Substituted quinoline compounds useful as inhibitors of TLR9

Abstract

Formula (I): TIFF2025538180000077.tif32153 (wherein L, R1, R2, R3 and R4 are defined herein) or a salt thereof. Also disclosed are methods of using the compounds as inhibitors of TLR9, and pharmaceutical compositions containing the compounds. These compounds are useful for treating, preventing, or slowing the progression of fibrosis.

Description

[Technical Field]

[0001] (Related Applications) This application claims priority to U.S. Provisional Application No. 63 / 42,4343, filed November 10, 2022, which is incorporated herein by reference in its entirety. [Background technology]

[0002] The present invention relates generally to substituted quinoline compounds useful as inhibitors of Toll-like receptor 9 (TLR9)-mediated signaling. The present invention provides substituted quinoline compounds, compositions containing the compounds, and methods of using them. The present invention also relates to pharmaceutical compositions containing at least one compound described herein, which are useful for treating conditions associated with the modulation of TLR9 (e.g., fibrosis), and methods of inhibiting TLR9 activity in a mammal.

[0003] Toll-like receptors (TLRs) are transmembrane proteins that can trigger inflammatory responses by recognizing pathogen-associated molecular patterns (PAMPs) or microbe-associated molecular patterns (MAMPs). A total of 10 TLRs have been identified in humans, and they can reside on the cell surface or, in the case of TLRs 7, 8, and 9, in endolysosomes. TLR9 recognizes unmethylated single-stranded DNA containing cytosine-phosphate-guanine (CpG) motifs, commonly found in bacterial DNA and mitochondrial DNA (mtDNA). TLR9 may be involved in fibrosis by promoting inflammation through a MyD88-dependent signaling pathway that ultimately involves the activation of cytokines such as IL-6, IFN-α, IL-1β, and TNF-α (Barton GM, Kagan JC (2009) Nat. Rev. Immunol. 9(8), 535-42; Li X, Jiang S, Tapping RI (2010) Cytokine 49(1), 1-9).

[0004] Lung biopsies from patients with rapidly progressing idiopathic pulmonary fibrosis (IPF) have higher TLR9 levels than healthy controls and patients with stable IPF (Sci. Transl. Med. 2010, 2(57):57ra82). Circulating mtDNA, a ligand for TLR9, has recently been identified as a mechanism-based prognostic biomarker for IPF (Am J. Resp. and Crit. Care Med. 2017, 196(12), 1502). Furthermore, elevated TLR9 expression has been observed in both human and murine nonalcoholic steatohepatitis (NASH) (Clin. Sci. 2017, 131(16), 2145), and hepatocyte mitochondrial DNA has been shown to promote NASH via TLR9 activation (J. Clin. Inv. 2016, 126(3), 859). Therefore, inhibitors / antagonists of TLR9 are thought to be effective as novel therapeutic agents for treating fibrosis.

[0005] Inhibition of TLR9 has been shown to improve 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), nonalcoholic 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, pages 251-255(2012)), and hypertension (McCarthy et al. Cardiovascular Research, 2015, Pages 119-130).

[0006] There is a need for compounds useful as inhibitors of TLR9. Additionally, there is a need for compounds useful as inhibitors of TLR9 that are selective for TLR9 over TLR7 or TLR8.

[0007] Considering the conditions that may benefit from treatment involving modulation of Toll-like receptors, it is clear that novel compounds capable of inhibiting TLR9 and methods of using those compounds could provide substantial therapeutic benefit to a wide range of patients.

[0008] Applicant has discovered potent compounds that have activity as TLR9 inhibitors. Furthermore, Applicant has discovered compounds that have activity as TLR9 inhibitors and are selective for TLR9 over TLR7 or TLR8. These compounds are provided as useful pharmaceuticals with desirable stability, bioavailability, therapeutic index, and toxicity values ​​that are important for their druggability.

[0009] SUMMARY OF THE INVENTION The present invention relates to novel substituted quinoline compounds that have been found to be effective inhibitors of TLR9-mediated signaling. These compounds are provided as useful pharmaceutical agents with desirable stability, bioavailability, therapeutic index, and toxicity profile, which are important for their druggability.

[0010] The present invention provides compounds of formula (I), or a stereoisomer, N-oxide, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof, which are effective as inhibitors of signaling through Toll-like receptor 9 and are effective in the treatment of fibrosis.

[0011] The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one compound of the present invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0012] The present invention also provides a method for inhibiting Toll-like receptor 9, comprising administering to a patient 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.

[0013] The present invention also provides a method for treating fibrosis, comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one compound of the present invention, or a stereoisomer, N-oxide, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0014] The present invention also provides a method for treating a disease or disorder associated with Toll-like receptor 9 activity, comprising administering to a mammal in need thereof at least one of a compound of formula (I), or a salt, solvate, and prodrug thereof.

