WO2018137655A1

WO2018137655A1 - Pyrrolo-pyridines n-oxide derivative, preparation method therefor, and application thereof

Info

Publication number: WO2018137655A1
Application number: PCT/CN2018/073989
Authority: WO
Inventors: 野国中; 李凯龙; 黄志强; 刘磊; 包如迪
Original assignee: 江苏豪森药业集团有限公司; 上海翰森生物医药科技有限公司
Priority date: 2017-01-25
Filing date: 2018-01-24
Publication date: 2018-08-02
Also published as: CN110198941B; CN110198941A

Abstract

A pyrrolo-pyridines N-oxide derivative shown in formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, and use of the compounds as a BRD4 inhibitor for treating related diseases, for example, cancers, inflammations, chronic liver diseases, diabetes, cardiovascular diseases, and AIDS.

Description

Pyrrolopyridine N-oxidation derivative and preparation method and application thereof

Technical field

The invention belongs to the field of medicine and relates to pyrrolopyridinium N-oxidized derivatives, a preparation method thereof and application of the pharmaceutical composition in medical research, and the invention discloses as a BRD4 inhibitor in treating cancer, inflammation, chronic liver disease and diabetes. The use of cardiovascular diseases and related diseases such as AIDS.

Background technique

Tumors are one of the major diseases that seriously endanger human life, and more than half of them occur in developing countries. The incidence of malignant tumors in China is generally on the rise, and the incidence rate is increasing at an average annual rate of 3% to 5%. It is estimated that by 2020, 4 million people will develop cancer in China and 3 million will die of cancer. The main reasons are: Ageing, urbanization, industrialization and lifestyle changes. In China's hospital drug market, the sales scale of anti-cancer drugs has been growing steadily in recent years. In 2012, it reached 66.42 billion yuan, an increase of 13.07% year-on-year. It is expected that by 2017, the market size of anti-cancer drugs will reach 105.57 billion yuan. The year-on-year growth was 7.57%.

Due to the unrestricted growth and infiltration and metastasis of malignant tumors, the three conventional treatment methods (surgery, radiotherapy and chemotherapy) used in clinical practice cannot completely remove or completely kill tumor cells, so tumor metastasis or recurrence often occurs. Tumor biotherapy is a new treatment for cancer prevention and treatment using modern biotechnology and related products. Because of its safety, effectiveness, and low adverse reactions, it has become the fourth mode of tumor treatment after surgery, radiotherapy and chemotherapy. The natural defense mechanism of the host or the naturally occurring highly targeted substance is obtained to obtain an anti-tumor effect.

Bromostructured protein 4 (BRD4) is a member of the bromodomain and extraterminal domain (BET) family, and BRD4 recruits different transcriptional regulators such as Mediator, positive transcription elongation factor b (positive transcription elongation factor b) , P-TEFb) to regulate the expression of the target gene. As a chromatin "reader" widely expressed in mammals, it can recognize acetylated proteins to bind to chromosomes throughout mitosis, recruit different chromatin-modifying proteins, and widely regulate gene expression. It plays an important role in regulating cell cycle progression, transcription, and inflammation. Recent studies have shown that dysregulation or dysfunction of BRD4 is associated with the occurrence of midline carcinoma with rearrangement of the nuclear protein intestis gene (NMC), melanoma, acute myeloid leukemia, colon cancer, breast cancer, etc. . BRD4 shRNA or BET inhibitor can induce cell cycle arrest, apoptosis and cell differentiation of the above tumors, and exhibits strong antitumor activity. These findings suggest that BET protein is expected to be a new therapeutic target for these and even other tumors. In addition, studies by the tool compound JQ1 and the like have found that BRD4 inhibitors may be widely used in various diseases such as viral infection, diabetes, metabolic diseases, liver diseases and Alzheimer's disease.

BRD4 inhibitors have good application prospects in the pharmaceutical industry as pharmaceuticals. Currently, there are no listed drugs. In order to achieve better therapeutic effects and meet market demand, we hope to develop a new generation of highly efficient and low toxicity selective BRD4. Inhibitor.

Summary of the invention

The object of the present invention is to provide a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer thereof, or a mixture form, or a pharmaceutically acceptable salt thereof, wherein the compound of the formula (I) has the following structure:

among them:

X, Y are each independently selected from the group consisting of a bond, N, O, -NR ₅ -, -(CR ₆ R ₇ ) _x -, and -(CR ₆ R ₇ ) _x N(R ₅ ) _y -;

Z is selected from -NR ₅ -, O and -O(CR ₆ R ₇ ) _x -;

Ring A is selected from the group consisting of a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

R _{1 is} selected from the group consisting of alkyl, cycloalkyl and alkenyl; wherein said alkyl, alkenyl and cycloalkyl are optionally further selected from the group consisting of alkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy Substituted by one or more substituents of a group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

R _{2 is} selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, an olefin, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -OR ₈ , -C(O)R ₈ , -C(O)OR ₈ , -S(O) _m R ₈ , -NR ₉ R ₁₀ , -C(O)NR ₉ R ₁₀ , -NR ₉ C( O) R ₁₀ and -NR ₉ S(O) _m R ₁₀ ; wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from alkyl, haloalkanes Base, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ₈ , -C(O) R ₈ , -C(O)OR ₈ , -S(O) _m R ₈ , -NR ₉ R ₁₀ , -C(O)NR ₉ R ₁₀ , -NR ₉ C(O)R ₁₀ and -NR ₉ S (O) substituted with one or more substituents in _m R ₁₀ ;

R _{3 is} selected from the group consisting of a non-existent hydrogen atom, an alkyl group, a halogenated alkyl group, an alkene group, an alkoxy group, a halogenated alkoxy group, a halogen group, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group, and a hetero group. Aryl, -OR ₈ , -C(O)R ₈ , -C(O)OR ₈ , -S(O) _m R ₈ , -NR ₉ R ₁₀ , -C(O)NR ₉ R ₁₀ , -NR ₉ C(O)R ₁₀ and -NR ₉ S(O) _m R ₁₀ ; wherein the alkyl, haloalkyl, olefin, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected From alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ₈ , -C(O)R ₈ , -C(O)OR ₈ , -S(O) _m R ₈ , -NR ₉ R ₁₀ , -C(O)NR ₉ R ₁₀ , -NR ₉ C(O)R ₁₀ And one or more substituents in -NR ₉ S(O) _m R ₁₀ are substituted;

Alternatively, R ₂ and R _{3 are} bonded to form a heterocyclic or heteroaryl group; wherein said heterocyclic group and heteroaryl are optionally further selected from the group consisting of alkyl, haloalkyl, alkene, alkoxy, haloalkoxy , halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR ₈ , -C(O)R ₈ , -C(O)OR ₈ , -S (O) _m R ₈ , -NR ₉ R ₁₀ , -C(O)NR ₉ R ₁₀ , -NR ₉ C(O)R ₁₀ and -NR ₉ S(O) _m One or more substitutions in R ₁₀ Substituted by

Further, R ₂ and R ₃ are each independently bonded to R ₆ , R ₇ or R ₅ on the X group to form a heterocyclic or heteroaryl group; wherein said heterocyclic group and heteroaryl group are optionally further Selected from alkyl, haloalkyl, olefin, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ₈ , -C(O)R ₈ , -C(O)OR ₈ , -S(O) _m R ₈ , -NR ₉ R ₁₀ , -C(O)NR ₉ R ₁₀ , -NR ₉ C(O)R ₁₀ And one or more substituents in -NR ₉ S(O) _m R ₁₀ are substituted;

R _{4 is} independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a hydroxyalkyl group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group, Heteroaryl, -OR ₈ , -C(O)R ₈ , -C(O)OR ₈ , -S(O) _m R ₈ , -(CH ₂ ) _t NR ₉ R ₁₀ , -(CH ₂ ) _t C(O)NR ₉ R ₁₀ , -NR ₉ C(O)R ₁₀ and -NR ₉ S(O) _m R ₁₀ ; wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group Further optionally, it is selected from the group consisting of alkyl, haloalkyl, olefin, alkoxy, haloalkoxy, hydroxyalkyl, halogen, haloalkyl, alkyl substituted heterocyclic, amino, nitro, hydroxy, cyano, cyclo Alkyl, heterocyclic, aryl, heteroaryl, -OR ₈ , -C(O)R ₈ , -C(O)OR ₈ , -S(O) _m R ₈ , -NR ₉ R ₁₀ ,- Substituting one or more substituents of C(O)NR ₉ R ₁₀ , -NR ₉ C(O)R ₁₀ and -NR ₉ S(O) _m R ₁₀ ;

R _{5 is} selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an alkoxy group, a halogenated alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

R ₆ and R ₇ are each independently selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group. , aryl, heteroaryl, -OR ₈ , -C(O)R ₈ , -C(O)OR ₈ , -S(O) _m R ₈ , -NR ₉ R ₁₀ , -C(O)NR ₉ R ₁₀ , -NR ₉ C(O)R ₁₀ and -NR ₉ S(O) _m R ₁₀ ;

Alternatively, R ₆ and R ₇ may form a cycloalkyl or heterocyclic group, which is optionally further selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, halogen , amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR ₈ , -C(O)R ₈ , -C(O)OR ₈ , -S(O _m R ₈ , -NR ₉ R ₁₀ , -C(O)NR ₉ R ₁₀ , -NR ₉ C(O)R ₁₀ and -NR ₉ S(O) _m One or more substituents in R ₁₀ Replace

R _{8 is} selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkenyl group, a hydroxyl group, an amino group, an alkoxy group, a halogenated alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; wherein the alkyl group, Haloalkyl, alkenyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from the group consisting of alkyl, halo, haloalkyl, amino, nitro, cyano, hydroxy, hydroxyalkyl, alkoxy Base, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR ₈ , -C(O)R ₈ , -C(O)OR ₈ , -S(O) _m R ₈ , -NR ₉ R Substituting one or more substituents of ₁₀ , -C(O)NR ₉ R ₁₀ , -NR ₉ C(O)R ₁₀ and -NR ₉ S(O) _m R ₁₀ ;

R ₉ and R _{10 are the} same or different and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, cycloalkyl group And a heterocyclic group, an aryl group and a heteroaryl group are further selected from the group consisting of an alkyl group, a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group. And substituted with one or more substituents in the heteroaryl;

m is an integer of 0, 1, or 2;

n is an integer of 0, 1, 2, 3, 4 or 5;

t is an integer of 0, 1, 2, 3, 4 or 5;

x is an integer of 0, 1, 2, 3 or 4;

y is an integer of 0 or 1.

In a preferred embodiment of the invention, the compound of the formula (I) is a compound of the formula (II):

Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them:

B is selected from CH and N;

R ₁ to R ₄ , Z, X, Y and n are as defined in the formula (I).

In a preferred embodiment of the invention, the compound of the formula (I) is a compound of the formula (III):

among them:

B is selected from CH and N;

R ₁ , R ₂ , R ₄ , Z, X and n are as defined in the formula (I).

In a preferred embodiment of the invention, the compound of the formula (I) is a compound of the formula (IV):

among them:

Z is selected from NH and O;

B is selected from CH and N;

Ring C is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from the group consisting of alkyl, halogen, amino, Substituted by one or more substituents of a nitro group, a hydroxyl group, a cyano group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

z is an integer of 0, 1, 2 or 3;

R ₁ , R ₂ , R ₄ , X and n are as defined in the formula (I).

In a preferred embodiment of the present invention, the compound represented by the formula (IV) is a compound represented by the formula (VA) or (VB):

among them:

Z is selected from NH and O;

X is selected from the group consisting of a bond, NH and -CR ₆ R ₇ -;

R _{4 is} selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, a cyano group, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, a C _1-6 hydroxyalkyl group, a C _3-6 cycloalkyl group, -(CH _{2 )} _t NR ₉ R ₁₀ and -(CH ₂ ) _t C(O)NR ₉ R ₁₀ ;

R _{2 is} selected from C _1-6 alkyl, halo C _1-6 alkyl, -NR ₉ R ₁₀ , C _3-6 cycloalkyl or 5-6 membered heteroaryl; wherein said C _1-6 The alkyl group, halo C _1-6 alkyl group, C _3-6 cycloalkyl group and 5-6 membered heteroaryl group are further optionally selected from C _1-6 alkyl groups, halogenated C _1-6 alkyl groups, halogen Substituting one or more substituents of an amino group, a cyano group and a hydroxyl group;

R ₆ and R _{7 are the} same or different and are each independently selected from a hydrogen atom and a C _1-3 alkyl group;

R ₉ and R _{10 are the} same or different and are each independently selected from a hydrogen atom and a C _1-3 alkyl group;

n, t is as defined in the general formula (I).

In a preferred embodiment of the invention, the compound of the formula (IV) is a compound of the formula (VIA) or (VIB):

among them:

Z is selected from NH and O;

X is selected from the group consisting of a bond, NH and -CR ₆ R ₇ -;

R _{C is} independently selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, a cyano group, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, a C _1-6 hydroxyalkyl group, a C _3-6 cycloalkyl group, a ( CH ₂ ) _t NR ₉ R ₁₀ or -(CH ₂ ) _t C(O)NR ₉ R ₁₀ ;

R _{2 is} selected from C _1-6 alkyl, halo C _1-6 alkyl, -NR ₉ R ₁₀ , C _3-6 cycloalkyl and 5-6 membered heteroaryl; wherein said C _1-6 The alkyl group, halo C _1-6 alkyl group, C _3-6 cycloalkyl group and 5-6 membered heteroaryl group are further optionally selected from C _1-6 alkyl groups, halogenated C _1-6 alkyl groups, halogen Substituting one or more substituents of an amino group, a cyano group and a hydroxyl group;

t as defined in claim 1.

In a preferred embodiment of the invention, the compound of the above formula, wherein R _{1 is} selected from the group consisting of C _1-8 alkyl, C _2-8 alkenyl and C _3-8 cycloalkyl; C _1-6 alkyl, C _2-6 alkenyl or C _3-6 cycloalkyl; more preferably C _1-3 alkyl, C _2-3 alkenyl or C _3-6 cycloalkyl; most preferably methyl .

In a preferred embodiment of the invention, the compound of the formula, wherein R _{2 is} selected from the group consisting of C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, and a -6 membered heteroaryl group, wherein said C _1-6 alkyl group, halogenated C _1-6 alkyl group, C _3-6 cycloalkyl group and 5-6 membered heteroaryl group are optionally further selected from C ₁ Substituted by one or more substituents of _-6 alkyl, halo C _1-6 alkyl, halogen, amino, cyano and hydroxy; preferably C _1-6 alkyl, halo C _1-6 alkyl or C _3-6 cycloalkyl; more preferably C _1-3 alkyl, halo C _1-3 alkyl or C _3-6 cycloalkyl, most preferably methyl, ethyl, isopropyl, cyclopropyl, Cyclobutyl,

In a preferred embodiment of the invention, the compound of formula (I) is selected from the group consisting of:

Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment of the present invention, an intermediate of the compound of the formula (I), which is a compound of the formula (V), a compound of the formula (VAA) or a compound of the formula (VBB) :

among them:

R ₁ to R ₄ , ring A, Z, X, Y and n are as defined in the formula (I).

In a preferred embodiment of the present invention, a method for preparing a compound of the formula (I) comprises the following steps:

The compound of the formula (V) is oxidized by an oxidizing agent to give a compound of the formula (I); the oxidizing agent is preferably m-chloroperoxybenzoic acid;

among them:

R ₁ to R ₄ , ring A, Z, X, Y and n are as defined in the formula (I);

In a preferred embodiment of the present invention, a method for preparing a compound represented by the formula (VA) comprises the following steps:

The compound of the formula (VAA) is oxidized by an oxidizing agent to give a compound of the formula (VA); the oxidizing agent is preferably m-chloroperoxybenzoic acid;

among them:

R ₂ , R ₄ , Z, X and n are as defined in the formula (VA);

In a preferred embodiment of the present invention, a method for preparing a compound represented by the formula (VB) comprises the following steps:

The compound of the formula (VBB) is oxidized by an oxidizing agent to give a compound of the formula (VB); the oxidizing agent is preferably m-chloroperoxybenzoic acid;

among them:

R ₂ , R ₄ , Z, X and n are as defined in the formula (VB);

Another aspect of the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients. The present invention also relates to a process for the preparation of the above pharmaceutical composition which comprises the compounds of the formulas or their tautomers, meso, racemates, enantiomers, non-pairs The conjugate, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is admixed with a pharmaceutically acceptable carrier, diluent or excipient.

The invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for use in the preparation of a medicament for the prophylaxis and/or treatment of a medicament for the treatment of cancer, inflammation, AIDS as a BRD4 inhibitor. .

The invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, in the manufacture of a BRD4 inhibitor drug.

The invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for use in the manufacture of a medicament for the treatment of cancer, inflammation, chronic liver disease, diabetes, cardiovascular disease and AIDS.

The present invention also relates to a method of treating a disease preventing and/or treating a BRD4-mediated pathological feature comprising administering to a patient a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof. , a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same

Another aspect of the invention relates to a method of treating cancer comprising administering to a patient a therapeutically effective amount of a compound of the formula (I) of the invention or a tautomer, a mesogen thereof, a foreign body A form of a rot, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof. This method shows outstanding efficacy and fewer side effects.

Another aspect of the invention relates to a method of treating inflammation comprising administering to a patient a therapeutically effective amount of a compound of the formula (I) of the invention or a tautomer, a mesogen thereof, a foreign body A form of a rot, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof. This method shows outstanding efficacy and fewer side effects.

Another aspect of the invention relates to a method of treating chronic liver disease, comprising administering to a patient a therapeutically effective amount of a compound of the formula (I) of the invention or a tautomer, a mesogen thereof, or an external Racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof. This method shows outstanding efficacy and fewer side effects.

The cancer of the present invention may be selected from the group consisting of breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, liver cancer, solid tumor, glioma, glioblastoma, leukemia, lymph. Tumor, myeloma and non-small cell lung cancer; said chronic liver disease is selected from the group consisting of: primary sclerosis (PBC), cerebral xanthoma (CTX), primary sclerosing cholecystitis (PSC), drug-induced Cholestasis, intrahepatic cholestasis of pregnancy, parenteral absorption-related cholestasis (PNAC), bacterial overgrowth or sepsis cholestasis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD) ), nonalcoholic steatohepatitis (NASH), liver graft-related graft-versus-host disease, live donor liver transplant regeneration, congenital liver fibrosis, common bile duct stones, granulomatous liver disease, intrahepatic or extraneous malignancy, Sjogren Syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis or alpha ₁ anti-membrane protease deficiency.

Detailed description of the invention

Terms used in the specification and claims have the following meanings unless stated to the contrary.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 8 carbon atoms, more preferably from 1 to 6 carbon atoms. The alkyl group is most preferably an alkyl group of 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 - dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2 , 5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-B Hexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-decyl, 2-methyl-2-ethylhexyl, 2-methyl-3-B Hexyl group, 2,2- Diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from the group consisting of an alkane Base, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, naphthenic An oxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.

The term "alkylene" means that one hydrogen atom of the alkyl group is further substituted, for example, "methylene" refers to -CH ₂ -, "ethylene" refers to -(CH ₂ ) ₂ -, "propylene" Refers to -(CH ₂ ) ₃ -, "butylene" means -(CH ₂ ) ₄ - and the like.

The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or -butenyl and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio group.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. One carbon atom. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.

The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Base, benzocycloheptyl and the like. The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more ring atoms are selected from nitrogen, oxygen or S(O). A hetero atom of _m (where m is an integer of 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. It preferably comprises from 3 to 12 ring atoms, wherein from 1 to 4 are heteroatoms; more preferably from 3 to 8 ring atoms; most preferably from 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine. The base, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl and the like are preferably tetrahydrofuranyl and pyranyl. Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.

The term "fused heterocyclyl" refers to 5 to 20 members, and each ring in the system shares an adjacent pair of atomic polycyclic heterocyclic groups with other rings in the system, and one or more rings may contain one or more Double bond, but none of the rings have a fully conjugated π-electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (where m is an integer from 0 to 2), and the remaining rings The atom is carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic ring, more preferably a 3 member/5 member or a 5 member/6 membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.

The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms) having a conjugated π-electron system, preferably 6 to 10 members, such as benzene. Base and naphthyl. More preferred is phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include:

The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle An alkylthio group, a carboxyl group or a carboxylate group.

The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 10 members, more preferably 5 or 6 members, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, A pyrimidinyl group, a thiadiazole, a pyrazinyl group or the like is preferably an imidazolyl group, a pyrazolyl group or a pyrimidinyl group, or a thiazolyl group; and a pyrimidyl group is more preferred. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples of which include:

The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.

The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.

The term "haloalkyl" refers to an alkyl group substituted by one or more halogens, wherein alkyl is as defined above.

The term "haloalkoxy" refers to an alkoxy group substituted by one or more halogens, wherein alkoxy is as defined above.

The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

The term "hydroxy" refers to an -OH group.

The term "halogen" means fluoro, chloro, bromo or iodo.

The term "amino" means -NH _2.

The term "cyano" refers to -CN.

The term "nitro" refers to -NO ₂ .

The term "oxo" refers to =0.

The term "carboxy" refers to -C(O)OH.

The term "carboxylate group" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl is as defined above.

"X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", and "X is A, B, and C" and the like are expressed in the same language. Meaning, that is, X can be any one or several of A, B, and C.

The hydrogen atom of the present invention may be substituted by its isotope ruthenium, and any of the hydrogen atoms in the examples of the present invention may also be substituted by a ruthenium atom.

"Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group. .

"Substituted" refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.

"Pharmaceutical composition" means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients. The purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.

"Pharmaceutically acceptable salt" refers to a salt of a compound of the invention which is safe and effective for use in a mammal and which possesses the desired biological activity.

detailed description

The invention is further described in the following examples, which are not intended to limit the scope of the invention.

Example

The structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). The NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard was four. Methylsilane (TMS), chemical shifts are given in units of 10 ^-6 (ppm).

The measurement of the MS was carried out using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

The HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).

The average value of ₅₀ measured kinase inhibition rate and IC NovoStar using a microplate reader (BMG, Germany).

The thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate. The specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm~0.2mm. The specification for separation and purification of thin layer chromatography is 0.4mm. ~0.5mm silica gel plate.

Column chromatography generally uses Yantai Yellow Sea 200-300 mesh silica gel as a carrier.

The known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organnics, Aldrich Chemical Company, Accela ChemBio Inc, Dari Companies such as chemicals.

In the examples, unless otherwise specified, the reactions were all carried out under an argon atmosphere or a nitrogen atmosphere.

An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.

The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.

The pressurized hydrogenation reaction was carried out using a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 type hydrogen generator or a HC2-SS type hydrogenation apparatus.

The hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.

The microwave reaction used a CEM Discover-S Model 908860 microwave reactor.

In the examples, the solution in the reaction means an aqueous solution unless otherwise specified.

In the examples, the temperature of the reaction was room temperature unless otherwise specified.

Room temperature is the most suitable reaction temperature, and the temperature range is from 20 ° C to 30 ° C.

The progress of the reaction in the examples was monitored by thin layer chromatography (TLC). The system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And the ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted depending on the polarity of the compound.

The system for the eluent of the column chromatography and the system for the thin layer chromatography of the developer used for the purification of the compound include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: n-hexane, acetic acid Ethyl ester and dichloromethane system, D: petroleum ether and ethyl acetate system, E: ethyl acetate, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine and acid or alkali may be added. The reagents and the like are adjusted.

Example 1

4-(2-(2,4-Difluorophenoxy)-5-(ethylsulfonylamino)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7- Oxide

First step: Preparation of 4-chloro-1H-pyrrolo[2,3-b]pyridine-7-oxide

m-Chloroperoxybenzoic acid (14 g, 69 mmol, w/w 85%) was added portionwise to a solution of 4-chloro-7- azaindole (7 g, 46 mmol) in tetrahydrofurane (150 mL). After 6 hours of reaction, a large amount of solid was formed, and solid was collected by filtration to give 4-chloro-1H-pyrrolo[2,3-b]pyridine-7-oxide (5.2 g, yield 67%).

^{1 H NMR (400MHz, DMSO-} d 6): δ12.85 (br, 1H), 8.15 (d, J = 6.6Hz, 1H), 7.57 (d, J = 3.3Hz, 1H), 7.21 (d, J =6.6 Hz, 1H), 6.60 (d, J = 3.3 Hz, 1H).

Second step: Preparation of (6-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)(phenyl)methanone

Benzoyl bromide (14.3 g, 77 mmol) and bis(trimethylsilyl)amine (5 g, 31 mmol) were added dropwise in parallel while slowly adding dropwise to 4-chloro-1H-pyrrolo[2,3-b]pyridine- In a solution of 7-oxide (5.2 g, 31 mmol) in tetrahydrofuran (75 mL) for about 30 minutes, the temperature was maintained at 20 to 30 °C. After the completion of the dropwise addition, the reaction was carried out for 3 hours at room temperature. The reaction was washed with saturated sodium bicarbonate solution and ethyl acetate (25mL × 2) and extracted, the organic phases are combined, dried Na ₂ SO ₄ dried and concentrated. The crude product was separated by column (ethyl acetate: petroleum ether = 1:10, V/V) to afford (6-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl) ) ketone (2.5 g, yield 24%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ7.81-7.74 (m, 3H), 7.69-7.63 (m, 1H), 7.51 (m, 2H), 7.41 (s, 1H), 6.74 (d, J = 4.0Hz, 1H).

The third step: preparation of 4-chloro-6-methyl-1H-pyrrolo[2,3-b]pyridine

A solution of dimethylzinc in toluene (4 mL, 4 mmol, 1 M) was slowly added dropwise to (6-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl) under nitrogen. Phenyl) ketone (1.7 g, 5 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (365 mg, 0.5 mmol) in tetrahydrofuran (20 mL). The reaction solution was reacted at 70 ° C for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled with EtOAc EtOAc m. The crude product was separated by column (ethyl acetate: petroleum ether = 1:1, V/V) to give 4-chloro-6-methyl-1H-pyrrolo[2,3-b]pyridine (290 mg, yield 35%) .

^{_{1 H NMR (400MHz, CDCl 3}} ): δ10.25 (br, 1H), 7.30 (d, J = 3.5Hz, 1H), 7.04 (s, 1H), 6.58 (d, J = 3.5Hz, 1H), 2.65 (s, 3H).

MS m/z (ESI): 167.0 [M+H] ⁺

The fourth step: preparation of 2-bromo-1-(2,4-difluorophenoxy)-4-nitrobenzene

2-Bromo-1-fluoro-4-nitrobenzene (14 g, 107.7 mmol), 2,4-difluorophenol (19.6 g, 89.7 mmol) was dissolved in DMSO (100 mL) and cesium carbonate was added at room temperature ( 35 g, 17.7 mmol), then stirred at 110 ° C for 2 hours. Water (150 mL) was added to the reaction mixture, and the mixture was evaporated. EtOAc (EtOAc) Phenoxy)-4-nitrobenzene, the crude product was used directly in the next reaction.

Step 5: Preparation of 3-bromo-4-(2,4-difluorophenoxy)aniline

2-Bromo-1-(2,4-difluorophenoxy)-4-nitrobenzene (29 g, 88.4 mmol) was dissolved in ethanol (160 mL), tetrahydrofuran (160 mL), water (56 mL). (24.7 g, 442 mmol), ammonium chloride (9.45 g, 176.8 mmol). The mixture was heated to 100 ° C, stirred for 1.5 hours, filtered through celite, and the solvent was evaporated to ethyl ether (250 mL). The organic phase was dried and filtered. 4-Phenoxyaniline (22.0 g, yield 83%).

MS m/z (ESI): 300.1 [M+H] ⁺

Step 6: Preparation of N-(3-bromo-4-(2,4-difluorophenoxy)phenyl)ethanesulfonamide

Ethyl sulfonyl chloride (5.52 g, 43.48 mmol), pyridine (5.28 g, 66.88 mmol), rt, 3-bromo-4-phenoxyaniline (10 g, 33.44 mmol). After stirring overnight, the organic phase was washed with hydrochloric acid (2M, 100 mL×2), water (100 mL×2), washed with brine (100 mL), dried over anhydrous sodium sulfate =5:1, V/V) Compound N-(3-bromo-4-(2,4-difluorophenoxy)phenyl)ethanesulfonamide (10.7 g, yield 82%).

MS m/z (ESI): 392.1.1 [M+H] ⁺

Step 7: N-(4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- Preparation of phenyl) ethanesulfonamide

N-(3-Bromo-4-(2,4-difluorophenoxy)phenyl)ethanesulfonamide (500 mg, 1.28 mmol), 4,4,4',4',5,5,5' , 5'-octamethyl-2,2'-linked (1,3,2-dioxaborolan) (648 mg, 2.55 mmol), 1,3,5,7-tetramethyl-6-phenyl -2,4,8-trioxa-6-phosphoryladamantane (37 mg, 0.128 mmol), tris(dibenzylideneacetone)dipalladium (35 mg, 0.038 mmol) and potassium acetate (275 mg, 2.82 mmol) In 1,4-dioxane (20 mL). The reaction solution was reacted at 80 ° C for 12 hours under nitrogen atmosphere, and then reacted at 105 ° C for 5 hours. The reaction solution was evaporated to dryness and then purified (jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -(4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) A mixture of ethanesulfonamide (500 mg) was used directly in the next step.

MS m/z (ESI): 440.1 [M+H] ⁺

Step 8: N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl) Preparation of sulfonamide

N-(4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene Ethyl sulfonamide (395 mg, 0.9 mmol), 4-chloro-6-methyl-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.6 mmol), tetratriphenylphosphine palladium (69 mg, 0.06) Methyl acetate and potassium carbonate (414 mg, 3 mmol) were added to ethanol/toluene/water (v/v/v = 9:3:1, 10 mL). The reaction solution was subjected to microwave reaction at 120 ° C for 0.5 hour under a nitrogen atmosphere. The reaction solution was evaporated to dryness, and then purified and purified using ethylamine (ethyl ether: ethyl acetate = 1:1, V/V) to give N-(4-(2,4-difluorophenoxy)-3-(6) Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)ethanesulfonamide (190 mg, yield 71%).

MS m/z (ESI): 444.1 [M+H] ⁺

Step 9: 4-(2-(2,4-Difluorophenoxy)-5-(ethylsulfonylamino)phenyl)-6-methyl-1H-pyrrolo[2,3-b] Preparation of pyridine-7-oxide

m-Chloroperoxybenzoic acid (41 mg, 0.2 mmol, 85%) was added to N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2, 3-b]pyridin-4-yl)phenyl)ethanesulfonamide (60 mg, 0.14 mmol) in THF (2 mL). After reacting at room temperature for 16 hours, the mixture was evaporated to dryness. EtOAc (EtOAc: EtOAc: EtOAc: EtOAc: 4-(2-(2,4-Difluorophenoxy)-5-(ethylsulfonylamino)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7- Oxide (12 mg, yield 19%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ12.06 (br, 1H), 9.01 (br, 1H), 7.43 (d, J = 2.4Hz, 1H), 7.31 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.21 (d, J = 3.2 Hz, 1H), 7.13 (d, J = 7.6 Hz, 1H), 6.87 - 6.77 (m, 2H), 6.74 (d, J = 8.8 Hz, 1H), 6.72 - 6.65 (m, 1H), 6.47 (d, J = 3.2 Hz, 1H), 3.12 (q, J = 7.4 Hz, 2H), 2.57 (s, 3H), 1.33 (t, J = 7.4 Hz, 3H).

MS m/z (ESI): 460.1 [M+H] ⁺

Example 2

4-(5-(Cyclopropanesulfonylamino)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7- Oxide

First step: Preparation of 6-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine

(6-Bromo-4-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)(phenyl)methanone (30.0 g, 89 mmol) dissolved in methanol (400 mL), sodium hydroxide Aqueous solution (1M, 178 mL) was added to the above solution. After a reaction at room temperature overnight, a large amount of white solid was precipitated, filtered, and the filter cake was washed with water (20 mL) and dried to give 6-bromo-4-chloro-1H-pyrrole[2 , 3-b]pyridine (17.0 g, yield 82.5%).

MS m/z (ESI): 231.1 [M+H] ⁺

Step 2: Preparation of 6-bromo-4-chloro-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine

6-Bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine (17.0 g, 74 mmol) was dissolved in N,N-dimethylformamide (50 mL). Sodium hydride (5.9 g, 147 mmol) was added portionwise to the above solution, and after stirring for 10 minutes at 0 ° C, 4-methylsulfonyl chloride (18.3 g, 96 mmol) was dissolved in N,N-dimethyl A solution of the amide (30 mL) was slowly added to the above reaction solution. After stirring at room temperature for 1 hour, the reaction was completed by LC/MS. The reaction solution was poured into ice water (500 mL) and stirred, a large white solid was precipitated, filtered, and the filter cake was washed with water (100 mL) and dried to give 6-bromo-4-chloro-1-toluenesulfonyl-1H-pyrrole And [2,3-b]pyridine (27.0 g, yield 94.7%).

MS m/z (ESI): 385.0 [M+H] ⁺

The third step: preparation of 4-chloro-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine

6-Bromo-4-chloro-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (15.5 g, 40 mmol) was dissolved in tetrahydrofuran (150 mL) and [1,1'-bis (two) Phenylphosphino)ferrocene]palladium dichloride (1.46 g, 2 mmol), replacing nitrogen, adding dimethyl zinc (20 mL, 1 M solution in toluene) under ice bath, heating to 70 ° C after completion of the addition. The reaction was carried out overnight, and the reaction was completed by LC/MS. Water (400 mL) was added to the reaction mixture, and the mixture was washed with ethyl acetate (300 mL). Ethyl ester = 10:1, V/V) gave 4-chloro-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (11.5 g, yield 89%).

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.05 - 8.03 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 4.0 Hz, 1H), 7.44 - 7.42 (d, J = 8.0 Hz) , 2H), 7.35 (s, 1H), 6.79 (d, J = 4.0 Hz, 1H), 2.56 (s, 3H), 2.35 (s, 3H).

