WO2014044025A1

WO2014044025A1 - Pyrimidineamide derivative and preparation method and use thereof

Info

Publication number: WO2014044025A1
Application number: PCT/CN2013/001107
Authority: WO
Inventors: 王爱臣; 钱林艺
Original assignee: 山东亨利医药科技有限责任公司
Priority date: 2012-09-20
Filing date: 2013-09-18
Publication date: 2014-03-27
Also published as: CN104640863A; CN104640863B

Abstract

Provided are a pyrimidineamide derivative as represented by general formula (I), pharmaceutically acceptable salt thereof, and stereoisomer thereof or solvent compound thereof, wherein X, Y, A, R¹ and R² are as defined in the specification; also provided are a preparation method of the compounds, pharmaceutical composition containing the compounds, and uses of the compounds in the preparation of drugs for treating and/or preventing syk-mediated signal-path-related diseases.

Description

Pyrimidine amine derivative, preparation method and application thereof

The present invention relates to the field of medical technology, and in particular to a pyrimidine amine derivative, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof, a process for preparing the same, a pharmaceutical composition containing the same, and the like, pharmaceutically acceptable salts thereof, a stereoisomer thereof or a solvate thereof for the treatment and / or prophylaxis of diseases associated signal path _S yk mediated by the medicament in.

Background technique

Protein tyrosine kinases (PTKs) are a group of proteases that catalyze the phosphorylation of substrate protein tyrosine residues, participate in many signal transduction pathways, and play an important role in controlling cell differentiation, proliferation and proliferation. . Depending on the cellular topology of members of the PTKs family, they can be divided into receptor and non-receptor types. Ligand binding to the extracellular domain of the PTKs receptor activates its intracellular tyrosine kinase domain, triggering specific signal transduction pathways. Intracellular non-receptor type PTKs play a important role in many aspects such as transmembrane receptors lacking endogenous PTKs in their ligand structure.

Syk is a soluble non-receptor tyrosine kinase. It was cloned from the pig spleen cDNA by Taniguchi in 991. The human Syk coding gene is a 5^: gene located on human chromosome 9q ²² . The protein has a molecular weight of 72KD and consists of 629 amino acids, which plays a key role in the maturation and activation of B cells.

Syk is one of the important factors affecting the B cell antigen receptor (BCR) signal transduction pathway. After BCR activation, Syk-dependent signal transduction pathways are involved in the regulation of B cell clone expression, differentiation or apoptosis. Syk is the most important kinase in B cell activation signaling, and it contains two Src homologous domains SH2 (N) and SH2 (C), thus becoming an immunotyrosine receptor activation motif (immunoreceptor tyrosine- Based activation motif, ITAM) The preferred target for acidification recruitment. The recruited Syk immediately became the second target of Src action, which in turn initiates three major pathways for B cell activation signaling (phosphatidylinositol pathway, MAP kinase-associated pathway and phosphoinositide 3-kinase pathway). Phospholipase C (PLC)-y 2, phosphatidylinositol! 3-kinase (PI3K) is a key substrate for Syk tyrosine phosphorylation. In B cells, Syk phosphorylation of PLC-y2 causes cascade activation of ERK and JNK kinase, whereas PI3-K is phosphorylated by Syk to mediate Akt activation. Syk preferentially phosphorylates the a subunit of tubulin, which is thought to regulate cytoskeletal tubulin as a scaffold for assembly of signal transduction complexes. Most The final activation of each transcription factor translocates into the nucleus and binds to various cis-acting elements or DNA cassettes in the promoter region of the gene, causing transcriptional activation and product expression of the corresponding gene.

ITA-mediated signaling events are key factors in the transmission of activated immune signals, such as T cell receptors, B cell receptors, Fc receptors, and GPVI in platelets, to downstream intracellular molecules such as syk. .

Syk inhibitors inhibit the tyrosine kinase activity of syk, control signal activation in mast cells, basophils and other immune cells, thereby inhibiting the release of cellular mediators associated with inflammatory responses, thus providing broad therapeutic prospects for inflammatory diseases. For example, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, hemolytic anemia, immune thrombocytopenic purpura, heparin-induced thrombocytopenia, and atherosclerosis.

A class of Syk inhibitors is disclosed in Japanese Patent No. JP2004203748, but such compounds have poor pK, poor absorption, poor bioavailability, poor drug use, and even some compounds have pK that do not meet the drug requirements.

Rheumatoid arthritis is a common joint disease with a high incidence and disability. Because there is no cure for rheumatoid, it is called "undead cancer." The existing therapeutic drugs mainly include non-steroidal anti-inflammatory drugs and steroids, but these drugs have large side effects and cannot meet clinical long-term use requirements. In addition, the latest advances in rheumatoid drugs are the use of some biological agents, such as TNF-α inhibitors, IL-Ι β antagonists. Although patients are well tolerated, they are expensive and difficult to widely promote. In summary, rheumatoid arthritis treatment drugs with a new mechanism of action with small side effects and low cost are still needed clinically. Therefore, there is an urgent need to study new Syk inhibitors with good therapeutic effects.

Summary of the invention

In order to solve the problems existing in the prior art, the present invention provides a kind of compound which has good absorption, good stability, high bioavailability and good medicinal properties, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof. . The technical scheme of the present invention is as follows:

Technical solution 1 :

a compound of the formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof:

Wherein X is selected from a phenylene group or a 5-6 membered heteroarylene group;

R ^{1 is} selected from a 5-6 membered heteroaryl group,

R ¹ may be optionally substituted with 1-3 substituents R ³ is further substituted, the substituents independently selected from R ^3. ₈ alkyl, C ₂ _ ₈ alkenyl group, an alkynyl group, an amino group, a hydroxyl group, D. ₈ alkoxy An oxy group, a halogen atom, an alkylamino group, a di(C^alkyl)amino group, an alkylcarbonyl group, a carbamoyl group, a d. ₈ alkylcarbonylamino group, (^ ₈ alkylcarbamoyl group, an amino group ( _μ8 alkyl group, Hydroxy d. ₈ alkyl, cyano, C ₈ alkyl, alkoxy or aminosulfonyl;

R ^{2 is} selected from a hydrogen atom or a C ₈ alkyl group;

Y is selected from C _3-8 cycloalkyl, 4-8 membered heterocycloalkyl, 7-12 membered saturated spiro group, 6-10 membered saturated fused ring group, C _3-8 cycloalkyl < ₁₄ alkyl group, 4-8 membered heterocycloalkyl C _M alkyl, 7-12 membered saturated spiro group d. ₄ alkyl or 6-10 membered saturated fused ring C _1-4 alkyl group, or Y and R ^{2 are} bonded and common The attached nitrogen atom forms an _8- cycloalkyl group, a 4-8 membered heterocycloalkyl group, a 7-12 membered saturated spiro group or a 6-10 membered saturated fused ring group.

The "C _3-8 cycloalkyl, 4-8 membered heterocycloalkyl, 7-12 membered saturated spiro group, 6-10 membered saturated fused ring group" may be further substituted with 1-3 substituents R ⁴ substituted, the substituents R ⁴ are independently selected from amino, hydroxy, alkyl, C _1-8 alkylamino, di (C ₈ alkyl) amino, amino (^ ₈ alkyl, carboxy, D ₈ Alkylamino d. ₈ alkyl, C _1-8 alkoxy C _1-8 alkyl, hydroxy d. ₈ alkyl, carboxy d. ₈ alkyl, carbamoyl, hydroxy d. ₈ alkoxy or d . ₈ -alkylcarbonyl,

Ring A is a 5-6 membered heteroaryl ring A may optionally be substituted with 1 to 3 R ⁵ groups further substituted, the substituent group R ⁵ is independently selected d_ ₈ alkyl, C _2-8 alkenyl group, C ₂ _.8 alkynyl, amino, hydroxy, (^ ₈ alkoxy, halogen atom, C _1-8 alkylamino, bis(d- ₈ alkyl)amino, C _1-8 alkylcarbonyl, carbamoyl, Alkylcarbamoyl, d. ₈ alkylcarbonylamino, aminoalkyl, hydroxy C _1-8 alkyl, cyano, |3⁄4 <3 _1-8 alkyl, C _{1 -8} alkoxy or amino Sulfonyl.

Technical Solution 2:

The compound according to the first aspect of the invention, the pharmaceutically acceptable salt thereof, and the stereoscopic Construct or its solvate:

R ^{1 is} selected from a 5-6 membered heteroaryl group,

R ¹ may be optionally substituted with 1-3 substituents R ³ is further substituted, the substituents R ³ are independently selected from C _1-6 alkyl, amino, hydroxy, d. ₆ alkoxy group, a halogen atom, C ₆ Alkylamino, di(C _1-6 alkyl)amino, amino C _1-6 alkyl, hydroxyalkyl, epi-C _1-6 alkyl or halogenated

Ci-6 alkyl;

R ^{2 is} selected from a hydrogen atom or a d ₆ alkyl group;

Y is selected from C _3. ₆ cycloalkyl, 5-6 membered heterocycloalkyl, 9-10-membered saturated spiro ring group, 8-10 membered unsaturated condensed ring group, C _3. ₆ cycloalkyl, d. ₂ alkyl a 5-6 membered heterocycloalkylalkyl group, a 9-10 membered saturated spirocycloalkyl group or a 8-10 membered saturated fused ring alkyl group, or Y and R ^{2 are} bonded to a covalently bonded nitrogen atom to form C ₃ . ₆ cycloalkyl, 5-6 membered heterocycloalkyl, 9-10 membered saturated spiro group or 8-10 membered saturated fused ring group,

The "C _3. ₆ cycloalkyl, 5-6 membered heterocycloalkyl, 9-10-membered saturated spiro ring group, 8-10 membered unsaturated condensed ring group ,, may be further substituted with 1 to 3 R ⁴ groups And the substituent R ^{4 is} independently selected from the group consisting of amino, hydroxy, CL ₆ alkyl, d. ₆ alkylamino, amino C _{1 -6} alkyl, carboxy, hydroxy (^. ₆ alkyl, carboxy d. ₆ Alkyl or C _1-6 alkylcarbonyl,

Ring A is a 5-6 membered heteroaryl ring A may optionally be further substituted with 3 substituents R ^5, said R ⁵ substituents independently selected from alkyl, amino, hydroxy, C _1-6 alkoxy, , halogen atom, C _{1 -6} alkylamino group, di(C _1-6 alkyl)amino group, aminoalkyl group, hydroxy C _{1 -6} alkyl group, cyano group, 13⁄4 generation (: _1-6 alkyl group or C _1-6 alkoxy group.

