CN110198941B - Pyrrolopyridine N-oxide derivative and preparation method and application thereof - Google Patents

Abstract

Pyrrolopyridine N-oxide derivatives of formula (I), process for their preparation, pharmaceutical compositions containing them and their use as BRD4 inhibitors in the treatment of related diseases, such as cancer, inflammation, chronic liver disease, diabetes, cardiovascular disease and AIDS.

Description

Pyrrolopyridine N-oxide derivative and preparation method and application thereof

Technical Field

The invention belongs to the field of medicines, relates to pyrrolopyridine N-oxide derivatives, a preparation method thereof and application of a pharmaceutical composition in medical research, and discloses application of the pyrrolopyridine N-oxide derivatives serving as a BRD4 inhibitor in treatment of cancers, inflammations, chronic liver diseases, diabetes, cardiovascular diseases, AIDS and other related diseases.

Background

Tumors are one of the major diseases that seriously harm human life, and more than half occur in developing countries. The incidence of malignant tumors in China generally tends to rise, the incidence is increased at a speed of 3% -5% per year, and 400 million people in China are expected to have cancer and 300 million people die of cancer by 2020, and the main reasons are that: aging, urbanization, industrialization and change of living habits. In the drug market of Chinese hospitals, the sales scale of the antitumor drugs is steadily increased in recent years, the sales scale of the antitumor drugs reaches 664.2 hundred million yuan in 2012 and is increased by 13.07 percent on a par, and the market scale of the antitumor drugs is estimated to reach 1055.7 hundred million yuan and is increased by 7.57 percent on a par by 2017.

Due to unlimited growth, infiltration and metastasis of malignant tumors, three conventional treatment methods (surgery, radiotherapy and chemotherapy) clinically adopted at present cannot completely remove or completely kill tumor cells, so that tumor metastasis or recurrence often occurs. The biological treatment of tumor is a new therapy for preventing and treating tumor by applying modern biotechnology and related products, is a fourth mode of tumor treatment after surgery, radiotherapy and chemotherapy due to the characteristics of safety, effectiveness, low adverse reaction and the like, and obtains the anti-tumor effect by mobilizing the natural defense mechanism of a host or giving naturally-produced substances with strong targeting property.

Bromodomain and extra-terminal domain (BET) family members are bromodomain and BRD4, and BRD4 regulates expression of target genes by recruiting different transcriptional regulators, such as Mediator, positive transcriptional elongation factor b (P-TEFb). As a chromatin adaptor which is widely expressed in mammals, the chromatin adaptor can recognize acetylated proteins to be combined on chromosomes in the whole mitosis process, recruit different chromatin modifying proteins and widely regulate the expression of genes, thereby playing an important role in the aspects of regulating cell cycle process, transcription, inflammation and the like. Recent studies have shown that deregulated expression levels or dysfunction of BRD4 are associated with the development of testicular nuclear protein midline carcinomas (NMCs), melanomas, acute myeloid leukemias, colon cancer, breast cancer and the like. The BRD4shRNA or BET inhibitor can induce the tumorigenesis cell cycle arrest, apoptosis and cell differentiation, and shows strong antitumor activity. These findings indicate that the BET protein is expected to be a novel therapeutic target for the above-mentioned tumors and even other tumors. In addition, the research of a tool compound JQ1 and the like shows that the inhibitor of BRD4 can be widely applied to various diseases such as virus infection, diabetes, metabolic diseases, liver diseases, senile dementia and the like.

The BRD4 inhibitor has good application prospect in the pharmaceutical industry, no medicine on the market exists at present, and in order to achieve the purpose of better treatment effect and meet the market demand, a new generation of high-efficiency low-toxicity selective BRD4 inhibitor is hoped to be developed.

Disclosure of Invention

The invention aims to provide a compound shown in a general formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of the compound shown in the general formula (I) is as follows:

wherein:

x, Y are each independently selected from bond, N, O, -NR₅-、-(CR₆R₇)_x-and- (CR)₆R₇)_xN(R₅)_y-；

Z is selected from-NR₅-, O and-O (CR)₆R₇)_x-；

Ring a is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

R₁selected from alkyl, cycloalkyl and alkenyl; wherein said alkyl, alkenyl and cycloalkyl are optionally further substituted with one or more substituents selected from the group consisting of alkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R₂selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkene, halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR₈、-C(O)R₈、-C(O)OR₈、-S(O)_mR₈、-NR₉R₁₀、-C(O)NR₉R₁₀、-NR₉C(O)R₁₀and-NR₉S(O)_mR₁₀(ii) a Wherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR₈、-C(O)R₈、-C(O)OR₈、-S(O)_mR₈、-NR₉R₁₀、-C(O)NR₉R₁₀、-NR₉C(O)R₁₀and-NR₉S(O)_mR₁₀Is substituted with one or more substituents of (1);

R₃selected from the group consisting of absent, hydrogen atom, alkyl, haloalkyl, alkene, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR₈、-C(O)R₈、-C(O)OR₈、-S(O)_mR₈、-NR₉R₁₀、-C(O)NR₉R₁₀、-NR₉C(O)R₁₀and-NR₉S(O)_mR₁₀(ii) a Wherein said alkyl, haloalkyl, alkene, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further selected from alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR₈、-C(O)R₈、-C(O)OR₈、-S(O)_mR₈、-NR₉R₁₀、-C(O)NR₉R₁₀、-NR₉C(O)R₁₀and-NR₉S(O)_mR₁₀Is substituted with one or more substituents of (1);

or, R₂And R₃Linked to form a heterocyclic or heteroaryl group; wherein said heterocyclyl and heteroaryl are optionally further selected from the group consisting of alkyl, haloalkyl, alkene, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR₈、-C(O)R₈、-C(O)OR₈、-S(O)_mR₈、-NR₉R₁₀、-C(O)NR₉R₁₀、-NR₉C(O)R₁₀and-NR₉S(O)_mR₁₀Is substituted with one or more substituents of (1);

or further alternatively, R₂、R₃Each independently of R on the X group₆、R₇Or R₅Linked to form a heterocyclic or heteroaryl group; wherein said heterocyclyl and heteroaryl are optionally further selected from the group consisting of alkyl, haloalkyl, alkene, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR₈、-C(O)R₈、-C(O)OR₈、-S(O)_mR₈、-NR₉R₁₀、-C(O)NR₉R₁₀、-NR₉C(O)R₁₀and-NR₉S(O)_mR₁₀In (1)Substituted by one or more substituents;

R₄independently selected from the group consisting of hydrogen atom, alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, halogen, amino group, nitro group, hydroxy group, cyano group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, -OR₈、-C(O)R₈、-C(O)OR₈、-S(O)_mR₈、-(CH₂)_tNR₉R₁₀、-(CH₂)_tC(O)NR₉R₁₀、-NR₉C(O)R₁₀and-NR₉S(O)_mR₁₀(ii) a Wherein said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further substituted with a group selected from alkyl, haloalkyl, alkene, alkoxy, haloalkoxy, hydroxyalkyl, halogen, haloalkyl, alkyl-substituted heterocyclyl, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR₈、-C(O)R₈、-C(O)OR₈、-S(O)_mR₈、-NR₉R₁₀、-C(O)NR₉R₁₀、-NR₉C(O)R₁₀and-NR₉S(O)_mR₁₀Is substituted with one or more substituents of (1);

R₅selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

R₆and R₇Each independently selected from the group consisting of hydrogen atom, alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, -OR₈、-C(O)R₈、-C(O)OR₈、-S(O)_mR₈、-NR₉R₁₀、-C(O)NR₉R₁₀、-NR₉C(O)R₁₀and-NR₉S(O)_mR₁₀；

Or, R₆And R₇May form a cycloalkyl or heterocyclyl group optionally further selected from alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxyHalogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR₈、-C(O)R₈、-C(O)OR₈、-S(O)_mR₈、-NR₉R₁₀、-C(O)NR₉R₁₀、-NR₉C(O)R₁₀and-NR₉S(O)_mR₁₀Is substituted with one or more substituents of (1);

R₈selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, alkenyl groups, hydroxyl groups, amino groups, alkoxy groups, haloalkoxy groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; wherein said alkyl, haloalkyl, alkenyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from alkyl, halo, haloalkyl, amino, nitro, cyano, hydroxy, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR₈、-C(O)R₈、-C(O)OR₈、-S(O)_mR₈、-NR₉R₁₀、-C(O)NR₉R₁₀、-NR₉C(O)R₁₀and-NR₉S(O)_mR₁₀Is substituted with one or more substituents of (1);

R₉and R₁₀The same or different, and each is independently selected from the group consisting of hydrogen atom, alkyl, hydroxyl, amino, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of alkyl, halogen, hydroxyl, amino, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and 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; and is

y is an integer of 0 or 1.

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

or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

b is selected from CH and N;

R₁～R₄z, X, Y and n are as defined in formula (I).

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

or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

b is selected from CH and N;

R₁、R₂、R₄z, X and n are as defined in formula (I).

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

or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

z is selected from NH and O;

b is selected from CH and N;

ring C is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from alkyl, halogen, amino, nitro, hydroxy, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and is

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

R₁、R₂、R₄x and n are as defined in formula (I).

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

or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

z is selected from NH and O;

x is selected from the group consisting of a bond, NH and-CR₆R₇-；

R₄Selected from hydrogen atom, halogen, hydroxy, cyano, C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Hydroxyalkyl radical, C_3-6Cycloalkyl, - (CH)₂)_tNR₉R₁₀And- (CH)₂)_tC(O)NR₉R₁₀；

R₂Is selected from C_1-6Alkyl, halo C_1-6Alkyl, -NR₉R₁₀、C_3-6Cycloalkyl or 5-6 membered heteroaryl; wherein said C_1-6Alkyl, halo C_1-6Alkyl radical, C_3-6Cycloalkyl and 5-6 membered heteroaryl optionally further selected from C_1-6Alkyl, halo C_1-6Alkyl, halogen, amino, cyano and hydroxyl;

R₆、R₇are the same or different and are each independently selected from hydrogen atomsAnd C_1-3An alkyl group;

R₉、R₁₀are the same or different and are each independently selected from the group consisting of a hydrogen atom and C_1-3An alkyl group;

n and t are as defined in formula (I).

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

or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

z is selected from NH and O;

x is selected from the group consisting of a bond, NH and-CR₆R₇-；

R_CIndependently selected from hydrogen atom, halogen, hydroxyl, cyano, C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Hydroxyalkyl radical, C_3-6Cycloalkyl, - (CH)₂)_tNR₉R₁₀Or- (CH)₂)_tC(O)NR₉R₁₀；

R₂Is selected from C_1-6Alkyl, halo C_1-6Alkyl, -NR₉R₁₀、C_3-6Cycloalkyl and 5-6 membered heteroaryl; wherein said C_1-6Alkyl, halo C_1-6Alkyl radical, C_3-6Cycloalkyl and 5-6 membered heteroaryl optionally further selected from C_1-6Alkyl, halo C_1-6Alkyl, halogen, amino, cyano and hydroxyl;

R₆、R₇are the same or different and are each independently selected from the group consisting of a hydrogen atom and C_1-3An alkyl group;

R₉、R₁₀are the same or different and are each independently selected from the group consisting of a hydrogen atom and C_1-3An alkyl group;

t is as defined in claim 1.

In a preferred embodiment of the invention, the compounds of the formulae in which R is₁Is selected from C_1-8Alkyl radical, C_2-8Alkenyl and C_3-8A cycloalkyl group; preferably C_1-6Alkyl radical, C_2-6Alkenyl or C_3-6A cycloalkyl group; more preferably C_1-3Alkyl radical, C_2-3Alkenyl or C_3-6A cycloalkyl group; most preferred is methyl.

In a preferred embodiment of the invention, the compounds of the formulae in which R is₂Is selected from C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-6Cycloalkyl and 5-6 membered heteroaryl, wherein said C_1-6Alkyl, halo C_1-6Alkyl radical, C_3-6Cycloalkyl and 5-6 membered heteroaryl optionally further selected from C_1-6Alkyl, halo C_1-6Alkyl, halogen, amino, cyano and hydroxyl; preferably C_1-6Alkyl, halo C_1-6Alkyl or C_3-6A cycloalkyl group; more preferably C_1-3Alkyl, halo C_1-3Alkyl or C_3-6Cycloalkyl groups, most preferably methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclohexyl,

In a preferred embodiment of the invention, the compounds of formula (I) shown are selected from the following compounds:

or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

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

or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

R₁～R₄ring A, Z, X, Y and n are as defined in formula (I).

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

oxidizing the compound of the general formula (V) with an oxidant to obtain a compound of a general formula (I); the oxidizing agent is preferably m-chloroperoxybenzoic acid;

wherein:

R₁～R₄ring A, Z, X, Y and n are as defined for formula (I);

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

oxidizing the compound of the general formula (VAA) by an oxidant to obtain a compound of a general formula (VA); the oxidizing agent is preferably m-chloroperoxybenzoic acid;

wherein:

R₂、R₄z, X and n are as defined in formula (VA);

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

oxidizing the compound with the general formula (VBB) with an oxidant to obtain a compound with a general formula (VB); the oxidizing agent is preferably m-chloroperoxybenzoic acid;

wherein:

R₂、R₄z, X and n are as defined in formula (VB);

another aspect of the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of each formula or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The invention also relates to a method for preparing the pharmaceutical composition, which comprises mixing the compound shown in the general formula or the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer or the mixture form thereof, or the pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier, a diluent or an excipient.

The invention further relates to application of the compound shown in the general formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof, or a pharmaceutically acceptable salt form thereof, or a pharmaceutical composition containing the compound in preparation of medicines for preventing and/or treating and preventing BRD4 serving as an inhibitor in treatment of cancers, inflammations and AIDS. .

The invention further relates to application of the compound shown in the general formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof, or a pharmaceutically acceptable salt form thereof, or a pharmaceutical composition containing the compound in preparation of BRD4 inhibitor medicines.

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

The invention also relates to a method for the treatment and/or prophylaxis of diseases which are mediated by BRD4 and which comprise administering to a patient a therapeutically effective dose of a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same

Another aspect of the present invention relates to a method for treating cancer, which comprises administering to a patient a therapeutically effective amount of a compound of formula (I) of the present invention, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof. The method has remarkable therapeutic effect and less side effects.

Another aspect of the present invention relates to a method of treating inflammation comprising administering to a patient a therapeutically effective amount of a compound of formula (I) of the present invention or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof. The method has remarkable therapeutic effect and less side effects.

Another aspect of the present invention relates to a method for treating chronic liver disease, which comprises administering to a patient a therapeutically effective amount of a compound of formula (I) according to the present invention, or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof. The method has remarkable therapeutic effect and less side effects.

The cancer of the present invention may be selected from breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, liver cancer, solid tumor, glioma, glioblastoma, leukemia, lymphoma, myeloma, and non-small cell lung cancer; said chronic liver disease is selected from: primary cirrhosis (PBC), brain xanthoma (CTX), Primary Sclerosing Cholecystitis (PSC), drug-induced cholestasis, intrahepatic cholestasis of pregnancy, extra-intestinal absorption-related cholestasis (PNAC), bacterial overgrowth or sepsis cholestasis, autoimmune hepatitis, chronic viral hepatitisInflammation, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver transplantation-associated graft-versus-host disease, liver transplantation regeneration of a live donor, congenital liver fibrosis, choledocholithiasis, granulation liver disease, intrahepatic or extrahepatic malignancy, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis or alpha₁It is used for treating deficiency of membrane protease.

Detailed description of the invention

Unless stated to the contrary, terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and 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-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 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-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-ethyl, 2-2, 2-2, 2-2, or, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 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 groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.

The term "alkylene" means that one hydrogen atom of an alkyl group is further substituted, for example: "methylene" means-CH₂-, "ethylene" means- (CH)₂)₂-, "propylene" means- (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, e.g., ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; 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, where the ring to which the parent structure is attached is cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.

The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O)_m(wherein m is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 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 heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, with tetrahydrofuranyl and pyranyl being preferred. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.

The term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system in which one or more ring atoms is selected from nitrogen, oxygen or S (O)_m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 3-or 5-or 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

the heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.

The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure 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 groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate.

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

heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.

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. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate groups.

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

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group 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" refers to fluorine, chlorine, bromine or iodine.

The term "amino" refers to the group-NH₂。

The term "cyano" refers to — CN.

The term "nitro group"means-NO₂。

The term "oxo" refers to ═ O.

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

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

Different terms such as "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C" and the like all express the same meaning, that is, X can be any one or more of A, B, C.

All hydrogen atoms described in the present invention can be replaced by deuterium, which is an isotope thereof, and any hydrogen atom in the compound of the embodiment related to the present invention can also be replaced by a deuterium atom.

"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.

"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.

"pharmaceutically acceptable salts" refers to salts of the compounds of the present invention which are safe and effective for use in the body of a mammal and which possess the requisite biological activity.

Detailed Description

The present invention is further described below with reference to examples, which are not intended to limit the scope of the present invention.

Examples

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or Mass Spectrometry (MS). NMR was measured using a Brukeravence-400 nuclear magnetic spectrometer using deuterated dimethyl sulfoxide (DMSO-d)₆) Deuterated chloroform (CDCl)₃) Deuterated methanol (CD)₃OD), internal standard Tetramethylsilane (TMS), chemical shift is 10^-6(ppm) is given as a unit.

MS was determined using a FINNIGAN LCQAD (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

HPLC was carried out using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150X 4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18150X 4.6mm column).

Average inhibition rate of kinase and IC₅₀The values were determined with a NovoStar microplate reader (BMG, Germany).

The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

The column chromatography generally uses 200-300 mesh silica gel of Taiwan yellow sea as a carrier.

Known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from companies such as ABCR GmbH & Co.KG, Acros Organnics, Aldrich Chemical Company, Shao Yuan Chemical technology (Accela ChemBio Inc), Darri Chemicals, and the like.

In the examples, the reaction was carried out under an argon atmosphere or a nitrogen atmosphere unless otherwise specified.

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

The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.

The pressure hydrogenation reaction used a hydrogenation apparatus of Parr 3916EKX type and a hydrogen generator of Qinglan QL-500 type or a hydrogenation apparatus of HC2-SS type.

The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.

The microwave reaction was carried out using a CEM Discover-S908860 type microwave reactor.

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

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

The room temperature is the optimum reaction temperature, and the temperature range is 20-30 ℃.

The progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC) using a developing solvent system of: a: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, D: the volume ratio of acetone and solvent is adjusted according to the polarity of the compound.

The system of eluents for column chromatography and developing agents for thin layer chromatography used for purifying compounds include: a: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: n-hexane, ethyl acetate and dichloromethane system, D: petroleum ether and ethyl acetate system, E: the volume ratio of ethyl acetate and solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine and acidic or basic reagent can be added for adjustment.

Example 1

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

The first step is as follows: preparation of 4-chloro-1H-pyrrolo [2, 3-b ] pyridine-7-oxide

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

¹H NMR(400MHz，DMSO-d₆)：δ12.85(br，1H)，8.15(d，J＝6.6Hz，1H)，7.57(d，J＝3.3Hz，1H)，7.21(d，J＝6.6Hz，1H)，6.60(d，J＝3.3Hz，1H).

The second step is that: preparation of (6-bromo-4-chloro-1H-pyrrolo [2, 3-b ] pyridin-1-yl) (phenyl) methanone

Benzoyl bromide (14.3g, 77mmol) and bis (trimethylsilyl) amine (5g, 31mmol) were added slowly in parallel and dropwise to 4-chloro-1H-pyrrolo [2, 3-b ]]Pyridine-7-oxide (5.2g, 31mmol) in tetrahydrofuran (75mL) for about 30 minutes at a temperature of 20-30 ℃. After the completion of the dropwise addition, the reaction was carried out at room temperature for 3 hours. The reaction mixture was neutralized with a saturated solution of sodium hydrogencarbonate, extracted with ethyl acetate (25 mL. times.2), the organic phases were combined and Na was added₂SO₄Drying and concentrating. The crude product was separated by column (ethyl acetate: petroleum ether ═ 1: 10, V/V) to give (6-bromo-4-chloro-1H-pyrrolo [2, 3-b)]Pyridin-1-yl) (phenyl) methanone (2.5g, 24% yield).

¹H NMR(400MHz，CDCl₃)：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 (4mL, 4mmol, 1M) was added slowly dropwise under nitrogen to a solution of (6-bromo-4-chloro-1H-pyrrolo [2, 3-b ] pyridin-1-yl) (phenyl) methanone (1.7g, 5mmol) and [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (365mg, 0.5mmol) in tetrahydrofuran (20 mL). The reaction solution was reacted at 70 ℃ for 16 hours under nitrogen protection. The reaction was cooled, quenched with saturated sodium bicarbonate solution (10mL), extracted with ethyl acetate (25 mL. times.2), the organic phases combined, dried and concentrated to give the crude product. The crude product was isolated by column (ethyl acetate: petroleum ether ═ 1: 1, V/V) to give 4-chloro-6-methyl-1H-pyrrolo [2, 3-b ] pyridine (290mg, 35% yield).

¹H NMR(400MHz，CDCl₃)：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 (14g, 107.7mmol), 2, 4-difluorophenol (19.6g, 89.7mmol) were dissolved in DMSO (100mL), cesium carbonate (35g, 17.7mmol) was added at room temperature, and then stirred at 110 ℃ for 2 hours. Water (150mL) was added to the reaction mixture, followed by extraction with ethyl acetate (200mL), and the organic phase was washed with saturated brine (100mL, dried over anhydrous sodium sulfate, and then concentrated to give 2-bromo-1- (2, 4-difluorophenoxy) -4-nitrobenzene, and the crude product was used directly in the next reaction.

The fifth step: preparation of 3-bromo-4- (2, 4-difluorophenoxy) aniline

2-bromo-1- (2, 4-difluorophenoxy) -4-nitrobenzene (29g, 88.4mmol) was dissolved in ethanol (160mL), tetrahydrofuran (160mL), water (56mL), and iron powder (24.7g, 442mmol), ammonium chloride (9.45g, 176.8mmol) were added. The temperature was raised to 100 ℃, stirred for 1.5 hours, filtered through celite, the solvent was removed from the filtrate, dichloromethane (250mL) was added for extraction, the organic phase was dried, and the dichloromethane was removed from the filtered filtrate under reduced pressure to give 3-bromo-4-phenoxyaniline (22.0g, 83% yield).

MS m/z(ESI)：300.1[M+H]⁺

And a sixth step: preparation of N- (3-bromo-4- (2, 4-difluorophenoxy) phenyl) ethanesulfonamide

3-bromo-4-phenoxyaniline (10g, 33.44mmol) was dissolved in dichloromethane (80mL) under ice bath, ethanesulfonyl chloride (5.52g, 43.48mmol), pyridine (5.28g, 66.88mmol) and the organic phase was washed with hydrochloric acid (2M, 100mL × 2), water (100mL × 2) and saturated brine (100mL), dried over anhydrous sodium sulfate and concentrated to give the compound N- (3-bromo-4- (2, 4-difluorophenoxy) phenyl) ethanesulfonamide (10.7g, 82% yield).

MS m/z(ESI)：392.1.1[M+H]⁺

The seventh step: preparation of N- (4- (2, 4-difluorophenoxy) -3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) ethanesulfonamide

N- (3-bromo-4- (2, 4-difluorophenoxy) phenyl) ethanesulfonamide (500mg, 1.28mmol), 4, 4, 4 ', 4 ', 5, 5, 5 ', 5 ' -octamethyl-2, 2 ' -bis (1, 3, 2-dioxaborolan) (648mg, 2.55mmol), 1, 3, 5, 7-tetramethyl-6-phenyl-2, 4, 8-trioxa-6-phosphamantadine (37mg, 0.128mmol), tris (dibenzylideneacetone) dipalladium (35mg, 0.038mmol) and potassium acetate (275mg, 2.82mmol) were dissolved in 1, 4-dioxane (20 mL). The reaction solution was reacted at 80 ℃ for 12 hours under nitrogen protection, and then at 105 ℃ for 5 hours. The reaction mixture was evaporated to dryness and crude column separation (petroleum ether: ethyl acetate 5: 1, V/V) gave a mixture of N- (4- (2, 4-difluorophenoxy) phenyl) ethanesulfonamide and N- (4- (2, 4-difluorophenoxy) -3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) ethanesulfonamide (500mg) which was used directly in the next step.

MS m/z(ESI)：440.1[M+H]⁺

Eighth step: preparation of N- (4- (2, 4-difluorophenoxy) -3- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) ethanesulfonamide

N- (4- (2, 4-difluorophenoxy) -3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) ethanesulfonamide (395mg, 0.9mmol), 4-chloro-6-methyl-1H-pyrrolo [2, 3-b ] pyridine (100mg, 0.6mmol), tetratriphenylphosphine palladium (69mg, 0.06mmol) and potassium carbonate (414mg, 3mmol) were added to ethanol/toluene/water (v/v/v ═ 9: 3: 1, 10 mL). The reaction solution is subjected to microwave reaction for 0.5 hour at the temperature of 120 ℃ under the protection of nitrogen. The reaction mixture was evaporated to dryness and the crude was separated using a preparative plate (petroleum 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 (190mg, 71% yield).

MS m/z(ESI)：444.1[M+H]⁺

The ninth step: preparation of 4- (2- (2, 4-difluorophenoxy) -5- (ethylsulfonylamino) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide

M-chloroperoxybenzoic acid (41mg, 0.2mmol, 85%) was added to a solution of N- (4- (2, 4-difluorophenoxy) -3- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) ethanesulfonamide (60mg, 0.14mmol) in tetrahydrofuran (2 mL). After 16H reaction at rt and concentration by evaporation, the crude product was first prepared using a reverse phase column (acetonitrile: water 2: 3, V/V) to give a crude product, which was then separated using preparative plates (dichloromethane: methanol 15: 1) to give 4- (2- (2, 4-difluorophenoxy) -5- (ethylsulfonamido) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (12mg, 19% yield).

¹H NMR(400MHz，CDCl₃)：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＝3.2Hz，1H)，7.13(d，J＝7.6Hz，1H)，6.87-6.77(m，2H)，6.74(d，J＝8.8Hz，1H)，6.72-6.65(m，1H)，6.47(d，J＝3.2Hz，1H)，3.12(q，J＝7.4Hz，2H)，2.57(s，3H)，1.33(t，J＝7.4Hz，3H).

