Piperazine compounds for the treatment of autoimmune diseases

Abstract

The present invention relates to compounds of Formula (I), wherein R 1 to R 4 As described herein, and pharmaceutically acceptable salts, enantiomers or diastereomers thereof, as well as compositions containing said compounds and methods of using said compounds.

Description

[0001] The present application relates to organic compounds useful for therapy and / or prophylaxis in a mammal, in particular to antagonists of TLR7 and / or TLR8 and / or TLR9 for the treatment of systemic lupus erythematosus or lupus nephritis. TECHNICAL FIELD

[0002] Autoimmune connective tissue diseases (CTD) include prototypical autoimmune syndromes such as systemic lupus erythematosus (SLE), primary Sjogren’s syndrome (pSjS), mixed connective tissue disease (MCTD), dermatomyositis / polymyositis (DM / PM), rheumatoid arthritis (RA), and systemic sclerosis (SSc). Except for RA, there are no truly effective and safe therapies for patients. SLE represents a prototypical CTD with a prevalence of 20-150 / 100,000 and causes extensive inflammation and tissue damage in different organs, from common symptoms in the skin and joints to kidney, lung, or heart failure. Traditionally, nonspecific anti-inflammatory or immunosuppressive drugs have been used for the treatment of SLE. However, long-term use of immunosuppressive drugs, e.g., corticosteroids, is only partially effective and is associated with adverse toxicity and side effects. Belimumab is the only FDA-approved drug for lupus in the past 50 years, although it has only modestly delayed efficacy in a subset of SLE patients (Navarra, S. V. et al. Lancet 2011, 377 , 721.). Other biologies, such as anti-CD20 mAbs, mAbs against specific cytokines, or soluble receptors of specific cytokines, have failed in most clinical studies. Thus, there is a need for novel therapies 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 (TLRs) are an important family of Pattern Recognition Receptors (PRRs) that can initiate broad immune responses in multiple immune cells. Endosomal TLRs 7, 8, and 9 act as natural host defense sensors that can recognize nucleic acids derived from viruses, bacteria; specifically, TLR7 / 8 and TLR9 recognize single-stranded RNA (ssRNA) and single-stranded CpG-DNA, respectively. However, aberrant nucleic acid sensing by TLR7, 8, 9 is thought to be a key node in a wide range of autoimmune and autoinflammatory diseases (Krieg, A.M. et al. Immunol. Ed. .2007, 220 , 251. Jiménez-Dalmaroni, M.J. et al. Autoimmun. Ed. 2016, 15 , 1 . Chen, J.Q. et al. Clinical Reviews in Allergy & Immunology to 2016, 50, 1). Anti-RNA and anti-DNA antibodies are recognized diagnostic markers of SLE, and these antibodies can deliver 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. Indeed, in patients with SLE (Systemic Lupus Erythematosus), defects in clearance of self-RNA and self-DNA from blood and / or tissues are evident. It has been reported that TLR7 and TLR9 are upregulated in SLE tissues and are associated with long-term and activity of lupus nephritis, respectively. In B cells of SLE patients, TLR7 expression is associated with anti-RNP antibody production, while TLR9 expression is associated with IL-6 and anti-dsDNA antibody levels. Likewise, in a mouse model of lupus, anti-RNA antibodies require TLR7, while anti-nucleosome antibodies require TLR9. On the other hand, overexpression of TLR7 in mice or human TLR8 promotes autoimmunity and autoinflammation. Moreover, TLR8 activation specifically contributes to inflammatory cytokine secretion by mDC / macrophages, neutrophil NETosis, induction of Th17 cells and suppression of Treg cells. In addition to the described role of TLR9 in promoting B cell autoantibody production, self-DNA-induced TLR9 activation in pDC also leads to induction of type I IFN and other inflammatory cytokines. Given these roles of TLR9 in pDC and B cells, both of which are key players in the pathogenesis of autoimmune diseases, and the widespread presence of self-DNA complexes in many patients with autoimmune diseases, which can easily activate TLR9, this can have additional benefits for further blocking self-DNA-mediated TLR9 pathway on top of inhibiting 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 oral drugs without steroids and without cytotoxicity, and inhibition of all these pathways from the uppermost stream can lead to a satisfactory therapeutic effect. Likewise, we have invented oral compounds targeting and inhibiting TLR7, TLR8 and TLR9 for the treatment of autoimmune and autoinflammatory diseases. SUMMARY

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

[0005] (I),

[0006] wherein

[0007] R 1 is , , or ; wherein R 5 is cyano, C 1-6 alkoxy, C 1-6 alkyl or halogen;

[0008] R 2 is C 1-6 alkyl;

[0009] R 3 is R 3a or -COR 3b ; wherein

[0010] R 3a is phenyl substituted by piperazinyl and (hydroxyC 1-6 alkyl)piperazinyl;

[0011] pyridinyl substituted by piperazinyl, C 1-6 alkylpiperazinyl, 9-oxa-3,7-diazabicyclo[3.3.1]nonanyl, (halopyrrolidinyl)amino, (pyrrolidinylcarbonyl)piperazinyl or (((C 1-6 alkyl)2amino)C 1-6 alkylcarbonyl)piperazinyl or

[0012] pyrimidinyl substituted by piperazinyl or (((C 1-6 alkyl)2amino)C 1-6 alkylcarbonyl)piperazinyl;

[0013] R 3b is 7,8-dihydro-5H-l,6-naphthyridinyl substituted by piperazinyl;

[0014] 3,4-dihydro-lH-isoquinolinyl substituted by piperazinyl;

[0015] isoindolinyl substituted by piperazinyl;

[0016] phenylamino substituted by piperazinyl;

[0017] 1,2,3,4-tetrahydroisoquinolinyl or

[0018] C 1-6 alkylpiperidinylpiperidinyl;

[0019] R 4 is C 1-6 alkyl or hydrogen;

[0020] or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

[0021] Another object of the present application relates to novel compounds of formula (I), their manufacture, medicaments based on compounds according to the application and their production and the use of the compounds of formula (I) as TLR7 and / or TLR8 and / or TLR9 antagonists and for the treatment or prophylaxis of systemic lupus erythematosus or lupus nephritis. The compounds of formula (I) show superior TLR7 and / or TLR8 and / or TLR9 antagonistic activity. In addition, the compounds of formula (I) also show good hPBMC, cytotoxic, lysosomal, human microsomal stability and SDPK profiles, as well as low CYP inhibition. DETAILED DESCRIPTION

[0022] DEFINITIONS

[0023] The term "C 1-6 "alkyl" denotes a saturated, straight chain or branched hydrocarbon group containing from 1 to 6, in particular 1 to 4 carbon atoms, for example methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl and the like. In particular, the term "C 1-6 "alkyl" group is methyl, ethyl and n-propyl.

[0024] The term "C 1-6 "alkoxy" denotes a C 1-6 alkyl-O- group.

[0025] The terms "halogen" and "halo" are used interchangeably herein to denote fluorine, chlorine, bromine or iodine.

[0026] The term "halo-pyrrolidinyl" denotes a pyrrolidinyl group, wherein one or more hydrogen atoms of the pyrrolidinyl group have been replaced with the same or different halogen atoms, in particular fluorine atoms. Examples of halo-pyrrolidinyl groups include fluoro-pyrrolidinyl, difluoro-pyrrolidinyl or trifluoro-pyrrolidinyl.

[0027] The term "enantiomer" denotes two stereoisomers of a compound which are non- superimposable mirror images of one another.

[0028] The term "diastereomer" denotes stereoisomers which have at least two asymmetric centers and whose molecules are not mirror images of one another. Diastereomers have the same molecular formula but different physical properties, such as melting point, boiling point, spectral properties, and reactivity.

[0029] The term "pharmaceutically acceptable salt" denotes a salt that is neither biologically nor otherwise undesirable. Pharmaceutically acceptable salts include both acid addition salts and base addition salts.

[0030] The term "pharmaceutically acceptable acid addition salt" denotes those pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and organic acids selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, Acc. Chem. Res. toluene sulfonic acid and salicylic acid.

[0031] The term "pharmaceutically acceptable base addition salt" denotes those pharmaceutically acceptable salts formed with inorganic or organic 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 nontoxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purines, piperizine, piperidine, N ethylpiperidine, and polyamine resins.

[0032] The term "pharmaceutically active metabolite" denotes a pharmacologically active product produced through metabolism in the body of a specified compound or salt thereof. Once in the body, most drugs undergo chemical changes, which can alter their physical properties and biological effects. These metabolic transformations, which usually affect the polarity of the compound, alter the way the drug is distributed in the body and excreted from it. In some cases, however, drug metabolism is necessary for therapeutic effects.

[0033] The term "therapeutically effective amount" means an amount of a compound or molecule of the present application that, when administered to a subject, (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The therapeutically effective amount will depend on the compound, the disease state being treated, the severity or the disease, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary practitioner, and other factors.

[0034] The term "pharmaceutical composition" refers to a mixture or solution of a therapeutically effective amount of an active pharmaceutical ingredient together with a pharmaceutically acceptable excipient, which will be administered to a mammal, e.g., a human in need thereof.

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

[0036] The present invention relates to compounds of formula (I),

[0037] (I),

[0038] wherein

[0039] R 1 is , , or ; wherein R 5 is cyano, C 1-6 alkoxy, C 1-6 alkyl or halogen;

[0040] R 2 is C 1-6 alkyl;

[0041] R 3 is R 3a or -COR 3b ; wherein

[0042] R 3a is phenyl substituted by piperazinyl and (hydroxyC 1-6 alkyl)piperazinyl;

[0043] pyridinyl substituted by piperazinyl, C 1-6 alkylpiperazinyl, 9-oxa-3,7-diazabicyclo[3.3.1]nonanyl, (halopyrrolidinyl)amino, (pyrrolidinylcarbonyl)piperazinyl or (((C 1-6 alkyl)2amino)C 1-6 alkylcarbonyl)piperazinyl or

[0044] pyrimidinyl substituted by piperazinyl or (((C 1-6 alkyl)2amino)C 1-6 alkylcarbonyl)piperazinyl;

[0045] R 3b is 7,8-dihydro-5H-l,6-naphthyridinyl substituted by piperazinyl;

[0046] 3,4-dihydro-lH-isoquinolinyl substituted by piperazinyl;

[0047] isoindolinyl substituted by piperazinyl;

[0048] phenylamino substituted by piperazinyl;

[0049] 1,2,3,4-tetrahydroisoquinolinyl or

[0050] C 1-6 alkylpiperidinylpiperidinyl;

[0051] R 4 is C 1-6 alkyl or hydrogen;

[0052] or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

[0053] Another embodiment of the present application is (ii) which is a compound of formula (I),

[0054] (I),

[0055] wherein

[0056] R 1 is ; wherein R 5 is cyano;

[0057] R 2 is C 1-6 alkyl;

[0058] R 3 is R 3a or -COR 3b ; wherein

[0059] R 3a is phenyl substituted by piperazinyl and (hydroxyC 1-6 alkyl)piperazinyl;

[0060] pyridinyl substituted by piperazinyl, C 1-6 alkylpiperazinyl, 9-oxa-3,7-diazabicyclo[3.3.1]nonanyl, (halopyrrolidinyl)amino, (pyrrolidinylcarbonyl)piperazinyl or (((C 1-6 alkyl)2amino)C 1-6 alkylcarbonyl)piperazinyl or

[0061] pyrimidinyl substituted by piperazinyl or (((C 1-6 alkyl)2amino)C 1-6 alkylcarbonyl)piperazinyl;

[0062] R 3b is 7,8-dihydro-5H-l,6-naphthyridinyl substituted by piperazinyl;

[0063] 3,4-dihydro-lH-isoquinolinyl substituted by piperazinyl;

[0064] isoindolinyl substituted by piperazinyl;

[0065] phenylamino substituted by piperazinyl;

[0066] 1,2,3,4-tetrahydroisoquinolinyl or

[0067] C 1-6 alkylpiperidinylpiperidinyl;

[0068] R 4 is C 1-6 alkyl or hydrogen;

[0069] or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

[0070] A further embodiment of the present application is (iii), which is a compound of formula (I) according to (i) or (ii), wherein

[0071] R 1 is ; wherein R 5 is cyano;

[0072] R 2 is methyl;

[0073] R 3 is R 3a or -COR 3b ; wherein

[0074] R 3a is piperazinylphenyl; (hydroxymethyl)piperazinylphenyl; piperazinylpyridinyl; (methylpiperazinyl)pyridinyl; 9-oxa-3,7-diazabicyclo[3.3.1]nonanylpyridinyl; ((fluoropyrrolidinyl)amino)pyridinyl; ((pyrrolidinylcarbonyl)piperazinyl)pyridinyl; (((dimethylamino)acetyl)piperazinyl)pyridinyl; piperazinylpyrimidinyl; or ((dimethylamino)acetyl)piperazinylpyrimidinyl;

[0075] R 3b is piperazinyl-7,8-dihydro-5H-l,6-naphthyridinyl; piperazinyl-3,4-dihydro-lH-isoquinolinyl; piperazinylisoindolinyl; piperazinylphenylamino; 1,2,3,4-tetrahydroisoquinolinyl; or methylpiperidinylpiperidinyl;

[0076] R 4 is methyl or hydrogen;

[0077] or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

[0078] A further embodiment of the present application is (iv) which is a compound of formula (I) according to any one of (i) to (iv), wherein R 3 is R 3a or -COR 3b ; wherein R 3a is pyridyl substituted by piperazinyl; R 3b is isoindolinyl substituted by piperazinyl.

