CN111440148B - Preparation method of adenosine receptor antagonist - Google Patents

Preparation method of adenosine receptor antagonist Download PDF

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CN111440148B
CN111440148B CN202010437230.XA CN202010437230A CN111440148B CN 111440148 B CN111440148 B CN 111440148B CN 202010437230 A CN202010437230 A CN 202010437230A CN 111440148 B CN111440148 B CN 111440148B
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CN111440148A (en
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刘世峰
俞智勇
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Xiamen Baotai Biotechnology Co ltd
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Hangzhou Arnold Biomedical Technology Co ltd
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    • 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
    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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Abstract

The invention provides a heterocyclic compound serving as an A2A and/or A2B receptor antagonist, and particularly provides a compound shown as the following formula I, wherein the definition of each group is described in the specification. The compound of the present invention has A2A and/or A2B inhibitory activity, and can be used for the prevention or treatment of diseases associated with A2A and/or A2B activity or expression level.

Description

Preparation method of adenosine receptor antagonist
The application is a divisional application, the Chinese application number of the parent case is 201980004345.5, the international application number is PCT/CN2019/074927, and the international application date is 2019, 02 and 13.
The present invention claims priority from chinese patent application CN201810165937.2, and the contents of the specification and claims of this priority document are incorporated in their entirety into the present specification and are included as part of the original description of the present specification. Applicants further claim that applicants have the right to amend the description and claims of this invention based on this priority document.
Technical Field
The invention provides a novel heterocyclic compound, synthesis thereof and application thereof as an adenosine receptor (A2A and/or A2B) antagonist.
Background
Checkpoint inhibitors make breakthrough progress in the field of immunotherapy, and a large number of clinical studies show that the PD-1/PDL-1 antibody has certain clinical effects on various tumors (small cell lung cancer, melanoma, head and neck cancer, kidney cancer and the like), but the single-drug response rate is generally low and is generally 20-40%. Solid tumors include not only tumor cell components but also considerable amounts of other non-tumor cell components in the tumor tissue, which constitute the so-called tumor microenvironment and play an important role in tumor infiltration, proliferation and metastasis. Research shows that the combined administration of the PD-1/PDL-1 antibody and other immune regulation small molecules (eliminating immune tolerance of tumor microenvironment) is one of effective means for solving low response rate.
Under normal conditions, a human body can effectively control cells by depending on a complete immune mechanism, and T lymphocytes, NK cells and macrophages all have killing effect on tumor cells, but when the function of cancer cells or the immune cells is changed, the cancer cells can escape from the elimination of the immune system of the body, and malignant hyperplasia forms tumors. Adenosine is a signaling molecule used in vivo to limit inflammation and immune responses, and is greatly elevated in metabolic disorders and cellular injury, and activated adenosine receptors participate in the immune regulation of the body, maintaining high levels in many different types of tumor microenvironments. Adenosine produced by tumors interacts with adenosine receptors on the surface of invading immune cells, of which there are four subtypes, a1, A2A, A2B and A3, all belonging to the family of G protein-coupled receptors, mainly coupled to Gs and G α proteins. Each receptor exhibits a different affinity for adenosine, A1R, A2AR, and A3R are high affinity receptors that can be activated by adenosine (250 nM) and 700nM), while A2BR is a low affinity receptor that requires higher adenosine concentrations (25. mu.M) for activation. Adenosine receptors can also be classified according to their ability to cause downstream signaling small molecule cAMP, and when A2A and A2B receptors are activated, receptor conformational changes result in the release of activated Gs protein, activating adenosine cyclase, accelerating the conversion of ATP to cAMP. Increased cAMP concentrations, usually accompanied by strong immunosuppression, inhibit cAMP production by activating the a1 and A3 receptors, and thus activation of the a1 and A3 receptors is generally considered to activate immunity.
The adenosine A2A receptor is mainly expressed in the striatum, spleen, thymus, lymphocytes and platelets of the brain, and is also found to be expressed in the heart, lungs and blood vessels, often in some cells of the immune system, such as T cells, NK cells, macrophages and dendritic cells. A2A receptor antagonist is mainly used for treating nervous system diseases such as Parkinson, Huntington, Alzheimer, attention-related diseases and psychosis in early stage. Recent research finds that the A2A receptor antagonist can improve dendritic cell antigen presentation, activation and killing capacity of T cells and natural killer cells, inhibit regulatory T cells (T-regs), MDSC and TAM, eliminate tumor immune tolerance, promote generation of anti-tumor immune response and further cause tumor regression, and therefore the A2A receptor antagonist is possibly one of effective methods for treating tumors. The A2A receptor antagonist can be used alone or in combination with other antitumor drugs, and particularly combined with an immune checkpoint inhibitor is the current clinical research hotspot.
Adenosine A2B receptor is expressed in various tissues, vasculature, brain, small intestine, and tumor, among others, and is also expressed in various cells, including mast cells, dendritic cells, neutrophils, macrophages, lymphocytes, among others, as well as endothelial cells, nerve cells, and glial cells, among others, in the immune system. The wide expression of the A2B receptor makes it a target for the research of various diseases, such as cardiovascular diseases, lung diseases, diabetes, cancer, etc. The research shows that the A2B antagonist can prevent the growth of tumors (bladder cancer and breast cancer), and the high expression of A2B in a patient with triple negative breast cancer tumor can also lead to the reduction of the treatment survival rate.
International patent application publication nos. WO2011/095625, WO2001/92264, WO2003/048165, WO2004/09443, WO2002/055083, etc. disclose compounds for A2A receptor antagonists, and international patent application publication nos. WO2005/040155, WO2016/164838, WO2016/150901, WO 1/35048, WO 20162015/05206, WO2012/076974, WO2011/005871, chinese patent application publication No. CN102532137, and U.S. patent application publication No. US20140142113, etc. disclose compounds for A2B receptor antagonists, but antagonists that inhibit both A2A and A2B receptors are currently reported to be less. After long and intensive studies, we have unexpectedly found a class of heterocyclic compounds having A2A and/or A2B receptor inhibitory activity.
Disclosure of Invention
In a first aspect of the present invention, there is provided a compound represented by formula I, a pharmaceutically acceptable salt, a prodrug, an isotopic derivative, a hydrate, an isomer, a solvate, or a metabolite thereof,
Figure GDA0002778345010000031
wherein,
Cy1selected from 5-12 membered aryl, 5-12 membered heteroaryl, C3-C9Cycloalkyl radical, C3-C9A heterocycloalkyl group;
Cy2selected from 5-12 membered aryl, 5-12 membered heteroaryl;
wherein, Cy1And Cy2Each independently may be selected from 0,1, 2 or 3RaWherein R is substituted with a group ofaSelected from hydrogen, C1-C8Alkyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, C3-C9Cycloalkyl radical, C1-C8Haloalkyl, C1-C8Alkylthio, halogen, cyano, sulfonic, nitro, OR6、SR6、NR6R7、C(＝O)R6、C(＝O)OR6、C(＝O)NR6R7、NR6C(＝O)R7Or S (O)2R6(ii) a Each R is6And R7Each independently is hydrogen, C1-C8Alkyl, 5-12 membered aryl, 5-12 membered heteroaryl, or R6And R7The nitrogen atoms adjacent to the nitrogen atoms are combined into a 3-6-membered ring which can also optionally contain 1-2 heteroatoms selected from N, O, S;
R1and R2Each independently selected from hydrogen,C1-C8Alkyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, C1-C8Alkoxy, - (CH)2)n5-12 membered aryl, C1-C8Haloalkyl, C3-C9Cycloalkyl, -C (═ O) R3、-SOR3、-SO2R3、-C(＝O)OR3Cyano, - (CH)2)nNR4R5、-C(＝O)(CH2)nNR4R5N is 0,1, 2,3,4 or 5; or, R1And R2The adjacent N atoms are combined together to form a 3-9-membered saturated or unsaturated ring, and the ring can also optionally contain 1-2 heteroatoms selected from N, O, S;
wherein R is3Selected from hydrogen, hydroxy, amino, optionally substituted C1-C8Alkyl, optionally substituted C1-C8Alkoxy, optionally substituted C1-C8Alkylcarbonyloxy, optionally substituted C3-C12Cycloalkyl, optionally substituted di (C)1-C8Alkyl) amino, optionally substituted C1-C8Alkylamino radical, optionally substituted C1-C8Alkylcarbamoyl, optionally substituted 5-12 membered aryl, optionally substituted 5-12 membered heteroaryl; wherein the optionally substituted substituents are selected from the group consisting of halogen, cyano, sulfonic acid, C1-C8Alkyl, 5-12 membered aryl, 5-12 membered heteroaryl, OR6、SR6、NR6R7、C(O)R6、C(O)OR6、C(O)NR6R7、NC(O)NR6R7Or S (O)2R6Or when the number of the substituents of the above aryl, heteroaryl or cycloalkyl groups is 2 or more, two adjacent substituents may form a 5-to 8-membered ring which may contain 2 to 4 heteroatoms;
wherein R is4And R5Selected from hydrogen, optionally substituted C1-C8Alkyl, optionally substituted C3-C12Cycloalkyl, optionally substituted 5-to 12-memberedAryl, optionally substituted 5-12 membered heteroaryl, wherein the optionally substituted substituents are selected from halogen, cyano, sulfonic acid, OR6、SR6、NR6R7、C(O)R6、C(O)OR6、C(O)NR6R7、NC(O)NR6R7Or S (O)2R6Substituted; or, R4And R5Together with the nitrogen atom to which they are attached form 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 substituted with 1,2 or 3R8Substituted, the site of substitution being on the C or N atom, provided that the structure formed is a reasonably stable structure; r8Each independently selected from hydrogen, halogen, C1-C8Alkyl radical, C3-C9Cycloalkyl, C (O) R9、S(O)2R93-9 membered heterocycloalkyl, 5-12 membered aryl, 5-12 membered heteroaryl, or ═ O; and R is8Optionally selected from halogen, -O (CH)2)pO(CH2)qOR10Substituted with a group of (a); wherein R is9、R10Are each independently hydrogen, C1-C8Alkyl or C3-C9A cycloalkyl group;
with the proviso that when R1And R2When both are hydrogen, Cy1Is a 5 membered heteroaryl group, which may optionally be substituted with 0,1, 2 or 3RaSubstituted with a group of (a).