MS m/z(ESI)：460.1[M+H]⁺

Example 2

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

The first step is as follows: 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 (30.0g, 89mmol) was dissolved in methanol (400mL), aqueous sodium hydroxide (1M, 178mL) was added to the above solution, and after overnight reaction at room temperature, a large amount of white solid precipitated, which was filtered, and the filter cake was washed with water (20mL) and dried to give 6-bromo-4-chloro-1H-pyrrolo [2, 3-b ] pyridine (17.0g, 82.5% yield).

MS m/z(ESI)：231.1[M+H]⁺

The second step is that: preparation of 6-bromo-4-chloro-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine

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

MS m/z(ESI)：385.0[M+H]⁺

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

6-bromo-4-chloro-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine (15.5g, 40mmol) is dissolved in tetrahydrofuran (150mL), [1, 1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (1.46g, 2mmol) is added to replace nitrogen, dimethylzinc (20mL, 1M toluene solution) is added dropwise under ice bath conditions, after dropwise addition, the mixture is heated to 70 ℃ for reaction overnight, and LC/MS detects that the reaction is complete. Water (400mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (300mL), and the organic phase was washed with saturated brine (300mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate: 10: 1, V/V) to give 4-chloro-6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine (11.5g, 89% yield).

¹H NMR(400MHz，DMSO-d₆)：δ8.05-8.03(d，J＝8.4Hz，2H)，7.90(d，J＝4.0Hz，1H)，7.44-7.42(d，J＝8.0Hz，2H)，7.35(s，1H)，6.79(d，J＝4.0Hz，1H)，2.56(s，3H)，2.35(s，3H)。

MS m/z(ESI)：321.1[M+H]⁺

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

4-chloro-6-methyl-1-tosyl-1H-pyrrolo [2, 3-b ] pyridine (6.0g, 18.8mmol), 4, 4, 4 ', 4', 5, 5, 5 ', 5' -octamethyl-2, 2 '-bis (1, 3, 2-dioxaborolane) (7.6g, 30mmol), palladium acetate (140mg, 0.63mmol), [1, 1' -biphenyl ] -3-yl dicyclohexyl phosphane (438mg, 1.25mmol), potassium acetate (9.2g, 93.8mmol) were dissolved in 1, 4-dioxane (100mL), nitrogen was replaced, heating to 90 ℃ was stirred overnight, and the reaction was detected to be complete by LC/MS. Water (200mL) was added to the reaction mixture, and extraction was performed with ethyl acetate (200mL), and the organic phase was washed with saturated brine (200mL), dried over anhydrous sodium sulfate, and concentrated and then purified by silica gel column chromatography (petroleum ether: ethyl acetate: 10: 1, V/V) to obtain 6-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine (5.5g, yield 71.2%).

MS m/z(ESI)＝413.1[M+H]⁺

The fifth step: preparation of 4- (2, 4-difluorophenoxy) -3- (6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) aniline

3-bromo-4- (2, 4-difluorophenoxy) aniline (2.0g, 6.67mmol), 6-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine (2.75g, 6.67mmol), [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (284mg, 0.38mmol), potassium carbonate (1.34g, 9.7mmol) were dissolved in a mixture of 1, 4-dioxane (16mL) and water (4mL) and reacted under nitrogen at 100 ℃ for 4 hours, the reaction was completed, the reaction solution was poured into water (50mL), extracted with ethyl acetate (50 mL. times.2), the organic phases were combined, washed with water (100mL), after washing with saturated brine (100mL), it was dried over anhydrous sodium sulfate, concentrated and subjected to column chromatography (petroleum ether: ethyl acetate: 1, V/V) to give 4- (2, 4-difluorophenoxy) -3- (6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) aniline (1.9g, 56% yield).

MS m/z(ESI)：506.1[M+H]⁺。

And a sixth step: preparation of N- (4- (2, 4-difluorophenoxy) -3- (6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) cyclopropanesulfonamide

Dissolving 4- (2, 4-difluorophenoxy) -3- (6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) aniline (100mg, 0.198mmol) in dichloromethane (2mL), adding cyclopropylsulfonyl chloride (36mg, 0.257mmol), pyridine (31mg, 0.394mmol) under ice bath, stirring overnight, quenching with saturated aqueous ammonium chloride (2mL), draining the reaction, adding 20mL of water, extracting with ethyl acetate (20mL × 2), combining the organic phases, washing with water (40mL) and saturated brine (40mL) in this order, drying over anhydrous sodium sulfate, concentrating, and performing column chromatography (petroleum ether: ethyl acetate ═ 3: 1, V/V) to obtain N- (4- (2, 4-difluorophenoxy) -3- (6-methyl-1-toluenesulfonyl) to obtain N- (4- (2, 4-difluorophenoxy) -3- (6-methyl-1-toluenesulfonyl) aniline -1H-pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) cyclopropanesulfonamide (93mg, 77% yield).

MS m/z(ESI)：610.1[M+H]⁺。

The seventh step: preparation of N- (4- (2, 4-difluorophenoxy) -3- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) cyclopropanesulfonamide

Dissolving N- (4- (2, 4-difluorophenoxy) -3- (6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) cyclopropanesulfonamide (93.0mg, 0.15mmol) in ethanol (3mL), adding sodium methoxide (25mg, 0.46mmol) at room temperature, stirring overnight at 50 ℃, quenching the reaction solution with a saturated aqueous ammonium chloride solution (1mL), extracting with ethyl acetate (20mL), combining the organic phases, washing with a saturated aqueous sodium bicarbonate solution (20mL), washing with water (20mL), washing with a saturated saline solution (20mL), drying over anhydrous sodium sulfate, concentrating, and subjecting to column chromatography (petroleum ether: ethyl acetate: 1, V/V) to obtain the compound N- (4- (2, 4-difluorophenoxy) -3- (6-methyl-1H-pirimic) Pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) cyclopropanesulfonamide (40mg, 58% yield).

MS m/z(ESI)：456.1[M+H]⁺。

Eighth step: preparation of 4- (5- (cyclopropylsulfonylamino) -2- (2, 4-difluorophenoxy) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide

Dissolving N- (4- (2, 4-difluorophenoxy) -3- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) cyclopropanesulfonamide (40mg, 0.087mmol) in THF (0.5mL), adding m-chloroperoxybenzoic acid (24mg, 0.114mmol) at room temperature, stirring at room temperature for reaction for ten minutes, quenching with a saturated aqueous solution of ammonium chloride (1mL), adding water (10mL), then extracting with ethyl acetate (10 mL. times.2), combining the organic phases, washing with a saturated aqueous solution of sodium hydrogencarbonate (20mL), water (20mL) and a saturated common salt solution (20mL), drying over anhydrous sodium sulfate, concentrating, subjecting to preparative chromatography to give 4- (5- (cyclopropylsulfonamido) -2- (2, 4-difluorophenoxy) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (25.5mg, 62% yield).

¹H NMR(400MHz，CDCl₃)：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＝2.9Hz，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)：472.1[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

The first step is as follows: preparation of N- (4- (2, 4-difluorophenoxy) -3- (6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) 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, reference was made to the sixth step of example 2, substituting 3, 5-dimethylisoxazole-4-sulfonyl chloride for cyclopropylsulfonyl chloride to give N- (4- (2, 4-difluorophenoxy) -3- (6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) -3, 5-dimethylisoxazole-4-sulfonamide (110mg, 87% yield).

MS m/z(ESI)：645.1[M+H]⁺。

The second step is that: preparation of N- (4- (2, 4-difluorophenoxy) -3- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) -3, 5-dimethylisoxazole-4-sulfonamide

Starting from N- (4- (2, 4-difluorophenoxy) -3- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) -3, 5-dimethylisoxazole-4-sulfonamide, the seventh step of reference example 2 gave the compound N- (4- (2, 4-difluorophenoxy) -3- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) -3, 5-dimethylisoxazole-4-sulfonamide (70mg, 83% yield).

MS m/z(ESI)：511.1[M+H]⁺。

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

Starting from N- (4- (2, 4-difluorophenoxy) -3- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) -3, 5-dimethylisoxazole-4-sulfonamide, according to the eighth step of example 2, 4- (2- (2, 4-difluorophenoxy) -5- ((3, 5-dimethylisoxazole) -4-sulfonylamino) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (30.1mg, 42% yield) was obtained.

¹H NMR(400MHz，CDCl₃)：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＝14.8，8.8Hz，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

The first step is as follows: preparation of N- (4- (2, 4-difluorophenoxy) -3- (6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) propane-2-sulfonamide

Starting from 4- (2, 4-difluorophenoxy) -3- (6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) aniline, according to the sixth step of example 2, propane-2-sulfonyl chloride was used instead of cyclopropylsulfonyl chloride to give N- (4- (2, 4-difluorophenoxy) -3- (6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) propane-2-sulfonamide (110mg, 91% yield).

MS m/z(ESI)：612.1[M+H]⁺.

The second step is that: preparation of N- (4- (2, 4-difluorophenoxy) -3- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) propane-2-sulfonamide

Starting from N- (4- (2, 4-difluorophenoxy) -3- (6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) propane-2-sulfonamide, the seventh step of reference example 2 was performed to give the compound N- (4- (2, 4-difluorophenoxy) -3- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) propane-2-sulfonamide (69mg, 84% yield).

MS m/z(ESI)：458.1[M+H]⁺。

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

Starting from N- (4- (2, 4-difluorophenoxy) -3- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) propane-2-sulfonamide, according to the eighth step of example 2, 4- (2- (2, 4-difluorophenoxy) -5- ((1-methylethyl) sulfonamido) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine 7-oxide was obtained (27.6mg, 39% yield).

¹H NMR(400MHz，DMSO-d₆)：δ12.38(s，1H)，9.84(s，1H)，7.47(d，J＝2.7Hz，1H)，7.42-7.34(m，2H)，7.29(dd，J＝8.9，2.7Hz，1H)，7.24(s，1H)，7.12(td，J＝9.2，5.6Hz，1H)，7.05-6.89(m，2H)，6.47(d，J＝3.3Hz，1H)，3.26(q，J＝6.8Hz)，2.52(s，3H)，1.27(d，J＝6.8Hz，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

The first step is as follows: 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 (0.065g, 0.13mmol) was dissolved in ethanol (5mL) at room temperature, and sodium methoxide (0.014g, 0.26mmol) was added to the reaction system, and the mixture was heated to 50 ℃ and reacted overnight. After the reaction was completed, ethanol was dried by spinning, and the residue was dissolved in ethyl acetate 20(mL), washed with brine (10mL × 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spinning to obtain a crude product, 4- (2, 4-difluorophenoxy) -3- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) aniline (0.04g, white solid, yield 89%).

MS m/z(ESI)：352.1[M+H]⁺.

The second step is that: n- (4- (2, 4-difluorophenoxy) -3- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) -2, 2, 2-trifluoroethane-1-sulfonamide

Pyridine (0.018g, 0.228mmol) and 4- (2, 4-difluorophenoxy) -3- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) aniline (0.040g, 0.114mmol) were dissolved in dichloromethane (8mL) under ice-bath, and then 2, 2, 2-trifluoroethylsulfonyl chloride (0.042g, 0.228mmol) was added to the reaction system, and stirred at room temperature overnight. The reaction was diluted with dichloromethane (30mL), washed with saturated sodium bicarbonate solution (10mL), brine (10mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and spun-dried to give the crude N- (4- (2, 4-difluorophenoxy) -3- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) -2, 2, 2-trifluoroethane-1-sulfonamide (0.06g) which 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 (0.04g, 0.08mmol) was dissolved in dichloromethane (8mL) at room temperature, and then m-chloroperoxybenzoic acid (0.02g, 85%, 0.097mmol) was added to the reaction solution and reacted at room temperature for half an hour. The reaction was diluted with dichloromethane (20mL), the organic phase was washed with saturated sodium bicarbonate solution (10mL), brine (10mL), the organic phase was dried over anhydrous sodium sulfate, filtered, spun-dried, and the crude product was isolated by preparative reverse phase 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 (0.015g, white solid, yield: 36%).

MS m/z(ESI)：514.1[M+H]⁺.

¹HNMR(400MHz，CD₃OD)：δ11.73(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＝2.8Hz，1H)，3.96(t，J＝8.8Hz，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

The first step is as follows: 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 (500mg, 1.21mmol), 2-bromo-1-fluoro-4-nitrobenzene (533mg, 2.42mmol), [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (88.5mg, 0.12mmol), potassium carbonate (500mg, 3.63mmol) were dissolved in a mixture of 1, 4-dioxane (10mL) and water (3mL), reacted at 100 ℃ under nitrogen for 4 hours and then detected by LC/MS for completion. Water (100mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100mL × 2), and the organic phase was washed with saturated brine (100mL), dried over anhydrous sodium sulfate, and concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 2: 1, V/V) to give 4- (2-fluoro-5-nitrophenyl) -6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine (400mg, yield 78%).

MS m/z(ESI)：426.1[M+H]⁺

The second step is that: preparation of 4- (2- (4-bromo-2-fluorophenoxy) -5-nitrophenyl) -6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine

4- (2-fluoro-5-nitrophenyl) -6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine (400mg, 0.94mmol), 4-bromo-2-fluorophenol (533mg, 2.42mmol) were dissolved in dimethyl sulfoxide (5mL), cesium carbonate (368mg, 1.13mmol) was added, heating was carried out to 100 ℃ and stirring was carried out for 1 hour, and the reaction was detected to be complete by LC/MS. Water (100mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL. times.2), and the organic phase was washed with a saturated sodium carbonate solution (50 mL. times.2) and a saturated brine (50mL), dried over anhydrous sodium sulfate, and concentrated to give 4- (2- (4-bromo-2-fluorophenoxy) -5-nitrophenyl) -6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine (500mg, 89% yield).

MS m/z(ESI)：596.0[M+H]⁺

The 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 (500mg, 0.84mmol) was dissolved in t-butanol (15mL), and aqueous potassium hydroxide (3M, 8mL) was added to the solution, heated to 75 deg.C, and stirred overnight. The reaction mixture was extracted with ethyl acetate (50 mL. times.2), and the organic phase was washed with saturated brine (50 mL. times.2), dried over anhydrous sodium sulfate, and concentrated to give 4- (2- (4-bromo-2-fluorophenoxy) -5-nitrophenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine (300mg, yield 81%).

MS m/z(ESI)：442.0[M+H]⁺

The 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 (300mg, 0.68mmol) was dissolved in a mixture of tetrahydrofuran (10mL), ethanol (10mL) and water (3mL), and reduced iron powder (280mg, 5mmol), ammonium chloride (265mg, 5mmol) were added to the above solution, heated to 100 ℃ and stirred for 1 hour. Filtration was carried out, and the residue was washed with ethyl acetate (50mL), and the filtrate was washed with saturated brine (50mL), dried over anhydrous sodium sulfate, and concentrated to give 4- (4-bromo-2-fluorophenoxy) -3- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) aniline (230mg, yield 82.1%).

MS m/z(ESI)：412.0[M+H]⁺

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

4- (4-bromo-2-fluorophenoxy) -3- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) aniline (100mg, 0.24mmol) was dissolved in dichloromethane (5mL), ethylsulfonyl chloride (88mg, 0.69mmol), pyridine (0.3mL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (50mL), and the organic phase was washed with a saturated ammonium chloride solution (50 mL. times.2) and a saturated brine (50 mL. times.2), dried over anhydrous sodium sulfate, and concentrated to give N- (4- (4-bromo-2-fluorophenoxy) -3- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) ethanesulfonamide (70mg, yield 57%).

MS m/z(ESI)：504.0[M+H]⁺

And a sixth step: preparation of 4- (2- (4-bromo-2-fluorophenoxy) -5- (ethylsulfonylamino) phenyl) -6-methyl-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) ethanesulfonamide (70mg, 0.14mmol) was dissolved in tetrahydrofuran (2mL), and m-chloroperoxybenzoic acid (42mg, 0.21mmol) was added and stirred at room temperature for 30 minutes. To the reaction solution was added ethyl acetate (50mL), which was washed with saturated sodium carbonate solution (30mL × 2) and then with saturated brine (30mL), followed by drying over anhydrous sodium sulfate, concentration and purification by silica gel preparative chromatography (dichloromethane: methanol ═ 10: 1, V/V) to give 4- (2- (4-bromo-2-fluorophenoxy) -5- (ethylsulfonamido) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (10.0mg, yield 13.7%).

¹H NMR(400MHz，CDCl₃)：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＝8.8Hz，1H)，6.91-6.88(d，J＝8.8Hz，1H)，6.77-6.75(t，J＝8.8Hz，1H)，6.51(d，J＝2.8Hz，1H)，3.23(q，J＝7.2Hz，2H)，2.63(s，3H)，1.43-1.41(t，J＝3.6Hz，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-pyrrolo [2, 3-b ] pyridine-7-oxide

The first step is as follows: preparation of N- (4- (4-bromo-2-fluorophenoxy) -3- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) -2, 2, 2-trifluoroethane-1-sulfonamide

Starting from 4- (4-bromo-2-fluorophenoxy) -3- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) aniline, in the fifth step of reference example 6, ethylsulfonyl chloride was substituted with 2, 2, 2-trifluoroethylsulfonyl 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 (60.0mg, 45.0% yield).

MS m/z(ESI)：558.0[M+H]⁺

The second step is that: preparation of 4- (2- (4-bromo-2-fluorophenoxy) -5- ((2, 2, 2-trifluoroethyl) sulfonylamino) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide

Starting from N- (4- (4-bromo-2-fluorophenoxy) -3- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) -2, 2, 2-trifluoroethane-1-sulfonamide, reference was made to the sixth step of example 6 to give 4- (2- (4-bromo-2-fluorophenoxy) -5- ((2, 2, 2-trifluoroethyl) sulfonamido) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (18.5mg, 35.8% yield).

¹H NMR(400MHz，CDCl₃)：δ12.29(s，1H)，1011(s，1H)，7.44-7.42(dd，J＝8.8Hz，2.0Hz，1H)，7.32(s，1H)，7.24(d，J＝2.0Hz，1H)，7.18(d，J＝2.4Hz，1H)，7.14-7.12(d，J＝8.8Hz，1H)，7.11(s，1H)，6.89-6.87(d，J＝8.8Hz，1H)，6.80-6.76(t，J＝8.8Hz，1H)，6.42(d，J＝2.8Hz，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

The first step is as follows: preparation of 2-bromo-1- (((1r, 4r) -4-methylcyclohexyl) oxo) -4-nitrobenzene

(1r, 4r) -4-methylcyclohexan-1-ol (1.6g, 13.6mmol) was dissolved in N, N-dimethylformamide (50mL), sodium hydride (0.5g, 13.6mmol) was added under nitrogen protection in ice bath, 2-bromo-1-fluoro-4-nitrobenzene (2.0g, 9mmol) was added after stirring for half an hour, and the reaction was stirred at room temperature overnight. The reaction was quenched by adding water (100mL) and a yellow solid precipitated, the mixture was filtered, the solid was washed with water (20 mL. times.2), and the solid was collected and dried by spinning to give 2-bromo-1- (((1r, 4r) -4-methylcyclohexyl) oxo) -4-nitrobenzene (2.8g, 98% yield).

¹H NMR(400MHz，CDCl₃)：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＝6.4Hz，3H).

The second step is that: preparation of 3-bromo-4- (((1r, 4r) -4-methylcyclohexyl) oxo) aniline

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

MS m/z(ESI)：284.0[M+H]⁺

The third step: preparation of N- (3-bromo-4- (((1r, 4r) -4-methylcyclohexyl) oxo) phenyl) ethanesulfonamide

3-bromo-4- (((1r, 4r) -4-methylcyclohexyl) oxo) aniline (2.0g, 7mmol) was dissolved in dichloromethane (40mL), pyridine (2.8g, 35mmol) and ethanesulfonyl chloride (2.7g, 21.0mmol) were added in this order, the reaction was stirred at room temperature for 1 hour, aqueous hydrochloric acid (1M, 50mL) was added, the aqueous phase was extracted with dichloromethane (30 mL. times.2), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the compound N- (3-bromo-4- (((1r, 4r) -4-methylcyclohexyl) oxo) phenyl) ethanesulfonamide (2.0g, yield: 76%).

MS m/z(ESI)：375.0[M]⁺

The fourth step: preparation of 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 (0.4g, 1.1mmol), 6-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine (0.5g, 1.3mmol), potassium carbonate (350mg, 2.8mmol) and [1, 1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (80mg, 0.1mmol) were dissolved in 1, 4 dioxane (10mL) and water (2mL) and the reaction was stirred at 90 ℃ for 2 hours under nitrogen. After the reaction solution was cooled to room temperature, ethyl acetate (50mL) was added, followed by washing with water (30mL), drying over anhydrous sodium sulfate, filtration, concentration, and purification of the crude product by column chromatography (petroleum ether: ethyl acetate ═ 50: 1 to pure ethyl acetate gradient rinse) 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 (0.4g, yield: 65%).

MS m/z(ESI)：582.2[M+H]⁺

The fifth step: preparation of N- (3- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) -4- (((1r, 4r) -4-methylcyclohexyl) oxo) phenyl) ethanesulfonamide

N- (3- (6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) -4- (((1r, 4r) -4-methylcyclohexyl) oxo) phenyl) ethanesulfonamide (0.4g, 0.69mmol) and potassium hydroxide (0.8g, 13.8mmol) were dissolved in t-butanol (20mL) and water (2mL) and the reaction stirred at 60 ℃ for 18 hours. The reaction solution was spin-dried, methylene chloride (20mL) was added, and the organic phase was washed with water (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the compound N- (3- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) -4- (((1r, 4r) -4-methylcyclohexyl) oxo) phenyl) ethanesulfonamide (0.2g, yield: 68%).

MS m/z(ESI)：428.1[M+H]⁺

And a sixth step: preparation of 4- (5- (ethylsulfonylamino) -2- (((1r, 4r) -4-methylcyclohexyl) oxo) phenyl) -6-methyl-1H-pyrrolo [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 (100mg, 0.23mmol) and m-chloroperoxybenzoic acid (95mg, 0.46mmol) were dissolved in tetrahydrofuran (4mL) and the reaction was stirred at 25 ℃ for 2 hours. After the reaction solution was concentrated, the crude product was separated by high performance liquid chromatography to give compound 4- (5- (ethylsulfonylamino) -2- (((1r, 4r) -4-methylcyclohexyl) oxo) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (11mg, yield: 11%).

¹H NMR(400MHz，CD₃OD)：δ7.30-7.29(m，2H)，7.21(dd，J＝8.8Hz，2.8Hz，1H)，7.17(s，1H)，7.05(d，J＝8.8Hz，1H)，6.43(d，J＝3.2Hz，1H)，4.11-3.98(m，1H)，2.99(q，J＝7.2Hz，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＝6.4Hz，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

The first step is as follows: preparation of 2-bromo-N- ((1r, 4r) -4-methylcyclohexyl) -4-nitroaniline

2-bromo-1-fluoro-4-nitrobenzene (4.0g, 18mmol), (1r, 4r) -4-methylcyclohexan-1-amine (6.2g, 55mmol) and N, N-diisopropylethylamine (11.6g, 90mmol) were dissolved in N-methyl-2-pyrrolidone (30mL) and stirred at 130 ℃ for 18 hours. After the reaction mixture was cooled to room temperature, water (200mL) was added and the mixture was stirred for 1 hour, whereby a yellow solid was precipitated. The mixture was filtered, the solid washed with water, collected and dried to give 2-bromo-N- ((1r, 4r) -4-methylcyclohexyl) -4-nitroaniline (4.5g, 79% yield).

¹H NMR(400MHz，CDCl₃)：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＝7.2Hz，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＝6.4Hz，3H)。

The second step is that: preparation of 2-bromo-N1- ((1r, 4r) -4-methylcyclohexyl) benzene-1, 4-diamine

2-bromo-N- ((1r, 4r) -4-methylcyclohexyl) -4-nitroaniline (4.5g, 14.4mmol) was dissolved in ethanol (100mL), iron powder (4g, 72.0mmol), ammonium chloride (15.3g, 0.3mol) and water (20mL) were added, and the reaction was stirred at 90 ℃ for 2 hours. Cooling the reaction solution to room temperature, filtering, and concentrating the filtrate to obtain a crude product. The crude product was purified by column chromatography (gradient 50: 1 to 1: 1 petroleum ether: ethyl acetate) to afford 2-bromo-N1- ((1r, 4r) -4-methylcyclohexyl) benzene-1, 4-diamine (4g, 98% yield).

¹H NMR(400MHz，CDCl₃)：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＝6.4Hz，3H)。

MS m/z(ESI)：283.0，285.0[M+H]⁺

The 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 (4.0g, 14mmol) was dissolved in dichloromethane (100mL), pyridine (3.3g, 42mmol), ethanesulfonyl chloride (1.8g, 14.0mmol) were added in that order, and the reaction was stirred at room temperature for 18 hours. Water (300mL) was added, the aqueous phase was extracted with dichloromethane (300mL), the organic phase was dried over anhydrous sodium sulphate, filtered, concentrated and the crude product was purified by column chromatography (petroleum ether: ethyl acetate ═ 50: 1 to 3: 1 gradient rinse) to give the compound N- (3-bromo-4- (((1r, 4r) -4-methylcyclohexyl) amino) phenyl) ethanesulfonamide (3.5g, yield: 66%).

¹H NMR(400MHz，CDCl₃)：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＝6.8，3.6Hz，1H)，1.37(t，J＝7.2Hz，3H)，1.27-1.16(m，2H)，1.12-1.00(m，2H)，0.93(d，J＝6.4Hz，3H)。

MS m/z(ESI)：375.0，377.0[M+H]⁺

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

Using N- (3-bromo-4- (((1r, 4r) -4-methylcyclohexyl) amino) phenyl) ethanesulfonamide (200mg, 0.5mmol) as a reaction material, the compound, N- (3- (6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) -4- (((1r, 4r) -4-methylcyclohexyl) amino) phenyl) ethanesulfonamide (180mg, yield: 58%) was obtained at the fourth step of reference example 8.

MS m/z(ESI)：581.2[M+H]⁺

The fifth step: preparation of N- (3- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) -4- (((1r, 4r) -4-methylcyclohexyl) amino) phenyl) ethanesulfonamide

Using N- (3- (6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) -4- (((1r, 4r) -4-methylcyclohexyl) amino) phenyl) ethanesulfonamide (180mg, 0.3mmol) as a reaction starting material, the fifth step of reference example 8 gave the compound N- (3- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) -4- (((1r, 4r) -4-methylcyclohexyl) amino) phenyl) ethanesulfonamide (120mg, yield: 91%).