Technical solution 3:

A compound according to claim 1 or 2, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof:

Wherein X is selected from a phenylene group or a pyridylene group;

R ^{1 is} selected from the group consisting of triazolyl, pyrazolyl, imidazolyl, pyrrolyl or pyridyl;

R ^{2 is} selected from a hydrogen atom, a methyl group or an ethyl group;

Y is selected from the group consisting of 2-amino-cyclohexane, piperidinyl, 7-azaspiro[3.5]decyl, cyclopenta[c]pyrrolidin-5-ylfluorenyl, 2-oxa-8 - azaspiro [4.5] decane, ^2,7 - diazaspiro ^[4.5] decane or 1, 7-diazaspiro [4.4] nonane, or Y and R ² is connected to the common connection The nitrogen atom forms 2-oxa-8-azaspiro[4.5]decane, 2,7-diazaspiro[4.5]decane or 1,7-diazaspiro[4.4]nonane; Y or Y and R ² are linked form a ⁴ group may be further substituted with 1-2 substituents R together with the nitrogen atom attached, the substituent R ⁴ is independently selected from amino, hydroxy, alkyl, _{C] -6} An alkylamino group, a di(Cw alkyl)amino group, an amino C alkyl group or a hydroxyl group d. ₆ alkyl group,

Ring A is selected from pyridinium, imidazole or pyrrole.

Ring A may optionally be further substituted with 1 to 3 substituents R ^5, the substituents R ^{5 are} independently selected from C _1-6 alkyl, amino, hydroxy, C _1-6 alkoxy group, a halogen atom, d _6. Alkyl alcohol, bis(Cw alkyl)amino, aminoalkyl, hydroxy d. ₆ alkyl, cyano, ! ^ Generation. ^Alkyl or substituted alkoxy.

Technical Solution 4:

The compound according to any one of claims 1 to 3, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof:

Wherein: The compound of formula (I) has the structure:

Wherein R ² , RR ⁵ , Y are as defined in the first, second or third embodiment.

Technical solution 5:

A compound according to any one of claims 1 to 4, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof:

Wherein R ^{2 is} selected from a hydrogen atom or a C _1-4 alkyl group;

Y is cycloalkyl, 5-6 membered heterocycloalkyl, 9-10 membered saturated spiro group, 8-10 membered saturated fused ring group, 8-10 membered saturated fused ring methyl group, or Y is attached to R ² formation of C _5. ₆ cycloalkyl group attached to the nitrogen atom, 5-6 membered heterocycloalkyl, 9-10-membered saturated spiro ring group or a fused 8-10 membered saturated ring group,

The "C _5-6 cycloalkyl, 5-6 membered heterocycloalkyl, 9-10 membered saturated spiro group, 8-10 membered saturated fused ring group" may be further substituted with 1 substituent R ⁴ . R ^{4 is} selected from amino, C _M alkylamino or di(Cw alkyl)amino;

R ^{3 is} selected from a hydrogen atom or a C ₁₄ alkyl group;

R ^{5 is} selected from a hydrogen atom or a C ₁₄ alkyl group. Technical solution 6:

The compound according to any one of claims 1 to 5, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof:

Wherein R ^{2 is} selected from a hydrogen atom or a methyl group;

Y is 2-amino-cyclohexane, piperidinyl, 7-azaspiro[3.5]decyl, cyclopenta[]pyrrolidin-5-ylmethyl, 2-oxa-8-nitrogen Heterospiro[4.5]decane, 2,7-diazaspiro[4.5]decane or 1,7-diazaspiro[4.4]decane, or Y and R ^{2 are} bonded to a co-linked nitrogen atom to form 2 - oxa-8-azaspiro[4.5]decane, 2,7-diazaspiro[4.5]decane or 1,7-diazaspiro[4.4]壬

R ^{3 is} selected from a hydrogen atom;

R ^{5 is} selected from a hydrogen atom, a methyl group or an ethyl group.

Technical Solution 7:

A compound according to any one of claims 1 to 6, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof:

Wherein R ^{2 is} selected from a hydrogen atom;

Y is 2-amino-cyclohexane, piperidinyl, 7-azaspiro[3.5]decyl or cyclopenta[c]pyrrolidin-5-ylmethyl, or Y is linked to R ² The co-linked nitrogen atom forms 2-oxa-8-azaspiro[4.5]decane, 2,7-diazaspiro[4.5]decane or 1,7-diazaspiro[4.4]nonane;

R ^{3 is} selected from a hydrogen atom;

R ^{5 is} selected from a hydrogen atom or a methyl group.

Technical solution 8:

A compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof, wherein the compound is selected from the group consisting of:

Number compound

-N

A pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof.

Technical solution 9:

The compound according to any one of claims 1-8, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof, wherein the pharmaceutically acceptable salt thereof is a benzoate or a benzenesulfonic acid Salt, p-toluenesulfonate, citrate, maleate, fumarate, tartrate, hydrobromide, hydrochloride, sulfate, nitrate, phosphate, arginine, Portuguese Indoleamine, glucosamine or ammonium salt, lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, zinc salt, barium salt.

Technical Solution 10:

A pharmaceutical composition, which comprises a compound according to any one of claims 1 to 8, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof, and one or more pharmaceutically acceptable carriers and/or Or thinner.

Technical solution 1 1 :

A compound, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof according to any one of claims 1 to 8 for the preparation of a disease for the treatment and/or prevention of a signal pathway mediated by syk The application of the drug.

Technical Solution 12:

The compound according to any one of the aspects of the invention, the pharmaceutically acceptable salt thereof, the stereoisomer thereof or the solvate thereof, for the treatment and/or prevention of the undesired inflammatory immune response or The use of drugs for inflammatory diseases or cell proliferative diseases associated with inflammatory immune responses is desired. Technical Solution 13:

The application according to claim 12, wherein the inflammatory disease is selected from the group consisting of asthma, allergy, rheumatoid arthritis, allergic conjunctivitis, allergic keratitis or dry eye, and the cell proliferative disease is selected from the group consisting of leukemia and lymphoma. And myeloproliferative disorders.

Technical Solution 14:

A method of treating and/or preventing a disease associated with a syk-mediated signaling pathway in an individual, comprising administering to the individual a compound of any one of claims 1-8, a pharmaceutically acceptable salt thereof, a stereo Isomer or solvate thereof.

Technical Solution 15:

Treating and/or preventing an inflammatory immune response in an individual characterized by an undesired inflammatory immune response or undesired in the first embodiment of the present invention, 'the pharmaceutically acceptable salt thereof' A conformation or a solvate thereof.

Technical solution 16:

The method according to claim 15, wherein the inflammatory disease is selected from the group consisting of asthma, allergy, rheumatoid arthritis, allergic conjunctivitis, allergic keratitis or dry eye, and the cell proliferative disease is selected from the group consisting of leukemia and lymphoma. And myeloproliferative disorders.

Technical Solution 17:

A pharmaceutical composition according to claim 10, which is in any of pharmaceutically acceptable dosage forms. Unless otherwise stated, it should be understood that the following terms used above and herein have the following meanings.

The "halogen atom" as used in the present invention means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The "C _{1 -8} alkyl group" as used in the present invention means a straight or branched alkyl group having 1 to 8 carbon atoms, and includes, for example, "C _1-6 alkyl group", "C _{] -4} alkyl group" , "C _1-3 alkyl", "C _1-2 alkyl", "C _2-4 alkyl", "Cw alkyl" and the like, examples of which include, but are not limited to, for example, methyl, ethyl, n-propyl Base, isopropyl, n-butyl, 2-methylpropyl, 1-methylpropyl, 1 ,1-dimethylethyl, n-pentyl,

3-mercaptobutyl, 2-mercaptobutyl, 1-methylbutyl, 1-ethylpropyl, n-hexyl, 4-decylpentyl, 3-methylpentyl, 2-methylpentyl 1, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-didecylbutyl, 1,2-dimethylbutyl, 1 , 3-dimercaptobutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1 ,2-dimethylpropyl, heptyl, octyl and the like.

The "C ₂ _.8 alkenyl group" as used in the present invention means a linear or branched alkenyl group having 2 to 8 carbon atoms and having a double bond, and includes, for example, "C _2-6 alkenyl group", "C _{2 " -4} alkenyl", "C _2-5 alkenyl", "C _2-3 Alkenyl "etc.; examples thereof include, but are not limited to, for example, ethenyl, 1-propenyl, 2-propenyl, 1-methylvinyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propanyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentyl, 2- Pentenyl, 3-pentenyl, 4-pentenyl, 1-decyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1 -methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-indolyl-3- Butenyl, 3-methyl-3-butenyl, 1,1-dimercapto-2-propenyl,

1.2-Dimethylpropenyl, 1,2-dimercapto-2-propenyl, 1-ethylpropenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexene , 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentyl Alkenyl, 4-mercapto-1-pentenyl, 1-decyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl 2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-mercapto-3-pentenyl, 4-methyl-3-pentene , 1-mercapto-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-decyl-4-pentenyl, 1,1- Dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimercapto-2-butene , 1,2-dimethyl-3-butenyl, 1,3-didecylbutenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl- 3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl, 2, 3-dimethyl-3-butenyl,

3.3-dimethyl-butylation, 3,3-dimethyl-2-butenyl, 1-ethyl-1-butanyl, 1-ethyl-2-butenyl, 1-ethyl 3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl- 2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methylpropenyl, 1-ethyl-2-methyl-2-propenyl, 1, 3-butadiene, 1,3-pentadiene, 1,4-pentadiene, 1,4-hexadiene, and the like.

