Substituted quinolones as tlr9 inhibitors

Abstract

Disclosed are compounds of Formula (I): # imgabs0 # or a salt thereof, wherein L, R1, R2, R3 and R4 are defined herein. Also disclosed are methods of using these compounds as TLR9 inhibitors and pharmaceutical compositions comprising these compounds. These compounds are useful for treating, preventing or slowing fibrotic diseases.

Description

[0001] Cross - reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 424,343, filed on November 10, 2022, the entire content of which is incorporated herein by reference. Technical field

[0003] The present invention generally relates to substituted quinolone compounds that act as Toll - like receptor 9 (TLR9) signaling inhibitors, compositions containing these compounds, and methods of using the same. The present invention further relates to pharmaceutical compositions containing at least one compound according to the present invention, which can be used to treat conditions related to TLR9 modulation (such as fibrotic diseases) and methods of inhibiting TLR9 activity in mammals. Background art

[0004] Toll - like receptors (TLRs) are transmembrane proteins that have the ability to initiate an inflammatory response upon recognition of pathogen - associated molecular patterns (PAMPs) or microbe - associated molecular patterns (MAMPs). A total of 10 human TLRs have been identified and can be located on the cell surface or, in the case of TLR7, 8, and 9, in lysosomes. TLR9 recognizes unmethylated single - stranded DNA containing cytosine - phosphate - guanine (CpG) motifs, which are typically found in bacterial and mitochondrial DNA (mtDNA). TLR9 can promote fibrosis by promoting inflammation via the MyD88 - dependent signaling pathway, which ultimately mediates the activation of IL - 6, IFN - α, IL - 1β, and TNF - α among other cytokines. (Barton GM, Kagan JC (2009) Nat. Rev. Immunol. 9(8), 535–42; Li X, Jiang S, Tapping RI (2010) Cytokine 49(1), 1–9).

[0005] Compared to healthy or stable idiopathic pulmonary fibrosis (IPF) progressors, TLR9 levels are higher in lung biopsy tissues of rapid idiopathic IPF progressors (Sci. Transl. Med. 2010, 2(57):57ra82). Circulating mtDNA (a ligand of TLR9) has recently been identified as a mechanism-based prognostic biomarker for IPF (Am J. Resp. and Crit. Care Med. 2017, 196(12), 1502). In addition, TLR9 has been observed to be upregulated in human and murine non-alcoholic steatohepatitis (NASH) (Clin. Sci. 2017, 131(16), 2145), and hepatocyte mitochondrial DNA drives NASH via activation of TLR9 (J. Clin. Invest. 2016, 126(3), 859). Therefore, inhibitors / antagonists of TLR9 are predicted to have efficacy as novel therapeutic agents for fibrotic diseases.

[0006] TLR9 inhibition has been identified as a potential pathway for the treatment of fibrotic diseases, including idiopathic pulmonary fibrosis (Trujillo et al. Sci. Transl. Med. 2010, 2(57):57ra82; Yoshizaki et al. Ann Rheum Dis. 2016 Oct; 75(10):1858-65), non-alcoholic steatohepatitis (Garcia-Martinez et al. J Clin Invest 2016, 126:859–864; Gabele et al. Biochem Biophys Res Commun. 2008; 376:271–276), liver injury (Shaker et al. Biochem Pharmacol. 2016.112:90-101; Hoeque et al. J. Immun. 2013, 190:4297-304) and scleroderma (systemic sclerosis or SSc) (Yoshizaki et al. Ann Rheum Dis. 2016 Oct; 75(10):1858-65); as well as heart failure (Oka et al. Nature 485, 251–255 (2012)) and hypertension (McCarthy et al. Cardiovascular Research, 2015, 119–130).

[0007] There is still a need for compounds that act as TLR9 inhibitors. Additionally, there is still a need for compounds that act as TLR9 inhibitors with superior selectivity over TLR7 or TLR8.

[0008] Based on medical conditions that can benefit from treatment involving modulation of Toll-like receptors, it is clear that novel compounds that can inhibit TLR9 can provide substantial therapeutic benefits to a wide variety of patients.

[0009] The applicant has discovered potent compounds having activity as TLR9 inhibitors. In addition, the applicant has discovered compounds having activity as TLR9 inhibitors and having superior selectivity over TLR7 or TLR8. These compounds are provided for use as drugs having desirable stability, bioavailability, therapeutic index, and toxicity values that are important for their medicinal use. Summary of the Invention

[0010] The present invention relates to a novel class of substituted quinolone compounds that have been found to be potent inhibitors of TLR9 signaling. These compounds are provided for use as drugs having desirable stability, bioavailability, therapeutic index, and toxicity values that are important for their medicinal use.

[0011] The present invention provides compounds of formula (I) or stereoisomers, N-oxides, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof that can be used as inhibitors of Toll-like receptor 9 and can be used to treat fibrotic diseases.

[0012] The present invention also provides pharmaceutical compositions that comprise a pharmaceutically acceptable carrier and at least one compound of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0013] The present invention also provides a method of inhibiting Toll-like receptor 9, which comprises administering to a subject in need of such treatment a therapeutically effective amount of at least one compound of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0014] The present invention also provides a method of treating fibrotic diseases, which comprises administering to a subject in need of such treatment a therapeutically effective amount of at least one compound of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0015] The present invention also provides a method of treating a disease or disorder associated with Toll-like receptor 9 activity, the method comprising administering to a mammalian subject in need thereof at least one compound of formula (I) or a salt, solvate, and prodrug thereof.

[0016] The present invention also provides methods and intermediates for preparing compounds of formula (I) (including salts, solvates, and prodrugs thereof).

[0017] The present invention also provides at least one compound of formula (I) or a salt, solvate, and prodrug thereof for use in therapy.

[0018] The present invention also provides the use of at least one compound of formula (I) or a salt, solvate and prodrug thereof for the preparation of a medicament for the treatment or prevention of Toll-like receptor 9-related conditions such as fibrotic diseases, autoimmune diseases or inflammatory diseases.

[0019] The compounds of formula (I) and the compositions comprising the compounds of formula (I) can be used for the treatment, prevention or cure of various Toll-like receptor 9-related conditions. The pharmaceutical compositions comprising these compounds can be used for the treatment, prevention or slowing of the progression of diseases or disorders in various therapeutic areas such as fibrotic diseases, which include non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), idiopathic pulmonary fibrosis, primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC).

[0020] These and other features of the invention will be set forth in an expanded form as the disclosure continues. Detailed Description

[0021] The first aspect of the present invention provides at least one compound of formula (I):

[0022]

[0023] or a salt thereof, wherein:

[0024] R 1 is phenyl, pyridyl, pyrimidinyl, indolyl, indazolyl or quinoxalinyl, each optionally substituted with from 0 to 5 R 1a substituents;

[0025] Each R 1a is independently F, Cl, -CN, -OH, C 1-2 alkyl, C 1-2 fluoroalkyl, C 1-2 alkoxy, C 1-2 fluoroalkoxy, -C(O)OH, -C(O)O(C 1-2 alkyl), -C(O)NR x R x , -NR x R x , -NR x C(O)(C 1-4 alkyl), -NHC(O)C(CH 3 ) 2 OH, -NHC(O)NR x R x , -NO 2 , -S(O) 2 (C 1-2 alkyl), -S(O) 2 NRx R x 、 -NR x S(O) 2 (C 1-2 alkyl), -NR x C(O)(pyridyl), -NR x (methylazetidinyl), -C(O)(morpholinyl), -C(O)(dimethylpyrrolidinyl), fluoropyrrolidinyl, hydroxypyrrolidinyl, pyrrolidinonyl, imidazolidinonyl or tetrazolyl;

[0026] R 2 is hydrogen, C 1-4 alkyl or C 1-4 hydroxyalkyl;

[0027] L is a bond or -NH-;

[0028] R 3 is phenyl or piperidinyl, each substituted by R 3a ;

[0029] R 3a is -CH 3 or a cyclic group selected from piperidinyl and piperazinyl, wherein said cyclic group is substituted by 0 or 1 R 3b ;

[0030] R 3b is C 1-3 alkyl or oxetanyl;

[0031] R 4 is hydrogen or C 1-2 alkyl; and

[0032] each R x is independently H or -CH 3 .

[0033] In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein:

[0034] R 1 is phenyl, pyridyl, pyrimidinyl, indolyl, indazolyl or quinoxalinyl, each substituted by 0 to 5 R 1a ;

[0035] each R 1a is independently F, Cl, -CN, -OH, -CH 3 , -CF 3 , -OCH 3 , -OCHF 2 , -OCF 3 , -C(O)OH, -C(O)OCH 3 , -C(O)NH 2, -C(O)NH(CH 3 ), -C(O)N(CH 3 ) 2 , -N(CH 3 ) 2 , -NHC(O)CH 3 , -NHC(O)CH 2 CH 3 , -NHC(O)CH(CH 3 ) 2 , -NHC(O)CH 2 CH 2 CH 2 CH 3 , -NHC(O)C(CH 3 ) 2 OH, -NHC(O)NH(CH 3 ), -NO 2 , -S(O) 2 CH 3 , -S(O) 2 NH 2 , -NHS(O) 2 CH 3 , -N(CH 3 )S(O) 2 CH 3 , -NHC(O)(pyridyl), -C(O)N(CH 3 )(oxetanyl), -N(CH 3 )(methylazetidinyl), -C(O)(morpholinyl), -C(O)(dimethylpyrrolidinyl), fluoropyrrolidinyl, hydroxypyrrolidinyl, pyrrolidinone, imidazolone or tetrazolyl;

[0036] R 2 is hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH or -CH 2 C(CH 3 ) 2 OH;

[0037] L is a bond or -NH-;

[0038] R 3 is phenyl or piperidinyl, each substituted by R 3a ;

[0039] R 3a is -CH 3 or a cyclic group selected from piperidinyl and piperazinyl, wherein said cyclic group is substituted by 0 or 1 R 3b ;

[0040] R 3b is -CH 3 , -CH(CH 3 ) 3 or oxetanyl; and

[0041] R 4 is hydrogen or -CH 2 CH 3 .

[0042] In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein R 1 is phenyl, pyridinyl or pyrimidinyl, each substituted by 0 to 5 R 1a . Included in this embodiment are compounds wherein R 1 is phenyl or pyridinyl, each substituted by 0 to 5 R 1a .

[0043] In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein R 1 is phenyl substituted by 0 to 5 R 1a . Included in this embodiment are compounds wherein R 1 is phenyl substituted by 0 to 4 R 1a . Also included in this embodiment are compounds wherein R 1 is phenyl substituted by 0 to 3 R 1a .

[0044] In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein R 1 is phenyl substituted by 0 to 5 R 1a ; and each R 1a is independently F, Cl, -CN, -CF 3 , -OCH 3 , -OCHF 2 , -OCF 3 , -C(O)OH, -C(O)OCH 3 , -C(O)NH 2 , -C(O)NH(CH 3 ), -C(O)N(CH 3 )2 , -NHC(O)CH 3 , -NHC(O)CH 2 CH 3 , -NHC(O)CH(CH 3 ) 2 , -NHC(O)CH 2 CH 2 CH 2 CH 3 , -NHC(O)C(CH 3 ) 2 OH, -NHC(O)NH(CH 3 ), -S(O) 2 CH 3 , -S(O) 2 NH 2 , -NHS(O) 2 CH 3 or -N(CH 3 )S(O) 2 CH 3 . In this embodiment, the compound also includes a compound in which R 1 is a phenyl group substituted with 0 to 5 R 1a ; and each R 1a is independently F, Cl, -CN, -CF 3 , -OCH 3 , -OCHF 2 , -OCF 3 , -NHC(O)CH 2 CH 3 , -S(O) 2 CH 3 , -S(O) 2 NH 2 , -NHS(O) 2 CH 3 or -N(CH 3 )S(O) 2 CH 3 .

[0045] In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein each R 1a is independently F, Cl, -CN, -OH, -CH 3 , -CF 3 , -OCH 3 , -OCHF 2 , -OCF 3 , -C(O)OH, -C(O)OCH 3 , -C(O)NH 2 , -C(O)NH(CH3 )、 -C(O)N(CH 3 ) 2 、 -N(CH 3 ) 2 、 -NHC(O)CH 3 、 -NHC(O)CH 2 CH 3 、 -NHC(O)CH(CH 3 ) 2 、 -NHC(O)CH 2 CH 2 CH 2 CH 3 、 -NHC(O)C(CH 3 ) 2 OH、 -NHC(O)NH(CH 3 )、 -NO 2 、 -S(O) 2 CH 3 、 -S(O) 2 NH 2 、 -NHS(O) 2 CH 3 、 -N(CH 3 )S(O) 2 CH 3 、 -NHC(O)(pyridyl), -C(O)N(CH 3 )(oxetanyl), -N(CH 3 )(methylazetidinyl), -C(O)(morpholinyl), -C(O)(dimethylpyrrolidinyl), fluoropyrrolidinyl, hydroxypyrrolidinyl, pyrrolidinone, imidazolone or tetrazolyl. Compounds are also included in this embodiment, wherein each R 1a is independently F, Cl, -CN, -OH, -CH 3 , -CF 3 , -OCH 3 , -OCHF 2 , -OCF 3 , -C(O)OH, -C(O)OCH 3 , -C(O)NH 2 , -C(O)NH(CH 3 ), -C(O)N(CH 3 ) 2 , -N(CH 3 ) 2 , -NHC(O)CH 3 , -NHC(O)CH 2 CH 3 , -NHC(O)CH(CH 3 )2 ,-NHC(O)CH 2 CH 2 CH 2 CH 3 ,-NHC(O)C(CH 3 ) 2 OH,-NHC(O)NH(CH 3 )、-NO 2 ,-S(O) 2 CH 3 ,-S(O) 2 NH 2 ,-NHS(O) 2 CH 3 or -N(CH 3 )S(O) 2 CH 3 . Also included in this embodiment are compounds wherein each R 1a is independently F, Cl, -CN, -CH 3 , -CF 3 , -OCH 3 , -OCHF 2 , -OCF 3 , -C(O)NH 2 , -C(O)NH(CH 3 ), -C(O)N(CH 3 ) 2 , -N(CH 3 ) 2 , -NHC(O)CH 3 , -NHC(O)CH 2 CH 3 , -NHC(O)CH(CH 3 ) 2 , -NHC(O)CH 2 CH 2 CH 2 CH 3 , -NHC(O)C(CH 3 ) 2 OH, -NHC(O)NH(CH 3 ), -NO 2 , -S(O) 2 CH 3 , -S(O) 2 NH 2 , -NHS(O) 2 CH 3 or -N(CH 3 )S(O) 2 CH 3 .

[0046] In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein R 2 is C 1-4 alkyl or C 1-4 hydroxyalkyl. Compounds are included in this embodiment wherein R 2 is C 1-4 alkyl. Compounds are also included in this embodiment wherein R 2 is C 1-4 hydroxyalkyl.

[0047] In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein R 2 is hydrogen.

[0048] In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein R 2 is hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH or -CH 2 C(CH 3 ) 2 OH. Compounds are also included in this embodiment wherein R 2 is hydrogen or -CH 3 .