In another embodiment of the present invention, Cy is1Independently selected from phenyl, pyridyl, pyrazinyl, cyclopropyl, cyclopentyl, cyclohexyl, furyl, thiazolyl, piperidinyl, piperazinyl, oxazolyl, imidazolyl, thienyl; preferably phenyl, furyl, oxazolyl or pyridyl; cy is a Cy-is2Independently selected from phenyl, pyridyl, pyrazinyl, furyl, thiazolyl, piperidinyl, piperazinyl, oxazolyl, imidazolyl, thienyl; preferably phenyl, pyridyl; wherein said Cy1And Cy2May be optionally substituted by 0,1, 2 or 3 substituents selected from C1-C8Alkyl radical, C1-C8Haloalkyl, C1-C8Alkoxy radical, C1-C8Alkyl sulfenyl, halogen, cyano, sulfonic group and nitro.
In another embodiment of the present invention, wherein Cy1And Cy2Can be independently selected from phenyl, pyridyl, pyrazinyl, cyclopropyl, cyclopentyl, cyclohexyl, furyl, thiazolyl, piperidinyl, piperazinyl, oxazolyl, imidazolyl, thienyl, said substituents can be optionally substituted with 0,1, 2 or 3RaIs substituted, wherein RaHas the definition of formula I.
Another aspect of the present invention provides a compound having the structure of formula II, a pharmaceutically acceptable salt, prodrug, isotopic derivative, hydrate, isomer, solvate, or metabolite thereof:
Figure GDA0002778345010000051
wherein, W1And W2Are each independently selected from CRbOr N, RbHaving RaThe definition of (1); ra、Cy1And R2Having the formula as defined in formula I, m is 0,1, 2 or 3.
In another embodiment of the present invention, when R is1And R2When both are hydrogen, Cy1Selected from five membered heteroaryl groups, for example: furyl, thiazolyl, oxazolyl, imidazolyl, thienyl; cy is a Cy-is2Selected from phenyl, pyridyl, pyrazinyl, piperidinyl, piperazinyl, preferably phenyl, pyridyl; wherein, said Cy1And Cy2May be optionally substituted by 0,1, 2 or 3 substituents selected from C1-C8Alkyl radical, C1-C8Haloalkyl, C1-C8Alkoxy radical, C1-C8Alkyl sulfenyl, halogen, cyano, sulfonic group and nitro.
Another aspect of the present invention provides a compound having the structure of formula III or formula IV, a pharmaceutically acceptable salt, prodrug, isotopic derivative, hydrate, isomer, solvate, or metabolite thereof:
Figure GDA0002778345010000052
wherein R isa、Cy1And R2Having the formula as defined in formula I, m is 0,1, 2 or 3.
In a preferred embodiment of the present invention, R2Is selected from-C (═ O) R3、-SOR3、-SO2R3、-C(＝O)(CH2)nNR4R5(ii) a Wherein R is3、R4、R5Has the definition of formula I; n is selected from 1,2 or 3.
In another preferred embodiment of the present invention, R2Is selected from-C (═ O) R3or-C (═ O) (CH)2)nNR4R5Wherein R is3、R4、R5Has the definition of formula I; n is selected from 1,2 or 3.
In another preferred embodiment of the present invention, R2Is selected from-C (═ O) R3；R3Selected from hydrogen, hydroxy, amino, optionally substituted C1-C8Alkyl, optionally substituted C3-C12Cycloalkyl or optionally substituted 5-12 membered aryl; preferably optionally substituted C1-C8Alkyl, optionally substituted C3-C12Cycloalkyl or optionally substituted 5-12 membered aryl, wherein said optionally substituted substituents are selected from C1-C8Alkyl radical, C1-C8Alkoxy, halogen, hydroxy, amino, cyano, sulfonic acid, 5-12 membered aryl, 5-12 membered heteroaryl.
In another preferred embodiment of the present invention, R2Is selected from-C (═ O) (CH)2)nNR4R5(ii) a n is 1,2 or 3; r4、R5Has the definition of formula I.
In another preferred embodiment of the present invention, R2Is selected from-C (═ O) (C)H2)nNR4R5(ii) a n is 1,2 or 3; r4And R5Together with the nitrogen atom to which they are attached form 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 substituted with 1,2 or 3R8Substituted, the site of substitution being on the C or N atom, provided that the structure formed is a reasonably stable structure; r8Each independently selected from hydrogen, halogen, C1-C8Alkyl radical, C3-C9Cycloalkyl, C (O) R9、S(O)2R93-9 membered heterocycloalkyl, 5-12 membered aryl, 5-12 membered heteroaryl, or ═ O; and R is8May also be optionally selected from halogen and-O (CH)2)pO(CH2)qOR10Wherein p and q are each independently 0,1, 2, 3; wherein R is9、R10Are each independently hydrogen, C1-C8Alkyl or C3-C9A cycloalkyl group.
In another preferred embodiment of the present invention, R2is-C (═ O) (CH)2)nNR4R5(ii) a n is 1,2 or 3, R4And R5Together with the nitrogen atom to which they are attached to form
Figure GDA0002778345010000061
Wherein
Figure GDA0002778345010000063
Is represented by (CH)2)nAttached bond, R11Selected from hydrogen, C1-C8Alkyl radical, C3-C9Cycloalkyl, C (O) R9、S(O)2R93-9 membered heterocycloalkyl, 5-12 membered aryl, 5-12 membered heteroaryl; and R is8May also be optionally selected from halogen and-O (CH)2)pO(CH2)qOR10Wherein p and q are each independently 0,1, 2, 3; r9、R10Are each independently hydrogen, C1-C8Alkyl or C3-C9A cycloalkyl group.
Preferably, the compounds of the present invention are selected from the following structures:
Figure GDA0002778345010000062
Figure GDA0002778345010000071
Figure GDA0002778345010000081
Figure GDA0002778345010000091
Figure GDA0002778345010000101
Figure GDA0002778345010000111
Figure GDA0002778345010000121
Figure GDA0002778345010000131
Figure GDA0002778345010000141
Figure GDA0002778345010000151
Figure GDA0002778345010000161
Figure GDA0002778345010000171
Figure GDA0002778345010000181
the compounds of the present invention may also be prepared in the form of pharmaceutically acceptable salts formed using, for example, inorganic or organic acids such as: hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, mandelic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, methanesulfonic, benzenesulfonic or toluenesulfonic 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 (e.g., acetone, methanol, ethanol and acetonitrile), adding thereto an excess of an organic acid or an aqueous solution of an inorganic acid to precipitate the salt from the resulting mixture, removing the solvent and the remaining free acid therefrom, and then separating the precipitated salt.
The compounds of the present invention or their pharmaceutically acceptable salts may include hydrates and solvates thereof.
The invention also provides the use of a compound of the invention in the preparation of a medicament for the prevention or treatment of cancer, a tumour, an inflammatory disease, an autoimmune disease or an immune-mediated disease.
In addition, the present invention provides a pharmaceutical composition for preventing or treating cancer, tumor, inflammatory disease, autoimmune disease, neurodegenerative disease, attention-related disease or immune-mediated disease, comprising the compound of the present invention as an active ingredient.
Furthermore, the present invention provides a method for preventing or treating cancer, tumor, inflammatory disease, autoimmune disease, neurodegenerative disease, attention-related disease, or immune-mediated disease, comprising administering the compound of the present invention to a mammal in need thereof.
Furthermore, the present invention provides a method of inhibiting the A2A and/or A2B receptor comprising exposing the A2A and/or A2B receptor to a compound of the invention.
Representative examples of cancers or tumors 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, neuroblastoma, rectal cancer, colon cancer, familial adenomatous polyposis carcinoma, hereditary nonpolyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharynx cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine corpus cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumor, hodgkin lymphoma, non-hodgkin lymphoma, burkitt lymphoma, Acute Lymphatic Leukemia (ALL), Chronic Lymphocytic Leukemia (CLL), Acute Myelogenous Leukemia (AML), Chronic Myelogenous Leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder carcinoma, bronchial carcinoma, small-cell lung carcinoma, non-small cell lung carcinoma, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, ewing's sarcoma, or plasmacytoma.
