WO2014032398A1

WO2014032398A1 - Pyridazinone compound, preparation method, pharmaceutical composition and use thereof

Info

Publication number: WO2014032398A1
Application number: PCT/CN2013/001018
Authority: WO
Inventors: 胡有洪; 耿美玉; 邢唯强; 丁健; 艾菁
Original assignee: 中国科学院上海药物研究所
Priority date: 2012-08-28
Filing date: 2013-08-28
Publication date: 2014-03-06
Also published as: CN103664895B; CN103664895A

Abstract

The present invention is in the scope of the field of pharmaceutical chemistry. Specifically, the present invention relates to pyridazinone compounds of formula (I) or isomers, pharmaceutically acceptable salts, esters, prodrugs or solvates thereof, preparation method, pharmaceutical compositions thereof and use in manufacture of tyrosine kinase inhibitors, specially c-Met inhibitors. Said compounds or pharmaceutical compositions are used to prevent and/or treat tumor diseases related to c-Met abnormality as tyrosine kinase inhibitors, specially c-Met inhibitors.

Description

A pyridazinone compound, a process for the preparation thereof, a pharmaceutical composition and use thereof TECHNICAL FIELD The present invention belongs to the field of medicinal chemistry. In particular, the present invention relates to a novel class of pyridazinone compounds or isomers thereof, or pharmaceutically acceptable salts, esters, prodrugs or solvates thereof, a process for the preparation thereof, a pharmaceutical composition and a process for preparing the same Uses of kinase inhibitors, particularly c-Met inhibitors. Such compounds or pharmaceutical compositions thereof are useful as tyrosine kinase inhibitors, particularly as c-Met inhibitors, for the prevention and/or treatment of neoplastic diseases associated with c-Met abnormalities. BACKGROUND OF THE INVENTION Malignant tumors pose a serious threat to human survival and health, and prevention and/or treatment of malignant tumors is a worldwide problem. At present, a large number of anti-tumor targets have been discovered, and protein tyrosine kinases have become a promising anti-tumor target.

The receptor-type protein tyrosine kinase c-Met is a hepatocyte growth factor receptor (HGFR) encoded by the MET proto-oncogene. c-Met is highly expressed in most cancers and some sarcomas and is closely related to poor prognosis, such as lung cancer, breast cancer, colon cancer, prostate cancer, pancreatic cancer, gastric cancer, liver cancer, ovarian cancer, glioma, etc. . Mature c-Met functions as a heterodimeric structure consisting of an extracellular (X chain (50 KDa) and a transmembrane beta chain (145 KDa, which anchors the intracellular domain of the kinase domain to the cell membrane). It has been found that HGF is a ligand for c-Met receptor displacement. c-Met induces cell proliferation, invasion, migration, inhibition by interacting with its ligand HGF/SF or by other pathways to activate intracellular tyrosine kinase. Apoptosis, which promotes angiogenesis, plays an important role in the development of tumors and has become an important target for anti-tumor drug research.

A class of c-Met inhibitors having a pyridazinone, a pyridone, and a pyrimidinone as a mother nucleus has been reported by Amgen in U.S. Patent Application Publication No. 2008/0280917 A1, the technical feature of which is that the pyridazinone 6 position All are carbon-bonded aryl groups such as phenyl. Moreover, this patent does not examine in detail the effect of introducing hydrophilic groups on such compounds.

Chinese Patent Application No. CN201110087884.5 reports a class of pyridazinone compounds linked by a 6-hetero atom, the general formula of which is as follows:

The technical feature of the invention is that the -phenyl-NH-L- moiety is mainly a linking group such as an amide, a carbamate or a urea. Molecular docking experiments show that the -phenyl-NH-L- moiety of the above-mentioned compound forms a hydrogen bond mainly with the c-Met protein. use. In this invention, some of the compounds exhibited better c-Met inhibitory activity at the molecular level, and some compounds inhibited NIH3T3-TPR-Met cells at the micromolar level at the cellular level. However, due to the poor physical and chemical properties of the amide and carbamate groups, the cell level activity of the compounds differs greatly from the enzyme level activity.

On the basis of the previously reported compounds, the inventors of the present invention obtained a novel class of pyridazinone compounds by rational design and comprehensive consideration of factors such as water solubility and metabolic stability of the compounds. Such compounds are more effective at inhibiting the activity of c-Met protein at both the enzyme and cell levels. At the same time, such compounds are capable of selectively inhibiting cell proliferation mediated by c-Met protein. After further optimization and screening, it is expected to be developed into a simple and more active anti-tumor drug.

Summary of the invention

Purpose of the invention

SUMMARY OF THE INVENTION One object of the present invention is to provide a pyridazinone compound of the formula I or an isomer thereof, or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof.

Another object of the invention is to provide a process for the preparation of the compounds provided herein.

Still another object of the present invention is to provide a pyridazinone compound of the formula I or an isomer thereof or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof as a c-Met inhibitor, And the use in the preparation of a medicament for preventing and/or treating a tumor disease associated with c-Met abnormality.

Still another object of the present invention is to provide a pyridazinone compound represented by Formula I or an isomer thereof, or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof, or one or more thereof. Pharmaceutical composition.

It is still another object of the present invention to provide a method of preventing and/or treating a tumor disease.

Technical solutions

According to an aspect of the present invention, the present invention provides a pyridazinone compound represented by the following formula I or an isomer thereof, or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof:

among them,

X ¹ and X ^{2 are the} same or different and are each independently N, CH or CR ⁶ ,

^地, X ¹ and X ² are each independently CH or CR ⁶ ,

More preferably, X ¹ is CH or CR ⁶ , and X ² is CH; X ³ is N or CH;

L ¹ is a C1-C10 straight or branched alkylene group which is unsubstituted or substituted by halogen, and the alkylene group may be replaced by a 0 or N atom except for a carbon atom at both ends of the main chain.

^, L ¹ is a C1-C8 straight or branched alkylene group which is unsubstituted or substituted by halogen, and the carbon atom other than the carbon atom at both ends of the main chain may be 0 or N atom Replaced,

More preferably, L ¹ is a C1-C6 straight or branched alkylene group which is unsubstituted or substituted by halogen, and the alkylene group may be 0 or N except for carbon atoms at both ends of the main chain. Replaced by atoms;

The presence or absence of M, in the presence of -0-, -NH -, -S -, -S(0)-, -S(0) ₂ -, -C(0)NH -, -NHC(0)- , -S(0) ₂ NH- or -HNC(0)NH-,

^地, M exists or does not exist, exists as -0-, -NH -, -S -, -S(O)- or -S(0) ₂ -,

More preferably, M is present or absent, and is -0- or -NH-; A when present;

When M is present, M is connected at position 1, 2 or 3 of the ³ '' part, and when M is not present, L ^{1 is} connected to ^^'

IA, -, - ^-R ⁵

a site of 1, 3 or 3 in the x ³ 'portion;

Α presence or absence, 5-10 aryl groups present, or 1-3 5-10 selected from N, 0 and S atoms

a heteroaryl group, the A and 0 moieties are fused at position 4,5, A is unsubstituted or monosubstituted by R ⁵ , when A is absent,

Partially unsubstituted or monosubstituted by R ⁵ ,

^, A is present or absent, is phenyl when present, or contains 1-3 5-6 membered heteroaryl selected from N, 0 and S atoms, and when A is phenyl, X ³ is N, When A is not a phenyl group, X ³ is N or CH,

More preferably, A is present or absent, in the presence of phenyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furyl, pyrazolyl, imidazolyl, oxazolyl or a thiazolyl group, and when A is a phenyl group, X ³ is N, and when A is not a phenyl group, X ³ is N or CH;

RR ² , R 3 and R ^{4 are the} same or different and are each independently H, halogen, COOL ¹ !^ CONHL ¹ !^ OL ^! R NHL'R or COI^R,

^tfcii, 1^ is 11, F, Cl, Br, COOL ¹ !^ CONHL ¹ !^ OL or NHI^R, R ² and R ⁴ are H, and R ³ is F, CI or Br,

More preferably, R R2 and R ⁴ are H, and R ³ is F, CI or Br, Most preferably, RR ² and R ⁴ are H, and R ³ is F;

R ⁵ and R ^{6 are the} same or different and are each independently a C1-C7 straight or branched alkyl group, CHO, COOR, COL ² R, COOL ² R, CONHL ² R, OL ² R, NHL ² R or L ² R,

Preferably, R ⁵ and R ⁶ are each independently methyl, ethyl, n-propyl, isopropyl, CHO, COOR, COL ² R, COOL ² R, CONHL ² R, OL ² R, NHL ² R or L ² R,

More preferably, R ⁵ and R ⁶ are each independently methyl, ethyl, n-propyl, isopropyl, CHO, COOR, COL ² R, CONHL ² R, OL ² R, NHL ³ R or L ² R ;

Wherein L ² is a C1-C10 straight or branched alkylene group which is unsubstituted or substituted by halogen, and the carbon atom other than the carbon atom at both ends of the main chain may be represented by 0 or N atom Or L ² is a 4-8 membered heterocyclic group having 1 to 3 hetero atoms selected from 0 and N; or L ³ is a 5-10 membered divalent aryl group or contains 1-3 selected a 5-10 membered divalent heteroaryl group from the N, 0 and S atoms;

^, L ² is a C1-C8 straight or branched alkylene group which is unsubstituted or substituted by halogen, and the carbon atom other than the carbon atom at both ends of the main chain may be 0 or N atom Or L ² is a 5-7 membered heterocyclic group having 1 to 2 heteroatoms selected from 0 and N; or L ³ is a 6-10 membered divalent aryl group or contains 1-2 a 5-10 membered divalent heteroaryl group selected from N and 0 atoms;

More preferably, L ² is a C1-C6 straight or branched alkylene group which is unsubstituted or substituted by halogen, and the alkylene group may be 0 or N except for carbon atoms other than the carbon atom at both ends of the main chain. Substituted by an atom; or L ² is pyrrolidinyl, piperazinyl, piperidinyl, phenylene, pyridylene, pyrimidinyl or pyrazolyl;

Wherein R is H; halogen; unsubstituted or substituted C1-C10 straight or branched alkyl group, said substituted substituent being selected from halogen, hydroxy, unsubstituted or C1-C5 straight or branched alkane a substituted amino group, and an unsubstituted 5-7 membered heterocyclic group containing 1-2 selected from N and 0 atoms, which is unsubstituted or substituted by a C1-C5 straight or branched alkyl group; unsubstituted or a C1-C5 linear or branched alkyl group or a C3-C6 cycloalkyl-substituted hydroxy group; an unsubstituted or substituted amino group substituted by a C1-C5 linear or branched alkyl group or a C3-C6 cycloalkyl group; methoxycarbonyl group ; a carboxamide; a carboxyl group; a C1-C6 straight or branched alkanoyl group which is unsubstituted or substituted by a halogen; or a 6-10 member saturated or unsaturated containing from 1 to 4 atoms selected from N, 0 and S atoms; Unsubstituted or C1-C5 linear or branched alkyl, C3-C6 cycloalkyl, containing 1-2 unsaturated 5-7 membered heterocyclic groups selected from N and 0 atoms, halogen, amino or hydroxy Substituted heterocyclic or aromatic heterocyclic group,

^, R is H; F; unsubstituted or substituted C1-C6 straight or branched alkyl group, the substituted substituent is selected from halogen, hydroxy, unsubstituted or C1-C2 straight or branched An alkyl group-substituted amino group, and an unsubstituted 5-6 membered heterocyclic group selected from N and 0 atoms, which are unsubstituted or substituted by a C1-C3 straight or branched alkyl group; unsubstituted Or a hydroxyl group substituted by methyl, ethyl, n-propyl, isopropyl or cyclopropyl; unsubstituted or by methyl, ethyl, n-propyl, iso a propyl or cyclopropyl substituted amino group; a methoxycarbonyl group; a carboxamide group; a carboxyl group; a C1-C4 straight or branched alkanoyl group which is unsubstituted or substituted by a halogen; or contains 1-3 selected from N, 0 And 6-10 members of the S atom are saturated or unsaturated unsubstituted or are methyl, ethyl, n-propyl, isopropyl, cyclopropyl, piperazinyl, pyrrolidinyl, morpholinyl, piperidine a heterocyclic or aromatic heterocyclic group substituted with a halogen, an amino group or a hydroxy group,

More preferably, R is H; F; an unsubstituted or substituted C1-C4 straight or branched alkyl group, said substituted substituent being selected from the group consisting of halogen, hydroxy, amino, dimethylamino, morpholinyl, A a piperidinyl group, a piperidinyl group and a aziridine group; a hydroxyl group which is unsubstituted or substituted with a methyl group, an ethyl group, a n-propyl group, an isopropyl group or a cyclopropyl group; an unsubstituted or methyl group, Ethyl, n-propyl, isopropyl or cyclopropyl substituted amino; pyridyl; pyrazinyl; pyrimidinyl; pyrazinyl; oxazolyl; isoxazolyl; thiazolyl; imidazolyl; pyrazolyl ; furanyl; thienyl; pyrrolyl; 1,2,3-triazolyl; 1,2,4-triazolyl; tetrazolyl; 1,2,4-oxadiazolyl; Morpholinyl; piperazinyl; piperidinyl; pyrrolidinyl; 2-fluoropyrrolidinyl; 3-fluoropyrrolidinyl; 3-hydroxypyrrolidinyl; 3-aminopyrrolidinyl; N-methylpiperazine N-ethylpiperazinyl; N-isopropylpiperazinyl; N-cyclopropylpiperazinyl; 2-methylmorpholinyl; 3-methylmorpholinyl; 4-piperidylpiper Zinyl; 4-hydroxypiperidinyl; 4-ammonia Piperidinyl; 3-hydroxypiperidinyl; 3-aminopiperidinyl; 4-piperidylpiperidinyl; cycloheptylamino; homopiperazinyl; N-methylhomopiperazinyl; fluorenyl; Benzofuranyl; quinolyl; benzopyrazolyl; or benzimidazolyl; acetyl; trifluoroacetyl.

In the above formula I, X ¹ is CH or CR ⁶ , X ² is CH, X ³ is N, L ¹ is -CH ₂ CH ₂ -, M is -0-, M

In part of the site 3, hydrazine is a phenyl group, a pyridyl group or a pyrrolyl group, and RR ² and R ⁴ are H, that is, the compound represented by the formula I is preferably a formula Π-al to II-a3 or Π- One of the compounds shown in all to II-a31:

II-a21 II-a3 II-a31 wherein R ⁷ is H or R ⁶ , and R ³ , R ⁵ and R ⁶ are as defined in the formula I. Further, in the compound represented by the above formula Π-al to II-a3 or Π-all to II-a31, further preferably, ¹⁷ is 15, methyl, ethyl, n-propyl, isopropyl, CHO, COOR, COL ¹ !^ CONHL or R;

R ⁵ is methyl, ethyl, n-propyl, isopropyl, OL ² R or L ² R;

Wherein L ¹ is a C1-C5 straight or branched alkylene group which is unsubstituted or substituted by halogen, and the alkylene group may be replaced by 0 atom except for a carbon atom at both ends of the main chain;

L ² is a C1-C5 straight or branched alkylene group which is unsubstituted or substituted by halogen, and the alkylene group may be replaced by a 0 atom except for a carbon atom at both ends of the main chain;

R is H; F; unsubstituted or substituted by methyl, ethyl, n-propyl, isopropyl or cyclopropyl; unsubstituted or methyl, ethyl, n-propyl, isopropyl Or a cyclopropyl-substituted amino group; pyridyl; pyrazinyl; imidazolyl; pyrazolyl; 1,2,3-triazolyl; 1,2,4-triazolyl; tetrazolyl; , 2,4-oxathiazolyl; morpholino; 2-methylmorpholinyl; 3-methylmorpholinyl; piperazinyl; N-methylpiperazinyl; N-ethylpiperazine N-isopropyl piperazinyl; N-cyclopropylpiperazinyl; pyrrolidinyl; 2-fluoropyrrolidinyl; 3-fluoropyrrolidinyl; 3-hydroxypyrrolidinyl; 3-aminopyrrolidine ; piperidinyl; 4-piperidyl piperazinyl; 4-hydroxypiperidinyl; 4-aminopiperidinyl; 3-hydroxypiperidinyl; 3-aminopiperidinyl; 4-piperidylpiperidine Or a piperazinyl group; or N-methylhomopiperazinyl,

R is further preferably H; unsubstituted or substituted by methyl, ethyl, n-propyl, isopropyl or cyclopropyl; unsubstituted or by methyl, ethyl, n-propyl, isopropyl Alkyl or cyclopropyl substituted amino; imidazolyl; pyrazolyl; 1,2,3-triazolyl; 1,2,4-triazolyl; tetrazolyl; 1,2,4-oxygen Heterazolyl; morpholinyl; piperazinyl; N-methylpiperazinyl; N-ethylpiperazinyl; pyrrolidinyl; 2-fluoropyrrolidinyl; 3-fluoropyrrolidinyl; Hydroxypyrrolidinyl; 3-aminopyrrolidinyl; piperidinyl; 4-hydroxypiperidinyl; or 4-aminopiperidinyl.

In the above formula I, X ¹ is CH or CR ⁶ , X ² is CH, X ³ is N, L ¹ is -CH ₂ CH ₂ -, M is -NH-,

In part of the site 3, hydrazine is a phenyl group, a pyridyl group or a pyrrolyl group, and I ¹ , R ² and R ⁴ are H, that is, the compound represented by the formula I is preferably the following formula Π-bl to II-b3 Or a compound of the formula -bll to Π-31

II-bl II-bll II-b2

II-b21 II-b3 II-b31

Wherein R ⁷ is H or R ⁶ , and R ³ , R ⁵ and R ⁶ are as defined in the formula I. Further, among the compounds represented by the above formulas Π-bl to II-b3 or Π-bl l to Π-31, further preferably,

1 ⁷ is 15, methyl, ethyl, n-propyl, isopropyl, CHO, COOR, COL ¹ !^ CONHL or R;

R ⁵ is methyl, ethyl, n-propyl, isopropyl, OL ² R or L ² R;

In the above formula I, X ¹ is CH or CR ⁶ , X ² is CH, X ³ is N, L ¹ is -CH ₂ CH ₂ -, M is -0- or -NH-, "A -^R ⁵

M is attached at position 3 of the x ³ ' moiety, Α is absent, RR ² and R ⁴ are H, R ⁵ is CONHL ² R and is located at position 2 of the pyridine ring, ie, the compound of formula I is preferred Is a compound represented by the following formula: Π-cl to II-c2

II-cl II-c2

Wherein R ⁷ is H or R ⁶ , and R ³ , L ² and R are as defined in the formula I.

