Patent Description:
Autoimmune connective tissue disease (CTD) include prototypical 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). With the exception of RA, no really effective and safe therapies are available to patients. SLE represents the prototypical CTD with a prevalence of <NUM>-<NUM> per <NUM>,<NUM> and causes broad inflammation and tissue damage in distinct organs, from commonly observed symptoms in the skin and joints to renal, lung, or heart failure. Traditionally, SLE has been treated with nonspecific anti-inflammatory or immunosuppressive drugs. However, long-term usage of immunosuppressive drug, e.g. corticosteroids is only partially effective, and is associated with undesirable toxicity and side effects. Belimumab is the only FDA-approved drug for lupus in the last <NUM> years, despite its modest and delayed efficacy in only a fraction of SLE patients (<NPL>. Other biologics, such as anti-CD20 mAbs, mAbs against or soluble receptors of specific cytokines, have failed in most clinical studies. Thus, novel therapies are required that provide sustained improvement in a greater proportion of patient groups and are safer for chronic use in many autoimmune as well as autoinflammation diseases.

Toll like Receptors (TLR) are an important family of pattern recognition receptors (PRR) which can initiate broad immune responses in a wide variety of immune cells. As natural host defense sensors, endosomal TLRs <NUM>, <NUM> and <NUM> recognize nucleic acids derived from viruses, bacteria; specifically, TLR7/<NUM> and TLR9 recognize single-stranded RNA (ssRNA) and single-stranded CpG-DNA, respectively. However, aberrant nucleic acid sensing of TRL7, <NUM>, <NUM> is considered as a key node in a broad of autoimmune and auto-inflammatory diseases (<NPL>. Anti-RNA and anti-DNA antibodies are well-established diagnostic markers of SLE, and these antibodies can deliver both self-RNA and self-DNA to endosomes. While self-RNA complexes can be recognized by TLR7 and TLR8, self-DNA complexes can trigger TLR9 activation. Indeed, defective clearance of self-RNA and self-DNA from blood and/or tissues is evident in SLE (Systemic Lupus Erythematosus) patients. TLR7 and TLR9 have been reported to be upregulated in SLE tissues, and correlate with chronicity and activity of lupus nephritis, respectively. In B cells of SLE patients, TLR7 expression correlates with anti-RNP antibody production, while TLR9 expression with IL-<NUM> and anti-dsDNA antibody levels. Consistently, in lupus mouse models, TLR7 is required for anti-RNA antibodies, and TLR9 is required for anti-nucleosome antibody. On the other hand, overexpression of TLR7 or human TLR8 in mice promotes autoimmunity and autoinflammation. Moreover, activation of TLR8 specifically contributes to inflammatory cytokine secretion of mDC/macrophages, neutrophil NETosis, induction of Th17 cells, and suppression of Treg cells. In addition to the described role of TLR9 in promoting autoantibody production of B cells, activation of TLR9 by self-DNA in pDC also leads to induction of type I IFNs and other inflammatory cytokines. Given these roles of TLR9 in both pDC and B cells, both as key contributors to the pathogenesis of autoimmune diseases, and the extensive presence of self-DNA complexes that could readily activate TLR9 in many patients with autoimmune diseases, it may have extra benefit to further block self-DNA mediated TLR9 pathways on top of inhibition of TLR7 and TLR8 pathways. Taken together, TLR7, <NUM> and <NUM> pathways represent new therapeutic targets for the treatment of autoimmune and auto-inflammatory diseases, for which no effective steroid-free and non-cytotoxic oral drugs exist, and inhibition of all these pathways from the very upstream may deliver satisfying therapeutic effects. As such, we invented oral compounds that target and suppress TLR7, TLR8 and TLR9 for the treatment of autoimmune and auto-inflammatory diseases.

<CIT> provides compounds for the treatment of disorders related to TLR7/<NUM> overexpression or abherrant activation, wherein the disorder is selected from multiple sclerosis, Alzheimer's Disease, myositis, stroke, ischemia, CNS neuropathies, systemic lupus erythematosus, lupus nephritis, Sjogren's syndrome, Guillain-Barr syndrome, alcoholic hepatitis, non-alcoholic steatohepatitis, congenital heart block, autoimmune hepatitis, autoimmune pancreatitis, adult onset Still's disease, drug-induced neurological disorders, and substance addiction.

<CIT> relates to compounds useful as toll-like receptor <NUM>/<NUM> (TLR7/<NUM>) antagonists.

<CIT> relates to compounds used for the treatment of inflammation and autoimmune disorders.

<CIT> relates to compounds for the treatment of autoimmune diseases.

The present application discloses novel compounds of formula (I) or (Ia),
<CHM>
wherein.

Another object of the present invention is related to novel compounds of formula (I) or (Ia). Their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of compounds of formula (I) or (Ia) as TLR7 and/or TLR8 and/or TLR9 antagonist, and for the treatment or prophylaxis of systemic lupus erythematosus or lupus nephritis. The compounds of formula (I) or (Ia) show superior TLR7 and TLR8 and TLR9 antagonism activity. In addition, the compounds of formula (I) or (Ia) also show good cytotoxicity, phototoxicity, solubility, hPBMC, human microsome stability and SDPK profiles, as well as low CYP inhibition.

The term "C<NUM>-<NUM>alkyl" denotes a saturated, linear or branched chain alkyl group containing <NUM> to <NUM>, particularly <NUM> to <NUM> carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the like. Particular "C<NUM>-<NUM>alkyl" groups are methyl, ethyl and n-propyl.

The term "halogen" and "halo" are used interchangeably herein and denote fluoro, chloro, bromo, or iodo.

The term "halopyrrolidinyl" denotes a pyrrolidinyl substituted once, twice or three times by halogen. Examples of halopyrrolidinyl include, but not limited to, difluoropyrrolidinyl and fluoropyrrolidinyl.

The term "aryl" denotes an aromatic hydrocarbon mono- or bicyclic ring system of <NUM> to <NUM> ring atoms. Examples of aryl include, but not limited to, phenyl and naphthyl. Aryl can be further substituted by substituents includes, but not limited to C<NUM>-<NUM>alkyl; <NUM>,<NUM>,4a,<NUM>,<NUM>,7a-hexahydro-<NUM>-pyrrolo[<NUM>,<NUM>-b][<NUM>,<NUM>]oxazinyl; <NUM>,<NUM>-diazepanyl; <NUM>,<NUM>-diazaspiro[<NUM>]heptanyl substituted by C<NUM>-<NUM>alkyl; <NUM>-oxa-<NUM>,<NUM>-diazaspiro[<NUM>]nonanyl; amino-<NUM>,<NUM>-oxazepanyl; azetidinyl substituted by one or two substituents independently selected from amino and C<NUM>-<NUM>alkyl; piperazinyl unsubstituted or substituted by C<NUM>-<NUM>alkyl; and pyrrolidinyl substituted by one or two substituents independently selected from amino, C<NUM>-<NUM>alkoxy and halogen.

The term "heteroaryl" denotes an aromatic heterocyclic mono- or bicyclic ring system of <NUM> to <NUM> ring atoms, comprising <NUM>, <NUM>, <NUM> or <NUM> heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Examples of heteroaryl moieties include, but 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, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl. Heteroaryl can be further substituted by substituents include, but not limited to C<NUM>-<NUM>alkyl; <NUM>,<NUM>,4a,<NUM>,<NUM>,7a-hexahydro-<NUM>-pyrrolo[<NUM>,<NUM>-b][<NUM>,<NUM>]oxazinyl; <NUM>,<NUM>-diazepanyl; <NUM>,<NUM>-diazaspiro[<NUM>]heptanyl substituted by C<NUM>-<NUM>alkyl; <NUM>-oxa-<NUM>,<NUM>-diazaspiro[<NUM>]nonanyl; amino-<NUM>,<NUM>-oxazepanyl; azetidinyl substituted by one or two substituents independently selected from amino and C<NUM>-<NUM>alkyl; piperazinyl unsubstituted or substituted by C<NUM>-<NUM>alkyl; and pyrrolidinyl substituted by one or two substituents independently selected from amino, C<NUM>-<NUM>alkoxy and halogen.

The term "heterocyclyl" or "heterocyclic" denotes a monovalent saturated or partly unsaturated mono or bicyclic ring system of <NUM> to <NUM> ring atoms, comprising <NUM> to <NUM> ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. In particular embodiments, heterocyclyl is a monovalent saturated monocyclic ring system of <NUM> to <NUM> ring atoms, comprising <NUM>, <NUM>, or <NUM> ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Examples for monocyclic saturated heterocyclyl are aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, <NUM>,<NUM>-dioxo-thiomorpholin-<NUM>-yl, azepanyl, diazepanyl, homopiperazinyl, oxazepanyl. Examples for bicyclic saturated heterocyclic ring are azabicyclo[<NUM>. <NUM>]octyl, quinuclidinyl, oxaazabicyclo[<NUM>. <NUM>]octanyl, azabicyclo[<NUM>. <NUM>]nonanyl, oxaaza-bicyclo[<NUM>. <NUM>]nonanyl, azabicyclo[<NUM>. <NUM>]hexanyl, oxodiazaspiro[<NUM>]octanyl, acetyloxodiazaspiro[<NUM>]octanyl, thiaazabicyclo[<NUM>. <NUM>]nonanyl, oxoazaspiro[<NUM>]heptanyl, oxoazaspiro[<NUM>]octanyl, oxoazabicyclo[<NUM>. <NUM>]hexanyl and dioxotetrahydropyrrolo[<NUM>,<NUM>-a]pyrazinyl. Examples for bicyclic heterocyclyl include, but not limited to, <NUM>,<NUM>,<NUM>,<NUM>-tetrahydroisoquinolinyl; <NUM>,<NUM>,<NUM>,<NUM>-tetrahydro-<NUM>,<NUM>-naphthyridinyl; <NUM>,<NUM>,<NUM>,<NUM>-tetrahydro-<NUM>,<NUM>-naphthyridinyl; <NUM>,<NUM>,<NUM>,<NUM>-tetrahydro-<NUM>,<NUM>-naphthyridinyl; <NUM>,<NUM>,<NUM>,<NUM>-tetrahydro-<NUM>,<NUM>-naphthyridinyl; isoindolinyl.

