Hydropyrazino[1,2-d][1,4]diazepine compounds for the treatment of autoimmune diseases

Abstract

The present invention relates to a compound of formula (I): TIFF2023500639000080.tif49165 (In the formula, R 1 ~R 3 and n is as defined herein) and pharmaceutically acceptable salts thereof, compositions comprising said compounds, and methods of using said compounds.

Description

[Technical field]

[0001] The present invention relates to organic compounds useful for the therapy and / or prophylaxis in mammals, in particular antagonists of TLR7 and / or TLR8 and / or TLR9 useful in the treatment of systemic lupus erythematosus or lupus nephritis.

[0002] FIELD OF THEINVENTION Autoimmune diseases of connective tissue (CTDs) include the prototypic autoimmune syndromes such as systemic lupus erythematosus (SLE), primary Sjogren's syndrome (pSjS), mixed connective tissue disease (MCTD), dermatomyositis / polymyositis (DM / PM), rheumatoid arthritis (RA), and systemic sclerosis (SSc). With the exception of RA, there are no really effective and safe treatments available to patients. SLE is the prototypic CTD with a prevalence of 20-150 cases per 100,000, resulting in widespread inflammation and tissue damage in different organs, from the usually observed symptoms in the skin and joints to kidney, lung or heart failure. Traditionally, SLE has been treated with nonspecific anti-inflammatory or immunosuppressive drugs. However, long-term use of immunosuppressive drugs, such as corticosteroids, is only partially effective and is associated with undesirable toxicity and side effects. Belimumab is the only lupus drug approved by the FDA in the past 50 years, but it only works in a small proportion of SLE patients, and that is modest and delayed (Navarra, SV et al Lancet 2011, 377, 721.). Other biologics, such as anti-CD20 mAbs, mAbs against certain cytokines or their soluble receptors, have failed in most clinical studies. Thus, novel therapies are needed that provide sustained improvement in larger patient populations and are safer for chronic use in many autoimmune and autoinflammatory diseases.

[0003] Toll-like receptors (TLRs) are an important family of pattern recognition receptors (PRRs) that can initiate a wide range of immune responses in a wide variety of immune cells. As innate host defense sensors, endosomal TLR7, 8, and 9 recognize nucleic acids derived from viruses, bacteria, and specifically, TLR7 / 8 and TLR9 recognize single-stranded RNA (ssRNA) and single-stranded CpG-DNA, respectively. However, aberrant nucleic acid detection of TLR7, 8, and 9 is considered as a key node in a wide range of autoimmune and autoinflammatory diseases (Krieg, AM et al. Immunol. Rev. 2007, 220, 251. Jimenez-Dalmaroni, MJ et al Autoimmun Rev. 2016, 15, 1. Chen, JQ, et al. Clinical Reviews in Allergy & Immunology 2016, 50, 1.). Anti-RNA and anti-DNA antibodies are well-established diagnostic markers of SLE and can deliver both self-RNA and self-DNA to endosomes. Self-RNA complexes can be recognized by TLR7 and TLR8, whereas self-DNA complexes can trigger activation of TLR9. Indeed, defects in the clearance of self-RNA and self-DNA from blood and / or tissues are evident in SLE (systemic lupus erythematosus) patients. TLR7 and TLR9 have been reported to be upregulated in SLE tissues and correlated with chronicity and activity of lupus nephritis, respectively. In B cells of SLE patients, TLR7 expression correlates with anti-RNP antibody production, whereas TLR9 expression correlates with IL-6 levels and anti-double-stranded DNA antibody levels. Consistently, in lupus mouse models, TLR7 is required for anti-RNA antibodies and TLR9 is required for anti-nucleosome antibodies. Meanwhile, overexpression of TLR7 or human TLR8 in mice promotes autoimmunity and autoinflammation. Moreover, TLR8 activation specifically contributes to mDC / macrophage inflammatory cytokine secretion, neutrophil nematosis, induction of Th17 cells, and suppression of Treg cells.In addition to the role of TLR9 in promoting B cell autoantibody production, the activation of TLR9 by self-DNA in pDCs also leads to the induction of type I IFN and other inflammatory cytokines. Given that TLR9 plays such an important role in the pathogenesis of autoimmune diseases in both pDCs and B cells, and that self-DNA complexes that can easily activate TLR9 exist widely in many patients with autoimmune diseases, there may be special advantages to further block the self-DNA-mediated TLR9 pathway in addition to inhibiting the TLR7 and TLR8 pathways. Taken together, the TLR7, 8, 9 pathways are new therapeutic targets for the treatment of autoimmune and autoinflammatory diseases for which there are no effective steroid-free and non-cytotoxic oral drugs, and the very upstream inhibition of all these pathways may provide satisfactory therapeutic effects. Therefore, the inventors have invented oral compounds that target and suppress TLR7, TLR8 and TLR9 for the treatment of autoimmune and autoinflammatory diseases. Summary of the Invention

[0004] The present invention relates to novel compounds of formula (I) or (Ia): [ka] (In the formula, R 1 teeth, [ka] where R 4 is C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 R is alkyl, halogen, nitro or cyano; 4a is C 1-6 Alkyl or C 3-7 Cycloalkyl; R 5 , R 5a and R 5b is independently selected from H and deuterium; R 6 is H or a halogen; R 2 is C 1-6 is alkyl; R 3 is a 5-7 membered monocyclic aryl or heteroaryl; or a 7-12 membered bicyclic heterocyclyl; n is 0, 1 or 2) or a pharma- ceutically acceptable salt thereof.

[0005] Another object of the present invention relates to novel compounds of formula (I) or (Ia). Their preparation, pharmaceuticals based on the compounds according to the present invention and their preparation, and the use of compounds of formula (I) or (Ia) as TLR7 and / or TLR8 and / or TLR9 antagonists, and for the treatment or prevention of systemic lupus erythematosus or lupus nephritis. Compounds of formula (I) or (Ia) show excellent TLR7 and TLR8 and TLR9 antagonistic activity. In addition, compounds of formula (I) or (Ia) also show good cytotoxicity, phototoxicity, solubility, hPBMC, human microsome stability and SDPK profile, and low CYP inhibition.

[0006] [Detailed Description of the Invention] definition "C 1-6 The term "alkyl" refers to saturated straight or branched chain alkyl groups containing 1 to 6, especially 1 to 4, carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc. 1-6 "Alkyl" groups are methyl, ethyl, and n-propyl.

[0007] The terms "halogen" and "halo" are used interchangeably herein and refer to fluoro, chloro, bromo or iodo.

[0008] The term "halopyrrolidinyl" refers to pyrrolidinyl substituted once, twice or three times with halogen. Examples of halopyrrolidinyl include, but are not limited to, difluoropyrrolidinyl and fluoropyrrolidinyl.

[0009] The term "aryl" refers to an aromatic hydrocarbon monocyclic or bicyclic ring system of 5 to 12 ring atoms. Examples of aryl include, but are not limited to, phenyl and naphthyl. Aryl includes, but is not limited to, C 1-6 Alkyl;3,4,4a,5,7,7a-Hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl;1,4-diazepanyl;C 1-6 Alkyl-substituted 2,6-diazaspiro[3.3]heptanyl; 5-oxa-2,8-diazaspiro[3.5]nonanyl; amino-1,4-oxazepanyl; amino and C 1-6 Azetidinyl substituted with one or two substituents independently selected from alkyl; unsubstituted or C 1-6 Alkyl-substituted piperazinyl; and amino, C 1-6 It may be further substituted by substituents including pyrrolidinyl substituted with one or two substituents independently selected from alkoxy and halogen.

[0010] The term "heteroaryl" refers to an aromatic heterocyclic monocyclic or bicyclic ring of 5 to 12 ring atoms containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon. Examples of heteroaryl include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl. Heteroaryl includes, but is not limited to, C 1-6Alkyl;3,4,4a,5,7,7a-Hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl;1,4-diazepanyl;C 1-6 Alkyl-substituted 2,6-diazaspiro[3.3]heptanyl; 5-oxa-2,8-diazaspiro[3.5]nonanyl; amino-1,4-oxazepanyl; amino and C 1-6 Azetidinyl substituted with one or two substituents independently selected from alkyl; unsubstituted or C 1-6 Alkyl-substituted piperazinyl; and amino, C 1-6 It may be further substituted by substituents including pyrrolidinyl substituted with one or two substituents independently selected from alkoxy and halogen.

[0011] The term "heterocyclyl" or "heterocyclic" refers to a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of 3 to 12 ring atoms containing 1 to 5 ring heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. In certain embodiments, a heterocyclyl is a monovalent saturated monocyclic ring system of 4 to 7 ring atoms containing 1, 2, or 3 ring heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. Examples of monocyclic saturated heterocyclyls are aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, or oxazepanyl. Examples of bicyclic saturated heterocycles are azabicyclo[3.2.1]octyl, quinuclidinyl, oxaazabicyclo[3.2.1]octanyl, azabicyclo[3.3.1]nonanyl, oxaza-bicyclo[3.3.1]nonanyl, azabicyclo[3.1.0]hexanyl, oxodiazaspiro[3.4]octanyl, acetyloxodiazaspiro[3.4]octanyl, thiazabicyclo[3.3.1]nonanyl, oxoazaspiro[2.4]heptanyl, oxoazaspiro[3.4]octanyl, oxoazabicyclo[3.1.0]hexanyl, and dioxotetrahydropyrrolo[1,2-a]pyrazinyl. Examples of bicyclic heterocyclyls include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl; 5,6,7,8-tetrahydro-1,6-naphthyridinyl; 5,6,7,8-tetrahydro-1,7-naphthyridinyl; 5,6,7,8-tetrahydro-2,6-naphthyridinyl; 5,6,7,8-tetrahydro-2,7-naphthyridinyl; isoindolinyl.

[0012] The term "pharmaceutically acceptable salts" refers to salts that are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid and base addition salts.

[0013] The term "pharmaceutically acceptable acid addition salts" refers to pharmaceutically acceptable salts such as those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and the like, and organic acids selected from aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.

[0014] The term "pharmaceutically acceptable basic addition salt" refers to a pharmaceutically acceptable salt formed with an organic or inorganic base. Examples of acceptable inorganic bases include sodium salts, potassium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts and aluminum salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines, including natural substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine and polyamine resins.

[0015] The term "pharmacologically active metabolite" refers to a pharmacologically active product produced through metabolism in the body of a particular compound or its salt. After entering the body, most drugs become substrates for chemical reactions that can change their physical properties and biological effects. These metabolic transformations usually affect the polarity of the compounds of the invention and change the way the drug is distributed in and excreted from the body. However, in some cases, metabolism of a drug is required for therapeutic effect.

[0016] The term "therapeutically effective amount" refers to an amount of a compound or molecule of the invention that, when administered to a subject, (i) treats or prevents a particular disease, condition or disorder, (ii) reduces, ameliorates or eliminates one or more symptoms of a particular disease, condition or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition or disorder described herein. The therapeutically effective amount will vary depending on the compound, the condition being treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0017] The term "pharmaceutical composition" refers to a mixture or solution containing a therapeutically effective amount of an active ingredient together with pharma- ceutically acceptable excipients to be administered to a mammal (e.g., a human) in need thereof.

[0018] TLR7 and / or TLR8 and / or TLR9 antagonists The present invention relates to a compound of formula (I): [ka] (In the formula, R 1 teeth, [ka] where R 4 is C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6R is alkyl, halogen, nitro or cyano; 4a is C 1-6 Alkyl or C 3-7 Cycloalkyl; R 5 , R 5a and R 5b are independently selected from H and deuterium; R 6 is H or a halogen; R 2 is C 1-6 is alkyl; R 3 is a 5-7 membered monocyclic aryl or heteroaryl; or a 7-12 membered bicyclic heterocyclyl; n is 0, 1 or 2) or a pharma- ceutically acceptable salt thereof.

[0019] A further embodiment of the present invention is a compound of formula (I) according to (ii)(i), wherein R 3 is 1,2,3,4-tetrahydroisoquinolinyl; 5,6,7,8-Tetrahydro-1,6-naphthyridinyl; 5,6,7,8-Tetrahydro-1,7-naphthyridinyl; 5,6,7,8-Tetrahydro-2,6-naphthyridinyl; 5,6,7,8-Tetrahydro-2,7-naphthyridinyl; morpholinyl substituted phenyl; piperazinyl substituted pyrazinyl; Halogen, piperazinyl, aminohalopyrrolidinyl, amino-1,4-oxazepanyl and amino(C 1-6 pyridinyl substituted by 1 or 2 substituents independently selected from (alkoxy)pyrrolidinyl; or Piperazinyl or amino (C 1-6 alkoxy)pyrrolidinyl substituted pyrimidinyl.

[0020] Another embodiment of the present invention is (iii) a compound of formula (Ia): [ka] [In the formula, R 1 teeth, [ka] where R 4 is C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 R is alkyl, halogen, nitro or cyano; 4a is C 1-6 Alkyl or C 3-7 Cycloalkyl; R 5 , R 5a and R 5b are independently selected from H and deuterium; R 6 is H or a halogen; R 2 is C 1-6 is alkyl; R 3 is 1,2,3,4-tetrahydroisoquinolinyl; 5,6,7,8-Tetrahydro-1,6-naphthyridinyl; 5,6,7,8-Tetrahydro-1,7-naphthyridinyl; 5,6,7,8-Tetrahydro-2,6-naphthyridinyl; 5,6,7,8-Tetrahydro-2,7-naphthyridinyl; morpholinyl substituted phenyl; piperazinyl substituted pyrazinyl; Halogen, piperazinyl, aminohalopyrrolidinyl, amino-1,4-oxazepanyl and amino(C 1-6 pyridinyl substituted by 1 or 2 substituents independently selected from (alkoxy)pyrrolidinyl; or Piperazinyl or amino (C 1-6 alkoxy)pyrrolidinyl substituted pyrimidinyl; n is 0, 1, or 2. or a pharma- ceutically acceptable salt thereof.

[0021] A further embodiment of the present invention is a compound of formula (I) or (Ia) as defined in any one of (iv)(i) to (iii) or a pharma- ceutically acceptable salt thereof, wherein R 1 teeth, [ka] where R 4 is cyano; R 4a is C 1-6 R is alkyl; 5 is H;R 6 is H or a halogen; and n is 0 or 1.

[0022] A further embodiment of the present invention relates to a compound of formula (I) or (Ia) according to any one of (i) to (iv), wherein R 1 teeth, [ka] where R 4 is cyano; R 4a is methyl; R 5 is H;R 6 is H or Fluor; R 2 is methyl; R 3 is 1,2,3,4-tetrahydroisoquinolin-6-yl; 1,2,3,4-Tetrahydroisoquinolin-7-yl; 5,6,7,8-Tetrahydro-1,6-naphthyridin-2-yl; 5,6,7,8-Tetrahydro-1,6-naphthyridin-3-yl; 5,6,7,8-Tetrahydro-1,7-naphthyridin-2-yl; 5,6,7,8-Tetrahydro-2,6-naphthyridin-3-yl; 5,6,7,8-Tetrahydro-2,7-naphthyridin-3-yl; 5,6,7,8-Tetrahydro-2,7-naphthyridin-4-yl; Morpholin-2-ylphenyl; Piperazin-1-ylpyrazinyl; pyridinyl substituted with one or two substituents independently selected from fluoro, piperazin-1-yl, 3-amino-4-fluoro-pyrrolidin-1-yl, 6-amino-1,4-oxazepan-4-yl and 3-amino-4-methoxy-pyrrolidin-1-yl; or pyrimidinyl substituted with piperazin-1-yl or 3-amino-4-methoxy-pyrrolidin-1-yl; (n is 0 or 1) or a pharma- ceutically acceptable salt thereof.

[0023] A further embodiment of the present invention is a compound of formula (I) or (Ia) as defined in any one of (i) to (v) or a pharma- ceutically acceptable salt thereof, wherein R 1 teeth, [ka] where R 4 is cyano; R 5 is H.

