Hexahydro-1H-pyrazino[1,2-a]pyrazine compounds for treating autoimmune diseases

Abstract

The present invention relates to compounds of formula (I), #imgabs0# wherein R 1 To R 3 , n and A are as described herein, and pharmaceutically acceptable salts thereof, as well as compositions comprising the compounds and methods of using the compounds.

Description

Technical Field

[0001] The present invention relates to organic compounds that can be used for the treatment and / or prevention of mammals, and in particular to antagonists of TLR7 and / or TLR8 and / or TLR9 that can be used for the treatment of systemic lupus erythematosus or lupus nephritis. Background Art

[0002] Autoimmune connective tissue disease (CTD) includes typical autoimmune syndromes, such as systemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSjS), mixed connective tissue disease (MCTD), dermatomyositis / polymyositis (DM / PM), rheumatoid arthritis (RA) and systemic sclerosis (SSc). Except RA, there is no real effective and safe therapy for patients. SLE represents a typical CTD, with a prevalence of 20-150 / 100,000, and causes extensive inflammation and tissue damage in different organs, from common symptoms of skin and joints to kidney, lung or heart failure. Traditionally, SLE has been treated with nonspecific anti-inflammatory drugs or immunosuppressants. However, long-term use of immunosuppressive drugs, for example, corticosteroids are only partially effective, and are accompanied by unexpected toxicity and side effects. Belimumab is the only FDA-approved drug for lupus in the past 50 years, although it has only a modestly delayed efficacy in some SLE patients (Navarra, SV et al., Lancet 2011, 377, 721.). Other biologics, such as anti-CD20 mAbs, mAbs against specific cytokines or their soluble receptors, have failed in most clinical studies. Therefore, new therapies are needed that provide sustained improvement in a larger proportion of patient groups and are safer for long-term use in many autoimmune and autoinflammatory diseases.

[0003] Toll-like receptors (TLR) are an important family of pattern recognition receptors (PRRs), which can trigger a wide range of immune responses in a variety of immune cells. Endosome TLR 7, TLR8 and TLR9, as natural host defense sensors, can identify nucleic acids derived from viruses and bacteria; specifically, TLR7 / TLR8 and TLR9 recognize single-stranded RNA (ssRNA) and single-stranded CpG-DNA, respectively. However, the abnormal nucleic acid sensing of TLR7, TLR8 and TLR9 is considered to be a key node of extensive autoimmunity and autoinflammatory diseases (Krieg, AM et al., Immunol. Rev. 2007, 220, 251. Jiménez-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 recognized diagnostic markers for SLE, and these antibodies can deliver both self-RNA and self-DNA to endosomes. Self-RNA complexes can be recognized by TLR7 and TLR8, while self-DNA complexes can trigger TLR9 activation. In fact, defective clearance of self-RNA and self-DNA from blood and / or tissues is evident in patients with SLE (systemic lupus erythematosus). TLR7 and TLR9 have been reported to be upregulated in SLE tissues and are associated with the chronicity and activity of lupus nephritis, respectively. In B cells of SLE patients, TLR7 expression is associated with the production of anti-RNP antibodies, while TLR9 expression is associated with IL-6 and anti-dsDNA antibody levels. Consistently, in a lupus mouse model, anti-RNA antibodies require TLR7 and anti-nucleosome antibodies require TLR9. On the other hand, overexpression of TLR7 or human TLR8 in mice promotes autoimmunity and autoinflammation. In addition, activation of TLR8 is particularly conducive to inflammatory cytokine secretion by mDC / macrophages, neutrophil extracellular trapping process (NETosis), induction of Th17 cells and suppression of Treg cells. In addition to the described role of TLR9 in promoting B cell autoantibody production, activation of TLR9 by self-DNA in pDCs also leads to the induction of type I interferons and other inflammatory cytokines. Given these roles of TLR9 in both pDCs and B cells, both of which are key players in the pathogenesis of autoimmune diseases, and the abundance of self-DNA complexes that readily activate TLR9 in many patients with autoimmune diseases, it may have additional benefits to further block the self-DNA-mediated TLR9 pathway in addition to inhibiting the TLR7 and TLR8 pathways.In summary, TLR7, 8 and 9 pathways represent 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 inhibition of all of these pathways very upstream may lead to satisfactory therapeutic effects. Therefore, we have invented oral compounds that target and inhibit 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) or (Ib),

[0005]

[0006] in

[0007] R 1 for Where R 4 C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogen, nitro or cyano; R 4a 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 halogen;

[0008] R 2 H or C 1-6 alkyl;

[0009] R 3 is H;

[0010] Ring A is a 5-7 membered monocyclic aromatic or heteroaromatic group; or a 7-12 membered bicyclic heterocyclic group;

[0011] or a pharmaceutically acceptable salt thereof.

[0012] Another object of the present invention relates to novel compounds of formula (I) or (Ia), their production, drugs based on 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. The compounds of formula (I) or (Ia) show excellent TLR7 and / or TLR8 and / or TLR9 antagonist activity. In addition, the compounds of formula (I) or (Ia) also show good cytotoxicity, phototoxicity, solubility, hPBMC, human microsomal stability and SDPK characteristics, as well as low CYP inhibition. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 .X-ray structure of compound N

[0014] Figure 2 .X-ray structure of compound P

[0015] Figure 3A . After 1 week of treatment with Example 106 or the control immunosuppressant MMF, the level of IP-10 in mouse serum was measured

[0016] Figure 3B After 2 weeks of treatment with Example 106 or the control immunosuppressant MMF, the level of anti-dsDNA antibodies in mouse serum was measured.

[0017] Figure 3C .After 5 weeks of treatment with Example 106 or the control immunosuppressant MMF, urine samples were collected. The levels of urine albumin (UALB) and urine creatinine (UCR) were measured to calculate the urine albumin to creatinine ratio (UACR)

[0018] Figure 3D . After 6 weeks of treatment with Example 106 or the control immunosuppressant MMF, the spleen was collected and weighed DETAILED DESCRIPTION

[0019] definition

[0020] The term "C 1-6 "Alkyl" means a saturated, straight-chain or branched alkyl group containing 1 to 6, especially 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc. In particular, "C 1-6 "Alkyl" groups are methyl, ethyl and n-propyl.

[0021] The terms "halogen" and "halo" are used interchangeably herein to refer to fluorine, chlorine, bromine or iodine.

[0022] The term "halogenated C 1-6 "Alkyl" means C 1-6 Alkyl groups, where C1-6 At least one hydrogen atom of the alkyl group has been replaced by identical or different halogen atoms, in particular fluorine atoms. 1-6 Examples of alkyl include monofluoro-, difluoro- or trifluoro-methyl, -ethyl or -propyl, such as 3,3,3-trifluoropropyl, 2-fluoroethyl, trifluoroethyl, fluoromethyl, difluoromethyl, difluoroethyl or trifluoromethyl.

[0023] The term "halopyrrolidinyl" refers to a pyrrolidinyl group substituted once, twice or three times with halogen. Examples of halopyrrolidinyl groups include, but are not limited to, difluoropyrrolidinyl and fluoropyrrolidinyl.

[0024] The term "C 3-7 "Cycloalkyl" means a saturated carbocyclic ring containing 3 to 7 carbon atoms, especially 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. In particular, "C 3-7 "Cycloalkyl" groups are cyclopropyl, cyclopentyl and cyclohexyl.

[0025] The term "aryl" refers to an aromatic hydrocarbon monovalent or bicyclic ring system having 5 to 12 ring atoms. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. Aryl groups may be further substituted with substituents, including, but 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]heptyl; 5-oxa-2,8-diazaspiro[3.5]nonyl; amino-1,4-oxazacycloheptyl; substituted by one or two independently selected from amino and C 1-6 Alkyl substituted with azetidinyl; unsubstituted or with C 1-6 alkyl-substituted piperazinyl; and one or two independently selected from amino, C 1-6 The pyrrolidinyl group is substituted with alkoxy and halogen substituents.

[0026] The term "heteroaryl" refers to an aromatic heterocyclic monocyclic or bicyclic ring system having 5 to 12 ring atoms, containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Examples of heteroaryl moieties include, but are not limited to, 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, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolyl, isoquinolyl, quinazolinyl or quinoxalinyl. The heteroaryl group may be further substituted with substituents, including but 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]heptyl; 5-oxa-2,8-diazaspiro[3.5]nonyl; amino-1,4-oxazacycloheptyl; substituted by one or two independently selected from amino and C 1-6 Alkyl substituted with azetidinyl; unsubstituted or with C 1-6 alkyl-substituted piperazinyl; and one or two independently selected from amino, C 1-6 The pyrrolidinyl group is substituted with alkoxy and halogen substituents.

[0027] The term "heterocyclyl" or "heterocycle" refers to a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system having 3 to 12 ring atoms, which contains 1 to 5 heteroatoms selected from N, O and S, and the remaining ring atoms are carbon. In specific embodiments, the heterocyclyl is a monovalent saturated monocyclic ring system of 4 to 7 ring atoms, which contains 1, 2 or 3 ring heteroatoms selected from N, O and S, and the remaining ring atoms are carbon. Examples of monocyclic saturated heterocyclyl are aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, oxazepanyl. Examples of bicyclic saturated heterocycles are azabicyclo[3.2.1]octyl, quinuclidinyl, oxazabicyclo[3.2.1]octyl, azabicyclo[3.3.1]nonyl, oxaza-bicyclo[3.3.1]nonyl, 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 heterocyclic groups include, but are not limited to, 2,5-diazabicyclo[2.2.1]heptyl; 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl; 3,6-diazabicyclo[3.1.1]heptyl; 3,8-diazabicyclo[3.2.1]octanyl; 5-oxa-2,8-diazaspiro[3.5]nonanyl; 9-oxa-3,7-diazabicyclo[3.3.1]nonanyl; 2,6-diazaspiro[3.3]heptanecarbonyl; 1,2,3,4-tetrahydroisoquinolinyl; 5,6,7,8-tetrahydro-1,6-naphthyridinyl; 5,6,7,8-tetrahydro-2,6-naphthyridinyl; 5,6,7,8-tetrahydro-2,7-naphthyridinyl; isoindolyl.

[0028] The terms "cis isomers" and "trans isomers" refer to the relative stereochemistry of a molecule or moiety. For example: Intermediate B As "trans isomer" refers to Similarly, intermediate A As "cis isomer" refers to The manner in which the relative stereochemistry is shown also applies to the final compound.

[0029] The term "pharmaceutically acceptable salts" refers to salts that are not biologically or otherwise undesirable. "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts.

[0030] "Pharmaceutically acceptable acid addition salts" refer to those pharmaceutically acceptable salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and the like, and organic acids, which may be selected from aliphatic, alicyclic, aromatic, aromatic aliphatic, heterocyclic, carboxylic and sulfonic acid organic 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, pamoic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid, and the like.

[0031] The term "pharmaceutical base addition salt" refers to those pharmaceutical salts formed with organic or inorganic bases. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese and aluminum salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines and basic ion exchange resins (such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine and polyamine resins).

[0032] The term "pharmaceutically active metabolite" refers to a pharmacologically active product produced by the metabolism of a specific compound or its salt in the body. After entering the human body, most drugs are substrates for chemical reactions that may change their physical properties and biological effects. These metabolic transformations, which usually affect the polarity of the compounds of the present invention, change the way the drug is distributed in the body and excreted from the body. However, in some cases, drug metabolism is necessary for therapeutic effects.

[0033] 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 as described herein. The therapeutically effective amount depends on the compound, the disease state 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 medical or veterinary doctor and other factors.

[0034] The term "pharmaceutical composition" means a mixture or solution comprising a therapeutically effective amount of an active drug ingredient together with a pharmaceutically acceptable excipient for administration to a mammal (eg, a human) in need thereof.

[0035] Antagonists of TLR7 and / or TLR8 and / or TLR9

[0036] The present invention relates to (i), which is a compound of formula (I),

[0037]

[0038] in

[0039] R 1 for Where R 4 C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogen, nitro or cyano; R 4a 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 halogen;

[0040] R 2 H or C 1-6 alkyl;

[0041] R 3 is H;

[0042] Ring A is an unsubstituted or substituted 5-7 membered monocyclic aryl or heteroaryl group; or an unsubstituted or substituted 7-12 membered bicyclic heterocyclic group;

[0043] n is 0, 1 or 2;

[0044] or a pharmaceutically acceptable salt thereof.

[0045] A further embodiment of the present invention is (ii), which is a compound of formula (I), wherein

[0046] Ring A is 1,2,3,4-tetrahydroisoquinolinyl;

[0047] 5,6,7,8-Tetrahydro-1,6-naphthyridinyl;

[0048] 5,6,7,8-Tetrahydro-2,6-naphthyridinyl;

[0049] 5,6,7,8-Tetrahydro-2,7-naphthyridinyl;

[0050] Isoindolyl;

[0051] Amino (C 1-6phenyl substituted with 5-oxa-2,8-diazaspiro[3.5]nonyl, morpholinyl or piperazinyl;

[0052] Pyridinyl substituted once or twice with substituents independently selected from: (halopyrrolidinyl)amino; 1,4-diazacycloheptyl; 2,5-diazabicyclo[2.2.1]heptyl; 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl; 3,6-diazabicyclo[3.1.1]heptyl; 3,8-diazabicyclo[3.2.1]octanyl; 5-oxa-2,8-diazaspiro[3.5]nonanyl; 9-oxa-3,7-diazabicyclo[3.3.1]nonanyl; amino(C 1-6 Alkoxy) pyrrolidinyl; amino (C 1-6 alkyl)azetidinyl; amino (C 1-6 alkyl) pyrrolidinyl; amino-1,4-oxazepanyl; amino-2-azaspiro[3.3]heptyl; aminoazetidinyl; aminohalogenated pyrrolidinyl; C 1-6 Alkyl; C 1-6 Alkyl-2,6-diazaspiro[3.3]heptanecarbonyl; C 1-6 Alkyl-2,6-diazaspiro[3.3]heptyl; C 1-6 Alkylpiperazinyl and piperazinyl; or

[0053] Pyrimidinyl substituted once or twice by substituents independently selected from: amino (C 1-6 Alkoxy) pyrrolidinyl, amino (C 1-6 alkyl)azetidinyl, aminoazetidinyl, C 1-6 Alkyl and piperazinyl.

[0054] Another embodiment of the present invention is (iii) a compound of formula (Ib),

[0055] in

[0056] R 1 for Where R 4 C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogen, nitro or cyano; R 4a C 1-6 Alkyl or C 3-7 Cycloalkyl; R 5 , R 5a and R 5b are independently selected from H and deuterium; R6 is H or halogen;

[0057] R 2 H or C 1-6 alkyl;

[0058] R 3 is H;

[0059] Ring A is 1,2,3,4-tetrahydroisoquinolinyl;

[0060] 5,6,7,8-Tetrahydro-1,6-naphthyridinyl;

[0061] 5,6,7,8-Tetrahydro-2,6-naphthyridinyl;

[0062] 5,6,7,8-Tetrahydro-2,7-naphthyridinyl;

[0063] Isoindolyl;

[0064] Amino (C 1-6 phenyl substituted with 5-oxa-2,8-diazaspiro[3.5]nonyl, morpholinyl or piperazinyl;

[0065] Pyridinyl substituted once or twice with substituents independently selected from: (halopyrrolidinyl)amino; 1,4-diazacycloheptyl; 2,5-diazabicyclo[2.2.1]heptyl; 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl; 3,6-diazabicyclo[3.1.1]heptyl; 3,8-diazabicyclo[3.2.1]octanyl; 5-oxa-2,8-diazaspiro[3.5]nonanyl; 9-oxa-3,7-diazabicyclo[3.3.1]nonanyl; amino(C 1-6 Alkoxy) pyrrolidinyl; amino (C 1-6 alkyl)azetidinyl; amino (C 1-6 alkyl) pyrrolidinyl; amino-1,4-oxazepanyl; amino-2-azaspiro[3.3]heptyl; aminoazetidinyl; aminohalogenated pyrrolidinyl; C 1-6 Alkyl; C 1-6 Alkyl-2,6-diazaspiro[3.3]heptanecarbonyl; C 1-6 Alkyl-2,6-diazaspiro[3.3]heptyl; C 1-6 Alkylpiperazinyl and piperazinyl; or

[0066] Pyrimidinyl substituted once or twice by substituents independently selected from: amino (C 1-6 Alkoxy) pyrrolidinyl, amino (C 1-6 alkyl)azetidinyl, aminoazetidinyl, C1-6 Alkyl and piperazinyl;

[0067] n is 0, 1 or 2;

[0068] or a pharmaceutically acceptable salt thereof.

[0069] Another embodiment of the present invention is (iv) a compound of formula (I) or (Ia) or (Ib) or a pharmaceutically acceptable salt thereof according to any one of (i) to (iii), wherein R 1 for Where R 4 is cyano; R 4a C 1-6 Alkyl; R 5 is H or deuterium; R 6 For H.

[0070] Another embodiment of the present invention is (v) a compound of formula (I) or (Ia) or (Ib) or a pharmaceutically acceptable salt thereof according to any one of (i) to (iv), wherein R 2 C 1-6 alkyl.

[0071] Another embodiment of the present invention is (vi) a compound of formula (I) or (Ia) or (Ib) or a pharmaceutically acceptable salt thereof according to any one of (i) to (v), wherein

[0072] R 1 for Where R 4 is cyano; R 4a C 1-6 Alkyl; R 5 is H or deuterium; R 6 is H;

[0073] R 2 is methyl;

[0074] R 3 is H;

[0075] Ring A is 1,2,3,4-tetrahydroisoquinolin-7-yl; 1,2,3,4-tetrahydroisoquinolin-5-yl; 1,2,3,4-tetrahydroisoquinolin-6-yl; 1,2,3,4-tetrahydroisoquinolin-7-yl; 1,2,3,4-tetrahydroisoquinolin-8-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-2,6-naphthyridin-1-yl; 5,6,7,8-tetrahydro-2,7-naphthyridin-4-yl; isoindolin-4-yl; 3-amino-4-methoxy-pyrrolidin-1-ylphenyl; 5-oxa-2,8-diazaspiro[3.5]nonan-2-ylphenyl; morpholin-2-ylphenyl ; piperazin-1-ylphenyl; (4-fluoropyrrolidin-3-yl)amino(methyl)pyridinyl; 1,4-diazacycloheptane-1-ylpyridinyl; 2,5-diazabicyclo[2.2.1]heptane-2-yl(methyl)pyridinyl; 2,5-diazabicyclo[2.2.1]heptane-2-ylpyridinyl; 2-methylpiperazin-1-yl(methyl)pyridinyl; 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl(methyl)pyridinyl; (3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl)pyridinyl; 3,6-diazabicyclo[3.1.1]heptane-3-yl(methyl) Pyridinyl; 3,8-diazabicyclo[3.2.1]octan-3-yl(methyl)pyridinyl; 3,8-diazabicyclo[3.2.1]octan-3-ylpyridinyl; 3-amino-3-methyl-azetidin-1-yl(methyl)pyridinyl; 3-amino-3-methyl-azetidin-1-ylpyridinyl; 3-amino-3-methyl-pyrrolidin-1-yl(methyl)pyridinyl; 3-amino-3-methyl-pyrrolidin-1-ylpyridinyl; 3-amino-4-fluoro-pyrrolidin-1-ylpyridinyl; 3-amino-4-methoxy-pyrrolidin-1-yl(methyl)pyridinyl; 3-amino-4-methoxy-pyrrolidin-1-ylpyridinyl; 3-aminoazetidin-1-ylpyridinyl; 3-methylpiperidin-1 oxazine-1-yl(methyl)pyridinyl; 3-methylpiperazine-1-ylpyridinyl; 5-oxa-2,8-diazaspiro[3.5]nonan-2-ylpyridinyl; 6-amino-1,4-oxazacycloheptane-4-yl(methyl)pyridinyl; 6-amino-1,4-oxazacycloheptane-4-ylpyridinyl; 6-amino-2-azaspiro[3.3]heptane-2-yl(methyl)pyridinyl; 6-methyl-2,6-diazaspiro[3.3]heptane-2-yl(methyl)pyridinyl; 6-methyl-2,6-diazaspiro[3.3]heptane-2-ylpyridinyl; 6-methyl-2,6-diazaspiro[3.3]heptane-2-carbonyl(methyl)pyridinyl; 9-oxa-3,7-diazabicyclo[3.3.1] Nonan-3-yl (methyl) pyridinyl; piperazin-1-yl (methyl) pyridinyl; piperazin-1-yl pyridinyl; 3-amino-3-methyl-azetidin-1-yl (methyl) pyrimidinyl; 3-amino-4-methoxy-pyrrolidin-1-yl (methyl) pyrimidinyl; 3-amino-4-methoxy-pyrrolidin-1-yl pyrimidinyl; 3-aminoazetidin-1-yl pyrimidinyl; piperazin-1-yl (methyl) pyrimidinyl or piperazin-1-yl pyrimidinyl;.

[0076] n is 0, 1 or 2;

[0077] or a pharmaceutically acceptable salt thereof.

[0078] Another embodiment of the present invention is (vii) a compound of formula (I) or (Ia) or (Ib) or a pharmaceutically acceptable salt thereof according to any one of (i) to (vi), wherein R 1 for Where R 4 is cyano; R 5 is H or deuterium.

[0079] Another embodiment of the present invention is (viii) a compound of formula (I) or (Ia) or (Ib) or a pharmaceutically acceptable salt thereof according to any one of (i) to (vii), wherein

[0080] Ring A is 1,2,3,4-tetrahydroisoquinolinyl;

[0081] Phenyl substituted with morpholinyl;

[0082] Pyridinyl substituted once or twice by substituents independently selected from: 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl; amino(C 1-6 Alkoxy) pyrrolidinyl; amino (C 1-6 alkyl)azetidinyl; aminohalogenated pyrrolidinyl; C 1-6 Alkyl; C 1-6 Alkyl-2,6-diazaspiro[3.3]heptyl and piperazinyl;

[0083] Pyrimidinyl substituted twice by substituents, the substituents being independently selected from: amino (C 1-6 Alkoxy) pyrrolidinyl; amino (C 1-6 alkyl)azetidinyl and C 1-6 alkyl.

[0084] Another embodiment of the present invention is (ix) a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof according to any one of (i) to (viii), wherein Ring A is 1,2,3,4-tetrahydroisoquinolyl; morpholinylphenyl; piperazinylpyridinyl; (amino(C 1-6(aminohalogenated pyrrolidinyl)pyridinyl; piperazinyl (C 1-6 alkyl)pyridinyl; (amino(C 1-6 (C alkyloxy)pyrrolidinyl)pyridinyl; (aminohalopyrrolidinyl)pyridinyl; 1-6 alkyl-2,6-diazaspiro[3.3]heptyl)pyridinyl; (amino(C 1-6 alkyl)azetidinyl)pyridinyl; C 1-6 Alkyl (amino (C 1-6 alkyl)azetidinyl)pyridinyl; 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl (C 1-6 (3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl)pyridinyl; C 1-6 Alkyl (amino (C 1-6 alkyl)azetidinyl)pyrimidinyl or C 1-6 Alkyl (amino (C 1-6 alkoxy)pyrrolidinyl)pyrimidinyl.

[0085] Another embodiment of the present invention is (ix") a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof according to any one of (i) to (viii), wherein Ring A is 1,2,3,4-tetrahydroisoquinolyl; morpholinylphenyl; piperazinylpyridinyl; (amino(C 1-6 (aminohalogenated pyrrolidinyl)pyridinyl; piperazinyl (C 1-6 alkyl)pyridinyl; (amino(C 1-6 (C alkyloxy)pyrrolidinyl)pyridinyl; (aminohalopyrrolidinyl)pyridinyl; 1-6 alkyl-2,6-diazaspiro[3.3]heptyl)pyridinyl; (amino(C 1-6 alkyl)azetidinyl)pyridinyl; C 1-6 Alkyl (amino (C 1-6 alkyl)azetidinyl)pyridinyl; C 1-6 Alkyl(3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl)pyridinyl; C 1-6 Alkyl (amino (C 1-6 alkyl)azetidinyl)pyrimidinyl or C 1-6 Alkyl (amino (C 1-6 alkoxy)pyrrolidinyl)pyrimidinyl.

[0086] Another embodiment of the present invention is (x) a compound of formula (I) or (Ia) or (Ib) according to any one of (i) to (ix), or a pharmaceutically acceptable salt thereof, wherein Ring A is 1,2,3,4-tetrahydroisoquinolin-7-yl; morpholin-2-ylphenyl; (3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl)-2-methyl-3-pyridinyl; (3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl)-3-pyridinyl; (3-amino-4-fluoro-pyrrolidin-1-yl)-3-pyridinyl; (3-amino-4-fluoro-pyrrolidin-1-yl)-3-pyridinyl; -methoxy-pyrrolidin-1-yl)-3-pyridinyl; (3-amino-4-methoxy-pyrrolidin-1-yl)-3-pyridinyl; 2-methyl-6-piperazin-1-yl-3-pyridinyl; 6-(3-amino-3-methyl-azetidin-1-yl)-2-methyl-3-pyridinyl; 6-(3-amino-3-methyl-azetidin-1-yl)-3-pyridinyl; 6-(6-methyl-2,6-diazaspiro[3.3]heptane-2-yl)-3-pyridinyl; 6-piperazin-1-yl-3-pyridinyl; (3-amino-4-methoxy-pyrrolidin-1-yl)-6-methyl-pyrimidin-4-yl or (3-amino-3-methyl-azetidin-1-yl)-6-methyl-pyrimidin-4-yl.

[0087] Another embodiment of the present invention is (x") a compound of formula (I) or (Ia) or (Ib) or a pharmaceutically acceptable salt thereof according to any one of (i) to (ix) and (ix"), wherein Ring A is 1,2,3,4-tetrahydroisoquinolin-7-yl; morpholin-2-ylphenyl; (3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl)-2-methyl-3-pyridinyl; (3-amino-4-fluoro-pyrrolidin-1-yl)-3-pyridinyl; (3-amino-4-fluoro-pyrrolidin-1-yl)-3-pyridinyl; (3-amino-4-methoxy-pyrrolidin-1-yl)-3-pyridinyl; -amino-4-methoxy-pyrrolidin-1-yl)-3-pyridinyl; 2-methyl-6-piperazin-1-yl-3-pyridinyl; 6-(3-amino-3-methyl-azetidin-1-yl)-2-methyl-3-pyridinyl; 6-(3-amino-3-methyl-azetidin-1-yl)-3-pyridinyl; 6-(6-methyl-2,6-diazaspiro[3.3]heptane-2-yl)-3-pyridinyl; 6-piperazin-1-yl-3-pyridinyl; (3-amino-4-methoxy-pyrrolidin-1-yl)-6-methyl-pyrimidin-4-yl or (3-amino-3-methyl-azetidin-1-yl)-6-methyl-pyrimidin-4-yl.

[0088] Another embodiment of the present invention is (xi) a compound of formula (I) or (Ia) or (Ib) or a pharmaceutically acceptable salt thereof according to any one of (i) to (x), wherein

[0089] R 1 for Where R 4 is cyano; R 5 is H or deuterium;

[0090] R 2 C 1-6 alkyl;

[0091] R 3 is H;

[0092] Ring A is 1,2,3,4-tetrahydroisoquinolinyl;

[0093] Phenyl substituted with morpholinyl;

[0094] Pyridinyl substituted once or twice by substituents independently selected from: 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl; amino(C 1-6 Alkoxy) pyrrolidinyl; amino (C 1-6 alkyl)azetidinyl; aminohalogenated pyrrolidinyl; C 1-6 Alkyl; C 1-6 Alkyl-2,6-diazaspiro[3.3]heptyl and piperazinyl;

[0095] Pyrimidinyl substituted twice by substituents, the substituents being independently selected from: amino (C 1-6 Alkoxy) pyrrolidinyl; amino (C 1-6 alkyl)azetidinyl and C 1-6 alkyl;

[0096] n is 0, 1 or 2;

[0097] or a pharmaceutically acceptable salt thereof.

[0098] Another embodiment of the present invention is (xii) a compound of formula (I) or (Ia) or (Ib) according to any one of (i) to (xi), wherein

[0099] R 1 for Where R 4 is cyano; R 5 is H or deuterium;

[0100] R 2 C 1-6 alkyl;

[0101] R 3 is H;

[0102] Ring A is 1,2,3,4-tetrahydroisoquinolyl; morpholinylphenyl; piperazinylpyridinyl; (amino(C 1-6 (aminohalogenated pyrrolidinyl)pyridinyl; piperazinyl (C 1-6 alkyl)pyridinyl; (amino(C 1-6 (C alkyloxy)pyrrolidinyl)pyridinyl; (aminohalopyrrolidinyl)pyridinyl; 1-6 alkyl-2,6-diazaspiro[3.3]heptyl)pyridinyl; (amino(C 1-6 alkyl)azetidinyl)pyridinyl; C 1-6 Alkyl (amino (C 1-6 alkyl)azetidinyl)pyridinyl; 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl (C 1-6 (3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl)pyridinyl; C 1-6 Alkyl (amino (C 1-6 alkyl)azetidinyl)pyrimidinyl or C 1-6 Alkyl (amino (C 1-6 alkoxy)pyrrolidinyl)pyrimidinyl;

[0103] n is 0, 1 or 2;

[0104] or a pharmaceutically acceptable salt thereof.

[0105] Another embodiment of the present invention is (xii") a compound of formula (I) or (Ia) or (Ib) according to any one of (i) to (xi), (ix") and (x"), wherein

[0106] R 1 for Where R 4 is cyano; R 5 is H or deuterium;

[0107] R 2 C 1-6 alkyl;

[0108] R 3 is H;

[0109] Ring A is 1,2,3,4-tetrahydroisoquinolyl; morpholinylphenyl; piperazinylpyridinyl; (amino(C 1-6 (aminohalogenated pyrrolidinyl)pyridinyl; piperazinyl (C 1-6 alkyl)pyridinyl; (amino(C 1-6(C alkyloxy)pyrrolidinyl)pyridinyl; (aminohalopyrrolidinyl)pyridinyl; 1-6 alkyl-2,6-diazaspiro[3.3]heptyl)pyridinyl; (amino(C 1-6 alkyl)azetidinyl)pyridinyl; C 1-6 Alkyl (amino (C 1-6 alkyl)azetidinyl)pyridinyl; C 1-6 Alkyl(3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl)pyridinyl; C 1-6 Alkyl (amino (C 1-6 alkyl)azetidinyl)pyrimidinyl or C 1-6 Alkyl (amino (C 1-6 alkoxy)pyrrolidinyl)pyrimidinyl;

[0110] n is 0, 1 or 2;

[0111] or a pharmaceutically acceptable salt thereof.

[0112] Another embodiment of the present invention is (xiii) a compound of formula (I) or (Ia) or (Ib) according to any one of (i) to (xii), wherein

[0113] R 1 for Where R 4 is cyano; R 5 is H or deuterium;

[0114] R 2 is methyl;

[0115] R 3 is H;

[0116] Ring A is 1,2,3,4-tetrahydroisoquinolin-7-yl; 4-(morpholin-2-yl)phenyl; (3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl)-2-methyl-3-pyridinyl; (3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl)-3-pyridinyl; (3-amino-4-fluoro-pyrrolidin-1-yl)-3-pyridinyl; (3-amino-4-fluoro-pyrrolidin-1-yl)-3-pyridinyl; (3-amino-4-methoxy-pyrrolidin-1-yl)-3-pyridinyl; (3-amino- 4-methoxy-pyrrolidin-1-yl)-3-pyridinyl; 2-methyl-6-piperazin-1-yl-3-pyridinyl; 6-(3-amino-3-methyl-azetidin-1-yl)-2-methyl-3-pyridinyl; 6-(3-amino-3-methyl-azetidin-1-yl)-3-pyridinyl; 6-(6-methyl-2,6-diazaspiro[3.3]heptane-2-yl)-3-pyridinyl; 6-piperazin-1-yl-3-pyridinyl; (3-amino-4-methoxy-pyrrolidin-1-yl)-6-methyl-pyrimidin-4-yl or (3-amino-3-methyl-azetidin-1-yl)-6-methyl-pyrimidin-4-yl;

[0117] n is 0, 1 or 2;

[0118] or a pharmaceutically acceptable salt thereof.

[0119] Another embodiment of the present invention is (xiii") a compound of formula (I) or (Ia) or (Ib) according to any one of (i) to (xii), (ix"), (x") and (xii"), wherein

[0120] R 1 for Where R 4 is cyano; R 5 is H or deuterium;

[0121] R 2 is methyl;

[0122] R 3 is H;

[0123] Ring A is 1,2,3,4-tetrahydroisoquinolin-7-yl; morpholin-2-ylphenyl; (3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl)-2-methyl-3-pyridyl; (3-amino-4-fluoro-pyrrolidin-1-yl)-3-pyridyl; (3-amino-4-fluoro-pyrrolidin-1-yl)-3-pyridyl; (3-amino-4-methoxy-pyrrolidin-1-yl)-3-pyridyl; (3-amino-4-methoxy-pyrrolidin-1-yl)-3-pyridyl; 2-methyl-6 -piperazin-1-yl-3-pyridinyl; 6-(3-amino-3-methyl-azetidin-1-yl)-2-methyl-3-pyridinyl; 6-(3-amino-3-methyl-azetidin-1-yl)-3-pyridinyl; 6-(6-methyl-2,6-diazaspiro[3.3]heptane-2-yl)-3-pyridinyl; 6-piperazin-1-yl-3-pyridinyl; (3-amino-4-methoxy-pyrrolidin-1-yl)-6-methyl-pyrimidin-4-yl or (3-amino-3-methyl-azetidin-1-yl)-6-methyl-pyrimidin-4-yl;

[0124] n is 0, 1 or 2;

[0125] or a pharmaceutically acceptable salt thereof.

[0126] The present invention relates to (i'), which is a compound of formula (I),

[0127]

[0128] in

[0129] R 1 for Where R 4 C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogen, nitro or cyano; R 4a 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 halogen;

[0130] R 2 H or C 1-6 alkyl;

[0131] R 3 is H;

[0132] Ring A is a 5-7 membered monocyclic aromatic or heteroaromatic group; or a 7-12 membered bicyclic heterocyclic group;

[0133] n is 0, 1 or 2;

[0134] or a pharmaceutically acceptable salt thereof.

[0135] Another embodiment of the present invention is a compound of formula (ii'), wherein

[0136] Ring A is 1,2,3,4-tetrahydroisoquinolinyl;

[0137] 5,6,7,8-Tetrahydro-1,6-naphthyridinyl;

[0138] 5,6,7,8-Tetrahydro-2,6-naphthyridinyl;

[0139] 5,6,7,8-Tetrahydro-2,7-naphthyridinyl;

[0140] Isoindolyl;

[0141] or in

[0142] A 1 N or CR a ;

[0143] A 2 N or CR b ;

[0144] A 3 N or CR c ;

[0145] A 4 N or CR d ;

[0146] A 5 N or CR e ;

[0147] Where R a , R b , R c , R d , R e Independently selected from H; 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]heptyl; 5-oxa-2,8-diazaspiro[3.5]nonyl; amino-1,4-oxazacycloheptyl; substituted by one or two independently selected from amino and C 1-6 Alkyl substituted with azetidinyl; unsubstituted or with C1-6 alkyl-substituted piperazinyl; or one or two independently selected from amino, C 1-6 The pyrrolidinyl group is substituted with alkoxy and halogen substituents.

[0148] Another embodiment of the present invention is a compound of formula (Ia) (iii'),

[0149] in

[0150] R 1 for Where R 4 C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogen, nitro or cyano; R 4a 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 halogen;

[0151] R 2 H or C 1-6 alkyl;

[0152] R 3 is H;

[0153] Ring A is 1,2,3,4-tetrahydroisoquinolinyl;

[0154] 5,6,7,8-Tetrahydro-1,6-naphthyridinyl;

[0155] 5,6,7,8-Tetrahydro-2,6-naphthyridinyl;

[0156] 5,6,7,8-Tetrahydro-2,7-naphthyridinyl;

[0157] Isoindolyl;

[0158] or in

[0159] A 1 N or CR a ;

[0160] A 2 N or CR b ;

[0161] A 3 N or CR c ;

[0162] A 4 N or CR d ;

[0163] A 5 N or CR e ;

[0164] Where R a , R b , R c , R d , R e Independently selected from H; 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]heptyl; 5-oxa-2,8-diazaspiro[3.5]nonyl; amino-1,4-oxazacycloheptyl; substituted by one or two independently selected from amino and C 1-6 Alkyl substituted with azetidinyl; unsubstituted or with C 1-6 alkyl-substituted piperazinyl; or one or two independently selected from amino, C 1-6 pyrrolidinyl substituted with alkoxy and halogen substituents;

[0165] n is 0, 1 or 2;

[0166] or a pharmaceutically acceptable salt thereof.

[0167] Another embodiment of the present invention is (iv') a compound of formula (I) or (Ia) or (Ib) or a pharmaceutically acceptable salt thereof according to any one of (i') to (iii'), wherein R 1 for Where R 4 is cyano; R 5 is H or deuterium; R 6 is H or halogen.

[0168] Another embodiment of the present invention is (v') a compound of formula (I) or (Ia) or (Ib) according to any one of (i') to (iv'), wherein

[0169] R 1 for Where R 4 is cyano; R 5 is H or deuterium; R 6 is H or fluorine;

[0170] R 2 is H or methyl;

[0171] R 3 is H;

[0172] Ring A is 1,2,3,4-tetrahydroisoquinolin-5-yl; 1,2,3,4-tetrahydroisoquinolin-6-yl; 1,2,3,4-tetrahydroisoquinolin-7-yl; 1,2,3,4-tetrahydroisoquinolin-8-yl; 1,4-diazepan-1-ylpyridinyl; 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-ylpyridinyl; 3-amino-3-methyl-azetidin-1-yl(methyl)pyridinyl pyrimidine; 3-amino-3-methyl-azetidin-1-yl (methyl) pyrimidine; 3-amino-3-methyl-azetidin-1-yl pyridinyl; 3-amino-4-fluoro-pyrrolidin-1-yl pyridinyl; 3-amino-4-methoxy-pyrrolidin-1-yl (methyl) pyrimidine; 3-amino-4-methoxy-pyrrolidin-1-yl phenyl; 3-amino-4-methoxy-pyrrolidin-1-yl pyridinyl; 3-amino-4-methoxy-pyrrolidin-1-yl pyrimidine 3-aminoazetidin-1-ylpyridinyl; 3-aminoazetidin-1-ylpyrimidinyl; 3-methylpiperazin-1-ylpyridinyl; 5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl; 5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl; 5,6,7,8-tetrahydro-2,7-naphthyridin-4-yl; 5-oxa-2,8-diazaspiro[3.5]nonan-2-ylphenyl; 5-oxa-2,8-diazaspiro[3.5]nonane alkyl-2-ylpyridinyl; 6-amino-1,4-oxazepan-4-yl(methyl)pyridinyl; 6-amino-1,4-oxazepan-4-ylpyridinyl; 6-methyl-2,6-diazaspiro[3.3]heptan-2-ylpyridinyl; isoindol-4-yl; piperazin-1-yl(methyl)pyridinyl; piperazin-1-yl(methyl)pyrimidinyl; piperazin-1-ylphenyl; piperazin-1-ylpyridinyl; or piperazin-1-ylpyrimidinyl; n is 0, 1 or 2;

[0173] or a pharmaceutically acceptable salt thereof.