MS m/z(ESI)：427.2[M+H]⁺

And a sixth step: preparation of 4- (5- (ethylsulfonylamino) -2- (((1r, 4r) -4-methylcyclohexyl) amino) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide

Using N- (3- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) -4- (((1r, 4r) -4-methylcyclohexyl) amino) phenyl) ethanesulfonamide (120mg, 0.28mmol) as a reaction starting material, the sixth step of reference example 8 gave the compound, 4- (5- (ethylsulfonamido) -2- (((1r, 4r) -4-methylcyclohexyl) amino) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (11.2mg, yield: 9.0%).

¹H NMR(400MHz，CD₃OD)：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＝8.8Hz，1H)，6.33(d，J＝3.2Hz，1H)，3.17-3.07(m，1H)，2.94(q，J＝7.2Hz，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＝6.4Hz，3H)。

MS m/z(ESI)：455.2[M+H]⁺

Example 10

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

The first step is as follows: preparation of (3-bromo-4-fluorophenyl) (methyl) sulfane

3-bromo-4-fluoroaniline (19g, 0.1mol) and copper powder (0.96g, 15mmol) were dissolved in 1, 2-dimethyldisulfane (50mL), and the reaction was heated to 80 ℃. Isoamyl nitrite (15g, 0.15mmol) was slowly added dropwise to keep the internal temperature of the reaction at not higher than 90 ℃. After the addition, the reaction was stirred at 90 ℃ for two hours. The reaction mixture was evaporated to dryness, toluene (250mL) and dilute aqueous hydrochloric acid (250mL, 1M) were added to the reaction system, the layers were separated, the organic phase was washed with dilute hydrochloric acid (1M, 150mL), water (150mL), saturated brine (150mL), the organic phase was dried and filtered, the filtrate was evaporated to dryness, and the residue was distilled under reduced pressure to collect a fraction with a vapor temperature of 50-60 ℃ to give (3-bromo-4-fluorophenyl) (ethyl) sulfane (15g, pale yellow oil, yield 68%).

¹H NMR(400MHz，CDCl₃)：δ7.46-7.38(m，1H)，7.21-7.12(m，1H)，7.08-6.99(m，1H)，2.46(s，3H).

The second step is that: preparation of 2-bromo-1-fluoro-4- (methylsulfonyl) benzene

M-chloroperoxybenzoic acid (860mg, 4.98mmol) was added to a solution of (3-bromo-4-fluorophenyl) (methyl) sulfane (500mg, 2.26mmol) in dichloromethane (10mL) and reacted at room temperature for 6 hours. The crude product after removal of the solvent was separated using a column (petroleum ether: ethyl acetate 5: 1, V/V) to give 2-bromo-1-fluoro-4- (methylsulfonyl) benzene (400mg, 70% yield).

¹H NMR(400MHz，CDCl₃)：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- (cyclohexatrienoxy) -4- (methylsulfonyl) benzene

Sodium hydride (38mg, 0.95mmol, 60%) was added to a solution of 2-bromo-1-fluoro-4- (methylsulfonyl) benzene (200mg, 0.79mmol) and cyclohexanol (95mg, 0.95mmol) in N, N-dimethylformamide (5mL) at 0 ℃ under nitrogen, reacted at room temperature for 30 minutes, and then reacted at 45 ℃ for 3 hours. The reaction mixture was cooled, quenched with water (5mL), extracted with ethyl acetate (25 mL. times.2), and the organic phase was dried to dryness. Crude column separation (petroleum ether: ethyl acetate 5: 1, V/V) afforded 2-bromo-1- (cyclohexatrienoxy) -4- (methylsulfonyl) benzene (170mg, 65% yield).

¹H NMR(400MHz，CDCl₃)：δ8.11(d，J＝2.3Hz，1H)，7.81(dd，J＝8.7Hz，2.3Hz，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: preparation of 2- (2- (cyclohexatrienoxy) -5- (methylsulfonyl) phenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane

2-bromo-1- (cyclohexatrienoxy) -4- (methylsulfonyl) benzene (1g, 3mmol), 4, 4, 4 ', 4', 5, 5, 5 ', 5' -octamethyl-2, 2 '-bis (1, 3, 2-dioxaborolane) (2.29g, 9mmol), potassium acetate (0.88g, 9mmol), tris (dibenzylideneacetone) dipalladium (137mg, 0.15mmol), 2-dicyclohexylphosphonium-2', 4 ', 6' -triisopropylbiphenyl (143mg, 0.3mmol) were added to 1, 4-dioxane (20mL), and the reaction mixture was reacted at 85 ℃ for 16 hours under nitrogen protection. The reaction solution was evaporated to dryness and the crude product was isolated by column chromatography (petroleum ether: ethyl acetate 6: 4, V/V) to give 2- (2- (cyclohexatrienoxy) -5- (methylsulfonyl) phenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan (400mg crude, 60% purity) which was used directly in the next reaction.

The fifth step: preparation of 4- (2- (cyclohexatrienoxy) -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 (380mg, 0.6mmol, crude), 4-chloro-6-methyl-1H-pyrrolo [2, 3-b ] pyridine (100mg, 0.6mmol), tetratriphenylphosphine palladium (70mg, 0.06mmol) and potassium carbonate (248mg, 3mol) were added to a mixed solvent of ethanol/toluene/water (v/v/v ═ 9: 3: 1, 10 mL). The reaction mixture was reacted with nitrogen at 120 ℃ for 0.5 hour in a microwave oven, and the reaction mixture was evaporated to dryness and separated using a preparation plate (petroleum ether: ethyl acetate 1: 1, V/V) to give 4- (2- (cyclohexatrienoxy) -5- (methylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine (75mg, yield 33%).

MS m/z(ESI)：385.1[M+H]⁺

And a sixth step: preparation of 4- (2- (cyclohexatrienoxy) -5- (methylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide

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

¹H NMR(400MHz，CDCl₃)：δ12.33(br，1H)，8.02(d，J＝2.4Hz，1H)，7.94(dd，J＝8.8Hz，2.4Hz，1H)，7.34(d，J＝3.3Hz，1H)，7.21-7.11(m，2H)，6.43(d，J＝3.3Hz，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

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

The first step is as follows: preparation of 2-bromo-N- (cyclopropylmethyl) -4- (methylsulfonyl) aniline

2-bromo-1-fluoro-4- (methylsulfonyl) benzene (700mg, 2.77mmol) was dissolved in 1, 4-dioxane (15mL), cyclopropylmethylamine (118g, 16.67mmol) was added at room temperature, the reaction was stirred at 140 ℃ for one hour under microwave, the reaction solution was concentrated after cooling, diluted with ethyl acetate (40mL), then washed with water (20mL × 2) and saturated brine (20mL), and dried over anhydrous sodium sulfate, and after concentration, column chromatography (petroleum ether: ethyl acetate ═ 5: 1, V/V) gave the compound 2-bromo-N- (cyclopropylmethyl) -4- (methylsulfonyl) aniline (680mg, 81% yield).

The second step is that: preparation of N- (cyclopropylmethyl) -4- (methylsulfonyl) -2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline

2-bromo-N- (cyclopropylmethyl) -4- (methylsulfonyl) aniline (680.0mg, 2.24mmol), pinacol diboron (1.71g, 6.73mmol), tris (dibenzylideneacetone) dipalladium (103mg, 0.112mmol), potassium acetate (483mg, 4.93mmol), 2-dicyclohexylphosphorus-2, 4, 6-triisopropylbiphenyl (107mg, 0.224mmol) were dissolved in 1, 4-dioxane (10mL), the reaction was stirred at 80 ℃ for 8 hours under nitrogen protection, the reaction mixture was spin-dried and water (20mL) was added, followed by extraction with ethyl acetate (20 mL. times.2), the organic phases were combined, washed with water (40mL) and saturated brine (40mL) in this order, and dried over anhydrous sodium sulfate, column chromatography was performed after concentration (eluent: petroleum ether: ethyl acetate: 5: 1, V/V) to give N- (cyclopropylmethyl) -4- (methylsulfonyl) -2- (4- (methylsulfonyl), 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (560.0mg, 71% yield).

The 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 (200.0mg, 0.57mmol) was dissolved in a mixed solvent of 1, 4-dioxane (4mL) and water (1mL), followed by addition of tris (dibenzylideneacetone) dipalladium (16mg, 0.0171mmol), tripotassium phosphate (302mg, 1.43mmol), 1, 3, 5, 7-tetramethyl-6-phenyl-2, 4, 8-trioxa-6-phosphamantane (18.3mg, 0.0627mmol), nitrogen aeration for 5 minutes, and stirring at 120 ℃ for one hour. After cooling, the reaction mixture was concentrated, diluted with ethyl acetate (40mL), then washed with water (20mL × 2) and saturated brine (20mL), and dried over anhydrous sodium sulfate, and concentrated, followed by column chromatography (dichloromethane: methanol ═ 20: 1) to give the compound N- (cyclopropylmethyl) -2- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) -4- (methylsulfonyl) aniline (21mg, yield 10%).

MS m/z(ESI)：356.1[M+H]⁺。

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

N- (cyclopropylmethyl) -2- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) -4- (methylsulfonyl) aniline (21.0mg, 0.056mmol) was dissolved in dichloromethane (2mL), m-chloroperoxybenzoic acid (14mg, 0.084mmol) was added with cooling in an ice bath, the reaction mixture was stirred at room temperature for one hour and then quenched with a solution of sodium thiosulfate (5mL), dichloromethane (15mL) was then added, and then washed with water (20mL × 2) and saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (dichloromethane: methanol ═ 20: 1) to give the compound 4- (2- ((cyclopropylmethyl) amino) -5- (methylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (2.5mg, 10% yield).

¹H NMR(400MHz，CDCl₃)：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＝3.4Hz，1H)，3.86(d，J＝6.4Hz，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)：372.1[M+H]⁺。

Example 12

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

The first step is as follows: preparation of 2-bromo-1-isobutoxy-4- (methylsulfonyl) benzene

Using 2-methylpropan-1-ol instead of cyclohexanol as a reaction material, the third step of example 10 was repeated to obtain 2-bromo-1-isobutoxy-4- (methylsulfonyl) benzene (1.01g, yield 83%).

The second step is that: preparation of 2- (2-isobutoxy-5- (methylsulfonyl) phenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane

Using 2-bromo-1-isobutoxy-4- (methylsulfonyl) benzene as a starting material, 2- (2-isobutoxy-5- (methylsulfonyl) phenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan (900mg, 78% yield) was obtained according to the fourth step of example 10.

The 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-dioxaborolane as a starting material, according to the fifth step of example 10, compound 4- (2-isobutoxy-5- (methylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine (45mg, yield 23%) was obtained.

MS m/z(ESI)：359.1[M+H]⁺。

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

Using 4- (2-isobutoxy-5- (methylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine as a reaction starting material, according to the sixth step of example 10, the compound 4- (2-isobutoxy-5- (methylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (16.4mg, 53% yield) was obtained.

¹H NMR(400MHz，CDCl₃)：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＝13.3，6.6Hz，1H)，0.88(d，J＝6.7Hz，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

The first step is as follows: 4- (2-fluoro-5- (methylsulfonyl) phenyl) -6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine

2-bromo-1-fluoro-4- (methylsulfonyl) benzene (0.42g, 1.66mmol), 6-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine (0.62g, 1.49mmol), potassium carbonate (0.41g, 2.98mmol), [1, 1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (0.12g, 0.16mmol), dioxane (16mL) and water (4mL) were added to a three-necked flask at room temperature, and heated to 90 ℃ overnight after displacement with nitrogen. After cooling to room temperature, it was diluted with ethyl acetate (20mL), filtered over celite, the celite was washed with ethyl acetate (20mL), the filtrate was washed with brine (10mL × 3), dried over anhydrous sodium sulfate, filtered, spun-dried, and the crude product was separated by column chromatography (petroleum ether: ethyl acetate ═ 3: 1, V/V) to give 4- (2-fluoro-5- (methanesulfonyl) phenyl) -6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine (0.65g, white solid, 94%).

MS m/z(ESI)：459.1[M+H]⁺.

The second step is that: 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 (0.53g, 1.16mmol) was added to a round bottom flask at room temperature, then dissolved in t-butanol (15mL), stirred at room temperature, then added aqueous potassium hydroxide (0.32g, 5.79mmol, 1mL water), heated to 65 ℃ overnight, cooled to room temperature and then most of the t-butanol was removed by rotary evaporation, the residue was dissolved in ethyl acetate (25mL), the organic phase was washed with brine (10 mL. times.3), dried over anhydrous sodium sulfate, filtered, and rotary dried to give 4- (2-fluoro-5- (methylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine (0.37g, white solid), the crude product was used directly in the next reaction.

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

After 4- (2-fluoro-5- (methylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine (0.32g, 1.05mmol) was dissolved in tetrahydrofuran (20mL) under ice-cooling, m-chloroperoxybenzoic acid (85%, 0.21g, 1.05mmol) was added to the reaction mixture, and after completion of the reaction, the reaction mixture was diluted with ethyl acetate (20mL), washed with a saturated aqueous sodium bicarbonate solution (10mL × 3), then with a saturated brine (10mL), the organic phase was dried over anhydrous sodium sulfate, filtered, dried, and the crude product was isolated by column chromatography (dichloromethane: methanol ═ 25: 1, V/V) to give 4- (2-fluoro-5- (methylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (0.23g, pale yellow solid, 68% yield).

MS m/z(ESI)：321.1[M+H]+.

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

4- (2-fluoro-5- (methylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (0.050g, 0.16mmol), trans-4-methylcyclohexylamine (0.5mL), and N-methylpyrrolidone (3mL) were added to a 10mL microwave tube, heated to 140 ℃ in an oil bath, and reacted overnight. The reaction was cooled to room temperature, diluted with ethyl acetate (20mL), washed with brine (10mL × 5), the organic phase was dried over anhydrous sodium sulfate, filtered, spun-dried, and the crude product was separated by reverse phase preparative chromatography to give 6-methyl-4- (2- ((trans) -4-methylcyclohexyl) amino) -5- (methylsulfonyl) phenyl) -1H-pyrrolo [2, 3-b ] pyridine-7-oxide (0.020g, white solid, 31% yield).

¹H NMR(400MHz，CDCl₃)：δ12.27(br，1H)，7.80(dd，J＝8.8Hz，2.4Hz，1H)，7.70(d，J＝2.0Hz，1H)，7.38(d，J＝3.2Hz，1H)，7.08(s，1H)，6.79(d，J＝8.8Hz，1H)，6.37(d，J＝3.2Hz，1H)，4.28(d，J＝7.6Hz，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＝6.4Hz，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

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

After trans-4-t-butylcyclohexanol (0.10g, 0.66mmol) was dissolved in N, N-dimethylformamide (3mL) at room temperature, sodium hydride (60%, 0.037g, 0.92mmol) was added to the reaction solution, and the mixture was stirred at room temperature for half an hour. Then 4- (2-fluoro-5- (methylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (0.04g, 0.13mmol) in N, N-dimethylformamide (1mL) was added dropwise to the reaction system, stirred at room temperature overnight, diluted with ethyl acetate (20mL), washed with saturated brine (20mL), the organic phase was dried over anhydrous sodium sulfate, filtered and dried by spinning, the crude product was chromatographed using reverse phase preparative chromatography to give 4- (2- ((trans) -4- (tert-butyl) cyclohexyl) oxo) -5- (methylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (0.030g, white solid, yield 53%).

MS m/z(ESI)：457.2[M+H]⁺.

¹H NMR(400MHz，CDCl₃)：δ11.96(br，1H)，8.00(d，J＝2.4Hz，1H)，7.94(dd，J 8.8Hz，2.4Hz 1H)，7.35(d，J＝3.2Hz，1H)，7.16(d，J＝8.8Hz，1H)，7.13(s，1H)，6.38(d，J＝3.2Hz，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) oxo) -5- (methylsulfonyl) phenyl) -1H-pyrrolo [2, 3-b ] pyridine-7-oxide

Following the experimental procedure of example 14, starting from trans-4-methylcyclohexanol instead of trans-4-tert-butylcyclohexanol, 4- (2- ((trans) -4-methylcyclohexyl) oxo) -5- (methylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (0.035g, white solid, 49% yield) was obtained.

MS m/z(ESI)：415.2[M+H]⁺.

¹H NMR(400MHz，CDCl₃)：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＝3.2Hz，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＝7.2Hz，3H).

Example 16

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

Following the experimental procedure of example 14, starting from trans-4-ethylcyclohexanol instead of trans-4-tert-butylcyclohexanol, 4- (2- ((trans) -4-ethylcyclohexyl) oxo) -5- (methylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (0.023g, white solid, 58% yield) was obtained.

MS m/z(ESI)：429.2[M+H]+.

¹HNMR(400MHz，CDCl₃)：δ11.86(br，1H)，7.99(s，1H)，7.94(d，J＝8.8Hz，1H)，7.35(d，J＝8.8Hz，1H)，7.17-7.13(m，2H)，6.42(d，J＝3.2Hz，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＝7.2Hz，3H).

Example 17

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

Following the experimental procedure of example 14, starting from trans-4-isopropylcyclohexanol instead of trans-4-tert-butylcyclohexanol, 4- (2- ((trans) -4-isopropylcyclohexyl) oxo) -5- (methylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (0.018g, 44% yield) was obtained.

MS m/z(ESI)：443.2[M+H]⁺.

¹H NMR(400MHz，CDCl₃)：δ11.96(br，1H)，8.00(d，J＝2.0Hz，1H)，7.96(dd，J8.8Hz，2.0Hz 1H)，7.36(d，J＝3.2Hz，1H)，7.17-7.14(m，2H)，6.43(d，J＝3.2Hz，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

Following the experimental procedure of example 14, starting from L-menthol instead of trans-4-tert-butylcyclohexanol, 4- (2- (((1S, 2R, 5S) -2-isopropyl-5-methylcyclohexyl) oxo) -5- (methylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (0.020g, white solid, 47% yield) was obtained.

MS m/z(ESI)：457.2[M+H]⁺.

¹H NMR(400MHz，CDCl₃)：δ11.59(br，1H)，8.00(d，J＝2.4Hz，1H)，7.94(dd，J＝8.8Hz，2.4Hz，1H)，7.30(d，J＝3.6Hz，1H)，7.16(d，J＝8.4Hz，1H)，7.12(s，1H)，6.40(d，J＝3.6Hz，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＝7.2Hz，3H)，0.66(d，J＝7.2Hz，3H).

Example 19

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

The first step is as follows: n- (4-ethylcyclohexyl) -2- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) -4- (methylsulfonyl) aniline

4- (2-fluoro-5- (methylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (0.040g, 0.125mmol), 4-ethylcyclohexylamine (0.3mL), and N-methylpyrrolidone (3mL) were added to a 10mL microwave tube, heated to 140 ℃ in an oil bath, reacted overnight, and cooled to room temperature. The reaction was diluted with ethyl acetate (20mL), washed with brine (10 mL. times.2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and spun to give crude N- (4-ethylcyclohexyl) -2- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) -4- (methylsulfonyl) aniline (0.060g, a yellow oil) which was used directly in the next reaction.

MS m/z(ESI)：412.2[M+H]⁺.

The second step is that: 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 (0.060g, yellow oil), was dissolved in dichloromethane (10mL), and then m-chloroperoxybenzoic acid (85%, 0.051g, 0.25mmol) was added to the reaction mixture and stirred at room temperature. After completion of the reaction, the reaction mixture was diluted with dichloromethane (40mL), washed with saturated aqueous sodium bicarbonate (25mL), washed with saturated brine (25mL), dried over anhydrous sodium sulfate, filtered, and dried by spinning, and the crude product was separated by reverse phase preparative chromatography to give 6-methyl-4- (2- ((trans) -4-ethylcyclohexyl) amino) -5- (methylsulfonyl) phenyl) -1H-pyrrolo [2, 3-b ] pyridine-7-oxide (0.012g, white solid, yield 19%).

MS m/z(ESI)：428.2[M+H]⁺.

¹H NMR(400MHz，CDCl₃)：δ12.2(br，1H)，7.80(dd，J＝8.8Hz，2.0Hz，1H)，7.70(d，J＝2.0Hz 1H)，7.39(d，J＝3.2Hz，1H)，7.08(s，1H)，6.79(d，J＝8.8Hz，1H)，6.37(d，J＝3.2Hz，1H)，4.30(d，J＝7.2Hz，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＝7.2Hz，3H).

Example 20

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

Following the experimental procedure of example 19, reverse phase preparative chromatography simultaneously afforded 6-methyl-4- (2- ((cis) -4-ethylcyclohexyl) amino) -5- (methylsulfonyl) phenyl) -1H-pyrrolo [2, 3-b ] pyridine-7-oxide (0.015g, white solid, 28% yield).

MS m/z(ESI)：428.2[M+H]⁺.

¹HNMR(400MHz，CDCl₃)：δ12.21(br，1H)，7.80(d，J＝8.8Hz，1H)，7.72(s，1H)，7.39(d，J＝3.2Hz，1H)，7.08(s，1H)，6.79(d，J＝8.8Hz，1H)，6.44(d，J＝3.2Hz，1H)，4.54(d，J＝6.4Hz，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＝7.2Hz，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, starting from 4-propylcyclohexylamine instead of 4-ethylcyclohexylamine, 6-methyl-4- (2- ((trans) -4-propylcyclohexyl) amino) -5- (methylsulfonyl) phenyl) -1H-pyrrolo [2, 3-b ] pyridine-7-oxide (0.010g, light yellow solid, 18% yield) was obtained.

MS m/z(ESI)：442.2[M+H]⁺.

¹H NMR(400MHz，CDCl₃)：δ12.14(br，1H)，7.80(dd，J＝8.8Hz，2.0Hz，1H)，7.71(d，J＝2.0Hz，1H)，7.39(d，J＝3.2Hz，1H)，7.08(s，1H)，6.80(d，J＝8.8Hz，1H)，6.38(d，J＝3.2Hz，1H)，4.30(d，J＝7.6Hz，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＝7.2Hz，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, starting from 4-propylcyclohexylamine instead of 4-ethylcyclohexylamine, 6-methyl-4- (2- ((cis) -4-propylcyclohexyl) amino) -5- (methylsulfonyl) phenyl) -1H-pyrrolo [2, 3-b ] pyridine-7-oxide (0.010g, light yellow solid, 18% yield) was obtained.

MS m/z(ESI)：442.2[M+H]⁺.

¹H NMR(400MHz，CDCl₃)：δ11.62(br，1H)，7.80(dd，J＝8.8Hz，2.0Hz，1H)，7.73(d，J＝2.0Hz，1H)，7.33(d，J＝3.2Hz，1H)，7.08(s，1H)，6.76(d，J＝8.8Hz，1H)，6.42(d，J＝3.2Hz，1H)，4.57(d，J＝6.8Hz，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＝7.2Hz，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 is as follows: preparation of 1, 2-bis (3-bromo-4-fluorophenyl) dithiolane.

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

The second step is that: preparation of 3-bromo-4-fluorobenzenethiol

A3L three-necked flask was charged with a solution of 1, 2-bis (3-bromo-4-fluorophenyl) dithioane (42g, 101.9mmol), methanol (300mL), tetrahydrofuran (1L), sodium hydroxide (10.3g, 257.5mmol) in water (300mL) in that order. Sodium borohydride (11.1g, 293.6mmol) was added in five portions at room temperature. After 1 hour of reaction, the mixture was concentrated, and a solution of sodium hydroxide (35g, 875.0mmol) in water (300mL) was added, followed by extraction with methyl t-butyl ether (500 mL. times.2) to remove impurities. The aqueous phase was added dropwise to an aqueous hydrochloric acid solution (3M, 800mL) while maintaining the system temperature at 0-5 ℃. The reaction solution was extracted with methyl tert-butyl ether (500 mL. times.3), dried over anhydrous sodium sulfate, and spin-dried to give 3-bromo-4-fluorobenzenethiol (16g, yellow oil, yield 38%).

¹H NMR(400MHz，CDCl₃)：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

Bromoacetonitrile (1.74g, 14.5mmol) was dissolved in N, N-dimethylformamide (10mL) under ice-bath, and then a solution of 4-fluoro-3-bromophenylthiophenol (1.50g, 7.25mmol) in N, N-dimethylformamide (5mL) was added to the reaction solution, and finally cesium carbonate (4.73g, 14.5mmol) was added and reacted at room temperature. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (30mL), washed with saturated brine (10mL × 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and dried, and the crude product was separated with a preparative plate (petroleum ether: ethyl acetate ═ 3: 1) to give 2- ((3-bromo-4-fluorophenyl) thio) acetonitrile (1.0g, yellow oil, yield: 56%).

¹H NMR(400MHz，CDCl₃)：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).

The fourth step: 2- ((3-bromo-4-fluorophenyl) sulfonyl) acetonitrile

2- ((3-bromo-4-fluorophenyl) thio) acetylnitrile (0.50g, 2.03mmol) was dissolved in dichloromethane (10mL) under ice-bath, and then m-chloroperoxybenzoic acid (0.93g, 4.06mmol) was added to the reaction system, and stirred at room temperature overnight. After the reaction was completed, the reaction system was diluted with dichloromethane (25mL), washed with saturated aqueous sodium bicarbonate (10mL), washed with brine (10mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spinning, and the crude product was isolated by column chromatography to give 2- ((3-bromo-4-fluorophenyl) sulfonyl) acetonitrile (0.30g, colorless oil, yield: 53%).

The fifth step: 2- ((3-bromo-4- (2, 4-difluorophenoxy) phenyl) sulfonyl) acetonitrile

2- ((3-bromo-4-fluorophenyl) sulfonyl) acetonitrile (0.29g, 1.04mmol), 2, 4-difluorophenol (0.41g, 3.12mmol) and sodium carbonate (0.33g, 3.12mmol) were dissolved in dimethyl sulfoxide (5mL) at room temperature under nitrogen, heated to 90 ℃ and reacted for two hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (35mL), washed with saturated brine (15mL × 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spinning, and the crude product was isolated by column chromatography (petroleum ether: ethyl acetate ═ 3: 1, V/V) to give 2- ((3-bromo-4- (2, 4-difluorophenoxy) phenyl) sulfonyl) acetonitrile (0.25g, white solid, yield: 62%).

MS m/z(ESI)：386.0，388.0[M-H]^-.

