CN106336413B

CN106336413B - Compounds as JAK inhibitors and uses thereof

Info

Publication number: CN106336413B
Application number: CN201610536665.3A
Authority: CN
Inventors: 刘兵; 黄九忠; 郑常春; 张英俊; 欧阳罗; 毛洪芬; 聂飚; 许娟; 陈红分
Original assignee: Sunshine Lake Pharma Co Ltd
Current assignee: Guangdong HEC Pharmaceutical
Priority date: 2015-07-09
Filing date: 2016-07-08
Publication date: 2021-04-20
Anticipated expiration: 2036-07-08
Also published as: CN106336413A

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 uses thereof

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a compound with JAK inhibitory activity, a pharmaceutical composition containing the compound, and application of the compound or the pharmaceutical composition containing the compound in medicines.

Background

Janus kinases (JAKs) belong to the tyrosine kinase family, consisting of JAK1, JAK2, JAK3 and TYK 2. 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 aberrant immune responses, such as allergy, asthma, autoimmune diseases, such as transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis, and multiple sclerosis, and solid and hematologic malignancies, such as leukemias and lymphomas. JAK1, JAK2 and TYK2 can inhibit multiple gene expression, whereas JAK3 only plays a role in granulocytes. Cytokine receptors typically function as heterodimers and are therefore not generally a JAK kinase interacting with cytokine receptors.

Genetic biological studies have shown that JAK1 functions by interacting with cytokine receptors such as IFNalpha, IFNgamma, IL-2, IL-6, and JAK1 knockout mice die due to loss of LIF receptor signaling. The characteristic tissues of JAK1 knockout mice are observed, and JAK1 is found to play an important role in cell pathways such as IFN, IL-10, IL-2/IL-4, IL-6 and the like.

JAK2 has also been implicated in myeloproliferative disorders, including polycythemia vera, essential thrombocythemia, chronic idiopathic myelofibrosis, myelogenous tissue deformation with myelofibrosis, chronic myelogenous leukemia, chronic myelomonocytic leukemia, chronic eosinophilic leukemia, hypereosinophilic syndrome, and systemic mast cell disease.

JAK3 specifically acts on the gamma cytokine receptor chain, which is present 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 serious immune deficiency can be caused by abnormality. 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, amyotrophic lateral sclerosis and multiple sclerosis, and solid and hematologic malignancies such as leukemia, lymphoma. JAK3 inhibitors are useful therapeutics as immunosuppressive agents 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 is unclear (J.Immunol.,2002,168: 2475-2482).

TYK2 acts on the receptor complexes of cytokines such as type I interferon, IL-6, IL-10, IL-12, IL-23, etc. In agreement, primary cells derived from TYK 2-deficient humans present obstacles in signaling of type I interferons, IL-6, IL-10, IL-12, IL-23.

Bruton's Tyrosine Kinase (BTK), a member of the Tec family of non-receptor tyrosine kinases, is a key signaling enzyme expressed in all hematopoietic cell types except T lymphocytes and natural killer cells. The effects of BTK on allergic disorders and/or autoimmune and/or inflammatory diseases have been demonstrated in BTK-deficient mouse models. For example, in a standard murine preclinical (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 cell membranes of various tissues of human bodies, and is an avian erythroblastic leukemia virus (v-erb-b) oncogene homolog. EGFR and the like are over-expressed in tumors of epithelial origin, such as head and neck squamous cell carcinoma, breast cancer, rectal cancer, ovarian cancer, prostate cancer, non-small cell lung cancer and the like, and the expression of the EGFR and the like is related to phenomena such as cancer cell proliferation, metastasis and the like.

The T790M mutation is a point mutation in the EGFR20 exon and is one of the more accepted drug resistance mechanisms. T790M is located at the entrance of the binding pocket of EGFR and ATP, and the size of its side chain directly affects the binding ability of EGFR and ATP. The T790M mutation sterically blocks the EGFR inhibitor's interaction with the ATP binding site, increasing the affinity of EGFR for ATP, and thus rendering the cell resistant to EGFR inhibitors. Originally, T790M was found only in NSCLC patient specimens that failed treatment, but was subsequently found in specimens that were not treated with any treatment, so it is presently believed that this mutation is also present in TKI-untreated tumor tissue, but is found in only a few clonal cells that were selected after treatment due to their resistance to TKI.

Accordingly, there is 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 invention are effective in inhibiting the activity of protein kinases such as JAK1, JAK2, JAK3, BTK, EGFR or EGFR T790M. Such compounds would play a potential role in the treatment of autoimmune and/or inflammatory diseases and/or cancer.

Disclosure of Invention

The compound of the invention has an inhibitory effect on the activity of protein kinase. It is further desirable that the compounds of the present invention have multiple inhibitory functions and may inhibit JAK1, JAK2, JAK3, BTK, EGFR or EGFR T790M. In particular, the compounds and pharmaceutically acceptable pharmaceutical compositions of the invention are effective 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, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of the compound represented by formula (I):

wherein the A ring is further independently optionally substituted with 1,2,3 or 4R¹Substitution;

ring A, ring E, each R¹、R²、R³、R⁵And m 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 (Ia) or a stereoisomer, geometric isomer, tautomer, racemate, nitrogen oxide, hydrate, solvate, metabolite, or pharmaceutically acceptable salt or prodrug of a compound of formula (Ia):

ring A, ring E, each R¹、R²、R³Each R⁴、R⁵And m has the meaning as described in the present invention.

In some embodiments, the present invention relates to a compound of formula (Ib) or a stereoisomer, geometric isomer, tautomer, racemate, nitrogen oxide, hydrate, solvate, metabolite, or pharmaceutically acceptable salt or prodrug of a compound of formula (Ib):

a ring, R⁵And each R¹Have the meaning as described in the present invention.

In some embodiments, the present invention relates to a compound that is a compound of formula (Ic) or a stereoisomer, geometric isomer, tautomer, racemate, nitrogen oxide, hydrate, solvate, metabolite, or pharmaceutically acceptable salt or prodrug of a compound of formula (Ic):

a ring, R⁵And each R¹Have the meaning as described in the present invention.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)): wherein ring A is C_3-9Cycloalkyl radical, C_5-9Cycloalkenyl radical, C_1-9Heterocyclic radical, C_6-10Aryl radical, C_1-9Heteroaryl group, C_6-12Condensed bicyclic group, C_5-12Condensed hetero bicyclic group, C_6-12Spiro bicyclic radical or C_5-12A spiro-heterobicyclic group; the A ring is further independently optionally substituted with 1,2,3 or 4R¹Substitution; each R¹Have the meaning as described in the present invention.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)): wherein ring A is

The A ring is further independently optionally substituted with 1,2,3 or 4R¹Substitution;

wherein, X¹And X²Each independently is-C (R)¹⁴R^14a)-，-N(R¹⁵)-，-O-，-S(＝O)_p-or-C (═ O) -;

X³，X⁴，X⁵and X⁶Each independently is CR¹⁴Or N;

each R¹⁴And R^14aIndependently of one another is hydrogen, deuterium, C_1-4Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl or C_1-4A haloalkyl group;

each R¹⁵Independently of one another is hydrogen, deuterium, C_1-4Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl or C_1-4A haloalkyl group;

each R¹And p has the meaning as described in the present invention.

each R¹Have 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, geometric isomer, tautomer, racemate, nitrogen oxide, hydrate, solvate, metabolite, or pharmaceutically acceptable salt or prodrug of a compound of formula (I) (or formula (Ia)): wherein ring E is a sub-structure as shown below:

"+" indicates with R⁵One end connected with the other end; wherein when ring E is

When the ring A is cyclopropyl;

wherein R is⁵Each R⁴And m has the meaning as described in the present invention.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)): wherein each R is¹Independently is H, deuterium, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, haloalkyl, R- (CR)⁶R⁷)_n-O-，R-(CR⁶R⁷)_n1-，R⁸O-(CR⁶R⁷)_n-，R⁸-C(＝O)-N(R⁹)-，CN-(CR⁶R⁷)_n-R⁰-(CR⁶R⁷)_n-N(R⁹)-，R^9a-N(R⁹) -C (═ O) -, R or R-N (R)⁹)-；

Wherein each R, each R⁰Each R⁶Each R⁷Each R⁸Each R⁹Each R^9aEach n and each n1 have the meaning as described herein.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)): wherein each R¹Independently is H, deuterium, F, Cl, Br, I, CN, C_1-4Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-4Haloalkyl, CN- (CR)⁶R⁷)_n-R⁰-(CR⁶R⁷)_n-N(R⁹)-，R-(CR⁶R⁷)_n-O-，R-(CR⁶R⁷)_n1-，R⁸O-(CR⁶R⁷)_n-，R⁸-C(＝O)-N(R⁹)-，CN-(CR⁶R⁷)_n-S(＝O)_p-R⁰-(CR⁶R⁷)_n-N(R⁹)-，R^9a-N(R⁹) -C (═ O) -, R or R-N (R)⁹)-；

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)): wherein each R¹Independently is H, deuterium, F, Cl, Br, I, CN, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, CN- (CR)⁶R⁷)_n-R⁰-(CR⁶R⁷)_n-N(R⁹)-，R-(CR⁶R⁷)_n-O-，R-(CR⁶R⁷)_n1-，R⁸O-(CR⁶R⁷)_n-，R⁸-C(＝O)-N(R⁹)-，CN-(CR⁶R⁷)_n-S(＝O)_p-R⁰-(CR⁶R⁷)_n-N(R⁹)-，R^9a-N(R⁹) -C (═ O) -, R or R-N (R)⁹) -; wherein each R is⁰Each R, each R⁶Each R⁷Each R⁸Each R⁹Each R^9aEach n and each n1 have the meaning as described herein.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)): wherein each R⁰Independently is C_3-9Cycloalkylene radical, C_5-9Cycloalkenylene radical, C_1-9Heterocyclylene radical, C_6-10Arylene radical, C_1-9Heteroarylene radical, C_6-12Subfenzenebicyclic radical, C_5-12Subfenzeneheterobicyclic radical, C_6-12Spiroidene bicyclic radical or C_5-12A spirolidene heterobicyclic group; each R⁰Independently optionally substituted by 1,2,3 or 4R^6aSubstitution;

each R is independently C_3-9Cycloalkyl radical, C_5-9Cycloalkenyl radical, C_1-9Heterocyclic radical, C_6-10Aryl radical, C_1-9Heteroaryl group, C_6-12Condensed bicyclic group, C_5-12Condensed hetero bicyclic group, C_6-12Spiro bicyclic radical or C_5-12A spiro-heterobicyclic group; each R is independently optionally substituted with 1,2,3 or 4R^6aSubstitution; wherein each R is^6aHave the meaning as described in the present invention.

In some embodiments, the invention relates to a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)) or formula (I) (or formula (Ia), formula (Ib), or formula (Ic) (Ia), formula (Ib), or formula (Ic))Ic)), stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceutically acceptable salts or prodrugs of the compound of formula: wherein each R⁰Independently is

Each R⁰Independently optionally substituted by 1,2,3 or 4R^6aSubstitution;

each R is independently

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

wherein, Y¹And Y²Each independently is-C (R)¹⁶R^16a)-，-N(R¹⁷)-，-O-，-S(＝O)_p-or-C (═ O) -;

Y³，Y⁴and Y⁵Each independently is CR¹⁶Or N;

each R¹⁶And R^16aIndependently of one another is hydrogen, deuterium, C_1-4Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl or C_1-4A haloalkyl group;

each R¹⁷Independently of one another is hydrogen, deuterium, C_1-4Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl or C_1-4A haloalkyl group;

wherein each R is^6aHave the meaning as described in the present invention.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)): wherein each R⁰Independently is

Each R⁰Independently optionally substituted by 1,2,3 or 4R^6aSubstitution;

each R is independently

Each R is independently optionally substituted with 1,2,3 or 4R^6aSubstitution; wherein each R is^6aHave the meaning as described in the present invention.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)): wherein each R^6aIndependently of one another is hydrogen, deuterium, C_1-4Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, F, Cl, Br, I, CN, R^6b-(CR⁶R⁷)_n-S(＝O)_p-, hydroxy, nitro, amino, carboxy or C_1-4An alkoxy group;

wherein each R is⁶Each R⁷、R^6bN and p have the meanings as described in the invention.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)): wherein each R^6bIndependently of one another is hydrogen, deuterium, C_1-4Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, F, Cl, Br, I, CN, hydroxy, nitro, C_1-4Haloalkyl, amino, carboxyl or C_1-4An alkoxy group.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)): wherein each R⁶Independently of one another is hydrogen, deuterium, C_1-4Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, F, Cl, Br, I, CN, hydroxy, nitro, C_1-4Haloalkyl, amino, carboxyl or C_1-4An alkoxy group.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)): wherein each R⁷Independently of one another is hydrogen, deuterium, C_1-4Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, F, Cl, Br, I, CN, hydroxy, nitro, C_1-4Haloalkyl, amino, carboxyl or C_1-4An alkoxy group.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)): wherein each R⁸Independently of one another is hydrogen, deuterium, C_1-4Alkyl radical, C_1-4Haloalkyl or HO- (CR)⁶R⁷)_n-; wherein each R is⁶Each R⁷And each n has the meaning as described in the present invention.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, or each other of a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)) or a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic))Variants, racemates, nitroxides, hydrates, solvates, metabolites and pharmaceutically acceptable salts or prodrugs: wherein each R⁹Independently of one another is hydrogen, deuterium, C_1-4Alkyl radical, C_1-4Haloalkyl or HO- (CR)⁶R⁷)_n-; wherein each R is⁶Each R⁷And each n has the meaning as described in the present invention.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)): wherein each R^9aIndependently of one another is hydrogen, deuterium, C_1-4Alkyl radical, C_1-4Haloalkyl or HO- (CR)⁶R⁷)_n-; wherein each R is⁶Each R⁷And 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, geometric isomer, tautomer, racemate, nitrogen oxide, hydrate, solvate, metabolite, or pharmaceutically acceptable salt or prodrug of a compound of formula (I) (or formula (Ia)): wherein R is²Is H, deuterium, F, Cl, Br, I, CN, C_1-4Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-4Haloalkyl, R⁸O-(CR⁶R⁷)_n-，R⁸-C(＝O)-N(R⁹)-，R^9a-N(R⁹) -C (═ O) -or R^9a-N(R⁹) -; wherein each R is⁶Each R⁷Each R⁸Each R⁹Each R^9aAnd 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, geometric isomer, tautomer, racemate, nitroxide, hydrate of a compound of formula (I) (or formula (Ia))A solvate, a metabolite and a pharmaceutically acceptable salt or prodrug thereof: wherein R is³Is H, deuterium, F, Cl, Br, I, CN, C_1-4Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-4Haloalkyl, R⁸O-(CR⁶R⁷)_n-，R⁸-C(＝O)-N(R⁹)-，R^9a-N(R⁹) -C (═ O) -or R^9a-N(R⁹) -; wherein each R is⁶Each R⁷Each R⁸Each R⁹Each R^9aAnd each n has the meaning as described in the present invention.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound represented by formula (I) (or formula (Ia)): wherein R is⁴Is H, deuterium, F, Cl, Br, I, CN, C_1-4Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-4Haloalkyl, R⁸O-(CR⁶R⁷)_n-，R⁸-C(＝O)-N(R⁹)-，R^9a-N(R⁹) -C (═ O) -or R^9a-N(R⁹) -; wherein each R is⁶Each R⁷Each R⁸Each R⁹Each R^9aAnd each n has the meaning as described in the present invention.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)): wherein R is⁵Is CN- (CR)¹⁰R¹¹)_n1-N(R¹²)-，CN-(CR¹⁰R¹¹)_n1-C(＝O)-N(R¹²)-，CN-(CR¹⁰R¹¹)_n-C_3-9cycloalkyl-N (R)¹²)-，R¹³-O-(CR¹⁰R¹¹)_n1-N(R¹²)-，CN-(CR¹⁰R¹¹)_n1-C_1-9heterocyclyl-C (═ O) -N (R)¹²)-，CN-(CR¹⁰R¹¹)_n-C(＝O)-C_1-9Heterocyclyl radical- (CR)¹⁰R¹¹)_n-N(R¹²)-，R¹³-(CR¹⁰R¹¹)_n1-S(＝O)_p-(CR¹⁰R¹¹)_n-N(R¹²)-，R¹³-(CR¹⁰R¹¹)_n-S(＝O)_p-(R^12a)N-C_3-9cycloalkyl-N (R)¹²)-，R¹³-(CR¹⁰R¹¹)_n-N(R¹²)-C(＝O)-(CR¹⁰R¹¹)_n-(R^12a)N-，CN-(CR¹⁰R¹¹)_n-N(R¹²)-C(＝O)-(CR¹⁰R¹¹)_n-(R^12a)N-，CN-(CR¹⁰R¹¹)_n-C_1-9Heterocyclyl radical- (CR)¹⁰R¹¹)_n-N(R¹²)-，CN-(CR¹⁰R¹¹)_n1-S(＝O)_p-(R^12a)N-，CN-(CR¹⁰R¹¹)_n-C(＝O)-C_1-9Heterocyclyl radical- (CR)¹⁰R¹¹)_n-，CN-(CR¹⁰R¹¹)_n-C_3-9Cycloalkyl- (CR)¹⁰R¹¹)_n1-，HO-(CR¹⁰R¹¹)_n-C_3-9Cycloalkyl- (CR)¹⁰R¹¹)_n1-，CN-(CR¹⁰R¹¹)_n-C_1-9Heterocyclyl radical- (CR)¹⁰R¹¹)_n1-，CN-(CR¹⁰R¹¹)_n1-N(R¹²)-C(＝O)-，CN-(CR¹⁰R¹¹)_n1-，C_6-10Aryl- (CR)¹⁰R¹¹)_n1-，(R^12a)N(R¹²)-C(＝O)-(CR¹⁰R¹¹)_n1-，CN-(CR¹⁰R¹¹)_n-C_1-9Heterocyclyl radical- (CR)¹⁰R¹¹)_n-N(R¹²)-S(＝O)_p-，CN-(CR¹⁰R¹¹)_n-C_1-9Heterocyclyl radical- (CR)¹⁰R¹¹)_n-S(＝O)_p-，CN-(CR¹⁰R¹¹)_n-S(＝O)_p-，R¹³-(CR¹⁰R¹¹)_n-(R^12a)N-S(＝O)_p-，R¹³-(CR¹⁰R¹¹)_n-N(R¹²)-C(＝O)-(CR¹⁰R¹¹)_n-(R^12a)N-S(＝O)_p-or CN- (CR)¹⁰R¹¹)_n1-(R^12a)N-S(＝O)_p-; wherein said aryl, heterocyclyl and cycloalkyl are independently optionally substituted with 1,2,3 or 4R^6cSubstitution; wherein each R is^6cEach R¹⁰Each R¹¹Each R¹²Each R^12aEach R¹³Each n, each n1 and each p have the meaning as described herein.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)): wherein R is⁵Is CN- (CR)¹⁰R¹¹)_n1-N(R¹²)-，CN-(CR¹⁰R¹¹)_n1-C(＝O)-N(R¹²)-，CN-(CR¹⁰R¹¹)_n-C_3-6cycloalkyl-N (R)¹²)-，R¹³-O-(CR¹⁰R¹¹)_n1-N(R¹²)-，CN-(CR¹⁰R¹¹)_n1-C_3-6heterocyclyl-C (═ O) -N (R)¹²)-，CN-(CR¹⁰R¹¹)_n-C(＝O)-C_3-6Heterocyclyl radical- (CR)¹⁰R¹¹)_n-N(R¹²)-，R¹³-(CR¹⁰R¹¹)_n-S(＝O)_p-(R^12a)N-C_3-6cycloalkyl-N (R)¹²)-，R¹³-(CR¹⁰R¹¹)_n-N(R¹²)-C(＝O)-(CR¹⁰R¹¹)_n-(R^12a)N-，CN-(CR¹⁰R¹¹)_n-N(R¹²)-C(＝O)-(CR¹⁰R¹¹)_n-(R^12a)N-，R¹³-(CR¹⁰R¹¹)_n1-S(＝O)_p-(CR¹⁰R¹¹)_n-N(R¹²)-，CN-(CR¹⁰R¹¹)_n-C_3-6Heterocyclyl radical- (CR)¹⁰R¹¹)_n-N(R¹²)-，CN-(CR¹⁰R¹¹)_n1-S(＝O)_p-(R^12a)N-，CN-(CR¹⁰R¹¹)_n-C(＝O)-C_3-6Heterocyclyl radical- (CR)¹⁰R¹¹)_n-，CN-(CR¹⁰R¹¹)_n-C_3-6Cycloalkyl- (CR)¹⁰R¹¹)_n1-，HO-(CR¹⁰R¹¹)_n-C_3-6Cycloalkyl- (CR)¹⁰R¹¹)_n1-，CN-(CR¹⁰R¹¹)_n-C_3-6Heterocyclyl radical- (CR)¹⁰R¹¹)_n1-，CN-(CR¹⁰R¹¹)_n1-, phenyl- (CR)¹⁰R¹¹)_n1-，(R^12a)N(R¹²)-C(＝O)-(CR¹⁰R¹¹)_n1-，CN-(CR¹⁰R¹¹)_n1-N(R¹²)-C(＝O)-，CN-(CR¹⁰R¹¹)_n-C_3-6Heterocyclyl radical- (CR)¹⁰R¹¹)_n-S(＝O)_p-，CN-(CR¹⁰R¹¹)_n-S(＝O)_p-，CN-(CR¹⁰R¹¹)_n-C_3-6Heterocyclyl radical- (CR)¹⁰R¹¹)_n-N(R¹²)-S(＝O)_p-，R¹³-(CR¹⁰R¹¹)_n-(R^12a)N-S(＝O)_p-，R¹³-(CR¹⁰R¹¹)_n-N(R¹²)-C(＝O)-(CR¹⁰R¹¹)_n-(R^12a)N-S(＝O)_p-or CN- (CR)¹⁰R¹¹)_n1-(R^12a)N-S(＝O)_p-; wherein said phenyl, heterocyclyl and cycloalkyl are independently optionally substituted by 1,2,3 or 4R^6cSubstitution; wherein each R is^6cEach R¹⁰Each R¹¹Each R¹²Each R^12aEach R¹³Each n, each n1 and each p have the meaning as described herein.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)): wherein R is⁵Is composed of

