CN117164560A - Piperazinone compound and preparation method and application thereof - Google Patents

Piperazinone compound and preparation method and application thereof Download PDF

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CN117164560A
CN117164560A CN202310645450.5A CN202310645450A CN117164560A CN 117164560 A CN117164560 A CN 117164560A CN 202310645450 A CN202310645450 A CN 202310645450A CN 117164560 A CN117164560 A CN 117164560A
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formula
compound
alkyl
compound shown
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杨康敏
吴菁
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Shanghai Xucheng Pharmaceutical Technology Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/695—Silicon compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages

Abstract

The invention discloses a piperazinone compound, a preparation method and application thereof. Specifically, the invention discloses a compound shown in a formula I, a tautomer, a stereoisomer or a pharmaceutically acceptable salt thereof, and the compound shown in the formula I has good inhibition effect on tumor cell proliferation and good pharmacokinetic property.

Description

Piperazinone compound and preparation method and application thereof
Technical Field
The invention relates to a piperazinone compound, a preparation method and application thereof.
Background
In 1997, professor Kawasala et al in japan reported the isolation of the natural product Phenylahistin from aspergillus pyrogallol. Studies have found that Phenylahistin exhibits strong cytotoxicity against a variety of tumor cells. The us NEREUS pharmaceutical company in 7 2004 disclosed for the first time a chemical modification of phenahistin in patent WO2004054498, where plinabulin (KPU-2, npi-2358, plinabulin) entered phase III clinical studies. The compound with the 2, 5-diketopiperazine parent nucleus structure has the anti-tumor effect, and also has the functions of relieving neutropenia of chemotherapy patients and the like.
Plinabulin can bind to tubulin near the colchicine binding site, stopping cells at an early stage of mitosis, thereby inducing cell death. At the same time, it can inhibit microtubule formation and endothelial cell migration, and make tumor microtubule system function abnormal.
Meanwhile, plinabulin proved to be a guanine nucleotide exchange factor (GEF-H1) activator, a drug different from granulocyte colony stimulating factor (G-CSF) class. Plinabulin achieves early protection of leukocytes in bone marrow by reversing neutrophil blocking formation in bone marrow induced by chemotherapeutic agents, maintaining neutrophil levels within normal ranges, and reducing the occurrence of early neutropenia by a mechanism of action different from G-CSF.
Disclosure of Invention
The invention aims to provide a novel piperazinone compound with anti-tumor activity, a preparation method and application thereof. The compound has good inhibition effect on tumor cell proliferation and good pharmacokinetic property.
The present invention solves the above-mentioned problems by the following method.
The invention provides a compound shown in a formula I, a tautomer, a stereoisomer or a pharmaceutically acceptable salt thereof;
Wherein R is 1 Is H, -O-R 1-1 or-C (=O) -R 1-2 ；
R 1-1 And R is 1-2 Each independently is C 6 -C 12 Aryl or C substituted by one or more halogens 6 -C 12 An aryl group;
R 2 is C 1 -C 8 Alkyl or
R 2-1 、R 2-2 And R is 2-3 Each independently is C 1 -C 6 An alkyl group;
is->
R 3 Independently is-R 3-1 -O-C(＝O)-O-R 3-2 ；R 3-1 Is C 1 -C 6 An alkylene group; r is R 3-2 Is C 1 -C 6 An alkyl group;
R 4 is H;
Y 1 is N or N (R) a )；
R a Is H or R 4 And R is R a Together forming a methylene or deuterated methylene group;
Y 2 and Y 3 Each independently is C (R) b )、N、N(R c ) Or O, provided that ring Y is an aromatic ring;
R b and R is c Each independently H, C 1 -C 6 Alkyl, substituted by 1, 2 or 3R d Substituted C 1 -C 6 Alkyl or R 3 ；
R d Each independently is-OH, -NR d-1 R d-2 Or C 1 -C 6 An alkoxy group; r is R d-1 And R is d-2 Each independently is H or C 1 -C 6 An alkyl group;
and, the compound as shown in formula I satisfies at least one of the following conditions:
(1)Y 1 is N (R) a ) And R is 4 And R is R a Together forming a deuterated methylene group;
(2)is->
(3)Y 2 N, N (R) c ) Or O.
In one embodiment of the invention, R 1-1 And R is 1-2 In the definition of (2), the halogen may independently be F, cl, br or I, such as F.
In one embodiment of the invention, R 1-1 And R is 1-2 In the definition of (C) 6 -C 12 Aryl groups may independently be phenyl or naphthyl, for example phenyl.
In one embodiment of the invention, R 2 In the definition of (C), said C 1 -C 8 Alkyl can be C 1 -C 8 Tertiary alkyl groups such as tertiary butyl.
In one embodiment of the invention, R 2-1 、R 2-2 And R is 2-3 In the definition of (C), said C 1 -C 6 Alkyl groups may independently be C 1 -C 3 Alkyl groups such as methyl.
In one embodiment of the invention, R 3-1 In the definition of (C), said C 1 -C 6 The alkylene group may be C 1 -C 3 Alkylene groups such as methylene.
In one embodiment of the invention, R 3-2 In the definition of (C), said C 1 -C 6 Alkyl can be C 1 -C 3 Alkyl groups such as methyl.
In one embodiment of the invention, when R 4 And R is R a When taken together to form a deuterated methylene group, the deuterated methylene group may be-CHD or-CD 2 For example CD 2 。
In one embodiment of the invention, R b And R is c In the definition of (C), said C 1 -C 6 Alkyl groups may independently be C 1 -C 3 Alkyl groups such as methyl, ethyl or n-propyl.
In one embodiment of the invention, R d In the definition of (C), said C 1 -C 6 Alkoxy can be C 1 -C 3 Alkoxy groups such as methoxy.
In one embodiment of the invention, R d-1 And R is d-2 In the definition of (C), said C 1 -C 6 Alkyl groups may independently be C 1 -C 3 Alkyl groups such as methyl.
In one embodiment of the invention, R 1 Is H,
In one embodiment of the invention, R 2-1 Is methyl.
In one embodiment of the invention, R 2-2 Is methyl.
In one embodiment of the invention, R 2-3 Is methyl.
In one embodiment of the invention, R 2 Is tert-butyl or
In one embodiment of the invention, R 3-1 Is methylene.
In one embodiment of the invention, R 3-2 Is methyl.
In one embodiment of the invention, R 3 is-CH 2 -O-C(＝O)-O-CH 3 。
In one embodiment of the present invention,is->
In one embodiment of the invention, Y 1 Is N or N (R) a ) Preferably, -n=, =n-, or N (R a ) When Y is 1 Is N (R) a ) R4 and R when a Together form methylene or-CD 2 -, wherein the label side represents Y 2 Are connected.
In one embodiment of the invention, Y 3 Is N or N (R) c )。
In one embodiment of the invention, R b H.
In one embodiment of the invention, R d-1 And R is d-2 Methyl groups are independently used.
In one embodiment of the invention, R d is-OH,Or methoxy.
In one embodiment of the invention, R c Is H, methyl, ethyl, n-propyl, hydroxy-substituted ethyl, hydroxy-substituted n-propyl, methoxy-substituted methyl, dimethylamino-substituted ethyl or-CH 2 -O-(C＝O)-O-CH 3 For example H, -CH 3 、-CH 2 CH 3 、-CH 2 CH 2 CH 3 、
In one embodiment of the invention, Y 2 Is CH, N, Preferably =ch-, -CH =, =n-, -and +_> Wherein the side denoted by the symbol is with Y 3 Are connected.
In one embodiment of the invention, Y 3 For N, NH or Preferably, the values are =, = N-, -NH-, or +.>Wherein the label side represents and Y 2 Are connected.
In one embodiment of the invention, the building blocksIs->
In one embodiment of the invention, the building blocksIs->
In one embodiment of the invention, Y 2 Is N (R) c )；R c Is C 1 -C 6 Alkyl, C substituted by 1, 2 or 3 Rd 1 -C 6 Alkyl or R 3 。
In one embodiment of the present invention,is->Structural unit->Is that
In one embodiment of the present invention, the compound of formula I is any one of the following structures:
wherein each substituent is as defined above.
