CN103373971B - Urea compounds as protein kinase inhibitors - Google Patents

Abstract

The invention provides a urea compound used as a protein kinase inhibitor and a medicinal salt thereof; pharmaceutical compositions containing such compounds and the use of such compounds as protein kinase inhibitors.

Description

Urea compounds as protein kinase inhibitors

Technical field:

The invention belongs to the field of medicine, and specifically relates to a new class of urea compounds and a preparation method thereof, and also relates to the application of such compounds as protein kinase inhibitors in the treatment of cancer.

technical background:

It is currently known that the Ras/Raf/Mek/Erk transduction pathway exists in all eukaryotic cells, and the Ras/Raf/MEK/ERK pathway cytokinin-activated protein kinases (MAPKs) mediate intracellular signals through a large number of cell surface receptors transfer. Most of the factors that stimulate cell growth, including EGF, PDGF, VEGF and c-KIT, after binding to receptors on the cell surface, can first activate Ras through the autophosphorylation of receptor tyrosine kinases, and Ras can be further activated The Raf/MEK/ERK signaling pathway brings growth factor signals into the nucleus, realizes the transmission of signals from the outside of the cell to the inside of the nucleus, and triggers cell biological responses, such as cell proliferation, differentiation, transformation, and apoptosis.

Many tumor cells have up-regulation of this pathway, and Raf, as a key kinase in this pathway, can exert its signaling transcriptional regulation in a Ras-dependent or Ras-independent manner. As a downstream substrate of Raf kinase, activated MEK phosphorylates ERK, which regulates cellular functions by acting on a variety of substrates. Once this pathway is overactivated, the acceleration of cell proliferation and the prolongation of cell survival can lead to the formation and development of tumors.

As a key kinase in this pathway, Raf has three isozymes, namely A-Raf, B-Raf and C-Raf, which are closely related to the regulation of cell proliferation, differentiation and angiogenesis. It is known that A-Raf and C-Raf mutations are very rare in human tumor cells, and B-Raf mutations account for 7%. The somatic mutation rate after B-Raf is activated is as high as 50%-70% in melanoma, 35% in ovarian cancer, 30% in thyroid cancer, and 10% in colon cancer. The target of cancer has been paid more and more attention by researchers, and it is one of the important targets of anti-tumor drug research.

Small molecule kinase inhibitors containing urea structures have been expected to treat cancer and inflammation since the early 1990s. And sorafenib, as the first Raf kinase inhibitor with urea structure, can hinder the signal transduction mediated by Raf/MEK/ERK pathway on the one hand, inhibit the proliferation of tumor cells, and directly inhibit tumor growth; , tumor growth and metastasis depend on the formation of new blood vessels. VEGF and PDGF are important pro-angiogenic factors. Sorafenib inhibits VEGFR (such as VEGER-2, VEGER-3) and PDGFR (PDGFR-β) The activity of tyrosine kinase blocks tumor angiogenesis and indirectly inhibits tumor growth. It has dual anti-tumor effects, so it is called a multi-kinase inhibitor.

Preclinical studies have shown that Sorafenib has a wide range of anti-tumor activity on animal transplantation models of human tumors, including colon cancer, pancreatic cancer, lung cancer, breast cancer and ovarian cancer, and its anti-tumor effect is related to the inhibition of Raf/MEK/ERK The antitumor activity of sorafenib was also observed in tumors with Ras or B-Raf gene mutations; in addition, in human colon cancer (HT-29 and Colo205) and breast cancer (MDA-MB-231 ) in animal transplantation models, Sorafenib can significantly inhibit the formation of new blood vessels.

Invention content:

The purpose of the present invention is to provide the urea compound represented by the general formula (I) as a protein kinase inhibitor, pharmaceutically acceptable salts, hydrates and solvates and their corresponding isomers, prodrugs or chemically protected forms.

in:

m is independently selected from 0, 1, 2, 3 or 4;

L is independently selected from

X is independently selected from O or (CH ₂ ) _n ;

The aforementioned n is selected from 0, 1, 2, 3 or 4;

Y is independently selected from CH or N;

S ring is independently selected from benzene ring, pyrrole ring;

R ₁ is independently selected from hydrogen, halogen, C _1-8 alkyl, halogenated C _1-8 alkyl, C _1-8 alkoxy, halogenated C _1-8 alkoxy, piperazinemethyl, methyl Basepiperazinylmethyl, ethylpiperazinylmethyl or morpholinylmethyl; but when L When, R ₁ is only selected from hydrogen, halogen, C _1-8 alkyl, halogenated C _1-8 alkyl;

R ₂ is independently selected from hydrogen, (CH ₂ ) _p R ₃ ;

The aforementioned R ₃ is independently selected from C _3-10 heteroaryl, chloro C _3-10 heteroaryl;

R ₄ is independently selected from hydrogen, halogen, C _1-8 alkyl;

R ₅ is independently selected from (CH ₂ ) _p R ₆ ;

The aforementioned R ₆ is independently selected from C _1-8 alkyl, C _6-14 aryl, and C _3-10 heteroaryl; the C _6-14 aryl or C _3-10 heteroaryl can be replaced by one or more halogens are independently substituted;

The aforementioned p is independently selected from 0, 1, 2, 3 or 4;

R ₇ is independently selected from hydrogen, C _3-10 heterocycloalkyl, O(CH ₂ ) _p R ₈ , NH(CH ₂ ) _p R ₉ or C _3-8 alkynyl, wherein the C _3-8 alkynyl The group is optionally further substituted by C _1-8 alkoxy, two C _1-8 alkylamino;

The aforementioned R ₈ is selected from C _1-8 alkoxy, C _6-14 aryl or C _3-10 heterocycloalkyl; the C _6-14 aryl or C _3-10 heterocycloalkyl is optionally Further substituted by C _1-8 alkyl;

The aforementioned R ₉ is selected from C _3-10 heterocycloalkyl, said C _3-10 heterocycloalkyl is optionally further substituted by C _1-8 alkyl;

Said p is independently selected from 0, 1, 2, 3 or 4.

When L is selected from As shown in general formula (I a):

in:

m is independently selected from 0, 1, 2, 3 or 4;

R is independently selected from hydrogen, halogen, C _1-8 alkyl, halogenated C _{1-8 alkyl} ; preferably R is hydrogen, halogen, C _1-5 alkyl, halogenated C _{1-5 alkyl} , halogenated C _1-5 alkoxy; more preferably R ₁ is hydrogen, Cl, Br, F, methyl, methoxy, trifluoromethyl;

R ₂ is independently selected from hydrogen, (CH ₂ ) _p R ₃ ;

The aforementioned R ₃ is independently selected from C _3-10 heteroaryl, halogenated C _3-10 heteroaryl;

Preferably R ₃ is C _3-7 heteroaryl, halogenated C _3-7 heteroaryl;

More preferably _R is pyrimidinyl, chloropyrimidinyl, pyridyl;

The aforementioned p is independently selected from 0, 1, 2, 3 or 4.

When L is selected from As shown in general formula (Ib):

in:

m is independently selected from 0, 1, 2, 3 or 4;

X is independently selected from O or (CH ₂ ) _n ;

The aforementioned n is selected from 0, 1, 2, 3 or 4;

R is independently selected from hydrogen, halogen, C _1-8 alkyl, halogenated C _{1-8 alkyl} ; preferably R is hydrogen, halogen, C _1-5 alkyl, halogenated C _{1-5 alkyl} , halogenated C _1-5 alkoxy; more preferably R is hydrogen, _F , Cl, Br, methyl, methoxy, trifluoromethyl;

R is independently selected from hydrogen, halogen, C _1-8 alkyl _; preferably R is hydrogen, F, Cl, Br, C _1-3 alkyl _; more preferably R is hydrogen _;

R ₅ is independently selected from (CH ₂ ) _p R ₆ ;

The aforementioned R ₆ is independently selected from C _1-8 alkyl, C _6-14 aryl, and C _3-10 heteroaryl; the C _6-14 aryl or C _3-10 heteroaryl can be replaced by one or more halogens are independently substituted;

Preferably R ₆ is independently C _1-5 alkyl, C _6-10 aryl, C _3-7 heteroaryl, and said C _6-10 aryl or C _3-7 heteroaryl is optionally further substituted by halogen ;

More preferably _R6 is independently selected from methyl, ethyl, phenyl, pyridyl, chlorophenyl, chloropyridyl.

The aforementioned p is independently selected from 0, 1, 2, 3 or 4.