The "C^ alkynyl group" as used in the present invention means a linear or branched alkynyl group having 2 to 8 carbon atoms, and includes, for example, "C _2-6 alkynyl group" and "C _2-5 ". alkynyl group "," C _2-4 alkynyl group "," C _2- 3 alkynyl group "and the like, examples of which include but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 3-butynyl , 1-mercapto-2-propenyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 1-mercapto-3-butan , 2-methyl-3-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexyl, 4-hexyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl- 3-pentynyl, 2-mercapto-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-2-pentynyl, 1,1-dimercapto-2-butene Alkynyl, U-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 1-ethyl-2- Butynyl, 1-ethyl-3-butenyl, 2-ethyl-3-butynyl, 1-ethyl small methyl-2-propynyl and the like. The "C _1-8 alkoxy group" as used in the present invention means a group which is bonded in the manner of "C _1-8 alkyl-0-,"

The definition of "c _1-8 alkyl" is as defined above; and includes, for example, "c _1-6 alkoxy", "C _M alkoxy", "c _1-3 alkoxy", "c ₂ . ₄ alkoxy", "c _2-5 alkoxy" and the like.

The present invention, "C _3-8 cycloalkyl" refers to cycloalkyl groups containing 3-8 carbon atoms, including, for example "C _3-6 cycloalkyl", "C ₄ - ₆ cycloalkyl", " C _5-6 cycloalkyl" and the like, examples thereof include, but are not limited to, cyclopropyl group, cyclobutylalkyl group, cyclopentyl group, cyclohexane group, cycloheptyl group, cyclooctyl group and the like.

The present invention "is substituted C ₈ alkyl", "Generation ₈ alkoxy", "substituted alkyl", "halo C _1-6 alkoxy" refers to a plurality of "[¾ prime atom" defined hereinbefore substituted _"alkyl", 'Ό Μ8 alkoxy "," the CM alkyl "or" C ₆ alkoxy "group is derived, preferably chloro or fluoro.

The "4-8 membered heterocycloalkyl group" of the present invention means a saturated group having 4 to 8 ring atoms, and the ring atom contains at least one hetero atom, and the hetero atom is selected from N, 0 or 3. These include, for example, "5-6 membered heterocycloalkyl group", "4-6 membered heterocycloalkyl group" and the like. Specific examples include, but are not limited to, azetidinyl, thietane, tetrahydrofuranyl, tetrahydropyrrolyl, imidazolidinyl, pyrazolidinyl, 1,4-dioxanyl , 1,3-dioxanyl group, 1,3-dithiacyclohexane group, piperidinyl group, morpholinyl group, piperazinyl group and the like. Further, CH ₂ as a ring atom may be oxidized, and the monocyclic heterocycloalkyl group may be oxo substituted, for example, piperidin-2-one or the like.

The "5-6 membered heteroaryl group" of the present invention means an aromatic group having 5 to 6 ring atoms, and the ring atom contains 1 to 4 hetero atoms selected from the group consisting of >1. O^ S. Specific examples include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, triazole (eg 1, 2, 3) - triazole, 1,2,4-triazole, etc.), pyridyl, pyrimidinyl, 1,4-dioxadienyl, 2/7-1,2-oxazinyl, 4H-1, 2-oxazinyl, 6 ,2-oxazinyl, 4 ,3-oxazinyl, 6 /-1,3-oxazinyl, 4-1,4-oxazinyl, pyridazinyl, pyrazinyl 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl and 1,2,4,5-tetraazinyl.

The "5-6 membered heteroarylene group" as used in the present invention means a functional group obtained by removing a hydrogen atom from the 5-6 membered heteroaryl group defined above.

The "7-12 member saturated spirocyclic group" as used in the present invention means a group having 7-12 carbon atoms or/and hetero atoms formed by sharing at least two rings with one atom, and the hetero atom is selected from the group consisting of N,

0 or S. These include, for example, "8-10 yuan saturated spiro group", "8-11 solid saturated spiro group", "9-10" "etc." 7- to 12-member saturated spiro ring, the specific examples of the spiro ring include but are not limited

The "6- to 10-membered saturated fused ring group" as used in the present invention means a group of 6-10 carbon atoms or/and formed by two or more ring structures which are connected to each other by two adjacent atoms. A saturated fused ring group of a hetero atom selected from N, 0 or 3. These include, for example, "8-9-membered saturated fused ring group" and "8-10-membered saturated fused ring group". Specific examples thereof include, but are not limited to,, for example, 3-azabicyclo[3.1.0]hexane, 2-azabicyclo[3.1.0]hexane, 3-azabicyclo[3.2.0]heptanyl, 3-azabicyclo[4.2.0]octyl, 3-azabicyclo[3.2.0]heptanyl, cyclopenta[c]pyrrolidinyl, octahydropyrrolo[3,4-c| Pyrrolyl, octahydrofluorenyl, octahydroisodecyl, decahydronaphthyl, decahydroisoquinolinyl, octahydrocyclopentadienyl, bicyclo[3.1.0]hexane, bicyclo[3.2. 0] heptyl, bicyclo[4.1.0]heptyl, bicyclo[4.2.0]octyl and the like.

A "pharmaceutically acceptable salt" of any of the above compounds of the invention includes a salt of the active compound which is prepared according to the particular substituents present on the compounds described herein using relatively non-toxic acids or bases. When a compound of the invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired base, either alone or in a suitable inert solvent. Examples of the salt derived from a pharmaceutically acceptable inorganic base include aluminum, ammonium, calcium, copper, ferric iron, ferrous iron, lithium, magnesium, manganese, divalent manganese, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, natural amines and the like, such as arginine, betaine, caffeine, choline, guanidine, Ν'-Dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, hydrazine-ethylmorpholine, hydrazine-ethylpiperidine, Glucosamine, methyl glucosamine, histidine, lysine, isopropylamine, morpholine, piperazine, piperidine, polyamine resin, procaine, guanidine, can Alkali, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When a compound of the invention contains a relatively basic functional group, the acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired acid, either alone or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochlorides, hydrobromides, nitrates, carbonates, bicarbonates, phosphates, hydrogen phosphates, dihydrogen phosphates. a salt, a sulfate, a hydrogen sulfate, a hydroiodide or a phosphite; or a salt derived from a relatively non-toxic organic acid such as acetic acid, propionic acid, isobutyric acid, malonic acid, Aspartic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid and the like. Also included are salts of amino acids such as arginine and the like, and salts of organic acids such as glucuronic acid or galactonic acid. Certain compounds of the invention contain a basic or acidic functional group such that the compound can be converted to a base or an acid addition salt.

"Solvate" of any of the above compounds of the invention refers to the physical association of a compound of the invention with one or more solvent molecules. This physical combination involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate can be separated, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" includes both solution phases and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate in which the solvent molecule is water.

One or more compounds of the invention may optionally be converted to a solvate. The preparation of solvates is generally known. Thus, for example, M. Caira et al. (J. Pharmaceutical Sci., 93(3). 601-61 1 (2004)) describes a solvent for preparing an antifungal fluconazole in ethyl acetate and from water. Compound. EC van Tonder sends MAAPS PharmSciTech 5(1), article 12 (2004)) and AL Bingham et al. (C/1⁄2m. Commun., 603-604 (2001)) describes solvates, hemisolvates, hydrates, etc. Similar preparation. A typical, non-limiting method involves: dissolving a compound of the invention in a target amount of a target solvent (organic solvent or water or a mixture thereof) above ambient temperature, cooling the solution at a rate sufficient to form crystals, and then passing Standard method separation. Analytical techniques such as, for example, spectroscopy, indicate that the solvent (or water) is present in the form of a solvate (or hydrate) form of the crystal.

The invention also includes stereoisomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may exist in the form of an optical isomer due to the presence of a chiral molecule, and therefore, the present invention also includes these optical isomers and mixtures thereof. When the compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof has a double bond or a small ring structure, the free rotation of a bond between atoms of a double bond or a ring in a molecule is hindered, and Stereoisomers, also known as cis-trans isomers, are produced by different spatial arrangements, and the invention also includes such cis-trans isomers and mixtures thereof. The present invention also includes stereoisomers which are caused by changes in the arrangement of atoms or radicals attached to carbon in a space due to the rotation of a single bond, and are also referred to as conformational isomers, and also include mixtures thereof.

The present invention claims a process for the preparation of a compound of formula (I). The compound of formula (I) can be synthesized using the methods described in the schemes below and/or other techniques known to those of ordinary skill in the art, but is not limited to the following methods.

Reaction equation:

Intermediate 4 Intermediate 5 Formula (I) The starting material 2 of the compound is Ε^ΧΝ3⁄4, the starting material 3 is YR ² NH, and the starting material 4 is an α-haloaldehyde or an α-haloketone.

Step 1: The raw material 1, the raw material 2 and the base (for example, triethylamine, DIEA, sodium carbonate, sodium acetate, etc.) are dissolved in an organic solvent (for example, DCM, THF, ethanol, etc.), and the reaction mixture is stirred at room temperature until the end, and filtered. The filter cake was washed with an organic solvent to obtain Intermediate 1.

Step 2: Dissolve intermediate 1 and aqueous ammonia in a polar organic solvent (eg THF, DMF,

DMA, etc., the reaction is heated to completion, cooled to room temperature, filtered with water, and the solid is washed with an organic solvent to afford Intermediate 2.

Step 3: Dissolve the intermediate 1 in an organic solvent (for example, DMF, THF, DCM, etc.), slowly add m-CPBA under a water bath, and raise to room temperature until the reaction is completed to obtain a reaction liquid of the intermediate 3, which is not It is directly used for the next reaction after treatment.

