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 auto-inflammation 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 substituted morpholines acting as antagonists for TLR.

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), 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/or TLR8 and/or TLR9 antagonism activity. In addition, the compounds of formula (I) or (Ia) 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. Examples of heterocyclyl can be further substituted by amino, C<NUM>-<NUM>alkyl, C<NUM>-<NUM>cycloalkyl, halogen, hydroxy or C<NUM>-<NUM>alkoxy.

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.

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) according to any one of (i) to (iii), or a pharmaceutically acceptable salt thereof, wherein R<NUM> is
<CHM>
wherein R<NUM> is cyano; R<NUM> is H or deuterium; R<NUM> is H or halogen.

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

A further embodiment of present invention is (vi) a compound of formula (I) or (Ia) according to any one of (i) to (v), or a pharmaceutically acceptable salt thereof, wherein Y is CH and A is N; or Y is N and A is CH.

A further embodiment of present invention is (vii) a compound of formula (I) or (Ia) according to any one of (i) to (vi), or a pharmaceutically acceptable salt thereof, wherein R<NUM> is amino(C<NUM>-<NUM>alkyl)azetidinyl; <NUM>,<NUM>,4a,<NUM>,<NUM>,7a-hexahydro-<NUM>-pyrrolo[<NUM>,<NUM>-b][<NUM>,<NUM>]oxazinyl or amino(C<NUM>-<NUM>alkoxy)pyrrolidinyl.

A further embodiment of present invention is (viii) a compound of formula (I) or (Ia) according to any one of (i) to (vii), or a pharmaceutically acceptable salt thereof, wherein R<NUM> is <NUM>-amino-<NUM>-methyl-azetidin-<NUM>-yl; <NUM>,<NUM>,4a,<NUM>,<NUM>,7a-hexahydro-<NUM>-pyrrolo[<NUM>,<NUM>-b][<NUM>,<NUM>]oxazin-<NUM>-yl or <NUM>-amino-<NUM>-methoxy-pyrrolidin-<NUM>-yl.

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

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

Another embodiment of present invention is that (ix) compounds of formula (I) or (Ia) are selected from the following:.

A number of compounds used as reference herein were disclosed in patent <CIT> showing TLR7 and TLR9 potency data summarized in table <NUM> (TLR8 data is not available). Compounds in Table <NUM> are all characterized with an aromatic ring at the terminal position (phenyl or pyridinyl). However, according to the potency data disclosed, only some of the compounds in Table <NUM> showed good TLR7 potency, and all of which were lack of TLR9 potency. More examples disclosed in <CIT> with same structural characteristics confirmed such trend, which suggests the terminal aryl/heteroaryl ring is not favorable for TLR9 activity.

Meanwhile, more analogues of the compounds disclosed in <CIT>, such as compound R1, compound R2 which bear some substituents on the terminal aryl ring, were synthesized to confirm the SAR (structure-activity-relationship). But according to the potency data shown in Table <NUM>, the substituents on the terminal aryl ring may not necessarily improve the potency of TLR9. Therefore, the skill of the art shall not obtain any incitation from the information disclosed in <CIT> to further optimize such chemical structures.

Surprisingly, the compounds of this invention significantly improved TLR9 potency (><NUM> folds compared to ER-<NUM>) while keeping excellent TLR7 and TLR8 potency. In another embodiment, hERG profile and safety ratio were greatly improved as compared with reference compounds from <CIT> and reference compounds R1 and R2 synthesized herein (see table <NUM>). The compounds of formula (I) or (Ia) also showed good hPBMC, cytotoxicity, solubility, human microsome stability and SDPK profiles, as well as low CYP inhibition.

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>
<CHM>
wherein X is halogen; LG is a leaving group, such as OTf, OTs and OMs; PG is a protecting group, such as Boc and Cbz.

The coupling of compound of formula (II) with R<NUM>-X can be achieved in the presence of a base, such as DIPEA or K<NUM>CO<NUM>, or under Buchwald-Hartwig amination conditions (ref: <NPL>; <NPL>; <NPL>; and references cited therein) with a catalyst, such as RuPhos Pd G2, and a base, such as Cs<NUM>CO<NUM>, to provide compound of formula (III). Subsequently the hydroxy group of compound of formula (III) is converted to a leaving group, such as OTf, OTs, and OMs, under basic condition, such as DIPEA, TEA, K<NUM>CO<NUM> and <NUM>,<NUM>-dimethylpyridine, with Tf<NUM>O, TsCl or MsCl. The protecting group of compound of formula (V) can be removed at high temperature or under acidic condition, such as TFA, or under hydrogenation condition with a catalyst, such as Pd/C and Pd(OH)<NUM>/C. Compound of formula (IV) is further substituted by compound of formula (VI) in the presence of a base, such as K<NUM>CO<NUM>, DIPEA and Cs<NUM>CO<NUM>, to afford compound of formula (VII). The coupling of compound of formula (VII) with (VIII) can be achieved under Buchwald-Hartwig amination conditions (ref: <NPL>; <NPL>; <NPL>; and references cited therein) with a catalyst, such as tBuXPhos Pd G3, RuPhos Pd G2, BrettPhos Pd G3, XPhos Pd G3, Pd<NUM>(dba)<NUM>/BINAP and Pd<NUM>(dba)<NUM>/XantPhos and a base, such as Cs<NUM>CO<NUM> or t-BuONa, to provide compound of formula (I). In some embodiment, the coupling of compound of formula (VII) with amine (VIII) may give a product containing a protecting group, e.g. Boc or Cbz, originated from (VIII), which will be removed before affording the final compound of formula (I).

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) 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:.

wherein, X is halogen, Y and A are independently selected from CH and N.

A compound of formula (I) or (Ia) 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) <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):.

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 title compound was prepared according to the following scheme:
<CHM>.

To a solution of <NUM>-chloropyrazolo[<NUM>,<NUM>-a]pyridine-<NUM>-carbonitrile (<NPL>, Vendor: Pharmablock, <NUM>, <NUM> mmol) in acetonitrile (<NUM>) was added SelectFluor (<NUM>, <NUM> mmol). After being stirred at rt for <NUM> hrs, the mixture was concentrated and diluted with water (<NUM>), extracted with DCM (<NUM>) twice. The organic layer was washed with sat. NH<NUM>Cl and brine, dried over Na<NUM>SO<NUM>, and concentrated to give a crude product which was purified by silica gel chromatography to give compound E1 (<NUM>) as a light yellow powder. MS: calc'd <NUM> (MH+), measured <NUM> (MH+). <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ = <NUM> (d, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>).

