CN116731035A

CN116731035A - Thienopyrimidine compound, intermediate, preparation method, composition and application thereof

Info

Publication number: CN116731035A
Application number: CN202310224041.8A
Authority: CN
Inventors: 王玉光; 张农; 吴添智; 吴新亮; 何敏
Original assignee: Guangzhou Maxinovel Pharmaceuticals Co Ltd
Current assignee: Shanghai Zaiji Pharmaceutical Technology Co ltd
Priority date: 2022-03-08
Filing date: 2023-03-08
Publication date: 2023-09-12
Also published as: WO2023169461A1

Abstract

The invention discloses a thienopyrimidine compound, an intermediate, a preparation method, a composition and application thereof; specifically discloses a compound shown as a formula I. The invention also discloses the thienopyrimidine compoundUse of an agent in the manufacture of a medicament for the prevention, alleviation or treatment of a kinase-induced related disease, said kinase being selected from one or more of ALK kinase, FGFR kinase and TRK kinase. The thienopyrimidine compound has strong inhibition effect on ALK kinase, FGFR kinase and TRK kinase.

Description

Thienopyrimidine compound, intermediate, preparation method, composition and application thereof

Technical Field

The invention relates to a thienopyrimidine compound, an intermediate, a preparation method, a composition and application thereof.

Background

Anaplastic lymphoma kinase (Anaplastic lymphoma kinase, ALK) was first found in anaplastic large cell lymphoma (Anaplastic large cell lymphoma, ALCL), and fusion proteins formed by chromosome 2 and 5 translocations contained the 3 'intracellular domain of ALK and the 5' domain of Nucleophosmin (NPM). The complete ALK has a typical RTK three-part structure, namely extracellular region, lipophilic transmembrane region, and intracellular tyrosine kinase. The extracellular region comprises a specific binding domain: n-terminal signal peptide, 2 methyldopa, A5 protein and receptor protein tyrosine phosphatase μ (MAM, meprin, A5 protein and receptor protein tyrosine phosphatase mu) domain, 1 Low density lipoprotein class A (LDLa, low-density lipoprotein A) motif and 1 Glycine enrichment region (G-rich, glycine-rich) near the cell membrane. The MAM domain and G-rich region may be involved in ALK activation. The first tyrosine residue of the yxxxxyy motif of the human ALK kinase region, tyr1604, has been shown to be involved in the autologous activation of the ALK kinase region (tartartari c.j., et al, j.bio.chem.,2008, 283 (7), 3743-3750).

ALK fusion genes are generated due to chromosomal translocation, and the fusion proteins encoded by the ALK fusion genes form ligand-independent dimers causing constitutive ALK activation. The activated ALK signal can cause cell hyperproliferation and malignant transformation by activating RAS-MEK-ERK, JAK-STAT3/5, PI3K-bKT and PLCgamma signaling pathways downstream thereof.

Since the first report of ALK fusion gene in the field of research of inter-enlarged cell lymphoma (anaplastie large cell lymphoma, ALCL) in 1994, ALK has been found to be fused with various genes, which are in turn closely related to the occurrence of various tumors. For example, NMP-bLK fusion genes have been implicated in Anaplastic Large Cell Lymphoma (ALCL) and diffuse large B-cell lymphoma (DLBCL); TPM3-bLK fusion genes are associated with anaplastic cell lymphoma (ALCL), inflammatory Myofibroblastic Tumor (IMT), histiocyte tumor (histioc. Tumor) and renal carcinoma; the EML4-bLK fusion gene is closely related to non-small cell lung cancer (NSCLC), kidney cancer, breast cancer and colon cancer, and is a hotspot of current research (Lin e., et al, mol. Cancer, 2009,7, 1466-1476). In addition, the ALK fusion gene was detected in neuroblastoma, melanoma, rhabdomyoma, and esophageal squamous cell carcinoma (Webb t.r., et al, experert rev. Anticancer therer, 2009,9 (3), 331-356).

Currently marketed ALK inhibitors are psizotinib (WO 2006021881, WO2007066185, WO 2008053157), ceritinib from North China (WO 2012106540) and Alectinib from Roche (WO 2010143664). The ALK kinase inhibitor is developed to effectively reduce the influence of the mutant ALK gene on a downstream signal path, further influence the effects of invasion, proliferation and the like of tumor cells, finally influence the growth of the tumor cells and play an anti-tumor role.

The fibroblast growth factor receptor (Fibroblast Growth Factor Receptor, FGFR) family belongs to a new family of receptor kinases, which includes four receptor subtypes (FGFR-1, FGFR-2, FGFR-3, FGFR-4) encoded by four closely related genes and a number of heterogeneous molecules, which participate in the regulation of physiological processes in organisms by forming ternary complexes with fibroblast growth factors (Fibroblast Growth Factor, FGF) and heparan sulfate, thereby triggering a series of signaling pathways. FGFRs have a wide range of physiological and pathological roles in vivo: (1) embryo development. Studies have shown that FGFR signaling is critical for most organ development and embryo pattern formation during embryo development. (2) division, migration and differentiation of cells. FGFR stimulates cell proliferation while participating in regulating cell transformation in pathological processes, there are many parallel pathways that can achieve FGFR-mediated signaling of cell division, which has been demonstrated by many studies (j.k.wang et al, oncogene 1997, 14, 1767-1778.). (3) skeletal diseases. Skeletal growth and differentiation is also regulated by the FGF family, and mutations in FGFR can lead to skeletal deformity (r.shang et al, cell 1994, 78, 335-342.). (4) occurrence of tumor. FGFRs are able to promote endothelial cell migration, proliferation and differentiation and play an important role in the regulation of angiogenesis and vasculogenesis, which can lead to the development of tumors and the growth of metastases (j. Folkman. Nat. Med.1995,1, 27-31.).

Tropomyosin receptor kinase (tropomyosin receptor kinase, TRK), also known as neurotrophic receptor tyrosine kinase (Neurotrophic Receptor Tyrosine Kinase, NTRK), is the product of the TRK gene and has a molecular weight of 120 to 160kD. It belongs to a member of the family of Receptor Tyrosine Kinases (RTKs) as a single transmembrane glycoprotein. RTK family members have similar structures, each consisting of a large glycosylated ligand binding region outside the cell, a transmembrane region (TM), an intracellular region (which can be divided into a membrane proximal region, a tyrosine kinase region, a carboxy-tail region), wherein the extracellular region contains a leucine rich structure (leucine rich motif, LRM) and an immunoglobulin region (IgG region). Two cysteine clusters flanking the LRM, distinguishing the TRK from other members of the tyrosine kinase family; while LRM determines the specificity of binding to the ligand. TRK receptors are classified into three subtypes TRK-A, TRK-B and TRK-C (or NTRK1, NTRK2 and NTRK 3). Abnormal activation of TRK-A, TRK-B and TRK-C kinases can cause a number of diseases such as cancer and autoimmune diseases.

Disclosure of Invention

The technical problem to be solved by the invention is to overcome the influence of related diseases caused by kinase, wherein the kinase is one or more selected from anaplastic lymphoma kinase (ALK kinase), fibroblast growth factor receptor (FGFR kinase) and tropomyosin receptor kinase (TRK kinase), and a thienopyrimidine compound, an intermediate, a preparation method, a composition and application thereof are provided. The thienopyrimidine compound has strong inhibition effect on ALK kinase, FGFR kinase and TRK kinase.

The invention provides a thienopyrimidine compound shown in a formula I, a stereoisomer, a crystal form, a solvate or pharmaceutically acceptable salt thereof:

wherein:

ring A is a 5-10 membered heterocycle or R ^A1 Substituted 5-10 membered heterocycles; in the 5-10 membered heterocyclic ring, the heteroatom is selected from one or more of nitrogen, oxygen and sulfur, and the heteroatom number is 1-4 (the rest is carbon atoms); r is R ^A1 1 or more, each R ^A1 Independently selected from C _1-20 Alkyl and halogen;

ring B is C _6-14 An aromatic ring or a 5-10 membered heteroaromatic ring; in the 5-10 membered heteroaromatic ring, a heteroatom is selected from one or more of nitrogen, oxygen and sulfur, and the number of the heteroatom is 1-4 (the rest is carbon atoms);

R ¹ is hydrogen, hydroxy, halogen, C _1-20 Alkyl, C _1-20 Alkoxy, -CONR ^1-1 R ^1-2 、C _3-20 Cycloalkyl, C _2-20 Heterocycloalkyl or R ^1-3 Substituted C _2-20 A heterocycloalkyl group;

R ^1-1 and R is ^1-2 Independently hydrogen or C _1-20 An alkyl group;

R ^1-3 number of (3)1 or more, each R ^1-3 Independently is hydroxy, C _1-20 Alkyl or-COR ^1-4 The method comprises the steps of carrying out a first treatment on the surface of the The R is ^1-4 Is C _1-20 Alkyl or C _1-20 Alkenyl groups.