Step 4: Raw material 3 and an organic base (e.g., TEA, DIEA, etc.) are directly added to the reaction liquid of Intermediate 3, the reaction is completed at room temperature, water is added, filtered, and the solid is washed with water. Intermediate 4 was obtained by vacuum drying. Step 5: Intermediate 4 was dissolved in DMSO and ethanol, aqueous NaOH was added, and hydrogen peroxide was slowly added dropwise. After completion of the reaction at room temperature, ice water is added, and the solid is isolated by preparative chromatography or silica gel column.

Step 6: Dissolve the intermediate 5 in an organic solvent (such as DMF, THF, etc.), add the raw material 4 (such as chloroacetaldehyde, etc.), react at room temperature until the starting material disappears, add ice water, extract with an organic solvent, dry, and concentrate. The compound of formula (I) is isolated by silica gel column.

X, Y, ring A, and RR ² in the above reaction equation are as defined above. If necessary, the functional group to be protected may be protected, and then the protective group may be removed by a conventional method; if necessary, the reaction solvent may be appropriately substituted according to the nature of the compound; if necessary, depending on the nature of the compound, the Certain compounds may be added to the preparation of certain compounds.

The compound of the formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof, may be formulated into a pharmaceutically acceptable pharmaceutical composition or pharmaceutical preparation with one or more pharmaceutically acceptable carriers, It is administered orally, parenterally, etc. to patients in need of such treatment. When administered orally, it can be prepared into conventional solid preparations such as tablets, capsules, pills, granules, etc. with conventional fillers, binders, disintegrators, lubricants, diluents, etc.; When administered externally, it can be prepared as an injection, including an injection solution, a sterile powder for injection, and a concentrated solution for injection. When the injection is prepared, it can be produced by a conventional method in the prior art, and when the injection is formulated, an additional agent may be added, or a suitable additive may be added depending on the nature of the drug. Actual methods of preparing such dosage forms are known or will be apparent to those skilled in the art.

The invention also provides a compound of the formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof, for use in the preparation and/or prevention of a signal pathway mediated by syk The use of a medicament for the disease, further for the preparation of a medicament for the treatment and/or prevention of an inflammatory disease or a cell proliferative disorder characterized by an undesired inflammatory immune response or associated with an undesired inflammatory immune response Application in .

"Treatment" as used herein means alleviating, ameliorating, eliminating or reducing the signs and symptoms associated with a disease or condition.

The term "prevention" as used in the present invention means preventing or delaying the occurrence or development of a disease or condition,

"The inflammatory disease is selected from the group consisting of allergies, asthma, rheumatoid arthritis, allergic conjunctivitis, allergic keratitis, dry eye, lupus erythematosus, psoriasis, multiple sclerosis, and the like. N2013/001107

The cell proliferative disorder is selected from the group consisting of leukemia, lymphoma, myelosynthesis, non-Hodgkin's lymphoma and the like.

The beneficial effects of the compounds of the present invention are further clarified by the in vitro pharmacological activities of some of the compounds of the present invention. Other compounds of the present invention have the same beneficial effects as the compounds enumerated in the test, but it should not be construed that the compounds of the present invention have only the following Advantageous Effects. Experimental Example 1 In vitro pharmacological activity of the compound of the present invention

Test sample: a part of the compound of the invention, prepared according to the method of the example;

Experimental method: enzyme assay

HTRF SYK experiment:

This experiment used the HTRFR KinEASETM-TK kit (Cisbio, 62ΤΚ0ΡΕΒ). The test sample was accurately weighed, dissolved in DMSO, and thoroughly mixed to prepare 10 mM. It was diluted to a final concentration of 50 times with DMSO. Transfer 30 μΐ of the compound to a 96-well plate and perform a 3-fold serial dilution for a total of 10 concentrations. Transfer 2 μΐ to a 38 μΐ Kinase buffer to obtain a working solution with a final concentration of up to 25 μΜ. The compounds were separately added to 384-well plates at 4 μl per well. Add SYK kinase 2 μΐ at a concentration of 0.04 ng/μΐ, incubate for 10 min, and add 4 μl of ATP and substrate mixture. 25 . After incubation for 30 min, add 10 μM of Streptavidin-XL665 and TK Antibody-Cryptate. After incubating for 1 h at 25 °C, the fluorescence values of the detected samples at 615 nm and 665 nm were detected by a microplate reader. Curve fitting was performed using GraphPad 5.0 software, and the fitting equation was Y=Bottom + (Top-Bottom)/(l + 10 ^A ((LoglC ₅₀ -X)*HillSlope)), and the 1C ₅₀ value was obtained.

Table 1 IC ₅₀ values of the compounds of the invention against SYK

Compound IC ₅₀ (nM)

Compound 1 35

Compound 2 60

Compound 6 64

In conclusion, it can be seen from the data of Table 1 that the compound of the present invention has a good inhibitory activity against SYK. Experimental Example 2 Rat pK evaluation test Buy design

2. Test sample

The control drug, self-made, was synthesized from the scope of the claims of JP2004203748 to select compound A, compound B, and compound C, and the structural formula is as follows:

C; The compound of the present invention, prepared by itself, is dissolved in a suitable solvent.

3. Equipment

Equipment: API4000 LC-MS/MS

Column: Agilent XDB C _]8 (2.1 x 50 mm, 5 μιη)

4. Blood collection

Rat blood collection: Animals were fixed, the tail was heated in a water bath 10 min before each time point, and about 100 μΐ of blood was collected through the tail vein. The blood was collected and placed in an anticoagulant tube containing sodium heparin. Blood samples were centrifuged at 8000 rpm for 6 min at 4 °C to obtain plasma samples. Plasma must be prepared within 30 min of blood collection. Store in a -80 °C water tank before testing for plasma.

5. Experimental methods

(1) Take the sample to be tested (-80 °C) from the water tank, vortex naturally at room temperature for 5 min; (2) accurately transfer 20 μΐ sample to ^96- well plate;

(3) Entering a 200 μΐ internal standard solution;

(4) After vortexing for 10 min, centrifuge for 10 min (12000 rpm);

(5) Precision transfer of 50 μM supernatant into 150 μΐ water, vortex for 5 min, and analysis by LC-MS/MS.

6. Data processing method The concentration of the test substance (plasma sample) was measured using Analyse 1.6.1 of AB SCIEX (Shanghai Aibo Caisi Analytical Instrument Trading Co., Ltd.). Microsoft Excel calculates the mean, standard deviation, coefficient of variation and other parameters (Analyst 1.6.1 direct output is not calculated), pK parameters are calculated using Pharsight Phoenix 6.3 software.

7. Experimental results and conclusions

Table 2 Bioavailability of the compound of the present invention in SD rats

Compound

Compound A rats had almost no absorption after oral administration and could not be calculated. % Compound B has poor plasma stability and cannot measure F%

Compound C

Compound 1

Compound 6

Conclusion: It can be seen from the data in Table 2 that the comparative compound has no absorption, or the plasma stability is poor, the pK is not good, and the bioavailability is low. The compound of the present invention has good absorption and high bioavailability, and can have a better therapeutic effect.

detailed description

The above contents of the present invention will be further described in detail below by way of specific embodiments in the form of the embodiments. However, the scope of the above-mentioned subject matter of the present invention should not be construed as being limited to the following embodiments.

Example 1 (i?)-7-[3-(2-1,2,3-triazol-2-yl)phenylamino-5piperidin-3-ylamino)imidazolium il,2-cl-pyrimidine- Preparation of 8-carboxamide (Compound 1)

(1) Preparation of 4-[3-(2 -1 ,2,3-triazol-2-yl)phenylamino]-6-chloro-2-(indolyl)pyrimidine-5-carbonitrile

4,6-Dichloro-2-(methylindenyl)pyrimidine-5-indolecarbonitrile (4.0 g, 18 mmol), 3-(2-1,2,3-triazol-2-yl)aniline (2.9 g , 18 mmol) and sodium acetate (3.0 g, 36 mmol) was dissolved in 100 mL of ethanol, the reaction solution was stirred for 5 h at room temperature, filtered, the filter cake was washed with ethanol to give a yellow solid ⁵ .0 g, 80% yield.

(2) 4-[3-(2/ -1,2,3-Triazol-2-yl)phenylamino]-6-amino-2-(indolyl)pyrimidine-5- Preparation of carbonitrile

4-[3-(2-l,2,3-Triazol-2-yl)phenylamino]-6-chloro-2-(methylindenyl)pyrimidine-5-carbonitrile (5.0 g, 14.5 mmol) Dissolve with 10 mL of ammonia in 30 mL of DMF, react at 60 ° C for 2 h, cool to room temperature, filter with water, and wash the solid with ethyl acetate to give 3.0 g of product, yield 64%.

(3) 4-[3-(2/M,2,3-Triazol-2-yl)phenylamino]-6-amino-2-(indenylsulfinyl)pyrimidine-5-

4-[3-(2H-l,2,3-Triazol-2-yl)phenylamino]-6-amino-2-(methylindenyl)pyrimidine-5-indolecarbonitrile (3.0 g, 9.3 mmol) Dissolved in 50 mL of DMF, slowly added m-CPBA (2.4 g, 13.9 mmol) in a water bath, and allowed to react to room temperature for 5 h. The reaction solution was used in the next step without treatment.

(4) (7?)-3-[4-[3-(2H-l,2,3-Triazol-2-yl)phenylamino]-6-amino-5-cyanopyrimidin-2-yl Preparation of amino]piperidine carboxylic acid tert-butyl ester

Triethylamine (2.8 g, 28 mmol) was added to the reaction mixture in the previous step, and (W)-tert-butyl 3-aminopiperidine-1-carboxylate hydrochloride (2.2 g, 9.3 mmol) was obtained. 10 h, add water, use Extract with ethyl acetate, wash with water and dry. The residue after concentration was separated through a silica gel column (dichloromethane:methanol = 20:1) to give product (yield:

(5) ( )-3-[4-[3-(2 /-l,2,3-Triazol-2-yl)phenylamino]-6-amino-5-(carbamoyl)

(-3-[4-[3-(2 -1,2,3-Triazol-2-yl)phenylamino]-6-amino-5-cyanopyrimidin-2-ylamino]piperidine- :!- tert-butyl phthalate (3.0 g, 6.3 mmol) was dissolved in 30 mL DMSO and 30 mL ethanol, then 25 mL of NaOH (1.3 g, 32 mmol) ice solution was added, and finally 10 mL of hydrogen peroxide was slowly added dropwise. After reacting for 2 h at room temperature, water was added, extracted with ethyl acetate, washed with water, dried and concentrated to give a product of 2.5 g.

