CN117402183A - Boron-containing compound and medical application thereof - Google Patents

Boron-containing compound and medical application thereof Download PDF

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Publication number
CN117402183A
CN117402183A CN202310858226.4A CN202310858226A CN117402183A CN 117402183 A CN117402183 A CN 117402183A CN 202310858226 A CN202310858226 A CN 202310858226A CN 117402183 A CN117402183 A CN 117402183A
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alkyl
membered
alkoxy
phenyl
membered heterocyclyl
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敖汪伟
徐斌
李煜
王辉
张寅生
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

The present application relates to boron-containing compounds and their medical uses, in particular to compounds of formula (I-0), stereoisomers thereof, pharmaceutically acceptable salts thereof, processes for their preparation, pharmaceutical compositions containing the compounds, and their use in the treatment or prophylaxis of diseases.

Description

Boron-containing compound and medical application thereof
Technical Field
The application belongs to the field of medicinal chemistry, and relates to a boron-containing compound and medicinal application thereof. The application relates to a compound of formula I, a stereoisomer or a pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition containing the compound and application of the compound in treating or preventing FXIa coagulation factor related diseases.
Background
Blood clotting is the result of the coordinated activation of various plasma proteins, cofactors and platelets. This cascade is divided into the endogenous (contact activation) pathway, the exogenous (tissue factor activation) pathway, and the common (prothrombin and thrombin generation) pathway. The most important physiological process in blood coagulation is the activation of tissue factors. Tissue factor forms a complex with factor VIIa, catalyzes the activation of factor ten (FX), which in turn cleaves prothrombin to produce activated thrombin (FIIa). Activated thrombin (FIIa) acts as a central catalytic enzyme in the clotting process, catalyzing the cleavage of fibrinogen to fibrin, and acting as a clotting function. The exogenous approach has less enzyme quantity and quick effect. The intrinsic pathway is the body's intrinsic coagulation pathway, activating the twelve (FXIIa), eleven (FXIa), nine (FIXa) and eight (FVIIIa) factors by a cascade of reactions, which in turn activates the ten factor (FXa) and downstream central thrombin (FIIa). Thrombin in turn activates the factor eleven (FXIa), producing an amplifying effect that accelerates clotting. The intrinsic pathway is involved in more thrombin and is entirely from blood, generally with slower onset of action.
FXa plays a very critical role in the whole coagulation process. Antagonists thereof are widely used for the prevention and treatment of various thrombosis as downstream co-modulators of the extrinsic and intrinsic coagulation pathways. Various FXa antagonists are marketed, and occupy the cardiovascular medicine market due to their remarkable therapeutic effects.
Many antibodies, small molecules and antisense nucleotides to FXIa have also been shown to be effective in preventing thrombosis in animals or clinically by inhibiting FXIa. But the risk of bleeding is greatly reduced compared to existing antithrombotic agents (e.g. enoxaparin). The above shows that FXIa is closely related to human thrombotic diseases, and inhibiting FXIa has remarkable anticoagulation effect, but has no obvious bleeding tendency, and can greatly reduce the bleeding risk in the clinical anticoagulation process. Antisense oligonucleotide (antisense oligonucleotides, ASO) BAY-2306001 from Bayer corporation entered clinical second-phase studies and achieved good results, showing the potential of FXIa as an emerging target (ArteriosclerThrombVasc Biol,2013,33 (7) 1670-1678).
Therefore, the research of the novel FXIa inhibitor has important significance.
Summary of The Invention
The present application provides a compound of formula (I-0), stereoisomers thereof, or a pharmaceutically acceptable salt thereof,
Wherein,
ring A is selected from C 6-10 C containing at least one B atom in the aryl, 5-to 10-membered heteroaryl, ring atom 6-10 Aryl 5-8 membered heterocyclyl or 5-10 membered heteroaryl 5-8 membered heterocyclyl containing at least one B atom in the ring atom, said C 6-10 Aryl or 5-to 10-membered heteroaryl groups are substituted by R a Substituted and optionally substituted with one or more R b Substitution, said C 6-10 The ring atoms in the aryl-5-8 membered heterocyclyl or 5-10 membered heteroaryl-5-8 membered heterocyclyl optionally contain one or more heteroatoms selected from N, O, S, said C 6-10 Aryl 5-8 membered heterocyclyl or 5-10 membered heteroaryl 5-8 membered heterocyclyl optionally substituted with one or more R b Substitution;
R a selected from- (CH) 2 ) p -BR c R d 、-O(CH 2 ) p -BR c R d - (CH) having at least one B atom in the ring 2 ) p -5-12 membered heterocyclyl or-O (CH) containing at least one B atom in the ring atom 2 ) p -a 5-12 membered heterocyclyl group, said- (CH) 2 ) p -5-12 membered heterocyclyl or-O (CH) 2 ) p The ring atoms in the 5-12 membered heterocyclyl optionally contain one or more heteroatoms selected from N, O, S, said- (CH) 2 ) p -5-12 membered heterocyclyl or-O (CH) 2 ) p -5-12 membered heterocyclyl optionally substituted with one or more R e Substitution;
p is selected from 0, 1, 2, 3 or 4;
R b independently selected from halogenElement, -CN, -OH, -NH 2 、-NH(C 1-6 Alkyl), -N (C) 1-6 Alkyl group 2 、C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, -C (O) OH, -C (O) NH 2 、-C(O)NH(C 1-6 Alkyl), -C (O) N (C) 1-6 Alkyl group 2 、-NHC(O)C 1-3 Alkyl, -S (O) 2 C 1-3 Alkyl, -S (O) 2 NH 2 、-S(O) 2 NH(C 1-6 Alkyl) or-S (O) 2 N(C 1-6 Alkyl group 2 ；
R c And R is d Each independently selected from-OH, C 1-6 Alkoxy or amino C 1-6 An alkyl group;
R e independently selected from oxo, halogen, -CN, -OH, -NH 2 、-NH(C 1-6 Alkyl), -N (C) 1-6 Alkyl group 2 、C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, -C (O) OH, -C (O) NH 2 、-C(O)NH(C 1-6 Alkyl) or-C (O) N (C) 1-6 Alkyl group 2 ；
Ring C is selected from phenyl, 6 membered heteroaryl, 6 membered heterocycloalkyl, or 6 membered heterocycloalkenyl;
each R is 1 Each independently selected from oxo, halogen, -CN, -OH, -NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl-O-, said C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl-O-optionally substituted with one or more groups selected from: -CN, -OH, -NH 2 Or halogen;
m is selected from 0, 1, 2, 3 or 4;
each R is 2 Each independently selected from halogen, -CN, -OH, -NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl optionally substituted with one or more halo;
n is selected from 0, 1, 2, 3 or 4;
R 3 selected from hydrogen, halogen, -CN, -OH, -NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl C (O) -or 5-6 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl C (O) -or 5-6 membered heteroaryl optionally substituted with one or more groups selected from: -CN, -OH, -NH 2 Halogen or halogenated C 1-6 An alkyl group;
l is selected from bond, O, S or-CR f R g -；
R f And R is g Each independently selected from H, halogen, -CN, -OH, -NH 2 、C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or halo C 1-6 An alkoxy group;
R 4 selected from C 1-6 Alkyl, C 1-8 Heteroalkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, said C 1-6 Alkyl, C 1-8 Heteroalkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl optionally substituted with one or more R 4a Substitution;
R 4a selected from oxo, halogen, -CN, -OH, -NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl or halo C 1-6 An alkoxy group;
R 5 selected from hydrogen, C 1-6 Alkyl or halo C 1-6 An alkyl group;
optionally, the R b 、R c 、R d 、R e 、R f 、R g 、R 4a 、R 1 、R 2 、R 3 、R 4 Or R 5 May be substituted with one or more substituents.
In some embodiments, the ring C is selected from phenyl, 6 membered heterocycloalkyl, or 6 membered heterocycloalkenyl.
In some embodiments, the ring C is selected from phenyl, 6-membered heterocycloalkyl, or 6-membered heterocycloalkenyl, the 6-membered heterocycloalkyl, or 6-membered heterocycloalkenyl containing one or two N atoms.
In some embodiments, the ring C is selected from phenyl, piperazinyl, dihydropyridazinyl, dihydropyridinyl, or dihydropyrimidinyl.
In some embodiments, the ring C is selected from phenyl, piperazinyl,
In some embodiments, the ring C is selected fromEach R is 1 Each independently selected from oxo or C 1-6 An alkoxy group.
In some embodiments, the building blockSelected from the group consisting of
In some embodiments, the R b 、R c 、R d 、R e 、R f 、R g 、R 4a 、R 1 、R 2 、R 3 、R 4 Or R 5 May be substituted with one or more substituents selected from the group consisting of: deuterium, -OH, -SH, halogen, -NH 2 Nitro, nitroso, -CN, azido, sulfoxide, sulfone, sulfonamide, carboxyl, carboxyaldehyde, imine, alkyl, halo-alkyl, cycloalkyl, halo-cycloalkyl, alkenyl, halo-alkenyl, cycloalkenyl, halo-cycloalkenyl, alkynyl, halo-alkynyl, cycloalkynyl, halo-cycloalkynyl, heteroalkyl, halo-heteroalkyl, alkoxy, alkylthio, aryl, aryloxy,arylthio, aralkyl, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroarylalkyl, heteroarylalkoxy, heteroarylalkylthio, heterocyclyl, heterocyclyloxy, heterocyclylthio, heterocyclylalkyl, heterocyclylalkoxy, heterocyclylalkylthio, acyl, acyloxy, carbamate, amide, urea, epoxy, ester groups, and the like.
In some embodiments, the compound of formula (I-0), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
wherein,
ring A is selected from C 6-10 C containing at least one B atom in the aryl, 5-to 10-membered heteroaryl, ring atom 6-10 Aryl 5-8 membered heterocyclyl or 5-10 membered heteroaryl 5-8 membered heterocyclyl containing at least one B atom in the ring atom, said C 6-10 Aryl or 5-to 10-membered heteroaryl groups are substituted by R a Substituted and optionally substituted with one or more R b Substitution, said C 6-10 The ring atoms in the aryl-5-8 membered heterocyclyl or 5-10 membered heteroaryl-5-8 membered heterocyclyl optionally contain one or more heteroatoms selected from N, O, S, said C 6-10 Aryl 5-8 membered heterocyclyl or 5-10 membered heteroaryl 5-8 membered heterocyclyl optionally substituted with one or more R b Substitution;
R a selected from- (CH) 2 ) p -BR c R d 、-O(CH 2 ) p -BR c R d - (CH) having at least one B atom in the ring 2 ) p -5-12 membered heterocyclyl or-O (CH) containing at least one B atom in the ring atom 2 ) p -a 5-12 membered heterocyclyl group, said- (CH) 2 ) p -5-12 membered heterocyclyl or-O (CH) 2 ) p The ring atoms in the 5-12 membered heterocyclyl optionally contain one or more heteroatoms selected from N, O, S, said- (CH) 2 ) p -5-12 membered heterocyclyl or-O (CH) 2 ) p -5-12 membered heterocyclyl optionally substituted with one or more R e Substitution;
p is selected from 0, 1, 2, 3 or 4;
R b independently selected from halogen, -CN, -OH, -NH 2 、-NH(C 1-6 Alkyl), -N (C) 1-6 Alkyl group 2 、C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, -C (O) OH, -C (O) NH 2 、-C(O)NH(C 1-6 Alkyl), -C (O) N (C) 1-6 Alkyl group 2 、-NHC(O)C 1-3 Alkyl, -S (O) 2 C 1-3 Alkyl, -S (O) 2 NH 2 、-S(O) 2 NH(C 1-6 Alkyl) or-S (O) 2 N(C 1-6 Alkyl group 2 ；
R c And R is d Each independently selected from-OH, C 1-6 Alkoxy or amino C 1-6 An alkyl group;
R e independently selected from oxo, halogen, -CN, -OH, -NH 2 、-NH(C 1-6 Alkyl), -N (C) 1-6 Alkyl group 2 、C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, -C (O) OH, -C (O) NH 2 、-C(O)NH(C 1-6 Alkyl) or-C (O) N (C) 1-6 Alkyl group 2 ；
Each R is 1 Each independently selected from halogen, -CN, -OH, -NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl-O-, said C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl-O-optionally substituted with one or more groups selected from: -CN, -OH, -NH 2 Or halogen;
m is selected from 0, 1, 2, 3 or 4;
each R is 2 Each independently selected from halogen, -CN, -OH, -NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl optionally substituted with one or more halo;
n is selected from 0, 1, 2, 3 or 4;
R 3 selected from halogen, -CN, -OH, -NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl C (O) -or 5-6 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl C (O) -or 5-6 membered heteroaryl optionally substituted with one or more groups selected from: -CN, -OH, -NH 2 Halogen or halogenated C 1-6 An alkyl group;
l is selected from bond, O, S or-CR f R g -；
R f And R is g Each independently selected from H, halogen, -CN, -OH, -NH 2 、C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or halo C 1-6 An alkoxy group;
R 4 selected from C 1-6 Alkyl, C 1-8 Heteroalkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, said C 1-6 Alkyl, C 1-8 Heteroalkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl optionally substituted with one or more R 4a Substitution;
R 4a selected from oxo, halogen, -CN, -OH, -NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl or halo C 1-6 An alkoxy group;
R 5 selected from hydrogen, C 1-6 Alkyl or halo C 1-6 An alkyl group.
The compound of formula (I-0) and the compound of formula (I) each independently include the following embodiments.
In some embodiments, ring a is selected from C 6-10 C containing at least one B atom in the aryl, 5-to 10-membered heteroaryl, ring atom 6-10 Aryl and 5-8 membered heterocyclic groups or ring atoms5-10 membered heteroaryl and 5-8 membered heterocyclyl containing at least one B atom, said C 6-10 Aryl or 5-to 10-membered heteroaryl groups are substituted by R a Substituted and optionally substituted with one or more R b Substitution, said C 6-10 The ring atoms in the aryl-5-8 membered heterocyclyl or 5-10 membered heteroaryl-5-8 membered heterocyclyl optionally contain one or more O atoms, said C 6-10 Aryl 5-8 membered heterocyclyl or 5-10 membered heteroaryl 5-8 membered heterocyclyl optionally substituted with one or more R b And (3) substitution.
In some embodiments, the C 6-10 The ring atoms of the aryl-5-8 membered heterocyclyl or 5-10 membered heteroaryl-5-8 membered heterocyclyl contain one B atom and one O atom, and optionally one or more N atoms.
In some embodiments, the C 6-10 Aryl and 5-8 membered heterocyclyl or 5-10 membered heteroaryl and 5-8 membered heterocyclyl ring atoms, said 5-8 membered heterocyclyl comprising one B atom and one O atom, said 5-10 membered heteroaryl comprising one or more N atoms.
In some embodiments, the C 6-10 Aryl and 5-8 membered heterocyclyl or 5-10 membered heteroaryl and 5-8 membered heterocyclyl ring atoms, said 5-8 membered heterocyclyl ring atoms having and only one B atom and one O atom, said 5-10 membered heteroaryl comprising one or more N atoms.
In some embodiments, the C 6-10 Aryl and 5-8 membered heterocyclic group or 5-10 membered heteroaryl and 5-8 membered heterocyclic group, wherein the 5-8 membered heterocyclic group has one and only one B atom and one O atom, and the 5-10 membered heteroaryl has one and only one N atom.
In some embodiments, the C 6-10 Aryl and 5-8 membered heterocyclic group is C 6-10 Aryl and 5-8 membered heterocycloalkyl, wherein the 5-10 membered heteroaryl and 5-8 membered heterocyclyl is 5-10 membered heteroaryl and 5-8 membered heterocycloalkyl.
In some embodiments, the C 6-10 Aryl 5-8 membered heterocyclyl or 5-10 membered heteroaryl 5-8 membered heterocyclyl, said 5-8 membered heterocyclyl moiety having one and only one double bond.
In some embodiments, ring A is selected from phenyl, 5-6 membered heteroaryl, phenyl and 5-8 membered heterocyclyl containing at least one B atom in the ring atom, or 5-6 membered heteroaryl and 5-8 membered heterocyclyl containing at least one B atom in the ring atom, said phenyl or 5-6 membered heteroaryl being substituted with R a Substituted and optionally substituted with one or more R b A substitution, the ring atoms in the phenyl-5-8 membered heterocyclyl or 5-6 membered heteroaryl-5-8 membered heterocyclyl optionally containing one or more heteroatoms selected from N, O, S, the phenyl-5-8 membered heterocyclyl or 5-6 membered heteroaryl-5-8 membered heterocyclyl optionally being substituted with one or more R b And (3) substitution.
In some embodiments, the phenyl-5-8 membered heterocyclyl is phenyl-5-8 membered heterocycloalkyl and the 5-6 membered heteroaryl-5-8 membered heterocyclyl is 5-6 membered heteroaryl-5-8 membered heterocycloalkyl.
In some embodiments, the phenyl-5-8 membered heterocyclyl is phenyl-5-8 membered heterocyclenyl and the 5-6 membered heteroaryl-5-8 membered heterocyclyl is 5-6 membered heteroaryl-5-8 membered heterocyclenyl.
In some embodiments, the phenyl-5-8 membered heterocyclyl or 5-6 membered heteroaryl-5-8 membered heterocyclyl, the 5-8 membered heterocyclyl moiety has and has only one double bond.
In some embodiments, ring A is selected from phenyl, pyridinyl, a phenyl 5-6 membered heterocyclyl containing at least one B atom in the ring atoms, or a pyridinyl 5-6 membered heterocyclyl containing at least one B atom in the ring atoms, said phenyl or pyridinyl being substituted with R a Substituted and optionally substituted with one or more R b Substituted, the ring atoms in the phenyl-5-6 membered heterocyclyl or the pyridinyl-5-6 membered heterocyclyl optionally contain one or more heteroatoms selected from N, O, S, the phenyl-5-6 membered heterocyclyl or the pyridinyl-5-6 membered heterocyclyl optionally being substituted with one or more R b And (3) substitution.
In some embodiments, the phenyl-5-6 membered heterocyclyl or pyridyl-5-6 membered heterocyclyl ring atom contains one B atom and one or more heteroatoms selected from N, O, S.
In some embodiments, the phenyl-5-6 membered heterocyclyl or pyridyl-5-6 membered heterocyclyl ring atom contains one B atom and one or more O atoms.
In some embodiments, the phenyl-5-6 membered heterocyclyl or pyridyl-5-6 membered heterocyclyl ring atom contains one B atom and one O atom.
In some embodiments, the phenyl-5-6 membered heterocyclyl or pyridyl-5-6 membered heterocyclyl has one and only one B atom and one O atom in the ring atoms.
In some embodiments, the phenyl-5-6 membered heterocyclyl is phenyl-5-6 membered heterocycloalkyl and the pyridinyl-5-6 membered heterocyclyl is pyridinyl-5-6 membered heterocycloalkyl.
In some embodiments, the phenyl-5-6 membered heterocycloalkyl is selected fromIn some embodiments, the pyrido 5-6 membered heterocycloalkyl is selected from
In some embodiments, the phenyl-5-6 membered heterocyclyl is phenyl-5-6 membered heterocyclenyl and the pyridinyl-5-6 membered heterocyclyl is pyridinyl-5-6 membered heterocyclenyl.
In some embodiments, the phenyl-5-6 membered heterocycloalkenyl is selected fromIn some embodiments, the pyrido 5-6 membered heterocycloalkenyl is selected from +.>
In some embodiments, the phenyl-5-6 membered heterocyclyl or pyridyl-5-6 membered heterocyclyl has one and only one double bond.
In some embodiments, ring A is selected from phenyl, 5-6 membered heteroaryl, phenyl-5-6 membered heterocycloalkyl, or pyridinyl-5-6 membered heterocycloalkyl, said phenyl or 5-6 membered heteroaryl being substituted with R a Substituted and optionally substituted with one or more R b Substituted, one and only one B atom and one O atom of the ring atoms of the phenyl-5-6 membered heterocycloalkyl or pyridinyl-5-6 membered heterocycloalkyl, optionally substituted with one or more R b And (3) substitution.
In some embodiments, ring A is selected from phenyl, pyridyl,The phenyl or pyridyl group being substituted by R a Substituted and optionally substituted with one or more R b Substitution, said->Optionally by one or more R b And (3) substitution.
In some embodiments, ring A is selected from phenyl, Said phenyl orQuilt R a Substituted and optionally substituted with one or more R b Substitution, said-> Optionally by one or more R b And (3) substitution.