R ² Is hydrogen, halogen or C _1-20 An alkyl group;

each R ³ Independently hydrogen, halogen, -OR ^3-1 、-COR ^3-2 、-NR ^3-3 R ^3-4 、-CONR ^3-5 R ^3-6 、-S(O) ₂ R ^3-7 、C _1-20 Alkyl, R ^3-8 Substituted C _1-20 Alkyl, C _1-20 Alkoxy, R ^3-9 Substituted C _1-20 Alkoxy, C _2-20 Heteroaryl or R ^3-10 Substituted C _2-20 Heteroaryl, or two adjacent R ³ Together with the two atoms of ring B to which they are attached form a 5-10 membered heterocyclic ring or R ^3-11 Substituted 5-10 membered heterocycles; in the 5-10 membered heterocyclic ring, a heteroatom is selected from one or two of oxygen and nitrogen, and the number of the heteroatom is 1-4 (the rest is carbon atoms); the C is _2-20 In the heteroaryl, the heteroatom is selected from one or two of oxygen and nitrogen, and the number of the heteroatom is 1-4;

R ^3-1 independently hydrogen, -S (O) ₂ R ^3-12 、C _3-20 Cycloalkyl or C _2-20 A heterocycloalkyl group;

R ^3-2 independently is hydroxy, C _1-20 Alkyl, C _1-20 Alkoxy, C _3-20 Cycloalkyl or C _2-20 A heterocycloalkyl group;

R ^3-3 and R is ^3-4 independently-S (O) ₂ R ^3-13 、C _1-20 Alkyl, C _3-20 Cycloalkyl or C _2-20 A heterocycloalkyl group;

R ^3-5 and R is ^3-6 Independently hydrogen, C _1-20 Alkyl or C _3-20 Cycloalkyl;

R ^3-7 independently C _1-20 Alkyl or C _3-20 Cycloalkyl;

R ^3-8 、R ^3-9 and R is ^3-10 Is independently 1 or more, eachR is a number of ^3-8 、R ^3-9 And R is ^3-10 Independently halogen, hydroxy, amino, -S (O) ₂ R ^3-14 、C _1-20 Alkyl, C _1-20 Alkoxy, C _3-20 Cycloalkyl or C _2-20 A heterocycloalkyl group;

R ^3-11 is independently 1 or more, each R ^3-11 Independently C _1-20 Alkyl or C _3-20 Cycloalkyl;

R ^3-12 、R ^3-13 and R is ^3-14 Independently C _1-20 Alkyl or C _3-20 Cycloalkyl;

each C is as described above _2-20 Heterocycloalkyl (e.g. R ¹ 、R ^3-1 、R ^3-2 、R ^3-3 、R ^3-4 、R ^3-8 、R ^3-9 And R is ^3-10 ) Wherein the hetero atoms are independently selected from one or two of oxygen and nitrogen, and the number of the hetero atoms is 1-4;

n is 1, 2, 3 or 4.

wherein:

R ^1-1 and R is ^1-2 Independently hydrogen or C _1-20 An alkyl group;

R ^1-3 1 or more, each R ^1-3 Independently is hydroxy, C _1-20 Alkyl or-COR ^1-4 The method comprises the steps of carrying out a first treatment on the surface of the The R is ^1-4 Is C _1-20 Alkyl or C _2-20 Alkenyl groups.

R ² Is hydrogen, halogen or C _1-20 An alkyl group;

R ^3-5 and R is ^3-6 Independent and independentThe ground is hydrogen, C _1-20 Alkyl or C _3-20 Cycloalkyl;

R ^3-7 independently C _1-20 Alkyl or C _3-20 Cycloalkyl;

R ^3-8 、R ^3-9 and R is ^3-10 Is independently 1 or more, each R ^3-8 、R ^3-9 And R is ^3-10 Independently halogen, hydroxy, amino, -S (O) ₂ R ^3-14 、C _1-20 Alkyl, C _1-20 Alkoxy, C _3-20 Cycloalkyl or C _2-20 A heterocycloalkyl group;

n is 1, 2, 3 or 4.

In the present invention, in the ring A, the 5-10 membered heterocyclic ring is preferably a 5-6 membered heterocyclic ring. In the 5-to 10-membered heterocyclic ring, the hetero atom is preferably oxygen, and the number of hetero atoms is 1 or 2 (the remainder are carbon atoms). The 5-6 membered heterocyclic ring is preferably tetrahydrofuran, 1, 3-dioxolane or 1, 4-dioxane. The R is ^A1 Preferably 1 or 2.

In the present invention, R ^A1 In the above, the C _1-20 Alkyl is preferably C _1-4 Alkyl groups, more preferably methyl groups. The halogen is preferably fluorine or chlorine.

In the present invention, in ring B, the C _6-14 The aromatic ring preferably being C _6-10 Aromatic rings, more preferably benzene. The 5-10 membered heteroaromatic ring is preferably a 5-6 membered heteroaromatic ring. In the 5-to 10-membered heteroaromatic ring, the preferred heteroatom is nitrogen, the number of heteroatoms is 1 or 2 (the remainder being carbon atoms)). The 5-6 membered heteroaromatic ring is preferably a pyrazole ring or a triazole.

In the present invention, R ¹ Preferably, the halogen is fluorine or chlorine. The C is _1-20 Alkyl is preferably C _1-4 Alkyl groups, more preferably methyl groups. The C is _1-20 Alkoxy is preferably C _1-4 Alkoxy, more preferably methoxy or ethoxy. The C is _3-20 Cycloalkyl is preferably C _3-6 Cycloalkyl, more preferably cyclopropane. The C is _2-20 The heterocycloalkyl group is preferably a monocyclic, parallel or bridged ring. The C is _2-20 Heterocyclylalkyl is preferably C _2-8 A heterocycloalkyl group. The C is _2-20 Among the heterocycloalkyl groups, the hetero atom is preferably one or both of oxygen and nitrogen, and the number of the hetero atom is 1 to 2. The C is _2-8 Heterocyclylalkyl is preferably piperidinyl, piperazinyl, 8-azabicyclo [3.2.1]Octyl or 3, 8-diazabicyclo [3.2.1]Octyl. The R is ^1-3 Preferably 1, 2 or 3.

In the present invention, R ^1-1 、R ^1-2 And R is ^1-3 In the above, the C _1-20 Alkyl is independently preferably C _1-4 Alkyl groups, more preferably methyl groups.

In the present invention, R ^1-4 In the above, the C _1-20 Alkyl is preferably C _1-4 Alkyl groups, more preferably methyl groups. The C is _1-20 Alkenyl is preferably C _1-4 Alkenyl groups are more preferably vinyl groups.

In the present invention, R ^1-4 In the above, the C _1-20 Alkyl is preferably C _1-4 Alkyl groups, more preferably methyl groups. The C is _2-20 Alkenyl is preferably C _2-4 Alkenyl groups are more preferably vinyl groups.

In the present invention, R ² In (2), the halogen is preferably fluorine. The C is _1-20 Alkyl is preferably C _1-4 Alkyl groups, more preferably methyl groups.

In the present invention, R ³ Preferably, the halogen is fluorine or chlorine. The C is _1-20 Alkyl is preferably C _1-4 Alkyl groups, more preferably methyl groups. The C is _1-20 Alkoxy is preferably C _1-4 Alkoxy, more preferably methoxy or ethoxy. The C is _2-20 Heteroaryl is preferably C _2-6 Heteroaryl groups. The C is _2-20 In heteroaryl groups, the preferred heteroatom is nitrogen, with 1 or 2 heteroatoms (the remainder being carbon atoms). The 5-10 membered heterocycle is preferably a 5-6 membered heterocycle. In the 5-to 10-membered heterocyclic ring, the hetero atom is preferably oxygen, and the number of hetero atoms is 1 or 2 (the remainder are carbon atoms). The R is ^3-8 、R ^3-9 、R ^3-10 And R is ^3-11 Independently 1 or 2.

In the present invention, R ^3-1 In the above, the C _3-20 Cycloalkyl is preferably C _3-6 Cycloalkyl, more preferably cyclopropane. The C is _2-20 Heterocyclylalkyl is preferably C _2-6 A heterocycloalkyl group. The C is _2-20 Among heterocycloalkyl groups, it is preferable that the hetero atom is one or both of oxygen and nitrogen, and the number of hetero atoms is 1 to 2 (the remainder are carbon atoms).

In the present invention, R ^3-2 In the above, the C _1-20 Alkyl is preferably C _1-4 Alkyl groups, more preferably methyl groups. The C is _1-20 Alkoxy is preferably C _1-4 Alkoxy, more preferably methoxy or ethoxy. The C is _3-20 Cycloalkyl is preferably C _3-6 Cycloalkyl, more preferably cyclopropane. The C is _2-20 Heterocyclylalkyl is preferably C _2-6 A heterocycloalkyl group. The C is _2-20 Among heterocycloalkyl groups, it is preferable that the hetero atom is one or both of oxygen and nitrogen, and the number of hetero atoms is 1 to 2 (the remainder are carbon atoms).

In the present invention, R ^3-3 And R is ^3-4 In the above, the C _1-20 Alkyl is independently preferably C _1-4 Alkyl groups, more preferably methyl groups. The C is _3-20 Cycloalkyl groups are independently preferably C _3-6 Cycloalkyl, more preferably cyclopropane. The C is _2-20 Heterocyclylalkyl is independently preferably C _2-6 A heterocycloalkyl group. The C is _2-20 Among heterocycloalkyl groups, it is preferable that the hetero atom is one or both of oxygen and nitrogen, and the number of hetero atoms is 1 to 2 (the remainder are carbon atoms).

In the present invention, R ^3-5 、R ^3-6 、R ^3-7 、R ^3-11 、R ^3-12 、R ^3-13 And R is ^3-14 In the above, the C _1-20 Alkyl is independently preferably C _1-4 Alkyl groups, more preferably methyl groups. The C is _3-20 Cycloalkyl groups are independently preferably C _3-6 Cycloalkyl, more preferably cyclopropane.

In the present invention, R ^3-8 、R ^3-9 And R is ^3-10 In (2), the halogen is independently preferably fluorine or chlorine. The C is _1-20 Alkyl is independently preferably C _1-4 Alkyl groups, more preferably methyl groups. The C is _1-20 Alkoxy groups are independently preferably C _1-4 Alkoxy, more preferably methoxy or ethoxy. The C is _3-20 Cycloalkyl groups are independently preferably C _3-6 Cycloalkyl, more preferably cyclopropane. The C is _2-20 Heterocyclylalkyl is independently preferably C _2-6 A heterocycloalkyl group. The C is _2-20 Among heterocycloalkyl groups, it is preferable that the hetero atom is one or both of oxygen and nitrogen, and the number of hetero atoms is 1 to 2 (the remainder are carbon atoms).

In the present invention, n is preferably 1 or 2, more preferably 2.

In one embodiment of the present invention, the ring A is preferably tetrahydrofuran, 2-dimethyltetrahydrofuran, 2-methyltetrahydrofuran, 1, 3-dioxolane or 1, 4-dioxane, more preferably tetrahydrofuran, 1, 3-dioxolane or 1, 4-dioxane.

In one embodiment of the present invention, the ring B is preferably a benzene ring, a pyrazole ring or a triazole, and more preferably a benzene ring.

