CN112608318B - Compound as protein kinase inhibitor and application thereof - Google Patents

Compound as protein kinase inhibitor and application thereof Download PDF

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CN112608318B
CN112608318B CN202011491197.5A CN202011491197A CN112608318B CN 112608318 B CN112608318 B CN 112608318B CN 202011491197 A CN202011491197 A CN 202011491197A CN 112608318 B CN112608318 B CN 112608318B
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CN112608318A (en
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刘冠锋
岳春超
李筛
李英富
原晨光
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Chengdu Haibowei Pharmaceutical Co ltd
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract

The invention discloses a compound serving as a protein kinase inhibitor and application thereof, wherein the compound has an obvious inhibition effect on protein kinase activity, can be used as a BTK inhibitor, and has wide application prospect in preparing medicines for treating diseases mediated by BTK, such as malignant tumors, autoimmune diseases and the like.

Description

Compound as protein kinase inhibitor and application thereof
Technical Field
The invention relates to the technical field of medicines, in particular to a compound serving as a protein kinase inhibitor and application thereof.
Background
Bruton's tyrosine protein kinase (BTK) is a member of the Tec family of non-receptor protein butyric acid kinases, expressed primarily in a variety of hematopoietic cell lines. The Tec family is the 2 nd largest family of human non-receptor kinases next to the Src family, whose major members include BTK, BMX (etk), ITK, tec, and TXK (RLK). BTK was identified in 1993 as a defective protein in human X-linked agaropectinemia (X-1inked agammaglobulinemia,XLA). BTK is a key regulator of B Cell Receptor (BCR) signaling pathways, playing an important role in B cell activation, proliferation, differentiation and survival, and being closely related to a variety of B cell tumors and autoimmune diseases.
The BTK structure contains 5 major domains, PH domain (Pleckstrin homology), TH domain (Tec homolog), SH3 domain (Src homolog 3), SH2 domain (Src homolog 2) and SHl domain (Src homolog 1), respectively, the activation (phosphorylation) of BTK occurs initially in the activation loop in SHl domain, and further activation occurs in SH2 and SH3 domains containing the primary autophosphorylation site. These SH domains also contain Nuclear Localization Signals (NLS) and Nuclear Export Sequences (NES) required for BTK to perform nuclear cytoplasmic shuttling.
BTK plays an irreplaceable role in the production process of B lymphocytes, and can control the development and differentiation of B cells by activating cell cycle forward regulation factors and differentiation factors, and can also control the survival and proliferation of B cells by regulating the expression of pro-apoptotic and anti-apoptotic proteins. Continuous activation of BTK is a prerequisite for the development of Chronic Lymphocytic Leukemia (CLL). BCR-BTK signaling abnormalities promote survival of activated B cell subtypes in Diffuse Large B Cell Lymphoma (DLBCL). BTK function-conferring mutations have also been confirmed in colorectal cancer, acute Lymphoblastic Leukemia (ALL), chronic Myelogenous Leukemia (CML). Thus, aberrant activation of BTK-dependent pathways has been shown to be closely related to the development and progression of a variety of tumors.
Irreversible BTK inhibitors approved for marketing, such as ibutenib (ibutinib), acartinib (acalabruinib), zambutinib (zambuntinib), are all selectively forming irreversible covalent bonds with the cysteine residue (Cys-481) of BTK, inhibiting BTK activity for the purpose of treating related diseases. However, a fraction of cancer patients develop resistance to the first generation BTK inhibitors, thus emerging an unmet new clinical need. There is evidence that BTK-C481S mutation is one of the major drug resistance mechanisms associated with this, and thus drugs capable of targeted inhibition of BTK-C481S mutant are expected to provide new therapeutic regimens.
Disclosure of Invention
The invention mainly solves the technical problem of providing a compound capable of effectively inhibiting protein kinase.
In order to solve the technical problems, the invention adopts a technical scheme that:
provided is a compound characterized by having a structure represented by formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable hydrate, solvate or salt thereof:
wherein:
A 1 、A 2 、A 3 、A 4 are respectively and independently selected from CR 9 、N；
Y is selected from CR 10 R 11 、O、NR 10 、S、S(O)、S(O) 2 C= O, C =s, alkynyl;
M is selected from substituted or unsubstituted aryl or heteroaryl, substituted or unsubstituted cycloalkyl or heterocycloalkyl;
R 1 、R 2 、R 9 、R 10 、R 11 each independently selected from hydrogen, halogen, substituted or unsubstituted alkyl or heteroalkyl, substituted or unsubstituted cycloalkyl or heterocycloalkyl, substituted or unsubstituted unsaturated cyclic or heterocyclic, substituted or unsubstituted aryl or heteroaryl, hydroxy, cyano, amino, ester, nitro, mercapto, amide, sulfonyl, phosphoryl, alkyloxyphospho, alkylsulfonyl, alkylsulfoxide; or R is 1 、R 2 Together with the N atom to which they are attached, form a substituted or unsubstituted heterocycloalkyl group;
the substituents are each independently selected from halogen, alkyl or heteroalkyl, cycloalkyl or heterocycloalkyl, methylene, unsaturated cyclic or heterocyclic, aryl, heteroaryl, phenolic, hydroxy, cyano, amino, ester, nitro, mercapto, amido, sulfonyl, phosphoryl, alkyloxyphosphoryl, alkylsulfonyl, alkylsulfoxide;
the cycloalkyl or cyclic group is selected from monocyclic, fused, bridged or spiro cycloalkyl or cyclic groups;
R 1 、R 2 not both hydrogen.
The heterocycloalkyl or heterocyclic group means a cycloalkyl or a cyclic group containing a heteroatom, and therefore, the heterocycloalkyl or heterocyclic group is also selected from a monocyclic, parallel, bridged or spiro heterocycloalkyl or heterocyclic group.
"Ring" refers to any covalently closed structure, including, for example, carbocycles (e.g., aryl or cycloalkyl), heterocycles (e.g., heteroaryl or heterocycloalkyl), aromatic groups (e.g., aryl or heteroaryl), non-aromatic groups (e.g., cycloalkyl or heterocycloalkyl). The ring may be optionally substituted and may be monocyclic or polycyclic. Typical polycyclic rings generally include bicyclic and tricyclic rings.
"cycloalkyl" as used herein refers to a saturated cyclic (monocyclic, parallel, bridged or spiro) alkyl group, and "unsaturated cyclic" refers to a cyclic (monocyclic, parallel, bridged or spiro) hydrocarbon group containing an unsaturated bond (e.g., a carbon-carbon double bond) in the ring backbone, typical cycloalkyl or unsaturated cyclic groups including, but not limited to:
similarly, the heterocycloalkyl or unsaturated heterocyclyl group may contain a heteroatom at any position on the backbone of the same structure, and typical heterocycloalkyl or heterocyclyl groups include, but are not limited to:
the methylene group refers to CH 2 Form a double bond terminal alkene with the substituted carbon atom.
Further, A 1 、A 2 、A 3 、A 4 At least one of them is CR 9 。
Further, the method comprises the steps of,
selected from the group consisting of substituted or unsubstituted indolyl, 7-azaindolyl, 5, 7-diazaindolyl, pyrazolopyrimidinyl, said indolyl, 7-azaindolyl, 5, 7-diazaindolyl, pyrazolopyrimidinyl having the structure:
Further, the R 9 Selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl or heteroalkyl, substituted or unsubstituted C3-6 cycloalkyl or heterocycloalkyl, hydroxy, cyano, amino, ester, amide, sulfonyl, phosphoryl, alkyloxyphospho, alkylsulfonyl, alkylsulfoxide;
further, the R 9 Selected from the group consisting of hydrogen, halogen, methyl, trifluoromethyl, difluoromethyl, isopropyl, cyclopropyl, isobutyl, amido, dimethylphosphino, diethyloxyphosphino, cyano, hydroxy, amino, methoxy, ethoxy, cyclopropoxy, isobutoxy, methylamino, dimethylamino, ethylamino, diethylamino, cyclopropylamino, methylsulfonyl;
further, the R 9 Selected from hydrogen, halogen, C1-C3 alkyl, trifluoromethyl, difluoromethyl, methoxy, amido, dimethyloxyphosphoryl and cyano.
Further, the compounds of the present invention have a structure represented by formula (II) or a tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, pharmaceutically acceptable hydrate, solvate or salt thereof:
R 3 selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl or heteroalkyl, substituted or unsubstituted cycloalkyl or heterocycloalkyl, substituted or unsubstituted aryl or heteroaryl, hydroxy, cyano, amino, ester, amide, substituted or unsubstituted aryl or heteroaryl, sulfonyl, phosphoryl, alkyloxyphosphoryl, wherein each of said substituents is independently selected from the group consisting of halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amide, aryl, heteroaryl, sulfonyl, phosphoryl, alkyloxyphosphoryl, alkylsulfonyl, and alkyl sulfoxide.
Further, A 1 Or A 2 Is CR (CR) 9 ，A 3 Is N;
further, A 1 Is CR (CR) 9 ，A 3 Is N.
Further, R 1 Selected from substituted or unsubstituted alkyl or heteroalkyl, substituted or unsubstituted cycloalkyl or heterocycloalkyl, substituted or unsubstituted unsaturated cyclic or heterocyclic groups, substituted or unsubstitutedAryl or heteroaryl of (a); further, R 1 Selected from substituted or unsubstituted alkyl, substituted or unsubstituted C3-15 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C3-15 unsaturated heterocyclyl, substituted or unsubstituted heteroaryl, wherein the heteroatoms in said heterocycloalkyl or heterocyclyl are selected from N, O, S;
R 2 selected from hydrogen, halogen, substituted or unsubstituted alkyl or heteroalkyl; further, R 2 H.
Further, R 1 Selected from substituted or unsubstituted alkyl, substituted or unsubstituted C3-15 cycloalkyl or oxygenated cycloalkyl, substituted or unsubstituted C3-15 unsaturated oxygenated heterocyclyl, substituted or unsubstituted nitrogenous heteroaryl, wherein the substituents are each independently selected from halogen, C1-6 alkyl, C3-6 cycloalkyl, methylene, hydroxy;
further, R 1 Selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted adamantyl, substituted or unsubstituted oxacycloalkyl, substituted or unsubstituted dihydropyran, substituted or unsubstituted nitrogen-containing heteroaryl, said oxacycloalkyl being selected from the group consisting of tetrahydropyranyl, 6-oxaspiro [2.5 ] ]Octyl, 3-oxo-bicyclo [4.1.0]A heptyl group, the nitrogen-containing heteroaryl group being selected from the group consisting of pyridinyl and pyrazinyl, wherein the substituents are each independently selected from the group consisting of halogen, C1-C6 alkyl substituted with one or more hydroxy groups, C1-C6 alkyl substituted with nitrogen-containing heterocycloalkyl groups, hydroxycyclopropyl, methylene, hydroxy; further, the dihydropyran is a 3, 6-dihydropyran.
The structures of the tetrahydropyran, the 6-oxaspiro [2.5] octane, the 3-oxabicyclo [4.1.0] heptane and the 3, 6-dihydropyran are as follows:
in the inventionTetrahydropyran substituted by methylene at the 4-position and R 1 Is of substituted fourHydropyranyl range.
Further, the compounds of the present invention have a structure represented by formula (III) or a tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, pharmaceutically acceptable hydrate, solvate or salt thereof:
e is selected from O, NR 12 、S、S(O)、S(O)2、C＝O、C＝S；
n 1 An integer selected from 0 to 8;
R 4 selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl or heteroalkyl, substituted or unsubstituted C3-6 cycloalkyl or heterocycloalkyl, methylene, substituted or unsubstituted aryl or heteroaryl, hydroxy, cyano, amino, ester, amide, sulfonyl, phosphoryl, or two adjacent R 4 The carbon atoms to which they are attached together form a substituted or unsubstituted C3-10 cycloalkyl or heterocycloalkyl radical, or R in two identical positions 4 The carbon atoms to which they are attached constituting substituted or unsubstituted C3-10 cycloalkyl or heterocycloalkyl, or two adjacent R 4 The carbon atoms bound thereto together form a carbon-carbon double bond, or two non-adjacent R 4 Together form a bridged ring structure, wherein the substituents are each independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amide, aryl, heteroaryl, sulfonyl;
"substituted or unsubstituted C1-6 alkyl or heteroalkyl" means: substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, and the like.
