CN106336413B - Compounds as JAK inhibitors and their uses - Google Patents

Abstract

The present invention provides compounds that are JAK inhibitors and uses thereof; specifically, the invention provides a compound (shown as a formula (I)) with JAK inhibitory activity or a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, and a pharmaceutical composition containing the compound. The invention also discloses the use of the compounds of the invention or pharmaceutical compositions thereof in the manufacture of a medicament for the treatment of autoimmune or proliferative diseases.

Description

Compounds as JAK inhibitors and their uses

Field of Invention

The present invention belongs to the technical field of medicine, and specifically relates to a class of compounds with JAK inhibitory activity, a pharmaceutical composition comprising the compound of the present invention, and the application of the compound of the present invention or the pharmaceutical composition pharmaceutically comprising the compound 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. Downstream substrates of JAK family kinases include transcriptional signal sensing and activation (STAT) proteins. JAK/STAT signaling has been implicated in the mediation of many abnormal immune responses, such as allergy, asthma, autoimmune diseases such as transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, and Solid and hematological malignancies such as leukemia and lymphoma. JAK1, JAK2 and TYK2 can inhibit the expression of various genes, whereas JAK3 only functions in granulocytes. Cytokine receptors typically function as heterodimers and are therefore not usually a JAK kinase interacting with cytokine receptors.

Genetic biology studies have shown that JAK1 acts by interacting with cytokine receptors such as IFNalpha, IFNgamma, IL-2, and IL-6, and JAK1 knockout mice die due to the lack 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.

JAK2 has also been implicated in myeloproliferative disorders, including polycythemia vera, idiopathic thrombocythemia, chronic idiopathic myelofibrosis, myeloid tissue deformity with myelofibrosis, chronic myeloid leukemia, chronic myelogenous monocytogenes Nucleocytic leukocytes, chronic eosinophilic leukemia, hypereosinophilic syndrome, and systemic mastocytosis.

JAK3 specifically acts on the γ-cytokine receptor chain, which exists in cytokine receptors such as IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. JAK3 plays an important role in the growth, proliferation and mutation of lymphocytes, and its abnormality can lead to severe immune deficiency. JAK3 has been implicated in the mediation of many abnormal immune responses, such as allergy, asthma, autoimmune diseases such as suppression of transplant rejection, rheumatoid arthritis, musculoskeletal lateral sclerosis and multiple sclerosis, as well as solid and hematological malignancies such as Leukemia, lymphoma. JAK3 inhibitors are useful therapeutics as immunosuppressants for organ transplantation, xenotransplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I 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).

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

Bruton's tyrosine kinase (BTK), a member of the Tec family of non-receptor tyrosine kinases, is critical for expression in all hematopoietic cell types except T lymphocytes and natural killer cells signaling enzymes. The effects of BTK on allergic disorders and/or autoimmune and/or inflammatory diseases have been demonstrated in BTK-null mouse models. For example, in a standard murine preclinical model of systemic lupus erythematosus (SLE), BTK deletion has been shown to significantly alter disease progression.

Epidermal growth factor receptor (EGFR) is a receptor-type tyrosine kinase, a multifunctional glycoprotein widely distributed on the cell membrane of various tissues of the human body. , v-erb-b) oncogene homologues. EGFR and other tumors are overexpressed in epithelial-derived tumors, such as head and neck squamous cell carcinoma, breast cancer, rectal cancer, ovarian cancer, prostate cancer, non-small cell lung cancer and other tumors. related to transfer.

T790M mutation is a point mutation in EGFR20 exon factor, which is one of the more recognized drug resistance mechanisms. T790M is located at the entrance of the EGFR and ATP binding pockets, and the size of its side chain directly affects the binding capacity of EGFR and ATP. The T790M mutation sterically hinders the action of EGFR inhibitors with the ATP binding site, increasing the affinity of EGFR for ATP, thereby making cells resistant to EGFR inhibitors. Initially, T790M was only found in specimens from patients with NSCLC who failed treatment, but was subsequently found in specimens without any treatment, so it is currently believed that this mutation is also present in TKI-untreated tumor tissues, but only in A small number of clones were selected after treatment due to their resistance to TKIs.

Accordingly, there exists a need to provide compounds that inhibit protein kinases for the treatment of diseases such as autoimmune diseases, inflammatory diseases, and cancer. The compounds of the present invention can effectively inhibit the activity of protein kinases, such as JAK1, JAK2, JAK3, BTK, EGFR or EGFR T790M. Such compounds would have potential roles in the treatment of autoimmune and/or inflammatory diseases and/or cancer.

SUMMARY OF THE INVENTION

The compounds of the present invention have inhibitory effects on protein kinase activity. More satisfyingly, the compounds of the present invention have multiple inhibitory functions, and can inhibit JAK1, JAK2, JAK3, BTK, EGFR or EGFR T790M. In particular, the compounds and pharmaceutically acceptable pharmaceutical compositions of the present invention can effectively act as JAK1, JAK2, JAK3, BTK, EGFR or EGFR T790M 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 of the compound represented by formula (I), Nitrogen oxides, hydrates, solvates, metabolites and pharmaceutically acceptable salts or prodrugs:

wherein the A ring is further independently optionally substituted with 1, 2, 3 or 4 R ¹ ;

Ring A, ring E, each of R ¹ , R ² , R ³ , R ⁵ and m have the meanings as described in the present invention.

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

wherein the A ring is further independently optionally substituted with 1, 2, 3 or 4 R ¹ ;

Ring A, ring E, each of R ¹ , R ² , R ³ , each of R ⁴ , R ⁵ and m have the meanings as described in the present invention.

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

wherein the A ring is further independently optionally substituted with 1, 2, 3 or 4 R ¹ ;

Ring A, R ⁵ and each R ¹ have the meanings as described in the present invention.

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

wherein the A ring is further independently optionally substituted with 1, 2, 3 or 4 R ¹ ;

Ring A, R ⁵ and each R ¹ have the meanings as described in the present invention.

In some embodiments, the present invention relates to a compound, which is a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)) or formula (I) (or formula (Ia) ), stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceuticals of compounds represented by formula (Ib) or formula (Ic)) The above acceptable salts or prodrugs: wherein, ring A is C _3-9 cycloalkyl, C _5-9 cycloalkenyl, C _1-9 heterocyclyl, C _6-10 aryl, C _1-9 heterocyclyl Aryl, C _6-12 fused bicyclic group, C _5-12 fused heterobicyclic group, C _6-12 spirobicyclic group or C _5-12 spiro heterobicyclic group; A ring is further independently optionally separated by 1,2 , 3 or 4 R ¹ substitutions; each R ¹ has the meaning as described in the present invention.

A环进一步独立任选地被1，2，3或4个R¹取代；In some embodiments, the present invention relates to a compound, which is a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)) or formula (I) (or formula (Ia) ), stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceuticals of compounds represented by formula (Ib) or formula (Ic)) An acceptable salt or prodrug of the above: wherein the A ring is

Ring A is further independently optionally substituted with ¹ , 2, 3 or 4 R1;

wherein, X ¹ and X ² are each independently -C(R ¹⁴ R ^14a )-, -N(R ¹⁵ )-, -O-, -S(=O) _p - or -C(=O)-;

X ³ , X ⁴ , X ⁵ and X ⁶ are each independently CR ¹⁴ or N;

each R ¹⁴ and R ^14a is independently hydrogen, deuterium, C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or C _1-4 haloalkyl;

each R ¹⁵ is independently hydrogen, deuterium, C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or C _1-4 haloalkyl;

Each of R ¹ and p has the meaning as described in the present invention.

A环进一步独立任选地被1，2，3或4个R¹取代；In some embodiments, the present invention relates to a compound, which is a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)) or formula (I) (or formula (Ia) ), stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceuticals of compounds represented by formula (Ib) or formula (Ic)) An acceptable salt or prodrug of the above: wherein the A ring is

Ring A is further independently optionally substituted with ¹ , 2, 3 or 4 R1;

Each R ¹ has the meaning as described in the present invention.

In some embodiments, the present invention relates to a compound, which is a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)) or formula (I) (or formula (Ia) ), stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceuticals of compounds represented by formula (Ib) or formula (Ic)) An acceptable salt or prodrug of the above: wherein the A ring is

“*”表示与R⁵相连的一端；其中，当E环为

时，A环为环丙基；In some embodiments, the present invention relates to a compound that is a compound of formula (I) (or formula (Ia)) or a stereoisomer of a compound of formula (I) (or formula (Ia)) , geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs: wherein the E ring is the substructure shown below :

"*" represents the end connected to R ⁵ ; wherein, when the E ring is

When, A ring is cyclopropyl;

Wherein, R ⁵ , each R ⁴ and m have the meanings as described in the present invention.

In some embodiments, the present invention relates to a compound, which is a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)) or formula (I) (or formula (Ia) ), stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceuticals of compounds represented by formula (Ib) or formula (Ic)) Acceptable salts or prodrugs of the above: wherein each R ¹ is independently H, deuterium, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, haloalkyl, R-(CR ⁶ R ⁷ ) _n -O-, R-(CR ⁶ R ⁷ ) _n1 -, R ⁸ O-(CR ⁶ R ⁷ ) _n -, R ⁸ -C(=O)-N(R ⁹ )-, CN-(CR ⁶ R ⁷ ) _n -R ⁰ -(CR ⁶ R ⁷ ) _n -N(R ⁹ )-, R ^9a -N(R ⁹ )-C(=O)-, R or RN(R ⁹ )-;

Here, each R, each R ⁰ , each R ⁶ , each R ⁷ , each R ⁸ , each R ⁹ , each R ^9a , each n and each n1 have the meanings as described in the present invention.

In some embodiments, the present invention relates to a compound, which is a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)) or formula (I) (or formula (Ia) ), stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceuticals of compounds represented by formula (Ib) or formula (Ic)) Acceptable salts or prodrugs of the above: wherein each R1 is independently H, deuterium, ^F , Cl, Br, I, CN, _C1-4 alkyl, _C2-6 alkenyl, _C2-6 alkynyl , C _1-4 haloalkyl, CN-(CR ⁶ R ⁷ ) _n -R ⁰ -(CR ⁶ R ⁷ ) _n -N(R ⁹ )-, R-(CR ⁶ R ⁷ ) _n -O-, R -(CR ⁶ R ⁷ ) _n1 -, R ⁸ O-(CR ⁶ R ⁷ ) _n -, R ⁸ -C(=O)-N(R ⁹ )-, CN-(CR ⁶ R ⁷ ) _n -S (=O) _p -R ⁰ -(CR ⁶ R ⁷ ) _n -N(R ⁹ )-, R ^9a -N(R ⁹ )-C(=O)-, R or RN(R ⁹ )-;

Here, each R, each R ⁰ , each R ⁶ , each R ⁷ , each R ⁸ , each R ⁹ , each R ^9a , each n and each n1 have the meanings as described in the present invention.

In some embodiments, the present invention relates to a compound, which is a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)) or formula (I) (or formula (Ia) ), stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceuticals of compounds represented by formula (Ib) or formula (Ic)) Acceptable salts or prodrugs of the above: wherein each R is independently H, deuterium, ^F , Cl, Br, I, CN, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, CN -(CR ⁶ R ⁷ ) _n -R ⁰ -(CR ⁶ R ⁷ ) _n -N(R ⁹ )-, R-(CR ⁶ R ⁷ ) _n -O-, R-(CR ⁶ R ⁷ ) _n1 - , R ⁸ O-(CR ⁶ R ⁷ ) _n -, R ⁸ -C(=O)-N(R ⁹ )-, CN-(CR ⁶ R ⁷ ) _n -S(=O) _p -R ⁰ - (CR ⁶ R ⁷ ) _n -N(R ⁹ )-, R ^9a -N(R ⁹ )-C(=O)-, R or RN(R ⁹ )-; wherein each R ⁰ , each R, each R ⁶ , each R ⁷ , each R ⁸ , each R ⁹ , each R ^9a , each n and each n1 have the meanings as described in the present invention.

In some embodiments, the present invention relates to a compound, which is a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)) or formula (I) (or formula (Ia) ), stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceuticals of compounds represented by formula (Ib) or formula (Ic)) Acceptable salts or prodrugs of the above ^: wherein each R is independently C _3-9 cycloalkylene, C _5-9 cycloalkenylene, C _1-9 heterocyclylene, C _6-10 arylene , C _1-9 heteroarylene, C _6-12 condensed bicyclic group, C _5-12 condensed heterobicyclic group, C _6-12 spiro bicyclic group or C _5-12 spiro heterobicyclic group; Each R ⁰ is independently optionally substituted with 1, 2, 3 or 4 R ^6a ;

Each R is independently C _3-9 cycloalkyl, C _5-9 cycloalkenyl, C _1-9 heterocyclyl, C _6-10 aryl, C _1-9 heteroaryl, C _6-12 fused Bicyclyl, _C5-12 fused heterobicyclyl, _C6-12 spirobicyclyl or _C5-12 spiroheterobicyclyl; each R is independently optionally substituted with 1, 2, 3 or 4 ^R6a ; wherein , each R ^6a has the meaning as described in the present invention.

各R⁰独立任选地被1，2，3或4个R^6a取代；In some embodiments, the present invention relates to a compound, which is a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)) or formula (I) (or formula (Ia) ), stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceuticals of compounds represented by formula (Ib) or formula (Ic)) An acceptable salt or prodrug of the above ^: wherein each R is independently

Each R ⁰ is independently optionally substituted with 1, 2, 3 or 4 R ^6a ;

各R独立任选地被1，2，3或4个R^6a取代；Each R is independently

Each R is independently optionally substituted with 1, 2, 3 or 4 R ^6a ;

wherein, Y ¹ and Y ² are each independently -C(R ¹⁶ R ^16a )-, -N(R ¹⁷ )-, -O-, -S(=O) _p - or -C(=O)-;

Y ³ , Y ⁴ and Y ⁵ are each independently CR ¹⁶ or N;

Each R ¹⁶ and R ^16a is independently hydrogen, deuterium, C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or C _1-4 haloalkyl;

each R ¹⁷ is independently hydrogen, deuterium, C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or C _1-4 haloalkyl;

Here, each R ^6a has the meaning as described in the present invention.

各R⁰独立任选地被1，2，3或4个R^6a取代；In some embodiments, the present invention relates to a compound, which is a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)) or formula (I) (or formula (Ia) ), stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceuticals of compounds represented by formula (Ib) or formula (Ic)) An acceptable salt or prodrug of the above ^: wherein each R is independently

Each R ⁰ is independently optionally substituted with 1, 2, 3 or 4 R ^6a ;

各R独立任选地被1，2，3或4个R^6a取代；其中，各R^6a具有如本发明所述的含义。Each R is independently

Each R is independently optionally substituted with 1, 2, 3 or 4 R ^6a ; wherein each R ^6a has the meaning as described herein.

In some embodiments, the present invention relates to a compound, which is a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)) or formula (I) (or formula (Ia) ), stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceuticals of compounds represented by formula (Ib) or formula (Ic)) Acceptable salts or prodrugs of the above: wherein each R is independently hydrogen, ^deuterium , C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, F, Cl, Br, I, CN , R ^6b -(CR ⁶ R ⁷ ) _n -S(=O) _p -, hydroxyl, nitro, amino, carboxyl or C _1-4 alkoxy;

Wherein, each R ⁶ , each R ⁷ , R ^6b , n and p has the meaning as described in the present invention.

In some embodiments, the present invention relates to a compound, which is a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)) or formula (I) (or formula (Ia) ), stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceuticals of compounds represented by formula (Ib) or formula (Ic)) Acceptable salts or prodrugs of the above: wherein each R is independently hydrogen, ^deuterium , C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, F, Cl, Br, I, CN , hydroxy, nitro, C _1-4 haloalkyl, amino, carboxyl or C _1-4 alkoxy.

In some embodiments, the present invention relates to a compound, which is a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)) or formula (I) (or formula (Ia) ), stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceuticals of compounds represented by formula (Ib) or formula (Ic)) Acceptable salts or prodrugs of the above: wherein each R is independently hydrogen, deuterium, C _1-4 alkyl, C ^2-6 alkenyl, C _{2-6 alkynyl} , F, Cl, Br, I, CN , hydroxy, nitro, C _1-4 haloalkyl, amino, carboxyl or C _1-4 alkoxy.

In some embodiments, the present invention relates to a compound, which is a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)) or formula (I) (or formula (Ia) ), stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceuticals of compounds represented by formula (Ib) or formula (Ic)) Acceptable salts or prodrugs of the above: wherein each R is independently hydrogen, ^deuterium , C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, F, Cl, Br, I, CN , hydroxy, nitro, C _1-4 haloalkyl, amino, carboxyl or C _1-4 alkoxy.

In some embodiments, the present invention relates to a compound, which is a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)) or formula (I) (or formula (Ia) ), stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceuticals of compounds represented by formula (Ib) or formula (Ic)) An acceptable salt or prodrug of the above: wherein each R ⁸ is independently hydrogen, deuterium, C _1-4 alkyl, C _1-4 haloalkyl or HO-(CR ⁶ R ⁷ ) _n -; wherein each R ⁶ , each R ⁷ and each n have the meanings as described in the present invention.

In some embodiments, the present invention relates to a compound, which is a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)) or formula (I) (or formula (Ia) ), stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceuticals of compounds represented by formula (Ib) or formula (Ic)) An acceptable salt or prodrug of the above: wherein each R ⁹ is independently hydrogen, deuterium, C _1-4 alkyl, C _1-4 haloalkyl or HO-(CR ⁶ R ⁷ ) _n -; wherein each R ⁶ , each R ⁷ and each n have the meanings as described in the present invention.

In some embodiments, the present invention relates to a compound, which is a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)) or formula (I) (or formula (Ia) ), stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceuticals of compounds represented by formula (Ib) or formula (Ic)) An acceptable salt or prodrug of the above: wherein each R ^9a is independently hydrogen, deuterium, C _1-4 alkyl, C _1-4 haloalkyl or HO-(CR ⁶ R ⁷ ) _n -; wherein each R ⁶ , each R ⁷ and each n have the meanings as described in the present invention.

In some embodiments, the present invention relates to a compound that is a compound of formula (I) (or formula (Ia)) or a stereoisomer of a compound of formula (I) (or formula (Ia)) , geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs ^: where R is H, deuterium, F, Cl , Br, I, CN, C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, R ⁸ O-(CR ⁶ R ⁷ ) _n -, R ⁸ -C(=O)-N(R ⁹ )-, R ^9a -N(R ⁹ )-C(=O)- or R ^9a -N(R ⁹ )-; wherein each R ⁶ , each R ⁷ , Each R ⁸ , each R ⁹ , each R ^9a and each n has the meaning as described in the present invention.

In some embodiments, the present invention relates to a compound that is a compound of formula (I) (or formula (Ia)) or a stereoisomer of a compound of formula (I) (or formula (Ia)) , geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs: wherein ^R is H, deuterium, F, Cl , Br, I, CN, C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, R ⁸ O-(CR ⁶ R ⁷ ) _n -, R ⁸ -C(=O)-N(R ⁹ )-, R ^9a -N(R ⁹ )-C(=O)- or R ^9a -N(R ⁹ )-; wherein each R ⁶ , each R ⁷ , Each R ⁸ , each R ⁹ , each R ^9a and each n has the meaning as described in the present invention.

In some embodiments, the present invention relates to a compound that is a compound of formula (I) (or formula (Ia)) or a stereoisomer of a compound of formula (I) (or formula (Ia)) , geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs: where R is H, ^deuterium , F, Cl , Br, I, CN, C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, R ⁸ O-(CR ⁶ R ⁷ ) _n -, R ⁸ -C(=O)-N(R ⁹ )-, R ^9a -N(R ⁹ )-C(=O)- or R ^9a -N(R ⁹ )-; wherein each R ⁶ , each R ⁷ , Each R ⁸ , each R ⁹ , each R ^9a and each n has the meaning as described in the present invention.

In some embodiments, the present invention relates to a compound, which is a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)) or formula (I) (or formula (Ia) ), stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceuticals of compounds represented by formula (Ib) or formula (Ic)) The above acceptable salts or prodrugs: wherein R ⁵ is CN-(CR ¹⁰ R ¹¹ ) _n1 -N(R ¹² )-, CN-(CR ¹⁰ R ¹¹ ) _n1 -C(=O)-N(R ¹² )-, CN-(CR ¹⁰ R ¹¹ ) _n -C _3-9 cycloalkyl-N(R ¹² )-, R ¹³ -O-(CR ¹⁰ R ¹¹ ) _n1 -N(R ¹² )-, CN- (CR ¹⁰ R ¹¹ ) _n1 -C _1-9 heterocyclyl-C(=O)-N(R ¹² )-, CN-(CR ¹⁰ R ¹¹ ) _n -C(=O)-C _1-9 heterocycle Cyclic group -(CR ¹⁰ R ¹¹ ) _n -N(R ¹² )-, R ¹³ -(CR ¹⁰ R ¹¹ ) _n1 -S(=O) _p -(CR ¹⁰ R ¹¹ ) _n -N(R ¹² )- , R ¹³ -(CR ¹⁰ R ¹¹ ) _n -S(=O) _p -(R ^12a )NC _3-9 cycloalkyl-N(R ¹² )-, R ¹³ -(CR ¹⁰ R ¹¹ ) _n -N (R ¹² )-C(=O)-(CR ¹⁰ R ¹¹ ) _n -(R ^12a )N-, CN-(CR ¹⁰ R ¹¹ ) _n -N(R ¹² )-C(=O)-(CR ¹⁰ R ¹¹ ) _n -(R ^12a )N-, CN-(CR ¹⁰ R ¹¹ ) _n -C _1-9 heterocyclyl-(CR ¹⁰ R ¹¹ ) _n -N(R ¹² )-, CN-(CR ¹⁰ R ¹¹ ) _n1 -S(=O) _p -(R ^12a )N-, CN-(CR ¹⁰ R ¹¹ ) _n -C(=O)-C _1-9 heterocyclyl-(CR ¹⁰ R ¹¹ ) _n -, CN-(CR ¹⁰ R ¹¹ ) _n -C _3-9 cycloalkyl-(CR ¹⁰ R ¹¹ ) _n1 -, HO-(CR ¹⁰ R ¹¹ ) _n -C _3-9 cycloalkyl-(CR ¹⁰ R ¹¹ ) _n1 -, CN-(CR ¹⁰ R ¹¹ ) _n -C _1-9 heterocyclyl-(CR ¹⁰ R ¹¹ ) _n1 -, CN-(CR ¹⁰ R ¹¹ ) _n1 -N(R ¹² )- C(=O)-, CN-(CR ¹⁰ R ¹¹ ) _n1 -, C _{6-1 0} aryl-(CR ¹⁰ R ¹¹ ) _n1 -, (R ^12a )N(R ¹² )-C(=O)-(CR ¹⁰ R ¹¹ ) _n1 -, CN-(CR ¹⁰ R ¹¹ ) _n -C _{1 -9} heterocyclyl-(CR ¹⁰ R ¹¹ ) _n -N(R ¹² )-S(=O) _p -, CN-(CR ¹⁰ R ¹¹ ) _n -C _1-9 heterocyclyl-(CR ¹⁰ R ¹¹ ) _n -S(=O) _p -, CN-(CR ¹⁰ R ¹¹ ) _n -S(=O) _p -, R ¹³ -(CR ¹⁰ R ¹¹ ) _n -(R ^12a )NS(=O) _p -, R ¹³ -(CR ¹⁰ R ¹¹ ) _n -N(R ¹² )-C(=O)-(CR ¹⁰ R ¹¹ ) _n -(R ^12a )NS(=O) _p - or CN-(CR ¹⁰ R ¹¹ ) _n1 -(R ^12a )NS(=O) _p -; wherein said aryl, heterocyclyl and cycloalkyl are independently optionally substituted with 1, 2, 3 or 4 R ^6c ; wherein , each R ^6c , each R ¹⁰ , each R ¹¹ , each R ¹² , each R ^12a , each R ¹³ , each n, each n1 and each p have the meanings described in the present invention.

In some embodiments, the present invention relates to a compound, which is a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)) or formula (I) (or formula (Ia) ), stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceuticals of compounds represented by formula (Ib) or formula (Ic)) The above acceptable salts or prodrugs: wherein R ⁵ is CN-(CR ¹⁰ R ¹¹ ) _n1 -N(R ¹² )-, CN-(CR ¹⁰ R ¹¹ ) _n1 -C(=O)-N(R ¹² )-, CN-(CR ¹⁰ R ¹¹ ) _n -C _3-6 cycloalkyl-N(R ¹² )-, R ¹³ -O-(CR ¹⁰ R ¹¹ ) _n1 -N(R ¹² )-, CN- (CR ¹⁰ R ¹¹ ) _n1 -C _3-6 heterocyclyl-C(=O)-N(R ¹² )-, CN-(CR ¹⁰ R ¹¹ ) _n -C(=O)-C _3-6 heterocycle Cyclo-(CR ¹⁰ R ¹¹ ) _n -N(R ¹² )-, R ¹³ -(CR ¹⁰ R ¹¹ ) _n -S(=O) _p -(R ^12a )NC _3-6 cycloalkyl-N( R ¹² )-, R ¹³ -(CR ¹⁰ R ¹¹ ) _n -N(R ¹² )-C(=O)-(CR ¹⁰ R ¹¹ ) _n -(R ^12a )N-, CN-(CR ¹⁰ R ¹¹ ) _n -N(R ¹² )-C(=O)-(CR ¹⁰ R ¹¹ ) _n -(R ^12a )N-, R ¹³ -(CR ¹⁰ R ¹¹ ) _n1 -S(=O) _p -(CR ¹⁰ R ¹¹ ) _n -N(R ¹² )-, CN-(CR ¹⁰ R ¹¹ ) _n -C _3-6 heterocyclyl-(CR ¹⁰ R ¹¹ ) _n -N(R ¹² )-, CN-(CR ¹⁰ R ¹¹ ) _n1 -S(=O) _p -(R ^12a )N-, CN-(CR ¹⁰ R ¹¹ ) _n -C(=O)-C _3-6 heterocyclyl-(CR ¹⁰ R ¹¹ ) _n -, CN-(CR ¹⁰ R ¹¹ ) _n -C _3-6 cycloalkyl-(CR ¹⁰ R ¹¹ ) _n1 -, HO-(CR ¹⁰ R ¹¹ ) _n -C _3-6 cycloalkyl-(CR ¹⁰ R ¹¹ ) _n1 -, CN-(CR ¹⁰ R ¹¹ ) _n -C _3-6 heterocyclyl-(CR ¹⁰ R ¹¹ ) _n1 -, CN-(CR ¹⁰ R ¹¹ ) _n1 -, phenyl-(CR ¹⁰ R ¹¹ ) _n1 -, (R ^12a )N(R ¹² )-C(= O)-(CR ¹⁰ R ¹¹ ) _n1 -, CN-(CR ¹⁰ R ¹¹ ) _n1 -N(R ¹² )-C(=O)-, CN-(CR ¹⁰ R ¹¹ ) _n -C _3-6 hetero Cyclyl-(CR ¹⁰ R ¹¹ ) _n -S(=O) _p -, CN-(CR ¹⁰ R ¹¹ ) _n -S(=O) _p -, CN-(CR ¹⁰ R ¹¹ ) _n -C _{3- 6heterocyclyl-} (CR ¹⁰ R ¹¹ ) _n -N(R ¹² )-S(=O) _p -, R ¹³ -(CR ¹⁰ R ¹¹ ) _n -(R ^12a )NS(=O) _p -, R ¹³ -(CR ¹⁰ R ¹¹ ) _n -N(R ¹² )-C(=O)-(CR ¹⁰ R ¹¹ ) _n -(R ^12a )NS(=O) _p - or CN-(CR ¹⁰ R ¹¹ ) _n1 -(R ^12a )NS(=O) _p -; wherein said phenyl, heterocyclyl and cycloalkyl are independently optionally substituted with 1, 2, 3 or 4 R ^6c ; wherein each R ^6c , each R ¹⁰ , each R ¹¹ , each R ¹² , each R ^12a , each R ¹³ , each n, each n1 and each p have the meanings as defined in the present invention.

In some embodiments, the present invention relates to a compound, which is a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)) or formula (I) (or formula (Ia) ), stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceuticals of compounds represented by formula (Ib) or formula (Ic)) An acceptable salt or prodrug of the above: wherein R ⁵ is

In some embodiments, the present invention relates to a compound, which is a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)) or formula (I) (or formula (Ia) ), stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceuticals of compounds represented by formula (Ib) or formula (Ic)) An acceptable salt or prodrug of the above: wherein each R ¹⁰ is independently hydrogen, deuterium, C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or C _1-4 haloalkyl.

In some embodiments, the present invention relates to a compound, which is a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)) or formula (I) (or formula (Ia) ), stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceuticals of compounds represented by formula (Ib) or formula (Ic)) An acceptable salt or prodrug of the above: wherein each R ¹⁰ is independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, 2,2,2-trifluoroethyl or trifluoromethyl.

In some embodiments, the present invention relates to a compound, which is a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)) or formula (I) (or formula (Ia) ), stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceuticals of compounds represented by formula (Ib) or formula (Ic)) An acceptable salt or prodrug of the above: wherein each R ¹¹ is independently hydrogen, deuterium, C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or C _1-4 haloalkyl.

In some embodiments, the present invention relates to a compound, which is a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)) or formula (I) (or formula (Ia) ), stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceuticals of compounds represented by formula (Ib) or formula (Ic)) An acceptable salt or prodrug of the above: wherein each R ¹¹ is independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, 2,2,2-trifluoroethyl or trifluoromethyl.

In some embodiments, the present invention relates to a compound, which is a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)) or formula (I) (or formula (Ia) ), stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceuticals of compounds represented by formula (Ib) or formula (Ic)) An acceptable salt or prodrug of the above: wherein each R ¹³ is independently hydrogen, deuterium, C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or C _1-4 haloalkyl.

In some embodiments, the present invention relates to a compound, which is a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)) or formula (I) (or formula (Ia) ), stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceuticals of compounds represented by formula (Ib) or formula (Ic)) An acceptable salt or prodrug of the above: wherein each R ¹³ is independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, 2,2,2-trifluoroethyl or trifluoromethyl.

