CN105732636A - Hetero-aromatic compounds and applications thereof in pharmacy - Google Patents

Abstract

The invention discloses heteroaryl compounds and their application in medicine; specifically, the invention provides a class of heteroaryl compounds or their stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides Compounds, hydrates, solvates, metabolites and pharmaceutically acceptable salts or prodrugs for the treatment of autoimmune or proliferative diseases. The present invention also discloses a pharmaceutical composition comprising the compound of the present invention and the use of the compound of the present invention or its pharmaceutical composition in the preparation of medicines for treating autoimmune diseases or proliferative diseases.

Description

Heteroaryl compounds and their application in medicine

field of invention

The invention belongs to the technical field of medicine, and specifically relates to a class of heteroaryl compounds with protein kinase inhibitory activity and a pharmaceutical composition comprising the compound of the invention. The present invention also relates to the use of the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention in medicine.

Background of the invention

Janus kinases (JAKs) belong to the tyrosine kinase family consisting of JAK1, JAK2, JAK3 and TYK2. JAKs play an important role in cytokine signaling. JAK1, JAK2 and TYK2 can repress the expression of multiple genes, whereas JAK3 only functions in granulocytes. Cytokine receptors typically function as heterodimers, and thus usually not one JAK kinase interacts with cytokine receptors.

Each JAK associates preferentially with the intracytoplasmic portion of a discrete cytokine receptor (Annu. Rev. Immunol. 1998, 16, pp. 293-322). JAKs are activated upon ligand binding and initiate signaling by phosphorylating cytokine receptors, which themselves lack intrinsic kinase activity. This phosphorylation creates docking sites on the receptor for other molecules called STAT proteins (Signal Transducers and Activators of Transcription), and phosphorylated JAKs bind various STAT proteins. STAT proteins, or STATs, are DNA-binding proteins activated by phosphorylation of tyrosine residues, and function as both signaling molecules and transcription factors, and ultimately bind to promoters present in cytokine-responsive groups On the specific DNA sequence (J. Allergy Clin. Immunol., Leonard, et al, 2000, 105:877-888).

Genetic biology studies have shown that JAK1 plays a role by interacting with cytokine receptors such as IFNalpha, IFNgamma, IL-2, and IL-6, and JAK1 knockout mice died due to the loss of LIF receptor signaling. Observing the characteristic tissues of JAK1 knockout mice, it was found that JAK1 plays an important role in cellular pathways such as IFN, IL-10, IL-2/IL-4 and IL-6.

Genetic biology studies have shown a link between JAK2 and the single chain, IL-3 and interferon gamma cytokine receptor families. In contrast, JAK2 knockout mice died of anemia. Kinase-mediated JAK2 variants are associated with myeloproliferative disorders in humans, including polycythemia vera, idiopathic thrombocytosis, chronic idiopathic myelofibrosis, myeloid transformation with myelofibrosis, chronic idiopathic myeloid leukemia, chronic myeloid monocytic leukemia etc.

JAK3 specifically acts on the γ cytokine receptor chain, which exists in IL-2, IL-4, IL-7, IL-9, IL-15, IL-21 and other cytokine receptors. JAK3 plays an important role in the process of lymphocyte growth, proliferation and mutation, and abnormality can lead to severe immune deficiency. Severely reduced levels of JAK3 protein or a genetic defect in its shared gamma chain have been detected in populations with XSCID, suggesting that the immunosuppressive effect is due to a blockage of signaling through the JAK3 pathway. Animal studies have shown that not only is JAK3 critical for the maturation of B and T lymphocytes, but that JAK3 is also constitutively required for T cell function. Based on its role in regulating lymphocytes, JAK3 and JAK3-mediated pathways are used to regulate immunosuppressive indications. JAK3 has been implicated in the mediation of many aberrant immune responses such as allergy, asthma, autoimmune diseases such as suppression of transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis as well as solid and hematological malignancies such as Leukemia, Lymphoma.

JAK3 inhibitors are useful therapeutic agents as immunosuppressants for organ transplantation, xenotransplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type 1 diabetes and complications from diabetes, cancer , asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other conditions where immunosuppression is appropriate.

Non-hematopoietic expression of JAK3 has also been reported, although the functional significance of this is unclear (J. Immunol., 2002, 168:2475-2482). Since bone marrow transplantation for SCID is curative (Blood, 2004, 103:2009-2018), it seems unlikely that JAK3 has an essential non-redundant function in other tissues or organs. Thus, in contrast to other targets of immunosuppressive drugs, the restricted distribution of JAK3 is attractive. Active agents acting on molecular targets with expression restricted to the immune system are likely to result in an optimal efficacy:toxicity ratio. Thus, in theory, targeting JAK3 would provide immunosuppression where it is needed (ie on cells actively participating in the immune response), without causing any effects outside of these cell populations. Although defective immune responses have been described in various STAT ^-/- strains (J. Investig. Med., 1996, 44:304-311; Curr. Opin. Cell Biol., 1997, 9: 233-239), but The ubiquitous distribution of STATs and the fact that these molecules lack enzymatic activity that can be targeted with small molecule inhibitors have contributed to their non-selectivity as key targets for immunosuppression.

TYK2 acts on type I interferon, IL-6, IL-10, IL-12, IL-23 and other cytokine receptor complexes. Consistent with this, primary cells derived from TYK2-deficient humans were impaired in the signaling of type I interferons, IL-6, IL-10, IL-12, and IL-23.

Accordingly, there is a need for compounds that inhibit the protein kinase JAK, thereby providing treatment for diseases such as autoimmune diseases, inflammatory diseases, and cancer.

Contents of the invention

The compounds of the present invention have inhibitory effect on protein kinase activity. More satisfactorily, the compounds of the present invention have multiple inhibitory functions, and can inhibit JAK1, JAK2, JAK3, BTK, EGFR or EGFRT790M. In particular, the compounds involved in the present invention and their pharmaceutically acceptable compositions can be effectively used as JAK1, JAK2, JAK3, BTK, EGFR or EGFRT790M inhibitors.

In one aspect, the present invention relates to a compound, which is a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, racemate, nitrogen Oxides, hydrates, solvates, metabolites and pharmaceutically acceptable salts or prodrugs:

in:

R is the following substructural formula:

Wherein, each of R ^1a , R ^1b , R ^1c and R ^1d is independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, C _1-6 alkyl, C _1-6 alkyl substituted by hydroxyl, C _2-6 Alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkylamino C _1-6 alkyl, C _1-6 alkane Sulfuryl, C _1-6 alkylsulfonyl, C _6-10 aryl C _1-6 alkyl or C _1-9 heteroaryl C _1-6 alkyl;

each of R and ^R is independently ^hydrogen , deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, carboxyl, or nitro;

Each R ^a and R ^b are independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino or C _1-6 alkyl; or R ^a and R ^b on the same carbon atom together Formation of oxo (=O);

m is 0, 1, 2, 3, 4, 5 or 6;

Each R ⁴ and R ⁵ is independently hydrogen, deuterium, C _1-6 alkyl, C _1-6 alkyl substituted by cyano, C _1-6 alkyl-C(=O)-, C cyano substituted _1-6 alkyl-C(=O)-, C _1-3 alkyl-OC(=O)-, C _5-6 alkyl-OC(=O)-, cyano-substituted C _1-6 alkane -OC(=O)-, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, C _1-6 alkylamino substituted C _3-8 cycloalkenyl, C _1-6 alkyl-NH- C(=O)- or cyano-substituted C _1-6 alkyl-NH-C(=O)-; or R ⁴ , R ⁵ , and the N atoms connected to them together form 3-12 atoms ring, with the proviso that said ring of 3-12 atoms is not pyrazole optionally substituted with methyl or triazole optionally substituted with methyl;

Each R ⁶ and R ⁷ are independently hydrogen, deuterium, C _1-8 alkyl, C _1-6 alkyl substituted by cyano, C _3-8 cycloalkyl, C _2-10 heterocyclyl, C _{6- 10} aryl, C _1-9 heteroaryl, C _3-8 cycloalkyl C _1-6 alkyl, C _2-10 heterocyclyl C _1-6 alkyl, C _2-10 heterocyclyl-C( =O)-C _1-6 alkyl-, C _6-10 aryl C _1-6 alkyl or C _1-9 heteroaryl C _1-6 alkyl; or R ⁶ , R ⁷ , and are connected to them The N atoms together form a ring composed of 3-12 atoms;

Each R ⁸ is independently hydrogen, C _1-6 alkyl, C _1-6 alkyl substituted by cyano, halogenated C _1-6 alkyl, C _3-8 cycloalkyl or C _2-10 heterocyclyl ;

Each of R ⁹ , R ¹⁰ and R ¹¹ is independently hydrogen, deuterium, C _1-6 alkyl or C _1-6 alkyl substituted by cyano;

n is 1, 2, 3, 4, 5 or 6;

R ¹² is hydrogen, deuterium, C _1-6 alkyl, C _1-6 alkyl substituted by cyano, C _3-8 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, C _{1 -9} heteroaryl, C _3-8 cycloalkyl C _1-6 alkyl, C _2-10 heterocyclyl C _1-6 alkyl, C _6-10 aryl C _1-6 alkyl or C _{1- 9} heteroaryl C _1-6 alkyl;

each X is independently _-CH2- , -NH-, -O-, -S-, -S(=O)- or -S(=O) _2- ;

each Y is independently -CH ₂ -, -NH- or -N(CH ₃ )-;

each r, s or u is independently 0, 1, 2 or 3;

each t, p, q or w is independently 1, 2 or 3;

Each R ¹³ is independently hydrogen, deuterium, C _1-6 alkyl substituted by cyano, or C _1-6 alkyl substituted by cyano-C(=O)-;

Each substructural formula (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix), (x), (xi), (xii) , (xiii), (xiv) and (xv) are independently optionally substituted by one or more R ¹⁴ ;

Each R ¹⁴ is independently hydrogen, deuterium, oxo (=O), cyano, C _1-6 alkyl substituted by cyano, R ¹⁵ -C(=O)-, R ¹⁶ -S(=O) ₂ -, C _1-6 alkylamino, C _1-6 alkylamino substituted by cyano, C _2-6 alkenyl, C _2-6 alkynyl, R ¹⁸ -C(=O)-N(R ¹⁷ )-C _1-6 alkyl-, R ¹⁸ -C(=O)-N(R ¹⁷ )-C _1-8 alkyl-C(=O)-, R ¹⁸ -S(=O) ₂ -N(R ¹⁷ )-C _1-6 alkyl-, R ¹⁸ -S(=O) ₂ -N(R ¹⁷ )-C _1-8 alkyl-C(=O)-, R ²⁰ R ¹⁹ NC(=O)- C _1-6 alkyl-, R ²⁰ R ¹⁹ NS(=O) ₂ -C _1-6 alkyl-, R ²⁰ R ¹⁹ NS(=O) ₂ -C _1-8 alkyl-C(=O) -, C _6-10 aryl C _1-6 alkyl, C _2-10 heterocyclyl C _1-6 alkyl, C _6-10 aryl-C(=O)-C _1-6 alkyl-, C _6-10 aryl-S(=O) ₂ -C _1-6 alkyl-, C _1-9 heteroaryl-C(=O)-C _1-6 alkyl-, C _1-9 heteroaryl -S(=O) ₂ -C _1-6 alkyl-, C _2-10 heterocyclyl-C(=O)-C _1-6 alkyl- or C _2-10 heterocyclyl-S(= O) ₂ -C _1-6 alkyl-;

Each of R ¹⁵ , R ¹⁶ and R ¹⁸ is independently C _1-8 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-8 alkyl substituted by cyano, halogenated C _1-6 Alkyl, C _1-6 alkyl substituted by hydroxy, C _1-6 alkyl amino, C _1-8 alkoxy, C _1-6 alkoxy substituted by cyano, C _6-10 aryl, C _{6 -10} aryl C _1-6 alkyl, C _1-9 heteroaryl, C _1-9 heteroaryl C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl C _{1 -6} alkyl, C _2-10 heterocyclyl or C _2-10 heterocyclyl C _1-6 alkyl;

Each of R ¹⁷ , R ¹⁹ and R ²⁰ is independently hydrogen, deuterium, C _1-6 alkyl, C _1-6 alkyl substituted by cyano, halogenated C _1-6 alkyl, C _3-8 cycloalkyl , C _2-10 heterocyclyl, C _6-10 aryl, C _1-9 heteroaryl, C _3-8 cycloalkyl C _1-6 alkyl, C _2-10 heterocyclyl C _1-6 alkane group, C _6-10 aryl C _1-6 alkyl or C _1-9 heteroaryl C _1-6 alkyl; or R ¹⁹ , R ²⁰ , together with the N atoms connected to them simultaneously form 3-12 A ring of atoms;

The rings each of which are composed of 3-12 atoms are independently the following substructural formulas:

each v, y, f and g is independently 0, 1, 2 or 3;

each K is independently -NH-, -O-, -S-, -S(=O)- or -S(=O) ₂ -;

L is -CH ₂ -, -NH-, -N(CH ₃ )- or -N(CH ₂ CH ₃ )-;

each J is independently _-CH2- , -NH-, -O-, -S-, -S(=O)-, or -S(=O) _2- ; and

Wherein each hydroxyl, carboxyl, C _1-6 alkyl, C _1-8 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-8 alkoxy C _1-6 alkylamino, C _1-6 alkylthio, C _1-6 alkylsulfonyl, C _1-6 alkyl substituted by hydroxy, C _1-6 alkyl substituted by cyano, cyano substituted C _1-8 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, amino C _1-6 alkyl, C _1-6 alkylamino C _1-6 alkane C _1-6 alkoxy group substituted by cyano, C _1-6 alkylamino substituted by cyano, C _1-6 alkyl-C(=O)-, C _1-6 alkyl substituted by cyano- C(=O)-, C _1-3 alkyl-OC(=O)-, C _5-6 alkyl-OC(=O)-, cyano-substituted C _1-6 alkyl-OC(=O )-, C _1-6 alkyl-NH-C(=O)-, C _1-6 alkyl-NH-C(=O)-substituted by cyano, a ring consisting of 3-12 atoms, C _{3 -8} cycloalkyl, C _3-8 cycloalkenyl, C _1-6 alkylamino substituted C _3-8 cycloalkenyl, C _2-10 heterocyclyl, C _6-10 aryl, C _1-9 hetero Aryl, C _3-8 cycloalkyl C _1-6 alkyl, C _2-10 heterocyclyl C _1-6 alkyl, C _2-10 heterocyclyl-C(=O)-C _1-6 alkane radical-, C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl, R ¹⁵ -C(=O)-, R ¹⁶ -S(=O) ₂ - , R ¹⁸ -C(=O)-N(R ¹⁷ )-C _1-6 alkyl-, R ¹⁸ -C(=O)-N(R ¹⁷ )-C _1-8 alkyl-C(=O )-, R ¹⁸ -S(=O) ₂ -N(R ¹⁷ )-C _1-6 alkyl-, R ¹⁸ -S(=O) ₂ -N(R ¹⁷ )-C _1-8 alkyl- C(=O)-, R ²⁰ R ¹⁹ NC(=O)-C _1-6 alkyl-, R ²⁰ R ¹⁹ NS(=O) ₂ -C _1-6 alkyl-, R ²⁰ R ¹⁹ NS( =O) ₂ -C _1-8 alkyl-C(=O)-, C _6-10 aryl-C(=O)-C _1-6 alkyl-, C _6-10 aryl-S(= O) ₂ -C _1-6 alkyl-, C _1-9 heteroaryl-C(=O)-C _1-6 alkyl-, C _1-9 heteroaryl-S(=O) ₂ -C _1-6 Alkyl-, C _2-10 Heterocyclyl-C(=O)-C _1-6 Alkyl- and C _2-10 Heterocyclyl-S(=O) ₂ -C _1-6 Alkyl - independently optionally replaced by one or more selected from deuterium, fluorine, chlorine, bromine, iodine, cyano, amino, nitro, carboxyl, oxo (=O), C _1-6 alkyl, halogenated C _{1 -6} alkyl, amino C _1-6 alkyl, cyano substituted C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkylamino substituted by cyano, C _1-6 alkoxy, C _1-6 alkoxy substituted by cyano, NH ₂ -S(=O) ₂ - or NH ₂ -C(=O)-substituent.

In some embodiments, R is the following substructural formula:

Wherein each of m, n, R ^1a , R ^1b , R ^1c , R ^1d , R ^a , R ^b , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and R ¹⁴ have the meanings described in the present invention.

Some of the embodiments are that the present invention relates to a compound, which is a compound represented by formula (Ia) or a stereoisomer, geometric isomer, tautomer, racemic bodies, nitrogen oxides, hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs:

Wherein each of m, R ^1a , R ^a , R ^b , R ² , R ³ , R ⁴ and R ⁵ has the meanings described in the present invention.

Some of the embodiments are that the present invention relates to a compound, which is a compound represented by formula (Ib) or a stereoisomer, geometric isomer, tautomer, racemic bodies, nitrogen oxides, hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs:

Wherein each of R ^1b , R ² , R ³ , R ⁶ and R ⁷ has the meanings described in the present invention.

In some embodiments, R ^1a is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, C _1-3 alkyl, C _1-3 alkyl substituted with hydroxy, C _2-4 alkenyl, C _2-4 alkyne C _1-3 alkoxy, C _1-3 alkoxy C _1-3 alkyl, C _1-3 alkylamino C _1-3 alkyl, C _1-3 alkylthio or C _1-3 alkane Sulfonyl.

In some of these embodiments, R is hydrogen, ^deuterium , fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl, hydroxy-substituted propyl, vinyl , propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl Base, ethoxyethyl, methylaminomethyl, dimethylaminomethyl, methylaminoethyl, dimethylaminoethyl, ethylaminomethyl, ethylaminoethyl, methylthio, ethylthio, methylsulfonyl Acyl or ethylsulfonyl.

In some embodiments, R ^1b is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, C _1-3 alkyl, C _1-3 alkyl substituted with hydroxy, C _2-4 alkenyl, C _2-4 alkyne C _1-3 alkoxy, C _1-3 alkoxy C _1-4 alkyl, C _1-3 alkylamino C _1-3 alkyl, C _1-3 alkylthio, C _1-3 alkane Sulfonyl, C _6-10 aryl C _1-3 alkyl or C _1-5 heteroaryl C _1-3 alkyl.

In some of these embodiments, R is hydrogen, ^deuterium , fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl, hydroxy-substituted propyl, vinyl , propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl Base, ethoxyethyl, methylaminomethyl, dimethylaminomethyl, methylaminoethyl, dimethylaminoethyl, ethylaminomethyl, ethylaminoethyl, methylthio, ethylthio, methylsulfonyl Acyl, ethanesulfonyl, benzyl, phenethyl, triazolylmethyl, triazolylethyl, imidazolylmethyl, imidazolylethyl, pyrazolylmethyl or pyrazolylethyl.

In some of these embodiments, each R and ^R is independently ^hydrogen , deuterium, fluoro, chloro, bromo, iodo, cyano, hydroxy, carboxy, or nitro.

In some embodiments, each R is independently hydrogen, ^deuterium , fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino or C _1-3 alkyl.

In some embodiments, each R ^b is independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, or C _1-3 alkyl.

In some of these embodiments, ^Ra and ^Rb on the same carbon atom are taken together to form oxo (=0).

In some of these embodiments, m is 0, 1, 2, 3, 4, 5 or 6.

^In some of these embodiments, R is hydrogen, deuterium, C _1-3 alkyl, cyano substituted C _1-3 alkyl, C _1-3 alkyl-C(=O)-, cyano substituted C _1-3 alkyl-C(=O)-, C _1-3 alkyl-OC(=O)-, cyano-substituted C _1-3 alkyl-OC(=O)-, C _3-6 ring Alkyl, C _3-6 cycloalkenyl, C _1-3 alkylamino substituted C _3-6 cycloalkenyl, C _1-3 alkyl-NH-C(=O)- or cyano substituted C _{1- 3} Alkyl-NH-C(=O)-.

^In some embodiments, R is hydrogen, deuterium, methyl, ethyl, propyl, cyano-substituted methyl, cyano-substituted ethyl, cyano-substituted propyl, C _1-3 alkyl- C(=O)-, cyano-substituted methyl-C(=O)-, cyano-substituted ethyl-C(=O)-, cyano-substituted propyl-C(=O)-, C _1-3 Alkyl-OC(=O)-, cyano-substituted methyl-OC(=O)-, cyano-substituted ethyl-OC(=O)-, cyano-substituted propyl-OC( =O)-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, C _1-3 alkyl-NH- C(=O)- or C _1-3 alkyl-NH-C(=O)- substituted by cyano.

^In some of these embodiments, R is hydrogen, deuterium, C _1-3 alkyl, C _1-3 alkyl substituted by cyano, C _1-3 alkyl-C(=O)-, C cyano substituted _1-3 alkyl-C(=O)-, C _1-3 alkyl-OC(=O)-, cyano-substituted C _1-3 alkyl-OC(=O)-, C _3-6 ring Alkyl, C _3-6 cycloalkenyl, C _1-3 alkylamino substituted C _3-6 cycloalkenyl, C _1-3 alkyl-NH-C(=O)- or cyano substituted C _{1- 3} Alkyl-NH-C(=O)-.

^In some embodiments, R is hydrogen, deuterium, methyl, ethyl, propyl, cyano-substituted methyl, cyano-substituted ethyl, cyano-substituted propyl, C _1-3 alkyl- C(=O)-, cyano-substituted methyl-C(=O)-, cyano-substituted ethyl-C(=O)-, cyano-substituted propyl-C(=O)-, C _1-3 Alkyl-OC(=O)-, cyano-substituted methyl-OC(=O)-, cyano-substituted ethyl-OC(=O)-, cyano-substituted propyl-OC( =O)-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, C _1-3 alkyl-NH- C(=O)- or C _1-3 alkyl-NH-C(=O)- substituted by cyano.

Some of these embodiments are, R ⁴ is the following substructural formula:

In some embodiments, R is the following substructural ^formula :

In some embodiments, R ⁴ , R ⁵ , and the N atoms connected to them together form the following substructural formula:

Some of these embodiments are, R ⁶ is hydrogen, deuterium, C _1-6 alkyl, C _1-4 alkyl substituted by cyano, C _3-6 cycloalkyl, C _2-6 heterocyclyl, C _{6- 10} aryl, C _1-5 heteroaryl, C _3-6 cycloalkyl C _1-3 alkyl, C _2-6 heterocyclyl C _1-3 alkyl, C _2-6 heterocyclyl-C( =O)-C _1-4 alkyl-, C _6-10 aryl C _1-3 alkyl or C _1-5 heteroaryl C _1-3 alkyl.

^In some of these embodiments, R is hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyano-substituted methyl, cyano-substituted ethyl , cyano-substituted propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, cyanomethyl-substituted nitrogen Heterocyclobutyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxothiomorpholinyl, Homopiperidinyl, homopiperazinyl, homomorpholinyl, phenyl, cyanomethyl-substituted phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, cyclopropylmethyl, Cyclopropyl ethyl, cyclobutyl methyl, cyclobutyl ethyl, cyclopentyl methyl, cyclopentyl ethyl, cyclohexyl methyl, cyclohexyl ethyl, C _2-6 heterocyclyl C _1-3 alkane Base, azetidinyl-C(=O)-C _1-3 alkyl-, cyano-substituted azetidinyl-C(=O)-C _1-3 alkyl-, pyrrolidinyl- C(=O)-C _1-3 alkyl-, benzyl, cyano-substituted benzyl, phenethyl or C _1-5 heteroaryl C _1-3 alkyl.

Some of these embodiments are, R ⁷ is hydrogen, deuterium, C _1-6 alkyl, C _1-4 alkyl substituted by cyano, C _3-6 cycloalkyl, C _2-6 heterocyclyl, C _{6- 10} aryl, C _1-5 heteroaryl, C _3-6 cycloalkyl C _1-3 alkyl, C _2-6 heterocyclyl C _1-3 alkyl, C _2-6 heterocyclyl-C( =O)-C _1-4 alkyl-, C _6-10 aryl C _1-3 alkyl or C _1-5 heteroaryl C _1-3 alkyl.

^In some embodiments, R is hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, cyano-substituted methyl, cyano-substituted ethyl , cyano-substituted propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, cyanomethyl-substituted nitrogen Heterocyclobutyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxothiomorpholinyl, Homopiperidinyl, homopiperazinyl, homomorpholinyl, phenyl, cyanomethyl-substituted phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, cyclopropylmethyl, Cyclopropyl ethyl, cyclobutyl methyl, cyclobutyl ethyl, cyclopentyl methyl, cyclopentyl ethyl, cyclohexyl methyl, cyclohexyl ethyl, C _2-6 heterocyclyl C _1-3 alkane Base, azetidinyl-C(=O)-C _1-3 alkyl-, cyano-substituted azetidinyl-C(=O)-C _1-3 alkyl-, pyrrolidinyl- C(=O)-C _1-3 alkyl-, benzyl, cyano-substituted benzyl, phenethyl or C _1-5 heteroaryl C _1-3 alkyl.

In some embodiments, R ⁶ , R ⁷ , and the N atoms connected to them together form the following substructural formula:

Some of these embodiments are, each of R ^1b , R ⁶ and R ⁷ described in C _1-3 alkyl, hydroxy-substituted C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-3 alkoxy, C _1-3 alkoxy C _1-4 alkyl, C _1-3 alkylamino C _1-3 alkyl, C _1-3 alkylthio, C _1-3 alkylsulfonate Acyl, C _6-10 aryl C _1-3 alkyl, C _1-5 heteroaryl C _1-3 alkyl, C _1-6 alkyl, C _1-4 alkyl substituted by cyano, C _{3- 6} Cycloalkyl, C _2-6 Heterocyclyl, C _6-10 Aryl, C _1-5 Heteroaryl, C _3-6 Cycloalkyl C _1-3 Alkyl, C _2-6 Heterocyclyl C _1-3 Alkyl and C _2-6 Heterocyclyl-C(=O)-C _1-4 Alkyl-independently and optionally one or more selected from deuterium, fluorine, chlorine, bromine, iodine, cyano , amino, nitro, carboxyl, oxo (=O), C _1-3 alkyl, halogenated C _1-3 alkyl, amino C _1-3 alkyl, cyano substituted C _1-3 alkyl, C _1-3 alkylamino, C _1-3 alkylamino substituted by cyano, C _1-3 alkoxy, C _1-3 alkoxy substituted by cyano, NH ₂ -S(=O) ₂ - or NH ₂ -C(=O)-substituent.

In some embodiments, each substructure formula formed by R ⁶ , R ⁷ , and the N atoms connected to them is independently and optionally selected from one or more of deuterium, fluorine, chlorine, bromine, iodine, cyano, Amino, nitro, carboxyl, oxo (=O), C _1-3 alkyl, halogenated C _1-3 alkyl, amino C _1-3 alkyl, cyano substituted C _1-3 alkyl, C _1-3 alkylamino, C _1-3 alkylamino substituted by cyano, C _1-3 alkoxy, C _1-3 alkoxy substituted by cyano, NH ₂ -S(=O) ₂ - or NH ₂ Substituents of -C(=O)-.

Some of the embodiments are that the present invention relates to a compound, which is a compound represented by formula (Ic) or a stereoisomer, geometric isomer, tautomer, racemic compound represented by formula (Ic) bodies, nitrogen oxides, hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs:

Wherein each of Y, t, u and R ¹⁴ has the meaning as described in the present invention.

Some of the embodiments are that the present invention relates to a compound, which is a compound represented by formula (Id) or a stereoisomer, geometric isomer, tautomer, racemic compound represented by formula (Id) bodies, nitrogen oxides, hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs:

Wherein each of p, q and R ¹⁴ has the meaning as described in the present invention.

In some of these embodiments, R ¹⁴ is hydrogen, deuterium, C _1-3 alkyl substituted with cyano, R ¹⁵ -C(=O)-, R ¹⁶ -S(=O) ₂ -, C _2-4 alkene radical, C _2-4 alkynyl, R ¹⁸ -C(=O)-N(R ¹⁷ )-C _1-6 alkyl-, R ¹⁸ -C(=O)-N(R ¹⁷ )-C _{1- 6} alkyl-C(=O)-, R ¹⁸ -S(=O) ₂ -N(R ¹⁷ )-C _1-3 alkyl-, R ¹⁸ -S(=O) ₂ -N(R ¹⁷ ) -C _1-6 alkyl-C(=O)-, R ²⁰ R ¹⁹ NC(=O)-C _1-4 alkyl-, R ²⁰ R ¹⁹ NS(=O) ₂ -C _1-3 alkyl -, R ²⁰ R ¹⁹ NS(=O) ₂ -C _1-6 alkyl-C(=O)-, C _6-10 aryl C _1-3 alkyl, C _2-6 heterocyclyl C _{1- 3} alkyl, C _6-10 aryl-C(=O)-C _1-3 alkyl-, C _6-10 aryl-S(=O) ₂ -C _1-3 alkyl-, C _{1- 5} Heteroaryl-C(=O)-C _1-3 Alkyl-, C _1-5 Heteroaryl-S(=O) ₂ -C _1-3 Alkyl-, C _2-6 Heterocyclyl- C(=O)-C _1-3 alkyl- or C _2-6 heterocyclyl-S(=O) ₂ -C _1-3 alkyl-;

Wherein each of R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²⁰ has the meanings described in the present invention.

In some embodiments, each R ¹⁵ is independently C _1-6 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-6 alkyl substituted by cyano, halogenated C _1-3 Alkyl, C _1-3 alkyl substituted by hydroxy, C _1-3 alkyl amino, C _1-6 alkoxy, C _1-3 alkoxy substituted by cyano, C _6-10 aryl, C _{6 -10} aryl C _1-3 alkyl, C _1-5 heteroaryl, C _1-5 heteroaryl C _1-3 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl C _{1 -3} alkyl, C _2-6 heterocyclyl or C _2-6 heterocyclyl C _1-3 alkyl.

In some embodiments, each R ¹⁶ is independently C _1-6 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-6 alkyl substituted by cyano, halogenated C _1-3 Alkyl, C _1-3 alkyl substituted by hydroxy, C _1-3 alkyl amino, C _1-6 alkoxy, C _1-3 alkoxy substituted by cyano, C _6-10 aryl, C _{6 -10} aryl C _1-3 alkyl, C _1-5 heteroaryl, C _1-5 heteroaryl C _1-3 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl C _{1 -3} alkyl, C _2-6 heterocyclyl or C _2-6 heterocyclyl C _1-3 alkyl.

In some embodiments, each R ¹⁸ is independently C _1-6 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-6 alkyl substituted by cyano, halogenated C _1-3 Alkyl, C _1-3 alkyl substituted by hydroxy, C _1-3 alkyl amino, C _1-6 alkoxy, C _1-3 alkoxy substituted by cyano, C _6-10 aryl, C _{6 -10} aryl C _1-3 alkyl, C _1-5 heteroaryl, C _1-5 heteroaryl C _1-3 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl C _{1 -3} alkyl, C _2-6 heterocyclyl or C _2-6 heterocyclyl C _1-3 alkyl.

In some embodiments, each R ¹⁷ is independently hydrogen, deuterium, C _1-6 alkyl, cyano substituted C _1-3 alkyl, halogenated C _1-3 alkyl, C _3-6 cycloalkyl , C _2-6 heterocyclyl, C _6-10 aryl, C _1-5 heteroaryl, C _3-6 cycloalkyl C _1-3 alkyl, C _2-6 heterocyclyl C _1-3 alkane group, C _6-10 aryl C _1-3 alkyl or C _1-5 heteroaryl C _1-3 alkyl.

In some embodiments, each R ¹⁹ is independently hydrogen, deuterium, C _1-6 alkyl, cyano substituted C _1-3 alkyl, halogenated C _1-3 alkyl, C _3-6 cycloalkyl , C _2-6 heterocyclyl, C _6-10 aryl, C _1-5 heteroaryl, C _3-6 cycloalkyl C _1-3 alkyl, C _2-6 heterocyclyl C _1-3 alkane group, C _6-10 aryl C _1-3 alkyl or C _1-5 heteroaryl C _1-3 alkyl.

^In some embodiments, each R is independently hydrogen, deuterium, C _1-6 alkyl, cyano substituted C _1-3 alkyl, halogenated C _1-3 alkyl, C _3-6 cycloalkyl , C _2-6 heterocyclyl, C _6-10 aryl, C _1-5 heteroaryl, C _3-6 cycloalkyl C _1-3 alkyl, C _2-6 heterocyclyl C _1-3 alkane group, C _6-10 aryl C _1-3 alkyl or C _1-5 heteroaryl C _1-3 alkyl.

In some embodiments, R ¹⁹ , R ²⁰ , and the N atoms connected to them at the same time optionally form the following substructural formula:

Some of these embodiments are, R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²⁰ each of C _1-6 alkyl, C _2-4 alkenyl, C _2-4 alkynyl C 1-3 alkyl group, cyano substituted C _1-3 alkyl, cyano substituted C _1-6 alkyl, halo C _1-3 alkyl, hydroxy substituted C _1-3 alkyl, amino C _1-3 alkyl , C _1-6 alkoxy, C _1-3 alkoxy substituted by cyano, R ¹⁵ -C(=O)-, R ¹⁶ -S(=O) ₂ -, R ¹⁸ -C(=O) -N(R ¹⁷ )-C _1-6 alkyl-, R ¹⁸ -C(=O)-N(R ¹⁷ )-C _1-6 alkyl-C(=O)-, R ¹⁸ -S(= O) ₂ -N(R ¹⁷ )-C _1-3 alkyl-, R ¹⁸ -S(=O) ₂ -N(R ¹⁷ )-C _1-6 alkyl-C(=O)-, R ²⁰ R ¹⁹ NC(=O)-C _1-4 alkyl-, R ²⁰ R ¹⁹ NS(=O) ₂ -C _1-3 alkyl-, R ²⁰ R ¹⁹ NS(=O) ₂ -C _1-6 Alkyl-C(=O)-, C _6-10 aryl, C _6-10 aryl C _1-3 alkyl, C _1-5 heteroaryl, C _1-5 heteroaryl C _1-3 alkane C _3-6 cycloalkyl, C _3-6 cycloalkyl C _1-3 alkyl, C _2-6 heterocyclyl, C _2-6 heterocyclyl C _1-3 alkyl, C _6-10 Aryl-C(=O)-C _1-3 alkyl-, C _6-10 aryl-S(=O) ₂ -C _1-3 alkyl-, C _1-5 heteroaryl-C(= O)-C _1-3 alkyl-, C _1-5 heteroaryl-S(=O) ₂ -C _1-3 alkyl-, C _2-6 heterocyclyl-C(=O)-C _{1 -3} alkyl- and C _2-6 heterocyclyl-S(=O) ₂ -C _1-3 alkyl- are independently optionally selected from one or more of deuterium, fluorine, chlorine, bromine, iodine, cyanide radical, amino, nitro, carboxyl, oxo (=O), C _1-3 alkyl, halogenated C _1-3 alkyl, amino C _1-3 alkyl, cyano substituted C _1-3 alkyl , C _1-3 alkylamino, C _1-3 alkylamino substituted by cyano, C _1-3 alkoxy, C _1-3 alkoxy substituted by cyano, NH ₂ -S(=O) ₂ - or Substituents of NH ₂ -C(=O)-.

Some of the embodiments are that each substructure formed by R ¹⁹ , R ²⁰ , and the N atoms connected to them at the same time is independently optionally replaced by one or more selected from deuterium, fluorine, chlorine, bromine, iodine, cyano , amino, nitro, carboxyl, oxo (=O), C _1-3 alkyl, halogenated C _1-3 alkyl, amino C _1-3 alkyl, cyano substituted C _1-3 alkyl, C _1-3 alkylamino, C _1-3 alkylamino substituted by cyano, C _1-3 alkoxy, C _1-3 alkoxy substituted by cyano, NH ₂ -S(=O) ₂ - or NH ₂ -C(=O)-substituent.