And a sixth step: 2- ((3-bromo-4- (2, 4-difluorophenoxy) phenyl) sulfonyl) -2-methylpropanenitrile

2- ((3-bromo-4- (2, 4-difluorophenoxy) phenyl) sulfonyl) acetonitrile (0.10g, 0.26mmol) and cesium carbonate (0.17g, 0.52mmol) were dissolved in tetrahydrofuran (10mL) at room temperature, and methyl iodide (0.5mL) was added dropwise to the reaction solution and reacted at room temperature for three hours. After the reaction, the reaction solution was diluted with ethyl acetate (25mL), washed with saturated brine (15mL × 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and dried to obtain a crude product, 2- ((3-bromo-4- (2, 4-difluorophenoxy) phenyl) sulfonyl) -2-methylpropanenitrile (0.10g, white solid), which was used directly in the next reaction.

MS m/z(ESI)：416.0，418.0[M+H]⁺.

The seventh step: 2- ((4- (2, 4-Difluorophenoxy) -3- (6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) sulfonyl) -2-methylpropanenitrile

2- ((3-bromo-4- (2, 4-difluorophenoxy) phenyl) sulfonyl) -2-methylpropanenitrile (0.10g, 0.24mmol), 6-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine (0.13g, 0.24mmol), potassium carbonate (0.066g, 0.48mmol), [1, 1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (0.018g, 0.024mmol) was dissolved in dioxane (4mL) and water (1mL) at room temperature, replaced with nitrogen three times, heated to 100 ℃ overnight, cooled to room temperature, diluted with ethyl acetate (20mL), filtered over celite, the filtrate was washed with saturated brine (20 mL. times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give a crude product which was isolated 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-methylpropanenitrile (0.12g, yellow oil, yield: 80%).

MS m/z(ESI)：622.1[M+H]⁺.

Eighth step: 2- ((4- (2, 4-Difluorophenoxy) -3- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) sulfonyl) -2-methylpropanenitrile

2- ((4- (2, 4-Difluorophenoxy) -3- (6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) sulfonyl) -2-methylpropanenitrile (0.10g, 0.16mmol) was dissolved in ethanol (3mL) at room temperature, and sodium methoxide (0.026g, 0.48mmol) was added to the reaction system, and the mixture was heated to 50 ℃ for three hours. After the reaction was completed, ethanol was dried by spinning, and the residue was dissolved in ethyl acetate (25mL), followed by washing with brine (15mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the crude product obtained after the filtrate was dried by spinning was separated with a preparative plate (petroleum ether: ethyl acetate ═ 1: 1, V/V) to give 2- ((4- (2, 4-difluorophenoxy) -3- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) sulfonyl) -2-methylpropanenitrile (0.06g, white solid, yield 80%).

MS m/z(ESI)：468.1[M+H]⁺.

The ninth step: 4- (5- ((2-cyanopropan-2-yl) 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) sulfonyl) -2-methylpropanenitrile (0.06g, 0.13mmol) was dissolved in tetrahydrofuran (5mL) under ice-bath, then m-chloroperoxybenzoic acid (0.031g, 0.15mmol) was added to the reaction, after stirring at room temperature for ten minutes, the reaction was diluted with ethyl acetate (25mL), washed with saturated aqueous sodium bicarbonate (20mL), washed with brine (20mL), the organic phase was dried over anhydrous sodium sulfate, filtered, spun-dried, and the crude product was chromatographed using reverse phase preparative chromatography to give 4- (5- ((2-cyanopropan-2-yl) sulfonyl) -2- (2, 4-Difluorophenoxy) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (0.025g, white solid, 40% yield).

MS m/z(ESI)：484.1[M+H]⁺.

¹H NMR(400MHz，CDCl₃)：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

The first step is as follows: 2- ((4- (2, 4-Difluorophenoxy) -3- (6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) sulfonyl) acetonitrile

Using 2- ((3-bromo-4- (2, 4-difluorophenoxy) phenyl) sulfonyl) acetonitrile as a reaction material, according 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 (0.056g, yellow solid, yield 37%) was obtained.

MS m/z(ESI)：594.1[M+H]⁺.

The second step is that: 2- ((4- (2, 4-Difluorophenoxy) -3- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) sulfonyl) acetonitrile

After 2- ((4- (2, 4-difluorophenoxy) -3- (6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) sulfonyl) acetonitrile (0.03g, 0.051mmol) was dissolved in N, N-dimethylformamide (2mL) at room temperature, sodium hydride (60%, 0.006g, 0.10mmol) was added to the reaction solution, and after 14 hours at room temperature, the reaction solution was diluted with ethyl acetate (40mL), a saturated brine (15mL × 3) was washed, the organic phase was dried over anhydrous sodium sulfate, filtered, dried, and the crude product was separated with a preparative plate (petroleum ether: ethyl acetate ═ 1: 1, V/V) to give 2- ((4- (2, 4-difluorophenoxy) -3- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) sulfonyl) acetonitrile (0.015g, white solid, 68% yield).

MS m/z(ESI)：440.1[M+H]⁺.

The 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) sulfonyl) acetonitrile (0.015g, 0.034mmol) was dissolved in tetrahydrofuran (3mL) at room temperature, then m-chloroperoxybenzoic acid (85%, 0.008g, 0.041mmol) was added to the reaction solution, after a reaction time of ten minutes, the reaction solution was diluted with ethyl acetate (20mL), then washed with a saturated sodium bicarbonate solution (10 mL. times.3), brine (10mL), the organic phase was dried over anhydrous sodium sulfate, filtered, spun-dried, and the crude product was chromatographed using reverse phase preparative chromatography to give 4- (5- ((cyanomethyl) sulfonyl) -2- (2, 4-difluorophenoxy) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (0.004g, white solid, 26% yield).

MS m/z(ESI)：456.1[M+H]⁺.

¹H NMR(400MHz，CDCl₃)：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

The first step is as follows: 1- ((3-bromo-4- (2, 4-difluorophenoxy) phenyl) sulfonyl) cyclopropane-1-carbonitrile

2- ((3-bromo-4- (2, 4-difluorophenoxy) phenyl) sulfonyl) acetonitrile (0.10g, 0.26mmol), 1, 2-dibromoethane (0.097g, 0.52mmol) and cesium carbonate (0.17g, 0.52mmol) were dissolved in tetrahydrofuran (8mL) at room temperature, heated to 60 ℃ and reacted for 14 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (25mL), washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and dried, and the crude product was separated with a preparative plate (petroleum ether: ethyl acetate ═ 3: 1, V/V) to give 1- ((3-bromo-4- (2, 4-difluorophenoxy) phenyl) sulfonyl) cyclopropane-1-carbonitrile (0.08g, colorless oil, yield 75%).

The second step is that: 1- ((4- (2, 4-Difluorophenoxy) -3- (6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) sulfonyl) cyclopropane-1-carbonitrile

Using 1- ((3-bromo-4- (2, 4-difluorophenoxy) phenyl) sulfonyl) cyclopropane-1-carbonitrile as a reaction material, according to the seventh step of example 23, 1- ((4- (2, 4-difluorophenoxy) -3- (6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) sulfonyl) cyclopropane-1-carbonitrile (0.05g, white solid, 42% yield) was obtained.

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) sulfonyl) cyclopropane-1-carbonitrile

Starting from 1- ((4- (2, 4-difluorophenoxy) -3- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) sulfonyl) cyclopropane-1-carbonitrile, according to an eighth step of example 23, 1- ((4- (2, 4-difluorophenoxy) -3- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) sulfonyl) cyclopropane-1-carbonitrile (0.01g, white solid, yield 44%) was obtained.

MS m/z(ESI)：466.1[M+H]⁺.

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

Starting from 1- ((4- (2, 4-difluorophenoxy) -3- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) sulfonyl) cyclopropane-1-carbonitrile, according to the ninth step of example 23, 4- (5- ((1-cyanocyclopropyl) sulfonyl) -2- (2, 4-difluorophenoxy) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (0.0024g, white solid, 24% yield) was obtained.

MS m/z(ESI)：482.1[M+H]⁺.

¹H NMR(400MHz，CDCl₃)：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＝3.2Hz，1H)，2.75(s，3H)，1.98-1.94(m，2H)，1.74-1.71(m，2H).

Example 26

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

The first step is as follows: preparation of (3-bromo-4-fluorophenyl) (ethyl) sulfane

3-bromo-4-fluoroaniline (19g, 0.1mol) and copper powder (0.96g, 15mmol) were dissolved in 1, 2-diethyldisulfane (50mL), and the reaction was heated to 80 ℃. Isoamyl nitrite (15g, 0.15mmol) was slowly added dropwise to keep the internal temperature of the reaction at not higher than 90 ℃. After the addition was complete, the reaction was stirred at nine 90 ℃ for two hours. The reaction solution was evaporated to dryness, toluene and dilute hydrochloric acid were added to the reaction system, liquid separation was performed, the toluene phase was washed with dilute hydrochloric acid, water and saturated brine, the organic phase was dried to dryness, and the residue was distilled under reduced pressure to collect a fraction having a vapor temperature of 60 to 70 ℃ to obtain 3-bromo-4-fluorophenyl) (ethyl) sulfane (15g, pale yellow oil, yield 64%).

¹H 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＝7.6Hz，2H)，1.29(t，J＝7.6Hz，3H).

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

(3-bromo-4-fluorophenyl) (ethyl) sulfane (4.0g, 17.09mmol) was dissolved in dichloromethane (50mL) and a solution of m-chloroperoxybenzoic acid (8.63g, 37.61mmol) in dichloromethane (50mL) was added dropwise at 0 ℃. The reaction was stirred at zero degrees for one hour, and then the reaction solution was washed with saturated sodium thiosulfate (50mL), then with saturated aqueous sodium bicarbonate (100mL × 2), water (100mL × 2) and saturated brine (100mL), and dried over anhydrous sodium sulfate, and after concentration, the column layer was separated (petroleum ether: ethyl acetate ═ 3: 1, V/V) to give the compound 2-bromo-1-fluoro-4- (ethylsulfonyl) benzene (4.0g, yield 88%).

The 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 (1.0g, 4.43mmol), 6-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine (1.83g, 4.43mmol), [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (220mg, 0.3mmol), potassium carbonate (1.04g, 7.52mmol) was dissolved in 1, 4-dioxane (16mL) and water (4mL), and stirred at 100 ℃ for 4 hours under nitrogen. After the reaction was cooled to room temperature, the reaction solution was poured into water (50mL), followed by extraction with ethyl acetate (50mL × 2), the organic phases were combined and washed with water (100mL), saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, and the crude product after concentration of the filtrate was purified by column chromatography (petroleum ether: ethyl acetate ═ 2: 1, V/V) to give 4- (5- (ethylsulfonyl) -2-fluorophenyl) -6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine (1.5g, yield 72%).

The 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-tosyl-1H-pyrrolo [2, 3-b ] pyridine (600mg, 1.27mmol) is dissolved in t-butanol (5mL) and tetrahydrofuran (2mL), an aqueous potassium hydroxide solution (3M, 3mL) is added, the reaction mixture is stirred at 70 ℃ overnight, the reaction mixture is spun dry, water (20mL) is added, then ethyl acetate is used for extraction (20 mL. times.2), after the organic phases are combined, water (40mL) and saturated brine (40mL) are sequentially used for washing, the mixture is dried by anhydrous sodium sulfate, after filtration and concentration, column chromatography (petroleum ether: ethyl acetate: 1, V/V) is carried out to obtain 4- (5- (ethylsulfonyl) -2-fluorophenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine (320mg, yield 79%).

The fifth step: 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 (280.0mg, 0.88mmol) is dissolved in tetrahydrofuran (3mL), m-chloroperoxybenzoic acid (284mg, 1.32mmol) is added at room temperature, the reaction mixture is stirred at room temperature for ten minutes, then quenched with saturated aqueous sodium thiosulfate (20mL), then extracted with ethyl acetate (20 mL. times.2), the organic phases are combined and washed with saturated aqueous sodium bicarbonate (20mL), washed with water (20mL) and saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatographed (dichloromethane: methanol ═ 20: 1, V/V) to give the compound 4- (5- (ethylsulfonyl) -2-fluorophenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (220mg, 75% yield).

And a sixth step: preparation of 4- (2- (cyclohexatrienoxy) -5- (ethylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide

4- (5- (ethylsulfonyl) -2-fluorophenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (30.0mg, 0.089mmol) was dissolved in N, N-dimethylformamide (2mL), and cyclohexanol (18mg, 0.18mmol), sodium hydride (11mg, 0.267mmol) were added under ice bath. After stirring overnight, the mixture was quenched with an aqueous solution of ammonium chloride (10mL), extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined, washed with water (10 mL. times.2) and saturated brine (10mL), dried over anhydrous sodium sulfate, and concentrated to give the compound 4- (2- (cyclohexatrienoxy) -5- (ethylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (15.4mg, 41% yield) by preparative chromatography.

¹H NMR(400MHz，CDCl₃)：δ11.75(s，1H)，7.98(d，J＝2.3Hz，1H)，7.91(dd，J＝8.7Hz，2.4Hz，1H)，7.36(d，J＝3.1Hz，1H)，7.21-7.12(m，2H)，6.45(d，J＝3.3Hz，1H)，4.56-4.37(m，1H)，3.15(q，J＝7.4Hz，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

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

Starting from cycloheptanol instead of cyclohexanol as a sixth step in reference example 26, compound 4- (2- (cycloheptatriyloxy) -5- (ethylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (18.0mg, yield 49%) was obtained.

¹H NMR(400MHz，CDCl₃)：δ12.37(s，1H)，7.96(d，J＝2.2Hz，1H)，7.90(dd，J＝8.7Hz，2.3Hz，1H)，7.33(d，J＝3.2Hz，1H)，7.14(s，1H)，7.09(d，J＝8.8Hz，1H)，6.40(d，J＝3.2Hz，1H)，4.62-4.58(m，1H)，3.14(q，J＝7.4Hz，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＝11.8，5.2Hz，2H)，1.32(t，J＝7.4Hz，3H).

MS m/z(ESI)：429.1[M+H]⁺。

Example 28

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

Starting from 4, 4-difluorocyclohexan-1-ol instead of cyclohexanol as a starting material, according to the sixth step of example 26, compound 4- (2- ((4, 4-difluorocyclohexyl) oxo) -5- (ethylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (13.0mg, yield 32%) was obtained.

¹H NMR(400MHz，CDCl₃)：δ12.17(s，1H)，8.00(d，J＝2.2Hz，1H)，7.93(dd，J＝8.7Hz，2.3Hz，1H)，7.34(d，J＝3.3Hz，1H)，7.16(d，J＝8.8Hz，1H)，7.10(s，1H)，6.41(d，J＝3.3Hz，1H)，4.65(d，J＝2.5Hz，1H)，3.15(q，J＝7.4Hz，2H)，2.77(s，3H)，1.99-1.78(m，8H)，1.33(t，J＝7.4Hz，3H).

MS m/z(ESI)：451.1[M+H]⁺。

Example 29

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

The first step is as follows: preparation of 4- (5- (ethylsulfonyl) -2- (3- (trifluoromethyl) phenoxy) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide

4- (5- (ethylsulfonyl) -2-fluorophenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (30.0mg, 0.089mmol) is dissolved in N-methylpyrrolidone (2mL), and 3- (trifluoromethyl) phenol ((32mg, 0.18mmol), cesium carbonate (87mg, 0.267mmol) is added under ice-cooling, and after reaction at 180 ℃ for 30 minutes, the mixture is cooled to room temperature, then quenched with an aqueous solution of ammonium chloride (20mL), then extracted with ethyl acetate (10 mL. times.3). the organic phases are combined, washed with water (10 mL. times.2) and saturated brine (10mL), dried over anhydrous sodium sulfate, and concentrated to give the compound 4- (5- (ethylsulfonyl) -2- (3- (trifluoromethyl) phenoxy) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] through preparative chromatography 2, 3-b ] pyridine-7-oxide (11.0mg, 26% yield).

¹H NMR(400MHz，CDCl₃)：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＝6.1Hz，3H)，6.45(d，J＝2.9Hz，1H)，3.19(q，J＝7.3Hz，2H)，2.76(s，3H)，1.40-1.28(m，3H).

MS m/z(ESI)：477.1[M+H]⁺。

Example 30

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

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

¹H NMR(400MHz，CDCl₃)：δ12.65(s，1H)，8.20-7.81(m，2H)，7.34(d，J＝3.3Hz，1H)，7.16(d，J＝8.7Hz，1H)，7.10(s，1H)，6.34(d，J＝3.3Hz，1H)，4.12(d，J＝5.7Hz，2H)，3.15(q，J＝7.4Hz，2H)，2.78(s，3H)，2.55-2.51(m，3H)，2.39-2.16(m，2H)，1.32(t，J＝7.4Hz，3H).

MS m/z(ESI)：437.1[M+H]⁺。

Example 31

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

Starting from cyclobutylmethanol instead of cyclohexanol as a starting material, according to the sixth step of example 26, compound 4- (2- (cyclobutyl) methoxy) -5- (ethylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (19.0mg, yield 53%) was obtained.

¹H NMR(400MHz，CDCl₃)：δ12.88(s，1H)，7.93(d，J＝2.3Hz，1H)，7.85(dd，J＝8.7，2.4Hz，1H)，7.26(d，J＝3.1Hz，1H)，7.13-7.03(m，2H)，6.32(d，J＝3.2Hz，1H)，3.96(d，J＝6.3Hz，2H)，3.07(q，J＝7.4Hz，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-oxide

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

¹H NMR(400MHz，CD₃OD)：δ7.97(d，J＝2.3Hz，1H)，7.83(dd，J＝8.7Hz，2.3Hz，1H)，7.33(d，J＝3.4Hz，1H)，7.26(s，1H)，7.13(td，J＝9.1Hz，5.4Hz，1H)，7.05(ddd，J＝11.2Hz，8.6Hz，2.9Hz，1H)，6.96(dd，J＝8.7Hz，0.7Hz，1H)，6.91-6.84(m，1H)，6.46(d，J＝3.4Hz，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

Starting from 4-bromo-2-fluorophenol instead of 3- (trifluoromethyl) phenol, with reference to example 29, the compound 4- (2- (2, 4-difluorophenoxy) -5- (ethylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (13.0mg, yield 29%) was obtained.

¹H NMR(400MHz，CD₃OD)：δ8.02-7.89(m，1H)，7.86(dd，J＝8.7Hz，2.3Hz，1H)，7.38(dd，J＝10.2Hz，2.3Hz，1H)，7.33(d，J＝3.4Hz，1H)，7.23(d，J＝8.9Hz，2H)，7.01(dd，J＝16.8Hz，8.5Hz，2H)，6.47-6.38(m，1H)，3.21(dd，J＝3.2Hz，1.6Hz，2H)，2.59(s，3H)，1.17(t，J＝7.4Hz，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

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

¹H NMR(400MHz，CDCl₃)：δ11.98(s，1H)，8.01(d，J＝2.4Hz，1H)，7.91(dd，J＝8.7Hz，2.4Hz，1H)，7.29(d，J＝3.3Hz，1H)，7.15(dd，J＝17.3Hz，8.4Hz，2H)，6.43(d，J＝3.3Hz，1H)，4.55(s，1H)，3.70(d，J＝8.6Hz，1H)，3.15(q，J＝7.4Hz，2H)，2.77(d，J＝9.0Hz，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

Starting from 4-cyclopropylphenol instead of 3- (trifluoromethyl) phenol, the compound 4- (2- (4-cyclopropylphenoxy) -5- (ethylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (10.0mg, 25% yield) was obtained according to example 29.

¹H NMR(400MHz，CDCl₃)：δ12.16(s，1H)，8.06(d，J＝2.2Hz，1H)，7.81(dd，J＝8.7Hz，2.3Hz，1H)，7.30(d，J＝3.3Hz，1H)，7.16(s，1H)，7.07(d，J＝8.6Hz，2H)，7.01(d，J＝8.7Hz，1H)，6.90(d，J＝8.6Hz，2H)，6.49(d，J＝3.3Hz，1H)，3.15(q，J＝7.4Hz，2H)，2.74(s，3H)，1.89(td，J＝8.4Hz，4.2Hz，1H)，1.33(t，J＝7.4Hz，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

Starting from (1- (trifluoromethyl) cyclopropyl) methanol instead of cyclohexanol as a starting material, according to the sixth step of example 26, compound 4- (5- (ethylsulfonyl) -2- ((1- (trifluoromethyl) cyclopropyl) methoxy) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (20.9mg, yield 52%) was obtained.

¹H NMR(400MHz，CDCl₃)：δ13.12(s，1H)，8.04(d，J＝2.3Hz，1H)，7.93(dd，J＝8.7Hz，2.3Hz，1H)，7.34(d，J＝3.3Hz，1H)，7.22(s，1H)，7.13(d，J＝8.8Hz，1H)，6.38(d，J＝3.3Hz，1H)，4.20(s，2H)，3.14(q，J＝7.4Hz，2H)，2.78(s，3H)，1.31(t，J＝7.4Hz，3H)，1.02(t，J＝6.2Hz，2H)，0.73(s，2H).

MS m/z(ESI)：455.1[M+H]⁺。

Example 37

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

Starting from 4, 4-dimethylcyclohexan-1-ol instead of cyclohexanol as a starting material, according to the sixth step of example 26, compound 4- (2- ((4, 4-dimethylcyclohexyl) oxo) -5- (ethylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (10.0mg, yield 25%) was obtained.

¹H NMR(400MHz，CDCl₃)：δ11.97(s，1H)，7.99(d，J＝2.3Hz，1H)，7.89(dd，J＝8.7Hz，2.3Hz，1H)，7.29(d，J＝3.3Hz，1H)，7.17-7.11(m，2H)，6.42(d，J＝3.3Hz，1H)，4.44(dd，J＝7.3Hz，3.7Hz，1H)，3.14(q，J＝7.4Hz，2H)，2.77(s，3H)，1.83-1.75(m，2H)，1.62(ddd，J＝16.8Hz，12.7Hz，3.8Hz，2H)，1.38-1.27(m，5H)，1.19(ddd，J＝13.2，9.0，3.9Hz，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

Starting from 4-chloro-2-fluorophenol instead of 3- (trifluoromethyl) phenol, referring to example 29, the compound 4- (2- (4-chloro-2-fluorophenoxy) -5- (ethylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (13.2mg, 32% yield) was obtained.

¹H NMR(400MHz，CDCl₃)：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＝7.5Hz，1H)，7.13(d，J＝8.7Hz，1H)，7.02(t，J＝8.4Hz，1H)，6.95(d，J＝8.6Hz，1H)，6.50(d，J＝2.5Hz，1H)，3.16(q，J＝7.3Hz，2H)，2.77(s，3H)，1.34(t，J＝7.3Hz，3H).

MS m/z(ESI)：461.1[M+H]⁺。

Example 39

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

Starting from 1H-indol-6-ol instead of 3- (trifluoromethyl) phenol, with reference to example 29, the compound 4- (2- ((1H-indol-6-yl) oxo) -5- (ethylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (12.2mg, 31% yield) was obtained.

¹H NMR(400MHz，CDCl₃)：δ12.75(s，1H)，8.97(s，1H)，8.05(s，1H)，7.75(d，J＝8.7Hz，1H)，7.58(d，J＝8.5Hz，1H)，7.31-7.16(m，3H)，7.09(s，1H)，6.98(d，J＝8.8Hz，1H)，6.80(d，J＝8.5Hz，1H)，6.50(d，J＝8.4Hz，2H)，3.14(q，J＝7.3Hz，2H)，2.68(s，3H)，1.31(t，J＝7.4Hz，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

Starting from 4-hydroxybenzamide instead of 3- (trifluoromethyl) phenol, the compound 4- (2- (4-carbamoylphenoxy) -5- (ethylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (22.2mg, 55% yield) was obtained according to example 29.

¹H NMR(400MHz，CD₃OD)：δ8.04(d，J＝2.3Hz，1H)，7.94(dd，J＝8.6Hz，2.3Hz，1H)，7.72(d，J＝2.1Hz，1H)，7.71(d，J＝2.1Hz，1H)，7.35(d，J＝3.4Hz，1H)，7.27(d，J＝8.6Hz，1H)，7.22(s，1H)，6.98-6.84(m，2H)，6.47(d，J＝3.4Hz，1H)，3.25(s，3H)，2.56(s，3H)，1.21(t，J＝7.4Hz，4H).

MS m/z(ESI)：452.1[M+H]⁺。

EXAMPLE 41

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

Starting from 4-hydroxybenzamide instead of 3- (trifluoromethyl) phenol, with reference to example 29, the compound 4- (2- (4- (tert-butyl) phenoxy) -5- (ethylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (22.5mg, 55% yield) was obtained.

¹H NMR(400MHz，CDCl₃)：δ13.22(s，1H)，8.10(d，J＝2.3Hz，1H)，7.83(dd，J＝8.7Hz，2.3Hz，1H)，7.37(d，J＝8.7Hz，2H)，7.32(d，J＝3.2Hz，1H)，7.21(s，1H)，7.06(d，J＝8.7Hz，1H)，6.95(d，J＝8.7Hz，2H)，6.49(d，J＝3.2Hz，1H)，3.16(q，J＝7.4Hz，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

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

¹H NMR(400MHz，CDCl₃)：δ12.25(s，1H)，8.01(d，J＝2.3Hz，1H)，7.94(dd，J＝8.7Hz，2.3Hz，1H)，7.32-7.27(m，2H)，7.25(d，J＝8.8Hz，1H)，7.21-7.04(m，2H)，7.08-6.86(m，1H)，6.39(d，J＝3.3Hz，1H)，5.21(s，2H)，3.15(q，J＝7.4Hz，2H)，2.75(s，3H)，1.32(t，J＝7.4Hz，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

Starting from 4-cyclopropyl-2-fluorophenol instead of 3- (trifluoromethyl) phenol, referring to example 29, compound 4- (2- (4-cyclopropyl-2-fluorophenoxy) -5- (ethylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (10.5mg, 25% yield) was obtained.

¹H NMR(400MHz，CD₃OD)：δ8.09(d，J＝2.3Hz，1H)，7.94(dd，J＝8.8Hz，2.4Hz，1H)，7.46(d，J＝3.4Hz，1H)，7.39(s，1H)，7.07(dt，J＝8.5Hz，4.7Hz，2H)，7.02-6.92(m，2H)，6.60(d，J＝3.5Hz，1H)，3.29(q，J＝7.4Hz，2H)，2.73(s，3H)，1.95(dq，J＝8.5Hz，5.1Hz，1H)，1.29(t，J＝7.4Hz，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) oxo) -5- (ethylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide

Starting from 1H-indol-5-ol instead of 3- (trifluoromethyl) phenol, referring to example 29, the compound 4- (2- ((1H-indol-5-yl) oxo) -5- (ethylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (10.0mg, 25% yield) was obtained.