MS m/z (ESI): 321.1 [M+H] ⁺

The fourth step: 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1H-pyrrole Preparation of [2,3-b]pyridine

4-Chloro-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (6.0 g, 18.8 mmol), 4,4,4',4',5,5, 5',5'-octamethyl-2,2'-linked (1,3,2-dioxaborolan) (7.6 g, 30 mmol), palladium acetate (140 mg, 0.63 mmol), [1,1' -biphenyl]-3-yldicyclohexylphosphane (438 mg, 1.25 mmol), potassium acetate (9.2 g, 93.8 mmol) dissolved in 1,4-dioxane (100 mL), replaced with nitrogen, heated to 90 After stirring at ° C overnight, the reaction was complete by LC/MS. Water (200 mL) was added to the reaction mixture, and the mixture was washed with ethyl acetate (200 mL). Ethyl ester = 10:1, V/V) gives 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 -Tosyl-1H-pyrrolo[2,3-b]pyridine (5.5 g, yield 71.2%).

MS m/z (ESI) = 413.1 [M+H] ⁺

Step 5: 4-(2,4-Difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)aniline Preparation

3-Bromo-4-(2,4-difluorophenoxy)phenylamine (2.0 g, 6.67 mmol), 6-methyl-4-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (2.75 g, 6.67 mmol), [1,1'-bis(diphenyl) a phosphinyl)ferrocene]palladium dichloride (284 mg, 0.38 mmol), potassium carbonate (1.34 g, 9.7 mmol) in a mixture of 1,4-dioxane (16 mL) and water (4 mL) Under a nitrogen atmosphere, the reaction was stirred at 100 ° C for 4 hours, and the reaction was completed. The reaction mixture was poured into water (50 mL), extracted with ethyl acetate (50 mL×2), and the organic phase was combined, washed with water (100 mL), and brine (100 mL) After drying with anhydrous sodium sulfate, and concentrated by column chromatography ( petroleum ether: ethyl acetate = 1:1, V/V) to give compound 4-(2,4-difluorophenoxy)-3- 6-Methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenylamine (1.9 g, yield 56%).

MS m/z (ESI): 506.1 [M+H] ⁺ .

Step 6: N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-4- Preparation of phenyl)phenylpropanesulfonamide

4-(2,4-Difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)aniline (100 mg, 0.198 mmol) was dissolved in methylene chloride (2 mL). EtOAc EtOAc (EtOAc (EtOAc) The mixture was evaporated to dryness. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj After concentration, column chromatography (petroleum ether: ethyl acetate = 3:1, V/V) afforded N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1-toluene Sulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)cyclopropanesulfonamide (93 mg, yield 77%).

MS m/z (ESI): 610.1 [M+H] ⁺ .

Step 7: N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl) ring Preparation of propanesulfonamide

N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)benzene The propyl sulfonamide (93.0 mg, 0.15 mmol) was dissolved in ethanol (3 mL), sodium methoxide (25 mg, 0.46 mmol) was added at room temperature and stirred at 50 ° C overnight. After quenching, the mixture was extracted with EtOAc EtOAc EtOAc (EtOAc) After concentration, column chromatography (petroleum ether: ethyl acetate = 1:1, V/V) gave compound N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1H) Pyrrolo[2,3-b]pyridin-4-yl)phenyl)cyclopropanesulfonamide (40 mg, yield 58%).

MS m/z (ESI): 456.1 [M+H] ⁺ .

Step 8: 4-(5-(Cyclopropanesulfonylamino)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-b] Preparation of pyridine-7-oxide

N-(4-(2,4-Difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)cyclopropanesulfonamide (40 mg, 0.087 mmol) was dissolved in THF (0.5 mL). m. m. m. m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m After adding water (10 mL), and then extracting with ethyl acetate (10 mL×2), the organic phase was combined and washed with a saturated aqueous solution of sodium hydrogen carbonate (20 mL), water (20 mL) and brine (20 mL) Drying with sodium sulfate and concentrating to give 4-(5-(cyclopropylsulfonylamino)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1H-pyrrole [2,3-b]pyridine-7-oxide (25.5 mg, yield 62%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ11.72 (s, 1H), 7.79 (s, 1H), 7.49 (s, 1H), 7.34 (d, J = 6.8Hz, 2H), 7.23 (s, 1H ), 7.00–6.86 (m, 2H), 6.85–6.76 (m, 2H), 6.59 (d, J = 2.9 Hz, 1H), 2.69 (s, 3H), 2.60-2.56 (m, 1H), 1.24– 1.17 (m, 2H), 1.03–0.97 (m, 2H).

MS m/z (ESI): 4721. [M+H] ⁺ .

Example 3

4-(2-(2,4-Difluorophenoxy)-5-((3,5-dimethylisoxazole)-4-sulfonylamino)phenyl)-6-methyl-1H- Pyrrolo[2,3-b]pyridine-7-oxide

First step: N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-4- Of phenyl)-3,5-dimethylisoxazole-4-sulfonamide

Starting from 4-(2,4-difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)aniline, Referring to the sixth step of Example 2, replacing cyclopropylsulfonyl chloride with 3,5-dimethylisoxazole-4-sulfonyl chloride to obtain N-(4-(2,4-difluorophenoxy)-3- (6-Methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)-3,5-dimethylisoxazole-4-sulfonamide (110 mg , yield 87%).

MS m/z (ESI): 645.1 [M+H] ⁺ .

Second step: N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)- Preparation of 3,5-dimethylisoxazole-4-sulfonamide

N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)benzene Starting from -3,5-dimethylisoxazole-4-sulfonamide as a starting material, referring to the seventh step of Example 2, the compound N-(4-(2,4-difluorophenoxy)-3- (6-Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)-3,5-dimethylisoxazole-4-sulfonamide (70 mg, yield 83%) .

MS m/z (ESI): 5121. [M+H] ⁺ .

The third step: 4-(2-(2,4-difluorophenoxy)-5-((3,5-dimethylisoxazole)-4-sulfonylamino)phenyl)-6-A Preparation of 7-oxidation of yl-1H-pyrrolo[2,3-b]pyridine

N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)-3,5 - dimethyl isoxazole-4-sulfonamide as a starting material, and referring to the eighth step of Example 2, 4-(2-(2,4-difluorophenoxy)-5-((3,5-di) Methylisoxazole)-4-sulfonylamino)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (30.1 mg, yield 42%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ11.56 (s, 1H), 9.05 (s, 1H), 7.33-7.31 (m, 2H), 7.21-7.10 (m, 2H), 6.95-6.85 (m, 2H), 6.78 (dd, J = 14.8, 8.8 Hz, 2H), 6.39 (s, 1H), 2.66 (s, 3H), 2.47 (s, 3H), 2.32 (s, 3H).

MS m/z (ESI): 527.1 [M+H] ⁺ .

Example 4

4-(2-(2,4-difluorophenoxy)-5-((1-methylethyl)sulfonylamino)phenyl)-6-methyl-1H-pyrrolo[2,3- b]pyridine-7-oxide

First step: N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-4- Of phenyl)propane-2-sulfonamide

Starting from 4-(2,4-difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)aniline, Referring to the sixth step of Example 2, substituting propane-2-sulfonyl chloride for cyclopropanesulfonyl chloride to obtain N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1-toluene) Sulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)propane-2-sulfonamide (110 mg, yield 91%).

MS m/z (ESI): 6121. [M+H] ⁺ .

Second step: N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)propane Preparation of -2-sulfonamide

N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)benzene The propane-2-sulfonamide was used as a starting material. Referring to the seventh step of Example 2, the compound N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrole was obtained. [2,3-b]pyridin-4-yl)phenyl)propane-2-sulfonamide (69 mg, yield 84%).

MS m/z (ESI): 458.1 [M+H] ⁺ .

Third step: 4-(2-(2,4-difluorophenoxy)-5-((1-methylethyl)sulfonylamino)phenyl)-6-methyl-1H-pyrrolo[ Preparation of 2,3-b]pyridine 7-oxidation

N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)propane-2- Sulfonamide was used as the starting material. Referring to the eighth step of Example 2, 4-(2-(2,4-difluorophenoxy)-5-((1-methylethyl)sulfonylamino)phenyl)- 6-Methyl-1H-pyrrolo[2,3-b]pyridine 7-oxide (27.6 mg, yield 39%). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.38 (s, 1H), 9.84 (s, 1H), 7.47 (d, J = 2.7 Hz, 1H), 7.42 - 7.34 (m, 2H), 7.29 (dd, J=8.9, 2.7 Hz, 1H), 7.24 (s, 1H), 7.12 (td, J=9.2, 5.6 Hz, 1H), 7.05–6.89 (m, 2H), 6.47 (d, J=3.3) Hz, 1H), 3.26 (q, J = 6.8 Hz), 2.52 (s, 3H), 1.27 (d, J = 6.8 Hz, 6H).

MS m/z (ESI): 474.1 [M+H] ⁺ .

Example 5

4-(2-(2,4-difluorophenoxy)-5-((2,2,2-trifluoroethyl)sulfonylamino)phenyl)-6-methyl-1H-pyrrolo[ 2,3-b]pyridine-7-oxide

First step: 4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)aniline

4-(2,4-Difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)aniline (at room temperature) 0.065 g, 0.13 mmol) was dissolved in ethanol (5 mL), then sodium methoxide (0.014 g, 0.26 mmol) was added to the reaction system and heated to 50 ° C overnight. After the completion of the reaction, the ethanol was evaporated to dryness. EtOAc mjjjjjjjjjjjjjjjjjjj , 4-Difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenylamine (0.04 g, white solid, yield 89%).

MS m/z (ESI): 3521. [M+H] ⁺ .

Second step: N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)- 2,2,2-trifluoroethane-1-sulfonamide

Pyridine (0.018 g, 0.228 mmol) and 4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridine-4- The aniline (0.040 g, 0.114 mmol) was dissolved in dichloromethane (8 mL), then 2,2,2-trifluoroethylsulfonyl chloride (0.042 g, 0.228 mmol) was added to the reaction system and stirred at room temperature overnight. . The reaction mixture was diluted with methylene chloride (30 mL). EtOAc (EtOAc) 2,4-Difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)-2,2,2-trifluoroethane 1-sulfonamide (0.06 g) was used directly in the next reaction.

MS m/z (ESI): 498.1 [M+H] ⁺ .

The third step: 4-(2-(2,4-difluorophenoxy)-5-((2,2,2-trifluoroethyl)sulfonylamino)phenyl)-6-methyl-1H -pyrrolo[2,3-b]pyridine-7-oxide

The crude product N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl) -2,2,2-Trifluoroethane-1-sulfonamide (0.04 g, 0.08 mmol) was dissolved in dichloromethane (8 mL), then m-chloroperoxybenzoic acid (0.02 g, 85%, 0.097 mmol) ) was added to the reaction solution and allowed to react at room temperature for half an hour. The reaction mixture was diluted with methylene chloride (20 mL). EtOAc (EtOAc)EtOAc. Chromatography to give 4-(2-(2,4-difluorophenoxy)-5-((2,2,2-trifluoroethyl)sulfonylamino)phenyl)-6-methyl-1H- Pyrrolo[2,3-b]pyridine-7-oxide (0.015 g, white solid, yield: 36%).

MS m/z (ESI): 514.1 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD): δ 11.73 (br, 1H), 9.12 (br, 1H), 7.38-7.36 (m, 2H), 7.24 (s, 1H), 7.17 (s, 1H), 6.98 -6.88 (m, 2H), 6.83-6.78 (m, 2H), 6.50 (d, J = 2.8 Hz, 1H), 3.96 (t, J = 8.8 Hz, 2H), 2.65 (s, 3H).

Example 6

4-(2-(4-Bromo-2-fluorophenoxy)-5-(ethylsulfonylamino)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7 -oxide

First step: Preparation of 4-(2-fluoro-5-nitrophenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine

6-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2 , 3-b]pyridine (500 mg, 1.21 mmol), 2-bromo-1-fluoro-4-nitrobenzene (533 mg, 2.42 mmol), [1,1'-bis(diphenylphosphino)ferrocene Palladium dichloride (88.5 mg, 0.12 mmol), potassium carbonate (500 mg, 3.63 mmol) dissolved in a mixture of 1,4-dioxane (10 mL) and water (3 mL). After 4 hours, the reaction was completed by LC/MS. Water (100 mL) was added to the reaction mixture, and the mixture was washed with ethyl acetate (100 mL×2). : ethyl acetate = 2:1, V/V) gave 4-(2-fluoro-5-nitrophenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b Pyridine (400 mg, yield 78%).

MS m/z (ESI): 426.1 [M+H] ⁺

Second step: 4-(2-(4-bromo-2-fluorophenoxy)-5-nitrophenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3- b] Preparation of pyridine

4-(2-Fluoro-5-nitrophenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (400 mg, 0.94 mmol), 4-bromo- 2-Fluorophenol (533 mg, 2.42 mmol) was dissolved in dimethyl sulfoxide (5 mL), cesium carbonate (368 mg, 1.13 mmol) was added, and the mixture was stirred at 100 ° C for 1 hour, and the reaction was confirmed by LC/MS. Water (100 mL) was added to the reaction mixture, and the mixture was evaporated to ethyl acetate (50 mL?? 4-(2-(4-Bromo-2-fluorophenoxy)-5-nitrophenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (500 mg, yield 89%).

MS m/z (ESI): 596.0 [M+H] ⁺

Third step: Preparation of 4-(2-(4-bromo-2-fluorophenoxy)-5-nitrophenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine

4-(2-(4-Bromo-2-fluorophenoxy)-5-nitrophenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (500 mg, 0.84 mmol) was dissolved in tert-butanol (15 mL), and aqueous potassium hydroxide (3M, 8 mL) was added to the above solution, and the mixture was stirred at 75 ° C overnight. The reaction mixture was extracted with ethyl acetate (50 mL×2). 5-)-nitrophenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine (300 mg, yield 81%).

MS m/z (ESI): 442.0 [M+H] ⁺

Fourth step: Preparation of 4-(4-bromo-2-fluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)aniline

4-(2-(4-Bromo-2-fluorophenoxy)-5-nitrophenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine (300 mg, 0.68 mmol) A mixture of tetrahydrofuran (10 mL), ethanol (10 mL) and water (3 mL) was added, and reduced iron powder (280 mg, 5 mmol), ammonium chloride (265 mg, 5 mmol) was added to the above solution, and the mixture was stirred at 100 ° C for 1 hour. Filtration, the residue was washed with ethyl acetate (50 mL), EtOAc (EtOAc) Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)aniline (230 mg, yield 82.1%).

MS m/z (ESI): 412.0 [M+H] ⁺

The fifth step: N-(4-(4-bromo-2-fluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl) Preparation of ethanesulfonamide

Dissolving 4-(4-bromo-2-fluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenylamine (100 mg, 0.24 mmol) Dichloromethane (5 mL) was added, EtOAc (EtOAc, m. The reaction mixture was diluted with ethyl acetate (50 mL). EtOAc (EtOAc m. -(4-bromo-2-fluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)ethanesulfonamide (70 mg, yield 57%).

MS m/z (ESI): 504.0 [M+H] ⁺

Step 6: 4-(2-(4-Bromo-2-fluorophenoxy)-5-(ethylsulfonylamino)phenyl)-6-methyl-1H-pyrrolo[2,3-b Preparation of pyridine-7-oxide

N-(4-(4-Bromo-2-fluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)ethanesulfonamide (70 mg, 0.14 mmol) was dissolved in tetrahydrofuran (2 mL), and m-chloroperoxybenzoic acid (42 mg, 0.21 mmol) was added and stirred at room temperature for 30 min. Ethyl acetate (50 mL) was added to the reaction mixture, and the mixture was washed with saturated aqueous sodium sulfate (30 mL×2) and then washed with brine (30 mL). Purification of dichloromethane (methanol = 10:1, V/V) gave 4-(2-(4-bromo-2-fluorophenoxy)-5-(ethylsulfonylamino)phenyl)-6- Base-1H-pyrrolo[2,3-b]pyridine-7-oxide (10.0 mg, yield 13.7%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ11.75 (s, 1H), 8.79 (s, 1H), 7.44 (s, 1H), 7.38-7.36 (d, J = 8.8Hz, 1H), 7.26-7.23 (m, 2H), 7.15 (s, 1H), 7.12-7.10 (d, J = 8.8 Hz, 1H), 6.91-6.88 (d, J = 8.8 Hz, 1H), 6.77-6.75 (t, J = 8.8 Hz, 1H), 6.51 (d, J = 2.8 Hz, 1H), 3.23 (q, J = 7.2 Hz, 2H), 2.63 (s, 3H), 1.43-1.41 (t, J = 3.6 Hz, 3H).

MS m/z (ESI): 520.0 [M+H] ⁺

Example 7

4-(2-(4-Bromo-2-fluorophenoxy)-5-((2,2,2-trifluoroethyl)sulfonylamino)phenyl)-6-methyl-1H-pyrrole [2,3-b]pyridine-7-oxide

First step: N-(4-(4-bromo-2-fluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl) -2,2,2-Trifluoroethane-1-sulfonamide preparation

Taking 4-(4-bromo-2-fluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)aniline as a starting material, refer to Example 6 Five steps, substituting 2,2,2-trifluoroethylsulfonyl chloride for ethylsulfonyl chloride to give N-(4-(4-bromo-2-fluorophenoxy)-3-(6-methyl-1H Pyrrolo[2,3-b]pyridin-4-yl)phenyl)-2,2,2-trifluoroethane-1-sulfonamide (60.0 mg, yield 45.0%).

MS m/z (ESI): 558.0 [M+H] ⁺

Second step: 4-(2-(4-bromo-2-fluorophenoxy)-5-((2,2,2-trifluoroethyl)sulfonylamino)phenyl)-6-methyl- Preparation of 1H-pyrrolo[2,3-b]pyridine-7-oxide

N-(4-(4-bromo-2-fluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)-2, Using 2,2-trifluoroethane-1-sulfonamide as the starting material, referring to the sixth step of Example 6, 4-(2-(4-bromo-2-fluorophenoxy)-5-((2,2) , 2-trifluoroethyl)sulfonylamino)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (18.5 mg, yield 35.8%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ12.29 (s, 1H), 10.11 (s, 1H), 7.44-7.42 (dd, J = 8.8Hz, 2.0Hz, 1H), 7.32 (s, 1H), 7.24 (d, J = 2.0 Hz, 1H), 7.18 (d, J = 2.4 Hz, 1H), 7.14 - 7.12 (d, J = 8.8 Hz, 1H), 7.11 (s, 1H), 6.89-6.87 (d , J = 8.8 Hz, 1H), 6.80-6.76 (t, J = 8.8 Hz, 1H), 6.42 (d, J = 2.8 Hz, 1H), 4.04-3.97 (m, 2H), 2.61 (s, 3H) .

MS m / z (ESI): 574.0 [M + H] +

Example 8

4-(5-(ethylsulfonylamino)-2-(((1r,4r)-4-methylcyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3 -b]pyridine-7-oxide

First step: Preparation of 2-bromo-1-(((1r,4r)-4-methylcyclohexyl)oxo)-4-nitrobenzene

(1r,4r)-4-methylcyclohexane-1-ol (1.6 g, 13.6 mmol) was dissolved in N,N-dimethylformamide (50 mL). 0.5 g, 13.6 mmol), after stirring for half an hour, 2-bromo-1-fluoro-4-nitrobenzene (2.0 g, 9 mmol) was added and the mixture was stirred at room temperature overnight. The reaction was quenched by the addition of water (100 mL), and then the mixture was evaporated. The mixture was filtered. The mixture was filtered and washed with water (20mL×2). Cyclohexyl)oxo)-4-nitrobenzene (2.8 g, yield 98%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ8.39 (d, J = 2.8Hz, 1H), 8.09 (dd, J = 9.2Hz, 2.8Hz, 1H), 6.87 (d, J = 9.2Hz, 1H) , 4.32–4.22 (m, 1H), 2.12–2.04 (m, 2H), 1.81– 1.72 (m, 2H), 1.52–1.46 (m, 2H), 1.46–1.38 (m, 1H), 1.08–0.96 ( m, 2H), 0.88 (d, J = 6.4 Hz, 3H).

Second step: Preparation of 3-bromo-4-(((1r,4r)-4-methylcyclohexyl)oxo)aniline

2-Bromo-1-(((1r,4r)-4-methylcyclohexyl)oxo)-4-nitrobenzene (2.8 g, 8.9 mmol) was dissolved in ethanol (40 mL) and iron powder (2.5) g, 44.6 mmol), ammonium chloride (2.4 g, 44.6 mmol) and water (20 mL), and the mixture was stirred at 90 ° C for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was dried. The crude product was purified by column chromatography ( petroleum ether: ethyl acetate = 30:1 to 2:1 gradient elution) to afford 3-bromo-4-(((1r,4r)-4-methylcyclohexyl) oxo Aniline (2.0 g, yield: 79%).

MS m/z (ESI): 284.0 [M+H] ⁺

Third step: Preparation of N-(3-bromo-4-(((1r,4r)-4-methylcyclohexyl)oxo)phenyl)ethanesulfonamide

3-Bromo-4-(((1r,4r)-4-methylcyclohexyl)oxy)aniline (2.0 g, 7 mmol) was dissolved in dichloromethane (40 mL), then pyridine (2.8 g, Ethyl sulfonyl chloride (2.7 g, 21.0 mmol) was stirred at room temperature for 1 hour, then aqueous hydrochloric acid (1M, 50 mL) was evaporated. Filtration and concentration gave the compound N-(3-bromo-4-(((1r,4r)-4-methylcyclohexyl)oxy)phenyl)ethanesulfonamide (2.0 g, yield: 76%) .

MS m/z (ESI): 375.0 [M] ⁺

The fourth step: N-(3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(((1r,4r)-4) -Methylcyclohexyl)oxo)phenyl)ethanesulfonamide

N-(3-Bromo-4-(((1r,4r)-4-methylcyclohexyl)oxo)phenyl)ethanesulfonamide (0.4 g, 1.1 mmol), 6-methyl-4-( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (0.5g , 1.3 mmol), potassium carbonate (350 mg, 2.8 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (80 mg, 0.1 mmol) dissolved in 1,4 dioxane Ring (10 mL) and water (2 mL) were stirred and stirred at 90 ° C for 2 hr under nitrogen. After the reaction mixture was cooled to room temperature, ethyl acetate (50 mL) was evaporated, evaporated, evaporated. Purification by ethyl acetate gradient elution to give the compound N-(3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-((1r) 4r)-4-methylcyclohexyl)oxo)phenyl)ethanesulfonamide (0.4 g, yield: 65%).

MS m/z (ESI): 582.2 [M+H] ⁺

Step 5: N-(3-(6-Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(((1r,4r)-4-methylcyclohexyl) Preparation of oxo)phenyl)ethanesulfonamide

N-(3-(6-Methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(((1r,4r)-4-methyl) Cyclohexyl)oxo)phenyl)ethanesulfonamide (0.4 g, 0.69 mmol) and potassium hydroxide (0.8 g, 13.8 mmol) were dissolved in tert-butanol (20 mL) and water (2 mL), and the mixture was stirred at 60 ° C. 18 hours. The reaction mixture was dried with EtOAc (EtOAc) (EtOAcjjjjjjjjjjjjj 2,3-b]pyridin-4-yl)-4-(((1r,4r)-4-methylcyclohexyl)oxo)phenyl)ethanesulfonamide (0.2 g, yield: 68%).

MS m / z (ESI): 428.1 [M + H] +

Step 6: 4-(5-(ethylsulfonylamino)-2-(((1r,4r)-4-methylcyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrole Preparation of [2,3-b]pyridine-7-oxide

N-(3-(6-Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(((1r,4r)-4-methylcyclohexyl)oxo) Phenyl)ethanesulfonamide (100 mg, 0.23 mmol) and m-chloroperoxybenzoic acid (95 mg, 0.46 mmol) were dissolved in tetrahydrofuran (4 mL), and the mixture was stirred at 25 ° C for 2 hours. After the reaction mixture is concentrated, the crude product is separated by high performance liquid chromatography to give the compound 4-(5-(ethylsulfonylamino)-2-(((1r,4r)-4-methylcyclohexyl)oxy)phenyl) 6-Methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (11 mg, yield: 11%).

¹ H NMR (400 MHz, CD ₃ OD): δ 7.30 - 7.29 (m, 2H), 7.21. (dd, J = 8.8 Hz, 2.8 Hz, 1H), 7.17 (s, 1H), 7.05 (d, J = 8.8 Hz, 1H), 6.43 (d, J = 3.2 Hz, 1H), 4.11 - 3.98 (m, 1H), 2.99 (q, J = 7.2 Hz, 2H), 2.60 (s, 3H), 1.95 - 1.86 ( m, 2H), 1.64 - 1.52 (m, 2H), 1.32 - 1.21 (m, 4H), 1.18 - 1.08 (m, 2H), 0.96 - 0.87 (m, 2H), 0.78 (d, J = 6.4 Hz, 3H).

MS m/z (ESI): 444.1 [M+H] ⁺ .

Example 9

4-(5-(ethylsulfonylamino)-2-(((1r,4r)-4-methylcyclohexyl)amino)phenyl)-6-methyl-1H-pyrrolo[2,3- b]pyridine-7-oxide

First step: Preparation of 2-bromo-N-((1r,4r)-4-methylcyclohexyl)-4-nitroaniline

2-Bromo-1-fluoro-4-nitrobenzene (4.0 g, 18 mmol), (1r, 4r)-4-methylcyclohexane-1-amine (6.2 g, 55 mmol) and N,N- Isopropylethylamine (11.6 g, 90 mmol) was dissolved in N-methyl-2-pyrrolidone (30 mL) and stirred at 130 ° C for 18 hours. After the reaction mixture was cooled to room temperature, water (200 mL) was added and stirred for 1 hour, and a yellow solid was precipitated. The mixture was filtered, and the solid was washed with water, and then evaporated to dryness to give the product of 2-bromo-N-((1r,4r)-4-methylcyclohexyl)-4-nitroaniline (4.5 g, yield 79%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ8.36 (d, J = 2.4Hz, 1H), 8.08 (dd, J = 9.2Hz, 2.4Hz, 1H), 6.58 (d, J = 9.2Hz, 1H) , 4.97 (d, J = 7.2 Hz, 1H), 3.40 - 3.28 (m, 1H), 2.17 - 2.07 (m, 2H), 1.87 - 1.80 (m, 2H), 1.50 - 1.40 (m, 1H), 1.35 -1.21 (m, 2H), 1.17 - 1.03 (m, 2H), 0.95 (d, J = 6.4 Hz, 3H).

Second step: Preparation of 2-bromo-N1-((1r,4r)-4-methylcyclohexyl)benzene-1,4-diamine

2-Bromo-N-((1r,4r)-4-methylcyclohexyl)-4-nitroaniline (4.5 g, 14.4 mmol) was dissolved in ethanol (100 mL) and iron powder (4 g, 72.0 mmol) was added. Ammonium chloride (15.3 g, 0.3 mol) and water (20 mL) were stirred at 90 ° C for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was evaporated. The crude product was purified by column chromatography ( petroleum ether: ethyl acetate = 50:1 to 1:1 gradient) to afford 2-bromo-N1-((1r,4r)-4-methylcyclohexyl)benzene-1, 4-Diamine (4 g, yield 98%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ6.87 (d, J = 2.4Hz, 1H), 6.62-6.53 (m, 2H), 3.40 (br, 3H), 3.14-3.04 (m, 1H), 2.13 -2.03 (m, 2H), 1.80 - 1.69 (m, 2H), 1.47 - 1.32 (m, 1H), 1.22 - 0.96 (m, 4H), 0.92 (d, J = 6.4 Hz, 3H).

MS m/z (ESI): 283.0, 285.0 [M+H] ⁺

Third step: Preparation of N-(3-bromo-4-(((1r,4r)-4-methylcyclohexyl)amino)phenyl)ethanesulfonamide

2-Bromo-N1-((1r,4r)-4-methylcyclohexyl)benzene-1,4-diamine (4.0 g, 14 mmol) was dissolved in dichloromethane (100 mL), then pyridine (3.3 g) , 42 mmol), ethanesulfonyl chloride (1.8 g, 14.0 mmol), and the mixture was stirred at room temperature for 18 hours. Water (300 mL) was added, the aqueous was extracted with methylene chloride (300 mL), EtOAcjjjjjjjjjjjj Purification by a gradient elution to give the compound N-(3-bromo-4-(((1r,4r)-4-methylcyclohexyl)amino)phenyl)ethanesulfonamide (3.5 g, yield: 66%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ7.36 (d, J = 2.4Hz, 1H), 7.09 (dd, J = 8.8,2.5Hz, 1H), 6.59 (d, J = 8.8Hz, 1H), 6.47(s,1H), 4.24(br,1H), 3.23–3.11(m,1H), 3.05(q,J=7.2Hz, 2H), 2.13–2.05(m,2H),1.81–1.74(m, 2H), 1.42 (dd, J = 6.8, 3.6 Hz, 1H), 1.37 (t, J = 7.2 Hz, 3H), 1.27 - 1.16 (m, 2H), 1.12 - 1.00 (m, 2H), 0.93 (d) , J = 6.4 Hz, 3H).

MS m/z (ESI): 375.0, 377.0 [M+H] ⁺

The fourth step: N-(3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(((1r,4r)-4) -Methylcyclohexyl)amino)phenyl)ethanesulfonamide

Taking N-(3-bromo-4-(((1r,4r)-4-methylcyclohexyl)amino)phenyl)ethanesulfonamide (200mg, 0.5mmol) as the starting material, refer to the fourth step of Example 8. , the compound N-(3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(((1r,4r)-4-) Methylcyclohexyl)amino)phenyl)ethanesulfonamide (180 mg, yield: 58%).

MS m/z (ESI): 581.2 [M+H] ⁺

Step 5: N-(3-(6-Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(((1r,4r)-4-methylcyclohexyl) Preparation of amino)phenyl)ethanesulfonamide

N-(3-(6-Methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(((1r,4r)-4-methyl) Cyclohexyl)amino)phenyl)ethanesulfonamide (180 mg, 0.3 mmol) was used as the starting material of the reaction, and the compound of N.sup. -b]pyridin-4-yl)-4-(((1r,4r)-4-methylcyclohexyl)amino)phenyl)ethanesulfonamide (120 mg, yield: 91%).

MS m/z (ESI): 427.2 [M+H] ⁺

Step 6: 4-(5-(Ethylsulfonylamino)-2-(((1r,4r)-4-methylcyclohexyl)amino)phenyl)-6-methyl-1H-pyrrolo[ Preparation of 2,3-b]pyridine-7-oxide

N-(3-(6-Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(((1r,4r)-4-methylcyclohexyl)amino)benzene Ethyl sulfonamide (120 mg, 0.28 mmol) was used as the starting material of the reaction, and the compound was obtained in the sixth step of Example 8 to give the compound 4-(5-(ethylsulfonylamino)-2-((1r,4r)-4- Methylcyclohexyl)amino)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (11.2 mg, yield: 9.0%).

^{_{1 H NMR (400MHz, CD 3}} OD): δ7.31 (d, J = 3.2Hz, 1H), 7.13-7.09 (m, 1H), 7.08 (s, 1H), 7.00 (d, J = 2.4Hz, 1H), 6.71 (d, J = 8.8 Hz, 1H), 6.33 (d, J = 3.2 Hz, 1H), 3.17 - 3.07 (m, 1H), 2.94 (q, J = 7.2 Hz, 2H), 2.60 ( s, 3H), 1.93–1.85 (m, 2H), 1.64–1.54 (m, 2H), 1.29–1.17 (m, 4H), 1.02–0.83 (m, 4H), 0.79 (d, J=6.4 Hz, 3H).

MS m/z (ESI): 455.2 [M+H] ⁺

Example 10

4-(2-(cyclohexanetrienoxy)-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide

First step: Preparation of (3-bromo-4-fluorophenyl)(methyl)sulfane

3-Bromo-4-fluoroaniline (19 g, 0.1 mol) and copper powder (0.96 g, 15 mmol) were dissolved in 1,2-dimethyldisulfane (50 mL), and the reaction was heated to 80 °C. Isoamyl nitrite (15 g, 0.15 mmol) was slowly added dropwise to maintain the internal temperature of the reaction not higher than 90 °C. After the dropwise addition, the reaction was stirred at 90 ° C for two hours. The reaction mixture was evaporated to dryness. EtOAc (EtOAc) The organic phase is dried and filtered, the filtrate is evaporated to dryness, and the residue is subjected to distillation under reduced pressure to obtain (3-bromo-4-fluorophenyl)(ethyl)sulfane (15 g, light) obtained from a fraction of steam at 50-60 ° C. Yellow oil, yield 68%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.46 - 7.38 (m, 1H), 7.21 - 7.12 (m, 1H), 7.08 - 6.99 (m, 1H), 2.46 (s, 3H).

The second step: preparation of 2-bromo-1-fluoro-4-(methanesulfonyl)benzene

m-Chloroperoxybenzoic acid (860 mg, 4.98 mmol) was added to a solution of (3-bromo-4-fluorophenyl)(methyl)sulfane (500 mg, 2.26 mmol) in dichloromethane (10 mL) 6 hours. After the solvent was removed, the crude product was purified (jjjjjjjjjjj

^{_{1 H NMR (400MHz, CDCl 3}} ): δ8.19 (dd, J = 6.2Hz, 2.3Hz, 1H), 7.91 (m, 1H), 7.37-7.29 (m, 1H), 3.08 (s, 3H).

The third step: preparation of 2-bromo-1-(cyclohexanetrienoxy)-4-(methanesulfonyl)benzene

Sodium hydride (38 mg, 0.95 mmol, 60%) was added to 2-bromo-1-fluoro-4-(methylsulfonyl)benzene (200 mg, 0.79 mmol) and cyclohexanol (95 mg, 0.95 mmol) of a solution of N,N-dimethylformamide (5 mL) was allowed to react at room temperature for 30 minutes and then at 45 ° C for 3 hours. After the reaction mixture was cooled, the mixture was evaporated. Crude column separation (petroleum ether: ethyl acetate = 5:1, V/V) afforded 2-bromo-1-(cyclohexanetrienoxy)-4-(methylsulfonyl)benzene (170 mg, yield 65 %).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ8.11 (d, J = 2.3Hz, 1H), 7.81 (dd, J = 8.7Hz, 2.3 Hz, 1H), 6.99 (d, J = 8.7Hz, 1H) , 4.53–4.44 (m, 1H), 3.04 (s, 3H), 2.00–1.89 (m, 2H), 1.89–1.78 (m, 2H), 1.78–1.65 (m, 2H), 1.60–1.37 (m, 4H).

