Spiro(isobenzofuranazetidine) compounds for the treatment of autoimmune diseases

Abstract

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

Description

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

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

[0003] Toll-like receptors (TLR) are an important family of pattern recognition receptors (PRRs), which can trigger a wide range of immune responses in a variety of immune cells. Endosome TLR 7, TLR8 and TLR9, as natural host defense sensors, can identify nucleic acids derived from viruses and bacteria; Specifically, TLR7 / TLR8 and TLR9 recognize single-stranded RNA (ssRNA) and single-stranded CpG-DNA, respectively. However, the abnormal nucleic acid sensing of TRL7, TRL8, and TRL9 is considered to be a key node of extensive autoimmunity and autoinflammatory diseases (Krieg, AM et al., Immunol. Rev. 2007, 220, 251. Jiménez-Dalmaroni, MJ et al., Autoimmun Rev. 2016, 15, 1. Chen, JQ et al., Clinical Reviews in Allergy & Immunology 2016, 50, 1.). Anti-RNA and anti-DNA antibodies are recognized diagnostic markers for SLE, and these antibodies can deliver both self RNA and self DNA to endosomes. Self-RNA complexes can be recognized by TLR7 and TLR8, while self-DNA complexes can trigger TLR9 activation. In fact, defective clearance of self-RNA and self-DNA from blood and / or tissues is evident in patients with SLE (systemic lupus erythematosus). TLR7 and TLR9 have been reported to be upregulated in SLE tissues and are associated with the chronicity and activity of lupus nephritis, respectively. In B cells of SLE patients, TLR7 expression is associated with the production of anti-RNP antibodies, while TLR9 expression is associated with IL-6 and anti-dsDNA antibody levels. Consistently, in a lupus mouse model, TLR7 is required for anti-RNA antibodies and TLR9 for anti-nucleosome antibodies. On the other hand, overexpression of TLR7 or human TLR8 in mice promotes autoimmunity and autoinflammation. In addition, activation of TLR8 is particularly conducive to the secretion of inflammatory cytokines by mDC / macrophages, the process of neutrophil extracellular trapping (NETosis), the induction of Th17 cells, and the suppression of Treg cells. In addition to the described role of TLR9 in promoting B cell autoantibody production, activation of TLR9 by self-DNA in pDCs also leads to the induction of type I IFN and other inflammatory cytokines. Considering these roles of TLR9 in both pDCs and B cells, both of which are key players in the pathogenesis of autoimmune diseases, and the abundance of self-DNA complexes that readily activate TLR9 in many patients with autoimmune diseases, it may have additional benefits to further block the self-DNA-mediated TLR9 pathway in addition to inhibiting the TLR7 and TLR8 pathways.In summary, TLR7, 8 and 9 pathways represent new therapeutic targets for the treatment of autoimmune and autoinflammatory diseases for which there are no effective steroid-free and non-cytotoxic oral drugs, and inhibition of all of these pathways very upstream may lead to satisfactory therapeutic effects. Therefore, we have invented oral compounds that target and inhibit TLR7, TLR8 and TLR9 for the treatment of autoimmune and autoinflammatory diseases. Summary of the invention

[0004] The present invention relates to novel compounds of formula (I) and formula (Ia),

[0005]

[0006] in

[0007] R 1 for Where R 4 C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogen, nitro or cyano; R 4a C 1-6 Alkyl or C 3-7 Cycloalkyl; R 5 , R 5a and R 5b are independently selected from H and deuterium; R 6 is H or halogen;

[0008] R 2 C 1-6 alkyl;

[0009] R 3 is an unsubstituted or substituted heterocyclic group;

[0010] Y and A are independently selected from CH and N;

[0011] or a pharmaceutically acceptable salt thereof.

[0012] Another object of the present invention relates to novel compounds of formula (I) or (Ia), their production, drugs based on compounds according to the present invention and their preparation, and the use of compounds of formula (I) or (Ia) as TLR7 and / or TLR8 and / or TLR9 antagonists, and for the treatment or prevention of systemic lupus erythematosus or lupus nephritis. The compounds of formula (I) or (Ia) show excellent TLR7 and / or TLR8 and / or TLR9 antagonistic activity. In addition, the compounds of formula (I) or (Ia) also show good hPBMC, cytotoxicity, solubility, human microsomal stability and SDPK characteristics, as well as low CYP inhibition. DETAILED DESCRIPTION

[0013] definition

[0014] The term "C 1-6 "Alkyl" means a saturated, straight-chain or branched alkyl group containing 1 to 6, especially 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc. In particular, "C 1-6 "Alkyl" groups are methyl, ethyl and n-propyl.

[0015] The term "C 3-7 "Cycloalkyl" means a saturated carbocyclic ring containing 3 to 7 carbon atoms, especially 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. In particular, "C 3-7 "Cycloalkyl" groups are cyclopropyl, cyclopentyl and cyclohexyl.

[0016] The terms "halogen" and "halo" are used interchangeably herein to refer to fluorine, chlorine, bromine or iodine.

[0017] The term "C 1-6 "Alkoxy" means C 1-6 Alkyl-O-.

[0018] The term "halopyrrolidinyl" refers to a pyrrolidinyl group substituted once, twice or three times with halogen. Examples of halopyrrolidinyl groups include, but are not limited to, difluoropyrrolidinyl and fluoropyrrolidinyl.

[0019] The term "heterocyclyl" or "heterocycle" refers to a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system having 3 to 12 ring atoms, which contains 1 to 5 heteroatoms selected from N, O and S, and the remaining ring atoms are carbon. In a specific embodiment, the heterocyclyl is a monovalent saturated monocyclic ring system of 4 to 7 ring atoms, which contains 1, 2 or 3 ring heteroatoms selected from N, O and S, and the remaining ring atoms are carbon. Examples of monocyclic saturated heterocyclyl are aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, oxazepanyl. Examples of bicyclic saturated heterocycles are azabicyclo[3.2.1]octyl, quinuclidinyl, oxazabicyclo[3.2.1]octyl, azabicyclo[3.3.1]nonanyl, oxaza-bicyclo[3.3.1]nonanyl, azabicyclo[3.1.0]hexanyl, oxodiazaspiro[3.4]octanyl, acetyloxodiazaspiro[3.4]octanyl, thiazabicyclo[3.3.1]nonanyl, oxoazaspiro[2.4]heptanyl, oxoazaspiro[3.4]octanyl, oxoazabicyclo[3.1.0]hexanyl and dioxotetrahydropyrrolo[1,2-a]pyrazinyl. Examples of bicyclic heterocyclic groups include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl; 5,6,7,8-tetrahydro-1,6-naphthyridinyl; 5,6,7,8-tetrahydro-1,7-naphthyridinyl; 5,6,7,8-tetrahydro-2,6-naphthyridinyl; 5,6,7,8-tetrahydro-2,7-naphthyridinyl; isoindolyl. Examples of heterocyclic groups may be further substituted with amino, C 1-6 Alkyl, C 3-7 Cycloalkyl, halogen, hydroxyl or C 1-6 Alkoxy substitution.

[0020] The term "pharmaceutically acceptable salts" refers to salts that are not biologically or otherwise undesirable. "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts.

[0021] "Pharmaceutically acceptable acid addition salts" refer to those pharmaceutically acceptable salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and the like, and organic acids, which may be selected from aliphatic, alicyclic, aromatic, aromatic aliphatic, heterocyclic, carboxylic and sulfonic acid organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, pamoic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid, and the like.

[0022] The term "pharmaceutical base addition salt" refers to those pharmaceutical salts formed with organic or inorganic bases. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese and aluminum salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines and basic ion exchange resins (such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine and polyamine resins).

[0023] The term "pharmaceutically active metabolite" refers to a pharmacologically active product produced by the metabolism of a specific compound or its salt in the body. After entering the human body, most drugs are substrates for chemical reactions that may change their physical properties and biological effects. These metabolic transformations, which usually affect the polarity of the compounds of the present invention, change the way the drug is distributed in the body and excreted from the body. However, in some cases, drug metabolism is necessary for therapeutic effects.

[0024] The term "therapeutically effective amount" refers to an amount of a compound or molecule of the invention that, when administered to a subject, (i) treats or prevents a particular disease, condition or disorder, (ii) reduces, ameliorates or eliminates one or more symptoms of a particular disease, condition or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition or disorder as described herein. The therapeutically effective amount depends on the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary doctor and other factors.

[0025] The term "pharmaceutical composition" means a mixture or solution comprising a therapeutically effective amount of an active drug ingredient together with a pharmaceutically acceptable excipient for administration to a mammal (eg, a human) in need thereof.

[0026] Antagonists of TLR7 and / or TLR8 and / or TLR9

[0027] The present invention relates to (i), which is a compound of formula (I),

[0028]

[0029] in

[0030] R 1 for Where R 4 C 1-6 Alkyl, C1-6 Alkoxy, halogenated C 1-6 Alkyl, halogen, nitro or cyano; R 4a C 1-6 Alkyl or C 3-7 Cycloalkyl; R 5 , R 5a and R 5b are independently selected from H and deuterium; R 6 is H or halogen;

[0031] R 2 C 1-6 alkyl;

[0032] R 3 is an unsubstituted or substituted heterocyclic group;

[0033] Y and A are independently selected from CH and N;

[0034] or a pharmaceutically acceptable salt thereof.

[0035] A further embodiment of the present invention is (ii), which is a compound of formula (I) according to (i), wherein

[0036] R 1 for Where R 4 is cyano; R 4a C 1-6 Alkyl; R 5 is H or deuterium; R 6 is H or halogen;

[0037] R 2 C 1-6 alkyl;

[0038] R 3 2,6-diazaspiro[3.3]heptyl; 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl; 5-oxa-2,8-diazaspiro[3.5]nonyl; amino(C 1-6 alkyl)azetidinyl; amino (C 1-6 alkyl)pyrrolidinyl; amino(C 1-6 (alkyloxy)pyrrolidinyl; amino(hydroxy)pyrrolidinyl; aminoazetidinyl; C 1-6 Alkyl-2,6-diazaspiro[3.3]heptyl; halogenated pyrrolidinylamino or piperazinyl;

[0039] Y and A are independently selected from CH and N, provided that Y and A are not N at the same time;

[0040] or a pharmaceutically acceptable salt thereof.

[0041] Another embodiment of the present invention is (iii), which is a compound of formula (Ia),

[0042]

[0043] in

[0044] R 1 for Where R 4 is cyano; R 4a C 1-6 Alkyl; R 5 is H or deuterium; R 6 is H or halogen;

[0045] R 2 C 1-6 alkyl;

[0046] R 3 2,6-diazaspiro[3.3]heptyl; 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl; 5-oxa-2,8-diazaspiro[3.5]nonyl; amino(C 1-6 alkyl)azetidinyl; amino (C 1-6 alkyl)pyrrolidinyl; amino(C 1-6 (alkyloxy)pyrrolidinyl; amino(hydroxy)pyrrolidinyl; aminoazetidinyl; C 1-6 Alkyl-2,6-diazaspiro[3.3]heptyl; halogenated pyrrolidinylamino or piperazinyl;

[0047] Y and A are independently selected from CH and N, provided that Y and A are not N at the same time;

[0048] or a pharmaceutically acceptable salt thereof.

[0049] A further embodiment of the present invention is (iv), which is a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof according to any one of (i) to (iii), wherein R 1 for Where R 4 is cyano; R 5 is H or deuterium; R 6 is H or halogen.

[0050] A further embodiment of the present invention is (v), which is a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof according to any one of (i) to (iv), wherein R 1 for Where R 4 is cyano; R 5 is H or deuterium; R6 is H or fluorine.

[0051] A further embodiment of the present invention is (vi), which is a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof according to any one of (i) to (v), wherein Y is CH and A is N; or Y is N and A is CH.

[0052] A further embodiment of the present invention is (vii), which is a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof according to any one of (i) to (vi), wherein R 3 Amino (C 1-6 alkyl)azetidinyl; 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl or amino(C 1-6 alkoxy)pyrrolidinyl.

[0053] A further embodiment of the present invention is (viii), which is a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof according to any one of (i) to (vii), wherein R 3 It is 3-amino-3-methyl-azetidin-1-yl; 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl or 3-amino-4-methoxy-pyrrolidin-1-yl.

[0054] A further embodiment of the present invention is (ix), which is a compound of formula (I) or (Ia) according to any one of (i) to (viii), wherein

[0055] R 1 for Where R 4 is cyano; R 5 Deuterium

[0056] R 2 C 1-6 alkyl;

[0057] R 3 Amino (C 1-6 alkyl)azetidinyl; 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl or amino(C 1-6 Alkoxy)pyrrolidinyl;

[0058] Y is CH and A is N; or Y is N and A is CH;

[0059] or a pharmaceutically acceptable salt thereof.

[0060] A further embodiment of the present invention is (x), which is a compound of formula (I) or (Ia) according to any one of (i) to (ix), wherein

[0061] R 1 for Where R 4 is cyano; R 5 for deuterium;

[0062] R 2 is methyl;

[0063] R 3 is 3-amino-3-methyl-azetidin-1-yl; 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl or 3-amino-4-methoxy-pyrrolidin-1-yl;

[0064] Y is CH and A is N; or Y is N and A is CH;

[0065] or a pharmaceutically acceptable salt thereof.