In one aspect of the invention, the R ¹ Preferably is More preferably +.>

In one aspect of the inventionThe R is ² Preferably fluorine, chlorine or methyl, more preferably methyl.

In one aspect of the invention, the R ³ Independently preferably fluorine, Methyl, trifluoromethyl, methoxy, ethoxy or +.>More preferably fluorine or methoxy.

In one embodiment of the present invention, when n is 2, R is ³ Independently may be halogen or alkoxy; preferably one is halogen and the other is alkoxy. The R is ³ More preferably independently fluorine or methoxy; most preferably one is fluorine and the other is methoxy.

In one aspect of the invention, thePreferably +.> More preferably +.>

In one embodiment of the present invention, the thienopyrimidine compound shown in formula I is preferably any one of the following compounds:

the invention also provides a preparation method of the thienopyrimidine compound shown in the formula I, a stereoisomer, a crystal form, a solvate or a pharmaceutically acceptable salt thereof, which can be synthesized by a known method from commercially available raw materials.

In the invention, the preparation method is preferably any one of the following methods:

The method one comprises the following steps: in a solvent, under the action of a deprotection reagent, carrying out deprotection reaction on a compound shown in a formula I-a to obtain the compound shown in the formula I;

wherein R is ¹ is-CONH ₂ 、C _2-20 Heterocycloalkyl or R ^1-3 Substituted C _2-20 A heterocycloalkyl group; PG is a protecting group, preferably a Boc protecting group;

R ^1-3 ring a, ring B, R ² 、R ³ And n is as defined above;

the second method comprises the following steps: in a solvent, under the action of a palladium catalyst, performing a coupling reaction on a compound shown in a formula I-b' and a compound shown in a formula II-a to obtain a compound shown in a formula I;

wherein R is ¹ Is hydrogen, hydroxy, halogen, C _1-20 Alkyl, C _1-20 Alkoxy, -CONR ^1-1 R ^1-2 Or C _3-20 Cycloalkyl;

R ^1-1 、R ^1-2 ring a, ring B, R ² 、R ³ And n are as defined above and R ^1-1 And R is ^1-2 Not both hydrogen.

In the present invention, in method one, the method and conditions of the deprotection reaction may be conventional methods and conditions for such reactions in the art.

In the first process of the present invention, the solvent may be a solvent conventional in such reactions in the art, preferably a chlorinated alkane, such as methylene chloride.

In the first method of the present invention, the deprotecting reagent may be an acid conventional in the art. The acid may be an organic acid, for example trifluoroacetic acid. The amount of the deprotection reagent used is not particularly limited as long as the protecting group to be removed can be removed.

In the present invention, in the first method, the temperature of the deprotection reaction may be a temperature conventional in such a reaction in the art, preferably room temperature, for example, 25 ℃.

In the present invention, the progress of the deprotection reaction can be monitored by methods conventional in the art, such as TLC, HPLC, GC or NMR.

In the first method of the present invention, the post-treatment step of the deprotection reaction may be a conventional post-treatment step of such a reaction in the art, for example: HPLC.

In the present invention, in the second method, the method and conditions of the coupling reaction may be conventional methods and conditions of such reactions in the art.

In the second method, alkali can be added in the coupling reaction.

In the second method of the present invention, in the coupling reaction, the alkali is preferably an alkali metal carbonate, and more preferably sodium carbonate, potassium carbonate or cesium carbonate.

In the second process of the present invention, the molar ratio of the base to the compound of formula II-a in the coupling reaction is preferably 1:1 to 5:1, for example 1:1, 2:1, 2.73:1 or 3:1.

In the second method of the present invention, the solvent may be an organic solvent or a mixture of an organic solvent and water.

In the second method of the present invention, the organic solvent may be an organic solvent commonly used in such a reaction in the art, and the organic solvent is selected from one or more of an ether solvent, a benzene solvent and an amide solvent, preferably one or more selected from 1, 4-dioxane, toluene, ethylene glycol dimethyl ether and N, N-dimethylformamide, more preferably 1, 4-dioxane or N, N-dimethylformamide.

In the second method of the present invention, when the solvent is a mixture of an organic solvent and water, the amount of water added is preferably 1 to 100% by volume of the organic solvent.

In the second method of the present invention, the mass/volume ratio of the organic solvent to the compound represented by the formula II-a is preferably 5g/L to 80g/L, for example, 14.22g/L, 10g/L, 61.6g/L or 5.08g/L.

In the second method of the present invention, the mass/volume ratio of the compound represented by the formula II-a to the solvent is preferably 5g/L to 80g/L, for example, 14.22g/L, 10g/L, 61.6g/L or 5.08g/L.

In the second method of the present invention, the palladium-containing catalyst may be a palladium-containing catalyst commonly used in such coupling reactions, preferably one or more of tris (dibenzylideneandentacetone) dipalladium, palladium acetate, tetrakis (triphenylphosphine) palladium, and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium.

In the process II according to the invention, the molar ratio of palladium-containing catalyst to compound II-a is preferably from 0.01:1 to 1:1, more preferably from 0.05:1 to 1:1, for example 1:1, 0.3:1, 0.2:1 or 0.18:1.

In the second method of the present invention, the molar ratio of the compound represented by the formula II-a to the compound represented by the formula I-b' in the coupling reaction is preferably 0.5:1 to 2:1, more preferably 0.9:1 to 1.5:1, for example 1.1:1 or 1:1.

In the second method of the present invention, the temperature of the coupling reaction is preferably 50℃to 150℃and more preferably 90℃to 120 ℃.

In the second method of the present invention, the progress of the coupling reaction can be monitored by TLC or HPLC, and the compound of formula II-a is generally used as the end point of the reaction when it disappears.

The invention also provides a thienopyrimidine compound shown in the formula I-a,

wherein R is ¹ is-CONH ₂ 、C _2-20 Heterocycloalkyl or R ^1-3 Substituted C _2-20 A heterocycloalkyl group; PG is a protecting group, preferably a Boc protecting group; r is R ^1-3 Ring a, ring B, R ² 、R ³ And n are as defined above.

In one embodiment of the present invention, the thienopyrimidine compound represented by formula I-a is preferably any one of the following compounds:

in the second method, when the coupling reaction is finished, the product can be further purified by post-treatment; the post-treatment preferably comprises the steps of: recrystallizing, purifying by silica gel thin layer chromatography, purifying by silica gel chromatographic column, and purifying by high performance liquid chromatography.

The invention also provides application of the thienopyrimidine compound shown in the formula I, a stereoisomer, a crystal form, a solvate or a pharmaceutically acceptable salt thereof in preparing medicaments for preventing, relieving or treating related diseases caused by kinase; the kinase is selected from one or more of ALK kinase, FGFR kinase and TRK kinase.

In the present invention, the kinase-induced related disease is selected from one or more of cancer, infection or autoimmune disease.

In the present invention, the cancer is preferably selected from one or more of lung cancer, esophageal cancer, gastric cancer, colorectal cancer, liver cancer, nasopharyngeal cancer, brain tumor, breast cancer, cervical cancer, blood cancer and bone cancer.

In the present invention, the autoimmune disease is preferably psoriasis and/or inflammation.

The invention also provides a pharmaceutical composition, which comprises the thienopyrimidine compound shown in the formula I, a stereoisomer, a crystal form, a solvate or pharmaceutically acceptable salt thereof and pharmaceutic adjuvant.

In the pharmaceutical composition of the present invention, the thienopyrimidines, stereoisomers thereof, crystalline forms thereof, solvates thereof and pharmaceutically acceptable salts thereof may be used in an amount effective for treatment.

In the pharmaceutical composition of the invention, the pharmaceutical excipients can be those which are widely used in the field of pharmaceutical production. Adjuvants are used primarily to provide a safe, stable and functional pharmaceutical composition, and may also provide means for allowing the subject to dissolve at a desired rate after administration, or for promoting effective absorption of the active ingredient after administration of the composition. The pharmaceutical excipients may be inert fillers or provide a function such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition. The pharmaceutical excipients can comprise one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, sizing agents, disintegrants, lubricants, anti-adherents, glidants, wetting agents, gelling agents, absorption retarders, dissolution inhibitors, enhancing agents, adsorbents, buffering agents, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

In the present invention, the pharmaceutical composition may be prepared according to the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, levigating, encapsulating, entrapping or lyophilizing processes.

In the present invention, the pharmaceutical composition may be formulated into various types of administration unit dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injections (solutions and suspensions), etc., preferably tablets or capsules, etc., depending on the purpose of the treatment.

In the present invention, for shaping the pharmaceutical composition in the form of a tablet, any excipient known and widely used in the art may be used. For example, carriers such as lactose, white sugar, sodium chloride, dextrose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, and the like; binders such as water, ethanol, propanol, ordinary syrup, dextrose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinyl pyrrolidone, and the like; disintegrants such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, calcium carbonate, fatty acid esters of polyethylene sorbitan, sodium lauryl sulfate, monoglyceride of stearic acid, starch, lactose, etc.; disintegration inhibitors such as white sugar, glycerol tristearate, coconut oil and hydrogenated oil; adsorption promoters such as quaternary ammonium bases and sodium lauryl sulfate; wetting agents such as glycerin, starch, and the like; adsorbents such as starch, lactose, kaolin, bentonite, colloidal silicic acid, etc.; and lubricants such as pure talc, stearate, boric acid powder, polyethylene glycol, and the like. The composition can be made into sugar coated tablet, tu Ming film coated tablet, enteric coated tablet, film coated tablet, double-layer film tablet and multilayer tablet by selecting common coating materials as required.

In the present invention, for shaping the pharmaceutical composition in the form of a pill, any known and widely used excipient in the art may be used, for example, carriers such as lactose, starch, coconut oil, hardened vegetable oil, kaolin, talc, etc.; binders such as gum arabic powder, tragacanth powder, gelatin, ethanol and the like; disintegrating agents such as agar and kelp powder.

In the present invention, for shaping the pharmaceutical composition in the form of suppositories, any excipient known and widely used in the art may be used, for example, polyethylene glycol, coconut oil, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides, and the like.