Further, among the compounds represented by the above formulas Π-cl to II-c2, further preferably,

1 ⁷ is 11, F; methyl, ethyl, n-propyl, isopropyl, CHO, COOR, COL ¹ !^ CONHL or R; wherein L ¹ is unsubstituted or halogen-substituted C1-C5 straight chain Or a branched alkylene group, wherein the carbon atom other than the carbon atom at both ends of the main chain can be replaced by 0 atom;

In the above formula I, X ¹ is CH or CR ⁶ , X ² is CH, X ³ is CH, L ¹ is -CH ₂ CH ₂ -, M is absent,

L ^{1 is} attached at position 2 of the ^ ³ '", - ^Α ^ moiety, Α is pyridinyl, pyrazinyl or pyrrolyl, and I ¹ , R ² and R ⁴ are H, ie, represented by Formula I The compound is preferably a compound represented by the following formula: Π-dl to II-d3 or Π-dll to II-d31.

II-d21 II-d3 II-d31 wherein R ⁷ is H or R ⁶ , and R ³ , R ⁵ and R ⁶ are as defined in the formula I.

Further, among the compounds represented by the above formulas Π-dl to II-d3 or Π-dll to II-d31, further preferably,

1 ⁷ is 15, methyl, ethyl, n-propyl, isopropyl, CHO, COOR, COL ¹ !^ CONHL or R; R ⁵ is methyl, ethyl, n-propyl, isopropyl, OL ² R or L ² R;

L ¹ is a C1-C5 straight or branched alkylene group which is unsubstituted or substituted by halogen, and the alkylene group may be replaced by a 0 atom except for a carbon atom at both ends of the main chain;

L ² is a C1-C5 straight or branched alkylene group which is unsubstituted or substituted by halogen, and the alkylene group may be replaced by 0 atom except for a carbon atom at both ends of the main chain; or L ² is a pyrrolidinyl group, a piperazinyl group, a piperidinyl group, a phenylene group, a pyridylene group, a pyrimidinyl group or a pyrazolyl group;

as well as

R is H; F; unsubstituted or substituted C1-C4 straight or branched alkyl group, the substituted substituent is selected from the group consisting of halogen, hydroxy, amino, dimethylamino, morpholinyl, methylpiperazinyl , piperidinyl and azetidinyl; unsubstituted or substituted by methyl, ethyl, n-propyl, isopropyl or cyclopropyl; unsubstituted or methyl, ethyl, positive a propyl, isopropyl or cyclopropyl substituted amino group; pyridyl; pyrazinyl; imidazolyl; pyrazolyl; 1,2,3-triazolyl; 1,2,4-triazolyl; Tetrazolyl; 1,2,4-oxadiazolyl; morpholino; 2-methylmorpholinyl; 3-methylmorpholinyl; piperazinyl; N-methylpiperazinyl; N-isopropylpiperazinyl; N-isopropyl piperazinyl; N-cyclopropylpiperazinyl; pyrrolidinyl; 2-fluoropyrrolidinyl; 3-fluoropyrrolidinyl; 3-hydroxypyrrolidinyl 3-aminopyrrolidinyl; piperidinyl; 4-piperidylpiperazinyl; 4-hydroxypiperidinyl; 4-aminopiperidinyl; 3-hydroxypiperidinyl; 3-aminopiperidinyl; - piperidinylpiperidinyl; homopiperazinyl; N-methylhomopiperazinyl; acetyl; Or a trifluoroacetyl group, R is still more preferably H; an unsubstituted or substituted C1-C4 straight or branched alkyl group, the substituted substituent being selected from the group consisting of halogen, hydroxy, amino, dimethylamino, morpholine -1-yl, 4-methylpiperazinyl and Aziridine-1-yl; unsubstituted or substituted by methyl, ethyl, n-propyl, isopropyl or cyclopropyl; unsubstituted or methyl, ethyl, n-propyl , isopropyl or cyclopropyl substituted amino; imidazolyl; pyrazolyl; 123-triazolyl; 124-triazolyl; tetrazolyl; 124-oxadiazolyl; morpholinyl ; piperazinyl; N-methylpiperazinyl; N-ethylpiperazinyl; pyrrolidinyl; 2-fluoropyrrolidinyl; 3-fluoropyrrolidinyl; 3-hydroxypyrrolidinyl; 3-aminopyrrole Alkyl; piperidinyl; 4-hydroxypiperidinyl; 4-aminopiperidinyl; acetyl; or trifluoroacetyl.

In the present invention, a particularly preferred specific compound is one of the following compounds:

8T0100/C10ZN3/X3d 86 £ and OZ OAV

810100/C10ZN3/X3d 86£ and OZ OAV

The pharmaceutically acceptable salt of the pyridazinone compound of the formula I provided by the present invention can be reacted by dissolving the pyridazinone compound represented by the formula I in an alcohol solution saturated with the corresponding acid. For example, the pyridazinone compound provided by the present invention is dissolved in a saturated methanol solution of HCl, stirred at room temperature for 30 minutes, and the solvent is evaporated to dryness to give the corresponding hydrochloride.

According to another aspect of the present invention, there is provided a process for the preparation of a pyridazinone compound of the formula I, which is carried out by the following reaction formula:

Wherein, when M is absent, the pyridazinone compound represented by the formula I is prepared by the compound represented by the formula II or III according to the route 1 or the route 3 in the above reaction formula, and when M is present, according to the above The pyridazinone compound of the formula I can be prepared from the compound represented by the formula Π, III or IV by the route 1, 2 or 3 in the reaction formula, respectively.

Wherein, X ¹ , x ² , x ³ , LM, A, RR ² , R ³ , R ⁴ and R ⁵ are as defined in the formula I, and the routes are as follows:

Route 1 : a compound represented by the formula ,, and a compound represented by the formula VI, by a metal catalyst or a base, a coupling reaction to obtain a pyridazinone compound represented by the formula I;

Route 2: a compound of the formula IV, and a chlorinated compound of the formula VII, which are subjected to a nucleophilic substitution reaction under the action of a metal catalyst or a base to obtain a pyridazinone compound represented by the formula I;

Route 3: Can be divided into two situations:

1) a pyridazinone compound represented by the formula III, which reacts with a compound represented by the formula V by a mitsimobu reaction to obtain a pyridazinone compound represented by the formula I;

2) A compound of the formula V, which is converted to a chlorine atom or a formazanoyl group which is easily removed by in situ under the action of thionyl chloride or methanesulfonyl chloride, and the resulting intermediate and formula The pyridazinone compound shown is subjected to a nucleophilic substitution reaction under the action of a base to give a compound of the formula I.

Further, the compound of the formula V can also be reacted with the chloropyridazinone of the formula VIII by two conditions similar to those of the route 3 to give a compound of the formula (SEQ ID NO: 4). Then, the pyridazinone compound represented by the formula I is obtained according to the route 1.

The coupling reaction conditions described in Scheme 1 are routine choices for those skilled in the art. In general, a solvent such as DMF (N,N-dimethylformamide) or toluene is selected, and the metal catalyst, the base and the ligand are heated under heating. The heating Conditions are well known to those skilled in the art, for example heating to reflux or heating in a microwave. The base is well known to those skilled in the art, such as cesium carbonate, potassium carbonate, potassium t-butoxide, sodium t-butoxide, and the like. The metal catalysts are well known to those skilled in the art, such as palladium acetate, Pd(PPh ₃ )Cl ₂ , Pd(dppf) ₂ Cl ₂ and the like. The ligands are well known to those skilled in the art, such as triphenylphosphine, DPPP (U'-bis(diphenylphosphino)ferrocene), BINAP (binaphthalene diphenylphosphine), Sphos (2- Dicyclohexylphosphine-2',6'-dimethoxy-biphenyl), Davephos (2-dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl).

The nucleophilic substitution reaction conditions in Route 2 and Route 3 Case 2) are routine choices for those skilled in the art. In general, solvents such as DMF (N,N-dimethylformamide), toluene, DMSO (dimethyl sulfoxide), and acetonitrile are selected. It is carried out under heating in the presence of a base or in a metal catalyst, a base and a ligand under heating. The base is well known to those skilled in the art, such as cesium carbonate, potassium carbonate, potassium t-butoxide, sodium t-butoxide, sodium hydride, and the like. The metal catalysts are well known to those skilled in the art, such as palladium acetate, Pd(PPh ₃ )Cl ₂ , Pd(dppf) ₂ Cl ₂ and the like. The ligands are well known to those skilled in the art, such as triphenylphosphine, DPPP (1,1'-bis(diphenylphosphino)ferrocene), BINAP (binaphthalene diphenylphosphine), Sphos ( 2-Dicyclohexylphosphine-2',6'-dimethoxy-biphenyl), Davephos (2-dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl).

Route 3 The mitsimobu reaction conditions in 1) are routine choices for those skilled in the art. In general, THF (tetrahydrofuran) or dichloromethane is used as a solvent, and a mitsimobu reaction is carried out under the action of an azo compound and a nucleophile. The azo compounds are well known to those skilled in the art, such as DEAD (diethyl azodicarboxylate), DIAD (diisopropyl azodicarboxylate), ADDP (azodiyldipiperidine). Such nucleophiles are well known to those skilled in the art, such as triphenylphosphine, tributylphosphine, and the like.

According to still another aspect of the present invention, the present invention provides the use of a pyridazinone compound represented by Formula I or an isomer thereof, or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof, as Use of a c-Met inhibitor, and in the preparation of a medicament for the prevention and/or treatment of a tumor disease associated with c-Met abnormalities. Specifically, the tumor diseases include, but are not limited to, melanoma, liver cancer, kidney cancer, acute leukemia, non-small cell lung cancer, prostate cancer, thyroid cancer, skin cancer, colon cancer, rectal cancer, pancreatic cancer, ovarian cancer, Breast cancer, myelodysplastic syndrome, esophageal cancer, gastrointestinal cancer, and mesothelioma.

According to a further aspect of the present invention, the present invention provides a therapeutically effective amount of a pyridazinone compound of the formula I or an isomer thereof, or a pharmaceutically acceptable salt, ester, prodrug thereof or A pharmaceutical composition of one or more of the solvates, which may act as a c-Met inhibitor, and the composition may optionally comprise a pharmaceutically acceptable carrier or excipient.

The above pharmaceutically acceptable carrier means a conventional pharmaceutical carrier in the pharmaceutical field, for example: a diluent such as water; a filler such as starch, sucrose, etc.; a binder such as a cellulose derivative, an alginate, gelatin, or a poly a vinylpyrrolidone; a wetting agent such as glycerin; a disintegrating agent such as agar, calcium carbonate and sodium hydrogencarbonate; an absorption enhancer such as a quaternary ammonium compound; a surfactant such as cetyl alcohol; an adsorbent carrier such as kaolin and soap clay. Lubricants such as talc, calcium stearate and magnesium stearate, and Polyethylene glycol and the like. Further, other adjuvants such as a flavoring agent and a sweetener may be added to the above pharmaceutical composition. According to still another aspect of the present invention, the present invention provides a method of preventing and/or treating a tumor disease associated with c-Met abnormality, the method comprising administering a therapeutically effective amount of a pyridazinone compound of the formula I One or more of or a tautomer thereof, or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof, or the above pharmaceutical composition of the present invention is administered to a patient.

The compounds or compositions provided herein can be administered to a patient in need of such treatment by oral, rectal or parenteral administration. When used orally, it can be formulated into a conventional solid preparation such as a tablet, a powder, a granule, a capsule, or the like, or as a liquid preparation such as a water or oil suspension, or other liquid preparation such as syrup; For parenteral administration, it may be prepared as a solution for injection, water or an oily suspension, or the like.

Beneficial effect

The pyridazinone compound of the formula I or a tautomer thereof, or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof, of the present invention, as disclosed in the present invention, is disclosed in US Patent Application Publication No. 2008/0280917A1. The compounds disclosed in (hereinafter referred to as Dl, Amgen) and Chinese Invention Patent Application No. CN201110087884.5 (hereinafter referred to as D2) have the following advantages:

First, the present invention replaces the structure of the patent -phenyl-NH-L- with a different aromatic heterocyclic ring, which maintains the water solubility of the pyridazinone compound while maintaining the formation of the pyridazinone compound and protein. The ability to hydrogen bond, thereby increasing the activity of pyridazinone compounds at the enzyme level, cell level.

Secondly, the 6-position of the pyridazinone compound in D2 has a large degree of rotational freedom and is not suitable for the relatively fixed conformation of the c-Met ATP binding pocket. The present invention relates to the 6-position substitution of the pyridazinone. The cyclic design of the cyclic azaaromatic substituent reduces the rotational freedom of the compound-oxime. The aromatic substituent is directly bonded to the pyridazinone via a nitrogen atom, and is substantially different in structural characteristics from the compound disclosed in D1.

Third, the present invention introduces a water-soluble group at a suitable position in the molecular skeleton to adjust the physicochemical properties, metabolic properties, and biological activity of the pyridazinone compound. Compared with the compounds disclosed in D1 and D2, the pyridazinone compounds provided by the present invention have a markedly improved activity at the molecular level and at the cellular level.

Biological experiments on the inhibitory activity of c-Met kinase phosphorylation indicate that the pyridazinone compounds of the formula I or isomers thereof, or pharmaceutically acceptable salts, esters, prodrugs thereof, or The solvate has a very strong inhibitory effect on c-Met phosphorylation and can be used as a c-Met inhibitor for the preparation of antitumor drugs.

The pyridazinone compound represented by Formula I or an isomer thereof, or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof, provided by the present invention has a novel skeleton and has a rich skeletal structure and is promising Developed into a class of anti-tumor drugs with simple preparation and higher activity. DRAWINGS Figure 1 is a western blot diagram of the effect of some compounds on the phosphorylation of the receptor tyrosine kinase c-Met in the examples of the present invention. The following examples are specifically used to specifically describe the preparation of the pyridazinone compounds provided by the present invention, and their biological activities as c-Met inhibitors, but the present invention is not limited to these examples.

The nuclear magnetic resonance spectrum was recorded using a Bruker AMX-400, Gemini-300 or AMX-600 nuclear magnetic resonance apparatus, and the unit of chemical shift δ was ppm. The specific optical rotation was measured by a Perkin-Elmer 241 type automatic polarimeter, and the microwave used was a CEM-discovery microwave reactor. All reaction solvents were purified according to a conventional method. Column chromatography with silica gel (200-300 mesh) is produced by Qingdao Ocean Chemical Branch. Thin layer chromatography was performed using the GF254 high efficiency plate for the Yantai Institute of Chemical Industry. Preparative thin-layer chromatography plates were prepared by themselves. The stationary phase was prepared by GF254 (HG/T2354-92) silica gel and sodium carboxymethylcellulose (800-1200), respectively, Qingdao Ocean Chemical Co., Ltd. and China Pharmaceutical (Group). Shanghai Chemical Reagent Company produces. All solvents were analytically pure reagents, and the reagents used were purchased from Sinopharm Chemical Reagent Co., Ltd. Color development was carried out by means of iodine or ultraviolet fluorescence. The organic solvent was distilled off under reduced pressure in a rotary evaporator.

Preparation of intermediates:

Preparation Example 1: Preparation of Intermediate-1:

40 ml of DMF was placed in a round bottom flask, and 6.89 ml of P0C1 ₃ (phosphorus oxychloride) was slowly added in an ice bath. After the addition was completed, the mixture was stirred for 35 minutes in an ice bath, and 5 g 6 was slowly added to the constant pressure dropping funnel. A solution of fluoroindole in DMF was stirred at 35 ° C for 40 min. The reaction solution gradually changed from colorless to red. After completion of the reaction by TLC, 100 ml of a 19.3 mmol/L aqueous NaOH solution was added, and vigorously stirred at 80 ° C for 30 min. The reaction solution was cooled, extracted with ethyl acetate, 30 ml each time, and extracted three times. The organic layers were combined, dried over anhydrous sodium sulfate, evaporated, evaporated.

1H NMR (300 MHz, D ₂ 0) δ 10.01 (s, 1H), 8.24 (dd, J = 8.4, 5.4 Hz, 1H), 7.84 (d, J = 3.1 Hz, 1H), 7.12 (d, J= 9.1 Hz, 1H), 7.09-6.98 (m, 1H), 1.81 (s, 1H).

Preparation Example 2: Preparation of Intermediate 1-2:

1.5 g of 3-aldehyde-6-fluoroindole (i.e., intermediate 1-1) was dissolved in isopropanol, 150 mg of palladium on carbon and 3.2 g of sodium borohydride were added, and refluxed at 80 ° C overnight. After the TLC showed that the substrate had disappeared, the palladium carbon was removed by filtration, and the filtrate was concentrated. Then, excess sodium borohydride was added to the mixture, and ethyl acetate was extracted, 15 ml each time, and extracted three times. The organic layer was combined, dried over anhydrous sodium sulfate and evaporated to dryness.

1H NMR (300 MHz, CDC1 ₃ ) δ 7.60 (s, 1H), 7.56 (dd, J = 7.5, 5.1 Hz, 1H), 7.03 (dd, J= 8.0, 1.4 Hz, 1H), 6.98 - 6.90 (m , 2H), 2.34 (s, 3H).