In some embodiments, the present invention relates to a compound, which is a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)) or formula (I) (or formula (Ia) ), stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceuticals of compounds represented by formula (Ib) or formula (Ic)) An acceptable salt or prodrug of the above: wherein each R ¹² is independently hydrogen, deuterium, C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or C _1-4 haloalkyl.

In some embodiments, the present invention relates to a compound, which is a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)) or formula (I) (or formula (Ia) ), stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceuticals of compounds represented by formula (Ib) or formula (Ic)) An acceptable salt or prodrug ^of the above: wherein each R is independently hydrogen, deuterium, methyl, n-propyl, ethyl or isopropyl;

In some embodiments, the present invention relates to a compound, which is a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)) or formula (I) (or formula (Ia) ), stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceuticals of compounds represented by formula (Ib) or formula (Ic)) An acceptable salt or prodrug of the above: wherein each R ^12a is independently hydrogen, deuterium, C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or C _1-4 haloalkyl.

In some embodiments, the present invention relates to a compound, which is a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)) or formula (I) (or formula (Ia) ), stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceuticals of compounds represented by formula (Ib) or formula (Ic)) An acceptable salt or prodrug of the above: wherein each R is independently hydrogen, ^deuterium , methyl, n-propyl, ethyl or isopropyl;

In some embodiments, the present invention relates to a compound, which is a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)) or formula (I) (or formula (Ia) ), stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceuticals of compounds represented by formula (Ib) or formula (Ic)) Acceptable salts or prodrugs of the above: wherein each ^R6c is independently hydrogen, deuterium, _C1-4 alkyl, F, Cl, Br, I, CN, hydroxy, nitro, amino, carboxyl or _C1-4 alkoxy.

In some embodiments, the present invention relates to a compound, which is a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)) or formula (I) (or formula (Ia) ), stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceuticals of compounds represented by formula (Ib) or formula (Ic)) Acceptable salts or prodrugs of the above: wherein each R is independently hydrogen, ^deuterium , methoxy, F, Cl, Br, I, CN, hydroxy, nitro, amino, methyl, n-propyl, ethyl or isopropyl.

In some embodiments, the present invention relates to a compound, which is a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)) or formula (I) (or formula (Ia) ), stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceuticals of compounds represented by formula (Ib) or formula (Ic)) An acceptable salt or prodrug of the above: wherein each n is independently 0, 1, 2 or 3.

In some embodiments, the present invention relates to a compound, which is a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)) or formula (I) (or formula (Ia) ), stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceuticals of compounds represented by formula (Ib) or formula (Ic)) An acceptable salt or prodrug of the above: wherein each n1 is independently 1, 2, 3 or 4.

In some embodiments, the present invention relates to a compound that is a compound of formula (I) (or formula (Ia)) or a stereoisomer of a compound of formula (I) (or formula (Ia)) , geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs: where m is 0, 1, 2, 3 or 4.

In some embodiments, the present invention relates to a compound, which is a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)) or formula (I) (or formula (Ia) ), stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceuticals of compounds represented by formula (Ib) or formula (Ic)) An acceptable salt or prodrug of the above: wherein each p is independently 0, 1 or 2

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

wherein the W ring is optionally further selected by 1, 2, 3 or 4 independently selected from fluoro, chloro, bromo, C _1-4 haloalkyl, nitro, cyano, HO-(CR ³ R ⁴ ) _m - , H-(CR ³ R ⁴ ) _m -O-, RN(R ⁵ )-C(=O)-, RC(=O)-N(R ⁵ )-, RN(R ⁵ )-, RC(= O)-, RC(=O)O-, R-OC(=O)-, RS(=O) ₂ -, RS(=O)-, RS-, RN(R ⁵ )-S(=O) _2- , RS(=O) ₂ -N(R ⁵ )-, RN(R ⁵ )-C(=O)-N(R ⁶ )- or R’s substituent;

R, R ³ , R ⁴ , R ⁵ , R ⁶ , m, W ring, R ⁰ , R ⁰⁰ , L, Z ¹ , Z ² and n have the meanings as described in the present invention.

In some embodiments, the present invention relates to a compound, which is a compound represented by formula (IIa) or a stereoisomer, geometric isomer, tautomer, racemic of a compound represented by formula (IIa) Forms, nitrogen oxides, hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs:

任选地进一步被1、2、3或4个独立地选自氟，氯，溴，C_1-4卤代烷基，硝基，氰基，HO-(CR³R⁴)_m-，H-(CR³R⁴)_m-O-，R-N(R⁵)-C(＝O)-，R-C(＝O)-N(R⁵)-，R-N(R⁵)-，R-C(＝O)-，R-C(＝O)O-，R-OC(＝O)-，R-S(＝O)₂-，R-S(＝O)-，R-S-，R-N(R⁵)-S(＝O)₂-，R-S(＝O)₂-N(R⁵)-，R-N(R⁵)-C(＝O)-N(R⁶)-或R的取代基所取代；

表示单键或双键；in,

optionally further selected by 1, 2, 3 or 4 independently selected from fluoro, chloro, bromo, C _1-4 haloalkyl, nitro, cyano, HO-(CR ³ R ⁴ ) _m -, H-( CR ³ R ⁴ ) _m -O-, RN(R ⁵ )-C(=O)-, RC(=O)-N(R ⁵ )-, RN(R ⁵ )-, RC(=O)-, RC(=O)O-, R-OC(=O)-, RS(=O) _2- , RS(=O) ^- , RS-, RN(R5)-S(=O) _2- , RS (=O) ₂ -N(R ⁵ )-, RN(R ⁵ )-C(=O)-N(R ⁶ )- or the substituent of R;

Indicates a single bond or a double bond;

R, R ³ , R ⁴ , R ⁵ , R ⁶ , m, X, Y, R ¹ , R ⁰ , R ⁰⁰ , L, Z ¹ , Z ² and n have the meanings as described in the present invention.

In some embodiments, the present invention relates to a compound that is a compound of formula (II) (or formula (IIa)) or a stereoisomer of a compound of formula (II) (or formula (IIa)) , geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs: wherein Z ¹ and Z ² are each independently N or CH.

W环任选地进一步被1、2、3或4个独立地选自氟，氯，溴，C_1-4卤代烷基，硝基，氰基，HO-(CR³R⁴)_m-，H-(CR³R⁴)_m-O-，R-N(R⁵)-C(＝O)-，R-C(＝O)-N(R⁵)-，R-N(R⁵)-，R-C(＝O)-，R-C(＝O)O-，R-OC(＝O)-，R-S(＝O)₂-，R-S(＝O)-，R-S-，R-N(R⁵)-S(＝O)₂-，R-S(＝O)₂-N(R⁵)-，R-N(R⁵)-C(＝O)-N(R⁶)-或R的取代基所取代；

表示单键或双键；In some embodiments, the present invention relates to a compound, which is a compound represented by formula (II) or a stereoisomer, geometric isomer, tautomer, racemic of a compound represented by formula (II) Forms, nitrogen oxides, hydrates, solvates, metabolites and pharmaceutically acceptable salts or prodrugs: wherein the W ring is a ring as shown below:

The W ring is optionally further 1, 2, 3 or 4 independently selected from fluoro, chloro, bromo, C _1-4 haloalkyl, nitro, cyano, HO-(CR ³ R ⁴ ) _m -, H -(CR ³ R ⁴ ) _m -O-, RN(R ⁵ )-C(=O)-, RC(=O)-N(R ⁵ )-, RN(R ⁵ )-, RC(=O) -, RC(=O)O-, R-OC(=O)-, RS(=O) _2- , RS(=O) ^- , RS-, RN(R5)-S(=O) _2- , RS(=O) ₂ -N(R ⁵ )-, RN(R ⁵ )-C(=O)-N(R ⁶ )- or R's substituent;

Indicates a single bond or a double bond;

wherein R, R ³ , R ⁴ , R ⁵ , R ⁶ , m, X, Y, R ¹ , R ⁰ , R ⁰⁰ , Z ¹ , Z ² and n have the meanings as described in the present invention.

In some embodiments, the present invention relates to a compound that is a compound of formula (II) (or formula (IIa)) or a stereoisomer of a compound of formula (II) (or formula (IIa)) , geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs: where X is N, NR ^a or CR ^b ; Y is CR ^c ;

R ^a , R ^b and R ^c are each independently hydrogen or C _1-4 alkyl; R ^a and R ^c together with the ring atoms to which they are attached form a five- or six-membered heteroaryl group; or R ^b and R ^c together with the ring atoms to which they are attached form a five- or six-membered heteroaryl; the heteroaryls may independently be optionally substituted with R ^;

wherein R ² has the meaning as described in the present invention.

In some embodiments, the present invention relates to a compound, which is a compound represented by formula (II) or a stereoisomer, geometric isomer, tautomer, racemic of a compound represented by formula (II) Forms, nitrogen oxides, hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs: wherein the W ring is the substructure shown below:

The W ring is optionally further 1, 2, 3 or 4 independently selected from fluoro, chloro, bromo, trifluoromethyl, 2,2-difluoroethyl, 3,3,3-trifluoropropyl, Nitro, cyano, HO-(CR ³ R ⁴ ) _m -, H-(CR ³ R ⁴ ) _m -O-, RN(R ⁵ )-C(=O)-, RC(=O)-N (R ⁵ )-, RN(R ⁵ )-, RC(=O)-, RC(=O)O-, R-OC(=O)-, RS(=O) ₂ -, RS(=O) -, RS-, RN(R ⁵ )-S(=O) ₂ -, RS(=O) ₂ -N(R ⁵ )-, RN(R ⁵ )-C(=O)-N(R ⁶ ) - or R substituents;

wherein R, R ³ , R ⁴ , R ⁵ , R ⁶ , m, R ¹ and R ² have the meanings as described in the present invention.

In some embodiments, the present invention relates to a compound that is a compound of formula (II) (or formula (IIa)) or a stereoisomer of a compound of formula (II) (or formula (IIa)) , geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs: wherein R ¹ is H, deuterium, C _{1 -4} alkyl, C _2-6 alkenyl, C _2-6 alkynyl or hydroxy.

In some embodiments, the present invention relates to a compound that is a compound of formula (II) (or formula (IIa)) or a stereoisomer of a compound of formula (II) (or formula (IIa)) , geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs: wherein R ¹ is H, deuterium, methyl , ethyl, isopropyl or n-propyl.

In some embodiments, the present invention relates to a compound that is a compound of formula (II) (or formula (IIa)) or a stereoisomer of a compound of formula (II) (or formula (IIa)) , geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs: wherein R ² is H, deuterium, C _{1 -4} alkyl, C _2-6 alkenyl, C _2-6 alkynyl or hydroxy.

In some embodiments, the present invention relates to a compound that is a compound of formula (II) (or formula (IIa)) or a stereoisomer of a compound of formula (II) (or formula (IIa)) , geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs ^: wherein R is H, deuterium, methyl , ethyl, isopropyl or n-propyl.

In some embodiments, the present invention relates to a compound that is a compound of formula (II) (or formula (IIa)) or a stereoisomer of a compound of formula (II) (or formula (IIa)) , geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceutically acceptable salts or prodrugs: wherein, R ⁰ is fluorine, chlorine, bromine, C _1-4 haloalkyl, nitro, cyano, HO-(CR ³ R ⁴ ) _m -, H-(CR ³ R ⁴ ) _m -O-, RN(R ⁵ )-C(=O)-, RC(=O)-N(R ⁵ )-, RN(R ⁵ )-, RC(=O)-, RC(=O)O-, R-OC(=O)-, RS(=O) ₂ -, RS(=O)-, RS-, RN(R ⁵ )-S(=O) ₂ -, RS(=O) ₂ -N(R ⁵ )-, RN(R ⁵ )-C(=O )-N(R ⁶ )- or R;

wherein R, R ³ , R ⁴ , R ⁵ , R ⁶ and m have the meanings as defined in the present invention.

In some embodiments, the present invention relates to a compound that is a compound of formula (II) (or formula (IIa)) or a stereoisomer of a compound of formula (II) (or formula (IIa)) , geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceutically acceptable salts or prodrugs: wherein, R ⁰ is fluorine, chlorine, bromine, Trifluoromethyl, 2,2-difluoroethyl, 3,3,3-trifluoropropyl, nitro, cyano, HO-(CR ³ R ⁴ ) _m -, H-(CR ³ R ⁴ ) _m -O-, RN(R ⁵ )-C(=O)-, RC(=O)-N(R ⁵ )-, RN(R ⁵ )-, RC(=O)-, RC(=O) O-, R-OC(=O)-, RS(=O) ₂ -, RS(=O)-, RS-, RN(R ⁵ )-S(=O) ₂ -, RS(=O) ₂ -N(R ⁵ )-, RN(R ⁵ )-C(=O)-N(R ⁶ )- or R;

wherein R, R ³ , R ⁴ , R ⁵ , R ⁶ and m have the meanings as defined in the present invention.

In some embodiments, the present invention relates to a compound that is a compound of formula (II) (or formula (IIa)) or a stereoisomer of a compound of formula (II) (or formula (IIa)) , geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceutically acceptable salts or prodrugs: wherein, R ⁰⁰ is fluorine, chlorine, bromine, Nitro, cyano, HO-, HS-, H ₂ NC(=O)-, HC(=O)-NH-, NH ₂ -, HC(=O)-, HC(=O)O-, H -OC(=O)-, HS(=O) ₄ -, HS(=O)-, H ₂ NS(=O) ₂ -, HS(=O) ₂ -NH-, H ₂ NC(=O) -NH-, CH ₃ O-, phenyl, C _1-4 alkyl, C _2-6 alkenyl, C _1-4 haloalkyl or C _2-6 alkynyl.

In some embodiments, the present invention relates to a compound that is a compound of formula (II) (or formula (IIa)) or a stereoisomer of a compound of formula (II) (or formula (IIa)) , geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceutically acceptable salts or prodrugs: wherein L is -NH-S(=O ) ₂ - or -NH-.

In some embodiments, the present invention relates to a compound that is a compound of formula (II) (or formula (IIa)) or a stereoisomer of a compound of formula (II) (or formula (IIa)) , geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs: wherein each R is independently H, deuterium, C _1-4 alkyl, C _2-6 alkenyl, C _1-4 haloalkyl or C _2-6 alkynyl.

In some embodiments, the present invention relates to a compound that is a compound of formula (II) (or formula (IIa)) or a stereoisomer of a compound of formula (II) (or formula (IIa)) , geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs: wherein each R is independently H, deuterium, Trifluoromethyl, 2,2-difluoroethyl, 3,3,3-trifluoropropyl, methyl, ethyl, isopropyl or n-propyl.

In some embodiments, the present invention relates to a compound that is a compound of formula (II) (or formula (IIa)) or a stereoisomer of a compound of formula (II) (or formula (IIa)) , geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs: wherein each ^R is independently H, deuterium , C _1-4 alkyl, C _2-6 alkenyl, C _1-4 haloalkyl or C _2-6 alkynyl.

In some embodiments, the present invention relates to a compound that is a compound of formula (II) (or formula (IIa)) or a stereoisomer of a compound of formula (II) (or formula (IIa)) , geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs: wherein each ^R is independently H, deuterium , trifluoromethyl, 2,2-difluoroethyl, 3,3,3-trifluoropropyl, methyl, ethyl, isopropyl or n-propyl.

In some embodiments, the present invention relates to a compound that is a compound of formula (II) (or formula (IIa)) or a stereoisomer of a compound of formula (II) (or formula (IIa)) , geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs: wherein each R is independently H, ^deuterium , C _1-4 alkyl, C _2-6 alkenyl, C _1-4 haloalkyl or C _2-6 alkynyl.

In some embodiments, the present invention relates to a compound that is a compound of formula (II) (or formula (IIa)) or a stereoisomer of a compound of formula (II) (or formula (IIa)) , geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs: wherein each R is independently H, ^deuterium , trifluoromethyl, 2,2-difluoroethyl, 3,3,3-trifluoropropyl, methyl, ethyl, isopropyl or n-propyl.

In some embodiments, the present invention relates to a compound that is a compound of formula (II) (or formula (IIa)) or a stereoisomer of a compound of formula (II) (or formula (IIa)) , geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs: wherein each R is independently H, ^deuterium , C _1-4 alkyl, C _2-6 alkenyl, C _1-4 haloalkyl or C _2-6 alkynyl.

In some embodiments, the present invention relates to a compound that is a compound of formula (II) (or formula (IIa)) or a stereoisomer of a compound of formula (II) (or formula (IIa)) , geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs: wherein each R is independently H, ^deuterium , trifluoromethyl, 2,2-difluoroethyl, 3,3,3-trifluoropropyl, methyl, ethyl, isopropyl or n-propyl.

In some embodiments, the present invention relates to a compound that is a compound of formula (II) (or formula (IIa)) or a stereoisomer of a compound of formula (II) (or formula (IIa)) , geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs: wherein each R is independently H, ^deuterium , C _1-4 alkyl, C _2-6 alkenyl, C _1-4 haloalkyl or C _2-6 alkynyl.

In some embodiments, the present invention relates to a compound that is a compound of formula (II) (or formula (IIa)) or a stereoisomer of a compound of formula (II) (or formula (IIa)) , geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs: wherein each R is independently H, ^deuterium , trifluoromethyl, 2,2-difluoroethyl, 3,3,3-trifluoropropyl, methyl, ethyl, isopropyl or n-propyl.

In some embodiments, the present invention relates to a compound that is a compound of formula (II) (or formula (IIa)) or a stereoisomer of a compound of formula (II) (or formula (IIa)) , geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs: wherein each n is independently 1, 2, 3 or 4.

In some embodiments, the present invention relates to a compound that is a compound of formula (II) (or formula (IIa)) or a stereoisomer of a compound of formula (II) (or formula (IIa)) , geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs: where m is 0, 1, 2, 3 or 4.

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

其中“*”表示与-NH-相连的一端；The V ring is

Wherein "*" represents the end connected to -NH-;

q is 1, 2, 3 or 4;

p is 1, 2, 3 or 4;

R ⁸ is HO-(CR ¹⁰ R ¹¹ ) _p -, H-(CR ¹⁰ R ¹¹ ) _p -O-, R ⁹ -N(R ¹² )-, R ⁹ -C(=O)O- or R ⁹ ;

R ¹² is H, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or C _1-4 haloalkyl;

Each of R ⁹ , R ¹¹ and R ¹⁰ is independently H, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl or C _1-4 alkoxy base.

In some embodiments, the present invention relates to a compound, which is a compound represented by formula (III) or a stereoisomer, geometric isomer, tautomer, racemic of a compound represented by formula (III) Forms, nitrogen oxides, hydrates, solvates, metabolites and pharmaceutically acceptable salts or prodrugs: wherein, R ¹² is H, deuterium, trifluoromethyl, 2,2-difluoroethyl, 3, 3,3-trifluoropropyl, methyl, ethyl, isopropyl or n-propyl;

Each of R ⁹ , R ¹¹ and R ¹⁰ is independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, tert-butyl, 2-methylpropyl, trifluoromethyl, methoxy or Ethoxy.

A compound that is a compound having one of the following structures or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite of a compound having one of the following structures, Pharmaceutically acceptable salts or prodrugs:

One aspect of the present invention pertains to pharmaceutical compositions comprising a compound of the present invention, or their stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites , metabolic precursors, pharmaceutically acceptable salts or prodrugs thereof, or optional pharmaceutically acceptable carriers, excipients, diluents, adjuvants, vehicles, or combinations thereof.

In some embodiments, the pharmaceutical composition of the present invention further comprises an additional therapeutic agent selected from chemotherapeutic agents or anti-proliferative agents, anti-inflammatory agents, immunomodulatory agents or immunosuppressive agents, neurotrophic factors for treatment Active agents for cardiovascular disease, active agents for the treatment of diabetes and active agents for the treatment of autoimmune diseases.

Another aspect of the present invention pertains to the use of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for the manufacture of a medicament for the prevention, management or treatment of, and alleviating the severity of, autoimmune or proliferative disease in a patient .

In some embodiments, the autoimmune disease of the present invention is lupus, multiple sclerosis, musculoskeletal lateral sclerosis, rheumatoid arthritis, psoriasis, type I diabetes, complications due to organ transplantation, Xenotransplantation, diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia or lymphoma.

In some embodiments, the proliferative disease of 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 (central nervous system) cancer, 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 manufacture of a medicament for inhibiting or modulating the activity of protein kinases.

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), formula (Ia), formula (Ib), formula (Ic), formula (II), formula (IIa) or formula (III).

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

The present invention also encompasses the use of the compounds of the present invention, and pharmaceutically acceptable salts thereof, for the manufacture of medicinal products for the treatment of autoimmune or proliferative diseases, including those described herein.

The present invention includes a pharmaceutical composition comprising a compound represented by formula (I), formula (Ia), formula (Ib), formula (Ic), formula (II), formula (IIa) or formula (III) The therapeutically effective amount required in combination with at least one pharmaceutically acceptable carrier, adjuvant or diluent.

The present invention also includes a method of treating, or susceptibility to, an autoimmune or proliferative disease in a patient comprising the use of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (II) , a therapeutically effective amount of a compound represented by formula (IIa) or formula (III) to treat a patient.

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

The compounds described herein may have one or more stereocenters, and each center may exist in the R or S configuration. The compounds provided herein include all diastereomeric, enantiomeric and epimeric forms, as well as suitable mixtures thereof. If desired, stereoisomers can be obtained by methods known in the art, such as separation of stereoisomers by chiral chromatography columns.

The salts of the compounds of the present invention also include those of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (II), formula (IIa) or formula (III) used in the preparation or purification Intermediates of compounds or separated enantiomers of compounds of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (II), formula (IIa) or formula (III) salts, but not necessarily pharmaceutically acceptable salts.

In addition, the compounds disclosed herein, including their salts, can also be obtained in their hydrate form or in a form containing a solvent (eg, ethanol, DMSO, etc.) for their crystallization. The compounds disclosed herein may form solvates, inherently or by design, with pharmaceutically acceptable solvents, including water; thus, the present invention is intended to include both solvated and unsolvated forms.

Any structural formula given herein is also intended to represent both isotopically unenriched as well as isotopically enriched forms of these compounds. Isotopically enriched compounds have the structures depicted by the general formulae given herein, except that one or more atoms are replaced by atoms having a selected atomic weight or mass number. Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of ^hydrogen , carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2H, ^3H , ^11C , ^13C , ^14C , ^15N , ^17O , 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 by the present invention, for example, those 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 kinetic studies (using eg ² H or ³ H), detection or imaging techniques such as positron emission tomography (PET) or including drugs or Single photon emission computed tomography (SPECT) for substrate tissue distribution measurements, or may be used in radiation therapy of patients. ¹⁸ F-enriched compounds are particularly ideal for PET or SPECT studies. Isotopically enriched compounds of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (II), formula (IIa) or formula (III) can be obtained by conventional methods familiar to those skilled in the art. The techniques or the examples and preparations described in this invention are prepared using a suitable isotopically-labeled reagent in place of the unlabeled reagent originally used.

In addition, substitution of heavier isotopes, particularly deuterium (ie, ² H or D), may provide certain therapeutic advantages that result from greater metabolic stability. For example, increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It should be understood that deuterium in the present invention is regarded as the substitution of compounds of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (II), formula (IIa) or formula (III) base. The concentration of such heavier isotopes, especially deuterium, can be defined by an isotopic enrichment factor. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a given isotope. If a substituent of a compound of the present 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 incorporated), at least 5000 (75% deuterium incorporated), at least 5500 (82.5% deuterium incorporated), at least 6000 (90% deuterium incorporated), at least 6333.3 (95% deuterium incorporated) 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 in which the crystallization solvent may be isotopically substituted, eg, _D2O , acetone _- d6, _DMSO -d6.

The foregoing has outlined only certain aspects of the present invention, but is not limited to these and other aspects which will be described in more detail below.

Detailed Description of the Invention

Definitions and General Terms

Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulae. The present invention is intended to cover all alternatives, modifications and equivalents, which are included within the scope of the present invention as defined by the claims. One skilled in the art will recognize that many methods and materials similar or equivalent to those described herein 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, terms defined, uses of terms, techniques described, etc.), this Application shall prevail.

It should further be appreciated that certain features of the invention, which are, for clarity, described in the context of multiple separate embodiments, can 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, can also be provided separately or in any suitable subcombination.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

Unless otherwise stated, the following definitions used herein shall apply. For the purposes of the present invention, chemical elements are in accordance with the Periodic Table of the Elements, CAS Edition, and Handbook of Chemistry and Physics, 75th Edition, 1994. In addition, general principles of organic chemistry may be referred to as described 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, Its entire contents 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 stated otherwise or otherwise clearly contradicted by context. Thus, as used herein, these articles refer to one or more than one (ie, at least one) object of the article. For example, "a component" refers to one or more components, i.e. there may be more than one component contemplated for adoption or use in the implementation of the described embodiments.

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

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

"Chiral" is a molecule that has the property of being non-superimposable with its mirror image; while "achiral" refers to a molecule that is superimposable with its mirror image.

"Enantiomer" refers to two nonsuperimposable, but mirror-image isomers of a compound.

"Diastereomer" refers to a stereoisomer having two or more centers of chirality and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting point, boiling point, 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, that is, 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 about one or more of its chiral centers. The prefixes d and 1 or (+) and (-) are symbols used to designate the rotation of plane polarized light by the 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, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

Any asymmetric atom (eg, carbon, etc.) of the compounds disclosed herein may exist in racemic or enantiomerically enriched forms, such as (R)-, (S)- or (R,S)-configurations 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 70% enantiomeric excess in the (R)- or (S)-configuration 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 process, the compounds of the present invention may be present as one of the possible isomers or as mixtures thereof, such as racemates and mixtures of diastereomers (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 have E or Z configuration; if the compound contains a disubstituted cycloalkyl, the substituent of the cycloalkyl may have cis or trans configuration; as in Example 37 of the present invention There are cis and trans configurations of pyrrolidinyl.

The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible through a low energy barrier. A chemical equilibrium of tautomers can be achieved if tautomerism is possible (eg, in solution). For example, proton tautomers (also known as prototropic tautomers) include interconversions by migration of protons, such as keto-enol isomerization and imine- Enamine isomerization. Valence tautomers include interconversions by recombination of some of the bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. A specific example of phenol-ketone tautomerism is the interconversion of pyridin-4-ol and pyridin-4(lH)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.

As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the general formula above, or as in the Examples, subclasses, and subclasses encompassed by the present invention. a class of compounds. It is to be understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted". In general, the term "substituted" means that one or more hydrogen atoms in a given structure have been replaced with a specified substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents can be substituted identically or differently at each position. The substituents mentioned therein can be, but are not limited to, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, alkyl, alkoxy, aryloxy, heteroaryl Oxy, heterocyclyloxy, arylalkoxy, heteroarylalkoxy, alkylacyl, heteroalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, heterocyclyl, heterocycle ylalkyl, heterocyclylacyl, aryl, arylalkyl, arylamino, heteroaryl, heteroarylalkyl, heteroarylamino, amido, sulfonyl, aminosulfonyl and the like.

In addition, it should be noted that, unless clearly stated otherwise, the description modes "each independently" and "...independently" and "...independently" used in the present invention can be interchanged, and both are interchangeable. It should be understood in a broad sense. It can either mean that in different groups, the specific options expressed between the same symbols do not affect each other, or it can mean that in the same group, the specific options expressed between the same symbols do not affect each other. Taking R ¹⁰ as an example, the structural formula "R ¹³ -(CR ¹⁰ R ¹¹ ) _n1 -S(=O) _p -(CR ¹⁰ R ¹¹ ) _n -N(R ¹² )-" and the structural formula "R ¹³ -(CR ¹⁰ )-" R ¹¹ ) _n -N(R ¹² )-C(=O)-(CR ¹⁰ R ¹¹ ) _n -(R ^12a )N-" The specific options of R ¹⁰ are not affected by each other, and at the same time, In the same chemical formula "R ¹³ -(CR ¹⁰ R ¹¹ ) _n -N(R ¹² )-C(=O)-(CR ¹⁰ R ¹¹ ) _n ^- (R ^12a )N-, the specific Options do not affect each other.

In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed in terms of group type or scope. Specifically, the present invention includes each and every independent subcombination of each member of these group species and ranges. For example, the term " _{C1 - C6} alkyl" or " _C1-6 alkyl" specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, _C4 alkyl, _C5 alkyl and _C6 alkanes base.

In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variables listed for that group should be understood to be the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable recites "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" respectively represents the linking An alkylene group or an arylene group. For example, "CN-(CR ¹⁰ R ¹¹ ) _n1 -C _1-9 heterocyclyl-C(=O)-N(R ¹² )-", connected to the rest of the formula through C _1-9 heterocyclyl, respectively , when listing a heterocyclyl group, it should be understood that "heterocyclyl" represents the attached heterocyclylene group. For another example, in "CN-(CR ⁶ R ⁷ ) _n -R ⁰ -(CR ⁶ R ⁷ ) _n -N(R ⁹ )-", R ⁰ is a cycloalkyl group, etc., and the cycloalkyl group etc. can be understood as Cycloalkylene groups, etc.

The term "alkyl" or "alkyl group" as used in the present invention refers to a saturated linear or branched monovalent hydrocarbon group containing 1 to 10 carbon atoms, wherein the alkyl group may be optionally is substituted with one or more substituents described herein. Unless otherwise specified, alkyl groups contain 1-6 carbon atoms; in yet another embodiment, alkyl groups contain 1-4 carbon atoms; in yet another embodiment, alkyl groups contain 1- 3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl , 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, n-hexyl, 2-hexyl, etc.

Examples of the term "alkenyl" group include, but are not limited to, vinyl, allyl, propenyl, and the like.

Examples of the term "alkynyl" group include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), ₁ -propynyl (-C≡C- _CH3) )and many more.

The term "alkoxy" means that an alkyl group is attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, 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 The group contains 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, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, and the like.

The term "haloalkyl" means an alkyl group substituted with one or more halogen atoms, examples of which include, but are not limited to, _-CH2F , _-CHF2 , trifluoromethyl, _-CH2Cl , -CHCl ₂ , -CCl ₃ , -CH ₂ CF ₃ , -CH ₂ CH ₂ CF ₃ , etc.