When L is selected from As shown in general formula (Ic):

in:

m is independently selected from 0, 1, 2, 3 or 4;

X is independently selected from O or (CH ₂ ) _n ;

The aforementioned n is selected from 0, 1, 2, 3 or 4;

Y is independently selected from CH or N;

S ring is independently selected from benzene ring, pyrrole ring;

R ₁ is independently selected from hydrogen, halogen, C _1-8 alkyl, halogenated C _1-8 alkyl, C _1-8 alkoxy, halogenated C _1-8 alkoxy, piperazinemethyl, 4 _{-Methylpiperazinemethyl, 4-ethylpiperazinemethyl or morpholinylmethyl; preferably R is hydrogen, halogen, C 1-5 alkyl, halogenated C 1-5 alkyl ,} C _{1- 5} alkoxy, halogenated C _1-5 alkoxy, piperazinemethyl, 4-methylpiperazinemethyl, ₄ -ethylpiperazinemethyl, or morpholinylmethyl; more preferably R is Hydrogen, Cl, Br, F, C _1-3 alkyl, halogenated C _1-3 alkyl, C _1-3 alkoxy, halogenated C _1-3 alkoxy, piperazine methyl, 4-methyl 4-ethylpiperazinylmethyl, 4-ethylpiperazinylmethyl or morpholinylmethyl;

R is independently selected from hydrogen, halogen, C _1-8 alkyl _; preferably R is hydrogen, F, Cl, Br, C _1-3 alkyl _; more preferably R is hydrogen _;

R ₇ is independently selected from hydrogen, C _3-10 heterocycloalkyl, O(CH ₂ ) _p R ₈ , NH(CH ₂ ) _p R ₉ or C _3-8 alkynyl, and said C _3-8 alkynyl Optionally further substituted by C _1-8 alkoxy, bis C _1-8 alkylamino;

Preferably R ₇ is hydrogen, C _3-8 heterocycloalkyl, O(CH ₂ ) _p R ₈ , NH(CH ₂ ) _p R ₉ or C _3-5 alkynyl, said C _3-5 alkynyl Optionally further substituted by C _1-5 alkoxy, bis C _1-5 alkylamino;

More preferably R ₇ is hydrogen, morpholinyl, methylpiperazinyl, tetrahydropyrrolyl, O(CH ₂ ) _p R ₈ , NH(CH ₂ ) _p R ₉ , 3-methoxypropynyl, 3-Dimethylaminopropynyl;

The aforementioned R ₈ is selected from C _1-8 alkoxy, C _6-14 aryl or C _3-10 heterocycloalkyl; the C _6-14 aryl or C _3-10 heterocycloalkyl is optionally Further substituted by C _1-8 alkyl;

Preferably R ₈ is selected from C _1-5 alkoxy, C _6-10 aryl or C _3-8 heterocycloalkyl, said C _6-10 aryl or C _3-18 heterocycloalkyl, optionally is further substituted by C _1-3 alkyl;

More preferably R _is selected from methoxy, piperazinyl, methylpiperazinyl, morpholinyl;

The aforementioned R ₉ is selected from C _3-10 heterocycloalkyl, said C _3-10 heterocycloalkyl is optionally further substituted by C _1-8 alkyl;

Preferably R ₉ is selected from C _3-8 heterocycloalkyl; said C _3-8 heterocycloalkyl is optionally further substituted by C _1-5 alkyl;

More preferably R is selected from piperazinyl, _{methylpiperazinyl} , morpholinyl;

The aforementioned p is independently selected from 0, 1, 2, 3 or 4.

The second aspect of the present invention relates to a pharmaceutical composition comprising a compound represented by general formula (I), wherein the pharmaceutical composition preferably further comprises an adjuvant, and the adjuvant is preferably a pharmaceutically acceptable carrier and/or excipient, wherein the The excipient is preferably a diluent.

The present invention also relates to the compound containing the general formula (I) and the medicine for treating or preventing tumor in the pharmaceutical composition or the application as preparation for treating or preventing tumor.

The present invention also relates to the use of the compound represented by the general formula (I) as a protein kinase inhibitor in the preparation of medicines. The drug use can inhibit the Raf/MEK/ERK signal transduction pathway, and can also block the formation of tumor neovascularization by inhibiting VEGF receptors, so as to achieve the effect of treating tumors.

The aforementioned tumors are preferably liver cancer, kidney cancer, breast cancer, lung cancer, non-small cell lung cancer, thyroid cancer, bladder cancer, colon cancer, rectal cancer, prostate cancer, pancreatic cancer, ovarian cancer, myeloma, head and neck cancer, bladder cancer, acute Myeloid leukocytosis, chronic myeloid leukocytosis, peritoneal carcinoma, mesothelioma, myelodysplastic syndrome, gastric cancer.

Unless otherwise stated, the term "halogen" as used herein means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

Unless otherwise stated, the term "C _6-14 aryl" used in the present invention refers to any functional group or substituent derived from a simple aromatic ring. C _6-10 aryl is preferred, C _6-8 aryl is more preferred, phenyl is especially preferred, and a suitable example is phenyl. The aryl group is optionally substituted by one or more substituents independently selected from halogen, alkyl, alkoxy, nitro or cyano, preferably halogen, a suitable example being fluorophenyl.

Unless otherwise specified, the term "C _3-10 heteroaryl" or "halogenated C _3-10 heteroaryl" used in the present invention means an aromatic group containing at least one heteroatom selected from N, O and S. A preferred heteroaryl is a C _3-8 heteroaryl or a halogenated C _3-8 heteroaryl, more preferably a C _3-7 heteroaryl or a halogenated C _3-7 heteroaryl. Examples of the heteroaryl group include, for example, imidazolyl, pyridyl, pyrimidinyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, isoxazolyl, isothiazolyl, triazolyl and halogen substituted groups group. More preferred are pyridyl, pyrimidyl, pyrrolyl, and triazolyl, and especially preferred are pyridyl, pyrimidyl, and chloropyrimidine.

Unless otherwise specified, the term "C _3-10 heterocycloalkyl" used in the present invention means an aliphatic cycloalkyl group containing at least one heteroatom selected from N, O and S. Preferably it is C _3-8 heterocycloalkyl. Examples of said heterocycloalkyl include, for example, piperazinyl, methylpiperazinyl, morpholinyl, tetrahydropyrrolyl, furyl.

Unless otherwise stated, the term "C _1-8 alkyl" or "C _1-8 alkoxy" used in the present invention means that the group is straight or branched, preferably C _1-5 alkyl or C _{1 -5} alkoxy. Examples of suitable alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl. Examples of suitable alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec- and tert-butoxy, pentoxy.

The "halogenated C _1-8 alkyl" or "halogenated C _1-8 alkoxy" mentioned herein means that the group is linear or branched, preferably a halogenated C _1-5 alkyl . Examples of suitable haloalkyl groups include eg trifluoromethyl, trifluoroethyl, difluoromethyl, difluoroethyl.

The "bis C _1-8 alkylamino" mentioned herein is preferably a bis C _1-5 alkylamino, more preferably a bis C _1-3 alkylamino, and examples of suitable bisalkylamino groups include dimethylamino, Diethylamino, dipropylamino.

The term "C _3-8 alkynyl" used in the present invention refers to straight chain and branched chain hydrocarbon groups containing a triple bond and having 3-8 carbon atoms, preferably "C _3-5 alkynyl";

The term "C _3-8 alkynyl substituted by dialkylamino" used in the present invention means that the α-position hydrogen atom on the C _3-8 alkynyl is substituted by bis C _1-8 alkylamino. C _3-5 alkynyl substituted with bis C _1-5 alkylamino is preferred, suitable examples include 3-dimethylaminopropynyl.

The term "C _3-8 alkynyl substituted by C _1-8 alkoxy" used in the present invention means that the α-position hydrogen atom on the C _3-8 alkynyl is substituted by C _1-8 alkoxy. Preferred is C _1-5 alkoxy substituted C _3-5 alkynyl, suitable examples include 3-methoxypropynyl.

The pharmaceutically acceptable salt referred to in the present invention is a salt formed by formula (I) with any acid, and is a pharmaceutically acceptable acid. Suitable acids include inorganic acids such as phosphoric acid, sulfuric acid, hydrochloric acid, nitric acid, hydrobromic acid, and similar acids; or organic acids such as acetic acid, trifluoroacetic acid, propionic acid, malonic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, Succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, mandelic acid, sulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, salicylic acid and similar acid.

The isomer referred to in the present invention refers to the existence of one or more stereoisomers, including various stereoisomers, diastereomers, tautomers and geometric isomers. The present invention includes compound formula (I), its stereoisomers and pharmaceutically acceptable salts thereof. The compounds of the present invention may occur as a mixture of stereoisomers, as a single stereoisomer or in optically active form.

"Solvate" referred to in the present invention is used herein in the conventional sense to denote a complex of a solute (eg, a compound, a salt of a compound) and a solvent. If the solvent is water, the solvate may conveniently be referred to as a hydrate, eg, monohydrate, dihydrate, trihydrate, and the like.

The term "chemically protected form" referred to in the present invention is used herein in the conventional sense to mean one or more reactive functional groups are protected from occurring under specified conditions (e.g., pH, temperature, irradiation, solvent, etc.). Compounds with undesired chemical reactions. In practice, well-known chemical methods can be used to reversibly render functional groups that would otherwise react unreactive under defined conditions. In chemically protected forms, one or more reactive functional groups are protected or protecting groups (also known as masked or masking groups or blocked or blocking groups). By protecting a reactive functional group, reactions involving other unprotected reactive functional groups can be performed without affecting the protected group; the protecting group can usually be removed in a subsequent step without substantially affecting the remainder of the molecule. At the same time, the invention discloses the preparation method of the compound of the invention and the pharmaceutically acceptable salt thereof.

"Prodrugs" as referred to herein relate to compounds that when metabolized (eg, in vivo) yield the desired active compound. Typically, prodrugs are inactive, or less active than the active compound, but may confer advantageous handling, administration or metabolism properties.

