CN117480164A - Factor XIa inhibitor and preparation method and application thereof - Google Patents

Factor XIa inhibitor and preparation method and application thereof Download PDF

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Publication number
CN117480164A
CN117480164A CN202180071331.2A CN202180071331A CN117480164A CN 117480164 A CN117480164 A CN 117480164A CN 202180071331 A CN202180071331 A CN 202180071331A CN 117480164 A CN117480164 A CN 117480164A
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alkyl
formula
compound
pharmaceutically acceptable
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冯焱
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Shanghai Lingtai Biomedical Technology Co ltd
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Shanghai Lingtai Biomedical Technology Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C07D257/06—Five-membered rings with nitrogen atoms directly attached to the ring carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

Provides a blood coagulation factor XIa inhibitor, a preparation method, a pharmaceutical composition and application thereof in preventing or treating FXIa activity related diseases. In particular to amide derivatives shown in a formula I, a preparation method thereof, a pharmaceutical composition containing the derivatives and application of the derivatives as therapeutic agents in preparing medicines for preventing or treating thromboembolic diseases. The compound of the formula I can obviously inhibit the activity of FXIa and has a large therapeutic safety window. The substituents in the formula I are defined in the specification.

Description

Factor XIa inhibitor and preparation method and application thereof Technical Field
The invention belongs to the field of medicines, and in particular relates to a blood coagulation factor XIa inhibitor, a pharmaceutical composition, a preparation method and application thereof in preventing or treating thromboembolic diseases.
Technical Field
Thrombus is a pathologically heterogeneous clot or precipitate of blood components in flowing blood formed in blood vessels or endocardium, and is mainly composed of platelets, fibrin or red and white blood cells. Thrombus can occur in blood vessels anywhere in the body, and the incidence of venous thrombus is 4 times that of arterial thrombus. The main reasons for venous thrombosis are that blood flow is slowed down, the venous thrombosis occurs in lower limbs and pelvic veins, viscera such as upper limbs and livers are easy to occur, arterial thrombosis is often related to atherosclerosis lesions, and coronary thrombosis and cerebral thrombosis are common. Thromboembolic diseases are the first leading cause of global disease death due to thromboembolic diseases, malignant tumors, systemic lupus erythematosus, cardiovascular and cerebrovascular diseases, diabetes, liver and kidney diseases, hyperlipidemia, and drugs.
The medicines for treating thromboembolic diseases which are widely applied clinically at present are anticoagulant medicines (such as heparin, warfarin, rivaroxaban and apixaban), antiplatelet medicines (such as aspirin and ADP clopidogrel) and thrombolytic medicines, and the medicines have good effects of treating, preventing or reducing thrombosis. However, these clinically used anticoagulants present a bleeding risk, particularly in patients prone to disease. Therefore, it is necessary to find a drug which can effectively inhibit or reduce thrombosis and reduce bleeding risk. In a study directed to hemophilia C patients (without factor XIa), it was found that these hemophilia C patients were not only at very low risk of stroke, but had little to no adverse bleeding without significant injury or surgery. The antithrombotic effect was also demonstrated in various in vitro models or factor XIa knockout models by using antibodies as factor XIa (FXIa) inhibitors, and little or no prolongation of bleeding time or expansion of bleeding volume, so FXIa is considered as an effective target for prevention or treatment of thrombus.
Human blood coagulation consists of an endogenous pathway, an exogenous pathway, and a common pathway. FXIa, which is essential for maintaining the intrinsic pathway during blood coagulation, is a plasma serine protease involved in the regulation of blood coagulation and plays a key role in the amplification of the coagulation cascade. In the coagulation cascade, thrombin feedback activates FXI, which in turn causes the production of large amounts of thrombin, thereby further expanding the coagulation process (Gailani, D. Et al, arterioscler. Thrombi. Vasc. Biol.,2007, 27:2507-2513), the thrombin burst caused by this process converts fibrinogen into fibrin, which polymerizes to form the structural framework of the Blood clot, and activates platelets, which are key cellular components of coagulation (Hoffman, M., blood Reviews,2003, 17:S1-S5). Thus, FXIa is critical in the overall clotting process and further reduces bleeding risk compared to FXa inhibitors, and has become a research hotspot for various large companies and research institutions. Early-developed FXIa inhibitors, including the oral FXIa inhibitor BMS-986177 (co-operating with the poplar company, ziram, when used), are currently being evaluated in a number of phase i studies. In addition to oral medications, parenteral administration such as BMS-962212 (Bristol-Myers quick), MAA-868 (Novartis), BAY1213790 (Bayer) and IONIS-FXIRx (Ionis and Bayer) are also currently in phase II development. The invention discloses a novel compound capable of effectively inhibiting FXIa activity, which not only has good biological inhibition activity, but also has good safety treatment window width, and can be used for treating various thromboembolic diseases or symptoms.
Disclosure of Invention
The present invention provides compounds of formula I, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof,
wherein:
R 1 selected from hydrogen, hydroxy, halogen, cyano, -OR e C1-C6 alkyl, C3-8 cycloalkyl, 3-8 heterocycloalkyl containing 1 to 2 heteroatoms selected from N, O or S, 6-10 aryl, 5-10 heteroaryl containing 1 to 4 heteroatoms selected from N, O or S, -NHS (O) 2 R e 、NHS(O) 2 OR e 、NHS(O) 2 NHR e 、-NHS(O)OR e 、-NHS(O)R e 、-NHS(O)NHR e 、-NHC(O)R e 、-NHC(O)OR e 、-NHC(O)NHR e 、-NR e R f 、-COR e 、-COOR e or-CONHR e ；
Each R is 2 Independently selected from hydrogen, hydroxy, halogen, cyano, -OR e C1-C6 alkyl, C3-8 cycloalkyl, 3-8 heterocycloalkyl containing 1 to 2 heteroatoms selected from N, O or S, 6-10 aryl, 5-10 heteroaryl containing 1 to 4 heteroatoms selected from N, O or S, -NHS (O) 2 R e 、NHS(O) 2 OR e 、NHS(O) 2 NHR e 、-NHS(O)OR e 、-NHS(O)R e 、-NHS(O)NHR e 、-NHC(O)R e 、-NHC(O)OR e 、-NHC(O)NHR e 、-NR e R f 、-COR e 、-COOR e or-CONHR e ；
R 1 And R is 2 Wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally substituted with one or more substituents selected from halogen, cyano, C1-C6 alkyl, halo C1-C6 alkyl, -COOR e 、-OR e C3-C8 cycloalkyl, 3-8 heterocycloalkyl, 6-10 aryl, 5-10 heteroaryl,-NHS(O) 2 R e 、NHS(O) 2 OR e 、NHS(O) 2 NHR e 、-NHS(O)OR e 、-NHS(O)R e 、-NHS(O)NHR e 、-NHC(O)R e 、-NHC(O)OR e 、-NHC(O)NHR e 、-NR e R f or-CONHR e Is substituted by a substituent of (a); the R is e And R is f Each independently is hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocycloalkyl containing 1 to 2 heteroatoms selected from N, O or S, 6-10 membered aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O or S;
n is 1, 2, 3 or 4;
a is-CH 2 CH 2 -、-CH＝CH-、-C≡C-、-CH 2 NH-or-NHCH 2 -；
R 3 Is hydrogen or C1-C4 alkyl;
or R is 3 And A together with the atoms to which they are attached form
R 5 Each independently is hydrogen, hydroxy, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, -O- (C3-C8 cycloalkyl), -O- (3-8 membered heterocycloalkyl), C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, or 5-10 membered heteroaryl;
R a 、R b 、R c and R is d Each independently hydrogen or C1-C4 alkyl;
or R is a And R is b Together with the carbon atom to which it is attached, form a C3-C8 cycloalkyl radicalA base;
or R is c And R is d Together with the carbon atom to which it is attached, form a C3-C8 cycloalkyl group;
p is 1, 2, 3 or 4;
q is 0, 1, 2, 3 or 4;
ring B is C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S, 6-10 membered aryl, or 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S; the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted with 1 or more substituents selected from halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or C1-C6 alkoxy;
X 1 is NR (NR) 6 Or O;
R 6 is hydrogen or C1-C4 alkyl;
R 4 is C1-C6 alkyl, - (CH) 2 ) r (OCH 2 CH 2 ) s O (C1-C6 alkyl), - (CH) 2 ) r (OCH 2 CH 2 ) s N (C1-C6 alkyl) 0-2 Or- (CH 2) r NH(CH 2 CH 2 O) s (C1-C6 alkyl), 3-8 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S; wherein r is 0, 1, 2, 3, 4, 5 or 6; s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; the alkyl or heterocycloalkyl is optionally substituted with 1 or more groups selected from hydroxy, oxo, C1-C6 alkyl, C1-C6 alkoxy, halogen, COOH, COO (C1-C4 alkyl), CONH 2 CON (C1-C4 alkyl) 1-2 Is substituted by a substituent of (a); provided that when R 4 When the heterocyclic alkyl is, piperazine is not included;
or R is 4 And R is 6 Together with the atoms to which they are attached form a 5-6 membered heterocycloalkyl; the heterocycloalkyl group being optionally substituted with 1 or more substituents selected from halogen, cyano, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or C1-C6 alkoxy;
d is-CONR g -、-NR g CO-, 6-10 membered aryl, or 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S; wherein Rg is hydrogen or C1-C4 alkyl; the aryl and heteroaryl are optionally substituted with 1 or more groups selected from halogen, hydroxy, oxo, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, - (CH 2) 0-4 COOH、-(CH2) 0-4 COO (C1-C4 alkyl), - (CH 2) 0-4 CONH 2 、-(CH2) 0-4 CON (C1-C4 alkyl) 1-2 、-(CH2) 0-4 S(O) 2 (C1-C4 alkyl), - (CH 2) 0-4 NH 2 、-(CH2) 0-4 N (C1-C4 alkyl) 1-2 、-(CH2) 0-4 S (C1-C4 alkyl) is substituted by a substituent;
Q 1 is C1-C6 alkyl, - (CH) 2 ) t (C3-C8 cycloalkyl), - (CH) 2 ) t (3-8 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S), - (CH) 2 ) t (6-10 membered aryl), - (CH) 2 ) t (5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S); wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl groups are each independently optionally substituted with R 7 Substitution; the R is 7 Selected from halogen, oxo, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, -COR e 、-COOR e 、-OR e 、-NHS(O) 2 R e 、NHS(O) 2 OR e 、NHS(O) 2 NHR e 、-NHS(O)OR e 、-NHS(O)R e 、-NHS(O)NHR e 、-NHC(O)R e 、-NHC(O)OR e 、-NHC(O)NHR e 、-NR e R f 、-CONHS(O) 2 R e or-CONHR e The method comprises the steps of carrying out a first treatment on the surface of the The R is e And R is f Each independently is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, 3-8 heterocycloalkyl containing 1 to 2 heteroatoms selected from N, O or S, 6-10 membered aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O or S; the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally selected from the group consisting of-OC (O) (C1-C4 alkyl), -COOH, -C (O) O (C1-C4 alkyl), -C (O) NH 2 -C (O) N (C1-C4 alkyl) 1-2 Amino, -C (O) (C1-C4 alkyl), -O (C1-C4 alkyl) substituents; and t is 0, 1, 2, 3 or 4.
In another preferred embodiment, R 1 And R is 2 Each independently is hydrogen, hydroxy, halogen, cyano, -OR e C1-C6 alkyl, C3-8 cycloalkyl, 3-8 heterocycloalkyl containing 1 to 2 heteroatoms selected from N, O or S, 6-10 aryl, 5-10 heteroaryl containing 1 to 4 heteroatoms selected from N, O or S, -NHS (O) 2 R e 、NHS(O) 2 OR e 、NHS(O) 2 NHR e 、-NHS(O)OR e 、-NHS(O)R e 、-NHS(O)NHR e 、-NHC(O)R e 、-NHC(O)OR e 、-NHC(O)NHR e 、-NR e R f 、-COR e 、-COOR e or-CONHR e The method comprises the steps of carrying out a first treatment on the surface of the Wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally substituted with one or more groups selected from halogen, cyano, C1-6 alkyl, halo C1-6 alkyl, -COOR e 、-OR e C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, -NHS (O) 2 R e 、NHS(O) 2 OR e 、NHS(O) 2 NHR e 、-NHS(O)OR e 、-NHS(O)R e 、-NHS(O)NHR e 、-NHC(O)R e 、-NHC(O)OR e 、-NHC(O)NHR e 、-NR e R f or-CONHR e Is substituted by a substituent of (a); the R is e And R is f Each independently is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S, 6-10 membered aryl, 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S;
n is 1, 2, 3 or 4;
a is-CH 2 CH 2 -、-CH＝CH-、-C≡C-、-CH 2 NH-or-NHCH 2 -；
R 3 Is hydrogen or C1-C4 alkyl;
or R is 3 And A together with the atoms to which they are attached form
R 5 Each independently is hydrogen, hydroxy, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, -O- (C3-C8 cycloalkyl), -O- (3-8 membered heterocycloalkyl), C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, or 5-10 membered heteroaryl;
R a 、R b 、R c And R is d Each independently hydrogen or C1-C4 alkyl;
or R is a And R is b Together with the carbon atom to which it is attached, form a C3-C8 cycloalkyl group;
or R is c And R is d Together with the carbon atom to which it is attached, form a C3-C8 cycloalkyl group;
p is 1, 2, 3 or 4;
q is 0, 1, 2, 3 or 4;
ring B is C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S, 6-10 membered aryl, or 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S; the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted with 1 or more substituents selected from halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or C1-C6 alkoxy;
X 1 is NR (NR) 6 Or O;
R 6 is hydrogen or C1-C4 alkyl;
R 4 is C1-C6 alkyl, - (CH) 2 ) r (OCH 2 CH 2 ) s O (C1-C6 alkyl), - (CH 2) r (OCH 2 CH 2 ) s N (C1-C6 alkyl) 0-2 Or- (CH 2) r NH(CH 2 CH 2 O) s (C1-C6 alkyl), 3-8 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S; wherein r is 0, 1, 2, 3, 4, 5 or 6; s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; the alkyl or heterocycloalkyl is optionally substituted with 1 or more groups selected from hydroxy, oxo, C1-C6 alkyl, C1-C6 alkoxy, halogen, COOH, COO (C1-C4 alkyl), CONH 2 CON (C1-C4 alkyl) 1-2 Is substituted by a substituent of (a); provided that when R 4 When the heterocyclic alkyl is, piperazine is not included;
or R is 4 And R is 6 Together with the atoms to which they are attached form a 5-6 membered heterocycloalkyl; the heterocycloalkyl group is optionally substituted with 1 or more substituents selected from halogen, cyano, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or C1-C6 alkoxy.
D is-CONR g -、-NR g CO-, 6-10 membered aryl, or 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S; wherein Rg is hydrogen or C1-C4 alkyl; the aryl and heteroaryl are optionally substituted with 1 or more groups selected from halogen, hydroxy, oxo, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, - (CH 2) 0-4 COOH、-(CH2) 0-4 COO (C1-C4 alkyl), - (CH 2) 0-4 CONH 2 、-(CH2) 0-4 CON (C1-C4 alkyl) 1-2 、-(CH2) 0-4 S(O) 2 (C1-C4 alkyl), - (CH 2) 0-4 NH 2 、-(CH2) 0-4 N (C1-C4 alkyl) 1-2 、-(CH2) 0-4 S (C1-C4 alkyl) is substituted by a substituent;
Q 1 is C1-C6 alkyl, - (CH) 2 ) t (C3-C8 cycloalkyl), - (CH) 2 ) t (3-8 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S), - (CH) 2 ) t (6-10 membered aryl), - (CH) 2 ) t (5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S); wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl groups are each independently optionally substituted with R 7 Substitution; the R is 7 Selected from halogen, oxo, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, -COR e 、-COOR e 、-OR e 、-NHS(O) 2 R e 、NHS(O) 2 OR e 、NHS(O) 2 NHR e 、-NHS(O)OR e 、-NHS(O)R e 、-NHS(O)NHR e 、-NHC(O)R e 、-NHC(O)OR e 、-NHC(O)NHR e 、-NR e R f 、-CONHS(O) 2 R e or-CONHR e The method comprises the steps of carrying out a first treatment on the surface of the The R is e And R is f Each independently is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, 3-8 heterocycloalkyl containing 1 to 2 heteroatoms selected from N, O or S, 6-10 membered aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O or S; the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally selected from the group consisting of-OC (O) (C1-C4 alkyl) -COOH, -C (O) O (C1-C4 alkyl), -C (O) NH 2 -C (O) N (C1-C4 alkyl) 1-2 Amino, -C (O) (C1-C4 alkyl), -O (C1-C4 alkyl) substituents; and t is 0, 1, 2, 3 or 4.
In a preferred embodiment of the compounds of formula i of the present invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, ra, rb, rc, rd are each independently hydrogen or methyl.