[0174] Another embodiment of the present invention is (vi') a compound of formula (I) or (Ia) or (Ib) or a pharmaceutically acceptable salt thereof according to any one of (i') to (v'), wherein R 1 for Where R 4 is cyano; R 5 is H or deuterium.

[0175] Another embodiment of the present invention is (vii') a compound of formula (I) or (Ia) or (Ib) or a pharmaceutically acceptable salt thereof according to any one of (i') to (vi'), wherein R 2 C 1-6 alkyl.

[0176] Another embodiment of the present invention is (viii') a compound of formula (I) or (Ia) or (Ib) or a pharmaceutically acceptable salt thereof according to any one of (i') to (vii'), wherein R 2 It is methyl.

[0177] Another embodiment of the present invention is (ix') a compound of formula (I) or (Ia) or (Ib) or a pharmaceutically acceptable salt thereof according to any one of (i') to (viii'), wherein

[0178] Ring A is 1,2,3,4-tetrahydroisoquinolinyl or in

[0179] A 1 for CH;

[0180] A 2 CR b , where R b H or C 1-6 alkyl;

[0181] A 3 N or CR c , where R c is piperazinyl; amino (C 1-6 Alkoxy)pyrrolidinyl; aminohalogenated pyrrolidinyl; C 1-6 Alkyl-2,6-diazaspiro[3.3]heptyl; or amino(C 1-6 alkyl)azetidinyl;

[0182] A 4 N or CR d , where R d or amino (C 1-6 Alkoxy) pyrrolidinyl or amino (C 1-6 alkyl)azetidinyl;

[0183] A 5 N or CR e , where R e H or C 1-6 alkyl.

[0184] Another embodiment of the present invention is (x') a compound of formula (I) or (Ia) or (Ib) or a pharmaceutically acceptable salt thereof according to any one of (i') to (ix'), wherein

[0185] Ring A is 1,2,3,4-tetrahydroisoquinolin-7-yl or in

[0186] A 1 for CH;

[0187] A 2 CRb , where R b is H or methyl;

[0188] A 3 N or CR c , where R c or piperazin-1-yl; 3-amino-4-methoxy-pyrrolidin-1-yl; 3-amino-4-fluoro-pyrrolidin-1-yl; 6-methyl-2,6-diazaspiro[3.3]heptane-2-yl; or 3-amino-3-methyl-azetidin-1-yl;

[0189] A 4 N or CR d , where R d is 3-amino-4-methoxy-pyrrolidin-1-yl or 3-amino-3-methyl-azetidin-1-yl;

[0190] A 5 N or CR e , where R e It is H or methyl.

[0191] Another embodiment of the present invention is (xi') a compound of formula (I) or (Ia) or (Ib) or a pharmaceutically acceptable salt thereof according to any one of (i') to (x'), wherein Ring A is 1,2,3,4-tetrahydroisoquinolin-7-yl; 3-amino-3-methyl-azetidin-1-yl(methyl)pyrimidinyl; 3-amino-3-methyl-azetidin-1-ylpyridinyl; 3-amino-4-fluoro-pyrrolidin-1-yl pyridinyl; 3-amino-4-fluoro-pyrrolidin-1-ylpyridinyl; 3-amino-4-methoxy-pyrrolidin-1-yl(methyl)pyrimidinyl; 3-amino-4-methoxy-pyrrolidin-1-ylpyridinyl; 3-amino-4-methoxy-pyrrolidin-1-ylpyridinyl; 6-methyl-2,6-diazaspiro[3.3]heptane-2-ylpyridinyl; piperazin-1-yl(methyl)pyridinyl; or piperazin-1-ylpyridinyl.

[0192] Another embodiment of the present invention is (xii') a compound of formula (I) or (Ia) or (Ib) according to any one of (i') to (xi'), wherein

[0193] R 1 for Where R 4 is cyano; R 5 is H or deuterium;

[0194] R 2 C 1-6 alkyl;

[0195] R 3 is H;

[0196] Ring A is 1,2,3,4-tetrahydroisoquinolinyl or in

[0197] A 1 for CH;

[0198] A 2 CR b , where R b H or C 1-6 alkyl;

[0199] A 3 N or CR c , where R c is piperazinyl; amino (C 1-6 Alkoxy)pyrrolidinyl;

[0200] Aminohalopyrrolidino; C 1-6 Alkyl-2,6-diazaspiro[3.3]heptyl; or amino(C 1-6 alkyl)azetidinyl;

[0201] A 4 N or CR d , where R d or amino (C 1-6 Alkoxy) pyrrolidinyl or amino (C 1-6 alkyl)azetidinyl;

[0202] A 5 N or CR e , where R e H or C 1-6 alkyl;

[0203] n is 0, 1 or 2;

[0204] or a pharmaceutically acceptable salt thereof.

[0205] Another embodiment of the present invention is (xiii') a compound of formula (I) or (Ia) or (Ib) according to any one of (i') to (xii'), wherein

[0206] R 1 for Where R 4 is cyano; R 5 is H or deuterium;

[0207] R 2 is methyl;

[0208] R 3 is H;

[0209] Ring A is 1,2,3,4-tetrahydroisoquinolin-7-yl; 3-amino-3-methyl-azetidin-1-yl(methyl)pyrimidinyl; 3-amino-3-methyl-azetidin-1-ylpyridinyl; 3-amino-4-fluoro-pyrrolidin-1-ylpyridinyl; 3-amino-4-fluoro-pyrrolidin-1-ylpyridinyl; 3-amino-4-methoxy-pyrrolidin-1-yl(methyl)pyrimidinyl; 3-amino-4-methoxy-pyrrolidin-1-ylpyridinyl; 3-amino-4-methoxy-pyrrolidin-1-ylpyridinyl; 6-methyl-2,6-diazaspiro[3.3]heptan-2-ylpyridinyl; piperazin-1-yl(methyl)pyridinyl; or piperazin-1-ylpyridinyl;

[0210] n is 0, 1 or 2;

[0211] or a pharmaceutically acceptable salt thereof.

[0212] Another embodiment of the present invention is a compound of formula (I) or (Ia) or (Ib) selected from the following compounds:

[0213] 5-[cis-4-methyl-8-(1,2,3,4-tetrahydroisoquinolin-7-ylmethyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0214] 5-[cis-4-methyl-8-(1,2,3,4-tetrahydroisoquinolin-5-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0215] 5-[cis-4-methyl-8-[(2-piperazin-1-yl-4-pyridinyl)methyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0216] 5-[cis-8-isoindolin-4-yl-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0217] 5-[(4R,9aS)-4-methyl-8-(1,2,3,4-tetrahydroisoquinolin-7-ylmethyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0218] 5-[(4R,9aS)-4-methyl-8-(5,6,7,8-tetrahydro-1,6-naphthyridin-3-ylmethyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0219] 5-[(4R,9aS)-4-methyl-8-[2-(4-piperazin-1-ylphenyl)ethyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0220] 5-[(4R,9aS)-4-methyl-8-[(6-piperazin-1-yl-3-pyridinyl)methyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0221] 5-[(4R,9aS)-8-isoindolin-4-yl-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0222] 5-[(4R,9aS)-4-methyl-8-(1,2,3,4-tetrahydroisoquinolin-6-ylmethyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0223] 5-[(4R,9aS)-4-methyl-8-[2-(6-piperazin-1-yl-3-pyridinyl)ethyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0224] 5-[(4R,9aS)-8-[2-[6-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0225] 5-[(4R,9aS)-8-[2-[5-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]-2-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0226] 5-[(4R,9aS)-8-[[6-(1,4-diazepan-1-yl)-3-pyridinyl]methyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0227] 5-[(4R,9aR)-4-methyl-8-(5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0228] 5-[(4R,9aS)-8-[2-[6-[(3R,4S)-3-amino-4-fluoro-pyrrolidin-1-yl]-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0229] 5-[(4R,9aS)-8-[2-[6-[(3R,4R)-3-amino-4-fluoro-pyrrolidin-1-yl]-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0230] 5-[(4R,9aS)-8-[2-[5-[(3R,4S)-3-amino-4-fluoro-pyrrolidin-1-yl]-2-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0231] 5-[(4R,9aS)-4-methyl-8-[2-[5-[(3S)-3-methylpiperazin-1-yl]-2-pyridinyl]ethyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0232] 5-[(4R,9aS)-4-methyl-8-[2-[6-[(3S)-3-methylpiperazin-1-yl]-2-pyridinyl]ethyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0233] 5-[(4R,9aS)-4-methyl-8-[2-[6-(6-methyl-2,6-diazaspiro[3.3]heptane-2-yl)-3-pyridinyl]ethyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0234] 5-[(4R,9aS)-8-[2-[6-[(3R,4S)-3-amino-4-methoxy-pyrrolidin-1-yl]-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0235] 5-[(4R,9aS)-8-[2-[6-[(3S,4S)-3-amino-4-methoxy-pyrrolidin-1-yl]-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0236] 5-[(4R,9aS)-8-[2-[4-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]phenyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0237] 5-[(4R,9aS)-4-methyl-8-[(6-piperazin-1-yl-2-pyridinyl)methyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0238] 5-[(4R,9aS)-4-methyl-8-[2-[4-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)phenyl]ethyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0239] 5-[(4R,9aR)-4-methyl-8-(4-piperazin-1-ylpyrimidin-2-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0240] 5-[(4R,9aR)-4-methyl-8-(6-methyl-2-piperazin-1-yl-pyrimidin-4-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0241] 5-[(4R,9aS)-4-methyl-8-(2-piperazin-1-yl-4-pyridinyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0242] 5-[(4R,9aR)-4-methyl-8-(2-piperazin-1-ylpyrimidin-4-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0243] 5-[(4R,9aR)-4-methyl-8-(4-piperazin-1-yl-2-pyridinyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0244] 5-(8-isoindolin-4-yl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl)quinoline-8-carbonitrile;

[0245] 5-[(4R,9aR)-8-[2-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]pyrimidin-4-yl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0246] 5-[(4R,9aR)-8-[4-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]pyrimidin-2-yl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0247] 5-[2-(4-methyl-6-piperazin-1-yl-3-pyridinyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-8-yl]quinoline-8-carbonitrile;

[0248] 5-[(4R,9aR)-8-[4-(3-aminoazetidin-1-yl)pyrimidin-2-yl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0249] 5-[(4R,9aS)-8-[2-[(3S,4R)-3-amino-4-fluoro-pyrrolidin-1-yl]-4-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0250] 5-[(4R,9aS)-8-[2-(3-aminoazetidin-1-yl)-4-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0251] 5-[(4R,9aS)-4-methyl-8-(5,6,7,8-tetrahydro-2,7-naphthyridin-4-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0252] 5-[(4R,9aR)-4-methyl-8-(5-methyl-4-piperazin-1-yl-pyrimidin-2-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0253] 5-[(4R,9aR)-4-methyl-8-(5,6,7,8-tetrahydro-2,7-naphthyridin-4-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0254] 5-[(4R,9aR)-8-[2-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]-6-methyl-pyrimidin-4-yl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0255] 5-[2-[6-[(6R)-6-amino-1,4-oxazepan-4-yl]-4-methyl-3-pyridyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-8-yl]quinoline-8-carbonitrile;

[0256] 5-[trans-4-methyl-8-(1,2,3,4-tetrahydroisoquinolin-5-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0257] 5-[(4R,9aS)-8-[2-[(6S)-6-amino-1,4-oxazepan-4-yl]-4-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0258] 5-[(4R,9aS)-8-[2-[(6R)-6-amino-1,4-oxazepan-4-yl]-4-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0259] 5-[(4R,9aR)-8-[2-(3-amino-3-methyl-azetidin-1-yl)-6-methyl-pyrimidin-4-yl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0260] 5-[(4R,9aS)-8-[2-(3-amino-3-methyl-azetidin-1-yl)-4-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0261] 5-[(4R,9aS)-4-methyl-8-[(5-piperazin-1-yl-3-pyridinyl)methyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0262] 5-[(4R,9aS)-4-methyl-8-[2-[6-[(3R)-3-methylpiperazin-1-yl]-2-pyridinyl]ethyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0263] 5-[(4R,9aS)-4-methyl-8-[2-[6-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)-3-pyridinyl]ethyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0264] 5-[(4R,9aS)-4-methyl-8-[(2-methyl-6-piperazin-1-yl-3-pyridinyl)methyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0265] 5-[(4R,9aS)-4-methyl-8-(1,2,3,4-tetrahydroisoquinolin-7-ylmethyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0266] 5-[(4R,9aS)-8-[2-[6-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0267] 5-[(4R,9aS)-8-[2-[6-[(3R,4S)-3-amino-4-fluoro-pyrrolidin-1-yl]-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0268] 5-[(4R,9aS)-4-methyl-8-[2-[6-(6-methyl-2,6-diazaspiro[3.3]heptane-2-yl)-3-pyridinyl]ethyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0269] 5-[(4R,9aS)-8-[2-[6-(3-amino-3-methyl-azetidin-1-yl)-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0270] 4-[(4R,9aS)-8-[2-[4-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]phenyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile;

[0271] 4-[(4R,9aS)-8-[2-[6-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile;

[0272] 4-[(4R,9aS)-8-[2-[4-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]phenyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile;

[0273] 4-[(4R,9aS)-4-methyl-8-(1,2,3,4-tetrahydroisoquinolin-7-ylmethyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile;

[0274] 5-[(4R,9aS)-4-methyl-8-(1,2,3,4-tetrahydroisoquinolin-5-ylmethyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0275] 5-[(4R,9aS)-4-methyl-8-(1,2,3,4-tetrahydroisoquinolin-8-ylmethyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0276] 5-[(4R,9aS)-8-(isoindolin-4-ylmethyl)-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0277] 5-[(4R,9aS)-8-[2-(3-amino-3-methyl-azetidin-1-yl)-6-methyl-4-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0278] 4-[(4R,9aS)-8-[2-[6-(3-amino-3-methyl-azetidin-1-yl)-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile;

[0279] 4-[(4R,9aS)-8-[2-[6-[(3R,4S)-3-amino-4-fluoro-pyrrolidin-1-yl]-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile;

[0280] 5-[(4R,9aS)-8-[[6-(3-amino-3-methyl-azetidin-1-yl)-2-methyl-3-pyridinyl]methyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0281] 5-[(4R,9aS)-8-[2-[6-[(4aR,7aR)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl]-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0282] 5-[(4R,9aS)-4-methyl-8-[(6-piperazin-1-yl-3-pyridinyl)methyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0283] 5-[(4R,9aS)-8-[[6-(3-amino-3-methyl-azetidin-1-yl)-2-methyl-3-pyridinyl]methyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0284] 5-[(4R,9aS)-4-methyl-8-[[2-methyl-6-(6-methyl-2,6-diazaspiro[3.3]heptane-2-yl)-3-pyridinyl]methyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0285] 5-[(4R,9aS)-8-[[6-[(3R)-3-amino-3-methyl-pyrrolidin-1-yl]-2-methyl-3-pyridinyl]methyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0286] 5-[(4R,9aS)-8-[[6-[[(3S,4R)-4-fluoropyrrolidin-3-yl]amino]-2-methyl-3-pyridinyl]methyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0287] 5-[(4R,9aS)-4-methyl-8-[[2-methyl-6-(9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl)-3-pyridinyl]methyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0288] 5-[(4R,9aS)-8-[2-[6-[(3R)-3-amino-3-methyl-pyrrolidin-1-yl]-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0289] 5-[(4R,9aS)-4-methyl-8-[[2-methyl-6-[(2S)-2-methylpiperazin-1-yl]-3-pyridinyl]methyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0290] 5-[(4R,9aS)-4-methyl-8-[[2-methyl-6-[(3R)-3-methylpiperazin-1-yl]-3-pyridinyl]methyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0291] 5-[(4R,9aS)-4-methyl-8-[(4-methyl-6-piperazin-1-yl-3-pyridinyl)methyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0292] 5-[(4R,9aS)-4-methyl-8-[(3-methyl-6-piperazin-1-yl-2-pyridinyl)methyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0293] 5-[(4R,9aS)-8-[2-[2-[(3R,4S)-3-amino-4-fluoro-pyrrolidin-1-yl]-4-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0294] 5-[(4R,9aS)-8-[[6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-methyl-3-pyridinyl]methyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0295] 5-[(4R,9aS)-8-[[6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-methyl-3-pyridyl]methyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0296] 5-[(4R,9aS)-8-[[6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-methyl-3-pyridinyl]methyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0297] 4-[(4R,9aR)-4-methyl-8-(3-methyl-5-piperazin-1-yl-2-pyridinyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-1-methyl-1,8-naphthyridin-2-one;

[0298] 5-[(4R,9aS)-8-[[6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-4-methyl-3-pyridinyl]methyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0299] 5-[(4R,9aR)-8-[5-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-3-methyl-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0300] 5-[(4R,9aR)-8-[5-[(3R,4S)-3-amino-4-methoxy-pyrrolidin-1-yl]-3-methyl-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0301] 5-[(4R,9aR)-8-[5-[(3R)-3-amino-3-methyl-pyrrolidin-1-yl]-3-methyl-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0302] 5-[(4R,9aS)-8-[[6-[(4aR,7aR)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl]-2-methyl-3-pyridinyl]methyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0303] 5-[(4R,9aR)-8-[5-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]-3-methyl-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0304] 5-[(4R,9aR)-8-[5-[(4aR,7aR)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl]-3-methyl-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0305] 5-[(4R,9aR)-8-[5-(6-amino-2-azaspiro[3.3]heptane-2-yl)-3-methyl-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0306] 5-[(4R,9aR)-4-methyl-8-[3-methyl-5-(6-methyl-2,6-diazaspiro[3.3]heptane-2-carbonyl)-2-pyridinyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0307] 5-[(4S,9aR)-4-methyl-8-[3-methyl-5-(6-methyl-2,6-diazaspiro[3.3]heptane-2-carbonyl)-2-pyridinyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0308] 5-[(4R,9aS)-8-[2-[(3R)-3-amino-3-methyl-pyrrolidin-1-yl]-4-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0309] 5-[(4S,9aS)-4-methyl-8-[4-[(2R)-morpholin-2-yl]phenyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0310] 5-[(4S,9aS)-4-methyl-8-[4-[(2S)-morpholin-2-yl]phenyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0311] 5-[(4S,9aR)-8-[5-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-3-methyl-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0312] 5-[(4R,9aR)-8-[5-[2-[(3S,4S)-3-amino-4-methoxy-pyrrolidin-1-yl]ethyl]-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0313] 5-[(4S,9aR)-8-[5-[(6R)-6-amino-1,4-oxazepan-4-yl]-3-methyl-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0314] 5-[(4S,9aR)-8-[5-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-3-methyl-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0315] 5-[(4S,9aR)-8-[6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-3-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0316] 4-[(4S,9aR)-4-methyl-8-[3-methyl-5-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)-2-pyridinyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-1-methyl-1,8-naphthyridin-2-one;

[0317] 5-[(4S,9aR)-8-[5-[(4aR,7aR)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl]-3-methyl-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0318] 5-[(4S,9aR)-8-[6-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]-3-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0319] 5-[(4S,9aR)-8-[6-[2-[(3R,4S)-3-amino-4-fluoro-pyrrolidin-1-yl]ethyl]-3-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0320] 5-[(4S,9aR)-8-[5-(3-amino-3-methyl-azetidin-1-yl)-3-methyl-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0321] 5-[(4S,9aR)-4-methyl-8-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0322] 5-[(4S,9aR)-8-[5-[2-[(3S,4S)-3-amino-4-methoxy-pyrrolidin-1-yl]ethyl]-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0323] 5-[(4S,9aR)-8-[5-[[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]methyl]-6-methyl-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile;

[0324] 5-[(4R,9aS)-8-[2-[6-[(4aR,7aR)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl]-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; and

[0325] 5-[(4S,9aS)-4-methyl-8-[4-[(2R)-morpholin-2-yl]phenyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

[0326] or a pharmaceutically acceptable salt thereof.

[0327] synthesis

[0328] The compounds of the present invention may be prepared by any conventional method. Suitable methods for synthesizing these compounds and their starting materials are provided in the following schemes and examples. Unless otherwise indicated, all substituents, especially R 1 To R 5 As defined above. Furthermore, unless otherwise specifically indicated, all reactions, reaction conditions, abbreviations and symbols have the meanings well known to one of ordinary skill in the art of organic chemistry.

[0329] The general synthetic routes for preparing compounds of formula (I), (VII) and (XI) are shown below.

[0330] Solution 1

[0331]

[0332] wherein n is 0, 1 or 2; X is halogen; Y is halogen or mesylate; R 7 and R 8 is aryl or heteroaryl; R 9 and R 10 Together with the nitrogen atom to which they are attached they form a heterocyclic group.

[0333] The synthesis of the compounds of the present invention starts with halide II. Halide II and a compound of formula III are reacted with a catalyst such as Ruphos Pd-G2 and a base such as Cs 2 CO 3Buchwald-Hartwig amination reaction occurs between the two to obtain a compound of formula IV (reference: Acc. Chem. Res. 1998, 31, 805-818; Chem. Rev. 2016, 116, 12564-12649; Topics in Current Chemistry, 2002, 219, 131-209; these documents are incorporated herein by reference). Alternatively, the compound of formula IV can also be prepared by reacting a halide II with a compound of formula III in the presence of a base such as DIPEA, NaHCO 3 and K 2 CO 3 Compound IV is subjected to Boc deprotection under acidic conditions (such as EtOAc containing HCl and DCM containing TFA) to give compound V, which can be obtained by reacting compound VI with a base such as DIPEA NaHCO 3 and K 2 CO 3 In the presence of amine X, a nucleophilic substitution reaction or a Buchwald-Hartwig amination reaction with a compound of formula VI is carried out, followed by appropriate deprotection, to convert the compound of formula VII. Meanwhile, a compound of formula V can react with a compound of formula VIII by nucleophilic substitution to obtain a compound of formula IX. A Buchwald-Hartwig amination reaction or a nucleophilic substitution reaction between a compound of formula IX and an amine X, followed by appropriate deprotection, can give a compound of formula XI.

[0334] Compounds of formula (Ia) can be synthesized according to Scheme 1 using chiral starting materials.

[0335] The compounds of the invention may be obtained in the form of diastereomers or mixtures of enantiomers which may be separated by methods well known in the art, for example, (chiral) HPLC or SFC.

[0336] The present invention also relates to a process for preparing a compound of formula (I) or (Ia), which comprises any of the following steps:

[0337] a) Compound of formula (IX) With amine (X) Buchwald-Hartwig amination or nucleophilic substitution occurs between them;

[0338] b) Compounds of formula (V) With the compound of formula (VI) (VI) undergoes a Buchwald-Hartwig amination reaction or a nucleophilic substitution;

[0339] wherein n is 0, 1 or 2; X is halogen; Y is halogen or mesylate; R 7 and R 8is aryl or heteroaryl; R 9 and R 10 Together with the nitrogen atom to which they are attached they form a heterocyclic group.

[0340] The compounds of formula (I) or (Ia) produced according to the above-described process are also an object of the present invention.

[0341] Indications and treatments

[0342] The present invention provides compounds that can be used as TLR7 and / or TLR8 and / or TLR9 antagonists, which inhibit activation of TLR7 and / or TLR8 and / or TLR9 pathways and corresponding downstream biological events, including but not limited to innate and adaptive immune responses mediated by the production of all types of cytokines and various forms of autoantibodies. Therefore, the compounds of the present invention can be used to block TLR7 and / or TLR8 and / or TLR9 in all types of cells expressing such receptors, including but not limited to plasmacytoid dendritic cells, B cells, T cells, macrophages, monocytes, neutrophils, keratinocytes, epithelial cells. In this way, the compound can be used as a therapeutic agent or preventive agent for systemic lupus erythematosus and lupus nephritis.

[0343] The present invention provides methods for treating or preventing systemic lupus erythematosus and lupus nephritis in a patient in need thereof.

[0344] Another embodiment includes a method of treating or preventing systemic lupus erythematosus and lupus nephritis in a mammal in need of such treatment, wherein the method comprises administering to the mammal a therapeutically effective amount of a compound of formula (I), a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof.

[0345] Examples

[0346] The present invention will be more fully understood by reference to the following examples. However, they should not be construed as limiting the scope of the present invention.

[0347] abbreviation

[0348] The present invention will be more fully understood by reference to the following examples. However, they should not be construed as limiting the scope of the present invention.

[0349] The abbreviations used in this article are as follows:

[0350] ACN: Acetonitrile

[0351] Boc 2 O: Di-tert-butyl dicarbonate

[0352] BINAP: 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl

[0353] DCM: Dichloromethane

[0354] DCE: dichloroethane

[0355] DIPEA or DIEA: N,N-diisopropylethylamine

[0356] DIBAL-H: Diisobutylaluminum hydride

[0357] DIAD: Diisopropyl azodicarboxylate

[0358] DMA: N,N-dimethylacetamide

[0359] DMAP: 4-dimethylaminopyridine

[0360] DMF: N,N-dimethylformamide

[0361] DPPP: 1,3-bis(diphenylphosphino)propane

[0362] EA or EtOAc: Ethyl acetate

[0363] FA: Formic acid

[0364] HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0365] IC 50 : Half inhibitory concentration

[0366] IPA: Isopropyl alcohol

[0367] LCMS Liquid chromatography-mass spectrometry

[0368] MS: mass spectrometry

[0369] NBS: N-bromosuccinamide

[0370] PE: Petroleum Ether

[0371] prep-HPLC: Preparative High Performance Liquid Chromatography

[0372] prep-TLC: Preparative Thin Layer Chromatography

[0373] PPh 3 : Triphenylphosphine

[0374] Pd 2 (dba) 3 : Tris(dibenzylideneacetone)dipalladium(0)

[0375] Rf: retention factor

[0376] rt: room temperature

[0377] RT: retention time

[0378] RuPhos Pd G2: Chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) 2nd generation

[0379] Selective fluorine reagent 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate)

[0380] SFC: Supercritical Fluid Chromatography

[0381] tBuXPhos Pd G3: Mesylate (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II)

[0382] TEA: Trimethylamine

[0383] TFA: trifluoroacetic acid

[0384] THF: Tetrahydrofuran

[0385] TLC: Thin layer chromatography

[0386] XantPhos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0387] XPhos: 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0388] XPhos Pd G2: Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)

[0389] v / v volume ratio

[0390] LYSA freeze-dried solubility assay

[0391] General experimental conditions

[0392] Intermediates and final compounds were purified by flash chromatography using one of the following instruments: i) Biotage SP1 system and Quad 12 / 25 Cartridge module. ii) ISCO combi-flash chromatograph. Silica gel brand and pore size: i) KP-SIL Particle size: 40-60 μm; ii) CAS registration number: silica gel: 63231-67-4, particle size: 47-60 micron silica gel; iii) ZCX from Qingdao Ocean Chemical Co., Ltd., pore size: 200-300 or 300-400.

[0393] Intermediates and final compounds were purified by preparative HPLC on a reverse phase column using XBridge TM Prep-C18 (5μm, OBDTM 30×100mm) column, SunFire TM Prep-C18(5μm,OBD TM 30×100mm) chromatographic column, Phenomenex Synergi-C18 (10μm, 25×150mm) or Phenomenex Gemini-C18 (10μm, 25×150mm). Waters AutoP purification system (sample manager 2767, pump 2525, detector: Micromass ZQ and UV 2487, 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 Gilson-281 purification system (pump 322, detector: UV 156, 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).

[0394] For SFC chiral separation, the intermediates were separated by chiral columns (Daicel chiralpak IC, 5 μm, 30 × 250 mm), AS (10 μm, 30 × 250 mm) or AD (10 μm, 30 × 250 mm) using Mettler Toledo Multigram III system SFC, Waters 80Q preparative SFC or Thar 80 preparative SFC, solvent system: CO 2 and IPA (0.5% TEA in IPA solution) or CO 2 and MeOH (0.1% NH 3 ·H 2 O in MeOH), back pressure 100 bar, UV detection at 254 or 220 nm.

[0395] Using LC / MS (Waters TMThe LC / MS spectra of the compounds were obtained using an Agilent Alliance 2795-Micromass ZQ, Shimadzu Alliance 2020-Micromass ZQ, or Agilent Alliance 6110-Micromass ZQ. The LC / MS conditions were as follows (run time 3 or 1.5 min):

[0396] Acidic conditions I: A: 0.1% TFA in HO 2 O solution; B: 0.1% TFA solution in acetonitrile;

[0397] Acidic conditions II: A: 0.0375% TFA in HO 2 O solution; B: 0.01875% TFA solution in acetonitrile;

[0398] Alkaline conditions I: A: 0.1% NH 3 ·H 2 O in H 2 O solution; B: acetonitrile;

[0399] Alkaline conditions II: A: 0.025% NH 3 ·H 2 O in H 2 O solution; B: acetonitrile;

[0400] Neutral conditions: A:H 2 O; B: acetonitrile.

[0401] Mass spectra (MS): Usually only ions representing the parent mass are reported, and unless otherwise stated, the mass ion quoted is the positive mass ion (MH) + .

[0402] NMR spectra were obtained using a Bruker Avance 400 MHz.

[0403] Microwave-assisted reactions were performed in a Biotage Initiator Sixty microwave synthesizer. All reactions involving air-sensitive reagents were performed under argon or nitrogen atmosphere. Unless otherwise stated, reagents were purchased from commercial suppliers as received without further purification.

[0404] Preparation Example

[0405] The following examples are intended to illustrate the meaning of the present invention, but are by no means intended to limit the meaning of the present invention:

[0406] Intermediate A

[0407] 5-[cis-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0408]

[0409] The title compound was prepared according to the following scheme:

[0410]

[0411] Step 1: Preparation of methyl 6-methylpyrazine-2-carboxylate (Compound A-2)

[0412] To a solution of 6-methylpyrazine-2-carboxylic acid (Compound A-1, 150 g, 1086 mmol) in methanol (1600 mL) was added thionyl chloride (388 g, 3258 mmol) dropwise at 0 ° C, and then the reaction was stirred at 25 ° C for 16 hours. The reaction mixture was concentrated and the residue was dissolved in ice water (1 L). The mixture was basified to pH = 8 and extracted twice with DCM (500 mL). The combined organic layers were purified by Na 2 SO 4 Dried and concentrated to give compound A-2 (161 g) as a yellow solid. LCMS (M+H) + :153.

[0413] Step 2: Preparation of methyl 6-methylpiperazine-2-carboxylate (Compound A-3)

[0414] To a solution of methyl 6-methylpyrazine-2-carboxylate (compound A-2, 40 g, 262 mmol) in methanol (900 mL) was added acetic acid (32 g, 526 mmol) and platinum (IV) oxide (4 g, 18 mmol). The reaction mixture was stirred at 50 ° C under a hydrogen atmosphere (50 psi) for 48 hours. A total of 4 batches of the same scale were combined and filtered. The filtrate was concentrated under vacuum to give compound A-3 (165 g) as a brown oil. LCMS (M+H) + :159.

[0415] Step 3: Preparation of methyl-4-benzyl-6-methyl-piperazine-2-carboxylate (Compound A-4)

[0416] At 0 ° C, sodium cyanoborohydride (163 g, 2590 mmol) was slowly added in batches to a solution of methyl 6-methylpiperazine-2-carboxylate (compound A-3, 240 g, 863 mmol) and benzaldehyde (92 g, 863 mmol) in methanol (2500 mL) over 30 minutes. The reaction mixture was stirred at 20 ° C for 12 hours, and then water (500 mL) was added. The mixture was extracted with EA (1500 mL), and the combined organic layers were then dried and concentrated. The residue was purified by silica gel column to obtain compound A-4 (225 g, crude product) as a yellow oil. LCMS (M+H) + :249.

[0417] Step 4: Preparation of 4-benzyl-1-[2-(tert-butoxycarbonylamino)acetyl]-6-methyl-piperazine-2-carboxylic acid methyl ester (Compound A-5)

[0418] A solution of Boc-glycine (193 g, 1099 mmol), HATU (418 g, 1099 mmol) and DIPEA (451 mL, 2537 mmol) in DMF (500 mL) was stirred at 20 ° C for 30 minutes. Then DMF (100 mL) containing 4-benzyl-6-methyl-piperazine-2-carboxylic acid methyl ester (compound A-4, 210 g, 846 mmol) was added, and the reaction mixture was stirred at 20 ° C for 15 hours under a nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried and concentrated. The residue was purified by column chromatography to obtain compound A-5 (260 g) as a yellow oil. LCMS (M+H) + :406.

[0419] Step 5: Preparation of 1-(2-aminoacetyl)-4-benzyl-6-methyl-piperazine-2-carboxylic acid methyl ester (Compound A-6)

[0420] To a solution of 4-benzyl-1-[2-(tert-butoxycarbonylamino)acetyl]-6-methyl-piperazine-2-carboxylic acid methyl ester (Compound A-5, 230 g, 567 mmol) in methanol (2300 mL) was slowly added a methanol solution of HCl (1150 mL, 4 M) at 0 ° C. The mixture was then stirred at 20 ° C for 16 hours. The reaction mixture was concentrated in vacuo to give Compound A-6 (150 g, crude product) as a light yellow solid. LCMS (M+H) + :306.

[0421] Step 6: Preparation of 2-benzyl-4-methyl-1,3,4,7,8,9a-hexahydropyrazino[1,2-a]pyrazine-6,9-dione (Compound A-7)

[0422] A mixture of 1-(2-aminoacetyl)-4-benzyl-6-methyl-piperazine-2-carboxylic acid methyl ester hydrochloride (Compound A-6, 150 g) and triethylamine (306 mL, 2194 mmol) in methanol (400 mL) was stirred at 70 ° C for 2 hours. The reaction mixture was concentrated and the residue was purified by flash column chromatography to obtain Compound A-7 (55 g) as a yellow solid. LCMS (M+H) + :274.

[0423] Step 7: Preparation of 2-benzyl-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazine (Compound A-8)

[0424] To a solution of 2-benzyl-4-methyl-1,3,4,7,8,9a-hexahydropyrazino[1,2-a]pyrazine-6,9-dione (Compound A-7, 27 g, 100 mmol) in THF (700 mL) was slowly added lithium aluminum hydride powder (38 g, 1006 mmol) at 0°C over 30 minutes. The reaction mixture was stirred at 0°C for 6 hours, then diluted with THF (1000 mL), and washed with H 2 O (60 mL), 15% aqueous NaOH (38 mL), and H 2 O (67 mL) to quench the reaction. The reaction mixture was filtered and the filtrate was purified by Na 2 SO 4 Dried and concentrated to give compound A-8 (23 g) as yellow oil. LCMS (M+H) + :246.

[0425] Step 8: Preparation of cis-2-benzyl-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazine-8-carboxylic acid tert-butyl ester (Compound A-9-cis)

[0426] (2-benzyl-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazine (compound A-8, 45.0 g, 117.4 mmol), DIPEA (51.1 mL, 293.5 mmol) and Boc 2 A mixture of 1-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2- + :346.

[0427] Compound A-9-cis, 1 H NMR (400MHz, chloroform-d) δppm: 7.36-7.30(m,4H),7.28-7.26(m,1H),4.10-3.94(m,1H),3 .86-3.70(m,1H),3.57-3.40(m,2H),3.16-2.85(m,2H),2.82-2.67(m,2H),2.58(br s,1H),2.42-2.17(m,2H),2.04-1.74(m,3H),1.46(s,9H),1.05(br d,J=5.6Hz,3H).

[0428] Compound A-9-trans, 1 H NMR (400MHz, chloroform-d) δppm: 7.35-7.29(m,4H),7.28-7.23(m,1H),4.09-3.70(m,2H),3.55-3.36(m,2H),3.05(br s,2H),2.71(br d,J=10.3Hz,2H),2.62(br d,J=9.5Hz,4H),2.44(br s,1H),2.02-1.76(m,1H),1.45(s,9H),1.16(br d,J=6.4Hz,3H).

[0429]

[0430] For compound A-9-cis, a NOESY correlation between C3'-H and C5'-H was observed. For compound A-9-trans, no NOESY correlation between C3'-H and C5'-H was observed.

[0431] Step 9: Preparation of cis-6-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (Compound A-10)

[0432] To a solution of cis-2-benzyl-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazine-8-carboxylic acid tert-butyl ester (Compound A-9-cis, 26.0 g, 75.3 mmol) in THF (500 mL) was added wet Pd / C (5.0 g), and the mixture was stirred at 50° C. for 3 hours under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated to give Compound A-10 (16.5 g) as a yellow oil. LCMS (M+H) + :256.

[0433] Step 10: Preparation of cis-2-(8-cyano-5-quinolyl)-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazine-8-carboxylic acid tert-butyl ester (Compound A-11)

[0434] 5-Bromoquinoline-8-carbonitrile (1.3 g, 5.6 mmol), cis-2-benzyl-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazine-8-carboxylic acid tert-butyl ester (Compound A-9-cis, 1.6 g, 6.2 mmol), Cs 2 CO 3 A mixture of (5.5 g, 16.9 mmol) and RuPhos Pd G2 (875.0 mg, 1.1 mmol) in dioxane (20 mL) was stirred at 90 ° C for 16 hours. Then the reaction mixture was filtered and concentrated. The residue was purified by silica gel column to obtain compound A-11 (1.5 g) as a yellow foam, LCMS (M+H) + :408.

[0435] Step 11: Preparation of 5-[cis-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Intermediate A)

[0436] A mixture of cis-2-(8-cyano-5-quinolyl)-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazine [1,2-a] pyrazine-8-carboxylic acid tert-butyl ester (Compound A-11, 1.6 g, 3.9 mmol) in EA (100 mL) containing 1 M HCl was stirred at rt for 16 hours, and then the reactant was concentrated. The residue was dissolved in NaOH (2N, 100 mL) and extracted twice with EA (100 mL). The organic layer was dried and concentrated to give Intermediate A (900 mg) as a light brown foam, LCMS (M+H) + :308.

[0437] Intermediate B

[0438] 5-[trans-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0439]

[0440] The preparation of intermediate B is the same as intermediate A, but compound A-9-trans is used instead of compound A-9-cis in step 10. Intermediate B (900 mg) is obtained as a light brown foam, LCMS (M+H) +:308.

[0441] Intermediate C

[0442] 5-[(4R,9aS)-4-Methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0443]

[0444] The title compound was prepared according to the following scheme:

[0445]

[0446] SFC (gradient: 30%, in EtOH (0.1% NH 3 ·H 2 O)CO 2 Column: Daicel ChiralPak AD, 250×50mm, 10μm) to separate compound A-11 (8.0g) to obtain compound C-1 (second peak, 3.5g) and compound C-2 (first peak, 3.0g), which are yellow solids. A mixture of (4R, 9aR)-2-(8-cyano-5-quinolyl)-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazine-8-carboxylic acid tert-butyl ester (compound C-1, 3.5g, 8.6mmol) in EA (100mL) containing 1M HCl was stirred at rt for 16 hours, and then the reactant was concentrated. The residue was dissolved in NaOH (2N, 100mL) and extracted with EA (100mL×2). The organic layer was dried and concentrated to give Intermediate C (2.5 g) as a light brown foam, LCMS (M+H): + :308.

