CN117343081A - MAT2A inhibitor, pharmaceutical composition and application thereof - Google Patents

MAT2A inhibitor, pharmaceutical composition and application thereof Download PDF

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Publication number
CN117343081A
CN117343081A CN202210741333.4A CN202210741333A CN117343081A CN 117343081 A CN117343081 A CN 117343081A CN 202210741333 A CN202210741333 A CN 202210741333A CN 117343081 A CN117343081 A CN 117343081A
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membered
cyclopropyl
optionally substituted
alkyl
hydrogen
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马昌友
苏进财
代清宇
吴叶彬
裴俊杰
吴舰
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Nanjing Chia Tai Tianqing Pharmaceutical Co Ltd
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Nanjing Chia Tai Tianqing Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

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  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
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Abstract

The invention provides an MAT2A inhibitor, a pharmaceutical composition and application thereof, wherein the structure of the MAT2A inhibitor is shown as a general formula (I), and the definition of each substituent is shown in the specification. The compound shown in the formula (I) has remarkable MAT2A inhibition activity and can be used for preventing and/or treating Methionine Adenosine Transferase (MAT) mediated diseases or disease states.

Description

MAT2A inhibitor, pharmaceutical composition and application thereof
Technical Field
The invention belongs to the field of biological medicine, and particularly relates to an MAT2A inhibitor, a pharmaceutical composition and application thereof.
Background
Cancer is a leading cause of death worldwide. A limitation of mainstream therapeutic methods, such as chemotherapy and immunotherapy, is that their cytotoxic effects are not limited to cancer cells, but adverse reactions can occur in normal tissues. Thus, new strategies are needed to better target cancer cells.
Methionine Adenosyltransferase (MAT), also known as S-adenosylmethionine synthetase, is a cellular enzyme that catalyzes the synthesis of S-adenosylmethionine (SAM or AdoMet) from methionine and ATP, and is considered to be the rate-limiting step in the methionine cycle. In the liver, methionine circulation has an additional function, mainly to rapidly remove excessive methionine in the blood after high methionine or high protein diet, and finally to be transported to other organs through homocysteine, cysteine, cystathionine, glutathione.
Methionine adenosyltransferase 2A (MAT 2A) is an enzyme that utilizes methionine and ATP to produce SAM. SAM is the primary methyl donor in cells for methylation of a variety of substrates including DNA, RNA and proteins. One methylase using SAM as a methyl donor is the protein arginine N-methyltransferase 5 (PRMT 5). Although SAM is required for PRMT5 activity, PRMT5 is competitively inhibited by 5' Methylthioadenosine (MTA). Since MTA is part of the methionine salvage pathway, the MTA level of the cell remains low during the initiation of the methionyl phosphorylase (MTAP).
MAT2A is a target of anti-tumor therapy because it plays a vital role in promoting liver cancer cell growth. Recent studies have shown that silencing by using small interfering RNAs substantially inhibits the growth of hepatoma cells and induces apoptosis. Some MTAP-deficient cancer cell lines are particularly sensitive to inhibiting MAT2A, an enzyme that is widely expressed in normal tissues that catalyzes the conversion of methylthioadenosine to adenine and 5-methylthioribose-1-phosphate. Adenine is remedied to produce adenosine monophosphate, and 5-methylthioribose-1-phosphate is converted to methionine and formate. Because of this salvage pathway, MTA can be an alternative source of purine when de novo synthesis of purine is blocked by, for example, antimetabolites such as L-alacinone. In other cancers lacking MTAP deletions (including hepatocellular carcinoma and leukemia), MAT2A is deregulated. Silencing MAT2A expression by RNA interference can produce antiproliferative effects in a variety of cancer models, many human and murine malignant cells lack MTAP activity. MTAP deficiency is present not only in tissue culture cells, but also in primary leukemias, gliomas, melanomas, pancreatic cancers, non-small cell lung cancer (NSCLC), bladder cancers, astrocytomas, osteosarcomas, head and neck cancers, myxochondrosarcoma, ovarian cancers, endometrial cancers, breast cancers, soft tissue sarcomas, non-hodgkin lymphomas and mesothelioma.
Thus, finding novel and effective MAT2A inhibitors may provide a novel treatment for cancer patients (including those with MTAP-deficient tumors), an important direction in current tumor-targeted drug development.
Disclosure of Invention
The object of the present invention is to provide a novel MAT2A inhibiting compound, which compounds and their pharmaceutical compositions are useful in methods of treating a variety of cancers, including those refractory to standard therapies such as surgery, radiation therapy, chemotherapy and hormonal therapy.
In an embodiment of the present invention, the present invention provides a compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the general formula (I) has the structure:
wherein:
R 1 or R is 2 Each independently selected from hydrogen, halogen, C1-C6 alkyl or C2-C6 alkynyl;
X 1 selected from N or CR a ；
X 2 Selected from N or CH;
R a selected from hydrogen, halogen, C1-C6 alkyl, amino, hydroxy, amido, 3-6 membered cycloalkyl, 5-7 membered heterocyclyl, benzo five membered heterocyclyl, 5-7 membered heteroaryl orWherein the C1-C6 alkyl is optionally substituted with hydroxy, 5-10 membered aryl, 5-10 membered aryloxy, halogen substituted 5-10 membered aryloxy, or 3-6 membered cycloalkyl, the amido is optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, 3-6 cycloalkyl, 5-10 membered aryl, halogen substituted 5-10 membered aryl, or halogen substituted 5-10 membered aralkyl, the amino is optionally substituted with 9-12 membered fused ring heteroaryl, 5-10 membered heteroaryl, C1-C3 alkyl substituted 5-10 membered heteroaryl, or pyridinyl substituted 5-10 membered heteroaryl, the hydroxy is optionally substituted with 5-10 membered aralkyl, 5-10 membered heteroaralkyl, halogen substituted 5-10 membered aralkyl, or a benzo five membered heterocyclyl, the 5-7 membered heterocyclyl is optionally substituted with 5-10 membered aryl, the 5-7 membered heteroaryl is optionally substituted with 3-6 membered cycloalkyl;
Alternatively, R a And R is R 1 And form a 3-6 membered heterocyclic ketone group with the carbon atom to which they are attached, said 3-6 membered heterocyclic ketone group being optionally substituted with a 5-7 membered aryl group or a 5-7 membered aralkyl group;
R 3 selected from hydrogen, C1-C6 alkyl, 5-10 membered aryl, C2-C6 alkenyl, 3-6 membered cycloalkyl, C1-C6 alkylthio or C1-C6 sulfonyl, said C1-C6 alkyl being optionally substituted by 3-6 membered cycloalkyl;
R 4 and R is 5 Each independently selected from hydrogen or C1-C6 alkyl.
In a further preferred embodiment of the invention, R 1 Selected from hydrogen, halogen or C2-C3 alkynyl; preferably hydrogen, chlorine or acetylene; more preferably hydrogen or chlorine; most preferred is hydrogen.
In a further preferred embodiment of the invention, R 2 Selected from hydrogen or halogen; preferably hydrogen or chlorine; more preferably hydrogen.
In a further preferred embodiment of the invention, X 1 Is CR (CR) a 。
In a further preferred embodiment of the invention, X 2 Is N.
In a further preferred embodiment of the invention, R a Selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, amino, hydroxy, amido, 3-4 membered cycloalkyl, 5 membered heterocyclyl, benzo five membered heterocyclyl containing 1-3 heteroatoms selected from N or O,5 membered heteroaryl orThe C1-C3 alkyl group is optionally substituted with a hydroxy, 5-7 membered aryl, 5-7 membered aryloxy, halogen substituted 5-7 membered aryloxy, or 3-4 membered cycloalkyl, the amido group is optionally substituted with a C1-C3 alkyl, C1-C3 haloalkyl, 3-4 membered cycloalkyl, 5-7 membered aryl, halogen substituted 5-7 membered aryl, or halogen substituted 5-7 membered aralkyl, the amino group is optionally substituted with a 9 membered fused ring heteroaryl containing 1-3 heteroatoms selected from N or O, a 5-7 membered heteroaryl, a C1-C3 alkyl substituted 5-7 membered heteroaryl, or a pyridinyl substituted 5-7 membered heteroaryl, the hydroxy group is optionally substituted with a 5-7 membered aralkyl, a 5-7 membered heteroaralkyl, a halogen substituted 5-7 membered aralkyl, or a benzo five membered heterocyclyl containing 1-3 heteroatoms selected from N or O, the 5 membered heterocyclyl group is optionally substituted with a 5-7 membered aryl, the 5-membered heteroaryl is optionally substituted with a 3 membered cycloalkyl;
Preferably, R a Selected from the group consisting of hydrogen, bromine, C1-C3 alkyl, amino, hydroxyl, amido, cyclopropyl, The C1-C3 alkyl is optionally substituted with hydroxy, cyclopropyl, phenyl, Substituted, said amide optionally being methyl, trifluoroethyl, cyclopropyl, phenyl,/-> Substituted, said amino group is optionally +.> Substituted, the hydroxy group optionally being Substitution, said->Optionally substituted by phenyl, said ++> Optionally substituted with cyclopropyl;
more preferably, R a Selected from hydrogen, bromine,
Further preferably, R a Selected from hydrogen, bromine,
Still more preferably, R a Selected from bromine,
In a further preferred embodiment of the invention, R a And R is R 1 And form a 5 membered heterocyclic ketone group with the carbon atom to which they are attached, optionally substituted with a 5-7 membered aryl or 5-7 membered aralkyl group;
preferably, R a And R is R 1 Form with the carbon atom to which they are attachedOptionally substituted with phenyl or benzyl;
more preferably, R a And R is R 1 Formation of carbon atoms to which they are attached
In a further preferred embodiment of the invention, R 3 Selected from hydrogen, C1-C3 alkyl, phenyl, C2-C4 alkenyl, 3-4 membered cycloalkyl, C1-C3 alkylthio or C1-C3 sulfonyl, said C1-C3 alkyl being optionally substituted by cyclopropyl;
preferably, R 3 Selected from hydrogen, methyl, ethyl, cyclopropyl, phenyl,
More preferably, R 3 Is cyclopropyl.
In a further preferred embodiment of the invention, R 4 And R is 5 Each independently selected from hydrogen or C1-C3 alkyl; preferably hydrogen or methyl; more preferably, R 4 And R is 5 And is methyl.
In a further preferred embodiment of the present invention, the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is further represented by formula (II-1):
wherein,
R 1 、R 3 、R 4 、R 5 as described in general formula (I) above.
In a further preferred embodiment of the present invention, the compound represented by the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which is further represented by the general formula (II-2),
wherein R is 3 、R 4 、R 5 、R a As described in general formula (I) above.
In a further preferred embodiment of the present invention, the compound represented by the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which is further represented by the general formula (II-3),
wherein R is 3 、R 4 、R 5 As described in the general formula (I) above,
R 6 selected from hydrogen, phenyl or benzyl.
In a further preferred embodiment of the present invention, the compound represented by the general formula (II-2), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is further represented by the general formula (III):
wherein:
L is selected from the group consisting of bond, -O-, -NH-, - (CH) 2 ) m -、 Wherein (1)>Is the site linked to the "benzene ring">Is the site of attachment to "ring C";
R C and R is D Each independently selected from hydrogen or C1-C3 alkyl;
ring C is selected from 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 5-7 membered aryl, 5-7 membered heteroaryl, 5-7 membered heterocyclyl, 9-12 membered fused ring heteroaryl, or benzo five membered heterocyclyl, said 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 5-7 membered aryl, 5-7 membered heteroaryl, or benzo five membered heterocyclyl optionally being further substituted with halogen, C1-C3 alkyl, 3-6 membered cycloalkyl, 5-7 membered aryl, or 5-7 membered heteroaryl;
R 3 、R 4 、R 5 as described in general formula (I) above;
m is 1 or 2;
z is 0, 1 or 2.
In a further preferred embodiment of the invention, L is selected from the group consisting of bond, -O-, -NH-, - (CH) 2 ) m -、 Wherein R is C And R is D Each independently selected from hydrogen or methyl, m is 1, z is 0 or 1;
preferably, L is selected from the group consisting of bond, -O-, -NH-, -CH 2 -、
More preferably, L is selected from the group consisting of a bond, -NH-
In a further preferred embodiment of the invention, ring C is selected from 3-6 membered cycloalkyl, 5-7 membered aryl, 5-7 membered heterocyclyl, 9 membered fused ring heteroaryl, 5-7 membered heteroaryl or benzo five membered heterocyclyl containing 1-3 heteroatoms selected from N or O, said 5-7 membered heteroaryl optionally being substituted with C1-C3 alkyl, 3-6 membered cycloalkyl or 5-7 membered heteroaryl, said 5-7 membered aryl optionally being substituted with halogen, said 5-7 membered heterocyclyl optionally being substituted with 5-7 membered aryl;
Preferably, ring C is selected from cyclopropyl, Wherein said->Optionally substituted by methyl or pyridyl, said +.>Optionally substituted with benzene, said ++>Optionally substituted by cyclopropyl, said +.>Optionally substituted with fluorine;
more preferably, ring C is selected from cyclopropyl,
Further preferably, ring C is selected from cyclopropyl,
In a further preferred embodiment of the present invention, the compound, stereoisomer or pharmaceutically acceptable salt thereof has the structure:
in a further preferred embodiment of the invention, the compoundsHas the following isomers:
in a further preferred embodiment of the invention, the compoundsHas the following isomers:
in a preferred form of the invention, the invention also provides a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds described above, stereoisomers thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers.
The pharmaceutical compositions of the invention may be administered by any suitable route or method, for example by oral or parenteral (e.g. intravenous) administration. For administration by the oral route, the pharmaceutical compositions of the present invention are typically provided in the form of tablets, capsules or solutions. A tablet may comprise a compound of the invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Such carriers include, but are not limited to, diluents, disintegrants, binders, lubricants, colorants, or preservatives. The capsule comprises hard capsule and soft capsule. Examples of suitable oral dosage forms are tablets comprising about 1mg, 2mg, 5mg, 10gm, 15mg, 25mg, 50mg, 100mg, 250mg, 500mg, 750mg, 1000mg, 1250mg, 1500mg, 1750mg or 2000mg of a compound of the invention.
For parenteral administration, the pharmaceutical compositions of the present invention may be administered by intravenous injection, intramuscular injection or subcutaneous injection. It is usually provided as a sterile aqueous solution or suspension or lyophilized powder and is adjusted for proper pH and isotonicity.
In a preferred form of the invention, the invention also provides the use of a compound of any one of the above, a stereoisomer or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prophylaxis and/or treatment of a Methionine Adenosyltransferase (MAT) -mediated disease or condition.
In a preferred form of the invention, the invention also provides a method for the prevention and/or treatment of Methionine Adenosyltransferase (MAT) -mediated diseases or conditions comprising administering to a subject in need thereof a compound of the invention, a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the invention.
In a preferred mode of the invention, examples of such Methionine Adenosyltransferase (MAT) -mediated diseases or conditions include, but are not limited to, cancer, such as pancreatic cancer, bladder cancer, neuroblastoma, intestinal cancer such as rectal cancer, colon cancer, familial adenomatous polyposis cancer and hereditary non-polyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharynx cancer, tongue cancer, salivary gland carcinoma, gastric cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, prostate cancer, testicular cancer, breast cancer, urinary system cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, neuroblastoma and peripheral neuroectodermal tumors hodgkin's lymphoma, non-hodgkin's lymphoma, burkitt's lymphoma, acute Lymphoblastic Leukemia (ALL), chronic Lymphocytic Leukemia (CLL), acute Myelogenous Leukemia (AML), chronic Myelogenous Leukemia (CML), adult T-cell leukemia, hepatocellular carcinoma, gall bladder carcinoma, bronchogenic carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choriocarcinoma, seminoma, rhabdomyosarcoma, craniopharyngeoma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, ewing's sarcoma, and plasmacytoma.