The said "two adjacent R' s 4 "means a substituent R on carbon atoms at two adjacent sites on an E-containing 6-membered ring skeleton 4 Such asThe situation shown;
the "two non-adjacent R' s 4 "means a substituent R on carbon atoms at two non-adjacent sites on the E-containing 6-membered ring skeleton 4 Such asAnd the like;
the "R at two identical sites 4 "means 2 substituents R on a carbon atom at a site on an E-containing 6-membered cyclic skeleton 4 Such asThe situation shown;
the said "two adjacent R' s 4 The carbon atoms to which they are attached together form a carbon-carbon double bond "means a substituent R on a carbon atom at two adjacent sites on the E-containing 6-membered ring base skeleton 4 Together with the two carbon atoms, form a carbon-carbon double bond, e.gAnd the like;
when two adjacent R 4 When the carbon atoms to which they are attached together form a carbon-carbon double bond, it is to be understood that n 1 2.
R 3 Selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl or heteroalkyl, substituted or unsubstituted C3-6 cycloalkyl or heterocycloalkyl, substituted or unsubstituted aryl or heteroaryl, hydroxy, cyano, amino, ester, amido, substituted or unsubstituted aryl or heteroaryl, sulfonyl, phosphoryl, alkyloxyphosphoryl, wherein the substituents are each independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amido, aryl, heteroaryl, sulfonyl, phosphoryl, alkyloxyphosphoryl, alkylsulfonyl, alkyl sulfoxide;
R 12 selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl or heteroalkyl, substituted or unsubstituted C3-6 cycloalkyl or heterocycloalkyl, substituted or unsubstituted aryl or heteroaryl, wherein each of said substituents is independently selected from halogen Alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amide, aryl, heteroaryl.
Further, A 1 Is CR (CR) 9 Or N, A 3 Is N;
e is selected from O;
n 1 an integer selected from 0 to 6;
R 4 selected from hydrogen, halogen, hydroxy, cyano, amino, methylene, substituted or unsubstituted C1-6 alkyl or heteroalkyl, substituted or unsubstituted C3-6 cycloalkyl or heterocycloalkyl, or two adjacent R' s 4 The carbon atoms to which they are attached constituting substituted or unsubstituted C3-10 cycloalkyl or heterocycloalkyl groups, or R in two identical positions 4 The carbon atoms to which they are attached constituting substituted or unsubstituted C3-10 cycloalkyl or heterocycloalkyl, or two adjacent R 4 The carbon atoms to which they are attached together form a carbon-carbon double bond, wherein the substituents are each independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amide, aryl, heteroaryl, sulfonyl;
R 3 selected from the group consisting of hydrogen, halogen, methyl, trifluoromethyl, difluoromethyl, isopropyl, cyclopropyl, isobutyl, amido, dimethylphosphino, diethyloxyphosphino, cyano, hydroxy, amino, methoxy, ethoxy, cyclopropoxy, isobutoxy, methylamino, dimethylamino, ethylamino, diethylamino, cyclopropylamino, methylsulfonyl;
Further, n 1 An integer selected from 0 to 4;
R 4 selected from hydrogen, halogen, hydroxy, cyano, amino, methylene, substituted or unsubstituted C1-6 alkyl or heteroalkyl, substituted or unsubstituted C3-6 cycloalkyl or heterocycloalkyl, or two adjacent R' s 4 The carbon atoms to which they are attached constituting substituted or unsubstituted C3-10 cycloalkyl or heterocycloalkyl groups, or R in two identical positions 4 The carbon atoms to which they are attached constituting substituted or unsubstituted C3-10 cycloalkyl or heterocycloalkyl, or two adjacent R 4 Together with the carbon atoms to which they are attachedA carbon-carbon double bond is formed, wherein the substituents are each independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano;
further, R 4 Selected from hydrogen, halogen, hydroxy, cyano, amino, methylene, C1-6 alkyl substituted by hydroxy, C3-6 cycloalkyl substituted by hydroxy, or two adjacent R 4 The carbon atoms to which they are attached constituting substituted or unsubstituted cycloalkyl groups of 3-10, or R in two identical positions 4 The substituents being attached to carbon atoms forming a substituted or unsubstituted cycloalkyl of 3-10 carbon atoms, or two adjacent R' s 4 The carbon atoms connected with the substituent groups form a carbon-carbon double bond, wherein the substituent groups are respectively and independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxyl and cyano;
Further, M is selected from substituted or unsubstituted aryl or heteroaryl, wherein the substituents are selected from halogen, alkyl or heteroalkyl, C3-C6 cycloalkyl or heterocycloalkyl, unsaturated cyclic or heterocyclic, aryl, heteroaryl, phenolic, hydroxyl, cyano, amino, ester, amide, sulfonyl, phosphoryl, alkyloxyphosphoryl;
further, M is selected from substituted or unsubstituted aryl, wherein the substituents are selected from halogen, alkyl or heteroalkyl, C3-C6 cycloalkyl or heterocycloalkyl, unsaturated cyclic or heterocyclic, phenoloxy, amide.
Further, the compounds of the present invention have a structure represented by formula (IV) or a tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, pharmaceutically acceptable hydrate, solvate or salt thereof:
b is selected from O,Wherein R is 13 、R 14 、R 15 Are respectively and independently selected from hydrogen and extractionSubstituted or unsubstituted C1-6 alkyl or heteroalkyl, substituted or unsubstituted C3-6 cycloalkyl or heterocycloalkyl, or with R 6 And the atoms to which they are together attached together form a substituted or unsubstituted C5-8 cycloalkyl or heterocycloalkyl, a substituted or unsubstituted C5-8 unsaturated cyclic or heterocyclic group, an aryl or heteroaryl group, wherein each of said substituents is independently selected from the group consisting of halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amide, aryl, heteroaryl, sulfonyl;
R 5 Selected from hydrogen, halogen, hydroxy, cyano, amino, substituted or unsubstituted C1-6 alkyl or heteroalkyl, substituted or unsubstituted C3-6 cycloalkyl or heterocycloalkyl, wherein each substituent is independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amide, aryl, heteroaryl, sulfonyl; n is n 2 Selected from 0, 1, 2, 3, 4;
R 6 selected from substituted or unsubstituted monocyclic, bicyclic, tricyclic aryl or heteroaryl groups, wherein the substituents are selected from nitro, hydroxy, amino, mercapto, halogen, cyano, ester, carboxyl, amido, phosphoramido, alkyloxyphospho, C1-6 alkyl or heteroalkyl, C3-6 cycloalkyl or heterocycloalkyl, 5-6 membered aryl or heteroaryl groups.
Further, A 1 Is CR (CR) 9 ；
n 1 An integer selected from 0 to 4;
R 4 selected from hydrogen, halogen, hydroxy, cyano, amino, methylene, substituted or unsubstituted C1-6 alkyl or heteroalkyl, substituted or unsubstituted C3-6 cycloalkyl or heterocycloalkyl, or two adjacent R' s 4 The carbon atoms to which they are attached constituting substituted or unsubstituted C3-10 cycloalkyl or heterocycloalkyl groups, or R in two identical positions 4 The carbon atoms to which they are attached constituting substituted or unsubstituted C3-10 cycloalkyl or heterocycloalkyl, or two adjacent R 4 The carbon atoms to which they are attached together form a carbon-carbon double bond, wherein the substituents are each independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxyCyano group;
R 3 selected from the group consisting of hydrogen, halogen, methyl, trifluoromethyl, difluoromethyl, isopropyl, cyclopropyl, isobutyl, amido, dimethylphosphino, diethyloxyphosphino, cyano, hydroxy, amino, methoxy, ethoxy, cyclopropoxy, isobutoxy, methylamino, dimethylamino, ethylamino, diethylamino, cyclopropylamino, methylsulfonyl;
b is selected from O,R 13 Selected from hydrogen, substituted or unsubstituted C1-6 alkyl or heteroalkyl, substituted or unsubstituted C3-6 cycloalkyl or heterocycloalkyl, or with R 6 And the atoms to which they are together attached together form a substituted or unsubstituted C5-8 heterocycloalkyl, a substituted or unsubstituted C5-8 unsaturated heterocyclyl, a heteroaryl, R 14 、R 15 Selected from hydrogen, substituted or unsubstituted C1-6 alkyl or heteroalkyl, substituted or unsubstituted C3-6 cycloalkyl or heterocycloalkyl, wherein each substituent is independently selected from halo, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amide, aryl, heteroaryl, sulfonyl;
R 5 Selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl or heteroalkyl, wherein each substituent is independently selected from halogen, alkyl; n is selected from 0, 1, 2;
R 6 selected from substituted or unsubstituted monocyclic, bicyclic aryl or heteroaryl groups, wherein the substituents are selected from hydroxy, halogen, cyano, C1-6 alkyl or heteroalkyl, C3-6 cycloalkyl or heterocycloalkyl.
In a specific embodiment of the present invention, B is selected from O,R 14 、R 15 Selected from hydrogen, substituted or unsubstituted C1-6 alkyl, or B and R 6 Together form->
R 5 Selected from hydrogen, halogen; n is n 2 Selected from 0, 1;
R 6 selected from substituted or unsubstituted phenyl, wherein the substituents are selected from halogen, cyano, C1-6 alkyl or heteroalkyl, C3-6 cycloalkyl or heterocycloalkyl.
Further, when R 1 In the case of substituted or unsubstituted tetrahydropyranyl, the compounds of the present invention have the structure of formula (V) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, pharmaceutically acceptable hydrate, solvate or salt thereof:
n 1 an integer selected from 0 to 7;
R 3 selected from hydrogen, halogen, hydroxy, cyano, amino, substituted or unsubstituted C1-6 alkyl or heteroalkyl, substituted or unsubstituted C3-6 cycloalkyl or heterocycloalkyl, wherein each substituent is independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amide, aryl, heteroaryl, sulfonyl;
R 8 Selected from the group consisting of hydrogen, nitro, hydroxy, amino, mercapto, halogen, cyano, ester, carboxyl, amide, phosphoryl, alkyloxyphosphoryl, substituted or unsubstituted C1-6 alkyl or heteroalkyl, substituted or unsubstituted C3-6 cycloalkyl or heterocycloalkyl, substituted or unsubstituted 5-6 membered aryl or heteroaryl, wherein each of said substituents is independently selected from the group consisting of halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amide, aryl, heteroaryl, sulfonyl; n is n 3 An integer selected from 0 to 5;
R 7 selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl or heteroalkyl, substituted or unsubstituted C3-6 cycloalkyl or heterocycloalkyl, substituted or unsubstituted aryl or heteroaryl, hydroxy, cyano,Amino, ester, amide, sulfonyl, phosphoryl, wherein the substituents are each independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amide, aryl, heteroaryl, sulfonyl;
further, A 1 When N is N, N is 1 +n 3 ≥2。
Further, A 1 Is CR (CR) 9 。
Further, n 1 An integer selected from 0 to 3;
R 4 selected from hydrogen, halogen, hydroxy, cyano, amino, methylene, substituted or unsubstituted C1-6 alkyl or heteroalkyl, substituted or unsubstituted C3-6 cycloalkyl or heterocycloalkyl, or two adjacent R' s 4 The carbon atoms to which they are attached constituting substituted or unsubstituted C3-10 cycloalkyl or heterocycloalkyl groups, or R in two identical positions 4 The carbon atoms to which they are attached constituting substituted or unsubstituted C3-10 cycloalkyl or heterocycloalkyl, or two adjacent R 4 The carbon atoms connected with the substituent groups form a carbon-carbon double bond, wherein the substituent groups are respectively and independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxyl and cyano;
R 3 selected from the group consisting of hydrogen, halogen, methyl, trifluoromethyl, difluoromethyl, isopropyl, cyclopropyl, isobutyl, amido, dimethylphosphino, diethyloxyphosphino, cyano, hydroxy, amino, methoxy, ethoxy, cyclopropoxy, isobutoxy, methylamino, dimethylamino, ethylamino, diethylamino, cyclopropylamino, methylsulfonyl;
R 5 selected from hydrogen, halogen;
R 8 selected from hydrogen, nitro, hydroxyl, amino, halogen, cyano, amido, substituted or unsubstituted C1-6 alkyl or heteroalkyl, substituted or unsubstituted C3-6 cycloalkyl or heterocycloalkyl, wherein each substituent is independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxyl, cyano, amino, ester, amido, aryl, heteroaryl, sulfonyl;
R 7 Is selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl or heteroalkyl, substituted or unsubstituted C3-6 cycloalkyl or heterocycloalkyl, wherein the substituents are each independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amide, aryl, heteroaryl, sulfonyl.