[0049] In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein L is a bond.

[0050] In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein L is -NH-.

[0051] In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein R 3 is phenyl substituted with R 3a .

[0052] In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein R 3 is piperidinyl substituted with R 3a .

[0053] In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein R 3a is -CH3 。

[0054] In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein R 3a is a cyclic group selected from piperidinyl and piperazinyl, wherein said cyclic group is optionally substituted with 0 or 1 R 3b substituent.

[0055] In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein R 3a is piperidinyl optionally substituted with 0 or 1 R 3b substituent. Compounds are included in this embodiment wherein R 3a is piperidinyl substituted with 0 R 3b substituents. Compounds are also included in this embodiment wherein R 3a is piperidinyl substituted with R 3b substituent.

[0056] In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein R 3a is piperazinyl optionally substituted with 0 or 1 R 3b substituent. Compounds are also included in this embodiment wherein R 3a is piperazinyl substituted with 0 R 3b substituents. Compounds are also included in this embodiment wherein R 3a is piperazinyl substituted with R 3b substituent.

[0057] In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein R 3a is piperidinyl or piperazinyl, each substituted with R 3b substituent; and R 3b is -CH 3 -, -CH(CH 3 ) 3 or oxetanyl. Compounds are also included in this embodiment wherein R 3a is piperidinyl or piperazinyl, each substituted with R 3b substituent; and R 3b is -CH(CH 3 ) 3 or oxetanyl.

[0058] In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein R 3a is piperidinyl substituted with R 3b substituent; and R 3b is -CH(CH 3 ) 3 or oxetanyl. Compounds are also included in this embodiment wherein R 3a is piperidinyl substituted with R 3bSubstituted piperidinyl; and R 3b is -CH(CH 3 ) 3 .

[0059] In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein R 3a is a piperazinyl substituted with R 3b ; and R 3b is -CH(CH 3 ) 3 or oxetanyl. Also included in this embodiment are compounds wherein R 3a is a piperazinyl substituted with R 3b ; and R 3b is -CH(CH 3 ) 3 .

[0060] In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein R 3 is:

[0061]

[0062] In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein R 3 is:

[0063]

[0064] In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein R 3 is a piperidinyl substituted with R 3a ; and R 3a is -CH 3 .

[0065] In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein R 4 is hydrogen or -CH 2 CH 3 .

[0066] In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein R 4 is hydrogen.

[0067] In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein R 1 is a phenyl substituted with 0 to 5 R 1a ; each R 1a is independently F, Cl, -CN, -OH, -CH 3 , -CF 3 , -OCH 3 , -OCHF 2, -OCF 3 , -C(O)OH, -C(O)OCH 3 , -C(O)NH 2 , -C(O)NH(CH 3 ), -C(O)N(CH 3 ) 2 , -N(CH 3 ) 2 , -NHC(O)CH 3 , -NHC(O)CH 2 CH 3 , -NHC(O)CH(CH 3 ) 2 , -NHC(O)CH 2 CH 2 CH 2 CH 3 , -NHC(O)C(CH 3 ) 2 OH, -NHC(O)NH(CH 3 ), -NO 2 , -S(O) 2 CH 3 , -S(O) 2 NH 2 , -NHS(O) 2 CH 3 , -N(CH 3 )S(O) 2 CH 3 , -NHC(O)(pyridyl), -C(O)N(CH 3 )(oxetanyl), -N(CH 3 )(methylazetidinyl), -C(O)(morpholinyl), -C(O)(dimethylpyrrolidinyl), fluoropyrrolidinyl, hydroxypyrrolidinyl, pyrrolidinone, imidazolone or tetrazolyl; R 2 is hydrogen; L is a bond; R 3 is phenyl substituted by R 3a ; R 3a is a cyclic group selected from piperidinyl and piperazinyl, wherein the cyclic group is substituted by 0 or 1 R 3b ; R 3b is -CH(CH 3 ) 3 ; and R 4 is hydrogen.

[0068] One embodiment provides a compound of formula (I) or a salt thereof, wherein the compound is: 6-(4-(4-Isopropylpiperazin-1-yl)phenyl)-1-methyl-3-(4-nitrophenyl)quinolin-2(1H)-one (1); 3-(4-Hydroxyphenyl)-6-(4-(4-isopropylpiperazin-1-yl)phenyl)quinolin-2(1H)-one (2); 6-((4-(4-Isopropylpiperazin-1-yl)phenyl)amino)-1-methyl-3-(4-(methylsulfonyl)phenyl)quinolin-2(1H)-one (3); 3-(4-Methanesulfonylphenyl)-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (4); N-[4-(2-Oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)phenyl]acetamide (5); 6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-3-(pyridin-2-yl)-1,2-dihydroquinolin-2-one (6); 3-(4-(1H-Tetrazol-1-yl)phenyl)-6-(4-(4-isopropylpiperazin-1-yl)phenyl)quinolin-2(1H)-one (7); N-[3-(2-Oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)phenyl]methanesulfonamide (8); 3-[4-(Dimethylamino)phenyl]-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (9); 6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-3-(2,4,5-trifluorophenyl)-1,2-dihydroquinolin-2-one (10); 4-(2-Oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)benzene-1-sulfonamide (11); 4-(2-Oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)benzonitrile (12); N-Methyl-N-(oxetan-3-yl)-4-(2-oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)benzamide (13); 3-[4-(2-Oxoimidazolidin-1-yl)phenyl]-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (14); 2-(2-Oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)benzonitrile (15); N-[4-(2-Oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)phenyl]methanesulfonamide (16);6-{4-[4-(Propan-2-yl)piperazin-1-yl]phenyl}-3-(pyridin-4-yl)-1,2-dihydroquinolin-2-one (17); 3-phenyl-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (18); 3-[4-(2,2-dimethylpyrrolidine-1-carbonyl)phenyl]-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (19); 3-(2,5-difluorophenyl)-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (20); N-[4-(2-oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)phenyl]butanamide (21); 3-{4-[(3S)-3-fluoropyrrolidin-1-yl]phenyl}-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (22); N-methyl-N-[4-(1-methyl-2-oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)phenyl]methanesulfonamide (23); 3-(2,3-difluorophenyl)-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (24); 3-(2-methylphenyl)-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (25); 2-methyl-N-[4-(1-methyl-2-oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)phenyl]propanamide (26); 3-(4-methanesulfonylphenyl)-1-methyl-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (27); Methyl 4-(2-oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)benzoate (28); N-[2-(2-oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)phenyl]methanesulfonamide (29); 3-(3-methoxyphenyl)-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (30); 3-(4-fluorophenyl)-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (31); 6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-3-(pyridin-3-yl)-1,2-dihydroquinolin-2-one (32);6-{4-[4-(Propan-2-yl)piperazin-1-yl]phenyl}-3-[2-(trifluoromethyl)phenyl]-1,2-dihydroquinolin-2-one (33); 6-{4-[4-(Propan-2-yl)piperazin-1-yl]phenyl}-3-(pyrimidin-5-yl)-1,2-dihydroquinolin-2-one (34); 3-(1-Methyl-1H-indazol-3-yl)-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (35); 3-[4-(Difluoromethoxy)phenyl]-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (36); 3-(2,6-Dichlorophenyl)-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (37); 3-(2,4-Dichlorophenyl)-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (38); 3-(4-Chlorophenyl)-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (39); 3-(2,3,4,5,6-Pentafluorophenyl)-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (40); 6-{4-[4-(Propan-2-yl)piperazin-1-yl]phenyl}-3-(2,4,6-trifluorophenyl)-1,2-dihydroquinolin-2-one (41); 3-(2-Fluorophenyl)-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (42); 3-(3,4-Dimethoxyphenyl)-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (43); 3-(2-Chlorophenyl)-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (44); 6-{4-[4-(Propan-2-yl)piperazin-1-yl]phenyl}-3-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinolin-2-one (45); 6-{4-[4-(Propan-2-yl)piperazin-1-yl]phenyl}-3-[3-(trifluoromethoxy)phenyl]-1,2-dihydroquinolin-2-one (46); 3-(3-Fluorophenyl)-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (47); 3-(1-Methyl-1H-indol-3-yl)-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (48); 3-Methyl-1-[4-(2-oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)phenyl]urea (49);N-[4-(1-Methyl-2-oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)phenyl]pyridine-2-carboxamide (50); 3-{4-[Methyl(1-methylazetidin-3-yl)amino]phenyl}-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (51); N-[4-(2-Oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)phenyl]propanamide (52); 4-(2-Oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)benzamide (53); N-Methyl-4-(2-oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)benzamide (54); 3-[4-(Morpholine-4-carbonyl)phenyl]-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (55); 3-[4-(2-Oxopyrrolidin-1-yl)phenyl]-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (56); N-[4-(1-Methyl-2-oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)phenyl]acetamide (57); 1-Methyl-3-phenyl-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (58); 2-Hydroxy-2-methyl-N-[4-(1-methyl-2-oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)phenyl]propanamide (59); N,N-Dimethyl-4-(2-oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)benzamide (60); 3-{4-[(3R)-3-Hydroxypyrrolidin-1-yl]phenyl}-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (61); 4-(2-Oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)benzoic acid (62); 3-(3,4-Dimethoxyphenyl)-4-ethyl-6-[1'-(propan-2-yl)-[1,4'-bipiperidin]-4-yl]-1,2-dihydroquinolin-2-one (63); 3-Phenyl-6-[1'-(propan-2-yl)-[1,4'-bipiperidin]-4-yl]-1,2-dihydroquinolin-2-one (64);4-(2-Oxo-6-{4-[1-(propan-2-yl)piperidin-4-yl]phenyl}-1,2-dihydroquinolin-3-yl)benzene-1-sulfonamide (65); 4-Ethyl-3-(4-methanesulfonylphenyl)-6-[1'-(propan-2-yl)-[1,4'-bipiperidin]-4-yl]-1,2-dihydroquinolin-2-one (66); N-[3-(2-Oxo-6-{4-[1-(propan-2-yl)piperidin-4-yl]phenyl}-1,2-dihydroquinolin-3-yl)phenyl]methanesulfonamide (67); 3-(4-Methanesulfonylphenyl)-1-methyl-6-{4-[1-(propan-2-yl)piperidin-4-yl]phenyl}-1,2-dihydroquinolin-2-one (68); 3-(2-Oxo-6-{4-[1-(propan-2-yl)piperidin-4-yl]phenyl}-1,2-dihydroquinolin-3-yl)benzonitrile (69); N-(4-{6-[4-(1-Methylpiperidin-4-yl)phenyl]-2-oxo-1,2-dihydroquinolin-3-yl}phenyl)methanesulfonamide (70); 3-(4-Methanesulfonylphenyl)-6-{4-[1-(propan-2-yl)piperidin-4-yl]phenyl}-1,2-dihydroquinolin-2-one (71); 1-(2-Hydroxyethyl)-3-(4-methanesulfonylphenyl)-6-{4-[1-(propan-2-yl)piperidin-4-yl]phenyl}-1,2-dihydroquinolin-2-one (72); 1-Methyl-3-phenyl-6-{4-[1-(propan-2-yl)piperidin-4-yl]phenyl}-1,2-dihydroquinolin-2-one (73); N-Methyl-N-[4-(1-methyl-2-oxo-6-{4-[1-(propan-2-yl)piperidin-4-yl]phenyl}-1,2-dihydroquinolin-3-yl)phenyl]methanesulfonamide (74); 3-(4-Methanesulfonylphenyl)-1-methyl-6-({4-[1-(propan-2-yl)piperidin-4-yl]phenyl}amino)-1,2-dihydroquinolin-2-one (75); 3-(4-Methanesulfonylphenyl)-6-[4-(1-methylpiperidin-4-yl)phenyl]-1,2-dihydroquinolin-2-one (76); 4-Ethyl-3-(4-methanesulfonylphenyl)-1-methyl-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (77); 3-(4-Methanesulfonylphenyl)-1-methyl-6-[4-(1-methylpiperidin-4-yl)phenyl]-1,2-dihydroquinolin-2-one (78); 1-Ethyl-3-(4-methanesulfonylphenyl)-6-{4-[1-(propan-2-yl)piperidin-4-yl]phenyl}-1,2-dihydroquinolin-2-one (79); 3-(4-Methanesulfonylphenyl)-6-{4-[1-(propan-2-yl)piperidin-4-yl]phenyl}-1-propyl-1,2-dihydroquinolin-2-one (80);N-[4-(2-oxo-6-{4-[1-(propan-2-yl)piperidin-4-yl]phenyl}-1,2-dihydroquinolin-3-yl)phenyl]acetamide (81); 1-(3-hydroxypropyl)-3-(4-methanesulfonylphenyl)-6-{4-[1-(propan-2-yl)piperidin-4-yl]phenyl}-1,2-dihydroquinolin-2-one (82); N-[4-(2-oxo-6-{4-[1-(propan-2-yl)piperidin-4-yl]phenyl}-1,2-dihydroquinolin-3-yl)phenyl]methanesulfonamide (83); 4-ethyl-3-(4-methanesulfonylphenyl)-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (84); 3-(4-methanesulfonylphenyl)-1-(2-methylpropyl)-6-{4-[1-(propan-2-yl)piperidin-4-yl]phenyl}-1,2-dihydroquinolin-2-one (85); 4-ethyl-3-(4-methanesulfonylphenyl)-1-methyl-6-{4-[1-(propan-2-yl)piperidin-4-yl]phenyl}-1,2-dihydroquinolin-2-one (86); 3-(4-methanesulfonylphenyl)-1-methyl-6-{4-[1-(oxetan-3-yl)piperidin-4-yl]phenyl}-1,2-dihydroquinolin-2-one (87); 3-[4-(dimethylamino)phenyl]-6-{4-[1-(propan-2-yl)piperidin-4-yl]phenyl}-1,2-dihydroquinolin-2-one (88); 1-(2-hydroxy-2-methylpropyl)-3-(4-methanesulfonylphenyl)-6-{4-[1-(propan-2-yl)piperidin-4-yl]phenyl}-1,2-dihydroquinolin-2-one (89); 3-(4-methanesulfonylphenyl)-6-({4-[4-(propan-2-yl)piperazin-1-yl]phenyl}amino)-1,2-dihydroquinolin-2-one (90); 3-[4-(difluoromethoxy)phenyl]-6-{4-[1-(oxetan-3-yl)piperidin-4-yl]phenyl}-1,2-dihydroquinolin-2-one (91); 4-(6-{4-[1-(oxetan-3-yl)piperidin-4-yl]phenyl}-2-oxo-1,2-dihydroquinolin-3-yl)benzene-1-sulfonamide (92); 6-{4-[1-(propan-2-yl)piperidin-4-yl]phenyl}-3-(quinoxalin-6-yl)-1,2-dihydroquinolin-2-one (93); 6-{4-[1-(oxetan-3-yl)piperidin-4-yl]phenyl}-3-(quinoxalin-6-yl)-1,2-dihydroquinolin-2-one (94); 3-(3,4-dimethoxyphenyl)-4-ethyl-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (95);3-[4-(Dimethylamino)phenyl]-1-methyl-6-{4-[1-(propan-2-yl)piperidin-4-yl]phenyl}-1,2-dihydroquinolin-2-one (96); 3-(4-Methanesulfonylphenyl)-6-(1-methylpiperidin-4-yl)-1,2-dihydroquinolin-2-one (97); N-[3-(6-{4-[1-(oxetan-3-yl)piperidin-4-yl]phenyl}-2-oxo-1,2-dihydroquinolin-3-yl)phenyl]methanesulfonamide (98); 3-(6-{4-[1-(oxetan-3-yl)piperidin-4-yl]phenyl}-2-oxo-1,2-dihydroquinolin-3-yl)benzonitrile (99); 1-methyl-6-{4-[1-(oxetan-3-yl)piperidin-4-yl]phenyl}-3-phenyl-1,2-dihydroquinolin-2-one (100); or 4-ethyl-3-(4-methanesulfonylphenyl)-1-methyl-6-{4-[1-(oxetan-3-yl)piperidin-4-yl]phenyl}-1,2-dihydroquinolin-2-one (101);

[0069] One embodiment provides a compound of formula (I) having a TLR9 IC 50 value ≤ 0.6 μM.