To a solution of <NUM>-chloro-<NUM>-fluoropyrazolo[<NUM>,<NUM>-a]pyridine-<NUM>-carbonitrile (compound E1, <NUM>, <NUM> mmol), [(2R,6R)-<NUM>-methylmorpholin-<NUM>-yl]methanol;<NUM>,<NUM>,<NUM>-trifluoroacetic acid (compound A1, <NUM>, <NUM> mmol) and Cs<NUM>CO<NUM> (<NUM>, <NUM> mmol) in <NUM>,<NUM>-dioxane (<NUM>) was added RuPhos Pd G2 (<NUM>, <NUM> mmol) under N<NUM>. The reaction mixture was heated at <NUM> for <NUM> hrs. After being cooled down, the mixture was diluted with EtOAc and filtered through celite. The filtrate was concentrated to give a brown oil which was purified by silica gel chromatography to give compound E2 (<NUM>) as a yellow oil. MS: calc'd <NUM> (MH+), measured <NUM> (MH+).

To a solution of <NUM>-fluoro-<NUM>-[(2R,6R)-<NUM>-(hydroxymethyl)-<NUM>-methyl-morpholin-<NUM>-yl]pyrazolo[<NUM>,<NUM>-a]pyridine-<NUM>-carbonitrile (compound E2, <NUM>, <NUM> mmol) in DCM (<NUM>) was added <NUM>,<NUM>-dimethylpyridine (<NUM>, <NUM>µL, <NUM> mmol) and Tf<NUM>O (<NUM>, <NUM>µL, <NUM> mmol) at rt. After being stirred for <NUM> hrs, the mixture was diluted with DCM, washed with sat. NH<NUM>Cl and brine. The organic layer was dried over Na<NUM>SO<NUM> and concentrated to give the crude product which was purified by silica gel chromatography to give Intermediate E (<NUM>) as a yellow solid. MS: calc'd <NUM> (MH+), measured <NUM> (MH+).

The title compound was prepared in analogy to the preparation of Intermediate E by using <NUM>-chloropyrazolo[<NUM>,<NUM>-a]pyridine-<NUM>-carbonitrile (<NPL>, Vendor: PharmaBlock) instead of <NUM>-chloro-<NUM>-fluoro-pyrazolo[<NUM>,<NUM>-a]pyridine-<NUM>-carbonitrile (compound E1). Intermediate F (<NUM>) was obtained as a white solid. MS: calc'd <NUM> (MH+), measured <NUM> (MH+).

The intermediate L was prepared according to the following scheme:
<CHM>.

To the solution of <NUM>-bromo-<NUM>-fluoroaniline (<NPL>, Vendor: TCI, <NUM>, <NUM> mmol) and methyl <NUM>,<NUM>-dimethoxypropionate (<NPL>, Vendor: Accela, <NUM>, <NUM> mmol) in THF (<NUM>) was added NaHMDS in THF (<NUM>, <NUM>, <NUM> mmol) dropwise at <NUM>. After being stirred at <NUM> for <NUM> mins, the mixture was warmed up to <NUM> and stirred for <NUM> hrs. The reaction was quenched by addition of <NUM> sat. NH<NUM>Cl and concentrated to about <NUM>. The solution was diluted with <NUM> water and extracted with <NUM> EA for three times. The combined organic layer was washed with <NUM> water twice and <NUM> brine, dried over Na<NUM>SO<NUM> and concentrated to give the crude product L1 (<NUM>) as a brown oil. MS calc'd <NUM>(MH+), measured <NUM> (MH+).

A solution of N-(<NUM>-bromo-<NUM>-fluoro-phenyl)-<NUM>,<NUM>-dimethoxy-propanamide (compound L1, <NUM>, <NUM> mmol) in DCM (<NUM>) was added to concentrated sulfuric acid (<NUM>) at <NUM>. After being stirred at <NUM> for <NUM> hrs, the mixture was poured slowly into <NUM> ice-water, a yellow precipitate was appeared. The mixture was filtered, and the wet-cake was washed with <NUM> water, <NUM> isopropyl alcohol and <NUM> PE. The solid was dried in vacuum to give compound L2 (<NUM>) as a yellow solid. MS calc'd <NUM> (MH+), measured <NUM> (MH+).

A solution of <NUM>-bromo-<NUM>-fluoro-<NUM>H-quinolin-<NUM>-one (compound L2, <NUM>, <NUM> mmol), zinc cyanide (<NUM>, <NUM> mmol), Pd(PPh<NUM>)<NUM> (<NUM>, <NUM> mmol) in DMF (<NUM>) was stirred at <NUM> for <NUM> hrs. After being cooled down, the reaction mixture was quenched with <NUM> saturated NH<NUM>Cl, diluted with <NUM> water and extracted with <NUM> DCM for three times. The combined organic layer was washed with <NUM> water twice and <NUM> brine once, dried over Na<NUM>SO<NUM> and concentrated to give the crude product which was purified by silica gel chromatography (PE/EA = <NUM>/<NUM>) to give compound L3 (<NUM>) as a yellow solid. MS calc'd <NUM> (MH+), measured <NUM> (MH+).

To the solution of <NUM>-fluoro-<NUM>-oxo-<NUM>H-quinoline-<NUM>-carbonitrile (compound L3, <NUM>, <NUM> mmol), <NUM>,<NUM>-dimethylpyridine (<NUM>, <NUM> mmol) in DCM (<NUM>) was added trifluoromethanesulfonic anhydride (<NUM>, <NUM> mmol) at <NUM>. After being stirred at <NUM> for <NUM>, the mixture was diluted with <NUM> water and extracted with <NUM> DCM for three times. The combined organic layer was washed with <NUM> water twice and <NUM> brine once, dried over Na<NUM>SO<NUM> and concentrated to give the crude product which was purified by silica gel chromatography (PE/EA = <NUM>/<NUM>) to give compound L4 (<NUM>) as a yellow solid. MS calc'd <NUM> (MH+), measured <NUM>(MH+).

To the solution of (<NUM>-cyano-<NUM>-fluoro-<NUM>-quinolyl) trifluoromethanesulfonate (compound L4, <NUM>, <NUM> mmol) in THF (<NUM>) and deuterium oxide (<NUM>) was added potassium carbonate (<NUM>, <NUM> mol) and Pd/C (<NUM> wt. The mixture was stirred at <NUM> for <NUM> hrs under deuterium atmosphere. Then the mixture was filtered and the filtrate was concentrated and purified by silica gel chromatography (PE/EA = <NUM>/<NUM>) to give compound L5 (<NUM>) as a light yellow solid. MS calc'd <NUM> (MH+), measured <NUM> (MH+).

