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> discloses polycyclic TLR7/<NUM> antagonists for the treatment of immune disorders.

Any references to methods of treatment in the subsequent paragraphs of this description are to be interpreted as references to the compounds, pharmaceutical compositions and medicaments of the present invention for use in a method for treatment of the human (or animal) body by therapy (or for diagnosis).

The present invention relates to novel compounds of formula (I) and (Ia),
<CHM>
wherein.

Another object of the present invention is related to novel compounds of formula (I) or (Ia) or (Ib), 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) or (Ib) 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) or (Ib) show superior TLR7 and/or TLR8 and/or TLR9 antagonism activity. In addition, the compounds of formula (I) or (Ia) or (Ib) also show good hPBMC, cytotoxicity, solubility, 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 "C<NUM>-<NUM>cycloalkyl" denotes a saturated carbon ring containing from <NUM> to <NUM> carbon atoms, particularly from <NUM> to <NUM> carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Particular "C<NUM>-<NUM>cycloalkyl" groups are cyclopropyl, cyclopentyl and cyclohexyl.

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

The term "C<NUM>-<NUM>alkoxy" denotes C<NUM>-<NUM>alkyl-O-.

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 "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; <NUM>-oxo-3a,<NUM>,<NUM>,<NUM>,<NUM>,7a-hexahydro-<NUM>-pyrrolo[<NUM>,<NUM>-c]pyridin-<NUM>-yl; <NUM>-oxo-3a,<NUM>,<NUM>,<NUM>,<NUM>,7a-hexahydro-<NUM>-pyrrolo[<NUM>,<NUM>-c]pyridin-<NUM>-yl; <NUM>-oxo-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,8a-hexahydroimidazo[<NUM>,<NUM>-a]pyrazin-<NUM>-yl. Examples of heterocyclyl can be further substituted by C<NUM>-<NUM>alkyl, C<NUM>-<NUM>cycloalkyl, halogen, hydroxy, aminoC<NUM>-<NUM>alkylcarbonyl, C<NUM>-<NUM>alkylpyrrolidinylcarbonyl oxo or C<NUM>-<NUM>alkoxy.

The term "heterocyclylamino" denotes heterocyclyl-NH-.

The term "heterocyclylC<NUM>-<NUM>alkylamino" denotes heterocyclyl-C<NUM>-<NUM>alkyl-NH-.

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.

A further embodiment of present invention is (ii) a compound of formula (I) according to (i), wherein R<NUM> is
<CHM>
wherein R<NUM> is cyano, R<NUM> is H or deuterium.

A further embodiment of present invention is (iii) a compound of formula (I) according to (i) or (ii), wherein R<NUM> is (aminoC<NUM>-<NUM>alkylcarbonyl)-<NUM>,<NUM>-diazabicyclo[<NUM>. <NUM>]heptanyl; (aminoC<NUM>-<NUM>alkylcarbonyl)piperazinyl; (C<NUM>-<NUM>alkoxypyrrolidinyl)amino; (C<NUM>-<NUM>alkyl)<NUM>aminoC<NUM>-<NUM>alkoxy; (C<NUM>-<NUM>alkylpyrrolidinylcarbonyl)piperazinyl; (halopyrrolidinyl)amino; (hydroxypyrrolidinyl)C<NUM>-<NUM>alkylamino; (morpholinyl)C<NUM>-<NUM>alkylamino; <NUM>-oxo-3a,<NUM>,<NUM>,<NUM>,<NUM>,7a-hexahydro-<NUM>-pyrrolo[<NUM>,<NUM>-c]pyridinyl; <NUM>,<NUM>,4a,<NUM>,<NUM>,7a-hexahydro-<NUM>-pyrrolo[<NUM>,<NUM>-b][<NUM>,<NUM>]oxazinyl; <NUM>-oxo-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,8a-hexahydroimidazo[<NUM>,<NUM>-a]pyrazinyl; <NUM>-oxo-3a,<NUM>,<NUM>,<NUM>,<NUM>,7a-hexahydro-<NUM>-pyrrolo[<NUM>,<NUM>-c]pyridinyl; amino(C<NUM>-<NUM>alkoxy)pyrrolidinyl; amino-<NUM>,<NUM>-oxazepanyl; aminohalopyrrolidinyl; aminooxopyrrolidinyl or azetidinylC<NUM>-<NUM>alkoxy.