(6) (W)-3-[7-[3-(2W-l,2,3-Triazol-2-yl)phenylamino]-8-(aminodecanoyl)imidazolium [1,

( )-3-[4-[3-(2//-1,2,3-triazol-2-yl)phenylamino]-6-amino-5-(aminodecanoyl)pyrimidin-2- The tert-butyl group of benzylaminopiperidine-1-decanoate (1.0 g, 2 mmol) was dissolved in 20 mL of DMF, chloroacetaldehyde (0.79 g, 10 mmol) was added, and the reaction was carried out at 60 ° C for 3 h. After adding water, the mixture was extracted with ethyl acetate, dried, and concentrated, and then evaporated to silica gel column (methanol: methylene chloride = ¹ : 20) to give 200 mg of product.

(7) (i?)-7-[3-(2H-l,2,3-triazol-2-yl)phenylamino]-5-(piperidin-3-ylamino)imidazo[1, Preparation of 2-c]pyrimidine-8-carboxamide

( )-3-[7-[3-(2//-l,2,3-triazol-2-yl)phenylamino]-8-(carbamoyl)imiindole[1,2- c]pyrimidin-5-ylamino]piperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.39 mmol) dissolved in 10 mL of DCM, hydrogen chloride gas, reaction at room temperature for 1 h, filtered, solid water and dichloropurine The alkane was washed and dried to give the product 150 mg (yield: 92%).

Mass spectrum (m/e): 419.2 (M+1)

^-NMR (400MHz, MeOD, 5 _ppm ): 8.56(s, 1H), 8.24(s, 1H), 8.00(s, 2H), 7.89(d, J = 8.0 Hz, 1H), 7.63(s, 1H ), 7.53~ 7.57(m, 1H), 7.38(d, J - 8.0 Hz, 1H), 4.54 ~ 4.59(m, 1H), 3.52~ 3.56(m, 1H), 3.08~ 3.26(m, 2H), 1.70 ~ 2.28 (m, 4H), 1.29 - 1.33 (m, 1H).

Example 2 0?)-7-[3-(2#-l,2,3-triazol-2-yl)phenylaminobu-3-methyl-5-(piperidine)

Preparation of -3-ylamino)imidazolium il,2-clpyrimidine-8-carboxamide (Compound 2)

(1) ( )-3-[7-[3-(2 -1,2,3-Triazol-2-yl)phenylamino]-8-(aminodecanoyl)-3-methylimidazo[ Preparation of tert-butyl 1,2-c]pyrimidin-5-ylamino]piperidinecarboxylate

(R)-3-[4-[3-(2H-l,2,3-Triazol-2-yl)phenylamino]-6-amino-5-(carbamoyl)pyrimidin-2-yl Amino] piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 4 mmol) was dissolved in 20 mL of DMF and added to 2-bromo-U-dimethoxypropane (1.8 g, 10 mmol) at 60 ° C 48h. Water was added and the mixture was extracted with EtOAc. EtOAc (EtOAc m.

(2) ( )-7-[3-(2H-l,2,3-Triazol-2-yl)phenylamino]-3-methyl-5-(piperidin-3-ylamino)imidazolium Preparation of [ 1 ,2-c]pyrimidine-8-(carbamoyl)

(i?)-3-[7-[3-(2H-l,2,3-triazol-2-yl)phenylamino]-8-(carbamoyl)-3-methylimidazo[ 1 ,2-c]pyrimidin-5-ylamino]piperidine-1-decanoic acid tert-butyl ester (202 mg, 0.38 mmol) dissolved in 10 mL of DCM, hydrogen chloride gas, reaction at room temperature for 1 h, with carbonic acid The sodium hydrogenate was adjusted to neutral pH, extracted with dichloromethane, dried and concentrated to yield 50 mg, yield 31%. Mass spectrum (m/e): 433.2 (M+ 1)

¹ H-NMR (400 MHz, d ₆ -DMSO, 5 _ppm ): 12.72 (s, 1H), 9.60 (s, 1H), 8.80 (s, 1H) 8.14 (s, 2H), 7.63 (d, J = 8.0 Hz, 1H), 7.44 ~ 7.48(m, 2H), 7.31(d, J = 8.0 Hz, 1 H), 7.03(s, 2H), 4.36(s, 1 H), 2.89 to 2.92(m, 2H) , 2.62 ~ 2.75 (m, 6H), 1.35 ~ 1.95 (m, 4H).

Example 3 7-i3-(2ff-l,2,3-triazol-2-yl)phenylamino-5-"cisV2-aminocyclohexylamino)-3-indolizido and n,2-d-pyrimidine- Preparation of 8-methanamine (Compound 3)

(1) 4-[3-(2 /-1,2,3-Triazol-2-yl)phenylamino]-6-amino-2-((cis)-2-aminocyclohexylamino)pyrimidine- Preparation of 5-carbonitrile

4-[3-(2,2,3-Triazol-2-yl)phenylamino]-6-amino-2-(methylsulfinyl)pyrimidine-5-indolecarbonitrile (2.0 g, 5.9 mmol Triethylamine (1.8 g, 17.7 mmol) and (cis)-cyclohexyl-1,2-diamine (0.74 g, 6.5 mmol) were dissolved in 20 mL DMF. The reaction was carried out for 10 h at room temperature, water was added, extracted with ethyl acetate, washed with water and dried. The residue after concentration was separated through a silica gel column (dichloromethane:methanol = 20:1) to afford product 1.5 g, yield 65%.

(2) 4-[3-(2 -1 ,2,3-Triazol-2-yl)phenylamino]-6-amino-2-((())-2-8002-aminocyclohexylamino) Preparation of pyrimidine-5-carbonitrile 丫N

NHBoc

§One

4-[3-(2/-l,2,3-Triazol-2-yl)phenylamino]-6-amino-2-((cis)-2-aminocyclohexylamino)pyrimidine-5- Formonitrile (1.5 g, 3.8 mmol), Boc ₂ 0 (0.99 g, 4.6 mmol) and triethylamine (1.2 g, 11.4 mmol) were dissolved in 20 mL THF. The reaction was carried out for 10 h at room temperature, water was added, extracted with ethyl acetate, washed with water and dried. The residue after concentration was separated through a silica gel column (dichloromethane:methanol = 20:1) to yield product 1.5 g, yield 80%.

(3) (cis)-2-[4-[3-(2/-l,2,3-triazol-2-yl)phenylamino]-6-amino-5-(carbamoyl)pyrimidine- Preparation of tert-butyl 2-methylamino]cyclohexylcarbamate

4-[3-(2H-l,2,3-Triazol-2-yl)phenylamino]-6-amino-2-((cis)-2-Boc-2-aminocyclohexylamino)pyrimidine -5-carbonitrile (1.5 g, 3 mmol) was dissolved in 15 mL of DMSO and 15 mL of ethanol, then 25 mL of NaOH (0.6 g, 15 mmol) was added, and then 10 mL of hydrogen peroxide was added dropwise. After reacting for 2 h at room temperature, ice water was added, extracted with ethyl acetate, washed with water, dried and concentrated to give a product (1 g, yield: 78.6%).

(4) (cis)-2-[7-[3-(2H-l,2,3-triazol-2-yl)phenylamino]-8-(carbamoyl)-3-methylimidazolium [1,2-c]pyrimidin-5-ylamine,

N \ ₂

'丫八 N'人 N '人 NH

NIIBoc 丄

(cis)-2-[4-[3-(2H-l,2,3-triazol-2-yl)phenylamino]-6-amino-5-(aminodecanoyl)pyrimidin-2-yl Amino]tert-butyl cyclohexylcarbamate (1.0 g, 2 mmol) dissolved in 20 mL DMF, 2-bromodimethoxypropane (8 g, 10 mmol) was added and the reaction was carried out at 60 ° C for 48 h. Water was added and the mixture was extracted with EtOAc. EtOAc (EtOAc)EtOAc.

(5) 7-[3-(2//-1,2,3-Triazol-2-yl)phenylamino]-5-((cis)-2-aminocyclohexylamino)-3-indenyl Preparation of imidazo[Uc]pyrimidine-8-carboxamide

(cis)-2-[7-[3-(2H-l,2,3-triazol-2-yl)phenylamino]-8-(aminodecanoyl)-3-methylimidazo[1 , 2-c]pyrimidin-5-ylamino]cyclohexylcarbamic acid tert-butyl ester (110 mg, 0.2 mmol) dissolved in 10 mL of DCM, hydrogen chloride gas, 1 h at room temperature, adjusted with sodium bicarbonate pH to neutral, extracted with dichloromethane, dried and concentrated to give 50 mg, yield 56%.

Mass spectrum (m/e): 447.2 (M+1)

Ή-NMR (400MHz, d ₆ -DMSO, 5 _ppm ): 11.58 (s, 1H), 8.91 (s, 1H), 8.10 ~ 8.19 (m, 4H), 7.84~ 7.94 (m, 2H), 7.48~ 7.62 (m, 2H), 4.51(s, 1H), 2.63(s, 2H), 1.64 ~ 1.88(m, 6H), 1.42(s, 2H), 1.19 - 1.22(m, 5H).