[0015] The present invention also provides processes and intermediates for making compounds of formula (I), including salts, solvates, and prodrugs thereof.

[0016] The present invention also provides at least one compound of formula (I), or a salt, solvate, or prodrug thereof, for use in therapy.

[0017] The present invention also provides the use of at least one of the compounds of formula (I), or salts, solvates, and prodrugs thereof, for the manufacture of a medicament for the treatment or prevention of a condition associated with Toll-like receptor 9 (e.g., fibrosis, autoimmune disease, or inflammatory disease).

[0018] Compounds of formula (I) and compositions comprising compounds of formula (I) may be used to treat, prevent, or ameliorate various conditions associated with Toll-like receptor 9. Pharmaceutical compositions comprising these compounds are effective in treating, preventing, or inhibiting the progression of diseases or disorders in various therapeutic areas (e.g., fibrosis, including non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), idiopathic pulmonary fibrosis, primary sclerosing cholangitis (PSC), and primary biliary cirrhosis (PBC)).

[0019] These and other features of the present invention are set forth in the broader disclosure that follows. DETAILED DESCRIPTION OF THE INVENTION

[0020] A first aspect of the present invention is a compound of formula (I): [ka] [In the formula, R1 is phenyl, pyridinyl, pyrimidinyl, indolyl, indazolyl, or quinoxalinyl, each of which is selected from 0 to 5 R 1a is replaced by; Each R 1a are 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(CH3)2OH, -NHC(O)NR x R x , -NO2, -S(O)2(C 1-2 alkyl), -S(O)NR x R x , -NR x S(O)2(C 1-2 alkyl), -NR x C(O)(pyridinyl), -NR x (methylazetidinyl), —C(O)(morpholinyl), —C(O)(dimethylpyrrolidinyl), fluoropyrrolidinyl, hydroxypyrrolidinyl, pyrrolidinonyl, imidazolonyl or tetrazolyl; R2 is hydrogen, C 1-4 Alkyl or C 1-4 is hydroxyalkyl; L is a bond or -NH-; R3 is R 3a phenyl or piperidinyl substituted with; R 3a is —CH3 or a cyclic group selected from piperidinyl and piperazinyl, said cyclic group being selected from zero or one R 3b is replaced by; R 3b is C 1-3 alkyl or oxetanyl; R4 is hydrogen or C 1-2 is alkyl; and Each R x are independently H or -CH3] or a salt thereof.

[0021] In one embodiment, there is provided a compound of formula (I) or a salt thereof: During the ceremony, R1 is phenyl, pyridinyl, pyrimidinyl, indolyl, indazolyl, or quinoxalinyl, each of which is selected from 0 to 5 R 1a is replaced by; Each R 1a are independently F, Cl, -CN, -OH, -CH3, -CF3, -OCH3, -OCHF2, -OCF3, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NH(CH3), -C(O)N(CH 3)2, -N(CH3)2, -NHC(O)CH3, -NHC(O)CH2CH3, -NHC(O)CH(CH3)2, -NHC(O)CH2CH2CH2CH3, -NHC(O)C(CH3)2OH, -NHC(O)N H(CH3), -NO2, -S(O)2CH3, -S(O)2NH2, -NHS(O)2CH3, -N(CH3)S(O)2CH3, -NHC(O)(pyridinyl), -C(O)N(CH3)(oxetanyl), -N(CH3)(methylazetidinyl), -C(O)(morpholinyl), -C(O)(dimethylpyrrolidinyl), fluoropyrrolidinyl, hydroxypyrrolidinyl, pyrrolidinonyl, imidazolonyl or tetrazolyl; R2 is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH(CH3)2, -CH2CH2OH, -CH2CH2CH2OH or -CH2C(CH3)2OH; L is a bond or -NH-; R3 is R 3a phenyl or piperidinyl substituted with; R 3a is —CH3 or a cyclic group selected from piperidinyl and piperazinyl, said cyclic group being selected from zero or one R3b is replaced by; R 3b is -CH3, -CH(CH3)3 or oxetanyl; and R4 is hydrogen or -CH2CH3.

[0022] In one embodiment, R1 is selected from the group consisting of 0 to 5 R 1a

[0023] Compounds of formula (I) or salts thereof are provided wherein R is phenyl, pyridinyl, or pyrimidinyl substituted with 0 to 5 R 1a and n is 0, 1 or 2. The compounds are phenyl or pyridinyl substituted with

[0023] In one embodiment, R1 is 0 to 5 R 1a In some embodiments, R is phenyl substituted with 0 to 4 R 1a In this embodiment, R is phenyl substituted with 0-3 R 1a Also included are compounds in which the phenyl is substituted with .