[0070] One embodiment provides a compound of formula (I) having a TLR9 IC 50 value ≤ 0.1 μM.

[0071] One embodiment provides a compound of formula (I) having a TLR9 IC 50 value ≤ 0.05 μM.

[0072] One embodiment provides a compound of formula (I) having a TLR9 IC 50 value ≤ 0.025 μM.

[0073] One embodiment provides a compound of formula (I) having a TLR9 IC 50 value ≤ 0.015 μM.

[0074] One embodiment provides a compound of formula (I) having a TLR9 IC 50 value ≤ 0.01 μM.

[0075] In another embodiment, the present invention provides a composition comprising at least one compound of the present invention or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0076] In another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound of the present invention or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0077] In another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof.

[0078] In another embodiment, the present invention provides a method for preparing a compound of the present invention.

[0079] In another embodiment, the present invention provides an intermediate for preparing a compound of the present invention.

[0080] In another embodiment, the present invention provides a pharmaceutical composition as defined above further comprising one or more additional therapeutic agents.

[0081] Definitions

[0082] The features and advantages of the present invention can be more readily understood by those of ordinary skill in the art after reading the following detailed description. It should be understood that, for clarity purposes, certain features of the present invention described above and below in the context of separate embodiments may be combined to form a single embodiment. Conversely, for the sake of brevity, the various features of the present invention described in the context of a single embodiment may be combined to form sub-combinations thereof. The embodiments identified herein as exemplary or preferably are intended to be illustrative and not limiting.

[0083] Unless expressly stated otherwise herein, references made in the singular may also include the plural. For example, "a" and "an" may refer to one, or one or more.

[0084] As used herein, the phrase "compound" refers to at least one compound. For example, a compound of formula (I) includes a compound of formula (I) and two or more compounds of formula (I).

[0085] Unless otherwise specified, any heteroatom presumed to have an unsatisfied valence has hydrogen atoms sufficient to satisfy the valence.

[0086] The definitions set forth herein supersede any definitions set forth in any patent, patent application, and / or patent application publication incorporated herein by reference.

[0087] The following are definitions of various terms used to describe the present invention. These definitions apply to the terms when used throughout the specification, either alone or as part of a larger group (unless the term is otherwise limited in a particular instance).

[0088] Throughout the specification, those of skill in the art can select groups and their substituents to provide stable moieties and compounds.

[0089] In accordance with the conventions used in the art, in the structural formulas herein,

[0090]

[0091] are used to describe the bonds that serve as the attachment points of parts or substituents to the core or backbone structure.

[0092] As used herein, the terms "halo" and "halogen" refer to F, Cl, Br, and I.

[0093] The term "cyano" refers to the group –CN.

[0094] The term "amino" refers to the group -NH 2 .

[0095] The term "oxo" refers to the group =O.

[0096] As used herein, the term "alkyl" refers to branched and straight-chain saturated aliphatic hydrocarbon groups containing, for example, 1 to 12 carbon atoms, 1 to 6 carbon atoms, and 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, sec-butyl, and tert-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl. When a number appears as a subscript after the symbol "C", the subscript more specifically defines the number of carbon atoms that a particular group may contain. For example, "C 1-6 alkyl" represents a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms.

[0097] As used herein, the term "fluoroalkyl" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups substituted with one or more fluorine atoms. For example, "C 1-4 fluoroalkyl" is intended to include C 1 , C 2 , C 3 , and C 4 alkyl groups substituted with one or more fluorine atoms. Representative examples of fluoroalkyl groups include, but are not limited to, -CF 3 and -CH 2 CF 3 .

[0098] The term "hydroxyalkyl" includes branched and straight-chain saturated alkyl groups substituted with one or more hydroxy groups. For example, "hydroxyalkyl" includes -CH 2 OH, -CH 2 CH 2 OH, and C 1-4 hydroxyalkyl.

[0099] As used herein, the term "alkoxy" refers to an alkyl group attached to a parent molecular moiety through an oxygen atom, e.g., a methoxy group (-OCH 3 ). For example, "C 1-3 alkoxy" represents an alkoxy group having 1 to 3 carbon atoms.

[0100] The terms "fluoroalkoxy" and "-O(fluoroalkyl)" represent a fluoroalkyl group as defined above attached through an oxygen bond (-O-). For example, "C 1-4 fluoroalkyl" is intended to include C 1 , C 2 , C 3 and C 4 fluoroalkoxy groups.

[0101] As used herein, the term "cycloalkyl" refers to a group derived from a monocyclic or polycyclic hydrocarbon molecule by removing a hydrogen atom from a saturated ring carbon atom. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl. When a number appears as a subscript after the symbol "C", the subscript more specifically defines the number of carbon atoms that a particular cycloalkyl may contain. For example, "C 3-6 cycloalkyl" represents a cycloalkyl group having 3 to 6 carbon atoms.

[0102] The phrase "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0103] The compounds of formula (I) can be provided as an amorphous solid or a crystalline solid. Lyophilization can be used to provide the compounds of formula (I) as an amorphous solid.

[0104] It should be further understood that solvates (e.g., hydrates) of the compounds of formula (I) are also within the scope of the present invention. The term "solvate" means a physical association of a compound of formula (I) with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In some cases, the solvate will be capable of separation, e.g., when one or more solvent molecules are incorporated into the lattice of a crystalline solid. "Solvate" encompasses both the solution phase and separable solvates. Exemplary solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates, and ethyl acetate solvates. Solvation methods are known in the art.

[0105] Various forms of prodrugs are well known in the art and are described in Rautio, J. et al., Nature Review Drug Discovery, 17, 559 - 587 (2018).

[0106] In addition, the compounds of formula (I) can be separated and purified after their preparation to obtain compositions containing the compound of formula (I) in an amount equal to or greater than 99% by weight ("substantially pure"), respectively, and then used or formulated as described herein. These "substantially pure" compounds of formula (I) are also covered herein as part of the present invention.

[0107] "Stable compound" and "stable structure" mean a compound that is stable enough to withstand isolation to a useful degree of purity from a reaction mixture and formulated into an effective therapeutic agent. The present invention is intended to embody stable compounds.

[0108] "Therapeutically effective amount" is intended to include the amount of the compounds of the present invention alone or in combination with other active ingredients that are effective as TLR9 inhibitors or effective in treating or preventing conditions associated with fibrotic diseases or disorders, bile acid disorders (such as pathological fibrosis), of the claimed compound or the compounds of the present invention.

[0109] As used herein, "treating" or "treatment" covers treating a disease state in a mammal (particularly a human), and includes: (a) preventing the disease state from occurring in a mammal, particularly when the mammal is predisposed to the disease state but has not been diagnosed as having the disease state; (b) inhibiting the disease state, i.e., preventing its development; and / or (c) alleviating the disease state, i.e., causing regression of the disease state.

[0110] The compounds of the present invention are intended to include all isotopes of the atoms present in the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include deuterium (D) and tritium (T). Isotopes of carbon include 13 C and 14 C. Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described herein, using appropriate isotopically labeled reagents in place of the non-labeled reagents originally used. For example, a methyl group (-CH 3 ) also includes deuterated methyl groups such as -CD 3 .

[0111] Utility

[0112] The compounds of the present invention can be used to inhibit the TLR9 receptor.

[0113] One embodiment provides a method for treating a disease, disorder or condition associated with a bile acid disorder in a patient in need thereof, and the method comprises administering to the patient a therapeutically effective amount of a compound of the invention or a stereoisomer, tautomer or pharmaceutically acceptable salt or solvate thereof.

[0114] One embodiment provides a method for treating a disease, disorder or condition associated with TLR9 receptor activity in a patient in need thereof, and the method comprises administering to the patient a therapeutically effective amount of a compound of the invention or a stereoisomer, tautomer or pharmaceutically acceptable salt or solvate thereof.

[0115] One embodiment provides a method for treating a disease, disorder or condition, which comprises administering to a patient in need thereof a therapeutically effective amount of at least one compound of the invention alone or optionally in combination with another compound of the invention and / or at least one other type of therapeutic agent.

[0116] One embodiment provides a method for inducing a TLR9 receptor antagonistic effect in a patient, which comprises administering to the patient a therapeutically effective amount of a compound of the invention or a stereoisomer, tautomer or pharmaceutically acceptable salt or solvate thereof.

[0117] In some embodiments, the diseases, disorders or conditions associated with TLR9 dysfunction include pathological fibrosis, cancer, inflammatory disorders, metabolic or cholestatic disorders.

[0118] In some embodiments, the disease, disorder or condition is associated with fibrosis, which includes liver fibrosis, biliary fibrosis, renal fibrosis, cardiac fibrosis, skin fibrosis, ocular fibrosis and pancreatic fibrosis.

[0119] In other embodiments, the disease, disorder or condition is associated with a cell proliferative disorder (such as cancer). In some embodiments, the cancer includes solid tumor growth or neoplasm formation. In other embodiments, the cancer includes tumor metastasis. In some embodiments, the cancer is liver cancer, gallbladder cancer, small intestine cancer, colorectal cancer, kidney cancer, prostate cancer, bladder cancer, blood cancer, bone cancer, brain cancer, breast cancer, central nervous system cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, genital cancer, urogenital cancer, head cancer, laryngeal cancer, lung cancer, muscle tissue cancer, cervical cancer, oral or nasal mucosa cancer, ovarian cancer, pancreatic cancer, skin cancer, spleen cancer, stomach cancer, testicular cancer or thyroid cancer. In other embodiments, the cancer is carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma or seminoma.

[0120] Examples of diseases, disorders or conditions related to TLR9 activity that can be prevented, modulated or treated according to the present invention include, but are not limited to, transplantation injection, fibrotic disorders (e.g., liver fibrosis, renal fibrosis), inflammatory disorders (e.g., acute hepatitis, chronic hepatitis, non-alcoholic steatohepatitis (NASH), irritable bowel syndrome (IBS), inflammatory bowel disease (IBD)), and cell proliferative disorders (e.g., cancer, myeloma, fibroma, hepatocellular carcinoma, colorectal cancer, prostate cancer, leukemia, Kaposi's sarcoma, solid tumors).

[0121] Fibrotic disorders suitable for prevention or treatment by the compounds of the present invention include, but are not limited to, non-alcoholic fatty liver disease (NAFLD), alcoholic or non-alcoholic steatohepatitis (NASH), acute hepatitis, chronic hepatitis, cirrhosis, primary biliary sclerosis, primary sclerosing cholangitis, drug-induced hepatitis, biliary cirrhosis, portal hypertension, failure of regeneration, hypofunction of the liver, hepatic blood flow disorder, renal disease, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), abnormal pancreatic secretion, benign prostatic hyperplasia, neurogenic bladder disease, diabetic nephropathy, focal segmental glomerulosclerosis, IgA nephropathy, drug- or transplantation-induced nephropathy, autoimmune nephropathy, lupus nephritis, liver fibrosis, renal fibrosis, chronic kidney disease (CKD), diabetic kidney disease (DKD), skin fibrosis, keloid, systemic sclerosis, scleroderma, virus-induced fibrosis, idiopathic pulmonary fibrosis (IPF), interstitial lung disease, non-specific interstitial pneumonia (NSIP), usual interstitial pneumonia (UIP), radiation-induced fibrosis, familial pulmonary fibrosis, airway fibrosis, chronic obstructive pulmonary disease (COPD), myeloma, intervertebral disc herniation, spinal stenosis, heart failure, cardiac fibrosis, vascular fibrosis, perivascular fibrosis, foot-and-mouth disease, cancer, myeloma, fibroma, hepatocellular carcinoma, colorectal cancer, prostate cancer, leukemia, chronic lymphocytic leukemia, Kaposi's sarcoma, solid tumors, cerebral infarction, cerebral hemorrhage, neuropathic pain, peripheral neuropathy, age-related macular degeneration (AMD), glaucoma, ocular fibrosis, corneal scar, diabetic retinopathy, proliferative vitreoretinopathy (PVR), cicatricial pemphigoid, glaucoma filtration surgery scar, Crohn's disease or systemic lupus erythematosus; keloid formation resulting from abnormal wound healing; fibrosis occurring after organ transplantation, myelofibrosis and fibroma. In one embodiment, the present invention provides a method for treating a fibrotic disorder, an inflammatory disorder or a cell proliferative disorder, which comprises administering to a patient in need of such treatment a therapeutically effective amount of at least one compound of the present invention alone or optionally in combination with another compound of the present invention and / or at least one other type of therapeutic agent.

[0122] In another embodiment, the present invention provides the compositions of the present invention for use in therapy.

[0123] In another embodiment, the present invention provides the compositions of the present invention for use in therapy for treating fibrotic, inflammatory or cell proliferative disorders thereof.

[0124] In another embodiment, the present invention also provides the use of the compounds of the present invention for the preparation of a medicament for use in therapy for treating fibrotic, inflammatory or cell proliferative disorders thereof.

[0125] In another embodiment, the present invention provides a method for treating a fibrotic, inflammatory or cell proliferative disorder, which comprises administering to a patient in need thereof a therapeutically effective amount of a first and a second therapeutic agent, wherein the first therapeutic agent is a compound of the present invention.

[0126] In another embodiment, the present invention provides a combination preparation of a compound of the present invention and an additional therapeutic agent for use simultaneously, separately or sequentially in therapy.

[0127] In another embodiment, the present invention provides a combination preparation of a compound of the present invention and an additional therapeutic agent for use simultaneously, separately or sequentially in treating fibrotic, inflammatory or cell proliferative disorders.

[0128] The compounds of the present invention can be used in combination with additional therapeutic agents such as one or more anti-fibrotic and / or anti-inflammatory therapeutic agents.