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

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

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

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

A further embodiment of present invention is (viii) a compound formula (I) or (Ia) or (Ib) according to any one of (i) to (vii), or a pharmaceutically acceptable salt thereof, wherein R3b is (<NUM>-amino-<NUM>-methyl-propanoyl)-<NUM>,<NUM>-diazabicyclo[<NUM>. <NUM>]heptan-<NUM>-yl; (<NUM>-amino-<NUM>-methylpropanoyl)piperazin-<NUM>-yl; (<NUM>-methylpyrrolidine-<NUM>-carbonyl)piperazin-<NUM>-yl; (<NUM>-fluoropyrrolidin-<NUM>-yl)amino; (<NUM>-methoxypyrrolidin-<NUM>-yl)amino; (azetidin-<NUM>-yl)methoxy; <NUM>-oxo-3a,<NUM>,<NUM>,<NUM>,<NUM>,7a-hexahydro-<NUM>-pyrrolo[<NUM>,<NUM>-c]pyridin-<NUM>-yl; <NUM>-(dimethylamino)ethoxy; <NUM>,<NUM>,4a,<NUM>,<NUM>,7a-hexahydro-<NUM>-pyrrolo[<NUM>,<NUM>-b][<NUM>,<NUM>]oxazin-<NUM>-yl; <NUM>-amino-<NUM>-fluoro-pyrrolidin-<NUM>-yl; <NUM>-amino-<NUM>-methoxy-pyrrolidin-<NUM>-yl; <NUM>-oxo-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,8a-hexahydroimidazo[<NUM>,<NUM>-a]pyrazin-<NUM>-yl; <NUM>-oxo-3a,<NUM>,<NUM>,<NUM>,<NUM>,7a-hexahydro-<NUM>-pyrrolo[<NUM>,<NUM>-c]pyridin-<NUM>-yl or <NUM>-amino-<NUM>-oxo-pyrrolidin-<NUM>-yl.

A further embodiment of present invention is (ix) a compound of formula (I) or (Ia) or (Ib) according to any one of (i) to (viii), or a pharmaceutically acceptable salt thereof, wherein R3b is (C<NUM>-<NUM>alkylpyrrolidinylcarbonyl)piperazinyl; <NUM>,<NUM>,4a,<NUM>,<NUM>,7a-hexahydro-<NUM>-pyrrolo[<NUM>,<NUM>-b][<NUM>,<NUM>]oxazinyl; <NUM>-oxo-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,8a-hexahydroimidazo[<NUM>,<NUM>-a]pyrazinyl or azetidinylC<NUM>-<NUM>alkoxy.

A further embodiment of present invention is (x) a compound of formula (I) or (Ia) or (Ib) according to any one of (i) to (ix), wherein R3b is (<NUM>-methylpyrrolidine-<NUM>-carbonyl)piperazin-<NUM>-yl; <NUM>,<NUM>,4a,<NUM>,<NUM>,7a-hexahydro-<NUM>-pyrrolo[<NUM>,<NUM>-b][<NUM>,<NUM>]oxazin-<NUM>-yl; <NUM>-oxo-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,8a-hexahydroimidazo[<NUM>,<NUM>-a]pyrazin-<NUM>-yl or (azetidin-<NUM>-yl)methoxy.

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

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

Another embodiment of present invention is that (xiii) compounds of formula (I) or (Ia) or (Ib) are 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> to 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.

A general synthetic route for preparing the compound of formula (I) is shown in Scheme <NUM> below. <CHM>
wherein X and Y are halogen or leaving group, for example, OTf or OMs; R<NUM> is protecting group, for example, Boc or benzyl.