In some embodiments, p is selected from 0, 1, or 2.
In some embodiments, p is selected from 0 or 1.
In some embodiments, R a Selected from-BR c R d 、-OBR c R d 、-CH 2 -BR c R d 、-OCH 2 -BR c R d Or a 5-12 membered heterocyclic group containing at least one B atom in the ring atoms, the ring atoms in the 5-12 membered heterocyclic group optionally containing one or more heteroatoms selected from N, O, S, the 5-12 membered heterocyclic group optionally being substituted with one or more R e And (3) substitution.
In some embodiments, R a Selected from-BR c R d 、-OBR c R d 、-CH 2 -BR c R d 、-OCH 2 -BR c R d Or a 5-12 membered heterocyclic group containing at least one B atom in the ring atoms, the ring atoms in the 5-12 membered heterocyclic group optionally containing one or more O atoms, the 5-12 membered heterocyclic group optionally being substituted with one or more R e And (3) substitution.
In some embodiments, R a Selected from-BR c R d 、-OBR c R d Or a 5-10 membered heterocyclic group containing at least one B atom in the ring atoms, the ring atoms in the 5-10 membered heterocyclic group optionally containing one or more heteroatoms selected from N, O, S, the 5-10 membered heterocyclic group optionally being substituted with one or more R e And (3) substitution.
In some embodiments, R a Selected from-BR c R d Or a 5-6 membered heterocyclic group containing at least one B atom in the ring atoms, the ring atoms in the 5-6 membered heterocyclic group containing one or two O atoms, the 5-6 membered heterocyclic group optionally being substituted with one or more R e And (3) substitution.
In some embodiments, the 5-12 membered heterocyclyl is a 5-10 membered heterocyclyl. In some embodiments, the 5-12 membered heterocyclyl is a 5-8 membered heterocyclyl. In some embodiments, the 5-12 membered heterocyclyl is a 5-6 membered heterocyclyl.
In some embodiments, the 5-12 membered heterocyclyl ring atom has and only has one B atom. In some embodiments, the 5-10 membered heterocyclyl ring atoms have and only one B atom. In some embodiments, the 5-8 membered heterocyclyl ring atoms have and only one B atom. In some embodiments, the 5-6 membered heterocyclyl ring atoms have and only one B atom.
In some embodiments, the ring atoms in the 5-12 membered heterocyclyl contain one or two O atoms. In some embodiments, the ring atoms in the 5-10 membered heterocyclyl contain one or two O atoms. In some embodiments, the ring atoms in the 5-8 membered heterocyclyl contain one or two O atoms. In some embodiments, the ring atoms in the 5-6 membered heterocyclyl contain one or two O atoms.
In some embodiments, the 5-12 membered heterocyclyl is a 5-12 membered heterocycloalkyl. In some embodiments, the 5-10 membered heterocyclyl is a 5-10 membered heterocycloalkyl. In some embodiments, the 5-8 membered heterocyclyl is a 5-8 membered heterocycloalkyl. In some embodiments, the 5-6 membered heterocyclyl is a 5-6 membered heterocycloalkyl.
In some embodiments, R a Selected from-BR c R d Or a 5-or 6-membered heterocycloalkyl group, the ring atoms in the 5-or 6-membered heterocycloalkyl group having one and only one B atom, and having one and only one or two O atoms, the 5-or 6-membered heterocycloalkyl group optionally being substituted with one or more R e And (3) substitution.
In some embodiments, R a Selected from-BR c R d 、Said->Optionally by one or more R e And (3) substitution.
In some embodiments, R c And R is d Each independently selected from-OH, C 1-4 Alkoxy or amino C 1-4 An alkyl group.
In some embodiments, R c And R is d Each independently selected from-OH, C 1-2 Alkoxy or amino C 1-2 An alkyl group.
In some embodiments, R c And R is d Each independently selected from-OH or C 1-2 An alkoxy group.
In some embodiments, R c And R is d Each independently is-OH.
In some embodiments, R e Independently selected from oxo, F, cl, br, -CN, -OH, -NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, -C (O) OH, -C (O) NH 2 、-C(O)NH(C 1-4 Alkyl) or-C (O) N (C) 1-4 Alkyl group 2 。
In some embodiments, R e Independently selected from oxo, F, cl, br, -CN, -OH, -NH 2 、-NHCH 3 、-N(CH 3 ) 2 、C 1-3 Alkyl, C 1-3 Alkoxy, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, hydroxy C 1-3 Alkyl, amino C 1-3 Alkyl, -C (O) OH, -C (O) NH 2 、-C(O)NHCH 3 or-C (O) N (CH) 3 ) 2 。
In some embodiments, R e Independently selected from oxo, F, cl, br, -OH, -NH 2 Methyl, methoxy, halomethyl, halomethoxy, hydroxymethyl or aminomethyl.
In some embodiments, R e Independently selected from F, cl, -OH, -NH 2 Methyl or fluoromethyl.
In some embodiments, R e Independently selected from F, cl, -OH or methyl.
In some embodiments, R e Independently selected from-OH or methyl.
In some embodiments, R a Selected from-B (OH) 2 、
In some embodiments, R b Independently selected from F, cl, br, -CN, -OH, -NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, -C (O) OH, -C (O) NH 2 、-C(O)NH(C 1-4 Alkyl), -C (O) N (C) 1-4 Alkyl group 2 、-NHC(O)C 1-3 Alkyl, -S (O) 2 C 1-3 Alkyl, -S (O) 2 NH 2 、-S(O) 2 NH(C 1-4 Alkyl) or-S (O) 2 N(C 1-4 Alkyl group 2 。
In some embodiments, R b Independently selected from F, cl, br, -CN, -OH, -NH 2 、-NHCH 3 、-N(CH 3 ) 2 、C 1-3 Alkyl, C 1-3 Alkoxy, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, hydroxy C 1-3 Alkyl, amino C 1-3 Alkyl, -C (O) OH, -C (O) NH 2 、-C(O)NHCH 3 、-C(O)N(CH 3 ) 2 or-NHC (O) CH 3 。
In some embodiments, R b Independently selected from F, cl, br, -CN, -OH, -NH 2 Methyl, methoxy, halomethyl, halomethoxy, hydroxymethyl or aminomethyl.
In some embodiments, R b Independently selected from F, cl, br, -CN, -OH, methyl or fluoromethyl.
In some embodiments, R b Independently selected from F, cl, -CN, -OH or methyl.
In some embodiments, ring a is selected from
In one placeIn some embodiments, ring A is selected from
In some embodiments, each R 1 Each independently selected from F, cl, br, -CN, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-5 cycloalkyl-O-, said C 1-4 Alkyl, C 1-4 Alkoxy or C 3-5 cycloalkyl-O-optionally substituted with one or more groups selected from: -OH, -NH 2 F, cl or Br.
In some embodiments, each R 1 Each independently selected from C 1-3 Alkyl, C 1-3 Alkoxy or C 3-4 cycloalkyl-O-, said C 1-3 Alkyl, C 1-3 Alkoxy or C 3-4 cycloalkyl-O-optionally substituted with one or more groups selected from: F. cl or Br.
In some embodiments, each R 1 Each independently selected from methoxy or cyclopropyl-O-, optionally substituted with one or more groups selected from: f or Cl.
In some embodiments, each R 1 Each independently selected from methoxy, cyclopropyl-O-or trifluoromethoxy.
In some embodiments, each R 1 Each independently is methoxy.
In some embodiments, m is selected from 0, 1, 2, or 3.
In some embodiments, m is selected from 0, 1, or 2.
In some embodiments, m is selected from 1 or 2.
In some embodiments, m is 1.
In some embodiments, each R 2 Each independently selected from F, cl, br, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-5 Cycloalkyl or 3-5 membered heterocycloalkylThe C is 1-4 Alkyl, C 1-4 Alkoxy, C 3-5 Cycloalkyl or 3-5 membered heterocycloalkyl is optionally substituted with one or more halo.
In some embodiments, each R 2 Each independently selected from F, cl, br, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-5 Cycloalkyl or 3-5 membered heterocycloalkyl.
In some embodiments, each R 2 Each independently selected from F, cl, br, -CN, C 1-3 Alkyl or C 3-4 Cycloalkyl groups.
In some embodiments, each R 2 Each independently selected from F, cl or Br.
In some embodiments, each R 2 Each independently Cl.
In some embodiments, n is selected from 0, 1, 2, or 3.
In some embodiments, n is selected from 0, 1, or 2.
In some embodiments, n is selected from 1 or 2.
In some embodiments, n is 1.
In some embodiments, R 3 Selected from F, cl, br, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl C (O) -or 5 membered heteroaryl, said C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl C (O) -or 5 membered heteroaryl optionally substituted with one or more groups selected from: -OH, -NH 2 F, cl, br or haloC 1-4 An alkyl group.
In some embodiments, R 3 Selected from-CN, C 1-4 Alkyl C (O) -or 5 membered heteroaryl, said C 1-4 Alkyl C (O) -or 5 membered heteroaryl optionally substituted with one or more groups selected from: -OH, -NH 2 F, cl, br or haloC 1-4 An alkyl group.
In some embodiments, R 3 Selected from-CN, C 1-4 Alkyl C (O) -or 5 membered heteroaryl containing 1-4 heteroatoms, said C 1-4 Alkyl C (O) -or 5 membered heteroaryl optionally substituted with one or moreSubstituted with a group selected from: F. cl, br or haloC 1-4 An alkyl group.
In some embodiments, R 3 Selected from-CN, CH 3 C (O) -, triazolyl or tetrazolyl optionally substituted with one or more groups selected from the group consisting of: F. cl, br or fluoro C 1-3 An alkyl group.
In some embodiments, R 3 Selected from-CN, CH 3 C (O) -or triazolyl optionally substituted with one or more groups selected from the group consisting of: F. cl, monofluoromethyl, difluoromethyl or trifluoromethyl.
In some embodiments, R 3 Selected from-CN,Or CH (CH) 3 C(O)-。
In some embodiments, R 3 Selected from-CN,
In some embodiments, L is selected from a bond or-CR f R g -。
In some embodiments, L is-CR f R g -。
In some embodiments, R f And R is g Each independently selected from H or C 1-6 An alkyl group.
In some embodiments, R f And R is g Each independently is H.
In some embodiments, L is-CH 2 -。
In some embodiments, R 4 Selected from C 1-4 Alkyl, C 1-6 Heteroalkyl, phenyl, 6-membered heteroaryl, C 3-5 Cycloalkyl or 5-6 membered heterocycloalkyl, said C 1-4 Alkyl, C 1-6 Heteroalkyl, phenyl, 6-membered heteroaryl, C 3-5 Cycloalkyl or 5-6 membered heterocycloalkyl optionally substituted with one or more R 4a And (3) substitution.
In some embodimentsWherein R is 4 Selected from C 1-3 Alkyl, C 1-4 alkyl-O-CH 2 -, phenyl, 6 membered heteroaryl, C 3-5 Cycloalkyl or 5-6 membered heterocycloalkyl, said C 1-3 Alkyl, C 1-4 alkyl-O-CH 2 -, phenyl, 6 membered heteroaryl, C 3-5 Cycloalkyl or 5-6 membered heterocycloalkyl optionally substituted with one or more R 4a And (3) substitution.
In some embodiments, R 4 Selected from methyl, C 1-2 alkyl-O-CH 2 -, phenyl, pyridyl, cyclopropyl orThe methyl group, C 1-2 alkyl-O-CH 2 -, phenyl, pyridyl, cyclopropyl or +.>Optionally by one or more R 4a And (3) substitution.
In some embodiments, R 4 Selected from methyl, CH 3 -O-CH 2 -, phenyl or pyridyl, said methyl, CH 3 -O-CH 2 -, phenyl or pyridinyl optionally substituted with one or more R 4a And (3) substitution.
In some embodiments, R 4a Independently selected from oxo, F, cl, br, -CN, -OH, -NH 2 、C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl or halo C 1-4 An alkoxy group.
In some embodiments, R 4a Independently selected from oxo, F, cl, br or fluoro C 1-2 An alkyl group.
In some embodiments, R 4a F.
In some embodiments, R 4 Selected from methyl, CH 3 -O-CH 2 -, phenyl group,
In some embodiments, R 5 Selected from hydrogen or C 1-6 An alkyl group.
In some embodiments, R 5 Selected from H or C 1-3 An alkyl group.
In some embodiments, R 5 Selected from H or methyl.
In some embodiments, R 5 H.
In some embodiments, the structural fragmentIs->
In some embodiments, the structural fragmentIs->
In some embodiments, the structural fragmentIs->
In some embodiments, the structural fragmentIs->/>
In some embodiments, the structural fragmentIs->
In some embodiments, the compound of formula (I-0), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula (I-1) or formula (I-2) or formula (I-3) or formula (I-4) or formula (I-5) or formula (I-1 ') or formula (I-2 ') or formula (I-3 ') or formula (I-4 ') or formula (I-5 '), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
wherein R is 1 、R 2 、R 3 、R 4 、R 5 The definition of n or ring A is as described herein.
In some embodiments, the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
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Wherein R is 1 、R 2 、R 3 、R 4 、R 5 The definition of n or ring A is as described herein.
In some embodiments, the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula (III), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
wherein R is 2 、R 4 Or ring a is as defined herein;
R 11 selected from-CN, -OH, -NH 2 Halogen or halogenated C 1-6 An alkyl group.
In some embodiments, R 11 Selected from F, cl, br or trifluoromethyl.
In some embodiments, R 11 Selected from F or Cl.
In some embodiments, the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula (IV), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
wherein R is 2 、R 4 、R a 、R b Or R is 11 Definition is as described herein;
z is selected from N or CH;
q is selected from 0, 1, 2 or 3.
In some embodiments, the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula (V), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
wherein R is 2 、R 4 、R b 、R 11 Or q is defined herein;
ring B is selected from a phenyl-5-6 membered heterocyclyl group containing at least one B atom in the ring atoms or a pyridinyl-5-6 membered heterocyclyl group containing at least one B atom in the ring atoms, said phenyl-5-6 membered heterocyclyl group or the ring atoms in the pyridinyl-5-6 membered heterocyclyl group optionally containing one or more heteroatoms selected from N, O, S.
In some embodiments, the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula (IA) or formula (IB), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
wherein R is 1 、R 2 、R 3 、R 4 、R 5 N or ring a are as defined herein.
In some embodiments, the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula (IIA) or formula (IIB), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
wherein R is 1 、R 2 、R 3 、R 4 、R 5 N or ring a are as defined herein.
In some embodiments, the compound of formula (III), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula (IIIA) or formula (IIIB), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
wherein R is 2 、R 4 Ring A or R 11 The definitions are as described herein.
In some embodiments, the compound of formula (IV), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula (IVA) or formula (IVB), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
wherein R is 2 、R 4 、R a 、R b 、R 11 Z or q are defined herein.
In some embodiments, the compound of formula (V), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from a compound of formula (VA) or formula (VB), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
Wherein R is 2 、R 4 、R b 、R 11 Or q is defined herein;
ring B is selected from a phenyl-5-6 membered heterocyclyl group containing at least one B atom in the ring atoms or a pyridinyl-5-6 membered heterocyclyl group containing at least one B atom in the ring atoms, said phenyl-5-6 membered heterocyclyl group or the ring atoms in the pyridinyl-5-6 membered heterocyclyl group optionally containing one or more heteroatoms selected from N, O, S.
In some embodiments, ring B is selected from a phenyl-5-6 membered heterocycloalkyl or a pyridinyl-5-6 membered heterocycloalkyl, said phenyl-5-6 membered heterocycloalkyl or pyridinyl-5-6 membered heterocycloalkyl having one and only one B atom and one O atom in the ring atoms.
In some embodiments, ring B is selected from
In some embodiments, the C 1-6 Alkyl or C 1-6 Alkoxy or C 1-6 Alkylamino or di-C 1-6 "C" in alkylamino 1-6 "selected from C 1-4 . Similarly, in some embodiments, "C 1-4 "selected from C 1-3 Or C 1-2 . Similarly, in some embodiments, the "C 1-6 "selected from C 1 、C 2 、C 3 、C 4 、C 5 Or C 6 。
In some embodiments, the halogen is selected from F, cl, br, or I. In some embodiments, the halogen is selected from F or Cl.
In some embodiments, the halo refers to substitution with one or more halogens. In some embodiments, the halo means substituted with one or more halogens selected from F, cl, br. In some embodiments, the halo refers to substitution with one or more F.
In some embodiments, the "one or more" is selected from 1, 2, 3, 4, 5, 6, 7, 8, or 9. In some embodiments, the "one or more" is selected from 1, 2, or 3. In some embodiments, the "one or more" is selected from 1 or 2.
In some embodiments, the C 3-6 Cycloalkyl is selected from C 3-5 Cycloalkyl groups. In some embodiments, the C 3-6 The cycloalkyl group is selected from 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl or 6-membered cycloalkyl.
In some embodiments, the 3-6 membered heterocycloalkyl is selected from 3-5 membered heterocycloalkyl or 5-6 membered heterocycloalkyl. In some embodiments, the 3-6 membered heterocycloalkyl is selected from 3-membered heterocycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, or 6-membered heterocycloalkyl. In some embodiments, the 3-6 membered heterocycloalkyl is selected from 5-membered heterocycloalkyl or 6-membered heterocycloalkyl.
In some embodiments, the heteroalkyl contains 1, 2, 3, 4, or 5 heteroatoms selected from N, O or S.
In some embodiments, the heteroalkyl contains 1, 2, or 3 heteroatoms selected from N, O or S.
In some embodiments, the heteroalkyl contains 1 or 2 heteroatoms selected from N or O.
In some embodiments, the heterocycloalkyl contains 1, 2, or 3 heteroatoms selected from N, O or S.
In some embodiments, the heterocycloalkyl contains 1 or 2 heteroatoms selected from N or O.
In some embodiments, the heterocycloalkyl group contains 1 or 2N atoms.
In some embodiments, the heterocycloalkyl group contains 1O atom.
In some embodiments, the heterocycloalkyl group contains 1N atom and 1O atom.
In some embodiments, the heteroaryl contains 1, 2, 3, or 4 heteroatoms selected from N, O or S.
In some embodiments, the heteroaryl contains 1, 2, 3, or 4N atoms.
In some embodiments, the heteroaryl contains 1 or 2N atoms.
In some embodiments, the heteroaryl contains 3 or 4N atoms.
In some embodiments, the 5-12 membered heterocyclyl is selected from 5-membered heterocyclyl, 6-membered heterocyclyl, 7-membered heterocyclyl, 8-membered heterocyclyl, 9-membered heterocyclyl, 10-membered heterocyclyl, 11-membered heterocyclyl, or 12-membered heterocyclyl.
In some embodiments, the 5-12 membered heterocyclyl is a fully saturated or partially unsaturated heterocyclyl. In some embodiments, the 5-12 membered heterocyclyl may be monocyclic, bridged, spiro, or fused polycyclic.
In some embodiments, the C 6-10 Aryl and 5-8 membered heterocyclic groups are selected from C 6-10 Aryl 5-8 membered heterocycloalkyl or C 6-10 Aryl and 5-8 membered heterocycloalkenyl.
In some embodiments, the C 6-10 Aryl and 5-8 membered heterocyclic groups are selected from C 6-10 Aryl and 5-8 membered heterocycloalkenyl, said 5-8 membered heterocycloalkenyl comprising one, two or three double bonds.
In some embodiments, the 5-10 membered heteroaryl and 5-8 membered heterocyclyl is selected from 5-10 membered heteroaryl and 5-8 membered heterocycloalkyl or 5-10 membered heteroaryl and 5-8 membered heterocycloalkenyl.
In some embodiments, the 5-10 membered heteroaryl and 5-8 membered heterocyclyl is selected from 5-10 membered heteroaryl and 5-8 membered heterocyclenyl, the 5-8 membered heterocyclenyl containing one, two or three double bonds.
In some embodiments, the present application includes the variables defined above and embodiments thereof, as well as any combination thereof.
In some embodiments, the present application provides the following compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof:
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in some embodiments, the present application provides the following compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof:
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in another aspect, the present application provides a pharmaceutical composition comprising a compound of the present application, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, optionally further comprising a pharmaceutically acceptable adjuvant.
In another aspect, the present application provides the use of a compound of the present application, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment or prevention of a disease.