[0447] Intermediate D

[0448] 5-[(4R,9aR)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0449]

[0450] The title compound was prepared according to the following scheme:

[0451]

[0452] SFC (gradient: 30%, in EtOH (0.1% NH 3 ·H 2 O)CO 2Column: Phenomenex cellulose-2, 250×30 mm, 10 μm) was used to separate compound B-2 (2.4 g) to obtain compound D-1 (second peak, 0.9 g) and compound D-2 (first peak, 0.9 g) as a yellow solid. A mixture of (4R, 9aS)-2-(8-cyano-5-quinolyl)-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazine-8-carboxylic acid tert-butyl ester (compound D-1, 0.9 g, 2.1 mmol) in EA (20 mL) containing 1 M HCl was stirred at rt for 16 hours, and then the reactant was concentrated. The residue was dissolved in NaOH (2N, 20 mL) and then extracted twice with EA (20 mL). The organic layer was dried and concentrated to give Intermediate D (550.0 mg) as a light brown foam, LCMS (M+H): + :308.

[0453] Intermediate E

[0454] 4-[(4R,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile

[0455]

[0456] The title compound was prepared according to the following scheme:

[0457]

[0458] Step 1: Preparation of cis-2-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazine-8-carboxylic acid tert-butyl ester (Compound E-2)

[0459] 4-Chloropyrazolo[1,5-a]pyridine-7-carbonitrile (Compound E-1, 1.0 g, 5.6 mmol), cis-6-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (Compound A-10, 1.6 g, 6.2 mmol), Cs 2 CO 3 A mixture of (5.5 g, 16.9 mmol) and Ruphos Pd G2 (875.0 mg, 1.1 mmol) in dioxane (20 mL) was stirred at 90 °C for 16 hours. The reaction was then concentrated and the residue was purified using silica gel to give compound E-2 (2.0 g) as a pale yellow solid. LCMS (M+H) + :397.

[0460] Step 2: Preparation of 4-[(4R,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile (Intermediate E)

[0461] SFC (gradient: 35%, in IPA (0.1% NH 3 ·H 2 O)CO 2 Column: Daicel ChiralPak AD, 250×20 mm, 5 μm) to separate compound E-2 (2.0 g) to obtain compound E-3 (second peak, 0.9 g) and compound E-4 (first peak, 0.9 g) as a light yellow solid. A solution of (4R, 9aR)-2-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazine-8-carboxylic acid tert-butyl ester (compound E-3, 0.9 g, 2.3 mmol) in EA (30 mL) containing 1 M HCl was stirred at rt for 16 hours, and then the reactant was concentrated to obtain intermediate E (0.7 g) as a light yellow solid. LCMS (M+H) + :297.

[0462] Intermediate F

[0463] 4-[(4R,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile

[0464]

[0465] The title compound was prepared according to the following scheme:

[0466]

[0467] Step 1: Preparation of 2,4,6-trimethylbenzenesulfonic acid amino ester (Compound F-5)

[0468] To a solution of (1E)-N-(2,4,6-trimethylphenyl)sulfonyloxyacetamidic acid ethyl ester (Compound F-4, 200 g, 700 mmol) in 1,4-dioxane (500 mL) was added perchloric acid (110 mL) over 0.5 hours and stirred at 0°C for 1 hour. 1000 mL of ice water was added and the mixture was filtered. The filter cake was dissolved in 1.5 L of EtOAc and purified by Na 2 SO 4Dry and stir for 30 minutes. Concentrate the organic layer (keep the temperature below 25°C) to obtain a crude product. The crude product is recrystallized (petroleum / EtOAc=10 / 1) to obtain compound F-5 (110 g) as a white solid. LCMS (M+H) + :216.

[0469] Step 2: Preparation of 2-bromo-5-fluoro-pyridin-1-ium-1-amine 2,4,6-trimethylbenzenesulfonate (Compound F-6)

[0470] A solution of 2,4,6-trimethylbenzenesulfonic acid aminoester (Compound F-5, 110 g, 511 mmol) and 2-bromo-5-fluoropyridine (60 g, 341 mmol) in DCM (1800 mL) was stirred at 10 ° C. for 18 hours. The mixture was concentrated and the residue was recrystallized in EtOAc to give Compound F-6 (90 g) as a white solid. LCMS (M+H) + :191.

[0471] Step 3: Preparation of 7-bromo-4-fluoro-pyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester (Compound F-7)

[0472] 2-Bromo-5-fluoro-pyridin-1-ium-1-amine; 2,4,6-trimethylbenzenesulfonate (Compound F-6, 90 g, 230 mmol); K 2 CO 3 A solution of ethyl propionate (64 g, 460 mmol) and ethyl propionate (28 mL, 276 mmol) in DMF (1300 mL) was stirred at 10 °C for 18 hours. The reaction was diluted with water and then extracted with EtOAc. The organic layer was purified by Na 2 SO 4 After drying and concentration, the residue was purified by chromatography to give compound F-7 (11 g) as a yellow solid. LCMS (M+H) + :287.

[0473] Step 4: Preparation of 7-bromo-4-fluoro-pyrazolo[1,5-a]pyridine-3-carboxylic acid (Compound F-8)

[0474] A mixture of ethyl 7-bromo-4-fluoro-pyrazolo[1,5-a]pyridine-3-carboxylate (Compound F-7, 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 hours. The reaction mixture was concentrated and then diluted with water. The pH of the reaction suspension was adjusted to 4 with 1M HCl, and a gray solid precipitated, which was collected by filtration to obtain Compound F-8 (4.0 g) as a gray solid. LCMS (M+H) + :259.

[0475] Step 5: Preparation of 7-bromo-3,4-difluoro-pyrazolo[1,5-a]pyridine (Compound F-9)

[0476] To a solution of 7-bromo-4-fluoro-pyrazolo[1,5-a]pyridine-3-carboxylic acid (compound F-8, 4.0 g, 15.4 mmol) and KF (3.6 g, 61.8 mmol) in 1,2-dichloroethane (60.0 mL) and water (50.0 mL) was added a selective fluorine reagent (10.9 g, 30.9 mmol). The reaction was stirred at 70 °C for 18 hours, then quenched with water and extracted twice with DCM. The combined organic layers were purified by Na 2 SO 4 Dried and concentrated to give crude compound F-9 (2.8 g) as a grey solid. LCMS (M+H) + :233.

[0477] Step 6: Preparation of 3,4-difluoropyrazolo[1,5-a]pyridine-7-carbonitrile (Compound F-10)

[0478] To a solution of 7-bromo-3,4-difluoro-pyrazolo[1,5-a]pyridine (Compound F-9, 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) and stirred at N 2 Stir at 120°C for 18 hours under atmosphere. The mixture was quenched with water and extracted twice with EtOAc. The combined organic layer was dried and concentrated, and then the residue was purified by column chromatography to obtain compound F-10 (810.0 mg) as a white solid. LCMS (M+H) + :180.

[0479] 1H NMR (400 MHz, 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).

[0480] Step 7: Preparation of (4R,9aR)-2-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazine-8-carboxylic acid tert-butyl ester (Compound F-11)

[0481] A mixture of 3,4-difluoropyrazolo[1,5-a]pyridine-7-carbonitrile (Compound F-10, 250 mg, 1.4 mmol), (6R,9aR)-6-methyloctahydro-2H-pyrazino[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (Compound F-3, 392 mg, 1.5 mmol) and DIPEA (731 μL, 4.2 mmol) in DMSO (10.0 mL) was stirred at 120 ° C for 16 hours. The reactant was then diluted with EA and washed with water and brine. The organic layer was dried and concentrated to give Compound F-11 (0.5 g) as a yellow oil. LCMS (M+H) + :415.

[0482] Step 8: Preparation of 4-[(4R,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile (Intermediate F)

[0483] A mixture of (4R,9aR)-2-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazine-8-carboxylic acid tert-butyl ester (Compound F-11, 0.5 g, 1.2 mmol) in EA (20.0 mL) containing 1 M HCl was stirred at rt for 16 hours, and then the reaction was concentrated to give Intermediate F (400 mg) as a yellow solid.

[0484] Compound F-3 was prepared according to the following scheme:

[0485]

[0486] SFC (gradient: 10%, in EtOH (0.1% NH 3 ·H 2 O)CO 2Column: Daicel ChiralPak AD, 250×20 mm, 5 μm) was used to separate compound A-9-cis (5.0 g) to obtain compound F-1 (second peak, 2.2 g) and compound F-2 (first peak, 2.2 g) as pale yellow oils. (4R,9aR)-2-benzyl-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazine-8-carboxylic acid tert-butyl ester (compound F-1, 2.2 g, 6.4 mmol) and Pd(OH) 2 A mixture of 1H 2 O (0.9 g) and C (0.9 g) in THF (50.0 mL) was stirred at 4 °C for 2 h. 2 The mixture was stirred at 50°C for 6 hours. The reaction was then filtered and the filtrate was concentrated to give compound F-3 (1.5) as a black oil. LCMS (M+H) + :256. The stereochemical structure of compound F-3 was confirmed by its derivative (compound P).

[0487] Intermediate G

[0488] 5-[(4R,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile

[0489]

[0490] The title compound was prepared according to the following scheme:

[0491]

[0492] Step 1: Preparation of N-(2-bromo-5-fluoro-phenyl)-3,3-dimethoxy-propionamide (Compound G-2)

[0493] To a solution of 2-bromo-5-fluoroaniline (50 g, 263 mmol) and methyl 3,3-dimethoxypropionate (45 mL, 316 mmol) in THF (150 mL) was added dropwise NaHMDS in THF (394 mL, 394 mmol) at 0°C. The mixture was stirred at this temperature for 10 minutes, then warmed to 15°C and stirred for 18 hours. The reactants were washed with saturated NH 4 The solution was quenched with aqueous Cl and concentrated to about 300 mL. The solution was diluted with water and extracted with EtOAc. The organic layer was purified by Na 2 SO 4 Dry and concentrate to give compound G-2 (100 g) as brown oil. LCMS (M+H) + :306.

[0494] Step 2: Preparation of 8-bromo-5-fluoro-1H-quinolin-2-one (Compound G-3)

[0495] To a solution of N-(2-bromo-5-fluoro-phenyl)-3,3-dimethoxy-propionamide (compound G-2, 100 g, 238 mmol) in DCM (500 mL) was added concentrated sulfuric acid (300 mL) at 0°C. The mixture was stirred at 15°C for 2 hours, then slowly poured into 2000 mL of ice water, and a yellow precipitate appeared. The mixture was filtered, and the wet cake was washed with 500 mL of water, 200 mL of isopropanol, and 300 mL of PE. The solid was dried to give compound G-3 (50 g) as a yellow solid. LCMS (M+H) + :242.

[0496] Step 3: Preparation of 5-fluoro-2-oxo-1H-quinoline-8-carbonitrile (Compound G-4)

[0497] 8-Bromo-5-fluoro-1H-quinolin-2-one (compound G-3, 50 g, 206 mmol), zinc cyanide (4820 mg, 412 mmol), Pd(PPh 3 ) 4 A solution of (2428 mg, 21 mmol) in DMF was stirred at 120°C for 5 hours. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried and concentrated to give a crude product, which was purified using a flash column to give compound G-4 (29 g) as a yellow solid. LCMS (M+H) + :189.

[0498] Step 4: Preparation of (8-cyano-5-fluoro-2-quinolyl) trifluoromethanesulfonate (Compound G-5)

[0499] Trifluoromethanesulfonic anhydride (51 g, 181 mmol) was added dropwise to a solution of 5-fluoro-2-oxo-1H-quinoline-8-carbonitrile (compound G-4, 17 g, 90 mmol) and 2,6-lutidine (39 g, 361 mmol) in DCM at 0°C. The mixture was stirred at 0°C for 1 hour, then the reactant was diluted with water and extracted with DCM. The combined organic layers were dried and concentrated. The residue was purified by flash column to obtain compound G-5 (23.0 g) as a yellow solid. LCMS (M+H) + :321.

[0500] Step 5: Preparation of 2-deuterated-5-fluoroquinoline-8-carbonitrile (Compound G-6)

[0501] To a solution of (8-cyano-5-fluoro-2-quinolyl) trifluoromethanesulfonate (compound G-5, 23 g, 72 mmol) and deuterium oxide (100 mL) in THF (230 mL), potassium carbonate (20 g, 144 mmol) and Pd / C (6 g) were added. The mixture was stirred at 40 ° C for 5 hours under a deuterium atmosphere (balloon). The mixture was filtered, and the filtrate was then concentrated and purified using a flash column to obtain compound G-6 (11 g) as a light yellow solid. LCMS (M+H) + :174.

[0502] Step 6-7: Preparation of 5-[(4R,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile (Intermediate G)

[0503] The preparation of the title compound is similar to Intermediate F, but using 2-deuterated-5-fluoro-quinoline-8-carbonitrile (Compound G-6) instead of 3,4-difluoropyrazolo[1,5-a]pyridine-7-carbonitrile (Compound F-10). Intermediate G (400 mg) was obtained as a yellow solid. LCMS (M+H) + :309.

[0504] Intermediate K

[0505] 5-[(4S,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile

[0506]

[0507] The title compound was prepared according to the following scheme:

[0508]

[0509] Step 1: Preparation of (6S,9aR)-6-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (Compound K-3)

[0510] SFC (gradient: 8%, in MeOH (0.1% NH 3 ·H 2 O)CO 2 Column: Daicel ChiralPak AD, 250×50 mm, 10 μm) was used to separate compound A-9-trans (7.0 g) to obtain compound K-1 (first peak, 3.4 g) and compound K-2 (second peak, 2.7 g) as light yellow oils.

[0511] (4S,9aR)-2-benzyl-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazine-8-carboxylic acid tert-butyl ester (compound K-1, 3.4 g, 9.8 mmol) and Pd(OH) 2 A mixture of 1H 2 O 4 4-nitropropene (C) (0.8 g) in THF was 2 The mixture was stirred at 50°C for 2 hours. The reaction mixture was then filtered, and the filtrate was concentrated to give compound K-3 (2.5 g) as a black oil, LCMS (M+H): + :256.The stereochemical structure of K-3 was confirmed by its derivative (compound N).

[0512] Step 2: Preparation of 5-[(4S,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile (Intermediate K)

[0513] The preparation of the title compound was similar to Intermediate G, but (6S,9aR)-6-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (Compound K-3) was used instead of (6R,9aR)-6-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (Compound F-3). Intermediate K (700 mg) was obtained as a yellow solid. LCMS (M+H) + :309.

[0514] Intermediate L

[0515] 4-[(4R,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]-1-methyl-1,8-naphthyridin-2-one

[0516]

[0517] The title compound was prepared according to the following scheme:

[0518]

[0519] Step 1: Preparation of 2-(methylamino)pyridine-3-carboxylic acid (Compound L-2)

[0520] 2-Chloronicotinic acid (Compound L-1, 1.0 kg, 6347 mmol) was dissolved in 33% monomethylamine (386349 mmol) in ethanol. The reaction mixture was stirred at 80 ° C in an autoclave for 80 hours. The reaction mixture was concentrated in vacuo to give Compound L-2 (1.4 kg, crude product). LCMS (M+H) + :153.

[0521] Step 2: Preparation of (1-methyl-2-oxo-1,8-naphthyridin-4-yl)acetate (Compound L-3)

[0522] A solution of 2-(methylamino)pyridine-3-carboxylic acid (Compound L-2, 1.4 kg, crude product) 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 in vacuo to give Compound L-3 (1.8 kg, crude product). LCMS (M+H) + :219.

[0523] Step 3: Preparation of 4-hydroxy-1-methyl-1,8-naphthyridin-2-one (Compound L-4)

[0524] To a solution of (1-methyl-2-oxo-1,8-naphthyridin-4-yl) acetate (compound L-3, 1.8 kg, crude product) in methanol (12.0 L) was added an aqueous solution of potassium carbonate (1.9 kg, 13748 mmol) in water (3.6 L). The mixture was stirred for 2 hours at 25 ° C. The reaction mixture was then concentrated under reduced pressure to remove MeOH. The residue was acidified to pH = 4-5 with HCl solution (6N) and then extracted three times with EA (1500 mL). The combined organic layers were washed with saturated brine (1500 mL) and purified by Na 2 SO 4 Dry and concentrate in vacuo to give compound L-4 (450 g, yield 40.2%). LCMS (M+H) + :177, 1 H NMR (400 MHz, DMSO-d 6 )δppm11.68(s,1H),8.63(dd,J=4.60,1.8Hz,1H),8.22(dd,J=7.8,1.80Hz,1H),7.27(dd,J=7.8,4.6Hz,1H),5.93(s,1H),3.59(s,3H).

[0525] Step 4: Preparation of 4-chloro-1-methyl-1,8-naphthyridin-2-one (Compound L-5)

[0526] A solution of 4-hydroxy-1-methyl-1,8-naphthyridin-2-one (Compound L-4, 150.0 g, 850 mmol) 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 heated to 40 °C by adding saturated NaHCO 3 The residue was neutralized to pH 7-8 with aqueous solution, and the mixture was extracted twice with DCM (1000 mL). The combined organic layers were washed with saturated brine (500 mL), 2 SO 4 Dry and concentrate in vacuo to obtain a crude product, which is purified by silica gel chromatography (PE / EtOAc=1:0 to 7:1) to obtain compound L-5 (39 g, yield 24%). LCMS (M+H) + :195, 1 H NMR (400 MHz, DMSO-d 6 )δppm 8.75(dd,J=4.6,1.6Hz,1H),8.32(dd,J=7.9,1.7Hz,1H),7.44(dd,J=8.0,4.6Hz,1H),7.03(s,1H),3.66(s,3H).

[0527] Step 5-6: Preparation of 4-[(4R,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]-1-methyl-1,8-naphthyridin-2-one (Intermediate L)

[0528] The title compound was prepared similarly to Intermediate F, but using 4-chloro-1-methyl-1,8-naphthyridin-2-one (Compound L-5) instead of 3,4-difluoropyrazolo[1,5-a]pyridine-7-carbonitrile (Compound F-10). Intermediate L (1.8 g) was obtained as a yellow solid. LCMS (M+H) + :314.

[0529] Intermediate M

[0530] 4-[(4S,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]-1-methyl-1,8-naphthyridin-2-one

[0531]

[0532] The preparation of the title compound was similar to Intermediate F, but 4-chloro-1-methyl-1,8-naphthyridin-2-one was used instead of 3,4-difluoropyrazolo[1,5-a]pyridine-7-carbonitrile (Compound F-10) and (6S,9aR)-6-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (Compound K-3) was used instead of (6R,9aR)-6-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (Compound F-3). Intermediate M (1.7 g) was obtained as a yellow solid. LCMS (M+H) + :314.

[0533] Compound N

[0534] (4S,9aR)-4-methyl-2-(1-methyl-2-oxo-1,8-naphthyridin-4-yl)-N-(3,4,5-trifluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazine-8-carboxamide

[0535]

[0536] A mixture of 4-[(4S,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]-1-methyl-1,8-naphthyridin-2-one (Intermediate M, 200 mg, 638 μmol), phenyl N-(3,4,5-trifluorophenyl)carbamate (171 mg, 638 μmol) and DIPEA (412 mg, 3.2 mmol) in DMF (5 mL) was stirred at 60°C overnight, then the reaction was diluted with EA, washed with water and brine, the organic layer was dried and concentrated, and the residue was purified on silica gel to give compound N as a yellow solid, 250 mg. LCMS (M+H) + :487.

[0537] Compound P

[0538] (4R,9aR)-2-(8-cyano-2-deuterated-5-quinolyl)-4-methyl-N-(3,4,5-trifluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazine-8-carboxamide

[0539]

[0540] A mixture of 5-[(4R,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile (Intermediate G, 100 mg, 324 μmol), phenyl (3,4,5-trifluorophenyl)carbamate (86.6 mg, 324 μmol) and DIPEA (170 μL, 973 μmol) in DMF (5 mL) was stirred at 50°C for 2 hours. The reaction was then diluted with EA, washed with water and brine, the organic layer was dried and concentrated, and the residue was purified on silica gel to give compound P as a pale yellow solid, 100 mg. LCMS (M+H) + :482.

[0541] Example 1

[0542] 5-[cis-4-methyl-8-(1,2,3,4-tetrahydroisoquinolin-7-ylmethyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0543]

[0544] The title compound was prepared according to the following scheme:

[0545]

[0546] Step 1: Preparation of tert-butyl 7-(bromomethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (Compound 1b)

[0547] To a solution of tert-butyl 7-(hydroxymethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (Compound 1a, 1.35 g, 5.13 mmol) in DCM (30 mL) was added carbon tetrabromide (2.55 g, 7.69 mmol) at 0°C. A solution of triphenylphosphine (2.02 g, 7.69 mmol) in DCM (5 mL) was then added dropwise at 0°C, and the resulting mixture was stirred at 25°C for 30 minutes. The reaction was concentrated and the residue was purified by flash column chromatography to give Compound 1b (1.20 g) as a light yellow solid. LCMS (M-56+H) + :270,LCMS(M-56+2+H) + :272.

[0548] Step 2: Preparation of tert-butyl 7-[[cis-2-(8-cyano-5-quinolyl)-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-8-yl]methyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (Compound 1c)

[0549] A mixture of 5-[cis-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Intermediate A, 30 mg, 98 μmol), tert-butyl 7-(bromomethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (Compound 1b, 38 mg, 117 μmol) and sodium bicarbonate (25 mg, 293 μmol) in DMF (2 mL) was stirred at 100° C. for 16 hours. The reaction was then filtered and the filtrate was purified by HPLC to give Compound 1c as a light yellow solid (30 mg), LCMS (M+H) + :553.

[0550] Step 3: Preparation of 5-[cis-4-methyl-8-(1,2,3,4-tetrahydroisoquinolin-7-ylmethyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Example 1)

[0551] A mixture of tert-butyl 7-[[cis-2-(8-cyano-5-quinolinyl)-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-8-yl]methyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (Compound 1c, 30 mg, 54 μmol) in EA (5 mL) containing 1M HCl was stirred at rt for 16 hours, and then the reaction was concentrated to give Example 1 as a light yellow solid (26 mg). LCMS (M+H) + :453, 1 H NMR (400 MHz, methanol-d 4 )δppm: 8.99(dd,J=1.5,4.6Hz,1H),8.81(dd,J=1.4,8.6Hz,1H),8.21(d,J=8.1 Hz,1H),7.74(dd,J=4.5,8.6Hz,1H),7.55-7.41(m,2H),7.38(d,J=8.1Hz,1H),7 .30(d,J=7.9Hz,1H),4.55-4.38(m,2H),4.37-4.25(m,3H),4.17-4.03(m,1H), 3.87-3.53(m,8H),3.44-3.32(m,4H),3.07(t,J=6.2Hz,2H),1.54-1.36(m,3H).

[0552] Example 2

[0553] 5-[cis-4-methyl-8-(1,2,3,4-tetrahydroisoquinolin-5-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0554]

[0555] The title compound was prepared according to the following scheme:

[0556]

[0557] Step 1: Preparation of tert-butyl 5-[cis-2-(8-cyano-5-quinolyl)-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-8-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (Compound 2b)

[0558] In N 2 5-[cis-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Intermediate A, 30 mg, 98 μmol), tert-butyl 5-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylate (Compound 2a, 46 mg, 146 μmol), RuPhos Pd G2 (8 mg, 10 μmol) and Cs 2 CO 3 (95 mg, 293 μmol) in dioxane (5 mL), and then the mixture was heated to 100 ° C overnight. After cooling, the solid was filtered off and washed with EA (10 mL). The filtrate was concentrated and the residue was purified by preparative HPLC to give compound 2b as a light yellow solid (25 mg), LCMS (M+H) + :539.

[0559] Step 2: Preparation of 5-[cis-4-methyl-8-(1,2,3,4-tetrahydroisoquinolin-5-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Example 2)

[0560] A mixture of tert-butyl 5-[cis-2-(8-cyano-5-quinolinyl)-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-8-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (Compound 2b, 25 mg, 46 μmol) in EA (5 mL) containing 1 M HCl was stirred at rt for 16 hours, and then the reaction was concentrated to give Example 2 as a light red solid (19 mg). LCMS (M+H) +:439, 1 H NMR (400MHz, methanol-d4) δppm: 9.11(dd,J=1.1,4.4Hz,1H), 8.96(d,J=7.5Hz,1H), 8.32(d,J=8.1Hz,1H), 7.86(dd,J=4.6,8 .5Hz,1H),7.50(d,J=8.1Hz,1H),7.40-7.31(m,1H),7.26(d,J=7.8Hz,1H),7.10(d,J=7.7Hz,1H),4.40(s,2H),4.19(br t,J=10.2Hz,1H),4.09-3.97(m,2H),3.87-3.72(m,2H),3.63-3.37(m,8H),3.30-3.13(m,3H),1.58(d,J=6.5Hz,3H).

[0561] Example 3

[0562] 5-[cis-4-methyl-8-[(2-piperazin-1-yl-4-pyridinyl)methyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0563]

[0564] The title compound was prepared according to the following scheme:

[0565]

[0566] Step 1: Preparation of 5-[cis-8-[(2-bromo-4-pyridinyl)methyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Compound 3b)

[0567] 2-Bromo-4-(bromomethyl)pyridine (compound 3a, 49 mg, 195 μmol), 5-(4-methyloctahydro-2H-pyrazino[1,2-a]pyrazin-2-yl)quinoline-8-carbonitrile (intermediate A, 30 mg, 98 μmol) and K 2 CO 3 A mixture of (41 mg, 293 μmol) in MeCN (5 mL) was stirred at rt for 16 hours. The reaction mixture was then concentrated and the residue was purified using a silica gel column to give compound 3b as a light yellow foam (30 mg). LCMS (M+H) + :477,LCMS(M+2+H) + :479.

[0568] Step 2: Preparation of tert-butyl 4-[4-[[cis-2-(8-cyano-5-quinolyl)-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-8-yl]methyl]-2-pyridinyl]piperazine-1-carboxylate (Compound 3c)

[0569] 5-[cis-8-[(2-bromo-4-pyridinyl)methyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Compound 3b, 30 mg, 63 μmol), tert-butyl piperazine-1-carboxylate (59 mg, 314 μmol), Cs 2 CO 3 A mixture of (61 mg, 189 μmol) and RuPhos Pd G2 (9 mg, 13 μmol) in dioxane (5 mL) was stirred at 100 °C for 16 hours. The reaction mixture was then concentrated and the residue was purified using a silica gel column to give compound 3c as a light yellow foam (20 mg). LCMS (M+H) + :583.

[0570] Step 3: Preparation of 5-[cis-4-methyl-8-[(2-piperazin-1-yl-4-pyridinyl)methyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Compound 3c)

[0571] A mixture of 4-[4-[[cis-2-(8-cyano-5-quinolyl)-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-8-yl]methyl]-2-pyridinyl]piperazine-1-carboxylic acid tert-butyl ester (compound 3c, 20 mg, 34 μmol) in EA (5 mL) containing 1M HCl was stirred at rt for 16 hours. After the reaction mixture was concentrated, the residue was dissolved in NaOH (1M, 5 mL) and extracted with DCM (10 mL). The organic layer was dried and concentrated, and the residue was lyophilized to give Example 3 as a light yellow powder (10 mg). LCMS (M+H) + :483, 1H NMR (400MHz, methanol-d4) δppm: 8.96 (dd, J=1.7, 4.3Hz, 1H), 8.60 (dd, J=1.7, 8.6Hz, 1H), 8.12 (d, J=8.1Hz, 1H), 8.04 (d, J=5.1H z,1H),7.62(dd,J=4.3,8.6Hz,1H),7.21(d,J=8.1Hz,1H),6.82(s,1H),6.73(d,J=5.3Hz,1H),3.54-3.44(m,6H),3.40(br d,J=11.0Hz,1H),3.33-3.22(m,2H),3.00-2.89(m,5H),2.84-2.70(m,5H),2.37-2.22(m,2H),2.09-1.92(m,1H),1.15(d,J=5.7Hz,3H).

[0572] Example 4

[0573] 5-[cis-8-isoindolin-4-yl-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0574]

[0575] The title compound was prepared according to the following scheme:

[0576]

[0577] Example 4 was prepared similarly to Example 2, but using Compound 4a instead of Compound 2a. Example 4 was obtained as a light brown solid (26 mg). LCMS (M+H) + :425, 1 H NMR (400MHz, methanol-d4) δppm: 9.03 (dd, J=1.7, 4.2Hz, 1H), 8.74 (dd, J=1.7, 8.6H z,1H),8.23(d,J=7.9Hz,1H),7.72(dd,J=4.3,8.6Hz,1H),7.51-7.34(m,2H), 7.19(dd,J=7.6,16.0Hz,2H),4.70(s,2H),4.64(s,2H),4.21-3.89(m,3H),3. 85-3.71(m,2H),3.62-3.37(m,4H),3.25-3.10(m,2H),1.54(d,J=6.6Hz,3H).

[0578] Example 5

[0579] 5-[(4R,9aS)-4-methyl-8-(1,2,3,4-tetrahydroisoquinolin-7-ylmethyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0580]

[0581] Example 5 was prepared similarly to Example 1, but Intermediate C was used instead of Intermediate A. Example 5 was obtained as an orange solid (113 mg). LCMS (M+H) + :453, 1 H NMR (400MHz, methanol-d4) δppm: 9.09 (dd, J=1.5, 4.5Hz, 1H), 8.88 (dd, J=1.6, 8.6Hz, 1H), 8.30 (d, J=8.1Hz, 1H), 7.83 (dd, J=4.5, 8.6Hz,1H),7.65-7.53(m,2H),7.48(d,J=8.1Hz,1H),7.42(d,J=7.9Hz,1H),4.63-4.48(m,2H),4.48-4.36(m,3H),4.22(br d,J=13.1Hz,1H),3.98-3.60(m,8H),3.58-3.39(m,4H),3.19(t,J=6.3Hz,2H),1.56(d,J=6.4Hz,3H).

[0582] Example 6

[0583] 5-[(4R,9aS)-4-methyl-8-(5,6,7,8-tetrahydro-1,6-naphthyridin-3-ylmethyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0584]

[0585] The title compound was prepared according to the following scheme:

[0586]

[0587] Step 1: Preparation of 7,8-dihydro-5H-1,6-naphthyridine-3,6-dicarboxylic acid O6-tert-butyl O3-methyl ester (Compound 6b)

[0588] 1,3-bis(diphenylphosphino)propane (1.7 g, 4.1 mmol), triethylamine (7.1 mL, 51.1 mmol) and palladium(II) acetate (0.9 mg, 4.0 mmol) were added to a solution of tert-butyl 3-bromo-7,8-dihydro-5H-1,6-naphthyridine-6-carboxylate (compound 6a, 3.2 g, 10.2 mmol) in methanol (50.0 mL). The mixture was purged with nitrogen three times. The reaction mixture was then stirred at 100 ° C for 16 hours under carbon monoxide (2280 mmHg). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 6b (2.6 g) as a light yellow solid. LCMS (M+H) + :293.

[0589] Step 2: Preparation of tert-butyl 3-(hydroxymethyl)-7,8-dihydro-5H-1,6-naphthyridine-6-carboxylate (Compound 6c)

[0590] To a solution of 7,8-dihydro-5H-1,6-naphthyridine-3,6-dicarboxylic acid O6-tert-butyl O3-methyl ester (compound 6b, 2.5 g, 8.5 mmol) in DCM (30.0 mL) was added DIBAL-H (17.0 mL, 17.0 mmol) at 0°C. The reaction mixture was then stirred at 0°C for 2 hours. The reaction mixture was quenched with aqueous potassium sodium tartrate solution and extracted with DCM. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography to give compound 6c (1.1 g) as a yellow solid. LCMS (M+H) + :265, 1 H NMR (400MHz, chloroform-d) δppm: 8.38(s,1H),7.46(s,1H),5.30(s,1H),4.71(s,2H),4.60(s,2H),3.75(t,J=5.9Hz,2H),2.99(br t,J=5.7Hz,2H),1.50(s,9H).

[0591] Step 3: Preparation of tert-butyl 3-(methylsulfonyloxymethyl)-7,8-dihydro-5H-1,6-naphthyridine-6-carboxylate (Compound 6d)

[0592] A mixture of tert-butyl 3-(hydroxymethyl)-7,8-dihydro-5H-1,6-naphthyridine-6-carboxylate (Compound 6c, 200 mg, 757 μmol), DIPEA (396 μL, 2270 μmol) and methanesulfonic anhydride (264 mg, 1510 μmol) in DCM (10 mL) was stirred at rt for 16 hours. The reaction was then diluted with DCM and washed with water, K 2 CO3 (1N aqueous solution) and brine, the organic layer was dried and concentrated to give compound 6d as a light yellow oil (200 mg). LCMS (M+H) + :343.

[0593] Step 4: Preparation of tert-butyl 3-[[(4R,9aS)-2-(8-cyano-5-quinolyl)-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-8-yl]methyl]-7,8-dihydro-5H-1,6-naphthyridine-6-carboxylate (Compound 6e)

[0594] Tert-butyl 3-(methylsulfonyloxymethyl)-7,8-dihydro-5H-1,6-naphthyridine-6-carboxylate (Compound 6d, 111 mg, 325 μmol), 5-[(4R,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Intermediate C, 50 mg, 163 μmol) and K 2 CO 3 A mixture of (67 mg, 488 μmol) in MeCN (5 mL) was stirred at rt for 16 hours. The reaction was then concentrated and the residue was purified by preparative HPLC to give compound 6e as a light yellow solid (15 mg). LCMS (M+H) + :554.

[0595] Step 5: Preparation of 5-[(4R,9aS)-4-methyl-8-(5,6,7,8-tetrahydro-1,6-naphthyridin-3-ylmethyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Example 6)

[0596] A mixture of tert-butyl 3-[[(4R,9aS)-2-(8-cyano-5-quinolyl)-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-8-yl]methyl]-7,8-dihydro-5H-1,6-naphthyridine-6-carboxylate (Compound 6e, 15 mg, 27 μmol) in EA (2 mL) containing 1M HCl was stirred at rt for 16 hours. The reaction was then concentrated to give Example 6 as an orange solid (15 mg). LCMS (M+H) + :454. 1H NMR (400MHz, methanol-d4) δppm: 9.08 (d, J = 3.8Hz, 1H), 8.94-8.83 (m, 2H), 8.55 (s, 1H), 8.28(d,J=7.9Hz,1H),7.82(dd,J=4.4,8.4Hz,1H),7.45(d,J=8.1Hz,1H),4.68(s ,2H),4.21-3.95(m,4H),3.94-3.86(m,1H),3.80-3.65(m,4H),3.54-3.46(m,2H) ,3.45-3.35(m,5H),3.13-3.00(m,1H),2.86-2.75(m,1H),1.54(d,J=6.5Hz,3H).

[0597] Example 7

[0598] 5-[(4R,9aS)-4-methyl-8-[2-(4-piperazin-1-ylphenyl)ethyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0599]

[0600] The title compound was prepared according to the following scheme:

[0601]

[0602] Step 1: Preparation of 5-[(4R,9aS)-8-[2-(4-bromophenyl)ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Compound 7b)

[0603] 1-Bromo-4-(2-bromoethyl)benzene (Compound 7a, 51.5 mg, 195 μmol), 5-[(4R,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Intermediate C, 40 mg, 130 μmol) and K 2 CO 3 A mixture of (54 mg, 390 μmol) in MeCN (3 mL) was stirred at 80 °C for 16 hours. The reaction mixture was then filtered and concentrated to give compound 7b as a light yellow solid (60 mg), LCMS (M+H) + :491.

[0604] Step 2: Preparation of 5-[(4R,9aS)-4-methyl-8-[2-(4-piperazin-1-ylphenyl)ethyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Example 7)

[0605] The preparation of Example 7 was similar to Example 3, but 5-[(4R,9aS)-8-[2-(4-bromophenyl)ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Compound 7b) was used instead of Compound 3b. Example 7 was obtained as an orange solid (58 mg). LCMS (M+H) + :496, 1 H NMR (400MHz, methanol-d4) δppm: 9.12 (dd, J=1.5, 4.6Hz, 1H), 8.96 (dd, J=1.6, 8.6Hz, 1H), 8.34 (d, J=8.1Hz, 1H), 7.88 (dd ,J=4.5,8.6Hz,1H),7.52(d,J=8.1Hz,1H),7.31(d,J=8.6Hz,2H),7.08(d,J=8.7Hz,2H),4.48-4.36(m,1H),4.26(br d,J=13.2Hz,1H),4.14-3.94(m,3H),3.88-3.75(m,3H),3.72-3.62(m,2H),3. 59-3.48(m,4H),3.48-3.38(m,8H),3.22-3.09(m,2H),1.58(d,J=6.4Hz,3H).

[0606] Example 8

[0607] 5-[(4R,9aS)-4-methyl-8-[(6-piperazin-1-yl-3-pyridinyl)methyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0608]

[0609] Example 8 was prepared similarly to Example 3, but Intermediate C was used instead of Intermediate A and 2-bromo-5-(bromomethyl)pyridine was used instead of Compound 3a. Example 8 was obtained as an orange solid (17 mg). LCMS (M+H) + :483, 1H NMR (400MHz, methanol-d4) δppm: 9.09(dd,J=1.4,4.5Hz,1H),8.87(dd,J=1.5,8.6Hz,1H),8.37-8.24(m,3H),7.82(dd,J=4.5,8.6Hz,1H),7.49(dd,J=8.7,1 4.3Hz,2H),4.43-4.11(m,4H),4.09-4.03(m,4H),3.99-3.86(m,1H),3.80- 3.66(m,4H),3.58-3.47(m,6H),3.45-3.38(m,3H),1.55(d,J=6.48Hz,3H).

[0610] Example 9

[0611] 5-[(4R,9aS)-8-isoindolin-4-yl-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0612]

[0613] Example 9 was prepared similarly to Example 2, but Intermediate C was used instead of Intermediate A and Compound 4a was used instead of Compound 2a. Example 9 was obtained as an orange solid (65 mg). LCMS (M+H) + :425, 1 H NMR (400MHz, methanol-d4) δppm: 9.08 (dd, J=1.6, 4.4Hz, 1H), 8.84 (dd, J=1.6, 8.6Hz, 1H), 8.28 (d, J=8.1Hz, 1H), 7. 78(dd,J=4.4,8.6Hz,1H),7.54-7.40(m,2H),7.21(dd,J=7.8,14.4Hz,2H),4.73(s,2H),4.66(s,2H),4.16(br t,J=10.9Hz,1H),4.10-3.96(m,2H),3.86-3.74(m,2H),3.62-3.53(m,2H),3.51-3.37(m,4H),3.28-3.19(m,1H),1.58(d,J=6.48Hz,3H).

[0614] Example 10

[0615] 5-[(4R,9aS)-4-methyl-8-(1,2,3,4-tetrahydroisoquinolin-6-ylmethyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0616]

[0617] The preparation of Example 10 was similar to Example 1, but Intermediate C was used instead of Intermediate A and 6-(bromomethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester was used instead of Compound 1b. Example 10 was obtained as a light yellow solid (46 mg). LCMS (M+H) + :453, 1 H NMR (400MHz, methanol-d4) δppm: 9.07(dd,J=1.6,4.4Hz,1H), 8.81(dd,J=1.6,8.7Hz,1H), 8.27(d,J=7.9Hz,1H), 7.78(dd,J=4.4,8.6Hz ,1H),7.60-7.55(m,2H),7.44(d,J=7.9Hz,1H),7.38(d,J=7.8Hz,1H),4.59-4.46(m,2H),4.43(s,2H),4.36-4.26(m,1H),4.17(br d,J=13.3Hz,1H),3.94-3.67(m,6H),3.65-3.48(m,4H),3.44-3.35(m,2H),3.26-3.17(m,2H),1.53(d,J=6.4Hz,3H).