[0024] A further embodiment of the present invention is a compound of formula (I) or (Ia) as defined in any one of (i) to (vi) or a pharma- ceutically acceptable salt thereof, wherein R 3 5,6,7,8-tetrahydro-2,6-naphthyridinyl; 5,6,7,8-tetrahydro-2,7-naphthyridinyl; amino (C 1-6 alkoxy)pyridinyl substituted with pyrrolidinyl; or pyrimidinyl substituted with piperazinyl.

[0025] A further embodiment of the present invention is a compound of formula (I) or (Ia) as defined in any one of (i) to (vii) or a pharma- ceutically acceptable salt thereof, wherein R 3is 5,6,7,8-tetrahydro-2,7-naphthyridin-4-yl; 5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl; piperazin-1-ylpyrimidinyl; or 3-amino-4-methoxy-pyrrolidin-1-ylpyridinyl.

[0026] A further embodiment of the present invention relates to a compound of formula (I) or (Ia) according to any one of (ix)(i) to (viii), wherein R 1 teeth, [ka] where R 4 is cyano; R 5 is H; R 2 is C 1-6 is alkyl; R 3 5,6,7,8-tetrahydro-2,6-naphthyridinyl; 5,6,7,8-tetrahydro-2,7-naphthyridinyl; amino (C 1-6 alkoxy)pyridinyl substituted with pyrrolidinyl; or pyrimidinyl substituted with piperazinyl; n is 0 or 1. or a pharma- ceutically acceptable salt thereof.

[0027] A further embodiment of the present invention relates to a compound of formula (I) or (Ia) according to any one of (x)(i) to (ix), wherein R 1 teeth, [ka] where R 4 is cyano; R 5 is H; R 2 is methyl; R 3is 5,6,7,8-tetrahydro-2,7-naphthyridin-4-yl; 5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl; piperazin-1-ylpyrimidinyl; or 3-amino-4-methoxy-pyrrolidin-1-ylpyridinyl; (n is 0 or 1) or a pharma- ceutically acceptable salt thereof.

[0028] Another embodiment of the present invention is a compound of formula (I) or (Ia) or a pharma- ceutically acceptable salt thereof, selected from: 5-[(4R,10aS)-4-methyl-8-(6-piperazin-1-yl-3-pyridyl)-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-4-methyl-8-(2-piperazin-1-ylpyrimidin-5-yl)-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-4-methyl-8-[4-[(2S)-morpholin-2-yl]phenyl]-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-4-methyl-8-(5,6,7,8-tetrahydro-2,7-naphthyridin-4-yl)-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-4-methyl-8-(5,6,7,8-tetrahydro-1,7-naphthyridin-2-yl)-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-4-methyl-8-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-4-methyl-8-(5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-4-methyl-8-(5,6,7,8-tetrahydro-2,7-naphthyridin-3-ylmethyl)-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-4-methyl-8-(5,6,7,8-tetrahydro-2,6-naphthyridin-3-ylmethyl)-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-4-methyl-8-(5,6,7,8-tetrahydro-1,6-naphthyridin-3-ylmethyl)-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-4-methyl-8-(1,2,3,4-tetrahydroisoquinolin-6-ylmethyl)-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-4-methyl-8-(1,2,3,4-tetrahydroisoquinolin-7-ylmethyl)-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-4-methyl-8-[(5-piperazin-1-ylpyrimidin-2-yl)methyl]-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-4-methyl-8-[(2-piperazin-1-ylpyrimidin-5-yl)methyl]-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-4-methyl-8-[(5-piperazin-1-ylpyrazin-2-yl)methyl]-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-4-methyl-8-[(5-piperazin-1-yl-3-pyridyl)methyl]-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-4-methyl-8-[(6-piperazin-1-yl-3-pyridyl)methyl]-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-4-methyl-8-[(6-piperazin-1-yl-2-pyridyl)methyl]-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-4-methyl-8-[(5-piperazin-1-yl-2-pyridyl)methyl]-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-8-[[5-[(3R,4S)-3-amino-4-fluoro-pyrrolidin-1-yl]-2-pyridyl]methyl]-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-8-[[5-[(6R)-6-amino-1,4-oxazepan-4-yl]-2-pyridyl]methyl]-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-8-[[5-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]-2-pyridyl]methyl]-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-8-[(3-fluoro-5-piperazin-1-yl-2-pyridyl)methyl]-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-8-[[5-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]-3-fluoro-2-pyridyl]methyl]-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 4-[(4R,10aS)-8-[[5-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]pyrazin-2-yl]methyl]-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile; 4-[(4R,10aS)-8-[[5-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]-3-fluoro-2-pyridyl]methyl]-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile; 4-[(4R,10aS)-8-[[5-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]-3-fluoro-2-pyridyl]methyl]-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile; and 4-[(4R,10aS)-4-Methyl-8-(1,2,3,4-tetrahydroisoquinolin-7-ylmethyl)-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]-1-methyl-1,8-naphthyridin-2-one

[0029] synthesis The compounds of the present invention can be prepared by any conventional means. Suitable methods for synthesizing these compounds and their starting materials are illustrated in the following schemes and examples. All substituents, particularly R 1 and R 2 are as defined above unless otherwise indicated, and all reactions, reaction conditions, abbreviations and symbols have the meanings familiar to one of ordinary skill in the art of organic chemistry, unless otherwise indicated.

[0030] General synthetic routes for preparing compounds of formulae (I), (VII) and (XI) are set out below.

[0031] Scheme 1 [ka]

[0032] where n is 0, 1 or 2; X is a halogen; Y is a halogen or methanesulfonate; R 7 and R 8 is aryl or heteroaryl; R 9 and R 10 together with the nitrogen atom to which they are attached form a heterocyclyl.

[0033] The synthesis of the compounds of the present invention started from halide II. 2 CO 3 Buchwald-Hartwig amination reaction between halide II and compound of formula III using bases such as 1,2-dichlorophenyl ether (D-PAH), ... 3 and K. 2 CO 3 Compound V can also be obtained via nucleophilic substitution between halide II and a compound of formula III in the presence of a base such as . Boc deprotection of a compound of formula IV under acidic conditions (e.g., HCl / EtOAc and TFA / DCM) gives compound V, which can be deprotected by addition of a base (e.g., DIPEA NaHCO 3 and K. 2 CO 3 The compound of formula V can be converted to the compound of formula VII via either nucleophilic substitution with a compound of formula VI in the presence of 2-(2-methylphenyl)-2-(2-phenylphenyl)-1,4-diaminetetraacetate or Buchwald-Hartwig amination reaction with a compound of formula VI, followed by appropriate deprotection. Meanwhile, the compound of formula V can be reacted with a compound of formula VIII via nucleophilic substitution to give a compound of formula IX. The compound of formula IX can be converted to the compound of formula VII via either nucleophilic substitution with a compound of formula VI in the presence of 2-(2-methylphenyl)-1,4-diaminetetraacetate or Buchwald-Hartwig amination reaction with a compound of formula VI, followed by appropriate deprotection. The compound of formula IX can be converted to the compound of formula VII via either nucleophilic substitution with a compound of formula VIII, followed by appropriate deprotection.

[0034] Compounds of formula (Ia) may be synthesised according to Scheme 1 using chiral starting materials.

[0035] The compounds of the invention may be obtained as mixtures of diastereomers or enantiomers, which may be separated by methods well known in the art, such as (chiral) HPLC or SFC.

[0036] The present invention also relates to a process for the preparation of a compound of formula (I) or (Ia), comprising any one of the following steps: a) Buchwald-Hartwig amination reaction or nucleophilic substitution between a compound of formula (IX) and an amine (X) [ka] b) A compound of formula (V) [ka] and a compound of formula (VI) [ka] Buchwald-Hartwig amination reaction or nucleophilic substitution between where n is 0, 1 or 2; X is a halogen; Y is a halogen or methanesulfonate; and R 7 and R 8 is aryl or heteroaryl; R 9 and R 10 together with the nitrogen atom to which they are attached form a heterocyclyl.

[0037] Compounds of formula (Ia) may also be synthesised according to Scheme 1 using chiral intermediates.

[0038] Compounds of formula (I) or (Ia) when prepared according to the above process are also an object of the present invention.

[0039] Indications and Treatments The present invention provides compounds that can be used as TLR7 and / or TLR8 and / or TLR9 antagonists, which inhibit pathway activation by TLR7 and / or TLR8 and / or TLR, and the respective downstream biological events, including but not limited to innate and adaptive immune responses mediated by the production of all kinds of cytokines and all forms of autoantibodies.Thus, the compounds of the present invention are useful for blocking such receptors in all kinds of cells that express TLR7 and / or TLR8 and / or TLR9, including but not limited to plasmacytoid dendritic cells, B cells, T cells, macrophages, monocytes, neutrophils, keratinocytes, epithelial cells.Thus, the compounds can be used as therapeutic or prophylactic agents for systemic lupus erythematosus and lupus nephritis.

[0040] The present invention provides methods for the treatment or prevention of systemic lupus erythematosus and lupus nephritis in a patient in need of such treatment or prevention.

[0041] Other embodiments include a method of treating or preventing systemic lupus erythematosus and lupus nephritis in a mammal in need of such treatment, comprising administering to said mammal a therapeutically effective amount of a compound of formula (I), a stereoisomer, tautomer, prodrug or a pharma- ceutically acceptable salt thereof. EXAMPLES

[0042] The present invention may be more fully understood by reference to the following examples, which should not be construed as limiting the scope of the invention.

[0043] Abbreviation The present invention may be more fully understood by reference to the following examples, which should not be construed as limiting the scope of the invention.

[0044] The abbreviations used herein are as follows: ACN: Acetonitrile DCM: dichloromethane DCE: Dichloroethane DIPEA or DIEA: N,N-Diisopropylethylamine DMF: N,N-dimethylformamide EA or EtOAc: Ethyl acetate FA: Formic acid HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate I C 50 : Half inhibitory concentration IPA: Isopropanol MS: Mass spectrometry prep-HPLC: Preparative high performance liquid chromatography prep-TLC: preparative thin-layer chromatography RuPhos Pd G2: Second generation chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) Selectfluor: 1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) SFC: Supercritical Fluid Chromatography TEA: Trimethylamine TFA: Trifluoroacetic acid THF: tetrahydrofuran XantPhos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene v / v: volume ratio

[0045] General experimental conditions Intermediates and final compounds were purified by flash chromatography using one of the following instruments: i) a Biotage SP1 system and Quad12 / 25 cartridge module, ii) an ISCO combi-flash chromatography instrument. Silica gel brands and pore sizes: i) KP-SIL 60A, particle size: 40-60 μM; ii) CAS Registry Number: Silica gel: 63231-67-4, particle size: 47-60 micron silica gel; iii) Qingdao Kaiyo Chemical's ZCX, pore size: 200-300 or 300-400.

[0046] Intermediates and final compounds were analyzed using XBridge 商標 Prep-C18 (5 μm, OBD 商標 30×100mm) column, SunFire 商標 Prep-C18 (5 μm, OBD 商標 Purification was performed by preparative HPLC on reversed-phase columns using a Phenomenex Synergi-C18 (10 μm, 25 × 150 mm) or Phenomenex Gemini-C18 (10 μm, 25 × 150 mm) column, a Waters AutoP purification system (sample manager 2767, pump 2525, detectors: Micromass ZQ and UV2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water; acetonitrile and 0.1% FA in water or acetonitrile and 0.1% TFA in water) or a Gilson-281 purification system (pump 322, detector: UV156, solvent system: acetonitrile and 0.05% ammonium hydroxide in water; acetonitrile and 0.225% FA in water; acetonitrile and 0.05% HCl in water; acetonitrile and 0.075% TFA in water; or acetonitrile and water).

[0047] For SFC chiral separation, the intermediates were purified by chiral column (Daicel chiralpak IC, 5 μm, 30 × 250 mm), AS (10 μm, 30 × 250 mm) or AD (10 μm, 30 × 250 mm) on a Mettler Toledo Multigram III system SFC, Waters 80Q preparative SFC or Thar80 preparative SFC, solvent system: CO 2 and IPA (0.5% TEA / IPA) or CO 2 and MeOH (0.1% NH 3 H 2 O / MeOH), 100 bar back pressure, and UV detection at 254 or 220 nm.

[0048] The LC / MS spectra of the compounds were analyzed by LC / MS (Waters 商標 The LC / MS conditions were as follows (run time 3 or 1.5 min): Alliance 2795-Micromass ZQ, Shimadzu Alliance 2020-Micromass ZQ, or Agilent Alliance 6110-Micromass ZQ. Acidic condition I:A:0.1%TFA / H 2 O; B: 0.1% TFA / acetonitrile; Acidic condition II:A:H 2 B: 0.0375% TFA in O; C: 0.01875% TFA in acetonitrile; Basic conditions I:A:H 2 0.1%NH in O 3 H 2 O; B: acetonitrile; Basic conditions II:A:H 2 0.025%NH in O 3 H 2 O; B: acetonitrile; Neutral condition: A:H 2 O; B: acetonitrile

[0049] Mass spectra (MS): Generally, only the ions representing the parent mass are reported; unless otherwise stated, the mass ions quoted are positive mass ions (MH). + It is.

[0050] NMR spectra were obtained using a Bruker Avance 400 MHz.

[0051] Microwave-assisted reactions were performed on a Biotage Initiator Sixty microwave synthesizer. All reactions requiring air-sensitive reagents were carried out under an argon or nitrogen atmosphere. Reagents were used as received and without further purification unless otherwise noted.

[0052] Preparation Examples The following examples are intended to illustrate the meaning of the invention but do not in any way represent a limitation within the scope of the meaning of the invention.

[0053] Intermediate A1 5-Fluoroquinoline-8-carbonitrile [ka]

[0054] The title compound was synthesized according to the following scheme. [ka]

[0055] Step (a): Preparation of 8-bromo-5-fluoro-quinoline (compound A1.2) In a 100 mL pear-shaped flask, 2-bromo-5-fluoroaniline (compound A1.1, 2.0 g, 10.5 mmol), propane-1,2,3-triol (969 mg, 10.5 mmol), and sodium 3-nitrobenzenesulfonate (2.4 g, 10.5 mmol) were added to a 70% H2 SO 4 (20 mL) to give a dark brown solution, which was heated to 150° C. and stirred for 3 h. After cooling to room temperature, the reaction mixture was poured into ice water and neutralized with sodium hydroxide solution. The resulting mixture was filtered. The filter cake was dissolved in EtOAc and filtered. The filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 30% EtOAc in PE) to give compound A1.2 (2.0 g, 84% yield). MS: calculated 226 and 228 [(M+H) + ], found values ​​226 and 228 [(M+H) + ].

[0056] Step (b): Preparation of 5-fluoroquinoline-8-carbonitrile (Intermediate A1) To a solution of 8-bromo-5-fluoroquinoline (compound A1.2, 4.9 g, 21.7 mmol) in DMF (30 mL) was added dicyanozinc (5.0 g, 43.4 mmol) and RuPhos Pd G2 (CAS: 1375325-68-0, Sigma-Aldrich, catalog: 753246, 842 mg, 1.1 mmol). The reaction mixture was stirred at 100° C. for 3 h and then cooled to room temperature. The reaction mixture was filtered and the filtrate was diluted with water (50 mL) and then extracted three times with EA (80 mL). The combined organic layers were washed with brine and diluted with Na 2 SO 4 The mixture was dried over 100 ml, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 40 g, 0% to 70% EtOAc in PE) to give compound A1 (3.0 g, 80% yield). MS: calculated 173 [(M+H) + ], measured value 173 [(M+H) + ]. 1 H NMR (400 MHz, METHANOL-d 4) δ ppm 9.11 (dd, J = 4.28, 1.71 Hz, 1 H), 8.64 (dd, J = 8.56, 1.71 Hz, 1 H), 8.29 (dd, J = 8.19, 5.62 Hz, 1 H), 7.76 (dd, J = 8.56, 4.28 Hz, 1 H), 7.49 (dd, J = 9.35, 8.25 Hz, 1 H).