The fourth step: 2-(2-(cyclohexanetrienoxy)-5-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxine Preparation of boron penta ring

2-Bromo-1-(cyclohexanetrienoxy)-4-(methanesulfonyl)benzene (1 g, 3 mmol), 4,4,4',4',5,5,5',5' - octamethyl-2,2'-linked (1,3,2-dioxaborolan) (2.29 g, 9 mmol), potassium acetate (0.88 g, 9 mmol), tris(dibenzylideneacetone) palladium (137 mg, 0.15 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (143 mg, 0.3 mmol) was added to 1,4-dioxane (20 mL). The solution was reacted at 85 ° C for 16 hours under a nitrogen atmosphere. The reaction mixture was evaporated to dryness, and then purified,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Base 4,4,5,5-tetramethyl-1,3,2-dioxaborolan (400 mg crude, 60% purity) was used directly in the next reaction.

Step 5: Preparation of 4-(2-(cyclohexanetrienoxy)-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine

2-(2-(Cyclohexatrienoxy)-5-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (380 mg, 0.6 mmol, crude), 4-chloro-6-methyl-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.6 mmol), tetratriphenylphosphine palladium (70 mg, 0.06 mmol) Potassium carbonate (248 mg, 3 mol) was added to a mixed solvent of ethanol/toluene/water (v/v/v = 9:3:1, 10 mL). The reaction solution was subjected to microwave reaction at 120 ° C for 0.5 hour under a nitrogen atmosphere, and the reaction liquid was evaporated to dryness and then separated using a preparative plate ( petroleum ether: ethyl acetate = 1:1, V/V) to obtain 4-(2-(cyclohexylenetriene). Andoxy)-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine (75 mg, yield 33%).

MS m/z (ESI): 385.1 [M+H] ⁺

Step 6: 4-(2-(Cyclohexatrienoxy)-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7- Preparation of oxide

Addition of m-chloroperoxybenzoic acid (65 mg, 0.29 mmol, 70%) to 4-(2-(cyclohexanetrienoxy)-5-(methylsulfonyl)phenyl)-6-methyl-1H - a solution of pyrrolo[2,3-b]pyridine (75 mg, 0.19 mmol) in tetrahydrofuran (2 mL). The solvent was evaporated to dryness at room temperature for 0.5 hour, and a plate was separated (dichloromethane:methanol = 15:1, V/V) to give 4-(2-(cyclohexanetrienoxy)-5-(methanesulfonyl) Phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (6 mg, yield 7.7%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ12.33 (br, 1H), 8.02 (d, J = 2.4Hz, 1H), 7.94 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.34 (d, J=3.3 Hz, 1H), 7.21–7.11 (m, 2H), 6.43 (d, J=3.3 Hz, 1H), 4.53–4.40 (m, 1H), 3.08 (s, 3H), 2.77 (s, 3H) ), 1.94–1.83 (m, 2H), 1.68–1.56 (m, 2H), 1.56–1.44 (m, 2H), 1.43–1.28 (m, 4H).

MS m/z (ESI): 401.1 [M+H] ⁺

Example 11

4-(2-((cyclopropylmethyl)amino)-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide preparation

First step: Preparation of 2-bromo-N-(cyclopropylmethyl)-4-(methylsulfonyl)aniline

2-Bromo-1-fluoro-4-(methylsulfonyl)benzene (700 mg, 2.77 mmol) was dissolved in 1,4-dioxane (15 mL) and cyclopropylmethylamine (1.18 g, 16.67) (mmol), the reaction was stirred at 140 ° C for one hour in the microwave. After cooling, the reaction mixture was concentrated, diluted with ethyl acetate (40 mL), then washed with water (20mL×2) and brine (20mL) After drying, concentration and column chromatography (petroleum ether: ethyl acetate = 5:1, V/V) afforded compound 2-bromo-N-(cyclopropylmethyl)-4-(methylsulfonyl)aniline (680 mg) , yield 81%).

Second step: N-(cyclopropylmethyl)-4-(methylsulfonyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -base) preparation of aniline

2-bromo-N-(cyclopropylmethyl)-4-(methylsulfonyl)aniline (680.0 mg, 2.24 mmol), dinacol borate (1.71 g, 6.73 mmol), tris(dibenzylidene) Acetone) dipalladium (103 mg, 0.112 mmol), potassium acetate (483 mg, 4.93 mmol), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (107 mg, 0.224 mmol) dissolved in 1,4 - Dioxane (10 mL), the reaction was stirred at 80 ° C for 8 hours under a nitrogen atmosphere. The reaction mixture was evaporated to dryness, then water (20mL), then ethyl acetate (20mL × 2), (40 mL) and saturated brine (40 mL), and dried over anhydrous sodium sulfate. Methyl)-4-(methylsulfonyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine (560.0 mg, produced) The rate is 71%).

Third step: Preparation of N-(cyclopropylmethyl)-2-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(methylsulfonyl)aniline

N-(cyclopropylmethyl)-4-(methylsulfonyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Aniline (200.0 mg, 0.57 mmol), dissolved in a mixed solvent of 1,4-dioxane (4 mL) and water (1 mL), followed by tris(dibenzylideneacetone) dipalladium (16 mg, 0.0171 mmol) , tripotassium phosphate (302 mg, 1.43 mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphoryladamantane (18.3 mg, 0.0627 mmol) The mixture was stirred with nitrogen for 5 minutes and stirred at 120 ° C for one hour. After the reaction mixture was cooled, the mixture was evaporated, evaporated, evaporated with with with with with with Methanol = 20:1) The compound N-(cyclopropylmethyl)-2-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(methane) was isolated. Acyl) aniline (21 mg, yield 10%).

MS m/z (ESI): 356.1 [M+H] ⁺ .

Fourth step: 4-(2-((cyclopropylmethyl)amino)-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7 - Preparation of oxides

N-(cyclopropylmethyl)-2-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(methylsulfonyl)aniline (21.0 mg, 0.056 Methyl acetate (2 mL) was added, and m-chloroperoxybenzoic acid (14 mg, 0.084 mmol) was added, and the mixture was stirred at room temperature for one hour and then quenched with sodium thiosulfate solution (5 mL). After the addition, dichloromethane (15 mL) was added, and then washed with water (20 mL×2) and brine (20 mL) and dried over anhydrous sodium sulfate. :1) Purification to give the compound 4-(2-((cyclopropylmethyl)amino)-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine -7-oxide (2.5 mg, yield 10%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ11.80 (s, 1H), 8.05 (s, 1H), 8.01 (d, J = 2.4Hz, 1H), 7.40 (d, J = 3.2Hz, 1H), 7.25–7.11 (m, 2H), 6.40 (d, J = 3.4 Hz, 1H), 3.86 (d, J = 6.4 Hz, 2H), 3.73 (s, 3H), 3.20 (s, 3H), 1.24–1.31 (m, 1H), 0.58–0.49 (m, 2H), 0.31–0.24 (m, 2H).

MS m/z (ESI): 3721. [M+H] ⁺ .

Example 12

Preparation of 4-(2-isobutoxy-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide

First step: Preparation of 2-bromo-1-isobutoxy-4-(methylsulfonyl)benzene

2-methylpropan-1-ol was used instead of cyclohexanol as the starting material. Referring to the third step of Example 10, the compound 2-bromo-1-isobutoxy-4-(methylsulfonyl)benzene (1.01 g) was obtained. , yield 83%).

Second step: Preparation of 2-(2-isobutoxy-5-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan

2-Bromo-1-isobutoxy-4-(methylsulfonyl)benzene was used as the starting material, and the fourth step of Example 10 was carried out to obtain 2-(2-isobutoxy-5-(methanesulfonyl). Phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (900 mg, yield 78%).

Third step: Preparation of 4-(2-isobutoxy-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine

Using 2-(2-isobutoxy-5-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan as the starting material, The fifth step of Example 10 gave the compound 4-(2-isobutoxy-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine (45 mg, Yield 23%).

MS m/z (ESI): 359.1 [M+H] ⁺ .

Fourth step: Preparation of 4-(2-isobutoxy-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide

Taking 4-(2-isobutoxy-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine as the starting material, refer to the sixth step of Example 10. To give the compound 4-(2-isobutoxy-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (16.4 mg, Yield 53%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ11.83 (s, 1H), 8.02 (s, 1H), 8.00 (d, J = 2.4Hz, 1H), 7.43 (d, J = 3.2Hz, 1H), 7.23–7.14(m,2H), 6.46(d,J=3.4Hz,1H),3.86(d,J=6.4Hz,2H),3.09(s,3H),2.78(s,3H),1.98(dt , J = 13.3, 6.6 Hz, 1H), 0.88 (d, J = 6.7 Hz, 6H).

MS m/z (ESI): 375.1 [M+H] ⁺

Example 13

6-Methyl-4-(2-((trans)-4-methylcyclohexyl)amino)-5-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine- 7-oxide

First step: 4-(2-Fluoro-5-(methylsulfonyl)phenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine

2-Bromo-1-fluoro-4-(methylsulfonyl)benzene (0.42 g, 1.66 mmol), 6-methyl-4-(4,4,5,5-tetramethyl) was added to a three-necked flask at room temperature. Base-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (0.62 g, 1.49 mmol), potassium carbonate (0.41 g) , 2.98 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.12 g, 0.16 mmol), dioxane (16 mL) and water (4 mL). After three times, it was heated to 90 ° C overnight. After cooling to room temperature, it was diluted with ethyl acetate (20 mL), EtOAc (EtOAc)EtOAc. The crude product was isolated by column chromatography (EtOAc:EtOAc:EtOAc:EtOAc:EtOAc 1-Toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (0.65 g, white solid, 94%).

MS m/z (ESI): 459.1 [M+H] ⁺ .

Step 2: 4-(2-Fluoro-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine

4-(2-Fluoro-5-(methylsulfonyl)phenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine was added to a round bottom flask at room temperature. (0.53 g, 1.16 mmol), then dissolved with t-butanol (15 mL), stirred at room temperature then aqueous potassium hydroxide (0.32 g, 5.79 mmol, 1 mL water), warmed to 65 ° C overnight, cooled to room temperature The residue was removed with EtOAc (25 mL). 5-(-Methanesulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine (0.37 g, white solid).

MS m/z (ESI): 305.1 [M+H] ⁺ .

The third step: 4-(2-fluoro-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide

4-(2-Fluoro-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine (0.32 g, 1.05 mmol) was dissolved in tetrahydrofuran under ice bath (20 mL), then m-chloroperoxybenzoic acid (85%, 0.21 g, 1.05 mmol) was added to the reaction mixture. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (20 mL) Wash (10 mL × 3), then wash with saturated brine (10 mL), EtOAc (EtOAc) /V), 4-(2-fluoro-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.23 g, light) Yellow solid, yield 68%).

MS m/z (ESI): 321.1 [M+H]+.

Fourth step: 6-methyl-4-(2-((trans)-4-methylcyclohexyl)amino)-5-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3- b]pyridine-7-oxide

Add 4-(2-fluoro-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.050g) to a 10 ml microwave tube , 0.16 mmol), trans-4-methylcyclohexylamine (0.5 mL) and N-methylpyrrolidone (3 mL) were heated to 140 ° C in an oil bath and allowed to react overnight. The reaction mixture was cooled to room temperature, then diluted with ethyl acetate (20 mL). -Methyl-4-(2-((trans)-4-methylcyclohexyl)amino)-5-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-7 - Oxide (0.020 g, white solid, yield 31%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ12.27 (br, 1H), 7.80 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.70 (d, J = 2.0Hz, 1H), 7.38 (d, J = 3.2 Hz, 1H), 7.08 (s, 1H), 6.79 (d, J = 8.8 Hz, 1H), 6.37 (d, J = 3.2 Hz, 1H), 4.28 (d, J = 7.6 Hz, 1H) , 3.37-3.26(m,1H), 3.05(s,3H), 2.78(s,3H),2.11-1.93(m,2H),1.75-1.73(m,2H),1.38-1.26(m,1H) , 1.11 - 0.98 (m, 4H), 0.90 (d, J = 6.4 Hz, 3H).

MS m/z (ESI): 414.2 [M+H] ⁺ .

Example 14

4-(2-((trans)-4-(tert-butyl)cyclohexyl)oxo)-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3- b]pyridine-7-oxide

First step: 4-(2-((trans)-4-(tert-butyl)cyclohexyl)oxo)-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[ 2,3-b]pyridine-7-oxide

Trans-4-tert-butylcyclohexanol (0.10 g, 0.66 mmol) was dissolved in N,N-dimethylformamide (3 mL), then sodium hydride (60%, EtOAc, The reaction solution was stirred at room temperature for half an hour. 4-(2-Fluoro-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.04 g, 0.13 mmol) N,N-dimethylformamide (1 mL) was added dropwise to the reaction mixture, and the mixture was stirred with EtOAc EtOAc (EtOAc) After spin-drying, the crude product was isolated by reverse phase preparative chromatography to give 4-(2-((trans)-4-(tert-butyl)cyclohexyl)oxy)-5-(methylsulfonyl)phenyl)-6 Methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.030 g, white solid, yield 53%).

MS m / z (ESI): 457.2 [M + H] +.

^{_{1 H NMR (400MHz, CDCl 3}} ): δ11.96 (br, 1H), 8.00 (d, J = 2.4Hz, 1H), 7.94 (dd, J 8.8Hz, 2.4Hz 1H), 7.35 (d, J = 3.2 Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H), 7.13 (s, 1H), 6.38 (d, J = 3.2 Hz, 1H), 4.36-4.24 (m, 1H), 3.08 (s, 3H), 2.77 (s, 3H), 2.15-2.12 (m, 2H), 1.85-1.82 (m, 2H), 1.34-1.25 (m, 2H), 1.17-0.97 (m, 3H), 0.85 (s, 9H).

Example 15

6-Methyl-4-(2-(((trans)-4-methylcyclohexyl)oxy)-5-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3-b] Pyridine-7-oxide

According to the experimental procedure of Example 14, trans-4-methylcyclohexanol was used instead of trans-4-tert-butylcyclohexanol to obtain 4-(2-((trans)-4-methylcyclohexyl)oxy). -5-(Methanesulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.035 g, white solid, yield 49%).

MS m/z (ESI): 415.2 [M+H] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ): δ11.70 (br, 1H), 7.99-7.94 (m, 2H), 7.41 (d, J = 3.2Hz, 1H), 7.18-7.16 (m, 2H), 6.46 (d, J=3.2 Hz, 1H), 4.39-4.28 (m, 1H), 3.09 (s, 3H), 2.79 (s, 3H), 2.09-2.06 (m, 2H), 1.78-1.75 (m, 2H) ), 1.38-1.28 (m, 3H), 1.09-1.00 (m, 2H), 0.91 (d, J = 7.2 Hz, 3H).

Example 16

4-(2-((trans)-4-ethylcyclohexyl)oxo)-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine -7-oxide

According to the experimental procedure of Example 14, trans-4-ethylcyclohexanol was used instead of trans-4-tert-butylcyclohexanol to obtain 4-(2-((trans)-4-ethylcyclohexyl)oxy). -5-(Methanesulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.023 g, white solid, yield 58%).

MS m/z (ESI): 429.2 [M+H]+.

¹ H NMR (400 MHz, CDCl ₃ ): δ 11.86 (br, 1H), 7.99 (s, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 7.17 -7.13 (m, 2H), 6.42 (d, J = 3.2 Hz, 1H), 4.35-4.27 (m, 1H), 3.08 (s, 3H), 2.76 (s, 3H), 2.10-2.07 (m, 2H) ), 1.84-1.81 (m, 2H), 1.36-1.08 (m, 5H), 1.04-0.96 (m, 2H), 0.87 (d, J = 7.2 Hz, 3H).

Example 17

4-(2-((trans)-4-isopropylcyclohexyl)oxo)-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b] Pyridine-7-oxide

According to the experimental procedure of Example 14, trans-4-isopropylcyclohexanol was used instead of trans-4-tert-butylcyclohexanol to obtain 4-(2-((trans))-4-isopropylcyclohexyl. Oxo)-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.018 g, yield 44%).

MS m/z (ESI): 443.2 [M+H] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ): δ11.96 (br, 1H), 8.00 (d, J = 2.0Hz, 1H), 7.96 (dd, J8.8Hz, 2.0Hz 1H), 7.36 (d, J = 3.2 Hz, 1H), 7.17-7.14 (m, 2H), 6.43 (d, J = 3.2 Hz, 1H), 4.34 - 4.26 (m, 1H), 3.09 (s, 3H), 2.77 (s, 3H), 2.13-2.10(m,2H),1.80-1.77(m,2H), 1.49-1.39(m,1H),1.35-1.25(m,2H),1.15-1.06(m,3H),0.86(d,J =6.8Hz, 6H).

Example 18

4-(2-((1S,2R,5S)-2-isopropyl-5-methylcyclohexyl)oxo)-5-(methylsulfonyl)phenyl)-6-methyl-1H- Pyrrolo[2,3-b]pyridine-7-oxide

According to the experimental procedure of Example 14, L-menthol was used instead of trans-4-tert-butylcyclohexanol to obtain 4-(2-((1(1,2R,5S)-2-isopropyl-5-) Cyclohexyl)oxo)-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.020 g, white solid, yield 47%).

MS m/z (ESI): 457.2 [M+H] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ): δ11.59 (br, 1H), 8.00 (d, J = 2.4Hz, 1H), 7.94 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.30 (d, J = 3.6 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.12 (s, 1H), 6.40 (d, J = 3.6 Hz, 1H), 4.25 - 4.19 (m, 1H), 3.09 ( s, 3H), 2.75 (s, 3H), 2.18-2.15 (m, 1H), 1.93-1.85 (m, 1H), 1.68-1.60 (m, 2H), 1.56-1.43 (m, 1H), 1.36- 1.29 (m, 1H), 1.12 - 0.85 (m, 6H), 0.77 (d, J = 7.2 Hz, 3H), 0.66 (d, J = 7.2 Hz, 3H).

Example 19

6-Methyl-4-(2-((trans)-4-ethylcyclohexyl)amino)-5-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine- 7-oxide

First step: N-(4-ethylcyclohexyl)-2-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(methylsulfonyl)aniline

Add 4-(2-fluoro-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.040g) to a 10 ml microwave tube , 0.125 mmol), 4-ethylcyclohexylamine (0.3 mL) and N-methylpyrrolidone (3 mL), heated to 140 ° C in an oil bath, and allowed to react overnight and cooled to room temperature. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc (EtOAc) 6-Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(methylsulfonyl)aniline (0.060 g, yellow oil) was used directly for next step.

MS m/z (ESI): 412.2 [M+H] ⁺ .

Second step: 6-methyl-4-(2-((trans)-4-ethylcyclohexyl)amino)-5-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3- b]pyridine-7-oxide

The crude product N-(4-ethylcyclohexyl)-2-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(methylsulfonyl)aniline (0.060) g, yellow oil) was dissolved in dichloromethane (10 mL), then m-chloroperoxybenzoic acid (85%, 0.051 g, 0.25 mmol) was added to the reaction mixture and stirred at room temperature. After completion of the reaction, the reaction mixture was diluted with methylene chloride (40 mL), EtOAc. Chromatography to give 6-methyl-4-(2-((trans)-4-ethylcyclohexyl)amino)-5-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3-b Pyridine-7-oxide (0.012 g, white solid, yield 19%).

MS m/z (ESI): 428.2 [M+H] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ): δ12.2 (br, 1H), 7.80 (dd, J = 8.8Hz, 2.0Hz, 1H), 7.70 (d, J = 2.0Hz 1H), 7.39 (d, J =3.2 Hz, 1H), 7.08 (s, 1H), 6.79 (d, J = 8.8 Hz, 1H), 6.37 (d, J = 3.2 Hz, 1H), 4.30 (d, J = 7.2 Hz, 1H), 3.39-3.26(br,1H), 3.05(s,3H), 2.78(s,3H),2.16-1.95(m,2H),1.82-1.78(m,2H),1.27-1.20(m,2H), 1.13-0.94 (m, 5H), 0.87 (t, J = 7.2 Hz, 3H).

Example 20

6-Methyl-4-(2-((cis)-4-ethylcyclohexyl)amino)-5-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine- 7-oxide

According to the experimental procedure of Example 19, reverse phase preparative chromatography was carried out to give 6-methyl-4-(2-((cis)-4-ethylcyclohexyl)amino)-5-(methylsulfonyl)phenyl. -1H-pyrrolo[2,3-b]pyridine-7-oxide (0.015 g, white solid, yield 28%).

MS m/z (ESI): 428.2 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.21. (br, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.72 (s, 1H), 7.39 (d, J = 3.2 Hz, 1H), 7.08 (s, 1H), 6.79 (d, J = 8.8 Hz, 1H), 6.44 (d, J = 3.2 Hz, 1H), 4.54 (d, J = 6.4 Hz, 1H), 3.66 (br, 1H), 3.05 (s, 3H), 2.79 (s, 3H), 1.74-1.48 (m, 6H), 1.25-1.12 (m, 3H), 1.02-0.86 (m, 2H), 0.82 (t, J = 7.2 Hz, 3H) ).

Example 21

6-Methyl-4-(5-(methylsulfonyl)-2-(((trans)-4-propylcyclohexyl)amino)phenyl)-1H-pyrrolo[2,3-b]pyridine -7-oxide

Following the experimental procedure of Example 19, 4-propylcyclohexylamine was used instead of 4-ethylcyclohexylamine to give 6-methyl-4-(2-((trans)-4-propylcyclohexyl). Amino)-5-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.010 g, pale yellow solid, yield 18%).

MS m/z (ESI): 442.2 [M+H] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ): δ12.14 (br, 1H), 7.80 (dd, J = 8.8Hz, 2.0Hz, 1H), 7.71 (d, J = 2.0Hz, 1H), 7.39 (d, J = 3.2 Hz, 1H), 7.08 (s, 1H), 6.80 (d, J = 8.8 Hz, 1H), 6.38 (d, J = 3.2 Hz, 1H), 4.30 (d, J = 7.6 Hz, 1H) , 3.32(br,1H), 3.05(s,3H), 2.78(s,3H),2.02(br,2H),1.80-1.78(m,2H),1.36-1.24(m,2H),1.20-1.16 (m, 3H), 1.04-1.00 (m, 4H), 0.87 (t, J = 7.2 Hz, 3H).

Example 22

6-Methyl-4-(5-(methylsulfonyl)-2-((cis)-4-propylcyclohexyl)amino)phenyl)-1H-pyrrolo[2,3-b]pyridine- 7-oxide

Following the experimental procedure of Example 19, 4-propylcyclohexylamine was used instead of 4-ethylcyclohexylamine to give 6-methyl-4-(2-((cis))-4-propylcyclohexyl. Amino)-5-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.010 g, pale yellow solid, yield 18%).

MS m / z (ESI): 442.2 [M + H] +.

^{_{1 H NMR (400MHz, CDCl 3}} ): δ11.62 (br, 1H), 7.80 (dd, J = 8.8Hz, 2.0Hz, 1H), 7.73 (d, J = 2.0Hz, 1H), 7.33 (d, J=3.2 Hz, 1H), 7.08 (s, 1H), 6.76 (d, J = 8.8 Hz, 1H), 6.42 (d, J = 3.2 Hz, 1H), 4.57 (d, J = 6.8 Hz, 1H) , 3.65 (br, 1H), 3.05 (s, 3H), 2.77 (s, 3H), 1.73-1.61 (m, 4H), 1.55-1.49 (m, 2H), 1.38-1.27 (m, 1H), 1.26 -1.20 (m, 2H), 1.13-1.07 (m, 2H), 0.95-0.88 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H).

Example 23

4-(5-((2-Cyanopropan-2-yl)sulfonyl)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1H-pyrrolo[2, 3-b]pyridine-7-oxide

The first step: the preparation of 1,2-bis(3-bromo-4-fluorophenyl)disulfane.

3-Bromo-4-fluoroaniline (60 g, 315.6 mmol), acetonitrile (600 mL), water (600 mL), and concentrated hydrochloric acid (300 mL). The mixture was cooled to 0-5 ° C in an ice bath, and a solution of sodium nitrite (23.4 g, 316 mmol) in water (300 mL) was added dropwise, maintaining the system temperature at 0-5 °C. After 1 hour of reaction, urea (3.6 g, 60 mmol) was added to quench excess sodium nitrite and stirred for 10 minutes. Sodium sulfide nonahydrate (100.8 g, 420 mmol), sulfur powder (13.2 g, 420 mmol), NaOH (17.4 g, 432 mmol), water (300 mL) were sequentially added to a 1 L three-necked flask. The oil bath was heated to 75 ° C for 1 hour until the solution became clear. The clear solution was cooled to room temperature and added dropwise to the above reaction liquid, and the temperature of the system was maintained at 0 to 5 °C. After completion of the dropwise addition, the reaction mixture was extracted with ethyl acetate (1L×2), filtered, dried over anhydrous sodium sulfate and evaporated to give the crude (1,2-bis(3-bromo-4-fluorophenyl)disulfane ( 42 g, yellow oil, yield 65%).

The second step: the preparation of 3-bromo-4-fluorobenzenethiol

1,2-bis(3-bromo-4-fluorophenyl)disulfane (42 g, 101.9 mmol), methanol (300 mL), tetrahydrofuran (1 L), sodium hydroxide (10.3 g, 257.5) were sequentially added to a 3L three-necked flask. A solution of mmol (300 mL) of water. Sodium borohydride (11.1 g, 293.6 mmol) was added in five portions at room temperature. After 1 hour of reaction, it was concentrated, and a solution of sodium hydroxide (35 g, 875.0 mmol) in water (300 mL) was added, and extracted with methyl tert-butyl ether (500 mL × 2) to remove impurities. The aqueous phase was added dropwise to aqueous hydrochloric acid (3M, 800 mL) and the system temperature was maintained from 0 to 5 °C. The reaction mixture was extracted with EtOAc (EtOAc)EtOAc.

^{_{1 H NMR (400MHz, CDCl 3}} ): δ7.50 (dd, J = 6.4Hz, 2.4Hz, 1H), 7.23-7.16 (m, 1H), 7.00 (t, J = 8.4Hz, 1H), 3.48 ( s, 1H).

The third step: 2-((3-bromo-4-fluorophenyl)thio)acetonitrile

Bromine acetonitrile (1.74 g, 14.5 mmol) was dissolved in N,N-dimethylformamide (10 mL), then 4-fluoro-3-bromothiophenol (1.50 g, 7.25 mmol) A solution of N,N-dimethylformamide (5 mL) was added to the reaction mixture, and finally cesium carbonate (4.73 g, 14.5 mmol) was added and reacted at room temperature. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (30 mL), brine, brine, evaporated, evaporated. Ethyl ester = 3:1) 2-((3-bromo-4-fluorophenyl)thio)acetonitrile (1.0 g, yellow oil, yield: 56%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ7.81 (dd, J = 6.4Hz, 2.4Hz, 1H), 7.58-7.54 (m, 1H), 7.18 (t, J = 8.4Hz, 1H), 3.57 ( s, 2H).

Step 4: 2-((3-Bromo-4-fluorophenyl)sulfonyl)acetonitrile

2-((3-Bromo-4-fluorophenyl)thio)acetonitrile (0.50 g, 2.03 mmol) was dissolved in dichloromethane (10 mL) and then m-chloroperoxybenzoic acid ( 0.93 g, 4.06 mmol) was added to the reaction system and stirred at room temperature overnight. After the reaction, the reaction mixture was diluted with methylene chloride (25 mL), EtOAc (EtOAc) Isolated to give 2-((3-bromo-4-fluorophenyl)sulfonyl)acetonitrile (0.30 g,yield:yield: 53%).

Step 5: 2-((3-Bromo-4-(2,4-difluorophenoxy)phenyl)sulfonyl)acetonitrile

2-((3-Bromo-4-fluorophenyl)sulfonyl)acetonitrile (0.29 g, 1.04 mmol), 2,4-difluorophenol (0.41 g, 3.12 mmol) and sodium carbonate (0.33) g, 3.12 mmol) was dissolved in dimethyl sulfoxide (5 mL), protected with nitrogen and heated to 90 ° C for two hours. After completion of the reaction, the mixture was cooled to room temperature. The mixture was diluted with ethyl acetate (35 mL). Petroleum ether: ethyl acetate = 3:1, V/V) 2-((3-bromo-4-(2,4-difluorophenoxy)phenyl)sulfonyl)acetonitrile (0.25 g, White solid, yield: 62%).

MS m/z (ESI): 386.0, 388.0 [MH] ^- .

Step 6: 2-((3-Bromo-4-(2,4-difluorophenoxy)phenyl)sulfonyl)-2-methylpropanenitrile

2-((3-Bromo-4-(2,4-difluorophenoxy)phenyl)sulfonyl)acetonitrile (0.10 g, 0.26 mmol) and cesium carbonate (0.17 g, 0.52 mmol) It was dissolved in tetrahydrofuran (10 mL), and then methyl iodide (0.5 mL) was added dropwise to the reaction mixture, and the mixture was reacted at room temperature for three hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (25 mL), EtOAc (EtOAc) 4-(2,4-Difluorophenoxy)phenyl)sulfonyl)-2-methylpropanenitrile (0.10 g, white solid) was used directly for next step.

MS m/z (ESI): 416.0, 418.0 [M+H] ⁺ .

Step 7: 2-((4-(2,4-Difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-4 -yl)phenyl)sulfonyl)-2-methylpropionitrile

2-((3-Bromo-4-(2,4-difluorophenoxy)phenyl)sulfonyl)-2-methylpropanenitrile (0.10 g, 0.24 mmol), 6-methyl -4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b] Pyridine (0.13 g, 0.24 mmol), potassium carbonate (0.066 g, 0.48 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.018 g, 0.024 mmol) dissolved in Dioxane (4 mL) and water (1 mL) were replaced with nitrogen three times, heated to 100 ° C overnight, cooled to room temperature, diluted with ethyl acetate (20 mL), filtered over Celite, and brine (20 mL×2 After washing, the organic phase is combined, dried over anhydrous sodium sulfate and filtered, and the crude product obtained by concentration of filtrate is separated by column chromatography ( petroleum ether: ethyl acetate = 3:1, V/V) to give 2-((4) -(2,4-difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)sulfonyl) 2-methylpropionitrile (0.12 g, yellow oil, yield: 80%).

MS m/z (ESI): 6221. [M+H] ⁺ .

Step 8: 2-((4-(2,4-Difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl) Sulfonyl-2-methylpropionitrile

2-((4-(2,4-Difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-4 at room temperature -Phenyl)sulfonyl)-2-methylpropionitrile (0.10 g, 0.16 mmol) was dissolved in ethanol (3 mL), then sodium methoxide (0.026 g, 0.48 mmol) was added to the reaction system and heated to The reaction was carried out for three hours at 50 °C. After completion of the reaction, the ethanol was evaporated to dryness, and the residue was crystallised eluted with ethyl acetate (25mL), and then washed with brine (15mL × 2) Separation by preparative plate (petroleum ether: ethyl acetate = 1:1, V/V) gave 2-((4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrole) And [2,3-b]pyridin-4-yl)phenyl)sulfonyl)-2-methylpropanenitrile (0.06 g, white solid, yield 80%).

MS m / z (ESI): 468.1 [M + H] +.

Step 9: 4-(5-((2-Cyanopropan-2-yl)sulfonyl)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1H-pyrrole And [2,3-b]pyridine-7-oxide

2-((4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl) Sulfonyl)-2-methylpropionitrile (0.06 g, 0.13 mmol) was dissolved in tetrahydrofuran (5 mL), then m-chloroperoxybenzoic acid (0.031 g, 0.15 mmol) was added to the reaction system and stirred at room temperature. After a few minutes, the reaction was diluted with EtOAc EtOAc EtOAc EtOAc. Chromatography to give 4-(5-((2-cyanopropan-2-yl)sulfonyl)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1H-pyrrole [2,3-b]pyridine-7-oxide (0.025 g, white solid, yield 40%).

MS m/z (ESI): 484.1 [M+H] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ): δ11.96 (br, 1H), 8.20-8.16 (m, 1H), 7.97-7.95 (m, 1H), 7.40 (s, 1H), 7.25-7.20 (m, 1H), 7.17-7.11 (m, 1H), 7.05-7.00 (m, 1H), 6.97-6.92 (m, 2H), 6.62 (s, 1H), 2.78 (s, 3H), 1.74 (s, 6H) .

Example 24

4-(5-((Cyanomethyl)sulfonyl)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine -7-oxide

First step: 2-((4-(2,4-difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-4 -yl)phenyl)sulfonyl)acetonitrile

Taking 2-((3-bromo-4-(2,4-difluorophenoxy)phenyl)sulfonyl)acetonitrile as the starting material, referring to the seventh step of Example 23, 2-((4-( 2,4-Difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)sulfonyl)acetonitrile (0.056 g, yellow solid, yield 37%).

MS m/z (ESI): 594.1 [M+H] ⁺ .

Second step: 2-((4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl) Sulfonyl acetonitrile

2-((4-(2,4-Difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-4 at room temperature -Phenyl)sulfonyl)acetonitrile (0.03 g, 0.051 mmol) was dissolved in N,N-dimethylformamide (2 mL), then sodium hydride (60%, 0.006 g, 0.10 mmol) After reacting for 14 hours at room temperature, the reaction mixture was diluted with ethyl acetate (40 mL), brine (15 mL×3), and the organic phase was dried over anhydrous sodium sulfate. Separation (petroleum ether: ethyl acetate = 1:1, V/V) gave 2-((4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2] , 3-b]pyridin-4-yl)phenyl)sulfonyl)acetonitrile (0.015 g, white solid, yield 68%).

MS m/z (ESI): 440.1 [M+H] ⁺ .