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)): wherein each R¹⁰Independently of one another is hydrogen, deuterium, C_1-4Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl or C_1-4A haloalkyl group.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)): wherein each R¹⁰Independently of one another is hydrogen, deuterium, or AEthyl, n-propyl, isopropyl, 2,2, 2-trifluoroethyl or trifluoromethyl.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)): wherein each R¹¹Independently of one another is hydrogen, deuterium, C_1-4Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl or C_1-4A haloalkyl group.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)): wherein each R¹¹Independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, 2,2, 2-trifluoroethyl or trifluoromethyl.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)): wherein each R¹³Independently of one another is hydrogen, deuterium, C_1-4Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl or C_1-4A haloalkyl group.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)): wherein each R¹³Independently are hydrogen, deuterium,methyl, ethyl, n-propyl, isopropyl, 2,2, 2-trifluoroethyl or trifluoromethyl.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)): wherein each R¹²Independently of one another is hydrogen, deuterium, C_1-4Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl or C_1-4A haloalkyl group.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)): wherein each R¹²Independently hydrogen, deuterium, methyl, n-propyl, ethyl or isopropyl;

in some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)): wherein each R^12aIndependently of one another is hydrogen, deuterium, C_1-4Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl or C_1-4A haloalkyl group.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)): wherein each R^12aIndependently of one another is hydrogen, deuterium, methyl, n-propyl, ethyl orIsopropyl group;

in some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)): wherein each R^6cIndependently of one another is hydrogen, deuterium, C_1-4Alkyl, F, Cl, Br, I, CN, hydroxy, nitro, amino, carboxyl or C_1-4An alkoxy group.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)): wherein each R^6cIndependently 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 that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)): wherein each n is independently 0, 1,2 or 3.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)): 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, geometric isomer, tautomer, racemate, nitrogen oxide, hydrate, solvate, metabolite, or pharmaceutically acceptable salt or prodrug of a compound of formula (I) (or formula (Ia)): wherein m is 0, 1,2,3 or 4.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (I) (or formula (Ia), formula (Ib), or formula (Ic)): 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, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound represented by formula (II):

wherein the W ring is optionally further substituted with 1,2,3 or 4 substituents independently selected from the group consisting of fluorine, chlorine, bromine, C_1-4Haloalkyl, nitro, cyano, HO- (CR)³R⁴)_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) -or R;

R、R³、R⁴、R⁵、R⁶m, W ring, R⁰、R⁰⁰、L、Z¹、Z²And 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 (IIa) or a stereoisomer, geometric isomer, tautomer, racemate, nitrogen oxide, hydrate, solvate, metabolite, or pharmaceutically acceptable salt or prodrug of a compound of formula (IIa):

wherein the content of the first and second substances,

optionally further substituted with 1,2,3 or 4 substituents independently selected from fluoro, chloro, bromo, C_1-4Haloalkyl, nitro, cyano, HO- (CR)³R⁴)_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) -or R;

represents a single bond or a double bond;

R、R³、R⁴、R⁵、R⁶、m、X、Y、R¹、R⁰、R⁰⁰、L、Z¹、Z²and n has the meaning as described in the present invention.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (II) (or formula (IIa)) or a compound of formula (II) (or formula (IIa)): wherein Z is¹And Z²Each independently is N or CH.

In some embodiments, the invention relates to a compound that is a compound of formula (II) or a compound of formula (II)Stereoisomers, geometric isomers, tautomers, racemates, nitric oxides, hydrates, solvates, metabolites and pharmaceutically acceptable salts or prodrugs of said compound: wherein, the W ring is as follows:

w ring is optionally further substituted by 1,2,3 or 4 substituents independently selected from fluoro, chloro, bromo, C_1-4Haloalkyl, nitro, cyano, HO- (CR)³R⁴)_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) -or R;

represents a single bond or a double bond;

r, R therein³、R⁴、R⁵、R⁶、m、X、Y、R¹、R⁰、R⁰⁰、Z¹、Z²And n has the meaning as described in the present invention.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (II) (or formula (IIa)) or a compound of formula (II) (or formula (IIa)): wherein X is N, NR^aOr CR^b(ii) a Y is CR^c；

R^a、R^bAnd R^cEach independently is hydrogen or C_1-4An alkyl group; r^aAnd R^cTogether with the ring atoms to which they are attached form a five-or six-membered heteroaryl group; or R^bAnd R^cTogether with the ring atoms to which they are attached form a five-or six-membered heteroaryl group; the heteroaryl group may be independentlyGround selecting quilt R²Substitution;

wherein R is²Have the meaning as described in the present invention.

In some embodiments, the present invention relates to a compound that is a compound of formula (II) or a stereoisomer, geometric isomer, tautomer, racemate, nitrogen oxide, hydrate, solvate, metabolite, or pharmaceutically acceptable salt or prodrug of a compound of formula (II): wherein the W ring is a sub-structural formula as shown below:

the W ring is optionally further substituted with 1,2,3 or 4 substituents independently selected from fluoro, chloro, bromo, trifluoromethyl, 2, 2-difluoroethyl, 3,3, 3-trifluoropropyl, nitro, cyano, HO- (CR)³R⁴)_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) -or R;

r, R therein³、R⁴、R⁵、R⁶、m、R¹And R²Have the meaning as described in the present invention.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (II) (or formula (IIa)) or a compound of formula (II) (or formula (IIa)): wherein R is¹Is H, deuterium, C_1-4Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl or hydroxy.

In some embodiments, the present inventionThe invention relates to a compound which is a compound shown as a formula (II) (or a formula (IIa)) or a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite and a pharmaceutically acceptable salt or prodrug of the compound shown as the formula (II) (or the formula (IIa)): wherein R is¹Is H, deuterium, methyl, ethyl, isopropyl or n-propyl.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (II) (or formula (IIa)) or a compound of formula (II) (or formula (IIa)): wherein R is²Is H, deuterium, C_1-4Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl or hydroxy.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (II) (or formula (IIa)) or a compound of formula (II) (or formula (IIa)): wherein R is²Is H, deuterium, methyl, ethyl, isopropyl or n-propyl.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (II) (or formula (IIa)) or a compound of formula (II) (or formula (IIa)): wherein R is⁰Is fluorine, chlorine, bromine, C_1-4Haloalkyl, nitro, cyano, HO- (CR)³R⁴)_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) -or R;

r, R therein³、R⁴、R⁵、R⁶And m has the meaning as described in the present invention.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (II) (or formula (IIa)) or a compound of formula (II) (or formula (IIa)): wherein R is⁰Is fluorine, chlorine, bromine, trifluoromethyl, 2, 2-difluoroethyl, 3,3, 3-trifluoropropyl, nitro, cyano, HO- (CR)³R⁴)_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) -or R;

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (II) (or formula (IIa)) or a compound of formula (II) (or formula (IIa)): wherein R is⁰⁰Is fluorine, chlorine, bromine, nitro, cyano, HO-, H-S-, H₂N-C(＝O)-，H-C(＝O)-NH-，NH₂-，H-C(＝O)-，H-C(＝O)O-，H-OC(＝O)-，H-S(＝O)₄-，H-S(＝O)-，H₂N-S(＝O)₂-，H-S(＝O)₂-NH-，H₂N-C(＝O)-NH-，CH₃O-, phenyl, C_1-4Alkyl radical, C_2-6Alkenyl radical, C_1-4Haloalkyl or C_2-6Alkynyl.

In some embodiments, the invention relates to a compound of formula (II)(or formula (IIa)) or a stereoisomer, geometric isomer, tautomer, racemate, nitrogen oxide, hydrate, solvate, metabolite, and pharmaceutically acceptable salt or prodrug of a compound of formula (II) (or formula (IIa)): wherein L is-NH-S (═ O)₂-or-NH-.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (II) (or formula (IIa)) or a compound of formula (II) (or formula (IIa)): wherein each R is independently H, deuterium, C_1-4Alkyl radical, C_2-6Alkenyl radical, C_1-4Haloalkyl or C_2-6Alkynyl.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (II) (or formula (IIa)) or a compound of formula (II) (or formula (IIa)): 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 stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (II) (or formula (IIa)) or a compound of formula (II) (or formula (IIa)): wherein each R is³Independently of one another is H, deuterium, C_1-4Alkyl radical, C_2-6Alkenyl radical, C_1-4Haloalkyl or C_2-6Alkynyl.

In some embodiments, the invention relates to a compound that is a compound of formula (II) (or formula (IIa)) or a stereoisomer, geometric isomer, tautomer, racemate, nitrogen oxide, hydrate, solvate, metabolite, and pharmaceutically acceptable salt or salt of a compound of formula (II) (or formula (IIa))Prodrug: wherein each R is³Independently 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 stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (II) (or formula (IIa)) or a compound of formula (II) (or formula (IIa)): wherein each R is⁴Independently of one another is H, deuterium, C_1-4Alkyl radical, C_2-6Alkenyl radical, C_1-4Haloalkyl or C_2-6Alkynyl.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (II) (or formula (IIa)) or a compound of formula (II) (or formula (IIa)): wherein each R is⁴Independently 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 stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (II) (or formula (IIa)) or a compound of formula (II) (or formula (IIa)): wherein each R is⁵Independently of one another is H, deuterium, C_1-4Alkyl radical, C_2-6Alkenyl radical, C_1-4Haloalkyl or C_2-6Alkynyl.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (II) (or formula (IIa)) or a compound of formula (II) (or formula (IIa)): wherein each R is⁵Independently is H, deuterium, trifluoromethyl, 2, 2-difluoroethyl, 3,3, 3-trifluoro-ethylPropyl, methyl, ethyl, isopropyl or n-propyl.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (II) (or formula (IIa)) or a compound of formula (II) (or formula (IIa)): wherein each R is⁶Independently of one another is H, deuterium, C_1-4Alkyl radical, C_2-6Alkenyl radical, C_1-4Haloalkyl or C_2-6Alkynyl.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (II) (or formula (IIa)) or a compound of formula (II) (or formula (IIa)): wherein each R is⁶Independently 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 stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (II) (or formula (IIa)) or a compound of formula (II) (or formula (IIa)): wherein each n is independently 1,2,3 or 4.

In some embodiments, the present invention relates to a compound that is a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (II) (or formula (IIa)) or a compound of formula (II) (or formula (IIa)): wherein m is 0, 1,2,3 or 4.

In one aspect, the invention relates to a compound, which is a compound represented by formula (III) or a stereoisomer, geometric isomer, tautomer, racemate, nitrogen oxide, hydrate, solvate, metabolite, and pharmaceutically acceptable salt or prodrug of a compound represented by formula (III):

the V ring is

Wherein "+" represents a terminal linked to-NH-;

q is 1,2,3 or 4;

p is 1,2,3 or 4;

R⁸is HO- (CR)¹⁰R¹¹)_p-，H-(CR¹⁰R¹¹)_p-O-，R⁹-N(R¹²)-，R⁹-C (═ O) O-or R⁹；

R¹²Is H, deuterium, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl or C_1-4A haloalkyl group;

each R⁹、R¹¹And R¹⁰Independently of one another is H, deuterium, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-4Haloalkyl or C_1-4An alkoxy group.

In some embodiments, the present invention relates to a compound that is a compound of formula (III) or a stereoisomer, geometric isomer, tautomer, racemate, nitrogen oxide, hydrate, solvate, metabolite, or pharmaceutically acceptable salt or prodrug of a compound of formula (III): wherein R is¹²Is H, deuterium, trifluoromethyl, 2, 2-difluoroethyl, 3,3, 3-trifluoropropyl, methyl, ethyl, isopropyl or n-propyl;

each R⁹、R¹¹And R¹⁰Independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, tert-butyl, 2-methylpropyl, trifluoromethyl, methoxy or ethoxy.

A compound which is a compound having one of the following structures or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug of a compound having one of the following structures:

one aspect of the present invention relates to a pharmaceutical composition comprising a compound of the present invention, or a stereoisomer, geometric isomer, tautomer, racemate, nitrogen oxide, hydrate, solvate, metabolite, metabolic precursor, pharmaceutically acceptable salt or prodrug thereof, or optionally a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof.

In some embodiments, the pharmaceutical composition of the present invention further comprises an additional therapeutic agent selected from the group consisting of a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating diabetes, and an agent for treating autoimmune disease.

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

In some embodiments, the autoimmune disease described herein is lupus, multiple sclerosis, amyotrophic lateral sclerosis, rheumatoid arthritis, psoriasis, type I diabetes, complications due to organ transplantation, foreign body transplantation, diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, crohn's disease, alzheimer's disease, leukemia, or lymphoma.

In some embodiments, the proliferative disease of the 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, cancer of the CNS (central nervous system), glioblastoma, myeloproliferative disease, atherosclerosis or pulmonary fibrosis.

In another aspect, the invention relates to the use of a compound of the invention or a pharmaceutical composition comprising a compound of the invention for the preparation of a medicament for inhibiting or modulating the activity of a protein kinase.

In some embodiments, the protein kinase is JAK1, JAK2, JAK3, BTK, EGFR or EGFR t 790M.

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

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

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

The invention also encompasses a method of treating an autoimmune disease or a proliferative disease, or a condition responsive thereto, in a subject, comprising treating the subject with a therapeutically effective amount of a compound represented by formula (I), formula (Ia), formula (Ib), formula (Ic), formula (II), formula (IIa) or formula (III).

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

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

Salts of the compounds of the invention also include, but are not necessarily pharmaceutically acceptable salts of isolated enantiomers of intermediates used in the preparation or purification of compounds of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (II), formula (IIa) or formula (III) or of compounds of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (II), formula (IIa) or formula (III).

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

Any formulae given herein are also intended to represent the non-isotopically enriched forms as well as the isotopically enriched forms of these compounds. Isotopically enriched compounds have the structure depicted by the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as²H， ³H，¹¹C，¹³C，¹⁴C，¹⁵N，¹⁷O，¹⁸O，¹⁸F，³¹P，³²P，³⁵S，³⁶Cl and¹²⁵I。

in another aspect, the compounds of the invention include isotopically enriched compounds as defined herein, e.g. wherein a radioisotope, e.g. is present³H，¹⁴C and¹⁸those compounds of F, or in which a non-radioactive isotope is present, e.g.²H and¹³C. the isotopically enriched compounds can be used for metabolic studies (use)¹⁴C) Reaction kinetics study (using, for example²H or³H) Detection or imaging techniques such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) including drug or substrate tissue distribution determination, or may be used in radiotherapy of a patient.¹⁸F-enriched compounds are particularly desirable 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 prepared by conventional techniques known to those skilled in the art or by the procedures and examples described in the present specification using an appropriate isotopically labelled reagent in place of the original used unlabelled reagent.

In addition, heavier isotopes are, in particular, deuterium (i.e.,²substitution of H or D) may provide certain therapeutic advantages resulting from greater metabolic stability. For example, increased in vivo half-life or decreased dosage requirements or improved therapeutic index. It is understood that deuterium in the present invention is contemplatedThe substituent of the compound shown as the formula (I), the formula (Ia), the formula (Ib), the formula (Ic), the formula (II), the formula (IIa) or the formula (III) is shown. The concentration of such heavier isotopes, particularly deuterium, can be defined by isotopic enrichment factors. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic and natural abundance of a given isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), 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 invention include those in which the crystallization solvent may be isotopically substituted, e.g. D₂O, acetone-d₆、DMSO-d₆Those solvates of (a).

The foregoing has outlined only certain aspects of the present invention but is not limited in that these and other aspects will be more fully described in the following detailed description.

Detailed description of the invention

Definitions and general terms

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. One skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can 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 documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.

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

Unless defined otherwise, 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.

The following definitions, as used herein, should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry can be referred to as described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and Jerry March, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.

The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, as used herein, the articles refer to articles of one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in embodiments of the described embodiments.

The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.

"stereoisomers" refers to compounds having the same chemical structure but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.

"chiral" is a molecule having the property of not overlapping its mirror image; and "achiral" refers to a molecule that can overlap with its mirror image.

"enantiomer" refers to two isomers of a compound that are not overlapping but are in mirror image relationship to each other.

"diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.

The stereochemical definitions and rules used in the present invention generally follow the general definitions of 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 an optically active form, i.e., 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 a molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as an enantiomeric mixture. A50: 50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.

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

Depending on the choice of starting materials and methods, the compounds of the invention may exist as one of the possible isomers or as mixtures thereof, for example as racemates and mixtures of non-corresponding isomers (depending on the number of asymmetric carbon atoms). 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 substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration; the cis and trans configurations of pyrrolidinyl exist as in inventive example 37.

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (prototropic tautomers), also known as proton transfer tautomers (prototropic tautomers), include interconversions by proton transfer, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers (valenctautomers) include interconversion by recombination of some of the bonding electrons. A specific example of keto-enol tautomerism is the tautomerism of the pentan-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the tautomerism of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

The compounds of the invention may be optionally substituted with one or more substituents, as described herein, in compounds of the general formula above, or as specifically exemplified, sub-classes, and classes of compounds encompassed by the invention. It is understood that the term "optionally substituted" may be used interchangeably with the term "substituted or unsubstituted". In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular 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 may be substituted at each position, identically or differently. Wherein said substituent may be, but is not limited to, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, alkyl, alkoxy, aryloxy, heteroaryloxy, heterocyclyloxy, arylalkoxy, heteroarylalkoxy, alkylacyl, heteroalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylacyl, aryl, arylalkyl, arylamino, heteroaryl, heteroarylalkyl, heteroarylamino, amido, sulfonyl, aminosulfonyl, and the like.

In addition, unless otherwise explicitly indicated, the descriptions of the terms "… independently" and "… independently" and "… independently" used in the present invention are interchangeable and should be understood in a broad sense to mean that the specific items expressed between the same symbols do not affect each other in different groups or that the specific items expressed between the same symbols in the same groups do not affect each other. With R¹⁰For example, the structural formula "R¹³-(CR¹⁰R¹¹)_n1-S(＝O)_p-(CR¹⁰R¹¹)_n-N(R¹²) - "and the formula" R¹³-(CR¹⁰R¹¹)_n-N(R¹²)-C(＝O)-(CR¹⁰R¹¹)_n-(R^12a) N- "between R¹⁰Are not affected by each other, and are in the same chemical formula¹³-(CR¹⁰R¹¹)_n-N(R¹²)-C(＝O)-(CR¹⁰R¹¹)_n-(R^12a) N- ", two R¹⁰Are not affected by each other.

In the various parts of this specification, the invention discloses compounds having substituents according to formulaThe cluster type or range is disclosed. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C₁-C₆Alkyl "or" C_1-6Alkyl "means in particular independently disclosed methyl, ethyl, C₃Alkyl radical, C₄Alkyl radical, C₅Alkyl and C₆An alkyl group.

In each of the parts of the invention, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively. For example, "CN- (CR)¹⁰R¹¹)_n1-C_1-9heterocyclyl-C (═ O) -N (R)¹²) - ", each through C_1-9The heterocyclyl group is attached to the remainder of the formula, and when heterocyclyl is recited, it is understood that "heterocyclyl" represents an attached heterocyclylene group. And for example "CN- (CR)⁶R⁷)_n-R⁰-(CR⁶R⁷)_n-N(R⁹) - "in R⁰Cycloalkyl and the like, wherein cycloalkyl and the like are understood to be cycloalkylene groups and the like.

The term "alkyl" or "alkyl group" as used herein, denotes a saturated, straight or branched chain monovalent hydrocarbon radical containing from 1 to 10 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents as described herein. Unless otherwise specified, alkyl groups contain 1-6 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 4 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 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-1-butyl, n-hexyl, 2-hexyl, and the like.

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.ident.CH), propargyl (-CH. ident.CH)₂C.ident.CH), 1-propynyl (-C.ident.C-CH)₃) And so on.

The term "alkoxy" means an alkyl group attached to the rest 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 to 6 carbon atoms; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group 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" denotes an alkyl group substituted with one or more halogen atoms, examples of which include, but are not limited to, -CH₂F，-CHF₂Trifluoromethyl, -CH₂Cl，-CHCl₂，-CCl₃，-CH₂CF₃，-CH₂CH₂CF₃And the like.

The term "carbocyclyl" or "carbocycle" refers to a monovalent or multivalent saturated or partially unsaturated monocyclic, bicyclic, or tricyclic ring system containing 3 to 12 carbon atoms, wherein the monocyclic, bicyclic, or tricyclic ring does not contain an aromatic ring. Carbobicyclic groups include spirocarbocyclic and fused carbocyclic groups, and suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl groups. Examples of carbocyclyl groups further include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, and the like.