[0057] Intermediate A2 4-Chloro-1-methyl-1,8-naphthyridin-2-one [ka]

[0058] The title compound was synthesized according to the following scheme. [ka]

[0059] Step (a): Preparation of 2-(methylamino)pyridine-3-carboxylic acid (compound A2.2) 2-Chloronicotinic acid (compound A2.1, 1.0 kg, 6.3 mmol) was dissolved in 33% monomethylamine (386.3 mol) in ethanol. The reaction mixture was stirred in an autoclave at 80° C. for 80 hours and then concentrated under reduced pressure to give compound A2.2 (1.4 kg, crude). MS: calculated value 153 [(M+H) + ], measured value 153 [(M+H) + ].

[0060] Step (b): Preparation of (1-methyl-2-oxo-1,8-naphthyridin-4-yl)acetate (Compound A2.3) A solution of 2-(methylamino)pyridine-3-carboxylic acid (compound A2.2, 1.4 kg, crude) in acetic anhydride (10.0 L, 105789 mmol) and acetic acid (5.0 L) was heated to reflux for 2 hours. The reaction mixture was concentrated under reduced pressure to give compound A2.3 (1.8 kg, crude). MS: calculated 219 [(M+H) +], measured value 219 [(M+H) + ].

[0061] Step (c): Preparation of 4-hydroxy-1-methyl-1,8-naphthyridin-2-one (compound A2.4) To a solution of (1-methyl-2-oxo-1,8-naphthyridin-4-yl)acetate (compound A2.3, 1.8 kg, crude) in methanol (12.0 L) was added a solution of potassium carbonate (1.9 kg, 13.75 mol) in water (3.6 L). The mixture was stirred at 25° C. for 2 h. The reaction mixture was then concentrated under reduced pressure to remove MeOH. The residue was acidified to pH 4-5 with HCl solution (6 N) and extracted three times with EA (1500 mL). The combined organic layers were washed with saturated brine (1500 mL) and concentrated with Na 2 SO 4 After drying over 100° C. and concentrating under reduced pressure, compound A2.4 (450 g, 40.2% yield) was obtained. MS: calculated 177 [(M+H) + ], measured value 177 [(M+H) + ]; 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.68 (s, 1H), 8.63 (dd, J = 4.60, 1.80 Hz, 1H), 8.22 (dd, J= 7.80, 1.80 Hz, 1H), 7.27 (dd, J= 7.80, 4.60 Hz, 1H), 5.93 (s, 1H), 3.59 (s, 3H)

[0062] Step (d): Preparation of 4-chloro-1-methyl-1,8-naphthyridin-2-one (Intermediate A2) A solution of 4-hydroxy-1-methyl-1,8-naphthyridin-2-one (compound A2.4, 150 g, 0.85 mol) in phosphorus oxychloride (300 mL) was stirred at 100° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to remove phosphorus oxychloride. The mixture was cooled to room temperature and cooled to room temperature with saturated NaHCO 3 The residue was neutralized to pH 7-8 by adding aqueous solution of DCM (1000 mL) and the mixture was extracted twice with DCM (1000 mL). The combined organic layers were washed with saturated brine (500 mL) and diluted with Na 2 SO 4The mixture was dried over water and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (PE / EtOAc = 1:0 to 7:1) to give intermediate A2 (39 g, 24% yield). MS: calculated 195 [(M+H) + ], measured value 195 [(M+H) + ]; 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.75 (dd, J = 4.60, 1.60 Hz, 1H), 8.32 (dd, J = 7.90, 1.70 Hz, 1H), 7.44 (dd, J = 8.00, 4.60 Hz, 1H), 7.03 (s, 1H), 3.66 (s, 3H).

[0063] Intermediate A3 4-Fluoropyrazolo[1,5-a]pyridine-7-carbonitrile [ka]

[0064] The title compound was synthesized according to the following scheme. [ka]

[0065] Step (a): Preparation of amino 2,4,6-trimethylbenzenesulfonate (compound A3.2) To a solution of ethyl (1E)-N-(2,4,6-trimethylphenyl)sulfonyloxyethanimidate (compound A3.1, CAS: 38202-27-6, Bide Pharmatech, catalog: BD129455, 200 g, 700 mmol) in 1,4-dioxane (500 mL), perchloric acid (110 mL) was added dropwise in 30 min and stirred at 0 °C for 1 h. 1000 mL of ice water was added and the mixture was filtered. The filter cake was dissolved in 1.5 L of EtOAc and then stirred for 30 min. The organic layer was concentrated (keeping the temperature below 25 °C) to give the crude product. The crude product was recrystallized (petroleum / EtOAc = 10 / 1) to give compound A3.2 (110 g, 73% yield). MS: calculated 216 [(M+H) + ], measured value 216 [(M+H) + ].

[0066] Step 2: 2-Bromo-5-fluoro-pyridin-1-ium-1-amine; Preparation of 2,4,6-trimethylbenzenesulfonate (compound A3.3) A solution of amino 2,4,6-trimethylbenzenesulfonate (compound A3.2, 110 g, 511 mmol) and 2-bromo-5-fluoropyridine (60 g, 341 mmol) in DCM (1800 mL) was stirred at 10° C. for 18 h. The mixture was concentrated and the residue was recrystallized in EtOAc to give compound A3.3 (90 g, 92% yield). MS: calculated 191 [(M+H) + ], measured value 191 [(M+H) + ].

[0067] Step (c): Preparation of ethyl 7-bromo-4-fluoro-pyrazolo[1,5-a]pyridine-3-carboxylate (compound A3.4) 2-Bromo-5-fluoro-pyridin-1-ium-1-amine; 2,4,6-trimethylbenzenesulfonate (compound A3.3, 90 g, 230 mmol), K 2 CO 3 A solution of (64 g, 460 mmol) and ethyl propiolate (28 mL, 276 mmol) in DMF (1300 mL) was stirred at 10° C. for 18 h. The reaction was diluted with water and extracted with EtOAc. The organic layer was extracted with Na2 SO 4 The mixture was dried at 40° C., filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography column to give compound A3.4 (11 g, 16.7% yield). MS: calculated 287 [(M+H) + ], measured value 287 [(M+H) + ].

[0068] Step (d): Preparation of 7-bromo-4-fluoropyrazolo[1,5-a]pyridine (compound A3.5) To a mixture of ethyl 7-bromo-4-fluoro-pyrazolo[1,5-a]pyridine-3-carboxylate (compound A3.4, 8.0 g, 26.7 mmol) in acetic acid (48 mL) and water (48 mL) was added concentrated HCl (36 mL, 432 mmol). The mixture was stirred at 100° C. for 18 h. The mixture was diluted with water (200 mL), basified to pH 8 with aqueous sodium hydroxide, and extracted three times with EA (200 mL). The combined organic layers were washed with brine and diluted with Na 2 SO 4 Drying over and concentration in vacuum gave compound A3.5 (5 g, 86.9% yield), which was used directly in the next step. MS: Calculated value 215 [(M+H) + ], measured value 215 [(M+H) + ].

[0069] Step (e): Preparation of 4-fluoropyrazolo[1,5-a]pyridine-7-carbonitrile (Intermediate A3) 7-Bromo-4-fluoro-pyrazolo[1,5-a]pyridine (compound A3.5, 1000 mg, 4.6 mmol), zinc cyanide (880 mg, 7.5 mmol), zinc (31 mg, 0.5 mmol), XantPhos (1076 mg, 1.8 mmol) and Pd(OAc). 2 A mixture of (209 mg, 0.9 mmol) in DMA (10 mL) was degassed and purged with Ar three times, then the mixture was stirred under Ar at 120° C. for 1 h. The mixture was diluted with EA (150 mL), filtered, and the filtrate was washed three times with water (50 mL), brine (50 mL), and added Na 2 SO4 The mixture was dried over hexane and concentrated under reduced pressure. The residue was purified by prep-TLC (PE:EA=3:1) to give intermediate A3 (600 mg, 68% yield). MS: calculated value 162 [(M+H) + ], measured value 162 [(M+H) + ].

[0070] Intermediate A4 3,4-Difluoropyrazolo[1,5-a]pyridine-7-carbonitrile [ka]

[0071] The title compound was synthesized according to the following scheme. [ka]

[0072] Step (a): Preparation of 7-bromo-4-fluoro-pyrazolo[1,5-a]pyridine-3-carboxylic acid (compound A4.1) A mixture of ethyl 7-bromo-4-fluoro-pyrazolo[1,5-a]pyridine-3-carboxylate (compound A3.4, 5.2 g, 18.1 mmol), NaOH (2.1 g, 54.3 mmol) in EtOH (90.0 mL) and water (70.0 mL) was stirred at 60° C. for 2 h. The reaction mixture was concentrated and then diluted with water. After adjusting the pH to 4 with 1N HCl, a grey solid was precipitated and collected by filtration to give compound A4.1 (4.0 g, 85.6% yield). MS: calculated 259 [(M+H) + ], measured value 259 [(M+H) + ].

[0073] Step (b): Preparation of 7-bromo-3,4-difluoro-pyrazolo[1,5-a]pyridine (compound A4.2) To a solution of 7-bromo-4-fluoro-pyrazolo[1,5-a]pyridine-3-carboxylic acid (compound A4.1, 4.0 g, 15.4 mmol) and KF (3.6 g, 61.8 mmol) in DCE (60.0 mL) and water (50.0 mL) was added Selectfluor (10.9 g, 30.9 mmol). The reaction was stirred at 70° C. for 18 hours. The reaction was quenched with water and extracted twice with DCM. The combined organic layers were washed with Na 2 SO 4 The mixture was dried over 100 ml, filtered, and the filtrate was concentrated under reduced pressure to give crude compound A4.2 (2.8 g, 78% yield). MS: calculated 233 [(M+H) + ], measured value 233 [(M+H) + ].

[0074] Step (c): Preparation of 3,4-difluoropyrazolo[1,5-a]pyridine-7-carbonitrile (Intermediate A4) To a solution of 7-bromo-3,4-difluoro-pyrazolo[1,5-a]pyridine (compound A4.2, 2.8 g, 12.0 mmol) and zinc cyanide (5.6 g, 48.0 mmol) in DMF (70.0 mL) was added tetrakis(triphenylphosphine)palladium (1.4 g, 1.2 mmol). The reaction mixture was cooled to room temperature and cooled to 37° C. for 1 hour. 2 The mixture was stirred at 120° C. under atmospheric pressure for 18 hours. The mixture was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with Na 2 SO 4 The mixture was dried over 100 ml, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate A4 (810 mg, 37.7% yield). MS: calculated 180 [(M+H) + ], measured value 180 [(M+H) + ]. 1 H NMR (400MHz, CHLOROFORM-d) δ ppm 8.00 (d, J = 3.6 Hz, 1H), 7.31 (dd, J = 4.7, 8.0 Hz, 1H), 6.83 (t, J = 8.4 Hz, 1H).

[0075] Intermediate B tert-Butyl (4R,10aS)-4-methyl-2,3,4,6,7,9,10,10a-octahydro-1H-pyrazino[1,2-d][1,4]diazepine-8-carboxylate [ka]

[0076] The title compound was synthesized according to the following scheme. [ka]

[0077] Step (a): Preparation of tert-butyl N-[(1R)-2-(benzylamino)-1-methyl-ethyl]carbamate (Compound B2) A mixture of tert-butyl (R)-(1-aminopropan-2-yl)carbamate (4.95 g, 28.40 mmol), benzaldehyde (2.86 g, 27 mmol) and DCE (80 mL) was stirred at room temperature for 30 min. Then, NaBH(OAc) 3 (12.0 g, 56.80 mmol) was added to the mixture. The resulting mixture was stirred at room temperature for 2 h, then quenched with water (100 mL) and extracted three times with DCM (80 mL). The combined organic layers were washed with brine and diluted with Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 80 g, 0% to 30% EtOAc in DCM) to give compound B2 (5.10 g, 68% yield). MS: calculated 265 [(M+H) + ], measured value 265 [(M+H) + ].

[0078] Step (b): Preparation of methyl (E)-4-[benzyl-[(2R)-2-(tert-butoxycarbonylamino)propyl]amino]but-2-enoate (Compound B3) A solution of tert-butyl N-[(1R)-2-(benzylamino)-1-methyl-ethyl]carbamate (compound B2, 5.10 g, 19.30 mmol) in acetone (150 mL) was added with methyl (E)-4-bromobut-2-enoate (3.45 g, 19.3 mmol) and K 2 CO 3 (5.33 g, 38.6 mmol) was added. The reaction mixture was stirred at room temperature for 20 h, then filtered through Celite, and the filtrate was concentrated. The residue was purified by flash chromatography (silica gel, 80 g, 0% to 30% EtOAc in PE) to give compound B3 (4.20 g, 60% yield). MS: calculated 363 [(M+H) + ], measured value 363 [(M+H) + ].

[0079] Step (c): Preparation of methyl 2-[(6R)-4-benzyl-6-methyl-piperazin-2-yl]acetate (Compound B4) A mixture of methyl (E)-4-[benzyl-[(2R)-2-(tert-butoxycarbonylamino)propyl]amino]butane-2-enoate (compound B3, 4.20 g, 11.60 mmol) and HCl / MeOH (1N, 70 mL, 70 mmol) was heated at reflux for 2 h. After cooling to room temperature, the reaction mixture was diluted with saturated K 2 CO 3 The mixture was neutralized with aqueous hexanes and extracted twice with DCM (80 mL). The combined organic layers were washed with brine and 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 40 g, 0% to 20% MeOH in DCM) to give compound B4 (2.40 g, 79% yield). MS: calculated 263 [(M+H) + ], measured value 263 [(M+H) + ].

[0080] Step (d): Preparation of methyl 2-[(6R)-4-benzyl-1-[2-(tert-butoxycarbonylamino)acetyl]-6-methyl-piperazin-2-yl]acetate (Compound B5) To a solution of (tert-butoxycarbonyl)glycine (3.50 g, 20.0 mmol) in DMF (40 mL) was added methyl 2-[(6R)-4-benzyl-6-methyl-piperazin-2-yl]acetate (compound B4, 5.24 g, 20.0 mmol), DIEA (7.74 g, 60.0 mmol) and HATU (7.60 g, 20.0 mmol). The resulting mixture was stirred at room temperature for 3 h. The reaction was quenched with water (100 mL) and extracted three times with DCM (80 mL). The combined organic layers were washed with brine and diluted with Na 2 SO 4 The mixture was dried over 100 ml, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 120 g, 0% to 60% EtOAc in PE) to give compound B5 (7.2 g, 85.9% yield). MS: calculated 420 [(M+H) + ], measured value 420 [(M+H) + ].

[0081] Step (e): Preparation of (4R)-2-benzyl-4-methyl-3,4,7,8,10,10a-hexahydro-1H-pyrazino[1,2-d][1,4]diazepine-6,9-dione (Compound B6) A mixture of methyl 2-[(6R)-4-benzyl-1-[2-(tert-butoxycarbonylamino)-acetyl]-6-methyl-piperazin-2-yl]acetate (compound B5, 5.0 g, 11.9 mmol) and HCl / MeOH (7% HCl in MeOH, 80 mL) was stirred at reflux for 2 h. The reaction mixture was concentrated and the residue was diluted with MeOH (100 mL), after which sodium methoxide (3.22 g, 59.60 mmol) was added. The resulting mixture was stirred at reflux for 5 h. After cooling to room temperature, the reaction was quenched with water (300 mL) and extracted three times with EA (100 mL). The combined organic layers were washed with brine and diluted with Na 2 SO 4 The mixture was dried over 100 ml, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography to give compound B6 (2.30 g, 67.3% yield). MS: calculated 288 [(M+H) + ], measured value 288 [(M+H) + ].

[0082] Step (f): (4R,10aR)-2-benzyl-4-methyl-3,4,7,8,10,10a-hexahydro-1H-pyrazino[1,2-d][1,4]diazepine-6,9-dione (compound B7a) and (4R,10aS)-2-benzyl-4-methyl-3,4,7,8,10,10a-hexahydro-1H-pyrazino[1,2-d][1,4]diazepine-6,9-dione (compound B7b) Compound B7a (2.30 g) was loaded onto an OJ (5 μm, 250 × 30 mm) column in 25% methanol / CO 2 The mixture was separated by SFC using 2-methyl-2,4-dichloro-1,4-diphenyl-2,4-diphenyl-1,4-diphenyl-2,5-diphenyl-1,6 ...