Preparation Example 3: Preparation of Intermediates 1-3:

Lg 3-methyl-6-fluoroindole (ie, intermediate 1-2) and lg-dichloropyridazine were dissolved in re-distilled THF and protected with nitrogen. 270 mg of NaH was added under ice bath and stirred rapidly. After the reaction was stabilized, the ice bath was removed and stirred at room temperature. After the TLC detection substrate was completely converted, the unreacted NaH was quenched by adding excess water, and extracted with ethyl acetate, 20 ml each time, and extracted twice. The organic layers were combined, dried and concentrated. The crude product was dissolved in glacial acetic acid and refluxed at 120 ° C overnight. After the reaction was stopped, glacial acetic acid was evaporated under reduced pressure, and the crude product was dissolved in ethyl acetate (100 ml) and washed with water five times, 50 ml each time. The organic layer was dried, concentrated and purified by silica gel chromatography eluting

1H NMR (300 MHz, CDC13) δ 13.04 (s, 1H), 7.75 (dd, J = 9.9, 2.2 Hz, 1H), 7.55 (d, J = 10.2 Hz, 1H), 7.48 (dd, J = 8.8, 5.6 Hz, 1H), 7.20-7.12 (m, 2H), 7.01 (td, J = 9.0, 2.3 Hz, 1H), 2.34 (s, 3H).

Preparation Example 4: Preparation of Intermediates 1-4

Intermediates 1-4 (off-white solid, yield quantitative) were prepared in the same manner as in Preparation Example 3 except that 6-fluoroindole was used instead of 3-methyl-6-fluoroindole.

1H NMR (300 MHz, DMSO) δ 12.95 (s, 1H), 7.99 (d, J = 10.1 Hz, 1H), 7.91 - 7.80 (m, 2H), 7.64 (dd, J = 8.6, 5.7 Hz, 1H) , 7.15-7.00 (m, 2H), 6.75 (d, J = 3.5 Hz, 1H). Preparation Example 5: Intermediates 1-5

100 mg of the intermediate 1-4 and 104 mg of 2-(tert-butyldimethylsilyloxy)bromoethane were dissolved in DMF, and 156 mg of cesium carbonate was added thereto, and the mixture was stirred at 50 ° C for about 4 hours, and the starting point of the TLC was disappeared. DMF was evaporated under reduced pressure, and THF was added to the residue, and 140 mg of TBAF (tetrabutylammonium fluoride) was added and stirred at room temperature for lh. The reaction was quenched, extracted with 20 ml of ethyl acetate and 20 ml of aqueous layer. The organic layer was dried and concentrated to give the title compound 1-5 (yellow solid, yield 80%).

^{_{! HNMR (300 MHz, CDC1 3}} ) δ 7.71 (dd, J = 10.2, 1.9 Hz, 1H), 7.57 (m, 2H), 7.38 (d, J = 3.5 Hz, 1H), 7.18 (d, J = 9.8 Hz, 1H), 7.01 (td, J= 9.0, 2.3 Hz, 1H), 6.71 (d, J= 3.5 Hz, 1H), 4.47 (t, J = 6.0 Hz, 2H ), 4.16 - 4.09 (m, 2H) ), 2.85 (s, 1H).

Preparation Example 6: Preparation of Intermediates 1-6

Intermediate 1-6 (yellow solid, yield 81%) was obtained in the same manner as in Preparation Example 5 except that Intermediate 1-3 was used instead of Intermediate 1-4.

1H NMR (300 MHz, CDC1 ₃ ) δ 7.71 (dd, J = 10.3, 2.2 Hz, 1H), 7.55 (d, J = 9.8 Hz, 1H), 7.50 (dd, J = 8.6, 5.4 Hz, 1H), 7.20-7.12 (m, 2H), 7.01 (td, J = 9.0, 2.3 Hz, 1H), 4.52-4.42 (m, 2H), 4.12 (s, 2H), 2.33 (s, 3H).

Preparation Example 7: Preparation of Intermediates 1-7:

100 mg of intermediate 1-4 and 98 mg of N-Boc bromoethylamine (N-tert-butoxycarbonyl bromide) were dissolved in DMF, and 156 mg of cesium carbonate was added thereto, and the mixture was stirred at 50 ° C for about 4 hours, and the TLC detection material disappeared. . DMF was evaporated under reduced pressure, and 10 ml of a 5N aqueous solution of hydrochloric acid was added to the residue. After stirring at 50 ° C for 5 h, the reaction was stopped, and the reaction mixture was evaporated. The residue was dissolved in 20 ml of ethyl acetate, then 20 ml of water, 10 ml of 3N NaHCO ₃ Wash once each. The organic layer was dried and concentrated to give crystalljjjjjjjjj

^{_{! HNMR (300 MHz, CDC1 3}} ) δ 7.71 (dd, J = 9.8, 1.3 Hz, 1H), 7.50 (m, 2H), 7.31 (d, J = 3.7 Hz, lH), 7.16 (d, J = 9.8 Hz, 1H), 6.93 (td, J= 9.2, 2.5 Hz, 1H), 6.71 (d, J= 3.5 Hz, 1H), 3.40 (t, J = 5.6 Hz, 2H,), 3.53 (t, J = 5.6 Hz, 2H).

Preparation Example 8: Preparation of Intermediates 1-8:

Intermediate 1-8 (yellow solid, yield 91%) was obtained in the same manner as in Preparation Example 7 except that Intermediate 1-3 was used instead of Intermediate 1-4.

^{_{! HNMR (300 MHz, CDC1 3}} ) δ 7.69 (dd, J = 10.3, 2.2 Hz, 1H), 7.55 (d, J = 9.8 Hz, 1H), 7.43 (dd, J = 8.6, 5.5 Hz, 1H), 7.18-7.12 (m, 2H), 6.97 (td, J = 9.0, 2.3 Hz, 1H), 3.60 (t, J = 5.6 Hz, 2H,), 3.54 (t, J = 5.6 Hz, 2H), 2.33 ( s, 3H).

Preparation Example 9: Preparation of Intermediates 1-9:

5g (synthesis method can refer to WO2008103277) dissolved in 50ml of toluene, added under ice bath

14 ml of triethylamine, slowly added 1.77 ml of methanesulfonyl chloride, and after stirring, the mixture was stirred for 30 min in an ice bath, and TLC showed the reaction was completed. The reaction solution was evaporated to dryness. EtOAc (EtOAc) (EtOAc)

After stirring at 50 ° C for 3 h, TLC showed the reaction was completed. The DMF was evaporated under reduced pressure, and 10 ml of ethyl acetate and 200 ml of water were added, and the organic layer was extracted and dried, and concentrated to give 6 g of Intermediate 1-9 (white solid, yield of 79% in two steps).

1H NMR (300 MHz, CDC1 ₃ ) 58.65 (d, J = 5.3 Hz, 1H), 8.05 (d, J = 9.2 Hz, 1H), 7.34 (d, J = 2.5 Hz, 1H), 7.18 (d, J = 9.7Hz, 1H), 7.14 (dd, J= 9.1, 2.4 Hz, 1H), 6.94 (d, J= 9.6 Hz, 1H), 6.64 (s, 1H), 4.67 (t, J= 5.4 Hz, 2H ), 4.55 (t, J = 5.3 Hz, 2H), 3.93 (s, 3H).

Preparation Example 10: Preparation of Intermediate 1-10:

H

first step:

/^OTBDMS

10 g ^HzN and 11. lg 1,5-naphthyridine derivatives were dissolved in DMF, and 2.51 g of sodium hydride was added in portions under ice bath. After the addition, the mixture was stirred at room temperature for 5 min, and stirred at 50 ° C for 2 h, TLC showed The raw material points basically disappeared. The reaction solution was cooled to an ice bath. Under ice bath, 2.51 g of sodium hydride was added, and after stirring for 5 min, 4.5 ml of acetyl chloride was added, and a large amount of white solid was precipitated in the solution. After stirring at room temperature for 3 hours, it was quenched by adding 200 ml of water. The sodium hydride was extracted with 400 ml of ethyl acetate and the organic layer was washed three times with 100 ml each time. The organic layer was dried, concentrated, and the obtained oil was dissolved in 200 ml of THF, and 37 g of TBAF was added thereto, and the mixture was stirred at room temperature, and the reaction liquid gradually turned black. After 30 min, the reaction was stopped, and the reaction solution was diluted with 100 ml of ethyl acetate and washed three times with 30 ml each time. The ethyl acetate layer was dried and concentrated to give a crude material.

The second step:

The crude product of the first step was dissolved in 100 ml of toluene, and 16 ml of triethylamine was added thereto under ice-cooling, and 5.2 ml of methanesulfonyl chloride was slowly added thereto. After the dropwise addition, the mixture was stirred for 30 minutes in an ice bath, and TLC showed the reaction was completed. The reaction mixture was evaporated to dryness. EtOAc EtOAc EtOAc EtOAc EtOAc DMF was distilled off under reduced pressure, and the reaction was dissolved in 60 ml of THF. After adding 30 ml of water, 4.5 g of NaOH was added under ice bath, and the reaction was allowed to proceed overnight at room temperature. After the TLC showed that the new point was no longer increased, the reaction liquid was extracted by adding 400 ml of ethyl acetate and 200 ml of water to the reaction mixture, and the mixture was extracted once. The ethyl acetate layer was dried over anhydrous sodium sulfate, and then concentrated, and then, then,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

1H NMR (300 MHz, CDC1 ₃ ) 58.46 (d, J = 5.3 Hz, 1H), 8.40 (d, J = 2.7 Hz, 1H), 7.52 (d, J = 9.8 Hz, 1H), 7.46 (d, J = 2.7 Hz, 1H), 7.16 (d, J = 1.2 Hz, 1H), 7.02 (t, J = 5.7 Hz, 1H), 6.56 (d, J = 5.5 Hz, lH), 4.58 (t, J = 6.1 Hz, 2H), 3.93 (s, 3H), 3.84 (q, J= 6.06 Hz, 2H).

Preparation Example 11: Preparation of Intermediates 1-11:

1-11 First step:

5 g of 6-fluoroindole was dissolved in diethyl ether, and 10.78 g of an oxalyl chloride solution in diethyl ether was added dropwise thereto under ice-cooling, and the mixture was reacted at 22 ° C for 5 hours. Ether was evaporated, and 10 ml of N-methylpiperazine was added to the obtained mixture, which was reacted at 22 ° C for 18 h. The reaction solution was poured into a large amount of ice water, and a large amount of white solid was precipitated. After filtration, the cake was dried to give the product (yield: white solid, yield 31%).

1H NMR (300 MHz, DMSO) δ 12.53-12.09 (m, 1H), 8.14 (s, 1H), 8.07 (dd, J = 8.5, 4.9 Hz, 1H), 7.31 (dd, J = 8.9, 1.0 Hz, 1H), 7.11 (t, J= 9.5 Hz, 1H), 3.60 (t, J= 3Hz, 2H), 3.25 (t, J= 3Hz _: 2H), 2.38 (t, J= 3Hz, 2H), 2.238 (m, t, J= 3Hz, 2H), 2.17 (s, 3H).

The second step:

The product of the first step of lg was dissolved in dry distilled THF, 920 mg of lithium aluminum hydride was added, and the reaction was refluxed overnight. TLC showed the reaction disappeared completely, the reaction was stopped, and the reaction mixture was cooled to room temperature. Under ice bath, water was slowly added to destroy excess lithium aluminum hydride, and the insoluble matter was removed by filtration. The filter cake was washed three times with ethyl acetate, 50 ml each time. 100 ml of water was added to the filtrate, and the aqueous layer was separated by extraction. The organic layer was dried and evaporated to dryness.

1H NMR (300 MHz, CDC1 ₃ ) δ 8.27 (s, 1H), 7.49 (dd, J = 8.7, 5.3 Hz, 1H), 7.00 (dd, J = 9.7, 2.2 Hz, 2H), 6.87 (ddd, J = 9.7, 8.7, 2.3 Hz, 1H), 2.98-2.88 (m, 2H), 2.77-2.39 (m, 10H), 2.34-2.28 (m, 3H).

The following intermediates were prepared in the same manner as in Preparation Example 11:

Preparation Example 12: Preparation of Intermediates 1-17:

2 g of Intermediate 1-1 and 6 g of ethoxycarbonylmethylenetriphenylphosphine were dissolved in dry 50 ml of acetonitrile and reacted overnight at 70 °. TLC showed complete conversion of the substrate. The reaction was stopped and the reaction solution was cooled to room temperature. 50 ml of ethyl acetate and 50 ml of water were added, and the aqueous layer was separated, and then dried, concentrated, and then purified to give 6.1 g of Intermediate 1-17 (white solid, yield 85%).

1H NMR (300 MHz, CDC13) δ 8.70 (s, 1H), 7.91-7.79 (m, 2H), 7.46 (d, J = 2.7 Hz, 1H), 7.10 (dd, J = 9.2, 2.1 Hz, 1H) , 7.05-6.92 (m, 1H), 6.43 (d, J = 16.0 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 1.36 (dd, J = 8.2, 6.0 Hz, 3H).

Preparation Example 13: Preparation of Intermediates 1-18:

Intermediate 1-17 was used as a starting material, and the intermediates 1-18 were synthesized by the method reported in Tetrahedron, 55(16), 5089-5112; 1999, yield 50%.

1H NMR (300 MHz, CDC1 ₃ ) δ 8.27 (s, 1H), 7.47 (dd, J = 8.6, 5.3 Hz, 1H), 6.98 (dd, J = 9.6 2.2 Hz, 2H), 6.89 (ddd, J = 9.7, 8.7, 2.3 Hz, 1H), 4.06 (q, J = 5.9 Hz, 2H), 3.03 (t, J = 5.6 Hz, 2H) _: 2.85 (t, J = 5.6 Hz, 2H), 1.20 (t, J= 5.9Hz, 3H).

Preparation Example 14: Preparation of Intermediates 1-19

The lg intermediate 1-18 was dissolved in 50 ml of re-distilled THF, and 320 mg of lithium aluminum hydride was added thereto. After stirring at 40 ° C for 4 hours, TLC showed the reaction disappeared completely, the reaction was stopped, and the reaction mixture was cooled to room temperature. Under ice bath, the excess lithium aluminum hydride was slowly added with water, and the insoluble matter was removed by filtration, and the filter cake was washed three times with ethyl acetate, 50 ml each time. 100 ml of water was added to the filtrate, and the aqueous layer was separated by extraction. The organic layer was dried and evaporated to dryness.

1H NMR (300 MHz, CDC1 ₃ ) δ 8.29 (s, 1H), 7.45 (dd, J = 8.6, 5.2 Hz, 1H), 6.98 (dd, J = 9.6, 2.2 Hz, 2H), 7.01 (s, 1H) ), 3.74-3.64(m, 2H), 2.64 (t, J= 5.8Hz, 2H), 1.96-1.84 (m, 2H).

Preparation Example 15: Preparation of -20

1-20

2 g of 6-fluoroindole was dissolved in the re-distilled DMF, and 2.7 mg of trifluoroacetic anhydride was slowly added thereto in an ice bath. A large amount of white smoke appeared during the dropwise addition, and after the dropwise addition was completed, the mixture was stirred at room temperature. After TLC showed complete disappearance of the substrate, a small amount of water was added under ice bath to quench the remaining trifluoroacetic anhydride, and a large amount of white solid precipitated. Filtration and drying of the filter cake gave 3.5 g of Intermediate 1-20 (white solid, yield quantitative).

1H NMR (300 MHz, acetone) δ 8.44 (s, 1H), 8.33-8.19 (m, 1H), 7.39 (d, J = 9.3 Hz, 1H), 7.18 (t, J = 10.4 Hz, 1H).

-21 preparation

100 mg of the intermediate 1-18 was dissolved in 1 ml of ethanol, 60 ml of N-methylpiperazine was added, and the mixture was stirred at 60 °C. After TLC showed complete reaction, the reaction mixture was evaporated to dryness mjjjjjjjjjjjj TLC showed the reaction disappeared completely, the reaction was stopped, and the reaction mixture was cooled to room temperature. Under ice bath, the excess lithium aluminum hydride was slowly added with water, and the insoluble matter was removed by filtration, and the cake was washed three times with ethyl acetate, 10 ml each time. 15 ml of water was added to the filtrate, and the aqueous layer was separated by extraction. The organic layer was dried and evaporated to dryness.

1H NMR (300 MHz, CDC1 ₃ ) δ 8.29 (s, 1H), 7.45 (dd, J = 8.6, 5.2 Hz, 1H), 7.02 (dd, J = 9.6, 2.2 Hz, 2H), 7.05-6.88 (m , 1H), 2.70-2.40 (m, 12H), 2.19(s, 3H), 1.86-1.72 (m, 2H).

The following intermediates were prepared in the same manner as in Preparation Example 16:

Preparation Example 17: Preparation of Intermediate 1-24

3 g of the intermediate 1-5 was dissolved in 20 ml of the re-distilled DMF, and 1.44 g of 2-chloro-4-fluoropyridine was added under the protection of N ₂ in two portions, and a total of 800 mg of sodium hydride was added thereto, and the mixture was stirred at 40 ° C overnight. TLC shows that after the intermediate 1-5 disappears completely, stop adding Heat and cool to room temperature. 40 ml of water was added to the reaction mixture to quench the remaining sodium hydride, and extracted with 40 ml of ethyl acetate. After separating the aqueous layer, the organic layer was washed three times with 30 ml each time. The organic layer was dried over anhydrous sodium sulfate and evaporated.

^{_{! HNMR (300 MHz, CDC1 3}} ) δ 8.20 (d, J = 6Hz, 1H), 7.80 (d, J = 10.5Hz, 1H), 7.52 (m, 2H), 7.40 (d, J = 3.9 Hz, 1H ), 7.18 (d, J = 10.1 Hz, 1H), 7.01 (td, J = 9.0, 2.3 Hz, 1H), 6.90-6.84 (m, 1H), 6.80-6.75 (m, 2H), 4.44 (t, J = 6.0 Hz, 2H ), 3.90 (t, J = 6.0 Hz, 2H).