After R<NUM> is removed from compound of formula (II) by selective deprotection, the resulting compound of formula (III) can react with compound of formula (IV) to afford compound of formula (V) by nucleophilic aromatic substitution in the presence of a base, such as DIEPA, or Buchwald-Hartwig amination conditions (e.g. heating with halide (IV) in the presence of a catalyst, such as Ruphos Pd-G2, and a base, such as Cs<NUM>CO<NUM>. Compound of formula (I) or (Ia) or (Ib) can be obtained from the reaction of compound of formula (V) and R<NUM>-H (R<NUM>-H can be an amine or an alcohol) via metal catalyzed coupling conditions: Buchwald-Hartwig amination in the presence of a catalyst, such as Ruphos Pd-G2, and a base, such as Cs<NUM>CO<NUM>; Suzuki coupling with R<NUM>-boronic acid, R<NUM>-boronic ester, in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(<NUM>) or [<NUM>,<NUM>'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane and a base, such as potassium carbonate in solvent; Stille coupling with organotin reagent, in the presence of a palladium(<NUM>) catalyst, such as tetrakis(triphenylphosphine)palladium(<NUM>); or Negishi coupling with organozinc reagent in the presence of a palladium(<NUM>) catalyst, such as tetrakis(triphenylphosphine)palladium(<NUM>) or [<NUM>,<NUM>'-bis(diphenylphosphino)ferrocene] dichloropalladium (II). In some embodiment, a protecting group, e.g. Boc, will be removed and may be further modified by amide formation reactions before affording the final compound of formula (I) or (Ia) or (Ib).

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. In another embodiment, compound of formula (Ia) or (Ib) can be obtained according to above scheme by using corresponding 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), (Ia) comprising the following step:.

A compound of formula (I) or (Ia) or (Ib) when manufactured according to the above process with achiral or chiral starting materials is also an object of the invention.

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-SIL <NUM>Å, particle size: <NUM>-<NUM>; ii) CAS registry NO: Silica Gel: <NUM>-<NUM>-<NUM>, 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):.

Mass spectra (MS): generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion (MH)+.

NMR Spectra were obtained using Bruker Avance <NUM>.

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> 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 A2 (<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 A2, <NUM>, <NUM> mmol) in DMF (<NUM>) was added dicyanozinc (<NUM>, <NUM> mmol) and RuPhos Pd G2 (<NPL>, 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>).

To a solution of methyl (S)-<NUM>-amino-<NUM>-(<NUM>-bromophenyl)propanoate hydrochloride (<NPL>, Bidepharm, Catalog: BD00815750) (compound B1, <NUM>, <NUM> mmol) in DCM (<NUM>) was added pyridine (<NUM>, <NUM>, <NUM> mmol) and methyl carbonochloridate (<NUM>, <NUM> mmol). The reaction mixture was stirred at room temperature overnight, then the mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with NaHCO<NUM> aqueous solution, <NUM>N HCl aqueous solution and brine respectively. The organic layer was dried over MgSO<NUM>, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatograph on a silica gel column using <NUM>% Ethyl acetate in hexane to afford the compound B2 (<NUM>, <NUM> % yield). MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+].

To a mixture of methyl (S)-<NUM>-(<NUM>-bromophenyl)-<NUM>-((methoxycarbonyl)amino)propanoate (compound B2, <NUM>, <NUM> mmol) and paraformaldehyde (<NUM>, <NUM> mmol) was added a mixture of concentrated sulfuric acid (<NUM>) and acetic acid (<NUM>). The resultant mixture was stirred at room temperature for <NUM> hrs. The reaction mixture was poured into ice-water, and extracted with DCM. The organic layer was washed with water, saturated NaHCO<NUM> aqueous solution and brine respectively, dried with MgSO<NUM>. After filtration, the filtrate was concentrated and the residue was purified by flash chromatography (silica gel, <NUM>, <NUM>% to <NUM>% EtOAc in hexanes) to afford compound B3 (<NUM>, <NUM> % yield). MS: calc'd <NUM> [(M+H)+], measured <NUM>[(M+H)+].

