WO2013107326A1

WO2013107326A1 - NEW-TYPE IMIDAZO [1, 2-a] PYRIDINE COMPOUNDS, PREPARATION METHOD THEREFOR, PHARMACEUTICAL COMPOSITION CONTAINING SAME AND USE THEREOF

Info

Publication number: WO2013107326A1
Application number: PCT/CN2013/070386
Authority: WO
Inventors: 柳红; 耿美玉; 张登友; 艾菁; 罗成; 李淳朴; 陈曦; 梁中洁; 彭霞; 季寅淳; 蒋华良; 丁健; 陈凯先
Original assignee: 中国科学院上海药物研究所
Priority date: 2012-01-21
Filing date: 2013-01-11
Publication date: 2013-07-25
Also published as: CN103214481A; CN103214481B

Abstract

The present invention relates to imidazo [1, 2-a] pyridine compounds as shown in general formula (I), a preparation method therefor, a pharmaceutical composition containing same and the use in preparing medicines for treating cell hyperplasia diseases relating to the tyrosine kinase c-Met signal transduction pathway.

Description

Novel imidazo[l,2-a]pyridine compound, preparation method thereof, pharmaceutical composition containing the same, and use thereof

The present invention relates to the field of medicinal chemistry and pharmacotherapeutics, and in particular to imidazo[l,2-a]pyridine compounds as receptor tyrosine kinase MET inhibitors, preparation methods thereof, pharmaceutical compositions containing the same, and Its use.

Background technique

Targeted therapy has undoubtedly had a major impact on cancer treatment. The occurrence, evolution, spread and tumor angiogenesis of tumors depend on various signal transduction pathways. Significant progress has been made in targeting these signaling pathways to achieve tumorigenesis, and many drugs have been successfully marketed. For example, imatinib, an anticancer drug based on ABL tyrosine kinase, has a good effect on chronic myeloid leukemia (CML). In recent years, members of the Met proto-oncogene family have received widespread attention. The Met family includes Met (also known as c-Met) and Ron receptors. The tyrosine protein kinase c-Met is a cell surface receptor, the hepatocyte growth factor receptor (HGFR), encoded by the Met proto-oncogene. Unlike most other receptor tyrosine kinases, mature Met consists of an extracellular alpha chain (50 kDa) and a transmembrane beta chain (140 kDa, which anchors the intracellular domain of the kinase domain to the cell membrane). The structure of the polymer functions. HGF is a ligand for Met and acts as a multifunctional cytokine that promotes migration, anti-apoptosis, and mitogenic effects.

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, kidney cancer, neutrophil. Tumor, melanoma, etc. c-Met induces cell proliferation, invasion, migration, inhibition of apoptosis, and promotes angiogenesis by interacting with its ligand HGF/SF or by other pathways to activate tyrosine kinases in the intracellular segment, during tumor development. Play an important role.

In tumors, the aberrant activation mechanisms of c-Met kinase are mainly Met gene amplification, Met gene mutation, c-Met transcriptional level upregulation, ligand-dependent autocrine and paracrine loops. Met gene amplification and consequent protein overexpression and constitutive activation are present in numerous human primary cancers, including gastric and esophageal cancer, non-small cell lung cancer and medulloblastoma with acquired resistance to EGFR inhibitors. in. The Met gene can also carry an activating mutation. Various Met germline and somatic mutations are associated with a lower incidence of tumors. The most common Met constitutive activation in human tumors is the upregulation of non-gene amplified Met transcription, resulting in increased protein expression. In addition, HGF itself can activate the transcription of Met, and can also promote the dispersion of cancer cells by positive feedback in a paracrine manner. HGF can also be autocrine Abnormal activation of Met, more common in glioblastoma, breast cancer, rhabdomyosarcoma and osteosarcoma.

Unlike other kinases, c-Met interacts with other tumor-associated molecules on the cell surface, such as the integrin family, death-related receptors, and other receptor tyrosine kinases, thereby cross-linking activation to amplify tumor-related effects, greatly It promotes the development of tumors, in which c-Met plays a pivotal role, inhibiting it can inhibit the effects of multiple tumor targets.

It is particularly noteworthy that the clinically acquired acquired resistance to EGFR receptor tyrosine kinase inhibitors (EGFR-TKIs) is due to the activation of the ERBB3 signaling pathway by the Met gene. Simultaneous in vitro tests have shown that Iressa can restore efficacy when c-Met is blocked. Therefore, the combination of c-Met inhibitor and EGFR inhibitor can delay the production of acquired resistance of EGFR-TKIs and prolong its clinical service life, which has important clinical significance.

As mentioned earlier, blocking HGF-c-Met signaling can be one of the strategies for anti-tumor therapy. Selective blocking of this pathway not only inhibits tumor growth, but also inhibits tumor metastasis. There are currently three strategies for targeting c-Met inhibitors targeting the HGF-c-Met signaling pathway: bio-antagonists of HGF and c-Met, small molecule inhibitors that inhibit PTK catalytic activity, and targeting HGF and c- Specific antibodies for Met. Most of them are in the preclinical research stage, and a few enter the clinical research stage. For example, Amgen's injectable human monoclonal antibody Rilotumumab is in the second phase of clinical trials, including non-small cell lung cancer, colorectal cancer, prostate cancer, and digestive tract cancer. The PF-02341066 small molecule inhibitor developed by Pfizer has been in the third phase of clinical practice.

Since c-Met inhibitors, especially small molecule inhibitors, are mostly in clinical research, they have not yet entered the market, and antibody drugs are often expensive, providing a broad space for the development of such drugs. Therefore, c-Met kinase is a promising target for anti-tumor drug research. Summary of the invention

It is an object of the present invention to provide an imidazo[l,2-a]pyridine compound of the formula (I), a pharmaceutically acceptable salt, an enantiomer thereof, a diastereomer or Racemic body.

Another object of the present invention is to provide a process for producing a compound of the above formula (I). A further object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of one or more of the compounds of the above formula (I) or a pharmaceutically acceptable salt thereof.

Still another object of the present invention is to provide a compound of the above formula (I) for the preparation of a cell proliferative disorder associated with the treatment of a tyrosine kinase c-Met signal transduction pathway, such as cancer, hyperplasia, restenosis, immune disorders And the use of inflammatory drugs.

The compounds of the invention are useful for inhibiting tyrosine kinases, particularly the receptor tyrosine kinase Met. The present invention provides a compound of the formula (I), a pharmaceutically acceptable salt, an enantiomer, a diastereomer or a racemate thereof,

X and Y are each independently hydrogen, halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, C1-C6 straight or branched fluorenyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched decyloxy group, C3-C12 cyclic hydrocarbon group, C1-C6 linear or branched decanoyl group, or C1-C6 linear chain Or branched guanidinium;

^ ^ is a substituted or unsubstituted saturated or unsaturated C3-C12 heterocyclic group, or a substituted or unsubstituted C6-C12 aryl group, wherein the substituted heterocyclic group or substituted aryl group includes 1~ 5 substituents, the heterocyclic group containing 1 to 4 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen; the substituents are halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoro Methyl, trifluoromethoxy, carboxy, fluorenyl, oxo, C1-C6 straight or branched fluorenyl, C2-C6 straight or branched unsaturated hydrocarbon;

R ¹ is hydrogen, halogen, C1-C12 linear or branched fluorenyl group, C2-C12 linear or branched unsaturated hydrocarbon group, C3-C12 cyclic hydrocarbon group, C3-C12 heterocyclic group, cyano group, nitro group , amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, fluorenyl, -SOR ² , -SO ₂ R ² , -COR ² , -COOR ² , -SO ₃ R ² , -CONR ² R ³ , -CON(R ² )R ⁸ NR ⁴ R ⁵ , -SO ₂ NR ² R ³ , -OCONR ² R ³ , -O ₃ CON ^{3 4} , -N( ² ) ⁸ CO \ N ^{2 3} CON ( ⁴ )-, -N(R ² )R ⁸ SO ₂ R ⁴ , N ^{2 3} SO ₂ N( ⁴ )-, -NR ² R ³ , -SR ² , -OR ² , -OR ⁸ NR ³ R ⁴ -OR ⁸ COR ² , -CON(R ⁶ )R ⁸ R ² , -CON(R ⁶ )R ⁸ NR ² R ³ , -R ⁸ CONR ² R ³ , -CO ⁸ OH _;

Is a substituted or unsubstituted saturated or unsaturated C3-C12 heterocyclic group, or a substituted or unsubstituted C6-C12 aryl group, wherein the substituted heterocyclic group or substituted aryl group includes 1 to 5 a substituent having 1 to 4 hetero atoms selected from the group consisting of oxygen, sulfur, and nitrogen; the substituent is a halogen, a C1-C12 linear or branched fluorenyl group, a C2-C12 linear or branched unsaturated hydrocarbon group, a C3-C12 cycloalkyl group, a cyano group, a nitro group, an amino group, a hydroxyl group, a hydroxymethyl group, a trifluoromethyl group, Trifluoromethoxy, carboxy, fluorenyl;

R ² , R ³ , R ⁴ and R ⁵ are each independently hydrogen, halogen, C1-C12 linear or branched fluorenyl group, C2-C12 linear or branched unsaturated hydrocarbon group, C3-C12 cyclic hydrocarbon group, a C1-C6 decyloxy group, a C1-C6 acyl group, a C6-C12 aryl group, or a substituted or unsubstituted saturated or unsaturated C3-C12 heterocyclic group; said substituted or unsubstituted saturated or unsaturated C3- The C12 heterocyclic group contains 1 to 4 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen, and the substituted C3-C12 heterocyclic group contains one or more fluorenyl groups selected from halogen, C1-C12 straight or branched chain, C2-C12 linear or branched unsaturated hydrocarbon group, C1-C6 decyloxy group, C3-C12 cyclic hydrocarbon group, saturated or unsaturated C3-C12 heterocyclic group, cyano group, nitro group, hydroxyl group, hydroxymethyl group, a substituent in a trifluoromethyl group, a trifluoromethoxy group, a carboxyl group, a fluorenyl group, -NR ⁶ R ⁷ , - ⁸ OH and -SO ₂ R ⁶ ; any two of R ² , R ³ , and RR ⁵ are the same The nitrogen atoms may form a ring with the attached nitrogen atom when they are connected; any two of R ² , R ³ , R ⁴ , and R ⁵ are bonded to the same carbon atom to form a ring; R ² , R ³ , R ^4, ⁵ It may be connected to form a ring with the two oxygen atoms attached to the same oxygen atom;

R ⁶ and R ⁷ are each independently hydrogen or a C1 to C6 fluorenyl group; and R ⁸ is a C1 to C6 fluorenylene group.

Preferably, in the compound of the formula (I) of the present invention, wherein

W is -CH ₂ -, -CF ₂ -, -CFH -, -CO-, -CH ₂ -O-, -CH ₂ -NH- or further;

X and Y are each independently hydrogen, halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, fluorenyl, C1-C6 straight or branched fluorene a C2-C6 straight or branched chain and a hydrocarbyl group; a substituted or unsubstituted saturated or unsaturated C3-C12 heterocyclic group, or a substituted or unsubstituted C6-C12 aryl group, wherein the substituted The heterocyclic group or substituted aryl group includes 1 to 3 substituents; the heterocyclic group contains 1 to 4 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen; the substituent is halogen, cyano, nitro , amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, fluorenyl, oxo, C1-C6 straight or branched fluorenyl;

R ¹ is hydrogen, halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, fluorenyl, C1-C10 straight or branched fluorenyl, C2- C10 linear or branched unsaturated hydrocarbon

Where 11 is (3, N or O; Q is N or O;

M, M, each independently being a C2-C3 fluorene group;

Z is a C1-C4 fluorene group;

r is 0 or 1;

T is a hydroxy group, an ester group, a carboxyl group, a C1-C6 linear or branched fluorenyl group, a C1-C6 linear or branched fluorenyloxy group, a C2-C6 linear or branched unsaturated hydrocarbon group, with one or a C1-C6 fluorenyl or decyloxy substituted amine group, an unsubstituted or substituted C3-C10 cycloalkyl group, an unsubstituted or substituted C6-C10 aryl group, an unsubstituted or substituted C3-C10 heterocyclic group; Wherein the substituent is halogen, cyano, hydroxy, nitro, amino, trifluoromethyl, benzhydryl, an amine group substituted with one or two C1-C6 fluorenyl groups, a C1-C6 fluorenyl group;

R ⁹ and R ^1Q are each independently halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, fluorenyl, C1-C6 straight or branched fluorene a C2-C6 linear or branched unsaturated hydrocarbon group, a C1-C6 linear or branched decyloxy group, a C3-C10 cyclic hydrocarbon group, a C3-C10 heterocyclic group, a C1-C6 straight or branched chain a decanoyl group, a spiro-C3-C10 cycloalkyl group, a spiro-C3-C10 heterocyclic group, or an amine group substituted with one or two C1-C6 fluorenyl groups;

R ¹¹ is hydrogen or a C1-C4 fluorenyl group;

R ¹² and R ¹³ are each independently hydrogen, halogen, C1 to C6 linear or branched fluorenyl group, C2 to C6 linear or branched unsaturated hydrocarbon group, cyano group, nitro group, amino group, hydroxy group, trifluoro group Methyl, trifluoromethoxy, carboxyl, fluorenyl

Is a substituted or unsubstituted saturated or unsaturated C3-C10 heterocyclic group, or a substituted or unsubstituted C6-C10 aryl group, wherein the substituted heterocyclic group or substituted aryl group includes 1 to 3 a substituent, the heterocyclic group containing 1 to 4 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen;

The substituent in the ^ is halogen, C1-C10 linear or branched fluorenyl group, C2-C10 linear or branched unsaturated hydrocarbon group, C3-C10 cycloalkyl group, cyano group, nitro group, amino group, hydroxyl group , hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, fluorenyl.

