CN117186097A

CN117186097A - Carboxamide derivative with RSK inhibition effect, pharmaceutical composition containing carboxamide derivative and application of carboxamide derivative

Info

Publication number: CN117186097A
Application number: CN202310663439.1A
Authority: CN
Inventors: 常少华; 陈晓飞; 闫宁; 李平; 方大为; 任小梅; 马大为
Original assignee: Shanghai Keentai Biomedical Technology Co ltd
Current assignee: Shanghai Keentai Biomedical Technology Co ltd
Priority date: 2022-06-07
Filing date: 2023-06-06
Publication date: 2023-12-08

Abstract

The invention provides a carboxamide derivative with an RSK inhibition effect, a pharmaceutical composition containing the carboxamide derivative and application thereof, and particularly provides a carboxamide derivative shown in a formula I, a tautomer, a stereoisomer, a hydrate, a solvate or pharmaceutically acceptable salt thereof, which can be used as a p90 Ribosome S6 Kinase (RSK) inhibitor, a pharmaceutical composition containing the carboxamide derivative and application thereof in preparation of the pharmaceutical composition.

Description

Carboxamide derivative with RSK inhibition effect, pharmaceutical composition containing carboxamide derivative and application of carboxamide derivative

Technical Field

The invention relates to the field of pharmaceutical chemistry, and in particular provides an RSK inhibitor with a novel structure.

Background

Ras-MAPK pathway and PI3K-PDK1 pathway are normally abnormally active in many cancers, and MAPK and PI3K signaling cascades converge on activation of downstream protein kinases RSK and YB-1 and lead to poor prognosis and resistance to chemotherapy, radiotherapy. The p90 Ribosomal S6 Kinase (RSKs) family belongs to the serine/threonine kinase family, which consists of RSK1, RSK2, RSK3 and RSK4, with RSK 1-4 having a high sequence homology (73-80%) but the greatest difference between the N-and C-termini. RSK comprises two functionally distinct kinase domains, an N-terminal kinase domain (NTKD) and a C-terminal kinase domain (CTKD), linked by a regulatory linker domain. Activation of RSK requires continuous phosphorylation of ERK1/2 at CTKD, autophosphorylation of the junction domain, and modulation of various cellular processes such as cell growth, proliferation, survival and motility by phosphorylating its various substrates such as YB-1, GSK3 beta, BAD, procaspase-8, TSC2 and c-Fos.

RSK1-3 expression status is widely present, RSK1 and RSK2 are the most common isoforms in cancer, their expression and activation promote tumor growth and survival, and RSK3 is not normally expressed in cancer, however, it is associated with drug resistance as with RSK1 and RSK 2. While RSK4 is mainly expressed during embryonic development, the role of RSK4 in malignancy is not yet defined, possibly with tissue specificity, RSK4 exhibits mainly cytoplasmic features and constitutive active states, and kinase active states independent of growth elements. By inhibiting the activation of RSK, a variety of RSK-associated tumors are treated by eliminating Cancer Stem Cells (CSCs) or Tumor Initiating Cells (TICs) and the like, including but not limited to breast, prostate, lung, brain, blood, skin, bone and ovarian cancers. Studies have reported that about 70% of patients with locally advanced breast cancer have RSK activation, and ER+/PR+ is taken as a main component, about 85% of TNBC tumors have RSK activation, and the study shows that the RSK inhibitor can trigger tumor cell apoptosis, inhibit tumor metastasis, and compared with MEK inhibitor, the inhibitor can not trigger Akt activation, has more advantages in the aspect of drug resistance solving by combined administration, and provides a new treatment approach for treating TNBC. In the field of prostate cancer treatment, the combination of RSK2 and p300 can be used for agonizing and regulating the transcription program of AR, and an RSK inhibitor can be used for blocking hormone paths and resisting medicine mediated by YB-1 paths, so that the RSK inhibitor has good prospect in the aspect of treating castration resistant prostate and the aspect of combined medication. In the field of Acute Myelogenous Leukemia (AML) treatment, high expression and abnormal activation of RSK subtypes lead to adverse outcomes and chemotherapy resistance, and RSK inhibitors can block Ser133 site phosphorylation of CREB, thereby blocking promotion of proliferation and survival of myeloid cells by inducing expression of Bcl-2, cyclin a, and cyclin D. .

Previous studies have demonstrated that RSK plays an important role in various vital activities of cell growth, proliferation, apoptosis, transformation, etc., and that increased RSK activation is involved in the etiology of a variety of pathologies, including various types of cancer, cardiovascular disease, liver and lung fibrosis, and infection. In recent years, few small-molecule inhibitors of RSK, such as SL0101, BI-D1870, FMK, PMD-026 and the like, are developed, and individual RSK inhibitors (PMD-026) enter a clinical stage, and some experiments have obtained encouraging early results (NCT 04115306), but most molecules have poor pharmacokinetic properties, which are unfavorable for in vivo research. Therefore, the RSK inhibitor with better development activity and better pharmacokinetics has good application prospect in the medicine industry.

Disclosure of Invention

The purpose of the present invention is to provide a carboxamide derivative having an RSK inhibitory effect.

In a first aspect of the present invention, there is provided a compound of formula I, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof:

wherein,

n is 1 or 2;

m is selected from N or CR _a ；

R _a Selected from the group consisting of: halogen, cyano, C _1-4 An alkoxy group;

x, Y and Q are each independently selected from the group consisting of: CR (computed radiography) _b Or N; z is selected from the group consisting of: s, O or NR _b The method comprises the steps of carrying out a first treatment on the surface of the The method comprises the steps of carrying out a first treatment on the surface of the And is also provided withIs aromatic, when the ligation site is located at CR _b Or NR _b When in use, the CR is _b Or NR _b Is C or N;

R ₄ selected from the group consisting of: c (C) _3-10 Carbocyclyl, 4-12 membered heterocyclyl;

R ₅ selected from the group consisting of: H. c (C) _1-6 An alkyl group;

alternatively, R ₄ And R is ₅ Together with the nitrogen atom to which it is attached, form a 5-12 membered heterocyclic group; and the heterocyclic group may be substituted with one or more R _b Substitution;

R ₁ selected from the group consisting of: H. d, halogen, amino, C _1-6 Alkyl, and R is as described ¹ May be one or more R _b Substitution;

R ₂ and R is ₃ Each independently selected from the group consisting of: H. d, C _1-6 Alkyl, C _1-6 Haloalkyl, and R as described ₂ And R is ₃ May be the same or different;

and, the R ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ May optionally be substituted with one or more R _b Substitution;

R _b selected from the group consisting of: D. halogen, hydroxy, cyano, amino, imino, C _1-4 Alkyl, C _1-4 Alkoxy, C _1-6 Alkylamino, C _1-4 Haloalkyl, C _1-4 Haloalkoxy, C _2-4 Alkenyl, C _1-4 Haloalkenyl, C _2-4 Alkynyl, C _1-4 Haloalkynyl, C _3-6 Cycloalkyl, C _6-10 Aryl, 5-12 membered heteroaryl;

wherein each of said carbocyclyl and heterocyclyl includes a saturated or partially unsaturated monocyclic, spiro, parallel or bridged ring structure.

In some embodiments, the R ₄ Has a structure selected from the group consisting of:

and the heterocyclic group may be substituted with one or more R _b Substitution; preferably, said R ₄ The position of attachment to N is not a heteroatom.

In some embodiments, the compound of formula I has a structure as shown below:

wherein R is ₇ Selected from the group consisting of: H. c (C) _1-6 Alkyl, C _1-6 Alkoxyalkyl, C _1-6 Haloalkyl, C _1-6 Haloalkoxyalkyl, C _3-6 Cycloalkyl, C _6-10 Aryl, 4-12 membered heterocyclyl, 5-12 membered heteroaryl; the heterocyclyl and heteroaryl groups independently contain 1-3 heteroatoms selected from N, O, S.

In another preferred embodiment, R ₁ H.

In another preferred embodiment, R ₇ Is CH ₃ 。

In another preferred embodiment, R ₅ H.

In some embodiments, the R ₄ 、R ₅ The heterocyclic group which together with the nitrogen atom to which it is attached constitutes has a structure selected from the group consisting of:

and the heterocyclic group may be substituted with one or more R _b And (3) substitution.

In some embodiments, the R ₂ 、R ₃ Selected from the group consisting of: H. c (C) _1-3 Alkyl, and said alkyl may be substituted with one or more R _b And (3) substitution.

In some embodiments, the R ₇ Independently selected from the group consisting of: H. c (C) _1-4 Alkyl, C _3-8 Cycloalkyl, and R is as described ₇ Can be independently one or more R _b And (3) substitution.

In some embodiments, the compound is selected from the group consisting of:

In a second aspect of the present invention, there is provided a pharmaceutical composition comprising: the compound of formula I according to the first aspect of the present invention, one or more of its pharmaceutically acceptable salts, racemates, R-isomers, S-isomers or mixtures thereof, and one or more pharmaceutically acceptable carriers, excipients, adjuvants and/or diluents.

In a third aspect of the invention there is provided the use of a compound of formula I according to the first aspect of the invention, a pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or a mixture thereof, for the preparation of a pharmaceutical composition for use in the treatment of a disease or condition associated with p90 Ribosomal S6 Kinase (RSK) activity.

In another preferred embodiment, the disease or condition is cancer.

In some embodiments, the disease or condition is selected from the group consisting of: breast cancer, prostate cancer, lung cancer, brain cancer, skin cancer, bone cancer, ovarian cancer, multiple myeloma or leukemia.

It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.

Detailed Description

The present inventors have conducted extensive and intensive studies to provide a carboxamide derivative having an RSK inhibitory activity, which has a good RSK inhibitory activity and thus can be used for the prevention, treatment and/or alleviation of indications associated with RSK activation. Based on the above findings, the inventors have completed the present invention.

Definition of the definition

As used herein, the term "alkyl" includes straight or branched chain alkyl groups. For example C ₁ -C ₈ Alkyl means a straight or branched alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc.

As used herein, the term "alkenyl" includes straight or branched alkenyl groups. For example C ₂ -C ₆ Alkenyl refers to straight-chain or branched alkenyl groups having 2 to 6 carbon atoms, e.g. vinyl, allyl1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or the like.

As used herein, the term "alkynyl" includes straight or branched chain alkynyl groups. For example C ₂ -C ₆ Alkynyl refers to straight or branched chain alkynyl groups having 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, or the like.

As used herein, the term "cycloalkyl" refers to a cyclic saturated aliphatic hydrocarbon group having a specific number of carbon atoms. For example C ₃ -C ₁₀ Alkenyl refers to a cyclic saturated aliphatic hydrocarbon group having 3 to 10 carbon atoms. It may be a single ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like. But also in the form of a bicyclic ring, for example a bridged or spiro ring.

As used herein, the term "alkylamino" refers to an amino group substituted with an alkyl group. For example, "C ₁ -C ₈ Alkylamino "means C ₁ -C ₈ The amine groups substituted by alkyl groups may be mono-or di-substituted; for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, t-butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, di-t-butylamino, etc.

As used herein, the term "alkoxy" refers to a group having an alkyl-oxy structure. For example, "C ₁ -C ₈ Alkoxy "refers to straight or branched chain alkoxy groups having 1 to 8 carbon atoms and includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy and the like.

As used herein, the term "haloalkyl" represents an alkyl group wherein one or more hydrogen atoms are replaced by halogen, wherein alkyl is as defined above.

As used herein, the term "haloalkoxy" represents an alkoxy group having one or more hydrogen atoms replaced with halogen, wherein the definition of alkoxy is as described above.

As used herein, the term "heterocyclyl" or "heterocycloalkyl" refers to a saturated or partially saturated cyclic group having a specified number of ring atoms (e.g., 3-10 ring atoms, or 4-12 ring atoms, or 5-12 ring atoms), and wherein 1-3 atoms are heteroatoms selected from N, S and O. It may be monocyclic or may be in the form of a double or multiple ring, for example in the form of a bridged or spiro ring. Specific examples may be oxetanyl, azetidinyl, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl and the like.

As used herein, the term "C ₆ -C ₁₀ Aryl "refers to aryl groups having 6 to 10 carbon atoms, for example, phenyl or naphthyl and the like.

As used herein, the term "5-12 membered heteroaryl" refers to a cyclic aromatic group having 5-12 atoms, and wherein 1-3 atoms are heteroatoms selected from the following groups N, S and O. It may be a single ring or may be in the form of a fused ring. Specific examples may be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1, 2, 3) -triazolyl, and (1, 2, 4) -triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, and the like.

Unless otherwise indicated as "substituted or unsubstituted", the radicals according to the invention may be substituted by substituents selected from the group consisting of: halogen, nitrile, nitro, hydroxy, amino, C ₁ -C ₆ Alkyl-amino, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, halo C ₁ -C ₆ Alkyl, halogenated C ₂ -C ₆ Alkenyl, halo C ₂ -C ₆ Alkynyl, halo C ₁ -C ₆ Alkoxy, allyl, benzyl, C ₆ -C ₁₂ Aryl, C ₁ -C ₆ alkoxy-C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy-carbonyl, phenoxycarbonyl, C ₂ -C ₆ Alkynyl-carbonyl, C ₂ -C ₆ Alkenyl-carbonyl, C ₃ -C ₆ Cycloalkyl-carbonyl, C ₁ -C ₆ Alkyl-sulfonyl, and the like.

As used herein, "halogen" or "halogen atom" refers to F, cl, br, and I. More preferably, the halogen or halogen atom is selected from F, cl and Br. "halogenated" means substituted with an atom selected from F, cl, br, and I.

Unless otherwise specified, the structural formulae described herein are intended to include all isomeric forms (e.g., enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example R, S configuration containing asymmetric centers, the (Z), (E) isomers of double bonds, etc. Thus, individual stereochemical isomers of the compounds of the invention or mixtures of enantiomers, diastereomers or geometric isomers (or conformational isomers) thereof are all within the scope of the invention.

As used herein, the term "tautomer" means that structural isomers having different energies can cross the low energy barrier, thereby interconverting. For example, proton tautomers (i.e., proton transfer) include tautomers by proton transfer, such as 1H-indazole and 2H-indazole. Valence tautomers include tautomers that undergo interconversion by recombination of some of the bond-forming electrons.

As used herein, the term "solvate" refers to a compound of the invention that coordinates to a solvent molecule to form a complex in a specific ratio.

As used herein, the term "hydrate" refers to a complex of a compound of the present invention coordinated to water.

