CN112778273B - Cyclic ketopyridone compounds and preparation method and application thereof - Google Patents
Cyclic ketopyridone compounds and preparation method and application thereof Download PDFInfo
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- C07D498/04—Ortho-condensed systems
Abstract
The invention belongs to the field of pharmaceutical chemistry. In particular, the invention relates to a cyclic ketopyridone compound and a preparation method and application thereof. The structure is shown in the following general formula (I). The compounds or stereoisomers, racemates, geometric isomers, tautomers, prodrugs, hydrates, solvates or pharmaceutically acceptable salts and pharmaceutical compositions thereof can be used for treating or/and preventing related diseases mediated by Factor XIa (FXIa).
Description
Technical Field
The invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to novel compounds which are inhibitors of Factor XIa (Factor XIa, abbreviated as FXIa) having a novel structure, or stereoisomers, racemates, geometric isomers, tautomers, prodrugs, hydrates, solvates or pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing the same.
Background
Thromboembolic disorders are diseases that result from abnormal blood clots that form within blood vessels during the life of humans and animals. The causes of thrombosis are three: i.e. damaged blood vessels, altered blood flow and stasis of blood flow; is a group of complications caused by many different diseases and different causes. Due to differences of various basic diseases and different thromboembolic sites, the clinical manifestations of thrombotic diseases are myocardial infarction, stroke, Deep Venous Thrombosis (DVT), pulmonary embolism, atrial fibrillation, cerebral infarction and the like, especially the myocardial infarction, cerebral infarction and pulmonary infarction which are the main causes of embolism and infarction are the first causes of various deaths, and nearly 1200 million people are seized in the world every year and nearly one fourth of the total deaths in the world.
The human blood coagulation process consists of intrinsic pathway (intrinsic pathway), extrinsic pathway (extrinsic pathway) and common pathway (common pathway), which is a coagulation cascade of fibrin formation through sequential activation and then amplification of a series of coagulation factors. The intrinsic pathway (also called contact activation pathway) and the extrinsic pathway (also called tissue Factor pathway) initiate the generation of coagulation Factor Xa (Factor Xa, abbreviated as FXa), and then thrombin IIa (Factor IIa, abbreviated as FIIa) is generated through the common pathway, finally fibrin is formed. Procoagulant blood (hemostasis) and anticoagulant blood (antithrombosis) oppose each other and maintain relative equilibrium in the human blood system. When the function of the anticoagulation fibrinolysis system in vivo is reduced and the blood coagulation and anticoagulation functions in blood are out of balance, blood coagulation occurs, thereby causing thrombus or embolism.
Along with the elucidation of the mechanism of thrombosis, antithrombotic drugs which have been studied and developed mainly include three major classes of anticoagulants (e.g., warfarin, heparin, etc.), antiplatelet aggregation drugs (e.g., aspirin, clopidogrel, etc.), and thrombolytic drugs (e.g., urokinase, reteplase, etc.). The domestic anticoagulant drug market is rapidly increased, wherein the traditional varieties such as heparin drugs still occupy the main share, but the market scale gradually tends to be stable. The novel therapeutic drugs, namely direct thrombin (FIIa) inhibitors (such as dabigatran etexilate and the like) and activated blood coagulation factor Xa (FXa) inhibitors (such as rivaroxaban, apixaban and the like), show strong market activity and are strong competitors of heparin drugs. The use of activated blood coagulation factor (FXa) inhibitors is rapidly increasing because of their efficacy and safety in preventing and treating thromboembolic disorders such as stroke, pulmonary embolism, and Venous Thromboembolism (VTE). But with an increase in hospitalization and mortality associated with bleeding, which is a major complication of anticoagulant therapy. In 2016, approximately 117,000 hospitalized patients died due to FXa inhibitor-related bleeding in the united states alone, which is equivalent to approximately 2000 bleeding-related deaths per month. Therefore, it is of great importance to develop an anticoagulant drug having a low bleeding tendency.
Factor xi (fxi), a plasma serine protease zymogen essential for the maintenance of the intrinsic pathway, is activated to produce activated factor xia (fxia), which plays a key role in the amplification of the coagulation cascade. In the coagulation cascade, thrombin can feedback-activate FXI, which in turn promotes the massive production of thrombin, thereby amplifying the coagulation cascade. Therefore, drugs directed against FXI targets can block the intrinsic pathway and inhibit the amplification of the coagulation cascade, thus having an antithrombotic effect. In recent years, clinical data related to human coagulation Factor XI (FXI) deficiency or FXI level increase and thrombotic disease occurrence and antithrombotic experimental studies of animal FXI deficiency or knockout or inhibition show that FXI inhibition is a new target for antithrombotic prevention and treatment, and the risk of hemorrhage is possibly lower than that of direct FXa inhibitors.
Human FXI deficiency, also known as hemophilia C, is characterized by mild bleeding phenotype, rare spontaneous bleeding, and rare cases of joint and intramuscular bleeding, which means that there is less risk of bleeding when FXI is inhibited. Secondly, the incidence of ischemic stroke and deep venous thrombosis in FXI-deficient patients is obviously reduced, which indicates that FXI inhibition is beneficial to reducing the incidence risk of ischemic stroke and deep venous thrombosis. Thirdly, in the thrombophilia study of 474 patients and controls, the risk of DVT development was 2.2-fold higher in the population with high FXI levels than in the other populations, indicating that high FXI levels are a risk factor for DVT development and that FXI levels are positively correlated with DVT development. Other researches show that the risk of cerebral apoplexy and venous thrombosis can be obviously increased by the increase of FXI level, and thrombotic diseases can be possibly reduced by inhibiting FXI.
FXI knockout mice survive healthily, have no difference in fertility and hemostatic function from wild mice, and show prolonged activated partial thromboplastin time (aPTT) and normal Prothrombin Time (PT) as in FXI-deficient patients. The mouse FXI gene knockout can inhibit arterial and venous thrombosis, and compared with several clinically applied antithrombotic medicaments, the antithrombotic effect is equal to or even more effective than that of high-dose heparin, and is more effective than other medicaments such as aspirin, clopidogrel or argatroban; moreover, these antithrombotic agents may cause a small amount of bleeding, and the tail bleeding time of mice in which the FXI gene was knocked out was not different from that of wild type. This suggests that FXI may be an antithrombotic target with little hemorrhagic side effects. The reported FXI inhibitors mainly comprise monoclonal antibodies, antisense oligonucleotides, chemical small molecules, polypeptides or proteins, polypeptide mimics and the like. At present, FXIa monoclonal antibody MAA-868 of Norway and BAY1213790 of Bayer have already entered clinical phase II research, and FXIa antisense oligonucleotide ISIS416858/BAY2306001/IONIX-FXIRx developed by Ionis and Bayer cooperation are currently in clinical phase II research. BMS and a small molecule oral FXIa inhibitor BMS-986177 developed by the cooperation of the strong life have completed a plurality of phase I clinical studies and enter a phase II clinical test; a small-molecule oral FXIa inhibitor ONO-7684 developed by Nippon Xiaoye corporation enters a clinical phase I study. The clinical phase I trial of the intravenous small molecule FXIa inhibitor BMS-962122 of BMS has been completed. The monoclonal antibody and the antisense oligonucleotide need to be injected and administered, and have the defects of high price, slow response, difficult control and the like, and the chemical micromolecule has the advantages of relatively good oral bioavailability, better patient compliance and the like. Therefore, the research and development of safe, effective, good-specificity and strong-activity novel FXIa micromolecule inhibitor medicines can possibly make up the defect that the existing clinical anticoagulant and antithrombotic medicines are easy to generate hemorrhagic complications and meet the clinical unmet requirements.
Plasma Kallikrein (PK) is a trypsin-like serine protease zymogen present in Plasma, similar to the factor XIa gene with up to 58% amino acid sequence similarity. In blood, most of plasma kallikrein exists in the form of a complex with High Molecular Weight Kininogen (HMWK). Plasma kininase is involved in blood coagulation, fibrinolysis and kinin production, and has a role in blood coagulation and many inflammatory diseases. Activated Factor XII (Factor XIIa, FXIIa) cleaves prekallikrein (prekallikrein) to form kallikrein (PK), which promotes the cleavage of HWMK to form Bradykinin (Bradykinin), thereby promoting blood coagulation. The plasma kallikrein inhibitor is possibly used for treating diseases such as Hereditary Angioneurotic Edema (HAE) and advanced diabetic macular edema (advanced diabetic macular edema). The plasma kininase inhibitor macromolecular protein drug Ecallantide (Kalbitor) has been approved by FDA to treat HAE, however, no small-molecule plasma kininase inhibitor is approved to be on the market at present, and the development of a safe and effective new Kallikrein small-molecule inhibitor drug can also meet the clinical unmet demand.
Disclosure of Invention
Through repeated experimental research, the inventor reasonably designs and synthesizes a series of small molecular compounds with novel structures represented by the following general formula (I), and the small molecular compounds have high blood coagulation factor XIa (FXIa) inhibition activity. The compounds or stereoisomers, racemates, geometric isomers, tautomers, prodrugs, hydrates, solvates or pharmaceutically acceptable salts and pharmaceutical compositions thereof can be used for treating or/and preventing related diseases mediated by FXIa.
The compound of the invention has high FXIa inhibition activity, and provides a new treatment option for treating diseases such as thromboembolism and the like.
The invention provides a compound shown in a formula (I), an optical isomer, a pharmaceutically acceptable salt or a prodrug thereof,
wherein the content of the first and second substances,
R 1 is selected from C 1-6 alkyl-C (═ O) -, 5-to 6-membered heteroaryl, and 5-to 6-membered heterocycloalkenyl, said C 1-6 alkyl-C (═ O) -, 5-6 membered heteroaryl or 5-6 membered heterocycloalkenyl optionally substituted with 1,2 or 3R;
R 2 selected from F, Cl, Br, I, OH, Me and NH 2 ；
R 3 Selected from H, halogen, OH, NH 2 、CN、C 1-6 Alkyl, phenyl-C 1-6 Alkyl-, 5-to 6-membered heteroaryl-C 1-6 Alkyl-, 3-to 6-membered heterocycloalkyl-C 1-6 Alkyl-and C 3-6 cycloalkyl-C 1-6 Alkyl-, said C 1-6 Alkyl, phenyl-C 1-6 Alkyl-, 5-to 6-membered heteroaryl-C 1-6 Alkyl-, 3-to 6-membered heterocycloalkyl-C 1-6 Alkyl-or C 3-6 cycloalkyl-C 1-6 Alkyl-optionally substituted with 1,2 or 3R;
R 4 each independently selected from halogen, OH, NH 2 、CN、C(＝O)OH、C(＝O)NH 2 、C 1-6 Alkyl radical, C 1-6 alkyl-O-C (═ O) -, C 1-6 alkyl-NH-C (═ O) -and 5-6 membered heteroaryl, said C 1-6 Alkyl radical, C 1-6 alkyl-O-C (═ O) -or C 1-6 alkyl-NH-C (═ O) -optionally substituted with 1,2 or 3R;
ring A is selected from phenyl, naphthyl, 5-10 membered heteroaryl, benzo 5-6 membered heterocycloalkyl, benzo C 5-6 Cycloalkyl, 5-to 6-membered heteroarylo 5-to 6-membered heterocycloalkyl, 5-to 10-membered heteroarylo 5-to 6-membered heterocyclic group and 5-to 6-membered heteroarylo C 5-6 A cycloalkyl group;
D 1 is selected from-N (R) 5 )-、-CH(R 5 ) -and-CH (R) 5 )CH(R 5 )-；
R 5 Are each independently selected from H and C 1-6 Alkyl radical, said C 1-6 Alkyl is optionally substituted with 1,2 or 3R;
r is respectively and independently selected from H, F, Cl, Br, I and NH 2 、CN、C 1-6 Alkyl and C 1-6 Heteroalkyl group of said C 1-6 Alkyl or C 1-6 Heteroalkyl is optionally substituted with 1,2, or 3R';
r' is respectively and independently selected from H, F, Cl, Br, I and NH 2 And CN;
n is selected from 0, 1,2 or 3;
the 5-to 6-membered heteroaryl, 5-to 6-membered heterocycloalkenyl, 3-to 6-membered heterocycloalkyl, 5EA 10-membered heteroaryl group, a 5-to 6-membered heteroaryl group and a 5-to 6-membered heterocycloalkyl group or a 5-to 6-membered heteroarylo group C 5-6 Cycloalkyl contains 1,2 or 3 substituents independently selected from-O-, -NH-, -S-, -C (═ O) O-, -S (═ O) 2 -and N.