[0618] Example 11

[0619] 5-[(4R,9aS)-4-methyl-8-[2-(6-piperazin-1-yl-3-pyridinyl)ethyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0620]

[0621] The title compound was prepared according to the following scheme:

[0622]

[0623] Step 1: Preparation of 2-(6-chloro-3-pyridyl)ethanol (Compound 11b)

[0624] A mixture of 2-(6-chloropyridin-3-yl)acetic acid (compound 11a, 4 g, 23 mmol) in borane-tetrahydrofuran complex (47 mL, 47 mmol) was stirred at rt for 1 hour. After the reaction was quenched with MeOH, the mixture was concentrated and the residue was purified by silica gel column to obtain compound 11b as a colorless oil (4 g). LCMS (M+H) + :158.

[0625] Step 2: Preparation of 2-(6-chloro-3-pyridyl)ethyl methanesulfonate (Compound 11c)

[0626] To a mixture of 2-(6-chloro-3-pyridyl)ethanol (compound 11b, 4.0 g, 25.4 mmol) and DIPEA (13.3 ml, 76.1 mmol) in DCM (50.0 mL) was slowly added methanesulfonic anhydride (6.6 g, 38.1 mmol) at rt. The reaction mixture was stirred at rt for 15 min and then washed with NaHCO 3 Diluted and extracted with EtOAc. The organic layer was dried and concentrated to give compound 11c as a light brown oil (5.0 g), LCMS (M+H): + :236.

[0627] Step 3: Preparation of 5-[(4R,9aS)-8-[2-(6-chloro-3-pyridinyl)ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Compound 11d)

[0628] A mixture of 2-(6-chloro-3-pyridyl)ethyl methanesulfonate (compound 11c, 173 mg, 732 μmol), 5-[(4R, 9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (intermediate C, 150 mg, 488 μmol) and potassium carbonate (202 mg, 1460 μmol) in MeCN (10 mL) was stirred at 80° C. for 16 hours. The reaction was then concentrated and the residue was purified using a silica gel column to give compound 11d as a light yellow solid (150 mg), LCMS (M+H) + :447.

[0629] Step 4: Preparation of 5-[(4R,9aS)-4-methyl-8-[2-[6-(4-methylpiperazin-1-yl)-3-pyridinyl]ethyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Compound 11e)

[0630] A mixture of 5-[(4R,9aS)-8-[2-(6-chloro-3-pyridinyl)ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (compound 11d, 60 mg, 134 μmol), tert-butyl piperazine-1-carboxylate (38 mg, 201 μmol), cesium carbonate (131 mg, 403 μmol) and RuPhos Pd G2 (19 mg, 27 μmol) in dioxane (5 mL) was stirred at 110° C. for 16 hours. The reaction was then concentrated and the residue was purified by preparative HPLC to give compound 11e as a light yellow powder (35 mg), LCMS (M+H) + :597.

[0631] Step 5: Preparation of 5-[(4R,9aS)-4-methyl-8-[2-(6-piperazin-1-yl-3-pyridinyl)ethyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Example 11)

[0632] A mixture of 5-[(4R,9aS)-4-methyl-8-[2-[6-(4-methylpiperazin-1-yl)-3-pyridinyl]ethyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (compound 11e, 35 mg, 59 μmol) in EA (5 mL) containing 1M HCl was stirred at rt for 16 hours. The reaction was then concentrated and the residue was lyophilized to give Example 11 as an orange solid (32 mg). LCMS (M+H) + :497. 1 H NMR (400MHz, methanol-d4) δppm: 9.08 (dd, J=1.6, 4.3Hz, 1H), 8.83 (dd, J=1.6, 8.6Hz, 1H), 8.28 (d, J =7.9Hz,1H),8.24-8.11(m,2H),7.80(dd,J=4.4,8.7Hz,1H),7.52(d,J=9.4Hz,1H),7.46(d,J= 7.9Hz,1H),4.38-4.24(m,1H),4.23-4.12(m,1H),4.07-3.95(m,6H),3.92-3.81(m,1H),3.78 -3.63(m,3H),3.63-3.47(m,8H),3.47-3.38(m,2H),3.27-3.19(m,2H),1.54(d,J=6.5Hz,3H).

[0633] Example 12

[0634] 5-[(4R,9aS)-8-[2-[6-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0635]

[0636] Example 12 was prepared similarly to Example 11, but using tert-butyl N-[(3R,4R)-4-methoxypyrrolidin-3-yl]carbamate instead of tert-butyl piperazine-1-carboxylate. Example 12 was obtained as an orange solid (34 mg). LCMS (M+H) + :527, 1 HNMR (400MHz, methanol-d4) δppm: 9.08 (dd, J=1.6, 4.4Hz, 1H), 8.82 (dd, J=1.6, 8.6Hz, 1H), 8.28 (d, J=8.1Hz ,1H),8.16(dd,J=2.1,9.4Hz,1H),8.07(d,J=1.6Hz,1H),7.79(dd,J=4.3,8.6Hz,1H),7.46(d,J=8.1Hz ,1H),7.24(d,J=9.3Hz,1H),4.36-4.23(m,2H),4.21-4.09(m,4H),4.05-3.94(m,2H),3.91-3.82(m,2 H), 3.81-3.64 (m, 4H), 3.63-3.45 (m, 7H), 3.43-3.36 (m, 2H), 3.26-3.18 (m, 2H), 1.54 (d, J = 6.4Hz, 3H).

[0637] Example 13

[0638] 5-[(4R,9aS)-8-[2-[5-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]-2-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0639]

[0640] The title compound was prepared according to the following scheme:

[0641]

[0642] The preparation of Example 13 was similar to Example 11, but using Compound 13a instead of Compound 11b and using tert-butyl N-[(3R, 4R)-4-methoxypyrrolidin-3-yl]carbamate instead of tert-butyl piperazine-1-carboxylate. Example 13 was obtained as an orange solid (22 mg). LCMS (M+H) + :527, 1 HNMR (400MHz, methanol-d4) δppm: 9.07 (dd, J=1.5, 4.3Hz, 1H), 8.85 (dd, J=1.5, 8.6Hz, 1H), 8.27 (d, J=7.9Hz, 1H), 8.12 ( d,J=2.7Hz,1H),7.91-7.86(m,1H),7.80(td,J=4.1,8.5Hz,2H),7.45(d,J=8.1Hz,1H),4.31-4.23(m,1H),4.17(br s,1H),4.04(br dd,J=3.7,6.8Hz,2H),3.96(dd,J=5.5,11.1Hz,1H),3.92-3.82(m,2H),3.79-3.65(m,4H),3. 64-3.59(m,1H),3.57-3.46(m,5H),3.45-3.35(m,7H),3.11-2.98(m,1H),1.59-1.46(m,3H).

[0643] Example 15

[0644] 5-[(4R,9aS)-8-[[6-(1,4-diazepan-1-yl)-3-pyridinyl]methyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0645]

[0646] The preparation of Example 15 was similar to Example 3, but Intermediate C was used instead of Intermediate A, 2-bromo-5-(bromomethyl)pyridine was used instead of Compound 3a, and 1,4-diazepane-1-carboxylic acid tert-butyl ester was used instead of piperazine-1-carboxylic acid tert-butyl ester. Example 15 was obtained as a light yellow solid (23 mg). LCMS (M+H) + :497, 1H NMR (400MHz, methanol-d4) δppm: 9.08 (dd, J=1.5, 4.5Hz, 1H), 8.86 (dd, J=1.6, 8.6Hz, 1H) ,8.36-8.24(m,3H),7.82(dd,J=4.5,8.6Hz,1H),7.51(d,J=9.4Hz,1H),7.49-7.44 (m,1H),4.50-4.39(m,1H),4.35-4.28(m,1H),4.25-4.14(m,4H),3.97-3.87(m,3H ),3.87-3.69(m,4H),3.61-3.38(m,9H),2.40-2.34(m,2H),1.55(d,J=6.4Hz,3H).

[0647] Example 16

[0648] 5-[(4R,9aR)-4-methyl-8-(5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0649]

[0650] The preparation of Example 16 was similar to Example 2, but Intermediate D was used instead of Intermediate A and 5-chloro-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylic acid tert-butyl ester was used instead of Compound 2a. Example 16 was obtained as an orange solid (20 mg). LCMS (M+H) + :440, 1 H NMR (400MHz, methanol-d4) δppm: 9.10 (dd, J=1.6, 4.4Hz, 1H), 8.99 (dd, J=1.3, 8.6Hz, 1H), 8.31 (d, J=8.1Hz, 1H), 8.26 (d, J=5.9Hz, 1H), 7.86 (dd, J= 4.5,8.6Hz,1H),7.51(d,J=8.1Hz,1H),7.28(d,J=5.9Hz,1H),4.57(s,3H),4.09-3.74(m,7H),3.67-3.47(m,5H),3.28-3.17(m,3H),1.85(br d,J=4.9Hz,3H).

[0651] Example 17

[0652] 5-[(4R,9aS)-8-[2-[6-[(3R,4S)-3-amino-4-fluoro-pyrrolidin-1-yl]-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0653]

[0654] Example 17 was prepared similarly to Example 11, but using tert-butyl N-[(3R,4S)-4-fluoropyrrolidin-3-yl]carbamate instead of tert-butyl piperazine-1-carboxylate. Example 17 was obtained as an orange solid (8 mg). LCMS (M+H) + :515, 1 H NMR (400MHz, methanol-d4) δppm: 9.28-9.06 (m, 2H), 8.42 (d, J = 8.2Hz, 1H), 8.20 (dd, J = 2.0, 9.4Hz ,1H),8.14(d,J=1.6Hz,1H),8.02(dd,J=4.9,8.6Hz,1H),7.60(d,J=8.2Hz,1H),7.26(d,J= 9.3Hz,1H),5.73(t,J=2.8Hz,0.5H),5.60(t,J=2.9Hz,0.5H),4.64-4.49(m,1H),4.44-4.2 6(m,3H),4.24-4.03(m,5H),3.97-3.48(m,10H),3.32-3.25(m,2H),1.61(d,J=6.5Hz,3H).

[0655] Example 18

[0656] 5-[(4R,9aS)-8-[2-[6-[(3R,4R)-3-amino-4-fluoro-pyrrolidin-1-yl]-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0657]

[0658] Example 18 was prepared similarly to Example 11, but using tert-butyl N-[(3R,4R)-4-fluoropyrrolidin-3-yl]carbamate instead of tert-butyl piperazine-1-carboxylate. Example 18 was obtained as an orange solid (5 mg). LCMS (M+H) + :515, 1H NMR (400MHz, methanol-d4) δppm: 8.95 (dd, J=1.5, 4.3Hz, 1H), 8.67 (dd, J=1.6, 8.6Hz, 1H), 8.14 (d, J=7.9Hz ,1H),8.06(dd,J=2.1,9.3Hz,1H),7.98(d,J=1.6Hz,1H),7.65(dd,J=4.4,8.6Hz,1H),7.32(d,J=8.1 Hz,1H),7.15(d,J=9.3Hz,1H),5.55(br,0.5H),5.42(br,0.5H),4.32-4.08(m,3H),4.07-3.91(m,3H ),3.89-3.74(m,3H),3.71-3.54(m,3H),3.50-3.25(m,7H),3.14-3.04(m,2H),1.38(d,J=6.4Hz,3H).

[0659] Example 19

[0660] 5-[(4R,9aS)-8-[2-[5-[(3R,4S)-3-amino-4-fluoro-pyrrolidin-1-yl]-2-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0661]

[0662] The preparation of Example 19 was similar to Example 11, but using Compound 13c instead of Compound 11d and using tert-butyl N-[(3R,4S)-4-fluoropyrrolidin-3-yl]carbamate instead of tert-butyl piperazine-1-carboxylate. Example 19 was obtained as an orange solid (48 mg). LCMS (M+H) + :515, 1 H NMR (400MHz, methanol-d4) δppm: 9.11 (dd, J=1.5, 4.5Hz, 1H), 8.94 (dd, J=1.5, 8.7Hz, 1 H),8.32(d,J=7.9Hz,1H),8.15(d,J=2.8Hz,1H),7.95-7.78(m,3H),7.50(d,J=8. 1Hz,1H),5.65(br,0.5H),5.52(br,0.5H),4.40-4.12(m,3H),4.11-4.02(m,1H), 4.02-3.84(m,5H),3.84-3.73(m,2H),3.68-3.38(m,10H),1.56(d,J=6.4Hz,3H).

[0663] Example 20

[0664] 5-[(4R,9aS)-4-methyl-8-[2-[5-[(3S)-3-methylpiperazin-1-yl]-2-pyridinyl]ethyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0665]

[0666] The preparation of Example 20 was similar to Example 11, but using Compound 13c instead of Compound 11d and using (2S)-2-methylpiperazine-1-carboxylic acid tert-butyl ester instead of piperazine-1-carboxylic acid tert-butyl ester. Example 20 was obtained as an orange solid (37 mg). LCMS (M+H) + :511, 1 H NMR (400 MHz, methanol-d4) δ ppm: 9.10 (d, J = 3.9 Hz, 1H), 8.92 (br d,J=8.4Hz,1H),8.50(s,1H),8.31(d,J=8.1Hz,1H),8.25-8.19(m,1H),7.95 (d,J=9.0Hz,1H),7.84(dd,J=4.6,8.4Hz,1H),7.49(d,J=8.1Hz,1H),4.37-4 .24(m,1H),4.18-4.06(m,3H),3.95-3.70(m,5H),3.64-3.35(m,12H),3.29- 3.20(m,1H),3.16-3.06(m,1H),1.55(d,J=6.2Hz,3H),1.46(d,J=6.5Hz,3H).

[0667] Example 21

[0668] 5-[(4R,9aS)-4-methyl-8-[2-[6-[(3S)-3-methylpiperazin-1-yl]-2-pyridinyl]ethyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0669]

[0670] The title compound was prepared according to the following scheme:

[0671]

[0672] The preparation of Example 21 was similar to Example 11, but using Compound 21a instead of Compound 11b and using (2S)-2-methylpiperazine-1-carboxylic acid tert-butyl ester instead of piperazine-1-carboxylic acid tert-butyl ester. Example 21 was obtained as an orange solid (14 mg). LCMS (M+H) + :511, 1 H NMR (400MHz, methanol-d4) δppm: 9.11 (dd, J=1.5, 4.5Hz, 1H), 8.95 (dd, J=1.5, 8.7Hz, 1H), 8.33 (d, J =8.1Hz,1H),8.00(dd,J=7.4,8.9Hz,1H),7.86(dd,J=4.5,8.6Hz,1H),7.51(d,J=8.1Hz,1H), 7.29(d,J=8.9Hz,1H),7.10(d,J=7.3Hz,1H),4.70-4.51(m,2H),4.49-4.36(m,1H),4.29-3.9 4(m,4H),3.87-3.71(m,5H),3.69-3.38(m,11H),1.57(d,J=6.5Hz,3H),1.47(d,J=6.5Hz,3H).

[0673] Example 22

[0674] 5-[(4R,9aS)-4-methyl-8-[2-[6-(6-methyl-2,6-diazaspiro[3.3]heptane-2-yl)-3-pyridinyl]ethyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0675]

[0676] A mixture of 5-[(4R,9aS)-8-[2-(6-chloro-3-pyridinyl)ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (compound 11d, 50 mg, 112 μmol), 2-methyl-2,6-diazaspiro[3.3]heptane (12 mg, 112 μmol), cesium carbonate (109 mg, 336 μmol) and RuPhos Pd G2 (16 mg, 22 μmol) in dioxane (5 mL) was stirred at 110° C. for 16 hours. The reaction was then concentrated and the residue was purified by preparative HPLC to give Example 22 as a light yellow solid (13 mg). LCMS (M+H) + :523, 1H NMR (400MHz, methanol-d4) δppm: 9.03 (dd, J=1.6, 4.3Hz, 1H), 8.66 (dd, J=1.6, 8.6Hz, 1H), 8.20 (d,J=8.1Hz,1H),7.96(d,J=1.8Hz,1H),7.78(dd,J=2.0,9.0Hz,1H),7.68(dd,J=4.2,8. 6Hz,1H),7.31(d,J=7.9Hz,1H),6.69(d,J=8.9Hz,1H),4.64-4.52(m,2H),4.44-4.26(m, 6H),3.71-3.46(m,6H),3.26-3.17(m,2H),3.10-2.88(m,9H),2.84-2.63(m,2H),1.28(br d,J=6.1Hz,3H).

[0677] Example 24

[0678] 5-[(4R,9aS)-8-[2-[6-[(3R,4S)-3-amino-4-methoxy-pyrrolidin-1-yl]-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0679]

[0680] Example 24 was prepared similarly to Example 11, but using tert-butyl N-[(3R,4S)-4-methoxypyrrolidin-3-yl]carbamate instead of tert-butyl piperazine-1-carboxylate. Example 24 was obtained as an orange solid (17 mg). LCMS (M+H) + :527, 1 HNMR (400MHz, methanol-d4) δppm: 9.07 (dd, J=1.5, 4.3Hz, 1H), 8.80 (dd, J=1.5, 8.5Hz, 1H), 8.27 (d ,J=7.9Hz,1H),8.15(dd,J=2.1,9.3Hz,1H),8.06(d,J=1.6Hz,1H),7.78(dd,J=4.3,8.6Hz,1H ),7.44(d,J=8.1Hz,1H),7.23(d,J=9.4Hz,1H),4.41-4.35(m,1H),4.28-4.07(m,4H),4.02- 3.90(m,3H),3.89-3.67(m,6H),3.65-3.38(m,9H),3.25-3.14(m,2H),1.52(d,J=6.4Hz,3H).

[0681] Example 25

[0682] 5-[(4R,9aS)-8-[2-[6-[(3S,4S)-3-amino-4-methoxy-pyrrolidin-1-yl]-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0683]

[0684] Example 25 was prepared similarly to Example 11, but using tert-butyl N-[(3S,4S)-4-methoxypyrrolidin-3-yl]carbamate instead of tert-butyl piperazine-1-carboxylate. Example 25 was obtained as an orange solid (23 mg). LCMS (M+H) + :527, 1 HNMR (400MHz, methanol-d4) δppm: 9.09 (dd, J=1.6, 4.4Hz, 1H), 8.84 (dd, J=1.6, 8.7Hz, 1H), 8.29 (d, J=8.1Hz, 1H), 8.16 (dd, J=2.1, 9.4Hz, 1H), 8.0 8(d,J=1.6Hz,1H),7.81(dd,J=4.5,8.6Hz,1H),7.47(d,J=7.9Hz,1H),7.24(d,J=9.3Hz,1H),4.40-4.28(m,2H),4.23-4.07(m,4H),4.02(br d,J=13.8Hz,2H),3.96-3.81(m,2H),3.80-3.68(m,4H),3.65-3.50(m,7H),3.48-3.37(m,2H),3.27-3.18(m,2H),1.55(d,J=6.4Hz,3H).

[0685] Example 26

[0686] 5-[(4R,9aS)-8-[2-[4-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]phenyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0687]

[0688] The preparation of Example 26 was similar to Example 3, but 5-[(4R, 9aS)-8-[2-(4-bromophenyl)ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazine-2-yl]quinoline-8-carbonitrile (Compound 7b) was used instead of Compound 3b and tert-butyl N-[(3R, 4R)-4-methoxypyrrolidin-3-yl]carbamate was used instead of tert-butyl piperazine-1-carboxylate. Example 26 was obtained as a brown solid (27 mg). LCMS (M+H) + :526, 1 H NMR (400MHz, methanol-d4) δppm: 9.01 (dd, J=1.4, 4.6Hz, 1H), 8.87 (dd, J=1.3, 8.6Hz, 1H), 8.23 ​​(d, J=8.1Hz, 1H) ,7.78(dd,J=4.6,8.6Hz,1H),7.41(d,J=8.2Hz,1H),7.12(d,J=8.6Hz,2H),6.57(d,J=8.7Hz,2H),4.31(br d,J=1.3Hz,1H),4.14(br d,J=13.0Hz,1H),4.03-3.85(m,4H),3.81-3.63(m,5H),3.60-3.48(m,3H),3.45-3 .29(m,8H),3.15(dd,J=3.5,10.7Hz,1H),3.06-2.93(m,2H),1.47(d,J=6.4Hz,3H).

[0689] Example 27

[0690] 5-[(4R,9aS)-4-methyl-8-[(6-piperazin-1-yl-2-pyridinyl)methyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0691]

[0692] Example 27 was prepared similarly to Example 3, but Intermediate C was used instead of Intermediate A and 2-bromo-6-(bromomethyl)pyridine was used instead of Compound 3a. Example 27 was obtained as a light brown solid (20 mg). LCMS (M+H) + :483, 1H NMR (400MHz, methanol-d4) δppm: 9.12 (dd, J=1.5, 4.6Hz, 1H), 8.97 (dd, J=1.5, 8.6Hz, 1H ),8.32(d,J=7.9Hz,1H),7.91-7.77(m,2H),7.50(d,J=8.1Hz,1H),7.11(d,J=8.8 Hz,1H),7.02(d,J=7.2Hz,1H),4.63-4.51(m,1H),4.47(s,2H),4.23-4.12(m,1H) ,4.08-3.97(m,5H),3.94-3.70(m,6H),3.56-3.37(m,7H),1.57(d,J=6.5Hz,3H).

[0693] Example 28

[0694] 5-[(4R,9aS)-4-methyl-8-[2-[4-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)phenyl]ethyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0695]

[0696] The preparation of Example 28 was similar to Example 3, but 5-[(4R,9aS)-8-[2-(4-bromophenyl)ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Compound 7b) was used instead of Compound 3b and tert-butyl 5-oxa-2,8-diazaspiro[3.5]nonane-8-carboxylate was used instead of tert-butyl piperazine-1-carboxylate. Example 28 was obtained as a brown solid (27 mg). LCMS (M+H) + :538, 1H NMR (400MHz, methanol-d4) δppm: 8.90 (dd, J=1.7, 4.2Hz, 1H), 8.52 (dd, J=1.7, 8.6Hz, 1H), 8.06 (d, J=8.1Hz ,1H),7.56(dd,J=4.2,8.6Hz,1H),7.17(d,J=8.1Hz,1H),7.06(d,J=8.6Hz,2H),6.43(d,J=8.4Hz,2H) ,3.90(d,J=8.6Hz,2H),3.86-3.79(m,2H),3.62(d,J=7.9Hz,3H),3.54-3.31(m,6H),3.28-3.22(m,2H ),3.18-3.13(m,2H),3.11-3.03(m,1H),2.99-2.69(m,7H),2.49-2.36(m,1H),1.10(d,J=5.9Hz,3H).

[0697] Example 30

[0698] 5-[(4R,9aR)-4-methyl-8-(4-piperazin-1-ylpyrimidin-2-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0699]

[0700] The title compound was prepared according to the following scheme:

[0701]

[0702] Step 1: Preparation of tert-butyl 4-(2-chloropyrimidin-4-yl)piperazine-1-carboxylate (Compound 30b)

[0703] 2,4-Dichloropyrimidine (Compound 30a, 100 mg, 671 μmol), K 2 CO 3 A mixture of 1,4-dihydro-1,4-dihydro-2-nitropropene (185 mg, 1340 μmol) and tert-butyl piperazine-1-carboxylate (138 mg, 738 μmol) in DMF (3 mL) was stirred at 50 °C for 2 hours. The reaction mixture was then diluted with EtOAc (40 mL) and washed with water. The organic layer was purified by Na 2 SO 4 Dried and concentrated. The residue was purified by flash column chromatography to give compound 30b (100 mg) as a white solid. LCMS (M+H) + :299,LCMS(M+H+2) + :301.

[0704] Step 2: Preparation of 5-[(4R,9aR)-4-methyl-8-(4-piperazin-1-ylpyrimidin-2-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0705] tert-Butyl 4-(2-chloropyrimidin-4-yl)piperazine-1-carboxylate (Compound 30b, 43 mg, 143 μmol), K 2 CO 3 A mixture of 5-[(4R,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Intermediate C, 40 mg, 130 μmol) in MeCN (1 mL) was stirred overnight at 120 °C. The reaction mixture was then concentrated and the residue was purified by flash column chromatography to give the coupled product, which was dissolved in dioxane (3 mL) and treated with HCl in dioxane (4 M, 2 mL). After the reaction mixture was stirred at rt for 2 hours, it was concentrated to give Example 30 (60 mg) as a yellow solid. LCMS (M+H) + :470. 1 H NMR (400MHz, methanol-d4) δppm: 8.99 (dd, J=1.3, 4.5Hz, 1H), 8.85 (dd, J=1.4, 8.6Hz, 1H), 8.21 (d, J=7.9Hz, 1H), 7.85 (d, J=7.5Hz, 1H), 7.76 (dd,J=4.6,8.6Hz,1H),7.41(d,J=8.1Hz,1H),6.62(d,J=7.6Hz,1H),4.75-4.62(m,2H),4.26-4.13(m,2H),4.13-4.04(m,1H),4.00(br d,J=12.5Hz,1H),3.95(br s,1H),3.90-3.82(m,1H),3.82-3.62(m,3H),3.59-3.45(m,2H),3.45-3.25(m,7H),1.48(d,J=6.4Hz,3H).

[0706] Example 31

[0707] 5-[(4R,9aR)-4-methyl-8-(6-methyl-2-piperazin-1-yl-pyrimidin-4-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0708]

[0709] The title compound was prepared according to the following scheme:

[0710]

[0711] Step 1: Preparation of 5-[(4R,9aR)-8-(2-chloro-6-methyl-pyrimidin-4-yl)-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Compound 31b)

[0712] 2,4-Dichloro-6-methylpyrimidine (Compound 31a, 29 mg, 179 μmol), 5-[(4R,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Intermediate C, 50 mg, 163 μmol) and Et 3 A solution of N (16.5 mg, 163 μmol) in ethanol (4 mL) was stirred at rt for 12 hours. The mixture was then concentrated and purified by flash column chromatography to give compound 31b (60 mg) as a yellow oil. LCMS (M+H) + :434,LCMS(M+H+2) + :436.

[0713] Step 2: Preparation of 5-[(4R,9aR)-4-methyl-8-(6-methyl-2-piperazin-1-yl-pyrimidin-4-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Example 31)

[0714] To a solution of 5-[(4R,9aR)-8-(2-chloro-6-methyl-pyrimidin-4-yl)-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (compound 31b, 60 mg, 138 μmol) in dioxane (5 mL) were added tert-butyl piperazine-1-carboxylate (31 mg, 166 μmol) and K 2 CO 3 (38 mg, 277 μmol). The suspension was washed with N 2Bubbling for 5 minutes, then RuPhos Pd G2 (11 mg, 14 μmol) was added. The reaction mixture was stirred at 100 °C overnight and then concentrated. The residue was purified by preparative HPLC to give the coupled product, which was dissolved in dioxane (5 mL) and treated with HCl in dioxane (4M, 2 mL). After the reaction mixture was stirred at rt for 2 hours, it was concentrated to give Example 31 (17 mg) as a yellow solid. LCMS (M+H) + :484. 1 H NMR (400MHz, methanol-d4) δppm: 9.09 (br d, J = 3.8Hz, 1H), 8.90 (br d, J = 8.1Hz, 1H), 8.30 (d, J = 7.7Hz, 1H), 7.83 (br dd, J = 4.2, 8.1Hz, 1H), 7.50 (br d,J=7.7Hz,1H),6.68(s,1H),5.38-5.22(m,1H),4.69-4.54(m,1H),4.23-4.06(m,6H),4.03 -3.83(m,3H),3.81-3.74(m,1H),3.55-3.37(m,7H),3.61-3.36(m,1H),2.49(s,3H),1.59(br d, J = 5.9 Hz, 3H).

[0715] Example 32

[0716] 5-[(4R,9aS)-4-methyl-8-(2-piperazin-1-yl-4-pyridinyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0717]

[0718] The title compound was prepared according to the following scheme:

[0719]

[0720] Step 1: Preparation of tert-butyl 4-(4-bromo-2-pyridyl)piperazine-1-carboxylate (Compound 32b)

[0721] Piperazine-1-carboxylic acid tert-butyl ester (111 mg, 597 μmol), 4-bromo-2-fluoropyridine (compound 32a, 70 mg, 398 μmol) and K 2 CO 3 A solution of (165 mg, 1.19 mmol) in DMSO (3 mL) was stirred at 100 °C overnight. The mixture was diluted with EtOAc (40 mL) and washed with water. The organic layer was purified by Na2 SO 4 Dried and concentrated. The residue was purified by flash column chromatography to give compound 32b (110 mg) as a white solid. LCMS (M+H) + :342,LCMS(M+H+2) + :344.

[0722] Step 2: Preparation of 5-[(4R,9aS)-4-methyl-8-(2-piperazin-1-yl-4-pyridinyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Compound 32)

[0723] To a solution of tert-butyl 4-(4-bromo-2-pyridyl)piperazine-1-carboxylate (compound 32b, 67 mg, 195 μmol) in dioxane (5 mL) were added 5-[(4R,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (intermediate C, 40 mg, 130 μmol) and Cs 2 CO 3 (127 mg, 390 μmol). The suspension was washed with N 2 Bubble for 5 minutes, then add Ruphos Pd G2 (10 mg, 13 μmol). After heating the reaction mixture at 100 ° C overnight, it was concentrated. The residue was purified by flash column chromatography to give the coupled product, which was dissolved in dioxane (5 mL) and treated with HCl in dioxane (4M, 2 mL). After the yellow suspension was stirred at rt for 2 hours, it was concentrated to give Example 32 (46 mg) as a yellow solid. LCMS (M+H) + :469. 1 H NMR (400MHz, methanol-d4) δppm: 8.98 (dd, J=1.5, 4.4Hz, 1H), 8.80 (dd, J=1.5, 8.6Hz, 1H), 8.19 (d, J=7.9Hz, 1H), 7.76-7.69 (m, 2H ),7.39(d,J=8.1Hz,1H),6.81(dd,J=1.9,7.4Hz,1H),6.48(d,J=1.8Hz,1H),4.63-4.46(m,2H),4.05-3.94(m,2H),3.85(br s,1H),3.82-3.77(m,4H),3.71-3.60(m,2H),3.58-3.55(m,1H),3.46-3.26(m,8H),1.47(d,J=6.5Hz,3H).

[0724] Example 33

[0725] 5-[(4R,9aR)-4-methyl-8-(2-piperazin-1-ylpyrimidin-4-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0726]

[0727] The title compound was prepared according to the following scheme:

[0728]

[0729] Step 1: Preparation of 5-[(4R,9aR)-8-(2-chloropyrimidin-4-yl)-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Compound 33a)

[0730] 2,4-Dichloropyrimidine (compound 30a, 27 mg, 179 μmol), K 2 CO 3 A mixture of 5-[(4R,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Intermediate C, 50 mg, 163 μmol) in DMF (3 mL) was stirred at 50 ° C for 2 hours, then the reaction was diluted with EtOAc (40 mL) and washed with water. The organic layer was purified by Na 2 SO 4 Drying and concentration gave compound 33a (70 mg crude product) as a yellow oil. LCMS (M+H) + :420,LCMS(M+H+2) + :422.

[0731] Step 2: Preparation of 5-[(4R,9aR)-4-methyl-8-(2-piperazin-1-ylpyrimidin-4-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Compound 33)

[0732] 5-[(4R,9aR)-8-(2-chloropyrimidin-4-yl)-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Compound 33a, 68 mg, 162 μmol), K 2 CO 3A suspension of 4-(4-(4-(2-piperazine-1-carboxylic acid)-1-yl)-piperazine-1-carboxylic acid tert-butyl ester (45 mg, 324 μmol) and tert-butyl piperazine-1-carboxylate (36 mg, 194 μmol) in MeCN (1 mL) was stirred at 120 °C overnight and then concentrated. The residue was purified by preparative HPLC to give the coupled product, which was dissolved in dioxane (2 mL) and treated with HCl in dioxane (4 M, 2 mL). The yellow suspension was stirred at rt for 2 hours. The reaction mixture was concentrated to give Example 33 (32 mg) as a yellow solid. LCMS (M+H) + :470. 1 H NMR (400MHz, methanol-d4) δppm: 8.98 (d, J = 3.9Hz, 1H), 8.79 (br d,J=8.3Hz,1H),8.19(d,J=7.9Hz,1H),7.85(d,J=7.5Hz,1H),7.72(dd,J=4.5,8.5Hz,1H),7.39(d,J=7.9Hz,1H),6.68(br d,J=7.5Hz,1H),5.31-5.11(m,1H),4.59-4.43(m,1H),4.00(br s,6H),3.84(br d,J=2.8Hz,2H),3.70-3.61(m,2H),3.60-3.52(m,2H),3.33(br s, 6H), 1.47 (br d, J = 6.2Hz, 3H).

[0733] Example 34

[0734] 5-[(4R,9aR)-4-methyl-8-(4-piperazin-1-yl-2-pyridinyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0735]

[0736] The title compound was prepared according to the following scheme:

[0737]

[0738] Step 1: Preparation of 5-[(4R,9aR)-8-(4-bromo-2-pyridinyl)-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Compound 34a)

[0739] To a solution of 5-[(4R,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Intermediate C, 40 mg, 130 μmol) in DMSO (3 mL) were added 4-bromo-2-fluoropyridine (Compound 32a, 28 mg, 156 μmol) and K 2 CO 3 (54 mg, 390 μmol). The reaction mixture was stirred at 120°C overnight, then diluted with EtOAc (40 mL), washed with water, and then the organic layer was purified by Na 2 SO 4 Dried and concentrated. The residue was purified by flash column chromatography to give compound 34a (52 mg) as a yellow oil. LCMS (M+H) + :463,LCMS(M+H+2) + :465.

[0740] Step 2: Preparation of 5-[(4R,9aR)-4-methyl-8-(4-piperazin-1-yl-2-pyridinyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Example 34)

[0741] To a solution of 5-[(4R,9aR)-8-(4-bromo-2-pyridinyl)-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (compound 34a, 50 mg, 108 μmol) in dioxane (5 mL) were added tert-butyl piperazine-1-carboxylate (30 mg, 162 μmol) and Cs 2 CO 3 (105 mg, 324 μmol). The suspension was washed with N 2 Bubble for 5 minutes, then add Ruphos Pd G2 (8 mg, 10 μmol). After heating the reaction mixture at 100 ° C overnight, it is filtered and the filtrate is concentrated. The residue is purified by preparative HPLC to give the coupled product, which is then dissolved in dioxane (5 mL) and treated with HCl in dioxane (4M, 2 mL), and the yellow suspension is stirred at rt for 2 hours. The reaction mixture is concentrated to give Example 34 (13 mg) as a yellow solid. LCMS (M+H) + :469. 1H NMR (400MHz, methanol-d4) δppm: 9.06 (dd, J=1.7, 4.3Hz, 1H), 8.78 (dd, J=1.6, 8.6Hz, 1H), 8.26 (d, J=7.9Hz, 1H), 7.86 (d, J=7.5Hz, 1H), 7.75(dd,J=4.3,8.6Hz,1H),7.46(d,J=8.1Hz,1H),6.88(dd,J=2.5,7.5Hz,1H),6.57(d,J=2.3Hz,1H),4.50-4.36(m,2H),4.13(br d,J=12.0Hz,2H),4.03-3.97(m,4H),3.97-3.91(m,1H),3.88-3.74(m,3H),3.55(br d,J=13.1Hz,1H),3.45-3.38(m,7H),1.59(d,J=6.5Hz,3H).

[0742] Example 35

[0743] 5-(8-isoindolin-4-yl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl)quinoline-8-carbonitrile

[0744]

[0745] The title compound was prepared according to the following scheme:

[0746]

[0747] Step 1: Preparation of tert-butyl 8-(8-cyano-5-quinolyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazine-2-carboxylate (Compound 35b)

[0748] A solution of 5-fluoroquinoline-8-carbonitrile (258 mg, 1.5 mmol), tert-butyl 1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazine-2-carboxylate (compound 35a, 241 mg, 1 mmol) and DIPEA (241 mg, 1 mmol) in DMSO (5 mL) was stirred at 120 °C overnight, then diluted with EtOAc (40 mL), washed with water, and purified by Na 2 SO 4 The organic layer was concentrated and the residue was purified by flash column chromatography to give compound 35b (390 mg) as a yellow oil. LCMS (M+H) + :394.

[0749] Step 2: Preparation of 5-(1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl)quinoline-8-carbonitrile (Compound 35c)

[0750] To a solution of 8-(8-cyano-5-quinolyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (compound 35b, 390 mg, 1 mmol) in dioxane (4 mL) was slowly added HCl in dioxane (4 M, 2 mL). The yellow suspension was stirred at rt for 2 hours and concentrated. The residue was dissolved in MeOH (4 mL), a few drops of NaOMe in MeOH were added to adjust the system to weak alkalinity, and then NaHCO 3 Solid was obtained and the suspension was stirred at rt for 30 minutes. The suspension was filtered and concentrated to give compound 35c (280 mg) as a yellow oil. LCMS (M+H) + :294.

[0751] Step 3: Preparation of 5-(8-isoindolin-4-yl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl)quinoline-8-carbonitrile (Compound 35)

[0752] To a solution of 5-(1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl)quinoline-8-carbonitrile (compound 35c, 50 mg, 170 μmol) in dioxane (5 mL) was added tert-butyl 4-bromoisoindoline-2-carboxylate (76 mg, 256 μmol) and tBuONa (49 mg, 511 μmol). The suspension was washed with N 2 Bubble for 5 minutes, then add Pd 2 (dba) 3 (16 mg, 17 μmol) and BINAP (21 mg, 34 μmol). After the reaction mixture was stirred at 100 °C overnight, it was concentrated. The residue was purified by preparative HPLC to give the coupled product, which was dissolved in dioxane (5 mL) and then treated with HCl in dioxane (4M, 2 mL), and the yellow suspension was stirred at rt for 2 hours. The reaction mixture was concentrated to give Example 35 (25 mg) as a yellow solid. LCMS (M+H) + :411. 1H NMR (400MHz, methanol-d4) δppm: 8.94 (dd, J=1.7, 4.3Hz, 1H), 8.65 (dd, J=1.7, 8.6Hz, 1H), 8.13 (d, J=8.1Hz, 1H), 7.62 (dd, J=4.3, 8.6Hz, 1H), 7.38-7.30 ( m,2H),7.09(dd,J=7.8,13.8Hz,2H),4.60(s,2H),4.54(s,2H),4.04-3.93 (m,1H),3.70-3.62(m,5H),3.54-3.49(m,1H),3.48-3.43(m,1H),3.41(br d,J=3.7Hz,1H),3.39-3.32(m,1H),3.31-3.25(m,1H),3.23(br d,J=1.7Hz,1H),3.07(dd,J=11.0,13.3Hz,1H).