Active ingredient

In the present invention, an active ingredient effective in inhibiting RSK is provided. The active ingredient is a compound shown in a general formula (I), and can effectively prevent, treat and/or relieve RSK related diseases.

Experiments show that the active ingredients of the invention can effectively inhibit RSK kinase protein, thereby preventing, treating and/or relieving RKS related diseases.

It is to be understood that the active ingredient of the present invention includes a compound represented by the general formula (I), or a pharmaceutically acceptable salt thereof, or a prodrug thereof. It is to be understood that the active ingredients of the present invention also include crystalline, amorphous, and deuterated forms of the compounds of formula (I).

The term "pharmaceutically acceptable salt" refers to salts of the compounds of the invention with acids or bases that are suitable for use as medicaments. Pharmaceutically acceptable salts include inorganic and organic salts. One preferred class of salts is the salts of the compounds of the present invention with acids. Suitable salts forming acids include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, and the like; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, and the like; amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid. Another preferred class of salts are salts of the compounds of the invention with bases, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (e.g., lower alkanolammonium salts and other pharmaceutically acceptable amine salts), such as methylamine, ethylamine, propylamine, dimethylamine, trimethylamine, diethylamine, triethylamine, tert-butylamine, ethylenediamine, hydroxyethylamine, dihydroxyethylamine, and triethylamine salts, and amine salts formed from morpholine, piperazine, lysine, respectively.

Pharmaceutical compositions and methods of administration

Because the compounds of the present invention have excellent RSK inhibitory activity, the compounds of the present invention and various crystalline forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and pharmaceutical compositions containing the compounds of the present invention as a main active ingredient are useful for preventing, treating and/or alleviating RKS-related diseases, such as treating cancer.

The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention within a pharmaceutically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical compositions contain 1-2000mg of the compound of the invention per dose, more preferably 10-200mg of the compound of the invention per dose. Preferably, the "one dose" is a capsule or tablet.

"pharmaceutically acceptable carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, and the like), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, and the like), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, and the like), emulsifiers (e.g. ) Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water and the like.

The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous).

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.

In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-agar or mixtures of these substances, and the like.

Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable therapeutic agents.

When administered in combination, the pharmaceutical composition also includes a pharmaceutical composition in combination with one or more (2, 3, 4, or more) other pharmaceutically acceptable therapeutic agents. One or more (2, 3, 4, or more) of the other pharmaceutically acceptable therapeutic agents may be used simultaneously, separately or sequentially with the compounds of the invention for preventing, treating and/or alleviating RSK-mediated diseases.

When a pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically effective dose, and the daily dose is usually 1 to 2000mg, preferably 20 to 500mg, for a human having a body weight of 60 kg. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.

Advantageous effects

According to the embodiment of the invention, the RSK inhibitor provided by the invention has the advantages of novel structure, excellent pharmacokinetic property and good drug effect or patentability, and can be used for effectively treating diseases and symptoms related to RSK.

The compound has good inhibition effect on RSK, good in-vitro efficacy and good solubility. In addition, the experimental result of mice shows that the compound of the invention has excellent pharmacokinetic property and good patentability.

The scheme of the present invention will be explained below with reference to examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the present invention and should not be construed as limiting the scope of the invention. The examples are not to be construed as limiting the specific techniques or conditions described in the literature in this field or as per the specifications of the product. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.

Unless otherwise indicated, the compounds of the present invention are structurally defined by Nuclear Magnetic Resonance (NMR) and/or Mass Spectrometry (MS). The unit of NMR shift is 10 ^-6 (ppm). The solvent for NMR determination was deuterated dimethylmethyleneSulfone, deuterated chloroform, deuterated methanol, etc., and the internal standard is Tetramethylsilane (TMS).

Abbreviations for the present invention are defined as follows:

m: molar concentration, e.g. 1M hydrochloric acid means 1mol/L hydrochloric acid solution

HATU: o- (7-azabenzotriazol-1-yl) -N, N, N, N-tetramethylurea hexafluorophosphine salt

DIPEA: also written as DIEA, diisopropylethylamine, i.e. N, N-diisopropylethylamine

NIS N-iodosuccinimide

DMF: n, N-dimethylformamide

PE: petroleum ether

LC-MS: liquid chromatography-mass spectrometry

DMSO: dimethyl sulfoxide

DTT: dithiothreitol

ATP: adenine nucleoside triphosphate

TLC: thin layer chromatography

IC ₅₀ : half inhibition concentration refers to the concentration at which half of the maximum inhibition effect is achieved.

Unless indicated to the contrary, the compounds exemplified herein are named and numbered using ChemBioDraw Ultra 14.0.14.0.

Example 1 (9R) -9-methyl-N- (1-methyl-2- (pyrrolidin-3-ylcarbamoyl) -1H-imidazol-4-yl) -6-oxo-6, 7,8, 9-tetrahydropyridine [3',2]:4,5] pyrrole [1,2-a ] pyrazine-2-carboxamide

First step 6-chloro-1H-pyrrolo [2,3-b ] pyridine-2-carboxylic acid ethyl ester 1b

Compound 1a (10.0 mmol,1.96 g) was dissolved in dichloromethane (50 mL), and thionyl chloride (20.0 mmol,14.0 mL) and 4 drops of DMF were added in this order at room temperature, followed by reaction at 50℃for 5h. The reaction mixture was cooled to room temperature, then slowly added dropwise to ethanol (100 mL), stirred for 1h, the mixture was concentrated under reduced pressure to give a crude product, which was purified by column chromatography (PE/etoac=5/1) to give compound 1b (1.70 g), a white solid.

MS(ESI)m/z 225[M+H] ⁺ 。

¹ H NMR(500MHz,DMSO-d ₆ )δ12.73(s,1H),8.16(d,J＝8.3Hz,1H),7.22(dd,J＝8.3,1.8Hz,1H),7.20-7.18(m,1H),4.34(q,J＝7.1Hz,2H),1.33(t,J＝7.1Hz,3H)。

Second step 1H-pyrrolo [2,3-b ] pyridine-2, 6-dicarboxylic acid diethyl ester 1c

To a high pressure reaction tube was added, in order, compound 1b (10.0 mmol,2.24 g), sodium acetate (30.0 mmol,2.46 g), 1' -bis-diphenylphosphino-ferrocene (0.50 mmol,270 mg), palladium acetate (0.25 mmol,60.0 mg), ethanol (50 mL). The reaction was warmed to 110 ℃ under CO pressure (250 psi) for 16h, monitored after completion of the reaction, cooled to room temperature, filtered through celite, extracted with ethyl acetate (50 ml×3), the organic phases were combined, washed with saturated brine (50 mL), concentrated under reduced pressure to give crude product, which was purified by column chromatography (PE/etoac=5/1) to give compound 1c (1.50 g) as a white solid.

MS(ESI)m/z 263[M+H] ⁺ 。

¹ H NMR(500MHz,DMSO-d ₆ )δ12.94(s,1H),8.28(d,J＝8.2Hz,1H),7.88(d,J＝8.2Hz,1H),4.36(p,J＝7.0Hz,4H),1.35(q,J＝7.0Hz,6H)。

Third step (R) -1- (1- (tert-Butoxycarbonyl) amino) propan-2-yl) -1H-pyrrolo [2,3-b ] pyridine-2, 6-dicarboxylic acid diethyl ester 1d

In a 50mL three-necked flask, sodium hydride (2.60mmol,104mg,60%in mineral oil) was dissolved in DMF (3 mL) to 0℃and a DMF solution (5 mL) of compound 1c (2.00 mmol,524 mg) was slowly added dropwise, after stirring for 1h, a DMF solution (5 mL) of (S) -5-methyl-1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide (2.40 mmol,540 mg) was slowly added dropwise and the reaction mixture was allowed to continue at room temperature for 16h. After completion of the TLC monitoring reaction, the reaction was quenched with saturated sodium bicarbonate solution (20 mL). Ethyl acetate extraction (50 ml×3), combined organic phases, washing with saturated brine (50 mL), and concentration under reduced pressure gave crude product, which was purified by column chromatography (PE/etoac=3/1) to give compound 1d (818 mg).

MS(ESI)m/z 420[M+H] ⁺ 。

¹ H NMR(500MHz,CDCl ₃ )δ8.10(d,J＝8.2Hz,1H),7.99(d,J＝8.2Hz,1H),7.30(s,1H),6.19(s,1H),5.92-5.84(m,1H),4.59-4.46(m,2H),4.43(q,J＝7.1Hz,2H),4.28(dt,J＝14.6,8.4Hz,1H),3.59(dt,J＝14.7,3.5Hz,2H),1.64(s,3H),1.49(t,J＝7.1Hz,3H),1.47-1.41(m,12H)。

Fourth step (R) -1- (1-aminopropane-2-yl) -1H-pyrrole [2,3-b ] pyridine-2, 6-dicarboxylic acid diethyl ester 1e

To a dichloromethane solution (5 mL) of compound 1d (1.95 mmol,818 mg) was added dropwise trifluoroacetic acid (1 mL), and the mixture was stirred at room temperature for 3h. After TLC monitored the reaction was complete, the reaction mixture was concentrated under reduced pressure, saturated sodium bicarbonate (50 mL) was added, extracted with ethyl acetate (50 ml×3), and the organic phase was concentrated under reduced pressure to give crude product, which was purified by column chromatography (PE/etoac=1/1) to give compound 1e (498 mg).

MS(ESI)m/z 320[M+H] ⁺ 。

¹ H NMR(500MHz,CDCl ₃ )δ8.20(d,J＝8.2Hz,1H),8.03(d,J＝8.2Hz,1H),7.35(s,1H),6.28(p,J＝7.0Hz,1H),4.51-4.40(m,4H),3.85(dd,J＝14.6,6.6Hz,1H),3.58(d,J＝14.5Hz,1H),1.71(d,J＝7.2Hz,3H),1.47(t,J＝7.1Hz,3H),1.43(t,J＝7.1Hz,3H)。

Fifth step (R) -9-methyl-6-oxo-6, 7,8, 9-tetrahydropyridine [3',2':4,5] pyrrole [1,2-a ] pyrazine-2-carboxylic acid ethyl ester 1f

Compound 1e (1.03 mmol,330 mg) was dissolved in ethanol (10 mL) and placed in a 50mL round bottom flask, potassium carbonate (3.09 mmol,428 mg) was added and heated to 60℃for reaction for 3h. After TLC monitoring the completion of the reaction, the reaction mixture was concentrated under reduced pressure, extracted with ethyl acetate (50 ml×3), the organic phases were combined, washed with saturated brine (50 mL), and the organic phase was concentrated to give a crude compound, which was purified by column chromatography (PE/etoac=1/1) to give compound 1f (225 mg).

MS(ESI)m/z 274[M+H] ⁺ 。

¹ H NMR(500MHz,CDCl ₃ )δ8.13(d,J＝8.2Hz,1H),7.98(d,J＝8.2Hz,1H),7.26(s,1H),6.42(s,1H),5.31(dt,J＝12.0,6.2Hz,2H),4.49(qd,J＝7.1,2.7Hz,2H),4.03(dd,J＝12.7,4.4Hz,1H),3.53(dd,J＝12.6,5.1Hz,1H),1.65(s,2H),1.55(d,J＝6.6Hz,3H),1.46(t,J＝7.1Hz,3H)。

Sixth step (R) -9-methyl-6-oxo-6, 7,8, 9-tetrahydropyridine [3',2':4,5] pyrrole [1,2-a ] pyrazine-2-carboxylic acid 1g

To a 1, 4-dioxane solution (6 mL) of compound 1f (1.31 mmol,362 mg) was slowly dropped an aqueous lithium hydroxide solution (1.2 mL, 2.0M), and stirred at room temperature for 1h. After completion of the TLC monitoring, the reaction mixture was concentrated under reduced pressure until a white solid was precipitated, and filtered to give 1g (148 mg) of a compound.

MS(ESI)m/z 246[M+H] ⁺ 。

¹ H NMR(500MHz,DMSO-d ₆ )δ8.26(d,J＝8.2Hz,1H),7.88(d,J＝8.2Hz,1H),7.12(s,1H),5.09-5.03(m,1H),3.87(dd,J＝13.1,4.7Hz,1H),3.42(ddd,J＝13.1,5.1,1.3Hz,2H),1.39(d,J＝6.6Hz,3H)。

Seventh step 1-methyl-4-nitro-1H-imidazole-2-carboxylic acid lithium 1i

Compound 1h (25.1 mmol,5.00 g) was dissolved in methanol (40 mL) and water (20 mL), then LiOH (27.5 mmol,0.66 g) was slowly added at room temperature and the reaction mixture was reacted at room temperature for 12h. After completion of the reaction by TLC, the reaction mixture was dried with spin-dry to give crude compound 1i (4.46 g, crude) which was used directly in the next step.

MS(ESI)m/z 178[M+H] ⁺ 。

Eighth step 3- (1-methyl-4-nitro-1H-imidazole-2-carboxamide) pyrrolidine-1-carboxylic acid tert-butyl ester 1k

Compound 1i (11.2 mmol,2.0 g) and compound 1j (12.5 mmol,2.31 g) were dissolved in DMF (20 mL), then DIPEA (19.3 mmol,2.34 g), HOBt (14.6 mmol,1.98 g) and EDCI (14.6 mmol,2.82 g) were added at room temperature and the reaction mixture was reacted at room temperature for 14h. After completion of the TLC monitoring reaction, water (50 mL) was added for dilution, ethyl acetate extraction (50 ml×4), the organic phases were combined, washed with saturated brine and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (PE/etoac=1/1) to give compound 1k (1.24 g).

MS(ESI)m/z 362[M+Na] ⁺ 。

¹ H NMR(500MHz,CDCl ₃ )δ1.46(s,9H),1.93(m,1H),2.19(m,1H),3.03(s,1H),3.45(m,1H),3.68(m,1H),4.15(s,3H),4.52(m,1H),7.36(d,J＝10Hz,1H),7.80(s,1H)。

Ninth step 3- (4-amino-1-methyl-1H-imidazole-2-carboxamide) pyrrolidine-1-carboxylic acid tert-butyl ester 1l

Compound 1k (0.55 mmol,0.20 g) was dissolved in tetrahydrofuran (10 mL) and 0.1g palladium on carbon (5%, wet basis) was added to the mixture at H ₂ The reaction was carried out for 5h under (15 psi) conditions. After completion of the TLC monitoring reaction, the reaction mixture was filtered through celite, and the cake was washed with tetrahydrofuran (50 mL), and the filtrate was spin-dried to give 1l (0.18 g, crude) of the crude compound, which was directly used in the next reaction.