In some embodiments of the present invention, each R is independently selected from H, F, Cl, Br, I, NH 2 、CN、C 1-3 Alkyl radical, C 1-3 Alkoxy and C 1-3 Alkylamino radical, said C 1-3 Alkyl radical, C 1-3 Alkoxy or C 1-3 Alkylamino is optionally substituted with 1,2 or 3R' and the remaining variables are as defined herein.
In some embodiments of the present invention, each of the above R is independently selected from H, F, Cl, Br, I, NH 2 、CN、Me、
The remaining variables are as defined herein.
In some embodiments of the present invention, R is 1 Selected from the group consisting of 1H-1,2, 3-triazolyl, 1H-tetrazolyl, isoxazolyl, oxazolyl, 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 4, 5-dihydroisoxazolyl and
the 1H-1,2, 3-triazolyl, 1H-tetrazolyl, isoxazolyl, oxazolyl, 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 4, 5-dihydroisoxazolyl or
Optionally substituted with 1,2 or 3R, the remaining variables being as defined herein.
In some embodiments of the invention, R is as defined above 1 Is selected from
The remaining variables are as defined herein.
In some embodiments of the invention, R is as defined above 3 Selected from H, Me,
The remaining variables are as defined herein.
In some embodiments of the invention, R is as defined above 4 Each independently selected from F, Me, CH 2 F、CHF 2 、CF 3 、C(＝O)OH、C(＝O)OEt、NH 2 、C(＝O)NH 2 、
The remaining variables are as defined herein.
In some embodiments of the present invention, the above-mentioned ring A is selected from the group consisting of phenyl, indolyl, 1H-pyrrolo [2,3-b ] pyridyl, 2, 3-dihydro-1H-indenyl, 6, 7-dihydro-5H-cyclopenta [ b ] pyridyl, 1H-benzo [ d ] imidazolyl, 1, 2-dihydro-3H-indazol-3-onyl, 1, 3-dihydro-2H-benzo [ d ] imidazol-2-onyl, 1H-indazolyl, imidazo [1,2-a ] pyridyl, pyrazolo [1,5-a ] pyridyl, pyrazoline [1,5-a ] pyridyl, imidazo [1,2-a ] pyridyl, benzofuranyl, benzo [ d ] isoxazolyl, 1H,3H oxazolo [3,4-a ] indol-1-onyl, 3, 4-dihydroquinolin-2 (1H) -onyl, indolinyl, 1,2,3, 4-tetrahydroquinolinyl, 3, 4-dihydroquinolin-2 (1H) -onyl, benzo [ d ] isoxazolyl and quinoxalinyl, the remaining variables being as defined herein.
In some embodiments of the invention, the structural unit
Is selected from
The remaining variables are as defined herein.
In some embodiments of the present invention, R is 5 Selected from H and Me, the remaining variables being as defined herein.
In some embodiments of the present invention, D is 1 Is selected from CH 2 、CH 2 CH 2 NH and N (CH) 3 ) The remaining variables are as defined herein.
The present invention also provides a compound of the formula, an optical isomer thereof, a pharmaceutically acceptable salt thereof or a prodrug thereof, selected from
In another aspect of the invention, the invention also discloses a pharmaceutical composition. The pharmaceutical composition comprises the aforementioned compound, an optical isomer thereof, a pharmaceutically acceptable salt thereof or a prodrug thereof.
In some embodiments of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, diluent, and excipient.
In another aspect of the present invention, the present invention also discloses the use of the aforementioned compound, its optical isomer, its pharmaceutically acceptable salt or its prodrug or the aforementioned pharmaceutical composition in the preparation of a medicament for preventing and/or treating cardiovascular and cerebrovascular diseases.
In some embodiments of the present invention, the cardiovascular and cerebrovascular diseases are selected from myocardial infarction, angina pectoris, reocclusion and restenosis after angioplasty or aortic coronary bypass, disseminated intravascular coagulation, stroke, transient ischemic attack, peripheral arterial occlusive disease, pulmonary embolism, or deep vein thrombosis.
In some embodiments of the present invention, the cardiovascular and cerebrovascular diseases are selected from thromboembolic diseases.
In a further aspect of the invention, the invention also discloses the use of the aforementioned compound, an optical isomer thereof, a pharmaceutically acceptable salt thereof or a prodrug thereof, or the aforementioned pharmaceutical composition for the preparation of a medicament for the prevention and/or treatment of diseases positively influenced by the inhibition of FXIa.
In a further aspect of the invention, the invention also discloses the application of the compound, the optical isomer, the pharmaceutically acceptable salt or the prodrug thereof or the pharmaceutical composition in preparing the FXIa preventing and/or treating drugs.
Definition of
The following terms and symbols used in the present application have the meanings as described below, unless otherwise indicated in the context.
A dash ("-") that is not between two letters or symbols indicates a point of attachment for a substituent. E.g. C 1-6 Alkylcarbonyl-refers to C attached to the rest of the molecule through a carbonyl group 1-6 An alkyl group. However, when the attachment site of a substituent is apparent to those skilled in the art, for example, a halogen substituent, "-" may be omitted.
With dotted lines at the valency of the group
When, for example, in
The dotted line represents the point of attachment of the group to the rest of the molecule.
The term "alkyl" as used herein refers to a straight or branched chain saturated monovalent hydrocarbon radical having from 1 to 8 carbon atoms, such as from 1 to 6 carbon atoms, such as from 1 to 4 carbon atoms, such as from 1,2 or 3 carbon atoms. For example, "C 1-8 Alkyl "denotes an alkyl group having 1 to 8 carbon atoms. Similarly, "C 1-6 Alkyl "represents an alkyl group having 1 to 6 carbon atoms; "C 1-4 Alkyl "represents an alkyl group having 1 to 4 carbon atoms; ' C 1-3 Alkyl "means an alkyl group having 1 to 3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl ("Me"), ethyl ("Et"), propyl such as n-propyl ("n-Pr") or isopropyl ("i-Pr"), butyl such as n-butyl ("n-Bu"), isobutyl ("i-Bu"), sec-butyl ("s-Bu"), or tert-butyl ("t-Bu"), pentyl, hexyl, and the like. This definition applies regardless of whether the term "alkyl" is used alone or as part of another group, such as haloalkyl, alkoxy, and the like.
The term "alkoxy" as used herein refers to the group-O-alkyl, wherein alkyl is as defined above. For example, "C 1-8 Alkoxy "denotes-O-C 1-8 Alkyl, i.e., alkoxy having 1 to 8 carbon atoms. Similarly, "C 1-6 Alkoxy "denotes-O-C 1-6 Alkyl, i.e., alkoxy having 1 to 6 carbon atoms; "C 1-4 Alkoxy "denotes-O-C 1-4 Alkyl, i.e., alkoxy having 1 to 4 carbon atoms; "C 1-3 Alkoxy "denotes-O-C 1-3 Alkyl, i.e., alkoxy having 1 to 3 carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, such as n-propoxy or isopropoxy, butoxy, such as n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, and the like. This definition applies regardless of whether the term "alkoxy" is used alone or as part of another group.
The term "cycloalkyl" as used herein refers to a cyclic alkyl group having 3 to 12 ring carbon atoms, e.g., having 3 to 8 ring carbon atoms, e.g., having 3 to 6 ring carbon atomsA saturated monovalent monocyclic or bicyclic hydrocarbon group of, for example, 3 to 4 ring carbon atoms. For example, "C 3-12 Cycloalkyl "denotes cycloalkyl having 3 to 12 ring carbon atoms. Similarly, "C 3-8 Cycloalkyl "denotes cycloalkyl having 3 to 8 ring carbon atoms; "C 3-6 Cycloalkyl "denotes cycloalkyl having 3 to 6 ring carbon atoms; "C 3-4 Cycloalkyl "denotes cycloalkyl having 3 to 4 ring carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, and the like.
As used herein, the term "3-6 membered heterocycloalkyl" by itself or in combination with other terms denotes a saturated cyclic group consisting of 3 to 6 ring atoms, 1,2,3 or 4 of which are heteroatoms independently selected from O, S and N, the remainder being carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S (O)) p And p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spiro, fused and bridged rings. Furthermore, with respect to the "3-6 membered heterocycloalkyl", the heteroatom may occupy the position of the heterocycloalkyl linkage to the rest of the molecule. The 3-6 membered heterocycloalkyl group includes 4-6 membered, 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl groups and the like. Examples of 3-6 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-3-yl, and the like), tetrahydrofuranyl (including tetrahydrofuran-2-yl, and the like), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, and the like), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1, 2-oxazinyl, 1, 2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, and the like.
The term "4-6 membered heterocycloalkyl" as used herein by itself or in combination with other terms denotes a saturated cyclic group consisting of 4 to 6 ring atoms, 1,2,3 or 4 of which are heteroatoms independently selected from O, S and N, the remainder being carbon atoms, wherein the nitrogen atom is optionally quarterly substitutedAmmonification, the nitrogen and sulfur heteroatoms optionally being oxidized (i.e. NO and S (O)) p And p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spiro, fused and bridged rings. Furthermore, with respect to the "4-6 membered heterocycloalkyl", the heteroatom may occupy the position of the heterocycloalkyl linkage to the rest of the molecule. The 4-6 membered heterocycloalkyl group includes 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl groups and the like. Examples of 4-6 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl, tetrahydrothien-3-yl, and the like), tetrahydrofuranyl (including tetrahydrofuran-2-yl, and the like), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, and the like), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1, 2-oxazinyl, 1, 2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, and the like.
As used herein, the term "5-6 membered heterocycloalkyl" by itself or in combination with other terms denotes a saturated cyclic group consisting of 5 to 6 ring atoms, 1,2,3 or 4 of which are heteroatoms independently selected from O, S and N, the remainder being carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S (O)) p And p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spiro, fused and bridged rings. Furthermore, with respect to the "5-6 membered heterocycloalkyl", the heteroatom may occupy the position of the heterocycloalkyl linkage to the rest of the molecule. The 5-6 membered heterocycloalkyl group includes 5-and 6-membered heterocycloalkyl groups. Examples of 5-6 membered heterocycloalkyl include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-3-yl, etc.), tetrahydrofuryl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1, 2-oxazinyl, etc1, 2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, and the like.