In a preferred embodiment of the compounds of formula i of the present invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, ra, rb, rc, rd are each independently hydrogen.
In a preferred embodiment of the compounds of formula i according to the invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs or pharmaceutically acceptable salts thereof, p is 1 and q is 0.
In a preferred embodiment of the compounds of formula I of the invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, X 1 Is NR (NR) 6 ；R 6 Is hydrogen or methyl.
In a preferred embodiment of the compounds of formula I of the invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, X 1 Is NR (NR) 6 ；R 6 Is hydrogen.
In a preferred embodiment of the compounds of formula I of the invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, R 4 Is C1-C6 alkyl; the alkyl group is optionally substituted with 1Or a plurality of halogen substitutions.
In another preferred embodiment, R 4 Is C1-C6 alkyl, the C1-C6 alkyl is perhalogenated C1-C6 alkyl, and all H of the C1-C6 alkyl is substituted by halogen.
In another preferred embodiment, R 4 Is an all F-substituted C1-C6 alkyl group including, but not limited to, the following: all-F C1 alkyl, all-F C2 alkyl, all-F C3 alkyl, all-F C4 alkyl, all-F C5 alkyl, and all-F C6 alkyl.
In another preferred embodiment, R 1 Is a 5-10 membered heteroaryl group containing 1-4 heteroatoms selected from N, O or S.
In another preferred embodiment, R 2 Selected from the group consisting of: F. cl, br, I.
In another preferred embodiment, n is 2.
In another preferred embodiment, a is-ch=ch-.
In another preferred embodiment, R 3 Is hydrogen.
In another preferred embodiment, D is-CONH-.
In another preferred embodiment, Q 1 Is phenyl substituted by carboxyl.
In another preferred embodiment, ring B is phenyl.
In another preferred embodiment, X 1 Is NH.
In a preferred embodiment of the compounds of formula I of the invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, R 4 Is C1-C6 alkyl; the alkyl is optionally substituted with 1 or more F.
In a preferred embodiment of the compounds of formula I of the invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, R 4 Is- (CH) 2 ) r O (C1-C6 alkyl) or- (CH) 2 ) r N (C1-C6 alkyl) 0-2 And r is 0, 1, 2, 3 or 4.
In a preferred embodiment of the compounds of formula I of the invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, R 4 is-O (C1-C6 alkyl).
In a preferred embodiment of the compounds of formula I of the invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, R 4 Is methoxy.
In a preferred embodiment of the compounds of formula I of the invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, R 4 is-N (CH) 3 ) 2 Or- (CH) 2 ) 2 N(CH 3 ) 2 。
In a preferred embodiment of the compounds of formula I of the invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, R 4 Is morpholinyl.
In a preferred embodiment of the compounds of formula I of the invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, R 4 Is a 3-8 membered heterocycloalkyl containing 1N heteroatom; the heterocycloalkyl group is optionally substituted with a substituent selected from hydroxy, oxo, halogen, C1-C6 alkyl or C1-C6 alkoxy.
In a preferred embodiment of the compounds of formula I of the invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, R 4 Is optionally hydroxyPyrrolidinyl substituted with a group or oxo group;
in a preferred embodiment of the compounds of formula I of the invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, R 4 Is- (CH) 2 ) r (OCH 2 CH 2 ) s O (C1-C6 alkyl), - (CH 2) r (OCH 2 CH 2 ) s N (C1-C6 alkyl) 0-2 Or- (CH) 2 ) r NH(CH 2 CH 2 O) s (C1-C6 alkyl), said r being 0 or 1; and s is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
In a preferred embodiment of the compounds of formula I of the invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, R 4 Is- (OCH) 2 CH 2 ) s O (C1-C6 alkyl), - (OCH) 2 CH 2 ) s N (C1-C6 alkyl) 0-2 or-NH (CH) 2 CH 2 O) s (C1-C6 alkyl); and s is 1, 2, 3, 4, 5, 6, 7, 8 or 9.
In a preferred embodiment of the compounds of formula I of the invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, R 4 Is- (OCH) 2 CH 2 ) s O (C1-C6 alkyl), - (OCH) 2 CH 2 ) s N (C1-C6 alkyl) 0-2 or-NH (CH) 2 CH 2 O) s (C1-C6 alkyl); and s is 3, 4, 5, 6 or 7.
The compounds of the invention of formula I, or stereoisomers, enantiomers, diastereomers, deuterides,In a preferred embodiment of the hydrate, solvate, metabolite, prodrug, or pharmaceutically acceptable salt thereof, R 4 is-CH 2 (OCH 2 CH 2 ) s O (C1-C6 alkyl), -CH 2 (OCH 2 CH 2 ) s N (C1-C6 alkyl) 0-2 or-CH 2 NH(CH 2 CH 2 O) s (C1-C6 alkyl) and s is 1, 2, 3, 4, 5, 6, 7, 8 or 9.
In a preferred embodiment of the compounds of formula I of the invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, R 4 is-CH 2 (OCH 2 CH 2 ) s O (C1-C6 alkyl), -CH2 (OCH) 2 CH 2 ) s N (C1-C6 alkyl) 0-2 or-CH 2 NH(CH 2 CH 2 O) s (C1-C6 alkyl) and s is 3, 4, 5, 6 or 7..
In a preferred embodiment of the compounds of formula I of the invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, R 4 Is- (OCH) 2 CH 2 ) 5 OCH 3 、-OCH 2 CH 2 OCH 3 、-(OCH 2 CH 2 ) 7 OCH 3 、-NHCH 2 CH 2 OCH 3 、-NH(CH 2 CH 2 O) 5 CH 3 、-NH(CH 2 CH 2 O) 7 CH 3 、-CH 2 OCH 2 CH 2 OCH 3 、-N(CH3) 2 Methyl, methoxy, trifluoromethyl, perfluoropropyl, perfluorobutyl,-OCH 2 CH 2 N(CH3) 2 、-(OCH 2 CH 2 ) 3 OCH 3 、-(OCH 2 CH 2 ) 2 OCH 3 、-CH 2 CH 2 N(CH3) 2 or-CH 2 (OCH 2 CH 2 ) 2 OCH 3 。
In a preferred embodiment of the compounds of formula I of the invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, R 4 And R is 6 Together with the atoms to which they are attached form
In a preferred embodiment of the compounds of formula I of the present invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, the compounds of formula I are compounds of formula IA,
wherein said R is 1 、R 2 、R 3 、R 4 Ra, rb, rc, rd, ring B, D, X 1 P, Q, n and Q 1 As defined above.
In a preferred embodiment of the compounds of formula i of the invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, D is a 5-6 membered heteroaryl group containing 1 or 2N heteroatoms; the heteroaryl groups are optionally substituted with 1 or more groups selected from halogen Hydroxy, oxo, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C2-C4 alkenyl, - (CH) 2 ) 0-4 COOH、-(CH 2 ) 0-4 COO (C1-C4 alkyl), - (CH) 2 ) 0-4 CONH 2 、-(CH 2 ) 0-4 CON (C1-C4 alkyl) 1-2 、-(CH 2 ) 0-4 S(O) 2 (C1-C4 alkyl), - (CH) 2 ) 0-4 NH 2 、-(CH 2 ) 0-4 N (C1-C4 alkyl) 1-2 、-(CH 2 ) 0-4 S (C1-C4 alkyl) is substituted by a substituent.
In a preferred embodiment of the compounds of formula i of the invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, D is imidazolyl, pyridinyl, pyridazinyl or pyrimidinyl; the imidazolyl, pyridyl, pyridazinyl or pyrimidinyl is optionally substituted with 1 or more substituents selected from oxo, cl, methyl, methoxy, ethoxy, -COOH, -CONH 2 、-CONCH 3 、-COOCH 3 Vinyl, cyano, SO 2 CH 3 、-CH 2 OH、-CH 2 CH 2 OH、-CH 2 COOH、-CH 2 COOCH 3 、-CH 2 SO 2 CH 3 Amino, -CH 2 NH 2 、-CH 2 N(CH 3 ) 1-2 Is substituted by a substituent of (a).
In a preferred embodiment of the compounds of formula I of the present invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, D is-CONR g -; wherein Rg is hydrogen or methyl.
The compounds of the invention of formula I, or stereoisomers, enantiomers, stereoisomers thereof, In a preferred embodiment of a diastereomer, deuteride, hydrate, solvate, metabolite, prodrug, or pharmaceutically acceptable salt thereof, D is-CONR g -; wherein Rg is hydrogen.
In a preferred embodiment of the compounds of formula I of the present invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, the compounds of formula I are compounds of formula IB,
wherein said R is 1 、R 2 、R 3 、R 4 Ra, rb, rc, rd, ring B, X 1 P, Q, n and Q 1 As defined above.
In a preferred embodiment of the compounds of formula I according to the invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, ring B is C3-C6 cycloalkyl, 3-6 heterocycloalkyl containing 1 or 2N heteroatoms, 5-6 heteroaryl containing 1 to 3N heteroatoms or phenyl; the cycloalkyl, heterocycloalkyl, phenyl, heteroaryl are optionally substituted with 1 or more substituents selected from halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy.
In a preferred embodiment of the compounds of formula I of the invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, ring B is a 5-6 membered heteroaryl group containing 1-3N heteroatoms; the heteroaryl is optionally substituted with 1 or more substituents selected from halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy.
In a preferred embodiment of the compounds of formula i of the invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, ring B is pyridine, pyrazole or imidazole; the pyridine, pyrazole or imidazole is optionally substituted with 1 or more substituents selected from halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy.
In a preferred embodiment of the compounds of formula i of the invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, ring B is phenyl; the benzene is optionally substituted with 1 or more substituents selected from halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy.
In a more preferred embodiment of the compounds of formula I of the present invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, said compounds of formula I are compounds of formula IC,
wherein said R is 1 、R 2 、R 3 、R 4 、Ra、Rb、Rc、Rd、X 1 P, Q, n and Q 1 As defined above.
In a preferred embodiment of the compounds of formula I of the invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, R 1 Is hydrogen, cyano, halogen, C1-C6 alkyl optionally substituted by halogen or hydroxy, C3-C6 cycloalkyl or-C (O) Re; re is C1-C6 alkyl, C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl containing 1-2 heteroatoms selected from N or O;the alkyl, cycloalkyl, heterocycloalkyl being optionally substituted with one or more groups selected from halogen, hydroxy or amino; or R is 1 is-OR; re is C1-C6 alkyl; the alkyl group is optionally substituted with halogen.
In a preferred embodiment of the compounds of formula I of the invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, R 1 Is hydrogen, cyano, F, cl, br, trifluoromethyl, difluoromethyl, cyclopropyl, formyl, acetyl, cyclopropylacyl, difluoromethoxy or trifluoromethoxy.
In a preferred embodiment of the compounds of formula I of the invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, R 1 Is a 5-6 heteroaryl group containing 1-4 heteroatoms selected from N or O; the heteroaryl is optionally substituted with one or more substituents selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy or C1-C4 hydroxyalkyl.
In a preferred embodiment of the compounds of formula I of the invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, R 1 Is a 5-6 heteroaryl group containing 1-4N heteroatoms, said heteroaryl group optionally being substituted with one or more substituents selected from F, cl, methyl, trifluoromethyl, trifluoroethyl or methoxy.
In a preferred embodiment of the compounds of formula I of the invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, R 1 Is pyrazolyl, imidazolyl, triazole or tetrazole.
The compounds of the invention of formula I, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates and generations thereofIn a preferred embodiment of the metabolite, prodrug, or pharmaceutically acceptable salt thereof, R 1 Is tetrazole.
In a preferred embodiment of the compounds of formula I of the present invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, the compounds of formula I are compounds of formula ID,
wherein said R is 2 、R 3 、R 4 、Ra、Rb、Rc、Rd、X 1 P, Q, n and Q 1 As defined above.
In a preferred embodiment of the compounds of formula I of the invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, R 2 Is hydrogen, halogen, C1-C6 alkyl optionally substituted by halogen or hydroxy, or-ORe; the Re is C1-C6 alkyl optionally substituted with one or more halogens or hydroxy.
In a preferred embodiment of the compounds of formula I of the invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, R 2 Is hydrogen, trifluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy, F or Cl.
In a preferred embodiment of the compounds of formula i according to the invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, n is 2.
In a preferred embodiment of the compounds of formula I of the present invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, the compounds of formula I are compounds of formula IE,
wherein said R is 3 、R 4 、Ra、Rb、Rc、Rd、X 1 P, Q and Q 1 As defined above.
In a preferred embodiment of the compounds of formula I of the invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, Q 1 Is a 5-6 membered heteroaryl group containing 1 or 2 heteroatoms selected from N, O or S, or Q 1 Is a 6-10 membered aryl group; the aryl and heteroaryl groups are optionally substituted with one or more R 7 And (3) substitution.
In a preferred embodiment of the compounds of formula I of the invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, Q 1 Is pyridine, indolyl, benzofuranyl, benzimidazolyl, quinoline or phenyl; the pyridyl, indolyl, benzofuranyl, benzimidazolyl, quinoline or phenyl group being optionally substituted with one or more R 7 And (3) substitution.
In a preferred embodiment of the compounds of formula I of the present invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, the compounds of formula I are compounds of formula IF,
wherein said R is 3 、R 4 、Ra、Rb、Rc、Rd、X 1 P, q and R 7 As defined above; the u is 1, 2 or 3;
in a preferred embodiment of the compounds of formula I of the invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, R 7 F, cl, oxo, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, 5-6 membered heteroaryl containing 1-4N heteroatoms, -COR e 、-COOR e 、-OR e 、-NHS(O) 2 R e 、NHS(O) 2 OR e 、NHS(O) 2 NHR e 、-NHS(O)OR e 、-NHS(O)R e 、-NHS(O)NHR e 、-NHC(O)R e 、-NHC(O)OR e 、-NHC(O)NHR e 、-NR e R f 、-CONHS(O) 2 R e or-CONHR e The method comprises the steps of carrying out a first treatment on the surface of the The R is e Each independently is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl containing 1-2 heteroatoms selected from N or O, 6-10 membered aryl, 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S; the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted with one or more groups selected from the group consisting of-OC (O) (C1-C4 alkyl), -COOH, -C (O) O (C1-C4 alkyl), -C (O) NH 2 -C (O) N (C1-C4 alkyl) 1-2 Amino, -C (O) (C1-C4 alkyl), -O (C1-C4 alkyl) substituents; the R is f Is hydrogen or C1-C6 alkyl.
In a preferred embodiment of the compounds of formula I of the invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, R 7 Is F, cl, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, 5-6 membered heteroaryl containing 1-4N heteroatoms、-COR e 、-COOR e 、-OR e 、-NHC(O)R e 、-NHC(O)OR e 、-NR e R f 、-CONHR e The method comprises the steps of carrying out a first treatment on the surface of the The R is e Each independently is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl containing 1-2 heteroatoms selected from N or O; the alkyl, cycloalkyl and heterocycloalkyl groups are optionally substituted with one or more groups selected from the group consisting of-OC (O) (C1-C4 alkyl), -COOH, -C (O) O (C1-C4 alkyl), -C (O) NH 2 -C (O) N (C1-C4 alkyl) 1-2 Amino, -C (O) (C1-C4 alkyl), -O (C1-C4 alkyl) substituents; the R is f Is hydrogen or C1-C6 alkyl.
In a preferred embodiment of the compounds of formula I of the invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, R 7 F, cl, tetrazole, -COOH, -COOC (CH) 3 ) 3 、-NHC(O)OCH 3 、-CONH 2、 -CONHCH 3 、-CON(CH 3 ) 2 or-NH 2。
In a preferred embodiment of the compounds of formula I of the invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, R 7 is-COOH.
In a preferred embodiment of the compounds of formula i according to the invention, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs or pharmaceutically acceptable salts thereof, u is 1.
The compound of the invention of the formula I, or stereoisomers, enantiomers, diastereoisomers, deuterides, hydrates, solvates, metabolites, prodrugs or pharmaceutically acceptable salts thereof, is a specific compound
The present invention provides a process for the preparation of a compound of formula I, formula IA, formula IB, formula IC, formula ID, formula IE or formula IF, and/or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable salts thereof,
when a is-ch=ch-, and Q1 is substituted with a carboxylic acid;
The method comprises the following steps:
wherein said R is 1 、R 2 、R 3 、R 4 、Ra、Rb、Rc、Rd、X 1 P, Q, n and Q 1 As defined above.
Comprises the following steps: carrying out condensation reaction on SM-1 and SM-2 under alkaline conditions to obtain SM-3; wherein the base is an organic base or an inorganic base including, but not limited to, triethylamine, N-diisopropylethylamine, potassium carbonate, sodium bicarbonate; such condensing agents include, but are not limited to DCC, DIC, EDC, HATU, HBTU, TBTU;
step 2: carrying out hydrolysis reaction on SM-3 under an acidic condition to obtain a target product; the acid is an organic acid or an inorganic acid including, but not limited to, hydrochloric acid, trifluoroacetic acid.