The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms, wherein the monocyclic, bicyclic or tricyclic ring does not contain an aromatic ring. In one embodiment, the cycloalkyl group contains 3 to 9 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3 to 6 carbon atoms. The cycloalkyl groups may be independently unsubstituted or substituted with one or more substituents described herein. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.

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

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic ring containing 3 to 12 ring atoms, wherein no aromatic ring is included in the monocyclic, bicyclic, or tricyclic ring, and at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, heterocyclyl may be carbon-or nitrogen-based, and-CH₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. In heterocyclic radicals of-CH₂Examples of-groups substituted by-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl. Examples of sulfur atoms in heterocyclic groups that are oxidized include, but are not limited to, sulfolane, 1, 1-dioxothiomorpholinyl.

In one embodiment, heterocyclyl is a 4-7 atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 4-7 ring atoms in which at least one ring atom is selected from the group consisting of 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-dioxolanylDithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, tetrahydropyridinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl. In heterocyclic radicals of-CH₂Examples of-groups substituted by-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl. Examples of sulfur atoms in heterocyclic groups that are oxidized include, but are not limited to, sulfolane, 1, 1-dioxothiomorpholinyl. Said heterocyclyl group of 4 to 7 atoms may be optionally substituted by one or more substituents as described herein. In another embodiment, heterocyclyl is a 4 atom heterocyclyl, examples include, but are not limited to: azetidinyl, oxetanyl, thietanyl. In another embodiment, heterocyclyl is a 5 atom heterocyclyl, examples include, but are not limited to: pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, sulfolane. In another embodiment, heterocyclyl is a 6 atom heterocyclyl, examples include, but are not limited to: tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxanyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl, 1, 1-dioxothiomorpholinyl. The 6-atom heterocyclyl group may be optionally substituted with one or more substituents described herein.

The terms "fused bicyclic ring" and "fused bicyclic group" are used interchangeably herein and refer to a monovalent or multivalent saturated or partially unsaturated bridged ring system, which refers to a bicyclic ring system. The term "bridged ring" means that any two rings share two atoms which may or may not be directly attached. Examples include, but are not limited to, hexahydrofuro [3,2-b ] furan, 2,3,3a,4,7,7 a-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,5,8,8 a-octahydronaphthalene.

The term "fused heterobicyclic ring" denotes a fused ring system which is saturated or partially unsaturated and at least one ring system comprises one or more heteroatoms, wherein each ring system comprises a 3-7 membered ring, i.e. comprises 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to give a fused ring system like SO, SO₂，PO，PO₂Examples of such 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, and the like, and the fused heterobicyclic group may be substituted or unsubstituted.

The terms "spirobicyclic group" or "spirobicyclic ring" are used interchangeably herein and refer to a monovalent or multivalent saturated or partially unsaturated ring system in which one ring is derived from a specific ring carbon atom on another ring. Each ring in the spirobicyclic group can be a carbocyclyl or heterocyclyl and each ring is optionally substituted with one or more substituents described herein.

The term "spiroheterobicyclic group" means that one ring originates from a specific cyclic carbon on another 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 is optionally substituted by one or more oxygen atoms to give, for example, SO₂，PO，PO₂Examples of such include, but are not limited to, 4-azaspiro [2.4 ]]Heptane-5-yl, 4-oxaspiro [2.4 ]]Heptane-5-yl, 5-azaspiro [2.4 ]]Heptane-5-yl, 7-hydroxy-5-azaspiro [2.4 ]]Heptane-5-yl, and the like.

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

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

The term "aryl" denotes monocyclic, bicyclic and tricyclic carbon ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system comprises a ring of 3 to 7 atoms with one or more attachment points to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring". Examples of the aryl group may include phenyl, indenyl, naphthyl and anthryl.

The term "heteroaryl" denotes monocyclic, bicyclic and tricyclic ring systems containing 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 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 to 7 atoms with one or more attachment points to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". 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 (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g. 2-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 3-triazolyl, 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, pyrazinyl, 1,3, 5-triazinyl, pyrimidinonyl, pyridonyl; the following bicyclic rings are also included, but are in no way limited to these: benzimidazolyl, benzofuranyl, benzotetrahydrofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), tetrahydroquinolyl (e.g., 1,2,3, 4-tetrahydroquinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl), tetrahydroisoquinolyl (e.g., 1,2,3, 4-tetrahydroisoquinolyl), imidazo [1,2-a ] pyridyl, pyrazolo [1,5-a ] pyrimidyl, 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 ] pyridinyl, and the like.

In one embodiment, the heteroaryl group is of the following sub-formula:

and so on.

The term "carboxy", whether used alone or in combination with other terms, such as "carboxyalkyl", denotes-CO₂H。

The ring system formed by the ring with the substituent R bonded to the center, as described herein, represents that the substituent R may be substituted at any substitutable or any reasonable position on the ring. For example, the ring represented by formula a may be substituted with R at any possible position on the ring D and the ring B, as shown by formula B, formula c, formula D, formula e, formula f, formula g and formula h.

As described herein, substituent (R)_nThe ring system formed by a ring with a bond to the center 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 may be substituted with n R.

As described herein, there are two attachment points on ring C that can be attached to the rest of the molecule, for example, as shown in formula j, meaning that either the E "or E' end is attached to the rest of the molecule, i.e., the attachment of the two ends can be interchanged.

The attachment point may be attached to the rest of the molecule at any point on the ring that is attachable, as described herein. For example, formula k represents any possible attachment location on the ring as a point of attachment.

As described herein, the attachment point can be attached to the rest of the molecule at any point on the ring that is attachable, while the two ends of the attachment can be interchanged. For example, the formula m represents that any possible connection position on the ring 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 and other functional groupsWhen reacted, are often used to block or protect specific functionalities. For example, "amino protecting group" means a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, and suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, "hydroxyl protecting group" refers to the functionality of a substituent of a hydroxyl group to block or protect the hydroxyl group, and suitable protecting groups include acetyl and silyl groups. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-CH₂CH₂SO₂Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General descriptions of protecting groups can be found in the literature: greene, Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005。

The term "prodrug" as used herein, represents a compound that is converted in vivo to a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (II), formula (IIa) or formula (III). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C)_1-24) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14of the A.C.S.symposium 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 S.J.Hecker et al.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。

"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, 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 are: berge et al, description of the scientific acceptable salts in detail in J. pharmaceutical Sciences,1977,66:1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or those obtained by other methods described in the literature above, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodiates2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N⁺(C_1-4Alkyl radical)₄A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C_1-8Sulfonates and aromatic sulfonates.

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

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

As used herein, "inflammation" refers to a local protective response caused by tissue damage or destruction that serves to destroy, dilute, or separate (sequester) harmful substances from damaged tissue. Inflammation is significantly linked to leukocyte influx and/or neutrophil chemotaxis. Inflammation can result 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 and autoimmune responses to foreign antigens. Thus, inflammatory diseases that may be treated with the disclosed compounds include: diseases associated with specific defense system reactions as well as non-specific defense system reactions.

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

As used herein, "arthritic disease" refers to any disease characterized by inflammatory injury to the joints attributable to various etiologies. As used herein, "dermatitis" refers to any of a large family of skin diseases characterized by skin inflammation attributable to various etiologies. As used herein, "transplant rejection" refers to any immune response against a transplanted tissue, such as an organ or cell (e.g., bone marrow), characterized by loss of function of the transplanted or surrounding tissue, pain, swelling, leukocytosis, and thrombocytopenia. The therapeutic methods of the invention include methods for treating diseases associated with inflammatory cell activation.

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

pharmaceutical compositions, formulations and administration of the compounds of the invention

The present invention provides a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle, or combination thereof. The amount of compound in the pharmaceutical compositions disclosed herein is that amount which is effective to detect inhibition of a protein kinase in a biological sample or patient.

It will also be appreciated that certain compounds of the invention may be present in free form for use in therapy or, if appropriate, in the form of a pharmaceutically acceptable derivative thereof. Some non-limiting embodiments of pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any additional adduct or derivative that upon administration to a patient in need thereof provides, directly or indirectly, a compound of the present invention or a metabolite or residue thereof.

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

As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, mixture or vehicle, which is compatible with the dosage form or pharmaceutical composition to be administered. Each excipient, when mixed, must be compatible with the other ingredients of the pharmaceutical composition to avoid interactions that would substantially reduce the efficacy of the disclosed compounds and which would result in a pharmaceutical composition that is not pharmaceutically acceptable when administered to a patient. Furthermore, each excipient must be pharmaceutically acceptable, e.g., 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, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants and buffers. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may provide more than one function, and provide alternative functions, depending on how many such excipients are present in the formulation and those other excipients are present in the formulation.

Exemplary pharmaceutically acceptable carriers or components thereof are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; tragacanth powder; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; synthetic oil; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; a phosphate buffer solution; emulsifiers, such as tweens; wetting agents, such as sodium lauryl sulfate; a colorant; a flavoring agent; tabletting; a stabilizer; an antioxidant; a preservative; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

The disclosed compounds may also be conjugated to soluble polymers as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol or polyoxyethylene polylysine substituted with palmitoyl residues. In addition, the disclosed compounds may be combined with a class of biodegradable polymers used in achieving controlled release of a drug, such as polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.

The pharmaceutical compositions provided by the present invention may 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 carriers include, but are not limited to: water, saline, normal saline or Phosphate Buffered Saline (PBS), sodium chloride injection, Ringers injection, isotonic glucose injection, sterile water injection, dextrose and lactated Ringers injection. Non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and the medium chain triglycerides of coconut oil, and palm seed oil. Water-miscible vehicles include, but are not limited to, ethanol, 1, 3-butanediol, liquid polyethylene glycols (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerol, N-methyl-2-pyrrolidone, N-dimethylacetamide, and dimethylsulfoxide.

Suitable antimicrobial agents or preservatives include, but are not limited to, phenol, cresol, mercurial, benzyl alcohol, chlorobutanol, methyl and propyl parabens, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl and propyl parabens, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerol and glucose. Suitable buffers include, but are not limited to, phosphate and citrate. 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 carboxymethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. Suitable emulsifiers include those described herein, including polyoxyethylene sorbitan monolaurate. Polyoxyethylene sorbitan monooleate 80 and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to, EDTA. Suitable pH adjusters 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 sulfobutyl ether 7-beta-cyclodextrin (f: (f))

CyDex,Lenexa,KS)。

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

Use of

The present invention provides methods of using the disclosed compounds and pharmaceutical compositions for treating, preventing, or ameliorating one or more symptoms of a disease or disorder mediated or otherwise affected by JAK kinase behavior, including JAK1, JAK2, JAK3, or TYK2, or a disease or disorder mediated or otherwise affected by JAK kinase behavior, including JAK1, JAK2, JAK3, or TYK 2.

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

In one embodiment, the present invention provides a class of compounds disclosed herein or pharmaceutical compositions comprising a compound disclosed herein for treating, preventing or ameliorating one or more symptoms of a disease or disorder mediated or otherwise affected by inappropriate JAK1 kinase behavior or 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 the disease or disorder is associated with inappropriate JAK2 kinase behavior.

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

By "inappropriate JAK kinase behavior" is meant JAK kinase behavior that occurs in a particular patient that deviates from normal JAK kinase behavior. Inappropriate JAK kinase behavior can be expressed in the form of, for example, abnormal increases in activity, or deviations in the time point and control of JAK kinase behavior. This inappropriate kinase behavior results, for example, from 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 above description, such diseases or disorders include, but are not limited to: myeloproliferative diseases, such as polycythemia vera (PCV), essential thrombocythemia, Idiopathic Myelofibrosis (IMF); leukemias, e.g., myeloid leukemias including Chronic Myeloid Leukemia (CML), imatinib-resistant CML forms, Acute Myeloid Leukemia (AML) and subtypes of AML, acute megakaryoblastic leukemia (AMKL); lymphoproliferative diseases, such as myeloma; cancers include head and neck cancer, prostate cancer, breast cancer, ovarian cancer, melanoma, lung cancer, brain tumor, pancreatic cancer, and renal cancer; and inflammatory diseases or disorders associated with immune dysfunction, immunodeficiency, immune modulation, autoimmune diseases, 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 eye syndrome (or keratoconjunctivitis sicca (KCS)).

In one aspect, the present invention provides a class of compounds disclosed herein or pharmaceutical compositions comprising a compound disclosed herein for use in the prevention and/or treatment of a proliferative disease, an autoimmune disease, an allergic disease, an inflammatory disease, or transplant rejection in a mammal (including a human).

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

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

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

In another aspect, provided herein is a class of compounds disclosed herein, or a pharmaceutical composition comprising a compound disclosed herein, for use in the preparation of a medicament for the treatment or prevention of a proliferative disease. In particular examples, the proliferative disease is selected from cancer (e.g., a solid tumor such as uterine leiomyosarcoma or prostate cancer), polycythemia vera, essential thrombocythemia, myelofibrosis, leukemia (e.g., AML, CML, ALL or CLL), and multiple myeloma.

In another aspect, 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 amount or a prophylactically effective amount of one or more of the pharmaceutical compositions or compounds disclosed herein. In a particular example, the autoimmune disease is selected from COPD, asthma, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, sjogren's syndrome, psoriasis, type I diabetes, and inflammatory bowel disease.

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

In another aspect, provided herein is a class of compounds disclosed herein, or a pharmaceutical composition comprising a compound disclosed herein, for use in the preparation of a medicament for treating or preventing an autoimmune disease. In a particular embodiment, the autoimmune disease is selected from COPD, asthma, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, sjogren's syndrome, psoriasis, type I diabetes, and inflammatory bowel disease.

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

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

In another aspect, provided herein is a class of compounds disclosed herein, or a pharmaceutical composition comprising a compound disclosed herein, for use in the preparation of a medicament for the treatment or prevention of an allergic disease. In a particular embodiment, the allergic disease is selected from respiratory allergic disease, sinusitis, eczema and measles, food allergy and insect venom allergy.

In another aspect, provided herein is a class of compounds disclosed herein for use in the treatment and/or prevention of an inflammatory disease. In particular embodiments, the inflammatory disease is selected from 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 a pharmaceutical composition comprising a compound disclosed herein, for use in the preparation of a medicament for the treatment or prevention of an inflammatory disease. In particular embodiments, the inflammatory disease is selected from 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 particular embodiments, the 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 a pharmaceutical composition comprising a compound disclosed herein, for use in the preparation of a medicament for treating or preventing transplant rejection. In particular examples, the 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 for use as a medicament in the treatment and/or prevention of the aforementioned diseases. Also provided is the use of a compound disclosed herein for the manufacture of a medicament for the treatment and/or prevention of the aforementioned diseases.

One particular embodiment of the present methods comprises administering to a subject having inflammation an effective amount of a compound disclosed herein for a time sufficient to reduce the level of inflammation in the subject, and preferably to stop the progression of the inflammation. Particular embodiments of the method comprise administering to a subject suffering from or susceptible to bone rheumatoid arthritis an effective amount of a compound disclosed herein for a time sufficient to reduce or prevent, respectively, inflammation of the joints of said subject, and preferably to stop the progression of said inflammation.

Another particular embodiment of the method comprises administering to a subject having a proliferative disease an effective amount of a compound of the disclosure for a time sufficient to reduce the level of the proliferative disease in the subject and preferably to stop the progression of the proliferative disease. Particular embodiments of the method comprise administering to a subject having cancer an effective amount of a compound disclosed herein for a time sufficient to reduce or prevent, respectively, the signs of cancer in said subject, and preferably to stop the progression of said cancer.

The compounds and pharmaceutical compositions disclosed herein are kinase inhibitors, including Btk inhibitors. These inhibitors are useful for treating one or more diseases in a mammal that respond to kinase inhibition, including diseases that respond to inhibition of Btk and/or inhibition of B-cell proliferation. 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 thus the pharmaceutical use of these compounds. Accordingly, the invention includes a method for treating a mammal, e.g., a human, having a disease that responds to inhibition of Btk activity and/or inhibition of B-cell proliferation, the method comprising: administering to a mammal having such a disease an effective amount of at least one chemical entity provided herein. Effective concentrations can be determined experimentally, for example, by measuring the blood concentration of the compound, or theoretically, by calculating bioavailability. In addition to Btk, other kinases that may also be affected include, but are not limited to, other tyrosine kinases and serine/threonine kinases.

Insofar as Btk is associated with disease, alleviation, prevention, and prophylactic treatment of disease and disease symptoms are within the scope of the 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 inflammatory response.

The invention encompasses methods of treating a patient suffering from cancer, bone disorders, allergic disorders, and/or autoimmune and/or inflammatory disorders and/or acute inflammatory responses by administering an effective amount of a compound of the present invention and pharmaceutically acceptable salts, solvates, and mixtures thereof.

In some embodiments, conditions and diseases that may be affected using 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, Sjogren's syndrome, tissue transplant rejection, and hyperacute rejection of transplanted organs, asthma, systemic lupus erythematosus (and associated glomerulonephritis), dermatomyositis, multiple sclerosis, scleroderma, vasculitis (ANCA-associated and other vasculitis), autoimmune hemolytic diseases and thrombocytopenic states, goodpasture's syndrome (and associated glomerulonephritis and pulmonary hemorrhage), atherosclerosis, rheumatoid arthritis, osteoarthritis, chronic Idiopathic Thrombocytopenic Purpura (ITP), Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes (type 1), septic shock, myasthenia gravis, ulcerative colitis, aplastic anemia, Coeliac disease, Wegener's granulomatosis, Crohn's disease, inflammatory bowel, And other diseases in which the cells and antibodies are caused by and directed against the subject'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;

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

bone diseases, 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, there is also provided a method of promoting or inducing apoptosis of cells expressing Btk comprising contacting the cells with a compound of the invention and pharmaceutically acceptable salts, solvates and mixtures thereof.

The compounds disclosed herein may be administered simultaneously, or before or after, one or more other therapeutic agents. The compounds of the invention may be administered separately from the other therapeutic agents, by the same or different routes of administration, or together with them in pharmaceutical compositions.

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

The above cited dose profiles have been demonstrated in vitro and in vivo tests using beneficial mammals (e.g., mice, rats, dogs, monkeys) or isolated organs, tissues and specimens thereof. The compounds disclosed herein are used in vitro in the form of solutions, e.g. aqueous solutions, and also enterally, parenterally, especially intravenously, in vivo, e.g. in the form of suspensions or aqueous solutions.

In one embodiment, a therapeutically effective dose of a compound of the present disclosure is from about 0.1mg to about 2,000mg per day. The pharmaceutical composition thereof should provide a dose of the compound of about 0.1mg to about 2,000 mg. In a particular embodiment, the pharmaceutical dosage unit form is prepared to provide from about 1mg to about 2,000mg, from about 10mg to about 1,000mg, from about 20mg to about 500mg, or from about 25mg to about 250mg of the principal active ingredient or a combination of principal ingredients per dosage unit form. In a particular embodiment, the pharmaceutical dosage unit form is prepared to provide about 10mg, 20mg, 25mg, 50mg, 100mg, 250mg, 500mg, 1000mg or 2000mg of the primary active ingredient.

In addition, the compounds disclosed herein may be administered in the form of a prodrug. In the present invention, a "prodrug" of a disclosed compound is a functional derivative that, when administered to a patient, is ultimately released in vivo. When administering the compounds disclosed herein in the form of a prodrug, one skilled in the art can practice one or more of the following: (a) altering the in vivo onset time of the compound; (b) altering the duration of action of the compound in vivo; (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 compounds. Typical functional derivatives useful for preparing prodrugs comprise variants of the compounds which are cleaved in vivo either chemically or enzymatically. These variants, which involve the preparation of phosphates, amides, esters, thioesters, carbonates and carbamates, are well known to those skilled in the art.

General synthetic procedure

In general, the compounds of the invention can be prepared by the processes described herein, unless otherwise indicated, 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 context of the present invention.

Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. 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 modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.

The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. 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. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin HaoLiyu chemical Co., Ltd., Qingdao Tenglong chemical reagent Co., Ltd., and Qingdao Kaihua factory.

The anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained through reflux drying of metal sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, petroleum ether, N-hexane, N, N-dimethylacetamide and N, N-dimethylformamide were used as they were previously dried over anhydrous sodium sulfate.

The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. The glassware was dried.

The column chromatography is performed using a silica gel column. Silica gel (300 and 400 meshes) was purchased from Qingdao oceanic chemical plants. The test conditions of the nuclear magnetic resonance hydrogen spectrum are as follows: brookfield (Bruker) nuclear magnetic instrument at 400MHz or 600MHz in CDC1 at room temperature₃，d₆-DMSO，CD₃OD or d₆Acetone as solvent (reported in ppm) with TMS (0ppm) or chloroform (7.26ppm) as reference standard. When multiple peaks occur, the following abbreviations will be used: s (singleton), d (doublet), t (triplet ), q (quatet, quartet), m (multiplet ), br (broadpede, broad), dd (doublet of doublets), ddd (doublet of doublets), dt (doublet of triplets). Coupling constants are expressed in hertz (Hz).

The conditions for low resolution Mass Spectrometry (MS) data determination were: agilent 6120Quadrupole HPLC-MS (column model: Zorbax SB-C18,2.1X30mm,3.5 μm,6min, flow rate 0.6mL/min, mobile phase 5% -95% (CH with 0.1% formic acid)₃CN) in (H containing 0.1% formic acid)₂Proportion in O)), at 210/254nm with UV detection, using electrospray ionization mode (ESI).