The compounds of the present invention or pharmaceutically acceptable salts thereof can provide enhanced anticancer effects when administered in combination with additional anticancer agents or checkpoint inhibitors for the treatment of cancer or tumors.
Representative examples of anticancer agents for the treatment of cancer or tumor may include, but are not limited to, cell signaling inhibitors, chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, daunomycin, mitoxantrone, bleomycin, mitomycin C, ixabepilone, tamoxifene, flutamide, gonadorelin analogs, megestrol, prednisone, dexamethasone, methylprednisolone, thalidomide, doxylamine, fludarabine, dacarbazine, and the like, Interferon alpha, calcium folinate, sirolimus, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, brimonib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, darnoutilinib, dasatinib, dovitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, erlotinib, imatinib, inrarib, lapatinib, lentivatinib, linifanib, linsitinib, masitinib, momelotinib, motertinib, lenalitinib, nilapartiib, niraparipariib, oprozolib, paucinib, sergentinib, valtinib, valacitinib, valtinib, valacitinib, valtinib, Vismodegib, volasertib, alemtuzumab, bevacizumab, bernetuzumab, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab; checkpoint inhibitors, including but not limited to anti-PD-1 antibodies, anti-PD-L1 antibodies, LAG3 antibodies, TIM-3 antibodies, and anti-CTLA-4 antibodies, or any combination thereof.
Representative examples of inflammatory, autoimmune and immune-mediated diseases can include, but are not limited to, arthritis, rheumatoid arthritis, spondyloarthritis, 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, and immune-mediated diseases, Scleroderma, organ transplant rejection, xenografts, Idiopathic Thrombocytopenic Purpura (ITP), parkinson's disease, alzheimer's disease, diabetes-related diseases, inflammation, pelvic inflammatory disease, allergic rhinitis, allergic bronchitis, allergic sinusitis, leukemia, lymphoma, B-cell lymphoma, T-cell lymphoma, myeloma, Acute Lymphocytic Leukemia (ALL), Chronic Lymphocytic Leukemia (CLL), Acute Myelogenous Leukemia (AML), Chronic Myelogenous Leukemia (CML), hairy cell leukemia, hodgkin's disease, non-hodgkin's lymphoma, multiple myeloma, myelodysplastic syndrome (MDS), myeloproliferative tumors (MPN), diffuse large B-cell lymphoma, and follicular lymphoma.
The compounds of the present invention or pharmaceutically acceptable salts thereof can provide enhanced therapeutic effects when administered in combination with additional therapeutic agents for the treatment of inflammatory diseases, autoimmune diseases, and immune-mediated diseases.
Representative examples of therapeutic agents for treating inflammatory diseases, autoimmune diseases, and immune-mediated diseases may include, but are not limited to, steroid drugs (e.g., prednisone, prednisolone, methyl prednisolone, cortisone, hydrocortisone, betamethasone, dexamethasone, etc.), methotrexate, leflunomide, anti-TNF α agents (e.g., etanercept, infliximab, adalimumab, etc.), calcineurin inhibitors (e.g., tacrolimus, pimecrolimus, etc.), and antihistamines (e.g., diphenhydramine, hydroxyzine, loratadine, ebastine, ketotifen, cetirizine, levocetirizine, fexofenadine, etc.), and at least one therapeutic agent selected therefrom 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 effective amount ranging from 0.1 to 2,000mg/kg body weight/day, preferably 1 to 1,000mg/kg body weight/day in the case of mammals including humans (body weight about 70kg), and administered in a single or 4 divided doses per day, or with/without following a predetermined time. The dosage of the active ingredient may be adjusted according to a variety 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. Amounts greater than the above doses may be used if they do not cause harmful side effects and may be administered in divided doses per day.
The pharmaceutical composition of the present invention may be formulated into dosage forms for oral administration or parenteral administration (including intramuscular, intravenous and subcutaneous routes) according to any one of conventional methods, such as tablets, granules, powders, capsules, syrups, emulsions, microemulsions, solutions or suspensions.
Pharmaceutical compositions of the invention for oral administration may be prepared by mixing the active ingredient with a carrier such as: cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifying agents, and diluents. Examples of carriers employed in the injectable compositions of the present invention are water, saline solutions, glucose-like solutions, alcohols, glycols, ethers (e.g., polyethylene glycol 400), oils, fatty acids, fatty acid esters, glycerol esters, surfactants, suspending agents, and emulsifiers.
Other features of this invention will become apparent in describing exemplary embodiments thereof which are given for illustration of the invention and are not intended to be limiting thereof, the following examples being prepared, isolated and characterized using the disclosed methods of this invention.
The compounds of the present invention can be prepared in a variety of ways known to those skilled in the art of organic synthesis, and can be synthesized using the methods described below, as well as synthetic methods known in the art of organic synthetic chemistry, or by variations thereof as would be understood by those skilled in the art. 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 material used and for the transformation effected. Those skilled in the art of organic synthesis will understand that the functionality present on the molecule is consistent with the proposed transformation. This sometimes requires a judgment to change the order of the synthetic steps or starting materials to obtain the desired compounds of the invention.
Detailed Description
The inventor of the present invention has long and intensive studies and unexpectedly found that a heterocyclic compound having A2A and/or A2B inhibitory activity can be used for preparing a pharmaceutical composition for treating diseases associated with A2A and/or A2B receptors. Based on the above findings, the inventors have completed the present invention.
Term(s) for
Unless otherwise defined, terms used in this application, including the specification and claims, are defined as follows. It must be noted that, in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Conventional methods of mass spectrometry, nuclear magnetism, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology are used, if not otherwise stated. In this application, "or" and "means" and/or "are used unless otherwise stated.
In the description and claims, a given formula or name shall encompass all stereo-and optical isomers and racemates in which the above-mentioned isomers are present. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are within the scope of the invention. Many geometric isomers of C ═ C double bonds, C ═ N double bonds, ring systems, and the like may also be present in the compounds, and all of the above stable isomers are encompassed within the present invention. The present invention describes cis-and trans- (or E-and Z-) geometric isomers of the compounds of the present invention, and which may be separated as mixtures of isomers or as separate isomeric forms. The compounds of the invention may be isolated in optically active or racemic form. All methods for preparing the compounds of the present invention and intermediates prepared therein are considered part of the present invention. In preparing the enantiomeric or diastereomeric products, they can be separated by conventional methods, for example, by chromatography or fractional crystallization. Depending on the process conditions, the end products of the invention are obtained in free (neutral) or salt form. Both free forms and salts of these end products are within the scope of the invention. If desired, one form of the compound may be converted to another. Free base or acid can be converted to a salt; the salt may be converted to the free compound or another salt; mixtures of the isomeric compounds of the present invention may be separated into the individual isomers. The compounds of the present invention, their free forms and salts may exist in various tautomeric forms wherein hydrogen atoms are transposed to other parts of the molecule and thus chemical bonds between atoms of the molecule are rearranged. It is to be understood that all tautomeric forms which may be present are included within the invention.
Unless otherwise defined, when a substituent is labeled "optionally substituted," the substituent is selected from, for example, substituents such as alkyl, cycloalkyl, aryl, heterocyclyl, halogen, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amine groups (wherein 2 amino substituents are selected from alkyl, aryl or arylalkyl), alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thio, alkylthio, arylthio, arylalkylthio, arylthiocarbonyl, arylalkylthiocarbonyl, alkanylthio, and alkanylArylsulfonyl, arylalkylsulfonyl, sulfonamido radicals such as-SO2NH2Substituted sulfonamido, nitro, cyano, carboxy, carbamoyl, e.g. -CONH2Substituted carbamoyl such as-CONH alkyl, -CONH aryl, -CONH arylalkyl or in the case of two substituents on the nitrogen selected from alkyl, aryl or arylalkyl, alkoxycarbonyl, aryl, substituted aryl, guanidino, heterocyclyl such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidinyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl and the like and substituted heterocyclyl.
The term "alkyl" or "alkylene" as used herein is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms. For example, "C1-C6 alkyl" represents an alkyl group having 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl).
The term "alkenyl" denotes a straight or branched chain hydrocarbon group containing one or more double bonds and typically 2 to 20 carbon atoms in length. For example, "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.
The term "alkynyl" denotes a straight or branched chain hydrocarbon group containing one or more triple bonds and typically from 2 to 20 carbon atoms in length. For example, "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.
The term "alkoxy" or "alkyloxy" refers to an-O-alkyl group. "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 (e.g., n-propoxy and isopropoxy), and t-butoxy. Similarly, "alkylthio" or "thioalkoxy" represents an alkyl group as defined above with the specified number of carbon atoms attached via a sulfur bridge; such as methyl-S-and ethyl-S-.
The term "carbonyl" refers to an organic functional group (C ═ O) formed by double bonding of two atoms, carbon and oxygen.
The term "aryl", alone or as part of a larger moiety such as "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to a monocyclic, bicyclic, or tricyclic ring system having a total of 5 to 12 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. In certain embodiments of the present invention, "aryl" refers to an aromatic ring system including, but not limited to, phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthyl. The term "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 on the cycloalkyl ring or the aromatic ring. For example, the arrowed lines drawn from the ring system indicate that the bond can be attached to any suitable ring atom.
The term "cycloalkyl" refers to a monocyclic or bicyclic cyclic alkyl group. Monocyclic cyclic alkyl refers to C3-C8 cyclic alkyl groups 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". Bicyclic cyclic alkyl groups include bridged, spiro or fused cyclic cycloalkyl groups.