[0753] Example 36

[0754] 5-[(4R,9aR)-8-[2-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]pyrimidin-4-yl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0755]

[0756] The title compound was prepared similarly to Example 33, but using tert-butyl N-[(3R,4R)-4-methoxypyrrolidin-3-yl]carbamate instead of tert-butyl piperazine-1-carboxylate. Example 36 (18 mg) was obtained as a yellow solid. LCMS (M+H) + : 500. 1 H NMR (400MHz, methanol-d4) δppm: 9.06 (dd, J = 1.6, 4.3Hz, 1H), 8.74 (d, J = 8.4Hz, 1H), 8.25 (d, J = 7.9Hz, 1H), 7. 94(d,J=7.6Hz,1H),7.73(dd,J=4.2,8.5Hz,1H),7.45(d,J=7.9Hz,1H),6.75(d,J=7.6Hz,1H),4.94(br s,2H),4.32-4.19(m,1H),4.14-3.96(m,5H),3.92-3.64(m,6H),3.63-3.58(m,1H),3.55-3.35(m,6H),1.56(d,J=6.4Hz,3H).

[0757] Example 37

[0758] 5-[(4R,9aR)-8-[4-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]pyrimidin-2-yl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0759]

[0760] The title compound was prepared similarly to Example 30, but using tert-butyl N-[(3R,4R)-4-methoxypyrrolidin-3-yl]carbamate instead of tert-butyl piperazine-1-carboxylate. Example 37 (24 mg) was obtained as a yellow solid. LCMS (M+H) + : 500. 1 H NMR (400MHz, methanol-d4) δppm: 9.08 (d, J = 4.4Hz, 1H), 8.90-8.82 (m, 1H), 8.29 (dd, J = 2.2, 7 .9Hz,1H),7.92(d,J=7.3Hz,1H),7.85-7.76(m,1H),7.50(d,J=8.1Hz,1H),6.48(dd,J= 3.9,7.3Hz,1H),4.86-4.75(m,2H),4.29-4.05(m,6H),4.05-3.90(m,2H),3.87-3.75( m,4H),3.72-3.57(m,2H),3.51-3.49(m,3H),3.48-3.39(m,2H),1.59(d,J=6.4Hz,3H).

[0761] Example 38

[0762] 5-[2-(4-methyl-6-piperazin-1-yl-3-pyridinyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-8-yl]quinoline-8-carbonitrile

[0763]

[0764] The title compound was prepared according to the following scheme:

[0765]

[0766] Step 1: Preparation of tert-butyl 4-(5-bromo-4-methyl-2-pyridyl)piperazine-1-carboxylate (Compound 38b)

[0767] A solution of 5-bromo-2-fluoro-4-methyl-pyridine (compound 38a, 190 mg, 1 mmol), tert-butyl piperazine-1-carboxylate (223 mg, 1.2 mmol) and DIPEA (616 mg, 5 mmol) in DMSO (5 mL) was stirred at 120 ° C overnight and then diluted with EtOAc (40 mL). The organic layer was washed with water and purified by Na 2 SO 4 Drying and then concentration. The residue was purified by flash chromatography to give compound 38b (282 mg) as a white solid. LCMS (M+H) + :356,LCMS(M+H+2) + :358.

[0768] Step 2: Preparation of 5-[2-(4-methyl-6-piperazin-1-yl-3-pyridinyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-8-yl]quinoline-8-carbonitrile (Compound 38)

[0769] To a solution of tert-butyl 4-(5-bromo-4-methyl-2-pyridyl)piperazine-1-carboxylate (compound 38b, 63 mg, 177 μmol) in dioxane (5 mL) were added 5-(1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl)quinoline-8-carbonitrile (compound 35c, 40 mg, 136 μmol) and tBuONa (26 mg, 273 μmol). The suspension was washed with N 2 Bubble for 5 minutes, then add Pd 2 (dba) 3 (13 mg, 14 μmol) and BINAP (17 mg, 27 μmol). After the reaction mixture was stirred at 110 °C overnight, it was concentrated. The residue was purified by preparative HPLC to give the coupled product, which was dissolved in dioxane (5 mL) and then treated with HCl in dioxane (4M, 2 mL), and the yellow suspension was stirred at rt for 2 hours. The reaction mixture was concentrated to give Example 38 (4 mg) as a yellow solid. LCMS (M+H) + :469. 1H NMR (400MHz, methanol-d4) δppm: 9.08 (dd, J=1.4, 4.3Hz, 1H), 8.84 (dd, J=1.5, 8.6H z,1H),8.28(d,J=7.9Hz,1H),7.86(s,1H),7.80(dd,J=4.4,8.6Hz,1H),7.50- 7.44(m,2H),4.20-4.10(m,1H),4.03-3.96(m,4H),3.83-3.74(m,5H),3.82- 3.73(m,1H),3.62(s,3H),3.53-3.45(m,7H),3.30-3.22(m,1H),2.61(s,3H).

[0770] Example 39

[0771] 5-[(4R,9aR)-8-[4-(3-aminoazetidin-1-yl)pyrimidin-2-yl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0772]

[0773] The title compound was prepared similarly to Example 30, but using tert-butyl N-(azetidin-3-yl)carbamate instead of tert-butyl piperazine-1-carboxylate. Example 39 (17 mg) was obtained as a yellow solid. LCMS (M+H) + :456. 1 H NMR (400 MHz, methanol-d4) δ ppm: 8.96 (dd, J = 1.4, 4.3 Hz, 1H), 8.71 (br d,J=8.6Hz,1H),8.16(d,J=7.9Hz,1H),7.76(d,J=7.2Hz,1H),7.67(dd,J=4.3, 8.4Hz,1H),7.36(d,J=8.1Hz,1H),6.18(d,J=7.3Hz,1H),4.72-4.49(m,4H),4.3 1-4.19(m,3H),4.09-3.96(m,2H),3.90-3.79(m,1H),3.73-3.62(m,3H),3.56(s ,1H),3.50(s,1H),3.47-3.40(m,1H),3.36-3.25(m,3H),1.46(d,J=6.4Hz,3H).

[0774] Example 40

[0775] 5-[(4R,9aS)-8-[2-[(3S,4R)-3-amino-4-fluoro-pyrrolidin-1-yl]-4-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0776]

[0777] The title compound was prepared similarly to Example 32, but using tert-butyl N-[(3S,4R)-4-fluoropyrrolidin-3-yl]carbamate instead of tert-butyl piperazine-1-carboxylate. Example 40 (19 mg) was obtained as a yellow solid. LCMS (M+H) + :487. 1 HNMR (400MHz, methanol-d4) δppm: 9.03 (dd, J=1.6, 4.3Hz, 1H), 8.68 (dd, J=1.7, 8.6Hz, 1H), 8.21 (d, J=8. 1Hz,1H),7.75-7.62(m,2H),7.36(d,J=8.1Hz,1H),6.82(dd,J=2.4,7.6Hz,1H),6.07(d,J=2.3Hz,1 H),5.68-5.45(m,1H),4.43-4.19(m,3H),4.18-4.11(m,1H),4.10-3.88(m,2H),3.78-3.57(m,4H), 3.48-3.37(m,1H),3.32-3.22(m,2H),3.20-3.01(m,3H),2.82-2.69(m,1H),1.37(d,J=6.4Hz,3H).

[0778] Example 41

[0779] 5-[(4R,9aS)-8-[2-(3-aminoazetidin-1-yl)-4-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0780]

[0781] The title compound was prepared similarly to Example 32, but using tert-butyl N-(azetidin-3-yl)carbamate instead of tert-butyl piperazine-1-carboxylate. Example 41 (6 mg) was obtained as a yellow solid. LCMS (M+H) + :455. 1H NMR (400MHz, methanol-d4) δppm: 8.94(dd,J=1.6,4.4Hz,1H),8.72-8.64(m,1H),8.15(d,J=7.9Hz,1H),7.67-7.59(m,2H),7.35(d,J=8 .1Hz,1H),6.69(dd,J=2.6,7.3Hz,1H),5.99(d,J=2.2Hz,1H),4.57-4.39(m,4H),4.27-4.19(m,2H),4.01-3.93(m,2H),3.89(br d,J=3.3Hz,1H),3.85-3.73(m,2H),3.70-3.53(m,4H),3.50(s,1H),3.36-3.24(m,3H),1.46(d,J=6.4Hz,3H).

[0782] Example 42

[0783] 5-[(4R,9aS)-4-methyl-8-(5,6,7,8-tetrahydro-2,7-naphthyridin-4-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0784]

[0785] The title compound was prepared according to the following scheme:

[0786]

[0787] To a solution of 5-[(4R,9aR)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Intermediate D, 50 mg, 163 μmol) in dioxane (5 mL) was added tert-butyl 5-bromo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxylate (Compound 42a, 61 mg, 195 μmol, CAS: 1251012-16-4, Supplier: Bepharm) and t-BuONa (31 mg, 325 μmol). The suspension was washed with N 2 Bubble for 5 minutes, then add Pd 2 (dba) 3(15 mg, 16 μmol) and BINAP (20 mg, 33 μmol). After stirring at 110 °C overnight, the reaction mixture was concentrated. The residue was purified by preparative HPLC to give the coupled product, which was dissolved in dioxane (5 mL) and then treated with HCl in dioxane (4 M, 2 mL), and the yellow suspension was stirred at rt for 2 hours. . The reaction mixture was concentrated to give Example 42 (4 mg) as a yellow solid. LCMS (M+H) + :440. 1 H NMR (400MHz, methanol-d4) δppm: 8.95 (d, J = 4.2Hz, 1H), 8.78-8.72 (m, 1H), 8.59-8.52 (m, 2H), 8.14 (d, J = 7.9Hz, 1H), 7.66 (dd, J = 4.3, 8. 6Hz,1H),7.35(d,J=7.9Hz,1H),4.53(s,2H),3.95-3.88(m,1H),3.75-3.62(m,5H),3.57-3.48(m,8H),3.41-3.31(m,3H),1.76(br d,J=6.6Hz,3H).

[0788] Example 43

[0789] 5-[(4R,9aR)-4-methyl-8-(5-methyl-4-piperazin-1-yl-pyrimidin-2-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0790]

[0791] The title compound was prepared according to the following scheme:

[0792]

[0793] Step 1: Preparation of 4-(2-chloro-5-methyl-pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Compound 43b)

[0794] 2,4-Dichloro-5-methyl-pyrimidine (compound 43a, 53 mg, 322 μmol) was added to CH 3 To the solution in CN (3 mL) were added tert-butyl piperazine-1-carboxylate (50 mg, 268 μmol) and K 2 CO 3 (74 mg, 537 μmol). The reaction mixture was stirred at rt overnight and then concentrated. The residue was purified by flash column chromatography to give compound 43b (70 mg) as a white solid. LCMS (M+H) +:313,LCMS(M+H+2) + :315.

[0795] Step 2: Preparation of 5-[(4R,9aR)-4-methyl-8-(5-methyl-4-piperazin-1-yl-pyrimidin-2-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Example 43)

[0796] To a solution of tert-butyl 4-(2-chloro-5-methyl-pyrimidin-4-yl)piperazine-1-carboxylate (compound 43b, 56 mg, 179 μmol) in dioxane (5 mL) were added 5-[(4R,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (intermediate C, 50 mg, 163 μmol) and K 2 CO 3 (45 mg, 325 μmol). The suspension was washed with N 2 Bubble for 5 minutes, then add Ruphos Pd G2 (13 mg, 16 μmol). The reaction mixture was stirred at 100 ° C overnight, the solid was filtered off and the filtrate was concentrated. The residue was purified by preparative HPLC (Boc group was removed during separation by TFA system) to give Example 43 (20 mg) as a yellow solid. LCMS (M+H) + :484. 1 H NMR (400MHz, methanol-d4) δppm: 8.91 (dd, J=1.6, 4.3Hz, 1H), 8.57 (dd, J=1.5, 8.6Hz, 1H), 8.09 (d, J=7.9H z,1H),7.80(s,1H),7.58(dd,J=4.3,8.6Hz,1H),7.28(d,J=8.1Hz,1H),4.72-4.53(m,2H),3.85(br d,J=12.2Hz,1H),3.82-3.75(m,4H),3.72-3.54(m,4H),3.44-3.31(m,1H) ,3.30-3.23(m,4H),3.20-2.94(m,4H),2.14(s,3H),1.37(d,J=6.4Hz,3H).

[0797] Example 44

[0798] 5-[(4R,9aR)-4-methyl-8-(5,6,7,8-tetrahydro-2,7-naphthyridin-4-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0799]

[0800] The preparation of the title compound was similar to Example 42, but using 5-[(4R,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Intermediate C) instead of 5-[(4R,9aR)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Intermediate D). Example 44 (25 mg) was obtained as a yellow solid. LCMS (M+H) + :440. 1 H NMR (400MHz, methanol-d4) δppm: 8.95 (dd, J=1.6, 4.4Hz, 1H), 8.72 (dd, J=1.6, 8.7Hz, 1H), 8.58 (s, 1H), 8.55 ( s,1H),8.15(d,J=7.9Hz,1H),7.66(dd,J=4.3,8.6Hz,1H),7.35(d,J=8.1Hz,1H),4.53(s,2H),4.16(br t,J=10.9Hz,1H),3.98(br d,J=11.4Hz,1H),3.94-3.86(m,1H),3.72-3.63(m,2H),3.60-3.40(m,7H),3.39-3.32(m,4H),3.32-3.25(m,1H),1.48(d,J=6.5Hz,3H).

[0801] Example 45

[0802] 5-[(4R,9aR)-8-[2-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]-6-methyl-pyrimidin-4-yl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0803]

[0804] The title compound was prepared similarly to Example 31, but using tert-butyl N-[(3R,4R)-4-methoxypyrrolidin-3-yl]carbamate instead of tert-butyl piperazine-1-carboxylate. Example 45 (30 mg) was obtained as a yellow solid. LCMS (M+H) + :514. 1H NMR (400MHz, methanol-d4) δppm: 8.94 (dd, J=1.5, 4.3Hz, 1H), 8.62 (dd, J=1.4, 8.6Hz, 1H), 8.13 (d, J=7.9Hz, 1H), 7.62 (dd, J=4.3, 8.6Hz, 1H), 7.34 (d ,J=7.9Hz,1H),6.51(s,1H),5.35-5.05(m,1H),4.61-4.41(m,1H),4.20 -4.09(m,1H),4.06-3.59(m,12H),3.38(td,J=1.6,3.2Hz,4H),3.26(br s,2H),2.36(s,3H),1.45(br d, J = 6.4 Hz, 3H).

[0805] Example 46

[0806] 5-[2-[6-[(6R)-6-amino-1,4-oxazepan-4-yl]-4-methyl-3-pyridyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-8-yl]quinoline-8-carbonitrile

[0807]

[0808] The preparation of the title compound was similar to Example 38, but using tert-butyl N-[(6R)-1,4-oxazepan-6-yl]carbamate (Catalog No.: PB97931, Supplier: PharmaBlock) instead of tert-butyl piperazine-1-carboxylate. Example 46 (2 mg) was obtained as a yellow solid. LCMS (M+H) + :499. 1 H NMR (400MHz, methanol-d4) δppm: 8.96 (d, J = 3.4Hz, 1H), 8.71 (d, J = 7.7Hz, 1H), 8.16 (d, J = 7.9Hz, 1H), 7.70-7.64 (m, 2H), 7.37 (s, 1H), 7.34 (d, J = 8.1Hz, 1H),4.25-4.16(m,2H),4.12-3.88(m,6H),3.85-3.72(m,4H),3.70-3.62 (m,5H),3.50(s,2H),3.40-3.25(m,4H),3.17-3.08(m,1H),2.50(s,3H).

[0809] Example 47

[0810] 5-[trans-4-methyl-8-(1,2,3,4-tetrahydroisoquinolin-5-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0811]

[0812] The title compound was prepared similarly to Example 2, but using Intermediate B instead of Intermediate A. Example 47 (3.9 mg) was obtained as a yellow solid. LCMS (M+H) + :439. 1 H NMR (400MHz, methanol-d4) δppm: 9.04 (dd, J = 1.5, 4.3Hz, 1H), 8.78 (br d, J = 8.2Hz, 1H), 8.23 ​​(d, J = 7.9Hz, 1H), 7.73 (dd, J = 4.3, 8.7Hz, 1H), 7.42 (br d,J=7.7Hz,1H),7.39-7.33(m,1H),7.25(br s,1H),7.09(d,J=7.8Hz,1H),4.39(s,3H),4.02(br s,1H),3.89-3.34(m,9H),3.31-2.94(m,5H),1.87(br s,3H).

[0813] Example 53

[0814] 5-[(4R,9aS)-8-[2-[(6S)-6-amino-1,4-oxazepan-4-yl]-4-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0815]

[0816] The preparation of the title compound was similar to Example 32, but using tert-butyl N-[(6S)-1,4-oxazepan-6-yl]carbamate (Catalog No.: PB97932, Supplier: PharmaBlock) instead of tert-butyl piperazine-1-carboxylate. Example 53 (10 mg) was obtained as a yellow solid. LCMS (M+H) + :499. 1H NMR (400MHz, methanol-d4) δppm: 8.95 (dd, J=1.5, 4.3Hz, 1H), 8.69 (s, 1H), 8.15 (d, J=7.9Hz, 1H) ,7.68-7.63(m,2H),7.36(d,J=7.9Hz,1H),6.75(dd,J=2.1,7.6Hz,1H),6.44(d,J=1.8Hz, 1H),4.72-4.63(m,1H),4.62-4.53(m,1H),4.22-4.14(m,1H),4.06-3.94(m,4H),3.94-3. 85(m,3H),3.83-3.63(m,6H),3.63-3.56(m,1H),3.41-3.24(m,4H),1.47(d,J=6.4Hz,3H).

[0817] Example 54

[0818] 5-[(4R,9aS)-8-[2-[(6R)-6-amino-1,4-oxazepan-4-yl]-4-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0819]

[0820] The preparation of the title compound was similar to Example 32, but using tert-butyl N-[(6R)-1,4-oxazepan-6-yl]carbamate (Catalog No.: PB97931, Supplier: PharmaBlock) instead of tert-butyl piperazine-1-carboxylate. Example 54 (10 mg) was obtained as a yellow solid. LCMS (M+H) + :499. 1H NMR (400MHz, methanol-d4) δppm: 8.95 (dd, J=1.5, 4.3Hz, 1H), 8.74 (dd, J=1.5, 8.6Hz, 1H), 8.16 (d, J=7.9Hz, 1H ),7.71-7.60(m,2H),7.36(d,J=8.1Hz,1H),6.74(dd,J=2.0,7.6Hz,1H),6.48(d,J=1.3Hz,1H),4.74(br d,J=1.7Hz,1H),4.53(br d,J=14.5Hz,1H),4.21-4.13(m,1H),4.07-3.91(m,5H),3.90-3.87(m,1H),3.87-3.80(m,2H),3.79-3.73(m,2H),3.72(s,1H),3.66(br dd,J=4.0,13.5Hz,2H),3.62-3.56(m,1H),3.41-3.24(m,4H),1.47(d,J=6.4Hz,3H).

[0821] Example 55

[0822] 5-[(4R,9aR)-8-[2-(3-amino-3-methyl-azetidin-1-yl)-6-methyl-pyrimidin-4-yl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0823]

[0824] The title compound was prepared according to the following scheme:

[0825]

[0826] Step 1: Preparation of 5-[(4R,9aR)-8-(2-chloro-6-methyl-pyrimidin-4-yl)-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Compound 31b)

[0827] 2,4-Dichloro-6-methylpyrimidine (Compound 31a, 117 mg, 716 μmol), 5-[(4R,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Intermediate C, 200 mg, 651 μmol) and K 2 CO 3A solution of (269 mg, 1.95 mmol) in DMF (3 mL) was stirred at 50 °C for 2 hours, then the reaction mixture was diluted with EtOAc (40 mL) and washed with water. The organic layer was dried and concentrated, and the residue was purified by flash column chromatography to give compound 31b (170 mg) as a yellow oil. LCMS (M+H) + :434,LCMS(M+H+2) + :436.

[0828] Step 2: Preparation of 5-[(4R,9aR)-8-[2-(3-amino-3-methyl-azetidin-1-yl)-6-methyl-pyrimidin-4-yl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Example 55)

[0829] To a solution of 5-[(4R,9aR)-8-(2-chloro-6-methyl-pyrimidin-4-yl)-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (compound 31b, 50 mg, 115 μmol) in dioxane (5 mL) were added tert-butyl N-(3-methylazetidin-3-yl)carbamate (26 mg, 138 μmol) and K 2 CO 3 (32 mg, 230 μmol). The suspension was washed with N 2 Bubble for 5 minutes, then add Ruphos Pd G2 (9 mg, 12 μmol). After stirring at 110 ° C overnight, the reaction mixture was concentrated. The residue was purified by preparative HPLC to give the coupled product, which was dissolved in dioxane (5 mL) and then treated with HCl in dioxane (4M, 2 mL), and the yellow suspension was stirred at rt for 2 hours. The reaction mixture was concentrated to give Example 55 (10 mg) as a yellow solid. LCMS (M+H) + :484. 1H NMR (400MHz, methanol-d4) δppm: 8.95 (dd, J=1.5, 4.3Hz, 1H), 8.69 (dd, J=1.6, 8.7Hz, 1H), 8.16 (d, J=7.9Hz, 1H), 7. 66(dd,J=4.4,8.6Hz,1H),7.36(d,J=8.1Hz,1H),6.50(s,1H),4.52-4.41(m,1H),4.40-4.19(m,4H),3.97(br d,J=11.5Hz,2H),3.90-3.60(m,4H),3.57-3.44(m,2H),3.41-3.25(m,3H),2.32(br s,3H),1.63(br s, 3H), 1.46 (br d, J = 6.2Hz, 3H).

[0830] Example 56

[0831] 5-[(4R,9aS)-8-[2-(3-amino-3-methyl-azetidin-1-yl)-4-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0832]

[0833] The preparation of the title compound was similar to Example 32, but using tert-butyl N-(3-methylazetidin-3-yl)carbamate instead of tert-butyl piperazine-1-carboxylate and using TFA / DCM (1:2) instead of EA containing 1M HCl. Example 56 (6 mg) was obtained as a yellow solid. LCMS (M+H) + :469. 1 H NMR (400MHz, methanol-d4) δppm: 8.90 (td, J=1.5, 4.2Hz, 1H), 8.57 (dd, J=1.5, 8.6Hz, 1H), 8.09 (dd, J=1.0, 7.9Hz, 1H), 7.65-7.54 (m ,2H),7.26(d,J=7.9Hz,1H),6.67(dd,J=2.4,7.6Hz,1H),5.88(d,J=2.1Hz,1H),4.38-4.23(m,4H),4.20-4.11(m,2H),3.81(br d,J=12.3Hz,1H),3.68-3.34(m,5H),3.19-3.01(m,3H),3.01-2.86(m,1H),1.62(s,3H),1.40-1.30(m,3H).

[0834] Example 57

[0835] 5-[(4R,9aS)-4-methyl-8-[(5-piperazin-1-yl-3-pyridinyl)methyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0836]

[0837] The title compound was prepared similarly to Example 3, but using Intermediate C instead of Intermediate A and using 3-bromo-5-(bromomethyl)pyridine instead of Compound 3a. Example 57 was obtained as a yellow foam (20 mg). LCMS (M+H) + :483, 1 HNMR (400MHz, methanol-d4) δppm: 9.15-9.06 (m, 1H), 8.99-8.88 (m, 1H), 8.57 (d, J = 2.4Hz, 1H), 8.46 (br s,1H),8.42(s,1H),8.31(d,J=8.1Hz,1H),7.93-7.80(m,1H),7.48(d,J=8.1Hz,1H),4.31-4 .21(m,2H),3.91-3.82(m,4H),3.80-3.53(m,11H),3.51-3.43(m,5H),1.55(d,J=6.5Hz,3H).

[0838] Example 58

[0839] 5-[(4R,9aS)-4-methyl-8-[2-[6-[(3R)-3-methylpiperazin-1-yl]-2-pyridinyl]ethyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0840]

[0841] The preparation of the title compound was similar to Example 11, but using Compound 21c instead of Compound 11d and using (2R)-2-methylpiperazine-1-carboxylic acid tert-butyl ester instead of piperazine-1-carboxylic acid tert-butyl ester. Example 58 was obtained as an orange solid (11 mg). LCMS (M+H) + :511, 1H NMR (400MHz, methanol-d4) δppm: 9.08 (dd, J=1.5, 4.4Hz, 1H), 8.88-8.78 (m, 1H), 8.27 (d, J=7.9Hz, 1H), 7.88 (br t,J=7.1Hz,1H),7.79(dd,J=4.3,8.7Hz,1H),7.45(d,J=7.9Hz,1H),7.14(br d,J=8.7Hz,1H),6.99(d,J=7.0Hz,1H),4.66-4.47(m,2H),4.24-4.08(m,2H),4.03-3.78(m,3H),3.78-3.63( m,5H),3.62-3.48(m,4H),3.47-3.37(m,6H),3.26-3.17(m,1H),1.52(d,J=6.1Hz,3H),1.44(d,J=6.6Hz,3H).

[0842] Example 59

[0843] 5-[(4R,9aS)-4-methyl-8-[2-[6-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)-3-pyridinyl]ethyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0844]

[0845] The preparation of the title compound was similar to Example 3, but 5-[(4R,9aS)-8-[2-(6-chloro-3-pyridyl)ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Compound 11d) was used instead of Compound 3b, 5-oxa-2,8-diazaspiro[3.5]nonane-8-carboxylic acid tert-butyl ester was used instead of piperazine-1-carboxylic acid tert-butyl ester, and TFA / DCM (1:2) was used instead of EA containing 1M HCl. Example 59 was obtained as a light yellow solid (36 mg). LCMS (M+H) + :539, 1H NMR (400MHz, methanol-d4) δppm: 8.99 (dd, J=1.6, 4.3Hz, 1H), 8.64 (dd, J=1.7, 8.6Hz, 1H), 8.16 (d,J=8.1Hz,1H),7.92(d,J=2.0Hz,1H),7.66(dd,J=4.2,8.6Hz,1H),7.51(dd,J=2.2,8.6 Hz,1H),7.25(d,J=8.1Hz,1H),6.46(d,J=8.7Hz,1H),3.96(d,J=8.9Hz,2H),3.81(d,J=8 .7Hz,2H),3.74-3.65(m,2H),3.48-3.37(m,3H),3.14-3.07(m,1H),3.01(s,2H),2.97(br d,J=11.0Hz,1H),2.90-2.70(m,8H),2.66-2.54(m,2H),2.33(br t,J=6.6Hz,2H),2.04(br t,J=10.5Hz,1H),1.19(d,J=5.9Hz,3H).

[0846] Example 60

[0847] 5-[(4R,9aS)-4-methyl-8-[(2-methyl-6-piperazin-1-yl-3-pyridinyl)methyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0848]

[0849] The title compound was prepared according to the following scheme:

[0850]

[0851] The title compound was prepared similarly to Example 11, but using Compound 60a instead of Compound 11a. Example 60 was obtained as a yellow solid (47 mg). LCMS (M+H) + :497, 1H NMR (400MHz, methanol-d4) δppm: 8.99 (dd, J=1.6, 4.6Hz, 1H), 8.83 (dd, J=1.6, 8.7Hz, 1H), 8.2 7-8.13(m,2H),7.75(dd,J=4.6,8.6Hz,1H),7.39(d,J=8.1Hz,1H),7.26(d,J=9.4Hz,1H) ,4.37-4.15(m,3H),4.12-4.03(m,1H),4.02-3.93(m,4H),3.89-3.78(m,1H),3.73-3.61 (m,4H),3.54-3.44(m,2H),3.43-3.32(m,7H),2.76-2.65(m,3H),1.45(d,J=6.4Hz,3H).

[0852] Example 61

[0853] 5-[(4R,9aS)-4-methyl-8-(1,2,3,4-tetrahydroisoquinolin-7-ylmethyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile

[0854]

[0855] The title compound was prepared similarly to Example 1, but using Intermediate G instead of Intermediate A. Example 61 was obtained as an orange solid (165 mg). LCMS (M+H) + :454, 1 H NMR (400MHz, methanol-d4) δppm: 8.89 (d, J = 8.7Hz, 1H), 8.31 (d, J = 8.1Hz, 1H), 7.83 (d, J = 8.6Hz, 1H), 7.61-7.55 (m, 2H),7.48(d,J=8.1Hz,1H),7.42(d,J=7.9Hz,1H),4.68-4.49(m,2H),4.45(s,2H),4.43-4.34(m,1H),4.22(br d,J=13.1Hz,1H),3.95(br d,J=2.6Hz,1H),3.91-3.58(m,7H),3.54(t,J=6.3Hz,2H),3.51-3.41(m,2H),3.18(t,J=6.4Hz,2H),1.56(d,J=6.4Hz,3H).

[0856] Example 62

[0857] 5-[(4R,9aS)-8-[2-[6-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile

[0858]

[0859] The title compound was prepared according to the following scheme:

[0860]

[0861] The title compound was prepared similarly to Example 11, but using tert-butyl N-[(3R,4R)-4-methoxypyrrolidin-3-yl]carbamate instead of tert-butyl piperazine-1-carboxylate and using Intermediate G instead of Intermediate C. Example 62 was obtained as an orange solid (86 mg). LCMS (M+H) + :528, 1 H NMR (400MHz, methanol-d4) δppm: 8.93 (d, J = 8.7Hz, 1H), 8.32 (d, J = 7.9Hz, 1H), 8.16 (dd, J = 2.0, 9.4Hz, 1H ),8.11-8.07(m,1H),7.86(d,J=8.6Hz,1H),7.51(d,J=8.1Hz,1H),7.24(d,J=9.4Hz,1H),4.45(br t,J=11.1Hz,1H),4.38-4.31(m,1H),4.26(br d,J=12.7Hz,1H),4.19-4.05(m,5H),4.03-3.95(m,1H),3.90-3.59(m,9H),3.56-3.44(m,5H),3.25(t,J=7.9Hz,2H),1.58(d,J=6.5Hz,3H).

[0862] Example 63

[0863] 5-[(4R,9aS)-8-[2-[6-[(3R,4S)-3-amino-4-fluoro-pyrrolidin-1-yl]-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile

[0864]

[0865] The title compound was prepared similarly to Example 11, but using tert-butyl N-[(3R,4S)-4-fluoropyrrolidin-3-yl]carbamate instead of tert-butyl piperazine-1-carboxylate and using Intermediate G instead of Intermediate C. Example 63 was obtained as an orange solid (60 mg). LCMS (M+H) + :516, 1 H NMR (400MHz, methanol-d4) δppm: 9.03 (d, J = 8.7Hz, 1H), 8.37 (d, J = 8.1Hz, 1H), 8.19 (dd, J = 2.1, 9.4Hz, 1H), 8.12 (d, J = 1.6Hz, 1H), 7 .93(d,J=8.6Hz,1H),7.55(d,J=8.1Hz,1H),7.26(d,J=9.4Hz,1H),5.71(t,J=2.9Hz,0.5H),5.58(t,J=3.1Hz,0.5H),4.50(br t,J=11.2Hz,1H),4.41-4.23(m,3H),4.22-3.98(m,5H),3.96-3.41(m,10H),3.27(t,J=8.0Hz,2H),1.59(d,J=6.4Hz,3H).

[0866] Example 64

[0867] 5-[(4R,9aS)-4-methyl-8-[2-[6-(6-methyl-2,6-diazaspiro[3.3]heptane-2-yl)-3-pyridinyl]ethyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile

[0868]

[0869] The title compound was prepared similarly to Example 22, but using compound 62a instead of intermediate 11d. Example 64 was obtained as a light yellow solid (70 mg). LCMS (M+H) + :524, 1H NMR (400MHz, methanol-d4) δppm: 8.52(d,J=8.7Hz,1H), 8.04(d,J=8.1Hz,1H), 7.79(d,J=2.0Hz,1H), 7.54(d,J=8.6Hz,1H), 7.37(dd,J=2.3,8.6Hz, 1H),7.13(d,J=8.1Hz,1H),6.29(d,J=8.4Hz,1H),3.94(s,4H),3.36(s ,4H),3.34-3.25(m,2H),3.19-3.10(m,1H),3.04-2.93(m,1H),2.85(br d,J=11.0Hz,1H),2.75-2.57(m,6H),2.52-2.43(m,2H),2.31-2.16(m,5H),1.91(br t,J=10.5Hz,1H),1.07(d,J=6.0Hz,3H).

[0870] Example 65

[0871] 5-[(4R,9aS)-8-[2-[6-(3-amino-3-methyl-azetidin-1-yl)-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0872]

[0873] The preparation of the title compound was similar to Example 11, but using tert-butyl N-(3-methylazetidin-3-yl)carbamate instead of tert-butyl piperazine-1-carboxylate and using TFA / DCM (1:2) instead of EA containing 1M HCl. Example 65 was obtained as a light yellow solid (40 mg). LCMS (M+H) + :497, 1H NMR (400MHz, methanol-d4) δppm: 8.99 (dd, J=1.6, 4.3Hz, 1H), 8.64 (dd, J=1.7, 8.6Hz, 1H), 8.16 (d, J=8.1Hz, 1H), 7.91 (d, J=1.8Hz, 1H), 7.66 (dd, J=4.3,8.6Hz,1H),7.50(dd,J=2.3,8.6Hz,1H),7.25(d,J=8.1Hz,1H),6.44(d,J=8.6Hz,1H),3.93-3.81(m,4H),3.49-3.37(m,2H),3.29(br d,J=2.7Hz,1H),3.16-3.07(m,1H),2.97(br d,J=11.0Hz,1H),2.88-2.68(m,6H),2.65-2.54(m,2H),2.41-2.27(m,2H),2.04(t,J=10.5Hz,1H),1.54(s,3H),1.18(d,J=6.0Hz,3H).

[0874] Example 66

[0875] 4-[(4R,9aS)-8-[2-[4-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]phenyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile

[0876]

[0877] The title compound was prepared according to the following scheme:

[0878]

[0879] The preparation of the title compound was similar to Example 11, but using tert-butyl N-[(3R,4R)-4-methoxypyrrolidin-3-yl]carbamate instead of tert-butyl piperazine-1-carboxylate, using compound 7a instead of compound 11c, and using intermediate F instead of intermediate C. Example 66 was obtained as a yellow solid (55 mg). LCMS (M+H) + :533, 1H NMR (400MHz, methanol-d4) δppm: 8.08 (d, J = 3.5Hz, 1H), 7.50 (d, J = 7.9Hz, 1H), 7.23 (d, J = 8.7Hz, 2H), 6.68 (dd, J = 3.9, 8.3Hz, 3H), 4.25-4.10 (m, 2H), 3.99 (br d,J=11.6Hz,3H),3.94-3.84(m,4H),3.78-3.54(m,5H),3.52-3.38(m,8H) ), 3.27 (dd, J = 3.5, 10.8 Hz, 1H), 3.17-3.04 (m, 2H), 1.53 (d, J = 6.4 Hz, 3H).

[0880] Example 67

[0881] 4-[(4R,9aS)-8-[2-[6-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile

[0882]

[0883] The title compound was prepared according to the following scheme:

[0884]

[0885] The title compound was prepared similarly to Example 11, but using tert-butyl N-[(3R,4R)-4-methoxypyrrolidin-3-yl]carbamate instead of tert-butyl piperazine-1-carboxylate and using Intermediate F instead of Intermediate C. Example 67 was obtained as a yellow solid (55 mg). LCMS (M+H) + :534, 1 H NMR (400MHz, methanol-d4) δppm: 8.09-8.00(m,1H),7.98-7.92(m,2H),7.38(d,J=7.8Hz,1H),7.12(d,J=9.3Hz,1H),6.56(d,J=7.9Hz,1H),4.27-4.16( m,1H),4.06-3.90(m,5H),3.89-3.71(m,5H),3.68-3.62(m,1H),3.60-3 .34(m,9H),3.33-3.25(m,2H),3.14-2.99(m,2H),1.41(d,J=6.4Hz,3H).

[0886] Example 68

[0887] 4-[(4R,9aS)-8-[2-[4-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]phenyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile

[0888]

[0889] The title compound was prepared according to the following scheme:

[0890]

[0891] The preparation of the title compound was similar to Example 11, but using tert-butyl N-[(3R,4R)-4-methoxypyrrolidin-3-yl]carbamate instead of tert-butyl piperazine-1-carboxylate, using compound 7a instead of compound 11c, and using intermediate E instead of intermediate C. Example 68 was obtained as an orange solid (70 mg). LCMS (M+H) + :515, 1 H NMR (400MHz, methanol-d4) δppm: 8.11(d,J=2.4Hz,1H),7.55(d,J=7.9Hz,1H),7.23(d,J=8.6Hz,2H),7.03(d,J=2.4Hz,1H),6.79(d,J=7.9Hz,1H),6.69(d,J =8.6Hz,2H),4.34-3.98(m,7H),3.94-3.76(m,4H),3.70-3.59(m,3H),3.58 -3.42(m,8H),3.31-3.22(m,1H),3.17-3.07(m,2H),1.59(d,J=6.5Hz,3H).

[0892] Example 69

[0893] 4-[(4R,9aS)-4-methyl-8-(1,2,3,4-tetrahydroisoquinolin-7-ylmethyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile

[0894]

[0895] The title compound was prepared similarly to Example 1, but using Intermediate E instead of Intermediate A. Example 69 was obtained as an orange solid (8 mg). LCMS (M+H) + :460, 1H NMR (400MHz, methanol-d4) δppm: 7.92 (d, J = 3.7Hz, 1H), 7.45-7.34 (m, 3H), 7.28 (d, J = 8.1Hz, 1H), 6.49 (d, J = 7.9Hz, 1H), 4.32 (s, 2H), 4.21 (br s,2H),3.77-3.57(m,3H),3.50-3.37(m,5H),3.15-2.82(m,8H),1.27(br d,J=6.2Hz,3H).

[0896] Example 70

[0897] 5-[(4R,9aS)-4-methyl-8-(1,2,3,4-tetrahydroisoquinolin-5-ylmethyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0898]

[0899] The preparation of the title compound was similar to Example 1, but Intermediate C was used instead of Intermediate A and 5-(bromomethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester (CAS: 2031269-14-2, catalog number: PB98143, PharmaBlock) was used instead of Compound 1b. Example 70 was obtained as an orange foam (10 mg). LCMS (M+H) + :453, 1 HNMR (400MHz, methanol-d4) δppm: 9.23-9.13(m,1H),9.11-9.04(m,1H),8.40(d,J=8.1Hz,1H),8.01-7.91(m,1H),7.75-7.65(m,1H),7.57(d,J=8. 1Hz,1H),7.49-7.35(m,2H),4.73-4.52(m,3H),4.44(s,2H),4.08-3.89(m,4H),3.87-3.50(m,9H),3.47-3.39(m,2H),1.60(d,J=6.4Hz,3H)

[0900] Example 71

[0901] 5-[(4R,9aS)-4-methyl-8-(1,2,3,4-tetrahydroisoquinolin-8-ylmethyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0902]

[0903] The preparation of the title compound was similar to Example 1, but using Intermediate C instead of Intermediate A and using 8-(bromomethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester (CAS: 2268818-17-1, catalog number: PB98142, PharmaBlock) instead of compound 1b. Example 71 was obtained as an orange foam (18 mg). LCMS (M+H) + :453, 1 HNMR (400MHz, methanol-d4) δppm: 9.13-9.01 (m, 1H), 8.87-8.71 (m, 1H), 8.26 (d, J = 7.9Hz, 1H), 7.91-7. 66(m,1H),7.52-7.27(m,4H),4.79-4.59(m,2H),4.29-3.83(m,5H),3.81-3.34(m,11H),3.19(br t, J=6.4Hz, 2H), 1.53 (d, J=6.5Hz, 3H).