The term "carbocyclyl" or "carbocycle" refers to a monovalent or polyvalent saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms in which no Contains aromatic rings. Carbobicyclyl groups include spirocarbobicyclyl groups and fused carbobicyclyl groups, and suitable carbocyclyl groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Examples of carbocyclyl groups further include, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl- 3-alkenyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl base, cyclononyl, etc.

The term "cycloalkyl" refers to a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms, wherein the monocyclic, bicyclic or tricyclic rings do not contain aromatic rings. In one embodiment, the cycloalkyl group contains 3-9 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3-6 carbon atoms. The cycloalkyl groups may independently be 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.

Examples of the term "cycloalkenyl" include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cyclooctene , cyclononenyl and cyclodecenyl, among others.

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein, and both refer to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring containing from 3 to 12 ring atoms, wherein a monocyclic, bicyclic or tricyclic ring The ring contains no aromatic rings and at least one ring atom is selected from nitrogen, sulfur and oxygen atoms. Unless otherwise specified, heterocyclyl can be carbon or nitrogen, and _-CH2- groups can be optionally replaced by -C(=O)-. Ring sulfur atoms can optionally be oxidized to S-oxides. The nitrogen atoms of the rings can be optionally oxidized to N-oxygen compounds. Examples of heterocyclyl groups where the _-CH2- group is substituted with -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidine Keto, 3,5-dioxopiperidinyl. Examples of oxidized sulfur atoms in a heterocyclyl group include, but are not limited to, sulfolanyl, 1,1-dioxothiomorpholinyl.

In one embodiment, the heterocyclyl group is a heterocyclyl 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 include, but are not limited to: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolidinyl, imidazolinyl, Imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, tetrahydropyridyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl , thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl. Examples of heterocyclyl groups where the _-CH2- group is substituted with -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidine Keto, 3,5-dioxopiperidinyl. Examples of oxidized sulfur atoms in heterocyclyl groups include, but are not limited to, sulfolanyl, 1,1-dioxothiomorpholinyl. Said heterocyclyl group consisting of 4-7 atoms can be optionally substituted by one or more substituents described in the present invention. In another embodiment, the heterocyclyl group is a 4-atom heterocyclyl group, examples include, but are not limited to: azetidine, oxetanyl, thietanyl. In another embodiment, the heterocyclyl group is a 5-atom heterocyclyl group, examples include, but are not limited to: pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolidinyl, pyrazolidinyl, imidazoline base, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, 2-oxopyrrolidinyl, oxo -1,3-thiazolidinyl, sulfolane. In another embodiment, the heterocyclyl group is a 6-atom heterocyclyl group, examples include, but are not limited to: tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl , tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, 2-piperidinyl, 3,5 -Dioxopiperidyl, 1,1-dioxothiomorpholinyl. The 6-atom heterocyclyl group may be optionally substituted with one or more substituents described herein.

The terms "fused bicyclic" and "fused bicyclyl" are used interchangeably herein to refer to a monovalent or polyvalent saturated or partially unsaturated bridged ring system, which refers to a bicyclic ring system. The term "bridged ring" refers to any two rings that share two atoms that may or may not be directly connected. Examples include, but are not limited to, hexahydrofuro[3,2-b]furan, 2,3,3a,4,7,7a-hexahydro-1H-indene, 7-azabicyclo[2.2.1] Heptane, fused bicyclo[3.3.0]octane, fused bicyclo[3.1.0]hexane, 1,2,3,4,4a,5,8,8a-octahydronaphthalene.

The term "fused heterobicycle" means a saturated or partially unsaturated fused ring system, and at least one ring system contains one or more heteroatoms, wherein each ring system contains a 3-7 membered ring, ie, contains 1-6 carbons atom and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or more oxygen atoms to give groups like SO, SO ₂ , PO, PO ₂ , such examples include, but are not limited to, hexahydrofuro[3,2-b]furan, 7-azabicyclo[2.2.1]heptane, 3-azabicyclo[3.3.0]octane, 3 , 5,8-trioxabicyclo[5,1,0]octane, 1-aza-4,6-dioxabicyclo[3.3.0]octane, etc., and the fused heterobicyclo group may be substituted or unsubstituted.

The terms "spirobicyclyl" or "spirobicycle" are used interchangeably herein and refer to a monovalent or polyvalent saturated or partially unsaturated ring system wherein one ring originates from a specified ring carbon atom on the other ring. Each ring in a spirobicyclyl can be carbocyclyl or heterocyclyl, and each ring is optionally substituted with one or more substituents described herein.

The term "spiroheterobicyclyl" means that one ring originates from a particular cyclic carbon on the other ring, and at least one ring system contains one or more heteroatoms, wherein each ring system contains a 3-7 membered ring, i.e. contains 1 - 6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P are optionally substituted by one or more oxygen atoms to give eg SO, SO ₂ , PO, PO ₂ groups, such examples include, but are not limited to, 4-azaspiro[2.4]heptan-5-yl, 4-oxaspiro[2.4]heptan-5-yl, 5-azaspiro[ 2.4]Heptan-5-yl, 7-hydroxy-5-azaspiro[2.4]heptan-5-yl and the like.

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

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

The term "aryl" refers to 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 A family of rings in which each ring system contains a ring of 3-7 atoms with 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 term "heteroaryl" refers to 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 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 "heteroaromatic ring" or "heteroaromatic". The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, a 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, pyrimidinonyl, pyridone; also including, but in no way limited to, the following bicyclic rings: benzimidazolyl, benzofuranyl, benzotetrahydrofuranyl, benzothienyl, indolyl (eg 2-indolyl), purinyl, quinolinyl (such as 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), tetrahydroquinolinyl (such as 1,2,3,4-tetrahydroquinolinyl) Hydroquinolyl), isoquinolyl (such as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl), tetrahydroisoquinolyl (such as 1,2,3,4- tetrahydroisoquinolinyl), imidazo[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]Triazolo[1,5-a]pyridyl, and the like.

In one embodiment, the heteroaryl group is of the following substructure:

等等。

and many more.

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

As described herein, a ring system in which a substituent R is attached to a central ring by a bond represents that the substituent R can be substituted at any substitutable or any reasonable position on the ring. For example, formula a represents ring D and any possible substituted position on ring B can be substituted by R, as shown in formula b, formula c, formula d, formula e, formula f, formula g and formula h.

As described in the present invention, a ring system formed by a substituent (R) _n attached to the central ring by a bond represents that the n substituents R may be substituted at any substitutable position on the ring. For example, Formula i represents that any possible substituted position on the D and B rings can be substituted with n Rs.

As described in the present invention, there are two points of attachment on the ring C that can be connected to the rest of the molecule, for example, as shown in formula j, indicating that either the E" end or the E' end is connected to the rest of the molecule, That is, the connection methods at both ends can be interchanged.

An attachment point can be attached to the rest of the molecule at any linkable position on the loop as described herein. For example, formula k represents that any position on the ring that may be attached can serve as a point of attachment.

As described herein, the point of attachment can be attached to the rest of the molecule at any attachable position on the loop, while the two ends of the attachment can be interchanged. For example, the formula m represents that any position on the ring that may be connected can be used as a connection point, and the two ends of the connection point can be interchanged.

The term "protecting group" or "PG" refers to a substituent group that is commonly used to block or protect specific functionality when it reacts with other functional groups. 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, t-butoxycarbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenemethoxycarbonyl (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. "Carboxyl protecting group" means that the substituent of the carboxyl group is used to block or protect the functionality of the carboxyl group. General carboxyl protecting groups include -CH ₂ CH ₂ SO ₂ Ph, cyanoethyl, 2-(trimethylsilane) yl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenyl) phosphino)ethyl, nitroethyl, and the like. For a general description of protecting groups, reference can be made to the literature: TW. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

The term "prodrug", as used in the present invention, represents the in vivo conversion of a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (II), formula (IIa) or formula ( The compound shown in III). Such conversion is effected by hydrolysis of the prodrug in blood or enzymatic conversion to the parent structure in blood or tissue. The prodrug compounds of the present invention can be esters. In the existing invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C _1-24 ) esters, acyloxymethyl esters, carbonate esters , carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxyl group, which can be acylated to give the compound in prodrug form. Other prodrug forms include phosphates, such as these phosphates are phosphorylated by the hydroxyl group on the parent. A complete discussion of prodrugs can be found in the following references: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

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

As used herein, "pharmaceutically acceptable salts" refer 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. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups including hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or obtained by other methods such as ion exchange method described in books and literature these salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, Gluconate, Hemisulfate, Heptanoate, Caproate, Hydroiodide, 2-Hydroxy-ethanesulfonate, Lacturonate, Lactate, Laurate, Lauryl Sulfate, Malonate, Malonate, Mesylate, 2-Naphthalenesulfonate, Nicotinate, Nitrate, Oleate, Palmitate, Pamoate, Pectate, Persulfate, 3 - Phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. 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 quaternary ammonium salts formed from any compound containing an N-group. Water- or oil-soluble or dispersible 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 appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations that resist the formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, _{C1 -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. Solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association in which the solvent molecule is water.

As used herein, "inflammatory disease" refers to any disease, disorder or symptom of excessive inflammatory symptoms, host tissue damage, or loss of tissue function due to an excessive or uncontrolled inflammatory response. "Inflammatory disease" also refers to pathological conditions mediated by leukocyte influx and/or neutrophil chemotaxis.

"Inflammation," as used herein, refers to a localized protective response caused by tissue damage or destruction, which serves to destroy, dilute, or isolate (sequester) harmful substances and damaged tissue. Inflammation is significantly associated with leukocyte influx and/or neutrophil chemotaxis. Inflammation can arise from infection by pathogenic organisms and viruses as well as from non-infectious means such as trauma or reperfusion following myocardial infarction or stroke, immune responses to foreign antigens and autoimmune responses. Accordingly, inflammatory diseases that can be treated with the disclosed compounds 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 associated with tissue damage associated with a humoral or cell-mediated response to the body's own components. Examples of autoimmune diseases include lupus, multiple sclerosis, lateral sclerosis, rheumatoid arthritis, psoriasis, type I diabetes, complications from organ transplantation, xenotransplantation, diabetes, cancer, asthma, Atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and lymphoma.

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

The terms "cancer" and "cancerous" refer to or describe the physiological condition in a patient that is often characterized by uncontrolled cell growth. A "tumor" includes 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 (eg, epithelial squamous cell carcinoma), lung cancer (including small cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, and lung squamous cell carcinoma), peritoneal carcinoma, hepatocellular cancer, gastric cancer (including gastrointestinal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, Breast, colon, rectal, colorectal, endometrial or uterine cancer, salivary gland cancer, kidney or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatic carcinoma ), anal cancer, penile cancer, and head and neck cancer.

In addition, the compounds disclosed herein, including their salts, can also be obtained in their hydrate form or in a form containing a solvent (eg, ethanol, DMSO, etc.) for their crystallization. Compounds of the present disclosure may form solvates, inherently or by design, with pharmaceutically acceptable solvents, including water; thus, the present invention is intended to include both solvated and unsolvated forms.

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

PHARMACEUTICAL COMPOSITIONS, FORMULATIONS AND ADMINISTRATION OF THE COMPOUNDS OF THE INVENTION

The present invention provides a pharmaceutical composition comprising a compound disclosed herein 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 the inhibition of protein kinases in biological samples or patients.

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

The pharmaceutical compositions disclosed herein can be prepared and packaged in bulk form, wherein a safe and effective amount of the compounds of the present invention can be extracted and then administered to patients in powder or syrup form. Alternatively, the pharmaceutical compositions disclosed herein can be prepared and packaged in unit dosage form, wherein each physically discrete unit contains a safe and effective amount of a compound described herein. When prepared in unit dosage form, the presently disclosed pharmaceutical compositions may generally contain, for example, 0.5 mg to 1 g, or 1 mg to 700 mg, or 5 mg to 100 mg of the presently disclosed compound.

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

Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents , solvent, co-solvent, suspending agent, emulsifier, sweetener, flavoring agent, taste masking agent, coloring agent, anti-caking agent, humectant, chelating agent, plasticizer, tackifier, antioxidant, Preservatives, stabilizers, surfactants and buffers. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may serve more than one function, and provide alternative functions, depending on how much of that excipient is present in the formulation and those other excipients present in the formulation. agent.

Exemplary pharmaceutically acceptable carriers or components thereof are carbohydrates such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and derivatives thereof such as sodium carboxymethyl cellulose, ethyl cellulose vegan and methylcellulose; tragacanth powder; malt; gelatin; talc; solid lubricants such as stearic acid and magnesium stearate; calcium sulfate; synthetic oils; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil Oils and corn oils; polyols such as propylene glycol, glycerol, sorbitol, mannitol and polyethylene glycol; alginic acid; phosphate buffered solutions; emulsifiers such as Tween; wetting agents such as sodium lauryl sulfate ; coloring agent; flavoring agent; compressed tablet; stabilizer; antioxidant; preservative; pyrogen-free water; isotonic saline; and phosphate buffered solution.

The disclosed compounds can also be combined with soluble polymers as targetable drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyoxyethylene polylysine substituted with palmitoyl residues. In addition, the compounds disclosed herein can be combined with a class of biodegradable polymers used in achieving controlled release of drugs, eg, polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters , crosslinked or amphiphilic block copolymers of polyacetal, polydihydropyran, polycyanoacrylate and hydrogel.

The pharmaceutical compositions provided by the present invention can be co-formulated with other active ingredients that do not impair the intended therapeutic effect, or with substances that supplement the intended effect.

Suitable aqueous vehicles include, but are not limited to: water, saline, normal saline or phosphate buffered saline (PBS), Sodium Chloride Injection, Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose and Lactated Ringers Injection. Non-aqueous carriers include, but are not limited to, medium of vegetable derived fixed oils, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil and coconut oil. Chain triglycerides, and palm seed oil. Water-miscible carriers include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycols (eg, polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerol, N-methyl- 2-pyrrolidone, N,N-dimethylacetamide and dimethylsulfoxide.

CyDex,Lenexa,KS)。Suitable antimicrobial agents or preservatives include, but are not limited to, phenol, cresol, amalgam, benzyl alcohol, chlorobutanol, methyl and propylparaben, thimerosal, benzalkonium chloride (eg benzethonium chloride), methyl and propyl parabens, and sorbic acid. Suitable isotonicity agents include, but are not limited to, sodium chloride, glycerol, and dextrose. Suitable buffers include, but are not limited to, phosphates and citrates. Suitable antioxidants are those as described herein, including bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are those as described herein including sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidone. Suitable emulsifiers include those described herein, including polyoxyethylene sorbitan monolaurate. Polyoxyethylene sorbitan monooleate 80 and triethanolamine oleate. Suitable sequestrants or chelating agents include, but are not limited to, EDTA. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin and sulfonic acid butyl ether 7-β-cyclodextrin (

CyDex, Lenexa, KS).

The pharmaceutical compositions provided by the present invention can be formulated for single-dose or multiple-dose administration. The single-dose formulation is packaged in ampoules, vials or syringes. The multiple-dose parenteral formulation must contain a bacteriostatic or fungistatic concentration of the antimicrobial agent. All parenteral formulations must be sterile, as known and practiced in the art.

use

The present invention provides the use of the compounds and pharmaceutical compositions disclosed herein for the treatment, prevention or amelioration of diseases or disorders mediated or otherwise affected by the behavior of JAK kinases including JAK1, JAK2, JAK3 or TYK2 kinases or by JAK kinases including JAK1, A method for one or more symptoms of a disease or disorder that is mediated or otherwise affected by the behavior of JAK2, JAK3 or TYK2 kinases.

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 treating, preventing, or ameliorating effects mediated or otherwise affected by inappropriate JAK1 kinase behavior disease or disorder, or one or more symptoms of a disease or disorder mediated or otherwise affected by inappropriate JAK1 kinase behavior.

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

In yet another embodiment, the disease, disorder, or one or more symptoms of a disease or disorder is associated with inappropriate JAK3 kinase behavior.

"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, an abnormal increase in activity, or deviations in timing and control of JAK kinase behavior. Such inappropriate kinase behavior results from, for example, inappropriate or uncontrolled behavior caused by overexpression or mutation of protein kinases. 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 diseases such as polycythemia vera (PCV), essential thrombocythemia, idiopathic myelofibrosis (IMF); leukemia, For example, myeloid leukemias 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, prostate, breast, ovarian, melanoma, lung, brain, pancreatic, and kidney cancers; and inflammatory diseases or disorders associated with immune dysfunction, immune deficiency, immune regulation , autoimmune disease, tissue transplant rejection, graft-versus-host disease, wound healing, kidney 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 Ocular 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 preventing and/or treating proliferative diseases, autoimmune diseases, allergic diseases in mammals (including humans) Disease, inflammatory disease, or transplant rejection.

In another aspect, the present invention provides a method of treating a mammal suffering from or at risk of suffering from a disorder disclosed herein, the method comprising administering an amount effective to treat a disorder or an amount effective to prevent a disorder of one or more of the agents disclosed herein composition or compound. In another aspect, provided herein is a method of treating a mammal suffering from or at risk of suffering from a proliferative disease, autoimmune disease, allergic disease, inflammatory disease, or transplant rejection.

In one method of therapy, the present invention provides a method of treating and/or preventing a mammal susceptible to or suffering from a proliferative disease, the method comprising administering a therapeutically effective or prophylactically effective amount of one or more of the herein Disclosed pharmaceutical compositions or compounds. In specific examples, the proliferative disease is selected from cancer (eg, solid tumors such as uterine leiomyosarcoma or prostate cancer), polycythemia vera, essential thrombocythemia, myelofibrosis, leukemia (eg, AML, CML, ALL) or CLL) and multiple myeloma.

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

In another aspect, provided herein is a class of compounds disclosed herein, or pharmaceutical compositions comprising the compounds disclosed herein, for use in the manufacture of a medicament for the treatment or prevention of proliferative diseases. In specific examples, the proliferative disease is selected from cancer (eg, solid tumors such as uterine leiomyosarcoma or prostate cancer), polycythemia vera, essential thrombocythemia, myelofibrosis, leukemia (eg, AML, CML, ALL) or CLL) and multiple myeloma.

In another aspect, provided herein is a method of treating and/or preventing a mammal susceptible to or suffering from an autoimmune disease, the method comprising administering a therapeutically effective or prophylactically effective amount of one or more of the pharmaceutical compositions disclosed herein or compound. In specific examples, the autoimmune disease is selected from the group consisting of COPD, asthma, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjögren's syndrome, psoriasis, type I diabetes, and inflammatory bowel disease.

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

In another aspect, provided herein is a class of compounds disclosed herein, or pharmaceutical compositions comprising the compounds disclosed herein, for use in the manufacture of a medicament for the treatment or prevention of autoimmune diseases. In specific embodiments, the autoimmune disease is selected from the group consisting of COPD, asthma, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjögren's syndrome, psoriasis, type I diabetes and inflammatory bowel disease .

In another aspect, provided herein are methods of treating and/or preventing mammals susceptible to or suffering from allergic disease, the methods comprising administering a therapeutically effective or prophylactically effective amount of one or more of the pharmaceutical compositions disclosed herein or compound. In particular embodiments, the allergic disease is selected from the group consisting of respiratory allergic disease, sinusitis, eczema and measles, food allergy and insect venom allergy.

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

In another aspect, provided herein is a class of compounds disclosed herein, or pharmaceutical compositions comprising the compounds disclosed herein, for use in the manufacture of a medicament for the treatment or prevention of allergic diseases. In particular embodiments, the allergic disease is selected from the group consisting of respiratory allergic disease, sinusitis, eczema and measles, food allergy and insect venom allergy.

In another aspect, provided herein is a class of compounds disclosed herein for use in the treatment and/or prevention of inflammatory diseases. In specific embodiments, the inflammatory disease is selected from the group consisting of inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, juvenile arthritis, and psoriatic arthritis.

In another aspect, provided herein is a class of compounds disclosed herein, or pharmaceutical compositions comprising the compounds disclosed herein, for use in the manufacture of a medicament for the treatment or prevention of inflammatory diseases. In specific embodiments, the inflammatory disease is selected from the group consisting of inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, juvenile arthritis, and psoriatic arthritis.

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

In another aspect, provided herein is a class of compounds disclosed herein, or pharmaceutical compositions comprising the compounds disclosed herein, for use in the manufacture of a medicament for the treatment or prevention of transplant rejection. In specific examples, transplant rejection is organ transplant rejection, tissue transplant rejection, and cell transplant rejection.

In another aspect, provided herein is a class of compounds disclosed herein for use as a medicament, particularly as a medicament for the treatment and/or prevention of the aforementioned diseases. Also provided is the use of the compounds disclosed herein for 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 of the present disclosure for a period of time sufficient to reduce the level of inflammation in the subject, and preferably to terminate the progression of said inflammation. Particular embodiments of this method comprise administering to a subject suffering from or susceptible to rheumatoid arthritis of the bone an effective amount of a compound of the present disclosure for a period of time sufficient to reduce or prevent, respectively, joint inflammation in said patient, and preferably The process of the inflammation is terminated.

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

The compounds and pharmaceutical compositions disclosed herein are kinase inhibitors, including Btk inhibitors. These inhibitors can be used to treat one or more diseases in mammals responsive to kinase inhibition, including diseases responsive to Btk inhibition and/or B-cell proliferation inhibition. Without wishing to be bound by any particular theory, it is believed that the interaction of the compounds of the present invention with Btk results in the inhibition of Btk activity and, therefore, the pharmaceutical use of these compounds. Accordingly, the present invention includes a method for treating a mammal, eg, a human, having a disease responsive to inhibition of Btk activity and/or inhibition of B-cell proliferation, the method comprising: administering to the mammal having such a disease an effective amount of At least one chemical entity provided herein. Effective concentrations can be determined experimentally, eg, by measuring blood concentrations of the compound, or theoretically by calculating bioavailability. In addition to Btk, other kinases that may be affected include, but are not limited to, other tyrosine kinases and serine/threonine kinases.

To the extent Btk is associated with disease, alleviation, prophylaxis and prophylactic treatment of disease and disease symptoms are within the scope of the present invention.

In some embodiments, the disorder responsive to inhibition of Btk activity and/or B cell and/or myeloid cell activity is cancer, bone disease, allergic disease and/or autoimmune and/or inflammatory disease and/or acute inflammation reaction.

The present invention includes methods of treating patients suffering from cancer, bone disease, allergic disease and/or autoimmune and/or inflammatory disease and/or acute inflammatory response by administering an effective amount of a compound of the present invention and the pharmacy thereof Acceptable salts, solvates and mixtures.

In some embodiments, conditions and diseases that can be affected by the use of the compounds of the present invention include, but are not limited to:

Allergic diseases, including but not limited to eczema, allergic rhinitis or rhinitis, hay fever, bronchial asthma, urticaria (hives) and food allergies and other atopic conditions;

Autoimmune and/or inflammatory diseases, including but not limited to psoriasis, Crohn's disease, irritable bowel syndrome, Sjögren's syndrome, tissue transplant rejection, and hyperacute rejection of transplanted organs, asthma, systemic Lupus erythematosus (and related glomerulonephritis), dermatomyositis, multiple sclerosis, scleroderma, vasculitis (ANCA-related and other vasculitis), autoimmune hemolytic diseases and thrombocytopenic states, pulmonary hemorrhagic nephritis complex symptoms (and associated glomerulonephritis and pulmonary hemorrhage), atherosclerosis, rheumatoid arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura (ITP), Addison's disease, Parkinson's disease, Alzheimer's disease Haimer's disease, diabetes (type 1), septic shock, myasthenia gravis, ulcerative colitis, aplastic anemia, Coeliac's disease, Wegener's granulomatosis, and where cells and antibodies arise from the individual's own tissues and directly against other diseases of the individual's own tissues;

Acute inflammatory reactions, including but not limited to skin sunburn, pelvic inflammatory disease, inflammatory bowel disease, urethritis, uveitis, sinusitis, pneumonia, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, Hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis and cholecystitis;

Cancer, including but not limited to hematological malignancies such as B-cell lymphoma, and acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic and acute lymphocytic leukemia, hairy cell leukemia, Hodgkin's disease, non- Hodgkin lymphoma, multiple myeloma, and other diseases characterized by cancers of the blood or lymphatic system; and

Bone disease, including but not limited to osteoporosis.

Btk is a known inhibitor of lymphoma B cell apoptosis. Defective apoptosis contributes to the pathogenesis and drug resistance of human leukemias and lymphomas. Accordingly, also provided are methods of promoting or inducing apoptosis in a Btk-expressing cell comprising contacting the cell with a compound of the present invention and pharmaceutically acceptable salts, solvates and mixtures thereof.

The disclosed compounds may be administered concurrently with, prior to or subsequent to one or more other therapeutic agents. The compounds of the present invention may be administered separately from the other therapeutic agents by the same or different route of administration, or in the same pharmaceutical composition.

For an individual of about 50-70 kg, the presently disclosed pharmaceutical compositions and combinations may contain about 1-1000 mg, or about 1-500 mg, or about 1-250 mg, or about 1-150 mg, or about 0.5-100 mg, or A unit dosage form of about 1-50 mg of active ingredient. A therapeutically effective amount of a compound, pharmaceutical composition or combination thereof will depend on the species, body weight, age and individual condition of the individual, the disorder or disease being treated or its severity. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient required to prevent, treat or inhibit the progression of a disorder or disease.

The dosage characteristics cited above have been demonstrated in in vitro and in vivo tests using advantageous mammals (eg, mice, rats, dogs, monkeys) or isolated organs, tissues and specimens thereof. The disclosed compounds are used in vitro as solutions, eg, aqueous solutions, and enterally, parenterally, especially intravenously, in vivo, eg, as suspensions or aqueous solutions.

In one embodiment, the therapeutically effective dose of the compounds disclosed herein is from about 0.1 mg to about 2,000 mg per day. Pharmaceutical compositions thereof should provide a dose of about 0.1 mg to about 2,000 mg of the compound. In a specific embodiment, pharmaceutical dosage unit forms are prepared to provide from about 1 mg to about 2,000 mg, from about 10 mg to about 1,000 mg, from about 20 mg to about 500 mg, or from about 25 mg to about 250 mg of the primary active ingredient or per dosage unit form combination of the main components. In a particular embodiment, a pharmaceutical dosage unit form is prepared to provide about 10 mg, 20 mg, 25 mg, 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg or 2000 mg of the primary active ingredient.

In addition, the compounds disclosed herein can be administered in prodrug form. In the present invention, "prodrugs" of the compounds disclosed in the present invention are functional derivatives that can eventually release the compounds disclosed in the present invention in vivo when administered to a patient. When administering the compounds disclosed herein in prodrug form, those skilled in the art can implement one or more of the following methods: (a) altering the in vivo onset time of the compound; (b) altering the in vivo duration of action of the compound; (c) ) altering the in vivo delivery or distribution of the compound; (d) altering the in vivo solubility of the compound; and (e) overcoming side effects or other difficulties faced by the compound. Typical functional derivatives used to prepare prodrugs include variants of compounds that are chemically or enzymatically cleaved in vivo. These variants, including the preparation of phosphates, amides, esters, thioesters, carbonates and carbamates, are well known to those skilled in the art.

General synthetic procedure

Generally, the compounds of the present invention can be prepared by the methods described in the present invention, unless otherwise specified, wherein the substituents are as defined in formula (I), formula (Ia), formula (Ib), formula (Ic), Formula (II), formula (IIa) or formula (III). The following reaction schemes and Examples 1-100 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 present invention, and that other methods for preparing the compounds of the present invention are considered to be within the scope of the present 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 by modifying methods, such as appropriate protection of interfering groups, by using other known reagents in addition to those described herein, or by combining The reaction conditions were modified routinely. In addition, the reactions disclosed herein or known reaction conditions are also acknowledged to be applicable to the preparation of other compounds of the present 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 Reagent Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd. and Qingdao Ocean Chemical Factory.

Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether were obtained by refluxing and drying with metallic sodium. Anhydrous dichloromethane and chloroform were obtained by refluxing with 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 are generally carried out under positive nitrogen or argon pressure or a drying tube is set over anhydrous solvent (unless otherwise indicated), the reaction flasks are plugged with suitable rubber stoppers, and the substrate is injected through a syringe. Glassware is dry.

The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory. The test conditions for NMR spectroscopy are: Bruker 400MHz or 600MHz NMR instrument at room temperature, 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 the reference standard. When multiplets are present, the following abbreviations are used: s (singlet, singlet), d (doublet, doublet), t (triplet, triplet), q (quartet, quartet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, double doublet), ddd (doublet of doublet of doublets, double doublet doublet), dt (doublet of triplets, double triplet) . Coupling constant, expressed in Hertz (Hz).

The conditions for low-resolution mass spectrometry (MS) data determination are: Agilent 6120Quadrupole HPLC-MS (column model: Zorbax SB-C18, 2.1x30mm, 3.5μm, 6min, flow rate 0.6mL/min, mobile phase: 5%-95% (Ratio of _CH3CN with 0.1% formic acid in ( _H2O with 0.1% formic acid))), detected by UV at 210/254 nm, in electrospray ionization mode (ESI).

The purity of the compound was characterized by: Agilent 1260 preparative high performance liquid chromatography (Pre-HPLC) or Calesep Pump 250 preparative high performance liquid chromatography (Pre-HPLC) (column type: NOVASEP, 50/80mm, DAC), at 210nm /254nm with UV detection.

The following abbreviations are used throughout this disclosure:

H ₂ O water; MeOH, CH ₃ OH methanol; CD ₃ OD deuterated methanol; SEMCl 2-(trisilyl)ethoxymethyl chloride;

CHCl ₃ chloroform, chloroform; CDCl ₃ deuterated chloroform; DMSO dimethyl sulfoxide; DMSO-d ₆ deuterated dimethyl sulfoxide;

DMF N,N-dimethylformamide; HOBT 1-hydroxybenzotriazole; Na ₂ SO ₄ sodium sulfate; Pd/C palladium carbon;

HATU 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; TsCl p-toluenesulfonyl chloride;

Pd(dppf)Cl ₂ [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; Xantphos 4,5-bisdiphenylphosphino-9,9-dimethylxanthene ;

X-Phos 2-dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl; Pd ₂ (dba) ₃ tris(dibenzylideneacetone)dipalladium;

t-BuDavePhos 2-(di-tert-butylphosphine)-2'-(N,N-dimethylamino)biphenyl; DBU 1,8-diazabicyclo[5.4.0]undec-7- alkene;

g grams; mg milligrams; mol moles; mmol millimoles; h hours; min minutes; L liters; mL, ml ml; r.t, RT room temperature;

Rt retention time; HEPES hydroxyethylpiperazine ethanethiosulfonic acid; Brij-35 dodecyl polyethylene glycol ether; DTT dithiothreitol;

EDTA ethylenediaminetetraacetic acid; EGFR epidermal growth factor receptor; BTK Bruton's tyrosine kinase;

EGFR T790M epidermal growth factor receptor T790M mutant; Peptide FAM-P22 fluorescein-labeled peptide 22;

ATP adenosine triphosphate; 96-well plate 96-well plate; 384-well plate 384-well plate; Staurosporine staurosporine;

Coating Reagent #3 #3 Coating Reagent.