¹H NMR(400MHz，CD₃OD)：δ8.08(d，J＝2.3Hz，1H)，7.87(dd，J＝8.8Hz，2.4Hz，1H)，7.46(dd，J＝15.7Hz，6.6Hz，3H)，7.30(dd，J＝9.4Hz，2.7Hz，2H)，7.05(d，J＝8.8Hz，1H)，6.87(dd，J＝8.7Hz，2.3Hz，1H)，6.66(d，J＝3.4Hz，1H)，6.46(dd，J＝3.1Hz，0.8Hz，1H)，3.27(q，J＝7.4Hz，2H)，2.74(s，3H)，1.29(t，J＝7.4Hz，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

Starting from 4- (trifluoromethyl) phenol instead of 3- (trifluoromethyl) phenol, the compound 4- (5- (ethylsulfonyl) -2- (4- (trifluoromethyl) phenoxy) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (8.0mg, 19% yield) was obtained according to example 29.

¹H NMR(400MHz，CDCl₃)：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＝10.9Hz，1H)，7.27(s，1H)，7.19(d，J＝8.6Hz，1H)，7.10(d，J＝8.1Hz，2H)，6.61(s，1H)，3.20(d，J＝6.9Hz，2H)，2.90(s，3H)，1.37(t，J＝6.3Hz，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

Starting from (1r, 4r) -cyclohexane-1, 4-diol instead of 3- (trifluoromethyl) phenol, the compound 4- (5- (ethylsulfonyl) -2- (((1r, 4r) -4-hydroxycyclohexyl) oxo) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (3.0mg, 8% yield) was obtained according to example 29.

¹H NMR(400MHz，CD₃OD)：δ7.85(dt，J＝5.7Hz，2.4Hz，2H)，7.29(dd，J＝34.4Hz，31.1Hz，2H)，7.17(s，1H)，6.34(d，J＝3.4Hz，1H)，4.56-4.38(m，1H)，3.60-3.37(m，1H)，3.14(q，J＝7.4Hz，2H)，2.60(s，3H)，2.01-1.91(m，2H)，1.75-1.52(m，2H)，1.33(td，J＝13.2Hz，2.7Hz，4H)，1.16(t，J＝7.4Hz，3H).

MS m/z(ESI)：431.1[M+H]⁺。

Example 47

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

Starting from 1H-indazol-5-ol instead of 3- (trifluoromethyl) phenol, according to example 29, the compound 4- (2- ((1H-indazol-5-yl) oxo) -5- (ethylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (5.0mg, 13% yield) was obtained.

¹H NMR(400MHz，CDCl₃)：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＝6.3Hz，1H)，7.40(dd，J＝12.1Hz，2.6Hz，2H)，7.29(s，1H)，7.09(dd，J＝8.9Hz，2.2Hz，1H)，7.02(t，J＝8.7Hz，1H)，6.59(d，J＝3.4Hz，1H)，3.17(q，J＝7.4Hz，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

Starting from (1-methylcyclopropyl) methanol instead of cyclohexanol as a starting material, according to the sixth step of example 26, compound 4- (5- (ethylsulfonyl) -2- ((1-methylcyclopropyl) methoxy) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (15.0mg, yield 42%) was obtained.

¹H NMR(400MHz，CD₃OD)：δ7.98-7.77(m，2H)，7.33(d，J＝3.4Hz，1H)，7.29-7.15(m，2H)，6.37(d，J＝3.4Hz，1H)，3.84(s，2H)，3.14(q，J＝7.4Hz，2H)，2.62(s，3H)，1.16(t，J＝7.4Hz，3H)，0.89(s，3H)，0.37(t，J＝5.0Hz，2H)，0.20(t，J＝5.1Hz，2H).

MS m/z(ESI)：401.1[M+H]⁺。

Example 49

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

Starting from 1-methyl-1H-indol-5-ol instead of 3- (trifluoromethyl) phenol, 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 (10.0mg, 24% yield) was obtained.

¹H NMR(400MHz，CDCl₃)：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＝3.1Hz，1H)，7.01-6.81(m，2H)，6.59(d，J＝3.4Hz，1H)，6.46(d，J＝3.0Hz，1H)，3.82(s，3H)，3.15(q，J＝7.4Hz，2H)，2.75(s，3H)，1.33(t，J＝7.4Hz，4H).

MS m/z(ESI)：462.1[M+H]⁺。

Example 50

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

Starting from 1H-pyrrolo [2, 3-b ] pyridin-5-ol instead of 3- (trifluoromethyl) phenol, with reference 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 was obtained (12.0mg, 25% yield).

¹H NMR(400MHz，CDCl₃)：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＝1.5Hz，1H)，7.43(d，J＝2.6Hz，1H)，7.35(d，J＝3.2Hz，1H)，7.28(s，1H)，7.00(d，J＝8.7Hz，1H)，6.56(d，J＝3.3Hz，1H)，6.49(d，J＝2.7Hz，1H)，3.17(q，J＝7.4Hz，2H)，2.79(s，3H)，1.34(t，J＝7.4Hz，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

Starting from trans-4-methylcyclohexylamine instead of cyclohexanol in the sixth step of example 26, 4- (5- (ethylsulfonyl) -2- ((trans) -4-methylcyclohexyl) amino) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (0.050g, white solid, yield 60%) was obtained.

MS m/z(ESI)：428.2[M+H]+.

¹H NMR(400MHz，CD₃OD)：δ12.35(br，1H)，7.76(dd，J＝8.8Hz，2.4Hz，1H)，7.65(d，J＝2.0Hz，1H)，7.35(d，J＝3.2Hz，1H)，7.04(s，1H)，6.78(d，J＝8.8Hz，1H)，6.35(d，J＝3.2Hz，1H)，4.27(d，J＝7.2Hz，1H)，3.37-3.25(m，1H)，3.09(q，J＝7.2Hz，2H)，2.77(s，3H)，2.03-1.90(m，4H)，1.74-1.72(m，2H)，1.30(t，J＝7.2Hz，3H)，1.10-0.96(m，3H)，0.90(d，J＝6.8Hz，3H).

Example 52

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

Starting from trans-4-tert-butylcyclohexanol instead of cyclohexanol in the sixth step of example 26, 4- (2- ((trans) -4- (tert-butyl) cyclohexyl) oxo) -5- (ethanesulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine 7-oxide (0.040g, white solid, yield 57%) was obtained.

MS m/z(ESI)：471.2[M+H]⁺.

¹H NMR(400MHz，CDCl₃)：δ12.63(s，1H)，7.97(d，J＝2.0Hz 1H)，7.89(dd，J＝8.4Hz，2.0Hz，1H)，7.30(d，J＝3.2Hz，1H)，7.16(d，J＝8.4Hz，1H)，7.12(s，1H)，6.38(d，J＝3.2Hz，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

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

After trans-4-ethylcyclohexanol (0.077g, 0.60mmol) was dissolved in N, N-dimethylformamide (4mL) at room temperature, sodium hydride (60%, 0.036g, 0.90mmol) was added to the reaction mixture, and after stirring at room temperature for half an hour, 4- (2-fluoro-5- (ethanesulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (0.04g, 0.12mmol) in N, N-dimethylformamide (1mL) was added dropwise to the reaction system. After stirring overnight at room temperature, the reaction was diluted with ethyl acetate (20mL), washed with brine (20mL), the organic phase was dried over anhydrous sodium sulfate, filtered, spun-dried and the crude product was chromatographed on reverse phase preparative chromatography to give 4- (2- ((trans) -4- (ethyl) cyclohexyl) oxo) -5- (ethanesulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (0.030g, white solid, 57% yield).

MS m/z(ESI)：443.2[M+H]⁺.

¹H NMR(400MHz，CDCl₃)：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＝3.2Hz，1H)，4.35-4.25(m，1H)，3.13(q，J＝7.2Hz，2H)，2.76(s，3H)，2.10-2.08(m，4H)，1.84-1.80(m，2H)，1.32(t，J＝7.2Hz，3H)，1.25-1.16(m，2H)，1.14-1.05(m，1H)，1.04-0.95(m，2H)，0.87(t，J＝7.2Hz，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, starting from trans-4-methylcyclohexanol instead of trans-4-ethylcyclohexanol, 4- (2- ((trans) -4- (methyl) cyclohexyl) oxo) -5- (ethanesulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine 7-oxy was obtained (0.040g, white solid, 63% yield).

MS m/z(ESI)：429.2[M+H]⁺.

¹H NMR(400MHz，CDCl₃)：δ12.13(br，1H)，7.96(d，J＝2.4Hz，1H)，7.90(dd，J＝8.4Hz，2.4Hz，1H)，7.33(d，J＝3.2Hz，1H)，7.16-7.13(m，2H)，6.40(d，J＝3.2Hz，1H)，4.35-4.27(m，1H)，3.14(q，J＝7.6Hz，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＝6.4Hz，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, starting from trans-4-propylcyclohexanol instead of trans-4-ethylcyclohexanol, 4- (2- ((trans) -4- (propyl) cyclohexyl) oxo) -5- (ethanesulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine 7-oxy (0.030g, white solid, 55% yield) was obtained.

MS m/z(ESI)：457.2[M+H]⁺.

¹H NMR(400MHz，CDCl₃)：δ11.67(br，1H)，7.96(d，J＝2.4Hz，1H)，7.90(dd，J＝8.4Hz，2.4Hz，1H)，7.34(d，J＝3.6Hz，1H)，7.17-7.14(m，2H)，6.42(d，J＝3.6Hz，1H)，4.35-4.27(m，1H)，3.15(q，J＝7.2Hz，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＝7.2Hz，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, starting from trans-4-isopropylcyclohexanol instead of trans-4-ethylcyclohexanol, 4- (2- ((trans) -4- (isopropyl) cyclohexyl) oxo) -5- (ethanesulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine 7-oxy (0.020g, white solid, 49% yield) was obtained.

MS m/z(ESI)：457.2[M+H]⁺.

¹H NMR(400MHz，CDCl₃)：δ11.70(br，1H)，7.96(d，J＝2.0Hz，1H)，7.90(dd，J＝8.8Hz，2.0Hz，1H)，7.33(d，J＝3.2Hz，1H)，7.17-7.14(m，2H)，6.42(d，J＝3.2Hz，1H)，4.35-4.23(m，1H)，3.15(q，J＝14.8Hz，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＝6.8Hz，6H).

Example 57

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

Following the experimental procedure of example 53, starting from 1H-indazol-6-ol instead of trans-4-ethylcyclohexanol, 4- (2- ((1H-indazol-6-yl) oxo) -5- (ethylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide was obtained.

¹H NMR(400MHz，CD₃OD)：δ8.18(d，J＝2.1Hz，1H)，8.13(dd，J＝8.3Hz，2.1Hz，1H)，7.99(s，1H)，7.90(d，J＝8.3Hz，1H)，7.83(s，1H)，7.36(d，J＝8.7Hz，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

Starting from p-hydroxyphenylmethyl cyanide instead of trans-4-ethylcyclohexanol, 4- (2- (4-cyanophenoxy) -5- (ethylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide was obtained according to the experimental procedure of example 53.

¹H 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＝9.5Hz，5.9Hz，2H)，7.17(s，1H)，6.95-6.86(m，2H)，6.42(d，J＝3.4Hz，1H)，3.27-3.18(m，2H)，2.53(s，3H)，1.19(t，J＝7.4Hz，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, starting from 4- (hydroxymethyl) phenol instead of trans-4-ethylcyclohexanol, 4- (5- (ethylsulfonyl) -2- (4- (hydroxymethyl) phenoxy) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide was obtained.

¹H NMR(400MHz，CD₃OD)：δ8.11(d，J＝2.3Hz，1H)，7.97(dd，J＝8.7Hz，2.4Hz，1H)，7.46(d，J＝3.4Hz，1H)，7.41-7.35(m，3H)，7.20(d，J＝8.7Hz，1H)，7.02(d，J＝8.6Hz，2H)，6.60(d，J＝3.4Hz，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-oxide

Starting from cyclopropylmethanol instead of cyclohexanol in the sixth step of example 26, 4- (2- (cyclopropylmethoxy) -5- (ethylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (22.8mg, 39.4% yield) was obtained.

¹H NMR(400MHz，CDCl₃)：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＝7.2Hz，2H)，2.93(s，3H)，1.34-1.31(t，J＝7.2Hz，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, starting from 2- (4-hydroxyphenyl) acetamide instead of trans-4-ethylcyclohexanol, 4- (2- (4- (2-amino-2-carbonylethyl) phenoxy) -5- (ethylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide was obtained.

¹H NMR(400MHz，CD₃OD)：δ8.12(d，J＝2.3Hz，1H)，7.99(dd，J＝8.8Hz，2.3Hz，1H)，7.55(d，J＝3.4Hz，1H)，7.48(s，1H)，7.34(d，J＝8.6Hz，2H)，7.23(d，J＝8.7Hz，1H)，7.03(d，J＝8.6Hz，2H)，6.68(d，J＝3.4Hz，1H)，3.51(s，2H)，3.34-3.27(m，2H)，2.77(s，3H)，1.30(t，J＝7.4Hz，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

The first step is as follows: n- (4-ethylcyclohexyl) -2- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) -4- (ethanesulfonyl) aniline

4- (2-fluoro-5- (ethylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (0.025g, 0.075mmol), 4-ethylcyclohexylamine (0.3mL), and N-methylpyrrolidone (3mL) were added to a 10mL microwave tube, heated to 140 ℃ in an oil bath, reacted overnight, and cooled to room temperature. The reaction was diluted with ethyl acetate (20mL), washed with brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and spun-dried to give the crude N- (4-ethylcyclohexyl) -2- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) -4- (ethanesulfonyl) aniline (0.050g, yellow oil). The crude product was used directly in the next reaction.

MS m/z(ESI)：426.2[M+H]⁺。

The second step is that: 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 (0.050g, yellow oil), was dissolved in dichloromethane (10mL), and then m-chloroperoxybenzoic acid (85%, 0.055g, 0.27mmol) was added to the reaction mixture and stirred at room temperature. After the reaction was completed, the reaction solution was diluted with dichloromethane (20mL), washed with saturated sodium bicarbonate solution, washed with brine, dried over anhydrous sodium sulfate, filtered, and dried, and the crude product was separated by reverse phase preparative chromatography to give 6-methyl-4- (2- ((trans) -4-ethylcyclohexyl) amino) -5- (ethanesulfonyl) phenyl) -1H-pyrrolo [2, 3-b ] pyridine-7-oxide (0.008g, white solid, yield 15%).

MS m/z(ESI)：442.2[M+H]⁺.

¹H NMR(400MHz，CDCl₃)：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＝8.8Hz，1H)，6.37(d，J＝3.2Hz，1H)，4.29(d，J＝8.0Hz，1H)，3.32(br，1H)，3.11(q，J＝7.2Hz，2H)，2.78(s，3H)，2.05(br，2H)，1.86-1.73(br，2H)，1.31(t，J＝7.2Hz，3H)，1.24-1.18(m，2H)，1.15-0.93(m，5H)，0.87(t，J＝7.2Hz，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, starting from 4-propylcyclohexylamine instead of 4-ethylcyclohexylamine, 6-methyl-4- (2- ((trans) -4-propylcyclohexyl) amino) -5- (ethanesulfonyl) phenyl) -1H-pyrrolo [2, 3-b ] pyridine-7-oxide (0.015g, white solid, 23% yield) was obtained.

MS m/z(ESI)：456.2[M+H]⁺.

¹H NMR(400MHz，CDCl₃)：δ12.25(br，1H)，7.76(dd，J＝8.8Hz，2.0Hz，1H)，7.66(d，J＝2.0Hz，1H)，7.43(d，J＝3.2Hz，1H)，7.09(s，1H)，6.81(d，J＝8.8Hz，1H)，6.39(d，J＝3.2Hz，1H)，4.30(d，J＝7.2Hz，1H)，3.31(br，1H)，3.10(q，J＝7.2Hz，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＝7.6Hz，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, starting from 4-propylcyclohexylamine instead of 4-ethylcyclohexylamine, 6-methyl-4- (2- ((cis) -4-propylcyclohexyl) amino) -5- (ethanesulfonyl) phenyl) -1H-pyrrolo [2, 3-b ] pyridine-7-oxide (0.010g, white solid, yield 15%) was obtained.

MS m/z(ESI)：456.2[M+H]⁺.

¹H NMR(400MHz，CDCl₃)：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＝9.2Hz，1H)，6.47(d，J＝2.8Hz，1H)，4.53(d，J＝6.4Hz，1H)，3.65(br，1H)，3.11(q，J＝7.2Hz，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＝7.6Hz，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, preparative isolation gave 6-methyl-4- (2- ((cis) -4-ethylcyclohexyl) amino) -5- (ethanesulfonyl) phenyl) -1H-pyrrolo [2, 3-b ] pyridine-7-oxide simultaneously (0.008g, white solid, 24% yield).

MS m/z(ESI)：442.2[M+H]⁺.

¹H NMR(400MHz，CDCl₃)：δ11.96(s，1H)，7.76(dd，J＝8.8Hz，2.0Hz，1H)，7.69(d，J＝2.0Hz 1H)，7.33(d，J＝3.2Hz，1H)，7.07(s，1H)，6.78(d，J＝8.8Hz，1H)，6.41(d，J＝3.2Hz，1H)，4.56(d，J＝6.4Hz，1H)，3.65(br，1H)，3.10(q，J＝7.2Hz，2H)，2.78(s，3H)，1.72-1.51(m，6H)，1.31(t，J＝7.2Hz，3H)，1.19-1.12(m，3H)，0.98-0.85(m，2H)，0.82(t，J＝7.2Hz，3H).

Example 66

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

The first step is as follows: 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 (0.050g, 0.224mmol) was dissolved in N, N-dimethylformamide (2mL) at room temperature, and then sodium hydride (60%, 0.012g, 0.30mmol) was added to the reaction solution, followed by stirring at room temperature for half an hour. Then 4- (2-fluoro-5- (ethanesulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (0.05g, 0.24mmol) in N, N-dimethylformamide (1mL) was added dropwise to the reaction system, and the mixture was heated to 80 ℃ for reaction for five hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (20mL), washed with saturated brine (10mL × 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spinning, and the crude product was isolated with a preparative plate (petroleum ether: ethyl acetate 1: 1, V/V) to give (0.030g, colorless oil, yield 37%).

MS m/z(ESI)：538.2[M+H]⁺.

The second step is that: 4- (2- (4- (aminomethyl) phenoxy) -5- (ethylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide

4- (2- (4- (((tert-butoxycarbonyl) amino) methyl) phenoxy) -5- (ethylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (30mg, 0.056mmol) was dissolved in dichloromethane (2mL) at room temperature, trifluoroacetic acid (0.5mL) was added dropwise to the reaction mixture, after two hours of reaction, the reaction mixture was evaporated to dryness, the residue was dissolved in ethyl acetate (20mL), the organic phase was washed with a saturated sodium bicarbonate solution (10mL), a saturated brine (10mL) was washed, the organic phase was dried over anhydrous sodium sulfate, filtered, spun-dried, and the crude product was isolated by reverse phase preparative chromatography to give 4- (2- (4- (aminomethyl) phenoxy) -5- (ethylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (12mg, grey solid, 49% yield).

MS m/z(ESI)：438.1[M+H]⁺.

¹H NMR(400MHz，CD₃OD)：δ8.39(br，1H)，8.02(d，J＝2.4Hz，1H)，7.90(dd，J＝8.8Hz，2.4Hz，1H)，7.34(d，J＝3.6Hz，1H)，7.28(d，J＝8.4Hz，2H)，7.22(s，1H)，7.18(d，J＝8.4Hz，1H)，6.91(d，J＝8.8Hz，2H)，6.46(d，J＝3.2Hz，1H)，4.50(br，2H)，3.94(s，2H)，3.19(q，J＝7.2Hz，2H)，2.56(s，3H)，1.19(t，J＝7.2Hz，3H).

Example 67

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

The first step is as follows: preparation of S- (3-bromo-4-fluorophenyl) ethanesulfate

Dissolving 2-bromo-1-fluoro-4-iodobenzene (8.8g, 29.3mmol), potassium thioacetate (4.7g, 411mmol), cuprous iodide (557mg, 2.93mmol), 1, 10-phenanthroline (1.05g, 5.86mmol) in toluene (100mL), replacing nitrogen, heating to 100 ℃, stirring overnight, and detecting complete reaction by LC/MS. Water (100mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (150mL), and the organic phase was washed with saturated brine (100mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate: 10: 1, V/V) to give S- (3-bromo-4-fluorophenyl) ethanesulfate (5.5g, yield 75%).

¹H NMR(400MHz，DMSO-d₆)：δ7.81-7.79(m，1H)，7.50-7.48(m，2H)，2.45(s，3H)。

The second step is that: preparation of (3-bromo-4-fluorophenyl) (2, 2, 2-trifluoroethyl) sulfane

S- (3-bromo-4-fluorophenyl) ethanesulfate (5.0g, 16.9mmol) was dissolved in an acetonitrile/methanol (20mL/20mL) mixed solvent, cesium carbonate (19.6g, 60mmol) was added, and after stirring for 5 minutes, 2-bromo-1, 1, 1-trifluoroethane (8.4g, 40mmol) was added, and the reaction was allowed to proceed at room temperature overnight. Water (100mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100mL), and the organic phase was washed with saturated brine (100mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate: 10: 1, V/V) to give (3-bromo-4-fluorophenyl) (2, 2, 2-trifluoroethyl) sulfane (3.0g, yield 52.0%).

¹H NMR(400MHz，CDCl₃)：δ7.74-7.72(m，1H)，7.47-7.43(m，1H)，7.11-7.05(m，1H)，3.42-3.35(q，J＝9.6Hz，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 (3.0g, 16.9mmol) was dissolved in dichloromethane (40mL), and m-chloroperoxybenzoic acid (5.36g, 3.12mmol) was added and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added saturated ethyl acetate (100mL), and the mixture was washed with saturated sodium carbonate solution (50mL × 2), then with saturated brine (50mL), dried over anhydrous sodium sulfate, and concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate: 10: 1, V/V) to give 2-bromo-1-fluoro-4- ((2, 2, 2-trifluoroethyl) sulfonyl) benzene (2.1g, yield 63%).

¹H NMR(400MHz，CDCl₃)：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)。

The 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 (600mg, 1.94mmol) was dissolved in tetrahydrofuran/hexamethylphosphoric triamide (10mL/8mL), methyl iodide (5mL) was added, cooled to-78 ℃ with a dry ice/acetone bath, a lithium diisopropylamide tetrahydrofuran solution (2M, 2.4mL, 4.8mmol) was added, stirred at-78 ℃ for 30 minutes, then warmed to-50 ℃ and stirred for 20 minutes. The reaction was then quenched by adding saturated ammonium chloride solution (50 mL). Extraction was performed with ethyl acetate (100mL), and the organic phase was washed with saturated brine (100mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 10: 1, V/V) to give 2-bromo-1-fluoro-4- ((1, 1, 1-trifluoro-2-methylpropan-2-yl) sulfonyl) benzene (300mg, yield 46%).

¹H NMR(400MHz，CDCl₃)：δ8.15-8.13(m，1H)，7.90-7.86(m，1H)，7.34-7.30(m，1H)，1.61(s，6H)。

The fifth step: preparation of 4- (2-fluoro-5- ((1, 1, 1-trifluoro-2-methylpropan-2-yl) sulfonyl) phenyl) -6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine

2-bromo-1-fluoro-4- ((1, 1, 1-trifluoro-2-methylpropan-2-yl) sulfonyl) benzene (930mg, 2.66mmol), 6-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine (1.6g, 2.93mmol), [1, 1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (39mg, 0.05mmol), potassium carbonate (0.74g, 5.32mmol) was dissolved in a mixed solvent of 1, 4-dioxane (32mL) and water (8mL), nitrogen was replaced, heating was carried out to 100 ℃ and stirring was carried out overnight, and LC/MS detection showed that the reaction was complete. Water (100mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100mL), and the organic phase was washed with saturated brine (100mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 2: 1, V/V) to give 4- (2-fluoro-5- ((1, 1, 1-trifluoro-2-methylpropan-2-yl) sulfonyl) phenyl) -6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine (0.88g, yield 60.0%).

MS m/z(ESI)＝555.1[M+H]⁺

And a sixth step: preparation of 4- (2-fluoro-5- ((1, 1, 1-trifluoro-2-methylpropan-2-yl) sulfonyl) phenyl) -6-methyl-1H-pyrrolo [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 (880mg, 1.59mmol) was dissolved in t-butanol (30mL), and aqueous potassium hydroxide (3M, 15mL) was added to the solution, heated to 70 ℃ and stirred overnight. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (80mL), washed with saturated brine (100mL), dried over anhydrous sodium sulfate, and concentrated to give 4- (2-fluoro-5- ((1, 1, 1-trifluoro-2-methylpropan-2-yl) sulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine (400mg, yield 63.0%).

MS m/z(ESI)：401.1[M+H]⁺

The seventh step: preparation of 4- (2-fluoro-5- ((1, 1, 1-trifluoro-2-methylpropan-2-yl) sulfonyl) phenyl) -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 (400mg, 1.0mmol) was dissolved in tetrahydrofuran (10mL), m-chloroperoxybenzoic acid (304mg, 1.5mmol) was added, and the reaction was complete after stirring at room temperature for 20 minutes by LC/MS. To the reaction mixture was added ethyl acetate (60mL), which was washed with a saturated sodium carbonate solution (50mL × 2) and then with a saturated brine (50mL), dried over anhydrous sodium sulfate, and concentrated to give 4- (2-fluoro-5- ((1, 1, 1-trifluoro-2-methylpropan-2-yl) sulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine 7-oxide (320mg, yield 77.0%).

MS m/z(ESI)：416.1[M+H]⁺

Eighth step: preparation of 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

4- (2-fluoro-5- ((1, 1, 1-trifluoro-2-methylpropan-2-yl) sulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (120mg, 0.29mmol) was dissolved in N-methylpyrrolidinone (3mL), 2, 4-difluorophenol (150mg, 1.15mmol), cesium carbonate (375mg, 1.15mmol) were added, and the mixture was heated to 180 ℃ under microwave conditions for reaction for 30 minutes. After cooling to room temperature, ethyl acetate (50mL) was added to the reaction mixture, which was then washed with saturated brine (50mL), dried over anhydrous sodium sulfate, concentrated and then separated and purified by silica gel plate preparation (dichloromethane: methanol ═ 10: 1, V/V) to give 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 (30.0mg, yield 20%).