In the present invention, in order to prepare a pharmaceutical composition in the form of an injection, the solution or suspension may be sterilized (preferably, a proper amount of sodium chloride, glucose or glycerin, etc. is added) to prepare an injection isotonic with blood. In preparing the injection, any carrier commonly used in the art may be used. For example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, fatty acid esters of polyethylene sorbitan, and the like. In addition, usual dissolving agents, buffers, analgesics, etc. may be added.

In the present invention, the diluent may be a diluent conventional in the art in the pharmaceutical composition.

In the present invention, the pharmaceutical composition may be in the form of oral administration or sterile injectable aqueous solutions, and the oral or injectable compositions may be prepared in accordance with any method known in the art for preparing pharmaceutical compositions.

In the present invention, the pharmaceutical composition may be used alone or in combination with one or more other drugs having antitumor activity.

Unless otherwise indicated, the following terms appearing in the present invention have the following meanings:

all the terms "heterocycle" (including when used alone and included in other groups) denote a 5-10 membered aromatic or non-aromatic heterocycle containing 1-4 heteroatoms selected from nitrogen, oxygen and sulfur. It comprises a bicyclic group, preferably a 5-6 membered aromatic or non-aromatic heterocyclic ring. Heterocycles within the scope of this definition include, but are not limited to: benzimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothienyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indazolyl, isobenzofuranyl, isoindenyl, isoquinolyl, isothiazolyl, isoxazolyl, napyrimidinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydropyranyl, tetrazolyl, tetrazolopyridinyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl 1, 4-dioxacycloalkyl, 1, 3-dioxolanyl, hexahydro-weed, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothienyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, indolinyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiodiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, and N-oxides thereof.

All the terms "alkyl" (including when used alone and included in other groups) denote branched and straight chain saturated aliphatic hydrocarbon groups containing from 1 to 20 carbon atoms, preferably from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, 4-dimethylpentyl, 2, 4-trimethylpentyl, undecyl, dodecyl, and the various isomers thereof and the like.

All terms "cycloalkyl" (including when used alone and included in other groups) denote cyclic hydrocarbon groups containing 1-3 rings, including mono-, di-and tricycloalkyl groups containing 3-20 ring-forming carbon atoms, preferably 3-6 ring-forming carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecane and cyclododecyl, cyclohexenyl, containing saturated or partially unsaturated (containing 1 or 2 double bonds).

All the terms "alkoxy" denote a cyclic or acyclic alkyl group having the stated number of carbon atoms, linked by an oxygen bridge. Thus, "alkoxy" includes the definition of alkyl and cycloalkyl above.

All the terms "heterocycloalkyl" (including when used alone and included in other groups) denote a saturated or partially unsaturated ring of 2 to 20 carbon atoms, preferably 2 to 6 carbon atoms or 2 to 8 carbon atoms, containing 1 to 4 heteroatoms selected from nitrogen and oxygen. In addition, any heterocycloalkyl ring may be fused to a cycloalkyl, aryl, heteroaryl, or heterocycloalkyl ring.

All terms "halogen" mean fluorine, chlorine, bromine, iodine, or astatine.

All terms "hydroxy" mean

The term "amino" as used herein means

All the terms "heteroaryl" denote a mono-or bi-cyclic ring with 2-20 carbon atoms comprising 1-4 heteroatoms selected from nitrogen and oxygen, wherein at least one ring is an aromatic ring. Heteroaryl groups within the scope of this definition include, but are not limited to: acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazole, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrahydroquinolinyl. "heteroaryl" shall also be understood to include any N-oxide derivative of a nitrogen-containing heteroaryl. In the case where the heteroaryl substituent is a bicyclic substituent and one ring is a non-aromatic ring or contains no heteroatoms, it is understood that the linkage occurs through the aromatic ring or through the heteroatom containing ring, respectively.

All terms "aromatic ring" denote any stable mono-or bi-cyclic ring containing 6 to 14 carbon atoms, wherein at least one ring is an aromatic ring, and aromatic rings within the scope of this definition include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, 2, 3-indanyl, biphenyl, phenanthryl, anthracyl, or acenaphthylenyl (acenaphthylyl).

The term "heteroaryl" as used herein means a 5-10 membered monocyclic or bicyclic ring containing 1-4 heteroatoms selected from nitrogen, oxygen and sulfur, wherein at least one ring is aromatic. Heteroaryl rings within the scope of this definition include, but are not limited to: acridine, carbazole, cinnoline, carboline, quinoxaline, imidazole, pyrazole, pyrrole, indole, indoline, benzotriazole, benzimidazole, furan, thiophene, isothiazole, benzothiophene, dihydrobenzothiophene, benzofuran, isobenzofuran, benzoxazole, benzofurazan, benzopyrazole, quinoline, isoindoline, isoquinoline, oxazole, oxadiazole, isoxazole, indole, pyrazine, pyridopyridine, tetrazolopyridine, pyridazine, pyridine, naphthyridine, pyrimidine, pyrrole, tetrazole, thiadiazole, thiazole, thiophene, triazole, quinazoline, tetrahydroquinoline, dihydrobenzimidazole, dihydrobenzofuran, dihydrobenzoxazole, dihydroquinoline.

All terms therapeutically effective amount refer to an amount of a compound that is sufficient to effectively treat a disease or disorder described herein when administered to a subject. Although the amount of the compound constituting the "therapeutically effective amount" will vary depending on the compound, the disorder and its severity, and the age of the subject to be treated, it can be determined by one skilled in the art in a conventional manner.

When referring to a particular salt, pharmaceutical composition, adjuvant, etc. as "pharmaceutically acceptable" it is meant that the salt, pharmaceutical composition, adjuvant, etc. is generally non-toxic, safe, and suitable for use by a subject, preferably a mammalian subject, more preferably a human subject.

All terms "pharmaceutically acceptable salts" refer to pharmaceutically acceptable organic or inorganic salts of the compounds of the present invention. Exemplary salts include, but are not limited to: sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, gluconate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1-1-methylene-bis (2-hydroxy-3-naphthoate)).

The compounds of the invention may contain one or more asymmetric centers ("stereoisomers"). As used herein, all terms "stereoisomers" refer to "pharmaceutically acceptable" when referring to a particular salt, pharmaceutical composition, adjuvant, etc., which is generally non-toxic, safe, and suitable for use by a subject, preferably a mammalian subject, more preferably a human subject.

All terms "subject" refer to any animal, preferably a mammal, most preferably a human, that is or has received administration of the compound or pharmaceutical composition according to embodiments of the present invention. All terms "mammal" as used herein include any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being preferred.

In certain embodiments, "treating" or "treating" refers to the amelioration, prevention, or reversal of a disease or disorder, or at least one discernible symptom thereof. In other embodiments, treating or being treated refers to an improvement, prevention, or reversal of at least one measurable physical parameter of a disease or condition being treated that may not be recognized in a mammal. In yet another embodiment, treating or being treated refers to slowing the progression of the disease or disorder, or is physical, such as stabilization of discernible symptoms, or physiological, such as stabilization of physical parameters, or both. In other embodiments, treating or being treated refers to delaying the onset of a disease or disorder.

In certain embodiments, the compounds of the present invention are administered as a prophylactic measure. As used herein, "preventing" or "preventing" refers to reducing the risk of acquiring a given disease or disorder. In a preferred mode of the embodiments, the indicated compounds are administered to a subject as a prophylactic measure, e.g., a subject having a family history or predisposition to cancer or autoimmune disease.

The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.

The reagents and materials used in the present invention are commercially available.

The invention has the positive progress effects that: the thienopyrimidine compound has strong inhibition effect on ALK kinase, FGFR kinase and TRK kinase, and can effectively relieve or treat related diseases such as cancers.

Detailed Description

The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.

The structure of the compound is determined by Nuclear Magnetic Resonance (NMR) or Mass Spectrometry (MS), nuclear magnetic resonance spectrum is obtained by Bruker Avance-500 instrument, deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol and the like are used as solvents, and tetramethyl silane (TMS) is used as an internal standard. Mass spectra were obtained by liquid chromatography-mass spectrometry (LC-MS) with instrument Agilent Technologies 6110 using ESI ion source.

The microwave reaction was carried out in an Explorer full-automatic microwave synthesizer manufactured by CEM company in the United states, the magnetron frequency was 2450MHz, and the continuous microwave output power was 300W.

The apparatus used for the high performance liquid phase preparation was Gilson 281, and the preparation column used was Shimadazu Shim-Pack, PRC-ODS,20X250mm,15 μm.

Example 1: synthesis of Compound 1

Synthesis of Compound 1-j

2, 4-dichloro-6-methylthiophene [3,2-d ]]And pyrimidine (10 g,45.6 mmol) in tetrahydrofuran (100 mL) andin ethanol (100 mL), the reaction was cooled to 0deg.C and sodium borohydride (12.5 g, 198mmol) was added in portions. The reaction solution was warmed to room temperature and stirred for 16 hours, diluted with water (500 mL) and then adjusted to ph=7 with 1N aqueous hydrochloric acid. The aqueous phase was extracted with ethyl acetate (150 mL. Times.3). The organic phase was washed successively with water (100 mL. Times.3) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 1-j (7.5 g, yield: 88%) as a white solid, which was not further purified. LC-MS (ESI): m/z=187 [ m+h ]] ⁺ 。

Synthesis of Compound 1-i

Compound 1-j (7.5 g,40 mmol) was dissolved in chloroform (300 mL) at 0deg.C, activated manganese dioxide (35 g,400 mmol) was added, the reaction was warmed to room temperature and stirring was continued for 16 hours. The reaction mixture was filtered through celite, and the cake was washed with chloroform (100 mL. Times.3). The combined filtrates were concentrated under reduced pressure to give 1-i (6.6 g, yield: 89%) as a white solid, which was not subjected to further purification. LC-MS (ESI): m/z=185 [ m+h ] ] ⁺ 。