A mixture of <NUM>-fluoroquinoline-<NUM>-carbonitrile-<NUM>-d (compound L5, <NUM>, <NUM> mmol), ((2R,6R)-<NUM>-methylmorpholin-<NUM>-yl)methanol hydrochloride salt (compound L6, <NUM>, <NUM> mmol), N-ethyl-N-isopropylpropan-<NUM>-amine (<NUM>, <NUM> mmol) in DMSO (<NUM>) was stirred at <NUM> for <NUM> hours. Then the solution was diluted with EA and washed with water and brine. The organic layer was dried and concentrated. The residue was purified by silica gel chromatography (EA/PE from <NUM>% to <NUM>%) to afford <NUM>-((2R,6R)-<NUM>-(hydroxymethyl)-<NUM>-methylmorpholino)quinoline-<NUM>-carbonitrile-<NUM>-d (compound L7, <NUM>) as a yellow solid. MS: calc'd <NUM> (MH+), measured <NUM> (MH+).

To a solution of <NUM>-((2R,6R)-<NUM>-(hydroxymethyl)-<NUM>-methylmorpholino) quinoline-<NUM>-carbonitrile-<NUM>-d (compound L7, <NUM>) and <NUM>,<NUM>-dimethylpyridine (<NUM>, <NUM>, <NUM> mmol) in CH<NUM>Cl<NUM> (<NUM>) was added trifluoromethanesulfonic anhydride (<NUM>, <NUM>, <NUM> mmol) dropwise at <NUM>. The mixture was stirred at <NUM> for <NUM>, then diluted with DCM and washed with saturated NH<NUM>Cl solution and brine. The organic layer was dried over Na<NUM>SO<NUM> and concentrated. The residue was purified by silica gel chromatography (EA/PE from <NUM>% to <NUM>%) to afford ((2R,6R)-<NUM>-(<NUM>-cyanoquinolin-<NUM>-yl-<NUM>-d)-<NUM>-methylmorpholin-<NUM>-yl)methyl trifluoromethanesulfonate (Intermediate L <NUM>) as a yellow solid. MS: calc'd <NUM> (MH+), measured <NUM> (MH+).

The title compound was prepared in analogy to the preparation of Intermediate A by using <NUM>-bromo-<NUM>-methyl-<NUM>,<NUM>-naphthyridin-<NUM>-one (compound M1) instead of <NUM>-bromoquinoline-<NUM>-carbonitrile (compound A2). Intermediate M (<NUM>) was obtained as a yellow solid. MS: calc'd <NUM> (MH+), measured <NUM> (MH+).

The compound M1 was prepared according to the following scheme:
<CHM>
preparation of <NUM>-bromo-<NUM>-methyl-<NUM>,<NUM>-naphthyridin-<NUM>-one (compound M1).

To the solution of <NUM>-bromo-<NUM>,<NUM>-naphthyridin-<NUM>(<NUM>)-one (<NPL>, Vendor: Accela, <NUM>, <NUM> mmol) in DMF (<NUM>) was added iodomethane (<NUM>, <NUM> mmol) and Cs<NUM>CO<NUM> (<NUM>, <NUM> mmol). The reaction mixture was stirred at <NUM> overnight. After being cooled down, the reaction was quenched by ice-water (<NUM>). The solid was collected by filtration to give crude compound M1 (<NUM>) which was used directly for next step. MS calc'd <NUM> (MH+), measured <NUM> (MH+). <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ = <NUM> (dd, J=<NUM>, <NUM>, <NUM>), <NUM> (dd, J=<NUM>, <NUM>, <NUM>), <NUM> (dd, J=<NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

To a solution of tert- butyl <NUM>-bromospiro[<NUM>-isobenzofuran-<NUM>,<NUM>'-azetidine]-<NUM>'-carboxylate (compound 1a, <NPL>, Pharmablock, <NUM>) in DCM (<NUM>) was added trifluoroacetic acid (<NUM>). After being stirred at rt for <NUM> hrs, the mixture was concentrated in vacuo to give a white oil which can be used without purification. <NUM> of <NUM>-bromospiro[<NUM>-isobenzofuran-<NUM>,<NUM>'-azetidine] (compound 1b) was obtained. MS calc'd <NUM> (MH+), measured <NUM> (MH+).

A solution of <NUM>-bromospiro[<NUM>-isobenzofuran-<NUM>,<NUM>'-azetidine] (compound 1b, <NUM>, <NUM>µmol) and [(2R,6R)-<NUM>-(<NUM>-cyano-<NUM>-fluoro-pyrazolo[<NUM>,<NUM>-a]pyridin-<NUM>-yl)-<NUM>-methyl-morpholin-<NUM>-yl]methyl trifluoromethanesulfonate (Intermediate E , <NUM>, <NUM>µmol) and DIPEA (<NUM>) in CH<NUM>Cl<NUM> (<NUM>) was stirred at room temperature for <NUM> hrs. The mixture was then diluted with DCM and washed with brine. The organic layer was dried over Na<NUM>SO<NUM> and concentrated. The residue was purified by silica gel chromatography (EA/PE from <NUM>% to <NUM>%) to get <NUM>-[(<NUM>,6R)-<NUM>-[(<NUM>-bromospiro[<NUM>-isobenzofuran-<NUM>,<NUM>'-azetidine]-<NUM>'-yl)methyl]-<NUM>-methyl-morpholin-<NUM>-yl]-<NUM>-fluoro-pyrazolo[<NUM>,<NUM>-a]pyridine-<NUM>-carbonitrile (compound 1c, <NUM>) as a yellow solid. MS: calc'd <NUM> (MH+), measured <NUM> (MH+).

To a solution of <NUM>-[(<NUM>,6R)-<NUM>-[(<NUM>-bromospiro[<NUM>-isobenzofuran-<NUM>,<NUM>'-azetidine]-<NUM>'-yl)methyl]-<NUM>-methyl-morpholin-<NUM>-yl]-<NUM>-fluoro-pyrazolo[<NUM>,<NUM>-a]pyridine-<NUM>-carbonitrile (compound 1c, <NUM>, <NUM>µmol) in dioxane (<NUM>) was added RuPhos-Pd-G2 (<NUM>, <NUM>µmol), tert-butyl (<NUM>-methylazetidin-<NUM>-yl)carbamate (compound 1d, <NUM>, <NUM>µmol) and K<NUM>CO<NUM> (<NUM>, <NUM>µmol). The reaction mixture was stirred at <NUM> under N<NUM> overnight. Then the mixture was filtered and the filtrate was concentrated under reduced pressure to afford crude product which can be used in next step without purification (compound 1e, <NUM>). MS: calc'd <NUM> (MH+), measured <NUM> (MH+).