In some embodiments, the disease is selected from FXIa coagulation factor related diseases.
In some embodiments, the FXIa coagulation factor related disorder is selected from cardiovascular and cerebrovascular disorders; in particular to thrombotic or thromboembolic disorders, and/or thrombotic or thromboembolic complications.
In some embodiments, the disease is selected from thrombosis or thromboembolic disorders.
In another aspect, the present application provides the use of a compound of the present application, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating or preventing a FXIa coagulation factor related disorder.
In another aspect, the present application provides the use of a compound of the present application, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment or prevention of a FXIa coagulation factor related disease.
In another aspect, the present application provides a compound of the present application, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment or prevention of a FXIa coagulation factor related disease.
In another aspect, the present application provides a method of treating or preventing a FXIa coagulation factor related disorder comprising administering to a mammal, preferably a human, in need of treatment a therapeutically effective amount of a compound of the present application, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
In another aspect, the present application provides the use of a compound of the present application, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating or preventing thrombosis or thromboembolic disorders.
In another aspect, the present application provides the use of a compound of the present application, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the treatment or prevention of a thrombotic or thromboembolic disorder.
In another aspect, the present application provides a compound of the present application, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment or prevention of a thrombotic or thromboembolic disorder.
In another aspect, the present application provides a method of treating or preventing thrombosis or thromboembolic disorders comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of the present application, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
In some embodiments, the FXIa coagulation factor related disorder described above is selected from cardiovascular and cerebrovascular disorders; in particular to thrombotic or thromboembolic disorders, and/or thrombotic or thromboembolic complications.
Technical effects
The compound has better in-vitro FXIa enzyme inhibition activity, can prolong aPTT (activated partial thromboplastin time) and realizes good anticoagulation.
Definition of the definition
The following terms used in this application have the following meanings, unless otherwise indicated. A particular term, unless otherwise defined, shall not be construed as being ambiguous or otherwise unclear, but shall be construed in accordance with the ordinary meaning in the art. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof.
The words "comprise" or "include" and variations thereof such as "comprises" or "comprising" are to be interpreted in an open, non-exclusive sense, i.e. "including but not limited to.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is substituted with a substituent, provided that the valence of the particular atom is normal and the substituted compound is stable.
"substituents" as used herein include the context of the present disclosure Including, for example, the terms "alkyl", "alkoxy", "cycloalkyl", "heteroalkyl", "heterocyclyl", "heterocycloalkyl", "heterocycloalkenyl", "aryl", "heteroaryl", and the like, as defined below, and corresponding non-limiting or exemplary groups, wherein some non-limiting examples of the "substituents" include deuterium, hydroxy, mercapto, halogen, amino, nitro, nitroso, cyano, azido, sulfoxide, sulfone, sulfonamide, carboxyl, carboxyaldehyde, imine, alkyl, halo-alkyl, cycloalkyl, halo-cycloalkyl, alkenyl, halo-alkenyl, cycloalkenyl, halo-cycloalkenyl, alkynyl, halo-alkynyl, cycloalkynyl, halo-cycloalkynyl, heteroalkyl, halo-heteroalkyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, aralkyl, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylalkylthio, heterocyclyl, heterocyclylthio, heterocyclylalkylene, heterocyclylalkoxy, heterocyclylalkylthio, acyl, acyloxy, carbamate, amide, ureido, epoxy, and ester groups, and the like, the groups being optionally substituted with one or more of the following groups: oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxy, -C (O) O-alkyl, -OC (O) -alkyl, -C (O) NH 2 -C (O) NH-alkyl, -C (O) N (alkyl) 2 -NHC (O) -alkyl, -C (O) -alkyl, -S (O) 2 -alkyl, -S (O) 2 NH 2 、-S(O) 2 NH-alkyl, -S (O) 2 N (alkyl) 2 Cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocyclylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.
In some embodiments herein, the substituents are selected fromFrom deuterium atoms, hydroxy groups, mercapto groups, halogen groups, amino groups, nitro groups, nitroso groups, cyano groups, azide groups, sulfoxide groups, sulfone groups, sulfonamide groups, carboxyl groups, aldehyde groups, imine groups, C 1-12 Alkyl, halo-C 1-12 Alkyl, 3-12 membered cycloalkyl, halo-3-12 membered cycloalkyl, C 2-12 Alkenyl, halo-C 2-12 Alkenyl, 3-12 membered cycloalkenyl, halo-3-12 membered cycloalkenyl, C 2-12 Alkynyl, halo-C 2-12 Alkynyl, 8-12 membered cycloalkynyl, halo-8-12 membered cycloalkynyl, C 1-12 Heteroalkyl, halo-C 1-12 Heteroalkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, 6-10 membered aryl, 6-10 membered aryloxy, 6-10 membered arylthio, 6-10 membered arylC 1-12 Alkylene, 6-10 membered aryl C 1-12 Alkoxy, 6-10 membered aryl C 1-12 Alkylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, 5-10 membered heteroarylalkylene, 5-10 membered heteroarylalkoxy, 5-10 membered heteroarylalkylthio, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, 3-12 membered heterocyclylthio, 3-12 membered heterocyclyl C 1-12 Alkylene, 3-12 membered heterocyclyl C 1-12 Alkoxy, 3-12 membered heterocyclyl C 1-12 Alkylthio, C 1-12 Acyl, C 1-12 Acyloxy, carbamate group, C 1-12 Amide groups, urea groups, epoxy groups, C 2-12 Ester groups, oxo and thioxo, and the like, said substituents optionally being substituted with one or more substituents selected from the group consisting of: deuterium atom, oxo, hydroxy, amino, nitro, halogen, cyano, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, halo C 1-12 Alkoxy, C 1-12 Alkylamino, di C 1-12 Alkylamino, halo C 1-12 Alkylamino, halo di-C 1-12 Alkylamino, carboxy, -C (O) O-C 1-12 Alkyl, -OC (O) -C 1-12 Alkyl, -C (O) NH 2 、-C(O)NH-C 1-12 Alkyl, -C (O) N (C) 1-12 Alkyl group 2 、-NHC(O)-C 1-12 Alkyl, -C (O) -C 1-12 Alkyl, -S (O) -C 1-12 Alkyl, -S (O) 2 -C 1-12 Alkyl, -S ]O) 2 NH 2 、-S(O) 2 NH-C 1-12 Alkyl, -S (O) 2 N(C 1-12 Alkyl group 2 3-12 membered cycloalkyl, 3-12 membered cycloalkyl C 1-12 Alkylene, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyl C 1-12 Alkylene, 3-12 membered heterocyclyloxy, 3-12 membered heterocycloalkyl C 1-12 Alkylene, 3-12 membered heterocycloalkyloxy, 5-10 membered heteroaryl, 5-10 membered heteroarylC 1-12 alkylene, 5-10 membered heteroaryloxy, 6-10 membered aryl, 6-10 membered arylC 1-12 Alkylene or 6-10 membered aryloxy.
The term "oxo" (i.e., =o) "means that the oxygen atom is attached to the atom being substituted by a double bond. In a non-limiting example, oxo may occur on a C atom, for example, to form-CO-; oxo may also occur on the S atom, e.g. to form-SO-or-SO 2 -。
The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, ethyl "optionally" substituted with halogen means that ethyl may be unsubstituted (CH 2 CH 3 ) Monosubstituted (e.g. CH 2 CH 2 F) Polysubstituted (e.g. CHFCH 2 F、CH 2 CHF 2 Etc.) or fully substituted (CF) 2 CF 3 ). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, no substitution or pattern of substitution is introduced that is sterically impossible and/or synthetic.
"one or more" herein refers to integers from one to ten or less. For example, "one or more" means one, two, three, four, five, six, seven, eight, nine, or ten; alternatively, "one or more" means one, two, three, four, five, or six; alternatively, "one or more" means one, two, or three.
C herein m-n It is that the moiety has an integer number of carbon atoms in the given range. For example "C 1-6 "means that the groupMay have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. For example C 1-3 Meaning that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms.
When any variable (e.g., R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. For example, if one group is substituted with 2R's, then each R has an independent option. Or for example, a plurality of groups are substituted with a certain R, each of which is independent of the other.
When the number of one linking group is 0, such as- (CH) 2 ) 0 -it is meant that the linking group is a covalent bond.
When one of the variables is selected from a covalent bond, the two groups representing its attachment are directly linked, e.g., when L 'in A-L' -Z represents a covalent bond, it is meant that the structure is actually A-Z.
When the bond of a substituent is cross-linked to two atoms on a ring, the substituent may be bonded to any atom on the ring. For example, structural units Meaning that it may be substituted at any one position on the cyclohexyl or cyclohexadiene.
The term "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine.
The term "alkyl" refers to a compound of the formula C n H 2n+1 Is a hydrocarbon group of (a). The alkyl group may be linear or branched. For example, the term "C 1-6 Alkyl "refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio have the same definition as above. Also for example, the term "C 1-3 Alkyl "means a radical containing 1 to 3 carbon atomsAlkyl groups (e.g., methyl, ethyl, propyl, and isopropyl).
The term "alkoxy" refers to an-O-alkyl group.
The term "cycloalkyl" refers to a carbocycle that is fully saturated and may exist as a single ring, bridged ring, or spiro ring. Unless otherwise indicated, the carbocycle is typically a 3 to 10 membered ring (e.g., a 5 to 8 membered ring; specifically such as a 4-, 5-, 6-, 7-, 8-, or 9-membered ring). Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo [ 2.2.1) ]Heptyl), bicyclo [2.2.2]Octyl, adamantyl, bicyclo [1.1.1 ]]Pent-1-yl, and the like. For example, C 3-4 Cycloalkyl includes cyclopropyl and cyclobutyl.
The term "heteroalkyl" refers to an alkyl structure containing a heteroatom. Unless otherwise indicated, the heteroalkyl group is typically an alkyl group containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, and/or nitrogen. Typically, where more than one heteroatom is present, the heteroatoms are not adjacent to each other. Exemplary heteroalkyl groups include alkoxy, alkoxyalkyl, alkylamino, alkylaminoalkyl, dialkylamino, dialkylaminoalkyl, and the like.
The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and may exist as a single ring, bridged ring, or spiro ring. Unless otherwise indicated, the heterocycle is typically a 3-to 10-membered ring (e.g., a 5-to 10-membered, 6-to 9-membered, 6-to 8-membered, or 6-to 7-membered ring) containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, and/or nitrogen. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, ethylene oxide, ethylene nitride, non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyrazolyl, examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1, 4-thiaalkyl, 1, 4-dioxanyl, thiomorpholinyl, 1, 3-dithianyl, 1, 4-dithianyl, examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxepinyl, thiepanyl.
The term "heterocycloalkenyl" refers to a non-aromatic ring that is partially unsaturated (but not fully unsaturated) and may exist as a single ring, bridged ring, and ring or spiro ring. Unless otherwise indicated, the heterocycle is typically a 3 to 12 membered, 3 to 10 membered, 4 to 8 membered, 5 to 6 membered, 3 to 7 membered, or 4 to 6 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon and/or boron. Non-limiting examples of heterocyclyl groups include, but are not limited to, dihydrofuryl, dihydropyrrole, dihydrothienyl, dihydropyranyl, dihydropyridyl, tetrahydropyridyl, and the like. The heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of: oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxy, -C (O) O-alkyl, -OC (O) -alkyl, -C (O) NH 2 -C (O) NH-alkyl, -C (O) N (alkyl) 2 -NHC (O) -alkyl, -C (O) -alkyl, -S (O) 2 -alkyl, -S (O) 2 NH 2 、-S(O) 2 NH-alkyl, -S (O) 2 N (alkyl) 2 Cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocyclylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.
The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S, the remaining ring atoms being C and having at least one aromatic ring. Preferred heteroaryl groups have a single 3 to 8 membered ring, especially a 5 to 8 membered ring, or multiple fused rings containing 6 to 14, especially 6 to 10 ring atoms. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, and the like.
The term "heterocyclyl" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaryl) and may exist as a single ring, bridged ring, spiro ring, or fused polycyclic ring. Unless otherwise indicated, the heterocycle is typically a 3 to 12 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from boron, sulfur, oxygen, nitrogen and/or phosphorus. Non-limiting examples of heterocyclyl groups include, but are not limited to, oxiranyl, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, borolane, borole, 1, 2-oxyborolane, 1,3, 2-dioxaborolane, and the like.
The compounds and intermediates of the present application may also exist in different tautomeric forms, and all such forms are included within the scope of the present application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include tautomers via proton transfer, such as keto-enol and imine-enamine isomerisation. A specific example of a proton tautomer is an imidazole moiety, where a proton can migrate between two ring nitrogens. Valence tautomers include tautomers by recombination of some bond-forming electrons.
For the purposes of this application, "thrombotic or thromboembolic disorders" include disorders that occur in the arterial and venous vascular systems and that can be treated with the compounds of the present invention.
Certain compounds of the present application may have asymmetric carbon atoms (stereocenters) or double bonds. Thus, racemates, diastereomers, enantiomers, geometric isomers and individual isomers are all included within the scope of the present application.
When the compounds of the present application contain olefinic double bonds or other centers of geometric asymmetry, they include E and Z geometric isomers unless specified otherwise.
The compounds of the present application may exist in particular geometric or stereoisomeric forms. The present application contemplates all such compounds, including tautomers, cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present application. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of the present application.
Optically active (R) -and (S) -isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present application is desired, it may be prepared by asymmetric synthesis or derivatization with chiral auxiliary wherein the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereomeric resolution is carried out by conventional methods well known in the art, and then the pure enantiomer is recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amine).
The present application also includes isotopically-labeled compounds identical to those recited herein, but for the replacement of one or more atoms by an atom having an atomic weight or mass number different from the atomic weight or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as, respectively 2 H、 3 H、 11 C、 13 C、 14 C、 13 N、 15 N、 15 O、 17 O、 18 O、 31 P、 32 P、 35 S、 18 F、 123 I、 125 I and 36 cl, and the like.
Certain isotopically-labeled compounds of the present application (e.g., with 3 H is H 14 C-labeled) can be used in compound and/or substrate tissue distribution analysis. Tritiation (i.e 3 H) And carbon-14 (i.e 14 C) Isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes, such as 15 O、 13 N、 11 C and C 18 F can be used in Positron Emission Tomography (PET) studies to determine substrate occupancy. Isotopically-labeled compounds of the present application can generally be prepared by following procedures analogous to those disclosed in the schemes and/or examples below by substituting an isotopically-labeled reagent for an non-isotopically-labeled reagent.
In addition, the use of heavier isotopes (such as deuterium (i.e. 2 H) Substitution may provide certain therapeutic advantages resulting from higher metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), and thus may be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is substituted with at least one deuterium, all such forms of the compounds are included within the scope of the present application.
The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As pharmaceutically acceptable salts, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like can be mentioned.
The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or salts thereof and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.
The term "pharmaceutically acceptable excipients" refers to those excipients which do not significantly stimulate the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to the person skilled in the art, such as carbohydrates, waxes, water soluble and/or water swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
The pharmaceutical compositions of the present application may be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols, and the like.
Typical routes of administration of the compounds of the present application or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
The term "treatment" means administration of a compound or formulation described herein to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
(i) Inhibiting a disease or disease state, i.e., inhibiting its progression;
(ii) The disease or condition is alleviated, even if the disease or condition subsides.
The term "preventing" means that the compounds or formulations described herein are administered to prevent one or more symptoms associated with the disease, and includes preventing the occurrence of the disease or disease state in a mammal, particularly when such a mammal is susceptible to the disease state, but has not yet been diagnosed as having the disease state.
The term "therapeutically effective amount" means an amount of a compound of the present application that (i) treats or prevents a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound of the present application that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one of ordinary skill in the art based on his own knowledge and disclosure.
In the present invention, the term "individual" includes humans and animals, for example, mammals (e.g., primates, cows, horses, pigs, dogs, cats, mice, rats, rabbits, goats, sheep, birds, etc.).
Therapeutic doses of the compounds of the present application may be determined, for example, according to the following: the specific use of the treatment, the manner in which the compound is administered, the health and condition of the patient, and the discretion of the prescribing physician. The proportion or concentration of the compounds of the present application in the pharmaceutical composition may be variable, depending on a variety of factors, including the dosage, chemical characteristics (e.g., hydrophobicity), and route of administration. The compounds of the present application may be provided, for example, by a physiologically buffered aqueous solution containing about 0.1 to 10% w/v of the compound for parenteral administration. In certain embodiments, the dosage ranges from about 0.001mg/kg to about 1000mg/kg body weight/day. Dosages will likely depend on such variables as the type and extent of progression of the disease or disorder, the general health of the particular patient, the relative biological efficacy of the compound selected, the excipient formulation and its route of administration. The effective dose can be obtained by extrapolation of the dose-response curve derived from in vitro or animal model test systems.
The compounds of the present application may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present application.
The chemical reactions of the embodiments of the present application are accomplished in a suitable solvent that is suitable for the chemical changes of the present application and the reagents and materials needed. In order to obtain the compounds of the present application, modifications or choices of synthesis steps or reaction schemes based on the existing embodiments are sometimes required by those skilled in the art.
An important consideration in the art of synthetic route planning is the selection of suitable protecting groups for reactive functionalities (e.g., amino groups as herein), for example, reference may be made to Greene's Protective Groups in Organic Synthesis (4 th Ed.) Hoboken, new Jersey: john Wiley & Sons, inc. all references cited herein are incorporated herein in their entirety.
In some embodiments, compounds of formula (I-0) and compounds of formula (I) herein may be prepared by one skilled in the art of organic synthesis by schemes 1 and 2, respectively, wherein R' represents a hydroxy protecting group, such as methyl, ethyl, t-butyl, t-butyldimethyl, benzyl, p-methoxybenzyl, benzhydryl:
Taking scheme 2 as an example, under suitable conditions, compound a is demethylated to give compound b, N-alkylated to give intermediate c, hydrolyzed to give carboxylic acid compound d, and finally condensed to give compound of formula (I).
Each of the products obtained by the reactions in the above schemes may be obtained by conventional separation techniques including, but not limited to, filtration, distillation, crystallization, chromatographic separation, and the like. The starting materials may be synthesized by themselves or purchased from commercial institutions (e.g., without limitation, adrich or Sigma). These materials can be characterized using conventional means such as physical constants and spectral data. The compounds described herein may be synthesized using synthetic methods to give single isomers or mixtures of isomers.
The application uses the following abbreviations:
PE is petroleum ether; pdCl 2 (dppf) is [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride; EA is ethyl acetate; DME is ethylene glycol dimethyl ether; DMF is N, N-dimethylformamide; meOH as the first partAn alcohol; HATU is urea N, N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluorophosphate; DCM is dichloromethane; DIPEA is N, N-diisopropylethylamine; TMS is trimethylsilyl; NCS is N-chlorosuccinimide; X-Phos Pd G2 is chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ]Palladium (II); EDCI is 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride; DMAP is 4-dimethylaminopyridine; THF is tetrahydrofuran; NBS is N-bromosuccinimide; DIEA is N, N-diisopropylethylamine; t (T) 3 P is 1-propyl phosphoric anhydride; liHMDS is lithium bistrimethylsilylamino; boc 2 O is di-tert-butyl dicarbonate; boc is t-butoxycarbonyl; X-Phos is 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl; HRMS is high resolution mass spectrometry; DMSO is dimethyl sulfoxide.
Detailed Description
The invention is further illustrated by examples, which are not intended to limit the scope of the present application, for clarity. All reagents used in this application are commercially available and can be used without further purification.
PREPARATION EXAMPLE A-7
Step A:
a mixed solution of t-butyl nitrite (8.52 g) and azido trimethylsilane (8.49 g) was slowly dropped into an acetonitrile solution (200 mL) of A-1 (10 g) at 0℃and stirred at room temperature for 4 hours after the completion of the dropping. After the completion of the reaction, 200mL of water was poured into the reaction mixture, and the reaction was quenched. Ethyl acetate (150 mL. Times.3), saturated sodium chloride (150 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to dryness, and the crude product obtained was subjected to silica gel column chromatography (eluent: PE) to give A-2 (7.56 g). 1 H NMR(500MHz,DMSO-d 6 )δ7.78(d,J＝2.4Hz,1H),7.53(dd,J＝8.6,2.4Hz,1H),7.44(d,J＝8.6Hz,1H).