Synthesis of Compounds 1-h

Compound 1-i (3.1 g,16.8 mmol) was dissolved in trifluoroacetic acid (30 mL) at 0deg.C, N-iodosuccinimide (5.7 g,25.3 mmol) was added in portions, the reaction was warmed to room temperature and stirring was continued for 1 hour. The reaction mixture was quenched with water (50 mL) and extracted with methylene chloride (50 mL. Times.3). The organic phase was washed successively with water (50 mL. Times.3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a white solid (4.9 g, yield: 94%) for 1-h, which was not further purified. LC-MS (ESI): m/z=311 [ m+h ]] ⁺ 。

Synthesis of Compound 1-g

Compound 1-h (616 mg,1.98 mmol), 2-methoxy-4-fluorophenylboronic acid (405 mg,2.38 mmol) and sodium carbonate (630 mg,5.94 mmol) were suspended in dioxane (5 mL) water (5 mL), and [1,1' -bis (diphenylphosphorus) ferrocene was added]Palladium dichloride dichloromethane complex (163 mg,0.2 mmol). The reaction was carried out by heating to 80℃for 16 hours by 3 times with nitrogen. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, the residue was separated into layers with dichloromethane (50 mL) and water (50 mL), and the organic phase was separated with anhydrous sulfuric acidSodium is dried, filtered, and the filtrate is concentrated and purified by silica gel column chromatography (petroleum ether: dichloromethane=1:1) to give 1-g (240 mg, yield: 39%) of a white solid. LC-MS (ESI): m/z=309 [ m+h ] ] ⁺ 。

Synthesis of Compound 1-f

2-methoxy-4-nitrophenol (4.0 g,23.6 mmol) was dissolved in tetrahydrofuran (150 mL) and N-bromosuccinimide (4.6278 g,25.96 mmol) was added. The reaction solution was stirred at room temperature for 3 hours. Diluted with ethyl acetate (200 mL), washed successively with water (150 mL. Times.1), a saturated aqueous sodium sulfite solution (150 mL. Times.1) and a saturated brine (150 mL. Times.1). Dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=3:1) to give 1-f (5.25 g, yield: 89.4%). LC-MS (ESI): m/z=246.0 [ m-H ]] ^- 。 ¹ H-NMR(400MHz，CDCl ₃ )δ：8.14-8.13(d，J＝2.4Hz，1H)，7.74-7.73(d，J＝2.4Hz，1H)，6.50(s，1H)，4.03(s，3H)ppm。

Synthesis of Compound 1-e

Compound 1-f (3.75 g,15.12 mmol) was dissolved in dry dichloromethane (200 mL), the reaction was cooled to-78℃and boron tribromide (22.73 g,90.72 mmol) was added, the reaction was stirred at-78℃for 15 min, and the reaction was warmed to room temperature and stirred for 12 hours. The reaction was quenched with water (200 mL) and the mixture extracted with dichloromethane (200 mL. Times.2). The combined organic phases were washed successively with water (120 mL. Times.1) and saturated brine (120 mL. Times.1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=3:1) to give 1-e (2.02 g, yield: 57.1%). LC-MS (ESI): m/z=233.0 [ m-H ] ] ^- 。 ¹ H-NMR(400MHz，CDCl ₃ )δ：8.03(d，J＝2.4Hz，1H)，7.80(d，J＝2.8Hz，1H)，6.18(br，1H)，5.98-5.97(br，1H)ppm。

Synthesis of Compound 1-d

Compound 1-e (1.92 g,8.205 mmol) and 1, 2-dibromoethane (3.853 g,20.512 mmol) were dissolved in N, N-dimethylformamide (20 mL), and potassium carbonate (4.536 g,32.82 mmol) was added. The reaction mixture was heated at 110℃with stirring for 4 hours. Will beThe reaction mixture was cooled to room temperature, diluted with ethyl acetate (20 mL), and washed with water (15 mL. Times.3) and then with saturated brine (15 mL. Times.1). Dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=3:1) to give 1-d (1.2 g, yield: 56.3%). ¹ H-NMR(400MHz，CDCl ₃ )δ：8.07-8.06(d，J＝2.8Hz，1H)，7.77-7.76(d，J＝2.8Hz，1H)，4.48-4.46(m，2H)，4.35-4.33(m，2H)ppm。

Synthesis of Compound 1-c

Compound 1-d (600 mg,2.307 mmol) and tert-butyl 4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (856.2 mg,2.769 mmol) were dissolved in 1, 4-dioxane (20 mL) and water (1 mL) and [1,1' -bis (diphenylphosphorus) ferrocene was added]Palladium dichloride (199.8 mg,0.231 mmol) and sodium carbonate (611.4 g,5.768 mmol). The reaction solution was purged three times with nitrogen to remove oxygen from the system, and then heated at 80℃for 16 hours. The reaction was cooled to room temperature, diluted with ethyl acetate (10 mL), and washed with water (10 mL. Times.3) and then with saturated brine (15 mL. Times.1). Dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=3:1) to give 1-c (602 mg, yield: 72.1%). LC-MS (ESI): m/z=263.0 [ m+h-Boc ] ⁺ 。

Synthesis of Compound 1-b

Compound 1-c (602 mg,1.66 mmol) was dissolved in ethyl acetate (20 mL), 10% palladium on charcoal (100 mg) was added, the reaction solution was replaced with hydrogen three times, and then hydrogenated at room temperature for 12 hours. The reaction mixture was filtered through celite, and the cake was washed with ethyl acetate (5 mL. Times.2). The combined filtrates were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 1-b (390 mg, yield: 70.3%). LC-MS (ESI): m/z=335 [ m+h ]] ⁺ 。

Synthesis of Compound 1-a

Compound 1-b (231 mg,0.691 mmol) and compound 1-g (213.4 mg,0.691 mmol) were dissolved in N, N-dimethylformamide (15 mL), and tris (dibenzylideneandene acetone) dipalladium (189.6 mg,0.207 mmol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy was added-1,1' -biphenyl (96.6 mg,0.207 mmol) and potassium carbonate (286.4 mg,2.072 mmol). The reaction solution was purged three times with nitrogen to remove oxygen from the system, and then heated at 110℃for 16 hours. Cooled to room temperature, diluted with ethyl acetate (10 mL), and washed successively with water (10 mL. Times.3) and saturated brine (10 mL. Times.1). Dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:1) to give 1-a (326 mg, yield: 77.6%). LC-MS (ESI): m/z=607.0 [ m+h ] ] ⁺ 。

Synthesis of Compound 1

Compound 1-a (100 mg,0.165 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (93.9 mg, 0.284 mmol) was added, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was subjected to high-performance liquid phase to prepare compound 1 (68.8 mg, yield: 82.4%). LC-MS (ESI): m/z=507.0 [ m+h ]] ⁺ 。 ¹ H-NMR(400MHz，CD ₃ OD)δ：8.78(s，1H)，7.31-7.26(m，2H)，6.96-6.81(m，3H)，4.22(s，4H)，3.77(s，3H)，3.46-3.43(d，J＝13.2Hz，2H)，3.12-3.00(m，3H)，2.45(s，3H)，1.98-1.86(m，4H)ppm。

Example 2: synthesis of Compound 2

Synthesis of Compound 2-d

7-Bromobenzo [ d ]][1，3]Dioxacyclopentene-5-carboxylic acid (770 mg,3.142 mmol) and diphenyl azide phosphate (951.4 mg,3.457 mmol) were dissolved in toluene (30 mL), and triethylamine (349.8 mg,3.457 mmol) and benzyl alcohol (6 mL) were added. The reaction solution was stirred at 90℃for 4 hours. Cooled to room temperature, diluted with ethyl acetate (20 mL), and washed successively with water (30 mL. Times.3) and saturated brine (30 mL. Times.1). Dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate=3:1) to give compound 2-d (406 mg, yield: 36.9%). LC-MS (ESI): m/z=350.0 [ m+h ]] ⁺ 。 ¹ H-NMR(400MHz，CDCl ₃ )δ：7.40-7.33(m，5H)，6.99-6.93(m，2H)，6.52(br，1H)，6.00(s，2H)，5.18(s，2)ppm。

Synthesis of Compound 2-c

Compound 2-d (344 mg,0.982 mmol) and tert-butyl 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (364.6 mg, 1.178 mmol) were dissolved in 1, 4-dioxane (20 mL) and water (1 mL) and [1,1' -bis (diphenylphosphorus) ferrocene was added ]Palladium dichloride (84.8 mg,0.098 mmol) and sodium carbonate (260.2 mg,2.45 mol). The reaction solution was purged three times with nitrogen to remove oxygen from the system, and then heated and stirred at 80℃for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (20 mL), and washed with water (15 mL. Times.3) and then with saturated brine (15 mL. Times.1). Dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate=3:1) to give compound 2-c (301 mg, yield: 67.8%). LC-MS (ESI): m/z=353.0 [ m+h-Boc] ⁺ 。

Synthesis of Compound 2-b

Compound 2-c (301 mg,0.665 mmol) was dissolved in isopropanol (10 mL), and 10% palladium on charcoal (100 mg) was added. The reaction solution was replaced with hydrogen three times, and then hydrogenated at room temperature for 12 hours. The reaction mixture was filtered through celite, and the cake was washed with isopropyl alcohol (5 mL. Times.2). The combined filtrates were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=3:1) to give compound 2-b (91 mg, yield: 42.7%).