In some of these embodiments, R ¹⁴ is hydrogen, deuterium, cyano-substituted methyl, cyano-substituted ethyl, cyano-substituted propyl, R ¹⁵ -C(=O)-, R ¹⁶ -S(= O) ₂ -, C _2-4 alkenyl, C _2-4 alkynyl, R ¹⁸ -C(=O)-N(R ¹⁷ )-C _1-3 alkyl-, R ¹⁸ -C(=O) -N(R ¹⁷ )-C _1-4alkyl -C(=O)-, R ¹⁸ -S(=O) ₂ -N(R ¹⁷ )-C _1-3alkyl- , R ¹⁸ -S( =O) ₂ -N(R ¹⁷ )-C _1-4 alkyl-C(=O)-, R ²⁰ R ¹⁹ NC(=O)-C _1-4 alkyl-, R ²⁰ R ¹⁹ NS(= O) ₂ -C _1-3 alkyl-, NH ₂ -S(=O) ₂ -C _1-4 alkyl-C(=O)-, benzyl, phenethyl, azetidinylmethyl, nitrogen Heterocyclobutylethyl, pyrrolidinylmethyl, pyrrolidinylethyl, piperidinylmethyl, piperidinylethyl, piperazinylmethyl, piperazinylethyl, morpholinylmethyl, morpholino Linylethyl, 3-oxomorpholinylmethyl, 3-oxomorpholinylethyl, thiomorpholinylmethyl, thiomorpholinylethyl, 1-oxothiomorpholinyl Methyl, 1-oxothiomorpholinoethyl, 1,1-dioxothiomorpholinomethyl, 1,1-dioxothiomorpholinoethyl, azetidinyl -C(=O)-methyl-, azetidinyl-C(=O)-ethyl-, cyano-substituted azetidinyl-C(=O)-ethyl-, pyrrolidinyl -C(=O)-methyl-, pyrrolidinyl-C(=O)-ethyl-, piperidinyl-C(=O)-methyl-, piperidinyl-C(=O)-ethyl Base-, piperazinyl-C(=O)-methyl-, piperazinyl-C(=O)-ethyl-, morpholinyl-C(=O)-methyl-, morpholinyl-C (=O)-ethyl-, azetidinyl-S(=O) ₂ -methyl-, azetidinyl-S(=O) ₂ -ethyl-, cyano substituted azacycles Butyl-S(=O) ₂ -ethyl-, pyrrolidinyl-S(=O) ₂ -methyl-, pyrrolidinyl-S(=O) ₂ -ethyl-, piperidinyl-S( =O) ₂ -methyl-, piperidinyl-S(=O) ₂ -ethyl-, piperazinyl-S(=O) ₂ -methyl-, piperazinyl-S(=O) ₂ - Ethyl-, morpholinyl-S(=O) ₂ -methyl- or morpholinyl-S(=O) ₂ -ethyl-;

Wherein each of R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²⁰ has the meanings described in the present invention.

In some embodiments, each R ¹⁵ is independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, -CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ , -CH (CH ₃ )CH ₂ CH ₂ CH ₃ , -CH(CH ₂ CH ₃ ) ₂ , -C(CH ₃ ) ₂ CH ₂ CH ₃ , -CH(CH ₃ )CH(CH ₃ ) ₂ , -CH ₂ CH ₂ CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ )CH ₂ CH ₃ , -CH ₂ C(CH ₃ ) ₃ , vinyl, propenyl, ethynyl, propynyl, cyano-substituted methyl , cyano-substituted ethyl, cyano-substituted propyl, cyano-substituted isopropyl, halogenated C _1-3 alkyl, hydroxyl substituted C _1-3 alkyl, amino C _1-3 alkyl, Methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, cyano substituted C _1-3 alkoxy, phenyl, aminosulfonyl substituted phenyl, cyanomethoxy substituted phenyl, benzyl, cyano substituted benzyl, aminosulfonyl substituted benzyl, phenethyl, C _1-5 heteroaryl, C _1-5 heteroaryl C _1-3 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl , cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, Morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxothiomorpholinyl, homopiperidinyl, homopiperazinyl, homomorpholinyl, aza Cyclobutylmethyl, cyano-substituted azetidinylmethyl, azetidinylethyl, pyrrolidinylmethyl, pyrrolidinylethyl, piperidinylmethyl, piperidinylethyl, piperazinylmethyl Base, piperazinylethyl, morpholinylmethyl, morpholinylethyl, 3-oxomorpholinylmethyl, 3-oxomorpholinylethyl, thiomorpholinylmethyl, thio Morpholinyl ethyl, 1-oxothiomorpholinomethyl, 1-oxothiomorpholinoethyl, 1,1-dioxothiomorpholinomethyl or 1,1-di Oxothiomorpholinoethyl.

In some embodiments, each R ¹⁶ is independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, -CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ , -CH (CH ₃ )CH ₂ CH ₂ CH ₃ , -CH(CH ₂ CH ₃ ) ₂ , -C(CH ₃ ) ₂ CH ₂ CH ₃ , -CH(CH ₃ )CH(CH ₃ ) ₂ , -CH ₂ CH ₂ CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ )CH ₂ CH ₃ , -CH ₂ C(CH ₃ ) ₃ , vinyl, propenyl, ethynyl, propynyl, cyano-substituted methyl , cyano-substituted ethyl, cyano-substituted propyl, cyano-substituted isopropyl, halogenated C _1-3 alkyl, hydroxyl substituted C _1-3 alkyl, amino C _1-3 alkyl, Methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, cyano substituted C _1-3 alkoxy, phenyl, aminosulfonyl substituted phenyl, cyanomethoxy substituted phenyl, benzyl, cyano substituted benzyl, aminosulfonyl substituted benzyl, phenethyl, C _1-5 heteroaryl, C _1-5 heteroaryl C _1-3 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl , cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, Morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxothiomorpholinyl, homopiperidinyl, homopiperazinyl, homomorpholinyl, aza Cyclobutylmethyl, cyano-substituted azetidinylmethyl, azetidinylethyl, pyrrolidinylmethyl, pyrrolidinylethyl, piperidinylmethyl, piperidinylethyl, piperazinylmethyl Base, piperazinylethyl, morpholinylmethyl, morpholinylethyl, 3-oxomorpholinylmethyl, 3-oxomorpholinylethyl, thiomorpholinylmethyl, thio Morpholinyl ethyl, 1-oxothiomorpholinomethyl, 1-oxothiomorpholinoethyl, 1,1-dioxothiomorpholinomethyl or 1,1-di Oxothiomorpholinoethyl.

In some embodiments, each R ¹⁸ is independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, -CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ , -CH (CH ₃ )CH ₂ CH ₂ CH ₃ , -CH(CH ₂ CH ₃ ) ₂ , -C(CH ₃ ) ₂ CH ₂ CH ₃ , -CH(CH ₃ )CH(CH ₃ ) ₂ , -CH ₂ CH ₂ CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ )CH ₂ CH ₃ , -CH ₂ C(CH ₃ ) ₃ , vinyl, propenyl, ethynyl, propynyl, cyano-substituted methyl , cyano-substituted ethyl, cyano-substituted propyl, cyano-substituted isopropyl, halogenated C _1-3 alkyl, hydroxyl substituted C _1-3 alkyl, amino C _1-3 alkyl, Methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, cyano substituted C _1-3 alkoxy, phenyl, aminosulfonyl substituted phenyl, cyanomethoxy substituted phenyl, benzyl, cyano substituted benzyl, aminosulfonyl substituted benzyl, phenethyl, C _1-5 heteroaryl, C _1-5 heteroaryl C _1-3 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl , cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, Morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxothiomorpholinyl, homopiperidinyl, homopiperazinyl, homomorpholinyl, aza Cyclobutylmethyl, cyano-substituted azetidinylmethyl, azetidinylethyl, pyrrolidinylmethyl, pyrrolidinylethyl, piperidinylmethyl, piperidinylethyl, piperazinylmethyl Base, piperazinylethyl, morpholinylmethyl, morpholinylethyl, 3-oxomorpholinylmethyl, 3-oxomorpholinylethyl, thiomorpholinylmethyl, thio Morpholinyl ethyl, 1-oxothiomorpholinomethyl, 1-oxothiomorpholinoethyl, 1,1-dioxothiomorpholinomethyl or 1,1-di Oxothiomorpholinoethyl.

^In some embodiments, each R is independently hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, cyano-substituted methyl, cyano-substituted Ethyl, cyano-substituted propyl, cyano-substituted isopropyl or halogenated C _1-3 alkyl.

^In some embodiments, each R is independently hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyano-substituted methyl, cyano-substituted Ethyl, cyano-substituted propyl, cyano-substituted isopropyl or halogenated C _1-3 alkyl.

^In some embodiments, each R is independently hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, cyano-substituted methyl, cyano-substituted Ethyl, cyano-substituted propyl, cyano-substituted isopropyl or halogenated C _1-3 alkyl.

In another aspect, the present invention relates to a compound, which is a compound represented by formula (II) or a stereoisomer, geometric isomer, tautomer, racemate, Nitrogen oxides, hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs:

in:

R ²¹ is hydrogen, deuterium, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxy substituted C _1-6 alkyl or cyano substituted C _1-6 alkyl;

R ²² is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, nitro, carboxyl, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxyl substituted C _1-6 Alkyl, C _1-6 alkyl substituted by cyano or R ²⁵ R ²⁶ NC(=O)-;

R ²³ is R ²⁸ -C(=O)-N(R ²⁷ )-, R ²⁸ -S(=O) ₂ -N(R ²⁷ )-, C _3-8 cycloalkyl C _1-6 alkyl, C _3-8 cycloalkenyl C _1-6 alkyl, C _2-10 heterocyclyl C _1-6 alkyl, C _6-10 aryl C _1-6 alkyl or C _1-9 heteroaryl C _{1 -6} alkyl;

Each ^R24 is independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, nitro, carboxyl, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxy-substituted C _1-6 alkyl, C _1-6 alkyl substituted by cyano, C _1-6 alkoxy or C _1-6 alkylamino;

each of R ²⁵ , R ²⁶ and R ²⁷ is independently hydrogen, deuterium or C _1-6 alkyl;

Each R ²⁸ is independently hydrogen, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkyl substituted by cyano, C _1-6 alkane substituted by hydroxy or haloC _1-6 alkyl; and

Each of the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, halogenated C _1-6 alkyl, hydroxyl substituted C _1-6 alkyl, cyano substituted C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, R ²⁵ R ²⁶ NC(=O)-, R ²⁸ -C(=O)-N(R ²⁷ )-, R ²⁸ -S(=O) ₂ -N(R ²⁷ )-, C _3-8 cycloalkyl C _1-6 alkyl, C _3-8 cycloalkenyl C _1-6 alkyl, C _2-10 heterocyclyl C _1-6 alkyl, C _6-10 aryl C _1-6 alkyl and C _1-9 heteroaryl C _1-6 alkyl are independently optionally selected from one or more of deuterium, fluorine, chlorine, Bromine, iodine, cyano, hydroxyl, amino, nitro, carboxyl, oxo (=O), C _1-6 alkyl, halogenated C _1-6 alkyl, amino C _1-6 alkyl, cyano C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkylamino substituted by cyano, C _1-6 alkoxy, C _1-6 alkoxy substituted by cyano, NH ₂ -S Substituents of (=O) ₂ - or NH ₂ -C(=O)-.

In some of these embodiments, R is hydrogen, ^deuterium , C _1-3 alkyl, halogenated C _1-3 alkyl, hydroxy substituted C _1-3 alkyl or cyano substituted C _1-3 alkyl.

In some embodiments, R is hydrogen, ^deuterium , fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, nitro, carboxyl, C _1-3 alkyl, halogenated C _1-3 alkyl, hydroxy Substituted C _1-3 alkyl, cyano substituted C _1-3 alkyl or R ²⁵ R ²⁶ NC(=O)-;

Wherein R ²⁵ and R ²⁶ have the meanings as described in the present invention.

In some embodiments, R ²³ is R ²⁸ -C(=O)-N(R ²⁷ )-, R ²⁸ -S(=O) ₂ -N(R ²⁷ )-, C _3-6 cycloalkyl C _1-3 alkyl, C _3-6 cycloalkenyl C _1-3 alkyl, C _2-6 heterocyclyl C _1-3 alkyl, C _6-10 aryl C _1-3 alkyl or C _{1- 5} Heteroaryl C _1-3 alkyl, wherein said C _2-6 heterocyclyl C _1-3 alkyl is optionally oxo (=O);

Wherein R ²⁷ and R ²⁸ have the meanings as described in the present invention.

In some embodiments, each R is independently hydrogen, ^deuterium , fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, nitro, carboxyl, C _1-3 alkyl, halogenated C _1-3 alkane C _1-3 alkyl group, C 1-3 alkyl group substituted by hydroxy group, C _1-3 alkyl group substituted by cyano group, C _1-3 alkoxy group or C _1-3 alkylamino group.

In some embodiments, each of R ²⁵ , R ²⁶ and R ²⁷ is independently hydrogen, deuterium or C _1-4 alkyl.

In some embodiments, each R ²⁸ is independently hydrogen, deuterium, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-3 alkyl substituted by cyano, substituted by hydroxy C _1-3 alkyl or halogenated C _1-3 alkyl.

On the other hand, the present invention includes but is not limited to compounds with one of the following structures or stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, and solvents of compounds with one of the following structures compounds, metabolites, pharmaceutically acceptable salts or prodrugs:

One aspect of the present invention relates to pharmaceutical compositions comprising the compounds described herein.

In some embodiments, the pharmaceutical composition of the present invention further comprises at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant and vehicle.

In some embodiments, the pharmaceutical composition of the present invention further comprises an additional therapeutic agent, which is selected from chemotherapeutics or antiproliferative agents, anti-inflammatory drugs, immunomodulators or immunosuppressants, neurotrophic factors, for the treatment of Agents for cardiovascular disease, agents for treating diabetes and agents for treating autoimmune diseases.

Another aspect of the present invention relates to the use of a compound of the present invention or a pharmaceutical composition comprising the compound of the present invention for the preparation of a medicament for preventing, treating or treating an autoimmune disease or a proliferative disease in a patient, and reducing the severity thereof .

In some embodiments, the autoimmune disease described in the present invention is lupus, multiple sclerosis, amyotrophic lateral sclerosis, rheumatoid arthritis, psoriasis, type 1 diabetes, complications caused by organ transplantation, Foreign body transplantation, diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and lymphoma.

In some embodiments, the proliferative disease described in the present invention is metastatic cancer, colon cancer, gastric adenocarcinoma, bladder cancer, breast cancer, kidney cancer, liver cancer, lung cancer, thyroid cancer, head and neck cancer, prostate cancer, pancreatic cancer, CNS cancer Cancer (central nervous system), malignant glioma, myeloproliferative disease, atherosclerosis, or pulmonary fibrosis.

In another aspect, the present invention relates to the use of a compound of the present invention or a pharmaceutical composition comprising the compound of the present invention for the preparation of a medicament for inhibiting or modulating protein kinase activity in a biological specimen, said use comprising using the compound of the present invention or comprising the compound of the present invention A pharmaceutical composition of compounds is contacted with the biological sample.

In some embodiments, the protein kinase is JAK1, JAK2, JAK3, BTK, EGFR or EGFRT790M.

In one aspect, the invention relates to intermediates for the preparation of compounds encompassed by formula (I), (Ia), (Ib), (Ic), (Id) or (II).

Another aspect of the present invention relates to processes for the preparation, isolation and purification of compounds encompassed by formula (I), (Ia), (Ib), (Ic), (Id) or (II).

The invention also encompasses the use of the compounds of the invention and their pharmaceutically acceptable salts for the manufacture of medicinal products for the treatment of autoimmune or proliferative diseases, including those described herein. The compounds of the present invention are also useful in the manufacture of a medicinal product for alleviating, preventing, controlling or treating disorders mediated by JAK1, JAK2, JAK3, BTK, EGFR or EGFRT790M.

The present invention includes a pharmaceutical composition comprising a compound represented by formula (I), (Ia), (Ib), (Ic), (Id) or (II) and at least one pharmaceutically acceptable carrier, The combination of adjuvants or diluents is required for a therapeutically effective amount.

The invention also encompasses a method of treating an autoimmune or proliferative disease in a patient, or susceptible thereto, comprising the use of formula (I), (Ia), (Ib), (Ic), (Id) or (II) A therapeutically effective amount of the represented compound is administered to the patient.

Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites, metabolic precursors, salts and Pharmaceutically acceptable prodrugs are within the scope of the present invention.

In particular, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes that the substance or composition must be chemically or toxicologically appropriate in relation to the other ingredients making up the formulation and the mammal being used for treatment.

The salts of the compounds of the present invention also include intermediates or formula (I), Salts of isolated enantiomers of compounds represented by (Ia), (Ib), (Ic), (Id) or (II), but not necessarily pharmaceutically acceptable salts.

Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids such as acetates, glycolates, aspartates, benzoates, benzenesulfonates, bromides/hydrobromides , bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorophylline salt, citrate, edisulphonate, fumarate, glucoheptin Sugarate, Gluconate, Glucuronate, Hippurate, Hydroiodide/Iodide, Isethionate, Lactate, Lacturonate, Lauryl Sulfate, Apple salt, maleate, malonate, mandelate, methanesulfonate, ethanesulfonate, methosulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, decamate Octamate, Oleate, Oxalate, Palmitate, Pamoate, Phosphate/Hydrogen Phosphate/Dihydrogen Phosphate, Polygalactonate, Propionate, Stearate, Succinate , sulfosalicylate, tartrate, tosylate and trifluoroacetate.

Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from Groups I to XII of the Periodic Table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

Organic bases from which salts can be derived include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include, for example, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine .

The pharmaceutically acceptable salts of this invention can be synthesized from the parent compound, a basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (such as Na, Ca, Mg or K hydroxides, carbonates, bicarbonates, etc.), or by They are prepared by reacting the free base forms of these compounds with stoichiometric amounts of the appropriate acid. Such reactions are usually carried out in water or organic solvents or a mixture of both. Generally, non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile will be required where appropriate. In, for example, "Remington's Pharmaceutical Sciences", 20th Edition, Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Stahland Wermuth (Wiley- Additional lists of suitable salts can be found in VCH, Weinheim, Germany, 2002).

In addition, the compounds disclosed in the present invention, including their salts, can also be obtained in the form of their hydrates or in the form of solvents (such as ethanol, DMSO, etc.) containing them for their crystallization. The compounds disclosed herein may inherently or by design form solvates with pharmaceutically acceptable solvents, including water; thus, it is intended that the present invention embrace both solvated and unsolvated forms.

Any structural formulas given herein are also intended to represent non-isotopically enriched as well as isotopically enriched forms of these compounds. Isotopically enriched compounds have structures depicted by the general formulas given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Exemplary isotopes that may be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O , ¹⁸ O, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl and ¹²⁵ I.

In another aspect, the compounds of the present invention include isotopically enriched compounds as defined in the present invention, for example, those compounds in which radioactive isotopes such as ³ H, ¹⁴ C and ¹⁸ F are present, or in which non-radioactive isotopes such as ² H and ¹³ C. Such isotopically enriched compounds can be used in metabolic studies (using ¹⁴ C), reaction kinetics studies (using e.g. ² H or ³ H), detection or imaging techniques such as positron emission tomography (PET) or including pharmaceutical or Single-photon emission computed tomography (SPECT) for the determination of substrate tissue distribution may be used in radiation therapy of patients. ¹⁸ F-enriched compounds are particularly ideal for PET or SPECT studies. Compounds shown in the isotopically enriched formula (I), (Ia), (Ib), (Ic), (Id) or (II) can be prepared by conventional techniques familiar to those skilled in the art or the examples and preparations in the present invention The procedure described was prepared using the appropriate isotopically labeled reagent in place of the unlabeled reagent previously used.

^In addition, substitution with heavier isotopes, particularly deuterium (ie,2H or D), may afford certain therapeutic advantages resulting from greater metabolic stability. For example, due to increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It should be understood that deuterium in the present invention is considered as a substituent of the compound represented by formula (I), (Ia), (Ib), (Ic), (Id) or (II). An isotopic enrichment factor can be used to define the concentration of such heavier isotopes, especially deuterium. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has, for each designated deuterium atom, at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), At least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation) Deuterium incorporation), an isotopic enrichment factor of at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the present invention include those wherein the solvent of crystallization may be isotopically substituted eg _D2O , acetone _- d6, _DMSO -d6.

The preceding description only outlines certain aspects of the invention, but is not limiting. These and other aspects will be described more specifically and fully below.

Detailed description of the invention

Definitions and General Terms

Certain embodiments of the invention are now described in detail, examples of which are illustrated by the accompanying Structural and Chemical Formulas. The present invention is intended to cover all alternatives, modifications and equivalent technical solutions, which are included within the scope of the present invention as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application (including but not limited to defined terms, term usage, described techniques, etc.), this Application shall prevail.

It is further appreciated that certain features of the invention, which, for clarity, are described in multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Unless otherwise specified, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications referred to herein are hereby incorporated by reference in their entirety.

As used herein, the following definitions shall apply unless otherwise stated. For the purposes of the present invention, the chemical elements correspond to the Periodic Table of the Elements, CAS Edition, and Handbook of Chemistry and Physics, 75th Edition, 1994. In addition, the general principles of organic chemistry can refer to the descriptions in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

As used herein, the articles "a", "an" and "the" are intended to include "at least one" or "one or more" unless otherwise stated or clearly contradicted by context. Therefore, these articles used in the present invention refer to articles of one or more than one (ie at least one) object. For example, "a component" refers to one or more components, ie there may be more than one component contemplated to be employed or used in the practice of the described embodiment.

The term "subject" as used in the present invention refers to an animal. Typically the animal is a mammal. Subjects, for example, also refer to primates (such as humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

The term "patient" as used herein refers to a human (including adults and children) or other animals. In some embodiments, "patient" refers to a human.

The term "comprising" is an open expression, that is, it includes the content specified in the present invention, but does not exclude other content.

"Stereoisomers" refer to compounds that have the same chemical structure, but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, etc. .

"Chiral" is a molecule that has the property of being nonsuperimposable to its mirror image; and "achiral" is a molecule that is superimposable to its mirror image.

"Enantiomer" refers to two non-superimposable isomers of a compound that are mirror images of each other.

"Diastereoisomer" refers to stereoisomers that have two or more chiral neutralities and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting points, boiling points, spectral properties and reactivity. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography, eg HPLC.

Stereochemical definitions and rules used in the present invention generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

Many organic compounds exist in optically active forms, ie they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to its chiral center or centers. The prefixes d and 1 or (+) and (-) are symbols used to designate rotation of plane polarized light by a compound, where (-) or 1 indicates that the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. A specific stereoisomer is an enantiomer and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate and can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein may exist in racemic or enantiomerically enriched form, such as (R)-, (S)- or (R,S)-configuration exist. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

Depending on the choice of starting materials and processes, the compounds of the invention can be obtained as one of the possible isomers or as mixtures thereof, such as racemates and diastereomer mixtures (depending on the number of asymmetric carbon atoms) form exists. Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may have the cis or trans configuration.

The resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereoisomers on the basis of differences in the physicochemical properties of the components, for example, by chromatography method and/or fractional crystallization.

The racemates of any resulting final products or intermediates can be resolved into the optical antipodes by known methods by methods familiar to those skilled in the art, e.g., by subjecting the obtained diastereomeric salts thereof to separate. Racemic products can also be separated by chiral chromatography, eg, high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by asymmetric synthesis, see for example Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 ^nd Ed. Robert E. Gawley, Jeffrey Aube, Elsevier, Oxford , UK, 2012); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolution sp. 268 (EL Liel, Ed., Univ. of Notre Dame Press, Notre Dame, IN1972); Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that are interconvertible through a low energy barrier. If tautomerism is possible (eg, in solution), then a chemical equilibrium of the tautomers can be achieved. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

As described in the present invention, the compounds of the present invention can be optionally substituted by one or more substituents, such as the above general formula compounds, or as specific examples in the examples, subclasses, and included in the present invention A class of compounds. It should be understood that the term "optionally substituted" and the term "substituted or unsubstituted" are used interchangeably. In general, the term "substituted" means that one or more hydrogen atoms in a given structure have been replaced by a particular substituent. Unless otherwise indicated, an optional substituent may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted by one or more substituents selected from a particular group, then the substituents can be substituted at each position the same or differently. The substituents mentioned therein can be, but are not limited to, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, oxo (=O), alkyl, alkoxy, Alkoxyalkyl, Alkoxyalkoxy, Alkoxyalkylamino, Aryloxy, Heteroaryloxy, Heterocyclyloxy, Arylalkoxy, Heteroarylalkoxy, Heterocyclic Alkylalkoxy, cycloalkylalkoxy, alkylamino, alkylaminoalkyl, alkylaminoalkylamino, cycloalkylamino, cycloalkylalkylamino, alkylthio, haloalkyl, haloalkoxy, hydroxy substituted Alkyl, hydroxy-substituted alkylamino, cyano-substituted alkyl, cyano-substituted alkoxy, cyano-substituted alkylamino, cyano-substituted alkylamido, amino-substituted alkyl, alkylacyl, Heteroalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylacyl, aryl, arylalkyl, arylamino, heteroaryl, heteroaryl arylalkyl, heteroarylamino, amido, sulfonyl, aminosulfonyl, etc.

In addition, it should be noted that, unless otherwise clearly stated, the descriptions used in the present invention "each...independently are" can be interchanged with "...independently" and "...independently". It should be understood in a broad sense. It can mean that in different groups, the specific options expressed between the same symbols do not affect each other, and it can also mean that in the same group, the specific options expressed between the same symbols do not affect each other.

In each part of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to the type or range of the group. It is specifically intended that the invention includes each individual subcombination of individual members of these radical classes and ranges. For example, the term "C ₁ -C ₆ alkyl" or "C _1-6 alkyl" specifically refers to independently disclosed methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl and C ₆ alkane base.

In various sections of the invention linking substituents are described. When the structure clearly requires a linking group, the Markush variables recited for that group are to be understood as linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable recites "alkyl" or "aryl," it is understood that "alkyl" or "aryl" respectively represents the linking group. An alkylene group or an arylene group.

The term "alkyl" or "alkyl group" used in the present invention means a saturated linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group can be optionally substituted by one or more of the substituents described herein. Unless otherwise specified, an alkyl group contains 1-20 carbon atoms. In one embodiment, the alkyl group contains 1-12 carbon atoms; in one embodiment, the alkyl group contains 1-8 carbon atoms; in another embodiment, the alkyl group contains 1- 6 carbon atoms; in yet another embodiment, the alkyl group contains 1-4 carbon atoms; in yet another embodiment, the alkyl group contains 1-3 carbon atoms.

Examples of alkyl groups include, but are not limited to, methyl (Me, -CH ₃ ), ethyl (Et, -CH ₂ CH ₃ ), n-propyl (n-Pr, -CH ₂ CH ₂ CH ₃ ), isopropyl (i-Pr, -CH(CH ₃ ) ₂ ), n-butyl (n-Bu, -CH ₂ CH ₂ CH ₂ CH ₃ ), isobutyl (i-Bu, -CH ₂ CH (CH ₃ ) ₂ ), sec-butyl (s-Bu, -CH(CH ₃ )CH ₂ CH ₃ ), tert-butyl (t-Bu, -C(CH ₃ ) ₃ ), n-pentyl (-CH 2CH ₂ CH ₂ CH ₂ CH ₃ ), ₂ -pentyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH(CH ₂ CH ₃ ) ₂ ), 2-methyl -2-butyl (-C(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1- Butyl (-CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), n-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH(CH ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ )), 2-methyl-2-pentyl (-C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH(CH ₃ )CH(CH ₃ )CH ₂ CH ₃ ), 4-methyl-2-pentyl (-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C(CH ₃ )(CH ₂ CH ₃ ) ₂ ), 2-methyl-3-pentyl (-CH(CH ₂ CH ₃ ) CH(CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl (-C(CH ₃ ) ₂ CH (CH ₃ ) ₂ ), 3,3-dimethyl-2-butyl (-CH(CH ₃ )C(CH ₃ ) ₃ ), n-heptyl, n-octyl, and the like.

The term "alkylene" denotes a saturated divalent hydrocarbyl group obtained by removing two hydrogen atoms from a saturated straight or branched chain hydrocarbon. Unless otherwise specified, an alkylene group contains 1-12 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, 1-4 carbon atoms, 1-3 carbon atoms or 1-2 carbon atom. Such examples include methylene ( _-CH2- ), ethylene ( _-CH2CH2- ), isopropylidene (-CH( _{CH3 )} CH2- ₎ , and the like.

The term "alkenyl" means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one unsaturated site, that is, a carbon-carbon sp ² double bond, wherein the alkenyl group Groups may be optionally substituted with one or more substituents described herein, including the "cis" and "tans" orientation, or the "E" and "Z" orientation. In one embodiment, an alkenyl group contains 2-8 carbon atoms; in another embodiment, an alkenyl group contains 2-6 carbon atoms; in yet another embodiment, an alkenyl group contains 2 - 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl (-CH= _CH2 ), allyl (-CH2CH= _CH2 ), propenyl ( _{CH3 -} CH=CH-), and the like.

The term "alkynyl" means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one unsaturated site, that is, a carbon-carbon sp triple bond, wherein the alkynyl group Can be optionally substituted with one or more substituents described herein. In one embodiment, the alkynyl group contains 2-8 carbon atoms; in another embodiment, the alkynyl group contains 2-6 carbon atoms; in yet another embodiment, the alkynyl group contains 2 - 4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), ₁ -propynyl (-C≡C- _CH3 ), and the like .

The term "alkoxy" denotes an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning described herein. Unless specified otherwise, the alkoxy groups contain 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms; in another embodiment, the alkoxy group contains 1-4 carbon atoms; in yet another embodiment, the alkoxy group Groups contain 1-3 carbon atoms. The alkoxy groups may be optionally substituted with one or more substituents described herein.

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH ₃ ), ethoxy (EtO, -OCH ₂ CH ₃ ), 1-propoxy (n-PrO, n- Propoxy, -OCH ₂ CH ₂ CH ₃ ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH ₃ ) ₂ ), 1-butoxy (n-BuO, n- Butoxy, -OCH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH ₂ CH(CH ₃ ) ₂ ), 2-butane Oxygen (s-BuO, s-butoxy, -OCH(CH ₃ )CH ₂ CH ₃ ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH ₃ ) ₃ ), 1-pentyloxy (n-pentyloxy, -OCH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyloxy (-OCH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyloxy (-OCH(CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butoxy (-OC(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butoxy (-OCH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-l-butoxy (-OCH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-l-butoxy ( _-OCH2CH ( _CH3 ) _{CH2CH3 )} , and so on.

The term "alkoxyalkyl" means that an alkyl group is substituted by one or more alkoxy groups, wherein the alkyl group and the alkoxy group have the meanings described herein, examples of which include , but not limited to methoxymethyl, methoxyethyl, ethoxyethyl, etc.

The term "alkoxyalkoxy" means that an alkoxy group is substituted by one or more alkoxy groups, wherein the alkoxy group has the meaning as described in the present invention, such examples include, but are not It is not limited to methoxymethoxy, methoxyethoxy, methoxypropoxy, ethoxymethoxy, ethoxyethoxy and the like.

The term "haloalkyl", "haloalkenyl" or "haloalkoxy" denotes an alkyl, alkenyl or alkoxy group respectively substituted with one or more halogen atoms, examples of which include, but are not limited to , trifluoromethyl, trifluoromethoxy, -CH ₂ Cl, -CH ₂ CF ₃ , -CH ₂ CH ₂ CF ₃ and the like.

The term "cyano-substituted alk(oxy)yl" means an alk(oxy)yl group substituted with one or more cyano groups, examples of which include, but are not limited to, -CH ₂ CN, -CH ₂ CH _{2 CN} , _-CH2CH2CH2CN , _-OCH2CN , _-OCH2CH2CN , _{-OCH2CH2CH2CN} , _{-OCH (} CN _{) CH3 ,} etc.

The term "hydroxyl _- substituted alk(oxy)yl" means an alk(oxy)yl group substituted with one or more hydroxy groups, examples of which include, but are not limited to, _-CH2OH , _-CH2CH2OH , _-CH2CH2CH2OH , _-OCH2OH , _-OCH2CH2OH , _{-OCH2CH2CH2OH} , _{-OCH ( OH ) CH3 ,} etc.

The term "alkylthio" refers to a C _1-10 linear or branched alkyl group connected to a divalent sulfur atom, wherein the alkyl group has the meaning as described in the present invention. Such examples include, but are not limited to, methylthio ( _CH3S- ), ethylthio, and the like.

The term "alkylsulfonyl" refers to alkyl-S(=O) ₂ -, wherein alkyl has the meaning as described in the present invention. Examples of such include, but are not limited to, _CH3 -S(=O) _2- , _CH3 - _CH2 -S(=O) _2- , _CH3 - _CH2 - _CH2 -S(=O) _2- , (CH ₃ ) ₂ CH-S(=O) ₂ -etc.

The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms. In one embodiment, cycloalkyl contains 3-12 carbon atoms; In another embodiment, cycloalkyl contains 3-8 carbon atoms; In yet another embodiment, cycloalkyl contains 3-6 carbon atom. The cycloalkyl groups can be independently unsubstituted or substituted with one or more substituents described herein. Such examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl Alkyl, etc.

The term "cycloalkenyl" refers to a monocyclic, bicyclic, or tricyclic hydrocarbon ring having one or more carbon-carbon double bonds, which is generally nonaromatic, and generally has a specified number of ring-forming carbon atoms (i.e., C _3-8 cycloalkenyl refers to cycloalkenyl having 3, 4, 5, 6, 7 or 8 carbon atoms as ring members). A cycloalkenyl group may be attached to the rest of the molecule through any ring atom, unless such attachment would violate valence requirements. The cycloalkenyl groups can be independently unsubstituted or substituted with one or more substituents described herein. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl -3-enyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, and the like.

The term "cycloalkenyl substituted with alkylamino" means that a cycloalkenyl group is substituted by one or more alkylamino groups, wherein cycloalkenyl and alkylamino groups have the meanings as described in the present invention, and the alkylamino and cycloalkenyl groups may independently be unsubstituted or substituted with one or more substituents described herein. Such examples include, but are not limited to, methylamino-substituted cyclobutenyl, ethylamino-substituted cyclobutenyl, or

The term "cycloalkylalkyl" means that an alkyl group is substituted by one or more cycloalkyl groups, wherein the alkyl group and the cycloalkyl group have the meanings described herein, examples of which include , but not limited to cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, etc.

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein, and both refer to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring containing 3-12 ring atoms, wherein the monocyclic, bicyclic or tricyclic The ring does not contain an aromatic ring, and at least one ring atom is selected from nitrogen, sulfur and oxygen atoms. Unless otherwise stated, a heterocyclyl group can be carbonyl or nitrogenyl, and a _-CH2- group can optionally be replaced by -C(O)-. Ring sulfur atoms can optionally be oxidized to S-oxides. Ring nitrogen atoms can optionally be oxidized to N-oxygen compounds. Examples of heterocyclic groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl , pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuryl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolyl, dithiocyclopentyl, tetrahydro Pyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, (1-oxo)-thio Morpholinyl, (1,1-dioxo)-thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, Oxepanyl, thiepanyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl. Examples of -CH ₂ - groups in heterocyclic groups replaced by -C(O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinone Base, 3,5-dioxopiperidinyl. Examples of oxidized sulfur atoms in heterocyclic groups include, but are not limited to, sulfolane, 1,1-dioxothiomorpholinyl. Said heterocyclyl groups may be optionally substituted with one or more substituents described herein.

