RU2811207C1 - Fgfr and its mutation inhibitor, method of its preparation and use - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a compound of formula (I), where the values of R₁, R₂, R₃, R₅, R₆, X, Y, Z₁-Z₄, m, n are defined in the formula of the invention, its stereoisomer or pharmaceutically acceptable salt, which has high activity against mutant forms of FGFR. The following is also proposed: a method of producing a compound containing a pharmaceutical composition thereof, its use for the production of a medicinal product intended for the treatment and/or prevention of tumors or malignancies mediated by FGFR kinase, as well as for the treatment of a patient with a tumor resistant to an FGFR inhibitor, in particular its use for obtaining a medicinal product intended for the treatment and/or prevention of a patient with a tumor carrying mutations V561, V565, N550, N540, V555, E566, K660 and/or V550 in the FGFR-dependent signaling pathway.

EFFECT: obtaining of FGFR and its mutation inhibitor and a method of its preparation and use.

23 cl, 2 tbl, 78 ex

Description

TECHNICAL FIELD

The present invention relates to the field of pharmaceutical synthesis and, in particular, to FGFR and its mutation inhibitor, a method for its preparation and its use.

BACKGROUND OF THE ART

Fibroblast growth factor receptors (FGFRs) are tyrosine kinase receptors that bind to fibroblast growth factor ligands. Currently, four types of FGFRs have been discovered that are capable of binding to ligands. Fibroblast growth factor (FGF)-dependent signaling pathways are believed to play important roles in many processes, such as embryogenesis, tissue differentiation, wound healing, and metabolic regulation; they are also believed to be closely related to the characteristics of many tumors. Binding of FGF to its receptor causes dimerization and phosphorylation of the receptor, as well as stimulation of its protein kinase activity, resulting in facilitated activation of a number of intracellular signal transduction pathways, including Ras-MAPK, AKT-PI3K and phosphatase C, which play an important role in growth, proliferation and cell survival.

Genetic alterations in FGFR family members are often associated with tumor growth, metastasis, angiogenesis, and survival. Many FGFR inhibitors have been shown to induce clinical responses in patients with FGFR abnormalities in clinical studies, and FGFR inhibitors have also recently been approved for commercialization. However, clinical trials have shown that FGFR inhibitors rapidly develop acquired resistance, leading to relatively short progression-free survival. Mutations that cause changes in FGFR amino acids can lead to resistance to FGFR inhibitors or decreased activity of the latter. An important mechanism for the acquisition of resistance to FGFR inhibition is secondary mutations in the FGFR kinase domain that occur under the influence of an FGFR inhibitor. Corresponding FGFR point mutations are also present in tumors. It has been reported that one of the main mechanisms of resistance to tyrosine kinases is mutation in “key” residues (gatekeeper mutation); however, mutations conferring resistance to FGFR have been detected both in in vitro cell systems and in clinical studies. Gatekeeper mutations include mutations FGFR3V555M, FGFR2V565F/V565I/V565L and others. In a recent study, the gatekeeper mutation FGFR2V565F was found in three patients with cholangiocarcinoma treated with BGJ398; two of them also had other mutations that were located in other kinase regions of FGFR2. In this regard, to solve the problem of acquired resistance that arises in the case of clinical use of first-generation FGFR inhibitors, it is necessary to quickly develop new-generation FGFR inhibitors that would act for a long time on tumors with mutations of genes involved in the FGFR-dependent pathway signal transmission. However, such second-generation FGFR inhibitors should not only have the same high inhibitory activity against FGFR, but also provide the same level of activity against gatekeeper mutations for which the activity of first-generation FGFR inhibitors is reduced.

DISCLOSURE OF INVENTION

After conducting comprehensive and in-depth research, the inventors of the present invention have developed for the first time FGFR and its mutation inhibitor, its production method and its use. A number of compounds of the present invention have high activity against mutant forms of FGFR, in particular against FGFR with gatekeeper mutations, and in particular against FGFR3 V555M, FGFR2 V565I, FGFR2 V565F, FGFR2 V565L and the gatekeeper mutation FGFR2 N550K; The development of new generation FGFR inhibitors is expected.

The first aspect of the present invention relates to a compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof:

Where " » represents a double bond or a single bond;

X represents O or S; Y is CR ₄ or N;

Z ₁ and Z ₄ are each independently N or CR ₇ ;

Z ₂ and Z ₃ are each independently N or C;

ring A is a 3-12 membered nitrogen-containing heterocyclyl, the nitrogen atom in which is bonded to the carbonyl;

R ₁ is selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl , C _5-10 aryl, 5-10-membered heteroaryl, -C _0-8 alkyl-SF ₅ , -C _0-8 alkyl-S(O) _r R ₈ , -C _0-8 alkyl-OR ₉ , - C _0-8 alkyl-C(O)OR ₉ , -C _0-8 alkyl-C(O)R ₁₀ , -C _0-8 alkyl-OC(O)R ₁₀ , -C _0-8 alkyl-NR ₁₁ R ₁₂ , -C _0-8 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-8 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-8 alkyl-C( O)NR ₁₁ R ₁₂ and -C _0-8 alkyl-N(R ₁₁ )-C(O)R ₁₀ , the above groups optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, cyano, nitro , azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _3-12 cycloalkyl, 3-12-membered heterocyclyl, C _5-10 aryl, 5-10-membered heteroaryl, =O, -C _0-8 alkyl-SF ₅ , -C _0-8 alkyl-S(O) _r R ₈ , -C _0-8 alkyl-OR ₉ , -C _{0 -8} alkyl-C(O)OR ₉ , -C _0-8 alkyl-C(O)R ₁₀ , -C _0-8 alkyl-OC(O)R ₁₀ , -C _0-8 alkyl-NR ₁₁ R ₁₂ , -C _0-8 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-8 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-8 alkyl-C(O) NR ₁₁ R ₁₂ and -C _0-8 alkyl-N(R ₁₁ )-C(O)R ₁₀ ;

R ₂ , R ₃ and R ₄ are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, -C _0-8 alkyl-SF ₅ , -C _0-8 alkyl -S(O) _r R ₈ , -C _0-8 alkyl-OR ₉ , -C _0-8 alkyl-C(O)OR ₉ , -C _0-8 alkyl-C(O)R ₁₀ , -C _{0 -8} alkyl-OC(O)R ₁₀ , -C _0-8 alkyl-NR ₁₁ R ₁₂ , -C _0-8 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-8 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-8 alkyl-C(O)NR ₁₁ R ₁₂ and -C _0-8 alkyl-N(R ₁₁ )-C(O)R ₁₀ ;

R ₅ and R ₇ are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, 3 -12-membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, -C _0-8 alkyl-SF ₅ , -C _0-8 alkyl-S(O) _r R ₈ , -C _0-8 alkyl -OR ₉ , -C _0-8 alkyl-C(O)OR ₉ , -C _0-8 alkyl-C(O)R ₁₀ , -C _0-8 alkyl-OC(O)R ₁₀ , -C _{0- 8} alkyl-NR ₁₁ R ₁₂ , -C _0-8 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-8 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _{0- 8} alkyl-C(O)NR ₁₁ R ₁₂ and -C _0-8 alkyl-N(R ₁₁ )-C(O)R ₁₀ , the above groups optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _{2-10 alkynyl, C 1-10 haloalkyl} , C _1-10 deuteroalkyl, C _3-12 cycloalkyl, 3-12-membered heterocyclyl , C _5-10 aryl, 5-10 membered heteroaryl, =O, -C _0-8 alkyl-SF ₅ , -C _0-8 alkyl-S(O) _r R ₈ , -C _0-8 alkyl-OR ₉ , -C _0-8 alkyl-C(O)OR ₉ , -C _0-8 alkyl-C(O)R ₁₀ , -C _0-8 alkyl-OC(O)R ₁₀ , -C _0-8 alkyl -NR ₁₁ R ₁₂ , -C _0-8 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-8 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-8 alkyl -C(O)NR ₁₁ R ₁₂ and -C _0-8 alkyl-N(R ₁₁ )-C(O)R ₁₀ ;

R ₆ is selected from the group consisting of C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, -C(O)R ₁₀ , -NR ₁₁ R ₁₂ , -C(=NR ₁₁ )R ₁₀ , -N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C(O)NR ₁₁ R ₁₂ and -N(R ₁₁ )-C(O) R ₁₀ , the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _{1- 10} haloalkyl, C _1-10 deuteroalkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, =O, -C _0-8 alkyl-SF ₅ , -C _0-8 alkyl-S(O) _r R ₈ , -C _0-8 alkyl-OR ₉ , -C _0-8 alkyl-C(O)OR ₉ , -C _0-8 alkyl-C(O)R ₁₀ , -C _0-8 alkyl-OC(O)R ₁₀ , -C _0-8 alkyl-NR ₁₁ R ₁₂ , -C _0-8 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-8 alkyl- N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-8 alkyl-C(O)NR ₁₁ R ₁₂ and -C _0-8 alkyl-N(R ₁₁ )-C(O)R ₁₀ ;

each R ₈ is independently selected from the group consisting of hydrogen, deuterium, hydroxy, C _1-10 alkyl, C _2-10 alkenyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _5-10 aryl, 5-10 -membered heteroaryl and -NR ₁₁ R ₁₂ , the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, hydroxy, oxo, C _1-10 alkyl, C _1-10 alkoxy, C _3-12 cycloalkyl, C _3-12 cycloalkyloxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C _5-10 aryl, C _5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR ₁₁ R ₁₂ ;

each R ₉ is independently selected from the group consisting of hydrogen, deuterium, C _1-10 alkyl, C _2-10 alkenyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _5-10 aryl and 5-10 membered heteroaryl, the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, hydroxy, oxo, cyano, C _1-10 alkyl, C _1-10 alkoxy, C _3-12 cycloalkyl, C _3-12 cycloalkyloxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C _5-10 aryl, C _5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR ₁₁ R ₁₂ ;

each R ₁₀ is independently selected from the group consisting of hydrogen, deuterium, hydroxy, C _1-10 alkyl, C _1-10 alkoxy, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, C _3-12 cycloalkyloxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C _5-10 aryl, C _5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR ₁₁ R ₁₂ , the above groups optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, hydroxy, cyano, _C1-10 alkyl, _C1-10 alkoxy, _C3-12 cycloalkyl, _C3-12 cycloalkyloxy, 3-12- membered heterocyclyl, 3-12 membered heterocyclyloxy, C _5-10 aryl, C _5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR ₁₁ R ₁₂ ;

R ₁₁ and R ₁₂ are each independently selected from the group consisting of hydrogen, deuterium, hydroxy, C _1-10 alkoxy, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, 3 -12-membered heterocyclyl, _C5-10 aryl, 5-10 membered heteroaryl, sulfinyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p -toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, monoalkylamino, dialkylamino and _C1-10 alkanoyl, the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, hydroxy, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C1-10 haloalkyl, _C1-10 deuteroalkyl , C _1-10 alkoxy, C _3-12 cycloalkyl, C _3-12 cycloalkyloxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C _5-10 aryl, C _5-10 aryloxy, 5-10 member heteroaryl, 5-10 membered heteroaryloxy, amino, monoalkylamino, dialkylamino and C _1-10 alkanoyl;

or R ₁₁ and R ₁₂ , together with the nitrogen atom directly attached thereto, form a 4-10 membered heterocyclyl, the above group being optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, hydroxy, C _{1- 10} alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _1-10 alkoxy, C _3-12 cycloalkyl, C _3-12 cycloalkyloxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C _5-10 aryl, C _5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, monoalkylamino, dialkylamino and C _1-10 alkanoyl;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

each r independently takes on the values 0, 1, or 2.

In a preferred embodiment of the invention, in a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt, R ₅ and R ₇ are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, -C _{0- 4} alkyl-SF ₅ , -C _0-4 alkyl-S(O) _r R ₈ , -C _0-4 alkyl-OR ₉ , -C _0-4 alkyl-C(O)OR ₉ , -C _0-4 alkyl-C(O)R ₁₀ , -C _0-4 alkyl-OC(O)R ₁₀ , -C _0-4 alkyl-NR ₁₁ R ₁₂ , -C _0-4 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-4 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-4 alkyl-C(O)NR ₁₁ R ₁₂ and -C _0-4 alkyl-N(R ₁₁ )-C(O)R ₁₀ ;

where R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and r correspond to those in the compound of formula (I).

In a preferred embodiment of the invention, in a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt, R ₂ , R ₃ and R ₄ are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, - C _0-4 alkyl-SF ₅ , -C _0-4 alkyl-S(O) _r R ₈ , -C _0-4 alkyl-OR ₉ , -C _0-4 alkyl-C(O)OR ₉ , -C _0-4 alkyl-C(O)R ₁₀ , -C _0-4 alkyl-OC(O)R ₁₀ , -C _0-4 alkyl-NR ₁₁ R ₁₂ , -C _0-4 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-4 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-4 alkyl-C(O)NR ₁₁ R ₁₂ and -C _0-4 alkyl-N (R ₁₁ )-C(O)R ₁₀ ;

where R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and r correspond to those in the compound of formula (I).

In a preferred embodiment of the invention, in a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt, R ₆ is selected from the group consisting of C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl , 3-6-membered heterocyclyl, -C(O)R ₁₀ , -NR ₁₁ R ₁₂ , -C(=NR ₁₁ )R ₁₀ , -N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C (O)NR ₁₁ R ₁₂ and -N(R ₁₁ )-C(O)R ₁₀ , the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, =O, -C _0-4 alkyl-SF ₅ , -C _0-4 alkyl-S(O) _r R ₈ , -C _0-4 alkyl-OR ₉ , -C _0-4 alkyl-C(O)OR ₉ , -C _0-4 alkyl-C(O)R ₁₀ , -C _0-4 alkyl-OC(O)R ₁₀ , -C _0-4 alkyl-NR ₁₁ R ₁₂ , -C _0-4 alkyl-C (=NR ₁₁ )R ₁₀ , -C _0-4 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-4 alkyl-C(O)NR ₁₁ R ₁₂ and -C _{0- 4} alkyl-N(R ₁₁ )-C(O)R ₁₀ ;

where R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and r correspond to those in the compound of formula (I).

In a preferred embodiment of the invention, in a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt, R ₁ is selected from the group consisting of hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _{2- 4} alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, -C _0-4 alkyl-SF ₅ , -C _0-4 alkyl-S(O) _r R ₈ , -C _0-4 alkyl-OR ₉ , -C _0-4 alkyl-C(O)OR ₉ , -C _0-4 alkyl-C(O)R ₁₀ , -C _0-4 alkyl-OC (O)R ₁₀ , -C _0-4 alkyl-NR ₁₁ R ₁₂ , -C _0-4 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-4 alkyl-N(R ₁₁ )-C(= NR ₁₂ )R ₁₀ , -C _0-4 alkyl-C(O)NR ₁₁ R ₁₂ and -C _0-4 alkyl-N(R ₁₁ )-C(O)R ₁₀ , the above groups optionally substituted by one or more additional substituents selected from the group consisting of deuterium, halogen, cyano, _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, _C1-4 haloalkyl, _C1-4 deuteroalkyl, _C3-6 cycloalkyl, 3-6-membered heterocyclyl, C _5-8 aryl, 5-8-membered heteroaryl, =O, -C _0-4 alkyl-SF ₅ , -C _0-4 alkyl-S(O) _r R ₈ , -C _0-4 alkyl-OR ₉ , -C _0-4 alkyl-C(O)OR ₉ , -C _0-4 alkyl-C(O)R ₁₀ , -C _0-4 alkyl-OC(O)R ₁₀ , -C _0-4 alkyl-NR ₁₁ R ₁₂ , -C _0-4 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-4 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-4 alkyl-C(O)NR ₁₁ R ₁₂ and -C _0-4 alkyl-N(R ₁₁ )-C(O)R ₁₀ ;

where R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and r correspond to those in the compound of formula (I).

In yet another preferred embodiment of the invention, in a compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, the compound of formula (I) is a compound whose structure is described by formula (II):

Where " » represents a double bond or a single bond;

X represents O or S; Y is CR ₄ or N;

Z ₁ and Z ₄ are each independently N or CR ₇ ;

Z ₂ and Z ₃ are each independently N or C;

ring A is a 3-8 membered nitrogen-containing heterocyclyl, the nitrogen atom in which is bonded to the carbonyl;

R ₁ is selected from the group consisting of hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, -SF ₅ , -S(O) _r R ₈ , -OR ₉ , -C(O)OR ₉ , -C(O)R ₁₀ , -OC(O)R ₁₀ , -NR ₁₁ R ₁₂ , -C(=NR ₁₁ )R ₁₀ , -N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C(O)NR ₁₁ R ₁₂ and -N(R ₁₁ )-C(O)R ₁₀ , the above groups are optionally substituted by one or several additional substituents selected from the group consisting of deuterium, halogen, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _3-6 cycloalkyl, 3-6-membered heterocyclyl, C _5-8 aryl, 5-8-membered heteroaryl, =O, -SF ₅ , -S(O) _r R ₈ , -OR ₉ , -C(O)OR ₉ , -C(O)R ₁₀ , -OC(O)R ₁₀ , -NR ₁₁ R ₁₂ , -C(=NR ₁₁ )R ₁₀ , -N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C (O)NR ₁₁ R ₁₂ and -N(R ₁₁ )-C(O)R ₁₀ ;

each R ₂ is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _{3 -6} cycloalkyl, 3-6-membered heterocyclyl, -SF ₅ , -S(O) _r R ₈ , -OR ₉ , -C(O)OR ₉ , -C(O)R ₁₀ , -OC(O)R ₁₀ , -NR ₁₁ R ₁₂ , -C(=NR ₁₁ )R ₁₀ , -N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C(O)NR ₁₁ R ₁₂ and -N(R ₁₁ ) -C(O)R ₁₀ ;

each R ₃ is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _{3 -6} cycloalkyl, 3-6-membered heterocyclyl, -SF ₅ , -S(O) _r R ₈ , -CH ₂ -OR ₉ , -C(O)OR ₉ , -C(O)R ₁₀ , -OC( O)R ₁₀ , -NR ₁₁ R ₁₂ , -C(=NR ₁₁ )R ₁₀ , -N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C(O)NR ₁₁ R ₁₂ and -N( R ₁₁ )-C(O)R ₁₀ ;

R ₄ is selected from the group consisting of hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _3-6 cycloalkyl, 3-6-membered heterocyclyl, -SF ₅ , -S(O) _r R ₈ , -OR ₉ , -C(O)OR ₉ , -C(O)R ₁₀ , -OC(O)R ₁₀ , -NR ₁₁ R ₁₂ , -C(=NR ₁₁ )R ₁₀ , -N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C(O)NR ₁₁ R ₁₂ and -N(R ₁₁ )-C (O)R ₁₀ ;

R ₆ is selected from the group consisting of C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, -C(O)R ₁₀ , -NR ₁₁ R ₁₂ , -C(=NR ₁₁ )R ₁₀ and -N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, cyano , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _3-6 cycloalkyl, 3-6-membered heterocyclyl, =O, -SF ₅ , -S(O) _r R ₈ , -OR ₉ , -C(O)OR ₉ , -C(O)R ₁₀ , -OC(O)R ₁₀ , -CH ₂ -NR ₁₁ R ₁₂ , -C( =NR ₁₁ )R ₁₀ , -N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C(O)NR ₁₁ R ₁₂ and -N(R ₁₁ )-C(O)R ₁₀ ;

each R ₇ is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _{3 -6} cycloalkyl, 3-6-membered heterocyclyl, -SF ₅ , -S(O) _r R ₈ , -OR ₉ , -C(O)OR ₉ , -C(O)R ₁₀ , -OC(O)R ₁₀ , -NR ₁₁ R ₁₂ , -C(=NR ₁₁ )R ₁₀ , -N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C(O)NR ₁₁ R ₁₂ and -N(R ₁₁ ) -C(O)R ₁₀ ;

where R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , m, n and r correspond to those in the compound of formula (I).

In yet another preferred embodiment of the invention, in a compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, the compound of formula (I) is a compound whose structure is described by formula (IIIa) or formula (IIIb):

where each X is independently O or S; each Y is independently CH or N;

in the compound of formula (IIIb) Z ₁ represents N or CR ₇ ;

each Z ₄ is independently N or CR ₇ ;

each ring A independently represents a 4-6 membered nitrogen-containing heterocyclyl, the nitrogen atom in which is bonded to the carbonyl;

each R ₁ is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, -SF ₅ , -OR ₉ , -C(O) OR ₉ , -C(O)R ₁₀ , -OC(O)R ₁₀ and -NR ₁₁ R ₁₂ , the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, cyano, C _{1- 4} alkyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, =O, -SF ₅ , -OR ₉ , -C(O)OR ₉ , -C( O)R ₁₀ , -OC(O)R ₁₀ and -NR ₁₁ R ₁₂ ;

R _2a and R _2b are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _3-6 cycloalkyl, 3-6- heterocyclyl member, -SF ₅ , -OR ₉ , -C(O)OR ₉ , -C(O)R ₁₀ , -OC(O)R ₁₀ and -NR ₁₁ R ₁₂ ;

each R ₃ is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, - SF ₅ , -CH ₂ -OR ₉ , -C(O)OR ₉ , -C(O)R ₁₀ , -OC(O)R ₁₀ and -NR ₁₁ R ₁₂ ;

each R ₆ independently represents vinyl, the above group is optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _{3 -6} cycloalkyl, 3-6 membered heterocyclyl, =O, -SF ₅ , -OR ₉ , -C(O)OR ₉ , -C(O)R ₁₀ , -OC(O)R ₁₀ and -CH ₂ - NR ₁₁ R ₁₂ ;

each R ₇ is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, - SF ₅ , -OR ₉ , -C(O)OR ₉ , -C(O)R ₁₀ , -OC(O)R ₁₀ and -NR ₁₁ R ₁₂ ;

where R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and n correspond to those in the compound of formula (I).

In yet another preferred embodiment of the invention, in a compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, ring A, together with -( _R3 ) _n , forms the following structures:

, or ;

R ₃ is selected from the group consisting of hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, -SF ₅ , -CH ₂ -OR ₉ , -C(O)OR ₉ , -C(O)R ₁₀ , -OC(O)R ₁₀ and -NR ₁₁ R ₁₂ ;

where R ₉ , R ₁₀ , R ₁₁ and R ₁₂ correspond to those in the compound of formula (I).