The term "3-5 membered heterocycloalkyl" as used herein by itself or in combination with other terms means a saturated monocyclic group consisting of 3 to 5 ring atoms, 1,2,3 or 4 of which are heteroatoms independently selected from O, S and N, the remainder being carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S (O) p And p is 1 or 2). Furthermore, with respect to the "3-5 membered heterocycloalkyl", the heteroatom may occupy the position of the heterocycloalkyl linkage to the rest of the molecule. The 3-5 membered heterocycloalkyl group includes 4-5 membered, 4-membered, and 5-membered heterocycloalkyl groups and the like. Examples of 3-5 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl, tetrahydrothien-3-yl, and the like), tetrahydrofuranyl (including tetrahydrofuran-2-yl, and the like), and the like.
Unless otherwise specified, the term "5-6 membered heterocycloalkenyl" by itself or in combination with other terms, means a partially unsaturated cyclic group consisting of 5 to 6 ring atoms containing at least one carbon-carbon double bond, 1,2,3, or 4 of which are heteroatoms independently selected from O, S and N, the remainder being carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S (O)) p And p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spiro, fused and bridged rings, any ring of the system being non-aromatic. Further, with respect to the "5-6 membered heterocycloalkenyl," a heteroatom may occupy the position of attachment of the heterocycloalkenyl to the rest of the molecule. The 5-6 membered heterocycloalkenyl group includes 5-and 6-membered heterocycloalkenyl groups and the like. Examples of 5-6 membered heterocycloalkenyl include, but are not limited to
Unless otherwise specified, the term "5-10 membered heteroaromatic ring" in the present invention "And "5-10 membered heteroaryl" are used interchangeably, the term "5-10 membered heteroaryl" is intended to denote a cyclic group consisting of 5 to 10 ring atoms with a conjugated pi-electron system, of which 1,2,3 or 4 ring atoms are heteroatoms independently selected from O, S and N, the remainder being carbon atoms. It may be a monocyclic, fused bicyclic or fused tricyclic ring system, wherein each ring is aromatic. Wherein the nitrogen atoms are optionally quaternized and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S (O)) p And p is 1 or 2). The 5-10 membered heteroaryl group may be attached to the rest of the molecule through a heteroatom or a carbon atom. The 5-to 10-membered heteroaryl group includes 5-to 8-membered, 5-to 7-membered, 5-to 6-membered, 5-and 6-membered heteroaryl groups and the like. Examples of such 5-to 10-membered heteroaryl groups include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, and the like), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl, and the like), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, and the like), oxazolyl (including 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, and the like), triazolyl (1H-1,2, 3-triazolyl, 2H-1,2, 3-triazolyl, 1H-1,2, 4-triazolyl, 4H-1,2, 4-triazolyl, and the like), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, and the like), Thiazolyl (including 2-thiazolyl, 4-thiazolyl, 5-thiazolyl and the like), furyl (including 2-furyl, 3-furyl and the like), thienyl (including 2-thienyl, 3-thienyl and the like), pyridyl (including 2-pyridyl, 3-pyridyl, 4-pyridyl and the like), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl, 4-pyrimidinyl and the like), benzothiazolyl (including 5-benzothiazolyl and the like), purinyl, benzimidazolyl (including 2-benzimidazolyl and the like), benzoxazolyl, indolyl (including 5-indolyl and the like), isoquinolyl (including 1-isoquinolyl, 5-isoquinolyl and the like), quinoxalinyl (including 2-quinoxalinyl, 5-quinoxalinyl and the like), or quinolyl (including 3-quinolyl, 6-quinolyl and the like).
Unless otherwise specified, the terms "5-6 membered heteroaromatic ring" and "5-6 membered heteroaryl" are used interchangeably herein, and the term "5-6 membered heteroaryl" denotes a monocyclic group consisting of 5 to 6 ring atoms with a conjugated pi-electron system, of which 1,2,3 or 4 ring atoms are heteroatoms independently selected from O, S and N, the remainder being carbon atoms. Wherein the nitrogen atoms are optionally quaternizedAmmonification, the nitrogen and sulfur heteroatoms optionally being oxidized (i.e. NO and S (O)) p And p is 1 or 2). The 5-6 membered heteroaryl group may be attached to the rest of the molecule through a heteroatom or a carbon atom. The 5-6 membered heteroaryl includes 5-and 6-membered heteroaryl. Examples of such 5-6 membered heteroaryl groups include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, and the like), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl, and the like), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, and the like), oxazolyl (including 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, and the like), triazolyl (1H-1,2, 3-triazolyl, 2H-1,2, 3-triazolyl, 1H-1,2, 4-triazolyl, and 4H-1,2, 4-triazolyl, and the like), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, and 5-isoxazolyl, and the like), Thiazolyl (including 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, and the like), furyl (including 2-furyl, 3-furyl, and the like), thienyl (including 2-thienyl, 3-thienyl, and the like), pyridyl (including 2-pyridyl, 3-pyridyl, 4-pyridyl, and the like), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl, 4-pyrimidinyl, and the like).
As used herein, the term "benzo 5-6 membered heterocycloalkyl" refers to a bicyclic ring formed by phenyl and 5-6 membered heterocycloalkyl, examples of which include, but are not limited to
And so on.
The term "benzo C" as used herein 5-6 Cycloalkyl "refers to a bicyclic ring of phenyl with 5-to 6-membered heterocycloalkyl, examples of which include but are not limited to
And the like.
The term "5-to 6-membered heteroaryland 5-to 6-membered heterocycloalkyl" as used herein refers to a bicyclic ring formed by phenyl and 5-to 6-membered heterocycloalkyl, examples of which include, but are not limited to
And the like.
The term "5-to 6-membered heteroaryl-C" as used herein 5-6 Cycloalkyl refers to a bis formed by phenyl and 5-to 6-membered heterocycloalkylAnd rings, examples of which include, but are not limited to
And the like.
The term "5-to 10-membered heteroaryl and 5-to 6-membered heterocyclyl" as used herein refers to a fused ring structure formed by a 5-to 10-membered heteroaryl and a 5-to 6-membered heterocyclyl, examples of which include, but are not limited to
And the like.
Unless otherwise specified, C n-n+m Or C n -C n+m Including any one particular case of n to n + m carbons, e.g. C 1-12 Comprising C 1 、C 2 、C 3 、C 4 、C 5 、C 6 、C 7 、C 8 、C 9 、C 10 、C 11 And C 12 Also included are any ranges of n to n + m, e.g. C 1-12 Comprising C 1-3 、C 1-6 、C 1-9 、C 3-6 、C 3-9 、C 3-12 、C 6-9 、C 6-12 And C 9-12 Etc.; similarly, n to n + m means the number of atoms on the ring is n to n + m, for example, the 3-12 membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, a 11-membered ring, and a 12-membered ring, and any range of n to n + m is also included, for example, the 3-12 membered ring includes a 3-6-membered ring, a 3-9-membered ring, a 5-6-membered ring, a 5-7-membered ring, a 6-8-membered ring, and a 6-10-membered ring, etc.
The term "optionally" as used herein means that the subsequently described event may or may not occur, and that the description includes instances where said event occurs and instances where it does not. For example, "optionally substituted alkyl" refers to unsubstituted alkyl and substituted alkyl, wherein alkyl is as defined herein. It will be understood by those skilled in the art that for any group containing one or more substituents, the group does not include any sterically impractical, chemically incorrect, synthetically infeasible and/or inherently unstable substitution pattern.
The term "substituted" or "substituted with … …" as used herein means that one or more hydrogen atoms on a given atom or group are replaced, for example by one or more substituents selected from a given group of substituents, provided that the normal valence of the given atom is not exceeded. When the substituent is oxo (i.e., ═ O), then two hydrogen atoms on a single atom are replaced with oxygen. Combinations of substituents and/or variables are permissible only if such combinations result in chemically correct and stable compounds. A chemically correct and stable compound means that the compound is sufficiently stable to be isolated from the reaction mixture and to determine the chemical structure of the compound, and can subsequently be formulated into a formulation that has at least practical utility. For example, as used herein, the term "substituted" or "substituted" without explicitly listing substituents means that one or more hydrogen atoms on a given atom or group are independently substituted with one or more, e.g., 1,2,3, or 4, substituents independently selected from: deuterium (D), halogen, -OH, mercapto, cyano, -CD 3 Alkyl (preferably C) 1-6 Alkyl group), alkoxy group (preferably C) 1-6 Alkoxy), haloalkyl (preferably halo C) 1-6 Alkyl), haloalkoxy (preferably halo C) 1-6 Alkoxy), -C (O) NR a R b and-N (R) a )C(O)R b and-C (O) OC 1-4 Alkyl (wherein R a And R b Each independently selected from hydrogen, C 1-4 Alkyl, halo C 1-4 Alkyl), carboxyl (-COOH), cycloalkyl (preferably 3-8 membered cycloalkyl), heterocyclyl (preferably 3-8 membered heterocyclyl), aryl, heteroaryl, aryl-C 1-6 Alkyl-, heteroaryl-C 1-6 Alkyl-, -OC 1-6 Alkylphenyl, -C 1-6 alkyl-OH (preferably-C) 1-4 alkyl-OH), -C 1-6 alkyl-SH, -C 1-6 alkyl-O-C 1-2 、-C 1-6 alkyl-NH 2 (preferably-C) 1-3 alkyl-NH 2 )、-N(C 1-6 Alkyl radical) 2 (preferably-N (C) 1-3 Alkyl radical) 2 )、-NH(C 1-6 Alkyl) (preferably-NH (C) 1-3 Alkyl)), -N (C) 1-6 Alkyl) (C) 1-6 Alkyl phenyl)、-NH(C 1-6 Alkylphenyl), nitro, -C (O) OC 1-6 Alkyl (preferably-C (O) OC 1-3 Alkyl), -NHC (O) (C) 1-6 Alkyl), -NHC (O) (phenyl), -N (C) 1-6 Alkyl radical C (O) (C) 1-6 Alkyl), -N (C) 1-6 Alkyl) C (O) (phenyl), -C (O) C 1 - 6 Alkyl, -C (O) heteroaryl (preferably-C (O) -5-7 membered heteroaryl), -C (O) C 1-6 Alkylphenyl, -C (O) C 1-6 Haloalkyl, -OC (O) C 1 - 6 Alkyl (preferably-OC (O) C) 1-3 Alkyl), alkylsulfonyl (e.g., -S (O) 2 -C 1-6 Alkyl), alkylsulfinyl (-S (O) -C) 1-6 Alkyl), -S (O) 2 -phenyl, -S (O) 2 -C 1-6 Haloalkyl, -S (O) 2 NH 2 、-S(O) 2 NH(C 1-6 Alkyl), -S (O) 2 NH (phenyl), -NHS (O) 2 (C 1 - 6 Alkyl), -NHS (O) 2 (phenyl) and-NHS (O) 2 (C 1-6 Haloalkyl), wherein said alkyl, cycloalkyl, phenyl, aryl, heterocyclyl and heteroaryl are each optionally further substituted with one or more substituents selected from the group consisting of: halogen, -OH, -NH 2 Cycloalkyl, 3-8 membered heterocyclyl, C 1-4 Alkyl radical, C 1-4 Haloalkyl-, -OC 1-4 Alkyl, -C 1-4 alkyl-OH, -C 1-4 alkyl-O-C 1-4 Alkyl, -OC 1-4 Haloalkyl, cyano, nitro, -C (O) -OH, -C (O) OC 1-6 Alkyl, -CON (C) 1-6 Alkyl radical) 2 、-CONH(C 1-6 Alkyl), -CONH 2 、-NHC(O)(C 1-6 Alkyl), -NH (C) 1-6 Alkyl radical C (O) (C) 1-6 Alkyl), -SO 2 (C 1-6 Alkyl), -SO 2 (phenyl), -SO 2 (C 1-6 Haloalkyl), -SO 2 NH 2 、-SO 2 NH(C 1-6 Alkyl), -SO 2 NH (phenyl), -NHSO 2 (C 1-6 Alkyl), -NHSO 2 (phenyl) and-NHSO 2 (C 1 - 6 Haloalkyl). When an atom or group is substituted with a plurality of substituents, the substituents may be the same or different.