Intermediate Synthesis Scheme 1

The intermediate compound (6) can be prepared by the intermediate synthesis scheme 1, wherein R ¹⁹ and R ^19a are each independently halogen; R ²⁰ is a protecting group such as Ph ₃ C-, SEM-, etc.; R ³ has the formula of the present invention The meaning described in (I). Compound (1) is catalyzed by transition metals to react with trimethylsilylacetylene in polar solvents (such as dimethyl sulfoxide, N,N-dimethylamide, 1,4-dioxane, etc.) to obtain compounds (3) ; Compound (3) obtains compound (4) under the effect of alkali (such as: sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide etc.), or fluoride (such as: tetrabutylammonium fluoride) ; Compound (4) can obtain compound (5) under the action of halogenated reagent (such as NIS, NBS, etc.); compound (5) is reacted with R ²⁰ Cl (such as Ph ₃ CCl, SEMCl, etc.) to form compound (6) .

Intermediate Synthesis Scheme 2

(如：二甲亚砜，N,N-二甲基酰胺，1,4-二氧六环等)中，反应得到化合物(7)；化合物(7)在碱(如：叔丁醇钠，叔丁醇钾，乙醇钠等)，或氟化物(如：四丁基氟化铵)的作用下得到化合物(8)；化合物(8)在卤代试剂(如：NIS，NBS等)作用下得到化合物(9)；化合物(9)与R²⁰Cl(如Ph₃CCl，SEMCl等)反应生成化合物(10)。The intermediate compound (10) can be prepared by the intermediate synthesis scheme 2, wherein R ¹⁹ and R ^19a are each independently halogen; R ²⁰ is a protecting group such as Ph ₃ C-, SEM-, etc.; R ³ and R ² have such as The meanings described in formula (I) of the present invention. Compound (1) is catalyzed by transition metals with

(such as: dimethyl sulfoxide, N,N-dimethylamide, 1,4-dioxane, etc.), the reaction obtains compound (7) ; compound (7) in a base (such as: sodium tert-butoxide, Under the action of potassium tert-butoxide, sodium ethoxide, etc.), or fluoride (such as: tetrabutylammonium fluoride), compound (8) is obtained; compound (8) is obtained under the action of halogenated reagents (such as: NIS, NBS, etc.) Compound (9) is obtained; compound (9) is reacted with R ²⁰ Cl (such as Ph ₃ CCl, SEMCl, etc.) to generate compound (10) .

Intermediate Synthesis Scheme 3

Intermediate compound (12) can be prepared by intermediate synthesis scheme 3, wherein R ¹⁹ and R ^19a are each independently halogen; R ²⁰ is Ph ₃ C-, SEM- and other protecting groups; E ring, m, R ⁴ , R ⁵ , R ³ and R ² have the meanings as described in formula (I) of the present invention. Compound (10) and compound (11) undergo Suzuki cross-coupling reaction under the catalysis of transition metal to obtain compound (12) .

Intermediate Synthesis Scheme 4

Intermediate compound (12) can be prepared by intermediate synthesis scheme 4, wherein R ¹⁹ and R ^19a are each independently halogen; R ²⁰ is Ph ₃ C-, SEM- and other protecting groups; E ring, m, R ⁴ , R ⁵ , R ³ and R ² have the meanings as described in formula (I) of the present invention. Compound (10) and compound (16) undergo Suzuki cross-coupling reaction under transition metal catalysis to obtain compound (12) .

Intermediate Synthesis Scheme 5

Intermediate compound (18) can be prepared by intermediate synthesis scheme 5, wherein R ¹⁹ and R ^19a are each independently halogen; R ²⁰ is Ph ₃ C-, SEM- and other protecting groups; A ring, R ³ and R ² has the meaning as described in formula (I) of the present invention. Compound (10) and compound (17) undergo Suzuki cross-coupling reaction under transition metal catalysis to obtain compound (18) .

Intermediate Synthesis Scheme 6

Intermediate compound (18) can be prepared by intermediate synthesis scheme 6, wherein R ¹⁹ and R ^19a are each independently halogen; R ²⁰ is Ph ₃ C-, SEM- and other protecting groups; A ring, R ³ and R ² has the meaning as described in formula (I) of the present invention. Compound (10) and compound (13) undergo Suzuki cross-coupling reaction under transition metal catalysis to obtain compound (18) .

Intermediate Synthesis Scheme 7

The intermediate compound (14) can be prepared through the intermediate synthesis scheme 7, wherein R ¹⁹ is halogen; R ²⁰ is a protecting group such as Ph ₃ C-, SEM-, etc.; A ring, E ring, m, R ⁴ , R ⁵ , R ³ and R ² have the meanings as described in formula (I) of the present invention. Compound (12) and compound (13) undergo Suzuki cross-coupling reaction under transition metal catalysis to obtain compound (14) .

Intermediate Synthesis Scheme 8

The intermediate compound (14) can be prepared by the intermediate synthesis scheme 8, wherein R ¹⁹ is halogen; R ²⁰ is a protecting group such as Ph ₃ C-, SEM-, etc.; A ring, E ring, m, R ⁴ , R ⁵ , R ³ and R ² have the meanings as described in formula (I) of the present invention. Compound (12) and compound (17) undergo Suzuki cross-coupling reaction under the catalysis of transition metal to obtain compound (14) .

Intermediate Synthesis Scheme 9

The intermediate compound (14) can be prepared through the intermediate synthesis scheme 9, wherein R ^19a is halogen; R ²⁰ is a protecting group such as Ph ₃ C-, SEM-, etc.; A ring, E ring, m, R ⁴ , R ⁵ , R ³ and R ² have the meanings as described in formula (I) of the present invention. Compound (18) and compound (16) undergo Suzuki cross-coupling reaction under transition metal catalysis to obtain compound (14) .

Intermediate Synthesis Scheme 10

The intermediate compound (14) can be prepared through the intermediate synthesis scheme 10, wherein R ^19a is halogen; R ²⁰ is a protecting group such as Ph ₃ C-, SEM-, etc.; A ring, E ring, m, R ⁴ , R ⁵ , R ³ and R ² have the meanings as described in formula (I) of the present invention. Compound (18) and compound (11) undergo Suzuki cross-coupling reaction under the catalysis of transition metal to obtain compound (14) .

Intermediate Synthesis Scheme 11

Intermediate compound (12a) can be prepared by intermediate synthesis scheme 11, wherein R ¹⁸ , R ¹⁹ and R ^19a are each independently halogen; R ²⁰ is Ph ₃ C-, SEM- and other protecting groups; Z ¹ , Z ² , R ⁰ , R ⁰⁰ , n and L have the meanings as described in formula (II) of the present invention. Compound (10a) and compound (16a) undergo Suzuki cross-coupling reaction under transition metal catalysis to obtain compound (12a) .

Intermediate Synthesis Scheme 12

Intermediate compound (12a) can be prepared by intermediate synthesis scheme 12, wherein R ¹⁸ , R ¹⁹ and R ^19a are each independently halogen; R ²⁰ is Ph ₃ C-, SEM- and other protecting groups; Z ¹ , Z ² , R ⁰ , R ⁰⁰ , n and L have the meanings as described in formula (II) of the present invention. Compound (10a) and compound (11a) undergo Suzuki cross-coupling reaction under the catalysis of transition metal to obtain compound (12a) .

Synthesis Scheme 1

Compound (15) can be prepared by synthetic scheme 1, R ²⁰ is a protecting group such as Ph ₃ C-, SEM-, etc.; A ring, E ring, m, R ⁴ , R ⁵ , R ³ and R ² have the same properties as the present invention. The meanings described in formula (I). Compound (14) is deprotected to obtain compound (15) .

Synthesis Scheme 2

Compound (15a) can be prepared by synthetic scheme 2, wherein R ¹⁸ and R ¹⁹ are each independently halogen; R ²⁰ is Ph ₃ C-, SEM- and other protecting groups; Z ¹ , Z ² , R ¹ , R ⁰ , R ⁰⁰ , n and L have the meanings as described in formula (II) of the present invention. Compound (12a) undergoes deprotection reaction to obtain compound (15a) .

Synthesis Scheme 3

Compound (2a) can be prepared by Synthesis Scheme 3, wherein R ^19a is halogen; Z ¹ , Z ² , W ring, R ⁰ , R ⁰⁰ , n and L have the meanings as described in formula (II) of the present invention. Compound (1a) and compound (16a) undergo Suzuki cross-coupling reaction under transition metal catalysis to obtain compound (2a) .

Synthesis Scheme 4

Compound (2a) can be prepared by Synthesis Scheme 4, wherein R ^19a is halogen; Z ¹ , Z ² , W ring, R ⁰ , R ⁰⁰ , n and L have the meanings as described in formula (II) of the present invention. Compound (1a) and compound (11a) undergo Suzuki cross-coupling reaction under transition metal catalysis to obtain compound (2a) .

Intermediate Example 1

2-Bromo-3-methyl-7-iodo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine

Step 1: Synthesis of compound 3,5-dibromo-6-chloropyrazin-2-amine

A solution of bromine (5.89 g, 36.54 mmol, 1.90 mL) in chloroform (15 mL) was slowly added dropwise to 6-methylpyrazin-2-amine (2.00 g, 18.33 mmol) in chloroform ( 170 mL) solution. After the dropwise addition, the reaction was stirred at room temperature for 4.5 h. Water (100 mL) was added to quench the reaction, the organic layer was washed with water (100 mL), dried over anhydrous magnesium sulfate, the organic layer was concentrated under reduced pressure, and subjected to column separation (petroleum ether/ethyl acetate (v/v)=2/1) to obtain 4.20 g beige solid, yield: 86.0%.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm) 6.83 (s, 2H), 2.34 (s, 3H);

MS(ESI, pos.ion) m/z: 266.0[M+1] ⁺ .

Step 2: Synthesis of compound 5-bromo-6-methyl-3-((trimethylsilyl)ethynyl)pyrazin-2-amine

Under nitrogen protection, at 15°C, trimethylsilylacetylene (1.50 g, 16.00 mmol) was slowly added to 3,5-dibromo-6-methylpyrazin-2-amine (4.00 g, 15.00 mmol), Cuprous iodide (600 mg, 3.15 mmol), bis(triphenylphosphine)palladium dichloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (600 mg, 0.85 mmol) and triethylamine (2.40 g, 24.00 mmol, 3.30 mL) in tetrahydrofuran (42 mL), after the dropwise addition was completed, the temperature was naturally raised to room temperature, and the reaction was continued for 16 h. Celite was filtered, washed with ethyl acetate, concentrated under reduced pressure, the concentrated residue was added with 100 mL of water, extracted with dichloromethane (100 mL x 3), the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column separation (petroleum ether). /ethyl acetate (v/v)=2/1) to give 3.50 g of a beige solid, yield: 82.0%.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm) 6.69 (s, 2H), 2.39 (s, 3H), 0.26 (s, 9H);

MS(ESI, pos.ion) m/z: 284.1[M+1] ⁺ .

Step 3: Synthesis of compound 2-bromo-3-methyl-5H-pyrrolo[2,3-b]pyrazine

Under _N2 protection, a solution of 5-bromo-6-methyl-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (3.50 g, 12.00 mmol) in tetrahydrofuran (11 mL) was added at -30 °C. ) was slowly added dropwise to a solution of potassium tert-butoxide (1.80 g, 16.00 mmol) in tetrahydrofuran (18 mL). After the dropwise addition, the reaction was carried out at -30° C. for 1 h, and then the reaction was naturally raised to room temperature and stirred overnight. The reaction solution was filtered through celite, washed with ethyl acetate, the filtrate was concentrated under reduced pressure, the concentrated residue was added with water (150 mL), extracted with ethyl acetate (150 mL x 3), the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2.1 g Orange solid, the crude product was used in the next reaction without further purification, yield: 60.0%.

MS(ESI, pos.ion) m/z: 212.1[M+1] ⁺ .

Step 4: Synthesis of compound 2-bromo-3-methyl-7-iodo-5H-pyrrolo[2,3-b]pyrazine

At 0°C, N-iodosuccinimide (2.60 g, 11.00 mmol) was added portionwise to 2-bromo-3-methyl-5H-pyrrolo[2,3-b]pyrazine (2.05 g , 7.25mmol) in acetone (30mL) solution, the reaction was stirred at room temperature for 3h. The solvent was removed under reduced pressure, water (30 mL) and dichloromethane (30 mL) were added to the residue, the solid was filtered, the solid was washed with a little water and dichloromethane, and the brown solid was vacuum-dried at 60°C to obtain 2.50 g of a brown solid. Further purification was used directly in the next reaction.

MS(ESI, pos.ion) m/z: 337.7[M+1] ⁺ .

Step 5: Compound 2-Bromo-3-methyl-7-iodo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyridine Synthesis of oxazine

At 0°C, sodium hydride (450 mg, 11.25 mmol) was added portionwise to 2-bromo-3-methyl-7-iodo-5H-pyrrolo[2,3-b]pyrazine (2.50 g, 7.4 mmol) of N,N-dimethylformamide (30 mL). After stirring for 2 h at room temperature. Trimethylsilylethoxymethyl chloride (1.90 g, 11.00 mmol, 2.00 mL) was slowly added dropwise at 0° C. After the dropwise addition, the reaction was stirred at room temperature overnight. The reaction was quenched by adding water (100 mL), extracted with dichloromethane (100 mL x 3), the organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated to remove the solvent, and the residue was separated by column chromatography (petroleum ether/ Ethyl acetate (v/v) = 10/1) gave 1.20 g of a pale yellow oil, two-step overall yield: 35.0%.

MS(ESI, pos.ion) m/z: 467.9[M+1] ⁺ .

Using the corresponding raw materials, the following intermediates were prepared according to the synthesis method of Intermediate Example 1:

Intermediate Example 6

2-Chloro-7-iodo-5-trityl-5H-pyrrolo[2,3-b]pyrazine

Step 1: Synthesis of compound 2-chloro-5H-pyrrolo[2,3-b]pyrazine

To a solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (3.1 g, 16 mmol) in 1,4-dioxane (20 mL) was added phosphorus oxychloride (2.27 mL, 24.1 mmol) and triethylamine (220 μL, 1.58 mmol), refluxed at 110 °C for 6 hours, slowly added to water (100 mL) to quench, potassium hydroxide solution was adjusted to pH>7, extracted with ethyl acetate (50 mL×3), anhydrous sulfuric acid It was dried over sodium, concentrated, slurried (petroleum ether/ethyl acetate (v/v)=2/1), filtered, and dried to obtain 1.3 g of a gray solid, yield: 54%.

MS(ESI, pos.ion) m/z: 154.1[M+1] ⁺ .

Step 2: Synthesis of compound 2-chloro-7-iodo-5H-pyrrolo[2,3-b]pyrazine

To a solution of 2-chloro-5H-pyrrolo[2,3-b]pyrazine (1.3 g, 8.5 mmol) in acetone (15 mL) was added N-iodosuccinimide (2.9 g, 13 mmol) and stirred at room temperature 12 hours, diluted with water (40 mL), extracted with dichloromethane (55 mL×3), dried over anhydrous sodium sulfate, concentrated by column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain 2.2 mg of off-white solid, Yield: 93%.

MS(ESI, pos.ion) m/z: 280.0[M+1] ⁺ .

Step 3: Synthesis of compound 2-chloro-7-iodo-5-trityl-5H-pyrrolo[2,3-b]pyrazine

To a solution of 2-chloro-7-iodo-5H-pyrrolo[2,3-b]pyrazine (300 mg, 1.07 mmol) in N,N-dimethylformamide (8 mL) was added sodium carbonate (230 mg, 2.17 mmol) and triphenylchloromethane (330 mg, 1.18 mmol), heated at 45°C for 5 hours, diluted with water (20 mL), extracted with dichloromethane (25 mL×3), dried over anhydrous sodium sulfate, and concentrated by column chromatography (petroleum ether/ Ethyl acetate (v/v)=8/1) gave 320 mg of white solid, yield: 57.13%.

MS(ESI, pos.ion) m/z: 522.10[M+1] ⁺ ;

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.92 (s, 1H), 7.65 (s, 1H), 7.31 (m, 9H), 7.17 (m, 6H).

Intermediate Example 7

2,7-Dibromo-6-methyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine

Step 1: Synthesis of compound 5-bromo-3-(propyn-1-yl)pyrazin-2-amine

To a solution of 3,5-dibromopyrazin-2-amine (200 mg, 0.79 mmol) in tetrahydrofuran (8 mL) were added cuprous iodide (15 mg, 0.07 mmol), followed by bis(triphenylphosphine)dichloride Palladium (56 mg, 0.08 mmol) and triethylamine (340 μL, 2.44 mmol), under nitrogen protection, slowly dropwise add 3% propyne n-heptane solution (2.3 mL, 1.2 mmol) under ice bath, and naturally warm to room temperature After stirring for 3 hours, diatom extraction and filtration, concentration, column chromatography (petroleum ether/ethyl acetate (v/v)=8/1) to obtain 150 mg of pale yellow solid, yield: 89.45%.

MS(ESI, pos.ion) m/z: 212.1, 214.1[M+1] ⁺ .

Step 2: Synthesis of compound 2-bromo-6-methyl-5H-pyrazolo[2,3-b]pyrazine

To a solution of potassium tert-butoxide (118 mg, 1.05 mmol) in tetrahydrofuran (8 mL) was added 5-bromo-3-(propyn-1-yl)pyrazin-2-amine (150 mg, 0.70 mmol) in tetrahydrofuran (5 mL), refluxed for 1 hour, filtered through celite, removed the solvent, and the residue was subjected to column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain 124 mg of pale yellow solid Product, yield: 82.67%.

MS(ESI, pos.ion) m/z: 212.1, 214.1[M+1] ⁺ ;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 12.19 (s, 1H), 8.21 (s, 1H), 6.35 (s, 1H), 2.49 (s, 3H).

Step 3: Synthesis of compound 2,7-dibromo-6-methyl-5H-pyrrolo[2,3-b]pyrazine

To a solution of 2-bromo-6-methyl-5H-pyrazolo[2,3-b]pyrazine (500 mg, 2.35 mmol) in N,N-dimethylformamide (12 mL) at room temperature was added N-bromosuccinimide (630 mg, 3.54 mmol), stirred at room temperature for 5 hours, diluted with water (20 mL), extracted with dichloromethane (25 mL×3), dried over anhydrous sodium sulfate, concentrated by column chromatography (petroleum ether/ethyl acetate) Ester (v/v)=2/1) to give 450 mg of pale yellow solid, yield: 65.95%.

MS(ESI, pos.ion) m/z: 292.0[M+1] ⁺ .

Step 4: Compound 2,7-Dibromo-6-methyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine Synthesis

To a solution of 2,7-dibromo-6-methyl-5H-pyrrolo[2,3-b]pyrazine (450 mg, 1.54 mmol) in tetrahydrofuran (12 mL) was added sodium hydride (92 mg, 2.30 mL) at 0°C mmol), continue to react at this temperature for 1 hour, slowly add SEMCl (410 μL, 2.32 mmol) dropwise, continue to stir at room temperature, add water (20 mL) to dilute, extract with dichloromethane (25 mL×3), dry over anhydrous sodium sulfate, and concentrate Column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) gave 360 mg of brown oil, yield: 55.26%.

MS(ESI, pos.ion) m/z: 422.1[M+1] ⁺ .

Intermediate Example 8

7-Bromo-2-(1-methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2, 3-b]pyrazine

To 2,7-dibromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (1.0 g, 2.5 mmol) To the acetonitrile (6 mL) solution was added 1-methylpyrazole-4-boronate (620 mg, 2.98 mmol), sodium carbonate (650 mg, 6.13 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (180 mg, 0.26 mmol) in turn and water (6 mL), heated and stirred at 80°C for 3 hours, diluted with water (40 mL), extracted with dichloromethane (25 mL×3), dried over anhydrous sodium sulfate, concentrated by column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) 1.0 g of a yellow solid was obtained, yield: 99%.

MS(ESI, pos.ion) m/z: 408.10, 410.10 [M+1] ⁺ .

Using the corresponding raw materials, the following intermediates were prepared according to the synthetic method of Intermediate Example 8:

Intermediate Example 12

N-(2-(Methylsulfonyl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)amine

Step 1: Synthesis of compound 4-iodo-N-(2-(methylsulfonyl)ethyl)amine

Under nitrogen protection, DMSO (15 mL) was added to p-diiodobenzene (408 mg, 1.24 mmol), 2-(methylsulfonyl)ethylamine hydrochloride (220 mg, 1.38 mmol), cuprous iodide (250 mg, 1.31 mmol) ), cesium carbonate (1.20g, 3.70mmol) and dimethylglycine (208mg, 1.21mmol), react at 80°C for 22h, the reaction solution was cooled to room temperature, extracted with ethyl acetate (50mL×3), and the organic phase was spin-dried , and separated by column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain 78 mg of white solid, yield: 19.4%.

MS(ESI, pos.ion) m/z: 326.1[M+1] ⁺ .

Step 2: Compound N-(2-(methylsulfonyl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)amine Synthesis

Under nitrogen, DMSO (12 mL) was added to 4-iodo-N-(2-(methylsulfonyl)ethyl)amine (78 mg, 0.24 mmol), pinacol biboronate (75 mg, 0.30 mmol), acetic acid Potassium (75mg, 0.76mmol), Pd(dppf)Cl ₂ (9mg, 0.01mmol) mixture, react at 105°C for 17h, the reaction solution was cooled to room temperature, extracted with ethyl acetate (50mL×3), the organic phase was concentrated, column chromatography Separation (petroleum ether/ethyl acetate (v/v)=1/2) gave 58 mg of colorless oil, yield: 74.4%.

MS(ESI, pos.ion) m/z: 326.3[M+1] ⁺ .

Using the corresponding raw materials, the following intermediates were prepared according to the synthetic method of Intermediate Example 12:

Intermediate Example 32

4,4,5,5-Tetramethyl-2-(1,4-dioxospiro[4.5]decane-7-en-8-yl)-1,3,2-dioxaboropentane

Step 1: Synthesis of Compound 1,4-dioxospiro[4.5]decane-7-ene-8-trifluoromethanesulfonate

To a solution of 1,4-dioxospiro[4.5]decane-8-one (2.0 g, 13 mmol) in tetrahydrofuran (15 mL) at -78 °C was added potassium hexamethyldisilazide (1 M, 26 mL, 26 mmol) in tetrahydrofuran (26 mL), continue to stir at this temperature, add N,N-bis(trifluoromethanesulfonyl)aniline (5.46 g, 15.3 mmol) in tetrahydrofuran (15 mL), naturally warm to room temperature and stir overnight , quenched with water (30 mL), extracted with dichloromethane (30 mL×3), dried over anhydrous sodium sulfate, concentrated by column chromatography (petroleum ether/ethyl acetate (v/v)=5/1) to obtain 4.5 g of pale yellow oil , Yield: 80.23%.

MS(ESI, pos.ion) m/z: 289.0[M+1] ⁺ .

Step 2: Compound 4,4,5,5-Tetramethyl-2-(1,4-dioxospiro[4.5]decane-7-en-8-yl)-1,3,2-dioxoboron Synthesis of Pentane

Potassium acetate ( 260mg _; Ether/ethyl acetate (v/v)=2/1) to give 540 mg of yellow oil, yield: 99%.

MS(ESI, pos.ion) m/z: 267.30[M+1] ⁺ .

Using the corresponding raw materials, the following intermediates were prepared according to the synthetic method of Intermediate Example 32:

Intermediate Example 34

(R)-2-Methyl-2-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)phenyl)amino)- N-(2,2,2-Trifluoroethyl)butanamide

Step 1: Synthesis of compound (R)-2-((3-bromophenyl)amino)-2-methylbutanoic acid

To a solution of m-bromoiodobenzene (500 mg, 1.76 mmol) in DMF (5 mL) were added cuprous iodide (340 mg, 1.78 mmol), cesium carbonate (870 mg, 2.67 mmol), (R)-2-amino-2- Methylbutyric acid (550mg, 4.55mmol), heated at 80°C for 8 hours, directly concentrated and mixed with sample, column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) gave 130mg of brown solid, yield : 27.02%.

MS(ESI, pos.ion) m/z: 271.9, 273.9[M+1] ⁺ .

Step 2: Synthesis of compound (R)-2-((3-bromophenyl)amino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide

To a solution of (R)-2-((3-bromophenyl)amino)-2-methylbutanoic acid (70 mg, 0.25 mmol) in DMF (5 mL) was sequentially added N-methylmorpholine (80 mg, 0.79 mmol) ), 2,2,2-trifluoroethylamine hydrochloride (60mg, 0.44mmol) and HATU (146mg, 0.38mmol), stirred at room temperature for 2 hours, diluted with water (30mL), extracted with dichloromethane (30mLx3), no It was dried over sodium sulfate and concentrated by column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain 70 mg of a yellow solid, yield: 77.05%.

MS(ESI, pos.ion) m/z: 353.2, 355.1[M+1] ⁺ .

Step 3: Compound (R)-2-methyl-2-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)phenyl) )amino)-N-(2,2,2-trifluoroethyl)butanamide

Dimethylidene to (R)-2-((3-bromophenyl)amino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide (350 mg, 0.99 mmol) To the sulfone (8 mL) solution was sequentially added potassium acetate (250 mg, 2.54 mmol), biboronic acid pinacol ester (380 mg, 1.49 mmol) and Pd(dppf)Cl ₂ (70 mg, 0.09 mmol), heated at 110 ° C under nitrogen atmosphere The reaction was carried out for 8 hours, diluted with water (30 mL), extracted with dichloromethane (30 mL x 3), dried over anhydrous sodium sulfate, and concentrated by column chromatography (petroleum ether/ethyl acetate (v/v)=8/1) to obtain 350 mg of light Yellow oil, yield: 60.52%.

MS(ESI, pos.ion) m/z: 401.0[M+1] ⁺ .

The intermediate shown below was prepared according to the synthetic method of Intermediate Example 34 using the corresponding raw materials:

Intermediate Example 37

1-(2-cyanoethyl)-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)phenyl)pyrrolidine- 3-Carboxamide

Step 1: Synthesis of compound 1-tert-butylcarboxylate-pyrrolidine-3-carboxylic acid

A solution of sodium hydroxide (0.80 g, 20.00 mmol) in water (15 mL) was added to a solution of methyl 1-carboxylate-pyrrolidine-3-carboxylate (2.30 g, 10.00 mmol) in methanol (30 mL), the reaction solution The reaction was carried out at room temperature for 3 hours, concentrated under reduced pressure to remove methanol, adjusted to pH=4 with 2M glacial acetic acid, extracted with dichloromethane (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain an oily product 1.80 g, Yield: 83.00%.

MS (ESI, pos.ion) m/z: 160.1 [M-55] ⁺ .

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

3-Bromoaniline (1.40 g, 8.40 mmol, 0.91 mL) was added to tert-butyl 1-carboxylate-pyrrolidine-3-carboxylic acid (1.80 g, 8.40 mmol), HATU (6.40 g, 17.00 mmol) and N, In a solution of N-diisopropylethylamine (3.30 g, 25.00 mmol, 4.40 mL) in dichloromethane (20 mL), the reaction was carried out at room temperature for 4 h. The reaction was quenched with water (50 mL), extracted with dichloromethane (50 mL×3), the organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate) (v/v)=2/1) to give 2.40 g of a brownish yellow oil, yield: 78.0%.

MS(ESI, pos.ion) m/z: 312.9[M-55] ⁺ .

Step 3: Compound 3-((3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)phenyl)carbamoyl)pyrrole Synthesis of tert-butyl alkane-1-carboxylate

Under nitrogen protection, tert-butyl 3-((3-bromophenyl)carbamoyl)pyrrolidine-1-carboxylate (2.40 g, 6.50 mmol), pinacol biboronate (9.80 mg, 2.50 mmol) was added , dimethyl sulfoxide (20 mL) was injected into the mixture of potassium acetate (1.30 mg, 13.00 mmol), and Pd(dppf)Cl ₂ (240 mg, 0.32 mmol), and the reaction solution was reacted at 100° C. for 12 h. Cooled to room temperature, the reaction solution was separated with water (150 mL) and ethyl acetate (150 mL), the aqueous phase was extracted with ethyl acetate (150 mL×3), the organic layer was washed with saturated brine (100 mL×2), dried over anhydrous sodium sulfate, It was concentrated under reduced pressure, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=2/1) to obtain 1.20 g of pale yellow oil, yield: 44.0%.

MS(ESI, pos.ion) m/z: 361.3[M+1] ⁺ .

Step 4: Compound N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)phenyl)pyrrolidine-3-carboxamide hydrochloride salt synthesis

A solution of hydrogen chloride in ethyl acetate (2M, 14.00 mmol, 7.00 mL) was added to 3-((3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxo) at room temperature Borpentan-2-yl)phenyl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.20g, 2.90mmol) in ethyl acetate (15mL) solution, react for 2h. Concentrate under reduced pressure to obtain 1.20g Oil, yield: 120.0%.

MS(ESI, pos.ion) m/z: 317.1[M+1] ⁺ .

Step 5: Compound 1-(2-cyanoethyl)-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)phenyl ) Synthesis of pyrrolidine-3-carboxamide

3-Bromopropionitrile (1.00 g, 7.00 mmol) was added to N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentane-2-) at room temperature yl)phenyl)pyrrolidine-3-carboxamide hydrochloride (1.20 g, 3.4 mmol) and cesium carbonate (5.50 g, 17.00 mmol) in acetonitrile (25 mL) solvent, the reaction was refluxed at 90 °C for 4 h. The filter cake was filtered through celite, washed with ethyl acetate, concentrated under reduced pressure, and the concentrated solution was subjected to column separation (dichloromethane/methanol (v/v)=15/1) to obtain 550 mg of pale yellow oil, yield: 44.0% .