To a solution of tert-butyl N-[<NUM>-[<NUM>'-[[(<NUM>,6R)-<NUM>-(<NUM>-cyano-<NUM>-fluoro-pyrazolo[<NUM>,<NUM>-a]pyridin-<NUM>-yl)-<NUM>-methyl-morpholin-<NUM>-yl]methyl]spiro[<NUM>-isobenzofuran-<NUM>,<NUM>'-azetidine]-<NUM>-yl]-<NUM>-methyl-azetidin-<NUM>-yl]carbamate (compound 1e, <NUM>) in DCM (<NUM>) was added TFA (<NUM>) at <NUM>. The reaction mixture was stirred at r. for <NUM> hrs. Then the mixture was concentrated to crude product, which was purified by prep-HPLC to afford Example <NUM> (<NUM>) as a yellow solid. MS calc'd <NUM> (MH+), measured <NUM> (MH+). <NUM>H NMR (METHANOL-d<NUM>, <NUM>) δ <NUM> (d, J = <NUM>, <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>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> ppm (d, J = <NUM>, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using <NUM>-methyl-<NUM>,<NUM>-diazaspiro[<NUM>]heptane instead of tert-butyl (<NUM>-methylazetidin-<NUM>-yl)carbamate (compound 1d ). Example <NUM> (<NUM>) was obtained as a yellow solid. MS: calc'd <NUM> (MH+), measured <NUM> (MH+). <NUM>H NMR (METHANOL-d<NUM>, <NUM>) δ <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> (br d, J=<NUM>, <NUM>), <NUM> (br d, J=<NUM>, <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, 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>-fluoropyrrolidine-<NUM>-carboxylate (CAS: <NUM>-<NUM>-<NUM>, vendor: PharmaBlock) instead of tert-butyl (<NUM>-methylazetidin-<NUM>-yl)carbamate (compound 1d ). Example <NUM> (<NUM>) was obtained as a light brown solid. MS: calc'd <NUM> (MH+), measured <NUM> (MH+). <NUM>H NMR (METHANOL-d<NUM>, <NUM>) δ <NUM> (d, J=<NUM>, <NUM>), <NUM> (br d, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (br d, J=<NUM>, <NUM>), <NUM> (s, <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> (br d, J=<NUM>, <NUM>), <NUM> (br t, J=<NUM>, <NUM>), <NUM> (br t, J=<NUM>, <NUM>), <NUM> (br t, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using tert-butyl <NUM>-oxa-<NUM>,<NUM>-diazaspiro[<NUM>]nonane-<NUM>-carboxylate (<NPL>, vendor: PharmaBlock) instead of tert-butyl (<NUM>-methylazetidin-<NUM>-yl)carbamate (compound 1d ). Example <NUM> (<NUM>) was obtained as a light brown solid. MS: calc'd <NUM> (MH+), measured <NUM> (MH+). <NUM>H NMR (METHANOL-d<NUM>, <NUM>) δ <NUM> (d, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (br 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 (S)-tert-Butyl (<NUM>-methylpyrrolidin-<NUM>-yl)carbamate (CAS: <NUM>-<NUM>-<NUM>, vendor: PharmaBlock) instead of tert-butyl (<NUM>-methylazetidin-<NUM>-yl)carbamate (compound 1d ). Example <NUM> (<NUM>) was obtained as a white solid. MS: calc'd <NUM> (MH+), measured <NUM> (MH+). <NUM>H NMR (METHANOL-d<NUM>, <NUM>) δ <NUM> (d, J=<NUM>, <NUM>), <NUM> (dd, J=<NUM>, <NUM>, <NUM>), <NUM> (dd, J=<NUM>, <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> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J=<NUM>, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using tert-butyl piperazine-<NUM>-carboxylate instead of tert-butyl (<NUM>-methylazetidin-<NUM>-yl)carbamate (compound 1d ). Example <NUM> (<NUM>) was obtained as a yellow solid. MS: calc'd <NUM> (MH+), measured <NUM> (MH+). <NUM>H NMR (METHANOL-d<NUM>, <NUM>) δ <NUM> (d, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (dd, J=<NUM>, <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> (t, 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 [(2R,6R)-<NUM>-(<NUM>-cyanopyrazolo[<NUM>,<NUM>-a]pyridin-<NUM>-yl)-<NUM>-methyl-morpholin-<NUM>-yl]methyl trifluoromethanesulfonate (Intermediate F) and tert-butyl <NUM>-oxa-<NUM>,<NUM>-diazaspiro[<NUM>]nonane-<NUM>-carboxylate (<NPL>, vendor: PharmaBlock) instead of [(2R,6R)-<NUM>-(<NUM>-cyano-<NUM>-fluoro-pyrazolo[<NUM>,<NUM>-a]pyridin-<NUM>-yl)-<NUM>-methyl-morpholin-<NUM>-yl]methyl trifluoromethanesulfonate (Intermediate E) and tert-butyl (<NUM>-methylazetidin-<NUM>-yl)carbamate (compound 1d ). Example <NUM> (<NUM>) was obtained as a white solid. MS: calc'd <NUM> (MH+), measured <NUM> (MH+). <NUM>H NMR (METHANOL-d<NUM>, <NUM>) δ <NUM> (d, J=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (dd, J=<NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (br s, <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, J=<NUM>, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using [(2R,6R)-<NUM>-(<NUM>-cyanopyrazolo[<NUM>,<NUM>-a]pyridin-<NUM>-yl)-<NUM>-methyl-morpholin-<NUM>-yl]methyl trifluoromethanesulfonate (Intermediate F) and <NUM>-methyl-<NUM>,<NUM>-diazaspiro[<NUM>]heptane instead of [(2R,6R)-<NUM>-(<NUM>-cyano-<NUM>-fluoro-pyrazolo[<NUM>,<NUM>-a]pyridin-<NUM>-yl)-<NUM>-methyl-morpholin-<NUM>-yl]methyl trifluoromethanesulfonate (Intermediate E) and tert-butyl (<NUM>-methylazetidin-<NUM>-yl)carbamate (compound 1d ). Example <NUM> (<NUM>) was obtained as a white solid. MS: calc'd <NUM> (MH+), measured <NUM> (MH+). <NUM>H NMR (METHANOL-d4 , <NUM>) δ <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> (dd, J=<NUM>, <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> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J=<NUM>, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by tert-Butyl azetidin-<NUM>-ylcarbamate (CAS: <NUM>-<NUM>-<NUM>, vendor: BePharm) instead of tert-butyl (<NUM>-methylazetidin-<NUM>-yl)carbamate (compound 1d ). Example <NUM> (<NUM>) was obtained as a white solid. MS: calc'd <NUM> (MH+), measured <NUM> (MH+). <NUM>H NMR (METHANOL-d4 , <NUM>) δ <NUM> (d, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM>-<NUM> (m, <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>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J=<NUM>, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by tert-Butyl ((3R,4R)-<NUM>-hydroxypyrrolidin-<NUM>-yl)carbamate hydrochloride (<NPL>, vendor: BePharm) instead of tert-butyl (<NUM>-methylazetidin-<NUM>-yl)carbamate (compound 1d ). Example <NUM> (<NUM>) was obtained as a light yellow solid. MS: calc'd <NUM> (MH+), measured <NUM> (MH+). <NUM>H NMR (METHANOL-d<NUM>, <NUM>) δ <NUM> (d, J=<NUM>, <NUM>), <NUM>-<NUM> (m, <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>), <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 [(2R,6R)-<NUM>-(<NUM>-cyano-<NUM>-deuterio-<NUM>-quinolyl)-<NUM>-methyl-morpholin-<NUM>-yl] methyl trifluoromethanesulfonate (Intermediate L) instead of [(2R,6R)-<NUM>-(<NUM>-cyano-<NUM>-fluoro-pyrazolo[<NUM>,<NUM>-a]pyridin-<NUM>-yl)-<NUM>-methyl-morpholin-<NUM>-yl]methyl trifluoromethanesulfonate (Intermediate E). Example <NUM> (<NUM>) was obtained as a yellow solid. MS: calc'd <NUM> (MH+), measured <NUM> (MH+). <NUM>H NMR (<NUM>, METHANOL-d4) δ <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> (dd, J = <NUM>, <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> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by tert-Butyl <NUM>,<NUM>-diazaspiro[<NUM>]heptane-<NUM>-carboxylate oxalate (CAS: <NUM>-<NUM>-<NUM>, vendor: PharmaBlock) instead of tert-butyl (<NUM>-methylazetidin-<NUM>-yl)carbamate (compound 1d ). Example <NUM> (<NUM>) was obtained as a light brown solid. MS: calc'd <NUM> (MH+), measured <NUM> (MH+). <NUM>H NMR (METHANOL-d4 , <NUM>) δ <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> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (t, 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 N-(azetidin-<NUM>-yl)carbamate and [(<NUM>R,<NUM>R)-<NUM>-methyl-<NUM>-(<NUM>-methyl-<NUM>-oxo-<NUM>,<NUM>-naphthyridin-<NUM>-yl)morpholin-<NUM>-yl]methyl trifluoromethanesulfonate (Intermediate M) instead of tert-butyl (<NUM>-methylazetidin-<NUM>-yl)carbamate (compound 1d ) and [(<NUM>R,<NUM>R)-<NUM>-(<NUM>-cyano-<NUM>-fluoro-pyrazolo[<NUM>,<NUM>-a]pyridin-<NUM>-yl)-<NUM>-methyl-morpholin-<NUM>-yl]methyl trifluoromethanesulfonate (Intermediate E). Example <NUM> (<NUM>) was obtained as a yellow solid. MS: calc'd <NUM> (MH+), measured <NUM> (MH+). <NUM>H NMR (<NUM>, METHANOL-d4) δ <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <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> (d, J = <NUM>, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using tert-butyl N-(azetidin-<NUM>-yl)carbamate and [(<NUM>R,<NUM>R)-<NUM>-(<NUM>-cyano-<NUM>-deuterio-<NUM>-quinolyl)-<NUM>-methyl-morpholin-<NUM>-yl]methyl trifluoromethanesulfonate (Intermediate L) instead of tert-butyl (<NUM>-methylazetidin-<NUM>-yl)carbamate (compound 1d ) and [(<NUM>R,<NUM>R)-<NUM>-(<NUM>-cyano-<NUM>-fluoro-pyrazolo[<NUM>,<NUM>-a]pyridin-<NUM>-yl)-<NUM>-methyl-morpholin-<NUM>-yl]methyl trifluoromethanesulfonate (Intermediate E). Example <NUM> (<NUM>) was obtained as a yellow solid. MS: calc'd <NUM> (MH+), measured <NUM> (MH+). <NUM>H NMR (<NUM>, METHANOL-d4) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <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>-oxa-<NUM>,<NUM>-diazaspiro[<NUM>]nonane-<NUM>-carboxylate and [(2R,6R)-<NUM>-(<NUM>-cyano-<NUM>-deuterio-<NUM>-quinolyl)-<NUM>-methyl-morpholin-<NUM>-yl]methyl trifluoromethanesulfonate (Intermediate L) instead of tert-butyl (<NUM>-methylazetidin-<NUM>-yl)carbamate (compound 1d ) and [(2R,6R)-<NUM>-(<NUM>-cyano-<NUM>-fluoro-pyrazolo[<NUM>,<NUM>-a]pyridin-<NUM>-yl)-<NUM>-methyl-morpholin-<NUM>-yl]methyl trifluoromethanesulfonate (Intermediate E). Example <NUM> (<NUM>) was obtained as a yellow solid. MS: calc'd <NUM> (MH+), measured <NUM> (MH+). <NUM>H NMR (<NUM>, METHANOL-d4) δ <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> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <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-[(3R,4R)-<NUM>-methoxypyrrolidin-<NUM>-yl]carbamate (PharmaBlock, PBZ4728, <NPL>) and [(2R,6R)-<NUM>-(<NUM>-cyano-<NUM>-deuterio-<NUM>-quinolyl)-<NUM>-methyl-morpholin-<NUM>-yl]methyl trifluoromethanesulfonate (Intermediate L) instead of tert-butyl (<NUM>-methylazetidin-<NUM>-yl)carbamate (compound 1d ) and [(2R,6R)-<NUM>-(<NUM>-cyano-<NUM>-fluoro-pyrazolo[<NUM>,<NUM>-a]pyridin-<NUM>-yl)-<NUM>-methyl-morpholin-<NUM>-yl]methyl trifluoromethanesulfonate (Intermediate E). Example <NUM> (<NUM>) was obtained as a yellow solid. MS: calc'd <NUM> (MH+), measured <NUM> (MH+). <NUM>H NMR (<NUM>, METHANOL-d4) δ <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> (dd, J = <NUM>, <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> ppm (d, J = <NUM>, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using tert-butyl (<NUM>aR,<NUM>aR)-<NUM>,4a,<NUM>,<NUM>,<NUM>,7a-hexahydro-<NUM>H-pyrrolo[<NUM>,<NUM>-b][<NUM>,<NUM>]oxazine-<NUM>-carboxylate (PharmaBlock, PBXA8123, <NPL>) and [(2R,6R)-<NUM>-(<NUM>-cyano-<NUM>-deuterio-<NUM>-quinolyl)-<NUM>-methyl-morpholin-<NUM>-yl]methyl trifluoromethanesulfonate (Intermediate L) instead of tert-butyl (<NUM>-methylazetidin-<NUM>-yl)carbamate (compound 1d ) and [(2R,6R)-<NUM>-(<NUM>-cyano-<NUM>-fluoro-pyrazolo[<NUM>,<NUM>-a]pyridin-<NUM>-yl)-<NUM>-methyl-morpholin-<NUM>-yl]methyl trifluoromethanesulfonate (Intermediate E). Example <NUM> (<NUM>) was obtained as a yellow solid. MS: calc'd <NUM> (MH+), measured <NUM> (MH+). <NUM>H NMR (<NUM>, METHANOL-d4) δ <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> (dd, J = <NUM>, <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> (d, J = <NUM>, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using tert-butyl piperazine-<NUM>-carboxylate and [(2R,6R)-<NUM>-(<NUM>-cyano-<NUM>-deuterio-<NUM>-quinolyl)-<NUM>-methyl-morpholin-<NUM>-yl]methyl trifluoromethanesulfonate (Intermediate L) instead of tert-butyl (<NUM>-methylazetidin-<NUM>-yl)carbamate (compound 1d ) and [(2R,6R)-<NUM>-(<NUM>-cyano-<NUM>-fluoro-pyrazolo[<NUM>,<NUM>-a]pyridin-<NUM>-yl)-<NUM>-methyl-morpholin-<NUM>-yl]methyl trifluoromethanesulfonate (Intermediate E). Example <NUM> (<NUM>) was obtained as a yellow solid. MS: calc'd <NUM> (MH+), measured <NUM> (MH+). <NUM>H NMR (<NUM>, METHANOL-d4) δ <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> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <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 [(2R,6R)-<NUM>-(<NUM>-cyanopyrazolo[<NUM>,<NUM>-a]pyridin-<NUM>-yl)-<NUM>-methyl-morpholin-<NUM>-yl]methyl trifluoromethanesulfonate (Intermediate F) and tert-Butyl azetidin-<NUM>-ylcarbamate (<NPL>, vendor: BePharm) instead of [(2R,6R)-<NUM>-(<NUM>-cyano-<NUM>-fluoro-pyrazolo[<NUM>,<NUM>-a]pyridin-<NUM>-yl)-<NUM>-methyl-morpholin-<NUM>-yl]methyl trifluoromethanesulfonate (Intermediate E) and tert-butyl (<NUM>-methylazetidin-<NUM>-yl)carbamate (compound 1d ). Example <NUM> (<NUM>) was obtained as a light yellow solid. MS: calc'd <NUM> (MH+), measured <NUM> (MH+). <NUM>H NMR (METHANOL-d<NUM>, <NUM>) δ <NUM> (d, J=<NUM>, <NUM>), <NUM> (dd, J=<NUM>, <NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (dd, J=<NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (br s, <NUM>), <NUM> (t, J=<NUM>, <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> (d, J=<NUM>, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using tert-butyl N-(azetidin-<NUM>-yl)carbamate and tert-butyl <NUM>-bromospiro[<NUM>-furo[<NUM>,<NUM>-b]pyridine-<NUM>,<NUM>'-azetidine]-<NUM>'-carboxylate (<NPL>, Cat. #: PBU1967, Vendor: Pharmablock) and [(2R,6R)-<NUM>-(<NUM>-cyano-<NUM>-deuterio-<NUM>-quinolyl)-<NUM>-methyl-morpholin-<NUM>-yl] methyl trifluoromethanesulfonate (Intermediate L) instead of tert-butyl (<NUM>-methylazetidin-<NUM>-yl)carbamate (compound 1d ) and tert- butyl <NUM>-bromospiro[<NUM>H-isobenzofuran-<NUM>,<NUM>'-azetidine]-<NUM>'-carboxylate(compound 1a) and [(2R,6R)-<NUM>-(<NUM>-cyano-<NUM>-fluoro-pyrazolo[<NUM>,<NUM>-a]pyridin-<NUM>-yl)-<NUM>-methyl-morpholin-<NUM>-yl]methyl trifluoromethanesulfonate (Intermediate E). Example <NUM> (<NUM>) was obtained as a yellow solid. MS: calc'd <NUM> (MH+), measured <NUM> (MH+). <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ <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> (t, 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>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using tert-butyl <NUM>-bromospiro[<NUM>-furo[<NUM>,<NUM>-b]pyridine-<NUM>,<NUM>'-azetidine]-<NUM>'-carboxylate and [(2R,6R)-<NUM>-(<NUM>-cyano-<NUM>-deuterio-<NUM>-quinolyl)-<NUM>-methyl-morpholin-<NUM>-yl]methyl trifluoromethanesulfonate (Intermediate L) instead of tert-butyl <NUM>-bromospiro[<NUM>-isobenzofuran-<NUM>,<NUM>'-azetidine]-<NUM>'-carboxylate(compound 1a) and [(2R,6R)-<NUM>-(<NUM>-cyano-<NUM>-fluoro-pyrazolo[<NUM>,<NUM>-a]pyridin-<NUM>-yl)-<NUM>-methyl-morpholin-<NUM>-yl]methyl trifluoromethanesulfonate (Intermediate E). Example <NUM> (<NUM>) was obtained as a yellow solid. MS: calc'd <NUM> (MH+), measured <NUM> (MH+). <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ <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>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using <NUM>-methyl-<NUM>,<NUM>-diazaspiro[<NUM>]heptane