Further, the method comprises the steps of,
n 1 an integer selected from 0 to 2;
R 4 selected from hydrogen, halogen, hydroxy, cyano, amino, methylene, C1-6 alkyl substituted by hydroxy or halogen, C3-6 cycloalkyl substituted by hydroxy or halogen, or two adjacent R' s 4 The carbon atoms to which they are attached constituting substituted or unsubstituted C3-6 cycloalkyl groups, or R in two identical positions 4 The substituents being attached to carbon atoms forming a substituted or unsubstituted C3-6 cycloalkyl group, or two adjacent R' s 4 The carbon atoms connected with the substituent groups form a carbon-carbon double bond, wherein the substituent groups are respectively and independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxyl and cyano;
R 5 selected from hydrogen, halogen;
R 8 selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl or heteroalkyl, substituted or unsubstituted C3-6 cycloalkyl or heterocycloalkyl, hydroxy, cyano wherein the substituents are selected from halogen, alkyl or heteroalkyl, cycloalkyl or heterocycloalkyl, hydroxy, cyano; n is n 3 Selected from 0 or 1;
R 7 selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl or heteroalkyl, substituted or unsubstituted C3-6 cycloalkyl or heterocycloalkyl, hydroxy, wherein said substituents are selected from halogen, alkyl or heteroalkyl, cycloalkyl or heterocycloalkyl, hydroxy.
In a specific embodiment of the present invention,
R 4 selected from hydrogen, halogen, hydroxy, cyano, methylene, C1-6 alkyl substituted by hydroxy or halogen, C3-6 cycloalkyl substituted by hydroxy or halogen, or two adjacent R' s 4 The constituent of carbon atoms to which it is attachedSubstituted or unsubstituted C3-6 cycloalkyl, or R at two identical positions 4 The substituents being attached to carbon atoms forming a substituted or unsubstituted C3-6 cycloalkyl group, or two adjacent R' s 4 The carbon atoms connected with the substituent groups form a carbon-carbon double bond, wherein the substituent groups are respectively and independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxyl and cyano;
R 5 selected from hydrogen, halogen;
R 8 selected from hydrogen, halogen, C1-6 alkyl, C3-6 cycloalkyl and cyano;
R 7 selected from hydrogen, halogen, C1-6 alkyl substituted by hydroxy or halogen, C3-6 cycloalkyl substituted by hydroxy or halogen; further, R 7 Selected from hydroxymethyl and hydroxycyclopropyl.
Further, R 4 Selected from hydrogen, halogen, hydroxy, or two adjacent R 4 The carbon atoms to which they are attached forming a substituted or unsubstituted C3-6 cycloalkyl group, or two adjacent R' s 4 The carbon atoms to which they are attached together form a carbon-carbon double bond, wherein the substituents are each independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano.
Further, R 5 Is halogen, R 8 Is hydrogen.
In some embodiments of the invention, R 4 Selected from hydrogen, F, hydroxy, or two adjacent R 4 The carbon atoms to which they are attached constituting a substituted or unsubstituted cyclopropyl group, or two adjacent R groups 4 The carbon atoms to which they are attached together form a carbon-carbon double bond; further, R 5 Is Cl, R 8 Is hydrogen.
Specifically, the compound structure is selected from one of the following:
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the invention also provides a medicinal composition, and the active ingredient of the medicinal composition is selected from one or more than two of the compounds or stereoisomers, solvates, hydrates, pharmaceutically acceptable salts or eutectic crystals thereof.
The invention also provides application of the compound or stereoisomer, solvate, hydrate, pharmaceutically acceptable salt or eutectic crystal thereof in preparing protein kinase inhibitor; further, the kinase inhibitor is a BTK inhibitor.
The invention also provides the use of the above compound or a stereoisomer, solvate, hydrate, pharmaceutically acceptable salt or co-crystal thereof in the manufacture of a medicament for the treatment of any one or more of autoimmune disease, inflammatory disease, thromboembolic disease, allergy, infectious disease, proliferative disorder and cancer.
Further, the disease is selected from: arthritis, rheumatoid arthritis, urticaria, vitiligo, organ transplant rejection, ulcerative colitis, crohn's disease, dermatitis, asthma, sjogren's syndrome, systemic lupus erythematosus, multiple sclerosis, idiopathic thrombocytopenic purpura, rash, anti-neutrophil cytoplasmic antibody vasculitis, tenascus, pemphigus vulgaris, chronic obstructive pulmonary disease, psoriasis; breast cancer, mantle cell lymphoma, ovarian cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, hepatocellular carcinoma, gastric cancer, glioma, endometrial cancer, melanoma, renal cancer, bladder cancer, melanoma, bladder cancer, biliary tract cancer, renal cancer, pancreatic cancer, lymphoma, hairy cell cancer, nasopharyngeal cancer, pharyngeal cancer, colorectal cancer, rectal cancer, cancer of the brain and central nervous system, cervical cancer, prostate cancer, testicular cancer, genitourinary tract cancer, lung cancer, non-small cell lung cancer, small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular cancer, hodgkin's leukemia, bronchogenic carcinoma, thyroid cancer, uterine cancer, cervical cancer, multiple myeloma, acute myelogenous leukemia, chronic myelogenous leukemia, lymphocytic leukemia, chronic lymphoid leukemia, myelogenous leukemia, non-hodgkin's lymphoma, primary macroglobulinemia.
The invention also provides application of the compound or stereoisomer, solvate, hydrate, pharmaceutically acceptable salt or eutectic crystal thereof in preparing medicaments for treating diseases causing over-expression of BTK kinase.
The invention also provides application of the compound or stereoisomer, solvate, hydrate, pharmaceutically acceptable salt or eutectic thereof in preparing medicaments for treating diseases caused by over-expression of BTK kinase. .
The pharmaceutical composition containing the compound or the stereoisomer, solvate, hydrate, pharmaceutically acceptable salt or eutectic crystal thereof can contain pharmaceutically acceptable auxiliary materials.
The term "pharmaceutically acceptable" as used herein is meant to include any material which does not interfere with the effectiveness of the biological activity of the active ingredient and which is not toxic to the host to which it is administered.
The pharmaceutically acceptable auxiliary materials are the general names of all additional materials except the main drugs in the medicine, and the auxiliary materials have the following properties: (1) no toxic or side effect to human body; (2) The chemical property is stable, and is not easily influenced by temperature, pH, preservation time and the like; (3) No incompatibility with the main medicine, and no influence on the curative effect and quality inspection of the main medicine; (4) does not interact with the packaging material. Adjuvants in the present invention include, but are not limited to, fillers (diluents), lubricants (glidants or anti-adherents), dispersants, wetting agents, binders, conditioning agents, solubilizing agents, antioxidants, bacteriostats, emulsifiers, disintegrants, and the like. The binder comprises syrup, acacia, gelatin, sorbitol, tragacanth, cellulose and its derivatives (such as microcrystalline cellulose, sodium carboxymethylcellulose, ethylcellulose or hydroxypropyl methylcellulose), gelatin slurry, syrup, starch slurry or polyvinylpyrrolidone; the filler comprises lactose, sugar powder, dextrin, starch and its derivatives, cellulose and its derivatives, inorganic calcium salt (such as calcium sulfate, calcium phosphate, calcium hydrogen phosphate, precipitated calcium carbonate, etc.), sorbitol or glycine, etc.; the lubricant comprises aerosil, magnesium stearate, talcum powder, aluminum hydroxide, boric acid, hydrogenated vegetable oil, polyethylene glycol and the like; disintegrants include starch and its derivatives (e.g., sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, modified starch, hydroxypropyl starch, corn starch, etc.), polyvinylpyrrolidone, microcrystalline cellulose, etc.; the wetting agent comprises sodium dodecyl sulfate, water or alcohol, etc.; the antioxidant comprises sodium sulfite, sodium bisulphite, sodium metabisulfite, dibutyl benzoic acid and the like; the bacteriostat comprises 0.5% phenol, 0.3% cresol, 0.5% chlorobutanol and the like; the regulator comprises hydrochloric acid, citric acid, potassium hydroxide (sodium), sodium citrate, buffer (including sodium dihydrogen phosphate and disodium hydrogen phosphate), etc.; the emulsifier comprises polysorbate-80, sorbitan without acid, pluronic F-68, lecithin, soybean lecithin, etc.; the solubilizer comprises Tween-80, bile, glycerol, etc. The term "pharmaceutically acceptable salt" refers to salts of the compounds of the invention with acids or bases that are suitable for use as medicaments. The acid base is a broad Lewis acid base. Suitable salts forming acids include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, and the like; acidic amino acids such as aspartic acid and glutamic acid.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.
In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-agar or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The compounds of the invention can likewise be used in injectable formulations. Wherein the injection is selected from liquid injection (water injection), sterile powder for injection (powder injection) or tablet for injection (refers to a stamped tablet or a machine pressed tablet prepared by a sterile operation method for medicines), and is dissolved by water for injection when in use for subcutaneous or intramuscular injection.
Wherein the powder for injection contains at least an excipient in addition to the above-mentioned compounds. The excipients described in the present invention, which are components intentionally added to a drug, should not have pharmacological properties in the amounts used, however, the excipients may aid in processing, dissolution or dissolution of the drug, delivery by targeted route of administration, or stability.
"alkyl" refers to an aliphatic hydrocarbon group, and to a saturated hydrocarbon group. The alkyl moiety may be a straight chain alkyl group or a branched alkyl group.
The C1-n used in the present invention includes C1-2, C1-3 … … C1-n. n is an integer greater than one. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, and the like.
"heteroalkyl" refers to an alkyl group containing a heteroatom, where the heteroatom includes, but is not limited to O, S, N, P and the like; alkoxy, sulfanyl, aminoalkyl and the like are heteroalkyl.
In the present invention, the "heteroalkyl group having 1 to n" is an integer greater than one, and n is the number of carbon atoms in the heteroalkyl group.
In the present invention, when "C3-6 cycloalkyl group or heterocycloalkyl group" defines a heterocycloalkyl group, it is to be understood that the same definition applies to the other heterocycloalkyl groups when the "C3-6" group is defined as a 3-6 membered heterocycloalkyl group.
"amido" is a chemical structure having the formula-C (O) NHR or-NHC (O) R wherein R is selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl.
"ester" means a chemical structure having the formula-COOR or-OC (O) R, wherein R is selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl.
"sulfonyl" is of formula-S (=o) 2 R has a chemical structure including sulfonamide groups, wherein R can be selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, amino, and the like;
"phosphoryl" is a chemical structure having the formula-P (=o) RR 'wherein R, R' can be independently selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, amino, and the like;
"alkynyl" refers to a group having a carbon-carbon triple bond.
"Yuan" means the number of skeleton atoms constituting a ring. Typical 5-membered rings can include cyclopentyl, pyrrole, imidazole, thiazole, furan, thiophene, and the like; typical 6-membered rings include cyclohexyl, pyridine, pyran, pyrazine, thiopyran, pyridazine, pyrimidine, benzene, and the like. Wherein, the ring containing hetero atoms in the skeleton atom is a heterocycle; aryl groups consisting of heterocycles are heteroaryl groups; the non-aromatic group consisting of a heterocycle is a heterocycloalkyl group.
Heteroatoms include, but are not limited to O, S, N, P and the like.
Typical heteroaryl or heteroaryl groups include, but are not limited to:
"aryl" means that the planar ring has a delocalized pi electron system and contains 4n+2 pi electrons, where n is an integer. The aryl ring may be composed of five, six, seven, eight, nine or more than nine atoms. Aryl groups include, but are not limited to, phenyl, naphthyl, phenanthryl, anthracyl, fluorenyl, indenyl, and the like.
"halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.