MS(ESI)m/z 310[M+H] ⁺ 。

¹ H NMR(500MHz,CDCl ₃ )δ9.65(s,1H),8.20(d,J＝8.3Hz,2H),8.13(d,J＝8.2Hz,1H),7.68(d,J＝8.4Hz,2H),7.67-7.66(m,1H),7.29(s,1H),7.01(d,J＝8.4Hz,2H),6.21(d,J＝4.9Hz,1H),5.25(s,2H),5.24-5.19(m,1H),4.09(dd,J＝12.6,4.4Hz,1H),3.57(ddd,J＝12.6,5.1,1.4Hz,1H),1.60(d,J＝6.7Hz,3H)。

Tenth step tert-butyl 3- (1-methyl-4- ((R) -9-methyl-6-oxo-6, 7,8, 9-tetrahydropyridine [3',2]:4,5] pyrrole [1,2-a ] pyrazine-2-carboxamide) -1H-imidazole-2-carboxamide) pyrrolidine-1-carboxylate 1m

Compound 1l (0.58 mmol,180 mg) was dissolved in N, N-dimethylformamide (5 mL), and 1g (0.60 mmol,144 mg), N, N-diisopropylethylamine (0.80 mmol,220 mg) and HATU (0.64 mmol,242 mg) were added at room temperature and the reaction mixture was reacted at room temperature for 14h. After TLC monitoring the completion of the reaction, water (30 mL) was added for dilution, extraction with ethyl acetate (30 ml×3), the organic phases were combined, washed with saturated brine and concentrated under reduced pressure to give crude product, which was purified by column chromatography (PE/etoac=0/1) to give compound 1m (140 mg) as a white solid.

MS(ESI)m/z 537[M+H] ⁺ 。

An eleventh step of (9R) -9-methyl-N- (1-methyl-2- (pyrrolidin-3-ylcarbamoyl) -1H-imidazol-4-yl) -6-oxo-6, 7,8, 9-tetrahydropyridine [3',2];4, 5-pyrrole [1,2-a ] pyrazine-2-carboxamide 1

Compound 1m (0.26 mmol,140 mg) was dissolved in ethanol (10 mL), concentrated hydrochloric acid (2 mL, 37%) was added, and the mixture was reacted at room temperature for 4h. After completion of the reaction, water (30 mL) was added for dilution, extraction with ethyl acetate (30 mL. Times.2) and the aqueous phase was directly lyophilized to give the hydrochloride salt of Compound 1 (52 mg) as a pale yellow solid.

MS(ESI)m/z 437[M+H] ⁺ 。

¹ H NMR(500MHz,D ₂ O)δ1.04(d,J＝4.0Hz,3H,),1.77(m,1H),2.15(m,1H),3.02(m,1H),3.18(m,2H),3.28(s,3H),3.32(m,1H),3.41(m,2H),4.22(m,1H),4.36(d,J＝5.5Hz,1H),6.26(s,1H),6.29(d,J＝8.0Hz,1H),6.80(t,J＝14.0,7.0Hz,1H),7.31(d,J＝8.5Hz,1H)。

Example 2 (R) -9-methyl-N- (1-methyl-2- ((R) -pyrrolidin-3-yl) carbamoyl) -1H-imidazol-4-yl) -6-oxo-6, 7,8, 9-tetrahydropyridine [3',2':4,5] pyrrole [1,2-a ] pyrazine-2-carboxamide

In a first step (R) -3- (1-methyl-4-nitro-1H-imidazole-2-carboxamide) pyrrolidine-1-carboxylic acid tert-butyl ester 2b Compound 2a (13.1 mmol,2.31 g) was dissolved in N, N-dimethylformamide (20 mL) and 1g (14.2 mmol,2.00 g), N, N-diisopropylethylamine (34.7 mmol,4.38 g) and HATU (16.9 mmol,6.44 g) were added at room temperature and the reaction mixture was reacted for 14H. After TLC monitoring the completion of the reaction, water (100 mL) was added for dilution, extraction with ethyl acetate (100 ml×3), the organic phases were combined, washed with saturated brine and concentrated under reduced pressure to give crude product, which was purified by column chromatography (PE/etoac=1/1) to give compound 2b (2.83 g) as a white solid.

MS(ESI)m/z 362[M+H] ⁺ 。

Second step (R) -3- (4-amino-1-methyl-1H-imidazole-2-carboxamide) pyrrolidine-1-carboxylic acid tert-butyl ester 2c

Compound 2b (0.55 mmol,0.20 g) was dissolved in tetrahydrofuran (10 mL) and 0.1g palladium on carbon (5%, wet basis) was added to the mixture at H ₂ The reaction was carried out for 5h under (15 psi) conditions. After completion of the TLC monitoring reaction, the reaction mixture was filtered through celite, the cake was washed with tetrahydrofuran (50 mL), and the filtrate was spin-dried to give a crude product Compound 2c (0.18 g, crude) was used directly in the next reaction.

MS(ESI)m/z 310[M+H] ⁺ 。

Third step (R) -3- (1-methyl-4- ((R) -9-methyl-6-oxo-6, 7,8, 9-tetrahydropyridine [3',2]:4,5] pyrrole [1,2-a ] pyrazine-2-carboxamide) -1H-imidazole-2-carboxamide) pyrrolidine-1-carboxylic acid tert-butyl ester 2d

Compound 2c (0.58 mmol,180 mg) was dissolved in N, N-dimethylformamide (5 mL), and 1g (0.60 mmol,144 mg), N, N-diisopropylethylamine (1.20 mmol,256 mg) and HATU (0.74 mmol,333 mg) were added at room temperature and the reaction mixture was reacted for 14h. After TLC monitoring the completion of the reaction, water (30 mL) was added for dilution, extraction with ethyl acetate (30 ml×3), the organic phases were combined, washed with saturated brine and concentrated under reduced pressure to give crude product, which was purified by column chromatography (PE/etoac=0/1) to give compound 2d (164 mg) as a white solid.

MS(ESI)m/z 537[M+H] ⁺ 。

Fourth step (R) -9-methyl-N- (1-methyl-2- ((R) -pyrrolidin-3-yl) carbamoyl) -1H-imidazol-4-yl) -6-oxo-6, 7,8, 9-tetrahydropyridine [3',2':4,5] pyrrole [1,2-a ] pyrazine-2-carboxamide 2

Compound 2d (0.052 mmol,28.0 mg) was dissolved in 1, 4-dioxane (5 mL) and HCl/dioxane (2 mL, 4.0M) was added and the reaction mixture was reacted at room temperature for 3h. After the completion of the reaction, TLC was monitored for solvent, and the solvent was dried by spinning, slurried with ethyl acetate (5 mL), and filtered to give the hydrochloride salt of Compound 2 (22 mg, yield: 89%) as a white solid.

MS(ESI)m/z 437[M+H] ⁺ 。

¹ H NMR(500MHz,D ₂ O)δ1.06(d,J＝4.0Hz,3H),1.82(m,1H),2.21(m,1H),3.10(m,1H),3.22(m,2H),3.32(s,3H),3.36(m,1H),3.41(m,2H),4.22(m,1H),4.36(d,J＝5.5Hz,1H),6.28(s,1H),6.32(d,J＝8.0Hz,1H),6.82(dd,J＝14.0,7.0Hz,1H,),7.34(d,J＝8.5Hz,1H)。

Example 3 (R) -9-methyl-N- (1-methyl-2- ((S) -pyrrolidin-3-yl) carbamoyl) -1H-imidazol-4-yl) -6-oxo-6, 7,8, 9-tetrahydropyridine [3',2':4,5] pyrrole [1,2-a ] pyrazine-2-carboxamide

First step (S) -3- (1-methyl-4-nitro-1H-imidazole-2-carboxamide) pyrrolidine-1-carboxylic acid tert-butyl ester 3b

Compound 3a (13.1 mmol,2.31 g) was dissolved in N, N-dimethylformamide (20 mL), and 1g (14.2 mmol,2.00 g) of N, N-diisopropylethylamine (34.7 mmol,4.38 g) and HATU (16.9 mmol,6.44 g) were added at room temperature and the reaction mixture was reacted at room temperature for 14h. After TLC monitoring the completion of the reaction, water (100 mL) was added for dilution, extraction with ethyl acetate (100 ml×3), the organic phases were combined, washed with saturated brine and concentrated under reduced pressure to give crude product, which was purified by column chromatography (PE/etoac=1/1) to give compound 3b (2.63 g) as a white solid.

MS(ESI)m/z 362[M+Na] ⁺ 。

Second step (S) -3- (4-amino-1-methyl-1H-imidazole-2-carboxamide) pyrrolidine-1-carboxylic acid tert-butyl ester 3c

Compound 3b (0.55 mmol,0.20 g) was dissolved in tetrahydrofuran (10 mL) and 0.1g palladium on carbon (5%, wet basis) was added to the mixture at H ₂ The reaction was carried out for 5h under (15 psi) conditions. After completion of the TLC monitoring reaction, the reaction mixture was filtered through celite, and the cake was washed with tetrahydrofuran (50 mL), and the filtrate was spin-dried to give crude compound 3c (0.182 g, crude) which was directly used for the next reaction.

MS(ESI)m/z 310[M+H] ⁺ 。

Third step (S) -3- (1-methyl-4- ((R) -9-methyl-6-oxo-6, 7,8, 9-tetrahydropyridine [3',2]:4,5] pyrrole [1,2-a ] pyrazine-2-carboxamide) -1H-imidazole-2-carboxamide) pyrrolidine-1-carboxylic acid tert-butyl ester 3d

Compound 3c (0.58 mmol,180 mg) was dissolved in N, N-dimethylformamide (5 mL), and 1g (0.60 mmol,144 mg), N, N-diisopropylethylamine (1.20 mmol,256 mg) and HATU (0.74 mmol,333 mg) were added at room temperature and the reaction mixture was reacted for 14h. After TLC monitoring the completion of the reaction, water (30 mL) was added for dilution, extraction with ethyl acetate (30 ml×3), the organic phases were combined, washed with saturated brine and concentrated under reduced pressure to give crude product, which was purified by column chromatography (PE/etoac=0/1) to give compound 3d (143 mg) as a white solid.

MS(ESI)m/z 537[M+H] ⁺ 。

Fourth step (R) -9-methyl-N- (1-methyl-2- ((S) -pyrrolidin-3-yl) carbamoyl) -1H-imidazol-4-yl) -6-oxo-6, 7,8, 9-tetrahydropyridine [3',2':4,5] pyrrole [1,2-a ] pyrazine-2-carboxamide 3

Compound 3d (0.054 mmol,30.0 mg) was dissolved in 1, 4-dioxane (5 mL) and HCl/dioxane (2 mL, 4.0M) was added and the reaction mixture was reacted at room temperature for 3h. After the completion of the reaction, TLC was monitored, the solvent was dried, slurried with ethyl acetate (5 mL) and filtered to give the hydrochloride salt of compound 3 (20 mg), as a white solid.

MS(ESI)m/z 437[M+H] ⁺ 。

¹ H NMR(500MHz,D ₂ O)δ1.12(d,J＝4.0Hz,3H),1.84(m,1H),2.18(m,1H),3.12(m,1H),3.22(m,2H),3.32(s,3H),3.36(m,1H),3.41(m,2H),4.22(m,1H),4.40(d,J＝5.5Hz,1H),6.30(s,1H),6.31(d,J＝8.0Hz,1H),6.81(t,J＝14.0,7.0Hz,1H),7.32(d,J＝8.5Hz,1H)。

Example 4 (R) -9-methyl-N- (1-methyl-2- (piperidin-4-ylcarbamoyl) -1H-imidazol-4-yl) -6-oxo-6, 7,8, 9-tetrahydropyridine [3',2]:4,5] pyrrole [1,2-a ] pyrazine-2-carboxamide

First step 4- (1-methyl-4-nitro-1H-imidazole-2-carboxamide) piperidine-1-carboxylic acid tert-butyl ester 4b

Compound 1i (2.86 mmol,0.49 g) was dissolved in N, N-dimethylformamide (10 mL), and compound 4a (2.91 mmol,0.50 g), N, N-diisopropylethylamine (7.80 mmol,0.97 g) and HATU (3.73 mmol,1.42 g) were added at room temperature and the reaction mixture was reacted at room temperature for 14h. After TLC monitoring the reaction, water (50 mL) was added for dilution, extraction with ethyl acetate (50 ml×3), the organic phases were combined, washed with saturated brine and concentrated under reduced pressure to give crude product, which was purified by column chromatography (PE/etoac=1/1) to give compound 4b (623 mg) as a white solid.

MS(ESI)m/z 376[M+Na] ⁺ 。

Second step 4- (4-amino-1-methyl-1H-imidazole-2-carboxamide) piperidine-1-carboxylic acid tert-butyl ester 4c

Compound 4b (0.42 mmol,0.145 g) was dissolved in tetrahydrofuran (10 mL) and 0.04g palladium on carbon (5%, wet basis) was added to the mixture at H ₂ The reaction was carried out for 5h under (15 psi) conditions. After completion of the TLC monitoring reaction, the reaction mixture was filtered through celite, and the cake was washed with tetrahydrofuran (50 mL), and the filtrate was spin-dried to give crude compound 4c (0.132 g, crude) which was directly used for the next reaction.

MS(ESI)m/z 324[M+H] ⁺ 。

Tertiary butyl (R) -4- (1-methyl-4- (9-methyl-6-oxo-6, 7,8, 9-tetrahydropyridine [3',2]:4,5] pyrrole [1,2-a ] pyrazine-2-carboxamide) -1H-imidazole-2-carboxamide) piperidine-1-carboxylate 4d

Compound 4c (0.41 mmol,132 mg) was dissolved in N, N-dimethylformamide (5 mL), and 1g (0.50 mmol,124 mg), N, N-diisopropylethylamine (1.20 mmol,256 mg) and HATU (0.74 mmol,333 mg) were added at room temperature and the reaction mixture was reacted at room temperature for 14h. After TLC monitoring the completion of the reaction, water (30 mL) was added for dilution, extraction with ethyl acetate (30 ml×3), the organic phases were combined, washed with saturated brine and concentrated under reduced pressure to give crude product, which was purified by column chromatography (PE/etoac=0/1) to give compound 4d (62 mg) as a white solid.