[0024] In one embodiment, R1 is 0 to 5 R 1a and each R 1a are independently F, Cl, -CN, -CF3, -OCH3, -OCHF2, -OCF3, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NH(CH3), -C(O)N(CH3)2, -NHC(O)CH3, -NHC(O)CH2CH3, -NHC(O)CH(CH3)2, -NHC(O)CH2CH2CH2CH3, -NHC(O)C(CH3)2OH, -NHC(O)NH(CH3), -S(O)2CH3, -S(O)2NH2, -NHS(O)2CH3, or -N(CH3)S(O)2CH3. Included in this embodiment are compounds of Formula (I) or salts thereof, wherein R1 is selected from 0 to 5 R 1a and each R 1aare compounds which are independently F, Cl, -CN, -CF3, -OCH3, -OCHF2, -OCF3, -NHC(O)CH2CH3, -S(O)2CH3, -S(O)2NH2, -NHS(O)2CH3 or -N(CH3)S(O)2CH3.

[0025] In one embodiment, each R 1a are independently F, Cl, -CN, -OH, -CH3, -CF3, -OCH3, -OCHF2, -OCF3, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NH(CH3), -C(O)N(CH3)2, - N(CH3)2, -NHC(O)CH3, -NHC(O)CH2CH3, -NHC(O)CH(CH3)2, -NHC(O)CH2CH2CH2CH3, -NHC(O)C(CH3)2OH, -NHC(O)NH(CH3), -NO 2, -S(O)2CH3, -S(O)2NH2, -NHS(O)2CH3, -N(CH3)S(O)2CH3, -NHC(O)(pyridinyl), -C(O)N(CH3)(oxetanyl), -N(CH3)(methylazetidinyl), -C(O)(morpholinyl), -C(O)(dimethylpyrrolidinyl), fluoropyrrolidinyl, hydroxypyrrolidinyl, pyrrolidinonyl, imidazolonyl, or tetrazolyl. Included in this embodiment is a compound of formula (I) or a salt thereof, wherein each R 1a are independently F, Cl, -CN, -OH, -CH3, -CF3, -OCH 3、 -OCHF, -OCF, -C(O)OH, -C(O)OCH, -C(O)NH, -C(O)NH(CH), -C(O)N(CH), -N(CH), -NHC(O)CH, -NHC(O)CHCH, -NHC(O)CH(CH), -NHC(O)CHCHCHCH, -NHC(O)C(CH)OH, -NHC(O)NH(CH), -NO, -S(O)CH, -S(O)NH, -NHS(O)CH or -N(CH)S(O)CH. 1a are independently F, Cl, -CN, -CH3, -CF3, -OCH 3、Also included are compounds which are -OCHF2, -OCF3, -C(O)NH2, -C(O)NH(CH3), -C(O)N(CH3)2, -N(CH3)2, -NHC(O)CH3, -NHC(O)CH2CH3, -NHC(O)CH(CH3)2, -NHC(O)CH2CH2CH2CH3, -NHC(O)C(CH3)2OH, -NHC(O)NH(CH3), -NO2, -S(O)2CH3, -S(O)2NH2, -NHS(O)2CH3 or -N(CH3)S(O)2CH3.

[0026] In one embodiment, R2 is C 1-4 Alkyl or C 1-4

[0023] Compounds of formula (I) or salts thereof are provided wherein R2 is hydroxyalkyl. Included in this embodiment are compounds wherein R2 is C 1-4 In this embodiment, R is C 1-4 Also included are compounds that are hydroxyalkyl.

[0027] In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein R2 is hydrogen.

[0028] In one embodiment, a compound of formula (I) or a salt thereof is provided wherein R2 is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH(CH3)2, -CH2CH2OH, -CH2CH2CH2OH, or -CH2C(CH3)2OH. Included in this embodiment are compounds where R2 is hydrogen or -CH3.

[0029] In one embodiment there is provided a compound of formula (I) or a salt thereof, wherein L is a bond.

[0030] In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein L is -NH-.

[0031] In one embodiment, R3 is R 3a or a salt thereof.

[0032] In one embodiment, R3 is R 3a or a salt thereof.

[0033] In one embodiment, R 3a is —CH 3 , or a salt thereof.

[0034] In one embodiment, R 3a is a cyclic group selected from piperidinyl and piperazinyl, and said cyclic group is selected from zero or one R 3b or a salt thereof, wherein the compound is substituted with

[0035] In one embodiment, R 3a but 0 or 1 R 3b

[0023] Compounds of formula (I) or salts thereof are provided wherein R is piperidinyl substituted with 3a But there are 0 R 3b In this embodiment, compounds are compounds which are piperidinyl substituted with R 3a But R 3b Also included are compounds which are piperidinyl substituted with:

[0036] In one embodiment, R 3a but 0 or 1 R 3b

[0023] Compounds of formula (I) or salts thereof are provided wherein R is piperazinyl substituted with 3a But there are 0 R 3b In this embodiment, the compound is piperazinyl substituted with R 3a But R 3b Also included are compounds which are piperazinyl substituted with:

[0037] In one embodiment, R 3a But R 3b piperidinyl or piperazinyl, each substituted with 3bis -CH3, -CH(CH3)3, or oxetanyl. Included in this embodiment are compounds of formula (I) or salts thereof, wherein R 3a However, each R 3b piperidinyl or piperazinyl substituted with R 3b is —CH(CH3)3 or oxetanyl.