Third step: 4-(5-((cyanomethyl)sulfonyl)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3 -b]pyridine-7-oxide

2-((4-(2,4-Difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl) at room temperature Sulfonyl acetonitrile (0.015 g, 0.034 mmol) was dissolved in tetrahydrofuran (3 mL), then m-chloroperoxybenzoic acid (85%, 0.008 g, 0.041 mmol) was added to the reaction mixture and reacted for ten minutes. The solution was diluted with ethyl acetate (20 mL), EtOAc (EtOAc)EtOAc. Preparative chromatography to give 4-(5-((cyanomethyl)sulfonyl)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3 -b]pyridine-7-oxide (0.004 g, white solid, yield 26%).

MS m/z (ESI): 456.1 [M+H] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ): δ11.51 (br, 1H), 8.21 (s, 1H), 8.00 (d, J = 8.8Hz, 1H), 7.44 (s, 1H), 7.31 (s, 1H ), 7.16-7.07 (m, 1H), 7.04-6.94 (m, 3H), 6.65 (s, 1H), 4.12 (s, 2H), 2.80 (s, 3H).

Example 25

4-(5-((1-Cyanocyclopropyl)sulfonyl)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3- b]pyridine-7-oxide

First step: 1-((3-bromo-4-(2,4-difluorophenoxy)phenyl)sulfonyl)cyclopropane-1-carbonitrile

2-((3-Bromo-4-(2,4-difluorophenoxy)phenyl)sulfonyl)acetonitrile (0.10 g, 0.26 mmol), 1,2-dibromoethane ( 0.097 g, 0.52 mmol) and cesium carbonate (0.17 g, 0.52 mmol) were dissolved in tetrahydrofuran (8 mL) and heated to 60 ° C for 14 hours. After completion of the reaction, the reaction mixture was diluted with EtOAc EtOAc EtOAc. 1, V/V) gave 1-((3-bromo-4-(2,4-difluorophenoxy)phenyl)sulfonyl)cyclopropane-1-carbonitrile (0.08 g, m. Yield 75%).

Second step: 1-((4-(2,4-difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-4 -yl)phenyl)sulfonyl)cyclopropane-1-carbonitrile

Taking 1-((3-bromo-4-(2,4-difluorophenoxy)phenyl)sulfonyl)cyclopropane-1-carbonitrile as the starting material, refer to the seventh step of Example 23 to obtain 1- ((4-(2,4-Difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl) Sulfonylcyclopropane-1-carbonitrile (0.05 g, white solid, yield 42%).

MS m/z (ESI): 620.1 [M+H] ⁺ .

The third step: 1-((4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl) Sulfonylcyclopropane-1-carbonitrile

1-((4-(2,4-Difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)sulfonyl) Cyclopropane-1-carbonitrile was used as the starting material of the reaction. Referring to the eighth step of Example 23, 1-((4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrole was obtained. [2,3-b]pyridin-4-yl)phenyl)sulfonyl)cyclopropane-1-carbonitrile (0.01 g, white solid, yield 44%).

MS m/z (ESI): 466.1 [M+H] ⁺ .

Fourth step: 4-(5-((1-cyanocyclopropyl)sulfonyl)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1H-pyrrolo[ 2,3-b]pyridine-7-oxide

1-((4-(2,4-Difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)sulfonyl) Cyclopropane-1-carbonitrile is the starting material of the reaction, and the ninth step of Example 23 is obtained to obtain 4-(5-((1-cyanocyclopropyl)sulfonyl)-2-(2,4-difluorophenoxy). Phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.0024 g, white solid, yield 24%).

MS m/z (ESI): 4821. [M+H] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ): δ10.55 (br, 1H), 8.15 (d, J = 2.4Hz, 1H), 7.93 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.33-7.30 ( m, 2H), 7.17-7.10 (m, 1H), 7.05-7.00 (m, 1H), 6.97-6.91 (m, 2H), 6.62 (d, J = 3.2 Hz, 1H), 2.75 (s, 3H) , 1.98-1.94 (m, 2H), 1.74-1.71 (m, 2H).

Example 26

4-(2-(cyclohexanetrienoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide preparation

First step: Preparation of (3-bromo-4-fluorophenyl)(ethyl)sulfane

3-Bromo-4-fluoroaniline (19 g, 0.1 mol) and copper powder (0.96 g, 15 mmol) were dissolved in 1,2-diethyldisulfane (50 mL), and the reaction was heated to 80 °C. Isoamyl nitrite (15 g, 0.15 mmol) was slowly added dropwise to maintain the internal temperature of the reaction not higher than 90 °C. The reaction was completed and the mixture was stirred at 90 ° C for two hours. The reaction liquid is evaporated to dryness, and toluene and dilute hydrochloric acid are added to the reaction system, and the toluene phase is washed with dilute hydrochloric acid, water and saturated brine, and the organic phase is dried and evaporated to dryness, and the residue is subjected to distillation under reduced pressure to collect steam temperature 60-70 ° C. 3-Bromo-4-fluorophenyl)(ethyl)sulfane (15 g, pale yellow oil, yield 64%).

^{1 H NMR (400MHz, CDCl3)} : δ7.53 (dd, J = 6.4Hz, 2.0Hz, 1H), 7.27-7.23 (m, 1H), 7.04 (t, J = 8.4Hz, 1H), 2.90 (q , J = 7.6 Hz, 2H), 1.29 (t, J = 7.6 Hz, 3H).

The second step: preparation of 2-bromo-4-(ethylsulfonyl)-1-fluorobenzene

(3-Bromo-4-fluorophenyl)(ethyl)sulfane (4.0 g, 17.09 mmol), dissolved in dichloromethane (50 mL), m. m. A solution of dichloromethane (50 mL). After the reaction was stirred at 0 °C for one hour, the reaction solution was washed with saturated sodium thiosulfate (50 mL) and then washed with saturated aqueous sodium hydrogen carbonate (100 mL×2), water (100 mL×2) and brine (100 mL) And dried over anhydrous sodium sulfate. After concentration, the column layer (petrole ether: ethyl acetate = 3:1, V/V) eluted to give compound 2-bromo-1-fluoro-4-(ethylsulfonyl)benzene (4.0 g, yield 88%).

Third step: Preparation of 4-(5-(ethylsulfonyl)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine

2-bromo-4-(ethylsulfonyl)-1-fluorobenzene (1.0 g, 4.43 mmol), 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (1.83 g, 4.43 mmol), [1,1'-bis(diphenylphosphine) Base) ferrocene] palladium dichloride (220 mg, 0.3 mmol), potassium carbonate (1.04 g, 7.52 mmol) dissolved in 1,4-dioxane (16 mL) and water (4 mL). Stir at °C for 4 hours. After the reaction mixture was cooled to room temperature, the reaction mixture was poured into water (50 mL), and then ethyl acetate (50 mL×2), and the organic phase was combined, washed with water (100 mL), and brine (100 mL) The crude product was purified by column chromatography (petrole ether: ethyl acetate = 2:1, V/V) to afford compound 4-(5-(ethylsulfonyl)-2-fluorophenyl)- 6-Methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (1.5 g, yield 72%).

Fourth step: Preparation of 4-(5-(ethylsulfonyl)-2-fluorophenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine

4-(5-(ethylsulfonyl)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (600 mg, 1.27 mmol) was dissolved To a solution of tert-butanol (5 mL) and tetrahydrofuran (2 mL), EtOAc (3M, 3 mL). 20 mL × 2), the organic phase was combined, washed with water (40 mL) and brine (40 mL) and dried over anhydrous sodium sulfate. V) 4-(5-(ethylsulfonyl)-2-fluorophenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine (320 mg, yield 79%).

Step 5: Preparation of 4-(5-(ethylsulfonyl)-2-fluorophenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide

4-(5-(ethylsulfonyl)-2-fluorophenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine (280.0 mg, 0.88 mmol) was dissolved in tetrahydrofuran (3 mL) m-Chloroperoxybenzoic acid (284 mg, 1.32 mmol) was added at room temperature, and the mixture was stirred for 10 min. The organic phase was combined and washed with saturated aqueous sodium hydrogen sulfate (20 mL), washed with water (20 mL) and brine (20 mL) and dried over anhydrous sodium sulfate. =20:1, V/V) gave the compound 4-(5-(ethylsulfonyl)-2-fluorophenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7- Oxide (220 mg, yield 75%).

Step 6: 4-(2-(Cyclohexanetrienoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7 - Preparation of oxides

Dissolving 4-(5-(ethylsulfonyl)-2-fluorophenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (30.0 mg, 0.089 mmol) To a solution of N,N-dimethylformamide (2 mL), EtOAc (EtOAc) After stirring overnight, it was quenched with aqueous ammonium chloride (10 mL), and then ethyl acetate (10 mL×3). The organic phase was combined and washed with water (10 mL×2) and brine (10 mL) The sodium is dried and concentrated to give the compound 4-(2-(cyclohexanetrienoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3 -b]pyridine-7-oxide (15.4 mg, yield 41%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ11.75 (s, 1H), 7.98 (d, J = 2.3Hz, 1H), 7.91 (dd, J = 8.7Hz, 2.4Hz, 1H), 7.36 (d, J=3.1 Hz, 1H), 7.21–7.12 (m, 2H), 6.45 (d, J=3.3 Hz, 1H), 4.56–4.37 (m, 1H), 3.15 (q, J=7.4 Hz, 2H), 2.77 (s, 3H), 1.88 (s, 2H), 1.60 (s, 2H), 1.56 - 1.46 (m, 3H), 1.39 - 1.24 (m, 6H).

MS m/z (ESI): 415.1 [M+H] ⁺ .

Example 27

4-(2-(cycloheptatrienoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide preparation

Using cycloheptanol instead of cyclohexanol as the starting material, referring to the sixth step of Example 26, the compound 4-(2-(cycloheptatrienoxy)-5-(ethylsulfonyl)phenyl)-6- Methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (18.0 mg, yield 49%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ12.37 (s, 1H), 7.96 (d, J = 2.2Hz, 1H), 7.90 (dd, J = 8.7Hz, 2.3Hz, 1H), 7.33 (d, J = 3.2 Hz, 1H), 7.14 (s, 1H), 7.09 (d, J = 8.8 Hz, 1H), 6.40 (d, J = 3.2 Hz, 1H), 4.62-4.58 (m, 1H), 3.14 ( q, J = 7.4 Hz, 2H), 2.77 (s, 3H), 1.95-1.92 (m, 2H), 1.74-1.72 (m, 2H), 1.59-1.53 (m, 6H), 1.42 (dd, J =11.8, 5.2 Hz, 2H), 1.32 (t, J = 7.4 Hz, 3H).

MS m/z (ESI): 429.1 [M+H] ⁺ .

Example 28

4-(2-((4,4-difluorocyclohexyl)oxo)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine- Preparation of 7-oxide

Using 4,4-difluorocyclohexane-1-ol instead of cyclohexanol as the starting material, referring to the sixth step of Example 26, the compound 4-(2-((4,4-difluorocyclohexyl)oxy)) was obtained. 5-(-Ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (13.0 mg, yield 32%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ12.17 (s, 1H), 8.00 (d, J = 2.2Hz, 1H), 7.93 (dd, J = 8.7Hz, 2.3Hz, 1H), 7.34 (d, J = 3.3 Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H), 7.10 (s, 1H), 6.41 (d, J = 3.3 Hz, 1H), 4.65 (d, J = 2.5 Hz, 1H) , 3.15 (q, J = 7.4 Hz, 2H), 2.77 (s, 3H), 1.99 - 1.78 (m, 8H), 1.33 (t, J = 7.4 Hz, 3H).

MS m / z (ESI): 451.1 [M + H] +.

Example 29

4-(5-(ethylsulfonyl)-2-(3-(trifluoromethyl)phenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7 - Preparation of oxides

First step: 4-(5-(ethylsulfonyl)-2-(3-(trifluoromethyl)phenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-b Preparation of pyridine-7-oxide

4-(5-(ethylsulfonyl)-2-fluorophenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (30.0 mg, 0.089 mmol) was dissolved N-methylpyrrolidone (2 mL), 3-(trifluoromethyl)phenol ((32 mg, 0.18 mmol), cesium carbonate (87 mg, 0.267 mmol) was added under ice-cooling. It is then quenched with aqueous ammonium chloride (20 mL), and then ethyl acetate (10 mL, 3). The organic phase is combined and washed with water (10 mL×2) and brine (10 mL) Drying, concentration and preparative chromatography to give the compound 4-(5-(ethylsulfonyl)-2-(3-(trifluoromethyl)phenoxy)phenyl)-6-methyl-1H-pyrrolo[ 2,3-b]pyridine-7-oxide (11.0 mg, yield 26%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ13.38 (s, 1H), 8.14 (d, J = 2.2Hz, 1H), 7.92 (dd, J = 8.6Hz, 2.3Hz, 1H), 7.48-7.29 ( m, 3H), 7.19 (s, 1H), 7.14 (d, J = 6.1 Hz, 3H), 6.45 (d, J = 2.9 Hz, 1H), 3.19 (q, J = 7.3 Hz, 2H), 2.76 ( s, 3H), 1.40–1.28 (m, 3H).

MS m/z (ESI): 477.1 [M+H] ⁺ .

Example 30

4-(2-((3,3-Difluorocyclobutyl)methoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b] Preparation of pyridine-7-oxide

Using (3,3-difluorocyclobutyl)methanol instead of cyclohexanol as the starting material, referring to the sixth step of Example 26, the compound 4-(2-((3,3-difluorocyclobutyl)methoxy) was obtained. 5-(Ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (14.0 mg, yield 36%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.65 (s, 1H), 8.20 - 7.81 (m, 2H), 7.34 (d, J = 3.3 Hz, 1H), 7.16 (d, J = 8.7 Hz, 1H) ), 7.10 (s, 1H), 6.34 (d, J = 3.3 Hz, 1H), 4.12 (d, J = 5.7 Hz, 2H), 3.15 (q, J = 7.4 Hz, 2H), 2.78 (s, 3H) ), 2.55-2.51 (m, 3H), 2.39 - 2.16 (m, 2H), 1.32 (t, J = 7.4 Hz, 3H).

MS m/z (ESI): 437.1 [M+H] ⁺ .

Example 31

4-(2-(cyclobutyl)methoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide preparation

Starting from cyclohexanol in place of cyclohexanol, the sixth step of Example 26 was carried out to obtain the compound 4-(2-(cyclobutyl)methoxy)-5-(ethylsulfonyl)phenyl)-6. Methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (19.0 mg, yield 53%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ12.88 (s, 1H), 7.93 (d, J = 2.3Hz, 1H), 7.85 (dd, J = 8.7,2.4Hz, 1H), 7.26 (d, J =3.1 Hz, 1H), 7.13 - 7.03 (m, 2H), 6.32 (d, J = 3.2 Hz, 1H), 3.96 (d, J = 6.3 Hz, 2H), 3.07 (q, J = 7.4 Hz, 2H) ), 2.71 (s, 3H), 2.65 - 2.55 (m, 1H), 1.93-1.91 (m, 2H), 1.86 - 1.76 (m, 1H), 1.76 - 1.66 (m, 3H), 1.24 (t, J =7.4Hz, 3H).

MS m/z (ESI): 401.1 [M+H] ⁺ .

Example 32

4-(2-(2,4-difluorophenoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxidation Object

Starting from 2,4-difluorophenol instead of 3-(trifluoromethyl)phenol, referring to Example 29, the compound 4-(2-(2,4-difluorophenoxy)-5-(ethyl) was obtained. Sulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (16.0 mg, yield 40%).

¹ H NMR (400 MHz, CD ₃ OD): δ 7.97 (d, J = 2.3 Hz, 1H), 7.83 (dd, J = 8.7 Hz, 2.3 Hz, 1H), 7.33 (d, J = 3.4 Hz, 1H) ), 7.26 (s, 1H), 7.13 (td, J = 9.1 Hz, 5.4 Hz, 1H), 7.05 (ddd, J = 11.2 Hz, 8.6 Hz, 2.9 Hz, 1H), 6.96 (dd, J = 8.7 Hz) , 0.7 Hz, 1H), 6.91 - 6.84 (m, 1H), 6.46 (d, J = 3.4 Hz, 1H), 3.21 - 3.16 (m, 2H), 2.60 (s, 3H), 1.17 (q, J = 7.3Hz, 3H).

MS m/z (ESI): 445.1 [M+H] ⁺ .

Example 33

4-(2-(4-Bromo-2-fluorophenoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7- Oxide

Using 4-bromo-2-fluorophenol instead of 3-(trifluoromethyl)phenol as the starting material, referring to Example 29, the compound 4-(2-(2,4-difluorophenoxy)-5-(B) was obtained. Sulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (13.0 mg, yield 29%).

¹ H NMR (400 MHz, CD ₃ OD): δ 8.02 - 7.89 (m, 1H), 7.86 (dd, J = 8.7 Hz, 2.3 Hz, 1H), 7.38 (dd, J = 10.2 Hz, 2.3 Hz, 1H) ), 7.33 (d, J = 3.4 Hz, 1H), 7.23 (d, J = 8.9 Hz, 2H), 7.01 (dd, J = 16.8 Hz, 8.5 Hz, 2H), 6.47 - 6.38 (m, 1H), 3.21 (dd, J = 3.2 Hz, 1.6 Hz, 2H), 2.59 (s, 3H), 1.17 (t, J = 7.4 Hz, 3H).

MS m/z (ESI): 505.1 [M+H] ⁺ .

Example 34

4-(5-(ethylsulfonyl)-2-(((1s,4s)-4-hydroxycyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3-b Pyridine-7-oxide

Using (1s, 4s)-cyclohexane-1,4-diol instead of cyclohexanol as the starting material, referring to the sixth step of Example 26, the compound 4-(5-(ethylsulfonyl)-2-(( (1s, 4s)-4-hydroxycyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (4.5 mg, yield 12%) .

¹ H NMR (400 MHz, CDCl ₃ ): δ 11.98 (s, 1H), 8.1 (d, J = 2.4 Hz, 1H), 7.91 (dd, J = 8.7 Hz, 2.4 Hz, 1H), 7.29 (d, J = 3.3 Hz, 1H), 7.15 (dd, J = 17.3 Hz, 8.4 Hz, 2H), 6.43 (d, J = 3.3 Hz, 1H), 4.55 (s, 1H), 3.70 (d, J = 8.6 Hz) , 1H), 3.15 (q, J = 7.4 Hz, 2H), 2.77 (d, J = 9.0 Hz, 3H), 2.01 - 1.89 (m, 2H), 1.72 - 1.57 (m, 4H), 1.50 - 1.37 ( m, 2H), 1.34–1.28 (m, 3H).

MS m/z (ESI): 431.1 [M+H] ⁺ .

Example 35

4-(2-(4-cyclopropylphenoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide

Using 4-cyclopropylphenol instead of 3-(trifluoromethyl)phenol as a starting material, referring to Example 29, the compound 4-(2-(4-cyclopropylphenoxy)-5-(ethylsulfonyl) was obtained. Phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (10.0 mg, yield 25%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ12.16 (s, 1H), 8.06 (d, J = 2.2Hz, 1H), 7.81 (dd, J = 8.7Hz, 2.3Hz, 1H), 7.30 (d, J = 3.3 Hz, 1H), 7.16 (s, 1H), 7.07 (d, J = 8.6 Hz, 2H), 7.01 (d, J = 8.7 Hz, 1H), 6.90 (d, J = 8.6 Hz, 2H) , 6.49 (d, J = 3.3 Hz, 1H), 3.15 (q, J = 7.4 Hz, 2H), 2.74 (s, 3H), 1.89 (td, J = 8.4 Hz, 4.2 Hz, 1H), 1.33 (t , J = 7.4 Hz, 3H), 1.03 - 0.92 (m, 2H), 0.71 - 0.61 (m, 2H).

MS m/z (ESI): 449.1 [M+H] ⁺ .

Example 36

4-(5-(ethylsulfonyl)-2-((1-(trifluoromethyl)cyclopropyl)methoxy)phenyl)-6-methyl-1H-pyrrolo[2,3- b]pyridine-7-oxide

Using (1-(trifluoromethyl)cyclopropyl)methanol instead of cyclohexanol as the starting material, referring to the sixth step of Example 26, the compound 4-(5-(ethylsulfonyl)-2-((1- (Trifluoromethyl)cyclopropyl)methoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (20.9 mg, yield 52%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ13.12 (s, 1H), 8.04 (d, J = 2.3Hz, 1H), 7.93 (dd, J = 8.7Hz, 2.3Hz, 1H), 7.34 (d, J = 3.3 Hz, 1H), 7.22 (s, 1H), 7.13 (d, J = 8.8 Hz, 1H), 6.38 (d, J = 3.3 Hz, 1H), 4.20 (s, 2H), 3.14 (q, J = 7.4 Hz, 2H), 2.78 (s, 3H), 1.31 (t, J = 7.4 Hz, 3H), 1.02 (t, J = 6.2 Hz, 2H), 0.73 (s, 2H).

MS m/z (ESI): 455.1 [M+H] ⁺ .

Example 37

4-(2-((4,4-Dimethylcyclohexyl)oxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine -7-oxide

Using 4,4-dimethylcyclohexane-1-ol instead of cyclohexanol as the starting material, referring to the sixth step of Example 26, the compound 4-(2-((4,4-dimethylcyclohexyl))oxy) was obtained. 5)(Ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (10.0 mg, yield 25%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ11.97 (s, 1H), 7.99 (d, J = 2.3Hz, 1H), 7.89 (dd, J = 8.7Hz, 2.3Hz, 1H), 7.29 (d, J=3.3 Hz, 1H), 7.17–7.11 (m, 2H), 6.42 (d, J=3.3 Hz, 1H), 4.44 (dd, J=7.3 Hz, 3.7 Hz, 1H), 3.14 (q, J= 7.4 Hz, 2H), 2.77 (s, 3H), 1.83 - 1.75 (m, 2H), 1.62 (ddd, J = 16.8 Hz, 12.7 Hz, 3.8 Hz, 2H), 1.38 - 1.27 (m, 5H), 1.19 (ddd, J = 13.2, 9.0, 3.9 Hz, 2H), 0.91 (s, 3H), 0.83 (s, 3H).

MS m/z (ESI): 443.1 [M+H] ⁺ .

Example 38

4-(2-(4-Chloro-2-fluorophenoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7- Oxide

4-Chloro-2-fluorophenol was used instead of 3-(trifluoromethyl)phenol as the starting material, and Example 29 was obtained to obtain the compound 4-(2-(4-chloro-2-fluorophenoxy)-5-( Ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (13.2 mg, yield 32%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ12.28 (s, 1H), 8.10 (s, 1H), 7.87 (d, J = 8.5Hz, 1H), 7.31 (s, 1H), 7.26 (s, 1H ), 7.22 (d, J = 7.5 Hz, 1H), 7.13 (d, J = 8.7 Hz, 1H), 7.02 (t, J = 8.4 Hz, 1H), 6.95 (d, J = 8.6 Hz, 1H), 6.50 (d, J = 2.5 Hz, 1H), 3.16 (q, J = 7.3 Hz, 2H), 2.77 (s, 3H), 1.34 (t, J = 7.3 Hz, 3H).

MS m/z (ESI): 461.1 [M+H] ⁺ .

Example 39

4-(2-((1H-吲哚-6-yl)oxo)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine- 7-oxide

Using 1H-indole-6-phenol instead of 3-(trifluoromethyl)phenol as a starting material, referring to Example 29, the compound 4-(2-((1H-indol-6-yl)oxy)-5 was obtained. -(Ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (12.2 mg, yield 31%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ12.75 (s, 1H), 8.97 (s, 1H), 8.05 (s, 1H), 7.75 (d, J = 8.7Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.31 - 7.16 (m, 3H), 7.09 (s, 1H), 6.98 (d, J = 8.8 Hz, 1H), 6.80 (d, J = 8.5 Hz, 1H), 6.50 (d , J = 8.4 Hz, 2H), 3.14 (q, J = 7.3 Hz, 2H), 2.68 (s, 3H), 1.31 (t, J = 7.4 Hz, 3H).

MS m/z (ESI): 448.1 [M+H] ⁺ .

Example 40

4-(2-(4-carbamoylphenoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide

Using 4-hydroxybenzamide instead of 3-(trifluoromethyl)phenol as a starting material, referring to Example 29, the compound 4-(2-(4-carbamoylphenoxy)-5-(ethylsulfonyl) was obtained. Phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (22.2 mg, 55% yield).

¹ H NMR (400 MHz, CD ₃ OD): δ 8.04 (d, J = 2.3 Hz, 1H), 7.94 (dd, J = 8.6 Hz, 2.3 Hz, 1H), 7.72 (d, J = 2.1 Hz, 1H) ), 7.71 (d, J = 2.1 Hz, 1H), 7.35 (d, J = 3.4 Hz, 1H), 7.27 (d, J = 8.6 Hz, 1H), 7.22 (s, 1H), 6.98 - 6.84 (m) , 2H), 6.47 (d, J = 3.4 Hz, 1H), 3.25 (s, 3H), 2.56 (s, 3H), 1.21 (t, J = 7.4 Hz, 4H).

MS m/z (ESI): 4521. [M+H] ⁺ .

Example 41

4-(2-(4-(tert-butyl)phenoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7 -oxide

Using 4-hydroxybenzamide instead of 3-(trifluoromethyl)phenol as a starting material, referring to Example 29, the compound 4-(2-(4-(tert-butyl)phenoxy)-5-(ethyl) was obtained. Sulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (22.5 mg, yield 55%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ13.22 (s, 1H), 8.10 (d, J = 2.3Hz, 1H), 7.83 (dd, J = 8.7Hz, 2.3Hz, 1H), 7.37 (d, J = 8.7 Hz, 2H), 7.32 (d, J = 3.2 Hz, 1H), 7.21 (s, 1H), 7.06 (d, J = 8.7 Hz, 1H), 6.95 (d, J = 8.7 Hz, 2H) , 6.49 (d, J = 3.2 Hz, 1H), 3.16 (q, J = 7.4 Hz, 2H), 2.77 (s, 3H), 1.36 - 1.23 (m, 12H).

MS m/z (ESI): 465.1 [M+H] ⁺ .

Example 42

4-(5-(ethylsulfonyl)-2-(thiophen-3-ylmethoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide

Using thiophen-3-ylmethanol instead of cyclohexanol as the starting material, referring to the sixth step of Example 26, the compound 4-(5-(ethylsulfonyl)-2-(thiophen-3-ylmethoxy)phenyl was obtained. 6-Methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (20.0 mg, yield 53%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.25 (s, 1H), 8.1 (d, J = 2.3 Hz, 1H), 7.94 (dd, J = 8.7 Hz, 2.3 Hz, 1H), 7.32 - 7.27 ( m, 2H), 7.25 (d, J = 8.8 Hz, 1H), 7.21 - 7.04 (m, 2H), 7.08 - 6.86 (m, 1H), 6.39 (d, J = 3.3 Hz, 1H), 5.21 (s) , 2H), 3.15 (q, J = 7.4 Hz, 2H), 2.75 (s, 3H), 1.32 (t, J = 7.4 Hz, 3H).

MS m/z (ESI): 429.1 [M+H] ⁺ .

Example 43

4-(2-(4-Cyclopropyl-2-fluorophenoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine- 7-oxide

Using 4-cyclopropyl-2-fluorophenol instead of 3-(trifluoromethyl)phenol as a starting material, referring to Example 29, the compound 4-(2-(4-cyclopropyl-2-fluorophenoxy) was obtained. 5-(Ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (10.5 mg, yield 25%).

¹ H NMR (400 MHz, CD ₃ OD): δ 8.09 (d, J = 2.3 Hz, 1H), 7.94 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.46 (d, J = 3.4 Hz, 1H) ), 7.39 (s, 1H), 7.07 (dt, J = 8.5 Hz, 4.7 Hz, 2H), 7.02 - 6.92 (m, 2H), 6.60 (d, J = 3.5 Hz, 1H), 3.29 (q, J) = 7.4 Hz, 2H), 2.73 (s, 3H), 1.95 (dq, J = 8.5 Hz, 5.1 Hz, 1H), 1.29 (t, J = 7.4 Hz, 3H), 1.09 - 0.93 (m, 2H), 0.83–0.55 (m, 2H).

MS m/z (ESI): 467.1 [M+H] ⁺ .

Example 44

4-(2-((1H-indol-5-yl)oxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine- 7-oxide

Using 1H-indole-5-phenol instead of 3-(trifluoromethyl)phenol as a starting material, referring to Example 29, the compound 4-(2-((1H-indol-5-yl)oxy)-5 was obtained. -(Ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (10.0 mg, yield 25%).

¹ H NMR (400 MHz, CD ₃ OD): δ 8.08 (d, J = 2.3 Hz, 1H), 7.78 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.46 (dd, J = 15.7 Hz, 6.6 Hz, 3H), 7.30 (dd, J = 9.4 Hz, 2.7 Hz, 2H), 7.05 (d, J = 8.8 Hz, 1H), 6.87 (dd, J = 8.7 Hz, 2.3 Hz, 1H), 6.66 (d , J = 3.4 Hz, 1H), 6.46 (dd, J = 3.1 Hz, 0.8 Hz, 1H), 3.27 (q, J = 7.4 Hz, 2H), 2.74 (s, 3H), 1.29 (t, J = 7.4) Hz, 3H).

MS m/z (ESI): 448.1 [M+H] ⁺ .

Example 45

4-(5-(ethylsulfonyl)-2-(4-(trifluoromethyl)phenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7 -oxide

4-(Trifluoromethyl)phenol was used as a starting material instead of 3-(trifluoromethyl)phenol. Referring to Example 29, the compound 4-(5-(ethylsulfonyl)-2-(4-trifluoro) was obtained. Methyl)phenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (8.0 mg, yield 19%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ12.55 (s, 1H), 8.12 (s, 1H), 7.99 (d, J = 8.6Hz, 1H), 7.66 (d, J = 7.9Hz, 2H), 7.53 (d, J = 10.9 Hz, 1H), 7.27 (s, 1H), 7.19 (d, J = 8.6 Hz, 1H), 7.10 (d, J = 8.1 Hz, 2H), 6.61 (s, 1H), 3.20 (d, J = 6.9 Hz, 2H), 2.90 (s, 3H), 1.37 (t, J = 6.3 Hz, 3H).

MS m/z (ESI): 477.1 [M+H] ⁺ .

Example 46

4-(5-(ethylsulfonyl)-2-(((1r,4r)-4-hydroxycyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3-b Pyridine-7-oxide

Using (1r,4r)-cyclohexane-1,4-diol instead of 3-(trifluoromethyl)phenol as a starting material, referring to Example 29, the compound 4-(5-(ethylsulfonyl)-2 was obtained. -(((1r,4r)-4-hydroxycyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (3.0 mg, yield 8%).

¹ H NMR (400 MHz, CD ₃ OD): δ 7.85 (dt, J = 5.7 Hz, 2.4 Hz, 2H), 7.29 (dd, J = 34.4 Hz, 31.1 Hz, 2H), 7.17 (s, 1H), 6.34 (d, J = 3.4 Hz, 1H), 4.56 - 4.38 (m, 1H), 3.60 - 3.37 (m, 1H), 3.14 (q, J = 7.4 Hz, 2H), 2.60 (s, 3H), 2.01 –1.91 (m, 2H), 1.75–1.52 (m, 2H), 1.33 (td, J = 13.2 Hz, 2.7 Hz, 4H), 1.16 (t, J = 7.4 Hz, 3H).

MS m/z (ESI): 431.1 [M+H] ⁺ .

Example 47

4-(2-((1H-carbazol-5-yl)oxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine- 7-oxide

Using 1H-carbazole-5-ol instead of 3-(trifluoromethyl)phenol as a starting material, referring to Example 29, the compound 4-(2-((1H-indazol-5-yl)oxy)-5 was obtained. -(Ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (5.0 mg, yield 13%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ11.98 (br, 1H), 8.10 (d, J = 2.3Hz, 1H), 8.04 (s, 1H), 7.86 (dd, J = 8.7Hz, 2.3Hz, 1H), 7.53 (t, J = 6.3 Hz, 1H), 7.40 (dd, J = 12.1 Hz, 2.6 Hz, 2H), 7.29 (s, 1H), 7.09 (dd, J = 8.9 Hz, 2.2 Hz, 1H) ), 7.02 (t, J = 8.7 Hz, 1H), 6.59 (d, J = 3.4 Hz, 1H), 3.17 (q, J = 7.4 Hz, 2H), 2.78 (s, 3H), 1.35 (t, J) =7.4Hz, 3H).

MS m/z (ESI): 449.1 [M+H] ⁺ .

Example 48

4-(5-(ethylsulfonyl)-2-((1-methylcyclopropyl)methoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine- 7-oxide

Using (1-methylcyclopropyl)methanol instead of cyclohexanol as the starting material, referring to the sixth step of Example 26, the compound 4-(5-(ethylsulfonyl)-2-((1-methylcyclopropane) was obtained. Methoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (15.0 mg, yield 42%).

¹ H NMR (400 MHz, CD ₃ OD): δ 7.98 - 7.77 (m, 2H), 7.33 (d, J = 3.4 Hz, 1H), 7.29 - 7.15 (m, 2H), 6.37 (d, J = 3.4) Hz, 1H), 3.84 (s, 2H), 3.14 (q, J = 7.4 Hz, 2H), 2.62 (s, 3H), 1.16 (t, J = 7.4 Hz, 3H), 0.89 (s, 3H), 0.37 (t, J = 5.0 Hz, 2H), 0.20 (t, J = 5.1 Hz, 2H).

MS m/z (ESI): 401.1 [M+H] ⁺ .

Example 49

4-(5-(ethylsulfonyl)-2-((1-methyl-1H-indol-5-yl)oxy)phenyl)-6-methyl-1H-pyrrolo[2,3 -b]pyridine-7-oxide

Using 1-methyl-1H-indol-5-phenol instead of 3-(trifluoromethyl)phenol as a starting material, referring to Example 29, the compound 4-(5-(ethylsulfonyl)-2-(( 1-methyl-1H-indol-5-yl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (10.0 mg, yield 24 %).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ11.38 (s, 1H), 8.08 (d, J = 2.3Hz, 1H), 7.77 (dd, J = 8.8Hz, 2.3Hz, 1H), 7.33-7.29 ( m, 4H), 7.12 (d, J = 3.1 Hz, 1H), 7.01 - 6.81 (m, 2H), 6.59 (d, J = 3.4 Hz, 1H), 6.46 (d, J = 3.0 Hz, 1H), 3.82 (s, 3H), 3.15 (q, J = 7.4 Hz, 2H), 2.75 (s, 3H), 1.33 (t, J = 7.4 Hz, 4H).