In yet another preferred embodiment of the invention, in a compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, the compound of formula (I) is a compound whose structure is described by formula (IVa ₁ ) or formula (IVa ₂ ):

where each X is independently O or S; each Y is independently CH or N;

ring A, together with -R ₃ , form the following structures:

, or ;

R ₃ is selected from the group consisting of hydrogen, deuterium, halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl and -CH ₂ -OR ₉ ;

each R ₁ is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, -SF ₅ , -OR ₉ , -C( O)OR ₉ , -C(O)R ₁₀ , -OC(O)R ₁₀ and -NR ₁₁ R ₁₂ , the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, fluorine, chlorine, cyano , C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _3-6 cycloalkyl, 3-6-membered heterocyclyl, =O, -SF ₅ , -OR ₉ , -C(O)OR ₉ , -C(O)R ₁₀ , -OC(O)R ₁₀ and -NR ₁₁ R ₁₂ ;

R _2a and R _2b are each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _3-6 cycloalkyl, -SF ₅ , -OR ₉ , -C(O)OR ₉ , -C(O)R ₁₀ , -OC(O)R ₁₀ and -NR ₁₁ R ₁₂ ;

each R ₆ independently represents vinyl, the above group being optionally substituted with one or more additional substituents selected from the group consisting of deuterium, fluorine, cyano, methyl, ethyl, n -propyl and -CH ₂ -NR ₁₁ R ₁₂ ;

where R ₉ , R ₁₀ , R ₁₁ and R ₁₂ correspond to those in the compound of formula (I).

In yet another preferred embodiment of the invention, in a compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, the compound of formula (I) is a compound whose structure is described by formula (IVb ₁ ) or formula (IVb ₂ ):

where each X is independently O or S; each Y is independently CH or N;

ring A, together with -R ₃ , form the following structures:

, or ;

R ₃ is selected from the group consisting of hydrogen, deuterium, halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl and -CH ₂ -OR ₉ ;

each R ₁ is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, -SF ₅ , -OR ₉ , -C( O)OR ₉ , -C(O)R ₁₀ , -OC(O)R ₁₀ and -NR ₁₁ R ₁₂ , the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, fluorine, chlorine, cyano , C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _3-6 cycloalkyl, 3-6-membered heterocyclyl, =O, -SF ₅ , -OR ₉ , -C(O)OR ₉ , -C(O)R ₁₀ , -OC(O)R ₁₀ and -NR ₁₁ R ₁₂ ;

R _2a and R _2b are each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _3-6 cycloalkyl, -SF ₅ , -OR ₉ , -C(O)OR ₉ , -C(O)R ₁₀ , -OC(O)R ₁₀ and -NR ₁₁ R ₁₂ ;

each R ₆ independently represents vinyl, the above group being optionally substituted with one or more additional substituents selected from the group consisting of deuterium, fluorine, cyano, methyl, ethyl, n -propyl and -CH ₂ -NR ₁₁ R ₁₂ ;

where R ₉ , R ₁₀ , R ₁₁ and R ₁₂ correspond to those in the compound of formula (I).

In a preferred embodiment of the invention, in a compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, each R ₈ is independently selected from the group consisting of hydrogen, deuterium, hydroxy, C _1-4 alkyl, C _2-4 alkenyl, C _{3- 6} cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl and -NR ₁₁ R ₁₂ , the above groups optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, hydroxy , oxo, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C _5-8 aryl, C _{5- 8} aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR ₁₁ R ₁₂ ;

each R ₉ is independently selected from the group consisting of hydrogen, deuterium, C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl and 5-8 membered heteroaryl, the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, hydroxy, oxo, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C _5-8 aryl, C _5-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR ₁₁ R ₁₂ ;

each R ₁₀ is independently selected from the group consisting of hydrogen, deuterium, hydroxy, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C _5-8 aryl, C _5-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR ₁₁ R ₁₂ , the above groups optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, hydroxy, cyano, _C1-4 alkyl, _C1-4 alkoxy, _C3-6 cycloalkyl, _C3-6 cycloalkyloxy, 3-6- membered heterocyclyl, 3-6 membered heterocyclyloxy, C _5-8 aryl, C _5-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR ₁₁ R ₁₂ ;

R ₁₁ and R ₁₂ are each independently selected from the group consisting of hydrogen, deuterium, hydroxy, C _1-4 alkoxy, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3 -6-membered heterocyclyl, _C5-8 aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p -toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, monoalkylamino, dialkylamino and _C1-4 alkanoyl, the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, hydroxy, _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, _C1-4 haloalkyl, _C1-4 deuteroalkyl , C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C _5-8 aryl, C _5-8 aryloxy, 5-8 member heteroaryl, 5-8 membered heteroaryloxy, amino, monoalkylamino, dialkylamino and C _1-4 alkanoyl;

or R ₁₁ and R ₁₂ , together with the nitrogen atom directly attached thereto, form a 4-6 membered heterocyclyl, the above group being optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, hydroxy, C _{1- 4} alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C _5-8 aryl, C _5-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, monoalkylamino, dialkylamino and C _1-4 alkanoyl.

In the most preferred embodiment of the invention, the compound of formula (I), a stereoisomer or pharmaceutically acceptable salt thereof includes, but is not limited to, the following compounds:

A second aspect of the present invention is a method for preparing a compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, comprising the following steps:

,

where ring A, X, Y, Z ₁ , Z ₂ , Z ₃ , Z ₄ , R ₁ , R ₂ , R ₃ , R ₅ , R ₆ , m and n correspond to those in the compound of formula (I).

A third aspect of the present invention is a pharmaceutical composition comprising a compound of formula (I), a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The present invention also relates to the use of a compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of a patient with a tumor resistant to an FGFR inhibitor.

In a preferred embodiment of the invention, the tumor patient has mutations in FGFR V561, V565, N550, N540, V555, E566, K660 and/or V550.

In another preferred embodiment of the invention, the tumor patient has the FGFR2 mutations V565F, V565I, V565L, V565M, N550K, N550H, E566A, E566G, K660M and/or K660Q.

In yet another preferred embodiment of the invention, the tumor patient has the FGFR3 V555M/L and/or N540K mutations.

The present invention also relates to the use of a compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, for the prevention or treatment of a disease or condition mediated by FGFR kinase.

The present invention also relates to the use of a compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof for the prevention or treatment of a tumor or malignancy mediated by FGFR kinase.

In a preferred embodiment of the invention, the tumor or malignancy is bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, stomach cancer, head and neck cancer, renal carcinoma, liver cancer, lung cancer, ovarian cancer, cancer prostate cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, thyroid cancer, skin cancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, acute myelocytic leukemia, Hodgkin's lymphoma or non-Hodgkin's lymphoma, Waldenström's macroglobulinemia, hairy cell lymphoma, cellular lymphoma, Burkitt's lymphoma, glioblastoma, melanoma or rhabdomyosarcoma.

The present invention also relates to the use of a compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of myeloproliferative disease, bone or cartilage cell disease and hypophosphatemia.

In the present invention, the myeloproliferative disorder is erythrocytosis, primary thrombocytosis or primary myelofibrosis; a bone or cartilage cell disease such as dysplasia, achondroplasia, dwarfism, thanatophore dysplasia (TD), Apert syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Beer-Stevenson cutis gyrus syndrome, Pfeiffer syndrome or cranial muscular atrophy syndrome; hypophosphatemia is X-linked hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, or neoplastic osteomalacia.

The present invention also relates to the use of a compound of formula (I), a stereoisomer or pharmaceutically acceptable salt thereof, or the above pharmaceutical composition for the treatment of diseases associated with aberrant expression and mutation of the FGFR2 or FGFR3 receptor, or aberrant expression and activity of the corresponding ligand as a selective inhibitor of FGFR2 and /or FGFR3.

The present invention also relates to a method of treating a patient with a tumor resistant to an FGFR inhibitor, which consists of administering to the patient in need of such treatment a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt.

The present invention also relates to a method of treating a patient with a tumor carrying the FGFR2 mutations V565F, V565I, V565L, V565M, N550K, N550H, E566A, E566G, K660M and/or K660Q, which consists of administering to the patient in need of such treatment a compound of formula ( I), a stereoisomer thereof or a pharmaceutically acceptable salt.

DETAILED DESCRIPTION OF THE INVENTION

After conducting comprehensive and in-depth research, the inventors of the present invention have developed for the first time FGFR and its mutation inhibitor, its production method and its use. A number of the compounds of the present invention are highly active against mutant forms of FGFR, in particular against FGFR with gatekeeper mutations, and in particular against the FGFR3 V555M, FGFR2 V565I, FGFR2 V565F, FGFR2 V565L and FGFR2 N550K mutations.

Detailed Description: Unless otherwise defined or indicated, the following terms as used in the specification and claims have the following meanings.

"Alkyl" refers to linear or branched saturated aliphatic alkyl groups, preferably linear or branched alkyl groups containing from 1 to 10, from 1 to 6 or from 1 to 4 carbon atoms, including, but not limited to, methyl, ethyl, n- propyl, isopropyl, n -butyl, isobutyl, tert -butyl, sec -butyl, n -pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3- methylbutyl, n -hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n -heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n -octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3, 3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or various branched isomers thereof, and the like. "C _1-10 alkyl" refers to linear alkyl or branched alkyl groups containing from 1 to 10 carbon atoms, "C _1-4 alkyl" refers to linear alkyl or branched alkyl groups containing from 1 to 4 carbon atoms, "C _"0-8 alkyl" refers to linear alkyl or branched alkyl groups containing from 0 to 8 carbon atoms, and "C _0-4 alkyl" refers to linear alkyl or branched alkyl groups containing from 0 to 4 carbon atoms.

Alkyl may be optionally substituted or unsubstituted, and if substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _5-10 aryl , 5-10-membered heteroaryl, =O, -C _0-8 alkyl-SF ₅ , -C _0-8 alkyl-S(O) _r R ₈ , -C _0-8 alkyl-OR ₉ , -C _{0- 8} alkyl-C(O)OR ₉ , -C _0-8 alkyl-C(O)R ₁₀ , -C _0-8 alkyl-OC(O)R ₁₀ , -C _0-8 alkyl-NR ₁₁ R ₁₂ , -C _0-8 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-8 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-8 alkyl-C(O)NR ₁₁ R ₁₂ and -C _0-8 alkyl-N(R ₁₁ )-C(O)R ₁₀ .

"Cycloalkyl" or "carbocyclyl" refers to a monocyclic or polycyclic hydrocarbon substituent that is saturated or partially unsaturated. By partially unsaturated cyclic hydrocarbon is meant a cyclic hydrocarbon that may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a fully conjugated π-electron system; The cycloalkyl may be a monocyclic cycloalkyl or a polycyclic cycloalkyl and is preferably a cycloalkyl containing 3 to 12, 3 to 8 or 3 to 6 carbon atoms. For example, "C _3-12 cycloalkyl" refers to a cycloalkyl containing from 3 to 12 carbon atoms, and "C _3-6 cycloalkyl" refers to a cycloalkyl containing from 3 to 6 carbon atoms.

Monocyclic cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl and the like;

polycyclic cycloalkyl includes spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl. "Spirocycloalkyl" refers to a polycyclic group in which a carbon atom (called spiroatom) is shared by monocyclic rings, these rings may contain one or more (preferably 1, 2 or 3) double bonds, but none of them have a fully conjugated π-electron system. According to the number of spiro atoms common to the rings, spirocycloalkyl may be monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl, including but not limited to:

.

"Fused cycloalkyl" refers to an all-carbon polycyclic group in which each ring shares two adjacent carbon atoms with other rings in the system, and one or more rings may contain one or more (preferably 1, 2 or 3) double bonds, but none one of them does not have a fully conjugated π-electron system. Depending on the number of rings formed, the fused cycloalkyl may be bicyclic, tricyclic, tetracyclic or polycyclic, including but not limited to:

.

"Bridged cycloalkyl" refers to an all-carbon polycyclic group in which any two rings have two carbon atoms that are not directly bonded to each other, which rings may contain one or more (preferably 1, 2 or 3) double bonds, but none one of them does not have a fully conjugated π-electron system. Depending on the number of rings formed, the bridged cycloalkyl may be bicyclic, tricyclic, tetracyclic or polycyclic, including but not limited to:

.

The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, where the ring attached to the parent structure is a cycloalkyl, which includes, but is not limited to, indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like.

The cycloalkyl may be optionally substituted or unsubstituted, and if substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _5-10 aryl , 5-10-membered heteroaryl, =O, -C _0-8 alkyl-SF ₅ , -C _0-8 alkyl-S(O) _r R ₈ , -C _0-8 alkyl-OR ₉ , -C _{0- 8} alkyl-C(O)OR ₉ , -C _0-8 alkyl-C(O)R ₁₀ , -C _0-8 alkyl-OC(O)R ₁₀ , -C _0-8 alkyl-NR ₁₁ R ₁₂ , -C _0-8 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-8 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-8 alkyl-C(O)NR ₁₁ R ₁₂ and -C _0-8 alkyl-N(R ₁₁ )-C(O)R ₁₀ .

"Heterocyclyl" or "heterocycle" refers to a monocyclic or polycyclic hydrocarbon substituent that is saturated or partially unsaturated. By partially unsaturated cyclic hydrocarbon is meant a cyclic hydrocarbon that may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a fully conjugated π-electron system; in a heterocyclyl, one or more (preferably 1, 2, 3 or 4) ring atoms are heteroatoms selected from the group consisting of nitrogen, oxygen, S(O)(=NH) and S(O) _r (where r is an integer 0, 1 or 2), excluding ring groups -OO-, -OS- or -SS-, and the remaining ring atoms are carbon atoms. Preferably, the heterocyclyl contains from 3 to 12, from 3 to 8 or from 3 to 6 ring atoms; for example, "3-6 membered heterocyclyl" refers to a cyclic group containing from 3 to 6 ring atoms, "4-6 membered heterocyclyl" refers to a cyclic group containing from 4 to 6 ring atoms, "4-10 membered heterocyclyl" refers to a cyclic group containing from 4 to 10 ring atoms, and "3-12 membered heterocyclyl" refers to a cyclic group containing from 3 to 12 ring atoms.

Monocyclic heterocyclyl includes, but is not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like.

Polycyclic heterocyclyl includes spiroheterocyclyl, fused heterocyclyl and bridged heterocyclyl. "Spiroheterocyclyl" refers to a polycyclic heterocyclyl group in which an atom (called spiroatom) is common to monocyclic rings, where one or more (preferably 1, 2, 3 or 4) ring atoms are heteroatoms selected from the group consisting of nitrogen, oxygen, S(O)(=NH) and S(O) _r (where r is an integer 0, 1 or 2), and the remaining ring atoms are carbon atoms. These rings may contain one or more (preferably 1, 2 or 3) double bonds, but none have a fully conjugated π electron system. According to the number of spiro atoms common to the rings, a spiroheterocyclyl may be a monospiroheterocyclyl, a bispiroheterocyclyl, or a polyspiroheterocyclyl, including but not limited to:

.

"Fused heterocyclyl" refers to a polycyclic heterocyclyl group in which each ring shares two adjacent atoms with other rings in the system, wherein one or more (preferably 1, 2, 3 or 4) rings may contain one or more (preferably 1, 2 or 3) double bonds, but none of them has a fully conjugated π-electron system, and one or more (preferably 1, 2, 3 or 4) ring atoms are heteroatoms selected from the group consisting of nitrogen, oxygen, S(O)(=NH) and S(O) _r (where r is an integer 0, 1 or 2), and the remaining ring atoms are carbon atoms. Depending on the number of rings formed, the fused heterocycloakyl may be bicyclic, tricyclic, tetracyclic or polycyclic, including but not limited to:

.

"Bridged heterocyclyl" refers to a polycyclic heterocyclyl group in which any two rings have two carbon atoms that are not directly bonded to each other, which rings may contain one or more (preferably 1, 2 or 3) double bonds, but none one of them does not have a fully conjugated π-electron system, and wherein one or more (preferably 1, 2, 3 or 4) ring atoms are heteroatoms selected from the group consisting of nitrogen, oxygen, S(O)(=NH ) and S(O) _r (where r is an integer 0, 1 or 2), and the remaining ring atoms are carbon atoms. Depending on the number of rings formed, the linked heterocyclyl may be bicyclic, tricyclic, tetracyclic or polycyclic, including but not limited to:

.

A heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, where the ring attached to the parent structure is a heterocyclyl, including but not limited to:

.

The heterocyclyl may be optionally substituted or unsubstituted, and if substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _5-10 aryl , 5-10-membered heteroaryl, =O, -C _0-8 alkyl-SF ₅ , -C _0-8 alkyl-S(O) _r R ₈ , -C _0-8 alkyl-OR ₉ , -C _{0- 8} alkyl-C(O)OR ₉ , -C _0-8 alkyl-C(O)R ₁₀ , -C _0-8 alkyl-OC(O)R ₁₀ , -C _0-8 alkyl-NR ₁₁ R ₁₂ , -C _0-8 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-8 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-8 alkyl-C(O)NR ₁₁ R ₁₂ and -C _0-8 alkyl-N(R ₁₁ )-C(O)R ₁₀ .

"Aryl" or "aromatic ring" means an all-carbon monocyclic group or a fused polycyclic group (i.e., rings that have a pair of adjacent carbon atoms) and a polycyclic group having a conjugated π-electron system (i.e., rings with adjacent pairs carbon atoms), and is preferably an all-carbon aryl containing from 5 to 10 carbon atoms or from 5 to 8 carbon atoms. For example, "C _5-10 aryl" refers to an all-carbon aryl containing from 5 to 10 carbon atoms, and "C _5-8 aryl" refers to an all-carbon aryl containing from 5 to 8 carbon atoms. It includes, but is not limited to, phenyl and naphthyl. An aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, the ring attached to the parent structure being an aryl ring, including but not limited to:

.

"Aryl" may be optionally substituted or unsubstituted, and if substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _3-12 cycloalkyl, 3-12-membered heterocyclyl, C _{5- 10} aryl, 5-10-membered heteroaryl, =O, -C _0-8 alkyl-SF ₅ , -C _0-8 alkyl-S(O) _r R ₈ , -C _0-8 alkyl-OR ₉ , -C _0-8 alkyl-C(O)OR ₉ , -C _0-8 alkyl-C(O)R ₁₀ , -C _0-8 alkyl-OC(O)R ₁₀ , -C _0-8 alkyl-NR ₁₁ R ₁₂ , -C _0-8 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-8 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-8 alkyl-C(O )NR ₁₁ R ₁₂ and -C _0-8 alkyl-N(R ₁₁ )-C(O)R ₁₀ .

"Heteroaryl" refers to a heteroaromatic system containing one or more (preferably 1, 2, 3 or 4) heteroatoms including nitrogen, oxygen and S(O) _r (where r is an integer of 0, 1 or 2), and preferably is a heteroaromatic system containing from 5 to 10, from 5 to 8 or from 5 to 6 ring atoms. For example, "5-8 membered heteroaryl" refers to a heteroaromatic system containing from 5 to 8 ring atoms, and "5-10 membered heteroaryl" refers to a heteroaromatic system containing from 5 to 10 ring atoms. Heteroaryl includes, but is not limited to, furyl, thiophenyl, pyridyl, pyrrolyl, N -alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazoyl, etc. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, with the ring attached to the parent structure , is a heteroaryl ring, including but not limited to:

.

"Heteroaryl" may be optionally substituted or unsubstituted, and if substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _3-12 cycloalkyl, 3-12-membered heterocyclyl, C _{5- 10} aryl, 5-10-membered heteroaryl, =O, -C _0-8 alkyl-SF ₅ , -C _0-8 alkyl-S(O) _r R ₈ , -C _0-8 alkyl-OR ₉ , -C _0-8 alkyl-C(O)OR ₉ , -C _0-8 alkyl-C(O)R ₁₀ , -C _0-8 alkyl-OC(O)R ₁₀ , -C _0-8 alkyl-NR ₁₁ R ₁₂ , -C _0-8 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-8 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-8 alkyl-C(O )NR ₁₁ R ₁₂ and -C _0-8 alkyl-N(R ₁₁ )-C(O)R ₁₀ .

“Alkenyl” refers to alkyl, as defined above, which contains at least two carbon atoms and at least one carbon-carbon double bond, and is preferably a linear or branched alkenyl containing from 2 to 10 or from 2 to 4 carbon atoms. For example, "C _2-10 alkenyl" refers to a linear or branched alkenyl containing from 2 to 10 carbon atoms, and "C _2-4 alkenyl" refers to a linear or branched alkenyl containing from 2 to 4 carbon atoms. Alkenyl includes, but is not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl and the like.

"Alkenyl" may be optionally substituted or unsubstituted, and if substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _3-12 cycloalkyl, 3-12-membered heterocyclyl, C _{5- 10} aryl, 5-10-membered heteroaryl, =O, -C _0-8 alkyl-SF ₅ , -C _0-8 alkyl-S(O) _r R ₈ , -C _0-8 alkyl-OR ₉ , -C _0-8 alkyl-C(O)OR ₉ , -C _0-8 alkyl-C(O)R ₁₀ , -C _0-8 alkyl-OC(O)R ₁₀ , -C _0-8 alkyl-NR ₁₁ R ₁₂ , -C _0-8 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-8 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-8 alkyl-C(O )NR ₁₁ R ₁₂ and -C _0-8 alkyl-N(R ₁₁ )-C(O)R ₁₀ .

"Alkynyl" refers to an alkyl, as defined above, which contains at least two carbon atoms and at least one carbon-carbon triple bond, and is preferably a linear or branched alkynyl containing from 2 to 10 or from 2 to 4 carbon atoms. For example, "C _2-10 alkynyl" refers to a linear or branched alkynyl containing from 2 to 10 carbon atoms, and "C _2-4 alkynyl" refers to a linear or branched alkynyl containing from 2 to 4 carbon atoms. Alkynyl includes, but is not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl and the like.

"Alkynyl" may be optionally substituted or unsubstituted, and if substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _3-12 cycloalkyl, 3-12-membered heterocyclyl, C _{5- 10} aryl, 5-10-membered heteroaryl, =O, -C _0-8 alkyl-SF ₅ , -C _0-8 alkyl-S(O) _r R ₈ , -C _0-8 alkyl-OR ₉ , -C _0-8 alkyl-C(O)OR ₉ , -C _0-8 alkyl-C(O)R ₁₀ , -C _0-8 alkyl-OC(O)R ₁₀ , -C _0-8 alkyl-NR ₁₁ R ₁₂ , -C _0-8 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-8 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-8 alkyl-C(O )NR ₁₁ R ₁₂ and -C _0-8 alkyl-N(R ₁₁ )-C(O)R ₁₀ .