In one embodiment, the heterocyclic group is a heterocyclic group consisting of 4-7 atoms, which refers to a saturated or partially unsaturated monocyclic ring containing 4-7 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms. Examples of heterocyclic groups consisting of 4-7 atoms include, but are not limited to: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrroline base, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuryl, tetrahydrothiophenyl, dihydrothienyl, 1,3-dioxolyl, dithiocyclopentyl, tetrahydrofuryl Hydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxane Dithianyl, Thioxanyl, Homopiperazinyl, Homopiperidinyl, Oxepanyl, Thiepanyl. Examples of -CH ₂ - groups in heterocyclic groups replaced by -C(O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinone Base, 3,5-dioxopiperidinyl. Examples of oxidized sulfur atoms in heterocyclic groups include, but are not limited to, sulfolane, 1,1-dioxothiomorpholinyl. The heterocyclyl group consisting of 4-7 atoms can be optionally substituted by one or more substituents described in the present invention.

In another embodiment, heterocyclyl is a 4-atom heterocyclyl, which refers to a saturated or partially unsaturated monocyclic ring comprising 4 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur and oxygen atoms . Examples of 4-atom heterocyclic groups include, but are not limited to: azetidinyl, oxetanyl, thietanyl. The 4-atom heterocyclyl group can be optionally substituted with one or more substituents described in the present invention.

In another embodiment, heterocyclyl is a 5-atom heterocyclyl, which refers to a saturated or partially unsaturated monocyclic ring comprising 5 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur and oxygen atoms . Examples of 5-atom heterocyclic groups include, but are not limited to: pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydro Furyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolyl, dithiocyclopentyl. Examples of -CH ₂ - groups replaced by -C(O)- in heterocyclic groups include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl. Examples of oxidized sulfur atoms in heterocyclic groups include, but are not limited to, sulfolane groups. The 5-atom heterocyclyl group may be optionally substituted with one or more substituents described herein.

In another embodiment, heterocyclyl is a 6-atom heterocyclyl, which refers to a saturated or partially unsaturated monocyclic ring comprising 6 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur and oxygen atoms . Examples of 6-atom heterocyclic groups include, but are not limited to: tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, Morpholinyl, Thiomorpholinyl, Piperazinyl, Dioxanyl, Dithianyl, Thioxanyl. Examples of -CH ₂ - groups replaced by -C(O)- in heterocyclic groups include, but are not limited to, 2-piperidinonyl, 3,5-dioxopiperidinyl. Examples of oxidized sulfur atoms in heterocyclic groups include, but are not limited to, 1,1-dioxothiomorpholinyl. The 6-atom heterocyclyl group can be optionally substituted with one or more substituents described in the present invention.

In another embodiment, the heterocyclic group is a heterocyclic group consisting of 7-12 atoms, which refers to a saturated or partially unsaturated spiro heterobicyclic or fused heterobicyclic ring containing 7-12 ring atoms, wherein at least one Ring atoms are selected from nitrogen, sulfur and oxygen atoms. Examples of heterocyclic groups consisting of 7-12 atoms include, but are not limited to: 2-oxa-5-azabicyclo[2.2.1]hept-5-yl. The heterocyclyl group consisting of 7-12 atoms can be optionally substituted with one or more substituents described in the present invention.

In yet another embodiment, heterocyclyl refers to heterocycloalkyl. The term "heterocycloalkyl" refers to a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing 3-12 ring atoms, at least one of which is selected from nitrogen, sulfur or oxygen atoms.

The term "heterocyclylalkyl" refers to a heterocyclyl-substituted alkyl group; wherein the heterocyclyl and alkyl groups have the meanings described herein. Such examples include, but are not limited to, thiomorpholin-4-ylmethyl, tetrahydrofuran-3-ylmethyl, oxetan-3-ylmethyl, pyrrolidin-2-ylmethyl, Lin-4-ylmethyl etc.

The terms "fused bicyclic", "fused ring", "fused bicyclyl" and "fused cycloyl" are used interchangeably herein, and all refer to monovalent or multivalent saturated or partially unsaturated bridged ring systems, so The bridged ring system refers to a non-aromatic bicyclic system. Such a system may contain independent or conjugated unsaturated systems, but its core structure does not contain aromatic rings or aromatic heterocycles (although aromatic groups may act as substituents thereon).

The terms "spirocyclyl", "spirocycle", "spirobicyclyl" or "spirobicyclo" are used interchangeably herein to refer to monovalent or multivalent saturated or partially unsaturated ring systems in which one ring is derived from the other A specific ring carbon atom on a ring. For example, a saturated bridged ring system (rings B and B') as described in formula a is called a "fused bicyclic ring", and rings A and B share a carbon atom in the two saturated ring systems, Known as "spirocycle" or "spirobicycle". Each ring in the fused bicyclyl and spirobicyclyl can be carbocyclyl or heterocyclyl, and each ring is optionally substituted with one or more substituents described herein.

The term "n atoms", where n is an integer, typically describes the number of ring atoms in a molecule, the number of ring atoms in said molecule being n. For example, piperidinyl is a heterocycloalkyl group consisting of 6 atoms.

As used herein, the term "unsaturated" means that a group contains one or more degrees of unsaturation.

The term "heteroatom" refers to O, S, N, P, and Si, including forms in any oxidation state of N, S, and P; forms of primary, secondary, and tertiary amines, and quaternary ammonium salts; or Hydrogen-substituted forms, for example, N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like N-substituted pyrrolidinyl NR).

The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

The term "aryl" denotes monocyclic, bicyclic and tricyclic carbocyclic ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic family in which each ring system contains rings of 3-7 atoms and has one or more points of attachment to the rest of the molecule. The term "aryl" is used interchangeably with the term "aromatic ring". Examples of aryl groups may include phenyl, indenyl, naphthyl and anthracenyl. The aryl groups may be independently optionally substituted with one or more substituents described herein.

The term "arylalkyl" or "aralkyl" means that an alkyl group is substituted by one or more aryl groups, wherein the alkyl and aryl groups have the meanings described herein, examples of which include, However, it is not limited to benzyl, phenethyl, p-tolylethyl and the like.

The term "heteroaryl" denotes monocyclic, bicyclic and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring system is aromatic, And at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring composed of 5-7 atoms and has one or more points of attachment to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl" or "heteroaromatic". The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, the heteroaryl group of 5-10 atoms contains 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.

Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl , 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2- Pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3- Triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5- Triazinyl; also includes, but is by no means limited to, the following bicyclic rings: benzimidazolyl, benzofuryl, benzothienyl, indolyl (eg 2-indolyl), purinyl, quinolinyl (such as 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (such as 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl), imidazole And[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazole And[1,5-a]pyridyl, etc.

The term "heteroarylalkyl" means that an alkyl group is substituted by one or more heteroaryl groups, wherein the alkyl group and the heteroaryl group have the meanings described herein, examples of which include , but not limited to pyridin-2-ylethyl, thiazol-2-ylmethyl, imidazol-2-ylethyl, pyrimidin-2-ylpropyl, etc.

The term "carboxy", whether used alone or in combination with other terms, such as "carboxyalkyl", means _-CO2H .

The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino", wherein the amino groups are each independently substituted with one or two alkyl groups. In some embodiments, alkylamino is a lower alkylamino group with one or two C _1-6 alkyl groups attached to a nitrogen atom. In some other embodiments, the alkylamino is a C _1-3 lower alkylamino group. Suitable alkylamino groups may be mono- or di-alkylamino, examples of which include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N- -Diethylamino and the like.

The term "cyano-substituted alkylamino" means that an alkylamino group is substituted with one or more cyano groups, examples of which include, but are not limited to, -NHCH ₂ CN, -N(CH ₃ )CH ₂ CN, - _NHCH2CH2CN , _{-NHCH2CH2CH2CN} , -N( _{CH3 ) CH} (CN _{) CH3} , etc.

The term "hydroxyl-substituted alkylamino" means that an alkylamino group is substituted with one or more hydroxyl groups, examples of which include, but are not limited to, -NHCH ₂ OH, -N(CH ₃ )CH ₂ OH, -NHCH ₂ CH2OH, _{-NHCH2CH2CH2OH} , -N( _{CH3 ) CH} (OH _{) CH3} , etc.

The term "alkylaminoalkyl" means that an alkyl group is substituted by one or more alkylamino groups, wherein the alkyl group and the alkylamino group have the meanings described herein, examples of which include, but do not Not limited to N-methylaminomethyl, N-ethylaminomethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl and the like.

The term "aminoalkyl" includes C _1-10 straight or branched chain alkyl groups substituted with one or more amino groups. In some embodiments, aminoalkyl is C _1-6 "lower aminoalkyl" substituted with one or more amino groups, examples of which include, but are not limited to, aminomethyl, amino Ethyl, aminopropyl, aminobutyl and aminohexyl.

The term "protecting group" or "PG" refers to a substituent that reacts with other functional groups, usually to block or protect specific functionality. For example, "amino-protecting group" refers to a substituent attached to the amino group to block or protect the functionality of the amino group in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, a "hydroxyl protecting group" refers to a substituent of a hydroxy group used to block or protect the functionality of the hydroxy group, suitable protecting groups include acetyl and silyl groups. "Carboxyl protecting group" refers to the substituent of carboxyl to block or protect the functionality of carboxyl. General carboxyl protecting groups include -CH ₂ CH ₂ SO ₂ Ph, cyanoethyl, 2-(trimethylsilane base) ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenyl phosphino)ethyl, nitroethyl, etc. For a general description of protecting groups, reference can be made to: TW. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and P.J. Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

The term "prodrug" used in the present invention means that a compound is transformed into a compound represented by formula (I), (Ia), (Ib), (Ic), (Id) or (II) in vivo. Such conversion is effected by prodrug hydrolysis in blood or enzymatic conversion in blood or tissue to the parent structure. The prodrug compound of the present invention can be an ester. In the existing invention, the ester can be used as a prodrug with phenyl esters, aliphatic (C _1-24 ) esters, acyloxymethyl esters, and carbonates. , carbamates and amino acid esters. For example, a compound of the present invention that contains a hydroxyl group can be acylated to give a prodrug form of the compound. Other prodrug forms include phosphate esters, eg, phosphorylated parent hydroxyl groups. A complete discussion of prodrugs can refer to the following literature: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A. CSS Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al., Prodrugs: Designs and Clinical Applic Nature Review Drug Discovery, 2008, 7, 255-270, and S.J. Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

"Metabolite" refers to a product obtained through metabolism of a specific compound or its salt in vivo. Metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized using assays as described herein. Such products can be obtained by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, degreasing, enzymatic cleavage and the like of the administered compound. Accordingly, the invention includes metabolites of the compounds, including metabolites produced by contacting a compound of the invention with a mammal for a substantial period of time.

The "pharmaceutically acceptable salt" used in the present invention refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. The present invention also contemplates the quaternary ammonium salts of any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations formed as counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C _{1 -8} sulfonates and aromatic sulfonates.

A "solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association of solvent molecules with water.

The term "treating" any disease or condition as used herein means, in some embodiments, ameliorating the disease or condition (ie, slowing or arresting or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to modulating a disease or condition either physically (eg, stabilizing a perceived symptom) or physiologically (eg, stabilizing a parameter of the body), or both. In other embodiments, "treating" refers to preventing or delaying the onset, development or worsening of a disease or condition.

"Inflammatory disease" as used herein refers to any disease, disorder or condition in which excessive inflammatory symptoms, host tissue damage or loss of tissue function result from an excessive or uncontrolled inflammatory response. "Inflammatory disease" also refers to pathological conditions mediated by leukocyte influx and/or neutrophil chemotaxis.

As used herein, "inflammation" refers to a localized protective response caused by tissue damage or destruction, which serves to destroy, dilute or compartmentalize (sequester) harmful substances and damaged tissue. Inflammation was significantly associated with leukocyte influx and/or neutrophil chemotaxis. Inflammation can arise from infection with pathogenic organisms and viruses as well as from non-infectious means such as trauma or reperfusion after myocardial infarction or stroke, immune response to foreign antigens and autoimmune response. Thus, inflammatory diseases that may be treated with the compounds disclosed herein include diseases associated with specific defense system responses as well as non-specific defense system responses.

As used herein, "autoimmune disease" or "autoimmune disease" refers to any collection of diseases that involve tissue damage associated with humoral or cell-mediated responses to the body's own components. Examples of autoimmune diseases include lupus, multiple sclerosis, amyotrophic lateral sclerosis, rheumatoid arthritis, psoriasis, type I diabetes, complications due to organ transplantation, foreign body transplantation, diabetes, cancer, asthma, Atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and lymphoma.

"Arthritic disease" as used herein refers to any disease characterized by arthritic damage attributable to various etiologies. "Dermatitis" as used herein refers to any of a large family of skin disorders characterized by inflammation of the skin attributable to various etiologies. "Transplant rejection" as used herein refers to any immune response against transplanted tissue, such as an organ or cells such as bone marrow, characterized by loss of function of the transplant or surrounding tissues, pain, swelling, leukocytosis and thrombocytopenia. The therapeutic methods of the invention include methods for treating diseases associated with inflammatory cell activation.

The terms "cancer" and "cancerous" refer to or describe a physiological condition in a patient that is often characterized by uncontrolled cell growth. A "tumor" comprises one or more cancer cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia, or lymphoid malignancies. More specific examples of such cancers include squamous cell carcinoma (such as epithelial squamous cell carcinoma), lung cancer (including small cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma and lung squamous carcinoma), peritoneal carcinoma, Hepatocellular carcinoma, gastric cancer (including gastrointestinal cancer), pancreatic cancer, malignant glioma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, Colon cancer, rectal cancer, colorectal cancer, endometrial or uterine cancer, salivary gland cancer, kidney or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer (hepaticcarcinoma), anal cancer, penile cancer and head and neck cancer.

The term "biological specimen" used in the present invention refers to specimens outside the living body, including but not limited to, cell culture or cell extraction; biopsy material obtained from mammals or their extracts; blood, saliva, urine, Feces, semen, tears, or other liquid substances of living tissue and their extracts. Inhibition or regulation of kinase activity in biological samples, particularly BLK, JAK1, JAK2, JAK3, BTK, BMX, TEC, ITK, TXK, HER2, HER4, EGFR or EGFRT790M kinase activity, can be used for various purposes known to those skilled in the art . Such uses include, but are by no means limited to, blood transfusions, organ transplantation, biospecimen storage, and bioassays.

Pharmaceutical compositions of compounds of the present invention

The present invention provides a pharmaceutical composition, which comprises the compound disclosed in the present invention and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or a combination thereof. The amount of the compound in the pharmaceutical composition disclosed in the present invention refers to the amount that can effectively detect and inhibit the protein kinase in biological samples or patients.

It will also be recognized that some of the compounds of the invention may exist in free form for use in therapy or, if appropriate, as a pharmaceutically acceptable derivative thereof. Some non-limiting embodiments of pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of these esters, or the ability to directly or indirectly provide the present invention when administered to a patient in need thereof. Any additional adducts or derivatives of the compound or its metabolites or residues.

The pharmaceutical composition disclosed in the present invention can be prepared and packaged in bulk form, wherein safe and effective amount of formula (I), (Ia), (Ib), (Ic), (Id) or (II) can be extracted The indicated compounds are then administered to the patient in powder or syrup form. Alternatively, the pharmaceutical compositions disclosed herein may be prepared and packaged in unit dosage form, wherein each physically discrete unit contains a safe and effective amount of Formula (I), (Ia), (Ib), (Ic), (Id) Or the compound shown in (II). When prepared in unit dosage form, the pharmaceutical compositions disclosed herein may generally contain, for example, 0.5 mg to 1 g, or 1 mg to 700 mg, or 5 mg to 100 mg of a compound disclosed herein. The dosage forms include those suitable for the following routes of administration: (1) Oral administration, such as tablets, capsules, caplets, pills, troches, powders, granules, syrups, elixirs, mixtures Suspensions, solutions, emulsions, sachets and cachets; (2) parenteral administration, such as sterile solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems and (3) transdermal administration, such as transdermal patch; (4) rectal administration, such as suppository; (5) inhalation, such as aerosol, solution and dry powder; and (6) topical Administration such as creams, ointments, lotions, solutions, pastes, sprays, foams and gels.

The "pharmaceutically acceptable excipient" used in the present invention means a pharmaceutically acceptable material, mixture or vehicle related to the consistency of the administered dosage form or pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when mixed to avoid interactions that would substantially reduce the efficacy of the compounds disclosed in this invention when administered to a patient and would result in a pharmaceutical composition that is not pharmaceutically acceptable Interaction. Furthermore, each excipient must be pharmaceutically acceptable, eg, of sufficiently high purity.

Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form chosen. Furthermore, pharmaceutically acceptable excipients can be selected according to their specific function in the composition. Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents , solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste-masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, tackifiers, antioxidants, Preservatives, stabilizers, surfactants and buffers. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may serve more than one function, and may serve alternative functions, depending on how much of that excipient and which other excipients are present in the formulation. agent.

The skilled artisan possesses the knowledge and skill in the art to enable them to select appropriate pharmaceutically acceptable excipients in appropriate amounts for use in the present invention. Furthermore, there are numerous resources available to the skilled artisan which describe pharmaceutically acceptable excipients and are useful in selecting suitable pharmaceutically acceptable excipients.

In Remington: The Science and Practice of Pharmacy, 21 stedition, 2005, ed.D.B.Troy, LippincottWilliams&Wilkins, Philadelphia, and EncyclopediaofPharmaceuticalTechnology, eds.J.SwarbrickandJ.C.Boylan, 1988-1999, MarcelDekker, NewYork Disclosed in the combination pharmaceutically acceptable various vectors, and known techniques for their preparation, the contents of each of these documents are incorporated into the present invention by reference. Concerned about the use of any of the compounds disclosed herein, except for any commonly used carriers that are incompatible with the compounds disclosed herein, such as by producing any undesired biological effects, or by interacting in a deleterious manner with any other ingredient in a pharmaceutically acceptable composition scope of the invention.

The pharmaceutical compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. Descriptions of some common methods in this field can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company).

Uses of the compounds and compositions of the invention

The present invention provides the use of the compounds and pharmaceutical compositions disclosed herein to treat, prevent, or ameliorate diseases or disorders mediated or otherwise affected by the action of JAK kinases, including JAK1, JAK2, JAK3, or TYK2 kinases, or by JAK kinases, including JAK1 , JAK2, JAK3, or TYK2 kinase activity mediated or otherwise affected by one or more symptoms of a disease or disorder.

The JAK kinase can be wild-type and/or mutated of a JAK1, JAK2, JAK3 or TYK2 kinase.

In one embodiment, the present invention provides a class of compounds disclosed herein or pharmaceutical compositions comprising compounds disclosed herein for use in the treatment, prevention or amelioration of JAK1 kinase mediated or otherwise affected by inappropriate JAK1 kinase activity or one or more symptoms of a disease or disorder mediated or otherwise affected by inappropriate JAK1 kinase activity.

In another embodiment, the disease, disorder, or one or more symptoms of the disease or disorder is associated with inappropriate JAK2 kinase activity or is associated with inappropriate JAK3 kinase activity.

"Inappropriate JAK kinase behavior" refers to JAK kinase behavior that deviates from normal JAK kinase behavior that occurs in a particular patient. Inappropriate JAK kinase behavior can take the form of, for example, abnormal increases in activity, or deviations in the timing and control of JAK kinase behavior. Such inappropriate kinase behavior arises from, for example, overexpression or mutation of protein kinases resulting in inappropriate or uncontrolled behavior. Accordingly, the present invention provides methods of treating these diseases and disorders.

Consistent with the description above, such diseases or disorders include, but are not limited to: myeloproliferative disorders such as polycythemia vera (PCV), essential thrombocythemia, idiopathic myelofibrosis (IMF); leukemia, Examples of myeloid leukemia include chronic myeloid leukemia (CML), imatinib-resistant forms of CML, acute myeloid leukemia (AML) and subtypes of AML, acute megakaryoblastic leukemia (AMKL); lymphoproliferative disorders such as Myeloma; cancers including head and neck cancer, prostate cancer breast cancer, ovarian cancer, melanoma, lung cancer, brain tumors, pancreatic cancer, and kidney cancer; and inflammatory diseases or disorders associated with immune dysfunction, immunodeficiency, and immune regulation , autoimmune disease, tissue transplant rejection, graft versus host disease, wound healing, renal disease, multiple sclerosis, thyroiditis, type I diabetes, sarcoidosis, psoriasis, allergic rhinitis, inflammatory bowel disease including Crohn's disease and ulcerative colitis (UC), systemic lupus erythematosus (SLE), arthritis, osteoarthritis, rheumatoid arthritis, osteoporosis, asthma and chronic obstructive pulmonary disease (COPD) and dry Eye syndrome (or keratoconjunctivitis sicca (KCS)).

In one aspect, the present invention provides a class of compounds disclosed in the present invention or pharmaceutical compositions comprising the compounds disclosed in the present invention, for the prevention and/or treatment of proliferative diseases, autoimmune diseases, allergic diseases in mammals (including humans) disease, inflammatory disease, or transplant rejection.

In another aspect, the invention provides a method of treating a mammal suffering from or at risk of suffering from a disease disclosed herein, the method comprising administering an amount effective to treat the condition or an amount effective to prevent the condition of one or more of the compounds disclosed herein. pharmaceutical compositions or compounds. In another aspect, the invention provides a method of treating a mammal suffering from, or at risk of developing, a proliferative disease, an autoimmune disease, an allergic disease, an inflammatory disease, or transplant rejection.

In one method of treatment, the present invention provides a method of treating and/or preventing a mammal susceptible to or suffering from a proliferative disease, said method comprising administering a therapeutically effective amount or an effective prophylactic amount of one or more of the present invention. The pharmaceutical composition or compound disclosed by the invention. In particular examples, the proliferative disorder is selected from cancer (e.g., solid tumors such as uterine leiomyosarcoma or prostate cancer), polycythemia vera, essential thrombocythemia, myelofibrosis, leukemia (e.g., AML, CML, ALL or CLL) and multiple myeloma.

In another aspect, the present invention provides a class of compounds disclosed herein for use in the treatment and/or prevention of proliferative diseases. In particular embodiments, the proliferative disease is selected from cancer (e.g., solid tumors such as uterine leiomyosarcoma or prostate cancer), polycythemia vera, essential thrombocythemia, myelofibrosis, leukemia (e.g., AML, CML , ALL or CLL) and multiple myeloma.

In another aspect, the present invention provides a class of compounds disclosed in the present invention, or a pharmaceutical composition comprising the compounds disclosed in the present invention, for the preparation of medicines for treating or preventing proliferative diseases. In particular examples, the proliferative disorder is selected from cancer (e.g., solid tumors such as uterine leiomyosarcoma or prostate cancer), polycythemia vera, essential thrombocythemia, myelofibrosis, leukemia (e.g., AML, CML, ALL or CLL) and multiple myeloma.

In another aspect, the present invention provides a method of treating and/or preventing a mammal susceptible to or suffering from an autoimmune disease, said method comprising administering a therapeutically effective amount or an effective prophylactic amount of one or more of the medicaments disclosed herein composition or compound. In particular examples, the autoimmune disease is selected from COPD, asthma, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjogren's syndrome, psoriasis, type I diabetes, and inflammatory bowel disease.

In another aspect, the present invention provides a class of compounds disclosed herein for use in the treatment and/or prevention of autoimmune diseases. In a particular embodiment, the autoimmune disease is selected from the group consisting of COPD, asthma, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjogren's syndrome, psoriasis, type I diabetes and inflammatory bowel disease .

In another aspect, the present invention provides a class of compounds disclosed in the present invention, or a pharmaceutical composition comprising the compounds disclosed in the present invention, for the preparation of medicines for treating or preventing autoimmune diseases. In a particular embodiment, the autoimmune disease is selected from the group consisting of COPD, asthma, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjogren's syndrome, psoriasis, type I diabetes and inflammatory bowel disease .

In another aspect, the present invention provides a method of treating and/or preventing a mammal susceptible to or suffering from an allergic disease, said method comprising administering a therapeutically effective amount or an effective prophylactically effective amount of one or more of the medicaments disclosed herein composition or compound. In a particular embodiment, the allergic disease is selected from respiratory allergic disease, sinusitis, eczema and measles, food allergy and insect venom allergy.

In another aspect, the present invention provides a class of compounds disclosed herein for use in the treatment and/or prevention of allergic diseases. In a particular embodiment, the allergic disease is selected from respiratory allergic disease, sinusitis, eczema and measles, food allergy and insect venom allergy.

In another aspect, the present invention provides a class of compounds disclosed in the present invention, or a pharmaceutical composition comprising the compounds disclosed in the present invention, for the preparation of medicines for treating or preventing allergic diseases. In a particular embodiment, the allergic disease is selected from respiratory allergic disease, sinusitis, eczema and measles, food allergy and insect venom allergy.

In another aspect, the present invention provides a method of treating and/or preventing a mammal susceptible to or suffering from an inflammatory disease, said method comprising administering a therapeutically effective amount or an effective prophylactic amount of one or more of the medicaments disclosed herein composition or compound. In a particular embodiment, the inflammatory disease is selected from inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, juvenile arthritis and psoriatic arthritis.

In another aspect, the present invention provides a class of compounds disclosed herein for use in the treatment and/or prevention of inflammatory diseases. In a particular embodiment, the inflammatory disease is selected from inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, juvenile arthritis and psoriatic arthritis.

In another aspect, the present invention provides a class of compounds disclosed in the present invention, or a pharmaceutical composition comprising the compounds disclosed in the present invention, for the preparation of medicines for treating or preventing inflammatory diseases. In a particular embodiment, the inflammatory disease is selected from inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, juvenile arthritis and psoriatic arthritis.

In another aspect, the present invention provides a method of treating and/or preventing a mammal susceptible to or suffering from transplant rejection, said method comprising administering a therapeutically effective amount or an effective prophylactic amount of one or more of the pharmaceutical combinations disclosed herein substance or compound. In particular examples, transplant rejection is organ transplant rejection, tissue transplant rejection, and cell transplant rejection.

In another aspect, the present invention provides a class of compounds disclosed herein for use in the treatment and/or prevention of transplant rejection. In specific embodiments, the transplant rejection is organ transplant rejection, tissue transplant rejection, and cell transplant rejection.

In another aspect, the present invention provides a class of compounds disclosed in the present invention, or a pharmaceutical composition comprising the compounds disclosed in the present invention, for the preparation of medicines for treating or preventing transplant rejection. In particular examples, transplant rejection is organ transplant rejection, tissue transplant rejection, and cell transplant rejection.

In another aspect, the present invention provides a class of compounds disclosed herein for use as a medicament, especially as a medicament for the treatment and/or prophylaxis of the aforementioned diseases. Also provided is the use of the disclosed compounds in the manufacture of medicaments for the treatment and/or prevention of the aforementioned diseases.

A particular aspect of the method comprises administering to a subject suffering from inflammation an effective amount of a compound disclosed herein for a period of time sufficient to reduce the level of inflammation in the subject, and preferably terminate the progression of said inflammation. A particular embodiment of the method comprises administering to a subject patient suffering from or susceptible to rheumatoid arthritis of bone an effective amount of a compound disclosed herein for a period of time sufficient to reduce or prevent joint inflammation, respectively, in said patient, and preferably Terminate the inflammatory process.

Another particular embodiment of this method comprises administering to a subject suffering from a proliferative disease an effective amount of a compound disclosed herein for a period of time sufficient to reduce the level of the proliferative disease in the subject, and preferably to terminate the progression of the proliferative disease. process. A particular embodiment of this method comprises administering to a subject having cancer an effective amount of a compound disclosed herein for a period of time sufficient to reduce or prevent, respectively, symptoms of, and preferably terminate the progression of, said cancer in said patient.

combination therapy

The compounds of the present invention may be administered as the sole active agent, or may be administered in combination with other therapeutic agents, including other compounds that have the same or similar therapeutic activity and are determined to be safe and effective for such combination administration.

In one aspect, the present invention provides a method for treating, preventing or ameliorating a disease or condition, comprising administering a safe and effective amount of a combination drug comprising a compound disclosed in the present invention and one or more therapeutically active agents. In one embodiment, the combination comprises one or two other therapeutic agents. For example, the combination of compounds disclosed in the present invention with β ₂ -adrenoceptor agonists, corticosteroids, non-steroidal GR agonists, non-steroidal anti-inflammatory drugs (NSAID's), phosphodiesterase 4 (PDE4) inhibitors, Combinations of anticholinergics, H1 antagonists, antihistamines or combinations thereof.

Examples of other therapeutic agents include, but are not limited to: anti-cancer agents, including chemotherapeutics and anti-proliferative agents; anti-inflammatory agents; and immunomodulators or immunosuppressants.

In another aspect, the invention provides a product comprising a compound of the invention and at least one other therapeutic agent, prepared as a combination for simultaneous, separate or sequential administration in therapy. In one embodiment, the treatment is for a disease or condition mediated by JAK kinase activity. Combination preparations provide products that include compositions comprising a compound of the invention and the other therapeutic agent in the same pharmaceutical composition, or in different forms, eg, a kit.

In another aspect, the invention provides a pharmaceutical composition comprising a compound disclosed herein and one or more additional therapeutic agents. In one embodiment, the pharmaceutical composition may comprise a pharmaceutically acceptable excipient, carrier, adjuvant or vehicle as described above.

In another aspect, the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which comprises a compound disclosed herein. In one embodiment, the kit includes means for individually maintaining the compositions, such as containers, divided bottles or divided foil boxes. An example of such a kit is a blister pack, which is commonly used for packaging tablets, capsules and the like.

The invention also provides the use of a compound of the invention in the treatment of a disease or condition mediated by JAK kinase activity, wherein the patient has been previously (eg, within 24 hours) treated with another therapeutic agent. The invention also provides the use of other therapeutic agents in the treatment of diseases and conditions mediated by JAK kinase activity, wherein the patient has been previously (eg, within 24 hours) treated with a compound of the invention.

The compounds disclosed herein may also be advantageously used in combination with other compounds, or in combination with other therapeutic agents, especially antiproliferative agents. Such antiproliferative agents include, but are not limited to, aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule activating agents; alkylating agents; histone deacetylation Enzyme inhibitors; compounds that induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platinum compounds; compounds that target/reduce protein or lipid kinase activity and other anti- Angiogenic compounds; Compounds that target, decrease, or inhibit protein or lipid phosphatase activity; Gonadorelin-like agonists; Antiandrogens; Methionine aminopeptidase inhibitors; Bisphosphonates; Biological response modifiers ; antiproliferative antibodies; heparanase inhibitors; Ras oncogenic isoform inhibitors; telomerase inhibitors; Inhibitor; Temozolomide and calcium folinate.

"Combination" means a fixed combination in a single dosage unit form or a kit of parts for combined administration wherein the compound disclosed herein and the combination partner may be administered independently at the same time or may be administered separately at intervals , especially to make joint partners exhibit cooperation, such as synergy. The terms "co-administration" or "combination administration" and the like are intended to encompass the administration of a selected combination partner to a single individual (e.g. a patient) in need thereof, and are intended to include treatments where the substances are not necessarily administered by the same route of administration or at the same time Program. The term "pharmaceutical combination" means a product resulting from the mixing or combination of more than one active ingredient and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredient, such as a compound disclosed herein, and the combination partner are administered to the patient simultaneously as a single entity or dosage. The term "non-fixed combination" means that the active ingredients, such as the compounds disclosed in the present invention, and the combination partner are administered to the patient as separate entities simultaneously, jointly or sequentially with no specific time limit, wherein the administration method provides two Therapeutically effective levels of compounds. The latter also applies to cocktail therapy, eg the administration of three or more active ingredients.

General Synthesis Process

Generally, the compounds of the present invention can be prepared by the methods described in the present invention, unless there are further instructions, wherein the substituents are defined as formula (I), (Ia), (Ib), (Ic), (Id) Or as shown in (II). The following reaction schemes and examples serve to further illustrate the present invention.

Those skilled in the art will recognize that the chemical reactions described herein can be used to suitably prepare many other compounds of the invention and that other methods for preparing the compounds of the invention are considered to be within the scope of the invention Inside. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art through modification methods, such as appropriate protection of interfering groups, by using other known reagents in addition to those described in the present invention, or by incorporating Reaction conditions with some routine modifications. In addition, reactions disclosed herein or known reaction conditions are also recognized to be applicable to the preparation of other compounds of this invention.

In the examples described below, all temperatures are in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. Common reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd. and Qingdao Haiyang Chemical Factory.

Anhydrous tetrahydrofuran, dioxane, toluene, and ether were obtained by reflux drying over sodium metal. Anhydrous dichloromethane and chloroform were obtained by refluxing and drying over calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.

The following reactions were generally carried out under a positive pressure of nitrogen or argon or over anhydrous solvents with a dry tube (unless otherwise indicated), the reaction vials were fitted with suitable rubber stoppers, and the substrate was introduced by syringe. Glassware is dried.

The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory. The test conditions of proton nuclear magnetic resonance spectrum are: under room temperature, Bruker 400MHz or 600MHz nuclear magnetic instrument, with CDC1 ₃ , d ⁶ -DMSO, CD ₃ OD or d ⁶ -acetone as solvent (reported in ppm) , with TMS (0ppm) or chloroform (7.26ppm) as a reference standard. When multiplets appear, the following abbreviations will be used: s (singlet, singlet), d (doublet, doublet), t (triplet, triplet), q (quartet, quartet), m (multiplet, multiplet), br (broadened, broad peak), dd (doubletofdoublets, double doublet), dt (doubletoftriplets, double triplet). Coupling constants are expressed in Hertz (Hz).

The conditions for low-resolution mass spectrometry (MS) data determination are: Agilent6120QuadrupoleHPLC-MS (column model: ZorbaxSB-C18, 2.1x30mm, 3.5μm, 6min, flow rate is 0.6mL/min, mobile phase: 5%-95% (containing 0.1 % formic acid ( _CH3CN ) in ( _H2O with 0.1% formic acid))) with UV detection at 210/254 nm in electrospray ionization mode (ESI).

The characterization method of compound purity is: Agilent1260 preparative high-performance liquid chromatography (Pre-HPLC) or CalesepPump250 preparative high-performance liquid chromatography (Pre-HPLC) (column model: NOVASEP, 50/80mm, DAC), used at 210nm/254nm UV detection.

The following abbreviations are used throughout this disclosure:

HPLC high performance liquid chromatography; H ₂ O water; MeOH, CH ₃ OH methanol; CD ₃ OD deuterated methanol; EtOH, ethanol ethanol; HCOOH formic acid; CH ₃ CN, MeCN acetonitrile; DCM, CH ₂ Cl ₂ dichloromethane; CHCl ₃ chloroform, chloroform; CDCl ₃ deuterochloroform; DMFN, N-dimethylformamide; DMACN, N-dimethylacetamide; EDCI 1-(3-dimethylaminopropyl)-3-ethyl Carbodiimide hydrochloride; HOBT1-hydroxybenzotriazole; HATU2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; SEMCl2 -(trimethylsilyl)ethoxymethyl chloride; NBSN-bromosuccinimide; THF tetrahydrofuran; TFA trifluoroacetic acid; PE, Petroleumether petroleum ether; EtOAc ethyl acetate; NaOH sodium hydroxide; _Na2 SO ₄ sodium sulfate; (Boc) ₂ O di-tert-butyl dicarbonate; BOC, Boc tert-butoxycarbonyl; CBZ, Cbz benzyloxycarbonyl; con.HCl concentrated hydrochloric acid; NH ₄ Cl ammonium chloride; H ₂ hydrogen.

