CN115611897A

CN115611897A - Compounds as RSK2 inhibitors and uses thereof

Info

Publication number: CN115611897A
Application number: CN202210817411.4A
Authority: CN
Inventors: 郑国闯; 全旭; 赵立文; 周峰; 高尚; 李雪; 李佳妮
Original assignee: Nanjing Sanhome Pharmaceutical Co Ltd
Current assignee: Nanjing Sanhome Pharmaceutical Co Ltd
Priority date: 2021-07-12
Filing date: 2022-07-12
Publication date: 2023-01-17

Abstract

The invention belongs to the field of medicinal chemistry, relates to a compound serving as an RSK2 inhibitor and application thereof, and particularly provides a compound shown in a formula (I) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, a preparation method of the compound, a pharmaceutical composition containing the compound, and application of the compound or the composition in treatment of RSK 2-related diseases.

Description

Compounds as RSK2 inhibitors and uses thereof

Technical Field

The invention belongs to the field of medicinal chemistry, and particularly relates to a compound serving as an RSK2 inhibitor or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, a preparation method of the compound, a pharmaceutical composition containing the compound, and application of the compound or the composition in treating RSK2 related diseases.

Background

Breast cancer is the second leading cause of death in women, second only to lung cancer, and is the most common female tumor. There are approximately a new 100 million breast cancer patients worldwide each year, of which approximately 190000 patients are triple negative breast cancer phenotypes, with a proportion of 15% to 25%. The Triple-negative breast cancer (TNBC for short) is a type with high malignancy degree, and is mainly characterized in that estrogen receptors (ER for short), progesterone Receptors (PR) and Human Epidermal Growth Factor-2 (HER 2 for short) are all negative (homer)

Et al, clinical Medicine instruments: oncology,2018, 12,1-10). The current treatment scheme aiming at the triple negative breast cancer mainly comprises combined chemotherapy of taxoids and anthracyclines; in the advanced stage of metastatic triple negative breast cancer, gemcitabine plus carboplatin or cisplatin (guidelines and regulations for diagnosis and treatment of breast cancer (2017 edition) of the Chinese anticancer Association) can be selected, and specific targeting drugs are not available temporarily. Therefore, the problem of lack of small molecule inhibitors against specific targets of triple negative breast cancer is urgently to be solved.

The P90 Ribosomal S6 Kinase (RSK) family is a highly conserved serine/threonine kinase, including four members RSK1-4, which have functional specificity despite high sequence homology (73-80%) (Rafael Cuesta1 and Marina k. Holz, oncotarget,2015, 19, 27567-27583). The RSK protein comprises two distinct functional domains: CTKD at the C terminal mediates RSK activation; NTKD at the N-terminus mediates substrate phosphorylation. Among them, RSK2 is highly expressed in TNBC and is associated with the development, metastasis and prognosis of TNBC. When the upstream growth factor receptor is activated, RSK2 is activated mainly through two signal pathways: 1) Promote ERK phosphorylation and further promote RSK2 phosphorylation upon MEK activation; 2) Phosphorylated PDK-1 promotes RSK2 phosphorylation. After being activated by phosphorylation, RSK promotes the activation of downstream multiple transcription factors and is closely related to biological processes such as tumor cell proliferation, migration and metabolism. Wherein the transcription factor YB-1 is a carcinogenic transcription factor and is involved in the occurrence and development of various tumors. YB-1 is highly expressed in 73% of basal-like Breast cancers (BLBC), with p-AKT deleted in some TNBC, but with activation of p-RSK and p-YB-1 present (Anna L Stratford and Christopher J Fry, breast Cancer Res,2008, 10 (6), R99). p-YB-1 is phosphorylated and enters the nucleus, initiating the expression of a number of genes, such as EGFR, PDL1, CD44, etc., which play important roles in tumor development, metastasis, immune escape and resistance (Rama Jain and Michelle Mathur, J.Med.Chem.2015, 58, 6766-6783, zhen Tao and Hailong Ruan, cancer Immunol Res,2019,7 (7), 1135-1147).

Disclosure of Invention

The invention aims to provide a compound with RSK2 inhibitory activity shown in a general formula (I) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof,

wherein the content of the first and second substances,

R ¹ selected from haloalkoxy and aminosulfonyl;

R ² selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino,Monoalkylamino, alkylacylamino, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, said groups being substituted with one or more groups selected from halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, monoalkylaminoalkyl, alkylacylamino, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, dialkylaminoalkyl, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylacyl, heterocyclylacyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, heteroaryl, and oxo groups;

R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, aminoacyl, alkylaminoacyl, dialkylamino, heterocyclyl, and cycloalkyl; and

x, Y, Z is each independently selected from N and C (R) ⁸ ) Wherein R is ⁸ Each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, aminoacyl, alkylaminoacyl, dialkylaminoalkyl, heterocyclyl, and cycloalkyl.

It is another object of the present invention to provide a method for preparing the compound of the general formula (I) of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug.

It is a further object of the present invention to provide a composition comprising a compound of formula (I) of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug and a pharmaceutically acceptable carrier, and a composition comprising a compound of formula (I) of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug and another drug or drugs.

It is still another object of the present invention to provide a method for treating RSK2 mediated diseases by the compound of formula (I) or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug of the present invention, and the use of the compound of formula (I) or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug of the present invention for the preparation of a medicament for treating RSK2 mediated diseases.

Aiming at the above purpose, the invention provides the following technical scheme:

in a first aspect, the invention provides a compound with RSK2 inhibitory activity, shown as a general formula (I), or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof,

wherein the content of the first and second substances,

R ¹ selected from haloalkoxy and aminosulfonyl;

R ² selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, said groups being substituted with one or more groups selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, monoalkylaminoalkyl, alkylacylamino, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, dialkylaminoalkyl, alkenyl, alkynyl, haloalkylacyl, hydroxyalkanoyl, cycloalkylacyl, heterocyclylacyl, cycloAlkyl, halocycloalkyl, heterocyclyl, aryl, heteroaryl, and oxo;

x, Y, Z is each independently selected from N and C (R) ⁸ ) Wherein R is ⁸ Each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, aminoacyl, alkylaminoacyl, dialkylamino, heterocyclyl and cycloalkyl.

In some preferred embodiments, the compounds of the present invention are of the general formula (I) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:

R ¹ selected from halogen C _1-6 Alkoxy and aminosulfonyl;

further preferably, it is halogenated C _1-3 Alkoxy and aminosulfonyl;

even more preferably, R ¹ Selected from the group consisting of halomethoxy, haloethoxy, halopropoxy, and aminosulfonyl.

R ² selected from hydrogen, halogen, hydroxy, C _1-6 Alkyl, halo C _1-6 Alkyl, hydroxy C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy, hydroxy C _1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C _1-6 Alkylamino radical, C _1-6 An alkyl acylamino group,C _1-6 Alkyl acyl radical, C _1-6 Alkylsulfonyl, aminoacyl, C _1-6 Alkylaminoacyl, di-C _1-6 Alkylamino, 3-8 membered cycloalkyl C _1-6 Alkyl, 3-8 membered heterocyclic group C _1-6 Alkyl, 6-8 membered aryl C _1-6 Alkyl, 5-8 membered heteroaryl and 5-8 membered heteroaryl C _1-6 Alkyl, said radical being substituted by one or more radicals selected from halogen, hydroxy, C _1-6 Alkyl, halo C _1-6 Alkyl, hydroxy C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy, hydroxy C _1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C _1-6 Alkylamino radical, mono C _1-6 Alkylamino radical C _1-6 Alkyl radical, C _1-6 Alkylacylamino group, C _1-6 Alkyl acyl radical, C _1-6 Alkylsulfonyl, aminoacyl, C _1-6 Alkylaminoacyl, di-C _1-6 Alkylamino, di-C _1-6 Alkylamino radical C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, halo C _1-6 Alkyl acyl, hydroxy C _1-6 Alkyl acyl, 3-8 membered ring alkyl acyl, 3-8 membered heterocyclic acyl, 3-8 membered ring alkyl, halogenated 3-8 membered ring alkyl, 3-8 membered heterocyclic, 6-8 membered aryl, 5-8 membered heteroaryl and oxo group;

further preferably, R ² Selected from hydrogen, halogen, hydroxy, C _1-3 Alkyl, halo C _1-3 Alkyl, hydroxy C _1-3 Alkyl radical, C _1-3 Alkoxy, halo C _1-3 Alkoxy, hydroxy C _1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C _1-3 Alkylamino radical, C _1-3 Alkylacylamino group, C _1-3 Alkyl acyl, C _1-3 Alkylsulfonyl, aminoacyl, C _1-3 Alkylaminoacyl, di-C _1-3 Alkylamino, 3-6-membered cycloalkyl C _1-3 Alkyl, 3-6 membered heterocyclic group C _1-3 Alkyl, aryl C _1-3 Alkyl, 5-6 membered heteroaryl and 5-6 membered heteroaryl C _1-3 Alkyl, said radical being substituted by one or more radicals selected from halogen, hydroxy, C _1-3 Alkyl, halo C _1-3 Alkyl, hydroxy C _1-3 Alkyl radical, C _1-3 Alkoxy, halo C _1-3 Alkoxy, hydroxy C _1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C _1-3 Alkylamino radical, mono C _1-3 Alkylamino radical C _1-3 Alkyl radical, C _1-3 Alkylacylamino group, C _1-3 Alkyl acyl radical, C _1-3 Alkylsulfonyl, aminoacyl, C _1-3 Alkylaminoacyl, di-C _1-3 Alkylamino, di-C _1-3 Alkylamino radical C _1-3 Alkyl radical, C _2-3 Alkenyl radical, C _2-3 Alkynyl, halo C _1-3 Alkyl acyl, hydroxy C _1-3 Alkyl acyl, 3-6 membered ring alkyl acyl, 3-6 membered heterocyclic acyl, 3-6 membered ring alkyl, halogenated 3-6 membered ring alkyl, 3-6 membered heterocyclic, aryl, 5-6 membered heteroaryl and oxo group;

more preferably, R ² Selected from the group consisting of hydrogen, fluorine, chlorine, bromine, hydroxyl, methyl, ethyl, propyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, 2-hydroxyethyl, hydroxypropyl, 2-hydroxypropyl, hydroxyisopropyl, 2-hydroxyisopropyl, methoxy, ethoxy, propoxy, halomethoxy, haloethoxy, halopropoxy, hydroxymethoxy, hydroxyethoxy, 2-hydroxyethoxy, hydroxypropoxy, 2-hydroxypropoxy, hydroxyisopropoxy, nitro, carboxyl, cyano, amino, methylamino, formylamino, formyl, methylsulfonyl, aminoacyl, methylaminoacyl, dimethylamino, cyclopropyl, cyclobutyl, 3-6 membered cycloalkyl C _1-3 Alkyl, 3-6 membered heterocyclic group C _1-3 Alkyl, aryl C _1-3 Alkyl, 5-6 membered heteroaryl and 5-6 membered heteroaryl C _1-3 Alkyl, said radical being substituted by one or more radicals selected from halogen, hydroxy, C _1-3 Alkyl, halo C _1-3 Alkyl, hydroxy C _1-3 Alkyl radical, C _1-3 Alkoxy, halo C _1-3 Alkoxy, hydroxy C _1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C _1-3 Alkylamino radical, mono C _1-3 Alkylamino radical C _1-3 Alkyl radical, C _1-3 Alkylacylamino group, C _1-3 Alkyl acyl radical, C _1-3 Alkylsulfonyl, aminoacyl, C _1-3 Alkylaminoacyl, di-C _1-3 Alkylamino, di-C _1-3 Alkylamino radical C _1-3 Alkyl radical, C _2-3 Alkenyl radical, C _2-3 Alkynyl, halo C _1-3 Alkyl acyl, hydroxy C _1-3 Alkyl acyl, 3-6 membered ring alkyl acyl, 3-6 membered heterocyclic acyl, 3-6 membered ring alkyl, halogenated 3-6 membered ring alkyl, 3-6 membered heterocyclic, aryl, 5-6 membered heteroaryl and oxo group.

R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ each independently selected from hydrogen, halogen, hydroxy, C _1-6 Alkyl, halo C _1-6 Alkyl, hydroxy C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy, hydroxy C _1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C _1-6 Alkylamino radical, C _1-6 Alkylacylamino group, C _1-6 Alkyl acyl, amino acyl, C _1-6 Alkylaminoacyl, di-C _1-6 Alkylamino, 3-8 membered heterocyclyl and 3-8 membered cycloalkyl;

further preferably, R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ Each independently selected from hydrogen, halogen, hydroxy, C _1-3 Alkyl, halo C _1-3 Alkyl, hydroxy C _1-3 Alkyl radical, C _1-3 Alkoxy, halo C _1-3 Alkoxy, hydroxy C _1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C _1-3 Alkylamino radical, C _1-3 Alkylacylamino group, C _1-3 Alkyl acyl, amino acyl, C _1-3 Alkylaminoacyl, di-C _1-3 Alkylamino, 3-6 membered heterocyclyl and 3-6 membered cycloalkyl;

even more preferably, R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ Each independently selected from hydrogen, halogen, hydroxy, methyl, ethyl,Propyl, isopropyl, halogeno C _1-3 Alkyl, hydroxy C _1-3 Alkyl radical, C _1-3 Alkoxy, halo C _1-3 Alkoxy, hydroxy C _1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C _1-3 Alkylamino radical, C _1-3 Alkylacylamino group, C _1-3 Alkyl acyl, amino acyl, C _1-3 Alkylaminoacyl, di-C _1-3 Alkylamino, 3-6 membered heterocyclyl and 3-6 membered cycloalkyl.

The compounds according to the invention are compounds of general formula (I) or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof, in some preferred embodiments X is N and Y is C (R) ⁸ ) Z is N; in some preferred embodiments, X is N and Y is C (R) ⁸ ) Z is C (R) ⁸ ) (ii) a In some preferred embodiments, X is N, Y is N, and Z is N; in some preferred embodiments, X is N, Y is N, and Z is C (R) ⁸ ) (ii) a In some embodiments, X is C (R) ⁸ ) Y is N, Z is N; in some embodiments, X is C (R) ⁸ ) Y is N, Z is C (R) ⁸ ) (ii) a In some embodiments, X is C (R) ⁸ ) Y is C (R) ⁸ ) Z is N; in some embodiments, X is C (R) ⁸ ) Y is C (R) ⁸ ) Z is C (R) ⁸ )。

In some preferred embodiments, the compounds of the present invention are compounds of general formula (I) or an isomer, a pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:

R ⁸ each independently selected from hydrogen, halogen, hydroxy, C _1-6 Alkyl, halo C _1-6 Alkyl, hydroxy C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy, hydroxy C _1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C _1-6 Alkylamino radical, C _1-6 Alkylacylamino group, C _1-6 Alkyl acyl, amino acyl, C _1-6 Alkylaminoacyl, di-C _1-6 Alkylamino, 3-8 membered heterocyclyl and 3-8 membered cycloalkyl;

further preferably, R ⁸ Each independently selected from hydrogen, halogenElement, hydroxy group, C _1-3 Alkyl, halo C _1-3 Alkyl, hydroxy C _1-3 Alkyl radical, C _1-3 Alkoxy, halo C _1-3 Alkoxy, hydroxy C _1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C _1-3 Alkylamino radical, C _1-3 Alkylacylamino group, C _1-3 Alkyl acyl, amino acyl, C _1-3 Alkylaminoacyl, di-C _1-3 Alkylamino, 3-6 membered heterocyclyl and 3-6 membered cycloalkyl;

even more preferably, R ⁸ Each independently selected from hydrogen, halogen, hydroxy, methyl, ethyl, propyl, isopropyl, halogenated C _1-3 Alkyl, hydroxy C _1-3 Alkyl radical, C _1-3 Alkoxy, halo C _1-3 Alkoxy, hydroxy C _1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C _1-3 Alkylamino radical, C _1-3 Alkylacylamino group, C _1-3 Alkyl acyl, amino acyl, C _1-3 Alkylaminoacyl, di-C _1-3 Alkylamino, 3-6 membered heterocyclyl and 3-6 membered cycloalkyl.

R ² selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, methoxy, ethoxy, propoxy,

And

the present invention provides the following specific compounds or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof:

in another aspect, the present invention provides a process for the preparation of a compound of formula (I) according to the invention, comprising the steps of:

1) Reacting the compound of the formula (1) to generate a compound of a formula (2);

2) Reacting a compound of formula (2) with a compound of formula (3) to produce a compound of formula (4);

3) Reacting the compound of the formula (4) to obtain a compound of a formula (5);

4) Carrying out ester hydrolysis reaction on the compound of the formula (5) to obtain a compound of a formula (6);

5) Carrying out reduction reaction on the compound of the formula (7) to obtain a compound of a formula (8);

4) Reacting the compound of the formula (6) with the compound of the formula (8) to obtain a compound of the formula (I);

wherein R is ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ X, Y and Z have the definitions described for general formula (I), M is absent or is an amino protecting group, and the compounds of formula (1), compounds of formula (3), compounds of formula (7) are commercially available compounds or can be synthesized using other techniques customary to those skilled in the art.

In a third aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or an isomer, a pharmaceutically acceptable salt, solvate, crystal or prodrug thereof.

In some embodiments, the present invention provides a compound of the present invention or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof and a pharmaceutical composition comprising a compound of the present invention or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof for use in the treatment of a disease associated with RSK 2.

In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, and a pharmaceutically acceptable carrier.

The compound of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug can be mixed with a pharmaceutically acceptable carrier, diluent or excipient to prepare a pharmaceutical preparation suitable for oral or parenteral administration. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes. The formulations may be administered by any route, for example by infusion or bolus injection, by a route of absorption through epithelial or cutaneous mucosa (e.g. oral mucosa or rectum, etc.). Administration may be systemic or local. Examples of the formulation for oral administration include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like. The formulations may be prepared by methods known in the art and include carriers, diluents or excipients conventionally used in the art of pharmaceutical formulation.

In a fourth aspect, the present invention provides a compound represented by formula (I) or formula (Ia) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, or a pharmaceutical composition comprising the same, for use in a method for treating a disease associated with RSK2, and in the preparation of a medicament for treating a disease associated with RSK 2.

In some preferred embodiments, the present invention provides a compound represented by formula (I), formula (Ia) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, or a pharmaceutical composition comprising the same, for use in a method for treating a disease associated with RSK2 and in the preparation of a medicament for treating a disease associated with RSK2, wherein the disease associated with RSK2 includes, but is not limited to, cancer. In some embodiments, the RSK 2-associated disease described herein is cancer.

In some embodiments, the RSK 2-associated diseases described herein include, but are not limited to: breast cancer, prostate cancer, lung cancer, brain cancer, skin cancer, bone cancer, ovarian cancer, multiple myeloma, or leukemia.

In some embodiments, the present invention provides a method of treating a disease or condition associated with RSK activity in a mammal, wherein the method comprises administering to the mammal a therapeutically effective amount of a compound provided herein or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof; in some embodiments, the method further comprises administering a second therapeutic agent. In some embodiments, the second therapeutic agent is a chemotherapeutic agent, a hormonal therapeutic agent, or an immunotherapeutic agent. In some embodiments, the second therapeutic agent is a poly ADP-ribose polymerase (PARP) inhibitor, a STAT 3 inhibitor, a Janus kinase inhibitor, or an EGFR inhibitor. In some embodiments, the second therapeutic agent is a chemotherapeutic agent (small molecule or antibody). In some embodiments, the second therapeutic agent is paclitaxel. In some embodiments, the second therapeutic agent is methotrexate. In some embodiments, the second therapeutic agent is 5_ fluorouracil. In some embodiments, the second therapeutic agent is doxorubicin.

Definition of terms

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

The "hydrogen", "carbon" and "oxygen" in the compounds of the present invention include all isotopes thereof. Isotopes are understood to include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include protium, tritium, and deuterium, and isotopes of carbon include ¹² C、 ¹³ C and ¹⁴ c, isotopes of oxygen including ¹⁶ O and ¹⁸ o, and the like.

"isomers" in the present invention refer to molecules having the same atomic composition and connection mode but different three-dimensional spatial arrangement, and include, but are not limited to, diastereomers, enantiomers, cis-trans isomers, and mixtures thereof, such as racemic mixtures. Many organic compounds exist in optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefix D, L or R, S is used to denote the absolute configuration of the chiral center of the molecule. The prefixes D, L or (+), (-) are used to designate the sign of the compound's plane-polarized light rotation, with (-) or L meaning that the compound is left-handed and the prefix (+) or D meaning that the compound is right-handed. The chemical structures of these stereoisomers are identical, but the stereo structures are different. A particular stereoisomer may be an enantiomer, and a mixture of isomers is commonly referred to as a mixture of enantiomers. A mixture of enantiomers of 50. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers, lacking optical activity.

Depending on the choice of starting materials and methods, the compounds of the invention may exist as one of the possible isomers or as mixtures thereof, for example as racemates and mixtures of non-corresponding isomers (depending on the number of asymmetric carbon atoms). Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.

Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography and/or fractional crystallization, depending on the differences in the physicochemical properties of the components.

The "halogen" in the present invention means fluorine, chlorine, bromine and iodine. "halo" as used herein means substituted by fluorine, chlorine, bromine or iodine.

"alkyl" in the present invention means a straight or branched chain saturated aliphatic hydrocarbon group, preferably a straight or branched chain group having 1 to 6 carbon atoms, further preferably a straight or branched chain group having 1 to 3 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be at any available point of attachment.

The "carbonyl group" and "acyl group" in the present invention are each-C (O) -.

"Sulfonyl" of the present invention means-S (O) ₂ -。

The "sulfonamide group" of the present invention means-S (O) ₂ NH-。

"haloalkyl" in the context of the present invention means an alkyl group substituted with at least one halogen.

"hydroxyalkyl" in the context of the present invention means an alkyl group substituted with at least one hydroxyl group.

"alkoxy" in the context of the present invention means-O-alkyl. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, n-propoxy, isopropoxy, isobutoxy, sec-butoxy and the like. An alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent may be at any available point of attachment.

The "cycloalkyl group" in the present invention means a cyclic saturated hydrocarbon group. Suitable cycloalkyl groups may be substituted or unsubstituted monocyclic, bicyclic or tricyclic saturated hydrocarbon groups having 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

"heterocyclyl" in the present invention refers to a group of a 3-to 12-membered non-aromatic ring system having 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon ("3-12 membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valency permits. Heterocyclyl groups can be either monocyclic ("monocyclic heterocyclyl") or fused, bridged or spiro ring systems (e.g., bicyclic systems (a.k.a. Bicyclic heterocyclyl ")) and can be saturated or partially unsaturated, wherein the bicyclic heterocyclyl includes, but is not limited to, benzoazacyclyl, benzoxacyclyl, benzothiepinyl, benzodiazacyclyl, benzodioxocyclyl, benzodithioheterocyclyl, benzoxazaheterocyclyl, benzothiepinyl. Suitable heterocyclic groups include, but are not limited to, piperidinyl, azetidinyl, aziridinyl, tetrahydropyrrolyl, piperazinyl, dihydroquinazolinyl, oxacyclopropyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, dihydroquinazolinyl, oxapiperazinyl, dihydroquinazolinyl, and dihydroquinazolinyl,

Dihydrobenzoxelocyclohexenyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, and tetrahydroisoquinolinyl, and the like. Each instance of a heterocyclyl group can be optionally substituted or unsubstituted, and when substituted, the substituent can be at any available point of attachment.

"aryl" as used herein refers to an aromatic system which may comprise a single ring or fused polycyclic ring, preferably a single ring or fused bicyclic ring, having from 6 to 12 carbon atoms, preferably from about 6 to about 10 carbon atoms. Suitable aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, indanyl. Aryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents may be at any available point of attachment.

The "heteroaryl group" in the present invention means an aryl group having at least one carbon atom replaced with a heteroatom, preferably consisting of 5 to 12 atoms (5-12 membered heteroaryl group), more preferably consisting of 5 to 10 atoms (5-10 membered heteroaryl group), said heteroatom being O, S, N. The heteroaryl group includes, but is not limited to, imidazolyl, pyrrolyl, furanyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, indolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, isoindolyl, benzopyrazolyl, benzimidazolyl, benzofuranyl, benzopyranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, quinoxalinyl, benzoxazinyl, benzothiazinyl, imidazopyridinyl, pyrimidopyrazolyl, pyrimidoimidazolyl, and the like. Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituent may be at any available point of attachment.

The term "pharmaceutically acceptable salt" as used herein 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.

"solvate" of the present invention refers in the conventional sense to a complex of a solute (e.g., active compound, salt of active compound) and a solvent (e.g., water) in combination. Solvent means a solvent known or readily determined by one skilled in the art. If water, the solvate is often referred to as a hydrate, e.g., a hemihydrate, monohydrate, dihydrate, trihydrate or a substitute amount thereof, and the like.

The in vivo effect of the compound of formula (I) may be exerted in part by one or more metabolites formed in the human or animal body after administration of the compound of formula (I). As mentioned above, the in vivo effect of the compounds of formula (I) may also be exerted via metabolism of the precursor compounds ("prodrugs"). The "prodrug" of the present invention refers to a compound which is converted into the compound of the present invention by reaction with an enzyme, gastric acid or the like under physiological conditions in a living body, that is, a compound which is converted into the compound of the present invention by oxidation, reduction, hydrolysis or the like by an enzyme, a compound which is converted into the compound of the present invention by hydrolysis reaction of gastric acid or the like, or the like.

The "crystal" of the present invention is a solid having an internal structure in which constituent atoms (or a group thereof) are regularly repeated in three dimensions, and is different from an amorphous solid having no such regular internal structure.

The term "pharmaceutical composition" as used herein is intended to encompass a mixture comprising any one of the compounds of the present invention, including the corresponding isomer, prodrug, solvate, pharmaceutically acceptable salt or chemically protected form thereof, and one or more pharmaceutically acceptable carriers and/or one or more other drugs. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism. The compositions are generally useful for the preparation of medicaments for the treatment and/or prevention of diseases mediated by one or more kinases.

The "pharmaceutically acceptable carrier" of the present invention means a carrier that does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the administered compound, and includes all solvents, diluents or other excipients, dispersants, surfactant isotonicity agents, thickeners or emulsifiers, preservatives, solid binders, lubricants and the like. Unless any conventional carrier medium is incompatible with the compounds of the present invention. Some examples of carriers that may be pharmaceutically acceptable include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, and cellulose acetate; malt, gelatin, and the like.

"excipients" in the context of the present invention refer to inert substances added to pharmaceutical compositions to further facilitate administration of the compounds. Excipients may include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols.

Detailed Description

The present invention will be further illustrated in detail with reference to the following examples, but the present invention is not limited to these examples. The materials used in the following examples are all commercially available unless otherwise specified.

Example 1 preparation of (R) -N- (4-bromo-2- (difluoromethoxy) phenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

Step 1 preparation of 2-Ethyl-6-methyl-1H-pyrrolo [2,3-b ] pyridine-2,6-dicarboxylate

Reacting 6-bromo-1H-pyrrolo [2,3-b]Pyridine-2-carboxylic acid ethyl ester (1.4g, 5.02mmol) was dissolved in a mixed solution of anhydrous dioxane (40 mL) and anhydrous methanol (20 mL), and palladium acetate (122mg, 0.502mmol), 4,5-bis-diphenylphosphine-9,9-dimethylxanthene (290mg, 1.85mmol), and potassium carbonate (3.835g, 27.75mmol) were added. After the addition was complete, the reaction was stirred in an oil bath at 70 ℃ overnight under carbon monoxide gas. After the reaction was completed, the mixture was suction-filtered, the filtrate was adjusted to pH 4 with dilute hydrochloric acid (2M), concentrated under reduced pressure, and subjected to column chromatography to give 0.9g of the title compound. ESI-MS m/z:249.1[ 2 ] M + H] ⁺ .

Step 2-Ethyl-6-methyl (R) -1- (1- ((tert-butoxycarbonyl) amino) propan-2-yl) -1H-pyrrolo [2,3-b ] pyridine-2,6-dicarboxylate preparation

2-ethyl-6-methyl-1H-pyrrolo [2,3-b]Pyridine-2,6-dicarboxylate (100mg, 0.4 mmol) was dissolved in N, N-dimethylformamide (3 mL), and the compound (S) -5-methyl-1,2,3-oxothiazolidine-3-carboxylic acid tert-butyl ester-2,2-dioxide (100.5mg, 0.42mmol) and cesium carbonate (260.6mg, 0.8mmol) were added. The reaction was placed in an 80 ℃ oil bath and stirred overnight under argon. After the reaction was complete, the reaction mixture was filtered with suction, the filtrate was extracted with ethyl acetate, and the combined organic phases were washed with waterWashed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (110 mg). ESI-MS m/z:406.2[ 2 ], [ M + H ]] ⁺ .

Step 3 preparation of methyl (R) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxylate

Reacting 2-ethyl 6-methyl (R) -1- (1- ((tert-butoxycarbonyl) amino) propan-2-yl) -1H-pyrrolo [2,3-b]Pyridine-2,6-dicarboxylate (500mg, 1.23mmol) was dissolved in hydrochloric acid-dioxane (4M, 4mL) and stirred at room temperature for 2 hours. After concentration under reduced pressure, it was redissolved in ethanol (20 ml), and potassium carbonate (680 mg, 4.92mmol) was added, followed by stirring at 80 ℃ for 12 hours. After the reaction was complete, the reaction mixture was filtered with suction and the filter cake was washed with methanol (20 mL). The filtrate was concentrated under reduced pressure to give the title compound 250mg. ESI-MS m/z 260.0[ 2 ] M + H] ⁺ .

Step 4 preparation of (R) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxylic acid

Mixing (R) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5]Pyrrolo [1,2-a]Pyrazine-2-carboxylic acid methyl ester (900mg, 3.47mmol) was dissolved in a mixed solution of water (2 mL) and methanol (8 mL), and lithium hydroxide (332.5mg, 13.88mmol) was slowly added thereto, and after completion of the addition, the mixture was stirred at room temperature for 12 hours. After the reaction was complete, suction filtration was carried out, and the filtrate was concentrated under reduced pressure. Methanol (10 mL) was added to the concentrate to dissolve it, and the pH was adjusted to about 4 with dilute hydrochloric acid (2M), followed by column chromatography to give 700mg of the title compound. ESI-MS m/z:246.1[ 2 ] M + H] ⁺ .

Step 5 preparation of 4-bromo-2- (difluoromethoxy) -1-nitrobenzene

5-bromo-2-nitrophenol (500mg, 2.30mmol) was dissolved in tetrahydrofuran (15 mL) and sodium hydride (60%, 185mg, 4.62mmol) was added in three portions while cooling on ice. After stirring for 30 minutes, diethyl (bromodifluoromethyl) phosphonate (1.23g, 4.61mmol) was added and stirred at room temperature for 12 hours. After completion of the reaction, the reaction solution was quenched with an ice-water mixture, extracted with ethyl acetate, and concentrated under reduced pressure to obtain 1.7g of the title compound as a crude product. ESI-MS m/z:268.0[ 2 ] M + H] ⁺ ,270.0[M+H] ⁺ .