Preferably, in the compound of the formula (I) of the present invention, wherein W is selected from -CH ₂ -, -CF ₂ -, -CFH -, -CH ₂ -O-, -CH ₂ -NH- or further;

X and Y are each independently hydrogen, halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, C1-C6 straight or branched fluorenyl;

Is a substituted or unsubstituted saturated or unsaturated C3-C10 heterocyclic group, or a substituted or unsubstituted C6-C10 aryl group, wherein the substituted heterocyclic group or substituted aryl group includes 1 or 2 a substituent; the heterocyclic group contains 1 to 3 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen; the substituent is halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl Base, trifluoromethoxy, carboxyl, oxo group,

a linear or branched fluorenyl group of C1-C6;

R ¹ is hydrogen, halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, fluorenyl, C1-C6 straight or branched fluorenyl, C2- C6 linear or branched unsaturated hydrocarbon group, N(R)—(Z) _r — T

Where 11 is (3, N or O; Q is N or O;

M, M, each independently being a C2-C3 fluorene group;

Z is a C1-C4 fluorene group;

r is 0 or 1;

T is a C1-C6 linear or branched fluorenyl group, a C2-C6 linear or branched unsaturated hydrocarbon group, an amine group substituted with one or two C1-C6 fluorenyl groups, an unsubstituted or substituted C3-C8 group. a cycloalkyl group, an unsubstituted or substituted C6-C8 aryl group, an unsubstituted or substituted C3-C8 heterocyclic group; wherein the substituent is halogen, hydroxy, nitro, amino, trifluoromethyl, diphenyl a group, an amine group substituted with one or two C1-C6 thiol groups, a C1-C6 fluorenyl group;

R ⁹ and R ^1Q are each independently halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, C1-C6 straight or branched fluorenyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched decyloxy group, C3-C8 cyclic hydrocarbon group, C3-C8 heterocyclic group, C1-C6 linear or branched decanoyl group , a spiro-C3-C8 cycloalkyl group, a spiro-C3-C8 heterocyclic group, or an amine group substituted with one or two C1-C6 thiol groups; R ¹¹ is hydrogen or a C1-C4 fluorenyl group;

R ¹² and R ¹³ are each independently hydrogen, halogen, C1 to C6 linear or branched fluorenyl group, C2 to C6 linear or branched unsaturated hydrocarbon group, cyano group, nitro group, amino group, hydroxy group, trifluoro group Methyl, trifluoromethoxy, carboxy;

Is a substituted or unsubstituted saturated or unsaturated C3-C8 heterocyclic group, or a substituted or unsubstituted C6-C10 aryl group, wherein the substituted heterocyclic group or substituted aryl group includes 1 or a substituent having 1 to 3 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen; the substituent in the group being a halogen, a C1-C6 linear or branched fluorenyl group, Cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy.

W is -CH ₂ -, -CF ₂ -, -CFH -, -CH ₂ -O-, -CH ₂ -NH- or further;

X and Y are each independently hydrogen, halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, C1-C4 straight or branched fluorenyl;

Is a substituted or unsubstituted saturated or unsaturated C3-C8 heterocyclic group, or a substituted or unsubstituted C6-C10 aryl group, wherein the substituted heterocyclic group or substituted aryl group includes 1 or 2 a substituent; the heterocyclic group contains 1 to 3 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen; the substituent is halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl a fluorenyl group, a trifluoromethoxy group, a carboxyl group, an oxo group, a C1-C4 straight or branched chain;

R ¹ is hydrogen, halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, carboxy, carboxy, fluorenyl, C1-C4 straight or branched fluorenyl, C3-C8 heterocyclic,

-

Where 11 is (3, N or O; Q is N or O;

M, M, each independently being a C2-C3 fluorene group;

Z is a C1-C4 fluorene group;

r is 0 or 1;

T is a C1-C4 linear or branched fluorenyl group, an amine group substituted with one or two C1-C4 thiol groups, Unsubstituted or substituted C6-C10 aryl, unsubstituted or substituted C3-C8 heterocyclic group; wherein the substituent is halogen, hydroxy, nitro, amino, trifluoromethyl, diphenylmethyl, One or two C1-C4 fluorenyl substituted amine groups, C1-C4 fluorenyl groups;

R ⁹ and R ^1Q are each independently halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, C1-C4 straight or branched fluorenyl, a C3-C6 heterocyclic group, a spiro-C3-C6 heterocyclic group, or an amine group substituted with one or two C1-C4 fluorenyl groups;

R ¹¹ is hydrogen or a C1-C4 fluorenyl group;

R ¹² and R ¹³ are each independently hydrogen, halogen, C1 to C4 linear or branched fluorenyl, cyano, nitro, amino, hydroxy, trifluoromethyl, trifluoromethoxy, carboxy;

® is a substituted or unsubstituted saturated or unsaturated C3-C8 heterocyclic group, or a substituted or unsubstituted C6-C10 aryl group, wherein the substituted heterocyclic group or substituted aryl group includes 1 or 2 a substituent, the heterocyclic group containing 1 to 3 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen;

The substituent in the ^Y is a halogen, a C1-C4 linear or branched fluorenyl group, a cyano group, a nitro group, an amino group, a hydroxyl group, a hydroxymethyl group, a trifluoromethyl group, a trifluoromethoxy group, or a carboxyl group.

Preferably, it is:

In a more preferred embodiment of the invention, the compound of the formula (I) of the invention is preferably a specific compound as follows:

Name in the number

6-{[8-fluoro-6-(l-methyl-1H-pyrazole)

DC381101 -4-yl)imidazo[l,2-a]pyridin-3-yl]methyl}quinoline

F

6-{[8-fluoro-6-(thiophen-2-yl)imidazole s / -Ν

DC381102 and [l,2-a]pyridin-3-yl]methyl}quina

Porphyrin

F

3-[8-fluoro-3-(quinolin-6-ylmethyl)

DC381103 Imidazo[l,2-a]pyridine-6-yl]benzene

Nitrile

F

6-{[6-(3,5-dichlorophenyl)-8-fluoro

DC381104 Imidazo[l,2-a]pyridine-3-yl]-

Quinoline

F

6-{[6-(1-methyl-1H-pyrazole-4-

DC381105 base;) -8-trifluoromethylimidazolium

[1,2- ]pyridin-3-yl]methyl}quinoline

CF ₃

6-{[6-(1-methyl-1H-pyrazole-4-

DC381106 base;) -7-trifluoromethylimidazolium

[1,2- ]pyridin-3-yl]methyl}quinoline

6-{[8-chloro-6-(1-methyl-1H-pyrazole)

DC381107 -4-yl)imidazo[l,2-a]pyridin-3-yl]methyl}quinoline

CI

6-{[7-chloro-6-(1-methyl-1H-pyrazole, _N

DC381108 -4-yl)imidazo[l,2-a]pyridin-3-yl]methyl}quinoline

6-{[8-cyano-6-(1-methyl-1H-pyridyl)

DC381109 oxazol-4-yl)imidazo[l,2-a]pyridine

-3-yl]methyl}quinoline

CN

The compounds of the invention may have asymmetric centers, chiral axes and chiral planes and may exist in the form of enantiomers, diastereomers, racemates, and mixtures thereof.

The present invention provides a pharmaceutically acceptable salt of the compound of the formula (I), in particular a compound of the formula (I) which is reacted with an inorganic or organic acid to form a conventional non-toxic salt. For example, a conventional non-toxic salt can be obtained by reacting a compound of the formula (I) with an inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aminosulfonic acid, phosphoric acid, etc., and Organic acids include citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalene disulfonic acid, maleic acid, malic acid, and acrylic acid. Diacid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-amino group Benzenesulfonic acid, 2-acetoxybenzoic acid and isethionate; or a compound of the formula (I) with propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid a sodium salt, a potassium salt, a calcium salt, an aluminum salt or an ammonium salt formed by forming an ester with tartaric acid, citric acid, aspartic acid or glutamic acid, or an inorganic base; or a compound of the formula (I) and an organic base Methylamine salt, ethylamine salt or ethanolamine salt; or (I) a compound of the compound with lysine, arginine or ornithine and then with hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, or with formic acid, acetic acid, bitter a corresponding organic acid salt formed from acid, methanesulfonic acid and ethanesulfonic acid.

The present invention provides a process for the preparation of a compound represented by the formula (I), which comprises the following steps, comprising:

Step b: The compound 1 is dissolved in chloroform, N-chlorosuccinimide is added at room temperature, and the reaction is stirred at room temperature to obtain a compound I _b;

Step c: 2-aminopyridine derivative is dissolved in a solvent, was added N- bromosuccinimide in an ice bath, an ice bath was stirred to give compound I _e, the solvent is acetonitrile;

Step d: Dissolving I _b in a solvent, adding I _e , protecting with argon gas, stirring the reaction in an oil bath at 80 ° C to obtain a compound I _d , the solvent is anhydrous ethanol;

Step e: catalytically coupling the compound I _d with a substituted boronic acid ester or boric acid under a palladium catalyst to obtain a final product;

Scenario 2

Step f: bromination of o with a brominating agent to obtain compound I _e , the brominating reagent is bromine; Step g: reacting compound I _e with DMA to obtain compound I _f;

Step h: The compound I _e and If are dissolved in a solvent, and stirred under an oil bath at 80 ° C to obtain a compound 3⁄4, the solvent is anhydrous ethanol;

Step i: catalytically coupling the compound I _g with a substituted boronic acid ester or boric acid under a palladium catalyst to obtain a compound I _h;

Step j; fluorinating the compound I _h using a fluorinating agent to obtain a final product, the fluorinating agent is DAST;

Option 3

Step k: dissolving compound I _e in a solvent and reacting with chloroacetaldehyde to obtain compound I _m , wherein the solvent is anhydrous ethanol;

Step 1: Hydroxymethylation of compound i _{m to} give compound i _η; Step m: nucleophilic substitution reaction of compound ^ with ^^^^) to obtain compound I. ; Step will be compound I. Catalytic coupling with a substituted boronic acid ester or boric acid under a palladium catalyst to obtain a product;

Option 4

Step p: Compound I. Azide to give compound I _{p ;}

Step q: reductive amination of compound Ip to give compound I _q; step r: performing the same reaction as step m to obtain compound ^ step s: performing the same reaction as step n to obtain the final product;

Step t: Dissolving W in DMF solvent and reacting with (trimethylsilyl) acetonitrile, post-treatment and then reacting with 1-bromo-2-chloroacetamidine to obtain compound I _s; Step u: Compound 1 _{8 is} dissolved in toluene and reacted with diisobutylaluminum hydride to obtain a compound

Step w: the compound I _t and chloro(methoxymethyl)triphenylphosphorus by Witting reaction to obtain a compound I _u;

Step X: Hydrolysis of the compound I _u with hydrochloric acid, followed by chlorosuccinimide chloroation to obtain the compound I _{w ;}

Step y: dissolving in a solvent, adding I _e , protecting with argon, stirring the reaction in an oil bath at 80 ° C to obtain a compound I _x , the solvent is anhydrous ethanol;

Step z: The same reaction as in the step n is carried out to obtain a final product. The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the above formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. The pharmaceutical composition may further comprise an odorant, a flavoring agent or the like.

The pharmaceutical composition provided by the present invention preferably contains an active ingredient in a weight ratio of 1 to 99%, preferably in a ratio of 65 wt% to 99 wt% of the total weight of the compound of the formula (I) as an active ingredient, the remainder being pharmaceutically An acceptable carrier, diluent or solution or salt solution.

The compounds and pharmaceutical compositions provided herein may be in a variety of forms, such as tablets, capsules, powders, syrups, solutions, suspensions, and aerosols, and may be presented in suitable solid or liquid carriers or diluents. Neutralizes a suitable sterilizing device for injection or drip.

Various dosage forms of the pharmaceutical compositions of the present invention can be prepared according to conventional methods of preparation in the pharmaceutical arts. The unit dosage of the preparation formulation contains 0.05 to 200 mg of the compound of the formula (I), and preferably, the unit dosage of the formulation contains 0.1 mg to 100 mg of the compound of the formula (I).

The compounds and pharmaceutical compositions of the present invention can be used clinically in mammals, including humans and animals, by route of administration to the mouth, nose, skin, lungs, or gastrointestinal tract. Most preferably oral. Most preferably, the daily dose is 0.01 to 200 mg/kg body weight, taken once, or 0.01 to 100 mg/kg body weight. Regardless of the method of administration, the optimal dosage for the individual should be based on the particular treatment. Usually starting with a small dose, gradually increase the dose until the most suitable dose is found.

Further, the inventors have found through experiments that the compound of the general formula (I) can be used to regulate receptor tyrosine kinase activity, particularly members of the receptor tyrosine kinase Met subfamily. The regulation described herein is to increase or decrease the activity of Met kinase. In one embodiment, the compounds of the invention inhibit the activity of Met kinase.

The compounds and compositions of the invention are useful in the treatment and prevention of cancer, hyperplasia, restenosis, immune disorders and inflammation, including, but not limited to, histiocytic lymphoma, ovarian cancer, head and neck squamous cell carcinoma, Gastric cancer, breast cancer, childhood hepatocellular carcinoma, colorectal cancer, cervical cancer, lung cancer, sarcoma, nasopharyngeal carcinoma, pancreatic cancer, glioblastoma, prostate cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma , thyroid cancer, testicular cancer, cervical cancer, lung adenocarcinoma, colon cancer, papillary renal cell carcinoma, glioblastoma, endometrial cancer, esophageal cancer, leukemia, renal cell carcinoma, bladder cancer, liver cancer and star Cell tumors and the like; more preferably used for the treatment of cancers such as head and neck squamous cell carcinoma, histiocytic lymphoma, lung adenocarcinoma, small cell lung cancer, non-small cell lung cancer, pancreatic cancer, papillary renal cell carcinoma, liver cancer, Gastric cancer, colon cancer, multiple myeloma, and glioblastoma.