The compounds of the invention, stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the invention may be administered prior to, simultaneously with, or after radiation therapy or cytostatic or anti-tumour chemotherapy. Suitable cytostatic chemotherapeutic compounds include, but are not limited to, (i) antimetabolites, such as cytarabine; (ii) a DNA-cleaving agent, such as bleomycin; (iii) DNA cross-linking agents, such as cisplatin; (iv) intercalating agents, such as doxorubicin; (v) protein synthesis inhibitors, such as L-asparaginase; (vi) topoisomerase I poisons, such as topotecan; (vii) topoisomerase II poisons, such as etoposide; (viii) microtubule targeting agents such as vinblastine; (ix) kinase inhibitors such as f staurosporine; (x) various test agents, such as thioplatin; polyphenols such as quercetin; (xi) hormones, such as glucocorticoids; (xii) hormone antagonists such as tamoxifen.
The compounds of the invention, stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions of the invention, may be used alone or in combination with an immunooncology therapy.
The compounds of the invention, stereoisomers thereof, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions of the invention may also be used in combination with radiation therapy.
Correlation definition
Unless specifically indicated, the following terms used in the specification and claims have the following meanings:
the "compounds" of the invention may be asymmetric, e.g., have one or more chiral centers. Unless otherwise indicated, "compounds" of the present invention refer to any one stereoisomer or a mixture of two or more stereoisomers. Stereoisomers include, but are not limited to, enantiomers and diastereomers. The asymmetric carbon atom-containing compounds of the present invention may be isolated in optically pure form or as a mixture of two or more stereoisomers. Optically pure forms can be resolved from mixtures of two or more stereoisomers, or synthesized by using chiral starting materials or chiral reagents. The "compounds" of the present invention also include tautomeric forms. Tautomers originate from the exchange of one single bond with an adjacent double bond and accompany the migration of one proton.
The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
The term "halogen" refers to fluorine, chlorine, bromine and iodine.
The term "member" refers to the number of backbone atoms or groups of atoms that make up the ring. For example, "5-10 membered" means that the number of backbone atoms or groups of atoms that make up the ring is 5, 6, 7, 8, 9, or 10. Thus, for example, pyridine, piperidine, piperazine and benzene are six-membered rings, while thiophene and pyrrole are five-membered rings.
The term "substituted" means that any one or more hydrogen atoms on a particular group is substituted with a substituent, provided that the valence of the particular group is normal and the substituted compound is stable. For example, "substituted with halogen" means that any one or more hydrogen atoms on a particular group is substituted with halogen, so long as the valence of the particular group is normal and the substituted compound is stable.
Numerical ranges herein refer to individual integers within a given range. For example, "C1-C6" means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms; "C1-C3" means that the group may have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight or branched chain saturated hydrocarbon groups, having the indicated number of carbon atoms. The term "C1-C6 alkyl" includes C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, n-hexyl, 2-hexyl, 3-hexyl, and the like.
The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced with halogen atoms (fluorine, chlorine, bromine, iodine), as the term "C1-C6 haloalkyl" refers to a haloalkyl group containing 1 to 6 carbon atoms, examples of which include, but are not limited to, trifluoromethyl, trifluoroethyl.
The term "amino" refers to-NH 2 。
The term "hydroxy" refers to-OH.
The term "amide" refers to-CO-NH 2 。
The term "cycloalkyl" refers to a monocyclic saturated hydrocarbon system, free of heteroatoms, and free of double bonds. Examples of the term "3-6 membered cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
The term "heterocyclyl" refers to saturated cyclic ketones wherein the carbonyl carbon atom is included in the heterocycloalkyl group, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen or S, the remaining ring atoms being carbon, preferably a 5-7 membered heterocyclyl group, more preferably a 5-membered heterocyclyl group. Examples of the term "5-7 membered heterocyclic ketone group" include
The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. The term "3-6 membered heterocyclyl" comprising 3 to 6 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S, the remaining ring atoms being carbon, preferably wherein 1 to 3 are heteroatoms.
The term "benzo five-membered heterocyclic group" refers to a ring system formed by the condensation of a benzene ring and a five-membered heterocyclic ringThe benzene ring and the five-membered heterocyclic group share a pair of adjacent ring atoms, and the connection site with the parent nucleus structure is positioned at the benzene ring part. Wherein the heterocyclic moiety is a saturated, partially unsaturated or fully unsaturated ring system having ring carbon atoms and 1 to 3 ring heteroatoms or groups of heteroatoms independently selected from nitrogen, sulfur, oxygen, sulfoxide, sulfone,Examples include, but are not limited to, ">
The term "aryl" refers to an all-carbon monocyclic or fused bicyclic aromatic ring radical having a conjugated pi-electron system, which is obtained by removing one hydrogen atom from a single carbon atom of the parent aromatic ring system. Including bicyclic groups fused to saturated, partially unsaturated, or aromatic carbocyclic rings; examples include, but are not limited to, phenyl, naphthyl, anthracenyl, indene, indane, 1, 2-dihydronaphthalene, 1,2,3, 4-tetrahydronaphthalene. The term "5-10 membered aryl" refers to a 5-10 membered aromatic ring group. The term "halogen substituted 5-10 membered aryl" refers to a 5-10 membered aromatic ring group, the hydrogen atoms on the aromatic group of which are further substituted with halogen, examples include, but are not limited to,
The term "heteroaryl" refers to a monovalent aryl group comprising at least one heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of "5-to 10-membered heteroaryl" include, but are not limited to, pyridinyl, thienyl, imidazolyl, pyrimidinyl, pyridinyl, furanyl, pyrazinyl, thiazolyl.
The term "fused ring heteroaryl" refers to an aromatic heterocyclic group formed by two or more cyclic structures sharing two adjacent atoms with each other, comprising at least one heteroatom independently selected from nitrogen, oxygen and sulfur. Examples include but are not limited to,
the term "aralkyl" refers to an alkyl group substituted with an aryl group. Aralkyl groups described herein are preferably C1-C6 alkyl groups substituted with aryl groups, more preferably C1-C3 alkyl groups substituted with aryl groups. Examples include, but are not limited to,the term "5-10 membered aralkyl" refers to an alkyl group substituted with a 5-10 membered aryl group. The term "halogen substituted 5-10 membered aralkyl" refers to a 5-10 membered aralkyl further substituted with halogen, examples include, but are not limited to,/-and->
The term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group. Examples include, but are not limited to,
the term "aryloxy" refers to a group formed by attachment of oxygen to an aromatic group. The term "5-10 membered aryloxy" refers to a group formed by attachment of oxygen to a 5-10 membered aromatic group, examples of which include, but are not limited to, The term "halogen substituted 5-10 membered aryloxy" refers to a group formed by attachment of oxygen to a 5-10 membered aromatic group, the hydrogen atoms of which are further substituted with halogen, examples include, but are not limited to, ">
And/or +.>Is->Refers to a chemical bond junction. When present in bicyclic or polycyclic ringsAnd/or +.>And in the case of an indeterminate connection position, it means that the connection site is limited to +.>And/orAny atom on the monocyclic ring where it is located is permissible only in terms of valency.
The term "pharmaceutically acceptable" means that the carrier, vehicle, adjuvant, diluent, and/or salt formed is generally chemically or irrational compatible with the other ingredients comprising the pharmaceutical dosage form, and physiologically compatible with the recipient.
The term "pharmaceutically acceptable carrier" refers to those carriers which have no significant irritating effects on the body and which do not impair the biological activity and properties of the active compound. Including but not limited to any diluents, disintegrants, binders, glidants, wetting agents permitted by the national food and drug administration to be useful in humans or animals.
The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness of the free acids and bases of the particular compounds without biological adverse effects. Such as acid (including organic and inorganic acids) addition salts or base addition salts (including organic and inorganic bases), and may also include zwitterionic salts, and also include quaternary ammonium salts, such as alkylammonium salts. Pharmaceutically acceptable salts of the invention can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, the preparation of such salts is as follows: prepared via reaction of these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both. Salts of the present invention include, but are not limited to, hydrochloride, sulfate, citrate, oxalate, malate, and fumarate.
The term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but achieves the desired effect. The precise dosage will vary depending on a variety of factors, such as subject-dependent variables (e.g., age, immune system health, etc.), disease or disorder, and the treatment being administered.
The abbreviations used in the claims and the specification have the following meanings:
M:mol/L
mM：mmol/L
μM：μmol/L
nM：nmol/L；
DMSO: dimethyl sulfoxide
1H NMR: nuclear magnetic resonance hydrogen spectrum
LCMS: liquid phase mass spectrum combination
The term "pharmaceutical composition" means a composition comprising a compound described in the present disclosure or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable ingredient selected from the following, including but not limited to: carriers, diluents, adjuvants, excipients, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, antibacterial agents, antifungal agents, lubricants, dispersing agents, temperature sensitive materials, temperature adjusting agents, adhesives, stabilizers, suspending agents, and the like.
The medicaments or pharmaceutical compositions of the present disclosure can be administered orally, topically, parenterally, or mucosally (e.g., buccally, by inhalation, or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers. It is generally desirable to use the oral route. The active agent may be administered orally in the form of capsules, tablets, etc. (see Remington: the Science and Practice of Pharmacy,20th Edition).
The medicaments or pharmaceutical compositions of the present disclosure may be administered parenterally, i.e. by intravenous (i.v.), intraventricular (i.c.v.), subcutaneous (s.c.), intraperitoneal (i.p.), intramuscular (i.m.), subcutaneous (s.d.), or intradermal (i.d.), by direct injection, via bolus injection or continuous infusion, for example. Formulations for injection may be presented in unit dosage form, for example, in ampules or multi-dose containers with added preservative. The compositions may take the form of suspensions, solutions or emulsions in oily or aqueous vehicles, in the form of excipients (vehicles), and may contain formulatory agents such as anti-settling agents, stabilisers and/or dispersants. Alternatively, the active ingredient may be reconstituted in powder form with a suitable carrier (e.g. sterile pyrogen-free water) prior to use.
The medicaments or pharmaceutical compositions of the present disclosure may also be formulated for rectal administration, for example, as suppositories or retention enemas (e.g., containing conventional suppository bases such as cocoa butter or other glycerides).
The term "treating" includes inhibiting, alleviating, preventing or eliminating one or more symptoms or side effects associated with the disease, condition or disorder being treated.
The terms "reduce", "inhibit", "reduce" or "reduce" are used relative to a control. One skilled in the art will readily determine the appropriate controls for each experiment. For example, a reduced response in a subject or cell treated with a compound is compared to a response in a subject or cell not treated with the compound.
Detailed Description
The preparation methods of the compounds of the present invention are described more specifically below, but these specific preparation methods do not set any limit to the scope of the present invention. In addition, the reaction conditions such as reactants, solvents, bases, amounts of compounds used, reaction temperatures, reaction times, and the like are not limited to the following examples.
The compounds of the present invention may also be conveniently prepared by optionally combining the various synthetic methods described in this specification or known in the art, such combination being readily carried out by one of ordinary skill in the art.
Examples section
Example 1:4- (2-chlorophenyl) -2-cyclopropyl-7- (methylamino) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
a) Preparation of 4- (carbamoylamino) -2- (methylsulfanyl) -1, 3-thiazole-5-carboxylic acid methyl ester
Methyl 4-amino-2- (methylsulfanyl) -1, 3-thiazole-5-carboxylate (5.00 g) and dissolved in methylene chloride (75 mL), chlorosulfonyl isocyanate (4.85 g) was added dropwise under nitrogen at-78 ℃, the reaction system was stirred at 0 ℃ for 30 minutes, the residue obtained by concentration under reduced pressure was dissolved in 4N hydrochloric acid (12 mL), stirred at 100 ℃ for 40 minutes, the reaction system was cooled to room temperature, and the precipitated solid was collected by filtration and washed with water (3×30 mL) and dried in vacuo to give the title compound 5.9g.
b) Preparation of 2- (methylsulfanyl) -4H,6H- [1,3] thiazolo [4,5-d ] pyrimidine-5, 7-dione
4- (carbamoyl) -2- (methylthio) -1, 3-thiazole-5-carboxylic acid methyl ester (5.90 g), methanol (200 mL), an methanolic ammonia solution (100 mL, 7M in MeOH) were added to a 500mL sealed tube, the reaction system was heated to stirring at 80℃for 5 hours, the reaction system was cooled to room temperature, and the resulting title compound was concentrated under reduced pressure to 4.8g.
c) Preparation of 5, 7-dichloro-2- (methylthio) - [1,3] thiazolo [4,5-d ] pyrimidine
2- (methylthio) -4H,6H- [1,3] thiazolo [4,5-d ] pyrimidine-5, 7-dione (3.50 g) was dissolved in phosphorus oxychloride (70 mL), stirred overnight at 110℃under nitrogen atmosphere, the reaction was cooled to room temperature, the resulting residue was concentrated under reduced pressure, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate (100 mL) at 0℃and extracted with ethyl acetate (3X 50 mL), the combined organic layers were washed with saturated brine (1X 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 3.2g.
d) Preparation of 5-chloro-N-methyl-2- (methylsulfanyl) - [1,3] thiazolo [4,5-d ] pyrimidin-7-amine
5, 7-dichloro-2- (methylthio) - [1,3] thiazolo [4,5-d ] pyrimidine (3.50 g), methylamine hydrochloride (1.41 g) were added dropwise to N-methylpyrrolidone (70 mL), N-diisopropylethylamine (7.18 g), the reaction was stirred under nitrogen at room temperature for 3 hours, extracted with ethyl acetate (3X 50 mL), the combined organic layers were washed with saturated brine (1X 100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the evaporated residue was washed with dichloromethane/ethyl acetate/petroleum ether (1/1/1) (3X 10 mL) to give the title compound 1.38g.
e) Preparation of 7- (methylamino) -2- (methylsulfanyl) -4H- [1,3] thiazolo [4,5-d ] pyrimidin-5-one
5-chloro-N-methyl-2- (methylsulfanyl) - [1,3] thiazolo [4,5-d ] pyrimidin-7-amine (700 mg) was added to acetic acid (14 mL), the reaction system was stirred under nitrogen at 100℃for 48 hours, concentrated under reduced pressure, and the solid was collected by filtration and washed with diethyl ether/dichloromethane=1:1 (3X 5 mL) to give 620mg of the title compound.
f) Preparation of 2-methanesulfonyl-7- (methylamino) -4H- [1,3] thiazolo [4,5-d ] pyrimidin-5-one
7- (methylamino) -2- (methylsulfanyl) -4H- [1,3] thiazolo [4,5-d ] pyrimidin-5-one (100 mg) was dissolved in water (1 mL) and acetonitrile (1 mL), hydrogen peroxide (441.99 mg) was added in portions, the reaction system was stirred under nitrogen at room temperature for 4 hours, the reaction solution was concentrated under reduced pressure to 5mL, the reaction system was adjusted to pH7 with saturated aqueous sodium carbonate solution, and the precipitated solid was collected by filtration and washed with brine (3X 5 mL) to give 50mg of the title compound.
g) Preparation of 2-cyclopropyl-7- (methylamino) -4H- [1,3] thiazolo [4,5-d ] pyrimidin-5-one
2-methanesulfonyl-7- (methylamino) -4H- [1,3]Thiazolo [4,5-d]Pyrimidin-5-one (10 mg) was dissolved in tetrahydrofuran (0.50 mL) and cooled to-10℃and magnesium bromide (cyclopropyl) was added in portions under nitrogen (0.058 mL). The reaction was stirred at-10 ℃ for 1 hour and warmed to room temperature and stirred at room temperature for a further 2 hours. The reaction was quenched by addition of saturated aqueous ammonium chloride (0.5 mL), filtered, the filter cake washed with N, N-dimethylformamide (3 x2 mL), and the filtrate concentrated under reduced pressure and purified by preparative HPLC to give 10mg of the title compound under the following conditions (column: xselect CSH OBD Column x 150mm 5 μm; mobile phase a: water (10 MMOL/LNH) 4 HCO 3 ) Mobile phase B is acetonitrile; the flow rate is 1mL/min; gradient 5%B to 40%B in 8min,40%B; the wavelength is 220nm; RT1 (mi)n):5.87)。
h) Preparation of 4- (2-chlorophenyl) -2-cyclopropyl-7- (methylamino) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
2-cyclopropyl-7- (methylamino) -4H- [1,3]Thiazolo [4,5-d]Pyrimidine-5-one (10 mg), 2-chlorophenyl boric acid (10.55 mg), 4-di-tert-butylbipyridine (12.08 mg), copper acetate (24.52 mg), N-dimethylformamide (0.50 mL) were added to a reaction flask, pyridine (35.59 mg) was added dropwise thereto, the reaction mixture was stirred at 60℃overnight, filtered, the cake was washed with dichloromethane/methanol (1/1) (3X 5 mL), the filtrate was concentrated under reduced pressure, and purified by Prep-HPLC to give the title compound 2.7mg under the following conditions (chromatographic column: xselect CSH OBD Column X150 mm 5 μm; mobile phase A: water (10 MMOL/LNH) 4 HCO 3 ) Mobile phase B is acetonitrile; the flow rate is 1mL/min; gradient of 5% B to 60% B in 8min, wavelength of 220nm; RT1 (min): 6.32).