The term "pharmaceutically acceptable" as used herein refers to non-toxic, biologically tolerable, and suitable for administration to an individual.
The term "pharmaceutically acceptable salt" as used herein refers to non-toxic, biologically tolerable acid or base addition salts of compounds of formula (I) suitable for administration to a subject, including but not limited to: acid addition salts of the compounds of formula (I) with inorganic acids, such as hydrochloride, hydrobromide, carbonate, bicarbonate, phosphate, sulfate, sulfite, nitrate, and the like; and acid addition salts of compounds of formula (I) with organic acids, for example formates, acetates, malates, maleates, fumarates, tartrates, succinates, citrates, lactates, methanesulfonates, p-toluenesulfonates, 2-hydroxyethanesulfonates, benzoates, salicylates, stearates and salts of formula HOOC- (CH) 2 ) n Salts with alkanedicarboxylic acids of-COOH (wherein n is 0 to 4), and the like. "pharmaceutically acceptable salts" also include the base addition salts of the compounds of formula (I) bearing an acidic group with pharmaceutically acceptable cations such as sodium, potassium, calcium, aluminum, lithium and ammonium.
Furthermore, if the compounds described herein are obtained in the form of an acid addition salt, the free base form thereof can be obtained by basifying a solution of the acid addition salt. Conversely, if the product is in the form of the free base, its acid addition salts, in particular the pharmaceutically acceptable acid addition salts, can be obtained by dissolving the free base in a suitable solvent and treating the solution with an acid, according to the usual procedures for preparing acid addition salts from basic compounds. Those skilled in the art will be able to determine, without undue experimentation, the various synthetic procedures which may be used to prepare non-toxic pharmaceutically acceptable acid addition salts.
The compounds of the invention may exist in the form of solvates. The term "solvate" means a solvent addition form comprising a stoichiometric or non-stoichiometric amount of a solvent. If the solvent is water, the solvate formed is a hydrate, and when the solvent is ethanol, the solvate formed is an ethanolate. Hydrates are formed by one or more molecules of water with one molecule of the substance, where the water retains its H 2 The molecular state of O, such combination being capable of forming one or more hydrates, such as hemihydrate, monohydrate and dihydrate.
The term "prodrug" as used herein refers to an active or inactive compound that is chemically modified to form the compound of the present invention by physiological effects in vivo such as hydrolysis, metabolism, and the like, after administration to a subject. The suitability and techniques involved in making and using prodrugs are well known to those skilled in the art. Exemplary prodrugs are, for example, esters of free carboxylic acids and S-acyl derivatives of thiols and O-acyl derivatives of alcohols or phenols. Suitable prodrugs are typically pharmaceutically acceptable ester derivatives which are convertible by solvolysis under physiological conditions to the parent carboxylic acid, e.g. lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono-or di-substituted lower alkyl esters, such as omega- (amino, mono-or di-lower alkylamino, carboxy, lower alkoxycarbonyl) -lower alkyl esters, alpha- (lower alkanoyloxy, lower alkoxycarbonyl or di-lower alkylaminocarbonyl) -lower alkyl esters, such as pivaloyloxymethyl ester and the like, as are conventionally used in the art.
It will be appreciated by those skilled in the art that some compounds of formula (I) may contain one or more chiral centres and so two or more stereoisomers are present. The compounds according to the invention can therefore be present as individual stereoisomers (e.g. enantiomers, diastereomers) and mixtures thereof in any proportion, for example racemates, and, where appropriate, as tautomers and geometrical isomers thereof.
The term "stereoisomer" as used herein refers to compounds having the same chemical constitution, but which differ in the spatial arrangement of the atoms or groups. Stereoisomers include enantiomers, diastereomers, and conformers, among others.
The term "enantiomer" as used herein refers to two stereoisomers of a compound that are non-superimposable mirror images of each other.
The term "diastereomer" as used herein refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectroscopic properties, or biological activities. Mixtures of diastereomers may be separated by high resolution analytical methods such as electrophoresis and chromatography such as HPLC.
Stereochemical definitions and conventions may be compiled following the s.p. parker, McGraw-Hill Dictionary of Chemical terminologies (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of a molecule with respect to its chiral center. The prefixes d and l or (+) and (-) are used to denote the symbols of a compound that rotates plane-polarized light, where (-) or l denotes that the compound is levorotatory. Compounds with a (+) or d prefix are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A particular stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is commonly referred to as a mixture of enantiomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur in chemical reactions or processes without stereoselectivity or stereospecificity. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers without optical activity.
The racemic mixture can be used as such or resolved into individual isomers. The resolution can result in a stereochemically pure compound or in an enriched mixture of one or more isomers. Methods for separating isomers are well known (see Allinger n.l. and Eliel e.l., "Topics in stereospecificity", volume 6, Wiley Interscience, 1971), including physical methods such as chromatography using chiral adsorbents. The individual isomers can be prepared in chiral form from chiral precursors. Alternatively, the individual isomers may be separated chemically from the mixture by forming diastereomeric salts with chiral acids (e.g., the individual enantiomers of 10-camphorsulfonic acid, camphoric acid, α -bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.), fractional crystallization of the salts, and subsequent liberation of one or both of the resolved bases, optionally repeating this process, to yield one or two isomers substantially free of the other isomer, i.e., the desired stereoisomer in optical purity, e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% by weight. Alternatively, the racemate may be covalently linked to a chiral compound (an auxiliary) to give diastereomers, as is well known to those skilled in the art.
The term "tautomer" or "tautomeric form" as used herein refers to structural isomers of different energies that may be interconverted via a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by recombination of some of the bonded electrons.
The term "treatment" as used herein refers to the administration of one or more pharmaceutical substances, in particular a compound of formula (I) and/or a pharmaceutically acceptable salt thereof as described herein, to an individual suffering from a disease or having symptoms of said disease, for the purpose of curing, alleviating, altering, healing, ameliorating, improving or affecting said disease or symptoms of said disease. The term "prevention" as used herein refers to the administration of one or more pharmaceutical substances, in particular a compound of formula (I) as described herein and/or a pharmaceutically acceptable salt thereof, to an individual having a predisposition to the disease, in order to prevent the individual from suffering from the disease. The terms "treating", "contacting" and "reacting" when referring to a chemical reaction refer to the addition or mixing of two or more reagents under appropriate conditions to produce the indicated and/or desired product. It will be appreciated that the reaction that produces the indicated and/or the desired product may not necessarily result directly from the combination of the two reagents that were initially charged, i.e., one or more intermediates that are formed may be present in the mixture that ultimately result in the formation of the indicated and/or the desired product.
The term "effective amount" as used herein refers to an amount generally sufficient to produce a beneficial effect in an individual. An effective amount of a compound of the invention can be determined by conventional methods (e.g., modeling, dose escalation studies, or clinical trials) in combination with conventional influencing factors (e.g., mode of administration, pharmacokinetics of the compound, severity and course of the disease, medical history of the individual, health of the individual, degree of responsiveness of the individual to the drug, etc.).
Technical and scientific terms used herein that are not specifically defined have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures in the following examples, if no specific conditions are indicated, are generally carried out according to the conditions customary for such reactions, or according to the conditions recommended by the manufacturer. Unless otherwise indicated, percentages and parts are percentages and parts by weight. Unless otherwise specified, the ratio of liquids is by volume.
The test materials and reagents used in the following examples are commercially available without specific reference.
In the following examples of the process of the present invention, 1 the H-NMR spectra were recorded on a Bluker AVANCE III HD 400MHz NMR spectrometer; 13 C-NMR spectra were recorded on a Bluker AVANCE III HD 400MHz NMR spectrometer with chemical shifts expressed in delta (ppm); mass spectra were recorded using a Shimadzu LCMS-2020(ESI model) or Agilent 6215(ESI) mass spectrometer; reversed-phase preparative HPLC separation is a full-automatic purification system guided by Gilson GX281 ultraviolet (
Prep C18 OBDTM 19 x 250mm 10 μm column)/or Waters QDa guided full automatic purification system (
Prep C18 OBD 29 x 250mm 10 μm column). Chiral analytical HPLC is performed using a Waters UPCC supercritical fluid analysis System (
OD-H4.6X 250mm 5 μm column or
AS-30.3 cm x 100mm 3 μm column); the chiral separation SFC is performed by a Waters-SFC80 supercritical fluid purification system (
OD 2.5 × 25cm,10 μm column or
AS 2.5 × 25cm,10 μm column), the 1 st peak was numbered absolute isomer 1, the 2 nd peak was numbered absolute isomer 2, and so on.
Wherein, the Chinese name table of the reagent represented by the chemical formula or English letter abbreviation is as follows:
aq represents an aqueous solution; BoC represents tert-butoxycarbonyl; BoC 2 O represents di-tert-butyl dicarbonate; br represents a broad peak; DEG C represents centigrade degree; CDCl 3 Represents deuterated chloroform; d represents a doublet; DAST represents diethylaminosulfur trifluoride; DBU represents 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene; DCM or CH 2 Cl 2 Represents dichloromethane; DMAP represents 4-dimethylaminopyridine or N, N-dimethyl-4-aminopyridine; DMF represents dimethylformamide; DMSO represents dimethyl sulfoxide; EA or EtOAc stands for ethyl acetate; et (Et) 3 N represents triethylamine; g represents g; h represents hour; h 2 O represents water; HATU represents 1- [ bis (dimethylamino) methylene]-1H-1,2, 3-triazolo [4,5-b]Pyridinium 3-oxide hexafluorophosphate; HCl represents hydrogen chloride or hydrochloric acid; HPLC for high performance liquid chromatography; LCMS stands for liquid chromatography-mass spectrometry combination; LiOH represents lithium hydroxide; m represents a multiplet; m represents molar concentration; m/z represents mass to charge ratio; MeCN, ACN or CH 3 CN represents acetonitrile; MeOH represents methanol; min represents min; mg represents mg; mL generationTable ml; mmol represents millimole; mol represents mol; n represents the equivalent concentration; n is a radical of 2 Represents nitrogen; NaHCO 2 3 Represents sodium bicarbonate; NaN 3 Represents sodium azide; NaNO 2 Represents sodium nitrite; na (Na) 2 SO 4 Represents sodium sulfate; NBS represents N-bromosuccinimide; NCS represents N-chlorosuccinimide; NH (NH) 4 Cl represents ammonium chloride; NH 4 HCO 3 Represents ammonium bicarbonate; pd (dppf) Cl 2 Or PdCl 2 (dppf) represents 1, 1' -bis (diphenylphosphino) ferrocene dichloropalladium; pd (PPh) 3 ) 4 Represents tetrakis (triphenylphosphine) palladium (0); PE represents petroleum ether; POCl 3 Represents phosphorus oxychloride; PTSA represents p-toluenesulfonic acid; r.t. or RT for room temperature; s represents a single peak; t represents a triplet; t is 3 P represents 1-propyl phosphoric anhydride; TEA stands for triethylamine; TFA or CF 3 COOH represents trifluoroacetic acid; THF represents tetrahydrofuran; μ M stands for micromoles per liter.