The term "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 norbornenyl. Branched cycloalkenyls such as 1-methylcyclopropenyl and 2-methylcyclopropenyl are included in the definition of "cycloalkenyl". Bicyclic cyclic alkenyl includes bridged, spiro or fused cyclic alkenyl.
"halo" or "halogen" includes fluorine, chlorine, bromine and iodine. "haloalkyl" is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms and substituted with 1 or more halogens. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2, 2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl also include "fluoroalkyl" groups intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted with 1 or more fluorine atoms.
"haloalkoxy" or "haloalkyloxy" represents a haloalkyl group as defined above attached via an oxygen bridge having the specified number of carbon atoms. For example, "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. Similarly, "haloalkylthio" or "thiohaloalkoxy" represents a haloalkyl group as defined above with the indicated number of carbon atoms attached via a sulfur bridge; such as trifluoromethyl-S-and pentafluoroethyl-S-.
The term "aryl" refers to a monocyclic or bicyclic (and more than bicyclic) aromatic radical of all carbon atoms. Monocyclic aromatic group means phenyl, bicyclic and bicyclic or higher aromatic group means naphthyl, anthryl, etc., and the aryl bicyclic group may be a ring fused with a cycloalkyl, or fused with a cycloalkenyl, or fused with a cycloalkynyl.
The term "heteroaryl", "aromatic heterocycle", "aromatic heterocyclyl" or "aromatic heterocyclic group" means a stable 3-, 4-, 5-, 6-, or 7-membered aromatic monocyclic or aromatic bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered aromatic polycyclic heterocycle which is fully unsaturated, partially unsaturated, and which contains carbon atoms and 1,2,3, or 4 heteroatoms independently selected from N, O and S; and includes any polycyclic group wherein any of the heterocyclic rings defined above are fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The nitrogen atom is substituted or unsubstituted (i.e., N or NR, where R is H or another substituent, if defined). The heterocyclic ring may 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 may be substituted on a carbon or nitrogen atom. The nitrogen in the heterocycle may optionally be quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle is no more than 1. When the term "heterocycle" is used, it is intended to include heteroaryl. Examples of aromatic heterocycles include, but are not limited to, acridinyl, azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4 aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5, 2-dithiazinyl, dihydrofuro [2,3-b ] tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazopyridinyl, indoxyl (indolynyl), indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl (isatinoyl) Isobenzofuranyl, isochromanyl, isoindolyl, isoindolinyl, isoindolyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl, oxazolidinyl, perimidine, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiin, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyranyl, and the like, Pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidinonyl, 2H-pyrrolyl, quinazolinyl, quinolyl, 4H-quinolizinyl, quinoxalyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2, 5-thiadiazinyl, 1,2, 3-thiadiazolyl, 1,2, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, 1,3, 4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thiazolopyridinyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 5-triazolyl, 1,3, 4-triazolyl and xanthenyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl, 1,2,3, 4-tetrahydroquinolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 5,6,7, 8-tetrahydro-quinolinyl, 2, 3-dihydro-benzofuranyl, chromanyl, 1,2,3, 4-tetrahydro-quinoxalinyl and 1,2,3, 4-tetrahydro-quinazolinyl. The present invention also includes fused ring and spiro compounds containing, for example, the above-described heterocycles.
The term "heterocycloalkyl" as used herein refers to a monocyclic heterocycloalkyl system, or a bicyclic heterocycloalkyl system, and also includes spiroheterocycles or bridged heterocycloalkyl groups. Monocyclic heterocycloalkyl refers to a 3-to 8-membered cyclic alkyl system containing at least one saturated or unsaturated but not aromatic ring selected from O, N, S, P. Bicyclic heterocycloalkyl systems refer to a heterocycloalkyl fused to a phenyl, or a cycloalkyl, or a cycloalkenyl, or a heterocycloalkyl, or a heteroaryl.
The term "bridged cycloalkyl" as used herein refers to a polycyclic compound that shares two or more carbon atoms. Can be divided into bicyclic bridged cyclic hydrocarbons and polycyclic bridged cyclic hydrocarbons. The former is composed of two alicyclic rings sharing two or more carbon atoms; the latter are bridged ring hydrocarbons consisting of more than three rings.
The term "spirocycloalkyl" as used herein refers to a polycyclic hydrocarbon in which one carbon atom (referred to as a spiro atom) is shared between the monocyclic rings.
The term "bridged heterocyclic group" as used herein refers to a polycyclic compound sharing two or more carbon atoms and containing at least one atom selected from the group consisting of O, N, S atoms in the ring. Can be divided into bicyclic bridged heterocycles and polycyclic bridged heterocycles.
The term "heterospirocyclic" as used herein refers to polycyclic hydrocarbons having a single ring with a common carbon atom (referred to as a spiro atom) and at least one ring atom selected from the group consisting of O, N, S atoms.
The term "substituted" as used herein means that at least one hydrogen atom is replaced with a non-hydrogen group, provided that the normal valency is maintained and that the substitution results in a stable compound. As used herein, a cyclic double bond is a double bond formed between two adjacent ring atoms (e.g., C ═ C, C ═ N or N ═ N).
In the case of nitrogen atoms (e.g., amines) present on the compounds of the invention, these nitrogen atoms may be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and/or hydrogen peroxide) to obtain other compounds of the invention. Thus, the nitrogen atoms shown and claimed are to be considered as both encompassing the nitrogen shown and the N-oxides thereof to obtain the derivatives of the invention.
When any variable occurs more than one time in any constituent or formula of a compound, its definition on each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown substituted with 0,1, 2 or 3R, said group may optionally be substituted with up to three R groups, and R is independently selected at each occurrence from the definition of R. Furthermore, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
The term "solvate" means a physical association of a compound of the invention with one or more solvent molecules (whether organic or inorganic). The physical association includes hydrogen bonding. In certain instances, the solvate will be able to be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. The solvent molecules in the solvate may be present in a regular and/or disordered arrangement. Solvates may comprise stoichiometric or non-stoichiometric amounts of solvent molecules. "solvate" encompasses solution phase and isolatable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.
The term "patient" as used herein refers to an organism treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians/monkeys, equines, bovines, porcines, canines, felines, and the like) and most preferably refer to humans.
The term "effective amount" as used herein means that amount of a drug or agent (i.e., a compound of the invention) that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for example, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means an amount of: the amount results in improved treatment, cure, prevention, or alleviation of the disease, disorder, or side effect, or a decrease in the rate of progression of the disease or disorder, as compared to a corresponding subject not receiving the above amount. An effective amount may be administered in one or more administrations, administrations or dosages and is not intended to be limited by a particular formulation or route of administration. The term also includes within its scope an effective amount to enhance normal physiological function.
The term "treating" as used herein includes any effect that results in an improvement in the condition, disease, disorder, etc., such as a reduction, modulation, amelioration or elimination, or amelioration of a symptom thereof.
The term "pharmaceutical composition" as used herein refers to a combination of an active agent and an inert or active carrier, such that the composition is particularly suitable for use in vivo or ex vivo diagnosis or treatment. Examples of bases include, but are not limited to, alkali metal (e.g., sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides, ammonia, and the like. For therapeutic use, salts of the compounds of the present invention are for therapeutic use, and salts of the compounds of the present invention are expected to be pharmaceutically acceptable. However, salts of acids and bases that are not pharmaceutically acceptable may also be used, for example, in the preparation or purification of pharmaceutically acceptable compounds.
The term "pharmaceutically acceptable" is used herein to refer to those compounds, substances, compositions and/or dosage forms as follows: it is suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, and/or other problem or complication, commensurate with a reasonable benefit/risk ratio, within the scope of sound medical judgment.
The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutical substance, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc, magnesium stearate, calcium or zinc stearate, or stearic acid), or solvent encapsulating material, which is involved in carrying or transporting the subject compound from one organ or portion of the body to another organ or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
The term "pharmaceutical composition" means a composition comprising a compound of the present invention in combination with at least one other pharmaceutically acceptable carrier. By "pharmaceutically acceptable carrier" is meant a medium commonly accepted in the art for delivering biologically active agents to animals, particularly mammals, including (i.e.) adjuvants, excipients, or vehicles such as diluents, preservatives, fillers, flow control agents, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavorants, fragrances, antibacterial agents, antifungal agents, lubricants, and dispersants, depending on the mode of administration and the nature of the dosage form.
Specific pharmaceutical and medical terms
The term "acceptable", as used herein, means that a prescribed component or active ingredient does not unduly adversely affect the health of the general therapeutic target.
The term "cancer", as used herein, refers to an uncontrolled abnormal growth of cells and under certain conditions is capable of metastasizing (spreading). This type of cancer includes, but is not limited to, solid tumors (e.g., bladder, intestine, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (e.g., thyroid), prostate, skin (melanoma), or hematologic tumors (e.g., non-leukemias).
The term "co-administration" or similar terms, as used herein, refers to the administration of several selected therapeutic agents to a patient, either in the same or different modes of administration, at the same or different times.