¹H NMR(400MHz，CDCl₃)：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

Following the experimental procedure of the eighth step of example 67, starting from 4-bromo-2-fluorophenol instead of 2, 4-difluorophenol, 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, 23.4% yield) was obtained.

¹H NMR(400MHz，CDCl₃)：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, starting from 4-cyclopropylphenol instead of 2, 4-difluorophenol, 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 was obtained (19.0mg, 21% yield).

¹H NMR(400MHz，CDCl₃)：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

Following the experimental procedure of the eighth step of example 67, starting from 4-hydroxypyridine instead of 2, 4-difluorophenol, 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 (17.5mg, 21% yield) was obtained.

¹H NMR(400MHz，CDCl₃)：δ12.42(s，1H)，8.18-8.12(m，2H)，7.70-7.68(d，J＝8.4Hz，1H)，7.35-7.34(d，J＝3.2Hz，1H)，7.28-7.26(m，2H)，6.75(s，1H)，6.27-6.25(d，J＝7.2Hz，2H)，6.21-6.20(d，J＝3.2Hz，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 (178mg, 1.56mmol) was dissolved in N-methylpyrrolidinone (2mL), sodium hydride (63.0mg, 1.56mmol) was added, and stirred at room temperature for 10 minutes to obtain 4- (2-fluoro-5- ((1, 1, 1-trifluoro-2-methylpropan-2-yl) sulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b-]Pyridine 7-oxide (65mg, 0.16mmol) was added to the above reaction solution, reacted at room temperature for 5 hours, and the reaction was completed by LCMS. Ethyl acetate (50mL) was added to the reaction mixture, which was washed with saturated brine (50mL), dried over anhydrous sodium sulfate, concentrated and then washed with waterPurification by phase preparative chromatography (C)₁₈Column, mobile phase (acetonitrile/water) to obtain 6-methyl-4- (2- (((trans) -4-methylcyclohexyl) oxo) -5- ((1, 1, 1-trifluoro-2-methylpropan-2-yl) sulfonyl) phenyl) -1H-pyrrolo [2, 3-b ] pyrrole]Pyridine-7-oxide (15.0mg, 19% yield).

¹H NMR(400MHz，CDCl₃)：δ11.76(s，1H)，7.97(d，J＝2.4Hz，1H)，7.93-7.90(dd，J＝8.8Hz，2.4Hz，1H)，7.35(d，J＝3.2Hz，1H)，7.16-7.13(m，2H)，6.41(d，J＝3.6Hz，1H)，4.36-4.31(m，1H)，2.76(s，3H)，2.09-2.07(t，J＝5.6Hz，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＝6.4Hz，3H)。

MS m/z(ESI)：511.1[M+H]⁺

Example 72

Preparation of 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

Trans-1, 4-cyclohexanediol (100mg, 0.86mmol) was dissolved in N-methylpyrrolidinone (2mL), sodium hydride (40.0mg, 5.2mmol) was added, the mixture was 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-oxide (80mg, 0.19mmol) was added to the reaction mixture, and the mixture was heated to 40 ℃ for reaction overnight and LCMS showed that the reaction was complete. To the reaction mixture was added ethyl acetate (50mL), followed by washing with saturated brine (50mL), drying over anhydrous sodium sulfate, concentration and purification by silica gel plate separation (dichloromethane: methanol ═ 10: 1, V/V) to give 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 (27.5mg, yield 28%).

¹H NMR(400MHz，CDCl₃)：δ12.30(s，1H)，7.97(d，J＝2.4Hz，1H)，7.94-7.91(dd，J＝8.8Hz，2.4Hz，1H)，7.32(d，J＝3.2Hz，1H)，7.17-7.14(m，2H)，6.39(d，J＝3.2Hz，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

Referring to example 71, (trans) -4-methyl-cyclohexanol was substituted with cyclopropylmethanol to give 4- (2- (cyclopropylmethoxy) -5- ((1, 1, 1-trifluoro-2-methylpropan-2-yl) sulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (15.5mg, 48.5% yield).

¹H NMR(400MHz，CDCl₃)：δ12.56(s，1H)，8.00(d，J＝2.4Hz，1H)，7.94-7.91(dd，J＝8.8Hz，2.0Hz，1H)，7.35(d，J＝3.2Hz，1H)，7.18(s，1H)，7.13-7.11(d，J＝8.8Hz，1H)，6.41(d，J＝3.2Hz，1H)，3.97(d，J＝6.8Hz，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, (trans) -4-methyl-cyclohexanol was substituted with 4, 4-difluorocyclohexanol to give 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 (11.0mg, yield 42.5%).

¹H NMR(400MHz，CDCl₃)：δ12.19(s，1H)，8.01(d，J＝2.4Hz，1H)，7.96-7.93(dd，J＝8.8Hz，2.0Hz，1H)，7.34(d，J＝3.2Hz，1H)，7.17-7.15(d，J＝8.8Hz，1H)，7.10(s，1H)，6.39(d，J＝3.2Hz，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

Reacting 4- (2-fluoro-5- ((1, 1, 1-trifluoro-2-methylpropan-2-yl) sulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b]Pyridine-7-oxide (70mg, 0.17mmol) and (trans) -4-methyl-cyclohexylamine (190mg, 1.68mmol) were dissolved in N-methylpyrrolidone (2mL), N-diisopropylethylamine (0.5mL) was added, and the mixture was heated to 120 ℃ and stirred overnight. After cooling to room temperature, ethyl acetate (50mL) was added to the reaction mixture, which was washed with saturated brine (50mL), dried over anhydrous sodium sulfate, concentrated and purified by reverse phase preparative chromatography (C)₁₈Column, mobile phase (acetonitrile/water)) to obtain 6-methyl-4- (2- (((trans) -4-methylcyclohexyl) amino) -5- ((1, 1, 1-trifluoro-2-methylpropan-2-yl) sulfonyl) phenyl) -1H-pyrrolo [2, 3-b ] pyrrole]Pyridine-7-oxide (12.0mg, 14.7% yield).

¹H NMR(400MHz，CDCl₃)：δ12.62(s，1H)，7.77-7.74(dd，J＝8.8Hz，1.6Hz，1H)，7.66(s，1H)，7.36(d，J＝2.0Hz，1H)，7.03(s，1H)，7.79-7.77(d，J＝9.2Hz，1H)，6.32(d，J＝2.8Hz，1H)，4.39-4.37(d，J＝7.2Hz，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＝7.2Hz，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

The first step is as follows: preparation of (3-bromo-4-fluorophenyl) (isopropyl) sulfane

S- (3-bromo-4-fluorophenyl) ethanesulfate (3.5g, 14.1mmol) was dissolved in a mixed solvent of acetonitrile/methanol (20mL/20mL), cesium carbonate (13.8g, 43.2mmol) was added thereto, and after stirring for 5 minutes, 2-iodo-propane (23.8g, 141mmol) was added thereto, and after reaction overnight at room temperature, water (80mL) was added to the reaction mixture, followed by extraction with ethyl acetate (100mL), and the organic phase was washed with saturated brine (80mL), dried over anhydrous sodium sulfate, and after concentration, purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 10: 1, V/V) to give (3-bromo-4-fluorophenyl) (isopropyl) sulfane (3.2g, yield 91.0%).

MS m/z(ESI)：249.0[M+H]⁺

The second step is that: preparation of (3-bromo-4-fluorophenyl) (isopropyl) sulfane

(3-bromo-4-fluorophenyl) (isopropyl) sulfane (3.2g, 12.9mmol) was dissolved in methylene chloride (50mL), m-chloroperoxybenzoic acid (7.8g, 38.6mmol) was added, the mixture was stirred at room temperature for 3 hours, and then saturated ethyl acetate (100mL) was added to the reaction mixture, which was washed with saturated sodium carbonate solution (50mL × 2), then with saturated brine (50mL), dried over anhydrous sodium sulfate, and concentrated and then subjected to silica gel column chromatography (petroleum ether: ethyl acetate: 10: 1, V/V) to obtain (3-bromo-4-fluorophenyl) (isopropyl) sulfane (2.1g, 58% yield).

¹H NMR(400MHz，CDCl₃)：δ8.13-8.10(m，1H)，7.86-7.82(m，1H)，7.34-7.27(m，1H)，3.24-3.18(m，1H)，1.31(d，J＝6.8Hz，6H)。

The 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 (1.00g, 3.56mmol), 6-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine (1.76g, 2.93mmol), [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (32mg, 0.18mmol), and potassium carbonate (1.47g, 10.68mmol) were dissolved in a mixed solvent of 1, 4-dioxane (30mL) and water (10mL), nitrogen was replaced, heating was carried out to 100 ℃ and stirring was carried out for 4 hours, and the reaction was detected to be complete by LC/MS. Water (100mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100mL), and the organic phase was washed with saturated brine (100mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate: 2: 1, V/V) to give 4- (2-fluoro-5- (isopropylsulfonyl) phenyl) -6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine (0.70g, 40% yield).

MS m/z(ESI)：487.1[M+H]⁺

The 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 (700mg, 1.44mmol) was dissolved in t-butanol (30mL), and a potassium hydroxide solution (3M, 15mL) was added to the above solution, heated to 70 ℃ and stirred overnight. After cooling to room temperature, ethyl acetate (60mL) was added to the reaction mixture, and the organic phase was washed with saturated brine (50 mL. times.2), dried over anhydrous sodium sulfate, and concentrated to give 4- (2-fluoro-5- (isopropylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine (450mg, yield 94%).

MS m/z(ESI)：333.1[M+H]⁺

The fifth step: 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 (450mg, 1.36mmol) was dissolved in tetrahydrofuran (5mL), m-chloroperoxybenzoic acid (411mg, 2.03mmol) was added, the mixture was stirred at room temperature for 1 hour, and the reaction was detected to be complete by LC/MS. To the reaction mixture was added ethyl acetate (80mL), which was washed with a saturated sodium carbonate solution (50mL × 2) and then with a saturated brine (50mL), dried over anhydrous sodium sulfate, and concentrated to give 4- (2-fluoro-5- (isopropylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine 7-oxide (400mg, yield 85%).

MS m/z(ESI)：348.1[M+H]⁺

And a sixth step: preparation of 4- (5- (isopropylsulfonyl) -2- (((trans) -4-methylcyclohexyl) oxo) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine 7-oxidation

Trans-4-methylcyclohexanol (200mg, 1.77mmol) was dissolved in N-methylpyrrolidone (2mL), sodium hydride (100mg, 2.5mmol) was added, and stirring was carried out at room temperature for 10 minutes to obtain 4- (2-fluoro-5- (isopropylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] -b]Pyridine 7-oxide (70mg, 0.20mmol) was added to the above reaction solution, reacted at room temperature for 3 hours, and the reaction was completed by LCMS. Ethyl acetate (50mL) was added to the reaction mixture, and the mixture was used as an organic phaseWashed with saturated brine (50mL), dried over anhydrous sodium sulfate, concentrated and purified by reverse phase preparative chromatography (C)₁₈Column, mobile phase (acetonitrile/water)) to obtain 4- (5- (isopropylsulfonyl) -2- (((trans) -4-methylcyclohexyl) oxo) phenyl) -6-methyl-1H-pyrrolo [2, 3-b)]Pyridine-7-oxide (21.0mg, 24% yield).

¹H NMR(400MHz，CDCl₃)：δ12.08(s，1H)，7.94(d，J＝2.4Hz，1H)，7.88-7.86(dd，J＝8.8Hz，2.4Hz，1H)，7.32(d，J＝3.2Hz，1H)，7.16-7.13(m，2H)，6.40(d，J＝3.2Hz，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＝6.4Hz，3H)。

MS m/z(ESI)：443.1[M+H]⁺

Example 77

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

Referring to example 76, the sixth step was carried out to substitute (trans) -4-methyl-cyclohexanol with (trans) -4-ethyl-cyclohexanol to give 4- (2- (((trans) -4-ethylcyclohexyl) oxo) -5- (isopropylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (14.0mg, yield 25.5%).

¹H NMR(400MHz，CDCl₃)：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＝3.6Hz，1H)，7.16-7.14(m，2H)，6.41(d，J＝3.2Hz，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＝7.2Hz，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, starting from 4- (2-fluoro-5- (isopropylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide, (trans) -4-methyl-cyclohexanol was 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 (11.0mg, 21.5% yield).

¹H NMR(400MHz，CDCl₃)：δ12.34(s，1H)，7.95(d，J＝2.4Hz，1H)，7.88-7.85(dd，J₁＝8.8Hz，J₂＝2.4Hz，1H)，7.31(d，J＝3.6Hz，1H)，7.16-7.13(m，2H)，6.39(d，J＝3.2Hz，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＝7.2Hz，3H)。

MS m/z(ESI)：471.2[M+H]⁺

Example 79

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

Referring to the sixth step of example 76, the (trans) -4-methyl-cyclohexanol was substituted with (trans) -4-isopropyl-cyclohexanol to give 4- (2- (((trans) -4-isopropylcyclohexyl) oxo) -5- (isopropylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (16.6mg, yield 28.0%).

¹H NMR(400MHz，CDCl₃)：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＝3.6Hz，1H)，7.17-7.14(m，2H)，6.43(d，J＝3.2Hz，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＝6.4Hz，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

Reacting 4- (2-fluoro-5- (isopropylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b]Pyridine-7-oxide (80mg, 0.24mmol) and (trans) -4-methyl-cyclohexylamine (1mL) were dissolved in N-methylpyrrolidone (2mL), heated to 140 ℃ and stirred for 5 hours. Ethyl acetate (50mL) was added to the reaction mixture, and the organic phase was washed with saturated brine (50mL), dried over anhydrous sodium sulfate, concentrated and purified by reverse phase preparative chromatography (C)₁₈Column, mobile phase (acetonitrile/water)) to obtain 4- (5- (isopropylsulfonyl) -2- (((trans) -4-methylcyclohexyl) amino) phenyl) -6-methyl-1H-pyrrolo [2, 3-b)]Pyridine-7-oxide (16.5mg, 16% yield).

¹H NMR(400MHz，CDCl₃)：δ12.45(s，1H)，7.75-7.72(dd，J＝8.8Hz，2.4Hz，1H)，7.64(d，J＝2.4Hz，1H)，7.06(s，1H)，6.80-6.78(d，J＝8.8Hz，1H)，6.36(d，J＝3.2Hz，1H)，4.28(d，J＝8.0Hz，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＝6.4Hz，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 is as follows: preparation of 1, 2-bis (3-bromo-4-fluorophenyl) dithiolane.

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

The second step is that: preparation of 3-bromo-4-fluorobenzenethiol

A3L three-necked flask was charged with a solution of 1, 2-bis (3-bromo-4-fluorophenyl) dithioane (42g, 101.9mmol), methanol (300mL), tetrahydrofuran (1L), sodium hydroxide (10.3g, 257.5mmol) in water (300mL) in that order. Sodium borohydride (11.1g, 293.6mmol) was added in five portions at room temperature. After 1 hour of reaction, the mixture was concentrated, and a solution of sodium hydroxide (35g, 875.0mmol) in water (300mL) was added, followed by washing with methyl t-butyl ether (500 mL. times.2). The aqueous phase was added dropwise to hydrochloric acid (800mL, 3mol/L) while maintaining the temperature of the system at 0-5 ℃. The reaction solution was extracted with methyl tert-butyl ether (500 mL. times.3), dried over anhydrous sodium sulfate, and spin-dried to give 3-bromo-4-fluorobenzenethiol (16g, yellow oil, yield 38%).

¹H NMR(400MHz，CDCl₃)：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: preparation of 1, 2-bis (3-bromo-4-fluorophenyl) dithiolane.

A500 mL three-necked flask was charged with 3-bromo-4-fluorobenzenethiol (14g, 68.0mmol) and acetonitrile (200mL) in this order. Iodobenzenediacetic acid (21.9g, 68.0mmol) was added in five portions at room temperature. After 1 hour reaction at room temperature, it was quenched with water (100mL), concentrated, extracted with ethyl acetate (100 mL. times.2), dried over anhydrous sodium sulfate, and column separated (petroleum ether) to give 1, 2-bis (3-bromo-4-fluorophenyl) dithioane (14g, yellow oil, 100% yield).

¹H NMR(400MHz，CDCl₃)：δ7.72-7.63(m，1H)，7.39-7.28(m，1H)，7.13-7.04(m，1H).

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

A250 mL three-necked flask was charged with 1, 2-bis (3-bromo-4-fluorophenyl) dithioane (8g, 19.4mmol), and tetrahydrofuran (40mL) in that order. Cyclopropyl magnesium bromide (60mL, 1M, 60mmol) was added dropwise at-70 ℃ under nitrogen. After 1 hour of reaction saturated NH was added₄Cl (100mL), extracted with ethyl acetate (100 mL. times.2), dried over anhydrous sodium sulfate, and column separated (petroleum ether) to give (3-bromo-4-fluorophenyl) (cyclopropyl) sulfane (4.3g, yellow oil, 90% yield).

¹H NMR(400MHz，DMSO-d₆)：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).

The fifth step: preparation of 2-bromo-4- (cyclopropylsulfonyl) -1-fluorobenzene

(3-bromo-4-fluorophenyl) (cyclopropyl) sulfane (4.0g, 6.50mmol) was dissolved in dichloromethane (20mL) and a solution of m-chloroperoxybenzoic acid (2.90g, 14.31mmol) in dichloromethane (20mL) was added dropwise at 0 ℃. The reaction was stirred at zero degrees for one hour to complete the reaction. The reaction solution was washed with saturated sodium thiosulfate (20mL), then with an aqueous sodium hydrogencarbonate solution (40mL × 2), water (40mL × 2) and saturated brine (40mL), and dried over anhydrous sodium sulfate, concentrated and subjected to column chromatography to give the compound 2-bromo-4- (cyclopropylsulfonyl) -1-fluorobenzene (4.0g, yield 89%).

And a sixth step: preparation of 4- (5- (cyclopropylsulfonyl) -2-fluorophenyl) -6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine

2-bromo-4- (cyclopropylsulfonyl) -1-fluorobenzene (1.9g, 6.81mmol), 6-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine (2.25g, 5.46mmol), [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (399mg, 0.54mmol), and potassium carbonate (1.88g, 13.66mmol) were dissolved in a mixed solvent of 1, 4-dioxane (24mL) and water (6mL), and reacted completely after stirring at 100 ℃ for 4 hours under nitrogen protection. The reaction solution was poured into water (50mL), extracted with ethyl acetate (50mL × 2), the organic phases were combined and washed with water (100mL), saturated brine (100mL), and column chromatography (petroleum ether: ethyl acetate ═ 3: 1, V/V) was performed to give 4- (5- (cyclopropylsulfonyl) -2-fluorophenyl) -6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine (1.38g, 52% yield).

The seventh step: 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 (1.28g, 2.64mmol) was dissolved in a mixed solvent of t-butanol (20mL) and tetrahydrofuran (5mL), potassium hydroxide (3M, 10mL) was added, the reaction was stirred at 70 ℃ overnight and then cooled to room temperature. The reaction mixture was spun to dryness, followed by extraction with ethyl acetate (2 × 20mL), and the organic phases were combined, washed with water (40mL) and saturated brine (40mL), dried over anhydrous sodium sulfate, and concentrated, followed by column chromatography (petroleum ether: ethyl acetate ═ 3: 1, V/V) to give 4- (5- (cyclopropylsulfonyl) -2-fluorophenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine (670mg, 77% yield).

Eighth step: 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 (670.0mg, 2.03mmol) was dissolved in tetrahydrofuran (7mL), m-chloroperoxybenzoic acid (616mg, 3.04mmol) was added at room temperature, the mixture was stirred at room temperature for ten minutes, the reaction mixture was quenched with sodium thiosulfate (20mL), followed by extraction with ethyl acetate (20 mL. times.2), organic phase was combined and washed with an aqueous solution of sodium hydrogencarbonate (20mL), water (20mL) and saturated brine (20mL) were washed, and the mixture was dried over anhydrous sodium sulfate, concentrated and column chromatography (dichloromethane: methanol 20: 1, V/V) was performed to give the compound 4- (5- (cyclopropylsulfonyl) -2-fluorophenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (410mg, 58% yield).

The ninth step: preparation of 4- (5- (cyclopropylsulfonyl) -2- (2, 4-difluorophenoxy) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide

4- (5- (cyclopropylsulfonyl) -2-fluorophenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (20.0mg, 0.057mmol) was dissolved in N-methylpyrrolidone (2mL), 2, 4-difluorophenol ((23mg, 0.17mmol), cesium carbonate (87mg, 0.267mmol) was added under ice bath, and the reaction was carried out at microwave 180 ℃ for 30 minutes and then cooled to room temperature, followed by quenching with an aqueous solution of ammonium chloride (10mL), ethyl acetate extraction (10 mL. times.2). after combining the organic phases, washing with water (10 mL. times.2) and a saturated saline solution (10mL), drying over anhydrous sodium sulfate, concentration and preparative chromatography gave the compound 4- (5- (cyclopropylsulfonyl) -2- (2, 4-difluorophenoxy) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (9.0mg, 34% yield).

¹H NMR(400MHz，CD₃OD)：δ7.99(d，J＝2.3Hz，1H)，7.85(dd，J＝8.7Hz，2.3Hz，1H)，7.35(d，J＝3.4Hz，1H)，7.27(s，1H)，7.15(td，J＝9.1，5.5Hz，1H)，7.06(ddd，J＝11.2Hz，8.6Hz，3.0Hz，1H)，6.96(dd，J＝8.7Hz，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＝5.5Hz，1.2Hz，2H)，0.99(qd，J＝5.5Hz，1.2Hz，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

Following the experimental procedure of step 9 of example 81, starting from 4-bromo-2-fluorophenol instead of 2, 4-difluorophenol, the compound 4- (2- (4-bromo-2-fluorophenoxy) -5- (cyclopropylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (8.4mg, 29% yield) was obtained.

¹H 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＝9.8Hz，2.2Hz，1H)，7.32(d，J＝3.3Hz，1H)，7.29(s，1H)，7.21(s，1H)，6.95(t，J＝8.4Hz，2H)，6.51(d，J＝3.3Hz，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

The first step is as follows: preparation of 4- (5- (cyclopropylsulfonyl) -2- (((1r, 4r) -4-hydroxycyclohexyl) oxo) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide

4- (5- (cyclopropylsulfonyl) -2-fluorophenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (20.0mg, 0.057mmol) was dissolved in N, N-dimethylformamide (2mL), and (1r, 4r) -cyclohexane-1, 4-diol ((40mg, 0.34mmol), sodium hydride (7mg, 0.17mmol) was added under ice bath, and after stirring overnight at room temperature, it was quenched with an aqueous solution of ammonium chloride (10mL), extracted with ethyl acetate (10 mL. times.2.) and the combined organic phases were washed with water (10 mL. times.2) and saturated brine (10mL), dried over anhydrous sodium sulfate, concentrated and subjected to preparative chromatography to give the compound 4- (5- (cyclopropylsulfonyl) -2- (((1r, 4r) -4-Hydroxycyclohexyl) oxo) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (2.0mg, 8% yield).

¹H NMR(400MHz，CD₃OD)：δ8.33(s，1H)，7.98-7.70(m，2H)，7.39-7.21(m，2H)，7.18(s，1H)，6.35(d，J＝3.4Hz，1H)，4.50(d，J＝3.3Hz，2H)，3.60-3.44(m，1H)，2.64(dd，J＝7.9Hz，4.7Hz，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, starting from (1r, 4r) -cyclohexane-1, 4-diol, trans-4-ethylcyclohexanol was used to give 4- (5- (cyclopropylsulfonyl) -2- (((trans) -4-ethylcyclohexyl) oxo) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (0.02g, white solid, yield: 38%).

MS m/z(ESI)：455.2[M+H]⁺.

¹H NMR(400MHz，CDCl₃)：δ12.27(br，1H)，7.95(d，J＝2.4Hz，1H)，7.89(dd，J＝8.4Hz，2.4Hz，1H)，7.34(d，J＝3.2Hz，1H)，7.15-7.11(m，2H)，6.42(d，J＝3.2Hz，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＝7.6Hz，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, starting from (1r, 4r) -cyclohexane-1, 4-diol, trans-4-isopropylcyclohexanol was used to give 4- (5- (cyclopropylsulfonyl) -2- (((trans) -4-isopropylcyclohexyl) oxo) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (0.020g, white solid, yield: 43%).

MS m/z(ESI)：469.2[M+H]⁺.

¹H NMR(400MHz，CDCl₃)：δ12.55(br，1H)，7.96(d，J＝2.4Hz，1H)，7.89(dd，J＝8.8Hz，2.4Hz，1H)，7.31(d，J＝3.2Hz，1H)，7.15-7.13(m，2H)，6.40(d，J＝3.2Hz，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＝6.8Hz，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, starting from (1r, 4r) -cyclohexane-1, 4-diol, trans-4-isopropylcyclohexanol was used to give 4- (5- (cyclopropylsulfonyl) -2- (((trans) -4-isopropylcyclohexyl) oxo) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (0.080g, white solid, yield: 50%).

MS m/z(ESI)：469.2[M+H]⁺.

¹H NMR(400MHz，CDCl₃)：δ11.62(s，1H)，7.96(d，J＝2.0Hz，1H)，7.90(dd，J＝8.8Hz，2.0Hz，1H)，7.33(d，J＝3.2Hz，1H)，7.15-7.13(m，2H)，6.45(d，J＝3.2Hz，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＝7.6Hz，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, starting from (1r, 4r) -cyclohexane-1, 4-diol, trans-4-tert-butylcyclohexanol was used to give 4- (5- (cyclopropylsulfonyl) -2- (((trans) -4-tert-butylcyclohexyl) oxo) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (0.025g, white solid, yield: 36%).

MS m/z(ESI)：483.2[M+H]⁺.

¹H NMR(400MHz，CDCl₃)：δ11.76(s，1H)，7.96(d，J＝2.4Hz，1H)，7.90(dd，J＝8.4Hz，2.8Hz，1H)，7.36(d，J＝3.2Hz，1H)，7.17-7.14(m，2H)，6.44(d，J＝3.2Hz，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- (cyclopropylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide

Following the experimental procedure of example 83, starting from L-menthol instead of (1R, 4R) -cyclohexane-1, 4-diol, 4- (2- (((1S, 2R, 5S) -2-isopropyl-5-methylcyclohexyl) oxo) -5- (cyclopropylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide was obtained (0.020g, white solid, 36% yield).

MS m/z(ESI)：483.2[M+H]⁺.