MS(ESI)m/z 551[M+H] ⁺ 。

Fourth step (R) -9-methyl-N- (1-methyl-2- (piperidin-4-ylcarbamoyl) -1H-imidazol-4-yl) -6-oxo-6, 7,8, 9-tetrahydropyridine [3',2]:4,5] pyrrole [1,2-a ] pyrazine-2-carboxamide 4

Compound 4d (0.064 mmol,35.0 mg) was dissolved in 1, 4-dioxane (5 mL), HCl/dioxane (2 mL, 4.0M) was added and the reaction mixture was reacted at room temperature for 3h. After the completion of the reaction, TLC was monitored, the solvent was dried, slurried with ethyl acetate (5 mL) and filtered to give the hydrochloride salt of compound 4 (26 mg), as a white solid.

MS(ESI)m/z 451[M+H] ⁺ 。

¹ H NMR(500MHz,D ₂ O)δ1.22(d,J＝4.0Hz,3H),1.88-1.82(m,4H),2.72-2.63(m,4H),3.29-3.12(m,2H),3.72-3.64(m,1H),3.82(s,3H),4.40(d,J＝5.5Hz,1H),6.30(s,1H),6.31(d,J＝8.0Hz,1H),8.37-8.22(m,2H)。

Example 5 (R) -9-methyl-N- (1-methyl-2- ((3-methylazetidin-3-yl) carbamoyl) -1H-imidazol-4-yl) -6-oxo-6, 7,8, 9-tetrahydropyridine [3',2':4,5] pyrrole [1,2-a ] pyrazine-2-carboxamide

First step 3-methyl-3- (1-methyl-4-nitro-1H-imidazole-2-carboxamide) azetidine-1-carboxylic acid tert-butyl ester 5b

Compound 1i (2.92 mmol,0.52 g) was dissolved in N, N-dimethylformamide (10 mL), and compound 5a (2.91 mmol,0.50 g), N, N-diisopropylethylamine (7.80 mmol,0.97 g) and HATU (3.73 mmol,1.42 g) were added at room temperature and the reaction mixture was reacted for 14h. After TLC monitoring the completion of the reaction, water (50 mL) was added for dilution, extraction with ethyl acetate (50 ml×3), the organic phases were combined, washed with saturated brine and concentrated under reduced pressure to give crude product, which was purified by column chromatography (PE/etoac=1/1) to give compound 5b (618 mg) as a white solid.

MS(ESI)m/z 340[M+H] ⁺ 。

Second step 3- (4-amino-1-methyl-1H-imidazole-2-carboxamide) -3-methylazetidine-1-carboxylic acid tert-butyl ester 5c

Compound 5b (0.41 mmol,0.140 g) was dissolved in tetrahydrofuran (10 mL) and 0.04g palladium on carbon (5%, wet basis) was added to the mixture at H ₂ The reaction was allowed to proceed for 6h under (15 psi). After completion of the TLC monitoring reaction, the reaction mixture was filtered through celite, and the cake was washed with tetrahydrofuran (50 mL), and the filtrate was spin-dried to give crude compound 5c (0.128 g, crude) which was directly used in the next reaction.

MS(ESI)m/z 310[M+H] ⁺ 。

Tertiary butyl (R) -3-methyl-3- (1-methyl-4- (9-methyl-6-oxo-6, 7,8, 9-tetrahydropyridine [3',2]:4,5] pyrrole [1,2-a ] pyrazine-2-carboxamide) -1H-imidazole-2-carboxamide) azetidine-1-carboxylate 5d

Compound 5c (0.39 mmol,128 mg) was dissolved in N, N-dimethylformamide (5 mL), and 1g (0.50 mmol,124 mg) of N, N-diisopropylethylamine (1.20 mmol,256 mg) and HATU (0.64 mmol,233 mg) were added at room temperature and the reaction mixture was reacted at room temperature for 14h. After TLC monitoring the completion of the reaction, water (30 mL) was added for dilution, extraction with ethyl acetate (30 ml×3), the organic phases were combined, washed with saturated brine and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (PE/etoac=0/1) to give compound 5d (54 mg) as a yellow solid.

MS(ESI)m/z 537[M+H] ⁺ 。

Fourth step (R) -9-methyl-N- (1-methyl-2- ((3-methylazetidin-3-yl) carbamoyl) -1H-imidazol-4-yl) -6-oxo-6, 7,8, 9-tetrahydropyridine [3',2':4,5] pyrrole [1,2-a ] pyrazine-2-carboxamide

Compound 4d (0.036 mmol,30.0 mg) was dissolved in 1, 4-dioxane (5 mL), HCl/dioxane (2 mL, 4.0M) was added and the reaction mixture was reacted at room temperature for 3h. After the completion of the reaction, TLC was monitored, the solvent was dried, slurried with ethyl acetate (5 mL) and filtered to give the hydrochloride salt of compound 5 (19 mg), as a white solid.

MS(ESI)m/z 437[M+H] ⁺ 。

¹ H NMR(500MHz,D ₂ O)δ1.22(d,J＝4.0Hz,3H),1.52(s,3H),3.32-3.22(m,2H),3.72-3.58(m,4H),3.82(s,3H),4.40(d,J＝5.5Hz,1H),6.30(s,1H),6.31(d,J＝8.0Hz,1H),8.37-8.22(m,2H)。

EXAMPLE 6 (R) -N- (2- ((3S, 4S) -4-fluoropyrrolidin-3-yl) carbamoyl) -1-methyl-1H-imidazol-4-yl) -9-methyl-6-oxo-6, 7,8, 9-tetrahydropyridine [3',2':4,5] pyrrole [1,2-a ] pyrazine-2-carboxamide

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First step (3S, 4R) -3-fluoro-4- (1-methyl-4-nitro-1H-imidazole-2-carboxamide) pyrrolidine-1-carboxylic acid tert-butyl ester 6b

Compound 1i (2.86 mmol,0.49 g) was dissolved in N, N-dimethylformamide (10 mL), and compound 6a (2.81 mmol,0.58 g), N, N-diisopropylethylamine (7.80 mmol,0.97 g) and HATU (3.73 mmol,1.42 g) were added at room temperature and the reaction mixture was reacted at room temperature for 14h. After TLC monitoring the completion of the reaction, water (50 mL) was added for dilution, extraction with ethyl acetate (50 ml×3), the organic phases were combined, washed with saturated brine and concentrated under reduced pressure to give crude product, which was purified by column chromatography (PE/etoac=1/1) to give compound 6b (643 mg) as a white solid.

MS(ESI)m/z 356[M+Na] ⁺ 。

Second step (3S, 4R) -3- (4-amino-1-methyl-1H-imidazole-2-carboxamide) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester 6c

Compound 6b (0.45 mmol,0.160 g) was dissolved in tetrahydrofuran (10 mL) and 0.04g palladium on carbon (5%, wet basis) was added to the mixture at H ₂ The reaction was carried out for 5h under (15 psi) conditions. After completion of the TLC monitoring reaction, the reaction mixture was filtered through celite, and the cake was washed with tetrahydrofuran (50 mL), and the filtrate was spin-dried to give crude compound 4c (0.145 g, crude), which was directly used in the next reaction.

MS(ESI)m/z 328[M+H] ⁺ 。

Third step (3S, 4S) -3-fluoro-4- (1-methyl-4- ((R) -9-methyl-6-oxo-6, 7,8, 9-tetrahydropyridine [3',2]:4,5] pyrrole [1,2-a ] pyrazine-2-carboxamide) -1H-imidazole-2-carboxamide) pyrrolidine-1-carboxylic acid tert-butyl ester 6d

Compound 6c (0.442 mmol,145 mg) was dissolved in N, N-dimethylformamide (5 mL), and 1g (0.44 mmol,109 mg) of N, N-diisopropylethylamine (1.35 mmol,172 mg) and HATU (0.65 mmol, 255 mg) were added at room temperature and the reaction mixture was reacted at room temperature for 14h. After TLC monitoring the completion of the reaction, water (30 mL) was added for dilution, extraction with ethyl acetate (30 ml×3), the organic phases were combined, washed with saturated brine and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (PE/etoac=0/1) to give compound 6d (104 mg) as a yellow solid.

MS(ESI)m/z 555[M+H] ⁺ 。

Fourth step (R) -N- (2- ((3S, 4S) -4-fluoropyrrolidin-3-yl) carbamoyl) -1-methyl-1H-imidazol-4-yl) -9-methyl-6-oxo-6, 7,8, 9-tetrahydropyridine [3',2':4,5] pyrrole [1,2-a ] pyrazine-2-carboxamide 6

Compound 6d (0.045 mmol,25.0 mg) was dissolved in 1, 4-dioxane (5 mL) and HCl/dioxane (2 mL, 4.0M) was added and the reaction mixture was reacted at room temperature for 3h. After the completion of the reaction, TLC was monitored, the solvent was dried, slurried with ethyl acetate (5 mL) and filtered to give the hydrochloride salt of Compound 6 (18 mg), as a white solid.

MS(ESI)m/z 455[M+H] ⁺ 。

¹ H NMR(500MHz,D ₂ O)δ1.42(d,J＝4.0Hz,3H),2.85-3.10(m,4H),3.22-3.32(m,2H),3.72(s,3H),3.92-4.04(m,1H),4.34-4.42(m,1H),6.28(s,1H),6.32(d,J＝8.0Hz,1H),6.82(dd,J＝14.0,7.0Hz,1H),7.34(d,J＝8.5Hz,1H)。

Example 7 (R) -9-methyl-N- (1-methyl-2- (((R) -1-methylpyrrolidin-3-yl) carbamoyl) -1H-imidazol-4-yl) -6-oxo-6, 7,8, 9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

First step (R) -1-methyl-N- (1-methylpyrrolidin-3-yl) -4-nitro-1H-imidazole-2-carboxamide 7b

Compound 7a (9.98 mmol,1.0 g) was dissolved in N, N-dimethylformamide (20 mL), and compound 1i (10.98 mmol,1.94 g), N, N-diisopropylethylamine (29.95 mmol,3.87 g) and HATU (14.97 mmol,5.69 g) were added at room temperature and the reaction mixture was reacted for 14h. After completion of TLC monitoring the reaction, water (100 mL) was added to dilute, extraction with ethyl acetate (100 mL. Times.3), the organic phases were combined, washed with saturated brine, and the organic phase was concentrated under reduced pressure to give a crude product, which was purified by column chromatography (PE/EtOAc=1/1) to give compound 7b (560)

mg), white solid.

MS(ESI)m/z 254[M+H] ⁺ 。

Second step (R) -4-amino-1-methyl-N- (1-methylpyrrolidin-3-yl) -1H-imidazole-2-carboxamide 7c

Compound 7b (0.40 mmol,100 mg) was dissolved in tetrahydrofuran (10 mL) and 5% palladium on carbon (0.02 g) was added to the mixture at H ₂ The reaction was carried out for 5h under (15 psi) conditions. After completion of the TLC monitoring reaction, the reaction mixture was filtered through celite, and the cake was washed with tetrahydrofuran (50 mL), and the filtrate was spin-dried to give crude compound 7c (88 mg, crude), which was directly used in the next reaction.

MS(ESI)m/z 224[M+H] ⁺ 。

(R) -9-methyl-N- (1-methyl-2- (((R) -1-methylpyrrolidin-3-yl) carbamoyl) -1H-imidazol-4-yl) -6-oxo-6, 7,8, 9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide 7

Compound 7c (0.39 mmol,88 mg) was dissolved in N, N-dimethylformamide (10 mL), and 1g (0.36 mmol,88 mg), N-diisopropylethylamine (1.08 mmol,139 mg) and HATU (0.54 mmol,204 mg) were added at room temperature and the reaction mixture was reacted for 14h. After completion of the TLC monitoring reaction, water (30 mL) was added to dilute, extraction was performed with ethyl acetate (30 mL. Times.3), the organic phases were combined, washed with saturated brine, and the organic phase was concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give Compound 7 (9 mg) as a white solid.

MS(ESI)m/z 451[M+H] ⁺ 。

¹ H NMR(400MHz,CD ₃ OD)δ8.22(d,J＝8.3Hz,1H),7.95(d,J＝8.2Hz,1H),7.52(s,1H),7.17(s,1H),5.25–5.17(m,1H),4.49(d,J＝8.3Hz,1H),3.96(s,3H),3.94–3.90(m,1H),3.51(dd,J＝13.2,1.5Hz,1H),3.03(d,J＝11.1Hz,2H),2.85(s,1H),2.77–2.71(m,1H),2.52(s,3H),2.40–2.31(m,1H),1.94–1.87(m,1H),1.45(d,J＝6.6Hz,3H).

Example 8 (R) -N- (2- (((R) -1-ethylpyrrolidin-3-yl) carbamoyl) -1-methyl-1H-imidazol-4-yl) -9-methyl-6-oxo-6, 7,8, 9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

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First step (R) -3- (1-methyl-4-nitro-1H-imidazole-2-carboxamide) pyrrolidine-1-carboxylic acid tert-butyl ester 8b

Compound 8a (3.11 mmol,0.58 g) was dissolved in N, N-dimethylformamide (20 mL), and compound 1i (2.82 mmol,0.5 g), N, N-diisopropylethylamine (8.47 mmol,1.10 g) and HATU (4.24 mmol,1.61 g) were added at room temperature and the reaction mixture was reacted for 14h. After TLC monitoring the completion of the reaction, water (100 mL) was added for dilution, extraction with ethyl acetate (100 ml×3), the organic phases were combined, washed with saturated brine and concentrated under reduced pressure to give crude product, which was purified by column chromatography (PE/etoac=1/1) to give compound 8b (620 mg) as a white solid.

MS(ESI)m/z 362[M+Na] ⁺ 。

Second step (R) -3- (4-amino-1-methyl-1H-imidazole-2-carboxamide) pyrrolidine-1-carboxylic acid tert-butyl ester 8c

Compound 8b (0.68 mmol,0.23 g) was dissolved in tetrahydrofuran (10 mL) and 5% palladium on carbon (0.1 g) was added to the mixture at H ₂ The reaction was carried out for 5h under (15 psi) conditions. After completion of the TLC monitoring reaction, the reaction mixture was filtered through celite, and the cake was washed with tetrahydrofuran (50 mL), and the filtrate was spin-dried to give crude compound 8c (0.16 g, crude) which was directly used for the next reaction.