In one embodiment of the present invention, the compound of formula I is any one of the following compounds:
the invention also provides a preparation method of the compound shown in the formula I, which is any one of the following methods:
method 1 comprising the steps of: in a solvent, under the action of alkali, reacting a compound shown in a formula 1a with a compound shown in a formula 1b to obtain a compound shown in a formula I;
wherein Y is 1 Is N, and the definition of each substituent is as described above;
the base may be a base commonly used in such reactions in the art, such as alkali metal carbonates, alkoxides, more such as cesium carbonate, potassium t-butoxide; the solvent may be a solvent commonly used in such reactions in the art, such as an amide-based solvent, more such as N, N-dimethylformamide;
Method 2 comprising the steps of: in a solvent, under the action of alkali, reacting the compound shown in the formula 2a with the compound shown in the formula 2b to obtain a compound shown in the formula I;
wherein,is->Y 1 Is N, and the definition of each substituent is as described above;
the base may be a base commonly used in such reactions in the art, such as alkali metal carbonates, more such as cesium carbonate; the solvent may be a solvent commonly used in such reactions in the art, such as an amide-based solvent, more such as N, N-dimethylformamide;
method 3 comprising the steps of: in a solvent, under the action of alkali, reacting the compound shown in the formula 3a with the compound shown in the formula 3b to obtain a compound shown in the formula I';
wherein,is->X is halogen, such as F, cl, br or I, more such as Cl;
when (when)Is->In the case of the compounds of formula I, -/-, a>Is thatIs->
When (when)Is->In the case of the compounds of formula I, -/-, a>Is thatIs->
When (when)Is->In the case of the compounds of formula I, -/-, a>Is that Is->The definition of the other substituents in the above formulae is as described above;
the base may be a base commonly used in such reactions in the art, such as alkali metal carbonates, more such as cesium carbonate; the solvent may be a solvent commonly used in such reactions in the art, such as an amide-based solvent, more such as N, N-dimethylformamide;
Method 4 comprising the steps of: in a solvent, under the action of alkali, reacting the compound shown in the formula 4a with the compound shown in the formula 4b to obtain a compound shown in the formula I;
wherein, in the compound shown in the formula I, Y 1 Is N (R) a )，R 4 And R is R a Together forming a methylene or deuterated methylene group; the compound of formula 4b isL is-CH 2 -CDH or-CD 2 Ar is C 6 -C 12 Aryl, preferably phenyl;x is halogen, such as F, cl, br or I, more such as Cl; the remaining substituents in the compounds of formula 4a and formula I are as described above;
the solvent may be a solvent commonly used in such reactions in the art, such as an ether solvent, more such as tetrahydrofuran; the base may be a base commonly used in such reactions in the art, such as an alkali metal hydride, more such as NaH;
method 5 comprising the steps of: in a solvent, under the action of alkali, reacting a compound shown in a formula 5a with a compound shown in a formula 5b to obtain a compound shown in a formula I;
wherein X' is halogen, such as F, C1, br or I, preferably Cl, br or I; in the compounds of the formula I shown in the specification,is->R c Is C 1 -C 6 Alkyl or C substituted by 1, 2 or 3 Rd 1 -C 6 Alkyl, other substituents in the above formulae are as defined above;
the solvent may be a solvent commonly used in such reactions in the art, such as an amide-based solvent, more such as DMF; the base may be a base commonly used in such reactions in the art, such as alkali metal carbonates, more such as potassium carbonate or sodium carbonate;
Method 6 comprising the steps of: in a solvent, under the action of alkali, reacting the compound shown in the formula 6a to obtain a compound shown in the formula I;
wherein K is 1 Is C 1 -C 6 Alkylene, K 2 Is C 1 -C 6 An alkyl group;in the compounds of the formula I shown in the specification,is thatR c For K 1 -OH, the other substituents in the formulae being as defined above;
the solvent may be a solvent commonly used in such reactions in the art, such as an alcoholic solvent, more such as methanol; the base may be a base commonly used in such reactions in the art, such as alkali metal carbonates, more such as potassium carbonate;
method 7 comprising the steps of: in a solvent, under the action of alkali, reacting a compound shown in a formula 7a with a compound shown in a formula 7b to obtain a compound shown in a formula I;
wherein,wherein "+" indicates that the marked carbon atom is achiral, R configuration or S configuration; in the compound shown in the formula I, +.>Is->The other substituents in the above formulae are as defined above;
the solvent may be a solvent commonly used in such reactions in the art, such as an amide-based solvent, more such as DMF; the base may be a base commonly used in such reactions in the art, such as an organic base, more such as triethylamine.
The invention also provides a compound shown as formula 1a, 2a, 3a, 4a, 5a, 6a or 7 a;
Wherein each substituent is as defined in any one of the preceding schemes.
The application also provides a pharmaceutical composition comprising a compound of formula I, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The application also provides application of the compound shown in the formula I, a tautomer, a stereoisomer, a pharmaceutically acceptable salt or a pharmaceutical composition thereof in preparing an anti-tumor medicament or a medicament for treating leucocyte or neutrophil cytopenia caused by chemotherapy.
In one embodiment of the application, the tumor may be a head and neck tumor, a respiratory tumor, a digestive tumor, a urinary tumor, a bone cancer, a gynecological tumor, a hematological tumor, a melanoma, a glioma, or a skin cancer; preferably, the respiratory tumor is lung cancer; preferably, the digestive system tumor is intestinal cancer or colon cancer.
Interpretation of the terms
Unless otherwise defined, terms used in the present application have the following definitions, and terms not referred to hereinafter are defined as commonly understood by those skilled in the art to which the present application pertains.
In the present application, the term "tautomer" refers to a functional group isomer generated by rapid movement of an atom in a molecule at two positions. For example, acetone and 1-propen-2-ol can be converted to each other by rapid movement of a hydrogen atom on oxygen and on the alpha-carbon.
In the present invention, the term "stereoisomer" refers to an isomer, including cis-trans isomers, enantiomers, diastereomers and mixtures of enantiomers or diastereomers, which are caused by the same order of connection of atoms or groups of atoms in a molecule to each other, but different spatial arrangements. These stereoisomers may be isolated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, rotary chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.), and may be obtained by chiral resolution by bonding (chemical bonding, etc.) or salifying (physical bonding, etc.) other chiral compounds. Optical isomers include enantiomers and diastereomers. All such isomers and mixtures thereof are included within the scope of the present invention.
In the present invention, the term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
In the present application, the term "pharmaceutically acceptable salt" refers to a salt of a compound prepared with a relatively non-toxic, pharmaceutically acceptable acid or base. When compounds contain relatively acidic functional groups, base addition salts may be obtained by contacting neutral forms of such compounds with a sufficient amount of a pharmaceutically acceptable base in pure solution or in a suitable inert solvent. When the compounds of the present application contain relatively basic functional groups, the acid addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in pure solution or in a suitable inert solvent. When the compound contains relatively acidic and relatively basic functional groups, it can be converted into a base addition salt or an acid addition salt.
In the present application, when numerical ranges are listed, it is intended to include each value and subranges within the range. For example "C 1 ～C 6 Alkyl "includes C 1 、C 2 、C 3 、C 4 、C 5 、C 6 、C 1 -C 6 、C 1 -C 5 、C 1 -C 4 、C 1 -C 3 、C 1 -C 2 、C 2 -C 6 、C 2 -C 5 、C 2 -C 4 、C 2 -C 3 、C 3 -C 6 、C 3 -C 5 、C 3 -C 4 、C 4 -C 6 、C 4 -C 5 And C 5 -C 6 An alkyl group.
In the present application, the term "aryl" means a compound having a specified number of carbon atoms (e.g., C 6 ～C 12 ) A cyclic group consisting of only carbon atoms, which is a single ring or multiple rings, and at least one ring has aromaticity (in accordance with the shock rule). Aryl groups are linked to other fragments in the molecule through aromatic or non-aromatic rings. Aryl groups include, but are not limited to, phenyl, naphthyl, and the like.