MS(ESI, pos.ion) m/z: 370.0[M+1] ⁺ .

Intermediate Example 38

(R)-2-Methyl-2-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)phenyl)amino)- N-(2,2,2-Trifluoroethyl)butanamide

Step 1: Synthesis of compound (R)-2-((tert-butoxycarbonyl)amino)-2-methylbutanoic acid

Under nitrogen protection, (R)-2-amino-2-methylbutanoic acid (2.05 g, 17.50 mmol), triethylamine (7.01 mL, 50.20 mmol), di-tert-butyl dicarboxylate (5.70 g, 26.00 mmol) were added together, then tetrahydrofuran (20 mL) was added, the temperature was raised to 70 °C and reacted for 3 h, the reaction solution was cooled to room temperature, extracted with ethyl acetate (50 mL×3), dried with anhydrous Na ₂ SO ₄ , removed the solvent, and carried out a column Separation (dichloromethane/methanol (v/v)=10/1) gave 3.60 g of colorless oil, yield: 97.0%.

MS(ESI, pos.ion) m/z: 118.2[M-99] ⁺ .

Step 2: Synthesis of compound (R)-(2-methyl-1-oxo-1-((2,2,2-trifluoroethyl)amino)butyl-2-yl)carbamate

Under nitrogen protection, 2,2,2-trifluoroethylamine hydrochloride (2.85 g, 21.01 mmol), (R)-2-((tert-butoxycarbonyl)amino)-2-methylbutanoic acid ( 3.71g, 17.01mmol), HATU (8.81g, 23.02mmol), N-methylmorpholine (5.21g, 51.01mmol) were added together, then DMF (30mL) was added, stirred at room temperature for 5h, ethyl acetate (100mL× 3) Extraction, drying with anhydrous Na ₂ SO ₄ , removing the solvent, and performing column separation (petroleum ether/ethyl acetate (v/v)=2/1) to obtain 3.57 g of white solid, yield: 70.1%.

MS(ESI, pos.ion) m/z: 199.1[M-99] ⁺ .

Step 3: Synthesis of compound (R)-2-((3-bromophenyl)amino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide

At room temperature, (R)-(2-methyl-1-oxo-1-((2,2,2-trifluoroethyl)amino)butyl-2-yl)carbamate (3.57g, 12.01 g mmol) was dissolved in an ethyl acetate solution of hydrogen chloride (15 mL), stirred at room temperature for 5 h, and the reaction solution was concentrated under reduced pressure. Under nitrogen protection, cuprous iodide (1.60g, 8.40mmol), cesium carbonate (11.80g, 36.20mmol), L-proline (970mg, 8.43mmol), m-bromoiodobenzene (3.73g, 13.20mmol) were added , DMF (40 mL), heated to 70 °C, stirred for 17 h, extracted with ethyl acetate (100 mL×3), dried with anhydrous Na ₂ SO ₄ , removed the solvent, and carried out column separation (petroleum ether/ethyl acetate (v/v) =2/1) 3.61 g of dark yellow oil were obtained, yield: 84.9%.

MS(ESI, pos.ion) m/z: 355.2[M+1] ⁺ .

Step 4: Compound (R)-2-methyl-2-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)phenyl) )amino)-N-(2,2,2-trifluoroethyl)butyramide

Under nitrogen protection, (R)-2-((3-bromophenyl)amino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide (3.59 g, 10.21 mmol) , pinacol biboronate (3.08 g, 12.11 mmol), potassium acetate (3.21 g, 33.02 mmol) and Pd(dppf)Cl ₂ (450 mg, 0.60 mmol) were added together, followed by DMSO (45.00 mL), 115 The reaction was carried out at ℃ for 17 h, the reaction solution was cooled to room temperature, extracted with ethyl acetate (100 mL×3), the organic phase was spin-dried, and separated by column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain 2.86 g Black oil, yield: 70.2%.

MS(ESI, pos.ion) m/z: 401.4[M+1] ⁺ .

The intermediate shown below was prepared according to the synthetic method of Intermediate Example 38 using the corresponding raw materials:

Intermediate Example 40

1-(2-Fluorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)-1H-pyrazole

Under nitrogen, DMF (12 mL) was added to o-fluorobenzyl bromide (706 mg, 3.71 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentane-2 -yl)-1H-pyrazole (480mg, 2.47mmol), cesium carbonate (2.10g, 6.19mmol) and potassium iodide (150mg, 1.24mmol) mixture, react at room temperature for 12h, extract with ethyl acetate (50mLx3), spin dry The organic phase was separated by column chromatography (petroleum ether/ethyl acetate (v/v)=10/1) to obtain 400 mg of colorless oil, yield: 53.5%.

MS(ESI, pos.ion) m/z: 303.3[M+1] ⁺ .

Using the corresponding raw materials, the following intermediates were prepared according to the synthetic method of Intermediate Example 40:

Intermediate Example 46

2-(1-(acetonitrilesulfonyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)-1H-pyrazole -1-yl)azetidin-3-yl)acetonitrile

Step 1: Compound 3-(cyanoethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)-1H- Synthesis of Pyrazol-1-yl)azetidine-1-carboxylate tert-butyl ester

To a solution of 1H-pyrazoleborate (200 mg, 1.03 mmol), tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (220 mg, 1.13 mmol) in acetonitrile (8 mL) was added DBU (80 μL, 0.53 mmol), heated at 50° C. for 4 hours, concentrated directly, column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) gave 340 mg of pale yellow oil, yield: 84.93%.

MS (ESI, pos.ion) m/z: 333.3[M-55] ⁺ .

Step 2: Compound 2-(1-(acetonitrilesulfonyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)- Synthesis of 1H-pyrazol-1-yl)azetidine-3-yl)acetonitrile

To 3-(cyanoethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)-1H-pyrazole- To a solution of tert-butyl 1-yl)azetidine-1-carboxylate (330 mg, 0.85 mmol) in dichloromethane (8 mL) was added trifluoroacetic acid (0.7 mL, 9 mmol), stirred at room temperature for 2 hours, concentrated the solvent, Add dichloromethane (8 mL) to dissolve, add Et ₃ N (400 μL, 2.8 mmol), ethylsulfonyl chloride (0.15 mL, 1.6 mmol) under ice bath, stir at room temperature for 2 hours, add water (30 mL) to quench, dichloromethane Extraction (30 mL x 3), drying over anhydrous sodium sulfate, and concentration column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) gave 120 mg of pale yellow oil, yield: 37.13%.

MS(ESI, pos.ion) m/z: 381.2[M+1] ⁺ .

Intermediate Example 47

tert-Butyl 1-carboxylate-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)-1H-pyrrol-1-yl )) Piperidine

Step 1: Synthesis of compound 1-tert-butyl formate-4-methanesulfonyloxypiperidine

Under ice bath, methanesulfonyl chloride (2.44g, 21.3mmol, 1.65mL) was slowly added dropwise to N-tert-butyl formate-4-hydroxypiperidine (3.10g, 15.00mmol) and triethylamine (3.00g, 30mmol, 4.00mL) in dichloromethane solution (40mL), after the dropwise addition, the reaction was carried out at room temperature for 1.5h. To the reaction solution was added hydrochloric acid (1 M, 40 mL) to quench the reaction, the organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 4.30 g of an off-white solid, yield: 100.0%.

MS(ESI, pos.ion) m/z: 224.2[M-55] ⁺ ;

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 4.90 (m, 1H), 3.72 (m, 2H), 3.31 (m, 2H), 3.05 (s, 3H), 1.97 (m, 2H), 1.84 (m, 2H), 1.47 (s, 9H).

Step 2: Compound 1-tert-butylcarboxylate-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)-1H-pyrrole Synthesis of -1-yl))piperidine

tert-Butyl 1-carboxylate-4-methanesulfonyloxypiperidine (2.00 g, 7.16 mmol) was added to 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron) Pentan-2-yl)-1H-pyrazole (1.50g, 7.70mmol) and cesium carbonate (3.50g, 11.00mmol) in N,N-dimethylformamide (15mL) solution, reaction solution 100 ℃ The reaction was carried out for 24 h, cooled to room temperature, extracted with water (100 mL) and ethyl acetate (100 mL), the aqueous phase was extracted with ethyl acetate (100 mL x 3), the organic phases were combined and washed with saturated brine (100 mL x 3), anhydrous It was dried over sodium sulfate, concentrated under reduced pressure, and the concentrated solution was mixed and passed through a column (petroleum ether/ethyl acetate (v/v)=2/1) to obtain 950 mg of a colorless solid, yield: 35.2%.

MS(ESI, pos.ion) m/z: 378.4[M+1] ⁺ ;

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.81 (s, 1H), 7.74 (s, 1H), 4.28 (m, 3H), 2.90 (m, 2H), 2.14 (m, 2H), 1.92 (m, 2H), 1.49 (s, 9H), 1.33 (s, 12H).

Using the corresponding raw materials, the following intermediates were prepared according to the synthetic method of Intermediate Example 47:

Intermediate Example 49

6-Fluoro-1-methyl-3-(tri-n-butyltinyl)-1H-indazole

Step 1: Synthesis of compound 6-fluoro-3-iodo-1H-indazole

To a solution of 6-fluoro-1H-indazole (97 mg, 0.71 mmol) in DMF (5 mL) at room temperature, potassium hydroxide (130 mg, 2.32 mmol) and iodine (280 mg, 1.10 mmol) were sequentially added, and the mixture was stirred at room temperature for 11 h. , quenched with saturated sodium thiosulfate solution (10 mL), extracted with ethyl acetate (15 mL×3), dried over anhydrous sodium sulfate, concentrated by column chromatography (petroleum ether/ethyl acetate (v/v)=6/1) to obtain 150 mg of brown solid, yield: 80.34%.

MS(ESI, pos.ion) m/z: 263.0[M+1] ⁺ .

Step 2: Synthesis of compound 6-fluoro-3-iodo-1-methyl-1H-indazole

To a solution of 6-fluoro-3-iodo-1H-indazole (97 mg, 0.37 mmol) in DMSO (5 mL) at room temperature, cesium carbonate (60 mg, 0.18 mmol) and methyl iodide (70 μL, 0.76 mmol) were sequentially added, Stir at room temperature for 1.5 hours, add water (10 mL) to quench, extract with ethyl acetate (15 mL×3), dry over anhydrous sodium sulfate, and concentrate by column chromatography (petroleum ether/ethyl acetate (v/v)=6/1) to obtain 100 mg of yellow Solid, yield: 99%.

MS(ESI, pos.ion) m/z: 277.0[M+1] ⁺ .

Step 3: Synthesis of compound 6-fluoro-1-methyl-3-(tri-n-butyltinyl)-1H-indazole

To a solution of 6-fluoro-3-iodo-1-methyl-1H-indazole (4.1 g, 15 mmol) in tetrahydrofuran (30 mL) at -16 °C, was sequentially added isopropylmagnesium chloride (2M, 9 mL, 18 mmol) , after stirring at this temperature for 20 minutes, after adding tri-n-butyltin chloride (4.8mL, 18mmol), naturally rising to room temperature and continuing to stir for 5 hours, adding saturated ammonium chloride solution (30mL) to quench, ethyl acetate Extraction (15 mL×3), drying over anhydrous sodium sulfate, and concentration column chromatography (petroleum ether/ethyl acetate (v/v)=8/1) gave 6.1 g of pale yellow oil, yield: 94%.

MS(ESI, pos.ion) m/z: 440.2[M+1] ⁺ .

Intermediate Example 50

N-(3-(2-Bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)benzene yl)-2-cyanoacetamide

To 2-bromo-7-iodo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (30 mg, 0.07 mmol), Acetonitrile (4 mL) and water ( 1 mL), heated at 65°C for 4.5 hours under nitrogen atmosphere. Saturated ammonium chloride solution (10 mL) was added to quench, extracted with ethyl acetate (15 mL×3), dried over anhydrous sodium sulfate, and concentrated by column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain 29 mg of yellow Solid, yield: 90%.

MS(ESI, pos.ion) m/z: 487.4[M+1] ⁺ .

Using the corresponding raw materials, the following intermediates were prepared according to the synthetic method of Intermediate Example 50:

Intermediate Example 65

(R)-2-((2-(2-Chloro-5-trityl-5H-pyrrolo[2,3-b]pyrazin-7-yl)pyrimidin-4-yl)amino)-2 -Methyl-N-(2,2,2-trifluoroethyl)butanamide

Step 1: Synthesis of compound (R)-2-((2-chloropyrimidin-4-yl)amino)-2-methylbutanoic acid

To the isopropanol (8 mL) solution of 2,4-dichloropyrimidine (600 mg, 4.02 mmol) was added R-isovaline (550 mg, 4.55 mmol), potassium carbonate (850 mg, 6.15 mmol) successively, and refluxed at 90°C After the reaction was carried out for 5.5 hours, silica gel was directly added to mix the sample, and column chromatography (petroleum ether/ethyl acetate (v/v)=0/1) was used to obtain 600 mg of white solid, yield: 93%.

MS(ESI, pos.ion) m/z: 230.0[M+1] ⁺ .

Step 2: Synthesis of compound (R)-2-((2-chloropyrimidin-4-yl)amino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide

0 °C, to (R)-2-((2-chloropyrimidin-4-yl)amino)-2-methylbutanoic acid (50 mg, 0.21 mmol), 2,2,2-trifluoroethylamine hydrochloride (44 mg, 0.32 mmol) and diisopropylethylamine (120 μL, 0.68 mmol) in N,N-dimethylformamide (4 mL) was added a 50% solution of propylphosphoric anhydride in ethyl acetate (510 mg, 0.80 mmol), stirred at room temperature for 12 hours, diluted with water (15 mL), extracted with dichloromethane (20 mL×3), dried over anhydrous sodium sulfate, concentrated by column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain 30 mg of pale yellow solid, yield: 44.35%.

MS(ESI, pos.ion) m/z: 311.1[M+1] ⁺ .

Step 3: Compound 2-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)-5-triphenylmethyl-5H- Synthesis of pyrrolo[2,3-b]pyrazine

-20 °C, to 2-chloro-7-iodo-5-trityl-5H-pyrrolo[2,3-b]pyrazine (380 mg, 0.73 mmol), isopropanol pinacol borate ( 200 μL, 0.98 mmol) in tetrahydrofuran (8 mL) was slowly added isopropylmagnesium chloride in tetrahydrofuran (2.0 M, 850 μL, 1.1 mmol), the reaction was continued at this temperature for 1.5 hours, and ethyl acetate (20 mL) was added to dilute, Saturated ammonium chloride solution (20 mL) was added to quench, extracted with ethyl acetate (25 mL×3), dried over anhydrous sodium sulfate, and concentrated by column chromatography (petroleum ether/ethyl acetate (v/v)=10/1) to obtain 320 mg of light Yellow solid, yield: 84.21%.

MS(ESI, pos.ion) m/z: 521.8[M+1] ⁺ .

Step 4: Compound (R)-2-((2-(2-Chloro-5-trityl-5H-pyrrolo[2,3-b]pyrazin-7-yl)pyrimidin-4-yl) Synthesis of Amino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide

To 2-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)-5-triphenylmethyl-5H-pyrrolo[ To a solution of 2,3-b]pyrazine (30 mg, 0.057 mmol) in 1,4-dioxane (4 mL) was added (R)-2-((2-chloropyrimidin-4-yl)amino)- 2-methyl-N-(2,2,2-trifluoroethyl)butanamide (17 mg, 0.05 mmol), potassium carbonate (12 mg, 0.08 mmol), Pd(dppf)Cl ₂ (5 mg, 0.01 mmol) and Water (1 mL), under nitrogen atmosphere, refluxed at 110°C for 4.5 hours, quenched by adding saturated ammonium chloride solution (20 mL), extracted with dichloromethane (25 mL×3), dried over anhydrous sodium sulfate, concentrated by column chromatography (petroleum ether/ Ethyl acetate (v/v)=2/1) gave 220 mg of pale yellow oil, yield: 46.72%.

MS(ESI, pos.ion) m/z: 669.7[M+1] ⁺ .

Using the corresponding raw materials, the following intermediates were prepared according to the synthetic method of Intermediate Example 65:

Intermediate Example 67

N-Isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)-1-((2-(trimethylsilyl )ethoxy)methyl)-1H-pyrazolo[2,3-b]pyridine-3-carboxamide

Step 1: Synthesis of compound 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid

Dissolve 5-bromo-7-azaindole (10.00 g, 50.75 mmol) in dichloromethane (200 mL), add aluminum trichloride (34.00 g, 254.99 mmol), stir at room temperature for 10 minutes, add trichloroethyl Acyl chloride (8.6 mL, 77 mmol), continued stirring at room temperature overnight, poured the reaction solution into ice water, stirred well, filtered to obtain a white solid, the filtrate was extracted with ethyl acetate (200 mL x 3), concentrated and combined the filtered white solid, added tetrahydrofuran (250 mL) and water (125 mL) were dissolved, triethylamine (50 mL) was added, stirred at room temperature for 24 h, the solvent was concentrated and evaporated to dryness, the pH was adjusted to 5-6 with 1.0 M dilute hydrochloric acid, filtered, and dried under vacuum at 50 °C to obtain the product as 8.20 g off-white solid, yield: 67.0%.

MS(ESI, pos.ion) m/z: 241.2[M+1] ⁺ .

Step 2: Synthesis of compound 5-bromo-N-isopropyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

To a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (600 mg, 2.49 mmol) in N,N-dimethylformamide (20 mL) was sequentially added 1-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.44 g, 7.43 mmol), 1-hydroxybenzotriazole (1.01 g, 7.46 mmol) and 2-isopropylamine (1.27 mL, 14.90 mmol) and stirred at room temperature overnight. Saturated brine (20 mL) was added, extracted with dichloromethane (15 mL×3), dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v)= 5/1) The product was obtained as 360 mg of brown solid, yield: 51.3%.

MS(ESI, pos.ion) m/z: 282.0[M+1] ⁺ .

Step 3: Compound 5-Bromo-N-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3- Synthesis of formamide

5-Bromo-N-isopropyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (360 mg, 1.28 mmol) was dissolved in N,N-dimethylformamide (20 mL), Under ice bath, 60% sodium hydride (102.1 mg, 2.55 mmol) was added, stirred at room temperature for 0.5 h, then 2-(trimethylsilyl)ethoxymethyl chloride (338.7 μL, 1.82 mmol) was added, and stirring was continued at room temperature overnight , added saturated brine (20 mL), extracted with dichloromethane (15 mL x 3), dried with anhydrous sodium sulfate, removed the solvent, and the concentrated solution was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v )=6/1) The product was obtained as 500 mg of brown solid, yield: 99.0%.

MS(ESI, pos.ion) m/z: 412.1[M+1] ⁺ .

Step 4: Compound N-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)-1-((2-(tri Synthesis of methylsilyl)ethoxy)methyl)-1H-pyrazolo[2,3-b]pyridine-3-carboxamide

5-Bromo-N-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide ( 600mg, 1.45mmol) was dissolved in 1,4-dioxane (10mL), followed by adding pinacol biboronate (443.7mg, 1.74mmol), potassium carbonate (357.3mg, 3.64mmol) and Pd (dppf) Cl ₂ (106.4 mg, 0.14 mmol), under nitrogen protection, refluxed at 115°C for 4 hours, cooled to room temperature, filtered through celite, concentrated filtrate, and the concentrated solution was subjected to column chromatography (eluent: petroleum ether/ethyl acetate ( v/v)=2/1) The product was obtained as 610 mg of yellow solid, yield: 91.25%.

MS(ESI, pos.ion) m/z: 460.30[M+1] ⁺ .

Example 1

3-((3-(2-(1-Methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)phenyl)amino)propionitrile

Step 1: Compound 3-((3-(2-(1-Methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)- Synthesis of 5H-pyrrolo[2,3-b]pyrazin-7-yl)phenyl)amino)propionitrile

To 7-bromo-2-(1-methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2 ,3-b]pyrazine (30mg, 0.07mmol) in 1,4-dioxane (4mL) solution was added 3-((3-(4,4,5,5-tetramethyl-1, 3,2-Dioxaboropentan-2-yl)phenyl)amino)propionitrile (24 mg, 0.08 mmol), potassium carbonate (16 mg, 0.12 mmol), Pd(dppf)Cl ₂ (10 mg, 0.01 mmol) and Water (1 mL), heated at 110°C for 7 hours under nitrogen atmosphere, diluted with water (10 mL), extracted with dichloromethane (15 mL×3), dried over anhydrous sodium sulfate, concentrated by column chromatography (petroleum ether/ethyl acetate (v/ v)=2/1) 26 mg of brown oil, yield: 74.74%.

MS(ESI, pos.ion) m/z: 474.3[M+1] ⁺ .

Step 2: Compound 3-((3-(2-(1-Methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)phenyl) Synthesis of Amino)Propionitrile

To 3-((3-(2-(1-methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrole To [2,3-b]pyrazin-7-yl)phenyl)amino)propionitrile (260 mg, 0.55 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (2.5 mL), and stirred at room temperature for 2 h , concentrated the solvent, added tetrahydrofuran (6 mL) to dissolve, added dropwise sodium hydroxide solution (2N) to pH>7, stirred at room temperature for 2 h, added water (20 mL) to dilute, extracted with dichloromethane (15 mL×3), dried over anhydrous sodium sulfate, concentrated Column chromatography (petroleum ether/ethyl acetate (v/v)=0/1) gave 50 mg of a yellow solid, yield: 31.83%.

MS(ESI, pos.ion) m/z: 344.2[M+1] ⁺ ;

¹ H NMR (600MHz, DMSO-d ₆ )δ(ppm) 12.10(s,1H), 8.62(m,1H), 8.37(s,1H), 8.26(s,1H), 8.15(s,1H), 7.67(m, 1H), 7.46(d, J=7.7Hz, 1H), 7.15(m, 1H), 6.52(dd, J=8.0, 1.7Hz, 1H), 5.95(t, J=6.2Hz, 1H) ), 3.94(s, 3H), 3.46(dd, J=12.9, 6.5Hz, 2H), 2.80(t, J=6.6Hz, 2H);

¹³ C NMR (150MHz, DMSO-d ₆ )δ(ppm) 148.3, 141.8, 140.9, 137.3, 136.3, 135.0, 134.4, 129.6, 129.3, 128.3, 121.8, 120.2, 114.8, 113.8, 110.7, 110.2, 40.5, 39 , 17.9.

Using the corresponding raw materials, the following compounds were prepared according to the synthetic method of Example 1:

Example 2

3-((3-(2-Cyclopropyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)phenyl)amino)propanamide

Step 1: Compound 3-((3-(2-Cyclopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyridine Synthesis of oxazin-7-yl)phenyl)amino)propionitrile

Under nitrogen, toluene (10 mL) and water (1.2 mL) were added to 7-bromo-2-cyclopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H- Pyrrolo[2,3-b]pyrazine (200mg, 0.42mmol), cyclopropylboronic acid (72mg, 0.85mmol), potassium phosphate heptahydrate (440mg, 1.36mmol), palladium acetate (6mg, 0.02mmol), tris Cyclohexylphosphorus (15mg, 0.04mmol) mixture was refluxed at 110°C for 19h, the reaction solution was cooled to room temperature, filtered through celite, the filtrate was concentrated under reduced pressure, and subjected to column separation (petroleum ether/ethyl acetate (v/v)= 4/1) 160 mg of light red solid were obtained, yield: 87.2%.

MS(ESI, pos.ion) m/z: 434.3[M ⁺ 1] ⁺ .

Step 2: Synthesis of compound 3-((3-(2-cyclopropyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)phenyl)amino)propionamide

3-((3-(2-Cyclopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine at room temperature -7-yl)phenyl)amino)propionitrile (158 mg, 0.36 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (6 mL) was added, and the reaction was stirred at room temperature for 12 h. The reaction solution was concentrated under reduced pressure, dichloromethane (6 mL) and ethylenediamine (1 mL) were added, stirred at room temperature for 2 h, silica gel was added to the reaction solution, the sample was directly spin-dried, and the sample was separated by column chromatography (dichloromethane/methanol (v/ v)=50/1) 86 mg of pale yellow solid were obtained, yield: 77.8%.

MS(ESI, pos.ion) m/z: 304.1[M+1] ⁺ ;

¹ H NMR (600MHz, DMSO-d ₆ ): δ(ppm) 11.99(s, 1H), 8.26(s, 1H), 8.21(s, 1H), 7.54(s, 1H), 7.36(d, J= 7.6Hz,1H),7.13(t,J=7.8Hz,1H),6.50(dd,J1 ₌ 8.0Hz,J2=1.9Hz,1H ₎ ,5.89(t,J=6.2Hz,1H),3.43 (q, J=6.6Hz, 2H), 2.79 (t, J=6.6Hz, 2H), 2.32–2.28 (m, 1H), 1.05–1.02 (m, 4H);

¹³ C NMR (150 MHz, DMSO-d ₆ ): δ (ppm) 151.1, 148.2, 141.3, 136.3, 136.0, 135.2, 129.5, 127.9, 120.1, 114.7, 113.5, 111.3, 109.5, 39.6, 18.0, 14.8, 10.3.

Using the corresponding raw materials, the following compounds were prepared according to the synthetic method of Example 2:

Example 3

3-((3-(2-(6-Fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)phenyl) amino)propionitrile

Step 1: Compound 3-((3-(2-(6-Fluoro-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy) Synthesis of methyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)phenyl)amino)propionitrile

Under nitrogen protection, 3-((3-(2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine -7-yl)phenyl)amino)propionitrile (200 mg, 0.42 mmol), 6-fluoro-1-methyl-3-(tributylstannane)-1H-indazole (380 mg, 0.85 mmol), iodide Copper (16 mg, 0.08 mmol) and palladium tetrakistriphenylphosphine (26 mg, 0.02 mmol) were added together, then DMF (15 mL) was added, the temperature was raised to 90° C. for 4.5 h, the reaction solution was cooled to room temperature, and ethyl acetate (50 mL) was added. ×3) extraction, drying with anhydrous Na ₂ SO ₄ , removing the solvent, and performing column separation (petroleum ether/ethyl acetate (v/v)=4/1) to obtain 200 mg of pale yellow oil, yield: 84.7%.

MS(ESI, pos.ion) m/z: 542.3[M+1] ⁺ .

Step 2: Compound 3-((3-(2-(6-Fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl Synthesis of )phenyl)amino)propionitrile

3-((3-(2-(6-Fluoro-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)- 5H-pyrrolo[2,3-b]pyrazin-7-yl)phenyl)amino)propionitrile (240 mg, 0.44 mmol) was prepared according to the synthetic method of Example 2, step 2 to obtain 180 mg of a pale yellow solid, yield: 96.2%.

MS(ESI, pos.ion) m/z: 412.2[M+1] ⁺ ;

¹ H NMR (600 MHz, DMSO-d ₆ ): δ (ppm) 12.34 (s, 1H), 9.05 (s, 1H), 8.71 (dd, J ₁ =8.7 Hz, J ₂ =5.5 Hz, 1H), 8.33 (s, 1H), 7.63 (dd, J ₁ =9.6 Hz, J ₂ =1.5 Hz, 1 H), 7.53 (d, J = 7.5 Hz, 1 H), 7.49 (s, 1 H), 7.30–7.19 (m, 2H), 6.60(d, J=7.9Hz, 1H), 5.92(t, J=6.0Hz, 1H), 4.14(s, 3H), 3.46(dd, J1 _{= 12.6Hz} , J2=6.3Hz, 1H), 2.79(t, J=6.5Hz, 2H);

¹³ C NMR (150MHz, DMSO-d ₆ ): δ(ppm) 162.9, 161.3, 148.6, 142.4, 142.1, 142.1, 141.8, 141.4, 135.9, 135.2, 134.8, 129.8, 128.8, 125.1, 125.0, 120.2, 119.0 115.4, 114.8, 111.8, 111.6, 111.4, 110.1, 96.4, 96.2, 39.5, 36.3, 18.0.

Using the corresponding raw materials, the following compounds were prepared according to the synthetic method of Example 3:

Example 16

1-(Cyanomethyl)-3-(4-(2-(1-methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl) phenyl)urea

Step 1: Compound 4-(2-(1-Methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo Synthesis of [2,3-b]pyrazin-7-yl)aniline

4-(4,4,5,5-Tetramethyl-1,3,2-dioxaboropentan-2-yl)aniline (120 mg, 0.55 mmol), 7-bromo-2-(1-methyl) -1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (114 mg, 0.28 mmol ), potassium carbonate (115 mg, 0.82 mmol) and Pd(dppf)Cl ₂ (13 mg, 0.02 mmol) were prepared according to the synthetic method of Example 1, step 1 to obtain 104 mg of a yellow solid, yield: 88.6%.

MS(ESI, pos.ion) m/z: 421.4[M+1] ⁺ .

Step 2: Synthesis of compound 4-(2-(1-methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)aniline

4-(2-(1-Methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3 -b]pyrazin-7-yl)aniline (300mg, 0.71mmol), trifluoroacetic acid (6mL) and ethylenediamine (1mL) were prepared according to the synthetic method of Example 2, step 2 to obtain 146mg of yellow solid, yield: 71.2 %.

MS(ESI, pos.ion) m/z: 291.4[M+1] ⁺ .

Step 3: Compound 1-(cyanomethyl)-3-(4-(2-(1-methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine- Synthesis of 7-yl)phenyl)urea

Toluene (5 mL) was added to 4-(2-(1-methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)aniline (36 mg, 0.12mmol) and triphosgene (33mg, 0.11mmol), then two drops of triethylamine were added, and the reaction was refluxed at 110°C for 5h. The reaction solution was cooled to room temperature, and aminoacetonitrile hydrochloride (28mg, 0.30mmol), triethylamine were added. (100mg, 0.10mmol), stirred at room temperature for 12h, added silica gel to the reaction, directly spin-dried and mixed the sample, and carried out column separation (dichloromethane/methanol (v/v)=15/1) to obtain 35mg of white solid, yield: 75.8% .