The second method is as follows:
wherein said R is 1 、R 2 、R 3 、R 4 、Ra、Rb、Rc、Rd、X 1 P, Q, n and Q 1 As defined above.
Step 1: carrying out hydrolysis reaction on SM-4 under an acidic condition to obtain SM-5; the acid is an organic acid or an inorganic acid, including but not limited to trifluoroacetic acid;
step 2: carrying out substitution reaction on SM-5 and SM-6 under alkaline conditions to obtain a target compound; the base is an organic base or an inorganic base including, but not limited to, triethylamine, N-diisopropylethylamine, potassium carbonate, sodium bicarbonate.
The present invention provides compounds of formula II, or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts thereof,
Wherein R is 9 Is hydrogen or an amino protecting group, preferably hydrogen or BOC; r is R 10 Is hydrogen or C1-C4 alkyl, preferably tert-butyl; r8 is halogen or-NR 6 (CR c R d ) q C(O)R 4 The method comprises the steps of carrying out a first treatment on the surface of the The R is 6 、R c 、R d 、q、R 4 As defined above.
The present invention provides a compound of formula II, or a stereoisomer, enantiomer, diastereomer, deuteride, hydrate, solvate, metabolite, prodrug, or pharmaceutically acceptable salt thereof, in a preferred embodiment selected from
The present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula i, formula ia, formula ib, formula ic, formula id, formula ie or formula if, and/or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable salts thereof, in combination with a pharmaceutically acceptable carrier, diluent or excipient.
The present invention provides the use of a compound of formula i, formula ia, formula ib, formula ic, formula id, formula ie or formula if, and/or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment or prophylaxis of a disease or condition associated with FXIa activity.
The present invention provides the use of a compound of formula I, formula IA, formula IB, formula IC, formula ID, formula IE or formula IF, and/or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment or prophylaxis of thromboembolic disorders.
The present invention provides methods of inhibiting FXIa activity comprising effectively contacting a compound of formula I, formula IA, formula IB, formula IC, formula ID, formula IE or formula IF, and/or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, with FXIa protein.
The present invention provides methods for treating or preventing diseases or conditions associated with FXIa activity comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula i, formula ia, formula ib, formula ic, formula id, formula ie or formula if, and/or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.
The present invention provides methods for treating or preventing thromboembolic disorders comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula i, formula ia, formula ib, formula ic, formula id, formula ie or formula if, and/or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.
The compounds of formula I, formula IA, formula IB, formula IC, formula ID, formula IE or formula IF, and/or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, of the invention may be used as medicaments for inhibiting FXIa activity.
The compounds of formula I, formula IA, formula IB, formula IC, formula ID, formula IE or formula IF, and/or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, of the invention are useful as medicaments for the treatment or prophylaxis of diseases or conditions associated with FXIa activity.
The compounds of formula I, formula IA, formula IB, formula IC, formula ID, formula IE or formula IF, and/or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, of the invention are useful as medicaments for the treatment or prophylaxis of thromboembolic disorders.
The thromboembolic diseases of the present invention include arterial cardiovascular and cerebrovascular thromboembolic diseases and venous cardiovascular and cerebrovascular thromboembolic diseases.
Thromboembolic disorders according to the present invention include, but are not limited to, unstable angina, acute coronary syndrome, atrial fibrillation, primary myocardial infarction, recurrent myocardial infarction, sudden ischemic death, transient ischemic attacks, joint replacement surgery thrombosis, hemodialysis thrombosis, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep venous thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism.
The compounds of formula i, formula ia, formula ib, formula ic, formula id, formula ie or formula if, and/or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, of the invention may be administered alone or, if desired, in combination with other pharmaceutically acceptable therapeutic agents, such as in combination with other therapeutic agents for the treatment or prevention of thromboembolic disorders. The individual components to be combined may be administered simultaneously or sequentially, in a single formulation or in different formulations. The combination may include not only a combination of a compound of the invention and one other active agent, but also a combination of a compound of the invention and two or more other active agents.
Other therapeutic agents useful in the treatment or prevention of thromboembolic disorders described herein are anticoagulants, antiplatelet agents, thrombin inhibitors, thrombolytic agents or fibrinolytic agents. Preferably, the other therapeutic agent for treating or preventing thromboembolic diseases according to the present invention is at least one drug selected from the group consisting of: warfarin, unfractionated heparin, low molecular weight heparin, synthetic pentasaccharide, hirudin, argatroban (argatroban), aspirin, ibuprofen (ibuprofen), naproxen (naproxen), sulindac (sulindac), indomethacin (indomethacin), mefenamate (mefenamate), drooxicam (droxicam), diclofenac (dichrofenac), sulfopirone (sulfopyrizone), piroxicam (piroxicam), ticlopidine (ticlopidine), clopidogrel, tirofiban (tirofiban), eptifibatide (epotide), abcixab (abciximab), melagatran), deglutaman (desthiobdellovine), tissue plasminogen activator, modified tissue plasminogen activator, amylase, epothilase (epothilone), or streptokinase (streptokinase).
Detailed description: unless stated to the contrary, the following terms used in the specification and claims have the following meanings.
"alkyl" refers to a saturated aliphatic hydrocarbon group, including straight or branched chain alkyl groups; C1-C8 means an alkyl group having 1 to 8 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, or various branched isomers thereof; preferably C1-C6 alkyl; more preferably C1-C4 alkyl. The alkyl group may be substituted or unsubstituted.
"cycloalkyl" refers to a saturated or partially unsaturated, monocyclic or polycyclic, cyclic hydrocarbon substituent; "C3-12 cycloalkyl" refers to cycloalkyl groups comprising 3 to 12 carbon atoms; "C3-C8 cycloalkyl" refers to cycloalkyl groups comprising 3 to 8 carbon atoms; "C5-C10 cycloalkyl" refers to cycloalkyl groups comprising 5 to 10 carbon atoms;
non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, with cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl being preferred; preferably C3-C8 cycloalkyl; more preferably C3-C6 cycloalkyl.
Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. "spirocycloalkyl" refers to a polycyclic group having one carbon atom (referred to as the spiro atom) shared between the monocyclic rings, which may contain one or more double bonds, but no one ring has a fully conjugated pi-electron system. Spirocycloalkyl groups are classified as mono-, di-or multicycloalkyl groups according to the number of common spiro atoms between rings. Non-limiting examples of spirocycloalkyl groups include:
"fused ring alkyl" refers to an all-carbon polycyclic group wherein each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group. Non-limiting examples of fused ring alkyl groups include:
"bridged cycloalkyl" refers to an all-carbon polycyclic group wherein any two rings share two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system, which may be classified as bicyclic, tricyclic, tetracyclic, or multicyclic bridged cycloalkyl, depending on the number of constituent rings. Non-limiting examples of bridged cycloalkyl groups include:
the cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring attached to the parent structure is cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like. The cycloalkyl group may be optionally substituted or unsubstituted.
"heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent in which one or more ring atoms are selected from nitrogen, oxygen, or S (O) r (where r is an integer 0, 1, or 2), but does not contain-O-; a ring moiety of O-S-or-S-S-, the remaining ring atoms are carbon. "3-12 membered heterocycloalkyl" means a cyclic group containing 3 to 12 ring atoms, "5-10 membered heterocycloalkyl" means a cyclic group containing 5 to 10 ring atoms, "3-8 membered heterocycloalkyl" means a cyclic group containing 3 to 8 ring atoms, preferably a "3-8 membered heterocycloalkyl" containing 1 to 3 heteroatoms selected from N, O or S, more preferably a 3-6 membered heterocycloalkyl containing 1 or 2N atoms.
Non-limiting examples of monocyclic heterocycloalkyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and the like.
Polycyclic heterocycloalkyl groups include spiro, fused and bridged heterocycloalkyl groups. "spiroheterocycloalkyl" refers to a polycyclic heterocycloalkyl group having one atom in common between the monocyclic rings (referred to as the spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen, or S (O) r (where r is an integer of 0, 1, 2) and the remaining ring atoms are carbon. They may contain one or more double bonds, but none of the rings has a fully conjugated pi electron system. The spirocycloalkyl groups are classified as mono-, di-or poly-spiroheterocycloalkyl groups according to the number of common spiro atoms between rings, preferably containing 1 to 3 saturated "3-to 12-membered bis-spiroheterocycloalkyl groups" selected from N, O or S heteroatoms; more preferred are saturated "3-12 membered bisspiroheterocycloalkyl groups" containing 1 or 2N atoms. Non-limiting examples of spiroheterocycloalkyl groups include:
"fused heterocycloalkyl" means that each ring in the system shares an adjacent pair of atoms of the polycyclic heterocycloalkyl group with the other rings in the system, one or more of which may contain one or more double bonds, but none of which has a fully conjugated pi electron system, wherein one or more ring atoms are selected from nitrogen, oxygen, or S (O) r (where r is an integer of 0, 1, 2) and the remaining ring atoms are carbon. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl group, preferably a "3-12 membered bicyclic fused heterocycloalkyl group" containing 1 to 3 hetero atoms selected from N, O or S; more preferred are saturated "3-12 membered bicyclic fused heterocycloalkyl" containing 1 or 2N atoms. Non-limiting examples of fused heterocycloalkyl groups include:
"bridged heterocycloalkyl" refers to a polycyclic heterocycloalkyl group wherein any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings has a fully conjugated pi electron system, wherein one or more of the ring atoms are selected from nitrogen, oxygen, or S (O) r (where r is an integer of 0, 1, 2) and the remaining ring atoms are carbon. Non-limiting examples of bridged heterocycloalkyl groups can be categorized as bicyclic, tricyclic, tetracyclic, or multicyclic bridged cycloalkyl groups, depending on the number of constituent rings, including:
the heterocycloalkyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocycloalkyl, non-limiting examples include:
the heterocycloalkyl group may be optionally substituted or unsubstituted.
"aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) polycyclic groups having a conjugated pi-electron system, and "6-10 membered aryl" refers to an all-carbon aryl group containing 6-10 carbons, such as phenyl and naphthyl; phenyl is preferred. The aryl ring may be fused to a heteroaryl, heterocycloalkyl, or cycloalkyl ring, where the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
The aryl group may be optionally substituted or unsubstituted.
"heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms including nitrogen, oxygen or S (O) r (where r is an integer of 0, 1, 2), 5-6 membered heteroaryl refers to a heteroaromatic system containing 5-6 ring atoms, 5-10 membered heteroaryl refers to a heteroaromatic system containing 5-10 ring atoms, preferably containing 1-4 5-6 membered heteroaryl groups selected from N, O or S heteroatoms; more preferably a 5-6 membered heteroaryl group containing 1-4N atoms; non-limiting examples include furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazole, imidazolyl, triazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocycloalkyl, or cycloalkyl ring, where the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:
the heteroaryl group may be optionally substituted or unsubstituted.
"alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, "C2-8 alkenyl" refers to a straight or branched alkenyl group containing 2 to 8 carbons, including but not limited to vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like, preferably "C2-6 alkenyl", more preferably "C2-4 alkenyl". The alkenyl group may be substituted or unsubstituted.
"alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, "C2-8 alkynyl" refers to a straight or branched chain alkynyl group containing 2 to 8 carbons, including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, preferably "C2-6 alkynyl", more preferably "C2-4 alkynyl". The alkynyl group may be substituted or unsubstituted.
"alkoxy" refers to-O- (alkyl) wherein the alkyl is as defined above. "C1-C8 alkoxy" refers to an alkyl oxy group containing 1 to 8 carbons, non-limiting examples include methoxy, ethoxy, propoxy, butoxy, and the like. The alkoxy groups may be optionally substituted or unsubstituted.
"haloalkyl" refers to an alkyl group optionally substituted with one or more fluorine, chlorine, bromine or iodine atoms, wherein the alkyl group is as defined above, non-limiting examples include difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, and the like.
"hydroxyalkyl" refers to an alkyl group optionally substituted with one or more —oh groups, wherein the alkyl group is as defined above, non-limiting examples include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl.
"haloalkoxy" refers to a group in which the hydrogen on the alkyl group is optionally substituted with one or more fluorine, chlorine, bromine or iodine atoms, wherein the alkoxy group is as defined above. Such as difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy and the like.
"aminoalkyl" means an amino group optionally substituted with one or more-NH groups 2 Substituted alkyl groups, wherein the alkyl groups are as defined above, non-limiting examples include aminomethyl, aminoethyl, aminopropyl, aminoisopropyl.
"amine" is art-recognized and refers to substituted ammonia.
"amino" means-NH 2 。
"cyano" refers to-CN.
"oxo" refers to an =o group.
"halogen" means F, cl, br or I, preferably F, cl.
"HATU" refers to 2- (7-azabenzotriazol) -N, N' -tetramethyluronium hexafluorophosphate.
"DPPA" refers to diphenyl azide phosphate.
"DIAD" refers to diisopropyl azodicarboxylate.
“PPh 3 "means triphenylphosphine.
"DMEDA" means N, N' -dimethylethylenediamine.
"DMF" refers to N, N' -dimethylformamide.
"DIEA" refers to N, N-diisopropylethylamine.
"DCC" refers to dicyclohexylcarbodiimide.
"EDC" refers to 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide.
"DIC" refers to N, N-diisopropylcarbodiimide.
"HBTU" refers to O-benzotriazol-tetramethyluronium hexafluorophosphate.
"TBTU" means O- (IH-benzotriazol-1-yl) -N, N, N ', N' -tetramethylisourea boron tetrafluoride.
"optional" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "heterocycloalkyl group optionally substituted with an alkyl group" means that an alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocycloalkyl group is substituted with an alkyl group and cases where the heterocycloalkyl group is not substituted with an alkyl group.
"substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.
"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.
The invention also provides pharmaceutically acceptable salts of the compounds of formula (I). The term "pharmaceutically acceptable salt" refers to the acid or base addition salts of the compounds of the invention which are relatively non-toxic. The acid addition salts are salts of the compounds of formula (I) according to the invention with suitable inorganic or organic acids, which salts can be prepared in the final isolation and purification of the compounds or can be prepared by reacting the purified compounds of formula (I) in their free base form with suitable organic or inorganic acids.
The compounds of the present invention or pharmaceutically acceptable salts thereof may be administered to mammals, including humans, orally, rectally, parenterally (intravenous, intramuscular or subcutaneous), topically (powders, ointments or drops), or intratumorally.
The compounds of the present invention may be administered in a dose of about 0.05 to 300mg/kg body weight/day, preferably 1 to 300mg/kg body weight/day, more preferably 1 to 150mg/kg body weight/day.
The compounds of the present invention or pharmaceutically acceptable salts thereof may be formulated into solid dosage forms for oral administration, including, but not limited to, capsules, tablets, pills, powders, granules and the like. In these solid dosage forms, the compounds of formula (I) according to the invention are mixed as active ingredient with at least one conventional inert excipient (or carrier), for example with sodium citrate or dicalcium phosphate, or with the following ingredients: (1) Fillers or compatibilizers such as starch, lactose, sucrose, glucose, mannitol, silicic acid, and the like; (2) Binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, acacia, and the like; (3) humectants, such as glycerin, etc.; (4) Disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, sodium carbonate, and the like; (5) a slow solvent such as paraffin wax or the like; (6) absorption accelerators such as quaternary ammonium compounds and the like; (7) wetting agents such as cetyl alcohol and glycerol monostearate, etc.; (8) adsorbents such as kaolin and the like; and (9) a lubricant such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and the like, or mixtures thereof. Buffering agents may also be included in capsules, tablets and pills.
The solid dosage forms such as tablets, dragees, capsules, pills and granules may be coated or microencapsulated with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active ingredient in such a composition may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active ingredient may also be in the form of microcapsules with one or more of the above excipients, if desired.
The compounds of the present invention or pharmaceutically acceptable salts thereof may be formulated into liquid dosage forms for oral administration, including, but not limited to, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, tinctures, and the like. In addition to the compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, the liquid dosage form may contain inert diluents commonly used in the art such as water and other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular cottonseed, groundnut, corn germ, olive, castor and sesame oils and the like or mixtures of these substances and the like. In addition to these inert diluents, the liquid dosage forms of the present invention can also include conventional adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents and the like.
The suspending agent includes, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan alone, microcrystalline cellulose, aluminum methoxide, agar, and the like, or a mixture of these substances.
The compounds of the present invention or pharmaceutically acceptable salts thereof may be formulated in dosage forms for parenteral injection including, but not limited to, physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
The compounds of the present invention or pharmaceutically acceptable salts thereof may also be formulated into dosage forms for topical administration including, for example, ointments, powders, suppositories, drops, sprays, inhalants and the like. The compounds of the formula (I) according to the invention or their pharmaceutically acceptable salts as active ingredients are admixed under sterile conditions with physiologically acceptable carriers and optionally with preservatives, buffers or, if appropriate, propellants which may be required.