In the present invention, the term "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group (hydrocarbon group means a functional group containing only two atoms of carbon and hydrogen), and examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl, t-butyl) and pentyl (e.g., n-pentyl, isopentyl, neopentyl) groups, and the like.
In the present invention, the term "alkylene" refers to a free divalent radical formed by the loss of 2 hydrogen atoms from the same 1 or different two carbons of an alkane.
In the present invention, the term "alkoxy" represents an alkyl group having a specific number of carbon atoms attached through an oxygen bridge, examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy and s-pentoxy.
In the present invention, the term "halogen" refers to F, cl, br or I.
In the present invention, the term "substituted" means that any one or more hydrogen atoms on a particular atom are substituted with substituents, including deuterium and variants of hydrogen, provided that the valence of the particular atom is normal and the substituted compound is stable. In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a specific substituent. Further, when the group is substituted with 1 or more of the substituents, the substituents are independent of each other, that is, the 1 or more substituents may be different from each other or the same. Unless otherwise indicated, a substituent group may be substituted at each substitutable position of the substituted group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, then the substituents may be the same or different at each position.
Where no substituent is explicitly indicated in a recited group, such a group is merely unsubstituted. For example when "C 1 ～C 8 Alkyl "without" unsubstituted or substituted or "before" is defined to mean only "C 1 ～C 8 Alkyl "as such or" unsubstituted C 1 ～C 8 An alkyl group. In addition, unless explicitly stated otherwise, the description used in this application ". In the broad sense, it is to be understood that each individual described is independent of the others and may be independently the same or different. In more detail, the description "..independently" may mean that specific options expressed between the same symbols in different groups do not affect each other; it may also be expressed that specific options expressed between the same symbols in the same group do not affect each other.
Those skilled in the art will appreciate that, in accordance with the convention used in the art, the present application describes the structural formula of the group usedMeaning that the corresponding group is linked to other fragments, groups in the compound through this site.
On the basis of conforming to the common knowledge in the field, the above preferred conditions can be arbitrarily combined to obtain the preferred examples of the application.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that: the invention provides novel diketopiperazine compounds which have good inhibitory activity on HT-29 cells and A549 cells, and part of compounds have good inhibitory activity on HCT116 cells and MC38 cells; and exhibit good pharmacokinetic properties.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
Example 1: synthesis of Compound I-1
/>
Step 1: synthesis of intermediate 1-2
Compound 1-1 (4.90 mL,40 mmol) was dissolved in 40mL of tetrahydrofuran, and n-butyllithium (2.6M, 16.92 mL) was slowly added dropwise to the above system at-78deg.C. After the completion of the dropwise addition, the reaction system was stirred at-78℃for 1 hour. Subsequently, 40mL of DMSO was added dropwise to the reaction system. After the addition was completed, the system was slowly warmed to 25℃and stirred for a further 12 hours. The reaction was quenched with saturated ammonium chloride solution (100 mL) and extracted with n-hexylamine (2X 100 mL). The organic phases were combined and washed with water (3×200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate evaporated to dryness under reduced pressure to give intermediate 1-2 as a pale yellow oil (3.6 g, crude). 1 H NMR(400MHz，CDCl 3 )δppm 9.36(S，1H)，1.31(s，9H)。
Step 2: synthesis of intermediates 1-3
Intermediate 1-2 (3 g,27.23 mmol) was dissolved in 20mL of DMSO and azido trimethylsilane (3.45 g,29.96 mmol) was added. The reaction was stirred at 20℃for 4 hours, and the reaction was complete as monitored by TLC. LCMS monitored the formation of the main product. The reaction was diluted with 20mL of water and extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried, filtered and the filtrate evaporated to dryness under reduced pressure to give a yellow oily residue. Subjecting the mixture to silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0% -34%)) Intermediate 1-3 was obtained as a white solid (260 mg, yield: 6.24%). LCMS (ESI): m/z C 7 H 12 N 3 O + .[M+H] + Calculated = 154.10, found 154.1. 1 H NMR(400MHz，DMSO-d6)δppm 15.46(br s，1H)，10.12(s，1H)，1.40-1.33(m，9H)。
Step 3: synthesis of intermediates 1-4
Intermediate 1-3a (505 mg,2.55 mmol) was dissolved in 5mL of DMF and cesium carbonate (830 mg,2.55 mmol) and intermediate I-3 (260 mg,1.70 mmol) were added. The reaction system was stirred at 25℃for 4 hours. LCMS monitored the formation of the main product. The reaction system is decompressed and evaporated to dryness to obtain solid residue. Intermediate 1-4 was isolated as a white solid (110 mg, yield: 22.25%) via reverse phase column. LCMS (ESI): m/z C 13 H 18 N 5 O 3 + ，[M+H] + Calculated = 292.14, found = 292.1.
Step 4: synthesis of Compound I-1
Intermediate 1-4 (110 mg, 378. Mu. Mol) was dissolved in 3mL of DMF and cesium carbonate (185 mg, 566. Mu. Mol) and benzaldehyde 1-4a (60.1 mg, 566. Mu. Mol) were added. The reaction system was stirred at 80℃for 12 hours. The reaction solution was evaporated to dryness under reduced pressure to give a residue. Compound I-1 was obtained as a pale yellow solid by reverse phase column chromatography (39.2 mg, yield: 30.77%). LCMS (ESI): m/z C 18 H 20 N 5 O 2 ，[M+H] + Calculated = 338.16, found = 338.1. 1 H NMR(400MHz，DMSO-d6)δppm 11.03(br s，1H)，10.63-9.87(m，1H)，7.55(brd，J＝7.5Hz，2H)，7.43(t，J＝7.6Hz，2H)，7.38-7.27(m，1H)，6.83(s，1H)，6.79(s，1H)，1.40(s，9H)。
Example 2: synthesis of Compound I-2
Step 1: synthesis of intermediate 2-2
Compound 2-1 (0.5 g,2.52 mmol) was dissolved in 5mL of DMF and cesium carbonate (1.23 g,3.78 mmol) and intermediate 1-3a (750mg,3.78 mmol). The reaction system was stirred at 25℃for 4 hours. TLC monitored reaction was complete and had the main product formed. The reaction solution was filtered, the filtrate was evaporated to dryness under reduced pressure, and the obtained product was subjected to silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0% -100%) to give intermediate 2-2 as a white solid (240 mg, yield: 28.3%). LCMS (ESI): m/z C 19 H 1 7N 2 O 4 + [M+H] + Calculated = 337.12, found = 337.0. 1 H NMR(400MHz，DMSO-d6)δppm 10.42(s，1H)，7.47-7.37(m，3H)，7.33(d，J＝7.7Hz，1H)，7.28(d，J＝1.8Hz，1H)，7.18-7.12(m，1H)，7.08-7.03(m，2H)，6.96(dd，J＝1.7，8.0Hz，1H)，6.93(s，1H)，4.35(s，2H)，2.49(br s，3H)。
Step 2: synthesis of Compound I-2
Intermediate 2-2 (30 mg, 89.2. Mu. Mol) was dissolved in 2mL of DMF, and cesium carbonate (58.12 mg, 178. Mu. Mol) and intermediate 1-3 (20.36 mg, 134. Mu. Mol) were added. The reaction system was stirred at 80℃for 2 hours. LCMS monitored the disappearance of starting material and the formation of the main product. The reaction was diluted with 10mL of water and extracted with ethyl acetate (5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to give a residue. Compound I-2 was obtained as a white solid (1.54 mg, yield: 4.03%) by reverse phase column chromatography. LCMS (EsI): m/z C 24 H 2 4N 5 O 3 + [M+H] + Calculated = 430.19, found = 430.2. 1 H NMR(400MHz，DMSO-d6)δppm 11.03(br，s，1H)，10.44(br，s，1H)，7.47-7.37(m，3H)，7.29(br，d，J＝7.6Hz，1H)，7.22(s，1H)，7.14(br，t，J＝7.3Hz，1H)，7.07(br，d，J＝8.0Hz，2H)，6.95(br，d，J＝8.0Hz，1H)，6.80(s，1H)，6.77(s，1H)，1.40(s，9H)。
Example 3: synthesis of Compound I-3
Step 1: synthesis of intermediate 3-2
Compound 3-1 (0.5)g,1.82 mmol) (CAS: 22071-24-5) was dissolved with 2mL of water and 2mL of dioxane, and calcium carbonate (363.77 mg,3.63 mmol) was added. The reaction system was stirred at 100℃for 12 hours. TLC monitored reaction was complete and had the main product formed. The reaction was diluted with 10mL of water and extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to give intermediate 3-2 as a colorless oil (350 mg, crude). LCMS (ESI): m/z C 14 H 13 O 2 + [M+H] + Calculated = 213.09, found = 213.1.