[0066] Another embodiment of the present invention is (ix), which is a compound of formula (I) or (Ia) selected from:

[0067] 4-[(2S,6R)-2-[[6-(3-amino-3-methyl-azetidin-1-yl)spiro[1H-isobenzofuran-3,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile;

[0068] 3-Fluoro-4-[(2R,6S)-2-methyl-6-[[6-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)spiro[1H-isobenzofuran-3,3'-azetidin-1'-yl]methyl]morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile;

[0069] 3-Fluoro-4-[(2S,6R)-2-[[6-[[(3S,4R)-4-fluoropyrrolidin-3-yl]amino]spiro[1H-isobenzofuran-3,3'-azetidin-1'-yl]methyl]-6-methyl-morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile;

[0070] 3-Fluoro-4-[(2R,6S)-2-methyl-6-[[6-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)spiro[1H-isobenzofuran-3,3'-azetidin-1'-yl]methyl]morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile;

[0071] 4-[(2S,6R)-2-[[6-[(3S)-3-amino-3-methyl-pyrrolidin-1-yl]spiro[1H-isobenzofuran-3,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile;

[0072] 3-Fluoro-4-[(2R,6S)-2-methyl-6-[(6-piperazin-1-ylspiro[1H-isobenzofuran-3,3'-azetidine]-1'-yl)methyl]morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile;

[0073] 4-[(2R,6S)-2-methyl-6-[[6-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)spiro[1H-isobenzofuran-3,3'-azetidin-1'-yl]methyl]morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile;

[0074] 4-[(2R,6S)-2-methyl-6-[[6-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)spiro[1H-isobenzofuran-3,3'-azetidin-1'-yl]methyl]morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile;

[0075] 4-[(2S,6R)-2-[[6-(3-aminoazetidin-1-yl)spiro[1H-isobenzofuran-3,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile;

[0076] 4-[(2S,6R)-2-[[6-[(3S,4S)-3-amino-4-hydroxy-pyrrolidin-1-yl]spiro[1H-isobenzofuran-3,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile;

[0077] 5-[(2S,6R)-2-[[6-(3-amino-3-methyl-azetidin-1-yl)spiro[1H-isobenzofuran-3,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-2-deutero-quinoline-8-carbonitrile;

[0078] 4-[(2S,6R)-2-[[6-(2,6-diazaspiro[3.3]heptane-2-yl)spiro[1H-isobenzofuran-3,3'-azetidin-1'-yl]methyl]-6-methyl-morpholin-4-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile;

[0079] 4-[(2S,6R)-2-[[6-(3-aminoazetidin-1-yl)spiro[1H-isobenzofuran-3,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-1-methyl-1,8-naphthyridin-2-one;

[0080] 5-[(2S,6R)-2-[[6-(3-aminoazetidin-1-yl)spiro[1H-isobenzofuran-3,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-2-deutero-quinoline-8-carbonitrile;

[0081] 2-deuterated-5-[(2R,6S)-2-methyl-6-[[6-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)spiro[1H-isobenzofuran-3,3'-azetidin-1'-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

[0082] 5-[(2S,6R)-2-[[6-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]spiro[1H-isobenzofuran-3,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-2-deutero-quinoline-8-carbonitrile;

[0083] 5-[(2S,6R)-2-[[6-[(4aR,7aR)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl]spiro[1H-isobenzofuran-3,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-2-deutero-quinoline-8-carbonitrile;

[0084] 2-deuterated-5-[(2R,6S)-2-methyl-6-[(6-piperazin-1-ylspiro[1H-isobenzofuran-3,3'-azetidine]-1'-yl)methyl]morpholin-4-yl]quinoline-8-carbonitrile;

[0085] 4-[(2S,6R)-2-[[6-(3-aminoazetidin-1-yl)spiro[1H-isobenzofuran-3,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile;

[0086] 5-[(2S,6R)-2-[[3-(3-aminoazetidin-1-yl)spiro[5H-furo[3,4-b]pyridine-7,3'-azetidin-1'-yl]methyl]-6-methyl-morpholin-4-yl]-2-deutero-quinoline-8-carbonitrile;

[0087] 5-[(2S,6R)-2-[[3-(3-amino-3-methyl-azetidin-1-yl)spiro[5H-furo[3,4-b]pyridine-7,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-2-deutero-quinoline-8-carbonitrile;

[0088] 3-Fluoro-4-[(2R,6S)-2-methyl-6-[[3-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)spiro[5H-furo[3,4-b]pyridine-7,3'-azetidin]-1'-yl]methyl]morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile;

[0089] 5-[(2S,6R)-2-[[6-(3-amino-3-methyl-azetidin-1-yl)spiro[1H-furo[3,4-c]pyridine-3,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-2-deutero-quinoline-8-carbonitrile;

[0090] 4-[(2S,6R)-2-[[6-(3-amino-3-methyl-azetidin-1-yl)spiro[1H-furo[3,4-c]pyridine-3,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile;

[0091] 4-[(2S,6R)-2-[[6-(3-amino-3-methyl-azetidin-1-yl)spiro[1H-furo[3,4-c]pyridine-3,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile;

[0092] 4-[(2S,6R)-2-[[3-(3-amino-3-methyl-azetidin-1-yl)spiro[5H-furo[3,4-b]pyridine-7,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile;

[0093] 5-[(2S,6R)-2-[[6-[(4aR,7aR)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl]spiro[1H-furo[3,4-c]pyridine-3,3'-azetidin-1'-yl]methyl]-6-methyl-morpholin-4-yl]-2-deutero-quinoline-8-carbonitrile;

[0094] 5-[(2S,6R)-2-[[3-[(4aR,7aR)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl]spiro[5H-furo[3,4-b]pyridine-7,3'-azetidin-1'-yl]methyl]-6-methyl-morpholin-4-yl]-2-deutero-quinoline-8-carbonitrile;

[0095] 5-[(2S,6R)-2-[[3-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]spiro[5H-furo[3,4-b]pyridine-7,3'-azetidin-1'-yl]methyl]-6-methyl-morpholin-4-yl]-2-deutero-quinoline-8-carbonitrile;

[0096] 5-[(2S,6R)-2-[[6-(3-aminoazetidin-1-yl)spiro[1H-furo[3,4-c]pyridine-3,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-2-deutero-quinoline-8-carbonitrile; and

[0097] 4-[(2S,6R)-2-[[3-(3-amino-3-methyl-azetidin-1-yl)spiro[5H-furo[3,4-b]pyridine-7,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile;

[0098] or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

[0099] Patent US20150105370 discloses a variety of compounds used as references herein, which show TLR7 and TLR9 efficacy data summarized in Table 1 (TLR8 data is not obtained). All compounds in Table 1 have aromatic rings (phenyl or pyridyl) at the terminal position. However, according to the disclosed efficacy data, only some compounds in Table 1 show good TLR7 efficacy, while all of these compounds lack TLR9 efficacy. More examples with the same structural features disclosed in US20150105370 confirm this trend, indicating that the terminal aryl / heteroaryl ring is not conducive to TLR9 activity.

[0100] At the same time, more analogs of the compounds disclosed in US20150105370, such as compounds R1 and R2 with some substituents on the terminal aromatic ring, were synthesized to confirm SAR (structure-activity-relationship). However, according to the efficacy data shown in Table 2, the substituents on the terminal aromatic ring may not necessarily improve the efficacy of TLR9. Therefore, those skilled in the art will not get any inspiration from the information disclosed in US20150105370 to further optimize this chemical structure.

[0101] Surprisingly, the compounds of the present invention significantly improved TLR9 potency (>8-fold compared to ER-888286) while maintaining excellent TLR7 and TLR8 potency. In another embodiment, the hERG characteristics and safety ratios are greatly improved compared to the reference compounds from US20150105370 and the reference compounds R1 and R2 synthesized herein (see Table 3). The compounds of formula (I) or formula (Ia) also show good hPBMC, cytotoxicity, solubility, human microsomal stability and SDPK characteristics, as well as low CYP inhibition.

[0102] Table 1. TLR7 and TLR9 potency of compounds disclosed in US20150105370

[0103]

[0104]

[0105] synthesis

[0106] The compounds of the present invention may be prepared by any conventional method. Suitable methods for synthesizing these compounds and their starting materials are provided in the following schemes and examples. Unless otherwise indicated, all substituents, especially R 1 To R 6 As defined above. Furthermore, unless otherwise specifically indicated, all reactions, reaction conditions, abbreviations and symbols have the meanings well known to one of ordinary skill in the art of organic chemistry.

[0107] A general synthetic route for preparing compounds of formula (I) is shown in Scheme 1 below.

[0108] Solution 1

[0109]

[0110] wherein X is a halogen; LG is a leaving group such as OTf, OT and OM; and PG is a protecting group such as Boc and Cbz.

[0111] The compound of formula (II) and R 1-X coupling can be in the presence of a base (such as DIPEA or K2CO3) or under Buchwald-Hartwig amination conditions (see: Acc.Chem.Res.1998,31,805-818; Chem.Rev.2016,116,12564-12649; Topics in Current Chemistry,2002,219,131-209; and references cited therein), using a catalyst (such as RuPhos Pd G2) and a base (such as Cs2CO3) to achieve to provide a compound of formula (III). Subsequently, the hydroxyl group of the compound of formula (III) is converted into a leaving group (such as OTf, OT and OM) using Tf2O, TsCl or MsCl under basic conditions (such as DIPEA, TEA, K2CO3) and 2,6-lutidine. The protecting group of the compound of formula (V) can be removed at high temperature or under acidic conditions (such as TFA), or under hydrogenation conditions, using a catalyst (such as Pd / C and Pd(OH) / C). In the presence of a base (such as KCO, DIPEA and CsCO), the compound of formula (IV) is further replaced by a compound of formula (VI) to obtain a compound of formula (VII). The coupling of compounds of formula (VII) with compounds of formula (VIII) can be achieved under Buchwald-Hartwig amination conditions (see: Acc. Chem. Res. 1998, 31, 805-818; Chem. Rev. 2016, 116, 12564-12649; Topics in Current Chemistry, 2002, 219, 131-209; and references cited therein) using a catalyst (such as tBuXPhos Pd G3, RuPhos Pd G2, BrettPhos Pd G3, XPhos Pd G3, Pd2(dba)3 / BINAP and Pd2(dba)3 / XantPhos) and a base (such as Cs2CO3 or t-BuONa) to provide compounds of formula (I). In some embodiments, coupling of compounds of formula (VII) with amines (VIII) may provide products containing protecting groups derived from (VIII) (eg, Boc or Cbz) which are removed prior to obtaining the final compounds of formula (I).

[0112] The compounds of the present invention can be obtained as diastereomers or mixtures of enantiomers, which can be separated by methods well known in the art, for example, (chiral) HPLC or SFC. In another embodiment, compounds of formula (Ia) can be obtained according to the above scheme using the corresponding chiral starting materials.

[0113] The compounds of the invention may be obtained in the form of diastereomers or mixtures of enantiomers which may be separated by methods well known in the art, for example, (chiral) HPLC or SFC.

[0114] The present invention also relates to a method for preparing a compound of formula (I) or (Ia), the method comprising the following steps:

[0115] a) a compound of formula (VII),

[0116]

[0117] With amine HR 3 (VIII) reacts via Buchwald-Hartwig amination;

[0118] wherein X is halogen, and Y and A are independently selected from CH and N.

[0119] It is also an object of the present invention to prepare compounds of formula (I) or (Ia) according to the above-mentioned process using achiral or chiral starting materials.

[0120] Indications and treatments

[0121] The present invention provides compounds that can be used as TLR7 and / or TLR8 and / or TLR9 antagonists, which inhibit activation of TLR7 and / or TLR8 and / or TLR9 pathways and corresponding downstream biological events, including but not limited to innate and adaptive immune responses mediated by the production of all types of cytokines and various forms of autoantibodies. Therefore, the compounds of the present invention can be used to block TLR7 and / or TLR8 and / or TLR9 in all types of cells expressing such receptors, including but not limited to plasmacytoid dendritic cells, B cells, T cells, macrophages, monocytes, neutrophils, keratinocytes, epithelial cells. In this way, the compound can be used as a therapeutic agent or preventive agent for systemic lupus erythematosus and lupus nephritis.

[0122] The present invention provides methods for treating or preventing systemic lupus erythematosus and lupus nephritis in a patient in need thereof.

[0123] Another embodiment includes a method of treating or preventing systemic lupus erythematosus and lupus nephritis in a mammal in need of such treatment, wherein the method comprises administering to the mammal a therapeutically effective amount of a compound of formula (I), a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof.

[0124] Examples

[0125] The present invention will be more fully understood by referring to the following examples. However, they should not be construed as limiting the scope of the present invention.

[0126] abbreviation

[0127] The present invention will be more fully understood by referring to the following examples. However, they should not be construed as limiting the scope of the present invention.

[0128] The abbreviations used in this article are as follows:

[0129] ACN: Acetonitrile

[0130] Boc2O: di-tert-butyl dicarbonate

[0131] Tf2O: trifluoromethanesulfonic anhydride

[0132] DCM: Dichloromethane

[0133] DDI Drug-Drug Interactions

[0134] DIPEA Diethylisopropylamine

[0135] EA or EtOAc: Ethyl acetate

[0136] FA: Formic acid

[0137] HLM Human Liver Microsomes

[0138] hr hour

[0139] hrs hours

[0140] IC 50 : Half inhibitory concentration

[0141] LCMS Liquid chromatography-mass spectrometry

[0142] LYSA freeze-dried solubility assay

[0143] MS: mass spectrometry

[0144] PE: Petroleum Ether

[0145] prep-HPLC: Preparative High Performance Liquid Chromatography

[0146] rt: rt

[0147] RT: retention time

[0148] RuPhos Pd G2: Chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) second generation

[0149] SFC: Supercritical Fluid Chromatography

[0150] TFA: trifluoroacetic acid

[0151] v / v volume ratio

[0152] General experimental conditions

[0153] Intermediates and final compounds were purified by flash chromatography using one of the following instruments: i) Biotage SP1 system and Quad 12 / 25 Cartridge module. ii) ISCO combi-flash chromatograph. Silica gel brand and pore size: i) KP-SIL Particle size: 40-60 μm; ii) CAS registration number: silica gel: 63231-67-4, particle size: 47-60 micron silica gel; iii) ZCX from Qingdao Ocean Chemical Co., Ltd., pore size: 200-300 or 300-400.

[0154] Intermediates and final compounds were purified by preparative HPLC on a reverse phase column using XBridge TM Prep-C18 (5μm, OBDTM 30×100mm) column, SunFire TM Prep-C18(5μm,OBD TM 30×100mm) chromatographic column, Phenomenex Synergi-C18 (10μm, 25×150mm) or Phenomenex Gemini-C18 (10μm, 25×150mm). Waters AutoP purification system (sample manager 2767, pump 2525, detector: Micromass ZQ and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water; acetonitrile and 0.1% FA in water, or acetonitrile and 0.1% TFA in water). Or Gilson-281 purification system (pump 322, detector: UV 156, solvent system: acetonitrile and 0.05% ammonium hydroxide in water; acetonitrile and 0.225% FA in water; acetonitrile and 0.05% HCl in water; acetonitrile and 0.075% TFA in water; or acetonitrile and water).