And (B) step (B):
to a 250mL single-necked flask, A-2 (4 g), (2, 5-dimethoxypyridin-4-yl) boric acid (4.72 g) and tripotassium phosphate were sequentially added(9.13 g), 1, 4-dioxane (120 mL), water (30 mL), and PdCl 2 (dppf)(1.26g)，N 2 Under the protection, the reaction solution is heated to 100 ℃ and reacts for 6 hours. After completion of the reaction, ethyl acetate (100 mL) and water (200 mL) were added to the reaction solution. The organic phase was separated, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to dryness, and the crude product obtained was subjected to silica gel column chromatography (eluent: PE/ea=50/1) to give a-3 (2.9 g). MS (ESI+ [ M+H)] + )m/z：290.96. 1 H NMR(500MHz,DMSO-d 6 )δ7.96(s,1H),7.54(dd,J＝8.6,2.5Hz,1H),7.42(d,J＝8.7Hz,1H),7.36(d,J＝2.5Hz,1H),6.71(s,1H),3.83(s,3H),3.76(s,3H).
Step C:
to a 250mL single-port flask, tetrabutylammonium iodide (0.74 g), cuprous iodide (0.38 g), DME (90 mL) and aqueous solution of A-3 (2.90 g), lithium hydroxide monohydrate (0.50 g) and ethyl 4, 4-trifluoro-2-butynoate (2.49 g), N were added in this order, followed by stirring at room temperature for 30min 2 The mixture was heated to 90 ℃ with protection and reacted for 12h. After completion of the reaction, celite was filtered, and ethyl acetate (200 mL) and water (500 mL) were added to the filtrate. The organic phase was separated, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and the crude product obtained was subjected to silica gel column chromatography (eluent: PE/EA=30/1) to give A-4 (2.63 g). MS (ESI+ [ M+H) ] + )m/z：385.08. 1 H NMR(500MHz,DMSO-d 6 ) δ9.14 (s, 1H), 7.82-7.81 (m, 2H), 7.73 (D, j=2.6 hz, 2H), 6.85 (s, 1H), 3.81 (s, 3H), 3.38 (s, 3H) ·step D:
to a 250mL single-necked flask, A-4 (2.63 g), lithium chloride (1.45 g), p-toluenesulfonic acid monohydrate (2.34 g) and isopropyl alcohol (90 mL) were sequentially added N 2 Under the protection, the reaction solution is heated to 100 ℃ for reaction for 24 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, the solvent was dried under reduced pressure, 100mL of water was added to slurry, the mixture was filtered, the cake was again washed with 200mL of water, and the cake was collected and dried under vacuum at 40℃to give A-5 (2.02 g). MS (ESI+ [ M+H)] + )m/z：371.12.
Step E:
a-5 (2.50 g) and DMF (30 mL) were added sequentially to a 25mL single-necked flask, cooled to 0℃in an ice bath, sodium hydride (0.54 g) was added, and stirred in an ice bath for 20min. Under ice bathLithium bromide (1.17 g) was added thereto, stirred at room temperature for 15 minutes, ethyl 2-bromobutyrate (1.97 g) was added thereto at room temperature, and stirred at room temperature overnight. After the completion of the reaction, the reaction was quenched with saturated ammonium chloride solution (30 mL), extracted with ethyl acetate (60 ml×2), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and the crude product obtained was subjected to silica gel column chromatography (eluent: PE/ea=1/1) to give a-6 (1.80 g). MS (ESI+ [ M+H)] + )m/z：485.09.
Step F:
a25 mL single-necked flask was charged with A-6 (1.8 g), meOH (30 mL) and a solution of lithium hydroxide monohydrate (0.31 g) in water (6 mL) in this order, and the reaction was stirred at room temperature for 2 hours after the addition. After the completion of the reaction, the solvent was dried under reduced pressure, 20mL of water was added, the pH of the system was adjusted to 3 to 4 with 4mL of 2N HCl, extraction was performed with ethyl acetate (30 mL. Times.3), washing was performed with saturated brine (30 mL), drying was performed with anhydrous sodium sulfate, filtration was performed, and the filtrate was concentrated to give A-7 (70 mg). MS (ESI+ [ M+H) ] + )m/z：457.06.
Example 1
Step A:
in a 25mL single-necked flask, intermediate A-7 (120 mg), HATU (200 mg) and DCM (6 mL) were added, followed by DIPEA (67.9 mg), and after stirring well, 1-1 (47 mg) was added and stirred at room temperature for 10h. After the reaction, the reaction was stopped, most of the solvent was removed by spinning, and 30mL of water was added. Extraction with ethyl acetate (15 mL x 3), combined organic phases, washing with 30mL saturated brine, drying over anhydrous sodium sulfate, concentrating under reduced pressure, purifying the crude product by silica gel column chromatography (eluent DCM/meoh=50/1) to give compound 1 (148 mg). MS (ESI+ [ M+H)] + )m/z：588.09.
And (B) step (B):
compound 1 (148 mg) was resolved by preparative HPLC (resolution conditions: column CHIRALART Amylose-SA 4.6X100mm,5 μm; mobile phase: ethanol: CO2=20:80; flow rate: 2mL/min; wavelength: 254 nm), compound 1_A (69 mg, retention time 3.206 min), compound 1_B (69 mg, retention time 4.210 min).
Chemical combinationArticle 1_a: 1 H NMR(500MHz,DMSO-d 6 )δ10.45(s,1H),9.21(s,1H),9.15(s,1H),8.01(d,J＝1.6Hz,1H),7.87–7.80(m,2H),7.78(d,J＝2.0Hz,1H),7.63(dd,J＝8.3,2.0Hz,1H),7.35(d,J＝8.3Hz,1H),7.18(s,1H),6.53(s,1H),5.59(dd,J＝9.7,5.8Hz,1H),4.94(s,2H),3.26(s,3H),2.17–1.97(m,2H),0.79(t,J＝7.1Hz,3H)。HRMS(ESI+,[M+H] + )m/z：588.1433.
compound 1_B: 1 H NMR(500MHz,DMSO-d 6 )δ10.45(s,1H),9.21(s,1H),9.15(s,1H),8.01(d,J＝1.5Hz,1H),7.84(dd,J＝8.3,5.3Hz,2H),7.78(d,J＝2.0Hz,1H),7.63(dd,J＝8.3,1.9Hz,1H),7.35(d,J＝8.3Hz,1H),7.18(s,1H),6.53(s,1H),5.58(d,J＝5.6Hz,1H),4.94(s,2H),3.26(s,3H),2.15–1.98(m,2H),0.79(t,J＝7.0Hz,3H)。HRMS(ESI+,[M+H] + )m/z：588.1435.
example 2
Step A:
reference example 1 step A, substituting intermediate 2-1 for 1-1, gave compound 2 (152 mg). MS (ESI+ [ M+H)] + ) m/z:602.13. and (B) step (B):
compound 2 (152 mg) was resolved by preparative HPLC (resolution: column: CHIRALPAK IG 4.6.6X250 mm,5 μm; mobile phase: n-hexane: ethanol=80:20; 254nm; flow: 1mL/min; wavelength: 254 nm), compound 2_A (69 mg, retention time 9.295 min), compound 2_B (69 mg, retention time 12.937 min).
Compound 2_A: 1 H NMR(500MHz,DMSO-d 6 )δ10.34(s,1H),9.14(s,1H),8.41(s,1H),7.88–7.80(m,3H),7.78(d,J＝2.0Hz,1H),7.61(dd,J＝8.2,2.1Hz,1H),7.15(d,J＝8.3Hz,2H),6.52(s,1H),5.55(s,1H),4.05(t,J＝5.9Hz,2H),3.26(s,3H),2.81(t,J＝5.8Hz,2H),2.12–2.00(m,2H),0.78(t,J＝7.1Hz,3H)。HRMS(ESI+,[M+H] + )m/z：602.1595.
compound 2_B: 1 H NMR(500MHz,DMSO-d 6 )δ10.34(s,1H),9.14(s,1H),8.40(d,J＝13.3Hz,1H),7.87–7.80(m,3H),7.78(d,J＝1.9Hz,1H),7.61(dd,J＝8.2,2.0Hz,1H),7.15(d,J＝8.3Hz,2H),6.52(s,1H),5.55(s,1H),4.05(t,J＝5.8Hz,2H),3.26(s,3H),2.81(t,J＝5.8Hz,2H),2.12–1.97(m,2H),0.78(t,J＝7.1Hz,3H)。HRMS(ESI+,[M+H] + )m/z：602.1591.
PREPARATION EXAMPLE B-2
Step A:
a-5 (100 mg) and DMF (5 mL) were added sequentially to a 25mL single-necked flask, the temperature was lowered to 0℃in an ice bath, sodium hydride (13.49 mg) was added, and the mixture was stirred in an ice bath for 20min. Lithium bromide (46.90 mg) was added to an ice bath, stirred at room temperature for 15min, added to a solution of methyl 2-bromo-3-phenylpropionate (82 mg) in DMF (1 mL), and stirred at room temperature overnight. After the completion of the reaction, the reaction was quenched with saturated ammonium chloride solution (10 mL), extracted with ethyl acetate (40 ml×2), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (eluent: PE/ea=1/1) to give B-1 (100 mg). MS (ESI+ [ M+H)] + )m/z：533.17.
And (B) step (B):
to a 25mL single flask were added in this order B-1 (100 mg), meOH (5 mL), sodium hydroxide (29.30 mg) and water (2 mL), and the reaction was stirred at room temperature for 2h after the addition. After completion of the reaction, 20mL of water was added, the pH of the system was adjusted to 3 to 4 with 0.4mL of 2N HCl, extracted with ethyl acetate (20 mL. Times.3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give B-2 (70 mg). MS (ESI+ [ M+H)] + )m/z：519.15. 1 H NMR(500MHz,DMSO-d6)δ13.04(s,1H),9.19(s,1H),7.79(s,2H),7.69(s,1H),7.24(t,J＝7.5Hz,2H),7.16(t,J＝7.4Hz,1H),7.00(d,J＝7.3Hz,2H),6.83(s,1H),6.41(s,1H),5.21(s,1H),3.36-3.35(m,2H),3.06(s,3H).
Example 3
Step A:
50mto the L single flask were added in this order B-2 (0.12 g), 1-1 (0.052 g), DCM (10 mL), HATU (0.176 g) and DIPEA (0.09 g), and stirred at room temperature for 17 hours. After the completion of the reaction, ethyl acetate (100 mL) was added to the reaction mixture to extract, the organic phases were washed with water, combined, dried, concentrated to dryness under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: DCM/meoh=100/1) to give compound 3 (114 mg). MS (ESI+ [ M+H) ] + )m/z：650.18.
And (B) step (B):
compound 3 (114 mg) was resolved by preparative HPLC (resolution: column CHIRALART Cellulose-SB (4.6X250 mm,5 μm; mobile phase: n-hexane: ethanol=70:30; flow rate: 1mL/min; wavelength: 254 nm), compound 3_A (46 mg, retention time 6.215 min), compound 3_B (47 mg, retention time 7.601 min).
Compound 3_A: 1 H NMR(500MHz,DMSO-d 6 )δ10.54(s,1H),9.22(s,1H),9.20(s,1H),8.02(d,J＝1.9Hz,1H),7.80(d,J＝1.4Hz,2H),7.68(s,1H),7.64(dd,J＝8.2,2.1Hz,1H),7.36(d,J＝8.3Hz,1H),7.33(s,1H),7.30–7.26(m,2H),7.22–7.16(m,3H),6.42(s,1H),5.98(dd,J＝10.8,5.2Hz,1H),4.95(s,2H),3.43(dd,J＝14.3,10.7Hz,1H),3.36(dd,J＝14.5,5.1Hz,1H),3.27(s,3H).HRMS(ESI+,[M+H]+)m/z：650.1588.
compound 3_B: 1 H NMR(500MHz,DMSO-d 6 )δ10.53(s,1H),9.21(s,1H),9.19(s,1H),8.02(d,J＝2.0Hz,1H),7.80(d,J＝1.4Hz,2H),7.68(s,1H),7.64(dd,J＝8.3,2.1Hz,1H),7.36(d,J＝8.3Hz,1H),7.33(s,1H),7.30–7.26(m,2H),7.22–7.16(m,3H),6.42(s,1H),5.97(dd,J＝10.6,5.4Hz,1H),4.95(s,2H),3.43(dd,J＝14.4,10.6Hz,1H),3.36(dd,J＝14.5,5.2Hz,1H),3.27(s,3H).HRMS(ESI+,[M+H]+)m/z：650.1593.
example 4
Step A:
reference example 3 step A, substituting 2-1 for 1-1, gave compound 4 (114 mg). MS (ESI+ [ M+H)] + ) m/z:664.19. and (B) step (B):
compound 4 (114 mg) was resolved by preparative HPLC (resolution: column CHIRALART Cellulose-SB (4.6X250 mm,5 μm; mobile phase: n-hexane: ethanol (0.1% acetic acid) =75:25; flow rate: 1mL/min; wavelength: 254 nm), compound 4_A (44 mg, retention time 5.120 min), compound 4_B (50 mg, retention time 6.092 min).
Compound 4_A: 1 H NMR(500MHz,DMSO-d 6 )δ10.44(s,1H),9.19(s,1H),8.43(s,1H),7.85(d,J＝2.3Hz,1H),7.84–7.76(m,2H),7.68(s,1H),7.64(dd,J＝8.2,2.3Hz,1H),7.32(s,1H),7.29–7.25(m,2H),7.22–
7.14(m,4H),6.41(s,1H),5.94(dd,J＝10.8,5.1Hz,1H),4.06(t,J＝5.9Hz,2H),3.45–3.40(m,1H),3.37–3.34(m,1H),3.27(s,3H),2.82(t,J＝5.9Hz,2H).HRMS(ESI+,[M+H]+)m/z：664.1763.
compound 4_B: 1 H NMR(500MHz,DMSO-d 6 )δ10.44(s,1H),9.19(s,1H),8.43(s,1H),7.85(d,J＝2.3Hz,1H),7.82–7.77(m,2H),7.68(s,1H),7.64(dd,J＝8.2,2.4Hz,1H),7.33–7.25(m,3H),7.21–7.15(m,4H),6.41(s,1H),5.94(dd,J＝10.7,5.2Hz,1H),4.06(t,J＝5.9Hz,2H),3.42(dd,J＝14.4,10.8Hz,1H),3.39–3.34(m,1H),3.27(s,3H),2.82(t,J＝5.9Hz,2H).HRMS(ESI+,[M+H]+)m/z：664.1764.
PREPARATION EXAMPLE C-6
Step A:
in a 250mL single-necked flask, A-2 (3.56 g) was dissolved in acetonitrile (50 mL), and cuprous oxide (3.29 g), N was added 2 Heating at 60℃under protection, and adding ethynyl trimethylsilane (15.04 g) in portions every 1h interval until the reaction is complete. After the reaction, diatomaceous earth was used for filtration, and 200mL of ethyl acetate and water were added to the filtrate. The organic phase was separated, washed with 100mL of saturated brine and dried over anhydrous sodium sulfate. Purification by column chromatography on silica gel (eluent: PE/EA=33/1) gives C-1 (4.1 g). MS (ESI+ [ M+H) ] + )m/z：329.89.
And (B) step (B):
in a 250mL single-necked flask, C-1 (4.1 g) was dissolved in acetonitrile (100 mL), NCS (5.79 g), p-toluenesulfonic acid monohydrate (0.71 g) was added, and the mixture was reacted at 80℃for 2 hours. After the reaction was completed, part of the solvent was removed by spin-drying, 100mL of water was added to the reaction mixture, and extraction was performed with ethyl acetate (3×40 mL). The organic phase was separated, washed with 100mL of saturated brine and dried over anhydrous sodium sulfate. Purification by column chromatography on silica gel (eluent: PE/EA=12/1) gave C-2 (2.54 g). 1 H NMR(500MHz,DMSO-d 6 )δ8.89(s,1H),8.14(d,J＝2.0Hz,1H),7.77(d,J＝8.5Hz,1H),7.75(dd,J＝8.5,2.0Hz,1H).
Step C:
in a 250mL single-necked flask, C-2 (2.54 g), (2, 5-dimethoxypyridin-4-yl) boric acid (2.22 g) and tripotassium phosphate (4.6 g) were sequentially added, and after dissolution with 1, 4-dioxane (40 mL) and water (10 mL), pdCl was added 2 (dppf)(0.63g)，N 2 Under the protection, the reaction solution is heated to 100 ℃ and stirred for reaction for 6 hours. After the reaction was completed, the mixture was filtered with celite, and 100mL of water was added to the filtrate to extract ethyl acetate (3×50 mL). The organic phase was separated, washed with 50mL of saturated brine and dried over anhydrous sodium sulfate. Filtration and column chromatography of the crude product over silica gel (eluent: PE/EA=10/1) gave C-3 (2.42 g). MS (ESI+ [ M+H)] + )m/z：351.01.
Step D:
in a 100mL single-necked flask, C-3 (2.42 g), lithium chloride (1.46 g) and p-toluenesulfonic acid monohydrate (2.36 g) were sequentially added, and after dissolution in 30mL of isopropanol, N 2 Under the protection, the reaction solution is heated to 100 ℃ and stirred for reaction for 12 hours. After the reaction, the reaction mixture was cooled in an ice bath, 100mL of water was added and stirring was continued for 1 hour, a large amount of solids were precipitated, suction filtration was performed, and the cake was dried to give C-4 (2.3 g). MS (ESI+ [ M+H)] + ) m/z:336.96. step E:
to a 100mL single-necked flask, C-4 (1 g) and DMF (15 mL) were added in this order, the temperature was lowered to 0℃in an ice bath, 60% sodium hydride (0.24 g) was added, and the mixture was stirred in an ice bath for 20min. Lithium bromide (0.51 g) was added to the ice bath, and after stirring at room temperature for 15min, ethyl 2-bromobutyrate (0.66 mL) was added, and the mixture was stirred at room temperature overnight. After the reaction was completed, 70mL of water was added to the reaction solution, followed by extraction with ethyl acetate (3×20 mL). The organic phase was separated, washed with 50mL of saturated brine and dried over anhydrous sodium sulfate. FiltrationThe crude product obtained was chromatographed on a column of silica gel (eluent: PE/EA=3/1) to give C-5 (0.62 g). MS (ESI+ [ M+H)] + )m/z：451.03.
Step F:
to a 100mL single-necked flask, C-5 (0.62 g) was added, and after dissolving with 10mL of ethanol, 15% aqueous sodium hydroxide solution (10 mL) was added, and the mixture was stirred at room temperature for 3 hours. After the completion of the reaction, 30mL of water was added, the ph=2 to 3 of the reaction mixture was adjusted with 2N diluted hydrochloric acid (20 mL), followed by extraction with ethyl acetate (30 ml×3), and the organic phases were separated and combined, washed with 50mL of saturated brine, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated to give C-6 (0.54 g). MS (ESI+ [ M+H) ] + )m/z：423.01.
Example 5
Step A:
to a 1L single-necked flask, 5-1 (30.00 g), pinacol biborate (32.20 g), 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride dichloromethane complex (9.42 g), 1, 4-dioxane (400 ml) and potassium acetate (34.00 g) were sequentially added, and heated to 70℃to stir for reaction for 3 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and was filtered through celite. The filtrate was concentrated to dryness under reduced pressure, and the residue was dissolved in ethyl acetate (500 mL), washed with water (200 mL) and saturated brine (100 mL) in this order, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (eluent: PE/ea=9/1) to give 5-2 (26.00 g). 1 H NMR(500MHz,DMSO-d 6 )δ8.56(d,J＝2.2Hz,1H),8.44(dd,J＝8.1,2.2Hz,1H),7.79(d,J＝8.1Hz,1H),3.93(s,3H),1.35(s,12H).