[0038] In one embodiment, R 3a But R 3b piperidinyl substituted with R 3b is —CH(CH) or oxetanyl. Included in this embodiment are compounds of formula (I) or salts thereof, wherein R 3a But R 3b piperidinyl substituted with R 3b is a compound where is -CH(CH3)3.

[0039] In one embodiment, R 3a But R 3b piperazinyl substituted with; and R 3b is —CH(CH) or oxetanyl. Included in this embodiment are compounds of formula (I) or salts thereof, wherein R 3a But R 3b piperazinyl substituted with; and R 3b is a compound where is -CH(CH3)3.

[0040] In one embodiment, R3 is [ka] or a salt thereof.

[0041] In one embodiment, R3 is [ka] or a salt thereof.

[0042] In one embodiment, R3 is R 3a piperidinyl substituted with; and R 3a is —CH 3 , or a salt thereof.

[0043] In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein R4 is hydrogen or -CH2CH3.

[0044] In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein R4 is hydrogen.

[0045] In one embodiment, R1 is 0 to 5 R 1a and each R 1a are independently F, Cl, -CN, -OH, -CH3, -CF3, -OCH3, -OCHF2, -OCF3, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NH(CH3), -C(O)N(CH3)2, -N (CH3)2, -NHC(O)CH3, -NHC(O)CH2CH3, -NHC(O)CH(CH3)2, -NHC(O)CH2CH2CH2CH3, -NHC(O)C(CH3)2OH, -NHC(O)NH(CH3), -NO2, -S(O)2CH3, -S(O)2NH2, -NHS(O)2CH3, -N(CH3)S(O)2CH3, -NHC(O)(pyridinyl), -C(O)N(CH3)(oxetanyl), -N(CH3)(methylazetidinyl), -C(O)(morpholinyl), -C(O)(dimethylpyrrolidinyl), fluoropyrrolidinyl, hydroxypyrrolidinyl, pyrrolidinonyl, imidazolonyl or tetrazolyl; R2 is hydrogen; L is a bond; R3 is R 3a phenyl substituted with R 3a is a cyclic group selected from piperidinyl and piperazinyl, and said cyclic group is selected from zero or one R 3b is substituted with;R 3b is —CH(CH 3 ) 3 ; and R 4 is hydrogen, or a salt thereof.

[0046] In one embodiment, 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-methacrylamide)-6-(4-hydroxyphenyl)-1-methyl-3-(4-(methylsulfonyl)phenyl)quinolin-2(1H)-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-tetrahydroquinolin-2-one) 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)benzo Nitrile (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-dimethylpyrrolidone) 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-fluorophenyl]-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (22); 3-(2,5-difluorophenyl)-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one (23); N-[4-(2-oxo-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl)phenyl]butanamide (24); 3-{4-[(3S)-3-fluorophenyl]-6-(4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-3-yl]phenyl]butanamide (25); 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-dihydro Quinolin-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-3-yl quinolin-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)piperazine -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)benzo Aromatic 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 Lin-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-dihydro quinolin-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-(propane -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-( 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 quinoxalin-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-dihydroquinoline 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), or a salt thereof.

[0047] In one embodiment, the TLR9 IC 50 The present invention provides compounds of formula (I) having a β-glucan value of ≦0.6 μM.

[0048] In one embodiment, the TLR9 IC 50 The present invention provides compounds of formula (I) having a value of ≦0.1 μM.

[0049] In one embodiment, the TLR9 IC 50 The present invention provides compounds of formula (I) having a value of ≦0.05 μM.

[0050] In one embodiment, the TLR9 IC 50 The present invention provides compounds of formula (I) having a value of ≦0.025 μM.

[0051] In one embodiment, the TLR9 IC 50 The present invention provides compounds of formula (I) having a value of ≦0.015 μM.

[0052] In one embodiment, the TLR9 IC 50 The present invention provides compounds of formula (I) having a value of ≦0.01 μM.

[0053] In another embodiment, the present invention provides a composition comprising at least one compound of the present invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0054] In another embodiment, the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one compound of the present invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0055] In another embodiment, the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound of the present invention or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0056] In another embodiment, the present invention provides a method for preparing a compound of the present invention.

[0057] In another embodiment, the present invention provides intermediates for preparing the compounds of the present invention.

[0058] In another embodiment, the present invention provides a pharmaceutical composition as defined above, further comprising one or more additional therapeutic agents.