Synthesis of examples
Example 1: preparation of Compound A1
Step 1: synthesis of intermediate 1-2
1, 3-Cycloglutarone (3.35g, 34.15mmol), tert-butyl glycinate (2g, 6.63mmol) and PTSA (649mg,3.42mmol) were added to toluene (100 mL). N for reaction system 2 Under protection, the temperature is raised to 130 ℃ and the reaction is carried out for 3 h. The reaction was spun dry, dissolved in 500mL EtOAc and washed with saturated NaHCO 3 Washing with an aqueous solution, drying, filtering and spin-drying to obtain 5g of a target product 1-2 as a yellow solid with yield: and 69 percent.
And 2, step: synthesis of intermediates 1 to 3
Compound 1-2(1.7g, 8.05mmol) and bis (2,4, 6-trichlorophenyl) malonate (3.95g, 8.05mmol) were added to toluene (100 mL). The reaction solution was stirred at 120 ℃ for 2h with microwave. Cooling the reaction solution to room temperature, spin-drying to obtain a crude product, and purifying the crude product by column chromatography (biotage,120g, silica gel column, UV254, EA/PE 0-100%) to obtain a target product1-3, yellow semisolid, 700mg, yield 31%. LC-MS M/z 280.2(M + H) + Purity: 91% (UV 254). 1 H NMR(400MHz,DMSO-d 6 )δ11.19(s,1H),5.54(s,1H),4.63(s,2H),2.91-2.89(m,2H),2.54-2.50(m,2H),1.42(s,9H).
And step 3: synthesis of intermediates 1 to 4
272mg (2.697. mu.M, 1.5 eq.) Et at 0 ℃ 3 N was added to a solution of 0.5g (1.79mM) of intermediates 1-3 in 21mL of DCM. Subsequently, 709mg (1.97mM, 1.1 equiv) of N, N-bis (trifluoromethanesulfonyl) aniline were added in portions. Stirred at room temperature for 2 days. The crude product is purified by column chromatography (biotage,120g, silica gel column, UV254, EA/PE 0-100%) to obtain the target product 1-4, yellow semisolid, 500mg, yield 48%. LC-MS M/z 412.1(M + H) + 。
Step 4. Synthesis of intermediates 1-6
A100 mL round bottom flask was charged with 2-bromo-4-chloroaniline (619mg, 3.00mmol) and water (12 mL). Then, 3.7mL of concentrated HCl was added and the reaction was cooled to-5 ℃. At-5 deg.C, adding NaNO 2 An aqueous solution (1.5mL) (228mg, 3.30mmol) was added to the reaction mixture and the temperature was maintained for 1 h. Then adding NaN 3 (215mg, 3.30mmol) of an aqueous solution (1.5mL) was added and the reaction was continued at-5 ℃ for 0.5 h. The reaction was extracted with EA (3X 40mL), the organic phases were combined and saturated NaHCO was used 3 The aqueous solution (100mL), water (100mL) and saturated brine (100mL) were washed successively with Na 2 SO 4 Drying, filtering and concentrating to obtain the product 1-6 of 600mg in total, yellow solid, yield: 85 percent. LC-MS: UV absorption and MS no response.
Step 5. Synthesis of intermediates 1-7
A100 mL round bottom flask was charged with intermediates 1-6(600mg, 2.57mmol), tributyl (ethynyl) stannane (971mg, 3.08mmol), and toluene (12mL), warmed to 110 deg.C, and reacted for 16 h. LC-MS showed the formation of product. The reaction was concentrated and purified using normal phase column (PE/EA 0-100%) to give 1.13g total product 1-7 as a yellow oil, yield: 80 percent. LCMS M/z 547.7(M + H) + 。
Step 6. Synthesis of intermediates 1 to 8
In a 100mL round-bottom flaskIntermediate 1-7(1.0g, 1.83mmol), NCS (366mg, 2.74mmol) and ACN (20mL) were added, the temperature was raised to 60 ℃ and the reaction was carried out for 16 h. LC-MS shows that most of the raw materials are consumed, products are generated, and the reaction is finished. The reaction was spin dried and the crude product was purified on normal phase column (PE/EA 0-100%) to give intermediate 1-8(300mg) as a white solid in yield: 50 percent. LCMS M/z 293.5(M + H) + 。
Step 7. Synthesis of intermediates 1-9
Intermediates 1-8(750mg, 2.56mmol) and hexamethylditin (1680mg, 5.12mmol) were added to toluene (40 mL). Pd (PPh) 3 ) 4 (591mg, 0.512mmol) was added to the above mixture. N for reaction system 2 Under protection, the temperature is raised to 150 ℃ and the reaction is carried out overnight. The reaction solution was dried by spinning and purified by column chromatography (biotage,80g, silica gel column, UV254, DCM/PE ═ 0-50%) to give intermediate 1-9, 681mg, colorless semisolid, yield: 70 percent. LC-MS M/z 378.1(M + H) + ； 1 H NMR(400MHz,DMSO-d 6 )δ8.90(s,1H),7.56(s,1H),7.55(d,J＝2.4H,1H),7.50(d,J＝2.0H,1H),0.0(s,9H).
Step 8. Synthesis of intermediates 1-10
Intermediates 1-4(740mg, 1.8mmol) and 1-9(678mg, 1.8mmol) were added to toluene (40 mL). Pd (PPh) 3 ) 4 (416mg, 0.36mmol) was added to the above mixture. N for reaction system 2 Protecting, heating to 150 ℃ and reacting for 5 hours under the microwave condition. The reaction solution was spin dried to give the product 1-10 as 660mg of crude, yellow semi-solid. Directly used for the next reaction. LC-MS M/z 419.1(M + H) + 。
Step 9. Synthesis of intermediates 1-12
Compounds 1-10(40mg,0.095mmol), compounds 1-11(27mg,0.114mmol) were dissolved in 1mL EA followed by the addition of pyridine (23mg,0.286mmol), T 3 P (76mg, 0.238). The reaction was stirred at 90 ℃ for 0.5 h, diluted with 20mL ethyl acetate, washed with 30mL saturated ammonium chloride, the aqueous phase extracted with ethyl acetate (20mL x 3), the combined organic phases washed with water (60mL), saturated brine (60mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was spun dry to give an intermediate (crude) which was purified by silica gel column (biotage, silica gel column, 20g, UV254, EA/PE ═ g)0-100%) to obtain the target product 1-12 as yellow solid with yield of 66% of 40 mg. LC-MS M/z 633.2(M + H) + 。
Step 10 Synthesis of example A1
Compound 1-12(40mg) was dissolved in a mixed solvent consisting of 3mL TFA and 9mL DCM, the reaction was stirred at room temperature for 2 hours, and the reaction was concentrated to afford the desired product a1, 25mg, 68% yield (acid preparation, formic acid system). LC-MS M/z 577.0(M + H) + ； 1 H NMR(400MHz,DMSO-d 6 )δ12.96(br,1H),11.75(s,1H),10.43(s,1H),8.67(s,1H),8.00(s,1H),7.80-7.78(m,1H),7.73-7.71(m,1H),7.66(d,J＝1.6Hz,1H),7.40-7.34(m,2H).7.04(s,1H),6.30(s,1H),4.91-4.83(m,2H),3.04-2.97(m,2H),2.40-2.33(m,2H).
Example 2: preparation of Compound A2
Compound 1-10(30mg,0.072mmol), compound 2-1(14mg,0.093mmol) was dissolved in 2mL acetonitrile, followed by the addition of N-methylimidazole (12mg,0.143mmol), N, N, N ', N' -tetramethylchlorourea hexafluorophosphate (26mg,0.093 mmol). The reaction mixture was stirred at room temperature overnight, and the reaction mixture was concentrated to prepare (neutral preparation, NH) 4 HCO 3 System) gave the desired product a2, 12mg, yield 30%. LC-MS M/z 555.0(M + H) + ； 1 H NMR(400MHz,DMSO-d 6 )δ10.87(s,1H),8.60(s,1H),7.74-7.71(m,1H),7.66-7.61(m,2H),7.60-7.54(m,2H),7.51-7.50(m,2H),7.27(dd,J＝2.0Hz,8.8Hz,1H),6.24(s,1H),4.84-4.82(m,2H),3.10-2.87(m,2H),2.36-2.21(m,2H).
Example 3: preparation of Compound A3
Wherein the intermediate 3-1 is synthesized as follows:
adding 2-bromo-4-chloroaniline (10.0g, 48mmol) (made by China) into a 100mL reaction flask, adding acetic acid (100mL), stirring at room temperature, adding trimethyl orthoformate (15.4g, 145mmol), stirring at room temperature for 30min, adding NaN 3 (11.0mg, 145mmol), stirring at 80 ℃ for 3h, sampling, monitoring by LC-MS, after the raw materials have reacted substantially, cooling to room temperature, adding saturated NaNO 2 Quenching with 100mL of aqueous solution, adding EA (200mL), stirring for 30min, standing, separating, back-extracting the aqueous phase with EA (100 mL. multidot.2), mixing the organic phases, and sequentially subjecting the organic phase to H 2 O (100 mL. multidot.2), saturated aqueous NaCl solution (100mL) wash, anhydrous NaSO 4 Drying, spin-drying and column chromatography gave 10.1g of product, yield: 80 percent. 1 H NMR(400MHz,CDCl 3 )δ8.99(s,1H),7.83–7.82(d,J＝2.0Hz,1H),7.56–7.50(m,2H).
Example A3 was synthesized analogous to the procedure for example A1 from intermediates 3-1 and 1-4. LC-MS M/z 544.0(M + H) + ； 1 H NMR(400MHz,DMSO-d 6 )δ12.94(br,1H),11.74(s,1H),10.42(s,1H),9.63(s,1H),8.00(d,J＝0.8Hz,1H),7.85-7.78(m,2H),7.71(d,J＝2.0Hz,1H),7.40-7.33(m,2H),7.04(d,J＝1.6Hz,1H),6.38(s,1H),4.91-4.86(m,2H),3.05-2.95(m,2H),2.45-2.29(m,2H).
Example 4: preparation of Compound A4
Wherein intermediates 4-4 were synthesized as follows.
Step 1. Synthesis of intermediate 4-1
A100 mL round bottom flask was charged with 2-bromo-4-chloroaniline (2500mg, 12.2mmol), formic acid (2245mg, 48.8mmol), and sodium formate (415mg, 6.1 mmol). The reaction was then stirred at room temperature for 16 hours. The reaction mixture was diluted with EA (50mL) and saturated with water (50 mL. about.3)And NaHCO 3 The aqueous solution (50mL) was washed successively with Na 2 SO 4 Drying, filtering and concentrating to obtain a target product 4-1, 2600mg, a gray solid, yield: 91 percent. 1 H NMR(400MHz,DMSO-d 6 )δ9.82(s,1H),8.36(d,J＝1.3Hz,1H),8.05(d,J＝8.8Hz,1H),7.80(d,J＝2.4Hz,1H),7.46(dd,J＝8.6,2.4Hz,1H).