And (B) step (B):
into 500mL three-necked flask, 5-2 (9.00 g), dichloromethane (150 mL) and N were sequentially added 2 Under protection, the temperature is reduced to-5 ℃. Toluene solution of diisobutylaluminum hydride (10) was slowly added using a dropping funnel1ml, 1M) was slowly added to the above-mentioned stirred solution, and after the completion of the addition, the reaction was continued at-5℃for 2 hours with stirring. After the reaction, 4N diluted hydrochloric acid was added to the reaction mixture to adjust the pH to 4. The organic phase was separated and the aqueous phase was extracted with dichloromethane (100 mL x 3), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated to dryness and the crude product obtained was chromatographed on a column of silica gel (eluent: PE/ea=4/1) to give 5-3 (2.18 g). 1 H NMR(500MHz,DMSO-d 6 ) δ8.30 (s, 1H), 8.07 (dd, j=8.1, 2.3hz, 1H), 7.83 (d, j=8.1 hz, 1H), 5.60 (s, 1H), 4.79 (s, 2H), 1.32 (s, 12H) ·step C:
to a 100mL single-necked flask, 5-3 (2.18 g) of a hydrochloric acid aqueous solution (6M, 20 mL) and N were sequentially added 2 Under the protection, the reaction is carried out for 12 hours at 60 ℃. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the cake was washed with 40mL of water, and the cake was collected and dried under vacuum at 40℃to give 5-4 (1.20 g). MS (ESI+ [ M-H)] + )m/z：178.06. 1 H NMR(500MHz,DMSO-d 6 )δ9.60(s,1H),8.35-8.27(m,1H),8.20(dd,J＝8.0,1.9Hz,1H),7.97(d,J＝8.0Hz,1H),5.11(s,2H).
Step D:
to a 50mL single-necked flask, 5-4 (200 mg), 10% Pd/C (40 mg), methanol (10 mL), nitrogen substitution 3 times and then hydrogen substitution 3 times were sequentially added, and the reaction was stirred at room temperature under the protection of hydrogen for 1.5 hours. After the reaction was completed, celite was filtered, washed with methanol (5 mL), and the filtrate was concentrated to dryness to give 5-5 (150 mg). 1 H NMR(500MHz,DMSO-d 6 )δ8.59(s,1H),7.34(d,J＝7.9Hz,1H),6.51(d,J＝7.9Hz,1H),6.48(s,1H),5.42(s,2H),4.78(s,2H).
Step E:
to a 25mL single-necked flask, C-6 (300 mg), DCM (10 mL), HATU (539 mg) and N, N-diisopropylethylamine (183 mg) were successively added, and after stirring uniformly, 5-5 (158 mg) was added and the reaction was stirred at room temperature overnight. After the reaction, methylene chloride (10 mL) and water (10 mL) were added to the reaction mixture, the organic phase was separated, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and subjected to preparative HPLC (column: XB-Phenyl 4.6 x 250mm,5 μm; mobile phase: water: acetonitrile=50:50; flow rate: 1mL/min; wavelength: 254 nm), to give a purified product Compound 5 (120 mg, retention time 12.369 min). HRMS (ESI+ [ M+H)] + )m/z：554.1178. 1 H NMR(500MHz,DMSO-d 6 )δ10.57(s,1H),9.08(s,1H),8.63(s,1H),7.81-7.72(m,4H),7.66(d,J＝8.0Hz,1H),7.52-7.47(m,1H),7.20(s,1H),6.47(s,1H),5.60(dd,J＝10.2,5.9Hz,1H),4.95(s,2H),3.31(s,3H),2.15-2.01(m,2H),0.82(t,J＝7.3Hz,3H).
Step F:
compound 5 (120 mg) was resolved by preparative HPLC (resolution conditions: column CHIRALART Cellulose-SB 4.6 x 250mm 5 μm; mobile phase: n-hexane: ethanol=85:15; flow rate: 1mL/min; wavelength: 254 nm), compound 5_A (49.7 mg, retention time 11.019 min), compound 5_B (34.1 mg, retention time 12.870 min).
Compound 5_A: 1 H NMR(500MHz,DMSO-d 6 )δ10.57(s,1H),9.08(s,1H),8.63(s,1H),7.82 -7.73(m,4H),7.66(d,J＝8.0Hz,1H),7.49(d,J＝7.9Hz,1H),7.20(s,1H),6.47(s,1H),5.60(dd,J＝10.1,5.9Hz,1H),4.95(s,2H),3.31(s,3H),2.13-2.00(m,2H),0.82(t,J＝7.3Hz,3H).HRMS(ESI+,[M+H] + )m/z：554.1178.
compound 5_B: 1 H NMR(500MHz,DMSO-d 6 )δ10.57(s,1H),9.08(s,1H),8.63(s,1H),7.81 -7.72(m,4H),7.66(d,J＝8.0Hz,1H),7.49(d,J＝8.0Hz,1H),7.20(s,1H),6.47(s,1H),5.60(dd,J＝10.1,5.9Hz,1H),4.95(s,2H),3.31(s,3H),2.14-2.02(m,2H),0.82(t,J＝7.3Hz,3H).HRMS(ESI+,[M+H] + )m/z：554.1178.
example 6
Step A:
6-1 (5.5 g) and concentrated sulfuric acid (40 mL) are sequentially added into a 250mL single-port bottle, concentrated nitric acid (2.1 g) is slowly added dropwise at 20 ℃, after the reaction is finished, the reaction solution is slowly added dropwise into 200mL ice water, suction filtration is carried out, and a filter cake is dried to obtain 6-2 (6.5 g). 1 H NMR(500MHz,DMSO-d 6 )δ8.34(d,J＝2.8Hz,1H),8.05(dd,J＝8.8,2.8Hz,1H),7.93(d,J＝8.7Hz,1H),3.93(s,2H).
And (B) step (B):
to a 250mL three-necked flask, 6-2 (6.5 g) and methanol (50 mL) were sequentially added, thionyl chloride (5.95 g) was added under an ice bath, and the mixture was reacted at room temperature for 30min and then heated to reflux for 15h. After the reaction, the reaction mixture was concentrated to dryness, and poured into 100mL of ice water to precipitate a solid, which was suction-filtered, and the cake was dried to give 6-3 (5.4 g). 1 H NMR(500MHz,DMSO-d 6 )δ8.37(d,J＝2.8Hz,1H),8.07(dd,J＝8.8,2.8Hz,1H),7.95(d,J＝8.7Hz,1H),4.03(s,2H),3.65(s,3H).
Step C:
to a 100mL single-port flask was added 6-3 (6 g), methanol (30 mL), THF (30 mL), sodium borohydride (8.28 g) was added in portions under ice bath, slowly warmed to room temperature, stirred for 1h, after the reaction was completed, the reaction solution was poured into 100mL saturated ammonium chloride solution, extracted with ethyl acetate (2 x 100 mL), washed with water, the organic phases were combined, dried, concentrated under reduced pressure to dryness, and the obtained crude product was purified by silica gel column chromatography (eluent: PE/ea=3/1) to give 6-4 (3.2 g). 1 H NMR(500MHz,DMSO-d 6 )δ8.21(d,J＝2.8Hz,1H),7.99(dd,J＝8.7,2.8Hz,1H),7.90(d,J＝8.7Hz,1H),4.82(t,J＝5.3Hz,1H),3.68(td,J＝6.5,5.2Hz,2H),2.98(t,J＝6.5Hz,2H).
Step D:
6-4 (1.4G), ethanol (30 mL), tetrahydroxyboric acid (1.53G), X-Phos (271 mg), X-Phos Pd G2 (894 mg), N were sequentially added to a 100mL single-necked flask 2 After substitution at N 2 Heating to 85deg.C under protection, filtering, washing the filter cake with ethyl acetate (50 mL), concentrating the filtrate, and purifying the crude product by silica gel column chromatography (eluent: PE/EA=20/1) to obtain 6-5 (400 mg). MS (ESI-, [ M-H ]] - )m/z：192.1。 1 H NMR(500MHz,DMSO-d 6 )δ8.87(s,1H),8.10–8.06(m,2H),7.91(d,J＝7.9Hz,1H),4.12(t,J＝5.9Hz,2H),3.03(t,J＝5.9Hz,2H).
Step E:
to a 100mL single-necked flask, 6-5 (400 mg), methanol (20 mL) and palladium on carbon (40 mg) were sequentially added, N 2 After replacement at H 2 The reaction is carried out for 2 hours at room temperature under atmosphere, after the reaction is finished, the filtration is carried out by suction, and the filtrate is concentrated and dried by spin to obtain 6-6 (310 mg). 1 H NMR(500MHz,DMSO-d 6 )δ7.84(s,1H),7.34(d,J＝7.9Hz,1H),6.43–6.30(m,3H),3.97(t,J＝5.9Hz,2H),2.67(t,J＝5.9Hz,2H).
Step F:
to a 100mL single-port flask, intermediate C-6 (100 mg), methylene chloride (10 mL), EDCI (68 mg), DMAP (43 mg) and 6-6 (46 mg) were sequentially added, and stirred at room temperature for 15 hours, after the completion of the reaction, the reaction mixture was directly fed to preparative HPLC (column: CHIRALART cellose-SB 4.6. Mu.100 mm 5 μm; mobile phase: water: acetonitrile=55:45; flow rate 1mL/min; wavelength: 254 nm) for purification to give Compound 6 (12 mg, retention time: 18.879 minutes). 1 H NMR(500MHz,DMSO-d 6 )δ10.47(s,1H),8.63(s,1H),8.33(s,1H),7.83–7.72(m,3H),7.62(d,J＝8.0Hz,1H),7.52(s,1H),7.47–7.40(m,1H),7.19(s,1H),6.47(s,1H),5.58(dd,J＝10.3,5.9Hz,1H),4.05(t,J＝5.9Hz,2H),3.31(s,3H),2.82(t,J＝5.9Hz,2H),2.05(ddd,J＝29.8,13.6,7.0Hz,2H),0.82(t,J＝7.4Hz,3H).HRMS(ESI+,[M+H] + )m/z：568.1329.
PREPARATION EXAMPLE D-2
Step A:
to a 100mL single-necked flask, C-4 (1.2 g) was added, the mixture was dissolved in DMF (20 mL), 60% sodium hydride (0.18 g) was added under ice-bath conditions, lithium bromide (0.62 g) was added after 20min, and methyl 2-bromo-3-phenylpropionate (1.08 g) was added, followed by stirring at room temperature for 10 hours. At the end of the reaction, 120mL of ice water was added to quench the reaction. Extraction with ethyl acetate (35 ml x 3), combining the organic phases, washing with saturated brine, drying over anhydrous sodium sulphate, filtration, concentration of the filtrate under reduced pressure, and column chromatography of the crude product over silica gel (eluent: PE/ea=3/1) gives D-1 (1.2 g). MS (ESI+ [ M+H) ] + )m/z：499.09.
And (B) step (B):
to a 100mL single-necked flask, D-1 (2 g) was added, and after dissolving with 15mL of methanol, 15% aqueous sodium hydroxide solution (10 mL) was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, 30mL of water was added, the ph=2 to 3 of the reaction mixture was adjusted with 2N diluted hydrochloric acid (20 mL), followed by extraction with ethyl acetate (30 ml×3), and the organic phases were separated, combined, and concentrated with 50mL of saturated saltWashing with water, drying over anhydrous sodium sulfate, suction filtration, and concentration of the filtrate to dryness gave D-2 (1.62 g). MS (ESI+ [ M+H)] + )m/z：485.01.
Example 7
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Step A:
to a 25mL single-necked flask, D-2 (140 mg), DCM (10 mL), HATU (219 mg) and N, N-diisopropylethylamine (74.60 mg) were successively added, and after stirring uniformly, 5-5 (51.60 mg) was added and the reaction was stirred at room temperature overnight. After completion of the reaction, methylene chloride (10 mL) and water (10 mL) were added to the reaction mixture, the organic phase was separated, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: DCM/meoh=20/1) to give compound 7 (120 mg). MS (ESI+ [ M+H)] + ) m/z:616.13. and (B) step (B):
compound 7 (120 mg) was resolved by preparative HPLC (resolution conditions: column (R, R) -Whelk O1.6X250 mm 5 μm; mobile phase: n-hexane: ethanol: dichloromethane=60:10:30; flow rate: 1mL/min; wavelength: 254 nm), compound 7_A (40 mg, retention time 7.610 min), compound 7_B (25 mg, retention time 8.947 min).
Compound 7_A: 1 H NMR(500MHz,DMSO-d 6 )δ10.66(s,1H),9.09(s,1H),8.59(s,1H),7.77(dd,J＝8.5,2.0Hz,2H),7.72(d,J＝8.5Hz,1H),7.69-7.62(m,2H),7.50(d,J＝7.9Hz,1H),7.35(s,1H),7.32-7.28(m,2H),7.20(t,J＝8.3Hz,3H),6.36(s,1H),5.98(dd,J＝10.0,5.3Hz,1H),4.96(s,2H),3.48-3.37(m,2H),3.32(s,3H).HRMS(ESI+,[M+H] + )m/z：616.1336.
compound 7_B: 1 H NMR(500MHz,DMSO-d 6 )δ10.65(s,1H),9.09(s,1H),8.59(s,1H),7.80 -7.75(m,2H),7.72(d,J＝8.5Hz,1H),7.68-7.62(m,2H),7.50(d,J＝8.0Hz,1H),7.35(s,1H),7.29(t,J＝7.5Hz,2H),7.20(t,J＝8.5Hz,3H),6.36(s,1H),5.97(dd,J＝10.6,5.0Hz,1H),4.96(s,2H),3.49-3.36(m,2H),3.32(s,3H).HRMS(ESI+,[M+H] + )m/z：616.1332.
example 8
Step A referring to step F of example 6, intermediate D-2 is substituted for intermediate C-6 to give compound 8. 1 H NMR(500MHz,DMSO-d 6 )δ10.56(s,1H),8.58(s,1H),8.34(s,1H),7.77(dd,J＝8.5,2.4Hz,1H),7.72(d,J＝8.5Hz,1H),7.67–7.61(m,2H),7.54–7.51(m,1H),7.45(dd,J＝8.1,1.9Hz,1H),7.34(s,1H),7.29(t,J＝7.5Hz,2H),7.20(dd,J＝10.6,7.4Hz,3H),6.36(s,1H),5.96(dd,J＝11.0,5.1Hz,1H),4.05(t,J＝6.0Hz,2H),3.44(dd,J＝14.3,10.8Hz,1H),3.39–3.35(m,1H),3.32(s,3H),2.84(t,J＝5.9Hz,2H).HRMS(ESI+,[M+H] + ) m/z:630.1485. preparation example E-3
Step A:
to a 50mL single flask, C-4 (400 mg) and tert-butyl 2-bromoacetate (347 mg) were successively added, and after dissolution in DMF (10 mL), potassium carbonate (246 mg) was added, and the reaction was stirred at room temperature for 2 hours after the addition. After the completion of the reaction, 50mL of water was added, extraction was performed with ethyl acetate (20 ml×3), the organic phases were combined, washed with 50mL of saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent: PE/ea=3/2) to give E-1 (400 mg). MS (ESI+ [ M+Na)] + )m/z：473.08.
And (B) step (B):
e-1 (450 mg), THF (15 mL) and N were sequentially added to a 100mL three-necked flask 2 Dropwise adding a THF solution of lithium bis (trimethylsilyl) amide (1M, 2 mL) at-78 ℃ under the protection, and continuously stirring for 30min at-78 ℃ after the dropwise addition is completed. To the reaction solution was added dropwise 3- (bromomethyl) pyridine (223 mg) dissolved in THF (2 mL), -stirring was continued at 78℃for 2 hours. After the reaction, the saturated ammonium chloride solution (10 mL) was quenched, 40mL of water was added, and acetic acid ethyl esterThe ester (25 mL. Times.2) was extracted, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product which was chromatographed on a silica gel column (eluent: PE/EA=1/1) to give E-2 (507 mg). MS (ESI+ [ M+H) ] + )m/z：542.08.
Step C:
e-2 (370 mg), 2M hydrochloric acid-dioxane solution (10 mL) and water (0.5 mL) were sequentially added to a 50mL single-necked flask, N 2 Stir overnight at room temperature under protection. After the completion of the reaction, the solvent was distilled off under reduced pressure to give E-3 (335 mg). MS (ESI+ [ M+H)] + )m/z：486.01.
Example 9
Step A:
in a 50mL single-necked flask, intermediate E-3 (250 mg), HATU (364 mg) and DCM (10 mL) were added, DIPEA (247 mg) were added, and after stirring uniformly, intermediate 9-1 (120 mg) was added and stirred at room temperature for 10h. After the reaction, the reaction was stopped, most of the solvent was removed by spinning, and 30mL of water was added. Extraction with ethyl acetate (15 mL x 3), combined organic phases, washing with 30mL saturated brine, drying over anhydrous sodium sulphate, concentrating under reduced pressure and purification of the crude product by silica gel column chromatography (eluent DCM/meoh=25/1) gives compound 9 (140 mg). MS (ESI+ [ M+H)] + )m/z：635.22.
And (B) step (B):
compound 9 (140 mg) was resolved by preparative HPLC (resolution conditions: column: CHIRALART Cellulose-SC 4.6x250mm,5 μm; mobile phase: n-hexane: ethanol: dichloromethane=65:15:20; flow rate: 1mL/min; wavelength: 254 nm), compound 9_A (54 mg, retention time 11.618 min), compound 9_B (60 mg, retention time 14.989 min).
Compound 9_A: 1 H NMR(500MHz,DMSO-d 6 )δ10.32(s,1H),9.28(s,1H),8.59(s,1H),8.53(s,1H),8.43(d,J＝4.6Hz,1H),8.14(d,J＝7.8Hz,1H),7.77(d,J＝2.3Hz,1H),7.73(d,J＝8.5Hz,1H),7.63(s,1H),7.49(s,1H),7.36(d,J＝10.6Hz,1H),7.33(d,J＝4.0Hz,2H),6.38(s,1H),6.11(dd,J＝10.4,5.4Hz,1H),4.96(s,2H),3.46(ddd,J＝12.1,10.6,7.9Hz,2H),3.31(s,3H)。HRMS(ESI+,[M+H] + )m/z：635.1211.
compound 9_B: 1 H NMR(500MHz,DMSO-d 6 )δ10.32(s,1H),9.28(s,1H),8.59(s,1H),8.53(s,1H),8.43(d,J＝4.6Hz,1H),8.14(d,J＝7.8Hz,1H),7.77(d,J＝2.2Hz,1H),7.73(d,J＝8.5Hz,1H),7.63(s,1H),7.49(s,1H),7.36(d,J＝10.6Hz,1H),7.33(s,2H),6.38(s,1H),6.11(dd,J＝10.5,5.4Hz,1H),4.96(s,2H),3.54–3.43(m,2H),3.31(s,3H)。HRMS(ESI+,[M+H] + )m/z：635.1198.
example 10
Step A:
Referring to step A of example 9, 9-1 was replaced with intermediate 1-1 to give compound 10 (152 mg). MS (ESI+ [ M+H)] + ) m/z:617.23. and (B) step (B):
compound 10 (152 mg) was subjected to preparative HPLC (resolution conditions: column: CHIRALART Amylose-SA4.6X100mm,5 μm; mobile phase: ethanol: CO) 2 =35:65; flow rate: 2mL/min; wavelength: 254 nm) and compound 10_a (25 mg, retention time 3.527 min) and compound 10_b (27 mg, retention time 4.850 min).
Compound 10_a: 1 H NMR(500MHz,DMSO-d 6 )δ10.53(s,1H),9.24(s,1H),8.61(s,1H),8.51(s,1H),8.43(d,J＝4.6Hz,1H),8.04(s,1H),7.78(dd,J＝8.6,2.2Hz,1H),7.74(s,1H),7.65(s,1H),7.64–7.60(m,1H),7.46(s,1H),7.40(s,1H),7.38(s,1H),7.32(dd,J＝7.6,4.8Hz,1H),6.38(s,1H),5.99(dd,J＝10.1,5.8Hz,1H),4.95(s,2H),3.51–3.40(m,2H),3.34(s,3H)。HRMS(ESI+,[M+H] + )m/z：617.1294.
compound 10_b: 1 H NMR(500MHz,DMSO-d 6 )δ10.53(s,1H),9.24(s,1H),8.61(s,1H),8.51(s,1H),8.43(s,1H),8.04(s,1H),7.77(s,1H),7.74(s,1H),7.65(s,1H),7.63(s,1H),7.46(s,1H),7.40(s,1H),7.37(d,J＝8.2Hz,1H),7.35–7.30(m,1H),6.38(s,1H),6.06–5.94(m,1H),4.95(s,2H),3.46(s,2H),3.33(s,3H)。HRMS(ESI+,[M+H] + )m/z：617.1292.