"Alkoxy" refers to -O-alkyl, where alkyl is as defined above. For example, "C _1-10 alkoxy" refers to an alkoxy group containing from 1 to 10 carbon atoms, and "C _1-4 alkoxy" refers to an alkoxy group containing from 1 to 4 carbon atoms. Alkoxy includes, but is not limited to, methoxy, ethoxy, propoxy, butoxy and the like.

"Alkoxy" may be optionally substituted or unsubstituted, and if substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _3-12 cycloalkyl, 3-12-membered heterocyclyl, C _{5- 10} aryl, 5-10-membered heteroaryl, =O, -C _0-8 alkyl-SF ₅ , -C _0-8 alkyl-S(O) _r R ₈ , -C _0-8 alkyl-OR ₉ , -C _0-8 alkyl-C(O)OR ₉ , -C _0-8 alkyl-C(O)R ₁₀ , -C _0-8 alkyl-OC(O)R ₁₀ , -C _0-8 alkyl-NR ₁₁ R ₁₂ , -C _0-8 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-8 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-8 alkyl-C(O )NR ₁₁ R ₁₂ and -C _0-8 alkyl-N(R ₁₁ )-C(O)R ₁₀ .

"Cycloalkyloxy" refers to -O-cycloalkyl, where cycloalkyl is as defined above. For example, "C _3-12 cycloalkyloxy" refers to a cycloalkyloxy group containing from 3 to 12 carbon atoms, and "C _3-6 cycloalkyloxy" refers to a cycloalkyloxy group containing from 3 to 6 carbon atoms. Cycloalkyloxy includes, but is not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc.

"Cycloalkyloxy" may be optionally substituted or unsubstituted, and if substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _3-12 cycloalkyl, 3-12-membered heterocyclyl, C _{5- 10} aryl, 5-10-membered heteroaryl, =O, -C _0-8 alkyl-SF ₅ , -C _0-8 alkyl-S(O) _r R ₈ , -C _0-8 alkyl-OR ₉ , -C _0-8 alkyl-C(O)OR ₉ , -C _0-8 alkyl-C(O)R ₁₀ , -C _0-8 alkyl-OC(O)R ₁₀ , -C _0-8 alkyl-NR ₁₁ R ₁₂ , -C _0-8 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-8 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-8 alkyl-C(O )NR ₁₁ R ₁₂ and -C _0-8 alkyl-N(R ₁₁ )-C(O)R ₁₀ .

"Heterocyclyloxy" refers to -O-heterocyclyl, where heterocyclyl is as defined above and heterocyclyloxy includes, but is not limited to, azacyclobutyloxy, oxacyclobutyloxy, azacyclopentyloxy, nitrogen, oxacylogexyloxy, etc.

"Heterocyclyloxy" may be optionally substituted or unsubstituted, and if substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _3-12 cycloalkyl, 3-12-membered heterocyclyl, C _{5- 10} aryl, 5-10-membered heteroaryl, =O, -C _0-8 alkyl-SF ₅ , -C _0-8 alkyl-S(O) _r R ₈ , -C _0-8 alkyl-OR ₉ , -C _0-8 alkyl-C(O)OR ₉ , -C _0-8 alkyl-C(O)R ₁₀ , -C _0-8 alkyl-OC(O)R ₁₀ , -C _0-8 alkyl-NR ₁₁ R ₁₂ , -C _0-8 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-8 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-8 alkyl-C(O )NR ₁₁ R ₁₂ and -C _0-8 alkyl-N(R ₁₁ )-C(O)R ₁₀ .

"C _1-10 alkanoyl" refers to the monovalent atomic group that is formed after removal of the hydroxy group from a C _1-10 alkyl acid, and is also commonly written as "C _0-9 -C(O)-", where "C _0-9 " refers to _C0-9 alkyl. For example, "C ₁ -C(O)-" refers to acetyl, "C ₂ -C(O)-" refers to propionyl, and "C ₃ -C(O)-" refers to butyryl or isobutyryl.

"-C _0-8 alkyl-S(O) _r R ₈ " means that the sulfur atom in -S(O) _r R ₈ is attached to a C _0-8 alkyl, where C _0-8 alkyl is as defined above.

" _-C0-8 alkyl- _OR9 " means that the oxygen atom in _-OR9 is attached to a _C0-8 alkyl, where _C0-8 alkyl is as defined above.

“ _-C0-8 alkyl-C(O)OR ₉ ” means that the carbonyl in -C(O)OR ₉ is attached to a _C0-8 alkyl, where _C0-8 alkyl is as defined above.

" _C0-8 alkyl-C(O) _R10 " means that the carbonyl in -C(O) _R10 is attached to a _C0-8 alkyl, where _C0 alkyl means there are 0 carbon atoms present and _{C1 -8} alkyl corresponds to the above definition.

"-C _0-8 -OC(O)R ₁₀ " means that the oxygen atom in -OC(O)R ₁₀ is attached to a C _0-8 alkyl, where C _0-8 alkyl is as defined above.

"-C _0-8 -NR ₁₁ R ₁₂ " means that the nitrogen atom in -NR ₁₁ R ₁₂ is attached to a C _0-8 alkyl, where C _0-8 alkyl is as defined above.

“-C _0-8 -C(=NR ₁₁ )R ₁₀ ” means that the carbon atom in -C(=NR ₁₁ )R ₁₀ is attached to a C _0-8 alkyl, where C _0-8 alkyl is as defined above.

“-C _0-8 -N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ ” means that the nitrogen atom in -N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ is attached to the C _0-8 alkyl , where C _0-8 alkyl corresponds to the above definition.

“-C _0-8 -C(O)NR ₁₁ R ₁₂ ” means that the carbonyl in -C(O)NR ₁₁ R ₁₂ is attached to a C _0-8 alkyl, where C _0-8 alkyl is as defined above.

“-C _0-8 -N(R ₁₁ )-C(O)R ₁₀ ” means that the nitrogen atom in -N(R ₁₁ )-C(O)R ₁₀ is attached to a C _0-8 alkyl, where C _{0 -8} alkyl corresponds to the above definition.

"C _1-10 haloalkyl" refers to an alkyl group containing from 1 to 10 carbon atoms in which the alkyl hydrogen atoms are optionally replaced by a fluorine, chlorine, bromine or iodine atom, and includes, but is not limited to, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, etc.

"C _1-10 haloalkoxy" refers to an alkoxy group containing from 1 to 10 carbon atoms, in which the alkyl hydrogen atoms are optionally replaced by a fluorine, chlorine, bromine or iodine atom, and includes, but is not limited to, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy , tribromomethoxy and the like.

“C _1-10 deuteroalkyl” refers to an alkyl group containing from 1 to 10 carbon atoms in which the alkyl hydrogen atoms are optionally replaced by a deuterium atom, and includes, but is not limited to, monodeuteromethyl, dideuteromethyl, trideuteromethyl and the like.

"Halogen" refers to fluorine, chlorine, bromine or iodine. "PE" refers to petroleum ether. "EtAc" refers to ethyl acetate. "DCM" refers to dichloromethane.

“Optional” or “optional” means that the event or circumstance described below may occur, but does not necessarily occur, and that the description includes cases in which the event or circumstance does or does not occur, that is, cases in which substitution does or does not occur. For example, “heterocyclyl group optionally substituted with alkyl” means that alkyl may be present, but is not necessarily present, and that the description includes cases where the heterocyclyl group is or is not substituted with alkyl.

The term "substituted" means that one or more hydrogen atoms in a group are independently substituted with an appropriate number of substituents. It goes without saying that the substituent is found only in its possible chemical position in accordance with the theory of valence chemical bonds, and those skilled in the art will be able to determine (experimentally or on the basis of theory) whether a substitution is possible or impossible without undue effort. For example, it may be unstable if an amino group or hydroxy group having a free hydrogen is bonded to a carbon atom having an unsaturated bond (eg, an olefin).

"Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, and can be subdivided into cis - trans isomers and enantiomers, as well as enantiomers and diastereomers. Stereoisomers formed as a result of rotation around single bonds are called conformational stereoisomers, and sometimes rotamers. Stereoisomers that differ in bond lengths, angles between bonds, intramolecular double bonds, rings, and the like are called configurational stereoisomers; In this case, configurational stereoisomers are divided into two categories. Isomers formed as a result of the fact that free rotation around the double bond or single bond at the carbon atom involved in the formation of the ring is impossible are called geometric isomers, as well as cis - trans isomers; such isomers are classified into Z and E configurations. For example, cis -2-butene and trans -2-butene are a pair of geometric isomers; in this case, stereoisomers that differ in optical rotation due to the lack of anti-axial symmetry in the molecule are called optical isomers and are divided into configurations R and S. In the present invention, the term “stereoisomer” is to be understood to include one or more of the above-mentioned enantiomers, configurational isomers, and conformational isomers, unless specifically stated otherwise.

The term "pharmaceutically acceptable salt" as used herein refers to pharmaceutically acceptable acid or base addition salts, including inorganic or organic acid salts, which can be prepared by methods known to those skilled in the art.

“Pharmaceutical composition” refers to a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or precursor thereof, as well as other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of this pharmaceutical composition is to facilitate the administration of the drug into the body, improving the absorption of the active substance and thereby facilitating the manifestation of its biological activity.

The following is a detailed explanation of the present invention with reference to examples of its implementation, which are not intended to limit the present invention; however, the present invention is not limited to the examples presented.

The structure of the compound of the present invention is determined using nuclear magnetic resonance (NMR) and/or liquid chromatography coupled with mass spectrometry (LC-MS). Chemical shifts of NMR spectra (δ) are given in parts per million (ppm). Determination by NMR spectrum is carried out using a Bruker AVANCE-400 nuclear magnetic resonance unit with hexadeuterodimethyl sulfoxide (DMSO- d ₆ ), tetradeuteromethanol (CD ₃ OD) and deuterated chloroform (CDCl ₃ ) as solvents, and tetramethylsilane (TMS) as internal standard

LC-MS determinations are performed using an Agilent 6120 mass spectrometer. HPLC determinations are performed using an Agilent 1200 DAD HPLC (Sunfire C18 150 x 4.6 mm chromatography column) and a Waters 2695-2996 HPLC (chromatographic column Gimini C18 150 × 4.6 mm).

The thin layer chromatography (TLC) plate used is Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate. The specification for TLC silica gel plate is 0.15-0.20 mm, and the specification for TLC separation and purification is 0.4-0.5 mm. Yantai Yellow Sea silica gel with a particle size of 200-300 mesh is usually used as a carrier for column chromatography.

The starting materials in the exemplary embodiments of the present invention are known and commercially available or can be synthesized by or in accordance with methods known in the art.

Unless otherwise specified, all reactions of the present invention are carried out under an atmosphere of dry nitrogen or argon with continuous stirring on a magnetic stirrer, where the solvent is a dry solvent and the reaction temperature is in degrees Celsius (°C).

Preparation of intermediate substances

Intermediate 1: Preparation of 2-cyclopropyl-5-ethynylbenzo[ d ]oxazole

Stage 1. Synthesis N -(5-bromo-2-hydroxyphenyl)cyclopropanecarboxamide

2-amino-4-bromophenol (2.0 g, 10.6 mmol) was dissolved in DCM (30 ml), after which triethylamine (1.29 g, 12.8 mmol) and cyclopropylcarbonyl chloride (1.11 g, 10.6 mmol) at 0°C. The reaction mixture was stirred at 0°C for 1 hour, diluted with aqueous sodium bicarbonate and extracted with DCM, the organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was separated by column chromatography to obtain N -(5-bromo-2-hydroxyphenyl)cyclopropanecarboxamide (1.34 g, yield: 49%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 256/258 [M + H] ⁺ .

Step 2. Synthesis of 5-bromo-2-cyclopropylbenzo[ d ]oxazole

N- (5-bromo-2-hydroxyphenyl)cyclopropanecarboxamide (1.04 g, 4.06 mmol) was dissolved in acetonitrile (30 ml), after which triphenylphosphine (4.26 g, 16.2 mmol) and carbon tetrachloride were added sequentially (1.25 g, 8.1 mmol) at room temperature. The reaction mixture was stirred at 60°C for 1 hour, diluted with water and extracted with ethyl acetate, after which the organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was separated by column chromatography to obtain 5-bromo-2-cyclopropylbenzo[ d ]oxazole (548 mg, yield: 55%). Electric field sputter ionization mass spectrometry (ESI-MS, m/z): 238/240 [M + H] ⁺ .

Step 3. Synthesis of 2-cyclopropyl-5-((trimethylsilyl)ethynyl)benzo[ d ]oxazole

5-bromo-2-cyclopropylbenzo[ d ]oxazole (200 mg, 0.84 mmol) was added to DMF (3 ml), followed by triethylamine (1 ml), copper iodide (16 mg, 0.08 mmol), sequentially added trimethylsilylacetylene (825 mg, 8.4 mmol) and tetrakis(triphenylphosphine) palladium (49 mg, 0.04 mmol) at room temperature. The reaction mixture was stirred at 80°C for 16 hours, diluted with water and extracted with ethyl acetate, after which the organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was separated by column chromatography to obtain 2-cyclopropyl-5-((trimethylsilyl)ethynyl)benzo[ d ]oxazole (204 mg, yield: 95%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 256 [M + H] ⁺ .

Step 4. Synthesis of 2-cyclopropyl-5-ethynylbenzo[ d ]oxazole

2-cyclopropyl-5-((trimethylsilyl)ethynyl)benzo[ d ]oxazole (204 mg, 0.8 mmol) was added to methanol (8 ml) and then potassium carbonate (1.1 g, 8 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 1 hour, diluted with water and extracted with ethyl acetate, after which the organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was separated by column chromatography to obtain 2-cyclopropyl-5-ethynylbenzo[ d ]oxazole (112 mg, yield: 76%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 184 [M + H] ⁺ .

Intermediates 2 - 7 can be prepared by selecting appropriate starting materials according to the method of synthesis (total or partial) of intermediate 1:

Intermediate number Structural formula Chemical name [M+H] ⁺ 2 2-ethyl-5-ethynylbenzo[ d ]oxazole 172 3 5-ethynyl-2-isopropylbenzo[ d ]oxazole 186 4 2-cyclobutyl-5-ethynylbenzo[ d ]oxazole 198 5 2-cyclobutyl-5-ethynyl-6-fluorobenzo
[ d ]oxazole 216 6 5-ethynyl-6-fluoro-2-cyclopropylbenzo
[ d ]oxazole 202 7 6-ethynyl-2-methylbenzo[ d ]oxazole 158

Intermediate 8: Preparation of 5-bromo-2-(trifluoromethyl)benzo[ d ]oxazole

Stage 1. Synthesis N -(5-bromo-2-hydroxyphenyl)-2,2,2-trifluoroacetamide

2-amino-4-bromophenol (2.0 g, 10.6 mmol) was dissolved in DCM (30 ml), after which triethylamine (1.29 g, 12.8 mmol) and trifluoroacetic anhydride (2.23 g) were added sequentially , 10.6 mmol) at 0°C. The reaction mixture was stirred at room temperature for 1 hour, diluted with aqueous sodium bicarbonate and extracted with DCM, and the organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was separated by column chromatography to obtain N -(5-bromo-2-hydroxyphenyl)-2,2,2-trifluoroacetamide (2.7 g, yield: 89%).

¹ H-NMR (400 MHz, DMSO- d6 ): δ 10.6 (s, 1 h), 10.3 ( _s , 1 h), 7.55-7.54 (d, J = 4 Hz, 1 h), 7.33-7.30 (dd, J = 4.8 Hz, 1 h), 6.92-6.91 (d, J = 4 Hz, 1 h).

Step 2. Synthesis of 5-bromo-2-(trifluoromethyl)benzo[ d ]oxazole

N- (5-bromo-2-hydroxyphenyl)-2,2,2-trifluoroacetamide (500 mg, 1.76 mmol) was dissolved in toluene (20 ml) and p -toluenesulfonic acid (303 mg, 1.76 mmol) was added. . The reaction mixture was stirred at 120°C for 24 hours and then concentrated as such. The residue was separated by column chromatography to obtain 5-bromo-2-(trifluoromethyl)benzo[ d ]oxazole (200 mg, yield: 43%).

¹ H-NMR (400 MHz, DMSO- d6 ): δ 8.25-8.23 (d, J = 8 Hz, 1 h) _, 7.92-7.88 (dd, J = 8.16 Hz , 1 h), 7.79-7.77 (d, J = 8 Hz, 1 h).

Intermediate 9: Preparation of 5-ethynyl- N -methylbenzo[ d ]oxazol-2-amine

Step 1. Synthesis of 1-(5-bromo-2-hydroxyphenyl)-3-methylthiourea

2-amino-4-bromophenol (1.0 g, 5.3 mmol) was added to tetrahydrofuran (20 ml), followed by the addition of isothiocyanatomethane (324 mg, 4.43 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 hours, diluted with water and extracted with ethyl acetate, after which the organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was separated by column chromatography to obtain 1-(5-bromo-2-hydroxyphenyl)-3-methylthiourea (1.05 g, yield: 90%). Electric field sputter ionization mass spectrometry (ESI-MS, m/z): 261/263 [M + H] ⁺ .

Stage 2. Synthesis of 5-bromo- N -methylbenzo[ d ]oxazol-2-amine

1-(5-bromo-2-hydroxyphenyl)-3-methylthiourea (970 mg, 3.71 mmol) was added to tetrahydrofuran (20 ml), followed by sequential addition of tetrabutylammonium iodide (14 mg, 0.04 mmol) and 30% hydrogen peroxide (841 mg, 7.42 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour, diluted with aqueous sodium sulfite and extracted with ethyl acetate, after which the organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was separated by column chromatography to obtain 5-bromo- N -methylbenzo[ d ]oxazol-2-amine (604 mg, yield: 72%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 227/229 [M + H] ⁺ .

Stage 3. Synthesis N -methyl-5-((trimethylsilyl)ethynyl)benzo[ d ]oxazol-2-amine

5-Bromo- N -methylbenzo[ d ]oxazol-2-amine (600 mg, 2.64 mmol) was added to DMF (5 ml), followed by triethylamine (1.5 ml), copper iodide (50 mg, 0.26 mmol), trimethylsilylacetylene (2.6 g, 26.4 mmol) and tetrakis(triphenylphosphine) palladium (153 mg, 0.13 mmol) at room temperature. The reaction mixture was stirred at 100°C for 16 hours, diluted with water and extracted with ethyl acetate, after which the organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was separated by column chromatography to obtain N -methyl-5-((trimethylsilyl)ethynyl)benzo[ d ]oxazol-2-amine (230 mg, yield: 36%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 245 [M + H] ⁺ .

Stage 4. Synthesis of 5-ethynyl- N -methylbenzo[ d ]oxazol-2-amine

N -methyl-5-((trimethylsilyl)ethynyl)benzo[ d ]oxazol-2-amine (100 mg, 0.4 mmol) was added to methanol (8 ml) and then potassium carbonate (566 mg, 4 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 1 hour, diluted with water and extracted with ethyl acetate, after which the organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was separated by column chromatography to obtain 5-ethynyl- N -methylbenzo[ d ]oxazol-2-amine (54 mg, yield: 77%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 173 [M + H] ⁺ .

Intermediates 10 - 14 can be prepared by selecting appropriate starting materials according to the method of synthesis (total or partial) of intermediate 9:

Intermediate number
substances Structural formula Chemical name [M+H] ⁺ 10 5-ethynyl-6-fluoro- N -methylbenzo
[ d ]oxazol-2-amine 191 eleven 5-ethynyl-6-fluoro- N , N -dimethylbenzo
[ d ]oxazol-2-amine 205 12 N -cyclopropyl-5-ethynyl-6-fluorobenzo
[ d ]oxazol-2-amine 217 13 2-(azetidin-1-yl)-5-ethynyl-6-
fluorobenzo[ d ]oxazole 217 14 N -ethyl-5-ethynyl-6-fluorobenzo
[ d ]oxazol-2-amine 205

Intermediate 15: Preparation of 2-cyclopropyl-5-ethynyl-6-fluorobenzo[ d ]thiazole

Stage 1. Synthesis N -(5-bromo-2,4-difluorophenyl)cyclopropanecarboxamide

5-bromo-2,4-difluoroaniline (1.04 g, 5.0 mmol) was dissolved in dichloromethane (20 ml) and then cyclopropylcarbonyl chloride (572 g, 5.5 mmol) was added. The reaction mixture was stirred overnight at room temperature and then concentrated as such. The residue was separated by column chromatography to obtain N -(5-bromo-2,4-difluorophenyl)cyclopropanecarboxamide (1.0 g, yield: 72%). Electric field sputter ionization mass spectrometry (ESI-MS, m/z): 276/278 [M + H] ⁺ .

Stage 2. Synthesis N -(5-bromo-2,4-difluorophenyl)cyclopropanecarbothiamide

N- (5-bromo-2,4-difluorophenyl)cyclopropanecarboxamide (1.0 g, 3.6 mmol) and Lawesson's reagent (750 mg, 1.85 mmol) were dissolved in acetonitrile (25 ml), after which the reaction mixture was heated to 85 ° C and stirred overnight. After completion of the reaction, the N- (5-bromo-2,4-difluorophenyl)cyclopropanecarbothiamide solution was used in the next step as is. Electric sputter ionization mass spectrometry (ESI-MS, m/z): 292/294 [M + H] ⁺ .

Step 3. Synthesis of 5-bromo-2-cyclopropyl-6-fluorobenzo[ d ]thiazole

Sodium tert -butoxide (1.7 g, 18 mmol) was added to a cooled solution of N- (5-bromo-2,4-difluorophenyl)cyclopropanecarbothiamide, after which the reaction mixture was heated to 50 ° C, stirred for 16 h and concentrated. The residue was separated by column chromatography to obtain 5-bromo-2-cyclopropyl-6-fluorobenzo[ d ]thiazole (0.82 g, yield: 83%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 272/274 [M + H] ⁺ .