1 H NMR(400MHz,DMSO-d 6 )δ8.31(d,J＝4.8Hz,1H),7.67–7.57(m,1H),7.46(dtt,J＝9.9,7.1,3.9Hz, 3H),2.92(d,J＝4.5Hz,3H),2.44(dq,J＝8.5,4.8,4.3Hz,1H),1.27–1.14(m,2H),0.87(dt,J＝8.5,6.1Hz, 2H).
LCMS m/z＝333[M+1] +
Example 2 4- (2-chlorophenyl) -7- (methylamino) -2- (methylsulfanyl) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
a) Preparation of 4- (2-chlorophenyl) -7- (methylamino) -2- (methylsulfanyl) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
7- (methylamino) -2- (methylsulfanyl) -4H- [1,3] thiazolo [4,5-d ] pyrimidin-5-one (1 g), 2-chlorophenylboronic acid (1.03 g), 4-di-tert-butylbipyridine (1.18 g), copper triflate (475.30 mg) were added to N, N-dimethylformamide (20.00 mL), pyridazine (3.51 g) was added dropwise at room temperature, the reaction mixture was stirred overnight at 60℃and concentrated under reduced pressure, and the residue was evaporated to dryness and purified by column chromatography (mobile phase: dichloromethane/methanol=25/1 (V/V)) to give 600mg of the title compound.
1 H NMR(400MHz,DMSO-d 6 )δ8.36(d,J＝4.7Hz,1H),7.65-7.62(m,1H),7.48(dh,J＝5.6,2.8Hz,3H), 2.93(d,J＝3Hz,3H),2.67(s,3H).
LCMS m/z＝339[M+1] +
Example 3 4- (2-chlorophenyl) -2-methanesulfonyl-7- (methylamino) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
a) Preparation of 4- (2-chlorophenyl) -2-methanesulfonyl-7- (methylamino) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
4- (2-chlorophenyl) -7- (methylamino) -2- (methylthio) - [1,3]Thiazolo [4,5-d]Pyrimidine-5-one (100.00 mg) was added to water (1 mL) and acetonitrile (1 mL), hydrogen peroxide (297.79 mg) was added in portions under nitrogen atmosphere, stirred at room temperature until the reaction was complete, the reaction mixture was filtered, the filter cake was washed with ethanol (3X 5 mL), the filtrate was concentrated under reduced pressure and purified by preparative HPLC to give the title compound 7.1mg under the following conditions (column: xselect CSH OBD Column X150 mm 5 μm; mobile phase A: water (10 MMOL/L NH) 4 HCO 3 ) Mobile phase B is acetonitrile; the flow rate is 1mL/min; gradient 5%B to 55%B in 8min; the wavelength is 220nm; RT1 (min): 5.9).
1 H NMR(400MHz,DMSO-d 6 )δ8.97(d,J＝4.7Hz,1H),7.72–7.64(m,1H),7.58–7.47(m,3H),3.42(s, 3H),3.00(d,J＝4.5Hz,3H).
LCMS m/z＝371[M+1] +
Example 4 4- (2-chlorophenyl) -2-ethyl-7- (methylamino) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
a) Preparation of 4- (2-chlorophenyl) -2-ethyl-7- (methylamino) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
4- (2-chlorophenyl) -2-methanesulfonyl-7- (methylamino) - [1,3]Thiazolo [4,5-d]Pyrimidin-5-one (30.00 mg) additionInto tetrahydrofuran (0.6 mL), a tetrahydrofuran solution (0.162 mL) of ethylmagnesium bromide was added in portions under nitrogen at-10℃and the reaction was stirred at-10℃for 1 hour and at room temperature for 2 hours, quenched with saturated aqueous ammonium chloride (1 mL), filtered, the filter cake was washed with N, N-dimethylformamide (3X 2 mL), the filtrate was concentrated under reduced pressure and purified by preparative HPLC to give the title compound 2mg under the following conditions (Column: XBridge Prep OBD C Column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) 4 HCO 3 ) Mobile phase B is acetonitrile; the flow rate is 1mL/min; gradient 5%B to 42%B in 8min; the wavelength is 220nm; RT1 (min): 7.37).
1 H NMR(400MHz,DMSO-d 6 )δ8.38(d,J＝4.8Hz,1H),7.68–7.59(m,1H),7.53–7.42(m,3H),3.01– 2.91(m,5H),1.22(t,J＝7.4Hz,3H).
LCMS m/z＝321[M+1] +
Example 5 4- (2-chlorophenyl) -2-methyl-7- (methylamino) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
Prepared according to the method of example 4 by substituting methyl magnesium bromide for ethyl magnesium bromide in step a).
1 H NMR(400MHz,DMSO-d 6 )δ8.37(d,J＝4.8Hz,1H),7.63(dd,J＝5.9,3.1Hz,1H),7.47(tq,J＝5.5, 3.0Hz,3H),2.93(d,J＝4.5Hz,3H),2.65(s,3H).
LCMS m/z＝307[M+1] +
Example 6 4- (2-chlorophenyl) -7- (methylamino) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
a) Preparation of 4- (2-chlorophenyl) -7- (methylamino) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
4- (2-chlorophenyl) -2-methylsulfonyl-7- (methylamino) - [1,3]]Thiazolo [4,5-d]Pyrimidin-5-one (10.00 mg) was added to tetrahydrofuran (0.25. 0.25 mL) and ethanol (0.25 mL), sodium borohydride (2.04 mg) was added in portions under nitrogen, the reaction system was stirred overnight at room temperature under nitrogen, and the title compound 1.8mg was purified by preparative HPLC under the following conditions (column: YMC-actual Triart C18, 30X 150mm,5 μm mobile phase A: water (10 mmol/LNH) 4 HCO 3 ) Mobile phase B is acetonitrile; the flow rate is 1mL/min; gradient 5%B to 35%B in 8min, wavelength 220nm; RT1 (min): 7.03).
1 H NMR(400MHz,DMSO-d 6 )δ9.23(s,1H),8.55(d,J＝4.8Hz,1H),7.68–7.60(m,1H),7.54–7.46(m, 3H),2.95(d,J＝4.4Hz,3H).
LCMS m/z＝293[M+1] +
Example 7 4- (2-chlorophenyl) -7- (methylamino) -2-phenyl- [1,3] thiazolo [4,5-d ] pyrimidin-5-one
Prepared according to the method of example 4 by substituting phenylmagnesium bromide for ethylmagnesium bromide in step a).
1 H NMR(400MHz,DMSO-d 6 )δ8.59(d,J＝5.0Hz,1H),7.82–7.76(m,2H),7.72–7.65(m,1H),7.61– 7.47(m,6H),2.98(d,J＝4.3Hz,3H).
LCMS m/z＝369[M+1] +
Example 8 2- (but-3-en-1-yl) -4- (2-chlorophenyl) -7- (methylamino) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
Prepared according to the method of example 4 by substituting ethyl magnesium bromide in step a) with bromo (cyclopropylmethyl) magnesium.
1 H NMR(400MHz,DMSO-d 6 )δ8.40(d,J＝5.2Hz,1H),7.68–7.59(m,1H),7.48(dh,J＝5.5,2.9Hz, 3H),5.79(ddt,J＝16.8,10.3,6.5Hz,1H),5.04-4.99(m,2H),3.05(t,J＝7.4Hz,2H),2.93(d,J＝4.5Hz,3H), 2.37(q,J＝7.1Hz,2H).
LCMS m/z＝347[M+1] +
Example 9 4- (2-chlorophenyl) -2- (cyclobutylmethyl) -7- (methylamino) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
Prepared according to the method of example 4 by substituting ethyl magnesium bromide in step a) with bromo (cyclobutylmethyl) magnesium.
1 H NMR(400MHz,DMSO-d 6 )δ8.37(d,J＝4.7Hz,1H),7.63(dd,J＝5.8,3.3Hz,1H),7.47(tq,J＝5.4, 2.9Hz,3H),3.04(d,J＝7.5Hz,2H),2.93(d,J＝4.5Hz,3H),2.61–2.51(m,1H),2.00(dq,J＝10.9,6.6,4.9Hz, 2H),1.88–1.66(m,4H).
LCMS m/z＝361[M+1] +
EXAMPLE 10 3- [ 2-cyclopropyl-7- (dimethylamino) -5-oxo- [1,3] thiazolo [4,5-d ] pyrimidin-4-yl ] -N-phenylbenzamide
a) Preparation of 5-chloro-N, N-dimethyl-2- (methylthio) - [1,3] thiazolo [4,5-d ] pyrimidin-7-amine
5, 7-dichloro-2- (methylthio) - [1,3] thiazolo [4,5-d ] pyrimidine (6.1 g), dimethylamine hydrochloride (2.96 g) were added dropwise to N-methylpyrrolidone (122 mL), N-diisopropylethylamine (12.51 g), the reaction was stirred at room temperature under a nitrogen atmosphere for 3 hours, extracted with ethyl acetate (3X 50 mL), the combined organic layers were washed with saturated brine (1X 100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 6g.
b) Preparation of 7- (dimethylamino) -2- (methylthio) -4H- [1,3] thiazolo [4,5-d ] pyrimidin-5-one
5-chloro-N, N-dimethyl-2- (methylthio) - [1,3] thiazolo [4,5-d ] pyrimidin-7-amine (6 g) was added to acetic acid (200 mL), and the reaction system was stirred under nitrogen at 100℃for 48 hours and concentrated under reduced pressure to give the title compound 4g.
c) Preparation of 7- (dimethylamino) -2-methanesulfonyl-4H- [1,3] thiazolo [4,5-d ] pyrimidin-5-one
7- (dimethylamino) -2- (methylthio) -4H- [1,3] thiazolo [4,5-d ] pyrimidin-5-one (2 g) was dissolved in water (20 mL) and acetonitrile (20 mL), hydrogen peroxide (8.33 g) was added in portions, the reaction system was stirred under nitrogen at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure, and the residue was evaporated to dryness and purified by column chromatography (mobile phase: dichloromethane/methanol=20/3 (V/V)) to give the title compound 1g.
d) Preparation of 2-cyclopropyl-7- (dimethylamino) -4H- [1,3] thiazolo [4,5-d ] pyrimidin-5-one
7- (dimethylamino) -2-methanesulfonyl-4H- [1,3] thiazolo [4,5-d ] pyrimidin-5-one (200 mg) was dissolved in tetrahydrofuran (2.67 mL) and cooled to-10℃and magnesium bromide (cyclopropyl) was added in portions under nitrogen (0.16 mL). The reaction was stirred at-10 ℃ for 1 hour and warmed to room temperature, stirred at room temperature for 2 hours, quenched by addition of saturated aqueous ammonium chloride (1 mL), filtered, concentrated under reduced pressure, and the residue evaporated to dryness was purified by column chromatography (mobile phase: dichloromethane/methanol=5/1 (V/V)) to give 80mg of the title compound.
e) Preparation of 3- [ 2-cyclopropyl-7- (dimethylamino) -5-oxo- [1,3] thiazolo [4,5-d ] pyrimidin-4-yl ] -N-phenylbenzamide
2-cyclopropyl-7- (dimethylamino) -4H- [1,3]Thiazolo [4,5-d]Pyrimidine-5-one (50 mg), 3- (phenylcarbamoyl) phenylboronic acid (76.51 mg), 4-di-tert-butylbipyridine (56.80 mg), copper triflate (229.59 mg), N-dimethylformamide (1 mL) were added to a reaction flask, pyridine (167.38 mg) was added dropwise thereto, the reaction mixture was stirred overnight at 40℃under an oxygen atmosphere, filtered, and the filtrate was concentrated under reduced pressure and purified by Prep-HPLC to give the title compound 60mg under the following conditions (column: YMC-structures Triart C18, 30X 150mm, 5 μm; mobile phase A: water (10 mmol/LNH) 4 HCO 3 ) Mobile phase B is acetonitrile; the flow rate is 1mL/min; gradient 15%B to 60%B in 8min, 60% B;the wavelength is UV220 nm; RT1 (min) 8.08; column temperature 25 deg.c).
1 H NMR(400MHz,DMSO-d 6 )δ10.30(s,1H),8.01(dt,J＝7.9,1.4Hz,1H),7.89(t,J＝1.9Hz,1H),7.81 –7.73(m,2H),7.64(t,J＝7.8Hz,1H),7.52(ddd,J＝7.9,2.1,1.1Hz,1H),7.36(dd,J＝8.6,7.3Hz,2H),7.17 –7.02(m,1H),3.32(s,6H),2.46–2.37(m,1H),1.24–1.13(m,2H),0.96–0.82(m,2H).
LCMS m/z＝432[M+1] +
Example 11 2-cyclopropyl-7- (dimethylamino) -4- [3- (1-phenoxyethyl) phenyl ] - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
a) Preparation of 1-bromo-3- (1-phenoxyethyl) benzene
1- (3-bromophenyl) ethanol (500 mg), phenol (234.04 mg), triphenylphosphine (1.1 g) and tetrahydrofuran (5 mL) were added to a reaction flask, diisopropyl azodicarboxylate (854.84 mg) was added dropwise at 0℃under a nitrogen atmosphere, the reaction system was stirred at room temperature for 2 hours, the reaction solution was decompressed, and the residue was evaporated to dryness and purified by column chromatography (mobile phase: petroleum ether/ethyl acetate=10/1 (V/V)), to give 170mg of the title compound.
b) Preparation of 3- (1-phenoxyethyl) phenylboronic acid
1-bromo-3- (1-phenoxyethyl) benzene (6 g) was dissolved in tetrahydrofuran (90 mL), n-butyllithium (1.66, g) was added dropwise at-78 ℃ under nitrogen atmosphere, the reaction system was stirred at-78 ℃ for 30 minutes, trimethyl borate (3.37 g) was added, gradually warmed to room temperature, stirred for 1 hour, 2M aqueous hydrochloric acid (20 mL) and ice water (300 mL) were added to quench the reaction, extraction was performed with ethyl acetate (3×200 mL), the combined organic layers were washed with saturated brine (2×300 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was evaporated to dryness and purified by column chromatography (mobile phase: petroleum ether/ethyl acetate=10/1 (V/V)), to give 1.2g of the title compound.
c) Preparation of 2-cyclopropyl-7- (dimethylamino) -4- [3- (1-phenoxyethyl) phenyl ] - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
Prepared according to the method of example 10 by replacing 3- (phenylcarbamoyl) phenylboronic acid in step e) with 3- (1-phenoxyethyl) phenylboronic acid.