[0129] In one embodiment, the additional therapeutic agent in the combined pharmaceutical composition or combined method or combined use is selected from one or more of the following therapeutic agents, preferably 1 to 3 kinds: TGFβ receptor inhibitor (e.g., galunisertib), TGFβ synthesis inhibitor (e.g., pirfenidone), vascular endothelial growth factor (VEGF) inhibitor, platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) receptor kinase (e.g., nintedanib), humanized anti-αvβ6 integrin monoclonal antibody (e.g., 3G9), human recombinant pentraxin-2, recombinant human serum amyloid P; recombinant human antibodies against TGFβ-1, -2 and -3, endothelin receptor antagonist (e.g., macitentan), interferon γ, c-Jun N-terminal kinase (JNK) inhibitor (e.g., 4-[[9-[(3S)-tetrahydro-3-furanyl]-8-[(2,4,6-trifluorophenyl)amino]-9H-purin-2-yl]amino]-trans-cyclohexanol), 3-pentylphenylacetic acid (PBI-4050), manganese(III)-containing tetrasubstituted porphyrin derivative, monoclonal antibody targeting eosinophil chemotactic factor-2 ((eotaxin)-2), interleukin-13 (IL-13) antibody (e.g., lebrikizumab, tralokinumab), bispecific antibody targeting interleukin 4 (IL-4) and interleukin 13 (IL-13), NK1 tachykinin receptor agonist (e.g., Sar 9 、Met(O 2 ) 11- Substance P), cintredekin besudotox, a human recombinant DNA-derived IgG1κ monoclonal antibody against connective tissue growth factor, and a fully human IgG1κ antibody selectively targeting CC-chemokine ligand 2 (e.g., carlumab, CCX140), antioxidants (e.g., N-acetylcysteine), phosphodiesterase 5 (PDE5) inhibitors (e.g., sildenafil), agents for treating obstructive airway diseases (such as muscarinic antagonists) (e.g., tiotropium, ipratropium bromide), adrenergic β2 agonists (e.g., salbutamol, salmeterol), corticosteroids (e.g., triamcinolone, dexamethasone, fluticasone), immunosuppressants (e.g., tacrolimus, rapamycin, pimecrolimus), and therapeutic agents that can be used to treat fibrotic conditions such as liver fibrosis, biliary fibrosis, and renal fibrosis, non-alcoholic fatty liver disease (NALFD), non-alcoholic steatohepatitis (NASH), cardiac fibrosis, idiopathic pulmonary fibrosis (IPF), and systemic sclerosis. Therapeutic agents that can be used to treat these fibrotic conditions include, but are not limited to, FXR agonists (e.g., OCA, GS-9674, and LJN452), LOXL2 inhibitors (e.g., simtuzumab), LPA1 antagonists (e.g., BMS-986020 and SAR 100842), PPAR modulators (e.g., elafibrinor, pioglitazone, and saroglitazar, IVA337), SSAO / VAP-1 inhibitors (e.g., PXS-4728A and SZE5302), ASK-1 inhibitors (e.g., GS-4997 or selonsertib), ACC inhibitors (e.g., CP-640186 and NDI-010976 or GS-0976), FGF21 analogs (e.g., LY2405319 and BMS-986036), caspase inhibitors (e.g., emricasan), NOX4 inhibitors (e.g., GKT137831), MGAT2 inhibitors (e.g., BMS-963272), αV integrin inhibitors (e.g., abituzumab), and bile acid / fatty acid conjugates (e.g., aramchol).The TLR9 inhibitors of various embodiments of the present invention can also be used in combination with one or more of the following therapeutic agents, such as: CCR2 / 5 inhibitors (e.g., cenicriviroc), galectin-3 inhibitors (e.g., TD-139, GR-MD-02), leukotriene receptor antagonists (e.g., tipelukast, montelukast), SGLT2 inhibitors (e.g., dapagliflozin, remogliflozin), GLP-1 receptor agonists (e.g., liraglutide and semaglutide), FAK inhibitors (e.g., GSK-2256098), CB1 inverse agonists (e.g., JD-5037), CB2 agonists (e.g., APD-371 and JBT-101), autotaxin inhibitors (e.g., GLPG1690), prolyl-tRNA synthetase inhibitors (e.g., halofugenone), FPR2 agonists (e.g., ZK-994), and THR agonists (e.g., MGL:3196). In another embodiment, the additional therapeutic agents for the combined pharmaceutical composition or combined method or combined use are selected from one or more of immuno-oncology agents (such as Alemtuzumab, Atezolizumab, Ipilimumab, Nivolumab, Ofatumumab, Pembrolizumab, and Rituximab), preferably 1 to 3 kinds.

[0130] As used herein, the terms "TLR9-related condition" or "TLR9-related disease or disorder" each are intended to encompass all of the conditions listed above (as if recited continuously), as well as any other condition affected by TLR9 inhibition.

[0131] When used in combination with the compounds of the present invention, the above other therapeutic agents can be used in amounts such as those in the Physicians' Desk Reference (PDR) or otherwise determined by those skilled in the art. In the methods of the present invention, these other therapeutic agents can be administered before, simultaneously with, or after the administration of the compounds of the present invention. The present invention also provides a pharmaceutical composition capable of treating TLR9-related conditions.

[0132] The composition of the present invention may contain other therapeutic agents as described above and may be formulated according to techniques well known in the art of pharmaceutical formulations, for example, by using conventional solid or liquid vehicles or diluents and pharmaceutical adjuvants of the type suitable for the desired mode of administration (e.g., excipients, binders, preservatives, stabilizers, flavoring agents, etc.).

[0133] Accordingly, the present invention further includes a composition comprising one or more compounds of formula (I) and a pharmaceutically acceptable carrier.

[0134] "Pharmaceutically acceptable carrier" refers to a medium generally acceptable in the art for delivering an active agent to an animal. Pharmaceutically acceptable carriers are formulated according to a variety of factors within the understanding of one of ordinary skill in the art. These include, but are not limited to, the type and nature of the active agent being formulated; the subject to whom the agent-containing composition will be administered; the intended route of administration of the composition; and the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. In addition to the active agent, these carriers may include a large number of different ingredients and adjuvants, which are included in the formulation for a variety of reasons well known to one of ordinary skill in the art (e.g., stabilization of the active agent, binder, etc.). Descriptions of suitable pharmaceutically acceptable carriers and the factors involved in their selection are common in a variety of readily available resources, such as, for example, Remington's Pharmaceutical Sciences, 17th Edition (1985), which is incorporated herein by reference in its entirety.

[0135] The compounds according to formula (I) can be administered by any means suitable for the condition to be treated, which may depend on the requirements of site-specific therapy or the amount of the compound of formula (I) to be delivered.

[0136] Also included within the present invention is a class of pharmaceutical compositions comprising a compound of formula (I) and one or more pharmaceutically acceptable carriers and / or diluents and / or adjuvants (collectively referred to herein as "carrier" materials) and, if desired, other active agents. The compound of formula (I) can be administered by any suitable route, preferably in the form of a pharmaceutical composition suitable for that route, and in an amount effective for the intended treatment. The compounds and compositions of the present invention can be administered, for example, orally, transmucosally or parenterally (including intravascular, intravenous, intraperitoneal, subcutaneous, intramuscular and intrasternal) in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants and vehicles. For example, the pharmaceutical carrier can contain a mixture of mannitol or lactose and microcrystalline cellulose. The mixture can contain additional ingredients such as a lubricant (e.g., magnesium stearate) and a disintegrant (e.g., crospovidone). The carrier mixture can be filled into gelatin capsules or compressed into tablets. For example, the pharmaceutical composition can be administered in an oral dosage form or as an infusion fluid.

[0137] For oral administration, the pharmaceutical composition may be in the form of, for example, tablets, capsules, liquid capsules, suspensions or liquids. The pharmaceutical composition is preferably provided in the form of dosage units containing a specific amount of the active ingredient. For example, the pharmaceutical composition may be provided as tablets or capsules containing an amount of the active ingredient in the range of from about 0.1 to 1000 mg, preferably from 0.25 to 250 mg, and more preferably from 0.5 to 100 mg. The appropriate daily dosage for humans or other mammals may vary widely depending on the condition of the patient and other factors, but can be determined using conventional methods.

[0138] Any pharmaceutical composition covered herein may be orally delivered, for example, via any acceptable and suitable oral formulation. Exemplary oral formulations include, but are not limited to, for example, tablets, lozenges, troches, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups and elixirs. The pharmaceutical composition intended for oral administration may be prepared according to any method known in the art for preparing pharmaceutical compositions intended for oral administration. To provide a pharmaceutically palatable formulation, the pharmaceutical composition according to the invention may contain at least one reagent selected from sweetening agents, flavoring agents, coloring agents, analgesics, antioxidants and preservatives.

[0139] Tablets may be prepared, for example, by mixing at least one compound of formula (I) with at least one non-toxic pharmaceutically acceptable excipient suitable for the preparation of tablets. Exemplary excipients include, but are not limited to, for example, inert diluents such as, for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate and sodium phosphate; granulating and disintegrating agents such as, for example, microcrystalline cellulose, croscarmellose sodium, corn starch and alginic acid; binders such as, for example, starch, gelatin, polyvinylpyrrolidone and gum arabic; and lubricants such as, for example, magnesium stearate, stearic acid and talc. Additionally, the tablets may be uncoated or coated by known techniques to mask the unpleasant taste of the drug or to delay the disintegration and absorption of the active ingredient in the gastrointestinal tract, thereby prolonging the action of the active ingredient for a longer period. Exemplary water-soluble taste masking materials include, but are not limited to, hydroxypropylmethylcellulose and hydroxypropylcellulose. Exemplary time delay materials include, but are not limited to, ethylcellulose and cellulose acetate butyrate.

[0140] Hard gelatin capsules may be prepared, for example, by mixing at least one compound of formula (I) with at least one inert solid diluent such as, for example, calcium carbonate; calcium phosphate; and kaolin.

[0141] Soft gelatin capsules may be prepared, for example, by mixing at least one compound of formula (I) with at least one water-soluble carrier such as, for example, polyethylene glycol; and at least one oil-soluble medium such as, for example, peanut oil, liquid paraffin and olive oil.

[0142] An aqueous suspension can be prepared, for example, by mixing at least one compound of formula (I) with at least one excipient suitable for preparing an aqueous suspension. Exemplary excipients suitable for preparing an aqueous suspension include, but are not limited to, for example, suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, alginic acid, polyvinylpyrrolidone, gum tragacanth, and gum arabic; dispersing or wetting agents such as, for example, naturally occurring phospholipids such as, for example, lecithin; condensation products of alkylene oxides and fatty acids such as, for example, polyethylene glycol stearate; condensation products of ethylene oxide and long-chain aliphatic alcohols such as, for example, heptadecaethyleneoxycetanol; condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol such as, for example, polyoxyethylene sorbitan monooleate; and condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol anhydrides such as, for example, polyoxyethylene sorbitan monooleate. The aqueous suspension may also contain at least one preservative such as, for example, ethyl p-hydroxybenzoate and n-propyl p-hydroxybenzoate; at least one colorant; at least one flavoring agent; and / or at least one sweetening agent, including but not limited to, for example, sucrose, saccharin, and aspartame.

[0143] An oily suspension can be prepared, for example, by suspending at least one compound of formula (I) in a vegetable oil such as, for example, peanut oil, olive oil, sesame oil, and coconut oil, or a mineral oil such as, for example, liquid paraffin. The oily suspension may also contain at least one thickening agent such as, for example, beeswax, paraffin wax, and cetyl alcohol. To provide a palatable oily suspension, at least one of the sweetening agents described above and / or at least one flavoring agent can be added to the oily suspension. The oily suspension may further contain at least one preservative, including but not limited to, for example, antioxidants such as, for example, butylated hydroxyanisole and α-tocopherol.

[0144] Dispersible powders and granules can be prepared, for example, by mixing at least one compound of formula (I) with at least one dispersing agent and / or wetting agent; at least one suspending agent; and / or at least one preservative. Suitable dispersing agents, wetting agents, and suspending agents have been described above. Exemplary preservatives include but are not limited to, for example, antioxidants such as, for example, ascorbic acid. In addition, the dispersible powders and granules may also contain at least one excipient, including but not limited to sweetening agents; flavoring agents; and colorants.

[0145] An emulsion of at least one compound of formula (I) can be prepared, for example, as an oil-in-water emulsion. The oil phase of the emulsion comprising the compound of formula (I) can be composed of known components in a known manner. The oil phase can be provided by, but is not limited to, for example, vegetable oils (such as, for example, olive oil and peanut oil); mineral oils (such as, for example, liquid paraffin); and mixtures thereof. Although the phase can contain only an emulsifier, it can contain at least one emulsifier and a mixture of fat or oil or both fat and oil. Suitable emulsifiers include, but are not limited to, naturally occurring phospholipids, such as, for example, soy lecithin; esters or partial esters derived from fatty acids and sorbitan anhydrides, such as, for example, sorbitan monooleate; and condensation products of partial esters and ethylene oxide, such as, for example, polyoxyethylene sorbitan monooleate. Preferably, it contains a hydrophilic emulsifier and a lipophilic emulsifier acting as a stabilizer. It also preferably contains both oil and fat. Together, the emulsifier with or without a stabilizer forms the emulsifying wax, and the wax together with the oil and fat forms the emulsifying ointment base, which forms the oily disperse phase of the cream formulation. The emulsion can also contain sweeteners, flavoring agents, preservatives, and / or antioxidants. Emulsifiers and emulsion stabilizers suitable for the formulations of the present invention include Tween 60, Span 80, cetearyl alcohol, myristyl alcohol, glyceryl monostearate, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate alone or in combination with waxes or other materials well known in the art.

[0146] The compound of formula (I) can also be delivered, for example, intravenously, subcutaneously, and / or intramuscularly via any pharmaceutically acceptable and suitably injectable form. Exemplary injectable forms include, but are not limited to, for example, sterile aqueous solutions containing acceptable vehicles and solvents (such as, for example, water, Ringer’s solution, and isotonic sodium chloride solution); sterile oil-in-water microemulsions; and aqueous or oily suspensions.

[0147] Emulsions for parenteral administration can be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions can be prepared from sterile powders or granules using one or more of the carriers or diluents mentioned for oral administration or by using other suitable dispersing or wetting agents and suspending agents. The compound can be dissolved in water, polyethylene glycol, glycerol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth, and / or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art. The active ingredient can also be administered by injection as a composition solubilized with a suitable carrier (including saline, dextrose, or water) or solubilized with cyclodextrin (i.e., Captisol), co-solvent (i.e., propylene glycol), or micellar solubilizer (i.e., Tween 80).

[0148] The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, a sterile fixed oil is conventionally used as a solvent or suspending medium. For this purpose, any mild fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectable preparations.

[0149] The sterile oil-in-water microemulsion may be prepared, for example, by: 1) dissolving at least one compound of formula (I) in an oil phase (such as, for example, a mixture of soybean oil and lecithin); 2) combining the oil phase containing the compound of formula (I) with a mixture of water and glycerol; and 3) treating the combination to form a microemulsion.

[0150] The sterile aqueous or oily suspension may be prepared by methods known in the art. For example, the sterile aqueous solution or suspension may be prepared with a non-toxic parenterally acceptable diluent or solvent (such as, for example, 1,3-butanediol); and the sterile oily suspension may be prepared with a sterile non-toxic acceptable solvent or suspending medium (such as, for example, a sterile fixed oil (e.g., synthetic mono- or diglycerides) and fatty acids (such as, for example, oleic acid)).