The purity of the compound is characterized in the following way: agilent 1260 preparative high performance liquid chromatography (Pre-HPLC) or Calesep Pump 250 preparative high performance liquid chromatography (Pre-HPLC) (column model: NOVASEP,50/80mm, DAC) with UV detection at 210nm/254 nm.

The following acronyms are used throughout the invention:

H₂o water; MeOH, CH₃OH methanol; CD (compact disc)₃OD deuterated methanol; SEMCl 2- (trimethylsilyl) ethoxymethyl chloride;

CHCl₃chloroform, chloroform; CDCl₃Deuterated chloroform; DMSO dimethyl sulfoxide; DMSO-d₆Deuterated dimethyl sulfoxide;

DMF N, N-dimethyl formamideAn amide; HOBT 1-hydroxybenzotriazole; na (Na)₂SO₄Sodium sulfate; Pd/C palladium on carbon;

HATU 2- (7-azobenzotriazol) -N, N' -tetramethyluronium hexafluorophosphate; TsCl tosyl chloride;

Pd(dppf)Cl₂[1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride; xanthphos 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene;

X-Phos 2-dicyclohexylphos-2, 4, 6-triisopropylbiphenyl; pd₂(dba)₃Tris (dibenzylideneacetone) dipalladium;

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

g, g; mg; mol; mmol millimole; h hours; min; l liter; mL, mL; r.t, RT room temperature;

rt retention time; HEPES hydroxyethylpiperazine ethanethiosulfonic acid; brij-35 dodecyl polyglycol ether; DTT dithiothreitol;

EDTA ethylene diamine tetraacetic acid; EGFR epidermal growth factor receptor; BTK bruton tyrosine kinase;

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

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

coating Reagent #3 #3 Coating agent.

Intermediate Synthesis scheme 1

Intermediate compound(6)Can be prepared by intermediate synthesis scheme 1, wherein R¹⁹And R^19aEach independently is halogen; r²⁰Is Ph₃C-, SEM-, etc. protecting groups; r³Have the meaning as described in formula (I) of the invention. Compound (I)(1)Catalyzing with trimethyl-silacetylene in polar solvent by transition metal(e.g. dimethyl sulfoxide, N, N-dimethyl amide, 1, 4-dioxane, etc.) to obtain a compound(3)(ii) a Compound (I)(3)Under the action of alkali (such as sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, etc.) or fluoride (such as tetrabutylammonium fluoride)(4)(ii) a Compound (I)(4)Obtaining the compound under the action of a halogenating reagent (such as NIS, NBS and the like)(5)(ii) a Compound (I)(5)And R²⁰Cl (e.g. Ph)₃CCl, SEMCl, etc.) to produce the compound(6)。

Intermediate Synthesis scheme 2

Intermediate compound(10)Can be prepared by intermediate synthesis scheme 2, wherein R¹⁹And R^19aEach independently is halogen; r²⁰Is Ph₃C-, SEM-, etc. protecting groups; r³And R²Have the meaning as described in formula (I) of the invention. Compound (I)(1)By transition metal catalysis with

(e.g. dimethyl sulfoxide, N, N-dimethyl amide, 1, 4-dioxane, etc.) to obtain a compound(7)(ii) a Compound (I)(7)Under the action of alkali (such as sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, etc.) or fluoride (such as tetrabutylammonium fluoride)(8)(ii) a Compound (I)(8)Obtaining the compound under the action of a halogenating reagent (such as NIS, NBS and the like)(9)(ii) a Compound (I)(9)And R²⁰Cl (e.g. Ph)₃CCl, SEMCl, etc.) to produce the compound(10)。

Intermediate Synthesis scheme 3

Intermediate compound(12)Can be prepared by intermediate synthesis scheme 3, wherein R¹⁹And R^19aEach independently is halogen; r²⁰Is Ph₃C-, SEM-, etc. protecting groups; e ring, m, R⁴、R⁵、R³And R²Have the meaning as described in formula (I) of the invention. Compound (I)(10)And compounds(11)The compound is obtained by Suzuki cross-coupling reaction under the catalysis of transition metal(12)。

Intermediate Synthesis scheme 4

Intermediate compound(12)Can be prepared by intermediate synthesis scheme 4, wherein R¹⁹And R^19aEach independently is halogen; r²⁰Is Ph₃C-, SEM-, etc. protecting groups; e ring, m, R⁴、R⁵、R³And R²Have the meaning as described in formula (I) of the invention. Compound (I)(10)And compounds(16)The compound is obtained by Suzuki cross-coupling reaction under the catalysis of transition metal(12)。

Intermediate Synthesis scheme 5

Intermediate compound(18)Can be prepared by intermediate synthesis scheme 5, wherein R¹⁹And R^19aEach independently is halogen; r²⁰Is Ph₃C-, SEM-, etc. protecting groups; a ring, R³And R²Have the meaning as described in formula (I) of the invention. Compound (I)(10)And compounds(17)The compound is obtained by Suzuki cross-coupling reaction under the catalysis of transition metal(18)。

Intermediate Synthesis scheme 6

Intermediate conversionCompound (I)(18)Can be prepared by intermediate synthesis scheme 6, wherein R¹⁹And R^19aEach independently is halogen; r²⁰Is Ph₃C-, SEM-, etc. protecting groups; a ring, R³And R²Have the meaning as described in formula (I) of the invention. Compound (I)(10)And compounds(13)The compound is obtained by Suzuki cross-coupling reaction under the catalysis of transition metal(18)。

Intermediate Synthesis scheme 7

Intermediate compound(14)Can be prepared by intermediate synthesis scheme 7, wherein R¹⁹Is halogen; r²⁰Is Ph₃C-, SEM-, etc. protecting groups; ring A, ring E, m, R⁴、R⁵、R³And R²Have the meaning as described in formula (I) of the invention. Compound (I)(12)And compounds(13)The compound is obtained by Suzuki cross-coupling reaction under the catalysis of transition metal(14)。

Intermediate Synthesis scheme 8

Intermediate compound(14)Can be prepared by intermediate synthesis scheme 8, wherein R¹⁹Is halogen; r²⁰Is Ph₃C-, SEM-, etc. protecting groups; ring A, ring E, m, R⁴、R⁵、R³And R²Have the meaning as described in formula (I) of the invention. Compound (I)(12)And compounds(17)The compound is obtained by Suzuki cross-coupling reaction under the catalysis of transition metal(14)。

Intermediate Synthesis scheme 9

Intermediate compound(14)Can be prepared by intermediate synthesis scheme 9, wherein R^19aIs halogen; r²⁰Is Ph₃C-, SEM-, etc. protecting groups; ring A, ring E, m, R⁴、R⁵、R³And R²Have the meaning as described in formula (I) of the invention. Compound (I)(18)And compounds(16)The compound is obtained by Suzuki cross-coupling reaction under the catalysis of transition metal(14)。

Intermediate Synthesis scheme 10

Intermediate compound(14)Can be prepared by intermediate synthesis scheme 10, wherein R^19aIs halogen; r²⁰Is Ph₃C-, SEM-, etc. protecting groups; ring A, ring E, m, R⁴、R⁵、R³And R²Have the meaning as described in formula (I) of the invention. Compound (I)(18)And compounds(11)The compound is obtained by Suzuki cross-coupling reaction under the catalysis of transition metal(14)。

Intermediate Synthesis scheme 11

Intermediate compound(12a)Can be prepared by intermediate synthesis scheme 11, wherein R¹⁸、R¹⁹And R^19aEach independently is halogen; r²⁰Is Ph₃C-, SEM-, etc. protecting groups; z¹、Z²、R⁰、R⁰⁰N and L have the meanings as indicated in formula (II) of the invention. Compound (I)(10a)And compounds(16a)The compound is obtained by Suzuki cross-coupling reaction under the catalysis of transition metal(12a)。

Intermediate Synthesis scheme 12

Intermediate compound(12a)Can be prepared by intermediate synthesis scheme 12, wherein R¹⁸、R¹⁹And R^19aEach independently is halogen; r²⁰Is Ph₃C-, SEM-, etc. protecting groups; z¹、Z²、R⁰、R⁰⁰N and L have the meanings as indicated in formula (II) of the invention. Compound (I)(10a)And compounds(11a)The compound is obtained by Suzuki cross-coupling reaction under the catalysis of transition metal(12a)。

Synthesis scheme 1

Compound (I)(15)Can be prepared by synthetic scheme 1, R²⁰Is Ph₃C-, SEM-, etc. protecting groups; ring A, ring E, m, R⁴、R⁵、R³And R²Have the meaning as described in formula (I) of the invention. Compound (I)(14)In deprotection reaction to obtain the compound(15)。

Synthesis scheme 2

Compound (I)(15a)Can be prepared by synthetic scheme 2, wherein R¹⁸And R¹⁹Each independently is halogen; r²⁰Is Ph₃C-, SEM-, etc. protecting groups; z¹、Z²、R¹、R⁰、R⁰⁰N and L have the meanings as indicated in formula (II) of the invention. Compound (I)(12a)Deprotection reaction is carried out to obtain a compound(15a)。

Synthesis scheme 3

Compound (I)(2a)Can be prepared by synthetic scheme 3, wherein R^19aIs halogen; z¹、Z²W ring, R⁰、R⁰⁰N and L have the meanings as indicated in formula (II) of the invention. Compound (I)(1a)And compounds(16a)The compound is obtained by Suzuki cross-coupling reaction under the catalysis of transition metal(2a)。

Synthesis scheme 4

Compound (I)(2a)Can be prepared by synthetic scheme 4, wherein R^19aIs halogen; z¹、Z²W ring, R⁰、R⁰⁰N and L have the meanings as indicated in formula (II) of the invention. Compound (I)(1a)And compounds(11a)The compound is obtained by Suzuki cross-coupling reaction under the catalysis of transition metal(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-chloropyrazine-2-amine

A solution of bromine (5.89g,36.54mmol,1.90mL) in chloroform (15mL) was added slowly dropwise over 5 minutes to a solution of 6-methylpyrazin-2-amine (2.00g,18.33mmol) in chloroform (170mL) at room temperature. After the addition was complete, the reaction was stirred at room temperature for 4.5 h. The reaction was quenched with water (100mL), the organic layer was washed with water (100mL), dried over anhydrous magnesium sulfate, and the organic layer was concentrated under reduced pressure and subjected to column separation (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give 4.20g of a beige solid, yield: 86.0 percent.

¹H NMR(400MHz,DMSO-d₆):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

Trimethylsilylacetylene (1.50g,16.00mmol) was slowly added to 3, 5-dibromo-6-methylpyrazin-2-amine (4.00g,15.00mmol), cuprous iodide (600mg,3.15mmol), bis (triphenylphosphine) palladium dichloride (Pd (PPh) at 15 ℃ under nitrogen protection₃)₂Cl₂) (600mg,0.85mmol) and triethylamine (2.40g,24.00mmol,3.30mL) in tetrahydrofuran (42mL) was added dropwise, and the mixture was allowed to warm to room temperature and allowed to react for 16 h. Celite was filtered, washed with ethyl acetate, concentrated under reduced pressure, and the concentrated residue was extracted with 100mL of water, dichloromethane (100mL × 3), dried over anhydrous sodium sulfate for the organic layer, concentrated under reduced pressure, and subjected to column separation (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give 3.50g of beige solid, yield: 82.0 percent.

¹H NMR(400MHz,DMSO-d₆):δ(ppm)6.69(s,2H),2.39(s,3H),0.26(s,9H)；

MS(ESI,pos.ion)m/z:284.1[M+1]⁺。

And step 3: synthesis of compound 2-bromo-3-methyl-5H-pyrrolo [2,3-b ] pyrazine

N₂A solution of 5-bromo-6-methyl-3- ((trimethylsilyl) ethynyl) pyrazin-2-amine (3.50g,12.00mmol) in tetrahydrofuran (11mL) was slowly added dropwise to a solution of potassium tert-butoxide (1.80g,16.00mmol) in tetrahydrofuran (18mL) at-30 ℃ with protection. After the dropwise addition, the reaction was carried out at-30 ℃ for 1 hour, and then the temperature was naturally raised to room temperature and the reaction was stirred overnight. The reaction solution was filtered through celite, washed with ethyl acetate, the filtrate was concentrated under reduced pressure, water (150mL) was added to the concentrated residue, extracted with ethyl acetate (150mL x3), the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2.1g of an orange solid, which was used in the next reaction without further purification, yield: 60.0 percent.

MS(ESI,pos.ion)m/z:212.1[M+1]⁺。

And 4, step 4: synthesis of compound 2-bromo-3-methyl-7-iodo-5H-pyrrolo [2,3-b ] pyrazine

N-iodosuccinimide (2.60g,11.00mmol) was added portionwise to a solution of 2-bromo-3-methyl-5H-pyrrolo [2,3-b ] pyrazine (2.05g,7.25mmol) in acetone (30mL) at 0 deg.C and the reaction stirred at room temperature for 3H. The solvent was removed under reduced pressure, water (30mL) and dichloromethane (30mL) were added to the residue, the solid was filtered, the solid was washed with a little water and dichloromethane, and the brown solid was dried under vacuum at 60 ℃ to give 2.50g of a brown solid which was used in the next reaction without further purification.

MS(ESI,pos.ion)m/z:337.7[M+1]⁺。

And 5: synthesis of the compound 2-bromo-3-methyl-7-iodo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine

Sodium hydride (450mg,11.25mmol) was added portionwise to a mixture of 2-bromo-3-methyl-7-iodo-5H-pyrrolo [2,3-b ] pyrazine (2.50g,7.4mmol) in N, N-dimethylformamide (30mL) at 0 ℃. After stirring at room temperature for 2 h. Trimethylsilyl ethoxymethyl chloride (1.90g,11.00mmol,2.00mL) was slowly added dropwise at 0 deg.C, after which the reaction was stirred at room temperature overnight. The reaction was quenched with water (100mL), extracted with dichloromethane (100mL x3), the organic layer was washed with saturated brine (100mL), dried over anhydrous sodium sulfate, concentrated to remove the solvent, and the residue was subjected to column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1) to give 1.20g of a pale yellow oil, two steps total yield: 35.0 percent.

MS(ESI,pos.ion)m/z:467.9[M+1]⁺。

The intermediates shown below were prepared following the synthetic procedure of intermediate example 1, using the corresponding starting materials:

intermediate example 6

2-chloro-7-iodo-5-trityl-5H-pyrrolo [2,3-b ] pyrazines

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 (3.1g,16mmol) in 1, 4-dioxane (20mL) was added phosphorus oxychloride (2.27mL,24.1mmol) and triethylamine (220 μ L,1.58mmol), reacted at 110 ℃ under reflux for 6 hours, quenched by slow addition to water (100mL), potassium hydroxide solution adjusted to pH >7, ethyl acetate extracted (50mLx3), dried over anhydrous sodium sulfate, concentrated, slurried (petroleum ether/ethyl acetate (v/v) ═ 2/1), filtered, dried to give 1.3g of a grey solid, yield: 54 percent.

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 (1.3g,8.5mmol) in acetone (15mL) was added N-iodosuccinimide (2.9g,13mmol), stirred at room temperature for 12 hours, diluted with water (40mL), extracted with dichloromethane (55mLx3), dried over anhydrous sodium sulfate, and concentrated column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to afford 2.2mg of an off-white solid, yield: 93 percent.

MS(ESI,pos.ion)m/z:280.0[M+1]⁺。

And 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 (300mg,1.07mmol) in N, N-dimethylformamide (8mL) were added sodium carbonate (230mg,2.17mmol) and triphenylchloromethane (330mg,1.18mmol), heated at 45 ℃ for 5 hours, diluted with water (20mL), extracted with dichloromethane (25mLx3), dried over anhydrous sodium sulfate, and concentrated by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 8/1) to give 320mg of a white solid, yield: 57.13 percent.

MS(ESI,pos.ion)m/z:522.10[M+1]⁺；

¹H NMR(400MHz,CDCl₃)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) pyrazine-2-amine

To a solution of 3, 5-dibromopyrazine-2-amine (200mg,0.79mmol) in tetrahydrofuran (8mL), cuprous iodide (15mg,0.07mmol), bis (triphenylphosphine) palladium dichloride (56mg,0.08mmol) and triethylamine (340 μ L,2.44mmol) were added in this order, 3% propyne-n-heptane solution (2.3mL,1.2mmol) was slowly added dropwise under nitrogen protection under ice bath, and after naturally rising to room temperature, stirring was carried out for 3 hours, celite extraction was carried out, concentration was carried out, column chromatography (petroleum ether/ethyl acetate (v/v) ═ 8/1) gave 150mg of a pale yellow solid, yield: 89.45 percent.

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 (118mg,1.05mmol) in tetrahydrofuran (8mL) under nitrogen at room temperature was added a solution of 5-bromo-3- (propyn-1-yl) pyrazin-2-amine (150mg,0.70mmol) in tetrahydrofuran (5mL), the reaction was refluxed for 1 hour, filtered through celite to remove the solvent, and column chromatography of the residue (petroleum ether/ethyl acetate (v/v) ═ 2/1) afforded 124mg of the product as a pale yellow solid, yield: 82.67 percent.

MS(ESI,pos.ion)m/z:212.1,214.1[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)12.19(s,1H),8.21(s,1H),6.35(s,1H),2.49(s,3H)。

And 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 (500mg,2.35mmol) in N, N-dimethylformamide (12mL) at room temperature was added N-bromosuccinimide (630mg,3.54mmol), stirred at room temperature for 5 hours, diluted with water (20mL), extracted with dichloromethane (25mL x3), dried over anhydrous sodium sulfate, and concentrated column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to afford 450mg of a pale yellow solid, yield: 65.95 percent.

MS(ESI,pos.ion)m/z:292.0[M+1]⁺。

And 4, step 4: synthesis of compound 2, 7-dibromo-6-methyl-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine

To a solution of 2, 7-dibromo-6-methyl-5H-pyrrolo [2,3-b ] pyrazine (450mg,1.54mmol) in tetrahydrofuran (12mL) at 0 ℃ was added sodium hydride (92mg,2.30mmol), and after continuing to react at this temperature for 1 hour, SEMCl (410 μ L,2.32mmol) was slowly added dropwise, stirring was continued at room temperature, water (20mL) was added for dilution, dichloromethane was extracted (25mLx3), dried over anhydrous sodium sulfate, concentrated column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) gave 360mg of a brown oil, yield: 55.26 percent.

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 (1.0g,2.5mmol) in acetonitrile (6mL) was added to 1-methylpyrazole-4-boronic acid ester (620mg,2.98mmol), sodium carbonate (650mg,6.13mmol), Pd (PPh) in that order₃)₂Cl₂(180mg,0.26mmol) and water (6mL), stirred at 80 ℃ for 3 hours, diluted with water (40mL), extracted with dichloromethane (25mLx3), dried over anhydrous sodium sulphate, concentrated column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give 1.0g of a yellow solid, yield: 99 percent.

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

The intermediates shown below were prepared following the synthetic procedure of intermediate example 8, using the corresponding starting materials:

intermediate example 12

N- (2- (methylsulfonyl) ethyl) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) amine

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

DMSO (15mL) was added to a mixture of p-diiodobenzene (408mg,1.24mmol), 2- (methylsulfonyl) ethylamine hydrochloride (220mg,1.38mmol), cuprous iodide (250mg,1.31mmol), cesium carbonate (1.20g,3.70mmol), dimethylglycine (208mg,1.21mmol) under nitrogen, reacted at 80 ℃ for 22h, the reaction was cooled to room temperature, extracted with ethyl acetate (50mLx3), the organic phase was spin dried, and column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) gave 78mg of a white solid, yield: 19.4 percent.

MS(ESI,pos.ion)m/z:326.1[M+1]⁺。

Step 2: synthesis of Compound N- (2- (methylsulfonyl) ethyl) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) amine

DMSO (12mL) was added to 4-iodo-N- (2- (methylsulfonyl) ethyl) amine (78mg,0.24mmol), pinacol diboron (75mg,0.30mmol), potassium acetate (75mg,0.76mmol), Pd (dppf) Cl under nitrogen₂(9mg,0.01mmol) of the mixture at 105 ℃ for 17h, cooling the reaction to room temperature, extracting with ethyl acetate (50mLx3), concentrating the organic phase, and column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/2) gives 58mg of a colorless oil, yield: 74.4 percent.

MS(ESI,pos.ion)m/z:326.3[M+1]⁺。

The intermediates shown below were prepared following the synthetic procedure of intermediate example 12, using the corresponding starting materials:

intermediate example 32

4,4,5, 5-tetramethyl-2- (1, 4-dioxaspiro [4.5] decan-7-en-8-yl) -1,3, 2-dioxaborolan

Step 1: synthesis of compound 1, 4-dioxyspiro [4.5] decane-7-ene-8-trifluoromethanesulfonate

To a solution of 1, 4-dioxyspiro [4.5] decan-8-one (2.0g,13mmol) in tetrahydrofuran (15mL) was added a solution of potassium hexamethyldisilazane (1M,26mL,26mmol) in tetrahydrofuran (26mL) and stirring was continued at this temperature, a solution of N, N-bis (trifluoromethanesulfonyl) aniline (5.46g,15.3mmol) in tetrahydrofuran (15mL) was added, the mixture was allowed to warm to room temperature and stirred overnight, quenched with water (30mL), extracted with dichloromethane (30mL x3), dried over anhydrous sodium sulfate, concentrated column chromatography (petroleum ether/ethyl acetate (v/v): 5/1) to give 4.5g of a pale yellow oil, yield: 80.23 percent.