The alkyl group, heteroalkyl group, cyclic group, heterocyclic group, amino group, ester group, carbonyl group, amide group, sulfonyl group, phosphoryl group and the like described herein may be unsubstituted alkyl group, heteroalkyl group, cyclic group, heterocyclic group, amino group, ester group, carbonyl group, amide group, sulfonyl group, phosphoryl group, or substituted alkyl group, heteroalkyl group, cyclic group, heterocyclic group, amino group, ester group, carbonyl group, amide group, sulfonyl group, phosphoryl group.
In the above, unless already indicated, "substituted" in the "substituted or unsubstituted" means that the mentioned group may be substituted with one or more additional groups each and independently selected from alkyl, cycloalkyl, aryl, carboxyl, heteroaryl, heterocycloalkyl, hydroxy, alkoxy, alkylthio, aryloxy, nitro, acyl, halogen, haloalkyl, amino, and the like.
"inhibitor" refers to a substance that decreases the activity of an enzyme.
The beneficial effects of the invention are as follows: the invention provides a series of compounds with BTK activity inhibition, and experiments show that the compounds have obvious inhibition effect on BTK, provide a new scheme for treating diseases taking BTK as a target point of treatment, such as malignant tumor diseases or autoimmune diseases, and the like, can be used for preparing medicaments for treating related diseases, and have wide application prospects.
Detailed Description
The following description of the present invention will be made clearly and fully, and it is apparent that the embodiments described are some, but not all, of the embodiments of the present invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
In the present invention, the structure of the compounds is determined by Mass Spectrometry (MS) and/or nuclear magnetic resonance (1 HNMR) equipment. The chemical abbreviations have the following meanings:
DMF: n, N-dimethylformamide
n-BuLi: n-butyllithium
THF: tetrahydrofuran (THF)
DIAD: diisopropyl azodicarboxylate
DIEA: n, N-diisopropylethylamine
PE: petroleum ether
EA: acetic acid ethyl ester
DCM: dichloromethane (dichloromethane)
TSOH: para-toluene sulfonic acid
HATU: o- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea
Pd 2 (DBA) 3 : tris (dibenzylideneacetone) dipalladium
BINAP:1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine
DMSO: dimethyl sulfoxide
m-CPBA: m-chloroperoxybenzoic acid
Dess-Martin: dess-martin oxidizing agent
TBAF: tetrabutylammonium fluoride
DAST: diethylaminosulfur trifluoride
DIBAL-H: diisobutyl aluminum hydride
Example 1
Step 1: synthesis of Compounds 1-3
To the reaction flask was added compound 1-1 (11.232 g,72.2 mmol), potassium carbonate (14.967 g,108.3 mmol), 1-2 (8.154 g,86.6 mmol), DMF (60 mL), and the reaction was stirred at room temperature overnight, TLC indicated completion. Pouring the reaction system into water, extracting with ethyl acetate twice, combining ethyl acetate layers, washing with water twice, washing with saturated saline solution, and anhydrous Na 2 SO 4 Drying and concentrating under reduced pressure to obtain 16.5g of a product 1-3, yield: 99%. The product was used directly in the next step without purification.
Step 2: synthesis of Compounds 1-4
To the reaction flask was added compound 1-3 (16.5 g,72 mmol), aqueous KOH (220 mL, 5M), and ethanol (45 mL), and the reaction was warmed to 100deg.C overnight, TLC indicated complete reaction of starting materials. Cooling the reaction system to 0 ℃, adding concentrated hydrochloric acid to adjust to acidity, precipitating solid, filtering, washing with water, and drying a filter cake to obtain 17.3g of a product 1-4, wherein the yield is: 96%. The product was used directly in the next step without purification.
Step 3: synthesis of Compounds 1-5
To the reaction flask was added compound 1-4 (17.3 g,69.6 mmol), potassium carbonate (14.4 g,76.6 mmol) and DMF (50 mL), methyl iodide (4.8 mL,76.6 mmol) was added dropwise to the reaction solution in ice bath, and after the addition was completed, the reaction solution was warmed to room temperature and stirred for 5 hours, and TLC showed completion of the reaction. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 18g of product 1-5, yield: 98%. The product was used directly in the next step without purification.
Step 4: synthesis of Compounds 1-7
Into a three-port reaction flask, compound 1-6 (1.00 g,3.8 mmol) was charged, nitrogen was replaced, tetrahydrofuran (35 mL) was added, the reaction mixture was cooled to-78℃and an n-BuLi tetrahydrofuran solution (3.2 mL, 2.5M) was added dropwise thereto, and after stirring for 30 minutes, 1-5 (887 mg,3.8 mmol) of the tetrahydrofuran solution was added dropwise to the reaction mixture, and the reaction was continued for 2 hours. The reaction solution was warmed to room temperature, quenched by addition of saturated ammonium chloride solution, extracted twice with ethyl acetate, the obtained organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give 850mg of the product 1-7, yield: 58%.
Step 5: synthesis of Compounds 1-9
Compounds 1-8 (2.5 g,10.361 mmol), tetrahydrofuran (12.5 mL), cooled to 0deg.C, and borane dimethyl sulfide solution (10 mL,20.723 mmol) were added slowly and the reaction mixture stirred at room temperature for 16 hours and TLC showed complete reaction. The reaction was quenched with methanol, water was added, extracted with ethyl acetate (2 x 50 ml), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give 2.1g of product 1-9, yield: 91%. The product was used directly in the next step without purification.
Step 6: synthesis of Compounds 1-10
To the reaction flask was added compound 1-9 (1.8 g,7.930 mmol), triphenylphosphine (3.1 g,11.894 mmol), phthalimide (1.2 g,7.930 mmol), tetrahydrofuran (25 mL), DIAD (2.4 g,11.894 mmol) was slowly added dropwise, and the reaction mixture was stirred at room temperature for 0.5 hours, and TLC showed complete reaction. The reaction was extracted with water, ethyl acetate (3 x 50 ml), the organic phases combined, washed with saturated brine, concentrated under reduced pressure, and the crude product purified by silica gel column chromatography (PE/ea=10/1) to give 2.6g of product 1-10, yield: 93%.
Step 7: synthesis of Compounds 1-11
To the reaction flask was added compound 1-10 (2.6 g,7.303 mmol), ethanol (25 mL), hydrazine hydrate (8.7 mL) was slowly added dropwise, and the reaction mixture was stirred at room temperature for 4 hours, TLC showed completion of the reaction. The reaction system was extracted with water, ethyl acetate (3 x 50 ml), the combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give 1.2g of product 1-11, yield: 75%. The product was used directly in the next step without purification.
Step 8: synthesis of Compounds 1-12
To the reaction flask was added compound 1-11 (30 mg,0.133 mmol), 1-7 (50 mg,0.133 mmol), n-butanol (2 mL) and DIEA (51 mg,0.3982 mmol), and the reaction mixture was heated to 100deg.C and stirred for 1 hour, TLC showed complete reaction. The reaction system is cooled and then is directly decompressed and concentrated. Purification of the crude product by preparative silica gel plate (DCM/meoh=20/1) gives 55mg of product 1-12, yield: 72%.
Step 9: synthesis of Compound 1
To the reaction flask were added the above-mentioned compounds 1-12 (55 mg,0.096 mmol) and hydrogen chloride dioxane solution (2 mL), and the reaction mixture was stirred at room temperature for 3 hours, and TLC showed complete reaction of the starting materials. The reaction solution was evaporated in vacuo and lyophilized to give 55mg of product 1 (hydrochloride), yield: 100%.
LC/MS:m/z＝474.2[M+H] + .
1 H NMR(400MHz,d6-DMSO)δ1.38-1.45(2H,m),1.49-1.57(2H,m),1.65-1.71(2H,m),1.93-2.01(2H,m),3.63-3.72(3H,m),7.04(1H,dd,J＝8.5,2.4Hz),7.18-7.32(5H,m),7.48-7.51(2H,m),7.59-7.64(2H,m),7.78-7.81(1H,m),8.25(1H,s),8.81-8.83(1H,m),12.79(1H,brs).
Example 2
Step 1: synthesis of Compound 2-2
To the reaction flask was added compound 2-1 (200 mg,1.31 mmol) and THF (6 mL), lithium aluminum hydride (100 mg,2.63 mmol) was added in portions, and the reaction was stirred at room temperature overnight, and TLC showed completion of the reaction. The reaction solution was cooled in an ice-water bath, and 200mg of water was slowly added dropwise to quench the reaction. The obtained suspension is filtered by suction, a filter cake is washed by THF, and the filtrate is concentrated to be dry under reduced pressure to obtain 120mg of a product 2-2, the yield: 74%. The product was used directly in the next step without purification.
Step 2: synthesis of Compound 2
To the reaction flask was added compound 1-7 (50 mg,0.13 mmol), 2-2 (32 mg,0.26 mmol), tsOH (25 mg,0.13 mmol) and n-butanol (2 ml), and the reaction was allowed to react at 120℃for 2 hours, and TLC showed completion. To the reaction was added water, extracted twice with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by preparation of silica gel plate (DCM/meoh=20/1) to give 30mg of product 2, yield: 49%.
LC/MS:m/z＝472.2[M+H] + .
1 H NMR(400MHz,d6-DMSO)δ4.66(2H,d,J＝5.5Hz),5.44(1H,t,J＝5.5Hz),7.05(1H,dd,J＝8.5,2.4Hz),7.19-7.29(4H,m),7.48-7.52(2H,m),7.68(1H,d,J＝8.5Hz),7.90(1H,s),8.24-8.38(2H,m),8.53(1H,s),8.94(1H,d,J＝2.2Hz),11.25(1H,s),13.10(1H,brs).
Example 3
To the reaction flask was added compound 1 (60 mg,0.126 mmol), potassium carbonate (53 mg,0.381 mmol), absolute ethanol (1 mL) and bromoethanol (16 mg,0.126 mmol), and the reaction mixture was heated to reflux and stirred for 1 hour, and TLC showed completion of the reaction. The reaction was cooled to room temperature and concentrated to dryness under reduced pressure and purified by preparative silica gel plate (DCM/meoh=10/1) to give 10mg of product 3, yield: 16%.
LC/MS:m/z＝518.2[M+H]+.
1H NMR(400MHz,d6-DMSO)δ1.33-1.38(2H,m),1.46-1.53(2H,m),1.61-1.70(2H,m),1.92-1.99(2H,m),3.54-3.67(3H,m),3.78-3.82(2H,m),3.88-3.93(1H,m),4.15-4.16(1H,m),4.53(1H,t,J＝5.7Hz),7.03(1H,dd,J＝8.5,2.5Hz),7.19-7.26(4H,m),7.47-7.51(2H,m),7.59-7.64(2H,m),8.25(1H,s),8.80-8.83(1H,m),12.67(1H,brs).
Example 4
To the reaction flask was added compound 1 (50 mg,0.110 mmol), glycolic acid (8 mg,0.110 mmol), DIEA (57 mg,0.44 mmol) and DCM (5 ml), then HATU (63 mg,0.165 mmol) was added in one portion and the reaction was allowed to react at room temperature for 2 hours, TLC showed complete reaction. To the reaction was added water, extracted twice with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by preparation of silica gel plate (DCM/meoh=20/1) to give 38mg of product 4, yield: 65.5%.
LC/MS:m/z＝532.2[M+H] + .
1 H NMR(400MHz,d6-DMSO)δ1.34-1.39(2H,m),1.48-1.55(2H,m),1.63-1.71(2H,m),1.92-1.99(2H,m),3.57-3.66(3H,m),3.90-3.96(1H,m),4.16-4.19(1H,m),4.57(1H,t,J＝5.7Hz),7.04(1H,dd,J＝8.5,2.5Hz),7.19-7.26(4H,m),7.47-7.51(2H,m),7.59-7.64(2H,m),8.25(1H,s),8.80-8.83(1H,m),12.76(1H,brs).
Example 5
To the reaction flask was added compound 1 (60 mg,0.126 mmol), DIEA (18 mg,0.126 mmol), absolute ethanol (1 mL) and glycidol (48 mg, 0.264 mmol), and the reaction mixture was heated to reflux and stirred for 4 hours, TLC showed completion of the reaction. The reaction was cooled to room temperature and concentrated to dryness under reduced pressure and purified by preparative silica gel plate (DCM/meoh=10/1) to give 10mg of product 5, yield: 14%.
LC/MS:m/z＝548.2[M+H] + .