MS m/z (ESI): 4621. [M+H] ⁺ .

Example 50

4-(2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[ 2,3-b]pyridine-7-oxide

Using 1H-pyrrolo[2,3-b]pyridine-5-phenol instead of 3-(trifluoromethyl)phenol as a starting material, referring to Example 29, the compound 4-(2-((1H-pyrrolo[2]] ,3-b]pyridin-5-yl)oxo)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide ( 12.0 mg, yield 25%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ12.38 (s, 1H), 10.25 (s, 1H), 8.13 (t, J = 14.3Hz, 2H), 7.84 (dd, J = 8.7Hz, 2.3Hz, 1H), 7.66 (d, J = 1.5 Hz, 1H), 7.43 (d, J = 2.6 Hz, 1H), 7.35 (d, J = 3.2 Hz, 1H), 7.28 (s, 1H), 7.00 (d, J=8.7 Hz, 1H), 6.56 (d, J=3.3 Hz, 1H), 6.49 (d, J=2.7 Hz, 1H), 3.17 (q, J=7.4 Hz, 2H), 2.79 (s, 3H) , 1.34 (t, J = 7.4 Hz, 3H).

MS m/z (ESI): 449.1 [M+H] ⁺ .

Example 51

4-(5-(ethylsulfonyl)-2-((trans)-4-methylcyclohexyl)amino)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine -7-oxide

Using trans-4-methylcyclohexylamine instead of cyclohexanol as the starting material, referring to the sixth step of Example 26, 4-(5-(ethylsulfonyl)-2-((trans)-4-methyl was obtained. Cyclohexyl)amino)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.050 g, white solid, yield 60%).

MS m/z (ESI): 428.2 [M+H]+.

^{_{1 H NMR (400MHz, CD 3}} OD): δ12.35 (br, 1H), 7.76 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.65 (d, J = 2.0Hz, 1H), 7.35 (d , J = 3.2 Hz, 1H), 7.04 (s, 1H), 6.78 (d, J = 8.8 Hz, 1H), 6.35 (d, J = 3.2 Hz, 1H), 4.27 (d, J = 7.2 Hz, 1H) ), 3.37-3.25 (m, 1H), 3.09 (q, J = 7.2 Hz, 2H), 2.77 (s, 3H), 2.03-1.90 (m, 4H), 1.74-1.72 (m, 2H), 1.30 ( t, J = 7.2 Hz, 3H), 1.10-0.96 (m, 3H), 0.90 (d, J = 6.8 Hz, 3H).

Example 52

4-(2-((trans)-4-(tert-butyl)cyclohexyl)oxo)-5-(ethanesulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3- b]pyridine-7-oxide

Using trans-4-tert-butylcyclohexanol instead of cyclohexanol as the starting material, referring to the sixth step of Example 26, 4-(2-((trans)-4-(tert-butyl)cyclohexyl)oxo)- 5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine 7-oxidation (0.040 g, white solid, yield 57%).

MS m/z (ESI): 471.2 [M+H] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ): δ12.63 (s, 1H), 7.97 (d, J = 2.0Hz 1H), 7.89 (dd, J = 8.4Hz, 2.0Hz, 1H), 7.30 (d, J =3.2 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.12 (s, 1H), 6.38 (d, J = 3.2 Hz, 1H), 4.33-4.22 (m, 1H), 3.15 (q) , J=7.2Hz, 2H), 2.77(s,3H), 2.16-2.13(m,2H),1.85-1.82(m,2H),1.34-1.25(m,5H),1.16-0.97(m,3H ), 0.85 (s, 9H).

Example 53

4-(2-((trans)-4-(ethyl)cyclohexyl)oxo)-5-(ethanesulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b Pyridine-7-oxide

First step: 4-(2-((trans)-4-(ethyl)cyclohexyl)oxo)-5-(ethanesulfonyl)phenyl)-6-methyl-1H-pyrrolo[2 ,3-b]pyridine-7-oxide

The trans-4-ethylcyclohexanol (0.077 g, 0.60 mmol) was dissolved in N,N-dimethylformamide (4 mL), then sodium hydride (60%, <RTIgt; After adding to the reaction solution, stirring at room temperature for half an hour, 4-(2-fluoro-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7- Oxide (0.04 g, 0.12 mmol) of N,N-dimethylformamide (1 mL) was added dropwise to the reaction mixture. After stirring at room temperature overnight, the reaction mixture was diluted w~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 2-((trans)-4-(ethyl)cyclohexyl)oxo-5-(ethanesulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine- 7-Oxide (0.030 g, white solid, yield 57%).

MS m/z (ESI): 443.2 [M+H] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ): δ11.81 (br, 1H), 7.95 (s, 1H), 7.89 (dd, J = 8.8Hz, 2.0Hz, 1H), 7.33 (d, J = 3.2Hz, 1H), 7.16-7.12 (m, 2H), 6.38 (d, J = 3.2 Hz, 1H), 4.35-4.25 (m, 1H), 3.13 (q, J = 7.2 Hz, 2H), 2.76 (s, 3H) ), 2.10-2.08 (m, 4H), 1.84-1.80 (m, 2H), 1.32 (t, J = 7.2 Hz, 3H), 1.25-1.16 (m, 2H), 1.14-1.05 (m, 1H), 1.04-0.95 (m, 2H), 0.87 (t, J = 7.2 Hz, 3H).

Example 54

4-(2-((trans)-4-(methyl)cyclohexyl)oxo)-5-(ethanesulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b Pyridine-7-oxide

Following the experimental procedure of Example 53, substituting trans-4-methylcyclohexanol for trans-4-ethylcyclohexanol as the starting material gave 4-(2-((trans)-4-(methyl)). Hexyl)oxo)-5-(ethanesulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine 7-oxo (0.040 g, white solid, yield 63%).

MS m/z (ESI): 429.2 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.13 (br, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.90 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 7.33 (d, J=3.2 Hz, 1H), 7.16-7.13 (m, 2H), 6.40 (d, J = 3.2 Hz, 1H), 4.35-4.27 (m, 1H), 3.14 (q, J = 7.6 Hz, 2H), 2.76(s,3H),2.09-2.05(m,2H),1.80-1.74(m,2H), 1.39-1.30(m,6H), 1.09-0.99(m,2H),0.90(t,J=6.4 Hz, 3H).

Example 55

4-(2-((trans)-4-(propyl)cyclohexyl)oxo)-5-(ethanesulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b Pyridine-7-oxide

Following the experimental procedure of Example 53, using trans-4-propylcyclohexanol in place of trans-4-ethylcyclohexanol as the starting material gave 4-(2-((trans))-4-(propyl) ring. Hexyl)oxo)-5-(ethanesulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine 7-oxo (0.030 g, white solid, yield 55%).

MS m / z (ESI): 457.2 [M + H] +.

^{_{1 H NMR (400MHz, CDCl 3}} ): δ11.67 (br, 1H), 7.96 (d, J = 2.4Hz, 1H), 7.90 (dd, J = 8.4Hz, 2.4Hz, 1H), 7.34 (d, J = 3.6 Hz, 1H), 7.17-7.14 (m, 2H), 6.42 (d, J = 3.6 Hz, 1H), 4.35-4.27 (m, 1H), 3.15 (q, J = 7.2 Hz, 2H), 2.76(s,3H), 2.10-2.07(m,2H),1.86-1.78(m,2H),1.34-1.28(m,8H),1.23-1.15(m,2H),1.04-0.95(m,2H ), 0.87 (t, J = 7.2 Hz, 3H).

Example 56

4-(2-((trans)-4-(isopropyl)cyclohexyl)oxo)-5-(ethanesulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3- b]pyridine-7-oxide

Following the experimental procedure of Example 53, substituting trans-4-isopropylcyclohexanol for trans-4-ethylcyclohexanol to give 4-(2-((trans))-4-(isopropyl) Cyclohexyl)oxo)-5-(ethanesulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine 7-oxo (0.020 g, white solid, yield 49%) ).

MS m / z (ESI): 457.2 [M + H] +.

^{_{1 H NMR (400MHz, CDCl 3}} ): δ11.70 (br, 1H), 7.96 (d, J = 2.0Hz, 1H), 7.90 (dd, J = 8.8Hz, 2.0Hz, 1H), 7.33 (d, J=3.2 Hz, 1H), 7.17-7.14 (m, 2H), 6.42 (d, J = 3.2 Hz, 1H), 4.35-4.23 (m, 1H), 3.15 (q, J = 14.8 Hz, 2H), 2.76(s,3H),2.13-2.08(m,2H),1.80-1.77(m,2H),1.51-1.39(m,1H),1.34-1.26(m,5H),1.15-1.06(m,3H ), 0.87 (t, J = 6.8 Hz, 6H).

Example 57

4-(2-((1H-carbazol-6-yl)oxo)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine- 7-oxide

According to the experimental procedure of Example 53, 1H-carbazole-6-ol was used instead of trans-4-ethylcyclohexanol to obtain 4-(2-((1H-carbazol-6-yl)oxy). 5-(Ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide.

^{_{1 H NMR (400MHz, CD 3}} OD): δ8.18 (d, J = 2.1Hz, 1H), 8.13 (dd, J = 8.3Hz, 2.1Hz, 1H), 7.99 (s, 1H), 7.90 (d , J = 8.3 Hz, 1H), 7.83 (s, 1H), 7.36 (d, J = 8.7 Hz, 1H), 7.15 - 7.05 (m, 1H), 6.87 (s, 1H), 6.53 (d, J = 8.7, 1H), 6.33 (s, 1H), 6.08-5.98 (m, 1H), 3.34 - 3.27 (m, 2H), 2.45 (s, 3H), 1.24 (t, 3H).

MS m/z (ESI): 449.1 [M+H] ⁺

Example 58

4-(2-(4-Cyanophenoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide

According to the experimental procedure of Example 53, using p-hydroxybenzoic acid instead of trans-4-ethylcyclohexanol as starting material, 4-(2-(4-cyanophenoxy)-5-(ethylsulfonyl) was obtained. Phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide.

^{1 H NMR (400MHz, MeOD)} : δ8.05 (d, J = 3.7Hz, 1H), 7.96 (d, J = 11.8Hz, 3.7Hz, 1H), 7.53-7.45 (m, 2H), 7.33 (dd , J = 9.5 Hz, 5.9 Hz, 2H), 7.17 (s, 1H), 6.95 - 6.86 (m, 2H), 6.42 (d, J = 3.4 Hz, 1H), 3.27 - 3.18 (m, 2H), 2.53 (s, 3H), 1.19 (t, J = 7.4 Hz, 3H).

MS m/z (ESI): 434.1 [M+H] ⁺

Example 59

4-(5-(ethylsulfonyl)-2-(4-(hydroxymethyl)phenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7- Oxide

Following the experimental procedure of Example 53, 4-(hydroxymethyl)phenol was used instead of trans-4-ethylcyclohexanol to give 4-(5-(ethylsulfonyl)-2-(4-(hydroxy) Methyl)phenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide.

¹ H NMR (400 MHz, CD ₃ OD): δ 8.11 (d, J = 2.3 Hz, 1H), 7.97 (dd, J = 8.7 Hz, 2.4 Hz, 1H), 7.46 (d, J = 3.4 Hz, 1H) ), 7.41 - 7.35 (m, 3H), 7.20 (d, J = 8.7 Hz, 1H), 7.02 (d, J = 8.6 Hz, 2H), 6.60 (d, J = 3.4 Hz, 1H), 4.58 (s) , 2H), 3.33–3.25 (m, 2H), 2.72 (s, 3H), 1.35–1.26 (m, 3H).

MS m/z (ESI): 439.1 [M+H] ⁺

Example 60

4-(2-(cyclopropylmethoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine 7-oxidation

Using cyclopropanol in place of cyclohexanol as a starting material, referring to the sixth step of Example 26, 4-(2-(cyclopropylmethoxy)-5-(ethylsulfonyl)phenyl)-6-methyl was obtained. -1H-pyrrolo[2,3-b]pyridine-7-oxidation (22.8 mg, yield 39.4%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ12.75 (s, 1H), 8.02 (s, 1H), 7.99 (d, J = 2.4Hz, 1H), 7.56 (d, J = 2.4Hz, 1H), 7.35(s,1H), 7.20-7.18 (d, J=8.4Hz, 1H), 6.55 (d, J=3.2Hz, 1H), 3.99–3.97 (d, J=6.8Hz, 2H), 3.19-3.13 (q, J = 7.2 Hz, 2H), 2.93 (s, 3H), 1.34 - 1.31 (t, J = 7.2 Hz, 3H), 1.18-1.16 (m, 1H), 0.62 - 0.60 (m, 2H), 0.31–0.29 (m, 2H).

MS m/z (ESI): 387.1 [M+H] ⁺ .

Example 61

4-(2-(4-(2-Amino-2-carbonylethyl)phenoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3- b]pyridine-7-oxide

Following the experimental procedure of Example 53, 2-(4-hydroxyphenyl)acetamide was used instead of trans-4-ethylcyclohexanol to give 4-(2-(4-(2-amino-2-carbonyl) Ethyl)phenoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide.

¹ H NMR (400 MHz, CD ₃ OD): δ 8.12 (d, J = 2.3 Hz, 1H), 7.99 (dd, J = 8.8 Hz, 2.3 Hz, 1H), 7.55 (d, J = 3.4 Hz, 1H) ), 7.48 (s, 1H), 7.34 (d, J = 8.6 Hz, 2H), 7.23 (d, J = 8.7 Hz, 1H), 7.03 (d, J = 8.6 Hz, 2H), 6.68 (d, J) = 3.4 Hz, 1H), 3.51 (s, 2H), 3.34 - 3.27 (m, 2H), 2.77 (s, 3H), 1.30 (t, J = 7.4 Hz, 3H).

MS m/z (ESI): 466.1 [M+H] ⁺

Example 62

6-Methyl-4-(2-((trans)-4-ethylcyclohexyl)amino)-5-(ethanesulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine- 7-oxide

First step: N-(4-ethylcyclohexyl)-2-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(ethanesulfonyl)aniline

Add 4-(2-fluoro-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.025 g) to a 10 mL microwave tube , 0.075 mmol), 4-ethylcyclohexylamine (0.3 mL) and N-methylpyrrolidone (3 mL) were heated to 140 ° C in an oil bath and allowed to react overnight and cooled to room temperature. The reaction mixture was diluted with EtOAc EtOAc (EtOAc)EtOAc. 1H-Pyrolo[2,3-b]pyridin-4-yl)-4-(ethanesulfonyl)aniline (0.050 g, yellow oil). The crude product was used directly in the next reaction.

MS m/z (ESI): 426.2 [M+H] ⁺ .

The second step: 6-methyl-4-(2-((trans)-4-ethylcyclohexyl)amino)-5-(ethanesulfonyl)phenyl)-1H-pyrrolo[2,3- b]pyridine-7-oxide

The crude product N-(4-ethylcyclohexyl)-2-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(ethanesulfonyl)aniline (0.050 g, yellow oil) was dissolved in dichloromethane (10 mL), then m-chloroperoxybenzoic acid (85%, 0.055 g, 0.27 mmol) was added to the reaction mixture and stirred at room temperature. After completion of the reaction, the reaction mixture was diluted with methylene chloride (20 mL), washed with NaHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 4-(2-((trans)-4-ethylcyclohexyl)amino)-5-(ethanesulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-7-oxide ( 0.008 g, white solid, yield 15%).

MS m / z (ESI): 442.2 [M + H] +.

^{_{1 H NMR (400MHz, CDCl 3}} ): δ12.26 (br, 1H), 7.78 (d, J = 8.8Hz 1H), 7.66 (s, 1H), 7.40 (s, 1H), 7.07 (s, 1H) , 6.79 (d, J = 8.8 Hz, 1H), 6.37 (d, J = 3.2 Hz, 1H), 4.29 (d, J = 8.0 Hz, 1H), 3.32 (br, 1H), 3.11 (q, J = 7.2 Hz, 2H), 2.78 (s, 3H), 2.05 (br, 2H), 1.86-1.73 (br, 2H), 1.31 (t, J = 7.2 Hz, 3H), 1.24-1.18 (m, 2H), 1.15-0.93 (m, 5H), 0.87 (t, J = 7.2 Hz, 3H).

Example 63

6-Methyl-4-(5-(ethanesulfonyl)-2-(((trans)-4-propylcyclohexyl)amino)phenyl)-1H-pyrrolo[2,3-b]pyridine -7-oxide

Following the experimental procedure of Example 62, 4-propylcyclohexylamine was used instead of 4-ethylcyclohexylamine to give 6-methyl-4-(2-((trans)-4-propylcyclohexyl). Amino)-5-(ethanesulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.015 g, white solid, yield 23%).

MS m/z (ESI): 456.2 [M+H] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ): δ12.25 (br, 1H), 7.76 (dd, J = 8.8Hz, 2.0Hz, 1H), 7.66 (d, J = 2.0Hz, 1H), 7.43 (d, J = 3.2 Hz, 1H), 7.09 (s, 1H), 6.81 (d, J = 8.8 Hz, 1H), 6.39 (d, J = 3.2 Hz, 1H), 4.30 (d, J = 7.2 Hz, 1H) , 3.31 (br, 1H), 3.10 (q, J = 7.2 Hz, 2H), 2.79 (s, 3H), 2.05 (br, 2H), 1.80-1.78 (m, 2H), 1.32-1.29 (m, 5H) ), 1.20-1.17 (m, 3H), 1.04-1.00 (m, 4H), 0.87 (t, J = 7.6 Hz, 3H).

Example 64

6-Methyl-4-(5-(ethanesulfonyl)-2-(((cis)-4-propylcyclohexyl)amino)phenyl)-1H-pyrrolo[2,3-b]pyridine -7-oxide

Following the experimental procedure of Example 62, 4-propylcyclohexylamine was used instead of 4-ethylcyclohexylamine to give 6-methyl-4-(2-((cis)-4-propylcyclohexyl). Amino)-5-(ethanesulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.010 g, white solid, yield 15%).

MS m/z (ESI): 456.2 [M+H] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ): δ11.92 (br, 1H), 7.76 (d, J = 9.2Hz, 1H), 7.69 (s, 1H), 7.43 (s, 1H), 7.11 (s, 1H ), 6.80 (d, J = 9.2 Hz, 1H), 6.47 (d, J = 2.8 Hz, 1H), 4.53 (d, J = 6.4 Hz, 1H), 3.65 (br, 1H), 3.11 (q, J) = 7.2 Hz, 2H), 2.79 (s, 3H), 1.64-1.49 (m, 6H), 1.33-1.22 (m, 6H), 1.14-1.08 (m, 2H), 1.01-0.90 (m, 2H), 0.86 (t, J = 7.6 Hz, 3H).

Example 65

6-Methyl-4-(2-((cis)-4-ethylcyclohexyl)amino)-5-(ethanesulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine- 7-oxide

Referring to the experimental procedure of Example 62, the separation was carried out to obtain 6-methyl-4-(2-((cis)-4-ethylcyclohexyl)amino)-5-(ethanesulfonyl)phenyl)-1H. Pyrrolo[2,3-b]pyridine-7-oxide (0.008 g, white solid, yield 24%).

MS m / z (ESI): 442.2 [M + H] +.

^{_{1 H NMR (400MHz, CDCl 3}} ): δ11.96 (s, 1H), 7.76 (dd, J = 8.8Hz, 2.0Hz, 1H), 7.69 (d, J = 2.0Hz 1H), 7.33 (d, J =3.2 Hz, 1H), 7.07 (s, 1H), 6.78 (d, J = 8.8 Hz, 1H), 6.41 (d, J = 3.2 Hz, 1H), 4.56 (d, J = 6.4 Hz, 1H), 3.65 (br, 1H), 3.10 (q, J = 7.2 Hz, 2H), 2.78 (s, 3H), 1.72-1.51 (m, 6H), 1.31 (t, J = 7.2 Hz, 3H), 1.19-1.12 (m, 3H), 0.98-0.85 (m, 2H), 0.82 (t, J = 7.2 Hz, 3H).

Example 66

4-(2-(4-(Aminomethyl)phenoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7- Oxide

First step: 4-(2-(4-((tert-butoxycarbonyl)amino)methyl)phenoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H -pyrrolo[2,3-b]pyridine-7-oxide

tert-Butyl (4-hydroxybenzyl)carbamate (0.050 g, 0.224 mmol) was dissolved in N,N-dimethylformamide (2 mL), then sodium hydride (60%, 0.012) g, 0.30 mmol) was added to the reaction mixture, and stirred at room temperature for half an hour. 4-(2-Fluoro-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.05 g, 0.24 mmol) N,N-dimethylformamide (1 mL) was added dropwise to the reaction system, and heated to 80 ° C for five hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (20 mL), and brine (10 mL×2) was evaporated. Ester = 1:1, V/V) isolated (0.030 g, colourless oil, yield 37%).

MS m/z (ESI): 538.2 [M+H] ⁺ .

Second step: 4-(2-(4-(aminomethyl)phenoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b] Pyridine-7-oxide

4-(2-(4-(((tert-Butyloxy)))amino)methyl)phenoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H- Pyrrolo[2,3-b]pyridine-7-oxide (30 mg, 0.056 mmol) was dissolved in dichloromethane (2 mL), then trifluoroacetic acid (0.5 mL) was added dropwise to the reaction mixture for two hours. The reaction mixture was evaporated to dryness. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Spin-drying, the crude product was isolated by reverse phase preparative chromatography to give 4-(2-(4-(aminomethyl)phenoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrole And [2,3-b]pyridine-7-oxide (12 mg, gray solid, yield 49%).

MS m/z (ESI): 438.1 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD): δ 8.39 (br, 1H), 8.02 (d, J = 2.4 Hz, 1H), 7.90 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.34 (d) , J = 3.6 Hz, 1H), 7.28 (d, J = 8.4 Hz, 2H), 7.22 (s, 1H), 7.18 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 8.8 Hz, 2H) ), 6.46 (d, J = 3.2 Hz, 1H), 4.50 (br, 2H), 3.94 (s, 2H), 3.19 (q, J = 7.2 Hz, 2H), 2.56 (s, 3H), 1.19 (t) , J = 7.2 Hz, 3H).

Example 67

4-(2-(2,4-Difluorophenoxy)-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6-A keto-1H-pyrrolo[2,3-b]pyridine-7-oxide

First step: Preparation of S-(3-bromo-4-fluorophenyl)ethyl sulfate

2-Bromo-1-fluoro-4-iodobenzene (8.8 g, 29.3 mmol), potassium thioacetate (4.7 g, 41.1 mmol), cuprous iodide (557 mg, 2.93 mmol), 1,10-phenanthrenequinone The porphyrin (1.05 g, 5.86 mmol) was dissolved in toluene (100 mL), and the mixture was replaced with nitrogen and heated to 100 ° C overnight. The reaction was completed by LC/MS. Water (100 mL) was added to the reaction mixture, and the mixture was washed with ethyl acetate (150 mL). Ethyl ester = 10:1, V/V) gave S-(3-bromo-4-fluorophenyl)ethylsulfate (5.5 g, yield 75%).

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.81 - 7.79 (m, 1H), 7.50 - 7.48 (m, 2H), 2.45 (s, 3H).

Second step: Preparation of (3-bromo-4-fluorophenyl)(2,2,2-trifluoroethyl)sulfane

S-(3-Bromo-4-fluorophenyl)ethylsulfate (5.0 g, 16.9 mmol) was dissolved in acetonitrile / methanol (20 mL / 20 mL) mixed solvent, cesium carbonate (19.6 g, 60 mmol) was added and stirred for 5 min. Thereafter, 2-bromo-1,1,1-trifluoroethane (8.4 g, 40 mmol) was added, and the mixture was reacted at room temperature overnight. Water (100 mL) was added to the reaction mixture, and the mixture was washed with ethyl acetate (100 mL). Ethyl ester = 10:1, V/V) gave (3-bromo-4-fluorophenyl)(2,2,2-trifluoroethyl)sulfane (3.0 g, yield 52.0%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.74 - 7.72 (m, 1H), 7.47 - 7.43 (m, 1H), 7.11 - 7.05 (m, 1H), 3.42-3.35 (q, J = 9.6 Hz, 2H).

The third step: preparation of 2-bromo-1-fluoro-4-((2,2,2-trifluoroethyl)sulfonyl)benzene

(3-Bromo-4-fluorophenyl)(2,2,2-trifluoroethyl)sulfane (3.0 g, 16.9 mmol) was dissolved in dichloromethane (40 mL) and m-chloroperoxybenzoic acid ( 5.36 g, 3.12 mmol), stirred at room temperature for 2 hours. Ethyl acetate (100 mL) was added to the mixture, and the mixture was washed with saturated aqueous sodium sulfate (50 mL×2) (petroleum ether: ethyl acetate = 10:1, V/V) gave 2-bromo-1-fluoro-4-((2,2,2-trifluoroethyl)sulfonyl)benzene (2.1 g, yield 63%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ8.21-8.19 (m, 1H), 7.96-7.92 (m, 1H), 7.37-7.33 (m, 1H), 3.97-3.90 (q, J = 8.8Hz, 2H).

Fourth step: Preparation of 2-bromo-1-fluoro-4-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)benzene

2-Bromo-1-fluoro-4-((2,2,2-trifluoroethyl)sulfonyl)benzene (600 mg, 1.94 mmol) was dissolved in tetrahydrofuran / hexamethylphosphoric acid triamine (10 mL / 8 mL) Add iodomethane (5 mL), cool to -78 ° C with dry ice / acetone bath, add diisopropylamino lithium tetrahydrofuran solution (2M, 2.4 mL, 4.8 mmol), stir at -78 ° C for 30 min, then warm to Stir at -50 ° C for 20 minutes. Then, a saturated ammonium chloride solution (50 mL) was added to the reaction mixture to quench the reaction. The mixture was extracted with EtOAc (EtOAc) (EtOAc)EtOAc. 2-Bromo-1-fluoro-4-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)benzene (300 mg, yield 46%). ^{_{1 H NMR (400MHz, CDCl 3}} ): δ8.15-8.13 (m, 1H), 7.90-7.86 (m, 1H), 7.34-7.30 (m, 1H), 1.61 (s, 6H).

Step 5: 4-(2-Fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6-methyl-1-toluene Preparation of acyl-1H-pyrrolo[2,3-b]pyridine

2-Bromo-1-fluoro-4-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)benzene (930 mg, 2.66 mmol), 6-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (1.6 g, 2.93 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (39 mg, 0.05 mmol), potassium carbonate (0.74 g, 5.32 mmol) dissolved in 1,4- A mixed solvent of dioxane (32 mL) and water (8 mL) was replaced with nitrogen, heated to 100 ° C overnight, and the reaction was completed by LC/MS. Water (100 mL) was added to the reaction mixture, and the mixture was washed with ethyl acetate (100 mL). Ethyl acetate = 2:1, V/V) gave 4-(2-fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)- 6-Methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (0.88 g, yield 60.0%).

MS m/z (ESI) = 555.1 [M+H] ⁺

Step 6: 4-(2-Fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6-methyl-1H-pyrrole Preparation of [2,3-b]pyridine

4-(2-Fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6-methyl-1-toluenesulfonyl-1H - Pyrrolo[2,3-b]pyridine (880 mg, 1.59 mmol) was dissolved in tert-butanol (30 mL), and aqueous potassium hydroxide (3M, 15 mL) was added to the above solution and heated to 70 ° C overnight. After cooling to room temperature, it was diluted with ethyl acetate (80 mL), and then washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and evaporated to give 4-(2-fluoro-5-((1,1, 1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine (400 mg, yield 63.0%).

MS m/z (ESI): 401.1 [M+H] ⁺

Step 7: 4-(2-Fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6-methyl-1H-pyrrole Preparation of [2,3-b]pyridine-7-oxide

4-(2-Fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6-methyl-1H-pyrrolo[2, 3-b]pyridine (400 mg, 1.0 mmol) was dissolved in tetrahydrofuran (10 mL). m. m. Ethyl acetate (60 mL) was added to the reaction mixture, which was washed with saturated aqueous sodium sulfate (50 mL×2), then washed with brine (50 mL) 5-((1,1,1-Trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine 7-oxidation (320 mg, yield 77.0%).

MS m/z (ESI): 416.1 [M+H] ⁺

Step 8: 4-(2-(2,4-Difluorophenoxy)-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl) Preparation of -6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide

4-(2-Fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6-methyl-1H-pyrrolo[2, 3-b]pyridine-7-oxidation (120 mg, 0.29 mmol) was dissolved in N-methylpyrrolidone (3 mL), 2,4-difluorophenol (150 mg, 1.15 mmol), cesium carbonate (375 mg, 1.15 mmol), The reaction was heated to 180 ° C for 30 minutes under microwave conditions. After cooling to room temperature, ethyl acetate (50 mL) was added, and the mixture was washed with brine (50 mL). 1,V/V) gives 4-(2-(2,4-difluorophenoxy)-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl) Phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (30.0 mg, yield 20%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ11.85 (s, 1H), 8.07 (s, 1H), 7.90-7.87 (d, J = 8.8Hz, 1H), 7.52 (s, 1H), 7.26-7.23 (m, 1H), 7.15-7.09 (m, 1H), 7.04-6.99 (m, 1H), 6.96-6.92 (m, 2H), 6.56 (s, 1H), 2.60 (s, 3H), 1.64 (s) , 6H).

MS m/z (ESI): 527.0 [M+H] ⁺

Example 68

4-(2-(4-Bromo-2-fluorophenoxy)-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6- Methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide

According to the experimental procedure of the eighth step of Example 67, 4-bromo-2-fluorophenol was used instead of 2,4-difluorophenol to obtain 4-(2-(4-bromo-2-fluorophenoxy)- 5-((1,1,1-Trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7- Oxide (16.5mg, yield 23.4%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ12.35 (s, 1H), 8.11 (s, 1H), 7.89-7.86 (m, 1H), 7.41-7.35 (m, 2H), 7.32-7.28 (m, 1H), 7.21 (s, 1H), 7.01-6.94 (m, 2H), 6.49 (s, 1H), 2.77 (s, 3H), 1.62 (s, 6H).

MS m/z (ESI): 587.0 [M+H] ⁺

Example 69

4-(2-(4-Cyclopropylphenoxy)-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6-methyl -1H-pyrrolo[2,3-b]pyridine-7-oxide

Following the experimental procedure of the eighth step of Example 67, 4-(4-cyclopropylphenoxy)-5-(( 1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxidation (19.0 mg , yield 21%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ11.60 (s, 1H), 8.07 (s, 1H), 7.83-7.81 (d, J = 8.0Hz, 1H), 7.36 (s, 1H), 7.21 (s , 1H), 7.10–7.08 (d, J=8.4Hz, 2H), 7.02–7.00 (d, J=8.8Hz, 1H), 6.94–6.92 (d, J=8.8Hz, 2H), 6.50(s, 1H), 2.75 (s, 3H), 1.92 - 1.88 (m, 1H), 1.63 (s, 6H), 1.00 - 0.96 (m, 2H), 0.69 - 0.65 (m, 2H).

MS m/z (ESI): 531.0 [M+H] ⁺

Example 70

6-Methyl-4-(2-(pyridin-4-yloxy)-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-1H -pyrrolo[2,3-b]pyridine-7-oxide

According to the experimental procedure of the eighth step of Example 67, 4-hydroxypyridine was used instead of 2,4-difluorophenol to obtain 6-methyl-4-(2-(pyridin-4-yloxy)-5-( (1,1,1-Trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-7-oxide (17.5 mg, yield twenty one%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.42 (s, 1H), 8.18-8.12 (m, 2H), 7.70-7.68 (d, J = 8.4 Hz, 1H), 7.35-7.34 (d, J = 3.2 Hz, 1H), 7.28–7.26 (m, 2H), 6.75 (s, 1H), 6.27–6.25 (d, J=7.2 Hz, 2H), 6.21–6.20 (d, J=3.2 Hz, 1H), 2.68 (s, 3H), 1.69 (s, 6H).

MS m/z (ESI): 492.1 [M+H] ⁺

Example 71

6-Methyl-4-(2-((trans)-4-methylcyclohexyl)oxo)-5-((1,1,1-trifluoro-2-methylpropan-2-yl) Sulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-7-oxide

(trans)-4-methyl-cyclohexanol (178 mg, 1.56 mmol) was dissolved in N-methylpyrrolidone (2 mL), sodium hydride (63.0 mg, 1.56 mmol) was added and stirred at room temperature for 10 min, 4 -(2-Fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3- b] Pyridine 7-oxidation (65 mg, 0.16 mmol) was added to the above reaction mixture, and the mixture was reacted at room temperature for 5 hours, and the reaction was confirmed by LCMS. The reaction mixture was added ethyl acetate (50mL), then with saturated brine (50mL), dried over anhydrous sodium sulfate ,, and concentrated Purification by reverse phase preparative chromatography (C ₁₈ column, mobile phase (acetonitrile / water To give 6-methyl-4-(2-((trans)-4-methylcyclohexyl)oxo)-5-((1,1,1-trifluoro-2-methylpropane-2) -yl)sulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-7-oxide (15.0 mg, yield 19%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 11.76 (s, 1H), 7.97 (d, J = 2.4 Hz, 1H), 7.93 - 7.90 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.35 ( d, J = 3.2 Hz, 1H), 7.16 - 7.13 (m, 2H), 6.41 (d, J = 3.6 Hz, 1H), 4.36 - 4.31 (m, 1H), 2.76 (s, 3H), 2.09 - 2.07 (t, J = 5.6 Hz, 2H), 1.78 - 1.75 (m, 2H), 1.62 (s, 6H), 1.40 - 1.30 (m, 3H), 1.10 - 1.00 (m, 2H), 0.92 - 0.90 (d , J = 6.4 Hz, 3H).