and tert-butyl <NUM>-bromospiro[<NUM>-furo[<NUM>,<NUM>-b]pyridine-<NUM>,<NUM>'-azetidine]-<NUM>'-carboxylate instead of tert-butyl (<NUM>-methylazetidin-<NUM>-yl)carbamate (compound 1d ) and tert-butyl <NUM>-bromospiro[<NUM>-isobenzofuran-<NUM>,<NUM>'-azetidine]-<NUM>'-carboxylate(compound 1a). Example <NUM> (<NUM>) was obtained as a yellow solid. MS: calc'd <NUM> (MH+), measured <NUM> (MH+). <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <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> (d, J = <NUM>, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using [(2R,6R)-<NUM>-(<NUM>-cyano-<NUM>-deuterio-<NUM>-quinolyl)-<NUM>-methyl-morpholin-<NUM>-yl]methyl trifluoromethanesulfonate (Intermediate L) and tert-Spiro[azetidine-<NUM>,<NUM>'(<NUM>'H)-furo[<NUM>,<NUM>-c] pyridine]-<NUM>-carboxylic acid, <NUM>'-chloro-, <NUM>,<NUM>-dimethylethyl ester (<NPL>, vendor: PharmaBlock) instead of [(2R,6R)-<NUM>-(<NUM>-cyano-<NUM>-fluoro-pyrazolo[<NUM>,<NUM>-a]pyridin-<NUM>-yl)-<NUM>-methyl-morpholin-<NUM>-yl]methyl trifluoromethanesulfonate (Intermediate E) and tert-butyl <NUM>-bromospiro[<NUM>-isobenzofuran-<NUM>,<NUM>'-azetidine]-<NUM>'-carboxylate (compound 1a ). Example <NUM> (<NUM>) was obtained as a light yellow solid. MS: calc'd <NUM> (MH+), measured <NUM> (MH+). <NUM>H NMR (METHANOL-d<NUM>, <NUM>) δ <NUM> (d, J=<NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (br d, J=<NUM>, <NUM>), <NUM> (br dd, J=<NUM>, <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (br t, J=<NUM>, <NUM>), <NUM> (t, J=<NUM>, <NUM>), <NUM> (dd, J=<NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J=<NUM>, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using tert-Spiro[azetidine-<NUM>,<NUM>'(<NUM>'H)- furo[<NUM>,<NUM>-c]pyridine]-<NUM>-carboxylic acid, <NUM>'-chloro-, <NUM>,<NUM>-dimethylethyl ester (<NPL>, vendor: PharmaBlock) instead of tert-butyl <NUM>-bromospiro[<NUM>H-isobenzofuran-<NUM>,<NUM>'-azetidine]-<NUM>'-carboxylate (compound 1a ). Example <NUM> (<NUM>) was obtained as a light yellow solid. MS: calc'd <NUM> (MH+), measured <NUM> (MH+). <NUM>H NMR (METHANOL-d<NUM>, <NUM>) δ <NUM> (s, <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>-<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 [(2R,6R)-<NUM>-(<NUM>-cyanopyrazolo[<NUM>,<NUM>-a]pyridin-<NUM>-yl)-<NUM>-methyl-morpholin-<NUM>-yl]methyl trifluoromethanesulfonate (Intermediate F) and tert-Spiro[azetidine-<NUM>,<NUM>'(<NUM>'H)-furo[<NUM>,<NUM>-c] pyridine]-<NUM>-carboxylic acid, <NUM>'-chloro-, <NUM>,<NUM>-dimethylethyl ester (<NPL>, vendor: PharmaBlock) instead of [(2R,6R)-<NUM>-(<NUM>-cyano-<NUM>-fluoro-pyrazolo[<NUM>,<NUM>-a]pyridin-<NUM>-yl)-<NUM>-methyl-morpholin-<NUM>-yl]methyl trifluoromethanesulfonate (Intermediate E) and tert-butyl <NUM>-bromospiro[<NUM>H-isobenzofuran-<NUM>,<NUM>'-azetidine]-<NUM>'-carboxylate (compound 1a ). Example <NUM> (<NUM>) was obtained as a light yellow solid. MS: calc'd <NUM> (MH+), measured <NUM> (MH+). <NUM>H NMR (METHANOL-d<NUM>, <NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (br dd, J=<NUM>, <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> (dd, J=<NUM>, <NUM>, <NUM>), <NUM> (dd, J=<NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J=<NUM>, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using [(2R,6R)-<NUM>-(<NUM>-cyanopyrazolo[<NUM>,<NUM>-a]pyridin-<NUM>-yl)-<NUM>-methyl-morpholin-<NUM>-yl]methyl trifluoromethanesulfonate (Intermediate F) and tert-butyl <NUM>-bromospiro[<NUM>-furo[<NUM>,<NUM>-b] pyridine-<NUM>,<NUM>-azetidine]-<NUM>-carboxylate (<NPL>, vendor: PharmaBlock) instead of [(2R,6R)-<NUM>-(<NUM>-cyano-<NUM>-fluoro-pyrazolo[<NUM>,<NUM>-a]pyridin-<NUM>-yl)-<NUM>-methyl-morpholin-<NUM>-yl]methyl trifluoromethanesulfonate (Intermediate E) and tert-butyl <NUM>-bromospiro[<NUM>H-isobenzofuran-<NUM>,<NUM>'-azetidine]-<NUM>'-carboxylate (compound 1a ). Example <NUM> (<NUM>) was obtained as a light yellow solid. MS: calc'd <NUM> (MH+), measured <NUM> (MH+). <NUM>H NMR (METHANOL-d<NUM>, <NUM>) δ <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>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (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>aR,<NUM>aR)-<NUM>,4a,<NUM>,<NUM>,<NUM>,7a-hexahydro-<NUM>H-pyrrolo[<NUM>,<NUM>-b][<NUM>,<NUM>]oxazine-<NUM>-carboxylate (PharmaBlock, PBXA8123, <NPL>), [(2R,6R)-<NUM>-(<NUM>-cyano-<NUM>-deuterio-<NUM>-quinolyl)-<NUM>-methyl-morpholin-<NUM>-yl]methyl trifluoromethanesulfonate (Intermediate L) and tert-Spiro[azetidine-<NUM>,<NUM>'(<NUM>'H)-furo[<NUM>,<NUM>-c]pyridine]-<NUM>-carboxylic acid, <NUM>'-chloro-, <NUM>,<NUM>-dimethylethyl ester (<NPL>, vendor: PharmaBlock) instead of tert-butyl (<NUM>-methylazetidin-<NUM>-yl)carbamate (compound 1d), [(2R,6R)-<NUM>-(<NUM>-cyano-<NUM>-fluoro-pyrazolo[<NUM>,<NUM>-a]pyridin-<NUM>-yl)-<NUM>-methyl-morpholin-<NUM>-yl]methyl trifluoromethanesulfonate (Intermediate E) and tert-butyl <NUM>-bromospiro[<NUM>-isobenzofuran-<NUM>,<NUM>'-azetidine]-<NUM>'-carboxylate (compound 1a ). Example <NUM> (<NUM>) was obtained as a light yellow solid. MS: calc'd <NUM> (MH+), measured <NUM> (MH+). <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <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> - <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>aR,7aR)-<NUM>,4a,<NUM>,<NUM>,<NUM>,7a-hexahydro-<NUM>H-pyrrolo[<NUM>,<NUM>-b][<NUM>,<NUM>]oxazine-<NUM>-carboxylate (PharmaBlock, PBXA8123, <NPL>) and tert-butyl <NUM>-bromospiro[<NUM>-furo[<NUM>,<NUM>-b]pyridine-<NUM>,<NUM>'-azetidine]-<NUM>'-carboxylate (<NPL>, PBU1967, Vendor: Pharmablock) and [(2R,6R)-<NUM>-(<NUM>-cyano-<NUM>-deuterio-<NUM>-quinolyl)-<NUM>-methyl-morpholin-<NUM>-yl]methyl trifluoromethanesulfonate (Intermediate L) instead of tert-butyl (<NUM>-methylazetidin-<NUM>-yl)carbamate (compound 1d ) and tert- butyl <NUM>-bromospiro[<NUM>H-isobenzofuran-<NUM>,<NUM>'-azetidine]-<NUM>'-carboxylate(compound 1a) and [(2R,6R)-<NUM>-(<NUM>-cyano-<NUM>-fluoro-pyrazolo[<NUM>,<NUM>-a]pyridin-<NUM>-yl)-<NUM>-methyl-morpholin-<NUM>-yl]methyl trifluoromethanesulfonate (Intermediate E). Example <NUM> (<NUM>) was obtained as a yellow solid. MS: calc'd <NUM> (MH+), measured <NUM> (MH+). <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ <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> ppm (d, J = <NUM>, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using tert-butyl N-[(3R,4R)-<NUM>-methoxypyrrolidin-<NUM>-yl]carbamate (PharmaBlock, PBZ4728, <NPL>) and tert-butyl <NUM>-bromospiro[<NUM>H-furo[<NUM>,<NUM>-b]pyridine-<NUM>,<NUM>'-azetidine]-<NUM>'-carboxylate (<NPL>, PBU1967, Vendor: Pharmablock) and [(2R,6R)-<NUM>-(<NUM>-cyano-<NUM>-deuterio-<NUM>-quinolyl)-<NUM>-methyl-morpholin-<NUM>-yl]methyl trifluoromethanesulfonate (Intermediate L) instead of tert-butyl (<NUM>-methylazetidin-<NUM>-yl)carbamate (compound 1d ) and tert- butyl <NUM>-bromospiro[<NUM>-isobenzofuran-<NUM>,<NUM>'-azetidine]-<NUM>'-carboxylate(compound 1a) and [(2R,6R)-<NUM>-(<NUM>-cyano-<NUM>-fluoro-pyrazolo[<NUM>,<NUM>-a]pyridin-<NUM>-yl)-<NUM>-methyl-morpholin-<NUM>-yl]methyl trifluoromethanesulfonate (Intermediate E). Example <NUM> (<NUM>) was obtained as a yellow solid. MS: calc'd <NUM> (MH+), measured <NUM> (MH+). <NUM>H NMR (<NUM>, METHANOL-d4) δ <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>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> ppm (d, J = <NUM>, <NUM>).