1 H NMR(400MHz,d6-DMSO)δ1.20-1.35(2H,m),1.53-1.62(1H,m),1.74-1.86(2H,m),1.96-2.02(1H,m),2.16-2.34(2H,m),3.37-3.44(4H,m),3.52-3.72(4H,m),4.46-4.48(1H,m),4.59-4.62(1H,m),7.04(1H,dd,J＝8.4,2.3Hz),7.19-7.20(3H,m),7.26(1H,t,J＝7.4Hz),7.47-7.51(2H,m),7.59(1H,d,J＝8.5Hz),7.62(1H,brs),8.24(1H,s),8.80-8.84(1H,m),12.74(1H,brs).
Example 6
To the reaction flask was added compound 1-7 (20 mg,0.052 mmol), 3-amino-1, 2-propanediol (6 mg,0.066 mmol), n-butanol (1 mL) and DIEA (20 mg,0.156 mmol), and the reaction mixture was heated to 100deg.C and stirred for 1 hour, TLC showed complete reaction. The reaction system is cooled and then is directly decompressed and concentrated. Purification of the crude product by preparative silica gel plate (DCM/meoh=10/1) gives 15mg of product 6, yield: 66%.
LC/MS:m/z＝439.1[M+H] + .
1 H NMR(400MHz,d6-DMSO)δ2.82-2.86(1H,m),3.28-3.32(1H,m),3.45-3.56(3H,m),4.84(1H,t,J＝5.8Hz),4.93-4.95(1H,m),7.03(1H,dd,J＝8.5,2.4Hz),7.18-7.20(3H,m),7.26(1H,t,J＝7.4Hz),7.49(2H,t,J＝8.0Hz),7.59-7.63(2H,m),8.25(1H,s),8.33(1H,d,J＝9.1Hz),12.73(1H,brs).
Examples 7 to 9
Prepared according to the detailed procedure of example 2 and example 6 above using commercially available starting materials, see table 1 for a specific summary:
TABLE 1
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Example 10
Step 1: synthesis of Compound 10-2
To the reaction flask were added compound 10-1 (2.0 g,8.65mmol, prepared by reference Eur. J. Org. Chem.2003, 2418-2427) and a solution of hydrogen chloride dioxane (20 mL), and the reaction mixture was stirred at room temperature for 3 hours, and TLC showed complete reaction of the starting materials. The reaction solution was directly evaporated to dryness in vacuo to give 1.5g of product 10-2, yield: 100%. The product was used directly in the next step without purification.
Step 2: synthesis of Compound 10-4
To the reaction flask was added compound 10-3 (5.0 g,20.3 mmol) and methanol (50 mL), concentrated sulfuric acid (5 mL) was warmed to 100deg.C overnight. TLC showed complete reaction and cooled. Pouring the reaction solution into water, extracting with ethyl acetate for 3 times, mixing the organic phases, washing with water, washing with saturated saline solution, and anhydrous Na 2 SO 4 Drying and evaporation in vacuo gave 5.3g of product 10-4, yield: 100%. The product was used directly in the next step without purification.
Step 3: synthesis of Compound 10-5
To a three-necked flask, compound 10-4 (2.0 g,7.72 mmol), tetrahydrofuran (20 mL), nitrogen substitution, ethanol-dry ice bath cooling to-70℃and ethyl magnesium bromide (28 mL,1 mol/L) were added dropwise, and the reaction was carried out at this temperature for 1h. The reaction was poured into saturated ammonium chloride solution, extracted three times with ethyl acetate, the organic phases combined, added to silica gel for sample mixing, and purified by silica gel column to give 680mg of product 10-5, yield: 45%.
Step 4: synthesis of Compound 10-7
To the reaction flask was added compound 10-5 (200 mg,0.93 mmol), DCM (10 mL), ice-cooled to 0deg.C, triflic acid (1410 mg,9.4 mmol) was added dropwise, reacted for 30min, compound 10-6 (330 mg,1.22mmol, prepared by refluxing 1-4 with thionyl chloride for 2 h and then concentrating and drying) was added to the reaction solution, the reaction solution was slowly warmed to room temperature and stirred for 1h, and TLC showed completion of the reaction. The reaction was quenched by addition of 1mL of methanol, the reaction was poured into saturated sodium bicarbonate solution, extracted 4 times with dichloromethane, the organic layers were combined, evaporated in vacuo and the crude product purified by silica gel column to give 240mg of product 10-7, yield: 60%.
1 H NMR(400MHz,CDCl 3 )δ4.02(3H,s),6.93(1H,dd,J＝8.5,2.4Hz),7.07(1H,d,J＝2.4Hz),7.10-7.13(2H,m),7.22-7.25(1H,m),7.42-7.45(2H,m),7.56(2H,dd,J＝8.3,4.3Hz),7.63(1H,d,J＝2.9Hz),7.82(1H,d,J＝8.1Hz),10.51(1H,s).
Step 5: synthesis of Compound 10-8
Into a reaction flask was charged compound 10-7 (100 mg,0.21 mmol), 10-2 (35 mg,0.21 mmol), pd 2 (DBA) 3 (10 mg,0.01 mmol), BINAP (6 mg,0.01 mmol), cesium carbonate (134 mg,0.41 mmol) and dioxane (4 mL), nitrogen substitution, and stirred overnight at 100deg.C. TLC showed complete reaction, cooled, the reaction was poured into water, extracted 3 times with ethyl acetate, dried over anhydrous sodium sulfate, evaporated in vacuo and purified by prep. silica gel plate (DCM/meoh=10/1) to give 20mg of compound 10-8. Yield: 19%.
Step 6: synthesis of Compound 10-9
To the reaction flask was added compound 10-8 (20 mg,0.041 mmol), lithium hydroxide monohydrate (9 mg,0.21 mmol), tetrahydrofuran (5 mL) and water (1 mL), and the mixture was warmed to 60℃and reacted overnight. TLC showed complete reaction and cooled. The reaction solution was poured into water, 200mg of glacial acetic acid was added, followed by extraction 3 times with ethyl acetate, and 15mg of compound 10-9 was obtained by vacuum evaporation. Yield: 70%. The product was used directly in the next step without purification.
Step 7: synthesis of Compound 10
Into the reaction flask was charged compound 10-9 (15 mg,0.029 mmol), DIEA (16 mg,0.12 mmol), NH 4 Cl (8 mg,0.15 mmol) and DMF (2 mL) were then added in one portion to HATU (17 mg,0.045 mmol) and reacted overnight at room temperature. The reaction was poured into water, extracted 3 times with ethyl acetate, the combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate and purified by prep. of silica gel plate (DCM/meoh=10/1) after evaporation in vacuo to give 8mg of product 10. Yield: 53%.
LC/MS:m/z＝520.1[M+H] + .
1 H NMR(400MHz,d6-DMSO)δ1.34-1.43(1H,m),1.53-1.62(1H,m),1.76-1.80(1H,m),2.17-2.22(1H,m),3.12(1H,t,J＝11.2Hz),3.40-3.46(3H,m),4.11-4.18(2H,m),4.68(1H,t,J＝5.4Hz,1H),6.88(1H,dd,J＝8.5,2.4Hz),7.02(1H,d,J＝2.4Hz),7.08-7.11(2H,m),7.20-7.22(1H,m),7.40-7.43(2H,m),7.54(2H,dd,J＝8.3,4.3Hz),7.61-7.65(3H,m),7.72(1H,d,J＝8.3Hz),10.50(1H,s).
Example 11
Synthesis of Compound 11-1 reference Synthesis of Compound 10-7.
Step 1: synthesis of Compound 11-2
To the flask was added compound 11-1 (70 mg,0.17 mmol), compound 10-2 (35 mg,0.21 mmol), DIEA (66 mg,0.51 mmol) and DMSO (5 mL), and the mixture was heated to 120℃for reaction for 12h. TLC showed complete reaction, cooled, the reaction was poured into water, extracted 3 times with ethyl acetate, the organic phases combined, washed with saturated brine, dried over anhydrous sodium sulfate, evaporated in vacuo and purified by prep. silica gel plate (DCM/meoh=10/1) to give 50mg of compound 11-2. Yield: 53.3%.
Step 2: synthesis of Compound 11-3
To the reaction flask was added compound 11-2 (50 mg,0.091 mmol), lithium hydroxide (19 mg,0.453 mmol), tetrahydrofuran (5 mL) and water (1 mL), and the mixture was heated to 60℃and reacted overnight. TLC showed complete reaction and cooled. The reaction solution was poured into water, 200mg of glacial acetic acid was added, followed by extraction 3 times with ethyl acetate, and 48mg of compound 11-3 was obtained by vacuum evaporation. Yield: 98%. The product was used directly in the next step without purification.
Step 3: synthesis of Compound 11
Into a reaction flask was charged compound 11-3 (48 mg,0.089 mmol), DIEA (46 mg,0356 mmol), NH 4 Cl (14 mg,0.267 mmol) and DMF (2 mL) were added in one portion and reacted overnight at room temperature. The reaction was poured into water, extracted 3 times with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and purified by prep. silica gel plate (DCM/meoh=10/1) after evaporation in vacuo to give 11mg of product 11. Yield: 23%.
LC/MS:m/z＝538.2[M+H] + .
1 H NMR(400MHz,d6-DMSO)δ1.34-1.44(1H,m),1.53-1.63(1H,m),1.76-1.80(1H,m),2.18-2.23(1H,m),3.14(1H,t,J＝10.8Hz),3.40-3.47(3H,m),4.11-4.18(2H,m),4.69(1H,t,J＝5.4Hz,1H),7.03(1H,d,J＝2.4Hz),7.08-7.11(2H,m),7.20-7.22(1H,m),7.40-7.43(2H,m),7.54(2H,dd,J＝8.3,4.3Hz),7.60-7.66(3H,m),7.70(1H,m),10.52(1H,s).
Example 12
Step 1: synthesis of Compound 12-2
To the reaction flask was added compound 12-1 (500 mg,2.124 mmol), potassium carbonate (439 mg,3.177 mmol) and DMF (5 mL). Cooled in an ice bath, methyl iodide (331 mg,2.332 mmol) was then added dropwise, and after the addition was completed, the reaction mixture was warmed to room temperature and stirred for 3 hours, and TLC showed completion of the reaction. Water was added to the reaction solution, extraction was performed twice with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give 520mg of Compound 12-2, yield: 98%. The product was used directly in the next step without purification.
Step 2: synthesis of Compound 12-4
Into a reaction flask was charged compound 12-2 (460 mg,1.844 mmol), 12-3 (220 mg,1.844 mmol), pd 2 (DBA) 3 (34 mg,0.037 mmol), X-Phos (35 mg,0.073 mmol), cesium carbonate (1.212 g,3.72 mmol) and dioxane (10 mL), the reaction liquid nitrogen was replaced with gas, and the reaction was carried out at 100deg.C for 5 hours, with TLC indicating complete reaction of the starting material. After the reaction system is cooled, directly adding silica gel for sample mixing, and purifying by a silica gel column to obtain 310mg of a product 12-4, wherein the yield is as follows: 70%.
Step 3: synthesis of Compound 12-5
To a three-port reaction flask, compound 1-6 (100 mg,0.43 mmol) was added, nitrogen was replaced, tetrahydrofuran (4 mL) was added, the reaction mixture was cooled to-72℃and an n-BuLi tetrahydrofuran solution (0.36 mL, 2.5M) was added dropwise thereto, and after stirring for 40 minutes, 12-4 (123 mg,0.43 mmol) was dissolved in tetrahydrofuran and added dropwise to the reaction mixture, and the reaction was continued for 2 hours. The reaction solution was warmed to room temperature, quenched by addition of saturated ammonium chloride solution, extracted twice with ethyl acetate, the organic phases combined, concentrated under reduced pressure, and purified by silica gel column chromatography to give 26mg of product 12-5, yield: 15%.
Step 4: synthesis of example 12
To the flask was added compound 12-5 (26 mg,0.063 mmol), 10-2 (10 mg,0.063 mmol), DIEA (32 mg,0.252 mmol) and n-butanol (1 mL), and the mixture was heated to 100 ℃ for 2 hours, and TLC showed complete reaction of the starting materials. Purification by preparative silica gel plate (DCM/meoh=15/1) after evaporation in vacuo gave 12mg of product 12, yield: 38%.
LC/MS:m/z＝504.2[M+H] + .