The term "pharmaceutically acceptable salts" denotes salts which are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid and base addition salts.

The term "pharmaceutically acceptable acid addition salt" denotes those pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and organic acids selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicyclic acid.

The term "pharmaceutically acceptable base addition salt" denotes those pharmaceutically acceptable salts formed with an organic or inorganic base. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of 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, <NUM>-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, and polyamine resins.

The term "A pharmaceutically active metabolite" denotes a pharmacologically active product produced through metabolism in the body of a specified compound or salt thereof. After entry into the body, most drugs are substrates for chemical reactions that may change their physical properties and biologic effects. These metabolic conversions, which usually affect the polarity of the compounds of the invention, alter the way in which drugs are distributed in and excreted from the body. However, in some cases, metabolism of a drug is required for therapeutic effect.

The term "therapeutically effective amount" denotes an amount of a compound or molecule of the present invention that, when administered to a subject, (i) treats or prevents the particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein. The therapeutically effective amount will vary depending on the compound, the disease state being treated, the severity of the disease treated, the age and relative health of the subject, the route and form of administration, the judgement of the attending medical or veterinary practitioner, and other factors.

The term "pharmaceutical composition" denotes a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient together with pharmaceutically acceptable excipients to be administered to a mammal, e.g., a human in need thereof.

The present invention relates to (i) a compound of formula (I),
<CHM>
wherein.

Further embodiment of present invention is (ii) a compound of formula (I) according to (i), wherein
R<NUM> is <NUM>,<NUM>,<NUM>,<NUM>-tetrahydroisoquinolinyl;.

Another embodiment of present invention is (iii) a compound of formula (Ia),
<CHM>
wherein.

A further embodiment of present invention is (iv) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (iii), wherein R<NUM> is
<CHM>
wherein R<NUM> is cyano; R4a is C<NUM>-<NUM>alkyl; R<NUM> is H; R<NUM> is H or halogen; and n is <NUM> or <NUM>.

A further embodiment of present invention is (v) a compound of formula (I) or (Ia) according to any one of (i) to (iv), wherein.

A further embodiment of present invention is (vi) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (v), wherein R<NUM> is
<CHM>
wherein R<NUM> is cyano; R<NUM> is H.

A further embodiment of present invention is (vii) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (vi), wherein R<NUM> is <NUM>,<NUM>,<NUM>,<NUM>-tetrahydro-<NUM>,<NUM>-naphthyridinyl; <NUM>,<NUM>,<NUM>,<NUM>-tetrahydro-<NUM>,<NUM>-naphthyridinyl; pyridinyl substituted by amino(C<NUM>-<NUM>alkoxy)pyrrolidinyl; or pyrimidinyl substituted by piperazinyl.

A further embodiment of present invention is (viii) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (vii), wherein R<NUM> is <NUM>,<NUM>,<NUM>,<NUM>-tetrahydro-<NUM>,<NUM>-naphthyridin-<NUM>-yl; <NUM>,<NUM>,<NUM>,<NUM>-tetrahydro-<NUM>,<NUM>-naphthyridin-<NUM>-yl; piperazin-<NUM>-ylpyrimidinyl; or <NUM>-amino-<NUM>-methoxy-pyrrolidin-<NUM>-ylpyridinyl.

A further embodiment of 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.

A further embodiment of present invention is (x) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (ix), wherein.

Another embodiment of present invention is a compound of formula (I) or (Ia) selected from the following:.

The compounds of the present invention can be prepared by any conventional means. Suitable processes for synthesizing these compounds as well as their starting materials are provided in the schemes below and in the examples. All substituents, in particular, R<NUM> and R<NUM> are as defined above unless otherwise indicated. Furthermore, and unless explicitly otherwise stated, all reactions, reaction conditions, abbreviations and symbols have the meanings well known to a person of ordinary skill in organic chemistry.

General synthetic routes for preparing the compound of formula(I), (VII) and (XI) are shown below.

Wherein n is <NUM>, <NUM> or <NUM>; X is halogen; Y is halogen or methanesulfonate; R<NUM> and R<NUM> is aryl or heteroaryl; R<NUM> and R<NUM> together with the nitrogen atom they are attached to form a heterocyclyl.

The synthesis of compounds of the present invention started from halide II. Buchwald-Hartwig amination reaction between halide II and compound of formula III with a catalyst, such as Ruphos Pd-G2, and a base, such as Cs<NUM>CO<NUM> provides compound of formula IV (ref: <NPL>; <NPL>; <NPL>; and references cited therein). Alternatively, compound of formula IV can also be obtained via nucleophilic substitution between halide II and compound of formula III in the presence of a base, such as DIPEA, NaHCO<NUM> and K<NUM>CO<NUM>. Boc deprotection of compound of formula IV in acidic condition (such as HCl in EtOAc and TFA in DCM) gives compound V, which can be transformed into compound of formula VII via either nucleophilic substitution with compound of formula VI in the presence of a base, such as DIPEA NaHCO<NUM> and K<NUM>CO<NUM>, or Buchwald-Hartwig amination reaction with compound of formula VI followed by appropriate deprotection. Meanwhile, compound of formula V can react with compound of formula VIII via nucleophilic substitution to give compound of formula IX. Buchwald-Hartwig amination reaction or nucleophilic substitution between compound of formula IX and amine X, followed by appropriate deprotection can provide compound of formula XI.

Compounds of formula (Ia) can be synthesized according to Scheme <NUM> using chiral starting materials.

Compounds of this invention can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art, e.g. (chiral) HPLC or SFC.

This invention also relates to a process for the preparation of a compound of formula (I) or (Ia) comprising any one of the following steps:.

wherein n is <NUM>, <NUM> or <NUM>; X is halogen; Y is halogen or methanesulfonate; R<NUM> and R<NUM> is aryl or heteroaryl; R<NUM> and R<NUM> together with the nitrogen atom they are attached to form a heterocyclyl.

Compound of formula (Ia) can also be synthesized according to Scheme <NUM> by using chiral intermediates.

A compound of formula (I) or (Ia) when manufactured according to the above process is also an object of the invention.

The references to the methods of treatment by therapy in the subsequent paragraphs of this description are to be interpreted as references to compounds, pharmaceutical compositions and medicaments of the present invention for use in those methods.

The present invention provides compounds that can be used as TLR7 and/or TLR8 and/or TLR9 antagonist, which inhibits pathway activation through TLR7 and/or TLR8 and/or TLR9 as well as respective downstream biological events including, but not limited to, innate and adaptive immune responses mediated through the production of all types of cytokines and all forms of auto-antibodies. Accordingly, the compounds of the invention are useful for blocking TLR7 and/or TLR8 and/or TLR9 in all types of cells that express such receptor(s) including, but not limited to, plasmacytoid dendritic cell, B cell, T cell, macrophage, monocyte, neutrophil, keratinocyte, epithelial cell. As such, the compounds can be used as a therapeutic or prophylactic agent for systemic lupus erythematosus and lupus nephritis.

The present invention provides methods for treatment or prophylaxis of systemic lupus erythematosus and lupus nephritis in a patient in need thereof.

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 said mammal a therapeutically effective amount of a compound of formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention.

Abbreviations used herein are as follows:.

Intermediates and final compounds were purified by flash chromatography using one of the following instruments: i) Biotage SP1 system and the Quad <NUM>/<NUM> Cartridge module. ii) ISCO combi-flash chromatography instrument. Silica gel brand and pore size: i) KP-SII, <NUM>Å, particle size: <NUM>-<NUM>; ii) <NPL>, particle size: <NUM>-<NUM> micron silica gel; iii) ZCX from Qingdao Haiyang Chemical Co. , Ltd, pore: <NUM>-<NUM> or <NUM>-<NUM>.

Intermediates and final compounds were purified by preparative HPLC on reversed phase column using XBridge™ Prep-C18 (<NUM>, OBDTM <NUM> × <NUM>) column, SunFire™ Prep-C18 (<NUM>, OBD™ <NUM> × <NUM>) column, Phenomenex Synergi-C18 (<NUM>, <NUM> × <NUM>) or Phenomenex Gemini-C18 (<NUM>, <NUM> × <NUM>). Waters AutoP purification System (Sample Manager <NUM>, Pump <NUM>, Detector: Micromass ZQ and UV <NUM>, solvent system: acetonitrile and <NUM>% ammonium hydroxide in water; acetonitrile and <NUM>% FA in water or acetonitrile and <NUM>% TFA in water). Or Gilson-<NUM> purification System (Pump <NUM>, Detector: UV <NUM>, solvent system: acetonitrile and <NUM>% ammonium hydroxide in water; acetonitrile and <NUM>% FA in water; acetonitrile and <NUM>% HCl in water; acetonitrile and <NUM>% TFA in water; or acetonitrile and water).