PREPARATION EXAMPLE F-3
Step A:
f-1 (4.50 g), THF (100 mL) and N were sequentially added to a 250mL three-necked flask 2 Under the protection, the reaction system was cooled to-78 ℃, lithium bis (trimethylsilylamide) (6.27 g) was added, stirred for 1h, trimethylchlorosilane (3.70 g) was added, stirred for 20min, NBS (6.06 g) dissolved in THF (10 ml) was added, and the reaction was continued at-78 ℃ for 2h. After the completion of the reaction, the reaction was quenched with saturated ammonium chloride solution (50 mL), extracted with EA (100 ml×3), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the crude product obtained was purified by silica gel column chromatography (eluent: PE/ea=25/1) to give F-2 (1.90 g). 1 H NMR(500MHz,DMSO-d 6 )δ4.51(dd,J＝8.0,6.4Hz,1H),3.67(s,3H),3.44-3.36(m,2H),3.19(s,3H),2.32-2.23(m,1H),2.04(m,1H).
And (B) step (B):
a-5 (1.15 g) and DMF (10 mL) were added sequentially to a 25mL single-necked flask, cooled to 0℃in an ice bath, sodium hydride (0.15 g) was added, and stirred in an ice bath for 20min. Lithium bromide (0.54 g) was added to the ice bath, stirred at room temperature for 15min, F-2 (0.92 g) was added at room temperature, and stirred at room temperature overnight. After the completion of the reaction, the reaction was quenched with saturated ammonium chloride solution (10 mL), extracted with ethyl acetate (40 ml×2), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (eluent: PE/ea=1/1) to give F-3 (900 mg). MS (ESI+ [ M+H) ] + )m/z：487.06. 1 H NMR(500MHz,DMSO-d 6 )δ12.94(s,1H),9.17(s,1H),7.82(d,J＝1.7Hz,2H),7.78(s,1H),7.07(s,1H),6.47(s,1H),4.99(s,1H),3.29-3.25(m,2H),3.21(s,3H),3.14(s,3H),2.29-2.26(m,2H).
Example 11
Step A:
f-3 (150 mg), DCM (10 mL), HATU (234 mg) and N, N-diisopropylethylamine (80 mg) were added sequentially to a 25mL single-necked flask, and after stirring uniformly, 5-5 (68.8 mg) was added thereto and the reaction was stirred at room temperature overnight. After completion of the reaction, methylene chloride (10 mL) and water (10 mL) were added to the reaction mixture, the organic phase was separated, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: DCM/meoh=20/1) to give compound 11 (150 mg). MS (ESI+ [ M+H)] + ) m/z:618.17. and (B) step (B):
compound 11 (150 mg) was resolved by preparative HPLC (resolution: column REFLECT I Amylose-A4.6x250mm 5 μm; mobile phase: n-hexane: ethanol=70:30; flow rate: 1mL/min; wavelength: 254 nm), compound 11_A (54 mg, retention time 16.708 min), compound 11_B (41.7 mg, retention time 20.673 min).
Compound 11_a: 1 H NMR(500MHz,DMSO-d 6 )δ10.50(s,1H),9.18(s,1H),9.07(s,1H),7.87-7.80(m,2H),7.79-7.73(m,2H),7.64(d,J＝8.0Hz,1H),7.49(dd,J＝8.1,1.4Hz,1H),7.16(s,1H),6.51(s,1H),5.68(s,1H),4.94(s,2H),3.31-3.27(m,1H),3.26(s,3H),3.18(s,3H),3.14-3.09(m,1H),2.33-2.29(m,2H)..HRMS(ESI+,[M+H] + )m/z：618.1538.
compound 11_b: 1 H NMR(500MHz,DMSO-d 6 )δ10.50(s,1H),9.18(s,1H),9.07(s,1H),7.86-7.80(m,2H),7.80-7.73(m,2H),7.64(d,J＝8.0Hz,1H),7.53-7.47(m,1H),7.16(s,1H),6.51(s,1H),5.69(s,1H),4.94(s,2H),3.31-3.26(m,4H),3.18(s,3H),3.15-3.08(m,1H),2.33-2.29(m,2H).HRMS(ESI+,[M+H] + )m/z：618.1544.
example 12
Step A:
f-3 (0.15 g), 12-1 (0.118 g), DCM (15 mL), HATU (0.234 g) and DIPEA (0.159 g) were added in this order to a 100mL single-port flask and stirred at room temperature for 16 hours. After the completion of the reaction, ethyl acetate (100 mL) was added to the reaction mixture to extract, the organic phases were washed with water, combined, dried, concentrated to dryness under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: DCM/meoh=100/1) to give compound 12 (175 mg). MS (ESI+ [ M+H) ] + )m/z：646.24.
And (B) step (B):
compound 12 (175 mg) was subjected to preparative HPLC (resolution conditions: chromatography column: CHIRALART Cellulose-SA (4.6X100 mm,5 μm), mobile phase: ethanol: CO) 2 =15:85; flow rate: 2mL/min; wavelength: 254 nm) =75:25; flow rate: 1mL/min; wavelength: 254 nm) and compound 12_a (80 mg, retention time 4.478 min) and compound 12_b (84 mg, retention time 6.827 min).
Compound 12_a: 1 H NMR(500MHz,DMSO-d 6 )δ10.38(s,1H),9.18(s,1H),9.04(s,1H),7.91(d,J＝1.9Hz,1H),7.86–7.81(m,2H),7.77(d,J＝2.0Hz,1H),7.60(dd,J＝8.2,2.1Hz,1H),7.34(d,J＝8.3Hz,1H),7.18(s,1H),6.51(s,1H),5.68(s,1H),3.30–3.27(m,1H),3.26(s,3H),3.19(s,3H),3.15–3.09(m,1H),2.35–2.26(m,2H),1.42(s,6H).HRMS(ESI+,[M+H]+)m/z：646.1863.
compound 12_b: 1 H NMR(500MHz,DMSO-d 6 )δ10.38(s,1H),9.18(s,1H),9.04(s,1H),7.91(d,J＝2.0Hz,1H),7.85–7.81(m,2H),7.77(d,J＝2.0Hz,1H),7.60(dd,J＝8.3,2.0Hz,1H),7.34(d,J＝8.3Hz,1H),7.18(s,1H),6.51(s,1H),5.68(s,1H),3.30–3.27(m,1H),3.26(s,3H),3.19(s,3H),3.14–3.09(m,1H),2.34–2.27(m,2H),1.42(s,6H).HRMS(ESI+,[M+H]+)m/z：646.1863.
example 13
Step A:
to a 50mL single-necked flask, intermediate C-6 (300 mg), 13-1 (147 mg), methylene chloride (15 mL), HATU (539 mg) and DIEA (183 mg) were successively added, and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, methylene chloride (100 mL) was added to the reaction mixture, which was washed with water, the organic phases were combined, dried, concentrated to dryness under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: DCM/meoh=20/1) to give compound 13 (280 mg). MS (ESI-, [ M-H ]] - )m/z：540.3。
And (B) step (B):
compound 13 (280 mg) was subjected to preparative HPLC (resolution: column: CHIRALPAK IG 4.6.6X 250mm 5 μm; mobile phase: n-hexane: ethanol (0.1% ammonia): dichloromethane=70:15:15; flow rate 1mL/min; wavelength: 254 nm) to give compound 13_A (64 mg, retention time: 7.872 min), and compound 13_B (68 mg, retention time: 12.906 min).
Compound 13_A:1H NMR (500 MHz, DMSO-d) 6 )δ10.44(s,1H),8.63(s,1H),7.93(s,2H),7.79(dd,J＝8.6,2.3Hz,1H),7.77–7.72(m,4H),7.60–7.54(m,2H),7.20(s,1H),6.47(s,1H),5.58(dd,J＝10.3,5.9Hz,1H),3.31(s,3H),2.14–2.02(m,2H),0.82(t,J＝7.2Hz,3H).HRMS(ESI+,[M+H] + )m/z：542.1171.
Compound 13_b: 1 H NMR(500MHz,DMSO-d 6 )δ10.44(s,1H),8.63(s,1H),7.93(s,2H),7.79(dd,J＝8.6,2.3Hz,1H),7.77–7.72(m,4H),7.60–7.54(m,2H),7.20(s,1H),6.47(s,1H),5.58(dd,J＝10.3,5.9Hz,1H),3.31(s,3H),2.14–2.02(m,2H),0.82(t,J＝7.2Hz,3H).HRMS(ESI+,[M+H] + )m/z：542.1165.
example 14
Step A:
reference example 13 step A, substituted by intermediate A-7Intermediate C-6 was exchanged to give compound 14.MS (ESI-, [ M-H ]] - )m/z：574.3。
And (B) step (B):
compound 14 was resolved by preparative HPLC (resolution: column CHIRALPAK IG 4.6.6×250mm 5 μm; mobile phase: n-hexane: ethanol=70:30; flow rate 1mL/min; wavelength 254 nm) to give compound 14_A (retention time 7.249 min) and compound 14_B (retention time 12.642 min).
Compound 14_a: 1 H NMR(500MHz,DMSO-d 6 )δ10.43(s,1H),9.14(s,1H),7.93(s,2H),7.86–7.82(m,2H),7.78(d,J＝2.2Hz,1H),7.73(d,J＝8.1Hz,2H),7.56(d,J＝8.2Hz,2H),7.15(s,1H),6.52(s,1H),5.57(dd,J＝10.4,5.8Hz,1H),3.26(s,3H),2.12–2.03(m,2H),0.78(t,J＝7.3Hz,3H).HRMS(ESI+,[M+H] + )m/z：576.1435.
compound 14_b: 1 H NMR(500MHz,DMSO-d 6 )δ10.44(s,1H),9.14(s,1H),7.93(s,2H),7.86–7.82(m,2H),7.78(d,J＝2.2Hz,1H),7.73(d,J＝8.1Hz,2H),7.56(d,J＝8.1Hz,2H),7.15(s,1H),6.53(s,1H),5.57(dd,J＝10.4,5.8Hz,1H),3.26(s,3H),2.07(ddd,J＝17.8,12.3,7.1Hz,2H),0.78(t,J＝7.2Hz,3H).HRMS(ESI+,[M+H] + )m/z：576.1438.
example 15
Step A:
to a 500mL single-necked flask, benzophenone (10 g), chloroform (200 mL) and aluminum trichloride (14.6 g) were successively added, and a solution of 4-bromo-3-fluoroaniline (15.6 g) in triethylamine (27.8 g) was slowly dropped in an ice bath and stirred at room temperature for 15 hours. After the reaction, 4N NaOH solution was added to the reaction solution to adjust PH to 7-8, dichloromethane (2 x 200 ml) was added for extraction, water washing, the organic phases were combined, dried, concentrated to dryness under reduced pressure, and the crude product obtained was purified by silica gel column chromatography (eluent: PE) to give intermediate 15-1 (17.8 g). MS (ESI+ [ M+H)] + )m/z：355.9. 1 H NMR(500MHz,DMSO-d 6 )δ7.69–7.64(m,2H),7.58–7.53(m,1H),7.46(dt,J＝23.4,8.0Hz,3H),7.36(dd,J＝5.2,1.9Hz,3H),7.19(dd,J＝4.9,1.8Hz,2H),6.79(dd,J＝10.3,2.3Hz,1H),6.51(dd,J＝8.5,2.3Hz,1H).
And (B) step (B):
to a 250mL three-necked flask, 15-1 (6.0 g) and THF (100 mL) were sequentially added, the temperature was lowered to-78 ℃, n-butyllithium (1.6M n-hexane solution, 1.30 g) was added dropwise, triisopropyl borate (3.5 g) was slowly added dropwise after 1.0h of reaction, after the reaction was completed, the reaction solution was poured into 100mL ice water, extracted with ethyl acetate (2×200 mL), washed with water, the organic phases were combined, dried, concentrated under reduced pressure to dryness, and the obtained crude product was purified by silica gel column chromatography (eluent: PE/ea=3/2) to obtain intermediate 15-2 (2.4 g). MS (ESI+ [ M+H) ] + )m/z：319.9.
Step C:
to a 100mL single-necked flask, 15-2 (2.4 g), ethyl acetate (50 mL) and HCl (1M in ethyl acetate HCl, 1.10 g) were sequentially added, and the mixture was stirred at room temperature for 16h, suction filtered, and the cake was dried to give 15-3 (1.1 g).
Step D:
referring to example 13, step A, 13-1 was replaced with 15-3 to give compound 15.MS (ESI-, [ M-H ]] - )m/z：558.3.
Step E:
compound 15 was resolved by preparative HPLC (resolution: column CHIRALPAK IG 4.6.6×250mm 5 μm; mobile phase: n-hexane: ethanol: dichloromethane=70:15:15; flow rate: 1mL/min; wavelength: 254 nm) to give Compound 15_A (retention time: 5.895 min), compound 15_B (retention time: 9.151 min).
Compound 15_a: 1 H NMR(500MHz,DMSO-d 6 )δ10.62(s,1H),8.62(s,1H),8.04(s,2H),7.78(dd,J＝9.1,6.9Hz,2H),7.74(t,J＝3.2Hz,1H),7.53(t,J＝7.7Hz,1H),7.48(dd,J＝11.8,1.8Hz,1H),7.29(dd,J＝8.1,1.8Hz,1H),7.18(s,1H),6.48(s,1H),5.55(dd,J＝10.3,5.9Hz,1H),3.31(s,3H),2.15–2.05(m,2H),0.82(t,J＝7.2Hz,3H).HRMS(ESI+,[M+H] + )m/z：560.1090.
compound 15_b: 1 H NMR(500MHz,DMSO-d 6 )δ10.62(s,1H),8.62(s,1H),8.04(s,2H),7.78(dd,J＝9.2,7.0Hz,2H),7.74(d,J＝2.3Hz,1H),7.53(t,J＝7.7Hz,1H),7.48(dd,J＝11.7,1.8Hz,1H),7.29(dd,J＝8.1,1.9Hz,1H),7.18(s,1H),6.47(s,1H),5.55(dd,J＝10.2,5.9Hz,1H),3.31(s,3H),2.10(dq,J＝13.2,7.2Hz,2H),0.82(t,J＝7.3Hz,3H).HRMS(ESI+,[M+H] + )m/z：560.1092.
example 16
Step A:
f-3 (200 mg), DCM (10 mL), HATU (312 mg) and N, N-diisopropylethylamine (106 mg) were added sequentially to a 50mL single-necked flask, and after stirring uniformly, 13-1 (107 mg) was added thereto, and the reaction was stirred at room temperature overnight. After completion of the reaction, methylene chloride (10 mL) and water (10 mL) were added to the reaction mixture, the organic phase was separated, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: DCM/meoh=20/1) to give compound 16 (125 mg). MS (ESI+ [ M+H) ] + )m/z：606.17.
And (B) step (B):
compound 16 (125 mg) was resolved by preparative HPLC (resolution conditions: column: CHIRALPAK IG 4.6.6X250 mm 5 μm; mobile phase: n-hexane: ethanol: dichloromethane=70:15:15; flow rate: 1mL/min; wavelength: 254 nm), compound 16_A (15 mg, retention time 20.545 min), compound 16_B (20 mg, retention time 25.499 min).
Compound 16_a: 1 H NMR(500MHz,DMSO-d 6 )δ10.38(s,1H),9.17(s,1H),7.92(s,2H),7.85-7.81(m,2H),7.78-7.76(m,1H),7.72(d,J＝8.3Hz,2H),7.57(d,J＝8.4Hz,2H),7.17(s,1H),6.51(s,1H),5.67(s,1H),3.29-3.25(m,4H),3.18(s,3H),3.13-3.08(m,1H),2.33-2.30(m,2H).HRMS(ESI+,[M+H] + )m/z：606.1549.
compound 16_b: 1 H NMR(500MHz,DMSO-d 6 )δ10.38(s,1H),9.17(s,1H),7.92(s,2H),7.85-7.81(m,2H),7.77(d,J＝1.6Hz,1H),7.72(d,J＝8.3Hz,2H),7.57(d,J＝8.4Hz,2H),7.17(s,1H),6.51(s,1H),5.67(s,1H),3.29-3.27(m,4H),3.18(s,3H),3.13-3.09(m,1H),2.33-2.30(m,2H).HRMS(ESI+,[M+H] + ) m/z:606.1551. example 17
Step A:
to a 100mL single port flask, intermediate E-3 (200 mg), DMF (8 mL), pyridine (65 mg), 15-3 (94 mg,0.494 mmol) and T were added sequentially 3 P (262 mg), stirring at room temperature for 20h, after the reaction, adding 100mL of saturated ammonium chloride solution to the reaction solution, extracting with ethyl acetate (2X 100 mL), washing with water, combining the organic phases, drying, concentrating under reduced pressure, and purifying the crude product by silica gel column chromatography (eluent: DCM/MeOH=20/1) to obtain compound 17 (120 mg). MS (ESI-, [ M-H ]] - )m/z：621.4.
And (B) step (B):
compound 17 (120 mg) was resolved by preparative HPLC (resolution: column: CHIRALPAK IG 4.6.6 x250mm 5 μm; mobile phase: n-hexane: ethanol=55:45; flow: 1mL/min; wavelength: 254 nm) to give compound 17_A (14 mg, retention time 8.637 min), followed by 17_B (16 mg, retention time 13.491 min).
Compound 17_a: 1 H NMR(500MHz,DMSO-d 6 )δ10.71(s,1H),8.60(s,1H),8.52(s,1H),8.44(d,J＝4.8Hz,1H),8.06(s,2H),7.79–7.72(m,2H),7.66–7.62(m,1H),7.55(t,J＝7.7Hz,1H),7.52–7.46(m,2H),7.36(q,J＝7.2,5.6Hz,2H),7.30(dd,J＝8.1,1.9Hz,1H),6.37(s,1H),5.94(dd,J＝10.1,6.1Hz,1H),3.51–3.46(m,2H),3.38(s,3H).HRMS(ESI+,[M+H] + )m/z：623.1206.
compound 17_b: 1 H NMR(500MHz,DMSO-d 6 )δ10.71(s,1H),8.60(s,1H),8.51(d,J＝2.3Hz,1H),8.43(dd,J＝4.7,1.7Hz,1H),8.06(s,2H),7.78(dd,J＝8.6,2.4Hz,1H),7.73(d,J＝8.5Hz,1H),7.64(d,J＝2.3Hz,1H),7.55(t,J＝7.7Hz,1H),7.50–7.45(m,2H),7.35(s,1H),7.34–7.32(m,1H),7.30(dd,J＝8.1,1.9Hz,1H),6.37(s,1H),5.94(dd,J＝10.2,5.9Hz,1H),3.46(d,J＝5.9Hz,2H),3.38(s,3H).HRMS(ESI+,[M+H] + )m/z：623.1205.
example 18
Step A:
referring to step A of example 9, substituting intermediate 13-1 for 9-1 gave compound 18 (237 mg). MS (ESI+ [ M+H)] + ) m/z:605.22. and (B) step (B):
compound 18 (237 mg) was subjected to preparative HPLC (resolution conditions: column: CHIRALART Cellulose-SB 4.6X100mm,5 μm; mobile phase: ethanol: CO) 2 =30:70; flow rate: 2mL/min; wavelength: 254 nm) and compound 18_a (50 mg, retention time 5.620 min) and compound 18_b (49 mg, retention time 7.737 min).
Compound 18_a: 1 H NMR(500MHz,DMSO-d 6 )δ10.52(s,1H),8.60(s,1H),8.51(s,1H),8.42(d,J＝4.0Hz,1H),7.95(s,2H),7.80–7.71(m,4H),7.65(s,1H),7.58(s,1H),7.56(s,1H),7.45(s,1H),7.38(s,1H),7.32(dd,J＝7.5,4.9Hz,1H),6.37(s,1H),5.98(dd,J＝10.4,5.4Hz,1H),3.52–3.41(m,2H),3.33(s,3H)。HRMS(ESI+,[M+H] + )m/z：605.1286.
compound 18_b: 1 H NMR(500MHz,DMSO-d 6 )δ10.52(s,1H),8.60(s,1H),8.51(s,1H),8.42(d,J＝4.0Hz,1H),7.95(s,2H),7.81–7.71(m,4H),7.65(s,1H),7.58(s,1H),7.56(s,1H),7.45(s,1H),7.38(s,1H),7.32(dd,J＝7.5,4.9Hz,1H),6.37(s,1H),5.98(dd,J＝10.4,5.4Hz,1H),3.46(dd,J＝16.8,7.8Hz,2H),3.33(s,3H)。HRMS(ESI+,[M+H] + )m/z：605.1296.
example 19
Step A:
to a 500mL three-necked flask, benzophenone (10 g), chloroform (200 mL), anhydrous aluminum trichloride (14.63 g) and a solution of 19-1 (17 g) in triethylamine (38 mL) were added dropwise slowly under ice bath conditions, and the mixture was stirred at room temperature for 12 hours. After the completion of the reaction, 4M sodium hydroxide solution (60 mL) was added to the reaction mixture to adjust the pH to 7-8. Water (200 mL) and DCM (100 mL) were added and the aqueous phase was extracted with DCM (60 mL x 2) and the organic phases combined100mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product obtained was purified by silica gel column chromatography (eluent: petroleum ether) to give 19-2 (20.3 g). MS (ESI+ [ M+H)] + )m/z：369.98.