[0083] Compound B7a: MS: Calculated value 288 (M+H) + , measured value 288 (M+H) + ; 1 H NMR (400 MHz, METHANOL-d 4 ) δ ppm 7.05-7.55 (m, 5H), 4.82 (ddd, J = 1.71, 4.03, 6.85 Hz, 1H), 4.04 (s, 2H), 3.91-4.01 (m, 1H), 3.54-3.64 (m, 1H), 3.43-3.49 (m, 1H), 2.95 (dd, J = 4.40, 14.43 Hz, 1H), 2.87 (td, J = 2.17, 11.19 Hz, 1H), 2.78 (dd, J = 7.76, 14.49 Hz, 1H), 2.72 (td, J = 1.71, 11.49 Hz, 1H), 2.14 (dd, J = 3.91, 11.49 Hz, 1H), 2.04 (t, J = 11.07 Hz, 1H), 1.32 (d, J = 6.85 Hz, 3H).

[0084] Compound B7b: MS: Calculated value 288 (M+H) + , measured value 288 (M+H) + ;1 H NMR (400 MHz, METHANOL-d 4 ) δ ppm 7.38-7.42 (m, 2H), 7.32-7.39 (m, 2H), 7.05-7.71 (m, 1H), 4.58 (d, J = 14.79 Hz, 1H), 4.45 (td, J = 3.81, 13.54 Hz, 1H), 4.30-4.39 (m, 1H), 3.52-3.65 (m, 2H), 3.46 (d, J = 14.92 Hz, 1H), 3.10 (dd, J = 13.45, 18.46 Hz, 1H), 2.75-2.82 (m,1H), 2.77 (s, 1H), 2.53 (dd, J = 2.87, 18.40 Hz, 1H), 2.39 (dd, J = 5.26, 12.10 Hz, 1H), 2.27 (dd, J = 4.46, 11.55 Hz, 1H), 1.27 (d, J = 6.72Hz, 3H).

[0085] Step (g): Preparation of tert-butyl (4R,10aS)-2-benzyl-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepine-8-carboxylate (compound B8) (4R,10aS)-2-benzyl-4-methyl-3,4,7,8,10,10a-hexahydro-1H-pyrazino[1,2-d][1,4]diazepine-6,9-dione (compound B7b, 1.56 g, 5.43 mmol) and BH 3A mixture of this solution (1M in THF, 40 mL, 40 mmol) was heated at 80° C. with stirring for 20 h. The reaction mixture was cooled to 0° C., then HCl solution (2N, 10 mL) was slowly added to the reaction mixture at the same temperature. The resulting mixture was stirred at reflux for 3 h, then the mixture was cooled back to room temperature. After removing the organic solvent under reduced pressure, the residue was diluted with DCM (100 mL). Boc anhydride (1.77 g, 8.12 mmol) and TEA (2.74 g, 27.1 mmol) were added, respectively. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with water (50 mL) and extracted three times with DCM (50 mL). The combined organic layers were washed with brine and Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 80 g, 20% to 30% EtOAc in DCM) to give compound B8 (1.8 g, 92.4% yield). MS: calculated 360 [(M+H) + ], measured value 360 ​​[(M+H) + ].

[0086] Step (h): Preparation of tert-butyl (4R,10aS)-4-methyl-2,3,4,6,7,9,10,10a-octahydro-1H-pyrazino[1,2-d][1,4]diazepine-8-carboxylate (Intermediate B) A mixture of tert-butyl (4R,10aS)-2-benzyl-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepine-8-carboxylate (compound B8, 1.8 g, 5.01 mmol) and Pd-C (100 mg) in MeOH (100 mL) was hydrogenated with a hydrogen balloon at room temperature for 5 h. After filtering off the catalyst, the filtrate was concentrated under reduced pressure to give intermediate B (1.2 g, 89% yield), which was used directly in the next step without further purification. MS: calculated 270 [(M+H) + ], measured value 270 [(M+H) + ].

[0087] Intermediate C1 5-[(4R,10aS)-4-Methyl-3,4,6,7,8,9,10,10a-octahydro-1H-pyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; trihydrochloride [ka]

[0088] The title compound was synthesized according to the following scheme. [ka]

[0089] Step (a): Preparation of tert-butyl (4R,10aS)-2-(8-cyano-5-quinolyl)-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepine-8-carboxylate (compound C1.1) To a solution of tert-butyl (4R,10aS)-4-methyl-2,3,4,6,7,9,10,10a-octahydro-1H-pyrazino[1,2-d][1,4]diazepine-8-carboxylate (Intermediate B, 1.20 g, 4.45 mmol) in DMSO (20 mL) was added 5-fluoroquinoline-8-carbonitrile (Intermediate A1, 0.77 g, 4.45 mmol) and DIEA (0.58 g, 4.45 mmol). The resulting mixture was stirred at 120 °C for 5 h. After cooling to room temperature, the reaction was quenched with water (100 mL) and extracted three times with EA (90 mL). The combined organic layers were washed with brine and diluted with Na 2 SO 4 The mixture was dried over ice, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 40 g, 0% to 100% EtOAc in PE) to give compound C1.1 (1.41 g, 75.1% yield). MS: calculated 422 [(M+H) + ], measured value 422 [(M+H) + ].

[0090] Step (b): Preparation of 5-[(4R,10aS)-4-methyl-3,4,6,7,8,9,10,10a-octahydro-1H-pyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; trihydrochloride (Intermediate C1) To a solution of tert-butyl (4R,10aS)-2-(8-cyano-5-quinolyl)-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepine-8-carboxylate (compound C1.1, 1.41 g, 3.34 mmol) in DCM (30 mL) was added HCl / dioxane (4N, 8 mL) dropwise at 0° C. After addition, the mixture was stirred at room temperature for 2 h, and then the reaction mixture was concentrated. The residue was dissolved in pure water (20 mL) and lyophilized to give intermediate C1 (1.44 g, 100% yield). MS: calculated 322 [(M+H) + ], measured value 322 [(M+H) + ].

[0091] Intermediate C2 4-[(4R,10aS)-4-Methyl-3,4,6,7,8,9,10,10a-octahydro-1H-pyrazino[1,2-d][1,4]diazepin-2-yl]-1-methyl-1,8-naphthyridin-2-one; trihydrochloride [ka]

[0092] 4-[(4R,10aS)-4-methyl-3,4,6,7,8,9,10,10a-octahydro-1H-pyrazino[1,2-d][1,4]diazepin-2-yl]-1-methyl-1,8-naphthyridin-2-one; trihydrochloride (Intermediate C2) was prepared similarly to Intermediate C1 by replacing 5-fluoroquinoline-8-carbonitrile (Intermediate A1) with 4-chloro-1-methyl-1,8-naphthyridin-2-one (Intermediate A2) and CsF with DIEA in step (a). MS: calculated 328 [(M+H) + ], measured value 328 [(M+H) + ].

[0093] Intermediate C3 4-[(4R,10aS)-4-Methyl-3,4,6,7,8,9,10,10a-octahydro-1H-pyrazino[1,2-d][1,4]diazepin-2-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile; trihydrochloride [ka]

[0094] 4-[(4R,10aS)-4-methyl-3,4,6,7,8,9,10,10a-octahydro-1H-pyrazino[1,2-d][1,4]diazepin-2-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile; trihydrochloride (Intermediate C3) was prepared similarly to Intermediate C1 by replacing 5-fluoroquinoline-8-carbonitrile (Intermediate A1) with 4-fluoropyrazolo[1,5-a]pyridine-7-carbonitrile (Intermediate A3) in step (a). MS: calculated 311 [(M+H) + ], measured value 311 [(M+H) + ].

[0095] Intermediate C4 4-[(4R,10aS)-4-Methyl-3,4,6,7,8,9,10,10a-octahydro-1H-pyrazino[1,2-d][1,4]diazepin-2-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile; trihydrochloride [ka]

[0096] 4-[(4R,10aS)-4-methyl-3,4,6,7,8,9,10,10a-octahydro-1H-pyrazino[1,2-d][1,4]diazepin-2-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile; trihydrochloride (Intermediate C4) was prepared similarly to Intermediate C1 by replacing 5-fluoroquinoline-8-carbonitrile (Intermediate A1) with 3,4-difluoropyrazolo[1,5-a]pyridine-7-carbonitrile (Intermediate A4) in step (a). MS: calculated 329 [(M+H) + ], measured value 329 [(M+H) + ].

[0097] Example 1 5-[(4R,10aS)-4-Methyl-8-(6-piperazin-1-yl-3-pyridyl)-1,3,4,6,7,9,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile [ka]

[0098] The title compound was synthesized according to the following scheme. [ka]

[0099] Step (a): Preparation of tert-butyl 4-[5-[(4R,10aS)-2-(8-cyano-5-quinolyl)-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-8-yl]-2-pyridyl]piperazine-1-carboxylate (compound 1.1) To a solution of 5-[(4R,10aS)-4-methyl-3,4,6,7,8,9,10a-octahydro-1H-pyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; trihydrochloride (intermediate C1, 70 mg, 162 μmol) in toluene (5 mL) was added tert-butyl 4-(5-bromopyridin-2-yl)piperazine-1-carboxylate (CAS: 153747-97-8, BePharm, catalog: BD94595, 55.6 mg, 162 μmol), tBuONa (78.1 mg, 812 μmol) and RuPhos Pd G2 (CAS: 1375325-68-0, ALDRICH, catalog: 753246, 12.6 mg, 16.2 μmol). The resulting mixture was stirred at 100° C. overnight. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted three times with EA (20 mL). The combined organic layers were washed with brine and diluted with Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 20 g, 0% to 100% EtOAc in PE) to give compound 1.1 (38 mg, 40.1% yield). MS: calculated 583 [(M+H) + ], measured value 583 [(M+H) + ].

[0100] Step (b): Preparation of 5-[(4R,10aS)-4-methyl-8-(6-piperazin-1-yl-3-pyridyl)-1,3,4,6,7,9,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile (Example 1) To a solution of tert-butyl 4-[5-[(4R,10aS)-2-(8-cyano-5-quinolyl)-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-8-yl]-2-pyridyl]piperazine-1-carboxylate (compound 1.1, 38 mg, 65.2 μmol) in DCM (2 mL), TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 2 hours and then concentrated to give the crude product, which was purified by pre-HPLC to give Example 1 (9.4 mg, 30.3% yield). MS: calculated 483 [(M+H) + ], measured value 483 [(M+H) + ]. 1 H NMR (400 MHz, METHANOL-d 4 ) δ ppm 9.07 - 8.97 (m, 1H), 8.76 - 8.62 (m, 1H), 8.19 (d, J= 8.1 Hz, 1H), 7.87 (d, J = 3.1 Hz, 1H), 7.75 - 7.62 (m, 1H), 7.40 - 7.28 (m, 2H), 6.95 (d, J = 9.2 Hz, 1H), 4.14 - 4.02 (m, 1H), 3.89 - 3.52 (m, 12H), 3.40 - 3.34 (m, 5H), 3.23 - 3.09 (m, 2H), 2.37 - 2.24 (m, 1H), 2.20 (br s, 1H), 1.53 (d, J= 6.5 Hz, 3H).

[0101] Example 2 5-[(4R,10aS)-4-Methyl-8-(2-piperazin-1-ylpyrimidin-5-yl)-1,3,4,6,7,9,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile [ka]

[0102] The title compound was prepared similarly to the preparation of Example 1, by using tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (CAS: 374930-88-8, BePharm, catalog: BD28540) instead of tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate in step (a). Example 2 was obtained. MS: calculated value 484 [(M+H) + ], measured value 484 [(M+H) + ]. 1 H NMR (400 MHz, METHANOL-d 4 ) δppm 9.11 - 9.02 (m, 1H), 8.75 - 8.66 (m, 1H), 8.32 - 8.20 (m, 3H), 7.76 - 7.60 (m, 1H), 7.39 (d, J = 8.1 Hz, 1H), 4.22 - 4.09 (m, 1H), 4.08 - 3.84 (m, 6H), 3.84 - 3.65 (m, 4H), 3.61 - 3.44 (m, 4H), 3.31 - 3.26 (m, 3H), 3.25 - 3.09 (m, 2H), 2.45 - 2.13 (m, 2H), 1.58 (d, J = 6.4 Hz, 3H).

[0103] Example 3 5-[(4R,10aS)-4-Methyl-8-[4-[(2S)-morpholin-2-yl]phenyl]-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile [ka]

[0104] The title compound was prepared similarly to the preparation of Example 1, by using tert-butyl (2S)-2-(4-bromophenyl)morpholine-4-carboxylate instead of tert-butyl 4-(5-bromopyridin-2-yl)piperazine-1-carboxylate in step (a). Example 3 was obtained. MS: calculated 483 [(M+H) + ], measured value 483 [(M+H) + ]. 1 H NMR (400 MHz, METHANOL-d 4 ) δppm 9.08 - 8.99 (m, 1H), 8.75 - 8.64 (m, 1H), 8.22 (d, J = 7.9 Hz, 1H), 7.73 - 7.63 (m, 1H), 7.38 (d, J = 8.1 Hz, 1H), 7.33 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 4.72 - 4.61 (m, 1H), 4.27 - 4.13 (m, 2H), 4.04 - 3.59 (m, 9H), 3.54 - 3.45 (m, 1H), 3.42 - 3.35 (m, 2H), 3.29 - 3.07 (m, 4H), 2.39 - 2.08 (m, 2H), 1.57 (d, J = 6.2 Hz, 3H).

[0105] Example 4 5-[(4R,10aS)-4-Methyl-8-(5,6,7,8-tetrahydro-2,7-naphthyridin-4-yl)-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile [ka]

[0106] The title compound was prepared similarly to the preparation of Example 1, by using tert-butyl 5-bromo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxylate (CAS: 1251012-16-4) instead of tert-butyl 4-(5-bromopyridin-2-yl)piperazine-1-carboxylate in step (a). Example 4 was obtained. MS: calculated value 454 [(M+H) + ], measured value 454 [(M+H) + ]. 1 H NMR (400 MHz, METHANOL-d 4 ) δppm 9.09 - 9.00 (m, 1H), 8.79 - 8.69 (m, 1H), 8.51 (s, 1H), 8.38 (s, 1H), 8.23 ​​(d, J = 7.9 Hz, 1H), 7.79 - 7.66 (m, 1H), 7.41 (d, J = 8.1 Hz, 1H), 4.55 (s, 2H), 4.17 (br s, 2H), 4.04 - 3.84 (m, 2H), 3.79 - 3.53 (m, 7H), 3.48 - 3.40 (m, 1H), 3.31 - 3.18 (m, 4H), 2.49 - 2.34 (m, 1H), 2.28 - 2.12 (m, 1H), 1.59 (d, J = 6.4 Hz, 3H).

[0107] Example 5 5-[(4R,10aS)-4-Methyl-8-(5,6,7,8-tetrahydro-1,7-naphthyridin-2-yl)-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile [ka]

[0108] The title compound was prepared similarly to the preparation of Example 1, by using tert-butyl 2-chloro-6,8-dihydro-5H-1,7-naphthyridine-7-carboxylate (CAS: 1211581-54-2, PharmaBlock, catalog: PBLJ8189) instead of tert-butyl 4-(5-bromopyridin-2-yl)piperazine-1-carboxylate in step (a). Example 5 was obtained. MS: calculated value 454 [(M+H) + ], measured value 454 [(M+H) + ]. 1 H NMR (400 MHz, METHANOL-d 4 ) δppm 9.04 - 8.98 (m, 1H), 8.70 - 8.62 (m, 1H), 8.19 (d, J = 7.9 Hz, 1H), 7.74 - 7.61 (m, 1H), 7.47 (d, J = 8.7 Hz, 1H), 7.35 (d, J = 7.9 Hz, 1H), 6.71 (d, J = 8.7 Hz, 1H), 4.57 - 4.45 (m, 1H), 4.24 (s, 2H), 4.11 - 3.99 (m, 1H), 3.88 - 3.56 (m, 7H), 3.54 - 3.44 (m, 2H), 3.25 (br t, J = 12.0 Hz, 1H), 3.20 - 3.07 (m, 2H), 3.01 (t, J= 6.1 Hz, 2H), 2.40 - 2.25 (m, 1H), 2.20 - 2.08 (m, 1H), 1.51 (d, J = 6.2 Hz, 3H).