Step 6 preparation of 4-bromo-2- (difluoromethoxy) -1-aniline

4-bromo-2- (difluoromethoxy) -1-nitrobenzene (1.70g, 6.34mmol) and nickel chloride (2.47g, 19.03mmol) were added to ethanol (30 mL). While stirring in an ice bath, sodium borohydride (2.40g, 63.43mmol) was added in portions, and stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was filtered, and the mother liquor was distilled under reduced pressure. Purification by column chromatography gave the title compound 200mg. ESI-MS m/z:237.9[ 2 ], [ M + H ]] ⁺ ,239.9[M+H] ⁺ .

Step 7 preparation of (R) -N- (4-bromo-2- (difluoromethoxy) phenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

4-bromo-2- (difluoromethoxy) -1-phenylamine (55mg, 0.231mmol) and (R) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5]Pyrrolo [1,2-a]Pyrazine-2-carboxylic acid (57mg, 0.231mmol), 2-chloro-1-methylpyridinium iodide (118mg, 0.462mmol), 4-dimethylaminopyridine (28mg, 0.231mmol) were dissolved in N, N-dimethylformamide (5 mL), followed by dropwise addition of N, N-diisopropylethylamine (90mg, 0.693mmol) and stirring at room temperature for 12 hours. After the reaction, the mixture was concentrated under pressure and purified by reverse phase column chromatography to obtain 13mg of the objective compound. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.64(s,1H),8.47(d,1H,J＝8.7Hz,),8.40(d,2H,J＝8.1Hz,),8.02(d,1H,J＝8.2Hz,),7.63(s,1H),7.58(d,1H,J＝8.6Hz,),7.44(d,J＝56Hz,1H),7.19(s,1H),5.05(m,1H),3.98–3.88(m,1H),3.54–3.45(m,1H),1.49(d,3H,J＝6.6Hz,).ESI-MS m/z:463.0[M-H] ^- .

Example 2 preparation of (R) -N- (4-cyclopropyl-2- (difluoromethoxy) phenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

Step 1 preparation of 4-cyclopropyl-2- (difluoromethoxy) -1-nitrobenzene

4-bromo-2- (difluoromethoxy) -1-nitrobenzene (400mg, 1.49mmol) and cyclopropylboronic acid (333mg, 3.880mmol), potassium carbonate (413mg, 2.985mmol), tricyclohexylphosphine (84mg, 2.985mmol), palladium acetate (34mg, 0.149mmol) were dissolved in toluene (6 mL) and water (2.5 mL). And carrying out microwave reaction at 90 ℃ for 2 hours under the protection of argon. After completion of the reaction, concentration under reduced pressure and purification by column chromatography gave the title compound 312mg. ESI-MS m/z 230.1[ 2 ] M + H] ⁺ .

Step 2 preparation of 4-cyclopropyl-2- (difluoromethoxy) aniline

4-cyclopropyl-2- (difluoromethoxy) -1-nitrobenzene (312mg, 1.361mmol) was dissolved in ethanol (10 mL) followed by palladium on carbon (156mg, 50wt%). The mixture was stirred under hydrogen at 30 ℃ for 12 hours. After completion of the reaction, concentration under reduced pressure and column chromatography were carried out to give the title compound (270 mg). ESI-MS m/z 200.1[ 2 ] M + H] ⁺ .

Step 3 preparation of (R) -N- (4-cyclopropyl-2- (difluoromethoxy) phenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

4-cyclopropyl-2- (difluoromethoxy) aniline (100mg, 0.50mmol) and (R) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5]Pyrrolo [1,2-a]Pyrazine-2-carboxylic acid (246mg, 1.0mmol), 2-chloro-1-methylpyridine iodide (257mg, 1.0mmol), 4-dimethylaminopyridine (61mg, 0.50mmol) were dissolved in N, N-dimethylformamide (5 mL), followed by dropwise addition of N, N-diisopropylethylamine (195mg, 1.506mmol). The reaction solution was stirred at room temperature for 4 hours. After completion of the reaction, concentration was performed under reduced pressure, and purification was performed by reverse phase column chromatography to give the title compound as 70mg. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.55(s,1H),8.37-8.50(m,3H),8.00(d,1H,J＝6.8Hz),7.54-7.18(m,1H),7.30(d,J＝55Hz,1H),7.17-6.90(m,2H),5.06-5.02(m,1H),3.95-3.92(m,1H),3.51-3.48(m,1H),1.98-1.94(m,1H),1.49(d,3H,J＝6.6Hz,),0.98-0.91(m,2H),0.75-0.70(m,2H).ESI-MS m/z:427.1[M+H] ⁺ .

Example 3: preparation of (R) -N- (2- (difluoromethoxy) -4-morpholinophenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

Step 1 preparation of 4- (3- (difluoromethoxy) -4-nitrophenyl) morpholine

Morpholine (195mg, 2.239mmol), 4-bromo-2- (difluoromethoxy) -1-nitrobenzene (400mg, 1.492mmol), cesium carbonate (973mg, 2.985mmol), tris (dibenzylideneacetone) dipalladium (137mg, 0.149mmol) and 2-dicyclohexylphosphino-2' - (N, N-dimethylamine) -biphenyl (117mg, 0.298mmol) were added to a mixture of 1,4-dioxane (12 mL) and water (2 mL). Under the protection of argon, microwave at 100 DEG CThe reaction was carried out for 2 hours. After completion of the reaction, concentration under reduced pressure and column chromatography were carried out to obtain the title compound (270 mg). ESI-MS m/z 275.1[ 2 ] M + H] ⁺ .

Step 2 preparation of 4- (3- (difluoromethoxy) -4-aminophenyl) morpholine

4- (3- (difluoromethoxy) -4-nitrophenyl) morpholine (270mg, 0.985 mmol) was dissolved in ethanol (10 mL), palladium on carbon (81 mg) was added, and the mixture was stirred under hydrogen at room temperature for 2 hours. After completion of the reaction, concentration under reduced pressure and purification by column chromatography gave the title compound 240mg. ESI-MS m/z:245.1[ 2 ] M + H] ⁺ .

Step 3 preparation of (R) -N- (2- ((difluoromethoxy) -4-morpholinophenyl)) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

4- (3- (Difluoromethoxy) -4-aminophenyl) morpholine (73mg, 0.297mmol) and (R) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5]Pyrrolo [1,2-a]Pyrazine-2-carboxylic acid (80mg, 0.326 mmol), 2-chloro-1-methylpyridinium iodide (152mg, 0.593mmol), 4-dimethylaminopyridine (36mg, 0.297mmol) were dissolved in N, N-dimethylformamide (5 mL), followed by dropwise addition of N, N-diisopropylethylamine (115mg, 0.890mmol). The reaction solution was stirred at room temperature for 2 hours. After completion of the reaction, concentration under reduced pressure and purification by column chromatography gave the title compound 45mg. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.42(s,1H),8.35-8.40(m,2H),8.28(d,1H,J＝9.6Hz),7.99(d,1H,J＝8.2Hz),7.32(d,1H,J＝50Hz),7.17(s,1H),7.02-6.93(m,2H),5.11-5.01(m,1H),3.97-3.88(m,1H),3.76-3.16(m,4H),3.53-3.43(m,1H),3.14-3.10(m,4H),1.49(d,3H,J＝6.5Hz).ESI-MS m/z:472.2[M+H] ⁺ .

Example 4: preparation of (R) -N- (2- (difluoromethoxy) -4- (4,7-diazaspiro [2.5] octan-7-yl) phenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

Step 1 preparation of tert-butyl 7- (3- (difluoromethoxy) -4-nitrophenyl) -4,7-diazaspiro [2.5] octane-4-carboxylate

4-bromo-2- (difluoromethoxy) -1-nitrobenzene (100mg, 0.37mmol) and 4,7-diazaspiro [2.5]]Octane-4-carboxylic acid tert-butyl ester (87mg, 0.41mmol), 2-dicyclohexylphosphino-2' - (N, N-dimethylamine) -biphenyl (29mg, 0.075mmol), tris (dibenzylideneacetone) dipalladium (34mg, 0.037mmol), cesium carbonate (243mg, 0.74mmol), dissolved in 1,4-dioxane (10 mL). And carrying out microwave reaction for 2 hours at 100 ℃ under the protection of argon. After the reaction is finished, filtering, spin-drying the solvent in the filtrate, and purifying by column chromatography to obtain 50mg of the target compound. ESI-MS m/z of 400.2[ 2 ] M + H] ⁺ .

Step 2 preparation of tert-butyl 7- (4-amino-3- (difluoromethoxy) phenyl) -4,7-diazaspiro [2.5] octane-4-carboxylate

The reaction product of 7- (3- (difluoromethoxy) -4-nitrophenyl) -4,7-diazaspiro [2.5]]Octane-4-carboxylic acid tert-butyl ester (500mg, 1.25mmol) and Pd/C (250 mg) were dissolved in ethanol (25 mL) and stirred under hydrogen at room temperature for 12 hours. And after the reaction is finished, filtering, spin-drying the solvent in the filtrate, and purifying by column chromatography to obtain 120mg of the target compound. ESI-MS m/z:370.1[ 2 ] M + H] ⁺ .

Step 3 preparation of tert-butyl (R) -7- (3- (difluoromethoxy) -4- (9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide) phenyl) -4,7-diazaspiro [2.5] octane-4-carboxylate

Reacting 7- (4-amino-3- (difluoromethoxy) phenyl) -4,7-diazaspiro [2.5]]Octane-4-carboxylic acid tert-butyl ester (120mg, 0.32mmol) and (R) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5]Pyrrolo [1,2-a]Pyrazine-2-carboxylic acid (159mg, 0.65mmol), 2-chloro-1-methylpyridine iodide (166mg, 0.65mmol), 4-dimethylaminopyridine (40mg, 0.32mmol) were dissolved in N, N-dimethylformamide (5 mL), followed by dropwise addition of N, N' -diisopropylethylamine (126mg, 0.97mmol). The reaction solution was stirred at room temperature for 12 hours. After the reaction is finished, the solvent is removed by rotary evaporation, and the target compound of 160mg is obtained by reverse phase column chromatography purification. ESI-MS m/z:597.2[ 2 ], [ M ] +H] ⁺ .

Step 4 preparation of (R) -N- (2- (difluoromethoxy) -4- (4,7-diazaspiro [2.5] octan-7-yl) phenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

Mixing (R) -7- (3- (difluoromethoxy) -4- (9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5)]Pyrrolo [1,2-a]Pyrazine-2-carboxamido) phenyl) -4,7-diazaspiro [2.5]]Octane-4-carboxylic acid tert-butyl ester (161mg, 0.270mmol) was dissolved in dichloromethane (5 mL). A solution of hydrogen chloride in 1,4-dioxane (0.5mL, 2.0 mmol) was then added and stirred at room temperature for 2 hours. After the reaction is finished, the solvent is removed by rotary evaporation, and the target compound 105mg is obtained by reverse phase column chromatography purification. , ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.44(s,1H),9.60(s,1H),8.30-8.40(m,2H),8.30(d,1H,J＝8.9Hz),7.99(d,1H,J＝8.2Hz),7.30(d,1H,J＝56Hz),7.18(s,1H),7.04–6.93(m,2H),5.01-5.06(m,1H),3.97–3.85(m,1H),3.50-3.40(m,3H),3.40-3.34(m,4H),1.49(d,3H,J＝6.5Hz),1.13-1.08(m,2H),1.02-0.94(m,2H).ESI-MS m/z:497.1[M+H] ⁺ .

example 5: preparation of (R) -9-methyl-6-oxo-N- (2-sulfamoylphenyl) -6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

Under ice bath, (R) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5]Pyrrolo [1,2-a]1-Ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (43.0 mg, 0.224mmol) and 1-hydroxybenzotriazole (30.3 mg, 0.224mmol) were slowly added to a N, N-dimethylformamide/dichloromethane (N, N-dimethylformamide 1mL, dichloromethane 3 mL) solution of pyrazine-2-carboxylic acid (50.00mg, 0.204mmol), stirred at room temperature for 2h, after which o-aminobenzenesulfonamide (35.1mg, 0.204mmol) was added, and after the addition, the reaction mixture was stirred at room temperature overnight. After the reaction, the reaction mixture was concentrated under reduced pressure and subjected to column chromatography to obtain the title compound (39 mg). ¹ H NMR(400MHz,DMSO-d ₆ ):δ12.02(s,1H),8.69(d,1H,J＝7.1Hz),8.38(s,2H),7.99-7.90(m,2H),7.65-7.60(m,3H),7.32(s,1H),7.17(s,1H),5.17-5.12(m,1H),3.95-3.89(m,1H),3.52-3.46(m,1H),1.38(d,3H,J＝67.6Hz).ESI-MS m/z:400.1[M+H] ⁺ ；

Example 6: preparation of (R) -N- (4-cyclopropyl-2-sulfamoylphenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

Step 1 preparation of 4-cyclopropyl-2-fluoro-1-nitrobenzene

Cyclopropylboronic acid (2.55g, 29.55mmol), potassium carbonate (6.25g, 45.50mmol), tricyclohexylphosphine (1.28g, 4.55mmol) and palladium acetate (0.51g, 2.28mmol) were added to a solution of 4-bromo-2-fluoro-1-nitrobenzene (5.0 g, 22.75mmol) in toluene/water (60 mL toluene, 25mL water). After 3 times replacement of argon, the reaction was stirred at 80 ℃ overnight. After the reaction, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. ColumnChromatography gave 3.4g of the title compound. ESI-MS m/z 182.0[ 2 ] M + H] ⁺ .

Step 2 preparation of 5-cyclopropyl-2-nitrobenzenesulfonic acid

A solution of 4-cyclopropyl-2-fluoro-1-nitrobenzene (2.80g, 15.46mmol) in ethanol (30 mL) was added to a suspension of sodium sulfite (4.48g, 35.55mmol) in ethanol/water (40/50 mL). The reaction was then stirred at 90 ℃ overnight. After the reaction was completed, the system was concentrated under reduced pressure, and then hydrogen chloride dioxane solution (4N, 40mL) was added thereto and stirred at normal temperature for 2 hours. The filter cake was filtered with suction and washed with methanol, and the filtrate was concentrated under reduced pressure to give 1.5g of the title compound. ESI-MS m/z of 242.0[ M-H ]] ^- .

Step 3 preparation of 5-cyclopropyl-2-nitrobenzenesulfonamide

N, N-dimethylformamide (0.2 mL) was added to 5-cyclopropyl-2-nitrobenzenesulfonic acid (1.50g, 6.17mmol) in thionyl chloride (15 mL). The reaction was then stirred at 90 ℃ for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the concentrated solution was added to an ammonia methanol solution (7N, 50mL, 350.0mmol), and stirred at room temperature for 2 hours. After the reaction was completed, suction filtration was carried out and the filtrate was concentrated under reduced pressure to obtain 1.5g of the title compound. ESI-MS m/z of 241.0[ m-H ]] ^- .

Step 4 preparation of tert-butyl ((5-cyclopropyl-2-nitrophenyl) sulfonyl) carbamate

Triethylamine (937mg, 9.26mmol), 4-dimethylaminopyridine (75mg, 0.62mmol) and di-tert-butyl dicarbonate (1.41g, 6.48mmol) were added to a solution of 4-chloro-2-nitrobenzenesulfonamide (1.50g, 6.17mmol) in dichloromethane (20 mL). The reaction was then stirred at ambient temperature overnight. After the reaction was completed, water was added and extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded the title compound, 2.00g. ESI-MS m/z:341.1[ 2 ] M-H] ^- .