Step 4. Synthesis of 2-cyclopropyl-5-ethynyl-6-fluorobenzo[ d ]thiazole

5-bromo-2-cyclopropyl-6-fluorobenzo[ d ]thiazole (0.82 g, 3.0 mmol) was dissolved in DMF (15 ml), after which tributyl(ethynyl) stannane (1.9 g, 6. 0 mmol) and tetrakis(triphenylphosphine)palladium (173 mg, 0.15 mmol). The reaction mixture was stirred in a microwave reactor at 130 ° C for 0.5 h and then concentrated. The residue was separated by column chromatography to obtain 2-cyclopropyl-5-ethynyl-6-fluorobenzo[ d ]thiazole (0.16 g, yield: 25%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 218 [M + H] ⁺ .

Intermediates 16 - 23 can be prepared by selecting appropriate starting materials according to the method of synthesis (total or partial) of intermediate 15:

Intermediate number Structural formula Chemical name [M+H] ⁺ 16 5-ethynyl-6-fluoro-2-methylbenzo[ d ]thiazole 192 17 2-(difluoromethyl)-5-ethynyl-6-fluorobenzo[ d ]thiazole 228 18 2-cyclobutyl-5-ethynylbenzo[ d ]thiazole 214 19 2-cyclopropyl-5-ethynylbenzo[ d ]thiazole 200 20 2-ethyl-5-ethynylbenzo[ d ]thiazole 188 21 5-ethynyl-2-methylbenzo[ d ]thiazole 174 22 2-(difluoromethyl)-5-ethynylbenzo[ d ]thiazole 210 23 2-cyclobutyl-5-ethynyl-6-fluorobenzo[ d ]thiazole 232

Intermediate 24: preparation ( S )-1-(3-(4-amino-5-iodine-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one

Stage 1. Synthesis rubs -butyl ( S )-3-(4-amino-5-iodine-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)pyrrolidin-1-carboxylate

5-iodo- 7H- pyrrolo[2,3- d ]pyrimidin-4-amine (520 mg, 2 mmol), tert -butyl-( R )-3-hydroxypyrrolidine-1-carboxylate (561 mg, 3 mmol) and triphenylphosphine (786 mg, 3 mmol) was dissolved in tetrahydrofuran (10 ml), and then diisopropyl azodiformate (0.6 ml, 3 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated to dryness and the residue was separated by column chromatography to give tert -butyl( S )-3-(4-amino-5-iodo- 7H -pyrrolo[2,3- d ]pyrimidine

-7-yl)pyrrolidin-1-carboxylate (300 mg, yield: 35%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 430 [M + H] ⁺ .

Stage 2. Synthesis ( S )-5-iodo-7-(pyrrolidin-3-yl)-7 H -pyrrolo[2,3- d ]pyrimidine-4-amine

Tert -butyl( S )-3-(4-amino-5-iodo- 7H -pyrrolo[2,3- d ]pyrimidin-7-yl)pyrrolidine-1-carboxylate (300 mg, 0.69 mmol) was dissolved in dichloromethane (10 ml) and then HCl/dioxane solution (5 ml) was added. The reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was concentrated to dryness to give ( S )-5-iodo-7-(pyrrolidin-3-yl) -7H -pyrrolo[2,3- d ]pyrimidin-4-amine (230 mg, yield: 100%). Electric field sputter ionization mass spectrometry (ESI-MS, m/z): 330 [M + H] ⁺ .

Stage 3. Synthesis ( S )-1-(3-(4-amino-5-iodine-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one

( S )-5-iodo-7-(pyrrolidin-3-yl) -7H- pyrrolo[2,3- d ]pyrimidin-4-amine (230 mg, 0.70 mmol) was dissolved in tetrahydrofuran (4 ml) and saturated aqueous sodium bicarbonate (1 ml), after which the mixture was cooled to 0 ° C and acryloyl chloride (65 mg, 0.7 mmol) was added. The reaction mixture was stirred in an ice bath for 0.5 h. After completion of the reaction, the reaction mixture was separated by reverse phase chromatography to give ( S )-1-(3-(4-amino-5-iodo- 7H -pyrrolo[ 2,3- d ]pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one (50 mg, yield: 18%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 384 [M + H] ⁺ .

Intermediate 25: receiving ( S )-1-(3-(4-amino-3-iodine-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one

Stage 1. Synthesis rubs -butyl ( S )-3-(4-amino-3-iodine-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)pyrrolidin-1-carboxylate

3-iodo- 1H- pyrazolo[3,4- d ]pyrimidin-4-amine (1000 mg, 3.82 mmol), tert -butyl-( R )-3-hydroxypyrrolidine-1-carboxylate (1070 mg, 5 .73 mmol) and triphenylphosphine (1500 mg, 5.73 mmol) were dissolved in tetrahydrofuran (100 ml), and then diisopropyl azodiformate (1150 ml, 5.73 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated to dryness and the residue was separated by column chromatography to give tert -butyl( S )-3-(4-amino-3-iodo- 1H -pyrazolo[3,4- d ]pyrimidin -1-yl)pyrrolidine-1-carboxylate (1100 mg, yield: 67%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 431 [M + H] ⁺ .

Stage 2. Synthesis ( S )-3-iodo-1-(pyrrolidin-3-yl)-1 H -pyrazolo[3,4- d ]pyrimidine-4-amine

Tert -butyl( S )-3-(4-amino-3-iodo- 1H -pyrazolo[3,4- d ]pyrimidin-1-yl)pyrrolidine-1-carboxylate (2000 mg, 4.65 mmol) was dissolved in dichloromethane (50 ml) and HCl/dioxane solution (10 ml) was added. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated to dryness to give ( S )-3-iodo-1-(pyrrolidin-3-yl) -1H -pyrazolo[3,4- d ]pyrimidin-4-amine (1540 mg, yield: 100%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 331 [M + H] ⁺ .

Stage 3. Synthesis ( S )-1-(3-(4-amino-3-iodine-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one

( S )-3-iodo-1-(pyrrolidin-3-yl)-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (1.54 mg, 4.65 mmol) was dissolved in tetrahydrofuran (20 ml) and saturated aqueous sodium bicarbonate (5 ml), after which the mixture was cooled to 0 ° C and acryloyl chloride (473 mg, 5.11 mmol) was added. The reaction mixture was stirred in an ice bath for 1 hour. After completion of the reaction, the reaction mixture was separated by reverse phase chromatography to give ( S )-1-(3-(4-amino-3-iodo- 1H -pyrazolo[3, 4- d ]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one (500 mg, yield: 28%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 385 [M + H] ⁺ .

Intermediate 26: Preparation ( S )-1-(3-(8-amino-1-iodimidazo[1,5- A ]pyrazin-3-yl)pyrrolidin-1-yl)prop-2-en-1-one

Stage 1. Synthesis of benzyl ( S )-3-(((3-chloropyrazin-2-yl)methyl)carbamoyl)pyrrolidine-1-carboxylate

3-chloropyrazine-2-methanamine dihydrochloride (4.45 g, 20.55 mmol), ( S )-1-((benzyloxy)carbonyl)pyrrolidine-3-carboxylic acid (5.12 g, 20.55 mmol), 2-(7-azabenzotriazol-1-yl) -N , N , N ', N' -tetramethyluronium hexafluorophosphate (8.2 g, 21.57 mmol) and triethylamine (8.3 g, 82.20 mmol) were dissolved in anhydrous dichloromethane (100 ml), after which the reaction mixture was stirred overnight at room temperature. To stop the reaction, saturated sodium bicarbonate solution (50 ml) was added and the resulting reaction mixture was extracted three times with dichloromethane (50 ml). The organic phases were combined, washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to give crude benzyl ( S )-3-(((3-chloropyrazin-2-yl)methyl)carbamoyl)pyrrolidine-1- carboxylate (8 g, yield: 95%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 375 [M + H] ⁺ .

Stage 2. Synthesis of benzyl ( S )-3-(8-chloroimidazo[1,5- A ]pyrazin-3-yl)pyrrolidin-1-carboxylate

Benzyl ( S )-3-(((3-chloropyrazin-2-yl)methyl)carbamoyl)pyrrolidine-1-carboxylate (8 g, 21.4 mmol) was dissolved in anhydrous acetonitrile (100 ml), then added dropwise phosphorus oxychloride (16.4 g, 107.0 mmol) in an ice bath. The reaction mixture was slowly heated to 80 ° C and stirred for 5 h. The reaction mixture was cooled, then saturated aqueous sodium bicarbonate was added dropwise to stop the reaction (being careful not to allow the temperature in the reaction vessel to rise above 5 ° C), and the resulting reaction mixture was extracted three times with ethyl acetate (60 ml). The organic phase was washed with brine (50 ml), dried over sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography to give benzyl( S )-3-(8-chloroimidazo[1,5- a ]pyrazine-3 -yl)pyrrolidin-1-carboxylate (3.8 g, yield: 50%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 357 [M + H] ⁺ .

Stage 3. Synthesis of benzyl ( S )-3-(8-chloro-1-iodimidazo[1,5- A ]pyrazin-3-yl)pyrrolidin-1-carboxylate

Benzyl ( S )-3-(8-chloroimidazo[1,5- a ]pyrazin-3-yl)pyrrolidin-1-carboxylate (0.65 g, 1.82 mmol) and N -iodosuccinimide (1.43 g, 6.37 mmol) was dissolved in DMF (10 ml) and the reaction mixture was stirred overnight at room temperature. Thereafter, deionized water was added and the resulting reaction mixture was extracted with ethyl acetate twice. The organic phases were combined, washed with brine (30 ml), dried over sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography to give benzyl( S )-3-(8-chloro-1-iodimidazo[1,5 - a ]pyrazin-3-yl)pyrrolidin-1-carboxylate (0.76 g, yield: 86%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 483 [M + H] ⁺ .

Stage 4. Synthesis of benzyl ( S )-3-(8-amino-1-iodimidazo[1,5- A ]pyrazin-3-yl)pyrrolidin-1-carboxylate

Benzyl ( S )-3-(8-chloro-1-iodimidazo[1,5- a ]pyrazin-3-yl)pyrrolidine-1-carboxylate (0.76 g, 1.57 mmol) was dissolved in dioxane (10 ml ), after which a concentrated ammonia solution (20 ml) was added to a hermetically sealed test tube. The reaction mixture was heated to 80 ° C, stirred overnight and then concentrated. The residue was separated by column chromatography to give benzyl ( S )-3-(8-amino-1-iodimidazo[1,5- a ]pyrazin-3-yl)pyrrolidin-1-carboxylate (0.64 g, yield: 88 %). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 464 [M + H] ⁺ .

Stage 5. Synthesis ( S )-1-iodo-3-(pyrrolidin-3-yl)imidazo[1,5- A ]pyrazine-8-amine

Benzyl ( S )-3-(8-amino-1-iodimidazo[1,5- a ]pyrazin-3-yl)pyrrolidine-1-carboxylate (0.64 g, 1.38 mmol) was dissolved in dichloromethane (15 ml ), then the mixture was cooled to 0 ° C and trimethylsilyl iodide (0.7 g, 2.76 mmol) was added dropwise. The reaction mixture was stirred at 0 ° C for 2 h. Saturated sodium thiosulfate solution was then added to stop the reaction, and the resulting reaction mixture was extracted with dichloromethane three times. The organic phases were combined, dried over sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography to give ( S )-1-iodo-3-(pyrrolidin-3-yl)imidazo[1,5- a ]pyrazine-8 -amine (95 mg, yield: 21%). Electric field sputter ionization mass spectrometry (ESI-MS, m/z): 330 [M + H] ⁺ .

Stage 6. Synthesis ( S )-1-(3-(8-amino-1-iodimidazo[1,5- A ]pyrazin-3-yl)pyrrolidin-1-yl)prop-2-en-1-one

( S )-1-iodo-3-(pyrrolidin-3-yl)imidazo[1,5- a ]pyrazin-8-amine (95 mg, 0.29 mmol) was dissolved in tetrahydrofuran (4 ml) and saturated aqueous solution sodium bicarbonate (2 ml), after which acryloyl chloride (31 mg, 0.35 mmol) was added in an ice bath. The reaction mixture was kept in an ice bath for 30 minutes, after which it was separated by reverse phase chromatography, and the resulting aqueous phase was lyophilized to give ( S )-1-(3-(8-amino-1-iodimidazo[1,5 - a ]pyrazin-3-yl)pyrrolidin-1-yl)prop-2-en-1-one (72 mg, yield: 65%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 384 [M + H] ⁺ .

Intermediate 27: Preparation of 1-(3-(4-amino-5-iodopyrrolo[2,1- f ][1,2,4]triazin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one

Step 1. Synthesis of 7-iodopyrrolo[2,1- f ][1,2,4]triazin-4-amine

4-chloro-7-iodopyrrolo[2,1- f ][1,2,4]triazine (1 g, 3.58 mmol) was dissolved in isopropanol (10 ml), after which a concentrated ammonia solution was added to a hermetically sealed test tube ( 10 ml). The reaction mixture was heated to 70 ° C and stirred for 3 h. After cooling, the reaction mixture as such was concentrated to give crude 7-iodopyrrolo[2,1- f ][1,2,4]triazin-4-amine (1 g , yield: 100%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 261 [M + H] ⁺ .

Stage 2. Synthesis rubs -butyl-3-(4-aminopyrrolo[2,1- f ][1,2,4]triazin-7-yl)-2,5-dihydro-1 H -pyrrole-1-carboxylate

7-iodopyrrolo[2,1- f ][1,2,4]triazin-4-amine (0.55 g, 2.11 mmol), tert -butyl-3-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)-2,5-dihydro- 1H -pyrrole-1-carboxylate (0.75 g, 2.54 mmol), [1,1'-bis(diphenylphosphino) Ferrocene]palladium dichloride (172 mg, 0.21 mmol) and potassium carbonate (0.87 g, 6.33 mmol) were dissolved in dioxane (10 ml) and water (2 ml), after which the reaction mixture was heated to 80 ° C , stirred overnight and then concentrated. The residue was separated by column chromatography to give tert -butyl-3-(4-aminopyrrolo[2,1- f ][1,2,4]triazin-7-yl)-2,5-dihydro- 1H- pyrrol- 1-carboxylate (0.5 g, yield: 79%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 302 [M + H] ⁺ .

Stage 3. Synthesis rubs -butyl-3-(4-aminopyrrolo[2,1- f ][1,2,4]triazin-7-yl)pyrrolidine-1-carboxylate

Tert -butyl-3-(4-aminopyrrolo[2,1- f ][1,2,4]triazin-7-yl)-2,5-dihydro- 1H- pyrrole-1-carboxylate (0.5 g , 1.66 mmol) was dissolved in methanol (10 ml), and 10% wet palladium on carbon (100 mg) was added to the resulting solution. The reaction mixture was heated to 50 ° C under hydrogen, stirred overnight and filtered, after which the filtrate was concentrated. The residue was dried to obtain tert -butyl-3-(4-aminopyrrolo[2,1- f ][1,2,4]triazin-7-yl)pyrrolidin-1-carboxylate (460 mg, yield: 91%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 304 [M + H] ⁺ .

Stage 4. Synthesis rubs -butyl-3-(4-amino-5-iodopyrrolo[2,1- f ][1,2,4]triazin-7-yl)pyrrolidine-1-carboxylate

Tert -butyl-3-(4-aminopyrrolo[2,1- f ][1,2,4]triazin-7-yl)pyrrolidine-1-carboxylate (0.46 g, 1.52 mmol) and N -iodosuccinimide (1.02 g, 4.55 mmol) was dissolved in N , N -dimethylformamide (5 ml) and the reaction mixture was stirred overnight at room temperature. Deionized water (50 ml) was added and a large amount of solid was precipitated. The mixture was filtered and the filter cake was washed twice with acetone (10 ml) and dried to obtain tert -butyl-3-(4-amino-5-iodopyrrolo[2,1- f ][1,2,4]triazin-7-yl )pyrrolidine-1-carboxylate (0.74 g, yield: 95%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 430 [M + H] ⁺ .

Step 5. Synthesis of 5-iodo-7-(pyrrolidin-3-yl)pyrrolo[2,1- f ][1,2,4]triazin-4-amine

Tert -butyl-3-(4-amino-5-iodopyrrolo[2,1- f ][1,2,4]triazin-7-yl)pyrrolidine-1-carboxylate (300 mg, 0.70 mmol) was dissolved in ethyl acetate (10 ml), and then 4 N HCl/dioxane solution (1 ml) was added dropwise. The reaction mixture was stirred at room temperature for 4 hours and concentrated, and the resulting residue was dried to give 5-iodo-7-(pyrrolidin-3-yl)pyrrolo[2,1- f ][1,2,4]triazin-4 -amine (300 mg, yield: 100%). Electric field sputter ionization mass spectrometry (ESI-MS, m/z): 330 [M + H] ⁺ .

Step 6. Synthesis of 1-(3-(4-amino-5-iodopyrrolo[2,1- f ][1,2,4]triazin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one

5-iodo-7-(pyrrolidin-3-yl)pyrrolo[2,1- f ][1,2,4]triazin-4-amine (300 mg, 0.91 mmol) was dissolved in tetrahydrofuran (10 ml) and saturated sodium bicarbonate solution (5 ml), after which the mixture was cooled to 0 ° C and acryloyl chloride (90 mg, 0.99 mmol) was added dropwise. The reaction mixture was stirred for 30 minutes, then separated as such by reverse phase chromatography, and the resulting aqueous phase was lyophied to give 1-(3-(4-amino-5-iodopyrrolo[2,1- f ][1, 2,4]triazin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one (300 mg, yield: 85%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 384 [M + H] ⁺ .

Intermediate 28: Preparation of 2-cyclopropyl-5-ethynyl-4,6-difluorobenzo[ d ]thiazole

Stage 1. Synthesis N -(2,4-difluorophenyl)cyclopropanecarboxamide

2,4-difluoroaniline (10 g, 77.45 mmol) was dissolved in dichloromethane (100 ml) and then triethylamine (15.64 g, 154.9 mmol) was added. Cyclopropylcarbonyl chloride (8.1 g, 77.45 mmol) was added dropwise in an ice bath, after which the reaction mixture was stirred overnight at room temperature. The reaction mixture was then washed with a sufficient amount of saturated aqueous ammonium chloride and brine, dried over anhydrous sodium sulfate and concentrated; the residue was separated by silica gel column chromatography to obtain N -(2,4-difluorophenyl)cyclopropanecarboxamide (10.1 g, yield: 66%). Electric field sputter ionization mass spectrometry (ESI-MS, m/z): 196 [M + H] ⁺ .

Stage 2. Synthesis N -(2,4-difluorophenyl)cyclopropanecarbothiamide

N- (2,4-difluorophenyl)cyclopropanecarboxamide (5 g, 25.36 mmol) was dissolved in xylene (80 ml) and Lawesson's reagent (7.18 g, 17.75 mmol) was added. The reaction mixture was heated to 120 ° C, stirred overnight and then concentrated. The residue was separated as such by silica gel column chromatography to obtain N- (2,4-difluorophenyl)cyclopropanecarbothiamide (4.1 g, yield: 75%). Electric field sputter ionization mass spectrometry (ESI-MS, m/z): 212 [M + H] ⁺ .

Step 3. Synthesis of 2-cyclopropyl-4,6-difluorobenzo[ d ]thiazole

N- (2,4-difluorophenyl)cyclopropanecarbothiamide (1 g, 4.69 mmol) was dissolved in sodium hydroxide solution (1.69 g, 42.21 mmol), after which the resulting solution was dissolved in ethanol (5 ml) and water ( 10 ml) (concentration by weight - about 30%). The resulting solution was added dropwise to an aqueous solution of potassium ferricyanide (6.18 g, 18.78 mmol) in 10 ml water heated to 90 ° C, and the reaction mixture was stirred for 2 h, after which heating was immediately stopped. The reaction mixture was cooled, slightly acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The resulting extract was washed with brine and concentrated, and the residue was separated by silica gel column chromatography to obtain 2-cyclopropyl-4,6-difluorobenzo[ d ]thiazole (500 mg, yield: 51%). Electric field sputter ionization mass spectrometry (ESI-MS, m/z): 212 [M + H] ⁺ .

Step 4. Synthesis of 2-cyclopropyl-4,6-difluorobenzo[ d ]thiazole-5-carbaldehyde

2-cyclopropyl-4,6-difluorobenzo[ d ]thiazole (980 mg, 4.64 mmol) was dissolved in tetrahydrofuran (15 ml), after which the mixture was cooled to -70 ° C and lithium diisopropylamide (2.55 ml) was added dropwise , 5.104 mmol, 2 M). After keeping the mixture at this temperature for 2 hours, N , N -dimethylformamide (1.01 g, 13.92 mmol) was added, then the mixture was kept at this temperature again for 2 hours, after which enough aqueous ammonium chloride was added to stopping the reaction. The reaction mixture was warmed to room temperature and extracted with ethyl acetate, after which the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography to obtain 2-cyclopropyl-4,6-difluorobenzo[ d ]thiazole-5-carbaldehyde (675 mg, yield: 65%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 240 [M + H] ⁺ .

Step 5. Synthesis of 2-cyclopropyl-5-ethynyl-4,6-difluorobenzo[ d ]thiazole

2-cyclopropyl-4,6-difluorobenzo[ d ]thiazole-5-carbaldehyde (122 mg, 0.51 mmol) was dissolved in methanol (10 ml), after which potassium carbonate (211 mg, 1.53 mmol) was added successively and (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (159 mg, 0.76 mmol). The reaction mixture was stirred overnight at room temperature and then concentrated. The residue was separated by silica gel column chromatography to obtain 2-cyclopropyl-5-ethynyl-4,6-difluorobenzo[ d ]thiazole (73 mg, yield: 61%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 236 [M + H] ⁺ .

Intermediate 29 can be prepared by selecting appropriate starting materials in accordance with the method of synthesis (total or partial) of intermediate 28:

Intermediate number
substances Structural formula Chemical name [M+H] ⁺ 29 5-ethynyl-4,6-difluoro-2-methylbenzo[ d ]thiazole 210

Intermediate 30: Preparation of 2-(azetidin-1-yl)-5-ethynyl-4,6-difluorobenzo[ d ]oxazole

Step 1. Synthesis of 2-amino-3,5-difluorophenol

3,5-difluoro-2-nitrophenol (10 g, 57.11 mmol) was dissolved in methanol (100 ml) and then palladium on carbon (1 g) was added. The reaction mixture was stirred overnight at room temperature and filtered, after which the filtrate was concentrated to obtain 2-amino-3,5-difluorophenol (8.5 g, yield: 100%). Electric field sputter ionization mass spectrometry (ESI-MS, m/z): 146 [M + H] ⁺ .