For SFC chiral separation, intermediates were separated by chiral column (Daicel chiralpak IC, <NUM>, <NUM> × <NUM>), AS (<NUM>, <NUM> × <NUM>) or AD (<NUM>, <NUM> × <NUM>) using Mettler Toledo Multigram III system SFC, Waters 80Q preparative SFC or Thar <NUM> preparative SFC, solvent system: CO<NUM> and IPA (<NUM>% TEA in IPA) or CO<NUM> and MeOH (<NUM>% NH<NUM>•H<NUM>O in MeOH), back pressure 100bar, detection UV@ <NUM> or <NUM>.

LC/MS spectra of compounds were obtained using a LC/MS (Waters™ Alliance <NUM>-Micromass ZQ, Shimadzu Alliance <NUM>-Micromass ZQ or Agilent Alliance <NUM>-Micromass ZQ), LC/MS conditions were as follows (running time <NUM> or <NUM> mins):.

The microwave assisted reactions were carried out in a Biotage Initiator Sixty microwave synthesizer. All reactions involving air-sensitive reagents were performed under an argon or nitrogen atmosphere. Reagents were used as received from commercial suppliers without further purification unless otherwise noted.

The following examples are intended to illustrate the meaning of the present invention but should by no means represent a limitation within the meaning of the present invention:.

The titled compound was synthesized according to the following scheme:
<CHM>.

In a <NUM> pear-shaped flask, <NUM>-bromo-<NUM>-fluoroaniline (compound A1. <NUM>, <NUM>, <NUM> mmol), propane-<NUM>,<NUM>,<NUM>-triol (<NUM>, <NUM> mmol) and sodium <NUM>-nitrobenzenesulfonate (<NUM>, <NUM> mmol) were combined with <NUM>% H<NUM>SO<NUM> (<NUM>) to afford a dark brown solution, which was heated to <NUM> and stirred for <NUM> hrs. After being cooled to room temperature, the reaction mixture was poured into ice-water, and neutralized with sodium hydroxide solution. The resultant mixture was filtered. The filter cake was dissolved in EtOAc and filtered. The resultant filtrate was concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, <NUM>, <NUM>% to <NUM>% EtOAc in PE) to afford compound A1. <NUM> (<NUM>, <NUM>% yield). MS: calc'd <NUM> and <NUM> [(M+H)+], measured <NUM> and <NUM> [(M+H)+].

To a solution of <NUM>-bromo-<NUM>-fluoroquinoline (compound A1. <NUM>, <NUM>, <NUM> mmol) in DMF (<NUM>) was added dicyanozinc (<NUM>, <NUM> mmol) and RuPhos Pd G2 (CAS: <NUM>-<NUM>-<NUM>, Sigma-Aldrich, Catalog: <NUM>, <NUM>, <NUM> mmol). The reaction mixture was stirred at <NUM> for <NUM> hrs, then cooled to room temperature. The reaction mixture was filtered and the filtrate was diluted with water (<NUM>), then extracted with EA (<NUM>) for three times. The combined organic layer was washed with brine, dried over Na<NUM>SO<NUM>, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, <NUM>, <NUM>% to <NUM>% EtOAc in PE) to afford intermediate A1 (<NUM>, <NUM> % yield). MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ ppm <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>).

<NUM>-chloronicotinic acid (compound A2. <NUM>, <NUM>, <NUM> mmol) was dissolved in <NUM>% monomethylamine (<NUM> mol) solution in ethanol. The reaction mixture was stirred in the autoclave at <NUM> for <NUM> hrs, then concentrated in vacuo to afford compound A2. <NUM> (<NUM>, crude). MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+].

A solution of <NUM>-(methylamino)pyridine-<NUM>-carboxylic acid (compound A2. <NUM>, <NUM>, crude) in acetic anhydride (<NUM>, <NUM> mmol) and acetic acid (<NUM>) was heated to reflux for <NUM> hrs. The reaction mixture was concentrated in vacuo to afford compound A2. <NUM> (<NUM>, crude). MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+].

To a solution of (<NUM>-methyl-<NUM>-oxo-<NUM>,<NUM>-naphthyridin-<NUM>-yl) acetate (Compound A2. <NUM>, <NUM>, crude) in methanol (<NUM>) was added a solution of potassium carbonate (<NUM>, <NUM> mol) in water (<NUM>). The mixture was stirred at <NUM> for <NUM> hrs. Then the reaction mixture was concentrated under reduced pressure to remove the MeOH. The residue was acidified with HCl solution (<NUM> N) to pH <NUM>-<NUM>, extracted with EA (<NUM>) for three times. The combined organic layer was washed with sat. brine (<NUM>), dried over Na<NUM>SO<NUM>, and concentrated in vacuo to afford compound A2. <NUM> (<NUM>, <NUM>% yield). MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]; <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ ppm <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

A solution of <NUM>-hydroxy-<NUM>-methyl-<NUM>,<NUM>-naphthyridin-<NUM>-one (compound A2. <NUM>, <NUM>, <NUM> mol) in phosphorus oxychloride (<NUM>) was stirred at <NUM> for <NUM> hrs. The reaction mixture was concentrated in reduced pressure to remove the phosphorus oxychloride. The residue was neutralized by adding saturated aqueous NaHCO<NUM> at room temperature to pH <NUM>-<NUM>, and the mixture was extracted with DCM (<NUM>) twice. The combined organic layer was washed sat. brine (<NUM>), dried over Na<NUM>SO<NUM> and concentrated in vacuo to give a crude product, which was purified by silica gel chromatography (PE/EtOAc = <NUM>:<NUM> to <NUM>:<NUM>) to afford Intermediate A2 (<NUM>, <NUM>% yield). MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]; <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ ppm <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

A solution of ethyl (<NUM>E)-N-(<NUM>,<NUM>,<NUM>-trimethylphenyl)sulfonyloxyethanimidate (compound A3. <NUM>, <NPL>, Bide Pharmatech, Catalog: BD129455, <NUM>, <NUM> mmol) in <NUM>,<NUM>-dioxane (<NUM>) was added perchloric acid (<NUM>) dropwise in <NUM> and stirred for <NUM> hr at <NUM>. <NUM> ice water was added and the mixture was filtered. The filter cake was dissolved in <NUM> EtOAc and then was stirred for <NUM> minutes. The organic layer was concentrated (keep the temperature below <NUM>) to afford crude product. The crude product was recrystallized (petroleum/EtOAc=<NUM>/<NUM>) to afford compound A3. <NUM> (<NUM>, <NUM>% yield). MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+].

A solution of amino <NUM>,<NUM>,<NUM>-trimethylbenzenesulfonate (compound A3. <NUM>, <NUM>, <NUM> mmol) and <NUM>-bromo-<NUM>-fluoropyridine (<NUM>, <NUM> mmol) in DCM (<NUM>) was stirred at <NUM> for <NUM> hrs. The mixture was concentrated, the residue was recrystallized in EtOAc to afford compound A3. <NUM> (<NUM>, <NUM>% yield). MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+].

A solution of <NUM>-bromo-<NUM>-fluoro-pyridin-<NUM>-ium-<NUM>-amine; <NUM>,<NUM>,<NUM>-trimethylbenzenesulfonate (compound A3. <NUM>, <NUM>, <NUM> mmol), K<NUM>CO<NUM> (<NUM>, <NUM> mmol) and ethyl propiolate (<NUM>, <NUM> mmol) in DMF (<NUM>) was stirred at <NUM> for <NUM> hrs. The reaction was diluted with water, extracted with EtOAc. The organic layer was dried over Na<NUM>SO<NUM>, filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography column to afford compound A3. <NUM> (<NUM>, <NUM>% yield). MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+].

To a mixture of ethyl <NUM>-bromo-<NUM>-fluoro-pyrazolo[<NUM>,<NUM>-a]pyridine-<NUM>-carboxylate (compound A3. <NUM>, <NUM>, <NUM> mmol) in acetic acid (<NUM>) and water (<NUM>) was added conc. HCl (<NUM>, <NUM> mmol). The mixture was stirred at <NUM> for <NUM> hrs. The mixture was diluted with water (<NUM>), basified with aq. NaOH (1N) to pH <NUM>, extracted with EA (<NUM>) for three times. The combined organic layer was washed with brine, dried over Na<NUM>SO<NUM> and concentrated in vacuo to afford compound A3. <NUM> (<NUM>, <NUM>% yield) which was used directly for the next step.

MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+].

A mixture of <NUM>-bromo-<NUM>-fluoro-pyrazolo[<NUM>,<NUM>-a]pyridine (compound A3. <NUM>, <NUM>, <NUM> mmol), zinc cyanide (<NUM>, <NUM> mmol), zinc (<NUM>, <NUM> mmol), XantPhos (<NUM>, <NUM> mmol) and Pd(OAc)<NUM> (<NUM>, <NUM> mmol) in DMA (<NUM>) was degassed and purged with Ar for <NUM> times, and then the mixture was stirred at <NUM> for <NUM> under Ar atmosphere. The mixture was diluted with EA (<NUM>), filtered and the filtrate was washed with water (<NUM>), brine (<NUM>) three times, dried over Na<NUM>SO<NUM> and concentrated in vacuo. The residue was purified by Prep-TLC (PE: EA=<NUM>:<NUM>) to afford Intermediate A3 (<NUM>, <NUM> % yield). MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+].