[0079] Another embodiment of the present application is (v) which is a compound of formula (I) selected from:

[0080] 5-[(3 R ,5 S )-3,5-dimethyl-4-[(4-piperazin-1-ylphenyl)methyl]piperazin-1-yl]quinoline-8- carbonitrile;

[0081] 5-[(3 R ,5 R )-3,5-dimethyl-4-[(4-piperazin-1-ylphenyl)methyl]piperazin-1-yl]quinoline-8- carbonitrile;

[0082] 5-[(3 R ,5 S )-3,5-dimethyl-4-[(6-piperazin-1-yl-3-pyridyl)methyl]piperazin-1-yl]quinoline-8- carbonitrile;

[0083] 5-[(3 S ,5 R )-3,5-dimethyl-4-[(5-piperazin-1-ylpyrimidin-2-yl)methyl]piperazin-1-yl]quinoline-8- carbonitrile;

[0084] 5-[(3 S ,5 R )-3,5-dimethyl-4-[(5-piperazin-1-yl-2-pyridyl)methyl]piperazin-1-yl]quinoline-8- carbonitrile;

[0085] 5-[(3 S ,5 R )-4-[[5-[4-[2-(dimethylamino)acetyl]piperazin-1-yl]pyrimidin-2-yl]methyl]-3,5- dimethyl-piperazin-1-yl]quinoline-8-carbonitrile;

[0086] 5-[(3 S ,5 R )-3,5-dimethyl-4-[[5-(4-methylpiperazin-1-yl)-2-pyridyl]methyl]piperazin-1- yl]quinoline-8-carbonitrile;

[0087] 5-[(3 S 5 R )-3,5-dimethyl-4-[[5-(9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-yl)-2-pyridyl]methyl]piperazin-1-yl]quinoline-8-nitrile;

[0088] 5-[(3 R 5 S )-3,5-dimethyl-4-[[5-[[(3 R 4 S )-4-fluoropyrrolidine-3-yl]amino]-2-pyridyl]methyl]piperazin-1-yl]quinoline-8-nitrile;

[0089] 5-[(3 R 5 S )-3,5-dimethyl-4-[[5-[4-(pyrrolidine-2-carbonyl)piperazin-1-yl]-2-pyridyl]methyl]piperazin-1-yl]quinoline-8-nitrile;

[0090] 5-[(3 S 5 R )-4-[[5-[4-[2-(dimethylamino)acetyl]piperazin-1-yl]-2-pyridyl]methyl]-3,5-dimethyl-piperazin-1-yl]quinoline-8-nitrile;

[0091] 5-[(3 R 5 S )-4-[[4-[2-(hydroxymethyl)piperazin-1-yl]phenyl]methyl]-3,5-dimethyl-piperazin-1-yl]quinoline-8-nitrile;

[0092] 5-[(3 R 5 S )-3,5-dimethyl-4-[2-oxo-2-(2-piperazin-1-yl-7,8-dihydro-5- H -1,6-naphthid-6-yl)ethyl]piperazin-1-yl]quinoline-8-nitrile;

[0093] 5-[(3 R 5 S )-3,5-dimethyl-4-[2-oxo-2-(6-piperazin-1-yl-3,4-dihydro-1-yl-2-( ... H -isoquinoline-2-yl)ethyl]piperazine-1-yl]quinoline-8-nitrile;

[0094] 5-[(3 R 5 S )-3,5-dimethyl-4-[2-oxo-2-(7-piperazin-1-yl-3,4-dihydro-1-yl-2-(7-piperazin-1-yl-3,4-dihydro-1-yl-2-(2-oxo ... H-isoquinoline-2-yl)ethyl]piperazine-1-yl]quinoline-8-nitrile;

[0095] 5-[(3 R 5 S )-3,5-dimethyl-4-[2-oxo-2-(5-piperazin-1-ylisoindoline-2-yl)ethyl]piperazin-1-yl]quinoline-8-nitrile;

[0096] 2-[4-(8-cyano-5-quinolinyl)-2-methyl-piperazin-1-yl]- N -(4-piperazin-1-ylphenyl)acetamide;

[0097] 2-[4-(8-cyano-5-quinolinyl)-2-methyl-piperazin-1-yl]- N -(1,2,3,4-tetrahydroisoquinoline-6-yl)acetamide; and

[0098] 5-[3-methyl-4-[2-[4-(1-methyl-4-piperidinyl)-1-piperidinyl]-2-oxo-ethyl]piperazin-1-yl]quinoline-8-nitrile;

[0099] Or its pharmaceutically acceptable salt, enantiomer or diastereomer.

[0100] synthesis

[0101] The compounds of the present invention can 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 stated, all substituents, especially R... 1 To R 6 As defined above. Furthermore, unless otherwise expressly stated, all reactions, reaction conditions, abbreviations, and symbols have meanings familiar to those skilled in the art of organic chemistry.

[0102] The general synthetic route for preparing compound (I) is shown in Scheme 1 below.

[0103] Option 1

[0104]

[0105] Where X is a halogen or leaving group, such as OTf or OM; Y is N or CH; R 6 It is a primary or secondary amine, including linear and cyclic amines, such as piperazine; R 7 and R 8 For protecting groups, such as R 7 For Boc and R 8 It is benzyl.

[0106] under basic conditions by alkylation of the protected amine (II) with an α-haloester (III), followed by selective removal of the protecting group R 7 The free amine (IV) can be obtained. Conversion of the carboxylic acid (VI) from the free amine (IV) can be achieved by nucleophilic aromatic substitution conditions (e.g. heating with an aryl halide (V) in DMSO in the presence of DIEPA) or Buchwald-Hartwig amination conditions (e.g. heating with a halide (V) in the presence of a catalyst such as Ruphos Pd-G2 and a base such as Cs2CO3), followed by removal of the protecting group R 8 Treatment of the carboxylic acid (VI) with an amine HR 3b in the presence of a coupling agent (such as HATU) and a base (such as DIPEA) can give the amide (VII).

[0107] Alternatively, the protected amine (II) can be alkylated by a halide (VIII), followed by removal of the protecting group R 7 The resulting free amine (IX) can be used to react with an aryl halide (V) under nucleophilic aromatic substitution conditions (e.g. heating with an aryl halide (V) in DMSO in the presence of DIEPA), giving intermediate (X). Compounds of formula (X) can be used as versatile intermediates for further functionalization under metal-catalyzed coupling conditions such as Buchwald-Hartwig amination, Suzuki coupling, Negishi coupling, Stille coupling or Pd-catalyzed C=O insertion. For example, under Buchwald-Hartwig amination conditions (cf. Chem. Rev. 1998, 31 , 805-818; Topics in Current Chemistry 2016, 116 , 12564-12649; Acc. Chem. Res. 2002, 219 , 131-209; and references cited therein), compounds of formula (XI) can be generated from compounds of formula (X) in the presence of an amine HR 6 and a catalyst such as Ruphos Pd-G2 and a base such as Cs2CO3.

[0108] Scheme 2

[0109]

[0110] wherein X is halogen or a leaving group, e.g. OTf or OM; Y is N or CH; R6 is a primary or secondary amine, including linear and cyclic amines, such as piperazine; R 7 and R 8 is a protecting group, for example R 7 is Boc and R 8 is benzyl.

[0111] In another synthetic route (Scheme 2), the protected amine (XII) can be reacted with aryl halide (V) under nucleophilic aromatic substitution conditions (for example heating with aryl halide (V) in DMSO in the presence of DIEPA) or Buchwald-Hartwig amination conditions (for example heating with halide (V) in the presence of a catalyst such as Ruphos Pd-G2 and a base such as Cs2CO3) to give the general intermediate (XIII), followed by removal of the protecting group R 7 . Under basic conditions, alkylation of amine (XIII) by a- halogenated ester (III), followed by selective removal of the protecting group R 8 , can give carboxylic acid (VI), which can be reacted with amine HR 3b in the presence of a coupling agent (such as HATU) and a base (such as DIPEA) to give amide (VII).

[0112] Alternatively, under basic conditions, alkylation of amine (XIII) by halide (VIII), followed by removal of the protecting group R 8 , can give aryl halide (X), which can be used as a general intermediate for further functionalization under metal-catalyzed coupling conditions, such as Buchwald-Hartwig amination, Suzuki coupling, Negishi coupling, Stille coupling or Pd-catalyzed C=0 insertion. For example, under Buchwald-Hartwig amination conditions (cf. Chem. Rev. 1998, 31 , 805-818; Topics in 2016, 116 , 12564-12649; Current Chemistry Examples , 2002, 219 , 131-209; and references cited therein), compounds of formula (XI) can be generated from compounds of formula (X) in the presence of amine HR 6 and a catalyst (such as Ruphos Pd-G2) and a base (such as Cs2CO3).

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

[0114] The application also relates to a process for preparing a compound of formula (I), comprising any one of the following steps:

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

[0116] (VI),

[0117] with an amine HR 3b in the presence of a coupling agent and a base;

[0118] b) a compound of formula (X),

[0119] (X),

[0120] with an amine HR 6 in the presence of a catalyst and a base;

[0121] wherein,

[0122] In step a), the coupling agent can be, for example, HATU; and the base can be, for example, DIPEA;

[0123] In step b), the catalyst can be, for example, Ruphos Pd G2; the base can be, for example, Cs2CO3.

[0124] It is also an object of the application to manufacture a compound of formula (I) according to the above process using achiral or chiral starting materials.

[0125] Indications and methods of treatment

[0126] The present application provides compounds that can be used as TLR7 and / or TLR8 and / or TLR9 antagonists, which inhibit the activation of the pathway through TLR7 and / or TLR8 and / or TLR9 and the corresponding downstream biological events, including but not limited to the innate and adaptive immune responses mediated through the production of all types of cytokines and various forms of autoantibodies. Thus, the compounds of the present application 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. As such, the compounds can be used as therapeutic or prophylactic agents for systemic lupus erythematosus and lupus nephritis.

[0127] The present application provides a method of treating or preventing systemic lupus erythematosus and lupus nephritis in a patient in need thereof.

[0128] 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.

[0129] δ

[0130] The application will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the application.

[0131] Abbreviations

[0132] The application will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the application.

[0133] Abbreviations used herein are as follows:

[0134] ACN: acetonitrile

[0135] Boc2O: di-tert-butyl dicarbonate

[0136] Tf2O: trifluoroacetic anhydride

[0137] DCM: dichloromethane

[0138] DDI drug-drug interaction

[0139] DIPEA diethylisopropylamine

[0140] DMA dimethylacetamide

[0141] EA or EtOAc: ethyl acetate

[0142] FA: formic acid

[0143] HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0144] HLM human liver microsomes

[0145] hr hour

[0146] hrs hours

[0147] IC 50 : half maximal inhibitory concentration

[0148] LCMS liquid chromatography-mass spectrometry

[0149] LYSA lyophilized solubility assay

[0150] MS: mass spectrum

[0151] PE: petroleum ether

[0152] Prep-HPLC: preparative high-performance liquid chromatography

[0153] rt: room temperature

[0154] RT: retention time

[0155] RuPhos Pd G2: chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'- biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) second generation

[0156] SFC: supercritical fluid chromatography

[0157] TFA: trifluoroacetic acid

[0158] v / v volume ratio

[0159] General experimental conditions

[0160] The following instrument was used for the purification of intermediates and final compounds by flash chromatography: i) Biotage SP1 system and Quad 12 / 25 Cartridge module, ii) ISCO combi-flash chromatograph. Silica gel brand and pore size: i) KP-SIL 60 Å, particle size: 40-60 pm; ii) CAS Registry Number: Silica gel: 63231-67-4, particle size: 47-60 microns silica gel; iii) ZCX from Qingdao Haiyang Chemical Co., Ltd, Pore: 200-300 or 300-400.