[0059] (definition) The features and advantages of the present invention will be more readily understood by those skilled in the art upon reading the following detailed description. It is understood that, for clarity, certain features of the invention that are described before or after the context of another embodiment may be combined to form a single embodiment. Conversely, various features of the invention that are, for brevity, described in a single embodiment may also be combined to form subcombinations thereof. Embodiments identified herein as exemplary or preferred are intended to be illustrative, not limiting.

[0060] Unless otherwise stated herein, words referred to in the singular may also include the plural. For example, "a" and "an" can refer to either "one" or "one or more."

[0061] As used herein, the phrase "compound" refers to at least one compound. For example, a compound of Formula (I) includes one compound of Formula (I) and two or more compounds of Formula (I).

[0062] Unless otherwise specified, any heteroatom with unsatisfied valences is assumed to have enough hydrogen atoms to satisfy the valences.

[0063] The definitions set forth herein supersede definitions set forth in any patents, patent applications, and / or published patent applications incorporated herein by reference.

[0064] Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout the specification, either individually or as part of a larger group (unless otherwise limited in specific instances).

[0065] Throughout the specification, groups and substituents may be chosen by one skilled in the art to provide stable moieties and compounds.

[0066] According to the practice used in the art, [ka] is used in structural formulas herein to represent the bond that is the point of attachment of a group or substituent to the core or backbone structure.

[0067] As used herein, the terms "halo" and "halogen" refer to F, Cl, Br, and I.

[0068] The term "cyano" refers to the group --CN.

[0069] The term "amino" refers to the group -NH2.

[0070] The term "oxo" refers to the group =O.

[0071] The term "alkyl" as used herein refers to both branched and straight-chain saturated aliphatic hydrocarbon groups, for example, having 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 i-propyl), butyl (e.g., n-butyl, i-butyl, sec-butyl, and t-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 qualifies the number of carbon atoms that a particular group may contain. For example, "C 1-6 "Alkyl" means straight and branched chain alkyl groups having from 1 to 6 carbon atoms.

[0072] As used herein, the term "fluoroalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups substituted with one or more fluorine atoms. For example, "C 1-4 The term "fluoroalkyl" is meant to include C, C, C, and C alkyl groups substituted with one or more fluorine atoms. Representative examples of fluoroalkyl groups include, but are not limited to, -CF and -CHCF.

[0073] The term "hydroxyalkyl" includes both branched and straight-chain saturated alkyl groups substituted with one or more hydroxyl groups. For example, "hydroxyalkyl" includes -CHOH, -CHCHOH, and C 1-4 Examples include hydroxyalkyl.

[0074] The term "alkoxy," as used herein, refers to an alkyl group attached to the parent molecular moiety through an oxygen atom, for example, a methoxy group (-OCH). 1-3 "Alkoxy" means an alkoxy group having 1 to 3 carbon atoms.

[0075] The terms "fluoroalkoxy" and "-O(fluoroalkyl)" refer to a fluoroalkyl group as defined above attached through an oxygen linkage (-O-). For example, "C 1-4 "Fluoroalkoxy" is intended to include C1, C2, C3, and C4 fluoroalkoxy groups.

[0076] As used herein, the term "cycloalkyl" refers to a group derived from a non-aromatic monocyclic or polycyclic hydrocarbon molecule by removing one 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 qualifies the number of carbon atoms that a particular cycloalkyl group may have. For example, "C3-C6 cycloalkyl" refers to a cycloalkyl group having from 3 to 6 carbon atoms.

[0077] As used herein, the phrase "pharmaceutically acceptable" refers to compounds, substances, compositions, and / or dosage forms that are, within the scope of ordinary medical judgment, suitable for contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, and that are presenting a reasonable benefit / risk ratio.

[0078] The compound of formula (I) may be provided as an amorphous solid or a crystalline solid. The compound of formula (I) may be provided as an amorphous solid by lyophilization.

[0079] Additionally, solvates (e.g., hydrates) of the compounds of formula (I) are also considered to be within the scope of the present invention. The term "solvate" refers to a physical association of a compound of formula (I) with one or more organic or inorganic solvent molecules. This physical association includes hydrogen bonding. In some cases, it is possible to isolate the solvate, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" includes both solution-phase and isolable solvates. Examples of solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates, and ethyl acetate solvates. Methods of solvation are known in the art.

[0080] 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).

[0081] Additionally, once the compound of formula (I) is produced, it can be isolated and purified to obtain a composition containing 99% or greater of the compound of formula (I) ("substantially pure"), which can then be used or formulated as described herein. Such "substantially pure" compounds of formula (I) are also considered to be part of the present invention.

[0082] By "stable compound" and "stable structure" is intended a compound that is sufficiently robust that it will not decompose upon isolation to a useful degree of purity from a reaction mixture, nor upon formulation into an efficacious therapeutic agent. The present invention embodies stable compounds.