[0151] Pharmaceutically acceptable carriers, adjuvants, and vehicles that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) (such as d-α-tocopherol polyethylene glycol 1000 succinate), surfactants for pharmaceutical dosage forms (such as Tween, polyoxyethylene castor oil (such as CREMOPHOR surfactants (BASF)) or other similar compound delivery matrices), serum proteins (such as human serum albumin), buffering substances (such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids), water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polypropylene block polymers, polyethylene glycol, and lanolin. Cyclodextrins (such as α-, β-, and γ-cyclodextrins) or chemically modified derivatives (such as hydroxyalkyl cyclodextrins, including 2- and 3-hydroxypropyl-cyclodextrins) or other solubilizing derivatives may also be advantageously used to enhance the delivery of the compounds of the formulas described herein.

[0152] The pharmaceutically active compounds of the present invention can be processed according to conventional pharmaceutical methods to produce pharmaceutical agents for administration to patients (including humans and other mammals). The pharmaceutical compositions can be subjected to conventional pharmaceutical operations (such as sterilization and / or can contain conventional adjuvants (such as preservatives, stabilizers, wetting agents, emulsifying agents, buffering agents, etc.)). Tablets and pills can additionally be prepared with enteric coatings. The compositions can also contain adjuvants (such as wetting agents, sweeteners, flavoring agents, and perfuming agents).

[0153] The amount of the compound administered and the dosing regimen for treating a disease condition using the compounds and / or compositions of the present invention depend on various factors, including the age, weight, sex, medical condition, type of disease, severity of the disease, route and frequency of administration, and the specific compound used. Accordingly, the dosing regimen can vary widely but can be routinely determined using standard methods. A daily dose of about 0.001 to 100 mg / kg body weight, preferably between about 0.0025 and about 50 mg / kg body weight and most preferably between about 0.005 and 10 mg / kg body weight can be suitable. The daily dose can be administered in 1 to 4 doses per day. Other dosing schedules include one dose per week and one dose every two days.

[0154] For therapeutic purposes, the active compounds of the present invention are generally combined with one or more adjuvants suitable for the designated route of administration. For oral administration, the compound can be mixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, alkyl cellulose esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol, and then formed into tablets or encapsulated for convenient administration. The capsules or tablets can contain controlled release formulations, such as can be provided by a dispersion of the active compound in hydroxypropyl methylcellulose.

[0155] The pharmaceutical compositions of the present invention comprise at least one compound of formula (I) and optionally additional agents selected from any pharmaceutically acceptable carrier, adjuvant, and vehicle. Alternative compositions of the present invention comprise a compound of formula (I) or a prodrug thereof as described herein and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0156] The present invention also encompasses articles. As used herein, an article is intended to include, but is not limited to, kits and packages. The articles of the present invention include: (a) a first container; (b) a pharmaceutical composition located within the first container, wherein the composition comprises: a first therapeutic agent, which comprises: a compound of the present invention or a pharmaceutically acceptable salt form thereof; and (c) instructions stating that the pharmaceutical composition can be used for treating cardiovascular disorders, diuresis, and / or natriuresis. In another embodiment, the instructions state that the pharmaceutical composition can be used in combination with a second therapeutic agent (as previously defined) for treating cardiovascular disorders, diuresis, and / or natriuresis. The article may further include: (d) a second container, wherein components (a) and (b) are located within the second container and component (c) is located either within or outside the second container. Being located within the first and second containers means that the respective containers enclose the articles within their boundaries.

[0157] The first container is a container for holding the pharmaceutical composition. This container can be used for preparation, storage, transportation, and / or individual / bulk sales. The first container is intended to cover bottles, cans, vials, flasks, syringes, tubes (e.g., for cream formulations), or any other container used for preparing, containing, storing, or dispensing pharmaceutical products.

[0158] The second container is a container for holding the first container and optionally the instructions. Examples of the second container include, but are not limited to, boxes (e.g., cardboard or plastic), crates, cartons, bags (e.g., paper bags or plastic bags), pouches, and sacks. The instructions can be physically attached to the outside of the first container via tape, glue, staples, or another attachment method, or it can be placed inside the second container without any physical method of attachment to the first container. Alternatively, the instructions are located outside the second container. When located outside the second container, preferably the instructions are physically attached via tape, glue, staples, or another attachment method. Or, it can be adjacent to or touch the outside of the second container without physical attachment.

[0159] The instructions are a label strip, label, marker, or other written sheet that details information related to the pharmaceutical composition located within the first container. The detailed information will generally be determined by the regulatory agency in the field that regulates the sale of the article (e.g., the United States Food and Drug Administration). Preferably, the instructions specifically detail the indications for which the approved pharmaceutical composition is targeted. The instructions can be prepared from any material on which a person can read the information contained therein or thereon. Preferably, the instructions are a printable material (e.g., paper, plastic, cardboard, foil, adhesive backing paper, or plastic) on which the required information has been formed (e.g., printed or coated).

[0160] Preparation Method

[0161] The compounds of the present invention can be prepared by a variety of methods well known to those skilled in the art of organic synthesis. The compounds of the present application can be synthesized using the methods described below in combination with synthetic methods known in the art of organic synthesis or variants thereof as understood by those skilled in the art. Preferred methods include, but are not limited to, those described below.

[0162] The reactions and techniques described in this section are carried out in solvents suitable for the reagents and materials used and are suitable for the transformations being effected. Similarly, in the description of the synthetic methods described below, it should be understood that all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment, and work procedure, are standard conditions for the reactions, which should be readily recognizable by those skilled in the art. Those skilled in the art of organic synthesis should understand that the functionality present on the various parts of the molecule must be compatible with the proposed reagents and reactions. These limitations on substituents that are compatible with the reaction conditions will be obvious to those skilled in the art and then alternative methods must be used. To obtain the desired compounds of the present invention, this will sometimes require judgment to modify the order of the synthetic steps or to choose one particular method scheme over another. It should also be recognized that another major consideration in the planning of any synthetic route in the art is the judicious choice of protecting groups for the reactive functional groups present in the compounds described in the present invention. An authoritative account of the need for alternatives for the trained practitioner is Greene et al. (Protective Groups in Organic Synthesis, Third Edition, Wiley and Sons (1999)).

[0163] Examples

[0164] The compounds of the present invention and the intermediates for preparing the compounds of the present invention can be prepared using the procedures shown in the following examples and related procedures. The methods and conditions used in these examples, and the actual compounds prepared in these examples, are not meant to be limiting, but are meant to demonstrate how the compounds of the present invention can be prepared. When not prepared by the procedures described herein, the starting materials and reagents used in these examples are generally commercially available, or reported in the chemical literature, or can be prepared using the procedures described in the chemical literature. The present invention is further defined in the following examples. It should be understood that these examples are provided in an illustrative form only. From the above discussion and examples, those skilled in the art can determine the basic features of the present invention, and various changes and modifications can be made without departing from its spirit and scope to adapt the present invention to various uses and conditions. Therefore, the present invention is not limited by the illustrative examples listed hereinbelow, but is defined by the claims appended hereto.

[0165] In the provided embodiments, the phrase "dried and concentrated" generally refers to a solution in an organic solvent being dried over sodium sulfate or magnesium sulfate, then filtered and the solvent removed from the filtrate, typically under reduced pressure and at a temperature suitable for the stability of the material.

[0166] Compound names were determined using ChemDraw Professional, version 20.1.0.110 (PerkinElmer Informatics, Inc.). The following abbreviations were used:

[0167] AA acetic acid

[0168] ACN acetonitrile

[0169] AcOH acetic acid

[0170] aq. aqueous

[0171] brine saturated aqueous sodium chloride solution

[0172] DCM dichloromethane

[0173] DIPEA diisopropylethylamine

[0174] DMF N,N-dimethylformamide

[0175] DMSO dimethyl sulfoxide

[0176] EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

[0177] EtOAc ethyl acetate

[0178] EtOH ethanol

[0179] g gram

[0180] h hour

[0181] HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0182] HPLC high performance liquid chromatography

[0183] IPA isopropanol

[0184] LCMS liquid chromatography

[0185] min minute

[0186] MeCN acetonitrile

[0187] MeOH methanol

[0188] NaOtBu sodium tert-butoxide

[0189] Pd 2 (dba) 3 Tris(dibenzylideneacetone)dipalladium

[0190] pet ether Petroleum ether

[0191] T3P solution Propylphosphonic anhydride solution

[0192] tBUBrettPhos Pd G3 [2'-(Amino-κN)[1,1'-biphenyl]-2-yl-κC][[3,6-dimethoxy-2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2-di-tert-butyl-[3,6-dimethoxy-2-[2,4,6-tris(propan-2-yl)phenyl]phenyl]phosphane; Methanesulfonic acid; Palladium; 2-Phenylaniline

[0193] TEA Triethylamine

[0194] TFA Trifluoroacetic acid

[0195] THF Tetrahydrofuran

[0196] Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethyloxanthene

[0197] Xphos Pd G2 Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)

[0198] General procedure for the synthesis of piperazinyl quinolones

[0199]

[0200] Step 1. General procedure for the preparation of compound 1:

[0201] Add 2-amino-5-bromobenzaldehyde (1.0 equiv), 1-isopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (1.0 equiv), XPhos Pd G2 (0.1 equiv) and 3MK 3 PO 4 (3.0 equiv). Bubble the vial with N 2 and a vent needle. Then, add 1,4-dioxane (0.2 M) and heat the mixture to 90 °C for 1 h. Load the compound onto a Celite pre-column and perform flash column chromatography using DCM / MeOH as the eluent. Combine the fractions containing the product and concentrate under reduced pressure to afford compound 1.

[0202] Synthesis of 4-amino-4'-(4-isopropylpiperazin-1-yl)-[1,1'-biphenyl]-3-carbaldehyde:

[0203]

[0204] Add 2-amino-5-bromobenzaldehyde (0.65 g, 3.2 mmol), 1-isopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (1.1 g, 3.2 mmol), XPhos Pd G2 (0.26 g, 0.32 mmol) and 3 M K 3 PO 4 (3.2 mL, 9.7 mmol) to a 40 mL vial. Bubble the vial with N 2 and a vent needle. Then, add 1,4-dioxane (11 mL) and heat the mixture to 90 °C for 1 h. Load the compound onto a Celite pre-column and perform flash column chromatography using DCM / MeOH as the eluent. Combine the fractions containing the product and concentrate under reduced pressure to obtain 4-amino-4'-(4-isopropylpiperazin-1-yl)-[1,1'-biphenyl]-3-carbaldehyde (929 mg, 2.9 mmol, 89% yield) as a green solid. Analytical method 3: Observed mass: 324.2 (MH + ); retention time 1.1 min. Analytical method 4 m / z 324.2 (MH + ); retention time 1.30 min. 1 1H NMR (500 MHz, chloroform-d) δ 9.94 (s, 1H), 7.66 (d, J = 2.2 Hz, 1H), 7.55 (dd, J = 8.5, 2.2 Hz, 1H), 7.45 (d, J = 8.7 Hz, 2H), 6.99 (d, J = 8.9 Hz, 2H), 6.71 (d, J = 8.6 Hz, 1H), 6.09 (br s, 2H), 3.28 - 3.21 (m, 4H), 2.74 - 2.67 (m, 5H), 1.10 (d, J = 6.5 Hz, 6H). Step 2. General procedure for the formation of R 1 substituted quinolone (Compound 2):

[0205] Add 4-amino-4'-(4-isopropylpiperazin-1-yl)-[1,1'-biphenyl]-3-carbaldehyde (1.0 equiv), T3P solution in 50% DMF (1.5 equiv), phenylacetic acid derivative (1.0 equiv), DIPEA (2.0 equiv) and DMF (0.2 M) to a 4 mL vial. Heat the mixture to 90 °C for 16 h. Then filter the mixture through a 0.45 μm syringe filter and purify by preparative HPLC. Combine the fractions containing the product and concentrate by centrifugal evaporation to obtain R 1 Substituted quinolone (Compound 2).

[0206] General procedure for the synthesis of N-alkylated quinolone (5) and O-alkylated quinolone (6)

[0207]

[0208] Step 1. General procedure for the formation of 6-bromoquinolone (3):

[0209] Add 2-amino-5-bromobenzaldehyde (1.0 equiv), phenylacetic acid derivative (1.0 equiv), T3P solution in 50% DMF (1.5 equiv), DIPEA (2.0 equiv) and DMF (0.2 M) to a glass bottle. Heat the mixture to 65 - 90 °C for 16 h. Dilute the mixture with at least 50 mL of water and precipitate the solid. Collect the solid by filtration to obtain 6-bromoquinolone (3).

[0210] Example of 6-bromoquinolone (3): Synthesis of 6-bromo-3-(4-nitrophenyl)quinolin-2(1H)-one

[0211]

[0212] Add 2-amino-5-bromobenzaldehyde (500 mg, 2.5 mmol), 2-(4-nitrophenyl)acetic acid (450 mg, 2.5 mmol), T3P solution in 50% DMF (2.2 mL, 3.8 mmol), DIPEA (0.9 ml, 5.0 mmol) and DMF (12 mL) to a 10 mL glass bottle. Heat the mixture to 65 °C for 16 h. Dilute the mixture with at least 50 mL of water and precipitate the solid. Collect the solid by filtration to obtain 6-bromo-3-(4-nitrophenyl)quinolin-2(1H)-one (810 mg, 2.3 mmol, 94% yield). 1 HNMR (500 MHz, DMSO-d 6)δ 8.36 - 8.29 (m, 2H), 8.09 - 8.04 (m, 2H), 8.04 - 7.97 (m, 1H), 7.75 - 7.68 (m, 1H), 7.37 - 7.26 (m, 1H).

[0213] General procedure for forming N-alkylated bromoquinolone (4):

[0214] Add 6-bromoquinolone (3) (1.0 equivalent), alkyl halide (3.0 equivalents), carbonate base (3.0 equivalents), and DMF (0.2 M) to a glass vial. Heat the mixture to 70 °C for 10 min to 1 hour. Dilute the mixture with 5 volumes of distilled water and precipitate the solid. Collect the solid by filtration to obtain a mixture of N- and O-alkylated products.

[0215] Examples of N-alkylated bromoquinolone (4): Synthesis of 6-bromo-1-methyl-3-(4-nitrophenyl)quinolin-2(1H)-one:

[0216]

[0217] Add 6-bromo-3-(4-nitrophenyl)quinolin-2(1H)-one (390 mg, 1.1 mmol), methyl iodide (0.2 mL, 3.4 mmol), cesium carbonate (1.1 g, 3.4 mmol), and DMF (5.7 mL) to a 20 mL glass vial. Heat the mixture to 70 °C for 10 min. Dilute the mixture with 5 volumes of distilled water and precipitate the solid. Collect the solid by filtration to obtain a mixture of 6-bromo-1-methyl-3-(4-nitrophenyl)quinolin-2(1H)-one (Analytical method 1: Observed mass: 358.8 (MH + ) ; Retention time 1.09 min) and 6-bromo-2-methoxy-3-(4-nitrophenyl)quinoline (Analytical method 2: Observed mass: 358.8 (MH + ) ; Retention time 1.18 min) (409 mg, 1.1 mmol, 100% yield).