[0161] The intermediates and final compounds were purified by preparative HPLC using XBridge TM Prep-C18 (5 pm, OBD™ 30 x 100 mm) column, SunFire TM Prep-C18 (5 pm, OBD TMPurification was performed by preparative HPLC on a reversed-phase column using a 30 × 100 mm column, a Phenomenex Synergi-C18 (10 µm, 25 × 150 mm) column, or a Phenomenex Gemini-C18 (10 µm, 25 × 150 mm) column. A Waters AutoP purification system (sample manager 2767, pump 2525, detectors: 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) was used. Alternatively, use the 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).

[0162] For SFC chiral separation, intermediates were separated using chiral columns (Daicel chiralpak IC, 5 µm, 30 × 250 mm), AS (10 µm, 30 × 250 mm), or AD (10 µm, 30 × 250 mm), employing a Mettler Toledo Multigram III SFC system, a Waters 80Q preparative SFC, or a Thar 80 preparative SFC. Solvent systems were CO2 and IPA (0.5% TEA in IPA) or CO2 and MeOH (0.1% NH3∙H2O in MeOH). The back pressure was 100 bar, and detection was performed at UV@ 254 or 220 nm.

[0163] Using LC / MS (Waters TM The LC / MS spectra of the compounds were obtained using an 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 minutes):

[0164] Acidic conditions I: A: 0.1% TFA solution in H2O; B: 0.1% TFA solution in acetonitrile;

[0165] Acidic condition II: A: 0.0375% TFA in H2O; B: 0.01875% TFA in acetonitrile;

[0166] Basic condition I: A: 0.1% NH3H2O in H2O; B: acetonitrile;

[0167] Basic condition II: A: 0.025% NH3H2O in H2O; B: acetonitrile;

[0168] Neutral condition: A: H2O; B: acetonitrile.

[0169] Mass Spectrometry (MS): Typically only ions representing the parent mass are reported, and unless otherwise stated, the mass ions quoted are positive mass ions (MH) + .

[0170] NMR spectra were obtained using a Bruker Avance 400 MHz.

[0171] Microwave assisted reactions were performed in a Biotage Initiator Sixty microwave synthesizer. All reactions involving air sensitive reagents were performed under an argon or nitrogen atmosphere. Reagents were used as obtained from commercial suppliers without further purification unless otherwise stated.

[0172] Preparative Examples

[0173] The following examples are intended to illustrate the meaning of the present application but by no means represent a limitation of the meaning of the present application:

[0174] Example 1

[0175] 5-[(3 R ,5 S )-3,5-dimethyl-4-[(4-piperazin-1-ylphenyl)methyl]piperazin-1-yl]quinoline-8- carbonitrile

[0176]

[0177] The title compound was prepared according to the following scheme:

[0178]

[0179] Step 1: Preparation of 8-bromo-5-fluoro-quinoline (compound 1b)

[0180] In a 100 mL flask, add 2-bromo-5-fluoroaniline (CAS: 1003-99-2, Accela ChemBio, Catalog: SY020710, 2.0 g, 10.5 mmol), propane-1,2,3-triol (CAS: 56-81-5, Accela ChemBio, Catalog: SY006578, 969 mg, 10.5 mmol) and sodium 3-nitrobenzenesulfonate (CAS: 127-68-4, Sigma Aldrich, Catalog: 225193, 2.4 g, 10.5 mmol) mixed with 70% H2SO4(20 mL) to give a dark brown solution, which was heated to 150 °C and stirred for 3 hours. After cooling to room temperature, the reaction mixture was poured into ice water and neutralized with sodium hydroxide solution. The resulting mixture was filtered. The filter cake was dissolved in EtOAc and filtered again. The resulting filtrate was concentrated in vacuo and the crude material was purified by flash chromatography (silica gel, 40 g, 0% to 30% EtOAc in PE) to give compound 1b (2.0 g, 84% yield). MS: calculated 226 and 228 [(M+H) + ], measured 226 and 228 [(M+H) + ].

[0181] Step 2: Preparation of 5-fluoroquinoline-8-carbonitrile (compound 1c)

[0182] To a solution of 8-bromo-5-fluoroquinoline (compound 1b, 4.9 g, 21.7 mmol) in DMF (30 mL) was added zinc cyanide (5.0 g, 43.4 mmol) and RuPhos Pd G2 (CAS: 1375325-68-0, Sigma-Aldrich, Catalog: 753246, 842 mg, 1.1 mmol). The reaction mixture was stirred at 100 °C for 3 hours, then cooled to room temperature. The reaction mixture was filtered, then the filtrate was diluted with water (50 mL) and extracted with EA (80 mL) 3 times. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 40 g, 0% to 70% EtOAc in PE) to give compound 1c (3.0 g, 80% yield). MS: calculated 173 [(M+H) + ], measured 173 [(M+H) + ]. 1 H NMR (400 MHz, Methanol- d 4) δppm 9.11 (dd, J = 4.28,1.71 Hz, 1 H)、8.64 (dd, J = 8.56, 1.71 Hz, 1 H)、8.29 (dd, J = 8.19, 5.62 Hz, 1H)、7.76 (dd, J = 8.56, 4.28 Hz, 1 H)、7.49 (dd, J = 9.35, 8.25 Hz, 1 H)。

[0183] Step 3: Preparation of (2 R ,6 S )-1-[(4-bromophenyl)methyl]-2,6-dimethyl-piperazine (Compound 1f)

[0184] To a solution of (3 R ,5 S )-tert-buty 1 3,5-dimethylpiperazine- 1 -carboxylate (Compound Id, CAS: 129779-30-2, PharmaBlock, Catalog: PB125871, 100 mg, 467 µmol) and K2CO3 (129 mg, 933 µmol) in MeCN (5 mL) was added l-bromo-4-(bromomethyl)benzene (Compound le, CAS: 589-15-1, Accela ChemBio, Catalog: SY001367, 117 mg, 467 µmol). The resulting mixture was heated to 80 °C for 14 hours, then cooled to room temperature. The reaction mixture was filtered and the filter cake was washed with EA (10 mL). The combined filtrate was concentrated in vacuo and purified by flash chromatography (silica gel, 12 g, 10% to 50% EtOAc in PE).

[0185] The purified intermediate was dissolved in DCM (2 mL) and TFA (0.5 mL) was added. The reaction mixture was stirred at room temperature for 3 hours, then concentrated to give crude Compound If, MS: calculated 283 and 285 [(M+H) + ], found 283 and 285 [(M+H) + ].

[0186] Step 4: Preparation of 5-[(3 R ,5 S )-4-[(4-bromophenyl)methyl]-3,5-dimethyl-piperazin-l-yl]quinoline-8-carbonitrile (Compound Ig)

[0187] To a solution of 5-fluoroquinoline-8-carbonitrile (compound lc, 80.9 mg, 470 pmol) in DMSO (2 mL) was added (2 R ,6 S )-1-(4-bromobenzyl)-2,6-dimethylpiperazine (compound If, 133 mg, 0.47 mmol) and DIEPA (243 mg, 1.88 mmol). The reaction mixture was stirred at 120 °C for 3 hours, then cooled to room temperature, diluted with water (10 mL) and extracted with EA (15 mL) twice. The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 24 g, 10% to 50% EtOAc in PE) to give compound lg (150 mg, 73% yield). MS: calculated 435 and 437 [(M+H) + ], found 435 and 437 [(M+H) + ].

[0188] Step 5: Preparation of 4-[4-[[(2 R ,6 S )-4-(8-cyano-5-quinolinyl)-2,6-dimethyl-piperazin-l-yl]methyl]phenyl]piperazine Tert-butyl-1-carboxylate (compound lh)

[0189] To a solution of 5-((3 R ,5 S )-4-(4-bromobenzyl)-3,5-dimethylpiperazin-l-yl)quinoline-8-carbonitrile (compound lg, 45 mg, 103 pmol) in dioxane (10 mL) was added piperazine-1-carboxylic acid tert-butyl ester (CAS: 57260-71-6, Accela ChemBio, Catalog: SY002528, 23.1 mg, 124 pmol), RuPhos Pd G3 (CAS: 1445085-77-7, Sigma-Aldrich, Catalog: 763403; 2.76 mg, 3.1 pmol) and sodium tert-butoxide (30.1 mg, 310 pmol). The reaction mixture was stirred at 80 °C for 14 hours, then cooled to room temperature, diluted with water (20 mL) and extracted with EA (20 mL) twice. The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 40 g, 20% to 100% EtOAc in PE) to give compound lh (35 mg, 62% yield). MS: calculated 541 [(M+H)+ ] measured 541 [(M+H) + ].

[0190] Step 6: Preparation of 5-[(3 R ,5 S )-3,5-dimethyl-4-[(4-piperazin-1-ylphenyl)methyl]piperazin-1-yl]quinoline-8- carbonitrile (Example 1)

[0191] To a solution of tert-butyl 4-[4-[[(2 R ,6 S )-4-(8-cyano-5-quinolinyl)-2,6-dimethyl-piperazin-1-yl]methyl]phenyl]piperazine-1- carboxylate (Compound 1h) (20 mg, 37 pmol) in DCM (2 mL) was added TFA (0.5 mL). The reaction mixture was stirred at room temperature for 3 hours, then concentrated to give the crude product, which was purified by preparative-HPLC to give Example 1 (5 mg, 30%). MS: calc’d 441 [(M+H) + ] measured 441 [(M+H) + ]. 1 H NMR (400 MHz, Methanol-d4 d 4) δ ppm 8.84 (dd, J = 4.2, 1.7 Hz, 1H), 8.40 (dd, J = 8.6, 1.5 Hz, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.48 (dd, J = 8.6, 4.3 Hz, 1H), 7.24 (d, J = 8.7 Hz, 2H), 7.09 (d, J = 8.1 Hz, 1H), 6.88 (d, J = 8.7 Hz, 2H), 4.49 (br s, 2H), 3.88 (s, 2H), 3.01-3.12 (m, 4H), 2.83-2.99 (m, 6H), 2.60-2.72 (m, 2H), 1.14 (d, J = 6.1 Hz, 6H).

[0192] Example 2

[0193] 5-[(3 R ,5 R)-3,5-dimethyl-4-[(4-piperazin-1-ylphenyl)methyl]piperazin-1-yl]quinoline-8- carbonitrile

[0194]

[0195] The title compound was prepared in analogy to the preparation of Example 1 by using (3 R ,5 R )-3,5-dimethylpiperazine-1-carboxylate (CAS: 438049-91-3, PharmaBlock, Catalog: PB05910) instead of (3 R ,5 S )-3,5-dimethylpiperazine-1-carboxylic acid (compound 1d). Example 2 (12 mg) was obtained. MS: calc’d 441 [(M+H) + ], measured 441 [(M+H) + ]. 1 H NMR (400 MHz, Methanol-d4 d 4) δ ppm 8.99 (dd, J = 4.3, 1.5 Hz, 1H), 8.71 (dd, J = 8.6, 1.5 Hz, 1H), 8.16 (d, J = 7.9 Hz, 1H), 7.69 (dd, J = 8.6, 4.3 Hz, 1H), 7.57 (d, J = 8.7 Hz, 2H), 7.35 (d, J = 8.1 Hz, 1H), 7.16 (d, J = 8.8 Hz, 2H), 4.80 (br d, J = 13.4 Hz, 1H), 4.27 (br d, J = 13.4 Hz, 1H), 4.17 (br s, 1H), 3.73 (br d, J = 12.5 Hz, 2H), 3.44-3.59 (m, 6H), 3.38-3.44 (m, 4H), 3.15-3.26 (m, 1H), 1.58-1.77 (m, 6H).