Step 2: synthesis of intermediate 3-3
Intermediate 3-2 (350 mg,1.65 mmol) was dissolved in 5mL of dichloromethane and dess-Martin oxidant (769 mg,1.81 mmol) was added. The reaction system was stirred at 20℃for 2 hours. LCMS monitored complete reaction of starting material and formation of main product. The reaction was diluted with 10mL of water and extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, the filtrate was evaporated to dryness under reduced pressure to give a residue. Intermediate 3-3 was obtained as a yellow oil (310 mg, yield: 89.33%) by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0% -100%). LCMS (EsI): m/z C 14 H 12 O 2 + [M+H] + Calculated = 211.07, found = 211.2.
Step 3: synthesis of intermediate 3-4
Intermediate 3-3 (310 mg,1.47 mmol) was dissolved in 4mL of DMF and cesium carbonate (721 mg,2.21 mmol) and intermediate 1-3a (438 mg,2.21 mmol) were added. The reaction system was stirred at 20℃for 4 hours. TLC monitored reaction was complete. The reaction was diluted with 10mL of water and extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was evaporated under reduced pressure to give a residue. Intermediate 3-4 was isolated as a yellow solid (189 mg, yield: 36.9%) by column chromatography on silica gel (mobile phase: ethyl acetate/petroleum ether, gradient 0% -100%). LCMS (ESI): m/zC 20 H 17 N 2 O 4 + [M+H] + Calculated = 349.12, found = 349.2.
Step 4: synthesis of Compound I-3
Intermediate 3-4 (40 mg, 115. Mu. Mol) was dissolved in 2mL of DMF, and cesium carbonate (74.8 mg, 230. Mu. Mol) and intermediate 1-3 (26.2 mg, 172. Mu. Mol) were added. The reaction system was stirred at 80℃for 2 hours. LCMS monitored reaction was complete. The reaction solution was evaporated to dryness under reduced pressure to give a solid residue. Compound I-3 was isolated as a pale yellow solid by reverse phase column chromatography (1.50 mg, yield: 2.97%). LCMS (ESI): m/z C 25 H 24 N 5 O 3 + ，[M+H] + Calculated = 442.19, found = 442.2. 1 H NMR(400MHz，DMSO-d6)δppm 11.05(br，s，1H)，10.63(br，s，1H)，7.88-7.80(m，3H)，7.77(br，d，J＝7.5Hz，1H)，7.73-7.64(m，2H)，7.62-7.54(m，3H)，6.89(s，1H)，6.78(s，1H)，1.40(s，9H)。
Example 4: synthesis of Compound I-4
Intermediate 4-1 (40 mg, 137. Mu. Mol) was dissolved in 2mL of DMF and cesium carbonate (67.1 mg, 206. Mu. Mol) and compound 4-1a (34.5 mg, 151. Mu. Mol) were added (see U.S. Pat. No. 3,262,1980, A for synthesis). The reaction system was stirred at 80℃for 12 hours. LCMS monitored complete reaction of starting material with formation of major product. The reaction system is filtered, and the filtrate is evaporated to dryness under reduced pressure to obtain a residue. And isolated by reverse phase column chromatography to give compound I-4 as a white solid (5.23 mg, yield: 8.3%) LCMS (ESI): m/z C 25 H 23 FN 5 O 3 + [M+H] + Calculated = 460.18, found = 460.1. 1 H NMR(400MHz，CD 3 OD)δppm 7.95(dd，J＝5.4，8.7Hz，2H)，7.88(s，1H)，7.77(brt，J＝7.7Hz，2H)，7.67-7.61(m，1H)，7.29(t，J＝8.8Hz，2H)，7.03(s，1H)，7.00(s，1H)，1.47(s，9H)。
Example 5: synthesis of Compound I-5
Step 1: synthesis of intermediate 5-2
Compound 5-1 (1 g,7.92 mmol) was dissolved in 10mL of toluene and azido trimethylsilane (1.00 g,8.71 mmol) was added and the reaction was stirred at 110℃for 2 hours. TLC monitored reaction was complete and had the main product formed. The reaction was quenched with 20mL of water and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride (10 ml x 2), dried over anhydrous sodium sulfate, filtered and the filtrate evaporated to dryness under reduced pressure to give a yellow oil. Intermediate 5-2 was obtained as a white solid (240 mg, yield: 17.9%) by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0% -35%). LCMS (ESI): m/z C 6 H 12 N 3 SiO+[M+H]+calculated = 170.2, found = 170.0.
Step 2: synthesis of intermediate 5-3
Intermediate 1-3a (4 g,20.18 mmol) was dissolved in 40mL of DMF and cesium carbonate (6.58 g,20.18 mmol) and benzaldehyde (2.14 g,20.18 mmol) were added sequentially. The reaction system was stirred at 20℃for 4 hours under nitrogen protection. TLC monitored reaction was complete. To the reaction was added 30mL of water and extracted with ethyl acetate (20 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to give intermediate 5-3 as a yellow solid (3.6 g, crude). LCMS (ESI): m/z C 13 H 13 N 2 O 3 + [M+H] + Calculated = 245.09, found = 245.1. 1 H NMR(400MHz，CDCl 3 )δppm 7.53-7.32(m，5H)，7.18(s，1H)，4.51(s，2H)，2.66(s，3H)。
Step 3: synthesis of Compound I-5
Intermediate 5-3 (400 mg,1.64 mmol) was dissolved in 10mL of DMF and potassium tert-butoxide (268 mg,3.28 mmol) and intermediate 5-2 (277 mg,1.64 mmol) were added. The reaction system was stirred at 80℃for 6 hours under nitrogen protection. LCMS monitored the disappearance of starting material and the formation of the main product. The reaction was diluted with 30mL of water and extracted with ethyl acetate (50 mL x 3). The organic phases are combined and evaporated to dryness under reduced pressure to obtain brown solid residue, and the brown solid residue is subjected to reversed phase column to prepare the compound I-5 as yellow solid (. About.)8.68mg, yield: 1.5%). LCMS (ESI): m/z C 17 H 20 N s O 2 Si + .[M+H] + Calculated = 354.1, found = 354.1. 1 H NMR(400MHz，CD 3 OD)δppm 7.55-7.45(m，4H)，7.42-7.36(m，1H)，7.01(s，1H)，6.89(s，1H)，0.44(s，9H)。
Example 6: synthesis of Compound I-6
Compound 6-1 (50 mg, 149. Mu. Mol) was dissolved in 2mL of tetrahydrofuran, and sodium hydrogen (23.8 mg, 595. Mu. Mol,60% purity) was added at 0deg.C. The reaction was stirred at 0deg.C and 6-1a (194.2 mg, 595. Mu. Mol) in tetrahydrofuran (3 mL) was added dropwise. After the completion of the dropwise addition, the reaction system was stirred at 20℃for 12 hours. LCMS monitored product formation and some starting material was not fully reacted. The reaction was quenched with 5mL of water and extracted with ethyl acetate (3 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to give a residue, which was separated by reverse phase column chromatography to give Compound I-6 as a pale yellow solid (4.1 mg, yield: 7.85%). LCMS (ESI): m/z C 20 H 19 D 2 N 4 O 2 + [M+H] + Calculated = 351.18, found = 351.2. 1 H NMR(400MHz，CD 3 OD)δppm 7.84(s，1H)，7.53-7.50(m，2H)，7.48-7.42(m，2H)，7.38-7.33(m，1H)，7.25(s，1H)，7.02(s，1H)，1.40(s，9H)。