The term "enhance" or "capable of enhancing", as used herein, means that the desired result can be increased or prolonged, both in potency and duration. Thus, in enhancing the therapeutic effect of a drug, the term "capable of enhancing" refers to the ability of the drug to increase or prolong the potency or duration of the drug in the system. As used herein, "potentiating value" refers to the ability to maximize the enhancement of another therapeutic agent in an ideal system.
The term "immunological disorder" refers to a disease or condition that produces an adverse or deleterious response to an endogenous or exogenous antigen. The result is often a dysfunction of the cells, or destruction thereof and dysfunction, or destruction of organs or tissues that may produce immune symptoms.
The term "kit" is synonymous with "product package".
The term "subject" or "patient" includes mammals and non-mammals. Mammals include, but are not limited to, mammals: human, non-human primates such as orangutans, apes, and monkeys; agricultural animals such as cattle, horses, goats, sheep, pigs; domestic animals such as rabbits, dogs; the experimental animals include rodents, such as rats, mice, guinea pigs and the like. Non-mammalian animals include, but are not limited to, birds, fish, and the like. In a preferred embodiment, the mammal of choice is a human.
The terms "treat," "treatment process," or "therapy" as used herein include alleviating, inhibiting, or ameliorating a symptom or condition of a disease; inhibiting the generation of complications; ameliorating or preventing underlying metabolic syndrome; inhibiting the development of a disease or condition, such as controlling the development of a disease or condition; alleviating the disease or symptoms; regression of the disease or symptoms; alleviating a complication caused by the disease or symptom, or preventing or treating a symptom caused by the disease or symptom.
As used herein, a compound or pharmaceutical composition, when administered, can ameliorate a disease, symptom, or condition, particularly severity, delay onset, slow progression, or reduce duration of a condition. Whether fixed or temporary, sustained or intermittent, may be due to or associated with administration.
Route of administration
Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transdermal, vaginal, auditory, nasal, and topical administration. In addition, by way of example only, parenteral administration includes intramuscular injection, subcutaneous injection, intravenous injection, intramedullary injection, ventricular injection, intraperitoneal injection, intralymphatic injection, and intranasal injection.
In one aspect, the administration of the compounds described herein is local rather than systemic. In particular embodiments, the depot is administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in another embodiment, the drug is administered by a targeted drug delivery system. For example, liposomes encapsulated by organ-specific antibodies. In this embodiment, the liposomes are selectively targeted to a particular organ and absorbed.
Pharmaceutical compositions and dosages
The present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of one or more compounds of the present invention formulated with one or more pharmaceutically acceptable carriers (additives) and/or diluents, and optionally one or more of the other therapeutic agents described above. The compounds of the invention may be administered for any of the above uses by any suitable means, for example, orally, such as tablets, pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions; under the tongue; taking orally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., in the form of sterile injectable aqueous or nonaqueous solutions or suspensions); nasally, including administration to nasal membranes, such as by inhalation spray; topical, such as in cream or ointment form; or rectally, such as in the form of suppositories. They may be administered alone, but are generally 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 purview of those skilled in the art. These factors include, but are not limited to: the type and nature of the active agent formulated; a subject to whom a composition comprising an active agent is to be administered; the intended route of administration of the composition; and targeted therapeutic indications. Pharmaceutically acceptable carriers include aqueous and non-aqueous liquid media and various solid and semi-solid dosage forms.
The carrier may include many different ingredients and additives in addition to the active agent, such other ingredients being included in the formulation for various reasons well known to those skilled in the art, e.g., to stabilize the active agent, binders, etc. A description of suitable Pharmaceutical carriers and The factors involved in The selection of carriers can be found in a number of readily available sources, such as Allen L.V.Jr.et al.Remington: The Science and Practice of Pharmacy (2Volumes),22nd Edition (2012), Pharmaceutical Press.
Of course, the dosage regimen for the compounds of the present invention will vary depending upon known factors, such as the pharmacodynamic properties of the particular agent and its mode and route of administration; species, age, sex, health condition, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient and the desired effect. According to general guidelines, when used for a given 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 from about 0.1 mg/day to about 250 mg/day. During constant rate infusion, the most preferred intravenous dose 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 generally administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, for example, oral tablets, capsules, elixirs and syrups, and consistent with conventional pharmaceutical practice.
Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1mg to about 2000 mg of active ingredient per dosage unit. In such pharmaceutical compositions, the active ingredient will generally be present in an amount of about 0.1 to 95 weight percent, based on the total weight of the composition.
A typical capsule for oral administration contains at least one compound of the invention (250mg), lactose (75mg) and magnesium stearate (15 mg). The mixture was passed through a 60 mesh screen and packaged into size 1 gelatin capsules.
A typical injectable formulation can be prepared as follows: at least one compound of the invention (250mg) was aseptically placed in a vial, lyophilized aseptically and sealed. For use, the vial contents were mixed with 2mL of normal saline to produce an injectable formulation.
The scope of the present invention includes (alone or in combination with a pharmaceutical carrier) pharmaceutical compositions comprising as an active ingredient a therapeutically effective amount of at least one compound of the present invention. Optionally, the compounds of the present invention may be used alone, in combination with other compounds of the present invention, or in combination with one or more other therapeutic agents (e.g., anti-cancer agents or other pharmaceutically active substances).
Regardless of the route of administration chosen, the compounds of the invention (which may be used in a suitable hydrated form) and/or the pharmaceutical compositions of the invention are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.
The actual dosage level of the active ingredient in the pharmaceutical compositions of the present invention can be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response, composition and mode of administration for a particular patient without being toxic 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 ester, salt or amide thereof employed; a route of administration; the time of administration; the rate of excretion of the particular compound used; rate and extent of absorption; the duration of the treatment; other drugs, compounds and/or substances used in combination with the particular compound used; age, sex, weight, condition, general health, and prior medical history of the patient being treated are factors well known in the medical arts.
A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the desired pharmaceutical composition. For example, to achieve a desired therapeutic effect, the physician or veterinarian can start a relatively large amount of a compound of the invention to be used in a pharmaceutical composition at a level below that required and gradually increase the dosage until the desired effect is achieved. In general, an appropriate daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such effective dosages will generally depend on the factors recited above. Typically, oral, intravenous, intracerebroventricular, and subcutaneous doses of a compound of the invention are in the range of about 0.01 to about 50mg/kg body weight/day in a patient. If desired, 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 daily.
Although the compound of the present invention can be administered alone, it is preferable to administer the compound in the form of a pharmaceutical preparation (composition).
Kit/product packaging
For use in the treatment of the above indications, kits/product packages are also described herein. These kits may consist of a conveyor, a pack or a container, which may be divided into compartments to accommodate one or more containers, such as vials, tubes, and the like, each containing a separate one of the components of the method. Suitable containers include bottles, vials, syringes, test tubes, and the like. The container is made of acceptable glass or plastic materials.
For example, the container may contain one or more compounds as described herein, which may be present as pharmaceutical components or as a mixture with other ingredients as described herein. The container may have a sterile outlet (e.g. the container may be an iv bag or vial, the stopper of which may be pierced by a hypodermic needle). Such kits may carry a compound, and instructions, labels, or instructions for use of the methods described herein.
A typical kit may include one or more containers, each containing one or more materials (e.g., reagents, optionally concentrated stock solutions, and/or instruments) to accommodate commercial deployment and use of the compound by the user. Such materials include, but are not limited to, buffers, diluents, filters, needles, syringes, conveyors, bags, containers, bottles and/or tubes, with a list of contents and/or instructions for use, and internal packaging with instructions. The entire specification is included.
The label may be displayed on or closely associated with the container. The presence of the label on the container means that the label letters, numbers or other features are affixed, molded, engraved on the container; labels may also be present in container boxes or shipping boxes that contain a variety of containers, such as in a product insert. A label may be used to indicate a particular therapeutic use of the contents. The label may also indicate instructions for use of the contents, such as described in the methods above.
All of the features described in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps involved in any method or process, may be present in any combination, except combinations where certain features or steps are mutually exclusive.
The features mentioned above with reference to the invention, or the features mentioned with reference to the embodiments, can be combined arbitrarily. All the features disclosed in this specification may be combined in any combination, and each feature disclosed in this specification may be replaced by alternative features serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, the features disclosed are merely generic examples of equivalent or similar features.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers. All percentages, ratios, proportions, or parts are by weight unless otherwise specified.
The weight volume percentage units in the present invention are well known to those skilled in the art and refer to, for example, the weight of solute in a 100ml solution. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
In a preferred embodiment of the invention, the following compounds are provided, but not limited to:
the invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
When no preparative route is included, relevant intermediates are commercially available (e.g., from Sigma Aldrich, Alfa)
General procedure
Commercial reagents were used without further purification. The room temperature is 20-27 ℃. 1H-NMR spectra were recorded on a Bruker instrument at 500 MHz. Chemical shift values are expressed in parts per million, i.e., delta values. The following abbreviations are used for multiplicity of NMR signals: s is singlet, brs is broad, d is doublet, t is triplet, and m is multiplet. Coupling constants are listed as J values, measured in Hz. NMR and mass spectrometry results were corrected for background peaks. Chromatography refers to column chromatography performed using 100 mesh silica gel and performed under nitrogen pressure (flash chromatography). TLC for monitoring the reaction refers to TLC performed using a specific mobile phase and silica gel F254 from Merck as stationary phase.