1 H NMR(400MHz,DMSO-d 6 )δ7.46–7.40(m,2H),7.32(d,J＝1.9Hz,1H),7.25–7.19(m,2H),7.19– 7.16(m,1H),6.94–6.84(m,3H),5.52(q,J＝6.4Hz,1H).3.29–3.29(m,6H),2.39(td,J＝8.3,4.2Hz,1H), 1.55(d,J＝6.4Hz,3H),1.22–1.11(m,2H),0.94–0.77(m,2H).
LCMS m/z＝433[M+1] +
Example 12 2-cyclopropyl-7- (dimethylamino) -4- [3- (phenoxymethyl) phenyl ] - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
Prepared according to the method of example 11 by substituting 3- (1-phenoxyethyl) phenylboronic acid in step c) with 3- (phenoxymethyl) phenylboronic acid.
1 H NMR(400MHz,DMSO-d 6 )δ7.52(dd,J＝4.8,1.3Hz,2H),7.40(d,J＝2.2Hz,1H),7.34–7.24(m, 3H),7.06–7.00(m,2H),6.95(t,J＝7.3Hz,1H),5.15(s,2H),3.35(s,6H),2.45(dd,J＝8.3,4.6Hz,1H),1.26 –1.17(m,2H),0.96–0.87(m,2H).
LCMS m/z＝419[M+1] +
Example 13 4- [3- (1, 3-Benzooxazol-2-ylamino) phenyl ] -2-cyclopropyl-7- (dimethylamino) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
a) Preparation of 4- (3-bromophenyl) -2-cyclopropyl-7- (dimethylamino) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
Prepared according to the method of example 10 by replacing 3- (phenylcarbamoyl) phenylboronic acid in step e) with 3-bromophenylboronic acid.
b) 4- [3- (1, 3-Benzooxazol-2-ylamino) phenyl group]-2-cyclopropyl-7- (dimethylamino) - [1,3]Thiazolo [4,5-d]Preparation of pyrimidin-5-one 4- (3-bromophenyl) -2-cyclopropyl-7- (dimethylamino) - [1,3]Thiazolo [4,5-d]Pyrimidine-5-one (80 mg), 2-aminobenzoxazole (82.27 mg), potassium carbonate (39.56 mg), methanesulfonic acid (2-di-tert-butylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (32.48 mg), t-butanol (1 mL) were added to a reaction flask, heated to 100deg.C under nitrogen atmosphere and stirred for 3 hours, and the title compound 7.5mg was purified by preparative HPLC under the following conditions (column: YMC-acts Triart C18, 30 x 150mm,5 μm; mobile phase A: water (10 mmol/LNH) 4 HCO 3 ) Mobile phase B is acetonitrile; the flow rate is 1mL/min; gradient 20% B to 45% B in 8min,45% B; the wavelength is 220nm; RT1 (min): 7.02).
1 H NMR(400MHz,DMSO-d 6 )δδ10.80(s,1H),7.73(dt,J＝6.3,1.8Hz,2H),7.53–7.39(m,3H),7.22(td, J＝7.6,1.2Hz,1H),7.14(td,J＝7.7,1.3Hz,1H),6.93(dt,J＝7.9,1.4Hz,1H),3.34(d,J＝6.6Hz,6H),2.42 (td,J＝8.3,4.1Hz,1H),1.18(dt,J＝8.1,3.5Hz,2H),0.95–0.88(m,2H).
LCMS m/z＝445[M+1] +
EXAMPLE 14 (E) -N "-cyano-N' - {3- [ 2-cyclopropyl-7- (dimethylamino) -5-oxo- [1,3] thiazolo [4,5-d ] pyrimidin-4-yl ] phenyl } -N-phenylguanidine
a) Preparation of 2-cyclopropyl-7- (dimethylamino) -4- (3-nitrophenyl) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
Prepared according to the method of example 10 by replacing 3- (phenylcarbamoyl) phenylboronic acid in step e) with 3-nitrophenylboronic acid.
b) Preparation of 4- (3-aminophenyl) -2-cyclopropyl-7- (dimethylamino) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
2-cyclopropyl-7- (dimethylamino) -4- (3-nitrophenyl) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one (70 mg), methanol (3 mL), palladium on carbon (2 mg) were added to a reaction flask, stirred at room temperature under a hydrogen atmosphere for 2 hours, filtered, and the filter cake was washed with methanol (2X 2 mL) and concentrated under reduced pressure to give 80mg of the title compound.
c) Preparation of (Z) -N' -cyano-N- {3- [ 2-cyclopropyl-7- (dimethylamino) -5-oxo- [1,3] thiazolo [4,5-d ] pyrimidin-4-yl ] phenyl } -1-phenoxyformamidine
4- (3-Aminophenyl) -2-cyclopropyl-7- (dimethylamino) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one (80 mg), cyano (diphenoxymethylene) amine (116.43 mg) were dissolved in isopropanol (2 mL), stirred at room temperature under nitrogen for 2 hours, concentrated under reduced pressure, and the residue was purified by column chromatography (mobile phase: dichloromethane/methanol=20/3 (V/V)) to give the title compound 15mg.
d) Preparation of (E) -N "-cyano-N' - {3- [ 2-cyclopropyl-7- (dimethylamino) -5-oxo- [1,3] thiazolo [4,5-d ] pyrimidin-4-yl ] phenyl } -N-phenylguanidine
(Z) -N' -cyano-N- {3- [ 2-cyclopropyl-7- (dimethylamino) -5-oxo- [1,3]Thiazolo [4,5-d]Mixture base of pyrimidine-4-, and its use]Phenyl } -1-phenoxyformamidine (15 mg), aniline (14.81 mg), 1, 4-dioxane (1 mL) were added to a reaction flask, and the reaction was stirred at 110℃for 2 hours, purified by Prep-HPLC to give 0.3mg of the title compound under the following conditions (column: YMC-actual Triart C18 ExRS, 30X 150mm, 5 μm; mobile phase A: water (10 mmol/LNH) 4 HCO 3 ) Mobile phase B is acetonitrile; the flow rate is 1mL/min; gradient 15%B to 50%B in 8min, 50% B; the wavelength is UV220 nm; RT1 (min) 7.28; column temperature 25 deg.c).
LCMS m/z＝471[M+1] +
Example 15 2-cyclopropyl-7- (dimethylamino) -4- (3- { [1,2,4] triazolo [1,5-a ] pyridin-2-ylamino } phenyl) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
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Prepared according to the method of example 13 by substituting 2-aminobenzoxazole in step b) with [1,2,4] triazolo [1,5-a ] pyridin-2-amine.
1 H NMR(400MHz,DMSO-d 6 )δ9.77(s,1H),8.78(d,J＝6.7Hz,1H),7.69(d,J＝7.9Hz,1H),7.62(t,J ＝2.0Hz,1H),7.59–7.50(m,2H),7.37(t,J＝8.1Hz,1H),7.09–6.93(m,1H),6.75(d,J＝7.7Hz,1H),3.32(s, 6H),2.43(d,J＝8.2Hz,1H),1.22–1.12(m,2H),0.91(dd,J＝4.6,2.8Hz,2H).
LCMS m/z＝445[M+1] +
Example 16 2-cyclopropyl-7- (dimethylamino) -4- [3- (1, 3-oxazol-2-ylamino) phenyl ] - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
Prepared according to the method described in example 13, substituting 2-aminobenzoxazole in step b) with oxazol-2-amine.
1 H NMR(400MHz,DMSO-d 6 )δ10.24(s,1H),7.65(d,J＝1.0Hz,1H),7.60–7.50(m,2H),7.37(t,J＝ 7.9Hz,1H),6.96(d,J＝1.0Hz,1H),6.87–6.68(m,1H),3.31(s,6H),2.47–2.36(m,1H),1.18(dd,J＝8.1, 3.0Hz,2H),0.90(dd,J＝4.7,2.7Hz,2H).
LCMS m/z＝395[M+1] +
EXAMPLE 17 4- [3- (benzyloxy) phenyl ] -2-cyclopropyl-7- (dimethylamino) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
a) Preparation of 4- [3- (benzyloxy) phenyl ] -2-cyclopropyl-7- (dimethylamino) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
4- (3-bromophenyl) -2-cyclopropyl-7- (dimethylamino) - [1,3]Thiazolo [4,5-d]Pyrimidine-5-one (20 mg), benzyl alcohol (8.29 mg), copper iodide (0.97 mg), 3,4,7, 8-tetramethyl-1, 10-phenanthroline (2.42 mg), cesium carbonate (24.98 mg), toluene (1.5 mL) were added to a microwave tube, reacted with microwaves at 150℃for 4 hours, and purified by Prep-HPLC to give the title compound2.1mg of the compound, purified by a chromatographic Column of XBridge Prep OBD C Column,30 x 150mm,5 μm; mobile phase A Water (10 mmol/LNH) 4 HCO 3 ) Mobile phase B is acetonitrile; the flow rate is 1 mL/min; gradient 30%B to 70%B in 8min,70%B; the wavelength is UV 220nm; RT1 (min) 6.33; column temperature 25 deg.c).
1 H NMR(400MHz,DMSO-d 6 )δ7.48–7.44(m,2H),7.42–7.34(m,4H),7.07–7.03(m,1H),6.94(t,J＝ 2.4Hz,1H),6.86–6.81(m,1H),5.10(s,2H),3.28(s,6H),2.42(t,J＝4.8Hz,1H),1.21–1.16(m,2H),0.91– 0.87(m,2H).
LCMS m/z＝419[M+1] +
Example 18 2-cyclopropyl-7- (dimethylamino) -4- {3- [ (5-methyl-1, 3-oxazol-2-yl) amino ] phenyl } - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
Prepared according to the method described in example 13, substituting 5-methyl-1, 3-oxazol-2-amine for 2-aminobenzoxazole in step b).
1 H NMR(400MHz,DMSO-d 6 )δ10.07(s,1H),7.52(dq,J＝7.8,1.2Hz,2H),7.35(td,J＝7.6,1.4Hz, 1H),6.86–6.71(m,1H),6.54(t,J＝1.4Hz,1H),3.30(s,6H),2.45–2.36(m,1H),2.22(d,J＝1.4Hz,3H), 1.29–1.08(m,2H),0.90(dd,J＝4.7,2.8Hz,2H).
LCMS m/z＝409[M+1] +
Example 19N-cyclopropyl-3- [ 2-cyclopropyl-7- (dimethylamino) -5-oxo- [1,3] thiazolo [4,5-d ] pyrimidin-4-yl ] benzamide
Prepared according to the method of example 10 by replacing 3- (phenylcarbamoyl) phenylboronic acid in step e) with 3- (cyclopropylcarbamoyl) phenylboronic acid.
1 H NMR(400MHz,DMSO-d 6 )δ8.48(d,J＝4.4Hz,1H),7.86(m,1H),7.72(t,J＝2.0Hz,1H),7.54(t,J ＝7.8Hz,1H),7.42(m,1H),3.29(s,6H),2.86(m,1H),2.45–2.40(m,1H),1.21–1.16(m,2H),0.91–0.86(m, 2H),0.69(m,2H),0.59–0.54(m,2H).
LCMS m/z＝396[M+1] +
Example 20 2-cyclopropyl-7- (dimethylamino) -4- {3- [ (2-fluorophenyl) methoxy ] phenyl } - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
a) Preparation of 2-cyclopropyl-7- (dimethylamino) -4- {3- [ (2-fluorophenyl) methoxy ] phenyl } - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
2-cyclopropyl-7- (dimethylamino) -4- (3-hydroxyphenyl) - [1,3]Thiazolo [4,5-d]Pyrimidine-5-one (20 mg), 1- (bromomethyl) -2-fluorobenzene (12.66 mg), potassium carbonate (16.83 mg) and acetonitrile (2 mL) were added to a reaction flask, and the reaction system was stirred under nitrogen at 82℃for 2 hours, and the title compound 10.9mg was purified by pre-HPLC as follows (column: YMC-actual Triart C18, 30X 150 mm,5 μm; mobile phase A: water (10 mmol/LNH) 4 HCO 3 ) Mobile phase B is acetonitrile; the flow rate is 1mL/min; gradient 15%B to 42%B in 8min,42%B; the wavelength is UV 220nm; RT1 (min) 7.52; column temperature 25 deg.c).
1 H NMR(400MHz,DMSO-d 6 )δ7.58(m,1H),7.47–7.34(m,2H),7.29–7.21(m,2H),7.07(m,1H),7.00 –6.92(m,1H),6.86(m,1H),5.13(s,2H),3.28(s,6H),2.42(d,J＝4.8Hz,1H),1.19(m,2H),0.94–0.87(m, 2H).
LCMS m/z＝437[M+1] +
Example 21 2-cyclopropyl-7- (dimethylamino) -4- {3- [ (4-fluorophenyl) methoxy ] phenyl } - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
Prepared according to the method of example 20 by replacing 1- (bromomethyl) -2-fluorobenzene in step a) with 1- (bromomethyl) -4-fluorobenzene.
1 H NMR(400MHz,DMSO-d 6 )δ7.54–7.49(m,2H),7.37(t,J＝8.0Hz,1H),7.26–7.19(m,2H),7.05(m, 1H),6.93(t,J＝2.4Hz,1H),6.84(m,1H),5.08(s,2H),3.29(s,6H),2.43–2.39(m,1H),1.22–1.16(m,2H), 0.91–0.86(m,2H).
LCMS m/z＝437[M+1] +
EXAMPLE 22 3- [ 2-cyclopropyl-7- (dimethylamino) -5-oxo- [1,3] thiazolo [4,5-d ] pyrimidin-4-yl ] -N- (2, 2-trifluoroethyl) benzamide
a) 3- [ 2-cyclopropyl-7- (dimethylamino) -5-oxo- [1,3]Thiazolo [4,5-d]Pyrimidin-4-yl]Preparation of N- (2, 2-trifluoroethyl) benzamide 3- [ 2-cyclopropyl-7- (dimethylamino) -5-oxo- [1,3]]Thiazolo [4,5-d]Pyrimidin-4-yl]Benzoic acid solution (30 mg), 2-trifluoroethylamine (11.67 mg), TBTU (35.14 mg), N-diisopropylethylamine (38.08 mg), dichloromethane (1.5 mL) were added to a reaction flask and stirred at room temperature under nitrogen for 1 hour, and the title compound 6.5mg was purified by preparative HPLC under the following conditions (Column: XBridge Prep OBD C Column,30 x 150mm,5 μm; mobile phase A: water (10 mmol/LNH) 4 HCO 3 ) Mobile phase B is acetonitrile; the flow rate is 1mL/min; gradient 10%B to 55%B in 8min,55%B; the wavelength is UV 220nm; RT1 (min) 6.98; column temperature 25 deg.c).
1 H NMR(400MHz,DMSO-d 6 )δ9.15(t,J＝6.0Hz,1H),7.94(m,1H),7.82(t,J＝2.0Hz,1H),7.61(t,J＝ 7.8Hz,1H),7.51(m,1H),4.09(m,2H),3.31(s,6H),2.44–2.40(m,1H),1.18(m,2H),0.94–0.84(m,2H).