Example 4 7-Γ3-ί27/-1,2,3-triazol-2-yl)phenylamino 1-5-Γ7-azaspiro ί3.51 decane

Preparation of -1-ylamino)imidazolium 11,2-cl pyrimidine-8-indoleamide (Compound 4)

(1) l-[4-[3-(2H-l,2,3-Triazol-2-yl)phenylamino]-6-amino-5-cyanopyrimidin-2-ylamino]-7- Preparation of aza-spiro[3.5]decane-7-decanoic acid tert-butyl ester

4-[3-(2H-l,2,3-Triazol-2-yl)phenylamino]-6-polyyl-2-(methyl-indolyl)pyrimidine-5-carbonitrile (1.0 g , 2.94 mmol), triethylamine (594 mg, 5.88 mmol) and (1-amino-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester hydrochloride (814 mg, 2.94 mmol). 50 mL In DMF. The reaction was carried out for 4 h at room temperature, water was added, filtered, and dried to give a product: 15 g, product 76%. (2) 1-[4-[3-(2 -1,2,3-Triazol-2-yl)phenylamino]-6-amino-5-(carbamoyl)pyrimidin-2-ylamino) Preparation of -7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester

1-[4-[3-(2 -1 ,2,3-triazol-2-yl)phenylamino]-6-amino-5-cyanopyrimidin-2-ylamino]-7-aza Spiro[3.5]decane-7-decanoic acid tert-butyl ester (1.15 g, 2.22 mmol) was dissolved in 25 mL of DMSO and 25 mL of ethanol, then 25 mL of NaOH (335 mg, 8.88 mmol) was added, and finally slowly added dropwise. 1 g of hydrogen peroxide, reacted at room temperature for 3 h, added with ice water, filtered, and dried for use in the next reaction.

(3) 1-[7-[3-(2 -1 ,2,3-Triazol-2-yl)phenylamino]-8-(carbamoyl)imidazo[1,2-c]pyrimidine- Preparation of 5-aminoamino]-7-azaspiro[3.5]decane-7-decanoic acid tert-butyl ester

Chloroacetaldehyde (2.6 g, 40%, 13.3 mmol) was added to the 20 mL DMF solution of the previous product. The reaction was carried out at 60 ° C for 3 h, added with water and extracted with ethyl acetate, dried and concentrated. Separation (methanol: dichloromethane = 1 : 70) gave 300 mg of product, yield 24%.

(4) 7-[3-(2 /-1 ,2,3-Triazol-2-yl)phenylamino]-5-(7-azaspiro[3.5]decane-ylamino)imidazo[ Preparation of 1,2-c]pyrimidine-8-carboxamide

1-[7-[3-(2//-1,2,3-Triazol-2-yl)phenylamino]-8-(carbamoyl)imidazo[1,2-c]pyrimidine- 5-Aminoamino-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (300 mg, 0.54 mmol) and 1 mL of trifluoroacetic acid dissolved in 4 mL of MeOH, reacted at room temperature for 2 h, with hydrogen carbonate The pH of sodium was extracted with ethyl acetate, dried and concentrated to give the product 100 mg, yield 41%

Mass Spectrum (m/e): 459.2 (M+1)

^{] H-NMR (400MHz, d} 6 -DMSO, 5 ppm): 12.73 (s, IH), 9.56 (d, IH), 8.96 (s, IH), 8.68 (d, IH), 8.35 (s, IH) , 8.18(s, 2H), 7.65-7.67(m, IH), 7.57(s, IH), 7.38-7.51(m, IH), 7.32(s, 1H), 7.30(d, IH), 4.88-5.00 (m, IH), 2.80-2.90 (m 3H), 2.30-2.42 (m, IH), 1.60-1.90 (m, 4H), 1.47-1.52 (m, 3H), 1.21 (br, 2H).

Example 5 7-ί3-(2^2,3-Triazol-2-yl)phenylaminol-5-(2-oxa-8-azaspiro 14.51-decane-8-yl)imidazolium , Preparation of 2-d-pyrimidine-8-carboxamide (Compound 5)

(1) 4-[3-( ² Hl, ² ,3-Triazol-2-yl)phenylamino] _ ⁶ _amino-2-( ² -oxa-8-azaspiro[4.5]decane Preparation of 8-(yl)pyrimidine-5-carbonitrile

4-[3-(2 -1,2,3-Triazol-2-yl)phenylamino]-6-amino-2-(methylsulfinyl)pyrimidine-5-carbonitrile (1.5 g, 4.4 mmol), triethylamine (1.1 g, 11 mmol) and 2-oxa-8-azaspiro[4,5]nonane (750 mg, 5.3 mmol) dissolved in 50 mL DMF at room temperature for 20 h Add water, extract with ethyl acetate, dry and concentrate to give product 1.3 g, product 70%

(2) 4-[3-(2H-l,2,3-Triazol-2-yl)phenylamino]-6-amino-2-(2-oxa-8-azaspiro[4.5]癸Preparation of alk-8-yl)pyrimidine-5-indoleamide

4-[3-(2/-l,2,3-Triazol-2-yl)phenylamino]-6-amino-2-(2-oxa-8-azaspiro[4.5]decane -8-yl)pyrimidine-5-carbonitrile (1.3 g 3.1 mmol) dissolved in 40 mL DMSO and 40 In mL ethanol, add 25 mL of NaOH (620 mg, 15.5 mmol) aqueous solution, and finally slowly add 4 mL of hydrogen peroxide. After reacting for 20 h at room temperature, add water, extract with ethyl acetate, dry and concentrate to obtain product 1.2 g. , yield 89%.

(3) 7-[3-(2 -1,2,3-Triazol-2-yl)phenylamino]-5-(2-oxa-8-azaspiro[4.5〗 decane-8- Of imidazo[1,2-c]pyrimidine-8-indoleamide

4-[3-(2 -1,2,3-triazol-2-yl)phenylamino]-6-amino-2-(2-oxa-8-azaspiro[4.5]decane- 8-yl)pyrimidine-5-indoleamide (1.2 g, 2.8 mmol) and 2.1 mL of chloroethene were added to 25 mL of DMF and reacted at 60 ° C for 2 h. After adding ice water, it was extracted with ethyl acetate, dried, and concentrated, and then purified by preparative chromatography (acetonitrile: water = 1 : 1) to give 40 mg of product.

Mass spectrum (m/e): 460.2 (M+1)

¹ H-NMR (400 MHz, d ₆ -DMSO, 5 _ppm ): 1.70~1.80 (m, 4H), 3.40~3.50 (m, 2H), 3.53~3.65 (m, 2H), 3.76 (m, 2H), 3.80(t, 2H), 7.30(d, IH), 7.42(s, IH), 7.45(t, IH), 7.65(m, 2H), 7.71(s, IH), 8.05-8.15(s, 2H) , 8.85~8.90(s, IH), 9.60~9.70(s, IH), 12.61(s, IH).

EXAMPLES ό 7-[3-f2 -1.2.3-Triazol-2-yl)phenylamino 5-f2,7-diaza snail

Preparation of [4.51 decane-7-yl)imidazo[1,2-cl-pyrimidine-8-carboxamide (Compound 6)

(1) 7-[4-[3-(2H-l,2,3-Triazol-2-yl)phenylamino]-6-amino-5-cyanopyrimidin-2-yl]-2,7 -Preparation of tert-butyl diazaspiro[4.5]decane-2-furoate

4-[3-(2H-l,2,3-Triazol-2-yl)phenylamino]-6-amino-2-(methylsulfinyl)pyrimidine-5-indolecarbonitrile (400 mg, 1.18 mmol), triethylamine (477 mg, 4.72 mmol) and 2,7-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (310 mg, 1.29 mmol) dissolved in 30 mL DMF in. 1: reaction at room temperature for 20 h, adding water, extracting with ethyl acetate, and drying and concentrating to give product 500 mg, product 82%.

(2) 7-[4-[3-(2 /-1,2,3-Triazol-2-yl)phenylamino]-6-amino-5-(carbamoyl)pyrimidin-2-yl] Preparation of -2,7-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ester

7-[4-[3-(2H-l,2,3-Triazol-2-yl)phenylamino]-6-amino-5-cyanopyrimidin-2-yl]-2,7-di Aza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester (500 mg, 0.97 mmol) was dissolved in 30 mL DMSO and 30 mL ethanol, then 25 mL of NaOH (193 mg, 4.8 mmol) was added, and finally slowly dripped After adding 1 mL of hydrogen peroxide and reacting at room temperature for 3 h, it was added; ice water was extracted with ethyl acetate, dried and concentrated to give the product 500 mg, yield 96%.

(3) 7-[7-[3-(2 -1,2,3-Triazol-2-yl)phenylamino]-8-(carbamoyl)imidazo[1,2-c]pyrimidine- Preparation of 5-yl]-2,7-diazaspiro[4.5]decane-2-furic acid tert-butyl ester

7-[4-[3-(2H-l,2,3-Triazol-2-yl)phenylamino]-6-amino-5-(aminodecanoyl)pyrimidin-2-yl]-2, 7-Diazaspiro[4.5]decane-2-furic acid tert-butyl ester (500 mg, 0.93 mmol) and 1.5 mL of chloroacetaldehyde were dissolved in 20 mL of DMF solution and reacted at 60 °C for 2 h. Water was added and the mixture was extracted with EtOAc. EtOAc (EtOAc)

(4) 7-[3-(2//-1,2,3-Triazol-2-yl)phenylamino]-5-(2,7-diazaspiro[4.5]decane-7- Of imidazo[1,2-c]pyrimidine-8-carboxamide

7-[7-[3-(2-l,2,3-Triazol-2-yl)phenylamino]-8-(carbamoyl)imidazo[1,2-c]pyrimidine-5- -2,7-diazaspiro[4.5]decane-2-furic acid tert-butyl ester (40 mg, 0.07 mmol) and 1 mL of trifluoroacetic acid dissolved in 10 mL of DCM, reacted for 4 h at room temperature The solvent was evaporated to dryness to give the product 40 mg, yield 100%.