And (B) step (B):
Into a 500mL three-necked flask, 19-2 (10.6 g), tetrahydrofuran (150 mL) and N were sequentially added 2 Under protection, after precooling at 78 ℃, an ether solution of n-butyllithium (1.6 m,19.66 ml) was slowly added dropwise, and stirring was continued for 1h at-78 ℃. Triisopropyl borate (6.99 g) was slowly added dropwise to the reaction solution, and the mixture was then transferred to room temperature and stirred for 1 hour. After the completion of the reaction, the reaction was quenched with saturated ammonium chloride solution (80 mL), 100mL of water was added, extracted with ethyl acetate (80 ml×2), washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (eluent: PE/ea=3/1) to give 19-3 (2.2 g). MS (ESI+ [ M+H)] + )m/z：335.98.
Step C:
to a 100mL single-necked flask, 19-3 (2.2 g) of an ethyl acetate solution of hydrogen chloride (2M, 40 mL) was successively added, and the mixture was stirred at room temperature for 12 hours. After the reaction, the mixture was filtered by suction, and 40mL of ethyl acetate was added to the filter cake, followed by stirring for 1 hour, followed by suction again, and the filter cake was dried to obtain 19-4 (1 g). 1 H NMR(500MHz,DMSO)δ7.45(d,J＝8.0Hz,1H),7.19(d,J＝1.5Hz,1H),7.10(dd,J＝7.9,1.7Hz,1H).
Step D:
in a 50mL single-necked flask, intermediate C-6 (220 mg), HATU (395 mg), DMF (6 mL) was dissolved, DIPEA (269 mg) was added, and intermediate 19-4 (216 mg) was added after stirring uniformly and stirred at room temperature for 10h. After the reaction, the reaction was stopped, the solvent was dried by spin-drying, and 30mL of water was added. Extraction with ethyl acetate (15 mL x 3), combined organic phases, washing with 30mL saturated brine, drying over anhydrous sodium sulphate, concentrating under reduced pressure and purification of the crude product by silica gel column chromatography (eluent DCM/meoh=25/1) gives compound 19 (146 mg). MS (ESI+ [ M+H) ] + )m/z：576.12.
Step E:
compound 19 (146 mg) was resolved by preparative HPLC (resolution: column CHIRALPAK IG 4.6.6X250 mm,5 μm; mobile phase: n-hexane: ethanol=70:30; flow rate: 1mL/min; wavelength: 254 nm), compound 19_A (55 mg, retention time 7.297 min), compound 19_B (60 mg, retention time 12.723 min).
Compound 19_a: 1 H NMR(500MHz,DMSO-d 6 )δ10.55(s,1H),8.62(s,1H),8.19(s,2H),7.79(d,J＝2.1Hz,1H),7.76(d,J＝8.5Hz,1H),7.74(s,2H),7.45–7.38(m,2H),7.18(s,1H),6.47(s,1H),5.54(dd,J＝9.9,6.0Hz,1H),3.31(s,3H),2.16–2.01(m,2H),0.82(t,J＝7.3Hz,3H).。HRMS(ESI+,[M+H] + )m/z：576.0783.
compound 19_b: 1 H NMR(500MHz,DMSO-d 6 )δ10.55(s,1H),8.62(s,1H),8.20(s,2H),7.79(d,J＝2.1Hz,1H),7.76(d,J＝8.5Hz,1H),7.74(s,2H),7.41(t,J＝7.1Hz,2H),7.18(s,1H),6.47(s,1H),5.54(dd,J＝9.8,5.9Hz,1H),3.31(s,3H),2.15–1.99(m,2H),0.81(t,J＝7.2Hz,3H).。HRMS(ESI+,[M+H] + ) m/z:576.0783. example 20
Step A:
f-3 (80 mg), DCM (10 mL), HATU (125 mg) and N, N-diisopropylethylamine (42.50 mg) were added sequentially to a 50mL single-necked flask, and after stirring uniformly, 1-1 (36.70 mg) was added thereto and the reaction was stirred at room temperature overnight. After completion of the reaction, methylene chloride (10 mL) and water (10 mL) were added to the reaction mixture, the organic phase was separated, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: DCM/meoh=20/1) to give compound 20 (41.70 mg). 1 H NMR(500MHz,DMSO-d 6 )δ10.40(s,1H),9.20(s,1H),9.19(s,1H),8.01(d,J＝1.5Hz,1H),7.88-7.80(m,2H),7.77(d,J＝1.7Hz,1H),7.63(dd,J＝8.3,1.9Hz,1H),7.34(d,J＝8.3Hz,1H),7.19(s,1H),6.51(s,1H),5.70(s,1H),4.94(s,2H),3.27(s,4H),3.19(s,3H),3.16-3.08(m,1H),2.34-2.30(m,2H).HRMS(ESI+,[M+H] + ) m/z:618.1551. example 21
Step A:
into a 250mL single-necked flask, 21-1 (3 g), 2, 5-dimethoxypyridine-4-boric acid (2.54 g), dioxane (50 mL), potassium carbonate (5.75 g) and [1,1' -bis (diphenylphosphine) ferrocene were sequentially added]Palladium dichloride dichloromethane complex (1.132 g), under the protection of nitrogen, the reaction solution is heated to 110 ℃ and stirred for 16h. After the completion of the reaction, ethyl acetate (200 mL) was added to the reaction mixture to extract, which was washed with water, the organic phases were combined, dried, concentrated to dryness under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: PE/ea=20/1) to give 21-2 (2.44 g). MS (ESI+ [ M+H) ] + )m/z：274.94. 1 H NMR(500MHz,DMSO-d 6 )δ8.07(s,1H),7.99(d,J＝8.2Hz,1H),7.73-7.71(m,2H),6.88(s,1H),3.86(s,3H),3.81(s,3H).
And (B) step (B):
a500 mL single-necked flask was charged with 21-2 (1.5 g), 2-propanol (50 mL), lithium chloride (1.157 g) and p-toluenesulfonic acid monohydrate (1.870 g) in this order, and the reaction mixture was heated to 100℃and stirred for 16h. After the reaction was stopped, the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure by a rotary evaporator, 50mL of distilled water was added to the residue, and the mixture was stirred and beaten at room temperature. Insoluble solids in the system were collected by suction filtration and dried in vacuo at 40℃in a vacuum oven to give 21-3 (1.47 g). MS (ESI+ [ M+H)] + )m/z：260.91. 1 H NMR(500MHz,DMSO-d 6 ) Delta 7.98 (d, j=8.3 hz, 1H), 7.71 (dd, j=8.3, 2.1hz, 1H), 7.69 (d, j=2.0 hz, 1H), 7.30 (s, 1H), 6.43 (s, 1H), 3.64 (s, 3H). Step C:
in a 100mL single-necked flask, 21-3 (0.5 g), DMF (15 mL), potassium carbonate (0.398 g) and tert-butyl bromoacetate (0.56 g,0.42 mL) were successively added, and the mixture was reacted at room temperature for 2.5 hours. After the completion of the reaction, ethyl acetate (100 mL) was added to the reaction mixture to extract, which was washed with water, the organic phases were combined, dried, concentrated to dryness under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: PE/ea=1/1) to give 21-4 (0.504 g). MS (ESI+ [ M+Na)] + )m/z：397.09. 1 H NMR(500MHz,DMSO-d 6 )δ7.99(d,J＝8.2Hz,1H),7.74–7.70(m,2H),7.56(s,1H),6.50(s,1H),4.60(s,2H),3.61(s,3H),1.44(s,9H).
Step D:
in a 100mL three-necked flask, 21-4 (0.5 g) was dissolved in THF (20 mL), and the mixture was transferred to a-78℃low temperature tank under nitrogen protection and stirred in a pre-chilled manner. LiHMDS (0.335 g,2.00 mL) was added dropwise to the system at-78deg.C, after which the reaction was continued with stirring at that temperature for 1h. THF (4 mL) dissolved p-fluorobenzyl bromide (0.30 g,0.2 mL) was added dropwise to the system at-78deg.C, and the reaction was quenched with 10mL saturated brine after stirring at this temperature for 3 h. Ethyl acetate (100 mL) was added to the reaction solution for extraction, water washing, the organic phases were combined, dried, concentrated to dryness under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: PE/ea=7/3) to obtain 21-5 (0.454 g). MS (ESI+ [ M+H) ] + )m/z：483.13. 1 H NMR(500MHz,DMSO-d 6 )δ7.96(d,J＝8.4Hz,1H),7.71(dd,J＝8.4,2.1Hz,1H),7.68–7.63(m,1H),7.19–7.15(m,2H),7.14(s,1H),7.07–7.02(m,2H),6.44(s,1H),5.27(dd,J＝8.8,7.1Hz,1H),3.46(s,3H),3.43–3.38(m,2H),1.41(s,9H).
Step E:
in a 100mL single-necked flask, 21-5 (0.44 g), DCM (25 mL) and trifluoroacetic acid (3.12 g,2.09 mL) were sequentially added, and the mixture was stirred at room temperature for 16h. The solvent was distilled off under reduced pressure by means of a rotary evaporator, ethyl acetate (100 mL) was added to the residue, the organic phases were combined, dried, concentrated to dryness under reduced pressure, and the resulting crude product was purified by column chromatography over silica gel (eluent: DCM/meoh=100/1) to give 21-6 (0.344 g). MS (ESI+ [ M+H)] + )m/z：427.09. 1 H NMR(500MHz,DMSO-d 6 )δ13.16(s,1H),7.96(d,J＝8.3Hz,1H),7.71(dd,J＝8.4,2.1Hz,1H),7.66(d,J＝2.1Hz,1H),7.18(s,1H),7.16–7.12(m,2H),7.05–6.99(m,2H),6.40(s,1H),5.38–5.23(m,1H),3.46(s,3H),3.45–3.41(m,2H).
Step F:
a100 mL single flask was charged with 21-6 (0.125 g), 1-1 (0.087 g), DCM (12 mL), HATU (0.278 g) and DIPEA (0.151 g) in this order and stirred at room temperature for 17 hours. After the reaction, ethyl acetate (100 mL) is added into the reaction solution for extraction, water washing is carried out, the organic phases are combined, and the mixture is dried and concentrated under reduced pressure to drynessThe crude product obtained was purified by column chromatography on silica gel (eluent: DCM/meoh=100/1) to give compound 21 (140 mg). MS (ESI+ [ M+H)] + )m/z：558.07.
Step G:
compound 21 (140 mg) was subjected to preparative HPLC (resolution conditions: chromatography column CHIRALPAK IG (4.6x250 mm,5 μm), mobile phase: n-hexane: ethanol=60:40, flow rate: 1mL/min, wavelength: 254 nm) =75:25; flow rate: 1mL/min; wavelength: 254 nm) and compound 21_a (65 mg, retention time 14.528 min) and compound 21_b (69 mg, retention time 23.701 min).
Compound 21_a: 1 H NMR(500MHz,DMSO-d 6 )δ10.57(s,1H),9.24(s,1H),8.06(d,J＝1.9Hz,1H),7.97(d,J＝8.4Hz,1H),7.71(dd,J＝8.4,2.2Hz,1H),7.68–7.61(m,3H),7.38(d,J＝8.3Hz,1H),7.34–7.29(m,2H),7.11–7.04(m,2H),6.40(s,1H),6.04(dd,J＝10.8,5.5Hz,1H),4.95(s,2H),3.69(s,3H),3.55(dd,J＝14.4,
10.9Hz,1H),3.46(dd,J＝14.3,5.5Hz,1H).HRMS(ESI+,[M+H]+)m/z：558.1416.
compound 21_b: 1 H NMR(500MHz,DMSO-d 6 )δ10.58(s,1H),9.24(s,1H),8.06(d,J＝2.0Hz,1H),7.97(d,J＝8.4Hz,1H),7.71(dd,J＝8.3,2.1Hz,1H),7.70–7.61(m,3H),7.38(d,J＝8.3Hz,1H),7.35–7.29(m,2H),7.12–7.04(m,2H),6.40(s,1H),6.04(dd,J＝10.8,5.4Hz,1H),4.95(s,2H),3.69(s,3H),3.55(dd,J＝14.3,10.9Hz,1H),3.46(dd,J＝14.5,5.3Hz,1H).HRMS(ESI+,[M+H]+)m/z：558.1411.
example 22
Step A:
to a 100mL single-necked flask, 22-1 (1.1 g), methanol (20 mL), a saturated aqueous ammonium chloride solution (10 mL), and iron powder (1.2 g) were sequentially added, N 2 Under the protection of the device, the device can be used for protecting the environment,heated to 65 ℃ and reacted for 4 hours. After completion of the reaction, 30mL of water was added, extraction was performed with ethyl acetate (30 mL. Times.3), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give 22-2 (450 mg). 1 H NMR(500MHz,DMSO-d 6 )δ7.29(d,J＝8.6Hz,1H),6.94(d,J＝2.8Hz,1H),6.63(dd,J＝8.6,2.8Hz,1H),5.55(s,2H),3.80(s,3H).
And (B) step (B):
to a 100mL single-necked flask, 22-2 (1 g), methanol (30 mL) and Boc were sequentially added 2 O (1.6 g), stirring at room temperature for 20h. After the reaction was completed, it was concentrated to dryness under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent DCM/meoh=25/1) to give example 22-3 (1.37 g). 1 HNMR(500MHz,DMSO-d 6 )δ9.71(s,1H),7.98(d,J＝2.5Hz,1H),7.61(d,J＝8.8Hz,1H),7.47(dd,J＝8.8,2.6Hz,1H),3.85(s,3H),1.48(s,9H).
Step C:
in a 100mL single-necked flask, 22-3, N was dissolved in tetrahydrofuran (20 mL) 2 After protection, a tetrahydrofuran solution of methyl magnesium bromide (3M, 3.94 mL) was slowly added dropwise under ice bath conditions, and the mixture was stirred for 20min under ice bath conditions, and then transferred to room temperature and stirred for 12h. After the completion of the reaction, the reaction was quenched with saturated ammonium chloride solution (20 mL), 40mL of water was added, extracted with ethyl acetate (30 ml×2), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to dryness, and the obtained crude product was subjected to silica gel column chromatography (eluent: PE/ea=3/1) to give 22-4 (1.1 g). 1 H NMR(500MHz,DMSO-d 6 )δ9.43(s,1H),8.02(d,J＝2.5Hz,1H),7.41(d,J＝8.6Hz,1H),7.26–7.14(m,1H),5.18(s,1H),1.58(s,6H),1.47(s,9H).
Step D:
in a 50mL single-necked flask, 22-4 (150 mg), tetrahydroxydiboron (122 mg), X-Phos (21.7 mg), potassium acetate (134 mg), ethanol (6 mL) and X-Phos Pd G2 (71.4 mg), N were sequentially added 2 And under the protection, refluxing and stirring for 16h at 85 ℃. After the reaction, the filtrate was concentrated to dryness under reduced pressure by filtration with the aid of celite, and the crude product was subjected to silica gel column chromatography (eluent: PE/ea=1/1) to give 22-5 (60 mg). 1 H NMR(500MHz,DMSO-d 6 )δ9.50(s,1H),8.83(s,1H),7.57(s,1H),7.51(d,J＝8.0Hz,1H),7.25(d,J＝7.9Hz,1H),1.48(s,9H),1.40(s,6H).
Step E:
to a 50mL single-necked flask, 22-5 (60 mg) of a hydrogen chloride-ethyl acetate solution (1N, 10 mL) was successively added, and the mixture was stirred at room temperature for 12 hours. After the completion of the reaction, the solvent was dried to obtain 22-6 (45 mg). 1 H NMR(500MHz,DMSO-d 6 )δ7.64(d,J＝8.3Hz,1H),7.09(s,1H),7.08(s,1H),1.43(s,6H).
Step F:
referring to step A of example 9, substituting intermediate 22-6 for 9-1 gave compound 22 (120 mg). MS (ESI+ [ M+H)] + ) m/z:645.25. step G:
compound 22 (146 mg) was resolved by preparative HPLC (resolution: column: region- (R, R) WHELK-O1.6X250 mm 5 μm; mobile phase: n-hexane: ethanol: dichloromethane=70:10:20; flow rate: 1mL/min; wavelength: 254 nm), compound 22_A (mg, retention time 15.059 min), compound 22_B (mg, retention time 18.018 min).
Compound 22_a: 1 H NMR(500MHz,DMSO-d 6 )δ10.64(s,1H),8.95(s,1H),8.59(s,1H),8.52(s,1H),8.43(dd,J＝4.7,1.5Hz,1H),7.77(d,J＝2.3Hz,1H),7.74(s,2H),7.64(d,J＝2.0Hz,1H),7.62(d,J＝7.9Hz,1H),7.44(dd,J＝8.0,1.6Hz,2H),7.37(s,1H),7.33(dd,J＝7.7,4.8Hz,1H),6.37(s,1H),5.98(dd,J＝10.8,5.3Hz,1H),3.48(ddd,J＝19.8,14.6,8.2Hz,2H),3.34(s,3H),1.43(d,J＝3.2Hz,6H)。HRMS(ESI+,[M+H] + )m/z：645.1600.
compound 22_b: 1 H NMR(500MHz,DMSO-d 6 )δ10.64(s,1H),8.95(s,1H),8.59(s,1H),8.52(s,1H),8.43(d,J＝4.2Hz,1H),7.78(dd,J＝8.6,2.3Hz,1H),7.74(s,2H),7.64(d,J＝2.0Hz,1H),7.62(d,J＝7.9Hz,1H),7.44(dd,J＝8.0,1.6Hz,2H),7.37(s,1H),7.33(dd,J＝7.7,4.8Hz,1H),6.37(s,1H),5.98(dd,J＝10.8,5.3Hz,1H),3.53–3.42(m,2H),3.34(s,3H),1.43(d,J＝3.2Hz,6H)。HRMS(ESI+,[M+H] + )m/z：645.1598.
example 23
Step A:
referring to step A of example 11, 5-5 was replaced with intermediate 22-6 to give compound 23 (200 mg). MS (ESI+ [ M+H) ] + ) m/z:646.28. and (B) step (B):
compound 23 (200 mg) was resolved by preparative HPLC (resolution: column: regis- (R, R) WHELK-O1.6X250 mm 5 μm; mobile phase: n-hexane: ethanol=80:15; flow rate: 1mL/min; wavelength: 254 nm), compound 23_A (46 mg, retention time 15.216 min), compound 23_B (32 mg, retention time 17.377 min).
Compound 23_a: 1 H NMR(500MHz,DMSO-d 6 )δ10.49(s,1H),9.15(s,1H),8.92(s,1H),7.86–7.80(m,2H),7.77(s,2H),7.58(d,J＝7.9Hz,1H),7.41(dd,J＝8.0,1.5Hz,1H),7.16(s,1H),6.51(s,1H),5.67(s,1H),3.27(s,3H),3.22–3.08(m,5H),2.33(dd,J＝13.5,6.8Hz,2H),1.41(d,J＝1.7Hz,6H)。HRMS(ESI+,[M+H] + )m/z：646.1851
compound 23_b: 1 H NMR(500MHz,DMSO-d 6 )δ10.49(s,1H),9.15(s,1H),8.92(s,1H),7.85–7.86(s,2H),7.77(s,2H),7.58(d,J＝8.0Hz,1H),7.41(dd,J＝8.0,1.5Hz,1H),7.16(s,1H),6.51(s,1H),5.67(s,1H),3.27(s,3H),3.20–3.10(m,5H),2.33(dd,J＝13.5,6.9Hz,2H),1.41(d,J＝1.7Hz,6H).。HRMS(ESI+,[M+H] + )m/z：646.1852.
example 24
Step A:
referring to example 21, in step F, 13-1 was used instead of 1-1 to obtain compound 24 (160 mg). 1 H NMR(500MHz,DMSO-d 6 )δ10.56(s,1H),7.97(d,J＝8.3Hz,1H),7.93(s,2H),7.76(d,J＝8.4Hz,2H),7.71(dd,J＝8.4,2.1Hz,1H),7.66(d,J＝2.1Hz,1H),7.64(s,1H),7.59(d,J＝8.4Hz,2H),7.34–7.29(m,2H),7.10–7.05(m,2H),6.39(s,1H),6.02(dd,J＝11.0,5.3Hz,1H),3.69(s,3H),3.55(dd,J＝14.4,11.0Hz,1H),3.45(dd,J＝14.4,5.3Hz,1H).HRMS(ESI+,[M+H] + )m/z：546.1406.