Synthetic method one

The target compound 8 can be prepared by Synthesis Method 1, wherein R ^1a , R ² , R ³ , R ⁴ and R ⁵ have the meanings as described in the present invention. Compound 2 is obtained by protecting compound 1 with di-tert-butyl dicarbonate, compound 2 and R ⁴ NH ₂ are condensed under the action of a condensation reagent to obtain amide compound 3, compound 3 is deprotected to obtain compound 4, compound 4 and compound 5 are catalyzed by base or acid Compound 6 is obtained by reaction, compound 6 is reduced to obtain compound 7, and compound 7 is condensed with acid to obtain target compound 8.

Synthetic method two

The target compound 14 can be prepared by Synthesis Method 2, wherein R ^1a , R ² , R ³ , R ⁴ and R ⁵ have the meanings as described in the present invention. Compound 9 is esterified to obtain compound 10. After compound 10 is reacted with a strong base, an electrophile is added to obtain compound 11. Compound 11 is hydrolyzed under concentrated hydrochloric acid to obtain compound 2. Compound 2 is condensed with amine R ⁴ -NH-R ⁵ to obtain compound 12. Compound 12 was deprotected to obtain compound 13, and compound 13 was reacted with compound 5 to obtain target compound 14.

Synthetic method three

The target compound 17 can be prepared by synthetic method three, wherein R ^1b , R ² , R ³ , R ⁶ and R ⁷ have the meanings as described in the present invention. Compound 15 is reacted with compound 5 under the action of base to obtain compound 16, and compound 16 is condensed with amine R ⁶ -NH-R ⁷ to obtain target compound 17.

Synthetic method four

The target compound 22 can be prepared by synthetic method 4, wherein R ^1d , R ² , R ³ , R ⁸ and R ¹² have the meanings as described in the present invention. Compound 18 is reacted with compound 5 under the action of base to obtain compound 19, compound 19 is condensed with amine R ⁸ -NH ₂ to obtain compound 20, compound 20 is reduced by borane or tetrahydrolithium aluminum to obtain compound 21, compound 21 and carboxylic acid R The target compound 22 was obtained by ¹² -COOH reaction.

Synthetic method five

The target compound 26 can be prepared by synthetic method five, wherein PG is a protecting group, such as Boc or Cbz, etc.; p, q and R ¹⁴ have the meanings as described in the present invention. Compound 23 was reacted with compound 5 to obtain compound 24, compound 24 was deprotected to obtain compound 25, and compound 25 was subjected to condensation reaction or alkylation reaction to obtain target compound 26.

Synthetic method six

The target compound 30 can be prepared by synthetic method 6, wherein PG is a protecting group, such as Boc or Cbz, etc.; r, s and R ¹⁴ have the meanings as described in the present invention. Compound 27 was reacted with compound 5 to obtain compound 28, compound 28 was deprotected to obtain compound 29, compound 29 was subjected to condensation reaction or alkylation reaction to obtain target compound 30.

Synthetic method seven

The target compound 34 can be prepared by synthetic method 7, wherein PG is a protecting group, such as Boc or Cbz, etc.; w and R ¹³ have the meanings as described in the present invention. Compound 31 was reacted with compound 5 to obtain compound 32, compound 32 was deprotected to obtain compound 33, compound 33 was subjected to condensation reaction or alkylation reaction to obtain target compound 34.

Synthetic method eight

Target compounds 43 and 46 can be prepared by synthetic method 8, wherein R ¹⁴ has the meaning as described in the present invention. Compound 35 was esterified to obtain compound 36, compound 36 was reacted with compound 37 to obtain compound 38, compound 38 was reacted with bromoacetonitrile under the action of a strong base to obtain compound 39, and compound 39 was reduced to obtain compound 40. Compound 41 was obtained by reacting in the presence of the compound 41, compound 42 was obtained by alkylation reaction of compound 41, and the target compound 43 was obtained by deprotection of compound 42.

Compound 41 was reduced by borane or lithium aluminum tetrahydrogen to obtain compound 44, compound 44 was subjected to alkylation reaction or condensation reaction to obtain compound 45, and compound 45 was deprotected to obtain the target compound 46.

Example

Example 1 (R)-N-((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methyl)-2-cyano-N-methyl Acetamide

Step 1: Synthesis of compound (R)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid

At room temperature, D-proline (10.0g, 86.80mmol) was dissolved in tetrahydrofuran (16mL) and water (40mL), and sodium bicarbonate (18.2g, 217.14mmol) and di-tert-butyl dicarbonate (27.3 mL, 130.20mmol), reacted overnight at room temperature, quenched with water (50mL), extracted with ethyl acetate (150mL×3), dried with anhydrous Na ₂ SO ₄ , removed the solvent, and the concentrated solution was separated by column chromatography (eluent : CH ₂ Cl ₂ /MeOH (v/v)=30/1), to obtain 9.3 g of colorless oil, yield: 50%.

MS(ESI,pos.ion)m/z:160.1[Mt-Bu+2] ⁺ .

Step 2: Synthesis of compound (R)-tert-butyl 2-(methylcarbamoyl)pyrrolidine-1-carboxylate

At room temperature, (R)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.30g, 6.03mmol) was dissolved in dichloromethane (15mL), and triethylamine (2.1mL, 15.1 mmol), EDCI (1.73g, 9.06mmol), HOBT (1.22g, 9.06mmol) and methylamine hydrochloride (611.82mg, 9.06mmol), react at room temperature for 16h, add saturated aqueous ammonium chloride solution (10mL) to quench , extracted with dichloromethane (15mL×3), the organic phases were combined and washed with saturated ammonium chloride solution (50mL), dried over anhydrous sodium sulfate, concentrated and separated by column chromatography (eluent: PE/EtOAc (v/v) =5/1), 800 mg of white solid was obtained, yield: 58%.

MS(ESI,pos.ion)m/z:229.2[M+1] ⁺ .

Step 3: Synthesis of compound (R)-N-methyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide

Dissolve (R)-tert-butyl 2-(methylcarbamoyl)pyrrolidine-1-carboxylate (1.0 g, 4.38 mmol) in dichloromethane (5 mL) at room temperature and add trifluoroacetic acid ( 1 mL), after stirring at room temperature for 2 h, the raw material disappeared, and the solvent was directly concentrated for the next reaction.

Take the deprotected product (300mg, 2.34mmol), add N,N-dimethylacetamide (6mL), 4-chloropyrrolo[2,3-d]pyrimidine (358.6mg, 2.34mmol), potassium carbonate (968.76 mg, 7.02mmol), reacted in an oil bath at 90°C for 5h, quenched with water (15mL), extracted with dichloromethane (15mL×3), dried with anhydrous Na ₂ SO ₄ , removed the solvent, and the concentrated solution was separated by column chromatography ( Eluent: CH ₂ Cl ₂ /MeOH (v/v)=30/1), to obtain 280 mg of white solid, yield: 49%.

MS(ESI,pos.ion)m/z:246.2[M+1] ⁺ .

Step 4: Synthesis of compound (R)-1-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)-N-methylmethylamine

Dissolve (R)-N-methyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (180mg, 0.73mmol) in anhydrous THF (7mL ), slowly added lithium aluminum tetrahydrogen (139.7mg, 3.07mmol) in batches, refluxed for 13h, quenched by adding methanol (5mL) dropwise in an ice bath, filtered, concentrated and separated by column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v)=10/1), to obtain 72 mg of colorless oil, yield: 43%.

MS(ESI,pos.ion)m/z:434.2[M+1] ⁺ .

Step 5: Compound (R)-N-((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methyl)-2-cyano-N- Synthesis of Methylacetamide

Dissolve (R)-1-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)-N-methylmethylamine (70mg, 0.30mmol) in In N,N-dimethylformamide (3mL), triethylamine (104.5μL, 0.75mmol), EDCI (86.26mg, 0.45mmol), HOBT (60.75mg, 0.75mmol) and cyanoacetic acid (37.35mg , 0.45mmol), reacted overnight at room temperature, directly concentrated and separated by column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v) = 30/1), and then separated by preparative thin-layer chromatography to obtain 31 mg of light yellow Solid, yield: 35%.

MS(ESI,pos.ion)m/z:299.2[M+1] ⁺ ;

¹ HNMR (400MHz, MeOH-d ₄ ): δ (ppm) 8.28 (d, J = 4.0Hz, 1H), 7.11 (dd, J = 3.4Hz, 15.0Hz, 1H), 6.61 (dd, J = 3.4Hz ,14.6Hz,1H),4.52-4.84(m,1H),4.01-4.33(m,1H),3.83-4.05(m,3H),3.3(d,2H),3.12-3.19(d,3H), 2.19(m,2H),1.98(m,2H).

Example 2 (S)-N-((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methyl)-2-cyanoacetamide

Step 1: Synthesis of compound (S)-tert-butyl-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate

At 0°C, dissolve tert-butyl L-prolinol-1-carboxylate (5.0g, 24.8mmol) in dichloromethane (50mL), add triethylamine (5.16mL, 38.2mmol), and slowly drop Add methanesulfonyl chloride (2.94mL, 38.2mmol), move to room temperature and stir overnight, the reaction solution is washed with saturated ammonium chloride solution (20mL×2), dried over anhydrous sodium sulfate, concentrated and separated by column chromatography (eluent: PE/EtOAc (v/v)=5/1), 6.0 g of colorless oil was obtained, yield: 87%.

MS(ESI,pos.ion)m/z:224.1[Mt-Bu+2] ⁺ .

Step 2: Synthesis of compound (S)-tert-butyl-2-(azidomethyl)pyrrolidine-1-carboxylate

At room temperature, add DMF (3 mL) to (S)-tert-butyl-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (724 mg, 2.60 mmol) to dissolve, add Sodium azide (253.5mg, 3.9mmol), reacted at 80°C for 16h, quenched by adding saturated aqueous ammonium chloride (10mL), extracted with dichloromethane (15mL×3), dried over anhydrous sodium sulfate, concentrated for column chromatography Separation by separation (eluent: PE/EtOAc (v/v) = 5/1), to obtain 580 mg of light yellow oil, yield: 99%.

MS(ESI,pos.ion)m/z:171.1[Mt-Bu+2] ⁺ .

Step 3: Synthesis of compound (S)-tert-butyl-2-(aminomethyl)pyrrolidine-1-carboxylate

To a methanol solution (15 mL) of (S)-tert-butyl-2-(azidomethyl)pyrrolidine-1-carboxylate (624 mg, 2.6 mmol) was added palladium on carbon (10%, 65 mg ), reacted at room temperature for 1h, the raw material disappeared, was filtered and concentrated, and the colorless oil was directly subjected to the next step of reaction.

MS(ESI,pos.ion)m/z:201.2[M+1] ⁺ .

Step 4: Synthesis of compound (S)-tert-butyl-2-((2-cyanoacetamido)methyl)pyrrolidine-1-carboxylate

Preparation of cyanoacetyl chloride: Add DMF (3 drops) to a solution of cyanoacetic acid (331.5mg, 3.9mmol) in dichloromethane (6mL), cool to 0°C, slowly add oxalyl chloride (370μL, 3.9mmol) ), stirred at room temperature for 30 minutes, and concentrated to obtain a brown oil.

Dissolve (S)-tert-butyl-2-(aminomethyl)pyrrolidine-1-carboxylate (crude product, 2.6 mmol) obtained in the previous step in dichloromethane (6 mL), add triethylamine (723 μL, 5.2mmol) was cooled to 0°C, the newly prepared cyanoacetyl chloride was dissolved in dichloromethane (3mL), slowly added dropwise to the reaction solution, reacted at room temperature for 1h, and quenched by adding saturated sodium bicarbonate solution (10mL) , extracted with dichloromethane (15mL×3), dried over anhydrous sodium sulfate, concentrated and separated by column chromatography (eluent: PE/EtOAc (v/v)=5/1), to obtain 153 mg of light yellow solid, the yield :twenty two%. MS(ESI,pos.ion)m/z:268.2[M+1] ⁺ .

Step 5: Compound (S)-N-((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methyl)-2-cyanoacetamide synthesis

Dissolve (S)-tert-butyl-2-((2-cyanoacetamido)methyl)pyrrolidine-1-carboxylate (153mg, 0.57mmol) in dichloromethane (6mL) and add trifluoro Acetic acid (212.3 μL, 2.85 mmol), stirred at room temperature for 2.5 h, concentrated for the next reaction.

Add isopropanol (6mL) to dissolve, add 4-chloropyrrolo[2,3-d]pyrimidine (107.10mg, 0.70mmol) and triethylamine (322.7μL, 2.32mmol) successively, and react at reflux at 90°C for 5.5h, Concentrated directly for column chromatography (eluent: DCM/MeOH (v/v) = 30/1), and then separated by preparative chromatography to obtain 47 mg of white solid, yield: 20%.

MS(ESI,pos.ion)m/z:285.2[M+1] ⁺ ;

¹ HNMR (400MHz, MeOH-d ₄ ): δ (ppm) 8.15 (s, 1H), 7.11 (d, J = 4.0Hz, 1H), 6.78 (d, J = 4.0Hz, 1H), 4.67 (m, 1H), 4.01(m, 1H), 3.86(m, 1H), 3.54(m, 2H), 2.00-2.31(m, 4H), 1.31(m, 2H).

Example 3 (S)-2-cyano-N-((4,4-difluoro-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-2-yl) Methyl)-N-methylacetamide

Step 1: Synthesis of compound (S)-1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylic acid

Dissolve (2S)-4-oxopyrrolidine-2-carboxylic acid (5.00g, 30.20mmol) in tetrahydrofuran (150mL), add triethylamine (15mL) and Boc ₂ O (7mL) in turn, and stir overnight at room temperature. After tetrahydrofuran was evaporated under reduced pressure, hydrochloric acid (1M) was added to acidify the pH to 2, extracted with ethyl acetate (200mL×3), the organic phase was washed with water (150mL), saturated sodium chloride solution (150mL), washed with anhydrous sulfuric acid Sodium-dried, concentrated under reduced pressure and fully dried, it was directly used in the next step of synthesis.

Step 2: Synthesis of compound (S)-diethyl 1-tert-butyl-2-methyl-4-oxopyrrolidine-1,2-dicarboxylate

Dissolve (S)-1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylic acid (3125 mg, 13.63 mmol) in N,N-dimethylformamide (20 mL), add sodium bicarbonate (5.73g, 68.16mmol), add iodomethane (1.70mL) dropwise, and stir overnight at room temperature. Add saturated aqueous sodium chloride solution (30 mL) to quench the reaction, extract with ethyl acetate (200 mL×3), wash the organic phase with water (150 mL), wash with saturated sodium chloride solution (150 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Separation by column chromatography (eluent: PE/EtOAc (v/v)=4/1) afforded 2.50 g of product, yield: 75%.

Step 3: Synthesis of compound (S)-diethyl 1-tert-butyl-2-methyl-4,4-difluoropyrrolidine-1,2-dicarboxylate

Dissolve (S)-1-tert-butyl-2-methyl-4-oxopyrrolidine-1,2-dicarboxylate diethyl ester (703mg, 2.89mmol) in dichloromethane (40mL) and cool to 0°C, diethylaminosulfur trifluoride (1.91mL, 14.45mmol) was added dropwise, stirred for 2h, concentrated under reduced pressure, and separated by column chromatography (eluent: PE/EtOAc(v/v)=10/ 1), to obtain 0.90g product, yield: 100%.

MS(ESI,pos.ion)m/z:266.2[M+1] ⁺ .

Step 4: Synthesis of compound (S)-tert-butyl 4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate

Dissolve (S)-1-tert-butyl-2-methyl-4,4-difluoropyrrolidine-1,2-dicarboxylate diethyl ester (800mg, 3.02mmol) in tetrahydrofuran (50mL) and cool to At 0° C., lithium borohydride (0.70 g) was added, and the mixture was slowly returned to room temperature and reacted overnight. Add water (100 mL) to quench the reaction, extract with ethyl acetate (150 mL×3), dry over anhydrous sodium sulfate, concentrate under reduced pressure and use directly in the next step.

Step 5: Synthesis of compound (S)-tert-butyl 4,4-difluoro-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate

Dissolve (S)-tert-butyl 4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (700mg, 2.95mmol) in dichloromethane (50mL), cool to 0°C, Triethylamine (4.10 mL) and methanesulfonyl chloride (1.20 mL) were successively added dropwise, and returned to room temperature to react for 1 h. Add water (50 mL) to quench the reaction, extract with dichloromethane (50 mL×3), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use directly in the next step.

Step 6: Synthesis of compound (S)-tert-butyl 4,4-difluoro-2-((methylamino)methyl)pyrrolidine-1-carboxylate

Dissolve (S)-tert-butyl 4,4-difluoro-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (600 mg, 1.90 mmol) in tetrahydrofuran (40 mL) , adding aqueous methylamine solution (40%, 30 mL), and reacting at 80° C. overnight. It was concentrated under reduced pressure and separated by column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v)=10/1) to obtain 0.40 g of the product, yield: 80%.

MS(ESI,pos.ion)m/z:251.3[M+1] ⁺ .

Step 7: Synthesis of compound (S)-tert-butyl 2-((2-cyano-N-methylacetamido)methyl)-4,4-difluoropyrrolidine-1-carboxylate

(S)-tert-butyl 4,4-difluoro-2-((methylamino)methyl)pyrrolidine-1-carboxylate (300mg, 1.20mmol), cyanoacetic acid (1.02g, 12.1mmol ), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.20g, 6.28mmol) and 1-hydroxybenzotriazole (0.80g, 5.92mmol) were dissolved in di In methyl chloride (30 mL), cool to 0°C, add triethylamine (1.70 mL) dropwise, return to room temperature and react overnight. Extract with ethyl acetate (100mL×3), wash the organic phase with water (50mL), wash with saturated sodium chloride solution (100mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate by column chromatography (eluent: PE/ EtOAc (v/v) = 1/1), yielded 0.29 g of product, yield: 76%.

MS(ESI,pos.ion)m/z:318.3[M+1] ⁺ .

Step 8: Synthesis of compound (S)-2-cyano-N-((4,4-difluoropyrrol-2-yl)methyl)-N-methylacetamide

Dissolve (S)-tert-butyl 2-((2-cyano-N-methylacetamido)methyl)-4,4-difluoropyrrolidine-1-carboxylate (0.29g, 0.91mmol) In dichloromethane (20 mL), cooled to 0 ° C, added dropwise trifluoroacetic acid (10 mL), slowly returned to room temperature for 3 h, concentrated under reduced pressure and fully dried, directly used in the next reaction.

Step 9: Compound (S)-2-cyano-N-((4,4-difluoro-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-2-yl )Methyl)-N-methylacetamide Synthesis

(S)-2-cyano-N-((4,4-difluoropyrrol-2-yl)methyl)-N-methylacetamide (0.20g, 0.91mmol) and 4-chloro-7H- Pyrrolo[2,3-d]pyrimidine (0.42g, 2.7mmol) was dissolved in isopropanol (40mL), 2 drops of concentrated hydrochloric acid were added dropwise, and the mixture was heated under reflux overnight. Concentrate under reduced pressure and separate by column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v)=20/1) to obtain 120 mg of solid, the total yield of two steps: 39%.

MS(ESI,pos.ion)m/z:335.0[M+1] ⁺ ;

¹ HNMR (400MHz, MeOH-d ₄ ): (exists as rotamers) δ (ppm) 8.20-8.14 (s, 1H), 7.13-7.10 (s, 1H), 4.31-4.25 (m, 1H), 4.08-4.01 (m ,1H),3.99-3.84(m,1H),3.58-3.51(m,3H),2.70-2.50(m,2H).

Example 4 (S)-2-((2-(((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methyl)amino)-3 ,4-diketosquarate-1-yl)amino)acetonitrile

Step 1: Synthesis of the Compound Diethyl Squarate

Squaric acid (1.00g, 8.77mmol) was dissolved in absolute ethanol (20mL), heated to reflux for 12h. After the reaction was completed, it was concentrated under reduced pressure to obtain 1.50 g of a colorless liquid, which was directly put into the next step without further purification.

MS(ESI,pos.ion)m/z:171.2[M+1] ⁺ .

Step 2: Synthesis of compound 2-((2-ethoxy-3,4-diketosquarate-1-yl)amino)acetonitrile

Triethylamine (1.64g, 16.20mmol) was added dropwise into a solution of diethyl squarylate (1.38g, 8.10mmol) and 2-aminoacetonitrile hydrochloride (500mg, 5.40mmol) in absolute ethanol (20mL), at room temperature React for 6 hours. Concentration under reduced pressure, the obtained residue was separated by silica gel column chromatography (eluent: CH ₂ Cl ₂ /CH ₃ OH (v/v) = 15/1), purified to obtain 793.8 mg of light yellow solid, yield: 82 %.

MS(ESI,pos.ion)m/z:181.2[M+1] ⁺ .

Step 3: Synthesis of compound (S)-2-((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

Methanesulfonyl chloride (740.0 mg, 6.46 mmol) was added dropwise to (S)-2-(hydroxymethyl)pyrrolidine-1-tert-butylmethyl ester (1.00 g, 4.97 mmol) and triethylamine (754.9 mg, 7.46 mmol) In dichloromethane (20 mL) solution, react overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the obtained residue was separated by silica gel column chromatography (eluent: PE/EtOAc (v/v)=5/1), and purified to obtain 877.2 mg of light yellow oil, yield: 63%. MS(ESI,pos.ion)m/z:224.2[M-(t-Bu)+2] ⁺ .

Step 4: Synthesis of compound (S)-2-(azidomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

Add sodium azide (296.4mg, 4.56mmol) into (S)-2-((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (850mg, 3.04mmol) in DMF (10mL ) solution, heated at 80°C overnight. After the reaction was completed, saturated aqueous ammonium chloride solution (30 mL) was added to the reaction liquid to quench the reaction, dichloromethane (50 mL×3) was extracted, and the combined organic phase was dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain The residue was separated by silica gel column chromatography (eluent: PE/EtOAc (v/v)=5/1), and purified to obtain 311.4 mg of light yellow oil, yield: 45%.

MS(ESI,pos.ion)m/z:171.2[M-(t-Bu)+2] ⁺ .

Step 5: Synthesis of compound (S)-2-(aminomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

Palladium on carbon (10%, 93 mg) was added to a solution of (S)-2-(azidomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (310 mg, 1.37 mmol) in MeOH (10 mL) under _H2 atmosphere The reaction was stirred at room temperature for 6 hours. After the reaction was completed, it was filtered, and the filtrate was concentrated under reduced pressure to obtain 275 mg of a colorless oil, which was directly put into the next step without further purification.

MS(ESI,pos.ion)m/z:146.2[M-(t-Bu)+2] ⁺ .

Step 6: Compound (S)-2-(((2-((cyanomethyl)amino)-3,4-diketosquarate-1-yl)amino)methyl)pyrrole-1-carboxylic acid Synthesis of tert-butyl ester

Triethylamine (156.8mg, 1.55mmol) was added to 2-((2-ethoxy-3,4-diketosquarate-1-yl)amino)acetonitrile (214.4mg, 1.19mmol) and (S) - In tert-butyl 2-(aminomethyl)pyrrolidine-1-carboxylate (275 mg, 1.37 mmol) in EtOH (20 mL), react at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was separated by silica gel column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v) = 20/1), and purified to obtain 268.6 mg of a light yellow solid, yield: 67 %.

MS(ESI,pos.ion)m/z:279.2[M-(t-Bu)+2] ⁺ .

Step 7: Compound (S)-2-((2-(((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methyl)amino)- Synthesis of 3,4-diketosquarate-1-yl)amino)acetonitrile

Add trifluoroacetic acid (456.1mg, 4.00mmol) to (S)-2-(((2-((cyanomethyl)amino)-3,4-diketonesquarate-1-yl)amino) In tert-butyl methyl)pyrrole-1-carboxylate (268.6 mg, 0.80 mmol) in DCM (20 mL), react at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, the resulting residue was dissolved in isopropanol (20 mL), 4-chloropyrrolopyrimidine (245.7 mg, 1.60 mmol) and triethylamine (323.8 mg, 3.20 mmol) were added, and the reaction was heated at 90°C for 9 hours . The reaction solution was concentrated under reduced pressure, and the obtained residue was separated by silica gel column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v) = 15/1), and purified to obtain 73.4 mg of white solid, yield: 26% .

MS(ESI,pos.ion)m/z:352.2[M+1] ⁺ ;

¹ HNMR (400MHz, DMSO-d ₆ ): δ (ppm) 11.80 (s, 1H), 8.18 (s, 1H), 7.18 (s, 1H), 6.65 (s, 1H), 4.87-4.95 (m, 1H ),4.71(d,J＝6.0Hz,1H),4.51-4.63(m,1H),4.09-4.26(m,2H),3.89-3.98(m,2H),3.77-3.83(m,2H), 1.99-2.11(m,4H).

Example 5N-(cyanomethyl)-N-methyl-3-(methylthio)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)tetrahydropyrrole-3-methyl Amide

Step 1: Synthesis of the compound pyrrolidine-3-carboxylate methyl ester

Under ice-cooling, slowly add thionyl chloride (12.00mL, 165.40mmol) dropwise into a mixture of pyrrolidine-3-carboxylic acid (9.10g, 79.00mmol) in methanol (120mL). After the dropwise addition, move to an oil bath React at 42°C for 6h. Concentration under reduced pressure gave an oil which was directly used in the next reaction without further purification.

Step 2: Synthesis of compound 1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid methyl ester

Under ice-cooling, triethylamine (35.00mL, 251.00mmol) was added to a solution of methyl pyrrolidine-3-carboxylate (13.50g, 81.50mmol) in dichloromethane (120mL), and reacted at room temperature for 2h after the dropwise addition . Under ice-cooling, di-tert-butyl carbonate (25.2 mL, 118.00 mmol) was slowly added to the above mixture, and reacted overnight at room temperature. The reaction was quenched with saturated ammonium chloride solution (200mL), extracted with dichloromethane (300mL×4), the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was separated by column chromatography (eluent: PE/ EtOAc (v/v)=5/1), to obtain 18.70 g of pale yellow oil, yield: 99%.

MS(ESI,pos.ion)m/z:252.1[M+Na] ⁺ ;

¹ HNMR (400MHz, CDCl ₃ ): δ (ppm) 3.60 (s, 3H), 3.55-3.18 (m, 4H), 3.01-2.88 (m, 1H), 2.02 (d, J = 5.8Hz, 2H), 1.35(s,9H).

Step 3: Synthesis of compound 1-tert-butyl 3-methyl 3-(methylthio)tetrahydropyrrole-1,3-dicarboxylate

Under nitrogen protection, n-butyllithium n-hexane solution (2.4M, 7.30mL, 18.00mmol) was slowly added dropwise to anhydrous tetrahydrofuran (30mL) solution except anhydrous diisopropylamine (2.70mL, 19.00mmol), Prepare lithium diisopropylamide by reacting at -40°C for 1 h. A solution of 1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid methyl ester (2.10g, 9.20mmol) in anhydrous tetrahydrofuran (30mL) was slowly added dropwise to the freshly prepared lithium diisopropylamide solution, at -78°C After reacting for 1.5h, dimethyl disulfide (2.0mL, 22.60mmo) was added dropwise, reacted at -78°C for 30 minutes, and slowly rose to room temperature for 18h. Add saturated ammonium chloride solution (200mL), stir for 5 minutes, extract with ethyl acetate (400mL×3), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and carry out column chromatography separation (eluent: PE/EtOAc (v/ v)=5/1), 1.20 g of yellow oil was obtained, yield: 48%.

MS(ESI,pos.ion)m/z:176.1[Mt-Bu+2] ⁺ .

Step 4: Synthesis of the compound 3-(methylthio)tetrahydropyrrole-3-carboxylate methyl trifluoroacetate

Under ice bath, trifluoroacetic acid (10mL) was added dropwise to 1-tert-butyl 3-methyl 3-(methylthio)tetrahydropyrrole-1,3-dicarboxylate (1.20g, 4.40mmol) In dichloromethane (20 mL) solution, react at room temperature for 6 h, concentrate under reduced pressure, and directly use in the next reaction without purification.

Step 5: Synthesis of the compound 3-(methylthio)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)tetrahydropyrrole-3-carboxylic acid methyl ester

Dissolve 3-(methylthio)tetrahydropyrrole-3-carboxylate methyl trifluoroacetate (0.90g, 3.31mmol) in N,N-dimethylformamide (10mL), slowly add N , N-diisopropylethylamine (6mL, 34.4mmol), react at room temperature for 1h, then add 4-chloropyrrolopyrimidine (0.75g, 4.9mmol), react overnight at 80°C. The reaction was quenched with water (100 mL), extracted with dichloromethane (100 mL×3), washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/ v)=50/1), 1.20 g of yellow oil solid was obtained, yield: 80%.

MS(ESI,pos.ion)m/z:293.0[M+1] ⁺ .

Step 6: Synthesis of compound 3-(methylthio)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)tetrahydropyrrole-3-carboxylic acid

3-(methylthio)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)tetrahydropyrrole-3-carboxylic acid methyl ester (1.00g, 3.42mmol) was dissolved in methanol (20mL ) solution, a mixture of lithium hydroxide (0.25 g, 10.44 mmol) and water (6 mL) was added. Stir at room temperature for 12 h, remove methanol under reduced pressure, adjust the pH to 6 with hydrochloric acid (6M), extract with dichloromethane (150 mL×3), dry the organic layer over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 200 mg of an oil. The aqueous layer was concentrated under reduced pressure to obtain a solid, soaked in CH ₂ Cl ₂ /MeOH (20 mL/20 mL), filtered, and the filtrate was concentrated under reduced pressure to obtain 600 mg of solid, yield: 84%.

MS(ESI,pos.ion)m/z:279.1[M+1] ⁺ .

Step 7: Compound N-(cyanomethyl)-N-methyl-3-(methylthio)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)tetrahydropyrrole-3 -Synthesis of formamide

Under ice-cooling, oxalyl chloride (0.15mL, 1.7mmol) and a catalytic amount of N,N-dimethylformamide (0.10mL) were slowly added dropwise to 3-(methylthio)-1-(7H-pyrrolo [2,3-d]pyrimidin-4-yl)tetrahydropyrrole-3-carboxylic acid (0.15g, 0.54mmol) in anhydrous dichloromethane (30mL) solution, react at room temperature for 10h, and concentrate the reaction solution under reduced pressure , the residue was dissolved in anhydrous dichloromethane (25mL), then slowly added dropwise to a solution of 2-(methylamino)acetonitrile (0.12g, 1.07mmol) and triethylamine (0.40mL, 3.00mmol) in anhydrous dichloromethane (10 mL) solution and react overnight at room temperature. Dilute with water (35mL), extract with dichloromethane (35mL×3), dry over anhydrous sodium sulfate, remove the solvent, and separate the concentrate by column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v) = 20/1), a yellow solid was obtained, and the crude product was further purified by preparative high-performance liquid chromatography to obtain 8 mg of a white solid, yield: 4.5%.

MS(ESI,pos.ion)m/z:331.1[M+1] ⁺ ;

¹ HNMR (600MHz, MeOH-d ₄ ): δ (ppm) 8.30 (s, 1H), 7.42 (s, 1H), 6.99 (d, J = 19.7Hz, 1H), 4.53-4.20 (m, 4H), 3.46(d, J=22.5Hz, 3H), 2.72(dd, J=67.1, 45.1Hz, 2H), 2.18(s, 3H), 1.36-1.32(m, 2H).

Example 6N-(cyanomethyl)-N-methyl-2-(methylthio)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-2-methan Amide

Step 1: Synthesis of the compound 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine

Under ice-water bath, sodium hydride (60%, 1.04g, 26.0mmol) was added to a solution of 4-chloropyrrolo[2,3-d]pyrimidine (2.0g, 13mmol) in DMF (15mL), stirred at room temperature for 1h, in SEMCl (3.5 mL, 20 mmol) was slowly added dropwise to the reaction liquid in a water bath to keep the reaction stable, the dropwise addition continued for about 10 minutes, and the reaction was stirred overnight at room temperature. Slowly add water (20mL) to quench, dichloromethane (25mL×3) to extract, dry with anhydrous Na ₂ SO ₄ , remove the solvent, and the concentrated solution is separated by column chromatography (eluent: PE/EtOAc (v/ v)=3/1), 2.0 g of colorless oil was obtained, yield: 55%.

MS(ESI,pos.ion)m/z:284.1[M+1] ⁺ .

Step 2: Compound 1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-2- Synthesis of methyl carboxylate

To 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1.0g, 3.5mmol) in DMF at room temperature (8mL) solution, add potassium carbonate (2.9g, 21mmol) and L-proline methyl ester (451.5mg, 3.5mmol) successively, react in an oil bath at 80°C for 4h, add water (20mL) to quench, dichloromethane ( 25mL×3) extracted, dried with anhydrous Na ₂ SO ₄ , removed the solvent, and the concentrated solution was subjected to column chromatography (eluent: PE/EtOAc (v/v)=3/1) to obtain 850 mg of a colorless oil , Yield: 64%.

MS(ESI,pos.ion)m/z:377.2[M+1] ⁺ .

Step 3: Compound 2-methylthio-1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl ) Synthesis of pyrrolidine-2-carboxylic acid methyl ester

At -15°C, under nitrogen protection, add n-butyllithium (1.4M, 3.8mL) to a solution of diisopropylamine (1.46mL, 10mmol) in THF (20mL), stir at this temperature for 10 minutes, and cool down After 30 minutes at -78°C, 1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl ) THF (12mL) solution of methyl pyrrolidine-2-carboxylate (850mg, 2.26mmol) was slowly added dropwise to the reaction solution, and the reaction was continued at -78°C for 1h; dimethyl disulfide (409.7μL, 4.63mmol), naturally warming up to room temperature and reacting overnight. Add saturated ammonium chloride solution (15 mL) to quench, dichloromethane (15 mL × 3) to extract, dry with anhydrous Na ₂ SO ₄ , remove the solvent, and concentrate the solution for column chromatography (eluent: PE/EtOAc ( v/v)=2/1), 560 mg of yellow oil was obtained, yield: 59%.

MS(ESI,pos.ion)m/z:423.2[M+1] ⁺ ;

¹ HNMR (600MHz, CDCl ₃ ): δ (ppm) 8.36 (s, 1H), 7.12 (d, J = 3.7Hz, 1H), 6.62 (d, J = 3.7Hz, 1H), 5.59 (d, J = 3.4Hz,2H),4.18(m,2H),3.73(s,3H),3.54(m,2H),2.54(m,2H),2.41(m,1H),2.29(m,1H),2.23( s,3H),0.92(t,J=6.0Hz,2H),-0.04(s,9H).

Step 4: Synthesis of the compound 2-methylthio-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid methyl ester

2-Methylthio-1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine - Methyl 2-carboxylate (490mg, 1.16mmol) was dissolved in dichloromethane (10mL), hydrogen chloride dioxane solution (4M, 5mL) was added, stirred overnight at room temperature, and concentrated to give a white solid. Add tetrahydrofuran (10mL), add sodium hydroxide solution (1M) to adjust to pH>8, stir at room temperature for 4h, extract with dichloromethane (15mL×3), dry with anhydrous Na ₂ SO ₄ , remove the solvent, and concentrate the solution for column After separation by chromatography (eluent: PE/EtOAc (v/v)=1/1), 180 mg of light yellow solid was obtained, yield: 38%.

MS(ESI,pos.ion)m/z:293.2[M+1] ⁺ .

Step 5: Synthesis of compound 2-methylthio-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid

Dissolve methyl 2-methylthio-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-2-carboxylate (130 mg, 0.44 mmol) in concentrated hydrochloric acid (5 mL) , reacted at 80°C for 7h, directly concentrated the solvent, and added water with toluene to obtain 123mg of brown solid, yield: 99%.

MS(ESI,pos.ion)m/z:279.1[M+1] ⁺ .