MS(ESI)m/z 310[M+H] ⁺ 。

Third step (R) -3- (1-methyl-4- ((R) -9-methyl-6-oxo-6, 7,8, 9-tetrahydropyridine [3',2]:4,5] pyrrole [1,2-a ] pyrazine-2-carboxamide) -1H-imidazole-2-carboxamide) pyrrolidine-1-carboxylic acid tert-butyl ester 8d

Compound 8c (0.52 mmol,160 mg) was dissolved in N, N-dimethylformamide (5 mL), and 1g (0.52 mmol,127 mg), N, N-diisopropylethylamine (1.55 mmol,200 mg) and HATU (0.78 mmol, 025 mg) were added at room temperature and the reaction mixture was reacted for 14h. After completion of the TLC monitoring reaction, water (30 mL) was added for dilution, extraction with ethyl acetate (30 mL. Times.3), the organic phases were combined, washed with saturated brine, and the organic phase was concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give Compound 8d (216 mg) as a white solid.

MS(ESI)m/z 537[M+H] ⁺ 。

Fourth step (R) -9-methyl-N- (1-methyl-2- ((R) -pyrrolidin-3-yl) carbamoyl) -1H-imidazol-4-yl) -6-oxo-6, 7,8, 9-tetrahydropyridine [3',2':4,5] pyrrole [1,2-a ] pyrazine-2-carboxamide 8e

Compound 8d (0.40 mmol,216 mg) was dissolved in 1, 4-dioxane (10 mL), a 1, 4-dioxane solution (5 mL, 4.0M) of hydrochloric acid was added, and the reaction mixture was reacted at room temperature for 3h. After completion of the reaction by TLC, the solvent was dried to give the hydrochloride salt of compound 8e (175 mg) as a white solid.

MS(ESI)m/z 437[M+H] ⁺ 。

Fifth step (R) -N- (2- (((R) -1-ethylpyrrolidin-3-yl) carbamoyl) -1-methyl-1H-imidazol-4-yl) -9-methyl-6-oxo-6, 7,8, 9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide 8

Compound 8e (0.40 mmol,175 mg) was dissolved in methanol (10 mL), acetaldehyde (0.48 mmol,22 mg) was added sequentially, sodium cyanoborohydride (0.80 mmol,51 mg) was added at 0deg.C, and the reaction mixture was reacted at room temperature overnight. After the completion of the reaction, the solvent was dried by TLC, dissolved in water (30 mL), saturated potassium carbonate solution (10 mL) was added, extracted with dichloromethane (20 ml×2), the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure to give a crude product, which was purified by thin layer chromatography (DCM/meoh=10/1) to give compound 8 (115 mg) as a pale yellow solid.

MS(ESI)m/z 464.7[M+H] ⁺ 。

¹ H NMR(400MHz,CD ₃ OD)δ8.21(d,J＝8.2Hz,1H),7.95(d,J＝8.2Hz,1H),7.52(s,1H),7.16(s,1H),5.17(tt,J＝7.1,5.4Hz,1H),4.50(ddd,J＝13.1,8.3,5.1Hz,1H),3.96(s,3H),3.93(dd,J＝13.1,4.5Hz,1H),3.50(dd,J＝13.1,1.6Hz,1H),3.33(d,J＝8.9Hz,2H),3.18-3.13(m,1H),3.08–2.96(m,3H),2.40(dtd,J＝14.1,8.3,5.8Hz,1H),2.02(td,J＝13.5,7.6Hz,1H),1.45(d,J＝6.6Hz,3H),1.22(t,J＝7.3Hz,3H).

Example 9 (R) -N- (2- (((R) -1-cyclopropylpyrrolidin-3-yl) carbamoyl) -1-methyl-1H-imidazol-4-yl) -9-methyl-6-oxo-6, 7,8, 9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

First step (R) - (1-Cyclopropylpyrrolidin-3-yl) carbamic acid tert-butyl ester 9b

Compound 9a (5.37 mmol,1 g) was dissolved in anhydrous methanol (60 mL), and compound 1-ethoxy-1-trimethylsiloxycyclopropane (16.10 mmol,2.81 g), sodium cyanoborohydride (16.10 mmol,1.01 g), acetic acid (64.43 mmol,3.87 g) and anhydrous sodium sulfate (1 g) were added at room temperature and the reaction mixture was reacted at 60℃for 14h.

After completion of the TLC monitoring, the solvent was dried by spin-drying, diluted with water (100 mL), extracted with ethyl acetate (100 mL. Times.3), the organic phases were combined, washed with saturated brine, and the organic phase was concentrated under reduced pressure to give crude product 9b (1.14 g), light cyan oil.

Second step (R) -1-cyclopropyl-pyrrolidin-3-amine 9c

Compound 9b (1.77 mmol,400 mg) was dissolved in 1, 4-dioxane (15 mL), 1, 4-dioxane solution of hydrochloric acid (6 mL, 4.0M) was added, and the reaction mixture was reacted at room temperature for 3h. After completion of the reaction by TLC, the solvent was dried to give the hydrochloride salt of compound 9c (210 mg) as a white solid.

Third step (R) -N- (1-cyclopropylpyrrolidin-3-yl) -1-methyl-4-nitro-1H-imidazole-2-carboxamide 9d

Compound 9c (13.1 mmol,2.31 g) was dissolved in N, N-dimethylformamide (20 mL), and compound 1i (14.2 mmol,2.00 g), N, N-diisopropylethylamine (34.7 mmol,4.38 g) and HATU (16.9 mmol,6.44 g) were added at room temperature and the reaction mixture was reacted at room temperature for 14h. After TLC monitoring the completion of the reaction, water (100 mL) was added for dilution, extraction with ethyl acetate (100 ml×3), the organic phases were combined, washed with saturated brine and concentrated under reduced pressure to give crude product, which was purified by column chromatography (PE/etoac=1/1) to give compound 9d (2.63 g) as a white solid.

MS(ESI)m/z 362[M+Na] ⁺ 。

Fourth step (R) -4-amino-N- (1-cyclopropylpyrrolidin-3-yl) -1-methyl-1H-imidazole-2-carboxamide 9e

Compound 9d (0.55 mmol, 0.2)0g) Dissolved in tetrahydrofuran (10 mL), 5% palladium on carbon (0.1 g) was added to the mixture at H ₂ The reaction was carried out for 5h under (15 psi) conditions. After completion of the TLC monitoring reaction, the reaction mixture was filtered through celite, and the cake was washed with tetrahydrofuran (50 mL), and the filtrate was spin-dried to give crude compound 9e (0.182 g, crude) which was directly used for the next reaction.

MS(ESI)m/z 310[M+H] ⁺ 。

Fifth step (R) -N- (2- (((R) -1-cyclopropylpyrrolidin-3-yl) carbamoyl) -1-methyl-1H-imidazol-4-yl) -9-methyl-6-oxo-6, 7,8, 9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide 9

Compound 9e (0.58 mmol,180 mg) was dissolved in N, N-dimethylformamide (5 mL), and 1g (0.60 mmol,144 mg), N, N-diisopropylethylamine (1.20 mmol,256 mg) and HATU (0.74 mmol,333 mg) were added at room temperature and the reaction mixture was reacted at room temperature for 14h. After completion of the TLC monitoring reaction, water (30 mL) was added for dilution, extraction with ethyl acetate (30 ml×3), the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (PE/etoac=0/1) to give compound 9 (143 mg),

white solid.

MS(ESI)m/z 477[M+H] ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ9.96(s,1H),8.12(d,J＝8.2Hz,1H),8.05(d,J＝8.2Hz,1H),7.53(s,1H),7.45(d,J＝5.0Hz,1H),7.39(d,J＝8.4Hz,1H),7.20(s,1H),5.21–5.15(m,1H),4.52(dtd,J＝11.5,8.3,4.2Hz,1H),4.04(d,J＝4.5Hz,1H),4.01(s,3H),3.58–3.50(m,1H),2.95(dt,J＝8.9,4.4Hz,1H),2.87(dd,J＝10.3,6.9Hz,1H),2.75(dd,J＝10.2,3.6Hz,1H),2.53(dt,J＝9.5,7.8Hz,1H),2.30(dtd,J＝13.1,8.4,4.5Hz,1H),1.70(ddd,J＝13.1,7.7,4.8Hz,1H),1.62(h,J＝5.1Hz,1H),1.53(d,J＝6.6Hz,3H),0.42(t,J＝4.6Hz,4H).

Example 10 (R) -N- (2- ((S) -3- (dimethylamino) pyrrolidine-1-carbonyl) -1-methyl-1H-imidazol-4-yl) -9-methyl-6-oxo-6, 7,8, 9-tetrahydropyridine [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

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In the first step (S) - (3- (dimethylamino) pyrrolidin-1-yl) (1-methyl-4-nitro-1H-imidazol-2-yl) methanone 10b compound 1i (4.82 mmol,0.85 g) was dissolved in N, N-dimethylformamide (20 mL) and compound 10a (4.38 mmol,0.5 g), N, N-diisopropylethylamine (13.14 mmol,1.70 g) and HATU (6.57 mmol,2.50 g) were added at room temperature and the reaction mixture was reacted at room temperature for 14H. After TLC monitoring the reaction, water (100 mL) was added for dilution, ethyl acetate extraction (100 ml×3), the organic phases were combined, washed with saturated brine and concentrated under reduced pressure to give crude product, which was purified by column chromatography (PE/etoac=1/1) to give compound 10b (260 mg) as a white solid.

MS(ESI)m/z 268[M+H] ⁺ 。

Second step (S) - (4-amino-1-methyl-1H-imidazol-2-yl) (3- (dimethylamino) pyrrolidin-1-yl) methanone 10c

Compound 10b (0.48 mmol,125 mg) was dissolved in tetrahydrofuran (10 mL) and 5% palladium on carbon (22 mg) was added to the mixture at H ₂ The reaction was carried out for 5h under (15 psi) conditions. After completion of the TLC monitoring reaction, the reaction mixture was filtered through celite, and the cake was washed with tetrahydrofuran (50 mL), and the filtrate was spin-dried to give crude compound 10c (94 mg, crude), which was directly used in the next reaction.

MS(ESI)m/z 238[M+H] ⁺ 。

Third step (R) -N- (2- ((S) -3- (dimethylamino) pyrrolidine-1-carbonyl) -1-methyl-1H-imidazol-4-yl) -9-methyl-6-oxo-6, 7,8, 9-tetrahydropyridine [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide 10

Compound 10c (0.40 mmol,94 mg) was dissolved in N, N-dimethylformamide (5 mL), and 1g (0.36 mmol,88 mg), N, N-diisopropylethylamine (1.08 mmol,140 mg) and HATU (0.54 mmol,206 mg) were added at room temperature and the reaction mixture was reacted at room temperature for 14h. After TLC monitoring the reaction was complete, water (30 mL) was added for dilution, extraction with ethyl acetate (30 ml×3), the combined organic phases were washed with saturated brine and the organic phase was concentrated under reduced pressure to give the crude product which was purified by column chromatography (DCM/meoh=10/1) to give compound 10 (12 mg) as a white solid.

MS(ESI)m/z 465[M+H] ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ9.94(d,J＝9.1Hz,1H),8.14(d,J＝8.2Hz,1H),8.09(d,J＝8.2Hz,1H),7.54(d,J＝1.9Hz,1H),7.22(s,1H),6.29(t,J＝4.3Hz,1H),5.19(dd,J＝12.0,6.0Hz,1H),4.26–4.13(m,1H),4.02(dt,J＝12.7,4.1Hz,1H),3.91(s,3H),3.83–3.69(m,1H),3.53(ddt,J＝18.1,11.6,6.2Hz,2H),3.36(dd,J＝12.1,8.8Hz,1H),2.73(dt,J＝23.1,7.9Hz,1H),2.27(d,J＝2.1Hz,6H),2.11(tt,J＝13.2,6.5Hz,1H),1.89–1.79(m,1H),1.52(dd,J＝6.6,1.6Hz,3H).

Example 11 (R) -N- (2- (((R) -3- (dimethylamino) pyrrolidine-1-carbonyl) -1-methyl-1H-imidazol-4-yl) -9-methyl-6-oxo-6, 7,8, 9-tetrahydropyridine [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

First step (R) - (3- (dimethylamino) pyrrolidin-1-yl) (1-methyl-4-nitro-1H-imidazol-2-yl) methanone 11b

Compound 1i (4.82 mmol,0.85 g) was dissolved in N, N-dimethylformamide (20 mL), and compound 11a (4.38 mmol,0.5 g), N-diisopropylethylamine (13.14 mmol,1.70 g) and HATU (6.57 mmol,2.50 g) were added at room temperature and the reaction mixture was reacted at room temperature for 14h. After TLC monitoring the completion of the reaction, water (100 mL) was added for dilution, extraction with ethyl acetate (100 ml×3), the organic phases were combined, washed with saturated brine and concentrated under reduced pressure to give crude product, which was purified by column chromatography (PE/etoac=1/1) to give compound 11b (300 mg) as a white solid.

MS(ESI)m/z 268[M+H] ⁺ 。

Second step (R) - (4-amino-1-methyl-1H-imidazol-2-yl) (3- (dimethylamino) pyrrolidin-1-yl) methanone 11c

Compound 11b (0.48 mmol,125 mg) was dissolved in tetrahydrofuran (10 mL) and 5% palladium on carbon (22 mg) was added to the mixture at H ₂ The reaction was carried out for 5h under (15 psi) conditions. After completion of the TLC monitoring reaction, the reactionThe mixture was filtered through celite, the filter cake was washed with tetrahydrofuran (50 mL), and the filtrate was dried to give crude compound 11c (100 mg, crude) which was used directly in the next reaction.

MS(ESI)m/z 238[M+H] ⁺ 。

(R) -N- (2- (((R) -3- (dimethylamino) pyrrolidine-1-carbonyl) -1-methyl-1H-imidazol-4-yl) -9-methyl-6-oxo-6, 7,8, 9-tetrahydropyridine [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide 11

Compound 11c (0.45 mmol,107 mg) was dissolved in N, N-dimethylformamide (5 mL), and 1g (0.41 mmol,100 mg) of N, N-diisopropylethylamine (1.23 mmol,158 mg) and HATU (0.61 mmol,233 mg) were added at room temperature and the reaction mixture was reacted at room temperature for 14h. After TLC monitoring the reaction was complete, water (30 mL) was added for dilution, extraction with ethyl acetate (30 ml×3), the combined organic phases were washed with saturated brine and the organic phase was concentrated under reduced pressure to give the crude product which was purified by column chromatography (DCM/meoh=0/1) to give compound 11 (13 mg) as a white solid.