The compounds and compositions of the present invention are useful for treating, preventing or regulating metastatic tumors of cancer cells and cancer, in particular for preventing or regulating ovarian cancer, childhood hepatocellular carcinoma, metastatic head and neck squamous cell carcinoma, Metastatic tumors of gastric cancer, breast cancer, colorectal cancer, cervical cancer, lung cancer, nasopharyngeal cancer, pancreatic cancer, glioblastoma and sarcoma.

DRAWINGS

Figure 1 shows the effect of the compounds of the present invention on TPR-Met phosphorylation in BaF3/TPR-Met cells; Figure 2 shows the growth inhibitory effect of the compounds on EBC-1 nude mice xenografts. detailed description

The invention will be further illustrated in the following examples. These examples are for illustrative purposes only, and are not intended to limit the invention in any way.

The starting materials used in the present invention are commercially available unless otherwise specified.

Some of the abbreviations used in the reaction schemes and examples are defined as follows:

DMF dimethylformamide

THF tetrachlorofuran

NBS bromosuccinimide

NCS chlorosuccinimide

PE petroleum ether

EA ethyl acetate

Pd ₂ (dba) ₃ tris(dibenzylideneacetone) dipalladium

Pd(dppf)Cl ₂ 1,Γ-bis(diphenylphosphino)ferrocene palladium(II) dichloromethane complex

HATU 2-(7-azobenzotriazole)-Ν,Ν,Ν',Ν'-tetramethylurea hexafluorophosphate

DIPEA Ν, Ν-diisopropylethylamine

HPLC high performance liquid chromatography

DMF-DMA Ν, Ν-dimethylformamide dimethyl acetal

DAST diethylaminosulfur trifluoride

Example 1 Reaction Formula 1

Step 1: Preparation of 3-(quinolin-6-yl)propanal Pd ₂ (dba) ₃ (32.66 mg, 34.95 μιηο1) and triphenylphosphorus tetrafluoride (20.92 mg, 9.93 μιηο1) were placed in a 25 mL two-necked flask and protected with argon. 6-bromoquinoline (500 mg, 2.33 mmol), allyl alcohol (0.32 mL, 4.66 mmol), N-methyldicyclohexylamine dissolved in 2 mL of 1,4-dioxane, and injected into the neck The reaction was stirred at 30 ° C in a bottle. When the reaction of the starting material was completely detected by TLC, it was suction filtered, and washed with a diethyl ether solution. The solvent was evaporated under reduced pressure and purified by flash chromatography (ethyl ether / ethyl acetate / 1 /1, v/v) to give a pale yellow oil 159 mg, yield 36.82% 1H NM (300 MHz, CDC1 ₃ ) δ 9.86 (s, 1Η), 8.87 (dd, J= 1.8, 4, 1Η), 8.11-8.04 (m, 2Η), 7.61-7.55 (m, J= 4.8, 2Η), 7.38 (dd, J = 4.5, 8.4 Hz, 1H), 3.15 (t, J= 7.2, 2H), 2.90 (t, J= 7.2, 2H).

Step 2: Preparation of 2-chloro-3-(quinolin-6-yl)propanal

3-(Quinolin-6-yl)propanal (159 mg, 858.43 μιηο1) was dissolved in 2 mL of chloroform, and L-valine (19.77 mg, 171.69 μιηο1) was added to the bath, NCS (120.36 mg, The chloroform solution of 901.35μιηο1) was added to the room temperature and then reacted to room temperature. The reaction of the starting material was completed by TLC, and the solvent was evaporated under reduced pressure and purified by flash column chromatography ( petroleum ether/ethyl acetate 1/1, v/v) to obtain a pale yellow solid (yield: 77.73%). MS (ESI, m/z): 254 [M+H] ⁺ .

Example 2

Reaction formula 2

Preparation of 2-amino-5-bromo-3-fluoropyridine

2-Amino-3-fluoropyridine (20.00 g, 178.40 mmol) was dissolved in 100 mL of acetonitrile, and a solution of NBS (31.75 g, 178.40 mmol) in acetonitrile was added dropwise. The reaction was completed by TLC. The solvent was evaporated under reduced pressure and purified by column chromatography ( petroleum ether/ethyl acetate 4/1, v/v) to give a pale yellow solid (29.3 g, yield: 85.99%). MS (ESI, m/z): 191 (M + H) ⁺ .

Example 3

3

Preparation of 6-({6-bromo-8-fluoroimidazo[l,2-a]pyridin-3-yl}methyl)quinoline 2-Chloro-3-(quinolin-6-yl)propanal (100 mg, 455.23 μιηο1) was dissolved in an appropriate amount of absolute ethanol, and 2-amino-5-bromo-3-fluoropyridine (104.34 mg, 546.28) was added. Ιιηο1), under a argon atmosphere, the reaction was stirred at 80 ° C under reflux. After TLC detection, the reaction was completed. The solvent was evaporated under reduced pressure. 30 mL of H ₂ O and dichloromethane (3×80 mL) were added. The organic layer was combined, then H ₂ O (3×50 mL) and saturated NaCl solution 50 mL. The mixture was washed with anhydrous Na ₂ SO ₄ , filtered, evaporated, evaporated, evaporated, evaporated, evaporated, . 1H NM (400 MHz, CDC1 ₃ ) δ 8.94 (d, J = 2.8, 1H), 8.14-8.09 (m, 2H), 7.81 (s, 1H), 7.62 (dd, J = 2.0, 8.8, 1H), 7.52 (s, 2H), 7.44 (dd, J= 4.4, 8.4, 1H), 7.05 (dd, J= 1.2, 9.2, 1H), 4.46(s, Example 4

Preparation of 6-{[8-fluoro-6-(l-methyl-1H-pyrazol-4-yl)imidazo[l,2-a]pyridin-3-yl]methyl}quinoline (DC381101)

6-({6-Bromo-8-fluoroimidazo[l,2-a]pyridin-3-yl}methyl)quinoline (50 mg, 140.37 μιηο1) and 1-methylimidazole-4-boronic acid The alcohol ester (30.67 mg, 147.39 μιηο1) was dissolved in 1.12 mL of DMF, and a 1 M solution of Na ₂ CO ₃ (28 μL, 280.75 mol) was added to [1, bis-bis(diphenylphosphino)ferrocene] Palladium dichloromethane ruthenium complex (5.73 η3⁄4, 7.019μιηο1), reacted at 80 ° C under argon atmosphere, and the reaction of the starting material was completely detected by TLC. EA 60 mL and 30 mL of water were added to the reaction solution for extraction. The organic phase was washed successively with 3×40 mL of water and brine, dried over anhydrous Na ₂ SO ₄ , filtered, and evaporated under reduced pressure and purified by column chromatography (dichloromethane/methanol 20/1, v/v) Isolated and purified to give a pale yellow solid (yield: 42.71%). 1H NM (400 MHz, DMSO) δ 9.20 (d, J= 4.8, 1Η), 8.87 (d, J=8.0, 1Η), 8.84 (s, 1Η), 8.40 (s, 1Η), 8.23(d, J =9.2, 1Η), 8.20-8.17 (m, 2Η), 8.11(s, 1H), 8.08 (d, J = 8.8, 1H), 8.02(s, 1H), 7.93(dd, J=5.2, 8.0, 1H), 4.79 (s, 2H), 3.90 (s, 3H).

Example 5

Preparation of 6-{[8-fluoro-6-(thiophen-2-yl)imidazo[l,2-a]pyridin-3-yl]methyl}quinoline (DC381102) except 1 - thiophene boronic acid Compound DC381102 was obtained in the same manner as in Example 4 except for the methylimidazole-4-boronic acid pinacol ester, yield 86.71%. 1H NMR (400 MHz, CDC1 ₃ ) δ 8.91 (dd, J = 1.6, 4.4, 1H), 8.13 (d, J = 8.4, 1H), 8.10 (d, J = 8.4, 1H), 7.85 (d, J = 0.8, 1H), 7.66 (dd, J=1.6, 8.8, 1H), 7.61 (s, 1H), 7.56(s,lH), 7.43 (dd, J=4.0, 8.4, 1H), 7.29-7.28(m , 1H), 7.17 (dd, J = 1.2, 10.8, 1H), 7.14 (dd, J = 1.2, 3.6, 1H), 7.06 (dd, J = 3.6, 4.8, lH), 4.49(s, 2H) o

Example 6

Preparation of 3-[8-fluoro-3-(quinolin-6-ylmethyl)imidazo[l,2-a]pyridin-6-yl]benzonitrile (DC381103) except 1 with 3-cyanobenzeneboronic acid Compound DC381103 was obtained in the same manner as in Example 4 except for the methylimidazole-4-boronic acid pinacol ester, yield 87.94%. 1H NMR (400 MHz, CDC1 ₃ ) δ 8.91 (dd, J = 1.6, 4.4, 1 Η), 8.16-8.11 (m, 2 Η), 7.78 (d, J = 1.2, 1 Η), 7.68-7.59 (m, 7H) ), 7.54 (d, J=7.6, 1H), 7.45 (dd, J=4.4, 8.0, 1H), 4.53 (s, 2H).

Example 7

Preparation of 6-{[6-(3,5-difluorophenyl)-8-fluoroimidazo[l,2-a]pyridin-3-yl]methyl}quinoline

(DC381104)

Compound DC381104 was prepared in the same manner as in Example 4 except that the 1-methylimidazole-4-boronic acid pinacol ester was replaced with 3,5-difluorophenylboronic acid in a yield of 86.90%. 1H NMR (400 MHz, CDC1 ₃ ) 5 8.95 (d, J = 2.8, 1H), 8.17 (d, J = 8.8, 1H), 8.13 (d, J = 8, 1H), 7.827 (s, 1H),

7.69-7.65 (m, 2H), 7.64(s, 1H), 4.47(dd, J=4.0, 8.0, 1H), 7.15(dd, J=1.2, 11.2, 1H ), 6.94(t, J=2.0, lH), 6.92 (t, J = 2.8, 1H), 6.87-6.82 (m, 1H), 4.54 (s, 2H).

Example 8

Step 1: Preparation of 3-trifluoromethyl-2-amino-5-bromopyridine

The reaction was carried out in the same manner as in Example 2 except that 2-trifluoromethyl-2-aminopyridine was substituted for 2-amino-3-fluoropyridine. 1, v/v) separation, yield 71.30%. 1H NM (400 MHz, CDC1 ₃ ) δ 8.30 (s, 1Η), 6.80 (s, lH), 4.76 (s, 2H).

Step 2: Preparation of 6-({6-bromo-8-trifluoromethylimidazo[l,2-a]pyridin-3-yl}methyl)quinoline except 3-trifluoromethyl-2-amino The reaction was carried out in the same manner as in Example 3 except that -5-bromopyridine was replaced with 2-amino-5-bromo-3-fluoropyridine, and the column was separated by rapid separation (dichloromethane/methanol 20/1, v /v) Separation and purification, yield 28.84% o MS (ESI, m/z): 406 (M + H)" o

Step 3: Preparation of 6-{[6-(l-methyl-1H-pyrazol-4-yl)-8-trifluoromethylimidazo[l,2-a]pyridin-3-yl]methyl} Quinoline (DC381105)

In addition to replacing 6-({6-bromo-8-fluoroimidazolium) with 6-({6-bromo-8-trifluoromethylimidazo[l,2-a]pyridin-3-yl}methyl)quinoline Compound DC381105 was obtained in the same manner as in Example 4 except for [l,2-a]pyridin-3-yl}methyl)quinoline in a yield of 21.19%. 1H NM (400 MHz, CDC1 ₃ ) δ 8.93 (dd, J= 1.6, 4.4, 1H), 8.13 (d, J=8.8, 1H), 8.10 (d, J=3.6, 1H), 7.99 (s, 1H) ), 7.70(s, 1H), 7.66 (dd, J=2.0, 8.8, 1H), 7.64(s, 1H), 7.60 (br, 2H), 7.54(s, 1H), 7.44(dd, J=4.0, 8.0, 1H), 4.53 (s, 2H), 3.95 (s, 3H).

Example

Step Preparation 4-Trifluoromethyl-2-amino-5-bromopyridine

The reaction was carried out in the same manner as in Example 2 except that 2-amino-3-fluoropyridine was replaced with 4-trifluoromethyl-2-aminopyridine by column chromatography (petroleum ether/ethyl acetate 1) /1, v/v) isolated, yield 58.70%. MS (ESI, m/z): 241 (M + H) ⁺ .

Step Preparation of 6-({6-bromo-7-trifluoromethylimidazo[l,2-a]pyridin-3-yl}methyl)quinoline except 4-trifluoromethyl-2-amino-5 The reaction was carried out in the same manner as in Example 3 except that the bromopyridine was replaced with 2-amino-5-bromo-3-fluoropyridine, and the column was separated by rapid separation (dichloromethane/methanol 20/1, v/v Isolated and purified, the yield was 23.71%. 1H NM (400 MHz, CDC1 ₃ ) δ 8.95 (s, 1Η), 8.17-8.09 (m, 5H), 7.62 (dd, J=1.6, 8.4, 1H), 7.58 (s, 1H), 7.46 (dd, J=4.0, 8.4, 1H), 4.49 (s, 2H

Step: Preparation of 6-{[6-(l-methyl-1H-pyrazol-4-yl)-7-trifluoromethylimidazo[l,2-a]pyridin-3-yl]methyl}quin Porphyrin (DC381106)

In addition to replacing 6-({6-bromo-8-fluoroimidazolium) with 6-({6-bromo-7-trifluoromethylimidazo[l,2-a]pyridin-3-yl}methyl)quinoline Compound DC381106 was obtained in the same manner as in Example 4 except for [l,2-a]pyridin-3-yl}methyl)quinoline in a yield of 41.98%. 1H NM (400 MHz, CDC1 ₃ ) δ 8.93 (dd, J= 1.6, 4.4, 1H), 8.18 (s, 1H), 8.13-8.09 (m, 2H), 7.78 (s, 1H), 7.74 (s, 1H), 7.60-7.58 (m, 2H), 7.43 (dd, J=4.0, 8.0, 1H), 7.41 (s, 1H), 7.38 (s. 1H), 4.48 (s, 2H), 3.93 (s, 3H

Example

Step Preparation 2-Amino-5-bromo-3-chloropyridine

The reaction was carried out in the same manner as in Example 2 except that 2-amino-3-chloropyridine was substituted for 2-amino-3-chloropyridine, and purified by column chromatography ( petroleum ether/ethyl acetate l/l, v/ v) Separation, yield 96.18%. MS (ESI, m/z): 207 (M + H) ⁺ .