1 H NMR(400MHz,d6-DMSO)δ1.37-1.44(1H,m),1.55-1.62(1H,m),1.77-1.81(1H,m),2.16-2.23(1H,m),2.49-2.50(1H,m),3.12-3.17(2H,m),3.27-3.33(1H,m),3.34-3.48(3H,m),4.03(1H,t,J＝8.5Hz),4.13-4.20(2H,m),4.65-4.70(1H,m),6.78-6.86(1H,m),7.14-7.21(1H,m),7.25-7.32(2H,m),7.53-7.59(1H,m),7.68-7.86(3H,m),8.25(1H,d,J＝8.4Hz),8.64(1H,dd,J＝16.3,7.4Hz),12.52(1H,brs).
Example 13
Step 1: synthesis of Compound 13-2
To the reaction flask were added compound 13-1 (11.0 g,32mmol, prepared by reference Eur. J. Org. Chem.2003, 2418-2427) and methylene chloride (110 mL), the reaction liquid nitrogen was replaced with air, cooled in an ice-water bath, then m-CPBA (11.1 g,64 mmol) was added in portions, ice was removed, the reaction mixture was stirred overnight at room temperature, and TLC showed completion of the reaction. The reaction system was filtered, washed with dichloromethane, the filtrate was added with sodium sulfite solution, stirred for 10min and extracted 2 times with dichloromethane, the organic phases were combined and extracted with NaHCO 3 Washing with aqueous solution for 2 times, washing with saturated saline, directly evaporating in vacuum, purifying by a silica gel column to obtain 8.6g of a product 13-2, yield: 75%.
Step 2: synthesis of Compounds 13-3a and 13-3b
LAH (1363 mg,35.9 mmol) and tetrahydrofuran (50 mL) were added to the flask, the reaction was replaced with liquid nitrogen, the ice salt bath was cooled, a tetrahydrofuran solution (50 mL) of Compound 13-2 (8.6 g,23.9 mmol) was added dropwise, ice was removed after stirring for 10min, and stirring was performed overnight at room temperature, and TLC showed complete reaction. The reaction solution was cooled with an ice-water bath, and then water (2.8 mL) was slowly added dropwise thereto to quench the reaction. The obtained suspension is filtered, filter cakes are washed by ethyl acetate, and after the filtrate is concentrated in vacuum, 300mg of a product 13-3a and 3237mg of a product 13-3b are obtained through silica gel column purification, and the yield is: 41%.
Step 3: synthesis of Compound 13-4
To the reaction flask was added compound 13-4 (1500 mg,4.15 mmol) and dichloromethane (30 mL), the reaction liquid nitrogen was replaced with air, dess-Martin oxidant (351 mg,8.30 mmol) was added to the flask in ice-water bath, and the reaction was stirred overnight at room temperature and TLC showed completion of the reaction. Directly adding silica gel into the reaction liquid for sample mixing, and purifying by a silica gel column to obtain 1158mg of a product 13-4, wherein the yield is as follows: 78%.
Step 4: synthesis of Compound 13-5
To the reaction flask was added compound 13-4 (550 mg,1.53 mmol), methyltriphenylphosphine bromide (2186 mg,6.12 mmol) and tetrahydrofuran solution (25 mL), the reaction liquid nitrogen was replaced with air, cooled in an ice-water bath, and then potassium t-butoxide (1373 mg,12.2 mmol) was added in one portion. After stirring for 30min, the mixture was slowly warmed to room temperature and stirred for 1.5h. TLC showed complete reaction of starting material. The reaction solution was quenched with aqueous ammonium chloride, extracted twice with ethyl acetate, the organic phases combined, washed with saturated brine, concentrated under reduced pressure and purified by silica gel column to give 302mg of product 13-5, yield: 55%.
Step 5: synthesis of Compound 13-6
Diiodomethane (375 mg,1.40 mmol) and methylene chloride (6 mL) were added to the reaction flask, the reaction mixture was replaced with nitrogen, diethyl zinc (1.4 mL, 1M) was added dropwise to the reaction mixture, and the mixture was stirred for 5 minutes and then cooled in an ice-water bath. To the reaction was added dropwise a dichloromethane solution (1 mL) of compound 13-5 (100 mg,0.28 mmol), and after the dropwise addition, the reaction mixture was slowly warmed to room temperature and stirred for 3 hours, TLC showed complete reaction, diluted hydrochloric acid (0.1 m,10 mL) was added to quench the reaction, stirred for 5 minutes, extracted twice with dichloromethane, the organic phases combined, concentrated under reduced pressure and purified by silica gel column to give 64mg of product 13-6, yield: 62%.
Step 6: synthesis of Compound 13-7
To the reaction flask were added compound 13-6 (40 mg,0.108 mmol) and tetrahydrofuran (2 mL), and TBAF (0.22 mL,1M in THF) was added to the reaction solution, and the reaction solution was stirred at room temperature for 2.5h. TLC showed complete reaction of the starting materials, water was added to the reaction solution, extracted twice with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. To the residue was added hydrogen chloride dioxane solution (2 mL), and the reaction mixture was stirred at room temperature for 3 hours, and the reaction mixture was directly evaporated to dryness in vacuo to give 13-7, which was used in the next step without purification.
Step 7: synthesis of Compound 13
To the reaction flask were added the above compound 13-7 (0.108 mmol, calculated on theory), 1-7 (41 mg,0.108 mmol), n-BuoH (2 mL) and DIPEA (70 mg,0.54 mmol), and the reaction was heated to 120℃and stirred for 2 hours, and TLC showed product formation. After cooling the reaction system, evaporation in vacuo, followed by purification by preparation of silica gel plate (DCM/meoh=10/1) gave 18mg of product 13, yield: 33% of the two steps.
LC/MS:m/z＝505.1[M+H] + .
1 H NMR(400MHz,d6-DMSO)δ0.26-0.37(2H,m),0.46-0.50(1H,m),0.77-0.81(1H,m),1.80-1.85(1H,m),1.97-2.03(1H,m),3.25(1H,t,J＝10.4Hz),3.42-3.52(3H,m),3.99(1H,dd,J＝10.4,4.4Hz),4.62-4.70(2H,m),7.02(1H,dd,J＝8.5,2.4Hz),7.18-7.20(3H,m),7.26(1H,t,J＝7.4Hz),7.49(2H,t,J＝8.0Hz),7.59(1H,d,J＝8.5Hz),7.65(1H,s),8.25(1H,s),8.33(1H,d,J＝9.1Hz),12.63(1H,brs).
Examples 14 to 15
Synthesis of Compound 14-1:
to the reaction flask was added compound 13-3a (200 mg,0.554 mmol), dichloromethane (2 mL), cooled to 0deg.C, DAST (94 mg, 0.552 mmol) was added and the reaction mixture stirred at 0deg.C for 0.5 h, TLC indicated complete reaction. The reaction system was directly purified by silica gel column chromatography (PE/ea=20/1) to give 75mg of product 14-1, yield: 38%.
Synthesis of Compound 15-1: reference is made to the detailed procedure of synthesis 14-1.
Synthesis of compounds 14, 15:
compounds 14 and 15 were synthesized by the method of reference example 13 via intermediates 14-1 and 15-1, and the specific structures of the compounds are shown in Table 2.
Example 16
To the reaction flask was added compound 13-4 (120 mg, 0.336 mmol), DCE (4 mL) and DAST (119 mg, 0.730 mmol), and the reaction mixture was warmed to 60℃and stirred for 1.5 h, and TLC showed a new spot. The reaction system was cooled and purified directly by silica gel column chromatography (PE/ea=10/1) to give 10mg of product 16-1, yield: 8%. Compound 16 was synthesized by the procedure of reference example 13 via intermediate 16-1, the specific structure of which is shown in table 2.
Examples 17 to 20
Compound 17: compound 17 was synthesized by the procedure of reference example 13 through intermediate 13-1.
Compound 18: compound 18 was synthesized by the procedure of reference example 13 through intermediate 13-3 a.
Compound 19: compound 19 was synthesized by the procedure of reference example 13 through intermediate 13-3 b.
Compound 20: compound 20 was synthesized by the procedure of reference example 13 through intermediate 13-5.
The specific structures of the compounds 17 to 20 are shown in Table 2
Example 21
Diiodomethane (312 mg,1.165 mmol) and methylene chloride (6 mL) were added to the reaction flask, the reaction mixture was replaced with nitrogen, diethyl zinc (1.2 mL, 1M) was added dropwise to the reaction mixture, after stirring at room temperature for 5 minutes, the reaction mixture was cooled with an ice-water bath, then a methylene chloride solution (1 mL) of compound 13-1 (100 mg,0.29 mmol) was added dropwise, the reaction mixture was slowly warmed to room temperature and stirred for 3h, and TLC showed substantially complete reaction. The reaction mixture was quenched by addition of dilute hydrochloric acid (0.1M, 10 mL), extracted twice with dichloromethane, the organic phases combined, concentrated under reduced pressure and purified by silica gel column to give 33mg of product 21-1, yield: 32%. Compound 21 was synthesized by the procedure of reference example 13 via intermediate 21-1, the specific structure of which is shown in table 2.
Example 22
Step 1: synthesis of Compound 22-1
Oxalyl chloride (110 mg,0.866 mmol) and dichloromethane (2 mL) were added to the reaction flask, cooled to-72 ℃, replaced with nitrogen, DMSO (101 mg,1.30 mmol) was slowly added dropwise, stirring was maintained at that temperature for 30min after dropwise addition, compound 10-1 (100 mg,0.433 mmol) was slowly added dropwise with dichloromethane (0.5 mL), stirring was maintained at that temperature for 30min after dropwise addition, triethylamine (220 mg,2.17 mmol) was slowly added, and the reaction mixture was stirred at-72℃for 0.5 h after dropwise addition, and TLC showed complete reaction. The reaction system was extracted 3 times with water and dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give 90mg of product 22-1, yield: 91%. The product was used directly in the next step without purification.
Step 2: synthesis of Compound 22-2
To the reaction flask was added compound 22-1 (90 mg,0.393 mmol) and dichloromethane (2 mL), cooled to-72℃and DAST (127 mg,0.786 mmol) was added and the reaction mixture stirred at-72℃for 0.5 h, TLC showed substantial reaction completion. The reaction system was extracted 3 times with water and dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give 90mg of product 22-2, yield: 91%. The product was used directly in the next step without purification. Compound 22 was synthesized via intermediate 22-2, again by reference to the procedure of example 13, with the specific structure shown in table 2.
Example 23
Step 1: synthesis of Compound 23-3
To the reaction flask was added compound 23-1 (200 mg,1.06 mmol), 23-2 (131 mg,1.17 mmol), potassium carbonate (220 mg,1.59 mmol) and DMF (3 mL). The reaction was heated to 80 ℃ and stirred overnight, TLC indicated complete reaction. Water was added to the reaction solution, extraction was performed twice with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by a silica gel column to give 232mg of compound 23-3, yield: 78%.
Step 2: synthesis of Compound 23-4
To a three-port reaction flask, compound 1-6 (192 mg,0.83 mmol) was added, nitrogen was replaced, tetrahydrofuran (5 mL) was added, the reaction mixture was cooled to-72℃and an n-BuLi tetrahydrofuran solution (0.73 mL,1.83mmol, 2.5M) was added dropwise thereto, and after stirring for 40 minutes, 23-3 (232 mg,0.83 mmol) was dissolved in tetrahydrofuran and the reaction mixture was added dropwise thereto, followed by continuing the reaction for 2 hours. The reaction solution was warmed to room temperature, quenched by addition of saturated ammonium chloride solution, extracted twice with ethyl acetate, the organic phases combined, concentrated under reduced pressure, and purified by silica gel column chromatography to give 140mg of the product 23-4, yield: 42%.
Step 3: synthesis of Compound 23
To the reaction flask was added compound 23-4 (50 mg,0.124 mmol), 10-2 (21 mg,0.124 mmol), DIEA (64 mg,0.496 mmol) and n-butanol (2 mL), heated to 120 ℃ for 2 hours, and TLC showed substantial reaction of the starting materials. The reaction solution was cooled and evaporated in vacuo and purified by preparation of silica gel plate (DCM/meoh=15/1) to give 15mg of product 23, yield: 24%.
LC/MS:m/z＝497.1[M+H] + .