MS(ESI)m/z 465[M+H] ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ9.92(d,J＝8.5Hz,1H),8.14(d,J＝8.2Hz,1H),8.09(dd,J＝8.2,1.2Hz,1H),7.54(d,J＝1.9Hz,1H),7.22(s,1H),6.29(t,J＝5.0Hz,1H),5.22–5.14(m,1H),4.21(dd,J＝20.9,9.8Hz,1H),4.02(dt,J＝12.7,4.1Hz,1H),3.92(s,3H),3.84–3.76(m,1H),3.54(ddt,J＝18.9,12.7,6.5Hz,2H),3.41(d,J＝10.6Hz,1H),2.77(s,1H),2.30(s,6H),2.15(s,1H),1.52(dd,J＝6.6,2.1Hz,3H).

Example 12 (R) -9-methyl-N- (1-methyl-2- (((R) -piperidin-3-yl) carbamoyl) -1H-imidazol-4-yl) -6-oxo-6, 7,8, 9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

First step (R) -3- (1-methyl-4-nitro-1H-imidazole-2-carboxamide) piperidine-1-carboxylic acid tert-butyl ester 12b

Compound 12a (2.50 mmol,0.49 g) was dissolved in N, N-dimethylformamide (20 mL), and compound 1i (2.75 mmol,0.5 g), N, N-diisopropylethylamine (7.49 mmol,0.97 g) and HATU (3.74 mmol,1.42 g) were added at room temperature and the reaction mixture was reacted for 14h. After TLC monitoring the completion of the reaction, water (100 mL) was added for dilution, extraction with ethyl acetate (100 ml×3), the organic phases were combined, washed with saturated brine and concentrated under reduced pressure to give crude product, which was purified by column chromatography (PE/etoac=1/1) to give compound 12b (610 mg) as a white solid.

MS(ESI)m/z 376[M+Na] ⁺ 。

Second step (R) -3- (4-amino-1-methyl-1H-imidazole-2-carboxamide) piperidine-1-carboxylic acid tert-butyl ester 12c

Compound 12b (0.40 mmol,0.14 g) was dissolved in tetrahydrofuran (10 mL) and 5% palladium on carbon (20 mg) was added to the mixture at H ₂ The reaction was carried out for 5h under (15 psi) conditions. After completion of the TLC monitoring reaction, the reaction mixture was filtered through celite, and the cake was washed with tetrahydrofuran (50 mL), and the filtrate was spin-dried to give crude compound 12c (0.12 g, crude) which was directly used for the next reaction.

MS(ESI)m/z 324[M+H] ⁺ 。

Third step (R) -3- (1-methyl-4- ((R) -9-methyl-6-oxo-6, 7,8, 9-tetrahydropyridine [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide) -1H-imidazole-2-carboxamide) piperidine-1-carboxylic acid tert-butyl ester 12d

Compound 12c (0.37 mmol,120 mg) was dissolved in N, N-dimethylformamide (5 mL), and 1g (0.37 mmol,91 mg), N, N-diisopropylethylamine (1.11 mmol,144 mg) and HATU (0.56 mmol,211 mg) were added at room temperature and the reaction mixture was reacted for 14h. After TLC monitoring the completion of the reaction, water (30 mL) was added for dilution, extraction with ethyl acetate (30 ml×3), the organic phases were combined, washed with saturated brine and concentrated under reduced pressure to give crude product, which was purified by column chromatography (PE/etoac=0/1) to give compound 12d (92 mg) as a white solid.

MS(ESI)m/z 573[M+Na] ⁺ 。

Fourth step (R) -9-methyl-N- (1-methyl-2- (((R) -piperidin-3-yl) carbamoyl) -1H-imidazol-4-yl) -6-oxo-6, 7,8, 9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide 12

Compound 12d (0.17 mmol,92.0 mg) was dissolved in 1, 4-dioxane (5 mL), 1, 4-dioxane solution (2 mL, 4.0M) of hydrochloric acid was added, and the reaction mixture was reacted at room temperature for 3h. After the completion of the reaction, TLC was monitored, the solvent was dried, slurried with ethyl acetate (5 mL) and filtered to give the hydrochloride salt of compound 12 (80 mg), as a white solid.

MS(ESI)m/z 451[M+H] ⁺ 。

¹ H NMR(400MHz,CD ₃ OD)δ8.21(d,J＝8.2Hz,1H),7.95(d,J＝8.2Hz,1H),7.61(s,1H),7.16(s,1H),5.22(ddd,J＝6.5,4.6,1.6Hz,1H),4.17(tt,J＝9.6,3.8Hz,1H),4.01(s,3H),3.94(dd,J＝13.2,4.5Hz,1H),3.53–3.49(m,1H),3.43(dd,J＝12.3,4.1Hz,1H),3.26(d,J＝12.9Hz,1H),3.03–2.95(m,2H),2.02(t,J＝8.9Hz,2H),1.82–1.71(m,2H),1.45(d,J＝6.6Hz,3H).

Example 13 (R) -9-methyl-N- (1-methyl-2- ((1-methylazetidin-3-yl) carbamoyl) -1H-imidazol-4-yl) -6-oxo-6, 7,8, 9-tetrahydropyridine [3',2':4,5] pyrrole [1,2-a ] pyrazine-2-carboxamide

First step 3- (1-methyl-4-nitro-1H-imidazole-2-carboxamide) azetidine-1-carboxylic acid tert-butyl ester 13b

Compound 1i (1.74 mmol,0.30 g) was dissolved in N, N-dimethylformamide (10 mL), and compound 13a (1.74 mmol,0.3 g), N-diisopropylethylamine (5.23 mmol,0.68 g) and HATU (2.61 mmol,0.99 g) were added at room temperature and the reaction mixture was reacted for 14h. After TLC monitoring the completion of the reaction, water (50 mL) was added for dilution, extraction with ethyl acetate (50 ml×3), the organic phases were combined, washed with saturated brine and concentrated under reduced pressure to give crude product, which was purified by column chromatography (PE/etoac=2/1) to give compound 13b (280 mg) as a white solid.

MS(ESI)m/z 326[M+H] ⁺ 。

Second step 3- (4-amino-1-methyl-1H-imidazole-2-carboxamide) azetidine-1-carboxylic acid tert-butyl ester 13c

Compound 13b (0.48 mmol,0.14 g) was dissolved in tetrahydrofuran (10 mL) and 5% palladium on carbon (30 mg) was added to the mixture at H ₂ The reaction was allowed to proceed for 6h under (15 psi). After completion of the TLC monitoring reaction, the reaction mixture was filtered through celite, and the cake was washed with tetrahydrofuran (50 mL), and the filtrate was spin-dried to give crude compound 13c (0.09 g, crude) which was directly used for the next reaction.

MS(ESI)m/z 296[M+H] ⁺ 。

Third step (R) -3- (1-methyl-4- (9-methyl-6-oxo-6, 7,8, 9-tetrahydropyrido [3',2]:4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide) -1H-imidazole-2-carboxamide) azetidine-1-carboxylic acid tert-butyl ester 13d

Compound 13c (0.34 mmol,90 mg) was dissolved in N, N-dimethylformamide (10 mL), and 1g (0.34 mmol,83 mg), N, N-diisopropylethylamine (1.02 mmol,132 mg) and HATU (0.51 mmol,132 mg) were added at room temperature and the reaction mixture was reacted at room temperature for 14h. After TLC monitoring the completion of the reaction, water (30 mL) was added for dilution, extraction with ethyl acetate (30 ml×3), the organic phases were combined, washed with saturated brine and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (PE/etoac=0/1) to give compound 13d (105 mg) as a yellow solid.

MS(ESI)m/z 523[M+H] ⁺ 。

Fourth step (R) -N- (2- (azetidin-3-ylcarbamoyl) -1-methyl-1H-imidazol-4-yl) -9-methyl-6-oxo

-6,7,8, 9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide 13e

Compound 13d (0.20 mmol,105 mg) was dissolved in 1, 4-dioxane (5 mL), 1, 4-dioxane solution (2 mL, 4.0M) of hydrochloric acid was added, and the reaction mixture was reacted at room temperature for 3h. After completion of the reaction, TLC monitored the solvent was dried to give the hydrochloride salt of compound 13e (86 mg) as a white solid.

MS(ESI)m/z 423[M+H] ⁺ 。

Fifth step (R) -9-methyl-N- (1-methyl-2- ((1-methylazetidin-3-yl) carbamoyl) -1H-imidazol-4-yl) -6-oxo-6, 7,8, 9-tetrahydropyridine [3',2':4,5] pyrrole [1,2-a ] pyrazine-2-carboxamide 13

Compound 13e (0.20 mmol,86 mg) was dissolved in methanol (10 mL) and paraformaldehyde (0.22 mmol,6 mg) was added sequentially, followed by catalytic amounts of acetic acid, sodium cyanoborohydride (0.41 mmol,26 mg) and the reaction mixture was reacted at room temperature overnight. After the completion of the reaction, the solvent was dried by TLC, dissolved in water (30 mL), saturated potassium carbonate solution (10 mL) was added, extracted with dichloromethane (20 ml×2), the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure to give a crude product, which was purified by thin layer chromatography (DCM/meoh=10/1) to give compound 13 (48 mg) as a pale yellow solid.

MS(ESI)m/z 437[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ10.47(s,1H),8.84(d,J＝8.0Hz,1H),8.43–8.40(m,2H),8.04(d,J＝8.2Hz,1H),7.75(s,1H),7.22(s,1H),5.29(t,J＝5.6Hz,1H),4.59(q,J＝7.4Hz,1H),4.04(s,3H),3.97(dd,J＝13.0,4.5Hz,2H),3.81(t,J＝7.7Hz,2H),3.54(dd,J＝12.8,5.2Hz,2H),2.48(s,3H),1.52(d,J＝6.6Hz,3H).

Example 14 (R) -9-methyl-N- (1-methyl-2- ((1-methylpiperidin-4-yl) carbamoyl) -1H-imidazol-4-yl) -6-oxo-6, 7,8, 9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

First step 1-methyl-N- (1-methylpiperidin-4-yl) -4-nitro-1H-imidazole-2-carboxamide 14b

Compound 1i (2.63 mmol,0.45 g) was dissolved in N, N-dimethylformamide (10 mL), and compound 14a (2.63 mmol,0.30 g), N, N-diisopropylethylamine (7.88 mmol,1.02 g) and HATU (3.94 mmol,1.50 g) were added at room temperature and the reaction mixture was reacted for 14h. After TLC monitoring the completion of the reaction, water (80 mL) was added for dilution, extraction with ethyl acetate (50 ml×3), the organic phases were combined, washed with saturated brine and concentrated under reduced pressure to give crude product, which was purified by column chromatography (PE/etoac=2/1) to give compound 14b (520 mg) as a white solid.

MS(ESI)m/z 268[M+H] ⁺ 。

Second step 4-amino-1-methyl-N- (1-methylpiperidin-4-yl) -1H-imidazole-2-carboxamide 14c

Compound 14b (0.45 mmol,0.12 g) was dissolved in tetrahydrofuran (10 mL) and 5% palladium on carbon (30 mg) was added to the mixture at H ₂ The reaction was allowed to proceed for 6h under (15 psi). After completion of the TLC monitoring reaction, the reaction mixture was filtered through celite, and the cake was washed with tetrahydrofuran (50 mL), and the filtrate was spin-dried to give crude compound 14c (0.10 g, crude) which was directly used for the next reaction.

MS(ESI)m/z 238[M+H] ⁺ 。

Third step (R) -9-methyl-N- (1-methyl-2- ((1-methylpiperidin-4-yl) carbamoyl) -1H-imidazol-4-yl) -6-oxo-6, 7,8, 9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide 14

Compound 14c (0.42 mmol,100 mg) was dissolved in N, N-dimethylformamide (10 mL), and 1g (0.42 mmol,103 mg), N, N-diisopropylethylamine (1.26 mmol,163 mg) and HATU (0.63 mmol,240 mg) were added at room temperature and the reaction mixture was reacted at room temperature for 14h. After TLC monitoring the reaction was complete, water (30 mL) was added for dilution, extraction with ethyl acetate (30 ml×3), the combined organic phases were washed with saturated brine and the organic phase was concentrated under reduced pressure to give the crude product which was purified by column chromatography (DCM/meoh=5/1) to give compound 14 (68 mg) as a yellow solid.

MS(ESI)m/z 465[M+H] ⁺ 。

¹ H NMR(400MHz,CD ₃ OD)δ8.16(d,J＝8.2Hz,1H),7.90(d,J＝8.2Hz,1H),7.46(d,J＝3.5Hz,1H),7.12(s,1H),5.14(tt,J＝7.0,5.3Hz,1H),3.92(s,3H),3.88(d,J＝4.4Hz,1H),3.53–3.38(m,2H),3.04(d,J＝12.2Hz,2H),2.50(t,J＝11.8Hz,2H),2.43(s,3H),1.94(dd,J＝13.5,3.9Hz,2H),1.75–1.62(m,2H),1.41(d,J＝6.7Hz,3H).

Example 15 (R) -N- (2- ((1, 3-Dimethylazetidin-3-yl) carbamoyl) -1-methyl-1H-imidazol-4-yl) -9-methyl-6-oxo-6, 7,8, 9-tetrahydropyridine [3',2':4,5] pyrrole [1,2-a ] pyrazine-2-carboxamide

First step 3-methyl-3- (1-methyl-4-nitro-1H-imidazole-2-carboxamide) azetidine-1-carboxylic acid tert-butyl ester 15b

Compound 1i (1.61 mmol,0.28 g) was dissolved in N, N-dimethylformamide (10 mL), and compound 15a (1.61 mmol,0.3 g), N, N-diisopropylethylamine (4.83 mmol,0.62 g) and HATU (2.42 mmol,0.92 g) were added at room temperature and the reaction mixture was reacted for 14h. After TLC monitoring the completion of the reaction, water (50 mL) was added for dilution, extraction with ethyl acetate (50 ml×3), the organic phases were combined, washed with saturated brine and concentrated under reduced pressure to give crude product, which was purified by column chromatography (PE/etoac=2/1) to give compound 15b (410 mg) as a white solid.

MS(ESI)m/z 340[M+H] ⁺ 。

Second step 3- (4-amino-1-methyl-1H-imidazole-2-carboxamide) -3-methylazetidine-1-carboxylic acid tert-butyl ester 15c

Compound 15b (0.62 mmol,0.21 g) was dissolved in tetrahydrofuran (10 mL) and 5% palladium on carbon (30 mg) was added to the mixture at H ₂ The reaction was allowed to proceed for 6h under (15 psi). After completion of the TLC monitoring reaction, the reaction mixture was filtered through celite, and the cake was washed with tetrahydrofuran (50 mL), and the filtrate was spin-dried to give crude compound 15c (0.19 g, crude) which was directly used for the next reaction.