Intermediate 1-25 was prepared in the same manner as in Preparation Example 17:

Preparation of solid 18: Preparation of intermediates 1-26

3 g of the intermediate 1-7 was dissolved in 20 ml of the re-distilled DMF, and 1.44 g of 2-chloro-4-fluoropyridine and 1.5 g of potassium carbonate were added, and the mixture was stirred at 40 ° C for 5 hours, and the reaction was completed by TLC. The DMF was evaporated under reduced pressure, and 40 ml of water and 40 ml of ethyl acetate were added to the residue, and the aqueous layer was separated, and the organic layer was washed three times, 30 ml each time. The organic layer was dried over anhydrous sodium sulfate and evaporated.

^{_{! HNMR (300 MHz, CDC1 3}} ) δ 7.91 (d, J = 3.5Hz, 1H), 7.73 (dd, J = 10.1, 1.5 Hz, 1H), 7.50 (m, 2H), 7.30 (d, J = 3.8 Hz, 1H), 7.16 (d, J= 9.8 Hz, 1H), 6.93 (td, J= 9.2, 2.5 Hz, 1H), 6.71 (d, J = 3.5 Hz, 1H), 6.48-6.40 (m, 2H) ), 4.44 (t, J = 5.6 Hz, 2H,), 3.61 (t, J = 5.6 Hz, 2H).

Intermediate 1-27 was prepared in the same manner as in Preparation Example 18: Intermediate preparation method and product structure

Prepared in the same manner as in Preparation Example 18 except that Intermediate 1-8 was used instead of Intermediate 1-7.

1-27

Intermediate 1-27 (light yellow solid, yield 82%)

^{_{! HNMR (300 MHz, CDC1 3}} ) 57.91 (d, J = 3.5Hz, 1H), 7.69 (dd, J = 10.3, 2.2 Hz, 1H), 7.58 (d, J = 10.1 Hz, 1H), 7.43 (dd , J = 8.8, 5.8 Hz, 1H), 7.18-7.12 (m, 2H), 6.97 (td, J = 9.3, 2.5 Hz, 1H), 6.67-6.65(m, 2H), 3.87 (t, J = 5.6 Hz, 2H,), 3.58 (t, J = 5.6 Hz, 2H), 2.33 (s, 3H).

Preparation example 19: Preparation of intermediates 1-28

The first step:

Will be 500 mg

Into 20 ml of tetrahydrofuran, 97 mg of lithium aluminum hydride in 10 ml of tetrahydrofuran was slowly added dropwise at -30 ° C, and stirred at -30 ° C for 30 minutes. TLC showed that the substrate completely disappeared. After slowly adding water to the reaction mixture to quench the reaction, 50 ml of water and ethyl acetate (50 ml *2) were added. The organic layer is dried and concentrated.

(Orange-red oil, yield 92.3%). The second step: 9.2 g ^^N^ of the crude product was dissolved in 500 ml of toluene, and 10.5 ml of triethylamine and 3.1 ml of methanesulfonyl chloride were slowly added thereto in an ice bath. After the addition, the mixture was stirred at room temperature for 30 min. 50 ml of ethyl acetate was added to the reaction system, and a water-soluble substance such as triethylamine hydrochloride was washed away with a large amount of water (200 ml). The organic layer is evaporated to dryness and concentrated.

The crude product was diluted with 200 ml of DMF, and then 23.8 g of cesium carbonate and 8.3 g of intermediate 1-4 were added, and stirred at 40 C for 6 h. TLC shows that ^^N^ has completely disappeared. Add to the reaction solution

500 ml of ethyl acetate was washed with a large amount of water (500 ml * 5 ). The organic layer was dried and concentrated, and then purified,jjjjjjj

1H NMR (300 MHz, acetone) δ 8.81 (d, J = 2.4 Hz, 1H), 8.47 (s, 1H), 8.02 - 7.93 (m, 1H), 7.89 (s, 1H), 7.81 - 7.72 (m, 2H), 7.68 (d, J= 3.6 Hz, 1H), 7.61 (dd, J= 8.6, 5.5 Hz, 2H), 7.10 (d, J= 9.9 Hz, 1H), 7.04 - 6.92 (m, 1H), 6.72 (d, J = 3.6 Hz, 1H), 4.59 (t, J = 7.1 Hz, 2H), 3.44 (t, J = 7.0 Hz, 2H).

The following intermediates were prepared in the same manner as in Preparation Example 19:

Preparation of the compound:

Example 1:

step 1 :

300 mg of 4-chloro-7-hydroxyquinoline was dissolved in DMF, 826 ml of 1-bromo-3-chloropropane and 2.3 g of potassium carbonate were added, and after stirring at 70 ° C for 3 h, 374 mg of sodium iodide and 5 ml of morpholine were added. , react at 70 ° C overnight. After TLC showed the reaction of the substrate, the heating was stopped. After the reaction solution was cooled to room temperature, 30 ml of ethyl acetate and 30 ml of water were added, and the pH of the aqueous layer was adjusted to 1-2 with 1N hydrochloric acid, and the organic layer was discarded after extraction. The aqueous layer was adjusted to pH 10 with an aqueous solution of 5N NaOH in an ice bath. At this time, a large amount of white solid was precipitated, and 50 ml of ethyl acetate was added to the aqueous layer to extract, and the organic layer was washed with water several times until the morpholine was completely washed with water. After the layer, the organic layer was dried over anhydrous sodium sulfate and evaporated.

Step 2:

220 mg of intermediate 1-5 and 224 mg of the crude product obtained in Step 1 were dissolved in 35 ml of toluene, and under nitrogen, 36 mg of palladium acetate, 60 mg of Sphos (2-dicyclohexylphosphine-2',6'-dimethoxy group were added in sequence. -biphenyl) and 262 mg of cesium carbonate were stirred at 90 ° C overnight. The TLC showed that the substrate completely disappeared, the reaction was stopped and the reaction solution was cooled to room temperature. 60 ml of ethyl acetate and 50 ml of water were added to the reaction mixture, and the insoluble material was removed by filtration. The filtrate was extracted and the organic layer was washed three times with 30 ml each time. The organic layer was dried over anhydrous sodium sulfate and evaporated.

1H NMR (400 MHz, DMSO) δ 8.60 (d, J = 5.2 Hz, 1H), 8.07 (d, J = 9.9 Hz, 1H), 7.99 (d, J = 10.7 Hz, 1H), 7.91 (d, J = 3.4 Hz, 1H), 7.88 (d, J = 9.1 Hz, 1H), 7.66 (dd, J = 8.6, 5.6 Hz, 1H), 7.23 (dd, J= 10.2, 6.1 Hz, 2H), 7.09 (t , J = 9.0 Hz, 1H), 6.94 (d, J = 5.3 Hz, 1H), 6.84 (dd, J = 9 丄 2.3 Hz, 1H), 6.78 (d, J = 3.5 Hz, 1H), 4.68 (dd , J = 12.4, 4.1 Hz, 4H), 4.09 (t, J = 6.3 Hz, 2H), 3.61-3.51 (m, 4H), 2.42 (t, J = 7.1 Hz, 2H), 2.36 (s, 4H) , 1.96-1.84 (m, 2H).

The following compounds were prepared in the same manner as in Example 1:

A-2 (light yellow solid, yield 75%) was obtained in the same manner as in Example 1 except that N-methylpiperazine was used instead of morpholine.

1H NMR (300 MHz, DMSO) δ 8.58 (d, J = 4.8 Hz, 1H), 8.05 (d, J = 10.2 Hz, 1H), 7.96 (d, J = 11.9 Hz, 1H), 7.92 - 7.81 (m (2, H), 7. J = 9.3 Hz, 1H), 6.75 (s, 1H), 4.78-4.55 (m, 4H), 4.11-4.03 (m, 2H), 2.50-2.22 (m, 8H), 2.11 (s, 3H), 1.92 - 1.81 (m, 2H).

Preparation of A-3 (light yellow solid, in the same manner as in Example 1, except that pyrrolidine was used instead of morpholine.

A-3 yield 75%).

1H NMR (300 MHz, DMSO) δ 8.58 (d, J = 5.2 Hz, 1H), 8.05 (d, J = 10.3 Hz, 1H), 7.97 (d, J = 10.8 Hz, 1H), 7.95-7.80 (m , 2H), 7.67 - 7.59 (m, 1H), 7.26-7.15 (m, 2H), 7.11 - 7.02 (m, 1H), 6.93 (d, J = 4.7 Hz, 1H), 6.82 (d, J = 10.5 Hz, 1H), 6.75 (s, 1H), 4.75-4.68 (m, 4H), 4.15-4.05 (m, 2H), 2.70-2.50 (m, 6H), 2.00-1.85 (m, 2H), 1.75- 1.68 (m, 4H).

F was prepared in the same manner as in Example 1 except that 1-chloro-2-bromoethane was used instead of 1-bromo-3-chloropropane.

A-4 A-4 (light yellow solid, yield 72%).

1H NMR (300 MHz, DMSO) δ 8.59 (d, J = 5.2 Hz, 1H), 8.05 (d, J = 10.0 Hz, 1H), 7.97 (d, J = 10.9 Hz, 1H), 7.92-7.82 (m , 2H), 7.64 (dd, J= 8.5, 5.7 Hz, 1H), 7.23 (d, J = 9.6 Hz, 2H), 7.07 (t, J = 9.0 Hz, 1H), 6.93 (d, J= 5.2 Hz (1, H), 6. -3.50 (m, 4H), 2.70 (t, J= 5.6 Hz, 2H), 2.49-2.41 (m, 4H). F was prepared in the same manner as in Example 1 except that 1-chloro-4-bromobutane was used instead of 1-bromo-3-chloropropane.

A-5 A-5 (light yellow solid, yield 92%).

1H NMR (300 MHz, DMSO) δ 8.58 (d, J = 5.2 Hz, 1H), 8.05 (d, J = 10.0 Hz, 1H), 7.97 (d, J = 10.8 Hz, 1H), 7.88 (dd, J = 9.9, 6.4 Hz, 2H), 7.64 (dd, J = 8.5, 5.6 Hz, 1H), 7.23 (d, J= 10.1 Hz, 2H), 7.06 (t, J= 8.1 Hz, 1H), 6.92 (d , J = 5.2 Hz, 1H), 6.81 (d, J = 9.1 Hz, 1H), 6.76 (d, J = 3.2 Hz, 1H), 4.73-4.57 (m, 4H), 4.05 (t, J = 6.5 Hz , 2H), 3.59-3.47 (m, 4H), 2.37-2.24 (m, 6H), 1.82-1.65 (m, 2H), 1.65-1.46 (m, 3H).

Q F , . 0 A-6 was prepared in the same manner as in Example 1 except that Intermediate 1-6 was used instead of Intermediate 1-5.

A-6 yellow solid, yield 88%).

1H NMR (300 MHz, acetone) δ 8.58 (d, J = 5.2 Hz, 1H), 8.02-7.93 (m, 2H), 7.83 (d, J = 10.0 Hz, 1H), 7.53 (dd, J = 8.6, 5.5 Hz, 1H), 7.44 (s, 1H), 7.23 (d, J = 2.4 Hz, 1H), 7.10 (d, J = 10.0 Hz, 1H), 7.06-6.97 (m, 1H), 6.90-6.80 ( m, 2H), 4.78-4.64 (m, 4H), 4.09 (t, J = 6.4 Hz, 2H), 3.64-3.56 (m, 4H), 2.46 (t, J = 7.1 Hz, 2H), 2.43-2.35 (m, 4H), 2.27 (s, 3H), 1.99-1.88 (m, 2H).

In addition to using intermediate 1-6 instead of intermediate 1-5, using N-methylpiperazine instead of morpholine,

A-7

A-7 (light yellow solid, yield 67%) was obtained by the same procedure.

1H NMR (300 MHz, acetone) δ 8.63 (d, J = 5.2 Hz, 1H), 8.04-7.95 (m, 2H), 7.86 (d, J = 9.8 Hz, 1H), 7.62 (dd, J = 8.8, 5.2 Hz, 1H), 7.49(s, 1H), 7.26 (d, J = 2.5 Hz, 1H), 7.23 (d, J = 10.2 Hz, 1H), 7.10-6.99 (m, 1H), 6.92-6.80 ( m, 2H), 4.78-4.64 (m, 4H), 4.13-4.06 (m, 2H), 2.64-2.48 (m, 2H), 2.31-2.24 (m, 2H), 2.37-2.16 (m, 10H), 1.85-1.73 (m, 2H).

step 1 :

300 mg of 4-chloro-1,5-naphthyridine was dissolved in DMF, 821 ml of 1-bromo-3-chloropropane and 2.3 g of potassium carbonate were added, and after stirring at 70 ° C for 3 h, 249 mg of sodium iodide and 5 ml of morpholine were added. , react at 70 ° C overnight. TLC showed that the substrate was reacted, the heating was stopped, and after the reaction solution was cooled to room temperature, 30 ml of ethyl acetate and 30 ml of water were added, and the pH of the aqueous layer was adjusted to 1-2 with 1N hydrochloric acid, and the organic layer was discarded after extraction. The aqueous layer was adjusted to pH 10 with an aqueous solution of 5N NaOH in an ice bath. At this time, a large amount of white solid was precipitated, and 50 ml of ethyl acetate was added to the aqueous layer for extraction. The organic layer was washed with water several times until the morpholine was completely washed to the aqueous layer. After that, the organic layer was dried over anhydrous sodium sulfate and evaporated, evaporated,,,,,,,,,,,,,,,,,,,,,,,,,,, 93%).

ESI[M+1]: 308

Step 2:

method 1 :

177 mg of Intermediate 1-7 and 200 mg of the crude product obtained in Step 1 were dissolved in 10 ml of DMF, 135 mg of cesium carbonate was added, and the mixture was stirred at 70 ° C overnight. The heating was stopped, and after the reaction liquid was cooled to room temperature, 50 ml of ethyl acetate and 30 ml of water and 30 ml of a saturated aqueous sodium chloride solution were added to extract. The organic layer was washed 5 times, 30 ml each time. The organic layer was dried over anhydrous sodium sulfate and evaporated.

Method 2:

194 mg of intermediate 1-7 and 200 mg of the crude product obtained in step 1 were dissolved in 30 ml of toluene, and under nitrogen, 29 mg of palladium acetate, 48 mg of Sphos (2-dicyclohexylphosphine-2',6'-dimethoxy group were added in sequence. -biphenyl) and 232 mg of cesium carbonate, stirred at 90 ° C overnight. The TLC showed that the substrate completely disappeared, the reaction was stopped and the reaction solution was cooled to room temperature. 45 ml of ethyl acetate and 45 ml of water were added to the reaction mixture, and the insoluble material was removed by filtration. The filtrate was extracted and the organic layer was washed three times with 30 ml each time. The organic layer was dried over anhydrous sodium sulfate and evaporated.

ESI[M+1]: 544 The following compounds were prepared in the same manner as in Example 2:

Real 3:

step 1 :

5 g of 2-methoxyethanol was dissolved in 10 ml of toluene, 5.6 ml of triethylamine was added, and 5.6 ml of methanesulfonyl chloride was slowly added thereto under ice-cooling, and a large amount of white solid was precipitated during the dropwise addition. After the addition was completed, the ice bath was removed and stirred at room temperature for 30 min. TLC shows the reverse of raw materials After completion of the reaction, the reaction mixture was evaporated to dryness, and then, 30 ml of ethyl acetate and 30 ml of water were added, and the aqueous layer was partitioned, and the organic layer was dried and concentrated to give a crude product of 2-methoxyethoxyacetate. 200 mg of the crude product was dissolved in 10 ml of DMF, and 230 mg of 4-chloro-7-hydroxyquinoline, 358 mg of cesium carbonate were successively added, and the mixture was stirred in an oil bath at 50 ° C for 3 hours, and TLC showed the completion of the reaction. After the reaction was stopped, the reaction liquid was cooled, and DMF was evaporated under reduced pressure. To the residue, 30 ml of ethyl acetate and 30 ml of water were added, and the aqueous layer was extracted and the organic layer was washed three times, 30 ml each time. The organic layer was dried and concentrated to give 4-chloro-7-methoxyethoxyquinoline as a crude product (yellow solid, yield quantitative).

Step 2:

The crude product of 100 mg of 4-chloro-7-methoxyethoxyquinoline was dissolved in 25 ml of toluene, and under nitrogen, 126 mg of intermediate 1-5, 19 mg of palladium acetate, 30 mg of Sphos (2-dicyclohexylphosphine) were added in sequence. 2',6'-dimethoxy-biphenyl) and 164 mg of cesium carbonate were stirred at 90 ° C overnight. The TLC showed that the substrate completely disappeared, the reaction was stopped and the reaction solution was cooled to room temperature. 30 ml of ethyl acetate and 20 ml of water were added to the reaction mixture, and the insoluble matter was removed by filtration. The filtrate was extracted and the organic layer was washed three times with 30 ml each time. The organic layer was dried with anhydrous sodium sulfate and evaporated.

1H NMR (300 MHz, acetone) δ 8.61 (d, J = 5.2 Hz, 1H), 8.08-7.93 (m, 3H), 7.78 (dd, J = 3.5, 2.0 Hz, 1H), 7.70-7.63 (m, 1H), 7.26 (s, 1H), 7.17 (dd, J = 10.0, 2.1 Hz, 1H), 7.10-7.00 (m, 1H), 6.90 (dd, J= 7.2, 2.0 Hz, 2H), 6.77 (s , 1H), 4.86-4.73 (m, 4H), 4.22 (t, J= 5.9Hz, 2H), 3.76 (t, J = 5.9Hz, 2H), 3.38 (s, 3H).

The following compounds were prepared in the same manner as in Example 3:

F was prepared in the same manner as in Example 3 except that diethylene glycol monomethyl ether was used instead of 2-methoxyethanol.

A-18 Compound A- 18 (light yellow solid, yield 79%).