Step 5 preparation of t-butyl ((2-amino-5-cyclopropylphenyl) sulfonyl) carbamate

Sodium borohydride (221.0 mg, 5.84mmol) was added to a solution of nickel chloride (151.4 mg, 1.17mmol) and tert-butyl ((5-cyclopropyl-2-nitrophenyl) sulfonyl) carbamate (200.0 mg, 0.58mmol) in ethanol (4 mL) under an ice-water bath. The reaction was then stirred at room temperature overnight. After the reaction, the reaction mixture was filtered through celite, concentrated under reduced pressure, and then separated and purified by column chromatography to obtain the title compound (100 mg). ESI-MS m/z of 311.1[ m-H ]] ^- .

Step 6 preparation of tert-butyl (R) - ((5-cyclopropyl-2- (9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamido) phenyl) sulfonyl) carbamate

Tert-butyl ((2-amino-5-cyclopropylphenyl) sulfonyl) carbamate (55.8mg, 0.18mmol), 2-chloro-1-methylpyridinium iodide (93.6mg, 0.37mmol), N, N-diisopropylethylamine (71.1mg, 0.55mmol), and 4-dimethylaminopyridine (1.8mg, 0.02mmol) were added to (R) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5: (R)]Pyrrolo [1,2-a]Pyrazine-2-carboxylic acid (45.0mg, 0.18mmol) in N, N-dimethylformamide (1.5 mL). The reaction was then stirred at ambient temperature overnight. After the reaction, water and methylene chloride were added to extract, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the title compound was obtained in 30mg. ESI-MS m/z:540.2[ 2 ], [ M + H ]] ⁺ .

Step 7 preparation of (R) -N- (4-cyclopropyl-2-sulfamoylphenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

Hydrogen chloride dioxane solution (5mL, 4N, 20mmol) was added to (R) - ((5-cyclopropyl-2- (9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5)]Pyrrolo [1,2-a]Pyrazine-2-carboxamido) phenyl) sulfonyl) carbamic acid tert-butyl ester (97.1mg, 0.18mmol) in dichloromethane (1 mL). The reaction was then stirred at ambient temperature overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and separated and purified by column chromatography to obtain the title compound (10 mg). ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.95(s,1H),8.58(d,1H,J＝8.4Hz),8.37-8.36(m,2H),8.01(d,1H,J＝8.0Hz),7.73-7.51(m,3H),7.40(d,1H,J＝7.6Hz),7.17(s,1H),5.15(s,1H),3.94(d,1H,J＝13.6Hz),3.52(d,1H,J＝8.8Hz),2.03-2.00(m,1H),1.47(d,3H J＝5.2Hz),1.02(d,2H,J＝7.2Hz),0.07(d,2H,J＝1.2Hz).ESI-MS m/z:440.1[M+H ⁺ ] ⁺ .

Example 7: preparation of (R) -9-methyl-N- (4-morpholino-2-sulfamoylphenyl) -6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

Step 1 preparation of tert-butyl ((5-bromo-2-nitrophenyl) sulfonyl) carbamate

The preparation was carried out in the same manner as in step 2-4 of example 6 except for replacing the starting material, 4-cyclopropyl-2-fluoro-1-nitrobenzene, with 4-bromo-2-fluoro-1-nitrobenzene, to obtain the title compound. ESI-MS m/z 381.0[ 2 ] M + H] ⁺ ,383.0[M+H] ⁺

Step 2 preparation of tert-butyl ((5-morpholino-2-nitrophenyl) sulfonyl) carbamate

The compound tert-butyl ((5-bromo-2-nitrophenyl) sulfonyl) carbamate (500mg, 1.31mmol), morpholine (230mg, 2.62mmol), tris (dibenzylideneacetone) dipalladium (120mg, 0.131mmol), 2-dicyclohexylphosphino-2' - (N, N-dimethylamine) -biphenyl (100mg, 0.262mmol), cesium carbonate (850mg, 2.6mmol) was added to a mixed solvent of 1,4-dioxane (10 mL) and water (2 mL). Under the protection of argon, the temperature is raised to 100 ℃ and the reaction is stirred for 12 hours. After the reaction, the mixture was filtered through celite, and the solvent was removed under reduced pressure, followed by addition of ethyl acetate to dissolve the resulting product. The organic solution was washed twice with water, dried over anhydrous sodium sulfate, and ethyl acetate was removed under reduced pressure to obtain 500mg of the title compound. ESI-MS m/z of 386.1[ 2 ] M-H] ^- .

Step 3 preparation of tert-butyl (2-amino-5-morpholinophenyl) sulfonylcarbamate

Compound ((5-morpholino-2-nitrophenyl) sulfonyl) carbamic acid tert-butyl ester (500mg, 1.3mmol) was dissolved in ethanol (20 mL), followed by addition of nickel chloride (510mg, 3.9mmol). Then, sodium borohydride (490 mg, 13mmol) was added under ice bath, and the reaction was stirred at room temperature for 2 hours. After the reaction is finished, filtering by using diatomite, spin-drying the filtrate, and separating and purifying by using column chromatography to obtain the target compound 335mg. ESI-MS m/z:356.1[ 2 ] M-H] ^- .

Step 4 preparation of tert-butyl (R) - ((2- (9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide) -5-morpholinophenyl) sulfonyl) carbamate

The compound (2-amino-5-morpholinophenyl) sulfonylcarbamic acid tert-butyl ester (110mg, 0.3mmol), the compound (R) -9-methyl-6-oxo-67,8,9-tetrahydropyrido [3',2':4,5]Pyrrolo [1,2-a]Pyrazine-2-carboxylic acid (50mg, 0.2mmol), 2-chloro-1-methylpyridine iodide (80mg, 0.3mmol), N, N-diisopropylethylamine (62mg, 0.48mmol), and 4-dimethylaminopyridine (2.4mg, 0.02mmol) were added to anhydrous N, N-dimethylformamide (2 mL), and the reaction was stirred at room temperature for 3 hours. After the reaction, water and methylene chloride were added to extract, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give 60mg of the objective compound. ESI-MS m/z of 585.2[ 2 ] M + H] ⁺ .

Step 5 preparation of (R) -9-methyl-N- (4-morpholino-2-sulfamoylphenyl) -6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

Mixing (R) - ((2- (9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5)]Pyrrolo [1,2-a]Pyrazine-2-carboxamido) -5-morpholinophenyl) sulfonyl) carbamic acid tert-butyl ester (60mg, 0.10 mmol) dissolved in dichloromethane (5 mL). Then, hydrogen chloride dioxane (4N, 10mL, 40mmol) was added thereto, and the reaction was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was removed under reduced pressure, followed by column chromatography to give the title compound (12 mg). ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.82(s,1H),8.55(d,1H,J＝8.9Hz),8.36(s,2H),7.99(d,1H,J＝8.1Hz),7.60-7.50(m,2H),7.44(s,1H),7.29(d,1H,J＝9.0Hz),7.16(s,1H),3.99–3.87(m,1H),3.84–3.70(m,4H),3.57–3.45(m,2H),3.19–3.12(m,4H),1.47(d,3H,J＝5.5Hz).ESI-MS m/z:485.0[M+H] ⁺

Example 8: preparation of (R) -N- (4- (cyclopropylmethoxy) -2-sulfamoylphenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

Step 1 preparation of 4- (cyclopropylmethoxy) -2-fluoro-1-nitrobenzene

3-fluoro-4-nitrophenol (10.00g, 63.69mmol) was added to acetonitrile (150 mL), followed by potassium carbonate (11.00g, 79.61mmol), and bromomethylcyclopropane (, 12.89g, 95.48mmol) was added with stirring at room temperature. After the addition was complete, the reaction was stirred at 80 ℃ overnight. After the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography to give 18g of the title compound. ESI-MS m/z 212.2[ 2 ] M + H] ⁺ .

Step 2 preparation of 5- (cyclopropylmethoxy) -2-nitrobenzenesulfonic acid

Sodium sulfite (17.86g, 141.60mmol) was added to ethanol/water (160/200 mL), a solution of 4- (cyclopropylmethoxy) -2-fluoro-1-nitrobenzene (13.00g, 61.50mmol) in ethanol (40 mL) was added with stirring at room temperature, and after the addition was complete, the reaction was stirred at 70 ℃ overnight. After the reaction was completed, the reaction solution was adjusted to pH 2 with aqueous hydrochloric acid (2N), and the solvent was removed under reduced pressure. To the resulting crude product was added a saturated sodium chloride solution (40 mL), and the mixture was heated and stirred at 100 ℃ for 2 hours. After cooling to room temperature, methanol (200 mL) was added while cooling on ice. After the reaction mixture was suction-filtered, the organic solvent was removed from the filtrate by distillation under the reduced pressure to obtain 16.10g of the title compound. ESI-MS m/z of 272.0[ m-H ]] ^- .

Step 3 preparation of 5- (cyclopropylmethoxy) -2-nitrobenzenesulfonamide

To a solution of 5- (cyclopropylmethoxy) -2-nitrobenzenesulfonic acid (5.20g, 19.0mmol) in thionyl chloride (40 mL) was added N, N-dimethylformamide (0.5 mL) with stirring at room temperature, and after the addition was completed, the reaction system was stirred at 70 ℃ for 1 hour. Reaction(s) ofAfter the reaction is finished, the mixture is concentrated under reduced pressure, water and dichloromethane are added into the reaction system for extraction, the organic phase is washed by saturated sodium bicarbonate for 1 time, and the organic phase is washed by saturated sodium chloride solution for 1 time, dried by anhydrous sodium sulfate, filtered by suction and concentrated under reduced pressure. Methanol (20 mL) was then added, and NH was added slowly ₃ (35 mL) methanol solution. After the addition was complete, the reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain 4.20g of the title compound. ESI-MS m/z of 271.0[ M-H ]] ^- .

Step 4 preparation of t-butyl ((5- (cyclopropylmethoxy) -2-nitrophenyl) sulfonyl) carbamate

To a solution of 5- (cyclopropylmethoxy) -2-nitrobenzenesulfonamide (250.00mg, 0.92mmol) in dichloromethane (8 mL) was slowly added 4-dimethylaminopyridine (11.23mg, 0.092mmol) and triethylamine (139.50mg, 1.38mmol) with stirring at room temperature. Di-tert-butyl dicarbonate (220.60mg, 1.01mmol) was then added, and after the addition was complete, the reaction was stirred at room temperature for 3 hours. After the reaction, the reaction system was washed with water 2 times, with saturated sodium chloride solution 1 time, and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound 320mg. ESI-MS m/z of 371.1[ m-H ]] ^- .

Step 5 preparation of tert-butyl ((2-amino-5- (cyclopropylmethoxy) phenyl) sulfonyl) carbamate

To a solution of tert-butyl ((5- (cyclopropylmethoxy) -2-nitrophenyl) sulfonyl) carbamate (400.00mg, 1.10 mmol) in ethanol (12 mL) was slowly added nickel chloride (417.90mg, 3.20 mmol) with stirring at room temperature. After cooling in an ice bath, sodium borohydride (406.60mg, 10.7mmol) was added to the reaction in 3 portions. After the addition was complete, the reaction was stirred at room temperature for 2 hours. After the reaction, suction filtration was carried out, and the filtrate was concentrated under reduced pressure and subjected to reverse phase column chromatography to give 80mg of the title compound. ES (ES)I-MS m/z:341.1[M-H] ^- .

Step 6 preparation of tert-butyl (R) - ((5- (cyclopropylmethoxy) -2- (9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamido) phenyl) sulfonyl) carbamate

The preparation was carried out in the same manner as in step 6 of example 6 except for replacing the starting material tert-butyl ((2-amino-5-cyclopropylphenyl) sulfonyl) carbamate with tert-butyl ((2-amino-5- (cyclopropylmethoxy) phenyl) sulfonyl) carbamate to obtain the title compound. ESI-MS m/z of 568.3[ M-H ]] ^- .

Step 7 preparation of (R) -N- (4- (cyclopropylmethoxy) -2-sulfamoylphenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The preparation method is the same as that of step 7 of example 6, except that the starting material (R) - ((5-cyclopropyl-2- (9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5)]Pyrrolo [1,2-a]Pyrazine-2-carboxamido) phenyl) sulfonyl) carbamic acid tert-butyl ester with (R) - ((5- (cyclopropylmethoxy) -2- (9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5)]Pyrrolo [1,2-a]Pyrazine-2-carboxamide) phenyl) sulfonyl) carbamic acid tert-butyl ester to afford the title compound. ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.83(s,1H),8.58(d,1H,J＝9.1Hz),8.36(d,2H,J＝8.2Hz),7.99(d,1H,J＝8.2Hz),7.66(s,2H),7.44(s,1H),7.27(d,1H,J＝9.1Hz),7.16(s,1H),5.14(m,1H),3.91(m,3H),3.51(m,1H,J＝8.4Hz),1.46(d,3H,J＝6.5Hz),1.25(m,1H),0.60(m,2H),0.36(m,2H).ESI-MS m/z:470.1[M+H] ⁺ .

Example 9 preparation of (R) -N- (2- (difluoromethoxy) phenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The title compound was obtained in the same manner as in example 1 except that 5-bromo-2-nitrophenol was replaced with 2-nitrophenol. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.65(s,1H),8.52(d,1H,J＝7.7Hz),8.40(d,1H,J＝8.2Hz),8.39(s,1H),8.02(d,1H,J＝8.2Hz),7.36(t,1H,J＝54Hz,),7.30-7.35(m,2H),7.27-7.15(m,2H),5.07-5.0(m,1H),3.98-3.87(m,1H),3.54-3.42(m,1H),1.50(d,3H,J＝6.5Hz).ESI-MS m/z:387.0[M+H] ⁺ .