[0155] For SFC chiral separation, the intermediates were separated by chiral columns (Daicel chiralpak IC, 5 μm, 30×250 mm), AS (10 μm, 30×250 mm) or AD (10 μm, 30×250 mm), using Mettler Toledo Multigram III system SFC, Waters 80Q preparative SFC or Thar 80 preparative SFC, solvent system: CO2 and IPA (0.5% TEA in IPA solution) or CO2 and MeOH (0.1% NH3·H2O in MeOH solution), back pressure 100 bar, UV detection at 254 or 220 nm.

[0156] Using LC / MS (Waters TM The LC / MS spectra of the compounds were obtained using an Agilent Alliance 2795-Micromass ZQ, Shimadzu Alliance 2020-Micromass ZQ, or Agilent Alliance 6110-Micromass ZQ. The LC / MS conditions were as follows (run time 3 or 1.5 min):

[0157] Acidic conditions I: A: 0.1% TFA solution in H2O; B: 0.1% TFA solution in acetonitrile;

[0158] Acidic conditions II: A: 0.0375% TFA solution in H2O; B: 0.01875% TFA solution in acetonitrile;

[0159] Basic conditions I: A: 0.1% NH3·H2O solution in H2O; B: acetonitrile;

[0160] Basic conditions II: A: 0.025% NH3·H2O solution in H2O; B: acetonitrile;

[0161] Neutral conditions: A: H2O; B: acetonitrile.

[0162] Mass spectra (MS): Usually only ions representing the parent mass are reported, and unless otherwise stated, the mass ion quoted is the positive mass ion (MH) + .

[0163] NMR spectra were obtained using a Bruker Avance 400 MHz.

[0164] Microwave-assisted reactions were performed in a Biotage Initiator Sixty microwave synthesizer. All reactions involving air-sensitive reagents were performed under argon or nitrogen atmosphere. Unless otherwise stated, reagents were used as received from commercial suppliers without further purification.

[0165] Preparation Example

[0166] The following examples are intended to illustrate the meaning of the present invention, but are by no means intended to limit the meaning of the present invention:

[0167] Intermediate E

[0168] [(2R,6R)-4-(7-Cyano-3-fluoro-pyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholin-2-yl]trifluoromethanesulfonic acid methyl ester

[0169]

[0170] The title compound was prepared according to the following scheme:

[0171]

[0172] Step 1: Preparation of 4-chloro-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile (Compound E1)

[0173] To a solution of 4-chloropyrazolo[1,5-a]pyridine-7-carbonitrile (CAS: 1268520-74-6, supplier: Pharmablock, 600 mg, 3.38 mmol) in acetonitrile (50 mL) was added a selective fluorine reagent (2.39 g, 6.76 mmol). After stirring at room temperature for 24 hours, the mixture was concentrated and diluted with water (30 mL) and extracted twice with DCM (30 mL). The organic layer was washed with NH4Cl and brine, dried over Na2SO4, and concentrated to give a crude product, which was purified by silica gel chromatography to give compound E1 (419 mg) as a light yellow powder. MS: calculated 196 (MH + ), measured 196 (MH + ). 1 H NMR (400 MHz, methanol-d4) δ = 8.17 (d, J = 3.5 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.35 (d, J = 7.7 Hz, 1H).

[0174] Step 2: Preparation of 3-fluoro-4-[(2R,6R)-2-(hydroxymethyl)-6-methyl-morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile (Compound E2)

[0175] To a solution of 4-chloro-3-fluoropyrazolo[1,5-a]pyridine-7-carbonitrile (compound E1, 419 mg, 2.14 mmol), [(2R,6R)-6-methylmorpholin-2-yl]methanol; 2,2,2-trifluoroacetic acid (compound A1, 526 mg, 2.14 mmol) and Cs2CO3 (2.79 g, 8.57 mmol) in 1,4-dioxane (10 mL) was added RuPhos Pd G2 (116 mg, 0.15 mmol) under N2. The reaction mixture was heated at 90 °C for 2 hours. After cooling, the mixture was diluted with EtOAc and filtered through diatomaceous earth. The filtrate was concentrated to give a brown oil, which was purified by silica gel chromatography to give compound E2 (325 mg) as a yellow oil. MS: calculated 291 (MH + ), measured 291(MH + ).

[0176] Step 3: Preparation of (2R,6R)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholin-2-yl]trifluoromethanesulfonic acid methyl ester (Intermediate E)

[0177] To a solution of 3-fluoro-4-[(2R,6R)-2-(hydroxymethyl)-6-methyl-morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile (Compound E2, 325 mg, 1.12 mmol) in DCM (3 mL) was added 2,6-lutidine (240 mg, 258 μL, 2.24 mmol) and Tf2O (474 ​​mg, 284 μL, 1.68 mmol) at room temperature. After stirring for 1.5 hours, the mixture was diluted with DCM, washed with saturated NH4Cl and brine. The organic layer was dried over Na2SO4 and concentrated to give the crude product, which was purified by silica gel chromatography to give Intermediate E (180 mg) as a yellow solid. MS: Calculated 423 (MH + ), measured 423 (MH + ).

[0178] Intermediate F

[0179] [(2R,6R)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholin-2-yl]trifluoromethanesulfonic acid methyl ester

[0180]

[0181] The title compound was prepared similarly to the preparation method of intermediate E, using 4-chloropyrazolo[1,5-a]pyridine-7-carbonitrile (CAS: 1268520-74-6, supplier: PharmaBlock) instead of 4-chloro-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile (Compound E1). Intermediate F (166 mg) was obtained as a white solid. MS: Calculated 405 (MH + ), measured 405(MH + ).

[0182] Intermediate L

[0183] [(2R,6R)-4-(8-Cyano-2-deuterated-5-quinolyl)-6-methyl-morpholin-2-yl]trifluoromethanesulfonic acid methyl ester

[0184]

[0185] Intermediate L was prepared according to the following scheme:

[0186]

[0187] Step 1: Preparation of N-(2-bromo-5-fluoro-phenyl)-3,3-dimethoxy-propionamide (Compound L1)

[0188] At 0°C, to a solution of 2-bromo-5-fluoroaniline (CAS: 1003-99-2, supplier: TCI, 50 g, 263.14 mmol) and 3,3-dimethoxypropionic acid methyl ester (CAS: 7424-91-1, supplier: Accela, 45 mL, 315.77 mmol) in THF (150 mL) was added dropwise NaHMDS (1 M, 394 mL, 394.72 mmol) in THF. After stirring at 0°C for 10 min, the mixture was warmed to 15°C and stirred for 18 hours. The reaction was quenched by adding 100 mL of saturated NH4Cl, and concentrated to about 300 mL. The solution was diluted with 500 mL of water and extracted three times with 200 mL of EA. The combined organic layers were washed twice with 200 mL of water and 100 mL of brine, dried over Na2SO4, and concentrated to give the crude product L1 (100 g) as a brown oil. MS calculated 321 (MH + ), measured value 321(MH + ).

[0189] Step 2: Preparation of 8-bromo-5-fluoro-1H-quinolin-2-one (Compound L2)

[0190] At 0°C, a solution of N-(2-bromo-5-fluoro-phenyl)-3,3-dimethoxy-propionamide (Compound L1, 100 g, 238.46 mmol) in DCM (500 mL) was added to concentrated sulfuric acid (300 mL). After stirring at 15°C for 2 hours, the mixture was slowly poured into 2000 mL of ice water, and a yellow precipitate appeared. The mixture was filtered, and the wet cake was washed with 500 mL of water, 200 mL of isopropanol, and 300 mL of PE. The solid was dried in vacuo to give Compound L2 (50 g) as a yellow solid. MS calculated value 242 (MH + ), measured value 242(MH + ).

[0191] Step 3: Preparation of 5-fluoro-2-oxo-1H-quinoline-8-carbonitrile (Compound L3)

[0192] A solution of 8-bromo-5-fluoro-1H-quinolin-2-one (compound L2, 50 g, 206.58 mmol), zinc cyanide (48.50 g, 413.15 mmol), Pd(PPh3)4 (24.29 g, 21.02 mmol) in DMF (1000 mL) was stirred at 120 ° C for 5 hours. After cooling, the reaction mixture was quenched with 300 mL of saturated NH4Cl, diluted with 2000 mL of water, and extracted three times with 500 mL of DCM. The combined organic layers were washed twice with 500 mL of water and once with 200 mL of brine, dried over Na2SO4, and concentrated to give a crude product, which was purified by silica gel chromatography (PE / EA=3 / 1) to give compound L3 (29 g) as a yellow solid. MS calculated value 189 (MH + ), measured value 189 (MH + ).

[0193] Step 4: Preparation of (8-cyano-5-fluoro-2-quinolyl) trifluoromethanesulfonate (Compound L4)

[0194] At 0°C, trifluoromethanesulfonic anhydride (51 g, 181 mmol) was added to a solution of 5-fluoro-2-oxo-1H-quinoline-8-carbonitrile (compound L3, 17 g, 90.35 mmol), 2,6-lutidine (38.7 g, 361 mmol) in DCM (500 mL). After stirring at 0°C for 1 h, the mixture was diluted with 500 mL of water and extracted three times with 200 mL of DCM. The combined organic layers were washed twice with 200 mL of water and once with 100 mL of brine, dried over Na2SO4, and concentrated to give a crude product, which was purified by silica gel chromatography (PE / EA=5 / 1) to give compound L4 (23 g) as a yellow solid. MS calculated value 321 (MH+ ), measured value 321(MH + ).

[0195] Step 5: Preparation of 2-deuterated-5-fluoro-quinoline-8-carbonitrile (Compound L5)

[0196] To a solution of (8-cyano-5-fluoro-2-quinolyl) trifluoromethanesulfonate (compound L4, 23 g, 71.83 mmol) in THF (230 mL) and deuterium oxide (100 mL) was added potassium carbonate (19.8 g, 1.44 mol) and Pd / C (10 wt %, 6 g). The mixture was stirred at 40 ° C for 5 hours under a deuterium atmosphere. The mixture was then filtered, and the filtrate was then concentrated and purified using silica gel chromatography (PE / EA=5 / 1) to obtain compound L5 (11.4 g) as a light yellow solid. MS calculated value 174 (MH + ), measured value 174(MH + ).

[0197] Step 6: Preparation of 5-((2R,6R)-2-(hydroxymethyl)-6-methylmorpholino)quinoline-8-carbonitrile-2-d (Compound L7)

[0198] A mixture of 5-fluoroquinoline-8-carbonitrile-2-d (compound L5, 611 mg, 3.53 mmol), ((2R, 6R)-6-methylmorpholin-2-yl)methanol hydrochloride (compound L6, 710 mg, 4.23 mmol), N-ethyl-N-isopropylpropane-2-amine (1.37 g, 10.6 mmol) in DMSO (3 mL) was stirred at 120 ° C for 16 hours. The solution was then diluted with EA and washed with water and brine. The combined organic layers were dried and concentrated. The residue was purified by silica gel chromatography (EA / PE was 20% to 80%) to give 5-((2R, 6R)-2-(hydroxymethyl)-6-methylmorpholino)quinoline-8-carbonitrile-2-d (compound L7, 990 mg) as a yellow solid. MS: calculated 285 (MH + ), measured 285(MH + ).

[0199] Step 7: Preparation of methyl ((2R,6R)-4-(8-cyanoquinolin-5-yl-2-d)-6-methylmorpholin-2-yl)trifluoromethanesulfonate (Intermediate L)

[0200] At 0 ° C, 5- ((2R, 6R) -2- (hydroxymethyl) -6- methylmorpholino) quinoline -8- carbonitrile -2-d (compound L7, 3g) and 2,6- lutidine (3.39g, 3.77ml, 31.7mmol) in CH2Cl2 (20ml) solution was added dropwise trifluoromethanesulfonic anhydride (4.47g, 2.67ml, 15.8mmol). The mixture was stirred at 0 ° C for 1h, then diluted with DCM, and washed with saturated NH4Cl solution and brine. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (EA / PE was 20% to 60%) to obtain ((2R, 6R) -4- (8- cyanoquinoline -5- base -2-d) -6- methylmorpholino) trifluoromethanesulfonic acid methyl ester (intermediate L 4.087g) as a yellow solid. MS: Calculation 417 (MH + ), measured 417 (MH + ).

[0201] Intermediate M

[0202] [(2R,6R)-6-Methyl-4-(1-methyl-2-oxo-1,8-naphthyridin-4-yl)morpholin-2-yl]trifluoromethanesulfonic acid methyl ester

[0203]

[0204] The title compound was prepared similarly to the preparation of Intermediate A, using 4-bromo-1-methyl-1,8-naphthyridin-2-one (Compound M1) instead of 5-bromoquinoline-8-carbonitrile (Compound A2). Intermediate M (140 mg) was obtained as a yellow solid. MS: Calculated 422 (MH + ), measured 422 (MH + ).

[0205] Compound M1 was prepared according to the following scheme:

[0206]

[0207] Preparation of 4-bromo-1-methyl-1,8-naphthyridin-2-one (Compound M1)

[0208] To a solution of 4-bromo-1,8-naphthyridine-2(1H)-one (CAS: 72235-36-0, supplier: Accela, 370 mg, 1.64 mmol) in DMF (15 mL) was added iodomethane (2.33 g, 16.40 mmol) and Cs2CO3 (1.07 g, 3.29 mmol). The reaction mixture was stirred at 80 ° C overnight. After cooling, the reaction was quenched with ice water (30 mL). The solid was collected by filtration to give crude compound M1 (419 mg), which was used directly in the next step. MS calculated value 239 (MH + ), measured value 239 (MH + ). 1 H NMR (400MHz, methanol-d4) δ = 8.72 (dd, J = 1.7, 4.7 Hz, 1H), 8.39 ( dd, J = 1.7, 7.9 Hz, 1H), 7.43 ( dd, J = 4.7, 8.0 Hz, 1H), 7.20 ( s, 1H), 3.83 ( s, 3H).