For example, some prodrugs are esters (eg, physiologically acceptable metabolically unstable esters) of the active compound. During metabolism, the ester group (-C(=O)OR) is cleaved, yielding the active drug. Such esters may be formed by esterification, for example, of any carboxylic acid group (-C(=O)OH) in the parent compound and, where appropriate, preprotecting any other reaction present in the parent compound. Reactive groups, if desired, are then deprotected.

Also, some prodrugs are activated by enzymes to generate the active compound or a compound that generates the active compound after further chemical reaction (eg in ADEPT, GDEPT, LIDEPT, etc.). For example, prodrugs may be sugar derivatives or other glycoside conjugates, or may be amino acid ester derivatives.

A "pharmaceutical composition" as referred to in the present invention refers to a product obtained by mixing or combining more than one active ingredient, including fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients, such as a compound of formula (I) and a co-medicine, are administered to a patient simultaneously as a single entity or dosage. The term "non-fixed combination" means that the active ingredients, such as a compound of formula (I) and a co-drug, are administered to a patient as separate entities simultaneously, concurrently or sequentially with no specific time limit, wherein such administration provides the patient with two or more Therapeutically effective levels of two or more compounds.

The present invention provides the following specific compounds:

1-(4-((9-Benzyl-9H-purin-6-yl)oxy)phenyl)-3-(4-chloro-3-trifluoromethylphenyl)urea

1-(4-((9-(pyridine-2-methyl)-9H-purin-6-yl)oxy)phenyl)-3-(4-chloro-3-trifluoromethylphenyl)urea

1-(4-((9-methyl-9H-purin-6-yl)oxy)phenyl)-3-(4-chloro-3-trifluoromethylphenyl)urea

1-(4-((9-(3-fluorobenzyl)-9H-purin-6-yl)oxy)phenyl)-3-(4-chloro-3-trifluoromethylphenyl)urea

1-(4-(3-Aminoisoquinolin-5-yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea

1-(4-(3-amino-1-(2-(4-methylpiperazin-1-yl)ethoxy)isoquinolin-5-yl)phenyl)-3-(2-fluoro- 5-(Trifluoromethyl)phenyl)urea

1-(4-(3-Amino-1-morpholinoisoquinolin-5-yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea

1-(4-(3-amino-1-(4-methylpiperazin-1-yl)isoquinolin-5-yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl ) phenyl) urea

1-(4-(3-amino-1-(3-(4-methylpiperazin-1-yl)propoxy)isoquinolin-5-yl)phenyl)-3-(2-fluoro- 5-(Trifluoromethyl)phenyl)urea

1-(4-(3-Amino-1-tetrahydropyrrolylisoquinolin-5-yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea

1-(4-(3-Aminoisoquinolin-5-yl)phenyl)-3-(2-fluoro-5-methylphenyl)urea

1-(4-(3-amino-1-(2-(4-methylpiperazin-1-yl)ethoxy)isoquinolin-5-yl)phenyl)-3-(2-fluoro- 5-methylphenyl)urea

1-(4-(3-amino-1-(2-morpholineethoxy)isoquinolin-5-yl)phenyl)-3-(2-fluoro-5-trifluoromethylphenyl)urea

1-(4-(3-amino-(2-methoxyethoxy)isoquinolin-5-yl)phenyl)-3-(2-fluoro-5-trifluoromethylphenyl)urea

1-(4-(3-Aminoisoquinolin-5-yl)phenyl)-3-(4-chloro-3-trifluoromethylphenyl)urea

1-(4-(3-amino-1-(3-(4-methylpiperazin-1-yl)propylamino)isoquinolin-5-yl)phenyl)-3-(2-fluoro-5 -(trifluoromethyl)phenyl)urea

1-(4-(3-aminoisoquinolin-5-yl)phenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl ) phenyl) urea

1-(4-(3-amino-1-(3-methoxypropynyl)isoquinolin-5-yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl)benzene base) urea

1-(4-(3-amino-1-(3-dimethylaminopropynyl)isoquinolin-5-yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl)benzene base) urea

1-(4-(2-Amino-7H-pyrrole[2,3-d]pyrimidine)(-7-yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl) Urea

1-(4-(2-amino-4-(4-methylpiperazin-1-yl)-7H-pyrrole[2,3-d]pyrimidine)(-7-yl)phenyl)-3-( 2-fluoro-5-(trifluoromethyl)phenyl)urea

1-(4-Chloro-3-trifluoromethylphenyl)-3-(2-oxo-3-(pyridin-2-yl-methyl)-2,3-dihydrobenzo[d]oxa Azol-6-yl)urea

1-Benzyl-3-(2-oxo-3-(pyridin-2-yl-methyl)-2,3-dihydrobenzo[d]oxazol-6-yl)urea

1-(4-chloro-3-trifluoromethylphenyl)-3-(2-oxo-3-(6-chloropyrimidin-4-yl)-2,3-dihydrobenzo[d]oxa Azol-6-yl)urea

1-Benzyl-3-(2-oxo-3-(6-chloropyrimidin-4-yl)-2,3-dihydrobenzo[d]oxazol-6-yl)urea

Unless otherwise specified, the term "compound of the present invention" used herein refers to the compound represented by the general formula (I), preferably the specific compound mentioned above, especially the compound of the example.

implementation plan

Compound shown in general formula (I) of the present invention can be prepared by the following method:

1) Preparation of compound shown in general formula (Ia):

a, with 2-amino-5-nitro-phenol as raw material, first make 6-nitrobenzoxazol-2(3H)-ketone (2),

b. Prepare substituted 6-nitrobenzoxazol-2(3H)-one (3);

c, prepared substituted 6-aminobenzoxazol-2(3H)-one (4) compound;

d. Reaction with substituted aniline to obtain the target compound.

2) preparation of compound shown in general formula (Ib):

a, using 6-chloro-9H-purine as a raw material, forming a 6-chloro-9H-purine compound of formula (III) with a compound of formula (II);

b, then form the substituted 6-oxo-aniline-9H-purine compound of formula (V) with the compound of formula (IV);

c. Reaction with formula (VI) to obtain the target compound.

3) When Y is C, the preparation of the compound shown in general formula (Ic):

a, using the substituted aniline compound (V) as a raw material to prepare a phenylurea compound of formula (VII);

b. Reaction of 5-bromo-3-aminoisoquinoline derivatives of formula (IV) with phenylurea compounds of formula (VII) to obtain the target compound:

4) When Y is N, the preparation of the compound shown in general formula (Ic):

A, with the aniline substituted by R1 as raw material, _first react to prepare phenylurea compounds;

b. Reaction with 7H-pyrrolo[2,3-d]pyrimidine- ₂ -amino substituted by R to obtain the target compound:

Description of some abbreviations:

CDI: N, N' carbonyl diimidazole, DMF: N, N-dimethylformamide, THF: tetrahydrofuran, EAC: ethyl acetate, Pd(PPH ₃ ) ₄ : tetrakistriphenylphosphine palladium, L-proline : L-proline.

Detailed ways

Example 1: 1-(4-((9-Benzyl-9H-purin-6-yl)oxy)phenyl)-3-(4-chloro-3-trifluoromethylphenyl)urea

Step A: Preparation of 4-(9-benzyl-9H-purine-6-oxy)aniline

Weigh 244mg of 6-chloro-9H-purine and dissolve it in 20ml of DMF, add K ₂ CO ₃ and stir for 0.5h, slowly add 205.2mg of chlorotoluene dropwise, react for 20h, pour the reaction solution into ice water, adjust the pH to 5-6 , extracted with ethyl acetate, and column chromatography gave a white solid.

Aminophenol 102mg, Cs ₂ CO ₃ 652mg, THF/DMF (9ml/3ml), stirred and activated for 2h, added 122mg of the compound obtained in the previous step, catalytic amounts of KI and Bu ₄ NBr, and heated to 85°C. TLC monitored almost complete reaction. Add water, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, and remove the solvent to obtain a pink solid.

Step B: Preparation of 1-(4-((9-benzyl-9H-purin-6-yl)oxy)phenyl)-3-(4-chloro-3-trifluoromethylphenyl)urea

0.317g (1mmol) 4-(9-benzyl-9H-purine-6-oxy)aniline was placed in a 100ml three-necked round-bottomed flask, and 20ml of dichloromethane was added and stirred to dissolve, and 0.243g (1.5mmol) of dicarbonylimidazole was added (CDI), after stirring at room temperature for 2 h, add 0.234 g (1.2 mmol) of 4-chloro-3-trifluoromethylaniline, continue to stir at room temperature, after the reaction is complete, concentrate, and separate by column chromatography to obtain a white solid.

¹ H NMR (CDCl ₃ , 300MHz) δ (ppm): 8.45 (s, 1H, purine-H), 8.44 (s, 1H, Ar-H), 8.00～7.99 (s, 1H, purine-H), 7.66 ～7.63(d, 1H, Ar-H), 7.56～7.53(d, 2H, Ar-H), 7.51～7.48(d, 1H, Ar-H), 7.38～7.31(m, 5H, Ar-H) , 7.24~7.21 (d, 2H, Ar-H), 5.54 (s, 2H, CH ₂ ).