1H NMR (300 MHz, acetone) δ 8.57 (d, J = 5.2 Hz, 1H), 7.97 (d, J = 9.1 Hz, 2H), 7.88 (d, J = 10.0 Hz, 1H), 7.71 (d, J = 3.6 Hz, 1H), 7.62 (dd, J= 8.6, 5.6 Hz, 1H), 7.25 (s, 1H), 7.11 (t, J= 11.4 Hz, 1H), 7.02 (td, J= 9.1, 2.3 Hz , 1H), 6.94-6.78 (m, 2H), 6.72 (d, J = 3.5 Hz, 1H), 4.80-4.65 (m, 4H), 4.21-4.10 (m, 2H), 3.90-3.79 (m, 2H ), 3.68-3.58 (m, 2H), 3.57-3.46 (m, 2H), 3.28 (s, 3H).

In addition to using intermediate 1-6 instead of intermediate 1-5, diethylene glycol monomethyl ether was used instead of 2-methoxyethanol.

A-19 Compound A-19 (light yellow solid, yield 82%) was obtained in the same manner as in Example 3.

1H NMR (300 MHz, acetone) δ 8.60 (d, J = 5.2 Hz, 1H), 8.04-7.95 (m, 2H), 7.83 (d, J = 10.1 Hz, 1H), 7.54 (dd, J = 8.6, 5.5 Hz, 1H), 7.45 (s, 1H), 7.23 (d, J = 2.4 Hz, 1H), 7.10 (d, J = 10.1 Hz, 1H), 7.07-6.94 (m, 1H), 6.91-6.78 ( m, 2H), 4.79-4.60 (m, 4H), 4.23-4.12 (m, 2H), 3.93-3.81 (m, 2H), 3.69-3.60 (m, 2H), 3.59-3.44 (m, 2H), 3.28 (s, 3H), 2.27 (s, 3H).

F A compound was prepared in the same manner as in Example 3 except that Intermediate 1-6 was used instead of Intermediate 1-5.

A-20

A-20 (light yellow solid, yield 88%).

1H NMR (300 MHz, acetone) δ 8.59 (d, J = 5.2 Hz, 1H), 8.02-7.93 (m, 2H), 7.80 (d, J = 9.8 Hz, 1H), 7.52 (dd, J = 8.6, 5.5 Hz, 1H), 7.45 (s, 1H), 7.23 (d, J = 2.4 Hz, 1H), 7.10 (d, J = 9.9 Hz, 1H), 7.07-6.94 (m, 1H), 6.91-6.78 ( m, 2H), 4.78-4.62 (m, 4H), 4.22 (t, J= 6.0Hz, 2H), 3.77 (t, J= 5.9Hz, 2H), 3.37 (s, 3H), 2.26 (s, 3H) ). Compound A-21 (light yellow solid, was prepared in the same manner as in Example 3 except that Intermediate 1-6 was used instead of Intermediate 1-5, and 3-methoxypropanol was used instead of 2-methoxyethanol. Yield 88%).

1H NMR (300 MHz, acetone) δ 8.60 (d, J = 5.2 Hz, 1H), 8.02-7.94 (m, 2H), 7.80 (d, J = 10.0 Hz, 1H), 7.52 (dd, J = 8.6, 5.5 Hz, 1H), 7.45 (s, 1H), 7.23 (d, J= 2.4 Hz, 1H), 7.10 (d, J =10.0 Hz, 1H), 7.09-6.92 (m, 1H), 6.90-6.76 ( m, 2H), 4.75-4.59 (m, 4H), 4.09 (t, J = 6.3 Hz, 2H), 3.47 (t, J = 6.2 Hz, 2H), 3.23 (s, 3H), 2.26 (s, 3H) ), 2.03-1.91 (m, 2H).

Example 4:

step 1 :

The crude product of 2-methoxyethoxycarboxylate was prepared from 2-methoxyethanol and methanesulfonyl chloride in the same manner as in the step 1 of Example 3.

Step 2:

234 mg of 4-chloro-7-hydroxy-1,5-naphthyridine was dissolved in DMF, 200 mg of 2-methoxyethoxyformate and 179 g of potassium carbonate were added, and the mixture was stirred at 70 ° C for 3 h, and the substrate was shown by TLC. After the completion of the reaction, the heating was stopped. After the reaction mixture was cooled to room temperature, ethyl acetate (20 ml) and 20 ml of water were added, and the organic layer was dried over anhydrous sodium sulfate and concentrated to give 4-chloro-7-methoxyethoxy-1 , 5-naphthyridine crude product (off-white solid, quantitative yield).

Step 3:

method 1 :

119 mg of Intermediate 1-8 and 100 mg of the crude product obtained in Step 2 were dissolved in 10 ml of DMF, and 63 mg of potassium carbonate was added thereto, and stirred at 70 ° C overnight. The heating was stopped, and after the reaction solution was cooled to room temperature, 35 ml of ethyl acetate and 35 ml of water and 30 ml of a saturated aqueous solution of sodium chloride were added. The organic layer was washed 5 times, 30 ml each time. Anhydrous sodium sulfate Drying, concentration and column chromatography gave 122 mg of Compound A-22 (light yellow solid, yield 60%).

Method 2:

131 mg of intermediate 1-8 and 100 mg of the crude product obtained in Step 2 were dissolved in 30 ml of toluene, and under nitrogen, 19 mg of palladium acetate and 31 mg of Sphos (2-dicyclohexylphosphine-2',6'-dimethoxy group were sequentially added. -biphenyl) and 150 mg of cesium carbonate were stirred at 90 ° C overnight. The TLC showed that the substrate completely disappeared, the reaction was stopped and the reaction solution was cooled to room temperature. 45 ml of ethyl acetate and 45 ml of water were added to the reaction mixture, and the insoluble material was removed by filtration. The filtrate was extracted and the organic layer was washed three times with 30 ml each time. The organic layer was dried over anhydrous sodium sulfate and evaporated and evaporated.

ESI[M+1]: 489

The following compounds were prepared in the same manner as in Example 4:

A-26

Compound A-26 (white solid, yield 90%) was obtained in the same manner as in the method of the method of Example 4 except that diethylene glycol monomethyl ether was used instead of 2-methoxyethanol.

ESI[M+1]: 533

Intermediate A was synthesized in the same manner as in Example 2 using Intermediate 1-7, 4-chloro-7-hydroxy-1,5-naphthyridine and 3-dimethyl-tert-butylsiloxypropanol as starting materials. -27i.

The lOOmg intermediate A-27i was dissolved in 40 ml of tetrahydrofuran, and 1 ml of TBAF was added and stirred at room temperature for 30 min, and TLC showed the reaction was completed. 30 ml of water and 30 ml of ethyl acetate were added to the reaction system, and the aqueous layer was separated by extraction. After the organic layer was dried, it was concentrated, and then was applied to the residue to afford 81 mg of Compound A-27 (white solid, yield quantitative).

ESI[M+1]: 475

The following compounds were prepared in the same manner as in Example 5:

7.99 (d, J= 9.1 Hz, 1H), 7.90-7.87 (m, 2H), 7.65 (dd, J= 8.6, 5.6 Hz, 1H), 7.26-7.18 (m, 2H), 7.07 (td, J= 8.6, 1.8 Hz, 1H), 6.92 (d, J= 5.1 Hz, 1H), 6.83 (dd, J= 9.0, 2.2 Hz, 1H), 6.76 (d, J= 3.5 Hz, 1H), 4.89 (t, J= 5.4 Hz, 1H), 4.67 (dd, J= 10.8, 3.9 Hz, 4H), 4.05 (t, J= 4.7 Hz, 2H), 3.73 (dd, J= 9.8, 5.1 Hz, 2H).

A-29

In the same manner as in Example 5 except that 2-dimethyl-tert-butylsiloxyethanol was used instead of 3-dimethyl-tert-butylsiloxypropanol, Compound A-29 (white solid, yield 84) %).

ESI[M+1]: 461

A-30

The same as Example 5 except that 2-dimethyl-tert-butylsiloxyethanol was used instead of 3-dimethyl-tert-butylsiloxypropanol, and Intermediate 1-8 was used instead of Intermediate 1-7. Method Compound A-30 (light yellow solid, yield 82%).

ESI[M+1]: 475

F

A-31

Compound A-31 was used in the same manner as in Example 5 except that Intermediate 1-8 was used instead of Intermediate 1-7.

(light yellow solid, yield 79%).

ESI[M+1]: 489

Wide

A-32F Compound A-32 (light yellow oil) was used in the same manner as in Example 5 except that 4-chloro-7-hydroxyquinoline was used instead of 4-chloro-7-hydroxy-1,5-naphthyridine. , yield 92%). NMR NMR (300 MHz, DMSO) δ 8.58 (d, J = 5.2 Hz, 1H), 8.05 (d, J = 10.0 Hz, 1H), 7.97 (dd, J = 10.8, 2.2 Hz, 1H), 7.91-7.87 (m, 2H), 7.64 (dd, J = 8.7, 5.6 Hz, 1H), 7.25 - 7.18 (m, 2H), 7.12 - 7.03 (m, 1H), 6.92 (d, J = 5.4 Hz, 1H), 6.82 (dd, J = 9.1, 2.4 Hz, 1H), 6.76 (d, J = 3.5 Hz, 1H), 4.67 (dd, J= 8.5, 3.7 Hz, 4H), 4.56 (t, J = 5.2 Hz, 1H ), 4.10 (t, J= 6.4 Hz, 2H), 3.60-3.55 (m, 2H), 1.93 - 1.81 (m, 2H)

Example 6:

method 1 :

41 mg of 6-fluoroindole and 42 mg of intermediate 1-9 were dissolved in 10 ml of toluene, 0.6 mg of palladium acetate was added under N ₂ protection, and 2.4 mg of Davephos O dicyclohexylphosphino-2'-CN, N-dimethylamine. After the biphenyl was dissolved by stirring, 32 mg of sodium t-butoxide was added. Re-vacuum, change nitrogen, and heat and stir under a 90 ° C oil bath. After the TLC showed that the substrate had completely disappeared, the reaction was stopped and the reaction solution was cooled to room temperature. The insoluble material was removed by suction filtration, and ethyl acetate (30 ml) was added to the filtrate, and the organic layer was washed with water, and then dried and filtered to give 80 mg of compound B- white solid (yield: 61.2%).

1H NMR (300 MHz, DMSO) δ 8.58 (d, J = 5.1 Hz, 1H), 8.04 (d, J = 10.0 Hz, 1H), 7.97 (d, J = 10.7 Hz, 1H), 7.86 (d, J = 11.2 Hz, 2H), 7.70-7.59 (m, 1H), 7.23 (d, J= 7.8 Hz, 2H), 7.06 (t, J = 9.1 Hz, 1H), 6.92 (d, J = 5.1 Hz, 1H ), 6.81 (d, J = 9.1 Hz, 1H), 6.76 (s, 1H), 4.67 (d, J = 6.4 Hz, 4H), 3.81 (s, 3H).

Method 2:

280 mg of triphenylphosphine was placed in a dry two-necked flask, and dissolved in 30 ml of re-distilled tetrahydrofuran. 210 microliters of DIAD was slowly added under ice bath and stirred for 5 min. 100 mg of intermediate 1-4 and 96 mg of 4-(hydroxyethoxy)-7-methoxyquinoline (for the synthesis method can be referred to WO2008103277), dissolved in 20 ml of dry tetrahydrofuran, and slowly added to the reaction using a constant pressure dropping funnel. In the liquid, about 1 hour is dripped. After the completion of the dropwise addition, the ice bath was removed and reacted at room temperature for 20 h. The substrate was completely converted by TLC, and the reaction mixture was evaporated to dryness. The product was obtained (yield: product: The following compounds were prepared in the same manner as in Method 1 in Example 6:

B-10

Compound B-10 (white solid, yield) was used in the same manner as in the method of Example 6 except that Intermediate 1-13 was used instead of 6-fluoroindole, and Intermediate 1-10 was used instead of Intermediate 1-9. 59%). ESI[M+1]: 544

B-ll

Compound B-11 (white solid, yield) was used in the same manner as in Method 1 of Example 6 except that Intermediate 1-15 was used instead of 6-fluoroindole, and Intermediate 1-10 was used instead of Intermediate 1-9. 68%). ESI[M+1]: 528

B-12

Compound B-12 (white solid, yield) was used in the same manner as in Method 1 of Example 6 except that Intermediate 1-23 was used instead of 6-fluoroindole, and Intermediate 1-10 was used instead of Intermediate 1-9. 47%). ESI[M+1]: 542

B-13

In addition to the use of intermediate 1-11 in place of 6-fluoroindole, the intermediate 1-10 was used in place of the intermediate 1-9, in the same manner as in the method of Example 6, Compound B-13 (white solid, Rate 66%).

ESI[M+1]: 557

B-14

In the same manner as in Process 1 of Example 6, except that Intermediate 1-12 was used instead of 6-fluoroindole, and Intermediate 1-10 was used instead of Intermediate 1-9 (yield white solid, yield 60%). ESI[M+1]: 542

B-15 except that Intermediate 1-14 is used instead of 6-fluoroantimony, and Intermediate 1-10 is used instead of Intermediate 1-9. The compound B-15 (white solid, yield 71%) was obtained in the same procedure as in the method of

ESI[M+1]: 502

B-16

Compound B-16 (white solid, yield) was used in the same manner as in Method 1 in Example 6 except that Intermediate 1-16 was used instead of 6-fluoroindole, and Intermediate 1-10 was used instead of Intermediate 1-9. 43%). ESI[M+1]: 475

B-17

In the same manner as in Process 1 of Example 6, except that Intermediate 1-19 was used instead of 6-fluoroindole, and Intermediate 1-10 was used instead of Intermediate 1-9 (white solid, yield 42%). ESI[M+1]: 489

B-18

Compound B-18 (white solid, yield) was used in the same manner as in the method of Example 6 except that the intermediate 1-21 was used instead of the 6-fluoroindole, and the intermediate 1-10 was used instead of the intermediate 1-9. 50%). ESI[M+1]: 571

B-19

Compound B-19 (white solid, yield) was used in the same manner as in Method 1 of Example 6 except that Intermediate 1-1-2 was used instead of 6-fluoroindole, and Intermediate 1-10 was used instead of Intermediate 1-9. 47%). ESI[M+1]: 558

Eight on

B-20

In the same manner as in Process 1 of Example 6, except for the use of Intermediate 1-20 in place of 6-fluoroindole, using Intermediate 1-10 in place of Intermediate 1-9 (yield, white solid, yield 15%). ESI[M+1]: 527 real

100 mg of the compound B-3 was dissolved in 1 2-dichloroethane, 90 μl of N-methylpiperazine and 185 mg of sodium triacetoxyborohydride were added, and the mixture was stirred overnight at 60 ° C in an oil bath. The TLC showed that the substrate completely disappeared, the heating was stopped, and the reaction solution was cooled to room temperature. 50 ml of water and 30 ml of ethyl acetate were added to the reaction mixture, and the aqueous layer was separated. The organic layer was washed 3 times, 30 ml each time. The organic layer was dried, concentrated and purified tolujjjjjjjj

1H NMR (300 MHz, acetone) δ 8.55 (d, J = 5.2 Hz, 1H), 8.06-7.92 (m 2H), 7.83 (d J = 10.2 Hz, 1H), 7.53 (dd J = 8.6 5.4 Hz 1H) , 7.46 (s 1H), 7.23 (d, J= 2.3 Hz, 1H), 7.10 (d, J= 10.1 Hz, 1H), 7.09-7.03 (m 1H), 6.93-6.78 (m 2H), 4.76-4.64 (m 4H), 3.93-3.90 (br, 2H), 3.85 (s 3H), 2.61-2.42 (m, 8H), 2.21 (s, 3H).

The following compounds were prepared in the same manner as in Example 7:

Example 8

30 mg of the compound B-9 was dissolved in ethanol, and 10 mg of sodium borohydride was added thereto, and the mixture was stirred at room temperature for 30 minutes, and TLC showed the complete reaction. After evaporating the reaction mixture, 10 ml of water was added to quench the unreacted sodium borohydride, and extracted with 30 ml of water. The organic layer was washed with water several times, dried over anhydrous sodium sulfate and evaporated to dryness to afford 30 mg of Compound B-24 (white solid, quantitative yield).

ESI[M+1]: 461

The following compounds were prepared in the same manner as in Example 8:

Compound preparation method and product structure

Compound B-25 was used in the same manner as in Example 8 except that Compound B-3 was used instead of Compound B-9.

B-25

(white solid, quantitative yield).

1H NMR (300 MHz, acetone) δ 8.60 (d, J = 5.2 Hz, 1H), 8.10-7.95 (m, 2H), 7.83 (d, J = 10.1 Hz, 1H), 7.55 (dd, J = 8.8, 5.8 Hz, 1H), 7.48 (s, 1H), 7.23 (d, J = 2.3 Hz, 1H), 7.10 (d, J = 10.1 Hz, 1H), 7.11-7.12 (m, 1H), 6.95-6.83 ( m, 2H), 4.78-4.58 (m, 6H), 3.85 (s, 3H)

Example 9

50 mg of the compound B-9 was dissolved in acetone, and 5 ml of Jones reagent was added under ice bath. After the completion of the dropwise addition, the ice bath was removed, and the reaction was carried out for 30 min at room temperature, and TLC showed that the starting material completely disappeared. The reaction solution was poured into a large amount of ice water, and 30 ml of dichloromethane was added. Insoluble matter was removed by filtration. The filtrate was extracted and the aqueous layer was separated. After dilute to dichloromethane, it was concentrated and purified by column chromatography to afford 12 mg of Compound B-26 (light yellow solid, yield 23%).