[0904] Example 72

[0905] 5-[(4R,9aS)-8-(isoindolin-4-ylmethyl)-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0906]

[0907] The preparation of the title compound was similar to Example 1, but Intermediate C was used instead of Intermediate A and tert-butyl 4-(bromomethyl)isoindoline-2-carboxylate (CAS: 1123176-01-1, catalog number: PB98141, PharmaBlock) was used instead of Compound 1b. Example 72 was obtained as an orange foam (20 mg). LCMS (M+H) + :439, 1H NMR (400MHz, methanol-d4) δppm: 9.14-9.05(m,1H),8.94-8.81(m,1H),8.30(d,J=7.9Hz,1H),7.88-7.75(m,1H),7.62(br d,J=6.0Hz,1H),7.57-7.51(m,2H),7.47(d,J=8.1Hz,1H),4.98(br d,J=8.6Hz,2H),4.70(s,2H),4.43-4.26(m,3H),4.13(br d,J=12.0Hz,1H),4.00-3.88(m,1H),3.82-3.56(m,6H),3.48-3.36(m,3H),1.55(d,J=6.5Hz,3H).

[0908] Example 73

[0909] 5-[(4R,9aS)-8-[2-(3-amino-3-methyl-azetidin-1-yl)-6-methyl-4-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0910]

[0911] The preparation of the title compound was similar to Example 32, but using tert-butyl N-(3-methylazetidin-3-yl)carbamate instead of tert-butyl piperazine-1-carboxylate, using 4-bromo-2-fluoro-6-methylpyridine instead of 4-bromo-2-fluoropyridine, and using TFA / DCM (1:2) instead of EA containing 1M HCl. Example 73 (35 mg) was obtained as a yellow foam. LCMS (M+H) + :483. 1H NMR (400MHz, methanol-d4) δppm: 8.88(dd,J=1.6,4.3Hz,1H), 8.54(dd,J=1.7,8.6Hz,1H), 8.05(d,J=8.1Hz,1H) ,7.55(dd,J=4.2,8.6Hz,1H),7.16(d,J=8.1Hz,1H),6.12(d,J=1.7Hz,1H),5.48(d,J=2.0Hz,1H),3.81(br d,J=11.7Hz,1H),3.77-3.69(m,3H),3.64(d,J=7.8Hz,2H),3.46-3.38(m,1H),3.37-3.25 (m,2H),2.89-2.61(m,5H),2.51(s,1H),2.18(s,4H),1.38(s,3H),1.11(d,J=6.1Hz,3H).

[0912] Example 74

[0913] 4-[(4R,9aS)-8-[2-[6-(3-amino-3-methyl-azetidin-1-yl)-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile

[0914]

[0915] The preparation of the title compound was similar to Example 11, but using tert-butyl N-(3-methylazetidin-3-yl)carbamate instead of tert-butyl piperazine-1-carboxylate, using Intermediate F instead of Intermediate C, and using TFA / DCM (1:2) instead of EA containing 1M HCl. Example 74 was obtained as a light yellow solid (14 mg). LCMS (M+H) + :504, 1H NMR (400MHz, methanol-d4) δppm: 7.88(d,J=3.7Hz,1H),7.79(d,J=1.8Hz,1H),7.37(dd,J=2.3,8.5Hz,1H),7.31(d,J=7.9Hz,1H),6.3 8(d,J=7.9Hz,1H),6.31(d,J=8.6Hz,1H),3.83-3.73(m,2H),3.71-3.63(m,2H),3.52-3.34(m,2H),3.17-3.09(m,1H),2.95(br dd,J=1.7,11.0Hz,1H),2.84(br d,J=11.0Hz,1H),2.72-2.57(m,4H),2.56-2.37(m,4H),2.25-2.05(m,2H),1.91(t,J=10.8Hz,1H),1.41(s,3H),1.06(d,J=6.2Hz,3H).

[0916] Example 75

[0917] 4-[(4R,9aS)-8-[2-[6-[(3R,4S)-3-amino-4-fluoro-pyrrolidin-1-yl]-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile

[0918]

[0919] The title compound was prepared analogously to Example 11, but using tert-butyl N-(3-methylazetidin-3-yl)carbamate instead of tert-butyl piperazine-1-carboxylate and Intermediate F instead of Intermediate C. MS (ESI): mass calcd.

[0920] Example 74 was obtained as a light yellow solid (21 mg). LCMS (M+H) + :522, 1H NMR (400MHz, methanol-d4) δppm: 8.00(d,J=3.5Hz,1H),7.93(d,J=2.1Hz,1H),7.49(dd,J=2.3,8.7Hz,1H),7.42(d,J=7.9Hz,1H),6.50( d,J=8.2Hz,2H),5.22-5.16(m,0.5H),5.05(t,J=3.1Hz,0.5H),3.89-3.77(m,2H),3.74-3.67(m,1H),3.65-3.49(m,3H),3.27(br d,J=11.0Hz,1H),3.18(t,J=9.6Hz,1H),3.12-3.05(m,1H),2.97(br d,J=11.0Hz,1H),2.84-2.69(m,4H),2.67-2.52(m,4H),2.40-2.18(m,2H),2.03(t,J=10.8Hz,1H),1.18(d,J=6.2Hz,3H).

[0921] Example 76

[0922] 5-[(4R,9aS)-8-[[6-(3-amino-3-methyl-azetidin-1-yl)-2-methyl-3-pyridinyl]methyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0923]

[0924] The title compound was prepared according to the following scheme:

[0925]

[0926] The preparation of the title compound was similar to Example 11, but using tert-butyl N-(3-methylazetidin-3-yl)carbamate instead of tert-butyl piperazine-1-carboxylate, using compound 60d instead of compound 11d, and using TFA / DCM (1:2) instead of EA containing 1M HCl. Example 76 was obtained as a light yellow solid (25 mg). LCMS (M+H) + :497, 1H NMR (400MHz, methanol-d4) δppm: 9.02 (dd, J=1.6, 4.3Hz, 1H), 8.67 (dd, J=1.6, 8.6Hz, 1H), 8.2 0(d,J=7.9Hz,1H),7.94(d,J=9.0Hz,1H),7.68(dd,J=4.3,8.6Hz,1H),7.36(d,J=7.9Hz ,1H),6.73(d,J=8.9Hz,1H),4.48(dd,J=2.5,10.3Hz,2H),4.40-4.29(m,2H),3.95-3.8 4(m,1H),3.83-3.58(m,6H),3.28-3.06(m,5H),2.78-2.68(m,1H),2.63(s,3H),2.48(br t,J=11.6Hz,1H),1.74(s,3H),1.45(d,J=6.4Hz,3H).

[0927] Example 77

[0928] 5-[(4R,9aS)-8-[2-[6-[(4aR,7aR)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl]-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile

[0929]

[0930] The preparation of the title compound was similar to Example 11, but using (4aR, 7aR)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-4-carboxylic acid tert-butyl ester (CAS: 1932337-68-2, catalog number: PBXA8123, supplier: Pharmablock) instead of piperazine-1-carboxylic acid tert-butyl ester and using Intermediate G instead of Intermediate C. Example 77 was obtained as a light yellow solid (44 mg). LCMS (M+H) + :540, 1H NMR (400MHz, methanol-d4) δppm: 8.65(d,J=8.7Hz,1H),8.16(d,J=8.1Hz,1H),7.91(d,J=2.2Hz,1H),7.66(d,J =8.6Hz,1H),7.48(dd,J=2.3,8.6Hz,1H),7.25(d,J=8.1Hz,1H),6.48(d,J=8.7Hz,1H),3.99(dd,J=2.4, 11.9Hz,1H),3.84-3.71(m,3H),3.69-3.61(m,1H),3.47-3.36(m,3H),3.26-3.08(m,3H),3.04-2.94(m, 4H), 2.88-2.67 (m, 6H), 2.64-2.54 (m, 2H), 2.40-2.29 (m, 2H), 2.11-2.00 (m, 1H), 1.19 (d, J = 6.0Hz, 3H).

[0931] Example 78

[0932] 5-[(4R,9aS)-4-methyl-8-[(6-piperazin-1-yl-3-pyridinyl)methyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile

[0933]

[0934] Example 78 was prepared similarly to Example 3, but Intermediate G was used instead of Intermediate A and 2-bromo-5-(bromomethyl)pyridine was used instead of Compound 3a. Example 78 was obtained as a light yellow solid (15 mg). LCMS (M+H) + :484, 1 H NMR (400MHz, methanol-d4) δppm: 8.61 (d, J = 8.7Hz, 1H), 8.14 (d, J = 8.1Hz, 1H), 8.06 (d, J = 2.2Hz, 1H), 7.68-7.55 (m, 2H), 7.23 (d, J = 8.1Hz, 1H), 6.84 (d,J=8.8Hz,1H),3.58-3.45(m,6H),3.44-3.39(m,1H),3.29-3.23(m,2H),3.00-2.92(m,5H),2.88-2.64(m,5H),2.37-2.21(m,2H),2.00(br t, J=10.3Hz, 1H), 1.17 (d, J=6.0Hz, 3H).

[0935] Example 79

[0936] 5-[(4R,9aS)-8-[[6-(3-amino-3-methyl-azetidin-1-yl)-2-methyl-3-pyridinyl]methyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile

[0937]

[0938] The preparation of the title compound was similar to Example 11, but using tert-butyl N-(3-methylazetidin-3-yl)carbamate instead of tert-butyl piperazine-1-carboxylate, using Intermediate G instead of Intermediate C, and using TFA / DCM (1:2) instead of EA containing 1M HCl. Example 79 was obtained as a light yellow solid (27 mg). LCMS (M+H) + :498, 1 H NMR (400MHz, methanol-d4) δppm: 8.61(d,J=8.6Hz,1H),8.14(d,J=8.1Hz,1H),7.63(d,J=8.6Hz,1H),7.42(d,J=8.3Hz,1H),7.23( d,J=8.1Hz,1H),6.24(d,J=8.3Hz,1H),3.95-3.85(m,2H),3.84-3.75(m,2H),3.48-3.38(m,3H),3.30-3.22(m,2H),2.92(br d,J=8.9Hz,1H),2.88-2.69(m,5H),2.46(s,3H),2.34-2.22(m,2H),2.07-1.95(m,1H),1.52(s,3H),1.17(d,J=6.1Hz,3H).

[0939] Example 80

[0940] 5-[(4R,9aS)-4-methyl-8-[[2-methyl-6-(6-methyl-2,6-diazaspiro[3.3]heptane-2-yl)-3-pyridinyl]methyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile

[0941]

[0942] The title compound was prepared according to the following scheme:

[0943]

[0944] Step 1: Preparation of 5-[(4R,9aS)-8-[(6-chloro-2-methyl-3-pyridinyl)methyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile (Compound 80b)

[0945] 5-[(4R,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile (Intermediate G, 500 mg, 1.6 mmol), 6-chloro-3-(chloromethyl)-2-methylpyridine (428 mg, 2.4 mmol) and K 2 CO 3 A mixture of (672 mg, 4.9 mmol) in MeCN (10 mL) was stirred at 80°C for 16 hours. The reaction was then concentrated and the residue was purified using silica gel to give compound 80b as a light yellow solid, 500 mg. LCMS (M+H) + :448.

[0946] Step 2: Preparation of 5-[(4R,9aS)-4-methyl-8-[[2-methyl-6-(6-methyl-2,6-diazaspiro[3.3]heptane-2-yl)-3-pyridinyl]methyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile (Example 80)

[0947] 5-[(4R,9aS)-8-[(6-chloro-2-methyl-3-pyridyl)methyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-d-quinoline-8-carbonitrile (Compound 80b, 80 mg, 179 μmol), 2-methyl-2,6-diazaspiro[3.3]heptane (30 mg, 268 μmol), Cs 2 CO 3 A mixture of (116 mg, 357 μmol) and Ruphos Pd G2 (13.9 mg, 17.9 μmol) in dioxane (5 mL) was stirred at 120° C. for 16 hours. The reaction was then concentrated and the residue was purified by preparative HPLC to give Example 80 as a light yellow powder, 30 mg. LCMS (M+H) + :524, 1HNMR (400MHz, methanol-d4) δppm: 8.61(d,J=8.6Hz,1H), 8.14(d,J=7.9Hz,1H), 7.63(d,J=8.6H z,1H),7.42(d,J=8.3Hz,1H),7.23(d,J=8.1Hz,1H),6.23(d,J=8.3Hz,1H),4.06(s,4H), 3.48(s,4H),3.46-3.38(m,3H),3.31-3.22(m,2H),2.96-2.87(m,1H),2.84-2.68(m,5H) ,2.45(s,3H),2.36(s,3H),2.32-2.23(m,2H),2.05-1.93(m,1H),1.17(d,J=6.1Hz,3H).

[0948] Example 81

[0949] 5-[(4R,9aS)-8-[[6-[(3R)-3-amino-3-methyl-pyrrolidin-1-yl]-2-methyl-3-pyridinyl]methyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile

[0950]

[0951] The title compound was prepared according to the following scheme:

[0952]

[0953] 5-[(4R,9aS)-8-[(6-chloro-2-methyl-3-pyridyl)methyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile (Compound 80b, 80 mg, 179 μmol), (R)-tert-butyl (3-methylpyrrolidin-3-yl)carbamate (53.6 mg, 268 μmol), Cs 2 CO 3 A mixture of (116 mg, 357 μmol) and Ruphos Pd G2 (14 mg, 18 μmol) in dioxane (5 mL) was stirred at 120 ° C for 16 hours. The reaction was concentrated and the residue was purified by preparative HPLC to give compound 81a (40 mg) as a light yellow solid. Compound 81a (40 mg, 65.4 μmol) was then treated with EA (3 mL) containing 1M HCl and stirred at rt for 16 hours. The reaction mixture was concentrated to give Example 81 (32 mg) as an orange solid. LCMS (M+H)+ :512, 1 H NMR (400MHz, methanol-d4) δppm: 8.90(d,J=8.6Hz,1H), 8.31(d,J=7.9Hz,1H), 8.21(d,J=9.3Hz,1 H),7.84(d,J=8.6Hz,1H),7.49(d,J=8.1Hz,1H),7.07(d,J=9.4Hz,1H),4.40-4.22(m,3H), 4.19-4.10(m,1H),4.03-3.89(m,4H),3.87-3.82(m,1H),3.82-3.70(m,4H),3.65-3.52(m, 2H),3.51-3.35(m,3H),2.80(s,3H),2.50-2.42(m,2H),1.66(s,3H),1.56(d,J=6.5Hz,3H).

[0954] Example 82

[0955] 5-[(4R,9aS)-8-[[6-[[(3S,4R)-4-fluoropyrrolidin-3-yl]amino]-2-methyl-3-pyridinyl]methyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile

[0956]

[0957] The title compound was prepared similarly to Example 81, but using (3S,4R)-tert-butyl 3-amino-4-fluoropyrrolidine-1-carboxylate instead of (R)-tert-butyl (3-methylpyrrolidin-3-yl)carbamate. Example 82 was obtained as an orange solid, 32 mg. LCMS (M+H) + :516, 1H NMR (400MHz, methanol-d4) δppm: 8.88(d,J=8.7Hz,1H),8.30(d,J=8.1Hz,1H),8.24(d,J=9.2Hz,1H),7.83(d,J=8.7Hz,1H),7.48(d,J=7 .9Hz,1H),7.21(d,J=9.2Hz,1H),5.57(t,J=2.9Hz,0.5H),5.44(t,J=2.9Hz,0.5H),5.19-5.01(m,1H),4.36-4.17(m,3H),4.13(br d,J=11.9Hz,1H),4.01-3.83(m,3H),3.82-3.60(m,5H),3.58-3.37(m,5H),3.27-3.21(m,1H),2.79(s,3H),1.56(d,J=6.4Hz,3H).

[0958] Example 83

[0959] 5-[(4R,9aS)-4-methyl-8-[[2-methyl-6-(9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl)-3-pyridinyl]methyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile

[0960]

[0961] The title compound was prepared similarly to Example 81, but using tert-butyl 9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (R)-tert-butyl(3-methylpyrrolidin-3-yl)carbamate. Example 83 was obtained as an orange solid, 12 mg. LCMS (M+H) + :540, 1 H NMR (400MHz, methanol-d4) δppm: 8.84 (d, J = 8.6 Hz, 1H), 8.28 (d, J = 7.9 Hz, 2H), 7.80 (d, J =8.6Hz,1H),7.45(d,J=7.9Hz,1H),7.34(d,J=9.2Hz,1H),4.41(brs,2H),4.30(br d,J=12.8Hz,2H),4.16-3.98(m,4H),3.94-3.82(m,1H),3.81-3.63(m,7H),3.61-3.38(m,8H),2.84(s,3H),1.54(d,J=6.4Hz,3H).

[0962] Example 84

[0963] 5-[(4R,9aS)-8-[2-[6-[(3R)-3-amino-3-methyl-pyrrolidin-1-yl]-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile

[0964]

[0965] The title compound was prepared similarly to Example 11, but using (R)-(3-methylpyrrolidin-3-yl)carbamic acid tert-butyl ester instead of piperazine-1-carboxylic acid tert-butyl ester and using Intermediate G instead of Intermediate C. Example 84 was obtained as an orange solid, 50 mg. LCMS (M+H) + :512, 1 H NMR (400MHz, methanol-d4) δppm: 8.85 (d, J = 8.7Hz, 1H), 8.28 (d, J = 8.1Hz, 1H), 8.19-8.11 (m, 1H), 8.07 (s, 1H),7.81(d,J=8.6Hz,1H),7.47(d,J=8.1Hz,1H),7.21(d,J=9.4Hz,1H),4.44-4.31(m,1H),4.22(br d,J=13.3Hz,1H),4.06(br t,J=10.9Hz,2H),3.98-3.83(m,4H),3.81-3.71(m,4H),3.69-3.54(m,4H),3.54-3. 38(m,2H),3.27-3.17(m,2H),2.55-2.38(m,2H),1.67(s,3H),1.56(d,J=6.4Hz,3H).

[0966] Example 85

[0967] 5-[(4R,9aS)-4-methyl-8-[[2-methyl-6-[(2S)-2-methylpiperazin-1-yl]-3-pyridinyl]methyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0968]

[0969] The title compound was prepared similarly to Example 11, but using (3S)-3-methylpiperazine-1-carboxylic acid tert-butyl ester instead of piperazine-1-carboxylic acid tert-butyl ester and using compound 60d instead of compound 11d. Example 85 was obtained as a light yellow solid, 5 mg. LCMS (M+H) + :511, 1H NMR (400MHz, methanol-d4) δppm: 9.01-8.94 (m, 1H), 8.69-8.56 (m, 1H), 8.14 (d, J = 7.9Hz, 1H), 7.7 1-7.59(m,1H),7.41(d,J=8.6Hz,1H),7.23(d,J=8.1Hz,1H),6.53(d,J=8.6Hz,1H),4.45(br d,J=4.8Hz,1H),3.99-3.88(m,1H),3.55-3.38(m,5H),3.32-3.21(m,1H),3.12-2.86 (m,6H),2.85-2.67(m,7H),2.37-2.23(m,2H),2.04-1.93(m,1H),1.20-1.13(m,6H).

[0970] Example 86

[0971] 5-[(4R,9aS)-4-methyl-8-[[2-methyl-6-[(3R)-3-methylpiperazin-1-yl]-3-pyridinyl]methyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[0972]

[0973] The title compound was prepared similarly to Example 11, but using (2R)-2-methylpiperazine-1-carboxylic acid tert-butyl ester instead of piperazine-1-carboxylic acid tert-butyl ester and using compound 60d instead of compound 11d. Example 86 was obtained as a light yellow solid, 15 mg. LCMS (M+H) + :511, 1 H NMR (400 MHz, METHANOL-d 4 )δppm 9.02-8.91(m,1H),8.67-8.54(m,1H),8.14(d,J=8.1Hz,1H),7.68-7.56(m,1H),7 .42(d,J=8.6Hz,1H),7.23(d,J=8.1Hz,1H),6.59(d,J=8.4Hz,1H),4.23-4.04(m, 2H),3.54-3.36(m,3H),3.32-3.21(m,2H),3.10-3.02(m,1H),2.98-2.66(m,9H), 2.51-2.38(m,4H),2.37-2.20(m,2H),2.00(t,J=10.2Hz,1H),1.18-1.15(m,6H).

[0974] Example 87

[0975] 5-[(4R,9aS)-4-methyl-8-[(4-methyl-6-piperazin-1-yl-3-pyridinyl)methyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile

[0976]

[0977] The title compound was prepared according to the following scheme:

[0978]

[0979] The title compound was prepared similarly to Example 11, but using Compound 87a instead of Compound 11c and Intermediate G instead of Intermediate C. Example 87 was obtained as an orange solid, 27 mg. LCMS (M+H) + :498, 1 H NMR (400MHz, methanol-d4) δppm: 8.98(d,J=8.6Hz,1H),8.34(d,J=8.1Hz,1H),8.24(s,1H),7.89(d,J=8.6Hz,1 H),7.51(d,J=8.1Hz,1H),7.44(s,1H),4.31-4.09(m,4H),4.08-4.02(m,4H),3.98-3.90(m,1H),3.77(br d,J=12.7Hz,2H),3.67(br d,J=9.7Hz,2H),3.59-3.36(m,8H),3.22-3.09(m,1H),2.66(s,3H),1.56(J=6.5Hz,3H).

[0980] Example 88

[0981] 5-[(4R,9aS)-4-methyl-8-[(3-methyl-6-piperazin-1-yl-2-pyridinyl)methyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile

[0982]

[0983] The title compound was prepared similarly to Example 11, but using 6-chloro-2-(chloromethyl)-3-methyl-pyridine instead of compound 11c and using Intermediate G instead of Intermediate C. Example 88 was obtained as an orange solid, 16 mg. LCMS (M+H) + :498, 1H NMR (400MHz, methanol-d4) δppm: 8.94(d,J=8.7Hz,1H),8.30(d,J=7.9Hz,1H),7.84(d,J=8.6Hz,1H),7.71(d,J=8 .8Hz,1H),7.48(d,J=8.1Hz,1H),7.06(d,J=8.8Hz,1H),4.69-4.57(m,1H),4.53(d,J=2.1Hz,2H),4.17(br d,J=12.5Hz,1H),4.09-4.03(m,1H),4.00-3.89(m,5H),3.89-3.67(m,5H),3.59-3.39(m,7H),2.32(s,3H),1.57(d,J=6.5Hz,3H).

[0984] Example 89

[0985] 5-[(4R,9aS)-8-[2-[2-[(3R,4S)-3-amino-4-fluoro-pyrrolidin-1-yl]-4-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile

[0986]

[0987] The preparation of the title compound was similar to Example 11, but using 2-(2-chloro-4-pyridyl)acetic acid instead of compound 11a, using intermediate G instead of intermediate C, and using tert-butyl N-[(3R,4S)-4-fluoropyrrolidin-3-yl]carbamate instead of tert-butyl piperazine-1-carboxylate. Example 89 was obtained as an orange solid, 60 mg. LCMS (M+H) + :516, 1 H NMR (400MHz, methanol-d4) δppm: 8.93 (d, J = 8.6 Hz, 1H), 8.32 (d, J = 7.9 Hz, 1H), 8.01 (d, J = 6.6 Hz, 1H),7.86(d,J=8.6Hz,1H),7.51(d,J=8.1Hz,1H),7.35(s,1H),7.18-7.11(m,1H),5.71(br s,0.5H),5.58(t,J=3.1Hz,0.5H),4.45(br t,J=11.2Hz,1H),4.39-4.16(m,4H),4.15-4.04(m,3H),4.03-3.94(m,1H),3.89-3.63(m,8H),3.57-3.37(m,4H),1.58(d,J=6.4Hz,3H).

[0988] Example 90

[0989] 5-[(4R,9aS)-8-[[6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-2-methyl-3-pyridinyl]methyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile

[0990]

[0991] The title compound was prepared similarly to Example 81, but using tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate instead of (R)-tert-butyl(3-methylpyrrolidin-3-yl)carbamate and TFA / DCM (1:2) instead of EA containing 1M HCl. Example 90 was obtained as a light solid, 15 mg. LCMS (M+H) + :510, 1 H NMR (400MHz, methanol-d4) δppm: 8.63 (d, J = 8.6 Hz, 1H), 8.17 (d, J = 7.9 Hz, 1H), 7.83 (d, J = 8.9 Hz, 1H), 7.65 (d, J = 8 .6Hz,1H),7.32(d,J=8.1Hz,1H),6.85(d,J=8.8Hz,1H),4.59(d,J=6.2Hz,2H),4.20-4.02(m,4H),3.95(br s,2H),3.83-3.73(m,1H),3.66-3.50(m,3H),3.48-3.33(m,3H),3.17-2.97(m,3H ),2.96-2.83(m,2H),2.70-2.57(m,4H),2.01-1.94(m,1H),1.36(d,J=6.4Hz,3H).

[0992] Example 91

[0993] 5-[(4R,9aS)-8-[[6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-methyl-3-pyridyl]methyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile

[0994]

[0995] The title compound was prepared similarly to Example 81, but using tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate instead of (R)-tert-butyl(3-methylpyrrolidin-3-yl)carbamate. Example 91 was obtained as an orange solid, 15 mg. LCMS (M+H) + :524, 1 H NMR (400MHz, methanol-d4) δppm: 8.80(d,J=8.6Hz,1H), 8.26(d,J=7.9Hz,1H), 8.17(d,J=9.2H z,1H),7.77(d,J=8.6Hz,1H),7.43(d,J=8.1Hz,1H),7.26(d,J=9.0Hz,1H),4.38-4.25(m ,4H),4.17-3.93(m,4H),3.91-3.79(m,1H),3.76-3.61(m,4H),3.56-3.34(m,4H),3.29 -3.08(m,2H),3.01-2.84(m,1H),2.77(s,3H),2.28-2.09(m,4H),1.53(d,J=6.4Hz,3H).

[0996] Example 92

[0997] 5-[(4R,9aS)-8-[[6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-methyl-3-pyridinyl]methyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile

[0998]

[0999] The title compound was prepared similarly to Example 81, but using (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester instead of (R)-(3-methylpyrrolidin-3-yl)carbamic acid tert-butyl ester. Example 92 was obtained as a light brown solid, 15 mg. LCMS (M+H) + :510, 1H NMR (400MHz, methanol-d4) δppm: 8.88(d,J=8.6Hz,1H),8.30(d,J=7.9Hz,1H),8.21(d,J=9.4Hz,1H),7.83(d,J=8.7Hz,1H),7.48(d,J=8.1Hz,1H),7.15(br d,J=9.0Hz,1H),5.30(br s,1H),4.74(s,1H),4.39-4.08(m,4H),4.04-3.86(m,3H),3.82-3.60(m,5H),3.58-3.36(m,5H ),3.30-3.15(m,1H),2.79(s,3H),2.47-2.37(m,1H),2.31-2.21(m,1H),1.55(d,J=6.4Hz,3H).

[1000] Example 93

[1001] 4-[(4R,9aR)-4-methyl-8-(3-methyl-5-piperazin-1-yl-2-pyridinyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-1-methyl-1,8-naphthyridin-2-one

[1002]

[1003] The title compound was prepared according to the following scheme:

[1004]

[1005] Step 1: Preparation of 4-[(4R,9aR)-8-(5-bromo-3-methyl-2-pyridinyl)-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-1-methyl-1,8-naphthyridin-2-one (Compound 93a)

[1006] A mixture of 4-[(4R,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]-1-methyl-1,8-naphthyridin-2-one (Intermediate L, 150 mg, 479 μmol), 5-bromo-2-fluoro-3-methylpyridine (136 mg, 718 μmol) and DIPEA (309 mg, 2.39 mmol) in NMP (5 mL) was stirred at 180 ° C for 16 hours. The reactant was then diluted with EA, washed with water and brine, and the organic layer was dried and concentrated. The residue was purified using silica gel to give compound 93a as a light brown foam, 100 mg. LCMS (M+H) + :483.

[1007] Step 2: Preparation of tert-butyl 4-[6-[(4R,9aR)-4-methyl-2-(1-methyl-2-oxo-1,8-naphthyridin-4-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-8-yl]-5-methyl-3-pyridyl]piperazine-1-carboxylate (Compound 93b)

[1008] 4-[(4R,9aR)-8-(5-bromo-3-methyl-2-pyridyl)-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-1-methyl-1,8-naphthyridin-2-one (Compound 93a, 100 mg, 207 μmol), tert-butyl piperazine-1-carboxylate (57.8 mg, 310 μmol), Cs 2 CO 3 A mixture of (135 mg, 414 μmol) and Ruphos Pd G2 (16.1 mg, 20.7 μmol) in dioxane (5 mL) was stirred at 115° C. for 16 hours. The reaction was then concentrated and the residue was purified by HPLC to give compound 93b as a light yellow solid, 30 mg. LCMS (M+H) + :589.

[1009] Step 3: Preparation of 4-[(4R,9aR)-4-methyl-8-(3-methyl-5-piperazin-1-yl-2-pyridinyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-1-methyl-1,8-naphthyridin-2-one (Example 93)

[1010] A mixture of tert-butyl 4-[6-[(4R,9aR)-4-methyl-2-(1-methyl-2-oxo-1,8-naphthyridin-4-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-8-yl]-5-methyl-3-pyridinyl]piperazine-1-carboxylate (compound 93b, 15 mg, 25.5 μmol) in 1M HCl in EA (2 mL) was stirred at rt for 16 h, then the reaction was concentrated to give Example 93 as a yellow solid, 14 mg. LCMS (M+H) + :489, 1H NMR (400MHz, methanol-d4) δppm: 8.74-8.66 (m, 1H), 8.44-8.37 (m, 1H), 8.14 (d, J = 2.6Hz, 1H ),7.85(d,J=2.9Hz,1H),7.45-7.35(m,1H),6.34(s,1H),4.25-4.15(m,1H),4.08(br d,J=12.3Hz,1H),4.01-3.87(m,3H),3.87-3.77(m,6H),3.69-3.59(m,5H) ,3.56-3.41(m,5H),3.40-3.33(m,2H),2.55(s,3H),1.59(d,J=6.5Hz,3H).

[1011] Example 94

[1012] 5-[(4R,9aS)-8-[[6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-4-methyl-3-pyridinyl]methyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile

[1013]

[1014] The title compound was prepared similarly to Example 81, but using (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester instead of (R)-(3-methylpyrrolidin-3-yl)carbamic acid tert-butyl ester and using compound 87b instead of compound 80b. Example 94 was obtained as an orange solid, 33 mg. LCMS (M+H) + :510, 1 H NMR (400MHz, methanol-d4) δppm: 8.94(d,J=8.6Hz,1H),8.33(d,J=8.1Hz,1H),8.13(br s,1H),7.87(d,J=8.7Hz,1H),7.49(d,J=8.1Hz,1H),7.23(br s,1H),5.19(s,1H),4.74(s,1H),4.27-4.02(m,4H),3.99-3.84(m,3H),3.81-3.70(m,2H),3.69-3.56(m,3H),3 .54-3.36(m,5H),3.12-2.97(m,1H),2.66(s,3H),2.46-2.38(m,1H),2.31-2.20(m,1H),1.56(d,J=6.5Hz,3H).

[1015] Example 95

[1016] 5-[(4R,9aR)-8-[5-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-3-methyl-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile

[1017]

[1018] The title compound was prepared similarly to Example 93, but using (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester instead of piperazine-1-carboxylic acid tert-butyl ester and using Intermediate G instead of Intermediate L. Example 95 was obtained as a dark brown solid, 8 mg. LCMS (M+H) + :496, 1 H NMR (400MHz, methanol-d4) δppm: 8.80 (d, J = 8.7Hz, 1H), 8.25 (d, J = 8.1Hz, 1H), 7.81-7.70 (m, 2H), 7.6 2(d,J=3.1Hz,1H),7.44(d,J=7.9Hz,1H),4.83(s,1H),4.60(s,1H),4.31-4.15(m,1H),4.07(br d,J=12.3Hz,1H),4.01-3.94(m,1H),3.84-3.66(m,6H),3.63-3.35(m,7H),2.52(s,3H),2.36-2.23(m,1H),2.13(br d,J=11.5Hz,1H),1.57(d,J=6.5Hz,3H).

[1019] Example 96

[1020] 5-[(4R,9aR)-8-[5-[(3R,4S)-3-amino-4-methoxy-pyrrolidin-1-yl]-3-methyl-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile

[1021]

[1022] The title compound was prepared similarly to Example 93, but using tert-butyl N-[(3R,4S)-4-methoxypyrrolidin-3-yl]carbamate instead of tert-butyl piperazine-1-carboxylate and using Intermediate G instead of Intermediate L. Example 96 was obtained as a dark brown solid, 14 mg. LCMS (M+H) + :514,1 H NMR (400MHz, methanol-d4) δppm: 8.86 (d, J = 8.6 Hz, 1H), 8.27 (d, J = 8.1 Hz, 1H), 7.79 ( d,J=8.6Hz,1H),7.71(d,J=2.8Hz,1H),7.52(d,J=2.9Hz,1H),7.46(d,J=8.1Hz ,1H),4.35-4.19(m,2H),4.16-4.02(m,2H),4.02-3.93(m,1H),3.87-3.72(m, 6H), 3.70-3.56 (m, 3H), 3.55-3.36 (m, 7H), 2.53 (s, 3H), 1.58 (d, J = 6.5Hz, 3H).

[1023] Example 97

[1024] 5-[(4R,9aR)-8-[5-[(3R)-3-amino-3-methyl-pyrrolidin-1-yl]-3-methyl-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile

[1025]

[1026] The title compound was prepared similarly to Example 93, but using (R)-(3-methylpyrrolidin-3-yl)carbamic acid tert-butyl ester instead of piperazine-1-carboxylic acid tert-butyl ester and using Intermediate G instead of Intermediate L. Example 97 was obtained as a light brown solid, 5 mg. LCMS (M+H) + :498, 1 H NMR (400 MHz, METHANOL-d 4 )δppm 8.79(d,J=8.6Hz,1H),8.25(d,J=7.9Hz,1H),7.74(d,J=8.7Hz,1H),7.69(d,J=2.7Hz,1H),7.51(d,J=3.1Hz,1H),7.44(d,J=8. 1Hz,1H),4.28-4.16(m,1H),4.12-4.04(m,1H),4.02-3.92(m,1H),3.83-3.69(m,6H),3.67-3.36(m,7H),2.53(s,3H),2.34(br d,J=7.9Hz,2H),1.65-1.51(m,6H).

[1027] Example 98

[1028] 5-[(4R,9aS)-8-[[6-[(4aR,7aR)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl]-2-methyl-3-pyridinyl]methyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile

[1029]

[1030] The title compound was prepared similarly to Example 81, but using (4aR,7aR)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-4-carboxylic acid tert-butyl ester (CAS: 1932337-68-2, catalog number: PBXA8123, supplier: Pharmablock) instead of (R)-(3-methylpyrrolidin-3-yl)carbamic acid tert-butyl ester. Example 98 was obtained as a light yellow solid, 30 mg. LCMS (M+H) + :540, 1 H NMR (400MHz, methanol-d4) δppm: 8.58 (d, J = 8.6 Hz, 1H), 8.12 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 8.6 Hz, 1H) ,7.37(d,J=8.6Hz,1H),7.21(d,J=8.1Hz,1H),6.26(d,J=8.4Hz,1H),4.05-3.92(m,1H),3.84- 3.69(m,3H),3.68-3.55(m,1H),3.49-3.36(m,3H),3.28-3.06(m,4H),3.05-2.88(m,4H),2.8 5-2.67(m,5H),2.44(s,3H),2.35-2.20(m,2H),1.97(t,J=10.0Hz,1H),1.15(d,J=6.1Hz,3H).

[1031] Example 99

[1032] 5-[(4R,9aR)-8-[5-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]-3-methyl-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile

[1033]

[1034] The title compound was prepared similarly to Example 93, but using tert-butyl N-[(3R,4R)-4-methoxypyrrolidin-3-yl]carbamate instead of tert-butyl piperazine-1-carboxylate and using Intermediate G instead of Intermediate L. Example 99 was obtained as an orange solid, 5 mg. LCMS (M+H) + :514, 1 H NMR(400MHz,METHANOL-d4)δppm 8.79(d,J=8.6Hz,1H),8.25(d,J=7.9Hz,1H),7.77-7.66(m,2H),7.54(d,J=2.9Hz,1H),7.44(d,J=8.1Hz,1H),4.27-4.16(m,2H),4 .14-4.04(m,1H),4.04-3.94(m,2H),3.94-3.86(m,1H),3.83-3.70(m,6H),3.61-3.35(m,9H),2.53(s,3H),1.57(d,J=6.4Hz,3H).

[1035] Example 100

[1036] 5-[(4R,9aR)-8-[5-[(4aR,7aR)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl]-3-methyl-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile

[1037]

[1038] The title compound was prepared similarly to Example 93, but using (4aR,7aR)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-4-carboxylic acid tert-butyl ester (CAS: 1932337-68-2, catalog number: PBXA8123, supplier: Pharmablock) instead of piperazine-1-carboxylic acid tert-butyl ester and using Intermediate G instead of Intermediate L. Example 100 was obtained as an orange solid, 5 mg. LCMS (M+H) + :526, 1 H NMR (400 MHz, METHANOL-d 4)δppm 8.75(d,J=8.6Hz,1H),8.23(d,J=7.9Hz,1H),7.72(d,J=8.6Hz,1H),7.61(d,J=2.7Hz,1H),7.52(d,J=2.9Hz,1H),7.42(d,J= 7.9Hz,1H),4.32-4.11(m,3H),4.10-3.92(m,3H),3.90-3.60(m,8H),3.58-3.35(m,8H),2.51(s,3H),1.56(d,J=6.5Hz,3H).

[1039] Example 101

[1040] 5-[(4R,9aR)-8-[5-(6-amino-2-azaspiro[3.3]heptane-2-yl)-3-methyl-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile

[1041]

[1042] The preparation of the title compound was similar to Example 93, but using tert-butyl N-(2-azaspiro[3.3]heptane-6-yl)carbamate instead of tert-butyl piperazine-1-carboxylate, using Intermediate G instead of Intermediate L, and using TFA / DCM (1:2) instead of EA containing 1M HCl. Example 101 was obtained as a light yellow solid, 30 mg. LCMS (M+H) + :510, 1 H NMR (400MHz, methanol-d4) δppm: 8.72 (d, J = 8.7Hz, 1H), 8.23 ​​(d, J = 7.9Hz, 1H), 7.71 (d, J = 8.7Hz, 1H), 7.47-7.35 (m, 2H), 7.07 (d, J = 2.6Hz, 1H), 4.11 (br s,1H),4.06-3.99(m,3H),3.92(s,3H),3.82-3.71(m,3H),3.66-3.53(m,2H),3.46-3.37 (m,2H),3.31-3.21(m,3H),2.75-2.65(m,2H),2.49-2.36(m,5H),1.53(d,J=6.5Hz,3H).