Step 6-({6-Bromo-8-chloroimidazo[l,2-a]pyridin-3-yl}methyl)quinoline

The reaction was carried out in the same manner as in Example 3 except that 2-amino-5-bromo-3-chloropyridine was substituted for 2-amino-5-bromo-3-fluoropyridine. The yield was 23.58%. MS (ESI, m/z): 372 (M+H) ⁺ .

Step Preparation of 6-{[8-chloro-6-(l-methyl-1H-pyrazol-4-yl)imidazo[l,2-a]pyridin-3-yl]methyl}quinoline (DC381107) In addition to 6-({6-bromo-8-chloroimidazo[l,2-a]pyridin-3-yl}methyl)quinoline, 6-({6-bromo-8-fluoroimidazo[1, Compound DC381107 was prepared in the same manner as in Example 4 except for 2-a]pyridin-3-yl}methyl)quinoline in a yield of 61.47%. 1H NM (400 MHz, CDC1 ₃ ) δ 8.90 (dd, J= 1.6, 4.0, 1Η), 8.10 (d, J=8.8, 1Η), 8.07 (d, J=8.0, 1H), 7.78 (d, J =1.6, 1H), 7.63 (dd, J=1.6, 8.4, 1H), 7.58(s, 1H), 7.56(br, 2H), 7.49 (s, 1H), 7.40 (dd, J=4.4, 8.4, 1H), 7.37 (d, J = 1.6, 1H), 4.47 (s, 2H), 3.92 (s, 3H).

Example 11

Step 1: Preparation of 2-amino-5-bromo-4-chloropyridine

The reaction was carried out in the same manner as in Example 2 except that 2-amino-4-chloropyridine was substituted for 2-amino-3-chloropyridine, and purified by column chromatography ( petroleum ether/ethyl acetate l/l, v/ v) Separation, yield 77.98%. MS (ESI, m/z): 207 (M+H) ⁺ .

Step 2: Preparation of 6-({6-bromo-7-chloroimidazo[l,2-a]pyridin-3-yl}methyl)quinoline

The reaction was carried out in the same manner as in Example 3 except that 2-amino-5-bromo-4-chloropyridine was substituted for 2-amino-5-bromo-3-fluoropyridine, and the yield was 28.88%. 1H NMR (400 MHz, CDCl ₃ ) 5 8.94 (d, J = 2.8, 1H), 8.15 (d, J = 8.8, 1H), 8.12 (d, J = 8.8, 1H), 8.08 (s, 1H), 7.86 (s, 1H), 7.63 (dd, J= 2.0, 8.8, 1H), 7.58 (br, 2H), 7.46 (dd, J=4.4, 8.4, 1H), 4.45 (s, 2H).

Step 3: Preparation of 6-{[7-chloro-6-(l-methyl-1H-pyrazol-4-yl)imidazo[l,2-a]pyridin-3-yl]methyl}quinoline ( DC381108)

In addition to 6-({6-bromo-7-chloroimidazo[l,2-a]pyridin-3-yl}methyl)quinoline, 6-({6-bromo-8-fluoroimidazo[1, Compound DC381108 was obtained in the same manner as in Example 4 except for 2-a]pyridin-3-yl}methyl)quinoline, yield 49.84%. 1H NM (300 MHz, CDCl ₃ ) δ 8.92 (dd J = 0.6, 3.9, 1H), 8.12-8.07 (m, 2H), 7.86 (s, 1H), 7.80 (s, 1H), 7.63-7.56 (m , 4H), 7.50 (s, 1H), 7.43 (dd, J= 3.9, 8.4, 1H), 4.47 (s, 2H), 3.94 (s, 3H).

Example 12

Step 1: Preparation of 2-amino-5-bromo-3-cyanopyridine

The reaction was carried out in the same manner as in Example 2 except that 2-amino-3-cyanopyridine was replaced with 2-amino-3-cyanopyridine. The solid was precipitated, suction filtered, and the filter cake was washed with EA. product. MS (ESI, m/z): 198 (M+H) ⁺ .

Step 2: Preparation of 6-({6-bromo-8-cyanoimidazo[l,2-a]pyridin-3-yl}methyl)quinoline

The reaction was carried out in the same manner as in Example 3 except that 2-amino-5-bromo-3-cyanopyridine was substituted for 2-amino-5-bromo-3-fluoropyridine, and the yield was 84.22%. MS (ESI, m/z): 363 (M + H) ⁺ . Step 3: Preparation of 6-{[8-cyano-6-(1-methyl-1H-pyrazol-4-yl)imidazo[l,2-a]pyridin-3-yl]methyl}quinoline (DC381109)

In addition to 6-({6-bromo-8-cyanoimidazo[l,2-a]pyridin-3-yl}methyl)quinoline, 6-({6-bromo-8-fluoroimidazo[1] Compound DC381109 was obtained in the same manner as in Example 4 except for 2-a]pyridin-3-yl}methyl)quinoline. Yield: 21.93%. 1H NM (400 MHz, DMSO) δ 8.90 (d, J = 0.8, 1H), 8.87 (dd, J=2, 4.4, 1H), 8.32-8.31 (br, 2H), 8.28 (s, 1H), 8.02 (br, 2H), 7.87 (d, J = 1.6, 1H), 7.75 (dd, J=2.4, 8.8, 1H), 7.55(s, 1H), 7.50 (dd, J=4.4, 8.4, 1H), 4.63

Example 13

Step 1: Preparation of 2-amino-5-bromo-4-cyanopyridine

The reaction was carried out in the same manner as in Example 2 except that 2-amino-4-cyanopyridine was substituted for 2-amino-3-fluoropyridine, and purified by column chromatography ( petroleum ether/ethyl acetate 1/1, v /v) Separation, yield 84.35%. MS (ESI, m/z): 198 (M+H) ⁺ .

Step 2: Preparation of 6-({6-bromo-7-cyanoimidazo[l,2-a]pyridin-3-yl}methyl)quinoline

The reaction was carried out in the same manner as in Example 3 except that 2-amino-5-bromo-4-cyanopyridine was substituted for 2-amino-5-bromo-3-fluoropyridine, and the yield was 32.66%. MS (ESI, m/z): 363 (M+H) ⁺ .

Step 3: Preparation of 6-{[7-cyano-6-(l-methyl-1H-pyrazol-4-yl)imidazo[l,2-a]pyridin-3-yl]methyl}quinoline (DC381110)

In addition to 6-({6-bromo-7-cyanoimidazo[l,2-a]pyridin-3-yl}methyl)quinoline, 6-({6-bromo-8-fluoroimidazo[1] Compound DC381110 was obtained in the same manner as in Example 4 except for 2-a]pyridin-3-yl}methyl)quinoline, yield 91.92%. 1H NMR (400 MHz, DMSO) δ 8.87 (dd, J = 1.6, 4.0, 1H), 8.60 (s, 1H), 8.46 (s, 1H), 8.31 (d, J = 7.2, 1H), 8.14 (s , 1H), 8.00 (d, J= 8.4, 1H), 7.86 (d, J= 1.2, 1H), 7.83 (s,lH), 7.75-7.72 (m, 2H), 7.52 (dd, J=4.4, 8.4, 1H) 4.64 (s, 2H), 3.93 (s, 3H).

Example 14

Reaction formula 5

Step 1: Preparation of 3-[8-fluoro-3-(quinolin-6-ylmethyl)imidazo[l,2-a]pyridin-6-yl]benzoic acid methyl ester except 3-methoxycarbonylbenzene The reaction was carried out in the same manner as in Example 4 except that the boronic acid was replaced with 1-methylimidazole-4-boronic acid pinacol ester, and the yield was 90.90%. 1H NMR (400 MHz, CDC1 ₃ ) δ 8.91-8.90 (m, 1 Η), 814-8.10 (m, 3 Η), 8.05-8.02 (m, 1H), 7.89 (d, J=1.6, 1H), 7.68- 7.63 (m, 2H), 7.61-7.57 (m, 2H), 7.51-7.47 (m, 1H), 7.43-7.40 (m, 1H), 7.18 (dd, J=1.6, 11.2, 1H), 4.52 (s , 2H), 3.94 (s, 3H).

Step 2: Preparation of 3-[8-fluoro-3-(quinolin-6-ylmethyl)imidazo[l,2-a]pyridin-6-yl]benzoic acid 3-[8-fluoro-3- (Quinoline-6-ylmethyl) imidazo[l,2-a]pyridin-6-yl]benzoic acid methyl ester (100 mg, 243.06 μιηο1) was dispersed in 12 ml of tetrahydrofuran/methanol/water (1/2/1, To ν/ν/ν), lithium hydroxide monohydrate (51 mg, 1.22 mmol) was added and stirred at room temperature. No raw materials were detected by TLC. EA and a small amount of water were added to the reaction solution for extraction. The aqueous layer was taken, and potassium hydrogen sulfate was added to adjust the pH to precipitate a gray solid. MS (ESI, m/z): 397 (M+H) ⁺ .

Step 3: Preparation of N-methyl-3-[8-fluoro-3-(quinolin-6-ylmethyl)imidazo[l,2-a]pyridin-6-yl]benzamide (DC381111)

Disperse 3-[8-fluoro-3-(quinolin-6-ylmethyl)imidazo[l,2-a]pyridin-6-yl]benzoic acid (80 mg, 201.31 μιηο1) in DMF on ice DIPEA (39.31 L, 221.44 μιηο1), HATU (84.20 mg, 221.44 μιηο1), and a solution of methylamine in tetrahydrofuran (131 μΙ^, 261·70 μιηο1) were added to the mixture and the mixture was transferred to room temperature. The reaction of the starting material to TLC was completed, and 60 mL of dichloromethane was added to the reaction solution, and 30 mL of a saturated sodium carbonate solution was extracted. The organic phase was washed with 3x40 mL saturated sodium carbonate solution, saturated brine, dried over anhydrous N SO _4, filtered, and the solvent was distilled off under reduced pressure, purified by flash column chromatography separation (of dichloromethane / methanol 20 / l, v / v) Separation and purification of 42 mg of a white solid in a yield of 50.83%. 1H NMR (400 MHz, CDC1 ₃ ) δ 8.90 (dd, J = 1.6, 4.0, 1H), 8.13-8.09 (m, 2H), 7.91 (s, 1H), 7.87 (d, J = 0.8, 1H), 7.71 (d, J=7.2, 1H), 7.64 (dd, J=2.0, 8.8, 1H), 7.61 (s, 1H), 7.55 (s, 1H), 7.51-7.44 (m, 2H), 7.42 (dd, J=4.4, 8.4, 1H), 7.15 (dd, J

(s, 1H), 4.49 (s, 2H), 3.04 (d, J=4.8, 3H).

Example 15

Reaction formula 6

Step 1: Preparation of 2-fluoro-4-[8-fluoro-3-(quinolin-6-ylmethyl)imidazo[l,2-a]pyridin-6-yl]benzoic acid methyl ester

6-({6-Bromo-8-fluoroimidazo[l,2-a]pyridin-3-yl}methyl)quinoline (95 mg, 266.7 Ιμιηοΐ), 3-fluoro-4-methoxycarbonylbenzeneboronic acid (57.15 mg, 280.05 μιηο1) was dissolved in 2.13 mL of DMF, and 1 M Na ₂ CO ₃ (533 L, 533.42 μιηο1) solution was added, and [1, bis-bis(diphenylphosphino)ferrocene]palladium dichloride was added. The chloroformin complex (10.89 mg, 13.34 μιηο1) was reacted at 80 ° C under argon atmosphere, and the reaction of the starting material was completely detected by TLC. EA 60 mL and 30 mL of water were added to the mixture. The organic phase was washed successively with 3×40 mL of water and brine, dried over anhydrous Na ₂ SO ₄ , filtered, and evaporated under reduced pressure and purified by column chromatography (dichloromethane/methanol 20/1, v/v) The pale yellow solid was isolated and purified to give a yield of 74.22%. 1H NM (400 MHz, CDC1 ₃ ) δ 8.91 (dd, J= 1.2, 4, 1Η), 8.16-8.08 (m, 3H), 7.86 (d, J = 1.2, 1H), 7.65-7.62 (m, 2H) ), 7.60 (s, 1H), 7.43 (dd, J = 4.4, 8.4, 1H ), 7.30-7.27 (m, J = 1H), 7.16 (s, 1H ), 7.13 (s, 1H), 6.80 (dd , J=4.8, 11.6, 1H), 4.53 (s, 2H), 3.05 (d

Step 2: Preparation of 2-fluoro-4-[8-fluoro-3-(quinolin-6-ylmethyl)imidazo[l,2-a]pyridine-6-yl]benzoic acid

Disperse 2-fluoro-4-[8-fluoro-3-(quinolin-6-ylmethyl)imidazo[l,2-a]pyridin-6-yl]benzoic acid methyl ester (85 mg, 197.94 μιηο1) Add 12 ml of tetrahydrofuran / methanol / water (1/2 / 1 ^ /, add lithium hydroxide monohydrate (41.53η3⁄4, 989.71μιηο1), stir at room temperature. No raw materials are detected by TLC, add to the reaction solution The EA and a small amount of water were extracted, and the aqueous layer was taken. The pH was adjusted to be acidic with concentrated HC1, and a white solid (35 mg) was obtained, yield 42.57%. MS (ESI, m/z): 415 (M+H) ⁺ .