[0109] Example 6 5-[(4R,10aS)-4-Methyl-8-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile [ka]

[0110] The title compound was prepared similarly to the preparation of Example 1, by using tert-butyl 2-chloro-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carboxylate (CAS: 1151665-15-4, PharmaBlock, catalog: PB06675) instead of tert-butyl 4-(5-bromopyridin-2-yl)piperazine-1-carboxylate in step (a). Example 6 was obtained. MS: calculated value 454 [(M+H) + ], measured value 454 [(M+H) + ]. 1 H NMR (400 MHz, METHANOL-d 4 ) δppm 9.04 - 8.92 (m, 1H), 8.80 - 8.70 (m, 1H), 8.17 (d, J = 8.1 Hz, 1H), 7.81 (d, J= 9.4 Hz, 1H), 7.74 - 7.64 (m, 1H), 7.34 (d, J = 7.9 Hz, 1H), 7.24 (d, J= 9.7 Hz, 1H), 4.26 (s, 2H), 4.23 - 4.01 (m, 4H), 3.99 - 3.78 (m, 3H), 3.71 - 3.46 (m, 5H), 3.30 - 3.23 (m, 4H), 2.63 - 2.47 (m, 1H), 2.27 - 2.10 (m, 1H), 1.54 (d, J = 6.4 Hz, 3H).

[0111] Example 7 5-[(4R,10aS)-4-Methyl-8-(5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile [ka]

[0112] The title compound was prepared similarly to the preparation of Example 1, by using tert-butyl 6-chloro-3,4-dihydro-1H-2,7-naphthyridine-2-carboxylate instead of tert-butyl 4-(5-bromopyridin-2-yl)piperazine-1-carboxylate in step (a). Example 7 was obtained. MS: calculated value 454 [(M+H) + ], measured value 454 [(M+H) + ]. 1 H NMR (400 MHz, METHANOL-d 4 ) δppm 9.06 - 8.98 (m, 1H), 8.73 - 8.61 (m, 1H), 8.19 (d, J = 7.9 Hz, 1H), 8.05 (s, 1H), 7.80 - 7.62 (m, 1H), 7.35 (d, J = 7.9 Hz, 1H), 6.62 (s, 1H), 4.55 - 4.45 (m, 1H), 4.32 (s, 2H), 4.15 - 4.03 (m, 1H), 3.86 - 3.66 (m, 6H), 3.64 - 3.57 (m, 1H), 3.51 (t, J = 6.5 Hz, 2H), 3.31 - 3.25 (m, 1H), 3.22 - 3.01 (m, 4H), 2.42 - 2.26 (m, 1H), 2.22 - 2.09 (m, 1H), 1.52 (d, J = 6.4 Hz, 3H).

[0113] Example 8 5-[(4R,10aS)-4-Methyl-8-(5,6,7,8-tetrahydro-2,7-naphthyridin-3-ylmethyl)-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile [ka]

[0114] The title compound was synthesized according to the following scheme. [ka]

[0115] Step (a): Preparation of tert-butyl 6-(methylsulfonyloxymethyl)-3,4-dihydro-1H-2,7-naphthyridine-2-carboxylate (Compound 8.2) To a solution of tert-butyl 6-(hydroxymethyl)-3,4-dihydro-1H-2,7-naphthyridine-2-carboxylate (compound 8.1, 40 mg, 151 μmol) and DIEA (58.7 mg, 454 μmol) in DCM (5 mL) was added methanesulfonyl chloride (19.1 mg, 166 μmol) dropwise. The resulting mixture was stirred at room temperature for 2 hours. The reaction was cooled to room temperature with NaHCO 3 The mixture was quenched with aqueous solution of 100 ml of DCM and extracted twice with DCM (20 mL). The combined organic layers were washed with brine and 2 SO 4 The mixture was dried over 100 ml of water, filtered, and the filtrate was concentrated to give compound 8.2 (52 mg, 100% yield), which was used directly in the next step without further purification. MS: calculated 343 [(M+H) + ], measured value 343 [(M+H) + ].

[0116] Step (b): tert-Butyl 6-[(4R,10aS)-2-(8-cyano-5-quinolyl)-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-8-yl]methyl]-3,4-dihydro-1H-2,7-naphthyridine-2-carboxylate (Compound 8.3) 5-[(4R,10aS)-4-methyl-3,4,6,7,8,9,10,10a-octahydro-1H-pyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; trihydrochloride (Intermediate C1, 80 mg, 186 μmol) in acetonitrile (10 mL) was added with tert-butyl 6-(methylsulfonyloxymethyl)-3,4-dihydro-1H-2,7-naphthyridine-2-carboxylate (Compound 8.2, 52 mg, 152 μmol) and DIEA (98.1 mg, 759 μmol). The resulting mixture was stirred at reflux for 5 h, then concentrated, and the residue was purified by flash chromatography to give Compound 8.3 (49 mg, 56.8% yield). MS: calculated 568 [(M+H) + ], measured value 568 [(M+H) + ].

[0117] Step (c): Preparation of 5-[(4R,10aS)-4-methyl-8-(5,6,7,8-tetrahydro-2,7-naphthyridin-3-ylmethyl)-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile (Example 8) To a solution of tert-butyl 6-[(4R,10aS)-2-(8-cyano-5-quinolyl)-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-8-yl]methyl]-3,4-dihydro-1H-2,7-naphthyridine-2-carboxylate (compound 8.3, 50 mg, 88.1 μmol) in DCM (10 mL), TFA (3 mL) was added. The reaction mixture was stirred at room temperature for 2 hours and then concentrated to give the crude product, which was purified by pre-HPLC to give Example 8 (18 mg, 43.7% yield). MS: calculated 468 [(M+H) + ], measured value 468 [(M+H) + ]. 1 H NMR (400 MHz, METHANOL-d 4) δppm 9.01 - 8.97 (m, 1H), 8.67 - 8.59 (m, 1H), 8.37 (s, 1H), 8.16 (d, J = 8.1 Hz, 1H), 7.74 - 7.61 (m, 1H), 7.38 (s, 1H), 7.25 (d, J = 8.1 Hz, 1H), 4.22 (s, 2H), 4.03 (br s, 2H), 3.45 - 3.36 (m, 3H), 3.29 - 3.24 (m, 1H), 3.19 - 2.97 (m, 8H), 2.92 - 2.70 (m, 4H), 2.14 - 1.99 (m, 1H), 1.90 - 1.78 (m, 1H), 1.22 (d, J = 6.1 Hz, 3H).

[0118] Example 9 5-[(4R,10aS)-4-Methyl-8-(5,6,7,8-tetrahydro-2,6-naphthyridin-3-ylmethyl)-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile [ka]

[0119] The title compound was prepared similarly to the preparation of Example 8, by using tert-butyl 7-(hydroxymethyl)-3,4-dihydro-1H-2,6-naphthyridine-2-carboxylate instead of tert-butyl 6-(hydroxymethyl)-3,4-dihydro-1H-2,7-naphthyridine-2-carboxylate in step (a). Example 9 was obtained. MS: calculated value 468 [(M+H) + ], measured value 468 [(M+H) + ]. 1 H NMR (400 MHz, METHANOL-d 4) δppm 9.06 - 8.98 (m, 1H), 8.69 - 8.64 (m, 1H), 8.62 (s, 1H), 8.19 (d, J = 8.1 Hz, 1H), 7.72 - 7.65 (m, 1H), 7.43 (s, 1H), 7.32 (d, J = 8.1 Hz, 1H), 4.49 (d, J = 6.6 Hz, 4H), 3.82 - 3.74 (m, 1H), 3.67 - 3.48 (m, 10H), 3.41 - 3.35 (m, 1H), 3.21 (t, J = 6.2 Hz, 2H), 3.13 - 3.06 (m, 1H), 3.03 - 2.94 (m, 1H), 2.31 - 2.11 (m, 2H), 1.39 (d, J = 6.1 Hz, 3H).

[0120] Example 10 5-[(4R,10aS)-4-Methyl-8-(5,6,7,8-tetrahydro-1,6-naphthyridin-3-ylmethyl)-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile [ka]

[0121] The title compound was prepared similarly to the preparation of Example 8, by using tert-butyl 3-(hydroxymethyl)-7,8-dihydro-5H-1,6-naphthyridine-6-carboxylate instead of tert-butyl 6-(hydroxymethyl)-3,4-dihydro-1H-2,7-naphthyridine-2-carboxylate in step (a). Example 10 was obtained. MS: calculated value 468 [(M+H) + ], measured value 468 [(M+H) + ]. 1 H NMR (400 MHz, METHANOL-d 4) δppm 9.07 - 8.98 (m, 1H), 8.72 - 8.60 (m, 2H), 8.19 (d, J = 8.1 Hz, 1H), 7.95 (d, J= 1.7 Hz, 1H), 7.72 - 7.62 (m, 1H), 7.34 (d, J = 8.1 Hz, 1H), 4.51 (s, 2H), 4.35 (s, 2H), 3.97 - 3.75 (m, 2H), 3.73 - 3.40 (m, 10H), 3.32 - 3.25 (m, 2H), 3.19 - 3.00 (m, 2H), 2.29 - 2.16 (m, 2H), 1.43 (d, J = 6.2 Hz, 3H).

[0122] Example 11 5-[(4R,10aS)-4-Methyl-8-(1,2,3,4-tetrahydroisoquinolin-6-ylmethyl)-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile [ka]

[0123] The title compound was prepared similarly to the preparation of Example 8, by using tert-butyl 6-(bromomethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate instead of tert-butyl 6-(methylsulfonyloxymethyl)-3,4-dihydro-1H-2,7-naphthyridine-2-carboxylate (compound 8.2) in step (b). Example 11 was obtained. MS: calculated 467 [(M+H) + ], measured value 467 [(M+H) + ]. 1 H NMR (400 MHz, METHANOL-d 4) δppm 9.05 - 8.95 (m, 1H), 8.67 - 8.57 (m, 1H), 8.15 (d, J = 8.1 Hz, 1H), 7.72 - 7.60 (m, 1H), 7.51 - 7.42 (m, 2H), 7.36 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 4.43 (s, 2H), 4.33 (s, 2H), 3.61 - 3.48 (m, 3H), 3.47 - 3.35 (m, 5H), 3.30 - 3.08 (m, 5H), 3.00 - 2.81 (m, 2H), 2.74 (t, J = 11.2 Hz, 1H), 2.30 - 2.14 (m, 1H), 2.00 - 1.86 (m, 1H), 1.23 (d, J = 6.1 Hz, 3H).

[0124] Example 12 5-[(4R,10aS)-4-Methyl-8-(1,2,3,4-tetrahydroisoquinolin-7-ylmethyl)-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile [ka]

[0125] The title compound was prepared similarly to the preparation of Example 8, by using tert-butyl 7-(hydroxymethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate instead of tert-butyl 6-(hydroxymethyl)-3,4-dihydro-1H-2,7-naphthyridine-2-carboxylate in step (a). Example 12 was obtained. MS: calculated 467 [(M+H) + ], measured value 467 [(M+H) + ]. 1 H NMR (400 MHz, METHANOL-d 4) δppm 9.04 - 8.96 (m, 1H), 8.67 - 8.59 (m, 1H), 8.15 (d, J = 8.1 Hz, 1H), 7.67 - 7.58 (m, 1H), 7.52 - 7.45 (m, 1H), 7.42 - 7.35 (m, 2H), 7.25 (d, J = 8.1 Hz, 1H), 4.43 (s, 2H), 4.34 (s, 2H), 3.55 (t, J = 6.4 Hz, 3H), 3.46 - 3.35 (m, 5H), 3.28 - 3.10 (m, 5H), 2.99 - 2.85 (m, 2H), 2.74 (t, J = 11.2 Hz, 1H), 2.33 - 2.15 (m, 1H), 2.04 - 1.86 (m, 1H), 1.23 (d, J = 6.1 Hz, 3H).

[0126] Example 13 5-[(4R,10aS)-4-Methyl-8-[(5-piperazin-1-ylpyrimidin-2-yl)methyl]-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile [ka]

[0127] The title compound was synthesized according to the following scheme. [ka]

[0128] Step (a): Preparation of 5-[(4R,10aS)-8-[(5-bromopyrimidin-2-yl)methyl]-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile (Compound 13.1) To a solution of 5-[(4R,10aS)-4-methyl-3,4,6,7,8,9,10,10a-octahydro-1H-pyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; trihydrochloride (Intermediate C1, 90 mg, 209 μmol) in acetonitrile (8 mL), 5-bromo-2-(bromomethyl)pyrimidine (CAS: 1193116-74-3, BePharm, Cat: BD266661, 105 mg, 418 μmol) and DIPEA (135 mg, 1.04 mmol) were added. The mixture was stirred at reflux for 2 h. The reaction mixture was concentrated and the residue was purified by flash chromatography to give compound 13.1 (32 mg, 31.1% yield). MS: calculated 492,494 [(M+H) + ], measured value 492,494 [(M+H) + ].

[0129] Step (b): Preparation of tert-butyl 4-[2-[(4R,10aS)-2-(8-cyano-5-quinolyl)-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-8-yl]methyl]pyrimidin-5-yl]piperazine-1-carboxylate (Compound 13.2) To a solution of 5-[(4R,10aS)-8-[(5-bromopyrimidin-2-yl)methyl]-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile (compound 13.1, 30 mg, 60.9 μmol) in toluene (5 mL) was added tert-butyl piperazine-1-carboxylate (22.7 mg, 122 μmol), tBuONa (11.7 mg, 122 μmol) and RuPhos Pd G2 (4.73 mg, 6.09 μmol). The reaction mixture was diluted to 100 o The mixture was stirred at rt overnight. The mixture was cooled to rt, diluted with water (20 mL) and extracted three times with EA (20 mL). The combined organic layers were washed with brine and diluted with Na 2 SO 4The mixture was dried over 100 ml of hexane, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (20 g of silica gel, 0% to 100% EtOAc in PE) to give compound 13.2 (20 mg, 54.9% yield). MS: calculated 598 [(M+H) + ], measured value 598 [(M+H) + ].

[0130] Step (c): Preparation of 5-[(4R,10aS)-4-methyl-8-[(5-piperazin-1-ylpyrimidin-2-yl)methyl]-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile (Example 13) To a solution of tert-butyl 4-[2-[(4R,10aS)-2-(8-cyano-5-quinolyl)-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-8-yl]methyl]pyrimidin-5-yl]piperazine-1-carboxylate (compound 13.2, 20 mg, 33.5 μmol) in DCM (5 mL), TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 2 hours and then concentrated to give the crude product, which was purified by pre-HPLC to give Example 13 (11 mg, 66.0% yield). MS: calculated 498 [(M+H) + ], measured value 498 [(M+H) + ]. 1 H NMR (400 MHz, METHANOL-d 4) δppm 9.11 - 8.94 (m, 1H), 8.72 - 8.60 (m, 3H), 8.16 (d, J = 7.9 Hz, 1H), 7.77 - 7.61 (m, 1H), 7.26 (d, J = 8.1 Hz, 1H), 4.48 (s, 2H), 3.65 - 3.36 (m, 15H), 3.30 - 3.09 (m, 2H), 3.06 - 2.96 (m, 1H), 2.95 - 2.85 (m, 1H), 2.84 - 2.71 (m, 1H), 2.22 (br d, J= 7.2 Hz, 1H), 1.98 (br d, J = 7.5 Hz, 1H), 1.27 (d, J = 6.1 Hz, 3H).