[0209] Example 1

[0210] 4-[(2S,6R)-2-[[6-(3-amino-3-methyl-azetidin-1-yl)spiro[1H-isobenzofuran-3,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile

[0211]

[0212] The title compound was prepared according to the following scheme:

[0213]

[0214] Step 1: 6-bromospiro[1H-isobenzofuran-3,3'-azetidine] (Compound 1b)

[0215] To a solution of 6-bromospiro[1H-isobenzofuran-3,3'-azetidine]-1'-carboxylic acid tert-butyl ester (Compound 1a, CAS: 1398609-80-7, Pharmablock, 260 mg) in DCM (2 mL) was added trifluoroacetic acid (0.5 mL). After stirring at room temperature for 3 hours, the mixture was concentrated in vacuo to give a white oil, which was used directly without purification. 184 mg of 6-bromospiro[1H-isobenzofuran-3,3'-azetidine] (Compound 1b) was obtained. MS calculated value 242 (MH + ), measured value 242(MH + ).

[0216] Step 2: 4-[(2S,6R)-2-[(6-bromospiro[1H-isobenzofuran-3,3'-azetidine]-1'-yl)methyl]-6-methyl-morpholin-4-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile (Compound 1c)

[0217] A mixture of 6-bromospiro[1H-isobenzofuran-3,3'-azetidine] (Compound 1b, 35 mg, 146 μmol) and [(2R,6R)-4-(7-cyano-3-fluoro-pyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholin-2-yl]trifluoromethanesulfonic acid methyl ester (Intermediate E, 62 mg, 146 μmol) and DIPEA (0.2 mL) in CH2Cl2 (20 mL) was stirred at room temperature for 2 hours. The mixture was then diluted with DCM and washed with brine. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (EA / PE 0% to 100%) to give 4-[(2S,6R)-2-[(6-bromospiro[1H-isobenzofuran-3,3'-azetidine]-1'-yl)methyl]-6-methyl-morpholin-4-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile (Compound 1c, 52 mg) as a yellow solid. MS: Calculated 513 (MH + ), measured value 513 (MH + ).

[0218] Step 3: N-[1-[1'-[[(2S,6R)-4-(7-cyano-3-fluoro-pyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholin-2-yl]methyl]spiro[3H-isobenzofuran-1,3'-azetidine]-5-yl]-3-methyl-azetidin-3-yl]carbamic acid tert-butyl ester (Compound 1e)

[0219] To a solution of 4-[(2S,6R)-2-[(6-bromospiro[1H-isobenzofuran-3,3'-azetidine]-1'-yl)methyl]-6-methyl-morpholin-4-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile (compound 1c, 74 mg, 144 μmol) in dioxane (10 mL) was added RuPhos-Pd-G2 (11 mg, 14.4 μmol), tert-butyl (3-methylazetidine-3-yl)carbamate (compound 1d, 40 mg, 217 μmol) and K2CO3 (100 mg, 722 μmol). The reaction mixture was stirred at 90 °C under N2 overnight. The mixture was then filtered and the filtrate was concentrated under reduced pressure to give the crude product, which was used directly in the next step without purification (compound 1e, 89 mg). MS: calculated 618 (MH +), measured 618 (MH + ).

[0220] Step 4: 4-[(2S,6R)-2-[[6-(3-amino-3-methyl-azetidin-1-yl)spiro[1H-isobenzofuran-3,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile (Example 1)

[0221] At 0 ° C, to N-[1-[1'-[[(2S,6R)-4-(7-cyano-3-fluoro-pyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholin-2-yl]methyl]spiro[3H-isobenzofuran-1,3'-azetidine]-5-yl]-3-methyl-azetidine-3-yl]carbamic acid tert-butyl ester (compound 1e, 89 mg) in DCM (10 mL) was added TFA (2 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was then concentrated to give a crude product, which was purified by preparative HPLC to give Example 1 (7 mg) as a yellow solid. MS calculated value 518 (MH + ), measured value 518 (MH + ). 1 H NMR (methanol-d4, 400MHz) δ7.91(d,J=3.7Hz,1H),7.46(d,J=8.3Hz,1H),7.35(d,J=7.9Hz,1H),6.42-6.56(m,2H),6.29-6.39(m,1H),5.00(s,2 H),4.35-4.57(m,3H),3.98-4.13(m,2H),3.76-3.95(m,5H),3.36-3.61(m,4H),2.49-2.80(m,2H),1.57(s,3H),1.18ppm(d,J=6.2Hz,3H).

[0222] Example 2

[0223] 3-Fluoro-4-[(2R,6S)-2-methyl-6-[[6-(6-methyl-2,6-diazaspiro[3.3]heptane-2-yl)spiro[1H-isobenzofuran-3,3'-azetidine]-1'-yl]methyl]morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile

[0224]

[0225] The title compound was prepared similarly to the preparation method of Example 1, using 2-methyl-2,6-diazaspiro[3.3]heptane instead of (3-methylazetidin-3-yl)carbamic acid tert-butyl ester (Compound 1d). Example 2 (26 mg) was obtained as a yellow solid. MS: Calculated 544 (MH + ), measured 544(MH + ). 1 H NMR (methanol-d4, 400MHz) δ8.01 (d, J = 3.7Hz, 1H), 7.53 (d J=8.2Hz,1H,),7.44(d,J=7.9Hz,1H),6.55(d,J=7.9Hz,2H),6.39(d,J=1.1Hz,1H),5.08(s,2H),4.53(br d,J=11.5Hz,5H),4.25(br d,J=11.1Hz,2H),4.0-4.2(m,6H),3.9-4.0(m,1H),3.5-3.7(m,4H),2.94(s,3H),2.7-2.8(m,1H),2.6-2.7(m,1H),1.28(d,J=6.2Hz,3H).

[0226] Example 3

[0227] 3-Fluoro-4-[(2S,6R)-2-[[6-[[(3S,4R)-4-fluoropyrrolidin-3-yl]amino]spiro[1H-isobenzofuran-3,3'-azetidine]-1'-yl]methyl]-6-methyl-morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile

[0228]

[0229] The title compound was prepared similarly to the preparation method of Example 1, using (3S,4R)-3-amino-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (CAS: 1174020-30-4, supplier: PharmaBlock) instead of (3-methylazetidin-3-yl)carbamic acid tert-butyl ester (Compound 1d). Example 3 (19 mg) was obtained as a light brown solid. MS: Calculated 536 (MH + ), measured 536 (MH + ). 1H NMR (methanol-d4, 400MHz) δ8.00(d,J=3.5Hz,1H),7.51(br d,J=8.3Hz,1H),7.44(d,J=7.9Hz,1H),6.85(br d,J=8.4Hz,1H),6.68(s,1H),6.55(d,J=7.9Hz,1H),5.2-5.4(m,1H),5.08(s,2 H),4.4-4.6(m,4H),4.1-4.2(m,1H),3.9-4.0(m,1H),3.7-3.8(m,2H),3.59(br d,J=12.7Hz,6H),3.21(br t,J=11.2Hz,1H),2.79(br t,J=11.2Hz,1H), 2.68(br t,J=11.3Hz,1H), 1.28(d,J=6.2Hz,3H).

[0230] Example 4

[0231] 3-Fluoro-4-[(2R,6S)-2-methyl-6-[[6-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)spiro[1H-isobenzofuran-3,3'-azetidine]-1'-yl]methyl]morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile

[0232]

[0233] The title compound was prepared similarly to the preparation method of Example 1, using tert-butyl 2-oxa-5,8-diazaspiro[3.5]nonane-8-carboxylate (CAS: 1367777-12-5, supplier: PharmaBlock) instead of tert-butyl (3-methylazetidin-3-yl)carbamate (Compound 1d). Example 4 (33 mg) was obtained as a light brown solid. MS: Calculated 560 (MH + ), measured 560(MH + ). 1H NMR (methanol-d4, 400 MHz) δ 8.01 (d, J = 3.7 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 6.59 (br d,J=8.6Hz,1H),6.55(d,J=7.9Hz,1H),6.44(d,J=1.3Hz,1H),5.10(s,2H),4.6-4.8(m,1H),4.4-4.6(m,3H),4.1-4.2(m,1H),4.0-4. 1(m,2H),3.9-4.0(m,3H),3.8-3.8(m,2H),3.5-3.7(m,4H),3.5-3.5(m,2H),3.2-3.3(m,2H),2.6-2.8(m,2H),1.28(d,J=6.2Hz,3H).

[0234] Example 5

[0235] 4-[(2S,6R)-2-[[6-[(3S)-3-amino-3-methyl-pyrrolidin-1-yl]spiro[1H-isobenzofuran-3,3'-azetidine]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile

[0236]

[0237] The title compound was prepared similarly to the preparation method of Example 1, using (S)-(3-methylpyrrolidin-3-yl)carbamic acid tert-butyl ester (CAS: 927652-04-8, supplier: PharmaBlock) instead of (3-methylazetidin-3-yl)carbamic acid tert-butyl ester (Compound 1d). Example 5 (13 mg) was obtained as a white solid. MS: Calculated 532 (MH + ), measured 532(MH + ). 1 HNMR (methanol-d4, 400MHz) δ7.89 (d, J=3.7Hz, 1H), 7.32 (dd, J=3.4, 8.1Hz, 2H), 6 .46(dd,J=1.9,8.4Hz,1H),6.41(d,J=7.9Hz,1H),6.27(s,1H),4.88(s,2H) ,3.7-3.8(m,2H),3.5-3.6(m,5H),3.4-3.4(m,2H),3.2-3.3(m,1H),3.09(s ,2H),2.5-2.7(m,4H),1.8-1.9(m,2H),1.25(s,3H),1.13(d,J=6.4Hz,3H).

[0238] Example 6

[0239] 3-Fluoro-4-[(2R,6S)-2-methyl-6-[(6-piperazin-1-ylspiro[1H-isobenzofuran-3,3'-azetidine]-1'-yl)methyl]morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile

[0240]

[0241] The title compound was prepared similarly to the preparation method of Example 1, using tert-butyl piperazine-1-carboxylate instead of tert-butyl (3-methylazetidin-3-yl)carbamate (Compound 1d). Example 6 (33 mg) was obtained as a yellow solid. MS: Calculated 518 (MH + ), measured 518 (MH + ). 1 H NMR (methanol-d4, 400MHz) δ8.01(d,J=3.5Hz,1H),7.63(d,J=8.4Hz,1H),7.44(d,J=7.9Hz ,1H),7.12(dd,J=2.1,8.5Hz,1H),6.9-7.0(m,1H),6.55(d,J=7.9Hz,1H),5.13(s,2 H),4.5-4.5(m,2H),4.1-4.2(m,1H),3.9-4.0(m,1H),3.5-3.6(m,4H),3.4-3.5(m,5 H),3.4-3.4(m,5H),2.78(t,J=11.2Hz,1H),2.6-2.7(m,1H),1.28(d,J=6.2Hz,3H).

[0242] Example 7

[0243] 4-[(2R,6S)-2-methyl-6-[[6-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)spiro[1H-isobenzofuran-3,3'-azetidine]-1'-yl]methyl]morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile

[0244]

[0245] The title compound was prepared similarly to the preparation method of Example 1, using [(2R,6R)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholin-2-yl]trifluoromethanesulfonic acid methyl ester (Intermediate F) and 2-oxa-5,8-diazaspiro[3.5]nonane-8-carboxylic acid tert-butyl ester (CAS: 1367777-12-5, supplier: PharmaBlock) instead of [(2R,6R)-4-(7-cyano-3-fluoro-pyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholin-2-yl]trifluoromethanesulfonic acid methyl ester (Intermediate E) and (3-methylazetidin-3-yl)carbamic acid tert-butyl ester (Compound 1d). Example 7 (7 mg) was obtained as a white solid. MS: Calculated 542 (MH + ), measured 542(MH + ). 1 H NMR (methanol-d4, 400MHz) δ7.93 (d, J = 2.3Hz, 1H), 7.4-7.4 (m, 1H), 7.36 (s, 1H), 6.77 (d, J = 2.4Hz ,1H),6.50(d,J=8.1Hz,1H),6.43(dd,J=1.8,8.2Hz,1H),6.27(s,1H),4.89(s,2H),4.49(br s,2H),3.8-3.8(m,4H),3.6-3.6(m,6H),3.5-3.6(m,2H),2.93(s,2H),2.7-2.7(m,4H),2.5-2.6(m,2H),1.15(d,J=6.2Hz,3H).

[0246] Example 8

[0247] 4-[(2R,6S)-2-methyl-6-[[6-(6-methyl-2,6-diazaspiro[3.3]heptane-2-yl)spiro[1H-isobenzofuran-3,3'-azetidine]-1'-yl]methyl]morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile

[0248]

[0249] The title compound was prepared similarly to the preparation method of Example 1, using [(2R,6R)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholin-2-yl]trifluoromethanesulfonic acid methyl ester (Intermediate F) and 2-methyl-2,6-diazaspiro[3.3]heptane instead of [(2R,6R)-4-(7-cyano-3-fluoro-pyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholin-2-yl]trifluoromethanesulfonic acid methyl ester (Intermediate E) and (3-methylazetidin-3-yl)carbamic acid tert-butyl ester (Compound 1d). Example 8 (25 mg) was obtained as a white solid. MS: Calculated 526 (MH + ), measured 526 (MH + ). 1 H NMR (methanol-d4, 400MHz) δ8.02(d,J=2.3Hz,1H),7.47(d,J=4.9Hz,1H),7.45(d,J=5.1Hz,1H),6.86(d,J=2.4Hz,1H), 6.59(d,J=7.9Hz,1H),6.48(dd,J=2.0,8.3Hz,1H),6.33(d,J=1.3Hz,1H),4.97(s,2H),3.8-3.9(m,7H),3.73(br d,J=12.1Hz,1H),3.6-3.7(m,4H),3.48(s,4H),2.7-2.8(m,3H),2.6-2.7(m,1H),2.36(s,3H),1.24(d,J=6.2Hz,3H).

[0250] Example 9

[0251] 4-[(2S,6R)-2-[[6-(3-aminoazetidin-1-yl)spiro[1H-isobenzofuran-3,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile

[0252]

[0253] The title compound was prepared similarly to the preparation method of Example 1, using tert-butyl azetidin-3-ylcarbamate (CAS: 91188-13-5, supplier: BePharm) instead of tert-butyl (3-methylazetidin-3-yl)carbamate (Compound 1d). Example 9 (7 mg) was obtained as a white solid. MS: Calculated 504 (MH + ), measure 504(MH + ). 1H NMR (methanol-d4, 400MHz) δ8.01(d,J=3.7Hz,1H),7.55(d,J=8.3Hz,1H),7.45(d,J=7.8Hz,1H),6.5-6.6(m,2H),6.44(s,1H),5.10(s,2H),4 .1-4.3(m,4H),3.9-4.0(m,3H),3.7-3.8(m,1H),3.5-3.7(m,4H),3.4-3.5(m,1H),2.6-2.8(m,2H),2.03(s,2H),1.28(d,J=6.2Hz,3H).