Example 10 preparation of (R) -N- (2- (difluoromethoxy) -4- (tetrahydro-2H-pyran-4-yl) phenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

Preparation method the title compound was prepared in the same manner as in example 2 except that the starting material cyclopropylboronic acid in step 1 was replaced with 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.58(s,1H),8.48-8.31(m,3H),8.01(d,1H,J＝8.1Hz),7.38(t,1H,J＝72Hz),7.26(d,2H,J＝7.1Hz),7.18(s,1H),5.06(s,1H),3.97-3.90(m,2H),3.58-3.38(m,4H),2.85-2.76(m,1H),1.79-1.63(m,4H),1.49(d,3H,J＝6.3Hz).ESI-MS m/z:469.1[M-H] ^-

Example 11 preparation of (R) -N- (4- (1-acetylpiperidin-4-yl) -2- (difluoromethoxy) phenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The preparation method was the same as that of example 2, except that the starting material cyclopropylboronic acid in step 1 was replaced with 1-acetylboronic acidbase-5,6-dihydro-2H-pyridine-4-boronic acid pinacol ester to give the title compound. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.58(s,1H),8.46-8.31(m,3H),8.01(d,1H,J＝8.2Hz),7.37(t,1H,J＝76Hz),7.25(d,2H,J＝13.1Hz),7.18(s,1H),5.05(s,1H),4.63-4.49(m,1H),4.01-3.87(m,2H),3.57-3.44(m,1H),3.20-3.08(m,1H),2.85-2.75(m,1H),2.65-2.54(m,1H),2.04(s,3H),1.88-1.75(m,2H),1.67-1.56(m,1H),1.49(d,3H,J＝6.4Hz),1.46-1.40(m,1H).ESI-MS m/z:512.2[M+H] ⁺

Example 12 preparation of (R) -N- (2- (difluoromethoxy) -4- (1-methyl-1H-pyrazol-4-yl) phenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The procedure was as in example 2 except for replacing cyclopropylboronic acid, which is the starting material in step 1, with 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole to give the title compound. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.62(s,1H),8.48(d,1H,J＝8.3Hz),8.39(d,2H,J＝7.2Hz),8.19(s,1H),8.02(d,1H,J＝8.1Hz),7.91(s,1H),7.55(d,2H,J＝9.4Hz),7.42(t,1H,J＝76Hz),7.19(s,1H),5.13-5.01(m,1H),4.01-3.91(m,1H),3.88(s,3H),3.55-3.48(m,1H),1.51(d,3H,J＝6.3Hz).ESI-MS m/z:467.2[M+H] ⁺

EXAMPLE 13 preparation of (R) -N- (2- (difluoromethoxy) -4- (1,3,5-trimethyl-1H-pyrazol-4-yl) phenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The procedure was as in example 2 except for substituting 1,3,5-trimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) -1H-pyrazole for the starting cyclopropylboronic acid in step 1 to give the title compound. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.65(s,1H),8.54(d,1H,J＝8.3Hz),8.40(d,2H,J＝8.0Hz),8.03(d,1H,J＝8.2Hz),7.41(t,1H,J＝76Hz),7.35-7.16(m,3H),5.17-4.99(m,1H),4.01-3.89(m,1H),3.72(s,3H),3.55-3.47(m,1H),2.30(d,3H,J＝25.9Hz),2.17(s,3H),1.51(d,3H,J＝6.4Hz).ESI-MS m/z:495.2[M+H] ⁺

EXAMPLE 14 preparation of (R) -N- (2- (difluoromethoxy) -4- (3,5-dimethylisoxazol-4-yl) phenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

Preparation method the title compound was prepared in the same manner as in example 2 except that the starting material cyclopropylboronic acid in step 1 was replaced with 3,5-dimethylisoxazole-4-boronic acid pinacol ester. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.71(s,1H),8.61(d,1H,J＝8.8Hz),8.41(d,2H,J＝8.2Hz),8.04(d,1H,J＝8.2Hz),7.44(t,1H,J＝72Hz),7.40(s,2H),7.20(s,1H),5.11-5.03(m,1H),3.99-3.89(m,1H),3.54-3.46(m,1H),2.45(s,3H),2.28(s,3H),1.51(d,3H,J＝6.4Hz).ESI-MS m/z:482.2[M+H] ⁺

Example 15 preparation of (R) -N- (2- (difluoromethoxy) -4- (1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) phenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The procedure was as in example 2 except for substituting the starting material cyclopropylboronic acid in step 1 with N, N-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole-1-ethylamine to give the title compound. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.63(s,1H),8.50(d,1H,J＝8.9Hz),8.40(d,2H,J＝8.1Hz),8.29(s,1H),8.05-7.99(m,2H),7.59(t,2H,J＝7.6Hz),7.42(t,1H,J＝84Hz),7.19(s,1H),5.11-5.04(m,1H),4.39(s,2H),3.96-3.91(m,1H),3.51-3.49(m,1H),3.32-3.31(m,6H),3.15(s,2H),1.50(d,3H,J＝6.5Hz).ESI-MS m/z:524.2[M+H] ⁺

Example 16: preparation of (R) -N- (2- (difluoromethoxy) -4- (1- (3- (dimethylamino) propyl) -1H-pyrazol-4-yl) phenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4.5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The procedure was as in example 2 except for substituting the starting cyclopropylboronic acid in step 1 with N, N-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole-1-propylamine to give the title compound. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.62(s,1H),8.48(d,1H,J＝8.2Hz),8.40(d,2H,J＝8.1Hz),8.24(s,1H),8.17(s,1H),8.02(d,1H,J＝8.2Hz),7.93(s,1H),7.58(s,1H),7.42(t,1H,J＝56Hz),7.19(s,1H),5.13-4.97(m,1H),4.16(t,2H,J＝6.8Hz),3.98-3.89(m,1H),3.54-3.45(m,1H),2.35-2.25(m,2H),2.21(s,6H),2.00-1.92(m,2H),1.50(d,3H,J＝6.5Hz).ESI-MS m/z:538.2[M+H] ⁺

Example 17: preparation of (R) -N- (2- (difluoromethoxy) -6- (tetrahydro-2H-pyran-4-yl) pyridin-3-yl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The procedure is as in example 2 except that the starting materials 4-bromo-2- (difluoromethoxy) -1-nitrobenzene and cyclopropylboronic acid are replaced with 6-chloro-2- (difluoromethoxy) -3-nitropyridine 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester to give the title compound. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.42(s,1H),8.65(d,1H,J＝8.1Hz),8.39(d,2H,J＝8.0Hz),8.00(d,1H,J＝8.1Hz),7.81(t,1H,J＝80Hz),7.26(d,1H,J＝8.1Hz),7.19(s,1H),5.12-4.97(m,1H),4.01-3.92(m,2H),3.92-3.85(m,1H),3.57-3.38(m,3H),2.97-2.81(m,1H),1.86-1.67(m,4H),1.54(d,3H,J＝6.4Hz).ESI-MS m/z:472.2[M+H] ⁺

Example 18: preparation of (R) -N- (2- (difluoromethoxy) -4- (1- (3- (dimethylamino) propyl) -1H-pyrazol-4-yl) -5-fluorophenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The procedure is as for preparation of example 2 except that the starting materials 4-bromo-2- (difluoromethoxy) -1-nitrobenzene and cyclopropylboronic acid in step 1 are replaced with 1-bromo-5- (difluoromethoxy) -2-fluoro-4-nitrobenzene and N, N-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole-1-propylamine to give the title compound. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.68(s,1H),8.41(d,3H,J＝8.8Hz),8.22(s,1H),8.03(d,1H,J＝8.1Hz),7.96(s,1H),7.75(d,1H,J＝6.8Hz),7.40(t,1H,J＝72Hz),7.20(s,1H),5.10-5.02(m,1H),4.19(t,2H,J＝6.7Hz),3.97-3.91(m,1H),3.51-3.48(m,1H),2.26(d,2H,J＝6.8Hz),2.19(s,6H),2.00-1.93(m,2H),1.50(d,3H,J＝6.5Hz).ESI-MS m/z:556.2[M+H] ⁺

Example 19: preparation of (R) -N- (2- (difluoromethoxy) -4- (4-methylpiperazin-1-yl) phenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The title compound was obtained by the same procedure as in example 3, except that the starting material morpholine in step 1 was replaced with N-methylpiperazine. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.42(s,1H),8.37(d,2H,J＝7.9Hz),8.27(d,1H,J＝9.6Hz),7.99(d,1H,J＝8.2Hz),7.34(t,1H,J＝76Hz),7.16(d,1H,J＝7.5Hz),6.93(s,2H),5.15-5.05(m,1H),3.96-3.89(m,1H),3.52-3.47(m,1H),3.24-3.15(m,4H),2.61-2.54(m,4H),2.32(s,3H),1.49(d,3H,J＝6.4Hz).ESI-MS m/z:485.2[M+H] ⁺

Example 20 preparation of (R) -N- (2- (difluoromethoxy) -4- ((S) -2,4-dimethylpiperazin-1-yl) phenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The title compound was obtained by the same procedure as in example 3 except for substituting morpholine as the starting material in step 1 with 3- (S) -1,3-dimethylpiperazine. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.41(s,1H),8.37(d,2H,J＝8.1Hz),8.27(d,1H,J＝8.7Hz),7.99(d,1H,J＝8.2Hz),7.33(t,1H,J＝78Hz),7.17(s,1H),6.89(d,2H,J＝9.6Hz),5.11-5.01(m,1H),4.03(s,1H),3.97-3.88(m,1H),3.52-3.46(m,1H),3.40(m,1H),3.16(s,1H),3.01(m,2H),2.86(m,2H),2.35(s,3H),1.48(d,3H,J＝6.5Hz),1.05(d,3H,J＝6.4Hz).ESI-MS m/z:499.2[M+H] ⁺

Example 21 preparation of (R) -N- (2- (difluoromethoxy) -4- ((R) -2,4-dimethylpiperazin-1-yl) phenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The title compound was prepared according to the same procedure as in example 3 except that the starting material morpholine in step 1 was replaced with (R) -1,3-dimethylpiperazine dihydrochloride. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.40(s,1H),8.37(d,2H,J＝7.8Hz),8.25(d,1H,J＝8.7Hz),7.99(d,1H,J＝8.1Hz),7.33(t,1H,J＝78Hz),7.17(s,1H),6.88(d,2H,J＝8.4Hz),5.11-5.00(m,1H),4.02(s,1H),3.97-3.89(m,1H),3.51-3.45(m,1H),3.10-2.94(m,2H),2.87(s,1H),2.71(d,1H,J＝23.4Hz),2.28(s,3H),2.06-1.91(m,2H),1.48(d,3H,J＝6.5Hz),1.05(d,3H,J＝6.4Hz).ESI-MS m/z:499.2[M+H] ⁺

Example 22 preparation of (R) -N- (2- (difluoromethoxy) -4- (4,4-difluoropiperidin-1-yl) phenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The title compound was obtained by the same procedure as in example 3 except that the starting material morpholine in step 1 was replaced with 4,4-difluoropiperidine. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.43(s,1H),8.37(d,2H,J＝7.8Hz),8.28(d,1H,J＝8.7Hz),7.99(d,1H,J＝8.2Hz),7.35(t,1H,J＝78Hz),7.17(s,1H),7.00(d,2H,J＝8.2Hz),5.11-5.01(m,1H),3.98-3.88(m,1H),3.52-3.45(m,1H),3.37(s,4H),2.07(t,4H,J＝13.5Hz),1.49(d,3H,J＝6.4Hz).ESI-MS m/z:506.2[M+H] ⁺ .

Example 23 preparation of (R) -N- (2- (difluoromethoxy) -4- (4- (2-hydroxyethyl) piperazin-1-yl) phenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The title compound was obtained by the same procedure as in example 3, except that the starting material morpholine in step 1 was replaced with N-hydroxyethylpiperazine. ¹ H NMR(400MHz,MeOD):δ8.36(m,3H),8.06(d,1H J＝7.5Hz),7.27(s,1H),7.00(t,1H,J＝72Hz),6.96(d,2H,J＝12.2Hz),6.81(s,1H),5.23-5.18(m,1H),4.05-3.99(m,1H),3.86-3.79(m,2H),3.63-3.56(m,2H),3.39-3.34(m,4H),3.14-3.07(m,4H),2.99-2.94(m,2H),1.57(d,3H J＝5.1Hz).ESI-MS m/z:515.3[M+H] ⁺

Example 24 preparation of (R) -N- (2- (difluoromethoxy) -4- (4- (2- (dimethylamino) ethyl) piperazin-1-yl) phenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The title compound was obtained by the same procedure as in example 3, except that the starting material morpholine in step 1 was replaced with N, N-dimethyl-2- (piperazin-1-yl) eth-1-amine. ¹ H NMR(400MHz,MeOD):δ8.53(s,1H),8.38-8.30(m,2H),8.06(d,1H,J＝8.2Hz),7.27(s,1H),6.98(t,1H,J＝78Hz),6.96-6.85(m,2H),5.23-5.17(m,1H),4.06-3.99(m,1H),3.62-3.57(m,1H),3.26(s,8H),3.07(s,2H),2.73(s,8H),1.57(d,3H,J＝6.6Hz).ESI-MS m/z:542.3[M+H] ⁺ .

Example 25 preparation of (R) -N- (2- (difluoromethoxy) -4- (4- (dimethylamino) piperidin-1-yl) phenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The title compound was obtained by the same procedure as in example 3, except that the starting material morpholine in step 1 was replaced with 4-dimethylaminopiperidine. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.42(s,1H),9.39(s,1H),8.37(d,2H,J＝7.6Hz),8.27(d,1H,J＝9.7Hz),7.99(d,1H,J＝8.2Hz),7.34(t,1H,J＝72Hz),7.18(s,1H),6.96(s,2H),5.11-5.01(m,1H),3.97-3.81(m,3H),3.52-3.43(m,1H),2.92-2.61(m,8H),2.11-2.01(m,2H),1.74-1.60(m,2H),1.49(d,3H,J＝6.5Hz).ESI-MS m/z:513.3[M+H] ⁺ .

Example 26: preparation of (R) -N- (2- (difluoromethoxy) -4- (4-hydroxy-4- (trifluoromethyl) piperidin-1-yl) phenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The preparation was carried out in the same manner as in example 3 except that morpholine as the starting material in step 1 was replaced with 4- (trifluoromethyl) piperidin-4-ol to obtain the title compound. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.42(s,1H),8.37(d,2H,J＝7.9Hz),8.26(d,1H,J＝9.6Hz),7.99(d,1H,J＝8.2Hz),7.35(t,1H,J＝78Hz),7.17(s,1H),6.96(s,2H),6.02(s,1H),5.11-5.01(m,1H),3.97-3.89(m,1H),3.67(d,2H,J＝12.5Hz),3.52-3.46(m,1H),2.99(t,2H,J＝11.2Hz),1.87-1.68(m,4H),1.49(d,3H,J＝6.4Hz).ESI-MS m/z:554.2[M+H] ⁺ .

Example 27: preparation of (R) -N- (4- (4-acetylpiperazin-1-yl) -2- (difluoromethoxy) phenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The preparation was carried out in the same manner as in example 3 except that morpholine as the starting material in step 1 was replaced with 1-acetylpiperazine to give the title compound. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.43(s,1H),8.37(d,2H,J＝8.2Hz),8.29(d,1H,J＝9.2Hz),7.99(d,1H,J＝8.2Hz),7.34(t,1H,J＝72Hz),7.17(s,1H),6.95(d,2H,J＝7.7Hz),5.06(m,1H),3.98-3.85(m,1H),3.64-3.55(m,4H),3.53-3.44(m,1H),3.20-3.14(m,4H),2.05(s,3H),1.49(d,3H,J＝6.5Hz).ESI-MS m/z:513.2[M+H] ⁺ .

Example 28: preparation of (R) -N- (2- (difluoromethoxy) -4- (4-hydroxy-4-methylpiperidin-1-yl) phenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The title compound was obtained by the same procedure as in example 3, except that the starting material morpholine in step 1 was replaced with 4-methyl-4-hydroxypiperidine. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.39(s,1H),8.36(d,2H,J＝7.9Hz),8.23(d,1H,J＝8.6Hz),7.98(d,1H,J＝8.2Hz),7.33(t,1H,J＝76Hz),7.17(s,1H),6.91(d,2H,J＝8.8Hz),5.06(s,1H),4.33(s,1H),3.97-3.88(m,1H),3.53-3.44(m,1H),3.38-3.34(m,2H),3.20-3.09(m,2H),1.63-1.53(m,4H),1.49(d,3H,J＝6.5Hz),1.16(s,3H).ESI-MS m/z:500.2[M+H] ⁺ .

Example 29: (R) -N- (2- (difluoromethoxy) -4- (4-methoxypiperidin-1-yl) phenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyridos

Preparation of [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The title compound was obtained by the same procedure as in example 3, except that the starting material morpholine in step 1 was replaced with 4-methoxypiperidine. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.40(s,1H),8.36(d,2H,J＝6.9Hz),8.24(d,1H,J＝9.0Hz),7.98(d,1H,J＝8.2Hz),7.33(t,1H,J＝72Hz),7.17(s,1H),6.98-6.88(m,2H),5.11-5.00(m,1H),3.98-3.87(m,1H),3.52-3.46(m,3H),3.28(s,3H),3.00-2.87(m,3H),2.00-1.89(m,2H),1.59-1.51(m,2H),1.48(d,3H,J＝6.1Hz).ESI-MS m/z:500.2[M+H] ⁺ .