[0196] Example 3

[0197] 5-[(3 R ,5 S)-3,5-dimethyl-4-[(6-piperazin-l-yl-3-pyridinyl)methyl]piperazin-l-yl]quinoline-8- carbonitrile

[0198]

[0199] The title compound was prepared according to the following scheme:

[0200]

[0201] Step 1 : Preparation of 5-((3 R ,5 S )-3,5-dimethylpiperazin-l-yl)quinoline-8-carbonitrile (Compound 3b)

[0202] To a solution of 5-fluoroquinoline-8-carbonitrile (Compound lc, 1.4 g, 8.1 mmol) in DMSO (20 mL) was added (3 R ,5 S )-3,5-dimethylpiperazine- 1 -carboxylate (Compound Id) (1.7 g, 1.7 mmol) and DIEA (878 mg, 6.8 mmol). The reaction mixture was stirred at 120 °C for 3 hours, then cooled to room temperature, diluted with water (100 mL) and extracted with EA (150 mL) twice. The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 80 g, 10% to 50% EtOAc in PE).

[0203] The purified intermediate was dissolved in DCM (20 mL) and TFA (5 mL) was added. The reaction mixture was stirred at room temperature for 3 hours, then concentrated to give crude Compound 3b (1.6 g, 75% yield). MS: calculated 266 [(M+H) + ], found 266 [(M+H) + ].

[0204] Step 2: Preparation of 5-[(3 S ,5 R )-4-[(6-chloro-3-pyridinyl)methyl]-3,5-dimethyl-piperazin-l-yl]quinoline-8-carbonitrile (Compound 3d)

[0205] To a solution of 5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)quinoline-8-carbonitrile (compound 3b) (95 mg, 357 µmol) and K2CO3 (98.6 mg, 713 µmol) in MeCN (5 mL) was added 2-chloro-5-(chloromethyl)pyridine (compound 3c, CAS: 70258-18-3, TCI, Catalog: C1628, 90 mg, 556 µmol). The resulting mixture was heated to 80 °C for 14 hours, then cooled to room temperature. The reaction mixture was filtered and the filter cake was washed with EA (10 mL). The combined filtrate was concentrated in vacuo and purified by flash chromatography (silica gel, 12 g, 10% to 100% EtOAc in PE) to give compound 3d (110 mg, 79% yield). MS: calculated 392 [(M+H) + ], measured 392 [(M+H) + ].

[0206] Step 3: Preparation of tert-butyl 4-[5-[[(2 R ,6 S )-4-(8-cyano-5-quinolinyl)-2,6-dimethyl-piperazin-1-yl]methyl]-2-pyridyl]piperazine-1- carboxylate (compound 3e)

[0207] To a solution of 5-((3 R ,5 S )-4-((6-chloropyridin-3-yl)methyl)-3,5-dimethylpiperazin-1-yl)quinoline-8-carbonitrile (compound 3d, 55 mg, 140 µmol) in dioxane (10 mL) was added tert-butyl piperazine-1-carboxylate (CAS: 57260-71-6, Accela ChemBio, Catalog: SY002528; 31.4 mg, 168 µmol), RuPhos Pd G2 (CAS: 1375325-68-0, Sigma-Aldrich, Catalog: 753246; 12.2 mg, 14 µmol) and sodium tert-butoxide (9.93 mg, 103 µmol). The reaction mixture was stirred at 80 °C for 14 hours, then cooled to room temperature, diluted with water (20 mL) and extracted with EA (10 mL) twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 12 g, 20% to 100% EtOAc in PE) to give compound 3e (50 mg, 66 % yield). MS: calculated 542 [(M+H) +The measured value was 542 [(M+H)]. + ].

[0208] Step 4: Prepare 5-[(3 R 5 S )-3,5-Dimethyl-4-[(6-piperazin-1-yl-3-pyridyl)methyl]piperazin-1-yl]quinoline-8-nitrile (Example 3)

[0209] 4-[5-[[(2)] in DCM (2 mL) R 6 S TFA (0.5 mL) was added to a solution of tert-butyl [(M+H)-4-(8-cyano-5-quinolinyl)-2,6-dimethyl-piperazin-1-yl]methyl]-2-pyridyl]piperazin-1-carboxylic acid (compound 1h) (50 mg, 92 µmol). The reaction mixture was stirred at room temperature for 3 hours, then concentrated to give a crude product, which was purified by preparative-HPLC to give Example 3 (28 mg, 69%). MS: Calculated 442 [(M+H) + The measured value was 442 [(M+H)]. + ]. 1 HNMR (400 MHz, methanol-) d 4) δ ppm 9.01 (dd, J = 1.6, 4.3 Hz, 1H), 8.56 (br d, J = 7.8 Hz, 1H), 8.47 (s, 1H), 8.20 (d, J = 7.9 Hz, 1H), 7.90 (br d, J = 8.9 Hz, 1H), 7.64 (dd, J =4.2, 8.5 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.08 (d, J = 8.9 Hz, 1H), 4.71 (br s,2H), 4.04 - 3.86 (m, 4H), 3.69 (br d, J = 13.6 Hz, 4H), 3.42 - 3.35 (m, 4H), 3.23 -3.06 (m, 2H), 1.68 (d, J=6.2 Hz, 6H).

[0210] Example 4

[0211] 5-[(3 S 5 R3,5-Dimethyl-4-[(5-piperazin-1-ylpyrimidin-2-yl)methyl]piperazin-1-yl]quinoline-8-nitrile

[0212]

[0213] Similar to the preparation of Example 3, the title compound was prepared by using 5-bromo-2-(bromomethyl)pyrimidine (CAS: 1193116-74-3, BePharm, catalog: BD266661) instead of 2-chloro-5-(chloromethyl)pyridine (compound 3c). Example 4 (23 mg) was obtained. MS: Calculated 443 [(M+H)] + The measured value was 443 [(M+H)]. + ]. 1 H NMR (400 MHz, methanol-) d 4) δ ppm 8.91 (dd, J = 4.2, 1.7 Hz, 1H), 8.42-8.50 (m, 3H), 8.07 (d, J = 8.1 Hz, 1H), 7.55 (dd, J = 8.6, 4.3 Hz, 1H), 7.14 (d, J = 8.1 Hz, 1H), 4.21 (s, 2H), 3.26-3.36 (m,7H), 3.17-3.22 (m, 1H), 2.97-3.06 (m, 4H), 2.77 (t, J = 11.2 Hz, 2H), 1.30 (d, J =6.2 Hz, 6H).

[0214] Example 5

[0215] 5-[(3 S 5 R 3,5-Dimethyl-4-[(5-piperazin-1-yl-2-pyridyl)methyl]piperazin-1-yl]quinoline-8-nitrile

[0216]

[0217] The title compound was prepared according to the following scheme:

[0218]

[0219] Step 1: Prepare 5-[(3 R 5 S)-4-[(5-bromo-2-pyridinyl)methyl]-3,5-dimethyl-piperazin-l-yl]quinoline-8- carbonitrile (Compound 5b)

[0220] To a solution of 5-(((3 R ,5 S )-3,5-dimethylpiperazin-l-yl)quinoline-8-carbonitrile (Compound 3b) (95 mg, 357 pmol) and K2CO3(98.6 mg, 713 pmol) in MeCN (5 mL) was added 5-bromo-2- (bromomethyl)pyridine (Compound 5a, CAS: 145218-19-5, Wuxi AppTec, Catalog: LN01365762; 90 mg, 359 pmol). The resulting mixture was heated to 80 °C for 14 hours, then cooled to room temperature. The reaction mixture was filtered and the filter cake was washed with EA (10 mL). The combined filtrate was concentrated in vacuo and purified by flash chromatography (silica gel, 12 g, 10% to 100% EtOAc in PE) to give Compound 3d (110 mg, 71 % yield). MS: calculated 436 and 438 [(M+H) + ], found 436 and 438 [(M+H) + ].

[0221] Step 2: Preparation of tert-butyl 4-[6-[[(2 R ,6 S )-4-(8-cyano-5-quinolinyl)-2,6-dimethyl-piperazin-l-yl]methyl]-3-pyridinyl]piperazine- 1-carboxylate (Compound 5c)

[0222] To a solution of 5-((3 R ,5 STo a solution of 4-((5-bromopyridin-2-yl)methyl)-3,5-dimethylpiperazin-l-yl)quinoline-8- carbonitrile (Compound 5b, 55 mg, 126 µmol) in DCM (2 mL) was added tert-butyl piperazine- 1-carboxylate (CAS: 57260-71-6, Accela ChemBio, Catalog: SY002528; 28.2 mg, 151 µmol), RuPhos Pd G3 (CAS: 1375325-68-0, Sigma-Aldrich, Catalog: 753246; 3.4 mg, 3.8 µmol) and sodium tert-butoxide (12.1 mg, 126 µmol). The reaction mixture was stirred at 80 °C for 14 hours, then cooled to room temperature, diluted with water (20 mL) and extracted with EA (10 mL) twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 12 g, 20% to 100% EtOAc in PE) to give Compound 3c (50 mg, 73 % yield). MS: calculated 542 [(M+H) + ], measured 542 [(M+H) + ].

[0223] Step 3: Preparation of 5-[(3 S ,5 R )-3,5-dimethyl-4-[(5-piperazin-l-yl-2-pyridinyl)methyl]piperazin-l-yl]quinoline-8- carbonitrile (Example 5)

[0224] To a solution of tert-butyl 4-[6-[[(2 R ,6 S )-4-(8-cyano-5-quinolinyl)-2,6-dimethyl-piperazin-l-yl]methyl]-3-pyridinyl]piperazine- 1-carboxylate (Compound 5c) (45 mg, 83 µmol) in DCM (2 mL) was added TFA (0.5 mL). The reaction mixture was stirred at room temperature for 3 hours, then concentrated to give the crude product which was purified by preparative-HPLC to give Example 5 (39 mg, 98 %). MS: calculated 442 [(M+H) + ], measured 442 [(M+H) + ].1H NMR (400 MHz, Methanol-d4) δ ppm 9.43 (dd, J = 8.6, 1.4 Hz, 1H), 9.27 (dd, J = 5.2, 1.4 Hz, 1H), 8.63 (d, J= 2.8 Hz, 1H), 8.51 (d, J = 8.2 Hz, 1H), 8.07-8.21 (m, 3H), 7.65(d, J = 8.3 Hz, 1H), 5.04 (s, 2H), 4.15-4.28 (m, 2H), 3.78-3.92 (m, 6H), 3.55-3.65 (m, 2H), 3.44-3.53 (m, 4H), 1.69 (d, J = 6.5 Hz, 6H).

[0225] Example 6

[0226] 5-[(3 S 5 R )-4-[[5-[4-[2-(dimethylamino)acetyl]piperazin-1-yl]pyrimidin-2-yl]methyl]-3,5-dimethyl-piperazin-1-yl]quinoline-8-nitrile

[0227]

[0228] The title compound was prepared according to the following scheme:

[0229]

[0230] Step 1: Preparation of 2-(dimethylamino)-1-piperazin-1-yl-acetylpyrimidine (compound 3b)

[0231] To a solution of 4-(2-chloroacetyl)piperazine-1-carboxylic acid tert-butyl ester (263 mg, 1 mmol) in acetonitrile (5 mL), dimethylamine hydrochloride (163 mg, 2 mmol) and K₂CO₃ (208 mg, 1.5 mmol) were added. The reaction mixture was stirred at room temperature for 3 hours. The solid was filtered off and washed with EA (10 mL), and the combined filtrates were concentrated under vacuum. The residue was dissolved in DCM (1 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 3 hours and then concentrated to give crude compound 6b (0.27 g, 94% yield). MS: Calculated 172 [(M+H) + The measured value was 172 [(M+H)]. + ].