MS(ESI,pos.ion)m/z:289.0[M+1]⁺。

Step 2: synthesis of compound 4,4,5, 5-tetramethyl-2- (1, 4-dioxyspiro [4.5] decan-7-en-8-yl) -1,3, 2-dioxyborole

1, 4-Dioxospiro [4.5]]To a solution of pelarganyl-7-en-8-triflate (500mg,1.73mmol) in 1, 4-dioxane (8mL) was added potassium acetate (260mg,2.64mmol), pinacolato diboron (530mg,2.08mmol), Pd (dppf) Cl₂(130mg,0.17mmol) under nitrogen at 110 ℃ for 10h under reflux, filtration and concentration by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) gave 540mg of a yellow oil in: 99 percent.

MS(ESI,pos.ion)m/z:267.30[M+1]⁺。

The intermediate shown below was prepared following the synthetic procedure of intermediate example 32, using the corresponding starting materials:

intermediate example 34

(R) -2-methyl-2- ((3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) amino) -N- (2,2, 2-trifluoroethyl) butanamide

Step 1: synthesis of compound (R) -2- ((3-bromophenyl) amino) -2-methylbutyric acid

To a solution of m-bromoiodobenzene (500mg,1.76mmol) in DMF (5mL) was added sequentially cuprous iodide (340mg,1.78mmol), cesium carbonate (870mg,2.67mmol), (R) -2-amino-2-methylbutyric acid (550mg,4.55mmol), the reaction was heated at 80 ℃ for 8 hours, directly concentrated and stirred, and column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) gave 130mg of a brown solid, yield: 27.02 percent.

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) butyramide

To a solution of (R) -2- ((3-bromophenyl) amino) -2-methylbutyric acid (70mg,0.25mmol) in DMF (5mL) were added N-methylmorpholine (80mg,0.79mmol), 2,2, 2-trifluoroethylamine hydrochloride (60mg,0.44mmol) and HATU (146mg,0.38mmol) in that order, stirred at room temperature for 2 hours, diluted with water (30mL), extracted with dichloromethane (30mLx3), dried over anhydrous sodium sulfate, concentrated column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to afford 70mg of a yellow solid, yield: 77.05 percent.

MS(ESI,pos.ion)m/z:353.2,355.1[M+1]⁺。

And step 3: synthesis of compound (R) -2-methyl-2- ((3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) amino) -N- (2,2, 2-trifluoroethyl) butanamide

To a solution of (R) -2- ((3-bromophenyl) amino) -2-methyl-N- (2,2, 2-trifluoroethyl) butanamide (350mg,0.99mmol) in dimethyl sulfoxide (8mL) were added, in order, potassium acetate (250mg,2.54mmol), pinacol diboron diborate (380mg,1.49mmol) and Pd (dppf) Cl₂(70mg, 0.09mmol), reaction under nitrogen at 110 ℃ for 8h, dilution with water (30mL), extraction with dichloromethane (30mL x3), drying over anhydrous sodium sulfate, concentration column chromatography (petroleum ether/ethyl acetate (v/v) ═ 8/1) afforded 350mg of a pale yellow oil, yield: 60.52 percent.

MS(ESI,pos.ion)m/z:401.0[M+1]⁺。

The intermediates shown below were prepared following the synthetic procedure of intermediate example 34, using the corresponding starting materials:

intermediate example 37

1- (2-cyanoethyl) -N- (3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) pyrrolidine-3-carboxamide

Step 1: synthesis of compound 1-tert-butyl formate-pyrrolidine-3-carboxylic acid

A solution of sodium hydroxide (0.80g,20.00mmol) in water (15mL) was added to a solution of 1-tert-butyl formate-pyrrolidine-3-carboxylic acid methyl ester (2.30g,10.00mmol) in methanol (30mL), the reaction was reacted at room temperature for 3 hours, the methanol was removed by concentration under reduced pressure, the pH was adjusted to about 4 with 2M glacial acetic acid, dichloromethane (50mL x3) was extracted, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1.80g of an oil, yield: 83.00 percent.

MS(ESI,pos.ion)m/z:160.1[M-55]⁺。

Step 2: synthesis of compound t-butyl 3- ((3-bromophenyl) carbamoyl) pyrrolidine-1-carboxylate

3-bromoaniline (1.40g,8.40mmol,0.91mL) was added to a solution of 1-carboxylic acid tert-butyl ester-pyrrolidine-3-carboxylic acid (1.80g,8.40mmol), HATU (6.40g,17.00mmol) and N, N-diisopropylethylamine (3.30g,25.00mmol,4.40mL) in dichloromethane (20mL) and reacted at room temperature for 4 h. The reaction was quenched with water (50mL), extracted with dichloromethane (50mL × 3), the organic layer was washed with saturated brine (50mL), 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 2.40g of a brown yellow oil, yield: 78.0 percent.

MS(ESI,pos.ion)m/z:312.9[M-55]⁺。

And step 3: synthesis of compound tert-butyl 3- ((3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) carbamoyl) pyrrolidine-1-carboxylate

To 3- ((3-bromophenyl) carbamoyl) pyrrolidine-1-carboxylic acid tert-butyl ester (2.40g,6.50mmol), pinacol diboron (9.80mg,2.50mmol), potassium acetate (1.30mg,13.00mmol), Pd (dppf) Cl under nitrogen₂Dimethyl sulfoxide (20mL) was added to the mixture (240mg,0.32mmol), and the reaction mixture was reacted at 100 ℃ for 12 hours. After cooling to room temperature, the reaction mixture was partitioned between water (150mL) and ethyl acetate (150mL), the aqueous phase was extracted with ethyl acetate (150mLx3), the organic layer was washed with saturated brine (100mL x 2), 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 1.20g of a pale yellow oil, yield: 44.0 percent.

MS(ESI,pos.ion)m/z:361.3[M+1]⁺。

And 4, step 4: synthesis of compound N- (3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) pyrrolidine-3-carboxamide hydrochloride

A solution of hydrogen chloride in ethyl acetate (2M,14.00mmol,7.00mL) was added to a solution of tert-butyl 3- ((3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) carbamoyl) pyrrolidine-1-carboxylate (1.20g,2.90mmol) in ethyl acetate (15mL) at room temperature, reacted for 2 h. concentrated under reduced pressure to give 1.20g of an oil in 120.0% yield.

MS(ESI,pos.ion)m/z:317.1[M+1]⁺。

And 5: synthesis of compound 1- (2-cyanoethyl) -N- (3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) pyrrolidine-3-carboxamide

3-Bromopropionitrile (1.00g,7.00mmol) was added to N- (3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) pyrrolidine-3-carboxamide hydrochloride (1.20g,3.4mmol) and cesium carbonate (5.50g,17.00mmol) in acetonitrile (25mL) at room temperature, and the reaction was refluxed at 90 ℃ for 4 h. Celite filtration, washing of the filter cake with ethyl acetate, concentration under reduced pressure, and column separation of the concentrate (dichloromethane/methanol (v/v) ═ 15/1) gave 550mg of a light yellow oil, yield: 44.0 percent.

MS(ESI,pos.ion)m/z:370.0[M+1]⁺。

Intermediate example 38

Step 1: synthesis of compound (R) -2- ((tert-butoxycarbonyl) amino) -2-methylbutyric acid

Under the protection of nitrogen, (R) -2-amino-2-methylbutyric acid (2.05g,17.50mmol), triethylamine (7.01mL,50.20mmol) and di-tert-butyl dicarboxylate (5.70g,26.00mmol) are added together, tetrahydrofuran (20mL) is added, the temperature is raised to 70 ℃ for reaction for 3h, the reaction solution is cooled to room temperature, ethyl acetate (50 mL. times.3) is used for extraction, anhydrous Na is used for extraction₂SO₄Drying, removal of solvent and column separation (dichloromethane/methanol (v/v) ═ 10/1) gave 3.60g of a colorless oil, yield: 97.0 percent.

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 (2.85g,21.01mmol), (R) -2- ((tert-butoxycarbonyl) amino) -2-methylbutyric acid (3.71g,17.01mmol), HATU (8.81g,23.02mmol), N-methylmorpholine (5.21g,51.01mmol)Adding DMF (30mL), stirring at room temperature for 5h, extracting with ethyl acetate (100 mL. times.3), and extracting with anhydrous Na₂SO₄Drying, removal of solvent and column separation (petroleum ether/ethyl acetate (v/v) ═ 2/1) gave 3.57g of a white solid, yield: 70.1 percent.

MS(ESI,pos.ion)m/z:199.1[M-99]⁺。

And step 3: synthesis of compound (R) -2- ((3-bromophenyl) amino) -2-methyl-N- (2,2, 2-trifluoroethyl) butyramide

(R) - (2-methyl-1-oxo-1- ((2,2, 2-trifluoroethyl) amino) butyl-2-yl) carbamate (3.57g,12.01mmol) was dissolved in a solution of hydrogen chloride in ethyl acetate (15mL) at room temperature, stirred at room temperature for 5 hours, 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), and DMF (40mL) were added, the mixture was heated to 70 ℃ and stirred for 17h, ethyl acetate (100 mL. times.3) was extracted, and anhydrous Na was used₂SO₄Drying, removal of solvent and column separation (petroleum ether/ethyl acetate (v/v) ═ 2/1) gave 3.61g of a dark yellow oil, yield: 84.9 percent.

MS(ESI,pos.ion)m/z:355.2[M+1]⁺。

And 4, step 4: synthesis of compound (R) -2-methyl-2- ((3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) amino) -N- (2,2, 2-trifluoroethyl) butanamide

(R) -2- ((3-bromophenyl) amino) -2-methyl-N- (2,2, 2-trifluoroethyl) butanamide (3.59g,10.21mmol), pinacol diboron diboride (3.08g,12.11mmol), potassium acetate (3.21g,33.02mmol) and Pd (dppf) Cl under nitrogen₂(450mg,0.60mmol) were added together, DMSO (45.00mL) was added thereto, reacted at 115 ℃ for 17h, the reaction solution was cooled to room temperature, extracted with ethyl acetate (100mL × 3), the organic phase was spin-dried, and separated by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give 2.86g of a black oil, yield: 70.2 percent.

MS(ESI,pos.ion)m/z:401.4[M+1]⁺。

The intermediates shown below were prepared following the synthetic procedure of intermediate example 38, using the corresponding starting materials:

intermediate example 40

1- (2-fluorophenyl) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole

DMF (12mL) was added to a mixture of o-fluorobenzyl bromide (706mg,3.71mmol), 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (480mg,2.47mmol), cesium carbonate (2.10g,6.19mmol) and potassium iodide (150mg,1.24mmol) under nitrogen, reacted at room temperature for 12H, extracted with ethyl acetate (50mLx3), the organic phase was spin dried, and column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1) gave 400mg of a colorless oil, yield: 53.5 percent.

MS(ESI,pos.ion)m/z:303.3[M+1]⁺。

The intermediate shown below was prepared following the synthetic procedure of intermediate example 40, using the corresponding starting materials:

intermediate example 46

2- (1- (Acetonitrilsulfonyl) -3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) azetidin-3-yl) acetonitrile

Step 1: synthesis of compound 3- (cyanoethyl) -3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) azetidine-1-carboxylic acid tert-butyl ester

To a solution of 1H-pyrazole borate (200mg,1.03mmol), tert-butyl 3- (cyanomethylene) azetidine-1-carboxylate (220mg,1.13mmol) in acetonitrile (8mL) was added DBU (80 μ L,0.53mmol), the reaction was heated at 50 ℃ for 4 hours, concentrated directly, and column chromatographed (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give 340mg of a pale yellow oil, yield: 84.93 percent.

MS(ESI,pos.ion)m/z:333.3[M-55]⁺。

Step 2: synthesis of Compound 2- (1- (Acetonitrilsulfonyl) -3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) azetidin-3-yl) acetonitrile

To a solution of tert-butyl 3- (cyanoethyl) -3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) azetidine-1-carboxylate (330mg,0.85mmol) in dichloromethane (8mL) was added trifluoroacetic acid (0.7mL,9mmol), stirred at room temperature for 2 hours, the solvent was concentrated, dissolved by addition of dichloromethane (8mL), Et was added under ice bath₃N (400 μ L,2.8mmol), ethylsulfonyl chloride (0.15mL,1.6mmol), stirred at room temperature for 2 hours, quenched with water (30mL), extracted with dichloromethane (30mL x3), dried over anhydrous sodium sulfate, concentrated column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give 120mg of a light yellow oil, yield: 37.13 percent.

MS(ESI,pos.ion)m/z:381.2[M+1]⁺。

Intermediate example 47

1-Carboxylic acid tert-butyl ester-4- ((4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrol-1-yl)) piperidine

Step 1: synthesis of compound 1-tert-butyl formate-4-methanesulfonyloxy piperidine

Methanesulfonyl chloride (2.44g,21.3mmol,1.65mL) was slowly added dropwise to a solution of tert-butyl N-carboxylate-4-hydroxypiperidine (3.10g,15.00mmol) and triethylamine (3.00g,30mmol,4.00mL) in dichloromethane (40mL) under ice-cooling, and after completion of the dropwise addition, the reaction was carried out at room temperature for 1.5 hours. The reaction solution was quenched by addition of hydrochloric acid (1M,40mL), and the organic layer was washed with saturated brine (30mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 4.30g of an off-white solid, yield: 100.0 percent.

MS(ESI,pos.ion)m/z:224.2[M-55]⁺；

¹H NMR(400MHz,CDCl₃):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: synthesis of compound 1-carboxylic acid tert-butyl ester-4- ((4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrol-1-yl)) piperidine

Tert-butyl 1-carboxylate-4-methanesulfonyloxypiperidine (2.00g,7.16mmol) was added to a solution of 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (1.50g,7.70mmol) and cesium carbonate (3.50g,11.00mmol) in N, N-dimethylformamide (15mL), the reaction mixture was reacted at 100 ℃ for 24 hours, cooled to room temperature, extracted with water (100mL) and ethyl acetate (100mL), the aqueous phase was extracted with ethyl acetate (100mL x3), the organic phases were combined, washed with saturated brine (100mL x3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was stirred over a column (petroleum ether/ethyl acetate (v/v) ═ 2/1) to obtain 950mg of a colorless solid, yield: 35.2 percent.

MS(ESI,pos.ion)m/z:378.4[M+1]⁺；

¹H NMR(400MHz,CDCl₃):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)。

The intermediate shown below was prepared following the synthetic procedure of intermediate example 47, using the corresponding starting materials:

intermediate example 49

6-fluoro-1-methyl-3- (tri-n-butylstannyl) -1H-indazole

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

To a solution of 6-fluoro-1H-indazole (97mg,0.71mmol) in DMF (5mL) at room temperature was added potassium hydroxide (130mg,2.32mmol) and elemental iodine (280mg,1.10mmol) in this order, stirred at room temperature for 11H, quenched with saturated sodium thiosulfate solution (10mL), extracted with ethyl acetate (15mLx3), dried over anhydrous sodium sulfate, concentrated column chromatography (petroleum ether/ethyl acetate (v/v) ═ 6/1) to give 150mg of a brown solid, yield: 80.34 percent.

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 (97mg,0.37mmol) in DMSO (5mL) at room temperature, cesium carbonate (60mg,0.18mmol) and iodomethane (70 μ L,0.76mmol) were added in sequence, stirred at room temperature for 1.5 hours, quenched with water (10mL), extracted with ethyl acetate (15mL x3), dried over anhydrous sodium sulfate, and concentrated by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 6/1) to afford 100mg of a yellow solid, yield: 99 percent.

MS(ESI,pos.ion)m/z:277.0[M+1]⁺。

And step 3: synthesis of compound 6-fluoro-1-methyl-3- (tri-n-butylstannyl) -1H-indazole

To a solution of 6-fluoro-3-iodo-1-methyl-1H-indazole (4.1g,15mmol) in tetrahydrofuran (30mL) at 16 ℃, isopropyl magnesium chloride (2M,9mL,18mmol) was sequentially added, and after stirring at this temperature for 20 minutes, tri-n-butyl tin chloride (4.8mL,18mmol) was added, followed by stirring naturally to room temperature for 5 hours, quenching by adding a saturated ammonium chloride solution (30mL), extraction with ethyl acetate (15mLx3), drying over anhydrous sodium sulfate, and concentration column chromatography (petroleum ether/ethyl acetate (v/v) ═ 8/1) gave 6.1g of a pale yellow oil, yield: 94 percent.

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) phenyl) -2-cyanoacetamide

To a mixture of 2-bromo-7-iodo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine (30mg,0.07mmol), pinacol diboron (25mg,0.08mmol), sodium carbonate (20mg,0.19mmol), and dichlorobis (triphenylphosphine) palladium (6mg,0.01mmol) were added acetonitrile (4mL) and water (1mL) in this order, and the reaction was heated at 65 ℃ for 4.5 hours under a nitrogen atmosphere. Quenching with saturated ammonium chloride solution (10mL), ethyl acetate extraction (15mLx3), drying over anhydrous sodium sulfate, concentration column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) afforded 29mg of a yellow solid, yield: 90 percent.

MS(ESI,pos.ion)m/z:487.4[M+1]⁺。

The intermediate shown below was prepared following the synthetic procedure of intermediate example 50, using the corresponding starting materials:

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-methylbutyric acid

To a solution of 2, 4-dichloropyrimidine (600mg,4.02mmol) in isopropanol (8mL) was added R-isovaline (550mg,4.55mmol), potassium carbonate (850mg,6.15mmol) in that order, the reaction was refluxed at 90 ℃ for 5.5 hours, silica gel was added directly to stir the sample, and column chromatography (petroleum ether/ethyl acetate (v/v) ═ 0/1) gave 600mg of a white solid, yield: 93 percent.

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

To a solution of (R) -2- ((2-chloropyrimidin-4-yl) amino) -2-methylbutyric acid (50mg,0.21mmol), 2,2, 2-trifluoroethylamine hydrochloride (44mg,0.32mmol) and diisopropylethylamine (120 μ L,0.68mmol) in N, N-dimethylformamide (4mL) at 0 ℃, 50% ethyl propylphosphate anhydride solution (510mg,0.80mmol) was added, stirred at room temperature for 12 hours, diluted with water (15mL), extracted with dichloromethane (20mL x3), dried over anhydrous sodium sulfate, and concentrated column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give 30mg of a pale yellow solid, yield: 44.35 percent.

MS(ESI,pos.ion)m/z:311.1[M+1]⁺。

And step 3: synthesis of compound 2-chloro-7- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5-triphenylmethyl-5H-pyrrolo [2,3-b ] pyrazine

To a solution of 2-chloro-7-iodo-5-trityl-5H-pyrrolo [2,3-b ] pyrazine (380mg,0.73mmol), isopropanol pinacol borate (200 μ L,0.98mmol) in tetrahydrofuran (8mL) was slowly added a solution of isopropyl magnesium chloride in tetrahydrofuran (2.0M,850 μ L,1.1mmol), the reaction was continued at this temperature for 1.5 hours, ethyl acetate (20mL) was added for dilution, saturated ammonium chloride solution (20mL) was added for quenching, ethyl acetate extraction (25mL x3), dried over anhydrous sodium sulfate, concentrated column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1) gave 320mg of a pale yellow solid, yield: 84.21 percent.

MS(ESI,pos.ion)m/z:521.8[M+1]⁺。

And 4, step 4: synthesis of compound (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

To 2-chloro-7- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5-triphenylmethyl-5H-pyrrolo [2,3-b ]]Pyrazine (30mg,0.057mmol) in 1, 4-dioxane (4mL) was added sequentially with (R) -2- ((2-chloropyrimidin-4-yl) amino) -2-methyl-N- (2,2, 2-trifluoroethyl) butanamide (17mg,0.05mmol), potassium carbonate (12mg,0.08mmol), Pd (dppf) Cl₂(5mg,0.01mmol) and water (1mL) under nitrogen at 110 ℃ for 4.5h under reflux, quenched by addition of saturated ammonium chloride solution (20mL), extracted with dichloromethane (25mLx3), dried over anhydrous sodium sulfate, and concentrated column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give 220mg of a pale yellow oil, yield: 46.72 percent.

MS(ESI,pos.ion)m/z:669.7[M+1]⁺。

The intermediate shown below was prepared following the synthetic procedure of intermediate example 65, using the corresponding starting materials:

intermediate example 67

N-isopropyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-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

Dissolving 5-bromo-7-azaindole (10.00g,50.75mmol) in dichloromethane (200mL), adding aluminum trichloride (34.00g,254.99mmol), stirring at room temperature for 10 minutes, adding trichloroacetyl chloride (8.6mL,77mmol), continuing to stir at room temperature overnight, pouring the reaction solution into ice water, stirring thoroughly, filtering to obtain a white solid, extracting the filtrate with ethyl acetate (200mL x3), concentrating and combining the filtered white solid, adding tetrahydrofuran (250mL) and water (125mL) to dissolve, adding triethylamine (50mL), stirring at room temperature for 24 hours, concentrating the solvent to dryness, adjusting the pH to 5-6 with 1.0M dilute hydrochloric acid, filtering, and vacuum drying at 50 ℃ to obtain the product as 8.20g of an off-white solid, yield: 67.0 percent.