To a solution of dimethyl (S)-<NUM>-bromo-<NUM>,<NUM>-dihydroisoquinoline-<NUM>,<NUM>(<NUM>H)-dicarboxylate (compound B3, <NUM>, <NUM> mmol) in DCM (<NUM>) was added iodotrimethylsilane (<NUM>, <NUM> mmol). The resultant mixture was stirred at <NUM> for <NUM> hrs. After being cooled to room temperature, methanol (<NUM>) was added, then the reaction mixture was stirred for additional <NUM>. The reaction mixture was concentrated in vacuo, the residue was diluted with diethyl ether and filtered. The collected solid was washed with ether, dried under vacuum to afford compound B4 (<NUM>, <NUM> % yield) which was directly used in the next step without further purification. MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+].

To a solution of methyl (S)-<NUM>-bromo-<NUM>,<NUM>,<NUM>,<NUM>-tetrahydroisoquinoline-<NUM>-carboxylate (compound B4, <NUM>, <NUM> mmol) and tert-butyl (<NUM>-oxopropyl)carbamate (<NUM>, <NUM> mmol) in methanol (<NUM>) was added <NUM> HOAc. After the resultant mixture was stirred at reflux for <NUM> hrs, NaBH<NUM>CN (<NUM>, <NUM> mmol) was added. Then the reaction mixture was stirred at reflux overnight. After the mixture being cooled to room temperature, diluted with water (<NUM>), 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. 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>-bromo-<NUM>-[<NUM>-(tert-butoxycarbonylamino)-<NUM>-methyl-ethyl]-<NUM>,<NUM>-dihydro-<NUM>-isoquinoline-<NUM>-carboxylate (compound B5, <NUM>, <NUM> mmol) and HCl/MeOH (<NUM>% W/W; <NUM>) was stirred at <NUM> overnight. After being cooled to room temperature, the reaction mixture was basified with sat. K<NUM>CO<NUM> (aq) to pH about <NUM>, and extracted with EA (<NUM>) for three times. The combined organic layer was washed with brine (<NUM>), dried over Na<NUM>SO<NUM> and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, <NUM>, <NUM>% to <NUM>% MeOH in DCM) to afford compound B6 (<NUM>, <NUM> % yield). MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+].

A mixture of (11aS)-<NUM>-bromo-<NUM>-methyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,11a-hexahydropyrazino[<NUM>,<NUM>-b] isoquinolin-<NUM>-one (compound B6, <NUM>, <NUM> mmol) and BH<NUM> solution (<NUM> in THF, <NUM>, <NUM> mmol) was heated at <NUM> with stirring on for <NUM> hrs. HCl solution (<NUM> N, <NUM>) was added slowly to the reaction mixture at <NUM>. After being stirred at <NUM> for <NUM> hrs, the mixture was cooled to room temperature, basified with <NUM> N NaOH solution (aq) to pH <NUM>, and extracted with EtOAc twice. The combined organic layer was dried over MgSO<NUM>, filtered and concentrated in vacuo to afford compound B7 (<NUM>, <NUM> % yield). MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+].

To a solution of (11aS)-<NUM>-bromo-<NUM>-methyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,11a-hexahydro-<NUM>H-pyrazino[<NUM>,<NUM>-b] isoquinoline (compound B7, <NUM>, <NUM> mmol) in DMSO (<NUM>) was added <NUM>-fluoroquinoline-<NUM>-carbonitrile (Intermediate A, <NUM>, <NUM> mmol) and DIEA (<NUM>, <NUM>, <NUM> mmol). The resultant mixture was stirred at <NUM> for <NUM> hrs. After being cooled to room temperature, the reaction was diluted with water (<NUM>) and extracted with EA (<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>% EtOAc in PE) to afford Intermediate B (<NUM>, <NUM> % yield) and compound B8 (<NUM>, <NUM> % yield). The stereochemistry was confirmed by NOESY.

Intermediate B 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> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <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> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

compound B8 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> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m,<NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>).