The present invention also provides a pharmaceutical composition comprising a compound of formula (I) according to the present invention or a pharmaceutically acceptable salt thereof as an active ingredient, together with a pharmaceutically acceptable carrier, excipient or diluent. In preparing pharmaceutical compositions, a compound of formula (I) or a pharmaceutically acceptable salt thereof of the present invention is typically admixed with a pharmaceutically acceptable carrier, excipient or diluent.
The compositions of the present invention may be formulated as conventional pharmaceutical formulations according to conventional methods of preparation. Such as tablets, pills, capsules, powders, granules, emulsions, suspensions, dispersions, solutions, syrups, elixirs, ointments, drops, suppositories, inhalants, sprays and the like.
The inhibition test of the activity of factor XIa proves that the compound can effectively and obviously reduce the activity of FXIa. For antithrombotic drugs, it is important to reduce the risk of exogenous bleeding and to increase the width of the safety treatment window, the dose range between the effective dose for inhibiting coagulation and the dose at which bleeding is likely to occur should be as large as possible to achieve the maximum therapeutic effect under the minimum risk condition, while the invention proves that the compound has a very wide safety treatment window by means of an Activated Partial Thromboplastin Time (APTT) assay experiment, and can not only effectively inhibit thrombosis, but also reduce bleeding risk within the safe and effective dose range.
Drawings
FIG. 1 is a graph showing the content of a compound detected by LC-MS after the compound of example 9 is dissolved in a dimethylsulfoxide solution
FIG. 2 is a graph showing the content of a compound detected by LC-MS after 5 minutes of sonication of the compound of example 9 in a buffer solution having a pH of 7.4
FIG. 3 is a graph showing the content of a compound detected by LC-MS after 5 minutes of sonication of the compound of example 9 in a buffer solution having a pH of 8.0
FIG. 4 is a graph showing the content of a compound detected by LC-MS after the compound of control group 1 is dissolved in a dimethylsulfoxide solution
FIG. 5 is a graph showing the content of a compound detected by LC-MS after sonicating a compound of control group 1 in a buffer solution having a pH of 7.4 for 30 seconds
FIG. 6 is a graph showing the content of a compound detected by LC-MS after 30 seconds of ultrasound in a buffer solution at pH 8.0 for the compound of control group 1
FIG. 7 is a graph showing the content of a compound detected by LC-MS after 5 minutes of ultrasound in a buffer solution at pH 7.4 of the compound of control group 1
FIG. 8 is a graph showing the content of a compound detected by LC-MS after 5 minutes of ultrasound in a buffer solution at pH 8.0 for the compound of control group 1
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The present invention will be described in more detail and fully hereinafter with reference to the accompanying examples, in which the invention is not limited, but is not limited to the examples. The starting materials in the examples of the present invention are known and are commercially available or may be synthesized using or according to methods known in the art. Unless otherwise specified, experimental methods without specifying specific conditions in the examples of the present invention are generally conducted under conventional conditions or under conditions recommended by the manufacturer of the raw materials or goods.
Preparation examples of compounds I
Intermediate 1: (S) -4- (3- (4-aminophenyl) -2- ((tert-Butoxycarbonyl) amino) propanamido) benzoic acid tert-butyl ester
Step 1: preparation of tert-butyl (S) -4- (2- ((tert-butoxycarbonyl) amino) -3- (4-nitrophenyl) propanamido) benzoate
To a solution of (S) -2- ((tert-butoxycarbonyl) amino) -3- (4-nitrophenyl) propionic acid (9.3 g,30 mmol) in pyridine (1000 mL) was added tert-butyl 4-aminobenzoate (5.8 g,30 mmol) and phosphorus oxychloride (3.4 mL) at 0deg.C. The resulting solution was stirred at 0 ℃ for 2 hours. Water (300 mL) was added. The aqueous layer was separated and extracted with ethyl acetate (300 mL. Times.3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column to give 8.0g of the objective compound.
LC-MS:(ES,m/z):[M+H] + ＝486.0
Step 2: preparation of (S) -4- (3- (4-aminophenyl) -2- ((tert-butoxycarbonyl) amino) propanamido) benzoic acid tert-butyl ester
To a solution of tert-butyl (S) -4- (2- ((tert-butoxycarbonyl) amino) -3- (4-nitrophenyl) propanamido) benzoate (8.0 g,16.5 mmol) in methanol (1000 mL) was added palladium on carbon (800 mg) at 0deg.C. The resulting solution was stirred at room temperature for 16 hours under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated to obtain 7.4g of a desired crude product. The crude product was used directly in the next step.
LC-MS:(ES,m/z):[M+H] + ＝456.0
Intermediate 2: (S) -4- (3- (4-bromophenyl) -2- ((tert-Butoxycarbonyl) amino) propanamido) benzoic acid tert-butyl ester
To a solution of (S) -3- (4-bromophenyl) -2- ((tert-butoxycarbonyl) amino) propionic acid (6.8 g,20 mmol) in pyridine (300 mL) at 0deg.C was added tert-butyl 4-aminobenzoate (3.8 g,20 mmol) and phosphorus oxychloride (2.3 mL). The resulting solution was reacted at 0℃with stirring for 4 hours. Water (300 mL) was added. The aqueous layer was separated and extracted with ethyl acetate (300 mL. Times.3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column to give 8.7g of the objective compound.
LC-MS:(ES,m/z):[M+H] + ＝519.1
Intermediate 3: (S) -4- (3- (3-bromophenyl) -2- ((tert-Butoxycarbonyl) amino) propanamido) benzoic acid tert-butyl ester
To a solution of (S) -3- (3-bromophenyl) -2- ((tert-butoxycarbonyl) amino) propionic acid (6.8 g,20 mmol) in pyridine (300 mL) at 0deg.C was added tert-butyl 4-aminobenzoate (3.8 g,20 mmol) and phosphorus oxychloride (2.3 mL). The resulting solution was stirred at 0 ℃ for 4 hours. Water (300 mL) was added. The aqueous layer was separated and extracted with ethyl acetate (300 mL. Times.3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column to give 8.7g of the objective compound.
LC-MS:(ES,m/z):[M+H] + ＝519.1
Intermediate 4: (E) -3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylic acid
Step 1: preparation of N- (4-chloro-3-fluorophenyl) -2, 2-trifluoroacetamide
A mixture of 4-chloro-3-fluoroaniline (50.0 g,0.345 mol), 2-2-trifluoroacetic anhydride (86.6 g,0.412 mol) in diethyl ether (1500 mL) was stirred at room temperature for 16h. The reaction mixture was diluted with n-hexane (1500 mL) and stirred at room temperature for 30 minutes. The mixture was filtered and the filtrate was concentrated to give the desired crude product as a white solid, 72.5g. The crude product was directly used in the next step.
LC-MS:(ESI,m/z):[M+H] + ＝241.0.
Step 2: preparation of 6-amino-3-chloro-2-fluorobenzaldehyde
To a solution of N- (4-chloro-3-fluorophenyl) -2, 2-trifluoroacetamide (60.0 g, 0.319 mol) in tetrahydrofuran (600 mL) was added N-butyllithium at-78deg.C under nitrogen. After stirring for 30 minutes, N-dimethylformamide (54.2 g,0.742 mol) was added, and the reaction was stirred at-78℃for 10 minutes. The reaction mixture was diluted with saturated ammonium chloride solution (1000 mL) and extracted with ethyl acetate (3X 300 mL). The organic layer was collected, washed with water (2×200 mL) and saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The concentrate was purified by a silica gel column to give 29.5g of a yellow solid target product.
LC-MS:(ES,m/z):[M+H] + ＝174.2.
Step 3: (E) -3- (6-amino-3-chloro-2-fluorophenyl) acrylic acid methyl ester
Sodium hydride (10.1 g,0.252mol,60% strength) was added to a mixture of methyl 2- (diethoxyphosphoryl) acetate (52.8 g,0.251 mol) in tetrahydrofuran (300 mL) at 0deg.C, and after stirring at 0deg.C for 10 minutes, 6-amino-3-chloro-2-fluorobenzaldehyde (29.0 g,0.168 mol) was added. The reaction mixture was stirred at room temperature for 30 minutes. The reaction was quenched with ice water (500 mL) and extracted with ethyl acetate (3X 200 mL). The organic phase was collected and washed with water (2×150 mL) and saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was purified by a silica gel column to obtain 12.2g of the objective product as a yellow solid.
LC-MS:(ESI,m/z):[M+H] + ＝230.1.
Step 4: (E) -methyl 3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylate
(E) A mixture of methyl 3- (6-amino-3-chloro-2-fluorophenyl) acrylate (12.2 g,0.53 mol) and trimethyl orthoformate (22.6 g,0.213 mol) in acetic acid (500 mL) was stirred at room temperature for 30 minutes, then azido trimethylsilane (73.6 g,0.640 mol) was added, and after stirring the reaction mixture at 30℃for 16 hours, the reaction mixture was diluted with water (1500 mL) and extracted with ethyl acetate (3X 400 mL), the organic layer was collected, washed with water (2X 300 mL) and saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was purified by a silica gel column to obtain 11.0g of a desired product as a yellow solid.
LC-MS:(ESI,m/z):[M+H] + ＝283.0.
Step 5: (E) Preparation of (E) -3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylic acid
(E) A mixture of methyl 3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylate (11.0 g,39.0 mmol) and sodium hydroxide (3.12 g,78.0 mmol) in water (200 mL) and methanol (200 mL) was stirred at room temperature for 2H. The pH of the aqueous layer was adjusted to 5-6 with 1M HCl and extracted with ethyl acetate (3X 200 mL). The organic layer was collected and washed with water (2×150 mL) and saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the desired crude product as a pale yellow solid 9.1g. The crude product was directly used in the next step.
LC-MS:(ESI,m/z):[M+H] + ＝269.0.
Intermediate 5: (E) -2, 5-dioxopyrrolidin-1-yl 3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylate
To a solution of (E) -3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylic acid (12.68 g,10.0 mmol) in tetrahydrofuran (100 ml) and N, N-dimethylformamide (10 ml) were added 1-hydroxypyrrolidinyl-2, 5-dione (1.15 g,10 mmol) and DIC (1.26 g,10 mmol), and the reaction was stirred at room temperature under nitrogen overnight. The reaction produced a white precipitate. The precipitate was collected by suction filtration. The solid was washed with methanol and water and dried in vacuo to give 3.65g of the title compound.
LC-MS:(ES,m/z):[M+H] + ＝366.0
Example 1: (S, E) -4- (3- (4-acetamidophenyl) -2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) propenamido) propanamido) benzoic acid
Step 1: preparation of (S) -3- (4-acetamidophenyl) -2- ((tert-butoxycarbonyl) amino) propionic acid
To a solution of (S) -3- (4-aminophenyl) -2- ((tert-butoxycarbonyl) amino) propionic acid (560 mg,2 mmol) in tetrahydrofuran (10 mL) was added triethylamine (404 mg,4 mmol) and acetyl chloride (160 mg,2 mmol). The reaction solution was stirred at 0℃for 2 hours. Water (10 mL) and ethyl acetate (50 mL) were added. The aqueous layer was separated and extracted with ethyl acetate (30 mL. Times.2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 250mg of the desired crude product. The crude product was used directly in the next reaction.
LC-MS:(ES,m/z):[M+NH 4 ] + ＝340.2
Step 2: preparation of (S) -4- (3- (4-acetamidophenyl) -2- ((tert-butoxycarbonyl) amino) propanamido) benzoic acid tert-butyl ester
To a solution of (S) -3- (4-acetamidophenyl) -2- ((tert-butoxycarbonyl) amino) propionic acid (250 mg,0.78 mmol) in pyridine (5 mL) was added tert-butyl 4-aminobenzoate (150 mg,0.78 mmol) and phosphorus oxychloride (0.2 mL) at 0deg.C. The reaction solution was stirred at 0℃for 2 hours. Water (10 mL) and ethyl acetate (50 mL) were added. The aqueous layer was separated and extracted with ethyl acetate (30 mL. Times.2). The organic layers were combined, washed with saturated brine (50 ml×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by a silica gel column to give 130mg of the objective product.
LC-MS:(ES,m/z):[M+H] + ＝498.2
Step 3: preparation of (S) -4- (3- (4-acetamidophenyl) -2-aminopropionamido) benzoic acid tert-butyl ester
Tert-butyl (S) -4- (3- (4-acetamidophenyl) -2- ((tert-butoxycarbonyl) amino) propionamido) benzoate (130 mg,0.26 mmol) was dissolved in ethyl acetate hydrochloric acid solution (1M, 2 mL) and the reaction was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give 80mg of the desired crude product.
LC-MS:(ES,m/z):[M+H]+＝398.0
Step 4: preparation of (S, E) -tert-butyl 4- (3- (4-acetamidophenyl) -2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) propanamide) benzoate
To a solution of tert-butyl (S) -4- (3- (4-acetamidophenyl) -2-aminopropionamido) benzoate (80 mg,0.23 mmol) in N, N-dimethylformamide (2 mL) were added (E) -3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylic acid, HATU (105 mg,0.28 mmol) and N, N-diisopropylethylamine (60 mg,0.46 mmol), and the reaction was stirred at room temperature for 16 hours. Water (10 mL) and ethyl acetate (50 mL) were added. The aqueous layer was separated and extracted with ethyl acetate (30 mL. Times.2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 100mg of the desired crude product.
LC-MS:(ES,m/z):[M+NH 4 ]+＝665.2
Step 5: preparation of (S, E) -4- (3- (4-acetamidophenyl) -2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) propenamido) propanamido) benzoic acid
To a solution of tert-butyl (S, E) -4- (3- (4-acetamidophenyl) -2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) propionamide) benzoate (100 mg,0.15 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 16 hours. Concentrating the reaction liquid to obtain the target crude product. The crude product was purified by preparative HPLC to give 29.11mg of the title compound.
LC-MS:(ES,m/z):[M+H]+＝592.2
1 H NMR(400MHz,DMSO-d 6 )δ10.47(s,1H),9.84(d,J＝8Hz,2H),8.90(d, J＝8Hz,1H)，7.80-8.00(m,3H),7.50-7.60(m,3H),7.40-7.50(m,2H),7.20-7.25(m,2H),6.75-6.80(m,2H),4.60-6.75(m,1H),2.75-3.00(m,2H),2.00(s,3H).
Example 2: (S, E) -4- (2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) -3- (4- ((methoxycarbonyl) amino) phenyl) propanamido) benzoic acid
Step 1: preparation of (S) -tert-butyl 4- (2- ((tert-butoxycarbonyl) amino) -3- (4- ((methoxycarbonyl) amino) phenyl) propanamido) benzoate
To a solution of tert-butyl (S) -4- (3- (4-aminophenyl) -2- ((tert-butoxycarbonyl) amino) propanamido) benzoate (180 mg,0.4 mmol) in dioxane (10 mL) and water (1 mL) was added sodium bicarbonate (100 mg,1.2 mmol) and methyl chloroformate (37 mg,0.4 mmol). The reaction mixture was stirred at room temperature for 16h. Water (10 mL) and ethyl acetate (50 mL) were added. The aqueous layer was separated and extracted with ethyl acetate (30 mL. Times.2). The organic layers were combined, washed with saturated brine (50 ml×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by a silica gel column to obtain 120mg of the objective product. The crude product was used directly in the next reaction.
LC-MS:(ES,m/z):[M+H]+＝514.2
Step 2: preparation of (S) -tert-butyl 4- (2-amino-3- (4- ((methoxycarbonyl) amino) phenyl) propanamido) benzoate
Tert-butyl (S) -4- (2- ((tert-butoxycarbonyl) amino) -3- (4- ((methoxycarbonyl) amino) phenyl) propanamido) benzoate (120 mg,0.23 mmol) was dissolved in ethyl acetate hydrochloric acid solution (1M, 2 mL) and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain 60mg of a desired crude product.
LC-MS:(ES,m/z):[M+H]+＝414.2
Step 3: preparation of (S, E) -4- (2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) -3- (4- ((methoxycarbonyl) amino) phenyl) propanamido) benzoic acid tert-butyl ester
The synthesis method of step 4 of example 1 was referenced to obtain the desired crude product.
LC-MS:(ES,m/z):[M+H + ] + ＝664.0
Step 4: preparation of (S, E) -4- (2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) -3- (4- ((methoxycarbonyl) amino) phenyl) propanamido) benzoic acid
The synthesis method of step 5 of example 1 was referred to obtain the objective product.