[1043] Example 102

[1044] 5-[(4R,9aR)-4-methyl-8-[3-methyl-5-(6-methyl-2,6-diazaspiro[3.3]heptane-2-carbonyl)-2-pyridinyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile

[1045]

[1046] The title compound was prepared according to the following scheme:

[1047]

[1048] Step 1: Preparation of 6-[(4R,9aR)-2-(8-cyano-2-deutero-5-quinolyl)-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-8-yl]-5-methyl-pyridine-3-carboxylic acid (Compound 102a)

[1049] A mixture of 5-[(4R,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile (Intermediate G, 100 mg, 324 μmol), 6-fluoro-5-methylnicotinic acid (101 mg, 648 μmol) and DIPEA (210 mg, 1.62 mmol) in DMSO (5 mL) was stirred at 120 °C for 16 hours and then the reaction was purified by flash preparative HPLC (water, MeCN containing TFA) to give compound 102a as a light yellow solid, 100 mg, LCMS (M+H) + :444.

[1050] Step 2: Preparation of 5-[(4R,9aR)-4-methyl-8-[3-methyl-5-(6-methyl-2,6-diazaspiro[3.3]heptane-2-carbonyl)-2-pyridinyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile (Example 102)

[1051] A mixture of 6-[(4R,9aR)-2-(8-cyano-2-deuterated-5-quinolyl)-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-8-yl]-5-methyl-pyridine-3-carboxylic acid (Compound 102a, 100 mg, 225 μmol), 2-methyl-2,6-diazaspiro[3.3]heptane (50.6 mg, 451 μmol), HATU (103 mg, 271 μmol) and DIPEA (87.4 mg, 676 μmol) in DMF (5 mL) was stirred at rt for 1 hour, then the reaction was diluted with EA and washed with water and brine. The organic layer was dried and concentrated, and the residue was purified by preparative HPLC to give Example 102 as a light yellow solid, 45 mg. LCMS (M+H) + :538, 1 H NMR (400MHz, methanol-d4) δppm: 8.62 (d, J = 8.6 Hz, 1H), 8.35 (d, J = 2.1 Hz, 1H), 8.11 (d, J = 8. 1Hz,1H),7.74(d,J=1.7Hz,1H),7.62(d,J=8.6Hz,1H),7.23(d,J=8.1Hz,1H),4.48(br s,2H),4.21(br s,2H),3.74-3.64(m,1H),3.58(br d,J=12.1Hz,1H),3.49-3.39(m,6H),3.35(br d,J=11.4Hz,1H),3.15-3.01(m,1H),2.94-2.74(m,5H),2.44-2.36(m,1H),2.34(s,3H),2.31(s,3H),1.19(d,J=5.6Hz,3H).

[1052] Example 103

[1053] 5-[(4S,9aR)-4-methyl-8-[3-methyl-5-(6-methyl-2,6-diazaspiro[3.3]heptane-2-carbonyl)-2-pyridinyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile

[1054]

[1055] The title compound was prepared similarly to Example 102, but using Intermediate K instead of Intermediate G. Example 103 was obtained as a light yellow solid, 35 mg. LCMS (M+H) + :538, 1H NMR (400MHz, methanol-d4) δppm: 8.73 (d, J = 8.6 Hz, 1H), 8.36 (d, J = 2.3 Hz, 1H), 8.15 (d, J = 7 .9Hz,1H),7.78-7.72(m,1H),7.65(d,J=8.6Hz,1H),7.27(d,J=8.1Hz,1H),4.49(br s,2H),4.22(br s,2H),3.69-3.54(m,2H),3.48(s,4H),3.44-3.32(m,5H),3.16-2.97(m, 2H), 2.86-2.72 (m, 3H), 2.36 (s, 3H), 2.34 (s, 3H), 1.46 (d, J = 6.5Hz, 3H).

[1056] Example 105

[1057] 5-[(4R,9aS)-8-[2-[(3R)-3-amino-3-methyl-pyrrolidin-1-yl]-4-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[1058]

[1059] The title compound was prepared similarly to Example 32, but using tert-butyl N-[(3R)-3-methylpyrrolidin-3-yl]carbamate instead of tert-butyl piperazine-1-carboxylate. Example 105 (20 mg) was obtained as an orange solid. LCMS (M+H) + :483. 1 HNMR (400MHz, methanol-d4) δppm: 9.06 (dd, J=1.6, 4.3Hz, 1H), 8.77 (dd, J=1.7, 8.6Hz, 1H), 8. 26(d,J=7.9Hz,1H),7.78-7.72(m,2H),7.46(d,J=8.1Hz,1H),6.83(dd,J=2.2,7.6Hz,1H ),6.19(d,J=2.2Hz,1H),4.68-4.52(m,2H),4.15-4.02(m,2H),3.95-3.83(m,4H),3.82 -3.64(m,4H),3.48-3.35(m,4H),2.45-2.36(m,2H),1.64(s,3H),1.58(d,J=6.5Hz,3H).

[1060] Example 106

[1061] 5-[(4S,9aS)-4-methyl-8-[4-[(2R)-morpholin-2-yl]phenyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile

[1062]

[1063] The title compound was prepared in a manner similar to Example 2, except that 5-[(4S,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile (Intermediate K) was used instead of 5-[cis-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Intermediate A), and (2R)-2-(4-bromophenyl)morpholine-4-carboxylic acid tert-butyl ester (CAS: 1312566-00-9, procedure see patent WO 2014041007A1 20140320) was used instead of tert-butyl 5-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylate (Compound 2a). Example 106 (11 mg) was obtained as an orange solid. LCMS (M+H) + :470. 1 H NMR (400MHz, methanol-d4) δppm: 8.71(d,J=8.6Hz,1H),8.13(d,J=8.1Hz,1H),7.65(d,J=8.6Hz,1H),7.27-7.21(m,3H),6.9 7(d,J=8.8Hz,2H),4.38(dd,J=2.3,10.5Hz,1H),3.95(dd,J=2.4,11.6Hz,1H),3.73(dt,J=3.2,11.4Hz,1H),3.62(br t,J=12.8Hz,2H),3.44(br d,J=11.4Hz,1H),3.34(br d,J=2.6Hz,2H),3.30-3.25(m,2H),3.03-2.79(m,6H),2.78-2.66(m,2H),2.51(br,1H),1.43(d,J=6.5Hz,3H).

[1064] Example 107

[1065] 5-[(4S,9aS)-4-methyl-8-[4-[(2S)-morpholin-2-yl]phenyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile

[1066]

[1067] The preparation of the title compound was similar to Example 2, except that 5-[(4S,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile (Intermediate K) was used instead of 5-[cis-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Intermediate A), and (2S)-2-(4-bromophenyl)morpholine-4-carboxylic acid tert-butyl ester (CAS: 1131220-37-5, procedure see patent WO 2014041007A1 20140320) was used instead of tert-butyl 5-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylate (Compound 2a). Example 107 (10 mg) was obtained as an orange solid. LCMS (M+H) + :470. 1 H NMR (400MHz, methanol-d4) δppm: 8.83 (d, J = 8.4Hz, 1H), 8.26 (d, J = 7.9Hz, 1H), 7.77 (d, J = 8.6Hz, 1H), 7.45 (d, J = 7.9Hz, 1H), 7.38 (br d,J=8.7Hz,2H),7.12(d,J=8.7Hz,2H),4.8-4.8(m,1H),4.4-4.3(m,1H),4.24(dd,J=3.3,13.2Hz,1H),4.1-3.9 (m,4H),3.9-3.6(m,6H),3.5-3.4(m,2H),3.3-3.2(m,1H),3.2-3.1(m,2H),2.98(br,1H),1.82(d,J=6.8Hz,3H).

[1068] Example 108

[1069] 5-[(4S,9aR)-8-[5-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-3-methyl-2-pyridyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile

[1070]

[1071] The title compound was prepared according to the following scheme:

[1072]

[1073] Step 1: Preparation of 5-[(4S,9aR)-8-(5-bromo-3-methyl-2-pyridyl)-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile (Compound 108b)

[1074] A solution of 5-bromo-2-fluoro-3-methylpyridine (compound 108a, 462 mg, 2.43 mmol), 5-[(4S,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile (intermediate K, 500 mg, 1.62 mmol) and DIPEA (1.1 g, 8.1 mmol) in NMP (6 mL) was stirred at 185 ° C for 20 hours, then the reaction was diluted with EtOAc (40 mL) and washed with water. The organic layer was dried and concentrated, and the residue was purified by flash column chromatography to give compound 108b (640 mg) as an orange oil. LCMS (M+1) + :478,LCMS(M+3) + :480.

[1075] Step 2: Preparation of 5-[(4S,9aR)-8-[5-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-3-methyl-2-pyridyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile (Compound 108)

[1076] To a solution of 5-[(4S,9aR)-8-(5-bromo-3-methyl-2-pyridinyl)-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-d-quinoline-8-carbonitrile (compound 108b, 100 mg, 209 μmol) in dioxane (4 mL) was added tert-butyl 3,6-diazabicyclo[3.1.1]-heptane-6-carboxylate (83 mg, 418 μmol) and tBuONa (41 mg, 418 μmol). The suspension was washed with N 2 Bubbling for 5 minutes, then tBuXPhos Pd G3 (33 mg, 41.8 μmol) was added. After the reaction mixture was heated at 110 °C overnight, it was filtered and the filtrate was concentrated. The residue was dissolved in DCM / TFA (4 mL, 1:1), stirred at rt for 10 min, the reaction mixture was concentrated and the residue was purified by preparative HPLC to give Example 108 (11 mg) as a light yellow foam. LCMS (M+H) + :496.1 H NMR (400MHz, methanol-d4) δppm: 8.79 (d, J = 8.6 Hz, 1H), 8.24 (d, J = 7.9 Hz, 1H), 7.80 (d, J = 2. 6Hz,1H),7.73(d,J=8.7Hz,1H),7.42(d,J=8.2Hz,1H),7.22(d,J=2.8Hz,1H),4.58(d, J=6.4Hz,2H),4.43-4.30(m,1H),3.95-3.90(m,2H),3.84-3.78(m,2H),3.52-3.43(m ,8H),3.30-3.24(m,2H),3.12-3.03(m,2H),2.43(s,3H),2.05(br,1H),1.85(br,3H).

[1077] Example 109

[1078] 5-[(4R,9aR)-8-[5-[2-[(3S,4S)-3-amino-4-methoxy-pyrrolidin-1-yl]ethyl]-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile

[1079]

[1080] The title compound was prepared according to the following scheme:

[1081]

[1082] Step 1: Preparation of N-[(3S,4S)-1-[2-(6-chloro-3-pyridinyl)ethyl]-4-methoxy-pyrrolidin-3-yl]carbamic acid tert-butyl ester (Compound 109a)

[1083] A mixture of 2-(6-chloro-3-pyridyl)ethyl methanesulfonate (compound 11c, 288 mg, 1.1 mmol), tert-butyl N-[(3S, 4S)-4-methoxypyrrolidin-3-yl]carbamate (216 mg, 1 mmol) and potassium carbonate (276 mg, 2 mmol) in MeCN (6 mL) was stirred at 80° C. for 16 hours. The mixture was then filtered, the filtrate was concentrated, and the residue was purified using a silica gel column to give compound 109a as a yellow oil (278 mg), LCMS (M). + :356,LCMS(M+2) + :358.

[1084] Step 2: Preparation of tert-butyl N-[(3S,4S)-1-[2-[6-[(4R,9aR)-2-(8-cyano-2-deutero-5-quinolyl)-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-8-yl]-3-pyridinyl]ethyl]-4-methoxy-pyrrolidin-3-yl]carbamate (Compound 109b)

[1085] A mixture of N-[(3S,4S)-1-[2-(6-chloro-3-pyridinyl)ethyl]-4-methoxy-pyrrolidin-3-yl]carbamic acid tert-butyl ester (compound 109a, 90 mg, 253 μmol), 5-[(4R,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile (Intermediate G, 60 mg, 195 μmol), cesium carbonate (190 mg, 584 μmol) and RuPhos Pd G2 (28 mg, 39 μmol) in dioxane (6 mL) was stirred at 110° C. overnight. The reaction was then concentrated and the residue was purified using a silica gel column to give compound 109b as a yellow oil (65 mg), LCMS (M+H) + :628.

[1086] Step 3: Preparation of 5-[(4R,9aR)-8-[5-[2-[(3S,4S)-3-amino-4-methoxy-pyrrolidin-1-yl]ethyl]-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile (Compound 109)

[1087] A mixture of N-[(3S,4S)-1-[2-[6-[(4R,9aR)-2-(8-cyano-2-deuterated-5-quinolyl)-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazine-8-yl]-3-pyridyl]ethyl]-4-methoxy-pyrrolidin-3-yl]carbamic acid tert-butyl ester (compound 109b, 65 mg, 104 μmol) in EA (5 mL) containing 1M HCl was stirred at rt for 16 hours. The reaction was then concentrated and the residue was lyophilized to give Example 109 as an orange solid (57 mg). LCMS (M+H) + :528. 1H NMR (400MHz, methanol-d4) δppm: 8.83 (d, J = 8.6 Hz, 1H), 8.28 (d, J = 7.9 Hz, 1H), 8.23-8.17 ( m,2H),7.78(d,J=8.6Hz,1H),7.57(d,J=9.3Hz,1H),7.49(d,J=7.9Hz,1H),4.62(br dd,J=11.3,12.3Hz,2H),4.32(td,J=2.7,5.2Hz,1H),4.26-4.03(m,4H),4.01-3.62(m ,10H),3.54-3.40(m,5H),3.36-3.34(m,1H),3.24-3.16(m,2H),1.59(d,J=6.4Hz,3H).

[1088] Example 110

[1089] 5-[(4S,9aR)-8-[5-[(6R)-6-amino-1,4-oxazepan-4-yl]-3-methyl-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile

[1090]

[1091] The title compound was prepared similarly to Example 108, but using tert-butyl N-[(6R)-1,4-oxazepan-6-yl]carbamate instead of tert-butyl 3,6-diazabicyclo[3.1.1]-heptane-6-carboxylate (Compound 108c). Example 110 (11 mg) was obtained as an orange solid. LCMS (M+H) + :514. 1 H NMR (400MHz, methanol-d4) δppm: 8.82(br d,J=7.8Hz,1H),8.23(d,J=7.9Hz,1H),7.77(s,2H),7.73(d,J=8.6Hz,1H),7.42(d,J=8.1Hz,1H),4.49-4.35(m,1H),4.15-4.04(m,3H),3.98(br dd,J=2.1,14.1Hz,2H),3.87(br d,J=3.3Hz,1H),3.85-3.81(m,2H),3.80-3.66(m,9H),3.62-3.54(m,3H),2.49(s,3H),1.83(br,3H).

[1092] Example 111

[1093] 5-[(4S,9aR)-8-[5-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-3-methyl-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile

[1094]

[1095] The title compound was prepared similarly to Example 108, but using (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester instead of 3,6-diazabicyclo[3.1.1]-heptane-6-carboxylic acid tert-butyl ester (Compound 108c). Example 111 (11 mg) was obtained as an orange solid. LCMS (M+H) + :496. 1 H NMR (400MHz, methanol-d4) δppm: 9.17-8.97(m,1H),8.32(d,J=7.8Hz,1H),7.88(br d,J=1.7Hz,1H),7.80(br s,1H),7.62(br s,1H),7.51(br d,J=7.9Hz,1H),4.86-4.81(m,2H),4.60(br,1H),4.57-4.45(m,1H),4.02(br d,J=3.2Hz,1H),3.92-3.83(m,2H),3.83-3.71(m,4H),3.67-3.49(m,4H),3.42(br,2H),3.29-3.24(m,1H),2.55(br,3H),2.32(br d,J=10.9Hz,1H), 2.14(br d,J=11.0Hz,1H), 1.83(br d,J=5.6Hz,3H).

[1096] Example 112

[1097] 5-[(4S,9aR)-8-[6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-3-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile

[1098]

[1099] The preparation of the title compound is similar to Example 32, but 5-bromo-2-fluoro-pyridine is used instead of 4-bromo-2-fluoropyridine (Compound 32a), 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester is used instead of piperazine-1-carboxylic acid tert-butyl ester, and 5-[(4S,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile (Intermediate K) is used instead of 5-[(4R,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Intermediate C). Example 112 was obtained as an orange solid (90 mg). LCMS (M+H) + :496, 1 HNMR (400MHz, methanol-d4) δppm: 8.79 (d, J = 8.6 Hz, 1H), 8.23 ​​(d, J = 7.9 Hz, 1H), 8.12 (dd, J = 2.9, 9.8 Hz, 1H),7.75(d,J=8.7Hz,1H),7.71(d,J=2.7Hz,1H),7.46-7.38(m,2H),4.40-4.26(m,5H),4.09(br d,J=12.6Hz,3H),3.76(br d,J=12.1Hz,3H),3.61(br,4H),3.46-3.36(m,1H),3.22-3.03(m,2H),2.25-2.17(m,2H),2.16-2.09(m,2H),1.80(br,3H).

[1100] Example 113

[1101] 4-[(4S,9aR)-4-methyl-8-[3-methyl-5-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)-2-pyridinyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-1-methyl-1,8-naphthyridin-2-one

[1102]

[1103] The preparation of the title compound was similar to Example 108, but 2-methyl-2,6-diazaspiro[3.3]heptane was used instead of tert-butyl 3,6-diazabicyclo[3.1.1]-heptane-6-carboxylate, and 4-[(4S,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]-1-methyl-1,8-naphthyridin-2-one (Intermediate M) was used instead of 5-[(4S,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile (Intermediate K). Example 113 (15 mg) was obtained as a white solid. LCMS (M+H) + :515. 1 H NMR (400MHz, methanol-d4) δppm: 8.63 (dd, J=1.8, 4.6Hz, 1H), 8.30 (dd, J=1.8, 8.0Hz, 1H), 7.35 (d, J=2.8Hz, 1H), 7. 32(dd,J=4.6,8.1Hz,1H),6.80(d,J=2.3Hz,1H),6.16(s,1H),3.97(s,4H),3.91(s,4H),3.76(s,3H),3.37(br d,J=11.1Hz,2H),3.29-3.21(m,2H),3.20-3.08(m,3H),3.05-2.94(m,2H),2.78(br d,J=9.0Hz,1H),2.75-2.66(m,2H),2.64(s,3H),2.29(s,3H),1.41(d,J=6.6Hz,3H).

[1104] Example 114

[1105] 5-[(4S,9aR)-8-[5-[(4aR,7aR)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl]-3-methyl-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile

[1106]

[1107] The title compound was prepared similarly to Example 108, but using (4aR,7aR)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-4-carboxylic acid tert-butyl ester instead of 3,6-diazabicyclo[3.1.1]-heptane-6-carboxylic acid tert-butyl ester. Example 114 (30 mg) was obtained as an orange solid. LCMS (M+H) + :526. 1 H NMR (400MHz, methanol-d4) δppm: 9.07-8.88 (m, 1H), 8.28 (d, J = 7.9Hz, 1H), 7.81 (br d,J=8.6Hz,1H),7.72(br,1H),7.61-7.53(m,1H),7.48(d,J=8.1Hz,1H),4.51(br t,J=10.1Hz,1H),4.33-4.18(m,2H),4.06(dt,J=2.7,12.7Hz,2H),3.87(td,J=8.0,19.7Hz,4H),3.77(br d,J=10.8Hz,3H),3.73-3.65(m,2H),3.65-3.59(m,2H),3.58-3.49(m,3H),3.49-3.41(m,1H),3.41-3.35(m,1H),3.25(br t,J=12.1Hz,1H),2.56(s,3H),1.86(d,J=6.7Hz,3H).

[1108] Example 115

[1109] 5-[(4S,9aR)-8-[6-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]-3-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile

[1110]

[1111] The preparation of the title compound was similar to Example 32, but 5-bromo-2-fluoro-pyridine was used instead of 4-bromo-2-fluoropyridine (Compound 32a), tert-butyl N-[(3R, 4R)-4-methoxypyrrolidin-3-yl]carbamate was used instead of tert-butyl piperazine-1-carboxylate, and 5-[(4S, 9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile (Intermediate K) was used instead of 5-[(4R, 9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Intermediate C). Example 115 was obtained as a light yellow foam (13 mg). LCMS (M+H) + :500, 1 H NMR (400MHz, methanol-d4) δppm: 8.72 (d, J = 8.6 Hz, 1H), 8.14 (d, J = 8.1 Hz, 1H), 7.76 (d, J = 2.7 Hz, 1H), 7.65 (d ,J=8.6Hz,1H),7.41(dd,J=2.9,9.2Hz,1H),7.26(d,J=8.1Hz,1H),6.51(d,J=9.2Hz,1H),3.79-3.72(m ,2H),3.61(dd,J=5.8,10.2Hz,1H),3.52(td,J=2.8,5.7Hz,1H),3.46-3.32(m,10H),3.29-3.27(m,1H ),3.24(dd,J=3.2,10.1Hz,1H),3.07-2.97(m,1H),2.92-2.81(m,2H),2.75(t,J=10.8Hz,1H),2.50(br t, J=10.8Hz, 1H), 1.44 (d, J=6.5Hz, 3H).

[1112] Example 117

[1113] 5-[(4S,9aR)-8-[6-[2-[(3R,4S)-3-amino-4-fluoro-pyrrolidin-1-yl]ethyl]-3-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile

[1114]

[1115] The title compound was prepared similarly to Example 109, except that tert-butyl N-[(3R,4S)-4-fluoropyrrolidin-3-yl]carbamate was used instead of tert-butyl N-[(3S,4S)-4-methoxypyrrolidin-3-yl]carbamate, 2-(5-bromo-2-pyridinyl)ethyl methanesulfonate (Compound 13b) was used instead of 2-(6-chloro-3-pyridinyl)ethyl methanesulfonate (Compound 11c), and 5-[(4S,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile (Intermediate K) was used instead of 5-[(4R,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile (Intermediate G). Example 117 was obtained as a yellow solid (48 mg). LCMS (M+H) + :516, 1 H NMR (400MHz, methanol-d4) δppm: 8.96 (br d,J=7.1Hz,1H),8.27(d,J=8.1Hz,1H),8.18(dd,J=2.1,9.4Hz,1H),8.10(d,J=1. 8Hz,1H),7.81(d,J=8.6Hz,1H),7.46(d,J=8.1Hz,1H),7.25(d,J=9.3Hz,1H),5.7 3-5.55(m,1H),4.61-4.49(m,1H),4.40-4.24(m,3H),4.21-4.09(m,2H),4.03-3. 72(m,9H),3.68-3.58(m,2H),3.48-3.35(m,2H),3.27-3.18(m,2H),1.67(br,3H).

[1116] Example 118

[1117] 5-[(4S,9aR)-8-[5-(3-amino-3-methyl-azetidin-1-yl)-3-methyl-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile

[1118]

[1119] The title compound was prepared similarly to Example 108, but using tert-butyl N-(3-methylazetidin-3-yl)carbamate instead of tert-butyl 3,6-diazabicyclo[3.1.1]-heptane-6-carboxylate. Example 118 (20 mg) was obtained as a light yellow foam. LCMS (M+H)+ :484. 1 H NMR (400MHz, methanol-d4) δppm: 8.71-8.62(m,1H),8.12(dd,J=1.2,7.9Hz,1H),7.67(d,J=2.8Hz,0.6H),7.61(dd,J=1.5, 8.6Hz,1H),7.39(d,J=2.7Hz,0.4H),7.30(dd,J=2.4,7.9Hz,1H),7.14(br,0.6H),6.83(br,0.4H),4.46(d,J=6.4Hz, 1H),4.23(br,1H),3.93-3.87(m,1H),3.84-3.77(m,3H),3.73-3.67(m,1H),3.65-3.46(m,4H),3.44-3.32(m,4H),2 .97(td,J=6.5,10.5Hz,1H),2.31(s,1.8H),2.25(s,1.2H),1.99-1.83(m,1.2H),1.72(br,3H),1.61-1.49(m,1.8H).

[1120] Example 121

[1121] 5-[(4S,9aR)-4-methyl-8-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile

[1122]

[1123] The preparation of Example 121 was the same as Example 2, but Intermediate K was used instead of Intermediate A, and 2-chloro-7,8-dihydro-5H-1,6-naphthyridine-6-carboxylic acid tert-butyl ester was used instead of 5-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (Compound 2a). Example 121 was obtained as a light brown solid (84 mg). LCMS (M+H) + :441, 1H NMR (400MHz, methanol-d4) δppm: 8.76 (d, J = 8.7 Hz, 1H), 8.21 (dd, J = 1.0, 8.1 Hz, 1H), 7. 72(d,J=8.7Hz,1H),7.48(d,J=8.6Hz,1H),7.39(dd,J=1.9,7.9Hz,1H),6.91(br d,J=8.8Hz,1H),4.49(br,2H),4.30(s,2H),4.02-3.81(m,2H),3.73-3.62(m,2H),3.59(t ,J=6.5Hz,2H),3.52-3.36(m,4H),3.27-3.12(m,2H),3.09(t,J=6.4Hz,2H),1.66(br,3H).

[1124] Example 122

[1125] 5-[(4S,9aR)-8-[5-[2-[(3S,4S)-3-amino-4-methoxy-pyrrolidin-1-yl]ethyl]-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile

[1126]

[1127] The preparation of Example 122 was the same as that of Example 2, except that Intermediate K was used instead of Intermediate A, and tert-butyl N-[(3S,4S)-1-[2-(6-chloro-3-pyridyl)ethyl]-4-methoxy-pyrrolidin-3-yl]carbamate (Compound 122a) was used instead of tert-butyl 5-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylate (Compound 2a). Example 122 was obtained as a light brown solid (64 mg). LCMS (M+H) + :528, 1H NMR (400MHz, methanol-d4) δppm: 8.76 (d, J = 8.6 Hz, 1H), 8.21 (d, J = 7.9 Hz, 1H), 8.08 (d, J = 2.2 Hz, 1H), 7.71 (d,J=8.6Hz,1H),7.63(dd,J=2.1,8.7Hz,1H),7.38(d,J=7.9Hz,1H),6.99(d,J=8.8Hz,1H),4.37(br t,J=11.4Hz,2H),4.01-3.96(m,1H),3.95-3.81(m,2H),3.74-3.70(m,1H),3.66(br t,J=12.0Hz,2H),3.44(br d,J=13.6Hz,2H),3.41(s,4H),3.39-3.34(m,2H),3.27-3.11(m,3H),3.00-2.87(m,4H),2.86-2.79(m,2H),1.64(br d,J=6.6Hz,3H).

[1128] Compound 122a was prepared according to the following scheme:

[1129]

[1130] Add 2-(6-chloropyridin-3-yl)ethyl methanesulfonate (288 mg, 1.1 mmol, Eq: 1.1), tert-butyl N-[(3S,4S)-4-methoxypyrrolidin-3-yl]carbamate (216 mg, 1 mmol), K 2 CO 3 (276 mg, 2 mmol) and acetonitrile (3 mL). The suspension was heated to 80 °C for 16 hours. The mixture was filtered; the filtrate was concentrated to give an oil. The oil was then purified on silica gel to give compound 122a (278 mg) as a yellow oil. LCMS (M+H) + :356.

[1131] Example 123

[1132] 5-[(4S,9aR)-8-[5-[[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]methyl]-6-methyl-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deuterated-quinoline-8-carbonitrile

[1133]

[1134] The preparation of Example 123 was the same as that of Example 2, except that Intermediate K was used instead of Intermediate A, and tert-butyl N-[(3R,4R)-1-[(6-chloro-2-methyl-3-pyridyl)methyl]-4-methoxy-pyrrolidin-3-yl]carbamate (Compound 123a) was used instead of tert-butyl 5-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylate (Compound 2a). Example 123 was obtained as a light brown solid (82 mg). LCMS (M+H) + :528, 1 H NMR (400MHz, methanol-d4) δppm: 8.64 (d, J = 8.7Hz, 1H), 8.08 (dd, J = 2.1, 7.9Hz, 1H), 7.65 (br d,J=8.8Hz,1H),7.62-7.56(m,1H),7.29(d,J=8.1Hz,1H),6.83(br d,J=8.7Hz,1H),4.63-4.40(m,2H),4.32(s,2H),4.12(br s,3H),3.90(br d,J=5.1Hz,1H),3.88-3.69(m,2H),3.69-3.53(m,4H),3.53-3.35(m,5H),3.33(s,3H),3.20-3.07(m,1H),2.45(s,3H),1.63(br d,J=5.3Hz,3H).

[1135] Compound 123a was prepared according to the following scheme:

[1136]

[1137] Add 6-chloro-3-(chloromethyl)-2-methylpyridine (88 mg, 500 μmol), tert-butyl N-[(3R,4R)-4-methoxypyrrolidin-3-yl]carbamate (108 mg, 500 μmol), K 2 CO 3 (138 mg, 1000 μmol) and acetonitrile (3 mL). The suspension was heated to 86°C for 2 hours. The mixture was filtered; the filtrate was concentrated to give an oil. The oil was then purified on silica gel to give compound 123a (170 mg) as a light yellow oil. LCMS (M+H) + :356

[1138] Example 124

[1139] 5-[(4R,9aS)-8-[2-[6-[(4aR,7aR)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl]-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[1140]

[1141] The preparation of the title compound was similar to Example 11, but using (4aR,7aR)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-4-carboxylic acid tert-butyl ester (CAS: 1932337-68-2, catalog number: PBXA8123, supplier: Pharmablock) instead of piperazine-1-carboxylic acid tert-butyl ester. Example 124 was obtained as a light yellow solid (60 mg). LCMS (M+H) + :539, 1 H NMR (400MHz, methanol-d4) δppm: 9.09 (dd, J=1.6, 4.5Hz, 1H), 8.90 (dd, J=1.5, 8.6Hz, 1H), 8.30 (d,J=7.9Hz,1H),8.15(dd,J=2.1,9.4Hz,1H),8.07(d,J=1.7Hz,1H),7.84(dd,J=4.5,8. 6Hz,1H),7.48(d,J=8.1Hz,1H),7.21(d,J=9.3Hz,1H),4.53-4.37(m,1H),4.37-4.20(m, 3H), 4.18-3.94 (m, 6H), 3.87-3.35 (m, 14H), 3.23 (t, J = 8.1Hz, 2H), 1.56 (d, J = 6.5Hz, 3H).

[1142] Example 125

[1143] 5-[(4S,9aS)-4-methyl-8-[4-[(2R)-morpholin-2-yl]phenyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile

[1144]

[1145] The title compound was prepared according to the following scheme:

[1146]

[1147] Step 1: Preparation of 5-[(4S,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Compound 125b)

[1148] A solution of (6S, 9aR) -6- methyl -1, 3, 4, 6, 7, 8, 9, 9a- octahydropyrazine [1, 2-a] pyrazine -2- carboxylic acid tert-butyl ester (compound K-3, 751 mg, 2.94 mmol), 5-fluoroquinoline -8- carbonitrile (compound 125a, 460 mg, 2.67 mmol) and DIPEA (1.7 g, 13.4 mmol) in DMSO (10 mL) was stirred overnight at 130 ° C, then the reactant was diluted with EtOAc (40 mL) and washed with water. The organic layer was dried and concentrated, and the residue was purified by flash column chromatography to obtain 1.1 g of an orange oil. The orange oil was dissolved in DCM / TFA (8 mL, 1: 1) and stirred at rt for 10 min, and then the reaction mixture was concentrated. The residue was dissolved in NaOH (2N), then extracted with DCM / iPrOH (2:1), the organic phase was dried and concentrated to give compound 125b (700 mg) as a yellow solid. LCMS (M+H) + :308.

[1149] Step 2: Preparation of 5-[(4S,9aS)-4-methyl-8-[4-[(2R)-morpholin-2-yl]phenyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (Example 125)

[1150] To a solution of 5-[(4S,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (compound 125b, 180 mg, 586 μmol) in dioxane (6 mL) were added tert-butyl (2R)-2-(4-bromophenyl)morpholine-4-carboxylate (CAS: 1312566-00-9, procedure see patent WO 2014041007A1 20140320, 240 mg, 703 μmol) and Cs 2 CO 3 (572 mg, 1.76 mmol). The suspension was washed with N 2Bubbling for 5 minutes, then RuPhos PdG2 (46 mg, 58.6 μmol) was added. After the reaction mixture was heated at 100 °C overnight, it was filtered and the filtrate was concentrated. The residue was dissolved in DCM / TFA (4 mL, 1:1), stirred at rt for 10 min, the reaction mixture was concentrated and the residue was purified by preparative HPLC to give Example 125 (38 mg) as a yellow foam. LCMS (M+H) + :469. 1 H NMR (400MHz, methanol-d4) δppm: 9.00-8.93(m,1H),8.71(dd,J=1.3,8.6Hz,1H),8.14(dd,J=1.4,8.0Hz,1H),7.69-7.61(m,1H),7.2 9-7.20(m,3H),6.97(d,J=8.6Hz,2H),4.38(dd,J=2.3,10.5Hz,1H),4.03-3.87(m,1H),3.73(dt,J=3.2,11.4Hz,1H),3.62(br t,J=12.5Hz,2H),3.44(brd,J=11.5Hz,1H),3.35(br s,2H),3.27(br s,2H),3.02-2.80(m,6H),2.79-2.65(m,2H),2.51(br t,J=10.7Hz,1H),1.43(d,J=6.2Hz,3H).

[1151] Example 126

[1152] To determine the activity of compounds of formula (I) and (Ia) in the HEK293-Blue-hTLR-7 / 8 / 9 cell assay, the following assay was performed.

[1153] HEK293-Blue-hTLR-7 Cell Assay:

[1154] The stable HEK293-Blue-hTLR-7 cell line was purchased from InvivoGen (Cat.#: hkb-htlr7, San Diego, California, USA). These cells were originally designed to study human TLR7 stimulation by monitoring NF-κB activation. The SEAP (secreted embryonic alkaline phosphatase) reporter gene was placed under the control of the IFN-β minimal promoter fused to five NF-κB and AP-1 binding sites. NF-κB and AP-1 were activated by stimulating HEK-Blue hTLR7 cells with TLR7 ligands to induce SEAP. Therefore, reporter gene expression was reduced by TLR7 antagonists after incubation for 20 hours under ligand stimulation such as R848 (Resiquimod). Using QUANTI-Blue TM The kit (Cat.#: rep-qb1, Invivogen, San Diego, Ca, USA) measures the activity of the SEAP reporter gene in the cell culture supernatant at a wavelength of 640 nm. The detection medium turns purple or blue under alkaline phosphatase.

[1155] HEK293-Blue-hTLR7 cells were cultured at a density of 250,000 to 450,000 cells / mL in a 96-well plate in 170 μL of 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, and 10% (v / v) heat-inactivated fetal bovine serum. 20 μL of the test compound and 10 μL of 20 uM R848 were added at a final dilution of 1% in the presence of DMSO in the above DMEM and incubated at 37°C in CO. 2 The cells were incubated in an incubator for 20 hours. 20 μL of supernatant from each well was then 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. The signaling pathway that TLR7 activation leads to downstream NF-κB activation is widely accepted, so a similar reporter gene assay was modified to evaluate TLR7 antagonists.

[1156] HEK293-Blue-hTLR-8 Cell Assay:

[1157] The stable HEK293-Blue-hTLR-8 cell line was purchased from InvivoGen (Cat.#: hkb-htlr8, San Diego, California, USA). These cells were originally designed to study human TLR8 stimulation by monitoring NF-κB activation. The SEAP (secreted embryonic alkaline phosphatase) reporter gene was placed under the control of the IFN-β minimal promoter fused to five NF-κB and AP-1 binding sites. NF-κB and AP-1 were activated by stimulating HEK-Blue hTLR8 cells with TLR8 ligands to induce SEAP. Therefore, reporter gene expression was reduced by TLR8 antagonists after incubation for 20 hours under ligand stimulation (such as R848). Using QUANTI-Blue TM The kit (Cat.#: rep-qb1, Invivogen, San Diego, Ca, USA) measures the activity of the SEAP reporter gene in the cell culture supernatant at a wavelength of 640 nm. The detection medium turns purple or blue under alkaline phosphatase.

[1158] HEK293-Blue-hTLR8 cells were cultured at a density of 250,000 to 450,000 cells / mL in a 96-well plate in 170 μL of 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, and 10% (v / v) heat-inactivated fetal bovine serum. 20 μL of the test compound and 10 μL of 60 uM R848 were added at a final dilution of 1% in the presence of DMSO in the above DMEM and incubated at 37°C in CO. 2 The cells were incubated in an incubator for 20 hours. 20 μL of supernatant from each well was then 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. The signaling pathway that TLR8 activation leads to downstream NF-κB activation is widely accepted, so a similar reporter gene assay was modified to evaluate TLR8 antagonists.

[1159] HEK293-Blue-hTLR-9 Cell Assay:

[1160] The stable HEK293-Blue-hTLR-9 cell line was purchased from InvivoGen (Cat.#:hkb-htlr9, San Diego, California, USA). These cells were originally designed to study human TLR9 stimulation by monitoring NF-κB activation. The SEAP (secreted embryonic alkaline phosphatase) reporter gene was placed under the control of the IFN-β minimal promoter fused to five NF-κB and AP-1 binding sites. NF-κB and AP-1 were activated by stimulating HEK-Blue hTLR9 cells with TLR9 ligands to induce SEAP. Therefore, reporter gene expression was reduced by TLR9 antagonists by incubation for 20 hours under stimulation with ligands such as ODN2006 (Cat.#:tlrl-2006-1, Invivogen, San Diego, California, USA). Using QUANTI-Blue TM The kit (Cat.#: rep-qb1, Invivogen, San Diego, California, USA) measures the activity of SEAP reporter gene in cell culture supernatant at a wavelength of 640 nm. The detection medium turns purple or blue under alkaline phosphatase.

[1161] HEK293-Blue-hTLR9 cells were cultured at a density of 250,000 to 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, to which 20 μL of the test compound and 10 μL of 20 μM ODN2006 were added in serial dilutions in the presence of 1% final DMSO at 37°C in CO. 2 Incubate in the incubator for 20 hours. 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. The signaling pathway that TLR9 activation leads to downstream NF-κB activation is widely accepted, so a similar reporter gene assay was modified to evaluate TLR9 antagonists.

[1162] The compounds of formula (I) or formula (Ia) have human TLR7 and / or TLR8 inhibitory activity (IC 50Value) <0.5 μM. In addition, the compounds of the present invention also have human TLR9 inhibitory activity <0.5 μM. Table 2 shows the activity data of the compounds of the present invention.

[1163] Table 2. Activity of compounds of the invention in HEK293-Blue-hTLR-7 / 8 / 9 cell assay

[1164]

[1165]

[1166]

[1167]

[1168] Example 127

[1169] hERG channel inhibition assay:

[1170] The hERG channel inhibition assay is a highly sensitive measurement that identifies compounds that exhibit hERG inhibition associated with in vivo cardiotoxicity. + The channel was cloned into human and stably expressed in CHO (Chinese Hamster Ovary) cell line. hERG Cells were used for patch clamp (voltage clamp, whole cell) experiments. Voltage mode stimulation of cells activated hERG channels and conducted I KhERG Current (fast delayed outward rectifier potassium current of hERG channels). After the cells were stable for several minutes, I was recorded at a stimulation frequency of 0.1 Hz (6 bpm). KhERG The amplitude and kinetics of the oscillations were then measured. Thereafter, the test compound was added to the formulation at increasing concentrations. For each concentration, an attempt was made to reach a steady-state effect, which was usually achieved within 3-10 minutes, at which time the next highest concentration was applied. The I KhERGThe amplitude and kinetics of QT were compared with the control value (considered as 100%) (References: 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).