¹H NMR(400MHz，CDCl₃)：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＝2.4Hz，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＝7.2Hz，3H)，0.67(d，J＝7.2Hz，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, starting from cyclopropylmethanol instead of (1r, 4r) -cyclohexane-1, 4-diol, 4- (2- (cyclopropylmethoxy) -5- (cyclopropylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (27.5mg, 47.6% yield) was obtained.

¹H NMR(400MHz，CDCl₃)：δ12.49(s，1H)，7.99(d，J＝2.4Hz，1H)，7.93-7.90(dd，J＝8.8Hz，2.4Hz，1H)，7.35-7.34(d，J＝3.2Hz，1H)，7.21(s，1H)，7.13-7.11(d，J＝8.8Hz，1H)，6.44(d，J＝3.2Hz，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, starting from 4, 4-difluorocyclohexane instead of (1r, 4r) -cyclohexane-1, 4-diol, 4- (5- (cyclopropylsulfonyl) -2- ((4, 4-difluorocyclohexyl) oxo) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (32.0mg, 47.8% yield) was obtained.

¹H NMR(400MHz，CDCl₃)：δ12.49(s，1H)，8.00(d，J＝2.4Hz，1H)，7.94(dd，J＝8.8Hz，2.4Hz，1H)，7.36(d，J＝3.2Hz，1H)，7.17-7.15(d，J＝8.8Hz，1H)，7.12(s，1H)，6.42(d，J＝3.2Hz，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, starting from (1r, 4r) -4-methylcyclohexan-1-ol instead of (1r, 4r) -cyclohexane-1, 4-diol, the compound 4- (5- (cyclopropylsulfonyl) -2- (((1r, 4r) -4-methylcyclohexyl) oxo) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (24.4mg, 32% yield) was obtained.

¹H NMR(400MHz，CD₃OD)：δ7.89-7.81(m，2H)，7.34-7.27(m，2H)，7.16(s，1H)，6.34(d，J＝3.2Hz，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＝6.4Hz，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, the starting material was (1r, 4r) -4-methylcyclohexylamine instead of (1r, 4r) -cyclohexane-1, 4-diol to give the compound 4- (5- (cyclopropylsulfonyl) -2- (((1r, 4r) -4-methylcyclohexyl) amino) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (23.4mg, yield: 38%).

¹H NMR(400MHz，CDCl₃)：δ12.18(s，1H)，7.76(dd，J＝8.7Hz，2.2Hz，1H)，7.66(d，J＝2.4Hz，1H)，7.34(d，J＝3.2Hz，1H)，7.06(s，1H)，6.78(d，J＝8.8Hz，1H)，6.36(d，J＝3.2Hz，1H)，4.27(d，J＝7.6Hz，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＝6.4Hz，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

The first step is as follows: n- (4-ethylcyclohexyl) -2- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) -4- (cyclopropylsulfonyl) aniline

4- (2-fluoro-5- (cyclopropylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine 7-oxide (0.060g, 0.17mmol), 4-ethylcyclohexylamine (0.3mL) and N-methylpyrrolidone (3mL) were added to a 10mL microwave tube, heated to 140 ℃ in an oil bath, reacted overnight, and cooled to room temperature. The reaction was diluted with ethyl acetate (20mL), washed with brine (20mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and spun to give the crude N- (4-ethylcyclohexyl) -2- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) -4- (cyclopropylsulfonyl) aniline (0.08g, yellow oil) which was used directly in the next reaction.

MS m/z(ESI)：438.2[M+H]⁺.

The second step is that: 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- (cyclopropylsulfonyl) aniline (0.080g, yellow oil), was dissolved in dichloromethane (20mL), and then m-chloroperoxybenzoic acid (85%, 0.045g, 0.22mmol) was added to the reaction and stirred at room temperature for two hours. After the reaction was complete, the reaction was diluted with dichloromethane (20mL), washed with saturated sodium bicarbonate solution (20mL), brine (20mL), dried over anhydrous sodium sulfate, filtered, spun-dried, and the crude product was isolated by reverse phase preparative chromatography to give 4- (5- (cyclopropylsulfonyl) -2- (((trans) -4-ethylcyclohexyl) amino) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (0.013g, white solid, 16% yield).

MS m/z(ESI)：454.2[M+H]⁺.

¹H NMR(400MHz，CDCl₃)：δ12.29(br，1H)，7.77(dd，J＝8.8Hz，2.4Hz，1H)，7.67(d，J＝2.4Hz 1H)，7.44(d，J＝2.8Hz，1H)，7.11(s，1H)，6.80(d，J＝8.8Hz，1H)，6.42(d，J＝2.8Hz，1H)，4.28(d，J＝7.6Hz，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＝7.6Hz，3H).

Example 94

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

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

MS m/z(ESI)：454.2[M+H]⁺.

¹H NMR(400MHz，CDCl₃)：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＝8.4Hz，1H)，6.48(d，J＝2.0Hz，1H)，4.52(d，J＝6.4Hz，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＝7.2Hz，3H).

Example 95

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

The first step is as follows: 1-bromo-2- (2, 4-difluorophenoxy) -4-iodo-5-nitrobenzene

1-bromo-2-fluoro-4-iodo-5-nitrobenzene (1.07g, 3.09mmol) was dissolved in acetonitrile (20mL) at room temperature, and then 2, 4-difluorophenol (0.80g, 6.18mmol) and sodium carbonate (0.66g, 6.18mmol) were added to the reaction solution, and stirred at room temperature overnight. After the reaction was completed, the reaction solution was diluted with ethyl acetate (40mL), the organic phase was washed with brine (20mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered, dried, and the crude product was separated by column chromatography (pure petroleum ether as mobile phase) to give 1-bromo-2- (2, 4-difluorophenoxy) -4-iodo-5-nitrobenzene (0.53g, yellow solid, yield 38%).

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

1-bromo-2- (2, 4-difluorophenoxy) -4-iodo-5-nitrobenzene (0.53g, 1.16mmol), cyclopropylboronic acid (0.15g, 1.74mmol), potassium phosphate (0.49g, 2.32mol) and [1, 1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (0.085g, 0.13mmol) were dissolved in anhydrous dioxane (10mL) at room temperature, replaced with nitrogen three times, heated to 90 ℃ and reacted for 14 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate (30mL), filtered through celite, the filtrate was washed with brine (30mL), dried over anhydrous sodium sulfate, filtered, dried by spinning, and the crude product was separated by column chromatography (pure petroleum ether as mobile phase) to give 1-bromo-4-cyclopropyl-2- (2, 4-difluorophenoxy) -5-nitrobenzene (0.35g, yellow solid, yield 81%).

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

1-bromo-4-cyclopropyl-2- (2, 4-difluorophenoxy) -5-nitrobenzene (0.15g, 0.41mol) and tin dichloride dihydrate (0.26g, 1.13mol) were dissolved in ethanol (10mL) and water (0.5mL) at room temperature and stirred at room temperature for 14 hours. After the reaction was completed, ethanol was spin-dried under reduced pressure, ice water (15mL) and aqueous sodium hydroxide solution (2M, 15mL) were added to the residue, the aqueous phase was extracted with ethyl acetate (15 mL. times.3), the organic phases were combined, the organic phase was washed with brine (15 mL. times.3), dried over anhydrous sodium sulfate, filtered, spin-dried, and the crude product was separated using a preparation plate to give 5-bromo-2-cyclopropyl-4- (2, 4-difluorophenoxy) aniline (0.08g, yield: 58%).

MS m/z(ESI)：340.0，342.0[M+H]⁺.

The fourth step: n- (5-bromo-2-cyclopropyl-4- (2, 4-difluorophenoxy) phenyl) ethanesulfonamide

5-bromo-2-cyclopropyl-4- (2, 4-difluorophenoxy) aniline (0.08g, 0.24mmol) and pyridine (0.037g, 0.47mmol) were dissolved in dichloromethane (10mL) at room temperature, and ethylsulfonyl chloride (0.06g, 0.47mmol) was added dropwise to the reaction system, heated to 50 ℃ and reacted for 4 hours. After the reaction was complete, the dichloromethane was spun off, the crude product was dissolved in ethyl acetate (30mL), the organic phase was washed with saturated sodium bicarbonate solution (15 mL. times.3), brine (15mL), the organic phase was dried over anhydrous sodium sulfate, filtered, spun off, and the crude product was isolated on a preparative plate to give N- (5-bromo-2-cyclopropyl-4- (2, 4-difluorophenoxy) phenyl) ethanesulfonamide (0.07g, white solid, 69% yield).

MS m/z(ESI)：432.0，434.0[M+H]⁺.

The fifth step: 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 (0.045g, 0.10mmol), 6-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine (0.045g, 0.10mmol), potassium carbonate (0.029g, 0.20mmol) and [1, 1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (0.01g, 0.01mmol) were dissolved in dioxane (4mL) and water (1mL) at room temperature, replaced three times with nitrogen, heated to 90 ℃ overnight, and cooled to room temperature. The reaction mixture was diluted with ethyl acetate (20mL), filtered through celite, the celite was washed with ethyl acetate (20mL), the organic phases were combined, the organic phase was washed with brine (20 mL. times.2), dried over anhydrous sodium sulfate, filtered, and dried by spinning, and the crude product was separated 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 (0.06g, colorless oil, yield: 90%).

MS m/z(ESI)：638.2[M+H]⁺.

And a sixth step: n- (2-cyclopropyl-4- (2, 4-difluorophenoxy) -5- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) ethanesulfonamide

N- (2-cyclopropyl-4- (2, 4-difluorophenoxy) -5- (6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) ethanesulfonamide (0.03g, 0.047mmol) was dissolved in ethanol (6mL) at room temperature, and sodium methoxide (0.03g, 0.047mmol) was added to the reaction mixture, which was heated to 50 ℃ for 14 hours. After completion of the reaction, ethanol was evaporated under reduced pressure, the residue was dissolved in ethyl acetate (30mL), the organic phase was washed with saturated brine (15mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spinning, and 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 (0.02g, colorless oil, yield: 88%).

MS m/z(ESI)：484.1[M+H]⁺.

The seventh step: 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 ] pyridin-4-yl) phenyl) ethanesulfonamide (0.02g, 0.04mmol) was dissolved in dichloromethane (5mL) under ice-bath, and m-chloroperoxybenzoic acid (0.011g, 0.06mmol) was added to the reaction mixture and reacted for half an hour. After completion of the reaction, the reaction mixture was diluted with dichloromethane (20mL), the organic phase was washed with saturated sodium bicarbonate solution (10 mL. times.3), brine (15mL), the organic phase was dried over anhydrous sodium sulfate, filtered, spun-dried, and the crude product was separated 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 (0.06g, pale yellow solid, 29% yield).

MS m/z(ESI)：500.1[M+H]⁺.

¹H NMR(400MHz，CDCl₃)：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＝7.2Hz，2H)，2.68(s，3H)，1.98-1.91(m，1H)，1.44(t，J＝7.2Hz，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

The first step is as follows: preparation of 4-fluoro-3- (6-methyl-1-tosyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) benzene (formaldehyde)

3-bromo-4-fluorobenzaldehyde (1.34g, 6.61mmol), 6-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine (3.0g, 7.28mmol), [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (386mg, 0.52mmol), potassium carbonate (1.82g, 13.32mmol) were dissolved in 1, 4-dioxane (16mL), water (4mL), nitrogen was introduced, and the reaction was complete after 4 hours at 100 ℃ under nitrogen protection. The reaction solution was poured into water (50mL), extracted with ethyl acetate (50mL × 2), the organic phases were combined and washed with water (100mL), washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, concentrated and subjected to column chromatography (petroleum ether: ethyl acetate ═ 2: 1) to give the compound 4-fluoro-3- (6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) benzene (meth) aldehyde (2.1g, yield 78%).

The second step is that: preparation of 4- (4-bromo-2-fluorophenoxy) -3- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) benzaldehyde

4-fluoro-3- (6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) benzene (formaldehyde) (1.0g, 2.45mmol) was dissolved in N-methylpyrrolidone (10mL), 4-bromo-2-fluorophenol (1.4g, 7.35mmol), cesium carbonate (2.39g, 7.35mmol) were added, microwave-reacted at 180 ℃ for 30 minutes and then cooled to room temperature, water (20mL) was added, followed by extraction with ethyl acetate (20 mL. times.2), the organic phases were combined, washed with water (40mL) and saturated brine (40mL) in this order, dried over anhydrous sodium sulfate, concentrated and column-chromatographed (petroleum ether: ethyl acetate ═ 1: 1, V/V) to give 4- (4-bromo-2-fluorophenoxy) -3- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) benzaldehyde (330mg, 32% yield).

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

4- (4-bromo-2-fluorophenoxy) -3- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) benzene (meth) aldehyde (330mg, 0.77mmol) was dissolved in methanol (5mL), and sodium borohydride (59mg, 1.56mmol) was added under ice-cooling, the reaction was stirred for 3 hours, quenched with saturated aqueous ammonium chloride (10mL), water (20mL) was added, followed by extraction with ethyl acetate (20mL × 2), the organic phases were combined, washed with water (40mL) and saturated brine (40mL) in this order, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (petroleum ether: ethyl acetate 1: 1, V/V) to give (4- (4-bromo-2-fluorophenoxy) -3- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) methanol (179mg, 54% yield).

The fourth step: preparation of 4- (2- (4-bromo-2-fluorophenoxy) -5- (bromomethyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine

(4- (4-bromo-2-fluorophenoxy) -3- (6-methyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) phenyl) methanol (179mg, 0.42mmol) was dissolved in dichloromethane (3mL), phosphorus dibromide (171mg, 0.63mmol) was added under ice-cooling, the mixture was stirred to room temperature overnight, the reaction mixture was adjusted to neutral with an aqueous solution of sodium carbonate (1M), water (20mL) was added, and then dichloromethane was extracted (20mL × 2), the organic phases were combined and washed with water (40mL) and saturated brine (40mL) in this order, and dried over anhydrous sodium sulfate, and after concentration, column chromatography (petroleum ether: ethyl acetate:. 2: 1, V/V) gave 4- (2- (4-bromo-2-fluorophenoxy) -5- (bromomethyl) phenyl) -6-methyl-1H-pyrrole-4 ═ methyl-1H-pyrrole And [2, 3-b ] pyridine (130mg, yield 63%).

The fifth step: preparation of 4- (2- (4-bromo-2-fluorophenoxy) -5- ((methylthio) methyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine

4- (2- (4-bromo-2-fluorophenoxy) -5- (bromomethyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine (130mg, 0.26mmol) was dissolved in N, N-dimethylformamide (3mL), sodium thiomethoxide (149mg, 0.43mmol) was added under ice-bath, stirred to room temperature overnight, quenched with an aqueous solution of ammonium chloride (10mL), water (20mL) was added, followed by extraction with dichloromethane (20 mL. times.2), the organic phases were combined and washed with water (40mL) and saturated brine (40mL) in this order, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatographed (petroleum ether: ethyl acetate 2: 1, V/V) to give 4- (2- (4-bromo-2-fluorophenoxy) -5- ((methylthio) methyl) phenyl) -6-methyl -1H-pyrrolo [2, 3-b ] pyridine (50mg, 41% yield).

And a sixth step: preparation of 4- (2- (4-bromo-2-fluorophenoxy) -5- ((methylsulfonyl) methyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide

4- (2- (4-bromo-2-fluorophenoxy) -5- ((methylthio) methyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine (50mg, 0.11mmol) is dissolved in THF (2mL), m-chloroperoxybenzoic acid (78mg, 0.39mmol) is added at room temperature, the reaction is stirred at room temperature for ten minutes, quenched with saturated aqueous ammonium chloride (10mL), water (10mL) is added, extraction is then carried out with ethyl acetate (10 mL. times.2), the organic phases are combined, washed successively with aqueous sodium bicarbonate (20mL), water (20mL) and saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, concentrated and chromatographed to give 4- (2- (4-bromo-2-fluorophenoxy) -5- ((methylsulfonyl) methyl) phenyl) -6-methyl-1H- Pyrrolo [2, 3-b ] pyridine-7-oxide (20mg, 36% yield).

¹H NMR(400MHz，DMSO-d₆)：δ12.31(s，1H)，7.61(s，2H)，7.40(d，J＝8.4Hz，1H)，7.30(dd，J＝16.7Hz，5.8Hz，2H)，7.18(s，1H)，7.09-6.91(m，2H)，6.45(d，J＝3.1Hz，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

The first step is as follows: preparation of 3-bromo-4- (2, 4-difluorophenoxy) benzaldehyde

A100 mL three-necked flask was charged with 2, 4-difluorophenol (1.47g, 11.33mmol), 3-bromo-4-fluorobenzaldehyde (2.30g, 11.33mmol), cesium carbonate (4.05g, 12.46mmol), and dimethyl sulfoxide (10mL) in that order. The reaction solution was diluted with ethyl acetate (30mL), washed with saturated brine (10 mL. times.3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was purified by column chromatography (petroleum ether: ethyl acetate 5: 1, V/V) to give 3-bromo-4- (2, 4-difluorophenoxy) benzaldehyde (2.60g, pale yellow oil, 73% yield).

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

3-bromo-4- (2, 4-difluorophenoxy) benzaldehyde (2.60g, 8.31mmol) was dissolved in a mixed solvent of methanol (10mL) and tetrahydrofuran (10mL), and after stirring at room temperature for 2 to 3 minutes, sodium borohydride (0.095g, 2.49mmol) was added, and after the addition, the mixture was stirred at room temperature for 2 hours, whereupon the reaction was terminated. The reaction mixture was spin-dried, the residue was dissolved in ethyl acetate (30mL), washed with saturated brine (10 mL. times.3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to give the crude product 3-bromo-4- (2, 4-difluorophenoxy) benzyl alcohol (2.6g, white solid) which was used directly in the next step.

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

Dissolving 3-bromo-4- (2, 4-difluorophenoxy) benzyl alcohol (2.60g, 8.25mmol) in dichloromethane (20mL), cooling to 0-5 ℃ in an ice bath, dropwise adding phosphorus tribromide (2.46g, 9.08mmol), naturally heating to room temperature after the addition is finished, and stirring for 3 hours to finish the reaction. The reaction solution was slowly poured into ice water (50mL), neutralized by dropwise addition of a saturated sodium carbonate solution, separated, the aqueous phase was extracted with dichloromethane (15 mL. times.3), the organic phases were combined, washed with a saturated saline solution (15 mL. times.2), dried over anhydrous sodium sulfate, filtered, and spin-dried to give 2-bromo-4- (bromomethyl) -1- (2, 4-difluorophenoxy) benzene (2.60g, white solid) which was used directly in the next reaction.

The fourth step: preparation of 3-bromo-4- (2, 4-difluorophenoxy) benzylethylsulfane

2-bromo-4- (bromomethyl) -1- (2, 4-difluorophenoxy) benzene (2.40g, 6.35mmol), sodium ethanethiol (0.53g, 6.35mmol) and N, N-dimethylformamide (40mL) were added in this order to a 100mL three-necked flask, and the reaction was terminated by stirring at room temperature for 4 hours. The reaction was diluted with ethyl acetate (50mL), washed with saturated brine (10mL × 5), and the organic phase was dried over anhydrous sodium sulfate, filtered, spun-dried, and separated by column chromatography (petroleum ether: ethyl acetate ═ 5: 1, V/V) to give 3-bromo-4- (2, 4-difluorophenoxy) benzylethylsulfane (1.30g, oil, yield 57%).

The fifth step: preparation of 2-bromo-1- (2, 4-difluorophenoxy) -4- ((ethylsulfonyl) methyl) benzene

3-bromo-4- (2, 4-difluorophenoxy) benzylethylsulfane (1.3g, 3.6mmol) was dissolved in dichloromethane (20mL), m-chloroperoxybenzoic acid (1.8g, 9.0mmol) was added at room temperature, the reaction was stirred for 1 hour, LC-MS checked for completion, saturated sodium carbonate solution (50mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL. times.2), the combined organic phases were washed with saturated sodium chloride solution (80 mL. times.2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 2-bromo-1- (2, 4-difluorophenoxy) -4- ((ethylsulfonyl) methyl) benzene (1.3g, 92%).

MS m/z(ESI)：391.2，393.2[M+H]⁺.

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

2-bromo-1- (2, 4-difluorophenoxy) -4- ((ethylsulfonyl) methyl) benzene (100mg, 0.26mmol), 6-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine (210mg, 0.51mmol), [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (18.6mg, 0.03mmol), potassium carbonate (70.6mg, 0.51mmol) were dissolved in 1, 4-dioxane (10mL) and water (3mL), nitrogen was replaced, heating to 100 ℃ was stirred for 4 hours, and LC/MS detected complete reaction. Water (50mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50mL), and the organic phase was washed with saturated brine (50mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate: 1, V/V) to give 4- (2- (2, 4-difluorophenoxy) -5- ((ethylsulfonyl) methyl) phenyl) -6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine (150mg, purity 70%, yield 68%).

MS m/z(ESI)：597.1[M+H]⁺

And a sixth step: preparation of 4- (2- (2, 4-difluorophenoxy) -5- ((ethylsulfonyl) methyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine

4- (2- (2, 4-Difluorophenoxy) -5- ((ethylsulfonyl) methyl) phenyl) -6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine (150mg, 70% purity, 0.25mmol) was dissolved in tert-butanol (10mL), and an aqueous potassium hydroxide solution (3M, 5mL) was added to the above solution, heated to 55 ℃ and stirred overnight. After the reaction mixture was cooled to room temperature, ethyl acetate (50mL) was added to the reaction mixture, the mixture was diluted with saturated brine (50mL × 2), dried over anhydrous sodium sulfate, and concentrated, followed by separation and purification on a silica gel preparation plate (dichloromethane: methanol ═ 10: 1, V/V) to give 4- (2- (2, 4-difluorophenoxy) -5- ((ethylsulfonyl) methyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine (40mg, yield 51.0%).

MS m/z(ESI)：443.1[M+H]⁺

The seventh step: preparation of 4- (2- (2, 4-difluorophenoxy) -5- ((ethylsulfonyl) methyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide

4- (2- (2, 4-Difluorophenoxy) -5- ((ethylsulfonyl) methyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine (40mg, 0.09mmol) was dissolved in tetrahydrofuran (2mL), and m-chloroperoxybenzoic acid (28mg, 0.14mmol) was added and the mixture was stirred at room temperature for 30 minutes. To the reaction solution was added ethyl acetate (50mL), which was washed with a saturated sodium carbonate solution (30mL × 2) and then with a saturated brine (30mL), dried over anhydrous sodium sulfate, concentrated, and purified by preparative chromatography on silica gel to give 4- (2- (2, 4-difluorophenoxy) -5- ((ethylsulfonyl) methyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (13.0mg, yield 31%).

¹H NMR(400MHz，CDCl₃)：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＝5.6Hz，2H)，2.94(s，3H)，1.27-1.25(t，J＝7.2Hz，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

The first step is as follows: 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 (469mg, 1.2mmol) was dissolved in tetrahydrofuran (10mL), cooled to 0 deg.C, sodium hydride (60%, 240mg, 6mmol) was added, stirred for 10 min, iodomethane (0.75mL, 12mmol) was added, and stirred at room temperature overnight. To the reaction mixture was added ethyl acetate (80mL), which was washed with brine (50mL × 2), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel preparative chromatography to give 2-bromo-1- (2, 4-difluorophenoxy) -4- (2- (ethylsulfonyl) propan-2-yl) benzene (400mg, yield 80%).

¹H NMR(400MHz，DMSO-d₆)：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＝8.8Hz，1H)，6.78(s，1H)，2.91-2.85(q，J＝7.6Hz，2H)，1.76(s，6H)，1.08-1.05(t，J＝6.4Hz，3H).

MS m/z(ESI)：419.2，421.2[M+H]⁺

The second step is that: preparation of 4- (2- (2, 4-difluorophenoxy) -5- (2- (ethylsulfonyl) propan-2-yl) phenyl) -6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine

Starting from 2-bromo-1- (2, 4-difluorophenoxy) -4- (2- (ethylsulfonyl) propan-2-yl) benzene, according to a fifth seventeenth step of EXAMPLE ninety, 4- (2- (2, 4-difluorophenoxy) -5- (2- (ethylsulfonyl) propan-2-yl) phenyl) -6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine (250mg, 55% yield) was obtained.

MS m/z(ESI)＝625.1[M+H]⁺

The third step: preparation of 4- (2- (2, 4-difluorophenoxy) -5- (2- (ethylsulfonyl) propan-2-yl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine

Starting from 4- (2- (2, 4-difluorophenoxy) -5- (2- (ethylsulfonyl) propan-2-yl) phenyl) -6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine, according to the seventh sixth step of example ninety, 4- (2- (2, 4-difluorophenoxy) -5- (2- (ethylsulfonyl) propan-2-yl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine was obtained (150mg, 80% yield).

MS m/z(ESI)：471.1[M+H]⁺

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

Starting from 4- (2- (2, 4-difluorophenoxy) -5- (2- (ethylsulfonyl) propan-2-yl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine, according to a seventh step ninety-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (32.4mg, 33.3% yield) was obtained (2- (2, 4-difluorophenoxy) -5- (2- (ethylsulfonyl) propan-2-yl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide).

MS m/z(ESI)：487.1[M+H]⁺

¹H NMR(400MHz，CDCl₃)：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＝3.6Hz，1H)，7.27(s，1H)，7.04-6.91(m，2H)，6.86-6.81(m，2H)，6.60(d，J＝3.2Hz，1H)，2.80-2.75(m，5H)，1.87(s，6H)，1.30-1.26(t，J＝7.2Hz，3H)。

Example 99

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

The first step is as follows: preparation of (3-bromo-4- (2, 4-difluorophenoxy) benzyl) (methyl) sulfane

2-bromo-4- (bromomethyl) -1- (2, 4-difluorophenoxy) benzene (2.00g, 5.29mmol), sodium thiomethoxide (0.45g, 6.35mmol) and N, N-dimethylformamide (35mL) were added in this order to a 100mL three-necked flask, and the reaction was terminated by stirring at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate (80mL), washed with saturated brine (50mL × 5), and the organic phase was dried over anhydrous sodium sulfate, filtered, spun-dried, and separated by column chromatography (petroleum ether: ethyl acetate: 5: 1) to give (3-bromo-4- (2, 4-difluorophenoxy) benzyl) (methyl) sulfane (1.00g, oil, 55% yield).