LC-MS:(ES,m/z):[M+NH 4 + ] + ＝625.0
1 H NMR(400MHz,DMSO-d 6 )δ12.70(s,1H),10.48(s,1H),9.83(s,1H),9.54(s,1H),8.85(d,J＝4Hz,1H),8.25(s,0.06H)，7.80-8.00(m,3H),7.50-7.60(m,3H),7.40-7.50(m,2H),7.20-7.25(m,2H),7.00-7.15(m,2H),6.80-7.00(m,2H),4.60-4.65(m,1H),3.63(s,1H),3.00-3.10(m,1H),2.60-2.70(m,1H).
Example 3: (S, E) -4- (2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) -3- (4- (2, 3, 4-heptafluorobutylamino) phenyl) propanamido) benzoic acid
Step 1: preparation of tert-butyl (S) -4- (2- ((tert-butoxycarbonyl) amino) -3- (4- (2,2,3,3,4,4,4,4-heptafluorobutylamino) phenyl) propanamido) benzoate
To a solution of tert-butyl (S) -4- (3- (4-aminophenyl) -2- ((tert-butoxycarbonyl) amino) propanamido) benzoate (45 mg,1 mmol) in methylene chloride (4 mL) were added 2,3, 4-heptafluorobutyryl chloride (232 mg,1 mmol) and triethylamine (760 mg,2 mmol) and N, N-diisopropylethylamine (303 mg,3 mmol), and the reaction was stirred at room temperature for 16 hours. Water (10 mL) and methylene chloride (50 mL) were added. The aqueous layer was separated and extracted with dichloromethane (30 mL. Times.2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give 150mg of the desired crude product.
LC-MS:(ES,m/z):[M+H + ]＝652.1
Step 2: preparation of (S) -4- (2-amino-3- (4- (2, 3, 4-heptafluorobutyramide) phenyl) propanamido) benzoic acid
To a solution of tert-butyl (S) -4- (2- ((tert-butoxycarbonyl) amino) -3- (4- (2, 3, 4-heptafluorobutylamino) phenyl) propanamido) benzoate (150 mg,0.23 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (1 mL). The reaction solution was stirred at room temperature for 16 hours. The reaction was concentrated under reduced pressure to give 100mg of the desired crude product.
LC-MS:(ES,m/z):[M+H + ]＝496.1
Step 3: preparation of (S, E) -4- (2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) -3- (4- (2, 3, 4-heptafluorobutylamino) phenyl) propanamido) benzoic acid
To a solution of (S) -4- (2-amino-3- (4- (2, 3, 4-heptafluorobutyramido) phenyl) propanamido) benzoic acid (100 mg,0.20 mmol) in dimethyl sulfoxide (2 mL) was added 2, 5-dioxopyrrolidin-1-yl (73 mg,0.20 mmol) of (E) -3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylate and N, N-diisopropylethylamine (0.2 mL). The reaction solution was stirred at room temperature for 16h. Water (10 mL) and ethyl acetate (50 mL) were added. The aqueous layer was separated and extracted with ethyl acetate (30 mL. Times.2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the desired crude product. The crude product was purified by preparative HPLC to give 29.39mg of the title compound.
LC-MS:(ES,m/z):[M+H + ]＝746.1
1 H NMR(400MHz,DMSO-d 6 )δ12.73(s,1H),11.21(s,1H),10.52(s,1H),9.83(s,1H),7.20-8.00(m,10H),6.80-6.90(m,2H),4.60-4.70(m,1H),3.00-3.05(m,1H),1.80-1.90(m,1H).
Example 4: (S, E) -4- (2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) -3- (4- (2,2,3,3,4,4,5,5,5-nonafluoropentanamido) phenyl) propanamido) benzoic acid
Step 1: preparation of tert-butyl (S) -4- (2- ((tert-butoxycarbonyl) amino) -3- (4- (2,2,3,3,4,4,5,5,5-nonafluoropentanamido) phenyl) propanamide) benzoate
To a solution of tert-butyl (S) -4- (3- (4-aminophenyl) -2- ((tert-butoxycarbonyl) amino) propanamido) benzoate (45 mg,1 mmol) in pyridine (10 mL) was added 2,2,3,3,4,4,5,5,5-nonafluoropentanoic acid (264 mg,1 mmol) and phosphorus oxychloride (0.2 mL) at 0deg.C. The reaction mixture was stirred at room temperature for 4 hours. Water (10 mL) and ethyl acetate (50 mL) were added. The aqueous layer was separated and extracted with ethyl acetate (30 mL. Times.2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give 150mg of the desired crude product.
LC-MS:(ES,m/z):[M+H + ]＝702.1
Step 2: preparation of (S) -4- (2-amino-3- (4- (2,2,3,3,4,4,5,5,5-nonafluoropentanamide) phenyl) propanamido) benzoic acid
The synthesis method of step 2 of example 3 was referenced to obtain the target product.
LC-MS:(ES,m/z):[M+H + ]＝546.0
Step 3: preparation of (S, E) -4- (2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) -3- (4- (2,2,3,3,4,4,5,5,5-nonafluoropentanamido) phenyl) propanamido) benzoic acid
The synthesis method of step 3 of example 3 was referenced to obtain the target product.
LC-MS:(ES,m/z):[M+H + ]＝795.9
1 H NMR(400MHz,DMSO-d 6 )δ12.70(s,1H),11.21(s,1H),10.52(s,1H),9.83(s,1H),7.20-8.00(m,10H),6.80-6.90(m,2H),4.60-4.70(m,1H),3.00-3.05(m,1H),1.80-1.90(m,1H).
Example 5: (S, E) -4- (2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) -3- (4- (2, 2-trifluoroacetamido) phenyl) propanamido) benzoic acid
Step 1: preparation of (S) -tert-butyl 4- (2- ((tert-butoxycarbonyl) amino) -3- (4- (2, 2-trifluoroacetamido) phenyl) propanamido) benzoate
The synthesis method of step 1 of example 4 was referenced to obtain the desired crude product.
LC-MS:(ES,m/z):[M+H + ]＝552.5
Step 2: preparation of (S) -4- (2-amino-3- (4- (2, 2-trifluoroacetamido) phenyl) propanamido) benzoic acid
The synthesis method of step 2 of example 3 was referenced to obtain the target product.
LC-MS:(ES,m/z):[M+H + ]＝396.1
Step 3: preparation of (S, E) -4- (2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) -3- (4- (2, 2-trifluoroacetamido) phenyl) propanamido) benzoic acid
The synthesis method of step 3 of example 3 was referenced to obtain the target product.
LC-MS:(ES,m/z):[M+H + ]＝646.1
1 H NMR(400MHz,DMSO-d 6 )δ12.71(s,1H),11.17(s,1H),10.52(s,1H),9.83(s,1H),8.88(d,J＝8.0,1H),7.20-8.00(m,10H),6.80-6.90(m,2H),4.60-4.70(m,1H),3.00-3.05(m,1H),1.80-1.90(m,1H).
Example 6: (S, E) -4- (3- (4- ((2,5,8,11,14,17,20,23-octaoxaditridinyl) amino) phenyl) -2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) propenamido) propanamido) benzoic acid
Step 1: preparation of tert-butyl (S) -4- (3- (4- ((2,5,8,11,14,17,20,23-octaoxaditridecanoyl) amino) phenyl) -2- ((tert-butoxycarbonyl) amino) benzoate
To a solution of tert-butyl (S) -4- (3- (4-aminophenyl) -2- ((tert-butoxycarbonyl) amino) propanamido) benzoate (228 mg,0.5 mmol) in dichloromethane (5 mL) at 0deg.C was added saturated aqueous sodium bicarbonate solution (5 mL) and triphosgene (53 mg,0.18 mmol). The reaction solution was stirred at room temperature for 4 hours. The aqueous layer was separated and extracted with dichloromethane (5 ml×2). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. Heptaglyme (CAS number: 4437-01-8) (170 mg,0.5 mmol) and triethylamine (0.1 mL) were added to the reaction solution of the above-mentioned methylene chloride. The reaction was stirred at room temperature overnight. Water (10 mL) and methylene chloride (50 mL) were added. The aqueous layer was separated and extracted with dichloromethane (30 ml×2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product as a yellow solid. The crude product was purified by prep HPLC to give 125mg of the title compound.
LC-MS:(ES,m/z):[M+H + ]＝722.1
Step 2: preparation of (S) -4- (3- (4- ((2,5,8,11,14,17,20,23-octaoxaditridinyl) amino) phenyl) -2-aminopropionamido) benzoic acid
The synthesis method of step 2 of example 3 was referenced to obtain the target product.
LC-MS:(ES,m/z):[M+H + ]＝666.4
Step 3: preparation of (S, E) -4- (3- (4- ((2,5,8,11,14,17,20,23-octaoxaditridinyl) amino) phenyl) -2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) propanamido) benzoic acid
The synthesis method of step 3 of example 3 was referenced to obtain the target product.
LC-MS:(ES,m/z):[M+H + ]＝916.2.
1 H NMR(400MHz,DMSO-d 6 )δ12.50(s,1H),10.51(s,1H),9.82(s,1H),9.66(s,1H),8.85(d,J＝8.0,1H),7.20-8.00(m,10H),6.80-6.90(m,2H),4.60-4.70(m,1H),4.20(s,2H),3.80(s,2H),3.65(s,2H),3.30(s,3H),3.00-3.05(m,1H),2.80-2.90(m,1H).
Example 7: (S, E) -4- (2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) -3- (4- (((2-methoxyethoxy) carbonyl) amino) phenyl) propanamido) benzoic acid
Step 1: preparation of tert-butyl (S) -4- (2- ((tert-butoxycarbonyl) amino) -3- (4- (((2-methoxyethoxy) carbonyl) amino) phenyl) propanamido) benzoate
The synthesis was carried out by the synthesis method of step 1 of example 6 using 2-methoxyethyl-1-ol as a starting material. Obtaining the target product.
LC-MS:(ES,m/z):[M+Na] + ＝580.0
Step 2: preparation of (S) -4- (2-amino-3- (4- (((2-methoxyethoxy) carbonyl) amino) phenyl) propanamido) benzoic acid
The synthesis method of step 2 of example 3 was referenced to obtain the target product.
LC-MS:(ES,m/z):[M+H] + ＝402.0
Step 3: preparation of (S, E) -4- (2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) -3- (4- (((2-methoxyethoxy) carbonyl) amino) phenyl) propanamido) benzoic acid
The synthesis method of step 3 of example 3 was referenced to obtain the target product.
LC-MS:(ES,m/z):[M+H + ]＝652.0
1 H NMR(400MHz,DMSO-d 6 )δ12.67(s,1H),10.49(s,1H),9.83(s,1H),9.64(s,1H),8.83(d,J＝8.0Hz,1H),8.00-7.80(m,3H),7.75-7.60(m,3H),7.354(d,J＝8.0Hz,2H),7.17(d,J＝8.0Hz,2H),7.76(dd,J 1 ＝16.0Hz,J 2 ＝16.0Hz,2H),6.14(t,J＝8.0Hz,1H),4.60-4.70(m,1H),4.19-4.15(m,2H),3.57-3.53(m,2H),3.30-3.20(m,3H),3.05-3.00(m,1H),2.90-2.80(m,1H).
Example 8: (S, E) -4- (2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) -3- (4- (3- (2-methoxyethyl) ureido) phenyl) propanamido) benzoic acid
Step 1: preparation of (S) -4- (2- ((tert-butoxycarbonyl) amino) -3- (4- (3- (2-methoxyethyl) ureido) phenyl) propanamido) benzoic acid tert-butyl ester
The synthesis was performed according to the synthesis method of step 1 of example 6 to obtain the target compound.
LC-MS:(ES,m/z):[M+Na] + ＝557.2
Step 2: preparation of (S) -4- (2-amino-3- (4- (3- (2-methoxyethyl) ureido) phenyl) propanamido) benzoic acid
The synthesis method of step 2 of example 3 was referenced to obtain the target product.
LC-MS:(ES,m/z):[M+H] + ＝401.1
Step 3: preparation of (S, E) -4- (2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) -3- (4- (3- (2-methoxyethyl) ureido) phenyl) propanamido) benzoic acid
The synthesis method of step 3 of example 3 was referred to obtain the target product.
LC-MS:(ES,m/z):[M+H] + ＝651.0
1 H NMR(400MHz,DMSO-d 6 )δ12.70(s,1H),10.49(s,1H),9.83(s,1H),8.83(d,J＝8.0,1H),8.43(s,1H),8.00-7.80(m,3H),7.75-7.60(m,3H),7.26(d,J＝8.0Hz,2H),7.12(d,J＝8.0Hz,2H),7.76(dd,J 1 ＝16.0Hz,J 2 ＝16.0Hz,2H),6.14(t,J＝8.0Hz,1H),4.70-4.60(m,1H),3.50-3.20(m,2H),3.30-3.25(m,3H),3.00-2.80(m,1H),2.90-2.80(m,1H).
Example 9: (S, E) -4- (2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) -3- (4- (morpholin-4-ylamino) phenyl) propanamido) benzoic acid
Step 1: preparation of (S) -tert-butyl 4- (2- ((tert-butoxycarbonyl) amino) -3- (4- (morpholin-4-amido) phenyl) propanamido) benzoate
The synthesis method of step 1 of example 6 was referenced to obtain the target compound.
LC-MS:(ES,m/z):[M+H] + ＝569.3
Step 2: preparation of (S) -4- (2-amino-3- (4- (morpholin-4-amido) phenyl) propanamido) benzoic acid
The synthesis method of step 2 of example 3 was referenced to obtain the target product.
LC-MS:(ES,m/z):[M+H] + ＝413.1
Step 3: preparation of (S, E) -4- (2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) -3- (4- (morpholin-4-amido) phenyl) propanamido) benzoic acid
The synthesis method of step 3 of example 3 was referenced to obtain the target product.
LC-MS:(ES,m/z):[M+H] + ＝663.2
1 H NMR(400MHz,DMSO-d 6 )δ12.60(s,1H),10.49(s,1H),9.83(s,1H),8.83(d,J＝8.0Hz,1H),8.44(s,1H),8.00-7.80(m,3H),7.75-7.60(m,3H),7.34(d,J＝8.0Hz,2H),7.14(d,J＝8.0Hz,2H),7.76(dd,J 1 ＝16.0Hz,J 2 ＝16.0Hz,2H),4.70-4.60(m,1H),3.60-3.50(m,4H),3.40-3.30(m,4H),3.05-3.00(m,1H),2.90-2.80(m,1H).
Example 10: (S, E) -4- (3- (4- (3- (2, 5,8,11,14,17, 20-heptaoxabehen-22-yl) ureido) phenyl) -2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) propanamido) benzoic acid
Step 1: preparation of 22-azido-2, 5,8,11,14,17, 20-heptaoxabehenate
DPPA (275 mg,1 mmol), DIAD (404 mg,2 mmol) and PPh were added to a solution of heptaglyme (340 mg,1 mmol) in tetrahydrofuran (5 mL) at 0deg.C 3 (524 mg,2 mmol). The reaction solution was stirred at room temperature for 16 hours. Water (10 mL) and ethyl acetate (50 mL) were added. The aqueous layer was separated and extracted with ethyl acetate (30 ml x 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by preparative HPLC to give the title compound 40mg.
LC-MS:(ES,m/z):[M+H 2 O] + ＝383.1
Step 2: preparation of 2,5,8,11,14,17, 20-heptaoxadocosyl-22-amine
To a solution of 22-azido-2, 5,8,11,14,17, 20-heptaoxadocosyl (40 mg,0.1 mmol) in tetrahydrofuran (4 mL) was added PPh3 (60 mg,0.2 mmol). The reaction solution was stirred at room temperature for 16 hours. Water (10 mL) and ethyl acetate (50 mL) were added. The aqueous layer was separated and extracted with ethyl acetate (30 mL. Times.2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give the desired crude product 35mg. The crude product was used directly in the next reaction.
LC-MS:(ES,m/z):[M+H 2 O] + ＝357.2
Step 3: preparation of (S) -tert-butyl 4- (3- (4- (3- (2, 5,8,11,14,17, 20-heptaoxabehen-22-yl) ureido) phenyl) -2- ((tert-butoxycarbonyl) amino) propanamido) benzoate
The target compound was synthesized by the synthesis method of step 1 of reference example 6 using 2,5,8,11,14,17, 20-heptaoxadocosyl-22-amine as a starting material.
LC-MS:(ES,m/z):[M+H] + ＝821.2
Step 4: preparation of (S) -4- (3- (4- (3- (2, 5,8,11,14,17, 20-heptaoxabehen-22-yl) ureido) phenyl) -2-aminopropionamido) benzoic acid
The synthesis method of step 2 of example 3 was referenced to obtain the target product.
LC-MS:(ES,m/z):[M+H] + ＝665.1
Step 5: preparation of (S, E) -4- (3- (4- (3- (2, 5,8,11,14,17, 20-heptaoxabehen-22-yl) ureido) phenyl) -2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) propanamido) benzoic acid
The synthesis method of step 3 of example 3 was referenced to obtain the target product.