The mixture of ethyl <NUM>-bromo-<NUM>-fluoro-pyrazolo[<NUM>,<NUM>-a]pyridine-<NUM>-carboxylate (compound A3. <NUM>, <NUM>, <NUM> mmol), NaOH (<NUM>, <NUM> mmol) in EtOH (<NUM>) and water (<NUM>) was stirred at <NUM> for <NUM> hrs. The reaction mixture was concentrated and then diluted with water. After adjusting pH to <NUM> with <NUM> N HCl, grey solid was precipitated, which was collected by filtration to afford compound A4. <NUM> (<NUM>, <NUM>% yield). MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+].

To a solution of <NUM>-bromo-<NUM>-fluoro-pyrazolo[<NUM>,<NUM>-a]pyridine-<NUM>-carboxylic acid (compound A4. <NUM>, <NUM>, <NUM> mmol) and KF (<NUM>, <NUM> mmol) in DCE (<NUM>) and water (<NUM>) was added Selectfluor (<NUM>, <NUM> mmol). The reaction was stirred at <NUM> for <NUM> hrs. The reaction was quenched with water, extracted with DCM twice. The combined organic layer was dried over Na<NUM>SO<NUM>, filtered and the filtrate was concentrated in vacuo to afford crude compound A4. <NUM> (<NUM>, <NUM>% yield). MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+].

A solution of <NUM>-bromo-<NUM>, <NUM>-difluoro-pyrazolo[<NUM>,<NUM>-a]pyridine (compound A4. <NUM>, <NUM>, <NUM> mmol) and zinc cyanide (<NUM>, <NUM> mmol) in DMF (<NUM>) was added tetrakis(triphenylphosphine)palladium (<NUM>, <NUM> mmol). The reaction mixture was stirred at <NUM> for <NUM> hrs under N<NUM> atmosphere. The mixture was quenched with water and extracted with EtOAc twice. The combined organic layer was dried over Na<NUM>SO<NUM>, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography to afford Intermediate A4 (<NUM>, <NUM>% yield). MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (<NUM>, CHLOROFORM-d) δ ppm <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

The mixture of tert-butyl (R)-(<NUM>-aminopropan-<NUM>-yl)carbamate (<NUM>, <NUM> mmol), benzaldehyde (<NUM>, <NUM> mmol) and DCE (<NUM>) was stirred at room temperature for <NUM>. Then NaBH(OAc)<NUM> (<NUM>, <NUM> mmol) was added to the mixture. The resultant mixture was stirred at room temperature for <NUM> hrs, then quenched with water (<NUM>), extracted with DCM ( <NUM>) for three times. The combined organic layer was washed with brine, dried over Na<NUM>SO<NUM> and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, <NUM>, <NUM>% to <NUM>% EtOAc in DCM) to afford compound B2 (<NUM>, <NUM> % yield). MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+].

To a solution of tert-butyl N-[(<NUM>R)-<NUM>-(benzylamino)-<NUM>-methyl-ethyl]carbamate (compound B2, <NUM>, <NUM> mmol) in acetone (<NUM>) was added methyl (E)-<NUM>-bromobut-<NUM>-enoate (<NUM>, <NUM> mmol) and K<NUM>CO<NUM> (<NUM>, <NUM> mmol). The reaction mixture was stirred at room temperature for <NUM> hrs, then filtered through celite and the filtrate was concentrated. The residue was purified by flash chromatography (silica gel, <NUM>, <NUM>% to <NUM>% EtOAc in PE) to afford compound B3 (<NUM>, <NUM> % yield). MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+].

The mixture of methyl (E)-<NUM>-[benzyl-[(2R)-<NUM>-(tert-butoxycarbonylamino)propyl]amino]but-<NUM>-enoate (compound B3, <NUM>, <NUM> mmol) and HCl/MeOH (<NUM> N, <NUM>, <NUM> mmol) was heated at reflux for <NUM> hrs. After being cooled to room temperature, the reaction mixture was neutralized with saturated aq. K<NUM>CO<NUM>, and extracted with DCM (<NUM>) twice. The combined organic layer was washed with brine, dried over Na<NUM>SO<NUM>, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, <NUM>, <NUM>% to <NUM>% MeOH in DCM) to afford compound B4 (<NUM>, <NUM>% yield). MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+].

To a solution of (tert-butoxycarbonyl)glycine (<NUM>, <NUM> mmol) in DMF (<NUM>) was added methyl <NUM>-[(<NUM>R)-<NUM>-benzyl-<NUM>-methyl-piperazin-<NUM>-yl]acetate (compound B4, <NUM>, <NUM> mmol), DIEA (<NUM>, <NUM> mmol) and HATU (<NUM>, <NUM> mmol). The resultant mixture was stirred at room temperature for <NUM> hrs. The reaction was quenched with water (<NUM>), and extracted with DCM (<NUM>) for three times. The combined organic layer was washed with brine, dried over Na<NUM>SO<NUM>, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (silica gel, <NUM>, <NUM>% to <NUM>% EtOAc in PE) to afford compound B5 (<NUM>, <NUM> % yield). MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+].

The mixture of methyl <NUM>-[(<NUM>R)-<NUM>-benzyl-<NUM>-[<NUM>-(tert-butoxycarbonylamino)-acetyl]-<NUM>-methyl-piperazin-<NUM>-yl]acetate (compound B5, <NUM>, <NUM> mmol) and HCl/MeOH (<NUM>% HCl in MeOH, <NUM>) was stirred at reflux for <NUM> hrs. The reaction mixture was concentrated, the residue was diluted with MeOH (<NUM>), and then sodium methoxide (<NUM>, <NUM> mmol) was added. The resultant mixture was stirred at reflux for <NUM> hrs. After being cooled to room temperature, the reaction was quenched with water (<NUM>), and extracted with EA (<NUM>) for three times. The combined organic layer was washed with brine, dried over Na<NUM>SO<NUM>, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography to afford compound B6 (<NUM>, <NUM> % yield). MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+].

Compound B7a (<NUM>) was resolved by SFC to give two single isomers: compound B7a (faster eluting, <NUM>, <NUM> % yield) and compound B7b (slower eluting, <NUM>, <NUM> % yield) with <NUM>% Methanol/CO<NUM> on OJ (<NUM>, <NUM>×<NUM>) column. The stereochemistry was confirmed by NOESY.

Compound B7a: MS: calc'd <NUM> (M+H) +, measured <NUM> (M+H)+; <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ ppm <NUM>-<NUM> (m, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

Compound B7b: MS: calc'd <NUM> (M+H) +, measured <NUM> (M+H)+; <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ ppm <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM>-<NUM> (m,<NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

A mixture of (<NUM>R,10aS)-<NUM>-benzyl-<NUM>-methyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,10a-hexahydro-<NUM>H-pyrazino[<NUM>,<NUM>-d] [<NUM>,<NUM>]diazepine-<NUM>,<NUM>-dione (Compound B7b,<NUM>, <NUM> mmol) and BH<NUM> solution (<NUM>M in THF, <NUM>, <NUM> mmol) was heated at <NUM> with stirring on for <NUM> hrs. The reaction mixture was cooled to <NUM> , then HCl solution (<NUM> N, <NUM>) was added slowly to the reaction mixture at same temperature. The resultant mixture was stirred at reflux for <NUM> hrs, then the mixture was cooled back to room temperature. After the organic solvent was removed in vacuo, the residue was diluted with DCM (<NUM>). Boc-Anhydride (<NUM>, <NUM> mmol) and TEA (<NUM>, <NUM> mmol) were added respectively. The resultant mixture was stirred at room temperature for <NUM> hrs. The reaction was quenched with water (<NUM>), and extracted with DCM (<NUM>) for three times. The combined organic layer was washed with brine, dried over Na<NUM>SO<NUM>, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, <NUM>, <NUM>% to <NUM>% EtOAc in DCM) to afford compound B8 (<NUM>, <NUM> % yield). MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+].

A mixture of tert-butyl (<NUM>R,10aS)-<NUM>-benzyl-<NUM>-methyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,10a-octahydropyrazino[<NUM>,<NUM>-d][<NUM>,<NUM>]diazepine-<NUM>-carboxylate (compound B8, <NUM>, <NUM> mmol) and Pd-C (<NUM>) in MeOH (<NUM>) was hydrogenated by a hydrogen balloon at room temperature for <NUM> hrs. After the catalyst was filtered off, the filtrate was concentrated in vacuo to afford Intermediate B (<NUM>, <NUM> % yield) which was used directly for the next step without further purification. MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+].

To a solution of tert-butyl (<NUM>R,10aS)-<NUM>-methyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,10a-octahydro-<NUM>H-pyrazino.

[<NUM>,<NUM>-d][<NUM>,<NUM>]diazepine-<NUM>-carboxylate (Intermediate B, <NUM>, <NUM> mmol) in DMSO (<NUM>) was added <NUM>-fluoroquinoline-<NUM>-carbonitrile (Intermediate A1, <NUM>, <NUM> mmol ) and DIEA (<NUM>, <NUM> mmol). The resultant mixture was stirred at <NUM> for <NUM> hrs. After being cooled to room temperature, the reaction was quenched with water (<NUM>) and extracted with EA (<NUM>) for three times. The combined organic layer was washed with brine, dried over Na<NUM>SO<NUM>, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, <NUM>, <NUM>% to <NUM>% EtOAc in PE) to afford compound C1. <NUM> (<NUM>, <NUM> % yield). MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+].