Example 16

Reaction formula 7

Preparation of N-methyl-2-fluoro-4-[8-fluoro-3-(quinolin-6-ylmethyl)imidazo[l,2-a]pyridin-6-yl]benzamide (DC381112)

2-Fluoro-4-[8-fluoro-3-(quinolin-6-ylmethyl)imidazo[l,2-a]pyridin-6-yl]benzoic acid

(35η3⁄4, 84.26μιηο1) was dispersed in DMF, and DIPEA (16.45 L, 92.68μιηο1), HATU (35.24mg, 92.68μιηο1), 2Μ methylamine in tetrahydrofuran solution (54·77μΙ^, 109.54μιηο1), Move to room temperature for reaction. The reaction of the starting material to TLC was completed, and 60 ml of dichloromethane was added to the reaction solution, and 30 ml of a saturated sodium carbonate solution was extracted. The organic phase was washed successively with 3×40 mL of saturated sodium carbonate solution and saturated brine, dried over anhydrous NaSO ₄ and filtered, and then evaporated under reduced pressure. The solvent was separated by column chromatography (dichloromethane/methanol 20/1, v/ v) 26 mg of a yellow solid was isolated and purified in a yield of 72.02%. 1H NM (400 MHz, CDC1 ₃ ) 5 8.91 (dd, J= 1.2, 4.0, 1H), 8.16-8.08 (m, 3H), 7.86 (d, J=1.2, 1H), 7.65-7.60 (m, 3H ), 7.42 (dd, J=4.4, 8.4, 1H), 7.30-7.27 (m, 1H), 7.16 (s, 1H), 7.13 (s, 1H), 6.79 (dd, J=4.4, 11.2, 1H) , 4.53 (s, 2H), 3.05 (d, J = 4.8, 3H).

Example 17

Preparation of 2-fluoro-N-[2-(piperidin-1-yl)ethyl]-4-[8-fluoro-3-(quinolin-6-ylmethyl)imidazo[1,2-a] Pyridine-6-yl]benzamide (DC381113)

Compound DC381 1 13 was obtained in the same manner as in Example 16 except that N-(2-aminoethyl)piperidine was used instead of 2M methylamine in tetrahydrofuran, yield of 90.10%.

Example 18

Preparation of 2-fluoro-N-[2-(morpholin-4-yl)ethyl]-4-[8-fluoro-3-(quinolin-6-ylmethyl)imidazo[1,2-a] Pyridine-6-yl]benzamide (DC381114)

Compound DC381114 was obtained in the same manner as in Example 16 except that N-(2-aminoethyl) morpholine was used to replace 2M methylamine in tetrahydrofuran, yield 91.34%. 1H NMR (400 MHz, CDC1 ₃ ) 5 8.94 - 8.81 (m, 1H), 8.09 (dd, J = 19.1 , 9.6 Hz, 3H), 7.83 (s, 1H), 7.67 - 7.53 (m, 3H), 7.53 - 7.33 (m, 2H), 7.33 - 7.18 (m, 1H), 7.18 - 7.02 (m, 2H), 4.49 (s, 2H), 3.81 - 3.61 (t, 4H), 3.57 (d, J = 5.2 Hz, 2H), 2.60 (t, J = 6.0 Hz, 2H), 2.51 (t, 4H).

Example 19

Preparation of 2-fluoro-N-[2-(diethylamino)ethyl]-4-[8-fluoro-3-(quinolin-6-ylmethyl)imidazo[1,2-a]pyridine- 6-yl]benzamide (DC381115)

Compound DC381115 was obtained in the same manner as in Example 16 except that a solution of 2M methylamine in tetrahydrofuran was replaced with N,N-diethylethylenediamine. The yield was 88.97%. 1H NMR (400 MHz, CDC1 ₃ ) δ 8.89 (dd, J = 4.2, 1.7 Hz, 1H), 8.09 (dt, J = 9.9, 6.5 Hz, 3H), 7.83 (d, J = 1.4 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.61 - 7.57 (m, 3H), 7.40 (dd, J= 8.2, 4.3 Hz, 1H), 7.25 (dd, J= 8.1, 1.8 Hz, 2H), 7.14 (d, J = 0.9 Hz, 1H), 7.11 (t, J = 1.8 Hz, 1H) 4.50 (s, 2H), 3.55 (dd, J = 10.7, 5.2 Hz, 2H), 2.70 (t, J = 5.9 Hz, 2H), 2.61 (q, J = 7.2 Hz, 4H), 1.06 (t, J = 7.1 Hz, 6H).

Example 20

Preparation of 2-fluoro-N-[2-(dimethylamino)ethyl]-4-[8-fluoro-3-(quinolin-6-ylmethyl)imidazo[1,2-a]pyridine- 6-yl]benzamide (DC381116)

Compound DC381116 was obtained in the same manner as in Example 16 except that N,N-dimethylethylenediamine was used instead of 2M methylamine in tetrahydrofuran, yield 90.69%. 1H NMR (400 MHz, CD3OD) δ 8.79 (s, 1H), 8.41 - 8.23 (m, 2H), 7.99 (d, J = 8.5 Hz, 1H), 7.88 - 7.66 (m, 3H), 7.54 - 7.40 ( m, 5H), 5.48 (s, 1H), 4.60 (s, 2H), 3.57 (t, J = 6.6 Hz, 2H), 2.70 (t, J = 6.6 Hz, 2H), 2.42 (s, 6H).

Example 21

Preparation of 6-[(8-fluoro-6-{3-fluoro-4-[(morpholin-4-yl)carbonyl]phenyl}imidazo[l,2-a]pyridin-3-yl)methyl] Quinoline (DC381117)

Compound DC381117 was prepared in the same manner as in Example 16 except that the morpholine was used to replace the 2M methylamine in tetrahydrofuran, yield 56.59%. 1H NMR (400 MHz, CDC1 ₃ ) δ 8.89 (d, J = 3.9 Hz, 1H), 8.09 (t, J = 8.8 Hz, 2H), 7.78 (s, 1H), 7.64 - 7.56 (m, 3H), 7.46 - 7.37 (m, 2H), 7.21 (dd, J= 8.0, 1.2 Hz, 1H), 7.11 (dd, J= 5.5, 2.5 Hz, 1H), 7.10 - 7.07 (m, 1H), 4.49 (s, 2H), 3.84 - 3.73 (m, 4H), 3.66 - 3.59 (m, 2H), 3.33 (s, 2H).

Example 22

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98C0.0/CT0ZN3/X3d 9ζε.οΐ/ειοζ OAV Compound DC381126 was obtained in the same manner as in Example 16 except that 3-amino-1-diphenylmethylazetidinium was substituted for a solution of 2M methylamine in tetrahydrofuran. The yield was 78.11%. MS (ESI, m/z): 636 (M + H) ⁺ .

Example 31

Preparation of N-[(5-fluoropyridin-3-yl)methyl]-2-fluoro-4-[8-fluoro-3-(quinolin-6-ylmethyl)imidazo[1,2-a] Pyridine-6-yl]benzamide (DC381127)

Compound DC381127 was obtained in the same manner as in Example 16 except that (5-fluoropyridin-3-yl)methylamine was used to replace 2M methylamine in tetrahydrofuran. MS (ESI, m/z): 524 (M + H) ⁺ .

Example 32

Preparation of N-(tetrahydrofuran-3-yl)-2-fluoro-4-[8-fluoro-3-(quinolin-6-ylmethyl)imidazo[l,2-a]pyridin-6-yl]benzene Formamide (DC381128)

Compound DC381128 was prepared in the same manner as in Example 16 except that a solution of 2M-methylamine in tetrahydrofuran was replaced with 3-aminotetrahydrofuran, yield 75.64%. MS (ESI, m/z): 495 (M + H) ⁺ .

Example 33

Preparation of N-(oxetanyl-3-methylene)-2-fluoro-4-[8-fluoro-3-(quinolin-6-ylmethyl)imidazole

[l,2-a]pyridine-6-yl]benzamide (DC381129)

Compound DC381129 was prepared in the same manner as in Example 16 except that a solution of 2M methylamine in tetrahydrofuran was replaced by 3-aminomethyl oxetane. The yield was 63.47%. MS (ESI, m/z): 495 (M + H) ⁺ .

Example 34

Step 1: N-(N-tert-Butoxycarbonylpiperidin-2-ylmethylene)-2-fluoro-4-[8-fluoro-3-(quinolin-6-ylmethyl)imidazo[l ,2-a]pyridin-6-yl]benzamide

The reaction was carried out in the same manner as in Example 16 except that 1-t-butoxycarbonyl-2-aminomethylpiperidine was used to replace the 2M methylamine in tetrahydrofuran, yield 77.21%. MS (ESI, m/z): 612 (M + H. Step 2: Preparation of N-(piperidin-2-ylmethylene)-2-fluoro-4-[8-fluoro-3- (quinoline- 6-ylmethyl)imidazo[l,2-a]pyridin-6-yl]benzamide (DC381130)

The resultant product of step a was dissolved in 2ml CH _₂ C1 _2, was added dropwise TFA 0.5 mL was stirred at room temperature 1 h, the reaction mixture was evaporated to dryness, the residue was taken up with _{_{CH 2 Cl 2 / MeOH (10}} / l, v / v), washed with saturated sodium bicarbonate solution, the aqueous phase was re-extracted, the organic layer was combined CH _₂ C1 _2, dried over anhydrous Na ₂ SO ₄ dried, filtered, and the solvent was distilled off under reduced pressure, to give compound DC381130, 80% yield. MS (ESI, m/z): 512 (M + H) ⁺ o

Example 35 Step 1: Preparation of N-(N-tert-Butoxycarbonylpiperidin-3-yl)-2-fluoro-4-[8-fluoro-3-(quinolin-6-ylmethyl)imidazo[1,2 -a]pyridine-6-yl]benzamide

The reaction was carried out in the same manner as in Example 16 except that N-tert-butoxycarbonyl-3-aminopiperidine was used to replace the 2M methylamine in tetrahydrofuran, and the yield was 80.05%. MS (ESI, m/z): 598 (M + H) ⁺ ₀ Step 2: Preparation of N-(piperidin-3-yl)-2-fluoro-4-[8-fluoro-3- (quinolin-6 -ylmethyl)imidazo[l,2-a]pyridin-6-yl]benzamide (DC381131)

The resultant product of step a was dissolved in 2ml CH _₂ C1 _2, was added dropwise TFA 0.5 mL was stirred at room temperature 1 h, the reaction mixture was evaporated to dryness, the residue was taken up with _{_{CH 2 Cl 2 / MeOH (10}} / l, v / v), washed with saturated sodium bicarbonate solution, the aqueous phase was re-extracted, the organic layer was combined CH _₂ C1 _2, dried over anhydrous Na ₂ SO ₄ dried, filtered, and the solvent was distilled off under reduced pressure, to give compound DC381131, 80% yield. MS (ESI, m/z): 498 (M + H) ⁺ o

Example 36

Preparation of N-[(l-ethylpyrrole-2-yl)methyl]-2-fluoro-4-[8-fluoro-3-(quinolin-6-ylmethyl)imidazo[1,2- a] Pyridin-6-yl]benzamide (DC381132)

Compound DC381132 was obtained in the same manner as in Example 16 except that 2-(aminomethyl)-l-ethylpyrrole was used to replace 2M methylamine in tetrahydrofuran, yield 56.84%. MS (ESI, m/z):

Example 37

Step 1: Preparation of 2-chloro-3-(l,3-benzothiazol-6-yl)propanal

The reaction was carried out in the same manner as in Example 1 except that 6-bromobenzothiazole was replaced with 6-bromobenzothiazole, and the yield was 43.37%. MS (ESI, m/z): 226 (M+H).

Step 2: Preparation of 6-({6-bromo-8-fluoroimidazo[l,2-a]pyridin-3-yl}methyl)-1,3-benzothiazole except 2-chloro-3-( The 1,3-benzothiazol-6-yl)propanal was replaced with 2-chloro-3-(quinolin-6-yl)propanal, and the reaction was carried out in the same manner as in Example 3 in a yield of 21.80%. MS (ESI, m/z): 362 (M + H) ⁺ .

Step 3: Preparation of 2-fluoro-4-[8-fluoro-3-(l,3-benzothiazol-6-ylmethyl)imidazo[l,2-a]pyridine-6-yl]benzoic acid

In addition to replacing 6-({6-bromo-8-) with 6-({6-bromo-8-fluoroimidazo[l,2-a]pyridin-3-yl}methyl)-1,3-benzothiazole The fluoroimidazo[l,2-a]pyridin-3-yl}methyl)quinoline was reacted in the same manner as in Example 15 in a yield of 70.28%. MS (ESI, m/z): 421 (M+H) ⁺ .

Step 4: Preparation of N-methyl-2-fluoro-4-[3-(1,3-benzothiazol-6-ylmethyl)imidazo[l,2-a]pyridin-6-yl]benzamide Amide (DC381133)

Replace 2- with 2-fluoro-4-[8-fluoro-3-(1,3-benzothiazol-6-ylmethyl)imidazo[l,2-a]pyridin-6-yl]benzoic acid Fluoro-4-[8-fluoro-3-(quinolin-6-ylmethyl)imidazo[l,2-a]pyridin-6-yl]benzoic acid Compound DC381133 was prepared in the same manner as in Example 16 in a yield of 78.92%. MS (ESI, m/z): 435

(M -i-H.

Example 38

Step 1: Preparation of 6-({8-fluoro-6-[1-(indolyl-tert-butoxycarbonylpiperidin-4-yl)-1H-pyrazol-4-yl]imidazo[1,2-a] Pyridin-3-yl}methyl)quinoline

The reaction was carried out in the same manner as in Example 4 except that the 1-methyl-4-pyrazoleboronic acid pinacol ester was replaced with N-tert-butoxycarbonyl-4-pyrazoleboronic acid pinacol ester. 65.1%. MS (ESI, /z): 527 (M

+H) ⁺ .