Example 30: preparation of (R) -N- (4- (4- (2,2-difluoroethyl) piperazin-1-yl) -2- (difluoromethoxy) phenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The procedure was as in example 3 except for substituting 1- (2,2-difluoroethyl) piperazine for the starting material morpholine in step 1 to give the title compound. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.41(s,1H),8.36(d,2H,J＝8.2Hz),8.27(d,1H,J＝9.3Hz),7.99(d,1H,J＝8.2Hz),7.34(t,1H,J＝78Hz),7.17(d,1H,J＝6.3Hz),6.92(d,2H,J＝7.0Hz),6.10-6.40(m,1H),5.12-5.02(m,1H),3.97-3.87(m,1H),3.51-3.47(m,1H),3.18(s,4H),2.84-2.79(m,2H),2.71(d,4H,J＝18.4Hz),1.49(d,3H,J＝6.4Hz).ESI-MS m/z:535.3[M+H] ⁺ .

Example 31: preparation of (R) -N- (2- (difluoromethoxy) -4- ((S) -3-methylpiperazin-1-yl) phenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The preparation method is the same as that of example 4, except that the raw material 4,7-diazaspiro [2.5] in step 1 is used]Tert-butyl octane-4-carboxylate was replaced with tert-butyl (S) -2-methylpiperazine-1-carboxylate to give the title compound. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.43(s,1H),8.37(d,2H,J＝7.9Hz),8.29(d,1H,J＝8.7Hz),7.99(d,1H,J＝8.1Hz),7.34(t,1H,J＝76Hz),7.18(s,1H),6.98(s,1H),6.95(s,1H),5.06(s,1H),3.97-3.88(m,1H),3.74-3.64(m,2H),3.54-3.45(m,2H),3.26-3.23(m,1H),3.18-3.13(m,1H),3.04-2.96(m,1H),2.89-2.80(m,1H),2.62-2.54(m,1H),1.49(d,3H,J＝6.4Hz),1.21(d,3H,J＝6.1Hz).ESI-MS m/z:485.3[M+H] ⁺ .

Example 32: preparation of (R) -N- (2- (difluoromethoxy) -4- ((R) -3-methylpiperazin-1-yl) phenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The preparation method is the same as that of example 4, except that the raw material 4,7-diazaspiro [2.5] in step 1 is used]Tert-butyl octane-4-carboxylate was replaced with tert-butyl (R) -2-methylpiperazine-1-carboxylate to give the title compound. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.41(s,1H),8.37(d,2H,J＝8.2Hz),8.27(d,1H,J＝9.4Hz),7.99(d,1H,J＝8.2Hz),7.33(t,1H,J＝76Hz),7.17(s,1H),6.92(s,2H),5.08-5.05(m,1H),3.96-3.89(m,1H),3.62-3.57(m,2H),3.50-3.47(m,1H),3.09-3.05(m,1H),2.93-2.85(m,2H),2.68--2.62(m,1H),2.36-2.31(m,1H),1.48(d,3H,J＝6.4Hz),1.29-1.20(m,1H),1.09(d,3H,J＝6.0Hz).ESI-MS m/z:485.2[M+H] ⁺ .

Example 33: preparation of (R) -N- (4-chloro-2-sulfamoylphenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

Preparation method the same as in example 5 was conducted, except that the starting material o-aminobenzenesulfonamide was replaced with 2-amino-5-chlorobenzenesulfonamide, to obtain the title compound. ¹ H NMR(400MHz,DMSO-d ₆ ):δ12.03(s,1H),8.74(d,1H,J＝6.6Hz),8.38(s,2H),8.03-7.81(m,5H),7.18(s,1H),5.25-5.05(m,1H),4.02-3.87(m,1H),3.57-3.49(m,1H),1.39(d,3H,J＝6.6Hz).ESI-MS m/z:434.1[M+H] ⁺

Example 34: preparation of (R) -9-methyl-6-oxo-N- (2-sulfamoyl-5- (trifluoromethyl) phenyl) -6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

Preparation method the same as in example 5 was conducted, except that the o-aminobenzenesulfonamide as a starting material was replaced with 2-amino-4- (trifluoromethyl) benzenesulfonamide, to obtain the title compound. ¹ H NMR(400MHz,DMSO-d ₆ ):δ12.19(s,1H),9.11(s,1H),8.41-8.39(m,2H),8.14(d,1H,J＝8.3Hz),8.03(d,1H,J＝8.2Hz),7.92(s,2H),7.72(d,1H,J＝8.2Hz),7.19(s,1H),5.17-5.15(m,1H),3.95-3.89(m,1H),3.55-3.51(m,1H),1.48(d,3H,J＝6.5Hz).ESI-MS m/z:468.1[M+H] ⁺

Example 35: preparation of (R) -9-methyl-N- (4-methyl-2-sulfamoylphenyl) -6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The title compound was obtained by the same procedure as in example 5 except that the starting o-aminobenzenesulfonamide was replaced with 2-amino-5-methylbenzenesulfonamide. ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.94(s,1H),8.58(d,1H,J＝8.4Hz),8.42-8.29(m,2H),8.00(d,1H,J＝8.2Hz),7.74(s,1H),7.59(s,2H),7.49(d,1H,J＝8.4Hz),7.17(s,1H),5.16-5.14(m,1H),3.95-3.90(m,1H),3.53-3.49(m,1H),2.35(s,3H),1.47(d,3H,J＝6.5Hz).ESI-MS m/z:414.1[M+H] ⁺

Example 36: preparation of (R) -N- (4-fluoro-2-sulfamoylphenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The title compound was obtained by the same procedure as in example 5 except that the starting o-aminobenzenesulfonamide was replaced with 2-amino-5-methylbenzenesulfonamide. ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.93(s,1H),8.73-8.69(m,1H),8.37(d,2H,J＝7.9Hz),8.01(d,1H,J＝8.1Hz),7.69(m,3H),7.59(d,1H,J＝8.4Hz),7.17(s,1H),5.16-5.14(m,1H),3.95-3.90(m,1H),3.53-3.49(m,1H),1.47(d,3H,J＝6.4Hz).ESI-MS m/z:418.1[M+H] ⁺

Example 37: preparation of (R) -N- (4,5-difluoro-2-sulfamoylphenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The procedure was as in example 5 except for substituting the starting material o-aminobenzenesulfonamide with 2-amino-4,5-difluorobenzenesulfonamide to give the title compound. ¹ H NMR(400MHz,CD ₃ OD-d ₆ ):δ8.79-8.69(m,1H),8.39(d,2H,J＝7.5Hz),8.02(d,1H,J＝8.2Hz),7.98-7.89(m,1H),7.19(s,1H),5.15(s,1H),3.97-3.89(m,1H),3.52(d,1H,J＝8.3Hz),1.47(d,3H,J＝6.4Hz).ESI-MS m/z:434.1[M-H] ^-

Example 38: preparation of (R) -N- (5-chloro-4-methyl-2-sulfamoylphenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The title compound was obtained by the same procedure as in example 5 except for substituting the starting anthranilamide with 2-amino-4-chloro-5-methylbenzenesulfonamide. ¹ H NMR(400MHz,DMSO-d ₆ ):δ12.03(s,1H),8.80(s,1H),8.38(d,J＝7.2Hz,2H),8.01(d,J＝8.2Hz,1H),7.89(s,1H),7.68(s,2H),7.18(s,1H),5.15(m,1H),3.93(m,J＝9.2Hz,1H),3.50(m,1H),2.40(s,3H),1.47(d,J＝6.2Hz,3H).ESI-MS m/z:446.1[M-H] ^- .

Example 39: preparation of (R) -9-methyl-N- (5-methyl-2-sulfamoylphenyl) -6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

Preparation method the same as in example 5 was conducted, except that the starting o-aminobenzenesulfonamide was replaced with 2-amino-4-methylbenzenesulfonamide, to prepare the title compound. ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.98(s,1H),8.54(s,1H),8.37(d,2H,J＝8.0Hz),8.01(d,1H,J＝8.2Hz),7.80(d,1H,J＝8.2Hz),7.56(s,2H),7.19-7.10(m,2H),5.16-5.14(m,1H),3.95-3.90(m,1H),2.42(s,3H),3.53-3.49(m,1H),1.46(d,3H,J＝6.4Hz).ESI-MS m/z:414.1[M+H] ⁺

Example 40: preparation of (R) -N- (5-chloro-2-sulfamoylphenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

Preparation method the same as in example 5 was conducted, except that the starting material o-aminobenzenesulfonamide was replaced with 2-amino-4-chlorobenzenesulfonamide, to obtain the title compound. ¹ H NMR(400MHz,DMSO-d ₆ ):δ12.11(s,1H),8.80(s,1H),8.40(d,2H,J＝7.2Hz),8.03(d,1H,J＝8.0Hz),7.94(d,1H,J＝8.0Hz),7.77(s,2H),7.43-7.41(m,1H),7.18(s,1H),5.20-5.11(m,1H),3.95-3.90(m,1H),3.54-3.50(m,1H),1.47(d,3H,J＝6.4Hz).ESI-MS m/z:434.1[M+H] ⁺

Example 41: preparation of (R) -9-methyl-6-oxo-N- (2-sulfamoylpyridin-3-yl) -6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The title compound was obtained by the same procedure as in example 5 except that the starting o-aminobenzenesulfonamide was replaced with 3-aminopyridine-2-sulfonamide. ¹ H NMR(400MHz,DMSO-d ₆ ):δ12.20(s,1H),9.16(d,1H,J＝8.3Hz),8.45(s,1H),8.39(d,2H,J＝7.6Hz),8.02(d,1H,J＝8.1Hz),7.89(s,2H),7.78-7.68(m,1H),7.19(s,1H),5.17-5.74(m,1H),3.96-3.93(m,1H),3.55-3.51(m,1H),1.48(d,3H,J＝6.2Hz).ESI-MS m/z:401.1[M+H] ⁺

Example 42: preparation of (R) -N- (5-fluoro-2-sulfamoylphenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The title compound was obtained by the same procedure as in example 5 except that the starting o-aminobenzenesulfonamide was replaced with 2-amino-4-fluorobenzenesulfonamide. ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.93(s,1H),8.73-8.69(m,1H),8.37(d,2H,J＝8.0Hz),8.01(d,1H,J＝8.0Hz),7.79(s,2H),7.73-7.66(m,1H),7.63-7.55(m,1H),7.17(s,1H),5.20-5.11(m,1H),3.95-3.90(m,1H),3.54-3.50(m,1H),1.47(d,3H,J＝6.4Hz).ESI-MS m/z:416.1[M+H] ⁺

Example 43: preparation of (R) -N- (4-methoxy-2-sulfamoylphenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

Preparation method the title compound was obtained in the same manner as in example 5 except that the starting o-aminobenzenesulfonamide was replaced with 2-amino-5-methoxybenzenesulfonamide. ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.82(s,1H),8.59(d,1H,J＝9.0Hz),8.36(d,2H,J＝6.4Hz),8.00(d,1H,J＝8.1Hz),7.67(s,2H),7.45(s,1H),7.28(d,1H,J＝7.5Hz),7.16(s,1H),5.20-5.11(m,1H),3.95-3.90(m,1H),3.83(s,3H),3.54-3.50(m,1H),1.47(d,3H,J＝6.4Hz).ESI-MS m/z:430.1[M+H] ⁺

Example 44: preparation of (R) -N- (5-cyclopropyl-2-sulfamoylphenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The title compound was obtained by the same procedure as in example 6 except for substituting 4-bromo-2-fluoro-1-nitrobenzene as the starting material with 5-bromo-2-fluoro-1-nitrobenzene. ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.98(s,1H),8.44(s,1H),8.37(d,2H,J＝7.1Hz),8.01(d,1H,J＝8.1Hz),7.78(d,1H,J＝8.0Hz),7.53(s,2H),7.17(s,1H),7.01(d,1H,J＝8.4Hz),5.21-5.07(m,1H),3.94-3.91(m,1H),3.54-3.51(m,1H),2.10-1.98(m,1H),1.46(d,3H,J＝6.1Hz),1.13-1.00(m,2H),0.82-0.70(m,2H).ESI-MS m/z:438.1[M-H] ^-

Example 45: preparation of (R) -9-methyl-6-oxo-N- (2-sulfamoyl-4- (tetrahydro-2H-pyran-4-yl) phenyl) -6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The preparation method is the same as that of example 6, except thatThe title compound was prepared by replacing the starting cyclopropylboronic acid with 2- (3,6-dihydro-2H-pyran-4-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborane. ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.97(s,1H),8.62(d,1H,J＝8.5Hz),8.37(d,2H,J＝7.4Hz),8.01(d,1H,J＝8.2Hz),7.81(s,1H),7.64(s,2H),7.59(d,1H,J＝8.5Hz),7.17(s,1H),5.21-5.08(m,1H),4.07-3.85(m,3H),3.56-3.43(m,3H),2.93-2.79(m,1H),1.86-1.59(m,4H),1.47(d,3H,J＝6.3Hz).ESI-MS m/z:482.2[M-H] ^-

Example 46: preparation of (R) -N- (4- (4,4-difluorocyclohexyl) -2-sulfamoylphenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The title compound was obtained by the same procedure as in example 6 except that the starting cyclopropylboronic acid was replaced with 4,4-difluorocyclohex-1-enylboronic acid pinacol ester. ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.99(s,1H),8.62(d,1H,J＝8.4Hz),8.37(d,2H,J＝6.9Hz),8.01(d,1H,J＝8.1Hz),7.82(s,1H),7.72-7.50(m,3H),7.17(s,1H),5.18-5.14(m,1H),3.94-3.92(m,1H),3.50-3.45(m,1H),2.81(t,1H,J＝6.9Hz),2.07(m,3H),2.03-1.87(m,3H),1.71(m,2H),1.48(d,3H,J＝5.9Hz).ESI-MS m/z:516.2[M-H] ^-

Example 47: preparation of (R) -N- (4-cyclopentyl-2-sulfamoylphenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The procedure was as in example 6 except for substituting the starting cyclopropylboronic acid with 2- (cyclopent-1-en-1-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborane to give the title compound. ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.96(s,1H),8.59(d,1H,J＝8.5Hz),8.36(d,2H,J＝7.8Hz),8.00(d,1H,J＝8.2Hz),7.79(s,1H),7.61(s,2H),7.56(d,1H,J＝8.3Hz),7.16(s,1H),5.15(s,1H),3.99-3.86(m,1H),3.57-3.45(m,1H),3.10-2.98(m,1H),2.13-2.02(m,2H),1.87-1.74(m,2H),1.74-1.62(m,2H),1.62-1.50(m,2H),1.47(d,3H,J＝6.4Hz).ESI-MS m/z:466.2[M-H] ^- Example 48: (R) -9-methyl-6-oxo-N- (4- (piperidin-4-yl) -2-sulfamoylphenyl) -6,7,8,9-tetrahydropyrido [3',2':4,5]Pyrrolo [1,2-a]Preparation of pyrazine-2-carboxamides