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 (600mg,2.49mmol) in N, N-dimethylformamide (20mL) were added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.44g,7.43mmol), 1-hydroxybenzotriazole (1.01g,7.46mmol) and 2-isopropylamine (1.27mL,14.90mmol) in that order, and the mixture was stirred at room temperature overnight. Saturated brine (20mL) was added, dichloromethane (15mLx3) was extracted, dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v) ═ 5/1) to give the product as 360mg of a brown solid, yield: 51.3 percent.

MS(ESI,pos.ion)m/z:282.0[M+1]⁺。

And step 3: synthesis of compound 5-bromo-N-isopropyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridine-3-carboxamide

5-bromo-N-isopropyl-1H-pyrrolo [2,3-b ] pyridine-3-carboxamide (360mg,1.28mmol) was dissolved in N, N-dimethylformamide (20mL), 60% sodium hydride (102.1mg,2.55mmol) was added under ice-bath, 2- (trimethylsilyl) ethoxymethyl chloride (338.7. mu.L, 1.82mmol) was added after stirring for 0.5H at room temperature, stirring was continued overnight at room temperature, saturated brine (20mL) was added, dichloromethane (15mL x3) was extracted, dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v) 6/1) to give the product as a 500mg brown solid in yield: 99.0 percent.

MS(ESI,pos.ion)m/z:412.1[M+1]⁺。

And 4, step 4: synthesis of compound N-isopropyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [2,3-b ] pyridine-3-carboxamide

Reacting 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), and pinacol ester of diboronic acid (443.7mg,1.74mmol), potassium carbonate (357.3mg,3.64mmol) and Pd (dppf) Cl were added sequentially₂(106.4mg,0.14mmol) under nitrogen at 115 ℃ for 4h under reflux, cooled to room temperature, filtered through celite, the filtrate concentrated and the concentrate subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the product as 610mg of a yellow solid, yield: 91.25 percent.

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

To a solution of 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) was added 3- ((3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) amino) propionitrile (24mg,0.08mmol), potassium carbonate (16mg,0.12mmol), Pd (dppf) Cl₂(10mg,0.01mmol) and water (1mL) were reacted under nitrogen at 110 ℃ for 7 hours, diluted with water (10mL), extracted with dichloromethane (15mLx3), dried over anhydrous sodium sulfate, and concentrated by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give 26mg of a brown oil, yield: 74.74 percent.

MS(ESI,pos.ion)m/z:474.3[M+1]⁺。

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

To a solution of 3- ((3- (2- (1-methyl-1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile (260mg,0.55mmol) in dichloromethane (6mL) was added trifluoroacetic acid (2.5mL), stirred at room temperature for 2H, the solvent was concentrated, tetrahydrofuran (6mL) was added dissolved, sodium hydroxide solution (2N) was added dropwise to pH >7, stirred at room temperature for 2H, diluted with water (20mL), dichloromethane extracted (15mLx3), dried over anhydrous sodium sulfate, and column chromatography was concentrated (petroleum ether/ethyl acetate (v/v) ═ 0/1) to give 50mg of a yellow solid, yield: 31.83 percent.

MS(ESI,pos.ion)m/z:344.2[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆)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)；

¹³C NMR(150MHz,DMSO-d₆)δ(ppm)148.3,141.8,140.9,137.3,136.3,135.0,134.4,129.6,129.3,128.3,121.8,120.2,114.8,113.8,110.7,110.2,40.5,39.2,17.9。

The following compounds were prepared according to the synthetic procedure of example 1, using the corresponding starting materials:

example 2

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

Step 1: synthesis of the compound 3- ((3- (2-cyclopropyl-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile

Toluene (10mL) and water (1.2mL) were added to a mixture of 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), tricyclohexylphosphorus (15mg,0.04mmol) under nitrogen, the reaction was refluxed at 110 ℃ for 19H, the reaction was cooled to room temperature, celite was filtered, the filtrate was concentrated under reduced pressure, and column separation (petroleum ether/ethyl acetate (v/v): 4/1) was performed to give 160mg of a pale red solid, yield: 87.2 percent.

MS(ESI,pos.ion)m/z:434.3[M⁺1]⁺。

Step 2: synthesis of the 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 ] pyrazin-7-yl) phenyl) amino) propionitrile (158mg,0.36mmol) was dissolved in dichloromethane (6mL) at room temperature, trifluoroacetic acid (6mL) was added, and the reaction was stirred at room temperature for 12H. The reaction solution was concentrated under reduced pressure, dichloromethane (6mL) and ethylenediamine (1mL) were added, stirring was performed at room temperature for 2 hours, silica gel was added to the reaction solution, and the mixture was directly spin-dried and sample-stirred, and column chromatography separation (dichloromethane/methanol (v/v) ═ 50/1) gave 86mg of a pale yellow solid, yield: 77.8 percent.

MS(ESI,pos.ion)m/z:304.1[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):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)；

¹³C NMR(150MHz,DMSO-d₆):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。

The following compounds were prepared according to the synthetic procedure of example 2, using the corresponding starting materials:

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: synthesis of compound 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

Under the protection of nitrogen, 3- ((3- (2-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-7-yl) phenyl) amino) propionitrile (200mg,0.42mmol), 6-fluoro-1-methyl-3- (tributylstannane) -1H-indazole (380mg,0.85mmol), cuprous iodide (16mg,0.08mmol), tetratriphenylphosphine palladium (26mg,0.02mmol) were added together, DMF (15mL) was added, the temperature was raised to 90 ℃ to react for 4.5H, the reaction solution was cooled to room temperature, ethyl acetate (50 mL. times.3) was extracted, anhydrous Na was used for₂SO₄Drying, removal of solvent and column separation (petroleum ether/ethyl acetate (v/v) ═ 4/1) gave 200mg of a light yellow oil, yield: 84.7 percent.

MS(ESI,pos.ion)m/z:542.3[M+1]⁺。

Step 2: synthesis of compound 3- ((3- (2- (6-fluoro-1-methyl-1H-indazol-3-yl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) 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 (240mg,0.44mmol) was prepared according to the synthetic method of example 2, step 2 to give 180mg of a light yellow solid in yield: 96.2 percent.

MS(ESI,pos.ion)m/z:412.2[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):δ(ppm)12.34(s,1H),9.05(s,1H),8.71(dd,J₁＝8.7Hz,J₂＝5.5Hz,1H),8.33(s,1H),7.63(dd,J₁＝9.6Hz,J₂＝1.5Hz,1H),7.53(d,J＝7.5Hz,1H),7.49(s,1H),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)；

¹³C NMR(150MHz,DMSO-d₆):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。

The following compounds were prepared according to the synthetic procedure of example 3, using the corresponding starting materials:

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: synthesis of the compound 4- (2- (1-methyl-1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) aniline

4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (120mg,0.55mmol), 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b [ -E]Pyrazine (114mg,0.28mmol), potassium carbonate (115mg,0.82mmol), and Pd (dppf) Cl₂(13mg,0.02mmol) prepared according to the synthesis of step 1 of example 1 gave 104mg of a yellow solid in yield: 88.6 percent.

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 give 146mg of a yellow solid in yield: 71.2 percent.

MS(ESI,pos.ion)m/z:291.4[M+1]⁺。

And step 3: synthesis of Compound 1- (cyanomethyl) -3- (4- (2- (1-methyl-1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) urea

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

MS(ESI,neg.ion)m/z:371.2[M-1]^-；

¹H NMR(600MHz,DMSO-d₆):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)；

¹³C NMR(150MHz,DMSO-d₆):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。

The compound shown below was prepared according to the synthetic method of example 16, using the corresponding starting materials:

example 20

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

Step 1: synthesis of compound 2- (1-methyl-1H-pyrazol-4-yl) -7- (1, 4-dioxaspiro [4.5] decan-7-en-8-yl) -5- ((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 (30mg,0.07mmol), 4,4,5, 5-tetramethyl-2- (1, 4-dioxaspiro [4.5]]Helian-7-en-8-yl) -1,3, 2-dioxaborolan (40mg,0.15mmol), potassium carbonate (15mg,0.10mmol), Pd (dppf) Cl₂(6mg,0.01mmol) and water (1mL) the synthesis was performed according to step 1 of example 1 to give 21mg of a light yellow oil, yield: 61.14 percent.

MS(ESI,pos.ion)m/z:468.3[M+1]⁺。

Step 2: synthesis of compound 2- (1-methyl-1H-pyrazol-4-yl) -7- (1, 4-dioxyspiro [4.5] decan-8-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine

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

MS(ESI,pos.ion)m/z:470.4[M+1]⁺。

And step 3: synthesis of the compound 4- (2- (1-methyl-1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) cyclohexanone

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

MS(ESI,pos.ion)m/z:426.4[M+1]⁺。

And 4, step 4: synthesis of compound 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

To a solution of 4- (2- (1-methyl-1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) cyclohexanone (15mg,0.03mmol), 3-aminopropionitrile (30 μ L,0.41mmol) in tetrahydrofuran (4mL) at room temperature was added sodium triacetoxyborohydride (12mg,0.05mmol), stirred at room temperature for 6 hours, quenched with water (20mL), extracted with dichloromethane (20mL x3), dried over anhydrous sodium sulfate, and concentrated column chromatography (dichloromethane/methanol (v/v) ═ 10/1) to give 12mg yellow oil, yield: 70.98 percent.

MS(ESI,pos.ion)m/z:480.0[M+1]⁺。

And 5: synthesis of compound 3- ((4- (2- (1-methyl-1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) cyclohexyl) 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 (130mg,0.27mmol), trifluoroacetic acid (2mL) and ethylenediamine (1mL) was prepared according to the synthetic method of example 2 step 2 to give 16mg of a pale yellow solid in yield: 16.90 percent.

MS(ESI,pos.ion)m/z:350.30[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆)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: synthesis of the 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

Sodium hydride (60%, 55mg,1.38mmol) was added portionwise to a mixture of 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 (320mg,0.54mmol) in N, N-dimethylformamide (15mL) at 0 ℃. After stirring at room temperature for 1.5h, methyl iodide (200mg,2.00mmol) was slowly added dropwise at 0 ℃ and after completion of the addition, the reaction was stirred at room temperature for 15 h. The reaction was quenched with water (50mL), extracted with ethyl acetate (50mL × 3), the organic layer was washed with saturated brine (50mL), dried over anhydrous sodium sulfate, concentrated to remove the solvent, and the residue was subjected to column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give 180mg of a pale yellow solid, yield: 54.6 percent.

MS(ESI,pos.ion)m/z:487.9[M+1]⁺。

Step 2: synthesis of compound 3- (methyl (4- (2- (1-methyl-1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) 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 (180mg,0.37mmol), trifluoroacetic acid (2mL) and ethylenediamine (1mL) were prepared according to the synthesis of example 2 step 2 to give 40mg of an orange solid in yield: 30.3 percent.

MS(ESI,pos.ion)m/z:376.1[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆):δ(ppm)11.97(d,J＝2.3Hz,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)；

¹³C NMR(100MHz,DMSO-d₆):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) butyronitrile

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

2-bromo-7-iodo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyri dinePyrrolo [2,3-b]Pyrazine (600mg,1.32mmol), 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (425mg,1.37mmol), sodium carbonate (356mg,3.35mmol), Pd (PPh)₃)₂Cl₂(100mg,0.14mmol) and water (6mL) the synthesis was prepared according to step 1 of example 1 to give 540mg of a light yellow solid in yield: 80.23 percent.

MS(ESI,pos.ion)m/z:509.2,511.2[M+1]⁺。

Step 2: synthesis of the compound 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

4- (2-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-7-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (325mg,0.63mmo), potassium carbonate (140mg,1.01mmol), 1-methylpyrazole boronate (172mg,0.82mmol) and Pd (dppf) Cl₂(50mg,0.06mmol) prepared according to the synthetic method of example 2 step 1 to give 270mg of a yellow solid, yield: 82.88 percent.

MS(ESI,pos.ion)m/z:511.4[M+1]⁺。

And step 3: synthesis of the compound tert-butyl 4- (2- (1-methyl-1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) piperidine-1-carboxylate

To a solution of 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 (270mg,0.52mmol) in methanol (8mL) was added Pd/C (10%, 30mg,0.028mmol), stirred under hydrogen atmosphere at room temperature overnight, filtered, concentrated, and column chromatographed (petroleum ether/ethyl acetate (v/v) ═ 0/1) to give 250mg of a yellow oil, yield: 92.23 percent.

MS(ESI,pos.ion)m/z:513.4[M+1]⁺。

And 4, step 4: synthesis of the compound 2- (1-methyl-1H-pyrazol-4-yl) -7- (piperidin-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine

To a solution of tert-butyl 4- (2- (1-methyl-1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) piperidine-1-carboxylate (250mg,0.48mmol) in methanol (8mL) under ice bath was added acetyl chloride (70 μ L,0.97mmol), stirred at room temperature overnight, after completion of the reaction, directly concentrated, and column chromatography (dichloromethane/methanol (v/v) ═ 8/1) gave 260mg of a yellow solid, yield: 99 percent.

MS(ESI,pos.ion)m/z:413.4[M+1]⁺。

And 5: synthesis of the compound 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

To a solution of 2- (1-methyl-1H-pyrazol-4-yl) -7- (piperidin-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine (130mg,0.31mmol) in acetonitrile (8mL) were added potassium carbonate (110mg,0.79mmol), potassium iodide (10mg,0.06mmol) and 4-chlorobutyronitrile (0.05mL,0.5mmol) in this order, the reaction was heated at 50 ℃ for 24 hours, diluted with water (20mL), extracted with dichloromethane (20mL x3), dried over anhydrous sodium sulfate, and concentrated column chromatography (dichloromethane/methanol (v/v) ═ 8/1) gave 120mg of a yellow oil, yield: 79.40 percent.

MS(ESI,pos.ion)m/z:480.0[M+1]⁺。

Step 6: synthesis of compound 4- (4- (2- (1-methyl-1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) piperidin-1-yl) 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 (120mg,0.25mmol) and trifluoroacetic acid (2mL) were prepared according to the synthetic method of example 2 step 2 to give 36mg of a light yellow solid in yield: 41.19 percent.

MS(ESI,pos.ion)m/z:351.00[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆)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: synthesis of the compound 3- (2- (1-methyl-1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) cyclohexenone

1, 4-Dioxahexacyclic (16 mL)/Water (4mL) was added to 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] under nitrogen]Pyrazine (500mg,1.22mmol), 3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclohexenone (650mg,2.34mmol), potassium carbonate (340mg,0.2.46mmol) and Pd (dppf) Cl₂(45mg,0.06mmol) of the mixture was reacted at 110 ℃ under reflux for 8 hours, the reaction solution was cooled to room temperature, filtered through celite, the filtrate was concentrated under reduced pressure, and column separation was performed (petroleum ether/ethyl acetate (v/v) ═ 0/1) to give 450mg of yellow solid, yield: 69.4 percent.

MS(ESI,pos.ion)m/z:424.0[M+1]⁺。

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

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

MS(ESI,pos.ion)m/z:428.0[M+1]⁺。

And step 3: synthesis of the compound 3- (2- (1-methyl-1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) cyclohexanone

Dess-Martin reagent (360mg,0.85mmol) was added to a solution of 3- (2- (1-methyl-1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) cyclohexanol (300mg,0.70mmol) in dichloromethane (15mL) and reacted at room temperature for 3 days, quenched with saturated sodium thiosulfate solution (30mL), the aqueous phase was extracted with dichloromethane (20mL x3), the organic layer was dried over anhydrous sodium sulfate and column separation was performed (petroleum ether/ethyl acetate (v/v) ═ 1/3) to give 100mg yellow oil, yield: 33.5 percent.

MS(ESI,pos.ion)m/z:426.0[M+1]⁺。

And 4, step 4: synthesis of the compound 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

Sodium triacetoxyborohydride (70mg,0.33mmol) was added to a solution of 3- (2- (1-methyl-1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) cyclohexanone (80mg,0.19mmol) and 3-aminopropionitrile (20mg,0.28mmol) in tetrahydrofuran (5mL) and reacted at room temperature for 2H. The reaction was quenched with water (30mL), extracted with dichloromethane (30mL x3), the organic layer dried over anhydrous sodium sulfate, and column separated (dichloromethane/methanol (v/v) ═ 30/1) to give 50mg yellow oil, yield: 55.4 percent.

MS(ESI,pos.ion)m/z:480.4[M+1]⁺。

And 5: synthesis of compound 3- ((3- (2- (1-methyl-1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) cyclohexane) amino) propionitrile

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 (110mg,0.20mmol), trifluoroacetic acid (2mL) and ethylenediamine (1mL) were prepared according to the synthetic method of example 2 step 2 to give 25mg of a yellow solid in yield: 76.3 percent.

MS(ESI,pos.ion)m/z:350.0[M+1]⁺。

¹H NMR(600MHz,DMSO-d₆):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)；

¹³C NMR(150MHz,DMSO-d₆):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) azetidine-3-carbonitrile

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

Dichloromethane (12mL) was added to 4-bromobenzenesulfonyl chloride (252mg,0.99mmol), 3-acetonitrile cyclobutylamine hydrochloride (90mg,0.76mmol), triethylamine (230mg,2.28mmol) under nitrogen, reacted at room temperature for 12h, the reaction solution was extracted with ethyl acetate (50mLx3), the organic phase was dried by spinning, and column chromatography (petroleum ether/ethyl acetate (v/v) ═ 3/1) gave 179mg of a white solid, yield: 78.3 percent.

¹H NMR(400MHz,DMSO-d₆):δ(ppm)7.94(d,J＝8.5Hz,2H),7.78(d,J＝8.5Hz,2H),4.00(t,J＝8.7Hz,2H),3.87(dd,J₁＝8.5Hz,J₂＝5.9Hz,2H),3.69–3.58(m,1H)。

Step 2: synthesis of the compound 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

Under nitrogen protection, 1, 4-dioxane (12mL) was added to 1- ((4-bromophenyl) sulfonyl) azetidine-3-carbonitrile (148mg,0.49mmol), pinacol ester diboron (138mg,0.54mmol), potassium acetate (150mg,1.53mmol), Pd (dppf) Cl₂(23mg,0.03mmol) to the mixture, reflux reaction at 110 ℃ for 11H, cooling the reaction to room temperature, adding water (2.5mL), potassium carbonate (130mg,0.93mmol), 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] under nitrogen protection]Pyrazine (120mg,0.29mmol), Pd (dppf) Cl₂(23mg,0.03mmol), reflux reaction at 110 deg.C for 10h, reactionThe solution was cooled to room temperature, filtered through celite, the filtrate was concentrated under reduced pressure, and column separation (petroleum ether/ethyl acetate (v/v) ═ 1/2) was performed to give 150mg of a yellow solid, yield: 55.5 percent.

MS(ESI,pos.ion)m/z:549.8[M+1]⁺。

And step 3: synthesis of compound 1- ((4- (2- (1-methyl-1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) 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 (150mg,0.27mmol), trifluoroacetic acid (6mL) and ethylenediamine (1mL) were prepared according to the synthetic procedure of example 2, step 2 to give 91mg of a pale yellow solid in yield: 79.5 percent.

MS(ESI,pos.ion)m/z:419.9[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆+D₂O):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,J₁＝8.3Hz,J₂＝6.2Hz,2H),3.65(m,1H)；

¹³C NMR(150MHz,DMSO-d₆):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) propionitrile

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

Potassium carbonate (76mg,0.55mmol), 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b]Pyrazine esters(90mg,0.22mmol), 3- ((4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) thio) propionitrile (95mg,0.33mmol) and Pd (dppf) Cl₂(7mg,0.01mmol) prepared according to the synthetic method of example 1, step 1, to give 45mg of a yellow oil, yield: 41.6 percent.

MS(ESI,pos.ion)m/z:491.3[M+1]⁺。

Step 2: synthesis of compound 3- ((4- (2- (1-methyl-1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) thio) propionitrile

3- ((4- (2- (1-methyl-1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) thio) propionitrile (45mg,0.09mmol), trifluoroacetic acid (6mL) and ethylenediamine (1mL) were prepared according to the synthetic method of example 2 step 2 to give 27mg of an off-white solid in yield: 81.7 percent.

MS(ESI,pos.ion)m/z:361.2[M+1]⁺。

And step 3: synthesis of compound 3- ((4- (2- (1-methyl-1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) sulfonyl) propionitrile

At room temperature, 3- ((4- (2- (1-methyl-1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) thio) propionitrile (36mg,0.10mmol) was dissolved in dichloromethane (10mL), m-chloroperoxybenzoic acid (60mg,0.30mmol) was added, reaction was carried out at room temperature for 12H, silica gel was added to the reaction solution, spin-dried and sample-stirred at room temperature, column chromatography (dichloromethane/methanol (v/v) ═ 20/1) gave 43mg of a pale yellow solid, which was then purified with a preparative thin layer to give 6mg of a beige solid, yield: 15.3 percent.

MS(ESI,pos.ion)m/z:393.2[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):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)；

¹³C NMR(150MHz,DMSO-d₆):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。

The following compounds were prepared according to the synthetic method of example 24, using the corresponding starting materials:

example 38

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

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-dioxaborolan-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 give 180mg of a yellow oil in yield: 72.3 percent.

MS(ESI,pos.ion)m/z:421.0[M+1]⁺。

Step 2: synthesis of the compound 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

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

MS(ESI,pos.ion)m/z:460.4[M+1]⁺。

And step 3: synthesis of Compound 2- ((4- (2- (1-methyl-1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) 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 (130mg,0.28mmol), trifluoroacetic acid (2mL) and ethylenediamine (1mL) were prepared according to the synthetic method of example 2 step 2 to give 50mg of a yellow solid in yield: 53.7 percent.