LC-MS:(ES,m/z):[M+H] + ＝915.1
1 H NMR(400MHz,DMSO-d 6 )δ12.62(s,1H),10.49(s,1H),9.83(s,1H),8.83(d,J＝8.0Hz,1H),8.45(s,1H),8.26(s,1.47H),8.00-7.80(m,3H),7.70-7.58(m,3H),7.34(d,J＝8.0Hz,2H),7.14(d,J＝8.0Hz,2H),7.76(dd,J 1 ＝16.0Hz andJ 2 ＝16.0Hz,2H),6.90-6.80(m,2H),4.70-4.60(m,1H),3.80-3.50(m,26H),3.35-3.25(m,5H),3.00-3.05(m,1H),2.80-2.90(m,1H).
Example 11: (S, E) -4- (2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) -3- (3- (2-oxopyrrolidin-1-yl) phenyl) propanamido) benzoic acid
Step 1: preparation of (S) -4- (2- ((tert-Butoxycarbonyl) amino) -3- (3- (2-oxopyrrolidin-1-yl) phenyl) propanamido) benzoic acid tert-butyl ester
To a solution of tert-butyl (S) -4- (3- (3-bromophenyl) -2- ((tert-butoxycarbonyl) amino) propanamido) benzoate (319 mg,0.5 mmol) in toluene (10 mL) was added pyrrolidin-2-one (43 mg,0.5 mmol) and cuprous iodide (95 mg,0.5 mmol) and DMEDA (44 mg,0.5 mmol). The reaction mixture was stirred at 100℃overnight. Water (10 mL) and ethyl acetate (50 mL) were added. The aqueous layer was separated and extracted with ethyl acetate (20 mL. Times.2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by silica gel column to give 180mg of the title compound as a yellow solid.
LC-MS:(ES,m/z):[M+Na] + ＝546.2
Step 2: preparation of (S) -4- (2-amino-3- (3- (2-oxopyrrolidin-1-yl) phenyl) propanamido) benzoic acid
The synthesis method of step 2 of example 3 was referenced to obtain the target product.
LC-MS:(ES,m/z):[M+H] + ＝368.1
Step 3: preparation of (S, E) -4- (2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) -3- (3- (2-oxopyrrolidin-1-yl) phenyl) propanamido) benzoic acid
The procedure of example 3, step 3, was followed to give the desired product as a yellow solid.
LC-MS:(ES,m/z):[M+H] + ＝618.1
1 H NMR(400MHz,DMSO-d 6 )δ12.71(s,1H),10.52(s,1H),9.83(s,1H),8.87(d,J＝8Hz,1H),8.17(s,0.45H),8.00-7.80(m,3H),7.60-7.50(m,3H),7.29(t,J＝8.0Hz,1H),7.23(s,1H),7.20-7.10(m,2H),6.76(dd,J 1 ＝16.0Hz and J 2 ＝16.0Hz,2H),4.60-4.70(m,1H),3.60-3.70(m,2H),3.00-3.05(m,1H),1.80-1.90(m,1H),2.40-2.50(m,2H),2.00-2.10(m,2H).
Example 12: (S, E) -4- (2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) -3- (3- (4-methyl-2-oxopiperazin-1-yl) phenyl) propanamido) benzoic acid
Step 1: preparation of (S) -4- (2- ((tert-butoxycarbonyl) amino) -3- (3- (4-methyl-2-oxopiperazin-1-yl) phenyl) propanamido) benzoic acid tert-butyl ester
The synthesis was performed by using 4-methylpiperazin-2-one as a starting material and by the synthesis method according to step 1 of example 11. The target compound is obtained.
LC-MS:(ES,m/z):[M+Na] + ＝553.2
Step 2: (S) -4- (2-amino-3- (3- (4-methyl-2-oxopiperazin-1-yl) phenyl) propanamido) benzoic acid
The synthesis method of step 2 of example 3 was referenced to obtain the target product.
LC-MS:(ES,m/z):[M+H] + ＝397.1
Step 3: preparation of (S, E) -4- (2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) -3- (3- (4-methyl-2-oxopiperazin-1-yl) phenyl) propanamido) benzoic acid
The synthesis method of step 3 of example 3 was referenced to obtain the target product.
LC-MS:(ES,m/z):[M+H + ]＝647.1
1 H NMR(400MHz,DMSO-d 6 )δ12.50(s,1H),10.50(s,1H),9.84(s,1H),8.87(d,J＝8Hz,1H),8.00-7.80(m,3H),7.75-7.60(m,3H),7.35-7.25(t,J＝8.0Hz,1H),7.23(s,1H),7.20-7.10(m,2H),7.76(dd,J 1 ＝16.0Hz,J 2 ＝16.0Hz,2H),4.60-4.70(m,1H),3.60-3.70(m,1H),3.40-3.50(m,1H),3.00-3.05(m,3H),2.70-2.80(m,1H),2.50-2.60(m,2H),2.27(s,3H).
Example 13: (S, E) -4- (2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) -3- (4- (2- (2-methoxyethoxy) acetamido) phenyl) propanamido) benzoic acid
Step 1: preparation of (S) -4- (2- ((tert-Butoxycarbonyl) amino) -3- (4- (2- (2-methoxyethoxy) acetamido) phenyl) propanamido) benzoic acid tert-butyl ester
To a solution of 2- (2-methoxyethoxy) acetic acid (55 mg,0.41 mmol) in DMF (2 mL) was added HATU (233 mg,0.61 mmol) and DIEA (158 mg,1.22 mmol). After stirring the reaction at room temperature for 10 minutes, tert-butyl (S) -4- (3- (4-aminophenyl) -2- ((tert-butoxycarbonyl) amino) propanamido) benzoate (205 mg,0.45 mmol) was added. The reaction mixture was stirred at room temperature for 16h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3X 10 mL). The organic layers were combined and washed with water (2X 10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was purified by a silica gel column to obtain 144mg of the objective product.
LC-MS:(ESI,m/z):[M+NH 4 ] + ＝589.3
Step 2: preparation of (S) -4- (2-amino-3- (4- (2- (2-methoxyethoxy) acetamido) phenyl) propanamido) benzoic acid
The synthesis method of step 2 of example 3 was referenced to obtain the target product.
LC-MS:(ESI,m/z):[M+H] + ＝416.0
Step 3: preparation of (S, E) -4- (2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) -3- (4- (2- (2-methoxyethoxy) acetamido) phenyl) propanamido) benzoic acid
The synthesis method of step 3 of example 3 was referenced to obtain the target product.
LC-MS:(ESI,m/z):[M+H] + ＝666.2
1 H NMR(400MHz,DMSO-d 6 )δ12.68(s,1H),10.50(s,1H),9.83(s,1H),9.55(s,1H),8.85(d,J＝8.0Hz,1H),7.91(dd,J＝18.1,8.6Hz,3H),7.70–7.61(m,3H),7.52(d,J＝8.5Hz,2H),7.22(d,J＝8.5Hz,2H),6.81–6.72(m,2H),4.74–4.70(m,1H),4.04(s,2H),3.65(dd,J＝5.6,3.6Hz,2H),3.51(dd,J＝5.6,3.6Hz,2H),3.28(s,3H),3.04(dd,J＝13.8,5.0Hz,1H),2.85(dd,J＝13.7,9.5Hz,1H).
Example 14: (S, E) -4- (2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) -3- (4- ((2- (dimethylamino) -2-oxoethyl) amino) phenyl) propanamido) benzoic acid
Step 1: preparation of (S) -4- (2- ((tert-Butoxycarbonyl) amino) -3- (4- ((2- (dimethylamino) -2-oxoethyl) amino) phenyl) propanamido) benzoic acid tert-butyl ester
To a solution of tert-butyl (S) -4- (3- (4-aminophenyl) -2- ((tert-butoxycarbonyl) amino) propanamido) benzoate (200 mg,0.44 mmol) in DMF (2 mL) was added 2-bromo-N, N-dimethylacetamide (145 mg,0.88 mmol) and triethylamine (113 mg,0.13 mmol). The reaction mixture was stirred at room temperature for 16h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3X 10 mL). The organic layers were combined, washed with water (2X 10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was purified by a silica gel column to give 130mg of the objective product.
LC-MS:[M+H] + ＝541.3
Step 2: preparation of (S) -4- (2-amino-3- (4- ((2- (dimethylamino) -2-oxoethyl) amino) phenyl) propanamido) benzoic acid
The synthesis method of step 2 of example 3 was referenced to obtain the target product.
LC-MS:(ESI,m/z):[M+H] + ＝385.2
Step 3: preparation of (S, E) -4- (2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) -3- (4- ((2- (dimethylamino) -2-oxoethyl) amino) phenyl) propanamido) benzoic acid
The synthesis method of step 3 of example 3 was referenced to obtain the target product.
LC-MS:(ESI,m/z):[M+H] + ＝635.0
1 H NMR(400MHz,DMSO-d 6 )δ12.69(s,1H),10.47(s,1H),9.84(s,1H),8.78(d,J＝7.9Hz,1H),7.94–7.87(m,4H),7.69(d,J＝8.8Hz,2H),7.63–7.61(m,1H),7.00(d,J＝8.5Hz,2H),6.80(s,1H),6.76–6.75(m,1H),6.55(d,J＝8.5Hz,2H),5.35–5.33(m,1H),3.82(d,J＝4.4Hz,2H),2.99(s,3H),2.95–2.90(m,2H),2.86(s,3H).
Example 15: (S, E) -4- (2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) -3- (4- (((dimethylamino) ethoxy) carbonyl) amino) phenyl) propanamido) benzoic acid
Step 1: preparation of tert-butyl (S) -4- (2- ((tert-butoxycarbonyl) amino) -3- (4- (((2- (dimethylamino) ethoxy) carbonyl) amino) phenyl) propanamido) benzoate
The synthesis was performed using 2- (dimethylamino) ethyl-1-ol as a starting material and with reference to the synthesis method of step 1 of example 6. The target compound is obtained.
LC-MS:(ES,m/z):[M+H] + ＝571.3
Step 2: preparation of (S) -4- (2-amino-3- (4- (((2- (dimethylamino) ethoxy) carbonyl) amino) phenyl) propanamido) benzoic acid
The synthesis method of step 2 of example 3 was referenced to obtain the target product.
LC-MS:(ES,m/z):[M+H] + ＝415.1
Step 3: preparation of (S, E) -4- (2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) -3- (4- (((dimethylamino) ethoxy) carbonyl) amino) phenyl) propanamido) benzoic acid
The synthesis method of step 3 of example 3 was referenced to obtain the target product.
LC-MS:(ES,m/z):[M+H] + ＝665.0
1 H NMR(400MHz,DMSO-d 6 )δ10.47(s,1H),9.83(s,1H),9.58(s,1H),8.85(d,J＝8.0Hz,1H),8.26(s,1.47H),8.00-7.80(m,3H),7.70-7.58(m,3H),7.35(d,J＝8.0Hz,2H),7.17(d,J＝8.0Hz,2H),7.76(dd,J 1 ＝16.0Hz,J 2 ＝16.0Hz,2H),6.90-6.80(m,2H),4.70-4.60(m,1H),4.13(t,J＝8.0Hz,2H),3.00-2.90(m,2H),2.70-2.80(m,2H)2.18(s,6H).
Example 16: (S, E) -4- (2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) -3- (4- (((2-methoxyethoxy) ethoxy) carbonyl) amino) phenylpropionamido) benzoic acid
Step 1: preparation of tert-butyl (S) -4- (2- ((tert-butoxycarbonyl) amino) -3- (4- (((2- (2-methoxyethoxy) ethoxy) carbonyl) amino) phenyl) propanamido) benzoate
The synthesis was carried out by the synthesis method of step 1 of example 6 using 2- (2-methoxyethoxy) ethyl-1-ol as a starting material. Obtaining the target compound
LC-MS:(ES,m/z):[M+H 2 O] + ＝619.3
Step 2 preparation of (S) -4- (2-amino-3- (4- (((2- (2-methoxyethoxy) ethoxy) carbonyl) amino) phenyl) propanamido) benzoic acid
The synthesis method of step 2 of example 3 was referenced to obtain the target product.
LC-MS:(ES,m/z):[M+H] + ＝446.0
Step 3: preparation of (S, E) -4- (2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) -3- (4- (((2-methoxyethoxy) ethoxy) carbonyl) amino) phenylpropionamido) benzoic acid
The synthesis method of step 3 of example 3 was referenced to obtain the target product.
LC-MS:(ES,m/z):[M+H] + ＝696.0
1 H NMR(400MHz,DMSO-d 6 )δ10.50(s,1H),9.84(s,1H),9.66(s,1H),8.87(d,J＝8.0Hz,1H),8.00-7.80(m,3H),7.70-7.58(m,3H),7.35(d,J＝8.0Hz,2H),7.17(d,J＝8.0Hz,2H),6.76(dd,J 1 ＝16.0Hz,J 2 ＝16.0Hz,2H),4.70-4.60(m,1H),4.20–4.15(m,2H),3.73-2.60(m,2H),2.60-2.50(m,2H)3.24(s,3H),3.10-3.00(m,1H),2.80-2.75(m,1H).
Example 17: (S, E) -4- (3- (4- ((2, 5,8, 11-tetraoxadodecanoyl) amino) phenyl) -2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) propenamido) propanamido) benzoic acid
Step 1: preparation of tert-butyl (S) -4- (3- (4- ((2, 5,8, 11-tetraoxadodecanoyl) amino) phenyl) -2- ((tert-butoxycarbonyl) amino) propanamido) benzoate
The synthesis was carried out by the synthesis method of step 1 with reference to reference example 6, starting from 2- (2- (2-methoxyethoxy) ethoxy) ethyl-1-ol. The target compound is obtained.
LC-MS:(ES,m/z):[M+H] + ＝645.9
Step 2: preparation of (S) -4- (3- (4- ((2, 5,8, 11-tetraoxadodecanoyl) amino) phenyl) -2-aminopropionamido) benzoic acid
The synthesis method of step 2 of example 3 was referenced to obtain the target product.
LC-MS:(ES,m/z):[M+H] + ＝490.1
Step 3: preparation of (S, E) -4- (3- (4- ((2, 5,8, 11-tetraoxadodecanoyl) amino) phenyl) -2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) propanamido) benzoic acid
The synthesis method of step 3 of example 3 was referenced to obtain the target product.
LC-MS:(ES,m/z):[M+H 2 O] + ＝757.0
1 H NMR(400MHz,DMSO-d 6 )δ12.72(s,1H),10.50(s,1H),9.83(s,1H),9.61(s,1H),8.84(d,J＝8.0Hz,1H),8.00-7.80(m,3H),7.69(d,J＝8.0Hz,2H),7.62(dd,J＝8.0,1.2Hz,1H),7.35(d,J＝8.0Hz,2H),7.18(d,J＝8.0Hz,2H),6.77(q,J＝16.0Hz,2H),4.80-4.60(m,1H),4.22–4.11(m,2H),3.68–3.59(m,2H),3.59–3.46(m,6H),3.44–3.39(m,2H),3.21(s,3H),3.10-2.90(m,1H),2.90-2.70(m,1H).
Example 18: (S, E) -4- (2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) -3- (4- (3- (dimethylamino) propanamido) phenyl) propanamido) benzoic acid
Step 1: preparation of (S) -4- (2- ((tert-Butoxycarbonyl) amino) -3- (4- (3- (dimethylamino) propanamido) phenyl) propanamido) benzoic acid tert-butyl ester
To a solution of tert-butyl (S) -4- (3- (4-aminophenyl) -2- ((tert-butoxycarbonyl) amino) propanamido) benzoate (319 mg,0.5 mmol) in pyridine (10 mL) was added 3- (dimethylamino) propionic acid (59 mg,0.5 mmol) and phosphorus oxychloride (0.2 mL). The reaction mixture was stirred at 0deg.C for 2h. Water (10 mL) and ethyl acetate (50 mL) were added. The aqueous layer was separated and extracted with ethyl acetate (30 mL. Times.2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by silica gel column to give 150mg of the objective compound.
LC-MS:(ES,m/z):[M+H] + ＝555.2
Step 2: preparation of (S) -4- (2-amino-3- (4- (3- (dimethylamino) propionamido) phenyl) propanamido) benzoic acid
The synthesis method of step 2 of example 3 was referenced to obtain the target product.
LC-MS:(ES,m/z):[M+H] + ＝399.1
Step 3: preparation of (S, E) -4- (2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) -3- (4- (3- (dimethylamino) propanamido) phenyl) propanamido) benzoic acid
The synthesis method of step 3 of example 3 was referenced to obtain the target product.