The title compound was prepared in analogy to the preparation of Example <NUM> by using [(2R,6R)-<NUM>-(<NUM>-cyano-<NUM>-deuterio-<NUM>-quinolyl)-<NUM>-methyl-morpholin-<NUM>-yl] methyl trifluoromethanesulfonate (Intermediate L) and tert-Spiro[azetidine-<NUM>,<NUM>'(<NUM>'H)-furo[<NUM>,<NUM>-c] pyridine]-<NUM>-carboxylic acid, <NUM>'-chloro-, <NUM>,<NUM>-dimethylethyl ester (<NPL>, vendor: PharmaBlock) instead of [(2R,6R)-<NUM>-(<NUM>-cyano-<NUM>-fluoro-pyrazolo[<NUM>,<NUM>-a]pyridin-<NUM>-yl)-<NUM>-methyl-morpholin-<NUM>-yl]methyl trifluoromethanesulfonate (Intermediate E) and tert-butyl <NUM>-bromospiro[<NUM>-isobenzofuran-<NUM>,<NUM>'-azetidine]-<NUM>'-carboxylate (compound 1a ). Example <NUM> (<NUM>) was obtained as a light yellow solid. MS: calc'd <NUM> (MH+), measured <NUM> (MH+). <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <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> - <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>-bromospiro[<NUM>-furo[<NUM>,<NUM>-b]pyridine-<NUM>,<NUM>-azetidine]-<NUM>-carboxylate (<NPL>, vendor: PharmaBlock) instead of tert-butyl <NUM>-bromospiro[<NUM>H-isobenzofuran-<NUM>,<NUM>'-azetidine]-<NUM>'-carboxylate (compound 1a). Example <NUM> (<NUM>) was obtained as a light yellow solid. MS: calc'd <NUM> (MH+), measured <NUM> (MH+). <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (d, <NUM>, J=<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> (s, <NUM>), <NUM>-<NUM> (m, <NUM>).