[0254] Example 10

[0255] 4-[(2S,6R)-2-[[6-[(3S,4S)-3-amino-4-hydroxy-pyrrolidin-1-yl]spiro[1H-isobenzofuran-3,3'-azetidine]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile

[0256]

[0257] The title compound was prepared similarly to the preparation method of Example 1, using ((3R,4R)-4-hydroxypyrrolidin-3-yl)carbamic acid tert-butyl ester hydrochloride (CAS: 1820575-70-9, supplier: BePharm) instead of (3-methylazetidin-3-yl)carbamic acid tert-butyl ester (Compound 1d). Example 10 (8 mg) was obtained as a light yellow solid. MS: Calculated 534 (MH + ), measured 534 (MH + ). 1 H NMR (methanol-d4, 400MHz) δ8.01(d,J=3.5Hz,1H),7.5-7.6(m,1H),7.44(d,J=7.9Hz,1H),6.7-6.8(m,1H),6.5-6.6(m,2H),5.11(br d,J=9.2Hz,2H),4.4-4.6(m,4H),4.38(d,J=3.8Hz,1H),4.1-4.2(m,2H),3.9-4.0(m,2H), 3.7-3.8(m,2H),3.5-3.7(m,4H),3.4-3.5(m,2H),2.7-2.8(m,2H),1.28(d,J=6.2Hz,3H).

[0258] Example 11

[0259] 5-[(2S,6R)-2-[[6-(3-amino-3-methyl-azetidin-1-yl)spiro[1H-isobenzofuran-3,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-2-deuterated-quinoline-8-carbonitrile

[0260]

[0261] The title compound was prepared similarly to the preparation method of Example 1, using [(2R,6R)-4-(8-cyano-2-deuterated-5-quinolinyl)-6-methyl-morpholin-2-yl]trifluoromethanesulfonic acid methyl ester (Intermediate L) instead of [(2R,6R)-4-(7-cyano-3-fluoro-pyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholin-2-yl]trifluoromethanesulfonic acid methyl ester (Intermediate E). Example 11 (13 mg) was obtained as a yellow solid. MS: Calculated 512 (MH + ), measured 512(MH + ). 1 H NMR (400MHz, methanol-d4) δ8.66(d,J=8.7Hz,1H),8.17(d,J=8.1Hz,1H),7.65(d,J=8. 7Hz,1H),7.55(d,J=8.3Hz,1H),7.28(d,J=8.1Hz,1H),6.59(dd,J=8.3,2.0Hz,1 H),6.44(s,1H),5.08(s,2H),4.21-4.68(m,5H),4.07-4.18(m,1H),3.86-4.01( m,4H),3.37-3.58(m,4H),2.64-2.91(m,2H),1.67(s,3H),1.28(d,J=6.2Hz,3H).

[0262] Example 12

[0263] 4-[(2S,6R)-2-[[6-(2,6-diazaspiro[3.3]heptane-2-yl)spiro[1H-isobenzofuran-3,3'-azetidine]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile

[0264]

[0265] The title compound was prepared similarly to the preparation method of Example 1, using tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate oxalate (CAS: 1041026-71-4, supplier: PharmaBlock) instead of tert-butyl (3-methylazetidin-3-yl)carbamate (Compound 1d). Example 12 (18 mg) was obtained as a light brown solid. MS: Calculated 530 (MH + ), measured 530(MH + ). 1 H NMR (methanol-d4, 400MHz) δ8.01 (d, J = 3.5Hz, 1H), 7.52 (d, J = 8.3Hz, 1H), 7.44 (d, J=7.8Hz,1H),6.55(d,J=7.9Hz,2H),6.39(d,J=1.3Hz,1H),5.08(s,2H),4.4 -4.6(m,4H),4.30(s,4H),4.1-4.2(m,1H),4.06(s,4H),3.9-4.0(m,1H),3.5 -3.6(m,4H),2.78(t,J=11.2Hz,1H),2.6-2.7(m,1H),1.28(d,J=6.2Hz,3H).

[0266] Example 13

[0267] 4-[(2S,6R)-2-[[6-(3-aminoazetidin-1-yl)spiro[1H-isobenzofuran-3,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-1-methyl-1,8-naphthyridin-2-one

[0268]

[0269] The title compound was prepared similarly to the preparation method of Example 1, using tert-butyl N-(azetidin-3-yl)carbamate and [(2R,6R)-6-methyl-4-(1-methyl-2-oxo-1,8-naphthyridin-4-yl)morpholin-2-yl]trifluoromethanesulfonic acid methyl ester (Intermediate M) instead of (3-methylazetidin-3-yl)carbamate (Compound 1d) and [(2R,6R)-4-(7-cyano-3-fluoro-pyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholin-2-yl]trifluoromethanesulfonic acid methyl ester (Intermediate E). Example 13 (4 mg) was obtained as a yellow solid. MS: Calculated 503 (MH + ), measure 503(MH + ). 1H NMR (400MHz, methanol-d4) δ8.64(dd,J=4.6,1.8Hz,1H),8.25(dd,J=8.0,1.8Hz,1H),7.43(d, J=8.3Hz,1H),7.30(dd,J=8.0,4.6Hz,1H),6.48(dd,J=8.3,2.0Hz,1H),6.33(d,J=0.9Hz ,1H),6.15(s,1H),4.96(s,2H),4.12(t,J=7.3Hz,2H),3.80-4.00(m,3H),3.72(d,J=2.9 Hz, 3H), 3.45-3.51 (m, 3H), 3.11-3.23 (m, 5H), 2.48-2.82 (m, 4H), 1.22 (d, J = 6.2Hz, 3H).

[0270] Example 14

[0271] 5-[(2S,6R)-2-[[6-(3-aminoazetidin-1-yl)spiro[1H-isobenzofuran-3,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-2-deuterated-quinoline-8-carbonitrile

[0272]

[0273] The title compound was prepared similarly to the preparation method of Example 1, using tert-butyl N-(azetidin-3-yl)carbamate and [(2R,6R)-4-(8-cyano-2-deuterated-5-quinolinyl)-6-methyl-morpholin-2-yl] trifluoromethanesulfonic acid methyl ester (Intermediate L) instead of (3-methylazetidin-3-yl)carbamate (Compound 1d) and [(2R,6R)-4-(7-cyano-3-fluoro-pyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholin-2-yl] trifluoromethanesulfonic acid methyl ester (Intermediate E). Example 14 (19 mg) was obtained as a yellow solid. MS: Calculated 498 (MH + ), measured 498 (MH + ). 1H NMR (400MHz, methanol-d4) δ8.66(d,J=8.6Hz,1H),8.17(d,J=7.9Hz,1H),7.65(d,J=8.6Hz,1H),7.56(br d,J=8.2Hz,1H),7.29(d,J=8.1Hz,1H),6.59(br d,J=8.1Hz,1H),6.45(d,J=1.5Hz,1H),5.11(s,2H),4.43-4.70(m,3H),4.08(m,5H ),3.84-3.99(m,2H),3.38-3.72(m,5H),2.62-2.91(m,2H),1.29(d,J=6.2Hz,3H).

[0274] Example 15

[0275] 2-Deuterated-5-[(2R,6S)-2-methyl-6-[[6-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)spiro[1H-isobenzofuran-3,3'-azetidine]-1'-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile

[0276]

[0277] The title compound was prepared similarly to the preparation method of Example 1, using tert-butyl 5-oxa-2,8-diazaspiro[3.5]nonane-8-carboxylate and [(2R,6R)-4-(8-cyano-2-deuterated-5-quinolinyl)-6-methyl-morpholin-2-yl]trifluoromethanesulfonic acid methyl ester (Intermediate L) instead of (3-methylazetidin-3-yl)carbamate (Compound 1d) and [(2R,6R)-4-(7-cyano-3-fluoro-pyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholin-2-yl]trifluoromethanesulfonic acid methyl ester (Intermediate E). Example 15 (9 mg) was obtained as a yellow solid. MS: Calculated 554 (MH + ), measured 554 (MH + ). 1H NMR (400MHz, methanol-d4) δ8.55(d,J=8.7Hz,1H),8.05(d,J=8.1Hz,1H),7.53(d,J=8.7Hz,1H) ,7.36(d,J=8.2Hz,1H),7.15(d,J=8.1Hz,1H),6.42(dd,J=8.3,2.0Hz,1H),6.27(d,J=1. 5Hz,1H),4.90(s,2H),3.88-4.08(m,2H),3.79(d,J=8.2Hz,2H),3.48-3.75(m,8H),3.27 -3.44(m,2H),2.97(s,2H),2.71-2.84(m,4H),2.48-2.72(m,2H),1.15(d,J=6.2Hz,3H).

[0278] Example 16

[0279] 5-[(2S,6R)-2-[[6-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]spiro[1H-isobenzofuran-3,3'-azetidine]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-2-deuterated-quinoline-8-carbonitrile

[0280]

[0281] The title compound was prepared similarly to the preparation method of Example 1, using tert-butyl N-[(3R,4R)-4-methoxypyrrolidin-3-yl]carbamate (PharmaBlock, PBZ4728, CAS: 1932066-52-8) and [(2R,6R)-4-(8-cyano-2-deuterated-5-quinolinyl)-6-methyl-morpholin-2-yl] trifluoromethanesulfonate (Intermediate L) instead of tert-butyl (3-methylazetidin-3-yl)carbamate (Compound 1d) and [(2R,6R)-4-(7-cyano-3-fluoro-pyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholin-2-yl] trifluoromethanesulfonate (Intermediate E). Example 16 (9 mg) was obtained as a yellow solid. MS: Calculated 542 (MH + ), measured 542(MH + ). 1H NMR (400MHz, methanol-d4) δ8.55(d,J=8.6Hz,1H),8.05(d,J=8.1Hz,1H),7.53(d,J=8.6Hz,1H), 7.35(d,J=8.3Hz,1H),7.15(d,J=8.1Hz,1H),6.51(dd,J=8.4,2.0Hz,1H),6.34(d,J=1.6H z,1H),4.90(s,2H),3.88-4.02(m,2H),3.70-3.80(m,1H),3.58-3.68(m,5H),3.37-3.52( m,2H),3.24-3.35(m,4H),3.02-3.20(m,2H),2.49-2.82(m,4H),1.15ppm(d,J=6.4Hz,3H).

[0282] Example 17

[0283] 5-[(2S,6R)-2-[[6-[(4aR,7aR)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl]spiro[1H-isobenzofuran-3,3'-azetidine]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-2-deuterated-quinoline-8-carbonitrile

[0284]

[0285] The title compound was prepared in analogy to the preparation method of Example 1, using (4aR,7aR)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-4-carboxylic acid tert-butyl ester (PharmaBlock, PBXA8123, CAS: 1932337-68-2) and [(2R,6R)-4-(8-cyano-2-deutero-5-quinolinyl)-6-methyl-morpholin-2-yl] trifluoromethanesulfonic acid methyl ester (Intermediate L) instead of (3-methylazetidin-3-yl)carbamic acid tert-butyl ester (Compound 1d) and [(2R,6R)-4-(7-cyano-3-fluoro-pyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholin-2-yl] trifluoromethanesulfonic acid methyl ester (Intermediate E). Example 17 (9 mg) was obtained as a yellow solid. MS: Calculated 554 (MH + ), measured 554 (MH + ). 1H NMR (400MHz, methanol-d4) δ8.55(d,J=8.6Hz,1H),8.05(d,J=8.1Hz,1H),7.53(d,J=8 .6Hz,1H),7.34(d,J=8.4Hz,1H),7.16(d,J=8.1Hz,1H),6.46(dd,J=8.5,1.9Hz, 1H),6.29(d,J=1.5Hz,1H),4.91(s,2H),3.82-4.07(m,3H),3.62-3.80(m,5H), 3.26-3.59(m,6H),2.82-3.12(m,6H),2.50-2.76(m,2H),1.15(d,J=6.2Hz,3H).

[0286] Example 18

[0287] 2-Deuterated-5-[(2R,6S)-2-methyl-6-[(6-piperazin-1-ylspiro[1H-isobenzofuran-3,3'-azetidine]-1'-yl)methyl]morpholin-4-yl]quinoline-8-carbonitrile

[0288]

[0289] The title compound was prepared similarly to the preparation method of Example 1, using tert-butyl piperazine-1-carboxylate and [(2R,6R)-4-(8-cyano-2-deuterated-5-quinolinyl)-6-methyl-morpholin-2-yl] trifluoromethanesulfonic acid methyl ester (Intermediate L) instead of (3-methylazetidin-3-yl)carbamic acid tert-butyl ester (Compound 1d) and [(2R,6R)-4-(7-cyano-3-fluoro-pyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholin-2-yl] trifluoromethanesulfonic acid methyl ester (Intermediate E). Example 18 (2 mg) was obtained as a yellow solid. MS: Calculated 512 (MH + ), measured 512(MH + ). 1 H NMR (400MHz, methanol-d4) δ8.55(d,J=8.6Hz,1H),8.06(d,J=7.9Hz,1H),7.53(d,J= 8.6Hz,1H),7.45(d,J=8.4Hz,1H),7.16(d,J=8.1Hz,1H),6.93(dd,J=8.3,2.2 Hz,1H),6.79(d,J=1.3Hz,1H),4.92(s,2H),3.86-4.12(m,2H),3.72(m,4H),3 .28-3.44(m,6H),3.08-3.17(m,4H),2.51-2.80(m,4H),1.14(d,J=6.2Hz,3H).