1 H NMR(400MHz,d6-DMSO)δ1.33-1.43(1H,m),1.52-1.62(1H,m),1.76-1.80(1H,m),2.17-2.23(1H,m),3.12(1H,t,J＝11.2Hz),3.38-3.46(3H,m),4.10-4.18(2H,m),4.68(1H,t,J＝5.4Hz,1H),7.03(1H,dd,J＝8.5,2.3Hz),7.22-7.28(2H,m),7.38(1H,m),7.51-7.56(2H,m),7.61(1H,d,J＝8.5Hz),7.69(1H,s),8.28(1H,s),8.83(1H,d,J＝7.4Hz),12.79(1H,brs).
Examples 24 to 26
Compounds 24 to 26 were synthesized with reference to the intermediates prepared above and with reference to example 23, and the specific structures of the compounds are shown in Table 2.
Example 27
Step 1: synthesis of Compound 27-1
To the reaction flask were added 22-1 (600 mg,2.64 mmol), t-butanol (7.5 mL), water (3 mL) and 2-methyl-2-butene (926 mg,13.2 mmol). To the reaction solution were added an aqueous solution (3 mL) of sodium dihydrogen phosphate (1584 mg,13.2 mmol) and sodium chlorite (955 mg,10.6 mmol). The reaction was stirred at room temperature for 1.5 hours, TLC showed complete reaction. The reaction system was quenched with aqueous sodium sulfite solution, then acidified with dilute hydrochloric acid, extracted 2 times with ethyl acetate, combined with organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness to give 500mg of product 27-1, yield: 78%. The product was used directly in the next step without purification.
Step 2: synthesis of Compound 27-2
To the reaction flask was added compound 27-1 (500 mg,2.06 mmol), potassium carbonate (426 mg,3.08 mmol) and DMF (6 mL), followed by methyl iodide (433 mg,3.08 mmol). The reaction was stirred overnight at room temperature and TLC showed complete reaction. Water was added to the reaction solution, extraction was performed twice with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by a silica gel column to give 310mg of Compound 27-2, yield: 58%.
Step 3: synthesis of Compound 27-3
To the reaction flask was added compound 27-2 (310 mg,1.2 mmol) and DMF (3 mL), nitrogen sparge, and ice-water bath cooling. To the reaction solution was added tetraisopropyl titanate (136 mg,0.48 mmol), followed by slowly dropwise addition of ethylmagnesium bromide (3 mL,3.0mmol, 1M). After the addition, the reaction was allowed to warm to room temperature and stirred for 2 hours, and TLC showed complete reaction. The reaction solution was poured into an aqueous ammonium chloride solution to quench, extracted twice with ethyl acetate, the organic phases were combined, washed with saturated brine, concentrated under reduced pressure to dryness and purified by a silica gel column to give 112mg of compound 27-3, yield: 37%. Compound 27 was synthesized via intermediate 27-3, again by reference to the procedure of example 13, with the specific structure shown in table 2.
TABLE 2
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Example 28
Step 1: synthesis of Compound 28-1
To a three-necked flask, compound 1-3 (2.0 g,8.7 mmol) and THF (10 mL) were added, the reaction liquid nitrogen was replaced with air, cooled in an ice-water bath, DIBAL-H (13.1mL,1M in toluene) was then added dropwise, ice was removed, and the reaction solution was stirred at room temperature for 5 hours, and TLC showed complete reaction. The reaction solution was introduced into dilute hydrochloric acid, stirred for 3 hours, extracted with ethyl acetate 2 times, the organic phases were combined, washed with saturated brine, concentrated under reduced pressure, and purified by a silica gel column to give 1.7g of a product 28-1, yield: 84%.
Step 2: synthesis of Compound 28-3
To the reaction flask was added compound 28-2 (500 mg,3.28 mmol), compound 28-1 (763 mg,3.28 mmol) and methanol (10 ml), followed by potassium tert-butoxide (1840 mg,16.4 mmol), and the reaction was stirred overnight at room temperature, and TLC showed product formation. The reaction solution was poured into water, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, concentrated under reduced pressure, and purified by preparative silica gel column to give 435mg of the product 28-3, yield: 28%.
Step 3: synthesis of Compound 28-4
To the reaction flask was added 28-3 (40 mg,0.104 mmol) and dichloromethane (2 mL), the reaction was replaced with liquid nitrogen and Dess-Martin oxidant (88 mg,0.208 mmol) was added to the flask under ice-water bath, and the reaction was stirred at room temperature for 1 hour and TLC showed complete reaction. The reaction solution was poured into water, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparing a silica gel plate to give 16mg of the product 28-4, yield: 40%.
Step 4: synthesis of example 28
To the reaction flask was added compound 28-4 (16 mg,0.042 mmol), 10-2 (21 mg,0.126 mmol), NMP (1 mL) and DIPEA (33 mg,0.252 mmol), and the reaction was heated to 180deg.C and stirred for 8 hours, and TLC showed product formation. After the reaction system was cooled, it was poured into water, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparing a silica gel plate to give 9mg of the product 28, yield: 45%.
LC/MS:m/z＝478.2[M+H] + .
1 H NMR(400MHz,d6-DMSO)δ1.41-1.56(2H,m),1.77-1.80(1H,m),2.21-2.26(1H,m),3.12(1H,t,J＝10.4Hz),3.34-3.45(3H,m),3.55-3.62(1H,m),4.11-4.14(1H,m),4.68(1H,t,J＝5.7Hz),6.41(1H,d,J＝5.7Hz),7.02(1H,dd,J＝8.4,2.3Hz),7.18-7.20(3H,m),7.26(1H,t,J＝7.4Hz),7.46-7.50(2H,m),7.53-7.55(2H,m),7.93(1H,d,J＝5.5Hz),8.39-8.43(1H,m),12.44(1H,brs).
Example 29
29-2 synthesis reference the method of synthesis 1-7, this step yield was very low.
29, synthesis reference synthesis 23.
LC/MS:m/z＝480.1[M+H] + .
Example 30
Step 1: synthesis of Compound 30-2
To a three-necked flask, compound 30-1 (2.5 g,12.7 mmol) and THF (25 mL) were added, the reaction liquid nitrogen was replaced with air, the mixture was cooled in an ice-water bath, sodium hydrogen (60%, 761mg,19.0 mmol) was added in portions, ice was removed, and the reaction solution was stirred at room temperature for 0.5 hours. The reaction was cooled again with an ice-water bath, TIPSCl (3.66 g,19.0 mmol) was added dropwise, ice was removed after the addition, and the reaction was stirred at room temperature for 1 hour. The reaction solution was slowly poured into ice water to quench, extracted 2 times with ethyl acetate, the organic phases were combined, washed with saturated brine, concentrated under reduced pressure, and purified by silica gel column to give 3.92g of the product 30-2, yield: 88%.
Step 2: synthesis of Compound 30-3
To the reaction flask were added compound 30-2 (3.92 g,11.1 mmol) and THF (25 mL), the reaction liquid nitrogen was replaced with air, the dry ice/ethanol bath was cooled to-72℃and n-butyllithium (2.5M, 8.9mL,22.2 mmol) was added dropwise, and the mixture was stirred at constant temperature for 0.5 hours. To the reaction solution was added dropwise a solution of NFSI (4.2 g,13.3 mmol) in THF (10 mL), and the reaction solution was slowly warmed to room temperature and stirred for 1 hour. The reaction solution was slowly poured into ice water to quench, extracted 2 times with ethyl acetate, the organic phases were combined, washed with saturated brine, concentrated under reduced pressure, and purified by silica gel column to give 1.69g of the product 30-3, yield: 52%.
Step 3: synthesis of Compound 30-4
To the reaction flask was added compound 30-3 (400 mg,1.37 mmol) and THF (5 mL), the reaction was replaced with liquid nitrogen, the dry ice/ethanol bath was cooled to-72℃and sec-butyllithium (1.3M, 2.1mL,2.74 mmol) was added dropwise, and the mixture was stirred at constant temperature for 0.5 hours. To the reaction solution was added dropwise a solution of NFSI (518 mg,1.64 mmol) in THF (3 mL), and the reaction solution was slowly warmed to room temperature and stirred for 1 hour. The reaction solution was slowly poured into ice water to quench, extracted with ethyl acetate 2 times, and the organic phases were combined, washed with saturated brine and concentrated under reduced pressure to give 800mg of crude product 30-4, which was used in the next step without purification.
Step 4: synthesis of Compound 30-5
To the reaction flask were added compound 30-4 (800 mg,2.58 mmol), THF (8 mL) and TBAF (1M, 3.2 mL), and the reaction was stirred at room temperature for 0.5 hours. The reaction solution is directly decompressed and concentrated and purified by a silica gel column to obtain 150mg of product 30-5, and the two steps of yields are as follows: 71%.
Step 5: synthesis of Compound 30-6
To the reaction flask were added compound 30-5 (95 mg,0.62 mmol) and DMF (4 mL), the reaction was cooled with an ice-water bath, NBS (110 mg,0.62 mmol) was added, and the reaction was slowly warmed to room temperature and stirred for 0.5 hours. The reaction solution was poured into water, extracted 2 times with ethyl acetate, the organic phases were combined, washed with saturated brine, concentrated under reduced pressure, and purified on a silica gel preparation plate to give 120mg of a product 30-6, yield: 83%.
30-7, and a method of synthesizing 1-7.
30, and synthesizing reference synthesis 28.
LC/MS:m/z＝496.1[M+H] + .
1 H NMR(400MHz,d6-DMSO)δ1.35-1.56(2H,m),1.75-1.78(1H,m),2.22-2.25(1H,m),3.14(1H,t,J＝10.7Hz),3.30-3.35(3H,m),3.78-3.83(1H,m),4.10-4.12(1H,m),7.02(1H,dd,J＝8.5,2.3Hz),7.18-7.20(2H,m),7.26(1H,t,J＝7.4Hz),7.48(2H,t,J＝8.0Hz),7.56(1H,d,J＝8.5Hz),7.66(1H,s),8.04(1H,d,J＝6.6Hz),8.43(1H,d,J＝8.4Hz),12.66(1H,brs).
Example 31
31-1 synthesis reference synthesis 30-4, NFSI was replaced with NCS.
31 by 30-4 synthesis of 30.
LC/MS:m/z＝512.2[M+H] + .
Example 32
32-1 synthesis reference synthesis 30-4, NFSI was replaced with carbon tetrabromide.
32-2 synthesis reference synthesis 30-5.
32-3 synthesis reference the method of synthesizing 30-6 replaces NBS with NIS.
32 by 30-6 synthesis of 30.
LC/MS:m/z＝556.1[M+H] + .
Example 33
Into a reaction flask was charged compound 32 (10 mg,0.018 mmol), zinc cyanide (4.2 mg,0.036 mmol), DMA (0.5 mL), zinc powder (1.0 mg), dppf (2.0 mg) and Pd 2 (dba) 3 (2.0 mg), the reaction mixture was purged with nitrogen, heated to 100℃and stirred for 2 hours. The reaction mixture was extracted 2 times with ethyl acetate, and the organic phases were combined, washed with saturated brine, concentrated under reduced pressure, and purified by silica gel preparation plate to give 3mg of the product 33, yield: 33%.
LC/MS:m/z＝503.1[M+H] + .
Example 34
34-1, synthesis reference synthesis 13-7.
34, and synthesizing reference synthesis 30.
LC/MS:m/z＝508.2[M+H] + .
Example 35
35, the method of synthesis reference synthesis 28.
LC/MS:m/z＝490.2[M+H] + .
1 H NMR(400MHz,d6-DMSO)δ0.71-0.75(1H,m),0.81-0.86(1H,m),1.26-1.34(1H,m),1.50-1.56(1H,m),2.70-2.75(1H,m),3.48-3.61(3H,m),3.88(1H,dd,J＝11.6,6.0Hz),4.13-4.23(1H,m),4.84(1H,t,J＝5.6Hz),6.47(1H,d,J＝5.8Hz),6.99-7.06(2H,m),7.18-7.20(2H,m),7.25(1H,t,J＝7.4Hz),7.40-7.56(4H,m),7.92(1H,d,J＝5.6Hz),8.54(1H,d,J＝7.7Hz),12.40(1H,brs).
Example 36
36-1 synthesis reference synthesis 13-7.
36, and the method of synthesis reference synthesis 28.
LC/MS:m/z＝476.1[M+H] + .