The title compound was prepared in analogy to the preparation of Intermediate B by using methyl (S)-<NUM>-amino-<NUM>-(<NUM>-bromophenyl)propanoate hydrochloride (<NPL>, Bidepharm, Catalog: BD00869561) instead of methyl (S)-<NUM>-amino-<NUM>-(<NUM>-bromophenyl)propanoate hydrochloride in step (a). Intermediate C was obtained. MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (CHLOROFORM-d, <NUM>) δ <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (br s, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, <NUM>, J=<NUM>). The stereochemistry was confirmed by NOESY.

To a solution of tert-butyl N-(<NUM>,<NUM>-oxazepan-<NUM>-yl)carbamate (<NPL>, PharmaBlock, Catalog: PB95734, <NUM>, <NUM>µmol) in dioxane (<NUM>) was added <NUM>-((<NUM>R,11aS)-<NUM>-bromo-<NUM>-methyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,11a-hexahydro-<NUM>H-pyrazino[<NUM>,<NUM>-b]isoquinolin-<NUM>-yl)quinoline-<NUM>-carbonitrile (Intermediate B1, <NUM>, <NUM>µmol), tBuONa (<NUM>, <NUM>µmol) and tBuXPhos Pd G3 (<NPL>, Sigma-Aldrich, Catalog: <NUM>, <NUM>, <NUM>µmol). The resultant mixture was stirred at <NUM> overnight. After being 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 N-[<NUM>-[(<NUM>R,11aS)-<NUM>-(<NUM>-cyano-<NUM>-quinolyl)-<NUM>-methyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,11a-hexahydropyrazino[<NUM>,<NUM>-b]isoquinolin-<NUM>-yl]-<NUM>,<NUM>-oxazepan-<NUM>-yl]carbamate (compound <NUM>, <NUM> mg, <NUM>µmol ) in DCM (<NUM>) was added TFA (<NUM>). The reaction mixture was stirred at room temperature for <NUM>, then concentrated to afford a crude product, which was purified by prep-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> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <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>-(<NUM>-aminoethyl)pyrrolidin-<NUM>-ol (<NPL>, Bide Pharmatech, Catalog: BD45313) instead of tert-butyl N-(<NUM>,<NUM>-oxazepan-<NUM>-yl)carbamate 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> - <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> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br 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 tert-butyl (<NUM>)-<NUM>-(aminomethyl)morpholine-<NUM>-carboxylate (<NPL>, PharmaBlock, Catalog: PBN20121306) instead of tert-butyl N-(<NUM>,<NUM>-oxazepan-<NUM>-yl)carbamate 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> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br d, J = <NUM>, <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>R)-<NUM>-amino-<NUM>-fluoro-pyrrolidine-<NUM>-carboxylate (<NPL> PharmaBlock, Catalog: PB07374) instead of tert-butyl N-(<NUM>,<NUM>-oxazepan-<NUM>-yl)carbamate 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> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <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>-(dimethylamino)ethanol (<NPL> Sigma-Aldrich, Catalog: <NUM>) instead of tert-butyl N-(<NUM>,<NUM>-oxazepan-<NUM>-yl)carbamate 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> - <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> (s, <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>R,<NUM>S)-<NUM>-amino-<NUM>-fluoro-pyrrolidine-<NUM>-carboxylate (<NPL>, PharmaBlock, Catalog: PB07375) instead of tert-butyl N-(<NUM>,<NUM>-oxazepan-<NUM>-yl)carbamate and <NUM>-[(4R,11aS)-<NUM>-bromo-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>-hexamethyl-<NUM>,<NUM>,<NUM>,11a-tetrahydro-<NUM>H-pyrazino[<NUM>,<NUM>-b]isoquinolin-<NUM>-yl]quinoline-<NUM>-carbonitrile (Intermediate C) instead of <NUM>-[(4R,11aS)-<NUM>-bromo-<NUM>-methyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,11a-hexahydropyrazino[<NUM>,<NUM>-b]isoquinolin-<NUM>-yl]quinoline-<NUM>-carbonitrile (Intermediate