[0131] Example 14 5-[(4R,10aS)-4-Methyl-8-[(2-piperazin-1-ylpyrimidin-5-yl)methyl]-1,3,4,6,7,9,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile [ka]

[0132] The title compound was synthesized according to the following scheme. [ka]

[0133] Step (a): Preparation of 5-[(4R,10aS)-8-[(2-chloropyrimidin-5-yl)methyl]-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile (Compound 14.1) To a solution of 5-[(4R,10aS)-4-methyl-3,4,6,7,8,9,10,10a-octahydro-1H-pyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; trihydrochloride (Intermediate C1, 90 mg, 209 μmol) in acetonitrile (8 mL), 2-chloro-5-(chloromethyl)pyrimidine (CAS: 148406-13-7, BePharm, Catalog: BD223762, 68.1 mg, 418 μmol) and DIEA (135 mg, 1.04 mmol) were added. The mixture was stirred at reflux for 2 h, then concentrated and the residue was purified by flash chromatography to give compound 14.1 (25 mg, 26.7% yield). MS: calculated 448,450 [(M+H) + ], measured value 448,450 [(M+H) + ].

[0134] Step (b): Preparation of tert-butyl 4-[5-[(4R,10aS)-2-(8-cyano-5-quinolyl)-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-8-yl]methyl]pyrimidin-2-yl]piperazine-1-carboxylate (Compound 14.2) To a 10 mL microwave vial was added 5-[(4R,10aS)-8-[(2-chloropyrimidin-5-yl)methyl]-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile (compound 14.1, 20 mg, 44.6 μmol), tert-butyl piperazine-1-carboxylate (16.6 mg, 89.3 μmol) and DIEA (5.77 mg, 7.8 μl, 44.6 μmol) in acetonitrile (2 ml). The vial was capped and heated in a microwave at 120° C. for 8 hours. The mixture was concentrated to give compound 14.2 (26.7 mg, 100% yield), which was used directly in the next step. 598[(M+H) + ], measured value 598 [(M+H) + ].

[0135] Step (c): Preparation of 5-[(4R,10aS)-4-methyl-8-[(2-piperazin-1-ylpyrimidin-5-yl)methyl]-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile (Example 14) To a solution of tert-butyl 4-[5-[(4R,10aS)-2-(8-cyano-5-quinolyl)-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-8-yl]methyl]pyrimidin-2-yl]piperazine-1-carboxylate (compound 14.2, 20 mg, 33.5 μmol) in DCM (6 mL), TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 2 hours and then concentrated to give the crude product, which was purified by pre-HPLC to give Example 14 (15 mg, 90.1% yield). MS: calculated 498 [(M+H) + ], measured value 498 [(M+H) + ]. 1 H NMR (400 MHz, METHANOL-d 4 ) δppm 9.05 - 8.97 (m, 1H), 8.65 - 8.60 (m, 1H), 8.55 (s, 2H), 8.16 (d, J = 7.9 Hz, 1H), 7.68 - 7.60 (m, 1H), 7.26 (d, J = 7.9 Hz, 1H), 4.21 (s, 2H), 4.18 - 4.11 (m, 4H), 3.52 - 3.36 (m, 6H), 3.31 - 3.13 (m, 5H), 2.99 - 2.85 (m, 2H), 2.81 - 2.71 (m, 1H), 2.30 - 2.12 (m, 1H), 2.02 - 1.84 (m, 1H), 1.26 (d, J = 6.1 Hz, 3H).

[0136] Example 15 5-[(4R,10aS)-4-Methyl-8-[(5-piperazin-1-ylpyrazin-2-yl)methyl]-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonyltolyl [ka]

[0137] The title compound was prepared similarly to the preparation of Example 14, by using 2-(bromomethyl)-5-chloropyrazine (CAS: 1433707-80-2, BePharm, catalog: BD00735886) instead of 2-chloro-5-(chloromethyl)pyrimidine in step (a). Example 15 was obtained. MS: calculated 498 [(M+H) + ], measured value 498 [(M+H) + ]. 1 H NMR (400 MHz, METHANOL-d 4 ) δppm 9.06 - 8.98 (m, 1H), 8.70 - 8.63 (m, 1H), 8.45 (d, J = 1.3 Hz, 1H), 8.30 (d, J= 1.3 Hz, 1H), 8.18 (d, J = 8.1 Hz, 1H), 7.73 - 7.60 (m, 1H), 7.31 (d, J= 8.1 Hz, 1H), 4.45 (s, 2H), 4.05 - 3.93 (m, 4H), 3.82 - 3.42 (m, 10H), 3.41 - 3.36 (m, 4H), 3.09 (d, J = 11.9Hz, 1H), 3.01 - 2.92 (m, 1H), 2.31 - 2.09 (m, 2H), 1.37 (d, J = 6.2 Hz, 3H).

[0138] Example 16 5-[(4R,10aS)-4-Methyl-8-[(5-piperazin-1-yl-3-pyridyl)methyl]-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile [ka]

[0139] The title compound was prepared similarly to the preparation of Example 13, by using 3-bromo-5-(bromomethyl)pyridine (CAS: 145743-85-7, BePharm, catalog: BD162034) instead of 5-bromo-2-(bromomethyl)pyrimidine in step (a). Example 16 was obtained. MS: calculated 497 [(M+H) + ], measured value 497 [(M+H) + ]. 1 H NMR (400 MHz, METHANOL-d 4 ) δppm 9.02 - 8.96 (m, 1H), 8.70 - 8.60 (m, 1H), 8.40 (d, J = 2.7 Hz, 1H), 8.22 (d, J= 1.5 Hz, 1H), 8.16 (d, J = 7.9 Hz, 1H), 7.70 - 7.60 (m, 2H), 7.27 (d, J= 8.1 Hz, 1H), 4.28 (s, 2H), 3.63 - 3.56 (m, 4H), 3.55 - 3.36 (m, 10H), 3.33 - 3.19 (m, 3H), 3.11 - 3.01 (m, 1H), 3.00 - 2.90 (m, 1H), 2.89 - 2.74 (m, 1H), 2.28 - 2.14 (m, 1H), 2.08 - 1.94 (m, 1H), 1.27 (d, J = 6.2 Hz, 3H).

[0140] Example 17 5-[(4R,10aS)-4-Methyl-8-[(6-piperazin-1-yl-3-pyridyl)methyl]-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile [ka]

[0141] The title compound was prepared similarly to the preparation of Example 13, by using 2-chloro-5-(chloromethyl)pyridine (CAS: 70258-18-3, TCI, catalog: C1628) instead of 5-bromo-2-(bromomethyl)pyrimidine in step (a). Example 17 was obtained. MS: calculated value 497 [(M+H) + ], measured value 497 [(M+H) + ]. 1 H NMR (400 MHz, METHANOL-d 4 ) δppm 9.04 - 8.99 (m, 1H), 8.73 - 8.61 (m, 1H), 8.33 (d, J = 2.2 Hz, 1H), 8.18 (d, J= 7.9 Hz, 1H), 7.91 - 7.78 (m, 1H), 7.73 - 7.62 (m, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.04 (d, J = 8.9 Hz, 1H), 4.37 (s, 2H), 4.00 - 3.89 (m, 4H), 3.84 (br d, J = 16.8 Hz, 1H), 3.71 - 3.47 (m, 8H), 3.46 - 3.34 (m, 5H), 3.17 - 3.07 (m, 1H), 3.06 - 2.97 (m, 1H), 2.36 - 2.14 (m, 2H), 1.39 (d, J = 6.1 Hz, 3H).

[0142] Example 18 5-[(4R,10aS)-4-Methyl-8-[(6-piperazin-1-yl-2-pyridyl)methyl]-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile [ka]

[0143] The title compound was prepared similarly to the preparation of Example 13, by using 2-chloro-6-(chloromethyl)pyridine (CAS: 78846-18-3, BePharm, catalog: BD120582) instead of 5-bromo-2-(bromomethyl)pyrimidine in step (a). Example 18 was obtained. MS: calculated value 497 [(M+H) + ], measured value 497 [(M+H) + ]. 1 H NMR (400 MHz, METHANOL-d 4 ) δppm 9.06 - 8.93 (m, 1H), 8.68 - 8.58 (m, 1H), 8.15 (d, J = 7.9 Hz, 1H), 7.78 - 7.68 (m, 1H), 7.68 - 7.58 (m, 1H), 7.24 (d, J = 8.1 Hz, 1H), 6.98 (d, J = 8.6 Hz, 1H), 6.89 (d, J = 7.2 Hz, 1H), 4.42 (s, 2H), 3.99 - 3.86 (m, 4H), 3.72 - 3.49 (m, 3H), 3.47 - 3.34 (m, 8H), 3.19 - 3.11 (m, 1H), 3.09 - 3.01 (m, 1H), 3.00 - 2.92 (m, 1H), 2.91 - 2.81 (m, 1H), 2.77 - 2.64 (m, 1H), 2.35 - 2.17 (m, 1H), 2.05 - 1.91 (m, 1H), 1.23 (d, J = 6.1 Hz, 3H).

[0144] Example 19 5-[(4R,10aS)-4-Methyl-8-[(5-piperazin-1-yl-2-pyridyl)methyl]-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile [ka]

[0145] The title compound was prepared similarly to the preparation of Example 13, by using 5-bromo-2-(chromomethyl)pyridine (CAS: 168823-76-5, BePharm, catalog: BD223172) instead of 5-bromo-2-(bromomethyl)pyrimidine in step (a). Example 19 was obtained. MS: calculated value 497 [(M+H) + ], measured value 497 [(M+H) + ]. 1 H NMR (400 MHz, METHANOL-d 4 ) δppm 9.14 - 8.95 (m, 1H), 8.71 - 8.62 (m, 1H), 8.48 (d, J = 2.8 Hz, 1H), 8.19 (d, J= 7.9 Hz, 1H), 7.75 - 7.59 (m, 2H), 7.52 (d, J = 8.7 Hz, 1H), 7.31 (d, J= 8.1 Hz, 1H), 4.40 (s, 2H), 3.65 (br s, 1H), 3.61 - 3.36 (m, 16H), 3.28 - 3.17 (m, 1H), 3.08 - 2.97 (m, 1H), 2.96 - 2.84 (m, 1H), 2.21 (br s, 1H), 2.11 (br s, 1H), 1.35 (d, J = 6.1 Hz, 3H).

[0146] Example 20 5-[(4R,10aS)-8-[[5-[(3R,4S)-3-amino-4-fluoro-pyrrolidin-1-yl]-2-pyridyl]methyl]-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile [ka]

[0147] The title compound was prepared similarly to the preparation of Example 19, by using tert-butyl N-[(3R,4S)-4-fluoropyrrolidin-3-yl]carbamate (CAS: 1033718-91-0, PharmaBlock, Cat: PB09204) instead of tert-butyl piperazine-1-carboxylate in step (b). Example 20 was obtained. MS: calculated value 515 [(M+H) + ], measured value 515 [(M+H) + ]. 1 H NMR (400 MHz, METHANOL-d 4 ) δppm 9.04 - 8.92 (m, 1H), 8.66 - 8.58 (m, 1H), 8.15 (d, J = 7.9 Hz, 1H), 8.10 (d, J= 2.8 Hz, 1H), 7.71 - 7.59 (m, 1H), 7.45 (d, J = 8.6 Hz, 1H), 7.25 (d, J= 8.1 Hz, 1H), 7.19 - 7.10 (m, 1H), 5.64 - 5.43 (m, 1H), 4.37 (s, 2H), 4.29 - 4.15 (m, 1H), 3.95 (t, J = 8.9 Hz, 1H), 3.89 - 3.84 (m, 1H), 3.79 (d, J= 2.0 Hz, 1H), 3.61 - 3.35 (m, 8H), 3.30 - 3.22 (m, 1H), 3.21 - 3.12 (m, 1H), 3.07 - 2.87 (m, 2H), 2.83 - 2.70 (m, 1H), 2.31 - 2.17 (m, 1H), 2.03 - 1.92 (m, 1H), 1.26 (d, J = 6.1 Hz, 3H).

[0148] Example 21 5-[(4R,10aS)-8-[[5-[(6R)-6-amino-1,4-oxazepan-4-yl]-2-pyridyl]methyl]-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile [ka]

[0149] The title compound was prepared similarly to the preparation of Example 19, by using tert-butyl N-[(6R)-1,4-oxazepan-6-yl]carbamate (PharmaBlock, catalog: PB97932) instead of tert-butyl piperazine-1-carboxylate in step (b). Example 21 was obtained. MS: calculated value 527 [(M+H) + ], measured value 527 [(M+H) + ]. 1 H NMR (400 MHz, METHANOL-d 4 ) δppm 9.06 - 8.91 (m, 1H), 8.67 - 8.59 (m, 1H), 8.34 (d, J = 2.8 Hz, 1H), 8.15 (d, J= 7.9 Hz, 1H), 7.75 - 7.59 (m, 1H), 7.51 - 7.31 (m, 2H), 7.25 (d, J = 8.1 Hz, 1H), 4.36 (s, 2H), 4.23 - 4.15 (m, 1H), 4.12 - 4.05 (m, 1H), 4.04 - 3.91 (m, 2H), 3.88 - 3.75 (m, 2H), 3.74 - 3.64 (m, 2H), 3.63 - 3.54 (m, 2H), 3.53 - 3.46 (m, 2H), 3.45 - 3.35 (m, 4H), 3.23 - 3.13 (m, 1H), 3.12 - 3.04 (m, 1H), 2.98 - 2.81 (m, 2H), 2.79 - 2.68 (m, 1H), 2.30 - 2.10 (m, 1H), 1.99 - 1.89 (m, 1H), 1.24 (d, J = 6.1 Hz, 3H).

[0150] Example 22 5-[(4R,10aS)-8-[[5-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]-2-pyridyl]methyl]-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile [ka]

[0151] The title compound was prepared similarly to the preparation of Example 19, by using tert-butyl N-[(3R,4R)-4-methoxypyrrolidin-3-yl]carbamate (CAS: 1932066-52-8, PharmaBlock, catalog: PBZ4728) instead of tert-butyl piperazine-1-carboxylate in step (b). Example 22 was obtained. MS: calculated value 527 [(M+H) + ], measured value 527 [(M+H) + ]. 1 H NMR (400 MHz, METHANOL-d 4 ) δppm 9.01 - 8.95 (m, 1H), 8.65 - 8.59 (m, 1H), 8.15 (d, J = 8.1 Hz, 1H), 8.11 (d, J= 2.9 Hz, 1H), 7.70 - 7.60 (m, 1H), 7.44 (d, J = 8.6 Hz, 1H), 7.25 (d, J= 8.1 Hz, 1H), 7.19 - 7.11 (m, 1H), 4.36 (s, 2H), 4.24 - 4.16 (m, 1H), 4.04 - 3.97 (m, 1H), 3.95 - 3.86 (m, 1H), 3.81 - 3.72 (m, 1H), 3.61 - 3.35 (m, 6H), 3.48 (s, 3H), 3.30 - 3.22 (m, 1H), 3.22 - 3.12 (m, 1H), 3.06 - 2.86 (m, 2H), 2.84 - 2.72 (m, 1H), 2.33 - 2.12 (m, 1H), 2.04 - 1.91 (m, 1H), 1.26 (d, J = 6.2 Hz, 3H).

[0152] Example 23 5-[(4R,10aS)-8-[(3-fluoro-5-piperazin-1-yl-2-pyridyl)methyl]-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile [ka]

[0153] The title compound was synthesized according to the following scheme. [ka]

[0154] Step (a): Preparation of (5-bromo-3-fluoro-2-pyridyl)methyl methanesulfonate (compound 23.2) To a solution of (5-bromo-3-fluoropyridin-2-yl)methanol (CAS: 1206968-92-4, BePharm, Catalog: BD264415, 300 mg, 1.46 mmol) and DIEA (565 mg, 4.37 mmol) in DCM (40 mL) was added methanesulfonyl chloride (183 mg, 1.6 mmol) dropwise. The resulting mixture was stirred at room temperature for 2 h, then NaHCO 3 The mixture was quenched with aqueous solution and extracted twice with DCM (20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give compound 23.2 (414 mg, 100% yield), which was used directly in the next step without further purification. MS: calcd 284 [(M+H) + ], measured value 284 [(M+H) + ].