Step 6: Compound N-(cyanomethyl)-N-methyl-2-(methylthio)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-2 -Synthesis of formamide

2-Methylthio-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (120mg, 0.43mmol) was dissolved in N,N-dimethylformaldehyde Amide (3mL), sequentially added triethylamine (180μL, 1.29mmol), EDCI (164.4mg, 0.85mmol), HOBT (116mg, 0.86mol) and 2-methylaminoacetonitrile hydrochloride (91mg, 0.86mmol) , stirred overnight at room temperature, quenched with water (15 mL), extracted with dichloromethane (15 mL×3), dried with anhydrous Na ₂ SO ₄ , and the concentrated solution was separated by column chromatography (eluent: CH ₂ Cl ₂ /MeOH ( v/v)=30/1), 11 mg of colorless oil was obtained, yield: 17%.

MS(ESI,pos.ion)m/z:331.2[M+1] ⁺ ;

¹ HNMR (600MHz, MeOH-d ₄ ): δ (ppm) 8.14 (s, 1H), 7.10 (s, 1H), 6.59 (s, 1H), 4.43 (s, 2H), 3.72 (t, J = 6.6 Hz,2H),3.06(s,3H),2.69(m,2H),2.11(s,3H),2.07(m,2H).

Example 7N-(3-cyanobenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxamide

Step 1: Synthesis of compound pyrrolidine-3-carboxylate ethyl ester

Concentrated hydrochloric acid (2 mL) was added to a solution of pyrrolidine-3-carboxylic acid (600 mg, 5.93 mmol) in EtOH (30 mL), and heated to reflux overnight. After the reaction was completed, it was concentrated under reduced pressure to obtain 1.87 g of light yellow liquid, which was directly put into the next step without further purification.

MS(ESI,pos.ion)m/z:144.3[M+1] ⁺ .

Step 2: Synthesis of compound 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxylic acid ethyl ester

Potassium carbonate (10.83g, 78.36mmol) was added to ethyl pyrrolidine-3-carboxylate (1.87g, 13.06mmol) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (3.01g, 19.59mmol) isopropanol (30 mL) solution, heated to reflux overnight, the reaction was completed, concentrated under reduced pressure, and the obtained residue was separated by silica gel column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v) = 20/ 1), purified to obtain 2.16g white solid, yield: 64%. MS(ESI,pos.ion)m/z:261.1[M+1] ⁺ .

Step 3: Synthesis of compound 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxylic acid

A solution of sodium hydroxide (0.66g, 16.60mmol) in water (2mL) was added to ethyl 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxylate (2.16g, 8.30 mmol) in EtOH (40 mL), react at room temperature for 3 hours. After the reaction was completed, the EtOH was removed by concentration under reduced pressure, the pH was adjusted to about 6 with concentrated hydrochloric acid, filtered, and the filter cake was dried to obtain 1.80 g of white solid, which was directly put into the next step without further purification. MS(ESI,pos.ion)m/z:233.1[M+1] ⁺ .

Step 4: Synthesis of the compound N-(3-cyanobenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxamide

3-(Aminomethyl)benzonitrile (170 mg, 1.29 mmol), HOBT (232 mg, 1.72 mmol), EDCI (330.0 mg, 1.72 mmol) and diisopropylethylamine (445.0 mg, 3.45 mmol) were added in 1 -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxylic acid (200.00mg, 0.86mmol) in DMF (20mL) solution, react overnight at room temperature. After the reaction was completed, water (30 mL) was added to the reaction liquid to quench the reaction, dichloromethane (50 mL × 3) was extracted, the combined organic phase was dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and the obtained residue was subjected to Silica gel column chromatography (eluent: CH ₂ Cl ₂ /CH ₃ OH (v/v) = 15/1), purified to obtain 210.0 mg of white solid, yield: 70%.

MS(ESI,pos.ion)m/z:347.0[M+1] ⁺ ;

¹ HNMR (400MHz, DMSO-d ₆ ): δ (ppm) 11.61 (s, 1H), 8.65 (t, J = 5.7Hz, 1H), 8.10 (s, 1H), 7.72-7.74 (m, 2H), 7.61-7.63(m,1H),7.53-7.57(m,1H),7.12(d,J=2.3Hz,1H),6.58(d,J=1.6Hz,1H),4.37(d,J=5.9Hz ,2H),3.75-4.02(m,4H),3.17-3.21(m,1H),2.16-2.27(m,2H).

Example 8 1-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-3-carbonyl)pyrrolidine-3-carbonitrile

3-cyanopyrrolidine hydrochloride (128.00mg, 0.97mmol), HOBT (174.00mg, 1.29mmol), EDCI (247.0mg, 1.29mmol) and diisopropylethylamine (333.0mg, 2.58mmol) Add 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxylic acid (150.00 mg, 0.65 mmol) in DMF (20 mL) and react at room temperature overnight. After the reaction was completed, water (30 mL) was added to the reaction liquid to quench the reaction, dichloromethane (50 mL × 3) was extracted, the combined organic phase was dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and the obtained residue was subjected to Separation by silica gel column chromatography (eluent: CH ₂ Cl ₂ /CH ₃ OH (v/v) = 15/1), purification to obtain 104.1 mg of white solid, yield: 52%.

MS(ESI,pos.ion)m/z:311.2[M+1] ⁺ ;

¹ HNMR (400MHz, DMSO-d ₆ ): δ(ppm) 12.28(s, 1H), 8.22(d, J=2.1Hz, 1H), 7.30(s, 1H), 6.76(s, 1H), 3.79- 3.97(m,5H),3.63-3.71(m,2H),3.52-3.58(m,1H),3.37-3.48(m,2H),2.12-2.38(m,4H).

Example 9N-isopropyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxamide

Diisopropylamine (101 mg, 1.71 mmol), HOBt (116 mg, 0.86 mmol) and EDCI (165 mg, 0.86 mmol) were added to 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine- 3-Formic acid (100 mg, 0.43 mmol) in DMF (5 mL) was reacted at room temperature for 17 hours. After the reaction was complete, water (20 mL) was added to the reaction liquid to quench the reaction, dichloromethane (30 mL × 3) was extracted, the combined organic phase was dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and the obtained residue was subjected to Separation by silica gel column chromatography (eluent: CH ₂ Cl ₂ /CH ₃ OH (v/v) = 15/1), purification to obtain 93.1 mg of white solid, yield: 79%.

MS(ESI,pos.ion)m/z:274.2[M+1] ⁺ ;

¹ HNMR (400MHz, DMSO-d ₆ ): δ (ppm) 11.56 (s, 1H), 8.08 (s, 1H), 7.89 (d, J = 7.5Hz, 1H), 7.10-7.11 (m, 1H), 6.55-6.56(m,1H),3.82-3.96(m,3H),3.72(s,2H),3.01-3.05(m,1H),2.09-2.19(m,2H),1.08(d,J＝6.6 Hz,6H).

Example 10N-(2-cyanoethyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxamide

3-Aminopropionitrile (29mg, 0.41mmol), HOBT (93mg, 0.69mmol), EDCI (132mg, 0.69mmol) and triethylamine (139mg, 1.37mmol) were added to 1-(7H-pyrrolo[2,3 -d] Pyrimidin-4-yl)pyrrolidine-3-carboxylic acid (80mg, 0.34mmol) in DMF (5mL) solution, react at room temperature for 17 hours. After the reaction was completed, water (20 mL) was added to the reaction solution to quench the reaction, dichloromethane (30 mL×3) was extracted, the combined organic phase was dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel It was separated by column chromatography (eluent: CH ₂ Cl ₂ /CH ₃ OH (v/v)=15/1), and purified to obtain 66.7 mg of white solid, yield: 68%.

MS(ESI,pos.ion)m/z:285.1[M+1] ⁺ ;

¹ HNMR (400MHz, DMSO-d ₆ ): δ (ppm) 11.61 (s, 1H), 8.46 (t, J = 5.6Hz, 1H), 8.09 (s, 1H), 7.12-7.13 (m, 1H), 6.57(d,J=2.3Hz,1H),3.75-3.99(m,4H),3.52(s,1H),3.11-3.18(m,2H),2.68(t,J=6.5Hz,2H),2.13 -2.23(m,2H).

Example 11 N-((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)methyl)-2-cyanoacetamide

Step 1: Synthesis of compound 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid

Under ice-cooling, sodium hydroxide solution (2M, 60 mL) and di-tert-butyl carbonate (10.45 g, 47.88 mmol) were successively added to a solution of 3-pyrrolidinecarboxylic acid (5.0 g, 43.43 mmol) in tetrahydrofuran (30 mL), It was then stirred at room temperature for 12 hours. Tetrahydrofuran was evaporated under reduced pressure, the reaction residue was adjusted to pH 2-3 with saturated citric acid solution, extracted with ethyl acetate (150 mL×3), dried and concentrated to obtain 7.4 g of light yellow oil, yield: 79%.

MS(ESI,pos.ion)m/z:160.07[Mt-Bu+2] ⁺ .

Step 2: Synthesis of compound 3-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

Under ice-cooling, slowly add borane tetrahydrofuran solution (1M, 54mL) to 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (4.0g, 19mmol), stir at room temperature overnight, and slowly add methanol ( 10 mL) was quenched, concentrated and separated by column chromatography (eluent: PE/EtOAc (v/v)=1/1) to obtain 2.4 g of colorless oil, yield: 70%.

MS(ESI,pos.ion)m/z:146.09[Mt-Bu+2] ⁺ .

Step 3: Synthesis of compound 3-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

At 0°C, tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (5.0g, 24.8mmol) was dissolved in dichloromethane (60mL), triethylamine (5.16mL, 38.2mmol) was added ), slowly added methanesulfonyl chloride (2.94mL, 38.2mmol), moved to room temperature and stirred overnight, the reaction solution was washed with saturated ammonium chloride solution (20mL), dried over anhydrous sodium sulfate, concentrated and separated by column chromatography (leaching Lotion: PE/EtOAc (v/v)=5/1), 6.0 g of colorless oil was obtained, yield: 87%.

MS(ESI,pos.ion)m/z:146.09[Mt-Bu+2] ⁺ .

Step 4: Synthesis of compound 3-(azidomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

At room temperature, add DMF (3 mL) to tert-butyl 3-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (724 mg, 2.6 mmol) to dissolve, add sodium azide ( 253.5mg, 3.9mmol), reacted at 80°C for 16h, quenched with water, quenched with saturated aqueous ammonium chloride (10mL), extracted with dichloromethane (15mL×3), dried over anhydrous sodium sulfate, concentrated for column chromatography After separation (eluent: PE/EtOAc (v/v)=5/1), 580 mg of light yellow oil was obtained, yield: 99%.

MS(ESI,pos.ion)m/z:171.05[Mt-Bu+2] ⁺ .

Step 5: Synthesis of compound 3-(aminomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

Add palladium on carbon (10%, 275.6 mg) to a solution of tert-butyl 3-(azidomethyl)pyrrolidine-1-carboxylate (624 mg, 2.6 mmol) in methanol (15 mL) at room temperature, and react at room temperature for 1 h , the raw material disappeared, filtered and concentrated, and the obtained colorless oil was directly subjected to the next reaction.

MS(ESI,pos.ion)m/z:145.06[Mt-Bu+2] ⁺ .

Step 6: Synthesis of compound 3-((2-cyanoacetyl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

Preparation of cyanoacetyl chloride: Add DMF (3 drops) to a solution of cyanoacetic acid (331.5mg, 3.9mmol) in dichloromethane (6mL), cool to 0°C, slowly add oxalyl chloride (370μL, 3.9mmol) ), stirred at room temperature for 30 minutes, and concentrated to obtain a brown oil.

Dissolve tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate (crude product, 2.6mmol) obtained in the previous step in dichloromethane (6mL), add triethylamine (723μL, 5.2mmol), and cool to 0°C, the freshly prepared cyanoacetyl chloride was dissolved in dichloromethane (3 mL), slowly added dropwise to the reaction solution, reacted at room temperature for 1 h, quenched by adding saturated sodium bicarbonate solution (10 mL), dichloromethane ( 15mL×3) extracted, dried over anhydrous sodium sulfate, concentrated and separated by column chromatography (eluent: PE/EtOAc (v/v)=5/1) to obtain 153 mg of light yellow solid, yield: 22%.

MS(ESI,pos.ion)m/z:212.07[Mt-Bu+2] ⁺ .

Step 7: Compound N-((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)methyl)-2-cyanoacetamide synthesis

Dissolve tert-butyl 3-((2-cyanoacetyl)methyl)pyrrolidine-1-carboxylate (153mg, 0.57mmol) in dichloromethane (6mL), add trifluoroacetic acid (212.3μL, 2.85 mmol), stirred at room temperature for 2.5h, concentrated for the next reaction; added isopropanol (6mL) to dissolve, added 4-chloropyrrolo[2,3-d]pyrimidine (107.10mg, 0.70mmol) and triethylamine ( 323μL, 2.32mmol), reflux at 90°C for 5.5h, directly concentrated and separated by column chromatography (eluent: DCM/MeOH (v/v)=30/1), and then separated by preparative chromatography to obtain 7 mg of white solid, Yield: 2.7%.

MS(ESI,pos.ion)m/z:285.2[M+1] ⁺ ;

¹ HNMR (600MHz, DMSO-d ₆ ): δ(ppm) 11.63(s, 1H), 8.47(t, J=5.1Hz, 1H), 8.08(s, 1H), 7.17(d, J=59.5Hz, 1H), 6.59(s, 1H), 3.93(dt, J=92.7, 25.9Hz, 2H), 3.68(s, 2H), 3.45(dd, J=33.6, 3.1Hz, 2H), 3.22(m, 2H ),2.43(d,J=40.6Hz,1H),2.04(m,1H),1.74(s,1H).

Example 12 N-((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)methyl)-2-cyano-N-methylacetamide

Step 1: Synthesis of compound 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxylic acid

4-chloropyrrolo[2,3-d]pyrimidine (1.0g, 6.50mmol), 3-pyrrolidinecarboxylic acid (902mg, 7.83mmol), potassium carbonate (2.70g, 20.00mmol) and N,N-di Methyl acetamide (10 mL) was mixed in a reaction flask, heated at 100°C for 11 hours, then mixed with silica gel, and separated by column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v) = 20/1 ), to obtain 4.0 g of yellow solid, yield: 260% (containing inorganic salt).

MS(ESI,pos.ion)m/z:233.1[M+1] ⁺ .

Step 2: Synthesis of the compound N-methyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxamide

1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxylic acid (100 mg, 0.43 mmol) was dissolved in N,N-dimethylformamide (5 mL), Add EDCI (164.3mg, 0.86mmol), HOBT (116.1mg, 0.86mmol), triethylamine (120μL, 0.86mmol) and methylamine hydrochloride (57mg, 0.85mmol) successively, and stir overnight at room temperature. Add saturated ammonium chloride aqueous solution (10mL) to quench, dichloromethane (15mL * 3) extraction, after the organic phase is combined, wash with saturated ammonium chloride solution (50mL), dry over anhydrous sodium sulfate, concentrate and carry out column chromatography separation ( Eluent: PE/EtOAc (v/v)=5/1), 50 mg of white solid was obtained, yield: 48%.

MS(ESI,pos.ion)m/z:246.2[M+1] ⁺ .

Step 3: Synthesis of compound 1-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-N-methylmethanamine

Dissolve N-methyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-carboxamide (150mg, 0.61mmol) in anhydrous tetrahydrofuran (8mL), add Lithium aluminum tetrahydrogen (116mg, 3.06mmol), reflux reaction for 5h, quenched with methanol, filtered with celite, concentrated the filtrate and separated by column chromatography (eluent: CH ₂ Cl ₂ /MeOH(v/v)=20 /1), to obtain 110 mg of gray solid, yield: 78%.

MS(ESI,pos.ion)m/z:232.2[M+1] ⁺ .

Step 4: Compound N-((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)methyl)-2-cyano-N-methylacetamide synthesis

Dissolve 1-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-N-methylmethanamine (150mg, 0.65mmol) in N,N- To dimethylformamide (6 mL), add EDCI (247.5 mg, 1.29 mmol), HOBT (175 mg, 1.30 mmol), triethylamine (180 μL, 1.29 mmol) and cyanoacetic acid (110.16 mg, 1.30 mmol) in sequence, Stir at room temperature overnight, add saturated ammonium chloride aqueous solution (10mL) to quench, dichloromethane (15mL×3) extract, combine the organic phases and wash with saturated ammonium chloride solution (50mL), dry over anhydrous sodium sulfate, concentrate for column Separation by chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v)=30/1), and separation by preparative thin-layer chromatography gave 38 mg of light yellow solid, yield: 20%.

MS(ESI,pos.ion)m/z:299.3[M+1] ⁺ ;

¹ HNMR (400MHz, DMSO-d ₆ ): δ (ppm) 11.62 (s, 1H), 8.07 (m, 1H), 7.11 (m, 1H), 6.56 (m, 1H), 4.06 (s, 2H), 3.68-3.85(m,5H),2.98(s,3H),2.90(m,1H),2.61(m,1H),2.06(m,1H),1.72(m,1H).

Example 13 N-((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)methyl)-2-cyano-N-cyclopropylacetamide

Step 1: Synthesis of the compound N-cyclopropyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxamide

1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxylic acid (100 mg, 0.43 mmol) was dissolved in N,N-dimethylformamide (5 mL), Add EDCI (164.3mg, 0.86mmol), HOBT (116.1mg, 0.86mmol), triethylamine (120μL, 0.86mmol) and cyclopropylamine (59μL, 0.85mmol) in sequence, and stir overnight at room temperature. Add saturated ammonium chloride aqueous solution (10mL) to quench, dichloromethane (15mL * 3) extraction, after the organic phase is combined, wash with saturated ammonium chloride solution (50mL), dry over anhydrous sodium sulfate, concentrate and carry out column chromatography separation ( Eluent: PE/EtOAc (v/v)=5/1), to obtain 30 mg of white solid, yield: 26%.

MS(ESI,pos.ion)m/z:272.3[M+1] ⁺ .

Step 2: Synthesis of the compound N-((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)methyl)cyclopropylamine

Dissolve N-cyclopropyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxamide (50mg, 0.18mmol) in borane tetrahydrofuran solution (1M, 5mL ), reflux the reaction overnight, add methanol (3mL) to quench, concentrate, add methanol (5mL) to dissolve, add sodium hydroxide solution (1M, 1mL), reflux for 2 hours, add silica gel to mix the sample, and carry out column chromatography separation (Eluent: CH ₂ Cl ₂ /MeOH (v/v)=20/1), 35 mg of light yellow oil was obtained, yield: 74%.

MS(ESI,pos.ion)m/z:258.1[M+1] ⁺ .

Step 3: Compound N-((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)methyl)-2-cyano-N-cyclopropylethyl Amide synthesis

N-((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)methyl)cyclopropylamine (200mg, 0.78mmol) was dissolved in N,N-di To methylformamide (6 mL), add EDCI (296.8 mg, 1.55 mmol), HOBT (209.8 mg, 1.55 mmol), triethylamine (216 μL, 1.55 mmol) and cyanoacetic acid (132.1 mg, 1.55 mmol) in sequence, Stir at room temperature overnight, add saturated ammonium chloride aqueous solution (10mL) to quench, dichloromethane (15mL×3) extract, combine the organic phases and wash with saturated ammonium chloride solution (50mL), dry over anhydrous sodium sulfate, concentrate for column Separation by chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v)=30/1), and separation by preparative thin-layer chromatography gave 12 mg of light yellow solid, yield: 4.8%.

MS(ESI,pos.ion)m/z:325.1[M+1] ⁺ ;

¹ HNMR (600MHz, DMSO-d ₆ ): δ (ppm) 11.62 (s, 1H), 8.07 (s, 1H), 7.11 (m, 1H), 6.56 (m, 1H), 4.27 (s, 2H), 3.66-3.89(m,4H),2.81(m,1H),2.63(m,1H),2.08(m,1H),1.72(m,1H),1.22(m,2H),0.82(m,4H) .

Example 14N-(cyanomethyl)-3-(methylthio)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)tetrahydropyrrole-3-carboxamide

3-(methylthio)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)tetrahydropyrrole-3-carboxylic acid (0.15g, 0.54mmol), aminoacetonitrile hydrochloride ( 75mg, 0.81mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.21g, 1.07mmol), 1-hydroxybenzotriazole (0.15g, 1.09mmol ) and triethylamine (0.30mL, 2.00mmol) were reacted overnight at room temperature in N,N-dimethylformamide (5mL). The reaction was quenched with water (20 mL), extracted with dichloromethane (20 mL×4), the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v )=20/1), 70 mg of yellow sticky substance was obtained, and then purified by preparative thin-layer chromatography to obtain 6 mg of solid.

MS(ESI,pos.ion)m/z:317.1[M+1] ⁺ ;

¹ HNMR (600MHz, MeOH-d ₄ ): δ (ppm) 8.15 (s, 2H), 8.15 (s, 1H), 7.21 (d, J = 3.4Hz, 1H), 6.79 (d, J = 3.0Hz, 1H),5.50(s,11H),4.87(s,58H),4.23(s,3H),4.23(s,2H),3.88-3.52(m,7H),3.36(s,15H),3.32(dt ,J=3.1,1.6Hz,14H),3.22(q,J=7.3Hz,9H),2.69(d,J=26.4Hz,2H),2.38(dd,J=28.8,5.8Hz,2H),2.17 (s,3H),2.17(s,4H),2.04(dd,J=12.0,6.2Hz,1H),1.42(s,10H),1.32(dd,J=16.0,8.6Hz,30H),0.91( s,12H).

Example 15 N-(cyanomethyl)-N-cyclopropyl-3-(methylthio)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)tetrahydropyrrole-3- Formamide

Under ice-cooling, oxalyl chloride (0.15mL, 1.70mmol) and a catalytic amount of N,N-dimethylformamide (0.10mL) were slowly added dropwise to 3-(methylthio)-1-(7H-pyrrolo[ 2,3-d]pyrimidin-4-yl)tetrahydropyrrole-3-carboxylic acid (0.15g, 0.54mmol) in anhydrous dichloromethane (30mL) solution, reacted at room temperature for 10h, the reaction solution was concentrated under reduced pressure, The residue was dissolved in anhydrous dichloromethane (25 mL). Then it was slowly added dropwise to a solution of 2-(methylamino)acetonitrile (114mg, 1.07mmol) and triethylamine (0.40mL, 3.00mmol) in anhydrous dichloromethane (10mL) and reacted overnight at room temperature. Dilute with water (35mL), extract with dichloromethane (35mL×3), dry over anhydrous sodium sulfate, remove the solvent, and separate the concentrate by column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v) = 20/1), yielding 20 mg of a white solid.

MS(ESI,pos.ion)m/z:357.2[M+1] ⁺ ;

¹ HNMR (600MHz, DMSO-d ₆ ): δ (ppm) 11.65 (s, 1H), 8.11 (s, 1H), 7.15 (d, J=2.5Hz, 1H), 6.57 (s, 1H), 4.48 ( s,2H),3.98(m,2H),2.04(s,3H),1.36-1.25(m,5H),0.88(tt,J＝21.8,8.3Hz,4H).

Example 16N-(2-cyanoethyl)-N-cyclopentyl-3-(methylthio)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)tetrahydropyrrole- 3-formamide

Under ice bath, oxalyl chloride (0.60mL, 7.00mmol) and a catalytic amount of N,N-dimethylformamide (0.10mL) were slowly added dropwise to 3-(methylthio)-1-(7H-pyrrolo[ 2,3-d]pyrimidin-4-yl)tetrahydropyrrole-3-carboxylic acid (0.40g, 1.44mmol) in anhydrous dichloromethane (30mL) solution, reacted at room temperature for 10h, the reaction solution was concentrated under reduced pressure, The residue was dissolved in anhydrous dichloromethane (25 mL). Then it was slowly added dropwise to a solution of 3-(cyclopentylamino)propionitrile (0.40g, 2.89mmol) and triethylamine (1.0mL, 7.10mmol) in anhydrous dichloromethane (20mL) and reacted overnight at room temperature. Dilute with water (35mL), extract with dichloromethane (35mL×3), dry over anhydrous sodium sulfate, remove the solvent, and separate the concentrated solution by column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v) = 20/1), the crude product was obtained, and further purified by high performance liquid chromatography to obtain 4 mg of white solid. MS(ESI,pos.ion)m/z:399.2[M+1] ⁺ ;

¹ HNMR (400MHz, MeOH-d ₄ ): δ (ppm) 8.26 (s, 1H), 7.41 (s, 1H), 6.98 (d, J = 3.5Hz, 1H), 4.43-4.09 (m, 2H), 3.62-3.45(m,2H),2.98-2.54(m,4H),2.21(s,3H),2.04(dd,J＝8.1,4.5Hz,2H),1.85(s,2H),1.66(d, J＝31.7Hz, 4H), 1.33 (dd, J＝8.5, 4.5Hz, 3H).

Example 17 1-(3-(methylthio)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-3-carbonyl)pyrrolidine-3-carbonitrile

Step 1: Synthesis of compound 1-tert-butoxycarbonylpyrrolidine-3-thiomethyl-3-carboxylic acid methyl ester

At -78°C, under nitrogen protection, n-butyllithium (2.4M, 24.00mL) was slowly added dropwise to a solution of diisopropylamine (7.77g, 76.80mmol) in anhydrous THF (70mL), and stirred at this temperature for 30min. , slowly added a solution of 1-tert-butoxycarbonylpyrrolidine-3-carboxylate (8.00 g, 34.89 mmol) in anhydrous THF (10 mL) dropwise, and stirred at the temperature for 1.5 h after the addition was complete. Dimethyl disulfide (6.57 g, 69.70 mmol) was slowly added dropwise to the reaction solution, then the temperature was slowly raised to room temperature, and the reaction was stirred overnight at room temperature. After the reaction was completed, saturated NH ₄ Cl solution (10 mL) was added to the reaction solution to quench the reaction, and concentrated under reduced pressure, the obtained residue was separated by silica gel column chromatography (eluent: PE/EtOAc (v/v)=5/ 1), purified to obtain 6.00 g of light yellow liquid, yield: 62%.

MS(ESI,pos.ion)m/z:298.2[M+23] ⁺ .

Step 2: Synthesis of the compound 3-(methylthio)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxylic acid methyl ester

TFA (24.80g, 217.50mmol) was slowly added dropwise into a solution of 1-tert-butoxycarbonylpyrrolidine-3-thiomethyl-3-carboxylic acid methyl ester (6.00g, 21.79mmol) in DCM (30mL) and reacted at room temperature for 4 hours, the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the obtained pyrrolidine-3-thiomethyl-3-formic acid methyl ester was a pale yellow oil, which was dissolved in DMF (50mL), and slowly added dropwise to triethyl Amine (15.40g, 152.00mmol) was reacted with stirring at room temperature for 0.5 hours, 4-chloropyrrolopyrimidine (3.35g, 21.80mmol) was added, and the reaction solution was heated at 80°C overnight. After the reaction was completed, the temperature was slowly lowered to room temperature, and water (30 mL) was added to quench the reaction. The reaction mixture was extracted with dichloromethane (50 mL×3), and the combined organic phases were dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to leave The product was separated by silica gel column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v)=20/1), and purified to obtain 4.70 g of light yellow solid, yield: 74%.

MS(ESI,pos.ion)m/z:293.1[M+1] ⁺ .

Step 3: Synthesis of compound 3-(methylthio)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxylic acid

A solution of NaOH (6.42g, 161mmol) in water (5mL) was slowly added dropwise to 3-(methylthio)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3- Methyl formate (4.70 g, 16.07 mmol) in MeOH (30 mL) was reacted overnight at room temperature. After completion of the reaction, concentrate under reduced pressure to remove MeOH, adjust the pH to about 6 with concentrated hydrochloric acid, and distill the residue obtained under reduced pressure to separate by silica gel column chromatography (eluent: CH ₂ Cl ₂ /CH ₃ OH (v/v) =8/1), purified to obtain 3.40 g light yellow solid, yield: 76%.

MS(ESI,pos.ion)m/z:279.1[M+1] ⁺ .

Step 4: Compound 1-(3-(methylthio)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-3-carbonyl)pyrrolidine-3-carbonitrile synthesis

At 0°C, oxalyl chloride (1.82g, 14.37mmol) was slowly added dropwise to 3-methylthio-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxylic acid ( 80mg, 0.29mmol) of anhydrous DCM (5mL) solution, 2 drops of DMF as a catalyst, after the dropwise addition, the temperature was slowly raised to room temperature, and the reaction was stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue which was dissolved in anhydrous DCM (5 mL), and slowly added dropwise to cyanocyclopentane hydrochloride (37 mg, 0.29 mmol) and triethyl ether at 0°C. A solution of amine (145mg, 1.44mmol) in anhydrous DCM (5mL) was added dropwise, slowly warmed to room temperature, and stirred overnight at room temperature. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was separated by silica gel column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v) = 18/1), and purified to obtain 30 mg of white solid, yield: 29% .

MS(ESI,pos.ion)m/z:357.2[M+1] ⁺ ;

¹ HNMR (600MHz, DMSO-d ₆ ): δ (ppm) 11.65 (s, 1H), 8.11 (s, 1H), 7.15 (s, 1H), 6.58 (s, 1H), 3.69-4.20 (m, 8H ),3.55(s,1H),2.55(s,1H),2.13-2.35(m,3H),2.03(s,3H).

Example 182-(1-(3-(methylthio)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-carbonyl)pyrrolidin-3-yl) Acetonitrile

Step 1: Synthesis of compound 2-(pyrrolidin-3-yl)acetonitrile trifluoroacetate

At 0°C, trifluoroacetic acid (542mg, 4.75mmol) was slowly added dropwise into a solution of tert-butyl 3-cyanomethylpyrrolidine-1-carboxylate (100mg, 0.48mmol) in DCM (5mL), and the addition was completed slowly The temperature was raised to room temperature, and the reaction was stirred at room temperature for 5 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain 110 mg of a yellow-brown liquid, which was directly used in the next reaction without purification.

MS(ESI,pos.ion)m/z:111.2[M+1] ⁺ .

Step 2: Compound 2-(1-(3-(methylthio)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-3-carbonyl)pyrrolidine-3- Base) Synthesis of Acetonitrile

At 0°C, oxalyl chloride (1.60 g, 12.60 mmol) was slowly added dropwise to 3-methylthio-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxylic acid ( 70mg, 0.25mmol) of anhydrous DCM (3mL) solution, 2 drops of DMF as a catalyst, slowly warmed up to room temperature after the dropwise addition, and stirred at room temperature for 5 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue which was dissolved in anhydrous DCM (3 mL), and slowly added dropwise to 2-(pyrrolidin-3-yl)acetonitrile trifluoroacetate ( 82.00 mg, 0.75 mmol) and triethylamine (204 mg, 2.02 mmol) in anhydrous DCM (5 mL), after the dropwise addition, slowly warm up to room temperature, and stir at room temperature overnight. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was separated by silica gel column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v) = 15/1), and purified to obtain 40 mg of white solid, yield: 43% . MS(ESI,pos.ion)m/z:371.2[M+1] ⁺ ;

¹ HNMR (400MHz, CDCl ₃ ): δ (ppm) 11.19 (s, 1H), 8.32 (s, 1H), 7.10 (d, J = 3.4Hz, 1H), 6.60 (d, J = 3.3Hz, 1H) ,4.07-4.23(m,5H),3.62-3.84(m,3H),2.48-2.67(m,7H),2.11(d,J=1.8Hz,3H).

Example 19 N-(cyanomethyl)-3-fluoro-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxamide

Step 1: Synthesis of compound 1-benzyl-3-fluoropyrrolidine-3-carboxylic acid methyl ester

At 0°C, trifluoroacetic acid (0.30g, 2.59mmol) was slowly added dropwise into 2-fluoromethylacrylate (1.50g, 14.41mmol) and N-(methoxymethyl)-N-(trimethylsilylmethyl) ) benzylamine (3.80g, 16.00mmol) in DCM (20mL), the dropwise addition was completed, the temperature was slowly raised to room temperature, and the reaction was stirred at room temperature for 12h. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was separated by silica gel column chromatography (eluent: PE/EtOAc (v/v)=5/1), and purified to obtain 2.59 g of colorless liquid, yield: 76%.

MS(ESI,pos.ion)m/z:238.2[M+1] ⁺ .

Step 2: Synthesis of compound 3-fluoropyrrolidine-3-carboxylic acid methyl ester

Pd/C (10%, 0.52g) was added to the MeOH (30mL) solution of 1-benzyl-3-fluoropyrrolidine-3-carboxylate (2.59g, 10.91mmol) and reacted at room temperature under H ₂ atmosphere for 8h . After the reaction was completed, the solid was filtered off, and the filtrate was concentrated under reduced pressure to obtain 1.54 g of a colorless liquid, which was directly put into the next step without further purification.

MS(ESI,pos.ion)m/z:148.1[M+1] ⁺ .

Step 3: Synthesis of the compound 3-fluoro-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxylic acid methyl ester

Add triethylamine (1.24g, 12.23mmol) to 3-fluoropyrrolidine-3-carboxylic acid methyl ester (0.60g, 4.08mmol) and 4-chloropyrrolopyrimidine (0.75g, 4.89mmol) in isopropanol (10mL ) solution, the reaction solution was heated at 80°C overnight. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was separated by silica gel column chromatography (eluent: DCM/MeOH (v/v)=25/1), and purified to obtain 680 mg of white solid, yield: 63%.

MS(ESI,pos.ion)m/z:265.1[M+1] ⁺ .

Step 4: Synthesis of compound 3-fluoro-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxylic acid

A solution of NaOH (0.294 g, 12.27 mmol) in water (1 mL) was added dropwise to methyl 3-fluoro-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxylate ( 0.670g, 2.54mmol) in MeOH (15mL) solution, react overnight at room temperature. After the reaction was completed, methanol was concentrated under reduced pressure to remove methanol, the pH was adjusted to about 6 with concentrated hydrochloric acid, and the residue obtained by distillation under reduced pressure was separated by silica gel column chromatography (eluent: CH ₂ Cl ₂ /CH ₃ OH (v/v) =8/1), purified to obtain 0.61 g of white solid, yield: 97%.

MS(ESI,pos.ion)m/z:251.1[M+1] ⁺ .

Step 5: Synthesis of the compound N-(cyanomethyl)-3-fluoro-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxamide

Add triethylamine (0.49g, 4.79mmol) to 3-fluoro-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxylic acid (0.20g, 0.80mmol), HOBT (0.216g, 1.60mmol), EDCI (0.31g, 1.60mmol) and aminoacetonitrile hydrochloride (0.11g, 1.19mmol) in DMF (10mL) were reacted overnight at room temperature. After the reaction was completed, water (10 mL) was added to quench the reaction, dichloromethane (20 mL×2) was extracted, the combined organic phase was dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography Separation (eluent: CH ₂ Cl ₂ /CH ₃ OH (v/v)=15/1), purification gave 85 mg of white solid, yield: 37%.

MS(ESI,pos.ion)m/z:289.1[M+1] ⁺ ;

¹ HNMR (600MHz, DMSO-d ₆ ): δ (ppm) 11.69 (s, 1H), 9.29 (t, J = 4.7Hz, 1H), 8.13 (s, 1H), 7.16-7.17 (m, 1H), 6.61-6.62(m,1H),4.25(d,J＝5.5Hz,2H),4.12-4.22(m,3H),3.87(s,1H),2.54-2.62(m,1H),2.40-2.46( m,1H).