MS(ESI,pos.ion)m/z:329.9[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):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)；

¹³C NMR(150MHz,DMSO-d₆):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) pyrimidin-4-yl) amino) -N- (2,2, 2-trifluoroethyl) butyramide

Step 1: synthesis of compound (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

(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 boronic acid ester (115mg,0.55mmol) and Pd (dppf) Cl₂(30mg,0.04mmol) prepared according to the synthetic method of example 2 step 1 to give 120mg of an off-white solid, yield: 46.81 percent.

MS(ESI,pos.ion)m/z:716.45[M+1]⁺。

Step 2: synthesis of compound 2-methyl-2- ((2- (2- (1-methyl-1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) 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 (110mg,0.15mmol), trifluoroacetic acid (330 μ L,4.443mmol) and triethylsilane (670 μ L,4.19mmol) were prepared according to the synthetic method of example 2 step 2 to give 20mg of a yellow solid in yield: 27.49 percent.

MS(ESI,pos.ion)m/z:474.30[M+1]⁺；

¹H NMR(600MHz,CD₃OD)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)；

¹³C NMR(150MHz,CD₃OD)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: synthesis of the compound (R) -N- (2-cyanoethyl) -3- (2- (1- (2-hydroxypropyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) benzenesulfonamide

Cesium carbonate (840mg,2.58mmol), 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (250mg,1.29mmol) and (R) -propylene oxide (285mg,4.91mmol) were added together at room temperature, acetonitrile (15mL) was added, the tube was sealed and the temperature was raised to 130 ℃ for reaction for 22H, the reaction solution was extracted with ethyl acetate (50 mL. times.3), and the organic phase was spin-dried. Under nitrogen protection, 3- (2-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -N- (2-cyanoethyl) benzenesulfonamide (150mg,0.28mmol), potassium carbonate (100mg,0.72mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (12mg,0.02mmol) was added followed by dioxane (15mL) and water (3mL), reacted at 110 ℃ for 24H, the reaction was cooled to room temperature, filtered over celite, the filtrate was concentrated under reduced pressure, and column separation (ethyl acetate) was performed to give 150mg of a yellow oil, yield: 92.2 percent.

MS(ESI,pos.ion)m/z:582.3[M+1]⁺。

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

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

MS(ESI,pos.ion)m/z:452.4[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):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)；

¹³C NMR(150MHz,DMSO-d₆):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。

The following compounds were prepared according to the synthetic method of example 62 using the corresponding starting materials:

example 72

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

Step 1: synthesis of compound 1-carboxylic acid tert-butyl ester-4- ((4- (2-cyclopropyl-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1H-pyrazol-1-yl)) piperidine

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

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 (260mg,0.48mmol), trifluoroacetic acid (2mL) and ethylenediamine (1mL) was prepared according to the synthetic method of example 2 step 2 to give 110mg of a pale yellow solid in yield: 73.9 percent.

MS(ESI,pos.ion)m/z:309.3[M+1]⁺。

And step 3: synthesis of compound 3- (4- (4- (2-cyclopropyl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -3-oxopropanenitrile

2-cyclopropyl-7- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazine (100mg,0.32mmol) was added to a mixture of cyanoacetic acid (65mg,0.76mmol), 1-Hydroxybenzotriazole (HOBT) (110mg,0.81mmol), 1-ethyl- (3-dimethylaminopropyl) carbonyl diimine hydrochloride (150mg,0.78mmol) and triethylamine (0.08g,0.1mL,0.80mmol) in N, N-dimethylformamide (5mL), reacted at room temperature for 6H, quenched with water (50mL), extracted with ethyl acetate (50mL x 4), the organic layer was washed with saturated brine (50mL x 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrated solution was subjected to column separation (dichloromethane/methanol (v/v) ═ 12/1) to obtain a solution To 80mg of a pale yellow solid, yield: 65.7 percent.

MS(ESI,pos.ion)m/z:375.9[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):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)；

¹³C NMR(150MHz,DMSO-d₆):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。

Prepared according to the synthetic method of example 72 using the corresponding starting materials, the following compounds were prepared:

example 90

5- ((3-Propylaminophenyl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxylic acid methyl ester

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

Pyrazolo [1,5-a ] pyrimidine-5-hydroxy (1g,7.40mmol) and N-iodosuccinimide (1.83g,8.14mmol) were dissolved in N, N-dimethylformamide (20mL) at room temperature, the reaction slowly exothermed with a large amount of solid formed in a few minutes, and the reaction was stirred at room temperature for 1 hour. Cooled under ice-bath, filtered, and the white solid collected and the cake washed with dichloromethane (20mL) and dried to give 1.7g white solid, yield: 88 percent.

¹H NMR(600MHz,DMSO-d₆):δ(ppm)12.24(s,1H),8.48(s,1H),7.84(s,1H),6.00(s,1H)。

Step 2: synthesis of compound methyl 5-hydroxypyrazole [1,5-a ] pyrimidine-3-carboxylate

N₂Methanol (10mL) was injected with 3-iodopyrazolo [1,5-a ] under protection]After introducing carbon monoxide into a mixture of pyrimidine-5-hydroxy (0.2g,0.76mmol), palladium acetate (35mg,0.15mmol) and triethylamine (0.32mL,2.3mmol), the reaction was carried out at 55 ℃ for 5 hours. Celite was filtered, concentrated under reduced pressure, the residue was washed with water (35mL), extracted with dichloromethane (35mLx3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column separated (dichloromethane/methanol (v/v) ═ 30/1) to give 45mg of a white solid, yield: 30.4 percent.

¹H NMR(400MHz,DMSO-d₆):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)。

And step 3: synthesis of compound methyl 5-chloropyrazolo [1,5-a ] pyrimidine-3-carboxylate

5-Hydroxypyrazole [1,5-a ] pyrimidine-3-carboxylic acid methyl ester (0.028g,0.14mmol), phosphorus oxychloride (0.8mL,8mmol) and N, N-diisopropylethylamine (0.01mL,0.06mmol) in toluene (2mL) solution were refluxed for 2 h. Cooling to room temperature, removing phosphorus oxychloride under reduced pressure, quenching the residue with warm water (35mL), extracting with dichloromethane (35mL × 3), drying over anhydrous sodium sulfate, concentrating under reduced pressure, and column separating (dichloromethane/methanol (v/v) ═ 80/1) to give 19mg of a white solid, yield: 61.9 percent.

¹H NMR(400MHz,DMSO-d₆):δ(ppm)9.33(d,J＝7.2Hz,1H),8.68(s,1H),7.41(d,J＝7.2Hz,1H),3.83(s,3H)。

And 4, step 4: synthesis of compound methyl 5- ((3-propionamidophenyl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxylate

N₂Under protection, 1, 4-dioxane (8mL) was added to 5-chloropyrazole [1,5-a ]]Pyrimidine-3-carboxylic acid methyl ester (0.08g,0.37mmol), Xantphos (0.011g,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 at 110 ℃ under reflux for 6h, filtration, washing of the filtrate with water (30mL), back-extraction of the aqueous phase with dichloromethane (30mL x3), combining the organic layers, drying over anhydrous sodium sulfate, concentration under reduced pressure, column separation (dichloromethane/methanol (v/v) ═ 30/1) to give a tan solid, and separation by high performance chromatography to give 20mg of a beige solid, yield: 15.59 percent.

MS(ESI,pos.ion)m/z:340.1[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):δ(ppm)10.08(s,1H),9.87(s,1H),8.75(d,J＝7.6Hz,1H),8.36(d,J＝6.7Hz,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)；

¹³C NMR(150MHz,DMSO-d₆):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] triazole [4,5-d ] pyridin-8-yl) benzenesulfonamide

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

4-chloro-1H-pyrrolo [2,3-b ] pyridine (1.50g,9.80mmol), triethylamine (1.81g,18.01mmol) and DMAP (205mg,1.59mmol) were added together at room temperature, and methylene chloride (20mL) and p-toluenesulfonyl chloride (2.25g,11.80mmol) were sequentially added to react at room temperature for 36 hours, the reaction mixture was quenched with water (50mL), extracted with methylene chloride (50 mL. times.3), the organic phase was spin-dried, and column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1) gave 1.46g of a white solid with 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-pyrrolo [2,3-b ] pyridine

4-chloro-1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridine (1.48g,4.82mmol), tetrabutylammonium nitrate (1.84g,5.86mmol), dichloromethane (30mL) were added together at 5 ℃, trifluoroacetic anhydride (0.92mL,6.50mmol) was slowly added, after addition the reaction was warmed to room temperature for 6H, -tetrabutylammonium nitrate (0.46g,1.45mmol), trifluoroacetic anhydride (0.28mL,2.01mmol) was added at 5 ℃, after addition the reaction was warmed to room temperature for 18H, the reaction was quenched with water (70mL), extracted with dichloromethane (100mL × 3), the organic phase was spin dried, and column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1) gave 1.21g of a white solid, yield: 71.6 percent.

MS(ESI,pos.ion)m/z:352.1[M+1]⁺。

And step 3: synthesis of compound 5-nitro-1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-4-amine

At room temperature, 4-chloro-5-nitro-1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridine (300mg,0.85mmol) and concentrated aqueous ammonia (2mL) were added together, dioxane (20mL) was added in that order, reaction was carried out at 80 ℃ for 6 hours, the reaction mixture was cooled to room temperature, diluted with water (50mL), extracted with dichloromethane (50mL × 3), the organic phase was dried by spinning, and column chromatography (petroleum ether/ethyl acetate (v/v) ═ 4/1) gave 130mg of a yellow solid, yield: 45.9 percent.

MS(ESI,pos.ion)m/z:333.2[M+1]⁺。

And 4, step 4: synthesis of compound 1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyrazine-4, 5-diamine

At room temperature, 5-nitro-1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-4-amine (130mg,0.39mmol), ammonium chloride (124mg,2.34mmol), iron powder (90mg,1.61mmol) were added together, ethanol (10mL), water (3mL) were then added, reaction was carried out at 90 ℃ for 4 hours, the reaction was cooled to room temperature, celite was filtered, water (50mL) was added and diluted, extraction was carried out with ethyl acetate (50mL × 3), the organic phase was dried, column chromatography (dichloromethane/methanol (v/v) ═ 20/1) gave 80mg of a brown oil, yield: 67.6 percent.

MS(ESI,pos.ion)m/z:303.2[M+1]⁺。

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

1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyrazine-4, 5-diamine (70mg,0.23mmol), sodium nitrite (19mg,0.28mmol) were added together, acetic acid (8mL) was added, reaction was carried out at room temperature for 3H, water (50mL) was added for dilution, extraction was carried out with ethyl acetate (50mL × 3), the organic phase was spun dry, and column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/2) gave 40mg of a pale yellow solid, yield: 55.2 percent.

MS(ESI,pos.ion)m/z:314.3[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ(ppm)9.19(s,1H),8.03(t,J＝5.5Hz,3H),7.43(d,J＝8.3Hz,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

6-p-toluenesulfonyl-1, 6-dihydropyrrolo [2,3-b ] [1,2,3] triazolo [4,5-d ] pyridine (150mg,0.48mmol), NBS (128mg,0.72mmol) were added together at room temperature, DMF (10mL) was added, reacted at room temperature for 10h, diluted with water (50mL), extracted with ethyl acetate (50 mL. times.3), the organic phase was spin dried, column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/2) afforded 160mg of a pale yellow solid, which was prepared by HPLC to give 79mg of a pale yellow solid, yield: 42.1 percent.

MS(ESI,pos.ion)m/z:392.0[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆+D₂O):δ(ppm)9.23(s,1H),8.26(s,1H),8.04(d,J＝8.4Hz,2H),7.42(d,J＝8.2Hz,2H),2.31(s,3H)。

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

1, 4-Dioxahexacyclic compound (12 mL)/water (3mL) was added under nitrogen to N- (2-cyanoethyl) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzenesulfonamide (132mg,0.39mmol), 8-bromo-6-p-toluenesulfonyl-1, 6-dihydropyrrole [2,3-b ] sulfonamide][1,2,3]Triazole [4,5-d]Pyridine (79mg,0.20mmol), potassium carbonate (73mg,0.52mmol), Pd (dppf) Cl₂To a mixture (12mg,0.02mmol), the reaction was refluxed at 110 ℃ for 7h, the reaction solution was cooled to room temperature, filtered through celite, the filtrate was concentrated under reduced pressure, and column separation was performed (petroleum ether/ethyl acetate (v/v) ═ 1/3) to give 95mg of a brown oil, yield: 90.5 percent.

MS(ESI,pos.ion)m/z:522.2[M+1]⁺。

And 8: synthesis of compound N- (2-cyanoethyl) -3- (1, 6-dihydropyrrole [2,3-b ] [1,2,3] triazole [4,5-d ] pyridin-8-yl) benzenesulfonamide

N- (2-cyanoethyl) -3- (6-p-toluenesulfonyl-1, 6-dihydropyrrolo [2,3-b ] [1,2,3] triazolo [4,5-d ] pyridin-8-yl) benzenesulfonamide (106mg,0.20mmol), potassium tert-butoxide (100mg,0.84mmol) were added together at room temperature, anhydrous tetrahydrofuran (5mL) was added thereto and reacted at room temperature for 3 hours, the reaction solution was added to silica gel and stirred at room temperature, column chromatography separation (dichloromethane/methanol (v/v) ═ 10/1) gave 100mg of a red solid, which was then prepared by HPLC to give 50mg of a white solid, yield: 67.0 percent.

MS(ESI,pos.ion)m/z:368.0[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):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)；

¹³C NMR(150MHz,DMSO-d₆):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 ] pyridin-8-yl) benzenesulfonamide

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

Prepared from 4-chloro-5-nitro-1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridine (300mg,0.85mmol), methylamine ethanol solution (6.38M,15mL,95.7mmol) according to the synthetic method of example 15 step 3 to give 184mg of a yellow solid in yield: 62.3 percent.

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

Prepared from N-methyl-5-nitro-1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-4-amine (40mg,0.12mmol), ammonium chloride (37mg,0.70mmol), iron powder (26mg,0.47mmol), ethanol (10mL), water (3mL) following the synthetic method of example 15 step 4 to give 20mg of a red solid in yield: 54.7 percent.

MS(ESI,pos.ion)m/z:317.2[M+1]⁺。

And 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-pyrrolo [2,3-b ] pyridine-4, 5-diamine (215mg,0.68mmol), sodium nitrite (56mg,0.81mmol), and acetic acid (8mL) were prepared according to the synthetic method of example 15 step 5 to give 150mg of a pale yellow solid in yield: 67.2 percent.

MS(ESI,pos.ion)m/z:328.2[M+1]⁺。

And 4, step 4: synthesis of compound 1-methyl-8-bromo-6-p-toluenesulfonyl-1, 6-dihydropyrrole [2,3-b ] [1,2,3] triazole [4,5-d ] pyridine

1-methyl-6-p-toluenesulfonyl-1, 6-dihydropyrrole [2,3-b ] [1,2,3] triazole [4,5-d ] pyridine (156mg,0.48mmol), NBS (128mg,0.72mmol), DMF (10mL) were prepared according to the synthetic method of example 15 step 6 to give 160mg of a pale yellow solid which was prepared by HPLC to give 53mg of a pale yellow solid, yield: 27.3 percent.

MS(ESI,pos.ion)m/z:406.1[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ(ppm)9.26(s,1H),8.34(s,1H),8.07(d,J＝8.4Hz,2H),7.44(d,J＝8.2Hz,2H),4.69(s,3H),2.34(s,3H)。

And 5: synthesis of compound N- (2-cyanoethyl) -3- (1-methyl-6-p-toluenesulfonyl-1, 6-dihydropyrrole [2,3-b ] [1,2,3] triazole [4,5-d ] pyridin-8-yl) benzenesulfonamide

1, 4-Dioxahexacyclic compound (12 mL)/Water (3mL), N- (2-cyanoethyl) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzenesulfonamide (82mg,0.24mmol), 1-methyl-8-bromo-6-p-toluenesulfonyl-1, 6-dihydropyrrole [2,3-b ]][1,2,3]Triazole [4,5-d]Pyridine (53mg,0.14mmol), potassium carbonate (50mg,0.36mmol), Pd (dppf) Cl₂(7mg,0.01mmol) of the mixture was prepared according to the synthesis method of example 15 step 7 to give 60mg of pale yellow solid, yield: 85.8 percent.

MS(ESI,pos.ion)m/z:536.2[M+1]⁺。

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

N- (2-cyanoethyl) -3- (6-p-toluenesulfonyl-1, 6-dihydropyrrolo [2,3-b ] [1,2,3] triazolo [4,5-d ] pyridin-8-yl) benzenesulfonamide (76mg,0.14mmol), potassium tert-butoxide (50mg,0.42mmol) prepared according to the synthesis procedure of example 15 step 8 gave 60mg of a pale yellow oil which was then slurried with a dichloromethane/methanol mixture to give 30mg of a grayish solid in yield: 55.4 percent.

MS(ESI,pos.ion)m/z:382.2[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):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)；

¹³C NMR(150MHz,DMSO-d₆):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: synthesis of compound tert-butyl (7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) carbamate

To a solution of 2, 7-dibromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine (100mg,0.24mmol) in 1, 4-dioxane (4mL) were added xanthphos (30mg,0.05mmol), potassium carbonate (50mg,0.36mmol), palladium acetate (6mg,0.03mmol) and tert-butyl carbamate (45mg,0.38mmol) in this order, the reaction was refluxed at 115 ℃ for 6 hours under a nitrogen atmosphere, filtered through celite, concentrated, and subjected to column chromatography (petroleum ether/ethyl acetate (v/v) ═ 8/1) to give 100mg of a brown oil, yield: 91.83 percent.

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 ] pyrazin-2-amino

To a solution of tert-butyl (7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) carbamate (100mg,0.22mmol) in dichloromethane (2mL) was added a solution of hydrogen chloride in isopropanol (7N,4mL), stirred at room temperature for 6 hours, the solvent was removed, saturated sodium bicarbonate was added to adjust to pH >7, dichloromethane extracted (25mL × 3), dried and concentrated, and the residue was column chromatographed (petroleum ether/ethyl acetate (v/v) ═ 0/1) to give 58mg of the product as a pale yellow solid, yield: 74.91 percent.

MS(ESI,pos.ion)m/z:343.2,345.1[M+1]⁺。

And step 3: synthesis of compound 1-bromo-3- ((2- (trimethylsilyl) ethoxy) methyl) -3H-imidazo [1,2-a ] pyrrolo [2,3-e ] pyrazine

To a solution of 7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine-2-amino (58mg,0.17mmol) in ethanol (6mL) was added in sequence 40% chloroacetaldehyde aqueous solution (70 μ L,0.42mmol), reacted at 85 ℃ under reflux for 6 hours, directly added silica gel to stir the sample, and column chromatography gave 60mg of a pale yellow solid, yield: 96.69 percent.

MS(ESI,pos.ion)m/z:368.6[M+1]⁺。

And 4, step 4: synthesis of compound N- (2-cyanoethyl) -3- (3- ((2- (trimethylsilyl) ethoxy) methyl) -3H-imidazo [1,2-a ] 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 (20mg,0.05mmol) in 1, 4-dioxane (5mL), potassium carbonate (12mg,0.08mmol), N- (2-cyanoethyl) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzenesulfonamide (30mg,0.09mmol), Pd (dppf) Cl₂(6mg,0.008mmol) and water (1mL) the synthesis was performed as in step 7 of example 15 to give 7mg of a yellow solid in yield: 25.88 percent.

MS(ESI,pos.ion)m/z:497.4[M+1]⁺。

And 5: synthesis of compound N- (2-cyanoethyl) -3- (3H-imidazo [1,2-a ] pyrrolo [2,3-e ] pyrazin-1-yl) benzenesulfonamide

To a solution of N- (2-cyanoethyl) -3- (3- ((2- (trimethylsilyl) ethoxy) methyl) -3H-imidazo [1,2-a ] pyrrolo [2,3-e ] pyrazin-1-yl) benzenesulfonamide (100mg,0.20mmol) in dichloromethane (6mL) was added trifluoroacetic acid (2mL,26.93mmol), stirred at room temperature for 3 hours, the solvent was concentrated, dissolved by addition of tetrahydrofuran (6mL), ethylenediamine was added to pH >7, stirring was continued at room temperature, water (20mL) was added for dilution, dichloromethane extracted (20mL x3), dried over anhydrous sodium sulfate, concentrated column chromatography (petroleum ether/ethyl acetate (v/v) ═ 0/1) gave 37mg yellow solid, yield: 50.16 percent.

MS(ESI,pos.ion)m/z:367.25[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):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)；

¹³C NMR(150MHz,DMSO-d₆):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

After addition of sodium hydride (60%, 3.1g,78mmol) to a solution of 2-bromo-5H-pyrrolo [2,3-b ] pyrazine (10g,50.5mmol) in tetrahydrofuran (150mL) at 15 ℃, stirring at room temperature for 1 hour, addition of p-toluenesulfonyl chloride (12.6g,65.4mmol) under ice bath, continued stirring at room temperature, dilution with water (100mL), dichloromethane extraction (100mL × 3), drying over anhydrous sodium sulfate, concentrated column chromatography (petroleum ether/ethyl acetate (v/v) ═ 8/1) gave 14.1g of a pale yellow flocculent solid, yield: 79.3 percent.