MS(ESI)m/z 310[M+H] ⁺ 。

Third step (R) -3-methyl-3- (1-methyl-4- (9-methyl-6-oxo-6, 7,8, 9-tetrahydropyrido [3',2]:4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide) -1H-imidazole-2-carboxamide) azetidine-1-carboxylic acid tert-butyl ester 15d

Compound 15c (0.61 mmol,190 mg) was dissolved in N, N-dimethylformamide (10 mL), and 1g (0.56 mmol,137 mg) of N, N-diisopropylethylamine (1.68 mmol,217 mg) and HATU (0.84 mmol,319 mg) were added at room temperature and the reaction mixture was reacted at room temperature for 14h. After TLC monitoring the completion of the reaction, water (30 mL) was added for dilution, extraction with ethyl acetate (30 ml×3), the organic phases were combined, washed with saturated brine and concentrated under reduced pressure to give crude product, which was purified by column chromatography (PE/etoac=0/1) to give compound 15d (190 mg) as a yellow solid.

MS(ESI)m/z 537[M+H] ⁺ 。

Fourth step (R) -9-methyl-N- (1-methyl-2- ((3-methylazetidin-3-yl) carbamoyl) -1H-imidazol-4-yl) -6-oxo-6, 7,8, 9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide 15e

Compound 15d (0.35 mmol,190 mg) was dissolved in 1, 4-dioxane (8 mL), 1, 4-dioxane solution of hydrochloric acid (3 mL, 4.0M) was added, and the reaction mixture was reacted at room temperature for 3h. After completion of the reaction by TLC, the solvent was dried to give the hydrochloride salt of compound 15e (154 mg) as a white solid.

MS(ESI)m/z 437[M+H] ⁺ 。

Fifth step (R) -N- (2- ((1, 3-Dimethylazetidin-3-yl) carbamoyl) -1-methyl-1H-imidazol-4-yl) -9-methyl-6-oxo-6, 7,8, 9-tetrahydropyridine [3',2':4,5] pyrrole [1,2-a ] pyrazine-2-carboxamide 15

Compound 15e (0.35 mmol,154 mg) was dissolved in methanol (10 mL), paraformaldehyde (0.39 mmol,11 mg), acetic acid (catalytic amount), sodium cyanoborohydride (0.71 mmol,45 mg) were added sequentially, and the reaction mixture was reacted at room temperature overnight. After TLC monitoring the reaction, the solvent was dried, water (30 mL) and saturated potassium carbonate solution (10 mL), extracted with dichloromethane (20 ml×2), the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure to give the crude product, which was purified by thin layer chromatography (DCM/meoh=10/1) to give compound 15 (70 mg) as a pale yellow solid.

MS(ESI)m/z 451[M+H] ⁺ 。

¹ HNMR(400MHz,CD ₃ OD)δ8.19(dd,J＝8.3,2.2Hz,1H),7.93(d,J＝8.2Hz,1H),7.50(s,1H),7.15(d,J＝5.7Hz,1H),5.18(dddd,J＝11.4,6.5,4.7,1.7Hz,1H),3.95(s,3H),3.95–3.87(m,1H),3.79(d,J＝9.1Hz,2H),3.71(dd,J＝13.0,1.7Hz,1H),3.65(d,J＝9.1Hz,2H),2.55(s,3H),1.58(s,3H),1.45(dd,J＝6.6,1.7Hz,3H).

Example 16 (R) -9-methyl-N- (1-methyl-2- (((S) -1-methylpyrrolidin-3-yl) carbamoyl) -1H-imidazol-4-yl) -6-oxo-6, 7,8, 9-tetrahydropyridine [3',2':4,5] pyrrole [1,2-a ] pyrazine-2-carboxamide

First step (S) -1-methyl-N- (1-methylpyrrolidin-3-yl) -4-nitro-1H-imidazole-2-carboxamide 16b

Compound 16a (4.99 mmol,0.5 g) was dissolved in N, N-dimethylformamide (15 mL), and compound 1i (4.99 mmol,884 mg), N, N-diisopropylethylamine (14.98 mmol,1.94 g) and HATU (7.49 mmol,2.85 g) were added at room temperature and the reaction mixture was reacted at room temperature for 14h. After TLC monitoring the reaction was complete, water (80 mL) was added for dilution, extraction with ethyl acetate (50 ml×3), the combined organic phases were washed with saturated brine and the organic phase was concentrated under reduced pressure to give the crude product which was purified by column chromatography (DCM/meoh=15/1) to give compound 16b (630 mg) as a white solid.

¹ H NMR(500MHz,CD ₃ OD)δ2.19-2.28(m,1H),2.52-2.59(m,1H),2.99(s,3H),3.35-3.42(m,1H),3.53-3.57(m,1H),3.60-3.71(m,2H),4.08(s,3H),4.58-4.65(m,1H),8.27(s,1H)。

Second step (S) -4-amino-1-methyl-N- (1-methylpyrrolidin-3-yl) -1H-imidazole-2-carboxamide 16c

Compound 16b (0.79 mmol,0.20 g) was dissolved in tetrahydrofuran (10 mL) and 5% palladium on carbon (17 mg) was added to the mixture at H ₂ The reaction was carried out for 5h under (15 psi) conditions. After completion of the TLC monitoring reaction, the reaction mixture was filtered through celite, and the cake was washed with tetrahydrofuran (50 mL), and the filtrate was spin-dried to give crude compound 16c (170 mg, crude), which was directly used in the next reaction.

MS(ESI)m/z 224[M+H] ⁺ 。

(R) -9-methyl-N- (1-methyl-2- (((S) -1-methylpyrrolidin-3-yl) carbamoyl) -1H-imidazol-4-yl) -6-oxo-6, 7,8, 9-tetrahydropyridine [3',2':4,5] pyrrole [1,2-a ] pyrazine-2-carboxamide 16

Compound 16c (0.43 mmol,97 mg) was dissolved in N, N-dimethylformamide (5 mL), and 1g (0.39 mmol,97 mg) of N, N-diisopropylethylamine (1.19 mmol,153 mg) and HATU (0.59 mmol,226 mg) were added at room temperature and the reaction mixture was reacted for 14h. After TLC monitoring the completion of the reaction, water (30 mL) was added for dilution, extraction with ethyl acetate (30 ml×3), the organic phases were combined, washed with saturated brine and concentrated under reduced pressure to give crude product, which was purified by column chromatography (PE/etoac=0/1) to give compound 16 (40 mg) as a white solid.

MS(ESI)m/z 451[M+H] ⁺ 。

¹ H NMR(400MHz,CD ₃ OD)δ8.19(d,J＝8.3Hz,1H),7.93(d,J＝8.2Hz,1H),7.50(s,1H),7.15(s,1H),5.18(dqt,J＝6.6,4.4,2.3Hz,1H),4.47(ddt,J＝9.2,7.2,4.7Hz,1H),3.95(s,3H),3.94–3.90(m,1H),3.50(dd,J＝13.1,1.5Hz,1H),3.03(dt,J＝10.5,7.2Hz,2H),2.83(dd,J＝10.8,4.6Hz,1H),2.76–2.69(m,1H),2.50(s,3H),2.35(dtd,J＝13.9,8.5,5.6Hz,1H),1.89(dddd,J＝13.3,6.3,4.8,1.8Hz,1H),1.45(d,J＝6.6Hz,3H).

Example 17 (R) -9-methyl-N- (1-methyl-2- (((R) -tetrahydrofurane-3-yl) carbamoyl) -1H-imidazol-4-yl) -6-oxo-6, 7,8, 9-tetrahydropyridine [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

First step (R) -1-methyl-4-nitro-N- (tetrahydrofuran-3-yl) -1H-imidazole-2-carboxamide 17b

Compound 1i (3.51 mmol,0.60 g) was dissolved in N, N-dimethylformamide (10 mL), and compound 17a (2.86 mmol,0.34 g), N, N-diisopropylethylamine (10.52 mmol,1.36 g) and HATU (5.26 mmol,2.00 g) were added at room temperature and the reaction mixture was reacted at room temperature for 14h. After TLC monitoring the completion of the reaction, water (50 mL) was added for dilution, extraction with ethyl acetate (50 ml×3), the organic phases were combined, washed with saturated brine and concentrated under reduced pressure to give crude product, which was purified by column chromatography (PE/etoac=2/1) to give compound 17b (670 mg) as a white solid.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.89(d,J＝7.1Hz,1H),8.57(s,1H),4.48–4.38(m,1H),4.00(s,3H),3.89–3.81(m,2H),3.76–3.69(m,1H),3.60(dd,J＝8.8,4.9Hz,1H),2.12(dtd,J＝12.6,8.0,6.6Hz,1H),2.04–1.95(m,1H).

Second step (R) -4-amino-1-methyl-N- (tetrahydrofuran-3-yl) -1H-imidazole-2-carboxamide 17c

Compound 17b (0.58 mmol,0.14 g) was dissolved in tetrahydrofuran (10 mL) and 5% palladium on carbon (28 mg) was added to the mixture at H ₂ The reaction was carried out for 5h under (15 psi) conditions. After completion of the TLC monitoring reaction, the reaction mixture was filtered through celite, and the filtrate was dried to give crude compound 17c (0.11 g, crude) which was directly used for the next reaction.

MS(ESI)m/z 211[M+H] ⁺ 。

(R) -9-methyl-N- (1-methyl-2- (((R) -tetrahydrofurane-3-yl) carbamoyl) -1H-imidazol-4-yl) -6-oxo-6, 7,8, 9-tetrahydropyridine [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide 17

Compound 17c (0.42 mmol,110 mg) was dissolved in N, N-dimethylformamide (5 mL), and 1g (0.42 mmol,102 mg) of N, N-diisopropylethylamine (1.37 mmol,138 mg) and HATU (0.69 mmol,261 mg) were added at room temperature and the reaction mixture was reacted at room temperature for 14h. After completion of the TLC monitoring reaction, water (30 mL) was added for dilution, extraction with ethyl acetate (30 ml×3), the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (PE/etoac=0/1) to give compound 17 (60 mg),

yellow solid.

MS(ESI)m/z 438[M+H] ⁺ 。

¹ H NMR(400MHz,D ₂ O)δ1.53(d,J＝6.8Hz,3H),2.35-2.24(m,2H),3.60-3.57(m,1H),3.76-3.73(m,1H),3.86-3.84(m,1H),3.96-3.92(m,1H),4.02-3.99(m,2H),4.04(s,3H),4.57-4.52(m,1H),5.28-5.26(m,1H),7.24(s,1H),7.59(s,1H),8.02(d,J＝8.0Hz,1H),8.28(d,J＝8.0Hz,1H)。

Example 18 (R) -N- (2- ((1, 3-Dimethylazetidin-3-yl) carbamoyl) -1-ethyl-1H-imidazol-4-yl) -9-methyl-6-oxo-6, 7,8, 9-tetrahydropyridine [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

/>

First step 3-methyl-3- (1-ethyl-4-nitro-1H-imidazole-2-carboxamido) azetidine-1-carboxylic acid tert-butyl ester 18b

Compound 18a (1.34 mmol,0.23 g) was dissolved in N, N-dimethylformamide (10 mL), and compound 15a (1.48 mmol,0.28 g), N, N-diisopropylethylamine (4.03 mmol,0.52 g) and HATU (2.02 mmol,0.77 g) were added at room temperature and the reaction mixture was reacted for 14h. After TLC monitoring the completion of the reaction, water (50 mL) was added for dilution, extraction with ethyl acetate (50 ml×3), the organic phases were combined, washed with saturated brine and concentrated under reduced pressure to give crude product, which was purified by column chromatography (PE/etoac=2/1) to give compound 18b (380 mg) as a white solid.

MS(ESI)m/z 354[M+H] ⁺ 。

Second step 3- (4-amino-1-ethyl-1H-imidazole-2-carboxamido) -3-methylazetidine-1-carboxylic acid tert-butyl ester 18c

Compound 18b (0.57 mmol,0.20 g) was dissolved in tetrahydrofuran (10 mL) and 5% palladium on carbon (30 mg) was added to the mixture at H ₂ The reaction was allowed to proceed for 6h under (15 psi). After completion of the TLC monitoring reaction, the reaction mixture was filtered through celite, and the cake was washed with tetrahydrofuran (50 mL), and the filtrate was spin-dried to give crude compound 18c (0.14 g, crude) which was directly used for the next reaction.

MS(ESI)m/z 324[M+H] ⁺ 。

(R) -3- (1-Ethyl-4- (9-methyl-6-oxo-6, 7,8, 9-tetrahydropyridine [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamido) -1H-imidazole-2-carboxamido) -3-methylazetidine-1-carboxylic acid tert-butyl ester 18d

Compound 18c (0.43 mmol,140 mg) was dissolved in N, N-dimethylformamide (10 mL), and 1g (0.43 mmol,106 mg), N, N-diisopropylethylamine (1.30 mmol,168 mg) and HATU (0.65 mmol,247 mg) were added at room temperature and the reaction mixture was reacted at room temperature for 14h. After completion of the TLC monitoring reaction, water (30 mL) was added for dilution, extraction with ethyl acetate (30 ml×3), the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (PE/etoac=0/1) to give compound 18d (76 mg),

Yellow solid.

MS(ESI)m/z 551[M+H] ⁺ 。

Fourth step (R) -9-methyl-N- (1-ethyl-2- ((3-methylazetidin-3-yl) carbamoyl) -1H-imidazol-4-yl) -6-oxo-6, 7,8, 9-tetrahydropyridine [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide 18e

Compound 18d (0.14 mmol,76 mg) was dissolved in 1, 4-dioxane (5 mL), 1, 4-dioxane solution (2 mL, 4.0M) of hydrochloric acid was added, and the reaction mixture was reacted at room temperature for 3h. After the completion of the reaction, TLC was monitored, the solvent was dried, slurried with ethyl acetate (5 mL) and filtered to give the hydrochloride salt of compound 18e (62 mg), as a white solid.

MS(ESI)m/z 451[M+H] ⁺ 。

Fifth step (R) -N- (2- ((1, 3-Dimethylazetidin-3-yl) carbamoyl) -1-ethyl-1H-imidazol-4-yl) -9-methyl-6-oxo-6, 7,8, 9-tetrahydropyridine [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide 18

Compound 18e (0.14 mmol,62 mg) was dissolved in methanol (10 mL) and paraformaldehyde (0.15 mmol,5 mg) was added sequentially, catalytic amounts of acetic acid, sodium cyanoborohydride (0.28 mmol,18 mg) and the reaction mixture was reacted at room temperature overnight. After the completion of the reaction, the solvent was dried by TLC, dissolved in water (30 mL), saturated potassium carbonate solution (10 mL) was added, extracted with dichloromethane (20 ml×2), the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure to give a crude product, which was purified by thin layer chromatography (DCM/meoh=10/1) to give compound 18 (42 mg) as a yellow solid.