[0155] Step (b): Preparation of 5-[(4R,10aS)-8-[(5-bromo-3-fluoro-2-pyridyl)methyl]-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile (Compound 23.3) To a solution of 5-[(4R,10aS)-4-methyl-3,4,6,7,8,9,10,10a-octahydro-1H-pyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; trihydrochloride (Intermediate C1, 320 mg, 743 μmol) in acetonitrile (30 mL), (5-bromo-3-fluoropyridin-2-yl)methyl methanesulfonate (Compound 23.2, 414 mg, 1.46 mmol) and DIEA (480 mg, 3.71 mmol) were added. The resulting mixture was stirred at reflux for 5 h. The mixture was concentrated and the residue was purified by flash chromatography to give Compound 23.3 (220 mg, 58.1% yield). MS: calculated 509,511 [(M+H) + ], measured value 509,511 [(M+H) + ].

[0156] Step (c): Preparation of tert-butyl 4-[6-[[(4R,10aS)-2-(8-cyano-5-quinolyl)-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-8-yl]methyl]-5-fluoro-3-pyridyl]piperazine-1-carboxylate (Compound 23.4) To a solution of 5-[(4R,10aS)-8-[(5-bromo-3-fluoro-2-pyridyl)methyl]-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile (compound 23.3, 45 mg, 88.3 μmol) in toluene (8 mL), tert-butyl piperazine-1-carboxylate (32.9 mg, 177 μmol), RuPhos Pd G2 (6.86 mg, 8.83 μmol) and tBuONa (17 mg, 177 μmol) were added. The resulting mixture was stirred at 100° C. overnight. The mixture was then cooled to room temperature, diluted with water (20 mL) and extracted three times with EA (20 mL). The combined organic layers were washed with brine and diluted with Na 2 SO 4 The mixture was dried over 100 ml, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to give compound 23.4 (27 mg, 49.7% yield). 615 [(M+H) + ], measured value 615 [(M+H) + ].

[0157] Step (d): Preparation of 5-[(4R,10aS)-8-[(3-fluoro-5-piperazin-1-yl-2-pyridyl)methyl]-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile (Example 23) To a solution of tert-butyl 4-[2-[(4R,10aS)-2-(8-cyano-5-quinolyl)-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-8-yl]methyl]-5-fluoro-3-pyridyl]piperazine-1-carboxylate (compound 23.4, 27 mg, 43.9 μmol) in DCM (8 mL), TFA (4 mL) was added. The reaction mixture was stirred at room temperature for 2 hours and then concentrated to give the crude product, which was purified by pre-HPLC to give Example 23 (20 mg, 88.6% yield). MS: calculated 515 [(M+H) + ], measured value 515 [(M+H) + ]. 1H NMR (400 MHz, METHANOL-d 4 ) δppm 9.09 - 8.94 (m, 1H), 8.68 - 8.60 (m, 1H), 8.33 (d, J = 1.3 Hz, 1H), 8.16 (d, J= 7.9 Hz, 1H), 7.70 - 7.61 (m, 1H), 7.42 - 7.35 (m, 1H), 7.26 (d, J = 8.1 Hz, 1H), 4.45 (s, 2H), 3.67 - 3.52 (m, 6H), 3.52 - 3.36 (m, 9H), 3.29 - 3.21 (m, 1H), 3.20 - 3.07 (m, 1H), 3.03 - 2.84 (m, 2H), 2.82 - 2.66 (m, 1H), 2.31 - 2.11 (m, 1H), 2.03 - 1.84 (m, 1H), 1.26 (d, J = 6.1 Hz, 3H).

[0158] Example 24 5-[(4R,10aS)-8-[[5-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]-3-fluoro-2-pyridyl]methyl]-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile [ka]

[0159] The title compound was prepared similarly to the preparation of Example 23, by using tert-butyl N-[(3R,4R)-4-methoxypyrrolidin-3-yl]carbamate (CAS: 1932066-52-8, PharmaBlock, catalog: PBZ4728) instead of tert-butyl piperazine-1-carboxylate in step (c). Example 24 was obtained. MS: calculated value 545 [(M+H) + ], measured value 545 [(M+H) + ]. 1 H NMR (400 MHz, METHANOL-d 4) δppm 9.03 - 8.96 (m, 1H), 8.65 - 8.59 (m, 1H), 8.16 (d, J = 7.9 Hz, 1H), 7.98 (d, J= 0.9 Hz, 1H), 7.68 - 7.61 (m, 1H), 7.25 (d, J = 8.1 Hz, 1H), 7.00 - 6.94 (m, 1H), 4.43 (s, 2H), 4.22 - 4.14 (m, 1H), 4.03 - 3.95 (m, 1H), 3.94 - 3.85 (m, 1H), 3.83 - 3.76 (m, 1H), 3.66 - 3.36 (m, 6H), 3.51 (s, 3H), 3.25 - 3.17 (m, 1H), 3.13 - 3.07 (m, 1H), 2.99 - 2.84 (m, 2H), 2.80 - 2.68 (m, 1H), 2.30 - 2.13 (m, 1H), 2.00 - 1.86 (m, 1H), 1.24 (d, J = 6.1 Hz, 3H).

[0160] Example 25 4-[(4R,10aS)-8-[[5-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]pyrazin-2-yl]methyl]-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile [ka]

[0161] The title compound can be prepared by using 4-[(4R,10aS)-4-methyl-3,4,6,7,8,9,10,10a-octahydro-1H-pyrazino[1,2-d][1,4]diazepin-2-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile; trihydrochloride (Intermediate C3) in place of 5-[(4R,10aS)-4-methyl-3,4,6,7,8,9,10,10a-octahydro-1H-pyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; trihydrochloride (Intermediate C1) in step (a) and tert-butyl piperazine-1-carboxylate in place of tert-butyl piperazine-1-carboxylate in step (b). Prepared in the same manner as in preparation of Example 15 by using N-[(3R,4R)-4-methoxypyrrolidin-3-yl]carbamate. Obtained Example 25. MS: Calculated value 517 [(M+H) + ], measured value 517 [(M+H) + ]. 1 H NMR (400 MHz, METHANOL-d 4 ) δppm 8.23 ​​(d, J = 1.3 Hz, 1H), 8.12 (d, J = 1.3 Hz, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.47 (d, J = 7.9 Hz, 1H), 6.85 (d, J = 2.4 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 4.38 (s, 2H), 4.27 - 4.17 (m, 1H), 4.04 - 3.91 (m, 3H), 3.82 - 3.57 (m, 5H), 3.56 - 3.45 (m, 2H), 3.51 (s, 3H), 3.10-2.88 (m, 3H), 2.79 - 2.70 (m, 1H), 2.33 - 2.20 (m, 1H), 1.96 (br d, J = 2.2 Hz, 1H), 1.24 (d, J = 6.0 Hz, 3H).

[0162] Example 26 4-[(4R,10aS)-8-[[5-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]-3-fluoro-2-pyridyl]methyl]-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile [ka]

[0163] The title compound was prepared similarly to the preparation of Example 24, by using 4-[(4R,10aS)-4-methyl-3,4,6,7,8,9,10,10a-octahydro-1H-pyrazino[1,2-d][1,4]diazepin-2-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile; trihydrochloride (Intermediate C3) instead of 5-[(4R,10aS)-4-methyl-3,4,6,7,8,9,10,10a-octahydro-1H-pyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; trihydrochloride (Intermediate C1) in step (a). Example 26 was obtained. MS: calculated value 534 [(M+H) + ], measured value 534 [(M+H) + ]. 1 H NMR (400 MHz, METHANOL-d 4) δppm 7.91 (d, J = 2.3 Hz, 1H), 7.72 (d, J = 1.0 Hz, 1H), 7.34 (d, J = 7.9 Hz, 1H), 6.76 - 6.67 (m, 2H), 6.45 (d, J = 8.1 Hz, 1H), 3.95 (s, 2H), 3.87 - 3.76 (m, 1H), 3.70 - 3.63 (m, 1H), 3.62 - 3.54 (m, 2H), 3.55 - 3.46 (m, 1H), 3.33 (s, 3H), 3.19 - 2.86 (m, 5H), 2.81 - 2.65 (m, 3H), 2.64 - 2.55 (m, 2H), 2.04 - 1.92 (m, 1H), 1.77 - 1.67 (m, 1H), 1.08 (d, J = 6.0 Hz, 3H).

[0164] Example 27 4-[(4R,10aS)-8-[[5-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]-3-fluoro-2-pyridyl]methyl]-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile [ka]

[0165] The title compound was prepared similarly to the preparation of Example 24, by using 4-[(4R,10aS)-4-methyl-3,4,6,7,8,9,10,10a-octahydro-1H-pyrazino[1,2-d][1,4]diazepin-2-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile; trihydrochloride (intermediate C4) instead of 5-[(4R,10aS)-4-methyl-3,4,6,7,8,9,10,10a-octahydro-1H-pyrazino[1,2-d][1,4]diazepin-2-yl]-quinoline-8-carbonitrile; trihydrochloride (intermediate C1) in step (a). Example 27 was obtained. MS: calculated 552 [(M+H) + ], measured value 552 [(M+H) + ]. 1 H NMR (400 MHz, METHANOL-d 4 ) δppm 8.00 (d, J = 3.7 Hz, 1H), 7.99 - 7.97 (m, 1H), 7.43 (d, J= 8.1 Hz, 1H), 6.97 (s, 1H), 6.51 (d, J= 8.1 Hz, 1H), 4.44 (s, 2H), 4.20 - 4.13 (m, 1H), 4.01 - 3.95 (m, 1H), 3.93 - 3.85 (m, 1H), 3.84 - 3.75 (m, 1H), 3.67 - 3.42 (m, 6H), 3.49 (s, 3H), 2.99 (br d, J = 2.7 Hz, 1H), 2.95 - 2.78 (m, 3H), 2.74 - 2.61 (m, 1H), 2.30 - 2.17 (m, 1H), 2.02 - 1.91 (m, 1H), 1.23 (d, J = 6.1 Hz, 3H).

[0166] Example 28 4-[(4R,10aS)-4-Methyl-8-(1,2,3,4-tetrahydroisoquinolin-7-ylmethyl)-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]-1-methyl-1,8-naphthyridin-2-one [ka]

[0167] The title compound was prepared similarly to the preparation of Example 12, by using 4-[(4R,10aS)-4-methyl-3,4,6,7,8,9,10,10a-octahydro-1H-pyrazino[1,2-d][1,4]diazepin-2-yl]-1-methyl-1,8-naphthyridin-2-one; trihydrochloride (Intermediate C2) instead of 5-[(4R,10aS)-4-methyl-3,4,6,7,8,9,10,10a-octahydro-1H-pyrazino[1,2-d][1,4]diazepin-2-yl]-quinoline-8-carbonitrile; trihydrochloride (Intermediate C1) in step (a). Example 28 was obtained. MS: calculated 473 [(M+H) + ], measured value 373 [(M+H) + ]. 1 H NMR (400 MHz, METHANOL-d 4 ) δ ppm 8.66 - 8.57 (m, 1H), 8.22 - 8.13 (m, 1H), 7.32 - 7.25 (m, 1H), 7.16 - 6.95 (m, 3H), 6.09 (s, 1H), 3.96 (s, 2H), 3.74 (s, 3H), 3.59 (s, 2H), 3.23 (br d, J = 11.9 Hz, 1H), 3.15 - 3.06 (m, 3H), 2.95 - 2.48 (m, 12H), 1.96 - 1.78 (m, 1H), 1.72 (br s, 1H), 1.13 (d, J = 6.1 Hz, 3H).

[0168] Example 29 The following test was carried out to determine the activity of compounds of formula (I), (Ia) or (Ib) in the HEK293-Blue-hTLR-7 / 8 / 9 cell assay.

[0169] HEK293-Blue-hTLR-7 Cell Assay: A stable HEK293-Blue-hTLR-7 cell line was purchased from InvivoGen (catalog number: hkb-htlr7, San Diego, CA, USA). These cells were originally designed to study the stimulation of human TLR7 by monitoring the activation of NF-κB. A SEAP (secreted embryonic alkaline phosphatase) reporter gene was placed under the control of an IFN-β minimal promoter fused to five NF-κB and AP-1 binding sites. SEAP was induced by activating NF-κB and AP-1 by stimulating HEK-Blue hTLR7 cells with TLR7 ligands. Thus, reporter expression was reduced by TLR7 antagonists for 20 h of incubation under the stimulation of ligands such as R848 (Resiquimod). The activity of the SEAP reporter in cell culture supernatants was measured using QUANTI-Blu 商標 The detection medium turned purple or blue in the presence of alkaline phosphatase, measured at a wavelength of 640 nm using a kit (catalog number: rep-qb1, Invivogen, San Diego, CA, USA).

[0170] HEK293-Blue-hTLR7 cells were incubated at a density of 250,000–450,000 cells / mL in a volume of 170 μL in 96-well plates in Dulbecco's modified Eagle's medium (DMEM) containing 4.5 g / L glucose, 50 U / mL penicillin, 50 mg / mL streptomycin, 100 mg / mL normocin, 2 mM L-glutamine, 10% (v / v) heat-inactivated fetal bovine serum, plus 20 μL of test compound serially diluted in the presence of 1% final DMSO and 10 μL of 20 μM R848 in the above DMEM, at CO. 2Incubation was performed at 37°C for 20 hours in an incubator. Then, 20 μL of supernatant from each well was incubated with 180 μL of Quanti-blue substrate solution at 37°C for 2 hours, and the absorbance was read at 620-655 nm using a spectrophotometer. Because the signaling pathway in which TLR7 activation leads to downstream NF-κB activation is widely accepted, a similar reporter assay was modified for the evaluation of TLR7 antagonists.

[0171] HEK293-Blue-hTLR-8 Cell Assay: A stable HEK293-Blue-hTLR-8 cell line was purchased from InvivoGen (catalog number: hkb-htlr8, San Diego, CA, USA). These cells were originally designed to study the stimulation of human TLR8 by monitoring the activation of NF-κB. A SEAP (secreted embryonic alkaline phosphatase) reporter gene was placed under the control of an IFN-β minimal promoter fused to five NF-κB and AP-1 binding sites. SEAP was induced by activating NF-κB and AP-1 by stimulating HEK-Blue hTLR8 cells with TLR8 ligands. Thus, reporter expression was reduced by TLR8 antagonists for 20 h of incubation under the stimulation of ligands such as R848. The activity of the SEAP reporter in cell culture supernatants was measured using QUANTI-Blu 商標 The detection medium turned purple or blue in the presence of alkaline phosphatase, measured at a wavelength of 640 nm using a kit (catalog number: rep-qb1, Invivogen, San Diego, CA, USA).

[0172] HEK293-Blue-hTLR8 cells were incubated at a density of 250,000–450,000 cells / mL in a volume of 170 μL in 96-well plates in Dulbecco's Modified Eagle Medium (DMEM) containing 4.5 g / L glucose, 50 U / mL penicillin, 50 mg / mL streptomycin, 100 mg / mL normocin, 2 mM L-glutamine, 10% (v / v) heat-inactivated fetal bovine serum, plus 20 μL of test compound serially diluted in the presence of 1% final DMSO and 10 μL of 60 μM R848 in the above DMEM, at CO. 2 Incubation was performed at 37°C for 20 hours in an incubator. Then, 20 μL of supernatant from each well was incubated with 180 μL of Quanti-blue substrate solution at 37°C for 2 hours, and the absorbance was read at 620-655 nm using a spectrophotometer. Since the signaling pathway in which TLR8 activation leads to downstream NF-κB activation is widely accepted, a similar reporter assay was modified for the evaluation of TLR8 antagonists.

