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

Abstract

The invention provides a carboxamide derivative with an RSK inhibition effect, a pharmaceutical composition containing the carboxamide derivative and application of the carboxamide derivative. The invention provides a carboxamide derivative which can be used as a p90 ribosome S6 kinase (RSK) inhibitor and is shown in a formula (I), a tautomer, a stereoisomer, a hydrate, a solvate and a pharmaceutically acceptable salt of the carboxamide derivative, a pharmaceutical composition containing the compound, and application of the carboxamide derivative in preparation of the pharmaceutical composition. # imgabs0 #

Description

A carboxamide derivative with RSK inhibitory effect, a pharmaceutical composition containing the same and its use Technical Field

[0001] The present invention relates to the field of medicinal chemistry. Specifically, the present invention provides a RSK inhibitor with a novel structure. Background Art

[0002] The Ras-MAPK and PI3K-PDK1 pathways are often aberrantly activated in many cancers. The MAPK and PI3K signaling cascades converge on the activation of the downstream protein kinases RSK and YB-1, leading to poor prognosis and resistance to chemotherapy and radiotherapy. The p90 ribosomal S6 kinases (RSKs) family belongs to the serine / threonine kinase family and consists of RSK1, RSK2, RSK3, and RSK4. RSK1-4 share high sequence homology (73-80%), but differ most significantly at the N- and C-termini. RSKs comprise two functionally distinct kinase domains—an N-terminal kinase domain (NTKD) and a C-terminal kinase domain (CTKD)—connected by a regulatory linker domain. Activation of RSK requires sequential phosphorylation of ERK1 / 2 at CTKD, autophosphorylation of the linker domain, and regulates diverse cellular processes such as cell growth, proliferation, survival, and motility by phosphorylating various substrates, such as YB-1, GSK3β, BAD, procaspase-8, TSC2, and c-Fos.

[0003] RSK1-3 expression states vary widely. RSK1 and RSK2 are the most common isoforms in cancer, and their expression and activation promote tumor growth and survival. RSK3 is not typically expressed in cancer, but like RSK1 and RSK2, it is associated with drug resistance. RSK4, on the other hand, is primarily expressed during embryonic development. Its role in malignant tumors remains unclear and may be tissue-specific. RSK4 exhibits primarily cytoplasmic characteristics and constitutively active states, as well as growth-element-independent kinase activity. Inhibiting RSK activation, through mechanisms such as elimination of cancer stem cells (CSCs) or tumor-initiating cells (TICs), can be used to treat a variety of RSK-related tumors, including but not limited to breast, prostate, lung, brain, blood, skin, bone, and ovarian cancers. Studies have reported that approximately 70% of patients with locally advanced breast cancer, predominantly ER+ / PR+, have RSK activation, and approximately 85% of TNBC tumors have RSK activation. Studies have shown that RSK inhibitors can induce tumor cell apoptosis and inhibit metastasis. Compared to MEK inhibitors, they do not induce Akt activation, making them more advantageous in combination therapy for addressing drug resistance and providing a new therapeutic approach for TNBC. In prostate cancer treatment, RSK2 binds to p300 and agonistsly regulates the AR transcriptional program. RSK inhibitors can block hormone pathways and induce drug resistance by blocking the YB-1 pathway. RSK inhibitors hold promise for the treatment of castration-resistant prostate cancer and in combination therapy. In acute myeloid leukemia (AML), overexpression and aberrant activation of RSK isoforms lead to adverse outcomes and chemotherapy resistance. RSK inhibitors block CREB phosphorylation at Ser133, thereby inhibiting the proliferation and survival of myeloid cells by inducing Bcl-2, cyclin A, and cyclin D expression.

[0004] Previous studies have confirmed that RSK plays a crucial role in various cell life processes, including growth, proliferation, apoptosis, and transformation. Increased RSK activation has been implicated in the etiology of numerous pathologies, including various types of cancer, cardiovascular disease, liver and pulmonary fibrosis, and infection. In recent years, numerous small molecule RSK inhibitors have emerged, such as SL0101, BI-D1870, FMK, and PMD-026. Some RSK inhibitors (PMD-026) have entered clinical trials, and some have achieved encouraging early results (NCT04115306). However, the pharmacokinetic properties of most molecules are poor, hindering in vivo studies. Therefore, the development of RSK inhibitors with enhanced activity and pharmacokinetics holds great promise for the pharmaceutical industry.

[0005] Summary of the Invention

[0006] The object of the present invention is to provide a carboxamide derivative having RSK inhibitory effect.

[0007] The first aspect of the present invention provides a compound represented by the following formula (I), its tautomers, stereoisomers, hydrates, solvates, or pharmaceutically acceptable salts thereof:

[0008] in,

[0009] n is 1 or 2;

[0010] M is each independently N or CR a ;

[0011] R a Selected from the group consisting of halogen, cyano, C 1-4 alkoxy;

[0012] X, Y and Q are each independently selected from the group consisting of: CR b , or N; Z is selected from the following group: S, O or NR b ;and For aromatic rings, when the connection site is located at CR b , or NR b When the CR b , or NR b C or N;

[0013] L is selected from the following group: chemical bond, -C(=O)-, CHR b 、C(R b )2, NH or O;

[0014] Ring A is selected from the group consisting of: C 6-10 Aryl, 5-12 membered heteroaryl;

[0015] R1 is selected from the group consisting of H, D, halogen, amino, C 1-4 alkyl;

[0016] R2 and R3 are each independently selected from the following group: H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, wherein R2 and R3 may be the same or different;

[0017] R4 is selected from the group consisting of H, D, halogen, hydroxy, amino, C 2-6 Sulfonyl, sulfinyl, -N=S(O)(CH3)2, Phosphoryl (-P(O)(CH3)2), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 1-6 Halogenated alkenyl, C2-6 Alkynyl, C 1-6 Haloalkynyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-12 membered heterocyclic group, 5-12 membered heteroaryl; the heterocyclic group and heteroaryl independently contain 1-3 heteroatoms selected from N, O, and S;

[0018] R5 is selected from the group consisting of H, halogen, hydroxy, amino, sulfonyl, sulfinyl, phosphoryl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 1-6 Halogenated alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkynyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-12 membered heterocyclic group, 5-12 membered heteroaryl; the heterocyclic group and heteroaryl independently contain 1-3 heteroatoms selected from N, O, and S;

[0019] R8 is selected from the group consisting of H, halogen;

[0020] Furthermore, the R1, R2, R3, R 4、 R5 may optionally be replaced by one or more R b replace;

[0021] R b Selected from the group consisting of D, halogen, hydroxy, cyano, amino, imino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 2-4 Alkenyl, C 1-4 Halogenated alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkynyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-12 membered heteroaryl;

[0022] When the compound has the structure shown in formula I-1, and M is N, ring A is not phenyl which is unsubstituted or substituted by a substituent selected from the group consisting of halogen, C 1-6 Alkyl, C 1-6 Haloalkyl-N(R 7 )2, or -C 1-6 Alkyl-N(R 7 )2; where R 7 H or C 1-6 alkyl .

[0023] In some embodiments, the compound has a structure shown in Formula I-1:

[0024] wherein L is selected from the group consisting of a chemical bond, CH2, CF2, CHMe, and C(Me)2;

[0025] When M is N, R4 is H, D, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy; R5 is -N=S(O)(CH3)2, Phosphoryl (-P(O)(CH3)2), C 1-6 Alkyl, C 3-6 Cycloalkyl;

[0026] In some embodiments, the compound has a structure shown in Formula I-2:

[0027] in,

[0028] wherein L is selected from the group consisting of a chemical bond, CH2, CF2, CHMe, and C(Me)2;

[0029] R6 is selected from the group consisting of H, D, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 1-6 Halogenated alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkynyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-12 membered heterocyclic group, 5-12 membered heteroaryl; the heterocyclic group and heteroaryl independently contain 1-3 heteroatoms selected from N, O, and S;

[0030] Furthermore, the R6 can be optionally replaced by one or more R b replace.

[0031] In some embodiments, the compound has the structure shown in Formula I-3

[0032] Wherein, R6 is selected from the following group: H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 6-10Aryl, 5-12 membered heterocyclic group, 5-12 membered heteroaryl; the heterocyclic group and heteroaryl independently contain 1-3 heteroatoms selected from N, O, S; and the R6 can be optionally replaced by one or more R b replace.

[0033] In some embodiments, R2 and R3 are preferably selected from the following groups: H, methyl, R 2, R3 are the same or different.

[0034] In some embodiments, R4 and R5 are each independently selected from the group consisting of H, halogen, amino, sulfinyl, phosphoryl, C 1-4 Alkyl, and the R4, R5 can be independently replaced by one or more R b replace.

[0035] In some embodiments, the compound is selected from the group consisting of:

[0036] In the second aspect of the present invention, a pharmaceutical composition is provided, comprising: one or more of the compound of formula I as described in the first aspect of the present invention, its pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or mixture thereof, and one or more pharmaceutically acceptable carriers, excipients, adjuvants, auxiliary materials and / or diluents.

[0037] In the third aspect of the present invention, there is provided a compound of formula I as described in the first aspect of the present invention, its pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or a mixture thereof, characterized in that it is used to prepare a pharmaceutical composition for diseases or conditions related to p90 ribosomal S6 kinase (RSK) activity.

[0038] In another preferred embodiment, the disease or condition is cancer.

[0039] 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.

[0040] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. DETAILED DESCRIPTION

[0041] After extensive and in-depth research, the present inventors have provided a carboxamide derivative with RSK inhibitory activity. These derivatives exhibit excellent RSK inhibitory activity and can therefore be used to prevent, treat, and / or alleviate RSK activation-related indications. Based on these findings, the present invention was completed.

[0042] definition

[0043] As used herein, the term "alkyl" includes straight or branched chain alkyl groups. For example, C1-C8 alkyl groups represent straight or branched chain alkyl groups having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and the like.

[0044] As used herein, the term "alkenyl" includes straight or branched alkenyl groups. For example, C2-C6 alkenyl refers to a straight or branched alkenyl group having 2 to 6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or the like.

[0045] As used herein, the term "alkynyl" includes straight or branched chain alkynyl groups. For example, C2-C6 alkynyl refers to a straight or branched chain alkynyl group having 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, or the like.

[0046] As used herein, the term "cycloalkyl" refers to a cyclic saturated aliphatic hydrocarbon group having a specific number of carbon atoms. 10 Alkenyl refers to a cyclic saturated aliphatic hydrocarbon group having 3 to 10 carbon atoms. It can be a monocyclic ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or similar groups. It can also be a bicyclic ring, such as a bridged ring or a spiro ring.

[0047] As used herein, the term "alkylamino" refers to an amino group substituted with an alkyl group. For example, a "C1-C8 alkylamino" refers to an amino group substituted with a C1-C8 alkyl group, which may be monosubstituted or disubstituted; for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, di-tert-butylamino, etc.

[0048] As used herein, the term "alkoxy" refers to a group having an alkyl-oxy structure. For example, "C1-C8 alkoxy" refers to a linear or branched alkoxy group having 1 to 8 carbon atoms, including methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, and the like.

[0049] As used herein, the term "haloalkyl" represents an alkyl group wherein one or more hydrogen atoms are replaced by a halogen, wherein alkyl is as defined above.

[0050] As used herein, the term "haloalkoxy" represents an alkoxy group having one or more hydrogen atoms replaced by a halogen, wherein alkoxy is as defined above.

[0051] As used herein, the term "heterocyclyl" or "heterocycloalkyl" refers to a saturated or partially saturated cyclic group having a specific number of ring atoms (e.g., 3-10 ring atoms), wherein 1-3 atoms are heteroatoms selected from N, S, and O. It can be a monocyclic, bicyclic, or polycyclic ring, such as a bridged ring or a spirocyclic ring. Specific examples include oxetanyl, azetidinyl, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, and pyrrolidinyl.

[0052] As used herein, the term "C6-C 10 The term "aryl" refers to an aromatic group having 6 to 10 carbon atoms, for example, phenyl or naphthyl and the like.

[0053] As used herein, the term "5-12 membered heteroaryl" refers to a cyclic aromatic group having 5-12 atoms, 1-3 of which are heteroatoms selected from the group consisting of N, S, and O. It may be a single ring or a condensed ring. Specific examples include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2,4)-triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, and oxazolyl.

[0054] Unless otherwise specified as "substituted or unsubstituted", the groups of the present invention may be substituted by substituents selected from the following groups: halogen, nitrile, nitro, hydroxyl, amino, C1-C6 alkyl-amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, halogenated C1-C6 alkoxy, allyl, benzyl, C6-C 12 Aryl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy-carbonyl, phenoxycarbonyl, C2-C6 alkynyl-carbonyl, C2-C6 alkenyl-carbonyl, C3-C6 cycloalkyl-carbonyl, C1-C6 alkyl-sulfonyl, etc.

[0055] 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.

[0056] Unless otherwise indicated, the structural formulae described herein are intended to include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers (or conformers)): for example, R and S configurations containing asymmetric centers, (Z) and (E) isomers of double bonds, etc. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformers) are all within the scope of the present invention.

[0057] As used herein, the term "tautomer" refers to structural isomers of different energies that can interconvert across a low energy barrier. For example, proton tautomers (i.e., prototropy) include interconversion via proton migration, such as 1H-indazole and 2H-indazole. Valence tautomers include interconversion via reorganization of some of the bonding electrons.

[0058] As used herein, the term "solvate" refers to a complex in which the compound of the present invention is coordinated with solvent molecules to form a specific ratio.

[0059] As used herein, the term "hydrate" refers to a complex formed by coordination of a compound of the present invention with water.

[0060] Active ingredient

[0061] The present invention provides an active ingredient that can effectively inhibit RSK. The active ingredient is a compound represented by general formula (I), and the active ingredient can effectively prevent, treat and / or alleviate RSK-related diseases.

[0062] Experiments have shown that the active ingredient of the present invention can effectively inhibit RSK kinase protein, thereby preventing, treating and / or alleviating RSK-related diseases.

[0063] It should be understood that the active ingredients of the present invention include compounds represented by general formula (I), or pharmaceutically acceptable salts thereof, or prodrugs thereof. It should be understood that the active ingredients of the present invention also include crystalline forms, amorphous compounds, and deuterated compounds of the compounds of general formula (I).

[0064] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention formed with an acid or base that is suitable for pharmaceutical use. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts are salts formed with a compound of the present invention and an acid. Suitable acids for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; 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, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid. Another preferred salt is a salt of the compound of the present invention formed with a base, such as an alkali metal salt (e.g., sodium salt or potassium salt), an alkaline earth metal salt (e.g., magnesium salt or calcium salt), an ammonium salt (e.g., lower alkanolammonium salt and other pharmaceutically acceptable amine salts), for example, methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0065] Pharmaceutical compositions and methods of administration

[0066] Since the compounds of the present invention have excellent RSK kinase inhibitory activity, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to prevent, treat and / or alleviate RSK-related diseases, such as the treatment of cancer.