Example 20N-(cyanomethyl)-3-(hydroxymethyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxamide

Step 1: Synthesis of the compound 2-(((tert-butyldimethylsilyl)oxy)methyl)acrylate

tert-Butyldimethylsilyl chloride (4.14 g, 27.47 mmol) was added to a solution of ethyl 2-hydroxymethacrylate (3.19 g, 27.47 mmol) and imidazole (1.87 g, 27.47 mmol) in anhydrous DMF (25 mL) , react overnight at room temperature. After the reaction was completed, H ₂ O (15 mL) was added to quench, dichloromethane (40 mL×2) was extracted, the combined organic phase was dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and the obtained residue was subjected to silica gel column layer It was separated by analysis (eluent: PE/EtOAc (v/v)=1/1), and purified to obtain 3.64 g of colorless liquid, yield: 58%.

MS(ESI,pos.ion)m/z:231.1[M+1] ⁺ .

Step 2: Synthesis of compound 1-benzyl-3-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidine-3-carboxylic acid methyl ester

At 0°C, TFA (324mg, 2.84mmol) was added dropwise to 2-(((tert-butyldimethylsilyl)oxy)methyl)acrylate (3.64g, 15.80mmol) and N-(methoxy To a solution of methyl)-N-(trimethylsilylmethyl)benzylamine (4.16g, 17.54mmol) in DCM (20mL), the dropwise addition was completed, and the temperature was slowly raised to room temperature, and reacted at room temperature overnight. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was separated by silica gel column chromatography (eluent: PE/EtOAc (v/v)=5/1), and purified to obtain 3.28 g of colorless liquid, yield: 57%.

MS(ESI,pos.ion)m/z:364.2[M+1] ⁺ .

Step 3: Synthesis of the compound 3-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidine-3-carboxylate

Palladium on carbon (10%, 280 mg) was added to methyl 1-benzyl-3-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidine-3-carboxylate (1.40 g, 3.85 mmol) Anhydrous MeOH (20 mL) solution was reacted overnight at room temperature under H ₂ atmosphere. After the reaction was completed, it was filtered, and the filtrate was concentrated under reduced pressure to obtain 1.05 g of a colorless liquid, which was directly put into the next step without further purification.

MS(ESI,pos.ion)m/z:274.2[M+1] ⁺ .

Step 4 compound 3-(((tert-butyldimethylsilyl)oxy)methyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxylic acid Synthesis of methyl esters

Triethylamine (1.55g, 15.36mmol) was added to 3-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidine-3-carboxylic acid methyl ester (1.05g, 3.84mmol) and 4- Chloropyrrolopyrimidine (884 mg, 5.76 mmol) in DMF (14 mL) was reacted overnight at 80°C. The reaction was completed, quenched by adding H ₂ O (10 mL), extracted with ethyl acetate (20 mL×2), the combined organic phase was dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and the obtained residue was subjected to silica gel column layer Separation by separation (eluent: PE/EtOAc (v/v)=1/1), purification gave 1.31 g of white solid, yield: 87%.

MS(ESI,pos.ion)m/z:391.2[M+1] ⁺ .

Step 5: Compound 3-(((tert-butyldimethylsilyl)oxy)methyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3- Synthesis of formic acid

A solution of sodium hydroxide (409 mg, 10.24 mmol) in water (1 mL) was added to 3-(((tert-butyldimethylsilyl)oxy)methyl)-1-(7H-pyrrolo[2,3- d] Pyrimidin-4-yl) methyl pyrrolidine-3-carboxylate (400 mg, 1.02 mmol) in MeOH (8 mL) was reacted overnight at room temperature. After the reaction was completed, the pH was adjusted to about 6 with concentrated hydrochloric acid, and the product was distilled under reduced pressure to obtain 400 mg of white solid, which was directly put into the next step without further purification.

MS(ESI,pos.ion)m/z:377.2[M+1] ⁺ .

Step 6: Compound 3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(cyanomethyl)-1-(7H-pyrrolo[2,3-d]pyrimidine-4 -Synthesis of pyrrolidine-3-carboxamide

At 0°C, oxalyl chloride (3.37g, 26.56mmol) was added dropwise to 3-(((tert-butyldimethylsilyl)oxy)methyl)-1-(7H-pyrrolo[2,3-d ]Pyrimidin-4-yl)pyrrolidine-3-carboxylic acid (200mg, 0.53mmol) in anhydrous DCM (5mL) solution, 2 drops of DMF as a catalyst, slowly warmed to room temperature after the dropwise addition, stirred at room temperature for 2h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the obtained residue was dissolved in anhydrous DCM (5 mL), and slowly added dropwise to aminoacetonitrile hydrochloride (72 mg, 0.80 mmol) and triethylamine ( 322mg, 3.19mmol) of anhydrous DCM (5mL) solution, slowly warmed up to room temperature after the dropwise addition, and stirred at room temperature overnight. After the reaction was complete, saturated brine (10 mL) was added to wash, the organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and the obtained residue was separated by silica gel column chromatography (eluent: CH ₂ Cl ₂ /CH ₃ OH (v/v)=15/1), purified to obtain 110 mg of light yellow solid, yield: 50%.

MS(ESI,pos.ion)m/z:415.3[M+1] ⁺ .

Step 7: Synthesis of the compound N-(cyanomethyl)-3-(hydroxymethyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxamide

Tetrabutylammonium fluoride (1M, 0.32mL, 0.32mmol) was slowly added dropwise to 3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(cyanomethyl)-1- (7H-Pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxamide (110 mg, 0.27 mmol) in THF (5 mL) was reacted at room temperature for 8 h. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was separated by silica gel column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v) = 15/1), and purified to obtain 18 mg of white solid, yield: 23% .

MS(ESI,pos.ion)m/z:301.2[M+1] ⁺ ;

¹ HNMR (600MHz, MeOH-d ₄ ): δ (ppm) 8.09 (s, 1H), 7.10 (d, J = 3.5Hz, 1H), 6.70 (d, J = 2.6Hz, 1H), 4.17-4.24 ( m,3H),3.91(s,3H),3.78(q,J=11.2Hz,2H),2.40(s,1H),2.22(m,1H).

Example 214-(2,6-diazaspiro[3.4]octane-6-yl)-7H-pyrrolo[2,3-d]pyrimidine dihydrochloride

Step 1: Synthesis of compound 6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,6-diazaspiro[3.4]octane-2-tert-butyl carbonate

Potassium carbonate (779mg, 5.64mmol) was added to a solution of 2,6-diazaspiro[3.4]octane-2-tert-butyl carbonate (400mg, 1.88mmol) in N,N-dimethylacetamide (15mL) , heated at 45°C for 0.5 hours, then added 4-chloropyrrolopyrimidine (374mg, 2.44mmol) and heated at 95°C for 6 hours. After the reaction was completed, water (30 mL) was added to quench the reaction, the reaction mixture was extracted with ethyl acetate (50 mL×3), the combined organic phase was dried over anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column layer Separated by separation (eluent: CH ₂ Cl ₂ /MeOH (v/v)=20/1), purified to obtain 524 mg of white solid, yield: 85%.

MS(ESI,pos.ion)m/z:330.3[M+1] ⁺ .

Step 2: Synthesis of compound 4-(2,6-diazaspiro[3.4]octan-6-yl)-7H-pyrrolo[2,3-d]pyrimidine dihydrochloride

At room temperature, a solution of hydrogen chloride in ethyl acetate (4.0 M, 8 mL) was added dropwise to 6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,6-diazaspiro[3.4 ] Octane-2-tert-butyl carbonate (500mg, 1.52mmol) in ethyl acetate (16mL) solution, stirred at room temperature for 4 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain 542.51 mg of white solid, yield: 99%.

MS(ESI,pos.ion)m/z:230.2[M+1] ⁺ ;

¹ HNMR (400MHz, MeOH-d ₄ ): δ (ppm) 7.83 (s, 1H), 7.00 (d, J = 3.6Hz, 1H), 6.41 (d, J = 3.2Hz, 1H), 3.68-3.88 ( m,8H),2.20(s,2H).

Example 22 3-(6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,6-diazaspiro[3.4]octane-2-yl)-3-carbonylpropionitrile

Add N,N-diisopropylethylamine (147mg, 1.14mmol) to 4-(2,6-diazaspiro[3.4]octane-6-yl)-7H-pyrrolo[2,3-d ] pyrimidine dihydrochloride (172mg, 0.57mmol) and 1-cyanoacetyl-3,5-dimethylpyrazole (140mg, 0.86mmol) in 1,4-dioxane (3mL) solution, 100 The reaction was heated at °C for 2.5 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v) = 10/1), and purified to obtain 78.3 mg of a white solid, yield: 46 %.

MS(ESI,pos.ion)m/z:297.2[M+1] ⁺ ;

¹ HNMR (400MHz, DMSO-d ₆ ): δ (ppm) 11.61 (s, 1H), 8.09 (s, 1H), 7.13 (t, J = 4.0Hz, 1H), 6.59 (s, 1H), 4.09- 4.19(m,2H),3.88-3.98(m,4H),3.70-3.79(m,4H),2.20(s,2H).

Example 23 4-(2,7-diazaspiro[4.4]nonan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine dihydrochloride

Step 1: Synthesis of compound 7-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl ester

Add potassium carbonate (734mg, 5.31mmol) to a solution of 2,7-diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl ester (400mg, 1.77mmol) in N,N-dimethylacetamide (15mL) , heated at 45°C for 0.5 hours, then added 4-chloropyrrolopyrimidine (353 mg, 2.30 mmol), and heated at 95°C for 6 hours. After the reaction was completed, water (30 mL) was added to quench the reaction, the reaction mixture was extracted with ethyl acetate (50 mL×3), the combined organic phase was dried over anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column layer Separation by separation (eluent: CH ₂ Cl ₂ /MeOH (v/v) = 20/1), purification to obtain 596.43 mg of white solid, yield: 98%.

MS(ESI,pos.ion)m/z:344.3[M+1] ⁺ .

Step 2: Synthesis of compound 4-(2,7-diazaspiro[4.4]nonan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine dihydrochloride

A solution of hydrogen chloride in ethyl acetate (4.0M, 8mL) was added dropwise to 7-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4] at room temperature In a solution of tert-butyl nonane-2-carboxylate (500 mg, 1.46 mmol) in ethyl acetate (16 mL), the reaction was heated at 65°C for 2 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain 519 mg of white solid, yield: 99%.

MS(ESI,pos.ion)m/z:244.20[M+1] ⁺ ;

¹ HNMR (400MHz, MeOH-d ₄ ): δ (ppm) 8.10 (s, 1H), 7.11 (d, J = 4Hz, 1H), 6.71 (d, J = 4Hz, 1H), 3.82-3.94 (m, 4H),3.18-3.22(m,2H),3.02-3.10(m,2H),2.12-2.13(m,2H),1.95-2.03(m,2H).

Example 24 3-(7-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)-3-carbonylpropionitrile

At 0°C, N,N-diisopropylethylamine (886mg, 6.86mmol) was slowly added dropwise to 4-(2,7-diazaspiro[4.4]nonan-2-yl)-7H-pyrrole And [2,3-d] pyrimidine dihydrochloride (309.91mg, 0.98mmol) in DMF (7mL) solution, stirred at 0 ℃ for 0.5 hours, then added cyanoacetic acid (166mg, 1.96mmol) and 2 -(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (745mg, 1.96mmol), the reaction mixture was stirred at room temperature for 30 hours. After the reaction was completed, water (20 mL) was added to quench the reaction, extracted with ethyl acetate (30 mL×3), the combined organic phase was dried over anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (Eluent: CH ₂ Cl ₂ /MeOH (v/v)=10/1), purified to obtain 77.1 mg of white solid, yield: 25%.

MS(ESI,pos.ion)m/z:311.2[M+1] ⁺ ;

¹ HNMR (400MHz, DMSO-d ₆ ): δ(ppm) 11.58(s, 1H), 8.08(t, J=2.4Hz, 1H), 7.12(t, J=2.8Hz, 1H), 6.59(t, J＝1.6Hz, 1H), 3.93(d, J＝14.0Hz, 2H), 3.67-3.84(m, 4H), 3.55(t, J＝7.0Hz, 1H), 3.38-3.49(m, 3H), 1.88-2.00(m,4H).

Example 254-(2,7-diazaspiro[4.5]decane-2-yl)-7H-pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of the compound 7-benzyloxycarbonyl-2-tert-butoxycarbonyl-2,7-diazaspiro[4.5]decane

At room temperature, tetrahydrofuran (5 mL), water (2 mL), potassium carbonate (363.2 mg, 2.63mmol) and benzyl chloroformate (224μL, 1.57mmol), stirred at room temperature for 4h, quenched by adding saturated aqueous ammonium chloride (10mL), extracted with dichloromethane (15mL×3), dried over anhydrous sodium sulfate, concentrated Separation by column chromatography (eluent: PE/EtOAc (v/v)=5/1) gave 320 mg of white solid, yield: 81%.

MS(ESI,pos.ion)m/z:319.2[Mt-Bu+2] ⁺ .

Step 2: Synthesis of compound 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decane-7-benzyloxycarbonyl

At room temperature, dissolve 7-benzyloxycarbonyl-2-tert-butoxycarbonyl-2,7-diazaspiro[4.5]decane (320mg, 0.86mmol) in dichloromethane (5mL), add trifluoroacetic acid (0.5mL), stirred at room temperature for 4h, after the reaction was completed, concentrated directly to obtain a light yellow oil, followed by adding N,N-dimethylacetamide (6mL), potassium carbonate (475.7mg, 3.42mmol) and 4-chloropyrrole And[2,3-d]pyrimidine (156.98mg, 1.03mmol), reacted at 90°C for 8h, quenched by adding saturated aqueous ammonium chloride (10mL), extracted with dichloromethane (15mL×3), dried over anhydrous sodium sulfate, Concentrate and separate by column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v) = 30/1) to obtain 325 mg of light yellow solid, yield: 97%.

MS(ESI,pos.ion)m/z:392.2[M+1] ⁺ .

Step 3: Synthesis of compound 4-(2,7-diazaspiro[4.5]decane-2-yl)-7H-pyrrolo[2,3-d]pyrimidine

At room temperature, 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decane-7-benzyloxycarbonyl (325mg, 0.83mmol) Dissolve in methanol (6mL), add palladium carbon (10%, 88.6mg), and react at 50°C for 10h. After the reaction, filter and concentrate to obtain a light yellow oil, which is separated by column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v)=15/1), to obtain 230 mg of white solid, yield: 99%.

MS(ESI,pos.ion)m/z:258.3[M+1] ⁺ ;

¹ HNMR (400MHz, CDCl ₃ ): δ (ppm) 10.07 (s, br, 1H), 8.29 (s, 1H), 7.01 (d, J = 4.0Hz, 1H), 6.59 (d, J = 4.0Hz, 1H),3.85(m,3H),3.57(m,1H),3.49(s,1H),2.71-2.87(m,4H),2.03(m,1H),1.83(m,1H),1.61(m ,4H).

Example 26 3-(2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decane-7-yl)-3-carbonylpropionitrile

At room temperature, 4-(2,7-diazaspiro[4.5]decane-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (100mg, 0.40mmol) was dissolved in N,N- To dimethylformamide (6mL), add HOBT (81mg, 0.60mmol), EDCI (115mg, 0.6mmol) and cyanoacetic acid (51mg, 0.60mmol) successively, react at room temperature for 18h, add saturated aqueous ammonium chloride (10mL ), extracted with dichloromethane (15mL×3), dried over anhydrous sodium sulfate, concentrated, and separated by preparative chromatography to obtain 47mg of white solid, yield: 37%.

MS(ESI,pos.ion)m/z:325.1[M+1] ⁺ ;

¹ HNMR (400MHz, CDCl ₃ ): δ (ppm) 8.08 (s, 1H), 7.09 and 7.12 (d, J = 4Hz, 1H), 6.69 and 6.72 (d, J = 4Hz, 1H), 4.0 ( s,2H),3.85(m,1H),3.77(m,1H),3.60(m,3H),3.50(m,2H),3.39(m,1H),1.79(m,6H).

Example 27 4-(2,7-diazaspiro[4.5]decane-7-yl)-7H-pyrrolo[2,3-d]pyrimidine dihydrochloride

Step 1: Synthesis of compound 7-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decane-2-tert-butyl carbonate

At room temperature, N, N-dimethylacetamide (6 mL), carbonic acid Potassium (463.68mg, 3.36mmol) and 4-chloropyrrolo[2,3-d]pyrimidine (128.84mg, 0.84mmol), react at 90°C for 8h, add saturated aqueous ammonium chloride (10mL) to quench, dichloromethane (15mL×3) extracted, dried over anhydrous sodium sulfate, concentrated and separated by column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v)=30/1), to obtain 234 mg of light yellow oil, yield : 94%.

MS(ESI,pos.ion)m/z:358.3[M+1] ⁺ .

Step 2: Synthesis of compound 4-(2,7-diazaspiro[4.5]decane-7-yl)-7H-pyrrolo[2,3-d]pyrimidine dihydrochloride

At room temperature, tert-butyl 7-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decane-2-carbonate (234mg, 0.66mmol ) was dissolved in dichloromethane (3mL), added hydrogen chloride in ethyl acetate solution (4M, 819μL, 3.27mmol), reacted at room temperature for 3h, after the reaction was completed, concentrated to obtain a white solid, added to saturated sodium bicarbonate solution (5mL) And, the mixed sample was concentrated by adding silica gel and separated by column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v) = 15/1) to obtain 144 mg of white solid, yield: 86%.

MS(ESI,pos.ion)m/z:258.1[M+1] ⁺ ;

¹ HNMR (400MHz, MeOH-d ₄ ): δ (ppm) 8.13 (s, 1H), 7.18 (d, J = 4Hz, 1H), 6.70 (d, J = 4Hz, 1H), 3.95-3.99 (m, 4H),3.46(m,2H),3.37(m,1H),3.08(m,1H),1.68-2.06(m,6H).

Example 28 3-(7-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decane-2-yl)-3-carbonylpropionitrile

At room temperature, 4-(2,7-diazaspiro[4.5]decane-7-yl)-7H-pyrrolo[2,3-d]pyrimidine dihydrochloride (120mg, 0.47mmol) was dissolved in In N,N-dimethylformamide (5mL), add HOBT (95.85mg, 0.71mmol), EDCI (136.11mg, 0.71mmol), cyanoacetic acid (60mg, 0.71mmol) and triethylamine (98.8μL) in sequence , 0.71mmol), reacted at room temperature for 18h, quenched by adding saturated aqueous ammonium chloride solution (10mL), extracted with dichloromethane (15mL×3), dried over anhydrous sodium sulfate, concentrated, and separated by preparative chromatography to obtain 50mg of a white solid. Rate: 33%.

MS(ESI,pos.ion)m/z:325.1[M+1] ⁺ ;

¹ HNMR (400MHz, MeOH-d ₄ ): δ(ppm) 8.12and8.15(s, 1H), 7.14and7.16(d, J＝4Hz, 1H), 6.55and6.60(d, J＝4Hz, 1H),4.30(m,1H),4.10(m,1H),2.97(m,1H),3.46-3.85(m,5H),3.14-3.23(m,2H),1.92(m,2H),1.82 (m,4H).

Example 29 3-(7-(5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)-3 -Carbonylpropionitrile

Step 1: Synthesis of compound 4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine

At room temperature, 4-chloropyrrolo[2,3-d]pyrimidine (153 mg, 1.0 mmol) was dissolved in acetonitrile (7.5 mL), and acetic acid (1.5 mL) and 1-chloromethyl-4-fluoro- 1,4-diazidebicyclo[2.2.2]octane bistetrafluoroborate (531.39mg, 1.5mmol), react in an oil bath at 70°C for 19h, stop the reaction, cool to room temperature, add saturated sodium bicarbonate solution ( 10 mL), quenched with ethyl acetate (15 mL×3), dried over anhydrous sodium sulfate, concentrated and separated by column chromatography (eluent: PE/EtOAc (v/v)=3/1), to obtain 86 mg of gray solid , Yield: 50%.

MS(ESI,pos.ion)m/z:172.1[M+1] ⁺ .

Step 2: Compound 7-(5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-tert-butyl carbonate synthesis

At room temperature, 4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (86mg, 0.50mmol) was dissolved in N,N-dimethylacetamide (3mL), and 2, tert-butyl 7-diazaspiro[4,4]nonane-2-carboxylate (49mg, 0.22mmol) and potassium carbonate (89.76mg, 0.66mmol) were reacted at 90°C for 5h, quenched by adding water (6mL), Dichloromethane (15mL×3) was extracted, dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was separated by column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v/)=30/1 ), to obtain 59 mg of yellow solid, yield: 41%.

MS(ESI,pos.ion)m/z:362.3[M+1] ⁺ .

Step 3: Compound 3-(7-(5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl) -Synthesis of 3-carbonylpropionitrile

At room temperature, tert-butyl 7-(5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carbonate (49mg, 0.14mmol) was dissolved in dichloromethane (5mL), added trifluoroacetic acid (0.25mL), stirred at room temperature for 5h, concentrated directly to obtain a yellow oil, added N,N-dimethylformamide (5mL) Dissolve, add triethylamine (55.6μL, 0.40mmol), EDCI (38.2mg, 0.20mmol), HOBT (27mg, 0.20mmol) and cyanoacetic acid (17.3mg, 0.20mmol) successively, react overnight at room temperature, concentrate directly, The solvent was removed, and the concentrate was subjected to column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v)=30/1) to obtain 11 mg of a white solid, yield: 24%.

MS(ESI,pos.ion)m/z:329.20[M+1] ⁺ ;

¹ HNMR (400MHz, CDCl ₃ ): δ (ppm) 11.52 (s, 1H), 8.10 (d, J = 2.4Hz, 1H), 7.14 (d, 1H), 3.92-3.96 (d, 2H), 3.41- 3.79(m,8H),1.99(m,4H).

Example 303-(7-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)- 3-Carbonylpropionitrile

Step 1: Compound tert-butyl 7-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate Synthesis

At room temperature, 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (80mg, 0.48mmol), 2,7-diazaspiro[4.4]nonane-2-carboxylic acid tert Butyl ester (90mg, 0.40mmol) and potassium carbonate (166mg, 1.20mmol) were added to N,N-dimethylacetamide (5mL), heated at 90°C overnight. Cool to room temperature, quench the reaction with water (50 mL), extract with ethyl acetate (50 mL×3), dry the organic layer over anhydrous sodium sulfate, concentrate under reduced pressure, and separate the concentrate by column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v)=20/1), to obtain 142 mg of white solid, yield: 100%.

MS(ESI,pos.ion)m/z:358.3[M+1] ⁺ .

Step 2: Synthesis of compound 5-methyl-4-(2,7-diazaspiro[4.4]nonan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine diacid salt

tert-butyl 7-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (142mg, 0.40mmol) and ethyl acetate (3mL) mixture was placed in an ice bath and stirred for 15 minutes, fully cooled, then slowly added hydrogen chloride in ethyl acetate solution (4M, 4mL), stirred in an ice bath for 30 minutes, and stirred at room temperature Reaction 6.5h. Concentration under reduced pressure gave 130 mg of white solid, which was directly used in the next reaction.

Step 3: Compound 3-(7-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl )-3-carbonyl propionitrile synthesis

At room temperature, 5-methyl-4-(2,7-diazaspiro[4.4]nonan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine dihydrochloride (132mg, 0.40mmol) was dissolved in N,N-dimethylformamide (6mL), and hydroxybenzotriazole (81mg, 0.60mmol), 1-(3-dimethylaminopropyl)-3-ethyl Carbodiimide hydrochloride (115mg, 0.60mmol), cyanoacetic acid (51mg, 0.6mmol) and triethylamine (1.60mmol, 0.22mL), react overnight at room temperature, add water (50mL) to quench, dichloromethane (50mL×3) extracted, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrated solution was separated by column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v)=15/1) to obtain 67 mg of white solid , and separated by preparative thin-layer chromatography (developing solvent: CH ₂ Cl ₂ /MeOH (v/v)=12/1) to obtain 59 mg of white solid, the total yield of two steps: 46%.

MS(ESI,pos.ion)m/z:325.1[M+1] ⁺ ;

¹ HNMR (400MHz, MeOH-d ₄ ): δ (ppm) 8.14-8.04 (m, 1H), 8.04-7.92 (m, 2H), 7.78-7.66 (m, 2H), 7.22-6.96 (m, 1H) ,6.77-6.59(m,1H),3.85-3.48(m,6H),2.17-2.02(m,3H),1.41-1.29(m,3H).

Example 314-(2-(7-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)-2- Oxoethyl)benzonitrile

At room temperature, 4-(2,7-diazaspiro[4.4]nonan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine dihydrochloride (82mg, 0.26mmol) was dissolved in In N,N-dimethylformamide (6mL), add 1-hydroxybenzotriazole (53mg, 0.39mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiethylene Amine hydrochloride (75mg, 0.39mmol), 4-cyanophenylacetic acid (63mg, 0.39mmol) and triethylamine (1.04mmol, 0.15mL), react at room temperature for 18h, add water (50mL) to quench, dichloromethane (100mL×3) extraction, drying over anhydrous sodium sulfate, concentration under reduced pressure, separation by column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v)=20/1), to obtain 100 mg of white solid, product Rate: 98%.

MS(ESI,pos.ion)m/z:387.1[M+1] ⁺ ;

¹ HNMR (400MHz, DMSO-d ₆ ): δ (ppm) 11.60 (s, 1H), 8.09 (d, J = 3.9Hz, 1H), 7.76 (dd, J = 15.0, 8.2Hz, 2H), 7.44 ( dd,J=10.5,8.3Hz,2H),7.13(d,J=3.1Hz,1H),6.59(d,J=1.7Hz,1H),3.79(s,1H),3.75(s,1H), 3.68(t, J=6.7Hz, 2H), 3.44(dt, J=18.5, 7.0Hz, 2H), 1.95(dd, J=21.0, 13.8Hz, 4H), 1.24(s, 4H).

Example 32 4-(7-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carbonyl)benzenesulfonamide

At room temperature, 4-(2,7-diazaspiro[4.4]nonan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine dihydrochloride (82mg, 0.26mmol) was dissolved in In N,N-dimethylformamide (6mL), add 1-hydroxybenzotriazole (53mg, 0.39mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiethylene Amine hydrochloride (75mg, 0.39mmol), 4-p-carboxybenzenesulfonamide (79mg, 0.39mmol) and triethylamine (1.04mmol, 0.15mL), react overnight at room temperature, add water (10mL) to quench, dichloro Extracted with methane (50mL×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrated solution was separated by column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v)=15/1) to obtain 88 mg of white Solid, yield: 80%.

MS(ESI,pos.ion)m/z:427.2[M+1] ⁺ ;

¹ HNMR (400MHz, MeOH-d ₄ ): δ (ppm) 8.14-8.04 (m, 1H), 8.04-7.92 (m, 2H), 7.78-7.66 (m, 2H), 7.22-6.96 (m, 1H) ,6.77-6.59(m,1H),3.85-3.48(m,6H),2.17-2.02(m,3H),1.41-1.29(m,3H).

Example 333-(2-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decane-7-yl)- 3-Carbonylpropionitrile

Step 1: Synthesis of compound 2,7-diazaspiro[4.5]decane-7-benzyloxycarbonyl-2-carboxylic acid tert-butyl ester

Dissolve tert-butyl 2,7-diazaspiro[4.5]decane-2-carboxylate oxalate (400 mg, 1.40 mmol) and potassium carbonate (1.16 g, 8.40 mmol) in THF (15 mL) and water ( 3 mL) of the mixed solvent, and then added benzyl chloroformate (1.43 g, 8.40 mmol), and the mixture was stirred at room temperature for 8 hours. After the reaction was complete, saturated NaHCO solution ( ₂₀ mL) was added to the reaction solution to quench the reaction, extracted with ethyl acetate (30 mL×3), and the combined organic phase was dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain The residue was separated by silica gel column chromatography (eluent: PE/EtOAc (v/v)=2/1), and purified to obtain 445.6 mg of colorless liquid, yield: 85%.

MS(ESI,pos.ion)m/z:319.3[Mt-Bu+2] ⁺ .

Step 2: Synthesis of compound 2,7-diazaspiro[4.5]decane-7-carboxylic acid benzyl ester hydrochloride

At room temperature, hydrogen chloride in ethyl acetate solution (4M, 20mL) was added dropwise to tert-butyl 2,7-diazaspiro[4.5]decane-7-benzyloxycarbonyl-2-carboxylate (445.6mg, 1.19 mmol), the reaction was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain 847.9 mg of a colorless liquid, which was directly used in the next reaction without purification.

MS(ESI,pos.ion)m/z:275.2[M+1] ⁺ .

Step 3: Compound 2-(5-Methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decane-7-carboxylic acid benzyl ester Synthesis

Potassium carbonate (497.6mg, 3.60mmol) was added to 2,7-diazaspiro[4.5]decane-7-carboxylic acid benzyl ester hydrochloride (225.0mg, 0.72mmol) in DMAC (8mL) solution, 45 The reaction was heated at ℃ for 0.5 hours, then 4-chloropyrrolopyrimidine (157.5mg, 0.94mmol) was added, and the reaction was heated at 90℃ for 7.5 hours. After the reaction was completed, water (20 mL) was added to quench the reaction, the reaction mixture was extracted with ethyl acetate (30 mL×3), the combined organic phase was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and the residue was subjected to silica gel column layer Separated by separation (eluent: CH ₂ Cl ₂ /MeOH (v/v)=15/1), purified to obtain 110.9 mg of white solid, yield: 38%.

MS(ESI,pos.ion)m/z:406.2[M+1] ⁺ .

Step 4: Synthesis of compound 5-methyl-4-(2,7-diazaspiro[4.5]decane-2-yl)-7H-pyrrolo[2,3-d]pyrimidine

Add palladium on carbon (10%, 77.0 mg) to 2-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decane - In a solution of benzyl 7-carboxylate (110.9 mg, 0.27 mmol) in MeOH (6 mL), heat the reaction at 45° C. for 17 hours under H ₂ atmosphere. After the reaction was completed, it was filtered, and the filtrate was concentrated under reduced pressure to obtain 62.0 mg of a white solid, which was directly put into the next step without further purification.

MS(ESI,pos.ion)m/z:272.1[M+1] ⁺ .

Step 5: Compound 3-(2-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decane-7-yl )-3-carbonyl propionitrile synthesis

5-Methyl-4-(2,7-diazaspiro[4.5]decane-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (62.0mg, 0.23mmol), cyano Acetic acid (39.1mg, 0.46mmol) and HATU (174.9mg, 0.46mmol) were dissolved in DMF (5mL), then N,N-diisopropylethylamine (89.2mg, 0.69mmol) was added, and the mixture was stirred and reacted at room temperature overnight. After the reaction was complete, water (20 mL) was added to the reaction solution to quench the reaction, extracted with ethyl acetate (20 mL×3), the combined organic phase was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and the obtained residue was subjected to Separation by silica gel column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v)=15/1) to obtain 18.5 mg of white solid, yield: 24%.

MS(ESI,pos.ion)m/z:339.3[M+1] ⁺ ;

¹ HNMR (400MHz, DMSO-d ₆ ): δ (ppm) 11.35 (s, 1H), 8.07 (s, 1H), 6.98 (s, 1H), 4.09 (d, J = 4.5Hz, 1H), 3.74- 3.84(m,3H),3.40-3.53(m,6H),2.31-2.35(m,3H),1.87(s,1H),1.54-1.69(m,5H).

Example 34 3-(2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,6-diazaspiro[3.4]octane-6-yl)-3-carbonylpropionitrile

Step 1: Synthesis of compound 2,6-diazaspiro[3.4]octane-6-benzyloxycarbonyl-2-carboxylic acid tert-butyl ester

Dissolve tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (160mg, 0.75mmol) and potassium carbonate (207.3mg, 1.50mmol) in THF (8mL) and water (2mL) To the mixed solvent, benzyl chloroformate (192.8 mg, 1.13 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. After the reaction was completed, water (10 mL) was added to the reaction solution to quench the reaction, extracted with ethyl acetate (15 mL×3), the combined organic phase was dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and the obtained residue was subjected to Separation by silica gel column chromatography (eluent: PE/EtOAc (v/v) = 2/1), purification to obtain 209.1 mg of colorless liquid, yield: 80%.

MS(ESI,pos.ion)m/z:291.2[M-(t-Bu)+2] ⁺ .

Step 2: Synthesis of compound 2,6-diazaspiro[3.4]octane-6-carboxylate benzyl ester hydrochloride

At room temperature, a solution of hydrogen chloride in ethyl acetate (4M, 4mL) was added dropwise to tert-butyl 2,6-diazaspiro[3.4]octane-6-benzyloxycarbonyl-2-carboxylate (209mg, 0.60mmol ) in ethyl acetate (3 mL), stirred at room temperature for 4 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain 218.8 mg of a colorless liquid, which was directly used in the next reaction without purification.

MS(ESI,pos.ion)m/z:247.3[M+1] ⁺ .

Step 3: Synthesis of compound 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,6-diazaspiro[3.4]octane-6-carboxylic acid benzyl ester

Potassium carbonate (497.6mg, 3.60mmol) was added into 2,6-diazaspiro[3.4]octane-6-carboxylic acid benzyl ester hydrochloride (218.8mg, 0.77mmol) in N,N-dimethylethyl Amide (10 mL) solution was heated at 45°C for 0.5 hours, then 4-chloropyrrolopyrimidine (119.8 mg, 0.78 mmol) was added, and heated at 95°C for 6 hours. After the reaction was completed, water (20 mL) was added to quench the reaction, the reaction mixture was extracted with ethyl acetate (30 mL×3), the combined organic phase was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and the residue was subjected to silica gel column layer Separated by separation (eluent: CH ₂ Cl ₂ /MeOH (v/v)=18/1), purified to obtain 191.1 mg of white solid, yield: 88%.

MS(ESI,pos.ion)m/z:364.2[M+1] ⁺ .

Step 4: Synthesis of compound 4-(2,6-diazaspiro[3.4]octan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine

Palladium on carbon (10%, 37.6 mg) was added to benzyl 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,6-diazaspiro[3.4]octane-6-carboxylate The reaction was heated at 45° C. for 5 hours under H ₂ atmosphere in MeOH (10 mL) solution of phenyl ester (188 mg, 0.52 mmol). After the reaction was completed, it was filtered, and the filtrate was concentrated under reduced pressure to obtain 185.3 mg of a light yellow solid, which was directly put into the next step without further purification.

MS(ESI,pos.ion)m/z:230.2[M+1] ⁺ .

Step 5: Compound 3-(2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,6-diazaspiro[3.4]octane-6-yl)-3-carbonyl Synthesis of propionitrile

Add N,N-diisopropylethylamine (76.3mg, 0.59mmol) to 4-(2,6-diazaspiro[3.4]octane-6-yl)-7H-pyrrolo[2,3- d] pyrimidine (90.0mg, 0.39mmol) and 1-cyanoacetyl-3,5-dimethylpyrazole (96.3mg, 0.59mmol) in 1,4-dioxane (8mL) solution, 100°C The reaction was heated for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v) = 10/1), and purified to obtain 31.4 mg of a white solid, yield: 27 %.

MS(ESI,pos.ion)m/z:297.3[M+1] ⁺ ;

¹ HNMR (400MHz, DMSO-d ₆ ): δ (ppm) 11.66 (s, 1H), 8.12 (m, J = 2.0Hz, 1H), 7.15-7.17 (m, 1H), 6.37-6.40 (m, 1H ),4.19-4.23(m,4H),3.95(s,2H),3.68(s,1H),3.59(s,1H),3.50(t,J＝6.9Hz,1H),3.41(t,J＝ 7.0Hz, 1H), 2.22(t, J=6.9Hz, 1H), 2.13(t, J=7.0Hz, 1H).