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) carbamic acid tert-butyl ester

A solution of 2-bromo-5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazine (100mg,0.28mmol) in 1, 4-dioxane (6mL), xanthphos (34mg,0.06mmol), potassium carbonate (60mg,0.43mmol), palladium acetate (7mg,0.03mmol), and tert-butyl carbamate (50mg,0.43mmol) was prepared according to the synthetic method of example 17 step 1 to give 87mg of a red-brown solid product in yield: 78.89 percent.

MS(ESI,pos.ion)m/z:389.3[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ(ppm)10.11(s,1H),8.77(s,1H),8.18(d,J＝4.0Hz,1H),7.97(d,J＝8.2Hz,2H),7.43(d,J＝8.2Hz,2H),6.85(d,J＝4.0Hz,1H),2.34(s,3H),1.37(s,10H)。

And 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 (900mg,2.32mmol) in dichloromethane (3mL) and hydrogen chloride-isopropanol solution (6N,7mL,42mmol) was prepared according to the synthetic method of example 17 step 2 to give 440mg of a light yellow dry solid in yield: 65.86 percent

MS(ESI,pos.ion)m/z:289.0[M+1]⁺。

And 4, step 4: synthesis of compound 3-p-toluenesulfonyl-imidazo [1,2-a ] pyrrolo [2,3-e ] pyrazine

A solution of 2-amino-5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazine (170mg,0.5897mmol) in ethanol (6mL) and 40% 2-chloroacetaldehyde (150 μ L,0.9mmol) was prepared according to the synthetic method of example 17 step 3 to give 170mg yellow-green, yield: 92.29 percent.

MS(ESI,pos.ion)m/z:313.2[M+1]⁺；

1H NMR(400MHz,DMSO-d₆):δ(ppm)8.90(s,1H),8.58(s,1H),8.04(dd,J＝13.5,6.1Hz,4H),7.45(d,J＝8.2Hz,2H),7.35(d,J＝3.8Hz,1H),2.35(s,3H)。

And 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 (420mg,1.34mmol) in DMF (8mL) was added N-iodosuccinimide (450mg,2.0mmol), stirred at room temperature for 3 hours, quenched by addition of sodium thiosulfate solution (20mL), extracted with dichloromethane (25mLx3), dried over anhydrous sodium sulfate, and concentrated by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to afford 599mg of a pale yellow solid, yield: 100 percent.

MS(ESI,pos.ion)m/z:439.10[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ(ppm)8.78(d,J＝6.7Hz,1H),8.00(m,3H),7.92(s,1H),7.72(d,J＝4.1Hz,1H),7.45(d,J＝8.3Hz,2H),2.35(s,3H)。

Step 6: synthesis of compound N- (2-cyanoethyl) -3- (3-p-toluenesulfonamide-3H-imidazo [1,2-a ] pyrrolo [2,3-e ] pyrazin-8-yl) benzenesulfonamide

8-iodo-3-p-toluenesulfonyl-3H-imidazo [1,2-a ]]Pyrrolo [2,3-e]Pyrazine (300mg, 0)68mmol) of 1, 4-dioxane (8mL), N- (2-cyanoethyl) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzenesulfonamide (210mg,0.62mmol), potassium carbonate (150mg,1.08mmol), Pd (dppf) Cl₂(50mg,0.07mmol) and water (2mL) the synthesis was performed according to step 7 of example 15 to give 200mg of a light yellow solid in yield: 56.11 percent.

MS(ESI,pos.ion)m/z:521.20[M+1]⁺。

And 7: synthesis of compound N- (2-cyanoethyl) -3- (3H-imidazo [1,2-a ] pyrrolo [2,3-e ] pyrazin-8-yl) benzenesulfonamide

To a solution of N- (2-cyanoethyl) -3- (3-p-toluenesulfonamide-3H-imidazo [1,2-a ] pyrrolo [2,3-e ] pyrazin-8-yl) benzenesulfonamide (180mg,0.35mmol) in tetrahydrofuran (8mL) at room temperature was added potassium tert-butoxide (124mg,1.10mmol), stirred at room temperature for 2 hours, silica gel was added directly to stir the sample, and column chromatography (petroleum ether/ethyl acetate (v/v) ═ 0/1) gave 98mg of a pale yellow solid, yield: 77.36%, purity: 96.08% (HPLC).

MS(ESI,pos.ion)m/z:367.25[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):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)；

¹³C NMR(150MHz,DMSO-d₆):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-pyrrolo [2,3-b ] pyrazine-7-carboxamide

Step 1: synthesis of compound N-cyclobutyl-2- (3-propionamidophenyl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine-7-formamide

1,4 dioxane (8 mL)/water (2mL), 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,1.44mmol) and Pd (dppf) Cl₂(18mg,0.02mmol) prepared according to the synthetic method of example 1, step 1, to give 220mg of an off-white solid, yield: 86.17 percent.

MS(ESI,Pos.ion)m/z:493.3[M+1]⁺。

Step 2: synthesis of compound N-cyclobutyl-2- (3-propionamidophenyl) -5H-pyrrole [2,3-b ] pyrazine-7-formamide

A solution of N-cyclobutyl-2- (3-propionamidophenyl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine-7-carboxamide (0.22g,0.44mmol) in dichloromethane (20mL) was dissolved at room temperature, trifluoroacetic acid (8mL) was added and the mixture was stirred at room temperature for 6H. Concentrated under reduced pressure, and the residue was taken up in tetrahydrofuran (15mL), made basic with saturated sodium bicarbonate solution and reacted at room temperature overnight. Dilution with water (30mL), extraction with dichloromethane (30mL × 3), drying of the organic layer over anhydrous sodium sulfate, concentration under reduced pressure (dichloromethane/methanol (v/v) ═ 30/1), and column separation afforded 150mg of a yellow solid, yield: 92.63 percent.

MS(ESI,pos.ion)m/z:364.2[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):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)；

¹³C NMR(150MHz,DMSO-d₆):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-Dioxothiomorpholine) methyl) phenyl) -N-isopropyl-1H-pyrrolo [2,3-b ] pyridine-3-carboxamide

Step 1: synthesis of the compound 5- (4- ((1, 1-dioxothiomorpholine) methyl) phenyl) -N-isopropyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyrazine-3-carboxamide

4- (4-bromobenzyl) dioxothiomorpholine (16mg,0.05mmol), N-isopropyl-5-boronate-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carboxamide (20mg,0.04mmol), Potassium carbonate (15mg,0.11mmol) and Pd (dppf) Cl₂(6.4mg,0.01mmol) were mixed, 1, 4-dioxane (8mL) was added, heating was performed at 115 ℃ for 4 hours under nitrogen atmosphere, filtration was performed, celite was performed, and the filtrate was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give 12.7mg of a yellow oil, yield: 52.4 percent.

MS(ESI,pos.ion)m/z:557.1[M+1]⁺。

Step 2: synthesis of compound 5- (4- ((1, 1-dioxothiomorpholine) methyl) phenyl) -N-isopropyl-1H-pyrrolo [2,3-b ] pyridine-3-carboxamide

Dissolving 5- (4- ((1, 1-dioxothiomorpholine) methyl) phenyl) -N-isopropyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridine-3-carboxamide (140mg,0.25mmol) in dichloromethane (6mL), adding trifluoroacetic acid (2mL), stirring at room temperature for 2H, concentrating the solvent, adding tetrahydrofuran (6mL) for dissolution, adding lithium hydroxide solution (2N) dropwise to pH >7, stirring at room temperature for 2H, diluting with water (20mL), dichloromethane extracting (15mLx3), drying over anhydrous sodium sulfate, concentrating column chromatography (petroleum ether/ethyl acetate (v/v): 1/1) to give 63mg of a white solid, yield: 58.75 percent.

MS(ESI,pos.ion)m/z:427.0[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):δ(ppm)12.13(s,1H),8.65(t,J＝9.2Hz,1H),8.56(d,J＝1.7Hz,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)；

¹³C NMR(150MHz,DMSO-d₆):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-Dioxothiomorpholine) methyl) phenyl) -N-isopropyl-1H-pyrrolo [2,3-b ] pyridine-3-carboxamide

Step 1: synthesis of the compound 5- (3- ((1, 1-dioxothiomorpholine) methyl) phenyl) -N-isopropyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyrazine-3-carboxamide

4- (3-bromobenzyl) dioxothiomorpholine (175mg,0.57mmol), N-isopropyl-5-boronate-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ]]Pyridine-3-carboxamide (220mg,0.47mmol), Potassium carbonate (165mg,1.19mmol), Pd (dppf) Cl₂(73mg,0.09mmol) and 1, 4-dioxane (10mL) were prepared according to the synthetic method of example 20, step 1 to give 190mg of a yellow solid in yield: 71.3 percent.

MS(ESI,pos.ion)m/z:557.1[M+1]⁺。

Step 2: synthesis of compound 5- (3- ((1, 1-dioxothiomorpholine) methyl) phenyl) -N-isopropyl-1H-pyrrolo [2,3-b ] pyridine-3-carboxamide

5- (3- ((1, 1-dioxothiomorpholine) methyl) phenyl) -N-isopropyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyrazine-3-carboxamide (190mg,0.34mmol), trifluoroacetic acid (2mL) and lithium hydroxide solution (2N) were prepared according to the synthetic method of example 20 step 2 to give 71mg of a white solid in yield: 48.78 percent.

MS(ESI,pos.ion)m/z:427.20[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):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)；

¹³C NMR(150MHz,DMSO-d₆):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

Reacting 5-bromo-3-iodo-1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ]]Pyridine (20mg,0.04mmol) was dissolved in acetonitrile (4mL), and 5-boronic acid pinacol ester-1H-indole (11.2mg,0.04mmol), 1N aqueous sodium carbonate (0.11mL,0.11mmol), Pd (dppf) Cl were added in this order₂(6.5mg,0.01mmol), exchange N₂After stirring at room temperature for 2 hours, saturated brine (10mL) and dichloromethane (10mL × 3) were added, and the mixture was extracted, dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v) ═ 6/1), whereby 7mg of a brown solid was obtained, yield: 35.8 percent.

MS(ESI,pos.ion)m/z:466.0[M+1]。

Step 2: synthesis of compound N- (3- (3- (1H-indol-5-yl) -1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyrazin-5-yl) phenyl) acrylamide

Reacting 5-bromo-3- (1H-indol-5-yl) -1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ]]Pyridine (10mg,0.02mmol), N- (3-phenylboronic acid pinacol ester phenyl) acrylamide (8.8mg,0.032mmol), Pd (dppf) Cl₂Compound (3.1mg,0.004mmol) and 1mol/L sodium carbonate solution (0.052mL,0.052mmol) was placed in a single-necked flask, dioxane (4mL) was added, stirring was performed at 115 ℃ for 5 hours at room temperature, saturated brine (10mL) was added, dichloromethane (10mL × 3) was extracted, dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give 3mg of a brown solid, yield: 26.27％。

MS(ESI,pos.ion)m/z:533.2[M+1]⁺。

And step 3: synthesis of the Compound N- (3- (3- (1H-indol-5-yl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) phenyl) -3-methoxypropionamide

N- (3- (3- (1H-indol-5-yl) -1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyrazin-5-yl) phenyl) acrylamide (7mg,0.01mmol) was dissolved in methanol (3mL), a 5N sodium hydroxide solution (13.1 μ L,0.06mmol) was added, the reaction was heated at 50 ℃ for 3 hours, diluted with water (10mL), extracted with dichloromethane (15mL × 3), dried over anhydrous sodium sulfate, the solvent was removed, the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give 2mg of a pale yellow solid, yield: 37.07 percent.

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)；

¹³C NMR(150MHz,CD₃OD):δ(ppm)171.0,148.0,140.9,140.0,139.1,135.3,129.1,129.1,128.6,126.4,125.5,124.7,122.7,122.6,121.0,119.2,118.4,118.4,118.2,117.9,111.2,101.1,68.2,57.5,37.0。

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

To a mixture of 2-bromo-5H-pyrrolo [2,3-b ] pyrazine (3g,15.15mmol) and p-nitrobenzaldehyde (5.4g,36mmol) was added methanol (25mL) at room temperature, after stirring for 10 minutes at room temperature potassium hydroxide (5.4g,96mmol) was added, stirring was continued at room temperature for 48 hours to stop the reaction, diluted with water (50mL), extracted with dichloromethane (50mL x3), dried over anhydrous sodium sulfate, concentrated column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) afforded 1.35g of a pale yellow solid, yield: 25.3 percent.

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 (210mg,0.60mmol) in tetrahydrofuran (7mL), DESS-MARTIN oxidant (530mg,1.23mmol) was added, stirred at room temperature for 4 hours, diluted with water (15mL), extracted with dichloromethane (20mLx3), dried over anhydrous sodium sulfate, and concentrated column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) afforded 170mg of a light yellow solid, yield: 81.42 percent.

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

And step 3: synthesis of compound (2-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -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) methanone (170mg,0.49mmol) in DMF (8mL) was added sodium hydride (60%, 40mg,1.0mmol), stirred at room temperature for 30 min, added SEMCl (120 μ L,0.67mmol), stirred at room temperature for 4H, quenched with water (30mL), extracted with dichloromethane (30mL x3), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (petroleum ether/ethyl acetate (v/v) ═ 3/1), filtered, dried to give 180mg of a yellow solid, yield: 76.98 percent.

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

And 4, step 4: synthesis of the compound (2- (1-methyl-1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) (4-nitrophenyl) methanone

To (2-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-7-yl) (4-nitrophenyl) methanone (180mg,0.37mmol) in 1, 4-dioxane (6mL) was added potassium carbonate (80mg,0.57mmol), 1-methylpyrazole borate (106mg,0.50mmol) and Pd (dppf) Cl in that order₂(30mg,0.04mmol), water (1.5 mL)) Under nitrogen, the reaction was heated at 115 ℃ under reflux for 5.5 hours, diluted with water (40mL), extracted with dichloromethane (55mLx3), dried over anhydrous sodium sulfate, and concentrated by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give 120mg of a yellow solid, yield: 66.50 percent.

MS(ESI,pos.ion)m/z:479.30[M+1]⁺。

And 5: synthesis of the compound (4-aminophenyl) (2- (1-methyl-1H-pyrrolo-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) methanone

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

MS(ESI,pos.ion)m/z:448.90[M+1]⁺。

Step 6: synthesis of compound 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

To a solution of (4-aminophenyl) (2- (1-methyl-1H-pyrrolo-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) methanone (100mg,0.22mmol) in acrylonitrile (10mL) was added aluminum trichloride (45mg,0.33mmol), reacted at 85 ℃ under reflux for 24 hours, quenched with a small amount of methanol (5mL), filtered, the filtrate was diluted with water (40mL), extracted with dichloromethane (55mLx3), dried over anhydrous sodium sulfate, concentrated column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give 70mg of a yellow oil, yield: 70.64 percent.

MS(ESI,pos.ion)m/z:502.3[M+1]⁺。

And 7: synthesis of compound 3- ((4- (2- (1-methyl-1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazine-7-carbonyl) phenyl) amino) propionitrile

To a solution of 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 (79mg,0.15mmol) in dichloromethane (6mL) was added trifluoroacetic acid (2mL) and stirred overnight at room temperature, the solvent was concentrated, dissolved by adding tetrahydrofuran (6mL), neutralized with ethylenediamine to pH >7, stirred at room temperature for 3 hours, diluted with water (20mL), extracted with dichloromethane (20mL x3), dried over anhydrous sodium sulfate, concentrated column chromatography (petroleum ether/ethyl acetate (v/v) ═ 0/1) and isolated via preparative plate to give 7mg yellow solid, yield: 11.97 percent.

MS(ESI,pos.ion)m/z:372.25[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):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)；

¹³C NMR(150MHz,DMSO-d₆):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

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

MS(ESI,pos.ion)m/z:337.7[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ(ppm)8.52–8.30(m,1H),8.18(d,J＝1.8Hz,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 (4mL), 2-bromo-7-iodo-5-methyl-5H-pyrrolo [2,3-b ]]Pyrazine (350mg,1.04mmol), 3- ((4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) amino) propionitrile (350mg,1.03mmol), sodium carbonate (330mg,3.11mmol) and bis (triphenylphosphine) palladium dichloride (Pd (PPh)₃)₂Cl₂) (40mg,0.05mmol) of the mixture was prepared according to the synthesis of step 1 of example 1 to give 80mg of a yellow solid in yield: 21.7 percent.

MS(ESI,pos.ion)m/z:356.2[M+1]⁺。

And step 3: synthesis of compound 3- ((4- (5-methyl-2- (1-methyl-1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile

1, 4-Dioxane (4 mL)/water (1mL) was added to 3- ((4- (2-bromo-5-methyl-5H-pyrrolo [2, 3-b) under nitrogen]Pyrazin-7-yl) phenyl) amino) propionitrile (75mg,0.18mmol), 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (65mg,0.31mmol), potassium carbonate (45mg,0.33mmol) and 1,1' -bisdiphenylphosphinoferrocene palladium dichloride (Pd (dppf) Cl₂) To the mixture (8mg,0.06mmol), the reaction was refluxed at 110 ℃ overnight, the reaction solution was cooled to room temperature, filtered through celite, the filtrate was concentrated under reduced pressure, and column separation was performed (petroleum ether/ethyl acetate (v/v) ═ 0/1) to give 52mg of a yellow solid, yield: 81.3 percent.

MS(ESI,pos.ion)m/z:358.0[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):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)；

¹³C NMR(150MHz,DMSO-d₆):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 performs biological tests on the indicated compounds using the following methods:

1. compounds were tested for JAK1/2/3 enzyme inhibition using Caliper Mobility Shift Assay.

2. Preparing a 1-time kinase reaction solution: JAK 2/3: 50mM HEPES, pH 7.5; 0.0015% Brij-35; 10mM MgCl₂；2mM DTT。JAK1：25mM HEPES,pH 7.5；0.001％Brij-35；0.01％Triton；0.5mM EGTA；10mM MgCl₂。

3. Preparing a reaction termination solution: 100mM HEPES, pH 7.5; 0.0015% Brij-35; 0.2% Coating Reagent #3(Caliper, cat # 760050); 50mM EDTA.

4. Enzyme formulation (JAK 1/2/3): enzyme solutions were prepared using 1-fold kinase reaction solutions at final concentrations of JAK1(30nM), JAK2(2nM), and JAK 3(4 nM).

5. Preparing a substrate: a substrate solution was prepared using 1-fold of the kinase reaction solution, and the final concentration of the substrate was shown in Table 1.

TABLE 1 Final substrate concentrations

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

TABLE 2 Compound vs JAK1/2/3 enzyme IC₅₀Detection system

The test was carried out using a 384-well plate, and a test sample well, a positive control well, and a negative control well were set in the experiment, and each sample was tested for the inhibitory effect of the compound on JAK1/2/3 enzyme at 8 concentrations in duplicate wells, with the enzyme and substrate reaction well as the positive control, and the enzyme-free well (kinase reaction solution) as the negative control. After adding corresponding samples, buffer solution and enzyme into each hole in sequence according to the table 2, incubating in a constant temperature box at 25 ℃ (RT) for 10min, adding prepared Peptide solution into each hole, incubating at the constant temperature of 28 ℃ for 60min, adding reaction termination solution, detecting by using a Caliper EZ Reader at the excitation wavelength of FP485 nM/525 nM, and reading data as conversion rate. The inhibition of JAK1/2/3 enzyme was plotted at different concentrations of compound using Graph Pad Prism 5 software to calculate IC₅₀The results are shown in Table 3.

Enzyme (JAK1/2/3) inhibition data for the compounds of Table 3

The data in Table 3 show that the partial compound of the invention has certain inhibition effect on JAK1, JAK2 and JAK3, particularly has stronger inhibition effect on JAK3, and can be effectively used for treating various indications.

Biological example 2 test compound rat in vivo PK studies

SD rats were dosed with 5mg/kg by oral gavage or 1mg/kg by tail vein injection of the test compound. Orbital vein bleeds were collected at time points (0.083 hr, 0.25 hr, 0.5 hr, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr and 24 hr) after dosing, collected at plus K₂EDTA in an anticoagulation tube. Plasma samples were subjected to liquid-liquid extraction and then quantitatively analyzed by multiplex reaction ion monitoring (MRM) on a triple quadrupole tandem mass spectrometer. Adopting WinNonlin 6.1 softwarePharmacokinetic parameters were calculated using a non-compartmental model.

And (4) conclusion: the compound has moderate clearance rate, shows higher blood exposure after the oral administration of 5mg/kg in SD rats, has reasonable half-life period and better druggability.

Claims

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 a compound of claim 1 and at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or vehicle;

wherein said pharmaceutical composition further optionally comprises an additional therapeutic agent selected from the group consisting of a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating diabetes, and an agent for treating autoimmune disease.

3. Use of a compound of claim 1 or a pharmaceutical composition of claim 2 in the manufacture of a medicament for preventing, treating, or ameliorating an autoimmune disease or a proliferative disease in a patient;

and/or wherein the medicament is for inhibiting or modulating protein kinase activity;

wherein the autoimmune disease is lupus, multiple sclerosis, amyotrophic lateral sclerosis, rheumatoid arthritis, psoriasis, type I diabetes, complications due to organ transplantation, foreign body transplantation, diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and lymphoma;

wherein the proliferative disease 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, cancer of the CNS (central nervous system), glioblastoma, myeloproliferative disease, atherosclerosis or pulmonary fibrosis;

wherein the protein kinase is JAK1, JAK2 or JAK 3.