Stage 2. Synthesis of 4,6-difluorobenzo[ d ]oxazole-2-thiol

2-amino-3,5-difluorophenol (8.5 g, 58.62 mmol) was dissolved in ethanol (100 ml) and then potassium O-ethyl disulfate (1.13 g, 70.34 mmol) was added. The reaction mixture was heated to 95 ° C and kept overnight. The reaction mixture was then cooled and filtered, and the filtrate was concentrated. The residue was separated by silica gel column chromatography to obtain 4,6-difluorobenzo[ d ]oxazole-2-thiol (11 g, yield: 95.31%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 188 [M + H] ⁺ .

Stage 3. Synthesis of 2-chloro-4,6-difluorobenzo[ d ]oxazole

4,6-Difluorobenzo[ d ]oxazole-2-thiol (4 g, 21.371 mmol) was dissolved in dichloromethane (50 ml), after which oxalyl chloride (10.85 g, 85.48 mmol) and N , N -dimethylformamide ( 0.16 g, 2.14 mmol). The reaction mixture was stirred at room temperature for 2 hours and concentrated to give 2-chloro-4,6-difluorobenzo[ d ]oxazole (4.05 g, yield: 100%), which was used as such in the next step. Electric field sputter ionization mass spectrometry (ESI-MS, m/z): 190 [M + H] ⁺ .

Step 4. Synthesis of 2-(azetidin-1-yl)-4,6-difluorobenzo[ d ]oxazole

Crude 2-chloro-4,6-difluorobenzo[ d ]oxazole (4.05 g, 21.36 mmol) was dissolved in tetrahydrofuran (50 ml), after which N , N -diisopropylethylamine (5.51 g, 42.72 mmol) and azetidine hydrochloride (2.40 g, 25.63 mmol). The reaction mixture was stirred at room temperature for 2 hours and then concentrated. Ethyl acetate was added to the residue, after which the mixture was washed twice with saturated aqueous ammonium chloride, then washed twice with saturated saline, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the residue was separated by silica gel column chromatography to obtain 2-(azetidin-1-yl)-4,6-difluorobenzo[ d ]oxazole (3.2 g, yield: 72%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 211 [M + H] ⁺ .

Step 5. Synthesis of 2-(azetidin-1-yl)-4,6-difluorobenzo[ d ]oxazole-5-carbaldehyde

2-(azetidin-1-yl)-4,6-difluorobenzo[ d ]oxazole (3 g, 14.28 mmol) was dissolved in tetrahydrofuran (100 ml), then the mixture was cooled to -70 ° C, after which it was added dropwise solution of lithium diisopropylamide in tetrahydrofuran (10.7 ml, 21.41 mmol, 2 M). The reaction mixture was stirred at low temperature for 1 hour and then N , N -dimethylformamide (11.04 mL, 142.73 mmol) was added in one portion. Thereafter, the reaction mixture was stirred at low temperature for 2 hours and a sufficient amount of saturated aqueous ammonium chloride solution was added to stop the reaction. The reaction mixture was then brought to room temperature and extracted twice with ethyl acetate. The ethyl acetate phases were combined, washed twice with brine, dried over sodium sulfate and filtered, and then the filtrate was concentrated. The residue was separated by silica gel column chromatography to obtain 2-(azetidin-1-yl)-4,6-difluorobenzo[ d ]oxazole-5-carbaldehyde (0.8 g, yield: 24%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 239 [M + H] ⁺ .

Step 6. Synthesis of 2-(azetidin-1-yl)-5-ethynyl-4,6-difluorobenzo[ d ]oxazole

2-(azetidin-1-yl)-4,6-difluorobenzo[ d ]oxazole-5-carbaldehyde (0.8 g, 3.40 mmol) was dissolved in methanol (10 ml) and tetrahydrofuran (10 ml), then potassium carbonate (1.17 g, 8.5 mmol) and (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (1.31 g, 6.801 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours, concentrated, and sufficient saturated aqueous ammonium chloride was added to stop the reaction. The reaction mixture was then brought to room temperature and extracted twice with ethyl acetate. The ethyl acetate phases were combined, washed twice with brine, dried over sodium sulfate and filtered, and then the filtrate was concentrated. The residue was separated by silica gel column chromatography to obtain 2-(azetidin-1-yl)-5-ethynyl-4,6-difluorobenzo[ d ]oxazole (0.75 g, yield: 94%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 235 [M + H] ⁺ .

Intermediate 31: Preparation of 5-ethynyl-4,6-difluoro- N -methylbenzo[ d ]oxazol-2-amine

Step 1. Synthesis of 2-amino-3,5-difluorophenol

3,5-difluoro-2-nitrophenol (10 g, 57.11 mmol) was dissolved in methanol (100 ml) and then palladium on carbon (1 g) was added. The reaction mixture was stirred overnight at room temperature and filtered, after which the filtrate was concentrated to obtain 2-amino-3,5-difluorophenol (8.5 g, yield: 100%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 146 [M + H] ⁺ .

Stage 2. Synthesis of 4,6-difluorobenzo[ d ]oxazole-2-thiol

2-amino-3,5-difluorophenol (8.5 g, 58.62 mmol) was dissolved in ethanol (100 ml) and then potassium O-ethyl disulfate (1.13 g, 70.34 mmol) was added. The reaction mixture was heated to 95 ° C and kept overnight. The reaction mixture was then cooled and filtered, and the filtrate was concentrated. The residue was separated by silica gel column chromatography to obtain 4,6-difluorobenzo[ d ]oxazole-2-thiol (11 g, yield: 95.31%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 188 [M + H] ⁺ .

Stage 3. Synthesis of 2-chloro-4,6-difluorobenzo[ d ]oxazole

4,6-difluorobenzo[ d ]oxazole-2-thiol (4 g, 21.37 mmol) was dissolved in dichloromethane (50 ml), after which oxalyl chloride (10.85 g, 85.48 mmol) and N , N- dimethylformamide (0.16 g, 2.14 mmol). The reaction mixture was stirred at room temperature for 2 hours, and after completion of the reaction, the reaction mixture as such was concentrated to give crude 2-chloro-4,6-difluorobenzo[ d ]oxazole (4.05 g), which was used as such for next stage. Electric field sputter ionization mass spectrometry (ESI-MS, m/z): 190 [M + H] ⁺ .

Stage 4. Synthesis of 4,6-difluoro- N -methylbenzo[ d ]oxazol-2-amine

2-chloro-4,6-difluorobenzo[ d ]oxazole (1 g, 5.28 mmol) was dissolved in tetrahydrofuran (10 ml) and a solution of methylamine in ethanol (7.92 ml, 15.84 mmol) was added to the resulting solution. The reaction mixture was stirred at room temperature for 2 hours and then concentrated, and the residue as such was separated by silica gel column chromatography to give 4,6-difluoro- N -methylbenzo[ d ]oxazol-2-amine (0.4 g , yield: 29%). Electric field sputter ionization mass spectrometry (ESI-MS, m/z): 190 [M + H] ⁺ .

Step 5. Synthesis of 4,6-difluoro-2-(methylamino)benzo[ d ]oxazole-5-carbaldehyde

4,6-Difluoro -N -methylbenzo[ d ]oxazol-2-amine (0.25 g, 1.36 mmol) was dissolved in tetrahydrofuran (25 ml), then the mixture was cooled to -70 ° C and diisopropylamide solution was added dropwise lithium in tetrahydrofuran (2.0 ml, 4.07 mmol, 2 M). The reaction mixture was stirred at low temperature for 1 hour and then N , N -dimethylformamide (2.1 mL, 27.15 mmol) was added in one portion. Thereafter, the reaction mixture was stirred at low temperature for 2 hours and a sufficient amount of saturated aqueous ammonium chloride solution was added to stop the reaction. The reaction mixture was then brought to room temperature and extracted twice with ethyl acetate. The ethyl acetate phases were combined, washed twice with brine, dried over sodium sulfate and filtered, and then the filtrate was concentrated. The residue was separated by silica gel column chromatography to obtain 4,6-difluoro-2-(methylamino)benzo[ d ]oxazole-5-carbaldehyde (0.12 g, yield: 41%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 213 [M + H] ⁺ .

Step 6. Synthesis of 5-ethynyl-4,6-difluoro- N -methylbenzo[ d ]oxazol-2-amine

4,6-difluoro-2-(methylamino)benzo[ d ]oxazole-5-carbaldehyde (120 mg, 0.57 mmol) was dissolved in methanol (5 ml) and tetrahydrofuran (5 ml), after which potassium carbonate (195) was added mg, 1.41 mmol) and (1-diazo-2-oxopropyl)-phosphonic acid dimethyl ester (217 mg, 1.13 mmol). The reaction mixture was stirred at room temperature for 2 hours, concentrated, and sufficient saturated aqueous ammonium chloride was added to stop the reaction. The reaction mixture was then brought to room temperature and extracted twice with ethyl acetate. The ethyl acetate phases were combined, washed twice with brine, dried over sodium sulfate and filtered, and then the filtrate was concentrated. The residue was separated by silica gel column chromatography to obtain 5-ethynyl-4,6-difluoro- N -methylbenzo[ d ]oxazol-2-amine (110 mg, yield: 91%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 209 [M + H] ⁺ .

Intermediate 32: making 1-((2 R ,4 S )-4-(4-amino-3-iodine-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)-2-(methoxymethyl)pyrrolidin-1-yl)prop-2-en-1-one

Stage 1. Synthesis of 1-( rubs -butyl)-2-methyl-(2 R ,4 R )-4-(benzyloxy)pyrrolidine-1,2-dicarboxylate

1-( tert -butyl)-2-methyl( 2R , 4R )-4-hydroxypyrrolidine-1,2-dicarboxylate (10 g, 40.77 mmol) was dissolved in N , N -dimethylformamide (120 ml), after whereupon the mixture was placed in ice water and sodium hydride (1.63 g, 40.77 mmol) was added. The reaction mixture was stirred for 0.5 h and then benzyl bromide (6.5 mL, 54.36 mmol) was added. The reaction mixture thus obtained was stirred overnight at room temperature. Upon completion of the reaction, dilute hydrochloric acid was added to stop the reaction, and the resulting mixture was extracted twice with sufficient ethyl acetate. The organic phases were combined, washed twice with brine, dried over sodium sulfate and filtered, and then the filtrate was concentrated. The residue was separated by silica gel column chromatography to give 1-( tert -butyl)-2-methyl-( 2R , 4R )-4-(benzyloxy)pyrrolidine-1,2-dicarboxylate (11.8 g, yield: 97%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 336 [M + H] ⁺ .

Stage 2. Synthesis rubs -butyl-(2 R ,4 R )-4-(benzyloxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate

1-( tert -butyl)-2-methyl-( 2R , 4R )-4-(benzyloxy)pyrrolidine-1,2-dicarboxylate (11.8 g, 26.39 mmol) was dissolved in tetrahydrofuran (150 ml) , after which lithium borohydride (0.86 g, 39.58 mmol) was added in an ice bath. The reaction mixture was stirred overnight at room temperature. Dilute hydrochloric acid was then added to stop the reaction, and the resulting mixture was extracted twice with sufficient ethyl acetate. The organic phases were combined, washed twice with brine, dried over sodium sulfate and filtered, and then the filtrate was concentrated. The residue was separated by silica gel column chromatography to obtain tert -butyl-( 2R , 4R )-4-(benzyloxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (8 g, yield: 98%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 308 [M + H] ⁺ .

Stage 3. Synthesis rubs -butyl-(2 R ,4 R )-4-(benzyloxy)-2-(methoxymethyl)pyrrolidine-1-carboxylate

Tert -butyl-( 2R , 4R )-4-(benzyloxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (8.00 g, 26.03 mmol) was dissolved in N , N -dimethylformamide (120 ml) , after which the mixture was placed in ice water and sodium hydride (3.12 g, 78.08 mmol) was added. The reaction mixture was stirred for 0.5 h and then iodomethane (16.2 mL, 260.26 mmol) was added. The reaction mixture thus obtained was stirred overnight at room temperature. Upon completion of the reaction, dilute hydrochloric acid was added to stop the reaction, and the resulting mixture was extracted twice with sufficient ethyl acetate. The organic phases were combined, washed twice with brine, dried over sodium sulfate and filtered, and then the filtrate was concentrated. The residue was separated by silica gel column chromatography to obtain tert -butyl-( 2R , 4R )-4-(benzyloxy)-2-(methoxymethyl)pyrrolidine-1-carboxylate (8 g, yield: 95%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 322 [M + H] ⁺ .

Stage 4. Synthesis rubs -butyl (2 R ,4 R )-4-hydroxy-2-(methoxymethyl)pyrrolidine-1-carboxylate

Tert -butyl-( 2R , 4R )-4-(benzyloxy)-2-(methoxymethyl)pyrrolidine-1-carboxylate (1.0 g, 3.11 mmol) was dissolved in ethanol (20 ml), and the resulting 10% palladium on carbon (0.15 g) was added to the solution. Hydrogen was introduced three times to replace the air by pumping, after which the reaction mixture was stirred overnight at room temperature and filtered. The filtrate was concentrated to give tert -butyl ( 2R , 4R )-4-hydroxy-2-(methoxymethyl)pyrrolidine-1-carboxylate (0.7 g, yield: 99%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 232 [M + H] ⁺ .

Stage 5. Synthesis rubs -butyl-(2 R ,4 R )-2-(methoxymethyl)-4-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate

Tert -butyl ( 2R , 4R )-4-hydroxy-2-(methoxymethyl)pyrrolidine-1-carboxylate (300 mg, 1.30 mmol) was dissolved in dichloromethane (10 ml) and N , N- was added to the resulting solution diisopropylethylamine (1 ml, 6.49 mmol) and methanesulfonyl chloride (0.3 ml, 3.89 mmol). The reaction mixture was stirred overnight at room temperature and then concentrated to give tert -butyl-( 2R , 4R )-2-(methoxymethyl)-4-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (355 mg, yield: 88%); the crude product in this form was used in the next step without further purification. Electric sputter ionization mass spectrometry (ESI-MS, m/z): 310 [M + H] ⁺ .

Stage 6. Synthesis rubs -butyl-(2 R ,4 S )-4-(4-amino-3-iodine-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)-2-(methoxymethyl)pyrrolidine-1-carboxylate

Tert -butyl-( 2R , 4R )-2-(methoxymethyl)-4-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (355 mg, 1.15 mmol) and 3-iodo- 1H- pyrazolo[ 3,4- d ]pyrimidin-4-amine (300 mg, 1.15 mmol) was sequentially dissolved in N , N -dimethylformamide (15 ml), and then cesium carbonate (1.12 g, 3.45 mmol). The reaction mixture was heated to 80 ° C and stirred overnight. Upon completion of the reaction, the reaction mixture was cooled to room temperature, a sufficient amount of saturated aqueous sodium bicarbonate was added, and the aqueous phase was extracted three times with a sufficient amount of ethyl acetate. The organic phases were combined, washed twice with brine, dried over sodium sulfate and filtered, and then the filtrate was concentrated. The residue was separated by silica gel column chromatography to give tert -butyl-( 2R , 4S )-4-(4-amino-3-iodo- 1H- pyrazolo[3,4- d ]pyrimidin-1-yl) -2-(methoxymethyl)pyrrolidine-1-carboxylate (456 mg, yield: 96%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 475 [M + H] ⁺ .

Stage 7. Synthesis of 3-iodo-1-((3 S ,5 R )-5-(methoxymethyl)pyrrolidin-3-yl)-1 H -pyrazolo[3,4- d ]pyrimidine-4-amine

Tert -butyl-( 2R , 4S )-4-(4-amino-3-iodo- 1H -pyrazolo[3,4- d ]pyrimidin-1-yl)-2-(methoxymethyl)pyrrolidine-1- carboxylate (456 mg, 0.96 mmol) was dissolved in tetrahydrofuran (10 ml) and a solution of hydrogen chloride in 1,4-dioxane (3.2 ml, 19.23 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture as such was concentrated and the residue was dried to obtain 3-iodo-1-(( 3S , 5R )-5-(methoxymethyl)pyrrolidine-3- yl) -1H -pyrazolo[3,4- d ]pyrimidin-4-amine (300 mg, yield: 69%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 375 [M + H] ⁺ .

Stage 8. Synthesis 1-((2 R ,4 S )-4-(4-amino-3-iodine-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)-2-(methoxymethyl)pyrrolidin-1-yl)prop-2-en-1-one

3-iodo-1-(( 3S , 5R )-5-(methoxymethyl)pyrrolidin-3-yl) -1H- pyrazolo[3,4- d ]pyrimidin-4-amine (300 mg, 0.67 mmol) was dissolved in tetrahydrofuran (10 ml) and water (5 ml), after which sodium bicarbonate (281.84 mg, 3.35 mmol) was added. The reaction mixture was placed in an ice bath and a solution of acryloyl chloride (0.07 mL, 0.87 mmol) in tetrahydrofuran (1 mL) was added slowly dropwise. After the dropwise addition was completed, the reaction mixture was stirred for 10 minutes, a sufficient amount of saturated aqueous sodium bicarbonate was added to stop the reaction, and the resulting reaction mixture was extracted three times with ethyl acetate. The organic phases were combined, washed twice with brine, dried over sodium sulfate, filtered and the residue was separated by silica gel column chromatography to give 1-(( 2R , 4S )-4-(4-amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)-2-(methoxymethyl)pyrrolidin-1-yl)prop-2-en-1-one (180 mg, yield: 63%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 429 [M + H] ⁺ .

Intermediate 33: Preparation rubs -butyl-3-(4-amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)azetidine-1-carboxylate

3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (2500 mg, 10.16 mmol), tert -butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate (2550 mg, 10.16 mmol) and cesium carbonate (4970 mg, 15.24 mmol) were dissolved in N , N -dimethylformamide (30 ml) and the reaction mixture was stirred at 80 ° C for 16 h. After completion of the reaction, water (60 ml) was added and the resulting reaction mixture was filtered to obtain tert -butyl-3-(4-amino-3-iodo- 1H- pyrazolo[3,4- d ]pyrimidin-1-yl)azetidin-1-carboxylate (2000 mg, yield: 47%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 417 [M + H] ⁺ .

II. Getting Compounds as Examples

Example 1: Getting ( S )-1-(3-(4-amino-5-((2-cyclopropylbenzo[ d ]oxazol-5-yl)ethynyl)-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one

( S )-1-(3-(4-amino-5-iodo- 7H -pyrrolo[2,3- d ]pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one (40 mg, 0.1 mmol), 2-cyclopropyl-5-ethynylbenzo[ d ]oxazole (23 mg, 0.12 mmol), triethylamine (0.4 ml), copper iodide (2 mg, 0.01 mmol) and tetrakis(triphenylphosphine)palladium (12 mg, 0.01 mmol) was added to DMF (2 ml). The reaction mixture was stirred at 80°C for 1 h under nitrogen atmosphere, after which it was separated by reverse phase column chromatography and lyophilized to give ( S )-1-(3-(4-amino-5-( (2-cyclopropylbenzo[ d ]oxazol-5-yl)ethynyl)-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one (29 .5 mg, yield: 65%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 439 [M + H] ⁺ .

^1H -NMR (400 MHz, DMSO- d6 ): δ 8.11 (s, 1H), 7.78-7.77 ( _d , J = 4 Hz, 1H), 7.69-7.65 ( d, J = 16 Hz, 1H), 7.61-7.59 (d, J = 8 Hz, 1H), 7.46-7.44 (m, 1H), 6.85-6.48 (m , 3H), 6.14-6.07 (m, 1H), 5.67-5.59 (m, 1H), 5.31-5.18 (m, 1H), 4.06-3.79 (m, 2H), 3.71-3.43 (m, 2H), 2.38-2.19 (m, 3H), 1.17-1.07 (m, 4H).

The substances of Examples 2 - 75 can be prepared by selecting appropriate starting materials in accordance with the method of synthesis (total or partial) of the substance from Example 1.