MS(ESI,neg.ion)m/z:371.2[M-1] ^- ;

¹ H NMR (600MHz, DMSO-d ₆ ): δ(ppm) 9.32(s,1H), 9.14(s,1H), 8.78(s,1H), 8.67(s,1H), 8.54(s,1H) ,8.28(d,J＝8.6Hz,2H),8.24(s,1H),7.57(d,J＝8.6Hz,2H),6.83(t,J＝5.7Hz,1H),4.17(d,J＝ 5.6Hz, 2H), 3.96(s, 3H);

¹³ C NMR (150MHz, DMSO-d ₆ ): δ(ppm) 155.2, 150.2, 144.5, 139.7, 139.6, 138.6, 137.7, 134.1, 130.4, 127.6, 125.7, 125.5, 120.6, 119.0, 118.7, 118.0, 117.0 39.3, 29.6.

Using the corresponding raw materials, the following compounds were prepared according to the synthetic method of Example 16:

Example 20

3-((4-(2-(1-Methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)cyclohexyl)amino)propionitrile

Step 1: Compound 2-(1-Methyl-1H-pyrazol-4-yl)-7-(1,4-dioxospiro[4.5]decane-7-en-8-yl)-5-( Synthesis of (2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine

7-Bromo-2-(1-methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2, 3-b]pyrazine (30 mg, 0.07 mmol), 4,4,5,5-tetramethyl-2-(1,4-dioxospiro[4.5]decane-7-en-8-yl)- 1,3,2-Dioxaboropentane (40 mg, 0.15 mmol), potassium carbonate (15 mg, 0.10 mmol), Pd(dppf)Cl2 ( ₆ mg, 0.01 mmol) and water (1 mL) according to Example 1, Step 1 The synthesis method of 21 mg of pale yellow oil was obtained, yield: 61.14%.

MS(ESI, pos.ion) m/z: 468.3[M+1] ⁺ .

Step 2: Compound 2-(1-methyl-1H-pyrazol-4-yl)-7-(1,4-dioxospiro[4.5]decan-8-yl)-5-((2-( Synthesis of Trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine

To 2-(1-methyl-1H-pyrazol-4-yl)-7-(1,4-dioxospiro[4.5]decane-7-en-8-yl)-5-((2- To a solution of (trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (320 mg, 0.68 mmol) and methanol (8 mL) was added Pd/C (10%, 156 mg) , 0.14 mmol), stirred at room temperature for 3 hours under a hydrogen atmosphere, filtered and concentrated to obtain 330 mg of crude yellow oily product, which was directly carried out to the next step, yield: 99%.

MS(ESI, pos.ion) m/z: 470.4[M+1] ⁺ .

Step 3: Compound 4-(2-(1-Methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo Synthesis of [2,3-b]pyrazin-7-yl)cyclohexanone

To 2-(1-methyl-1H-pyrazol-4-yl)-7-(1,4-dioxospiro[4.5]decan-8-yl)-5-((2-(trimethyl To a solution of silyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (330 mg, 0.70 mmol) in acetone (10 mL) was added p-toluenesulfonic acid (363 mg, 2.10 mmol), The mixture was stirred at room temperature for 8 hours, and was directly concentrated by column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain 180 mg of a yellow solid, yield: 60.18%.

MS(ESI, pos.ion) m/z: 426.4[M+1] ⁺ .

Step 4: Compound 3-((4-(2-(1-Methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)- Synthesis of 5H-pyrrolo[2,3-b]pyrazin-7-yl)cyclohexyl)amino)propionitrile

To 4-(2-(1-methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo at room temperature To a solution of [2,3-b]pyrazin-7-yl)cyclohexanone (15 mg, 0.03 mmol), 3-aminopropionitrile (30 μL, 0.41 mmol) in tetrahydrofuran (4 mL) was added sodium triacetoxyborohydride (12 mg, 0.05 mmol), stirred at room temperature for 6 hours, quenched by adding water (20 mL), extracted with dichloromethane (20 mL×3), dried over anhydrous sodium sulfate, concentrated by column chromatography (dichloromethane/methanol (v/v)=10 /1) 12 mg of yellow oil was obtained, yield: 70.98%.

MS(ESI, pos.ion) m/z: 480.0[M+1] ⁺ .

Step 5: Compound 3-((4-(2-(1-Methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)cyclohexyl) Synthesis of Amino)Propionitrile

3-((4-(2-(1-Methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo [2,3-b]pyrazin-7-yl)cyclohexyl)amino)propionitrile (130 mg, 0.27 mmol), trifluoroacetic acid (2 mL) and ethylenediamine (1 mL) according to the synthesis method of Example 2, Step 2 16 mg of pale yellow solid were prepared, yield: 16.90%.

MS(ESI, pos.ion) m/z: 350.30[M+1] ⁺ ;

¹ H NMR (600MHz, DMSO-d ₆ )δ(ppm) 11.72(s,1H), 9.27(s,1H), 8.55(s,1H), 8.29(s,1H), 8.03(s,1H), 7.58(d, J＝103.8Hz, 1H), 3.91(s, 3H), 2.94(m, 5H), 2.19(d, J＝7.4Hz, 1H), 1.82(m, 6H), 1.26(d, J =28.4Hz, 2H).

Example 21

3-(methyl(4-(2-(1-methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)phenyl)amino) Propionitrile

Step 1: Compound 3-(methyl(4-(2-(1-methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl) )-5H-pyrrolo[2,3-b]pyrazin-7-yl)phenyl)amino)propionitrile synthesis

At 0°C, sodium hydride (60%, 55 mg, 1.38 mmol) was added portionwise to 3-((4-(2-(1-methyl-1H-pyrazol-4-yl)-5-((2 -(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)phenyl)amino)propionitrile (320 mg, 0.54 mmol) in N, N-dimethylformamide (15 mL) mixture. After stirring at room temperature for 1.5 h, methyl iodide (200 mg, 2.00 mmol) was slowly added dropwise at 0 °C. After the dropwise addition, the reaction was stirred at room temperature for 15 h. The reaction was quenched by adding water (50 mL), extracted with ethyl acetate (50 mL x 3), the organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated to remove the solvent, and the residue was separated by column chromatography (petroleum ether/ Ethyl acetate (v/v)=1/1) gave 180 mg of pale yellow solid, yield: 54.6%.

MS(ESI, pos.ion) m/z: 487.9[M+1] ⁺ .

Step 2: Compound 3-(methyl(4-(2-(1-methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)benzene Synthesis of base)amino)propionitrile

3-(methyl(4-(2-(1-methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H- Pyrrolo[2,3-b]pyrazin-7-yl)phenyl)amino)propionitrile (180 mg, 0.37 mmol), trifluoroacetic acid (2 mL) and ethylenediamine (1 mL) were prepared as in Example 2, Step 2 The synthetic method prepared 40 mg of orange-yellow solid, yield: 30.3%.

MS(ESI, pos.ion) m/z: 376.1[M+1] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm) 11.97 (d, J=2.3 Hz, 1H), 8.61 (s, 1H), 8.36 (s, 1H), 8.16 (m, 2H), 8.13 (s,1H),8.11(s,1H),6.87(d,J=8.9Hz,2H),3.94(s,3H),3.71(t,J=6.7Hz,2H),2.99(s,3H) ,2.75(t,J=6.7Hz,2H);

¹³ C NMR (100MHz, DMSO-d ₆ ): δ(ppm) 146.80, 141.5, 140.9, 137.1, 136.2, 134.2, 129.3, 127.2, 126.4, 123.1, 121.9, 120.1, 113.7, 113.1, 48.4, 38.4, 32.0, 15.2.

Example 22

4-(4-(2-(1-Methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)piperidin-1-yl)butane Nitrile

Step 1: Compound 4-(2-Bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl) Synthesis of -5,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester

2-Bromo-7-iodo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (600 mg, 1.32 mmol), 4-( 4,4,5,5-Tetramethyl-1,3,2-dioxaboropentan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (425 mg, 1.37 mmol), sodium carbonate (356 mg, 3.35 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (100 mg, 0.14 mmol) and water (6 mL) were prepared according to the synthetic method of Example 1, step 1 to obtain 540 mg of pale yellow solid, yield: 80.23%.

MS(ESI, pos.ion) m/z: 509.2,511.2[M+1] ⁺ .

Step 2: Compound 4-(2-(1-Methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo Synthesis of [2,3-b]pyrazin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

4-(2-Bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)-5,6 - tert-butyl dihydropyridine-1(2H)-carboxylate (325mg, 0.63mmol), potassium carbonate (140mg, 1.01mmol), 1-methylpyrazole boronate (172mg, 0.82mmol) and Pd(dppf) Cl ₂ (50 mg, 0.06 mmol) was prepared according to the synthetic method of Example 2, step 1 to obtain 270 mg of a yellow solid, yield: 82.88%.

MS(ESI, pos.ion) m/z: 511.4[M+1] ⁺ .

Step 3: Compound 4-(2-(1-Methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo Synthesis of [2,3-b]pyrazin-7-yl)piperidine-1-carboxylate tert-butyl ester

To 4-(2-(1-methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2, 3-b]pyrazin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (270 mg, 0.52 mmol) in methanol (8 mL) was added Pd/C (10%, 30 mg, 0.028 mmol), stirred overnight at room temperature under a hydrogen atmosphere, filtered, concentrated, and subjected to column chromatography (petroleum ether/ethyl acetate (v/v)=0/1) to obtain 250 mg of yellow oil, yield: 92.23 %.

MS(ESI, pos.ion) m/z: 513.4[M+1] ⁺ .

Step 4: Compound 2-(1-Methyl-1H-pyrazol-4-yl)-7-(piperidin-4-yl)-5-((2-(trimethylsilyl)ethoxy) Synthesis of methyl)-5H-pyrrolo[2,3-b]pyrazine

Under ice bath, add 4-(2-(1-methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrole Acetyl chloride (70 μL, 0.97 mmol) was added to a solution of tert-butyl iso[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate (250 mg, 0.48 mmol) in methanol (8 mL), and stirred at room temperature After overnight, the reaction was completed, directly concentrated, and column chromatography (dichloromethane/methanol (v/v)=8/1) obtained 260 mg of yellow solid, yield: 99%.

MS(ESI, pos.ion) m/z: 413.4[M+1] ⁺ .

Step 5: Compound 4-(4-(2-(1-Methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrole Synthesis of [2,3-b]pyrazin-7-yl)piperidin-1-yl)butyronitrile

To 2-(1-methyl-1H-pyrazol-4-yl)-7-(piperidin-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl) To a solution of -5H-pyrrolo[2,3-b]pyrazine (130 mg, 0.31 mmol) in acetonitrile (8 mL) were sequentially added potassium carbonate (110 mg, 0.79 mmol), potassium iodide (10 mg, 0.06 mmol) and 4-chlorobutane Nitrile (0.05mL, 0.5mmol), heated at 50°C for 24 hours, diluted with water (20mL), extracted with dichloromethane (20mL x 3), dried over anhydrous sodium sulfate, concentrated by column chromatography (dichloromethane/methanol (v /v)=8/1) to give 120 mg of yellow oil, yield: 79.40%.

MS(ESI, pos.ion) m/z: 480.0[M+1] ⁺ .

Step 6: Compound 4-(4-(2-(1-Methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)piperidine-1 -Base) Synthesis of Butyronitrile

4-(4-(2-(1-Methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2, 3-b]pyrazin-7-yl)piperidin-1-yl)butyronitrile (120 mg, 0.25 mmol) and trifluoroacetic acid (2 mL) were prepared according to the synthetic method of Example 2, step 2 to obtain 36 mg of a pale yellow solid, yielding Rate: 41.19%.

MS(ESI, pos.ion) m/z: 351.00[M+1] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm) 11.69(s,1H), 8.55(s,1H), 8.32(s,1H), 8.04(s,1H), 7.58(s,1H), 3.91(s, 3H), 3.01(dd, J=126.5, 49.0Hz, 5H), 2.57(s, 2H), 1.99(m, 8H).

Example 23

3-((3-(2-(1-Methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)cyclohexyl)amino)propionitrile

Step 1: Compound 3-(2-(1-Methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo Synthesis of [2,3-b]pyrazin-7-yl)cyclohexenone

Under nitrogen, 1,4-dioxane (16 mL)/water (4 mL) was added to 7-bromo-2-(1-methyl-1H-pyrazol-4-yl)-5-((2 -(Trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (500 mg, 1.22 mmol), 3-(4-(4,4,5,5- Tetramethyl-1,3,2-dioxaboropentan-2-yl)cyclohexenone (650 mg, 2.34 mmol), potassium carbonate (340 mg, 0.2.46 mmol) and Pd(dppf)Cl ₂ (45 mg, 0.06mmol) mixture, refluxed at 110°C for 8h, the reaction solution was cooled to room temperature, filtered through celite, the filtrate was concentrated under reduced pressure, and subjected to column separation (petroleum ether/ethyl acetate (v/v)=0/1) to obtain 450mg Yellow solid, yield: 69.4%.

MS(ESI, pos.ion) m/z: 424.0[M+1] ⁺ .

Step 2: Compound 3-(2-(1-Methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo Synthesis of [2,3-b]pyrazin-7-yl)cyclohexanol

Pd/C (10%, 200 mg) was added to 3-(2-(1-methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy) Methyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)cyclohexenone in methanol solution, react at room temperature for 24h, the reaction solution is filtered through celite, and the filter cake is washed with dichloromethane , the filtrate was concentrated under reduced pressure and subjected to column separation (dichloromethane/methanol (v/v)=15/1) to obtain 350 mg of yellow oil, yield: 77.0%.

MS(ESI, pos.ion) m/z: 428.0[M+1] ⁺ .

Step 3: Compound 3-(2-(1-Methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo Synthesis of [2,3-b]pyrazin-7-yl)cyclohexanone

Dess-Martin reagent (360 mg, 0.85 mmol) was added to 3-(2-(1-methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy ) methyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)cyclohexanol (300 mg, 0.70 mmol) in dichloromethane (15 mL) solution, reacted at room temperature for 3 days, saturated with of sodium thiosulfate solution (30 mL) to quench the reaction, the aqueous phase was extracted with dichloromethane (20 mL x 3), the organic layer was dried over anhydrous sodium sulfate, and subjected to column separation (petroleum ether/ethyl acetate (v/v) = 1/3) 100 mg of yellow oil was obtained, yield: 33.5%.

MS(ESI, pos.ion) m/z: 426.0[M+1] ⁺ .

Step 4: Compound 3-((3-(2-(1-Methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)- Synthesis of 5H-pyrrolo[2,3-b]pyrazin-7-yl)cyclohexyl)amino)propionitrile

Sodium triacetoxyborohydride (70 mg, 0.33 mmol) was added to 3-(2-(1-methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl) Ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)cyclohexanone (80 mg, 0.19 mmol) and 3-aminopropionitrile (20 mg, 0.28 mmol) in tetrahydrofuran (5mL), the reaction was carried out at room temperature for 2h. The reaction was quenched by adding water (30 mL), extracted with dichloromethane (30 mL x 3), the organic layer was dried over anhydrous sodium sulfate, and subjected to column separation (dichloromethane/methanol (v/v)=30/1) to obtain 50 mg of yellow oil product, yield: 55.4%.

MS(ESI, pos.ion) m/z: 480.4[M+1] ⁺ .

Step 5: Compound 3-((3-(2-(1-methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)cyclohexane ) Amino) Propionitrile Synthesis

3-((3-(2-(1-Methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo [2,3-b]pyrazin-7-yl)cyclohexyl)amino)propionitrile (110 mg, 0.20 mmol), trifluoroacetic acid (2 mL) and ethylenediamine (1 mL) were synthesized according to Example 2, Step 2 25 mg of yellow solid were prepared, yield: 76.3%.

MS(ESI, pos.ion) m/z: 350.0[M+1] ⁺ .

¹ H NMR (600MHz, DMSO-d ₆ ): δ(ppm) 11.58(d, J=1.8Hz, 1H), 8.54(s, 1H), 8.26(s, 1H), 8.03(s, 1H), 7.51 (d, J=2.3Hz, 1H), 3.91(s, 3H), 2.94(s, 1H), 2.86(m, 2H), 2.65(td, J=6.7, 1.7Hz, 2H), 2.04(dd, J=31.6, 10.8Hz, 2H), 1.80(m, 2H), 1.64(m, 2H), 1.51(m, 2H);

¹³ C NMR (150 MHz, DMSO-d ₆ ): δ (ppm) 140.7, 140.6, 137.3, 136.9, 134.0, 129.0, 126.7, 121.9, 120.7, 119.6, 51.8, 43.0, 39.1, 36.9, 32.6, 30.9, 28.1, 20.7, 18.7.

Example 24

1-((4-(2-(1-Methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)phenyl)sulfonyl)nitrogen tetracyclobutane-3-carbonitrile

Step 1: Synthesis of compound 1-((4-bromophenyl)sulfonyl)azetidine-3-carbonitrile

Under nitrogen protection, dichloromethane (12 mL) was added to 4-bromobenzenesulfonyl chloride (252 mg, 0.99 mmol), 3-acetonitrile cyclobutylamine hydrochloride (90 mg, 0.76 mmol), triethylamine (230 mg, 2.28 mmol) ), reacted at room temperature for 12 h, the reaction solution was extracted with ethyl acetate (50 mL×3), the organic phase was spin-dried, and separated by column chromatography (petroleum ether/ethyl acetate (v/v)=3/1) to obtain 179 mg of white solid, the product Rate: 78.3%.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm) 7.94 (d, J=8.5 Hz, 2H), 7.78 (d, J=8.5 Hz, 2H), 4.00 (t, J=8.7 Hz, 2H) ), 3.87 (dd, J ₁ =8.5 Hz, J ₂ =5.9 Hz, 2H), 3.69-3.58 (m, 1H).

Step 2: Compound 1-((4-(2-(1-methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)- Synthesis of 5H-pyrrolo[2,3-b]pyrazin-7-yl)phenyl)sulfonyl)azetidine-3-carbonitrile

Under nitrogen, 1,4-dioxane (12 mL) was added to 1-((4-bromophenyl)sulfonyl)azetidine-3-carbonitrile (148 mg, 0.49 mmol), biboronic acid In a mixture of pinacol ester (138 mg, 0.54 mmol), potassium acetate (150 mg, 1.53 mmol) and Pd(dppf)Cl ₂ (23 mg, 0.03 mmol), the reaction was refluxed at 110° C. for 11 h, and the reaction solution was cooled to room temperature under nitrogen protection. , added water (2.5 mL), potassium carbonate (130 mg, 0.93 mmol), 7-bromo-2-(1-methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilane) Base)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (120mg, 0.29mmol), Pd(dppf)Cl ₂ (23mg, 0.03mmol), 110 ℃ reflux reaction for 10h, the reaction The liquid was cooled to room temperature, filtered through celite, the filtrate was concentrated under reduced pressure, and subjected to column separation (petroleum ether/ethyl acetate (v/v)=1/2) to obtain 150 mg of yellow solid, yield: 55.5%.

MS(ESI, pos.ion) m/z: 549.8[M+1] ⁺ .

Step 3: Compound 1-((4-(2-(1-methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)phenyl) Synthesis of sulfonyl)azetidine-3-carbonitrile

1-((4-(2-(1-Methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo [2,3-b]pyrazin-7-yl)phenyl)sulfonyl)azetidine-3-carbonitrile (150 mg, 0.27 mmol), trifluoroacetic acid (6 mL) and ethylenediamine (1 mL) According to the synthesis method of Example 2, step 2, 91 mg of light yellow solid was obtained, yield: 79.5%.

MS(ESI, pos.ion) m/z: 419.9[M+1] ⁺ ;

¹ H NMR (600MHz, DMSO-d ₆ +D ₂ O): δ(ppm) 8.72(d, J=8.4Hz, 2H), 8.72(s, 1H), 8.65(s, 1H), 8.49(s, 1H), 8.21(s, 1H), 7.90(d, J=8.4Hz, 2H), 4.02(t, J=8.7Hz, 2H), 3.95(s, 3H), 3.88(dd, J ₁ =8.3Hz , J ₂ =6.2Hz, 2H), 3.65(m, 1H);

¹³ C NMR (150MHz, DMSO-d ₆ ): δ(ppm) 142.5, 141.2, 140.2, 137.4, 136.3, 135.1, 130.6, 129.8, 129.3, 129.2, 126.3, 121.5, 120.3, 111.3, 53.8, 40.5, 39.3, 17.2.

Example 25

3-((4-(2-(1-Methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)phenyl)sulfonyl)propane Nitrile

Step 1: Compound 3-((4-(2-(1-Methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)- Synthesis of 5H-pyrrolo[2,3-b]pyrazin-7-yl)phenyl)thio)propionitrile

Potassium carbonate (76 mg, 0.55 mmol), 7-bromo-2-(1-methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl )-5H-pyrrolo[2,3-b]pyrazine (90 mg, 0.22 mmol), 3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron) Pentan-2-yl)phenyl)thio)propionitrile (95 mg, 0.33 mmol) and Pd(dppf)Cl ₂ (7 mg, 0.01 mmol) were prepared according to the synthetic method of Example 1, step 1 to give 45 mg of yellow oil, Yield: 41.6%.

MS(ESI, pos.ion) m/z: 491.3[M+1] ⁺ .

Step 2: Compound 3-((4-(2-(1-Methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)phenyl) Synthesis of Thio)propionitrile

3-((4-(2-(1-Methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo Synthesis of [2,3-b]pyrazin-7-yl)phenyl)thio)propionitrile (45 mg, 0.09 mmol), trifluoroacetic acid (6 mL) and ethylenediamine (1 mL) according to Example 2, Step 2 The method prepared 27 mg of light white solid, yield: 81.7%.

MS(ESI, pos.ion) m/z: 361.2[M+1] ⁺ .

Step 3: Compound 3-((4-(2-(1-Methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)phenyl) Synthesis of Sulfonyl)Propionitrile

3-((4-(2-(1-Methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)phenyl)sulfur at room temperature Substance) propionitrile (36mg, 0.10mmol) was dissolved in dichloromethane (10mL), m-chloroperoxybenzoic acid (60mg, 0.30mmol) was added, and the reaction was carried out at room temperature for 12h. Chromatography (dichloromethane/methanol (v/v) = 20/1) gave 43 mg of a pale yellow solid, which was then purified by preparative thin layer to give 6 mg of an earthy grey solid, yield: 15.3%.

MS(ESI, pos.ion) m/z: 393.2[M+1] ⁺ ;

¹ H NMR (600MHz, DMSO-d ₆ ): δ(ppm) 8.71(s, 1H), 8.66(d, J=8.4Hz, 2H), 8.64(s, 1H), 8.48(s, 1H), 8.19 (s, 1H), 7.97 (d, J=8.4Hz, 2H), 3.95 (s, 3H), 3.74 (t, J=6.8Hz, 2H), 2.89 (t, J=6.8Hz, 2H);

¹³ C NMR (150 MHz, DMSO-d ₆ ): δ (ppm) 142.5, 140.5, 137.4, 136.3, 135.1, 134.4, 130.7, 130.1, 129.8, 129.0, 126.2, 121.5, 118.3, 111.3, 50.3, 39.3, 12.1.

Using the corresponding raw materials, the following compounds were prepared according to the synthetic method of Example 24:

Example 38

2-((4-(2-(1-Methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)phenyl)amino)acetonitrile

Step 1: Compound 4-(2-(1-Methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo Synthesis of [2,3-b]pyrazin-7-yl)aniline

7-Bromo-2-(1-methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2, 3-b]pyrazine (200mg, 0.49mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)aniline (150mg, 0.68mmol) ), potassium carbonate (120mg, 0.87mmol) and 1,1'-bisdiphenylphosphinoferrocene palladium dichloride (20mg, 0.03mmol) were prepared according to the synthetic method of Example 1, step 1 to obtain 180mg of yellow oil, Yield: 72.3%.

MS(ESI, pos.ion) m/z: 421.0[M+1] ⁺ .

Step 2: Compound 2-((4-(2-(1-Methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)- Synthesis of 5H-pyrrolo[2,3-b]pyrazin-7-yl)phenyl)amino)acetonitrile

p-2-Bromoacetonitrile (70 mg, 0.60 mmol, 0.04 mL) was added to 4-(2-(1-methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl) )ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)aniline (180 mg, 0.42 mmol) and potassium carbonate (90 mg, 0.65 mmol), potassium iodide (110 mg, 0.66 mmol) ) in acetonitrile (15 mL), the reaction solution was refluxed at 90°C overnight, cooled to room temperature, filtered through celite, concentrated under reduced pressure, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)= 0/1) gave 140 mg of a khaki solid, yield: 71.2%.

MS(ESI, pos.ion) m/z: 460.4[M+1] ⁺ .

Step 3: Compound 2-((4-(2-(1-Methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)phenyl) Synthesis of amino)acetonitrile

2-((4-(2-(1-Methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo [2,3-b]pyrazin-7-yl)phenyl)amino)acetonitrile (130 mg, 0.28 mmol), trifluoroacetic acid (2 mL) and ethylenediamine (1 mL) were prepared according to the synthetic method of Example 2, Step 2 50 mg of yellow solid were obtained, yield: 53.7%.

MS(ESI, pos.ion) m/z: 329.9[M+1] ⁺ ;

¹ H NMR (600MHz, DMSO-d ₆ ): δ(ppm) 11.99(s, 1H), 8.62(s, 1H), 8.38(s, 1H), 8.17(d, J=2.6Hz, 1H), 8.13 (s,1H),8.12(s,2H),6.83(d,J=8.6Hz,2H),6.24(t,J=6.9Hz,1H),4.30(d,J=6.8Hz,2H),3.94 (s, 3H);

¹³ C NMR (150 MHz, DMSO-d ₆ ): δ (ppm) 145.1, 141.5, 140.8, 137.1, 136.1, 134.3, 129.4, 127.1, 126.6, 124.4, 121.8, 119.2, 113.7, 113.6, 40.4, 39.2.

Example 40

2-Methyl-2-((2-(2-(1-methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)pyrimidine- 4-yl)amino)-N-(2,2,2-trifluoroethyl)butanamide

Step 1: Compound (R)-2-methyl-2-((2-(2-(1-methyl-1H-pyrazol-4-yl)-5-trityl-5H-pyrrolo[ Synthesis of 2,3-b]pyrazin-7-yl)pyrimidin-4-yl)amino)-N-(2,2,2-trifluoroethyl)butanamide

(R)-2-((2-(2-Chloro-5-trityl-5H-pyrrolo[2,3-b]pyrazin-7-yl)pyrimidin-4-yl)amino)-2 - methyl-N-(2,2,2-trifluoroethyl)butanamide (240mg, 0.36mmol), potassium carbonate (75mg, 0.54mmol), 1-methyl-4-pyrazole boronate (115mg , 0.55 mmol) and Pd(dppf)Cl ₂ (30 mg, 0.04 mmol) were prepared according to the synthetic method of Example 2, step 1 to obtain 120 mg of off-white solid, yield: 46.81%.

MS(ESI, pos.ion) m/z: 716.45[M+1] ⁺ .

Step 2: Compound 2-methyl-2-((2-(2-(1-methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine-7- Synthesis of pyrimidin-4-yl)amino)-N-(2,2,2-trifluoroethyl)butanamide

(R)-2-Methyl-2-((2-(2-(1-methyl-1H-pyrazol-4-yl)-5-trityl-5H-pyrrolo[2,3- b] Pyrazin-7-yl)pyrimidin-4-yl)amino)-N-(2,2,2-trifluoroethyl)butanamide (110 mg, 0.15 mmol), trifluoroacetic acid (330 μL, 4.443 mmol) and triethylsilane (670 μL, 4.19 mmol) according to the synthesis method of Example 2, step 2, to obtain 20 mg of a yellow solid, yield: 27.49%.

MS(ESI, pos.ion) m/z: 474.30[M+1] ⁺ ;

¹ H NMR (600MHz, CD ₃ OD) δ(ppm) 8.70(s, 1H), 8.49(s, 1H), 8.45(s, 1H), 8.31(s, 1H), 8.26(m, 1H), 6.62 (s,1H),4.02(s,3H),3.85(m,2H),2.24(dd,J=21.7,6.4Hz,1H),2.03(dd,J=19.9,10.2Hz,1H),1.66( s, 3H), 0.98(t, J=9.4Hz, 3H);

¹³ C NMR (150MHz, CD ₃ OD) δ (ppm) 175.8, 161.2, 143.2, 140.8, 137.4, 135.8, 135.3, 129.9, 129.4, 128.4, 125.5, 125.3, 123.5, 121.2, 103.8, 60.8, 48.1, 40.1 37.7, 20.5, 6.7.

Example 62

(R)-N-(2-cyanoethyl)-3-(2-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b ]pyrazin-7-yl)benzenesulfonamide

Step 1: Compound (R)-N-(2-cyanoethyl)-3-(2-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-5-((2- Synthesis of (trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)benzenesulfonamide

Cesium carbonate (840 mg, 2.58 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)-1H-pyrazole ( 250mg, 1.29mmol) and (R)-propylene oxide (285mg, 4.91mmol) were added together, then acetonitrile (15ml) was added, the temperature was heated to 130°C for 22h in a sealed tube, and the reaction solution was extracted with ethyl acetate (50mL×3 ), spin dry the organic phase. Under nitrogen protection, 3-(2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl was added )-N-(2-cyanoethyl)benzenesulfonamide (150mg, 0.28mmol), potassium carbonate (100mg, 0.72mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloro Palladium (12 mg, 0.02 mmol) was added, dioxane (15 mL) and water (3 ml) were added, and the reaction was carried out at 110° C. for 24 h. The reaction solution was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure, and subjected to column separation (acetic acid). ethyl ester) to give 150 mg of yellow oil, yield: 92.2%.

MS(ESI, pos.ion) m/z: 582.3[M+1] ⁺ .

Step 2: Compound (R)-N-(2-cyanoethyl)-3-(2-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-5H-pyrrolo[2 Synthesis of ,3-b]pyrazin-7-yl)benzenesulfonamide

(R)-N-(2-cyanoethyl)-3-(2-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-5-((2-(trimethyl) Silyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)benzenesulfonamide (160 mg, 0.28 mmol), trifluoroacetic acid (6 mL) and ethylenediamine ( 1 mL) was prepared according to the synthetic method of step 2 of Example 2 to obtain 56 mg of white solid, yield: 45.1%.