Example 7: synthesis of Compound I-7
Compound I-1 (30 mg, 88.92. Mu. Mol) was dissolved in 2mL of DMF, and potassium carbonate (18.85 mg, 136.59. Mu. Mol) and methyl iodide (18.93 mg, 133.38. Mu. Mol) were sequentially added with stirring, and the reaction system was stirred at 20℃for 1 hour. LCMS monitors completion of the reaction and the reaction system uses 8mL of saturated ammonium chloride solutionQuench and extract with ethyl acetate (5 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to give a residue, which was separated by reverse phase column chromatography to give Compound I-7 as a white solid (10 mg, yield: 32%). LCMS (ESI): m/z C 19 H 22 N 5 O 2 + [M+H] + Calculated = 352.18, found = 352.4. 1 H NMR(400MHz，CD 3 OD)δppm 7.55-7.50(m，2H)，7.50-7.44(m，2H)，7.50-7.44(m，1H)，7.01(s，1H)，6.96(s，1H)，4.22(s，3H)，1.44-1.42(m，9H)。
Example 8: synthesis of Compound I-8
According to the synthesis method of example 7, starting from Compound I-1 and ethyl iodide, compound I-8 was prepared as a white solid (18 mg, yield: 52%). LCMS (ESI): m/z C 20 H 24 N 5 O 2 + .[M+H] + Calculated = 366.19, found = 366.3. 1 H NMR(400MHz，DMSO-d6)δppm 10.40(br s，1H)，10.32(br s，1H)，7.55(d，J＝7.5Hz，2H)，7.44-7.40(m，2H)，7.37-7.30(m，1H)，6.83(s，1H)，6.76(s，1H)，4.56-4.43(m，2H)，1.49(t，J＝7.3Hz，3H)，1.38(s，9H)。
Example 9: synthesis of Compound I-9
According to the synthesis method of example 7, starting from compound I-1 and 1-iodopropane, compound I-9 was prepared as a white solid (22 mg, yield: 62%). LCMS (EsI): m/z C 21 H 26 N 5 O 2 + [M+H] + Calculated = 380.21, found = 380.2. 1 H NMR(400MHz，DMSO-d6)δppm 10.43(br s，1H)，10.33(s，1H)，7.56(d，J＝7.4Hz，2H)，7.43(t，J＝7.6Hz，2H)，7.37-7.31(m，1H)，6.84(s，1H)，6.77(s，1H)，4.43(t，J＝7.0Hz，2H)，1.93-1.90(m，2H)，1.38(s，9H)，0.91(t，J＝7.4Hz，3H)。
Example 10: synthesis of Compound I-10
Step 1: synthesis of intermediate 10-2
Compound I-1 (33 mg, 98. Mu. Mol) was dissolved in 1mL of DMF, and sodium carbonate (20.7 mg, 196. Mu. Mol) and ethyl 2-bromoacetate (21.2 mg, 127. Mu. Mol) were added. The reaction system was stirred at 20℃for 2 hours. LCMS monitored complete reaction of starting material with formation of major product. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give intermediate 10-2 as a white solid (42 mg, crude product). LCMS (ESI): m/z C 22 H 26 N 5 O 4 + .[M+H] + Calculated = 424.20, found = 424.0.
Step 2: synthesis of Compound I-10
Crude 10-2 (42 mg) as a white solid was dissolved in 1mL of methanol, and potassium carbonate (27.0 mg, 196. Mu. Mol) was added. The reaction system was stirred at 20℃for 2 hours. LCMS monitored complete reaction of starting material with formation of major product. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was separated by reverse phase column chromatography to give Compound I-10 as a white solid (22.6 mg, yield: 60.5%). LCMS (ESI): m/z C 20 H 24 N 5 O 3 + ，[M+H] + Calculated = 382.19, found = 382.1. 1 H NMR(400MHz，DMSO-d6)δppm 10.30(brs，2H)，7.57(d，J＝7.5Hz，2H)，7.45-7.41(m，2H)，7.38-7.33(m，1H)，6.85(s，1H)，6.78(s，1H)，5.04(t，J＝5.5Hz，1H)，4.50(t，J＝5.4Hz，2H)，3.93-3.89(m，2H)，1.39(s，9H)。
Example 11: synthesis of Compound I-11
Compound I-1 (30 mg, 88.92. Mu. Mol) was dissolved in 2mL of DMF, and triethylamine (36 mg, 356. Mu. Mol) and compound 11-1 (26.4 mg, 356. Mu. Mol) were added. The reaction system was nitrogen-protected and stirred at 40℃for 12 hours. LCMS monitored complete reaction of starting material with formation of major product. The reaction solution was concentrated under reduced pressure to give a pale yellow oily substance, and Compound I-11 was isolated by reverse phase column chromatography as a white solid (21.4 mg, yield: 58.6%). LCMS (ESI): m/z C 21 H 26 N 5 O 4 + [M+H] + Calculated = 412.20, found = 412.2. 1 H NMR(400MHz，CD 3 OD)δppm 7.54-7.49(m，2H)，7.49-7.42(m，2H)，7.38(br d，J＝6.8Hz，1H)，6.99(s，1H)，6.97(s，1H)，4.66-4.55(m，1H)，4.53-4.42(m，1H)，4.23(br s，1H)，3.63(brd，J＝4.5Hz，2H)，1.43(s，9H)。
Example 12: synthesis of Compound I-12
According to the synthesis method of example 7, starting from compound I-1 and 2-bromo-N, N-dimethylethylamine, compound I-12 was prepared as a white solid (5.0 mg, yield: 56%). LCMS (ESI): m/z C 22 H 29 N 6 O 2 + .[M+H] + Calculated = 409.24, found = 409.2. 1 H NMR(400MHz，DMSO-d6)δppm 7.54(d，J＝7.5Hz，2H)，7.43-7.40(m，2H)，7.36-7.31(m，1H)，6.83(s，1H)，6.75(s，1H)，4.54(t，J＝6.3Hz，2H)，2.80(t，J＝6.3Hz，2H)，2.18(s，6H)，1.37(s，9H)。
Example 13: synthesis of Compound I-13
According to the synthesis method of example 7, starting from compound I-1 and chloromethyl methyl ether, compound I-13 was prepared as a white solid (5.1 mg, yield: 14%).LCMS(ESI)：m/z C 20 H 24 N 5 O 3 + .[M+H] + Calculated = 382.19, found = 382.0. 1 H NMR(400MHz，CD 3 OD)δppm 7.55-7.50(m，2H)，7.49-7.44(m，2H)，7.41-7.34(m，1H)，7.08(s，1H)，7.00(s，1H)，5.92(s，2H)，3.35(s，3H)，1.58(s，9H)。
Example 14: synthesis of Compound Q-1 and Compound Q-2
After compound 6-1 (170 mg, 505. Mu. Mol) was dissolved in 5mL of DMF, cesium carbonate (659 mg,2.02 mmol) and chloromethyl methyl carbonate (252 mg,2.02 mmol) were added. The reaction system was stirred at 50℃for 5 hours. LCMS monitored reaction was complete with two major products formed. The reaction system was filtered, the filtrate was evaporated to dryness under reduced pressure to give a yellow oily substance, and after separation by reverse phase column chromatography to give a fraction containing the compound Q-1, extraction was performed with methylene chloride (10 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to give the compound Q-1 as a white solid (31.0 mg, yield: 14.4%). LCMS (ESI): m/z C 22 H 25 N 4 O 5 + .[M+H]+calculated = 425.18, found = 425.2. 1 H NMR (400 MHz, DMSO-d 6) delta ppm 12.39 (br s, 1H), 12.15 (s, 1H), 8.07 (br d, J=7.4 Hz, 2H), 7.87 (s, 1H), 7.45-7.31 (m, 3H), 7.16 (s, 1H), 6.63 (s, 1H), 6.09 (s, 2H), 3.77 (s, 3H), 1.38 (s, 9H). And separating the mixture by a reverse phase column to obtain a fraction containing the compound Q-2, extracting the fraction by methylene dichloride (10 mL of 3), drying the fraction by anhydrous sodium sulfate, filtering the dried fraction, and evaporating the filtrate under reduced pressure to obtain the compound Q-2 as a white solid (29.3 mg, yield: 11.3%). LCMS (ESI): m/z C 25 H 29 N 4 O 8 + [M+H] + Calculated = 513.20, found = 513.2. 1 H NMR(400MHz，DMSO-d6)δppm 11.89(s，1H)，8.16-8.03(m，3H)，7.47-7.29(m，3H)，7.18(s，1H)，6.73(s，1H)，6.18(s，2H)，6.09(s，2H)，3.77(s，3H)，3.76(s，3H)，1.47(s，9H)。