MS m/z (ESI): 511.1 [M+H] ⁺

Example 72

4-(2-(((trans)-4-hydroxycyclohexyl)oxy)-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl Preparation of 6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide

The trans-1,4-cyclohexanediol (100 mg, 0.86 mmol) was dissolved in N-methylpyrrolidone (2 mL), sodium hydride (40.0 mg, 5.2 mmol) was added, and stirred at room temperature for 10 minutes, 4-( 2-fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b] Pyridine 7-oxidation (80 mg, 0.19 mmol) was added to the above reaction mixture, and the mixture was heated at 40 ° C overnight, and the reaction was completed by LCMS. Ethyl acetate (50 mL) was added to the mixture, and the mixture was washed with brine (50 mL) V) gives 4-(2-((trans)-4-hydroxycyclohexyl)oxo)-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl Phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (27.5 mg, yield 28%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.30 (s, 1H), 7.97 (d, J = 2.4 Hz, 1H), 7.94 - 7.91 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.32 ( d, J = 3.2 Hz, 1H), 7.17 - 7.14 (m, 2H), 6.39 (d, J = 3.2 Hz, 1H), 4.53 - 4.49 (m, 1H), 3.76 - 3.66 (m, 2H), 2.78 (s, 3H), 2.12 - 2.05 (m, 2H), 2.00 - 1.97 (m, 2H), 1.84 - 1.80 (m, 2H), 1.62 (s, 6H), 1.60 - 1.45 (m, 2H).

MS m/z (ESI): 513.1 [M+H] ⁺

Example 73

4-(2-(cyclopropylmethoxy)-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6-methyl-1H -pyrrolo[2,3-b]pyridine-7-oxide

Refer to Example 71, substituting (trans)-4-methyl-cyclohexanol with cyclopropylmethanol to give 4-(2-(cyclopropylmethoxy)-5-((1,1,1- Trifluoro-2-methylpropan-2-ylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (15.5 mg, yield 48.5%) ).

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.56 (s, 1H), 8.00 (d, J = 2.4 Hz, 1H), 7.94 - 7.91 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 7.35 ( d, J = 3.2 Hz, 1H), 7.18 (s, 1H), 7.13 - 7.11 (d, J = 8.8 Hz, 1H), 6.41 (d, J = 3.2 Hz, 1H), 3.97 (d, J = 6.8) Hz, 2H), 2.79 (s, 3H), 1.62 (s, 6H), 1.19 - 1.13 (m, 1H), 0.60 - 0.56 (m, 2H), 0.31 - 0.28 (m, 2H).

MS m/z (ESI): 469.1 [M+H] ⁺

Example 74

4-(2-((4,4-Difluorocyclohexyl)oxo)-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)- 6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide

Referring to Example 71, substituting 4,4-difluorocyclohexanol for (trans)-4-methyl-cyclohexanol gave 4-(2-((4,4-difluorocyclohexyl)oxo) -5-((1,1,1-Trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7 - Oxide (11.0 mg, yield 42.5%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.19 (s, 1H), 8.1 (d, J = 2.4 Hz, 1H), 7.96-7.93 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 7.34 ( d, J = 3.2 Hz, 1H), 7.17 - 7.15 (d, J = 8.8 Hz, 1H), 7.10 (s, 1H), 6.39 (d, J = 3.2 Hz, 1H), 4.72-4.64 (m, 1H) ), 2.83 (s, 3H), 2.13 - 1.70 (m, 8H), 1.63 (s, 6H).

MS m/z (ESI): 533.1 [M+H] ⁺

Example 75

6-Methyl-4-(2-(((trans)-4-methylcyclohexyl)amino)-5-((1,1,1-trifluoro-2-methylpropan-2-yl)) Sulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-7-oxide

4-(2-Fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6-methyl-1H-pyrrolo[2, 3-b]pyridine-7-oxide (70 mg, 0.17 mmol) and (trans)-4-methyl-cyclohexylamine (190 mg, 1.68 mmol) were dissolved in N-methylpyrrolidone (2 mL). N-Diisopropylethylamine (0.5 mL) was heated to 120 ° C and stirred overnight. After cooling to room temperature, ethyl acetate (50 mL) was added, and then washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated and purified by reverse phase preparative chromatography ( _C18 column, mobile phase ( Acetonitrile/water)) gives 6-methyl-4-(2-((trans)-4-methylcyclohexyl)amino)-5-((1,1,1-trifluoro-2-methyl) Propane-2-yl)sulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-7-oxide (12.0 mg, yield 14.7%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ12.62 (s, 1H), 7.77-7.74 (dd, J = 8.8Hz, 1.6Hz, 1H), 7.66 (s, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.03 (s, 1H), 7.79 - 7.77 (d, J = 9.2 Hz, 1H), 6.32 (d, J = 2.8 Hz, 1H), 4.39 - 4.37 (d, J = 7.2 Hz, 1H) ), 3.37-3.30 (m, 1H), 2.79 (s, 3H), 2.05–1.93 (m, 2H), 1.75–1.64 (m, 2H), 1.59 (s, 6H), 1.32–1.25 (m, 3H) ), 1.10 - 0.91 (m, 2H), 0.88 - 0.86 (d, J = 7.2 Hz, 3H).

MS m/z (ESI): 510.2 [M+H] ⁺

Example 76

4-(5-(isopropylsulfonyl)-2-(((trans)-4-methylcyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3- b]pyridine-7-oxide

First step: Preparation of (3-bromo-4-fluorophenyl)(isopropyl)sulfane

S-(3-Bromo-4-fluorophenyl)ethylsulfate (3.5 g, 14.1 mmol) was dissolved in acetonitrile / methanol (20 mL / 20 mL) mixed solvent, cesium carbonate (13.8 g, 43.2 mmol) was added and stirred 5 After a few minutes, 2-iodo-propane (23.8 g, 141 mmol) was added, and the mixture was stirred at room temperature overnight. Water (80 mL) was evaporated. Drying with anhydrous sodium sulfate, concentrating and purifying by silica gel column chromatography (petrole ether: ethyl acetate = 10:1, V/V) to give (3-bromo-4-fluorophenyl)(isopropyl)sulfide Alkane (3.2 g, yield 91.0%).

MS m/z (ESI): 249.0 [M+H] ⁺

Second step: Preparation of (3-bromo-4-fluorophenyl)(isopropyl)sulfane

(3-Bromo-4-fluorophenyl)(isopropyl)sulfane (3.2 g, 12.9 mmol) was dissolved in dichloromethane (50 mL) and m-chloroperoxybenzoic acid (7.8 g, 38.6 mmol). After stirring for 3 hours at room temperature, ethyl acetate (100 mL) was added, and the mixture was washed with saturated aqueous sodium carbonate (50 mL×2), then washed with brine (50 mL) Separation and purification by silica gel column chromatography (petrole ether: ethyl acetate = 10:1, V/V) afforded (3-bromo-4-fluorophenyl)(isopropyl)sulfane (2.1 g, yield: 58%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.13 - 8.10 (m, 1H), 7.86 - 7.82 (m, 1H), 7.34 - 7.27 (m, 1H), 3.24 - 3.18 (m, 1H), 1.31 ( d, J = 6.8 Hz, 6H).

Third step: Preparation of 4-(2-fluoro-5-(isopropylsulfonyl)phenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine

(3-Bromo-4-fluorophenyl)(isopropyl)sulfane (1.00 g, 3.56 mmol), 6-methyl-4-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (1.76 g, 2.93 mmol), [1,1'-bis(diphenyl) a phosphinyl) ferrocene] palladium dichloride (32 mg, 0.18 mmol), potassium carbonate (1.47 g, 10.68 mmol) dissolved in a mixed solvent of 1,4-dioxane (30 mL) and water (10 mL) The nitrogen gas was replaced, heated to 100 ° C and stirred for 4 hours, and the reaction was confirmed by LC/MS. Water (100 mL) was added to the reaction mixture, and the mixture was washed with ethyl acetate (100 mL). Ethyl ester = 2:1, V/V) gave 4-(2-fluoro-5-(isopropylsulfonyl)phenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2, 3-b]pyridine (0.70 g, yield 40%).

MS m/z (ESI): 487.1 [M+H] ⁺

Fourth step: Preparation of 4-(2-fluoro-5-(isopropylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine

4-(2-Fluoro-5-(isopropylsulfonyl)phenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (700 mg, 1.44 mmol) Dissolved in tert-butanol (30 mL), potassium hydroxide solution (3M, 15 mL) was added to the above solution, and the mixture was stirred at 70 ° C overnight. After cooling to room temperature, ethyl acetate (60 mL) was added, and the organic layer was washed with brine (50 mL×2). Sulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine (450 mg, yield 94%).

MS m/z (ESI): 333.1 [M+H] ⁺

Step 5: Preparation of 4-(2-fluoro-5-(isopropylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine 7-oxidation

4-(2-Fluoro-5-(isopropylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine (450 mg, 1.36 mmol) was dissolved in tetrahydrofuran (5 mL) m-Chloroperoxybenzoic acid (411 mg, 2.03 mmol) was added, and the mixture was stirred at room temperature for 1 hour, and the reaction was confirmed by LC/MS. Ethyl acetate (80 mL) was added to the mixture, and the mixture was washed with saturated sodium sulfate (50 mL×2) -5-(Isopropylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine 7-oxidation (400 mg, yield 85%).

MS m/z (ESI): 348.1 [M+H] ⁺

Step 6: 4-(5-(Isopropylsulfonyl)-2-(((trans)-4-methylcyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[ Preparation of 2,3-b]pyridine 7-oxidation

Trans-4-methylcyclohexanol (200 mg, 1.77 mmol) was dissolved in N-methylpyrrolidone (2 mL), sodium hydride (100 mg, 2.5 mmol) was added and stirred at room temperature for 10 min, 4-(2- Fluoro-5-(isopropylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine 7-oxidation (70 mg, 0.20 mmol) was added to the above reaction solution, and reacted at room temperature. After 3 hours, the LCMS assay was complete. To the reaction solution was added ethyl acetate (50mL), the organic phase was washed with saturated brine (50mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification by reverse phase preparative chromatography (C ₁₈ column, mobile phase (acetonitrile / water )) 4-(5-(isopropylsulfonyl)-2-(((trans)-4-methylcyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2] , 3-b]pyridine-7-oxide (21.0 mg, yield 24%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.08 (s, 1H), 7.94 (d, J = 2.4 Hz, 1H), 7.88-7.86 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.32 ( d, J = 3.2 Hz, 1H), 7.16 - 7.13 (m, 2H), 6.40 (d, J = 3.2 Hz, 1H), 4.34 - 4.28 (m, 1H), 3.24 - 3.17 (m, 1H), 2.76 (s, 3H), 2.08–2.01 (m, 2H), 1.77–1.74 (m, 2H), 1.39–1.25 (m, 9H), 1.09–1.02 (m, 2H), 0.91-0.90 (d, J= 6.4 Hz, 3H).

MS m/z (ESI): 443.1 [M+H] ⁺

Example 77

4-(2-(((trans)-4-ethylcyclohexyl)oxy)-5-(isopropylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3- b]pyridine-7-oxide

Referring to the sixth step of Example 76, substituting (trans)-4-ethyl-cyclohexanol for (trans)-4-methyl-cyclohexanol gives 4-(2-((trans))- 4-ethylcyclohexyl)oxo)-5-(isopropylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (14.0 mg, Yield 25.5%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ12.09 (s, 1H), 7.94 (d, J = 2.4Hz, 1H), 7.89-7.86 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.34 ( d, J = 3.6 Hz, 1H), 7.16 - 7.14 (m, 2H), 6.41 (d, J = 3.2 Hz, 1H), 4.34 - 4.29 (m, 1H), 3.24 - 3.17 (m, 1H), 2.76 (s, 3H), 2.25–2.17 (m, 2H), 1.84–1.81 (m, 2H), 1.37–1.32 (m, 8H), 1.28–1.22 (m, 3H), 1.05–0.99 (m, 2H) , 0.89-0.85 (t, J = 7.2 Hz, 3H).

MS m/z (ESI): 457.2 [M+H] ⁺

Example 78

4-(5-(isopropylsulfonyl)-2-(((trans)-4-propylcyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3- b]pyridine-7-oxide

Referring to the sixth step of Example 76, 4-(2-fluoro-5-(isopropylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxidation The material is used as a starting material, and (trans)-4-methyl-cyclohexanol is substituted with (trans)-4-propyl-cyclohexanol to give 4-(5-(isopropylsulfonyl)-2-( ((trans)-4-propylcyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (11.0 mg, yield 21.5%) ).

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.34 (s, 1H), 7.95 (d, J = 2.4 Hz, 1H), 7.88-7.85 (dd, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz, 1H ), 7.31 (d, J = 3.6 Hz, 1H), 7.16 - 7.13 (m, 2H), 6.39 (d, J = 3.2 Hz, 1H), 4.33 - 4.28 (m, 1H), 3.24 - 3.17 (m, 1H), 2.76 (s, 3H), 2.10–2.00 (m, 2H), 1.82–1.79 (m, 2H), 1.37–1.20 (m, 11H), 1.19–1.14 (m, 2H), 1.05–0.99 ( m, 2H), 0.89-0.85 (t, J = 7.2 Hz, 3H).

MS m/z (ESI): 471.2 [M+H] ⁺

Example 79

4-(2-(((trans)-4-isopropylcyclohexyl)oxy)-5-(isopropylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3 -b]pyridine-7-oxide

Referring to the sixth step of Example 76, substituting (trans)-4-isopropyl-cyclohexanol for (trans)-4-methyl-cyclohexanol gives 4-(2-((trans)) 4-isopropylcyclohexyl)oxo)-5-(isopropylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (16.6 Mg, yield 28.0%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ11.84 (s, 1H), 7.95 (d, J = 2.4Hz, 1H), 7.89-7.86 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.36 ( d, J = 3.6 Hz, 1H), 7.17 - 7.14 (m, 2H), 6.43 (d, J = 3.2 Hz, 1H), 4.31 - 4.27 (m, 1H), 3.23 - 3.19 (m, 1H), 2.76 (s, 3H), 2.14–2.11 (m, 2H), 1.80–1.78 (m, 2H), 1.46–1.43 (m, 1H), 1.35–1.26 (m, 8H), 1.12–1.06 (m, 3H) , 0.87-0.85 (d, J = 6.4 Hz, 6H).

MS m/z (ESI): 471.2 [M+H] ⁺

Example 80

4-(5-(isopropylsulfonyl)-2-(((trans)-4-methylcyclohexyl)amino)phenyl)-6-methyl-1H-pyrrolo[2,3-b Pyridine-7-oxide

4-(2-Fluoro-5-(isopropylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (80 mg, 0.24 mmol) and (trans)-4-methyl-cyclohexylamine (1 mL) was dissolved in N-methylpyrrolidone (2 mL), and stirred at 140 ° C for 5 hours. To the reaction solution was added ethyl acetate (50mL), the organic phase was washed with saturated brine (50mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification by reverse phase preparative chromatography (C ₁₈ column, mobile phase (acetonitrile / water )) 4-(5-(isopropylsulfonyl)-2-(((trans)-4-methylcyclohexyl)amino)phenyl)-6-methyl-1H-pyrrolo[2, 3-b]pyridine-7-oxide (16.5 mg, yield 16%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.45 (s, 1H), 7.75-7.72 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.06 ( s, 1H), 6.80-6.78 (d, J = 8.8 Hz, 1H), 6.36 (d, J = 3.2 Hz, 1H), 4.28 (d, J = 8.0 Hz, 1H), 3.32 - 3.28 (m, 1H) ), 3.20–3.13 (m, 1H), 2.78 (s, 3H), 2.04–2.00 (m, 2H), 1.75–1.72 (m, 2H), 1.32–1.30 (m, 7H) 1.11–0.96 (m, 4H), 0.91 (d, J = 6.4 Hz, 3H).

MS m/z (ESI): 442.1 [M+H] ⁺

Example 81

4-(5-(cyclopropylsulfonyl)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7- Oxide

The first step: the preparation of 1,2-bis(3-bromo-4-fluorophenyl)disulfane.

3-Bromo-4-fluoroaniline (60 g, 315.6 mmol), acetonitrile (600 mL), water (600 mL), and concentrated hydrochloric acid (300 mL). The mixture was cooled to 0-5 ° C in an ice bath, and a solution of sodium nitrite (23.4 g, 316 mmol) in water (300 mL) was added dropwise, maintaining the system temperature at 0-5 °C. After 1 hour of reaction, urea (3.6 g, 60 mmol) was added to quench excess sodium nitrite and stirred for 10 minutes. Sodium sulfide nonahydrate (100.8 g, 420 mmol), sulfur powder (13.2 g, 420 mmol), NaOH (17.4 g, 432 mmol), water (300 mL) were sequentially added to a 1 L three-necked flask. The oil bath was heated to 75 ° C for 1 hour until the solution became clear. The clear solution was cooled to room temperature and added dropwise to the above reaction liquid, and the temperature of the system was maintained at 0 to 5 °C. After completion of the dropwise addition, the reaction mixture was extracted with ethyl acetate (1L×2), filtered, dried over anhydrous sodium sulfate and evaporated to give the crude (1,2-bis(3-bromo-4-fluorophenyl)disulfane ( 42 g, yellow oil, yield 64%).

The second step: the preparation of 3-bromo-4-fluorobenzenethiol

1,2-bis(3-bromo-4-fluorophenyl)disulfane (42 g, 101.9 mmol), methanol (300 mL), tetrahydrofuran (1 L), sodium hydroxide (10.3 g, 257.5) were sequentially added to a 3L three-necked flask. A solution of mmol (300 mL) of water. Sodium borohydride (11.1 g, 293.6 mmol) was added in five portions at room temperature. After 1 hour of reaction, the mixture was concentrated. EtOAc EtOAc m. The aqueous phase was added dropwise to hydrochloric acid (800 mL, 3 mol/L) and the system temperature was maintained at 0-5 °C. The reaction mixture was extracted with EtOAc (EtOAc)EtOAc.

^{_{1 H NMR (400MHz, CDCl 3}} ): δ7.50 (dd, J = 6.3Hz, 2.3Hz, 1H), 7.23-7.16 (m, 1H), 7.00 (t, J = 8.4Hz, 1H), 3.48 ( s, 1H).

The third step: the preparation of 1,2-bis(3-bromo-4-fluorophenyl)disulfane.

3-Bromo-4-fluorobenzenethiol (14 g, 68.0 mmol), acetonitrile (200 mL) was added to a 500 mL three-necked flask. Iodophthalic acid (21.9 g, 68.0 mmol) was added in five portions at room temperature. After reacting at room temperature for 1 hour, it was quenched with water (100 mL), concentrated, ethyl acetate (100 mL×2), and dried over anhydrous sodium sulfate. Phenyl) disulfane (14 g, yellow oil, yield 100%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.72 - 7.63 (m, 1H), 7.39 - 7.28 (m, 1H), 7.13 - 7.04 (m, 1H).

The fourth step: the preparation of (3-bromo-4-fluorophenyl) (cyclopropyl) sulane.

1,2-bis(3-bromo-4-fluorophenyl)disulfane (8 g, 19.4 mmol) and tetrahydrofuran (40 mL) were sequentially added to a 250 mL three-necked flask. Cyclopropylmagnesium bromide (60 mL, 1 M, 60 mmol) was added dropwise at 70 ° C under nitrogen. After 1 hour the reaction was added saturated NH ₄ Cl (100mL) was quenched with ethyl acetate (100mL × 2) and extracted, dried over anhydrous sodium sulfate, and separated by column (petroleum ether) to give (3-bromo-4-fluorophenyl) ( Cyclopropyl)sulfane (4.3 g, yellow oil, yield 90%).

^{1 H NMR (400MHz, DMSO-} d 6): δ7.65 (s, 1H), 7.40-7.31 (m, 2H), 2.35 (m, 4.3Hz, 1H), 1.13-1.06 (m, 2H), 0.63 –0.56(m,2H).

Step 5: Preparation of 2-bromo-4-(cyclopropylsulfonyl)-1-fluorobenzene

(3-Bromo-4-fluorophenyl)(cyclopropyl)sulfane (4.0 g, 6.50 mmol), dissolved in dichloromethane (20 mL), m. m. Methylene chloride solution (20 mL). The reaction was stirred at zero for one hour and the reaction was complete. The reaction mixture was washed with EtOAc EtOAc (EtOAc) After column chromatography, the compound 2-bromo-4-(cyclopropylsulfonyl)-1-fluorobenzene (4.0 g, yield 89%) was obtained.

Step 6: Preparation of 4-(5-(cyclopropylsulfonyl)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine

2-bromo-4-(cyclopropylsulfonyl)-1-fluorobenzene (1.9 g, 6.81 mmol), 6-methyl-4-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (2.25 g, 5.46 mmol), [1,1'-bis(diphenyl) Phosphyl)ferrocene]palladium dichloride (399 mg, 0.54 mmol), potassium carbonate (1.88 g, 13.66 mmol) dissolved in a mixed solvent of 1,4-dioxane (24 mL) and water (6 mL) The reaction was completed after stirring at 100 ° C for 4 hours under a nitrogen atmosphere. The reaction mixture was poured into water (50 mL), EtOAc (EtOAc (EtOAc)EtOAc. :1, V/V) gave the compound 4-(5-(cyclopropylsulfonyl)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b Pyridine (1.38 g, yield 52%).

Step 7: Preparation of 4-(5-(cyclopropylsulfonyl)-2-fluorophenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine

4-(5-(Cyclopropylsulfonyl)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (1.28 g, 2.64 mmol) In a mixed solvent of tert-butanol (20 mL) and tetrahydrofuran (5 mL), potassium hydroxide (3M, 10 mL) was added, and the mixture was stirred at 70 ° C overnight and then cooled to room temperature. The reaction mixture was dried with EtOAc EtOAc (EtOAc) After column chromatography (petroleum ether: ethyl acetate = 3:1, V/V) gave 4-(5-(cyclopropylsulfonyl)-2-fluorophenyl)-6-methyl-1H-pyrrole [2,3-b]pyridine (670 mg, yield 77%).

Step 8: Preparation of 4-(5-(cyclopropylsulfonyl)-2-fluorophenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide

4-(5-(Cyclopropylsulfonyl)-2-fluorophenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine (670.0 mg, 2.03 mmol), dissolved in tetrahydrofuran (7 mL) To the mixture, m-chloroperoxybenzoic acid (616 mg, 3.04 mmol) was added at room temperature, and the mixture was stirred at room temperature for ten minutes. The reaction mixture was quenched with sodium thiosulfate (20 mL) and then ethyl acetate (20mL×2) The organic phase was combined and washed with aqueous sodium hydrogen carbonate (20 mL), washed with water (20 mL) and brine (20 mL) and dried over anhydrous sodium sulfate. :1, V/V) gave the compound 4-(5-(cyclopropylsulfonyl)-2-fluorophenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxidation (410 mg, yield 58%).

Step 9: 4-(5-(Cyclopropylsulfonyl)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-b] Preparation of pyridine-7-oxide

4-(5-(Cyclopropylsulfonyl)-2-fluorophenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (20.0 mg, 0.057 mmol) To N-methylpyrrolidone (2 mL), 2,4-difluorophenol ((23 mg, 0.17 mmol), cesium carbonate (87 mg, 0.267 mmol) was added under ice-cooling, and the mixture was reacted at 180 ° C for 30 minutes, and then cooled to room temperature. The organic layer was washed with water (10 mL×2) and brine (10 mL) and dried over anhydrous sodium sulfate. After concentration, by preparative chromatography to give the compound 4-(5-(cyclopropylsulfonyl)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3 -b]pyridine-7-oxide (9.0 mg, yield 34%).

¹ H NMR (400 MHz, CD ₃ OD): δ 7.99 (d, J = 2.3 Hz, 1H), 7.85 (dd, J = 8.7 Hz, 2.3 Hz, 1H), 7.35 (d, J = 3.4 Hz, 1H) ), 7.27 (s, 1H), 7.15 (td, J = 9.1, 5.5 Hz, 1H), 7.06 (ddd, J = 11.2 Hz, 8.6 Hz, 3.0 Hz, 1H), 6.96 (dd, J = 8.7 Hz, 0.8Hz, 1H), 6.90 (tdd, J=9.Hz 4, 2.9Hz, 1.7Hz, 1H), 6.48(d, J=3.4Hz, 1H), 2.69–2.62(m,1H), 2.61(s , 3H), 1.16 (qd, J = 5.5 Hz, 1.2 Hz, 2H), 0.99 (qd, J = 5.5 Hz, 1.2 Hz, 2H).

MS m/z (ESI): 457.1 [M+H] ⁺ .

Example 82

4-(2-(4-Bromo-2-fluorophenoxy)-5-(cyclopropylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7 -oxide

According to the experimental procedure of the first step of Example 81, 4-bromo-2-fluorophenol was used instead of 2,4-difluorophenol to obtain the compound 4-(2-(4-bromo-2-fluorophenoxy). 5-(-Cyclopropylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (8.4 mg, yield 29%).

^{1 H NMR (400MHz, CDCl3)} : δ12.54 (s, 1H), 8.09 (d, J = 2.2Hz, 1H), 7.86 (dd, J = 8.7Hz, 2.3Hz, 1H), 7.38 (dd, J = 9.8 Hz, 2.2 Hz, 1H), 7.32 (d, J = 3.3 Hz, 1H), 7.29 (s, 1H), 7.21 (s, 1H), 6.95 (t, J = 8.4 Hz, 2H), 6.51 ( d, J = 3.3 Hz, 1H), 2.77 (s, 3H), 2.60 - 2.44 (m, 1H), 1.43 - 1.34 (m, 2H), 1.13 - 1.00 (m, 2H).

MS m/z (ESI): 517.1 [M+H] ⁺ .

Example 83

4-(5-(cyclopropylsulfonyl)-2-(((1r,4r)-4-hydroxycyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3- b]pyridine-7-oxide

First step: 4-(5-(cyclopropylsulfonyl)-2-(((1r,4r)-4-hydroxycyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[ Preparation of 2,3-b]pyridine-7-oxide

4-(5-(Cyclopropylsulfonyl)-2-fluorophenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (20.0 mg, 0.057 mmol) Add (1r,4r)-cyclohexane-1,4-diol (40mg, 0.34mmol), sodium hydride (7mg, 0.17mmol) in N,N-dimethylformamide (2mL). After stirring overnight at room temperature, it was quenched with EtOAc EtOAc EtOAc (EtOAc) The sodium is dried and concentrated to give the compound 4-(5-(cyclopropylsulfonyl)-2-(((1r,4r)-4-hydroxycyclohexyl)oxy)phenyl)-6-methyl. -1H-pyrrolo[2,3-b]pyridine-7-oxide (2.0 mg, yield 8%).

¹ H NMR (400 MHz, CD ₃ OD): δ 8.33 (s, 1H), 7.98 - 7.70 (m, 2H), 7.39 - 7.21 (m, 2H), 7.18 (s, 1H), 6.35 (d, J) = 3.4 Hz, 1H), 4.50 (d, J = 3.3 Hz, 2H), 3.60 - 3.44 (m, 1H), 2.64 (dd, J = 7.9 Hz, 4.7 Hz, 1H), 2.61 (s, 3H), 1.96 (s, 2H), 1.68 (s, 2H), 1.45 - 1.25 (m, 4H), 1.19 - 1.06 (m, 2H), 1.04 - 0.87 (m, 2H).

MS m/z (ESI): 443.1 [M+H] ⁺ .

Example 84

4-(5-(cyclopropylsulfonyl)-2-(((trans)-4-ethylcyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3- b]pyridine-7-oxide

Following the experimental procedure of Example 83, substituting trans-4-ethylcyclohexanol for (1r,4r)-cyclohexane-1,4-diol as starting material gave 4-(5-(cyclopropylsulfonyl) )-2-(((trans)-4-ethylcyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.02 g , white solid, yield: 38%).

MS m/z (ESI): 455.2 [M+H] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ): δ12.27 (br, 1H), 7.95 (d, J = 2.4Hz, 1H), 7.89 (dd, J = 8.4Hz, 2.4Hz, 1H), 7.34 (d, J=3.2 Hz, 1H), 7.15-7.11 (m, 2H), 6.42 (d, J=3.2 Hz, 1H), 4.36-4.26 (m, 1H), 2.77 (s, 3H), 2.52-2.46 (m) , 1H), 2.16-2.08 (m, 2H), 1.84-1.81 (m, 2H), 1.37-1.20 (m, 6H), 1.16-1.07 (m, 1H), 1.07-0.95 (m, 4H), 0.87 (d, J = 7.6 Hz, 3H).

Example 85

4-(5-(cyclopropylsulfonyl)-2-(((trans)-4-isopropylcyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3 -b]pyridine-7-oxide

Following the experimental procedure of Example 83, using trans-4-isopropylcyclohexanol instead of (1r,4r)-cyclohexane-1,4-diol as the starting material gave 4-(5-(cyclopropylsulfonyl) Acyl)-2-(((trans)-4-isopropylcyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide ( 0.020 g, white solid, yield: 43%).

MS m/z (ESI): 469.2 [M+H] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ): δ12.55 (br, 1H), 7.96 (d, J = 2.4Hz, 1H), 7.89 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.31 (d, J=3.2 Hz, 1H), 7.15-7.13 (m, 2H), 6.40 (d, J=3.2 Hz, 1H), 4.32-4.25 (m, 1H), 2.77 (s, 3H), 2.52-2.46 (m) ,1H),2.14-2.11(m,2H), 1.80-1.77(m,2H), 1.48-1.40(m,1H),1.37-1.26(m,4H),1.16-1.02(m,5H),0.86 (t, J = 6.8 Hz, 6H).

Example 86

4-(5-(cyclopropylsulfonyl)-2-(((trans)-4-propylcyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3- b]pyridine-7-oxide

Following the experimental procedure of Example 83, using trans-4-isopropylcyclohexanol instead of (1r,4r)-cyclohexane-1,4-diol as the starting material gave 4-(5-(cyclopropylsulfonyl) Acyl)-2-(((trans)-4-isopropylcyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide ( 0.080 g, white solid, yield: 50%).

MS m/z (ESI): 469.2 [M+H] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ): δ11.62 (s, 1H), 7.96 (d, J = 2.0Hz, 1H), 7.90 (dd, J = 8.8Hz, 2.0Hz, 1H), 7.33 (d, J=3.2 Hz, 1H), 7.15-7.13 (m, 2H), 6.45 (d, J=3.2 Hz, 1H), 4.34-4.27 (m, 1H), 2.76 (s, 3H), 2.52-2.46 (m) , 1H), 2.10-2.05 (m, 2H), 1.82-1.75 (m, 2H), 1.38-1.14 (m, 9H), 1.07-0.94 (m, 4H), 0.87 (t, J = 7.6 Hz, 3H ).

Example 87

4-(5-(cyclopropylsulfonyl)-2-(((trans)-4-tert-butylcyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3-b Pyridine-7-oxide

Following the experimental procedure of Example 83, substituting trans-t-t-butylcyclohexanol for (1r,4r)-cyclohexane-1,4-diol as starting material gave 4-(5-(cyclopropylsulfonyl) -2-(((trans)-4-tert-butylcyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.025 g, white Solid, yield: 36%).

MS m/z (ESI): 483.2 [M+H] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ): δ11.76 (s, 1H), 7.96 (d, J = 2.4Hz, 1H), 7.90 (dd, J = 8.4Hz, 2.8Hz, 1H), 7.36 (d, J=3.2 Hz, 1H), 7.17-7.14 (m, 2H), 6.44 (d, J=3.2 Hz, 1H), 4.32-4.24 (m, 1H), 2.76 (s, 3H), 2.52-2.46 (m) , 1H), 2.16-2.13 (m, 2H), 1.86-1.83 (m, 2H), 1.38-1.25 (m, 4H), 1.04-1.01 (m, 5H), 0.86 (s, 9H).

Example 88

4-(2-((1S,2R,5S)-2-isopropyl-5-methylcyclohexyl)oxo)-5-(cyclopropanesulfonyl)phenyl)-6-methyl-1H -pyrrolo[2,3-b]pyridine-7-oxide

Following the experimental procedure of Example 83, L-menthol was used instead of (1r,4r)-cyclohexane-1,4-diol to give 4-(2-((1S,2R,5S)-2). -isopropyl-5-methylcyclohexyl)oxo)-5-(cyclopropanesulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxidation ( 0.020 g, white solid, yield 36%).

MS m/z (ESI): 483.2 [M+H] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ): δ11.68 (br, 1H), 7.95-7.92 (m, 2H), 7.43 (d, J = 3.2Hz, 1H), 7.20-7.17 (m, 2H), 6.48 (d, J=2.4 Hz, 1H), 4.28-4.21 (m, 1H), 2.78 (s, 3H), 2.53-2.46 (m, 1H), 2.19-2.15 (m, 1H), 1.93-1.82 (m) , 1H), 1.75-1.64 (m, 2H), 1.56-1.44 (m, 1H), 1.39-1.30 (m, 3H), 1.09-0.99 (m, 3H), 0.94-0.90 (m, 5H), 0.78 (d, J = 7.2 Hz, 3H), 0.67 (d, J = 7.2 Hz, 3H).

Example 89

4-(2-(cyclopropylmethoxy)-5-(cyclopropylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide

Following the experimental procedure of Example 83, cyclopropanol was used instead of (1r,4r)-cyclohexane-1,4-diol to give 4-(2-(cyclopropylmethoxy)-5-( Cyclopropylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (27.5 mg, yield 47.6%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.49 (s, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.93 - 7.90 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.35- 7.34 (d, J = 3.2 Hz, 1H), 7.21 (s, 1H), 7.13 - 7.11 (d, J = 8.8 Hz, 1H), 6.44 (d, J = 3.2 Hz, 1H), 3.96 - 3.92 (d , J=6.8Hz, 2H), 2.78(s,3H), 2.50–2.47(m,1H), 1.37–1.34(m,2H),1.17-1.15(m,1H),1.07–1.04(m,2H ), 0.62–0.60 (m, 2H), 0.32–0.30 (m, 2H).

MS m/z (ESI): 399.1 [M+H] ⁺ .