The following tests were carried out in order to determine the activity of the compounds of formula (I) and (Ia) 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-qbl, 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 In vivoGen (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-qbl, 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 In vivoGen (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-qbl, 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) or (Ia) have human TLR7 and/or TLR8 inhibitory activities (IC<NUM> value) <<NUM>. Moreover, some compounds also have human TLR9 inhibitory activity <<NUM>. Activity data of the compounds of the present invention were shown 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>. A safety ratio (hERG IC<NUM> /EC<NUM>) > <NUM> suggests a sufficient window to differentiate the pharmacology by inhibiting TLR7/<NUM>/<NUM> pathways from the potential hERG related cardiotoxicity. According to the calculation of hERG IC<NUM> / TLR7/<NUM>/<NUM> IC<NUM> below which serves as early selectivity index to assess hERG liability, obviously reference compounds ER-<NUM>, ER-<NUM>, ER-<NUM>, R1 and R2 have much narrower safety window compared to the compounds of this invention.

The compounds would be desirable to have minimal DDI liabilities. Therefore, the effects of compounds of formula (I) of (Ia) on major CYP isoforms, e.g. CYP2C9, CYP2D6 and CYP3A4, are determined.

This is a high throughput screening assay used for assessment of reversible inhibition of CYP2C9, CYP2D6, and CYP3A4 activity of test compounds in human liver microsome (HLM) in early discovery stage.

<NUM> DMSO stock solutions of test compounds were diluted in DMSO to generate <NUM> intermediate stock solution. <NUM> nL of intermediate stock solution were transferred in duplicate into <NUM> separate <NUM> well microtitre plates (assay-ready plates). A mixture of HLM and each substrate was made up. <NUM>µL of HLM substrate mix was then transferred to each well of an assay ready plate and mixed. The negative (solvent) and positive controls (standard inhibitor for each CYP) were included in each assay ready plate. The assay ready plate was warmed to <NUM> in an incubator over <NUM> minutes. <NUM>µL pre-warmed NADPH regenerating system was added to each incubation well to start the reaction. Final incubation volume was <NUM>µL. The assay plate then was placed back in the <NUM> incubator. After incubation (<NUM> minutes for CYP2D6) for <NUM> minutes, incubates were quenched by addition of <NUM>µL <NUM>% acetonitrile containing internal standards (<NUM> ng/mL 13C6-<NUM>'-OH-Diclofenac, <NUM> ng/mL D3-Dextrorphan and <NUM> ng/mL D4-<NUM>'OH-Midazolam). The supernatants were collected for RapidFire/MS/MS analysis.

RapidFire online solid phase extraction/sample injection system (Agilent) coupled with API4000 triple quadrupole mass spectrometer (AB Sciex) were used for sample analysis. The mobile phase composed of acetonitrile and water supplemented with <NUM>% formic acid. A C4 solid phase extraction cartridge is used for sample separation. MS detection is achieved in positive ion MRM mode.

Peak areas for substrate, metabolite and internal standard are determined using the RapidFire integrator software (version <NUM>. Peak area ratios (PAR) of metabolite and internal standard (stable-labelled metabolite) are then calculated. The measurement window for each experiment is then defined: <MAT> <MAT> <MAT> <MAT>.

The compounds of present invention were found to have low CYP inhibition for CYP2D6 determined in the assays described above.

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;
Y and A are independently selected from CH and N;
or a pharmaceutically acceptable salt thereof.