[0067] The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention and a pharmaceutically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-200 mg per dose. Preferably, "one dose" is one capsule or tablet.

[0068] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compound of the present invention and with each other without significantly reducing the efficacy of the compound. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0069] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration methods include (but are not limited to): oral administration, parenteral administration (intravenous administration, intramuscular administration, or subcutaneous administration).

[0070] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0071] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0072] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0073] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0074] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0075] 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 non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0076] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable therapeutic agents.

[0077] When administered in combination, the pharmaceutical composition may further comprise 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 compound of the present invention to prevent, treat, and / or alleviate RSK-mediated diseases.

[0078] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician. Beneficial effects

[0079] According to embodiments of the present invention, the present invention provides RSK inhibitors with novel structures, excellent pharmacokinetic properties, and good efficacy or drugability, which can be used to effectively treat RSK-related diseases and disorders.

[0080] The compound of the present invention has a good inhibitory effect on RSK and good in vitro efficacy. In addition, the results of mouse experiments show that the compound of the present invention exhibits excellent pharmacokinetic properties and good drugability.

[0081] Below, the scheme of the present invention will be explained in conjunction with embodiment.It will be understood by those skilled in the art that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention.In the embodiment, if specific technology or conditions are not indicated, the technology or conditions described in the literature in this area or the product instructions are used.The reagents or instruments used are not indicated by the manufacturer, and are all conventional products that can be obtained by commercial purchase.

[0082] Unless otherwise specified, the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The unit of NMR shift is 10 -6 The solvents for NMR measurements are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and tetramethylsilane (TMS) is the internal standard.

[0083] The abbreviations of the present invention are defined as follows:

[0084] M: molar concentration, such as 1M hydrochloric acid means 1 mol / L hydrochloric acid solution

[0085] HATU: O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphonate

[0086] DIPEA: also written as DIEA, diisopropylethylamine, also known as N,N-diisopropylethylamine

[0087] NIS: N-iodosuccinimide

[0088] AIBN: Azobisisobutyronitrile

[0089] DMF: N,N-dimethylformamide

[0090] THF: Tetrahydrofuran

[0091] PE: Petroleum ether

[0092] DBAD: dibenzyl azodicarboxylate

[0093] LC-MS: Liquid chromatography-mass spectrometry

[0094] DMSO: dimethyl sulfoxide

[0095] DTT: dithiothreitol

[0096] ATP: adenosine triphosphate

[0097] Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0098] PyBOP: 1H-Benzotriazol-1-yloxytripyrrolidino hexafluorophosphate

[0099] TLC: Thin layer chromatography

[0100] IC 50 : Half-maximal inhibitory concentration refers to the concentration at which half of the maximum inhibitory effect is achieved.

[0101] Unless otherwise indicated, compounds exemplified herein are named and numbered using ChemBioDraw Ultra 14.0.

[0102] Intermediate 13a (R)-1-(1-((tert-Butoxycarbonyl)amino)propan-2-yl)-7-fluoro-1H-indole-2,6-dicarboxylic acid diethyl ester

[0103] The first step is diethyl 7-fluoro-1H-indole-2,6-dicarboxylate 13a-2

[0104] To a 50 mL round-bottom flask were added compound 13a-1 (564 mg, 2.34 mmol), palladium dichloride (13 mg, 0.059 mmol), 1,1'-bis(diphenylphosphino)ferrocene (65 mg, 0.12 mmol), sodium acetate (576 mg, 7.02 mmol), ethanol (10 mL), and DMF (10 mL) in sequence. The gas was replaced with CO three times, and the temperature was raised to 110°C under 300 psi pressure. The reaction was allowed to react overnight. After the reaction was monitored, the mixture was filtered through celite, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and purified by normal phase chromatography to obtain compound 13a-2 (white solid, 316 mg).

[0105] MS (ESI) m / z 280.2 [M+H] +

[0106] 1 H NMR (500MHz, CDCl3) δ9.28 (s, 1H), 7.66 (dd, J = 8.5, 6.3Hz, 1H), 7.46 (d, J = 8.5Hz, 1H),7.24–7.22(m,1H),4.44(dq,J=8.8,7.2Hz,4H),1.43(td,J=7.1,5.3Hz,6H).

[0107] Step 2: (R)-Diethyl 1-(1-((tert-Butoxycarbonyl)amino)propan-2-yl)-7-fluoro-1H-indole-2,6-dicarboxylate 13a

[0108] In a three-necked flask, NaH (60%, 54 mg) was dispersed in anhydrous DMF (2 mL) under ice bath conditions, and a DMF solution (5 mL) of compound 13a-1 (316 mg, 1.13 mmol) was added dropwise. After stirring for 30 min, a DMF solution (5 mL) of (S)-5-methyl-1,2,3-oxothiazolidine-3-carboxylic acid tert-butyl ester-2,2-dioxide (13a-3) (295 mg, 1.24 mmol) was slowly added dropwise. After completion, the mixture was brought to room temperature and reacted overnight. After monitoring the reaction completion, water was added to quench the mixture, the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and purified by normal phase chromatography to obtain compound 13a (white solid, 270 mg).

[0109] MS (ESI) m / z 437.2 [M+H] +

[0110] Example 1 (R)-N-(1-(4-(dimethylphosphoryl)benzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine-2-carboxamide

[0111] Step 1: Ethyl 6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate 1b

[0112] Compound 1a (10.0 mmol, 1.96 g) was dissolved in dichloromethane (50 mL). Thionyl chloride (20.0 mmol, 14.0 mL) and 4 drops of DMF were added sequentially at room temperature. The mixture was then heated to 50°C and reacted for 5 h. The reaction mixture was cooled to room temperature and then slowly added dropwise to ethanol (100 mL). The mixture was stirred for 1 h, and the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE / EtOAc = 5 / 1) to obtain compound 1b (1.70 g) as a white solid.

[0113] MS (ESI) m / z 225.2 [M+H] + .

[0114] 1 H NMR(500MHz,DMSO-d6)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).

[0115] Step 2: Diethyl 1H-pyrrolo[2,3-b]pyridine-2,6-dicarboxylate 1c

[0116] Compound 1b (10.0 mmol, 2.24 g), sodium acetate (30.0 mmol, 2.46 g), 1,1'-bis(diphenylphosphino)ferrocene (0.50 mmol, 270 mg), palladium acetate (0.25 mmol, 5.60.0 mg), and ethanol (50 mL) were added sequentially to a high-pressure reaction tube. The reaction was heated to 110°C under CO pressure (250 psi) for 16 h. After monitoring the reaction completion, the mixture was cooled to room temperature, filtered through celite, and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), and concentrated under reduced pressure to afford the crude product. The crude product was purified by column chromatography (PE / EtOAc = 5 / 1) to afford compound 1c (1.50 g) as a white solid.

[0117] MS (ESI) m / z 263.2 [M+H] + .

[0118] 1 H NMR (500MHz, DMSO-d6) δ 12.94 (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).

[0119] Step 3: (R)-1-(1-(tert-Butyloxycarbonyl)amino)propan-2-yl)-1H-pyrrolo[2,3-b]pyridine-2,6-dicarboxylic acid diethyl ester 1d

[0120] In a 50 mL three-necked flask, sodium hydride (2.60 mmol, 104 mg, 60% in mineral oil) was dissolved in DMF (3 mL) and the mixture was slowly added dropwise at 0°C. A solution of compound 1c (2.00 mmol, 524 mg) in DMF (5 mL) was added dropwise. After stirring for 1 h, a solution of (S)-tert-butyl 5-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (2.40 mmol, 540 mg) in DMF (5 mL) was slowly added dropwise. The reaction mixture was allowed to react at room temperature for 16 h. After completion of the reaction, as monitored by TLC, the reaction was quenched with saturated sodium bicarbonate solution (20 mL). The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL) and concentrated under reduced pressure to afford the crude product, which was then purified by column chromatography (PE / EtOAc = 3 / 1) to afford compound 1d (818 mg).

[0121] MS (ESI) m / z 420.3 [M+H] + .

[0122] 1 H NMR(500MHz, CDCl3)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),4.4 3(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).

[0123] Step 4: (R)-1-(1-aminopropane-2-yl)-1H-pyrrolo[2,3-b]pyridine-2,6-dicarboxylic acid diethyl ester 1e

[0124] To a solution of compound 1d (1.95 mmol, 818 mg) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL) dropwise, and the mixture was stirred at room temperature for 3 h. After completion of the reaction, as monitored by TLC, the reaction mixture was concentrated under reduced pressure, saturated sodium bicarbonate (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (PE / EtOAc = 1 / 1) to obtain compound 1e (498 mg).

[0125] MS (ESI) m / z 320.2 [M+H] + .

[0126] 1H NMR (500MHz, CDCl3) 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).

[0127] Step 5 (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

[0128] Compound 1e (1.03 mmol, 330 mg) was dissolved in ethanol (10 mL) in a 50 mL round-bottom flask, and potassium carbonate (3.09 mmol, 428 mg) was added. The mixture was heated to 60°C for 3 h. After completion of the reaction as monitored by TLC, the reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed with saturated brine (50 mL). The organic phases were concentrated to give the crude compound, which was then purified by column chromatography (PE / EtOAc = 1 / 1) to give compound 1f (225 mg).

[0129] MS (ESI) m / z 274.2 [M+H] + .

[0130] 1H NMR (500MHz, CDCl3) 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).

[0131] Step 6 (R)-9-methyl-6-oxo-6,7,8,9-tetrahydropyridine [3',2':4,5] pyrrole [1,2-a] pyrazine-2-carboxylic acid 1 g

[0132] To a solution of compound 1f (1.31 mmol, 362 mg) in 1,4-dioxane (6 mL) was slowly added dropwise a 2.0 M aqueous lithium hydroxide solution (1.2 mL). The mixture was stirred at room temperature for 1 h. After completion of the reaction as monitored by TLC, the reaction mixture was concentrated under reduced pressure until a white solid precipitated. This solid was then filtered to afford compound 1g (148 mg).

[0133] MS (ESI) m / z 246.3 [M+H] + .

[0134] 1H NMR(500MHz,DMSO-d6)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).

[0135] Step 7 1-(4-iodobenzene)-4-nitro-1H-pyrazole 1j

[0136] 4-Iodobenzyl alcohol (23.1 mmol, 5.40 g) was dissolved in dichloromethane (50 mL), and thionyl chloride (34.7 mmol, 4.10 g) was slowly added, followed by reaction at room temperature for 4 hours. The reaction mixture was dried and dissolved in acetone (80 mL), and 4-nitro-1H-pyrazole (32.3 mmol, 3.65 g), potassium carbonate (46.5 mmol, 6.42 g), and sodium iodide (4.66 mmol, 0.70 g) were added, and the mixture was heated to reflux for 2 hours. The reaction mixture was concentrated and extracted with ethyl acetate (50 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 = 2 / 1) to give compound 1j (6.21 g).

[0137] MS (ESI) m / z 330.0 [M+H] + .

[0138] 1H NMR (500MHz, CDCl3) δ 8.09 (s, 1H), 8.07 (s, 1H), 7.74 (d, J = 8.3Hz, 2H), 7.04 (d, J = 8.3Hz, 2H), 5.25 (s, 2H).

[0139] Step 8 1-(4-iodophenyl)-1H-pyrazol-4-amine 1k

[0140] Compound 1j (8.27 mmol, 2.72 g) was dissolved in ethanol (30 mL), and water (30 mL), ammonium chloride (16.6 mmol, 0.88 g), and iron powder (246 mmol, 1.38 g) were added sequentially. The mixture was heated to 70°C for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, monitored by TLC. The reaction mixture was filtered through celite, and the filter cake was washed with ethyl acetate (50 mL). The filtrate was extracted with ethyl acetate (50 mL x 3), washed with saturated brine, and the organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE / EtOAc = 1 / 1) to obtain compound 1k (1.61 g).

[0141] MS (ESI) m / z 300.10 [M+H] + .

[0142] 1H NMR (500MHz, CDCl3) δ7.66–7.63 (m, 2H), 7.19 (d, J = 0.7Hz, 1H), 6.97 (d, J = 0.8Hz, 1H), 6.92 (d, J = 8.4Hz, 2H), 5.11 (s, 2H).

[0143] Step 9 (R)-N-(1-(4-iodophenyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine-2-carboxamide 1l

[0144] Compound 1k (0.40 mmol, 120 mg) and compound 1g (0.42 mmol, 108 mg) were dissolved in DMF (10 mL), followed by the addition of DIPEA (0.64 mmol, 0.11 mL) and HATU (0.64 mmol, 242 mg) at room temperature. The reaction mixture was allowed to react at room temperature for 24 h. After completion of the reaction, as monitored by TLC, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure to afford the crude product, which was then purified by column chromatography (PE / EtOAc = 1 / 1) to afford compound 1l (157 mg).

[0145] MS (ESI) m / z 527.3 [M+H] + .

[0146] 1H NMR (500MHz, CDCl3) 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).

[0147] Step 10 (R)-N-(1-(4-(dimethylphosphoryl)benzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyridine[3',2':4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide 1

[0148] Compound 11 (0.16 mmol, 84.0 mg) was dissolved in ethanol (3 mL), followed by the addition of tetrakistriphenylphosphine palladium (0.016 mmol, 19.0 mg), dimethylphosphine oxide (0.19 mmol, 16 mg), and triethylamine (0.32 mmol, 45 μL). The mixture was purged with argon three times, and then heated to 100°C for 6 h. After completion of the reaction as monitored by TLC, the reaction mixture was cooled to room temperature and filtered through celite. The filter cake was washed with ethyl acetate (50 mL), and the filtrate was extracted with ethyl acetate (50 mL × 3). The organic phase was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography (PE / EtOAc = 1 / 1) to obtain compound 1 (29 mg).

[0149] MS (ESI) m / z 477.2 [M+H] + .

[0150] 1 H NMR(500MHz,CD3OD)δ8.28(s,1H),8.27(d,J=8.3Hz,1H),8.01(d,J=8.2Hz,1H) ,7.88(d,J=0.5Hz,1H),7.79(dd,J=11.7,8.3Hz,1H),7.44(dd,J=8.2,2.3Hz,1 H),7.24(s,1H),5.45(s,2H),5.39–5.32(m,1H),4.00(dd,J=13.1,4.5Hz,1H), 3.57(dd,J=13.1,1.3Hz,1H),1.78(s,3H),1.76(s,3H),1.51(d,J=6.6Hz,3H).