ESI[M+1]: 475

Example 10:

50 mg of compound B-26 was dissolved in dichloromethane (DCM), and 20 mg of EDCI (l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride), 14 mg, was sequentially added in an ice bath. HOAt (N-hydroxy-7-azabenzotriazole), 15 microliters of triethylamine. After the addition was completed, the ice bath was removed and reacted at room temperature for 5 min. 30 mg of 2-morpholinethylamine was added and stirred at room temperature overnight. After the TLC showed that the substrate had completely disappeared, a large amount of water was added to the reaction mixture, and a solid was precipitated, which was filtered, and the cake was dried to obtain 37 mg of Compound B-27 (light yellow solid, yield 60%).

ESI[M+1]: 587

Example 11

The lllmg 4-chloro-7-azaindole was dissolved in 25 ml of toluene, and under nitrogen, 220 mg of intermediate 1-5, 32 mg of palladium acetate, 54 mg of Sphos (2-dicyclohexylphosphine-2', 6' were added in sequence. -Dimethoxy-biphenyl) and 230 mg of cesium carbonate were stirred at 90 ° C overnight. The TLC showed that the substrate completely disappeared, the reaction was stopped and the reaction solution was cooled to room temperature. 30 ml of ethyl acetate and 20 ml of water were added to the reaction mixture, and the insoluble material was removed by filtration. The filtrate was extracted and the organic layer was washed three times with 30 ml each time. The organic layer was dried over anhydrous sodium sulfate and evaporated.

^{_{! HNMR (300 MHz, CDC1 3}} ) 59.55 (s, 1H), 8.10 (d, J = 6.6 Hz, 1H), 7.73 (dd, J = 10.1, 1.5 Hz, 1H), 7.58 (m, 2H), 7.42 -7.35 (m, 2H), 7.18 (d, J= 9.8 Hz, 1H), 7.01 (td, J= 9.0, 2.3 Hz, 1H), 6.71 (d, J= 3.5 Hz, 1H), 6.40 (d, J = 6.6 Hz, 1H), 6.30-6.25 (m, 1H). 4.75-4.52 (m, 4H)

The following compounds were prepared in the same manner as in Example 11:

2.2 Hz, 1H), 7.62-7.53 (m, 2H), 7.40-7.35 (m, 1H), 7.20-7.12 (m, 2H), 7.01 (td, J = 9.0, 2.3 Hz, 1H), 6.40 (d , J = 6.6 Hz, 1H), 6.30-6.25 (m, 1H), 4.75-4.52 (m, 4H), 2.33 (s, 3H).

Example 12: rr° 丄

CI

100 mg of the intermediate 1-24 was dissolved in the re-distilled DMF, and 12 mg of palladium acetate and 36 mg of DPPPG, 3-bis(diphenylphosphine)propene) were added under nitrogen atmosphere. After stirring for 5 minutes, nitrogen was removed and charged. After multiple substitutions of CO, 400 μl of triethylamine and 186 mg of 2-(4-methylpiperazin-1-yl)ethylamine were added and stirred at 80 ° C in an oil bath overnight. After completion of the reaction by TLC, CO was evaporated, and the mixture was evaporated to dryness, and ethyl acetate (30 ml) and 20 ml of water were added to the residue, and the insoluble material was removed by filtration. The organic layer was separated by chromatography, dried and concentrated to give crystals of crystals (yield: 61%).

ESI[M+1]: 520

The following compounds were prepared in the same manner as in Example 12:

Compound preparation method and product structure

C-3 Compound C-3 (colorless oil was obtained in the same manner as in Example 12, except that the alcohol solution of methylamine was used instead of 2-(4-methylpiperazin-1-yl)ethylamine. The rate is 31%).

^{_{! HNMR (300 MHz, CDC1 3}} ) δ 8.26 (d, J = 6.2 Hz, 1H), 7.69 (dd, J = 10.2, 1.9 Hz, 1H), 7.59-7.47 (m, 3H), 7.38 (d, J = 3.5 Hz, 1H), 7.18 (d, J = 9.8 Hz, 1H), 7.05-6.98 (m, 2H), 6.73 (d, J = 3.5 Hz, 1Η), 4.75-4.52 (m, 4H), 2.92 (d, J = 3.0Hz, 1H).

C- Compound C-5 was prepared in the same manner as in Example 12 except for using 3-morpholinylpropylamine instead of 2-(4-methylpiperazin-1-yl)ethylamine (white solid, yield 58 %). ^{_{! HNMR (300 MHz, CDC1 3}} ) δ 8.28 (d, J = 6.2 Hz, 1H), 7.71 (dd, J = 10.2, 1.9 Hz, 1H), 7.63-7.46 (m, 3H), 7.38 (d, J = 3.5 Hz, 1H), 7.18 (d, J = 9.9 Hz, 1H), 7.05-6.98 (m, 2H), 6.76 (d, J = 3.5 Hz, 1Η), 4.78-4.54 (m, 4H), 3.72 -3.60 (m, 4H), 3.52-3.41 (m, 2H), 2.65-2.54 (m, 2H), 2.45-2.3 -1.80 (m, 2H).

C-6 Compound C-6 was obtained in the same manner as in Example 12 except that 2-morpholinylethylamine was used instead of 2-(4-methylpiperazin-1-yl)ethylamine. Rate 55%).

^{_{! HNMR (300 MHz, CDC1 3}} ) δ 8.34 (d, J = 6.2 Hz, 1H), 7.69-7.47 (m, 3H), 7.38 (d, J = 3.6Hz, 1H), 7.23 (d, J = 9.8 Hz, 1H), 7.05-6.98 (m, 2H), 6.73 (d, J = 3.6 Hz, 1Η), 4.75-4.52 (m, 4H), 3.80-3.71 (m, 4H), 3.66-3.56 (m, 2H), 2.66-2.47 (m, 6H).

Instead of using intermediates 1-25 in place of intermediates 1-24, an alcoholic solution of methylamine was used in place of 2-(4-methylpiperazin-1-yl)

C-7

Compound C-7 (oily substance, yield 29%) was obtained in the same manner as in Example 12 except for ethylamine. 1H NMR (300 MHz, CDC1 ₃ ) δ 8.30 (d, J = 6.3 Hz, 1H), 7.71 (dd, J = 10.3, 2.2 Hz, lH), 7.44 - 7.39 (m, 1H), 7.55 (d, J = 9.8 Hz, 1H), 7.50 (dd, J = 8.6, 5.4 Hz, 1H), 7.20-7.12 (m, 2H), 7.08-6.93 (m, 2H), 4.75-4.52 (m, 4H), 2.93 ( d, J = 3.0Hz, 1H), 2.33 (s, 3H).

C-8 except that Intermediate 1-25 was used instead of Intermediate 1-24, 2-morpholinylethylamine was used instead of 2-(4-methylpiperazin-1-yl)ethylamine, and Example 12 Compound C-8 (white solid, yield 49%) was obtained by the same procedure. 1H NMR (300 MHz, CDC1 ₃ ) δ 8.28 (d, J = 6.3 Hz, 1H), 7.69 (dd, J = 10.0, 2.4 Hz, lH), 7.46-7.42 (m, 1H), 7.55 (d, J = 9.9 Hz, 1H), 7.52 (dd, J = 8.6, 5.4 Hz, 1H), 7.24-7.11 (m, 2H), 7.12-6.88 (m, 2H), 4.75-4.50 (m, 4H), 3.82- 3.73 (m, 4H),

Example 13

step 1:

0.9 g of 6-iodo-3-hydroxyquinoline and 0.508 g of 2-methoxybromoethane were dissolved in 50 ml of DMF, and 2.16 g of cesium carbonate was added thereto, and the mixture was stirred at 40 ° C for 3 hours. TLC showed the reaction was completed. 80 ml of ethyl acetate was added to the reaction mixture, followed by washing with a large amount of water (50 ml * 5). The organic layer was dried and concentrated, and then purified,jjjjjjjjjjj 1HNMR (400 MHz, DMSO) δ 8.66 (d, J = 3.0 Hz, 1H), 8.32 (d, J = 1.9 Hz, 1H), 7.83 (dd, J= 8.7, 2.0 Hz, 1H), 7.72 (t, J= 5.8 Hz, 2H), 4.30 - 4.21 (m, 2H), 3.77 - 3.66 (m,

2H), 3.34 (s, 3H).

Step 2: Dissolve 200 mg in THF and add 791 mg

THF solution 17ml, and added 70mg

PdPPh ₃ ) ₄ , stirred at 75 ° C overnight under nitrogen atmosphere, TLC showed the reaction was completed. The reaction solution was evaporated to dryness.

(yellow solid, yield 77%). ('HNMR (400MHz, acetone) δ 8.61

(d, J = 2.9 Hz, 1H), 7.94 (d, J = 8.6 Hz, 1H), 7.72 (d, J = 1.4 Hz, 1H), 7.64 (d, J = 2.9 Hz, 1H), 7.52 (dd , J = 8.6, 2.0 Hz, 2H), 4.33 - 4.29 (m, 2H), 3.85 - 3.77 (m, 2H), 3.74 (s, 2H), 3.41 (d, J = 2.6 Hz, 3H), 1.48- 1.41 (m, 9H).)

Step 3: In addition to using

Compound D-1 (yellow-yellow solid, yield 71%) was obtained in the same manner as in Preparation Example 19, except for ethyl 2-(6-(3-bromoquinolinyl)).

1H NMR (300 MHz, acetone δ 8.53 (t, J = 3.6 Hz, 1H), 7.98 - 7.82 (m, 2H), 7.80 - 7.42 (m, 6H), 7.19 - 7.04 (m, 1H), 6.99 (t , J = 8.9 Hz, 1H), 6.72 (d, J = 4.7 Hz, 1H), 4.57 (dd, J = 8.8, 5.8 Hz, 2H), 4.37-4.16 (m, 2H), 3.79 (dd, J= 6.0, 3.5 Hz, 2H), 3.48-3.25 (m, 5H).

The following compounds were prepared in the same manner as in Example 13:

Compound preparation method and product structure

In the same manner as in Example 13, except that N-(3-chloropropyl)morpholine was used instead of 2-bromoethyl methyl ether.

Compound D-2 (light yellow solid, yield 72%) was obtained by D-2.

1H NMR (300 MHz, acetone - ί ₆ ) δ 8.15 (t, J = 2.6 Hz, 1H), 7.61 - 7.45 (m, 2H), 7.38 - 7.29 (m, 3H), 7.29 - 7.19 (m, 1H) , 7.19 - 7.07 (m, 2H), 6.73 (dd, J = 9.9, 2.4 Hz, 1H), 6.17- 6.09 (m, 1H), 6.34 (dt, J = 3.6, 1.3 Hz, 1H), 4.19 (dd , J = 8.4, 6.1 Hz, 2H), 3.81 (td, J = 6.4, 2.3 Hz, 2H), 3.35 - 3.14 (m, 6H), 3.00 (td, J = 7.3, 2.4 Hz, 2H), 2.15 ( Td, J = 7.0, 2.3 Hz, 2H), 1.77- 1.53 (m, 4H). Compound D-2 was prepared in the same manner as in Example 13 except that 1-(3-chloropropyl)-4-methylpiperazine was used instead of 2-bromoethylmethylether. 72%).

1H NMR (300 MHz, acetone - ) δ 8.51 (dt, J = 3.5, 1.8 Hz, 1H), 8.00 - 7.82 (m, 2H), 7.80 - 7.46 (m, 6H), 7.17 - 7.07 (m, 1H) , 6.99 (t, J= 9.3 Hz, 1H), 6.72 (s, 1H), 4.57 (t, J = 7.3 Hz, 2H), 2.31 - 2.23 (m, 2H), 4.27 - 4.11 (m, 2H), 3.39 (t, J = 7.3 Hz, 2H), 2.48 (m, J = 26.6, 9.5 Hz, 8H), 2.22 (s, 3H), 1.39 - 1.09 (m, 2H).

step 1 :

1 g of intermediate 1-28 was dissolved in 70 ml of toluene, and 0.804 g of N-Boc piperazine, 0.395 g of Pd ₂ (dba) ₃ , 0.411 g of X-phos and 1.406 g of cesium carbonate were added in sequence, under nitrogen protection 110. After 6 ° reaction at ° C, TLC showed the reaction was completed. The reaction solution was cooled to room temperature, 150 ml of ethyl acetate was added, and the organic layer was washed with water three times, 100 ml each time. The ethyl acetate layer was dried, concentrated and purified tolulululululululu

Step 2:

100 mg of intermediate D-4i was dissolved in ethanol, 2 ml of concentrated hydrochloric acid was added, and the mixture was stirred in an oil bath at 70 ° C for 3 h, and TLC showed complete reaction. The reaction solution was diluted with 80 ml of ethyl acetate, and a small amount of about 30 ml of water was added, and the aqueous layer was adjusted to pH 8 with a 3N NaOH solution. The aqueous layer was separated, and the organic layer was washed with 30 ml of saturated aqueous sodium chloride, and then dried and concentrated to afford compound D-4 (light yellow solid, yield 89%).

1H NMR (300 MHz, acetone - ) δ 8.74 (d, J = 2.9 Hz, 1H), 7.91 (d, J = 9.9 Hz, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.75 - 7.70 ( m, 1H), 7.68 (d, J= 3.6 Hz, 1H), 7.66 - 7.58 (m, 2H), 7.44 (dd, J= 8.5, 2.0 Hz, 1H), 7.38 (d, J= 2.9 Hz, 1H), 7.10 (d, J= 9.9 Hz, 1H), 7.05 - 6.94 (m, 1H), 6.72 (dd, J = 3.5, 0.9 Hz, 1H), 4.56 (dd, J= 8.0, 6.6 Hz, 2H), 3.36 (t, J= 7.3 Hz, 2H), 3.29 - 3.17 (m, 4H), 3.04 - 2.94 (m, 4H).

The following compounds were prepared in the same manner as in Example 14:

Example 15

19.2 mg of acetic acid was dissolved in 30 ml of DCM, and 61.4 mg of 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC), 43.6 mg of HOAt and 0.118 ml of triethylamine were added sequentially at room temperature. After stirring for about 15 min, 100 mg of compound D-4 was added and stirred at room temperature overnight. The reaction was diluted with 50 ml of DCM and washed twice with water (30 ml each time). The aqueous layer was separated, and the organic layer was dried.

1H NMR (300 MHz, acetone - ) δ 8.78 (d, J = 2.9 Hz, 1H), 7.91 (d, J = 9.9 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.75 - 7.57 ( m, 4H), 7.51 - 7.39 (m, 2H), 7.10 (d, J = 9.9 Hz, 1H), 6.99 (ddd, J = 9.5, 8.6, 2.4 Hz, 1H), 6.72 (dd, J = 3.6, 0.9 Hz, 1H), 4.65 - 4.48 (m, 2H), 3.79 - 3.64 (m, 4H), 3.43 - 3.31 (m, 4H), 3.31 - 3.18 (m, 2H), 2.09 (s, 3H).

The following compounds were prepared in the same manner as in Example 15:

Compound preparation method and product structure

Example 16:

1 g of intermediate 1-28 was dissolved in 70 ml of toluene, followed by the addition of 0.437 g of 4-hydroxypiperidine, 0.395 g of Pd ₂ (dba) ₃ 0.411 g of X-phos and 1.406 g of cesium carbonate were reacted at 110 ° C for 6 h under nitrogen atmosphere, and TLC showed the reaction was completed. The reaction solution was cooled to room temperature, 150 ml of ethyl acetate was added, and the organic layer was washed three times with water (100 ml). The ethyl acetate layer was dried, concentrated, and then purified,jjjjjjj

1H NMR (300 MHz, methanol δ 8.59 (d, J = 2.7 Hz, 1H), 7.90 (d, J = 9.9 Hz, 1H), 7.74 (d, J = 8.6 Hz, 1H), 7.62 - 7.32 (m, 6H), 7.14 (dd, J= 9.8, 1.2 Hz, 1H), 6.95 - 6.84 (m, 1H), 6.64 (dd, J = 3.6, 0.9 Hz, 1H), 5.49 (d, J= 1.3 Hz, 1H ), 4.58 (t, J = 6.7 Hz, 2H), 3.79 (dt, J = 9.0, 4.7 Hz, 1H), 3.71 - 3.55 (m, 2H), 3.36 (t, J = 6.8 Hz, 2H), 3.05 - 2.89 (m, 2H), 2.05 - 1.91 (m, 2H), 1.78 - 1.56 (m, 2H).

The following compounds were prepared in the same manner as in Example 16:

7.81 (d, J = 8.5 Hz, 1H), 7.75 - 7.66 (m, 2H), 7.66 - 7.58 (m, 2H), 7.48 - 7.36 (m, 2H), 7.11 (d, J = 9.9 Hz, 1H) , 7.00 (ddd, J= 9.4, 8.7, 2.4 Hz, 1H), 6.72 (dd, J = 3.5, 0.8 Hz, 1H), 4.56 (t, J= 7.3 Hz, 2H), 3.90 (d, J = 12.4 Hz, 2H), 3.36 (t, J = 7.3 Hz, 2H), 2.60 (s, 5H), 1.83 - 1.38 m, 10H), 1.29 (m, 2H).

The synthesis was carried out in the same manner as in Example 16 except that 4-Bocamino-piperidine was used instead of 4-hydroxypiperidine, and the obtained product was refluxed in a hydrochloric acid-ethanol solution at 70 ° C for 5 hours to remove the Boc protecting group. steam

D-13

Solvent was removed to prepare compound D-13 (light yellow solid, yield quantitative).

1H NMR (300 MHz, methanol δ 8.51 (dd, J = 8.6, 2.8 Hz, 1H), 7.71 - 7.59 (m, 2H), 7.45 - 7.29 (m, 4H), 7.22 (dq, J = 6.4, 2.1 Hz , 2H), 6.95 (d, J = 9.9 Hz, 1H), 6.88 - 6.77 (m, 1H), 6.54 (dt, J= 3.7, 0.8 Hz, 1H), 4.35 (td, J= 7.1, 2.3 Hz, 2H), 3.66 (tt, J = 13.4, 3.6 Hz, 2H), 3.51-3.20 (m, 2H), 3.16 (td, J = 7.0, 2.4 Hz, 2H), 2.85 - 2.55 (m, 3H), 2.13 (s, 2H), 2.03-1.71 m, 2H).