ESI-MS m/z: 539 [M+H] ⁺ , calculated: 539.

Example 2: 1-(4-((9-(pyridine-2-methyl)-9H-purin-6-yl)oxy)phenyl)-3-(4-chloro-3-trifluoromethylbenzene base) urea

Using 4-(9-(pyridine-2-methyl)-9H-purine-6-oxygen)aniline and 4-chloro-3-trifluoromethylaniline as raw materials, the same preparation method as in Example 1, to obtain a white solid .

¹ H NMR (CDCl ₃ , 500MHz) δ (ppm): 9.18 (s, 1H, NH), 8.92 (s, 1H, NH), 8.60 (s, 1H, purine-H,), 8.48～8.47 (d, 1H, pyridine-H), 8.39 (s, 1H, purine-H,) 8.11 (s, 1H, Ar-H), 7.81~7.80 (t, 1H, pyridine-H), 7.67~7.65 (d, 1H, Ar-H), 7.62～7.61(d, 1H, Ar-H), 7.55～7.52(d, 2H, Ar-H), 7.36～7.35(d, 1H, pyridine-H), 7.32～7.30(m, 1H, pyridine-H), 7.24-7.22 (d, 2H, Ar-H), 5.64 (s, 2H, CH ₂ ).

ESI-MS m/z: 540 [M+H] ⁺ , calculated: 540.

Example 3: 1-(4-((9-methyl-9H-purin-6-yl)oxy)phenyl)-3-(4-chloro-3-trifluoromethylphenyl)urea

Using 4-(9-methyl-9H-purine-6-oxy)aniline and 3-trifluoromethyl-4-chloroaniline as raw materials, the preparation method of Example 1 was used to obtain a light yellow solid.

¹ H NMR (CDCl ₃ , 500MHz) δ (ppm): 9.20 (s, 1H, NH), 9.14 (s, 1H, NH), 8.46 (d, 2H, purine-H,), 8.12 (s, 1H, Ar-H), 7.68～7.60(d, 2H, Ar-H), 7.55～7.52(d, 2H, Ar-H), 7.22～7.19(d, 2H, Ar-H), 3.86(s, 3H, _CH3 ).

ESI-MS m/z: 464 [M+H] ⁺ , calculated: 464.

Example 4: 1-(4-((9-(3-fluorobenzyl)-9H-purin-6-yl)oxy)phenyl)-3-(4-chloro-3-trifluoromethylbenzene base) urea

4-(9-(3-fluorobenzyl)-9H-purine-6-oxygen)aniline and 4-chloro-3-trifluoromethylaniline are raw materials, and the preparation method of Example 1 is used to obtain light yellow solid .

¹ HNMR (CDCl ₃ , 500MHz) δ (ppm): 9.18 (s, 1H, NH), 8.92 (s, 1H, NH), 8.65 (s, 1H, purine-H,), 8.47 (s, 1H, purine -H,) 8.11(s, 1H, Ar-H), 7.67～7.65(d, 1H, Ar-H), 7.62～7.61(d, 2H, Ar-H), 7.54～7.52(d, 2H, Ar-H) -H), 7.48～7.40(m, 1H, Ar-H), 7.23～7.22(d, 2H, Ar-H), 7.18～7.13(m, 2H, Ar-H), 5.54(s, 2H, CH ₂ ).

ESI-MS m/z: 557 [M+H] ⁺ , calculated: 557.

Example 5: 1-(4-(3-aminoisoquinolin-5-yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea

Step A: 1-(2-Fluoro-5-(trifluoromethyl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3-dioxolane-2 Preparation of -yl)phenyl)urea

5.37g (30mmol) of 2-fluoro-5-trifluoromethylaniline and 3.03g (30mmol) of triethylamine were mixed and dissolved in 20mL of dichloromethane under ice bath conditions. Dissolve 2.97g (10mmol) of triphosgene in 20ml of dichloromethane, slowly add dropwise to the above reaction solution (keep the temperature of the reaction solution between 5 and 10°C), and continue to react under ice bath conditions after the dropwise addition 0.5h. The ice bath was removed, and 20 ml of dichloromethane mixed with 30 mmol of p-aminoboronic acid pinacol ester and 3.03 g (30 mmol) of triethylamine was added dropwise to the reaction solution at room temperature, and stirred overnight. After the reaction was completed, 50ml of water was poured into the reaction solution to quench, extracted with dichloromethane (2×20ml), washed with water (40ml) and saturated sodium chloride (40mL) successively, dried over anhydrous sodium sulfate and concentrated. The concentrated solution was separated by silica gel column chromatography to obtain a white powdery solid, which was 1-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(4-(4,4,5,5-tetrafluoromethyl) methyl-1,3-dioxolan-2-yl)phenyl)urea.

Step B: Preparation of 1-(4-(3-aminoisoquinolin-5-yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea

0.6mmol 1-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3-dioxolane-2 -base) phenyl) urea, 0.3mmol 5-bromo-3-aminoisoquinoline, 0.018mmol tetrakistriphenylphosphine palladium, 1ml10% sodium carbonate aqueous solution, 2ml ethanol and 2ml toluene join in the 25ml two-necked flask, nitrogen protection Then, heat to reflux at 110°C, react for 8 hours, remove the reaction solution under reduced pressure, add dichloromethane and water to dissolve, extract and remove the solvent, pass through the column, and recrystallize to obtain a light yellow solid, melting point: 152.3～153.2°C.

¹ H NMR (DMSO-D6, 500MHz) δ (ppm): 9.29 (s, 1H, NH), 8.91 (d, 1H, NH), 8.84 (s, 1H, quinoline-H), 8.65～8.63 (d, 1H, Ar-H), 7.79～7.78(d, 1H, Ar-H), 7.61～7.37(dd, 4H, Ar-H), 7.51～7.48(t, 1H, quinoline-H), 7.39～7.38( m, 1H, quinoline-H), 7.35～7.33(d, 1H, Ar-H), 7.20～7.17(t, 1H, quinoline-H), 6.62(s, 1H, quinoline-H), 5.88(s, 2H, _NH2 ).

ESI-MS m/z: 439 [MH] ^- , calcd: 439.

Example 6: 1-(4-(3-amino-1-(2-(4-methylpiperazin-1-yl)ethoxy)isoquinolin-5-yl)phenyl)-3-( 2-fluoro-5-(trifluoromethyl)phenyl)urea

With 1-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl ) phenyl) urea and 5-bromo-3-amino-1-(2-(4-methylpiperazin-1-yl) ethoxy) isoquinoline as raw material, the same as the preparation method of Example 5 step B , the target compound was obtained as a pale yellow solid.

¹ H NMR (DMSO-D6, 300MHz) δ (ppm): 9.28 (s, 1H, NH), 8.92 (d, 1H, NH), 8.66-8.64 (d, 1H, quinoline-H), 7.90-7.88 ( d, 1H, Ar-H), 7.60～7.36(dd, 4H, Ar-H), 7.53～7.49(t, 1H, Ar-H), 7.41～7.40(m, 1H, quinoline-H), 7.33～ 7.31(d, 1H, Ar-H), 7.13～7.10(t, 1H, quinoline-H), 6.18(s, 1H, quinoline-H), 5.74(s, 2H, NH ₂ ), 4.52～4.50(t , 2H, CH ₂ ), 2.81～2.80(t, 2H, CH ₂ ), 2.54～2.52(m, 4H, CH ₂ ), 2.36～2.32(m, 4H, CH ₂ ), 2.15(s, 3H, CH 2 ₃ ).

ESI-MS m/z: 583 [M+H] ⁺ , calculated: 583.

Example 7: 1-(4-(3-amino-1-morpholinoisoquinolin-5-yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea

With 1-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl ) phenyl) urea and 5-bromo-3-amino-1-morpholino isoquinoline as raw materials, with the preparation method of step B in Example 5, to obtain the light yellow solid target compound.

¹ H NMR (DMSO-D6, 500MHz) δ (ppm): 9.29 (s, 1H, NH), 8.93～8.92 (d, 1H, NH), 8.66～8.64 (d, 1H, quinoline-H), 7.87～ 7.85(d, 1H, Ar-H), 7.60～7.37(dd, 4H, Ar-H), 7.53～7.49(t, 1H, Ar-H), 7.41～7.40(m, 1H, quinoline-H), 7.29～7.28(d, 1H, Ar-H), 7.13～7.10(t, 1H, quinoline-H), 6.28(s, 1H, quinoline-H), 5.64(s, 2H, NH ₂ ), 3.85～3.84 (t, 4H, CH ₂ ), 3.26-3.24 (t, 4H, CH ₂ ).

ESI-MS m/z: 526 [M+H] ⁺ , calculated: 526.

Example 8: 1-(4-(3-amino-1-(4-methylpiperazin-1-yl)isoquinolin-5-yl)phenyl)-3-(2-fluoro-5-( Trifluoromethyl)phenyl)urea

With 1-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl ) phenyl) urea and 5-bromo-3-amino-1-(4-methylpiperazin-1-yl) isoquinoline as raw materials, with the preparation method of Example 5 step B, to obtain light yellow solid target compound .