[0232] Step 2: Prepare 5-[(3 S 5 R)-4-[[5-[4-[2-(dimethylamino)acetyl]piperazin-1-yl]pyrimidin-2-yl]methyl]-3,5- dimethyl-piperazin-1-yl]quinoline-8-carbonitrile (Example 6)

[0233] To a solution of 5-[(3 R ,5 S )-4-[(5-bromopyrimidin-2-yl)methyl]-3,5-dimethyl-piperazin-1-yl]quinoline-8-carbonitrile (45 mg, 103 µmol) in dioxane (10 mL) was added 2-(dimethylamino)-1-(piperazin-1-yl)ethan-1-one-2,2,2-trifluoroacetate (Compound 6a, 35.2 mg, 123 µmol), RuPhos Pd G3 (CAS: 1445085-77-7, Sigma-Aldrich, Catalog: 763403; 2.75 mg, 3.1 µmol) and sodium tert-butoxide (29.7 mg, 309 µmol). The reaction mixture was stirred at 80 °C for 14 hours, then cooled to room temperature, diluted with water (20 mL) and extracted with EA (10 mL) twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 12 g, 20% to 100% EtOAc in PE) to give Example 6 (20 mg, 98% yield). MS: calc’d 528 [(M+H) + ], measured 528 [(M+H) + ]. 1 H NMR (400 MHz, Methanol-d4) δ 8.92 (dd, d 4) δ ppm 8.92 (dd, J = 4.2, 1.6 Hz, 1H), 8.51 (s, 2H), 8.46 (dd, J = 8.6, 1.5 Hz, 1H), 8.08 (d, J = 8.1 Hz, 1H), 7.56 (dd, J = 8.6, 4.3 Hz, 1H), 7.15 (d, J = 8.2 Hz, 1H), 4.23 (s, 2H), 3.74-3.85 (m, 4H), 3.29-3.42 (m, 8H), 3.27 (s, 2H), 2.78 (t, J = 11.2 Hz, 2H), 2.32 (s, 6H), 1.30 (d, J= 6.1 Hz, 6H).

[0234] Example 7

[0235] 5-[(3 S 5 R )-3,5-dimethyl-4-[[5-(4-methylpiperazin-1-yl)-2-pyridyl]methyl]piperazin-1-yl]quinoline-8-nitrile

[0236]

[0237] 5-((3) in dioxane (10 mL) R 5 S 1-methylpiperazine (12.4 mg, 124 µmol), RuPhos Pd G3 (CAS: 1375325-68-0, Sigma-Aldrich, catalog: 753246; 2.8 mg, 3.1 µmol), and sodium tert-butoxide (9.9 mg, 103 µmol) were added to a solution of 4-((5-bromopyridin-2-yl)methyl)-3,5-dimethylpiperazin-1-yl)quinoline-8-onitrile (compound 5b, 45 mg, 103 µmol). The reaction mixture was stirred at 80 °C for 14 h, then cooled to room temperature, diluted with water (20 mL), and extracted twice with EA (10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid chromatography (silica gel, 12 g, PE solution of 20% to 100% EtOAc) to give Example 7 (47 mg, 98% yield). MS: calculated 456 [(M+H)] + The measured value was 456 [(M+H)]. + ]. 1 H NMR (400 MHz, methanol-) d 4 ) δ ppm 8.96 (dd, J = 4.2, 1.7 Hz, 1H), 8.58 (dd, J = 8.6, 1.7 Hz, 1H), 8.20 (d, J = 2.8 Hz, 1H), 8.13 (d, J = 8.1 Hz, 1H), 7.62 (dd, J = 8.6, 4.3 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.43 (dd, J= 8.8, 2.9 Hz, 1H), 7.21 (d, J = 8.1 Hz, 1H), 4.00 (s, 2H), 3.39 (br d, J = 11.9 Hz, 2H), 3.25-3.31 (m,4H), 3.03-3.14 (m, 2H), 2.75-2.84 (m, 2H), 2.62-2.69 (m, 4H), 2.38 (s, 3H), 1.16(d, J = 6.1 Hz, 6H).

[0238] Example 8

[0239] 5-[(3 S 5 R )-3,5-dimethyl-4-[[5-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-2-pyridyl]methyl]piperazin-1-yl]quinoline-8-nitrile

[0240]

[0241] Similar to the preparation of Example 5, the title compound was prepared by using tert-butyl 9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate instead of piperazine-1-carboxylate. Example 8 (10.0 mg) was obtained. MS: Calculated 484 [(M+H)] + The measured value was 484 [(M+H)]. + ]. 1 H NMR (400 MHz, methanol-) d 4) δ ppm 8.89 (dd, J = 4.2, 1.5Hz, 1H), 8.51 (dd, J = 8.6, 1.3 Hz, 1H), 8.43 (d, J = 2.7 Hz, 1H), 8.07 (d, J = 7.9Hz, 1H), 7.51-7.57 (m, 2H), 7.44-7.49 (m, 1H), 7.26 (d, J = 8.1 Hz, 1H), 4.56-4.68(m, 2H), 4.21 (br s, 2H), 3.93-4.06 (m, 2H), 3.83 (d, J= 12.1 Hz, 2H), 3.38-3.65(m, 7H), 3.19 (br s, 1H), 3.07-3.18 (m, 2H), 1.39 (br d, J = 6.4 Hz, 6H)

[0242] Example 9

[0243] 5-[(3 R 5 S )-3,5-dimethyl-4-[[5-[[(3 R 4 S )-4-fluoropyrrolidine-3-yl]amino]-2-pyridyl]methyl]piperazin-1-yl]quinoline-8-nitrile

[0244]

[0245] Similar to the preparation of Example 5, the title compound was prepared by using (3 R 4 S 3-Amino-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (25.2 mg, 123 µmol, Eq: 1.2) was used instead of piperazine-1-carboxylic acid tert-butyl ester. Example 9 (14.0 mg) was obtained. MS: calculated 460 [(M+H)] + The measured value is 460 [(M+H)]. + ]. 1 H NMR (400 MHz, methanol-) d 4) δ ppm 8.93 (dd, J = 4.3, 1.6 Hz, 1H), 8.53 (dd, J = 8.6, 1.7 Hz, 1H), 8.09 (d, J = 8.1 Hz, 1H), 8.03 (d, J = 2.7 Hz, 1H), 7.59 (dd, J = 8.6, 4.3 Hz, 1H), 7.44 (d, J = 8.6 Hz, 1H), 7.12-7.22 (m, 2H), 5.07-5.26 (m, 1H), 3.91-4.09 (m, 3H), 3.36-3.42 (m, 2H), 3.35-3.34 (m, 1H), 3.12-3.29 (m, 2H), 2.98-3.11 (m, 2H), 2.77 (q, J = 10.1 Hz, 3H), 1.17 (d, J= 6.1 Hz, 6H).

[0246] Example 10

[0247] 5-[(3 R 5 S )-3,5-dimethyl-4-[[5-[4-(pyrrolidine-2-carbonyl)piperazin-1-yl]-2-pyridyl]methyl]piperazin-1-yl]quinoline-8-nitrile

[0248]

[0249] Add 5-((3) to DMF (2 mL) R 5 S HATU (17.2 mg, 45.3 µmol) and DIEPA (5.8 mg, 45 µmol) were added to a stirred solution of 3,5-dimethyl-4-((5-(piperazin-1-yl)pyridin-2-yl)methyl)piperazin-1-yl)quinoline-8-onitrile (Example 5, 20 mg, 45 mmol) and tert-butyloxycarbonylproline (9.75 mg, 45.3 µmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours and then concentrated under vacuum.

[0250] The residue was dissolved in DCM (2 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 30 minutes, then concentrated to obtain a crude product, which was purified by preparative-HPLC to give Example 10 (11 mg, 51% yield). MS: Calculated 539 [(M+H)] + The measured value was 539 [(M+H)]. + ]. 1 H NMR (400 MHz, methanol-) d 4) δ ppm 8.96 (dd, J = 4.2, 1.7 Hz, 1H), 8.58 (dd, J = 8.6, 1.7 Hz, 1H), 8.23 ​​(d, J = 2.8 Hz, 1H), 8.13 (d, J = 7.9 Hz, 1H), 7.56-7.65 (m, 2H), 7.46 (dd, J = 8.7, 2.9 Hz, 1H), 7.21(d, J = 8.2 Hz, 1H), 3.97-4.08 (m, 3H), 3.68-3.86 (m, 4H), 3.39 (br d,J = 11.7 Hz, 2H), 3.23-3.32 (m, 4H), 3.15-3.22 (m, 1H), 3.04-3.14 (m, 2H), 2.76-2.89 (m, 3H), 2.20-2.31 (m, 1H), 1.67-1.94 (m, 3H), 1.16 (d, J = 6.2 Hz, 6H).

[0251] Example 11

[0252] 5-[(3 S 5 R )-4-[[5-[4-[2-(dimethylamino)acetyl]piperazin-1-yl]-2-pyridyl]methyl]-3,5-dimethyl-piperazin-1-yl]quinoline-8-nitrile

[0253]

[0254] Similar to the preparation of Example 6, the title compound was prepared by using 5-((3) R 5 S )-4-((5-bromopyridin-2-yl)methyl)-3,5-dimethylpiperazin-1-yl)quinoline-8-nitrile instead of 5-[(3 R 5 S It was prepared by means of )-4-[(5-bromopyrimidin-2-yl)methyl]-3,5-dimethyl-piperazin-1-yl]quinoline-8-nitrile. Example 11 (66 mg) was obtained. MS: Calculated 527 [(M+H) + The measured value was 527 [(M+H)]. + ]. 1 H NMR (400 MHz, methanol-) d 4) δ ppm 8.97 (dd, J = 4.3, 1.6 Hz, 1H), 8.60 (dd, J = 8.7, 1.6 Hz, 1H), 8.47 (t, J = 1.6 Hz, 1H), 8.15 (d, J = 7.9 Hz, 1H), 7.65 (dd, J = 8.6, 4.3 Hz, 1H), 7.55 (d, J = 1.7 Hz, 2H), 7.35 (d, J= 8.1 Hz, 1H), 4.70 (s, 2H), 4.36 (s, 2H), 4.01-4.15 (m, 2H), 3.80-3.89 (m, 2H), 3.57-3.69 (m,4H), 3.43 (dt, J = 14.4, 5.3 Hz, 4H), 3.27 (dd, J = 13.3, 11.4 Hz, 2H), 3.00 (s, 6H), 1.52 (d, J = 6.5 Hz, 6H).

[0255] Example 12

[0256] 5-[(3 R 5 S )-4-[[4-[2-(hydroxymethyl)piperazin-1-yl]phenyl]methyl]-3,5-dimethyl-piperazin-1-yl]quinoline-8-nitrile

[0257]

[0258] Similar to the preparation of Example 1, the title compound was prepared by using tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (CAS: 301673-16-5, Accela ChemBio, catalog: SY008701) instead of tert-butyl piperazine-1-carboxylate. Example 12 (10.0 mg) was obtained. MS: Calculated 471 [(M+H)] + The measured value was 471 [(M+H)]. + ]. 1 H NMR (400 MHz, methanol-) d 4) δ ppm 8.89-9.10 (m, 1H), 8.51 (br d, J = 8.6 Hz, 1H), 8.18 (d, J = 7.9 Hz, 1H), 7.50-7.73 (m, 3H), 7.33 (br d, J = 7.9 Hz, 1H), 7.17 (d, J = 8.7 Hz, 2H), 4.70 (s, 2H), 4.26 (br s, 1H), 3.88-3.97 (m, 1H), 3.59-3.86 (m, 8H), 3.54 (br d, J = 12.7 Hz, 1H), 3.45 (dd, J= 12.8, 4.5 Hz, 1H), 3.24-3.31 (m, 1H), 3.17 (br t, J = 11.6 Hz, 2H), 1.69 (br d, J = 6.2 Hz, 6H).

[0259] Example 13

[0260] 5-[(3 R 5 S )-3,5-dimethyl-4-[2-oxo-2-(2-piperazin-1-yl-7,8-dihydro-5- H -1,6-naphthid-6-yl)ethyl]piperazin-1-yl]quinoline-8-nitrile

[0261]

[0262] The title compound was prepared according to the following scheme:

[0263]

[0264] Step 1: Preparation of 2-chloro-7,8-dihydro-5 H -1,6-Naphthyl-6-carboxylic acid benzyl ester (compound 13b)

[0265] Triethylamine (5.9 mL, 42.6 mmol) and benzyl chloroformate (831.8 mg, 4.9 mmol) were added to a solution of 2-chloro-5,6,7,8-tetrahydro-1,6-naphthidine hydrochloride (compound 13a, CAS: 766545-20-4, PharmaBlock, catalog: PB06676-01, 1.0 g, 4.9 mmol) in DCM (25 mL). The resulting mixture was stirred at room temperature for 2 hours, then diluted with H2O (50 mL) and extracted twice with DCM (30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid chromatography (silica gel, 120 g, PE solution of 9% to 17% EtOAc) to give compound 13b (450 mg, 26% yield). MS: Calculated 303 [(M+H) + The measured value was 303 [(M+H)]. + ].