LC-MS:(ES,m/z):[M+H] + ＝649.0
1 H NMR(400MHz,DMSO-d 6 )δ10.48(s,1H),9.97(s,1H),9.83(s,1H),8.88(d,J＝8Hz,1H),8.33(s,1H),8.00-7.80(m,3H),7.60-7.50(m,3H),7.46(d,J＝8.0Hz,2H),7.19(d,J＝8.0Hz,2H),6.78(dd,J 1 ＝16.0Hz,J 2 ＝16.0Hz,2H),4.60-4.70(m,1H),3.10-3.00(m,1H),2.80-2.75(m,1H),2.60-2.50(m,2H),2.50-2.40(m,2H),2.46(s,6H).
Example 19: (S, E) -4- (2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) -3- (4- (2- (2- (2-methoxyethoxy) ethoxy) acetamido) phenyl) propanamido) benzoic acid
Step 1: preparation of tert-butyl 2- (2- (2-methoxyethoxy) ethoxy) acetate
To a solution of 2- (2-methoxyethoxy) ethyl-1-ol (480 mg,4 mmol) in tetrahydrofuran (20 mL) was added 60% sodium hydride (192 mg,4.8 mmol) at 0deg.C. The resulting solution was reacted at 0℃with stirring for 2 hours. Tert-butyl 2-bromoacetate (4571 mg,4.8 mmol) was added thereto, and the reaction mixture was stirred at room temperature for 16h. The reaction solution was poured into ice water. Water (10 mL) and ethyl acetate (50 mL) were added. The aqueous layer was separated and extracted with ethyl acetate (30 mL. Times.2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 600mg of crude product. The crude product was used directly in the next step.
Step 2: preparation of 2- (2- (2-methoxyethoxy) ethoxy) acetic acid
To a solution of tert-butyl 2- (2- (2-methoxyethoxy) ethoxy) acetate (300 mg,1.28 mmol) in methylene chloride (4 mL) was added trifluoroacetic acid (1 mL). The reaction solution was stirred at room temperature for 16 hours. The reaction solution was concentrated to obtain 200mg of a crude product. The crude product was used directly in the next step.
Step 3: preparation of (S) -tert-butyl 4- (2- ((tert-butoxycarbonyl) amino) -3- (4- (2- (2- (2-methoxyethoxy) ethoxy) acetamido) phenyl) propanamido) benzoate
To a solution of 2- (2- (2-methoxyethoxy) ethoxy) acetic acid (100 mg,0.55 mmol) in DMF (5 mL) was added tert-butyl (S) -4- (3- (4-aminophenyl) -2- ((tert-butoxycarbonyl) amino) propanamido) benzoate (250 mg,0.55 mmol), N, N-diisopropylethylamine (0.2 mL) and HATU (418 mg,1.1 mmol). The resulting solution was stirred at room temperature for 16h. Water (10 mL) and ethyl acetate (50 mL) were added. The aqueous layer was separated and extracted with ethyl acetate (30 mL. Times.2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by silica gel column to give 120mg of the objective compound.
LC-MS:(ES,m/z):[M+H 2 O] + ＝633.1
Step 4: preparation of (S) -4- (2-amino-3- (4- (2- (2- (2-methoxyethoxy) ethoxy) acetamido) phenyl) propanamido) benzoic acid
The synthesis method of step 2 of example 3 was referenced to obtain the target product.
LC-MS:(ES,m/z):[M+H] + ＝460.0
Step 5: preparation of (S, E) -4- (2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) -3- (4- (2- (2- (2-methoxyethoxy) ethoxy) acetamido) phenyl) propanamido) benzoic acid
The synthesis method of step 3 of example 3 was referenced to obtain the target product.
LC-MS:(ES,m/z):[M+H] + ＝710.1
1 H NMR(400MHz,DMSO-d 6 )δ10.48(s,1H),9.83(s,1H),9.49(s,1H),8.86(d,J＝8.0Hz,1H),8.00-7.80(m,3H),7.70-7.65(m,3H),7.53(d,J＝8.0Hz,2H),7.22(d,J＝8.0Hz,2H),6.75(dd,J 1 ＝16.0Hz,J 2 ＝16.0Hz,2H),4.70-4.60(m,1H),4.06–4.02(m,2H),3.70-3.50(m,6H),2.60-2.40(m,2H)3.21(s,3H),3.10-3.00(m,1H),2.80-2.75(m,1H).
Example 20: (S, E) -4- (2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) -3- (4- (4-methyl-2-oxopiperazin-1-yl) phenyl) propanamido) benzoic acid
Step 1: preparation of (S) -tert-butyl 4- (2- ((tert-butoxycarbonyl) amino) -3- (4- (4-methyl-2-oxopiperazin-1-yl) phenyl) propanamido) benzoate
To a solution of tert-butyl (S) -4- (3- (4-bromophenyl) -2- ((tert-butoxycarbonyl) amino) propanamido) benzoate (319 mg,0.5 mmol) in toluene (10 mL) was added 4-methylpiperazin-2-one (77 mg,0.5 mmol) and cuprous iodide (95 mg,0.5 mmol) and DMEDA (44 mg,0.5 mmol). The resulting solution was stirred at 100 ℃ overnight. Water (10 mL) and ethyl acetate (50 mL) were added. The aqueous layer was separated and extracted with ethyl acetate (30 mL. Times.2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column to give 80mg of the objective compound.
LC-MS:(ES,m/z):[M+Na] + ＝553.2
Step 2: preparation of (S) -4- (2-amino-3- (4- (4-methyl-2-oxopiperazin-1-yl) phenyl) propanamido) benzoic acid
The synthesis method of step 2 of example 3 was referenced to obtain the target product.
LC-MS:(ES,m/z):[M+H] + ＝397.1
Step 3: preparation of (S, E) -4- (2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) -3- (4- (4-methyl-2-oxopiperazin-1-yl) phenyl) propanamido) benzoic acid
The synthesis method of step 3 of example 3 was referenced to obtain the target product.
LC-MS:(ES,m/z):[M+H] + ＝647.2
1 H NMR(400MHz,DMSO-d 6 )δ12.50(s,1H),10.51(s,1H),9.84(s,1H),8.87(d,J＝8Hz,1H),8.00-7.80(m,3H),7.70-7.55(m,3H),7.30(d,J＝8.0Hz,2H),7.24(d,J＝8.0Hz,2H),7.77(dd,J 1 ＝16.0Hz,J 2 ＝16.0Hz,2H),4.70-4.60(m,1H),3.70-3.60(m,2H),3.30-3.20(m,3H),3.00-2.90(m,1H),2.80-2.70(m,2H),2.30-2.20(m,3H).
Example 21:4- ((S) -2- ((E) -3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) -3- (4- ((R) -3-hydroxypyrrolidine-1-carboxamido) phenylpropionamido) benzoic acid
Synthesized by the method of example 6.
LC-MS:(ES,m/z):[M+H] + ＝663.4.
1 H NMR(400MHz,DMSO-d 6 )δ10.48(s,1H),9.84(s,1H),8.86(d,J＝8.0Hz,1H),8.31(s,1H),8.01(s,1H),7.96–7.85(m,3H),7.67(d,J＝8.7Hz,2H),7.62(dd,J＝8.6,1.3Hz,1H),7.38(d,J＝8.5Hz,2H),7.13(d,J＝8.5Hz,2H),6.77(q,J＝16.1Hz,2H),4.93(br,1H),4.75-4.65(m,1H),4.30–4.25(m,1H),3.43–3.40(m,2H),3.26-3.23(m,1H),3.06–2.95(m,1H),2.88–2.76(m,1H),1.95-1.85(m,1H),1.83–1.71(m,1H).
Control group 1: (S, E) -4- (2- (3- (3-chloro-2-fluoro-6- (1H-tetrazol-1-yl) phenyl) acrylamido) -3- (4- (4-methylpiperazine-1-carboxamido) phenyl) propanamido) benzoic acid
Synthesized by the method of example 6.
LC-MS：(ES,m/z):[M+H] + ＝676.1.
1 H NMR(400MHz,DMSO-d 6 )δ12.64(s,1H),10.49(s,1H),9.83(s,1H),8.83(d,J＝8.0Hz,1H),8.41(s,1H),8.00-7.95(m,3H),7.69(d,J＝8.7Hz,2H),7.62(d,J＝8.7Hz,1H),7.34(d,J＝8.5Hz,2H),7.13(d,J＝8.5Hz,2H),6.77(q,J＝16.1Hz,2H),4.80-4.65(m,1H),3.50-3.40(m,4H),3.05-2.95(m,1H),2.90-2.75(m,1H),2.36–2.24(m,4H),2.18(s,3H).
II biological Activity test examples
Test example 1: inhibition assay of coagulation factor 11a Activity
The test compound of the present invention was first dissolved in dimethyl sulfoxide to a final concentration of 20mM. The test compound was then diluted isocratically with dimethyl sulfoxide. And then, 50mM of hydroxyethylpiperazine Qin Yi sulfuric acid buffer (pH 7.4, containing 145mM sodium chloride, 5mM calcium chloride and 0.05% polyethylene glycol 8000) is used for secondary dilution, so that the final concentration of the tested compound in the reaction system is 1000 nM-0.004 nM and the final concentration of dimethyl sulfoxide is 0.5%. The test compound was added to 384 well plates (Greiner) with a final concentration of 0.1nM activated human coagulation factor 11 protein (Abcam) and 75. Mu.M 6-amino-1-naphthalenesulfonamide fluorogenic substrate (Haematologic Technologies) and incubated for 30 min at 37 ℃. After the incubation, the excitation wavelength was 33 on an enzyme-labeled instrument EnVision The fluorescence signal value was read at an emission wavelength of 460nm at 5 nm. Calculating the inhibition rate of the test compound at each concentration by comparing with the fluorescence signal value of the control group, and further calculating the IC of the test compound by performing nonlinear curve fitting of the GraphPad Prism 8 with the logarithmic concentration-inhibition rate 50 Values. The specific results are shown in Table 1.
Test example 2: activated Partial Thromboplastin Time (APTT) assay
The test compound of the present invention was first dissolved in dimethyl sulfoxide to a final concentration of 20mM. The test compound was then diluted isocratically with dimethyl sulfoxide. And diluting with ultrapure water for the second time to ensure that the final concentration range of the tested compound in the reaction system is 60 mu M-0.03 mu M and the final concentration of dimethyl sulfoxide is 0.5%. The test was performed according to the activated partial thrombin time measurement kit (TECO) instructions. The method is described as follows: test compounds and resuspended lyophilized standard human plasma (SIEMENS) were mixed and 100 μl was added to the hemagglutination cup and incubated at 37 ℃ for 2 minutes. Then 100. Mu.L of pre-warmed APTT reagent was added and incubated for another 5 minutes at 37 ℃. Finally, 100. Mu.L of 25mM pre-heated calcium chloride was added. The clotting time was recorded by a coagulometer (TECO) test. Calculating the effect multiple of the tested compound at each concentration by the ratio of the coagulation time to the control group, and further calculating the EC of the tested compound by performing nonlinear curve fitting of the GraphPad Prism 8 with the logarithmic concentration-effect multiple 1.5× And EC (EC) 2.0× Values. The specific results are shown in Table 1.
Table 1:
conclusion: as shown in Table 1, the compounds of the invention have better FXIa inhibition activity and have wider therapeutic safety window.
Test example 3: solubility test experiment
Sodium dihydrogen phosphate-disodium hydrogen Phosphate Buffer (PBS) and glycine-sodium hydroxide buffer (0.1M) at pH6.5, pH 7.4 and pH 8.0 were prepared, respectively, 10mg of the sample was added to the above 1mL of the buffer, and the mixture was centrifuged at 15200rpm for 10 minutes at room temperature on a shaker, and the supernatant was analyzed for the compound content by a conventional LC-MS (liquid chromatography) method, and the specific results are shown in Table 2:
table 2:
conclusion: the compound of the present invention had better solubility, and example 9 had improved solubility over the compound of control group 1, especially at pH 8.0.
Test example 4: stability test experiment
Sodium dihydrogen phosphate-disodium hydrogen Phosphate Buffer Solutions (PBS) at 0.1m pH 7.4 and pH 8.0 were respectively prepared. Immediately after 1.8mg of the compound of example 9 and 1.8mg of the compound of control group 1 were each dissolved in 0.5mL of dimethylsulfoxide solution, samples were taken and analyzed for sample content by LC-MS; 2.5mg and 5.2mg of the compound of example 9 were added to 0.5ml of a sodium dihydrogen phosphate-disodium hydrogen phosphate buffer solution having pH 7.4 and pH 8.0, respectively, and after 5 minutes of sonication, samples were taken for analysis of sample content by LC-MS; 2.6mg and 5.4mg of the compound of control group 1 were added to 0.5mL of sodium dihydrogen phosphate-disodium hydrogen phosphate buffer solution at pH 7.4 and pH 8.0, respectively, and after 5 minutes of sonication, samples were taken for sample content analysis by LC-MS; 2.4mg and 5.4mg of the compound of control group 1 were further added to 0.5mL of sodium dihydrogen phosphate-disodium hydrogen phosphate buffer solution at pH 7.4 and pH 8.0, respectively, and after 30 seconds of sonication, samples were taken for analysis of sample content by LC-MS.
Table 3:
note that: and/indicates non-ultrasound.
Conclusion: the compound of the invention has better stability, and the compound of the example 9 is more stable than the compound of the control group 1, thereby being more beneficial to preservation and application in pharmaceutical production.

Claims (32)

  1. A compound of formula I, or a stereoisomer, enantiomer, diastereomer, deuteride, hydrate, solvate, metabolite, prodrug, or pharmaceutically acceptable salt thereof,
    wherein:
    R 1 selected from hydrogen, hydroxy, halogen, cyano, -OR e C1-C6 alkyl, C3-8 cycloalkyl, 3-8 heterocycloalkyl containing 1 to 2 heteroatoms selected from N, O or S, 6-10 aryl, 5-10 heteroaryl containing 1 to 4 heteroatoms selected from N, O or S, -NHS (O) 2 R e 、NHS(O) 2 OR e 、NHS(O) 2 NHR e 、-NHS(O)OR e 、-NHS(O)R e 、-NHS(O)NHR e 、-NHC(O)R e 、-NHC(O)OR e 、-NHC(O)NHR e 、-NR e R f 、-COR e 、-COOR e or-CONHR e ；
    Each R is 2 Independently selected from hydrogen, hydroxy, halogen, cyano, -OR e C1-C6 alkyl, C3-8 cycloalkyl, 3-8 heterocycloalkyl containing 1 to 2 heteroatoms selected from N, O or S, 6-membered heterocycloalkyl10 membered aryl, 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, -NHS (O) 2 R e 、NHS(O) 2 OR e 、NHS(O) 2 NHR e 、-NHS(O)OR e 、-NHS(O)R e 、-NHS(O)NHR e 、-NHC(O)R e 、-NHC(O)OR e 、-NHC(O)NHR e 、-NR e R f 、-COR e 、-COOR e or-CONHR e ；
    R 1 And R is 2 Wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally substituted with one or more substituents selected from halogen, cyano, C1-C6 alkyl, halo C1-C6 alkyl, -COOR e 、-OR e C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, -NHS (O) 2 R e 、NHS(O) 2 OR e 、NHS(O) 2 NHR e 、-NHS(O)OR e 、-NHS(O)R e 、-NHS(O)NHR e 、-NHC(O)R e 、-NHC(O)OR e 、-NHC(O)NHR e 、-NR e R f or-CONHR e Is substituted by a substituent of (a); the R is e And R is f Each independently is hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocycloalkyl containing 1 to 2 heteroatoms selected from N, O or S, 6-10 membered aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O or S;
    n is 1, 2, 3 or 4;
    a is-CH 2 CH 2 -、-CH＝CH-、-C≡C-、-CH 2 NH-or-NHCH 2 -；
    R 3 Is hydrogen or C1-C4 alkyl;
    or R is 3 And A and the atoms to which they are attached togetherFinished products
    R 5 Each independently is hydrogen, hydroxy, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, -O- (C3-C8 cycloalkyl), -O- (3-8 membered heterocycloalkyl), C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, or 5-10 membered heteroaryl;
    R a 、R b 、R c and R is d Each independently hydrogen or C1-C4 alkyl;
    or R is a And R is b Together with the carbon atom to which it is attached, form a C3-C8 cycloalkyl group;
    or R is c And R is d Together with the carbon atom to which it is attached, form a C3-C8 cycloalkyl group;
    p is 1, 2, 3 or 4;
    q is 0, 1, 2, 3 or 4;
    ring B is C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S, 6-10 membered aryl, or 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S; the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted with 1 or more substituents selected from halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or C1-C6 alkoxy;
    X 1 Is NR (NR) 6 Or O;
    R 6 is hydrogen or C1-C4 alkyl;
    R 4 is C1-C6 alkyl, - (CH) 2 ) r (OCH 2 CH 2 ) s O (C1-C6 alkyl), - (CH) 2 ) r (OCH 2 CH 2 ) s N (C1-C6 alkyl) 0-2 Or- (CH 2) r NH(CH 2 CH 2 O) s (C1-C6 alkyl), 3-8 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S; wherein r is 0, 1, 2, 3, 4, 5 or 6; s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; the alkyl or heterocycloalkyl is optionally substituted with 1 or more groups selected from hydroxy, oxo, C1-C6 alkyl, C1-C6 alkoxy, halogen, COOH, COO (C1-C4 alkyl), CONH 2 CON (C1-C4 alkyl) 1-2 Is substituted by a substituent of (a); provided that when R 4 When the heterocyclic alkyl is, piperazine is not included;
    or R is 4 And R is 6 Together with the atoms to which they are attached form a 5-6 membered heterocycloalkyl; the heterocycloalkyl group being optionally substituted with 1 or more substituents selected from halogen, cyano, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or C1-C6 alkoxy;
    d is-CONR g -、-NR g CO-, 6-10 membered aryl, or 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S; wherein Rg is hydrogen or C1-C4 alkyl; the aryl and heteroaryl are optionally substituted with 1 or more groups selected from halogen, hydroxy, oxo, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, - (CH 2) 0-4 COOH、-(CH2) 0-4 COO (C1-C4 alkyl), - (CH 2) 0-4 CONH 2 、-(CH2) 0-4 CON (C1-C4 alkyl) 1-2 、-(CH2) 0-4 S(O) 2 (C1-C4 alkyl), - (CH 2) 0-4 NH 2 、-(CH2) 0-4 N (C1-C4 alkyl) 1-2 、-(CH2) 0-4 S (C1-C4 alkyl) is substituted by a substituent;
    Q 1 is C1-C6 alkyl, - (CH) 2 ) t (C3-C8 cycloalkyl), - (CH) 2 ) t (3-8 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S), - (CH) 2 ) t (6-10 membered aryl), - (CH) 2 ) t (5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S); wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl groups are each independently optionally substituted with R 7 Substitution; the R is 7 Selected from halogen, oxo, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, -COR e 、-COOR e 、-OR e 、-NHS(O) 2 R e 、NHS(O) 2 OR e 、NHS(O) 2 NHR e 、-NHS(O)OR e 、-NHS(O)R e 、-NHS(O)NHR e 、-NHC(O)R e 、 -NHC(O)OR e 、-NHC(O)NHR e 、-NR e R f 、-CONHS(O) 2 R e or-CONHR e The method comprises the steps of carrying out a first treatment on the surface of the The R is e And R is f Each independently is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, 3-8 heterocycloalkyl containing 1 to 2 heteroatoms selected from N, O or S, 6-10 membered aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O or S; the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally selected from the group consisting of-OC (O) (C1-C4 alkyl), -COOH, -C (O) O (C1-C4 alkyl), -C (O) NH 2 -C (O) N (C1-C4 alkyl) 1-2 Amino, -C (O) (C1-C4 alkyl), -O (C1-C4 alkyl) substituents; and t is 0, 1, 2, 3 or 4.