Example 15: synthesis of Compound Q-3
Compound Q-3-1 (10 mg, 28.7. Mu. Mol) (synthetic methods reference Bioorg. Med. Chem.,2020, 28 (1): 115186.) was dissolved in 1mL of DMF and cesium carbonate (14 mg, 43. Mu. Mol) and chloromethyl methyl carbonate Q-1a (10.7 mg, 86. Mu. Mol) were added. The reaction system was stirred at 20℃for 2 hours. LCMS monitored reaction was complete. The reaction system was filtered, and the filtrate was concentrated, followed by reverse phase column chromatography to give Compound Q-3 as a pale yellow solid (5.0 mg, yield: 39.4%). LCMS (ESI): m/z C 23 H 25 N 4 O 5 + [M+H] + Calculated = 437.18, found = 437.2. 1 H NMR(400MHz，DMSO-d6)δppm 8.08(br d，J＝7.3Hz，2H)，7.89(s，1H)，7.45-7.34(m，3H)，7.24(s，1H)，6.76(s，1H)，6.10(s，2H)，5.93(s，2H)，3.78(s，3H)，1.32(s，9H)。
Example 16: synthesis of Compound Q-4
According to the synthesis method of example 15, compound Q-4 was prepared using compound I-6 as a starting material. LCMS (ESI): m/z C 23 H 23 D 2 N 4 O 5 + .[M+H] + Calculated = 439.20, found = 439.2. 1 H NMR(400MHz，CD 3 CN)δppm 8.09(d，J＝7.3Hz，2H)，7.63(s，1H)，7.47-7.39(m，3H)，7.31(s，1H)，6.89(s，1H)，6.12(s，2H)，3.83(s，3H)，1.38(s，9H)。
Example 17: synthesis of Compound Q-5
Will be combinedThe product I-1 (8.0 mg, 23.7. Mu. Mol) was dissolved in 2mL of DMF, and sodium carbonate (5.0 mg, 47.4. Mu. Mol) and chloromethyl methyl carbonate Q-1a (2.9 mg, 23.7. Mu. Mol) were added. The reaction system was stirred at 25℃for 5 hours. The reaction system was filtered, and the filtrate was evaporated to dryness under reduced pressure to give a yellow oil. Compound Q-5 was prepared as a white solid by reverse phase column chromatography (2.1 mg, yield: 20.8%). LCMS (ESI): m/z C 21 H 24 N 5 O 5 + [M+H] + Calculated = 426.18, found = 426.1. 1 H NMR(400MHz，DMSO-d6)δppm 10.05(br，s，1H)，10.21(s，1H)，7.56-7.54(m，2H)，7.44-7.41(m，2H)，7.38-7.30(m，1H)，6.68(s，1H)，6.74(s，1H)，6.41(s，2H)，3.82(s，3H)，1.44-1.35(m，9H)。
Example 18: synthesis of Compound Q-6
Compound I-1 (10.0 mg, 29.6. Mu. Mol) was dissolved in 2mL of DMF, and cesium carbonate (14.5 mg, 44.5. Mu. Mol) and chloromethyl methyl carbonate Q-1a (22.1 mg, 178. Mu. Mol) were added. The reaction system was stirred at 50℃for 5 hours. The reaction system was filtered, and the filtrate was evaporated to dryness under reduced pressure to give a yellow oil. Compound Q-6 was prepared by reverse phase column chromatography as a pale yellow solid (4.1 mg, yield: 26.9%). LCMS (ESI): m/z C 24 H 28 N 5 O 8 + .[M+H] + Calculated = 514.19, found = 514.2. 1 H NMR(400MHz，CD 3 Cl)δppm 10.34(s，1H)，8.06(d，J＝7.3Hz，2H)，7.47(s，1H)，7.45-7.32(m，3H)，6.54(s，1H)，6.29(s，2H)，6.16(s，2H)，3.88(d，J＝10.0Hz，6H)，1.43(s，9H)。
Example 19: synthesis of Compound Q-7
The synthetic method of reference example 18, using I-4 as a starting material, produced compound Q-7 as a pale yellow solidBody (15 mg, yield: 35.8%). LCMS (ESI): m/z C 31 H 31 FN 5 O 9 + .[M+H] + Calculated = 636.21, found = 636.2. 1 H NMR(400MHz，DMSO-d6)δppm 10.17(s，1H)，8.64(s，1H)，8.28(d，J＝7.8Hz，1H)，7.86(dd，J＝5.6Hz，8.7Hz，2H)，7.76(d，J＝7.8Hz，1H)，7.69-7.60(m，1H)，7.44-7.35(m，3H)，6.46(s，1H)，6.40(s，2H)，5.83(s，2H)，3.79(s，3H)，3.75(s，3H)，1.37(s，9H)。
Example 20: synthesis of intermediate 6-1a
Compound 6-1a-1 (5.00 g,57.5 mmol) and boron tribromide (0.35 g,1.39 mmol) were mixed and placed in a round bottom flask, stirred and cooled to 0℃and the reaction was gradually clarified. To the above system, 50% fuming sulfuric acid (10.8 mL) was slowly added dropwise, the temperature was controlled to be 0-10deg.C, and the reaction system was yellow brown. After the completion of the dropwise addition, the reaction was kept at 0-10℃with stirring for 4 hours, and the reaction was stopped. The reaction was added dropwise to saturated aqueous sodium bicarbonate (50 mL), stirred at a temperature between 0-10 ℃ for 10 min, the organic phase separated, the aqueous phase extracted with DCM (20 ml×3), the organic phases combined, washed with saturated brine (20 ml×1), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure at 5 ℃ to give intermediate 6-1a-2 as a yellow oil (3.80 g, crude).
Intermediate 6-1a-2 (3.80 g, crude) was dissolved in 38mL of dichloromethane, and compound 6-1a-3 (4.55 g,16.35 mmol) was added and dissolved after stirring. 38mL of an aqueous solution of tetrabutylammonium bisulfate (30.90 g,91.0 mmol) was added dropwise to the reaction solution at 25℃and the reaction system was stirred at 25℃for 2 hours. LCMS detected that product was formed and that a portion of starting material remained. The reaction system was extracted with dichloromethane (15 ml x 3), the organic phases were combined, washed with saturated brine (10 ml x 2), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated to a residue under reduced pressure, and isolated by silica gel column chromatography to give intermediate 6-1a as a yellow oilThe product was obtained as a solid (920 mg, yield: 17.11%). LCMS (ESI): m/z: c (C) 15 H 15 D 2 ClO 4 P + .[M+H] + Calculated = 329.07, found = 329.1. 1 H NMR(400MHz，CDCl 3 )δppm 7.39-7.27(m，10Hz)，5.09(d，4H，J＝8Hz)。
Biological test example 1: test of the tumor cell proliferation inhibitory Activity of the Compounds of the invention
The activity of the compound for inhibiting tumor cell proliferation is determined by using four kinds of cells HT-29, A549, HCT-116 and MC 38.