Step 2. Synthesis of Compound 4-2
Intermediate 4-1(2600mg, 11.2mmol), triethylamine (3393mg, 33.6mmol) and anhydrous THF (30mL) were added to a 250mL three-necked round bottom flask and the system was cooled to 0 ℃ with nitrogen protection and ice bath. Maintaining the temperature of the system, adding POCl 3 (2050mg, 13.4mmol) was dissolved in anhydrous THF (10mL) and added dropwise slowly to the above reaction mixture. After the addition, the temperature was maintained at 0 ℃ for 1 hour. LC-MS shows that a new product is generated and the reaction is finished. The reaction was poured into saturated aqueous potassium carbonate (60mL) at 0 deg.C, extracted with methyl tert-butyl ether (50 mL. about.2), and Na 2 SO 4 Drying, filtering and concentrating. Purification with normal phase column (PE/DCM ═ 0-30%) yielded target 4-2, 1750mg, black solid, yield: 72 percent. 1 H NMR(400MHz,CDCl 3 )δ7.68(d,J＝2.1Hz,1H),7.39(d,J＝8.5Hz,1H),7.34(dd,J＝8.5,2.1Hz,1H).
Step 3. Synthesis of intermediate 4-4
A100 mL round bottom flask was charged with intermediate 4-2(1650mg, 7.6mmol), 4-3(30mL, 0.3-0.4M in toluene), silver carbonate (416mg, 1.52mmol),
molecular sieves (900mg) and DMF (10mL) were heated to 40 ℃ and reacted for 16 hours. LC-MS showed the product to be formed and the reaction was terminated. The reaction was filtered and the toluene in the filtrate was spun dry and then diluted with water (50mL) and EA (50 mL). Extracting with EA (50mL by 3), combining the organic phases, washing with saturated brine (200mL), anhydrous Na 2 SO 4 Drying and concentrating. The crude product was purified on normal phase column (PE/DCM ═ 0-50%) to give the desired product 4-4, 920mg, yellow oil, yield: 37 percent. LCMS M/z 328.0(M + H) + 。
Example A4 from the middleForms 4-4 and 1-4 were synthesized analogously to example A1. LCMS: m/z 609.0[ M-H] + ； 1 H NMR(400MHz,DMSO-d 6 )δ12.92(s,1H),11.74(d,J＝2.3Hz,1H),10.42(s,1H),9.20(s,1H),8.00(d,J＝1.8Hz,1H),7.89–7.73(m,2H),7.71(d,J＝2.2Hz,1H),7.43–7.24(m,2H),7.07–6.93(m,1H),6.36(s,1H),4.88(d,J＝23.0Hz,2H),3.01(m,2H),2.26(m,2H).
Example 5: preparation of Compound A5
The crude compound A4(100mg) was dissolved in 2mL DMF and HATU (93mg, 0.24mmol), TEA (42mg, 0.8mmol), NH 4 Cl (80mg, 0.8mmol) was added to the reaction solution and stirred at room temperature overnight. 10mL of water was added and extracted with ethyl acetate (10 mL. multidot.3) and the combined organic phases were dried to yield 10mg of A5. LCMS: m/z 608.2(M-H) + ； 1 H NMR(400MHz,DMSO-d 6 )δ11.51(s,1H),10.38(s,1H),9.19(s,1H),7.95(d,J＝12.8Hz,2H),7.81(q,J＝8.8Hz,2H),7.71(s,1H),7.36(d,J＝9.2Hz,2H),7.27(d,J＝9.0Hz,1H),7.06(s,1H),6.36(s,1H),4.91(s,2H),3.02(m,2H),2.67(m,2H).
Example 6: preparation of Compound A6
Wherein the intermediate 6-3 is synthesized as follows:
step 1. Synthesis of intermediate 6-1
Intermediate 1-6(1150mg, 4.98mmol), 3, 3-diethoxyprop-1-yne (956mg, 7.47mmol) and toluene (10mL) were added to a 100mL round bottom flask, the temperature was raised to 110 ℃ and the reaction was stirred for 16 h. LC-MS shows the product is formed and the reaction is over. The reaction solution is dried by spinning, purified by normal phase column (PE/EA is 0-50 percent) to obtain 1.40g intermediate 6-1, yellow oil, yield: and 78 percent. LCMS M/z 362.0(M + H) + 。
Step 2. Synthesis of intermediate 6-2
HCl (20mL) and dioxane (20mL) were added to a 100mL round bottom flask, then compound 6-1(1.2g, 3.34mmol) was added to the above mixed solution, the temperature was raised to 30 ℃ and reaction was carried out for 16 h. LC-MS detection shows that the product is generated and the reaction is finished. The reaction mixture was diluted with water (40mL) and extracted with EA (200 mL). The organic phase was washed successively with water (100 mL. times.2) and saturated sodium chloride (100 mL. times.2), then with Na 2 SO 4 Drying, filtration, concentration gave intermediate 6-2, 950mg, yellow solid, yield: 99 percent. LCMS M/z 288.0(M + H) + 。
Step 3. Synthesis of intermediate 6-3
Intermediate 6-2(950mg, 3.33mmol), DAST (1072mg, 6.66mmol) and DCM (20mL) were added to a 100mL round bottom flask and reacted at room temperature for 2 h. LC-MS detection shows that a product is generated, and the reaction is finished. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution (60mL) at 0 deg.C, extracted with DCM (60 mL. times.2), the organic phases were combined, washed with water (100mL) and saturated brine (100mL) in that order, and dried over anhydrous Na 2 SO 4 Drying and concentrating. The crude product was purified by normal phase column (PE/EA ═ 0-15%) to give the desired product 6-3, 579mg, white solid, yield: 56 percent. LCMS M/z 310.0(M + H) + 。
Example A6 was synthesized analogous to example A1 from intermediates 6-3 and 1-4. LCMS: m/z 591.2(M-H) + ； 1 H NMR(400MHz,DMSO-d 6 )δ11.50(s,1H),10.33(s,1H),8.67(s,1H),7.89(d,1H),7.74–7.67(m,2H),7.61(d,1H),7.30–7.17(m,3H),6.86(s,1H),6.26(s,1H),4.84(d,2H),2.94(m,2H).
Example 7: preparation of Compound A7
Step 1 preparation of intermediate 7-2
Mixing 1, 3-cyclopentanedione (2.5g,25.48mmol), (S) -2-aminobenzoic acid methyl ester hydrochlorideSalt (3.91g,25.48mmol), PTSA (485mg, 2.55mmol) was added to toluene (100 mL). The reaction system is heated to 130 ℃ under the protection of nitrogen and reacts for 3 hours. The reaction solution was spun dry, dissolved in 500mL ethyl acetate and saturated NaHCO 3 Washing, drying, filtering and spin-drying to obtain 7-2, 5g of a target product, a yellow solid and a yield: 99 percent. LCMS: m/z 198.1(M + H) + 。
Step 2. preparation of intermediate 7-3
Compound 7-2(5.0g, 25.35mmol) and bis (2,4, 6-trichlorophenyl) malonate (12.45g,25.35mmol) were added to toluene (100 mL). The reaction solution was stirred at 100 ℃ for 2 hours. And cooling the reaction liquid to room temperature, carrying out spin drying to obtain a crude product, and purifying the crude product by using column chromatography (biotage,120g, silica gel column, UV254, EA/PE is 0-100%) to obtain a target product 7-3, which is yellow semisolid, 1.2g and has the yield of 18%. LCMS: m/z 266.1(M + H) + 。
Step 3. preparation of intermediate 7-4
Triethylamine (456mg,4.52mmol) was added to intermediate 7-3(1.2g,4.52mmol) at 0 deg.C, and 25mL of dichloromethane was added. Subsequently, N-bis (trifluoromethanesulfonyl) aniline (1.62mg,4.52mmol) was added in portions. Stirred at room temperature for 2 days. And (3) purifying the crude product by column chromatography (biotage,120g, silica gel column, UV254, EA/PA is 0-100%) to obtain a target product 7-4, yellow semisolid, 450mg and 25% of yield. LCMS: m/z 398.0(M + H) + 。
Step 4. preparation of intermediates 7-5
Mixing the compounds 7-4(0.150mg, 0.377mmol), 1-8(221mg, 0.755mmol), K 2 CO 3 (209mg, 1.51mmol) was added to 1, 4-dioxane (30mL) and water (10 mL). Pd (dppf) Cl 2 (30mg) was added to the above mixture. The reaction system is heated to 110 ℃ under the protection of nitrogen. Bis (pinacolato) borate (382mg,1.51mmol) is dissolved in 1, 4-dioxane (5mL) and slowly added into the mixture dropwise, after the reaction is detected by LCMS, ethyl acetate is used for extraction, spin-drying is carried out, and the crude product is purified by column chromatography (biotage,40g, silica gel column, UV254, EA/PE is 0-100%) to obtain the target product 7-5, 66mg and the yield is 30%. LCMS: m/z 461.2(M + H) + 。
Step 5 preparation of intermediates 7-6
Compound 7-5(61mg, 0.132mmol) was dissolved in a mixed solvent composed of 2mL of 1M aqueous LiOH and 9mL of DCM, the reaction was stirred at room temperature for 2 hours, and the reaction was concentrated to give the desired product 7-6(61mg, crude) as a yellow solid. The crude product was used directly in the next step.
Intermediates 7-6 and 1-11 were synthesized by an analogous experimental procedure to A1 to give example A7. LCMS: m/z 603.2(M-H) + ； 1 H NMR(400MHz,DMSO-d 6 )δ12.89(br,1H),11.72(s,1H),9.46(br,1H),8.56(s,1H),7.81-7.70(m,3H),7.64(s,1H),7.37-7.28(m,2H),7.05(d,J＝1.2Hz,1H),6.31-6.21(m,1H),5.06-4.96(m,1H),3.12-3.00(m,2H),2.49-2.19(m,4H),0.850.71(m,3H).
Example 8: preparation of Compound A8
Step 1: preparation of intermediate 8-2
Potassium tert-butoxide (3g,26.93mmol) was added to 20mL of tetrahydrofuran under argon at 0 ℃ and the mixture was stirred at 0 ℃ for 10 min. Ethyl N- (diphenylmethylene) glycinate (6g,22.44mmol) was added portionwise and aged for 30 min. Trifluoroethyl iodide (4.71g,22.44mmol) was added dropwise and the mixture was stirred for 60 min. 150mL of saturated aqueous ammonium chloride solution were then added, and the reaction mixture was extracted twice with in each case 100mL of ethyl acetate. The collected organic phases were dried over magnesium sulfate, filtered and concentrated to give the crude product. Yield: 5.0 g. Directly used for the next reaction. LCMS: m/z 350.2(M + H) + 。
Step 2: preparation of intermediate 8-3
8-2(5g crude, 14.31mmol) was added to tetrahydrofuran (100 mL). 20mL of 3N aqueous hydrochloric acid solution was added dropwise to the reaction system, and reacted for 3 hours. And (4) spin-drying the reaction solution. Dissolved in 100mL ethyl acetate, washed with water, the aqueous phases combined and adjusted to alkalinity of about 8 to 9 with solid potassium carbonate. The reaction mixture was then extracted twice with in each case 100mL of ethyl acetate, dried and spin-dried to give the desired product 8-3, 1g of a yellow oily compound, which was used directly in the next reaction.
