血病(CLL)、急性骨髓性白血病(AML)、慢性粒细胞白血病(CML)、成人T细胞白血病淋巴瘤、弥漫性大B细胞淋巴瘤(DLBCL)、肝细胞癌、胆囊癌、支气管癌、小细胞肺癌、非小细胞肺癌、多发性骨髓瘤、基底细胞瘤、畸胎瘤、成视网膜细胞瘤、脉络膜黑素瘤、精原细胞瘤、横纹肌肉瘤、颅咽管瘤、骨肉瘤、软骨肉瘤、肌肉瘤、脂肪肉瘤、纤维肉瘤、尤因肉瘤或浆细胞瘤。
  19. 一种预防或治疗肿瘤、癌症、病毒感染、器官移植排斥、神经退行性疾病、注意力相关疾病或自身免疫性疾病的方法，其包括向有此需要的哺乳动物施用权利要求1-14所述的化合物、其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物、或其代谢产物或权利要求15-16所述的药物组合物或者药物制剂。
  20. 一种抑制A2A和/或A2B受体的方法，其包括使A2A和/或A2B受体暴露于如权利要求1-14任一项所述的化合物、其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物、或其代谢产物。
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