Step 2: Preparation of 6-({8-fluoro-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]imidazo[l,2-a]pyridin-3-yl} Methyl)quinoline (DC381134)

6-({8-Fluoro-6-[1-(Ν-tert-butoxycarbonylpiperidin-4-yl)-1H-pyrazol-4-yl]imidazo[1,2-a] obtained in the above step pyridin-3-yl} methyl) quinoline (30.00mg, 56.97μιηο1) was dissolved in 2ml CH _₂ C1 _2, was added dropwise TFA 0.5 mL LH stirred at room temperature, the reaction solution was evaporated to dryness, the residue was treated with CH _₂ Cl ₂ / MeOH (10 / l, v / v) was dissolved, washed with saturated sodium bicarbonate solution, the organic layer the aqueous phase was extracted with CH _₂ C1 _2, was combined, dried over anhydrous Na ₂ SO _4, filtered, and the solvent was distilled off under reduced pressure , the yield is 80%. MS (ESI, m/z): 627 (M+H) ⁺ .

Example 39

Preparation of 6-[(8-fluoro-6-{4-[2-oxo-2-(piperazin-4-yl)ethoxy]phenylpyridazolo[1,2-a]pyridine-3 -yl)methyl]quinoline (DC381135)

In addition to tert-butyl (2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)phenoxy)acetyl)piperazine Compound DC381135 was prepared in the same manner as in Example 30, except for the N-tert-butoxycarbonyl-4-pyrazoleboronic acid pinacol ester. The yield was 76.23%. MS (ESI, m/z): 495 (M+H) ⁺ .

Example 40 Preparation of 5-[8-fluoro-3-(quinolin-6-ylmethyl)imidazo[l,2-a]pyridin-6-yl]-2,3-dihydro-1H-indole-2- Ketone (DC381136)

Compound DC381136 was prepared in the same manner as in Example 4 except that the 1-methyl-4-pyrazoleboronic acid pinacol ester was replaced with indole-2-one-5-boronic acid pinacol ester. The yield was 54.74. %. MS (ESI, m/z): 409 (M+H).

Example 40

Reaction formula 9

Step 1: Preparation of 6-bromo-8-fluoroimidazo[1,2-a]pyridine

2-Amino-3-fluoro-5-bromopyridine (500 mg, 2.62 mmol) and chloroacetaldehyde hydrate (863.40 L, 5.24 mmol) were dissolved in 5 mL of absolute ethanol, and stirred under microwave at 80 ° C for 50 minutes. The reaction solution was extracted with EA, washed with a saturated aqueous solution of sodium carbonate, and the organic layer was washed with saturated NaCI, dried over anhydrous Na ₂ SO ₄ and evaporated to dryness. , v/v ) The product was isolated and purified, 450 mg, yield 79.94%. MS (ESI, m/z): 215 (M + H) ⁺ o

Step 2: Preparation of 3-hydroxymethyl-6-bromo-8-fluoroimidazo[1,2-a]pyridine

The product obtained in the above step (450 mg, 2.09 mmol) was dissolved in EtOAc (EtOAc) (EtOAc) Reaction, TLC detection reaction, until the reaction is complete, adding saturated sodium carbonate to the reaction solution, extracting with EA, washing the organic layer with saturated NaCl, drying with anhydrous Na ₂ SO ₄ , evaporating the solvent, column chromatography (petroleum ether) /ethyl acetate 4/1, v/v) product was isolated and purified, yield 53.70%. MS (ESI, m/z): 245 (M+H) ⁺ .

Example 41

Reaction formula 10

Step 1 : Preparation of 4-({6-bromo-8-fluoroimidazo[l,2-a]pyridin-3-yl}methoxy)quinoline

3-Hydroxymethyl-6-bromo-8-fluoroimidazo[l,2-a]pyridine and 4-chloroquinoline were dissolved in mL DMSO, and cesium carbonate was added at room temperature, and the reaction was carried out in a microwave at 120 ° C. The reaction was stirred for two hours. After extracting with EA, the organic layer was washed with saturated NaCl, dried over anhydrous Na ₂ SO ₄ and evaporated to dryness, and then purified by column chromatography (dichloromethane/methanol 10/1, v/v). The rate is 40.50%. MS (ESI, m/z): 373 (M+H) ⁺ .

Step 2: Preparation of N-methyl-2-fluoro-4-{8-fluoro-3-[(quinolin-4-oxy)methyl]imidazo[l,2-a]pyridin-6-yl] Benzoylamide (DC381137)

In addition to 4-({6-bromo-8-fluoroimidazo[l,2-a]pyridin-3-yl}methoxy)quinoline, 6-({6-bromo-8-fluoroimidazo[1] , 2-a]pyridin-3-yl}methyl)quinoline, a compound was prepared in the same manner as in Example 14 except that 3-methoxy-4-methoxycarbonylbenzeneboronic acid was substituted for 3-methoxycarbonylbenzeneboronic acid. DC381137, the yield was 68.59%. MS (ESI, m/z): 445 (M+H) ⁺ .

Example 42

Reaction formula 11

Step 1: Preparation of 3-azidomethyl-6-bromo-8-fluoropyridine

3-Hydroxymethyl-6-bromo-8-fluoroimidazo[1,2-a]pyridine was dissolved in DMF, NaN _{3 was} added, and the mixture was stirred at room temperature overnight, and the reaction was completed by TLC, and EA 60 mL was added to the reaction mixture. 30 mL of water was extracted. The organic phase was washed successively with 3×40 mL of water and brine, dried over anhydrous Na ₂ SO ₄ , filtered, evaporated and evaporated. Yes, yield. MS (ESI, m/z): 271

(M + H)+.

Step 2: 3-Aminomethyl-6-bromo-8-fluoroimidazo[l,2-a]pyridine

The product obtained in the above step is dissolved in an ethanol-water mixed solvent, NH ₄ C1 is added, and zinc powder is added under stirring at room temperature, and the reaction is carried out at 80 ° C. The reaction is completely detected by TLC, and dichloromethane is added to the reaction flask. After filtration, the filtrate was evaporated to dryness. Water was added to the reaction mixture, and the mixture was washed with methylene chloride, washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated. MS (ESI, m/z): 245 (M + H) ⁺ . Step 3: Preparation of N-methyl-2-fluoro-4-(8-fluoro-3-{[(quinolin-4-yl)amino Methyl}imidazo[l,2-a]pyridin-6-yl]benzamide (DC381138)

Replacing 3-hydroxymethyl-6-bromo-8-fluoroimidazo[l,2-a]pyridine with 3-aminomethyl-6-bromo-8-fluoroimidazo[l,2-a]pyridine Further, Compound DC381138 was obtained in the same manner as in Example 41 in a yield of 20.45%. MS (ESI, m/z): 444 (M + H) ^;

Example 43

Preparation of 2-bromo-1-(quinolin-6-yl)ethanone

1-(Quinolin-6-yl)ethanone (200 mg, 1.17 mmol) was dissolved in hydrobromic acid/acetic acid solution, and bromine water (59.43 uL, 1.16 mmol) was slowly added dropwise with stirring at room temperature, and reacted at room temperature. The TLC was tested to be completely reacted, and a solid precipitated. After suction filtration, the cake was washed with diethyl ether to obtain 280 mg of the hydrobromide salt of the product, yield 72.40%.

MS (ESI, m/z): 332 (M + H) ¹ .

Example 44

Reaction formula 13

Step 1: N'-(3-Fluoro-5-bromo-pyridin-2-yl)-N,N-dimethylformamidine

2-Amino-3-fluoro-5-bromopyridine (505 mg, 2.64 mmol) was dissolved in 4 mL DMF-DMA at 100

! The mixture was stirred under reflux for 3 hours in an oil bath, and the reaction was completed by TLC. The mixture was extracted with EtOAc, washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , filtered, and evaporated in vacuo. . MS (ESI, m/z): 247 (M+H) ⁺ .

Step 2: 6-({6-Bromo-8-fluoroimidazo[l,2-a]pyridin-3-yl}carbonyl)quinoline

The product obtained in the above step (400 mg, 1.63 mmol) and 2-bromo-1-(quinolin-6-yl)ethanone (406.52 mg, 1.63 mmol) were dissolved in anhydrous ethanol and refluxed in an oil bath at 80 ° C. After stirring, the reaction was completed by TLC. After cooling to room temperature, solids were precipitated, and filtered to give 353 mg of crude product. The yield was 60.97%. MS (ESI,

Step 3: 6-{[8-Fluoro-6-(l-methyl-1H-pyrazol-4-yl)imidazo[l,2-a]pyridin-3-yl]carbonyl}quinoline

In addition to 6-({6-bromo-8-fluoroimidazo[l,2-a]pyridin-3-yl}carbonyl)quinoline, 6-({6-bromo-8-fluoroimidazo[1,2 The reaction was carried out in the same manner as in Example 4 except that -a]pyridin-3-yl}methyl)quinoline, yield 73.96%. MS (ESI, m/z): 372 (M+H. Step 4: Preparation of 6-{difluoro[8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)imidazo[l,2-a]pyridin-3-yl]methyl}quin Porphyrin (DC381139)

The product obtained in the above step was dissolved in dichloromethane, and protected with argon. Stirred in an ice bath at 0 ° C. DAST was taken out with a syringe and slowly poured into the reaction flask. After the addition, the mixture was stirred at room temperature until TLC. After the reaction was completed, the reaction mixture was poured into ice water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , filtered, and evaporated. /Methanol 10/1, v/v) The compound DC381139 was isolated and purified in a yield of 55.09%. MS (ESI, m/z): 394 (M + H) ⁺ .

Example 45

Preparation of N-methyl-2-fluoro-4-{8-fluoro-3-[difluoro(quinolin-6-yl)methyl]imidazo[l,2-a]pyridin-6-yl]benzamide Amide (DC381140)

Compound DC381140 was obtained in the same manner as in Example 43 except that 3-fluoro-4-methoxycarbonylbenzeneboronic acid was substituted for 1-methylimidazole-4-boronic acid pinacol ester. The yield was 45.68%. MS (ESI, m / z) : 465 (M + H) f.

Implementing rust 46

Step 1: Preparation of quinoline-6-yl acetonitrile

6-Bromoquinoline (10 g, 48 mmol), (9,9-dimethyl-9H-oxaindole-4,5-diyl)bis(diphenylphosphine) (558 mg, 1 mmol), Pd ₂ (dba) ₃ (833 mg, 1 mmol) was dissolved in 100 mL of DMF, and (trimethylsilyl) acetonitrile (8.2 mL, 60 mmol) was added with stirring, followed by the addition of zinc difluoride (3.5 g, 33.3 mmol). After argon gas protection, the reaction was stirred under an oil bath at 105 ° C for 20 h. Completion of the reaction, after cooling to room temperature, the reaction mixture was quenched with aqueous ammonia solution and extracted with EA, washed with water, brine, dried over anhydrous Na ₂ SO _4, filtered, and the solvent was distilled off under reduced pressure, the residue was purified by flash chromatography (petroleum ether Purification with ethyl acetate 2/1, v/v) gave product 5 g, yield 72%. MS (ESI, m/z): 169 (M+H) ⁺ .

Step 2: Preparation of 1-quinolin-6-ylcyclopropanacetonitrile

The 50% aqueous sodium hydroxide solution was added to the product obtained in the above step (4 g, 16.65 mmol) at 50 ° C, and chlorobromo-2-chloroacetone (5.5 mL, 66.25 mmol) and benzyltriethyl chloride. Mixture of ammonium (247.5 mg, 1.08 mmol). The reaction mixture was stirred at 50 ° C for 3 h. After cooling to room temperature, the reaction mixture was poured into 60 mL of dichloromethane, and extracted with dichloromethane, washed with saturated brine, dried over anhydrous Na ₂ SO ₄ and filtered. The solvent was evaporated under reduced pressure and the residue was purifiedjjjjjjjjjj Used directly in the next step.

Step 3: Preparation of 1-quinoline-6-ylcyclopropylformaldehyde

The product obtained in the above step (3.1 g, 15.98 mmol) was dissolved in toluene, and was then applied to hexanes, and the mixture was stirred at -78 °, and diisobutylaluminum hydride (1M/THF, 24 mL, 24 mmol) was added to the reaction mixture. In the middle, the temperature was raised to -5 ° C for 3 h. The reaction solution was cooled to -60 ° C, isopropyl alcohol (3 mL) was added dropwise, and after stirring for 30 min, the reaction mixture was warmed to 0. The reaction was quenched with EA reaction was diluted with water and extracted with EA, washed with water, brine, dried over anhydrous Na ₂ SO _4, filtered, and solvent was distilled off under reduced pressure, the residue was purified by column chromatography (petroleum ether / ethyl acetate 2 Purification with /1, v/v) gave product 3 g, yield 95.1%. MS (ESI, m/z): 198 (M+H) ⁺ .

Step 4: Preparation of 6-l-[(E 2-methoxyvinyl]cyclopropylquinoline

To a suspension of chloro(methoxymethyl)triphenylphosphorane (3 g, 10 mmol) in THF, THF (1 mL) After lh, the reaction solution was cooled to 0 ° C and a solution of 1-quinolin-6-ylcyclopropylcarbaldehyde (500 mg, 2.5 mmol) in THF was added. The reaction was stirred for lh at rt, extracted with EA, washed with water and saturated brine, dried over anhydrous Na ₂ SO _4, filtered, and the solvent was distilled off under reduced pressure, the residue was purified by column chromatography (petroleum ether / ethyl acetate 3/1, v /v) Purification gave the product 450 mg, yield 78.8%. MS (ESI, m/z): 226 (M+H).

Step 5: Preparation of 1-quinolin-6-ylcyclopropylacetaldehyde

The product of the above step (450 mg, 2 mmol) was dissolved in THF, and 3 mL of 10% HCl solution was added with stirring, and the mixture was stirred at room temperature for 2 h, then neutralized with saturated sodium hydrogen carbonate. EA was extracted with saturated brine, dried over anhydrous Na ₂ SO _4, filtered, and the solvent was evaporated under reduced pressure to give 410 mg of product, a yield of 97.2%.

MS (ESI, m/z): 212 (M + H) ⁺ . Used directly in the next step.