[0218] General procedure for forming compound 5:

[0219] Add aryl borate ester (1.1 equivalents), bromoquinolone (1.0 equivalent), XPhos Pd G2 (0.1 equivalent), and 3 M K 3 PO 4 (3.0 equivalents) to a glass vial. Use N 2Bubble with a ventilation needle for 5 minutes, add dioxane (0.2 M), and heat the mixture to 90 °C for 20 min to 1 h. Perform normal-phase flash column chromatography on the crude reaction mixture. Combine the fractions containing the product and concentrate under reduced pressure to obtain the Suzuki-coupled adduct.

[0220] Example of Compound 5: Synthesis of 6-(4-(4-isopropylpiperazin-1-yl)phenyl)-1-methyl-3-(4-nitrophenyl)quinolin-2(1H)-one: (Example 1)

[0221]

[0222] Add 1-isopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (198 mg, 0.60 mmol), 6-bromo-1-methyl-3-(4-nitrophenyl)quinolin-2(1H)-one (196 mg, 0.50 mmol), XPhos Pd G2 (43 mg, 0.055 mmol) and 3 M K 3 PO 4 (0.55 mL, 1.6 mmol) to a 4 mL glass vial. Bubble the mixture with N 2 and heat to 90 °C for 20 min. Perform flash column chromatography on the crude reaction mixture using DCM / MeOH as the eluent. Combine the fractions containing the compound and concentrate under reduced pressure to obtain 6-(4-(4-isopropylpiperazin-1-yl)phenyl)-1-methyl-3-(4-nitrophenyl)quinolin-2(1H)-one (263 mg, 0.55 mmol, 100% yield). Analytical method 1: Observed mass: 483.3 (MH + ); retention time 0.848 min.

[0223] General procedure for the reduction of nitroarenes to anilines

[0224]

[0225] Under N 2 , add nitroarene (1 equiv), wet Pd / C (0.1 equiv) and ethanol (0.2 M) to a thick-walled round-bottom flask equipped with a magnetic stir bar. Evacuate the flask and refill with N 2 three times. Then, evacuate the flask and refill with H 2 (50 psi) and stir at 23 °C for 1 h. Filter the reaction mixture through diatomaceous earth and concentrate under reduced pressure to obtain aniline.

[0226] General procedure for the preparation of amide derivative 7

[0227]

[0228] Add carboxylic acid (1.5 equiv), HATU (1.5 equiv), DMF (0.2 M), and DIPEA (2 equiv) to a glass vial equipped with a magnetic stir bar and stir the mixture at 23 °C for 2 min. Add aniline compound (1 equiv) and stir the mixture at 23 °C for 1 h. Purify the mixture by preparative reverse-phase HPLC to afford amide 7.

[0229] General procedure for amide derivative 9

[0230]

[0231] Step 1. General procedure for the formation of benzoic acid (8):

[0232] Add benzoate (1.0 equiv), 1 M lithium hydroxide solution (1.5 equiv), and THF / H2O / MeOH (1 / 1 / 5, 0.1 M) to a glass vial. Heat the reaction mixture to 80 °C for 1 h. Dry the reaction mixture by centrifugal evaporation to afford benzoic acid 8 as the lithium salt, which is used directly in the amide bond coupling step.

[0233] Step 2. General procedure for the formation of amide derivative (9):

[0234] Add carboxylic acid (1.0 equiv), 50% T3P in DMF (2.0 equiv), DMF (0.1 M), and DIPEA (3 equiv) to a glass vial equipped with a magnetic stir bar. Stir the mixture at 23 °C for 2 min. Add aniline (1.2 equiv) and stir the mixture at 23 °C for 1 h. Purify the mixture by preparative reverse-phase HPLC to afford amide 9.

[0235] General procedure for aniline derivative 11

[0236]

[0237] Step 1. General procedure for the formation of bromobenzene 10:

[0238] Add 2-aminoaldehyde (1.0 equiv), 2-(4-bromophenyl)acetic acid (1.2 equiv), 50% T3P in DMF (1.5 equiv), DIPEA (4.0 equiv), and DMF (0.2 M) to a glass vial. Heat the mixture by microwave to 150 °C for 1 h. Quench the reaction mixture with 5x volume of 10% saturated LiCl and extract with 3x equal volume of EtOAc or DCM + 5% MeOH. Combine the organic layers, dry over sodium sulfate, and concentrate under reduced pressure to afford bromobenzene 10.

[0239] Step 2. General procedure for the formation of aniline derivative 11:

[0240] Add bromobenzene 10 (1.0 equiv), amine (2.0 equiv), sodium tert-butoxide (3 equiv), tBuBrettPhos Pd G3 (0.1 equiv), and DMF (0.1 M) to a glass vial equipped with a magnetic stir bar. Bubble the mixture with N 2 and a vent needle for 5 min. Heat the mixture at 80 °C for 1 h. Add Si-thiol resin (0.5 equiv, 1.0 mmol / g), stir the solution at 23 °C for 30 min and filter through a 0.45 μm syringe filter. Purify the mixture by preparative reverse-phase HPLC to obtain aniline derivative 11.

[0241] Procedure for the formation of 3-(4-hydroxyphenyl)-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one: (Example 2)

[0242]

[0243] Add 3-(4-bromophenyl)-6-(4-(4-isopropylpiperazin-1-yl)phenyl)quinolin-2(1H)-one (30 mg, 0.060 mmol), sodium tert-butoxide (17.2 mg, 0.18 mmol), tBuBrettPhos PdG3 (5.1 mg, 6.0 μmol), and dioxane (1 mL) to a glass vial equipped with a magnetic stir bar. Bubble the mixture with N 2 and a vent needle for 5 min. Heat the mixture at 90 °C for 3 h. Concentrate the mixture by centrifugal evaporation and purify by preparative reverse-phase HPLC (Preparative Method 1) to obtain 3-(4-hydroxyphenyl)-6-(4-(4-isopropylpiperazin-1-yl)phenyl)quinolin-2(1H)-one (12) (3.1 mg, 0.0070 mmol, 12% yield). Analytical Method 5: Purity: 100%; Observed mass: 440.2 (MH + ); Retention time 1.2 min. Analytical Method 6: Purity: 100%; Observed mass: 440.0 (MH + ); Retention time 1.58 min. 1 1H NMR (500 MHz, DMSO-d 6)δ 11.87 (s, 1H), 9.64 (s, 1H), 8.04 (s, 1H), 7.94 (s, 1H), 7.74 (dd, J = 8.5, 1.7 Hz, 1H), 7.63 (d, J = 8.6 Hz, 2H), 7.60 (br d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.5 Hz, 1H), 7.07 (br d, J = 8.2 Hz, 2H), 6.82 (d, J = 8.5 Hz, 2H), 3.28 - 2.88 (m, 8H), 1.18 (br d, J = 2.7 Hz, 7H).

[0244] General Scheme for the Synthesis of C4 - Alkylated Intermediate 15

[0245]

[0246] Step 1. General Procedure for the Formation of Ketone 13:

[0247] Add 2 - amino - 5 - bromobenzonitrile (1.0 equiv) and THF (0.5 M) to a glass vial equipped with a magnetic stir bar. Cool the mixture to 0 °C. Then, add dropwise a 1.0 M Grignard solution in THF (3.0 equiv) and stir the solution at 0 °C for 20 min and then warm to 23 °C and hold for 16 h. Cool the solution to 0 °C. Quench the reaction with 6 M HCl (5.0 equiv). Stir the solution for 1 h, neutralize the solution with 1 N NaOH and extract with EtOAc. Dry the organic layer over sodium sulfate, filter and concentrate under reduced pressure to obtain ketone 13.

[0248] Example of Ketone 13: Synthesis of 1 - (2 - amino - 5 - bromophenyl)propan - 1 - one:

[0249]

[0250] Add 2 - amino - 5 - bromobenzonitrile (2.1 g, 10.5 mmol) and THF (21 mL) to a 20 mL glass vial equipped with a magnetic stir bar. Cool the mixture to 0 °C. Then, add dropwise a 1.0 M Grignard solution in THF (32 mL, 31.5 mmol) and stir the solution at 0 °C for 20 min and then warm to 23 °C and hold for 16 h. Cool the solution to 0 °C. Quench the reaction with 6 M HCl (8.8 mL, 53 mmol). Stir the solution for 1 h, neutralize the solution with 1 N NaOH and extract with EtOAc. Dry the organic layer over sodium sulfate, filter and concentrate under reduced pressure to obtain 1 - (2 - amino - 5 - bromophenyl)propan - 1 - one (2.35 g, 10.3 mmol, 98% yield). Analytical Method 1: Observed mass: 229.8 (MH +); Retention time 0.967 min. 1 1H NMR (500 MHz, chloroform-d) δ 7.84 (d, J = 2.2 Hz, 1H), 7.32 (dd, J = 8.8, 2.3 Hz, 1H), 6.56 (d, J = 8.9 Hz, 1H), 6.29 (br s, 2H), 2.95 (q, J = 7.2 Hz, 2H), 1.21 (t, J = 7.3 Hz, 3H).

[0251] Step 2. General procedure for the formation of ketoamide 14:

[0252] Add 13 (1.0 equiv), EDCI (2.0 equiv), phenylacetic acid (2.0 equiv), DIPEA (3.0 equiv) and DCM (0.2 M) to a glass vial equipped with a magnetic stir bar. Stir the mixture at 23 °C for 2 h. Perform flash column chromatography on the reaction mixture and concentrate the fractions containing the product under reduced pressure to obtain ketoamide 14.

[0253] Examples of ketoamide 14: Synthesis of N-(4-bromo-2-propionylphenyl)-2-(4-(methylsulfonyl)phenyl)acetamide:

[0254]

[0255] Add 1-(2-amino-5-bromophenyl)propan-1-one (500 mg, 2.2 mmol), EDCI (840 mg, 4.4 mmol), phenylacetic acid (940 mg, 4.4 mmol), DIPEA (1.1 mL, 6.6 mmol) and DCM (11 mL) to a 40 mL glass vial equipped with a magnetic stir bar. Stir the mixture at 23 °C for 2 h. Perform flash column chromatography on the reaction mixture and concentrate the fractions containing the product under reduced pressure to obtain N-(4-bromo-2-propionylphenyl)-2-(4-(methylsulfonyl)phenyl)acetamide (560 mg, 1.3 mmol, 60% yield). Analytical method 1: Observed mass: 425.9 (MH + ); Retention time 0.940 min. Step 3. General procedure for the formation of quinolone 15:

[0256] Add ketoamide 14 (1.0 equiv) and EtOH (0.2 M) to a glass vial equipped with a magnetic stir bar. Cool the mixture to 0 °C. Add 60% sodium hydride (3.0 equiv) to the stirred mixture and after 5 min, stir the mixture at 23 °C for 1 h. Evaporate the solvent under N 2 stream and add water (5 volumes) to dissolve the residual sodium ethoxide. Filter the solid precipitate through a sintered glass funnel, air dry and collect quinolone 15.

[0257] Example of Quinoline 14: Synthesis of 6-Bromo-4-ethyl-3-(4-(methylsulfonyl)phenyl)quinolin-2(1H)-one:

[0258]

[0259] Add N-(4-bromo-2-propionylphenyl)-2-(4-(methylsulfonyl)phenyl)acetamide (558 mg, 1.3 mmol) and EtOH (6.6 mL) to a 20 mL glass vial equipped with a magnetic stir bar. Cool the reaction mixture to 0 °C. Add 60% sodium hydride (158 mg, 4.0 mmol) to the stirred mixture and after 5 min, stir the mixture at 23 °C for 1 h. Evaporate the solvent by N 2 stream evaporation and add water (33 mL) to dissolve the residual sodium ethoxide. Filter the solid precipitate through a sintered glass funnel, air-dry and collect 6-bromo-4-ethyl-3-(4-(methylsulfonyl)phenyl)quinolin-2(1H)-one (480 mg, 1.2 mmol, 90% yield). Analytical method 3: Observed mass: 407.8 (MH + ); Retention time 1.712 min.

[0260] General procedure for the synthesis of dipiperidine compound 18

[0261]

[0262] Step 1. General procedure for the formation of compound 16:

[0263] Add compound 15 (1.0 equiv), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.5 equiv), XPhos PdG2 (0.1 equiv), 3M K 3 PO 4 (3.0 equiv) and dioxane (0.2 M) to a glass vial equipped with a magnetic stir bar. Heat the mixture to 90 °C under N 2 for 2 h. Perform flash column chromatography on the reaction mixture and combine the fractions containing the product and concentrate under reduced pressure.

[0264] Example of compound 16: Synthesis of tert-butyl 4-(4-ethyl-3-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydroquinolin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate:

[0265]

[0266] To an 8 mL glass vial equipped with a magnetic stir bar was added 6-bromo-4-ethyl-3-(4-(methylsulfonyl)phenyl)quinolin-2(1H)-one (135 mg, 0.33 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (154 mg, 0.50 mmol), XPhos Pd G2 (26 mg, 0.033 mmol), 3M K 3 PO 4 (0.33 mL, 1.0 mmol) and dioxane (1.6 mL). The reaction mixture was heated to 90 °C and maintained for 2 h under N 2 . The reaction mixture was subjected to flash column chromatography and the fractions containing the product were combined and concentrated under reduced pressure to afford the title compound (108 mg, 0.21 mmol, 64% yield). Analytical method 1: Observed mass: 509.1 (MH + ); retention time 0.958 min.

[0267] General procedure for the formation of compound 17:

[0268] To a thick-walled round-bottom flask equipped with a magnetic stir bar was added compound 16 (1.0 equiv), wet Pd / C (0.1 equiv) and ethanol (minimum volume to dissolve the residue). The flask was evacuated and backfilled with N 2 three times. Subsequently, the flask was evacuated and backfilled with H 2 (50 psi) and stirred at 23 °C for 1 h. The reaction mixture was filtered through Celite and concentrated under reduced pressure. The residue was dissolved in 4M HCl / dioxane (0.2 M) and stirred at 23 °C for 1 h and concentrated under reduced pressure to afford compound 17 as the hydrochloride salt.

[0269] Example of compound 17: Synthesis of 4-ethyl-3-(4-(methylsulfonyl)phenyl)-6-(piperidin-4-yl)quinolin-2(1H)-one:

[0270]

[0271] To a thick-walled round-bottom flask equipped with a magnetic stir bar was added 4-(4-ethyl-3-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydroquinolin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (108 mg, 0.21 mmol), wet Pd / C (71 mg, 0.033 mmol) and ethanol (10 mL). The flask was evacuated and backfilled with N 2 three times. Subsequently, the flask was evacuated and backfilled with H 2(50 psi) Recharge and stir at 23 °C for 1 h. Filter the reaction mixture through diatomaceous earth and concentrate under reduced pressure. Dissolve the residue in 4M HCl / dioxane (1.5 mL), stir at 23 °C for 1 h, and concentrate under reduced pressure. Further purify the material by reverse-phase preparative HPLC (Preparative Method 2) to obtain the title compound as the hydrochloride salt (1.6 mg, 0.0039 mmol, 1% yield). Analytical Method 5: Purity: 100%; Observed mass: 411.0 (MH + ); Retention time 1.02 min; Analytical Method 6: Purity: 100%; Observed mass: 411.0 (MH + ); Retention time 1.02 min.