Example 35 3-(2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-diazaspiro[3.4]octane-5-yl)-3-carbonylpropionitrile

Step 1: Synthesis of compound 2,5-diazaspiro[3.4]octane-5-benzyloxycarbonyl-2-carboxylic acid tert-butyl ester

Dissolve tert-butyl 2,5-diazaspiro[3.4]octane-2-carboxylate oxalate (400 mg, 1.55 mmol) and potassium carbonate (1.29 g, 9.30 mmol) in THF (16 mL) and water ( 4 mL) of the mixed solvent, and then added benzyl chloroformate (1.59 g, 9.30 mmol), and the mixture was stirred at room temperature for 22 hours. After completion of the reaction, water (20 mL) was added to the reaction liquid to quench the reaction, extracted with ethyl acetate (30 mL×3), the combined organic phase was dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and the obtained residue was subjected to Separation by silica gel column chromatography (eluent: PE/EtOAc (v/v) = 2/1), purification to obtain 353.7 mg of colorless liquid, yield: 66%.

MS(ESI,pos.ion)m/z:291.2[M-(t-Bu)+2] ⁺ .

Step 2: Synthesis of compound 2,5-diazaspiro[3.4]octane-5-carboxylic acid benzyl ester

At room temperature, hydrogen chloride in ethyl acetate solution (4M, 16mL) was added dropwise to tert-butyl 2,5-diazaspiro[3.4]octane-5-benzyloxycarbonyl-2-carboxylate (353.7mg, 1.02 mmol) in ethyl acetate (8 mL), the reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain 315 mg of white solid, which was directly used in the next reaction without further purification.

MS(ESI,pos.ion)m/z:247.1[M+1] ⁺ .

Step 3: Synthesis of compound 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-diazaspiro[3.4]octane-5-carboxylic acid benzyl ester

Potassium carbonate (2.04g, 3.84mmol) was added into 2,5-diazaspiro[3.4]octane-5-carboxylate (315.0mg, 1.28mmol) in N,N-dimethylacetamide ) solution, heated at 45°C for 0.5 hours, then added 4-chloropyrrolopyrimidine (254.9 mg, 1.66 mmol), and reacted at 95°C for 6 hours. After the reaction was completed, water (20 mL) was added to quench the reaction, the reaction mixture was extracted with ethyl acetate (30 mL×3), the combined organic phase was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and the residue was subjected to silica gel column layer Separation by separation (eluent: CH ₂ Cl ₂ /MeOH (v/v) = 12/1), purification to obtain 284.6 mg of white solid, yield: 61%.

MS(ESI,pos.ion)m/z:364.2[M+1] ⁺ .

Step 4: Synthesis of compound 4-(2,5-diazaspiro[3.4]octan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine

Palladium on carbon (10%, 56.9 mg) was added to benzyl 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-diazaspiro[3.4]octane-5-carboxylate The reaction was heated at 45°C under H ₂ atmosphere for 24 hours. After the reaction was completed, it was filtered, and the filtrate was concentrated under reduced pressure to obtain 220.1 mg of a white solid, which was directly put into the next step without further purification.

MS(ESI,pos.ion)m/z:230.1[M+1] ⁺ .

Step 5: Compound 3-(2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-diazaspiro[3.4]octane-5-yl)-3-carbonyl Synthesis of propionitrile

Add N,N-diisopropylethylamine (620.4mg, 4.80mmol) to 4-(2,5-diazaspiro[3.4]octane-2-yl)-7H-pyrrolo[2,3- d] In a solution of pyrimidine (220.1mg, 0.96mmol) and 1-cyanoacetyl-3,5-dimethylpyrazole (235mg, 1.44mmol) in 1,4-dioxane (8mL), heat at 100°C React for 10 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v) = 10/1), and purified to obtain 49 mg of white solid, yield: 17% .

MS(ESI,pos.ion)m/z:297.1[M+1] ⁺ ;

¹ HNMR (400MHz, DMSO-d ₆ ): δ (ppm) 11.66 (s, 1H), 8.12 (s, 1H), 7.15 (s, 1H), 6.37 (s, 1H), 4.88 (s, 2H), 4.00(m,6H),2.29(m,2H),1.83(m,2H).

Example 36 2-(7-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)-1-acetylmorpholine

Step 1: Synthesis of compound 2-chloro-1-acetylmorpholine

Under ice-cooling, chloroacetyl chloride (24mmol, 1.92mL) was slowly added dropwise to a mixture of morpholine (20mmol, 1.74mL) and triethylamine (30mmol, 4.18mL) in anhydrous tetrahydrofuran (40mL). Reacted for 4h and reacted overnight at room temperature. Add water (100mL) to quench, remove tetrahydrofuran under reduced pressure, extract with dichloromethane (100mL×3), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate the concentrated solution by column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v)=50/1), to obtain 3.24 g of yellow oil, yield: 100%.

MS(ESI,pos.ion)m/z:164.1[M+1] ⁺ .

Step 2: Compound 2-(7-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)-1-acetyl Synthesis of Morpholine

At room temperature, 4-(2,7-diazaspiro[4.4]nonan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine dihydrochloride (95mg, 0.30mmol) was dissolved in N,N-Dimethylacetamide (5mL), add potassium carbonate (83mg, 0.60mmol) and 2-chloro-1-acetylmorpholine (98mg, 0.60mmol) respectively, react overnight at 90°C, add water (50mL ), extracted with dichloromethane (50mL×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrated solution was separated by column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v)=15/ 1), a white solid was obtained, and further purified by preparative thin-layer chromatography to obtain 50 mg of a white solid, yield: 45%.

MS(ESI,pos.ion)m/z:371.3[M+1] ⁺ .

Example 374-(2-(7-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)-2- Oxoethyl)morpholin-3-one

Step 1: Synthesis of compound 2-(3-oxomorpholine) benzyl acetate

Under nitrogen protection, sodium hydride (1.05g, 26.30mmol) was added in portions to a solution of 3-morpholinone (2.20g, 22.00mmol) in N,N-dimethylformamide (22mL) under ice-cooling, Reaction at room temperature for 1h. Benzyl 2-bromoacetate (24 mmol, 3.8 mL) was added, and the reaction solution was stirred at room temperature for 2 h. Add water (100mL) to quench, ethyl acetate (100mL×3) to extract, the organic layer was washed with water (100mL) and saturated brine (100mL) respectively, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was subjected to column chromatography After separation (eluent _{: CH2Cl2} /MeOH (v/v) = 15/1), 3.40 g of product was obtained, yield: 63%.

MS(ESI,pos.ion)m/z:250.2[M+1] ⁺ .

Step 2: Synthesis of compound 2-(3-oxomorpholine)acetic acid

Palladium hydroxide on carbon (20%, 1.00 g) was added to a solution of benzyl 2-(3-oxomorpholine)acetate (3.4 g, 13.64 mmol) in methanol (50 mL) at room temperature. The reaction was stirred at room temperature under a hydrogen atmosphere for 2 h, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain 1.70 g of the product with a yield of 78%. ¹ HNMR (400MHz, DMSO-d ₆ ): δ (ppm) 4.05 (d, J = 11.8Hz, 4H), 3.93-3.76 (m, 2H), 3.45-3.33 (m, 2H).

Step 3: Compound 4-(2-(7-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)- Synthesis of 2-oxoethyl)morpholin-3-one

At room temperature, 4-(2,7-diazaspiro[4.4]nonan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine dihydrochloride (85mg, 0.27mmol) was dissolved in N,N-Dimethylformamide (5mL), were added 2-(3-oxomorpholine)acetic acid (65mg, 0.40mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbon Diimine hydrochloride (80mg, 0.40mmol), hydroxybenzotriazole (58mg, 0.40mmol) and triethylamine (1.07mmol, 25μL), react overnight at room temperature, add water (50mL) to quench, dichloro Extracted with methane (50mL×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrated solution was separated by column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v)=15/1) to obtain a white solid , and further purified by preparative thin-layer chromatography to obtain 45 mg of white solid, yield: 44%.

MS(ESI,pos.ion)m/z:385.1[M+1] ⁺ ;

¹ HNMR (400MHz, MeOH-d ₄ ): δ (ppm) 8.10 (d, J = 2.5Hz, 1H), 7.15-7.06 (m, 1H), 6.71 (d, J = 3.6Hz, 1H), 4.30- 4.23(m,1H),4.21-4.16(m,2H),3.98-3.91(m,3H),3.75-3.58(m,3H),3.55-3.46(m,3H),2.18-2.02(m,4H ),1.34-1.23(m,4H).

Example 38 1-(7-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane 2-yl)ethanone

Add triethylamine (100 mg, 1.00 mmol) to 4-(2,7-diazaspiro[4.4]nonan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine dihydrochloride ( 80mg, 0.25mmol) and acetic anhydride (520mg, 0.51mmol) in dichloromethane (6mL) solution, the reaction mixture was stirred at room temperature for 17 hours. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was separated by silica gel column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v) = 15/1), and purified to obtain 18 mg of white solid, yield: 25% .

MS(ESI,pos.ion)m/z:286.1[M+1] ⁺ ;

¹ HNMR (400MHz, MeOH-d ₄ ): δ (ppm) 8.11 (d, J = 2.9Hz, 1H), 7.11 (dd, J = 3.4, 2.6Hz, 1H), 6.66 (dd, J = 3.5, 2.2 Hz,1H),3.92(s,2H),3.74-3.78(m,2H),3.65-3.69(m,1H),3.54-3.56(m,2H),3.46(d,J＝8.9Hz,1H) ,3.37(s,1H),2.02-2.11(m,6H).

Example 39 1-(7-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)propenone

At 0°C, add acryloyl chloride (23mg, 0.21mmol) to 4-(2,7-diazaspiro[4.4]nonan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine disalt Acid salt (80mg, 0.25mmol) and triethylamine (51mg, 0.50mmol) in dichloromethane (8mL) solution, the reaction mixture was stirred at room temperature for 17 hours. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was separated by silica gel column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v) = 5/1), and purified to obtain 22.00 mg of white solid, yield: 29 %.

MS(ESI,pos.ion)m/z:298.2[M+1] ⁺ ;

¹ HNMR (400MHz, CDCl ₃ ): δ (ppm) 11.19 (s, 1H), 8.24 (d, J = 4.0Hz, 1H), 7.05 (t, J = 3.6Hz, 1H), 6.52 (d, J = 3.2Hz,1H),6.35-6.47(m,2H),5.64-5.71(m,1H),4.89(s,1H),3.96(s,1H),3.52-3.84(m,5H),3.07-3.13 (m,2H),2.01-2.09(m,4H).

Example 40 2-(7-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)acetonitrile

Triethylamine (77 mg, 0.76 mmol) was added to 4-(2,7-diazaspiro[4.4]nonan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine dihydrochloride ( 60 mg, 0.19 mmol) and bromoacetonitrile (30 mg, 0.25 mmol) in MeOH (6 mL), the reaction mixture was stirred at room temperature for 17 hours. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was separated by silica gel column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v) = 15/1), and purified to obtain 45 mg of white solid, yield: 84% .

MS(ESI,pos.ion)m/z:283.1[M+1] ⁺ ;

¹ HNMR (400MHz, MeOH-d ₄ ): δ(ppm) 8.10(s, 1H), 7.10(d, J=3.6Hz, 1H), 6.68(d, J=3.6Hz, 1H), 3.85(s, 3H),3.77(s,3H),2.76-2.89(m,3H),2.68-2.70(m,1H),1.94-2.13(m,4H).

Example 41 1-(7-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)-2-hydroxyethanone

4-(2,7-diazaspiro[4.4]nonan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine dihydrochloride (60mg, 0.19mmol), 2-hydroxyacetic acid (24mg, 0.32mmol), HOBt (51mg, 0.38mmol) and EDCI (72mg, 0.38mmol) were dissolved in DMF (5mL), then triethylamine (96mg, 0.95mmol) was added, and the mixture was stirred at room temperature overnight. After the reaction was completed, water (20 mL) was added to the reaction liquid to quench the reaction, dichloromethane (20 mL × 3) was extracted, the combined organic phase was dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and the obtained residue was subjected to Silica gel column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v) = 15/1), purified to obtain 12 mg of white solid, yield: 21%.

MS(ESI,pos.ion)m/z:302.2[M+1] ⁺ ;

¹ HNMR(400MHz,DMSO-d ₆ ):δ(ppm)11.57(s,1H),8.07(s,1H),7.10-7.12(m,1H),6.59-6.60(m,1H),4.54-4.55 (m,1H),4.01(dd,J＝21.3,5.0Hz,2H),3.84(s,1H),3.69(s,1H),3.46-3.51(m,6H),1.98-2.01(m,4H ).

Example 427-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl ester

At room temperature, tert-butyl 2,7-diazaspiro[4.4]nonane-2-carboxylate (236mg, 1.05mmol) and potassium carbonate (450mg, 3.20mmol) were added to N,N-dimethylethane Amide (10 mL) was heated at 45°C for 0.5 h, cooled to room temperature, and 4-chloropyrrolopyrimidine (250 mg, 1.60 mmol) was added, and the mixture was heated and stirred at 95°C for 12 h. Cool to room temperature, quench the reaction with water (50 mL), extract with dichloromethane (100 mL×3), dry the organic layer over anhydrous sodium sulfate, concentrate under reduced pressure, and separate by column chromatography (eluent: CH ₂ Cl ₂ / MeOH (v/v)=30/1), 270 mg of white solid was obtained, yield: 75%.

MS(ESI,pos.ion)m/z:344.3[M+1] ⁺ ;

¹ HNMR (400MHz, DMSO-d ₆ ): δ (ppm) 11.57 (s, 1H), 8.08 (s, 1H), 7.11 (s, 1H), 6.59 (s, 1H), 3.76 (d, J = 57.8 Hz, 6H), 3.27(d, J=7.1Hz, 2H), 1.94(d, J=34.7Hz, 5H), 1.41(d, J=7.1Hz, 9H).

Example 43 1-(7-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)-3,3-di Methylbutyl-1-one

4-(2,7-diazaspiro[4.4]nonan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine trifluoroacetate (60mg, 0.13mmol), 3,3 -Dimethyl-1-butyric acid (22mg, 0.19mmol), HOBt (34mg, 0.26mmol) and EDCI (48mg, 0.26mmol) were dissolved in DMF (5mL), then triethylamine (51mg, 0.51mmol) was added , the mixture was stirred at room temperature overnight. After the reaction was completed, water (20 mL) was added to the reaction liquid to quench the reaction, dichloromethane (20 mL × 3) was extracted, the combined organic phase was dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and the obtained residue was subjected to Separation by silica gel column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v) = 15/1), purification to obtain 38.50 mg of white solid, yield: 89%. MS(ESI,pos.ion)m/z:342.2[M+1] ⁺ ;

¹ HNMR (400MHz, DMSO-d ₆ ): δ (ppm) 11.58 (s, 1H), 8.08 (s, 1H), 7.11 (s, 1H), 6.58 (s, 1H), 3.57-3.84 (m, 5H ),3.40-3.50(m,3H),2.14(d,J=12.1Hz,2H),1.84-1.97(m,4H),1.00(d,J=10.8Hz,9H).

Example 44 2-(7-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)-N-(2, 2,2-Trifluoroethyl)propionamide

Step 1: Compound 2-(7-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)propanoic acid ethyl ester Synthesis

Add ethyl 2-bromoacetate (54 mg, 0.30 mmol) to 4-(2,7-diazaspiro[4.4]nonan-2-yl)-7H-pyrrolo[2,3-d]pyrimidinetrifluoro Acetate (102mg, 0.22mmol) and triethylamine (87mg, 0.09mmol) in DCM/DMF (9mL, v/v=8/1) mixed solution were reacted overnight at room temperature. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent CH ₂ Cl ₂ /MeOH (v/v) = 15/1), and purified to obtain 43.10 mg of a light yellow solid. The yield was : 58%.

MS(ESI,pos.ion)m/z:344.20[M+1] ⁺ .

Step 2: Compound 2-(7-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)-N-( Synthesis of 2,2,2-trifluoroethyl)propionamide

A solution of NaOH (52 mg, 1.30 mmol) in water (0.5 mL) was added to 2-(7-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4 ]nonan-2-yl) ethyl propionate (43mg, 0.13mmol) in THF (5mL) solution, react at room temperature for 24h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, the resulting residue was dissolved in DMF (8 mL), and 2,2,2-trifluoroethylamine hydrochloride (3 mg, 0.25 mmol), HOBt (34 mg, 0.25 mmol ), EDCI (48mg, 0.25mmol) and triethylamine (76mg, 0.75mmol), the mixture was stirred at room temperature overnight. After the reaction was completed, water (20 mL) was added to the reaction liquid to quench the reaction, dichloromethane (20 mL × 3) was extracted, the combined organic phase was dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and the obtained residue was subjected to Separation by silica gel column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v) = 15/1), purification to obtain 8 mg of white solid, yield: 16%.

MS(ESI,pos.ion)m/z:397.2[M+1] ⁺ ;

¹ HNMR (600MHz, MeOH-d ₄ ): δ (ppm) 8.09 (s, 1H), 7.10 (d, J = 2.7Hz, 1H), 6.70 (d, J = 3.3Hz, 1H), 3.84-4.00 ( m,4H),3.67-3.70(m,2H),3.21(q,J＝7.3Hz,1H),3.05-3.06(m,1H),2.75-2.82(m,2H),2.65-2.66(m, 1H),2.05-2.13(m,2H),1.91-1.97(m,2H),1.30-1.35(m,3H).

Example 45N-(4-(7-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)-4- Oxobutyl)acetamide

Step 1: Synthesis of compound 4-acetamidobutanoic acid

Acetic anhydride (79mg, 0.78mmol) was added to a solution of 4-aminobutyric acid (80mg, 0.78mmol) in methanol (4mL), and reacted overnight at room temperature. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v) = 20/1), and purified to obtain 60 mg of white solid, yield: 53%.

MS(ESI,pos.ion)m/z:146.2[M+1] ⁺ .

Step 2: Compound N-(4-(7-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)- Synthesis of 4-oxobutyl)acetamide

4-(2,7-diazaspiro[4.4]nonan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine trifluoroacetate (52mg, 0.11mmol), 4-ethane Aminobutyric acid (32mg, 0.22mmol), HOBT (29mg, 0.22mmol) and EDCI (42mg, 0.22mmol) were dissolved in DMF (5mL), then triethylamine (44mg, 0.44mmol) was added, and the mixture was stirred at room temperature React overnight. After the reaction was completed, water (20 mL) was added to the reaction liquid to quench the reaction, dichloromethane (20 mL × 3) was extracted, the combined organic phase was dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and the obtained residue was subjected to Silica gel column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v) = 15/1), purified to obtain 14 mg of white solid, yield: 34%. MS(ESI,pos.ion)m/z:371.2[M+1] ⁺ ;

¹ HNMR (600MHz, MeOH-d ₄ ): δ (ppm) 8.12 (d, J = 2.1Hz, 1H), 7.16 (d, J = 2.9Hz, 1H), 6.76 (t, J = 3.7Hz, 1H) ,3.49-3.71(m,7H),3.20-3.25(m,2H),2.37-2.43(m,2H),2.03-2.15(m,5H),1.95(d,J＝21.1Hz,3H),1.80 -1.84(m,2H).

Example 46 2-(6-carbonyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,7-diazaspiro[4.4]nonan-7-yl)acetonitrile

Step 1: Synthesis of the compound 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine

At -5°C, sodium hydride (60%, 5.08g, 127mmol) was added in portions to a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (15g, 97.67mmol) in anhydrous DMF (30mL) After the reaction solution was stirred and reacted at this temperature for 2.5h, 2-(trimethylsilyl)ethoxymethyl chloride (19.54g, 117.21mmol) was slowly added dropwise. After the addition was complete, the reaction was stirred overnight at this temperature. , then reacted at room temperature for 24h, the reaction was completed, adding water (30mL) to quench the reaction, the reaction mixture was extracted with ethyl acetate (50mL×3), the combined organic phase was dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure , the residue was separated by silica gel column chromatography (eluent: PE/EtOAc (v/v)=10/1), and purified to obtain 20.61 g of white solid, yield: 74%.

MS(ESI,pos.ion)m/z:284.2[M+1] ⁺ .

Step 2: Synthesis of compound pyrrolidine-2-carboxylate ethyl ester hydrochloride

Concentrated hydrochloric acid (2 mL) was added to a solution of pyrrolidine-2-carboxylic acid (1.60 g, 13.90 mmol) in ethanol (30 mL), and heated to reflux overnight. After the reaction was completed, it was concentrated under reduced pressure to obtain 2.51 g of a colorless liquid, which was directly put into the next step without further purification.

MS(ESI,pos.ion)m/z:144.3[M+1] ⁺ .

Step 3: Compound 1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid ethyl Synthesis of esters

Add triethylamine (2.80g, 28.00mmol) to a solution of ethyl pyrrolidine-2-carboxylate hydrochloride (2.51g, 14.00mmol) in isopropanol (30mL), react at room temperature for 0.5h, and then add 4-chloro -7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (2.60 g, 9.20 mmol), the reaction solution was heated under reflux overnight. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was separated by silica gel column chromatography (eluent: PE/EtOAc (v/v)=5/1), and purified to obtain 2.60 g of white solid, yield: 72%.

MS(ESI,pos.ion)m/z:391.2[M+1] ⁺ .

Step 4: Compound 2-(acetonitrile)-1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl) Synthesis of ethyl pyrrolidine-2-carboxylate

At -78°C, under nitrogen protection, n-butyllithium (2.4M, 14.00mL) was slowly added dropwise into a solution of diisopropylamine (3.60g, 36.00mmol) in anhydrous THF (5mL), and the reaction was stirred at this temperature for 15min. Slowly add ethyl 1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-2-carboxylate dropwise (2.60g, 6.66mmol) solution in anhydrous THF (2mL), the dropwise addition was completed, and the reaction was stirred at this temperature for 0.5h. After bromoacetonitrile (2.40 g, 20.00 mmol) was slowly added dropwise to the reaction solution, the temperature was slowly raised to room temperature, and the reaction was stirred overnight at room temperature. After the reaction was completed, saturated NH ₄ Cl solution (1 mL) was added to the reaction solution to quench the reaction, concentrated under reduced pressure, and the obtained residue was separated by silica gel column chromatography (eluent: PE/EtOAc (v/v)=5/ 1), purified to obtain 716.00 mg of light yellow liquid, yield: 25%.

MS(ESI,pos.ion)m/z:430.2[M+1] ⁺ .

Step 5: Compound 2-(2-aminoethyl)-1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4 -Synthesis of ethyl)pyrrolidine-2-carboxylate

Add ammonia in methanol (7.0M, 7mL) and Raney nickel (14mg, 0.16mmol) to 2-(acetonitrile)-1-(7-((2-(trimethylsilyl)ethoxy)methyl )-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid ethyl ester (716mg, 1.67mmol) in MeOH (15mL) solution, hydrogenation at 40℃ under H ₂ atmosphere for 5h . After the reaction was complete, the solid was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v) = 15/1), and purified to obtain 288 mg of a white solid. Yield: 40%.

MS(ESI,pos.ion)m/z:434.2[M+1] ⁺ .

Step 6: Compound 1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,7-diaze Synthesis of heterospiro[4.4]nonan-6-one

Potassium tert-butoxide (149 mg, 1.33 mmol) was added to 2-(2-aminoethyl)-1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2 ,3-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid ethyl ester (288mg, 0.66mmol) in toluene (8mL) solution, heated under reflux overnight. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was separated by silica gel column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v) = 15/1), and purified to obtain 185 mg of white solid, yield: 72% .

MS(ESI,pos.ion)m/z:388.2[M+1] ⁺ .

Step 7: Compound 2-(6-carbonyl-1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl) Synthesis of -1,7-diazaspiro[4.4]nonan-7-yl)acetonitrile

At -15°C, sodium hydride (60%, 51mg, 1.29mmol) was added in portions to 1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3 -d] In a solution of pyrimidin-4-yl)-1,7-diazaspiro[4.4]nonan-6-one (10 mg, 0.26 mmol) in anhydrous DMF (5 mL), the reaction was stirred at this temperature for 2 h. Then bromoacetonitrile (155mg, 1.29mmol) was added, stirred at this temperature for 0.5h, then slowly raised to room temperature, stirred at room temperature for 48h, water (10mL) was slowly added to the reaction liquid to quench the reaction, dichloromethane (15mL× 3) extraction, the combined organic phases were dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and the obtained residue was separated by silica gel column chromatography (eluent: PE/EtOAc (v/v)=5/1 ), purified to obtain 38 mg of yellow-brown liquid, yield: 35%.

MS(ESI,pos.ion)m/z:427.2[M+1] ⁺ .

Step 8: Compound 2-(6-carbonyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,7-diazaspiro[4.4]nonan-7-yl) Synthesis of acetonitrile

At room temperature, trifluoroacetic acid (41 mg, 0.36 mmol) was slowly added to 2-(6-carbonyl-1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2, 3-d] pyrimidin-4-yl)-1,7-diazaspiro[4.4]nonan-7-yl) acetonitrile (38mg, 0.09mmol) in dichloromethane (5mL) solution, react at room temperature for 24h. After the reaction was completed, the reaction solution was adjusted to alkaline with saturated sodium bicarbonate solution, extracted with dichloromethane (15 mL×3), the combined organic phase was dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain a residue After separation and purification by silica gel column chromatography (eluent: CH ₂ Cl ₂ /CH ₃ OH (v/v)=15/1), 18 mg of white solid was obtained, yield: 68%.

MS(ESI,pos.ion)m/z:297.2[M+1] ⁺ ;

¹ HNMR (600MHz, MeOH-d ₄ ): δ (ppm) 8.15 (s, 1H), 7.10 (d, J = 3.6Hz, 1H), 6.68 (d, J = 3.6Hz, 1H), 4.58-4.61 ( m,2H),4.27(d,J＝17.4Hz,1H),4.15-4.19(m,1H),4.03-4.07(m,1H),3.84-3.88(m,1H),3.59-3.64(m, 1H),2.63-2.68(m,1H),2.06-2.32(m,4H).

Example 47 2-(6-carbonyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,7-diazaspiro[4.4]nonan-7-yl)propionitrile

Step 1: Compound 2-(6-carbonyl-1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl) Synthesis of -1,7-diazaspiro[4.4]nonan-7-yl)propionitrile

At -15°C, sodium hydride (60%, 40mg, 1.00mmol) was added in portions to 1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3 -d]pyrimidin-4-yl)-1,7-diazaspiro[4.4]nonan-6-one (78mg, 0.20mmol) and potassium iodide (33mg, 0.20mmol) in anhydrous DMF (5mL) solution , Stir the reaction at this temperature for 2h. Then 3-bromopropionitrile (268mg, 2.00mmol) was added. After stirring the reaction at this temperature for 0.5h, the temperature was slowly raised to room temperature, and the reaction was stirred at room temperature for 48h. Water (10mL) was slowly added to the reaction liquid to quench the reaction, dichloromethane (15mL×3) extraction, the combined organic phases were dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain 110.00 mg of a yellow-brown liquid, which was directly put into the next step without further purification.

MS(ESI,pos.ion)m/z:441.3[M+1] ⁺ .

Step 2: Compound 2-(6-carbonyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,7-diazaspiro[4.4]nonan-7-yl) Synthesis of propionitrile

At room temperature, trifluoroacetic acid (229 mg, 2.00 mmol) was slowly added to 2-(6-carbonyl-1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2 ,3-d]pyrimidin-4-yl)-1,7-diazaspiro[4.4]nonan-7-yl)propionitrile (110mg, 0.25mmol) in dichloromethane (5mL) solution, react at room temperature 24h. After the reaction was completed, the reaction solution was adjusted to alkaline with saturated sodium bicarbonate solution, extracted with dichloromethane (15 mL×3), the combined organic phase was dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain a residue Separation by silica gel column chromatography (eluent: CH ₂ Cl ₂ /CH ₃ OH (v/v) = 15/1) and purification to obtain 8 mg of white solid, yield: 13%.

MS(ESI,pos.ion)m/z:311.3[M+1] ⁺ ;

¹ HNMR (400MHz, MeOH-d ₄ ): δ (ppm) 8.12 (s, 1H), 7.10 (d, J = 3.6Hz, 1H), 6.68 (d, J = 3.6Hz, 1H), 4.16-4.24 ( m,2H),4.05-4.07(m,1H),3.85-3.86(m,1H),3.59-3.70(m,2H),2.77-2.89(m,3H),2.06-2.29(m,5H).

Example 48 2-cyano-N-(3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)acetamide

Step 1: Synthesis of the compound (3-aminophenyl) benzyl carbamate

Dissolve m-phenylenediamine (5.0g, 50.0mmol) in dichloromethane (100mL), cool to 0°C, add N,N-diisopropylethylamine (25.00mL) and benzyl chloroformate ( 3.20 mL), slowly returned to room temperature and stirred overnight. It was concentrated under reduced pressure and separated by column chromatography (eluent: PE/EtOAc (v/v)=2/1) to obtain 9.00 g of product, yield: 74%.

MS(ESI,pos.ion)m/z:243.2[M+1] ⁺ .

Step 2: Synthesis of the compound (benzyl 3-(methylamino)phenyl)carbamate

Benzyl (3-aminophenyl)carbamate (2.00g, 8.25mmol) was dissolved in N,N-dimethylformamide (20mL), sodium bicarbonate (2.08g, 24.7mmol) and iodomethane (0.50 mL, 8.02mmol), stirred at room temperature for 3h, added saturated aqueous sodium chloride solution (150mL) to quench the reaction, extracted with ethyl acetate (200mL×3), washed the organic phase with water (150mL), and saturated sodium chloride solution (150mL) Washed, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (eluent: PE/EtOAc (v/v) = 10/1) to obtain 1.80 g of product, yield: 85%.

MS(ESI,pos.ion)m/z:257.2[M+1] ⁺ .

Step 3: Synthesis of the compound (benzyl 3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)carbamate

Benzyl (3-(methylamino)phenyl)carbamate (0.66g, 2.60mmol) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.40g, 2.60mmol) were dissolved in iso Add 3 drops of concentrated hydrochloric acid to propanol (50 mL), heat and stir under reflux overnight. It was concentrated under reduced pressure and separated by column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v)=20/1) to obtain 0.70 g of the product, yield: 70%.

MS(ESI,pos.ion)m/z:374.3[M+1] ⁺ .

Step 4: Synthesis of compound N ¹ -methyl-N ¹ -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzene-1,3-diamine

Benzyl (3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)carbamate (0.50 g, 1.34 mmol) was dissolved in methanol (50 mL) and palladium was added Carbon (10%, 0.10g), pumped and ventilated three times, stirred and reacted under hydrogen balloon pressure for 3h. Celite was filtered, and the filtrate was concentrated under reduced pressure, which was directly used in the next reaction.

Step 5: Synthesis of compound 2-cyano-N-(3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)acetamide

Dissolve cyanoacetic acid (0.90g, 10.45mmol) in tetrahydrofuran (50mL), add a catalytic amount of N,N-dimethylformamide (0.1mL) dropwise, cool to 0°C, and slowly add oxalyl chloride (2.70mL , 31.34mmol), returned to room temperature and stirred for 1h, concentrated under reduced pressure, dried and then dissolved in tetrahydrofuran (50mL) for later use.

N ¹ -methyl-N ¹ -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzene-1,3-diamine (0.50 g, 2.00 mmol) was dissolved in tetrahydrofuran (50 mL), Add triethylamine (6.00 mL), cool to 0° C., add dropwise the freshly prepared acid chloride solution, and slowly return to room temperature for 5 h. Add saturated sodium bicarbonate solution (30 mL) to quench the reaction, extract with dichloromethane (30 mL×3), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate by column chromatography (eluent: CH ₂ Cl ₂ /MeOH ( v/v)=20/1), 0.40 g of solid was obtained, yield: 60%.

MS(ESI,pos.ion)m/z:307.1[M+1] ⁺ ;

¹ HNMR (400MHz, CDCl ₃ ): δ (ppm) 8.27 (s, 1H), 7.67-7.66 (m, 1H), 7.62 (s, 1H), 7.58-7.47 (m, 1H), 7.16-7.15 (m ,1H),6.83(d,J=4.0,1H),3.60(s,3H),3.37-3.32(m,2H).

Example 49 4-(4-fluoro-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)benzyl)morpholin-3-one

Step 1: Synthesis of the compound (3-amino-4-fluorophenyl)methanol

The compound 3-amino-4-fluoro-benzoic acid (3.00g, 19.34mmol) was dissolved in tetrahydrofuran (50mL), cooled to 0°C, lithium aluminum hydride (3.67g, 96.69mmol) was added, and the solution was heated under reflux overnight. The reaction was quenched by adding methanol (20 mL), filtered, and the filtrate was directly concentrated and separated by column chromatography (eluent: PE/EtOAc (v/v)=1/1) to obtain 2.20 g of the product, yield: 81%.

MS(ESI,pos.ion)m/z:142.2[M+1] ⁺ .

Step 2: Synthesis of compound (4-fluoro-3-(methylamino)phenyl)methanol

The compound (3-amino-4-fluorophenyl)methanol (2.00g, 14.17mmol) was dissolved in N,N-dimethylformamide (20mL), cooled to 0°C, and sodium bicarbonate (3.57g, 42.5 mmol), iodomethane (0.85mL, 13.6mmol) was added dropwise, and the solution was returned to room temperature to react overnight. Add saturated aqueous sodium chloride (100mL) to quench the reaction, extract with ethyl acetate (100mL×3), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate by column chromatography (eluent: PE/EtOAc (v/v )=3/1), 1.50 g of product was obtained, yield: 68%.

MS(ESI,pos.ion)m/z:156.0[M+1] ⁺ .

Step 3: Synthesis of compound (4-fluoro-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)methanol

Dissolve (4-fluoro-3-(methylamino)phenyl)methanol (1.20g, 7.73mmol) in isopropanol (50mL), add 4-chloro-7H-pyrrolo[2,3-d] Pyrimidine (1.20g, 7.84mmol), stirred evenly, added 3 drops of concentrated hydrochloric acid dropwise, and heated to reflux overnight. It was concentrated under reduced pressure and separated by column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v)=20/1) to obtain 1.10 g of the product, yield: 52%.

MS(ESI,pos.ion)m/z:273.2[M+1] ⁺ .

Step 4: Synthesis of the compound N-(5-(bromomethyl)-2-fluorophenyl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

(4-Fluoro-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)methanol (800 mg, 2.94 mmol) was dissolved in dichloromethane (50 mL), Cool to 0°C, add phosphorus tribromide (0.55mL, 5.88mmol) dropwise, return to room temperature and stir the reaction overnight. The reaction was quenched by adding saturated aqueous sodium chloride (100 mL), extracted with dichloromethane (100 mL×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was directly used in the next step.

Step 5: Synthesis of compound 4-(4-fluoro-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)benzyl)morpholin-3-one

Dissolve morpholin-3-one (1.51g, 14.92mmol) in N,N-dimethylformamide (20mL), cool to 0°C, add sodium hydride (60%, 0.90g, 2.25mmol), and After stirring for 1 h at ℃, N-(5-(bromomethyl)-2-fluorophenyl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.50g, 1.49mmol), return to room temperature and react overnight, add saturated aqueous sodium chloride (100mL) to quench the reaction, extract with ethyl acetate (100mL×3), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and carry out column chromatography separation (leaching Lotion: CH ₂ Cl ₂ /MeOH (v/v)=15/1), to obtain 200 mg of solid, yield: 40%.

MS(ESI,pos.ion)m/z:356.1[M+1] ⁺ ;

¹ HNMR (400MHz, MeOH-d ₄ ): δ (ppm) 8.31 (s, 1H), 7.48-7.43 (m, 2H), 7.36-7.31 (m, 1H), 6.92 (d, J = 4.0Hz, 1H ),4.64(s,2H),4.15(s,2H),3.84(t,J=4.0,4.0Hz,2H),3.60(s,3H),3.39-3.33(m,2H).