Synthesis of Compound 2-a

Compound 2-b (100 mg,0.52 mmol) and compound 1-g (100 mg,0.52 mmol) were dissolved in N, N-dimethylformamide (10 mL), and tris (dibenzylideneandene acetone) dipalladium (100 mg,0.52 mmol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (100 mg,0.52 mmol) and potassium carbonate (100 mg,0.52 mmol) were added. The reaction solution was purged three times with nitrogen to remove oxygen from the system, and then heated at 110℃for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), and washed with water (10 mL. Times.3) and then with saturated brine (10 mL. Times.1). Drying with anhydrous sodium sulfate The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=3:1) to give compound 2-a (90 mg, yield: 53.6%). LC-MS (ESI): m/z=593.0 [ m+h ]] ⁺ 。

Synthesis of Compound 2

Compound 2-a (90 mg,0.152 mmol) was dissolved in methylene chloride (5 mL), trifluoroacetic acid (1 mL) was added, and the reaction solution was stirred at room temperature for 0.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to high-performance liquid phase to prepare compound 2 (49.4 mg, yield: 66.0%). LC-MS (ESI): m/z=493.0 [ m+h ]] ⁺ 。 ¹ H-NMR(400MHz，CD ₃ OD)δ：8.79(s，1H)，7.32-7.25(m，2H)，7.01-6.94(m，2H)，6.87-6.82(m，1H)，5.89(s，2H)，3.77(s，3H)，3.48-3.45(m，2H)，3.11-3.03(m，2H)，2.79-2.73(m，1H)，2.45(s，3H)，2.05-1.99(m，4H)ppm。

Example 3: synthesis of Compound 3

Synthesis of Compound 3-f

Sodium hydroxide (8.8 g,0.22 mol) was dissolved in water (200 mL), and 2, 6-dibromophenol (50.38 g,0.2 mol) and 1, 2-dibromoethane (41.32 g,0.22 mol) were added sequentially. The reaction mixture was heated at 110℃with stirring for 16 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (500 mL), washed successively with sodium hydroxide solution (300 mL. Times.3) and saturated brine (300 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (100% petroleum ether) to give compound 3-f (40.7 g, yield: 59%).

Synthesis of Compound 3-e

Compound 3-f (13.7 g,38.26 mmol) was dissolved in dry tetrahydrofuran (100 mL), the reaction solution was cooled to-78℃and n-butyllithium solution (26.3 mL,42.09 mmol) was added and the reaction solution was reacted at-78℃for 2 hours. The reaction mixture was warmed to room temperature, water (200 mL) was added to the reaction mixture, and the reaction mixture was quenched, and the mixture was extracted with ethyl acetate (200 mL. Times.2). The combined organic phases were washed successively with water (120 mL. Times.2) and saturated brine (120 mL. Times.1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=30:1) to give 3-e (7.0 g, yield: 90%) as a colorless oil. ¹ H-NMR：(400MHz CDCl ₃ )δ：7.29-7.26(m，1H)，7.15-7.12(m，1H)，6.74(t，J＝8.0Hz，1H)，4.68(t，J＝8.8Hz，2H)，3.33(t，J＝8.8Hz，2H)ppm。

Synthesis of Compound 3-d

Compound 3-e (7.0 g,35.0 mmol) was dissolved in trifluoroacetic acid (28.0 mL), the reaction solution was cooled to 0℃and concentrated nitric acid (14.0 mL) was added. The reaction solution was stirred at 0℃for 2 hours. Ice water (50 mL) was added, and the mixture was extracted with ethyl acetate (100 ml×2). The combined organic phases were washed successively with saturated aqueous sodium bicarbonate (50 mL. Times.2) and saturated brine (50 mL. Times.2). Dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=10:1) to give 3-d (6.5 g, yield: 75%) as a yellow solid.

Synthesis of Compound 3-c

The compound 3-d (4.9 g,20.0 mmol) and tert-butyl 4-) 4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (7.41 g,24.0 mmol) were dissolved in 1, 4-dioxane (100 mL) and water (10 mL) and [1,1' -bis (diphenylphosphorus) ferrocene was added ]Palladium dichloride (1.46 g,2.0 mmol), potassium carbonate (8.28 g,60.0 mmol). The reaction solution was heated and stirred at 90℃for 16 hours. The reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=5:1) to give 3-c (6.1 g, yield: 88%) as a pale yellow solid. LC-MS (ESI): m/z=347.2 [ m+h ]] ⁺ 。

Synthesis of Compound 3-b

Compound 3-c (6.1 g,17.6 mmol) was dissolved in anhydrous methanol (200 ml), 5% palladium on charcoal (2.0 g) was added, the reaction solution was replaced with hydrogen three times, then hydrogenated at room temperature for 16 hours, filtered, and the filtrate was concentrated under reduced pressure to give colorless solid 3-b (6.2 g, yield: 95%), which was obtained without further purification。LC-MS(ESI)：m/z＝319.3[M+H] ⁺ 。

Synthesis of Compound 3-a

Compound 3-b (6.2 g,20.0 mmol) and compound 1-g (6.16 g,20.0 mmol) were dissolved in N, N-dimethylformamide (100 mL), and tris (dibenzylideneandene acetone) dipalladium (3.66 g,4.0 mmol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (1.86 g,4.0 mmol) and potassium carbonate (5.52 g,40.0 mmol) were added. The reaction solution was purged three times with nitrogen to remove oxygen from the system, and then heated at 110℃for 16 hours. The reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=5:1) to give 3-a (11.1 g, yield: 94%) as a yellow viscous solid. LC-MS (ESI): m/z=591.2 [ m+h ] ] ⁺ 。

Synthesis of Compound 3

Compound 3-a (11.1 g,18.8 mmol) was dissolved in methylene chloride (60 ml), and trifluoroacetic acid (40 ml) was added thereto, and the reaction solution was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, water (100 mL) was added thereto, the pH of the reaction solution was adjusted to 8 with a saturated aqueous sodium carbonate solution, and the residue was filtered to give pale yellow solid 3 (4.71 g, yield: 52%) via a high-performance liquid phase. LC-MS (ESI): m/z=491.3 [ m+h ]] ⁺ 。 ¹ H-NMR：(400MHz CD ₃ OD)δ：8.78(s，1H)，7.49(s，1H)，7.32(t，J＝8.0Hz，1H)，7.19(s，1H)，7.00-6.97(m，1H)，6.88-6.84(m，1H)，4.52(t，J＝8.8Hz，2H)，3.78(s，3H)，3.30-3.29(m，2H)，3.13(t，J＝8.8Hz，2H)，2.94-2.87(m，2H)，2.77-2.74(m，1H)，2.46(s，3H)，1.91-1.84(m，4H)ppm。

Example 4: synthesis of Compound 4

Synthesis of Compound 4-c

The compound 3-d (244.0 mg,1.0 mmol) and tert-butyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -8-azabicyclo [3.2.1]Oct-2-ene-8-carboxylic acid tert-butyl ester (335.0 mg,1.0 mm)ol) dissolved in 1, 4-Dioxahexacyclic ring (30 mL) and water (3 mL), and [1,1' -bis (diphenylphosphorus) ferrocene was added]Palladium dichloride (73.1 mg,0.1 mmol), potassium carbonate (414.0 mg,3.0 mmol). The reaction mixture was heated and stirred at 95℃for 12 hours. The reaction solution was cooled to room temperature, the reaction solution was then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=5:1) to give 4-c (370 mg, yield: 99.4%) as a colorless oil. LC-MS (ESI): m/z=373.2 [ m+h] ⁺ 。

Synthesis of Compound 4-b

Compound 4-c (370.0 mg,0.99 mmol) was dissolved in anhydrous methanol (30 ml), 5% palladium on charcoal (100 mg) was added, the reaction solution was replaced with hydrogen gas three times, then hydrogenated at room temperature for 16 hours, filtered, and the filtrate was concentrated under reduced pressure to give 4-b (340 mg, yield: 95%), which product was not further purified. LC-MS (ESI): m/z=345.2 [ m+h ]] ⁺ 。

Synthesis of Compound 4-a

Compound 4-b (103 mg,0.3 mmol) and compound 1-g (101.6 mg,0.33 mmol) were dissolved in N, N-dimethylformamide (20 mL), and tris (dibenzylideneandene acetone) dipalladium (55.0 mg,0.06 mmol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (27.9 mg,0.06 mmol) and potassium carbonate (124.2 mg,0.9 mmol) were added. The reaction solution was purged three times with nitrogen to remove oxygen from the system, and then heated at 110℃for 12 hours. The reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=4:1) to give 4-a (105 mg, yield: 57%) as a yellow viscous solid. LC-MS (ESI): m/z=617.3 [ m+h ]] ⁺ 。

Synthesis of Compound 4

Compound 4-a (105 mg,0.17 mmol) was dissolved in dichloromethane (6 ml), trifluoroacetic acid (4 ml) was added, and the reaction solution was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, water (10 mL) was added, the pH of the reaction solution was adjusted to 8 with a saturated aqueous sodium carbonate solution, and the residue was filtered to give pale yellow solid 4 (71.7 mg, yield: 81.7%) via a high-performance liquid phase. LC-MS (ESI): m/z=517.4 [ m+h ] ] ⁺ 。 ¹ H-NMR：(400MHz CD ₃ OD)δ：8.80(d，J＝3.6Hz，1H)，7.58(s，1H)，7.34-7.10(m，2H)，6.99(d，J＝11.2Hz，1H)，6.88-6.84(m，1H)，4.55(t，J＝8.4Hz，2H)，4.02(d，J＝33.6Hz，2H)，3.78(s，3H)，3.16-3.12(m，3H)，2.46(s，3H)，2.39-2.34(m，1H)，2.19-1.84(m，7H)ppm。

Effect example 1: anaplastic lymphoma kinase ALK enzyme activity inhibition IC ₅₀ Evaluation experiment

Buffer solution preparation: 50mM HEPES,pH7.5,0.00015%Brij-35.

Compounds were formulated in a concentration gradient in 100% DMSO, added to 384 well plates, and the final DMSO concentration was 2%.

1. ALK enzyme (purchased from Carna Biosciences, inc.) was diluted to optimal concentration with the following buffers: 50mM HEPES,pH7.5,0.00015%Brij-35,2mM DTT. Transfer to 384 well plates and incubate with the compound for a period of time.

2. The substrate was diluted to optimal concentration with the following buffer: 50mM HEPES,pH7.5,0.00015%Brii-35 mM MgCl ₂ Adenosine triphosphate at Km. The reaction was initiated by addition of 384 well plates and allowed to react for 1 hour at 28 ℃.

3. Conversion was read with a Caliper Reader and inhibition was calculated as the average of two tests.

The compounds of the present invention were tested for ALK kinase inhibitory activity according to the above assays, with the following results (table 1):

TABLE 1 IC for inhibition of ALK kinase Activity by some of the compounds of the invention ₅₀ Value of

Compounds of formula (I)	IC ₅₀ (nM)
		1	24
2	35
		3	7.1
4	11

Effect example 2: FGFR-1, FGFR-2 and FGFR-3 kinase activity inhibition IC ₅₀ Evaluation experiment

The experimental steps are as follows:

1. the compounds were dissolved in 100% dmso, diluted with water to the appropriate concentration gradient, and added to 96-well plates as required for the experiment.