MS(ESI)m/z 465[M+H] ⁺ 。

¹ H NMR(400MHz,D ₂ O)δ1.38(t,J＝7.2Hz,3H),1.45(d,J＝6.8Hz,3H),1.60(s,3H),2.72(s,3H),3.5(d,J＝12Hz,1H),3.84(d,J＝10Hz,2H),3.95-3.90(m,1H),4.13(d,J＝9.6Hz,2H),4.45(q,J＝7.2Hz,2H),5.22-5.16(m,1H),7.18(d,J＝6.4Hz,1H),7.59(s,1H),7.96(d,J＝8.4Hz,1H),8.22(dd,J＝1.6Hz,6.4Hz,1H)。

Example 19 (R) -9-methyl-N- (1-methyl-2- ((1-ethyl-3-methylazacyclobuten-3-yl) carbamoyl) -1-H-imidazol-4-yl) -6-oxo-6, 7,8, 9-tetrahydropyridine [3',2':4,5] pyrrole [1,2-a ] pyrazine-2-carboxamide

Compound 15e (0.18 mmol,80 mg) was dissolved in methanol (10 mL) and acetaldehyde (0.22 mmol,10 mg) was added sequentially, catalytic amounts of acetic acid, sodium cyanoborohydride (0.37 mmol,23 mg) and the reaction mixture was reacted at room temperature overnight. After the completion of the reaction, the solvent was dried by TLC, dissolved in water (30 mL), saturated potassium carbonate solution (10 mL) was added, extracted with dichloromethane (20 ml×2), the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure to give a crude product, which was purified by thin layer chromatography (DCM/meoh=10/1) to give compound 19 (20 mg) as a yellow solid.

MS(ESI)m/z 465[M+H] ⁺ 。

¹ H NMR(400MHz,D ₂ O)δ1.07(t,J＝7.2Hz,3H),1.45(d,J＝6.8Hz,3H),1.61(s,3H),3.04-2.99(m,2H),3.52-3.48(m,1H),3.82(d,J＝10Hz,2H),3.92(dd,J＝4.4Hz,13.2Hz,1H),3.97(s,3H),4.10(d,J＝12.4Hz,2H),5.20-5.14(m,1H),7.16(s,1H),7.53(s,1H),7.95(d,J＝8.0Hz,1H),8.22(d,J＝8Hz,1H)。

Example 20 (R) -N- (2- ((1, 3-Dimethylazetidin-3-yl) carbamoyl) -1-methyl-1H-imidazol-5-yl) -9-methyl-6-oxo-6, 7,8, 9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide

First step 3-methyl-3- (1-methyl-4-nitro-1H-imidazole-2-carboxamido) azetidine-1-carboxylic acid tert-butyl ester 20b

Compound 20a (1.34 mmol,0.23 g) was dissolved in N, N-dimethylformamide (10 mL), and compound 15a (1.48 mmol,0.28 g), N-diisopropylethylamine (4.03 mmol,0.52 g) and HATU (2.02 mmol,0.77 g) were added at room temperature and the reaction mixture was reacted for 14h. After TLC monitoring the completion of the reaction, water (50 mL) was added for dilution, extraction with ethyl acetate (50 ml×3), the organic phases were combined, washed with saturated brine and concentrated under reduced pressure to give crude product, which was purified by column chromatography (PE/etoac=2/1) to give compound 20b (380 mg) as a white solid.

MS(ESI)m/z 340[M+H] ⁺ 。

Second step 3- (5-amino-1-methyl-1H-imidazole-2-carboxamido) -3-methylazetidine-1-carboxylic acid tert-butyl ester 20c

Compound 20b (0.57 mmol,0.20 g) was dissolved in tetrahydrofuran (10 mL) and 5% palladium on carbon (30 mg) was added to the mixture at H ₂ The reaction was allowed to proceed for 6h under (15 psi). After completion of the TLC monitoring reaction, the reaction mixture was filtered through celite, and the cake was washed with tetrahydrofuran (50 mL), and the filtrate was spin-dried to give crude compound 20c (0.14 g, crude) which was directly used in the next reaction.

MS(ESI)m/z 310[M+H] ⁺ 。

Third step (R) -3-methyl-3- (1-methyl-5- (9-methyl-6-oxo-6, 7,8, 9-tetrahydropyridine [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide) -1H-imidazole-2-carboxamide) azetidine-1-carboxylic acid tert-butyl ester 20d

Compound 20c (0.43 mmol,140 mg) was dissolved in N, N-dimethylformamide (10 mL), and 1g (0.43 mmol,106 mg), N, N-diisopropylethylamine (1.30 mmol,168 mg) and HATU (0.65 mmol,247 mg) were added at room temperature and the reaction mixture was reacted at room temperature for 14h. After TLC monitoring the completion of the reaction, water (30 mL) was added for dilution, extraction with ethyl acetate (30 ml×3), the organic phases were combined, washed with saturated brine and concentrated under reduced pressure to give crude product, which was purified by column chromatography (PE/etoac=0/1) to give compound 20d (76 mg) as a yellow solid.

MS(ESI)m/z 537[M+H] ⁺ 。

Fourth step (R) -9-methyl-N- (1-methyl-2- ((3-methylazetidin-3-yl) carbamoyl) -1H-imidazol-4-yl) -6-oxo-6, 7,8, 9-tetrahydropyridine [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide 20e

Compound 20d (0.19 mmol,100 mg) was dissolved in 1, 4-dioxane (5 mL), 1, 4-dioxane solution (2 mL, 4.0M) of hydrochloric acid was added, and the reaction mixture was reacted at room temperature for 3h. After completion of the reaction by TLC, the solvent was dried to give the hydrochloride salt of compound 20e (80 mg) as a white solid.

MS(ESI)m/z 437[M+H] ⁺ 。

Fifth step (R) -N- (2- ((1, 3-Dimethylazetidin-3-yl) carbamoyl) -1-methyl-1H-imidazol-5-yl) -9-methyl-6-oxo-6, 7,8, 9-tetrahydropyrido [3',2':4,5] pyrrolo [1,2-a ] pyrazine-2-carboxamide 20

Compound 20e (0.18 mmol,80 mg) was dissolved in methanol (10 mL) and acetaldehyde (0.22 mmol,10 mg) was added sequentially, catalytic amounts of acetic acid, sodium cyanoborohydride (0.37 mmol,23 mg) and the reaction mixture was reacted at room temperature overnight. After the completion of the reaction, the solvent was dried by TLC, dissolved in water (30 mL), saturated potassium carbonate solution (10 mL) was added, extracted with dichloromethane (20 ml×2), the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure to give a crude product, which was purified by thin layer chromatography (DCM/meoh=10/1) to give compound 20 (20 mg) as a yellow solid.

MS(ESI)m/z 465[M+H] ⁺ 。

Control Compound I (BI-D1870)

The compound was purchased commercially, manufacturer: MCE, cargo number: HY-10510

Control Compound II

Reference patent WO2017141116 A1.

Test example 1: compounds inhibit RSK2 kinase in vitro activity ₅₀ Evaluation test

The inhibition of RSK2 kinase by small molecule compounds was tested using HTRF KinEASE-STK Assay. The RSK2 kinase reaction system is 5uL, and the final concentration of each component is as follows: RSK2 recombinase (Carna, cat. No. 01-150), small molecule inhibitors at different concentration gradients, 5mM MgCl2, 1mM DTT, 10. Mu.M ATP, 1. Mu.MSTK 1-substate (Cisbio, cat. No. 611 ST1 BLC), 1X kinase reaction buffer (Cisbio, cat. No. #62 EzBFDD). Specifically, the reaction was terminated by adding 2.5×RSK2 recombinase with 5×inhibitor to a buffer system in 384 well plates for 10 minutes at room temperature while setting a negative control well containing no enzyme and a positive control well containing no compound, then adding 2.5×polypeptide substrate with ATP, starting the reaction, adding 5 μl of a mixture of the corresponding 2×phosphorylated antibody STK-anti-crynate (Cisbio, cat No. 62ST0PEB) and the substrate tag antibody Sa-XL 665 (Cisbio, cat No. 610SAXLA) after 30 minutes at room temperature, and standing at room temperature for 60 minutes. Reading the values excited at 320nm, emitted at 620nm and emitted at 665nm on an HTS high-flux drug sieve multifunctional enzyme-labeled instrument, calculating RFU 620nm/RFU 665nm, calculating inhibition rate by the following formula, drawing a curve by taking the Log value of the concentration of the inhibitor as an X axis and the inhibition rate as a Y axis, and calculating by using Graphpad 7.0 to obtain the IC ₅₀ Values.

Average value of positive control well ratio (10. Mu.M BI-D1870)

Average value of negative control well ratio (0.5% DMSO)

TABLE 1 test of compounds for in vitro inhibitory Activity against RSK2 kinase

Experimental results show that the compound has good inhibition effect on RSK2 kinase.

Test example 2: compounds for inhibiting proliferation of triple negative breast cancer cells

Compound or vehicle control (DMSO) was diluted in 96-well plates at final concentrations of 50, 25, 12.5, 6.25, 3.13.1.56, 0.78, 0.39, 0.2, 0.1 μm in culture medium. Inoculating 1X10 per well ³ MDA-MB-453 cells were plated and the plates were incubated in an incubator for 5 days. After the incubation period, cell viability was quantified by the Cell Counting Kit-8 (abbreviated CCK-8) reagent. Briefly, cells were incubated with CCK8 for 2-4 hours and absorbance at 450nm and 650nm was measured. CCK-8 is WST-8 (chemical name: 2- (2-Methoxy-4-nitrophenyl) -3- (4-nitrophenyl) -5- (2, 4-disulfonic acid benzene) -2H-tetrazolium monosodium salt), which is reduced by dehydrogenase in cells to yellow Formazan product (Formazan dye) with high water solubility under the action of electron carrier 1-Methoxy-5-methylphenazinium dimethyl sulfate (1-Methoxy PMS). The number of formazans produced is proportional to the number of living cells, and thus this property can be exploited to calculate percent survival as shown in the following formula:

Cell viability (%) = [ (As-Ac)/(Ab-Ac) ] ×100% ]

As: experimental hole (treatment holes containing cells and different concentrations)

Ab: solvent control well (solvent treatment well with cell and drug concentration of 0)

Ac: blank hole (hole without cell and medicine)

Cell viability data and concentrations of their corresponding compounds were entered into GraphPad Prism software fit to calculate IC50 values.

TABLE 1 test Compounds for MDA-MB-453 cell proliferation inhibiting Activity

Experimental results show that the compound has good proliferation inhibition activity on MDA-MB-453 cells.

Test example 3: pharmacokinetic test

Mouse pharmacokinetic experiments Male ICR mice, 20-25g, were used. 3 overnight fasted mice were taken and administered orally by gavage (10 mg/kg). Blood was collected before dosing, and 15, 30 minutes and 1, 2, 4, 8, 24 hours after dosing; in addition, 3 mice were taken and administered intravenously (1 mg/kg), and blood was collected before administration, and 15, 30 minutes and 1, 2, 4, 8, and 24 hours after administration. Blood samples 6800g were centrifuged at 2-8deg.C for 6 minutes, and plasma was collected and stored at-80deg.C. Plasma at each time point is taken, 10-20 times of methanol or acetonitrile solution containing an internal standard is added for mixing, vortex mixing is carried out for 1 minute, 18000 revolutions per minute and centrifugation is carried out at 4 ℃ for 10 minutes, and supernatant is taken for direct LC-MS/MS analysis. The principal pharmacokinetic parameters were analyzed using the WinNonlin 7.0 software non-compartmental model.

All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims

1. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof:

wherein,

n is 1 or 2;

m is selected from N or CR _a ；

R ₅ selected from the group consisting of: H. c (C) _1-6 An alkyl group;

R _b selected from the group consisting of: D. halogen, hydroxy, cyano, amino, imino, C _1-4 Alkyl, C _1-4 Alkoxy, C _1-6 Alkylamino, C _1-4 Haloalkyl, C _1-4 Haloalkoxy, C _2-4 Alkenyl, C _1-4 Haloalkenyl, C _2-4 Alkynyl, C _1-4 Haloalkynyl、C _3-6 Cycloalkyl, C _6-10 Aryl, 5-12 membered heteroaryl;

In another preferred embodiment, R ₄ Selected from 4-12 membered heterocyclyl; and the heterocyclic group is preferably a nitrogen-containing heterocyclic group.

2. The compound of formula I according to claim 1, wherein R is a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof ₄ Has a structure selected from the group consisting of:

3. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I has the structure shown below:

In another preferred embodiment, R ₁ H.

In another preferred embodiment, R ₇ Is CH ₃ 。

In another preferred embodiment, R ₅ H.

4. The compound of formula I according to claim 1, wherein R is a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof ₄ 、R ₅ Together with the nitrogen atom to which it is attached, forms a heterocyclic group having a structure selected from the group consisting of:

，

5. The compound of formula I according to claim 1, wherein R is a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof ₂ 、R ₃ Each independently selected from the group consisting of: H. c (C) _1-3 Alkyl, and said alkyl may be substituted with one or more R _b And (3) substitution.

6. The compound of formula I according to claim 1, wherein R is a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof ₇ Selected from the group consisting of: H. c (C) _1-4 Alkyl, C _3-8 Cycloalkyl, and R is as described ₇ Can be independently one or more R _b And (3) substitution.

7. A compound of formula I according to claim 1, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

8. a pharmaceutical composition, said pharmaceutical composition comprising: a compound of formula I as defined in claim 1, one or more of its pharmaceutically acceptable salts, racemates, R-isomers, S-isomers or mixtures thereof, together with one or more pharmaceutically acceptable carriers, excipients, adjuvants and/or diluents.

9. The use of a compound of formula I as defined in claim 1, in the form of a pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or a mixture thereof, for the preparation of a pharmaceutical composition for use in the treatment of a disease or condition associated with p90 Ribosomal S6 Kinase (RSK) activity.

In another preferred embodiment, the disease or condition is cancer.

10. The use according to claim 9, wherein the disease or condition is selected from the group consisting of: breast cancer, prostate cancer, lung cancer, brain cancer, skin cancer, bone cancer, ovarian cancer, multiple myeloma or leukemia.