[0151] Example 2 (R)-N-(1-(4-((dimethyl(oxo)-λ 6 -sulfenyl)amino)benzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyridinyl[3',2':4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide

[0152] Compound 11 (0.5 mmol, 260 mg) was dissolved in 1,4-dioxane (3 mL). Dimethylsulfenyl imide (0.60 mmol, 60.0 mg), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (0.10 mmol, 50.0 mg), Pd2(dba)3 (0.05 mmol, 46.0 mg), and cesium carbonate (0.75 mmol, 240 mg) were added at room temperature. The mixture was purged with argon three times and then heated to 100°C for 6 h. After completion of the reaction, as monitored by TLC, the reaction mixture was cooled to room temperature and filtered through celite. The filter cake was washed with ethyl acetate (50 mL), and the filtrate was extracted with ethyl acetate (50 mL x 3). The organic phase was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (PE / EtOAc = 1 / 1) to obtain compound 2 (50 mg) as a light yellow solid.

[0153] MS (ESI) m / z 492.2 [M+H] + .

[0154] 1H NMR(500MHz,DMSO-d6)δ10.64(s,1H),8.35(d,J=4.9Hz,1H),8.29(d,J=8.2Hz,1H),8 .17(s,1H),7.91(d,J=8.2Hz,1H),7.77(s,1H),7.14(d,J=7.1Hz,3H),6.90(d,J=8.4 Hz,2H),5.31–5.25(m,1H),5.22(s,2H),3.91(dd,J=13.0,4.3Hz,1H),3.47(dd,J=12.2,5.2Hz,1H),3.20(s,6H),1.42(d,J=6.6Hz,3H).

[0155] Example 3 (9R)-9-methyl-N-(1-(4-(S-methylsulfoximino)benzyl)-1H-pyrazol-4-yl)-6-oxo-6,7,8,9-tetrahydropyridine[3',2]:4,5]pyrrole[1,2-a]pyrazine-2-carboxamide

[0156] Step 1-(4-(Methylthio)benzyl)-4-nitro-1H-pyrazole 3b

[0157] Compound 3a (4.50 g, 26.2 mmol) was dissolved in acetone (80 mL), and 4-nitro-1H-pyrazole (31.2 mmol, 3.54 g) and potassium carbonate (52.2 mmol, 7.20 g) were added. The mixture was heated to 60°C and reacted for 4 hours. After completion of the reaction, as monitored by TLC, the mixture was concentrated under reduced pressure. The resulting solid was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (PE / EtOAc = 10 / 1) to give compound 3b (5.20 g) as a white solid.

[0158] MS (ESI) m / z 250.2 [M+H] + .

[0159] 1H NMR (500MHz, CDCl3) δ 8.08 (s, 1H), 8.03 (s, 1H), 7.26 (d, J = 8.0Hz, 2H), 7.22 (d, J = 8.3Hz, 2H), 5.25 (s, 2H), 2.48 (s, 3H).

[0160] Step 2 1-(4-(Methylthio)benzyl)-1H-pyrazol-4-amine 3c

[0161] Compound 3b (7.90 mmol, 1.97 g) was dissolved in tetrahydrofuran (50 mL), and 0.20 g of palladium on carbon (5%, wet basis) was added. The mixture was reacted under H2 (15 psi) for 8 hours. After completion of the reaction as monitored by TLC, the reaction mixture was filtered through celite, the filter cake was washed with tetrahydrofuran (100 mL), and the filtrate was evaporated to dryness to obtain a crude product. The crude product was purified by column chromatography (PE / EtOAc = 0 / 1) to obtain compound 3c (1.55 g).

[0162] MS (ESI) m / z 220.2 [M+H] + .

[0163] 1H NMR (500MHz, CDCl3) δ7.20 (d, J = 8.3 Hz, 2H), 7.17 (s, 1H), 7.11 (d, J = 8.2 Hz, 2H), 5.12 (s, 2H), 2.45 (s, 3H).

[0164] Step 3 (R)-9-methyl-N-(1-(4-(methylthio)benzyl)-1H-pyrazol-4-yl)-6-oxo-6,7,8,9-tetrahydropyridine[3',2':4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide 3d

[0165] Compound 3c (1.50 mmol, 329 mg) and compound 1g (1.65 mmol, 419 mg) were dissolved in DMF (5 mL), followed by the addition of DIPEA (2.25 mmol, 0.40 mL) and HATU (2.25 mmol, 855 mg). The reaction mixture was allowed to react at room temperature for 24 h. After completion of the reaction, as monitored by TLC, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 4). The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure to afford the crude product. The crude product was then purified by column chromatography (PE / EtOAc = 1 / 1) to afford compound 3d (408 mg).

[0166] MS (ESI) m / z 447.1 [M+H] + .

[0167] 1H NMR (500MHz, DMSO-d6) δ10.65(s,1H),8.36(d,J=4.8Hz,1H),8.30(d,J=8.2Hz,1H),8.21(s,1H),7.91(d,J=8.2Hz,1H),7.78(s,1H),7.2 7–7.22(m,4H),7.13(s,1H),5.29(m,3H),3.91(dd,J=13.0,4.4Hz,1H),3.48(dd,J=12.8,5.0Hz,1H),2.46(s,3H),1.42(d,J=6.6Hz,3H).

[0168] Step 4 (9R)-9-methyl-N-(1-(4-(S-methylsulfoximino)benzyl)-1H-pyrazol-4-yl)-6-oxo-6,7,8,9-tetrahydropyridine[3',2]:4,5]pyrrole[1,2-a]pyrazine-2-carboxamide 3

[0169] Compound 3d (0.50 mmol, 223 mg) was dissolved in DMF (5 mL), followed by the addition of aminoammonium acetate (1.00 mmol, 78.0 mg) and iodobenzene diacetate (1.25 mmol, 403 mg) at room temperature. The reaction mixture was allowed to react for 2 h. After completion of the reaction, as monitored by TLC, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine and concentrated under reduced pressure to yield the crude product, which was then purified by column chromatography (PE / EtOAc = 1 / 1) to afford compound 3 (55 mg).

[0170] MS (ESI) m / z 478.2 [M+H] + .

[0171] 1H NMR (500MHz, DMSO-d6) δ10.68(s,1H),8.35(d,J=5.0Hz,1H),8.30(d,J=9.0Hz,2H),7.91(dd,J=8.2,3.5Hz,3H),7.82(s,1H),7.44(d,J=8.3H z,2H),7.13(s,1H),5.47(s,2H),5.28(m,1H),3.91(dd,J=12.9,4.4Hz,1H),3.48(dd,J=12.6,4.6Hz,1H),3.05(s,3H),1.43(d,J=6.6Hz,3H).

[0172] Example 4 (R)-N-(1-((2-(2-hydroxypropane-2-yl)pyridin-4-yl)methyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine-2-carboxamide

[0173] Step 1: Methyl 5-(4-nitro-1H-pyrazol-1-yl)methyl)picolinate 4b

[0174] Compound 4a (4.00 g, 23.95 mmol), compound 1i (3.14 g, 27.78 mmol), and triphenylphosphine (6.90 g, 26.33 mmol) were dissolved in tetrahydrofuran (50 mL), the argon atmosphere was replaced three times, and the temperature was lowered to 0°C. Di-tert-butyl azodicarboxylate (6.03 g, 27.33 mmol) was added, and the reaction mixture was reacted at room temperature for 24 h. After completion of the reaction as monitored by TLC, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (PE / EtOAc = 2 / 1) to obtain compound 4b (5.9 g).

[0175] MS (ESI) m / z 263.1 [M+H] + .

[0176] 1H NMR (500MHz, DMSO-d6) δ3.85(3H,s),5.57(2H,s),7.47(1H,dd,J=1.5Hz,J=5Hz),7.95(1H,s),8.33(1H,S),8.67(1H,d,J=5Hz),9.09(1H,s).

[0177] Step 2: Methyl 5-(4-amino-1H-pyrazol-1-yl)methyl)picolinate 4c

[0178] Compound 4b (5.72 mmol, 1.50 g) was dissolved in tetrahydrofuran (50 mL), and 0.3 g of palladium on carbon (5%, wet basis) was added. The mixture was reacted under H₂ (15 psi) for 5 h. After completion of the reaction as monitored by TLC, the reaction mixture was filtered through celite, the filter cake was washed with tetrahydrofuran (100 mL), and the filtrate was dried to afford crude compound 4c (1.04 g, crude product), which was used directly in the next reaction.

[0179] MS m / z(ESI):233[M+H] + .

[0180] Step 3: Methyl 5-((4-((tert-Butyloxycarbonyl)amino)-1H-pyrazol-1-yl)methyl)picolinate 4d

[0181] Compound 4c (4.46 mmol, 1.04 g) was dissolved in tetrahydrofuran (50 mL), and DMAP (0.196 mmol, 22.0 mg) and di-tert-butyl dicarbonate (4.48 mmol, 0.99 g) were added at 0°C. The reaction mixture was allowed to react at room temperature for 14 h. After completion of the reaction, as monitored by TLC, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (PE / EtOAc = 1 / 1) to give compound 4d (0.70 g, yield: 47%).

[0182] MS (ESI) m / z 333.25 [M+H] + .

[0183] Step 4: Tert-butyl (1-((6-(2-hydroxypropane-2-yl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)carbamate 4e

[0184] Compound 4d (2.11 mmol, 700 mg) was dissolved in ultra-dry tetrahydrofuran (20 mL), and a solution of methylmagnesium bromide (8.42 mmol, 8.42 mL, 1.0 M) in tetrahydrofuran was added dropwise at -70°C. The reaction mixture was reacted at room temperature for 2 h, and the reaction was quenched by adding saturated ammonium chloride (30 mL). The mixture was stirred for 30 minutes and extracted with ethyl acetate solution (30 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a crude product. The crude product was purified by column chromatography (PE / EtOAc = 1 / 1) to give compound 4e (155 mg).

[0185] MS (ESI) m / z 333.30 [M+H] + .

[0186] Step 5: 2-(5-((4-amino-1H-pyrazol-1-yl)methyl)pyridin-2-yl)propan-2-ol 4f

[0187] Compound 4f (0.47 mmol, 155 mg) was dissolved in ethanol (10 mL), and concentrated hydrochloric acid (2 mL, 38%) was added. The mixture was reacted at room temperature for 4 hours. After the reaction, the solvent was evaporated to obtain compound 4f (100 mg, crude product), which was used directly in the next reaction.

[0188] MS (ESI) m / z 233.30 [M+H] + .

[0189] Step 6 (R)-N-(1-((6-(2-hydroxypropane-2-yl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine-2-carboxamide 4

[0190] Compound 4f (0.43 mmol, 100 mg) was dissolved in N,N-dimethylformamide (10 mL). Compound 1g (0.42 mmol, 104 mg), N,N-diisopropylethylamine (0.80 mmol, 220 mg), and HATU (0.64 mmol, 242 mg) were added at room temperature. The reaction mixture was allowed to react for 14 h. After completion of the reaction, as monitored by TLC, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE / EtOAc = 1 / 1) to obtain compound 4 (44 mg) as a light yellow solid.

[0191] MS (ESI) m / z 460.30 [M+H] + .

[0192] 1H NMR(500MHz,CD3OD)δ1.50(3H,d,J=6.5Hz),1.53(6H,s),3.55(1H,d,J=12.5Hz),3.98(1H,dd,J=4.5Hz,J=13.5Hz),5.30(1H,m),5.46(2H, s),7.06(1H,d,J=5Hz),7.21(1H,s),7.57(1H,s),7.92(1H,s),7.98(1H,d,J=5Hz),8.19(1H,d,J=8.5Hz),8.31(1H,s),8.43(1H,d,J=5Hz).

[0193] Example 5 (R)-N-(1-((6-(2-hydroxypropane-2-yl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine-2-carboxamide

[0194] Step 1: Methyl 5-(hydroxymethyl)picolinate 5b

[0195] Compound 5a (27.3 mmol, 4.50 g) was dissolved in methanol (50 mL), and 1.13 g of sodium borohydride (29.7 mmol, 1.13 g) was added at 0°C. The mixture was allowed to react at room temperature for 3 h. After completion of the reaction, as monitored by TLC, the mixture was diluted with water (60 mL) and extracted with ethyl acetate (60 mL x 3). The combined organic phases were washed with saturated brine and concentrated under reduced pressure to yield crude compound 5b (4.2 g, crude) as a colorless oil.

[0196] MS (ESI) m / z 168.30 [M+H] + .

[0197] Step 2: Methyl 5-(4-nitro-1H-pyrazol-1-yl)methyl)picolinate 5c

[0198] Compound 5b (4.20 g, 25.0 mmol), compound 1i (3.14 g, 27.78 mmol), and triphenylphosphine (7.30 g, 28.2 mmol) were dissolved in tetrahydrofuran (50 mL). The argon atmosphere was replaced three times, and the temperature was lowered to 0°C. Di-tert-butyl azodicarboxylate (6.03 g, 27.33 mmol) was added, and the reaction mixture was allowed to react at room temperature for 24 h. After completion of the reaction, as monitored by TLC, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (PE / EtOAc = 2 / 1) to give compound 4b (5.7 g) as a light yellow solid.

[0199] MS m / z(ESI):234[M+H] + .

[0200] 1H NMR (500 MHz, DMSO-d 6 )δ3.85(3H,s),5.55(2H,s),7.86(1H,dd,J=2Hz,J=8Hz),8.03(1H,d,J=8Hz),8.30(1H,S),8.70(1H,d,J=2Hz),9.08(1H,s).

[0201] Step 3: Methyl 5-(4-amino-1H-pyrazol-1-yl)methyl)picolinate 5d

[0202] Compound 5c (5.13 mmol, 1.20 g) was dissolved in tetrahydrofuran (50 mL), and 0.3 g of palladium on carbon (5%, wet basis) was added. The mixture was reacted under H₂ (15 psi) for 5 h. After completion of the reaction as monitored by TLC, the reaction mixture was filtered through celite, the filter cake was washed with tetrahydrofuran (100 mL), and the filtrate was dried to afford crude compound 5d (928 mg, crude product), which was used directly in the next reaction.

[0203] MS m / z(ESI):233.2[M+H] + .

[0204] Step 4: 5-((4-((tert-Butyloxycarbonyl)amino)-1H-pyrazol-1-yl)methyl)picolinate 5e

[0205] Compound 5d (4.00 mmol, 928 mg) was dissolved in tetrahydrofuran (50 mL), and DMAP (0.196 mmol, 22.0 mg) and di-tert-butyl dicarbonate (4.50 mmol, 1.00 g) were added at 0°C. The reaction mixture was allowed to react at room temperature for 14 h. After completion of the reaction, as monitored by TLC, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (PE / EtOAc = 1 / 1) to give compound 5e (0.57 g).