¹ H NMR (DMSO-D6, 300MHz) δ (ppm): 9.30 (s, 1H, NH), 8.95～8.94 (d, 1H, NH), 8.67～8.64 (d, 1H, quinoline-H), 7.82～ 7.79(d, 1H, Ar-H), 7.60～7.36(dd, 4H, Ar-H), 7.55～7.48(t, 1H, Ar-H), 7.43～7.40(m, 1H, quinoline-H), 7.28～7.26(d, 1H, Ar-H), 7.13～7.08(t, 1H, quinoline-H), 6.24(s, 1H, quinoline-H), 5.62(s, 2H, NH ₂ ), 3.27(s , 4H, CH ₂ ), 2.58 (s, 4H, CH ₂ ), 2.28 (s, 3H, CH ₃ ).

ESI-MS m/z: 539 [M+H] ⁺ , calculated: 539.

Example 9: 1-(4-(3-amino-1-(3-(4-methylpiperazin-1-yl)propoxy)isoquinolin-5-yl)phenyl)-3-( 2-fluoro-5-(trifluoromethyl)phenyl)urea

With 1-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl ) phenyl) urea and 5-bromo-3-amino-1-(3-(4-methylpiperazin-1-yl) propoxy) isoquinoline as raw materials, with the preparation method of Example 5, to obtain Pale yellow solid target compound.

¹ HNMR (DMSO-D6, 300MHz) δ (ppm): 9.29 (s, 1H, NH), 8.92 (d, 1H, NH), 8.66-8.64 (d, 1H, quinoline-H), 7.92-7.90 (d , 1H, Ar-H), 7.60～7.35(dd, 4H, Ar-H), 7.53～7.50(t, 1H, Ar-H), 7.41～7.39(m, 1H, quinoline-H), 7.32～7.31 (d, 1H, Ar-H), 7.13～7.10(t, 1H, quinoline-H), 6.18(s, 1H, quinoline-H), 5.71(s, 2H, NH ₂ ), 4.43～4.40(t, 2H, CH ₂ ), 2.70～2.69(m, 2H, CH ₂ ), 2.45～2.33(m, 8H, CH ₂ ), 2.15(s, 3H, CH ₃ ), 1.98～1.95(m, 2H, CH ₂ ).

ESI-MS m/z: 597 [M+H] ⁺ , calculated: 597.

Example 10: 1-(4-(3-Amino-1-tetrahydropyrrolylisoquinolin-5-yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl) Urea

With 1-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl ) phenyl) urea and 5-bromo-3-amino-1-tetrahydropyrrolylisoquinoline as raw materials, with the preparation method of step B in Example 5, to obtain the light brown solid target compound.

¹ H NMR (DMSO-D6, 300MHz) δ (ppm): 9.28 (s, 1H, NH), 8.94 ~ 8.93 (d, 1H, NH), 8.67 ~ 8.64 (d, 1H, quinoline-H), 7.96 ~ 7.93 (d, 1H, Ar-H), 7.59～7.34(dd, 4H, Ar-H), 7.52～7.48(t, 1H, Ar-H), 7.41～7.40(m, 1H, quinoline-H), 7.21 ～7.18(d, 1H, Ar-H), 7.00～6.95(t, 1H, quinoline-H), 6.00(s, 1H, quinoline-H), 5.37(s, 2H, NH ₂ ), 3.71～3.67( s, 4H, CH ₂ ), 1.92-1.88 (s, 4H, CH ₂ ).

ESI-MS m/z: 510 [M+H] ⁺ , calculated: 510.

Example 11: 1-(4-(3-aminoisoquinolin-5-yl)phenyl)-3-(2-fluoro-5-methylphenyl)urea

With 1-(2-fluoro-5-methylphenyl)-3-(4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl) Urea and 5-bromo-3-aminoisoquinoline were used as raw materials, and the target compound was obtained as a light brown solid in the same way as the preparation method in Step B of Example 5.

¹ H NMR (DMSO-D6, 500MHz) δ (ppm): 9.18 (s, 1H, NH), 8.85 (d, 1H, NH), 8.51 (s, 1H, quinoline-H), 8.02～8.01 (d, 1H , Ar-H), 7.79～7.78(d, 1H, Ar-H), 7.60～7.36(dd, 4H, Ar-H), 7.36～7.34(t, 1H, quinoline-H), 7.22～7.19(t , 1H, quinoline-H), 7.11～7.10(t, 1H, Ar-H), 6.81(m, 1H, quinoline-H), 6.65(s, 1H, quinoline-H), 5.89(s, 2H, NH ₂ ), 2.50 (s, 3H, _CH3 ).

ESI-MS m/z: 387 [M+H] ⁺ , calculated: 387.

Example 12: 1-(4-(3-amino-1-(2-(4-methylpiperazin-1-yl)ethoxy)isoquinolin-5-yl)phenyl)-3-( 2-Fluoro-5-methylphenyl)urea (SHP-12)

With 1-(2-fluoro-5-methylphenyl)-3-(4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl) Urea and 5-bromo-3-amino-1-(2-(4-methylpiperazin-1-yl)ethoxy)isoquinoline are raw materials, the same as the preparation method of Example 5 step B, to obtain light yellow Solid target compound.

¹ H NMR (DMSO-D6, 500MHz) δ (ppm): 9.18 (s, 1H, NH), 8.50 (s, 1H, NH), 8.02-8.00 (d, 1H, quinoline-H), 7.90-7.88 (d , 1H, Ar-H), 7.58～7.32(dd, 4H, Ar-H), 7.32～7.30(d, 1H, Ar-H), 7.13～7.11(m, 1H, quinoline-H), 7.11～7.09 (d, 1H, Ar-H), 6.82～6.80(m, 1H, quinoline-H), 6.20(s, 1H, quinoline-H), 5.72(s, 2H, NH ₂ ), 4.52～4.50(t, 2H, CH ₂ ), 2.81(s, 2H, CH ₂ ), 2.66～2.58(m, 4H, CH ₂ ), 2.38～2.30(m, 4H, CH ₂ ), 2.28(s, 3H, CH ₃ ), 2.23 (s, 3H, _CH3 ).

ESI-MS m/z: 529 [M+H] ⁺ , calculated: 529.

Example 13: 1-(4-(3-amino-1-(2-morpholineethoxy)isoquinolin-5-yl)phenyl)-3-(2-fluoro-5-trifluoromethyl Phenyl)urea

With 1-(2-fluoro-5-trifluoromethylphenyl)-3-(4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)benzene Base) urea and 5-bromo-3-amino-1-(2-morpholineethoxy) isoquinoline as raw materials, with the synthesis method of Example 5, the light yellow solid target compound was obtained.

¹ HNMR (DMSO-D6, 300MHz) δ (ppm): 9.18 (s, 1H, NH), 8.50 (s, 1H, NH), 8.02-8.00 (d, 1H, quinoline-H), 7.90-7.88 (d , 1H, Ar-H), 7.58～7.32(dd, 4H, Ar-H), 7.32～7.30(d, 1H, Ar-H), 7.13～7.11(m, 1H, quinoline-H), 7.11～7.09 (d, 1H, Ar-H), 6.82～6.80(m, 1H, quinoline-H), 6.20(s, 1H, quinoline-H), 5.72(s, 2H, NH ₂ ), 4.52～4.50(t, 2H, CH ₂ ), 2.81 (s, 2H, CH ₂ ), 2.66-2.58 (m, 4H, CH ₂ ), 2.38-2.30 (m, 4H, CH ₂ ).

ESI-MS m/z: 570 [M+H] ⁺ , calculated: 570.

Example 14: 1-(4-(3-amino-(2-methoxyethoxy)isoquinolin-5-yl)phenyl)-3-(2-fluoro-5-trifluoromethylbenzene base) urea

With 1-(2-fluoro-5-trifluoromethylphenyl)-3-(4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)benzene Base) urea and 5-bromo-3-amino-1-(2-methoxyethoxy) isoquinoline as raw materials, with the synthesis method of Example 5, the light yellow solid target compound was obtained.

¹ H NMR (DMSO-D6) δ (ppm): 9.29 (s, 1H, NH), 8.92 (d, 1H, NH), 8.66-8.64 (d, 1H, quinoline-H), 7.92-7.91 (d, 1H , Ar-H), 7.60～7.5(dd, 4H, Ar-H), 7.32～7.30(d, 1H, Ar-H), 7.13～7.11(m, 1H, quinoline-H), 7.11～7.09(d , 1H, Ar-H), 6.82～6.80(m, 1H, quinoline-H), 6.20(s, 1H, quinoline-H), 5.72(s, 2H, NH ₂ ), 4.54～4.52(t, 2H, CH ₂ ), 3.78-3.76 (t, 2H, CH ₂ ), 3.36 (s, 3H, CH ₃ ).

ESI-MS m/z: 515[M+H] ⁺ , calculated: 515

Example 15: 1-(4-(3-Aminoisoquinolin-5-yl)phenyl)-3-(4-chloro-3-trifluoromethylphenyl)urea

With 1-(4-chloro-3-trifluoromethylphenyl)-3-(4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)benzene base) urea and 5-bromo-3-aminoisoquinoline as raw materials, with the synthetic method of Example 5, to obtain the light yellow solid target compound.