MS(ESI, pos.ion) m/z: 452.4[M+1] ⁺ ;

¹ H NMR (600MHz, DMSO-d ₆ ): δ(ppm) 8.98(s, 1H), 8.71(s, 1H), 8.52(s, 1H), 8.49(d, J=7.3Hz, 1H), 8.39 (s, 1H), 8.19 (s, 1H), 7.72–7.63 (m, 2H), 5.00 (s, 2H), 4.16–3.99 (m, 3H), 3.09 (t, J=6.4Hz, 2H), 2.68 (t, J=6.4Hz, 2H), 1.10 (d, J=5.8Hz, 3H);

¹³ C NMR (150MHz, DMSO-d ₆ ): δ(ppm) 142.3, 141.0, 140.9, 137.4, 136.0, 135.5, 135.0, 130.1, 129.4, 129.4, 129.3, 123.9, 123.8, 121.2, 119.4, 111.5, 65.9, 59.4, 39.2, 21.4, 19.1.

Using the corresponding raw materials, the following compounds were prepared according to the synthetic method of Example 62:

Example 72

3-(4-(4-(2-Cyclopropyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)-1H-pyrazol-1-yl)piperidin-1-yl) -3-Oxypropionitrile

Step 1: Compound 1-tert-Butylcarboxylate-4-((4-(2-cyclopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[ Synthesis of 2,3-b]pyrazin-7-yl)-1H-pyrazol-1-yl))piperidine

1,4-dioxane (16 mL)/water (4 mL), tert-butyl 1-carboxylate-4-((4-(2-bromo-5-((2-(trimethylsilyl)ethoxy) yl)methyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)-1H-pyrazol-1-yl))piperidine (430mg, 0.74mmol), cyclopropylboronic acid (95mg , 1.11 mmol), potassium carbonate (160 mg, 1.16 mmol) and 1,1'-bis-diphenylphosphinoferrocene palladium dichloride (30 mg, 0.04 mmol) were prepared according to the synthetic method of Example 2, step 1 280 mg of yellow oil, yield: 69.8%.

MS(ESI, pos.ion) m/z: 539.4[M+1] ⁺ .

Step 2: Synthesis of compound 2-cyclopropyl-7-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine

tert-Butyl 1-carboxylate-4-((4-(2-cyclopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3- b] Pyrazin-7-yl)-1H-pyrazol-1-yl))piperidine (260 mg, 0.48 mmol), trifluoroacetic acid (2 mL) and ethylenediamine (1 mL) Synthesis according to Example 2, Step 2 The method prepared 110 mg of pale yellow solid, yield: 73.9%.

MS(ESI, pos.ion) m/z: 309.3[M+1] ⁺ .

Step 3: Compound 3-(4-(4-(2-Cyclopropyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)-1H-pyrazol-1-yl)piperidine- Synthesis of 1-yl)-3-oxopropionitrile

2-Cyclopropyl-7-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine (100 mg, 0.32 mmol) Added to cyanoacetic acid (65mg, 0.76mmol), 1-hydroxybenzotriazole (HOBT) (110mg, 0.81mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide salt A mixture of acid salt (150 mg, 0.78 mmol) and triethylamine (0.08 g, 0.1 mL, 0.80 mmol) in N,N-dimethylformamide (5 mL), reacted at room temperature for 6 h, and quenched with water (50 mL) , extracted with ethyl acetate (50 mL x 4), the organic layer was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was subjected to column separation (dichloromethane/methanol (v/v) =12/1) 80 mg of pale yellow solid were obtained, yield: 65.7%.

MS(ESI, pos.ion) m/z: 375.9[M+1] ⁺ ;

¹ H NMR (600MHz, DMSO-d ₆ ): δ (ppm) 11.81 (s, 1H), 8.23 (d, J=6.8Hz, 2H), 8.01 (s, 1H), 8.00 (d, J=2.6Hz ,1H),4.52(m,1H),4.43(d,J＝13.2Hz,1H),4.12(q,J＝18.9Hz,2H),3.79(d,J＝13.7Hz,1H),3.25(m ,1H),2.86(t,J＝11.8Hz,1H),2.28(m,1H),2.09(m,2H),1.99(m,1H),1.82(m,1H),1.03(m,4H) ;

¹³ C NMR (150MHz, DMSO-d ₆ ): δ(ppm) 161.8, 150.8, 140.8, 136.4, 136.1, 135.8, 125.9, 124.7, 116.6, 114.2, 106.5, 57.9, 44.8, 41.1, 32.7, 32.1, 25.3, 14.8, 10.2.

The corresponding raw materials are used to prepare according to the synthetic method of Example 72, and the following compounds are prepared:

Example 90

Methyl 5-((3-Propionamidophenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate

Step 1: Synthesis of compound 3-iodopyrazolo[1,5-a]pyrimidine-5-hydroxy

Pyrazo[1,5-a]pyrimidine-5-hydroxy (1 g, 7.40 mmol) and N-iodosuccinimide (1.83 g, 8.14 mmol) were dissolved in N,N-dimethyl dimethyl at room temperature Formamide (20 mL), the reaction was slowly exothermic, a large amount of solid formed within a few minutes, and the reaction was stirred at room temperature for 1 hour. Cool under an ice bath, filter, collect the white solid, wash the filter cake with dichloromethane (20 mL), and dry to obtain 1.7 g of white solid, yield: 88%.

¹ H NMR (600 MHz, DMSO-d ₆ ): δ (ppm) 12.24 (s, 1H), 8.48 (s, 1H), 7.84 (s, 1H), 6.00 (s, 1H).

Step 2: Synthesis of compound 5-hydroxypyrazo[1,5-a]pyrimidine-3-carboxylic acid methyl ester

Methanol (10 mL) was injected under _N2 into 3-iodopyrazolo[1,5-a]pyrimidine-5-hydroxy (0.2 g, 0.76 mmol), palladium acetate (35 mg, 0.15 mmol) and triethylamine ( 0.32 mL, 2.3 mmol), carbon monoxide was introduced into the mixture, and the reaction was carried out at 55° C. for 5 h. Celite was filtered, concentrated under reduced pressure, the residue was washed with water (35 mL), extracted with dichloromethane (35 mL×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column separation (dichloromethane/methanol (v/v)=30 /1) 45 mg of white solid were obtained, yield: 30.4%.

¹ H NMR (400MHz, DMSO-d ₆ ): δ(ppm) 11.87(s, 1H), 8.57(d, J=7.9Hz, 1H), 8.15(s, 1H), 6.16(s, 1H), 3.77 (s, 3H).

Step 3: Synthesis of compound 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylic acid methyl ester

Methyl 5-hydroxypyrazo[1,5-a]pyrimidine-3-carboxylate (0.028 g, 0.14 mmol), phosphorus oxychloride (0.8 mL, 8 mmol) and N,N-diisopropylethylamine (0.01 mL, 0.06 mmol) was refluxed in toluene (2 mL) solution for 2 h. Cooled to room temperature, phosphorus oxychloride was removed under reduced pressure, the residue was quenched with warm water (35 mL), extracted with dichloromethane (35 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column separation (dichloromethane/methanol). (v/v)=80/1) 19 mg of white solid were obtained, yield: 61.9%.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm) 9.33 (d, J=7.2 Hz, 1H), 8.68 (s, 1H), 7.41 (d, J=7.2 Hz, 1H), 3.83 (s , 3H).

Step 4: Synthesis of compound 5-((3-propionamidophenyl)amino)pyrazo[1,5-a]pyrimidine-3-carboxylic acid methyl ester

Under _N2 protection, 1,4-dioxane (8 mL) was added to methyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (0.08 g, 0.37 mmol), Xantphos (0.011 g , 0.02mmol), palladium acetate (4mg, 0.02mmol), cesium carbonate (0.14g, 0.42mmol) and N-(3-aminobenzene) propionamide (0.08g, 0.48mmol) in a mixture, 110 ° C reflux reaction 6h, filtered, the filtrate was washed with water (30 mL), the aqueous phase was back-extracted with dichloromethane (30 mL x 3), the organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column separation (dichloromethane/methanol (v /v)=30/1) to obtain a brownish-yellow solid, which was then separated by high performance chromatography to obtain 20 mg of a beige solid, yield: 15.59%.

MS(ESI, pos.ion) m/z: 340.1[M+1] ⁺ ;

¹ H NMR (600 MHz, DMSO-d ₆ ): δ (ppm) 10.08 (s, 1H), 9.87 (s, 1H), 8.75 (d, J=7.6 Hz, 1H), 8.36 (d, J=6.7 Hz) ,1H),8.29(s,1H),7.94(s,1H),7.30(t,J＝8.1Hz,1H),7.12(d,J＝7.8Hz,1H),6.70(d,J＝7.6Hz , 1H), 3.81(s, 3H), 2.34(q, J=7.5Hz, 2H), 1.11(t, J=7.5Hz, 3H);

¹³ C NMR (150 MHz, DMSO-d ₆ ): δ (ppm) 172.0, 162.6, 154.7, 147.2, 146.0, 140.0, 139.4, 136.4, 129.0, 114.2, 113.9, 110.3, 102.2, 98.5, 50.7, 29.5, 9.7.

Example 91

N-(2-cyanoethyl)-3-(1,6-dihydropyrrole[2,3-b][1,2,3]triazolo[4,5-d]pyridin-8-yl) Benzenesulfonamide

Step 1: Synthesis of compound 4-chloro-1-p-toluenesulfonyl-1H-pyrro[2,3-b]pyridine

4-Chloro-1H-pyrrole[2,3-b]pyridine (1.50 g, 9.80 mmol), triethylamine (1.81 g, 18.01 mmol), DMAP (205 mg, 1.59 mmol) were added together at room temperature, and then Dichloromethane (20 mL) and p-toluenesulfonyl chloride (2.25 g, 11.80 mmol) were successively added, and the reaction was carried out at room temperature for 36 h. The reaction solution was quenched by adding water (50 mL), extracted with dichloromethane (50 mL×3), and the organic phase was spin-dried. Column chromatography separation (petroleum ether/ethyl acetate (v/v)=10/1) gave 1.46 g of white solid in a yield of 49.1%.

MS(ESI, pos.ion) m/z: 306.9[M+1] ⁺ .

Step 2: Synthesis of compound 4-chloro-5-nitro-1-p-toluenesulfonyl-1H-pyrro[2,3-b]pyridine

At -5 °C, 4-chloro-1-p-toluenesulfonyl-1H-pyrrole[2,3-b]pyridine (1.48g, 4.82mmol), tetrabutylammonium nitrate (1.84g, 5.86mmol), di Chloromethane (30 mL) was added together, then trifluoroacetic anhydride (0.92 mL, 6.50 mmol) was slowly added, and after the addition, the reaction was raised to room temperature for 6 h, and tetrabutylammonium nitrate (0.46 g, 1.45 mmol) was added at -5°C. ), trifluoroacetic anhydride (0.28mL, 2.01mmol), after adding, the reaction was raised to room temperature for 18h, the reaction solution was quenched by adding water (70mL), extracted with dichloromethane (100mL×3), spin-dried the organic phase, the column layer Separation (petroleum ether/ethyl acetate (v/v)=10/1) gave 1.21 g of white solid, yield: 71.6%.

MS(ESI, pos.ion) m/z: 352.1[M+1] ⁺ .

Step 3: Synthesis of compound 5-nitro-1-p-toluenesulfonyl-1H-pyrro[2,3-b]pyridin-4-amine

At room temperature, 4-chloro-5-nitro-1-p-toluenesulfonyl-1H-pyrrole[2,3-b]pyridine (300 mg, 0.85 mmol) and concentrated ammonia (2 mL) were added together, followed by Dioxane (20 mL) was reacted at 80 °C for 6 h, the reaction solution was cooled to room temperature, diluted with water (50 mL), extracted with dichloromethane (50 mL×3), the organic phase was spin-dried, separated by column chromatography (petroleum ether/acetic acid) Ethyl ester (v/v)=4/1) gave 130 mg of yellow solid, yield: 45.9%.

MS(ESI, pos.ion) m/z: 333.2[M+1] ⁺ .

Step 4: Synthesis of Compound 1-p-Tosyl-1H-pyrrole[2,3-b]pyrazine-4,5-diamine

At room temperature, 5-nitro-1-p-toluenesulfonyl-1H-pyrrole[2,3-b]pyridin-4-amine (130mg, 0.39mmol), ammonium chloride (124mg, 2.34mmol), iron powder (90 mg, 1.61 mmol) were added together, then ethanol (10 mL) and water (3 mL) were added, and the reaction was carried out at 90° C. for 4 h. The reaction solution was cooled to room temperature, filtered through celite, diluted with water (50 mL), and extracted with ethyl acetate ( 50 mL×3), spin dry the organic phase, and separate by column chromatography (dichloromethane/methanol (v/v)=20/1) to obtain 80 mg of brown oil, yield: 67.6%.

MS(ESI, pos.ion) m/z: 303.2[M+1] ⁺ .

Step 5: Synthesis of compound 6-p-toluenesulfonyl-1,6-dihydropyrrole[2,3-b][1,2,3]triazole[4,5-d]pyridine

1-p-Tosyl-1H-pyrrole[2,3-b]pyrazine-4,5-diamine (70 mg, 0.23 mmol), sodium nitrite (19 mg, 0.28 mmol) were added together followed by acetic acid (8mL), react at room temperature for 3h, add water (50mL) to dilute, extract with ethyl acetate (50mL×3), spin dry the organic phase, separate by column chromatography (petroleum ether/ethyl acetate (v/v)=1/2 ) to obtain 40 mg of a pale yellow solid, yield: 55.2%.

MS(ESI, pos.ion) m/z: 314.3[M+1] ⁺ ;

¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm) 9.19 (s, 1H), 8.03 (t, J=5.5 Hz, 3H), 7.43 (d, J=8.3 Hz, 2H), 7.07 (d , J=3.9Hz, 1H), 2.34 (s, 3H).

Step 6: Synthesis of compound 8-bromo-6-p-toluenesulfonyl-1,6-dihydropyrrole[2,3-b][1,2,3]triazole[4,5-d]pyridine

At room temperature, 6-p-toluenesulfonyl-1,6-dihydropyrrole[2,3-b][1,2,3]triazole[4,5-d]pyridine (150 mg, 0.48 mmol), NBS (128 mg, 0.72 mmol) was added together, then DMF (10 mL) was added, the reaction was carried out at room temperature for 10 h, diluted with water (50 mL), extracted with ethyl acetate (50 mL×3), the organic phase was spin-dried, separated by column chromatography (petroleum ether/ethyl acetate (v/v)=1/2) to obtain 160 mg of pale yellow solid, which was sent to HPLC to prepare 79 mg of pale yellow solid, yield: 42.1%.

MS(ESI, pos.ion) m/z: 392.0[M+1] ⁺ ;

¹ H NMR (400 MHz, DMSO-d ₆ +D ₂ O): δ (ppm) 9.23 (s, 1H), 8.26 (s, 1H), 8.04 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.2Hz, 2H), 2.31 (s, 3H).

Step 7: Compound N-(2-cyanoethyl)-3-(6-p-toluenesulfonyl-1,6-dihydropyrrole[2,3-b][1,2,3]triazole[4 Synthesis of ,5-d]pyridin-8-yl)benzenesulfonamide

Under nitrogen, 1,4-dioxane (12 mL)/water (3 mL) was added to N-(2-cyanoethyl)-3-(4,4,5,5-tetramethyl-1, 3,2-dioxaboran-2-yl)benzenesulfonamide (132 mg, 0.39 mmol), 8-bromo-6-p-toluenesulfonyl-1,6-dihydropyrrole[2,3-b][ 1,2,3]Triazolo[4,5-d]pyridine (79mg, 0.20mmol), potassium carbonate (73mg, 0.52mmol), Pd(dppf)Cl ₂ (12mg, 0.02mmol) mixture, 110°C The reaction was refluxed for 7 h, the reaction solution was cooled to room temperature, filtered through celite, the filtrate was concentrated under reduced pressure, and subjected to column separation (petroleum ether/ethyl acetate (v/v)=1/3) to obtain 95 mg of brown oil, yield: 90.5 %.

MS(ESI, pos.ion) m/z: 522.2[M+1] ⁺ .

Step 8: Compound N-(2-cyanoethyl)-3-(1,6-dihydropyrrole[2,3-b][1,2,3]triazole[4,5-d]pyridine- Synthesis of 8-yl)benzenesulfonamide

At room temperature, N-(2-cyanoethyl)-3-(6-p-toluenesulfonyl-1,6-dihydropyrrole[2,3-b][1,2,3]triazole[4 ,5-d]pyridin-8-yl)benzenesulfonamide (106mg, 0.20mmol), potassium tert-butoxide (100mg, 0.84mmol) were added together, then anhydrous tetrahydrofuran (5mL) was added, and the reaction was carried out at room temperature for 3h. The reaction solution Silica gel was added to dry at room temperature, and the sample was mixed, and separated by column chromatography (dichloromethane/methanol (v/v)=10/1) to obtain 100 mg of red solid, which was then prepared by HPLC to obtain 50 mg of white solid, yield: 67.0%.

MS(ESI, pos.ion) m/z: 368.0[M+1] ⁺ ;

¹ H NMR (600MHz, DMSO-d ₆ ): δ(ppm) 11.77(s, 1H), 9.16(d, J=7.8Hz, 1H), 8.94(s, 1H), 8.75(s, 1H), 7.80 (s, 1H), 7.65 (t, J=7.8Hz, 1H), 7.57 (d, J=7.9Hz, 1H), 5.33 (t, J=4.6Hz, 1H), 3.21 (t, J=6.3Hz) ,2H),2.80(t,J=6.3Hz,2H);

¹³ C NMR (150 MHz, DMSO-d ₆ ): δ (ppm) 143.5, 143.3, 141.1, 138.1, 136.2, 130.7, 130.1, 129.7, 123.9, 122.5, 119.7, 119.4, 114.8, 105.1, 35.6, 19.2.

Example 92

N-(2-cyanoethyl)-3-(1-methyl-1,6-dihydropyrrole[2,3-b][1,2,3]triazole[4,5-d]pyridine -8-yl)benzenesulfonamide

Step 1: Synthesis of compound N-methyl-5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-amine

4-Chloro-5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (300 mg, 0.85 mmol), methylamine ethanol solution (6.38 M, 15 mL, 95.7 mmol) were combined according to The synthetic method of step 3 of Example 15 prepared 184 mg of yellow solid, yield: 62.3%.

MS(ESI, pos.ion) m/z: 333.2[M+1] ⁺ .

Step 2: Synthesis of compound N-methyl-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-4,5-diamine

N-methyl-5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-amine (40 mg, 0.12 mmol), ammonium chloride (37 mg, 0.70 mmol) , iron powder (26 mg, 0.47 mmol), ethanol (10 mL) and water (3 mL) were prepared according to the synthesis method of step 4 of Example 15 to obtain 20 mg of red solid, yield: 54.7%.

MS(ESI, pos.ion) m/z: 317.2[M+1] ⁺ .

Step 3: Synthesis of compound 1-methyl-6-p-toluenesulfonyl-1,6-dihydropyrrole[2,3-b][1,2,3]triazole[4,5-d]pyridine

N-methyl-1-p-toluenesulfonyl-1H-pyrro[2,3-b]pyridine-4,5-diamine (215 mg, 0.68 mmol), sodium nitrite (56 mg, 0.81 mmol) and acetic acid ( 8 mL) was prepared according to the synthesis method of step 5 of Example 15 to obtain 150 mg of light yellow solid, yield: 67.2%.

MS(ESI, pos.ion) m/z: 328.2[M+1] ⁺ .

Step 4: Compound 1-methyl-8-bromo-6-p-toluenesulfonyl-1,6-dihydropyrrole[2,3-b][1,2,3]triazole[4,5-d ] Pyridine Synthesis

1-Methyl-6-p-toluenesulfonyl-1,6-dihydropyrrole[2,3-b][1,2,3]triazole[4,5-d]pyridine (156 mg, 0.48 mmol ), NBS (128 mg, 0.72 mmol), DMF (10 mL) were prepared according to the synthetic method of step 6 of Example 15 to obtain 160 mg of light yellow solid, and sent to HPLC to prepare 53 mg of light yellow solid, yield: 27.3%.

MS(ESI, pos.ion) m/z: 406.1[M+1] ⁺ ;

¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm) 9.26 (s, 1H), 8.34 (s, 1H), 8.07 (d, J=8.4 Hz, 2H), 7.44 (d, J=8.2 Hz , 2H), 4.69(s, 3H), 2.34(s, 3H).

Step 5: Compound N-(2-cyanoethyl)-3-(1-methyl-6-p-toluenesulfonyl-1,6-dihydropyrrole[2,3-b][1,2,3] Synthesis of Triazolo[4,5-d]pyridin-8-yl)benzenesulfonamide

1,4-dioxane (12mL)/water (3mL), N-(2-cyanoethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxo Boran-2-yl)benzenesulfonamide (82 mg, 0.24 mmol), 1-methyl-8-bromo-6-p-toluenesulfonyl-1,6-dihydropyrrole[2,3-b][1 ,2,3] A mixture of triazo[4,5-d]pyridine (53 mg, 0.14 mmol), potassium carbonate (50 mg, 0.36 mmol), Pd(dppf)Cl ₂ (7 mg, 0.01 mmol) according to Example 15 The synthesis method of step 7 prepared 60 mg of pale yellow solid, yield: 85.8%.

MS(ESI, pos.ion) m/z: 536.2[M+1] ⁺ .

Step 6: Compound N-(2-cyanoethyl)-3-(1-methyl-1,6-dihydropyrrole[2,3-b][1,2,3]triazole[4,5 Synthesis of -d]pyridin-8-yl)benzenesulfonamide

N-(2-cyanoethyl)-3-(6-p-toluenesulfonyl-1,6-dihydropyrrole[2,3-b][1,2,3]triazole[4,5-d ] Pyridin-8-yl)benzenesulfonamide (76mg, 0.14mmol), potassium tert-butoxide (50mg, 0.42mmol) were prepared according to the synthetic method of Example 15 step 8 to obtain 60mg of pale yellow oil, and then dichloromethane/ The methanol mixture was slurried to obtain 30 mg of earthy gray solids, yield: 55.4%.

MS(ESI, pos.ion) m/z: 382.2[M+1] ⁺ ;

¹ H NMR (600MHz, DMSO-d ₆ ): δ(ppm) 12.67(s, 1H), 9.08(s, 1H), 8.15(s, 1H), 7.98(s, 1H), 7.92(d, J= 7.5Hz, 1H), 7.87(d, J=7.8Hz, 1H), 7.73(t, J=7.7Hz, 1H), 7.69(s, 1H), 3.82(s, 3H), 3.05(t, J= 6.3Hz, 2H), 2.65(t, J=6.3Hz, 2H);

¹³ C NMR (150 MHz, DMSO-d ₆ ): δ (ppm) 145.5, 140.5, 140.2, 137.6, 137.5, 134.8, 132.9, 130.0, 128.3, 125.9, 124.1, 119.4, 114.9, 101.5, 39.0, 38.2, 19.2.

Example 93

N-(2-cyanoethyl)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-1-yl)benzenesulfonamide

Step 1: Compound (7-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)carbamic acid Synthesis of tert-butyl ester

To 2,7-dibromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (100 mg, 0.24 mmol) in 1 , 4-dioxane (4mL) solution was successively added xantphos (30mg, 0.05mmol), potassium carbonate (50mg, 0.36mmol), palladium acetate (6mg, 0.03mmol) and tert-butyl carbamate (45mg, 0.38mmol) ), under nitrogen atmosphere, refluxed at 115°C for 6 hours, filtered through celite, concentrated, column chromatography (petroleum ether/ethyl acetate (v/v)=8/1) to obtain 100 mg of brown oil, yield: 91.83 %.

MS(ESI, pos.ion) m/z: 443.2, 445.3[M+1] ⁺ .

Step 2: Synthesis of compound 7-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-2-amino

tert-butyl to (7-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)carbamate (100mg, 0.22mmol) in dichloromethane (2mL), add hydrogen chloride isopropanol solution (7N, 4mL), stir at room temperature for 6 hours, remove the solvent, add saturated sodium bicarbonate to adjust pH>7, dichloromethane Extraction (25 mL x 3), drying and concentration, the residue was subjected to column chromatography (petroleum ether/ethyl acetate (v/v)=0/1) to obtain 58 mg of pale yellow solid product, yield: 74.91%.

MS(ESI, pos.ion) m/z: 343.2,345.1[M+1] ⁺ .

Step 3: Compound 1-bromo-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyridine Synthesis of oxazine

To 7-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-2-amino (58 mg, 0.17 mmol) 40% aqueous chloroacetaldehyde solution (70 μL, 0.42 mmol) was sequentially added to the ethanol (6 mL) solution, and the reaction was refluxed at 85° C. for 6 hours. Silica gel was directly added to stir the sample, and 60 mg of pale yellow solid was obtained by column chromatography, yield: 96.69%.

MS(ESI, pos.ion) m/z: 368.6[M+1] ⁺ .

Step 4: Compound N-(2-cyanoethyl)-3-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a] Synthesis of pyrrolo[2,3-e]pyrazin-1-yl)benzenesulfonamide

1-Bromo-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine (20 mg, 0.05 mmol) in 1,4-dioxane (5 mL), potassium carbonate (12 mg, 0.08 mmol), N-(2-cyanoethyl)-3-(4,4,5,5-tetramethyl) yl-1,3,2-dioxaboropentan-2-yl)benzenesulfonamide (30 mg, 0.09 mmol), Pd(dppf)Cl ₂ (6 mg, 0.008 mmol) and water (1 mL) following the procedure of Example 15 The synthetic method of 7 prepared 7 mg of yellow solid, yield: 25.88%.

MS(ESI, pos.ion) m/z: 497.4[M+1] ⁺ .

Step 5: Synthesis of Compound N-(2-cyanoethyl)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-1-yl)benzenesulfonamide

to N-(2-cyanoethyl)-3-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[ Trifluoroacetic acid (2 mL, 26.93 mmol) was added to a solution of 2,3-e]pyrazin-1-yl)benzenesulfonamide (100 mg, 0.20 mmol) in dichloromethane (6 mL), stirred at room temperature for 3 hours, and the solvent was concentrated, Add tetrahydrofuran (6mL) to dissolve, add ethylenediamine to adjust to pH>7, continue to stir at room temperature, add water (20mL) to dilute, extract with dichloromethane (20mL x 3), dry over anhydrous sodium sulfate, and concentrate by column chromatography (petroleum ether). /ethyl acetate (v/v)=0/1) to give 37 mg of yellow solid, yield: 50.16%.

MS(ESI, pos.ion) m/z: 367.25[M+1] ⁺ ;

¹ H NMR (600MHz, DMSO-d ₆ ): δ(ppm) 12.62(s, 1H), 8.74(s, 1H), 7.99(s, 1H), 7.89(d, J=7.6Hz, 1H), 7.85 (d, J=7.9Hz, 1H), 7.78(d, J=7.8Hz, 1H), 7.77(s, 1H), 7.74(s, 1H), 7.69(s, 1H), 3.09(t, J= 6.3Hz, 2H), 2.66(t, J=6.3Hz, 2H);

¹³ C NMR (150 MHz, DMSO-d ₆ ): δ (ppm) 141.1, 140.0, 135.3, 134.7, 134.6, 134.4, 133.4, 130.4, 127.0, 125.3, 122.0, 119.3, 112.9, 112.2, 110.3, 39.1, 19.1.

Example 94

N-(2-cyanoethyl)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)benzenesulfonamide

Step 1: Synthesis of compound 2-bromo-5-p-toluenesulfonyl-5H-pyrrolo[2,3-b]pyrazine

-15°C, sodium hydride (60%, 3.1 g, 78 mmol) was added to a solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (10 g, 50.5 mmol) in tetrahydrofuran (150 mL). Stir for 1 hour, add p-toluenesulfonyl chloride (12.6 g, 65.4 mmol) under ice bath, continue to stir at room temperature, add water (100 mL) to dilute, extract with dichloromethane (100 mL x 3), dry over anhydrous sodium sulfate, and concentrate for column chromatography (Petroleum ether/ethyl acetate (v/v)=8/1) 14.1 g of pale yellow flocculent solid were obtained, yield: 79.3%.

MS(ESI, pos.ion) m/z: 352.1, 354.1[M+1] ⁺ .

Step 2: Synthesis of compound (5-p-toluenesulfonyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)carbamate tert-butyl ester

2-Bromo-5-p-toluenesulfonyl-5H-pyrrolo[2,3-b]pyrazine (100 mg, 0.28 mmol) in 1,4-dioxane (6 mL), xantphos (34 mg, 0.06 mmol) ), potassium carbonate (60mg, 0.43mmol), palladium acetate (7mg, 0.03mmol) and tert-butyl carbamate (50mg, 0.43mmol) were prepared according to the synthetic method of Example 17 step 1 to obtain 87mg reddish-brown solid product, the yield : 78.89%.

MS(ESI, pos.ion) m/z: 389.3[M+1] ⁺ ;

¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm) 10.11 (s, 1H), 8.77 (s, 1H), 8.18 (d, J=4.0 Hz, 1H), 7.97 (d, J=8.2 Hz , 2H), 7.43 (d, J=8.2Hz, 2H), 6.85 (d, J=4.0Hz, 1H), 2.34 (s, 3H), 1.37 (s, 10H).

Step 3: Synthesis of compound 2-amino-5-p-toluenesulfonyl-5H-pyrrolo[2,3-b]pyrazine

A solution of tert-butyl (5-p-toluenesulfonyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)carbamate (900 mg, 2.32 mmol) in dichloromethane (3 mL) and hydrogen chloride-isopropyl Alcohol solution (6N, 7mL, 42mmol) was prepared according to the synthetic method of step 2 of Example 17 to obtain 440mg of light yellow dry solid, yield: 65.86%

MS(ESI, pos.ion) m/z: 289.0[M+1] ⁺ .

Step 4: Synthesis of Compound 3-p-Tosyl-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine

2-Amino-5-p-toluenesulfonyl-5H-pyrrolo[2,3-b]pyrazine (170 mg, 0.5897 mmol) in ethanol (6 mL) and 40% 2-chloroacetaldehyde (150 μL, 0.9 mmol) According to the synthetic method of step 3 of Example 17, 170 mg of yellow-green color was obtained, yield: 92.29%.