[0083] A "therapeutically effective amount" is intended to include an amount of a compound of the invention alone, or a combination of the claimed compounds, or a compound of the invention in combination with other active ingredients effective to act as inhibitors of TLR9 or to treat or prevent fibrotic diseases or disorders, disorders associated with bile acid dysregulation (e.g., pathological fibrosis).

[0084] As used herein, the term "treating" or "treatment" includes the treatment of a condition in a mammal, particularly a human, and includes (a) preventing the mammal from acquiring a condition that arises in that mammal if the mammal is prone to the condition, but particularly if the mammal has not yet been diagnosed as suffering from the condition; (b) inhibiting the condition, i.e., arresting the progression of the condition; and / or (c) palliating the condition, i.e., reducing the condition.

[0085] The compounds of the present invention are intended to encompass all isotopes of atoms contained in the compounds. Isotopes include atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium (D) and tritium (T). Isotopes of carbon include 13 C and 14 C. Isotopically labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described herein, substituting the appropriate isotopically labeled reagent for the non-labeled reagent otherwise used. For example, methyl (-CH3) also includes deuterated methyl groups (e.g., -CD3).

[0086] (Usefulness) The compounds of the present invention are effective in inhibiting the TLR9 receptor.

[0087] One embodiment provides a method of treating a disease, disorder, or condition associated with bile acid dysregulation in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of the invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0088] One embodiment provides a method of treating a disease, disorder, or condition associated with activity of the TLR9 receptor in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of the invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0089] One embodiment provides a method for treating a disease, disorder, or condition, comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound of the invention, alone or in combination with another compound of the invention and / or at least one other type of therapeutic agent, as appropriate.

[0090] One embodiment provides a method of producing an agonist effect of a TLR9 receptor in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0091] In some embodiments, the disease, disorder, or condition is associated with impaired function of TLR9 and includes pathological fibrosis, cancer, an inflammatory disease, a metabolic disease, or a cholestatic disease.

[0092] In some embodiments, the disease, disorder, or condition is associated with fibrosis, eg, fibrosis of the liver, bile duct, kidney, heart, skin, eye, and pancreas.

[0093] In other embodiments, the disease, disorder, or symptom is associated with a cell proliferative disorder (e.g., cancer). In some embodiments, the cancer includes solid tumor growth or neoplasia. In other embodiments, the cancer includes metastatic tumors. In some embodiments, the cancer is cancer of the liver, gallbladder, small intestine, large intestine, kidney, prostate, bladder, blood, bone, brain, breast, central nervous system, cervix, colon, endometrium, esophagus, reproductive organs, genitourinary tract, head, larynx, lung, muscle tissue, neck, oral or nasal mucosa, ovary, pancreas, skin, spleen, stomach, testicle, or thyroid. In other embodiments, the cancer is carcinoma, non-carcinoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, or seminoma.

[0094] Examples of diseases, disorders, or conditions associated with TLR9 activity that can be prevented, modulated, or treated in accordance with the present invention include, but are not limited to, transplant-related disorders, fibrosis (e.g., liver fibrosis, kidney fibrosis), inflammatory diseases (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, colon cancer, prostate cancer, leukemia, Kaposi's sarcoma, solid tumors).

[0095] Fibrosis, inflammatory diseases, and cell proliferative disorders suitable for prevention or treatment with the compounds of the invention include, but are not limited to, non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver or non-alcoholic steatohepatitis (NASH), acute hepatitis, chronic hepatitis, cirrhosis, primary biliary cirrhosis, primary sclerosing cholangitis, drug-induced hepatitis, biliary cirrhosis, portal hypertension, regenerative failure, decreased liver function, liver blood flow, and the like. Disorders, nephropathy, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), pancreatic secretory disorders, benign prostatic hyperplasia, neurogenic bladder, diabetic nephropathy, focal segmental glomerulosclerosis, IgA nephropathy, drug-induced or transplant-induced nephropathy, autoimmune nephropathy, lupus nephritis, liver fibrosis, renal fibrosis, chronic kidney disease (CKD), diabetic kidney disease (DKD), skin fibrosis, keloid, systemic sclerosis, scleroderma, viral fibrosis, idiopathic Pulmonary fibrosis (IPF), interstitial pneumonia, nonspecific interstitial pneumonia (NSIP), usual interstitial pneumonia (UIP), radiation-induced fibrosis, familial pulmonary fibrosis, airway fibrosis, chronic obstructive pulmonary disease (COPD), spinal tumors, herniated disc, spinal stenosis, heart failure, myocardial fibrosis, vascular fibrosis, perivascular fibrosis, foot-and-mouth disease, cancer, myeloma, fibroma, hepatocellular carcinoma, colorectal cancer, prostate cancer, leukemia, chronic lymphocytic leukemia In certain embodiments, the present invention provides a method for treating fibrosis, inflammatory disease, or cell proliferative disorder, comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound of the present invention, alone or in combination with another compound of the present invention and / or at least one other type of therapeutic agent, as appropriate.