The LC-MS experiment was measured under the following conditions:
the instrument comprises the following steps: thermo U3000, ALLtech ELSD, MSQ, UV detector combined ELSD and MSD (outflow ratio 4: 1). Column: waters X-Bridge C-18,3.5 μm, 4.6X50 mm; column temperature: at 30 ℃. Gradient [ time (min)/solvent B in a (%) ]: 0.00/5.0,0.70/95,1.40/95,1.41/5,1.50/5. (solvent a ═ 0.01% trifluoroacetic acid in water; solvent B ═ 0.01% trifluoroacetic acid in acetonitrile). And (4) UV detection: 214/254/280/300 nm; and D, DAD detection: 200-400 nm; flow rate: 4 mL/min; MS: ESI, 100-1500m/z
Preparative HPLC typically used an acidic method (gradient of acetonitrile and water, each containing 0.1% formic acid) with Thermo U3000 AFC-3000; column: globalsil C-1812 nm,250X20mm,10 μm, or equivalent; flow rate: 20mL/min, separation was performed.
Synthesis of intermediates
Preparation of Compound INT-1:
Figure GDA0002778345010000341
pinacol diboron (19.9g,78.4mmol), 4, 4' -di-tert-butylbipyridine (848mg,3.14mmol) and compound INT-1a (1.04g,1.57mmol) were added to a round-bottomed flask under nitrogen; the mixture was repeatedly purged with nitrogen for 3 times, and n-heptane (130mL) was added by syringe. The resulting system was reacted at 50 ℃ for 10 minutes, followed by addition of 2-chloro-6-methylpyridine (10g,78.4mmol) via syringe; the obtained system is continuously reacted for 6 hours at the same temperature, and the thin layer chromatography is used for detecting that the reaction of the raw materials is finished. The reaction system was filtered, and the crude product obtained after concentrating the filtrate was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20: 1) to obtain compound INT-1(19g, yield: 95%) as a white solid.1H NMR(CDCl3,500MHz):δ7.49(s,1H),7.42(s,1H)；2.55(s,3H),1.35(s,12H).
Preparation of Compound INT-3 b:
Figure GDA0002778345010000351
compound INT-3a (1.0g,7.1mmol) was dissolved in dichloromethane (20mL) and diethylaminosulfur trifluoride (2.5g,15.5mmol) was added under nitrogen and ice bath conditions. The reaction solution is gradually heated to room temperature and stirred for 2 hours at room temperature, and the thin layer chromatography detects that the raw materials are completely reacted. The reaction solution was quenched with ice water and made weakly basic (pH 8) with saturated sodium bicarbonate solution. The aqueous phase was back-extracted with dichloromethane (20 mL. times.2), the combined organic layers were washed successively with water, saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated to give INT-3b (750mg, yield: 65%) as a yellow oil.
According to the preparation method of the compound INT-1, compounds INT-2, INT-3, INT-4 and INT-5 can be prepared, and the specific spectrogram information is as follows:
Figure GDA0002778345010000352
Figure GDA0002778345010000361
preparation of Compound INT-6:
Figure GDA0002778345010000362
thiourea (33g,0.36mol) and methyl iodide (24.8mL,0.40mol) were added to methanol (200mL), and the reaction was stirred at room temperature overnight. The reaction solution was concentrated to give INT-6(84g, yield: 99%) as a pale yellow solid.
Preparation of Compound INT-7:
Figure GDA0002778345010000363
compound INT-7a (2.0g,13mmol), dimethylhydroxylamine hydrochloride (3.8g,38.9mmol), 1-hydroxybenzotriazole (3.5g,26mmol), N, N-diisopropylethylamine (5.0g,38.9mmol) and 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (5.0g,26mmol) were added sequentially to dichloromethane (40 mL). The reaction solution was stirred at room temperature for 1 hour, and the completion of the reaction of the raw materials was detected by thin layer chromatography. After completion of the reaction, the reaction mixture was washed with water, 10% sodium carbonate solution and saturated brine in this order (50mL each). The organic layer was dried over anhydrous sodium sulfate, and the filtrate was concentrated to give Compound INT-7b (2.3g, yield: 90%) as a yellow oil.
A solution of methylmagnesium bromide (3 mol/L2-methyltetrahydrofuran, 5.8mL) was slowly added to a solution of compound INT-7b (2.3g,11.7mmol) in tetrahydrofuran (40mL) at 0 deg.C. The reaction system is stirred and gradually heated to the room temperature, and reacts for 1 hour at the room temperature, and the thin layer chromatography detects that the raw materials completely react. After the reaction was complete, the reaction was cooled to 0 ℃ and ammonium chloride solution (1M,50mL) was added slowly and the aqueous phase was extracted with ether (100 mL. times.2). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated to give Compound INT-7(1.62g, yield: 91%) as a yellow oil. LC-MS purity 95%
With reference to the preparation method of the compound INT-7, the compounds INT-8, INT-9, INT-10, INT-11 and INT-13 can be prepared, and the structure and spectrogram information is shown in the following table:
Figure GDA0002778345010000371
preparation of Compound INT-12:
Figure GDA0002778345010000372
oxalyl chloride (496mg,3.9mmol) and 1 drop of N, N' -dimethylformamide were added sequentially to a solution of compound INT-12a (150mg,0.98mmol) in dichloromethane (2 mL). The reaction solution was stirred at room temperature for 1 hour, and the completion of the reaction of the raw materials was detected by thin layer chromatography. The reaction solution was concentrated and spin-dried to obtain INT-12(168mg, yield: 99%)
Preparation of Compound INT-13 g:
Figure GDA0002778345010000381
a mixed solution of compound INT-13a (4.0g,21mmol) and thionyl chloride (3.95mL,54mmol) in methanol was stirred at room temperature overnight and the starting material was detected to be completely reacted by thin layer chromatography. Concentrating and spin-drying the reaction solution, and dissolving the crude product by using ethyl acetate (150 mL); the organic layer was washed with water and saturated brine (150mL each), dried over anhydrous sodium sulfate, and the filtrate was concentrated to give INT-13b (4.0g, yield: 93%) as a pale yellow solid.
Compound INT-13b (4.0g,19.5mmol), compound INT-13c (1.43g,1.95mmol), compound INT-13d (3.15g,23.4mmol) and potassium carbonate (5.4g,39mmol) were added to a mixed solution of dioxane (80mL) and water (25mL) under nitrogen. After the reaction system is replaced by nitrogen for 3 times, the mixture is stirred overnight under the condition of 80 ℃, and the LC-MS detects that the raw materials are completely reacted. The reaction mixture was diluted with ethyl acetate (200mL), and washed with water and saturated brine (300 mL each). The organic layer was dried over anhydrous sodium sulfate, and the filtrate was concentrated to give a crude product, which was purified by silica gel column chromatography to give INT-13e (2.23g, yield: 75%) as a yellow oil.1H NMR(CDCl3,500MHz):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)。
A solution of compound INT-13e (2.23g,14.7mmol) and 10% palladium on charcoal (1.5g,1.5mmol) in methanol was stirred under hydrogen (15psi) at room temperature for 4 hours. And (5) detecting that the raw materials react completely by crude nuclear magnetism. The filtrate was concentrated to give INT-13f (2.0g, yield: 88%) as a pale yellow oil.1HNMR(CDCl3,500MHz):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)。
A mixed solution of compound INT-13f (2.4g,15.6mmol) and sodium hydroxide (1.25g,31.2mmol) in ethanol (10mL) and water (10mL) was stirred for 2 hours at 80 deg.C and the starting material was detected to be completely reacted by thin layer chromatography. The reaction solution was adjusted to pH 4-5 with hydrochloric acid solution (1mol/L) and diluted with ethyl acetate (100 mL). The organic layer was washed with water and saturated brine (100mL each), dried over anhydrous sodium sulfate, and the filtrate was concentrated to give INT-13g (2.13g, yield: 98%) as a pale yellow solid.
Example 1: preparation of Compound 1
Figure GDA0002778345010000391
Dissolving compound 1a (8.0g,57.9mmol) in a mixed solution of dioxane (180mL) and water (5mL), followed by the addition of selenium dioxide (7.07g,63.7 mmol); the reaction temperature is raised to 55 ℃ and stirred until the selenium dioxide is completely dissolved. The reaction was then stirred at reflux temperature overnight and the completion of the reaction of the starting materials was detected by thin layer chromatography. The reaction was filtered and the filtrate was concentrated to give the crude product as an oil, which was added to water (120mL) and extracted with ethyl acetate (100 mL. times.3). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 1b as a pale yellow oil (6.5g, yield: 66%).