Mass Spectrum (m/e): 459.3 (M+1)

¹ H-NMR (400 MHz, d ₆ -DMSO, 5 _ppm ): 1.65~1.85 (m, 6H), 3.00-3.10 (m, IH), 3.12~3.32 (m, 4H), 3.40~3.48 (d, IH) ), 3.62~3.75(m, 2H), 7.23~7.28(d, IH), 7.45~7.53(t, 2H), 7.62~7.68(m, 2H), 7.80(m, IH), 8.1 1-8.15( s, 2H), 8.65~8.75(m, IH), 8.83-8.95(m, 2H), 9.68(m, IH), 12.65(s, IH).

Example 7 7-|3-(2-l,2,3-Triazol-2-yl)phenylaminobu 5-(1,7-diazaspiro[4.41 dec-7-yl)imidazolium Preparation of [l, 2-cl pyrimidine-8-carboxamide (Compound 7)

7-[4-[3-(2/ -1 ,2,3-triazol-2-yl)phenylamino]-6-amino-5-cyanopyrimidin-2-yl]-1,7-di -

4-[3-(2H-l,2,3-Triazol-2-yl)phenylaminobu 6-amino-2-(methylsulfinyl)pyrimidine-5-carbonitrile (1.7 g, 5 Methyl), triethylamine (1.4 mL, 10 mmol) and 1,7-diazaspiro[4.4]decane-1-carboxylic acid tert-butyl ester (1.13 g, 5 mmol) were dissolved in 50 mL DMF. The reaction was carried out at room temperature for 12 h, water was added, extracted with ethyl acetate, dried and concentrated, and then, then,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

(2) 7-[4-[3-(2H-l,2,3-Triazol-2-yl)phenylamino]-6-amino-5-(aminodecanoyl)pyrimidin-2-yl]- Preparation of 1,7-diazaspiro[4.4]decane-1-carboxylic acid tert-butyl ester

7-[4-[3-(2 /-l,2 -2-yl)phenylamino]-6-amino-5-cyanopyrimidin-2-yl]-1,7-diazaspiro[ 4.4] tert-butyl decane-1-carboxylate (1.1 g, 2.2 mmol) was dissolved in 20 mL DMSO and 20 mL ethanol, then 25 mL of NaOH (440 mg, 11 mmol) was added, and finally hydrogen peroxide (375) was slowly added dropwise. Mg, 11 mmol). After reacting for 3 h at room temperature, it was added, water, extracted with ethyl acetate, dried and concentrated to give product 500 mg, yield 44%.

(3) 7-[7-[3-(2/7-1,2,3-Triazol-2-yl)phenylamino]-8-(carbamoyl)imidazo[1,2-c] Preparation of pyrimidin-5-yl]-1,7-diazaspiro[4.4]decane-1-carboxylic acid tert-butyl ester

7-[4-[3-(2 -l,2,3-Triazol-2-yl)phenylamino]-6-amino-5-(carbamoyl)pyrimidin-2-yl]-1, 7-Diazaspiro[4.4]decane-1-carboxylic acid tert-butyl ester (500 mg, 0.96 mmol) and chloroacetaldehyde (450 mg, 5.73 mmol) were dissolved in 30 mL of DMF solution and reacted at 60 °C for 2 h. „ Adding ice water, extracting with ethyl acetate, drying, concentrating and then separating on silica gel column (methanol:dichloromethane = 1:50) afforded 60 mg of product.

(4) 7-[3-(2H-l,2,3-Triazol-2-yl)phenylamino]-5-(1,7-diazaspiro[4.4]decane-7-yl) mum

7-[7-[3-(2H-l,2,3-Triazol-2-yl)phenylamino]-8-(carbamoyl)imidazo[1,2-c]pyrimidine-5- -1,7-diazaspiro[4.4]decane decanoic acid tert-butyl ester (60 mg, 0.11 01107

Methyl) and 0.2 mL of trifluoroacetic acid were dissolved in 20 mL of DCM. After reacting for 4 h at room temperature, the solvent was evaporated to dryness to give 40 mg (yield: 82%).

Mass spectrum (m/e): 445.2 (M+1)

^, H-NMR (400MHz, d ₆ -DMSO, 8 _ppm ): 1.25 (m, lH), 1.44 (m, 1H), 2.01-2.38 (m, 2H), 2.43 (m, 2H), 4.13-4.32 ( m, 4H), 7.25(d, 1H), 7.39(s, 1H) 7.48(t, 1H), 7.65(m, IH), 7.67(d,lH), 7.99(s, 1H), 8.13(s, 2H), 8.87-8.94(m, 3H), 9.61 (d, 1H), 12.7(s, 1H).

Example 8 7-[3-ί2#-1,2,3-triazol-2-yl)phenylamino 5-ticyclopentane-klpyrrolidine-5-yl)nonanylaminol imidazolium il,2 Preparation of -cl pyrimidine-8-ylcarbamoyl) (Compound 8)

(1) 5-[[4-[3-(2H-l,2,3-Triazol-2-yl)phenylamino]-6-amino-5-cyanopyrimidin-2-ylamino]fluorenyl Preparation of cyclopenta[c]pyrrolidine-2(1/7)-tert-butyl phthalate

4-[3-(2-l,2,3-Triazol-2-yl)phenylamino]-6-amino-2-(methylsulfinyl)pyrimidine-5-carbonitrile (1.05 g, 3.1 mmol), triethylamine (1.2 g, 12 mmol) and 5-(aminomethyl)cyclopenta[c]pyrrolidine-2(1/)-tert-butyl phthalate (0.9 g, 3.7 mmol) Dissolved in 30 mL DMF. The mixture was reacted at room temperature for 18 h, added with water, filtered, dried, evaporated and evaporated.

(2) 5-[[4-[3-(2/ -1,2,3-Triazol-2-yl)phenylamino]-6-amino-5-(aminodecanoyl)pyrimidin-2-yl Preparation of amino]methyl]cyclopenta[c]pyrrolidine-2(1//)-carboxylic acid tert-butyl ester

5-[[4-[3-(2H-l,2,3-Triazol-2-yl)phenylamino]-6-amino-5-cyanopyrimidin-2-ylamino]indolyl] ring Pentane[c]pyrrolidine-2 (1H-tert-butyl formate (900 mg, 1.7 mmol) was dissolved in 20 mL DMSO and 20 mL ethanol, then NaOH (344 mg, 8.6 mmol) aqueous solution 25 mL, and finally slowly Add hydrogen peroxide (1 g, 30%, 8.8 mmol) dropwise. After reacting for 2 h, ice water was added, extracted with ethyl acetate, and dried and evaporated to ethylamine.

(3) 5-[[7-[3-(2 -1,2,3-Triazol-2-yl)phenylamino]-8-(carbamoyl)imidazo[1,2-c]pyrimidine Preparation of -5-ylamino]fluorenyl]cyclopenta[c]pyrrolidine-2 (1H-tert-butyl formate)

5-[[4-[3-(2/ -l,2,3-Triazol-2-yl)phenylamino]-6-amino-5-(aminodecanoyl)pyrimidin-2-ylamino] Methyl]cyclopenta[c]pyrrolidine-2(1//)-tert-butyl phthalate (900 mg, 1.68 mmol) and chloroacetaldehyde (1.0 g, 12.7 mmol) dissolved in 30 mL of DMF solution , react at 60 °C for 3 h. Water was added and the mixture was extracted with EtOAc. EtOAc (EtOAc)

(4) 7-[3-(2H-l,2,3-Triazol-2-yl)phenylamino]-5-[(cyclopenta[c]pyrrolidin-5-yl)methylamino] Preparation of imidazo[1,2-c]pyrimidine-8-(carbamoyl)

5-[[7-[3-(2 -l,2,3-Tris-p-yl-2-yl)phenylamino]-8-(aminodecanoyl)imidazo[1,2-c]pyrimidine- 5-Aminoamino]methyl]cyclopenta[c]pyrrolidine-2 (1H-tert-butyl formate (150 mg, 0.26 mmol) and 3 mL of trifluoroacetic acid were dissolved in 5 mL of DCM for 3 h at room temperature The solvent was evaporated to dryness to give the product 70 mg (yield: 59%).

Mass spectrum (m/e): 458.9 (M+1)

^-NMR (400 MHz, d ₆ -DMSO, 5 _ppm ): 0.83 (m, IH), 1.09 (m, IH), 1.60 (m, 2H), 2.01 (m, 2H), 2.67 (m, 3H), 2.98(m, IH), 3.06(M, IH), 3.67(d, 2H), 7.36(d, 2H), 7.49(m, 2H), 7.63(d, IH), 7.95(d, IH), 8.12 (s, 2H), 8.47 (m, 2H), 8.83 (m, IH), 8.86 (d, IH), 9.54 (s, IH), 12.76 (d, IH).