Compound D-14 (light yellow solid, yield 86%) was obtained in the same manner as in Example 16 except that 4-amino-1-methylpiperidine was used instead of 4-hydroxypiperidine.

D-14

1H NMR (300 MHz, acetone - ) δ 8.45 (d, J = 2.8 Hz, 1H), 7.92 (d, J = 9.9 Hz, 1H), 7.80 - 7.66 (m, 3H), 7.63 (dd, J = 8.7 , 5.5 Hz, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.32 (dd, J = 8.4, 1.9 Hz, 1H), 7.14 - 7.06 (m, 2H), 7.00 (ddd, J = 9.3, 8.7, 2.4 Hz, 1H), 6.77 - 6.69 (m, 1H), 4.61 - 4.46 (m, 2H), 3.61 (s, 1H), 3.39 - 3.27 (m, 2H), 3.20 (d, J = 9.6 Hz , 2H), 2.55 (s, 3H), 2.31 - 2.13 (m, 2H), 2.10 - 2.06 (m, 2H), 1.98 - 1.81 (m, 2H).

Example 17

1 g of intermediate 1-29 was dissolved in 70 ml of toluene, and 0.424 g of 4-hydroxypiperidine, 0.395 g of Pd ₂ (dba) ₃ , 0.411 g of X-phos and 1.406 g of cesium carbonate were added in sequence, under nitrogen protection 110. After 6 ° reaction at ° C, TLC showed the reaction was completed. The reaction solution was cooled to room temperature, 150 ml of ethyl acetate was added, and the organic layer was washed with water three times, and the ethyl acetate layer was dried (100 mL), and concentrated to give the compound D-16 (light yellow solid, yield 67%). .

ESI[M+1]: 498

The following compounds were prepared in the same manner as in Example 17:

Example 18

Body 1-28 was dissolved in 40 ml of a mixture of DMF-water (8:1 by volume) and 97.7 mg was added in sequence.

114.8 mg of potassium hydrate hydrate, 35.3 mg of Pd(PPh ₃ ) ₂ Cl ₂ .DCM, reacted at 100 ° C for 4 h under nitrogen. After cooling the reaction mixture to room temperature, 150 ml of ethyl acetate was added, and the organic layer was washed with water three times, 50 ml each time. The ethyl acetate layer was dried, concentrated and purified tolululululululu

1H NMR (300 MHz, chloroform - δ 9.00 (d, J = 2.2 Hz, 1H), 8.13 - 8.05 (m, 1H), 8.02 (d, J = 8.6 Hz, 1H), 7.89 (d, J = 0.9 Hz , 1H), 7.78 (s, 1H), 7.70 (d, J = 1.5 Hz, 1H), 7.62 - 7.46 (m, 4H), 7.27 (d, J = 3.6 Hz, 1H), 7.13 (d, J= 9.8 Hz, 1H), 7.02 - 6.92 (m, 1H), 6.71 - 6.60 (m, 1H), 4.60 (t, J = 7.4 Hz, 2H), 4.00 (s, 3H), 3.42 (t, J= 7.4 Hz, 2H).

The following compounds were prepared in the same manner as in Example 18:

Compound preparation method and product structure

apart from

18, the synthesis was carried out in the same manner, and the obtained product was refluxed in a hydrochloric acid-ethanol solution at 70 ° C for 5 hours, and the solvent was removed by removing the Boc protecting group.

D-23

Thus, Compound D-23 (off-white solid, quantitative yield) was prepared.

1H NMR (300 MHz, acetone-^) δ 9.11 (d, J = 2.3 Hz, 1H), 8.37 - 8.27 (m, 2H), 8.01 (d, J = 0.8 Hz, 1H), 7.93 (dd, J = 10.9, 9.3 Hz, 2H), 7.77 (d, J= 1.9 Hz, 1H), 7.74 - 7.57 (m, 4H), 7.11 (d, J= 9.9 Hz, 1H), 6.99 (ddd, J= 9.4, 8.6 , 2.4 Hz, 1H), 6.72 (dd, J = 3.6, 0.9 Hz, 1H), 4.60 (td, J = 7.4, 1.4 Hz, 2H), 4.36 - 4.23 (m, 1H), 3.42 (t, J = 7.2 Hz, 2H), 3.16 (dt, J = 12.6, 3.3 Hz, 2H), 2.72 (td, J = 12.4, 2.5 Hz, 2H), 1.97 - 1.84 (m, 2H), 1.52-1.34 (m, 3H ).

. ' : B 1

D-24 is used instead of °. Compound D-24 (as an off-white solid, yield: 85%) was obtained in the same manner as in Example 18.

1H NMR (300 MHz, Acetone-ί ₆ ) δ 9.08 (d = 2.3 Hz, 1H), 8.36 - 8.26 (m, 2H), 8.01 (d 0.8 Hz, 1H), 7.93 (dd, 10.4, 9.3 Hz, 2H ), 7.77 (d 1.9 Hz, 1H), 7.75 - 7.57 (m, 4H), 7.11 (d 9.9 Hz, 1H), 6.99 (ddd, 9.4, 8.7, 2.4 Hz, 1H), 6.72 (dd, 3.6, 0.8 Hz, 1H), 4.60 (t, 7.2 Hz, 2H), 4.34 (t, 6.5 Hz, 2H), 3.66 - 3.53 (m, 4H), 3.42 (t, 7.2 Hz, 2H), 2.87 - 2.78 (m, 2H), 2.48 (t 4.7 Hz, 4H).

D-25 uses ^ ⁰ instead of +. Than ^'N, was prepared in the same manner as in Example 18 compound D-25 (; an off-white solid, yield 85%).

1H NMR (300 MHz, Acetone-ί ₆ ) δ 9.08 (d = 2.2 Hz, 1H), 8.35 - 8.21 (m, 2H), 8.01 (d 0.9 Hz, 1H), 7.92 (dd, 12.5, 9.2 Hz, 2H ), 7.80 - 7.56 (m, 5H), 7.11 (d 9.9 Hz, 1H), 6.99 (ddd 9.4, 8.6, 2.4 Hz, 1H), 6.71 (dd, 3.5, 0.9 Hz, 1H), 4.59 (t, 7.2 Hz, 2H), 4.29 (t, 6.9 Hz, 2H), 3.67 - 3.56 (m, 4H), 3.42 (t, 7.2 Hz, 2H), 2.38 (s, 4H), 2.33 (t, 6.8 Hz, 2H) , 2.12 - 2.06 (m, 2H).

Except that instead of ^ ^ ^ ° ^dB addition, with the same method as Example 18 Preparation of Compound D-28 embodiment (; an off-white solid, yield 85%).

1H NMR (300 MHz, acetone - ) δ 9.07 (d, J = 2.2 Hz, 1H), 8.27 (q, J = 1.3 Hz, 2H), 8.00 (d, J = 0.8 Hz, 1H), 7.90 (dd, J = 18.0, 9.2 Hz, 2H), 7.78 - 7.52 (m, 5H), 7.09 (d, J = 9.9 Hz, 1H), 6.98 (ddd, J = 9.4, 8.6, 2.3 Hz, 1H), 6.70 (dd , J = 3.6, 0.8 Hz, 1H), 4.56 (t, J = 7.3 Hz, 2H), 4.33 (t, J = 6.6 Hz, 2H), 3.39 (t, J = 7.2 Hz, 2H), 2.96 (t , J = 6.6 Hz, 2H), 2.54 (td, J = 5.4, 4.2, 2.6 Hz, 4H), 1.79 - 1.63 (m, 4H).

i^. F

D-29 Compound D-29 (; off-white solid, yield 81%) was obtained in the same manner as in Example 18, except that ^^^^O^ was used instead of ^^^.

1H NMR (300 MHz, Acetone-ί ₆ ) δ 9.08 (d, J = 2.3 Hz, 1H), 8.33 - 8.24 (m, 2H), 8.04 - 7.85 (m, 3H), 7.80 - 7.51 (m, 5H) , 7.11 (d, J = 9.9 Hz, 1H), 7.05 - 6.92 (m, 1H), 6.76 - 6.66 (m, 1H), 4.59 (t, J = 7.2 Hz, 2H), 4.32 (t, J= 6.5 Hz, 2H), 3.42 (t, J = 7.2 Hz, 2H), 2.83 (t, J = 6.5 Hz, 2H), 2.64 - 2.31 (m, 8H), 2.21 (s, 3H).

OH

F

D-30

The synthesis was carried out in the same manner as in Example 18, and the obtained product was refluxed in a hydrochloric acid-ethanol solution at 70 ° C for 5 hours, and the tetrahydropyran protecting group was removed and evaporated to dissolve. To prepare Compound D-30 (off-white solid, quantitative yield).

1H NMR (300 MHz, acetone-d ₆ ) δ 9.10 (d, J = 2.3 Hz, 1H), 8.37 - 8.22 (m, 2H), 8.02 (d, J = 0.8 Hz, 1H), 7.93 (dd, J = 11.5, 9.2 Hz, 2H), 7.81 - 7.45 (m, 5H), 7.11 (d, J = 9.9 Hz, 1H), 7.04 - 6.93 (m, 1H), 6.72 (dd, J= 3.6, 0.8 Hz, 1H), 4.60 (t, J = 7.2 Hz, 2H), 4.31 (t, J = 5.4 Hz, 2H), 3.96 (t, J = 5.4 Hz, 2H), 3.42 (t, J = 7.2 Hz, 2H) , 1.41 (s, 1H).

Example 19

Body 1-29 was dissolved in 40 ml of a mixture of DMF-water (8:1 by volume) and 97.7 mg was added in sequence.

114.8 mg of potassium hydrate hydrate, 35.3 mg of Pd(PPh ₃ ) ₂ Cl ₂ .DCM, reacted at 100 ° C for 4 h under nitrogen. After cooling the reaction mixture to room temperature, 150 ml of ethyl acetate was added, and the organic layer was washed with water three times, 50 ml each time. The ethyl acetate layer was dried, concentrated, and then purified,jjjjjjj

ESI[M+1]: 479

The following compounds were prepared in the same manner as in Example 19:

Preparation of compound D-32 (off-white solid, quantitative yield). ESI[M+1]: 548

D-33

_N r?

Compounds were prepared in the same manner as in Example 18 except that ° was used instead of +° ' ^N.

D-33 (off-white solid, yield 85%). ESI[M+1]: 578

/ , 1

F

D-34

_v - except that instead of ^ ^N ^^ addition to the same manner as in Example preparation of compound D-34 (an off-white solid, yield 85%) 18. ESI[M+1]: 592

『 όN

D-35 F

Compound D-35 (yield white solid, yield 84%) was obtained in the same manner as in Example 18 except for using EtOAc. ESI[M+1]: 562

\ N—

F

D-36

In addition to using ^N ~ ^N , instead of +. Than ^'N, prepared in the same manner as in Example 18 compound D-27 (; an off-white solid, yield 85%). ESI[M+1]: 536

D-37

Except that instead of ^^ ^N O ^{^ ^:} Β addition, in the same manner as Example 18 Preparation of Compound D-37 C an off-white solid, yield 82%). ESI[M+1]: 562

D-38

Compound D-38 (as an off-white solid, yield: 83%) was obtained in the same manner as in Example 18. ESI[M+1]: 591

Test Example 1: Effect of the compound prepared in the examples of the present invention on c-Met enzyme activity at the molecular level

(1) Enzyme reaction substrate PolyCGlu, Tyr) 4:1 diluted with potassium-free PBSGOmM sodium phosphate buffer, 150 mM NaCl, pH 7.2-7.4) into 20 g/mL, 125 μΙ 7-well coated ELISA plate, The reaction was carried out at 37 ° C for 12-16 hours. Discard the liquid in the well. The plate was washed and washed three times with 200 μΙ 7-well T-PBS (PBS containing 0.1% Tween-20 in potassium free) for 5 minutes each time. The plate was dried in an oven at 37 ° C for 1-2 hours.

(2) Add 49 L of ATP solution diluted with reaction buffer (50 mM HEPES H 7.4, 50 mM MgCl ₂ , 0.5 mM MnCl ₂ , 0.2 mM Na ₃ V0 ₄ , 1 mM DTT) to each well, and add 1 to each well. The compound to be tested was further added with 50 μ of the recombinant protein of c-Met kinase domain diluted with the reaction buffer, and two wells without the ATP control well were required for each experiment. The reaction was carried out for 1 hour at 37 ° C on a shaker (100 rpm). The liquid in the well was discarded and the plate was washed three times with T-PBS.

(3) Addition of antibody PY99 100 μΙ 7 well (antibody diluted with BSA 5 mg/mL T-PBS 1:500), shaken at 37 ° C for 0.5 hour. The liquid in the well was discarded and the plate was washed three times with T-PBS.

(4) Horseradish peroxidase-labeled goat anti-mouse secondary antibody 100 μΙ 7 well (antibody diluted with BSA 5 mg/ml T-PBS 1:2000) was added, and the mixture was shaken at 37 ° C for 0.5 hour. The liquid in the well was discarded and the plate was washed three times with T-PBS.

(5) Add 2 mg/ml OPD coloring solution 100 μΙ 7 wells (diluted with 0.1 M citric acid-sodium citrate buffer CpH=5.4 containing 0.03% Η ₂ Ο ₂ ), 25 ° C protected from light reaction 1-10 minute.

(6) The reaction was stopped by adding 2 M H ₂ S0 ₄ 50 μΙ 7 well, and read with a VERSAmax tunable wavelength microplate reader at a wavelength of 490 nm.

(7) Analysis of results Compound OD value - No enzyme control well OD value

(1 - ) χ 100

Sample inhibition rate (negative control well OD value - no enzyme control well OD value) The inhibition rate of the compound tyrosine kinase protein c-Met enzyme activity was measured. The IC _5Q assay was based on the inhibition rate of each concentration, and the half-inhibitory concentration IC ₅ o was calculated by a four-parameter method.

Experimental Results: Molecular level enzyme activity tests showed that the compounds of the present invention were able to significantly inhibit c-Met tyrosine kinase activity, and some of the compounds had IC _5Q values superior to similar compounds Bl in US Patent Application Publication No. US 2008/0280917 A1.

Table 1: Half-inhibitory concentration or ΙΟΟηΜ concentration inhibition rate of the compound prepared in the examples of the present invention on the receptor tyrosine kinase c-Met

C-4 76% C-5 79% C-6 57%

C-7 61% C-8 47% C-9 48%

C-10 72% C-ll 71% C-12 76%

C-13 67% C-14 73% C-15 61%

C-16 72% C-17 69%

D-l 52% D-2 71% D-3 75%

D-4 92.2% D-5 89.7% D-6 80.0%

D-7 95.1% D-8 88.3% D-9 93.9%

D-10 95.0% D-ll 93.5% D-12 96.6%

D-13 96.4% D-14 92.3% D-15 81.4%

D-16 94.1% D-17 90.8% D-18 94.5%

D-19 90.1% D-20 89.3% D-21 80.7%

D-22 80.2% D-23 78.6% D-24 98.2%

D-25 97.8% D-26 97.8% D-27 96.3%

D-28 95.5% D-29 93.0% D-30 92.7%

D-31 83.1% D-32 77.9% D-33 97.3%

D-34 95.7% D-35 96.2% D-36 93.3%

D-37 93.3% D-38 91.6% D-39 91.0% Test Example 2: Effect of some compounds prepared in the examples of the present invention on TPR-Met phosphorylation in BaF3/TPR-Met stably transfected cells

BaF3/TPR-Met was inoculated into a 12-well plate (500,000/well), and after 18-24 hours of culture, cells were added for 4 hours (final concentration of 0.1, ΙμΜ) for 4 hours, and the cells were collected. Wash once with cold PBS (containing 1 mM sodium vanadate); then add lxSDS gel loading buffer (50 mM Tris-HCl (pH 6.8), 100 mM DTT, 2% SDS, 10% glycerol, 1 mM sodium vanadate , 0.1% bromophenol blue) lysed cells. After the cell lysate was heated in a boiling water bath for 10 minutes, it was centrifuged at 12,000 rpm for 10 minutes at 4 °C.

The supernatant was taken for SDS-PAGE electrophoresis (Mini-PROTEA 3 Cell, Bio-Rad, Hercules, CA, USA), and after electrophoresis, the protein was transferred to a nitrocellulose membrane using a semi-dry electrotransfer system (Amersham Life Sciences, Arlington Heights, IL, USA), the nitrocellulose membrane was placed in a blocking solution (5% skimmed milk powder diluted in TBS containing 1 mM sodium vanadate) for 2 hours at room temperature, and then the membrane was placed in anti-pc-Met (Y1234/ 1235, Cell Sinaling Technology Xl: 1000) or anti-GAPDH (Kangcheng Bio) (l: 6000) antibody in 4 C overnight. Containing 1 mM vanadium The sodium TBS was washed three times for 15 min each time. The membrane was placed in a secondary antibody solution for 1-2 hours at room temperature; after washing the membrane three times as above, it was developed with ECL (Picece, Rockford, IL) reagent and developed.