To a solution of tert-butyl (<NUM>R,10aS)-<NUM>-(<NUM>-cyano-<NUM>-quinolyl)-<NUM>-methyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,10a-octahydropyrazino[<NUM>,<NUM>-d][<NUM>,<NUM>]diazepine-<NUM>-carboxylate (compound C1. <NUM>,<NUM>, <NUM> mmol) in DCM (<NUM>) was added dropwise HCl/dioxane (<NUM> N, <NUM>) at <NUM>. After addition, the mixture was stirred at rt for <NUM> hrs, then the reaction mixture was concentrated. The residue was dissolved in pure water (<NUM>), and dried by lyophilization to afford Intermediate C1 (<NUM>,<NUM> % yield). MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+].

<NUM>-[(<NUM>R,10aS)-<NUM>-methyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,10a-octahydro-<NUM>H-pyrazino[<NUM>,<NUM>-d][<NUM>,<NUM>]diazepin-<NUM>-yl]-<NUM>-methyl-<NUM>,<NUM>-naphthyridin-<NUM>-one;trihydrochloride (Intermediate C2) was prepared in analogy to Intermediate C1, by replacing <NUM>-fluoroquinoline-<NUM>-carbonitrile (Intermediate A1) with <NUM>-chloro-<NUM>-methyl-<NUM>,<NUM>-naphthyridin-<NUM>-one (Intermediate A2) and CsF with the DIEA in step (a). MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+].

<NUM>-[(<NUM>R,10aS)-<NUM>-methyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,10a-octahydro-<NUM>H-pyrazino[<NUM>,<NUM>-d][<NUM>,<NUM>]diazepin-<NUM>-yl] pyrazolo[<NUM>,<NUM>-a]pyridine-<NUM>-carbonitrile;trihydrochloride (Intermediate C3) was prepared in analogy to Intermediate C1, by replacing <NUM>-fluoroquinoline-<NUM>-carbonitrile (Intermediate A1) with <NUM>-fluoropyrazolo[<NUM>,<NUM>-a]pyridine-<NUM>-carbonitrile (Intermediate A3) in step (a). MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+].

<NUM>-[(<NUM>R,10aS)-<NUM>-methyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,10a-octahydro-<NUM>H-pyrazino[<NUM>,<NUM>-d][<NUM>,<NUM>]diazepin-<NUM>-yl]-<NUM>-fluoro-pyrazolo[<NUM>,<NUM>-a]pyridine-<NUM>-carbonitrile;trihydrochloride (Intermediate C4) was prepared in analogy to Intermediate C1, by replacing <NUM>-fluoroquinoline-<NUM>-carbonitrile (Intermediate A1) with <NUM>,<NUM>-difluoropyrazolo[<NUM>,<NUM>-a]pyridine-<NUM>-carbonitrile (Intermediate A4) in step (a). MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+].

To a solution of <NUM>-[(<NUM>R,10aS)-<NUM>-methyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,10a-octahydro-<NUM>H-pyrazino[<NUM>,<NUM>-d] [<NUM>,<NUM>]diazepin-<NUM>-yl]quinoline-<NUM>-carbonitrile;trihydrochloride (Intermediate C1, <NUM>, <NUM>µmol) in toluene (<NUM>) was added tert-butyl <NUM>-(<NUM>-bromopyridin-<NUM>-yl)piperazine-<NUM>-carboxylate (<NPL>, BePharm, Catalog: BD94595, <NUM>, <NUM>µmol), tBuONa (<NUM>, <NUM>µmol) and RuPhos Pd G2 (<NPL>, ALDRICH, Catalog: <NUM>, <NUM>, <NUM>µmol). The resultant mixture was stirred at <NUM> overnight. After being cooled to room temperature, the mixture was diluted with water (<NUM>) and extracted with EA (<NUM>) for three times. The combined organic layer was washed with brine, dried over Na<NUM>SO<NUM>, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, <NUM>, <NUM>% to <NUM>% EtOAc in PE) to afford compound <NUM> (<NUM>, <NUM> % yield). MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+].

To a solution of tert-butyl <NUM>-[<NUM>-[(<NUM>R,10aS)-<NUM>-(<NUM>-cyano-<NUM>-quinolyl)-<NUM>-methyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>, <NUM>,10a-octahydropyrazino[<NUM>,<NUM>-d][<NUM>,<NUM>]diazepin-<NUM>-yl]-<NUM>-pyridyl]piperazine-<NUM>-carboxylate (compound <NUM>, <NUM>, <NUM>µmol) in DCM (<NUM>) was added TFA (<NUM>). The reaction mixture was stirred at room temperature for <NUM> hrs, then concentrated to afford a crude product, which was purified by pre-HPLC to afford Example <NUM> (<NUM>, <NUM> % yield). MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ ppm <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br s, <NUM>), <NUM> (d, J= <NUM>, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using tert-Butyl <NUM>-(<NUM>-bromopyrimidin-<NUM>-yl)piperazine-<NUM>-carboxylate (<NPL>, BePharm, Catalog: BD28540) instead of tert-butyl <NUM>-(<NUM>-bromopyridin-<NUM>-yl) piperazine-<NUM>-carboxylate in step (a). Example <NUM> was obtained. MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ ppm <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using tert-butyl (<NUM>S)-<NUM>-(<NUM>-bromophenyl)morpholine-<NUM>-carboxylate instead of tert-butyl <NUM>-(<NUM>-bromopyridin-<NUM>-yl) piperazine-<NUM>-carboxylate in step (a). Example <NUM> was obtained. MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ ppm <NUM>-<NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using tert-butyl <NUM>-bromo-<NUM>,<NUM>-dihydro-<NUM>H-<NUM>,<NUM>-naphthyridine-<NUM>-carboxylate (<NPL>) instead of tert-butyl <NUM>-(<NUM>-bromopyridin-<NUM>-yl)piperazine-<NUM>-carboxylate in step (a). Example <NUM> was obtained. MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ ppm <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (br s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using tert-butyl <NUM>-chloro-<NUM>,<NUM>-dihydro-<NUM>H-<NUM>,<NUM>-naphthyridine-<NUM>-carboxylate (<NPL>, PharmaBlock, Catalog: PBLJ8189) instead of tert-butyl <NUM>-(<NUM>-bromopyridin-<NUM>-yl)piperazine -<NUM>-carboxylate in step (a). Example <NUM> was obtained. MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ ppm <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J= <NUM>, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using tert-butyl <NUM>-chloro-<NUM>,<NUM>,<NUM>,<NUM>-tetrahydro-<NUM>,<NUM>-naphthyridine-<NUM>-carboxylate (CAS: <NUM>-<NUM>-<NUM>, PharmaBlock, Catalog: PB06675) instead of tert-butyl <NUM>-(<NUM>-bromopyridin-<NUM>-yl)piperazine-<NUM>-carboxylate in step (a). Example <NUM> was obtained. MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ ppm <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using tert-butyl <NUM>-chloro-<NUM>,<NUM>-dihydro-<NUM>H-<NUM>,<NUM>-naphthyridine-<NUM>-carboxylate instead of tert-butyl <NUM>-(<NUM>-bromopyridin-<NUM>-yl)piperazine-<NUM>-carboxylate in step (a). Example <NUM> was obtained. MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ ppm <NUM>-<NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

To a solution of tert-butyl <NUM>-(hydroxymethyl)-<NUM>,<NUM>-dihydro-<NUM>H-<NUM>,<NUM>-naphthyridine-<NUM>-carboxylate (compound <NUM>, <NUM>, <NUM>µmol) and DIEA (<NUM>, <NUM>µmol) in DCM (<NUM>) was added dropwise methanesulfonyl chloride (<NUM>, <NUM>µmol). The resultant mixture was stirred at room temperature for <NUM> hrs. The reaction was quenched with aq. NaHCO<NUM>, extracted with DCM (<NUM>) twice. The combined organic layer was washed with brine, dried over Na<NUM>SO<NUM>, filtered and the filtrate was concentrated to afford compound <NUM> (<NUM>, <NUM> % yield) which was used directly for the next step without further purification. MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+].

To a solution of <NUM>-[(<NUM>R,10aS)-<NUM>-methyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,10a-octahydro-<NUM>H-pyrazino[<NUM>,<NUM> -d] [<NUM>,<NUM>]diazepin-<NUM>-yl]quinoline-<NUM>-carbonitrile;trihydrochloride (Intermediate C1, <NUM>, <NUM>µmol) in acetonitrile (<NUM>) was added tert-butyl <NUM>-(methylsulfonyloxymethyl)-<NUM>,<NUM>-dihydro-<NUM>H -<NUM>,<NUM>-naphthyridine-<NUM>-carboxylate (compound <NUM>, <NUM>, <NUM>µmol) and DIEA (<NUM>, <NUM>µmol). The resultant mixture was stirred at reflux for <NUM> hrs, then concentrated, the residue was purified by flash chromatography to afford compound <NUM> (<NUM>, <NUM> % yield). MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+].