And step 3: preparation of intermediate 8-4
1, 3-cyclopentadione (0.7g,7.14mmol), 8-3(1g,1.07mmol), PTSA (204mg, 4.69mmol) was added to toluene (100 mL). The reaction system is heated to 130 ℃ under the protection of nitrogen and reacts for 3 hours. The reaction solution was spun dry, dissolved in 500mL ethyl acetate, and saturated NaHCO was used 3 Washing, drying, filtering and spin-drying to obtain 8-4 of a target product, 1.2g of a yellow solid, yield: and 63 percent. LCMS: m/z 266.0(M + H) + 。 1 H NMR(400MHz,CDCl 3 )δ6.09(s,1H),5.08(s,1H),4.32-4.26(m,3H),2.84-2.70(m,2H),2.69-2.66(m,2H),2.48-2.45(m,2H),1.32(t,J＝6.8Hz,3H).
And 4, step 4: preparation of intermediate 8-5
Compound 8-4(1.2g, 4.52mmol) and bis (2,4, 6-trichlorophenyl) malonate (3.14g, 6.79mmol) were added to toluene (50 mL). The reaction solution was stirred at 180 ℃ for 2 hours. And cooling the reaction liquid to room temperature, carrying out spin drying to obtain a crude product, and purifying the crude product by using column chromatography (biotage,120g, silica gel column, UV254, EA/PE is 0-100%) to obtain 8-5 of a target product, which is yellow semisolid, 0.75g and has the yield of 50%. LCMS: m/z 334.0(M + H) + 。
And 5: preparation of intermediates 8 to 6
Triethylamine (665mg,6.57mmol) was added to intermediate 8-5(0.73g,2.19mmol) at 0 deg.C, and 25mL of dichloromethane was added. Subsequently, N-bis (trifluoromethanesulfonyl) aniline (939mg,2.63mmol) was added in portions. Stirred at room temperature for 2 days. The crude product is purified by column chromatography (biotage,120g, silica gel column, UV254, EA/PE 0-100%) to obtain the target product 8-6, yellow semisolid, 0.750mg, yield 74%. LCMS: m/z 466.0(M + H) + 。
Step 6: preparation of intermediates 8 to 7
Mixing the compounds 8-6(0.300mg,0.644mmol), 1-8(337mg,1.29mmol), K 2 CO 3 (356mg,2.58mmol) was added to 1, 4-dioxane (30mL) and water (10 mL).Pd(dppf)Cl 2 (30mg) was added to the above mixture. The reaction system was warmed to 110 ℃ under nitrogen protection. After the reaction is finished, LCMS detection reaction is finished, ethyl acetate is used for extraction, spin drying is carried out, and a crude product is purified by column chromatography (biotage,40g, silica gel column, UV254, EA/PE is 0-100%) to obtain 8-7, 120mg and 35% of a target product. LCMS: m/z 529.2(M + H) + 。
And 7: preparation of intermediates 8 to 8
Compound 8-7(120mg, 0.226mmol) was dissolved in a mixed solvent consisting of 3mL of 1N aqueous LiOH and 9mL of DCM, the reaction was stirred at room temperature for 2 hours, and checked by TLC. The reaction was concentrated to give 114mg of the desired product 8-8 as a yellow solid. The crude product was used directly in the next step.
Example A8 was synthesized in analogy to the synthesis of example A1, from intermediates 8-8 and 1-11. LCMS: m/z 659.2(M + H) + ； 1 H NMR(400MHz,DMSO-d 6 )δ11.41(s,1H),9.47(s,1H),8.38(s,1H),7.72-7.62(m,3H),7.54(s,1H),7.27(d,J＝8.8Hz,1H),7.14(d,J＝8.4Hz,1H),6.83(s,1H),6.34(s,1H),5.39(s,1H),3.37-3.09(m,3H),2.95-2.77(m,1H),2.51-2.29(m,2H).
Example 9: preparation of Compound A9
Example A9 was synthesized in analogy to the synthesis of example A7 from intermediates 7-3 and 4-4 and 1-11. LCMS: m/z 637.2(M + H) + ； 1 H NMR(400MHz,DMSO-d 6 )δ12.87(s,1H),11.64(s,1H),9.36(s,1H),8.98(s,1H),7.74(m,3H),7.62(s,1H),7.29–7.26(m,2H),7.01-6.97(m,1H),6.29-6.21(m,1H),4.90(s,1H),3.13-3.02(m,2H),2.26-2.13(m,4H),0.66(s,3H).
Example 10: preparation of Compound A10
The method comprises the following steps: preparation of example A10
The crude product of Compound A9 (200mg) was dissolved in 2mL of DMF and HATU (100mg, 0.25mmol), TEA (174mg, 1.72mmol), NH 4 Cl (46mg, 0.86mmol) was added to the reaction solution, and stirred at room temperature overnight. Water 10mL was added and extracted with ethyl acetate (10mL x 3) and the combined organic phases were dried to give 19.10mg of a 10. LCMS: m/z 636.2(M + H) + ； 1 H-NMR(400MHz,DMSO-d 6 )δ11.42(s,1H),9.30(s,1H),8.98(s,1H),7.86(S,1H),7.74-7.72(m,2H),7.62(d,1H),7.26-7.24(m,2H),7.17-7.14(m,1H),6.99(s,1H),6.28(s,1H),4.87(s,1H),3.02-2.79(m,2H),2.26-2.15(m,4H),0.66(s,3H).
Example 11: preparation of Compound A11
Synthesis of intermediate 11-5
Step 1. Synthesis of intermediate 11-2
NBS (2.9g,16.21mmol) was added portionwise to a solution of starting material 11-1 (made in China) (2.5g,14.74mmol) in water (15mL) at 60 ℃. The mixture was stirred at 60 ℃ for 2 hours. And cooling the reaction liquid to 0-5 ℃, and adjusting the pH value to 7 by using a 2N NaOH solution. Extract 1 time with EA (20mL) and spin dry the aqueous phase. The residue was slurried with DCM/MeOH (10:1,50mL) and filtered. The filtrate was spin-dried to give 4.0g of crude product. The crude product was dissolved in water (15mL), left to stand for 24 hours, whereupon a solid precipitated and was filtered. The solid was spun dry to give intermediate 11-2(900 mg). LCMS: m/z 212.3(M + H) + 。
Step 2. Synthesis of intermediate 11-3
Intermediate 11-2(900mg,4.24mmol), Boc 2 A solution of O (926mg,4.24mmol) and TEA (858mg,8.48mmol) in THF (10mL) was stirred at room temperature for 2 hours. The reaction solution was spin-dried, and the residue was purified by silica gel column chromatography (EA/PE 0-100%) to obtain intermediate 11-3 (1.0)g,76％)。LCMS：m/z 256.1(M+H) + 。
Step 3. Synthesis of intermediate 11-4
To intermediate 11-3(500mg,1.60mmol), molybdenum hexacarbonyl (423mg,1.60mmol), tri-tert-butylphosphine tetrafluoroborate (93mg,0.32mmol), trans-bis (acetyl) bis [ o- (di-formylphosphino) benzyl]Dipalladium (II) (Hermann's catalyst) (150mg,0.16mmol), DBU (481mg,3.20mmol), CH 3 A mixture of CN (4mL) and MeOH (4mL) was stirred under nitrogen at 120 ℃ for 1 hour. The reaction solution was cooled and spin dried. The residue was purified by silica gel column chromatography (EA/PE 0-100%) to obtain compound 11-4(400mg, 86%). LCMS: m/z 236.3(M-56+ H)]) + 。
Step 4. Synthesis of intermediate 11-5
A solution of compound 11-4(60mg,0.20mmol) in DCM/TFA (3:1,2ml) was stirred at room temperature for 2 h. The reaction solution was spin-dried to give the desired product 11-5(39mg, crude). LCMS: m/z 192.3(M + H).
Example A11 was synthesized in analogy to the synthesis of example A1 from intermediates 1-10 and 11-5. LCMS: m/z 578.4(M + H) + ； 1 H NMR(400MHz,DMSO-d 6 )δ10.43(s,1H),8.66(s,1H),7.84–7.63(m,3H),7.55–7.49(m,1H),7.32–7.26(m,1H),7.19–7.11(m,1H),6.29(s,1H),4.97–4.76(m,2H),3.26–3.20(m,3H),3.07(dd,J＝13.6,7.4Hz,4H),2.38(d,J＝4.9Hz,2H).
In analogy to the synthesis of the above examples, the following examples a12-a62 were synthesized as shown in table 1 below:
table 1: examples A12-A62 structural formulae and analytical data thereof
Effect embodiment:
biological activity of the compound of the invention on inhibition of coagulation factor XIa (FXIa)
1. Test method
Factor XIa protease (FXIa) cleaves specific substrates to produce yellow p-nitroaniline (pNA), which is strongly absorbed at 405 nM. The inhibitory activity of a compound on factor XIa was determined by measuring the absorbance of the compound at 405 nM.
2. Reagent, consumable and instrument
The factor XIa protease used in the experiments was purchased from Abcam, cat No. ab 62411; factor XIa-specific substrates were purchased from HYPHEN BioMed, cat # Biophen cs-21 (66); tris-HCl was purchased from Invitrogen, cat # 15567-; NaCl available from ABCONE, cat # S39168; tween 20 was purchased from Amersham, cat # 0777-1L.
Buffer solution: 100mM tris-HCl, 200mM NaCl, 0.02% Tween 20, pH 7.4.
The ECHO liquid workstation is purchased from Labcyte, model number ECHO 550; the Bravo liquid workstation was purchased from Agilent, model 16050-; a multifunctional microplate reader is available from PerkinElmer, model EnVision; 384 well compound plates were purchased from Labcyte, cat # LP-0200; 384 well assay plates were purchased from PerkinElmer, cat # 6007650.
3. Compound preparation
Compounds were dissolved in 100% DMSO, 20mM and stored at room temperature in a nitrogen cabinet.
4. The test method comprises the following steps:
a. 20mM test compound was diluted to 2mM using 100% DMSO, and reference compound was diluted to 0.4 mM; compounds were serially diluted using a Bravo liquid workstation 3-fold gradient, 10 concentration points.
b. Transfer 10nL of compound to the corresponding 384 well assay plate, duplicate wells, using the ECHO liquid workstation; the final concentrations of the compounds were 1000, 333.3, 111.1, 37.0, 12.3, 4.1, 1.37, 0.46, 0.15, 0.05 nM. The final reference compound reaction concentrations were 200, 66.7, 22.2, 7.4, 2.47, 0.82, 0.27, 0.09, 0.03, 0.01 nM.
c. Transfer 10nL DMSO to the high signal control wells, transfer 10nL 0.4mM reference compound to the low signal control wells.
d. Preparing FXIa enzyme solution with 0.1 mu g/mL by using buffer solution, and adding 10 mu L of enzyme solution to a 384-hole experimental plate; 5mM substrate solution was prepared using buffer, and 10. mu.L of substrate solution was added to 384-well plates. The final concentration of FXIa was 0.05. mu.g/mL and the final concentration of substrate was 2.5 mM.
e. The 384 well assay plates were centrifuged and incubated at 37 ℃ for 15 minutes.
f. Absorbance was measured at 405nM using EnVision.