[0266] Step 2: Preparation of 2-(4-tert-butoxycarbonylpiperazin-1-yl)-7,8-dihydro-5 H -1,6-Naphthyl-6-carboxylic acid benzyl ester (compound 13c)

[0267] To a solution of 1-Boc-piperazine (CAS 57260-71-6, PharmaBlock, Catalog: PB002528, 415.2 mg, 2.2 mmol) and 2-chloro-7,8-dihydro-5 H -1,6-naphthyridine-6-carboxylic acid benzyl ester (compound 13b, 450.0 mg, 1.5 mmol) was added palladium (II) acetate (33.37 mg, 0.150 mmol), sodium tert-butoxide (214.26 mg, 2.23 mmol) and ( R )-binap (CAS 98327-87-8, PharmaBlock, Catalog: PB92651, 185.1 mg, 0.3 mmol). The resulting mixture was stirred under N2at 100 °C for 5 hours, then diluted with water (50 mL) and extracted with EA (30 mL) twice. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 80 g, 17% to 25% EtOAc in PE) to give compound 1d (330 mg, 43% yield). MS: calculated 453 [(M+H + ], found 453 [(M+H + ].

[0268] Step 3: Preparation of 4-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)piperazine-1- carboxylic acid tert-butyl ester (compound 13d)

[0269] To a solution of 2-(4-tert-butoxycarbonylpiperazin-1-yl)-7,8-dihydro-5 H -1,6-naphthyridine-6-carboxylic acid benzyl ester (compound 13c, 330 mg, 0.73 mmol) was added Pd / C (80 mg, 0.73 mmol). The resulting mixture was degassed then charged with three rounds of hydrogen gas. After stirring at room temperature for 0.5 hours, the reaction mixture was filtered through celite. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 12 g, 10% to 90% EtOAc in PE) to give compound 13d (200 mg, 84 % yield). MS: calculated 319 [(M+H + ], found 319 [(M+H + ].

[0270] Step 4: Preparation of 2-[(2 R ,6 S)-4-(8-cyano-5-quinolinyl)-2,6-dimethyl-piperazin-l-yl]acetic acid (Compound 13e)

[0271] To a solution of 5-[(3 R ,5 S )-3,5-dimethylpiperazin-l-yl]quinoline-8-carbonitrile (Compound 3b, 1000 mg, 3.8 mmol) in ACN (40 mL) was added sodium iodide (56.3 mg, 0.38 mmol) and tert-butyl bromoacetate (1098 mg, 5.6 mmol). The resulting mixture was stirred at 65 °C for 4 hours, then cooled to room temperature, diluted with H2O (50 mL) and extracted with EtOAc (50 mL) twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo.

[0272] The residue was dissolved in DCM (30 mL) and TFA (5 mL) was added. The reaction mixture was stirred at room temperature for 12 hours, then concentrated to give crude Compound 13e (1.0 g, 68% yield). MS: calc'd 325 [(M+H) + ], measured 325 [(M+H) + ].

[0273] Step 5: Preparation of 5-[(3 R ,5 S )-3,5-dimethyl-4-[2-oxo-2-(2-piperazin-l-yl-7,8-dihydro-5 H -1,6-naphthyridin-6-yl)ethyl]piperazin-l-yl]quinoline-8-carbonitrile (Compound 13)

[0274] To a stirred solution of 2-[(2 R ,6 S )-4-(8-cyano-5-quinolinyl)-2,6-dimethyl-piperazin-l-yl]acetic acid (Compound 13e, 50.0 mg, 0.150 mmol) and HATU (70.3 mg, 0.18 mmol) and DIEPA (0.08 mL, 0.460 mmol) in DMF (2 mL) at room temperature was added tert-butyl 4-(5,6,7,8-tetrahydro-l,6-naphthyridin-2-yl)piperazine-l-carboxylate (Compound 13d, 54.53 mg, 0.170 mmol). The reaction mixture was stirred at room temperature for 3 hours, then concentrated in vacuo.

[0275] The residue was dissolved in DCM (2 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 30 minutes, then concentrated to obtain a crude product, which was purified by preparative-HPLC to give Example 13 (18 mg, 22% yield). MS: calculated 525 [(M+H) + ]; The measured value was 525 [(M+H) + ]. 1 H NMR (400 MHz, methanol-d4) δ = 9.05 (d, J = 4.2 Hz, 1H), 8.69 (br d, J = 8.4 Hz, 1H), 8.23 ​​(d, J = 8.1 Hz, 1H), 7.72 (dd, J =4.2, 8.6 Hz, 1H), 7.51 (br d, J = 8.8 Hz, 1H), 7.44 - 7.32 (m, 1H), 6.92 - 6.82 (m, 1H), 4.92 (br s, 4H), 4.75 (s, 2H), 4.50 - 4.35 (m, 1H), 4.30 - 4.07 (m, 2H), 4.00 (t, J =6.1 Hz, 1H), 3.95 - 3.86 (m, 1H), 3.86 - 3.80 (m, 4H), 3.64 (br s, 2H), 3.40 - 3.34 (m, 3H), 3.04 (br t, J = 5.7 Hz, 1H), 2.92 (t, J = 6.0 Hz, 1H), 1.41(br s, 6H).

[0276] Example 14

[0277] 5-[(3 R 5 S )-3,5-dimethyl-4-[2-oxo-2-(6-piperazin-1-yl-3,4-dihydro-1-yl-2-( ... H -isoquinoline-2-yl)ethyl]piperazin-1-yl]quinoline-8-nitrile

[0278]

[0279] Similar to the preparation of Example 13, the title compound was prepared by using 6-bromo-1,2,3,4-tetrahydroisoquinoline hydrochloride (CAS: 215798-19-9, PharmaBlock, catalog: PB07543-1) instead of 2-chloro-5,6,7,8-tetrahydro-1,6-naphthylidine hydrochloride. Example 14 (5.2 mg) was obtained. MS: Calculated 524 [(M+H)] + The measured value was 524 [(M+H)]. + ]. 1 HNMR (400 MHz, methanol-) d 4) δ ppm 8.92 (dd, J = 1.6, 4.3 Hz, 1H), 8.63 - 8.51 (m, 1H), 8.18 - 8.05 (m, 1H), 7.65 - 7.56 (m, 1H), 7.37 - 7.22 (m, 1H), 7.06 (dd, J = 8.4,13.1 Hz, 1H), 6.84 (br t, J = 7.8 Hz, 1H), 6.79 (br d, J = 4.3 Hz, 1H), 4.63 (s, 2H), 4.54 (br s, 1H), 4.17 - 3.89 (m, 2H), 3.80 - 3.73 (m, 1H), 3.68 (br s, 1H), 3.61 - 3.39 (m, 2H), 3.35 - 3.24 (m, 10H), 3.17 - 3.01 (m, 1H), 2.91 (br t, J =5.8 Hz, 1H), 2.81 (br t, J = 6.1 Hz, 1H), 1.37 - 1.17 (m, 6H).

[0280] Example 15

[0281] 5-[(3 R 5 S )-3,5-dimethyl-4-[2-oxo-2-(7-piperazin-1-yl-3,4-dihydro-1-yl-2-(7-piperazin-1-yl-3,4-dihydro-1-yl-2-(2-oxo ... H -isoquinoline-2-yl)ethyl]piperazin-1-yl]quinoline-8-nitrile

[0282]

[0283] The title compound was prepared in analogy to the preparation of Example 13 by using 7-bromo-1,2,3,4-tetrahydroisoquinoline hydrochloride (CAS: 2200274-73-4, Oakwood Chemical, Catalog: 077414) instead of 2-chloro-5,6,7,8-tetrahydro-1,6-naphthyridine hydrochloride. Example 15 (44 mg) was obtained. MS: calc’d 524 [(M+H) + ], measured 524 [(M+H) + ]. 1 HNMR (400 MHz, Methanol- d 4) δ ppm 9.05 (dd, J = 1.5, 4.2 Hz, 1H), 8.69 (br s, 1H), 8.24 (d, J = 7.9 Hz, 1H), 7.72 (dd, J = 4.2, 8.6 Hz, 1H), 7.41 (br s, 1H), 7.18 (br d, J = 8.4 Hz, 1H), 6.99 - 6.93 (m, 1H), 6.90 (s, 1H), 4.80 (s, 2H), 4.67 (br s, 1H), 4.37 (br s, 1H), 4.29 - 4.00 (m, 2H), 3.91 (t, J = 6.0 Hz, 1H), 3.79 (br s, 1H), 3.66 (br s, 1H), 3.56 (br s, 1H), 3.44 - 3.35 (m, 10H), 3.04 - 2.83 (m, 2H), 1.42 (br s, 6H).

[0284] Example 16

[0285] 5-[(3 R ,5 S )-3,5-dimethyl-4-[2-oxo-2-(5-piperazin-1-ylisoindolin-2-yl)ethyl]piperazin-1-yl]quinoline-8-carbonitrile

[0286]

[0287] Similar to the preparation of Example 13, the title compound was prepared by using 5-bromoisoindoline hydrochloride (CAS: 919346-89-7, PharmaBlock, catalog: PBY2010168-01) instead of 2-chloro-5,6,7,8-tetrahydro-1,6-naphthylidine hydrochloride. Example 15 (22 mg) was obtained. MS: Calculated 510 [(M+H)] + The measured value was 510 [(M+H)]. + ]. 1 H NMR (400MHz, methanol-) d 4) δ ppm 9.43 (br dd, J = 19.2, 8.3 Hz, 1H), 9.24-9.32 (m, 1H), 8.48-8.58 (m, 1H), 8.19 (dd, J = 8.6, 5.3 Hz, 1H), 7.62-7.79 (m, 1H), 7.35-7.58 (m, 3H), 5.11-5.25 (m, 2H), 4.91 (br d, J = 14.7 Hz, 2H), 4.71 (br d, J = 3.3 Hz, 1H), 4.45 (br d, J = 3.1 Hz, 1H), 4.25-4.40 (m, 2H), 3.43-3.89 (m, 12H), 1.41-1.55 (m, 6H).

[0288] Example 17

[0289] 2-[4-(8-cyano-5-quinolinyl)-2-methyl-piperazin-1-yl]- N -(4-piperazin-1-ylphenyl)acetamide

[0290]

[0291] The title compound was prepared according to the following scheme:

[0292]

[0293] Step 1: Preparation of methyl 2-(2-methylpiperazin-1-yl)acetate (compound 17b)

[0294] To a solution of 3-methylpiperazine-1-carboxylic acid tert-butyl ester (CAS: 120737-59-9, AccelaChem bio, Catalog: SY002666, 1.0 g, 5.0 mmol) in acetonitrile (15 mL) was added K2CO3(690 mg, 5.0 mmol) and methyl 2-bromoacetate (764 mg, 5.0 mmol). The resulting mixture was stirred at 80 °C for 3 hours, then cooled to room temperature and filtered through celite. The filter cake was washed with EA (10 mL) twice. The combined organic layers were concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 25 g, 9% to 100% EtOAc in PE).

[0295] The purified intermediate was dissolved in DCM (2 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 30 minutes, then concentrated to give crude compound 17b (500 mg, 58% yield). MS: calculated 173 [(M+H) + ] ; found 173 [(M+H) + ].

[0296] Step 2: Preparation of 2-chloro-7,8-dihydro-5 H -benzyl 6-carboxylate (compound 17c)

[0297] To a solution of 5-bromoquinoline-8-carbonitrile (CAS: 96-32-2, Alfa Aesar, Catalog: A10605, 300 mg, 1.29 mmol) in dioxane (10 mL) was added methyl 2-(2-methylpiperazin-1-yl)acetate (compound 17b, 200 mg, 1.2 mmol), RuPhos G2 (CAS: 1375325-68-0, Sigma-Aldrich, Catalog: 753246, 27.1 mg, 34.8 µmol) and Cs2CO3(568 mg, 1.7 mmol). The reaction mixture was stirred at 80 °C for 13 hours, then cooled to room temperature. The reaction mixture was filtered, then the filtrate was diluted with water (10 mL) and extracted with EA (40 mL) 3 times. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 40 g, 16% to 100% EtOAc in PE) to give compound 17c (300 mg, 80% yield). MS: calculated 325 [(M+H) + ] ; found 325 [(M+H) +].