To a solution of tert-butyl <NUM>-[[(<NUM>R,10aS)-<NUM>-(<NUM>-cyano-<NUM>-quinolyl)-<NUM>-methyl-<NUM>,<NUM>,<NUM>, <NUM>,<NUM>,<NUM>,<NUM>,10a-octahydropyrazino[<NUM>,<NUM>-d][<NUM>,<NUM>]diazepin-<NUM>-yl]methyl]-<NUM>,<NUM>-dihydro-<NUM>H-<NUM>,<NUM>-naphthyridine-<NUM>-carboxylate (compound <NUM>, <NUM>, <NUM>µmol) in DCM (<NUM>) was added TFA (<NUM>). The reaction mixture was stirred at room temperature for <NUM> hrs, then concentrated to afford a crude product, which was purified by pre-HPLC to afford Example <NUM> (<NUM>, <NUM> % yield). MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ ppm <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (br s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using tert-butyl <NUM>-(hydroxymethyl)-<NUM>,<NUM>-dihydro-<NUM>H-<NUM>,<NUM>-naphthyridine-<NUM>-carboxylate instead of tert-butyl <NUM>-(hydroxymethyl)-<NUM>,<NUM>-dihydro-<NUM>H-<NUM>,<NUM>-naphthyridine-<NUM>-carboxylate in step (a). Example <NUM> was obtained. MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ ppm <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using tert-butyl <NUM>-(hydroxymethyl)-<NUM>,<NUM>-dihydro-<NUM>H-<NUM>,<NUM>-naphthyridine-<NUM>-carboxylateinstead instead of tert-butyl <NUM>-(hydroxymethyl)-<NUM>,<NUM>-dihydro-<NUM>H-<NUM>,<NUM>-naphthyridine-<NUM>- carboxylate in step (a). Example <NUM> was obtained. MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ ppm <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using tert-butyl <NUM>-(bromomethyl)-<NUM>,<NUM>-dihydro-<NUM>H-isoquinoline-<NUM>-carboxylate instead of tert-butyl <NUM>-(methylsulfonyloxymethyl)-<NUM>,<NUM>-dihydro-<NUM>H-<NUM>,<NUM>- naphthyridine-<NUM>-carboxylate (compound <NUM>) in step (b). Example <NUM> was obtained. MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ ppm <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using tert-butyl <NUM>-(hydroxymethyl)-<NUM>,<NUM>-dihydro-<NUM>-isoquinoline-<NUM>-carboxylate instead of tert-butyl <NUM>-(hydroxymethyl)-<NUM>,<NUM>-dihydro-<NUM>H-<NUM>,<NUM>-naphthyridine-<NUM>-carboxylate in step (a). Example <NUM> was obtained. MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ ppm <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

To a solution of <NUM>-[(<NUM>R,10aS)-<NUM>-methyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,10a-octahydro-<NUM>H-pyrazino[<NUM>,<NUM> -d] [<NUM>,<NUM>]diazepin-<NUM>-yl]quinoline-<NUM>-carbonitrile;trihydrochloride (Intermediate C1, <NUM>, <NUM>µmol) in acetonitrile (<NUM>) was added <NUM>-bromo-<NUM>-(bromomethyl)pyrimidine (CAS: <NUM>-<NUM>-<NUM>, BePharm, Catalog: BD266661, <NUM>, <NUM>µmol) and DIPEA (<NUM>, <NUM> mmol). The mixture was stirred at reflux for <NUM> hrs. The reaction mixture was concentrated, the residue was purified by flash chromatography to afford compound <NUM> (<NUM>, <NUM> % yield). MS: calc'd <NUM>,<NUM> [(M+H)+], measured <NUM>,<NUM> [(M+H)+].

To a solution of <NUM>-[(<NUM>R,10aS)-<NUM>-[(<NUM>-bromopyrimidin-<NUM>-yl)methyl]-<NUM>-methyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>, 10a-octahydropyrazino[<NUM>,<NUM>-d][<NUM>,<NUM>]diazepin-<NUM>-yl]quinoline-<NUM>-carbonitrile (compound <NUM>, <NUM>, <NUM>µmol) in toluene (<NUM>) was added tert-butyl piperazine-<NUM>-carboxylate (<NUM>, <NUM>µmol), tBuONa (<NUM>, <NUM>µmol) and RuPhos Pd G2 (<NUM>, <NUM>µmol). The reaction mixture was stirred at <NUM> overnight. The mixture was cooled to room temperature, diluted with water (<NUM>) and extracted with EA (<NUM>) for three times. The combined organic layer was washed with brine, dried over Na<NUM>SO<NUM>, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel <NUM>, <NUM>% to <NUM>% EtOAc in PE) to afford compound <NUM> (<NUM>, <NUM> % yield). MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+].

To a solution of tert-butyl <NUM>-[<NUM>-[[(<NUM>R,10aS)-<NUM>-(<NUM>-cyano-<NUM>-quinolyl)-<NUM>-methyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>, <NUM>,10a-octahydropyrazino[<NUM>,<NUM>-d][<NUM>,<NUM>]diazepin-<NUM>-yl]methyl]pyrimidin-<NUM>-yl]piperazine-<NUM>-carboxylate (compound <NUM>, <NUM>, <NUM>µmol) in DCM (<NUM>) was added TFA (<NUM>). The reaction mixture was stirred at room temperature for <NUM> hrs, then concentrated to afford a crude product, which was purified by pre-HPLC to afford Example <NUM> (<NUM>, <NUM> % yield). MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ ppm <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

To a solution of <NUM>-[(<NUM>R,10aS)-<NUM>-methyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,10a-octahydro-<NUM>H-pyrazino[<NUM>,<NUM> -d] [<NUM>,<NUM>]diazepin-<NUM>-yl]quinoline-<NUM>-carbonitrile;trihydrochloride (Intermediate C1, <NUM>, <NUM>µmol) in acetonitrile (<NUM>) was added <NUM>-chloro-<NUM>-(chloromethyl)pyrimidine (CAS: <NUM>-<NUM>-<NUM>, BePharm, Catalog: BD223762, <NUM>, <NUM>µmol) and DIEA (<NUM>, <NUM> mmol). The mixture was stirred at reflux for <NUM> hrs, then concentrated, the residue was purified by flash chromatography to afford compound <NUM> (<NUM>, <NUM> % yield). MS: calc'd <NUM>,<NUM> [(M+H)+], measured <NUM>,<NUM> [(M+H)+].

To a <NUM> microwave vial was added <NUM>-[(<NUM>R,10aS)-<NUM>-[(<NUM>-chloropyrimidin-<NUM>-yl)methyl]-<NUM>-methyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,10a-octahydropyrazino[<NUM>,<NUM>-d][<NUM>,<NUM>]diazepin-<NUM>-yl]quinoline-<NUM>-carbonitrile (compound <NUM>, <NUM>, <NUM>µmol), tert-butyl piperazine-<NUM>-carboxylate (<NUM>, <NUM>µmol) and DIEA (<NUM>, <NUM>µl, <NUM>µmol) in acetonitrile (<NUM>). The vial was capped and heated in the microwave at <NUM> for <NUM>. The mixture was concentrated to afford compound <NUM> (<NUM>, <NUM> % yield), which was used directly to the next step. <NUM> [(M+H)+], measured <NUM> [(M+H)+].

To a solution of tert-butyl <NUM>-[<NUM>-[[(<NUM>R,10aS)-<NUM>-(<NUM>-cyano-<NUM>-quinolyl)-<NUM>-methyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>, <NUM>,10a-octahydropyrazino[<NUM>,<NUM>-d][<NUM>,<NUM>]diazepin-<NUM>-yl]methyl]pyrimidin-<NUM>-yl]piperazine-<NUM>-carboxylate (compound <NUM>, <NUM>, <NUM>µmol) in DCM (<NUM>) was added TFA (<NUM>). The reaction mixture was stirred at room temperature for <NUM> hrs, then concentrated to afford a crude product, which was purified by pre-HPLC to afford Example <NUM> (<NUM>, <NUM> % yield). MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ ppm <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using <NUM>-(Bromomethyl)-<NUM>-chloropyrazine (<NPL>, BePharm, Catalog: BD00735886) instead of <NUM>-chloro-<NUM>-(chloromethyl)pyrimidine in step (a). Example <NUM> was obtained. MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ ppm <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using <NUM>-Bromo-<NUM>-(bromomethyl)pyridine (<NPL>, BePharm, Catalog: BD162034) instead of <NUM>-bromo-<NUM>-(bromomethyl)pyrimidine in step (a). Example <NUM> was obtained. MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ ppm <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using <NUM>-Chloro-<NUM>-(chloromethyl)pyridine (<NPL>, TCI, Catalog: C1628) instead of <NUM>-bromo-<NUM>-(bromomethyl)pyrimidine in step (a). Example <NUM> was obtained. MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ ppm <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using <NUM>-Chloro-<NUM>-(chloromethyl)pyridine (<NPL>, BePharm, Catalog: BD120582) instead of <NUM>-bromo-<NUM>-(bromomethyl)pyrimidine in step (a). Example <NUM> was obtained. MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ ppm <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using <NUM>-Bromo-<NUM>-(chloromethyl)pyridine (<NPL>, BePharm, Catalog: BD223172) instead of <NUM>-bromo-<NUM>-(bromomethyl)pyrimidine in step (a). Example <NUM> was obtained. MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ ppm <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (br s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br s, <NUM>), <NUM> (br s, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using tert-butyl N-[(<NUM>R,<NUM>S)-<NUM>-fluoropyrrolidin-<NUM>-yl]carbamate (<NPL>, PharmaBlock, Catalog: PB09204) instead of tert-butyl piperazine-<NUM>-carboxylate in step (b). Example <NUM> was obtained. MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ ppm <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using tert-butyl N-[(<NUM>R)-<NUM>,<NUM>-oxazepan-<NUM>-yl]carbamate (PharmaBlock, Catalog: PB97932) instead of tert-butyl piperazine-<NUM>-carboxylate in step (b). Example <NUM> was obtained. MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ ppm <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using tert-butyl N-[(<NUM>R,<NUM>R)-<NUM>-methoxypyrrolidin-<NUM>-yl]carbamate (<NPL>, PharmaBlock, Catalog: PBZ4728) instead of tert-butyl piperazine-<NUM>-carboxylate in step (b). Example <NUM> was obtained. MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ ppm <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