Step 6: Preparation of chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde

The above product (410 mg, 1.9 mmol) and D-valine (45 mg, 0.39 mmol) were dissolved in dichloromethane, and NCS (311 mg, 2.33 mmol) was added with stirring at 0 ° C, and the reaction was stirred for 1 h. The reaction was allowed to rise to room temperature, and the reaction was carried out by TLC. After the reaction was completed, the reaction was quenched with water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , filtered, and evaporated. Purification (petroleum ether / ethyl acetate 4/1, v/v) afforded product 320 mg, yield 67.1%. MS (ESI, m/z): 246 (M + H) ⁺ .

Implementation key 47

Reaction formula 15

Step 1: Preparation of 6-({6-bromo-8-fluoroimidazo[l,2-a]pyridin-3-yl}cyclopropylmethyl)quinoline in addition to chloro(1-quinoline-6- The reaction was carried out in the same manner as in Example 3 except that 2-cyclo-3-(quinolin-6-yl)propanal was replaced by acetaldehyde, and subjected to rapid separation column chromatography (dichloromethane/ Methanol 20/1, v/v) isolated and purified, yield 34.45% c MS (ESI, m/z): 383 (M -iH) ⁺ ₀

Step 2: Preparation of 2-fluoro-4-[8-fluoro-3-(quinolin-6-ylmethylcyclopropyl)imidazo[l,2-a]pyridine-6-yl: Benzoic acid

In addition to replacing 6-({6-bromo-8-fluoroimidazolium) with 6-({6-bromo-8-fluoroimidazo[l,2-a]pyridin-3-yl}cyclopropylmethyl)quinoline The reaction was carried out in the same manner as in Example 15 except for [l,2-a]pyridin-3-yl}methyl)quinoline. The total yield of the two steps was 50.28%. MS (ESI, m/z): 442 (M + H) ⁺ .

Step 3: N-Methyl-2-fluoro-4-[8-fluoro-3-(quinolin-6-ylmethylcyclopropyl)imidazo[l,2-a]pyridin-6-yl]benzene Formamide (DC381141)

In addition to 2-fluoro-4-[8-fluoro-3-(quinolin-6-ylmethylcyclopropyl)imidazo[l,2-a]pyridin-6-yl]benzoic acid instead of 2-fluoro- Compound DC381141 was prepared in the same manner as in Example 16 except for 4-[8-fluoro-3-(quinolin-6-ylmethyl)imidazo[l,2-a]pyridin-6-yl]benzoic acid. , the yield was 80.23%. MS (ESI, m/z): 455 (M + H) ⁺ .

Implementation 锕 48

Reaction formula 16

Step 1: Preparation of {6-bromo-8-fluoroimidazo[l,2-a]pyridin-3-yl Kquinolin-6-yl)methanol

6-({6-Bromo-8-fluoroimidazo[l,2-a]pyridin-3-yl}carbonyl)quinoline (350 mg, 0.95 mmol) was dissolved in 5 mL of methanol and NaBH was added to the ice bath. ₄ (72mg, 1.9mmol), the reaction with stirring until completion of the reaction, extracted with EA, washed with water, brine, dried over anhydrous Na ₂ SO _4, filtered, and the solvent was distilled off under reduced pressure, to give 320 mg of product, a yield of 90.93 %. MS (ESI, m/z): 373 (M+H) ⁺ .

Step 2: Preparation of 6-({6-bromo-fluoroimidazo[l,2-a]pyridin-3-yl K-fluoro)methyl)quinoline

The product obtained in the previous step (320 mg, 0.86 mmol) was dissolved in EtOAc (EtOAc), EtOAc (EtOAc) Slowly inject into the reaction flask, add, and stir at room temperature. After TLC detection, the reaction is complete. Pour the reaction solution into ice water, extract with dichloromethane, wash with saturated brine, dry with anhydrous Na ₂ SO ₄ , filter The solvent was evaporated under reduced pressure and purified by column chromatography (dichloromethane/methanol 20/1, v/v) to afford product 240 mg, yield: 74.6% MS (ESI, m/z): 375 (M +H)+.

Step 3: Preparation of 2-fluoro-4-{8-fluoro-3-[fluoro(quinolin-6-yl)methyl]imidazo[l,2-a]pyridine-6-yl}benzoic acid

In addition to 6-({6-bromo-fluoroimidazo[l,2-a]pyridin-3-yl-K-fluoro)methyl)quinoline, 6-({6-bromo-8-fluoroimidazo[1, The reaction was carried out in the same manner as in Example 15 except for 2-a]pyridin-3-yl}methyl)quinoline. The total yield in two steps was 56.43%.

Step 4: Preparation of N-methyl-2-fluoro-4-{8-fluoro-3-[fluoro(quinolin-6-yl)methyl]imidazo[l,2-a]pyridine-6-yl} Benzoylamide

Substituting 2-fluoro-4-{8-fluoro-3-[fluoro(quinolin-6-yl)methyl]imidazo[l,2-a]pyridin-6-yl}benzoic acid for 2-fluoro- The reaction was carried out in the same manner as in Example 16 except for 4-[8-fluoro-3-(quinolin-6-ylmethyl)imidazo[l,2-a]pyridin-6-yl]benzoic acid. The yield was 83.27%. MS (ESI, m/z): 447 (M + H) ⁺ . Preparation of N-methyl- ² -fluoro- ^4- {8-fluoro-3-[(S)-fluoro(quinolin-6-yl)methyl]imidazo[l, ^2-a ]pyridine-6- Benzoylamide (DC381142)

Example 48 The obtained compound was isolated by preparative HPLC. Separation conditions: Chiralpak IA chiral column (10 x 250 mm); flow rate: 6 mL/min; eluent: ethanol / hexane = 87/13.

Implement rust 50

Preparation of N-methyl-2-fluoro-4-{8-fluoro-3-[(R)-fluoro(quinolin-6-yl)methyl]imidazo[l,2-a]pyridine-6- Benzoylamide (DC381143)

Test example

Example 1: Molecular level receptor tyrosine kinase c-Met activity inhibition experiment

1, experimental methods

(1) Enzyme reaction substrate Poly(Glu, Tyr) _4:1 diluted with potassium-free PBS (10 mM sodium phosphate buffer, 150 mM NaCl, pH 7.2-7.4) to 20 g/ml, 125 μl/well coated enzyme The target plate was reacted at 37 ° C for 12-16 hours. Discard the liquid in the well. Plates were washed and washed three times with 200 μl/well of 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) 50 μM of ATP solution diluted with reaction buffer (50 mM HEPES pH 7.4, 50 mM MgCl ₂ , 0.5 mM MnCl ₂ , 0.2 mM Na ₃ VO ₄ , 1 mM DTT) was added to each well to a final concentration of 5 μM. 1 μM compound (1% DMSO dissolved in a final concentration of 10 μM) was added to each well, and 50 μl of the c-Met tyrosine kinase protein diluted with the reaction buffer was added. The reaction was carried out for 1 hour at 37 ° C on a shaker (100 rpm). For each experiment, two wells without ATP control wells and corresponding DMSO solvent control wells (negative control wells) were required. The liquid in the well was discarded and the plate was washed three times with T-PBS.

(3) The antibody PY99 ΙΟΟμΙ/well was added (the antibody was diluted with BSA 5 mg/ml in T-PBS at a concentration of 0.4 g/ml), and 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 ΙΟΟμΙ/well (antibody diluted with BSA 5 mg/ml T-PBS at a concentration of 0.5 g/ml) and shaken at 37 ° C for 0.5 hour . Discard the liquid in the well and wash the plate three times with T-PBS.

(5) Add 2mg/ml OPD chromogenic solution ΙΟΟμΙ/well (diluted with 0.1M citrate-sodium citrate buffer (ρΗ=5.4) containing 0·03% Η ₂ Ο ₂ ), protected from light at 25 °C The reaction is 1-10 minutes. (Ultrasound is required for the dissolution of OPD, and the coloring solution needs to be used now).

(6) Add 2M H ₂ SO ₄ 50μ1/well to stop the reaction, using a tunable wavelength microplate microplate reader The VERSAmax reading has a wavelength of 490 nm.

(7) The inhibition rate of the sample is obtained by the following formula:

Compound OD value - no enzyme control well OD value

Inhibition rate (%) -) χ 100

Negative control well OD value - no enzyme control well OD value

The screened compound c-Met inhibitory activity has a clear (compound 10- ⁵ Μ tyrosine kinase inhibition rate of c-Met receptor> 50%) dubbed a concentration gradient, for IC _5. Evaluation. The IC _{5 of the} inhibitory protein tyrosine kinase at the molecular level of each compound was calculated by a four-parameter method. Values, the results are listed in Table 1.

2, the experimental results

Table 1 shows the results of the biological test of the selected compounds of the invention, expressed as Ι(3 ₅ (μΜ).

Example 2: Effect of Compounds on TPR-Met Phosphorylation in BaF3/TPR-Met Cells

1, experimental methods

BaF3/TP-Met cells (without Met extracellular interference, the TPR-Met fusion protein in cells is expressed in the cytoplasm and can be continuously activated independently of HGF-like stimulation; BaF3 background cells need to be supplemented with IL-3 to proliferate Survival, but after introduction of TPR-Met, it became a Met-dependent sensitive cell line) inoculated in a 12-well plate (500,000/well), and cultured for 18-24 hours, and added to the molecular level to obtain a clear inhibition of c-Met activity. After the action of each compound (final concentration was ΙΟμΜ), the cells were collected 4 hours later. Wash once with cold PBS (containing 1 mM sodium vanadate); then add 85-100 ° C lxSDS gel loading buffer (50 mM Tris-HCl (pH 6.8), lOOmM DTT, 2% SDS, 10% Glycerin, 1 mM sodium vanadate, 0.1% bromophenol blue) lysate cells. The cell lysate was heated in a boiling water bath for 10 minutes at 4. Centrifuge at 12,000 rpm for 10 minutes. The supernatant was taken for SDS-PAGE electrophoresis (Mini-PROTEAN 3 Cell, Bio-ad, 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) (1:1000) or anti-GAPDH (Kangcheng Bio) (1:6000) antibody overnight at 4 °C. Wash three times with TBS containing 1 mM sodium vanadate for 15 min each. The membrane was placed in a secondary antibody solution for 1-2 hours at room temperature; after washing the membrane three times, it was color-developed with ECL (Picece, ockford, IL) reagent, tableted, and developed. The results of the biological activity test are shown in Figure 1.

2, the experimental results

The experimental results are shown in Figure 1.

Example 3: Effect of compounds on c-Met-mediated cell proliferation

1, experimental methods

In this example, two MET-dependent tumor cell lines were used: BaF3/TPR-Met cells (suspended cells, no Met extracellular interference, TPR-Met fusion protein expression in the cytoplasm, independent of HGF stimulation Continuous activation; BaF3 background cells need to be supplemented with IL-3 to proliferate, but after introduction of TPR-Met, become Met-dependent sensitive cell lines) and EBC-1 cells (adherent cells, non-small cell lung cancer cell lines, Μ Gene amplification results in sustained activation of Met, a Met-dependent cell line).

Growth inhibition assay of tumor cells staining of adherent cells and suspension cells using sulforhodamine B (SB) and microculture tetrozolium (MTT), respectively. The specific steps are as follows: Cells in logarithmic growth phase are inoculated to 96-well microplates at a suitable density (BaF3/TPR-Met, 8000/well; EBC-1, 5000/well) at 100 L per well, after overnight incubation. Compounds with different concentrations (10, 1, Ο.Ι μΜ) were added for 72 h, three wells were set for each concentration, and the corresponding concentration of saline control vehicle and cell-free zero-adjusted wells were set. After the end of the action, the adherent cells were de-cultured, added with 10% (w/v) trichloroacetic acid (ΙΟΟμΐν well) and fixed at 4 ° C for 1 h, then rinsed with distilled water five times, after drying at room temperature, each Add SRB solution (4 mg/mL, dissolved in 1% glacial acetic acid) 100 L, 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 VE SMax plate reader. After the suspension cell treatment, add 20 L MTT (5 mg/mL), incubate at 37 °C for 4 h, then add 100 μL of triad (10% SDS-5% isobutanol-0.01 M HC1), overnight at 37 °C. The OD value was measured at a wavelength of 570 nm. 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 χ 100%. Experimental repetition Twice.

2, the experimental results

Table 1 Inhibition rate of BaF3/TPR-Met cell proliferation by the compound of the present invention (%)

Table 2 The inhibition rate of the compound of the present invention on EBC-1 cell proliferation (%;)

80.1 71.2 9.3

DC381122 Nd

89.5 85.9 30.7

76.3 12.8 -10.1

DC381123 Nd

84.9 37.5 -8.5

76.9 79.6 78.8

DC381124 Nd

89.0 88.3 86.7

80.6 54.8 -2.6

DC381125 Nd

89.1 71.4 4.3

(positive drug) 86.2 80.1 75.6

47.0± 18.1 PF02341066 93.3 89.3 87.0

(positive drug) 86.6 82.1 78.8

Nd

XL880 93.6 91.4 88.1

As can be seen from the table, the level of inhibition of tumor cells by such compounds is on the nanomolar scale, and some of the compounds exhibit a considerable effect on the cellular level with the positive compound PF02341066.

Example 3: Growth inhibition of compound on EBC-1 nude mice xenografts

1, experimental methods

EBC-1 was subcutaneously inoculated into the right axilla of nude mice by 5×10 ⁶ / each, and the transplanted tumor was formed and then used in nude mice for three generations. The tumor tissue in the vigorous growth stage was cut into 1.5 mm ³ under aseptic conditions, and inoculated into the right axilla of the nude mice. The diameter of the transplanted tumor was measured with a vernier caliper. When the tumor volume was grown until the tumor volume reached 100-200 mm ³ , the animals were randomly divided into tumor volumes, 12 in the negative control group, 6 in the positive control group, and 6 in the experimental group. only. The experimental group received different concentrations of DC381112 (50mg/kg, 100mg/kg) daily. The positive control group received daily oral JNJ-38877605 (50mg/kg), once daily, for 17 days, negative control group. Give the same amount of normal saline at the same time.