LCMS m/z＝438[M+1] +
Example 23 2-cyclopropyl-7- (dimethylamino) -4- [3- (hydroxymethyl) phenyl ] - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
a) Preparation of [ (3-bromophenyl) methoxy ] (tert-butyl) dimethylsilane
(3-bromophenyl) methanol (10 g), t-butyldimethylchlorosilane (9.67 g), triethylamine (16.23 g), and methylene chloride (100 mL) were added to a reaction flask, stirred at room temperature under a nitrogen atmosphere for 1 hour, concentrated under reduced pressure, and the residue was evaporated to dryness and purified by column chromatography (mobile phase: petroleum ether/ethyl acetate=20/3 (V/V)) to give 14g of the title compound.
b) Preparation of 3- { [ (tert-butyldimethylsilyl) oxy ] methyl } phenylboronic acid
[ (3-bromophenyl) methoxy ] (tert-butyl) dimethylsilane (2 g) was dissolved in tetrahydrofuran (40 mL), n-butyllithium (0.64 g) was added dropwise under nitrogen atmosphere at-78℃and stirred for 30 minutes, then trimethyl borate (1.03 g) was added, stirred at room temperature for 2 hours, water (40 mL) was added at 0℃to quench the reaction, extraction was performed with ethyl acetate (3X 40 mL), the combined organic layers were washed with saturated brine (1X 40 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by reverse flash chromatography under the following conditions: xselect CSH OBD Column 30 x 150mm 5 μm; mobile phase A water (10 MMOL/LNH4HCO 3), mobile phase B acetonitrile; the flow rate is 1 mL/min; gradient 10%B to 40%B in 8min,40%B; the wavelength is 220nm, and the chromatographic column temperature is 25 ℃ to obtain 500mg of the title compound.
c) Preparation of 4- (3- { [ (tert-butyldimethylsilyl) oxy ] methyl } phenyl) -2-cyclopropyl-7- (dimethylamino) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
Prepared according to the method of example 10 by replacing 3- (phenylcarbamoyl) phenylboronic acid in step e) with 3- { [ (tert-butyldimethylsilyl) oxy ] methyl } phenylboronic acid.
d) Preparation of 2-cyclopropyl-7- (dimethylamino) -4- [3- (hydroxymethyl) phenyl ] - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
2-cyclopropyl-7- (dimethylamino) -4- [3- (hydroxymethyl) phenyl ]]-[1,3]Thiazolo [4,5-d]Pyrimidin-5-one (2)10 mg) was dissolved in tetrahydrofuran (2 mL), tetrabutylammonium fluoride (120.23 mg) was added, and the reaction system was stirred at room temperature under nitrogen for 0.5 hour, and purified by Prep-HPLC to give the title compound 12.2mg under the following conditions (Column: XBridge Prep OBD C Column,30 x 150mm,5 μm; mobile phase A water (10 mmol/L NH) 4 HCO 3 ) Mobile phase B is acetonitrile; the flow rate is 1mL/min; gradient 5%B to 40%B in 8min; the wavelength is UV220 nm; RT1 (min) 7.18; column temperature 25 deg.c).
1 H NMR(400MHz,DMSO-d 6 )7.41(m,1H),7.33(m,1H),7.18(s,1H),7.11(m,1H),5.29(t,J＝5.8 Hz,1H),4.54(d,J＝5.0Hz,2H),3.31(m,6H),2.40(m,1H),1.19(m,2H),0.89(m,2H).
LCMS m/z＝343[M+1] +
Example 24 2-cyclopropyl-7- (dimethylamino) -4- [3- (pyridin-2-ylmethoxy) phenyl ] - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
Prepared according to the method of example 20 by replacing 1- (bromomethyl) -2-fluorobenzene in step a) with 2- (bromomethyl) pyridine.
1 H NMR(400MHz,DMSO-d 6 )δ8.58(m,1H),7.85(m,1H),7.55(m,1H),7.40–7.33(m,2H),7.07(m, 1H),6.97–6.94(m,1H),6.86(m,1H),5.18(s,2H),3.29(s,6H),2.41(m,1H),1.22–1.16(m,2H),0.91–0.86 (m,2H).
LCMS m/z＝420[M+1] +
Example 25 2-cyclopropyl-7- (dimethylamino) -4- (3- (pyridin-3-ylmethoxy) phenyl) thiazolo [4,5-d ] pyrimidin-5-one
Prepared according to the method of example 20 by replacing 1- (bromomethyl) -2-fluorobenzene in step a) with 3- (bromomethyl) pyridine.
1 H NMR(400MHz,DMSO-d 6 )δ8.68(s,1H),8.56(d,J＝4.0Hz,1H),7.89(dt,J＝7.9,1.9Hz,1H),7.46 –7.41(m,1H),7.38(d,J＝8.0Hz,1H),7.10–7.05(m,1H),6.97(t,J＝2.2Hz,1H),6.89–6.84(m,1H),5.16 (s,2H),3.30(s,6H),2.42(d,J＝4.5Hz,1H),1.19(dt,J＝8.1,3.5Hz,2H),0.92–0.86(m,2H).
LCMS m/z＝420[M+1] +
EXAMPLE 26 2-cyclopropyl-7- (dimethylamino) -4- [3- (pyridin-4-ylmethoxy) phenyl ] - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
Prepared according to the method of example 20 by replacing 1- (bromomethyl) -2-fluorobenzene in step a) with 4- (bromomethyl) pyridine.
1 H NMR(400MHz,DMSO-d 6 )δ8.51(d,J＝5.2Hz,2H),7.40–7.30(m,3H),7.00(dd,J＝8.3,2.6Hz, 1H),6.89(d,J＝2.3Hz,1H),6.80(dd,J＝7.7,1.8Hz,1H),5.12(s,2H),3.22(s,6H),2.33(dq,J＝8.5,4.7,4.3 Hz,1H),1.15–1.09(m,2H),0.84–0.79(m,2H).
LCMS m/z＝420[M+1] +
EXAMPLE 27 2-cyclopropyl-7- (dimethylamino) -4- {3- [ (4-methyl-1, 3-oxazol-2-yl) amino ] phenyl } - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
Prepared according to the method described in example 13, substituting 4-methyl-1, 3-oxazol-2-amine for 2-aminobenzoxazole in step b).
1 H NMR(400MHz,DMSO-d 6 )δ10.12(s,1H),7.66–7.47(m,2H),7.43–7.23(m,2H),6.86–6.60(m, 1H),3.31(s,6H),2.41(dq,J＝8.5,4.9,4.2Hz,1H),2.02(d,J＝1.4Hz,3H),1.22–1.10(m,2H),0.96–0.86 (m,2H).
LCMS m/z＝409[M+1] +
EXAMPLE 28 4- [ 2-cyclopropyl-7- (dimethylamino) -5-oxo- [1,3] thiazolo [4,5-d ] pyrimidin-4-yl ] -2-phenyl-3H-isoindol-1-one
Prepared according to the method of example 10 by substituting 2-cyclopropyl-7- (dimethylamino) -4H- [1,3] thiazolo [4,5-d ] pyrimidin-5-one in step e) with 4- [ 2-cyclopropyl-7- (dimethylamino) -5-oxo- [1,3] thiazolo [4,5-d ] pyrimidin-4-yl ] -2, 3-dihydro-isoindol-1-one and 3- (phenylcarbamoyl) phenylboronic acid.
1 H NMR(400MHz,DMSO-d 6 )δ7.87(m,3H),7.71–7.59(m,2H),7.45–7.35(m,2H),7.17(t,J＝7.3 Hz,1H),4.78(s,2H),3.33(m,6H),2.45–2.40(m,1H),1.29–1.10(m,2H),0.95–0.79(m,2H).
LCMS m/z＝444[M+1] +
Example 29 2-cyclopropyl-7- (dimethylamino) -4- {3- [ (3-fluorophenyl) methoxy ] phenyl } - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
Prepared according to the method of example 20 by replacing 1- (bromomethyl) -2-fluorobenzene in step a) with 1- (bromomethyl) -3-fluorobenzene.
1 H NMR(400MHz,DMSO-d 6 )δ7.44(m,1H),7.38(t,J＝8.0Hz,1H),7.30(m,2H),7.20–7.13(m,1H), 7.06(m,1H),6.94(t,J＝2.4Hz,1H),6.85(m,1H),5.13(s,2H),3.29(s,6H),2.41(m,1H),1.22–1.16(m,2H), 0.91–0.84(m,2H).
LCMS m/z＝487[M+1] +
Example 30 4- [ 2-cyclopropyl-7- (dimethylamino) -5-oxo- [1,3] thiazolo [4,5-d ] pyrimidin-4-yl ] -2, 3-dihydro-isoindol-1-one
Prepared according to the method of example 10 by replacing 3- (phenylcarbamoyl) phenylboronic acid in step e) with 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-isoindol-1-one.
1 H NMR(400MHz,DMSO-d 6 )δ8.56(s,1H),7.73(m,1H),7.60(m,1H),7.51(m,1H),4.17(d,J＝17.7 Hz,1H),4.05(d,J＝17.7Hz,1H),2.46(m,3H),2.45–2.42(m,3H),2.40(m,1H),1.27–1.13(m,2H),0.96– 0.80(m,2H).
LCMS m/z＝368[M+1] +
Example 31 4- [3- (1, 3-Benzooxazol-2-yloxy) phenyl ] -2-cyclopropyl-7- (dimethylamino) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
Prepared according to the method of example 20 by replacing 1- (bromomethyl) -2-fluorobenzene in step a) with 2-chlorobenzoxazole.
1 H NMR(400MHz,DMSO-d 6 )δ7.67–7.62(m,1H),7.62–7.58(m,2H),7.56–7.52(m,2H),7.34–7.29 (m,3H),3.32(s,6H),2.47–2.40(m,1H),1.20(dt,J＝8.2,3.5Hz,2H),0.99–0.93(m,2H).
LCMS m/z＝446[M+1] +
Example 32 3- [ 2-cyclopropyl-7- (dimethylamino) -5-oxo- [1,3] thiazolo [4,5-d ] pyrimidin-4-yl ] -N-methyl-N- (2, 2-trifluoroethyl) benzamide
a) Preparation of methyl 3- [ 2-cyclopropyl-7- (dimethylamino) -5-oxo- [1,3] thiazolo [4,5-d ] pyrimidin-4-yl ] benzoate
Prepared according to the method of example 10 by replacing 3- (phenylcarbamoyl) phenylboronic acid in step e) with 3- (methoxycarbonyl) phenylboronic acid.
b) Preparation of 3- [ 2-cyclopropyl-7- (dimethylamino) -5-oxo- [1,3] thiazolo [4,5-d ] pyrimidin-4-yl ] benzoic acid
Methyl 3- [ 2-cyclopropyl-7- (dimethylamino) -5-oxo- [1,3] thiazolo [4,5-d ] pyrimidin-4-yl ] benzoate (200 mg), lithium hydroxide (38.79 mg), tetrahydrofuran (10 mL) were added to a reaction flask, the reaction was stirred at 25 ℃ for 1 hour, and the reaction solution was purified by reverse flash chromatography under the following conditions to give 180mg of the title compound: a chromatographic Column XBridge Prep OBD C Column,30 x 150mm,5 μm; mobile phase A is water (10 mmol/L NH4HCO 3), mobile phase B is acetonitrile; the flow rate is 1mL/min; gradient 20%B to 55%B in 8min,55%B; the wavelength is UV220 nm; the column temperature was 25 ℃.
c) Preparation of 3- [ 2-cyclopropyl-7- (dimethylamino) -5-oxo- [1,3] thiazolo [4,5-d ] pyrimidin-4-yl ] -N-methyl-N- (2, 2-trifluoroethyl) benzamide
3- [ 2-cyclopropyl-7- (dimethylamino) -5-oxo- [1,3]Thiazolo [4,5-d]Pyrimidin-4-yl]Benzoic acid (50 mg), oxalyl chloride (35.61 mg) and dichloromethane (1 mL) were added to a reaction flask, then N, N-dimethylformamide (0.01 mL) was added, the reaction was stirred at 25 ℃ for 1 hour, the reaction solution was concentrated under reduced pressure, dissolved with tetrahydrofuran, and the reaction solution was alkalified to ph=8 with N, N-diisopropylethylamine, methyl (2, 2-trifluoroethyl) amine (23.80 mg) was added, stirred at 25 ℃ for 2 hours, and the title compound 9.6mg was purified by Prep-HPLC under the following purification conditions: (chromatographic Column: XBridge Prep OBD C Column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/LNH) 4 HCO 3 ) Mobile phase B is acetonitrile; the flow rate is 1mL/min; gradient 20%B to 50%B in 8min,50%B; the wavelength is UV 220nm; RT1 (min) 6.80; column temperature 25 deg.c).
1 H NMR(400MHz,DMSO-d 6 )δ7.57(t,J＝7.8Hz,1H),7.50–7.30(m,3H),4.36(d,J＝5.6Hz,2H), 3.07(s,3H),2.49(d,J＝2.0Hz,6H),2.46–2.37(m,1H),1.21–1.13(m,2H),0.93–0.82(m,2H).
LCMS m/z＝452[M+1] +
Example 33 2-cyclopropyl-7- (dimethylamino) -4- [3- (2-fluorophenoxymethyl) phenyl ] - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
a) Preparation of methyl {3- [ 2-cyclopropyl-7- (dimethylamino) -5-oxo- [1,3] thiazolo [4,5-d ] pyrimidin-4-yl ] phenyl } methanesulfonate
2-cyclopropyl-7- (dimethylamino) -4- [3- (hydroxymethyl) phenyl ] - [1,3] thiazolo [4,5-d ] pyrimidin-5-one solution (50 mg), triethylamine (59.10 mg) were dissolved in tetrahydrofuran (1 mL), methanesulfonyl chloride (33.45 mg) was added under ice bath, the reaction was stirred at room temperature for 4 hours under nitrogen atmosphere, the reaction was quenched with water (1 mL) at room temperature, extracted with ethyl acetate (3×1 mL), and the combined organic layers were washed with saturated brine (2 mL) and concentrated under reduced pressure to give 50mg of the title compound.
b) Preparation of 2-cyclopropyl-7- (dimethylamino) -4- [3- (2-fluorophenoxymethyl) phenyl ] - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
Sodium hydride (5.71 mg) was added to a solution of o-fluorophenol (26.66 mg) in N, N-dimethylformamide (1 mL) under nitrogen with stirring for 30 min, and {3- [ 2-cyclopropyl-7- (dimethylamino) -5-oxo- [1,3 ]Thiazolo [4,5-d]Pyrimidin-4-yl]Phenyl } methanesulfonate (50 mg), the reaction was stirred at room temperature for 4 hours, filtered, the filter cake was washed with N, N-dimethylformamide (1X 1 mL), the filtrate was concentrated under reduced pressure, and the title compound 5.8mg was obtained by preparative HPLC as follows: (chromatographic column: YMC-actual Triart C18,30 x 150mm,5 μm; mobile phase A: water (10 mmol/LNH) 4 HCO 3 ) Mobile phase B is acetonitrile; the flow rate is 1mL/min; gradient 30%B to 65%B in 8min, 65% B; the wavelength is UV 220nm; RT1 (min) 8.07; column temperature 25 deg.c).
1 H NMR(400MHz,DMSO-d 6 )δ7.55–7.46(m,2H),7.39–7.17(m,4H),7.16–6.90(m,2H),5.21(s, 2H),3.30-3.27(m,6H),2.41(m,1H),1.27–1.08(m,2H),0.96–0.79(m,2H).
LCMS m/z＝437[M+1] +
Example 34 2-cyclopropyl-7- (dimethylamino) -4- [3- (3-fluorophenoxymethyl) phenyl ] - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
Prepared according to the method of example 33, by replacing the o-fluorophenol in step b) with m-fluorophenol.