Claims

Rights request

1. The compound represented by the general formula (I), its pharmaceutically acceptable salt, its stereoisomer or its solvate:

Wherein, X is selected from phenylene or 5-6 membered heteroarylene;

R ¹ is selected from 5-6 membered heteroaryl,

R ¹ may be optionally further substituted by 1-3 substituents R ³ , which substituents R ³ are independently selected from _d.8 alkyl, alkenyl _{, C 2.8} _alkynyl , amino, hydroxyl, C _{1- 8} alkoxy group, halogen atom, alkylamino group, di(C^alkyl)amino group, C _1-8 alkylcarbonyl group, carbamoyl group, alkylcarbonylamino group, C _1-8 alkylcarbamoyl group, amino group . ₈ alkyl, hydroxyl C _1-8 alkyl, cyano group, halogenated C ₈ alkyl, substituted ₈ alkoxy or aminosulfonyl group;

R ² is selected from hydrogen atom or d. ₈ alkyl;

Y is selected from C _3.8 cycloalkyl, _4-8 membered heterocycloalkyl, 7-12 membered saturated spirocyclic group, 6-10 membered saturated fused ring group, C _3-8 cycloalkyl CM alkyl, 4 -8-membered heterocycloalkyl C _1-4 alkyl, 7-12-membered saturated spirocyclic group CM alkyl or 6-10-membered saturated fused cyclic group CM alkyl, or Y and R ² are connected to a common nitrogen atom Forming C^ ₈ cycloalkyl, 4-8 membered heterocycloalkyl, 7-12 membered saturated spirocyclic group or 6-10 membered saturated fused ring group,

The "C^ cycloalkyl group, 4-8 membered heterocycloalkyl group, 7-12 membered saturated spirocyclic group, 6-10 membered saturated fused ring group" can be further substituted by 1-3 substituents R ⁴ , The substituent R ⁴ is independently selected from amino, hydroxyl, CL ₈ alkyl, alkylamino, di(C _1-8 alkyl) amino, amino C ₈ alkyl, carboxyl, C,. ₈ alkylamino C _1-8 alkyl, C _1-8 alkoxy C _1-8 alkyl, hydroxyl d. ₈ alkyl, carboxyl d. ₈ alkyl, carbamoyl, hydroxyl d- ₈ alkoxy or C _1-8 alkyl basecarbonyl,

Ring A is a 5-6 membered heteroaryl group, and Ring A may be optionally further substituted by 1-3 substituents R ⁵ , and the substituents R ⁵ are independently selected from _d.s alkyl, alkenyl, C _{2- 8} alkynyl group, amino group, hydroxyl group, C _1-8 alkoxy group, 123 element atom, C _1-8 alkylamino group, two (C _1-8 alkyl) amino group, C _1-8 alkylcarbonyl group, carbamoyl group, C _1-8 alkylaminoformyl, C _1-8 alkylcarbonylamino, amino C _1-8 Alkyl group, hydroxy C _1-8 alkyl group, cyano group, C _1-8 alkyl group, C _1S alkoxy group or aminosulfonyl group.

2. The compound of claim 1, its pharmaceutically acceptable salt, its stereoisomer or its solvate:

Wherein, X is selected from phenylene or 5-6 membered heteroarylene;

R ¹ is selected from 5-6 membered heteroaryl,

R ¹ may be optionally further substituted by 1-3 substituents R ³ , which substituents R ³ are independently selected from C _1-6 alkyl, amino, hydroxyl, d- ₆ alkoxy, element atom, C _6- alkylamino, di(C _1-6 alkyl) amino, amino- ₆ alkyl, hydroxyl C- ₆ alkyl, halo-substituted C _1-6 alkyl or halo-substituted C- ₆ alkoxy;

R ² is selected from hydrogen atom or d. ₆ alkyl;

Y is selected from C _3-6 cycloalkyl _{, 5-6 membered heterocycloalkyl, 9-10 membered saturated spirocyclic group, 8-10 membered saturated fused ring group, C 3.6} _cycloalkyl.2 alkyl, 5-6 membered heterocycloalkyl C _1-2 alkyl, 9-10 membered saturated spirocyclic group _{d_2} alkyl or 8-10 membered saturated fused ring group d. ₂ alkyl, or Y and R ² are connected together with _{The connected nitrogen atoms form a C 3_6} _cycloalkyl group, a 5-6 membered heterocycloalkyl group, a 9-10 membered saturated spirocyclic group or an 8-10 membered saturated fused cyclic group,

The "C _3.6 cycloalkyl group, 5-6 membered heterocycloalkyl group, 9-10 membered saturated spirocyclic group, 8-10 membered saturated fused ring group, can be further substituted _by 1-3 substituents R ⁴ Substituted, the substituent R ⁴ is independently selected from amino, hydroxyl, CL ₆ alkyl, d. ₆ alkylamino, amino C _{1 -6} alkyl, carboxyl, hydroxyl d_ ₆ alkyl, carboxyl d. ₆ alkyl or C _{1 -6} alkylcarbonyl,

Ring A is a 5-6 membered heteroaryl group, and Ring A may be optionally further substituted by 1-3 substituents R ⁵ , and the substituents R ⁵ are independently selected from alkyl, amino, hydroxyl, C _1-6 alkyl Oxygen group, halogen atom, C _1-6 alkylamino group, di(C _1-6 alkyl) amino group, amino C _1-6 alkyl group, hydroxyl C _1-6 alkyl group, cyano group, C _1-6 alkyl group Base or substitute _{d_6} alkoxy group.

3. The compound of claim 2, its pharmaceutically acceptable salt, its stereoisomer or its solvate:

Wherein, X is selected from phenylene or pyridylene;

R ¹ is selected from triazolyl, pyrazolyl, imidazolyl, pyrrolyl or pyridyl;

R ² is selected from a hydrogen atom, methyl or ethyl;

Y is selected from 2-amino-cyclohexyl, piperidinyl, 7-azaspiro[3.5]nonyl, cyclopenta[ _C ]pyrrolidin-5-ylmethyl, 2-oxa-8 -Azaspiro[4.5]decane, 2,7-diazaspiro[4.5]decane or 1,7-diazaspiro[4.4]nonane, or Y and R ² are connected to a common nitrogen atom shape into 2-oxa-8-azaspiro[4.5]decane, 2,7-diazaspiro[4.5]decane or 1,7-diazaspiro[4.4]nonane;

The group formed by Y or Y and R ² connected to the common nitrogen atom may be further substituted by 1-2 substituents R ⁴ , and the substituents R ⁴ are independently selected from amino, hydroxyl, C _alkyl , d .6 alkylamino, di( _d.6alkyl )amino, _{aminod.6alkyl} or _{hydroxyd.6alkyl} ,

Ring A is selected from pyrazole, imidazole or pyrrole,

Ring A may be optionally further substituted by 1-3 substituents ^R5 , which substituents ^R5 are independently selected from _C6 alkyl, amino, hydroxyl, _C1-6 alkoxy, halogen atom, alkylamino , two (C alkyl) amino, amino d. ₆ alkyl, hydroxyalkyl, cyano, generation. ^Alkyl or haloalkoxy.

4. The compound of claim 1, its pharmaceutically acceptable salt, its stereoisomer or its solvate:

The object has the following structure:

Among them, R ² , R ³ , R ⁵ and Y are as defined in claim 1.

5. The compound of claim 4, its pharmaceutically acceptable salt, its stereoisomer or its solvate:

in,

R ² is selected from hydrogen atom or d. ₄ alkyl;

Y is C ₅ - ₆ cycloalkyl, 5-6 membered heterocycloalkyl, 9-10 membered saturated spirocyclic group, 8-10 membered saturated fused cyclic group, 8-10 membered saturated fused cyclic methyl group, or Y The nitrogen atom connected to R ² forms a C _5-6 cycloalkyl group, a 5-6 membered heterocycloalkyl group, a 9-10 membered saturated spirocyclic group or an 8-10 membered saturated fused ring group,

The "C _5.6 cycloalkyl group, _5-6 membered heterocycloalkyl group, 9-10 membered saturated spirocyclic group, 8-10 membered saturated fused ring group, can be further substituted by 1 substituent R ⁴ , R ⁴ is selected from amino, C _1-4 alkylamino or di(CL ₄ alkyl) amino;

R ³ is selected from a hydrogen atom or a C ₁₄ alkyl group; ^R5 is selected from hydrogen atom or _{d_4} alkyl group.

6. The compound of claim 5, its pharmaceutically acceptable salt, its stereoisomer or its solvate:

Wherein, R ² is selected from hydrogen atom or methyl group;

Y is 2-amino-cyclohexyl, piperidinyl, 7-azaspiro[3.5]nonyl, cyclopenta[c]pyrrolidin-5-ylmethyl, 2-oxa-8- Azaspiro[4.5]decane, 2,7-diazaspiro[4.5]decane or 1,7-diazaspiro[4.4]nonane, or Y and R ² connected with a commonly connected nitrogen atom. 2-oxa-8-azaspiro[4.5]decane, 2,7-diazaspiro[4.5]decane or 1,7-diazaspiro[4.4]nonane;

R ³ is selected from hydrogen atoms;

R ⁵ is selected from hydrogen atom, methyl group or ethyl group.

7. The compound of claim 6, its pharmaceutically acceptable salt, its stereoisomer or its solvate:

in,

R ² is selected from hydrogen atoms;

Y is 2-amino-cyclohexyl, piperidinyl, 7-azaspiro[3.5]nonyl or cyclopenta[c]pyrrolidin-5-ylmethyl, or Y is connected to R ² Commonly linked nitrogen atoms form 2-oxa-8-azaspiro[4.5]decane, 2,7-diazaspiro[4.5]decane or 1,7-diazaspiro[4.4]nonane;

R ³ is selected from hydrogen atoms;

R ⁵ is selected from a hydrogen atom or a methyl group.

8. The compound of claim 7, its pharmaceutically acceptable salt, its stereoisotope

Its pharmaceutically acceptable salts, its stereoisomers or its solvates.

9. The compound according to any one of claims 1 to 8, its pharmaceutically acceptable salt, its stereoisomer or its solvate, wherein the pharmaceutically acceptable salt is benzoate, Benzenesulfonate, p-toluenesulfonate, citrate, maleate, fumarate, tartrate, hydrobromide, hydrochloride, sulfate, nitrate, phosphate, arginine acid salt, meglumine salt, glucosamine salt or ammonium salt, lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, zinc salt, barium salt.

10. The pharmaceutical combination of the compound according to any one of claims 1 to 8, its pharmaceutically acceptable salt, its stereoisomer or its solvate and one or more pharmaceutical carriers and/or diluents substance, in any pharmaceutically acceptable dosage form.

1 1. The compound according to any one of claims 1 to 8, its pharmaceutically acceptable salt, Ί-U ^ - J(i 'J-poor' Vc syk-mediated signaling pathway-mediated drug application in diseases related.

12. The compound according to any one of claims 1 to 8, its pharmaceutically acceptable salts, and medicines for inflammatory diseases or cell proliferative diseases characterized by immune responses or associated with undesirable inflammatory immune responses. Applications.

13. The application according to claim 12, wherein the inflammatory disease is selected from asthma, allergy, rheumatoid arthritis, allergic conjunctivitis, allergic keratitis or dry eye, and the cell proliferative disease is selected from leukemia, lymphoma neoplasia and myeloproliferation.