[0290] Example 19

[0291] 4-[(2S,6R)-2-[[6-(3-aminoazetidin-1-yl)spiro[1H-isobenzofuran-3,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile

[0292]

[0293] The title compound was prepared similarly to the preparation method of Example 1, using [(2R,6R)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholin-2-yl]trifluoromethanesulfonic acid methyl ester (Intermediate F) and azetidin-3-ylcarbamic acid tert-butyl ester (CAS: 91188-13-5, supplier: BePharm) instead of [(2R,6R)-4-(7-cyano-3-fluoro-pyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholin-2-yl]trifluoromethanesulfonic acid methyl ester (Intermediate E) and (3-methylazetidin-3-yl)carbamic acid tert-butyl ester (Compound 1d). Example 19 (12 mg) was obtained as a light yellow solid. MS: Calculated 486 (MH + ), measured 486 (MH + ). 1 H NMR (methanol-d4, 400MHz) δ8.02 (d, J = 2.3Hz, 1H), 7.46 (dd, J = 6.0, 8.1Hz, 2H), 6.87 (d, J = 2.3Hz, 1H),6.59(d,J=7.9Hz,1H),6.49(dd,J=1.7,8.3Hz,1H),6.34(s,1H),4.97(s,2H),4.58(br s,3H),4.12(t,J=7.3Hz,2H),3.9-3.9(m,3H),3.73(brd,J=12.0Hz,1H),3.6-3.7 (m,3H),3.5-3.5(m,2H),2.7-2.8(m,2H),2.6-2.7(m,1H),1.24(d,J=6.2Hz,3H).

[0294] Example 20

[0295] 5-[(2S,6R)-2-[[3-(3-aminoazetidin-1-yl)spiro[5H-furo[3,4-b]pyridine-7,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-2-deuterated-quinoline-8-carbonitrile

[0296]

[0297] Similar to the preparation method of Example 1, tert-butyl N-(azetidin-3-yl)carbamate and tert-butyl 3-bromospiro[5H-furo[3,4-b]pyridine-7,3'-azetidine]-1'-carboxylate (CAS: 1575836-59-7, catalog number: PBU1967, supplier: Pharmablock) and [(2R,6R)-4-(8-cyano-2-deutero-5-quinolyl)-6-methyl-morpholine-2 -yl] trifluoromethanesulfonic acid methyl ester (Intermediate L) was used to replace (3-methylazetidin-3-yl)carbamic acid tert-butyl ester (Compound 1d) and 6-bromospiro[1H-isobenzofuran-3,3'-azetidin]-1'-carboxylic acid tert-butyl ester (Compound 1a) and [(2R,6R)-4-(7-cyano-3-fluoro-pyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholin-2-yl] trifluoromethanesulfonic acid methyl ester (Intermediate E) to prepare the title compound. Example 20 (3 mg) was obtained as a yellow solid. MS: Calculated 499 (MH + ), measured 499(MH + ). 1 H NMR (400MHz, methanol-d4) δ8.66(d,J=8.6Hz,1H),8.16(d,J=7.9Hz,1H),7.75(d ,J=2.6Hz,1H),7.65(d,J=8.7Hz,1H),7.27(d,J=8.1Hz,1H),6.81(d,J=2.4 Hz,1H),5.04(s,2H),4.22(t,J=7.4Hz,2H),3.91-4.12(m,3H),3.67-3.82 (m,4H),3.60(dd,J=7.7,5.6Hz,2H),3.35-3.50(m,5H),2.55-2.92(m,4H).

[0298] Example 21

[0299] 5-[(2S,6R)-2-[[3-(3-amino-3-methyl-azetidin-1-yl)spiro[5H-furo[3,4-b]pyridine-7,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-2-deuterated-quinoline-8-carbonitrile

[0300]

[0301] The title compound was prepared similarly to the preparation method of Example 1, using 3-bromospiro[5H-furo[3,4-b]pyridine-7,3'-azetidine]-1'-carboxylic acid tert-butyl ester and [(2R,6R)-4-(8-cyano-2-deuterated-5-quinolinyl)-6-methyl-morpholin-2-yl] trifluoromethanesulfonic acid methyl ester (Intermediate L) instead of 6-bromospiro[1H-isobenzofuran-3,3'-azetidine]-1'-carboxylic acid tert-butyl ester (Compound 1a) and [(2R,6R)-4-(7-cyano-3-fluoro-pyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholin-2-yl] trifluoromethanesulfonic acid methyl ester (Intermediate E). Example 21 (10 mg) was obtained as a yellow solid. MS: Calculated 513 (MH + ), measured 513 (MH + ). 1 H NMR (400MHz, methanol-d4) δ8.66(d,J=8.6Hz,1H),8.16(d,J=8.1Hz,1H),7.75(d, J=2.4Hz,1H),7.65(d,J=8.7Hz,1H),7.27(d,J=8.1Hz,1H),6.82(d,J=2.4H z,1H),5.04(s,2H),3.95-4.18(m,2H),3.83-3.90(m,2H),3.61-3.80(m,6H ),3.36-3.52(m,2H),2.56-2.93(m,4H),1.54(s,3H),1.24(d,J=6.2Hz,3H).

[0302] Example 22

[0303] 3-Fluoro-4-[(2R,6S)-2-methyl-6-[[3-(6-methyl-2,6-diazaspiro[3.3]heptane-2-yl)spiro[5H-furo[3,4-b]pyridine-7,3'-azetidin]-1'-yl]methyl]morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile

[0304]

[0305] The title compound was prepared similarly to the preparation method of Example 1, using 2-methyl-2,6-diazaspiro[3.3]heptane and 3-bromospiro[5H-furo[3,4-b]pyridine-7,3'-azetidine]-1'-carboxylic acid tert-butyl ester instead of (3-methylazetidin-3-yl)carbamic acid tert-butyl ester (Compound 1d) and 6-bromospiro[1H-isobenzofuran-3,3'-azetidine]-1'-carboxylic acid tert-butyl ester (Compound 1a). Example 22 (15 mg) was obtained as a yellow solid. MS: Calculated 545 (MH +), measured 545(MH + ). 1 H NMR (400MHz, methanol-d4) δ7.91(d,J=3.7Hz,1H),7.76(s,1H),7.35(d,J=7.9Hz,1H),6.75(d,J=2.4Hz,1H),6.46(d,J=7.9Hz,1H),5.02(s,2 H),4.31-4.61(m,6H),4.00-4.23(m,7H),3.79-3.94(m,1H),3.41-3.67(m,4H),2.85(s,3H),2.48-2.74(m,2H),1.18(d,J=6.2Hz,3H).

[0306] Example 23

[0307] 5-[(2S,6R)-2-[[6-(3-amino-3-methyl-azetidin-1-yl)spiro[1H-furo[3,4-c]pyridine-3,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-2-deuterated-quinoline-8-carbonitrile

[0308]

[0309] The title compound was prepared similarly to the preparation method of Example 1, using [(2R,6R)-4-(8-cyano-2-deuterated-5-quinolinyl)-6-methyl-morpholin-2-yl] trifluoromethanesulfonic acid methyl ester (Intermediate L) and tert-spiro[azetidine-3,3'(1'H)-furo[3,4-c]pyridine]-1-carboxylic acid, 6'-chloro-, 1,1-dimethylethyl ester (CAS: 1575836-95-1, supplier: PharmaBlock) instead of [(2R,6R)-4-(7-cyano-3-fluoro-pyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholin-2-yl] trifluoromethanesulfonic acid methyl ester (Intermediate E) and 6-bromospiro[1H-isobenzofuran-3,3'-azetidine]-1'-carboxylic acid tert-butyl ester (Compound 1a). Example 23 (38 mg) was obtained as a light yellow solid. MS: Calculated 513 (MH + ), measured 513 (MH + ). 1HNMR (methanol-d4, 400MHz) δ8.63(d,J=8.7Hz,1H),8.54(s,1H),8.13(d,J=7.9Hz,1H),7 .63(d,J=8.6Hz,1H),7.25(d,J=8.1Hz,1H),6.7-6.8(m,1H),5.17(s,2H),4.81(br d,J=8.4Hz,2H),4.63(br dd,J=12.0,17.2Hz,2H),4.4-4.4(m,2H),4.3-4.4(m,3H),4.1-4.2(m,1H),3.6-3.7(m,1H),3.5-3.6(m,1H),3.41(br t,J=11.5Hz,2H),2.79(t,J=11.1Hz,1H),2.70(dd,J=10.4,12.1Hz,1H),1.73(s,3H),1.28(d,J=6.2Hz,3H).

[0310] Example 24

[0311] 4-[(2S,6R)-2-[[6-(3-amino-3-methyl-azetidin-1-yl)spiro[1H-furo[3,4-c]pyridine-3,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile

[0312]

[0313] The title compound was prepared similarly to the preparation method of Example 1, using tert-spiro[azetidine-3,3'(1'H)-furo[3,4-c]pyridine]-1-carboxylic acid, 6'-chloro-, 1,1-dimethylethyl ester (CAS: 1575836-95-1, supplier: PharmaBlock) instead of 6-bromospiro[1H-isobenzofuran-3,3'-azetidine]-1'-carboxylic acid tert-butyl ester (Compound 1a). Example 24 (3 mg) was obtained as a light yellow solid. MS: Calculated 519 (MH + ), measured 519 (MH + ). 1H NMR (methanol-d4, 400MHz) δ8.47(s,1H),8.01(d,J=3.5Hz,1H),7.44(d,J=7.8Hz,1H),6.55(d,J=7.9Hz,1H),6.51(d,J=0.7Hz,1H),5.11(s,2H),4.6 -4.7(m,2H),4.5-4.6(m,2H),4.2-4.2(m,2H),4.1-4.2(m,3H),3.9-4.0 (m,1H),3.5-3.7(m,4H),2.6-2.8(m,2H),1.69(s,3H),1.3-1.3(m,3H).

[0314] Example 25

[0315] 4-[(2S,6R)-2-[[6-(3-amino-3-methyl-azetidin-1-yl)spiro[1H-furo[3,4-c]pyridine-3,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile

[0316]

[0317] Similar to the preparation method of Example 1, [(2R,6R)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholin-2-yl]trifluoromethanesulfonic acid methyl ester (Intermediate F) and tert-spiro[azetidine-3,3'(1'H)-furo[3,4-c]pyridine]-1-carboxylic acid, 6'-chloro-, 1,1-dimethylethyl ester (CAS: 157583) were used. 6-95-1, supplier: PharmaBlock) was used to replace [(2R,6R)-4-(7-cyano-3-fluoro-pyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholin-2-yl]trifluoromethanesulfonic acid methyl ester (Intermediate E) and 6-bromospiro[1H-isobenzofuran-3,3'-azetidine]-1'-carboxylic acid tert-butyl ester (Compound 1a) to prepare the title compound. Example 25 (22 mg) was obtained as a light yellow solid. MS: Calculated 501 (MH + ), measure 501(MH + ). 1H NMR (methanol-d4, 400MHz) δ8.52 (s, 1H), 8.03 (d, J = 2.3Hz, 1H), 7.46 (d, J = 7.9Hz, 1H), 6.89 (d, J=2.4Hz,1H),6.71(s,1H),6.62(d,J=7.9Hz,1H),5.16(s,2H),4.7-4.8(m,2H),4.62(br dd,J=12.0,17.4Hz,2H),4.38(d,J=9.9Hz,2H),4.2-4.3(m,2H),4.2-4.2(m,1H),3.9-4.0(m,1H),3.7-3.8(m,2H),3.7-3.7 (m,1H),3.5-3.6(m,1H),2.77(dd,J=10.8,11.9Hz,1H),2.70(dd,J=10.6,12.3Hz,1H),1.73(s,3H),1.29(d,J=6.2Hz,3H).

[0318] Example 26

[0319] 4-[(2S,6R)-2-[[3-(3-amino-3-methyl-azetidin-1-yl)spiro[5H-furo[3,4-b]pyridine-7,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile

[0320]

[0321] The title compound was prepared similarly to the preparation method of Example 1, using [(2R,6R)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholin-2-yl] trifluoromethanesulfonic acid methyl ester (Intermediate F) and 3-bromospiro[5H-furo[3,4-b]pyridine-7,3-azetidine]-1-carboxylic acid tert-butyl ester (CAS: 1575836-59-7, supplier: PharmaBlock) instead of [(2R,6R)-4-(7-cyano-3-fluoro-pyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholin-2-yl] trifluoromethanesulfonic acid methyl ester (Intermediate E) and 6-bromospiro[1H-isobenzofuran-3,3'-azetidine]-1'-carboxylic acid tert-butyl ester (Compound 1a). Example 26 (7 mg) was obtained as a light yellow solid. MS: Calculated 501 (MH + ), measure 501(MH + ). 1H NMR (methanol-d4, 400MHz) δ8.04(d,J=2.3Hz,1H),7.92(d,J=1.5Hz,1H),7.49(d,J=8 .1Hz,1H),6.9-6.9(m,2H),6.64(d,J=8.1Hz,1H),5.13(s,2H),4.6-4.7(m,1H), 4.5-4.6(m,2H),4.1-4.2(m,1H),4.10(d,J=8.6Hz,2H),4.0-4.0(m,3H),3.7-3 .9(m,3H),3.5-3.6(m,2H),2.7-2.8(m,2H),1.69(s,3H),1.30(d,J=6.1Hz,3H).

[0322] Example 28

[0323] 5-[(2S,6R)-2-[[6-[(4aR,7aR)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl]spiro[1H-furo[3,4-c]pyridine-3,3'-azetidine]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-2-deuterated-quinoline-8-carbonitrile

[0324]

[0325] The preparation method was similar to that of Example 1, using (4aR,7aR)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-4-carboxylic acid tert-butyl ester (PharmaBlock, PBXA8123, CAS: 1932337-68-2), [(2R,6R)-4-(8-cyano-2-deutero-5-quinolyl)-6-methyl-morpholin-2-yl]trifluoromethanesulfonic acid methyl ester (Intermediate L) and tert-spiro[azetidine-3,3'(1'H)-furo[3,4-c]pyridine]-1 The title compound was prepared by replacing tert-butyl (3-methylazetidin-3-yl)carbamate (compound 1d), [(2R,6R)-4-(7-cyano-3-fluoro-pyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholin-2-yl]trifluoromethanesulfonate (Intermediate E) and tert-butyl 6-bromospiro[1H-isobenzofuran-3,3'-azetidine]-1'-carboxylate (compound 1a). Example 28 (2 mg) was obtained as a light yellow solid. MS: Calculated 555 (MH + ), measure 555(MH + ). 1HNMR (400 MHz, methanol-d4) δ8.67 (d, J = 8.7 Hz, 1H), 8.34 (s, 1H), 8.18 (d, J = 8.1 Hz, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 6.39 (s, 1H), 4.99 (s, 2H), 4.11–3.96 (m, 3H), 3.83–3.72 (m, 3H), 3 .71–3.62(m,5H),3.52–3.44(m,1H),3.43–3.37(m,1H),3.17–3.12(m,1H),3.06–2.92(m,3H),2. 80–2.77(m,2H),2.71–2.64(m,1H),2.24–2.18(m,1H),2.07–2.03(m,1H),1.26(d,J=6.4Hz,3H).