[0206] MS (ESI) m / z 333.25 [M+H] + .

[0207] Step 5: Tert-butyl (1-((6-(2-hydroxypropane-2-yl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)carbamate 5f

[0208] Compound 5e (1.71 mmol, 568 mg) was dissolved in ultra-dry tetrahydrofuran (20 mL), and a solution of methylmagnesium bromide (6.84 mmol, 6.84 mL, 1.0 M) in tetrahydrofuran was added dropwise at -70°C. The reaction mixture was allowed to react at room temperature for 2 h. After completion of the reaction, as monitored by TLC, saturated ammonium chloride (30 mL) was added to quench the reaction, stirred for 30 minutes, and extracted with ethyl acetate (30 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the crude product, which was then purified by column chromatography (PE / EtOAc = 1 / 1) to give compound 5f (430 mg).

[0209] MS (ESI) m / z 333.30 [M+H] +.

[0210] Step 6: 2-(5-((4-amino-1H-pyrazol-1-yl)methyl)pyridin-2-yl)propan-2-ol 5g

[0211] Compound 4f (0.57 mmol, 190 mg) was dissolved in ethanol (10 mL), and concentrated hydrochloric acid (2 mL, 38%) was added. The mixture was reacted at room temperature for 4 hours. After the reaction, the solvent was evaporated to obtain compound 5g (150 mg, crude product), which was used directly in the next reaction.

[0212] MS (ESI) m / z 233.30 [M+H] + .

[0213] Step 7 (R)-N-(1-((6-(2-hydroxypropane-2-yl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine-2-carboxamide 5

[0214] Compound 5g (0.53 mmol, 133 mg) was dissolved in N,N-dimethylformamide (10 mL). Compound 1g (0.55 mmol, 128 mg), N,N-diisopropylethylamine (1.10 mmol, 270 mg), and HATU (0.71 mmol, 297 mg) were added at room temperature. The reaction mixture was allowed to react for 14 h. After completion of the reaction, as monitored by TLC, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (PE / EtOAc = 1 / 1) to obtain compound 5 (59 mg) as a light yellow solid.

[0215] MS (ESI) m / z 460.30 [M+H] + .

[0216] 1H NMR (500MHz, CDCl3) δ1.53 (6H, s), 1.59 (3H, d, J = 6.5Hz), 3.57 (1H, dd, J = 5Hz, J =12.5Hz),4.07(1H,dd,J=4.5Hz,J=12.5Hz),5.23(1H,m),5.35(2H,s),6.82(1 H,s),7.29(1H,s),7.37(1H,d,J=8Hz),7.62(1H,d,J=7.5Hz),7.69(1H,s),8.1 3(1H,d,J=8Hz), 8.20(1H,d,J=8.5Hz), 8.26(1H,s), 8.48(1H,s), 9.69(1H,s).

[0217] Example 6 (R)-1-(4-aminobenzyl)-N-(3-fluoro-9-methyl-6-oxo-6,7,8,9-tetrahydropyridinium[3',2":4,5]pyrrolo[1,2-a]pyrazin-2-yl)-1H-pyrazole-4-carboxamide

[0218] Step 1: tert-Butyl (4-(bromomethyl)phenyl)carbamate 6b

[0219] Compound 6a (1.12 g, 5 mmol) was dissolved in anhydrous diethyl ether (50 mL). Phosphorus tribromide (0.16 mL, 1.75 mmol) was added dropwise at -10°C, and the reaction temperature was then raised to 0°C for 1 h. After completion of the reaction, as monitored by TLC, the mixture was diluted with saturated sodium bicarbonate (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure to afford crude compound 6b (1.4 g, crude) as a white solid.

[0220] MS (ESI) m / z 286.20 [M+H] + .

[0221] 1H-NMR (400MHz, CDCl3) δ7.34-7.30 (m, 4H), 6.53 (s, 1H), 4.48 (s, 2H), 1.51 (s, 9H).

[0222] Step 2: Ethyl 1-(4-(tert-Butyloxycarbonyl)amino)benzyl)-1H-pyrazole-4-carboxylate 6d

[0223] Compound 6b (315 mg, 1.10 mmol) and compound 6c (140 mg, 1.00 mmol) were dissolved in anhydrous acetone (10 mL). Anhydrous potassium carbonate (276 mg, 2.00 mmol) was added, and the reaction mixture was heated at reflux for 18 h. After completion of the reaction, the solid was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE / EtOAc = 3:1) to afford 6d (310 mg).

[0224] MS (ESI): m / z 368.10 [M+Na] + .

[0225] 1H-NMR (500MHz, CDCl3) δ7.90 (s, 1H), 7.79 (s, 1H), 7.36 (d, J = 8.3Hz, 2H), 7.16 (d, J = 8.6Hz ,2H),6.80(s,1H),5.21(s,2H),4.24(q,J=7.1Hz,2H),1.48(s,9H),1.29(t,J=7.1Hz,3H).

[0226] Step 3 1-(4-(tert-Butyloxycarbonyl)amino)benzyl)-1H-pyrazole-4-carboxylic acid 6e

[0227] Compound 6d (310 mg, 0.9 mmol) was dissolved in methanol (5 mL), and 2.0 M sodium hydroxide solution (2.25 mL, 4.5 mmol) was added. The reaction mixture was heated to 65°C for 4 h. After completion of the reaction, as monitored by TLC, the reaction mixture was cooled to 0°C and glacial acetic acid was added dropwise to adjust the pH to 4-5. The aqueous phase was extracted with dichloromethane (50 mL x 3). The combined organic phases were washed with saturated brine and concentrated under reduced pressure to afford crude compound 6e (258 mg, crude product), which was used directly in the next step.

[0228] MS (ESI): m / z 340 [M+Na] + .

[0229] 1 H-NMR (500MHz, CDCl3) δ7.98 (s, 1H), 7.85 (s, 1H), 7.35 (d, J = 8.2Hz, 2H), 7.19 (d, J = 8.1Hz, 2H), 6.78 (s, 1H), 5.24 (s, 2H), 1.50 (s, 9H).

[0230] Step 4: tert-butyl (6-bromo-5-fluoropyridin-2-yl) carbamate 6g

[0231] Compound 6f (11.0 g, 50.0 mmol) was dissolved in anhydrous tert-butanol (200 mL). Triethylamine (6.90 mL, 50.0 mmol) and diphenylphosphoryl azide (11.0 mL, 50.0 mmol) were added dropwise at room temperature. The reaction mixture was heated to 85°C for 3 h. After completion of the reaction, as monitored by TLC, the solvent was removed by rotary evaporation, diluted with water (100 mL), and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure to obtain the crude compound. The crude product was purified by column chromatography (PE / EtOAc = 20:1) to afford 6 g (12 g) of a light yellow oil.

[0232] MS (ESI): m / z 313.15 [M+Na] + .

[0233] 1H-NMR (400MHz, CDCl3) δ7.89 (dd, J=8.9, 3.2Hz, 1H), 7.40 (dd, J=8.9, 6.9Hz, 1H), 7.25 (brs, 1H), 1.50 (s, 9H).

[0234] Step 5: 6-Bromo-5-fluoropyridin-2-amine 6h

[0235] Compound 6g (12.0 g, 41.0 mmol) was dissolved in anhydrous dichloromethane (100 mL). Trifluoroacetic acid (31.0 mL, 410 mmol) was added dropwise at room temperature and allowed to react for 3 h. After completion of the reaction as monitored by TLC, the reaction mixture was evaporated to remove the solvent, diluted with saturated sodium bicarbonate (100 mL), and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude compound 6h (7.7 g, crude product), which was used directly in the next reaction.

[0236] MS (ESI): m / z 191.10 [M+H] + .

[0237] 1H-NMR (500MHz, CDCl3) δ7.16 (dd, J=8.7, 7.2Hz, 1H), 6.36 (dd, J=8.7, 2.7Hz, 1H), 4.75 (s, 2H).

[0238] Step 6: 6-Bromo-5-fluoro-3-iodopyridin-2-amine 6i

[0239] Compound 6h (7.70 g, 40.0 mmol) was suspended in acetic acid (70 mL). NIS (9.90 g, 44.0 mmol) was added at room temperature, followed by the dropwise addition of trifluoroacetic acid (0.70 mL). The reaction mixture was allowed to react at room temperature for 3 h. After completion of the reaction, saturated aqueous ammonia was added dropwise at 0°C to adjust the pH to 9. The mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the crude compound. The crude product was purified by column chromatography (PE / EtOAc = 10:1) to afford 6i (10.0 g) as a red solid.

[0240] MS (ESI): m / z 317.20 [M+H] + .

[0241] 1H-NMR (500MHz, CDCl3) δ7.62 (d, J=6.4Hz, 1H), 4.94 (s, 2H).

[0242] Step 7: 6-Bromo-5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid 6k

[0243] Compound 6i (5.10 g, 16.0 mmol), DABCO (5.40 g, 48.0 mmol), and palladium acetate (0.36 g, 1.60 mmol) were added to a sealed tube. The atmosphere was replaced with argon three times, and ultra-dry DMF (50 mL) and pyruvic acid (3.30 mL, 48.0 mmol) were added. The mixture was allowed to react at 110°C for 3 h. After completion of the reaction, as monitored by TLC, the reaction mixture was filtered to remove solids. The solid residue was washed with a small amount of DMF, and the solvent was evaporated by rotary evaporation. The product was then pumped dry to afford 6k (4.50 g, crude) as a dark brown oil, which was used directly in the next step without purification.

[0244] MS (ESI): m / z 259.10 [M+H] + .

[0245] Step 8: Ethyl 6-bromo-5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate

[0246] Compound 6k (4.50 g, crude) was dissolved in anhydrous ethanol (300 mL), and concentrated sulfuric acid (9 mL) was added dropwise at room temperature. The mixture was heated under reflux for 18 h. After completion of the reaction, as monitored by TLC, the reaction mixture was cooled to 0°C, and saturated sodium bicarbonate (70 mL) was added dropwise. The solvent was removed by rotary evaporation, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound. The crude product was purified by column chromatography (PE / EtOAc / Et3N = 6:1:0.05) to afford 6l (1.10 g) as a white solid.

[0247] MS (ESI): m / z 287.10 [M+H] + .

[0248] 1H-NMR (400MHz, CDCl3) δ9.20 (s, 1H), 7.73 (d, J = 7.8Hz, 1H), 7.14 (d, J = 1.9Hz, 1H), 4.43 (q, J = 7.2Hz, 2H), 1.42 (t, J = 7.2Hz, 3H).

[0249] Step 9 (R)-6-bromo-1-(1-(tert-butoxycarbonyl)amino)propan-2-yl)-5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester 6m

[0250] Sodium hydride (96.0 mg, 2.40 mmol, 60% in mineral oil) was added to a reaction flask. The atmosphere was replaced with argon, and ultra-dry DMF (3 mL) was added. A solution of compound 6l (574 mg, 2.00 mmol) in DMF (10 mL) was added dropwise at 0°C. The mixture was allowed to react at 0°C for half an hour. Subsequently, a solution of (S)-tert-butyl 5-methyl-1-oxa-2,2-dioxo-2,3-thiazolidine-3-carbonate (498 mg, 2.10 mmol) in DMF (6 mL) was added dropwise. The mixture was allowed to react at room temperature for 18 hours. After completion of the reaction, as monitored by TLC, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE / EtOAc / Et3N = 6:1:0.05) to afford 6m (0.70 g) as a white solid.

[0251] MS (ESI): m / z 443.10 [M+H] + .

[0252] 1H-NMR (500MHz, CDCl3) δ7.65(d,J=7.8Hz,1H),7.18(s,1H),5.75(m,1H),4.85(s,1H),4.38(q,J=7.0H z, 2H), 4.07-4.00 (m, 1H), 3.63-3.58 (m, 1H), 1.67 (d, J = 7.1Hz, 3H), 1.40 (t, J = 7.0Hz, 3H), 1.34 (s, 9H).

[0253] Step 10 (R)-1-(1-aminopropane-2-yl)-6-bromo-5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester 6n

[0254] Compound 6m (0.70 g, 1.60 mmol) was dissolved in anhydrous dichloromethane (8 mL). Trifluoroacetic acid (3 mL) was added dropwise at room temperature and allowed to react for 3 h. After completion of the reaction, as monitored by TLC, the reaction mixture was rotary evaporated to remove the solvent and pumped dry to afford 6n (0.75 g, crude) as a brown-yellow foamy solid. This was used directly in the next reaction without purification.

[0255] MS (ESI): m / z 344.10 [M+H] + .

[0256] Step 11 (R)-2-bromo-3-fluoro-9-methyl-8,9-dihydropyridin[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one 6o

[0257] Compound 6n (0.75 g, crude) was dissolved in anhydrous methanol (20 mL), and anhydrous potassium carbonate (1.38 g, 10.0 mmol) was added at room temperature. The reaction mixture was allowed to react for 18 h. After completion of the reaction, the solvent was removed by rotary evaporation, and the reaction mixture was diluted with water (30 mL). The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford crude compound 6o (0.60 g, crude), which was used directly in the next step.

[0258] MS (ESI): m / z 320,322 [M+Na] + .

[0259] 1 H-NMR (500MHz, CDCl3) δ7.73 (d, J = 7.9Hz, 1H), 7.34 (m, 1H), 7.17 (s, 1H), 5.09-5.04 (m, 1H) ), 4.01 (dd, J = 12.8, 4.5 Hz, 1H), 3.53 ( dd, J = 12.8, 5.1, 1.6 Hz, 1H), 1.52 ( d, J = 6.6 Hz, 3H).

[0260] Step 12 (R)-2-amino-3-fluoro-9-methyl-8,9-dihydropyridin[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one 6p

[0261] Compound 6o (298 mg, 1.00 mmol), cuprous iodide (19.0 mg, 0.10 mmol), ligand N 1 ,N 2 bis(5-methyl-[1,1'-biphenyl]-2-yl)oxalyldiamide (BPMPO) (42.0 mg, 0.10 mmol) and anhydrous potassium phosphate (318 mg, 1.50 mmol) were replaced with argon three times. Ultra-dry DMSO (3 mL) and aqueous ammonia (25%, 0.2 mL, 3 mmol) were added, and the mixture was sealed and heated to 80°C for 18 h. After completion of the reaction, as monitored by TLC, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to afford crude compound 6p (0.18 g, crude product), which was used directly in the next step.

[0262] MS (ESI): m / z 235.20 [M+H] + .