Tumor length (A), width (B) were measured twice a week, and the tumor volume V = AxB ² /2 was calculated therefrom. Calculate relative tumor volume (RTV) follows: RTV = V _t / V. , V _t is the tumor volume at a given time, V. The resulting tumor volume was measured before the caged administration. The relative tumor proliferation rate T/C (%) was used as an index for evaluating antitumor activity, and T/C (%) = mean RTV of the administration group / mean RTV x 100% of the control group. If T/C% ≤ 60%, there is a significant difference in statistical tests, which is considered to have significant anti-tumor effects in vivo. At the same time, the weight of each group of nude mice was weighed twice a week to initially evaluate the toxic side effects of the drug.

2, the experimental results

The experimental results are shown in Figure 1.

Compound DC38112 showed significant growth inhibition on non-small cell lung cancer Lung cancer cell line EBC-1 at 50 and 100 mg/kg doses, and each dose group had no significant effect on mouse body weight. Compound JNJ-38877605 showed a very significant anti-tumor effect on the xenograft model at a dose of 50 mg/kg, and the transplanted tumor of 4 mice regressed, and the compound had no significant effect on the body weight of the mice.

Claims

1. A class of imidazo[l,2-a]pyridines of the formula (I), pharmaceutically acceptable salts, enantiomers, diastereomers or racemates thereof ,

(I)

among them,

W is -CH ₂ -, -CF ₂ -, -CFH -, -CO-, -CH ₂ -O-, -CH ₂ -NH -, again;

^ is a substituted or unsubstituted saturated or unsaturated C3-C12 heterocyclic group, or a substituted or unsubstituted C6-C12 aryl group, wherein the substituted heterocyclic group or substituted aryl group includes 1 to 5 a substituent, the heterocyclic group containing 1 to 4 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen; the substituent is halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl , trifluoromethoxy, carboxyl, thiol, oxo group,

a C1-C6 linear or branched fluorenyl group, a C2-C6 linear or branched unsaturated hydrocarbon group;

® is a substituted or unsubstituted saturated or unsaturated C3-C12 heterocyclic group, or a substituted or unsubstituted C6-C12 aryl group, wherein the substituted heterocyclic group or substituted aryl group includes 1 to 5 Take The heterocyclic group contains 1 to 4 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen; the substituent is a halogen, a C1-C12 linear or branched fluorenyl group, a C2-C12 straight chain or Branched unsaturated hydrocarbon group, C3-C12 cycloalkyl, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, fluorenyl; wherein R ² , R ³ , R ⁴ and R ⁵ are each independently hydrogen, halogen, C1-C12 linear or branched fluorenyl group, C2-C12 linear or branched unsaturated hydrocarbon group, C3-C12 cyclic hydrocarbon group, C1-C6 decyloxy group. , a C1-C6 acyl group, a C6-C12 aryl group, or a substituted or unsubstituted saturated or unsaturated C3-C12 heterocyclic group; the substituted or unsubstituted saturated or unsaturated C3-C12 heterocyclic group contains 1 - 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, and the substituted C3-C12 heterocyclic group contains one or more thiol groups selected from halogen, C1 - C12 straight or branched, C2-C12 straight Chain or branched unsaturated hydrocarbon group, C1-C6 decyloxy group, C3-C12 cycloalkyl group, saturated or unsaturated C3-C12 heterocyclic group, cyano group, nitro group, hydroxy group, hydroxymethyl group, trifluoromethyl group a substituent in a trifluoromethoxy group, a carboxyl group, a fluorenyl group, -NR ⁶ R ⁷ , - ⁸ OH and -SO ₂ R ⁶ ; any two of R ² , R ³ , R ⁴ , ⁵ and the same nitrogen When the atoms are connected, they may form a ring with the attached nitrogen atom; any two of R ² , R ³ and R ⁵ may form a ring with the attached carbon atom when they are connected to the same carbon atom; R ² , R ³ , R ⁴ , R ⁵ Any two of them may form a ring with a linked oxygen atom when they are bonded to the same oxygen atom; wherein R ⁶ and R ⁷ are each independently hydrogen or a C1 to C6 fluorenyl group; and R ⁸ is a C1 to C6 fluorenylene group.

The imidazo[l,2-a]pyridine compound according to claim 1, a pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof, wherein

W is selected from -CH ₂ -, -CF ₂ -, -CFH -, -CO-, -CH ₂ -O-, -CH ₂ -NH- or further;

X and Y are each independently hydrogen, halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, fluorenyl, C1-C6 straight or branched fluorene a C2-C6 straight or branched chain and a hydrocarbyl group; an unsubstituted or substituted saturated or unsaturated C3-C12 heterocyclic group, or an unsubstituted or substituted C6-C12 aryl group, wherein the substituted The heterocyclic group or substituted aryl group includes 1 to 3 substituents; the heterocyclic group contains 1 to 4 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen; the substituent is halogen, cyano, nitro , amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, oxo, C1-C6 straight or branched fluorenyl;

Where 11 is (3, N or O; Q is N or O;

M, M, each independently being a C2-C3 fluorene group;

Z is a C1-C4 fluorene group;

r is 0 or 1;

T is a C1-C6 linear or branched fluorenyl group, a C2-C6 linear or branched unsaturated hydrocarbon group, an amine group substituted with one or two C1-C6 fluorenyl groups, an unsubstituted or substituted C3-C10 a cycloalkyl group, an unsubstituted or substituted C6-C12 aryl group, an unsubstituted or substituted C3-C10 heterocyclic group; wherein the substituent is halogen, hydroxy, nitro, amino, trifluoromethyl, diphenyl a group, an amine group substituted with one or two C1-C6 thiol groups, a C1-C6 fluorenyl group;

R ⁹ and R ¹⁽⁾ are each independently halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, decyl, C1-C6 straight or branched Mercapto group, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched decyloxy group, C3-C10 cyclic hydrocarbon group, C3-C10 heterocyclic group, C1-C6 straight chain or branch a decanoyl group, a spiro-C3-C10 cycloalkyl group, a spiro-C3-C10 heterocyclic group, or an amine group substituted with one or two C1-C6 fluorenyl groups;

R ¹¹ is hydrogen or a C1-C4 fluorenyl group;

^ is an unsubstituted or substituted saturated or unsaturated C3-C10 heterocyclic group, or an unsubstituted or substituted C6-C10 aryl group, wherein the substituted heterocyclic group or substituted aryl group includes 1 to 3 a substituent, the heterocyclic group containing 1 to 4 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen; wherein the substituent is a halogen, a C1-C10 linear or branched fluorenyl group, and a C2-C10 straight A chain or branched unsaturated hydrocarbon group, a C3-C10 cycloalkyl group, a cyano group, a nitro group, an amino group, a hydroxyl group, a hydroxymethyl group, a trifluoromethyl group, a trifluoromethoxy group, a carboxyl group, a fluorenyl group.

The imidazo[l,2-a]pyridine compound according to claim 2, a pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof, wherein W is selected from -CH ₂ -, -CF ₂ -, -CFH -, -CH ₂ -O-, -CH ₂ -NH- or further;

Is a substituted or unsubstituted saturated or unsaturated C3-C10 heterocyclic group, or a substituted or unsubstituted C6-C10 aryl group, wherein the substituted heterocyclic group or substituted aryl group includes 1 or 2 a substituent; the heterocyclic group contains 1 to 3 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen; the substituent is halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl a trifluoromethoxy group, a carboxyl group, a C1-C6 linear or branched fluorenyl group;

Where 11 is (3, N or O; Q is N or O;

M, M, each independently being a C2-C3 fluorene group;

Z is a C1-C4 fluorene group;

r is 0 or 1;

T is a C1-C6 linear or branched fluorenyl group, a C2-C6 linear or branched unsaturated hydrocarbon group, an amine group substituted with one or two C1-C6 fluorenyl groups, an unsubstituted or substituted C3-C8 group. a cycloalkyl group, an unsubstituted or substituted C6-C12 aryl group, an unsubstituted or substituted C3-C8 heterocyclic group; wherein the substituent is halogen, hydroxy, nitro, amino, trifluoromethyl, diphenyl a group, an amine group substituted with one or two C1-C6 thiol groups, a C1-C6 fluorenyl group;

R ⁹ and R ^1Q are each independently halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, C1-C6 straight or branched fluorenyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched decyloxy group, C3-C8 cyclic hydrocarbon group, C3-C8 heterocyclic group, C1-C6 linear or branched decanoyl group a spiro C3-C8 cycloalkyl, a spiro C3-C8 heterocyclyl, or an amine substituted with one or two C1-C6 thiol groups; R ¹¹ is hydrogen or a C1-C4 fluorenyl group;

R ¹² and R" are each independently hydrogen, halogen, C1 to C6 linear or branched fluorenyl, C2 to C6 linear or branched unsaturated hydrocarbon, cyano, nitro, amino, hydroxy, trifluoro Methyl, trifluoromethoxy, carboxy;

Is a substituted or unsubstituted saturated or unsaturated C3-C8 heterocyclic group, or a substituted or unsubstituted C6-C10 aryl group, wherein the substituted heterocyclic group or substituted aryl group includes 1 or 2 a substituent, the heterocyclic group having 1 to 3 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen; the substituent is a halogen,

C1-C6 linear or branched fluorenyl, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy.

The imidazo[l,2-a]pyridine compound according to claim 3, a pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof, wherein

W is selected from -CH ₂ -, -CF ₂ -, -CFH -, -CH ₂ -O-, -CH ₂ -NH- or further;

X and Y are each independently hydrogen, halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, C1-C4 straight or branched fluorenyl; Is a substituted or unsubstituted saturated or unsaturated C3-C8 heterocyclic group, or a substituted or unsubstituted C6-C10 aryl group, wherein the substituted heterocyclic group or substituted aryl group includes 1 or 2 a substituent; the heterocyclic group contains 1 to 3 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen; the substituent is halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl Base, trifluoromethoxy, carboxyl, oxo group,

a linear or branched fluorenyl group of C1-C4;

R ¹ is hydrogen, halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, fluorenyl, C1-C4 straight or branched fluorenyl, C3- C8 heterocyclic group,

-

Where 11 is (3, N or O; Q is N or O;

M, M, each independently being a C2-C3 fluorene group;

Z is a C1-C4 fluorenylene group; r is 0 or 1;

T is a C1-C4 linear or branched fluorenyl group, an amine group substituted with one or two C1-C4 fluorenyl groups, an unsubstituted or substituted C6-C10 aryl group, an unsubstituted or substituted C3-C8 heterocyclic ring. Wherein the substituent is a halogen, a hydroxyl group, a nitro group, an amino group, a trifluoromethyl group, a diphenylmethyl group, an amine group substituted with one or two C1-C4 fluorenyl groups, a C1-C4 fluorenyl group;

R ¹¹ is hydrogen or a C1-C4 fluorenyl group;

® ^A is a substituted or unsubstituted saturated or unsaturated C3-C8 heterocyclic group, or a substituted or unsubstituted C6-C10 aryl group, wherein the substituted heterocyclic group or substituted aryl group includes 1 or 2 a substituent having 1 to 3 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen; the substituent is a halogen, a C1-C4 linear or branched fluorenyl group, a cyano group, a nitro group , amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy.

The imidazo[l,2-a]pyridine compound according to claim 1, a pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof, wherein Said imidazo[l,2-a]pyridines as the next:

98£OLO/£lOZbl3/13d

9ζε.οι/ειοΓ OAV

6. A process for the preparation of the imidazo[l,2-a]pyridine compound of claim 1, which is carried out by a reaction route as shown below:

The reaction is stirred to obtain the compound I _a , the solvent is dioxane; the base is N-methyldicyclohexylamine; Step b: The compound 1 is dissolved in chloroform, and N-chloro is added at room temperature. a _d -butylimide, stirred at room temperature to obtain a compound I _b;

or,

Step h: The compound I _e and If are dissolved in a solvent, and stirred under an oil bath at 80 ° C to obtain a compound I _g , the solvent is anhydrous ethanol;

Step i: catalytically coupled compound I _g with a substituted boronic acid ester or boric acid under a palladium catalyst to obtain compound Ih;

Step j; fluorinating the compound I _h using a fluorinating agent to obtain a final product, the fluorinating agent is DAST; or

Step 1: Hydroxymethylation of compound i _{m to} give compound i _η; Step m: nucleophilic substitution reaction of compound ^ with ^^4 to give compound I. ; Step will be compound I. Catalytic coupling with a substituted boronic acid ester or boric acid under a palladium catalyst to obtain a product;

or,

Step p: Compound I. Azide to give compound I _{p ;} Step q: Reductive amination of compound Ip to give compound I _{q ;} Step r: The same reaction as step m is carried out to obtain compound ^ Step s: The same reaction as in step n is carried out to obtain End product; or,

Step w: reacting compound I _t with chloro(methoxymethyl)triphenylphosphorane to obtain compound I _u; Step X: hydrolyzing compound _Iu with hydrochloric acid, followed by chlorosuccinyl chloro amine, to give compound I _w; step y: dissolving in a solvent, was added I _e, after protection with argon, the reaction was stirred at 80 ° C for an oil bath, to give compound I _x, the solvent is ethanol Step z: The same reaction as in step n is carried out to obtain the final product.

The imidazo[l,2-a]pyridine compound according to any one of claims 1 to 5, a pharmaceutically acceptable salt, enantiomer, diastereomer or racemic thereof Use of the body for the preparation of a medicament for the treatment of a cell proliferative disorder associated with the tyrosine kinase c-Met signal transduction pathway.

The use according to claim 7, wherein the cell proliferative diseases associated with the tyrosine kinase c-Met signal transduction pathway are cancer, hyperplasia, restenosis, immune disorder, and inflammation.

A pharmaceutical composition comprising one or more therapeutically effective amounts of the imidazo[l,2-a]pyridine compound according to any one of claims 1 to 5, which is pharmaceutically acceptable Salts, enantiomers, diastereomers or racemates and pharmaceutically acceptable excipients.