Compound 1b (6.5g,38mmol) was dissolved in ethanol (100mL) and sodium bicarbonate (8.0g,96mmol) and compound INT-6(9.8g,42mmol) were added sequentially. The reaction solution is stirred for 2 hours at the reflux temperature, and the thin layer chromatography detects that the reaction of the raw materials is finished. The reaction was concentrated to give the crude product which was added to water (100mL) and extracted with ethyl acetate (100 mL. times.3). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product which was purified by column chromatography to give compound 1c as a pale yellow solid (8.2g, yield: 97%). MS 222.1[ M + H ]]+
Compound 1c (2g,9.0mmol) was dissolved in dichloromethane (120mL) and then m-chloroperoxybenzoic acid (4.6g,22.6mmol) was added under ice bath conditions. After the reaction system is gradually heated to room temperature under the stirring condition, the reaction system is stirred for 5 hours, and the LC-MS detects that the reaction of the raw materials is finished. The reaction was washed with saturated sodium carbonate solution (100 mL. times.2) and the aqueous phase was back-extracted with dichloromethane (100 mL. times.2). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 1d (2.0g, yield: 87%) as a pale yellow solid. MS 254.1[ M + H ]]+
Compound 1d (2.0g,8.0mmol) was added to a sealed tube containing aqueous ammonia (25-28% w/w,10mL) and dioxane (1mL), heated to 50 ℃ with stirring, and reacted for 2 hours. And detecting the completion of the reaction of the raw materials by LC-MS. The reaction solution was poured into water (20mL), stirred vigorously and filtered. The filter cake was washed successively with water, petroleum ether/ethyl acetate (v/v ═ 5/1), and dried under vacuum to give compound 1e (1.32g, yield: 87%) as a pale yellow solid. MS 191.0[ M + H ]]+
Compound 1e (950mg,5mmol) was added to N 'N' -dimethylformamide (5mL), followed by stirring at room temperatureN-bromosuccinimide (1.33g,7.5mmol) was added slowly. The reaction solution is continuously stirred for 2 hours at the same temperature, and the thin layer chromatography detects that the reaction of the raw materials is finished. The reaction mixture was added to saturated brine (50mL), and the aqueous phase was extracted with ethyl acetate (50 mL. times.3). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by column chromatography to give compound 1f as a pale yellow solid (850mg, yield: 64%).1H NMR(DMSO-d6,500MHz)δ7.86-7.79(m,2H),7.53(s,2H),7.41-7.33(m,2H)；MS:268.8[M+H]+
Compound 1f (200mg,0.74mmol), Compound INT-1(225mg,0.89mmol), Compound 1g (54mg,0.074mmol) and potassium carbonate (306mg,2.22mmol) were added to a mixed solution of dioxane (3mL) and water (1mL) under nitrogen. The reaction system is repeatedly replaced by nitrogen for 3 times, and then stirred for 6 hours under the condition of 90 ℃ until the LC-MS detects that the reaction of the raw materials is finished. The reaction was poured into water (20mL) and the aqueous phase was extracted with ethyl acetate (30 mL. times.2). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product which was purified by column chromatography (petroleum ether/ethyl acetate 1: 2) to give a pale yellow solid compound 1h (160mg, yield: 68%).1H NMR(DMSO-d6,500MHz):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]+
Compound 1h (80mg,0.25mmol) was dissolved in a mixed solution of dichloromethane (3mL) and pyridine (0.5mL) at-10 deg.C, followed by addition of compound 1i (208mg,2 mmol). The reaction solution reacts for 15min at the same temperature, and LC-MS detects that the reaction of the raw materials is finished. The reaction was poured into water (10mL) and the aqueous phase was extracted with dichloromethane (10 mL. times.2). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product which was purified by preparative thin layer chromatography to give Compound 1 as a pale yellow solid (40mg, yield: 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]+
Referring to the preparation method of compound 1, compounds 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 can be prepared. The specific spectrogram information is as follows:
Figure GDA0002778345010000411
Figure GDA0002778345010000421
Figure GDA0002778345010000431
Figure GDA0002778345010000441
Figure GDA0002778345010000451
Figure GDA0002778345010000461
Figure GDA0002778345010000471
Figure GDA0002778345010000481
Figure GDA0002778345010000491
referring to the preparation method of the compound 1h, compounds 17h,43,44,58 and 64 can be prepared, and the specific spectrogram information is as follows:
Figure GDA0002778345010000492
Figure GDA0002778345010000501
example 2: preparation of Compound 45
Figure GDA0002778345010000502
Chlorosulfonic isocyanate (15.5mg,0.11mmol) was added at 0 deg.C to a solution of compound in dichloromethane (3mL) for 1 h. The reaction solution is stirred for 2 hours under the condition of 0 ℃, and LC-MS detects that the reaction of the raw materials is finished. The reaction was diluted with dichloromethane (30mL) and washed with saturated brine (30 mL. times.2). The organic layer was dried over anhydrous sodium sulfate, and the filtrate was concentrated to give a crude product, which was isolated by preparative high performance liquid chromatography (5-95% acetonitrile, 0.1% formic acid) to give compound 45(8mg, yield: 22%) as a pale yellow solid.1HNMR(500MHz,MeOH-d4):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]+
Example 3: preparation of Compound 46
Figure GDA0002778345010000511
Isoamyl nitrite (148mg,1.27mmol) and iminobromide (273mg,1.9mmol) were added to a solution of compound 1h (200mg,0.63mmol) in acetonitrile (5 mL). The reaction solution was stirred under reflux for 1 hour and LC-MS detected that the reaction of the raw materials was complete. The reaction mixture was diluted with ethyl acetate (30mL), and washed with water and saturated brine (30mL each). The organic layer was dried over anhydrous sodium sulfate, and the filtrate was concentrated to give a crude product which was purified by column chromatography to give compound 46a (30mg, yield: 13%) as a yellow solid.
To a solution of compound 46a (30mg,0.079mmol) in acetonitrile (3mL) was added cyanamide (6.6mg,0.16mmol) and potassium carbonate (33mg,0.24 mmol). The reaction solution is stirred for 2 hours in a sealed tube at 100 ℃, and LC-MS detects that the reaction of the raw materials is finished. The reaction mixture was diluted with tetrahydrofuran (30mL), and washed with water and saturated brine (30mL each). The organic layer was dried over anhydrous sodium sulfate, and the filtrate was concentrated to give a crude product, which was purified by preparative high performance liquid chromatography (5-95% acetonitrile, 0.1% formic acid) to give compound 46(10mg, yield: 37%) as a yellow solid.1HNMR(500MHz,DMSO-d6):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]+
Example 4: preparation of Compound 47
Figure GDA0002778345010000512
Sodium hydrogen (60% in kerosene, 10.0mg,0.25mmol) was added to a solution of compound 17h (50mg,0.17mmol) in N, N' -dimethylformamide (2mL), stirred at room temperature for 10 minutes, and then compound 47a (28mg,0.20mmol) was slowly added dropwise. The obtained reaction solution is stirred at room temperature overnight, and LC-MS detects that the reaction of the raw materials is finished. The reaction mixture was diluted with methylene chloride (20mL), and washed with water and saturated brine (20mL each). The organic layer was dried over anhydrous sodium sulfate, and the filtrate was concentrated to give a crude product, which was purified by preparative high performance liquid chromatography (5-95% acetonitrile, 0.1% formic acid) to give compound 47(8mg, yield: 12%) as a yellow solid. 1HNMR (500MHz, DMSO-d6): δ 7.58-7.52(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 ]]+
Example 5: preparation of Compound 48
Figure GDA0002778345010000521
Iron powder (41mg,0.73mmol) was added to dissolve compound 19(50mg, 0).12mmol) of acetic acid (0.2mL) and methanol (0.8mL), stirring the reaction solution at 50 ℃ for 2 hours, and detecting the completion of the reaction of the raw materials by LC-MS. The reaction solution was diluted with ethyl acetate (20mL), followed by filtration through celite, and the filtrate was concentrated to give the crude product, which was purified by high performance liquid chromatography (5-95% acetonitrile, 0.1% formic acid) to give compound 48(25mg, yield: 54%) as a pale yellow solid.1HNMR(500MHz,DMSO-d6):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]+
Example 6: preparation of Compound 51
Figure GDA0002778345010000522
Boron tribromide (76mg,0.30mmol) was slowly added to a solution of compound 26(50mg,0.15mmol) in dichloromethane (3mL) at 0 ℃ with stirring under nitrogen. The reaction solution is continuously stirred for 1 hour under the condition of 0 ℃, and the disappearance of the raw materials is detected by LC-MS. The reaction was quenched with water (10mL) and the aqueous phase extracted with dichloromethane (10 mL. times.2). The organic layer was concentrated to give a crude product, which was purified by high performance liquid chromatography (5-95% acetonitrile, 0.1% formic acid) to give compound 51(6mg, yield: 13%) as a white solid.1HNMR(500MHz,MeOH-d4):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]+
Example 7: preparation of Compound 52
Figure GDA0002778345010000531
Isoamyl nitrite (62mg,0.50mmol) and iminobromide (96mg,0.67mmol) were added to a solution of compound 17h (100mg,0.34mmol) in acetonitrile (5 mL). The reaction solution was stirred under reflux for 1.5 hours and LC-MS detected that the reaction of the raw materials was complete. The reaction mixture was diluted with ethyl acetate (30mL), and washed with water and saturated brine (30mL each). The organic layer was dried over anhydrous sodium sulfate, and the filtrate was concentrated to give a crude product which was purified by column chromatography (petroleum ether/ethyl acetate 3: 1) to give compound 52a (40mg, yield: 33%) as a yellow solid.