Example 25
Step A:
referring to example 13, in step A, 22-6 was used instead of 13-1 to obtain compound 25 (28 mg). 1 H NMR(500MHz,DMSO-d 6 )δ10.55(s,1H),8.92(s,1H),8.62(s,1H),7.79(dd,J＝8.5,2.3Hz,1H),7.77–7.72(m,3H),7.59(d,J＝7.9Hz,1H),7.41(dd,J＝8.0,1.7Hz,1H),7.18(s,1H),6.47(s,1H),5.57(dd,J＝10.3,5.8Hz,1H),3.31(s,3H),2.16–2.04(m,2H),1.41(s,6H),0.83(t,J＝7.2Hz,3H).HRMS(ESI+,[M+H] + )m/z：582.1486.
Examples 26 to 33
Referring to the synthetic methods of the present application, compounds 26-33 were prepared.
Test example 1: in vitro FXIa enzyme inhibition Activity
FXIa enzyme solution (concentration 2.5 ng/. Mu.L) was added to the wells at a concentration of 10. Mu.L per well, and different compounds dissolved in DMSO were added to the wells using a nanoliter sample applicator to give final concentrations of 1000nM to 0.061nM for the compounds, 2 multiplex wells, and a control was set. The above system was incubated for 10 minutes, and p-Glu-Pro-Arg-pNa.HCl substrate (manufacturer: HYPHEN BioMed, concentration 2 mM) was added to the detection wells at a concentration of 10. Mu.L per well; the room temperature reaction 30min,PerkinElmer Envision multifunctional enzyme label instrument detects (OD 405 nm) and adopts four-parameter fitting to calculate IC 50 . The test results are shown in Table 1.
TABLE 1 in vitro FXIa enzyme inhibitory Activity of some of the Compounds of the present application
Compounds of formula (I) hFXIa IC 50 (nM) Compounds of formula (I) hFXIa IC 50 (nM)
3_B ＜30 13_B ＜30
4_B ＜30 14_B ＜30
5 ＜100 15_B ＜30
5_B ＜30 16_B ＜30
7_B ＜30 17_B ＜30
8 ＜100 18_B ＜30
9_B ＜30 19_A ＜30
10_B ＜30 20 ＜100
11_B ＜30 25 ＜100
12_B ＜100
。

Claims (10)

1. A compound of formula (I-0), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
wherein,
ring A is selected from C 6-10 C containing at least one B atom in the aryl, 5-to 10-membered heteroaryl, ring atom 6-10 Aryl 5-8 membered heterocyclyl or 5-10 membered heteroaryl 5-8 membered heterocyclyl containing at least one B atom in the ring atom, said C 6-10 Aryl or 5-to 10-membered heteroaryl moieties
R a Substituted and optionally substituted with one or more R b Substitution, said C 6-10 Aryl and 5-8 membered heterocyclyl or 5-10 membered heteroarylAnd the ring atoms in the 5-8 membered heterocyclyl optionally contain one or more heteroatoms selected from N, O, S, said C 6-10 Aryl 5-8 membered heterocyclyl or 5-10 membered heteroaryl 5-8 membered heterocyclyl optionally substituted with one or more R b Substitution;
R a selected from- (CH) 2 ) p -BR c R d 、-O(CH 2 ) p -BR c R d - (CH) having at least one B atom in the ring 2 ) p -5-12 membered heterocyclyl or-O (CH) containing at least one B atom in the ring atom 2 ) p -a 5-12 membered heterocyclyl group, said- (CH) 2 ) p -5-12 membered heterocyclyl or-O (CH) 2 ) p The ring atoms in the 5-12 membered heterocyclyl optionally contain one or more heteroatoms selected from N, O, S, said- (CH) 2 ) p -5-12 membered heterocyclyl or
-O(CH 2 ) p -5-12 membered heterocyclyl optionally substituted with one or more R e Substitution;
p is selected from 0, 1, 2, 3 or 4;
R b independently selected from halogen, -CN, -OH, -NH 2 、-NH(C 1-6 Alkyl), -N (C) 1-6 Alkyl group 2 、C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, -C (O) OH, -C (O) NH 2 、-C(O)NH(C 1-6 Alkyl), -C (O) N (C) 1-6 Alkyl group 2 、-NHC(O)C 1-3 Alkyl, -S (O) 2 C 1-3 Alkyl, -S (O) 2 NH 2 、-S(O) 2 NH(C 1-6 Alkyl) or
-S(O) 2 N(C 1-6 Alkyl group 2 ；
R c And R is d Each independently selected from-OH, C 1-6 Alkoxy or amino C 1-6 An alkyl group;
R e independently selected from oxo, halogen, -CN, -OH, -NH 2 、-NH(C 1-6 Alkyl), -N (C) 1-6 Alkyl group 2 、C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, -C (O) OH, -C (O) NH 2 、
-C(O)NH(C 1-6 Alkyl) or-C (O) N (C) 1-6 Alkyl group 2 ；
Ring C is selected from phenyl, 6 membered heteroaryl, 6 membered heterocycloalkyl, or 6 membered heterocycloalkenyl;
each R is 1 Each independently selected from oxo, halogen, -CN, -OH, -NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl-O-, said C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl-O-optionally substituted with one or more groups selected from: -CN, -OH, -NH 2 Or halogen;
m is selected from 0, 1, 2, 3 or 4;
each R is 2 Each independently selected from halogen, -CN, -OH, -NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl optionally substituted with one or more halo;
n is selected from 0, 1, 2, 3 or 4;
R 3 selected from hydrogen, halogen, -CN, -OH, -NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl C (O) -or 5-6 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl C (O) -or 5-6 membered heteroaryl optionally substituted with one or more groups selected from:
-CN、-OH、-NH 2 halogen or halogenated C 1-6 An alkyl group;
l is selected from bond, O, S or-CR f R g -；
R f And R is g Each independently selected from H, halogen, -CN, -OH, -NH 2 、C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or halo C 1-6 An alkoxy group;
R 4 selected from C 1-6 Alkyl, C 1-8 Heteroalkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, said C 1-6 Alkyl, C 1-8 Heteroalkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl optionally substituted with one or more R 4a Substitution;
R 4a selected from oxo, halogen, -CN, -OH, -NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl or halo C 1-6 An alkoxy group;
R 5 selected from hydrogen, C 1-6 Alkyl or halo C 1-6 An alkyl group;
optionally, the R b 、R c 、R d 、R e 、R f 、R g 、R 4a 、R 1 、R 2 、R 3 、R 4 Or R 5 May be substituted with one or more substituents.
2. The compound of formula (I-0), stereoisomer thereof, or pharmaceutically acceptable salt thereof, as claimed in claim 1, which is selected from the group consisting of a compound of formula (I), stereoisomer thereof, or pharmaceutically acceptable salt thereof,
Wherein,
ring A is selected from C 6-10 C containing at least one B atom in the aryl, 5-to 10-membered heteroaryl, ring atom 6-10 Aryl 5-8 membered heterocyclyl or 5-10 membered heteroaryl 5-8 membered heterocyclyl containing at least one B atom in the ring atom, said C 6-10 Aryl or 5-to 10-membered heteroaryl moieties
R a Substituted and optionally substituted with one or more R b Substitution, said C 6-10 The ring atoms in the aryl-5-8 membered heterocyclyl or 5-10 membered heteroaryl-5-8 membered heterocyclyl optionally contain one or more heteroatoms selected from N, O, S,the C is 6-10 Aryl 5-8 membered heterocyclyl or 5-10 membered heteroaryl 5-8 membered heterocyclyl optionally substituted with one or more R b Substitution;
R a selected from- (CH) 2 ) p -BR c R d 、-O(CH 2 ) p -BR c R d - (CH) having at least one B atom in the ring 2 ) p -5-12 membered heterocyclyl or-O (CH) containing at least one B atom in the ring atom 2 ) p -a 5-12 membered heterocyclyl group, said- (CH) 2 ) p -5-12 membered heterocyclyl or-O (CH) 2 ) p The ring atoms in the 5-12 membered heterocyclyl optionally contain one or more heteroatoms selected from N, O, S, said- (CH) 2 ) p -5-12 membered heterocyclyl or
-O(CH 2 ) p -5-12 membered heterocyclyl optionally substituted with one or more R e Substitution;
p is selected from 0, 1, 2, 3 or 4;
R b independently selected from halogen, -CN, -OH, -NH 2 、-NH(C 1-6 Alkyl), -N (C) 1-6 Alkyl group 2 、C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, -C (O) OH, -C (O) NH 2 、-C(O)NH(C 1-6 Alkyl), -C (O) N (C) 1-6 Alkyl group 2 、-NHC(O)C 1-3 Alkyl, -S (O) 2 C 1-3 Alkyl, -S (O) 2 NH 2 、-S(O) 2 NH(C 1-6 Alkyl) or
-S(O) 2 N(C 1-6 Alkyl group 2 ；
R c And R is d Each independently selected from-OH, C 1-6 Alkoxy or amino C 1-6 An alkyl group;
R e independently selected from oxo, halogen, -CN, -OH, -NH 2 、-NH(C 1-6 Alkyl), -N (C) 1-6 Alkyl group 2 、C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxyC 1-6 Alkyl, amino C 1-6 Alkyl, -C (O) OH, -C (O) NH 2 、
-C(O)NH(C 1-6 Alkyl) or-C (O) N (C) 1-6 Alkyl group 2 ；
Each R is 1 Each independently selected from halogen, -CN, -OH, -NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl-O-, said C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl-O-optionally substituted with one or more groups selected from: -CN, -OH, -NH 2 Or halogen;
m is selected from 0, 1, 2, 3 or 4;
each R is 2 Each independently selected from halogen, -CN, -OH, -NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl optionally substituted with one or more halo; n is selected from 0, 1, 2, 3 or 4;
R 3 selected from halogen, -CN, -OH, -NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl C (O) -or 5-6 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl C (O) -or 5-6 membered heteroaryl optionally substituted with one or more groups selected from: -CN, -OH, -NH 2 Halogen or halogenated C 1-6 An alkyl group;
l is selected from bond, O, S or-CR f R g -；
R f And R is g Each independently selected from H, halogen, -CN, -OH, -NH 2 、C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or halo C 1-6 An alkoxy group;
R 4 selected from C 1-6 Alkyl, C 1-8 Heteroalkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, said C 1-6 Alkyl, C 1-8 Heteroalkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl or3-6 membered heterocycloalkyl optionally substituted with one or more R 4a Substitution;
R 4a selected from oxo, halogen, -CN, -OH, -NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl or halo C 1-6 An alkoxy group;
R 5 selected from hydrogen, C 1-6 Alkyl or halo C 1-6 An alkyl group.
3. A compound of formula (I-0), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as claimed in claim 1 or 2 wherein ring a is selected from C 6-10 C containing at least one B atom in the aryl, 5-to 10-membered heteroaryl, ring atom 6-10 Aryl 5-8 membered heterocyclyl or 5-10 membered heteroaryl 5-8 membered heterocyclyl containing at least one B atom in the ring atom, said C 6-10 Aryl or 5-to 10-membered heteroaryl groups are substituted by R a Substituted and optionally substituted with one or more R b Substitution, said C 6-10 The ring atoms in the aryl-5-8 membered heterocyclyl or 5-10 membered heteroaryl-5-8 membered heterocyclyl optionally contain one or more O atoms, said C 6-10 Aryl 5-8 membered heterocyclyl or 5-10 membered heteroaryl 5-8 membered heterocyclyl optionally substituted with one or more R b Substitution;
or, ring A is selected from phenyl, 5-6 membered heteroaryl, phenyl and 5-8 membered heterocyclyl containing at least one B atom in the ring atom, or 5-6 membered heteroaryl and 5-8 membered heterocyclyl containing at least one B atom in the ring atom, said phenyl or 5-6 membered heteroaryl being substituted with R a Substituted and optionally substituted with one or more R b A substitution, the ring atoms in the phenyl-5-8 membered heterocyclyl or 5-6 membered heteroaryl-5-8 membered heterocyclyl optionally containing one or more heteroatoms selected from N, O, S, the phenyl-5-8 membered heterocyclyl or 5-6 membered heteroaryl-5-8 membered heterocyclyl optionally being substituted with one or more R b Substitution;
or, ring A is selected from phenyl, pyridyl, a phenyl 5-6 membered heterocyclic group containing at least one B atom in the ring atoms, or a pyridyl 5-6 membered heterocyclic group containing at least one B atom in the ring atoms, said phenyl or pyridyl being substituted with R a Substitution ofAnd optionally by one or more R b Substituted, the ring atoms in the phenyl-5-6 membered heterocyclyl or the pyridinyl-5-6 membered heterocyclyl optionally contain one or more heteroatoms selected from N, O, S, the phenyl-5-6 membered heterocyclyl or the pyridinyl-5-6 membered heterocyclyl optionally being substituted with one or more R b Substitution;
alternatively, ring A is selected from phenyl, 5-6 membered heteroaryl, phenyl-5-6 membered heterocycloalkyl or pyridinyl-5-6 membered heterocycloalkyl, said phenyl or 5-6 membered heteroaryl being substituted with R a Substituted and optionally substituted with one or more R b Substituted, one and only one B atom and one O atom of the ring atoms of the phenyl-5-6 membered heterocycloalkyl or pyridinyl-5-6 membered heterocycloalkyl, optionally substituted with one or more R b Substitution;
or, ring A is selected from phenyl, pyridyl,The phenyl or pyridyl group being substituted by R a Substituted and optionally substituted with one or more R b Substitution, said->Optionally by one or more R b Substitution;
alternatively, ring A is selected from phenyl,Said phenyl or->Quilt R a Substituted and optionally substituted with one or more R b Substitution, said->
Optionally by one or more R b Substitution;
alternatively, ring A is selected from
Alternatively, ring A is selected from
4. A compound of formula (I-0), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3 wherein each R 1 Each independently selected from F, cl, br, -CN, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-5 cycloalkyl-O-, said C 1-4 Alkyl, C 1-4 Alkoxy or C 3-5 cycloalkyl-O-optionally substituted with one or more groups selected from: -OH, -NH 2 F, cl or Br;
alternatively, each R 1 Each independently selected from C 1-3 Alkyl, C 1-3 Alkoxy or C 3-4 cycloalkyl-O-, said C 1-3 Alkyl, C 1-3
Alkoxy or C 3-4 cycloalkyl-O-optionally substituted with one or more groups selected from: F. cl or Br;
alternatively, each R 1 Each independently selected from methoxy or cyclopropyl-O-, optionally substituted with one or more groups selected from: f or Cl;
alternatively, each R 1 Each independently selected from methoxy, cyclopropyl-O-or trifluoromethoxy;
alternatively, each R 2 Each independently selected from F, cl, br, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-5 Cycloalkyl or 3-5 membered heterocycloalkyl, said C 1-4 Alkyl, C 1-4 Alkoxy, C 3-5 Cycloalkyl or 3-5 membered heterocycloalkyl optionally substituted with one or more halo;
alternatively, each R 2 Each independently selected from F, cl, br, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-5 Cycloalkyl or 3-5 membered heterocycloalkyl;
alternatively, each R 2 Each independently selected from F, cl, br, -CN, C 1-3 Alkyl or C 3-4 Cycloalkyl;
alternatively, each R 2 Each independently selected from F, cl or Br;
Alternatively, each R 2 Each independently Cl.
5. A compound of formula (I-0), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 4 wherein R 3 Selected from F, cl, br, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl C (O) -or 5 membered heteroaryl, said C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl C (O) -or 5 membered heteroaryl optionally substituted with one or more groups selected from: -OH, -NH 2 F, cl, br or haloC 1-4 An alkyl group;
alternatively, R 3 Selected from-CN, C 1-4 Alkyl C (O) -or 5 membered heteroaryl, said C 1-4 Alkyl C (O) -or 5 membered heteroaryl optionally substituted with one or more groups selected from: -OH, -NH 2 F, cl, br or haloC 1-4 An alkyl group;
alternatively, R 3 Selected from-CN, C 1-4 Alkyl C (O) -or 5 membered heteroaryl containing 1-4 heteroatoms, said C 1-4 Alkyl C (O) -or 5 membered heteroaryl optionally substituted with one or more groups selected from: F. cl, br or haloC 1-4 An alkyl group;
alternatively, R 3 Selected from-CN, CH 3 C (O) -, triazolyl or tetrazolyl optionally substituted with one or more groups selected from the group consisting of: F. cl, br or fluoro C 1-3 An alkyl group;
alternatively, R 3 Selected from-CN, CH 3 C (O) -or triazolyl optionally substituted with one or more groups selected from the group consisting of: F. cl, monofluoromethyl, difluoromethyl or trifluoromethyl;
Alternatively, R 3 Selected from-CN,Or CH (CH) 3 C(O)-；
Alternatively, R 3 Selected from-CN,
6. A compound of formula (I-0), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 5 wherein C 1-4 Alkyl, C 1-6 Heteroalkyl, phenyl, 6-membered heteroaryl, C 3-5 Cycloalkyl or 5-6 membered heterocycloalkyl, said C 1-4 Alkyl, C 1-6 Heteroalkyl, phenyl, 6-membered heteroaryl, C 3-5 Cycloalkyl or 5-6 membered heterocycloalkyl optionally substituted with one or more R 4a Substitution;
alternatively, R 4 Selected from C 1-3 Alkyl, C 1-4 alkyl-O-CH 2 -, phenyl, 6 membered heteroaryl, C 3-5 Cycloalkyl or 5-6 membered heterocycloalkyl, said C 1-3 Alkyl, C 1-4 alkyl-O-CH 2 -, phenyl, 6 membered heteroaryl, C 3-5 Cycloalkyl or 5-6 membered heterocycloalkyl optionally substituted with one or more R 4a Substitution;
alternatively, R 4 Selected from methyl, C 1-2 alkyl-O-CH 2 -, phenyl, pyridyl, cyclopropyl orThe methyl group, C 1-2 alkyl-O-CH 2 -, phenyl, pyridyl, cyclopropyl or +.>Optionally by one or more R 4a Substitution;
alternatively, R 4 Selected from methyl, CH 3 -O-CH 2 -, phenyl or pyridyl, said methyl, CH 3 -O-CH 2 -, phenyl or pyridinyl optionally substituted with one or more R 4a Substitution;
alternatively, R 4 Selected from methyl, CH 3 -O-CH 2 -, phenyl group,
7. The compound of formula (I-0), stereoisomer thereof, or pharmaceutically acceptable salt thereof as claimed in any one of claims 1-6 wherein the compound of formula (I-0) is selected from the group consisting of compounds of formula (II), (III), (IV) or (V)
Wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R a 、R b N or ring a is as defined in any one of claims 1 to 40;
R 11 selected from-CN, -OH, -NH 2 Halogen or halogenated C 1-6 An alkyl group;
z is selected from N or CH;
q is selected from 0, 1, 2 or 3;
ring B is selected from a phenyl-5-6 membered heterocyclyl group containing at least one B atom in the ring atoms or a pyridinyl-5-6 membered heterocyclyl group containing at least one B atom in the ring atoms, said phenyl-5-6 membered heterocyclyl group or the ring atoms in the pyridinyl-5-6 membered heterocyclyl group optionally containing one or more heteroatoms selected from N, O, S.
8. The compound of formula (I-0), stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-7, wherein the compound of formula (I-0) is selected from the group consisting of:
alternatively, the compound of formula (I-0) is selected from the following compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof:
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9. a pharmaceutical composition comprising a compound of formula (I-0), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 8, optionally further comprising a pharmaceutically acceptable adjuvant.
10. Use of a compound of formula (I-0), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 8, or a pharmaceutical composition as claimed in claim 9, for the manufacture of a medicament for the treatment or prophylaxis of a disease.
CN202310858226.4A 2022-07-13 2023-07-13 Boron-containing compound and medical application thereof Pending CN117402183A (en)

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