(1) Cell plating
a. Preparing a culture medium, and fully and uniformly mixing.
b. HT-29, A549, HCT-116 and MC38 cell lines with good growth state were selected.
c. The cell suspension was pipetted into a centrifuge tube and centrifuged at 800-1000rmp for 3-5 minutes.
d. The cell supernatant in the centrifuge tube is sucked and removed, a proper volume of culture medium is added into the centrifuge tube, and the cells are gently beaten to be resuspended uniformly.
e. The Cell suspension was brought to the appropriate concentration using a Vi-Cell XR cytometer.
f. The cell suspension was added to 384 well plates at 36 μl/well. Labeling detailed information such as cell name, plate density, date, etc., placing the culture plate in CO 2 Culturing in an incubator.
(2) Cell experiment:
a. test compounds were prepared as 200 Xstock solutions in DMSO and 3-fold concentration gradients of the compounds were diluted in DMSO to give 10 concentration gradients of the compounds.
b. After 24 hours of cell plating, 1. Mu.L of the compound was added to 19. Mu.L of the medium to prepare a 10X intermediate plate, and then 4. Mu.L of the 10X corresponding compound was added to each well, followed by incubation in an incubator at 37℃for 72 hours.
c. Cell morphology was observed under an inverted microscope.
d. The cell culture plates were left to equilibrate at room temperature for 30 minutes, 25 μl of CTG was added to each well, and then mixed on a plate shaker for 10 minutes to induce cell lysis.
e. The 384 well plates were left at room temperature for 10 minutes to stabilize their luminescence signal, and Flexstation 3 read plates were used.
f. The test results obtained by the analysis were recorded as shown in table 1. Wherein a represents: IC50 is less than or equal to 1nM and less than or equal to 50nM; b represents: 50nM < IC50.ltoreq.500 nM; c represents: 500nM < IC50.ltoreq.2000 nM.
Table 1. Test results of inhibition of tumor cell proliferation by some compounds:
/>
biological test example 2: pharmacokinetic properties of the compounds of the invention in rats were tested.
Pharmacokinetic parameters such as in vivo exposure, half-life and bioavailability are calculated according to the blood concentration of the compound in vivo after oral administration of SD rats for 0-24 hours.
1. Material and article
The main used reagents and consumables are as follows: DMSO, PEG400, vitamin E TPGS, lavage and blood collection needles, EDTA-K2 anticoagulated blood collection tubes, 96-well plates, acetonitrile, and the like.
The main laboratory instrument used was AB 5500LC-MS/MS.
2. Operating program
In vivo administration:
the experimental animals were grouped and numbered, 3 test compounds were administered by gavage, the vehicle for the administration was 30%PEG400+10%Vitamin E TPGS aqueous solution, the concentration of the gavage administration formulation was 1mg/mL, and the gavage administration dose was 5mg/kg.
Plasma sample collection:
0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24h after oral administration were bled 0.2mL via the jugular vein and placed in EDTA-K2 anticoagulant tubes. The whole blood sample is centrifuged at 12000rpm for 3min, the plasma is separated, and the whole blood sample is preserved below-70 ℃ to be tested.
Plasma sample analysis:
after melting the plasma samples on wet ice, 30. Mu.L of the samples were taken in 96-well plates, 200. Mu.L of glacial acetonitrile containing IS (100 nM tolbutamide) was added for precipitation, vortexing was performed for 10min, the samples were centrifuged at 5000rpm for 5min (4 ℃), 100. Mu.L of the sample supernatant was taken in 96-well liquid samples, diluted with 100. Mu.L of pure water and vortexing was performed, and analyzed in a sample injection LC-MS/MS.
Summarizing concentration results of different animal tests at different time points, taking an average value to calculate T max 、C max . Calculation of T using non-compartmental model 1/2 、AUC 0-t And the like. The test results are shown below:
TABLE 2 determination of 6-1 pharmacokinetic parameters in plasma by intragastric administration of 6-1, Q-2 in rats
Under the test condition, only 6-1 is detected in the plasma after the administration of Q-1 and Q-2 by the intragastric administration of rats, which shows that: (1) The compound can be rapidly metabolized into 6-1 in vivo in the absorption process; (2) T of Q-1, Q-2 max Less than 6-1 indicates faster absorption of the prodrug compound; (3) Q-1 and Q-2 have a molecular weight of greater than 6-1 and C at the same dosage max Increase by more than 3 times AUC 0-t The increase of more than 1.5 times indicates that the bioavailability of the compound is obviously improved. The above demonstrates that compounds Q-1 and Q-2 have good prodrug characteristics.
After the administration of Q-3-1 and Q-3 by gavage, only Q-3-1 was detected in the plasma, and after the administration of I-6,Q-4 by gavage, only I-6 was detected in the plasma, and the data indicate that: (1) The Q-3 compound can be rapidly metabolized into Q-3-1 in vivo during the absorption process; (2) T of Q-3 max Less than Q-3-1, indicating that the compound is capable of rapid absorption; (3) Q-3 administration group C under the same administration dose of Q-3-1, Q-3 max And AUC 0-t The bioavailability of the prodrug Q-3 is obviously improved; (4) I-6 shows that compound Q-4 absorbs more rapidly as a prodrug than Q-4 And the bioavailability is higher; (5) I-6 has a significantly longer half-life of deuterated compound I-6 than Q-3-1.
After the rats were given I-1, Q-5 by lavage, only I-1 was detected in the plasma, and the data indicated: (1) The Q-5 compound can be rapidly metabolized to I-1 in vivo during absorption; (2) T of Q-5 max Less than I-1, indicating that compound Q-5 is capable of rapid absorption; (3) Q-5 administration group C under the same administration dose of I-1, Q-5 max And AUC 0-t The bioavailability of the prodrug compound Q-5 is obviously improved. The above demonstrates that compound Q-5 has good prodrug characteristics.
After the rats were given I-4, Q-7 by lavage, only I-4 was detected in the plasma, and the data indicated that: (1) The Q-7 compound can be rapidly metabolized to I-4 in vivo during absorption; (2) T (T) max The results show that Q-7 can be absorbed rapidly; (3) Measurement of C of I-4 by Q-7 administration group at the same administration dose max And AUC 0-t The bioavailability of the prodrug compound is obviously improved. The above demonstrates that compound Q-7 has good prodrug characteristics.
Compound I-1 shows C as compared with control compound 6-1 max And AUC 0-t More preferably, I-1 was shown to have better exposure.

Claims (14)

1. A compound of formula I, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof;
Wherein R is 1 Is H, -O-R 1-1 or-C (=O) -R 1-2 ；
R 1-1 And R is 1-2 Each independently is C 6 -C 12 Aryl or C substituted by one or more halogens 6 -C 12 An aryl group;
R 2 is C 1 -C 8 Alkyl or
R 2-1 、R 2-2 And R is 2-3 Each independently is C 1 -C 6 An alkyl group;
is->
R 3 Independently is-R 3-1 -O-C(＝O)-O-R 3-2 ；R 3-1 Is C 1 -C 6 An alkylene group; r is R 3-2 Is C 1 -C 6 An alkyl group;
R 4 is H;
Y 1 is N or N (R) a )；
R a Is H or R 4 And R is R a Together forming a methylene or deuterated methylene group;
Y 2 and Y 3 Each independently is C (R) b )、N、N(R c ) Or O, provided that ring Y is an aromatic ring;
R b and R is c Each independently H, C 1 -C 6 Alkyl, substituted by 1, 2 or 3R d Substituted C 1 -C 6 Alkyl or R 3 ；
R d Each independently is-OH, -NR d-1 R d-2 Or C 1 -C 6 An alkoxy group; r is R d-1 And R is d-2 Each independently is H or C 1 -C 6 An alkyl group;
and, the compound as shown in formula I satisfies 1, 2 or 3 of the following conditions:
(1)Y 1 is N (R) a ) And R is 4 And R is R a Together forming a deuterated methylene group;
(2)is->
(3)Y 2 N, N (R) c ) Or O.