Example 90

4-(5-(cyclopropylsulfonyl)-2-((4,4-difluorocyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine -7-oxide

Following the experimental procedure of Example 83, 4,4-difluorocyclohexane was used instead of (1r,4r)-cyclohexane-1,4-diol to give 4-(5-(cyclopropylsulfonyl). --2-((4,4-Difluorocyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (32.0 mg, yield 47.8%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ12.49 (s, 1H), 8.00 (d, J = 2.4Hz, 1H), 7.94 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.36 (d, J = 3.2 Hz, 1H), 7.17-7.15 (d, J = 8.8 Hz, 1H), 7.12 (s, 1H), 6.42 (d, J = 3.2 Hz, 1H), 4.66 - 4.64 (m, 1H), 2.77 (s, 3H), 2.49 - 2.47 (m, 1H), 1.96 - 1.73 (m, 8H), 1.38-1.36 (m, 2H), 1.17 - 1.14 (m, 2H).

MS m/z (ESI): 463.1 [M+H] ⁺

Example 91

4-(5-(cyclopropylsulfonyl)-2-(((1r,4r)-4-methylcyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3 -b]pyridine-7-oxide

Following the experimental procedure of Example 83, (1r,4r)-4-methylcyclohexane-1-ol was used instead of (1r,4r)-cyclohexane-1,4-diol to give compound 4- (5-(Cyclopropylsulfonyl)-2-(((1r,4r)-4-methylcyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3-b Pyridine-7-oxide (24.4 mg, yield 32%).

¹ H NMR (400 MHz, CD ₃ OD): δ 7.89 - 7.81 (m, 2H), 7.34 - 7.27 (m, 2H), 7.16 (s, 1H), 6.34 (d, J = 3.2 Hz, 1H), 4.41–4.31 (m, 1H), 2.67–2.57 (m, 4H), 2.04–1.95 (m, 2H), 1.69–1.60 (m, 2H), 1.33–1.10 (m, 5H), 1.06–0.94 (m) , 4H), 0.81 (d, J = 6.4 Hz, 3H).

MS m/z (ESI): 441.1 [M+H] ⁺

Example 92

4-(5-(cyclopropylsulfonyl)-2-(((1r,4r)-4-methylcyclohexyl)amino)phenyl)-6-methyl-1H-pyrrolo[2,3- b]pyridine-7-oxide

Following the experimental procedure of Example 83, substituting (1r,4r)-4-methylcyclohexylamine for (1r,4r)-cyclohexane-1,4-diol as the starting material gave the compound 4-(5-(ring) Propylsulfonyl)-2-(((1r,4r)-4-methylcyclohexyl)amino)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxidation (23.4 mg, yield: 38%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ12.18 (s, 1H), 7.76 (dd, J = 8.7Hz, 2.2Hz, 1H), 7.66 (d, J = 2.4Hz, 1H), 7.34 (d, J = 3.2 Hz, 1H), 7.06 (s, 1H), 6.78 (d, J = 8.8 Hz, 1H), 6.36 (d, J = 3.2 Hz, 1H), 4.27 (d, J = 7.6 Hz, 1H) , 3.38–3.23 (m, 1H), 2.77 (s, 3H), 2.52–2.42 (m, 1H), 2.10–1.97 (m, 2H), 1.73–1.67 (m, 2H), 1.36–1.27 (m, 3H), 1.11 - 0.94 (m, 6H), 0.90 (d, J = 6.4 Hz, 3H).

MS m/z (ESI): 440.2 [M+H] ⁺

Example 93

4-(5-(cyclopropylsulfonyl)-2-(((trans)-4-ethylcyclohexyl)amino)phenyl)-6-methyl-1H-pyrrolo[2,3-b Pyridine-7-oxide

First step: N-(4-ethylcyclohexyl)-2-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(cyclopropanesulfonyl)aniline

Add 4-(2-fluoro-5-(cyclopropanesulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine 7-oxo (0.060 g, in a 10 ml microwave tube). 0.17 mmol), 4-ethylcyclohexylamine (0.3 mL) and N-methylpyrrolidone (3 mL) were heated to 140 ° C in an oil bath and allowed to react overnight and then cooled to room temperature. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(cyclopropanesulfonyl)aniline (0.08 g, yellow oil) was used directly for next step.

MS m/z (ESI): 438.2 [M+H] ⁺ .

Second step: 4-(5-(cyclopropylsulfonyl)-2-(((trans)-4-ethylcyclohexyl)amino)phenyl)-6-methyl-1H-pyrrolo[2 ,3-b]pyridine-7-oxide

The crude product N-(4-ethylcyclohexyl)-2-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(cyclopropanesulfonyl)aniline ( 0.080 g (yellow oil) was dissolved in dichloromethane (20 mL), then m-chloroperoxybenzoic acid (85%, 0.045 g, 0.22 mmol) was added to the reaction mixture and stirred at room temperature for two hours. After completion of the reaction, the reaction mixture was diluted with methylene chloride (20 mL), EtOAc (EtOAc) 4-(5-(Cyclopropylsulfonyl)-2-(((trans)-4-ethylcyclohexyl)amino)phenyl)-6-methyl-1H-pyrrolo[2,3- b] Pyridine-7-oxide (0.013 g, white solid, yield 16%).

MS m/z (ESI): 454.2 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.29 (br, 1H), 7.77 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.67 (d, J = 2.4 Hz 1H), 7.44 (d, J) = 2.8 Hz, 1H), 7.11 (s, 1H), 6.80 (d, J = 8.8 Hz, 1H), 6.42 (d, J = 2.8 Hz, 1H), 4.28 (d, J = 7.6 Hz, 1H), 3.32(br,1H), 2.80(s,3H), 2.50-2.43(m,1H), 2.04(br,2H), 1.80(br,2H),1.33-1.15(m,4H),1.14-0.93( m, 7H), 0.87 (t, J = 7.6 Hz, 3H).

Example 94

4-(5-(cyclopropylsulfonyl)-2-(((cis)-4-ethylcyclohexyl)amino)phenyl)-6-methyl-1H-pyrrolo[2,3-b Pyridine-7-oxide

According to the experimental procedure of Example 93, reverse phase preparative chromatography gave 4-(5-(cyclopropylsulfonyl)-2-(((cis)-4-ethylcyclohexyl)amino)phenyl)- 6-Methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.019 g, white solid, yield 24%).

MS m/z (ESI): 454.2 [M+H] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ): δ12.20 (br, 1H), 7.78 (dd, J = 8.4Hz, 2.0Hz, 1H), 7.69 (s, 1H), 7.45 (s, 1H), 7.14 ( s, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.48 (d, J = 2.0 Hz, 1H), 4.52 (d, J = 6.4 Hz, 1H), 3.66 (br, 1H), 2.80 ( s, 3H), 2.50-2.44 (m, 1H), 1.74-1.47 (m, 6H), 1.33-1.29 (m, 2H), 1.22-1.17 (m, 1H), 1.16-1.13 (m, 2H), 1.03-0.98 (m, 4H), 0.83 (t, J = 7.2 Hz, 3H).

Example 95

4-(4-cyclopropyl-2-(2,4-difluorophenoxy)-5-(ethylsulfonylamino)phenyl)-6-methyl-1H-pyrrolo[2,3- b]pyridine-7-oxide

First step: 1-bromo-2-(2,4-difluorophenoxy)-4-iodo-5-nitrobenzene

1-Bromo-2-fluoro-4-iodo-5-nitrobenzene (1.07 g, 3.09 mmol) was dissolved in acetonitrile (20 mL) at room temperature then 2,4-difluorophenol (0.80 g, 6.18) Methyl) and sodium carbonate (0.66 g, 6.18 mmol) were added to the reaction mixture and stirred at room temperature overnight. After completion of the reaction, the reaction mixture was diluted with EtOAc EtOAc (EtOAc)EtOAc. Ether as the mobile phase gave 1-bromo-2-(2,4-difluorophenoxy)-4-iodo-5-nitrobenzene (0.53 g, mp.

The second step: 1-bromo-4-cyclopropyl-2-(2,4-difluorophenoxy)-5-nitrobenzene

1-Bromo-2-(2,4-difluorophenoxy)-4-iodo-5-nitrobenzene (0.53 g, 1.16 mmol), cyclopropylboronic acid (0.15 g, 1.74 mmol) Potassium phosphate (0.49 g, 2.32 mol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.085 g, 0.13 mmol) were dissolved in anhydrous dioxane (10 mL) In the process, nitrogen was replaced three times, heated to 90 ° C, and reacted for 14 hours. After completion of the reaction, the reaction mixture was diluted with EtOAc EtOAc EtOAc EtOAc. As mobile phase, 1-bromo-4-cyclopropyl-2-(2,4-difluorophenoxy)-5-nitrobenzene (0.35 g, yellow solid, yield 81%) was obtained.

The third step: 5-bromo-2-cyclopropyl-4-(2,4-difluorophenoxy)aniline

1-Bromo-4-cyclopropyl-2-(2,4-difluorophenoxy)-5-nitrobenzene (0.15 g, 0.41 mol) and tin dichloride dihydrate (0.26 g) at room temperature 1.13 mol) was dissolved in ethanol (10 mL) and water (0.5 mL) and stirred at room temperature for 14 hr. After the reaction was completed, the ethanol was evaporated to dryness. EtOAc (EtOAc) (EtOAc) The organic phase was washed with brine (15 mL×3), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was obtained from 5-bromo-2-cyclopropyl-4-(2,4-difluorobenzene. Oxy)aniline (0.08 g, yield: 58%).

MS m/z (ESI): 340.0, 342.0 [M+H] ⁺ .

Fourth step: N-(5-bromo-2-cyclopropyl-4-(2,4-difluorophenoxy)phenyl)ethanesulfonamide

5-Bromo-2-cyclopropyl-4-(2,4-difluorophenoxy)phenylamine (0.08 g, 0.24 mmol) and pyridine (0.037 g, 0.47 mmol) were dissolved in dichloromethane at room temperature. In 10 mL), ethylsulfonyl chloride (0.06 g, 0.47 mmol) was added dropwise to the reaction system, and the mixture was heated to 50 ° C for 4 hours. After completion of the reaction, the methylene chloride was evaporated to dryness. mjjjjjjjjjjjjjjjjjjjjjjjjj Drying, filtration, spin-drying, and the crude product was purified by preparative chromatography to give N-(5-bromo-2-cyclopropyl-4-(2,4-difluorophenoxy)phenyl)ethanesulfonamide (0.07 g, White solid, yield 69%).

MS m/z (ESI): 432.0, 434.0 [M+H] ⁺ .

Step 5: N-(2-cyclopropyl-4-(2,4-difluorophenoxy)-5-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3- b]pyridin-4-yl)phenyl)ethanesulfonamide

N-(5-Bromo-2-cyclopropyl-4-(2,4-difluorophenoxy)phenyl)ethanesulfonamide (0.045 g, 0.10 mmol), 6-methyl-4 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine ( 0.045 g, 0.10 mmol), potassium carbonate (0.029 g, 0.20 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.01 g, 0.01 mmol) dissolved in dioxane Six rings (4 mL) and water (1 mL) were replaced with nitrogen three times, heated to 90 ° C overnight and cooled to room temperature. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. Filtration, spin-drying, and the crude product was isolated on a preparative plate to give N-(2-cyclopropyl-4-(2,4-difluorophenoxy)-5-(6-methyl-1-toluenesulfonyl-1H Pyrrolo[2,3-b]pyridin-4-yl)phenyl)ethanesulfonamide (0.06 g, colorless oil, yield: 90%).

MS m/z (ESI): 638.2 [M+H] ⁺ .

Step 6: N-(2-cyclopropyl-4-(2,4-difluorophenoxy)-5-(6-methyl-1H-pyrrolo[2,3-b]pyridine-4- Phenyl)ethanesulfonamide

N-(2-cyclopropyl-4-(2,4-difluorophenoxy)-5-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3- at room temperature b] Pyridin-4-yl)phenyl)ethanesulfonamide (0.03 g, 0.047 mmol) was dissolved in ethanol (6 mL), then sodium methoxide (0.03 g, 0.047 mmol) was added to the reaction mixture and heated to 50 ° C , the reaction was 14 hours. After the completion of the reaction, the ethanol was evaporated to dryness EtOAcjjjjjjjjjjjjjjjjj The crude product was separated with a preparative plate (petroleum ether: ethyl acetate = 1:1, v/v) to give N-(2-cyclopropyl-4-(2,4-difluorophenoxy)-5- ( 6-Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)ethanesulfonamide (0.02 g, colorless oil, yield: 88%).

MS m/z (ESI): 484.1 [M+H] ⁺ .

Step 7: 4-(4-Cyclopropyl-2-(2,4-difluorophenoxy)-5-(ethylsulfonylamino)phenyl)-6-methyl-1H-pyrrolo[ 2,3-b]pyridine-7-oxide

N-(2-cyclopropyl-4-(2,4-difluorophenoxy)-5-(6-methyl-1H-pyrrolo[2,3-b]pyridine-4 under ice bath -yl)phenyl)ethanesulfonamide (0.02 g, 0.04 mmol) was dissolved in dichloromethane (5 mL), then m-chloroperoxybenzoic acid (0.011 g, 0.06 mmol) was added to the reaction mixture for half an hour. . After completion of the reaction, the reaction mixture was diluted with methylene chloride (20 mL). EtOAc (EtOAc m. The crude product was isolated by reverse phase preparative chromatography to give 4-(4-cyclopropyl-2-(2,4-difluorophenoxy)-5-(ethylsulfonylamino)phenyl)-6-methyl -1H-pyrrolo[2,3-b]pyridine-7-oxide (0.06 g, pale yellow solid, yield 29%).

MS m/z (ESI): 500.1 [M+H] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ): δ11.72 (br, 1H), 7.63 (s, 1H), 7.28 (d, J = 2.8Hz, 1H), 7.20 (s, 1H), 7.08 (s, 1H ), 6.90-6.79 (m, 2H), 6.75-6.70 (m, 1H), 6.60-6.59 (m, 2H), 3.23 (q, J = 7.2 Hz, 2H), 2.68 (s, 3H), 1.98- 1.91 (m, 1H), 1.44 (t, J = 7.2 Hz, 3H), 1.06-1.02 (m, 2H), 0.64-0.60 (m, 2H).

Example 96

4-(2-(4-Bromo-2-fluorophenoxy)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine -7-oxide

First step: Preparation of 4-fluoro-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)benzene (meth)aldehyde

3-bromo-4-fluorobenzene(meth)aldehyde (1.34 g, 6.61 mmol), 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro Cyclo-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (3.0 g, 7.28 mmol), [1,1'-bis(diphenylphosphino)ferrocene Palladium dichloride (386 mg, 0.52 mmol), potassium carbonate (1.82 g, 13.32 mmol) dissolved in 1,4-dioxane (16 mL), water (4 mL), EtOAc The reaction was complete after 4 hours. The reaction mixture was poured into water (50 mL), and extracted with ethyl acetate (50 mL×2), and the organic phase was combined, washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate Analysis (petroleum ether: ethyl acetate = 2:1) gave the compound 4-fluoro-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl) Phenyl (meth)aldehyde (2.1 g, yield 78%).

Second step: 4-(4-bromo-2-fluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)benzene (meth)aldehyde preparation

4-Fluoro-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)benzene(meth)aldehyde (1.0 g, 2.45 mmol) dissolved in N -Methylpyrrolidone (10 mL), 4-bromo-2-fluorophenol (1.4 g, 7.35 mmol), cesium carbonate (2.39 g, 7.35 mmol), microwaved at 180 ° C for 30 minutes, cooled to room temperature, added water (20 mL), then extracted with ethyl acetate (20 mL×2). The organic phase was washed with water (40 mL) and brine (40 mL) and dried over anhydrous sodium sulfate. Ethyl acetate = 1:1, V/V) gave 4-(4-bromo-2-fluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridine-4 -yl) phenyl (meth)aldehyde (330 mg, yield 32%).

The third step: (4-(4-bromo-2-fluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)methanol preparation

4-(4-Bromo-2-fluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)benzene(methyl)aldehyde (330 mg, 0.77 mmol) Dissolved in methanol (5 mL), and added sodium borohydride (59 mg, 1.56 mmol), and the mixture was stirred for 3 hr, then quenched with saturated aqueous ammonium chloride (10 mL), water (20 mL) The organic phase was combined and washed with water (40 mL) and brine (40 mL) and dried over anhydrous sodium sulfate. 1,V/V) gives (4-(4-bromo-2-fluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl Methanol (179 mg, yield 54%).

Fourth step: 4-(2-(4-bromo-2-fluorophenoxy)-5-(bromomethyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine Preparation

(4-(4-Bromo-2-fluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)methanol (179 mg, 0.42 mmol Dissolved in dichloromethane (3 mL), added phosphorus tribromide (171 mg, 0.63 mmol) under ice bath, stirred at room temperature overnight, and the reaction solution was adjusted to neutral with sodium carbonate aqueous solution (1 M), and water was added. 20 mL), then extracted with dichloromethane (20 mL×2). The organic phase was combined, washed with water (40 mL) and brine (40 mL) and dried over anhydrous sodium sulfate. Ethyl ester = 2:1, V/V) gave 4-(2-(4-bromo-2-fluorophenoxy)-5-(bromomethyl)phenyl)-6-methyl-1H-pyrrole [2,3-b]pyridine (130 mg, yield 63%).

Step 5: 4-(2-(4-Bromo-2-fluorophenoxy)-5-((methylthio)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3 -b]Preparation of pyridine

4-(2-(4-Bromo-2-fluorophenoxy)-5-(bromomethyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine (130 mg, 0.26 Ethyl acetate (3 mL) was dissolved in EtOAc (3 mL). After adding water (20 mL), and then extracting with dichloromethane (20 mL × 2), the organic phase was combined, washed with water (40 mL) and brine (40 mL), and dried over anhydrous sodium sulfate (petroleum ether: ethyl acetate = 2:1, V/V) gave 4-(2-(4-bromo-2-fluorophenoxy)-5-((methylthio)methyl)phenyl)- 6-Methyl-1H-pyrrolo[2,3-b]pyridine (50 mg, yield 41%).

Step 6: 4-(2-(4-Bromo-2-fluorophenoxy)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3 -b]Preparation of pyridine-7-oxide

4-(2-(4-Bromo-2-fluorophenoxy)-5-((methylthio)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine (50 mg, 0.11 mmol) was dissolved in THF (2 mL), EtOAc (EtOAc (EtOAc,EtOAc) Water (10 mL), then extracted with ethyl acetate (10 mL×2), EtOAc (EtOAc) Drying with sodium, concentration by filtration and preparative chromatography to give 4-(2-(4-bromo-2-fluorophenoxy)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrole And [2,3-b]pyridine-7-oxide (20 mg, yield 36%).

^{1 H NMR (400MHz, DMSO-} d 6): δ12.31 (s, 1H), 7.61 (s, 2H), 7.40 (d, J = 8.4Hz, 1H), 7.30 (dd, J = 16.7Hz, 5.8 Hz, 2H), 7.18 (s, 1H), 7.09 - 6.91 (m, 2H), 6.45 (d, J = 3.1 Hz, 1H), 4.51 (s, 2H), 2.90 (s, 3H), 2.45 (s) , 3H).

MS m/z (ESI): 505.1 [M+H] ⁺ .

Example 97

4-(2-(2,4-difluorophenoxy)-5-((ethylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine -7-oxide

First step: Preparation of 3-bromo-4-(2,4-difluorophenoxy)benzaldehyde

In a 100 mL three-necked flask, 2,4-difluorophenol (1.47 g, 11.33 mmol), 3-bromo-4-fluorobenzaldehyde (2.30 g, 11.33 mmol), cesium carbonate (4.05 g, 12.46 mmol), dimethyl Sulfone (10 mL). The mixture was heated to 100 ° C in an oil bath, and the mixture was cooled to room temperature. The reaction mixture was diluted with ethyl acetate (30 mL) and brine (10 mL×3). dry. The crude product was purified by column chromatography (EtOAc:EtOAc:EtOAc:EtOAc: Oil, yield 73%).

The second step: preparation of 3-bromo-4-(2,4-difluorophenoxy)benzyl alcohol

3-bromo-4-(2,4-difluorophenoxy)benzaldehyde (2.60 g, 8.31 mmol) was dissolved in methanol (10 mL) and tetrahydrofuran (10 mL). Sodium borohydride (0.095 g, 2.49 mmol) was added, and the mixture was stirred at room temperature for 2 hours, and the reaction was completed. The reaction mixture was dried with EtOAc (3 mL). -(2,4-Difluorophenoxy)benzyl alcohol (2.6 g, white solid) was used directly in the next step.

The third step: preparation of 2-bromo-4-(bromomethyl)-1-(2,4-difluorophenoxy)benzene

3-Bromo-4-(2,4-difluorophenoxy)benzyl alcohol (2.60 g, 8.25 mmol) was dissolved in dichloromethane (20 mL), cooled to 0 to 5 ° C, and tribromide was added dropwise. Phosphorus (2.46 g, 9.08 mmol) was heated to room temperature after the addition, and the reaction was completed after stirring for 3 hours. The reaction solution was slowly poured into ice water (50 mL), neutralized with saturated sodium carbonate solution, and the mixture was separated, and the aqueous phase was extracted with dichloromethane (15 mL×3), and the organic phase was combined. ×2) Washed, dried over anhydrous sodium sulfate, filtered, and dried to give 2-bromo-4-(bromomethyl)-1-(2,4-difluorophenoxy)benzene (2.60 g, white solid) , used directly in the next reaction.

Step 4: Preparation of 3-bromo-4-(2,4-difluorophenoxy)benzylethylsulfane

2-Bromo-4-(bromomethyl)-1-(2,4-difluorophenoxy)benzene (2.40 g, 6.35 mmol) and sodium ethanethiolate (0.53 g, 6.35 mmol) were sequentially added to a 100 mL three-necked flask. N,N-dimethylformamide (40 mL) was stirred at room temperature for 4 hours and the reaction was completed. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. 1, V/V) gave 3-bromo-4-(2,4-difluorophenoxy)benzylethylsulfane (1.30 g, oil, yield 57%).

Step 5: Preparation of 2-bromo-1-(2,4-difluorophenoxy)-4-((ethylsulfonyl)methyl)benzene

3-Bromo-4-(2,4-difluorophenoxy)benzylethylsulfane (1.3 g, 3.6 mmol) was dissolved in dichloromethane (20 mL), and m-chloroperoxybenzoic acid was added at room temperature. (1.8g, 9.0mmol), stirred for 1 hour, the reaction was completed by LC-MS. A saturated sodium carbonate solution (50 mL) was added to the reaction solution, and then extracted with ethyl acetate (50 mL×2), and the organic phase was combined and saturated. The solution was washed with sodium chloride solution (80 mL×2), dried over anhydrous sodium sulfate Benzene (1.3 g, 92%). MS m/z (ESI): 391.2, 393.2 [M+H] ⁺ .

The fifth step: 4-(2-(2,4-difluorophenoxy)-5-((ethylsulfonyl)methyl)phenyl)-6-methyl-1-toluenesulfonyl-1H- Preparation of pyrrolo[2,3-b]pyridine

2-Bromo-1-(2,4-difluorophenoxy)-4-((ethylsulfonyl)methyl)benzene (100 mg, 0.26 mmol), 6-methyl-4-(4,4 ,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (210 mg, 0.51 mmol) , [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (18.6 mg, 0.03 mmol), potassium carbonate (70.6 mg, 0.51 mmol) dissolved in 1,4-dioxane (10 mL) and water (3 mL) were replaced with nitrogen and heated to 100 ° C for 4 hours. The reaction was confirmed by LC/MS. Water (50 mL) was added to the reaction mixture, and the mixture was washed with ethyl acetate (50 mL). Ethyl ester = 1:1, V / V) gave 4-(2-(2,4-difluorophenoxy)-5-((ethylsulfonyl)methyl)phenyl)-6-methyl- 1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (150 mg, purity 70%, yield 68%).

MS m/z (ESI): 597.1 [M+H] ⁺

Step 6: 4-(2-(2,4-Difluorophenoxy)-5-((ethylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3 -b] Preparation of pyridine

4-(2-(2,4-Difluorophenoxy)-5-((ethylsulfonyl)methyl)phenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[ 2,3-b]pyridine (150 mg, purity 70%, 0.25 mmol) was dissolved in tert-butanol (10 mL), and aqueous potassium hydroxide (3M, 5 mL) was added to the above solution, and the mixture was stirred at 55 ° C overnight. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, and evaporated. 10:1, V/V) gave 4-(2-(2,4-difluorophenoxy)-5-((ethylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrole And [2,3-b]pyridine (40 mg, yield 51.0%).

MS m/z (ESI): 443.1 [M+H] ⁺

Step 7: 4-(2-(2,4-Difluorophenoxy)-5-((ethylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3 -b]Preparation of pyridine-7-oxide

4-(2-(2,4-Difluorophenoxy)-5-((ethylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b] Pyridine (40 mg, 0.09 mmol) was dissolved in tetrahydrofuran (2 mL). m. Ethyl acetate (50 mL) was added to the mixture, and the mixture was washed with saturated aqueous sodium sulfate (30 mL) 4-(2-(2,4-difluorophenoxy)-5-((ethylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine -7-Oxide (13.0 mg, yield 31%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ12.48 (s, 1H), 7.68 (s, 1H), 7.47-7.43 (m, 3H), 7.08-7.06 (m, 1H), 7.01-6.96 (m, 1H), 6.91-6.84 (m, 2H), 6.78 (s, 1H), 4.31 (s, 2H), 3.07-3.05 (q, J = 5.6 Hz, 2H), 2.94 (s, 3H), 1.27-1.25 (t, J = 7.2 Hz, 3H).

MS m/z (ESI) = 459.1 [M+H] ⁺

Example 98

4-(2-(2,4-difluorophenoxy)-5-(2-(ethylsulfonyl)propan-2-yl)phenyl)-6-methyl-1H-pyrrolo[2, 3-b]pyridine-7-oxide

First step: Preparation of 2-bromo-1-(2,4-difluorophenoxy)-4-(2-(ethylsulfonyl)propan-2-yl)benzene

2-Bromo-1-(2,4-difluorophenoxy)-4-((ethylsulfonyl)methyl)benzene (469 mg, 1.2 mmol) was dissolved in tetrahydrofuran (10 mL) and cooled to 0. Sodium hydride (60%, 240 mg, 6 mmol) was added and stirred for 10 min. Ethyl acetate (80 mL) was added to the reaction mixture, which was washed with saturated brine (50 mL×2) and dried over anhydrous sodium sulfate. -Difluorophenoxy)-4-(2-(ethylsulfonyl)propan-2-yl)benzene (400 mg, yield 80%).

^{1 H NMR (400MHz, DMSO-} d 6): δ7.88 (d, J = 2.4Hz, 1H), 7.58-7.50 (m, 2H), 7.31-7.25 (m, 1H), 7.18-7.13 (m, 1H), 6.90 (d, J = 8.8 Hz, 1H), 6.78 (s, 1H), 2.91-2.85 (q, J = 7.6 Hz, 2H), 1.76 (s, 6H), 1.08-1.05 (t, J =6.4Hz, 3H).

MS m/z (ESI): 419.2, 421.2 [M+H] ⁺

Second step: 4-(2-(2,4-difluorophenoxy)-5-(2-(ethylsulfonyl)propan-2-yl)phenyl)-6-methyl-1-toluene Preparation of sulfonyl-1H-pyrrolo[2,3-b]pyridine

Taking 2-bromo-1-(2,4-difluorophenoxy)-4-(2-(ethylsulfonyl)propan-2-yl)benzene as a raw material, refer to the fifth step of the ninety-seventh step of the embodiment. 4-(2-(2,4-Difluorophenoxy)-5-(2-(ethylsulfonyl)propan-2-yl)phenyl)-6-methyl-1-toluenesulfonyl- 1H-pyrrolo[2,3-b]pyridine (250 mg, yield 55%).

MS m/z (ESI) = 625.1 [M+H] ⁺

Third step: 4-(2-(2,4-difluorophenoxy)-5-(2-(ethylsulfonyl)propan-2-yl)phenyl)-6-methyl-1H-pyrrole Preparation of [2,3-b]pyridine

4-(2-(2,4-difluorophenoxy)-5-(2-(ethylsulfonyl)propan-2-yl)phenyl)-6-methyl-1-toluenesulfonyl- 1H-pyrrolo[2,3-b]pyridine is used as a raw material, and the sixth step of the seventy-seventh step of the embodiment is given to obtain 4-(2-(2,4-difluorophenoxy)-5-(2-(B) Sulfonyl)propan-2-yl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine (150 mg, yield 80%).

MS m/z (ESI): 471.1 [M+H] ⁺

Fourth step: 4-(2-(2,4-difluorophenoxy)-5-(2-(ethylsulfonyl)propan-2-yl)phenyl)-6-methyl-1H-pyrrole Preparation of [2,3-b]pyridine-7-oxide

4-(2-(2,4-difluorophenoxy)-5-(2-(ethylsulfonyl)propan-2-yl)phenyl)-6-methyl-1H-pyrrolo[2 , 3-b]pyridine as a raw material, referring to the seventh step of the seventy-seventh step of the example, 4-(2-(2,4-difluorophenoxy)-5-(2-(ethylsulfonyl)propane- 2-yl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (32.4 mg, yield 33.3%).

MS m/z (ESI): 487.1 [M+H] ⁺

^{_{1 H NMR (400MHz, CDCl 3}} ): δ12.35 (s, 1H), 7.84 (d, J = 2.4Hz, 1H), 7.59-7.56 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.36- 7.35 (d, J = 3.6 Hz, 1H), 7.27 (s, 1H), 7.04 - 6.91 (m, 2H), 6.86 - 6.81 (m, 2H), 6.60 (d, J = 3.2 Hz, 1H), 2.80 -2.75 (m, 5H), 1.87 (s, 6H), 1.30-1.26 (t, J = 7.2 Hz, 3H).

Example 99

4-(2-(2,4-Difluorophenoxy)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine- 7-oxide

First step: Preparation of (3-bromo-4-(2,4-difluorophenoxy)benzyl)(methyl)sulfane

2-Bromo-4-(bromomethyl)-1-(2,4-difluorophenoxy)benzene (2.00 g, 5.29 mmol), sodium methanethiolate (0.45 g, 6.35 mmol) was sequentially added to a 100 mL three-necked flask. N,N-dimethylformamide (35 mL) was stirred at room temperature for 3 hours. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. 1) (3-Bromo-4-(2,4-difluorophenoxy)benzyl)(methyl)sulfane (1.00 g, oil, yield 55%).

Second step: Preparation of 2-bromo-1-(2,4-difluorophenoxy)-4-((methanesulfonyl)methyl)benzene

(3-Bromo-4-(2,4-difluorophenoxy)benzyl)(methyl)sulfane (1.00 g, 2.90 mmol) was dissolved in dichloromethane (20 mL). Chloroperoxybenzoic acid (1.76 g, 8.70 mmol), stirred for 1 hour, the reaction was completed by LC-MS, and saturated sodium carbonate solution (50 mL) was added to the reaction solution, then extracted with ethyl acetate (50 mL×2), and mixed. The organic phase was washed with a saturated aqueous sodium chloride solution (yield: EtOAc, EtOAc) Acyl)methyl)benzene (1.0 g, yield 92%).

MS m/z (ESI): 377.2, 379.2 [M+H] ⁺ .

Third step: 4-(2-(2,4-difluorophenoxy)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrole Preparation of [2,3-b]pyridine

2-Bromo-1-(2,4-difluorophenoxy)-4-((methylsulfonyl)methyl)benzene (110 mg, 0.29 mmol), 6-methyl-4-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (190 mg, 0.35 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (22.0 mg, 0.03 mmol), potassium carbonate (82.0 mg, 0.60 mmol) dissolved in 1,4-dioxane ( 10 mL) and water (3 mL) were replaced with nitrogen, heated to 100 ° C for 4 hours, and the reaction was confirmed by LC/MS. Water (50 mL) was added to the reaction mixture, and the mixture was washed with ethyl acetate (50 mL). Ethyl ester = 1:1) gave 4-(2-(2,4-difluorophenoxy)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-toluenesulfonyl -1H-pyrrolo[2,3-b]pyridine (130 mg, yield 77.0%).

MS m/z (ESI): 583.1 [M+H] ⁺

Fourth step: 4-(2-(2,4-difluorophenoxy)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3- b] Preparation of pyridine

4-(2-(2,4-Difluorophenoxy)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2 3-B]pyridine (130 mg, 0.22 mmol) was dissolved in tert-butanol (15 mL). EtOAc (3M, EtOAc) Ethyl acetate (50 mL) was added to the mixture, and washed with brine (50 mL×2) and dried over anhydrous sodium sulfate. 4-(2-(2,4-difluorophenoxy)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine ( 60mg, yield 63%).

MS m/z (ESI): 429.1 [M+H] ⁺

Step 5: 4-(2-(2,4-Difluorophenoxy)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3- b] Preparation of pyridine-7-oxide

4-(2-(2,4-Difluorophenoxy)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine (60 mg, 0.14 mmol) was dissolved in tetrahydrofuran (2 mL). m. Ethyl acetate (50 mL) was added to the mixture, and the mixture was washed with saturated aqueous sodium sulfate (30 mL×2), and then washed with brine (30 mL) -(2-(2,4-difluorophenoxy)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7 - Oxide (13.0 mg, yield: 21%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ12.24 (s, 1H), 7.64 (d, J = 2.0Hz, 1H), 7.39-7.36 (dd, J = 8.4Hz, 2.4Hz, 1H), 7.35 ( d, J = 3.2 Hz, 1H), 7.26 (s, 1H), 7.04 - 6.91 (m, 2H), 6.86 - 6.81 (m, 2H), 6.60 (d, J = 3.2 Hz, 1H), 4.28 (s) , 2H), 2.88 (s, 3H), 2.75 (s, 3H).