[0326] Example 29

[0327] 5-[(2S,6R)-2-[[3-[(4aR,7aR)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl]spiro[5H-furo[3,4-b]pyridine-7,3'-azetidine]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-2-deuterated-quinoline-8-carbonitrile

[0328]

[0329] The preparation method was similar to that of Example 1, using (4aR,7aR)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-4-carboxylic acid tert-butyl ester (PharmaBlock, PBXA8123, CAS: 1932337-68-2) and 3-bromospiro[5H-furo[3,4-b]pyridine-7,3'-azetidine]-1'-carboxylic acid tert-butyl ester (CAS: 1575836-59-7, PBU1967, supplier: Pharmablock) and [(2 The title compound was prepared by replacing tert-butyl (3-methylazetidin-3-yl)carbamate (compound 1d) and tert-butyl 6-bromospiro[1H-isobenzofuran-3,3'-azetidine]-1'-carboxylate (compound 1a) with methyl [(2R,6R)-4-(7-cyano-3-fluoro-pyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholin-2-yl] trifluoromethanesulfonate (intermediate E). Example 29 (13 mg) was obtained as a yellow solid. MS: calculated 555 (MH + ), measure 555(MH + ). 1 H NMR (400MHz, methanol-d4) δ8.54(d,J=8.6Hz,1H),8.04(d,J=8.1Hz,1H),7.73(d,J=2.4Hz,1H),7.53(d,J=8.6Hz,1H),7.15(d,J=8.1Hz,1H),6 .76(d,J=2.4Hz,1H),4.94(s,2H),3.84-4.05(m,3H),3.43-3.78(m,8H),3.25-3.40(m,2H),2.48-3.15(m,9H),1.13ppm(d,J=6.2Hz,3H).

[0330] Example 31

[0331] 5-[(2S,6R)-2-[[3-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]spiro[5H-furo[3,4-b]pyridine-7,3'-azetidine]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-2-deuterated-quinoline-8-carbonitrile

[0332]

[0333] Similar to the preparation method of Example 1, tert-butyl N-[(3R,4R)-4-methoxypyrrolidin-3-yl]carbamate (PharmaBlock, PBZ4728, CAS: 1932066-52-8) and tert-butyl 3-bromospiro[5H-furo[3,4-b]pyridine-7,3'-azetidine]-1'-carboxylate (CAS: 1575836-59-7, PBU1967, supplier: Pharmablock) and [(2R,6R)-4-(8-cyano)- -2-deuterated-5-quinolinyl)-6-methyl-morpholin-2-yl] trifluoromethanesulfonic acid methyl ester (intermediate L) was used to replace (3-methylazetidin-3-yl)carbamic acid tert-butyl ester (compound 1d) and 6-bromospiro[1H-isobenzofuran-3,3'-azetidin]-1'-carboxylic acid tert-butyl ester (compound 1a) and [(2R,6R)-4-(7-cyano-3-fluoro-pyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholin-2-yl] trifluoromethanesulfonic acid methyl ester (intermediate E) to prepare the title compound. Example 31 (13 mg) was obtained as a yellow solid. MS: calculated value 543 (MH+), found value 543 (MH+). 1 H NMR (400MHz, methanol-d4) δ8.54(d,J=8.7Hz,1H),8.05(d,J=7.9Hz,1H),7.75(d,J= 2.4Hz,1H),7.53(d,J=8.7Hz,1H),7.15(d,J=8.1Hz,1H),6.79(d,J=2.4Hz,1H ),4.94(s,2H),3.87-4.00(m,2H),3.57-3.78(m,6H),3.39-3.55(m,2H),3.23 -3.38(m,6H),2.97-3.09(m,1H),2.44-2.81(m,4H),1.13ppm(d,J=6.2Hz,3H).

[0334] Example 32

[0335] 5-[(2S,6R)-2-[[6-(3-aminoazetidin-1-yl)spiro[1H-furo[3,4-c]pyridine-3,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-2-deuterated-quinoline-8-carbonitrile

[0336]

[0337] The title compound was prepared similarly to the preparation method of Example 1, using [(2R,6R)-4-(8-cyano-2-deuterated-5-quinolinyl)-6-methyl-morpholin-2-yl] trifluoromethanesulfonic acid methyl ester (Intermediate L) and tert-spiro[azetidine-3,3'(1'H)-furo[3,4-c]pyridine]-1-carboxylic acid, 6'-chloro-, 1,1-dimethylethyl ester (CAS: 1575836-95-1, supplier: PharmaBlock) instead of [(2R,6R)-4-(7-cyano-3-fluoro-pyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholin-2-yl] trifluoromethanesulfonic acid methyl ester (Intermediate E) and 6-bromospiro[1H-isobenzofuran-3,3'-azetidine]-1'-carboxylic acid tert-butyl ester (Compound 1a). Example 32 (2 mg) was obtained as a light yellow solid. MS: Calculated 499 (MH + ), measured 499(MH + ). 1 HNMR (400MHz, methanol-d4) δ8.65(d,J=8.6Hz,1H),8.32(s,1H),8.15(d,J=7.9Hz,1H),7.6 3(d,J=8.7Hz,1H),7.25(d,J=8.1Hz,1H),6.32(s,1H),4.96(s,2H),4.26(d,J=7.6Hz, 1H),4.09–4.02(m,2H),3.78(dd,J=8.1,4.8Hz,2H),3.72–3.62(m,4H),3.49–3.41(m ,2H),3.40–3.35(m,2H),2.81–2.71(m,3H),2.69–2.62(m,1H),1.24(d,J=6.2Hz,3H).

[0338] Example 33

[0339] 4-[(2S,6R)-2-[[3-(3-amino-3-methyl-azetidin-1-yl)spiro[5H-furo[3,4-b]pyridine-7,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile

[0340]

[0341] The title compound was prepared similarly to the preparation method of Example 1, using 3-bromospiro[5H-furo[3,4-b]pyridine-7,3-azetidine]-1-carboxylic acid tert-butyl ester (CAS: 1575836-59-7, supplier: PharmaBlock) instead of 6-bromospiro[1H-isobenzofuran-3,3'-azetidine]-1'-carboxylic acid tert-butyl ester (Compound 1a). Example 33 (3 mg) was obtained as a light yellow solid. MS: Calculated 519 (MH + ), measured 519 (MH + ). 1 H NMR (400MHz, methanol-d4) δ7.9-8.0(m,1H),7.8-7.9(m,1H),7.35(d,1H,J=7.9Hz),6.82(d,1H,J=2.6Hz),6.3-6.5(m,1H ),5.04(s,2H),3.9-4.1(m,5H),3.3-3.6(m,6H),2.5-2.8(m,2H),2.96–3.10(m,3H),1.59(s,3H),1.1-1.3(m,3H).

[0342] Example 34

[0343] To determine the activity of compounds of formula (I) and (Ia) in the HEK293-Blue-hTLR-7 / 8 / 9 cell assay, the following assay was performed.

[0344] HEK293-Blue-hTLR-7 Cell Assay:

[0345] The stable HEK293-Blue-hTLR-7 cell line was purchased from InvivoGen (Cat.#: hkb-htlr7, San Diego, California, USA). These cells were originally designed to study human TLR7 stimulation by monitoring NF-κB activation. The SEAP (secreted embryonic alkaline phosphatase) reporter gene was placed under the control of the IFN-β minimal promoter fused to five NF-κB and AP-1 binding sites. NF-κB and AP-1 were activated by stimulating HEK-Blue hTLR7 cells with TLR7 ligands to induce SEAP. Therefore, reporter gene expression was reduced by TLR7 antagonists after incubation for 20 hours under ligand stimulation such as R848 (Resiquimod). Using QUANTI-Blue TM The kit (Cat.#: rep-qb1, Invivogen, San Diego, Ca, USA) measures the activity of the SEAP reporter gene in the cell culture supernatant at a wavelength of 640 nm. In the presence of alkaline phosphatase, the detection medium turns purple or blue.

[0346] HEK293-Blue-hTLR7 cells were cultured at 250,000 cells / well in a 96-well plate in a volume of 170 μL in Dulbecco's Modified Eagle Medium (DMEM) containing 4.5 g / L glucose, 50 U / mL penicillin, 50 mg / mL streptomycin, 100 mg / mL normocin, 2 mM L-glutamine, and 10% (v / v) heat-inactivated fetal bovine serum. The cells were incubated at a density of 450,000 cells / mL, and 20 μL of the test compound and 10 μL of 20uM R848 were added at a final dilution of 1% in the presence of DMSO in the above DMEM, and cultured in a CO2 incubator at 37°C for 20 hours. Then 20 μL of the supernatant in each well was incubated with 180 μL of Quanti-blue substrate solution at 37°C for 2 hours and the concentration was measured using a spectrophotometer at 620 The absorbance was read at 655 nm. The signaling pathway by which TLR7 activation leads to downstream NF-κB activation is widely accepted, so a similar reporter gene assay was modified to evaluate TLR7 antagonists.

[0347] HEK293-Blue-hTLR-8 Cell Assay:

[0348] The stable HEK293-Blue-hTLR-8 cell line was purchased from InvivoGen (Cat.#: hkb-htlr8, San Diego, California, USA). These cells were originally designed to study human TLR8 stimulation by monitoring NF-κB activation. The SEAP (secreted embryonic alkaline phosphatase) reporter gene was placed under the control of the IFN-β minimal promoter fused to five NF-κB and AP-1 binding sites. NF-κB and AP-1 were activated by stimulating HEK-Blue hTLR8 cells with TLR8 ligands to induce SEAP. Therefore, reporter gene expression was reduced by TLR8 antagonists after incubation for 20 hours under ligand stimulation (such as R848). Using QUANTI-Blue TM The kit (Cat.#: rep-qb1, Invivogen, San Diego, Ca, USA) measures the activity of the SEAP reporter gene in the cell culture supernatant at a wavelength of 640 nm. In the presence of alkaline phosphatase, the detection medium turns purple or blue.

[0349] HEK293-Blue-hTLR8 cells were cultured at 250,000 cells / well in a 96-well plate in a volume of 170 μL in Dulbecco's Modified Eagle Medium (DMEM) containing 4.5 g / L glucose, 50 U / mL penicillin, 50 mg / mL streptomycin, 100 mg / mL normocin, 2 mM L-glutamine, and 10% (v / v) heat-inactivated fetal bovine serum. 450,000 cells / mL were incubated, 20 μL of the test compound and 10 μL of 60uM R848 were added at a final dilution of 1% in the presence of DMSO in the above DMEM, and cultured in a CO2 incubator at 37°C for 20 hours. Then 20 μL of the supernatant in each well was incubated with 180 μL of Quanti-blue substrate solution at 37°C for 2 hours and the concentration was measured using a spectrophotometer at 620 The absorbance was read at 655 nm. The signaling pathway by which TLR8 activation leads to downstream NF-κB activation is widely accepted, so a similar reporter gene assay was modified to evaluate TLR8 antagonists.

[0350] HEK293-Blue-hTLR-9 cell assay:

[0351] The stable HEK293-Blue-hTLR-9 cell line was purchased from InvivoGen (Cat.#:hkb-htlr9, San Diego, California, USA). These cells were originally designed to study human TLR9 stimulation by monitoring NF-κB activation. The SEAP (secreted embryonic alkaline phosphatase) reporter gene was placed under the control of the IFN-β minimal promoter fused to five NF-κB and AP-1 binding sites. NF-κB and AP-1 were activated by stimulating HEK-Blue hTLR9 cells with TLR9 ligands to induce SEAP. Therefore, reporter gene expression was reduced by TLR9 antagonists by incubation for 20 hours under stimulation with ligands such as ODN2006 (Cat.#:tlrl-2006-1, Invivogen, San Diego, California, USA). Using QUANTI-Blue TM The kit (Cat.#: rep-qb1, Invivogen, San Diego, California, USA) measures the activity of the SEAP reporter gene in the cell culture supernatant at a wavelength of 640 nm. In the presence of alkaline phosphatase, the detection medium turns purple or blue.

[0352] HEK293-Blue-hTLR9 cells were cultured at 250,000 450,000 cells / mL were cultured in a 96-well plate in a volume of 170 μL in Dulbecco's Modified Eagle Medium (DMEM) containing 4.5 g / L glucose, 50 U / mL penicillin, 50 mg / mL streptomycin, 100 mg / mL Normocin, 2 mM L-glutamine, 10% (v / v) heat-inactivated fetal bovine serum, wherein 20 μL of the test compound and 10 μL of 20 uM DMEM solution of DMEM were added in serial dilutions in the presence of 1% final DMSO, and incubated in a CO2 incubator at 37°C for 20 hours. Then 20 μL of the supernatant in each well was incubated with 180 μL Quanti-blue substrate solution at 37°C for 2 hours and measured using a spectrophotometer at 620 The absorbance was read at 655 nm. The signaling pathway by which TLR9 activation leads to downstream NF-κB activation is widely accepted, so similar reporter gene assays were modified to evaluate TLR9 antagonists.

[0353] The compounds of formula (I) or formula (Ia) have human TLR7 and / or TLR8 inhibitory activity (IC 50 In addition, some compounds also have human TLR9 inhibitory activity <0.5 μM. Table 2 shows the activity data of the compounds of the present invention.