1 H NMR(400MHz,DMSO-d 6 )δ7.53–7.45(m,2H),7.36(m,1H),7.31(m,1H),7.25(m,1H),6.96– 6.85(m,2H),6.82–6.74(m,1H),5.16(s,2H),3.30-3.27(m,6H),2.41(m,1H),1.28–1.09(m,2H),0.96– 0.81(m,2H).
LCMS m/z＝437[M+1] +
Example 35 2-cyclopropyl-7- (dimethylamino) -4- [3- (4-fluorophenoxymethyl) phenyl ] - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
Prepared according to the method of example 33, by replacing the o-fluorophenol of step b) with p-fluorophenol.
1 H NMR(400MHz,DMSO-d 6 )δ7.56–7.46(m,2H),7.38(S,1H),7.27(m,1H),7.18–7.09(m,2H), 7.08–6.99(m,2H),5.13(s,2H),3.34(s,6H),2.42(m,1H),1.30–1.14(m,2H),1.00–0.81(m,2H).
LCMS m/z＝437[M+1] +
Example 36 2-benzyl-4- [ 2-cyclopropyl-7- (dimethylamino) -5-oxo- [1,3] thiazolo [4,5-d ] pyrimidin-4-yl ] -3H-isoindol-1-one
a) Preparation of 2-benzyl-4- [ 2-cyclopropyl-7- (dimethylamino) -5-oxo- [1,3] thiazolo [4,5-d ] pyrimidin-4-yl ] -3H-isoindol-1-one
Sodium hydride (2.61 mg) was added to a solution of benzyl bromide (18.62 mg) in N, N-dimethylformamide (1 mL) under nitrogen with stirring for 30 min, and 4- [ 2-cyclopropyl-7- (dimethylamino) -5-oxo- [1,3]Thiazolo [4,5-d]Pyrimidin-4-yl]-2, 3-dihydro-isoindol-1-one (20 mg), the reaction stirred at room temperature for 2 hours, filtered, the filter cake washed with N, N-dimethylformamide (1 x1 mL), the filtrate concentrated under reduced pressure and purified by preparative HPLC to give the title compound 6.8mg, purification method as follows: (chromatographic Column: XBridge Prep OBD C Column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/LNH) 4 HCO 3 ) Mobile phase B is acetonitrile; the flow rate is 1mL/min; gradient 15%B to 62%B in 8min,62%B; the wavelength is UV 220nm; RT1 (min) 9.02; column temperature 25 deg.c).
1 H NMR(400MHz,DMSO-d 6 )δ7.80(m,1H),7.63(t,J＝7.7Hz,1H),7.53(m,1H),7.34(m,2H), 7.31–7.20(m,3H),4.69(s,2H),4.25–3.96(m,2H),3.32(m,6H),2.38(m,1H),1.20–1.06(m,2H),0.91 –0.69(m,2H).
LCMS m/z＝458[M+1] +
Example 37 3- [ 2-cyclopropyl-7- (dimethylamino) -5-oxo- [1,3] thiazolo [4,5-d ] pyrimidin-4-yl ] -N- (3-fluorophenyl) benzamide
Prepared according to the method of example 32 by replacing the methyl (2, 2-trifluoroethyl) amine of step c) with 3-fluoroaniline.
1 H NMR(400MHz,DMSO-d 6 )δ10.47(s,1H),8.01(dt,J＝7.9,1.4Hz,1H),7.88(t,J＝1.9Hz,1H),7.75 (dt,J＝11.7,2.3Hz,1H),7.65(t,J＝7.8Hz,1H),7.61–7.48(m,2H),7.39(td,J＝8.2,6.7Hz,1H),6.94(td,J ＝8.5,2.6Hz,1H),3.31(s,6H),2.44(dt,J＝9.0,4.7Hz,1H),1.26–1.08(m,2H),0.98–0.81(m,2H).
LCMS m/z＝450[M+1] +
EXAMPLE 38 3- [ 2-cyclopropyl-7- (dimethylamino) -5-oxo- [1,3] thiazolo [4,5-d ] pyrimidin-4-yl ] -N- (2-fluorophenyl) benzamide
Prepared according to the method of example 32 by replacing the methyl (2, 2-trifluoroethyl) amine of step c) with 2-fluoroaniline.
1 H NMR(400MHz,DMSO-d 6 )δ10.18(s,1H),8.03(dt,J＝8.0,1.3Hz,1H),7.91(t,J＝1.9Hz,1H),7.64 (t,J＝7.9Hz,1H),7.59(td,J＝7.9,1.5Hz,1H),7.53(ddd,J＝7.9,2.0,1.1Hz,1H),7.32–7.26(m,2H),7.26– 7.19(m,1H),3.31(s,6H),2.47–2.40(m,1H),1.23–1.16(m,2H),0.96–0.88(m,2H).
LCMS m/z＝450[M+1] +
Example 39 4- [3- (1, 3-Benzooxazol-2-yloxy) phenyl ] -2-cyclopropyl-7- (dimethylamino) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
Prepared according to the method of example 32 by replacing methyl (2, 2-trifluoroethyl) amine in step c) with 4-fluorobenzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ9.10(t,J＝6.0Hz,1H),7.93(dt,J＝7.9,1.4Hz,1H),7.80(t,J＝1.9Hz, 1H),7.58(t,J＝7.8Hz,1H),7.46(ddd,J＝7.8,2.1,1.1Hz,1H),7.41–7.30(m,2H),7.22–7.07(m,2H),4.46 (d,J＝5.9Hz,2H),3.30(s,6H),2.42(td,J＝8.2,4.3Hz,1H),1.23–1.11(m,2H),0.97–0.80(m,2H).
LCMS m/z＝464[M+1] +
EXAMPLE 40 1- {3- [ 2-cyclopropyl-7- (dimethylamino) -5-oxo- [1,3] thiazolo [4,5-d ] pyrimidin-4-yl ] phenyl } -3-phenylimidazolin-2-one
a) Preparation of 1- {3- [ 2-cyclopropyl-7- (dimethylamino) -5-oxo- [1,3] thiazolo [4,5-d ] pyrimidin-4-yl ] phenyl } -3-phenylimidazolin-2-one
4- (3-bromophenyl) -2-cyclopropyl-7- (dimethylamino) - [1,3]Thiazolo [4,5-d]Pyrimidine-5-one (30 mg), 1-phenylimidazolin-2-one (18.7 mg), potassium phosphate (32.7 mg), cuprous iodide (2.9 mg), N' -dimethylethylenediamine (1.4 mg) were added to N, N-dimethylformamide (1 mL), stirred at 130℃under a reaction nitrogen atmosphere for 5 hours, filtered, the filter cake was washed with N, N-dimethylformamide (3X 1 mL), and the filtrate was concentrated under reduced pressure to give 15mg of the title compound by preparative HPLC purification under the following conditions: (chromatographic Column: XBridge Prep OBD C Column, 30X 150 mm,5 μm; mobile phase A: water (10 mmol/LNH) 4 HCO 3 ) Mobile phase B is acetonitrile; the flow rate is 1mL/min; gradient 20%B to 55%B in 8min,55%B; the wavelength is UV 220nm; RT1 (min) 8.12; column temperature 25 deg.c).
1 H NMR(400MHz,DMSO-d 6 )δ7.67–7.55(m,4H),7.50–7.31(m,3H),7.11–6.92(m,2H),3.98(s,4H), 3.30(s,6H),2.43(ddd,J＝8.2,4.7,3.4Hz,1H),1.19(dt,J＝8.2,3.5Hz,2H),0.96–0.89(m,2H).
LCMS m/z＝473[M+1] +
EXAMPLE 41 3- [ 2-cyclopropyl-7- (dimethylamino) -5-oxo- [1,3] thiazolo [4,5-d ] pyrimidin-4-yl ] -N- (4-fluorophenyl) benzamide
Prepared according to the method of example 32 by replacing the methyl (2, 2-trifluoroethyl) amine of step c) with 4-fluoroaniline.
1 H NMR(400MHz,DMSO-d 6 )δ10.36(s,1H),8.02(d,J＝7.8Hz,1H),7.88(t,J＝1.9Hz,1H),7.84– 7.72(m,2H),7.65(t,J＝7.9Hz,1H),7.58–7.47(m,1H),7.20(t,J＝8.9Hz,2H),3.33(s,6H),2.44(td,J＝8.5, 4.2Hz,1H),1.25–1.14(m,2H),0.98–0.81(m,2H).
LCMS m/z＝450[M+1] +
Example 42 4- [3- (1, 3-Benzooxazol-2-yl) phenyl ] -2-cyclopropyl-7- (dimethylamino) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
a) Preparation of 4- [3- (1, 3-benzoxazol-2-yl) phenyl ] -2-cyclopropyl-7- (dimethylamino) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
4- (3-bromophenyl) -2-cyclopropyl-7- (dimethylamino) - [1,3]Thiazolo [4,5-d]Pyrimidine-5-one (45 mg), benzoxazole (23.29 mg), cuprous bromide (4.95 mg), cesium carbonate (112.41 mg), [1,1' -bis (di-t-butylphosphine) ferrocene]Palladium (II) dichloride (7.50 mg) and N, N-dimethylformamide (1 mL) were added to a reaction flask, and the reaction system was stirred at 130℃for 1 hour under a nitrogen atmosphere, and the title compound 14.4mg was obtained by separation and purification by preparative HPLC under the following purification conditions: (chromatographic Column: XBridge Prep OBD C Column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/LNH) 4 HCO 3 ) Mobile phase B is acetonitrile; the flow rate is 1mL/min; gradient 20%B to 50%B in 8min,55%B; the wavelength is UV220 nm; column temperature 25 deg.c).
1 H NMR(400MHz,DMSO-d 6 )δ8.23(dt,J＝7.9,1.3Hz,1H),8.11(t,J＝1.9Hz,1H),7.85–7.78(m,2H), 7.73(t,J＝7.9Hz,1H),7.60–7.56(m,1H),7.45(tt,J＝7.4,5.8Hz,2H),3.32(s,6H),2.45–2.41(m,1H),1.21 –1.15(m,2H),0.93–0.88(m,2H).
LCMS m/z＝430[M+1] +
EXAMPLE 43 2-cyclopropyl-4- (3-cyclopropylphenyl) -7- (dimethylamino) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
a) Preparation of 2-cyclopropyl-4- (3-cyclopropylphenyl) -7- (dimethylamino) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
4- (3-bromophenyl) -2-cyclopropyl-7- (dimethylamino) - [1,3]Thiazolo [4,5-d]Pyrimidine-5-one (50 mg), cyclopropylboronic acid (21.95 mg),Potassium phosphate (81.37 mg), palladium acetate (2.90 mg), tricyclohexylphosphine (3.58 mg), toluene (1 mL) and water (0.1 mL) were added to a reaction flask, and the mixture was stirred at 80℃for 2 hours under a nitrogen atmosphere, and the reaction solution was concentrated under reduced pressure and purified by preparative HPLC to give the title compound 4.1mg under the following purification conditions: (chromatographic Column: XBridge Prep OBD C Column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) 4 HCO 3 ) Mobile phase B is acetonitrile; the flow rate is 1mL/min; gradient 20%B to 53%B in 8min,53%B; the wavelength is UV 220nm; RT1 (min) 7.72; column temperature 25 deg.c).
1 H NMR(400MHz,DMSO-d 6 )δ7.32(t,J＝7.8Hz,1H),7.08(dt,J＝7.8,1.4Hz,1H),7.01(ddd,J＝7.8, 2.1,1.1Hz,1H),6.96(t,J＝1.9Hz,1H),3.29(s,6H),2.42(ddd,J＝8.1,4.7,3.4Hz,1H),1.95(tt,J＝8.4,5.1 Hz,1H),1.18(dt,J＝8.2,3.5Hz,2H),1.03–0.93(m,2H),0.92–0.82(m,2H),0.73–0.57(m,2H).
LCMS m/z＝353[M+1] +
EXAMPLE 44 3- [ 2-cyclopropyl-7- (dimethylamino) -5-oxo- [1,3] thiazolo [4,5-d ] pyrimidin-4-yl ] -N- (2, 3, 6-trifluorophenyl) benzamide
Prepared according to the method of example 32 by replacing the methyl (2, 2-trifluoroethyl) amine of step c) with 2,3, 6-trifluoroaniline.
1 H NMR(400MHz,DMSO-d 6 )δ10.42(s,1H),8.18–7.97(m,1H),7.92(s,1H),7.67(t,J＝8.2Hz,1H), 7.57(d,J＝8.2Hz,1H),7.52(s,1H),7.29(s,1H),3.31(s,6H),2.33(s,1H),1.20(d,J＝8.1Hz,2H),0.91(d,J ＝4.9Hz,2H).
LCMS m/z＝486[M+1] +
Example 45 3- [ 2-cyclopropyl-7- (dimethylamino) -5-oxo- [1,3] thiazolo [4,5-d ] pyrimidin-4-yl ] -N- (2, 6-difluorophenyl) benzamide
Prepared according to the method of example 32 by replacing the methyl (2, 2-trifluoroethyl) amine of step c) with 2, 6-difluoroaniline.
1 H NMR(400MHz,DMSO-d 6 )δ10.24(s,1H),8.07(dt,J＝7.8,1.4Hz,1H),7.94(t,J＝1.9Hz,1H),7.68 (t,J＝7.9Hz,1H),7.58(ddd,J＝7.9,2.1,1.1Hz,1H),7.49–7.35(m,1H),7.24(q,J＝8.4Hz,2H),3.35(s, 6H),2.46(dd,J＝8.2,4.7Hz,1H),1.21(dt,J＝8.3,3.6Hz,2H),0.96–0.87(m,2H).
LCMS m/z＝468[M+1] +
Example 46 3- [ 2-cyclopropyl-7- (dimethylamino) -5-oxo- [1,3] thiazolo [4,5-d ] pyrimidin-4-yl ] -N- (2, 5-difluorophenyl) benzamide
Prepared according to the method of example 32 by replacing the methyl (2, 2-trifluoroethyl) amine of step c) with 2, 5-difluoroaniline.
1 H NMR(400MHz,DMSO-d 6 )δ10.28(s,1H),8.02(dt,J＝7.9,1.3Hz,1H),7.90(t,J＝1.9Hz,1H),7.65 (t,J＝7.8Hz,1H),7.61–7.45(m,2H),7.36(ddd,J＝10.0,9.1,5.1Hz,1H),7.13(ddt,J＝7.9,5.8,4.0Hz,1H), 3.31(s,6H),2.47–2.38(m,1H),1.27–1.13(m,2H),0.96–0.85(m,2H).
LCMS m/z＝468[M+1] +
Example 47 3- [ 2-cyclopropyl-7- (dimethylamino) -5-oxo- [1,3] thiazolo [4,5-d ] pyrimidin-4-yl ] -N- (2-fluorophenyl) -N-methylbenzamide
Prepared according to the method of example 32 by replacing the methyl (2, 2-trifluoroethyl) amine of step c) with 2-fluoro-N-methylaniline.
1 H NMR(400MHz,DMSO-d 6 )δ7.44(t,J＝8.0Hz,1H),7.37–7.09(m,7H),3.29(s,6H),2.49(s,3H), 2.40(tt,J＝8.1,4.7Hz,1H),1.26–1.16(m,2H),0.95–0.85(m,2H)
LCMS m/z＝464[M+1] +
EXAMPLE 48 2-cyclopropyl-7- (dimethylamino) -4- (pyridin-3-yl) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
Prepared according to the method of example 10 by replacing 3- (phenylcarbamoyl) phenylboronic acid in step e) with pyridin-3-ylboronic acid.