[0263] 1H-NMR (500MHz, CDCl3) δ7.50 (d, J = 10.8Hz, 1H), 7.08 (s, 1H), 6.26 (s, 1H), 4.89-4.84 (m, 1H), 4.7 7(s,2H),3.96(dd,J=12.6,4.4Hz,1H),3.43(ddd,J=12.5,5.1,1.6Hz,1H),1.46(d,J=6.6Hz,3H).

[0264] Step 13: Tert-butyl (R)-(4-((3-fluoro-9-methyl-6-oxo-6,7,8,9-tetrahydropyridinium[3',2]:4,5]pyrrolo[1,2-a]pyrazin-2-yl)carbamoyl)-1H-pyrazol-1-yl)methyl)phenylcarbamate 6q

[0265] Compound 6p (24.0 mg, 0.10 mmol), compound 6e (32.0 mg, 0.10 mmol), and PyCIU (50.0 mg, 0.15 mmol) were added to a sealed tube. Ultra-dry dichloroethane (5 mL) and DIPEA (0.07 mL, 0.4 mmol) were also added. The tube was sealed and heated to 80°C for 18 h. After completion of the reaction, as monitored by TLC, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE / EtOAc / Et3N = 2:1:0.05) to afford 6q (10.0 mg) as a pale yellow solid.

[0266] MS (ESI): m / z 556 [M+Na] + .

[0267] 1H-NMR (500MHz, CDCl3) δ7.92(s,1H),7.92(s,1H),7.50(d,J=10.6Hz,1H),7.35(d,J=8.1Hz,2H),7.23(s,1H),7.21(d,J=8.3Hz,2H),6.50(s,1H) ,5.26(d,J=15.0Hz,1H),5.22(d,J=15.0Hz,1H),4.88(s,2H),4.43(dd,J =13.5, 2.0Hz, 1H), 4.00-3.95 (m, 1H), 1.51 (s, 9H), 1.50 (d, J = 6.6Hz, 3H).

[0268] Step 14 (R)-1-(4-aminobenzyl)-N-(3-fluoro-9-methyl-6-oxo-6,7,8,9-tetrahydropyridinium[3',2":4,5]pyrrolo[1,2-a]pyrazin-2-yl)-1H-pyrazole-4-carboxamide 6

[0269] Compound 6q (10.0 mg, 0.019 mmol) was dissolved in anhydrous dichloromethane (2 mL), and trifluoroacetic acid (0.50 mL) was added dropwise at room temperature. The reaction was allowed to react at room temperature for 4 h. After completion of the reaction, as monitored by TLC, the solvent was removed by rotary evaporation, and the mixture was diluted with saturated sodium bicarbonate (30 mL). The mixture was extracted with dichloromethane (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the crude compound. The crude product was purified by column chromatography (DCM / MeOH / Et3N = 100:5:1) to afford 6 (3.7 mg) as a pale yellow solid.

[0270] MS (ESI): m / z 434 [M+H] + .

[0271] 1H NMR (500MHz, CD3OD) δ8.25(s,1H),7.87(s,1H),7.57(d,J=11.1Hz,1H),7.30(d,J=8.4Hz,2H),7.21(s,1H),7.09(d,J=8 .4Hz,2H),5.32(s,2H),4.94(m,1H),4.39(dd,J=13.5,2.0Hz,1H),4.00(dd,J=13.5,4.0Hz,1H),1.50(d,J=6.6Hz,3H).

[0272] Example 7 (R)-N-(1-(4-aminobenzyl)-1H-pyrazol-4-yl)-6-fluoro-4-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-7-carboxamide

[0273] Step 1: tert-Butyl (4-((4-amino-1H-pyrazol-1-yl)methyl)phenyl)carbamate 7b

[0274] To a solution of compound 7a (105 mg, 0.33 mmol) in methanol (10 mL) was added palladium on carbon (16 mg), and the mixture was allowed to react under hydrogen (15 psi) for 5 h. After completion of the reaction as monitored by TLC, the reaction mixture was filtered through celite, the filter cake was washed with tetrahydrofuran (10 mL), and the filtrate was dried to afford crude compound 7b (90 mg) as an orange solid.

[0275] 1H NMR (400MHz, DMSO-d6) δ9.36(s,1H),7.38(d,J=8.4Hz,2H),7.11–7.07(m,2H),7.01(d,J=0.9Hz,1H),6.91(d,J=0.9Hz,1H),5.02(s,2H),1.46(s,9H).

[0276] Step 2: tert-Butyl (R)-(4-((4-(6-fluoro-4-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-7-carboxamide)-1H-pyrazol-1-yl)methyl)phenyl)carbamate 7c

[0277] Under argon protection, compound 13d (80 mg, 0.30 mmol), 7b (86 mg, 0.30 mmol), HATU (170 mg, 0.45 mmol), DIPEA (116 mg, 0.89 mmol) and DMF (5 mL) were added sequentially to a 50 mL three-necked flask and reacted at room temperature for 24 h. After the completion of the reaction monitored by TLC, the reaction system was diluted with water and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure to give a crude product, which was separated and purified by column chromatography to give compound 7c (25 mg) as a white solid.

[0278] 1 H NMR (400MHz, CD3OD) δ7.98(d,J=0.7Hz,1H),7.62(d,J=0.7Hz,1H),7.46(d,J=8.4Hz,1H),7.30(dt,J=8.5,3.0Hz,3H),7.15(d,J=2.2Hz,1H),7 .12–7.08(m,2H),5.17(s,2H),5.04(q,J=6.8,6.2Hz,1H),3.93(dd,J=13.3,4.4Hz,1H),3.45(dd,J=13.3,1.3Hz,1H),1.41(d,J=2.1Hz,12H).

[0279] Step 3 (R)-N-(1-(4-aminobenzyl)-1H-pyrazol-4-yl)-6-fluoro-4-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-7-carboxamide 7

[0280] Compound 7c (25 mg) was placed in a 25 mL round-bottom flask, and a 1,4-dioxane solution of hydrochloric acid (2 mL, 4.0 M) was slowly added dropwise. The reaction was allowed to react at room temperature for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure, neutralized by adding saturated sodium bicarbonate solution, and extracted with dichloromethane. The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure to give a crude product. The crude product was separated and purified by column chromatography to obtain compound 7 (11 mg) as a yellow solid.

[0281] MS (ESI) m / z 433 [M+H] + .

[0282] 1 H NMR (400MHz, CD3OD) δ8.08(s,1H),7.62(s,1H),7.47(d,J=8.4Hz,1H),7.36–7.19(m,5H),7.16(s,1H) ,5.29(s,2H),5.06–5.03(m,1H),3.92(t,J=5.4Hz,1H),3.45(d,J=13.4Hz,1H),1.41(d,J=6.6Hz,3H).

[0283] Example 8 (9R)-N-(1-(1-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyridine[3',2':4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide

[0284] Step 1: 2-(5-(1-hydroxyethyl)pyridin-2-yl)propan-2-ol 8a

[0285] Compound 5a (1 g, 6 mmol) was dissolved in THF (10 mL). Methylmagnesium bromide (36 mL, 36 mmol, 1.0 M) was added dropwise in an ice bath, and the mixture was allowed to react at room temperature for 3 h. After completion, the reaction was quenched with saturated ammonium chloride solution (10 mL). The mixture was extracted with dichloromethane (25 mL), and the organic phase was washed with saturated brine and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE / EtOAc = 10 / 1) to obtain compound 8a (0.57 g).

[0286] MS (ESI) m / z 182 [M+H] +

[0287] 1H NMR (400MHz, CDCl3) δ8.49 (s, 1H), 7.76 (d, J = 8.33, 1H), 7.36 (d, J = 8.33Hz, 1H), 4.97 (m, 1H), 1.47-1.58 (m, 9H).

[0288] Step 2 2-(5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridin-2-yl)propan-2-ol 8b

[0289] Compound 8a (0.57 g, 3.15 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and 4-nitropyrazole (0.39 g, 3.45 mmol) and triphenylphosphine (2.48 g, 9.45 mmol) were added. The reaction was placed in an ice bath, and DBAD (1.45 g, 6.3 mmol) was added portionwise. The reaction was allowed to react at room temperature for 16 h. After completion, saturated sodium bicarbonate solution (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE / EtOAc = 5 / 1) to obtain compound 8b (200 mg).

[0290] MS (ESI) m / z 277 [M+H] + .

[0291] 1 H NMR (400MHz, CDCl3) δ8.49(m,1H),8.22(d,1H),8.10(d,1H),7.66(m,1H),7.42(m,1H),5.58(m,1H),1.96(m,3H),53(m,6H).

[0292] Step 3 2-(5-(1-(4-amino-1H-pyrazol-1-yl)ethyl)pyridin-2-yl)propan-2-ol 8c

[0293] Compound 8b (200 mg, 0.54 mmol) was dissolved in methanol (5 mL), and then Pd / C and ammonium formate (1 g) were added under nitrogen. The reaction was allowed to react at room temperature for 3 h. After completion of the reaction, the mixture was filtered and concentrated under reduced pressure to obtain crude product 8c (200 mg), which was used directly in the next reaction.

[0294] MS (ESI) m / z 247 [M+H] + .

[0295] Step 4 (9R)-N-(1-(1-(6-(2-hydroxypropyl-2-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyridine[3',2':4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide 8

[0296] Compound 8c (40 mg, 0.16 mmol) was dissolved in DMF (2 mL), and then compound 1g (40 mg, 0.16 mmol), HATU (60 mg, 0.19 mmol) and DIPEA (62 mg, 0.48 mmol) were added. The mixture was reacted at room temperature for 3 h. After completion of the reaction, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (50 mL), and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (DCM / MeOH=10 / 1) to give compound 8 (52 mg).

[0297] MS (ESI) m / z 474 [M+H] + .

[0298] 1 H NMR (400MHz, CDCl3) δ10.61(s,1H),8.44(d,1H),8.33-8.28(m,2H),8.26(s,1H),7.92(d,1H),7.83(s,1H),7.66(m,2H) ,7.14(s,1H),5.74-5.65(m,1H),5.38-5.22(m,1H),5.16(s,1H),3.92(dd,1H),3.48(dd,1H),1.85(m,3H),1.42(m,9H).

[0299] Example 9 (R)-N-(1-((6-(2-hydroxypropan-2-yl)pyridin-3-yl)methyl)-5-methyl-1H-pyrazol-3-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyridine[3',2':4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide

[0300] Step 1: Methyl 5-((5-methyl-3-nitro-1H-pyrazol-1-yl)methyl)picolinate 9b

[0301] Compound 5b (1.2 g, 7.2 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and compound 9a (1.4 g, 10.8 mmol) and triphenylphosphine (5.66 g, 21.6 mmol) were added. The reaction mixture was placed in an ice bath, and DBAD (3.3 g, 14.4 mmol) was added portionwise. The reaction was allowed to react at room temperature for 16 h. After completion, the mixture was added with saturated sodium bicarbonate solution (250 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by column chromatography (PE / EtOAc = 6 / 1) to afford compound 9b (560 mg).

[0302] MS (ESI) m / z 277 [M+H] + .

[0303] 1 H NMR (400MHz, CDCl3) δ8.67(d,1H),8.15(d,1H),7.68(d,1H),6.75(s,1H),5.46(s,1H),4.03(s,3H),2.31(s,3H).

[0304] Step 2: Methyl 5-((3-amino-5-methyl-1H-pyrazol-1-yl)methyl)picolinate 9c

[0305] Compound 9b (560 mg, 2.0 mmol) was dissolved in methanol (25 mL). Pd / C and ammonium formate (1.5 g) were added under nitrogen and reacted at room temperature for 3 h. After completion of the reaction, the mixture was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (PE / EtOAc = 2 / 1) to obtain compound 9c (600 mg), which was used in the next reaction.

[0306] MS (ESI) m / z 247 [M+H] + .

[0307] 1 H NMR (400MHz, CDCl3) δ8.60(d,1H),8.08(d,1H),7.69(d,1H),5.46(s,1H),5.24(s,2H),4.01(s,3H),3.42(s,2H),2.19(s,3H).

[0308] Step 3: Methyl 5-((3-((tert-Butoxycarbonyl)amino)-5-methyl-1H-pyrazol-1-yl)methyl)picolinate 9d

[0309] Compound 9c (600 mg, 2.4 mmol) was dissolved in DCM (20 mL), and triethylamine (480 mg, 4.8 mmol) and di-tert-butyl dicarbonate (780 mg, 3.6 mmol) were added. The mixture was reacted at room temperature for 3 h. After completion of the reaction, water (20 mL) was added, and the mixture was extracted with ethyl acetate (40 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (DCM / MeOH = 10 / 1) to give compound 9d (0.5 g).

[0310] MS (ESI) m / z 347 [M+H] + .

[0311] 1 H NMR (400MHz, CDCl3) δ8.67(s,1H),8.10(d,1H),7.71(d,1H),6.00(s,1H),5.17(s,2H),4.02(s,3H),2.29(s,3H),1.33(s,9H).

[0312] Step 4: Tert-butyl (1-((6-(2-hydroxypropan-2-yl)pyridin-3-yl)methyl)-5-methyl-1H-pyrazol-3-yl)carbamate 9e

[0313] Compound 9d (0.45 g, 1.3 mmol) was dissolved in anhydrous THF (15 mL). MeMgBr (5.8 mL, 5.8 mmol) was added dropwise under an ice bath and allowed to react at room temperature for 3 h. After completion, the reaction was quenched with saturated ammonium chloride solution (10 mL), extracted with dichloromethane (25 mL), and washed with saturated brine (10 mL). The organic phase was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (PE / EtOAc = 10 / 1) to afford compound 9e (0.17 g).

[0314] MS (ESI) m / z 347 [M+H] + .

[0315] 1 H NMR (400MHz, CDCl3) δ8.29(s,1H),7.46(d,1H),7.25(d,1H),6.05(s,1H),5.92(s,1H),5.12(s,2H),2.16(s,3H),1.45(s,6H),1.39(s,9H).

[0316] Step 5: 2-(5-((3-amino-5-methyl-1H-pyrazol-1-yl)methyl)pyridin-2-yl)propan-2-ol hydrochloride 9f

[0317] Compound 9e (0.15 g mg, 0.43 mmol) was dissolved in methanol (5 mL), and a 1,4-dioxane solution of hydrochloric acid (5 mL, 4.0 M) was added. The mixture was reacted at room temperature for 3 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain crude compound 9f (150 mg), which was used directly in the next step.

[0318] MS (ESI) m / z 247 [M+H] + .