The procedure was as in example 6 except that the starting cyclopropylboronic acid was replaced with 1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester to give the title compound. ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.96(s,1H),8.63(d,1H,J＝8.2Hz),8.35(d,2H,J＝19.4Hz),8.01(d,1H,J＝8.4Hz),7.79(s,1H),7.56(s,1H),7.17(s,1H),5.18-5.14(m,1H),3.94-3.92(m,1H),3.50-3.45(m,1H),2.86-2.67(m,4H),1.99-1.86(m,3H),1.71-1.68(m,2H),1.46(d,3H,J＝8Hz).ESI-MS m/z:483.2[M+H] ⁺

Example 49; preparation of (R) -9-methyl-6-oxo-N- (3-sulfamoyl- [1,1' -biphenyl ] -4-yl) -6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The title compound was obtained by the same procedure as in example 6, except that cyclopropylboronic acid, which is a raw material, was replaced with phenylboronic acid. ¹ H NMR(400MHz,DMSO-d ₆ ):δ12.14(s,1H),8.82(d,1H,J＝8.8Hz),8.38(d,2H，J＝8.2Hz),8.22(s,1H),8.05-8.00(m,2H),7.74-7.27(m,4H),7.53(t,2H，J＝7.6Hz),7.42(t,1H,J＝7.3Hz),7.18(s,1H),5.22-5.11(m,1H),3.96-3.92(m,1H),3.55-3.51(m,1H),1.49(d,3H,J＝6.5Hz).ESI-MS m/z:474.1[M-H] ^-

Example 50: preparation of (R) -N- (4 '-fluoro-3-sulfonamido- [1,1' -biphenyl ] -4-yl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The procedure was as in example 6 except for substituting 2- (4-fluorophenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborane for the starting cyclopropylboronic acid to give the title compound. ¹ H NMR(400MHz,DMSO-d ₆ ):δ12.13(s,1H),8.81(d,1H,J＝8.7Hz,),8.40-8.38(m,2H),8.19(s,1H),8.05-7.99(m,2H),7.78-7.76(m,4H),7.37(t,2H,J＝8.7Hz),7.20(s,1H),5.23-5.12(m,1H),3.99-3.89(m,1H),3.17-3.17(m,1H),1.48(d,3H,J＝6.4Hz).ESI-MS m/z:494.1[M+H] ⁺

Example 51: preparation of (R) -9-methyl-6-oxo-N- (2-sulfamoyl-4- (6- (trifluoromethyl) pyridin-3-yl) phenyl) -6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The title compound was obtained by the same procedure as in example 6 except for substituting 2-trifluoromethylpyridine-4-boronic acid pinacol ester with the starting cyclopropylboronic acid. ¹ H NMR(400MHz,DMSO-d ₆ ):δ12.21(s,1H),9.16(s,1H),8.91(d,1H,J＝8.7Hz),8.41(t,3H,J＝10.2Hz),8.34(s,1H),8.19(d,1H,J＝8.4Hz),8.11-8.00(m,2H),7.81(s,2H),7.19(s,1H),5.26-5.09(m,1H),4.03-3.86(m,1H),3.65-3.47(m,1H),1.49(d,3H,J＝6.4Hz).ESI-MS m/z:543.1[M-H] ^-

Example 52: preparation of (R) -N- (4- (1H-pyrazol-4-yl) -2-sulfamoylphenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

Preparation methodThe title compound was obtained by the same procedures as those used in example 6 except for replacing the starting cyclopropylboronic acid with 4-pyrazoleboronic acid pinacol ester. ¹ H NMR(400MHz,DMSO-d ₆ ):δ13.08(s,1H),12.05(s,1H),8.69(d,1H,J＝7.3Hz),8.46-8.17(m,3H),8.13(s,1H),8.07-7.85(m,3H),7.70(s,2H),7.18(s,1H),5.18-5.14(m,1H),3.94-3.92(m,1H),3.50-3.45(m,1H),1.48(d,3H,J＝4Hz).ESI-MS m/z:466.2[M+H] ⁺

Example 53: preparation of (R) -9-methyl-N- (4- (1-methyl-1H-pyrazol-4-yl) -2-sulfamoylphenyl) -6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The procedure was as in example 6 except for substituting the starting cyclopropylboronic acid with 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole to give the title compound. ¹ H NMR(400MHz,DMSO-d ₆ ):δ12.03(s,1H),8.69(d,1H,J＝8.6Hz),8.37(d,2H,J＝8.1Hz),8.21(s,1H),8.10(s,1H),8.02(d,1H,J＝8.2Hz),7.91

-7.83(m,2H),7.70(s,2H),7.17(s,1H),5.18-5.14(m,1H),3.94-3.92(m,1H),3.90(s,3H),3.55-3.48(m,1H),1.48(d,3H,J＝4Hz).ESI-MS m/z:478.2[M-H] ^-

Example 54: preparation of (R) -9-methyl-N- (4- (1-methyl-1H-pyrazol-3-yl) -2-sulfamoylphenyl) -6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The procedure was as in example 6 except for substituting the starting cyclopropylboronic acid with 1-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxabenzaldehyde-2-yl) -1H-pyrazole to give the title compound. ¹ H NMR(400MHz,DMSO-d ₆ ):δ12.07(s,1H),8.73(d,1H,J＝8.7Hz),8.38(d,3H,J＝5.7Hz),8.03(t,2H,J＝9.0Hz),7.79(s,1H),7.70(s,2H),7.17(s,1H),6.74(s,1H),5.23-5.11(m,1H),3.93-3.89(m,4H),3.57-3.48(m,1H),1.48(d,3H,J＝6.4Hz).ESI-MS m/z:478.1[M-H] ^-

Example 55: preparation of (R) -N- (4- (1- (3- (dimethylamino) propyl) -1H-pyrazol-4-yl) -2-sulfamoylphenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The procedure was as in example 6 except for substituting the starting cyclopropylboronic acid with N, N-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole-1-propylamine to give the title compound. ¹ H NMR(400MHz,DMSO-d ₆ ):δ12.03(s,1H),8.69(d,1H,J＝8.6Hz),8.37(d,2H,J＝8.1Hz),8.24(s,1H),8.10(s,1H),8.02(d,1H,J＝8.2Hz),7.94-7.84(m,2H),7.68(s,2H),7.17(s,1H),5.18-5.14(m,1H),4.17(t,2H,J＝6.7Hz),3.94-3.92(m,1H),3.54-3.50(m,1H),2.28(t,2H,J＝6.9Hz),2.20(s,6H),2.01-1.94(m,2H),1.48(d,3H,J＝6.4Hz).ESI-MS m/z:449.2[M-H] ^-

Example 56: preparation of (R) -9-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -2-sulfamoylphenyl) -6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

Preparation method the same as that of example 6 was conducted, except that cyclopropylboronic acid, which was a starting material, was replaced with potassium 1-methyl-4-trifluoroboratrimethylpiperazine to obtain the title compound. ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.97(s,1H),8.62(d,1H,J＝7.8Hz),8.38(s,2H),8.01(d,1H,J＝7.7Hz),7.85(s,1H),7.63(s,2H),7.57(d,1H,J＝7.6Hz),7.17(s,1H),5.25-5.04(m,1H),4.01-3.85(m,2H),3.45-3.32(m,6H),2.42-2.32(m,4H),2.17(s,3H),1.47(d,3H,J＝4.5Hz).ESI-MS m/z:512.1[M+H] ⁺

Example 57: preparation of (R) -N- (4- (4,4-difluoropiperidin-1-yl) -2-sulfamoylphenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The title compound was obtained by the same procedure as in example 7 except that the starting morpholine was replaced with 4,4-difluoropiperidine. ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.84(s,1H),8.55(d,1H,J＝8.7Hz),8.36(d,2H,J＝8.9Hz),7.99(d,1H,J＝7.8Hz),7.64(s,2H),7.50(s,1H),7.35(d,1H,J＝8.2Hz),7.16(s,1H),5.18-5.14(m,1H),3.94-3.92(m,1H),3.50-3.45(m,5H),2.18-2.00(m,4H),1.47(d,3H,J＝5.1Hz).ESI-MS m/z:517.1[M-H] ^- Example 58: (R) -9-methyl-6-oxo-N- (4- (pyrrolidin-1-yl) -2-sulfamoylphenyl) -6,7,8,9-tetrahydropyrido [3',2':4,5]Pyrrolo [1,2-a]Preparation of pyrazine-2-carboxamides

The title compound was obtained by the same procedure as in example 7, except that the starting material morpholine was replaced with pyrrolidine. ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.67(s,1H),8.45(d,1H,J＝8.7Hz),8.34(d,2H,J＝8.2Hz),7.97(d,1H,J＝8.2Hz),7.54(s,2H),7.15(s,1H),7.06(d,1H,J＝8.2Hz),6.84(d,1H,J＝8.2Hz),5.18-5.08(m,1H),3.99-3.86(m,1H),3.53-3.48(m,1H),3.33-3.23(m,4H),2.07-1.99(m,4H),1.46(d,3H,J＝6.5Hz).ESI-MS m/z:469.1[M+H] ⁺

Example 59: preparation of (R) -N- (4- (4- (dimethylamino) piperidin-1-yl) -2-sulfamoylphenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The title compound was obtained by the same procedure as in example 7 except that starting morpholine was replaced with N, N-dimethylpiperidin-4-amine. ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.80(s,1H),8.52(d,1H,J＝9.0Hz),8.35(d,2H,J＝8.1Hz),7.98(d,1H,J＝8.2Hz),7.60(s,2H),7.44(s,1H),7.28(d,1H,J＝8.5Hz),7.16(s,1H),5.15-5.12(m,1H),3.96-3.88(m,1H),3.79-3.77(m,2H),3.56-3.47(m,1H),2.79-2.67(m,3H),2.36(s,6H),1.95-1.92(m,2H),1.57-1.54(m,2H),1.46(d,3H,J＝6.5Hz).ESI-MS m/z:526.1[M+H] ⁺

Example 60: preparation of (R) -9-methyl-N- (4- (4-methylpiperazin-1-yl) -2-sulfamoylphenyl) -6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The title compound was obtained by the same procedure as in example 7, except that 1-methylpiperazine was replaced with morpholine as the starting material. ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.81(s,1H),8.53(d,1H,J＝9.0Hz),8.35(d,2H,J＝8.2Hz),7.98(d,1H,J＝8.2Hz),7.59(s,2H),7.43(s,1H),7.27(d,1H,J＝8.2Hz),7.16(s,1H),5.18-5.09(m,1H),3.95-3.87(m,1H),3.54-3.48(m,1H),3.22-3.13(m,4H),2.48-2.35(m,4H),2.24(s,3H),1.46(d,3H,J＝6.4Hz).ESI-MS m/z:496.2[M-H] ^-

Example 61: preparation of (R) -9-methyl-6-oxo-N- (4- (4-phenylpiperazin-1-yl) -2-sulfamoylphenyl) -6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The title compound was obtained by the same procedure as in example 7 except that morpholine as the starting material was replaced with N-phenylpiperazine. ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.85(s,1H),8.58(d,1H,J＝8.2Hz),8.48-8.29(m,2H),8.00(d,1H,J＝7.3Hz),7.66(s,2H),7.51(s,1H),7.37(d,1H,J＝8.0Hz),7.27(s,2H),7.17(s,1H),7.04(d,2H,J＝6.4Hz),6.84(s,1H),5.18-5.12(m,1H),3.96-3.92(m,1H),3.50-3.37(m,9H),1.46(d,3H,J＝6.5Hz).ESI-MS m/z:558.2[M-H] ^-

Example 62: preparation of (R) -9-methyl-N- (4- (4- (oxetan-3-yl) piperazin-1-yl) -2-sulfamoylphenyl) -6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The preparation was carried out in the same manner as in example 7 except that 1- (oxetan-3-yl) piperazine was replaced with morpholine as the starting material to obtain the title compound. ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.82(s,1H),8.54(d,1H,J＝8.5Hz),8.35(d,2H,J＝8.1Hz),7.99(d,1H,J＝8.2Hz),7.61(s,2H),7.44(s,1H),7.30(s,1H),7.16(s,1H),5.19-5.07(m,1H),4.73-4.39(m,4H),3.97-3.87(m,1H),3.56-3.48(m,1H),3.26-3.14(m,4H),3.08-2.99(m,1H),2.46-2.31(m,4H),1.46(d,3H,J＝6.4Hz).ESI-MS m/z:540.1[M+H] ⁺

Example 63: preparation of (R) -9-methyl-6-oxo-N- (4- (piperazin-1-yl) -2-sulfamoylphenyl) -6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The title compound was obtained by the same procedure as in example 7, except that the starting morpholine was replaced with tert-butylpiperazine-1-carboxylate. ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.81(s,1H),8.53(d,1H,J＝8.9Hz),8.35(d,1H,J＝7.8Hz),8.19(s,1H),7.98(d,1H,J＝8.4Hz),7.59(s,2H),7.43(s,1H),7.27(d,1H,J＝8.9Hz),7.16(s,1H),5.19-5.06(m,1H),3.95-3.91(m,1H),3.52-3.48(m,1H),3.21-3.11(m,4H),3.04-2.90(m,4H),1.46(d,3H,J＝6.5Hz),1.24(s,1H).ESI-MS m/z:484.1[M+H] ⁺

Example 64: preparation of (R) -9-methyl-N- (4- (2-methylpiperazin-1-yl) -2-sulfamoylphenyl) -6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The title compound was obtained by the same procedure as in example 7 except for substituting 4-tert-butoxycarbonyl-2-methylpiperazine for morpholine which was the starting material. ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.80(s,1H),8.53(d,1H,J＝9.0Hz),8.35(d,2H,J＝8.4Hz),8.24(s,1H),7.99(d,1H,J＝8.1Hz),7.61(s,2H),7.41(s,1H),7.25(d,1H,J＝8.7Hz),7.16(s,1H),5.20-5.07(m,1H),3.93(d,2H,J＝12.9Hz),3.57-3.44(m,1H),3.32-3.22(m,1H),3.15-2.80(m,5H),1.47(d,3H,J＝6.1Hz),1.05(d,3H,J＝5.8Hz).ESI-MS m/z:498.1[M+H] ⁺

Example 65: preparation of (R) -9-methyl-N- (4- (3-methylpiperazin-1-yl) -2-sulfamoylphenyl) -6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The title compound was obtained by the same procedure as in example 7 except that the starting material morpholine was replaced with tert-butyl 2-methylpiperazine-1-carboxylate. ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.82(s,1H),8.54(d,1H,J＝9.1Hz),8.35(d,2H,J＝6.5Hz),8.26(s,1H),8.02-7.93(m,1H),7.61(s,2H),7.44(s,1H),7.29(d,1H),7.16(s,1H),5.16-5.12(m,1H),3.98-3.85(m,1H),3.64-3.59(m,2H),3.55-3.42(m,1H),3.14-2.91(m,3H),2.75-2.70(m,2H),1.46(d,3H,J＝6.5Hz),1.13(d,3H,J＝5.1Hz).ESI-MS m/z:498.0[M+H] ⁺

Example 66: preparation of (R) -N- (4- ((3S, 5R) -3,5-dimethylpiperazin-1-yl) -2-sulfamoylphenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

Preparation method the title compound was prepared in the same manner as in example 7 except that the starting material morpholine was replaced with (3s, 5r) -3,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester. ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.83(s,1H),8.53(d,1H,J＝8.8Hz),8.43-8.31(m,2H),7.98(d,1H,J＝8.2Hz),7.62(s,2H),7.42(s,1H),7.30-7.27(m,1H),7.16(s,1H),5.17-5.09(m,1H),3.94-3.91(m,2H),3.64-3.59(m,2H),3.05-3.03(m,2H),2.31-2.19(m,2H),1.44(d,3H,J＝8.7Hz),1.23(s,1H),1.11(d,6H,J＝8.2Hz).ESI-MS m/z:512.1[M+H] ⁺