Example 50 4-((3-acrylamide phenyl)amino)-N-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

Step 1: Synthesis of compound 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine

The compound 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (14.1 g, 91.8 mmol) was dissolved in chloroform (200 mL), and NBS (17.17 g, 96.4 mmol) was added slowly. Heated to reflux for 2 h, cooled to room temperature, filtered to remove the solid, and the filtrate was concentrated to obtain 18.1 g of gray solid, yield: 85%.

MS(ESI,pos.ion)m/z:234.0[M+1] ⁺ .

Step 2: Synthesis of compound 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid

The compound 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (3g, 12.9mmol) was dissolved in dry THF (50mL), protected by _N2 , and slowly injected into n-butyl at -78°C Lithium (2.4M, 16.2mL, 38.7mmol) was reacted at -78°C for 1h. Then, CO ₂ gas was introduced into the reaction system, and the reaction was continued at -78°C for 1 h. The reaction temperature was slowly returned to room temperature, and the reaction at room temperature was continued for 12 h. Water (20 mL) was added to quench, and the reaction solution was adjusted to pH=3-4 with HCl (1M). Filtration afforded 1.53 g of solid, yield: 60%.

MS(ESI,pos.ion)m/z:198.1[M+1] ⁺ .

Step 3: Synthesis of compound 4-chloro-N-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

Compound 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (198mg, 1mmol) was dissolved in dichloromethane (15mL), a catalytic amount of DMF (1 drop) was added, and Oxalyl chloride (381mg, 3mmol) was added at 0°C and reacted at 0°C for 0.5h and at room temperature for 1h. The solvent was spin-dried to obtain the crude acid chloride product for later use. Isopropylamine (89mg, 1.5mmol) was dissolved in dichloromethane (10mL), a dichloromethane (5mL) solution of the crude acid chloride product was added at 0°C, and reacted overnight at room temperature. Quenched with saturated NH ₄ Cl solution (15 mL), extracted with dichloromethane (15 mL×3), dried over Na ₂ SO ₄ , and separated by column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v)=10/ 1), to obtain 155 mg of yellow solid, yield: 65%.

MS(ESI,pos.ion)m/z:239.15[M+1] ⁺ .

Step 4: Synthesis of the compound (benzyl 3-((5-(isopropylformamide)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)carbamate

Compound 4-chloro-N-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (200mg, 0.84mmol) and compound (3-aminophenyl)carbamate benzyl ester (224mg , 0.92mmol) was dissolved in isopropanol (200mL), concentrated hydrochloric acid (3 drops) was added, and the reaction was heated under reflux overnight. The solvent was evaporated to dryness and separated by direct column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v)=10/1) to obtain 152 mg of product, yield: 41%.

MS(ESI,pos.ion)m/z:445.20[M+1] ⁺ .

Step 5: Synthesis of compound 4-((3-aminophenyl)amino)-N-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

The compound (3-((5-(isopropylformamide)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)carbamate benzyl ester (152mg, 0.34mmol) was dissolved in Add methanol (10 mL), add palladium carbon (30 mg), react at room temperature under hydrogen atmosphere for 6 h, filter, evaporate the filtrate to dryness, and separate by column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v) = 10/1 ), yielding 101 mg of product, yield: 95%.

MS(ESI,pos.ion)m/z:311.0[M+1] ⁺ .

Step 6: Synthesis of compound 4-((3-acrylamidephenyl)amino)-N-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

Compound 4-((3-aminophenyl)amino)-N-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (50mg, 0.16mmol) was dissolved in DMF (5mL) , add triethylamine (24mg, 0.24mmol), HOBT (32mg, 0.24mmol) and EDCI (46mg, 0.24mmol), react at room temperature for 10h. Dilute with water (20 mL), extract with dichloromethane (15 mL×3), dry over Na ₂ SO ₄ , evaporate the solvent to dryness, and separate by column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v)=10/1 ), to obtain 25 mg of white solid, yield: 35%.

MS(ESI,pos.ion)m/z:365.20[M+1] ⁺ ;

¹ HNMR (400MHz, DMSO-d ₆ ): δ (ppm) 12.34 (d, J = 8.3Hz, 1H), 10.20 (s, 1H), 8.71-8.25 (m, 1H), 8.17 (d, J = 2.1 Hz,1H),8.00(d,J=1.7Hz,1H),7.74(d,J=7.8Hz,1H),7.48(d,J=7.8Hz,1H),7.28(dd,J=27.2,19.1 Hz, 1H), 6.48(dd, J=16.9, 10.2Hz, 1H), 6.27(dd, J=17.0, 1.7Hz, 1H), 5.77(d, J=1.8Hz, 1H), 5.46-5.24(m ,1H),4.22(td,J=13.6,6.8Hz,1H),4.18-4.08(m,1H),1.42-1.12(m,6H).

Example 51N-(3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)acrylamide

N ¹ -methyl-N ¹ -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzene-1,3-diamine (0.32g, 1.34mmol), acrylic acid (1.02g, 14.2 mmol), EDCI (1.2g, 6.28mmol) and HOBT (0.8g, 5.9mmol) were dissolved in dichloromethane (30mL), cooled to 0°C, triethylamine (1.7mL, 12.2mmol) was added dropwise, and returned to React at room temperature for 12 hours, add ethyl acetate (20 mL) to dilute, wash the organic phase with water (15 mL), wash with saturated aqueous sodium chloride (15 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate by column chromatography (eluent: CH ₂ Cl ₂ /MeOH (v/v)=30/1), to obtain 100 mg of light yellow solid, yield: 25%.

MS(ESI,pos.ion)m/z:294.1[M+1] ⁺ ;

¹ HNMR (600MHz, MeOH-d ₄ ): δ (ppm) 8.27 (s, 1H), 7.80-7.68 (m, 2H), 7.49 (t, J = 8.0Hz, 1H), 7.14 (d, J = 6.9 Hz,1H),6.86-6.75(m,1H),6.40(ddd,J=18.8,17.0,5.9Hz,3H),5.79(dd,J=9.9,1.8Hz,2H),4.92(d,J= 3.5Hz,1H),3.61(s,3H).

Through the similar synthetic method of the embodiment of the present invention and the synthetic method described in the present invention, with suitable optional starting materials, the compounds shown in Table 1 were prepared:

Table 1 The name and characterization data of the compound

biological activity

Biological Example 1 JAK1/2/3 in vitro activity test method one

(1) Use CaliperMobilityShiftAssay to detect the inhibitory effect of compounds on JAK1/2/3 enzymes; (2) Prepare 1-fold kinase reaction solution: 50mM HEPES, pH7.5, 0.0015% Brij-35, 10mMMgCl ₂ , 2mMDTT; (3) Terminate the reaction Solution: 100mM HEPES, pH7.5, 0.0015% Brij-35, 0.2% CoatingReagent#3 (Caliper, product number 760050), 50mM EDTA; (4) Enzyme preparation (JAK1/2/3): prepare enzyme solution with reaction system diluent, The final concentration of enzyme preparation is JAK1 (30nM), JAK2 (2nM), JAK3 (4nM); (5) Substrate preparation: use the reaction system diluent to prepare substrate solution, and the final concentration of substrate preparation is shown in Table 2.

Table 2 Substrate preparation final concentration

According to the optimization results of the experimental method, the experiment was performed on a 384-well plate (Corning, Cat.No.3573, Lot.No.12608008), and the JAK1/2/3 enzyme concentration was prepared as JAK1 (75nM), JAK2 (5nM), JAK3 (10nM), the final concentration is JAK1 (30nM), JAK2 (2nM), JAK3 (4nM); the concentration of the substrate PeptideFAM-P22 is prepared as 7.5μM, and the final concentration of the reaction is 3μM; the concentration of ATP preparation is JAK1 (225μM), JAK2 ( 50 μM), JAK3 (15.5 μM), the final concentration is JAK1 (90 μM), JAK2 (20 μM), JAK3 (6.2 μM); 3μM; Enzymes and substrates were prepared using 1X kinase reaction solution. The reaction system is shown in Table 3.

Table 3 IC ₅₀ detection system of compounds on JAK1/2/3 enzymes

A 384-well plate was used for detection, and the experiment set up test sample wells, positive control wells, and negative control wells. Each sample was tested for the inhibitory effect of the compound on the JAK1/2/3 enzyme concentration at 8 concentrations in duplicate wells. and substrate reaction wells were used as positive controls, and no enzyme wells (kinase reaction solution) were used as negative controls. After adding the corresponding samples, buffers and enzymes to each well in the order shown in Table 3, incubate in an incubator at 25°C (RT) for 10 minutes, then add the prepared Peptidesolution to each well, and incubate at a constant temperature of 28°C for 60 minutes, add the reaction stop solution, CaliperEZReader was used to detect at FP485nm excitation/525nm emission wavelength, and the read data was the conversion rate. GraphPadPrism5 software was used to plot the inhibitory effects of the compounds on JAK1/2/3 enzymes at different concentrations, and calculate the IC ₅₀ . The experimental results are shown in Table 4.

Enzyme (JAK1/2/3) inhibition data of the compound of table 4

The data in Table 4 shows that the compounds of the present invention have strong inhibitory effects on JAK1, JAK2 or JAK3, or have strong inhibitory effects on JAK1, JAK2 and JAK3 at the same time. The examples in Table 4 are typical representatives of the compounds of the present invention, which makes it possible to infer the activity of other structurally similar compounds therefrom.

Biological Example 2 JAK1/2/3 in vitro activity test method two

(1) Use LanceAssay to detect the inhibitory effect of compounds on JAK1/2/3 enzymes; (2) Prepare kinase buffer: 50mM HEPES pH7.5, 1mMEGTA, 10mMMgCl ₂ , 2mMDTT and 0.01% Tween-20; (3) Prepare reaction termination solution: Dissolve 40mM EDTA in 1×DetectionBuffer; (4) Prepare detection mixture: Dilute Eu-anti-phosphotyrosine antibody (PT66) with 1×LANCEDetectionBuffer to 8nM; (5) Use white 384-well plate for detection, the reaction system is as follows:

Table 5 IC ₅₀ detection system of compounds on JAK1/2/3 enzymes

The experiment set up test sample wells, positive control wells, and negative control wells. For each sample, the inhibitory effect of the compound on the JAK1/2/3 enzyme concentration at 8 concentrations was detected using double wells, and the JAK enzyme and substrate-free reaction wells were used. As a positive control, wells without enzyme (kinase reaction solution) as a negative control. After adding the corresponding samples, buffers and enzymes to each well in the order shown in Table 5, incubate in an incubator at 25°C (RT) for 5 minutes, then add the prepared Eu-anti-phospho–tyrosine Antibody (PT66) to each well, and keep the temperature at 25°C Incubate for 60min, using MultilabelReader detects and reads data at FP320nm excitation/665nm emission wavelength.

Determination result is expressed as (test compound activity/contrast compound activity) * 100 with the percentage of test compound and contrast compound assay activity, and obtains the percentage that is 100-(test compound activity/contrast) to be tested compound and contrast compound inhibitory activity compound activity)*100. The average value of the measurement results was calculated by Hill equation curve fitting, the inhibition/concentration-response curve was drawn, and the _IC50 value, _EC50 value and Hill coefficient (nH ). The Hill equation is:

$\mathrm{<span\; class="notranslate">\; Y</span>}<span\; class="notranslate">\; =</span>\mathrm{<span\; class="notranslate">\; D.</span>}<span\; class="notranslate">\; +</span><span\; class="notranslate">\; \&lsqb;</span>\frac{\mathrm{<span\; class="notranslate">\; A</span>}<span\; class="notranslate">\; -</span>\mathrm{<span\; class="notranslate">\; D.</span>}}{\mathrm{<span\; class="notranslate">\; 1</span>}<span\; class="notranslate">\; +</span><span\; class="notranslate">\; (</span>\mathrm{<span\; class="notranslate">\; C</span>}<span\; class="notranslate">\; /</span>{\mathrm{<span\; class="notranslate">\; C</span>}}_{\mathrm{<span\; class="notranslate">\; 50</span>}}<span\; class="notranslate">\; )</span>\mathrm{<span\; class="notranslate">\; no</span>}\mathrm{<span\; class="notranslate">\; h</span>}}<span\; class="notranslate">\; \&rsqb;</span>$

Where Y = specific activity, A = left asymptotic line of the curve, D = right asymptotic line of the curve, C = compound concentration, C ₅₀ = IC ₅₀ or EC ₅₀ , nH = slope factor. The result analysis adopts Hill software, and is applied to business software The data generated by 4.0 are compared for verification, and the experimental results are shown in Table 6.

Enzyme (JAK1/2/3) inhibition data of the compound of table 6

The data in Table 6 shows that the compounds of the present invention have strong inhibitory effects on JAK1, JAK2 or JAK3, or have strong inhibitory effects on JAK1, JAK2 and JAK3 at the same time. The examples in Table 6 are typical representatives of the compounds of the present invention, which makes it possible to infer the activity of other structurally similar compounds therefrom.

Claims (10)

1. A compound, which is a stereoisomer, geometric isomer, tautomer, racemate, nitrogen oxide, hydration of the compound shown in the formula (I) or the compound shown in the formula (I) Compounds, solvates, metabolites and pharmaceutically acceptable salts or prodrugs: in: R is the following substructural formula: Wherein, each of R ^1a , R ^1b , R ^1c and R ^1d is independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, C _1-6 alkyl, C _1-6 alkyl substituted by hydroxyl, C _2-6 Alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkylamino C _1-6 alkyl, C _1-6 alkane Sulfuryl, C _1-6 alkylsulfonyl, C _6-10 aryl C _1-6 alkyl or C _1-9 heteroaryl C _1-6 alkyl; each of R and ^R is independently ^hydrogen , deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, carboxyl, or nitro; Each R ^a and R ^b are independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino or C _1-6 alkyl; or R ^a and R ^b on the same carbon atom together Formation of oxo (=O); m is 0, 1, 2, 3, 4, 5 or 6; Each R ⁴ and R ⁵ is independently hydrogen, deuterium, C _1-6 alkyl, C _1-6 alkyl substituted by cyano, C _1-6 alkyl-C(=O)-, C cyano substituted _1-6 alkyl-C(=O)-, C _1-3 alkyl-OC(=O)-, C _5-6 alkyl-OC(=O)-, cyano-substituted C _1-6 alkane -OC(=O)-, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, C _1-6 alkylamino substituted C _3-8 cycloalkenyl, C _1-6 alkyl-NH- C(=O)- or cyano-substituted C _1-6 alkyl-NH-C(=O)-; or R ⁴ , R ⁵ , and the N atoms connected to them together form 3-12 atoms ring, with the proviso that said ring of 3-12 atoms is not pyrazole optionally substituted with methyl or triazole optionally substituted with methyl; Each R ⁶ and R ⁷ are independently hydrogen, deuterium, C _1-8 alkyl, C _1-6 alkyl substituted by cyano, C _3-8 cycloalkyl, C _2-10 heterocyclyl, C _{6- 10} aryl, C _1-9 heteroaryl, C _3-8 cycloalkyl C _1-6 alkyl, C _2-10 heterocyclyl C _1-6 alkyl, C _2-10 heterocyclyl-C( =O)-C _1-6 alkyl-, C _6-10 aryl C _1-6 alkyl or C _1-9 heteroaryl C _1-6 alkyl; or R ⁶ , R ⁷ , and are connected to them The N atoms together form a ring composed of 3-12 atoms; Each R ⁸ is independently hydrogen, C _1-6 alkyl, C _1-6 alkyl substituted by cyano, halogenated C _1-6 alkyl, C _3-8 cycloalkyl or C _2-10 heterocyclyl ; Each of R ⁹ , R ¹⁰ and R ¹¹ is independently hydrogen, deuterium, C _1-6 alkyl or C _1-6 alkyl substituted by cyano; n is 1, 2, 3, 4, 5 or 6; R ¹² is hydrogen, deuterium, C _1-6 alkyl, C _1-6 alkyl substituted by cyano, C _3-8 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, C _{1 -9} heteroaryl, C _3-8 cycloalkyl C _1-6 alkyl, C _2-10 heterocyclyl C _1-6 alkyl, C _6-10 aryl C _1-6 alkyl or C _{1- 9} heteroaryl C _1-6 alkyl; each X is independently _-CH2- , -NH-, -O-, -S-, -S(=O)- or -S(=O) _2- ; each Y is independently -CH ₂ -, -NH- or -N(CH ₃ )-; each r, s or u is independently 0, 1, 2 or 3; each t, p, q or w is independently 1, 2 or 3; Each R ¹³ is independently hydrogen, deuterium, C _1-6 alkyl substituted by cyano, or C _1-6 alkyl substituted by cyano-C(=O)-; Each substructural formula (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix), (x), (xi), (xii) , (xiii), (xiv) and (xv) are independently optionally substituted by one or more R ¹⁴ ; Each R ¹⁴ is independently hydrogen, deuterium, oxo (=O), cyano, C _1-6 alkyl substituted by cyano, R ¹⁵ -C(=O)-, R ¹⁶ -S(=O) ₂ -, C _1-6 alkylamino, C _1-6 alkylamino substituted by cyano, C _2-6 alkenyl, C _2-6 alkynyl, R ¹⁸ -C(=O)-N(R ¹⁷ )-C _1-6 alkyl-, R ¹⁸ -C(=O)-N(R ¹⁷ )-C _1-8 alkyl-C(=O)-, R ¹⁸ -S(=O) ₂ -N(R ¹⁷ )-C _1-6 alkyl-, R ¹⁸ -S(=O) ₂ -N(R ¹⁷ )-C _1-8 alkyl-C(=O)-, R ²⁰ R ¹⁹ NC(=O)- C _1-6 alkyl-, R ²⁰ R ¹⁹ NS(=O) ₂ -C _1-6 alkyl-, R ²⁰ R ¹⁹ NS(=O) ₂ -C _1-8 alkyl-C(=O) -, C _6-10 aryl C _1-6 alkyl, C _2-10 heterocyclyl C _1-6 alkyl, C _6-10 aryl-C(=O)-C _1-6 alkyl-, C _6-10 aryl-S(=O) ₂ -C _1-6 alkyl-, C _1-9 heteroaryl-C(=O)-C _1-6 alkyl-, C _1-9 heteroaryl -S(=O) ₂ -C _1-6 alkyl-, C _2-10 heterocyclyl-C(=O)-C _1-6 alkyl- or C _2-10 heterocyclyl-S(= O) ₂ -C _1-6 alkyl-; Each of R ¹⁵ , R ¹⁶ and R ¹⁸ is independently C _1-8 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-8 alkyl substituted by cyano, halogenated C _1-6 Alkyl, C _1-6 alkyl substituted by hydroxy, C _1-6 alkyl amino, C _1-8 alkoxy, C _1-6 alkoxy substituted by cyano, C _6-10 aryl, C _{6 -10} aryl C _1-6 alkyl, C _1-9 heteroaryl, C _1-9 heteroaryl C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl C _{1 -6} alkyl, C _2-10 heterocyclyl or C _2-10 heterocyclyl C _1-6 alkyl; Each of R ¹⁷ , R ¹⁹ and R ²⁰ is independently hydrogen, deuterium, C _1-6 alkyl, C _1-6 alkyl substituted by cyano, halogenated C _1-6 alkyl, C _3-8 cycloalkyl , C _2-10 heterocyclyl, C _6-10 aryl, C _1-9 heteroaryl, C _3-8 cycloalkyl C _1-6 alkyl, C _2-10 heterocyclyl C _1-6 alkane group, C _6-10 aryl C _1-6 alkyl or C _1-9 heteroaryl C _1-6 alkyl; or R ¹⁹ , R ²⁰ , together with the N atoms connected to them simultaneously form 3-12 A ring of atoms; The rings each of which are composed of 3-12 atoms are independently the following substructural formulas: each v, y, f and g is independently 0, 1, 2 or 3; each K is independently -NH-, -O-, -S-, -S(=O)- or -S(=O) ₂ -; L is -CH ₂ -, -NH-, -N(CH ₃ )- or -N(CH ₂ CH ₃ )-; each J is independently _-CH2- , -NH-, -O-, -S-, -S(=O)-, or -S(=O) _2- ; and Wherein each hydroxyl, carboxyl, C _1-6 alkyl, C _1-8 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-8 alkoxy C _1-6 alkylamino, C _1-6 alkylthio, C _1-6 alkylsulfonyl, C _1-6 alkyl substituted by hydroxy, C _1-6 alkyl substituted by cyano, cyano substituted C _1-8 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, amino C _1-6 alkyl, C _1-6 alkylamino C _1-6 alkane C _1-6 alkoxy group substituted by cyano, C _1-6 alkylamino substituted by cyano, C _1-6 alkyl-C(=O)-, C _1-6 alkyl substituted by cyano- C(=O)-, C _1-3 alkyl-OC(=O)-, C _5-6 alkyl-OC(=O)-, cyano-substituted C _1-6 alkyl-OC(=O )-, C _1-6 alkyl-NH-C(=O)-, C _1-6 alkyl-NH-C(=O)-substituted by cyano, a ring consisting of 3-12 atoms, C _{3 -8} cycloalkyl, C _3-8 cycloalkenyl, C _1-6 alkylamino substituted C _3-8 cycloalkenyl, C _2-10 heterocyclyl, C _6-10 aryl, C _1-9 hetero Aryl, C _3-8 cycloalkyl C _1-6 alkyl, C _2-10 heterocyclyl C _1-6 alkyl, C _2-10 heterocyclyl-C(=O)-C _1-6 alkane radical-, C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl, R ¹⁵ -C(=O)-, R ¹⁶ -S(=O) ₂ - , R ¹⁸ -C(=O)-N(R ¹⁷ )-C _1-6 alkyl-, R ¹⁸ -C(=O)-N(R ¹⁷ )-C _1-8 alkyl-C(=O )-, R ¹⁸ -S(=O) ₂ -N(R ¹⁷ )-C _1-6 alkyl-, R ¹⁸ -S(=O) ₂ -N(R ¹⁷ )-C _1-8 alkyl- C(=O)-, R ²⁰ R ¹⁹ NC(=O)-C _1-6 alkyl-, R ²⁰ R ¹⁹ NS(=O) ₂ -C _1-6 alkyl-, R ²⁰ R ¹⁹ NS( =O) ₂ -C _1-8 alkyl-C(=O)-, C _6-10 aryl-C(=O)-C _1-6 alkyl-, C _6-10 aryl-S(= O) ₂ -C _1-6 alkyl-, C _1-9 heteroaryl-C(=O)-C _1-6 alkyl-, C _1-9 heteroaryl-S(=O) ₂ -C _1-6 Alkyl-, C _2-10 Heterocyclyl-C(=O)-C _1-6 Alkyl- and C _2-10 Heterocyclyl-S(=O) ₂ -C _1-6 Alkyl - independently optionally replaced by one or more selected from deuterium, fluorine, chlorine, bromine, iodine, cyano, amino, nitro, carboxyl, oxo (=O), C _1-6 alkyl, halogenated C _{1 -6} alkyl, amino C _1-6 alkyl, cyano substituted C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkylamino substituted by cyano, C _1-6 alkoxy, C _1-6 alkoxy substituted by cyano, NH ₂ -S(=O) ₂ - or NH ₂ -C(=O)-substituent. 2. The compound according to claim 1, wherein R is the following substructural formula: 3. The compound according to claim 1, which is a stereoisomer, a geometric isomer, a compound shown in formula (Ia), formula (Ib) or formula (Ia), formula (Ib), Tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceutically acceptable salts or prodrugs: 4. The compound according to claim 1 or 3, wherein R ^1a is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, C _1-3 alkyl, C _1-3 alkyl substituted by hydroxyl, C _2-4 Alkenyl, C _2-4 alkynyl, C _1-3 alkoxy, C _1-3 alkoxy C _1-3 alkyl, C _1-3 alkylamino C _1-3 alkyl, C _1-3 alkane Sulfuryl or C _1-3 alkylsulfonyl; R ^1b is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, C _1-3 alkyl, C _1-3 alkyl substituted by hydroxy, C _2-4 alkenyl, C _2-4 alkynyl, C _1-3 Alkoxy, C _1-3 alkoxy C _1-4 alkyl, C _1-3 alkylamino C _1-3 alkyl, C _1-3 alkylthio, C _1-3 alkylsulfonyl, C _{6 -10} aryl C _1-3 alkyl or C _1-5 heteroaryl C _1-3 alkyl; each of R and ^R is independently ^hydrogen , deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, carboxyl, or nitro; Each R ^a and R ^b are independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino or C _1-3 alkyl; or R ^a and R ^b on the same carbon atom together Formation of oxo (=O); m is 0, 1, 2, 3, 4, 5 or 6; Each R ⁴ and R ⁵ is independently hydrogen, deuterium, C _1-3 alkyl, C _1-3 alkyl substituted by cyano, C _1-3 alkyl-C(=O)-, C cyano substituted _1-3 alkyl-C(=O)-, C _1-3 alkyl-OC(=O)-, cyano-substituted C _1-3 alkyl-OC(=O)-, C _3-6 ring Alkyl, C _3-6 cycloalkenyl, C _1-3 alkylamino substituted C _3-6 cycloalkenyl, C _1-3 alkyl-NH-C(=O)- or cyano substituted C _{1- 3} alkyl-NH-C(=O)-; or R ⁴ , R ⁵ , together with the N atom connected to them, form the following substructural formula: Each R ⁶ and R ⁷ are independently hydrogen, deuterium, C _1-6 alkyl, C _1-4 alkyl substituted by cyano, C _3-6 cycloalkyl, C _2-6 heterocyclyl, C _{6- 10} aryl, C _1-5 heteroaryl, C _3-6 cycloalkyl C _1-3 alkyl, C _2-6 heterocyclyl C _1-3 alkyl, C _2-6 heterocyclyl-C( =O)-C _1-4 alkyl-, C _6-10 aryl C _1-3 alkyl or C _1-5 heteroaryl C _1-3 alkyl; or R ⁶ , R ⁷ , and are connected to them The N atoms together form the following substructure: Each of the C _1-3 alkyl, C _1-3 alkyl substituted by hydroxy, C _2-4 alkenyl, C _2-4 alkynyl, C _1-3 alkoxy, C _1-3 alkoxy C _1-4 alkyl, C _1-3 alkylamino C _1-3 alkyl, C _1-3 alkylthio, C _1-3 alkylsulfonyl, C _6-10 aryl C _1-3 alkyl , C _1-5 heteroaryl C _1-3 alkyl, C _1-6 alkyl, C _1-4 alkyl substituted by cyano, C _3-6 cycloalkyl, C _2-6 heterocyclyl, C _6-10 aryl, C _1-5 heteroaryl, C _3-6 cycloalkyl C _1-3 alkyl, C _2-6 heterocyclyl C _1-3 alkyl and C _2-6 heterocyclyl- C(=O)-C _1-4 alkyl-independently optionally replaced by one or more selected from deuterium, fluorine, chlorine, bromine, iodine, cyano, amino, nitro, carboxyl, oxo (=O) , C _1-3 alkyl, halogenated C _1-3 alkyl, amino C _1-3 alkyl, cyano substituted C _1-3 alkyl, C _1-3 alkylamino, cyano substituted C _1- Substituents of ₃ alkylamino, C _1-3 alkoxy, C _1-3 alkoxy substituted by cyano, NH ₂ -S(=O) ₂ - or NH ₂ -C(=O)-; and Each substructural formula formed by R ⁶ , R ⁷ , and the N atoms connected to them is independently and optionally selected from deuterium, fluorine, chlorine, bromine, iodine, cyano, amino, nitro, carboxyl , oxo (=O), C _1-3 alkyl, halogenated C _1-3 alkyl, amino C _1-3 alkyl, cyano substituted C _1-3 alkyl, C _1-3 alkylamino, C _1-3 alkylamino substituted by cyano, C _1-3 alkoxy, C _1-3 alkoxy substituted by cyano, NH ₂ -S(=O) ₂ - or NH ₂ -C(=O) -Substituted by substituents. 5. compound according to claim 1, it is the stereoisomer of the compound shown in formula (Id) or formula (Id), geometric isomer, tautomer, racemate, Nitrogen oxides, hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs: 6. The compound according to claim 1 or 5, wherein each p or q is independently 1, 2 or 3; R ¹⁴ is hydrogen, deuterium, C _1-3 alkyl substituted by cyano, R ¹⁵ -C(=O)-, R ¹⁶ -S(=O) ₂ -, C _2-4 alkenyl, C _2-4 Alkynyl, R ¹⁸ -C(=O)-N(R ¹⁷ )-C _1-6 alkyl-, R ¹⁸ -C(=O)-N(R ¹⁷ )-C _1-6 alkyl-C( =O)-, R ¹⁸ -S(=O) ₂ -N(R ¹⁷ )-C _1-3 alkyl-, R ¹⁸ -S(=O) ₂ -N(R ¹⁷ )-C _1-6 alkane -C(=O)-, R ²⁰ R ¹⁹ NC(=O)-C _1-4 alkyl-, R ²⁰ R ¹⁹ NS(=O) ₂ -C _1-3 alkyl-, R ²⁰ R ¹⁹ NS(=O) ₂ -C _1-6 alkyl-C(=O)-, C _6-10 aryl C _1-3 alkyl, C _2-6 heterocyclyl C _1-3 alkyl, C _{6 -10} aryl-C(=O)-C _1-3 alkyl-, C _6-10 aryl-S(=O) ₂ -C _1-3 alkyl-, C _1-5 heteroaryl-C (=O)-C _1-3 alkyl-, C _1-5 heteroaryl-S(=O) ₂ -C _1-3 alkyl-, C _2-6 heterocyclyl-C(=O)- C _1-3 alkyl- or C _2-6 heterocyclyl-S(=O) ₂ -C _1-3 alkyl-; Each of R ¹⁵ , R ¹⁶ and R ¹⁸ is independently C _1-6 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-6 alkyl substituted by cyano, halogenated C _1-3 Alkyl, C _1-3 alkyl substituted by hydroxy, C _1-3 alkyl amino, C _1-6 alkoxy, C _1-3 alkoxy substituted by cyano, C _6-10 aryl, C _{6 -10} aryl C _1-3 alkyl, C _1-5 heteroaryl, C _1-5 heteroaryl C _1-3 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl C _{1 -3} alkyl, C _2-6 heterocyclyl or C _2-6 heterocyclyl C _1-3 alkyl; Each of R ¹⁷ , R ¹⁹ and R ²⁰ is independently hydrogen, deuterium, C _1-6 alkyl, C _1-3 alkyl substituted by cyano, halogenated C _1-3 alkyl, C _3-6 cycloalkyl , C _2-6 heterocyclyl, C _6-10 aryl, C _1-5 heteroaryl, C _3-6 cycloalkyl C _1-3 alkyl, C _2-6 heterocyclyl C _1-3 alkane group, C _6-10 aryl C _1-3 alkyl or C _1-5 heteroaryl C _1-3 alkyl; or R ¹⁹ , R ²⁰ , together with the N atoms connected to them at the same time optionally form the following Substructure: Each of the C _1-6 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-3 alkyl substituted by cyano, C _1-6 alkyl substituted by cyano, halogenated C _1-3 alkyl, hydroxy substituted C _1-3 alkyl, amino C _1-3 alkyl, C _1-6 alkoxy, cyano substituted C _1-3 alkoxy, R ¹⁵ -C( =O)-, R ¹⁶ -S(=O) ₂ -, R ¹⁸ -C(=O)-N(R ¹⁷ )-C _1-6 alkyl-, R ¹⁸ -C(=O)-N( R ¹⁷ )-C _1-6 alkyl-C(=O)-, R ¹⁸ -S(=O) ₂ -N(R ¹⁷ )-C _1-3 alkyl-, R ¹⁸ -S(=O) ₂ -N(R ¹⁷ )-C _1-6 alkyl-C(=O)-, R ²⁰ R ¹⁹ NC(=O)-C _1-4 alkyl-, R ²⁰ R ¹⁹ NS(=O) ₂ -C _1-3 alkyl-, R ²⁰ R ¹⁹ NS(=O) ₂ -C _1-6 alkyl-C(=O)-, C _6-10 aryl, C _6-10 aryl C _{1- 3} alkyl, C _1-5 heteroaryl, C _1-5 heteroaryl C _1-3 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl C _1-3 alkyl, C _{2 -6} heterocyclyl, C _2-6 heterocyclyl C _1-3 alkyl, C _6-10 aryl-C(=O)-C _1-3 alkyl-, C _6-10 aryl-S( =O) ₂ -C _1-3 alkyl-, C _1-5 heteroaryl-C(=O)-C _1-3 alkyl-, C _1-5 heteroaryl-S(=O) ₂ - C _1-3 alkyl-, C _2-6 heterocyclyl-C(=O)-C _1-3 alkyl- and C _2-6 heterocyclyl-S(=O) ₂ -C _1-3 alkane Group-independently optionally replaced by one or more selected from deuterium, fluorine, chlorine, bromine, iodine, cyano, amino, nitro, carboxyl, oxo (=O), C _1-3 alkyl, halogenated C _1-3 alkyl, amino C _1-3 alkyl, cyano substituted C _1-3 alkyl, C _1-3 alkylamino, cyano substituted C _1-3 alkylamino, C _1-3 alkoxy , cyano-substituted C _1-3 alkoxy, NH ₂ -S(=O) ₂ - or NH ₂ -C(=O)-; and Each substructural formula formed by R ¹⁹ , R ²⁰ , and the N atoms connected to them at the same time is independently optionally selected from one or more of deuterium, fluorine, chlorine, bromine, iodine, cyano, amino, nitro, Carboxyl, oxo (=O), C _1-3 alkyl, halogenated C _1-3 alkyl, amino C _1-3 alkyl, cyano substituted C _1-3 alkyl, C _1-3 alkylamino , C _1-3 alkylamino substituted by cyano, C _1-3 alkoxy, C _1-3 alkoxy substituted by cyano, NH ₂ -S(=O) ₂ - or NH ₂ -C(=O )-substituted by substituents. 7. A compound, which is a compound with one of the following structures or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite of a compound with one of the following structures Products, pharmaceutically acceptable salts or prodrugs: 8. A pharmaceutical composition comprising the compound of any one of claims 1-7, said pharmaceutical composition further comprising a pharmaceutically acceptable carrier, excipient, diluent, adjuvant and vehicle at least one of; or/and The pharmaceutical composition further comprises an additional therapeutic agent selected from chemotherapeutic agents or antiproliferative agents, anti-inflammatory drugs, immunomodulators or immunosuppressants, neurotrophic factors, and Active agents, active agents for treating diabetes and active agents for treating autoimmune diseases. 9. Use the compound according to any one of claims 1-7 or the pharmaceutical composition according to claim 8 to prepare medicines for preventing, treating, treating or alleviating autoimmune diseases or proliferative diseases in patients , wherein the autoimmune disease is lupus, multiple sclerosis, amyotrophic lateral sclerosis, rheumatoid arthritis, psoriasis, type I diabetes, complications due to organ transplantation, foreign body transplantation, diabetes, cancer, Asthma, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia, or lymphoma; the proliferative disease is metastatic cancer, colon cancer, gastric adenocarcinoma, bladder cancer Cancer, breast cancer, kidney cancer, liver cancer, lung cancer, thyroid cancer, head and neck cancer, prostate cancer, pancreatic cancer, CNS (central nervous system) cancer, malignant glioma, myeloproliferative disease, atherosclerosis or pulmonary fibrosis . 10. A use of the compound according to any one of claims 1-7 or the pharmaceutical composition according to claim 8 to prepare a medicine for inhibiting or regulating protein kinase activity in a biological specimen, said use comprising The compound according to any one of claims 1-7 or the pharmaceutical composition according to claim 8 is used to contact the biological specimen, and the protein kinase is JAK1, JAK2, JAK3, BTK, EGFR or EGFRT790M.