MS(ESI, pos.ion) m/z: 313.2[M+1] ⁺ ;

1H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 8.90 (s, 1H), 8.58 (s, 1H), 8.04 (dd, J=13.5, 6.1 Hz, 4H), 7.45 (d, J=8.2 Hz, 2H), 7.35 (d, J=3.8 Hz, 1H), 2.35 (s, 3H).

Step 5: Synthesis of compound 8-iodo-3-p-toluenesulfonyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine

To a solution of 3-p-toluenesulfonyl-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine (420 mg, 1.34 mmol) in DMF (8 mL) was added N-iodosuccinimide (450 mg, 2.0 mmol), stirred at room temperature for 3 hours, quenched by adding sodium thiosulfate solution (20 mL), extracted with dichloromethane (25 mL×3), dried over anhydrous sodium sulfate, concentrated by column chromatography (petroleum ether/ethyl acetate ( v/v)=1/1) 599 mg of pale yellow solid were obtained, yield: 100%.

MS(ESI, pos.ion) m/z: 439.10[M+1] ⁺ ;

¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm) 8.78 (d, J=6.7 Hz, 1H), 8.00 (m, 3H), 7.92 (s, 1H), 7.72 (d, J=4.1 Hz) , 1H), 7.45 (d, J=8.3 Hz, 2H), 2.35 (s, 3H).

Step 6: Compound N-(2-cyanoethyl)-3-(3-p-toluenesulfonamide-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8- Synthesis of phenyl)benzenesulfonamide

8-Iodo-3-p-toluenesulfonyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine (300 mg, 0.68 mmol) in 1,4-dioxane (8 mL) ), N-(2-cyanoethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)benzenesulfonamide (210mg, 0.62 mmol), potassium carbonate (150 mg, 1.08 mmol), Pd(dppf)Cl ₂ (50 mg, 0.07 mmol) and water (2 mL) 200 mg of pale yellow solid were obtained according to the synthetic method of Example 15, step 7, yield: 56.11% .

MS(ESI, pos.ion) m/z: 521.20[M+1] ⁺ .

Step 7: Synthesis of Compound N-(2-cyanoethyl)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)benzenesulfonamide

At room temperature, to N-(2-cyanoethyl)-3-(3-p-toluenesulfonamide-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8- To the solution of tetrahydrofuran (8 mL) of benzenesulfonamide (180 mg, 0.35 mmol), potassium tert-butoxide (124 mg, 1.10 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Ester (v/v)=0/1) gave 98 mg of pale yellow solid, yield: 77.36%, purity: 96.08% (HPLC).

MS(ESI, pos.ion) m/z: 367.25[M+1] ⁺ ;

¹ H NMR (600MHz, DMSO-d ₆ ): δ (ppm) 12.38 (s, 1H), 8.72 (s, 1H), 8.22 (t, J=5.8Hz, 1H), 8.09 (d, J=15.1Hz ,1H),7.96(m,2H),7.92(s,1H),7.84(t,J＝7.8Hz,1H),7.37(t,J＝3.1Hz,1H),6.06(dd,J＝3.0, 2.0Hz, 1H), 3.09 (q, J=6.2Hz, 2H), 2.66 (t, J=6.4Hz, 2H);

¹³ C NMR (150 MHz, DMSO-d ₆ ): δ (ppm) 141.1, 140.3, 134.8, 134.8, 134.6, 133.7, 130.5, 130.4, 127.3, 126.9, 125.2, 122.2, 119.3, 114.8, 95.2, 39.1, 19.1.

Example 95

N-Cyclobutyl-2-(3-propionamidophenyl)-5H-pyrro[2,3-b]pyrazine-7-carboxamide

Step 1: Compound N-Cyclobutyl-2-(3-propionamidophenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrole[2,3 -b]Synthesis of pyrazine-7-carboxamide

1,4 dioxane (8 mL)/water (2 mL), 2-bromo-N-cyclobutyl-5-(2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrole[ 2,3-b]pyrazine-7-carboxamide (0.22g, 0.51mmol), N-(3-phenylboronic acid pinacol ester phenyl)propionamide (0.21g, 0.76mmol), potassium carbonate (0.2g , 1.44 mmol) and Pd(dppf)Cl ₂ (18 mg, 0.02 mmol) were prepared according to the synthesis method of Example 1, step 1 to obtain 220 mg of an off-white solid, yield: 86.17%.

MS(ESI, Pos.ion) m/z: 493.3[M+1] ⁺ .

Step 2: Synthesis of compound N-cyclobutyl-2-(3-propionamidophenyl)-5H-pyrro[2,3-b]pyrazine-7-carboxamide

At room temperature, N-cyclobutyl-2-(3-propionamidophenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrole[2,3 -b] Pyrazine-7-carboxamide (0.22 g, 0.44 mmol) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (8 mL) was added, and the mixture was stirred at room temperature for 6 h. Concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (15 mL), made basic with saturated sodium bicarbonate solution, and reacted overnight at room temperature. Diluted with water (30 mL), extracted with dichloromethane (30 mL x 3), the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure (dichloromethane/methanol (v/v)=30/1), and subjected to column separation to obtain Yellow solid 150 mg, yield: 92.63%.

MS(ESI, pos.ion) m/z: 364.2[M+1] ⁺ ;

¹ H NMR (600MHz, DMSO-d ₆ ): δ(ppm) 12.79(s, 1H), 10.05(s, 1H), 8.96(s, 1H), 8.84(s, 1H), 8.59(d, J= 8.2Hz, 1H), 8.41(s, 1H), 7.85(d, J=7.5Hz, 1H), 7.52–7.43(m, 2H), 4.56(dd, J=16.5, 8.2Hz, 1H), 2.38( q, J=7.5Hz, 2H), 2.33 (dd, J=16.5, 8.0Hz, 2H), 2.19 (dd, J=15.0, 5.8Hz, 2H), 1.83–1.66 (m, 2H), 1.12 (t , J=7.5Hz, 3H);

¹³ C NMR (150MHz, DMSO-d ₆ ): δ(ppm) 172.6, 161.6, 146.1, 141.6, 140.7, 137.7, 136.1, 135.7, 135.1, 129.8, 121.4, 120.1, 117.7, 109.2, 43.9, 31.5, 30.0, 15.2, 10.0.

Example 96

5-(4-((1,1-Dioxythiomorpholine)methyl)phenyl)-N-isopropyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

Step 1: Compound 5-(4-((1,1-Dioxythiomorpholine)methyl)phenyl)-N-isopropyl-1-((2-(trimethylsilyl)ethoxy Synthesis of yl)methyl)-1H-pyrrolo[2,3-b]pyrazine-3-carboxamide

4-(4-Bromobenzyl)dioxothiomorpholine (16 mg, 0.05 mmol), N-isopropyl-5-boronate-1-((2-(trimethylsilyl)ethoxy yl)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (20 mg, 0.04 mmol), potassium carbonate (15 mg, 0.11 mmol) and Pd(dppf)Cl ₂ (6.4 mg, 0.01 mmol) and mixed, 1,4-dioxane (8 mL) was added, heated at 115 °C for 4 hours under nitrogen atmosphere, filtered, filtered through celite, and the filtrate was concentrated by stirring column chromatography (petroleum ether/ethyl acetate (v /v)=2/1) to give 12.7 mg of yellow oil, yield: 52.4%.

MS(ESI, pos.ion) m/z: 557.1[M+1] ⁺ .

Step 2: Compound 5-(4-((1,1-Dioxothiomorpholine)methyl)phenyl)-N-isopropyl-1H-pyrrolo[2,3-b]pyridine-3- Synthesis of formamide

5-(4-((1,1-Dioxythiomorpholine)methyl)phenyl)-N-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl base)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (140 mg, 0.25 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, stirred at room temperature for 2 h, and the solvent was concentrated , add tetrahydrofuran (6mL) to dissolve, dropwise add lithium hydroxide solution (2N) to pH>7, stir at room temperature for 2h, add water (20mL) to dilute, extract with dichloromethane (15mLx3), dry over anhydrous sodium sulfate, and concentrate for column chromatography (Petroleum ether/ethyl acetate (v/v)=1/1) 63 mg of white solid were obtained, yield: 58.75%.

MS(ESI, pos.ion) m/z: 427.0[M+1] ⁺ ;

¹ H NMR (600 MHz, DMSO-d ₆ ): δ (ppm) 12.13 (s, 1H), 8.65 (t, J=9.2 Hz, 1H), 8.56 (d, J=1.7 Hz, 1H), 8.21 (d ,J=2.3Hz,1H),7.83(d,J=7.7Hz,1H),7.68(d,J=8.0Hz,2H),7.47(d,J=7.8Hz,2H),4.12(dt,J =13.5,6.7Hz,1H),3.75(d,J=25.8Hz,2H),3.13(s,4H),2.92(s,4H),1.19(d,J=6.5Hz,6H);

¹³ C NMR (150 MHz, DMSO-d ₆ ): δ (ppm) 163.6, 148.4, 142.7, 138.2, 137.1, 130.0, 129.7, 129.1, 127.6, 127.3, 119.1, 110.4, 59.7, 50.8, 50.6, 40.6, 23.1.

Example 97

5-(3-((1,1-Dioxythiomorpholine)methyl)phenyl)-N-isopropyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

Step 1: Compound 5-(3-((1,1-Dioxythiomorpholine)methyl)phenyl)-N-isopropyl-1-((2-(trimethylsilyl)ethoxy Synthesis of yl)methyl)-1H-pyrrolo[2,3-b]pyrazine-3-carboxamide

4-(3-Bromobenzyl)dioxothiomorpholine (175 mg, 0.57 mmol), N-isopropyl-5-boronate-1-((2-(trimethylsilyl)ethoxy) )methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (220 mg, 0.47 mmol), potassium carbonate (165 mg, 1.19 mmol), Pd(dppf)Cl ₂ (73 mg, 0.09 mmol) and 1,4-dioxane (10 mL) were prepared according to the synthetic method of step 1 of Example 20 to obtain 190 mg of yellow solid, yield: 71.3%.

MS(ESI, pos.ion) m/z: 557.1[M+1] ⁺ .

Step 2: Compound 5-(3-((1,1-Dioxythiomorpholine)methyl)phenyl)-N-isopropyl-1H-pyrrolo[2,3-b]pyridine-3- Synthesis of formamide

5-(3-((1,1-Dioxythiomorpholine)methyl)phenyl)-N-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl )-1H-pyrrolo[2,3-b]pyrazine-3-carboxamide (190 mg, 0.34 mmol), trifluoroacetic acid (2 mL) and lithium hydroxide solution (2N) according to the synthesis method of Example 20, Step 2 71 mg of white solid were prepared, yield: 48.78%.

MS(ESI, pos.ion) m/z: 427.20[M+1] ⁺ ;

¹ H NMR (600MHz, DMSO-d ₆ ): δ(ppm) 12.16(s, 1H), 8.70(s, 1H), 8.59(s, 1H), 8.25(s, 1H), 7.86(d, J= 7.5Hz, 1H), 7.68(s, 1H), 7.62(d, J=7.4Hz, 1H), 7.46(t, J=7.5Hz, 1H), 7.34(d, J=7.3Hz, 1H), 4.14 (dq,J=13.1,6.4Hz,1H),3.76(s,2H),3.16(d,J=24.8Hz,4H),2.93(s,4H),1.19(d,J=6.4Hz,6H) ;

¹³ C NMR (150MHz, DMSO-d ₆ ): δ(ppm) 163.6, 148.4, 142.9, 139.3, 139.0, 129.8, 129.5, 129.1, 128.1, 127.8, 127.6, 126.3, 119.1, 110.3, 60.0, 50.7, 50.6, 40.6, 23.1.

Example 98

N-(3-(3-(1H-Indol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-methoxypropionamide

Step 1: Synthesis of compound 5-bromo-3-(1H-indol-5-yl)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine

5-Bromo-3-iodo-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (20 mg, 0.04 mmol) was dissolved in acetonitrile (4 mL), followed by the addition of 5-boronic acid pinacol Ester-1H-indole (11.2 mg, 0.04 mmol), 1N aqueous sodium carbonate solution (0.11 mL, 0.11 mmol), Pd(dppf)Cl ₂ (6.5 mg, 0.01 mmol), changed to N ₂ , stirred at room temperature for 2 h, added saturated Brine (10 mL), extracted with dichloromethane (10 mL x 3), dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=6/1) to obtain 7 mg of brown solid, yield: 35.8%.

MS (ESI, pos.ion) m/z: 466.0 [M+1].

Step 2: Compound N-(3-(3-(1H-Indol-5-yl)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyrazin-5-yl)phenyl ) Synthesis of acrylamide

5-Bromo-3-(1H-indol-5-yl)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (10 mg, 0.02 mmol), N-(3-benzene The compound of pinacol borate phenyl)acrylamide (8.8mg, 0.032mmol), Pd(dppf)Cl ₂ (3.1mg, 0.004mmol) and 1mol/L sodium carbonate solution (0.052mL, 0.052mmol) was placed in In a single-necked flask, add dioxane (4 mL), stir at room temperature at 115°C for 5 hours, add saturated brine (10 mL), extract with dichloromethane (10 mL x 3), dry with anhydrous sodium sulfate, remove the solvent, and concentrate the solution Column separation (petroleum ether/ethyl acetate (v/v)=2/1) was performed to obtain 3 mg of a brown solid, yield: 26.27%.

MS(ESI, pos.ion) m/z: 533.2[M+1] ⁺ .

Step 3: Compound N-(3-(3-(1H-Indol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-methoxyprop amide synthesis

N-(3-(3-(1H-Indol-5-yl)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyrazin-5-yl)phenyl)acrylamide (7 mg, 0.01 mmol) was dissolved in methanol (3 mL), 5N sodium hydroxide solution (13.1 μL, 0.06 mmol) was added, the reaction was heated at 50°C for 3 hours, diluted with water (10 mL), and extracted with dichloromethane (15 mL x 3 ), dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=2/1) to obtain 2 mg of pale yellow solid, yield: 37.07%.

MS(ESI, pos.ion) m/z: 411.15[M+1] ⁺ ;

1H NMR (600MHz, _CD3OD ): δ(ppm) 8.49(s,1H), 8.48(s,1H), 7.91(s,1H), 7.87(s,1H), 7.65–7.58(m,2H) ,7.47(m,4H),7.28(d,J＝3.0Hz,1H),6.53(d,J＝2.9Hz,1H),3.81–3.70(m,3H),3.39(s,3H),2.66( t, J=6.1Hz, 2H);

¹³ C NMR (150MHz, CD ₃ OD): δ(ppm) 171.0, 148.0, 140.9, 140.0, 139.1, 135.3, 129.1, 129.1, 128.6, 126.4, 125.5, 124.7, 122.7, 122.6, 121.0, 119.2, 118.4, 1 , 118.2, 117.9, 111.2, 101.1, 68.2, 57.5, 37.0.

Example 99

3-((4-(2-(1-Methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl)phenyl)amino)propionitrile

Step 1: Synthesis of compound (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)(4-nitrophenyl)methanol

At room temperature, methanol (25 mL) was added to a mixture of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (3 g, 15.15 mmol) and p-nitrobenzaldehyde (5.4 g, 36 mmol), and the mixture was stirred at room temperature After 10 minutes, potassium hydroxide (5.4 g, 96 mmol) was added, and stirring was continued for 48 hours at room temperature. The reaction was stopped, diluted with water (50 mL), extracted with dichloromethane (50 mL×3), dried over anhydrous sodium sulfate, and concentrated by column chromatography (petroleum Ether/ethyl acetate (v/v)=2/1) gave 1.35 g of pale yellow solid, yield: 25.3%.

MS(ESI, pos.ion) m/z: 348.8, 350.8[M+1] ⁺ .

Step 2: Synthesis of compound (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)(4-nitrophenyl)methanone

To a solution of (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)(4-nitrophenyl)methanol (210 mg, 0.60 mmol) in tetrahydrofuran (7 mL) was added DESS- MARTIN oxidant (530 mg, 1.23 mmol), stirred at room temperature for 4 hours, diluted with water (15 mL), extracted with dichloromethane (20 mL×3), dried over anhydrous sodium sulfate, concentrated by column chromatography (petroleum ether/ethyl acetate (v/v) =2/1) 170 mg of pale yellow solid were obtained, yield: 81.42%.

MS (ESI, pos.ion) m/z: 347.05, 349.10 [M+1] ⁺ .

Step 3: Compound (2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(4 Synthesis of -nitrophenyl)methanone

To a solution of (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)(4-nitrophenyl)methanone (170 mg, 0.49 mmol) in DMF (8 mL) was added sodium hydride (60%, 40 mg, 1.0 mmol), stirred at room temperature for 30 minutes, added SEMCl (120 μL, 0.67 mmol), continued to stir at room temperature for 4 hours, quenched by adding water (30 mL), extracted with dichloromethane (30 mL×3), and dried over anhydrous sodium sulfate , after concentration, column chromatography (petroleum ether/ethyl acetate (v/v)=3/1), filtration and drying to obtain 180 mg of yellow solid, yield: 76.98%.

MS(ESI, pos.ion) m/z: 477.75.479.75[M+1] ⁺ .

Step 4: Compound (2-(1-Methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3 Synthesis of -b]pyrazin-7-yl)(4-nitrophenyl)methanone

To (2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(4-nitro Phenyl)methanone (180mg, 0.37mmol) in 1,4-dioxane (6mL) solution, potassium carbonate (80mg, 0.57mmol), 1-methylpyrazole borate (106mg, 0.50mmol) were added successively ) and Pd(dppf)Cl ₂ (30mg, 0.04mmol), water (1.5mL), nitrogen protection, heated at 115°C under reflux for 5.5 hours, diluted with water (40mL), extracted with dichloromethane (55mLx3), anhydrous sodium sulfate It was dried and concentrated by column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain 120 mg of a yellow solid, yield: 66.50%.

MS(ESI, pos.ion) m/z: 479.30[M+1] ⁺ .

Step 5: Compound (4-aminophenyl)(2-(1-methyl-1H-pyrrolo-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl) Synthesis of -5H-pyrrolo[2,3-b]pyrazin-7-yl)methanone

To (2-(1-methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b] Palladium on carbon (10%, 10 mg, 0.01 mmol) was added to a solution of pyrazin-7-yl)(4-nitrophenyl)methanone (120 mg, 0.25 mmol) in methanol (6 mL), replaced with hydrogen, and stirred at room temperature for 1.5 hours , filtered, and concentrated by column chromatography (petroleum ether/ethyl acetate (v/v)=0/1) to obtain 44 mg of pale yellow oil, yield: 39.12%.

MS(ESI, pos.ion) m/z: 448.90[M+1] ⁺ .

Step 6: Compound 3-((4-(2-(1-methyl-1H-pyrrol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H - Synthesis of pyrrolo[2,3-b]pyrazine-7-carbonyl)phenyl)amino)propionitrile

To (4-aminophenyl)(2-(1-methyl-1H-pyrrolo-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H- To a solution of pyrrolo[2,3-b]pyrazin-7-yl)methanone (100 mg, 0.22 mmol) in acrylonitrile (10 mL), was added aluminum trichloride (45 mg, 0.33 mmol), and the reaction was carried out at 85 °C for 24 After 1 hour, a small amount of methanol (5 mL) was added to quench the reaction, filtered, the filtrate was diluted with water (40 mL), extracted with dichloromethane (55 mL×3), dried over anhydrous sodium sulfate, and concentrated by column chromatography (petroleum ether/ethyl acetate (v/v) )=2/1) to give 70 mg of yellow oil, yield: 70.64%.

MS(ESI, pos.ion) m/z: 502.3[M+1] ⁺ .

Step 7: Compound 3-((4-(2-(1-Methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl)phenyl) Synthesis of Amino)Propionitrile

To 3-((4-(2-(1-methyl-1H-pyrrol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo [2,3-b]pyrazine-7-carbonyl)phenyl)amino)propionitrile (79 mg, 0.15 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (2 mL), stirred at room temperature overnight, and the solvent was concentrated , add tetrahydrofuran (6mL) to dissolve, add ethylenediamine to neutralize to pH>7, stir at room temperature for 3 hours, add water (20mL) to dilute, extract with dichloromethane (20mL x 3), dry over anhydrous sodium sulfate, and concentrate for column chromatography (Petroleum ether/ethyl acetate (v/v) = 0/1), 7 mg of yellow solid was obtained by preparative plate isolation, yield: 11.97%.

MS(ESI, pos.ion) m/z: 372.25[M+1] ⁺ ;

¹ H NMR (600MHz, DMSO-d ₆ ): δ(ppm) 12.75(s, 1H), 8.69(s, 1H), 8.31(s, 1H), 8.26(s, 1H), 7.99(s, 1H) ,7.88(d,J＝8.7Hz,2H),6.88(t,J＝6.0Hz,1H),6.74(d,J＝8.7Hz,2H),3.90(s,3H),3.48(dd,J＝ 12.6,6.3Hz,2H),2.79(t,J=6.5Hz,2H);

¹³ C NMR (150MHz, DMSO-d ₆ ): δ(ppm) 207.0, 152.1, 143.1, 140.4, 137.3, 136.8, 136.0, 135.3, 132.7, 129.5, 127.1, 121.5, 120.0, 115.2, 111.2, 45.8, 40.5, 17.8.

Example 100

3-((4-(5-Methyl-2-(1-methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)phenyl )amino)propionitrile

Step 1: Synthesis of compound 2-bromo-7-iodo-5-methyl-5H-pyrrolo[2,3-b]pyrazine

At 0°C, sodium hydride (550 mg, 13.75 mmol) was added portionwise to a solution of 2-bromo-7-iodo-5H-pyrrolo[2,3-b]pyrazine (3.00 g, 8.37 mmol) in N,N- dimethylformamide (20 mL) mixture. After stirring at room temperature for 1.5 h, methyl iodide (2.2 g, 16.00 mmol) was slowly added dropwise at 0°C. After the dropwise addition, the reaction was stirred at room temperature for 5 h. The reaction was quenched by adding water (50 mL), extracted with ethyl acetate (50 mL x 3), the organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated to remove the solvent, and the residue was separated by column chromatography (petroleum ether/ Ethyl acetate (v/v)=3/1) gave 2.00 g of a pale yellow solid, yield: 64.2%.

MS(ESI, pos.ion) m/z: 337.7[M+1] ⁺ ;

¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm) 8.52-8.30 (m, 1H), 8.18 (d, J=1.8 Hz, 1H), 3.85 (s, 3H).

Step 2: Synthesis of compound 3-((4-(2-bromo-5-methyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)phenyl)amino)propionitrile

Acetonitrile (12 mL)/water (4 mL), 2-bromo-7-iodo-5-methyl-5H-pyrrolo[2,3-b]pyrazine (350 mg, 1.04 mmol), 3-((4-( 4,4,5,5-Tetramethyl-1,3,2-dioxaboropentan-2-yl)phenyl)amino)propionitrile (350 mg, 1.03 mmol), sodium carbonate (330 mg, 3.11 mmol) A mixture of bis(triphenylphosphine) palladium dichloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (40 mg, 0.05 mmol) was prepared according to the synthetic method of Example 1, step 1 to obtain 80 mg of a yellow solid, yield: 21.7% .

MS(ESI, pos.ion) m/z: 356.2[M+1] ⁺ .

Step 3: Compound 3-((4-(5-Methyl-2-(1-methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine-7- Synthesis of base)phenyl)amino)propionitrile

Under nitrogen, 1,4-dioxane (4 mL)/water (1 mL) was added to 3-((4-(2-bromo-5-methyl-5H-pyrrolo[2,3-b]) Pyrazin-7-yl)phenyl)amino)propionitrile (75 mg, 0.18 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron) Pentan-2-yl)-1H-pyrazole (65 mg, 0.31 mmol), potassium carbonate (45 mg, 0.33 mmol) and 1,1'-bisdiphenylphosphinoferrocene palladium dichloride (Pd(dppf) Cl ₂ ) (8 mg, 0.06 mmol), refluxed at 110° C. overnight for reaction, the reaction solution was cooled to room temperature, filtered through celite, the filtrate was concentrated under reduced pressure, and subjected to column separation (petroleum ether/ethyl acetate (v/v)= 0/1) gave 52 mg of a yellow solid, yield: 81.3%.

MS(ESI, pos.ion) m/z: 358.0[M+1] ⁺ ;

¹ H NMR (600MHz, DMSO-d ₆ ): δ(ppm) 8.64(s, 1H), 8.38(s, 1H), 8.14(s, 1H), 8.11(s, 1H), 8.00(d, J= 8.6Hz, 2H), 6.73(d, J=8.7Hz, 2H), 3.94(s, 3H), 3.85(s, 3H), 3.82(s, 1H), 3.40(t, J=6.4Hz, 2H) ,2.76(t,J=6.5Hz,2H);

¹³ C NMR (150MHz, DMSO-d ₆ ): δ(ppm) 146.4, 141.5, 140.0, 137.1, 136.3, 136.2, 134.0, 129.8, 129.4, 127.1, 122.5, 121.7, 120.2, 113.1, 39.5, 39.2, 31.4, 17.9.

biological activity

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

The present invention adopts the following methods to carry out biological tests on the compounds shown:

1. Caliper Mobility Shift Assay was used to detect the inhibitory effect of compounds on JAK1/2/3 enzymes.

2. Prepare 1x kinase reaction solution: JAK2/3: 50 mM HEPES, pH 7.5; 0.0015% Brij-35; 10 mM MgCl ₂ ; 2 mM DTT. JAK1: 25 mM HEPES, pH 7.5; 0.001% Brij-35; 0.01% Triton; 0.5 mM EGTA; 10 mM _MgCl2 .

3. Prepare reaction stop solution: 100 mM HEPES, pH 7.5; 0.0015% Brij-35; 0.2% Coating Reagent #3 (Caliper, Cat. No. 760050); 50 mM EDTA.

4. Enzyme preparation (JAK1/2/3): prepare enzyme solution with 1-fold kinase reaction solution, and the final concentration of enzyme preparation is JAK1 (30nM), JAK2 (2nM), JAK3 (4nM).

5. Substrate preparation: prepare the substrate solution with 1-fold kinase reaction solution. The final concentration of the substrate preparation is shown in Table 1.

Table 1 Substrate preparation final concentration

According to the optimization results of the experimental method, the experiment used 384-well plate (Corning, Cat.No.3573, Lot.No.12608008) for detection, and the concentration of JAK1/2/3 enzymes was prepared as JAK1 (75nM), JAK2 (5nM), JAK 3 (10nM), the final reaction concentration was JAK1 (30nM), JAK2 (2nM), JAK 3 (4nM); the substrate Peptide FAM-P22 was prepared at a concentration of 7.5μM, and the final reaction concentration was 3μM; ATP was prepared at a concentration of JAK1 (225μM) ), JAK2 (50μM), JAK3 (15.5μM), the final reaction concentration is JAK1 (90μM), JAK2 (20 μM), JAK3 (6.2μM); Peptide D (sequence 5-FAM-C6-KKHTDDGYMPMSPGVA-NH2) concentration preparation 7.5 μM, the final reaction concentration is 3 μM; both enzyme and substrate are prepared with 1-fold kinase reaction solution. The reaction system is shown in Table 2.

Table 2 IC ₅₀ detection system for JAK1/2/3 enzymes

A 384-well plate was used for detection. The test sample wells, positive control wells and negative control wells were set up in the experiment. Each sample was tested by double wells to detect the inhibitory effect of compounds on JAK1/2/3 enzymes at 8 concentrations. 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 of Table 2, incubate at 25°C (RT) for 10 minutes, then add the prepared Peptide solution to each well, and incubate at 28°C for 60 minutes. After adding the reaction stop solution , detected at FP485nM excitation/525nM emission wavelength using Caliper EZ Reader, and read the data as conversion rate. The Graph Pad Prism 5 software was used to plot the inhibitory effects of compounds on JAK1/2/3 enzymes at different concentrations, and IC ₅₀ was calculated. The experimental results are shown in Table 3.

Table 3 Enzyme (JAK1/2/3) Inhibition Data for Compounds

The data in Table 3 shows that some of the compounds of the present invention have certain inhibitory effects on JAK1, JAK2 and JAK3, and especially have a strong inhibitory effect on JAK3, which can be effectively used for the treatment of various indications.

Biological Example 2 In vivo PK study of test compounds in rats

SD rats were orally administered 5 mg/kg or 1 mg/kg of the test compound via tail vein injection. Orbital vein blood was collected at time points (0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours and 24 hours) after administration, and collected in anticoagulant tubes with K ₂ EDTA. After liquid-liquid extraction, the plasma samples were quantitatively analyzed on a triple quadrupole tandem mass spectrometer with multiple reactive ion monitoring (MRM). Pharmacokinetic parameters were calculated by non-compartmental model method using WinNonlin 6.1 software.

Conclusion: The compound of the present invention has a moderate clearance rate. After oral administration of 5 mg/kg in SD rats, it shows a higher blood drug exposure, and at the same time, the half-life is reasonable, and it has a relatively good druggability.

Claims (3)

1. A compound, which is a compound having one of the following structures or a stereoisomer or a pharmaceutically acceptable salt of a compound having one of the following structures:

2. A pharmaceutical composition comprising the compound of claim 1 and at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant or vehicle; The pharmaceutical composition described therein further optionally comprises additional therapeutic agents selected from chemotherapeutic agents or anti-proliferative agents, anti-inflammatory agents, immunomodulatory agents or immunosuppressive agents, neurotrophic factors, for Active agents for the treatment of cardiovascular disease, active agents for the treatment of diabetes, and active agents for the treatment of autoimmune diseases. 3. Use of the compound of claim 1 or the pharmaceutical composition of claim 2 in the preparation of a medicament, wherein the medicament is used to prevent, treat, treat or alleviate an autoimmune disease or a proliferative disease in a patient; and/or the drugs described therein are used to inhibit or modulate the activity of protein kinases; Among the autoimmune diseases are lupus, multiple sclerosis, ALS, rheumatoid arthritis, psoriasis, type I diabetes, complications due to organ transplantation, xenotransplantation, diabetes, cancer, asthma, special Atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and lymphoma; Among the proliferative diseases are 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 (central nervous system) cancer, malignant stromal tumor, myeloproliferative disease, atherosclerosis or pulmonary fibrosis; wherein the protein kinase is JAK1, JAK2 or JAK3.