[0298] Step 3: Preparation of 2-[4-(8-cyano-5-quinolinyl)-2-methyl-piperazin-l-yl]acetic acid (Compound 17d)

[0299] To a stirred solution of methyl 2-(4-(8-cyanoquinolin-5-yl)-2-methylpiperazin-l- yl)acetate (Compound 17c, 300 mg, 925 pmol) in THF (5 mL) and water (5 mL) was added lithium hydroxide monohydrate (58.3 mg, 1.4 mmol). The resulting mixture was stirred at room temperature for 4 hours, then neutralized with 1 M HC1. The mixture was concentrated in vacuo to give a light yellow solid which was used directly in the next step without further purification.

[0300] Step 4: Preparation of 2-[4-(8-cyano-5-quinolinyl)-2-methyl-piperazin-l-yl]- N -(4-piperazin-l-ylphenyl)acetamide (Example 17)

[0301] To a stirred solution of 2-(4-(8-cyanoquinolin-5-yl)-2-methylpiperazin-l-yl)acetic acid (Compound 17d, 35.0 mg, 113 pmol) and HATU (51.5 mg, 135 pmol) and DIEPA (29.2 mg, 226 pmol) in DMF (2 mL) was added tert-butyl 4-(4-aminophenyl)piperazine-l-carboxylate (37.5 mg, 135 pmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours, then concentrated in vacuo.

[0302] The residue was dissolved in DCM (2 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 30 minutes, then concentrated in vacuo to give the crude product which was purified by preparative-HPLC to give Example 17 (39 mg, 57% yield). MS: calc’d 470 [(M+H) + ]; measured 470 [(M+H) + ]. 1 H NMR (400 MHz, Methanol-d4) d = 9.02 (dd, J = 4.6, 1.5 Hz, 1H), 8.89 (d, J = 8.6 Hz, 1H), 8.24 (d, J = 8.1 Hz, 1H), 7.79 (dd, J = 8.6, 4.6 Hz, 1H), 7.53 (d,J = 9.0 Hz, 2H), 7.40 (br d, J = 7.9 Hz, 1H), 7.04 (d, J = 9.0 Hz, 2H), 4.51 (br d, J = 16.1 Hz, 1H), 3.96-4.29 (m, 3H), 3.92 (br d, J = 12.1 Hz, 1H), 3.74 (br t, J = 10.1 Hz, 1H), 3.56-3.69 (m, 2H), 3.31-3.47 (m, 9H), 1.42-1.59 (m, 3H)

[0303] Example 18

[0304] 2-[4-(8-cyano-5-quinolinyl)-2-methyl-piperazin-l-yl]- N -(l,2,3,4-tetrahydroisoquinolin-6-yl)acetamide

[0305]

[0306] The title compound was prepared in analogy to the preparation of Example 17 by using 6-amino-3,4-dihydro-l H -isoquinoline-2-carboxylic acid tert-butyl ester (CAS: 164148-92-9, PharmaBlock, Catalog: PB03559) instead of 4-(4-aminophenyl)piperazine-l-carboxylic acid tert-butyl ester. Example 18 (40 mg) was obtained. MS: calc’d 441 [(M+H) + ], measured 441 [(M+H) + ]. 1 HNMR (400 MHz, Methanol-d4) d 4 ) by ppm 9.09 (dd, J = 4.5, 1.4 Hz, 1H), 8.88 (br d, J = 8.4 Hz, 1H), 8.29 (d, J = 7.9 Hz, 1H), 7.83 (dd, J = 8.6, 4.5 Hz, 1H), 7.65 (s, 1H), 7.57 (dd, J = 8.3, 2.0 Hz, 1H), 7.47 (br d, J = 7.9 Hz, 1H), 7.28 (d,J = 8.4 Hz, 1H), 4.66 (br d, J = 15.6 Hz, 1H), 4.40-4.27 (m, 3H), 4.25 (br d, J = 15.8 Hz, 1H), 4.04 (brd, J = 11.6 Hz, 1H), 3.86 (br t, J = 10.1 Hz, 1H), 3.62-3.80 (m, 2H), 3.46-3.59 (m, 3H), 3.34-3.40 (m, 1H), 3.13 (t, J = 6.4 Hz, 2H), 1.54-1.72 (m, 3H).

[0307] Example 19

[0308] 5-[3-methyl-4-[2-[4-(1-methyl-4-piperidinyl)-1-piperidinyl]-2-oxo-ethyl]piperazin-1-yl]quinoline-8-nitrile

[0309]

[0310] To a stirred solution of 2-(4-(8-cyanoquinolin-5-yl)-2-methylpiperazin-1-yl)acetic acid (compound 17d, 35.0 mg, 113 µmol), HATU (51.5 mg, 135 µmol), and DIEPA (29.2 mg, 226 µmol) in DMF (2 mL), 1-methyl-4,4'-bispiperidine (CAS: 122373-80-2, J&K Scientific, catalog: K66-4018200, 24.7 mg, 135 µmol) was added at room temperature. The reaction mixture was stirred at room temperature for 3 hours, then concentrated under vacuum. The residue was dissolved in EA (20 mL) and washed with aqueous NaOH solution (0.5 N, 5 mL) and water (5 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to obtain a crude product, which was then purified by preparative-HPLC to obtain Example 19 (25 mg, 45% yield). MS: calculated 475 [(M+H)] + ]; The measured value was 475 [(M+H) + ]. 1 ¹H NMR (400 MHz, methanol-d⁴) δ = 8.96 (dd, J = 4.2, 1.6 Hz, 1H), 8.60 (dd,J = 8.6, 1.6 Hz,1H), 8.11 (d, J = 8.1 Hz, 1H), 7.62 (dd, J = 8.6, 4.3 Hz, 1H), 7.21 (dd, J = 8.1, 2.1 Hz, 1H), 4.48-4.64 (m, 1H), 4.19-4.38 (m, 1H), 3.68-3.94 (m, 1H), 3.35-3.42 (m, 1H), 2.71-3.19 (m, 9H), 2.53-2.68 (m, 1H), 2.26 (d, J = 3.1 Hz, 3H), 1.68-2.03 (m, 7H), 1.24-1.47 (m, 4H), 1.22 (d, J = 6.0 Hz, 3H), 1.12 (td, J = 12.0, 3.8 Hz, 2H).

[0311] Example 20

[0312] To determine the activity of the compounds of formula (I) in the HEK293-Blue-hTLR-7 / 8 / 9 cell assay, the following test was performed.

[0313] HEK293-Blue-hTLR-7 cell assay:

[0314] 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-κΒ activation. The SEAP (secreted embryonic alkaline phosphatase) reporter gene is placed under the control of the IFN-β minimal promoter fused to five NF-κΒ and AP-1 binding sites. byStimulation of HEK-Blue hTLR7 cells with TLR7 ligands activates NF-κΒ and AP-1 to induce SEAP. Thus, reporter gene expression is reduced by TLR7 antagonists upon 20 hours incubation with stimulation of ligands such as R848 (Resiquimod). The activity of the SEAP reporter gene in cell culture supernatant is determined using the QUANTI-Blue™ kit (Cat.#: rep-qb1, Invivogen, San Diego, Ca, USA) at a wavelength of 640 nm, where the detection medium turns purple or blue under alkaline phosphatase.

[0315] HEK293-Blue-hTLR7 cells were incubated in 96-well plates containing Dulbecco's Modified Eagle Medium (DMEM) with 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 calf serum in a volume of 170 µL at a density of 250,000 to 450,000 cells / mL, in the above-mentioned DMEM, 20 µL of test compound and 10 µL of 20 uM R848 were added in a final DMSO concentration of 1% for 20 hours incubation in a CO2 incubator at 37 °C. Then 20 µL supernatant in each well was incubated with 180 µL Quanti-blue substrate solution for 2 hours at 37 °C and the absorbance was read using a spectrophotometer at 620 to 655 nm. The signaling pathway leading to downstream NF-κΒ activation by TLR7 activation has been well accepted, therefore a similar reporter gene detection method was modified to assess TLR7 antagonists.

[0316] HEK293-Blue-hTLR-8 cell assay:

[0317] 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-κΒ activation. A SEAP (secreted embryonic alkaline phosphatase) reporter gene was placed under the control of an IFN-β minimal promoter fused to five NF-κΒ and AP-1 binding sites. byStimulation of HEK-Blue hTLR8 cells with TLR8 ligands activates NF-κΒ and AP-1 to induce SEAP. Thus, incubation for 20 hours under stimulation of ligands such as R848, the reporter gene expression is reduced by TLR8 antagonists. The activity of the SEAP reporter gene in cell culture supernatants was determined using the QUANTI-Blue™ kit (Cat.#: rep-qb1, Invivogen, San Diego, Ca, USA) at a wavelength of 640 nm, the detection medium turns purple or blue under alkaline phosphatase.

[0318] HEK293-Blue-hTLR8 cells were incubated in 96-well plates containing Dulbecco's Modified Eagle Medium (DMEM) with 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 calf serum in a volume of 170 μΙ_ at a density of 250,000 to 450,000 cells / mL, in the above-mentioned DMEM, 20 μΙ_ of test compound and 10 μΙ_ of 60 uM R848 were added in a final DMSO concentration of 1% for a 20-hour incubation in a CO2 incubator at 37 °C. Then 20 μΙ_ of supernatant per well was incubated with 180 μΙ_ of Quanti-blue substrate solution for 2 hours at 37 °C and the absorbance was read using a spectrophotometer at 620 to 655 nm. The signaling pathway leading to downstream NF-κΒ activation by TLR8 has been well accepted, therefore a similar reporter gene detection method was modified to assess TLR8 antagonists.

[0319] HEK293-Blue-hTLR-9 cell assay:

[0320] 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-κΒ activation. A SEAP (secreted embryonic alkaline phosphatase) reporter gene was placed under the control of an IFN-β minimal promoter fused to five NF-κΒ and AP-1 binding sites. data analysisStimulation of HEK-Blue hTLR9 cells with TLR9 ligands activates NF-κΒ and AP-1 to induce SEAP. Thus, reporter gene expression is reduced by TLR9 antagonists upon 20 hours incubation with stimulation of ligands such as ODN2006 (Cat.#: tlrl-2006-1, Invivogen, San Diego, California, USA). The activity of the SEAP reporter gene in cell culture supernatants was determined using the QUANTI-Blue™ kit (Cat.#: rep-qb1, Invivogen, San Diego, California, USA) at a wavelength of 640 nm, where the detection medium turns purple or blue under alkaline phosphatase.

[0321] HEK293-Blue-hTLR9 cells were incubated in 96-well plates containing Dulbecco's Modified Eagle Medium (DMEM) with 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 calf serum in a volume of 170 μΙ_ at a density of 250,000 to 450,000 cells / mL, in the above-mentioned DMEM, 20 μΙ_ of test compound and 10 μΙ_ of 20 uM ODN2006 were added in a final DMSO concentration of 1%, incubated for 20 hours at 37 °C in a CO2 incubator. Then 20 μΙ_ of supernatant per well was incubated with 180 μΙ_ of Quanti-blue substrate solution for 2 hours at 37 °C and the absorbance was read using a spectrophotometer at 620 to 655 nm. The signaling pathway leading to downstream NF-κΒ activation by TLR9 activation has been well accepted, therefore a similar reporter gene detection method was modified to assess TLR9 antagonists.

[0322] The compounds of formula (I) have human TLR7 and / or TLR8 inhibitory activity (IC 50 values) < 0.1 μΜ. Furthermore, the compounds of the present application also have human TLR9 inhibitory activity < 0.2 μΜ. Table 1 shows the activity data of the compounds of the present application.