MS m/z (ESI): 445.1 [M+H] ⁺

Example 100

4-(2-(2,4-difluorophenoxy)-5-(2-(methylsulfonyl)propan-2-yl)phenyl)-6-methyl-1H-pyrrolo[2,3 -b]pyridine-7-oxide

First step: 2-bromo-1-(2,4-difluorophenoxy)-4-(2-(methylsulfonyl)propan-2-yl)benzene and 2-bromo-1-(2,4 Of -difluorophenoxy)-4-(1-(methylsulfonyl)ethyl)benzene

2-Bromo-1-(2,4-difluorophenoxy)-4-((methylsulfonyl)methyl)benzene (300 mg, 0.80 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to 0 ° C, Sodium hydride (60%, 160 mg, 6 mmol) was stirred for 10 min. Ethyl acetate (80 mL) was added to the reaction mixture, which was washed with saturated brine (50 mL×2) and dried over anhydrous sodium sulfate. -difluorophenoxy)-4-(2-(methylsulfonyl)propan-2-yl)benzene (150 mg, yield 48%) and 2-bromo-1-(2,4-difluorophenoxy) 4-(1-(Methanesulfonyl)ethyl)benzene (100 mg, yield 31%).

2-bromo-1-(2,4-difluorophenoxy)-4-(2-(methylsulfonyl)propan-2-yl)benzene:

^{_{1 H NMR (400MHz, CDCl 3}} ): δ7.85 (d, J = 2.4Hz, 1H), 7.52-7.49 (dd, J = 8.4Hz, 2.4Hz, 1H), 7.16-7.06 (m, 1H), 7.01-6.95 (m, 1H), 6.92-6.87 (m, 1H), 6.72 (d, J = 8.4 Hz, 1H), 2.59 (s, 3H), 1.82 (s, 6H).

2-bromo-1-(2,4-difluorophenoxy)-4-(1-(methylsulfonyl)ethyl)benzene:

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.62 (d, J = 2.0 Hz, 1H), 7.24 - 7.22 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 7.02 - 6.97 (m, 1H), 6.93-6.88 (m, 1H), 6.84-6.82 (m, 1H), 6.67 (d, J = 8.4 Hz, 1H), 4.10-4.07 (q, J = 7.2 Hz, 1H), 2.64 (s, 3H) , 1.70-1.68 (d, J = 7.2 Hz, 3H).

Second step: 4-(2-(2,4-difluorophenoxy)-5-(2-(methylsulfonyl)propan-2-yl)phenyl)-6-methyl-1-toluene Preparation of acyl-1H-pyrrolo[2,3-b]pyridine

2-Bromo-1-(2,4-difluorophenoxy)-4-(2-(methylsulfonyl)propan-2-yl)benzene (120 mg, 0.30 mmol), 6-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (200mg , 0.36 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (22.0 mg, 0.03 mmol), potassium carbonate (82.0 mg, 0.60 mmol) dissolved in 1,4- Dioxane (6 mL) and water (2 mL) were replaced with nitrogen and heated to 100 ° C overnight. The reaction was completed by LC/MS. Water (50 mL) was added to the reaction mixture, and the mixture was washed with ethyl acetate (50 mL). Ethyl ester = 1:1) 4-(2-(2,4-difluorophenoxy)-5-(2-(methylsulfonyl)propan-2-yl)phenyl)-6-methyl- 1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (120 mg, yield 66%).

MS m/z (ESI): 611.1 [M+H] ⁺

Third step: 4-(2-(2,4-difluorophenoxy)-5-(2-(methylsulfonyl)propan-2-yl)phenyl)-6-methyl-1H-pyrrole Preparation of [2,3-b]pyridine

4-(2-(2,4-Difluorophenoxy)-5-(2-(methylsulfonyl)propan-2-yl)phenyl)-6-methyl-1-toluenesulfonyl-1H - Pyrrolo[2,3-b]pyridine (120 mg, 0.20 mmol) was dissolved in tert-butanol (15 mL), and potassium hydroxide solution (3M, 8 mL) was added to the above solution and heated to 75 ° C overnight. The reaction mixture was extracted with ethyl acetate (50 mL). EtOAcjjjjjjjj -5-(2-(Methanesulfonyl)propan-2-yl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine (80 mg, yield 89%).

MS m/z (ESI): 457.1 [M+H] ⁺

Fourth step: 4-(2-(2,4-difluorophenoxy)-5-(2-(methylsulfonyl)propan-2-yl)phenyl)-6-methyl-1H-pyrrole [2,3-b]pyridine-7-oxide

4-(2-(2,4-Difluorophenoxy)-5-(2-(methylsulfonyl)propan-2-yl)phenyl)-6-methyl-1H-pyrrolo[2, 3-b]pyridine (80 mg, 0.17 mmol) was dissolved in tetrahydrofuran (5 mL). m. Ethyl acetate (50 mL) was added to the reaction mixture, and the mixture was washed with saturated aqueous sodium sulfate (30 mL? 4-(2-(2,4-difluorophenoxy)-5-(2-(methylsulfonyl)propan-2-yl)phenyl)-6-methyl-1H-pyrrolo[2,3 -b]pyridine-7-oxide (20.0 mg, yield 24%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 12.21. (s, 1H), 7.85 (d, J = 2.8 Hz, 1H), 7.59-7.56 (dd, J = 8.8 Hz, 2.8 Hz, 1H), 7.37 ( d, J = 3.6 Hz, 1H), 7.28 (s, 1H), 7.04 - 6.92 (m, 2H), 6.87 - 6.82 (m, 2H), 6.61 (d, J = 3.2 Hz, 1H), 2.76 (s) , 3H), 2.67 (s, 3H), 1.88 (s, 6H).

MS m/z (ESI): 473.1 [M+H] ⁺

Example 101

4-(2-(2,4-Difluorophenoxy)-5-(1-(methylsulfonyl)ethyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b] Pyridine-7-oxide

First step: 4-(2-(2,4-difluorophenoxy)-5-(1-(methylsulfonyl)ethyl)phenyl)-6-methyl-1-toluenesulfonyl-1H -Preparation of pyrrolo[2,3-b]pyridine

Taking 2-bromo-1-(2,4-difluorophenoxy)-4-(1-(methylsulfonyl)ethyl)benzene as a raw material, referring to the second step of the first embodiment, 4-(2) -(2,4-difluorophenoxy)-5-(1-(methylsulfonyl)ethyl)phenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3- b] pyridine (80 mg, yield 52.4%).

MS m/z (ESI): 597.1 [M+H] ⁺

Second step: 4-(2-(2,4-difluorophenoxy)-5-(1-(methylsulfonyl)ethyl)phenyl)-6-methyl-1H-pyrrolo[2, Preparation of 3-b]pyridine

4-(2-(2,4-difluorophenoxy)-5-(1-(methylsulfonyl)ethyl)phenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrole [2,3-b]pyridine as a raw material, referring to the third step of the twenty-third step of the example, 4-(2-(2,4-difluorophenoxy)-5-(1-(methylsulfonyl) Phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine (50 mg, yield 84.4%).

MS m/z (ESI): 443.1 [M+H] ⁺

The third step: 4-(2-(2,4-difluorophenoxy)-5-(1-(methylsulfonyl)ethyl)phenyl)-6-methyl-1H-pyrrolo[2, Preparation of 3-b]pyridine-7-oxide

4-(2-(2,4-difluorophenoxy)-5-(1-(methylsulfonyl)ethyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b ] Pyridine as a raw material, referring to the fourth step of the example, 4-(2-(2,4-difluorophenoxy)-5-(1-(methylsulfonyl)ethyl)phenyl)-6 -Methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (18.5 mg, yield 35.7%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ12.38 (s, 1H), 7.66 (d, J = 2.0Hz, 1H), 7.41-7.38 (dd, J = 8.4Hz, 2.0Hz, 1H), 7.34- 7.33 (d, J = 3.6 Hz, 1H), 7.26 (s, 1H), 7.03 - 6.91 (m, 2H), 6.85 - 6.81 (m, 2H), 6.58 (d, J = 3.2 Hz, 1H), 4.27 - 4.21 (q, J = 7.2 Hz, 1H), 2.78 (s, 3H), 2.76 (s, 3H), 1.83-1.81 (d, J = 7.2 Hz, 3H).

MS m/z (ESI): 459.1 [M+H] ⁺

Example 102

6-Cyclopropyl-4-(2-(2,4-difluorophenoxy)-5-(ethylsulfonylamino)phenyl)-1H-pyrrolo[2,3-b]pyridine-7 -oxide

First step: Preparation of 4-chloro-6-cyclopropyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine

6-Bromo-4-chloro-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (500 mg, 1.3 mmol), cyclopropylboronic acid (110 mg, 1.3 mmol), [1,1' - bis(diphenylphosphino)ferrocene]palladium dichloride (95 mg, 0.13 mmol) and potassium carbonate (537 mg, 3.9 mmol) were added to dioxane/water (v/v = 4:1, 20 mL) ) mixed solvent. The reaction solution was subjected to a nitrogen atmosphere at 100 ° C for 10 hours, and then allowed to reach room temperature. The reaction mixture was evaporated to dryness, and then purified (ethyl ether: ethyl acetate = 10:1) to give 4-chloro-6-cyclopropyl-1- Tosyl-1H-pyrrolo[2,3-b]pyridine (170 mg, yield 38%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.03 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 4.0 Hz, 1H), 7.29 (d, J = 8.4 Hz, 2H), 7.09 ( s, 1H), 6.59 (d, J = 4.0 Hz, 1H), 2.40 (s, 3H), 2.06 - 1.97 (m, 1H), 1.14 - 1.06 (m, 2H), 1.05 - 0.99 (m, 2H) .

Second step: 6-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1H- Preparation of pyrrolo[2,3-b]pyridine

4-Chloro-6-cyclopropyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (170 mg, 0.49 mmol), 4,4,4',4',5,5,5 ',5'-octamethyl-2,2'-linked (1,3,2-dioxaborolan) (373 mg, 1.47 mmol), potassium acetate (144 mg, 1.47 mmol), palladium acetate (5.5 mg, 24.6 umol) and [1,1'-biphenyl]-2-yldicyclohexylphosphane (17.2 mg, 49 umol) were added to dioxane (10 mL), and the reaction was carried out under nitrogen at 90 ° C. After 10 hours, the reaction mixture was evaporated to dryness and purified (jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjs Dioxaborolan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (165 mg, yield 77%).

MS m/z (ESI): 439.1 [M+H] ⁺

The third step: N-(3-(6-cyclopropyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(2,4-difluorobenzene Preparation of oxy)phenyl)ethanesulfonamide

6-Cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[ 2,3-b]pyridine (165 mg, 0.38 mmol), N-(3-bromo-4-(2,4-difluorophenoxy)phenyl)ethanesulfonamide (177 mg, 0.45 mmol), [1, 1'-bis(diphenylphosphino)ferrocene]palladium dichloride (27.8 mg, 0.038 mmol) and potassium carbonate (130 mg, 0.94 mmol) were added to dioxane/water (v/v = 4: 1,10 mL) in a mixed solvent. The reaction solution was reacted at 100 ° C for 10 hours under nitrogen, and then cooled to room temperature. The reaction mixture was evaporated to dryness and then purified by column ( petroleum ether: ethyl acetate = 10:3) to give N-(3-(6-cyclopropyl) -1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(2,4-difluorophenoxy)phenyl)ethanesulfonamide (100 mg, yield 43 %).

MS m/z (ESI): 624.1 [M+H] ⁺

Fourth step: N-(3-(6-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(2,4-difluorophenoxy)phenyl) Preparation of ethanesulfonamide

Potassium hydroxide (45 mg, 0.8 mmol) was added to N-(3-(6-cyclopropyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4- (2,4-Difluorophenoxy)phenyl)ethanesulfonamide (100 mg, 0.16 mmol) in tetrahydrofuran (2 mL) and water (3 drops), the reaction mixture was reacted at 50 ° C for 12 hours, LCMS showed The reaction was not carried out. After the reaction solution was cooled, ethanol (1 mL) was added, and the reaction mixture was reacted at 70 ° C for 5 hours. After the reaction solution was cooled, dichloromethane (15 mL) was added and washed with saturated brine (10 mL×2). After drying over anhydrous sodium sulfate and filtering, the filtrate was concentrated to give crude N-(3-(6-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(2,4- Difluorophenoxy)phenyl)ethanesulfonamide (78 mg) was used directly in the next step.

MS m/z (ESI): 470.1 [M+H] ⁺

Step 5: 6-Cyclopropyl-4-(2-(2,4-difluorophenoxy)-5-(ethylsulfonylamino)phenyl)-1H-pyrrolo[2,3-b Preparation of pyridine-7-oxide

m-Chloroperoxybenzoic acid (29 mg, 0.12 mmol, 75%) was added to N-(3-(6-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4- (2,4-Difluorophenoxy)phenyl)ethanesulfonamide (39 mg, 0.083 mmol) in tetrahydrofuran (1 mL). After reacting for 10 minutes at room temperature, it was diluted with EtOAc EtOAc (EtOAc m. After filtration, the filtrate was evaporated to dryness to give a crude material, which was purified (yield: methylene chloride:methanol = 20:1) to give 6-cyclopropyl-4-(2-(2,4-difluorophenoxy)-5 -(Ethylsulfonylamino)phenyl)-1H-pyrrolo[2,3-b]pyridine-7-oxide (5 mg, yield 12%).

^{_{1 H NMR (400MHz, CDCl 3}} ): δ11.90 (br, 1H), 9.13 (br, 1H), 7.44-7.32 (m, 2H), 7.25 (s, 1H), 6.91-6.79 (m, 3H) , 6.78–6.68 (m, 2H), 6.48 (s, 1H), 3.29–3.13 (m, 2H), 2.90–2.72 (m, 1H), 1.42 (t, J = 7.1 Hz, 3H), 1.10–0.94 (m, 2H), 0.78–0.64 (m, 2H).

MS m/z (ESI): 486.1 [M+H] ⁺

Example 103

The synthesis process of Compound 103 to Compound 609 is basically referred to the experimental procedure of Example 26.

Biological evaluation

The following test examples are intended to further illustrate the invention, but these test examples are not intended to limit the scope of the invention.

Test Example 1. Determination of the inhibitory effect of the compound of the present invention on BRD4 binding activity

The BRD4 binding activity test was tested by the following method.

Experimental procedure

In order to test the effect of compounds on the binding activity of BRD4 to acetylated protein, this experiment used fluorescence resonance energy transfer (TR-FRET) method to test the inhibitory effect of compounds on the binding activity of BRD4 to acetylated substrate, and obtained the compound against BRD4. binding activity half maximal inhibitory concentration IC _50.

The specific experimental operation is as follows:

1. Add 1 to 5 ul of BRD4 enzyme solution to the 384-well plate, and the final concentration of the enzyme is 1 to 20 nM;

2. Add 1 to 5 ul of the gradient diluted compound solution;

3, adding 1 ~ 5ul substrate mixture containing acetylated substrate polypeptide final concentration of 2 ~ 50nM;

4. Incubate for 0.5 to 3 hours at room temperature;

5. Add 10 ul of EDTA and the labeled antibody-containing test solution, incubate for 1 hour at room temperature;

6. The 665 nm fluorescence signal value of each plate hole was measured by a microplate reader;

7. Calculate the inhibition rate by the fluorescence signal value;

8. A compound according to obtain IC ₅₀ inhibition rate of different concentration by curve fitting.

The inhibitory effect of the compound of the present invention on the binding activity of BRD4 was measured by the above test, and the IC ₅₀ values measured are shown in Table 1.

Table 1 IC ₅₀ values of the compounds of the invention against BRD4 binding activity

实施例编号Example number	IC ₅₀(nM) IC ₅₀ (nM)	实施例编号Example number	IC ₅₀(nM) IC ₅₀ (nM)
11	7.37.3	5151	5.15.1
22	24.124.1	5252	16.316.3
44	29.129.1	5353	14.414.4
55	15.915.9	5454	19.319.3
66	19.619.6	5555	40.540.5
77	23.123.1	5656	17.517.5

88	6.06.0	5959	18.418.4
99	12.412.4	6060	9.99.9
1010	14.414.4	6161	17.317.3
1212	31.231.2	6262	17.817.8
1313	9.39.3	6363	21.121.1
1414	26.326.3	6767	26.426.4
1515	28.828.8	6868	20.720.7
1616	13.013.0	6969	19.019.0
1717	9.19.1	7171	9.89.8
1919	32.332.3	7272	14.814.8
21twenty one	29.929.9	7373	14.114.1
22twenty two	34.334.3	7474	16.916.9
23twenty three	11.511.5	7575	11.611.6
2626	6.76.7	7676	6.16.1
2727	15.915.9	7777	12.612.6
2828	12.212.2	7878	23.023.0
3030	30.530.5	7979	25.125.1
3131	15.415.4	8080	22.022.0
3232	15.915.9	8181	21.521.5
3333	3.93.9	8282	16.516.5
3434	4.54.5	8383	21.821.8
3535	4.24.2	8484	9.99.9
3636	8.98.9	8585	35.535.5
3737	20.120.1	8686	10.810.8
3838	32.332.3	8787	26.926.9
3939	34.134.1	8989	18.918.9
4040	38.238.2	9090	13.813.8
4141	27.327.3	9191	3.23.2
4242	44.544.5	9292	2.42.4
4343	31.931.9	9393	22.322.3
4444	18.418.4	9595	19.619.6
4545	46.246.2	9696	45.045.0
4646	5.75.7	9797	8.08.0
4747	21.921.9	9898	8.78.7

4848	27.427.4	9999	27.527.5
4949	30.230.2	100100	11.911.9
5050	23.423.4	101101	16.416.4

Conclusion: The compounds of the present invention have a significant inhibitory effect on BRD4 binding activity.

Test Example 2, Determination of the inhibitory effect of the compound of the present invention on the proliferation activity of colon cancer tumor cell colo205

The compound's proliferative activity against colon cancer tumor cell colo205 was tested by the following method.

Experimental procedure

Inhibitory activity of the present study, the method of CellTiter-Glo colo205 test compound on the proliferation of cells, inhibit cell proliferation and the compound obtained half maximal inhibitory concentration IC ₅₀ activity.

1. Inoculate 50-100 μL of colo205 cell suspension in a 96-well cell culture plate at a density of 1 to 5×10 ⁴ cells/mL. Incubate the plate in an incubator for 16 to 24 hours (37 ° C, 5% CO _{2 ).} ).

2. Add gradient dilutions of different concentrations of the test compound solution to the culture plate cells, and incubate the culture plates in the incubator for 6 days (37 ° C, 5% CO ₂ ).

3. Add 50-100 μL of CellTiter-Glo reagent to each well, shake for 10 minutes, and let stand for 10 minutes at room temperature.

4. The plate reader measures the chemiluminescence signal value of each plate.

5. Calculate the inhibition rate by the value of the chemiluminescence signal.

6, obtained according to compound IC ₅₀ inhibition rate of different concentration by curve fitting.

The compound of the present invention was assayed for the proliferative activity of colon cancer tumor cell colo205, and the measured IC ₅₀ values are shown in Table 2.

Table 2 IC ₅₀ values of the compounds of the present invention inhibiting the proliferation activity of colon cancer tumor cell colo205

实施例编号Example number	IC ₅₀(nM) IC ₅₀ (nM)
11	3636
1010	42.242.2
2626	6.76.7
2727	66.666.6
2828	65.265.2
3131	67.367.3
3232	80.280.2
3333	55.455.4
3535	53.753.7
3737	76.676.6
4444	46.246.2
6060	31.631.6

9797	46.746.7
9898	3.43.4

Conclusion: The compound of the present invention has a significant inhibitory effect on the proliferation activity of colon cancer tumor cell colo205.

Test Example 3, Determination of the inhibitory effect of the compound of the present invention on the proliferative activity of leukemia cell MV4-11

The inhibitory effect of the compound on the proliferative activity of leukemia cell MV4-11 was tested by the following method.

This experiment uses the CellTiter-Glo method for testing compounds for inhibition of the proliferation of MV4-11 cells, the compounds inhibit cell proliferation and draw half maximal inhibitory concentration IC ₅₀ activity.

Experimental steps:

1. Inoculate 50-100 μL of MV4-11 cell suspension in a 96-well cell culture plate at a density of 1 to 5×10 ⁴ cells/mL. Incubate the plate in an incubator for 16 to 24 hours (37 ° C, 5%). CO ₂ ).

2. Add gradient dilutions of different concentrations of the test compound solution to the culture plate cells, and incubate the plate for 72 hours (37 ° C, 5% CO ₂ ) in the incubator.

4. The plate reader measures the chemiluminescence signal value of each plate.

5. Calculate the inhibition rate by the value of the chemiluminescence signal.

The compound of the present invention was assayed for the proliferative activity of leukemia cell MV4-11, and the measured IC ₅₀ values are shown in Table 3.

Table 3 IC ₅₀ values of the compounds of the present invention inhibiting the proliferation of leukemia cell MV4-11

实施例编号Example number	IC ₅₀(nM) IC ₅₀ (nM)	实施例编号Example number	IC ₅₀(nM) IC ₅₀ (nM)
11	3.93.9	5252	1.71.7
22	6.06.0	5353	0.200.20
44	6.06.0	5454	1.61.6
55	2.92.9	5555	2.52.5
66	1.41.4	5656	4.04.0
77	9.59.5	5959	9.29.2
88	0.700.70	6060	6.56.5
99	1.51.5	6161	9.79.7
1010	3.33.3	6262	6.36.3
1212	11.111.1	6363	6.56.5
1313	1.41.4	6464	12.812.8

1414	2.12.1	6565	21.921.9
1515	1.91.9	6666	9.29.2
1616	4.64.6	6767	1.41.4
1717	3.93.9	6868	2.22.2
1818	16.616.6	6969	2.72.7
1919	24.624.6	7171	2.22.2
2020	14.914.9	7272	1.61.6
21twenty one	26.226.2	7373	1.61.6
23twenty three	3.63.6	7474	2.12.1
2525	46.946.9	7575	1.11.1
2626	1.41.4	7676	0.80.8
2727	2.72.7	7777	0.30.3
2828	4.34.3	7878	4.64.6
2929	12.112.1	7979	14.114.1
3030	14.814.8	8080	2.12.1
3131	5.35.3	8181	4.64.6
3232	10.610.6	8282	5.45.4
3333	3.23.2	8383	2.02.0
3434	11.211.2	8484	1.51.5
3535	1.81.8	8585	10.310.3
3636	7.17.1	8686	2.02.0
3737	5.25.2	8787	13.413.4
3838	8.28.2	8888	40.940.9
3939	6.46.4	8989	4.04.0
4040	40.240.2	9090	4.04.0
4141	4.74.7	9191	0.50.5
4242	17.217.2	9292	1.11.1
4343	3.23.2	9393	7.97.9
4444	2.22.2	9494	28.028.0
4545	34.934.9	9595	2.32.3
4646	4.74.7	9696	39.039.0
4747	12.012.0	9797	7.37.3
4848	21.021.0	9898	1.81.8
4949	3.03.0	9999	11.611.6

5050	5.15.1	100100	1.71.7
5151	0.80.8	101101	2.52.5
		102102	48.048.0

Test Example 4, PK analysis test of the compound of the present invention on mice

The mouse pharmacokinetic test of the preferred embodiment of the present invention was carried out using Balb/c mice (Shanghai Jiesijie Experimental Animal Co., Ltd.).

Mode of administration: single intragastric administration

Dosage: 5 mg / 10 ml / kg

Formulation formulation: 0.5% CMC-Na and 1% Tween 80, sonicated

Sampling point: 0.5, 1, 2, 4, 6, 8 and 24 hours after administration

Sample processing:

0.1 mL of venous blood was collected and placed in a K ₂ EDTA test tube, and the plasma was separated by centrifugation at 1000 to 3000 × g for 5 to 20 minutes at room temperature, and stored at -80 ° C.

The plasma sample was added to 160 uL of acetonitrile precipitate, and after mixing, it was centrifuged at 500 to 2000 × g for 5 to 20 minutes.

The treated supernatant solution was taken for 100 uL, and the concentration of the test compound was analyzed by LC/MS/MS. LC/MS/MS analytical instrument: AB Sciex API 4000.

Liquid phase conditions: Shimadzu LC-20AD pump

Column: phenomenex Gemiu 5μm C18 50×4.6mm

Mobile phase: solution A is 0.1% aqueous formic acid, and solution B is acetonitrile.

Flow rate: 0.8mL/min

Pharmacokinetics:

The main parameters were calculated using WinNonlin 6.1, and the results of the mouse pharmacokinetic experiments are shown in Table 4 below.

It can be seen from the results of the mouse pharmacokinetic experiments in the table that the compounds of the examples of the present invention exhibited good metabolic properties, and both the exposure AUC and the maximum blood concentration Cmax performed well.

Claims

A compound of the formula (I):

Or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them:

X, Y are each independently selected from the group consisting of a bond, N, O, -NR 5 -, -(CR 6 R 7 ) x -, and -(CR 6 R 7 ) x N(R 5 ) y -;

Z is selected from -NR 5 -, O and -O(CR 6 R 7 ) x -;

Ring A is selected from the group consisting of a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

R 1 is selected from the group consisting of alkyl, cycloalkyl and alkenyl; wherein said alkyl, alkenyl and cycloalkyl are optionally further selected from the group consisting of alkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy Substituted by one or more substituents of a group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

R 2 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, an olefin, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C( O) R 10 and -NR 9 S(O) m R 10 ; wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from alkyl, haloalkanes Base, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 8 , -C(O) R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S (O) substituted with one or more substituents in m R 10 ;

R 3 is selected from the group consisting of a non-existent hydrogen atom, an alkyl group, a halogenated alkyl group, an alkene group, an alkoxy group, a halogenated alkoxy group, a halogen group, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group, and a hetero group. Aryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m R 10 ; wherein the alkyl, haloalkyl, olefin, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected From alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 And one or more substituents in -NR 9 S(O) m R 10 are substituted;

Alternatively, R 2 and R 3 are bonded to form a heterocyclic or heteroaryl group; wherein said heterocyclic group and heteroaryl are optionally further selected from the group consisting of alkyl, haloalkyl, alkene, alkoxy, haloalkoxy , halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S (O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m One or more substitutions in R 10 Substituted by

Further, R 2 and R 3 are each independently bonded to R 6 , R 7 or R 5 on the X group to form a heterocyclic or heteroaryl group; wherein said heterocyclic group and heteroaryl group are optionally further Selected from alkyl, haloalkyl, olefin, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 And one or more substituents in -NR 9 S(O) m R 10 are substituted;

R 4 is independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a hydroxyalkyl group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group, Heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -(CH 2 ) t NR 9 R 10 , -(CH 2 ) t C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m R 10 ; wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group Further optionally, it is selected from the group consisting of alkyl, haloalkyl, olefin, alkoxy, haloalkoxy, hydroxyalkyl, halogen, haloalkyl, alkyl substituted heterocyclic, amino, nitro, hydroxy, cyano, cyclo Alkyl, heterocyclic, aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 ,- Substituting one or more substituents of C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m R 10 ;

R 5 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an alkoxy group, a halogenated alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

R 6 and R 7 are each independently selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group. , aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m R 10 ;

Alternatively, R 6 and R 7 may form a cycloalkyl or heterocyclic group, which is optionally further selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, halogen , amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m One or more substituents in R 10 Replace

R 8 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkenyl group, a hydroxyl group, an amino group, an alkoxy group, a halogenated alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; wherein the alkyl group, Haloalkyl, alkenyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from the group consisting of alkyl, halo, haloalkyl, amino, nitro, cyano, hydroxy, hydroxyalkyl, alkoxy Base, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R Substituting one or more substituents of 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m R 10 ;

R 9 and R 10 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, cycloalkyl group And a heterocyclic group, an aryl group and a heteroaryl group are further selected from the group consisting of an alkyl group, a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group. And substituted with one or more substituents in the heteroaryl;

m is an integer of 0, 1, or 2;

n is an integer of 0, 1, 2, 3, 4 or 5;

t is an integer of 0, 1, 2, 3, 4 or 5;

x is an integer of 0, 1, 2, 3 or 4;

y is an integer of 0 or 1.
A compound according to claim 1 which is a compound of the formula (II):

Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them:

B is selected from CH and N;

R 1 to R 4 , Z, X, Y and n are as defined in claim 1.
A compound according to claim 1 which is a compound of the formula (III):

Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them:

B is selected from CH and N;

R 1 , R 2 , R 4 , Z, X and n are as defined in claim 1.
a compound of the formula (IV):

Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them:

Z is selected from NH and O;

B is selected from CH and N;

Ring C is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from the group consisting of alkyl, halogen, amino, Substituted by one or more substituents of a nitro group, a hydroxyl group, a cyano group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

z is an integer of 0, 1, 2 or 3;

R 1 , R 2 , R 4 , X and n are as defined in claim 1.
The compound according to claim 4 which is a compound represented by the formula (VA) or (VB):

Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them:

Z is selected from NH and O;

X is selected from the group consisting of a bond, NH and -CR 6 R 7 -;

R 4 is independently selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, a cyano group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a C 1-6 hydroxyalkyl group, a C 3-6 cycloalkyl group, -( CH 2 ) t NR 9 R 10 and -(CH 2 ) t C(O)NR 9 R 10 ;

R 2 is selected from C 1-6 alkyl, halo C 1-6 alkyl, -NR 9 R 10 , C 3-6 cycloalkyl and 5-6 membered heteroaryl; wherein said C 1-6 The alkyl group, halo C 1-6 alkyl group, C 3-6 cycloalkyl group and 5-6 membered heteroaryl group are further optionally selected from C 1-6 alkyl groups, halogenated C 1-6 alkyl groups, halogen Substituting one or more substituents of an amino group, a cyano group and a hydroxyl group;

R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom and a C 1-3 alkyl group;

R 9 and R 10 are the same or different and are each independently selected from a hydrogen atom and a C 1-3 alkyl group;

n, t as defined in claim 1.
A compound according to claim 4 which is a compound of the formula (VIA) or (VIB):

Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them:

Z is selected from NH and O;

X is selected from the group consisting of a bond, NH and -CR 6 R 7 -;

R 4 is independently selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, a cyano group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a C 1-6 hydroxyalkyl group, a C 3-6 cycloalkyl group, -( CH 2 ) t NR 9 R 10 and -(CH 2 ) t C(O)NR 9 R 10 ;

R 2 is selected from C 1-6 alkyl, halo C 1-6 alkyl, -NR 9 R 10 , C 3-6 cycloalkyl and 5-6 membered heteroaryl; wherein said C 1-6 The alkyl group, halo C 1-6 alkyl group, C 3-6 cycloalkyl group and 5-6 membered heteroaryl group are further optionally selected from C 1-6 alkyl groups, halogenated C 1-6 alkyl groups, halogen Substituting one or more substituents of an amino group, a cyano group and a hydroxyl group;

R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom and a C 1-3 alkyl group;

R 9 and R 10 are the same or different and are each independently selected from a hydrogen atom and a C 1-3 alkyl group;

t as defined in claim 1.
The compound according to any one of claims 1 to 4, wherein R 1 is selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl and C 3-8 cycloalkyl; preferably C 1-6 alkyl, C 2-6 alkenyl or C 3-6 cycloalkyl; more preferably C 1-3 alkyl, C 2-3 alkenyl or C 3-6 cycloalkyl; most preferred is methyl.
The compound according to any one of claims 1 to 6, wherein R 2 is selected from the group consisting of C 1-6 alkyl, halogenated C 1-6 alkyl, C 3-6 cycloalkyl and 5-6 membered heteroaryl a group wherein the C 1-6 alkyl group, halogenated C 1-6 alkyl group, C 3-6 cycloalkyl group and 5-6 membered heteroaryl group are further selected from a C 1-6 alkyl group, Substituted by one or more substituents of a halogenated C 1-6 alkyl, halogen, amino, cyano and hydroxy; preferably C 1-6 alkyl, halo C 1-6 alkyl or C 3-6 ring Alkyl; more preferably C 1-3 alkyl, halo C 1-3 alkyl or C 3-6 cycloalkyl, most preferably methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl,
The compound according to any one of claims 1-8, which is selected from the group consisting of:

Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.
An intermediate of the compound according to any one of claims 1-9, which is a compound of the formula (V), a compound of the formula (VAA) or a compound of the formula (VBB):

Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them:

R 1 ~ R 4, ring A, Z, X, Y and n are as defined in claim 1.
A method of preparing a compound according to any one of claims 1-9, comprising the steps of:

The compound of the formula (V) is oxidized by an oxidizing agent to give a compound of the formula (I); the oxidizing agent is preferably m-chloroperoxybenzoic acid;

among them:

R 1 to R 4 , ring A, Z, X, Y and n are as defined in claim 1.
The method of preparing a compound according to claim 5, comprising the steps of:

The compound of the formula (VAA) is oxidized by an oxidizing agent to give a compound of the formula (VA); the oxidizing agent is preferably m-chloroperoxybenzoic acid;

among them:

R 2 , R 4 , Z, X and n are as defined in claim 5.
The method of preparing a compound according to claim 5, comprising the steps of:

The compound of the formula (VBB) is oxidized by an oxidizing agent to give a compound of the formula (VB); the oxidizing agent is preferably m-chloroperoxybenzoic acid;

among them:

R 2 , R 4 , Z, X and n are as defined in claim 5.
A pharmaceutical composition comprising a therapeutically effective amount of a compound of any of claims 1-9 and one or more pharmaceutically acceptable carriers, diluents or excipients.
Use of a compound according to any one of claims 1-9, or a pharmaceutical composition according to claim 14 for the preparation of a medicament for BRD4 inhibitor.
Use of the compound according to any one of claims 1 to 9, or the pharmaceutical composition according to claim 14, for the preparation of a medicament for the treatment of cancer, inflammation, chronic liver disease, diabetes, cardiovascular disease and AIDS.
The use according to claim 16, wherein said cancer is selected from the group consisting of breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, liver cancer, solid tumor, glioma, and nerve glue. Maternal tumor, leukemia, lymphoma, myeloma and non-small cell lung cancer; said chronic liver disease is selected from the group consisting of: primary sclerosis, cerebral xanthoma, primary sclerosing cholecystitis, drug-induced cholestasis , intrahepatic cholestasis of pregnancy, parenteral absorption-related cholestasis, bacterial overgrowth or sepsis cholestasis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis , liver graft-related graft-versus-host disease, live donor liver transplant regeneration, congenital liver fibrosis, common bile duct stones, granulomatous liver disease, intrahepatic or extraneous malignancy, Sjogren syndrome, sarcoidosis, Wilson's disease, Gaucher's Disease, hemochromatosis or α 1 -antimembrane protease deficiency.