[0096] In another embodiment, the present invention provides a compound of the present invention for use in therapy.

[0097] In another embodiment, the present invention provides a compound of the present invention for use in the treatment of a fibrotic disease, an inflammatory disease, or a cell proliferative disorder thereof.

[0098] In another embodiment, the present invention also provides use of a compound of the present invention for the manufacture of a medicament for the treatment of a fibrotic disease, an inflammatory disease, or a cell proliferative disorder thereof.

[0099] In another embodiment, the present invention provides a method of treating a fibrotic disease, inflammatory disease, or cell proliferative disorder, comprising administering to a patient in need thereof therapeutically effective amounts of a first therapeutic agent and a second therapeutic agent, wherein the first therapeutic agent is a compound of the present invention.

[0100] In another embodiment, the present invention provides a pharmaceutical combination of a compound of the present invention and another therapeutic agent for simultaneous, separate or sequential use in therapy.

[0101] In another embodiment, the present invention provides a pharmaceutical combination of a compound of the present invention and another therapeutic agent for simultaneous, separate or sequential use in the treatment of a fibrotic disease, an inflammatory disease, or a cell proliferative disorder.

[0102] The compounds of the present invention may be used in combination with another therapeutic agent (eg, one or more anti-fibrotic and / or anti-inflammatory agents).

[0103] In certain embodiments, the additional therapeutic agent used in the combination pharmaceutical composition or combination method or combination is one of the following: a TGFβ receptor inhibitor (e.g., galunisertib), a TGFβ synthesis inhibitor (e.g., pirfenidone), a vascular endothelial growth factor (VEGF) inhibitor, a platelet-derived growth factor (PDGF) inhibitor, and a fibroblast growth factor (FGF) receptor kinase inhibitor (e.g., nintedanib), a humanized anti-alpha Vβ6 integrin monoclonal antibodies (e.g., 3G9), human recombinant pentraxin 2, recombinant human serum amyloid P, anti-TGFβ-1, anti-TGFβ-2, and anti-TGFβ-3 recombinant human antibodies, endothelin receptor antagonists (e.g., macitentan), interferon-γ, c-Jun N-terminal kinase (JNK) inhibitors (e.g., 4-[[9-[(3S)-tetrahydro-3-furanyl]-8-[(2,4,6-trifluorophenyl)amino]-9H-purin-2-yl]amino]-trans-cyclohexanol), 3-pentylbenzeneacetic acid (PBI-4050), manganese(III)-containing tetrasubstituted porphyrin derivatives, monoclonal antibodies targeting eotaxin-2, interleukin-13 (IL-13) antibodies (e.g., lebrikizumab, tralokinumab), bispecific antibodies targeting interleukin-4 (IL-4) and interleukin-13 (IL-13), NK1 tachykinin receptor agonists (e.g., [Sar 9 , Met(O2) 11]-Substance P), Syntredekin Besdotox, human recombinant DNA-derived IgG1κ monoclonal antibody against connective tissue growth factor, and CC chemokine ligand 2-selective fully human IgG1κ antibody (e.g., carlumab, CCX140), antioxidants (e.g., N-acetylcysteine), phosphodiesterase 5 (PDE5) inhibitors (e.g., sildenafil), therapeutic agents for airway obstructive diseases (e.g., muscarinic antagonists (e.g., tiotropium, ipratropium bromide)), adrenergic β2 agonists The therapeutic agent may be selected from one or more, preferably one to three, therapeutic agents effective in treating fibrotic conditions (e.g., liver fibrosis, biliary fibrosis, and renal fibrosis, nonalcoholic fatty liver disease (NALFD), nonalcoholic steatohepatitis (NASH), cardiac fibrosis, idiopathic pulmonary fibrosis (IPF), and systemic sclerosis). The therapeutic agents effective in treating the above 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., elafibranor, 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 may be administered in combination with one or more 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), FAs, or other anti-cancer drugs. It may also be used in combination with K 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., halofuginone), FPR2 agonists (e.g., ZK-994), and THR agonists (e.g., MGL-3196). In another embodiment, the other therapeutic agent used in the combined pharmaceutical composition, combination method, or combination is selected from one or more, preferably one to three, immuno-oncology agents (e.g., alemtuzumab, atezolizumab, ipilimumab, nivolumab, ofatumumab, pembrolizumab, and rituximab).

[0104] As used herein, the terms "TLR9-associated condition" or "TLR9-associated disease or disorder" are meant to encompass all of the symptoms listed above, as they recur over time, as well as any other condition that is affected by TLR9 inhibition.

[0105] When used in combination with the compounds of the present invention, the other therapeutic agents described above may be used in amounts, for example, as described in the Pharmaceutical and Medical Devices Manual (PDR) or as determined by one skilled in the art. In the methods of the present invention, the other therapeutic agents may be administered before, simultaneously with, or after the administration of the compounds of the present invention. The present invention also provides pharmaceutical compositions capable of treating TLR9 receptor-related conditions.