[0323] Table 1 : Activity of the compounds of the present application in the HEK293-Blue-hTLR-7 / 8 / 9 cell assay

[0324] Table 1 : Activity of the compounds of the present application in the HEK293-Blue-hTLR-7 / 8 / 9 cell assay

[0325] Example 21

[0326] Human microsomal stability assay

[0327] Human liver microsomes and test compound (Cat. NO.: 452117, Corning, USA) were pre-incubated in 100 mM potassium phosphate buffer (pH 7.4) for 10 minutes at 37 °C. The reaction was initiated by the addition of the NADPH regenerating system. The final incubation mixture contained 1 mM test compound, 0.5 mg / mL liver microsomal protein, 1 mM MgCl2, 1 mM NADP, 1 unit / mL isocitrate dehydrogenase, and 6 mM isocitric acid in 100 mM potassium phosphate buffer (pH 7.4). After incubation at 37 °C for 0, 3, 6, 9, 15, and 30 minutes, 300 pL cold ACN (including internal standard) was added to 100 pL of the incubation mixture to stop the reaction. After precipitation and centrifugation, 100 uL of the supernatant was taken and 300 uL of water was added. The amount of compound remaining in the sample was determined by LC-MS / MS. Zero and 30 minute controls without the NADPH regenerating system were also prepared and analyzed. The test results are summarized in Table 2.

[0328] Table 2: Human microsomal stability results

[0329]

[0330] Example 22

[0331] hERG channel inhibition assay

[0332] The hERG channel inhibition assay is a highly sensitive measure that identifies compounds that show hERG inhibition associated with cardiac toxicity in vivo. The hERG K + channel is cloned into human and stably expressed in a CHO (Chinese hamster ovary) cell line. CHO hERG cells are used for patch clamp (voltage clamp, whole cell) experiments. Voltage- mode stimulation of the cells activates the hERG channel and conducts I KhERG current (rapid delayed outward rectifying potassium current of the hERG channel). After a few minutes of cell stabilization, the amplitude and kinetics of I KhERG are recorded at a stimulation frequency of 0.1 Hz (6 bpm). Thereafter, test compounds are added to the preparation in increasing concentrations. For each concentration, a steady-state effect is attempted, usually within 3-10 minutes, before the next highest concentration is applied. IKhERG The amplitude and kinetics of the peak tail current were measured and compared to control values (taken as 100%). (Ref: Redfern WS, Carlsson L, Davis AS, Lynch WG, MacKenzie I, Palethorpe S, Siegl PK, Strang I, Sullivan AT, Wallis R, Camm AJ, Hammond TG. 2003; Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc. Res. 58:32-45, Sanguinetti MC, Tristani-Firouzi M. 2006; hERG potassium channels and cardiac arrhythmia. Nature 440:463-469, Webster R, Leishman D, Walker D. 2002; Towards a drug concentration effect relationship for QT prolongation and torsades de pointes. Curr. Opin. Drug Discov. Devel. 5:116-26).

[0333] hERG results are shown in Table 3. A safety ratio (hERG IC 20 / EC 50 )>30 indicates a sufficient window to differentiate pharmacology from potential hERG-related cardiac toxicity by inhibiting TLR7 / 8 / 9 pathways.

[0334] Table 3: hERG results

[0335]

[0336] Example 23

[0337] These compounds are expected to have minimal DDI liability. Therefore, the effect of the compounds of Formula (I) on CYP2D6 was determined.

[0338] CYP inhibition assay

[0339] This is a high-throughput screening assay to assess the reversible inhibition of CYP2D6 activity in early discovery stage human liver microsomes (HLM) by test compounds.

[0340] Table 4. Chemicals and materials used in the CYP inhibition rating

[0341]

[0342] Procedure

[0343] A 10 mM DMSO stock solution of test compound was diluted in DMSO to generate a 2 mM intermediate stock solution. 250 nL of the intermediate stock solution was transferred in duplicate to 3 separate 384-well microtiter plates (assay plates). A mixture of HLM and each substrate was prepared. Then 45 µL of the HLM substrate mixture was transferred to each well of the assay plates and mixed. Negative (solvent) and positive controls (standard inhibitors of CYP 2D6) were included in each assay plate. The assay plates were warmed to 37 °C in an incubator for 10 minutes. 5 µL of pre-warmed NADPH regenerating system was added to each incubation well to start the reaction. The final incubation volume was 50 µL. The assay plates were then returned to the 37 °C incubator. After 10 minutes of incubation, the incubations were quenched by the addition of 50 µL of 100% acetonitrile containing an internal standard (20 ng / mL D3 dextrorphan). The supernatant was collected for RapidFire / MS / MS analysis.

[0344] 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. A C4 solid phase extraction cartridge was used for sample separation. MS detection was done in positive ion MRM mode.

[0345] ​

[0346] The peak areas of the substrate, metabolite, and internal standard were determined using the RapidFire integrator software (version 3.6.12009.12296). The peak area ratio (PAR) of the metabolite and internal standard (stably labeled metabolite) was then calculated. A measurement window was then defined for each experiment:

[0347] PAR (0% activity) = average PAR of all incubations containing concentrated inhibitor;

[0348] PAR (100% activity) = average PAR of all incubations not containing inhibitor (DMSO control);

[0349] Activity % (test inhibitor)

[0350] = [PAR (test inhibitor) - PAR (0% activity)] / [PAR (100% activity) - PAR (0% activity)];

[0351] Inhibition % (test inhibitor) = 100 - Activity % (test inhibitor).

[0352] It was found that the compounds of the application determined in the above assay have low CYP inhibition of CYP2D6.

[0353] Table 5. CYP inhibition of CYP2D6 by compounds of the application

[0354]

[0355] Percent Inhibition <0: no or weak inhibition

Claims

1. A compound of formula (I), (I)， in R 1 for ;where R 5 It is cyano; R 2 C 1-6 alkyl; R 3 For R 3a or -COR 3b ;in R 3a For piperazine group and (hydroxy C) 1-6 Alkyl)piperazinyl substituted phenyl; Piperazine group, C 1-6 Alkylpiperazinyl, 9-oxa-3,7-diazabicyclo[3.3.1]nonyl, (halopyrrolyl)amino, (pyrrolylcarbonyl)piperazinyl or (((C 1-6 alkyl)2amino)C 1-6 Alkyl carbonyl) piperazine-substituted pyridyl; or Piperazine or (((C) 1-6 alkyl)2amino)C 1-6 Alkyl carbonyl) piperazine-substituted pyrimidinyl group; R 3b It is 7,8-dihydro-5H-1,6-naphthidium substituted with piperazine; 3,4-dihydro-1H-isoquinolinyl group substituted with piperazine group; Isoindolinyl group substituted with piperazine group; Phenylamino group substituted with piperazine group; 1,2,3,4-Tetrahydroisoquinolinyl; or C 1-6 alkylpiperidinylpiperidinyl; R 4 C 1-6 Alkyl or H; Or its pharmaceutically acceptable salt, enantiomer or diastereomer.

2. The compound according to claim 1, wherein... R 1 for ;where R 5 It is cyano; R 2 It is methyl; R 3 For R 3a or -COR 3b ;in R 3a Piperazinylphenyl; (hydroxymethyl)piperazinylphenyl; piperazinylpyridinyl; (methylpiperazinyl)pyridinyl; 9-oxa-3,7-diazabicyclo[3.3.1]nonylpyridinyl; ((fluoropyrrolidinyl)amino)pyridinyl; ((pyrrolidinylcarbonyl)piperazinyl)pyridinyl; (((dimethylamino)acetyl)piperazinyl)pyridinyl; piperazinylpyrimidinyl; or ((dimethylamino)acetyl)piperazinylpyrimidinyl; R 3b It is piperazinyl-7,8-dihydro-5H-1,6-naphthodinyl; piperazinyl-3,4-dihydro-1H-isoquinolinyl; piperazinyl isoindololinyl; piperazinylphenylamino; 1,2,3,4-tetrahydroisoquinolinyl; or methylpiperidinylpiperidinyl; R 4 It can be methyl or hydrogen; Or its pharmaceutically acceptable salt, enantiomer or diastereomer.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof, wherein R 3 For R 3a or -COR 3b ;where R 3a R is a pyridinyl group substituted with a piperazine group; 3b It is an isoindoline group substituted with piperazine group.

4. A compound selected from: 5-[(3 R 5 S )-3,5-dimethyl-4-[(4-piperazin-1-ylphenyl)methyl]piperazin-1-yl]quinoline-8-nitrile; 5-[(3 R 5 R )-3,5-dimethyl-4-[(4-piperazin-1-ylphenyl)methyl]piperazin-1-yl]quinoline-8-nitrile; 5-[(3 R 5 S )-3,5-dimethyl-4-[(6-piperazin-1-yl-3-pyridyl)methyl]piperazin-1-yl]quinoline-8-nitrile; 5-[(3 S 5 R )-3,5-dimethyl-4-[(5-piperazin-1-ylpyrimidin-2-yl)methyl]piperazin-1-yl]quinoline-8-nitrile; 5-[(3 S 5 R )-3,5-dimethyl-4-[(5-piperazin-1-yl-2-pyridyl)methyl]piperazin-1-yl]quinoline-8-nitrile; 5-[(3 S 5 R )-4-[[5-[4-[2-(dimethylamino)acetyl]piperazin-1-yl]pyrimidin-2-yl]methyl]-3,5-dimethyl-piperazin-1-yl]quinoline-8-nitrile; 5-[(3 S 5 R )-3,5-dimethyl-4-[[5-(4-methylpiperazin-1-yl)-2-pyridyl]methyl]piperazin-1-yl]quinoline-8-nitrile; 5-[(3 S 5 R )-3,5-dimethyl-4-[[5-(9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-yl)-2-pyridyl]methyl]piperazin-1-yl]quinoline-8-nitrile; 5-[(3 R 5 S )-3,5-dimethyl-4-[[5-[[(3 R 4 S )-4-fluoropyrrolidine-3-yl]amino]-2-pyridyl]methyl]piperazin-1-yl]quinoline-8-nitrile; 5-[(3 R 5 S )-3,5-dimethyl-4-[[5-[4-(pyrrolidine-2-carbonyl)piperazin-1-yl]-2-pyridyl]methyl]piperazin-1-yl]quinoline-8-nitrile; 5-[(3 S 5 R )-4-[[5-[4-[2-(dimethylamino)acetyl]piperazin-1-yl]-2-pyridyl]methyl]-3,5-dimethyl-piperazin-1-yl]quinoline-8-nitrile; 5-[(3 R 5 S )-4-[[4-[2-(hydroxymethyl)piperazin-1-yl]phenyl]methyl]-3,5-dimethyl-piperazin-1-yl]quinoline-8-nitrile; 5-[(3 R 5 S )-3,5-dimethyl-4-[2-oxo-2-(2-piperazin-1-yl-7,8-dihydro-5- H -1,6-naphthid-6-yl)ethyl]piperazin-1-yl]quinoline-8-nitrile; 5-[(3 R 5 S )-3,5-dimethyl-4-[2-oxo-2-(6-piperazin-1-yl-3,4-dihydro-1-yl-2-( ... H -isoquinoline-2-yl)ethyl]piperazine-1-yl]quinoline-8-nitrile; 5-[(3 R 5 S )-3,5-dimethyl-4-[2-oxo-2-(7-piperazin-1-yl-3,4-dihydro-1-yl-2-(7-piperazin-1-yl-3,4-dihydro-1-yl-2-(2-oxo ... H -isoquinoline-2-yl)ethyl]piperazine-1-yl]quinoline-8-nitrile; 5-[(3 R 5 S )-3,5-dimethyl-4-[2-oxo-2-(5-piperazin-1-ylisoindoline-2-yl)ethyl]piperazin-1-yl]quinoline-8-nitrile; 2-[4-(8-cyano-5-quinolinyl)-2-methyl-piperazin-1-yl]- N -(4-piperazin-1-ylphenyl)acetamide; 2-[4-(8-cyano-5-quinolinyl)-2-methyl-piperazin-1-yl]- N -(1,2,3,4-tetrahydroisoquinoline-6-yl)acetamide; and 5-[3-methyl-4-[2-[4-(1-methyl-4-piperidinyl)-1-piperidinyl]-2-oxo-ethyl]piperazin-1-yl]quinoline-8-nitrile; Or its pharmaceutically acceptable salt, enantiomer or diastereomer.

5. Use of the compound according to any one of claims 1 to 4 in the preparation of a medicament for the treatment or prevention of systemic lupus erythematosus or lupus nephritis mediated by TLR7 / 8 / 9.

6. Use of the compound according to any one of claims 1 to 4 in the preparation of a medicament used as a TLR7, TLR8 and TLR9 antagonist.

Images