[1171] The results of hERG are given in Table 3. Safety ratio (hERG IC 20 / EC 50 )>30 represents an adequate safety window to distinguish pharmacology from potential hERG-related cardiotoxicity by inhibiting TLR7 / 8 / 9 pathways. 20 / TLR7 / 8 / 9IC 50 The calculation of can be used as an early selectivity index to assess hERG tendency.

[1172] Table 3. hERG and safety ratio results

[1173]

[1174]

[1175] Example 128

[1176] 3T3 in vitro phototoxicity assay

[1177] Phototoxicity is defined as the toxic response induced after the first exposure of the skin to certain chemicals and subsequent exposure to light, or similarly the toxic response induced by skin irradiation after systemic administration of chemicals. The assay used in this study is designed to detect the phototoxic potential of chemicals by a simple in vitro cytotoxicity assay using Balb / c 3T3 mouse fibroblasts. The principle of this test is to compare the cytotoxicity of chemicals when tested with or without exposure to non-toxic doses of UVA-light. Cytotoxicity is expressed as a dose-dependent decrease in the cell growth rate, which is determined by the absorption of the vital dye neutral red one day after treatment.

[1178] 1. Methods

[1179] Preparation of stock solutions and doses of test articles

[1180] Just before starting exposure to cells, weigh a small amount of material and prepare freshly in DMSO. Add this stock solution or an appropriate DMSO dilution to the cell suspension to obtain the desired final concentration. All solutions are typically prepared in Eppendorf bottle caps and discarded after use.

[1181] Reference material

[1182] Chlorpromazine (HCL) (Sigma, batch / lot number: 120M1328V), test concentration: 300 μg / mL, solvent: PBS / 3% DMSO

[1183] Measurement of UV absorption spectrum

[1184] Absorption spectra were recorded either as such or after pre-irradiation with UV-A or UV-B between 240 nm and 400 nm using a Lambda-2 spectrophotometer (Perkin Elmer).

[1185]

[1186] Determination of phototoxicity

[1187] For this study, the improved neutral red absorption (NRU) analysis of Borenfreund and Puerner (Borenfreund, E, Puerner JA. Toxicity determined in vitro by morphological alterations and Neutral Red absorption. Toxicology Lett. 1985; 24: 119-124.) was adjusted according to the 78th INVITTOX scheme (ERGATT / FRAME data bank of in vitro techniques intoxicology. INVITTOX PROTOCOL No 78.3T3 NRU Phototoxicity Assay. March 1994) to examine the possible phototoxic potential of the test article. The assay is based on the active absorption of neutral red dye into the lysosomes of cultured mouse fibroblasts. Because the lysosomal membrane is known to be the site of action of many phototoxic compounds, the assay can provide a measure of potential phototoxic damage.

[1188] Preparation of cell culture

[1189] At 37 °C in 6% CO 2 Murine fibroblast clone A31 (ATCC No. CCL 163, passage 108) was cultured in a humidified atmosphere at 175 cm 3 with sDMEM (Dulbecco's minimal essential medium supplemented with 10% calf serum, 2 mM L-glutamine, 100 units / mL penicillin, and 100 μg / mL streptomycin). 2 Before the cells approached confluence, they were removed from the flask by trypsinization. Prior to use in the assay, the cells were plated at 1 × 10 4 Cells were transferred to a 96-well microtiter plate at a concentration of 10 cells / well and allowed to attach for 24 hours.

[1190] Exposure to test article

[1191] For incubation with murine fibroblasts, test articles were diluted in PBS / 3% DMSO (see Results for detailed concentrations).

[1192] The culture medium (Dulbecco's Modified Eagle's Medium (DMEM), GlutaMAX (Gibco Ref 21885-025), 10% fetal bovine serum (FBS) (Gibco Ref 10270-106), 100 IU / mL penicillin and 100 μg / ml streptomycin (Gibco Ref 15140-122)) was removed from the wells and the mouse fibroblasts were washed with PBS. Then 100 μL of PBS / 3% DMSO containing the test article was added and the target cells were incubated at 37°C with 6% CO 2 Incubate for 1 hr.

[1193] UV exposure

[1194] For each test article, a microtiter plate was prepared according to Table 4. The "UVA plate" was exposed to approximately 5 J / cm 2 The “dark plate” was placed in the dark under UVA light as a cytotoxicity control. The plate containing chlorpromazine hydrochloride served as a positive control. UV flux was measured using a UV meter (Dr. RM21) measurement.

[1195] After UV irradiation, the test articles were removed from the wells (one washing step with PBS) and replaced with sDMEM. The target cells were then incubated at 37°C in 6% CO 2 Incubate overnight.

[1196] Table 4. 96-well microtiter plate setup

[1197]

[1198] A 96-well microtiter plate was prepared as follows:

[1199] Each plate contained wells with cells and solvent but no test article, which were not incubated with neutral red solution (0% standard - S1), or stained with neutral red (100% standard - S2) to calculate a standard cell viability curve. Wells labeled U01-U08 contained different test article concentrations.

[1200] Neutral red absorption

[1201] Make a fresh preparation of the Neutral Red (NR) staining solution as follows:

[1202] • The 0.4% stock aqueous solution was protected from light and filtered to remove NR crystals before use.

[1203] A 1:40 dilution of the stock solution was then prepared in sDMEM and added to the cells.

[1204] After incubation, the wells to be tested were filled with 100 μL of sDMEM containing neutral red. The target cells were incubated with NR at 37°C in 6% CO. 2 Incubate for 3 hours.

[1205] Neutral red absorption measurement

[1206] Unincorporated neutral red was removed from the target cells and the wells were washed with at least 100 μL PBS. 150 μL neutral red desorption solution (1% glacial acetic acid, 50% ethanol in water) was then added to quantitatively extract the incorporated dye. After vigorous shaking on a microtiter plate oscillator for at least 10 minutes, until neutral red was extracted from the cells and a homogeneous solution was formed, the absorption of the resulting colored solution was measured at 540 nm using a SPECTRAmax PLUS microtiter plate reader (Molecular Devices).

[1207] Calculation of cell viability

[1208] Cell viability was calculated using the SOFTmax Pro software package (Molecular Devices). A two-point standard curve (0% and 100% viability) was first calculated using the linear curve fitting option of the program according to the following formula:

[1209] Y=A+(B×X)

[1210] (A = y-intercept of the line; B = slope of the line;

[1211] 0% cell viability = cells with solvent but no test article and neutral red;

[1212] 100% cell viability = cells with solvent and neutral red but no test article)

[1213] In this way, the viability of cells incubated with increasing concentrations of the test chemicals was calculated.Chlorpromazine (HCl) served as a positive control for the experiment.

[1214] IC 50 Calculation of values

[1215] All calculations were performed using the SOFTmax Pro analysis software package (Molecular Devices - For details see:

[1216] http: / / www.mbl.edu / jbpc / files / 2014 / 05 / SoftMax_Pro_User_Guide.pdf)

[1217] Calculation of phototoxicity discrimination factor

[1218] To assess the phototoxic potential, compare the IC determined with and without UV exposure.50 value.

[1219] Factor = IC 50 (-UV) / IC 50 (+UV)

[1220] To distinguish between phototoxic and non-phototoxic test chemicals, a cutoff factor of >5 was used (Liebsch M, Spielmann H, Balls M, Brand M, B,Dupuis J,Holzhüter HG,Klecak G,L.Eplattenier H,Lovell W,Maurer T,Moldenhauer F,Moore L,Pape W,PfannenbeckerU,Potthast JM,De Silva O,Steiling W,Willshaw A.First results of the EC / COLIPAValidation Project.In Vitro Phototoxicity Testing.In:In Vitro SkinToxicology: Irritation, Phototoxicity, Sensitization; Vol. 10. Alternative Methods in Toxicology, -Eds. Rougier A, Maibach HI, Goldberg AM; Mary Ann Liebert Publ.: New York, USA 1994, pp. 243-251).

[1221] Test articles that were not cytotoxic to mouse fibroblasts even at the highest tested concentration, but showed a strong dose-dependent decrease in cell viability after UV exposure, were also considered phototoxic (Spielmann H, Balls M, Dupuis J, Pape WJW, Pechovitch G, Silva DeO, Holzhütter, HG, Clothier R, Desolle P, Gerberick F, Liebsch M, Lowell WW, Maurer T, Pfannenbecker U, Potthast JM, Csato M, Sladowski D, Steiling W, Brantom P. The international EU / COLIPA in vitro phototoxicity validation study: Results of phase II (blind trial). Part 1: The 3T3 NRU phototoxicity test. Toxicology in Vitro 1998, 12: 305-327).

[1222] The test results are shown below, and the compounds of the present invention show very good phototoxicity.

[1223] Table 5. 3T3 test results of the compounds of the present invention

[1224] Instance Number Phototoxicity factors <![CDATA[IC 50 (UV-A)(μg / mL) <!-- 130 -->]]> 5 >1.39 23.3 9 >3.9 26.3 12 >2.53 - 68 1.53 65.9 77 >1.9 52.5 106 >1.67 60.25

[1225] Example 129

[1226] Agonist-induced lupus nephritis model in mice

[1227] To evaluate the efficacy of compounds against lupus nephritis in vivo, a TLR7 agonist-induced lupus-like disease mouse model was utilized, in which TLR7 activation leads to the development of systemic autoimmune symptoms accompanied by increased levels of double-stranded DNA autoantibodies (anti-dsDNA), inflammatory cytokines such as IP10, and multi-organ involvement (especially the kidneys and spleen).

[1228] BALB / c mice were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd. All mice were female mice aged 7 to 8 weeks. To induce disease, the right ear of the animals was topically treated with 100 μg of Resiquimod (R848) dissolved in 20 μL of acetone 3 times a week. In compound or vehicle treatment, oral administration was performed once a day; if the treatment and R848 transdermal treatment were on the same day, administration was performed 30 minutes before R848 transdermal treatment.

[1229] Blood samples were collected once a week to determine the levels of autoantibodies and multiple cytokines against double-stranded DNA in serum. Total anti-dsDNA immunoglobulins in serum were measured using commercially available ELISA assays (catalog number 5110, Alpha Diagnostic Inti Inc.) according to the manufacturer's instructions. Cytokine levels in serum were measured using the ProcartaPlex Immunoassay Kit (catalog number PPX-08-MXNKR2Z, Thermo Fisher). Specifically, 10 μL of premixed magnetic capture beads were added to the DropArray DA-bead plate (catalog number 969-CC-BD-05, Curiox). After washing, 10 μL of diluted serum (1:5) was incubated overnight at 4 ° C on the DA-bead plate. After washing three times, 5 μL of premixed detection antibodies were added to the plate and incubated at room temperature for 60 minutes. After washing, 10 μL of streptavidin-PE was added and incubated at room temperature for 30 minutes. The microbeads were then resuspended in 55 μL of reading buffer. The samples were analyzed using Luminex 200 (Millipore).

[1230] Urine samples were collected once a week, the animals were housed in metabolic cages for 24 h, and urine albumin (UALB), urine creatinine (UCR), and urine total protein (UTP) were measured using a Roche Cobas6000 chemistry analyzer (Roche Diagnostics, Mannheim, Germany).

[1231] To evaluate renal histopathology, kidney samples were fixed with neutral buffered formalin and embedded in paraffin. Sections were stained with hematoxylin and eosin, and periodic acid-Schiff stain was performed. Pathologists then examined samples in a blinded manner, and used the total glomerulonephritis score, the sum of glomerular scores, inflammation scores, PAS scores, and tubular protein scores to perform semiquantitative grading of glomerular lesions.

[1232] Specifically, the glomerular score of 0 to 6 is based on the evaluation of the outer half of the cortex of the glomerulus and the most common grade in this area. Grade 1: trace increase in cellularity and / or mesangial expansion; Grade 2: mild increase in cellularity and mesangial expansion; Grade 3: moderate increase in cellularity in most affected glomeruli, and some areas of marked mesangial expansion and / or capillary proliferation; Grade 4: marked increase in cellularity in most affected glomeruli, and some areas of marked mesangial expansion and / or capillary proliferation; rare sclerotic glomeruli; parietal cell hypertrophy may occur; Grade 5: above the above degree, <25% of glomeruli are sclerotic and / or capillary hypertrophy in most affected glomeruli; Grade 6: >25% of glomeruli are sclerotic, characterized in part by a decrease in the number of tufted cells + / - periglomerular fibrosis + / - parietal cell hypertrophy.

[1233] The inflammation score of 0 to 3 is based on both the number and size of inflamed areas.

[1234] The PAS score of 0 to 3 is based on increased staining of the glomerular mesangial matrix in the outer half of the cortex. Grade 1: minimal increase in mesangial staining in scattered glomeruli; Grade 2: more extensive mesangial expansion (and PAS staining) affecting more glomeruli; Grade 3: marked mesangial expansion in most glomeruli.

[1235] The tubular protein score of 0 to 3 is based on the percentage of tubules containing protein fluid. Grade 1: <25% of tubules affected; Grade 2: 25% to 50% of tubules affected; Grade 3: >50% of tubules affected. At the end of the study, the spleen was harvested and weighed to assess splenomegaly.

[1236] The main findings of Example 106 in the R848 agonist-induced mouse lupus nephritis model are as follows:

[1237] a. 10 mg / kg of Example 106 inhibited the production of interferon gamma-induced protein 10 (IP-10) in serum after 1 week of treatment (see Figure 3A );

[1238] b. 10 mg / kg of Example 106 significantly reduced the level of anti-dsDNA autoantibodies in serum after 2 weeks of treatment (see Figure 3B );

[1239] c. Example 106 at 10 mg / kg showed benefit in preventing renal injury, with clear evidence that there was no increase in R848-induced proteinuria after 5 weeks of treatment (see Figure 3C );

[1240] d. Example 106 at 10 mg / kg inhibited the over-activation of immune cells in the spleen, thus preventing spleen enlargement in this model with normal spleen weight compared to healthy animals after 6 weeks of treatment (see Figure 3D ).

[1241] In summary, the above test results demonstrate that Example 106 and potential compounds of the present invention have good therapeutic potential in treating systemic lupus erythematosus (SLE) and lupus nephritis (LN).

Claims

1. A compound of formula (I), in R 1 for Where R 4 is cyano; R 4a C 1-6 Alkyl; R 5 is H or deuterium; R 6 is H; R 2 H or C 1-6 alkyl; R 3 is H; Ring A is 1,2,3,4-tetrahydroisoquinolinyl; 5,6,7,8-Tetrahydro-1,6-naphthyridinyl; 5,6,7,8-Tetrahydro-2,6-naphthyridinyl; 5,6,7,8-Tetrahydro-2,7-naphthyridinyl; Isoindolyl; Amino (C 1-6 phenyl substituted with 5-oxa-2,8-diazaspiro[3.5]nonyl, morpholinyl or piperazinyl; Pyridinyl substituted once or twice with substituents independently selected from: (halopyrrolidinyl)amino; 1,4-diazacycloheptyl; 2,5-diazabicyclo[2.2.1]heptyl; 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl; 3,6-diazabicyclo[3.1.1]heptyl; 3,8-diazabicyclo[3.2.1]octanyl; 5-oxa-2,8-diazaspiro[3.5]nonanyl; 9-oxa-3,7-diazabicyclo[3.3.1]nonanyl; amino(C 1-6 Alkoxy) pyrrolidinyl; amino (C 1-6 alkyl)azetidinyl; amino (C 1-6 alkyl) pyrrolidinyl; amino-1,4-oxazepanyl; amino-2-azaspiro[3.3]heptyl; aminoazetidinyl; aminohalogenated pyrrolidinyl; C 1-6 Alkyl; C 1-6 Alkyl-2,6-diazaspiro[3.3]heptanecarbonyl; C 1-6 Alkyl-2,6-diazaspiro[3.3]heptyl; C 1-6 Alkylpiperazinyl and piperazinyl; or Pyrimidinyl substituted once or twice by substituents independently selected from: amino (C 1-6 Alkoxy) pyrrolidinyl, amino (C 1-6 alkyl)azetidinyl, aminoazetidinyl, C 1-6 Alkyl and piperazinyl; n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

2. A compound of formula (Ib), in R 1 for Where R 4 is cyano; R 4a C 1-6 Alkyl; R 5 is H or deuterium; R 6 is H; R 2 H or C 1-6 alkyl; R 3 is H; Ring A is 1,2,3,4-tetrahydroisoquinolinyl; 5,6,7,8-Tetrahydro-1,6-naphthyridinyl; 5,6,7,8-Tetrahydro-2,6-naphthyridinyl; 5,6,7,8-Tetrahydro-2,7-naphthyridinyl; Isoindolyl; Amino (C 1-6 phenyl substituted with 5-oxa-2,8-diazaspiro[3.5]nonyl, morpholinyl or piperazinyl; Pyridinyl substituted once or twice with substituents independently selected from: (halopyrrolidinyl)amino; 1,4-diazacycloheptyl; 2,5-diazabicyclo[2.2.1]heptyl; 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl; 3,6-diazabicyclo[3.1.1]heptyl; 3,8-diazabicyclo[3.2.1]octanyl; 5-oxa-2,8-diazaspiro[3.5]nonanyl; 9-oxa-3,7-diazabicyclo[3.3.1]nonanyl; amino(C 1-6 Alkoxy) pyrrolidinyl; amino (C 1-6 alkyl)azetidinyl; amino (C 1-6 alkyl) pyrrolidinyl; amino-1,4-oxazepanyl; amino-2-azaspiro[3.3]heptyl; aminoazetidinyl; aminohalogenated pyrrolidinyl; C 1-6 Alkyl; C 1-6 Alkyl-2,6-diazaspiro[3.3]heptanecarbonyl; C 1-6 Alkyl-2,6-diazaspiro[3.3]heptyl; C 1-6 Alkylpiperazinyl and piperazinyl; or Pyrimidinyl substituted once or twice by substituents independently selected from: amino (C 1-6 Alkoxy) pyrrolidinyl, amino (C 1-6 alkyl)azetidinyl, aminoazetidinyl, C 1-6 Alkyl and piperazinyl; n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 or 2, wherein R 2 C 1-6 alkyl.

4. The compound according to claim 3, wherein R 1 for Where R 4 is cyano; R 4a C 1-6 Alkyl; R 5 is H or deuterium; R 6 is H; R 2 is methyl; R 3 is H; Ring A is 1,2,3,4-tetrahydroisoquinolin-5-yl; 1,2,3,4-tetrahydroisoquinolin-6-yl; 1,2,3,4-tetrahydroisoquinolin-7-yl; 1,2,3,4-tetrahydroisoquinolin-8-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-2,6-naphthyridin-1-yl; 5,6,7,8-tetrahydro-2,7-naphthyridin-4-yl; isoindolin-4-yl; 3-amino-4-methoxy-pyrrolidin-1-ylphenyl; 5-oxa-2,8-diazaspiro[3.5]nonan-2-ylphenyl; morpholin-2-ylphenyl; piperazin-1-ylphenyl; (4- 1,4-diazacycloheptane-1-ylpyridinyl; 2,5-diazabicyclo[2.2.1]heptane-2-yl(methyl)pyridinyl; 2,5-diazabicyclo[2.2.1]heptane-2-ylpyridinyl; 2-methylpiperazin-1-yl(methyl)pyridinyl; 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl(methyl)pyridinyl; (3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl)pyridinyl; 3,6-diazabicyclo[3.1.1]heptane-3-yl(methyl)pyridinyl; 3,8-diazabicyclo[3.1.1]heptane-3-yl(methyl)pyridinyl; Azabicyclo[3.2.1]octan-3-yl(methyl)pyridinyl; 3,8-diazabicyclo[3.2.1]octan-3-ylpyridinyl; 3-amino-3-methyl-azetidin-1-yl(methyl)pyridinyl; 3-amino-3-methyl-azetidin-1-ylpyridinyl; 3-amino-3-methyl-pyrrolidin-1-yl(methyl)pyridinyl; 3-amino-3-methyl-pyrrolidin-1-ylpyridinyl; 3-amino-4-fluoro-pyrrolidin-1-ylpyridinyl; 3-amino-4-methoxy-pyrrolidin-1-yl(methyl)pyridinyl; 3-amino-4-methoxy-pyrrolidin-1-ylpyridinyl; 3-aminoazetidin-1-ylpyridinyl; 3-methylpiperazine-1- pyridinyl; 3-methylpiperazin-1-ylpyridinyl; 5-oxa-2,8-diazaspiro[3.5]nonan-2-ylpyridinyl; 6-amino-1,4-oxazacycloheptane-4-yl(methyl)pyridinyl; 6-amino-1,4-oxazacycloheptane-4-ylpyridinyl; 6-amino-2-azaspiro[3.3]heptane-2-yl(methyl)pyridinyl; 6-methyl-2,6-diazaspiro[3.3]heptane-2-yl(methyl)pyridinyl; 6-methyl-2,6-diazaspiro[3.3]heptane-2-ylpyridinyl; 6-methyl-2,6-diazaspiro[3.3]heptane-2-carbonyl(methyl)pyridinyl; 9-oxa-3,7-diazabicyclo[3.3.1] Nonan-3-yl (methyl) pyridinyl; piperazin-1-yl (methyl) pyridinyl; piperazin-1-yl pyridinyl; 3-amino-3-methyl-azetidin-1-yl (methyl) pyrimidinyl; 3-amino-4-methoxy-pyrrolidin-1-yl (methyl) pyrimidinyl; 3-amino-4-methoxy-pyrrolidin-1-yl pyrimidinyl; 3-aminoazetidin-1-yl pyrimidinyl; piperazin-1-yl (methyl) pyrimidinyl or piperazin-1-yl pyrimidinyl;. n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 3, wherein R 1 for Where R 4 is cyano; R 5 is H or deuterium.

6. The compound according to claim 5, wherein Ring A is 1,2,3,4-tetrahydroisoquinolinyl; Phenyl substituted with morpholinyl; Pyridinyl substituted once or twice by substituents independently selected from: 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl; amino(C 1-6 Alkoxy) pyrrolidinyl; amino (C 1-6 alkyl)azetidinyl; aminohalogenated pyrrolidinyl; C 1-6 Alkyl; C 1-6 Alkyl-2,6-diazaspiro[3.3]heptyl and piperazinyl; Pyrimidinyl substituted twice by substituents, the substituents being independently selected from: amino (C 1-6 Alkoxy) pyrrolidinyl; amino (C 1-6 alkyl)azetidinyl and C 1-6 alkyl.

7. The compound according to claim 6, wherein ring A is 1,2,3,4-tetrahydroisoquinolyl; morpholinylphenyl; piperazinylpyridinyl; (amino(C 1-6 (aminohalogenated pyrrolidinyl)pyridinyl; piperazinyl (C 1-6 alkyl)pyridinyl; (C 1-6 alkyl-2,6-diazaspiro[3.3]heptyl)pyridinyl; (amino(C 1-6 alkyl)azetidinyl)pyridinyl; C 1-6 Alkyl (amino (C 1-6 alkyl)azetidinyl)pyridinyl; 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl (C 1-6 (3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl)pyridinyl; C 1-6 Alkyl (amino (C 1-6 alkyl)azetidinyl)pyrimidinyl or C 1-6 Alkyl (amino (C 1-6 alkoxy)pyrrolidinyl)pyrimidinyl.

8. The compound according to claim 7, wherein Ring A is 1,2,3,4-tetrahydroisoquinolin-7-yl; morpholin-2-ylphenyl; (3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl)-2-methyl-3-pyridinyl; (3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl)-3-pyridinyl; (3-amino-4-fluoro-pyrrolidin-1-yl)-3-pyridinyl; (3-amino-4-fluoro-pyrrolidin-1-yl)-3-pyridinyl; (3-amino-4-methoxy-pyrrolidin-1-yl)-3-pyridinyl ; (3-amino-4-methoxy-pyrrolidin-1-yl)-3-pyridinyl; 2-methyl-6-piperazin-1-yl-3-pyridinyl; 6-(3-amino-3-methyl-azetidin-1-yl)-2-methyl-3-pyridinyl; 6-(3-amino-3-methyl-azetidin-1-yl)-3-pyridinyl; 6-(6-methyl-2,6-diazaspiro[3.3]heptane-2-yl)-3-pyridinyl; 6-piperazin-1-yl-3-pyridinyl; (3-amino-4-methoxy-pyrrolidin-1-yl)-6-methyl-pyrimidin-4-yl or (3-amino-3-methyl-azetidin-1-yl)-6-methyl-pyrimidin-4-yl.

9. The compound according to claim 1 or 2, wherein R 1 for Where R 4 is cyano; R 5 is H or deuterium; R 2 C 1-6 alkyl; R 3 is H; Ring A is 1,2,3,4-tetrahydroisoquinolinyl; Phenyl substituted with morpholinyl; Pyridinyl substituted once or twice by substituents independently selected from: 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl; amino(C 1-6 Alkoxy) pyrrolidinyl; amino (C 1-6 alkyl)azetidinyl; aminohalogenated pyrrolidinyl; C 1-6 Alkyl; C 1-6 Alkyl-2,6-diazaspiro[3.3]heptyl and piperazinyl; Pyrimidinyl substituted twice by substituents, the substituents being independently selected from: amino (C 1-6 Alkoxy) pyrrolidinyl; amino (C 1-6 alkyl)azetidinyl and C 1-6 alkyl; n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 9, wherein R 1 for Where R 4 is cyano; R 5 is H or deuterium; R 2 C 1-6 alkyl; R 3 is H; Ring A is 1,2,3,4-tetrahydroisoquinolyl; morpholinylphenyl; piperazinylpyridinyl; (amino(C 1-6 (aminohalogenated pyrrolidinyl)pyridinyl; piperazinyl (C 1-6 alkyl)pyridinyl; (C 1-6 alkyl-2,6-diazaspiro[3.3]heptyl)pyridinyl; (amino(C 1-6 alkyl)azetidinyl)pyridinyl; C 1-6 Alkyl (amino (C 1-6 alkyl)azetidinyl)pyridinyl; 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl (C 1-6 (3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl)pyridinyl; C 1-6 Alkyl (amino (C 1-6 alkyl)azetidinyl)pyrimidinyl or C 1-6 Alkyl (amino (C 1-6 alkoxy)pyrrolidinyl)pyrimidinyl; n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 10, wherein R 1 for Where R 4 is cyano; R 5 is H or deuterium; R 2 is methyl; R 3 is H; Ring A is 1,2,3,4-tetrahydroisoquinolin-7-yl; 4-(morpholin-2-yl)phenyl; (3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl)-2-methyl-3-pyridinyl; (3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl)-3-pyridinyl; (3-amino-4-fluoro-pyrrolidin-1-yl)-3-pyridinyl; (3-amino-4-fluoro-pyrrolidin-1-yl)-3-pyridinyl; (3-amino-4-methoxy-pyrrolidin-1-yl)-3-pyridinyl; (3-amino- 4-methoxy-pyrrolidin-1-yl)-3-pyridinyl; 2-methyl-6-piperazin-1-yl-3-pyridinyl; 6-(3-amino-3-methyl-azetidin-1-yl)-2-methyl-3-pyridinyl; 6-(3-amino-3-methyl-azetidin-1-yl)-3-pyridinyl; 6-(6-methyl-2,6-diazaspiro[3.3]heptane-2-yl)-3-pyridinyl; 6-piperazin-1-yl-3-pyridinyl; (3-amino-4-methoxy-pyrrolidin-1-yl)-6-methyl-pyrimidin-4-yl or (3-amino-3-methyl-azetidin-1-yl)-6-methyl-pyrimidin-4-yl; n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

12. A compound selected from: 5-[cis-4-methyl-8-(1,2,3,4-tetrahydroisoquinolin-7-ylmethyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[cis-4-methyl-8-(1,2,3,4-tetrahydroisoquinolin-5-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[cis-4-methyl-8-[(2-piperazin-1-yl-4-pyridinyl)methyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[cis-8-isoindolin-4-yl-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aS)-4-methyl-8-(1,2,3,4-tetrahydroisoquinolin-7-ylmethyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aS)-4-methyl-8-(5,6,7,8-tetrahydro-1,6-naphthyridin-3-ylmethyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aS)-4-methyl-8-[2-(4-piperazin-1-ylphenyl)ethyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aS)-4-methyl-8-[(6-piperazin-1-yl-3-pyridinyl)methyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aS)-8-isoindolin-4-yl-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aS)-4-methyl-8-(1,2,3,4-tetrahydroisoquinolin-6-ylmethyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aS)-4-methyl-8-[2-(6-piperazin-1-yl-3-pyridinyl)ethyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aS)-8-[2-[6-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aS)-8-[2-[5-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]-2-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aS)-8-[[6-(1,4-diazepan-1-yl)-3-pyridinyl]methyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aR)-4-methyl-8-(5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aS)-8-[2-[6-[(3R,4S)-3-amino-4-fluoro-pyrrolidin-1-yl]-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aS)-8-[2-[6-[(3R,4R)-3-amino-4-fluoro-pyrrolidin-1-yl]-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aS)-8-[2-[5-[(3R,4S)-3-amino-4-fluoro-pyrrolidin-1-yl]-2-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aS)-4-methyl-8-[2-[5-[(3S)-3-methylpiperazin-1-yl]-2-pyridinyl]ethyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aS)-4-methyl-8-[2-[6-[(3S)-3-methylpiperazin-1-yl]-2-pyridinyl]ethyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aS)-4-methyl-8-[2-[6-(6-methyl-2,6-diazaspiro[3.3]heptane-2-yl)-3-pyridinyl]ethyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aS)-8-[2-[6-[(3R,4S)-3-amino-4-methoxy-pyrrolidin-1-yl]-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aS)-8-[2-[6-[(3S,4S)-3-amino-4-methoxy-pyrrolidin-1-yl]-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aS)-8-[2-[4-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]phenyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aS)-4-methyl-8-[(6-piperazin-1-yl-2-pyridinyl)methyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aS)-4-methyl-8-[2-[4-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)phenyl]ethyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aR)-4-methyl-8-(4-piperazin-1-ylpyrimidin-2-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aR)-4-methyl-8-(6-methyl-2-piperazin-1-yl-pyrimidin-4-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aS)-4-methyl-8-(2-piperazin-1-yl-4-pyridinyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aR)-4-methyl-8-(2-piperazin-1-ylpyrimidin-4-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aR)-4-methyl-8-(4-piperazin-1-yl-2-pyridinyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-(8-isoindolin-4-yl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl)quinoline-8-carbonitrile; 5-[(4R,9aR)-8-[2-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]pyrimidin-4-yl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aR)-8-[4-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]pyrimidin-2-yl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[2-(4-methyl-6-piperazin-1-yl-3-pyridinyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-8-yl]quinoline-8-carbonitrile; 5-[(4R,9aR)-8-[4-(3-aminoazetidin-1-yl)pyrimidin-2-yl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aS)-8-[2-[(3S,4R)-3-amino-4-fluoro-pyrrolidin-1-yl]-4-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aS)-8-[2-(3-aminoazetidin-1-yl)-4-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aS)-4-methyl-8-(5,6,7,8-tetrahydro-2,7-naphthyridin-4-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aR)-4-methyl-8-(5-methyl-4-piperazin-1-yl-pyrimidin-2-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aR)-4-methyl-8-(5,6,7,8-tetrahydro-2,7-naphthyridin-4-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aR)-8-[2-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]-6-methyl-pyrimidin-4-yl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[2-[6-[(6R)-6-amino-1,4-oxazepan-4-yl]-4-methyl-3-pyridyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-8-yl]quinoline-8-carbonitrile; 5-[trans-4-methyl-8-(1,2,3,4-tetrahydroisoquinolin-5-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aS)-8-[2-[(6S)-6-amino-1,4-oxazepan-4-yl]-4-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aS)-8-[2-[(6R)-6-amino-1,4-oxazepan-4-yl]-4-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aR)-8-[2-(3-amino-3-methyl-azetidin-1-yl)-6-methyl-pyrimidin-4-yl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aS)-8-[2-(3-amino-3-methyl-azetidin-1-yl)-4-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aS)-4-methyl-8-[(5-piperazin-1-yl-3-pyridinyl)methyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aS)-4-methyl-8-[2-[6-[(3R)-3-methylpiperazin-1-yl]-2-pyridinyl]ethyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aS)-4-methyl-8-[2-[6-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)-3-pyridinyl]ethyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aS)-4-methyl-8-[(2-methyl-6-piperazin-1-yl-3-pyridinyl)methyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aS)-4-methyl-8-(1,2,3,4-tetrahydroisoquinolin-7-ylmethyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(4R,9aS)-8-[2-[6-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(4R,9aS)-8-[2-[6-[(3R,4S)-3-amino-4-fluoro-pyrrolidin-1-yl]-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(4R,9aS)-4-methyl-8-[2-[6-(6-methyl-2,6-diazaspiro[3.3]heptane-2-yl)-3-pyridinyl]ethyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(4R,9aS)-8-[2-[6-(3-amino-3-methyl-azetidin-1-yl)-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 4-[(4R,9aS)-8-[2-[4-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]phenyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile; 4-[(4R,9aS)-8-[2-[6-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile; 4-[(4R,9aS)-8-[2-[4-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]phenyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile; 4-[(4R,9aS)-4-methyl-8-(1,2,3,4-tetrahydroisoquinolin-7-ylmethyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile; 5-[(4R,9aS)-4-methyl-8-(1,2,3,4-tetrahydroisoquinolin-5-ylmethyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aS)-4-methyl-8-(1,2,3,4-tetrahydroisoquinolin-8-ylmethyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aS)-8-(isoindolin-4-ylmethyl)-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aS)-8-[2-(3-amino-3-methyl-azetidin-1-yl)-6-methyl-4-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 4-[(4R,9aS)-8-[2-[6-(3-amino-3-methyl-azetidin-1-yl)-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile; 4-[(4R,9aS)-8-[2-[6-[(3R,4S)-3-amino-4-fluoro-pyrrolidin-1-yl]-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile; 5-[(4R,9aS)-8-[[6-(3-amino-3-methyl-azetidin-1-yl)-2-methyl-3-pyridinyl]methyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aS)-8-[2-[6-[(4aR,7aR)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl]-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(4R,9aS)-4-methyl-8-[(6-piperazin-1-yl-3-pyridinyl)methyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(4R,9aS)-8-[[6-(3-amino-3-methyl-azetidin-1-yl)-2-methyl-3-pyridinyl]methyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(4R,9aS)-4-methyl-8-[[2-methyl-6-(6-methyl-2,6-diazaspiro[3.3]heptane-2-yl)-3-pyridinyl]methyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(4R,9aS)-8-[[6-[(3R)-3-amino-3-methyl-pyrrolidin-1-yl]-2-methyl-3-pyridinyl]methyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(4R,9aS)-8-[[6-[[(3S,4R)-4-fluoropyrrolidin-3-yl]amino]-2-methyl-3-pyridinyl]methyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(4R,9aS)-4-methyl-8-[[2-methyl-6-(9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl)-3-pyridinyl]methyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(4R,9aS)-8-[2-[6-[(3R)-3-amino-3-methyl-pyrrolidin-1-yl]-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(4R,9aS)-4-methyl-8-[[2-methyl-6-[(2S)-2-methylpiperazin-1-yl]-3-pyridinyl]methyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aS)-4-methyl-8-[[2-methyl-6-[(3R)-3-methylpiperazin-1-yl]-3-pyridinyl]methyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,9aS)-4-methyl-8-[(4-methyl-6-piperazin-1-yl-3-pyridinyl)methyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(4R,9aS)-4-methyl-8-[(3-methyl-6-piperazin-1-yl-2-pyridinyl)methyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(4R,9aS)-8-[2-[2-[(3R,4S)-3-amino-4-fluoro-pyrrolidin-1-yl]-4-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(4R,9aS)-8-[[6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-methyl-3-pyridinyl]methyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(4R,9aS)-8-[[6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-methyl-3-pyridyl]methyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(4R,9aS)-8-[[6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-methyl-3-pyridinyl]methyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 4-[(4R,9aR)-4-methyl-8-(3-methyl-5-piperazin-1-yl-2-pyridinyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-1-methyl-1,8-naphthyridin-2-one; 5-[(4R,9aS)-8-[[6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-4-methyl-3-pyridinyl]methyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(4R,9aR)-8-[5-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-3-methyl-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(4R,9aR)-8-[5-[(3R,4S)-3-amino-4-methoxy-pyrrolidin-1-yl]-3-methyl-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(4R,9aR)-8-[5-[(3R)-3-amino-3-methyl-pyrrolidin-1-yl]-3-methyl-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(4R,9aS)-8-[[6-[(4aR,7aR)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl]-2-methyl-3-pyridinyl]methyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(4R,9aR)-8-[5-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]-3-methyl-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(4R,9aR)-8-[5-[(4aR,7aR)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl]-3-methyl-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(4R,9aR)-8-[5-(6-amino-2-azaspiro[3.3]heptane-2-yl)-3-methyl-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(4R,9aR)-4-methyl-8-[3-methyl-5-(6-methyl-2,6-diazaspiro[3.3]heptane-2-carbonyl)-2-pyridinyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(4S,9aR)-4-methyl-8-[3-methyl-5-(6-methyl-2,6-diazaspiro[3.3]heptane-2-carbonyl)-2-pyridinyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(4R,9aS)-8-[2-[(3R)-3-amino-3-methyl-pyrrolidin-1-yl]-4-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4S,9aS)-4-methyl-8-[4-[(2R)-morpholin-2-yl]phenyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(4S,9aS)-4-methyl-8-[4-[(2S)-morpholin-2-yl]phenyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(4S,9aR)-8-[5-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-3-methyl-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(4R,9aR)-8-[5-[2-[(3S,4S)-3-amino-4-methoxy-pyrrolidin-1-yl]ethyl]-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(4S,9aR)-8-[5-[(6R)-6-amino-1,4-oxazepan-4-yl]-3-methyl-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(4S,9aR)-8-[5-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-3-methyl-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(4S,9aR)-8-[6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-3-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 4-[(4S,9aR)-4-methyl-8-[3-methyl-5-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)-2-pyridinyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-1-methyl-1,8-naphthyridin-2-one; 5-[(4S,9aR)-8-[5-[(4aR,7aR)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl]-3-methyl-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(4S,9aR)-8-[6-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]-3-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(4S,9aR)-8-[6-[2-[(3R,4S)-3-amino-4-fluoro-pyrrolidin-1-yl]ethyl]-3-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(4S,9aR)-8-[5-(3-amino-3-methyl-azetidin-1-yl)-3-methyl-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(4S,9aR)-4-methyl-8-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(4S,9aR)-8-[5-[2-[(3S,4S)-3-amino-4-methoxy-pyrrolidin-1-yl]ethyl]-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(4S,9aR)-8-[5-[[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]methyl]-6-methyl-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(4R,9aS)-8-[2-[6-[(4aR,7aR)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl]-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; and 5-[(4S,9aS)-4-methyl-8-[4-[(2R)-morpholin-2-yl]phenyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; or a pharmaceutically acceptable salt thereof.

13. Use of a compound according to any one of claims 1 to 12 for preparing a medicament for treating or preventing systemic lupus erythematosus or lupus nephritis mediated by TLR7 / 8 / 9.

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