Example 37
Synthesizing step 1: synthesis of Compound 37-2
To the reaction flask were added compound 37-1 (652-67-5, 200mg,1.37 mmol), phthalimide (201 mg,1.37 mmol), triphenylphosphine (428 mg,2.74 mmol) and THF (5 mL), DIAD (553 mg,2.74 mmol) was added dropwise, the temperature of the reaction solution was elevated significantly, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was directly concentrated under reduced pressure and purified by a silica gel column to give 351mg of a product 37-2 (containing triphenylphosphine oxide), yield: 93%.
Step 2: synthesis of Compound 37-3
To the reaction flask were added compound 37-2 (200 mg,0.73 mmol), ethanol (4 ml) and hydrazine hydrate (80%, 91mg,1.45 mmol), and the reaction was stirred overnight at room temperature. The reaction solution was filtered off with suction, washed with a small amount of ethanol, and the filtrate was concentrated to dryness under reduced pressure to give crude 37-3 without further purification.
37 by reference to methods of synthesis 1-12.
LC/MS:m/z＝492.9[M+H] + .
1 H NMR(400MHz,d6-DMSO)δ3.69(1H,d,J＝9.6Hz),3.80-3.85(2H,m),3.93(1H,dd,J＝9.5,4.2Hz),4.14(1H,s),4.45(1H,d,J＝3.6Hz),4.60(2H,d,J＝3.5Hz),5.24(1H,d,J＝3.8Hz),7.02(1H,dd,J＝8.5,2.4Hz),7.17-7.20(3H,m),7.23-7.27(1H,m),7.45-7.51(2H,m),7.59(1H,d,J＝8.5Hz),7.68(1H,s),8.30(1H,s),8.87(1H,d,J＝7.1Hz),12.82(1H,brs).
Example 38
Synthesizing step 1: synthesis of Compound 38-2
Into a reaction flask was charged compound 38-1 (60 mg,0.215 mmol), phenylacetylene (44 mg,0.429 mmol), DMF (1 mL), TEA (43 mg,0.429 mmol), cuI (10 mg) and PdCl 2 (PPh) 3 (20 mg) the reaction mixture was purged with nitrogen, heated to 120℃and stirred for 5 hours. The reaction mixture was extracted 2 times with ethyl acetate, and the organic phases were combined, washed with saturated brine, concentrated under reduced pressure, and purified by silica gel preparation plate to give 46mg of product 38-2, yield: 84%.
38, reference is made to methods of synthesis 1-12.
LC/MS:m/z＝349.1[M+H] + .
Example 39
39 synthesis method referring to the method of synthesizing 37 from 37-1, the starting material is replaced with 39-1 (641-74-7).
LC/MS:m/z＝493.0[M+H] + .
1 H NMR(400MHz,d6-DMSO)δ3.44(1H,d,J＝8.0Hz),3.78(1H,dd,J＝8.4,6.6Hz),3.93(1H,d,J＝9.3Hz),4.02(1H,dd,J＝9.5,4.3Hz),4.14-4.20(1H,m),4.46-4.51(2H,m),4.58-4.61(1H,m),4.94(1H,d,J＝6.3Hz),7.02(1H,dd,J＝8.5,2.4Hz),7.17-7.21(3H,m),7.26(1H,t,J＝7.4Hz),7.46-7.50(2H,m),7.58(1H,d,J＝8.5Hz),7.66(1H,s),8.30(1H,s),8.89(1H,d,J＝6.9Hz),12.81(1H,brs).
Example 40
40, and substituting the raw material phenylacetylene with 2-chloroacetylene.
LC/MS:m/z＝383.0[M+H] + .
Example 41
41-1, organic Letters,2015, vol.17, #18, p.4640-4643.
41 with reference to the method of synthesis 38, the raw material phenylacetylene is replaced by 41-1.
LC/MS:m/z＝441.0[M+H] + .
Test of efficacy
Test example 1: in vitro assay for BTK inhibition kinase activity
1: compound formulation
The compound powder was dissolved in 100% dmso to prepare a 10mM stock solution. -20-DEG light-shielding frozen storage.
2: kinase reaction process
(1) Preparing a 1 XKinase buffer;
(2) Preparing a compound concentration gradient: test compounds were tested at 1 μm and diluted in 384source plates to 100-fold final concentrations of 100% dmso solution, 3-fold diluted compounds, 10 concentrations. The 250nL of 100-fold final concentration of compound was transferred to the destination plate OptiPlate-384F using a dispenser Echo 550;
(3) Preparing a Kinase solution with a final concentration of 2.5 times by using a 1 XKinase buffer;
(4) Adding 10 mu L of kinase solution with 2.5 times of final concentration to each of the compound well and the positive control well; add 10. Mu.L of 1 XKinase buffer to the negative control wells;
(5) Centrifuging at 1000rpm for 30 seconds, shaking and uniformly mixing a reaction plate, and incubating at room temperature for 10 minutes;
(6) A mixed solution of ATP and Kinase substrate2 was prepared at 5/3 times the final concentration using a 1 XKinase buffer;
(7) Adding 15 mu L of a mixed solution of ATP and a substrate with 5/3 times of the final concentration, and initiating a reaction;
(8) Centrifuging the 384-well plate at 1000rpm for 30 seconds, shaking and uniformly mixing, and incubating for 10 minutes at room temperature;
(9) Adding 30 mu L of stop detection solution to stop kinase reaction, centrifuging at 1000rpm for 30 seconds, and shaking and mixing uniformly;
(10) The conversion was read with Caliper EZ Reader.
3: data analysis
The calculation formula is as follows:
wherein: conversion% _sample is a Conversion reading of the sample; convertion% _min: negative control Kong Junzhi, representing conversion reading without enzyme wells; convesion% _max: positive control Kong Bizhi mean represents conversion readings for wells without compound inhibition.
Fitting dose-response curve
The log of concentration was used as X-axis and the percent inhibition was Y-axis, and the analytical software GraphPad Prism5 log (inhibitor) vs. response-Variable slope fitted-in-dose-response curve was used to obtain the IC50 values of each compound for enzyme activity.
The calculation formula is that the compound y=bottom+ (Top-Bottom)/(1+10+ (log ic 50-X) HillSlope) has inhibitory activity on BTK wild-type and BTK mutant C481S kinase as shown in table 3.
Table 3: compounds having BTK and BTK-C481S kinase inhibitory activity
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Test example 2: liver microsome stability experiment
1: adding 10 mu L of test or control working solution and 80 mu L of microsome working solution (liver microsome protein concentration is 0.5 mg/mL) into T0, T5, T10, T20, T30, T60 and NCF60 sample hole sites, adding only microsome working solution into Blank60 hole sites, and then pre-incubating samples Blank60, T5, T10, T20, T30 and T60 except for T0 and NCF60 in a 37 ℃ water bath for about 10 minutes;
2: adding 300 mu L of stop solution (containing 200ng/mL tolbutamide and ng/mL of labetanol acetonitrile solution) into a T0 sample, and then adding 10ul of NADPH regeneration system working solution;
3: after the incubation plates Blank60, T5, T10, T20, T30 and T60 were pre-incubated, 10 μl of NADPH regeneration system working solution was added to each sample well to initiate the reaction, and 10ul of 100mm potassium phosphate buffer was added to NCF60 sample wells;
4: after incubation for a suitable period of time (e.g., 5, 10, 20, 30, and 60 minutes), 300. Mu.L of stop solution was added to each of the test sample wells and control sample wells of the Blank60, T5, T10, T20, T30, T60, and NCF60 plates, respectively, to terminate the reaction.
5: all sample plates were shaken and centrifuged at 4000rpm for 20 minutes, and 100. Mu.L of the supernatant of the test or control sample was diluted into 300. Mu.L of pure water for LC-MS/MS analysis, respectively
6: data analysis, T1/2 and CL are calculated according to first order elimination kinetics int(mic) Values (. Mu.L/min/mg), first order elimination kinetics equation:
/>
the results of the human and rat liver microsome stability test are shown in Table 4.
TABLE 4 results of liver microsome stability test of the inventive compounds
Test example 3: determination of in vitro cell proliferation (TMD 8) inhibitory Activity of Compounds
1: cell lines
Culturing at 37deg.C under 5% CO2 and 95% humidity.
2: compound arrangement
The test compounds were diluted with DMSO to give a final concentration of 10mM stock for use.
3: cell culture and seeding
(1) Cells in the logarithmic growth phase were harvested and counted using a platelet counter. Detecting the cell activity by trypan blue exclusion method, and ensuring the cell activity to be more than 90%;
(2) Regulating the cell concentration; add 90. Mu.L of cell suspension to 96-well plates, respectively;
(3) Cells in 96-well plates were incubated overnight at 37 ℃, 5% co2, 95% humidity.
4: drug dilution and dosing
(1) Preparing 10 times of medicine solution, wherein the highest concentration is 10 mu M,9 concentrations are diluted by 3.16 times, adding 10 mu L of medicine solution into each hole of a 96-well plate inoculated with cells, setting three compound holes for each medicine concentration, wherein the final concentration of the compound is 1 mu M,9 concentrations are diluted by 3.16 times, and the final concentration of DMSO is 0.1%;
(2) Cells in the dosed 96-well plates were incubated at 37℃under 5% CO2 at 95% humidity for a further 72 hours before CTG analysis.
5: terminal reading board
(1) Thawing CTG reagent and equilibration of cell plates to room temperature for 30 min;
(2) Adding an equal volume of CTG solution to each well;
(3) Vibrating on an orbital shaker for 5 minutes to lyse cells;
(4) The cell plates were left at room temperature for 20 min to stabilize the luminescence signal;
(5) The luminescence value is read.
6: data processing
The data were analyzed using GraphPad Prism 7.0 software, and non-linear S-curve regression was used to fit the data to yield the dose-response curve, and IC50 values were calculated therefrom.
Cell viability (%) = (Lum test drug-Lum broth control)/(Lum cell control-Lum broth control) ×100%.
The results of the in vitro TMD8 cell proliferation inhibitory activity are shown in Table 5.
Table 5: some of the compounds of the invention have TMD8 cell proliferation inhibitory Activity
Examples TMD8 IC50(nm)
17 36
21 24
34 61
35 71
ARQ-531 35
From the above examples, the compound serving as the BTK protein kinase inhibitor has strong inhibition effect on wild type BTK and mutant BTK (C481S) kinase, has good stability of liver microsome and good cell activity, and can be used for preparing medicines for treating diseases caused by over-expression of BTK kinase.
Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made therein without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.

Claims (7)

1. A compound having the structure or a pharmaceutically acceptable salt thereof, as shown below:
。
2. a pharmaceutical composition comprising an active ingredient selected from the group consisting of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
3. Use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, for the preparation of a protein kinase inhibitor, wherein the kinase inhibitor is a BTK inhibitor.
4. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of any one or more of autoimmune disease, inflammatory disease, thromboembolic disease, allergies, infectious disease, proliferative disorder, and cancer.
5. The use according to claim 4, wherein the disease is selected from: arthritis, urticaria, vitiligo, organ transplant rejection, ulcerative colitis, crohn's disease, dermatitis, asthma, sjogren's syndrome, systemic lupus erythematosus, multiple sclerosis, idiopathic thrombocytopenic purpura, rash, anti-neutrophil cytoplasmic antibody vasculitis, polycystic skin sore, pemphigus vulgaris, chronic obstructive pulmonary disease, psoriasis; mantle cell lymphoma, ovarian cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, hepatocellular carcinoma, glioma, endometrial cancer, melanoma, renal cancer, bladder cancer, biliary tract cancer, lymphoma, hairy cell cancer, nasopharyngeal cancer, pharyngeal cancer, colorectal cancer, rectal cancer, brain and central nervous system cancer, cervical cancer, testicular cancer, genitourinary cancer, lung cancer, small cell cancer, bone cancer, colon cancer, adenoma, adenocarcinoma, follicular cancer, hodgkin's leukemia, bronchial carcinoma, uterine cancer, cervical cancer, multiple myeloma, acute myelogenous leukemia, chronic myelogenous leukemia, lymphoblastic leukemia, chronic lymphoid leukemia, myelogenous leukemia, non-hodgkin's lymphoma, primary macroglobulinemia.
6. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease that causes overexpression of BTK kinase.
7. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease caused by overexpression of BTK kinase.
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