B) in step (a). Example <NUM> was obtained. MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (METHANOL-d<NUM>, <NUM>) δ <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (br d, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (br d, <NUM>, J=<NUM>), <NUM> (br t, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, <NUM>, J=<NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using tert-butyl (<NUM>R,<NUM>)-<NUM>-amino-<NUM>-methoxy-pyrrolidine-<NUM>-carboxylate (<NPL>, BePharm, Catalog: BD285562) instead of tert-butyl (<NUM>R,<NUM>S)-<NUM>-amino-<NUM>-fluoro-pyrrolidine-<NUM>-carboxylate in step (a). Example <NUM> was obtained. MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (METHANOL-d<NUM>, <NUM>) δ <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (br d, <NUM>, J=<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> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, <NUM>, J=<NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using tert-butyl N-[(<NUM>,4R)-<NUM>-fluoropyrrolidin-<NUM>-yl]carbamate (<NPL>, PharmaBlock, Catalog: PB09206) instead of tert-butyl (<NUM>R,<NUM>S)-<NUM>-amino-<NUM>-fluoro-pyrrolidine-<NUM>-carboxylate in step (a). Example <NUM> was obtained. MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (METHANOL-d<NUM>, <NUM>) δ ppm <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<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> (br d, <NUM>, J=<NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using tert-butyl N-[(<NUM>R,<NUM>S)-<NUM>-methoxypyrrolidin-<NUM>-yl]carbamate (<NPL> PharmaBlock, Catalog: PBZ4729) instead of tert-butyl (<NUM>R,<NUM>S)-<NUM>-amino-<NUM>-fluoro-pyrrolidine-<NUM>-carboxylate in step (a). Example <NUM> was obtained. MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (METHANOL-d<NUM>, <NUM>) δ <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<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> (dd, <NUM>, J=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using tert-butyl (4aR,7aR)-<NUM>,4a,<NUM>,<NUM>,<NUM>,7a-hexahydro-<NUM>H-pyrrolo[<NUM>,<NUM>-b][<NUM>,<NUM>]oxazine-<NUM>-carboxylate (<NPL>, PharmaBlock, Catalog: PBXA8123) instead of tert-butyl (<NUM>R,<NUM>S)-<NUM>-amino-<NUM>-fluoro-pyrrolidine-<NUM>-carboxylate in step (a). Example <NUM> was obtained. MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (METHANOL-d<NUM>, <NUM>) δ <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (br d, <NUM>, J=<NUM> Hz), <NUM> (br d, <NUM>, J=<NUM> Hz), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, <NUM>, J=<NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using <NUM>-(dimethylamino)ethanol instead of tert-butyl (<NUM>R,<NUM>S)-<NUM>-amino-<NUM>-fluoro-pyrrolidine-<NUM>-carboxylate in step (a). Example <NUM> was obtained. MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (METHANOL-d<NUM>, <NUM>) δ <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (br d, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (br t, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (br d, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (br dd, <NUM>, J=<NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, <NUM>, J=<NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using tert-butyl (<NUM>S)-<NUM>-(hydroxymethyl)azetidine-<NUM>-carboxylate (<NPL>, PharmaBlock, Catalog: PB03034) instead of tert-butyl (<NUM>R,<NUM>S)-<NUM>-amino-<NUM>-fluoro-pyrrolidine-<NUM>-carboxylate in step (a). Example <NUM> was obtained. MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (METHANOL-d<NUM>, <NUM>) δ <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (br d, <NUM>, J=<NUM>), <NUM> (br d, <NUM>, J=<NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, <NUM>, J=<NUM>).