Figure 1 shows the effect of some of the compounds, positive control drugs PF2341066 and JNJ38877605 on the phosphorylation of the receptor tyrosine kinase c-Met in the examples of the present invention. As shown in Fig. 1, some of the compounds of the present invention can effectively inhibit the phosphorylation of TPR-Met in BaF3/TPR-Met cells after 4 hours of action with BaF3/TPR-Met at a concentration of ΙμΜ or Ο.ΙμΜ. And with the positive control drug PF2341066(3-[(lR)-l-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(4-piperidinyl)-1H- Pyrazol-4-yl]-2-pyridinamine) and JNJ38877605(6-[difluoro-[6-(1-methyl-1H-pyrazol-4-yl)-1,2,4-triazole [4,3-b]pyridazin-3-yl]methyl]-quinoline) is equivalent in activity. The inhibitory activity of the compound at the cellular level on TPR-Met phosphorylation in BaF3/TPR-Met cells is significantly stronger than that of the similar compound in US Patent Application Publication No. US2008/0280917A1 B-l o

Test Example 3: Effect of the compound prepared in the examples of the present invention on Met-mediated cell proliferation ability

Tumor cell growth inhibition assays were performed using sulforhodamine B (SRB) staining. The specific steps are as follows: EBC-1 cells in logarithmic growth phase are inoculated to a 96-well microplate at a suitable density (5000/well) at 100 μί per well. After overnight incubation, different concentrations (1, 0.1, 0.01, Ο) are added. The compound of ΟΟΙμΜ) was applied for 72 hr, and each concentration was set to three replicate wells, and the corresponding concentration of physiological saline vehicle control and cell-free zero-adjustment were set. After the end of the action, the adherent cells were removed from the culture medium, and 10% (w/v) trichloroacetic acid (100 μΙ 7 well) was added and fixed at 4 ° C for 1 hr, followed by rinsing with distilled water five times, after drying at room temperature, each time. Add SRB solution (4 mg/mL, dissolved in 1% glacial acetic acid) 100 μΐ, incubate for 15 min at room temperature, rinse with unwashed SRB five times with 1% glacial acetic acid, and dry at room temperature. The optical density (OD value) at a wavelength of 515 nm was measured by adding a 10 mM Tris solution to a 100 VERSMax plate reader. The inhibition rate of the drug on tumor cell growth was calculated according to the following formula: Inhibition rate (%) = (00 control well - OD administration well) / OD control well χΐοο%.

Experimental results:

The experimental results show that some of the compounds of the present invention can significantly inhibit the proliferation of EBC-1 cells under ΙμΜ or Ο.ΙμΜ. A similar compound B-1 is apparently stronger than in U.S. Patent Application Publication No. US 2008/0280917 A1. Some of the compounds of the present invention have a strong inhibitory activity against the proliferation of EBC-1 cells at concentrations of Ο.ΟΙμΜ and Ο.ΟΟΙμΜ. The strength of action is higher than that of the marketed drug PF2341066 3-[GR)-1-P,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(4-piperidin)-1H-pyrazole- 4-yl]-2-pyridinamine).

Table 2: Proliferation inhibition rate of some of the compounds of the present invention against EBC-1 cells

A-2 88.3 87.8 88.1

88.9 86.9 87.2

82.4 16.4 0.8

A-3

85.2 35.0 5.9

75.4 72.4 75.2

A-4

75.6 73.0 75.3

73.8 72.5 72.1

A-5

74.3 69.8 71.8

77.3 76.0 77.3

A-6

76.1 75.1 75.3

73.7 72.4 73.5

A-16

74.5 73.5 75.0

74.6 72.5

A-17

70.9 59.6

75.1 73.8 71.5

A-18

76.5 74.0 74.3

72.6 73.4 72.2

A-28

72.6 72.4 73.1

76.4 75.8 75.9

A-32

77.1 76.3 75.5

15.6 6.1 6.0

B-l

8.9 1.6 3.4

D-6 79.5 77.4 60.3

D-22 83.0 75.4

D-23 80.8 76.8 72.1

85.6 85.7 9.8

PF02341066

87.3 86.6 14.2

The above examples are for illustrative purposes only, and the scope of the invention is not limited thereto. Modifications will be obvious to those skilled in the art, and the invention is only limited by the scope of the appended claims.

Claims

Rights request

A pyridazinone compound or an isomer thereof represented by the following formula I or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof:

among them,

X ¹ and X ^{2 are the} same or different and are each independently N, CH or CR ⁶ ;

X ³ is N or CH;

L ¹ is a C1-C10 straight or branched alkylene group which is unsubstituted or substituted by halogen, and the alkylene group may be replaced by a 0 or N atom except for a carbon atom at both ends of the main chain;

The presence or absence of M, in the presence of -0-, -NH -, -S -, -S(0)-, -S(0) ₂ -, -C(0)NH -, -NHC(0)- , -S(0) ₂ NH- or -HNC(0)NH-;

A is present or absent, is 5-10 membered aryl groups when present, or contains 1-3 5-10 membered heteroaryl groups selected from N, 0 and S atoms. When A is absent, X ³ moiety is unsubstituted. Or replaced by R ⁵ ;

RR ² , R 3 and R ^{4 are the} same or different and are each independently H, halogen, COOL ¹ !^ CONHL ¹ !^ OL ^! R

NHL'R or CO R;

R ⁵ and R ^{6 are the} same or different and are each independently a C1-C7 straight or branched alkyl group, CHO, COOR, COL ² R, COOL ² R, CONHL ² R, OL ² R, NHL ² R or L ² R;

L ² is a C1-C10 straight or branched alkylene group which is unsubstituted or substituted by halogen, and the carbon atom other than the carbon atom at both ends of the main chain may be replaced by 0 or N atom; Or L ² is a 4-8 membered heterocyclic group having 1 to 3 hetero atoms selected from 0 and N; or L ³ is a 5-10 membered divalent aryl group or 1-3 selected from N a 5-10 membered divalent heteroaryl group of 0, S and S atoms;

R is H; halogen; unsubstituted or substituted C1-C10 straight or branched alkyl group, the substituted substituent is selected from halogen, hydroxy, unsubstituted or C1-C5 straight or branched alkyl Substituted amino, and unsubstituted or C1-C5 straight chain Or branched alkyl substituted 1-2 unsaturated 5-7 membered heterocyclyl selected from N and 0 atoms; unsubstituted or C1-C5 straight or branched alkyl or C3-C6 naphthenic a substituted hydroxy group; an unsubstituted or substituted amino group substituted by a C1-C5 linear or branched alkyl group or a C3-C6 cycloalkyl group; a methoxycarbonyl group; a carboxamide group; a carboxyl group; an unsubstituted or halogen-substituted C1 a -C6 straight or branched alkanoyl group; or a 6-10 membered saturated or unsaturated unsubstituted or C1-C5 straight or branched alkyl group having from 1 to 4 selected from N, 0 and S atoms, C3-C6 cycloalkyl, heterocyclic or heterocyclic group containing 1-2 unsaturated 5-7 membered heterocyclic groups selected from N and 0 atoms, halogen, amino or hydroxy substituted.

The pyridazinone compound or an isomer thereof, or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof, according to claim 1, wherein

X ¹ and X ² are each independently CH or CR ⁶ ;

L ¹ is a C1-C8 straight or branched alkylene group which is unsubstituted or substituted by halogen, and the alkylene group may be replaced by a 0 or N atom except for a carbon atom at both ends of the main chain;

The presence or absence of M, when present, is -0-, -NH-, -S-, -S(O)- or -S(0) ₂ -;

A is present or absent, is phenyl when present, or contains 1-3 5-6 membered heteroaryl selected from N, 0 and S atoms, and when A is phenyl, X ³ is N, A is not In the case of phenyl, X ³ is N or CH;

1^为11, F, Cl, Br, COOL ¹ !^ CONHL ¹ !^ OL or NHI^R, R ² and R ⁴ are H, and R ³ is F, CI or Br;

R ⁵ and R ⁶ are each independently methyl, ethyl, n-propyl, isopropyl, CHO, COOR, COL ² R, COOL ² R, CONHL ² R, OL ² R, NHL ² R or L ² R ;

L ² is a C1-C8 straight or branched alkylene group which is unsubstituted or substituted by halogen, and the alkylene group may be replaced by a 0 or N atom except for a carbon atom at both ends of the main chain; Or L ² is a 5-7 membered heterocyclic group having 1 to 2 hetero atoms selected from 0 and N; or L ³ is a 6-10 membered divalent aryl group or 1-2 selected from N And a 5-10 membered divalent heteroaryl group of 0 atom;

R is H; F; unsubstituted or substituted C1-C6 straight or branched alkyl group, the substituted substituent is selected from halogen, hydroxy, unsubstituted or C1-C2 straight or branched alkyl a substituted amino group, and an unsaturated 5-6 membered heterocyclic group containing 1-2 selected from N and 0 atoms, which is unsubstituted or substituted by a C1-C3 straight or branched alkyl group; unsubstituted or substituted a hydroxyl group substituted with a group, an ethyl group, a n-propyl group, an isopropyl group or a cyclopropyl group; an amino group which is unsubstituted or substituted with a methyl group, an ethyl group, a n-propyl group, an isopropyl group or a cyclopropyl group; a methoxycarbonyl group; Carboxamide; carboxy; unsubstituted or halogen-substituted C1-C4 straight or branched alkanoyl; or 1-3 selected from N, 0 and S atoms, 6-10 memberd saturated or unsaturated Substituted or by methyl, ethyl, n-propyl, isopropyl, cyclopropyl, piperazinyl, pyrrolidinyl, morpholinyl, piperidinyl, halogen, amino or A hydroxy-substituted heterocyclic group or an aromatic heterocyclic group.

The pyridazinone compound or an isomer thereof, or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof, according to claim 2, wherein

X ¹ is CH or CR ⁶ , and X ² is CH;

L ¹ is a C1-C6 straight or branched alkylene group which is unsubstituted or substituted by halogen, and the alkylene group may be replaced by a 0 or N atom except for a carbon atom at both ends of the main chain;

M exists or does not exist, when present is -0- or -NH-;

The presence or absence of A, when present, is phenyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furyl, pyrazolyl, imidazolyl, oxazolyl or thiazolyl, and When A is a phenyl group, X ³ is N, and when A is not a phenyl group, X ³ is N or CH;

RR ² and R ⁴ are H, and R ³ is F, C1 or Br;

R ⁵ and R ⁶ are each independently methyl, ethyl, n-propyl, isopropyl, CHO, COOR, COL ² R, CONHL ² R, OL ² R, NHL ² R or L ² R;

L ² is a C1-C6 straight or branched alkylene group which is unsubstituted or substituted by halogen, and the alkylene group may be replaced by a 0 or N atom except for a carbon atom at both ends of the main chain; Or L ² is pyrrolidinyl, piperazinyl, piperidinyl, phenylene, pyridylene, pyrimidinyl or pyrazolyl;

R is H; F; unsubstituted or substituted C1-C4 straight or branched alkyl group, the substituted substituent is selected from the group consisting of halogen, hydroxy, amino, dimethylamino, morpholinyl, methylpiperazinyl , piperidinyl and azetidinyl; unsubstituted or substituted by methyl, ethyl, n-propyl, isopropyl or cyclopropyl; unsubstituted or methyl, ethyl, positive a propyl, isopropyl or cyclopropyl substituted amino group; acetyl; trifluoroacetyl; pyridyl; pyrazinyl; pyrimidinyl; pyrazinyl; oxazolyl; isoxazolyl; thiazolyl; ; pyrazolyl; furyl; thienyl; pyrrolyl; 1,2,3-triazolyl; 1,2,4-triazolyl; tetrazolyl; 1,2,4-oxa Azulazolyl; morpholino; piperazinyl; piperidinyl; pyrrolidinyl; 2-fluoropyrrolidinyl; 3-fluoropyrrolidinyl; 3-hydroxypyrrolidinyl; 3-aminopyrrolidinyl; Methyl piperazinyl; N-ethylpiperazinyl; N-isopropyl piperazinyl; N-cyclopropylpiperazinyl; 2-methylmorpholinyl; 3-methylmorpholinyl; 4- Piperidinyl piperazinyl; 4-hydroxypiperidine 4-aminopiperidinyl; 3-hydroxypiperidinyl; 3-aminopiperidinyl; 4-piperidylpiperidinyl; cycloheptylamino; homopiperazinyl; N-methylhomopiperazinyl; Mercapto; benzofuranyl; quinolyl; benzopyrazolyl; or benzimidazolyl.

The pyridazinone compound or an isomer thereof, or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof, according to claim 1, wherein the compound represented by the formula I is the following compound one:

Ζπο-

II-d3 II-d31 wherein R ⁷ is H or R ⁶ , and R ³ , R ⁵ , R ⁶ , L ² and R have the same meanings as defined in the formula I.

The pyridazinone compound or an isomer thereof, or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof, according to claim 4, wherein

In the formulae ΙΙ-al to II-a3, ΙΙ-all to II-a31, ΙΙ-bl to II-b3, ΙΙ-bll to II-b31, and Π-cl to II-c2,

R ⁵ is methyl, ethyl, n-propyl, isopropyl, OL ² R or L ² R;

R is H; F; unsubstituted or substituted by methyl, ethyl, n-propyl, isopropyl or cyclopropyl; unsubstituted or methyl, ethyl, n-propyl, isopropyl Or a cyclopropyl-substituted amino group; pyridyl; pyrazinyl; imidazolyl; pyrazolyl; 1,2,3-triazolyl; 1,2,4-triazolyl; tetrazolyl; , 2,4-oxathiazolyl; morpholino; 2-methylmorpholinyl; 3-methylmorpholinyl; piperazinyl; N-methylpiperazinyl; N-ethylpiperazine N-isopropyl piperazinyl; N-cyclopropyl Piperazinyl; pyrrolidinyl; 2-fluoropyrrolidinyl; 3-fluoropyrrolidinyl; 3-hydroxypyrrolidinyl; 3-aminopyrrolidinyl; piperidinyl; 4-piperidylpiperazinyl; -hydroxypiperidinyl; 4-aminopiperidinyl; 3-hydroxypiperidinyl; 3-aminopiperidinyl; 4-piperidylpiperidinyl; homopiperazinyl; or N-methylhomopiperazinyl .

The pyridazinone compound or an isomer thereof, or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof, according to claim 5, wherein

R is H; unsubstituted or substituted by methyl, ethyl, n-propyl, isopropyl or cyclopropyl; unsubstituted or by methyl, ethyl, n-propyl, isopropyl or cyclic Propyl substituted amino; imidazolyl; pyrazolyl; 1,2,3-triazolyl; 1,2,4-triazolyl; tetrazolyl; 1,2,4-oxadiazepine Azolyl; morpholino; piperazinyl; N-methylpiperazinyl; N-ethylpiperazinyl; pyrrolidinyl; 2-fluoropyrrolidinyl; 3-fluoropyrrolidinyl; 3-hydroxypyrrolidine 3-aminopyrrolidinyl; piperidinyl; 4-hydroxypiperidinyl; or 4-aminopiperidinyl.

In the formulas ΙΙ-dl to II-d3 and ΙΙ-dll to II-d31,

R ⁵ is methyl, ethyl, n-propyl, isopropyl, OL ² R or L ² R;

L ² is a C1-C5 straight or branched alkylene group which is unsubstituted or substituted by halogen, and the alkylene group may be replaced by 0 atom except for a carbon atom at both ends of the main chain; or L ² is pyridene alkyl, piperazinyl, piperidinyl, phenylene, pyridylene, pyrimidinyl or pyrazolyl;

R is H; F; unsubstituted or substituted C1-C4 straight or branched alkyl group, the substituted substituent is selected from the group consisting of halogen, hydroxy, amino, dimethylamino, morpholinyl, methylpiperazinyl , piperidinyl and azetidinyl; unsubstituted or substituted by methyl, ethyl, n-propyl, isopropyl or cyclopropyl; unsubstituted or methyl, ethyl, positive a propyl, isopropyl or cyclopropyl substituted amino group; acetyl; trifluoroacetyl; pyridyl; pyrazinyl; imidazolyl; pyrazolyl; 1,2,3-triazolyl; , 4-triazolyl; tetrazolyl; 1,2,4-oxathiazolyl; morpholinyl; 2-methylmorpholinyl; 3-methylmorpholinyl; piperazinyl; N-methylpiperazinyl; N-ethylpiperazinyl; N-isopropylpiperazinyl; N-cyclopropylpiperazinyl; pyrrolidinyl; 2-fluoropyrrolidinyl; 3-fluoropyrrolidine 3-hydroxypyrrolidinyl; 3-aminopyrrolidinyl; piperidinyl; 4-piperidylpiperazinyl; 4-hydroxypiperidinyl; 4-aminopiperidinyl; 3-hydroxypiperidinyl; 3-aminopiperidinyl; 4-piperidylpiperidinyl; homopiperazinyl; Or N-methyl homopiperazinyl.

The pyridazinone compound or an isomer thereof according to claim 7, or a pharmaceutically acceptable salt, ester or ester thereof Medicine or solvate, wherein

R is H; unsubstituted or substituted C1-C4 straight or branched alkyl group, the substituted substituent is selected from the group consisting of halogen, hydroxy, amino, dimethylamino, morpholin-1-yl, 4-methyl Piperazine and azetidin-1-yl; unsubstituted or substituted by methyl, ethyl, n-propyl, isopropyl or cyclopropyl; unsubstituted or methyl, ethyl , n-propyl, isopropyl or cyclopropyl substituted amino; acetyl; trifluoroacetyl; imidazolyl; pyrazolyl; 1,2,3-triazolyl; 1,2,4-triazo Azolyl; tetrazolyl; 1,2,4-oxadiazolyl; morpholinyl; piperazinyl; N-methylpiperazinyl; N-ethylpiperazinyl; pyrrolidinyl; -fluoropyrrolidinyl; 3-fluoropyrrolidinyl; 3-hydroxypyrrolidinyl; 3-aminopyrrolidinyl; piperidinyl; 4-hydroxypiperidinyl; or 4-aminopiperidinyl.

The pyridazinone compound or an isomer thereof, or a pharmaceutically acceptable salt, ester, prodrug or solvent thereof, according to claim 1.

82

lOTOO/flOZM3/X3d 86CJ£0/M0Z OAV

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810100/C10ZN3/X3d 86£ and OZ OAV

86

The pyridazinone compound or an isomer thereof according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof, as a c-Met inhibitor, for preparation Use in the prevention and/or treatment of a tumor disease drug associated with c-Met abnormalities.

A pharmaceutical composition, in particular a c-Met inhibitor, comprising a therapeutically effective amount of a pyridazinone compound or an isomer thereof according to any one of claims 1 to 9 or a pharmaceutically acceptable substance thereof An acceptable salt, ester, prodrug or solvate, and optionally a pharmaceutically acceptable carrier or excipient.