2. A compound of formula I, a tautomer, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, which meets one or more of the following conditions:
(1)R 1-1 and R is 1-2 In the definition of (2), the halogen is independently F, cl, br or I, such as F;
(2)R 1-1 and R is 1-2 In the definition of (C) 6 -C 12 Aryl is independently phenyl or naphthyl, such as phenyl;
(3)R 2 In the definition of (C), said C 1 -C 8 Alkyl is C 1 -C 8 Tertiary alkyl groups such as tertiary butyl;
(4)R 2-1 、R 2-2 and R is 2-3 In the definition of (C), said C 1 -C 6 Alkyl is independently C 1 -C 3 Alkyl groups such as methyl;
(5)R 3-1 in the definition of (C), said C 1 -C 6 Alkylene is C 1 -C 3 Alkylene groups such as methylene;
(6)R 3-2 in the definition of (C), said C 1 -C 6 Alkyl is C 1 -C 3 Alkyl groups such as methyl;
(7) When R is 4 And R is R a When the deuterated methylene groups are formed together, the deuterated methylene groups are-CHD or-CD 2 For example CD 2 ；
(8)R b And R is c In the definition of (C), said C 1 -C 6 Alkyl is independently C 1 -C 3 Alkyl groups such as methyl, ethyl or n-propyl;
(9)R d in the definition of (C), said C 1 -C 6 Alkoxy is C 1 -C 3 Alkoxy group, exampleSuch as methoxy;
(10)R d-1 and R is d-2 In the definition of (C), said C 1 -C 6 Alkyl is independently C 1 -C 3 Alkyl groups such as methyl.
3. A compound of formula I, a tautomer, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1 or 2, which meets one or more of the following conditions:
(1)R 2-1 is methyl;
(2)R 2-2 is methyl;
(3)R 2-3 is methyl;
(4)R 3-1 is methylene;
(5)R 3-2 is methyl;
(6)Y 3 is N or N (R) c )；
(7)R b Is H;
(8)R c is H, methyl, ethyl, n-propyl, hydroxy-substituted ethyl, hydroxy-substituted n-propyl, methoxy-substituted methyl, dimethylamino-substituted ethyl or-CH 2 -O-(C＝O)-O-CH 3 For example H, -CH 3 、-CH 2 CH 3 、-CH 2 CH 2 CH 3 、
4. A compound of formula I, a tautomer, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, which meets one or more of the following conditions:
(1)R 1 is H,
(2)R 2 Is tert-butyl or
(3)R 3 is-CH 2 -O-(C＝O)-O-CH 3 ；
(4)Is->
(5)Y 1 Is N or N (R) a ) Preferably, -n=, =n-, or N (R a ) When Y is 1 Is N (R) a ) When R is 4 And R is R a Together form methylene or-CD 2 -, wherein the label side represents Y 2 Are connected;
(6)Y 2 is CH, N, Preferably =ch-, -CH =, =n-, -and +_> Wherein the side denoted by the symbol is with Y 3 Are connected;
(7)Y 3 for N, NH orPreferably, the values are =, = N-, -NH-, or +.>Wherein the label side represents and Y 2 Are connected.
5. A compound of formula I, a tautomer, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein the structural unitIs-> For example->
6. A compound of formula I, a tautomer, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 wherein Y 2 Is N (R) c )；R c Is C 1 -C 6 Alkyl, substituted by 1, 2 or 3R d Substituted C 1 -C 6 Alkyl or R 3 。
7. The compound of formula I, tautomer, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1 to 5, Is->Structural unit->Is that
8. The compound of any one of claims 1-5, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein the compound of formula I is any one of the following structures:
the definition of substituents in each structure is as defined in any one of claims 1 to 5.
9. The compound of any one of claims 1-8, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein the compound of formula I is any one of the following:
10. a process for the preparation of a compound of formula I according to any one of claims 1 to 9, characterized in that it is any one of the following processes:
method 1 comprising the steps of: in a solvent, under the action of alkali, reacting a compound shown in a formula 1a with a compound shown in a formula 1b to obtain a compound shown in a formula I;
wherein Y is 1 N, the remaining substituents being as defined in any one of claims 1 to 9;
method 2 comprising the steps of: in a solvent, under the action of alkali, reacting the compound shown in the formula 2a with the compound shown in the formula 2b to obtain a compound shown in the formula I;
Wherein,is->Y 1 N, the remaining substituents being as defined in any one of claims 1 to 9;
method 3 comprising the steps of: in a solvent, under the action of alkali, reacting the compound shown in the formula 3a with the compound shown in the formula 3b to obtain a compound shown in the formula I';
wherein,is->X is halogen, such as F, cl, br or I, more such as Cl;
when (when)Is->In the case of the compounds of formula I, -/-, a>Is->Is->
When (when)Is->In the case of the compounds of formula I, -/-, a>Is->Is->
When (when)Is->When the reaction is carried out, the reaction is shown as the formula IOf the compounds, the->Is that Is->The remaining substituents in the formulae above are as defined in any one of claims 1 to 9;
method 4 comprising the steps of: in a solvent, under the action of alkali, reacting the compound shown in the formula 4a with the compound shown in the formula 4b to obtain a compound shown in the formula I;
wherein, in the compound shown in the formula I, Y 1 Is N (R) a )，R 4 And R is R a Together forming a methylene or deuterated methylene group; the compound of formula 4b isL is-CH 2 -CDH or-CD 2 Ar is C 6 -C 12 Aryl, preferably phenyl; x is halogen, such as F, cl, br or I, more such as Cl; the remaining substituents in the compounds of formula 4a and in the compounds of formula I are as defined in any one of claims 1 to 9;
Method 5 comprising the steps of: in a solvent, under the action of alkali, reacting a compound shown in a formula 5a with a compound shown in a formula 5b to obtain a compound shown in a formula I;
wherein X' is halogen, such as F, cl, br or I, preferably Cl, br or I; in the compounds of the formula I shown in the specification,is thatR c Is C 1 -C 6 Alkyl or by 1, 2 or 3R d Substituted C 1 -C 6 Alkyl, wherein the other substituents in the formulae above are as defined in any one of claims 1 to 9;
method 6 comprising the steps of: in a solvent, under the action of alkali, reacting the compound shown in the formula 6a to obtain a compound shown in the formula I;
wherein K is 1 Is C 1 -C 6 Alkylene, K 2 Is C 1 -C 6 An alkyl group; in the compounds of the formula I shown in the specification,is->R c For K 1 -OH, the other substituents of the formulae above being as defined in any one of claims 1 to 9;
method 7 comprising the steps of: in a solvent, under the action of alkali, reacting a compound shown in a formula 7a with a compound shown in a formula 7b to obtain a compound shown in a formula I;
wherein,wherein "+" indicates that the marked carbon atom is achiral, R configuration or S configuration; in the compound shown in the formula I, +.>Is->The other substituents in the formulae above are as defined in any of claims 1 to 9.
11. A compound represented by formula 1a, 2a, 3a, 4a, 5a, 6a or 7 a;
Wherein each substituent is as defined in any one of claims 1 to 10.
12. A pharmaceutical composition comprising a compound of formula I, a tautomer, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, and a pharmaceutically acceptable carrier.
13. Use of a compound of formula I, a tautomer, stereoisomer, pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 9, or a pharmaceutical composition according to claim 12, for the manufacture of a medicament for the anti-tumour or treatment of chemotherapy-induced leukopenia or neutropenia.
14. The use according to claim 13, wherein the tumor is a tumor of the head and neck, a tumor of the respiratory system, a tumor of the digestive system, a tumor of the urinary system, a bone cancer, a gynecological tumor, a tumor of the blood system, a melanoma, a glioma or a skin cancer; preferably, the respiratory tumor is lung cancer; preferably, the digestive system tumor is intestinal cancer or colon cancer.
CN202310645450.5A 2022-06-02 2023-06-01 Piperazinone compound and preparation method and application thereof Pending CN117164560A (en)

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