To a solution of tert-butyl piperazine-<NUM>-carboxylate (<NUM>, <NUM>µmol) in dioxane (<NUM>) was added <NUM>-((4R,11aS)-<NUM>-bromo-<NUM>-methyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,11a-hexahydro-<NUM>H-pyrazino[<NUM>,<NUM>-b]isoquinolin-<NUM>-yl) quinoline-<NUM>-carbonitrile (Intermediate C, <NUM>, <NUM>µmol), tBuONa (<NUM>, <NUM>µmol) and tBuXPhos Pd G3 (<NPL>, Sigma-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>R,11aS)-<NUM>-(<NUM>-cyano-<NUM>-quinolyl)-<NUM>-methyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,11a-hexahydropyrazino[<NUM>,<NUM>-b]isoquinolin-<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>, quenched with saturated aq. NaHCO<NUM>, washed with brine and dried over Na<NUM>SO<NUM>, then concentrated to afford compound <NUM> (<NUM>, <NUM>% yield). MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+].

To a solution of <NUM>-[(<NUM>R,11aS)-<NUM>-methyl-<NUM>-piperazin-<NUM>-yl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,11a-hexahydropyrazino[<NUM>,<NUM>-b]isoquinolin-<NUM>-yl]quinoline-<NUM>-carbonitrile (compound <NUM>, <NUM>, <NUM>µmol), <NUM>-(tert-butoxycarbonylamino)-<NUM>-methyl-propanoic acid (<NPL>, Sigma-Aldrich, Catalog: <NUM>, <NUM>, <NUM>µmol) and HATU in DMF (<NUM>) was added DIEA (<NUM>, <NUM>µmol). The reaction mixture was stirred at room temperature for <NUM> hrs, then quenched with water, extracted with EA. The organic layer was washed with brine, dried over Na<NUM>SO<NUM>, and then concentrated in vacuo to afford compound <NUM> (<NUM>, <NUM>% yield). MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+].

To a solution of tert-butyl N-[<NUM>,<NUM>-dimethyl-<NUM>-oxo-<NUM>-[<NUM>-[(<NUM>R,11aS)-<NUM>-(<NUM>-cyano-<NUM>-quinolyl)-<NUM>-methyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,11a-hexahydropyrazino[<NUM>,<NUM>-b]isoquinolin-<NUM>-yl]piperazin-<NUM>-yl]ethyl]carbamate (compound <NUM>, <NUM>, <NUM>µmol ) in DCM (<NUM>) was added TFA (<NUM>). The reaction mixture was stirred at room temperature for <NUM>, then concentrated to afford a crude product, which was purified by prep-HPLC to afford Example <NUM> (<NUM>, <NUM>% yield). MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (METHANOL-d<NUM>, <NUM>) δ <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (br s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, <NUM>, J=<NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using (<NUM>S)-<NUM>-tert-butoxycarbonyl-<NUM>-methyl-pyrrolidine-<NUM>-carboxylic acid (<NPL>, PharmaBlock, Catalog: PBN20121551) instead of <NUM>-(tert-butoxycarbonylamino)-<NUM>-methyl-propanoic acid in step (c). Example <NUM> was obtained. MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (METHANOL-d<NUM>, <NUM>) δ <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (br d, <NUM>, J=<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> (s, <NUM>), <NUM>-<NUM> (m, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using tert-butyl (<NUM>S,<NUM>S)-<NUM>,<NUM>-diazabicyclo[<NUM>. <NUM>]heptane-<NUM>-carboxylate (<NPL>, PharmaBlock, Catalog: PBN20120579) instead of tert-butyl piperazine-<NUM>-carboxylate in step (a). Example <NUM> was obtained. MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (METHANOL-d<NUM>, <NUM>) δ <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (br d, <NUM>, J=<NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM> (br, d, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, <NUM>, J=<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> (br s, <NUM>), <NUM> (d, <NUM>, J=<NUM>).