FGFR1 enzyme (Carna, cat. No.08-133, lot. No. 09CBS-0989), FGFR2 enzyme (Carna, cat. No.08-134, lot. No.07 CBS-2468), FGFR3 enzyme (Carna, cat. No.08-135, lot. No.06 CBS-3177) was diluted to optimal concentration with the following buffers: 50mM HEPES,pH 7.5,0.0015%Brij-35,2mM DTT. Transferred to 96-well plates and incubated with the compounds for a period of time at 28 ℃.

3. The reaction was stopped by adding buffer 100mM HEPES,pH 7.5,0.0015%Brij-35,0.2%Coating Reagent and 50mM EDTA.

4. Conversion was read with a Caliper Reader and inhibition was calculated as the average of two tests.

Experimental results:

the biological activity of some of the compounds of the present invention was measured by the above test, and the measured results are shown in table 2.

TABLE 2 results of inhibition of the activity of FGFR-1, FGFR-2, FGFR-3 kinase by some of the compounds of the present invention IC50 (nM)

Effect example 3: TRK-A, TRK-B and TRK-C kinase Activity-inhibiting IC ₅₀ Evaluation experiment

The experimental steps are as follows:

1. the compound was diluted with 100% dimethyl sulfoxide to 50X of the final desired maximum inhibitor concentration. 100 μl of this compound dilution was transferred to the wells of a 96-well plate.

TRK-A (CarnA, cat. No.08-186, lot. No.08 CBS-0292), TRK-B (CarnA, cat. No.08-187, lot. No.12 CBS-0461Q), TRK-C (CarnA, cat. No.08-197, lot. No.11 CBS-0047F) was diluted to optimal concentration with the following buffers: 50mM HEPES,pH 7.5,0.0015%Brij-35. Transferred to 384 well plates and incubated with the compound for a period of time at room temperature.

3. The reaction was stopped by adding buffer 100mM HEPES,pH 7.5,0.015%Brij-35,0.2%Coating Reagent#3 and 50mM EDTA.

Experimental results:

the biological activity of a part of the compounds of the present invention was measured by the above test, and the measured results are shown in table 3.

TABLE 3 results of inhibition of the activity of TRK-A, TRK-B and TRK-C kinases by certain compounds of the invention IC50 (nM)

The biological activity experimental results of the effect embodiment show that the thienopyrimidine compound has good inhibition activity on ALK kinase, FGFR-1 kinase, FGFR-2 kinase, FGFR-3 kinase, TRK-A kinase, TRK-B kinase and TRK-C kinase.

Claims

1. A thienopyrimidine compound of formula I, a stereoisomer thereof, a crystalline form thereof, a solvate thereof or a pharmaceutically acceptable salt thereof:

wherein:

ring A is a 5-10 membered heterocycle or R ^A1 Substituted 5-10 membered heterocycles; in the 5-10 membered heterocyclic ring, hetero atoms are selected from one or more of nitrogen, oxygen and sulfur, and the number of the hetero atoms is 1-4; r is R ^A1 1 or more, each R ^A1 Independently selected from C _1-20 Alkyl and halogen;

ring B is C _6-14 An aromatic ring or a 5-10 membered heteroaromatic ring; in the 5-10 membered heteroaromatic ring, hetero atoms are selected from one or more of nitrogen, oxygen and sulfur, and the number of the hetero atoms is 1-4;

R ¹ Is hydrogen, hydroxy, halogen, C _1-20 Alkyl, C _1-20 Alkoxy, -CONR ^1-1 R ^1-2 、C _3-20 Cycloalkyl, C _2-20 Heterocycloalkyl or R ¹ ^-3 Substituted C _2-20 A heterocycloalkyl group;

R ^1-1 and R is ^1-2 Independently hydrogen or C _1-20 An alkyl group;

R ^1-3 1 or more, each R ^1-3 Independently is hydroxy, C _1-20 Alkyl or-COR ^1-4 The method comprises the steps of carrying out a first treatment on the surface of the The R is ^1-4 Is C _1-20 Alkyl or C _2-20 Alkenyl groups;

R ² is hydrogen, halogen or C _1-20 An alkyl group;

each R ³ Independently hydrogen, halogen, -OR ^3-1 、-COR ^3-2 、-NR ^3-3 R ^3-4 、-CONR ^3-5 R ^3-6 、-S(O) ₂ R ^3-7 、C _1-20 Alkyl, R ^3-8 Substituted C _1-20 Alkyl, C _1-20 Alkoxy, R ^3-9 Substituted C _1-20 Alkoxy, C _2-20 Heteroaryl or R ^3-10 Substituted C _2-20 Heteroaryl, or two adjacent R ³ Together with the two atoms of ring B to which they are attached form a 5-10 membered heterocyclic ring or R ^3-11 Substituted 5-10 membered heterocycles; in the 5-10 membered heterocyclic ring, hetero atoms are selected from one or two of oxygen and nitrogen, and the number of the hetero atoms is 1-4; the C is _2-20 In the heteroaryl groups, the hetero atoms are selected from oxygen and nitrogenOne or two of the hetero atoms is 1-4;

R ^3-7 independently C _1-20 Alkyl or C _3-20 Cycloalkyl;

each C is as described above _2-20 In the heterocycloalkyl group, the hetero atom is independently selected from one or two of oxygen and nitrogen, and the number of the hetero atom is 1-4;

n is 1, 2, 3 or 4.

2. The thienopyrimidines, stereoisomers thereof, crystalline forms thereof, solvates thereof, or pharmaceutically acceptable salts thereof, of claim 1, wherein in ring a, the 5-10 membered heterocycle is a 5-6 membered heterocycle;

and/or, in the 5-10 membered heterocyclic ring, the heteroatom is oxygen, and the number of the heteroatom is 1 or 2;

and/or, the R ^A1 The number of (2) is 1 or 2;

and/or, the R ^A1 In the above, the C _1-20 Alkyl is C _1-4 An alkyl group;

and/or, the R ^A1 Wherein the halogen is fluorine or chlorine;

and/or, in the ring B, the C _6-14 The aromatic ring being C _6-10 An aromatic ring;

and/or, in the ring B, the 5-10 membered heteroaromatic ring is a 5-6 membered heteroaromatic ring;

and/or in the ring B, in the 5-10 membered heteroaromatic ring, a heteroatom is nitrogen, and the number of heteroatoms is 1 or 2;

And/or, the R ¹ Wherein the halogen is fluorine or chlorine;

and/or, the R ¹ In the above, the C _1-20 Alkyl is C _1-4 An alkyl group;

and/or, the R ¹ In the above, the C _1-20 Alkoxy is C _1-4 An alkoxy group;

and/or, the R ¹ In the above, the C _3-20 Cycloalkyl radicals are C _3-6 Cycloalkyl;

and/or, the R ¹ In the above, the C _2-20 Heterocycloalkyl is a monocyclic, fused or bridged ring;

and/or, the R ¹ In the above, the C _2-20 Heterocyclylalkyl is C _2-8 A heterocycloalkyl group;

and/or, the R ¹ In the above, the C _2-20 In the heterocycloalkyl group, the heteroatom is selected from one or two of oxygen and nitrogen, and the number of the heteroatom is 1-2;

and/or, the R ^1-3 Is 1, 2 or 3;

and/or, the R ^1-1 Said R is ^1-2 And said R ^1-3 In the above, the C _1-20 Alkyl is independently C _1-4 An alkyl group;

and/or, the R ^1-4 In the above, the C _1-20 Alkyl is C _1-4 An alkyl group;

and/or, the R ^1-4 In the above, the C _2-20 Alkenyl group is C _2-4 Alkenyl groups;

and/or, the R ² Wherein the halogen is fluorine;

and/or, the R ² In the above, the C _1-20 Alkyl is C _1-4 An alkyl group;

and/or, the R ³ Wherein the halogen is fluorine or chlorine;

and/or, the R ³ In the above, the C _1-20 Alkyl is C _1-4 An alkyl group;

and/or, the R ³ In the above, the C _1-20 Alkoxy is C _1-4 An alkoxy group;

and/or, the R ³ In the above, the C _2-20 Heteroaryl is C _2-6 Heteroaryl;

and/or, the R ³ In the above, the C _2-20 In heteroaryl, the heteroatom is nitrogen, and the number of the heteroatom is 1 or 2;

and/or, the R ³ Wherein the 5-10 membered heterocycle is a 5-6 membered heterocycle;

and/or, the R ³ In the 5-10 membered heterocyclic ring, the hetero atom is oxygen, and the number of the hetero atom is 1 or 2;

and/or, the R ^3-8 、R ^3-9 、R ^3-10 And R is ^3-11 Is independently 1 or 2;

and/or, the R ^3-1 In the above, the C _3-20 Cycloalkyl radicals are C _3-6 Cycloalkyl;

and/or, the R ^3-1 In the above, the C _2-20 Heterocyclylalkyl is C _2-6 A heterocycloalkyl group;

and/or, the R ^3-1 In the above, the C _2-20 In the heterocycloalkyl group, the heteroatom is selected from one or two of oxygen and nitrogen, and the number of the heteroatom is 1-2;

and/or, the R ^3-2 In the above, the C _1-20 Alkyl is C _1-4 An alkyl group;

and/or, the R ^3-2 In the above, the C _1-20 Alkoxy is C _1-4 An alkoxy group;

and/or, the R ^3-2 In the above, the C _3-20 Cycloalkyl radicals are C _3-6 Cycloalkyl;

and/or, the R ^3-2 In the above, the C _2-20 Heterocyclylalkyl is C _2-6 A heterocycloalkyl group;

and/or, the R ^3-2 In the above, the C _2-20 In the heterocycloalkyl group, the heteroatom is selected from one or two of oxygen and nitrogen, and the number of the heteroatom is 1-2;

and/or, the R ^3-3 And R is ^3-4 In the above, the C _1-20 Alkyl is independently C _1-4 An alkyl group;