[0354] Table 2. Activity of compounds of the invention in HEK293-Blue-hTLR-7 / 8 / 9 cell assay

[0355]

[0356]

[0357] Example 35

[0358] hERG channel inhibition assay:

[0359] The hERG channel inhibition assay is a highly sensitive measurement that identifies compounds that exhibit hERG inhibition associated with in vivo cardiotoxicity. + The channel was cloned into human and stably expressed in CHO (Chinese Hamster Ovary) cell line. hERG Cells were used for patch clamp (voltage clamp, whole cell) experiments. Voltage mode stimulation of cells activated hERG channels and conducted I KhERG Current (fast delayed outward rectifier potassium current of hERG channels). After the cells were stable for several minutes, I was recorded at a stimulation frequency of 0.1 Hz (6 bpm). KhERGThe amplitude and kinetics of the oscillations were then measured. Thereafter, the test compound was added to the formulation at increasing concentrations. For each concentration, an attempt was made to reach a steady-state effect, which was usually achieved within 3-10 minutes, at which time the next highest concentration was applied. The I KhERG The amplitude and kinetics of the oscillations were measured and compared with the control values ​​(considered as 100%). (Reference: Redfern WS, Carlsson L, Davis AS, Lynch WG, MacKenzie I, PalethorpeS, Siegl PK, Strang I, Sullivan AT, Wallis R, Camm AJ, Hammond TG.2003; Relationships between preclinical cardiac electrophysiology, clinical QTinterval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drugdevelopment.Cardiovasc.Res.58:32-45,Sanguinetti MC,Tristani-Firouzi M.2006;hERG potassium channels and cardiac arrhythmia.Nature 440:463-469,Webster R,Leishman D,Walker D.2002;Towards a drug concentration effect relationship for QT prolongation and torsades de points.Curr.Opin.Drug Discov.Devel.5:116-26).

[0360] The results of hERG are given in Table 3. Safety ratio (hERG IC 20 / EC 50 )>30 represents an adequate safety window to distinguish pharmacology by inhibiting TLR7 / 8 / 9 pathway from potential hERG-related cardiotoxicity. 20 / TLR7 / 8 / 9IC 50From the calculation of (hereinafter used as an early selectivity indicator for assessing hERG liability), it is apparent that the reference compounds ER-887258, ER-888285, ER-888286, R1 and R2 have narrower safety windows than the compounds of the present invention.

[0361] Table 3. hERG and safety ratio results

[0362]

[0363] Example 36

[0364] These compounds are expected to have minimal DDI indicators. Therefore, the effects of compounds of formula (I) having formula (Ia) on major CYP isoforms (eg, CYP2C9, CYP2D6 and CYP3A4) were determined.

[0365] CYP inhibition assay

[0366] This is a high-throughput screening assay designed to evaluate the reversible inhibition of CYP2C9, CYP2D6, and CYP3A4 activity by test compounds in early discovery human liver microsomes (HLM).

[0367] Table 4. Chemicals and materials used in CYP inhibition assays

[0368]

[0369] program

[0370] A 10mM DMSO stock solution of the test compound was diluted in DMSO to generate a 2mM intermediate stock solution. 250nL of the intermediate stock solution was transferred in duplicate to 3 separate 384-well microtiter plates (test plates). A mixture of HLM and each substrate was prepared. Then 45μL of the HLM substrate mixture was transferred to each well of the test plate and mixed. Negative (solvent) and positive controls (standard inhibitors of each CYP) were included in each test plate. The test plate was warmed to 37°C in an incubator for 10 minutes. 5μL of preheated NADPH regeneration system was added to each culture well to start the reaction. The final incubation volume was 50μL. The assay plate was then returned to the incubator at 37°C. After 5 minutes of incubation (10 minutes for CYP2D6), 50 μL of 100% acetonitrile containing internal standards (400 ng / mL 13C6-4'-OH-diclofenac, 20 ng / mL D3-dextrorphan and 20 ng / mL D4-1'OH-midazolam) was added to quench the incubation. The supernatant was collected for RapidFire / MS / MS analysis.

[0371] Sample analysis was performed using a RapidFire online solid phase extraction / sample injection system (Agilent) coupled to an API4000 triple quadrupole mass spectrometer (AB Sciex). The mobile phase consisted of acetonitrile and water supplemented with 0.1% formic acid. Sample separation was performed using a C4 solid phase extraction cartridge. MS detection was performed in positive ion MRM mode.

[0372] Data analysis

[0373] The peak areas of substrate, metabolites and internal standards were determined using RapidFire Integrator software (version 3.6.12009.12296). The peak area ratio (PAR) of metabolites and internal standards (stable labeled metabolites) was then calculated. The measurement window for each experiment was then defined:

[0374] PAR (0% activity) = average PAR of all incubations containing concentrated inhibitor;

[0375] PAR (100% activity) = average PAR of all incubations containing no inhibitor (DMSO control);

[0376] % activity (test inhibitor) = [PAR (test inhibitor) - PAR (0% activity)] / [PAR (100% activity) - PAR (0% activity)];

[0377] Inhibition % (test inhibitor) = 100 - Activity % (test inhibitor).

[0378] The compounds of the invention determined in the above assay were found to have low CYP inhibition on CYP2D6.

[0379] Table 5. CYP inhibitory effects of the compounds of the present invention on CYP2D6

[0380] Instance Number CYP(%)2C9 / 2D6 / 3A4 ER-888286 29.5 / 52.5 / 5.5 7 0 / -2 / 16.5 8 -8.5 / 5 / -8.5 11 4 / 5.5 / 12 17 3.5 / 18.5 / 14 20 13.5 / 13 / 40.5 21 4.5 / 5 / 12.5 24 21 / 3.5 / -0.5

[0381] Inhibition percentage < 0: non-inhibitor or weak inhibitor.

Claims

1. A compound of formula (I), in R 1 for Where R 4 is cyano; R 4a C 1-6 Alkyl; R 5 is H or deuterium; R 6 is H or halogen; R 2 C 1-6 alkyl; R 3 2,6-diazaspiro[3.3]heptyl; 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl; 5-oxa-2,8-diazaspiro[3.5]nonyl; amino(C 1-6 alkyl)azetidinyl; amino (C 1-6 alkyl)pyrrolidinyl; amino(C 1-6 (alkyloxy)pyrrolidinyl; amino(hydroxy)pyrrolidinyl; aminoazetidinyl; C 1-6 Alkyl-2,6-diazaspiro[3.3]heptyl; halogenated pyrrolidinylamino or piperazinyl; Y and A are independently selected from CH and N, provided that Y and A are not N at the same time; or a pharmaceutically acceptable salt thereof.

2. A compound of formula (Ia), in R 1 for Where R 4 is cyano; R 4a C 1-6 Alkyl; R 5 is H or deuterium; R 6 is H or halogen; R 2 C 1-6 alkyl; R 3 2,6-diazaspiro[3.3]heptyl; 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl; 5-oxa-2,8-diazaspiro[3.5]nonyl; amino(C 1-6 alkyl)azetidinyl; amino (C 1-6 alkyl)pyrrolidinyl; amino(C 1-6 (alkyloxy)pyrrolidinyl; amino(hydroxy)pyrrolidinyl; aminoazetidinyl; C 1-6 Alkyl-2,6-diazaspiro[3.3]heptyl; halogenated pyrrolidinylamino or piperazinyl; Y and A are independently selected from CH and N, provided that Y and A are not N at the same time; or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 or 2, wherein R 1 for Where R 4 is cyano; R 5 is H or deuterium; R 6 is H or halogen.

4. The compound according to claim 3, wherein R 1 for Where R 4 is cyano; R 5 is H or deuterium; R 6 is H or fluorine.

5. The compound according to claim 4, wherein Y is CH and A is N; or Y is N and A is CH.

6. The compound according to claim 5, wherein R 3 Amino (C 1-6 alkyl)azetidinyl; 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl or amino(C 1-6 alkoxy)pyrrolidinyl.

7. The compound according to claim 6, wherein R 3 It is 3-amino-3-methyl-azetidin-1-yl; 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl or 3-amino-4-methoxy-pyrrolidin-1-yl.

8. The compound according to claim 1 or 2, wherein R 1 for Where R 4 is cyano; R 5 for deuterium; R 2 C 1-6 alkyl; R 3 Amino (C 1-6 alkyl)azetidinyl; 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl or amino(C 1-6 Alkoxy)pyrrolidinyl; Y is CH and A is N; or Y is N and A is CH; or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 8, wherein R 1 for Where R 4 is cyano; R 5 for deuterium; R 2 is methyl; R 3 is 3-amino-3-methyl-azetidin-1-yl; 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl or 3-amino-4-methoxy-pyrrolidin-1-yl; Y is CH and A is N; or Y is N and A is CH; or a pharmaceutically acceptable salt thereof.

10. A compound selected from: 4-[(2S,6R)-2-[[6-(3-amino-3-methyl-azetidin-1-yl)spiro[1H-isobenzofuran-3,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile; 3-Fluoro-4-[(2R,6S)-2-methyl-6-[[6-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)spiro[1H-isobenzofuran-3,3'-azetidin-1'-yl]methyl]morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile; 3-Fluoro-4-[(2S,6R)-2-[[6-[[(3S,4R)-4-fluoropyrrolidin-3-yl]amino]spiro[1H-isobenzofuran-3,3'-azetidin-1'-yl]methyl]-6-methyl-morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile; 3-Fluoro-4-[(2R,6S)-2-methyl-6-[[6-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)spiro[1H-isobenzofuran-3,3'-azetidin-1'-yl]methyl]morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile; 4-[(2S,6R)-2-[[6-[(3S)-3-amino-3-methyl-pyrrolidin-1-yl]spiro[1H-isobenzofuran-3,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile; 3-Fluoro-4-[(2R,6S)-2-methyl-6-[(6-piperazin-1-ylspiro[1H-isobenzofuran-3,3'-azetidine]-1'-yl)methyl]morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile; 4-[(2R,6S)-2-methyl-6-[[6-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)spiro[1H-isobenzofuran-3,3'-azetidin-1'-yl]methyl]morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile; 4-[(2R,6S)-2-methyl-6-[[6-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)spiro[1H-isobenzofuran-3,3'-azetidin-1'-yl]methyl]morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile; 4-[(2S,6R)-2-[[6-(3-aminoazetidin-1-yl)spiro[1H-isobenzofuran-3,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile; 4-[(2S,6R)-2-[[6-[(3S,4S)-3-amino-4-hydroxy-pyrrolidin-1-yl]spiro[1H-isobenzofuran-3,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile; 5-[(2S,6R)-2-[[6-(3-amino-3-methyl-azetidin-1-yl)spiro[1H-isobenzofuran-3,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-2-deutero-quinoline-8-carbonitrile; 4-[(2S,6R)-2-[[6-(2,6-diazaspiro[3.3]heptane-2-yl)spiro[1H-isobenzofuran-3,3'-azetidin-1'-yl]methyl]-6-methyl-morpholin-4-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile; 4-[(2S,6R)-2-[[6-(3-aminoazetidin-1-yl)spiro[1H-isobenzofuran-3,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-1-methyl-1,8-naphthyridin-2-one; 5-[(2S,6R)-2-[[6-(3-aminoazetidin-1-yl)spiro[1H-isobenzofuran-3,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-2-deutero-quinoline-8-carbonitrile; 2-deuterated-5-[(2R,6S)-2-methyl-6-[[6-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)spiro[1H-isobenzofuran-3,3'-azetidin-1'-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile; 5-[(2S,6R)-2-[[6-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]spiro[1H-isobenzofuran-3,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(2S,6R)-2-[[6-[(4aR,7aR)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl]spiro[1H-isobenzofuran-3,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-2-deutero-quinoline-8-carbonitrile; 2-deuterated-5-[(2R,6S)-2-methyl-6-[(6-piperazin-1-ylspiro[1H-isobenzofuran-3,3'-azetidine]-1'-yl)methyl]morpholin-4-yl]quinoline-8-carbonitrile; 4-[(2S,6R)-2-[[6-(3-aminoazetidin-1-yl)spiro[1H-isobenzofuran-3,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile; 5-[(2S,6R)-2-[[3-(3-aminoazetidin-1-yl)spiro[5H-furo[3,4-b]pyridine-7,3'-azetidin-1'-yl]methyl]-6-methyl-morpholin-4-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(2S,6R)-2-[[3-(3-amino-3-methyl-azetidin-1-yl)spiro[5H-furo[3,4-b]pyridine-7,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-2-deutero-quinoline-8-carbonitrile; 3-Fluoro-4-[(2R,6S)-2-methyl-6-[[3-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)spiro[5H-furo[3,4-b]pyridine-7,3'-azetidin]-1'-yl]methyl]morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile; 5-[(2S,6R)-2-[[6-(3-amino-3-methyl-azetidin-1-yl)spiro[1H-furo[3,4-c]pyridine-3,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-2-deutero-quinoline-8-carbonitrile; 4-[(2S,6R)-2-[[6-(3-amino-3-methyl-azetidin-1-yl)spiro[1H-furo[3,4-c]pyridine-3,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile; 4-[(2S,6R)-2-[[6-(3-amino-3-methyl-azetidin-1-yl)spiro[1H-furo[3,4-c]pyridine-3,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile; 4-[(2S,6R)-2-[[3-(3-amino-3-methyl-azetidin-1-yl)spiro[5H-furo[3,4-b]pyridine-7,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile; 5-[(2S,6R)-2-[[6-[(4aR,7aR)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl]spiro[1H-furo[3,4-c]pyridine-3,3'-azetidin-1'-yl]methyl]-6-methyl-morpholin-4-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(2S,6R)-2-[[3-[(4aR,7aR)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl]spiro[5H-furo[3,4-b]pyridine-7,3'-azetidin-1'-yl]methyl]-6-methyl-morpholin-4-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(2S,6R)-2-[[3-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]spiro[5H-furo[3,4-b]pyridine-7,3'-azetidin-1'-yl]methyl]-6-methyl-morpholin-4-yl]-2-deutero-quinoline-8-carbonitrile; 5-[(2S,6R)-2-[[6-(3-aminoazetidin-1-yl)spiro[1H-furo[3,4-c]pyridine-3,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-2-deutero-quinoline-8-carbonitrile; and 4-[(2S,6R)-2-[[3-(3-amino-3-methyl-azetidin-1-yl)spiro[5H-furo[3,4-b]pyridine-7,3'-azetidin]-1'-yl]methyl]-6-methyl-morpholin-4-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

11. Use of a compound according to any one of claims 1 to 10 for preparing a medicament for treating or preventing systemic lupus erythematosus or lupus nephritis mediated by TLR7 / 8 / 9.

12. Use of a compound according to any one of claims 1 to 10 for the preparation of a medicament for a TLR7, TLR8 and TLR9 antagonist.

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