To a solution of (<NUM>-bromo-<NUM>-fluoropyridin-<NUM>-yl)methanol (<NPL>, BePharm, Catalog: BD264415, <NUM>, <NUM> mmol) and DIEA (<NUM>, <NUM> mmol) in DCM (<NUM>) was added dropwise methanesulfonyl chloride (<NUM>, <NUM> mmol). The resultant mixture was stirred at room temperature for <NUM> hrs, then quenched with aq. NaHCO<NUM>, extracted with DCM(<NUM>) twice. The combined organic layer was washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated to afford compound <NUM> (<NUM>, <NUM> % yield) which was used directly for the next step without further purification. MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+].

To a solution of <NUM>-[(<NUM>R,10aS)-<NUM>-methyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,10a-octahydro-<NUM>H-pyrazino[<NUM>,<NUM>-d] [<NUM>,<NUM>]diazepin-<NUM>-yl]quinoline-<NUM>-carbonitrile;trihydrochloride (Intermediate C1, <NUM>, <NUM>µmol) in acetonitrile (<NUM>) was added (<NUM>-bromo-<NUM>-fluoropyridin-<NUM>-yl)methyl methanesulfonate (compound <NUM>, <NUM>, <NUM> mmol) and DIEA (<NUM>, <NUM> mmol). The resultant mixture was stirred at reflux for <NUM> hrs. The mixture was concentrated, the residue was purified by flash chromatography to afford compound <NUM> (<NUM>, <NUM> % yield). MS: calc'd <NUM>,<NUM> [(M+H)+], measured <NUM>,<NUM>[(M+H)+],.

To a solution of <NUM>-[(<NUM>R,10aS)-<NUM>-[(<NUM>-bromo-<NUM>-fluoro-<NUM>-pyridyl)methyl]-<NUM>-methyl - <NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,10a-octahydropyrazino[<NUM>,<NUM>-d][<NUM>,<NUM>]diazepin-<NUM>-yl]quinoline-<NUM>-carbonitrile (compound <NUM>, <NUM>, <NUM>µmol) in toluene (<NUM>) was added tert-butyl piperazine-<NUM>-carboxylate (<NUM>, <NUM>µmol), RuPhos Pd G2 (<NUM>, <NUM>µmol) and tBuONa (<NUM>, <NUM>µmol). The resultant mixture was stirred at <NUM> overnight. Then the mixture was cooled to room temperature, diluted with water (<NUM>) and extracted with EA (<NUM>) for three times. The combined organic layer was washed with brine, dried over Na<NUM>SO<NUM>, filtered and concentrated in vacuo. The residue was purified by flash chromatography to afford compound <NUM> (<NUM>, <NUM> % yield). <NUM> [(M+H)+], measured <NUM>[(M+H)+].

To a solution of tert-butyl <NUM>-[<NUM>-[[(<NUM>R,10aS)-<NUM>-(<NUM>-cyano-<NUM>-quinolyl)-<NUM>-methyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>, <NUM>,10a-octahydropyrazino[<NUM>,<NUM>-d][<NUM>,<NUM>]diazepin-<NUM>-yl]methyl]-<NUM>-fluoro-<NUM>-pyridyl]piperazine-<NUM>-carboxylate (compound <NUM>, <NUM>, <NUM>µmol) in DCM (<NUM>) was added TFA (<NUM>). The reaction mixture was stirred at room temperature for <NUM> hrs, then concentrated to afford a crude product, which was purified by pre-HPLC to afford Example <NUM> (<NUM>, <NUM> % yield). MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ ppm <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using tert-butyl N-[(<NUM>R,<NUM>R)-<NUM>-methoxypyrrolidin-<NUM>-yl]carbamate (<NPL>, PharmaBlock, Catalog: PBZ4728) instead of tert-butyl piperazine-<NUM>-carboxylate in step (c). Example <NUM> was obtained. MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ ppm <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J= <NUM>, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using <NUM>-[(<NUM>R,10aS)-<NUM>-methyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,10a-octahydro-<NUM>H-pyrazino[<NUM>,<NUM>-d][<NUM>,<NUM>]diazepin-<NUM>-yl]pyrazolo[<NUM>,<NUM>-a]pyridine-<NUM>-carbonitrile;trihydrochloride (Intermediate C3) instead of <NUM>-[(<NUM>R,10aS)-<NUM>-methyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,10a-octahydro-<NUM>H-pyrazino[<NUM>,<NUM>-d][<NUM>,<NUM>]diazepin-<NUM>-yl]quinoline-<NUM>-carbonitrile;trihydrochloride (Intermediate C1) in step (a) and tert-butyl N-[(<NUM>R,<NUM>R)-<NUM>-methoxypyrrolidin-<NUM>-yl]carbamate instead of tert-butyl piperazine-<NUM>-carboxylate in step (b). Example <NUM> was obtained. MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ ppm <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using <NUM>-[(<NUM>R,10aS)-<NUM>-methyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,10a-octahydro-<NUM>H-pyrazino[<NUM>,<NUM>-d][<NUM>,<NUM>]diazepin-<NUM>-yl]pyrazolo[<NUM>,<NUM>-a]pyridine-<NUM>-carbonitrile;trihydrochloride (Intermediate C3) instead of <NUM>-[(<NUM>R,10aS) -<NUM>-methyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,10a-octahydro-<NUM>H-pyrazino[<NUM>,<NUM>-d][<NUM>,<NUM>]diazepin-<NUM>-yl]quinoline-<NUM>-carbonitrile;trihydrochloride (Intermediate C1) in step (a). Example <NUM> was obtained. MS: calc'd <NUM> [(M+H)+], measured <NUM>[(M+H)+]. <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ ppm <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using <NUM>-[(<NUM>R,10aS)-<NUM>-methyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,10a-octahydro-<NUM>H-pyrazino[<NUM>,<NUM>-d][<NUM>,<NUM>]diazepin-<NUM>-yl]-<NUM>-fluoro-pyrazolo[<NUM>,<NUM>-a]pyridine-<NUM>-carbonitrile;trihydrochloride (Intermediate C4) instead of <NUM>-[(<NUM>R,10aS)-<NUM>-methyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,10a-octahydro-<NUM>H-pyrazino[<NUM>,<NUM>-d][<NUM>,<NUM>]diazepin-<NUM>-yl]quinoline-<NUM>-carbonitrile;trihydrochloride (Intermediate C1) in step (a). Example <NUM> was obtained. MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ ppm <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using <NUM>-[(<NUM>R,10aS)-<NUM>-methyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,10a-octahydro-<NUM>H-pyrazino[<NUM>,<NUM>-d][<NUM>,<NUM>]diazepin-<NUM>-yl]-<NUM>-methyl-<NUM>,<NUM>-naphthyridin-<NUM>-one;trihydrochloride (Intermediate C2) instead of <NUM>-[(<NUM>R,10aS)-<NUM>-methyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,10a-octahydro-<NUM>H-pyrazino[<NUM>,<NUM>-d][<NUM>,<NUM>]diazepin-<NUM>-yl]quinoline-<NUM>-carbonitrile;trihydrochloride (Intermediate C1) in step (a). Example <NUM> was obtained. MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ ppm <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br s, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

The following tests were carried out in order to determine the activity of the compounds of formula (I), (Ia) or (Ib) in HEK293-Blue-hTLR-<NUM>/<NUM>/<NUM> cells assay.

A stable HEK293-Blue-hTLR-<NUM> cell line was purchased from InvivoGen (Cat. #: hkb-htlr7, San Diego, California, USA). These cells were originally designed for studying the stimulation of human TLR7 by monitoring the activation of NF-κB. A SEAP (secreted embryonic alkaline phosphatase) reporter gene was placed under the control of the IFN-β minimal promoter fused to five NF-κB and AP-<NUM>-binding sites. The SEAP was induced by activating NF-κB and AP-<NUM> via stimulating HEK-Blue hTLR7 cells with TLR7 ligands. Therefore the reporter expression was declined by TLR7 antagonist under the stimulation of a ligand, such as R848 (Resiquimod), for incubation of <NUM> hrs. The cell culture supernatant SEAP reporter activity was determined using QUANTI-Blue™ kit (Cat. #: rep-qb1, Invivogen, San Diego, Ca, USA) at a wavelength of <NUM>, a detection medium that turns purple or blue in the presence of alkaline phosphatase.