[0173] HEK293-Blue-hTLR-9 Cell Assay: A stable HEK293-Blue-hTLR-9 cell line was purchased from InvivoGen (catalog number: hkb-htlr9, San Diego, CA, USA). These cells were originally designed to study the stimulation of human TLR9 by monitoring the activation of NF-κB. A SEAP (secreted embryonic alkaline phosphatase) reporter gene was placed under the control of an IFN-β minimal promoter fused to five NF-κB and AP-1 binding sites. SEAP was induced by activating NF-κB and AP-1 by stimulating HEK-Blue hTLR9 cells with TLR9 ligands. Thus, reporter expression was reduced by TLR9 antagonists for 20 h of incubation under the stimulation of ligands such as ODN2006 (catalog number: tlrl-2006-1, Invivogen, San Diego, CA, USA). The activity of the SEAP reporter in cell culture supernatants was measured using QUANTI-Blue 商標The detection medium turned purple or blue in the presence of alkaline phosphatase, measured at a wavelength of 640 nm using a kit (catalog number: rep-qb1, Invivogen, San Diego, CA, USA).

[0174] HEK293-Blue-hTLR9 cells were incubated at a density of 250,000–450,000 cells / mL in a volume of 170 μL in 96-well plates in Dulbecco's Modified Eagle Medium (DMEM) containing 4.5 g / L glucose, 50 U / mL penicillin, 50 mg / mL streptomycin, 100 mg / mL normocin, 2 mM L-glutamine, 10% (v / v) heat-inactivated fetal bovine serum, with 20 μL of test compound serially diluted in the presence of 1% final DMSO and 10 μL of 20 μM ODN2006 in the above DMEM, at CO. 2 Incubation was performed at 37°C for 20 hours in an incubator. Then, 20 μL of supernatant from each well was incubated with 180 μL of Quanti-blue substrate solution at 37°C for 2 hours, and the absorbance was read at 620-655 nm using a spectrophotometer. Since the signaling pathway in which TLR8 activation leads to downstream NF-κB activation is widely accepted, a similar reporter assay was modified for the evaluation of TLR9 antagonists.

[0175] The compounds of formula (I) have TLR7 and / or TLR8 inhibitory activity (IC 50 In addition, most of the compounds have TLR9 inhibitory activity of less than 0.3 μM. The activity data of the compounds of the present invention are shown in Table 1.

[0176] Table 1: Activity of compounds of the invention in the HEK293-Blue-hTLR-7 / 8 / 9 cell assay [Table 1]

[0177] Example 30 Human microsome stability assay Human liver microsomes (Cat. No.: 452117, Corning, USA) were preincubated with test compounds in 100 mM potassium phosphate buffer (pH 7.4) at 37 °C for 10 min. The reaction was started by adding an NADPH regenerating system. The final incubation mixture contained 1 μM test compound, 0.5 mg / mL liver microsomal protein, 1 mM MgCl in 100 mM potassium phosphate buffer (pH 7.4). 2 , 1 mM NADP, 1 unit / mL isocitrate dehydrogenase and 6 mM isocitrate. After incubation times of 0, 3, 6, 9, 15 and 30 min at 37 °C, 300 μL of cold ACN (containing the internal standard) was added to 100 μL of the incubation mixture to terminate the reaction. After precipitation and centrifugation, 100 μL of the supernatant was removed and 300 μL of water was added. The amount of compound remaining in the sample was measured by LC-MS / MS. Controls without the NADPH regenerating system at 0 and 30 min were also prepared and analyzed. The results were classified as low (<7.0 mL / min / kg), medium (7.0-16.2 mL / min / kg) and high (16.2-23.2 mL / min / kg). The test results are summarized in Table 2.

[0178] Table 2: Human microsome stability results [Table 2]

[0179] Example 31 hERG channel inhibition assay The hERG channel inhibition assay is a highly sensitive measure to identify compounds that exhibit hERG inhibition associated with cardiotoxicity in vivo. + The channel was cloned in human and stably expressed in a CHO (Chinese Hamster Ovary) cell line. hERG The cells were used for patch clamp (voltage clamp, whole cell) experiments. The cells were stimulated with a voltage pattern to activate the hERG channel and induce I KhERGThe cells were allowed to stabilize for a few minutes, after which the I KhERG The amplitude and kinetics of I was recorded at a stimulation frequency of 0.1 Hz (6 bpm). Test compounds were then added to the preparation in increasing concentrations. Each concentration was tried until a steady state was reached, usually achieved within 3-10 min, at which point the next higher concentration was applied. KhERG The amplitude and kinetics of the responses are recorded at each concentration of drug compared to the control value (set at 100%). (Reference: Redfern WS, Carlsson L, Davis AS, Lynch WG, MacKenzie I, Palethorpe S, Siegl PK, Strang I, Sullivan AT, Wallis R, Camm AJ, Hammond TG. 2003; Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc. Res. 58:32-45, Sanguinetti MC, Tristani-Firouzi M. 2006; hERG potassium channels and cardiac arrhythmia. Nature 440:463-469, Webster R, Leishman D, Walker D. 2002; Towards a drug concentration effect relationship for QT prolongation and torsades de pointes. Curr. Opin. Drug Discov. Devel. 5:116-26). The hERG results are shown in Table 3.

[0180] Table 3: hERG results [Table 3]

Claims

1. Compounds of formula (I): 【Chemistry 1】 (In the formula, R １ teeth, 【Chemistry 2】 where R ４ is C １－６ Alkyl, C １－６ Alkoxy, HaloC １－６ alkyl, halogen, nitro or cyano; R ４ａ is C １－６ Alkyl or C ３－７ is cycloalkyl; R ５ , R ５ａ and R ５ｂ is independently selected from H and deuterium; R ６ is H or a halogen; R ２ is C １－６ is alkyl; R ３ is a 5-7 membered monocyclic aryl or heteroaryl; or a 7-12 membered bicyclic heterocyclyl; n is 0, 1 or 2. or a pharma- ceutically acceptable salt thereof.

2. R ３ but, 1,2,3,4-tetrahydroisoquinolinyl; 5,6,7,8-tetrahydro-1,6-naphthyridinyl; 5,6,7,8-tetrahydro-1,7-naphthyridinyl; 5,6,7,8-tetrahydro-2,6-naphthyridinyl; 5,6,7,8-tetrahydro-2,7-naphthyridinyl; phenyl substituted with morpholinyl; piperazinyl substituted pyrazinyl; Halogen, piperazinyl, aminohalopyrrolidinyl, amino-1,4-oxazepanyl and amino(C １－６ pyridinyl substituted by 1 or 2 substituents independently selected from (alkoxy)pyrrolidinyl; or Piperazinyl or amino (C １－６ Alkoxy)pyrrolidinyl-substituted pyrimidinyl 2. The compound of claim 1, wherein:

3. Compound of formula (Ia): 【Chemistry 3】 [In the formula, R １ teeth, 【Chemistry 4】 where R ４ is C １－６ Alkyl, C １－６ Alkoxy, HaloC １－６ alkyl, halogen, nitro or cyano; R ４ａ is C １－６ Alkyl or C ３－７ is cycloalkyl; R ５ , R ５ａ and R ５ｂ is independently selected from H and deuterium; R ６ is H or a halogen; R ２ is C １－６ is alkyl; R ３ is 1,2,3,4-tetrahydroisoquinolinyl; 5,6,7,8-tetrahydro-1,6-naphthyridinyl; 5,6,7,8-tetrahydro-1,7-naphthyridinyl; 5,6,7,8-tetrahydro-2,6-naphthyridinyl; 5,6,7,8-tetrahydro-2,7-naphthyridinyl; phenyl substituted with morpholinyl; piperazinyl substituted pyrazinyl; Halogen, piperazinyl, aminohalopyrrolidinyl, amino-1,4-oxazepanyl and amino(C １－６ pyridinyl substituted by 1 or 2 substituents independently selected from (alkoxy)pyrrolidinyl; or Piperazinyl or amino (C １－６ alkoxy)pyrrolidinyl substituted pyrimidinyl; n is 0, 1 or 2. or a pharma- ceutically acceptable salt thereof.

4. R １ but, 【Chemistry 5】 where R ４ is cyano; R ４ａ is C １－６ alkyl; R ５ is H; R ６ is H or a halogen; 4. The compound according to claim 2 or 3, wherein n is 0 or 1, or a pharma- ceutically acceptable salt thereof.

5. R １ but, 【Chemistry 6】 where R ４ is cyano; R ４ａ is methyl; R ５ is H; R ６ is H or fluoro; R ２ is methyl; R ３ is 1,2,3,4-tetrahydroisoquinolin-6-yl; 1,2,3,4-tetrahydroisoquinolin-7-yl; 5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl; 5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl; 5,6,7,8-tetrahydro-1,7-naphthyridin-2-yl; 5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl; 5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl; 5,6,7,8-tetrahydro-2,7-naphthyridin-4-yl; morpholin-2-ylphenyl; Piperazin-1-ylpyrazinyl; pyridinyl substituted by 1 or 2 substituents independently selected from fluoro, piperazin-1-yl, 3-amino-4-fluoro-pyrrolidin-1-yl, 6-amino-1,4-oxazepan-4-yl and 3-amino-4-methoxy-pyrrolidin-1-yl; or pyrimidinyl substituted with piperazin-1-yl or 3-amino-4-methoxy-pyrrolidin-1-yl; 5. The compound of claim 4, or a pharma- ceutically acceptable salt thereof, wherein n is 0 or 1.

6. R １ but, 【Chemistry 7】 where R ４ is cyano; R ５ is H; or a pharma- ceutically acceptable salt thereof.

7. R ３ 5,6,7,8-tetrahydro-2,6-naphthyridinyl; 5,6,7,8-tetrahydro-2,7-naphthyridinyl; amino (C １－６ 7. The compound of claim 6, which is pyridinyl substituted with alkoxy)pyrrolidinyl; or pyrimidinyl substituted with piperazinyl; or a pharma- ceutically acceptable salt thereof.

8. R ３ The compound according to claim 7, or a pharma- ceutically acceptable salt thereof, wherein is 5,6,7,8-tetrahydro-2,7-naphthyridin-4-yl; 5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl; piperazin-1-ylpyridinyl; or 3-amino-4-methoxy-pyrrolidin-1-ylpyridinyl.

9. R １ but, 【Chemistry 8】 where R ４ is cyano; R ５ is H; R ２ is C １－６ is alkyl; R ３ is 5,6,7,8-tetrahydro-2,6-naphthyridinyl; 5,6,7,8-tetrahydro-2,7-naphthyridinyl; amino (C １－６ pyridinyl substituted with alkoxy)pyrrolidinyl; or pyrimidinyl substituted with piperazinyl; 5. The compound of claim 4, or a pharma- ceutically acceptable salt thereof, wherein n is 0 or 1.

10. R １ but, 【Chemistry 9】 where R ４ is cyano; R ５ is H; R ２ is methyl; R ３ is 5,6,7,8-tetrahydro-2,7-naphthyridin-4-yl; 5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl; piperazin-1-ylpyrimidinyl; or 3-amino-4-methoxy-pyrrolidin-1-ylpyridinyl; 10. The compound of claim 9, or a pharma- ceutically acceptable salt thereof, wherein n is 0 or 1.

11. below: 5-[(4R,10aS)-4-methyl-8-(6-piperazin-1-yl-3-pyridyl)-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-4-methyl-8-(2-piperazin-1-ylpyrimidin-5-yl)-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-4-methyl-8-[4-[(2S)-morpholin-2-yl]phenyl]-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-4-methyl-8-(5,6,7,8-tetrahydro-2,7-naphthyridin-4-yl)-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-4-methyl-8-(5,6,7,8-tetrahydro-1,7-naphthyridin-2-yl)-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-4-methyl-8-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-4-methyl-8-(5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-4-methyl-8-(5,6,7,8-tetrahydro-2,7-naphthyridin-3-ylmethyl)-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-4-methyl-8-(5,6,7,8-tetrahydro-2,6-naphthyridin-3-ylmethyl)-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-4-methyl-8-(5,6,7,8-tetrahydro-1,6-naphthyridin-3-ylmethyl)-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-4-methyl-8-(1,2,3,4-tetrahydroisoquinolin-6-ylmethyl)-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-4-methyl-8-(1,2,3,4-tetrahydroisoquinolin-7-ylmethyl)-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-4-methyl-8-[(5-piperazin-1-ylpyrimidin-2-yl)methyl]-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-4-methyl-8-[(2-piperazin-1-ylpyrimidin-5-yl)methyl]-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-4-methyl-8-[(5-piperazin-1-ylpyrazin-2-yl)methyl]-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-4-methyl-8-[(5-piperazin-1-yl-3-pyridyl)methyl]-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-4-methyl-8-[(6-piperazin-1-yl-3-pyridyl)methyl]-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-4-methyl-8-[(6-piperazin-1-yl-2-pyridyl)methyl]-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-4-methyl-8-[(5-piperazin-1-yl-2-pyridyl)methyl]-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-8-[[5-[(3R,4S)-3-amino-4-fluoro-pyrrolidin-1-yl]-2-pyridyl]methyl]-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-8-[[5-[(6R)-6-amino-1,4-oxazepan-4-yl]-2-pyridyl]methyl]-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-8-[[5-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]-2-pyridyl]methyl]-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-8-[(3-fluoro-5-piperazin-1-yl-2-pyridyl)methyl]-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 5-[(4R,10aS)-8-[[5-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]-3-fluoro-2-pyridyl]methyl]-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile; 4-[(4R,10aS)-8-[[5-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]pyrazin-2-yl]methyl]-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile; 4-[(4R,10aS)-8-[[5-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]-3-fluoro-2-pyridyl]methyl]-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile; 4-[(4R,10aS)-8-[[5-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]-3-fluoro-2-pyridyl]methyl]-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile; and 4-[(4R,10aS)-4-methyl-8-(1,2,3,4-tetrahydroisoquinolin-7-ylmethyl)-1,3,4,6,7,9,10,10a-octahydropyrazino[1,2-d][1,4]diazepin-2-yl]-1-methyl-1,8-naphthyridin-2-one or a pharma- ceutically acceptable salt thereof.

12. A method for preparing a compound according to any one of claims 1 to 11 or a pharma- ceutically acceptable salt thereof, comprising the steps of: Compound of formula (IX) 【Chemistry 10】 and amine (X) 【Chemistry 11】 Buchwald-Hartwig amination reaction or nucleophilic substitution between where n is 0, 1 or 2; X is a halogen; R ８ is aryl or heteroaryl; R ９ and R １０ together with the nitrogen atom to which they are attached form a heterocyclyl) A method comprising:

13. A method for producing a compound according to any one of claims 1 to 11 or a pharma- ceutically acceptable salt thereof, comprising the steps of: Compound of formula (V) 【Chemistry 12】 and a compound of formula (VI) 【Chemistry 13】 Buchwald-Hartwig amination reaction or nucleophilic substitution between where n is 0, 1 or 2; Y is halogen or methanesulfonate; and R 7 is aryl or heteroaryl. Includes, a method.

14. 12. A compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, for use as a therapeutically active substance.

15. 12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 or a pharma- ceutically acceptable salt thereof.

16. 16. The pharmaceutical composition according to claim 15 for the treatment or prevention of systemic lupus erythematosus or lupus nephritis.

17. The pharmaceutical composition according to claim 15, for use as at least one selected from the group consisting of a TLR7 antagonist, a TLR8 antagonist, and a TLR9 antagonist.

18. 12. Use of a compound according to any one of claims 1 to 11 or a pharma- ceutically acceptable salt thereof for the preparation of a medicament for the treatment or prevention of systemic lupus erythematosus or lupus nephritis.

19. 12. Use of a compound according to any one of claims 1 to 11 or a pharma- ceutically acceptable salt thereof for the preparation of a medicament for use as at least one selected from the group consisting of a TLR7 antagonist, a TLR8 antagonist, and a TLR9 antagonist.

20. 12. A compound according to any one of claims 1 to 11 or a pharma- ceutically acceptable salt thereof for the treatment or prevention of systemic lupus erythematosus or lupus nephritis.

21. A compound according to any one of claims 1 to 11 or a pharma- ceutically acceptable salt thereof for use as at least one selected from the group consisting of a TLR7 antagonist, a TLR8 antagonist, and a TLR9 antagonist.

Images