Under the condition of 100 ℃, a tube sealing system containing the compound 52a (40mg,0.11mmol), the compound 52b (19.5mg,0.22mmol) and potassium carbonate (46mg,0.33mmol) dissolved in 1, 4-dioxane (3mL) is stirred for 2 hours, and the raw materials are detected to be reacted by LC-MS. The reaction solution was cooled to room temperature, and concentrated to give a crude product, which was purified by high performance liquid chromatography (5-95% acetonitrile, 0.1% formic acid) to give compound 52(10mg, yield: 25%) as a yellow solid.1HNMR(500MHz,MeOH-d4):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]+
Referring to the preparation method of compound 52, compounds 53,54 and 55 can be prepared, and the specific spectrum information is shown in the following table:
Figure GDA0002778345010000541
example 8: preparation of Compounds 59,60
Figure GDA0002778345010000542
Starting from compound INT-11, compound 59a was obtained as a yellow solid with reference to the synthesis of compound 1 c.
MS272.3[M+H]+
Compound 1c (2.7g,9.9mmol) and sodium nitrite (2.05g,29.7mmol) were added to acetic acid (20mL), the mixture was stirred at 70 ℃ for 3 hours under a sealed tube, and the starting material reaction was detected by LC-MS. The reaction mixture was concentrated, and the resulting crude product was diluted with ethyl acetate (100mL) and washed with water and saturated brine (100mL each). The organic layer was dried over anhydrous sodium sulfate, and the filtrate was concentrated to give a crude product which was purified by column chromatography to give 59b (1.8g, yield: 76%) as a yellow oily compound.
Starting from compound 59b, reference compound 1h was synthesized to give compound 59 as a yellow solid. 1HNMR (500MHz, DMSO-d6): delta 7.91(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]+
Starting from compound 59, reference was made to the synthesis of compound 1 to give compound 60 as a yellow solid.1HNMR(500MHz,DMSO-d6):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]+
Example 9: preparation of Compound 61
Figure GDA0002778345010000551
Compound 60(48mg,0.12mmol) was added to a mixed solution of concentrated hydrochloric acid (2mL) and 1, 4-dioxane (0.5mL), the reaction system was stirred at 40 ℃ for 1 hour, and LC-MS detected that the starting material was completely reacted. The reaction was diluted with water (10mL) and extracted with dichloromethane (20 mL. times.3). The organic layer was washed with water, saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated to give a crude product which was subjected to preparative thin layer chromatography (petroleum ether/ethyl acetate 4: 1) to give compound 61(32mg, yield: 69%) as a yellow solid.1HNMR(500MHz,DMSO-d6):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]+
Example 10: preparation of Compound 62
Figure GDA0002778345010000561
Compound 61(20mg,0.05mmol) and potassium carbonate (200mg,1.45mmol) were added to a solution of methanol (3mL), the reaction was stirred at room temperature for 1 hour, and LC-MS detection was performedThe raw materials are reacted completely. The reaction was diluted with water (10mL) and extracted with ethyl acetate (10 mL. times.3). The organic layer was washed with water, 0.1N hydrochloric acid, saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated to give the crude product which was subjected to preparative thin layer chromatography to give compound 62(6mg, yield: 38%) as a yellow solid.1HNMR(500MHz,MeOH-d4):δ7.42(s,1H),7.39(s,1H),7.15(s,1H),6.50(s,1H),2.55(s,3H)；MS322.3[M+H]+
Test examples
Affinity assay for A2A/A2B receptor binding assays
A2A receptor binding assay affinity testing procedure reference: british Journal of Pharmacology (1997)121, 353-360; wherein the A2A receptor (expressed by HEK cells) is derived from Perkin Elmer (product number: RBHA2AM400 UA); the competitive isotope labels are: [3H]SCH 58261. The specific test was carried out by the department of biology of Shanghai Ruizi chemical research, Inc.
A2B receptor binding assay affinity testing procedure reference: ACS Medicinal Chemistry Letters (2011)2, 213-; wherein the A2B receptor (expressed by HEK cells) was constructed by the biology department of shanghai drug minkangdi new drug development ltd and is commercially available as part of the CRO service; the competitive isotope labels are: [3H]DPCPX. The specific test is completed by the biological department of Shanghai medicine Mingkude New drug research and development Co., Ltd.
A2A/A2B receptor antagonistic function test:
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 procedures refer to ACS Medicinal Chemistry Letters (2011)2, 213-; the specific test is completed by Beijing Conlong formation new drug technology GmbH, and the steps are as follows:
10nL of compound in DMSO stock (10mM), 10. mu.LA 2A or A2B cell suspension (30000 cells/mL) were transferred sequentially to assay wells of a 384-well plate at room temperature and incubated for 20 minutes at room temperature. To EC80The corresponding amount of 5' -N-ethyllcarboxamidonosine at the activation concentration was transferred to each test well at 37 ℃ with 5% CO295% humidity conditionAfter further incubation for 30 minutes, Eu-cAMP tracer working solution and Ulight-anti-cAMP working solution were added to the cell culture plate at 5 uL/well in sequence, and the fluorescence values of the cell plate were read with Envision (excitation light wavelength: 320nm, emission light wavelength: 665nm and 615 nm). Obtaining the corresponding inhibition rate in each hole according to the following formula, drawing an S-shaped dosage-inhibition rate curve by using a nonlinear regression model, and calculating to obtain IC50The value is obtained.
Figure GDA0002778345010000571
The results for binding affinity and antagonistic functional activity of the compounds listed in the examples for the A2A/A2B receptor:
Figure GDA0002778345010000572
Figure GDA0002778345010000581
Figure GDA0002778345010000591

Claims (8)

1. a process for preparing a compound of formula 1, characterized by comprising the steps of:
Figure FDA0002778345000000011
2. the method of claim 1, comprising the steps of: step I: dissolving the compound 1a in a mixed solution of dioxane and water, and immediately adding selenium dioxide; and (3) raising the reaction temperature to 55 ℃, stirring until selenium dioxide is completely dissolved, then stirring the reaction system at the reflux temperature overnight, detecting the completion of the reaction of the raw materials by thin layer chromatography, filtering the reaction solution, concentrating the filtrate to obtain an oily crude product, adding the oily crude product into water, extracting with ethyl acetate, combining the organic layers, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate to obtain a light yellow oily compound 1 b.
3. The method of claim 1, comprising the steps of: step II: dissolving the compound 1b in ethanol, sequentially adding sodium bicarbonate and a compound INT-6, stirring the reaction solution at a reflux temperature for 2 hours, detecting the completion of the reaction of the raw materials by thin-layer chromatography, concentrating the reaction solution to obtain a crude product, adding the crude product into water, extracting with ethyl acetate, combining organic layers, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate to obtain a crude product, and purifying by column chromatography to obtain a light yellow solid compound 1 c.
4. The method of claim 1, comprising the steps of: step III: dissolving the compound 1c in dichloromethane, then adding m-chloroperoxybenzoic acid under an ice bath condition, gradually heating the reaction system to room temperature under a stirring condition, stirring for 5 hours, detecting the completion of the reaction of the raw materials by LC-MS, washing the reaction liquid by using a saturated sodium carbonate solution, back-extracting the water phase by using dichloromethane, combining the organic layers, washing by using saturated saline solution, drying by using anhydrous sodium sulfate, filtering, and concentrating the filtrate to obtain a light yellow solid compound 1 d.
5. The method of claim 1, comprising the steps of: step IV: adding the compound 1d into a sealed tube containing ammonia water and dioxane, stirring and heating to 50 ℃, reacting for 2 hours, detecting the reaction of raw materials by LC-MS, pouring the reaction liquid into water, stirring violently, filtering, sequentially using water, petroleum ether/ethyl acetate and volume ratio of a filter cake: v/v-5/1, washed and dried under vacuum to give compound 1e as a pale yellow solid.
6. The method of claim 1, comprising the steps of: step V: adding the compound 1e into N, N' -dimethylformamide, slowly adding N-bromosuccinimide under stirring at room temperature, continuously stirring the reaction solution at the same temperature for 2 hours, detecting the reaction completion of the raw materials by thin-layer chromatography, adding the reaction solution into saturated saline solution, extracting the water phase by ethyl acetate, combining the organic layers, washing by the saturated saline solution, drying by anhydrous sodium sulfate, filtering, concentrating the filtrate to obtain a crude product, and purifying by column chromatography to obtain a light yellow solid compound.
7. The method of claim 1, comprising the steps of: step VI: adding a compound 1f, a compound INT-1, a compound 1g and potassium carbonate into a mixed solution of dioxane and water under the protection of nitrogen, repeatedly replacing the reaction system with nitrogen for 3 times, stirring for 6 hours under the condition of 90 ℃ until the LC-MS detection raw material reaction is finished, pouring the reaction liquid into water, extracting the water phase with ethyl acetate, combining the organic layers, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate to obtain a crude product, and performing column chromatography to obtain a chromatographic solution, wherein the chromatographic solution is petroleum ether/ethyl acetate ═ 1: 2, purifying to obtain a light yellow solid compound for 1 h.
8. The method of claim 1, comprising the steps of: step VII: dissolving the compound 1h in a mixed solution of dichloromethane and pyridine at-10 ℃, then adding the compound 1i, reacting the reaction solution at the same temperature for 15min, detecting by LC-MS that the reaction of the raw materials is finished, pouring the reaction solution into water, extracting a water phase by using dichloromethane, combining organic layers, washing by using saturated saline solution, drying by using anhydrous sodium sulfate, filtering, concentrating the filtrate to obtain a crude product, and purifying by using preparative thin-layer chromatography to obtain the light yellow solid compound 1.
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