¹ HNMR (DMSO-D6, 300MHz) δ (ppm): 9.21 (s, 1H, NH), 9.00 (d, 1H, NH), 8.86 (d, 1H, quinoline-H), 8.14 (d, 1H, Ar -H), 7.90～7.78(d, 1H, Ar-H), 7.70～7.66(m, 2H, quinoline-H), 7.62～7.59(m, 2H, Ar-H), 7.40～7.37(m, 2H , Ar-H), 7.34(s, 1H, Ar-H), 7.22～7.17(m, 1H, quinoline-H), 6.64(m, 1H, quinoline-H), 5.92(s, 2H, NH ₂ ) .

ESI-MS m/z: 457[M+H] ⁺ , calculated: 457

Example 16: 1-(4-(3-amino-1-(3-(4-methylpiperazin-1-yl)propylamino)isoquinolin-5-yl)phenyl)-3-(2 -Fluoro-5-(trifluoromethyl)phenyl)urea

With 1-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl ) phenyl) urea and 5-bromo-3-amino-1-(3-(4-methylpiperazin-1-yl) propylamino) isoquinoline as raw materials, with the synthetic method of embodiment 5 step B, to obtain Pale yellow solid target compound.

¹ HNMR (DMSO-D6, 500MHz) δ (ppm): 9.29 (s, 1H, NH), 8.91 (d, 1H, NH), 8.66-8.64 (d, 1H, quinoline-H), 7.92-7.90 (d , 1H, Ar-H), 7.57～7.55(d, 2H, Ar-H), 7.52～7.48(t, 1H, quinoline-H), 7.41～7.39(m, 1H, Ar-H), 7.34～7.32 (d, 2H, Ar-H), 7.26～7.24(t, 1H, Ar-H), 7.20～7.18(t, 1H, quinoline-H), 7.00～6.97(t, 1H, quinoline-H), 5.81 (s, 1H, NH), 5.28 (s, 2H, NH ₂ ), 3.48-3.44 (m, 2H, CH ₂ ), 2.41-2.36 (m, 10H, CH ₂ ), 2.16 (s, 3H, CH ₃ ), 1.82-1.76 (m, 2H, CH ₂ ).

ESI-MS m/z: 596 [M+H] ⁺ , calculated: 596.

Example 17: 1-(4-(3-aminoisoquinolin-5-yl)phenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-( Trifluoromethyl)phenyl)urea

With 1-(4-((4-methylpiperazin-1-yl)methyl))-3-trifluoromethylphenyl)-3-(4-(4,4,5,5-tetramethyl Base-1,3-dioxolan-2-yl)phenyl)urea and 5-bromo-3-aminoisoquinoline were used as raw materials, and the target compound was obtained as a pale yellow solid according to the synthesis method of step B in Example 5.

¹ H NMR (DMSO-D6, 500MHz) δ (ppm): 9.03 (s, 1H, NH), 8.89 (s, 1H, NH), 8.85 (s, 1H, quinoline-H), 7.98 (s, 1H, Ar -H), 7.79(d, 1H, Ar-H), 7.65～7.59(m, 4H, Ar-H), quinoline-H), 7.39～7.34(m, 3H, Ar-H), 7.20(t, 1H, quinoline-H), 6.65 (s, 1H, quinoline-H), 5.89 (s, 2H, NH ₂ ), 3.53 (s, 2H, CH ₂ ), 2.47～2.24 (m, 8H, CH ₂ ), 2.16 (s, 3H, _CH3 )

ESI-MS m/z: 535 [M+H] ⁺ , calculated: 535.

Example 18: 1-(4-(3-Amino-1-(3-methoxypropynyl)isoquinolin-5-yl)phenyl)-3-(2-fluoro-5-(trifluoro Methyl)phenyl)urea

With 1-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl ) phenylurea and 5-bromo-1-(3-methoxypropynyl)isoquinoline-3-amino as raw materials, the same synthesis method as in Example 5, Step B, to obtain a light yellow solid.

¹ H NMR (DMSO-D6, 500MHz) δ (ppm): ¹ H NMR (DMSO-D6) δ (ppm): 9.32 (s, 1H, NH), 8.93 (d, 1H, NH), 8.66-8.64 (d , 1H, quinoline-H), 8.06～8.05(d, 1H, Ar-H), 7.63～7.61(m, 2H, Ar-H), 7.53～7.49(m, 1H, quinoline-H), 7.40～7.38 (m, 4H, quinoline-H, Ar-H), 7.30～7.27 (d, 1H, quinoline-H), 6.70 (s, 1H, Ar-H), 6.05 (s, 2H, NH ₂ ), 4.50 ( m, 2H, _CH2 ), 3.43 (s, 3H, _CH3 ).

ESI-MS m/z: 509 [M+H] ⁺ , calculated: 509.

Example 19: 1-(4-(3-amino-1-(3-dimethylaminopropynyl)isoquinolin-5-yl)phenyl)-3-(2-fluoro-5-(trifluoro Methyl)phenyl)urea

With 1-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl ) phenylurea and 5-bromo-1-(3-dimethylaminopropynyl) isoquinoline-3-amino as raw materials, with the synthetic method of step B in Example 5, to obtain a light yellow solid.

¹ HNMR (DMSO-D6) δ (ppm): 9.33 (s, 1H, NH), 8.94 (d, 1H, NH), 8.67-8.64 (d, 1H, quinoline-H), 8.10-8.07 (d, 1H , Ar-H), 7.63～7.60(m, 2H, Ar-H, quinoline-H), 7.54～7.40(m, 1H, quinoline-H), 7.40～7.37(dd, 4H, Ar-H), 7.30 ~7.25 (d, 1H, quinoline-H), 6.67 (s, 1H, Ar-H), 6.04 (s, 2H, NH ₂ ), 3.64 (m, 2H, CH ₂ ), 2.33 (s, 6H, CH ₃ ).

ESI-MS m/z: 522 [M+H] ⁺ , calculated: 522.

Example 20: 1-(4-(2-Amino-7H-pyrrole[2,3-d]pyrimidine)(-7-yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl ) phenyl) urea

Step A Preparation of 1-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(4-iodophenyl)urea

Dissolve 2.97g (10mmol) of triphosgene in 20ml of dichloromethane, then mix 5.37g (30mmol) of 2-fluoro-5-trifluoromethylaniline with 3.03g (30mmol) of triethylamine in an ice bath Dissolve in 20ml of dichloromethane, and slowly add dropwise to the above reaction solution (keep the temperature of the reaction solution between 5-10°C), and continue to react under ice bath conditions for 0.5h after the dropwise addition is complete. The ice bath was removed, and 20 ml of dichloromethane mixed with 30 mmol of substituted 4-iodoaniline and 3.03 g (30 mmol) of triethylamine was added dropwise to the reaction solution at room temperature, and stirred overnight. After the reaction, pour 50 mL of water into the reaction solution to quench, extract with dichloromethane (2×20 ml), wash with water (40 ml), saturated sodium chloride (40 ml) successively, dry over anhydrous sodium sulfate and concentrate. The concentrated solution was separated by silica gel column chromatography to obtain a white powdery solid.

Step B Preparation of 1-(4-(2-amino-7H-pyrrole[2,3-d]pyrimidine)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea

0.75mmol 1-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(4-iodophenyl)urea, 0.5mmol 7H-pyrrolo[2,3-d]pyrimidine-2- Amino, 0.05mmol cuprous iodide, 1mmol L-proline, 2mmol potassium carbonate, and 5mL DMSO were placed in a 50mL single-necked bottle, and reacted at 110°C under nitrogen protection for 16h. After the reaction was completed, water and ethyl acetate were added for extraction, and the organic layer was taken, desolvated, and separated by column chromatography to obtain a light yellow solid.

¹ H NMR (DMSO-D6) δ (ppm): 9.25 (s, 1H, NH), 8.87 (d, 1H, NH), 8.68 (s, 1H, pyrimidine-H), 8.55～8.53 (d, 1H, Ar -H), 7.6(m, 1H, pyrimidine-H), 7.5(t, 1H, Ar-H), 7.61～7.37(dd, 4H, Ar-H), 7.4(m, 1H, Ar-H), 6.72 (s, 1H, pyrimidine-H), 5.88 (s, 2H, _NH2 ).

ESI-MS m/z: 431 [M+H] ⁺ , calculated: 431.

Example 21: 1-(4-(2-Amino-4-(4-methylpiperazin-1-yl)-7H-pyrrole[2,3-d]pyrimidine)(-7-yl)phenyl) -3-(2-fluoro-5-(trifluoromethyl)phenyl)urea

With 1-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(4-iodophenyl)urea and 4-(4-methylpiperazin-1-yl)-7H-pyrrole[ 2,3-d] pyrimidine-2-amino as raw material, the same synthesis method as in Example 20, step B, to obtain a light yellow solid.

¹ H NMR (DMSO-D6) δ (ppm): 9.25 (s, 1H, NH), 8.87 (d, 1H, NH), 8.68 (s, 1H, pyrimidine-H), 8.55～8.53 (d, 1H, Ar -H), 7.6(m, 1H, pyrimidine-H), 7.5(t, 1H, Ar-H), 7.61～7.37(dd, 4H, Ar-H), 7.4(m, 1H, Ar-H), 5.88 (s, 2H, _NH2 ), 3.27 (s, 4H, _CH2 ), 2.58 (s, 4H, _CH2 ), 2.28 (s, 3H, _CH3 ).