1 H NMR(400MHz,DMSO-d 6 )δ8.62(s,2H),7.78(d,J＝8.0Hz,1H),7.56(s,1H),3.30(s,6H),2.44(dd, J＝8.5,4.1Hz,1H),1.19(dq,J＝7.1,4.1Hz,2H),0.98–0.84(m,2H).
LCMS m/z＝314[M+1] +
Example 49 4-chloro-N-cyclopropyl-3- [ 2-cyclopropyl-7- (dimethylamino) -5-oxo- [1,3] thiazolo [4,5-d ] pyrimidin-4-yl ] benzamide
Prepared according to the method of example 10 by replacing 3- (phenylcarbamoyl) phenylboronic acid in step e) with 2-chloro-5- (cyclopropylcarbamoyl) phenylboronic acid.
1 H NMR(400MHz,DMSO-d 6 )δ8.59(d,J＝4.5Hz,1H),7.56(d,J＝8.5Hz,1H),7.36(dd,J＝8.5,2.5 Hz,1H),7.33(d,J＝2.5Hz,1H),3.31(s,6H),2.81(td,J＝7.4,3.7Hz,1H),2.43(dq,J＝8.2,4.3,3.7Hz,1H), 1.21(td,J＝7.3,4.2Hz,2H),1.03–0.82(m,2H),0.67(dt,J＝6.9,3.3Hz,2H),0.58–0.48(m,2H).
LCMS m/z＝430[M+1] +
Example 50 2-cyclopropyl-4- [3- (5-cyclopropyl-1, 3, 4-oxadiazol-2-yl) phenyl ] -7- (dimethylamino) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
a) Preparation of 2-cyclopropyl-1, 3, 4-oxadiazole
Cyclopropanecarbohydrazide (10 g), p-toluenesulfonic acid (50 mg), trimethyl orthoformate (15.90 g) were added to a reaction flask, stirred overnight at 110℃under nitrogen atmosphere, distilled under reduced pressure, and a fraction at 50-80℃was collected to give 8g of the title compound.
b) Preparation of 2-cyclopropyl-4- [3- (5-cyclopropyl-1, 3, 4-oxadiazol-2-yl) phenyl ] -7- (dimethylamino) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one by the method of preparation according to example 42, the benzoxazole in step a) was replaced by 2-cyclopropyl-1, 3, 4-oxadiazole.
1 H NMR(400MHz,DMSO-d 6 )δ7.98(m,1H),7.87(t,J＝2.0Hz,1H),7.68(t,J＝8.0Hz,1H),7.53(m, 1H),7.08(s,2H),2.48(m,2H),2.42(m,2H),2.37–2.24(m,2H),1.20–1.12(s,6H),0.92–0.87(m,2H). LCMS m/z＝421[M+1] +
Example 51 2-cyclopropyl-4- [3- (5-cyclopropyl-1, 3, 4-oxadiazol-2-yl) phenyl ] -7- (dimethylamino) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
a) Preparation of 3- [ 2-cyclopropyl-7- (dimethylamino) -5-oxo- [1,3] thiazolo [4,5-d ] pyrimidin-4-yl ] benzaldehyde
Prepared according to the method of example 10 by replacing 3- (phenylcarbamoyl) phenylboronic acid in step e) with 3-formylphenylboronic acid.
b) Preparation of N' - [ (1E) - {3- [ 2-cyclopropyl-7- (dimethylamino) -5-oxo- [1,3] thiazolo [4,5-d ] pyrimidin-4-yl ] phenyl } methylene ] -4-methylbenzenesulfonyl hydrazide
TsNHNH 2 (109.42 mg) was dissolved in methanol (1 mL) at room temperature under nitrogen, and 3- [ 2-cyclopropane was added1, 3-hydroxy-7- (dimethylamino) -5-oxo-1]Thiazolo [4,5-d]Pyrimidin-4-yl]Benzaldehyde (200 mg) was stirred at room temperature for 1 hour, and the precipitated solid was collected by filtration and washed with methanol (1×1 mL) to give the title compound 190mg.
c) Preparation of 2-cyclopropyl-4- [3- (5-cyclopropyl-1, 3, 4-oxadiazol-2-yl) phenyl ] -7- (dimethylamino) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
N' - [ (1E) - {3- [ 2-cyclopropyl-7- (dimethylamino) -5-oxo- [1,3]Thiazolo [4,5-d]Pyrimidin-4-yl]Phenyl } methylene]4-Methylbenzenesulfonyl hydrazide (50 mg), cyclopropylboronic acid (12.7 mg), potassium carbonate (40.8 mg), 1, 4-dioxane (0.5 mL) were added to the reaction flask, and reacted at 110℃for 2 hours under a nitrogen atmosphere to give the title compound 10.5mg by preparative HPLC under the following conditions: (Column temperature: XBridge Prep OBD C Column,30 x 150mm,5um; mobile phase A: water (10 mmol/LNH) 4 HCO 3 ) Mobile phase B is acetonitrile; the flow rate is 1mL/min; gradient 10%B to 67%B in 10min,67%B; the wavelength is UV 220nm; RT1 (min) 9.13; column temperature 25 deg.c).
1 H NMR(400MHz,DMSO-d 6 )(400MHz,DMSO-d 6 ,ppm):δ7.37(m,1H),7.28(m,1H),7.13(s,1H), 7.08(m,1H),3.29(s,6H),2.56(m,2H),2.41(m,1H),1.18(m,2H),1.03–0.95(m,1H),0.93–0.84(m, 2H),0.55–0.40(m,2H),0.31–0.15(m,2H).
LCMS m/z＝367[M+1] +
Example 52 2-cyclopropyl-4- [3- (5-cyclopropyl-1, 3, 4-oxadiazol-2-yl) phenyl ] -7- (dimethylamino) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
a) Preparation of ethyl 2-oxo-2- (pyridin-2-yl) acetate
2-bromo-1- (pyridin-2-yl) ethanone hydrobromide (5 g), sodium acetate (4.1 g), ethanol (150 mL) were added to the reaction flask and stirred at 80℃for 2 hours, the reaction mixture was cooled to room temperature, filtered, the filtrate was washed with dichloromethane and concentrated under reduced pressure to give the title compound 6.2g.
b) Preparation of 2-hydroxy-1- (pyridin-2-yl) ethanone
Ethyl 2-oxo-2- (pyridin-2-yl) acetate (4.5 g) was dissolved in hydrogen chloride (6 m 125 ml), heated to 50 ℃ and stirred for 1.5h, the reaction was neutralized to pH7 with aqueous sodium bicarbonate, extracted with ethyl acetate (100 ml x 3), the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the title compound 2g.
c) Preparation of 4- (pyridin-2-yl) -1, 3-oxazol-2-amine
2-hydroxy-1- (pyridin-2-yl) ethanone (2 g) was dissolved in 95% ethanol (25 mL), cyanamide (0.92 g) was added, heated under reflux for 14 hours, after the reaction solution was cooled to room temperature, the pH was adjusted to 10 using 1M aqueous sodium hydroxide solution, the aqueous phase was extracted with ethyl acetate (3×40 mL), the combined organic phases were dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the evaporated residue was purified by column chromatography (mobile phase: dichloromethane/methanol=20/1 (V/V)) to give 300mg of the title compound.
d) Preparation of 2-cyclopropyl-4- [3- (5-cyclopropyl-1, 3, 4-oxadiazol-2-yl) phenyl ] -7- (dimethylamino) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one by the method of preparation according to example 13, the 2-aminobenzooxazol in step b) was replaced by 4- (pyridin-2-yl) -1, 3-oxazol-2-amine.
1 H NMR(400MHz,DMSO-d 6 )(400MHz,DMSO-d 6 ,ppm):δ10.68(s,1H),8.55(ddd,J＝4.8,1.8,1.0 Hz,1H),7.85(td,J＝7.8,1.8Hz,1H),7.64–7.60(m,2H),7.59(s,1H),7.57(dt,J＝8.0,1.1Hz,1H),7.44– 7.39(m,1H),7.26(ddd,J＝7.6,4.8,1.1Hz,1H),6.89–6.84(m,1H),3.31(s,6H),2.43–2.39(m,1H),1.21– 1.16(m,2H),0.94–0.89(m,2H).
LCMS m/z＝472[M+1] +
Example 53 4- (3-Benzylphenyl) -2-cyclopropyl-7- (dimethylamino) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
Prepared according to the method of example 10 by replacing 3- (phenylcarbamoyl) phenylboronic acid in step e) with 3-benzylphenylboronic acid.
1 H NMR(400MHz,DMSO-d 6 )(400MHz,DMSO-d 6 ,ppm):7.40-7.34(m,1H),7.31–7.22(m,5H), 7.22-7.16(m,1H),7.14-7.12(m,1H),7.11-7.06(m,1H),3.98(s,2H),3.30(m,6H),1.25(m,3H),0.84(m,2H). LCMS m/z＝403[M+1] +
Example 54 6-cyclopropyl-4- (dimethylamino) -1- (pyridin-3-yl) thieno [3,2-d ] pyrimidin-2-one
Prepared according to the method of example 10 by substituting 2-cyclopropyl-7- (dimethylamino) -4H- [1,3] thiazolo [4,5-d ] pyrimidin-5-one in step e) with 6-cyclopropyl-4- (dimethylamino) -1H-thieno [3,2-d ] pyrimidin-2-one and 3- (phenylcarbamoyl) phenylboronic acid with pyridin-3-ylboronic acid.
1 H NMR(400MHz,DMSO-d 6 )(400MHz,DMSO-d 6 ,ppm):δ8.67(s,1H),8.59–8.48(m,1H),7.81(d,J ＝8.0Hz,1H),7.59(dd,J＝8.2,4.4Hz,1H),6.20(s,1H),3.32(s,6H),2.21(tt,J＝8.6,4.9Hz,1H),1.08(td,J ＝7.0,4.4Hz,2H),0.79–0.71(m,2H).
LCMS m/z＝313[M+1] +
Example 55 4- (2-chlorophenyl) -2-cyclopropyl-7- (dimethylamino) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
Prepared according to the method of example 10 by replacing step e) 3- (phenylcarbamoyl) phenylboronic acid with 2-chlorophenyl boronic acid. Chiral resolution was performed according to the following method (column: CHIRAL ART Cellulose-SB, 2X 25cm,5 μm; mobile phase A: mtBE (0.1% DEA) -HPLC; mobile phase B: meOH-HPLC; flow rate: 20mL/min; gradient: 20%B to 20%B in 11min; wavelength: UV 220/254nm; RT1 (min): 6.01; RT2 (min): 7.51; sample solvent: meOH-HPLC; injection: 1 mL), under specific chromatographic conditions (column: CHIRAL Cellulose SB 4.6.4.6X 100mm,3 μm; mobile phase A: mtBE (0.1% DEA): B: meOH=80:20; flow rate: 1.0mL/min; wavelength: UV254 nm; RT1 (min): 2.459RT2 (min): 3.071; sample solvent: meOH HPLC; injection: 1 mL), retention time 2.459 min: 55A, retention time 3.071 min: 55B.
55A: 1 H NMR(400MHz,Chloroform-d)δ7.62(dt,J＝6.0,3.3Hz,1H),7.50–7.44(m,2H),7.44–7.37 (m,1H),3.31(s,6H),2.42(tt,J＝8.2,4.8Hz,1H),1.19(ddd,J＝8.2,4.2,1.3Hz,2H),0.87(ddd,J＝7.8,4.9, 1.4Hz,2H).
55B: 1 H NMR(400MHz,Chloroform-d)δ7.65–7.59(m,1H),7.50–7.44(m,2H),7.44–7.39(m,1H), 3.31(s,6H),2.46–2.38(m,1H),1.24–1.12(m,2H),0.92–0.80(m,2H).
LCMS m/z＝347[M+1] +
Example 56 2-cyclopropyl-7- (dimethylamino) -4- (2-ethynylphenyl) thiazolo [4,5-d ] pyrimidin-5 (4H) -one
Prepared according to the method described in example 10, by replacing step e) 3- (phenylcarbamoyl) phenylboronic acid with 2-ethynylphenylboronic acid.
Chiral resolution was performed according to the following method (column: CHIRALART Cellulose-SB, 2X 25cm,5 μm; mobile phase A: mtBE (0.1% DEA) -HPLC, mobile phase B: etOH-HPLC; flow rate: 1mL/min; gradient: 20%B to 20%B in 9.5min; wavelength: UV 220/254nm; RT1 (min): 5.5; RT2 (min): 8.61; sample: meOH-HPLC; injection amount: 1.2 mL), under specific chromatographic conditions (column: CHIRAL Cellulose SB 4.6.4.6X 100mm,3 um; mobile phase: mtBE (0.1% DEA): meOH=80:20; flow rate: 1.0mL/min; wavelength: UV254nm; RT1 (min): 2.230RT2 (min): 3.354; sample S: meOH-HPLC; injection amount: 1 mL), retention time 2.230 min: 56A, retention time 3.354 min: 56B.
56A: 1 HNMR(400MHz,Chloroform-d)δ7.61(dd,J＝7.6,1.6Hz,1H),7.52(td,J＝7.6,1.6Hz,1H),7.44(td, J＝7.6,1.4Hz,1H),7.32(dd,J＝7.9,1.3Hz,1H),4.06(s,1H),3.31(s,6H),2.46–2.36(m,1H),1.18(dtd,J＝ 8.0,4.1,2.8Hz,2H),0.94–0.76(m,2H).
56B: 1 HNMR(400MHz,Chloroform-d)δ7.61(dd,J＝7.7,1.6Hz,1H),7.52(td,J＝7.7,1.7Hz,1H),7.44(td,J ＝7.6,1.4Hz,1H),7.32(dd,J＝7.8,1.3Hz,1H),4.06(s,1H),3.31(s,6H),2.46–2.37(m,1H),1.18(dtd,J＝ 8.1,4.1,2.8Hz,2H),0.92–0.81(m,2H).
Example 57 3- [ 6-cyclopropyl-4- (dimethylamino) -2-oxothieno [3,2-d ] pyrimidin-1-yl ] -N- (2-fluorophenyl) -N-methylbenzamide
a) Preparation of 6-bromo-2-chloro-N, N-dimethylthieno [3,2-d ] pyrimidin-4-amine
6-bromo-2, 4-dichlorothieno [3,2-d ] pyrimidine (2 g), dimethylamine (0.64 g), N-diisopropylethylamine (3.64 g), 1, 4-dioxane (15 mL) were added to a reaction flask, the reaction was stirred at room temperature for 2 hours, extracted with ethyl acetate (3X 20 mL), the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 2g.
b) Preparation of 6-bromo-4- (dimethylamino) -1H-thieno [3,2-d ] pyrimidin-2-one
6-bromo-2-chloro-N, N-dimethylthieno [3,2-d ] pyrimidin-4-amine (2 g) was dissolved in acetic acid (40 mL), stirred at 100℃for 12 hours, the reaction solution was concentrated under reduced pressure, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography, and the residue was evaporated to dryness and purified by column chromatography (mobile phase: dichloromethane/methanol=20/1 (V/V)), to give the title compound 1.9g.
c) Preparation of 6-cyclopropyl-4- (dimethylamino) -1H-thieno [3,2-d ] pyrimidin-2-one
6-bromo-4- (dimethylamino) -1H-thieno [3,2-d ] pyrimidin-2-one (2 g), cyclopropylboronic acid (1.88 g), palladium acetate (0.33 g), tricyclohexylphosphine (0.41 g), potassium phosphate (6.97 g), toluene (8 mL), water (2 mL) were stirred under nitrogen at 80℃for 2 hours, the reaction solution was concentrated under reduced pressure, and the residue was evaporated to dryness and purified by column chromatography (mobile phase: dichloromethane/methanol=20/1 (V/V)) to give 210mg of the title compound.
d) Preparation of methyl 3- [ 6-cyclopropyl-4- (dimethylamino) -2-oxothieno [3,2-d ] pyrimidin-1-yl ] benzoate
Prepared according to the method described in example 10, by replacing step e) 3- (phenylcarbamoyl) phenylboronic acid with 3- (methoxycarbonyl) phenylboronic acid.
e) Preparation of 3- [ 6-cyclopropyl-4- (dimethylamino) -2-oxothiophen [3,2-d ] pyrimidin-1-yl ] benzoic acid
Prepared according to the method of example 32 by substituting methyl 3- [ 6-cyclopropyl-4- (dimethylamino) -2-oxothieno [3,2-d ] pyrimidin-1-yl ] benzoate for methyl 3- [ 2-cyclopropyl-7- (dimethylamino) -5-oxo- [1,3] thiazolo [4,5-d ] pyrimidin-4-yl ] benzoate of step b).
f) Preparation of 3- [ 6-cyclopropyl-4- (dimethylamino) -2-oxothieno [3,2-d ] pyrimidin-1-yl ] -N- (2-fluorophenyl) -N-methylbenzamide
Prepared according to the method of example 32, replacing step c) methyl (2, 2-trifluoroethyl) amine with 2-fluoro-N-methylaniline.