[0319] Step 6 (R)-N-(1-((6-(2-hydroxypropane-2-yl)pyridin-3-yl)methyl)-5-methyl-1H-pyrazol-3-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyridine[3',2':4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide 9

[0320] Compound 9f (50 mg, 0.2 mmol) was dissolved in DMF (2 mL), and then compound 1g (59 mg, 0.24

[0321] mmol), HATU (91 mg, 0.24 mmol) and DIPEA (92 mg, 0.72 mmol), and the reaction was carried out at room temperature for 3 h. After the reaction was completed as monitored by TLC, ethyl acetate (20 mL) and water (10 mL) were added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), and the organic phase was concentrated under reduced pressure to give a crude product, which was purified by column chromatography (DCM / MeOH = 10 / 1) to give compound 9 (38 mg).

[0322] MS (ESI) m / z 474 [M+H] + .

[0323] 1 H NMR (400MHz, CDCl3) δ8.34(s,1H),8.15-8.10(m,2H),7.45(m,1H),7.30(m,1H),7. 22(s,1H),6.77(s,1H),5.66(m,1H),5.20-5.13(m,4H),4.01(dd,1H),3.46(m,2H), 2.26(s,3H),1.56(m,3H),0.81(s,6H).

[0324] Example 10 (R)-N-(1-((6-(1-hydroxycyclopropyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyridine[3',2':4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide

[0325] First step: tert-Butyl (1-((6-(1-hydroxycyclopropyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)carbamate 10a

[0326] EtMgBr (1.6 mL, 1.6 mol) was dissolved in anhydrous THF (5 mL) at -20°C. Ti(OiPr)4 (206 mg, 0.73 mmol) was slowly added dropwise to the solution, stirred for 1 hour, and compound 5e (180 mg, 0.52 mmol) was added. The mixture was allowed to react at room temperature for 3 hours. After completion, the reaction was quenched with saturated ammonium chloride solution (10 mL), extracted with dichloromethane (50 mL), and washed with saturated brine. The organic phase was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (PE / EtOAc = 10 / 1) to afford compound 10a (50 mg).

[0327] MS (ESI) m / z 331 [M+H] + .

[0328] 1 H NMR(400MHz, CDCl3)δ8.65(d,1H),8.07(d,J=8.06Hz,1H),7.72(br.s.,1H),7.62(dd,J= 8.06,2.15Hz,1H),7.37(s,1H),6.26(br.s.,1H),5.28-5.34(m,2H),1.37-1.44(m,4H).

[0329] Step 2 1-(5-((4-amino-1H-pyrazol-1-yl)methyl)pyridin-2-yl)cyclopropan-1-ol hydrochloride 10b

[0330] Compound 10a (23 mg, 0.07 mmol) was dissolved in methanol (2 mL), and then a 1,4-dioxane solution of hydrochloric acid (2 mL, 4.0 M) was added under nitrogen. The mixture was reacted at room temperature for 3 h and concentrated under reduced pressure to obtain crude product 10b (25 mg), which was used directly in the next reaction.

[0331] MS (ESI) m / z 231 [M+H] + .

[0332] Step 3 (R)-N-(1-((6-(1-hydroxycyclopropyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyridine[3',2':4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide 10

[0333] Compound 10b (25 mg, 0.07 mmol) was dissolved in DMF (2 mL), and then compound 1g (17 mg, 0.07 mmol), HATU (32 mg, 0.08 mmol) and DIPEA (27 mg, 0.21 mmol) were added. After reacting at room temperature for 3 h, water (30 mL) was added and extracted with ethyl acetate (20 mL×3). The organic phases were combined and washed with saturated brine. The organic phase was concentrated under reduced pressure to give a crude product, which was purified by column chromatography (DCM / MeOH=10 / 1) to give compound 10 (5.3 mg).

[0334] MS (ESI) m / z 458 [M+H] + .

[0335] 1 H NMR (400MHz, CDCl3) δ9.67(s,1H),8.60(d,1H),8.29(s,1H),8.22(d,J=8.19Hz,1H),8.14(d,J=8.19Hz,1H),8.03(d,1H),7.73-7 .66(m,2H),7.31(s,1H),5.41(s,2H),5.29-5.17(m,1H),4.10(dd,1H),3.65-3.53(m,1H),3.23(q,2H),1.58(m,3H),1.22(t,4H).

[0336] Example 11 (R)-N-(1-((6-(1-hydroxycyclobutyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide

[0337] Step 1: 2-Bromo-5-(((tert-butyldimethylsilyl)oxy)methyl)pyridine 11b

[0338] Compound 11a (10 g, 53.2 mmol) and imidazole (7.2 g, 106 mmol) were dissolved in dichloromethane (100 mL). Tert-butyldimethylsilyl chloride (9.57 g, 63.8 mmol) was added portionwise at room temperature. The mixture was allowed to react for 3 h. Saturated ammonium chloride solution (100 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (250 mL). The organic phase was washed with saturated brine (100 mL). The organic phase was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography (PE / EtOAc = 10 / 1) to obtain compound 11b (13 g).

[0339] 1H NMR (400MHz, CDCl3) δ8.32(d,1H),7.53(d,1H),7.45(d,1H),4.71(s,2H),0.88-0.97(m,9H),0.06-0.13(m,6H).

[0340] Step 2: 1-(5-(((tert-Butyldimethylsilyl)oxy)methyl)pyridin-2-yl)cyclobutan-1-ol 11d

[0341] Compound 11b (5 g, 16.6 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL). The reaction system was cooled to -78°C, and butyllithium (60 mL, 19.9 mmol) was added dropwise. Stirring was continued for 20 minutes. Cyclobutanone (11c) (1.39 g, 19.9 mmol) was added dropwise at -78°C. The mixture was allowed to react for 30 minutes at -78°C, then slowly warmed to room temperature and allowed to react for 3 hours. After completion, the reaction was quenched by the addition of saturated ammonium chloride solution (100 mL). The mixture was extracted with ethyl acetate (200 mL), and the organic phase was washed three times with saturated brine (100 mL). The organic phase was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (PE / EA = 10 / 1) to obtain compound 11d (2.2 g) as a colorless oil.

[0342] MS (ESI) m / z 294 [M+H] + .

[0343] 1 HNMR (400MHz, CDCl3) δ8.52-8.42(m,1H),7.79(dd,J=8.06,2.15Hz,1H),7.57(d,J=8.06Hz,1H),4.73(s,2H),3 .79-3.70(m,1H),2.63-2.40(m,2H),2.16-2.00(m,2H),1.94-1.78(m,2H),0.99-0.88(m,9H),0.15-0.07(m,6H)

[0344] Step 3 1-(5-(Hydroxymethyl)pyridin-2-yl)cyclobutan-1-ol 11e

[0345] Compound 11d (2.0 g, 16.6 mmol) was dissolved in anhydrous dichloromethane (40 mL). A solution of hydrochloric acid in 1,4-dioxane (20 mL, 4.0 M) was added and allowed to react for 30 minutes. After completion of the reaction, the crude product was spin-dried and purified by column chromatography (PE / EA = 10 / 1) to afford compound 11e (0.61 g) as a colorless oil.

[0346] MS (ESI) m / z 180 [M+H] + .

[0347] Step 4: 1-(5-((4-nitro-1H-pyrazol-1-yl)methyl)pyridin-2-yl)cyclobutan-1-ol 11f

[0348] 3-Nitropyrazole (536 mg, 4.74 mmol) was dissolved in degassed anhydrous tetrahydrofuran (15 mL), followed by the addition of compound 11e (567 mg, 3.16 mmol) and triphenylphosphine (2.48 g, 9.48 mmol). DBAD (1.09 g, 4.24 mmol) was then added portionwise under ice-cooling. The mixture was stirred at room temperature for 16 h. After completion of the reaction, ethyl acetate (20 mL) and saturated sodium bicarbonate solution (10 mL) were added, and extraction with ethyl acetate (20 mL x 3) was performed. The organic phases were combined, washed with saturated brine (50 mL), and concentrated under reduced pressure to yield the crude product. The crude product was then purified by column chromatography (PE / EtOAc = 3 / 1) to afford compound 11f (210 mg).

[0349] MS (ESI) m / z 275 [M+H] + .

[0350] 1 H NMR(400MHz, CDCl3)δ8.55(d,1H),8.22(s,1H),8.11(s,1H),7.77-7.61(m,1H) ,7.61-7.52(m,1H),5.38(s,2H),4.13(d,1H),2.66-2.42(m,2H),2.06(m,4H).

[0351] Step 5: 11g of 1-(5-((4-amino-1H-pyrazol-1-yl)methyl)pyridin-2-yl)cyclobutan-1-ol

[0352] Compound 11f (150 mg, 0.54 mmol) was dissolved in methanol (5 mL). Pd / C and ammonium formate (1 g) were then added under nitrogen. The mixture was allowed to react at room temperature for 3 h. After completion of the reaction, the mixture was filtered and concentrated under reduced pressure to obtain a crude product 11 g (60 mg), which was used directly in the next reaction.

[0353] MS (ESI) m / z 245 [M+H] + .

[0354] Step 6 (R)-N-(1-((6-(1-hydroxycyclobutyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide 11

[0355] Compound 11g (50 mg, 0.14 mmol) was dissolved in DMF (2 mL), followed by the addition of compound 1g (50 mg, 0.16 mmol), HATU (75 mg, 0.16 mmol), and DIPEA (58 mg, 0.45 mmol). The reaction was stirred at room temperature for 3 h. After completion, ethyl acetate (20 mL) and water (10 mL) were added, and extraction was performed with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), and concentrated under reduced pressure to give a crude product, which was then purified by column chromatography (DCM / MeOH = 10 / 1) to afford compound 11 (36.8 mg).

[0356] MS (ESI) m / z 472 [M+H] + .

[0357] 1 H NMR (400MHz, CDCl3) δ10.64 (s, 1H), 8.51 (d, J = 1.75Hz, 1H), 8.35-8.25 (d, 2H), 7.9 2(d,J=8.19Hz,1H),7.80(s,1H),7.66(dd,J=8.19,1H),7.55(d,1H),7.13(s,1H), 5.71(s,1H),5.38(s,2H),5.28(br.s.,1H),3.91(dd,1H),3.48(d,J=6.72Hz,1H), 3.10(m,1H),2.26-2.13(m,2H),1.87(s,2H),1.79(s,2H),1.42(d,J=6.45Hz,3H).

[0358] Example 12 (8S,9R)-N-(1-((6-(2-hydroxypropan-2-yl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)-8,9-dimethyl-6-oxo-6,7,8,9-tetrahydropyridine[3',2':4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide

[0359] Step 1: tert-Butyl ((2S,3S)-3-hydroxybutan-2-yl)carbamate 12b

[0360] Compound 12a (3.83 g, 22.1 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL). MeCuLi (97 mL, 48.6 mmol, 0.5 M in diethyl ether) was added at -55°C and allowed to react for 4 hours. The reaction was then continued in an ice bath for 3 hours. Saturated ammonium chloride solution (20 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (PE / EtOAc = 3 / 1) to obtain compound 12b (2.3 g).

[0361] MS (ESI) m / z 190 [M+H] +

[0362] Step 2: Diethyl 1-((2R,3S)-3-((tert-Butoxycarbonyl)amino)butan-2-yl)-1H-pyrrolo[2,3-b]pyridine-2,6-dicarboxylate 12c

[0363] Compound 12b (2.3 g, 12.3 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), and compound 1c (3.98 g, 15.2 mmol) and triphenylphosphine (7.97 g, 30.4 mmol) were added. The reaction mixture was placed in an ice bath, and DBAD (5.24 g, 22.8 mmol) was added portionwise. The mixture was stirred at room temperature for 16 h. After completion of the reaction, ethyl acetate (50 mL) and saturated sodium bicarbonate solution (10 mL) were added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE / EtOAc = 2 / 1) to obtain compound 12c (1.8 g).

[0364] MS (ESI) m / z 434 [M+H] +

[0365] 1 H NMR (400MHz, CDCl3) δ8.15-8.02(m,1H),8.01-7.90(m,1H),7.29(d,1H),4.55- 4.34(m,4H),1.84(d,1H),1.68(s,1H),1.55-1.45(m,15H),1.45-1.38(m,6H).

[0366] Step 3: 1-((2R,3S)-3-aminobutan-2-yl)-1H-pyrrolo[2,3-b]pyridine-2,6-dicarboxylic acid diethyl ester hydrochloride 12d

[0367] Compound 12c (0.14 g, 0.32 mmol) was dissolved in methanol (10 mL), and a solution of hydrochloric acid in 1,4-dioxane (5 mL, 4.0 M) was added. The mixture was stirred at room temperature for 3 h. After completion of the reaction, the mixture was concentrated under reduced pressure to give a crude product 12d (140 mg), which was used directly in the next reaction.

[0368] MS (ESI) m / z 334 [M+H] + .

[0369] Step 4: (8S,9R)-8,9-dimethyl-6-oxo-6,7,8,9-tetrahydropyridine [3',2':4,5] pyrrolo [1,2-a] pyrazine-2-carboxylic acid ethyl ester 12e

[0370] Compound 12d (140 mg, 0.32 mmol) was dissolved in ethanol (5 mL), and potassium carbonate (88 mg, 0.64 mmol) was added. The mixture was stirred at 70°C for 3 h. After completion of the reaction, the mixture was filtered and concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography (DCM / MeOH = 10 / 1) to obtain compound 12e (0.3 g).

[0371] MS (ESI) m / z 288 [M+H] + .

[0372] 1 H NMR(400MHz, CDCl3)δ8.14(d,1H),7.99(d,1H),7.26(s,1H),5.21-5.03(m,1 H),4.63-4.38(m,2H),4.26(dd,1H),1.47(s,3H),1.42(d,3H),1.36(d,3H).

[0373] Step 5 (8S,9R)-8,9-dimethyl-6-oxo-6,7,8,9-tetrahydropyridine [3',2':4,5] pyrrolo [1,2-a] pyrazine-2-carboxylic acid 12f

[0374] Compound 12e (45 mg, 0.15 mmol) was dissolved in tetrahydrofuran (2 mL) and water (2 mL), and lithium hydroxide monohydrate (19 mg, 0.3 mmol) was added. The mixture was reacted at room temperature for 3 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain compound 12f (45 mg), which was used directly in the next step.

[0375] MS (ESI) m / z 260 [M+H] + .

[0376] Step 6 (8S,9R)-N-(1-((6-(2-hydroxypropan-2-yl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)-8,9-dimethyl-6-oxo-6,7,8,9-tetrahydropyridine[3',2':4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide 12

[0377] Compound 12f (40 mg, 0.15 mmol) was dissolved in DMF (2 mL), and then compound 5g (30 mg, 0.12 mmol), HATU (71 mg, 0.18 mmol) and DIPEA (60 mg, 0.46 mmol) were added. The reaction was carried out at room temperature for 3 h. After the reaction was completed, ethyl acetate (20 mL) and water (10 mL) were added, and extraction was carried out with ethyl acetate (20 mL×3). The organic phases were combined and washed with saturated brine (50 mL). The organic phase was concentrated under reduced pressure to give a crude product, which was purified by column chromatography (DCM / MeOH=10 / 1) to give compound 12 (2.6 mg).