ESI-MS m/z: 527 [M+H] ⁺ , calculated: 527.

Example: 22: 1-(4-chloro-3-trifluoromethylphenyl)-3-(2-oxo-3-(pyridin-2-yl-methyl)-2,3-dihydrobenzene and[d]oxazol-6-yl)urea

Step A: Preparation of 6-nitrobenzo[d]oxazolidin-2-one

Add 3.08g (20mmol) of 2-amino-5-nitrophenol, 3.24g (10mmol) of CDI, and anhydrous THF into a 100ml round bottom flask, heat to 65°C, and reflux for 5h. After TLC detected that the reaction of the raw materials was complete, the reaction was stopped, and the solvent was spin-dried to obtain an oily substance. Add 2M hydrochloric acid solution to form a salt, filter to obtain a yellow solid, and recrystallize from acetonitrile to obtain brown needle-like crystals.

Step B: Preparation of 6-nitrobenzo[d]3-(pyridin-2-ylmethyl)oxazolidin-2-one

Dissolve 1.81 g (10 mmol) of the product obtained in step A in a three-necked flask containing 70 ml of acetonitrile, and heat to reflux. After all of the solution is dissolved, add 1 ml of chloromethylpyridine, and reflux at 65° C. for 8 h. It was detected by TLC that the reaction was complete, the reaction was stopped, the solvent was spin-dried, and recrystallized from isopropanol (about 150ml) to obtain pale yellow needle-like crystals.

Step C: Preparation of 6-aminobenzo[d]3-(pyridin-2-ylmethyl)oxazolidin-2-one

0.5 g (1.8 mmol) of the product obtained in step B was dissolved in a round-bottomed flask containing 40 ml of a mixed solvent of ethyl acetate and ethanol, and heated to 60°C. Add 3.0 g of tin protochloride after all dissolving, the reaction solution changes from clarification to milky white, after reacting for 2 hours, TLC detects, when the raw material point disappears, stop the reaction, at this moment the reaction solution is pink. Cool to room temperature, adjust the pH to neutral or slightly alkaline 7-8, extract three times with dichloromethane (20ml×3), dry the organic layer with Na ₂ SO ₄ overnight, and spin the solvent to obtain a reddish solid.

Step D: 1-(4-Chloro-3-trifluoromethylphenyl)-3-(2-oxo-3-(pyridin-2-yl-methyl)-2,3-dihydrobenzo[ d] Preparation of oxazol-6-yl)urea

Add 0.22g (0.9mmol) of step C resultant and CDI 0.21g (1.3mmol) into a 50ml three-neck flask, under nitrogen protection conditions, add 15ml of anhydrous dichloromethane, react at room temperature for 12h, and detect the reaction by TLC , when the raw material point disappears, the solution is white slurry, add 0.3g (1.5mmol) of 4-chloro-3-fluoromethylaniline, the solution becomes clear from the white slurry, continue to react for 4h, the solution has a white precipitate, the solution is Slurry. Filtrate, wash with dichloromethane to obtain the crude product, and recrystallize from THF to obtain the title compound as a white solid.

¹ H NMR (DMSO-d ₆ , 300MHz) δ (ppm): 9.19 (s, 1H, NH), 8.92 (s, 1H, NH), 8.49 (d, 1H, pyridine-H), 8.09 (s, 1H , Ar-H), 7.83-7.78 (t, 1H, pyridine-H), 7.64-7.58 (m, 3H, Ar-H, Benzoxazol-H), 7.43 (d, 1H, Benzoxazol-H), 7.34-7.30 (m, 1H, Ar-H), 7.11-7.01 (m, 2H, Pyridine-H), 5.13 (s, 2H, _CH2 ).

ESI-MS m/z: 463 [M+H] ⁺ , calculated: 463.

Example 23: 1-Benzyl-3-(2-oxo-3-(pyridin-2-yl-methyl)-2,3-dihydrobenzo[d]oxazol-6-yl)urea

Using 2-amino-5-nitrophenol, chloromethylpyridine and benzylamine as raw materials, the same synthesis method as in Example 22 was used to obtain a light yellow solid.

¹ H NMR (DMSO-d ₆ , 300MHz) δ (ppm): 8.63 (s, 1H, NH), 8.49 (d, 1H, NH), 7.82～7.77 (t, 1H, pyridine-H), 7.64 (s , 1H, pyridine-H), 7.41-7.38(d, 1H, Benzoxazol-H), 7.35～7.23(m, 5H, Ar-H), 6.97(s, 2H, Benzoxazo-H), 6.87(s, 1H , pyridine-H,) 6.63~6.60 (d, 1H, pyridine-H), 5.10 (s, 2H, CH ₂ ), 4.29 (d, 2H, CH ₂ ).

ESI-MS m/z: 375 [M+H] ⁺ , calculated: 375.

Example: 24: 1-(4-chloro-3-trifluoromethylphenyl)-3-(2-oxo-3-(6-chloropyrimidin-4-yl)-2,3-dihydrobenzene and[d]oxazol-6-yl)urea

Using 2-amino-5-nitrophenol, 4,6-dichloropyrimidine and 4-chloro-3-trifluoromethylaniline as raw materials, the synthesis method was the same as in Example 22 to obtain a pale white solid.

¹ HNMR (DMSO-d ₆ , 300MHz) δ (ppm): 9.36 (s, 1H, NH), 9.26 (s, 1H, NH), 9.08 (s, 1H, Pyrimidine-H), 8.26～8.23 (m, 2H, Ar-H, Benzoxazol-H), 8.10(s, 1H, Ar-H), 7.77(s, 1H, Ar-H), 7.63-7.59(m, 2H, Benzoxazol-H), 7.25(d, 1H, pyrimidine-H).

ESI-MS m/z: 484 [M+H] ⁺ , calculated: 484.

Example 25: 1-Benzyl-3-(2-oxo-3-(6-chloropyrimidin-4-yl)-2,3-dihydrobenzo[d]oxazol-6-yl)urea

Using 2-amino-5-nitrophenol, 4,6-dichloropyrimidine and benzylamine as raw materials, the synthesis method was the same as in Example 22 to obtain a pale white solid.

¹ HNMR (DMSO-d ₆ , 300MHz) δ (ppm): 9.07 (s, 1H, NH), 8.94 (s, 1H, NH), 8.27～8.18 (m, 2H, Pyrimidine-H, Benzoxazol-H), 7.79(s, 1H, Benzoxazol-H), 7.32～7.27(m, 5H, Ar-H), 7.16～7.13(d, 1H, Benzoxazol-H), 6.74(s, 1H, Pyrimidine-H), 4.32～ 4.30 (d, 2H, _CH2 ).

ESI-MS m/z: 396 [M+H] ⁺ , calculated: 396.

Example 26: In vitro anti-tumor activity test of some compounds

Using MTT test

1. Collect the logarithmic phase cells, adjust the concentration of the cell suspension so that the cell concentration is about 1×10 ⁵ , and inoculate them into 96-well plates, 100ul per well.

2. Cultivate the cells in a 37°C, 5% CO ₂ incubator to make the cells adhere to the wall.

3. Add different concentrations of drugs (drugs should be properly treated, such as solubility, sterilization, etc.), the time is based on the needs of the experiment, generally 48 hours.

4. Carefully suck off the supernatant, wash gently with PBS, and discard the supernatant again.

5. Add 180ul of fresh RPMI1640 culture solution to each space, and then add 20ul of MTT solution (5mg/ml, ie 0.5% MTT), and continue to cultivate for 4h.

6. Terminate the culture, carefully aspirate the culture medium in the well.

7. Add 150ul dimethyl sulfoxide to each well, shake on a shaker at a low speed for 10 minutes, and fully dissolve the crystals.

8. Measure the absorbance of each well at 490 nm in an enzyme-linked immunosorbent assay instrument.

9. Calculate the IC ₅₀ value, the experimental results are shown in the table below

In vitro activity test results of some compounds

Embodiment 27: B-raf enzyme activity test

Test the ability of Example 13 of the present invention to inhibit the activity of B-raf

1), the compound to be tested (Example 13), the reference compound or water (control) and the buffer containing enzyme (24ng) are mixed. For the control base test, no enzyme was added to the reaction solution. The buffer contained 40 mM Hepes/Tris (pH 7.4), 0.8 mM EGTA/Tris, 8 mM MgCl ₂ , 1.6 mM DTT and 0.008% Tween 20.

2) Add 15nM substrate (Histidine-tagged unactivated MEK1) and 1μM ATP, and incubate at room temperature for 30min.

3) At the end of incubation, add 13mM EDTA to stop the reaction.

4) After 5 minutes, the phosphorylated MEK1/2 antibody labeled with europium chelate was added, followed by the addition of Ulight-anti-histidine tag.

5) After 1 hour, measure the fluorescence shift with a microplate reader, the wavelengths are λex=337nm, λem=620nm and λem=665nm.

6), the enzyme activity is measured by the ratio of 665nm and 620nm signals. The test results are expressed as the percentage inhibition relative to the enzyme activity of the control group. The reference substance of the standard inhibition curve is Raf-1 inhibitor, and several concentrations are set in each test to determine its IC ₅₀ value.