1 H NMR(400MHz,DMSO-d 6 ,)δ7.43(d,J＝15.4Hz,3H),7.34–7.26(m,1H),7.16(td,J＝19.9,19.2, 9.4Hz,4H),5.46(s,1H),3.32(s,3H),3.29(s,6H),2.17(tt,J＝8.2,4.9Hz,1H),1.21–1.08(m,2H),0.69(dd,J ＝4.9,2.1Hz,2H).
LCMS m/z＝463[M+1] +
Example 58 2-cyclopropyl-4- [3- (1-cyclopropylpyrazol-4-yl) phenyl ] -7- (dimethylamino) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
a) Preparation of 2-cyclopropyl-4- [3- (1-cyclopropylpyrazol-4-yl) phenyl ] -7- (dimethylamino) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
4- (3-bromophenyl) -2-cyclopropyl-7- (dimethylamino) - [1,3] thiazolo [4,5-d ] pyrimidin-5-one (30 mg), 1-cyclopropyl-4- (4, 5-dioxaborolan-2-yl) pyrazole (23.3 mg), sodium carbonate (24.3 mg), ditriphenylphosphine palladium dichloride (5.3 mg), 1, 4-dioxane (3 mL) and water (0.2 mL) were added to the reaction flask, and after stirring at 80℃for 2 hours under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure and purified by Prep-HPLC to give the title compound 9.8mg.
1 H NMR(400MHz,DMSO-d 6 )δ8.26(s,1H),7.87(s,1H),7.61(d,J＝8.0Hz,1H),7.48(d,J＝1.9 Hz,1H),7.43(t,J＝7.8Hz,1H),7.06(dd,J＝8.0,2.1Hz,1H),3.73(dt,J＝7.4,3.6Hz,1H),3.30(s,6H), 2.41(tt,J＝8.5,4.7Hz,1H),1.26–1.12(m,2H),1.07(p,J＝4.0Hz,2H),1.03–0.94(m,2H),0.94–0.82 (m,2H).
LCMS m/z＝419[M+1] +
Example 59 2-cyclopropyl-7- (dimethylamino) -4- [3- (1H-pyrazol-3-yl) phenyl ] - [1,3] thiazolo [4,5-d ] pyrimidin-5-one
Prepared according to the method of example 58 by substituting 1-cyclopropyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazole of step a) into 1-cyclopropyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole.
1 H NMR(400MHz,DMSO-d 6 )δ7.86–7.76(m,2H),7.65(t,J＝1.9Hz,1H),7.48(t,J＝7.8Hz,1H), 7.20–7.13(m,1H),6.71(d,J＝2.4Hz,1H),3.75(tt,J＝7.4,3.8Hz,1H),3.30(s,6H),2.42(ddd,J＝8.2,6.5, 4.1Hz,1H),1.17(dt,J＝8.1,3.5Hz,2H),1.09(dd,J＝5.3,2.5Hz,2H),0.97(td,J＝7.3,4.8Hz,2H),0.94– 0.80(m,2H).
LCMS m/z＝419[M+1] +
Biological Activity test
1. MAT2A enzymology test method
1. Experimental procedure
a) First, 5 XMAT 2AAssay Buffer (250 mM Tris-HCl, pH8.0;250mM KCl;75mM MgCl2;0.025% bsa; 0.05% brij35;1.5mM EDTA), partially diluted to 1X for use;
b) MAT2A enzyme (BPS, 71401) was formulated and added: MAT2A enzyme was formulated with 1 XMAT 2AAssay Buffer to 3.674 ng/. Mu.L (1.67×, final concentration 2.20 ng/. Mu.L), and 15. Mu.L of 1.67 XMAT 2A enzyme solution was added to each of the compound test well and the negative control well, respectively, using a BioTek (MultiFlo FX) automatic liquid separator, while 15. Mu.L of 1 XMAT 2AAssay Buffer was added to the blank control well;
c) Compound preparation and addition: test compounds were diluted from 10mM stock solution to 100. Mu.M using DMSO, and the positive drug AGI-24512 (commercially available) was diluted under the same conditions, and automatically injected into each well using a Tecan compound titrator (D300 e) according to a preset concentration gradient, with a very small injection volume. The concentration gradient was initially 1. Mu.M, diluted 1/2log, and a total of 8 gradients were set. Centrifuging at 2500rpm for 30s, and incubating at 25 ℃ for 30min;
d) Preparing ATP: 10mM TP (Sigma, A7699) was diluted to 700. Mu.M for use using a 1 XMAT 2AAssay Buffer;
e) Preparing and adding a substrate and ATP mixed solution: 5 XMAT 2AAssay Buffer, 3. Mu.L/well; 750 μ M L-metanine (Adamas, 01100469), 2.5 μl/well;700 μMATP,2.5 μL/well; ddH 2 O, 2. Mu.L/well. Preparing the total amount of the required mixed liquid according to the number of detection holes, and adding 10 mu L of the mixed liquid into each hole by using a BioTek (MultiFlo FX) automatic liquid separator; centrifuging at 2500rpm for 30s, and reacting at 25 ℃ for 150min;
f) Biomol Green detection reagent addition: mu.L of Biomol Green (Enzo, BML-AK 111) was added to each well using a BioTek (MultiFlo FX) automatic liquid separator, centrifuged at 2500rpm for 30s, and incubated at 25℃for 20min;
g) After the reaction was completed, OD was read using a Perkin Elmer (Envision 2105) multifunctional plate reader 620 Values.
2. Data analysis
The inhibition rate calculation formula is as follows:
ODsample: OD620 value of sample well;
ODmin: OD620 mean of blank wells representing no enzyme and no test compound;
ODmax: represents the average OD620 of the negative control wells with enzyme and without compound.
The IC50 values for MAT2A enzyme inhibition of the compounds were obtained using GraphPad Prism 5 software log (inhibitor) vs. response-Variable slope fit.
3. Experimental results:
the experimental results of the compounds of the present invention are shown below:
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Claims (10)

1. a compound of the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein:
R 1 or R is 2 Each independently selected from hydrogen, halogen, C1-C6 alkyl or C2-C6 alkynyl;
X 1 selected from N or CR a ；
X 2 Selected from N or CH;
R a selected from hydrogen, halogen, C1-C6 alkyl, amino, hydroxy, amido, 3-6 membered cycloalkyl, 5-7 membered heterocyclyl, benzo five membered heterocyclyl, 5-7 membered heteroaryl orWherein the C1-C6 alkyl is optionally substituted with hydroxy, 5-10 membered aryl, 5-10 membered aryloxy, halogen substituted 5-10 membered aryloxy, or 3-6 membered cycloalkyl, the amido is optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, 3-6 cycloalkyl, 5-10 membered aryl, halogen substituted 5-10 membered aryl, or halogen substituted 5-10 membered aralkyl, the amino is optionally substituted with 9-12 membered fused ring heteroaryl, 5-10 membered heteroaryl, C1-C3 alkyl substituted 5-10 membered heteroaryl, or pyridinyl substituted 5-10 membered heteroaryl, the hydroxy is optionally substituted with 5-10 membered aralkyl, 5-10 membered heteroaralkyl, halogen substituted 5-10 membered aralkyl, or a benzo five membered heterocyclyl, the 5-7 membered heterocyclyl is optionally substituted with 5-10 membered aryl, the 5-7 membered heteroaryl is optionally substituted with 3-6 membered cycloalkyl;
Alternatively, R a And R is R 1 And form a 3-6 membered heterocyclic ketone group with the carbon atom to which they are attached, said 3-6 membered heterocyclic ketone group being optionally substituted with a 5-7 membered aryl group or a 5-7 membered aralkyl group;
R 3 selected from hydrogen, C1-C6 alkyl, 5-10 membered aryl, C2-C6 alkenyl, 3-6 membered cycloalkyl, C1-C6 alkylthio or C1-C6 sulfonyl, said C1-C6 alkyl being optionally substituted by 3-6 membered cycloalkyl;
R 4 and R is 5 Each independently selected from hydrogen or C1-C6 alkyl.
2. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1,
R 1 selected from hydrogen, halogen or C2-C3 alkynyl; preferably hydrogen, chlorine or acetylene; more preferably hydrogen or chlorine; most preferably hydrogen;
X 1 is CR (CR) a ；
X 2 Is N;
R a selected from hydrogen, halogen, C1-C3 alkyl, amino, hydroxy, amido, 3-4 membered cycloalkyl, 5 membered heterocyclyl, benzo five membered heterocyclyl containing 1-3 heteroatoms selected from N or O, 5 membered heteroaryl orThe C1-C3 alkyl group is optionally substituted with a hydroxy, 5-7 membered aryl, 5-7 membered aryloxy, halogen substituted 5-7 membered aryloxy, or 3-4 membered cycloalkyl, the amido group is optionally substituted with a C1-C3 alkyl, C1-C3 haloalkyl, 3-4 membered cycloalkyl, 5-7 membered aryl, halogen substituted 5-7 membered aryl, or halogen substituted 5-7 membered aralkyl, the amino group is optionally substituted with a 9 membered fused ring heteroaryl containing 1-3 heteroatoms selected from N or O, a 5-7 membered heteroaryl, a C1-C3 alkyl substituted 5-7 membered heteroaryl, or a pyridinyl substituted 5-7 membered heteroaryl, the hydroxy group is optionally substituted with a 5-7 membered aralkyl, a 5-7 membered heteroaralkyl, a halogen substituted 5-7 membered aralkyl, or a benzo five membered heterocyclyl containing 1-3 heteroatoms selected from N or O, the 5 membered heterocyclyl group is optionally substituted with a 5-7 membered aryl, the 5-membered heteroaryl is optionally substituted with a 3 membered cycloalkyl;
Preferably, R a Selected from the group consisting of hydrogen, bromine, C1-C3 alkyl, amino, hydroxyl, amido, cyclopropyl, The C1-C3 alkyl is optionally substituted with hydroxy, cyclopropyl, phenyl, Substituted, said amide optionally being methyl, trifluoroethyl, cyclopropyl, phenyl,/-> Substituted, said amino group is optionally +.> Substituted, the hydroxy group optionally being Substitution, said->Optionally substituted by phenyl, said ++> Optionally substituted with cyclopropyl;
more preferably, R a Selected from hydrogen, bromine,
Further preferably, R a Selected from hydrogen, bromine,
Still more preferably, R a Selected from bromine,
R a And R is R 1 And form a 5 membered heterocyclic ketone group with the carbon atom to which they are attached, optionally substituted with a 5-7 membered aryl or 5-7 membered aralkyl group;
preferably, R a And R is R 1 Form with the carbon atom to which they are attachedOptionally substituted with phenyl or benzyl;
more preferably, R a And R is R 1 Formation of carbon atoms to which they are attached
R 3 Selected from hydrogen, C1-C3 alkyl, phenyl, C2-C4 alkenyl, 3-4 membered cycloalkyl, C1-C3 alkylthio or C1-C3 sulfonyl, said C1-C3 alkyl being optionally substituted by cyclopropyl;
preferably, R 3 Selected from hydrogen, methyl, ethyl, cyclopropyl, phenyl,
More preferably, R 3 Is cyclopropyl;
R 4 And R is 5 Each independently selected from hydrogen or C1-C3 alkyl; preferably hydrogen or methyl; more preferably, R 4 And R is 5 And is methyl.
3. The compound according to claim 1 or 2, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, further represented by the general formula (II-1):
wherein,
R 1 、R 3 、R 4 and R is 5 The method of claim 1.
4. The compound according to claim 1 or 2, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, further represented by the general formula (II-2):
wherein,
R 3 、R 4 、R 5 and R is a The method of claim 1.
5. The compound according to claim 1 or 2, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, further represented by the general formula (II-3):
wherein R is 3 、R 4 And R is 5 As set forth in the claim 1, the method can be used for the treatment of a cancer,
R 6 selected from hydrogen, phenyl or benzyl.
6. The compound of claim 4, a stereoisomer or pharmaceutically acceptable salt thereof, further represented by the general formula (III):
wherein:
l is selected from the group consisting of bond, -O-, -NH-, - (CH) 2 ) m -、
R C And R is D Each independently selected from hydrogen or C1-C3 alkyl;
ring C is selected from 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 5-7 membered aryl, 5-7 membered heteroaryl, 5-7 membered heterocyclyl, 9-12 membered fused ring heteroaryl, or benzo five membered heterocyclyl, said 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 5-7 membered aryl, 5-7 membered heteroaryl, or benzo five membered heterocyclyl optionally being further substituted with halogen, C1-C3 alkyl, 3-6 membered cycloalkyl, 5-7 membered aryl, or 5-7 membered heteroaryl;
R 3 、R 4 、R 5 The method of claim 1;
m is 1 or 2;
z is 0, 1 or 2.
7. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 6,
l is selected from the group consisting of bond, -O-, -NH-, - (CH) 2 ) m -、 Wherein R is C And R is D Each independently selected from hydrogen or methyl, m is 1, z is 0 or 1;
preferably, L is selected from the group consisting of bond, -O-, -NH-, -CH 2 -、
More preferably, L is selected from the group consisting of a bond, -NH-
Ring C is selected from 3-6 membered cycloalkyl, 5-7 membered aryl, 5-7 membered heterocyclyl, 9 membered fused ring heteroaryl, 5-7 membered heteroaryl, optionally substituted with C1-C3 alkyl, 3-6 membered cycloalkyl or 5-7 membered heteroaryl, optionally substituted with halogen, or benzo five membered heterocyclyl containing 1-3 heteroatoms selected from N or O, said 5-7 membered heterocyclyl optionally substituted with 5-7 membered aryl;
preferably, ring C is selected from cyclopropyl, Wherein said->Optionally substituted by methyl or pyridyl, said +.>Optionally substituted with benzene, said ++>Optionally substituted by cyclopropyl, said +.>Optionally substituted with fluorine;
more preferably, ring C is selected from cyclopropyl,
Further preferably, ring C is selected from cyclopropyl,
8. A compound according to any one of claims 1 to 7, a stereoisomer or a pharmaceutically acceptable salt thereof, having the structure:
9. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-8, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
10. Use of a compound according to claims 1-8, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention and/or treatment of a methionine adenosyltransferase mediated disease or condition according to claim 9.
CN202210741333.4A 2022-06-28 2022-06-28 MAT2A inhibitor, pharmaceutical composition and application thereof Pending CN117343081A (en)

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CN117343081A true CN117343081A (en) 2024-01-05

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