Example 67: preparation of (R) -N- (4- (4,7-diazaspiro [2.5] octan-7-yl) -2-sulfamoylphenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The preparation method is the same as that of example 7, except that the raw material morpholine is replaced by 4,7-diazaspiro [2.5]]Octane-4-carboxylic acid tert-butyl ester to give the title compound. ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.81(s,1H),8.51(d,1H,J＝9.1Hz),8.35(d,2H,J＝8.1Hz),8.16(s,1H),7.98(d,1H,J＝8.2Hz),7.58(s,2H),7.38(s,1H),7.23(d,1H,J＝8.4Hz),7.16(s,1H),5.19-5.09(m,1H),3.94-3.90(m,2H),3.16-3.12(m,2H),3.05-3.01(m,2H),2.98-2.94(m,2H),1.46(d,3H,J＝6.5Hz),0.58-0.53(m,4H).ESI-MS m/z:510.1[M+H] ⁺

Example 68: preparation of (R) -N- (4- (3,3-dimethylpiperazin-1-yl) -2-sulfamoylphenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The preparation method is the same as that of example 7, except that the raw material isThe quinoline was replaced with 2,2-dimethylpiperazine-1-carboxylic acid tert-butyl ester to give the title compound. ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.83(s,1H),8.54(d,1H,J＝9.0Hz),8.35(d,1H,J＝7.4Hz),8.28(s,1H),7.99(d,1H,J＝8.2Hz),7.62(s,2H),7.43(s,1H),7.28(d,1H,J＝8.3Hz),7.16(s,1H),5.18-5.08(m,1H),3.94-3.89(m,1H),3.53-3.50(m,2H),3.41-3.36(m,1H),3.08(s,2H),3.06-3.02(m,2H),1.46(d,3H,J＝6.2Hz),1.25(s,6H),0.85(s,1H).ESI-MS m/z:512.1[M+H] ⁺

Example 69: preparation of (R) -N- (4- ((4,4-difluorocyclohexyl) amino) -2-sulfamoylphenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The procedure was as in example 7 except for substituting the starting morpholine by 4,4-difluorocyclohexylamine to give the title compound. ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.61(s,1H),8.37-8.34(m,3H),7.97(d,1H,J＝8.1Hz),7.49(s,2H),7.16(d,2H,J＝4.5Hz),6.90(d,1H,J＝8.3Hz),6.04(s,1H),5.17-5.06(m,1H),3.97-3.86(m,1H),3.51-3.48(m,1H),2.55-2.50(m,1H),2.03-2.00(m,6H),1.50-1.46(m,5H).ESI-MS m/z:533.0[M+H] ⁺ .

Example 70: preparation of (R) -N- (4- (2-methoxyethoxy) -2-sulfamoylphenyl) -9-methyl-6-oxo-6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The title compound was obtained by the same procedure as in example 8 except that bromomethylcyclopropane as a raw material was replaced with 2-bromoethyl methyl ether. ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.84(s,1H),8.60(d,1H,J＝9.1Hz),8.36(d,2H,J＝8.0Hz),8.00(d,1H,J＝8.2Hz),7.69(s,2H),7.47(s,1H),7.30(d,1H,J＝7.2Hz),7.17(s,1H),5.16-5.12(m,1H),4.18-4.14(m,2H),3.95-3.92(m,1H),3.73-3.69(m,2H),3.54-3.52(m,1H),3.40(s,3H),1.47(d,3H,J＝6.3Hz).ESI-MS m/z:472.2[M-H] ^- .

Example 71: preparation of (R) -9-methyl-6-oxo-N- (2-sulfamoyl-4- ((tetrahydro-2H-pyran-4-yl) methoxy) phenyl) -6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

Preparation method the title compound was obtained in the same manner as in example 8 except that bromomethylcyclopropane as a raw material was replaced with 4- (bromomethyl) tetrahydro-2H-pyran. ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.83(s,1H),8.59(d,1H,J＝9.1Hz),8.36(d,2H,J＝7.8Hz),7.99(d,1H,J＝8.2Hz),7.66(s,2H),7.45(d,1H,J＝2.3Hz),7.29(d,1H,J＝9.1Hz),7.16(s,1H),5.14(s,1H),3.95-3.82(m,4H),3.57-3.44(m,1H),3.40-3.34(m,1H),3.17(d,2H,J＝5.2Hz),2.09-1.96(m,1H),1.76-1.62(m,2H),1.47(d,3H,J＝6.5Hz),1.40-1.29(m,2H).ESI-MS m/z:512.2[M-H] ^- .

Example 72: preparation of (R) -9-methyl-6-oxo-N- (2-sulfamoyl-4- (2,2,2-trifluoroethoxy) phenyl) -6,7,8,9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

The procedure was as in example 8 except that the starting bromomethylcyclopropane was replaced with 2,2,2-trifluoroethyl methanesulfonate to give the title compound. ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.88(s,1H),8.65(d,1H,J＝9.2Hz),8.38-8.34(m,2H),8.01-7.99(m,1H),7.72(s,2H),7.56(s,1H),7.45-7.42(m,1H),7.17(s,1H),5.22-5.06(m,1H),4.95-4.68(m,2H),3.94-3.91(m,1H),3.53-3.50(m,1H),1.47(d,3H,J＝8.6Hz).ESI-MS m/z:496.1[M-H] ^- .

Experimental example 1 evaluation of in vitro RSK2 kinase Activity of Compounds

1. Experimental Material

Preparation of compound: the compounds of the invention prepared in the above examples were formulated at 10mM in DMSO and then diluted sequentially with DMSO at 1:3 to 125. Mu.M, 31.25. Mu.M, 7.8125. Mu.M, 1953.125nM, 488.28125nM, 122.07nM, 30.518nM, 7.629nM, 1.907nM (50X).

Reagent: RSK2, available from Carna corporation, cat. No.01-150; peptide 11, available from Carna corporation, cat.no.117885; DMSO, available from Sigma, cat.no. d2650; EDTA, available from Sigma, cat.no. e5134; 96-well plates, available from Corning, cat.no.3365; 96-well plates, available from Corning, cat.no.3797;384 well plates, available from Corning, cat. No.3573; staurosporine, available from MCE, cat.No. HY-15141.

The instrument comprises the following steps: .

2. Experimental methods

2.1. Preparing 1 XKinase base buffer solution and 1 Xstop solution

1 × Kinase base buffer:

50mM HEPES，pH 7.5

0.0015％Brij-35

1 × stop solution:

100mM HEPES，pH 7.5

0.015％Brij-35

0.2％Coating Reagent#3

50mM EDTA

2.2. 10mM compound was diluted to 125. Mu.M with DMSO, 100. Mu.L of this solution was added to a 96-well plate, followed by 20. Mu.L of 125. Mu.M solution and 60. Mu.L of DMSO to the next well, and so on for a 4-fold gradient dilution for a total of 10 gradients. 100 μ L/well DMSO was added to 2 wells as a no enzyme control. This version is labeled as the source plate.

2.3. Preparing a middle plate: each concentration solution in 10 μ L source plate was transferred to a new 96-well plate, which was designated as the intermediate plate. Add 90. Mu.L of 1 × Kinase base buffer to each well of the intermediate plate and shake on a shaker for 10min.

2.4. Pipette 5 μ L of the middle plate well solution into a new 384 well and set 2 replicate wells. And is recorded as a detection board.

2.5. Preparation of 2.5 × peptide solution: FAM-labeled peptide and ATP were added to 1 XKinase base buffer.

2.6. mu.L of 2.5 Xenzyme solution was added to each well of the assay plate and incubated at room temperature for 10min.

2.7 Add 10. Mu.L of 2.5 XPeptide solution to each well of assay plate and incubate for a period of time at 28 ℃.

2.8 Add 30. Mu.L of stop solution per well

2.9 read and calculate. Inhibition% = (max-measured value)/(max-min) 100. The data are XLfit processed and fitted to obtain IC ₅₀ The results are shown in Table 1.

EXAMPLE 2 evaluation of in vitro cell Activity of Compound (Breast cancer cell line MDA-MB-468)

1. Experimental Material

Test compounds: the compounds of the invention prepared in the above examples. 20mM stock solution was prepared in DMSO and used.

The breast cancer cell line MDA-MB-468 was purchased from American Type Culture Collection (ATCC).

2. Experimental methods

2.1 cell culture:

cell recovery: the cells were lysed in a 37 ℃ water bath, transferred to 15mL of pre-warmed medium, centrifuged at 1000rpm for 5 minutes, the medium was discarded, the cells were resuspended in 15mL of fresh medium, transferred to a 10cm petri dish, placed at 37 ℃,5% CO ₂ The culture was performed in the incubator (1), and after 24 hours, the cells were replaced with fresh medium.

Cell passage: transferring the above recovered cells into a 50mL sterile centrifuge tube, centrifuging at 1000rpm for 5 minutes, discarding the culture medium, counting the uniformly dispersed cells, adjusting the appropriate cell concentration to 15mL fresh culture medium, adding to a 10cm petri dish, placing at 37 degrees, 5% CO ₂ The incubator of (2).

2.2 Experimental procedures:

cells were grown to 1X 10 in culture flasks ⁵ -1×10 ⁶ After one cell/mL, it was resuspended using fresh medium (L-15 +10% FBS +1% penicillin-streptomycin solution) and counted. Adjusting the cell concentration of the resuspended cellsDegree to 2X 10 ⁴ Individual cells/mL. The cell suspension of the above concentration was added to a 96-well cell culture plate at 100. Mu.L (2X 10) per well ³ Individual cells/well). Placing the 96 well plates plated with cells at 37 ℃ 5% ₂ After 24 hours the compound was added. Compounds were diluted with DMSO to make 200 × solutions, and compounds at each concentration were diluted with fresh medium to 2 × solutions, 100 μ L of 2 × solution was added per well, with two more wells per concentration. After 7 days, the culture medium was aspirated and 100. Mu.L of the culture medium was added to the wells to be assayed

Luminescent Cell visual availability buffer. Shake the mixture gently. After 10 minutes, a backseat membrane is attached to the bottom of the Assay plate, the plate is placed on an Envison to read a fluorescence reading, the cell survival rate (cell survival (%)) is calculated, the formula is cell survival (%) = (Com-Min)/(Max-Min), max is the reading of a solvent control group, min is the reading of a cell-free control group, com is the reading of a compound treatment group, data are processed by XLFit, and IC is obtained by fitting ₅₀ The results are shown in Table 1.

TABLE 1

"-" indicates not tested

Experimental results show that the compound has good RSK2 kinase inhibitory activity and has good inhibitory effect on breast cancer cells.

Although the present invention has been described in detail above, those skilled in the art will appreciate that various modifications and changes can be made to the present invention without departing from the spirit and scope of the invention. The scope of the invention is not to be limited by the above detailed description but is only limited by the claims.

Claims

1. A compound shown in a general formula (I) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof,

wherein the content of the first and second substances,

R ¹ selected from haloalkoxy and aminosulfonyl;

R ² a group selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl substituted with one or more groups selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, monoalkylaminoalkyl, alkylacylamino, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, dialkylaminoalkyl, alkenyl, alkynyl, haloalkylacyl, hydroxyalkanoyl, cycloalkylacyl, heterocyclylacyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, heteroaryl, and oxo groups;

R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, aminoacyl, alkylaminoacyl, dialkylaminoalkyl, heterocyclyl, and cycloalkyl; and

x, Y, Z is each independently selected from N and C (R) ⁸ ) Wherein R is ⁸ Each independently selected from hydrogen, halogen, hydroxy,Alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, aminoacyl, alkylaminoacyl, dialkylamino, heterocyclyl and cycloalkyl.

2. The compound of claim 1, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein R ¹ Selected from halogeno C _1-6 Alkoxy and aminosulfonyl.

3. The compound according to claim 1 or 2, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein R ² Selected from hydrogen, halogen, hydroxy, C _1-6 Alkyl, halo C _1-6 Alkyl, hydroxy C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy, hydroxy C _1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C _1-6 Alkylamino radical, C _1-6 Alkylacylamino group, C _1-6 Alkyl acyl radical, C _1-6 Alkylsulfonyl, aminoacyl, C _1-6 Alkylaminoacyl, di-C _1-6 Alkylamino, 3-8 membered cycloalkyl C _1-6 Alkyl, 3-8 membered heterocyclic group C _1-6 Alkyl, 6-8 membered aryl C _1-6 Alkyl, 5-8 membered heteroaryl and 5-8 membered heteroaryl C _1-6 Alkyl, said radical being substituted by one or more radicals selected from halogen, hydroxy, C _1-6 Alkyl, halo C _1-6 Alkyl, hydroxy C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy, hydroxy C _1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C _1-6 Alkylamino radical, mono C _1-6 Alkylamino radical C _1-6 Alkyl radical, C _1-6 Alkylacylamino group, C _1-6 Alkyl acyl radical, C _1-6 Alkylsulfonyl, aminoacyl, C _1-6 Alkylaminoacyl, di-C _1-6 Alkylamino radical, di-C _1-6 Alkylamino radical C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, halo C _1-6 Alkyl acyl, hydroxy C _1-6 Alkanoyl, 3-8 membered cycloalkylacyl, 3-8 membered heterocycloyl, 3-8 membered cycloalkyl, halo 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 6-8 membered aryl, 5-8 membered heteroaryl and oxo.

4. The compound according to any one of claims 1 to 3, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ Each independently selected from hydrogen, halogen, hydroxy, C _1-6 Alkyl, halo C _1-6 Alkyl, hydroxy C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy, hydroxy C _1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C _1-6 Alkylamino radical, C _1-6 Alkylacylamino group, C _1-6 Alkyl acyl, amino acyl, C _1-6 Alkylaminoacyl, di-C _1-6 Alkylamino, 3-8 membered heterocyclyl and 3-8 membered cycloalkyl.

5. The compound according to any one of claims 1 to 4, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein X is N and Y is C (R) ⁸ ) Z is N; or X is N and Y is C (R) ⁸ ) Z is C (R) ⁸ ) (ii) a Or X is N, Y is N, and Z is N; or X is N, Y is N, Z is C (R) ⁸ ) (ii) a Or X is C (R) ⁸ ) Y is N, Z is N; or X is C (R) ⁸ ) Y is N, Z is C (R) ⁸ ) (ii) a Or X is C (R) ⁸ ) Y is C (R) ⁸ ) Z is N; or X is C (R) ⁸ ) Y is C (R) ⁸ ) Z is C (R) ⁸ )。

6. The compound according to any one of claims 1 to 5, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein R ⁸ Each independently selected from hydrogen, halogen, hydroxy, C _1-6 Alkyl, halo C _1-6 Alkyl, hydroxy C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy, hydroxy C _1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C _1-6 Alkylamino radical, C _1-6 Alkylacylamino group, C _1-6 Alkyl acyl, amino acyl, C _1-6 Alkylaminoacyl, di-C _1-6 Alkylamino, 3-8 membered heterocyclyl and 3-8 membered cycloalkyl.

7. The compound according to any one of claims 1 to 6, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein R ² Selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, methoxy, ethoxy, propoxy,

8. The compound of claim 1, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein the compound is a compound selected from the group consisting of:

9. a pharmaceutical composition comprising a compound of any one of claims 1 to 8, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, and a pharmaceutically acceptable carrier.

10. Use of a compound of any one of claims 1-8, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, or a pharmaceutical composition of claim 9 for the manufacture of a medicament for the treatment of a disorder associated with RSK 2.