Embodiment 13 of the present invention is relative to the inhibition percentage of control group enzyme activity

Example 28: VEGFR-2 enzyme activity test

Test the ability of Example 17 of the present invention to inhibit VEGFR-2 activity

1), the compound to be tested (Example 17), the reference compound or water (control) and the buffer containing enzyme (0.88ng) are mixed. For the control base test, no enzyme was added to the reaction solution. The buffer contained 40 mM Hepes/Tris (pH 7.4), 0.8 mM EGTA/Tris, 8 mM MgCl ₂ , 1.6 mM DTT and 0.008% Tween 20.

2) Add 100 nM substrate Ulight-CAGAGAIETDKEYYTVKD (JAK1) and 25 μM ATP, and incubate at room temperature for 60 min.

3) At the end of incubation, add 13mM EDTA to stop the reaction.

4) After 5 minutes, add phosphorylated PT66 antibody labeled with europium chelate

5) After 1 hour, measure the fluorescence shift with a microplate reader, the wavelengths are λex=337nm, λem=620nm and λem=665nm

6), the enzyme activity is measured by the ratio of 665nm and 620nm signals. The test results are expressed as the percentage inhibition relative to the enzyme activity of the control group. The reference substance of the standard inhibition curve is staurosporine, and several concentrations are set in each test to determine its IC ₅₀ value.

Embodiment 17 of the present invention is relative to the inhibition percentage of control group enzyme activity

Embodiment 29: Pharmacokinetic evaluation

The pharmacokinetic test of embodiment 12 compound of the present invention

Taking SD rats as the test animals, the drug concentration in the blood plasma at different times after intragastric administration of the compound of Example 12 to the rats was determined by LC/MS/MS method. Study the pharmacokinetic behavior of the compound of the present invention in rats, and evaluate its oral absorption pharmacokinetic characteristics.

1. Test plan:

Test drug: compound of Example 12

Test animals: 12 healthy SD rats (male, body weight 224-300g)

2. Test method:

1) Liquid-mass spectrometry analysis method

LC-MS/MS system: Shimadzu UFLC 20-AD XR ultra-fast liquid phase system and the American Department of Applied Biology

          System Company API-5000 Triple Quadrupole Mass Spectrometry

Column: ACE 5μC18, 50×2.1mm

Mobile phase: 0.4% aqueous formic acid (pH 3.2): acetonitrile

Ion pair: 529.4/127.2

2) Linear quantitative range: Linear range: 0.5-250ng/mL; linear correlation (R ² ): 0.9960

3. Drug administration and blood collection plan

Twelve healthy SD rats (male, body weight 224-300g), 3 in each group, were fasted for about 16 hours before the test, and had free access to drinking water; the pharmaceutical excipients were 10% ethanol, 20% PEG200, and 70% saline.

The compound of Example 12 was intragastrically administered, the dosage was 7 mg/kg, and the volume of administration was 5 mL/kg. Feeds were given uniformly 4 hours after administration. Before administration and at 0.17, 0.33, 0.67, 1, 2, 4, 8, and 24 hours after administration, 0.3 mL of blood was collected through the jugular vein cannula, placed in an EDTA centrifuge tube, and centrifuged at 3200 g for 10 min at 4°C to separate plasma. Except during sample analysis, all plasma samples were collected and stored in a -20C refrigerator.

4. Operation: Take 50uL of plasma sample, add 150uL of methanol to precipitate, suspend and oscillate, then centrifuge twice, and take the supernatant for LC-MS/MS analysis. The main pharmacokinetic parameters were calculated using WinNonlin (version 5.3) according to the non-compartmental model.

5. Results of pharmacokinetic parameters

The hemopharmacokinetic parameter of embodiment 12 after male SD rat is given 7mg/kg embodiment 12 by intragastric administration

Claims (19)

1. Compounds represented by general formula (I) or their pharmaceutically acceptable salts or enantiomers: in: m is 0; L is in X is O; R ₄ is selected from hydrogen, halogen and C _1-8 alkyl; R ₅ is selected from (CH ₂ ) _p R ₆ , wherein R ₆ is selected from C _6-14 aryl and C _3-10 heteroaryl, the C _6-14 aryl or C _3-10 heteroaryl can be independently substituted by one or more halogens, p is 1; R ₁ is selected from hydrogen, halogen, C _1-8 alkyl and halogenated C _1-8 alkyl. 2. The compound of general formula (I) according to claim ₁ or its pharmaceutically acceptable salt or enantiomer, wherein R is selected from hydrogen, halogen, C _1-5 alkyl and halogenated C _1-5 alkyl. 3. The compound of general formula (I) or a pharmaceutically acceptable salt or enantiomer thereof according to claim 2, wherein R ₁ is selected from hydrogen, Cl, Br, F, methyl and trifluoromethyl. 4. The compound of general formula (I) according to any one of claims 1-3, or its pharmaceutically acceptable salt or enantiomer, wherein R ₄ is selected from hydrogen, F, Cl, Br and C _{1- 3} alkyl. 5. The compound of general formula (I) or a pharmaceutically acceptable salt or enantiomer thereof according to claim 4, wherein R ₄ is hydrogen. 6. The compound of general formula (I) according to any one of claims 1-3, or a pharmaceutically acceptable salt or enantiomer thereof, wherein R _{is selected from C 6-10 aryl} and C _3-7 Heteroaryl, the C _6-10 aryl or C _3-7 heteroaryl is optionally further substituted by halogen. 7. The compound of general formula (I) or its pharmaceutically acceptable salt or enantiomer according to claim 4, wherein R _{is selected from C 6-10 aryl} and C _3-7 heteroaryl, said The C _6-10 aryl or C _3-7 heteroaryl is optionally further substituted by halogen. 8. The compound of general formula (I) or its pharmaceutically acceptable salt or enantiomer according to claim 6, wherein R ₆ is selected from phenyl, pyridyl, chlorophenyl and chloropyridyl. 9. The compound of general formula (I) or its pharmaceutically acceptable salt or enantiomer according to claim 7, wherein R ₆ is selected from phenyl, pyridyl, chlorophenyl and chloropyridyl. 10. The compound of general formula (I) or its pharmaceutically acceptable salt or enantiomer according to claim 1, wherein said compound of general formula (I) is selected from: 1-(4-((9-Benzyl-9H-purin-6-yl)oxy)phenyl)-3-(4-chloro-3-trifluoromethylphenyl)urea; 1-(4-((9-(pyridine-2-methyl)-9H-purin-6-yl)oxy)phenyl)-3-(4-chloro-3-trifluoromethylphenyl)urea; and 1-(4-((9-(3-fluorobenzyl)-9H-purin-6-yl)oxy)phenyl)-3-(4-chloro-3-trifluoromethylphenyl)urea. 11. The compound or pharmaceutically acceptable salt or enantiomer thereof according to any one of claims 1-3, 5 and 7-10, wherein said pharmaceutically acceptable salt is obtained by said general formula (I) The corresponding salt of the compound formed with an acid selected from inorganic acids and organic acids. 12. The compound according to claim 4 or its pharmaceutically acceptable salt or enantiomer, wherein said pharmaceutically acceptable salt is composed of said compound of general formula (I) and an acid selected from inorganic acids and organic acids The corresponding salt is formed. 13. The compound according to claim 6 or its pharmaceutically acceptable salt or enantiomer, wherein said pharmaceutically acceptable salt is composed of said compound of general formula (I) and an acid selected from inorganic acids and organic acids The corresponding salt is formed. 14. The compound according to claim 11 or its pharmaceutically acceptable salt or enantiomer, wherein said inorganic acid is selected from phosphoric acid, sulfuric acid, hydrochloric acid, nitric acid and hydrobromic acid, and said organic acid is selected from acetic acid, Trifluoroacetic acid, propionic acid, malonic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, mandelic acid, sulfonic acid, p-toluenesulfonic acid , methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid and salicylic acid. 15. The compound according to claim 12 or 13, or a pharmaceutically acceptable salt or enantiomer thereof, wherein the inorganic acid is selected from phosphoric acid, sulfuric acid, hydrochloric acid, nitric acid and hydrobromic acid, and the organic acid is selected from Acetic acid, trifluoroacetic acid, propionic acid, malonic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, mandelic acid, sulfonic acid, p-toluene Sulfonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid and salicylic acid. 16. A pharmaceutical composition comprising a compound of general formula (I) or a pharmaceutically acceptable salt or enantiomer thereof and a pharmaceutically acceptable carrier or excipient according to any one of claims 1-15 . 17. The compound of general formula (I) described in any one in claim 1-15 or its pharmaceutically acceptable salt or enantiomer or the pharmaceutical composition described in claim 16 is used for treating or preventing tumor application in medicines. 18. The application according to claim 17, wherein said tumor is melanoma, liver cancer, kidney cancer, breast cancer, lung cancer, thyroid cancer, bladder cancer, colon cancer, rectal cancer, prostate cancer, pancreatic cancer, ovarian cancer, head and neck cancer Carcinoma, acute myeloid leukocytosis, chronic myeloid leukocytosis, peritoneal carcinoma, mesothelioma, myelodysplastic syndrome, or gastric cancer. 19. The use according to claim 18, wherein said tumor is non-small cell lung cancer or myeloma.