Example number Structural formula Chemical name [M+H] ⁺ 2 ( S )-1-(3-(4-amino-5-((2-methylbenzo[ d ]oxazol-5-yl)ethynyl)-7H - pyrrolo[2,3- d ]pyrimidin-7-yl) pyrrolidin-1-yl)prop-2-en-1-one 413 3 ( S )-1-(3-(4-amino-5-((2-ethylbenzo[ d ]oxazol-5-yl)ethynyl)-7H - pyrrolo[2,3- d ]pyrimidin-7-yl) pyrrolidin-1-yl)prop-2-en-1-one 427 4 ( S )-1-(3-(4-amino-5-((2-isopropylbenzo[ d ]oxazol-5-yl)ethynyl)-7H - pyrrolo[2,3- d ]pyrimidin-7-yl) pyrrolidin-1-yl)prop-2-en-1-one 441 5 ( S )-1-(3-(4-amino-5-((2-cyclobutylbenzo[ d ]oxazol-5-yl)ethynyl)-7H - pyrrolo[2,3- d ]pyrimidin-7-yl) pyrrolidin-1-yl)prop-2-en-1-one 453 6 ( S )-1-(3-(4-amino-5-(benzo[ d ]oxazol-5-ylethynyl)-7H - pyrrolo[2,3- d ]pyrimidin-7-yl)pyrrolidin-1-yl )prop-2-en-1-one 399 7 ( S )-1-(3-(4-amino-5-((2-(methylamino)benzo[ d ]oxazol-5-yl)ethynyl)-7 H- pyrrolo[2,3-d]pyrimidine-7 -yl)pyrrolidin-1-yl)prop-2-en-1-one 428 8 ( S )-1-(3-(4-amino-5-((2-(ethylamino)benzo[ d ]oxazol-5-yl)ethynyl)-7 H- pyrrolo[2,3- d ]pyrimidine-7 -yl)pyrrolidin-1-yl)prop-2-en-1-one 442 9 ( S )-1-(3-(4-amino-5-((2-(cyclopropylamino)benzo[ d ]oxazol-5-yl)ethynyl)-7 H -pyrrolo[2,3- d ]pyrimidine-7 -yl)pyrrolidin-1-yl)prop-2-en-1-one 454 10 ( S )-1-(3-(4-amino-5-((2-(dimethylamino)benzo[ d ]oxazol-5-yl)ethynyl)-7 H- pyrrolo[2,3- d ]pyrimidine-7 -yl)pyrrolidin-1-yl)prop-2-en-1-one 442 eleven ( S )-1-(3-(4-amino-5-((2-(azetidin-1-yl)benzo[ d ]oxazol-5-yl)ethynyl)-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one 454 12 ( S )-1-(3-(4-amino-5-((6-fluoro-2-(methylamino)benzo[ d ]oxazol-5-yl)ethynyl)-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one 446 13 ( S )-1-(3-(4-amino-5-((2-(dimethylamino)-6-fluorobenzo[ d ]oxazol-5-yl)ethynyl) -7H- pyrrolo[2,3- d ] pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one 460 14 ( S )-1-(3-(4-amino-5-((2-(ethylamino)-6-fluorobenzo[ d ]oxazol-5-yl)ethynyl) -7H- pyrrolo[2,3- d ] pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one 460 15 ( S )-1-(3-(4-amino-5-((2-(cyclopropylamino)-6-fluorobenzo[ d ]oxazol-5-yl)ethynyl) -7H- pyrrolo[2,3- d ] pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one 472 16 ( S )-1-(3-(4-amino-5-((2-(azetidin-1-yl)-6-fluorobenzo[ d ]oxazol-5-yl)ethynyl)-7 H -pyrrolo[2, 3- d ]pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one 472 17 1-(3-(4-amino-5-((2-cyclopropylbenzo[ d ]oxazol-5-yl)ethynyl)-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)azetidin-1- yl)prop-2-en-1-one 425 18 ( S )-1-(3-(4-amino-5-((2-cyclopropylbenzo[ d ]oxazol-5-yl)ethynyl)pyrrolo[2,1- f ][1,2,4]triazine-7 -yl)pyrrolidin-1-yl)prop-2-en-1-one 439 19 ( S )-1-(3-(8-amino-1-((2-cyclopropylbenzo[ d ]oxazol-5-yl)ethynyl)imidazo[1,5- a ]pyrazin-3-yl)pyrrolidin-1- yl)prop-2-en-1-one 439 20 ( S )-1-(3-(4-amino-3-((2-cyclopropylbenzo[ d ]oxazol-5-yl)ethynyl)-1H - pyrazolo[3,4- d ]pyrimidin-1-yl) pyrrolidin-1-yl)prop-2-en-1-one 440 21 ( S )-1-(3-(4-amino-3-((2-cyclobutylbenzo[ d ]oxazol-5-yl)ethynyl)-1H - pyrazolo[3,4- d ]pyrimidin-1-yl) pyrrolidin-1-yl)prop-2-en-1-one 454 22 ( S )-1-(3-(4-amino-3-((2-isopropylbenzo[ d ]oxazol-5-yl)ethynyl)-1H - pyrazolo[3,4- d ]pyrimidin-1-yl) pyrrolidin-1-yl)prop-2-en-1-one 442 23 1-(3-(4-amino-3-((2-cyclopropylbenzo[ d ]oxazol-5-yl)ethynyl)-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)azetidin-1- yl)prop-2-en-1-one 426 24 ( S )-1-(3-(4-amino-3-((2-(methylamino)benzo[ d ]oxazol-5-yl)ethynyl)-1 H -pyrazolo[3,4- d ]pyrimidine-1 -yl)pyrrolidin-1-yl)prop-2-en-1-one 429 25 ( S )-1-(3-(4-amino-3-((2-(dimethylamino)benzo[ d ]oxazol-5-yl)ethynyl)-1 H -pyrazolo[3,4- d ]pyrimidine-1 -yl)pyrrolidin-1-yl)prop-2-en-1-one 443 26 ( S )-1-(3-(
4-amino-3-((2-(ethylamino)benzo[ d ]oxazol-5-yl)ethynyl)-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)pyrrolidin-1-yl)prop -2-en-1-on 443 27 ( S )-1-(3-(4-amino-3-((2-(cyclopropylamino)benzo[ d ]oxazol-5-yl)ethynyl)-1 H -pyrazolo[3,4- d ]pyrimidine-1 -yl)pyrrolidin-1-yl)prop-2-en-1-one 455 28 ( S )-1-(3-(4-amino-3-((2-(azetidin-1-yl)benzo[ d ]oxazol-5-yl)ethynyl)-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one 455 29 ( S )-1-(3-(4-amino-3-((6-fluoro-2-(methylamino)benzo[ d ]oxazol-5-yl)ethynyl)-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one 447 thirty ( S )-1-(3-(4-amino-3-((2-(ethylamino)-6-fluorobenzo[ d ]oxazol-5-yl)ethynyl) -1H- pyrazolo[3,4- d ] pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one 461 31 ( S )-1-(3-(4-amino-3-((2-(dimethylamino)-6-fluorobenzo[ d ]oxazol-5-yl)ethynyl) -1H- pyrazolo[3,4- d ] pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one 461 32 ( S )-1-(3-(4-amino-3-((2-(isopropylamino)-6-fluorobenzo[ d ]oxazol-5-yl)ethynyl) -1H- pyrazolo[3,4- d ] pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one 473 33 ( S )-1-(3-(4-amino-3-((2-(cyclopropylamino)-6-fluorobenzo[ d ]oxazol-5-yl)ethynyl) -1H- pyrazolo[3,4- d ] pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one 473 34 ( S )-1-(3-(4-amino-3-((2-(azetidin-1-yl)-6-fluorobenzo[ d ]oxazol-5-yl)ethynyl)-1 H -pyrazolo[3, 4- d ]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one 473 35 ( S )-1-(3-(4-amino-3-((2-cyclopropyl-6-fluorobenzo[ d ]oxazol-5-yl)ethynyl)-1 H -pyrazolo[3,4- d ]pyrimidin- 1-yl)pyrrolidin-1-yl)prop-2-en-1-one 458 36 ( S )-1-(3-(4-amino-3-((6-fluoro-2-(1-fluorocyclopropyl)benzo[ d ]oxazol-5-yl)ethynyl)-1 H -pyrazolo[3,4 - d ]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one 476 37 ( S )-1-(3-(4-amino-3-((6-fluoro-2-(1-methylcyclopropyl)benzo[ d ]oxazol-5-yl)ethynyl)-1 H -pyrazolo[3,4 - d ]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one 472 38 ( S )-1-(3-(4-amino-3-((2-cyclobutyl-6-fluorobenzo[ d ]oxazol-5-yl)ethynyl)-1 H -pyrazolo[3,4- d ]pyrimidin- 1-yl)pyrrolidin-1-yl)prop-2-en-1-one 472 39 ( S )-1-(3-(4-amino-3-((2-(1-methylcyclopropyl)benzo[ d ]oxazol-5-yl)ethynyl)-1 H -pyrazolo[3,4- d ]pyrimidine -1-yl)pyrrolidin-1-yl)prop-2-en-1-one 454 40 ( S )-1-(3-(4-amino-3-((2-(1-fluorocyclopropyl)benzo[ d ]oxazol-5-yl)ethynyl)-1 H -pyrazolo[3,4- d ]pyrimidine -1-yl)pyrrolidin-1-yl)prop-2-en-1-one 458 41 ( S )-1-(3-(4-amino-3-((2-methylthiazolo[5,4- b ]pyridin-6-yl)ethynyl)-1 H -pyrazolo[3,4- d ]pyrimidin- 1-yl)pyrrolidin-1-yl)prop-2-en-1-one 431 42 ( S )-1-(3-(4-amino-5-((2-methylbenzo[ d ]thiazol-5-yl)ethynyl)-7H - pyrrolo[2,3- d ]pyrimidin-7-yl) pyrrolidin-1-yl)prop-2-en-1-one 429 43 ( S )-1-(3-(4-amino-5-((2-cyclopropylbenzo[ d ]thiazol-5-yl)ethynyl)-7H - pyrrolo[2,3- d ]pyrimidin-7-yl) pyrrolidin-1-yl)prop-2-en-1-one 455 44 ( S )-1-(3-(4-amino-5-((2-ethylbenzo[ d ]thiazol-5-yl)ethynyl)-7H - pyrrolo[2,3- d ]pyrimidin-7-yl) pyrrolidin-1-yl)prop-2-en-1-one 443 45 ( S )-1-(3-(4-amino-5-((2-(difluoromethyl)benzo[ d ]thiazol-5-yl)ethynyl)-7 H- pyrrolo[2,3- d ]pyrimidine-7 -yl)pyrrolidin-1-yl)prop-2-en-1-one 465 46 ( S )-1-(3-(4-amino-5-((2-cyclobutylbenzo[ d ]thiazol-5-yl)ethynyl)-7H - pyrrolo[2,3- d ]pyrimidin-7-yl) pyrrolidin-1-yl)prop-2-en-1-one 469 47 ( S )-1-(3-(4-amino-5-((6-fluoro-2-methylbenzo[ d ]thiazol-5-yl)ethynyl)-7H - pyrrolo[2,3- d ]pyrimidin- 7-yl)pyrrolidin-1-yl)prop-2-en-1-one 447 48 ( S )-1-(3-(4-amino-5-((2-cyclopropyl-6-fluorobenzo[ d ]thiazol-5-yl)ethynyl)-7H - pyrrolo[2,3- d ]pyrimidin- 7-yl)pyrrolidin-1-yl)prop-2-en-1-one 473 49 ( S )-1-(3-(4-amino-5-((2-cyclobutyl-6-fluorobenzo[ d ]thiazol-5-yl)ethynyl) -7H- pyrrolo[2,3- d ]pyrimidin- 7-yl)pyrrolidin-1-yl)prop-2-en-1-one 487 50 ( S )-1-(3-(4-amino-5-((2-(difluoromethyl)-6-fluorobenzo[ d ]thiazol-5-yl)ethynyl) -7H- pyrrolo[2,3- d ] pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one 483 51 ( S )-1-(3-(4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[ d ]thiazol-5-yl)ethynyl) -7H- pyrrolo[2,3- d ] pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one 490 52 ( S )-1-(3-(4-amino-3-((2-methylbenzo[ d ]thiazol-5-yl)ethynyl)-1H - pyrazolo[3,4- d ]pyrimidin-1-yl) pyrrolidin-1-yl)prop-2-en-1-one 430 53 ( S )-1-(3-(4-amino-3-((2-ethylbenzo[ d ]thiazol-5-yl)ethynyl)-1H - pyrazolo[3,4- d ]pyrimidin-1-yl) pyrrolidin-1-yl)prop-2-en-1-one 444 54 ( S )-1-(3-(4-amino-3-((2-cyclopropylbenzo[ d ]thiazol-5-yl)ethynyl)-1H - pyrazolo[3,4- d ]pyrimidin-1-yl) pyrrolidin-1-yl)prop-2-en-1-one 456 55 ( S )-1-(3-(4-amino-3-((2-(difluoromethyl)benzo[ d ]thiazol-5-yl)ethynyl)-1 H -pyrazolo[3,4- d ]pyrimidine-1 -yl)pyrrolidin-1-yl)prop-2-en-1-one 466 56 ( S )-1-(3-(4-amino-3-((2-cyclobutylbenzo[ d ]thiazol-5-yl)ethynyl)-1H - pyrazolo[3,4- d ]pyrimidin-1-yl) pyrrolidin-1-yl)prop-2-en-1-one 470 57 ( S )-1-(3-(4-amino-3-((6-fluoro-2-methylbenzo[ d ]thiazol-5-yl)ethynyl)-1H - pyrazolo[3,4- d ]pyrimidin- 1-yl)pyrrolidin-1-yl)prop-2-en-1-one 448 58 ( S )-1-(3-(4-amino-3-((2-ethyl-6-fluorobenzo[ d ]thiazol-5-yl)ethynyl)-1H - pyrazolo[3,4- d ]pyrimidin- 1-yl)pyrrolidin-1-yl)prop-2-en-1-one 462 59 ( S )-1-(3-(4-amino-3-((2-cyclopropyl-6-fluorobenzo[ d ]thiazol-5-yl)ethynyl)-1 H -pyrazolo[3,4- d ]pyrimidin- 1-yl)pyrrolidin-1-yl)prop-2-en-1-one 474 60 ( S )-1-(3-(4-amino-3-((2-(difluoromethyl)-6-fluorobenzo[ d ]thiazol-5-yl)ethynyl) -1H- pyrazolo[3,4- d ] pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one 484 61 ( S )-1-(3-(4-amino-3-((2-cyclobutyl-6-fluorobenzo[ d ]thiazol-5-yl)ethynyl)-1 H -pyrazolo[3,4- d ]pyrimidin- 1-yl)pyrrolidin-1-yl)prop-2-en-1-one 488 62 ( S )-1-(3-(4-amino-3-((2-cyclopropyl-4,6-difluorobenzo[ d ]thiazol-5-yl)ethynyl) -1H- pyrazolo[3,4- d ] pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one 492 63 1-(3-(4-amino-5-((2-cyclopropylbenzo[ d ]oxazol-5-yl)ethynyl)pyrrolo[2,1- f ][1,2,4]triazin-7-yl)pyrrolidine -1-yl)prop-2-en-1-one 439 64 1-(3-(4-amino-5-((2-cyclopropylbenzo[ d ]oxazol-5-yl)ethynyl)pyrrolo[2,1- f ][1,2,4]triazin-7-yl)azetidine -1-yl)prop-2-en-1-one 425 65 ( S )-1-(3-(4-amino-5-((2-cyclopropyl-6-fluorobenzo[ d ]oxazol-5-yl)ethynyl) -7H- pyrrolo[2,3- d ]pyrimidin- 7-yl)pyrrolidin-1-yl)prop-2-en-1-one 457 67 ( S )-1-(3-(4-amino-3-((4,6-difluoro-2-(methylamino)benzo[ d ]oxazol-5-yl)ethynyl)-1 H -pyrazolo[3,4 - d ]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one 465 68 1-((2 R ,4 S )-4-(4-amino-3-((2-cyclopropyl-4,6-difluorobenzo[ d ]thiazol-5-yl)ethynyl)-1 H -pyrazolo[3, 4-d]pyrimidin-1-yl)-2-(methoxymethyl)pyrrolidin-1-yl)prop-2-en-1-one 536 69 1-((2 R ,4 S )-4-(4-amino-3-((2-(azetidin-1-yl)-4,6-difluorobenzo[ d ]thiazol-5-yl)ethynyl)-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)-2-(methoxymethyl)pyrrolidin-1-yl)prop-2-en-1-one 551 70 1-(3-(4-amino-5-((2-methylbenzo[ d ]thiazol-5-yl)ethynyl)pyrrolo[2,1- f ][1,2,4]triazin-7-yl)pyrrolidine -1-yl)prop-2-en-1-one 429 71 ( S )-1-(3-(4-amino-5-((2-(difluoromethyl)benzo[ d ]oxazol-5-yl)ethynyl)-7 H- pyrrolo[2,3- d ]pyrimidine-7 -yl)pyrrolidin-1-yl)prop-2-en-1-one 449 72 ( S )-1-(3-(4-amino-5-((6-fluoro-2-(trifluoromethyl)benzo[ d ]oxazol-5-yl)ethynyl)-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one 485 73 ( S )-1-(3-(4-amino-5-((2-(azetidin-1-yl)-4,6-difluorobenzo[ d ]oxazol-5-yl)ethynyl)-7 H -pyrrolo[ 2,3- d ]pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one 490 74 ( S )-1-(3-(4-amino-3-((2-(azetidin-1-yl)-4,6-difluorobenzo[ d ]oxazol-5-yl)ethynyl)-1 H -pyrazolo[ 3,4- d ]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one 491 75 ( S )-1-(3-(4-amino-5-((4,6-difluoro-2-methylbenzo[ d ]thiazol-5-yl)ethynyl) -7H- pyrrolo[2,3- d ] pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one 465

Data obtained by NMR on nuclei ¹ H, about the compounds obtained in the above examples:

Number
connections (example) ¹ H-NMR 2 (400 MHz, MeOH -d4 ): δ 8.07 (s, 1H), 7.66 ( _d , J = 1.5 Hz, 1H), 7.51-7.33 (m, 3H), 6 .69-6.41 (m, 1H), 6.32-6.14 (m, 1H), 5.76-5.59 (m, 1H), 5.38-5.16 (m, 1H) , 4.17-3.92 (m, 1H), 3.91-3.55 (m, 3H), 2.55 (s, 3H), 2.50-2.33 (m, 2H), 3 (400 MHz, DMSO- d6 ): δ 8.11 (s, 1H), 7.86-7.85 ( _d , J = 4.0 Hz, 1H), 7.70-7.63 (t, J = 12 Hz, 2H), 7.51-7.48 (d, J = 12 Hz, 1H), 6.78-6.48 (m, 3H), 6.14-6.07 (m, 1H ), 5.67-5.59 (m, 1H), 5.33-5.19 (m, 1H), 4.06-3.79 (m, 2H), 3.71-3.43 (m , 2H), 2.94-2.88 (q, J = 8 Hz, 2H), 2.40-2.35 (m, 1H), 2.33-2.27 (m, 1H), 1, 30-1.27 (t, J = 8 Hz, 3H), 4 (400 MHz, DMSO- d6 ): δ 8.16 (s, 1H), 7.87 (s, 1H), 7.73-7.65 (t _, J = 16 Hz, 2H), 7.52 -7.49 (d, J = 8 Hz, 1H), 7.02-6.48 (m, 3H), 6.14-6.07 (m, 1H), 5.67-5.59 (m , 1H), 5.34-5.21 (m, 1H), 4.07-3.79 (m, 2H), 3.71-3.41 (m, 2H), 3.24-3.18 (t, J = 8 Hz, 1H), 2.41-2.28 (m, 2H), 1.33-1.31 (d, J = 8 Hz, 6H), 5 (400 MHz, DMSO- d6 ): δ 8.11 (s, 1H), 7.87-7.86 ( _m , 1H), 7.70-7.64 (m, 2H), 7.51- 7.49 (m, 1H), 6.79-6.48 (m, 3H), 6.14-6.07 (m, 1H), 5.67-5.59 (m, 1H), 5. 33-5.19 (m, 1H), 4.06-3.44 (m, 5H), 2.40-2.28 (m, 6H), 2.09-1.86 (m, 2H), 6 (400 MHz, DMSO- d6 ): δ 8.82 (s, 1H), 8.18 (d, J = 1.4 Hz, 1H), 8.07 (d _, J = 1.7 Hz, 1H ), 7.83 (d, J = 8.5 Hz, 1H), 7.75 (d, J = 16.0 Hz, 1H), 7.65 (dd, J = 8.2, 1.5 Hz , 1H), 6.71 (br s, 1H), 6.69-6.55 (m, 1H), 6.21-6.14 (m, 1H), 5.74-5.66 (m, 1H), 5.40-5.30 (m, 1H), 4.13-3.52 (m, 4H), 2.46-2.42 (m, 1H), 2.39-2.32 ( m, 1H), 7 (400 MHz, DMSO- d ₆ ): δ 8.11 (s, 1H), 7.90-7.86 (m, 1H), 7.66-7.62 (d, J = 16 Hz, 1H) , 7.36-7.30 (m, 2H), 7.14-7.12 (m, 1H), 6.78-6.48 (m, 3H), 6.14-6.07 (m, 1H), 5.67-5.59 (m, 1H), 5.32-5.18 (m, 1H), 4.06-3.79 (m, 2H), 3.70-3.43 ( m, 2H), 2.85-2.84 (d, J = 4 Hz, 3H), 2.40-2.28 (m, 2H), 20 (400 MHz, DMSO- d6 ): δ 8.29 (s, 1H), 8.03 ( _s , 1H), 7.80-7.49 (m, 3H), 6.73-6.51 ( m, 1H), 6.24-6.10 (m, 1H), 5.78-5.64 (m, 1H), 5.57-5.42 (m, 1H), 4.12-3, 63 (m, 4H), 2.99-2.83 (m, 1H), 2.39-2.16 m, 3H), 1.32-1.11 (m, 4H), 29 (400 MHz, DMSO- d6 ): δ 8.29 (s, 1H), 8.05 ( _q , J = 4.4 Hz, 1H), 7.62 (dd, J = 6.4, 2, 4 Hz, 1H), 7.58 (d, J = 9.1 Hz, 1H), 6.70-6.50 (m, 1H), 6.20-6.14 (m, 1H), 5, 73-5.65 (m, 1H), 5.60-5.41 (m, 1H), 4.12-3.78 (m, 3H), 3.75-3.56 (m, 1H), 2.91 (d, J = 4.7 Hz, 3H), 2.47-2.30 (m, 2H), thirty (400 MHz, DMSO- d6 ): δ 8.29 (s, 1H), 8.16 (t, J = 5.5 Hz, 1H), 7.61 (dd _, J = 6.4, 2, 4 Hz, 1H), 7.58 (d, J = 9.1 Hz, 1H), 6.72-6.53 (m, 1H), 6.22-6.12 (m, 1H), 5, 75-5.64 (m, 1H), 5.58-5.42 (m, 1H), 4.16-3.56 (m, 4H), 3.38-3.31 (m, 2H), 2.48-2.30 (m, 2H), 1.19 (t, J = 7.2 Hz, 3H), 31 (400 MHz, DMSO- d6 ): δ 8.29 (s, 1H), 7.67-7.59 ( _m , 2H), 6.70-6.50 (m, 1H), 6.20- 6.14 (m, 1H), 5.73-5.65 (m, 1H), 5.60-5.41 (m, 1H), 4.12-3.79 (m, 3H), 3, 74-3.56 (m, 1H), 3.14 (s, 6H), 2.46-2.30 (m, 2H), 33 (400 MHz, DMSO- d6 ): δ 8.41 (s, 1H), 8.29 (s, 1H), 7.66 ( _dd , J = 6.3, 2.2 Hz, 1H), 7 .61 (d, J = 9.0 Hz, 1H), 6.70-6.55 (m, 1H), 6.20-6.14 (m, 1H), 5.73-5.65 (m , 1H), 5.60-5.41 (m, 1H), 4.12-3.79 (m, 3H), 3.73-3.58 (m, 1H), 2.77-2.72 (m, 1H), 2.45-2.33 (m, 2H), 0.77-0.71 (m, 2H), 0.60-0.56 (m, 2H), 34 (400 MHz, DMSO- d6 ): δ 8.29 (s, 1H), 7.66 (dd, J = 13.8, _7.6 Hz, 2H), 6.70-6.55 (m, 1H), 6.20-6.14 (m, 1H), 5.73-5.65 (m, 1H), 5.60-5.41 (m, 1H), 4.22 (t, J = 7.6 Hz, 4H), 4.12-3.76 (m, 3H), 3.71-3.58 (m, 1H), 2.45-2.34 (m, 4H), 35 (400 MHz, DMSO- d6 ): δ 8.29 (s, 1H), 8.11 (dd, J = 6.5, _2.4 Hz, 1H), 7.86 (d, J = 9, 0 Hz, 1H), 6.72-6.53 (m, 1H), 6.22-6.12 (m, 1H), 5.75-5.64 (m, 1H), 5.59-5 .43 (m, 1H), 4.17-3.56 (m, 4H), 2.47-2.26 (m, 3H), 1.28-1.12 (m, 4H), 36 (400 MHz, DMSO- d ₆ ): δ 8.28-8.17 (m, 2H), 7.94 (d, J = 8.9 Hz, 1H), 6.67-6.46 (m, 1H), 6.16-6.06 (m, 1H), 5.69-5.56 (m, 1H), 5.54-5.34 (m, 1H), 4.14-3.48 ( m, 4H), 2.40-2.21 (m, 2H), 1.81-1.64 (m, 2H), 1.54-1.43 (m, 2H), 38 (400 MHz, DMSO- d6 ): δ 8.30 (s, 1H), 8.21 (dd, J = 6.5, _2.4 Hz, 1H), 7.90 (d, J = 9, 0 Hz, 1H), 6.76-6.49 (m, 1H), 6.22-6.10 (m, 1H), 5.78-5.62 (m, 1H), 5.60-5 .41 (m, 1H), 4.16-3.56 (m, 5H), 3.02-2.78 (m, 1H), 2.48-2.34 (m, 6H), 2.19 -1.92 (m, 2H), 39 (400 MHz, DMSO- d6 ): δ 8.28 (d, J = 1.0 Hz, 1H), 8.05 ( _s , 1H), 7.73-7.67 (m, 2H), 6 .71-6.55 (m, 1H), 6.21-6.14 (m, 1H), 5.74-5.66 (m, 1H), 5.58-5.45 (m, 1H) , 4.15-4.10 (m, 0.5H), 3.99 - 3.71 (m, 3H), 3.70-3.61 (m, 0.5H), 2.48-2, 33 (m, 2H), 1.58 (s, 3H), 1.41-1.34 (m, 2H), 1.11-1.08 (m, 2H), 41 (400 MHz, DMSO- d6 ): δ 8.89 (s, 1H), 8.72 (s, 1H), _8.29 (s, 1H), 6.76-6.51 (m, 1H) , 6.26-6.10 (m, 1H), 5.78-5.62 (m, 1H), 5.62-5.42 (m, 1H), 4.20-3.58 (m, 4H), 2.87 (s, 3H), 2.48-2.30 (m, 2H), 42 (400 MHz, DMSO- d6 ): δ 8.18 (s, 1H), 8.13 ( _s , 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.77 (d , J = 16.2 Hz, 1H), 7.58 (d, J = 8.3 Hz, 1H), 6.94-6.61 (m, 2H), 6.65-6.54 (m, 1H), 6.23-6.12 (m, 1H), 5.76-5.63 (m, 1H), 5.43-5.23 (m, 1H), 4.16-3.86 ( m, 2H), 3.78-3.51 (m, 2H), 2.82 (s, 3H), 2.50-2.32 (m, 2H), 43 (400 MHz, MeOH -d4 ): δ 8.17 (s, 1H), 7.99 (s, 1H), 7.85 (d _, J = 8.3 Hz, 1H), 7.51 (d , J = 8.4 Hz, 1H), 7.42 (d, J = 4.0 Hz, 1H), 6.63-6.48 (m, 1H), 6.27-6.20 (m, 1H), 5.73-5.66 (m, 1H), 5.36-5.24 (m, 1H), 4.15-3.96 (m, 1H), 3.89-3.57 ( m, 3H), 2.55-2.34 (m, 3H), 1.27-1.08 (m, 4H), 44 (400 MHz, MeOH -d4 ): δ 8.10 (s, 1H), 7.94 (dd, J = 3.9, _1.5 Hz, 1H), 7.85 (dd, J = 8, 3, 3.8 Hz, 1H), 7.59-7.37 (m, 2H), 6.67-6.44 (m, 1H), 6.27-6.20 (m, 1H), 5 .73-5.05 (m, 1H), 5.37-5.20 (m, 1H), 4.15-3.96 (m, 1H), 3.93-3.57 (m, 3H) , 3.11-3.05 (m, 2H), 2.55-2.31 (m, 2H), 1.37 (t, J = 7.5 Hz, 3H), 45 (400 MHz, MeOH -d4 ): δ 8.18 (d, J = 4.6 Hz _, 1H), 8.09 (d, J = 2.0 Hz, 1H), 8.04 (dd, J = 8.6, 3.6 Hz, 1H), 7.61 (dd, J = 8.8, 3.6 Hz, 1H), 7.51 (dd, J = 13.6, 3.1 Hz, 1H), 7.06 (t, J = 54.2 Hz, 1H), 6.62-6.48 (m, 1H), 6.26-6.20 (m, 1H), 5.72-5 .65 (m, 1H), 5.35-5.26 (m, 1H), 4.15-3.96 (m, 1H), 3.90-3.57 (m, 3H), 2.51 -2.38 (m, 2H), 47 (400 MHz, DMSO- d ₆ ): δ 8.23-8.15 (m, 2H), 8.11 (d, J = 9.3 Hz, 1H), 7.82 (d, J = 16, 7 Hz, 1H), 6.71-6.54 (m, 1H), 6.23-6.12 (m, 1H), 5.76-5.65 (m, 1H), 5.43-5 .24 (m, 1H), 4.16-3.48 (m, 4H), 2.81 (s, 3H), 2.47-2.30 (m, 2H), 48 (400 MHz, DMSO- d6 ): δ 8.21 (s, 1H), 8.15-8.01 ( _m , 2H), 7.81 (d, J = 16.8 Hz, 1H), 6 .80 (brs, 2H), 6.73-6.52 (m, 1H), 6.27-6.14 (m, 1H), 5.81-5.66 (m, 1H), 5.42 -5.22 (m, 1H), 4.18-3.86 (m, 2H), 3.79-3.49 (m, 2H), 2.65-2.51 (m, 1H), 2 .49-2.29 (m, 2H), 1.27-1.09 (m, 4H), 50 (400 MHz, DMSO- d6 ): δ 8.50 (dd, J = 6.4, 3.6 Hz, 1H), 8.32 (d _, J = 6.4 Hz, 1H), 8.20 (s, 1H), 7.84 (d, J = 16.8 Hz, 1H), 7.50 (t, J = 53.6 Hz, 1H), 7.00-6.68 (m, 2H) , 6.65-6.59 (m, 1H), 6.20-6.14 (m, 1H), 5.73-5.67 (m, 1H), 5.39-5.27 (m, 1H), 4.12-3.88 (m, 2H), 3.72-3.52 (m, 2H), 2.45-2.32 (m, 2H), 51 (400 MHz, DMSO- d6 ): δ 8.20 (s, 1H), 7.90 (d, J = 17.8 _Hz , 1H), 6.78 (brs, 2H), 6.71-6 .52 (m, 1H), 6.25-6.11 (m, 1H), 5.73-5.66 (m, 2H), 5.43-5.23 (m, 1H), 4.19 -3.84 (m, 2H), 3.80-3.49 (m, 2H), 2.65-2.53 (m, 1H), 2.49-2.33 (m, 2H), 1 .33-1.13 (m, 4H), 52 (400 MHz, DMSO- d6 ): δ 8.32 (s, 1H), 8.28 ( _s , 1H), 8.12 (d, J = 8.3 Hz, 1H), 7.72 (d , J = 8.3 Hz, 1H), 6.74-6.53 (m, 1H), 6.24-6.11 (m, 1H), 5.75-5.63 (m, 1H), 5.60-5.42 (m, 1H), 4.18-3.57 (m, 4H), 2.83 (s, 3H), 2.47-2.30 (m, 2H), 53 (400 MHz, MeOH -d4 ): δ 8.18 (s, 1H), 8.09 (s, 1H), 7.91 (d _, J = 8.4 Hz, 1H), 7.56 (d , J = 8.3 Hz, 1H), 6.64-6.49 (m, 1H), 6.25-6.21 (m, 1H), 5.76-5.63 (m, 1H), 5.50-5.45 (m, 1H), 4.12-3.66 (m, 4H), 3.12-3.07 (q, J = 7.5 Hz, 2H), 2.50- 2.41 (m, 2H), 1.39 (t, J = 7.5 Hz, 3H), 54 (400 MHz, MeOH -d4 ): δ 8.17 (s, 1H), 7.99 (s, 1H), 7.85 (d _, J = 8.3 Hz, 1H), 7.51 (d , J = 8.4 Hz, 1H), 6.64-6.48 (m, 1H), 6.29-6.18 (m, 1H), 5.71-5.65 (m, 1H), 5.51-5.44 (m, 1H), 4.12-3.65 (m, 4H), 2.55-2.34 (m, 3H), 1.27-1.08 (m, 4H ), 55 (400 MHz, MeOH -d4 ): δ 8.32 (s, 1H), 8.17 (s, 1H), 8.09 (d _, J = 8.4 Hz, 1H), 7.72 (d , J = 8.4 Hz, 1H), 7.07 (t, J = 54.2 Hz, 1H), 6.64-6.48 (m, 1H), 6.33-6.13 (m, 1H), 5.71-6.65 (m, 1H), 5.60-5.40 (m, 1H), 4.15-4.00 (m, 1H), 4.00-3.63 ( m, 3H), 2.52-2.39 (m, 2H), 57 (400 MHz, DMSO- d6 ): δ 8.40 (dd, J = 6.5, 2.5 Hz, 1H), 8.30 ( _s , 1H), 8.16 (d, J = 9, 3 Hz, 1H), 6.73-6.54 (m, 1H), 6.23-6.12 (m, 1H), 5.76-5.64 (m, 1H), 5.60-5 .44 (m, 1H), 4.17-3.57 (m, 4H), 2.82 (s, 3H), 2.48-2.31 (m, 2H), 59 (400 MHz, DMSO- d6 ): δ 8.47-8.25 (m, 2H), 8.12 ( _d , J = 9.3 Hz, 1H), 6.76-6.51 (m, 1H), 6.29-6.07 (m, 1H), 5.79-5.61 (m, 1H), 5.62-5.43 (m, 1H), 4.15-3.62 ( m, 4H), 2.69-2.55 (m, 1H), 2.48-2.30 (m, 2H), 1.38-1.02 (m, 4H), 60 (400 MHz, DMSO- d6 ): δ 8.73 (dd, J = 6.4, 3.6 Hz, 1H), 8.37 (d _, J = 9.2 Hz, 1H), 8.30 (s, 1H), 7.68-7.38 (m, 1H), 7.52 (t, J = 53.6 Hz, 1H), 7.00-6.70 (m, 1H), 6, 66-6.60 (m, 1H), 6.20-6.14 (m, 1H), 5.72-5.66 (m, 1H), 5.57-5.47 (m, 1H), 4.12-3.92 (m, 1H), 3.92-3.80 (m, 2H), 3.72-3.61 (m, 1H), 2.53-2.32 (m, 2H ), 62 (400 MHz, DMSO- d6 ): δ 8.31 (s, 1H), 8.04 ( _d , J = 8.7 Hz, 1H), 6.91-6.54 (brs, 2H), 6 .73-6.55 (m, 1H), 6.25-6.11 (m, 1H), 5.76-5.63 (m, 1H), 5.61-5.44 (m, 1H) , 4.22-3.88 (m, 4H), 2.69-2.56 (m, 2H), 2.47-2.30 (m, 1H), 1.43-1.05 (m, 4H), 63 (400 MHz, DMSO- d6 ): δ 7.99 (s, 1H), 7.87 (s, 1H), 7.68 ( _d , J = 8.4 Hz, 1H), 7.54 (dd , J = 8.4, 1.7 Hz, 1H), 6.84 (d, J = 12.5 Hz, 1H), 6.68-6.56 (m, 1H), 6.23-6, 13 (m, 1H), 5.83-5.60 (m, 1H), 4.12-3.58 (m, 4H), 3.54-2.03 (m, 2H), 2.37- 2.25 (m, 2H), 1.29-1.12 (m, 4H), 64 (400 MHz, DMSO- d6 ): δ 8.19 (s, 1H), 7.90-7.8 ( _m , 1H), 7.82-7.7 (m, 2H), 6.85- 6.5 (m, 3H), 6.21-6.10 (m, 1H), 5.74-5.6 (m, 1H), 5.38-5.21 (m, 1H), 4, 13-3.86 (m, 2H), 3.77-3.50 (m, 2H), 2.47-2.26 (m, 3H), 1.24-1.13 (m, 3H), 65 (400 MHz, DMSO- d6 ): δ 8.19 (s, 1H), 7.90-7.88 ( _m , 1H), 7.83-.74 (m, 2H), 6.68-6 .55 (m, 3H), 6.21-6.14 (m, 1H), 5.74-5.66 (m, 1H), 5.38-5.27 (m, 1H), 4.13 -4.09 (m, 0.5H), 3.96-3.87 (m,1.5H), 3.77-3.67 (m, 1.5H), 3.57-3.50 ( m, 0.5H), 2.46-2.42 (m,1H), 2.39-2.36 (m, 1H), 2.31-2.26 (m, 1H), 1.24- 1.19 (m, 2H), 1.17-1.13 (m, 2H), 67 (400 MHz, DMSO- d6 ): δ 8.29 (s, 1H),8.31-8.26( _m , 1H), 7.56 (d, J = 8.4 Hz, 1H), 6 .71-6.55 (m, 1H), 6.71(brs, 2H), 6.24-6.12 (m, 1H), 6.74-5.64 (m, 1H), 5.61 -5.38 (m, 1H), 4.17-3.57 (m, 4H), 2.93 (d, J = 4.7 Hz, 3H), 2.49-2.30 (m, 2H ), 68 (400 MHz, MeOH -d4 ): δ 8.29 (s, 1H), 7.71 ( _d , J = 8.5 Hz, 1H), 6.88-6.55 (m, 1H), 6 .38-6.27 (m, 1H), 5.83-5.67 (m, 2H), 4.73-4.63 (m, 1H), 4.20-4.11 (m, 1H) , 3.97-3.80 (m, 1H), 3.64-3.56 (m, 1H), 3.44 (d, J = 2.3 Hz, 3H), 2.93-2.66 (m, 2H), 2.60-2.47 (m, 2H), 1.37-1.24 (m, 4H), 69 (400 MHz, MeOH- d4 ): δ 8.28 (s, 1H), 7.27 (d, J = 8.2 _Hz , 1H), 6.90-6.54 (m, 1H), 6 .38-6.24 (m, 1H), 5.84-5.67 (m, 2H), 4.72-4.62 (m, 1H), 4.35 (t, J = 7.7 Hz , 4H), 4.19-4.09 (m, 2H), 3.96-3.80 (m, 1H), 3.59 (td, J = 5.9, 5.3, 3.5 Hz , 1H), 3.43 (d, J = 2.2 Hz, 3H), 2.94-2.69 (m, 2H), 2.60-2.54 (m, 2H), 70 (400 MHz, MeOH- d4 ): δ 7.94 (s, 1H), 7.83-7.79 ( _m , 1H), 7.75 (s, 1H), 7.57-7.50 ( m, 1H), 7.46-7.44 (m, 1H), 6.68 (d, 1H), 6.57-6.53 (m, 1H), 6.25 (d, 1H), 6 .50-6.45 (m, 1H), 4.02-3.54 (m, 4H), 2.75 (s, 3H), 2.48-2.30 (m, 1H), 2.20 -2.25 (m, 1H) 71 (400 MHz, DMSO- d ₆ ): δ 8.28-8.15 (m, 2H), 7.95 (d, J = 8.6 Hz, 1H), 7.85-7.71 (m, 2H), 7.44 (t, J = 51.9 Hz, 1H), 6.92-6.51 (m, 3H), 6.24-6.11 (m, 1H), 5.78-5 .61 (m, 1H), 5.44-5.22 (m, 1H), 4.18-3.50 (m, 4H), 2.45-2.27 (m, 2H), 72 (400 MHz, DMSO- d6 ): δ 8.40-8.37 (m, 1H), 8.22-8.19 ( _m , 1H), 7.83 (d, J = 16.3 Hz, 1H), 6.81-6.55 (m, 3H), 6.21-6.14 (m, 1H), 5.74-5.66 (m, 1H), 5.39-5.26 ( m, 1H), 4.14-4.09 (m, 0.5H), 3.97-3.86 (m, 2H), 3.78-3.68 (m, 2H), 3.58- 3.50 (m, 0.5H), 2.48-2.32 (m, 2H), 73 (400 MHz, DMSO- d6 ): δ 8.13 (d, J = 1.4 Hz _, 1H), 7.78 (d, J = 17.7 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 6.72 (brs, 2H), 6.61-6.47 (m, 1H), 6.19-6.01 (m, 1H), 5.74-5, 55 (m, 1H), 5.37-5.15 (m, 1H), 4.17 (t, J = 7.6 Hz, 4H), 4.09-3.78 (m, 2H), 3 ,69-3.46 (m, 2H), 2.45-2.25 (m, 4H), 74 (400 MHz, DMSO- d6 ): δ 8.30 (s, 1H), 7.63 ( _d , J = 8.7 Hz, 1H), 6.75 (brs, 2H), 6.72-6 .52 (m, 1H), 6.22-6.11 (m, 1H), 5.75-5.62 (m, 1H), 5.60-5.42 (m, 1H), 4.25 (t, J = 7.7 Hz, 4H), 4.15-3.86 (m, 2H), 3.87-3.58 (m, 2H), 2.49-2.31 (m, 4H ), 75 (400 MHz, DMSO- d6 ): δ 8.14 (s, 1H), 7.96 ( _d , J = 8.8 Hz, 1H), 7.84 (d, J = 17.9 Hz, 1H ), 7.06-6.41 (m, 3H), 6.20-6.04 (m, 1H), 5.73-5.53 (m, 1H), 5.39-5.14 (m , 1H), 4.16-3.41 (m, 4H), 2.77 (s, 3H), 2.37-2.24 (m, 2H),

Example 76: Getting ( S )-1-(3-(4-amino-5-((2-(trifluoromethyl)benzo[ d ]oxazol-5-yl)ethynyl)-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one

( S )-1-(3-(4-amino-5-ethynyl- 7H -pyrrolo[2,3- d ]pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one (30 mg, 0.1 mmol), 5-bromo-2-(trifluoromethyl)benzo[ d ]oxazole (28 mg, 0.1 mmol), triethylamine (0.2 ml), copper iodide (2 mg, 0.01 mmol ) and tetrakis(triphenylphosphine)palladium (12 mg, 0.01 mmol) were added to DMF (1 ml). The reaction mixture was stirred at 80°C for 12 h under nitrogen atmosphere, after which it was separated by reverse phase column chromatography and lyophilized to give ( S )-1-(3-(4-amino-5-( (2-(trifluoromethyl)benzo[ d ]oxazol-5-yl)ethynyl)-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1- she (3.5 mg, yield: 6%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 467 [M + H] ⁺ .

^1H -NMR (400 MHz, DMSO- d6 ): δ 8.21 (s, 1H), 8.12 (s, 1H), 7.96-7.94 (d _, J = 8 Hz, 1H) , 7.81-7.79 (d, J = 8 Hz, 1H), 7.75-7.73 (d, 1H J = 8 Hz, 1H), 6.85-6.48 (m, 3H) , 6.14-6.07 (m, 1H), 5.67-5.59 (m, 1H), 5.34-5.18 (m, 1H), 4.06-3.43 (m, 4H), 2.40-2.28 (m, 2H).

Example 77. Getting ( E )-1-(3-(4-amino-3-((2-(azetidin-1-yl)-4,6-difluorobenzo[ d ]oxazol-5-yl)ethynyl)-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)azetidin-1-yl)-4-(dimethylamino)but-2-en-1-one

Step 1. Synthesis of 1-(azetidin-3-yl)-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidine-4-amine

Tert -butyl-3-(4-amino-3-iodo- 1H -pyrazolo[3,4- d ]pyrimidin-1-yl)azetidine-1-carboxylate (2000 mg, 4.81 mmol) was dissolved in dichloromethane ( 20 ml) and HCl/dioxane solution (5 ml) was added. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated to dryness to obtain 1-(azetidin-3-yl)-3-iodo- 1H- pyrazolo[3,4- d ]pyrimidine-4 -amine (1400 mg, yield: 82.64%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 317 [M + H] ⁺ .

Stage 2. Synthesis ( E )-1-(3-(4-amino-3-iodine-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)azetidin-1-yl)-4-(dimethylamino)but-2-en-1-one

1-(azetidin-3-yl)-3-iodo- 1H -pyrazolo[3,4- d ]pyrimidin-4-amine (700 mg, 1.99 mmol) was dissolved in N , N -dimethylformamide (5 ml) , after which (2 E )-4-(dimethylamino)but-2-enoic acid (394.59 mg, 2.38 mmol), 2-(7-azabenzotriazol-1-yl) -N , N , N ' was added , N' -tetramethyluronium hexafluorophosphate (1132.38 mg, 2.98 mmol) and N , N -diisopropylethylamine (769.79 mg, 5.96 mmol). The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was separated by reverse phase chromatography to give ( E )-1-(3-(4-amino-3-iodo- 1H -pyrazolo[3, 4- d ]pyrimidin-1-yl)azetidin-1-yl)-4-(dimethylamino)but-2-en-1-one (400 mg, yield: 47%). Electric field sputter ionization mass spectrometry (ESI-MS, m/z): 428 [M + H] ⁺ .

Stage 3. Synthesis ( E )-1-(3-(4-amino-3-((2-(azetidin-1-yl)-4,6-difluorobenzo[ d ]oxazol-5-yl)ethynyl)-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)azetidin-1-yl)-4-(dimethylamino)but-2-en-1-one

( E )-1-(3-(4-amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)azetidin-1-yl)-4-(dimethylamino)but-2 -en-1-one (100 mg, 0.23 mmol), 2-(azetidin-1-yl)-5-ethynyl-4,6-difluoro-1,3-benzoxazole (65.77 mg, 0.28 mmol), triethylamine (1 ml), copper iodide (4.46 mg, 0.02 mmol) and bis[5-(diphenylphosphinoalkyl)cyclopent-1,3-dien-1-yl]iron palladium dichloride (8.56 mg , 0.01 mmol) was added to DMF (5 ml). The reaction mixture was stirred at 60°C for 2 h under a nitrogen atmosphere and then separated as such by reverse phase column chromatography to give ( E )-1-(3-(4-amino-3-((2 -(azetidin-1-yl)-4,6-difluorobenzo[ d ]oxazol-5-yl)ethynyl)-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)azetidin-1-yl)- 4-(dimethylamino)but-2-en-1-one (30 mg, yield: 24%). Electric sputter ionization mass spectrometry (ESI-MS, m/z): 534 [M + H] ⁺ .