In this example, half inhibitory activity (IC) of the compounds of the present invention against FXIa was determined 50 ) As shown in the following table, wherein:
TABLE 2 IC inhibition of FXIa by the compounds of the invention 50 Value (nM)
| Numbering | FXIa IC 50 | Number of | FXIa IC 50 | Numbering | FXIa IC 50 | Numbering | FXIa IC 50 |
| A1 | 0.60 | A3 | 0.31 | A4 | 0.5 | A5 | 0.75 |
| A6 | 0.60 | A7 | 4.17 | A9 | 1.56 | A10 | 5.02 |
| A11 | 11.49 | A12 | 4.12 | A15 | 9.32 | A16 | 1.80 |
| A18 | 5.20 | A19 | 6.10 | A21 | 0.50 | A22 | 5.2 |
| A23 | 5.2 | A24 | 4.1 | A25 | 9.2 | A27 | 1.33 |
| A29 | 3.5 | A30 | 1.6 | A31 | 7.82 | A32 | 4.78 |
| A34 | 0.72 | A35 | 3.20 | A36 | 1.83 | A37 | 3.95 |
| A39 | 5.11 | A40 | 4.38 | A41 | 6.11 | A42 | 9.07 |
| A43 | 2.07 | A44 | 6.93 | A47 | 1.74 | A49 | 5.36 |
| A53 | 7.62 | A55 | 7.96 | A56 | 6.31 | A57 | 9.94 |
Therefore, the compound has obvious FXIa inhibiting activity.
Second, testing the in vitro anticoagulant effect of the compound of the invention on human blood
1. Test method
Activated Partial Thrombin Time (APTT) measuring reagent is mixed with plasma and then reacts continuously to change optical density until reaching a freezing point, and a semi-automatic coagulation analyzer is used for measuring the Coagulation Time (CT) by an optical turbidimetry method. The in vitro anticoagulation activity of the compound on human blood is determined by detecting the coagulation time of plasma treated by the compound with different concentrations, and the concentration corresponding to the coagulation time prolongation of the compound is calculated.
2. Reagent, consumable and instrument
The human plasma used in the experiment was from Hai-source Biotechnology (Shanghai) Ltd; the activated partial thromboplastin time assay kit was purchased from saidi biotechnology limited, china, No. SS 00220005.
The semi-automatic coagulation analyzer is purchased from Shengxinkang science and technology Limited, Shenzhen, model SK 5004; the measuring cup is purchased from shenzhen shengxikang science and technology limited. The Bravo liquid workstation was purchased from Agilent, model 16050-; 384 well compound plates were purchased from Labcyte, cat # LP-0200.
3. Compound preparation
Compounds were dissolved in 100% DMSO, 20mM and stored at room temperature in a nitrogen cabinet.
4. Test method
a. The NaCl reagent in the kit was incubated half an hour in advance and the APTT reagent equilibrated to room temperature.
b. Compounds were serially diluted using a Bravo liquid workstation 2-fold gradient, 14 concentration points.
c. Add 0.75. mu.L of compound in the measuring cup, duplicate wells; adding 50 μ L of plasma, adding 50 μ L of APTT reagent, mixing, and incubating at 37 deg.C for 3 min.
d. The APTT assay was started and the reaction was initiated by the addition of 50. mu.L NaCl and the clotting time was counted.
e. Control clotting times were determined using 100% DMSO instead of compound, final DMSO concentration 0.5%.
5. Data processing
Curve fitting data was performed using Graphpad Prism to calculate the compound concentration corresponding to CT2.0, the aPTT for the 2-fold blank. In this example, the inhibition of human blood coagulation by the compounds of the invention was determined as shown in the following table, in which:
TABLE 3 CT2.0 (. mu.M) of the inventive Compounds
| Numbering | CT2.0 | Number of | CT2.0 | Numbering | CT2.0 | Numbering | CT2.0 |
| A1 | 0.41 | A3 | 0.21 | A4 | 0.27 | A5 | 1.68 |
| A6 | 0.72 | A7 | 3.84 | A9 | 2.88 | A12 | 3.60 |
| A15 | 4.41 | A16 | 1.35 | A21 | 1.56 | A22 | 1.56 |
| A23 | 1.17 | A24 | 3.24 | A25 | 3.72 | A27 | 0.93 |
| A29 | 1.62 | A30 | 2.52 | A31 | 1.95 | A32 | 1.08 |
| A34 | 0.78 | A35 | 0.86 | A36 | 0.24 | A37 | 0.96 |
| A39 | 1.38 | A40 | 0.78 | A41 | 1.31 | A43 | 0.38 |
| A47 | 2.16 | A48 | 3.27 | A49 | 2.53 |
Therefore, the compound has obvious inhibitory activity on human blood coagulation.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (14)
1. A compound represented by formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof,
wherein the content of the first and second substances,
R 1 selected from the group consisting of 1H-1,2, 3-triazolyl and 1H-tetrazolyl, said 1H-1,2, 3-triazolyl or 1H-tetrazolyl optionally substituted with 1R;
R 2 selected from F, Cl, Br, I, OH, Me and NH 2 ；
R 3 Selected from H, halogen, OH, NH 2 、CN、C 1-6 Alkyl, phenyl-C 1-6 Alkyl-, 5-to 6-membered heteroaryl-C 1-6 Alkyl-, 3-to 6-membered heterocycloalkyl-C 1-6 Alkyl-and C 3-6 cycloalkyl-C 1-6 Alkyl-, said C 1-6 Alkyl, phenyl-C 1-6 Alkyl-, 5-to 6-membered heteroaryl-C 1-6 Alkyl-, 3-to 6-membered heterocycloalkyl-C 1-6 Alkyl-or C 3-6 cycloalkyl-C 1-6 Alkyl-optionally substituted with 1,2 or 3R;
R 4 each independently selected from halogen, OH, NH 2 、CN、C(＝O)OH、C(＝O)NH 2 、C 1-6 Alkyl radical, C 1-6 alkyl-O-C (═ O) -, C 1-6 alkyl-NH-C (═ O) -and 5-6 membered heteroaryl, said C 1-6 Alkyl radical, C 1-6 alkyl-O-C (═ O) -or C 1-6 alkyl-NH-C (═ O) -optionally substituted with 1,2 or 3R;
ring A is selected from phenyl, naphthyl, 5-10 membered heteroaryl, benzo 5-6 membered heterocycloalkyl, benzo C 5-6 Cycloalkyl, 5-to 6-membered heteroarylo 5-to 6-membered heterocycloalkyl, 5-to 10-membered heteroarylo 5-to 6-membered heterocyclic group and 5-to 6-membered heteroarylo C 5-6 A cycloalkyl group;
D 1 is selected from-N (R) 5 )-、-CH(R 5 ) -and-CH (R) 5 )CH(R 5 )-；
R 5 Are each independently selected from H and C 1-6 Alkyl radical, said C 1-6 Alkyl is optionally substituted with 1,2 or 3R;
r is respectively and independently selected from H, F, Cl, Br, I and NH 2 、CN、C 1-6 Alkyl and C 1-6 Heteroalkyl group of said C 1-6 Alkyl or C 1-6 Heteroalkyl is optionally substituted with 1,2, or 3R';
r' is respectively and independently selected from H, F, Cl, Br, I and NH 2 And CN;
n is selected from 0, 1,2 or 3;
the 5-to 6-membered heteroaryl, 3-to 6-membered heterocycloalkyl, 5-to 10-membered heteroaryl, 5-to 6-membered heteroarylo 5-to 6-membered heterocycloalkyl or 5-to 6-membered heteroarylo C 5-6 Cycloalkyl contains 1,2 or 3 substituents independently selected from-O-, -NH-, -S-, -C (═ O) O-, -S (═ O) 2 -and N, or a heteroatom or heteroatom group.
2. The compound according to claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein each R is independently selected from H, F, Cl, Br, I, NH 2 、CN、C 1-3 Alkyl radical, C 1-3 Alkoxy and C 1-3 Alkylamino radical, said C 1-3 Alkyl radical, C 1-3 Alkoxy or C 1-3 Alkylamino is optionally substituted with 1,2 or 3R'.
3. The compound according to claim 2, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein R is independently selected from H, F, Cl, Br, I, NH 2 、CN、Me、
4. The compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 Is selected from
5. The compound according to any one of claims 1 to 3An object, an optical isomer thereof or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from H, Me,
6. The compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 4 Each independently selected from F, Me, CH 2 F、CHF 2 、CF 3 、C(＝O)OH、C(＝O)OEt、NH 2 、C(＝O)NH 2 、
7. The compound according to claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of phenyl, indolyl, 1H-pyrrolo [2,3-b ] pyridyl, 2, 3-dihydro-1H-indenyl, 6, 7-dihydro-5H-cyclopenta [ b ] pyridyl, 1H-benzo [ d ] imidazolyl, 1, 2-dihydro-3H-indazol-3-onyl, 1, 3-dihydro-2H-benzo [ d ] imidazol-2-onyl, 1H-indazolyl, imidazo [1,2-a ] pyridyl, pyrazolo [1,5-a ] pyridyl, pyrazoline [1,5-a ] pyridyl, imidazo [1,2-a ] pyridyl, pyrazoline [1,5-a ] pyridyl, and imidazo [1,2-a ] pyridyl, Benzofuranyl, benzo [ d ] isoxazolyl, 1H,3H oxazolo [3,4-a ] indol-1-onyl, 3, 4-dihydroquinolin-2 (1H) -onyl, indolinyl, 1,2,3, 4-tetrahydroquinolinyl, 3, 4-dihydroquinolin-2 (1H) -onyl, benzo [ d ] isoxazolyl and quinoxalinyl.
8. The compound, its optical isomer, or its pharmaceutically acceptable salt according to claim 6 or 7, wherein the structural unit
Is selected from
9. A compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R 5 Selected from H and Me.
10. A compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof according to claim 9, wherein D 1 Is selected from CH 2 、CH 2 CH 2 NH and N (CH) 3 )。
11. A compound of the formula, an optical isomer thereof or a pharmaceutically acceptable salt thereof, selected from
12. A pharmaceutical composition comprising a compound of any one of claims 1-11, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
13. Use of a compound according to any one of claims 1 to 11, an optical isomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 12 for the preparation of a medicament for the prevention and/or treatment of cardiovascular and cerebrovascular diseases.
14. Use of a compound of any one of claims 1 to 11, an optical isomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 12 for the preparation of a medicament for the prevention and/or treatment of FXIa inhibition.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101137412A (en) * | 2005-01-13 | 2008-03-05 | 布里斯托尔-迈尔斯·斯奎布公司 | Substituted biaryl compounds as factor xia inhibitors |
| CN105555767A (en) * | 2013-07-23 | 2016-05-04 | 拜耳制药股份公司 | Substituted oxopyridine derivatives and use thereof as factor XIA/plasma |
| CN107074821A (en) * | 2014-09-04 | 2017-08-18 | 百时美施贵宝公司 | It is used as the diamines macrocyclic compound of FXIA inhibitor |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101137412A (en) * | 2005-01-13 | 2008-03-05 | 布里斯托尔-迈尔斯·斯奎布公司 | Substituted biaryl compounds as factor xia inhibitors |
| CN105555767A (en) * | 2013-07-23 | 2016-05-04 | 拜耳制药股份公司 | Substituted oxopyridine derivatives and use thereof as factor XIA/plasma |
| CN107074821A (en) * | 2014-09-04 | 2017-08-18 | 百时美施贵宝公司 | It is used as the diamines macrocyclic compound of FXIA inhibitor |
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