[0378] MS (ESI) m / z 474 [M+H] + .

[0379] 1 HNMR(400MHz, CDCl3)δ9.57(s,1H),8.42(s,1H),8.18(s,1H),8.13(d,1H),8.06(d,1H),7.62(s,1H),7.57(dd,1H),7 .31(d,1H),5.59(s,1H),5.35(s,2H),5.01(s,1H),5.00-4.83(m,1H),4.23(dd,1H),2.02-1.86(m,6H),1.47(m,6H).

[0380] Example 13 (R)-6-Fluoro-N-(1-((6-(2-hydroxypropan-2-yl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)-4-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-7-carboxamide

[0381] Step 1: (R)-1-(1-aminopropan-2-yl)-7-fluoro-1H-indole-2,6-dicarboxylic acid diethyl ester 13b

[0382] Compound 13a (335 mg, 0.77 mmol) was dissolved in dichloromethane solution (6 mL), and trifluoroacetic acid (2 mL) was added dropwise. The mixture was stirred at room temperature for 3 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and saturated sodium bicarbonate solution (100 mL) was added. The mixture was extracted with ethyl acetate (50 mL×3) and purified by normal phase chromatography on silica gel to obtain compound 13b (258 mg) as a colorless oily liquid.

[0383] Step 2: (R)-6-Fluoro-4-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-7-carboxylic acid ethyl ester 13c

[0384] Compound 13b (258 mg, 0.77 mmol) was dissolved in ethanol (10 mL), and potassium carbonate (428 mg, 2.30 mmol) was added. The mixture was heated to 60°C for 3 h. After completion of the reaction monitored by TLC, the mixture was concentrated under reduced pressure and extracted with ethyl acetate (50 mL×3). The organic phases were combined and washed with saturated brine (50 mL). The crude product was separated and purified by normal phase chromatography on silica gel to give compound 13c (225 mg) as a white solid.

[0385] 1 H NMR (400MHz, CDCl3) δ7.57(dd,J=8.5,6.3Hz,1H),7.39(d,J=8.5Hz,1H),7.27(d,J=5.3Hz,1H),7.20(d,J=2.1Hz,1H),5.11–5.01(m,1H),4 .36(qd,J=7.1,1.1Hz,2H),4.04(dd,J=12.9,4.4Hz,1H),3.46(ddd,J=12.7,5.4,1.3Hz,1H),1.47(d,J=6.6Hz,3H),1.36(t,J=7.1Hz,3H).

[0386] Step 3 (R)-6-Fluoro-4-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-7-carboxylic acid 13d

[0387] Compound 13c (187 mg) was dissolved in 1,4-dioxane (6 mL), and lithium hydroxide (19 mg, 0.77 mmol) was slowly added. The mixture was stirred at room temperature for 1 h. After completion of the reaction monitored by TLC, the mixture was concentrated under reduced pressure until a white solid precipitated. The mixture was filtered to obtain compound 13d (white solid, 148 mg, 46%).

[0388] MS (ESI) m / z 261 [MH] + .

[0389] Step 4 (R)-6-fluoro-N-(1-((6-(2-hydroxypropan-2-yl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)-4-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-7-carboxamide 13

[0390] Under argon protection, compound 13d (25 mg, 0.095 mmol), compound 5g (24 mg, 0.11 mmol), PyBop (74 mg, 0.14 mmol), DIPEA (37 mg, 0.29 mmol) and DMF (3 mL) were added in sequence to a 50 mL three-necked flask and reacted at room temperature for 24 h. After the completion of the reaction monitored by TLC, water was added to the reaction system, and the mixture was extracted with ethyl acetate (50 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 to give compound 13 (18 mg) as a white solid.

[0391] MS (ESI) m / z 477 [M+H] + .

[0392] 1 H NMR (400MHz, CD3OD) δ8.34(t,J=1.5Hz,1H),8.11(s,1H),7.64–7.56(m,3H),7.46(d,J=8.4Hz,1H),7.30(dd,J=8.4,6.1Hz,1H),7.15(d,J= 2.2Hz,1H),5.30(s,2H),5.08–5.00(m,1H),3.94(dd,J=13.2,4.5Hz,1H),3.43(dd,J=13.2,1.3Hz,1H),1.43(s,6H),1.41(d,J=6.5Hz,3H).

[0393] Example 14 (S)-N-(1-((6-(2-hydroxypropan-2-yl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)-8-methyl-6-oxo-6,7,8,9-tetrahydropyridine[3',2':4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide

[0394] Step 1: (S)-1-(2-(tert-Butyloxycarbonyl)amino)propyl)-1H-pyrrolo[2,3-b]pyridine-2,6-dicarboxylic acid diethyl ester 14b

[0395] Compound 14a (0.4 g, 2.3 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and compound 1c (0.5 g, 1.9 mmol) and triphenylphosphine (1.25 g, 4.75 mmol) were added. The reaction was placed in an ice bath, and DBAD (0.87 g, 3.8 mmol) was added portionwise. The mixture was stirred at room temperature for 16 h. After completion of the reaction, monitored by TLC, ethyl acetate (50 mL) and saturated sodium bicarbonate solution (10 mL) were added, and extraction with ethyl acetate (20 mL x 3) was performed. The organic phases were combined, washed with saturated brine (10 mL), and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE / EtOAc = 5 / 1) to obtain compound 14b (500 mg).

[0396] MS (ESI) m / z 420 [M+H] +

[0397] 1 H NMR(400MHz, CDCl3)δ8.07(d,1H),7.96(d,1H),7.29(s,1H),6.23(br.s.,1H),4.81( d,2H),4.57-4.35(m,4H),4.25-4.17(m,1H),1.53-1.45(m,12H),1.34-1.21(m,6H).

[0398] Step 2 (S)-1-(2-Aminopropyl)-1H-pyrrolo[2,3-b]pyridine-2,6-dicarboxylic acid diethyl ester hydrochloride 14c

[0399] Compound 14b (0.5 g, 1.2 mmol) was dissolved in methanol (5 mL), and a solution of hydrochloric acid in 1,4-dioxane (5 mL, 4.0 M) was added. The mixture was stirred at room temperature for 3 h. After completion of the reaction monitored by TLC, the mixture was concentrated under reduced pressure to give crude product 14c (500 mg), which was used directly in the next step.

[0400] MS (ESI) m / z 320 [M+H] + .

[0401] Step 3 (S)-8-Methyl-6-oxo-6,7,8,9-tetrahydropyridine [3',2':4,5] pyrrolo [1,2-a] pyrazine-2-carboxylic acid ethyl ester 14d

[0402] Compound 14c (500 mg, 1.2 mmol) was dissolved in ethanol (5 mL), and potassium carbonate (331 mg, 2.4 mmol) was added. The mixture was reacted at 70°C for 3 h. After completion of the reaction monitored by TLC, the mixture was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (DCM / MeOH = 10 / 1) to obtain compound 14d (0.3 g).

[0403] MS (ESI) m / z 274 [M+H] + .

[0404] Step 4: (S)-8-methyl-6-oxo-6,7,8,9-tetrahydropyridine [3',2':4,5] pyrrolo [1,2-a] pyrazine-2-carboxylic acid 14e

[0405] Compound 14d (208 mg, 0.76 mmol) was dissolved in tetrahydrofuran (5 mL) and water (5 mL), and lithium hydroxide monohydrate (94 mg, 2.28 mmol) was added. The mixture was reacted at room temperature for 3 h. After completion of the reaction monitored by TLC, the mixture was filtered and concentrated under reduced pressure to give a crude product 14e (0.3 g), which was used directly in the next step.

[0406] MS (ESI) m / z 246 [M+H] + .

[0407] Step 5 (S)-N-(1-((6-(2-hydroxypropan-2-yl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)-8-methyl-6-oxo-6,7,8,9-tetrahydropyridine[3',2':4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide 14

[0408] Compound 14e (30 mg, 0.12 mmol) was dissolved in DMF (2 mL), and then compound 5g (30 mg, 0.12 mmol), HATU (46 mg, 0.12 mmol) and DIPEA (46 mg, 0.36 mmol) were added. The reaction was allowed to react at room temperature for 3 h. After completion of the reaction as monitored by TLC, ethyl acetate (20 mL) and water (10 mL) were added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (50 mL), and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (DCM / MeOH=10 / 1) to give compound 14 (52 mg).

[0409] MS (ESI) m / z 460 [M+H] + .

[0410] 1 H NMR(400MHz, CDCl3)δ8.59(s,2H),8.46-8.39(m,2H),8.05(d,1H),7.93(s,1H),7.85-7.70(m, 2H),5.49(s,2H),5.33(s,1H),4.93(d,1H),4.28-4.13(m,2H),1.59-1.51(m,6H),1.45(d,3H).

[0411] Example 15 (R)-N-(1-((5-fluoro-6-(2-hydroxypropan-2-yl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyridine[3',2':4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide

[0412] Step 1: 3-Fluoro-5-methylpicolinic acid phenyl ester 15b

[0413] Compound 15a (5 g, 26.3 mmol) was dissolved in anhydrous acetonitrile (50 mL), and phenyl formate (4.17 g, 34.2 mmol), triethylamine (6.6 g, 19.5 mmol), Pd(OAc)2 (217 mg, 1.31 mmol), and Xantphos (1.1 g, 2.62 mmol) were added. The reaction was allowed to proceed at 80°C for 4 hours. After cooling to room temperature, saturated ammonium chloride solution (20 mL) was added, and the mixture was extracted with ethyl acetate (250 mL x 3). The organic phases were combined, washed with saturated brine (200 mL), and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE / EtOAc = 5 / 1) to obtain compound 15b (3.6 g).

[0414] 1 H NMR (400MHz, CDCl3) δ8.47(s,1H),7.48-7.39(m,3H),7.34-7.22(m,4H),2.49(s,3H).

[0415] Step 2 Ethyl 3-fluoro-5-methylpicolinate 15c

[0416] Compound 15b (3.52 g, 15.2 mmol) was dissolved in anhydrous ethanol (30 mL), and sodium ethoxide (0.1 g, 1.5 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, the mixture was monitored by TLC. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (10 mL), and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (PE / EtOAc = 2 / 1) to obtain compound 15c (2.2 g).

[0417] MS (ESI) m / z 184 [M+H] +

[0418] Step 3 Ethyl 5-(bromomethyl)-3-fluoropicolinate 15d

[0419] Compound 15c (2.1 g, 11.5 mmol) was dissolved in 1,2-dichloroethane (40 mL), and then N-bromosuccinimide (2.6 g, 14.9 mmol) was added. AIBN (0.18 g, 1.15 mmol) was added portionwise at 85°C. After completion of the reaction monitored by TLC, the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EtOAc = 3 / 1) to obtain compound 15d (1.2 g).

[0420] 1 H NMR (400MHz, CDCl3) δ8.57(d,1H),7.80(d,1H),4.58-4.40(m,2H),2.45-2.26(m,3H),1.52-1.36(m,3H).

[0421] Step 4: Ethyl 3-fluoro-5-((4-nitro-1H-pyrazol-1-yl)methyl)picolinate 15e

[0422] Compound 15d (2 g, 7.6 mmol) was dissolved in acetonitrile (30 mL), and 4-nitropyrazole (858 mg, 7.6 mmol) and potassium carbonate (1.46 g, 15 mmol) were added. The mixture was reacted at 70°C for 3 h. After completion of the reaction monitored by TLC, ethyl acetate (30 mL) was added. The mixture was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (DCM / MeOH = 10 / 1) to obtain compound 15e (0.8 g).

[0423] MS (ESI) m / z 295 [M+H] + .

[0424] Step 5: Ethyl 5-((4-amino-1H-pyrazol-1-yl)methyl)-3-fluoropicolinate 15f

[0425] Compound 15e (800 mg, 0.54 mmol) was dissolved in methanol (50 mL), and then Pd / C and ammonium formate (3 g) were added under nitrogen. The mixture was stirred at room temperature for 3 h. After completion of the reaction monitored by TLC, the mixture was filtered and concentrated under reduced pressure to give crude product 15f (800 mg), which was used directly in the next reaction.

[0426] MS (ESI) m / z 265 [M+H] + .

[0427] Step 6: 15g of ethyl 5-((4-((tert-butyloxycarbonyl)amino)-1H-pyrazol-1-yl)methyl)-3-fluoropicolinate

[0428] Compound 15f (800 mg, 0.54 mmol) was dissolved in DCM (20 mL), and then triethylamine (110 mg, 1.1 mmol) and di-tert-butyl dicarbonate (130 mg, 0.6 mmol) were added. The reaction was stirred at room temperature for 3 h. After the completion of the reaction monitored by TLC, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (50 mL), and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (DCM / MeOH=10 / 1) to give compound 15g (0.5 g).

[0429] MS (ESI) m / z 365 [M+H] + .

[0430] 1 H NMR(400MHz, CDCl3)δ8.43(s,1H),7.76(br.s.,1H),7.63(br.s.,1H),7.38(s,1H ),7.30(dd,1H),5.32(s,2H),4.48(q,2H),1.55-1.46(m,9H),1.46-1.38(m,3H).

[0431] Step 7: Tert-butyl (1-((5-fluoro-6-(2-hydroxypropan-2-yl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)carbamate 15h

[0432] Compound 15g (0.5g, 1.37mmol) was dissolved in THF (10mL). Methylmagnesium bromide (5.48mL, 5.48mmol) was added dropwise under an ice bath and allowed to react at room temperature for 3h. Saturated ammonium chloride solution (10mL) was added to the reaction mixture to quench the reaction. The mixture was extracted with dichloromethane (25mL), and the organic phase was washed with saturated brine (100mL). The organic phase was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (PE / EtOAc = 10 / 1) to obtain compound 15h (0.25g).

[0433] MS (ESI) m / z 351 [M+H] + .

[0434] Step 8 2-(5-((4-amino-1H-pyrazol-1-yl)methyl)-3-fluoropyridin-2-yl)propan-2-ol hydrochloride 15i

[0435] Compound 15h (250 mg, 0.71 mmol) was dissolved in methanol (5 mL), and then a 1,4-dioxane solution of hydrochloric acid (5 mL, 4 M) was added under nitrogen. The reaction was stirred at room temperature for 3 h. After completion of the reaction monitored by TLC, the mixture was concentrated under reduced pressure to obtain the crude product, compound 15i (800 mg), which was directly used in the next step.

[0436] MS (ESI) m / z 251 [M+H] + .