[0272] General procedure for forming Compound 18:

[0273] Add Compound 17 as the HCl salt (1.0 equiv), 1-isopropylpiperidin-4-one (10 equiv), MgSO 4 (10 equiv) and 10 / 1 DMF / AcOH (0.1 M) to a glass vial equipped with a magnetic stir bar. Stir the reaction mixture at 60 °C for 15 min and then add NaCNBH 3 (10 equiv). Stir the reaction mixture at 60 °C for 72 h. Quench the reaction with 1M NaOH (20 volumes) and extract the reaction mixture with DCM (20 volumes). Concentrate the organic layer under reduced pressure and dissolve the residue in DMF and perform preparative reverse-phase HPLC. Concentrate the fractions containing the product by centrifugal evaporation to obtain Compound 18.

[0274] Example of Compound 18: Synthesis of 4-ethyl-6-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-3-(4-(methylsulfonyl)phenyl)quinolin-2(1H)-one:

[0275]

[0276] Add Compound 17 as the HCl salt (28 mg, 0.063 mmol), 1-isopropylpiperidin-4-one (88 mg, 0.63 mmol), MgSO 4 (75 mg, 0.63 mmol) and 10 / 1 DMF / AcOH (0.6 mL / 0.06 mL) to a glass bottle equipped with a magnetic stir bar. Stir the reaction mixture at 60 °C for 15 min and then add NaCNBH 3(39 mg). The reaction mixture was stirred at 60 °C for 72 h. The reaction was quenched with 1 M NaOH (10 mL). The reaction mixture was extracted with DCM (10 mL). The organic layer was concentrated under reduced pressure and the residue was dissolved in DMF and subjected to reverse-phase HPLC (Preparative Method 1). The fractions containing the product were concentrated by centrifugal evaporation to give the title compound (5.2 mg, 0.0097 mmol, 15% yield). Analytical Method 5: Purity: 100%; Observed mass: 536.3 (MH + ); Retention time 0.94 min; Analytical Method 6: Purity: 100%; Observed mass: 536.5 (MH + ); Retention time 1.12 min. 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.84 (br s, 1H), 7.99 (d, J = 8.0 Hz, 2H), 7.62 (s, 1H), 7.50 (d, J = 7.9 Hz, 2H), 7.45 (br d, J = 8.8 Hz, 1H), 7.30 (d, J = 8.5 Hz, 1H), 3.28 (s, 3H), 3.04 - 2.95 (m, 2H), 2.89 (br dd, J = 5.1, 1.9 Hz, 2H), 2.79 - 2.72 (m, 1H), 2.67 - 2.59 (m, 3H), 2.31 - 2.12 (m, 4H), 1.84 - 1.74 (m, 4H), 1.73 - 1.62 (m, 2H), 1.55 - 1.30 (m, 3H), 1.09 (brt, J = 7.4 Hz, 3H), 0.98 (br d, J = 6.5 Hz, 6H).

[0277] General Scheme for the Synthesis of Compound 19:

[0278]

[0279] General Procedure for the Formation of Compound 19:

[0280] To a glass bottle equipped with a magnetic stir bar was added Compound 15 (1.0 equiv), amine (1.2 equiv), Pd 2 (dba) 3 (0.1 equiv), Xantphos (0.1 equiv), NaOtBu (2.0 equiv) and dioxane (0.2 M). The reaction mixture was bubbled with N 2 and a vent needle for 5 min and stirred at 90 °C under N 2 for 1 h. The mixture was subjected to normal-phase flash column chromatography followed by preparative reverse-phase HPLC. The fractions containing the product were concentrated by centrifugal evaporation to give Compound 19.

[0281] Example of Compound 19: Synthesis of 6-((4-(4-Isopropylpiperazin-1-yl)phenyl)amino)-1-methyl-3-(4-(methylsulfonyl)phenyl)quinolin-2(1H)-one (Example 3)

[0282]

[0283] To an 8 mL glass vial equipped with a magnetic stir bar was added 6-bromo-1-methyl-3-(4-(methylsulfonyl)phenyl)quinolin-2(1H)-one (50 mg, 0.13 mmol), 4-(4-isopropylpiperazin-1-yl)aniline (33.5 mg, 0.15 mmol), Pd 2 (dba) 3 (11.7 mg, 0.013 mmol), Xantphos (7.4 mg, 0.013 mmol), NaOtBu (24.5 mg, 0.26 mmol), and dioxane (0.6 mL). The reaction mixture was bubbled with N 2 for 5 min using a N and vent needle and stirred at 90 °C under N 2 for 1 h. The mixture was subjected to normal phase flash column chromatography (DCM / MeOH), followed by preparative reverse phase HPLC (Preparative Method 1). The fractions containing the product were concentrated by centrifugal evaporation to afford the title compound (5.8 mg, 0.011 mmol, 9% yield). Analytical Method 5: Purity: 100%; Observed mass: 531.1 (MH + ); Retention time 1.30 min; Analytical Method 6: Purity: 100%; Observed mass: 531.1 (MH + ); Retention time 1.47 min. 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.12 (s, 1H), 8.02 - 7.98 (m, 2H), 7.97 - 7.93 (m, 2H), 7.91 (s, 1H), 7.45 (d, J = 9.1 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.28 (dd, J = 9.0, 2.5 Hz, 1H), 7.03 (d, J = 8.9 Hz, 2H), 6.89 (d, J = 8.9 Hz, 2H), 3.67 (s, 3H), 3.24 (s, 3H), 3.06 - 3.00 (m, 4H), 2.69 - 2.62 (m, 1H), 2.59 - 2.55 (m, 4H), 1.00 (d, J = 6.5 Hz, 6H).

[0284] The following examples were prepared according to the general procedures described hereinabove using the appropriate starting materials, reagents, and conditions.

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316] Analytical LC / MS method

[0317] Method 1 (TFA, 1 min): Starting B% = 0, final B% = 100 over 1 min gradient; flow rate = 1.0 mL / min; wavelength = 254 nm; solvent A = 0.05% TFA in MeCN:H 2 O(5:95); solvent B = 0.05% TFA / MeCN:H 2 O(95:5); column = Acquity BEH C18 1.7 μm particles; 2.1 x 50 mm; temperature = 50 °C.

[0318] Method 2 (ammonium acetate, 1 min): Starting B% = 0, final B% = 100 over 1 min gradient; flow rate = 1.0 mL / min; wavelength = 220 nm; solvent A = 10 mM NH 4 OAc / MeCN:H 2 O(5:95); solvent B = 10 mM NH 4 OAc / MeCN:H 2 O(95:5); column = Acquity BEH C18 1.7 μm particles; 2.1 x 50 mm; temperature = 50 °C.

[0319] Method 3 (TFA, 3 min): Starting B% = 0, final B% = 100 over 3 min gradient; flow rate = 1.0 mL / min; wavelength = 254 nm; solvent A = 0.05% TFA / MeCN:H 2 O(5:95); solvent B = 0.05% TFA in MeCN:H 2 O(95:5); column = Acquity BEH C18 1.7 μm particles; 2.1 x 50 mm; temperature = 50 °C.

[0320] Method 4 (ammonium acetate, 3 min): Starting B% = 0, final B% = 100 over 3 min gradient; flow rate = 1.0 mL / min; wavelength = 254 nm; solvent A = 10 mM NH 4 OAc / MeCN:H2 O(5:95); Solvent B = 10 mM NH 4 OAc / MeCN:H 2 O(95:5); Column = Acquity BEH C18 1.7 μm particles; 2.1 x 50 mm; Temperature = 50 °C;

[0321] Method 5 (SCP TFA, 3 min): Initial B% = 0, Final B% = 100 over 3 min gradient; Flow rate = 1.0 mL / min; Wavelength = 254 nm; Solvent A = 0.05% TFA / MeCN:H 2 O(5:95); Solvent B = 0.05% TFA / MeCN:H 2 O(95:5); Column = XBridge C18 1.7 μm particles; 2.1 x 50 mm; Temperature = 50 °C.

[0322] Method 6 (SCP ammonium acetate, 3 min): Initial B% = 0, Final B% = 100 over 3 min gradient; Flow rate = 1.0 mL / min; Wavelength = 254 nm; Solvent A = 10 mM NH 4 OAc / MeCN:H 2 O(5:95); Solvent B = 10 mM NH 4 OAc / MeCN:H 2 O(95:5); Column = XBridge C18 1.7 μm particles; 2.1 x 50 mm; Temperature = 50 °C.

[0323] Preparative HPLC purification method:

[0324] Method 1 (SCP ammonium acetate): Column: XBridge C18, 19 mm x 200 mm, 5-μm particles; Flow rate: 20 mL / min; Mobile phase A: 10 mM NH 4 OAc / MeCN:H 2 O(5:95); Mobile phase B: 10 mM NH 4 OAc / MeCN:H 2 O(95:5); Column temperature: 25 °C. Fraction collection is triggered by MS signal. The fractions containing the desired product are combined and dried by centrifugal evaporation.

[0325] Method 2 (SCP TFA): Column: XBridge C18, 19 mm x 200 mm, 5-μm particles; Flow rate: 20 mL / min; Column mobile phase A: 0.05% TFA / MeCN:H 2 O(5:95); Mobile phase B: 0.05% TFA / MeCN:H 2O(95:5); Column temperature: 25 °C. Fraction collection was triggered by the MS signal. The fractions containing the desired product were combined and dried by centrifugal evaporation.

[0326] Method 3: Column: XBridge C18, 200 mm x 19 mm, 5-μm particles; Mobile phase A: 5:95 acetonitrile: water containing 10-mM ammonium acetate; Mobile phase B: 95:5 acetonitrile: water containing 10-mM ammonium acetate; Gradient: Held at 40% B for 0 min, 40 - 80% B over 20 min, then held at 100% B for 4 min; Flow rate: 20 mL / min; Column temperature: 25 °C. Fraction collection was triggered by the MS signal. The fractions containing the desired product were combined and dried by centrifugal evaporation.

[0327] Method 4: The crude material was purified via preparative LC / MS under the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5-μm particles; Mobile phase A: 5:95 acetonitrile: water containing 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile: water containing 0.1% trifluoroacetic acid; Gradient: Held at 32% B for 0 min, 32 - 72% B over 20 min, then held at 100% B for 4 min; Flow rate: 20 mL / min; Column temperature: 25 °C. Fraction collection was triggered by the MS signal. The fractions containing the desired product were combined and dried by centrifugal evaporation.

[0328] Method 5: Column: XBridge C18, 200 mm x 19 mm, 5-μm particles; Mobile phase A: 5:95 acetonitrile: water containing 10-mM ammonium acetate; Mobile phase B: 95:5 acetonitrile: water containing 10-mM ammonium acetate; Gradient: Held at 34% B for 0 min, 34 - 84% B over 20 min, then held at 100% B for 4 min; Flow rate: 20 mL / min; Column temperature: 25 °C. Fraction collection was triggered by the MS signal. The fractions containing the desired product were combined and dried by centrifugal evaporation.

[0329] Biological Assays

[0330] The pharmacological properties of the compounds of the present invention can be confirmed by a number of biological assays. The following illustrative biological assays have been performed with the compounds of the present invention.

[0331] TLR7 / 8 / 9 Inhibition Reporter Assay

[0332] HEK-Blue overexpressing the human TLR7, TLR8 or TLR9 receptor TM-Cells (Invivogen) were used to screen for inhibitors of these receptors using an inducible SEAP (secreted embryonic alkaline phosphatase) reporter gene under the control of the IFN-β minimal promoter fused to 5 NF-κB and AP-1 binding sites. Briefly, cells were seeded in Greiner 384-well plates (15,000 cells per well for TLR7, 20,000 cells per well for TLR8, and 25,000 cells per well for TLR9) and then treated with the test compound in DMSO to generate a final dose-response concentration range of 0.05 nM - 50 μM. After pre-treating the compound at room temperature for 30 minutes, the cells were then stimulated with the TLR7 ligand (gardiquimod, at a final concentration of 7.5 μM), the TLR8 ligand (R848, at a final concentration of 15.9 μM), or the TLR9 ligand (ODN2006, at a final concentration of 5 nM) to activate NF-κB and AP-1, which induces the production of SEAP. After incubation at 37 °C, 5% CO 2 for 22 hours, the SEAP level was determined using the addition of HEK-Blue TM detection reagent (Invivogen), a cell culture medium that allows the detection of SEAP. The percentage of inhibition was determined as the percent decrease in the HEK-Blue signal present in the agonist-treated plus DMSO-treated alone wells compared to the wells treated with a known inhibitor.

[0333]

[0334]

[0335]

Claims

1. A compound of formula (I) or a salt thereof, wherein: R 1 is phenyl, pyridyl, pyrimidyl, indolyl, indazolyl or quinoxalinyl, each optionally substituted with 0 to 5 R 1a substituents; Each R 1a is independently F, Cl, -CN, -OH, C 1-2 alkyl, C 1-2 fluoroalkyl, C 1-2 alkoxy, C 1-2 fluoroalkoxy, -C(O)OH, -C(O)O(C 1-2 alkyl), -C(O)NR x R x , -NR x R x , -NR x C(O)(C 1-4 alkyl), -NHC(O)C(CH 3 ) 2 OH, -NHC(O)NR x R x , -NO 2 , -S(O) 2 (C 1-2 alkyl), -S(O) 2 NR x R x , -NR x S(O) 2 (C 1-2 alkyl), -NR x C(O)(pyridyl), -NR x (methylazetidinyl), -C(O)(morpholinyl), -C(O)(dimethylpyrrolidinyl), fluoropyrrolidinyl, hydroxypyrrolidinyl, pyrrolidinonyl, imidazolonyl or tetrazolyl; R 2 is hydrogen, C 1-4 alkyl or C 1-4 hydroxyalkyl; L is a bond or -NH-; R 3 is phenyl or piperidinyl, each substituted by R 3a substituted; R 3a is -CH 3 or a cyclic group selected from piperidinyl and piperazinyl, wherein said cyclic group is substituted with 0 or 1 R 3b substituent; R 3b is C 1-3 alkyl or oxetanyl; R 4 is hydrogen or C 1-2 alkyl; and Each R x is independently H or -CH 3 .