HEK293-Blue-hTLR7 cells were incubated at a density of <NUM>,<NUM>-<NUM>,<NUM> cells/mL in a volume of <NUM>µL in a <NUM>-well plate in Dulbecco's Modified Eagle's medium (DMEM) containing <NUM>/L glucose, <NUM> U/mL penicillin, <NUM>/mL streptomycin, <NUM>/mL Normocin, <NUM> L-glutamine, <NUM>% (v/v) heat-inactivated fetal bovine serum with addition of <NUM>µL test compound in a serial dilution in the presence of final DMSO at <NUM>% and <NUM>µL of <NUM> R848 in above DMEM, perform incubation under <NUM> in a CO<NUM> incubator for <NUM> hrs. Then <NUM>µL of the supernatant from each well was incubated with <NUM>µL Quanti-blue substrate solution at <NUM> for <NUM> hrs and the absorbance was read at <NUM>-<NUM> using a spectrophotometer. The signaling pathway that TLR7 activation leads to downstream NF-κB activation has been widely accepted, and therefore similar reporter assay was modified for evaluating TLR7 antagonist.

A stable HEK293-Blue-hTLR-<NUM> cell line was purchased from InvivoGen (Cat. #: hkb-htlr8, San Diego, California, USA). These cells were originally designed for studying the stimulation of human TLR8 by monitoring the activation of NF-κB. A SEAP (secreted embryonic alkaline phosphatase) reporter gene was placed under the control of the IFN-β minimal promoter fused to five NF-κB and AP-<NUM>-binding sites. The SEAP was induced by activating NF-κB and AP-<NUM> via stimulating HEK-Blue hTLR8 cells with TLR8 ligands. Therefore the reporter expression was declined by TLR8 antagonist under the stimulation of a ligand, such as R848, for incubation of <NUM> hrs. The cell culture supernatant SEAP reporter activity was determined using QUANTI-Blue™ kit (Cat. #: rep-qb1, Invivogen, San Diego, Ca, USA) at a wavelength of <NUM>, a detection medium that turns purple or blue in the presence of alkaline phosphatase.

HEK293-Blue-hTLR8 cells were incubated at a density of <NUM>,<NUM>-<NUM>,<NUM> cells/mL in a volume of <NUM>µL in a <NUM>-well plate in Dulbecco's Modified Eagle's medium (DMEM) containing <NUM>/L glucose, <NUM> U/mL penicillin, <NUM>/mL streptomycin, <NUM>/mL Normocin, <NUM> L-glutamine, <NUM>% (v/v) heat-inactivated fetal bovine serum with addition of <NUM>µL test compound in a serial dilution in the presence of final DMSO at <NUM>% and <NUM>µL of <NUM> R848 in above DMEM, perform incubation under <NUM> in a CO<NUM> incubator for <NUM> hrs. Then <NUM>µL of the supernatant from each well was incubated with <NUM>µL Quanti-blue substrate solution at <NUM> for <NUM> hrs and the absorbance was read at <NUM>-<NUM> using a spectrophotometer. The signaling pathway that TLR8 activation leads to downstream NF-κB activation has been widely accepted, and therefore similar reporter assay was modified for evaluating TLR8 antagonist.

A stable HEK293-Blue-hTLR-<NUM> cell line was purchased from InvivoGen (Cat. #: hkb-htlr9, San Diego, California, USA). These cells were originally designed for studying the stimulation of human TLR9 by monitoring the activation of NF-xB. A 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-<NUM>-binding sites. The SEAP was induced by activating NF-κB and AP-<NUM> via stimulating HEK-Blue hTLR9 cells with TLR9 ligands. Therefore the reporter expression was declined by TLR9 antagonist under the stimulation of a ligand, such as ODN2006 (Cat. #: tlrl-<NUM>-<NUM>, Invivogen, San Diego, California, USA), for incubation of <NUM> hrs. The cell culture supernatant SEAP reporter activity was determined using QUANTI-Blue™ kit (Cat. #: rep-qb1, Invivogen, San Diego, California, USA) at a wavelength of <NUM>, a detection medium that turns purple or blue in the presence of alkaline phosphatase.

HEK293-Blue-hTLR9 cells were incubated at a density of <NUM>,<NUM>-<NUM>,<NUM> cells/mL in a volume of <NUM>µL in a <NUM>-well plate in Dulbecco's Modified Eagle's medium (DMEM) containing <NUM>/L glucose, <NUM> U/mL penicillin, <NUM>/mL streptomycin, <NUM>/mL Normocin, <NUM> L-glutamine, <NUM>% (v/v) heat-inactivated fetal bovine serum with addition of <NUM>µL test compound in a serial dilution in the presence of final DMSO at <NUM>% and <NUM>µL of <NUM> ODN2006 in above DMEM, perform incubation under <NUM> in a CO<NUM> incubator for <NUM> hrs. Then <NUM>µL of the supernatant from each well was incubated with <NUM>µL Quanti-blue substrate solution at <NUM> for <NUM> and the absorbance was read at <NUM>-<NUM> using a spectrophotometer. The signaling pathway that TLR9 activation leads to downstream NF-κB activation has been widely accepted, and therefore similar reporter assay was modified for evaluating TLR9 antagonist.

The compounds of formula (I) have TLR7 and/or TLR8 inhibitory activities (IC<NUM> value) <<NUM>. Moreover, most compounds also have TLR9 inhibitory activity <<NUM>. Activity data of the compounds of the present invention were shown in Table <NUM>.

Human liver microsomes (Cat. : <NUM>, Corning, USA) were preincubated with test compound for <NUM> minutes at <NUM> in <NUM> potassium phosphate buffer, pH <NUM>. The reactions were initiated by adding NADPH regenerating system. The final incubation mixtures contained <NUM> test compound, <NUM>/mL liver microsomal protein, <NUM> MgCl<NUM>, <NUM> NADP, <NUM> unit/mL isocitric dehydrogenase and <NUM> isocitric acid in <NUM> potassium phosphate buffer, pH <NUM>. After incubation times of <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM> minutes at <NUM>, <NUM>µL of cold ACN (including internal standard) was added to <NUM>µL incubation mixture to terminate the reaction. Following precipitation and centrifugation, 100uL supernatant will be taken out and added 300uL water. The amount of compound remaining in the samples was determined by LC-MS/MS. Controls of no NADPH regenerating system at zero and <NUM> minutes were also prepared and analyzed. The results were categorized as: low (<<NUM>/min/kg), medium (<NUM>-<NUM>/min/kg) and high (<NUM>-<NUM>/min/kg). Test results were summarized in Table <NUM>.

The hERG channel inhibition assay is a highly sensitive measurement that identifies compounds exhibiting hERG inhibition related to cardiotoxicity in vivo. The hERG K+ channels were cloned in humans and stably expressed in a CHO ( Chinese hamster ovary) cell line. CHOhERG cells were used for patch-clamp (voltage-clamp, whole-cell) experiments. Cells were stimulated by a voltage pattern to activate hERG channels and conduct IKhERG currents (rapid delayed outward rectifier potassium current of the hERG channel). After the cells were stabilized for a few minutes, the amplitude and kinetics of IKhERG were recorded at a stimulation frequency of <NUM> (<NUM> bpm). Thereafter, the test compound was added to the preparation at increasing concentrations. For each concentration, an attempt was made to reach a steady-state effect, usually, this was achieved within <NUM>-<NUM> at which time the next highest concentration was applied. The amplitude and kinetics of IKhERG are recorded in each concentration of the drug which were compared to the control values (taken as <NUM>%). (references: <NPL>, <NPL>, <NPL>). Results of hERG are given in Table <NUM>.

Claim 1:
A compound of formula (I),
<CHM>
wherein
R<NUM> is
<CHM>
<CHM>
<CHM>
wherein R<NUM> is C<NUM>-<NUM>alkyl, C<NUM>-<NUM>alkoxy, haloC<NUM>-<NUM>alkyl, halogen, nitro or cyano; R4a is C<NUM>-<NUM>alkyl or C<NUM>-<NUM>cycloalkyl; R<NUM>, R5a and R5b are independently selected from H and deuterium; R<NUM> is H or halogen;
R<NUM> is C<NUM>-<NUM>alkyl;
R<NUM> is <NUM>,<NUM>,<NUM>,<NUM>-tetrahydroisoquinolinyl;
<NUM>,<NUM>,<NUM>,<NUM>-tetrahydro-<NUM>,<NUM>-naphthyridinyl;
<NUM>, <NUM>, <NUM>, <NUM>-tetrahydro-<NUM>, <NUM>-naphthyri dinyl;
<NUM>,<NUM>,<NUM>,<NUM>-tetrahydro-<NUM>,<NUM>-naphthyridinyl;
<NUM>,<NUM>,<NUM>,<NUM>-tetrahydro-<NUM>,<NUM>-naphthyridinyl;
phenyl substituted by morpholinyl;
pyrazinyl substituted by piperazinyl;
pyridinyl which is substituted by one or two substituents independently selected from halogen, piperazinyl, aminohalopyrrolidinyl, amino-<NUM>,<NUM>-oxazepanyl and amino(C<NUM>-<NUM>alkoxy)pyrrolidinyl; or
pyrimidinyl substituted by piperazinyl or amino(C<NUM>-<NUM>alkoxy)pyrrolidinyl;
n is <NUM>, <NUM> or <NUM>;
or a pharmaceutically acceptable salt thereof.