[0437] Step 9 (R)-N-(1-((5-fluoro-6-(2-hydroxypropyl-2-yl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyridine[3',2':4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide 15

[0438] Compound 15i (250 mg, 1.0 mmol) was dissolved in DMF (5 mL), followed by the addition of compound 1g (254 mg, 1.0 mmol), HATU (380 mg, 1.0 mmol), and DIPEA (390 mg, 3.0 mmol). The reaction was stirred at room temperature for 3 h. After completion of the reaction, monitored by TLC, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), and concentrated under reduced pressure to give the crude product, which was then purified by column chromatography (DCM / MeOH = 10 / 1) to afford compound 15 (31.7 mg).

[0439] MS (ESI) m / z 478 [M+H] + .

[0440] 1 H NMR(400MHz, CDCl3)δ9.69(s,1H),8.30(s,2H),8.21(d,1H),8.14(d,1H),7.70(s,1H),7.34-7.28( m,2H),6.57(d,1H),5.37(s,2H),5.28-5.13(m,1H),4.09(dd,1H),3.59(dd,1H),1.62-1.47(m,9H).

[0441] Example 16 (8S,9R)-N-(1-((5-fluoro-6-(2-hydroxypropan-2-yl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)-8,9-dimethyl-6-oxo-6,7,8,9-tetrahydropyridine[3',2':4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide

[0442] Compound 12f (100 mg, 0.38 mmol) was dissolved in DMF (2 mL), and then compound 15i (128 mg, 0.36 mmol), HATU (164 mg, 0.43 mmol) and DIPEA (129 mg, 1.08 mmol) were added. The reaction was incubated at room temperature for 3 h. After completion of the reaction as monitored by TLC, water (10 mL) was added and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (30 mL), and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (DCM / MeOH=10 / 1) to give compound 16 (6.8 mg).

[0443] MS (ESI) m / z 492 [M+H] + .

[0444] 1 H NMR(400MHz, CDCl3)δ9.67(s,1H),8.31(s,1H),8.18(dd,2H),7.70(s,1H),7.31(d,2H),5.60(s,1H),5.4 5(s,1H),5.36(s,2H),5.03(m,1H),4.33-4.30(m,1H),1.57(s,6H),1.49-1.47(d,3H),1.41-1.44(d,3H).

[0445] Example 17 (R)-N-(1-((6-(2-hydroxypropyl-2-yl-1,1,3,3-d6)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyridine[3',2':4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide

[0446] First step: tert-Butyl (1-((6-(2-hydroxypropan-2-yl-1,1,1,3,3-d6)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)carbamate 17a

[0447] Compound 5e (0.22 g, 0.63 mmol) was dissolved in THF (10 mL) and CD3MgBr (2.86 mL, 2.86 mmol) was added dropwise under an ice bath. The mixture was allowed to react at room temperature for 3 h. After completion, the reaction was quenched with saturated ammonium chloride solution (10 mL), extracted with dichloromethane (25 mL), and washed with saturated brine. The organic phase was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (PE / EtOAc = 10 / 1) to afford compound 17a (0.1 g).

[0448] MS (ESI) m / z 339 [M+H]+ .

[0449] Step 2 2-(5-((4-amino-1H-pyrazol-1-yl)methyl)pyridin-2-yl)propyl-1,1,1,3,3,3-d6-2-ol hydrochloride 17b

[0450] Compound 17a (250 mg, 0.71 mmol) was dissolved in methanol (5 mL), and then a 1,4-dioxane solution of hydrochloric acid (5 mL, 4.0 M) was added under nitrogen. The mixture was reacted at room temperature for 3 h. After completion of the reaction as monitored by TLC, the mixture was concentrated under reduced pressure to obtain the crude product, compound 17b (100 mg), which was used directly in the next reaction.

[0451] MS (ESI) m / z 239 [M+H] + .

[0452] Step 3 (R)-N-(1-((6-(2-hydroxypropyl-2-yl-1,1,3,3-d6)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyridine[3',2':4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide 17

[0453] Compound 17b (76 mg, 0.32 mmol) was dissolved in DMF (5 mL), and then compound 1g (93 mg, 0.38 mmol), HATU (144 mg, 0.38 mmol) and DIPEA (147 mg, 1.1 mmol) were added. The reaction was stirred at room temperature for 3 h. After completion of the reaction monitored by TLC, water (10 mL) was added and extracted with ethyl acetate (20 mL×3). The organic phases were combined and washed with saturated brine (50 mL). The organic phases were concentrated under reduced pressure to give a crude product, which was purified by column chromatography (DCM / MeOH=10 / 1) to give compound 17 (28.4 mg).

[0454] MS (ESI) m / z 466 [M+H] +

[0455] 1 H NMR(400MHz, CDCl3)δ9.66(s,1H),8.49(d,1H),8.26(s,1H),8.22(d,1H),8.14(d,1H),7.68(s,1H),7.63(dd,1H),7.37 (d,1H),7.31(s,1H),6.13(d,1H),5.35(s,2H),5.18-5.27(m,1H),4.81(s,1H),4.10(dd,1H),3.57(m,1H),1.62(m,3H).

[0456] Reference compound I (BI-D1870)

[0457] This compound was purchased from a commercial source, manufacturer: MCE, product number: HY-10510

[0458] Control compound II

[0459] Prepared according to patent WO2017141116A1.

[0460] Test Example 1: IC inhibition of the compound on RSK2 kinase activity in vitro 50 Evaluation test

[0461] The HTRF KinEASE-STK Assay was used to detect the inhibitory effects of small molecule compounds on RSK2 kinase. The RSK2 kinase reaction system was prepared in 5 μL and contained the following components at the following final concentrations: 0.18 nM RSK2 recombinant enzyme (Carna, Cat. No. 01-150), a small molecule inhibitor at varying concentrations, 5 mM MgCl2, 1 mM DTT, 10 μM ATP, 1 μM STK1-Substrate (Cisbio, Cat. No. 61ST1BLC), and 1X kinase reaction buffer (Cisbio, Cat. No. 62EZBFDD). Specifically, 2.5× RSK2 recombinant enzyme and 5× inhibitor were first added to the buffer system in a 384-well plate and incubated at room temperature for 10 minutes. At the same time, negative control wells without enzyme and positive control wells without compound were set. Then, 2.5× peptide substrate and ATP were added to start the reaction. After incubation at room temperature for 30 minutes, 5 μL of the corresponding 2× phosphorylated antibody STK-antibody-Cryptate (Cisbio, Cat NO.62ST0PEB) and substrate tag antibody Sa-XL 665 (Cisbio, Cat NO.610SAXLA) were added to terminate the reaction and placed at room temperature for 60 minutes. The values ​​of excitation at 320 nm and emission at 620 nm and 665 nm were read on the HTS high-throughput drug screening multifunctional microplate reader, and RFU 620 nm / RFU 665 nm were calculated. The inhibition rate was calculated by the following formula, and then the curve was drawn with the Log value of the inhibitor concentration as the X axis and the inhibition rate as the Y axis. The IC was calculated using Graphpad 7.0. 50 value.

[0462] Average value of positive control well ratio (10 μM BI-D1870)

[0463] Average value of negative control well ratio (0.5% DMSO)

[0464] Table 1 In vitro inhibitory activity of test compounds on RSK2 kinase

[0465] The experimental results show that the compound of the present invention has a good inhibitory effect on RSK2 kinase.

[0466] Test Example 2: Compound inhibition of triple-negative breast cancer cell proliferation test

[0467] Compounds or vehicle control (DMSO) were diluted in culture medium in 96-well plates to final concentrations of 50, 25, 12.5, 6.25, 3.13, 1.56, 0.78, 0.39, 0.2, and 0.1 μM. 1×10 3 MDA-MB-453 cells were plated and the plates were incubated in an incubator for 5 days. After the incubation period, cell survival was quantified using the Cell Counting Kit-8 (CCK-8) reagent. Briefly, cells were incubated with CCK8 for 2-4 hours, and the absorbance at 450 nm and 650 nm was measured. CCK-8 is WST-8 (chemical name: 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfonic acid benzene)-2H-tetrazole monosodium salt), which is reduced by dehydrogenases in the cell to a highly water-soluble yellow formazan product (Formazan dye) under the action of the electron carrier 1-methoxy-5-methylphenazinium dimethyl sulfate (1-Methoxy PMS). The amount of formazan produced is proportional to the number of living cells, so this property can be used to calculate the survival percentage as shown in the following formula: Cell survival rate (%) = [(As-Ac) / (Ab-Ac)] x 100%]

[0468] As: experimental wells (wells containing cells and drugs at different concentrations)

[0469] Ab: vehicle control wells (vehicle-treated wells containing cells and drug concentration of 0)

[0470] Ac: blank well (well without cells and drugs)

[0471] The cell viability data and the corresponding compound concentrations were input into GraphPad Prism software to fit and calculate IC 50 value.

[0472] Table 2 Proliferation inhibition activity of test compounds on MDA-MB-453

[0473] The experimental results show that the compound of the present invention has good proliferation inhibition activity on MDA-MB-453.

[0474] Test Example 3: Pharmacokinetic Test

[0475] Mouse pharmacokinetic studies were conducted using male ICR mice weighing 20-25 g, provided by the Laboratory Animal Management Department of the Shanghai Institute of Family Planning Sciences. Three mice fasted overnight were administered the drug (10 mg / kg) orally by gavage. Blood was collected before dosing, and 15, 30 minutes, and 1, 2, 4, 8, and 24 hours after dosing. Three additional mice were administered the drug (1 mg / kg) intravenously, and blood was collected before dosing, and 15, 30 minutes, and 1, 2, 4, 8, and 24 hours after dosing. Blood samples were centrifuged at 6800 g for 6 minutes at 2-8°C, and plasma was collected and stored at -80°C. Plasma was collected at each time point and mixed with 10-20 times the volume of methanol or acetonitrile containing the internal standard. The mixture was vortexed for 1 minute and centrifuged at 18,000 rpm at 4°C for 10 minutes. The supernatant was directly analyzed by LC-MS / MS. Key pharmacokinetic parameters were analyzed using WinNonlin 7.0 software using a non-compartmental model.

[0476] Table 3 Pharmacokinetic test results of test compounds in mice

[0477] The results of the mouse pharmacokinetic experiment showed that the compound of the present invention has a high oral exposure, good pharmacokinetic properties and good drugability.

[0478] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound represented by the following formula (I), its tautomers, stereoisomers, hydrates, solvates, or pharmaceutically acceptable salts thereof: in, n is 1 or 2; M is each independently N or CR a ; R a Selected from the group consisting of halogen, cyano, C 1-4 alkoxy; X, Y and Q are each independently selected from the group consisting of: CR b , or N; Z is selected from the following group: S, O or NR b ;and For aromatic rings, when the connection site is located at CR b , or NR b When the CR b , or NR b C or N; L is selected from the following group: chemical bond, -C(=O)-, CHR b 、C(R b )2, NH or O; Ring A is selected from the group consisting of: C 6-10 Aryl, 5-12 membered heteroaryl; R1 is selected from the group consisting of H, D, halogen, amino, C 1-4 alkyl; R2 and R3 are each independently selected from the following group: H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, wherein R2 and R3 may be the same or different; R4 is selected from the group consisting of H, D, halogen, hydroxy, amino, C 2-6 Sulfonyl, sulfinyl, -N=S(O)(CH3)2, Phosphoryl (-P(O)(CH3)2), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 1-6 Halogenated alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkynyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-12 membered heterocyclic group, 5-12 membered heteroaryl; the heterocyclic group and heteroaryl independently contain 1-3 heteroatoms selected from N, O, and S; R5 is selected from the group consisting of H, halogen, hydroxy, amino, sulfonyl, sulfinyl, phosphoryl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 1-6 Halogenated alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkynyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-12 membered heterocyclic group, 5-12 membered heteroaryl; the heterocyclic group and heteroaryl independently contain 1-3 heteroatoms selected from N, O, and S; R8 is selected from the group consisting of H, halogen; Furthermore, the R1, R2, R3, R4, and R5 can be optionally replaced by one or more R b replace; R b Selected from the group consisting of D, halogen, hydroxy, cyano, amino, imino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 2-4 Alkenyl, C 1-4 Halogenated alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkynyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-12 membered heteroaryl; When the compound has the structure shown in formula I-1 and M is N, ring A is not phenyl which is unsubstituted or substituted by a substituent selected from the group consisting of halogen, C 1-6 Alkyl, C 1-6 Haloalkyl-N(R 7 )2, or -C 1-6 Alkyl-N(R 7 )2; where R 7 H or C 1-6 alkyl; 2. The compound of formula I according to claim 1, its tautomers, stereoisomers, hydrates, solvates, or pharmaceutically acceptable salts thereof, characterized in that: The compound has the structure shown in formula I-1: wherein L is selected from the group consisting of a chemical bond, CH2, CF2, CHMe, and C(Me)2; When M is N, R4 is H, D, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy; R5 is -N=S(O)(CH3)2, Phosphoryl (-P(O)(CH3)2), C 1-6 Alkyl, C 3-6 Cycloalkyl.

3. The compound of formula I according to claim 1, its tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, characterized in that: The compound has the structure shown in formula I-2: in, wherein L is selected from the group consisting of a chemical bond, CH2, CF2, CHMe, and C(Me)2; R6 is selected from the group consisting of H, D, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 1-6 Halogenated alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkynyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-12 membered heterocyclic group, 5-12 membered heteroaryl; the heterocyclic group and heteroaryl independently contain 1-3 heteroatoms selected from N, O, and S; Furthermore, the R6 can be optionally replaced by one or more R b replace.

4. The compound of formula I according to claim 1, its tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, characterized in that: The compound has the structure shown in formula I-3 Wherein, R6 is selected from the following group: H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-12 membered heterocyclic group, 5-12 membered heteroaryl; the heterocyclic group and heteroaryl independently contain 1-3 heteroatoms selected from N, O, S; and the R6 can be optionally replaced by one or more R b replace.

5. The compound of formula I according to claim 1, its tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, characterized in that: R2, R3 are selected from the following groups: H, methyl, R 2, R3 are the same or different.

6. The compound of formula I according to claim 1, its tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, characterized in that: R4 and R5 are each independently selected from the following groups: H, halogen, amino, sulfinyl, phosphoryl, C 1-4 Alkyl, and the R4, R5 can be independently replaced by one or more R b replace.

7. The compound of formula I according to claim 1, its tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from the following group:

8. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises: one or more of the compound of formula I according to claim 1, its pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or mixture thereof, and one or more pharmaceutically acceptable carriers, excipients, adjuvants, auxiliary materials and / or diluents.

9. The use of the compound of formula I according to claim 1, its pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or mixture thereof, characterized in that: For use in the preparation of a pharmaceutical composition for diseases or conditions 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, characterized in that 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.

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