  2. The compound of formula I as defined in claim 1, or a stereoisomer, enantiomer, diastereomer, deuteride, hydrate, solvate, metabolite, prodrug, or pharmaceutically acceptable salt thereof, R a 、R b 、R c 、R d Each independently is hydrogen or methyl.
  3. The compound of formula i as defined in claim 1, or a stereoisomer, enantiomer, diastereomer, deuteride, hydrate, solvate, metabolite, prodrug, or pharmaceutically acceptable salt thereof, p is 1 and q is 0.
  4. A compound of formula I as defined in claim 1, or a stereoisomer, enantiomer, diastereomer, deuteride, hydrate, solvate, metabolite, prodrug, or pharmaceutically acceptable salt thereof, X 1 Is NR (NR) 6 ；R 6 Is hydrogen or methyl.
  5. The compound of formula I as defined in claim 1, or a stereoisomer, enantiomer, diastereomer, deuteride, hydrate, solvate, metabolite, prodrug, or pharmaceutically acceptable salt thereof, R 4 Is C1-C6 alkyl; the alkyl group is optionally substituted with 1 or more halogens.
  6. The compound of formula I as defined in claim 1, or a stereoisomer, enantiomer, diastereomer, deuteride, hydrate, solvate, metabolite, prodrug, or pharmaceutically acceptable salt thereof, R 4 Is- (CH) 2 ) r O (C1-C6 alkyl) or- (CH) 2 ) r N (C1-C6 alkyl) 0-2 And r is 0, 1, 2, 3 or 4.
  7. The compound of formula I as defined in claim 1, or a stereoisomer, enantiomer, diastereomer, deuteride, hydrate, solvate, metabolite, prodrug, or pharmaceutically acceptable salt thereof, R 4 Is morpholinyl or pyrrolidinyl optionally substituted with hydroxy or oxo.
  8. The compound of formula I as defined in claim 1, or a stereoisomer, enantiomer, diastereomer, deuteride, hydrate, solvate, metabolite, prodrug, or pharmaceutically acceptable salt thereof, R 4 Is- (CH) 2 ) r (OCH 2 CH 2 ) s O (C1-C6 alkyl), - (CH 2) r (OCH 2 CH 2 ) s N (C1-C6 alkyl) 0-2 Or- (CH) 2 ) r NH(CH 2 CH 2 O) s (C1-C6 alkyl), said r being 0 or 1; and s is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  9. The compound of formula I as defined in claim 1, or a stereoisomer, enantiomer, diastereomer, deuteride, hydrate, solvate, metabolite, prodrug, or pharmaceutically acceptable salt thereof, R 4 Is- (OCH) 2 CH 2 ) 5 OCH 3 、-OCH 2 CH 2 OCH 3 、-(OCH 2 CH 2 ) 7 OCH 3 、-NHCH 2 CH 2 OCH 3 、-NH(CH 2 CH 2 O) 5 CH 3 、-NH(CH 2 CH 2 O) 7 CH 3 、-CH 2 OCH 2 CH 2 OCH 3 、-N(CH3) 2 Methyl, methoxy, trifluoromethyl, perfluoropropyl, perfluorobutyl, -OCH 2 CH 2 N(CH3) 2 、-(OCH 2 CH 2 ) 3 OCH 3 、-(OCH 2 CH 2 ) 2 OCH 3 、-CH 2 CH 2 N(CH3) 2 or-CH 2 (OCH 2 CH 2 ) 2 OCH 3 。
  10. The compound of formula I as defined in claim 1, or a stereoisomer, enantiomer, diastereomer, deuteride, hydrate, solvate, metabolite, prodrug, or pharmaceutically acceptable salt thereof, R 4 And R is 6 Together with the atoms to which they are attached form
  11. The compound of formula i as defined in claim 1, or a stereoisomer, enantiomer, diastereomer, deuteride, hydrate, solvate, metabolite, prodrug, or pharmaceutically acceptable salt thereof, D is a 5-6 membered heteroaryl containing 1 or 2N heteroatoms; the heteroaryl group is optionally substituted with 1 or more groups selected from halogen, hydroxy, oxo, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C2-C4 alkenyl, - (CH) 2 ) 0-4 COOH、-(CH 2 ) 0-4 COO (C1-C4 alkyl), - (CH) 2 ) 0-4 CONH 2 、-(CH 2 ) 0-4 CON (C1-C4 alkyl) 1-2 、-(CH 2 ) 0-4 S(O) 2 (C1-C4 alkyl), - (CH) 2 ) 0-4 NH 2 、-(CH 2 ) 0-4 N (C1-C4 alkyl) 1-2 、-(CH 2 ) 0-4 S (C1-C4 alkyl) is substituted by a substituent; preferred D is imidazolyl, pyridinyl, pyridazinyl or pyrimidinyl; the imidazolyl, pyridyl, pyridazinyl or pyrimidinyl groups are optionally substituted with 1 or more groups selected from oxo, cl, methyl Oxy, ethoxy, -COOH, -CONH 2 、-CONCH 3 、-COOCH 3 Vinyl, cyano, SO 2 CH 3 、-CH 2 OH、-CH 2 CH 2 OH、-CH 2 COOH、-CH 2 COOCH 3 、-CH 2 SO 2 CH 3 Amino, -CH 2 NH 2 、-CH 2 N(CH 3 ) 1-2 Is substituted by a substituent of (a).
  12. The compound of formula I, as recited in claim 1, or a stereoisomer, enantiomer, diastereomer, deuteride, hydrate, solvate, metabolite, prodrug, or pharmaceutically acceptable salt thereof, wherein the compound of formula I is a compound of formula IB,
    wherein said R is 1 、R 2 、R 3 、R 4 Ra, rb, rc, rd, ring B, X 1 P, Q, n and Q 1 As defined in claim 1.
  13. The compound of formula i as defined in claim 1, or a stereoisomer, enantiomer, diastereomer, deuteride, hydrate, solvate, metabolite, prodrug, or pharmaceutically acceptable salt thereof, ring B is C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl containing 1 or 2N heteroatoms, 5-6 membered heteroaryl containing 1 to 3N heteroatoms, or phenyl; the cycloalkyl, heterocycloalkyl, phenyl, heteroaryl are optionally substituted with 1 or more substituents selected from halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy.
  14. The compound of formula I, as defined in claim 1, or a stereoisomer, enantiomer, diastereomer, deuteride, hydrate, solvate, metabolite, prodrug, or pharmaceutically acceptable salt thereof, wherein the compound of formula I is a compound of formula IC,
    Wherein said R is 1 、R 2 、R 3 、R 4 、Ra、Rb、Rc、Rd、X 1 P, Q, n and Q 1 As defined in the above claim 1.
  15. The compound of formula I as defined in claim 1, or a stereoisomer, enantiomer, diastereomer, deuteride, hydrate, solvate, metabolite, prodrug, or pharmaceutically acceptable salt thereof, R 1 Is hydrogen, cyano, halogen, C1-C6 alkyl optionally substituted by halogen or hydroxy, C3-C6 cycloalkyl or-C (O) Re; re is C1-C6 alkyl, C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl containing 1-2 heteroatoms selected from N or O; the alkyl, cycloalkyl, heterocycloalkyl being optionally substituted with one or more groups selected from halogen, hydroxy or amino; or R is 1 is-ORe; re is C1-C6 alkyl; the alkyl group is optionally substituted with halogen.
  16. The compound of formula I as defined in claim 1, or a stereoisomer, enantiomer, diastereomer, deuteride, hydrate, solvate, metabolite, prodrug, or pharmaceutically acceptable salt thereof, R 1 Is hydrogen, cyano, F, cl, br, trifluoromethyl, difluoromethyl, cyclopropyl, formyl, acetyl, cyclopropylacyl, difluoromethoxy or trifluoromethoxy.
  17. As claimed in A compound of formula I as defined in claim 1, or a stereoisomer, enantiomer, diastereomer, deuteride, hydrate, solvate, metabolite, prodrug, or pharmaceutically acceptable salt thereof, R 1 Is a 5-6 heteroaryl group containing 1-4 heteroatoms selected from N or O; the heteroaryl is optionally substituted with one or more substituents selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl; preferably R 1 Is a 5-6 heteroaryl group containing 1-4N heteroatoms, said heteroaryl group optionally substituted with a substituent selected from F, cl, methyl, trifluoromethyl, trifluoroethyl, methoxy; more preferably R 1 Is pyrazolyl, imidazolyl, triazole or tetrazole; most preferably R 1 Is tetrazole.
  18. The compound of formula I, as recited in claim 1, or a stereoisomer, enantiomer, diastereomer, deuteride, hydrate, solvate, metabolite, prodrug, or pharmaceutically acceptable salt thereof, wherein the compound of formula I is a compound of formula ID,
    wherein said R is 2 、R 3 、R 4 、Ra、Rb、Rc、Rd、X 1 P, Q, n and Q 1 As defined in claim 1.
  19. The compound of formula I as defined in claim 1, or a stereoisomer, enantiomer, diastereomer, deuteride, hydrate, solvate, metabolite, prodrug, or pharmaceutically acceptable salt thereof, R 2 Is hydrogen, halogen, C1-C6 alkyl optionally substituted by halogen or hydroxy, or-ORe; the Re is C1-C6 alkyl optionally substituted with one or more halogens or hydroxy.
  20. The compound of formula I as defined in claim 1, or a stereoisomer, enantiomer, diastereomer, deuteride, hydrate, solvate, metabolite, prodrug, or pharmaceutically acceptable salt thereof, R 2 Is hydrogen, trifluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy, F or Cl.
  21. The compound of formula I, as recited in claim 1, or a stereoisomer, enantiomer, diastereomer, deuteride, hydrate, solvate, metabolite, prodrug, or pharmaceutically acceptable salt thereof, wherein the compound of formula I is a compound of formula IE,
    wherein said R is 3 、R 4 、Ra、Rb、Rc、Rd、X 1 P, Q and Q 1 As defined in claim 1.
  22. The compound of formula I as defined in claim 1, or a stereoisomer, enantiomer, diastereomer, deuteride, hydrate, solvate, metabolite, prodrug, or pharmaceutically acceptable salt thereof, Q 1 Is a 5-6 membered heteroaryl or a 6-10 membered aryl containing 1 or 2 heteroatoms selected from N, O or S; the heteroaryl, aryl being optionally substituted with one or more R 7 And (3) substitution.
  23. The compound of formula I as defined in claim 1, or a stereoisomer, enantiomer, diastereomer, deuteride, hydrate, solvate, metabolite, prodrug, or pharmaceutically acceptable salt thereof, Q 1 Is pyridine, indolyl, benzofuranyl, benzimidazolyl, quinoline or phenyl; the pyridyl, indolyl, benzofuranyl, benzimidazolyl, quinoline or phenyl group being optionallyIs/are R 7 And (3) substitution.
  24. The compound of formula I, as defined in claim 1, or a stereoisomer, enantiomer, diastereomer, deuteride, hydrate, solvate, metabolite, prodrug, or pharmaceutically acceptable salt thereof, wherein the compound of formula I is a compound of formula IF,
    wherein said R is 3 、R 4 、Ra、Rb、Rc、Rd、X 1 P, q and R 7 As defined in claim 1; the u is 1, 2 or 3;
  25. the compound of formula I as recited in claim 1, or a stereoisomer, enantiomer, diastereomer, deuteride, hydrate, solvate, metabolite, prodrug, or pharmaceutically acceptable salt thereof, wherein R 7 F, cl, oxo, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, 5-6 membered heteroaryl containing 1-4N heteroatoms, -COR e 、-COOR e 、-OR e 、-NHS(O) 2 R e 、NHS(O) 2 OR e 、NHS(O) 2 NHR e 、-NHS(O)OR e 、-NHS(O)R e 、-NHS(O)NHR e 、-NHC(O)R e 、-NHC(O)OR e 、-NHC(O)NHR e 、-NR e R f 、-CONHS(O) 2 R e or-CONHR e The method comprises the steps of carrying out a first treatment on the surface of the The R is e Each independently is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, 3-8 heterocycloalkyl containing 1 to 2 heteroatoms selected from N or O, 6-10 aryl, and containing 1 to 4 heteroatoms selected from N, O or SA 5-10 membered heteroaryl of an atom; the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted with one or more groups selected from the group consisting of-OC (O) (C1-C4 alkyl), -COOH, -C (O) O (C1-C4 alkyl), -C (O) NH 2 、
    -C (O) N (C1-C4 alkyl) 1-2 Amino, -C (O) (C1-C4 alkyl), -O (C1-C4 alkyl) substituents; the R is f Is hydrogen or C1-C6 alkyl.
  26. The compound of formula I as recited in claim 1, or a stereoisomer, enantiomer, diastereomer, deuteride, hydrate, solvate, metabolite, prodrug, or pharmaceutically acceptable salt thereof, wherein R 7 F, cl, tetrazole, -COOH, -COOC (CH) 3 ) 3 、-NHC(O)OCH 3 、-CONH 2 、-CONHCH 3 、-CON(CH 3 ) 2 or-NH 2 。
  27. The compound of formula I as defined in claim 1, or a stereoisomer, enantiomer, diastereomer, deuteride, hydrate, solvate, metabolite, prodrug, or pharmaceutically acceptable salt thereof, wherein the compound of formula I is selected from
  28. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-27, and/or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
  29. Use of a compound according to any one of claims 1-27, and/or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment or prophylaxis of a disease or condition associated with FXIa activity.
  30. Use of a compound according to any one of claims 1-27, and/or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment or prophylaxis of thromboembolic disorders.
  31. Use of a compound according to any one of claims 1-27, and/or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment or prophylaxis of arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, arterial cerebrovascular thromboembolic disorders and venous cerebrovascular thromboembolic disorders.
  32. Use of a compound according to any one of claims 1-27, and/or stereoisomers, enantiomers, diastereomers, deuterides, hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment or prophylaxis of unstable angina, acute coronary syndrome, atrial fibrillation, primary myocardial infarction, recurrent myocardial infarction, sudden ischemic death, transient ischemic attacks, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep venous thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism diseases.
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