To a solution of tert-butyl N-(<NUM>-oxopyrrolidin-<NUM>-yl)carbamate (<NPL>, BePharm, Catalog: BD165019, <NUM>, <NUM>µmol) in dioxane (<NUM>) was added <NUM>-((4R,11aS)-<NUM>-bromo-<NUM>-methyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,11a-hexahydro-<NUM>H-pyrazino[<NUM>,<NUM>-b]isoquinolin-<NUM>-yl)quinoline-<NUM>-carbonitrile (Intermediate C, <NUM>, <NUM>µmol), Cs<NUM>CO<NUM> (<NUM>, <NUM>µmol) and Pd<NUM>(dba)<NUM> (<NUM>, <NUM>µmol) and Xantphos (<NPL>, Sigma-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 N-[<NUM>-oxo-<NUM>-[(<NUM>R,11aS)-<NUM>-(<NUM>-cyano-<NUM>-quinolyl)-<NUM>-methyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,11a-hexahydropyrazino[<NUM>,<NUM>-b]isoquinolin-<NUM>-yl]pyrrolidin-<NUM>-yl]carbamate (compound <NUM>, <NUM>, <NUM>µmol ) in DCM (<NUM>) was added TFA (<NUM>). The reaction mixture was stirred at room temperature for <NUM>, then concentrated to afford a crude product, which was purified by prep-HPLC to afford Example <NUM> ( <NUM>, <NUM>% yield). MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (METHANOL-d<NUM>, <NUM>) δ <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (br d, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (br d, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>).

The title compounds were prepared according to the following scheme:
<CHM>.

The compound <NUM> was prepared in analogy to the preparation of Example <NUM> by using tert-butyl <NUM>-oxo-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,8a-hexahydroimidazo[<NUM>,<NUM>-a]pyrazine-<NUM>-carboxylate (<NPL>, BePharm, Catalog: BD286163) instead of tert-butyl N-(<NUM>-oxopyrrolidin-<NUM>-yl)carbamate in step (a). Then Compound <NUM> was resolved by SFC to give two single isomers: Example 17A (faster eluting) and Example 17B (slower eluting) with <NUM>% methanol (<NUM>% NH<NUM>H<NUM>O)/CO<NUM> on DAICEL CHIRALPAK AD (<NUM>, <NUM>×<NUM>) column.

Example 17A MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (METHANOL-d<NUM>, <NUM>) δ <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (br d, <NUM>, J=<NUM>), <NUM> (br d, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (br d, <NUM>, J=<NUM>), <NUM> (br d, <NUM>, J=<NUM>), <NUM> (br d, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, <NUM>, J=<NUM>).

Example 17B MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (METHANOL-d<NUM>, <NUM>) δ <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (br d, <NUM>, J=<NUM>), <NUM> (br d, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, <NUM>, J=<NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using tert-butyl <NUM>-oxo-<NUM>,3a,<NUM>,<NUM>,<NUM>,7a-hexahydro-<NUM>H-pyrrolo[<NUM>,<NUM>-c]pyridine-<NUM>-carboxylate (<NPL>, PharmaBlock, Catalog: PBWBD0104) instead of tert-butyl N-(<NUM>-oxopyrrolidin-<NUM>-yl)carbamate in in step (a). Example <NUM> was obtained. MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (METHANOL-d<NUM>, <NUM>) δ <NUM> (d, <NUM>, J=<NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (br d, <NUM>, J=<NUM>), <NUM> (br d, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (td, <NUM>, J=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (br d, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (br dd, <NUM>, J=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, <NUM>, J=<NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using tert-butyl <NUM>-oxo-<NUM>,3a,<NUM>,<NUM>,<NUM>,7a-hexahydro-<NUM>H-pyrrolo[<NUM>,<NUM>-c]pyridine-<NUM>-carboxylate (<NPL>, PharmaBlock, Catalog: PBWBD0105) instead of tert-butyl N-(<NUM>-oxopyrrolidin-<NUM>-yl)carbamate in in step (a). Example <NUM> was obtained. MS: calc'd <NUM> [(M+H)+], measured <NUM> [(M+H)+]. <NUM>H NMR (METHANOL-d<NUM>, <NUM>) δ <NUM> (d, <NUM>, J=<NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (br d, <NUM>, J=<NUM>), <NUM> (br d, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (br d, <NUM>, J=<NUM>), <NUM> (br dd, <NUM>, J=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, <NUM>, J=<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-xB 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-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 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 unsubstituted or substituted heterocyclyl, heterocyclylamino, heterocyclylC<NUM>-<NUM>alkylamino or substituted C<NUM>-<NUM>alkoxy;
or a pharmaceutically acceptable salt thereof.