^1H -NMR (400 MHz, DMSO- d6 ): δ 8.51-7.86 (m, 2H), 7.55 (d, J = 8.4 Hz, 1H) _, 6.77-6, 28 (m, 2H), 6.11 (d, J = 15.4 Hz, 1H), 5.82-5.52 (m, 1H), 4.67 (t, J = 8.6 Hz, 1H ), 4.54 (dd, J = 9.3, 5.2 Hz, 1H), 4.38 (t, J = 9.3 Hz, 1H), 4.24 (dd, J = 10.6, 5.2 Hz, 1H), 4.18 (t, J = 7.6 Hz, 4H), 2.97 (d, J = 6.2 Hz, 2H), 2.40-2.34 (m, 2H), 2.08 (s, 6H).

The substance of Example 78 can be prepared by selecting appropriate starting materials in accordance with the method of synthesis (whole or partial) of the substance of Example 77.

Number
connections (example) Structural formula Chemical name [M+H] ⁺ 78 ( E )-1-(3-(4-amino-3-((2-cyclopropyl-4,6-difluorobenzo[ d ]thiazol-5-yl)ethynyl) -1H- pyrazolo[3,4- d ] pyrimidin-1-yl)azetidin-1-yl)-4-(dimethylamino)but-2-en-1-one 535

Data obtained by NMR on nuclei ¹ H, about the compounds obtained in the above examples:

Example number ¹ H-NMR 78 (400 MHz, DMSO- d6 ): δ 8.51-8.17 (m, 2H), 8.04 (dd, J = 8.8, _1.3 Hz, 1H), 6.89-6, 29 (m, 2H), 6.33-6.10 (m, 1H), 5.88-5.54 (m, 1H), 4.76 (t, J = 8.7 Hz, 1H), 4 .62 (dd, J = 9.2, 5.2 Hz, 1H), 4.46 (t, J = 9.4 Hz, 1H), 4.32 (dd, J = 10.6, 5.3 Hz, 1H), 3.15-3.08 (m, 2H), 2.65-2.54 (m, 1H), 2.21 (s, 6H), 1.36-1.15 (m, 4H).

Assessment during biological analysis

I. Analysis of cell proliferation in the case of Tel-FGFR2 wild type (WT) and various mutant forms of FGFR2 in Baf3 cells

By transfecting Baf cells, cell lines stably expressing the TEL-FGFR2 WT intracellular kinase domain fusion protein or intracellular domain fusion proteins containing the FGFR2 V564I, V564F, V564L, N549K, and K659M mutations were generated. On day 1, the cell suspension was seeded into a 96-well plate containing growth medium (DMEM containing 1% Glutamax, 10% FBS and 1% Pen/Strep) at 2000-4000 cells/90 µl per well, after which the mixture was incubated overnight at 37 ° C in the presence of 5% CO ₂ . On day 2, 10 μl of growth medium containing a 10-fold stock solution of the test substance was added to the cell culture (9 concentrations; serial dilution in steps of 3, starting from 1 μM; final concentration of DMSO - 0.3%). On day 3, after incubation at 37 ° C in the presence of 5% CO ₂ for 48 hours, 50 μl of CellTiter Glo (CTG) reagent was added to the wells of a 96-well plate with cells, after which the plate was incubated at room temperature for 10 min. Luminescence intensity was then measured in relative light units (RLU) using a microplate reader with a luminescence detection module. Luminescence values in RLU were normalized to the % of surviving cells, after which concentration-response curves were plotted using the Prism program to calculate IC ₅₀ (nM).

Table 1. Results of biological analysis Example number BaF3 IC ₅₀ (nM) W.T.
(FGFR2) V564F
(FGFR2) V564L
(FGFR2) V564I
(FGFR2) N549K
(FGFR2) K659M
(FGFR2) 1 ++++ ++++ ++++ +++++ ++++ ++++ 2 ++++ +++++ ++++ NI ++++ NI 3 ++++ ++++ ++++ NI ++++ NI 4 ++++ ++++ NI NI NI NI 5 ++++ ++++ NI NI NI NI 6 NI NI NI NI NI NI 7 ++++ ++++ +++ NI +++ NI 8 NI NI NI NI NI NI 9 NI NI NI NI NI NI 10 NI NI NI NI NI NI eleven NI NI NI NI NI NI 12 NI NI NI NI NI NI 13 NI NI NI NI NI NI 14 NI NI NI NI NI NI 15 NI NI NI NI NI NI 16 NI NI NI NI NI NI 17 NI NI NI NI NI NI 18 ++++ NI NI NI NI NI 19 NI NI NI NI NI NI 20 ++++ ++++ ++++ +++++ ++++ +++ 21 NI NI NI NI NI NI 22 NI NI NI NI NI NI 23 NI NI NI NI NI NI 24 NI NI NI NI NI NI 25 NI NI NI NI NI NI 26 NI NI NI NI NI NI 27 NI NI NI NI NI NI 28 NI NI NI NI NI NI 29 +++ ++++ NI NI NI NI thirty +++ ++++ NI NI NI NI 31 +++ ++++ NI NI NI NI 32 NI NI NI NI NI NI 33 +++ ++++ NI NI NI NI 34 ++++ ++++ NI NI NI NI 35 ++++ +++++ NI NI NI NI 36 +++++ +++++ NI +++++ NI ++++ 37 NI NI NI NI NI NI 38 ++++ ++++ NI NI NI NI 39 ++++ ++++ NI NI NI NI 40 NI NI NI NI NI NI 41 ++ +++ ++++ NI +++ NI 42 ++++ +++++ ++++ NI ++++ +++ 43 +++ ++++ NI NI NI NI 44 ++++ ++++ ++++ +++++ ++++ NI 45 +++ ++++ ++++ NI ++++ NI 46 NI NI NI NI NI NI 47 ++++ +++++ NI NI NI NI 48 ++++ ++++ ++++ +++++ ++++ NI 49 NI NI NI NI NI NI 50 ++++ ++++ NI NI NI NI 51 ++++ +++++ ++++ +++++ ++++ NI 52 ++++ ++++ +++ NI +++ NI 53 ++++ ++++ ++++ +++++ ++++ NI 54 +++ ++++ ++++ NI ++++ NI 55 +++ +++ +++ NI ++++ NI 56 NI NI NI NI NI NI 57 ++++ +++++ ++++ +++++ ++++ NI 58 NI NI NI NI NI NI 59 ++++ ++++ ++++ +++++ ++++ NI 60 +++ ++++ NI NI NI NI 61 NI NI NI NI NI NI 62 ++++ +++++ ++++ +++++ ++++ +++ 63 +++ ++++ NI NI NI NI 64 NI NI NI NI NI NI 65 +++++ +++++ NI NI NI NI 67 +++ ++++ NI NI NI NI 68 +++++ +++++ +++++ NI +++++ ++++ 69 ++++ +++++ ++++ NI ++++ +++ 70 +++ ++++ NI NI NI NI 71 ++++ ++++ +++ NI ++++ NI 72 +++ +++ NI NI NI NI 73 +++++ +++++ NI NI NI NI 74 ++++ +++++ ++++ +++++ ++++ +++ 75 ++++ ++++ NI +++++ NI ++++ 76 NI NI NI NI NI NI 77 ++++ +++++ ++++ NI ++++ +++ 78 ++++ +++++ ++++ NI ++++ +++ Notes 1. NI - not studied, that is, the object has not yet been discovered.
2. “+++++” indicates that IC ₅₀ ≤ 0.5 nM;
“++++” indicates that 0.5 nM < IC ₅₀ ≤ 5.0 nM;
“+++” indicates that 5.0 nM < IC ₅₀ ≤ 50.0 nM;
“++” indicates that 50.0 nM < IC ₅₀ ≤ 500.0 nM;
"+" indicates that the IC ₅₀ is >500.0 nM.

II. Cell proliferation analysis of Tel-FGFR3 wild type (WT) and FGFR3 V555M in BaF3 cells

By transfecting Baf cells, cell lines stably expressing the TEL-FGFR3 WT intracellular kinase domain fusion protein or intracellular domain fusion proteins containing the FGFR3 V555M or FGFR3 N540K mutation were generated, and the compounds of the examples of the present invention were used to determine their effect on the proliferation of BaF3 - cells. Tel-FGFR3 WT, FGFR3 V555M or FGFR3 N540K. The analysis methodology was as follows:

1) The cell suspension was seeded into a 96-well plate containing growth medium (DMEM containing 1% Glutamax, 10% FBS and 1% Pen/Strep) at 2000-4000 cells/90 µl per well, after which the mixture was incubated in overnight at 37 ° C in the presence of 5% CO ₂ .

2) 10 μl of growth medium containing a 10-fold stock solution of the test substance was added to the cell culture (9 concentrations; serial dilution in steps of 3, starting from 1 μM; final concentration of DMSO - 0.3%).

3) The mixture was incubated at 37 ° C in the presence of 5% _CO2 for 48 hours.

4) 50 μl of CellTiter Glo (CTG) reagent was added to the wells of a 96-well plate with cells and the plate was incubated at room temperature for 10 minutes.

5) The luminescence intensity was measured in relative light units (RLU) using a microplate reader with a luminescence detection module. Luminescence values in RLU were normalized to the % of surviving cells, after which concentration-response curves were plotted using the Prism program to calculate IC ₅₀ (nM). The results of the analysis are shown in the table below.

Table 2. Results of biological analysis Example number BaF3 IC ₅₀ (nM) WT (FGFR3) V555M (FGFR3) N540K (FGFR3) 1 ++++ ++++ ++++ 2 ++++ +++ NI 3 ++++ +++ NI 4 NI NI NI 5 NI NI NI 6 NI NI NI 7 +++ +++ NI 8 NI NI NI 9 NI NI NI 10 NI NI NI eleven NI NI NI 12 NI NI NI 13 NI NI NI 14 NI NI NI 15 NI NI NI 16 NI NI NI 17 NI NI NI 18 NI NI NI 19 NI NI NI 20 ++++ ++++ ++++ 21 NI NI NI 22 NI NI NI 23 NI NI NI 24 NI NI NI 25 NI NI NI 26 NI NI NI 27 NI NI NI 28 NI NI NI 29 +++ +++ NI thirty +++ +++ NI 31 +++ +++ NI 32 NI NI NI 33 +++ ++ NI 34 +++ ++++ NI 35 ++++ ++++ NI 36 +++++ ++++ NI 37 NI NI NI 38 ++++ +++ NI 39 NI NI NI 40 NI NI NI 41 ++ ++ NI 42 ++++ +++ NI 43 NI NI NI 44 +++ +++ NI 45 +++ +++ NI 46 NI NI NI 47 ++++ +++ NI 48 ++++ ++++ NI 49 NI NI NI 50 +++ +++ NI 51 ++++ ++++ NI 52 ++++ +++ NI 53 +++ +++ NI 54 +++ +++ NI 55 +++ +++ NI 56 NI NI NI 57 ++++ +++ NI 58 NI NI NI 59 ++++ ++++ NI 60 NI NI NI 61 NI NI NI 62 ++++ ++++ ++++ 63 +++ +++ NI 64 NI NI NI 65 ++++ ++++ NI 67 ++++ ++++ +++ 68 +++++ +++++ ++++ 69 ++++ +++++ NI 70 NI NI NI 71 ++++ +++ NI 72 +++ ++ NI 73 ++++ ++++ NI 74 ++++ +++++ ++++ 75 +++++ ++++ NI 76 ++ ++ NI 77 ++++ ++++ +++ 78 +++++ +++++ +++ Notes 1. NI - not studied, that is, the object has not yet been discovered.
2. “+++++” indicates that IC ₅₀ ≤ 0.5 nM;
“++++” indicates that 0.5 nM < IC ₅₀ ≤ 5.0 nM;
“+++” indicates that 5.0 nM < IC ₅₀ ≤ 50.0 nM;
“++” indicates that 50.0 nM < IC ₅₀ ≤ 500.0 nM;
"+" indicates that the IC ₅₀ is >500.0 nM.

From the data on the biological activity of the compounds indicated in the specific examples, it is clear that many of the compounds of the present invention have a pronounced inhibitory effect on wild-type FGFR and mutant forms of FGFR at the cellular level, and the inhibitory effect on the mutant forms is not weakened.

All documents mentioned in the present invention are incorporated by reference, and each document is cited individually by reference. In addition, it should be understood that various modifications or changes may be made by those skilled in the art upon reading the foregoing information regarding the present invention, and these equivalent forms are also intended to be within the scope of the claims.

Claims (94)

1. A compound of formula (I), its stereoisomer or pharmaceutically acceptable salt: Where represents a double bond or single bond; X represents O or S; Y is CR ₄ or N; Z ₁ and Z ₄ are each independently N or CR ₇ ; Z ₂ and Z ₃ are each independently N or C; ring A is a 4-6 membered nitrogen-containing heterocyclyl, the nitrogen atom in which is bonded to the carbonyl; R ₁ is selected from the group consisting of hydrogen, C _1-10 alkyl, C ₃ - ₁₂ cycloalkyl and C _0-8 alkyl-NR ₁₁ R ₁₂ , the above groups being optionally substituted by one or more additional substituents selected from halogen and _{1- 10} alkyl; R ₂ , R ₃ and R ₄ are each independently selected from hydrogen, halogen, -C _0-8 alkyl-O-R ₉ ; R ₅ and R ₇ represent hydrogen; R ₆ is selected C _2-10 alkenyl, optionally substituted with the substituent -C _0-8 alkyl-NR ₁₁ R ₁₂ ; each R ₉ independently represents C _1-10 alkyl; R ₁₁ and R ₁₂ are each independently selected from the group consisting of hydrogen, C _1-10 alkyl and C _3-12 cycloalkyl; or R ₁₁ and R ₁₂ , together with the nitrogen atom directly attached to them, form a 4-10 membered heterocyclyl; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; unless specifically defined, a "heterocyclyl" heteroatom in the substituents mentioned above represents a single nitrogen atom. 2. A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt according to claim 1, wherein R ₂ , R ₃ and R ₄ are each independently selected from hydrogen, halogen and -C _0-4 alkyl-NR ₁₁ R ₁₂ , where R ₉ corresponds to the definition in paragraph 1. 3. A compound of formula (I), its stereoisomer or pharmaceutically acceptable salt according to claim 1, where R ₆ is selected from C _2-4 alkynyl, optionally substituted with a -C _0-4 alkyl-NR ₁₁ R ₁₂ substituent, where R ₁₁ and R ₁₂ correspond to the definitions in paragraph 1. 4. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt according to claim 1, wherein R ₁ is selected from the group consisting of hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl and -C _0-4 alkyl-NR ₁₁ R ₁₂ , wherein the above groups are optionally substituted with one or more additional substituents selected from halogen and C _1-4 alkyl, where R ₁₁ and R ₁₂ correspond to the definitions in paragraph 1. 5. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt according to claim 1, wherein the compound of formula (I) is a compound whose structure is described by formula (II) Where represents a double bond or single bond; X represents O or S; Y is CR ₄ or N; Z ₁ and Z ₄ are each independently N or CR ₇ ; Z ₂ and Z ₃ are each independently N or C; ring A is a 6-membered nitrogen-containing heterocyclyl, the nitrogen atom in which is bonded to the carbonyl; R ₁ is selected from the group consisting of hydrogen, C _1-4 alkyl and -NR ₁₁ R ₁₂ , the above groups being optionally substituted by one or more additional substituents selected from halogen and C _1-4 alkyl; each R ₂ is independently selected from hydrogen and halogen; each R ₃ is independently selected from hydrogen and -CH ₂ -OR ₉ ; R ₄ represents hydrogen; R ₆ is C _2-4 alkenyl, optionally substituted with one or more additional substituents selected from -CH ₂ -NR ₁₁ R ₁₂ ; each R ₇ represents hydrogen, where R ₉ , R ₁₁ , R ₁₂ , type correspond to the definitions in paragraph 1. 6. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt according to claim 1, wherein the compound of formula (I) is a compound whose structure is described by formula (IIIa) or formula (IIIb): where each X is independently O or S; each Y is independently CH or N; in the compound of formula (IIIb) Z ₁ represents N or CR ₇ ; each Z ₄ is independently N or CR ₇ ; each ring A independently represents a 4-6 membered nitrogen-containing heterocyclyl, the nitrogen atom in which is bonded to the carbonyl; each R ₁ is independently selected from the group consisting of hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl and -NR ₁₁ R ₁₂ , the above groups being optionally substituted by one or more additional substituents selected from halogen and C _1-4 alkyl; R _2a and R _2b are each independently selected from hydrogen and halogen; each R ₃ is independently selected from hydrogen H-CH ₂ -OR ₉ ; each R ₆ is independently vinyl, optionally substituted with one or more additional substituents selected from -CH ₂ -NR ₁₁ R ₁₂ ; each R ₇ represents hydrogen, where R ₉ , R ₁₁ , R ₁₂ and n are as defined in paragraph 1. 7. A compound of formula (I), its stereoisomer or pharmaceutically acceptable salt according to claim 6, where ring A together with -(R ₃ ) _n form the following structures: R ₃ is selected from the group consisting of hydrogen and -CH ₂ -OR ₉ , where R ₉ corresponds to the definition in paragraph 1. 8. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt according to claim 1, wherein the compound of formula (I) is a compound whose structure is described by formula (IVa ₁ ) or formula (IVa ₂ ): where each X is independently O or S; each Y is independently CH or N; ring A, together with -R ₃ , form the following structures: R ₃ is selected from the group consisting of hydrogen and -CH ₂ -OR ₉ ; each R ₁ is independently selected from the group consisting of hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl and -NR ₁₁ R ₁₂ , the above groups being optionally substituted with one or more additional substituents selected from fluorine, chlorine and C _1-4 alkyl; each of R _2a and R _2b is independently selected from the group consisting of hydrogen, fluorine and chlorine; each R ₆ is independently vinyl, optionally substituted with one or more additional substituents selected from -CH ₂ -NR ₁₁ R ₁₂ , where R ₉ , R ₁₁ and R ₁₂ correspond to the definitions in paragraph 1. 9. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt according to claim 1, wherein the compound of formula (I) is a compound whose structure is described by formula (IVb ₁ ) or formula (IVb ₂ ): where each X is independently O or S; each Y is independently CH or N; ring A, together with -R ₃ , form the following structures: R ₃ is selected from hydrogen and -CH ₂ -OR ₉ ; each R ₁ is independently selected from the group consisting of hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl and -NR ₁₁ R ₁₂ , the above groups being optionally substituted by one or more additional substituents selected from fluorine, chlorine and C _1-4 alkyl; R _2a and R _2b are each independently selected from hydrogen, fluorine and chlorine; each R ₆ is independently vinyl, optionally substituted with one or more additional substituents selected from -CH ₂ -NR ₁₁ R ₁₂ , where R ₉ , R ₁₁ and R ₁₂ correspond to the definitions in paragraph 1. 10. The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt according to claim 1, where each R ₉ is independently selected C _1-4 alkyl; R ₁₁ and R ₁₂ are each independently selected from hydrogen, C _1-4 alkyl and C _3-6 cycloalkyl; or R ₁₁ and R ₁₂ , together with the nitrogen atom directly attached to them, form a 4-6 membered heterocyclyl. 11. A compound of formula (I), its stereoisomer or pharmaceutically acceptable salt according to any one of paragraphs. 1-10, selected from the following connections: 12. A method for producing a compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt according to any one of paragraphs. 1-11, including the following stage: where ring A, X, Y, Z ₁ , Z ₂ , Z ₃ , Z ₄ , R ₁ , R ₂ , R ₃ , R ₅ , R ₆ , m and n correspond to the definitions in paragraph 1. 13. A pharmaceutical composition for the prevention or treatment of a disease or condition mediated by FGFR kinase, comprising a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt according to any one of claims. 1-11, as well as a pharmaceutically acceptable carrier. 14. Use of a compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt according to any one of paragraphs. 1-11 to obtain a medicinal product for the treatment of a patient with a tumor resistant to an FGFR inhibitor. 15. Use according to claim 14, where the patient with the tumor has mutations in FGFR V561, V565, N550, N540, V555, E566, K660 and/or V550. 16. Use according to claim 15, where the patient with the tumor has the FGFR2 mutations V565F, V565I, V565L, V565M, N550K, N550H, E566A, E566G, K660M and/or K660Q. 17. Use according to claim 15, where the patient with the tumor has the FGFR3 V555M, V555L and/or N540K mutations. 18. Use of a compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt according to any one of paragraphs. 1-11 for the prevention or treatment of a disease or condition mediated by FGFR kinase. 19. Use of a compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt according to any one of paragraphs. 1-11 for the prevention or treatment of a tumor or malignancy mediated by FGFR kinase. 20. Use according to claim 19, wherein the tumor or malignancy is bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, stomach cancer, head and neck cancer, kidney carcinoma, liver cancer, lung cancer, ovarian cancer, prostate cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, thyroid cancer, skin cancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, acute myelocytic leukemia, Hodgkin lymphoma or non-Hodgkin's lymphoma, Waldenström's macroglobulinemia, hairy cell lymphoma, cellular lymphoma, Burkitt's lymphoma, glioblastoma, melanoma, or rhabdomyosarcoma. 21. Use of a compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt according to any one of paragraphs. 1-11 for the preparation of a medicament for the treatment of a disease mediated by FGFR kinase selected from myeloproliferative disease, bone or cartilage cell disease and hypophosphatemia. 22. Use according to claim 21, wherein the myeloproliferative disease is erythrocytosis, primary thrombocytosis or primary myelofibrosis; a bone or cartilage cell disease such as dysplasia, achondroplasia, dwarfism, thanatophore dysplasia (TD), Apert syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Beer-Stevenson cutis gyrus syndrome, Pfeiffer syndrome or cranial muscular atrophy syndrome; hypophosphatemia is X-linked hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, or ovarian osteomalacia. 23. Use of a compound of formula (I), its stereoisomer or pharmaceutically acceptable salt according to any one of paragraphs. 1-11 or a pharmaceutical composition according to claim 13 for the treatment of diseases associated with aberrant expression and mutation of the FGFR2 or FGFR3 receptor or aberrant expression and activity of the corresponding ligand as a selective inhibitor of FGFR2 and/or FGFR3.