The second step is that: preparation of 2-bromo-1- (2, 4-difluorophenoxy) -4- ((methylsulfonyl) methyl) benzene

(3-bromo-4- (2, 4-difluorophenoxy) benzyl) (methyl) sulfane (1.00g, 2.90mmol) was dissolved in dichloromethane (20mL), m-chloroperoxybenzoic acid (1.76g, 8.70mmol) was added at room temperature, the reaction was stirred for 1 hour, LC-MS monitored for completion, saturated sodium carbonate solution (50mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL. times.2), mixing of the organic phases, washing with saturated sodium chloride solution (80 mL. times.2), drying over anhydrous sodium sulfate, and concentration under reduced pressure to give 2-bromo-1- (2, 4-difluorophenoxy) -4- ((methylsulfonyl) methyl) benzene (1.0g, 92% yield).

MS m/z(ESI)：377.2，379.2[M+H]⁺.

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

2-bromo-1- (2, 4-difluorophenoxy) -4- ((methylsulfonyl) methyl) benzene (110mg, 0.29mmol), 6-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine (190mg, 0.35mmol), [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (22.0mg, 0.03mmol), potassium carbonate (82.0mg, 0.60mmol) were dissolved in 1, 4-dioxane (10mL) and water (3mL), nitrogen was replaced, heating to 100 ℃ was stirred for 4 hours, and LC/MS detected complete reaction. Water (50mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50mL), and the organic phase was washed with saturated brine (50mL), dried over anhydrous sodium sulfate, and concentrated and then purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 1: 1) to give 4- (2- (2, 4-difluorophenoxy) -5- ((methanesulfonyl) methyl) phenyl) -6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine (130mg, yield 77.0%).

MS m/z(ESI)：583.1[M+H]⁺

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

4- (2- (2, 4-Difluorophenoxy) -5- ((methylsulfonyl) methyl) phenyl) -6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine (130mg, 0.22mmol) was dissolved in tert-butanol (15mL), and aqueous potassium hydroxide (3M, 8mL) was added to the solution, heated to 75 ℃ and stirred overnight. To the reaction mixture was added ethyl acetate (50mL), which was washed with saturated brine (50mL × 2), dried over anhydrous sodium sulfate, and concentrated, followed by separation and purification on a silica gel preparation plate (dichloromethane: methanol ═ 10: 1) to give 4- (2- (2, 4-difluorophenoxy) -5- ((methanesulfonyl) methyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine (60mg, yield 63%).

MS m/z(ESI)：429.1[M+H]⁺

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

4- (2- (2, 4-Difluorophenoxy) -5- ((methylsulfonyl) methyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine (60mg, 0.14mmol) was dissolved in tetrahydrofuran (2mL), and m-chloroperoxybenzoic acid (57mg, 0.28mmol) was added and the mixture was stirred at room temperature for 30 minutes. To the reaction solution was added ethyl acetate (50mL), which was washed with a saturated sodium carbonate solution (30mL × 2) and then with a saturated brine (30mL), dried over anhydrous sodium sulfate, concentrated, and then purified by preparative chromatography on silica gel to isolate 4- (2- (2, 4-difluorophenoxy) -5- ((methanesulfonyl) methyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (13.0mg, yield: 21%).

¹H NMR(400MHz，CDCl₃)：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＝3.2Hz，1H)，7.26(s，1H)，7.04-6.91(m，2H)，6.86-6.81(m，2H)，6.60(d，J＝3.2Hz，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

The first step is as follows: preparation of 2-bromo-1- (2, 4-difluorophenoxy) -4- (2- (methylsulfonyl) propan-2-yl) benzene and 2-bromo-1- (2, 4-difluorophenoxy) -4- (1- (methylsulfonyl) ethyl) benzene

2-bromo-1- (2, 4-difluorophenoxy) -4- ((methanesulfonyl) methyl) benzene (300mg, 0.80mmol) was dissolved in tetrahydrofuran (10mL), cooled to 0 deg.C, sodium hydride (60%, 160mg, 6mmol) was added, stirred for 10 min, iodomethane (1mL, 16mmol) was added, and stirred at room temperature overnight. To the reaction mixture was added ethyl acetate (80mL), which was washed with brine (50mL × 2), dried over anhydrous sodium sulfate, concentrated, and purified by preparative chromatography on silica gel to give 2-bromo-1- (2, 4-difluorophenoxy) -4- (2- (methylsulfonyl) propan-2-yl) benzene (150mg, yield 48%) and 2-bromo-1- (2, 4-difluorophenoxy) -4- (1- (methylsulfonyl) ethyl) benzene (100mg, yield 31%).

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

¹H NMR(400MHz，CDCl₃)：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＝8.4Hz，1H)，2.59(s，3H)，1.82(s，6H).

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

¹H NMR(400MHz，CDCl₃)：δ7.62(d，J＝2.0Hz，1H)，7.24-7.22(dd，J＝8.4Hz，2.4Hz，1H)，7.02-6.97(m，1H)，6.93-6.88(m，1H)，6.84-6.82(m，1H)，6.67(d，J＝8.4Hz，1H)，4.10-4.07(q，J＝7.2Hz，1H)，2.64(s，3H)，1.70-1.68(d，J＝7.2Hz，3H).

the second step is that: preparation of 4- (2- (2, 4-difluorophenoxy) -5- (2- (methylsulfonyl) propan-2-yl) phenyl) -6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine

2-bromo-1- (2, 4-difluorophenoxy) -4- (2- (methylsulfonyl) propan-2-yl) benzene (120mg, 0.30mmol), 6-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine (200mg, 0.36mmol), [1, 1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (22.0mg, 0.03mmol), potassium carbonate (82.0mg, 0.60mmol) were dissolved in 1, 4-dioxane (6mL) and water (2mL), replaced with nitrogen, heated to 100 ℃ and stirred overnight, and the reaction was detected to be complete by LC/MS. Water (50mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50mL), and the organic phase was washed with saturated brine (50mL), dried over anhydrous sodium sulfate, and concentrated and then purified by silica gel column chromatography (petroleum ether: ethyl acetate 1: 1) to give 4- (2- (2, 4-difluorophenoxy) -5- (2- (methylsulfonyl) propan-2-yl) phenyl) -6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine (120mg, yield 66%).

MS m/z(ESI)：611.1[M+H]⁺

The third step: preparation of 4- (2- (2, 4-difluorophenoxy) -5- (2- (methylsulfonyl) propan-2-yl) phenyl) -6-methyl-1H-pyrrolo [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 (120mg, 0.20mmol) was dissolved in t-butanol (15mL), and potassium hydroxide solution (3M, 8mL) was added to the solution, heated to 75 ℃ and stirred overnight. The reaction mixture was extracted with ethyl acetate (50mL), and the organic phase was washed with saturated brine (50 mL. times.2), dried over anhydrous sodium sulfate, and concentrated to give 4- (2- (2, 4-difluorophenoxy) -5- (2- (methylsulfonyl) propan-2-yl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine (80mg, 89% yield).

MS m/z(ESI)：457.1[M+H]⁺

The fourth step: 4- (2- (2, 4-difluorophenoxy) -5- (2- (methylsulfonyl) propan-2-yl) phenyl) -6-methyl-1H-pyrrolo [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 (80mg, 0.17mmol) was dissolved in tetrahydrofuran (5mL), and m-chloroperoxybenzoic acid (55mg, 0.26mmol) was added and stirred at room temperature for 30 minutes. To the reaction mixture was added ethyl acetate (50mL), which was washed with a saturated sodium carbonate solution (30mL × 2) and then with a saturated brine (30mL), dried over anhydrous sodium sulfate, concentrated, and purified by preparative chromatography on silica gel to give 4- (2- (2, 4-difluorophenoxy) -5- (2- (methylsulfonyl) propan-2-yl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (20.0mg, 24% yield).

¹H NMR(400MHz，CDCl₃)：δ12.21(s，1H)，7.85(d，J＝2.8Hz，1H)，7.59-7.56(dd，J＝8.8Hz，2.8Hz，1H)，7.37(d，J＝3.6Hz，1H)，7.28(s，1H)，7.04-6.92(m，2H)，6.87-6.82(m，2H)，6.61(d，J＝3.2Hz，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

The first step is as follows: preparation of 4- (2- (2, 4-difluorophenoxy) -5- (1- (methylsulfonyl) ethyl) phenyl) -6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine

Starting from 2-bromo-1- (2, 4-difluorophenoxy) -4- (1- (methylsulfonyl) ethyl) benzene, one hundred second steps according to example gave 4- (2- (2, 4-difluorophenoxy) -5- (1- (methylsulfonyl) ethyl) phenyl) -6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine (80mg, 52.4% yield).

MS m/z(ESI)：597.1[M+H]⁺

The second step is that: preparation of 4- (2- (2, 4-difluorophenoxy) -5- (1- (methylsulfonyl) ethyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine

Starting from 4- (2- (2, 4-difluorophenoxy) -5- (1- (methylsulfonyl) ethyl) phenyl) -6-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine, reference was made to the twenty-third step of the example to give 4- (2- (2, 4-difluorophenoxy) -5- (1- (methylsulfonyl) ethyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine (50mg, 84.4% yield).

MS m/z(ESI)：443.1[M+H]⁺

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

Starting from 4- (2- (2, 4-difluorophenoxy) -5- (1- (methylsulfonyl) ethyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine, reference example one hundred fourth steps gave 4- (2- (2, 4-difluorophenoxy) -5- (1- (methylsulfonyl) ethyl) phenyl) -6-methyl-1H-pyrrolo [2, 3-b ] pyridine-7-oxide (18.5mg, 35.7% yield).

¹H NMR(400MHz，CDCl₃)：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＝3.6Hz，1H)，7.26(s，1H)，7.03-6.91(m，2H)，6.85-6.81(m，2H)，6.58(d，J＝3.2Hz，1H)，4.27-4.21(q，J＝7.2Hz，1H)，2.78(s，3H)，2.76(s，3H)，1.83-1.81(d，J＝7.2Hz，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

The first step is as follows: preparation of 4-chloro-6-cyclopropyl-1-tosyl-1H-pyrrolo [2, 3-b ] pyridine

6-bromo-4-chloro-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine (500mg, 1.3mmol), cyclopropylboronic acid (110mg, 1.3mmol), [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (95mg, 0.13mmol) and potassium carbonate (537mg, 3.9mmol) were added to a mixed solvent of dioxane/water (v/v ═ 4: 1, 20 mL). The reaction mixture was reacted at 100 ℃ under nitrogen for 10 hours, then brought to room temperature, evaporated to dryness, and subjected to column separation (petroleum ether: ethyl acetate: 10: 1) to give 4-chloro-6-cyclopropyl-1-tosyl-1H-pyrrolo [2, 3-b ] pyridine (170mg, 38% yield).

¹H NMR(400MHz，CDCl₃)：δ8.03(d，J＝8.4Hz，2H)，7.65(d，J＝4.0Hz，1H)，7.29(d，J＝8.4Hz，2H)，7.09(s，1H)，6.59(d，J＝4.0Hz，1H)，2.40(s，3H)，2.06-1.97(m，1H)，1.14-1.06(m，2H)，1.05-0.99(m，2H).

The second step is that: preparation of 6-cyclopropyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine

4-chloro-6-cyclopropyl-1-tosyl-1H-pyrrolo [2, 3-b ] pyridine (170mg, 0.49mmol), 4, 4, 4 ', 4', 5, 5, 5 ', 5' -octamethyl-2, 2 '-bis (1, 3, 2-dioxaborolan) (373mg, 1.47mmol), potassium acetate (144mg, 1.47mmol), palladium acetate (5.5mg, 24.6umol) and [1, 1' -biphenyl ] -2-yl dicyclohexyl phosphane (17.2mg, 49umol) were added to dioxane (10mL), the reaction solution was reacted at 90 ℃ under nitrogen protection for 10 hours, the reaction solution was evaporated to dryness, column separation (petroleum ether: ethyl acetate ═ 10: 1) was carried out to give 6-cyclopropyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-Dioxaborolan-2-yl) -1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine (165mg, 77% yield).

MS m/z(ESI)：439.1[M+H]⁺

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

6-cyclopropyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridine (165mg, 0.38mmol), N- (3-bromo-4- (2, 4-difluorophenoxy) phenyl) ethanesulfonamide (177mg, 0.45mmol), [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (27.8mg, 0.038mmol) and potassium carbonate (130mg, 0.94mmol) were added to a dioxane/water (v/v ═ 4: 1, 10mL) mixed solvent. The reaction mixture was reacted at 100 ℃ under nitrogen protection for 10 hours, then cooled to room temperature, evaporated to dryness, and then separated 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 (100mg, 43% yield).

MS m/z(ESI)：624.1[M+H]⁺

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

Adding potassium hydroxide (45mg, 0.8mmol) to a solution of N- (3- (6-cyclopropyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) -4- (2, 4-difluorophenoxy) phenyl) ethanesulfonamide (100mg, 0.16mmol) in tetrahydrofuran (2mL) and water (3 drops), reacting the reaction mixture at 50 ℃ for 12 hours, LCMS showing that no reaction had occurred, cooling the reaction mixture, adding ethanol (1mL), reacting the reaction mixture at 70 ℃ for 5 hours, cooling the reaction mixture, adding dichloromethane (15mL), washing with saturated brine (10 mL. times.2), drying over anhydrous sodium sulfate, filtering, concentrating the filtrate to obtain crude N- (3- (6-cyclopropyl-1H-pyrrolo [2 ], 3-b ] pyridin-4-yl) -4- (2, 4-difluorophenoxy) phenyl) ethanesulfonamide (78mg), and the crude product was used directly in the next step.

MS m/z(ESI)：470.1[M+H]⁺

The fifth step: preparation of 6-cyclopropyl-4- (2- (2, 4-difluorophenoxy) -5- (ethylsulfonylamino) phenyl) -1H-pyrrolo [2, 3-b ] pyridine-7-oxide

M-chloroperoxybenzoic acid (29mg, 0.12mmol, 75%) was added to a solution of N- (3- (6-cyclopropyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl) -4- (2, 4-difluorophenoxy) phenyl) ethanesulfonamide (39mg, 0.083mmol) in tetrahydrofuran (1 mL). After 10 min reaction at rt, it was quenched with saturated sodium thiosulfate (10mL), extracted with dichloromethane (10mL × 2), the organic phases were combined and washed with saturated sodium bicarbonate (10mL × 2), dried over anhydrous sodium sulfate, filtered and the filtrate evaporated to dryness to give crude product, which was separated on a preparative plate (dichloromethane: methanol ═ 20: 1) to give 6-cyclopropyl-4- (2- (2, 4-difluorophenoxy) -5- (ethylsulfonamido) phenyl) -1H-pyrrolo [2, 3-b ] pyridine-7-oxide (5mg, 12% yield).

¹H NMR(400MHz，CDCl₃)：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＝7.1Hz，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 of compounds 103 to 609 was substantially carried out according to the experimental procedure of example 26.

Biological evaluation

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

Test example 1 determination of inhibitory Effect of the Compound of the present invention on BRD4 binding Activity

BRD4 binding activity assay was tested by the following method.

Experimental procedure

To test the effect of compounds on the binding activity of BRD4 to acetylated proteins, the assay used a fluorescence resonance energy transfer (TR-FRET) method to test the inhibitory effect of compounds on the binding activity of BRD4 to acetylated substrates and to derive the half inhibitory concentration IC of compounds on the binding activity of BRD4₅₀。

The specific experimental operations were as follows:

1. adding 1-5 ul BRD4 enzyme solution into a 384-well plate, wherein the final enzyme concentration is 1-20 nM;

2. adding 1-5 ul of the compound solution which is diluted in a gradient manner;

3. adding 1-5 ul of substrate mixed solution containing acetylated substrate polypeptide with the final concentration of 2-50 nM;

4. incubating for 0.5-3 hours at room temperature;

5. adding 10ul EDTA and detection solution containing labeled antibody, and incubating at room temperature for 1 hour;

6. the enzyme-linked immunosorbent assay measures the 665nm fluorescence signal value of each plate hole;

7. calculating the inhibition rate through the fluorescence signal value;

8. obtaining the IC of the compound by curve fitting according to the inhibition rates of different concentrations₅₀。

Inhibition of BRD4 binding Activity by Compounds of the invention, IC determined by the above assay₅₀The values are shown in Table 1.

TABLE 1 inhibition of BRD4 binding Activity IC by Compounds of the invention₅₀Value of

And (4) conclusion: the compound of the invention has obvious inhibition effect on BRD4 binding activity.

Test example 2 measurement of inhibitory Effect of the Compound of the present invention on the proliferation Activity of Colo205 on colorectal cancer tumor cells

The proliferation activity of the compound on colon cancer tumor cells colo205 was tested by the following method.

Experimental procedure

The experiment adopts a CellTiter-Glo method to test the inhibition effect of the compound on the proliferation activity of colo205 cells and obtains the half inhibition concentration IC of the compound for inhibiting the cell proliferation activity₅₀。

1. Inoculating 50-100 mu L of colo205 cell suspension in a 96-well cell culture plate, wherein the density is 1-5 multiplied by 10⁴cells/mL, the plates were incubated in an incubator for 16-24 hours (37 ℃ C., 5% CO)₂)。

2. To the cells of the plate, solutions of the test compounds at different concentrations were added in a gradient and the plate was incubated in an incubator for 6 days (37 ℃ C., 5% CO)₂)。

3. 50-100. mu.L of CellTiter-Glo reagent was added to each well, shaken for 10 minutes, and allowed to stand at room temperature for 10 minutes.

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

5. The inhibition rate was calculated from the chemiluminescence signal value.

6. Obtaining the IC of the compound by curve fitting according to the inhibition rates of different concentrations₅₀。

The proliferation activity of colon cancer tumor cells colo205 is measured by the compound of the invention, and the IC is measured₅₀The values are shown in Table 2.

TABLE 2 inhibition of proliferation Activity of Compounds of the invention on Colo205 colon cancer tumor cells₅₀Value of

And (4) conclusion: the compound has obvious inhibition effect on the proliferation activity of colon cancer tumor cells colo 205.

Test example 3 determination of inhibitory Effect of the Compound of the present invention on the proliferative Activity of leukemia cell MV4-11

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

The experiment adopts a CellTiter-Glo method to test the inhibition effect of the compound on the proliferation of MV4-11 cells and obtains the half inhibition concentration IC of the compound for inhibiting the cell proliferation activity₅₀。

The experimental steps are as follows:

1. inoculating 50-100 mu L of MV4-11 cell suspension with the density of 1-5 multiplied by 10 in a 96-well cell culture plate⁴cells/mL, the plates were incubated in an incubator for 16-24 hours (37 ℃ C., 5% CO)₂)。

2. To the cells of the plate, solutions of the test compounds at different concentrations were added in a gradient and the plate was incubated in an incubator for 72 hours (37 ℃ C., 5% CO)₂)。

3. 50-100. mu.L of CellTiter-Glo reagent was added to each well, shaken for 10 minutes, and allowed to stand at room temperature for 10 minutes.

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

5. The inhibition rate was calculated from the chemiluminescence signal value.

6. Obtaining the IC of the compound by curve fitting according to the inhibition rates of different concentrations₅₀。

The compound of the invention measures the proliferative activity of leukemia cell MV4-11 and the measured IC₅₀The values are shown in Table 3.

TABLE 3 inhibition of the proliferative Activity of the Compounds of the invention on leukemia cells MV4-11 IC₅₀Value of

Test example 4 PK assay test of the Compound of the present invention on mice

The pharmacokinetic experiments in mice according to the preferred embodiment of the invention were carried out using Balb/c mice (Shanghai Jitsie laboratory animals Co., Ltd.).

The administration mode comprises the following steps: single administration by gavage

Administration dose: 5 mg/10 ml/kg

The preparation prescription is as follows: 0.5% CMC-Na and 1% Tween 80, ultrasonic dissolving

Sampling points are as follows: 0.5, 1, 2, 4, 6, 8 and 24 hours after administration

Sample treatment:

collecting blood by vein in 0.1mL, placing in a K2EDTA test tube, centrifuging at room temperature of 1000-3000 Xg for 5-20 min to separate blood plasma, and storing at-80 ℃.

Adding 160uL acetonitrile into 40uL of the plasma sample for precipitation, and centrifuging for 5-20 minutes at 500-2000 Xg after mixing.

Taking 100uL of the treated supernatant solution, and analyzing the concentration of the compound to be detected by adopting an LC/MS/MS analyzer: AB Sciex API 4000.

Liquid phase conditions: shimadzu LC-20AD pump

A chromatographic column: phenomenex Gemiu 5 mu m C1850X 4.6mm

Mobile phase: the solution A is 0.1% formic acid water solution, and the solution B is acetonitrile

Flow rate: 0.8mL/min

Pharmacokinetics:

the main parameters were calculated by WinNonlin 6.1, and the mouse pharmacokinetic experiment results are shown in Table 4

As can be seen from the results of the mouse pharmacokinetic experiments in the table: the compounds of the examples of the invention show good metabolic properties, and the exposure AUC and the maximum blood concentration Cmax are good.

Claims (19)

1. A compound of the general formula (III):

or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

b is selected from CH;

x is selected from the group consisting of a bond, -NR₅-or- (CR)₆R₇)-；

Z is selected from-NR₅-, O or-O (CR)₆R₇)-；

R₁Selected from methyl or cyclopropyl;

R₂is selected from C_1-6Alkyl, halo C_1-6Alkyl or cyclopropyl; wherein said C_1-6Alkyl, halo C_1-6Alkyl and cyclopropyl optionally further selected from C_1-6Alkyl, halogen, amino, cyano and hydroxyl;

R₄independently selected from hydrogen atom, C_1-6Alkyl radical, C_3-12Cycloalkyl, aryl, or 5-10 membered heteroaryl; wherein said C_1-6Alkyl radical, C_3-12Cycloalkyl, aryl and 5-10 membered heteroaryl optionally further substituted by C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Hydroxyalkyl, halogen, amino, hydroxy, cyano, cyclopropyl and-C (O) NR₉R₁₀Is substituted with one or more substituents of (1); and is

R₅Selected from hydrogen atoms;

R₆and R₇Each independently selected from a hydrogen atom or C_1-3An alkyl group;

R₉and R₁₀Each independently selected from a hydrogen atom;

n is 0 or 1.

2. A compound represented by the general formula (IV):

or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

z is selected from NH or O;

b is selected from CH;

ring C is selected from C_3-12Cycloalkyl, aryl or 5-10 membered heteroaryl, wherein said C_3-12Cycloalkyl, aryl and 5-10 membered heteroaryl optionally further substituted by C_1-6Alkyl, halogen, hydroxy, cyano, C_1-6Hydroxyalkyl and cyclopropyl;

R₄independently selected from hydrogen atom, C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Hydroxyalkyl, halogen, hydroxy, cyano, cyclopropyl, - (CH)₂)_tNR₉R₁₀Or- (CH)₂)_tC(O)NR₉R₁₀；

z is 0 or 1; and is

t is 0 or 1;

R₁、R₂、R₉、R₁₀x and n are as defined in claim 1.

3. The compound of claim 2, which is a compound of formula (VA) or (VB):

or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

z is selected from NH or O;

x is selected from a bond, NH or-CR₆R₇-；

R₄Independently selected from hydrogen atom, halogen, hydroxyl, cyano, C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Hydroxyalkyl, cyclopropyl, - (CH)₂)_tNR₉R₁₀Or- (CH)₂)_tC(O)NR₉R₁₀；

R₂Is selected from C_1-6Alkyl, halo C_1-6Alkyl or cyclopropyl; wherein said C_1-6Alkyl, halo C_1-6Alkyl and cyclopropyl optionally further selected from C_1-6Alkyl, halogen, amino, cyano and hydroxyl;

R₆、R₇each independently selected from a hydrogen atom or C_1-3An alkyl group;

R₉、R₁₀each independently selected from a hydrogen atom;

t is 0 or 1;

n is as defined in claim 1.

4. The compound of claim 2, which is a compound of formula (VIA) or (VIB):

or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

z is selected from NH or O;

x is selected from the group consisting of a bond, NH, -CH₂-、-CH(CH₃) -or C (CH)₃)₂-；

R₄Independently selected from hydrogen atom, halogen, hydroxyl, cyano, C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Hydroxyalkyl, cyclopropyl, - (CH)₂)NH₂Or- (CH)₂)C(O)NH₂；

R₂Is selected from C_1-6Alkyl, halo C_1-6Alkyl or cyclopropyl; wherein said C_1-6Alkyl, halo C_1-6Alkyl and cyclopropyl optionally further selected from C_1-6Alkyl, halogen and cyano.

5. The compound of any one of claims 1-2, wherein R₁Selected from methyl.

6. The compound of any one of claims 1-4, wherein R₂Is selected from C_1-6Alkyl, halo C_1-6Alkyl or cyclopropyl.

7. The compound of any one of claims 1-4, wherein R₂Is selected from C_1-3Alkyl, halo C_1-3Alkyl or cyclopropyl.

8. The compound of any one of claims 1-4, wherein R₂Selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, and,

9. A compound selected from the group consisting of:

or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

10. An intermediate of a compound according to any one of claims 1 to 9, which is a compound of general formula (VAA) or a compound of general formula (VBB):

or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

R₂、R₄z, X and n are as defined in claim 1.

11. A process for the preparation of a compound according to claim 3, comprising the steps of:

oxidizing the compound of the general formula (VAA) by an oxidant to obtain a compound of a general formula (VA); the oxidant is selected from m-chloroperoxybenzoic acid;

wherein:

R₂、R₄z, X and n are as defined in claim 3.

12. A process for the preparation of a compound according to claim 3, comprising the steps of:

oxidizing the compound with the general formula (VBB) with an oxidant to obtain a compound with a general formula (VB); the oxidant is selected from m-chloroperoxybenzoic acid;

wherein:

R₂、R₄z, X and n are as defined in claim 3.

13. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 9 together with one or more pharmaceutically acceptable carriers, diluents or excipients.

14. Use of a compound according to any one of claims 1-9, or a pharmaceutical composition according to claim 13, for the manufacture of a medicament for the treatment of a BRD4 inhibitor.

15. Use of a compound according to any one of claims 1 to 9, or a pharmaceutical composition according to claim 13, for the manufacture of a medicament for the treatment of cancer, inflammation, diabetes, cardiovascular disease or AIDS.

16. The use according to claim 15, wherein the cancer is selected from a solid tumor or leukemia.

17. The use according to claim 16, wherein the solid tumor is selected from breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, liver cancer, glioma, glioblastoma, lymphoma or myeloma.

18. The use according to claim 17, wherein the lung cancer is selected from non-small cell lung cancer.

19. The use of claim 17, wherein the liver cancer is selected from intrahepatic or extrahepatic malignancies.