2. The compound or a salt thereof according to claim 1, wherein: Each R 1a is independently F, Cl, -CN, -OH, -CH 3 , -CF 3 , -OCH 3 , -OCHF 2 , -OCF 3 , -C(O)OH, -C(O)OCH 3 , -C(O)NH 2 , -C(O)NH(CH 3 ), -C(O)N(CH 3 )( 2 , -N(CH 3 )( 2 , -NHC(O)CH 3 , -NHC(O)CH 2 CH 3 , -NHC(O)CH(CH 3 )( 2 , -NHC(O)CH 2 CH 2 CH 2 CH 3 , -NHC(O)C(CH 3 )( 2 OH, -NHC(O)NH(CH 3 ), -NO 2 , -S(O) 2 CH 3 , -S(O) 2 NH 2 , -NHS(O) 2 CH 3 , -N(CH 3 )(S(O) 2 CH 3 , -NHC(O)(pyridyl), -C(O)N(CH 3 )(oxetanyl), -N(CH 3 )(methylazetidinyl), -C(O)(morpholinyl), -C(O)(dimethylpyrrolidinyl), fluoropyrrolidinyl, hydroxypyrrolidinyl, pyrrolidinonyl, imidazolonyl or tetrazolyl; R 2 is hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH or -CH 2 C(CH 3 ) 2 OH; L is a bond or -NH-; R 3 is phenyl or piperidinyl, each substituted by R 3a substituted; R 3a is -CH 3 or a cyclic group selected from piperidinyl and piperazinyl, wherein said cyclic group is substituted with 0 or 1 R 3b substituent; R 3b is -CH 3 , -CH(CH 3 ) 3 or oxetanyl; and R 4 is hydrogen or -CH 2 CH 3 .

3. The compound or its salt according to claim 1, wherein R 1 is phenyl, pyridyl or pyrimidyl, each of which is substituted with 0 to 5 R 1a substituents.

4. The compound or its salt according to claim 1, wherein R 1 is phenyl substituted with 0 to 5 R 1a groups.

5. The compound or a salt thereof according to claim 1, wherein the compound has the structure of formula (I) and L is a bond.

6. The compound or its salt according to claim 1, wherein the compound has the structure of formula (I), wherein R 3 is phenyl substituted with 0 to 1 R 3a substituent.

7. The compound or its salt according to claim 1, wherein the compound has the structure of formula (I), where R 3a is a cyclic group selected from piperidinyl and piperazinyl, wherein the cyclic group is substituted with 0 or 1 R 3b substituent.

8. The compound or its salt according to claim 1, wherein the compound has the structure of formula (I), and R 3 is as follows: (i) piperidinyl or phenyl, each substituted by piperidinyl; or (ii) piperazinyl substituted by phenyl.

9. The compound or its salt according to claim 1, wherein the compound has the structure of formula (I), and R 3 is as follows:

10. The compound or its salt according to claim 1, wherein R 1 is:

11. The compound or a salt thereof according to claim 1, wherein the compound is: 6-(4-(4-Isopropylpiperazin-1-yl)phenyl)-1-methyl-3-(4-nitrophenyl)quinolin-2(1H)-one (1); 3-(4-Hydroxyphenyl)-6-(4-(4-isopropylpiperazin-1-yl)phenyl)quinolin-2(1H)-one (2); 6-((4-(4-Isopropylpiperazin-1-yl)phenyl)amino)-1-methyl-3-(4-(methylsulfonyl)phenyl)quinolin-2(1H)-one (3); 3-(4-Methanesulfonylphenyl)-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (4); N-[4-(2-Oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)phenyl]acetamide (5); 6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-3-(pyridin-2-yl)-1,2-dihydroquinolin-2-one (6); 3-(4-(1H-Tetrazol-1-yl)phenyl)-6-(4-(4-isopropylpiperazin-1-yl)phenyl)quinolin-2(1H)-one (7); N-[3-(2-Oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)phenyl]methanesulfonamide (8); 3-[4-(Dimethylamino)phenyl]-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (9); 6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-3-(2,4,5-trifluorophenyl)-1,2-dihydroquinolin-2-one (10); 4-(2-Oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)benzene-1-sulfonamide (11); 4-(2-Oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)benzonitrile (12); N-Methyl-N-(oxetan-3-yl)-4-(2-oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)benzamide (13); 3-[4-(2-Oxoimidazolidin-1-yl)phenyl]-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (14); 2-(2-Oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)benzonitrile (15); N-[4-(2-Oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)phenyl]methanesulfonamide (16); 6-{4-[4-(Propan-2-yl)piperazin-1-yl]phenyl}-3-(pyridin-4-yl)-1,2-dihydroquinolin-2-one (17); 3-Phenyl-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (18); 3-[4-(2,2-Dimethylpyrrolidine-1-carbonyl)phenyl]-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (19); 3-(2,5-Difluorophenyl)-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (20); N-[4-(2-Oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)phenyl]butanamide (21); 3-{4-[(3S)-3-Fluoropyrrolidin-1-yl]phenyl}-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (22); N-Methyl-N-[4-(1-methyl-2-oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)phenyl]methanesulfonamide (23); 3-(2,3-Difluorophenyl)-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (24); 3-(2-Methylphenyl)-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (25); 2-Methyl-N-[4-(1-methyl-2-oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)phenyl]propanamide (26); 3-(4-Methanesulfonylphenyl)-1-methyl-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (27); Methyl 4-(2-oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)benzoate (28); N-[2-(2-Oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)phenyl]methanesulfonamide (29); 3-(3-Methoxyphenyl)-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (30); 3-(4-Fluorophenyl)-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (31); 6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-3-(pyridin-3-yl)-1,2-dihydroquinolin-2-one (32); 6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-3-[2-(trifluoromethyl)phenyl]-1,2-dihydroquinolin-2-one (33); 6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-3-(pyrimidin-5-yl)-1,2-dihydroquinolin-2-one (34); 3-(1-Methyl-1H-indazol-3-yl)-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (35); 3-[4-(Difluoromethoxy)phenyl]-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (36); 3-(2,6-Dichlorophenyl)-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (37); 3-(2,4-Dichlorophenyl)-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (38); 3-(4-Chlorophenyl)-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (39); 3-(2,3,4,5,6-Pentafluorophenyl)-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (40); 6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-3-(2,4,6-trifluorophenyl)-1,2-dihydroquinolin-2-one (41); 3-(2-Fluorophenyl)-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (42); 3-(3,4-Dimethoxyphenyl)-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (43); 3-(2-Chlorophenyl)-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (44); 6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-3-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinolin-2-one (45); 6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-3-[3-(trifluoromethoxy)phenyl]-1,2-dihydroquinolin-2-one (46); 3-(3-Fluorophenyl)-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (47); 3-(1-Methyl-1H-indol-3-yl)-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (48); 3-Methyl-1-[4-(2-oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)phenyl]urea (49); N-[4-(1-Methyl-2-oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)phenyl]pyridine-2-carboxamide (50); 3-{4-[Methyl(1-methylazetidin-3-yl)amino]phenyl}-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (51); N-[4-(2-Oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)phenyl]propanamide (52); 4-(2-Oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)benzamide (53); N-Methyl-4-(2-oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)benzamide (54); 3-[4-(Morpholine-4-carbonyl)phenyl]-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (55); 3-[4-(2-Oxopyrrolidin-1-yl)phenyl]-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (56); N-[4-(1-Methyl-2-oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)phenyl]acetamide (57); 1-Methyl-3-phenyl-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (58); 2-Hydroxy-2-methyl-N-[4-(1-methyl-2-oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)phenyl]propanamide (59); N,N-Dimethyl-4-(2-oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)benzamide (60); 3-{4-[(3R)-3-Hydroxypyrrolidin-1-yl]phenyl}-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (61); 4-(2-Oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)benzoic acid (62); 3-(3,4-Dimethoxyphenyl)-4-ethyl-6-[1'-(propan-2-yl)-[1,4'-bipiperidin]-4-yl]-1,2-dihydroquinolin-2-one (63); 3-Phenyl-6-[1'-(propan-2-yl)-[1,4'-bipiperidin]-4-yl]-1,2-dihydroquinolin-2-one (64); 4-(2-Oxo-6-{4-[1-(propan-2-yl)piperidin-4-yl]phenyl}-1,2-dihydroquinolin-3-yl)benzene-1-sulfonamide (65); 4-Ethyl-3-(4-methanesulfonylphenyl)-6-[1'-(propan-2-yl)-[1,4'-bipiperidin]-4-yl]-1,2-dihydroquinolin-2-one (66); N-[3-(2-Oxo-6-{4-[1-(propan-2-yl)piperidin-4-yl]phenyl}-1,2-dihydroquinolin-3-yl)phenyl]methanesulfonamide (67); 3-(4-Methanesulfonylphenyl)-1-methyl-6-{4-[1-(propan-2-yl)piperidin-4-yl]phenyl}-1,2-dihydroquinolin-2-one (68); 3-(2-Oxo-6-{4-[1-(propan-2-yl)piperidin-4-yl]phenyl}-1,2-dihydroquinolin-3-yl)benzonitrile (69); N-(4-{6-[4-(1-Methylpiperidin-4-yl)phenyl]-2-oxo-1,2-dihydroquinolin-3-yl}phenyl)methanesulfonamide (70); 3-(4-Methanesulfonylphenyl)-6-{4-[1-(propan-2-yl)piperidin-4-yl]phenyl}-1,2-dihydroquinolin-2-one (71); 1-(2-Hydroxyethyl)-3-(4-methanesulfonylphenyl)-6-{4-[1-(propan-2-yl)piperidin-4-yl]phenyl}-1,2-dihydroquinolin-2-one (72); 1-Methyl-3-phenyl-6-{4-[1-(propan-2-yl)piperidin-4-yl]phenyl}-1,2-dihydroquinolin-2-one (73); N-Methyl-N-[4-(1-methyl-2-oxo-6-{4-[1-(propan-2-yl)piperidin-4-yl]phenyl}-1,2-dihydroquinolin-3-yl)phenyl]methanesulfonamide (74); 3-(4-Methanesulfonylphenyl)-1-methyl-6-({4-[1-(propan-2-yl)piperidin-4-yl]phenyl}amino)-1,2-dihydroquinolin-2-one (75); 3-(4-Methanesulfonylphenyl)-6-[4-(1-methylpiperidin-4-yl)phenyl]-1,2-dihydroquinolin-2-one (76); 4-Ethyl-3-(4-methanesulfonylphenyl)-1-methyl-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (77); 3-(4-Methanesulfonylphenyl)-1-methyl-6-[4-(1-methylpiperidin-4-yl)phenyl]-1,2-dihydroquinolin-2-one (78); 1-Ethyl-3-(4-methanesulfonylphenyl)-6-{4-[1-(propan-2-yl)piperidin-4-yl]phenyl}-1,2-dihydroquinolin-2-one (79); 3-(4-Methanesulfonylphenyl)-6-{4-[1-(propan-2-yl)piperidin-4-yl]phenyl}-1-propyl-1,2-dihydroquinolin-2-one (80); N-[4-(2-Oxo-6-{4-[1-(propan-2-yl)piperidin-4-yl]phenyl}-1,2-dihydroquinolin-3-yl)phenyl]acetamide (81); 1-(3-Hydroxypropyl)-3-(4-methanesulfonylphenyl)-6-{4-[1-(propan-2-yl)piperidin-4-yl]phenyl}-1,2-dihydroquinolin-2-one (82); N-[4-(2-Oxo-6-{4-[1-(propan-2-yl)piperidin-4-yl]phenyl}-1,2-dihydroquinolin-3-yl)phenyl]methanesulfonamide (83); 4-Ethyl-3-(4-methanesulfonylphenyl)-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (84); 3-(4-Methanesulfonylphenyl)-1-(2-methylpropyl)-6-{4-[1-(propan-2-yl)piperidin-4-yl]phenyl}-1,2-dihydroquinolin-2-one (85); 4-Ethyl-3-(4-methanesulfonylphenyl)-1-methyl-6-{4-[1-(propan-2-yl)piperidin-4-yl]phenyl}-1,2-dihydroquinolin-2-one (86); 3-(4-Methanesulfonylphenyl)-1-methyl-6-{4-[1-(oxetan-3-yl)piperidin-4-yl]phenyl}-1,2-dihydroquinolin-2-one (87); 3-[4-(Dimethylamino)phenyl]-6-{4-[1-(propan-2-yl)piperidin-4-yl]phenyl}-1,2-dihydroquinolin-2-one (88); 1-(2-Hydroxy-2-methylpropyl)-3-(4-methanesulfonylphenyl)-6-{4-[1-(propan-2-yl)piperidin-4-yl]phenyl}-1,2-dihydroquinolin-2-one (89); 3-(4-Methanesulfonylphenyl)-6-({4-[4-(propan-2-yl)piperazin-1-yl]phenyl}amino)-1,2-dihydroquinolin-2-one (90); 3-[4-(Difluoromethoxy)phenyl]-6-{4-[1-(oxetan-3-yl)piperidin-4-yl]phenyl}-1,2-dihydroquinolin-2-one (91); 4-(6-{4-[1-(oxetan-3-yl)piperidin-4-yl]phenyl}-2-oxo-1,2-dihydroquinolin-3-yl)benzene-1-sulfonamide (92); 6-{4-[1-(Propan-2-yl)piperidin-4-yl]phenyl}-3-(quinoxalin-6-yl)-1,2-dihydroquinolin-2-one (93); 6-{4-[1-(Oxetan-3-yl)piperidin-4-yl]phenyl}-3-(quinoxalin-6-yl)-1,2-dihydroquinolin-2-one (94); 3-(3,4-Dimethoxyphenyl)-4-ethyl-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (95); 3-[4-(Dimethylamino)phenyl]-1-methyl-6-{4-[1-(propan-2-yl)piperidin-4-yl]phenyl}-1,2-dihydroquinolin-2-one (96); 3-(4-Methanesulfonylphenyl)-6-(1-methylpiperidin-4-yl)-1,2-dihydroquinolin-2-one (97); N-[3-(6-{4-[1-(Oxetan-3-yl)piperidin-4-yl]phenyl}-2-oxo-1,2-dihydroquinolin-3-yl)phenyl]methanesulfonamide (98); 3-(6-{4-[1-(Oxetan-3-yl)piperidin-4-yl]phenyl}-2-oxo-1,2-dihydroquinolin-3-yl)benzonitrile (99); 1-Methyl-6-{4-[1-(Oxetan-3-yl)piperidin-4-yl]phenyl}-3-phenyl-1,2-dihydroquinolin-2-one (100); or 4-Ethyl-3-(4-methanesulfonylphenyl)-1-methyl-6-{4-[1-(oxetan-3-yl)piperidin-4-yl]phenyl}-1,2-dihydroquinolin-2-one (101).

12. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 11 and a pharmaceutically acceptable carrier or diluent.

13. A compound according to any one of claims 1 to 9 or a salt thereof, or a composition according to claim 12, for use in therapy.

14. A compound according to any one of claims 1 to 9 or a salt thereof, or a composition according to claim 12, for use in the treatment of inflammatory diseases, autoimmune diseases or cancer.

15. A compound according to any one of claims 1 to 11 or a salt thereof, or a composition according to claim 12, for use in therapy.

16. A compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, for use in the treatment of pathological fibrosis.

17. The compound for use according to claim 16, wherein the pathological fibrosis is liver fibrosis, kidney fibrosis, biliary fibrosis or pancreatic fibrosis.

18. A compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, for use in the treatment of non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic nephropathy, primary sclerosing cholangitis (PSC) or primary biliary cirrhosis (PBC).

19. A compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, for use in the treatment of idiopathic pulmonary fibrosis (IPF).

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