and/or, the R ^3-3 And R is ^3-4 In the above, the C _3-20 Cycloalkyl is independently C _3-6 Cycloalkyl;

and/or, the R ^3-3 And R is ^3-4 In the above, the C _2-20 Heterocyclyl is independently C _2-6 A heterocycloalkyl group;

and/or, the R ^3-3 And R is ^3-4 In the above, the C _2-20 In the heterocycloalkyl group, the heteroatom is selected from one or two of oxygen and nitrogen, and the number of the heteroatom is 1-2;

and/or, the R ^3-5 Said R is ^3-6 Said R is ^3-7 Said R is ^3-11 Said R is ^3-12 Said R is ^3-13 And said R ^3-14 In the above, the C _1-20 Alkyl is independently C _1-4 An alkyl group;

and/or, the R ^3-5 Said R is ^3-6 Said R is ^3-7 Said R is ^3-11 Said R is ^3-12 Said R is ^3-13 And said R ^3-14 In the above, the C _3-20 Cycloalkyl is independently C _3-6 Cycloalkyl;

and/or, the R ^3-8 Said R is ^3-9 And said R ^3-10 Wherein the halogen is independently fluorine or chlorine;

and/or, the R ^3-8 Said R is ^3-9 And said R ^3-10 In the above, the C _1-20 Alkyl is independently C _1-4 An alkyl group;

and/or, the R ^3-8 Said R is ^3-9 And said R ^3-10 In the above, the C _1-20 Alkoxy is independently C _1-4 An alkoxy group;

and/or, the R ^3-8 Said R is ^3-9 And said R ^3-10 In the above, the C _3-20 Cycloalkyl is independently C _3-6 Cycloalkyl;

and/or, the R ^3-8 Said R is ^3-9 And said R ^3-10 In the above, the C _2-20 Heterocyclyl is independently C _2-6 A heterocycloalkyl group;

and/or, the R ^3-8 Said R is ^3-9 And said R ^3-10 In the above, the C _2-20 In the heterocycloalkyl group, the heteroatom is selected from one or two of oxygen and nitrogen, and the number of the heteroatom is 1-2;

And/or, n is 1 or 2.

3. The thienopyrimidines, stereoisomers thereof, crystalline forms thereof, solvates thereof, or pharmaceutically acceptable salts thereof of claim 2, wherein in ring a, the 5-6 membered heterocycle is tetrahydrofuran, 1, 3-dioxolane, or 1, 4-dioxane;

and/or, the R ^A1 In the above, the C _1-20 Alkyl is methyl;

and/or, in the ring B, the C _6-14 The aromatic ring is benzene;

and/or, in the ring B, the 5-6 membered heteroaromatic ring is a pyrazole ring or a triazole;

and/or, the R ¹ In the above, the C _1-20 Alkyl is methyl;

and/or, the R ¹ In the above, the C _1-20 Alkoxy is methoxy or ethoxy;

and/or, the R ¹ In the above, the C _3-20 Cycloalkyl is cyclopropane;

and/or, the R ¹ In the above, the C _2-8 Heterocyclylalkyl is pyridinyl, piperazinyl, 8-azabicyclo [3.2.1]Octyl or 3, 8-diazabicyclo [3.2.1]An octyl group;

and/or, the R ^1-1 Said R is ^1-2 And said R ^1-3 In the above, the C _1-20 Alkyl is independently methyl;

and/or, the R ^1-4 In the above, the C _1-20 Alkyl is methyl;

and/or, the R ^1-4 In the above, the C _2-20 Alkenyl is vinyl;

and/or, the R ² In the above, the C _1-20 Alkyl is methyl;

and/or, the R ³ In the above, the C _1-20 Alkyl is methyl;

and/or, the R ³ In the above, the C _1-20 Alkoxy is methoxy or ethoxy;

and/or, the R ^3-1 In the above, the C _3-20 Cycloalkyl is cyclopropane;

and/or, the R ^3-2 In the above, the C _1-20 Alkyl is methyl;

and/or, the R ^3-2 In the above, the C _1-20 Alkoxy is methoxy or ethoxy; the C is _3-20 Cycloalkyl is cyclopropane;

and/or, the R ^3-3 And R is ^3-4 In the above, the C _1-20 Alkyl is independently methyl;

and/or, the R ^3-3 And R is ^3-4 In the above, the C _3-20 Cycloalkyl is independently cyclopropane;

and/or, the R ^3-5 Said R is ^3-6 Said R is ^3-7 Said R is ^3-11 Said R is ^3-12 Said R is ^3-13 And said R ^3-14 In the above, the C _1-20 Alkyl is independently methyl;

the R is ^3-5 Said R is ^3-6 Said R is ^3-7 Said R is ^3-11 Said R is ^3-12 Said R is ^3-13 And said R ^3-14 In the above, the C _3-20 Cycloalkyl groups are independentlyIs cyclopropane;

and/or, the R ^3-8 Said R is ^3-9 And said R ^3-10 In the above, the C _1-20 Alkyl is independently methyl;

and/or, the R ^3-8 Said R is ^3-9 And said R ^3-10 In the above, the C _1-20 Alkoxy is independently methoxy or ethoxy;

and/or, the R ^3-8 Said R is ^3-9 And said R ^3-10 In the above, the C _3-20 Cycloalkyl is independently cyclopropane;

and/or, n is 2.

4. A thienopyrimidine compound of any one of claims 1 to 3, a stereoisomer thereof, a crystalline form thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, wherein said ring a is tetrahydrofuran, 2-dimethyltetrahydrofuran, 2-methyltetrahydrofuran, 1, 3-dioxolane or 1, 4-dioxane;

And/or, the ring B is benzene ring, pyrazole ring or triazole;

and/or, the R ¹ Is that

And/or, the R ² Is fluorine, chlorine or methyl;

and/or, the R ³ Independently is fluorine,Methyl, trifluoromethyl, methoxy, ethoxy or +.>

And/or, when n is 2, the R ³ Independently a halogen or an alkoxy groupA radical, preferably one halogen and the other alkoxy;

and/or, theIs->

And/or, theIs->

5. The thienopyrimidines, stereoisomers thereof, crystalline forms thereof, solvates thereof, or pharmaceutically acceptable salts thereof, according to claim 4, wherein said ring a is tetrahydrofuran, 1, 3-dioxolane, or 1, 4-dioxane;

and/or, the ring B is a benzene ring;

and/or, the R ¹ Is that

And/or, the R ² Is methyl;

and/or, the R ³ Independently fluorine or methoxy;

and/or, when n is 2, the R ³ Independently fluorine or methoxy, preferably one is fluorine and the other is methoxy;

and/or, theIs->

And/or, theIs->

6. The thienopyrimidine compound, a stereoisomer thereof, a crystal form thereof, a solvate thereof or a pharmaceutically acceptable salt thereof according to claim 1, wherein the thienopyrimidine compound is any one of the following:

7. The process for the preparation of a thienopyrimidine compound of any one of claims 1 to 6, a stereoisomer thereof, a crystal form thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, which is prepared by any one of the following processes:

the method one comprises the following steps:

in a solvent, under the action of a deprotection reagent, carrying out deprotection reaction on a compound shown in a formula I-a to obtain the compound shown in the formula I;

wherein R is ¹ is-CONH ₂ 、C _2-20 Heterocycloalkyl or R ^1-3 Substituted C _2-20 A heterocycloalkyl group; PG is a protecting group, preferablyA Boc protecting group; r is R ^1-3 Ring a, ring B, R ² 、R ³ And n is as defined in claims 1 to 6;

R ^1-1 、R ^1-2 ring a, ring B, R ² 、R ³ And n is as defined in claims 1 to 6; and R is ^1-1 And R is ^1-2 Not both hydrogen.

8. The method according to claim 7, wherein in the first method, the solvent is chlorinated alkane;

and/or, in the first method, the deprotection reagent is an organic acid;

And/or, in the first method, the temperature of the deprotection reaction is room temperature;

and/or, in the second method, the coupling reaction is further added with a base; the alkali is carbonate of alkali metal;

and/or in the second method, in the coupling reaction, the molar ratio of the alkali to the compound shown in the formula II-a is 1:1-5:1;

and/or, in the second method, the solvent is an organic solvent or a mixture of an organic solvent and water; the organic solvent is selected from one or more of ether solvents, benzene solvents and amide solvents, preferably one or more of 1, 4-dioxane, toluene, ethylene glycol dimethyl ether and N, N-dimethylformamide; when the solvent is a mixture of an organic solvent and water, the addition amount of the water is 1-100% of the volume of the organic solvent;

and/or, in the second method, the mass-volume ratio of the compound shown in the formula II-a to the solvent is 5 g/L-80 g/L;

and/or in the second method, the palladium-containing catalyst is selected from one or more of tris (dibenzylideneandenone) dipalladium, palladium acetate, tetrakis (triphenylphosphine) palladium and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium;

And/or, in the second method, the molar ratio of the catalyst containing palladium to the compound shown in the formula II-a is 0.01:1-1:1;

and/or in the second method, in the coupling reaction, the molar ratio of the compound shown in the formula II-a to the compound shown in the formula I-b' is 0.5:1-2:1;

and/or, in the second method, the temperature of the coupling reaction is 50-150 ℃.

9. A pharmaceutical composition comprising a therapeutically effective amount of the thienopyrimidine compound of any one of claims 1 to 6, a stereoisomer thereof, a crystal form thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutical excipient.

10. Use of a thienopyrimidine compound, a stereoisomer thereof, a crystal form thereof, a solvate thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 for the preparation of a medicament for the prevention, alleviation or treatment of a kinase-induced related disease; the kinase is selected from one or more of ALK kinase, FGFR kinase and TRK kinase.

11. The use according to claim 10, wherein the kinase-induced related disease is selected from one or more of cancer, infection or autoimmune disease.

12. The use according to claim 11, wherein: the cancer is one or more selected from lung cancer, esophageal cancer, gastric cancer, carcinoma of large intestine, liver cancer, nasopharyngeal cancer, brain tumor, breast cancer, cervical cancer, blood cancer and bone cancer; the autoimmune disease is psoriasis and/or inflammation.