[0106] The compositions of the present invention may contain and be formulated with other therapeutic agents as described above according to techniques well known to those skilled in the art of pharmaceutical formulation, using, for example, conventional solid or liquid vehicles or diluents, as well as pharmaceutical excipients (e.g., additives, binders, preservatives, stabilizers, flavoring agents, etc.) of a type appropriate to the desired method of administration.

[0107] Accordingly, the present invention further includes compositions comprising one or more compounds of Formula (I) and a pharmaceutically acceptable carrier.

[0108] A "pharmaceutically acceptable carrier" refers to a vehicle generally accepted in the field of delivering biologically active agents to animals, particularly mammals. Pharmaceutically acceptable carriers are formulated according to many factors well within the expertise of those skilled in the art. These factors include, but are not limited to, the type and nature of the active agent being formulated, the patient to whom the composition containing the active agent will be administered, the intended route of administration of the composition, and the targeted therapeutic index. Pharmaceutically acceptable carriers encompass both aqueous and non-aqueous liquid media, as well as various solid and semi-solid dosage forms. Such carriers can contain many different components and additives in addition to the active agent; such additional components are included in the formulation for various reasons (e.g., stabilization of the active agent, binders, etc.) known to those skilled in the art. Descriptions of suitable pharmaceutically acceptable carriers and the factors involved in their selection can be found in a variety of readily available references, such as Remington's Pharmaceutical Sciences, 17th Edition (1985), the entire contents of which are incorporated herein by reference.

[0109] The compounds according to formula (I) may be administered by any method appropriate to the condition to be treated, which may vary depending on the treatment required per site or the amount of compound of formula (I) to be delivered.

[0110] The present invention also encompasses a class of pharmaceutical compositions comprising a compound of Formula (I) and one or more nontoxic, pharmaceutically acceptable carriers and / or diluents and / or adjuvants (collectively referred to herein as "carriers"), and optionally other active ingredients. The compound of Formula (I) may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted for such a route, and in a dosage effective for the intended treatment. The compounds and compositions of the present invention may be administered, for example, orally, transmucosally, or parenterally, such as intravascularly, intravenously, intraperitoneally, subcutaneously, intramuscularly, and intrasternally, in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles. For example, the pharmaceutical carrier may include a mixture of mannitol or lactose and microcrystalline cellulose. The mixture may also include additional ingredients, such as a lubricant (e.g., magnesium stearate) and a disintegrant (e.g., crospovidone). The carrier mixture may be filled into gelatin capsules or compressed into tablets. The pharmaceutical composition may be administered, for example, as an oral dosage form or as an infusion.

[0111] For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, liquid capsule, suspension, or liquid. The pharmaceutical composition is preferably formulated in a dosage unit form containing a specific amount of active ingredient. For example, the pharmaceutical composition may be provided as a tablet or capsule containing an amount of active ingredient ranging from about 0.1 to 1000 mg, preferably from about 0.25 to 250 mg, more preferably from about 0.5 to 100 mg. The appropriate daily dose for administration to humans or other mammals may vary greatly depending on the patient's condition and other factors, but can be determined using conventional methods.

[0112] Any pharmaceutical composition discussed herein can be orally administered, for example, by any suitable acceptable oral preparation. Examples of oral preparations include, but are not limited to, tablets, troches, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups and elixirs. Pharmaceutical compositions for oral administration can be prepared according to any method known in the art for preparing pharmaceutical compositions for oral administration. In order to provide a medicament that is easy to swallow, the pharmaceutical compositions described in the present invention can include at least one substance selected from sweeteners, flavoring agents, coloring agents, demulcents, antioxidants, and preservatives.

[0113] Tablets can be prepared, for example, by mixing at least one compound of formula (I) with at least one non-toxic, pharmaceutically acceptable additive suitable for tablet manufacture. Examples of additives include, but are not limited to, inert diluents (e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate), granulating and disintegrating agents (e.g., microcrystalline cellulose, croscarmellose sodium, corn starch, and alginic acid), binders (e.g., starch, gelatin, polyvinylpyrrolidone, and gum arabic), and lubricants (e.g., magnesium stearate, stearic acid, and talc). Furthermore, tablets can be uncoated or coated by known techniques to mask the unpleasant taste of unpleasant drugs or to delay disintegration and absorption of the active ingredient in the gastrointestinal tract, thereby prolonging the effect of the active ingredient. Examples of water-soluble taste-masking materials include, but are not limited to, hydroxypropylmethylcellulose and hydroxypropylcellulose. Examples of time delay materials include, but are not limited to, ethyl cellulose and cellulose acetate butyrate.

[0114] Hard gelatin capsules may be prepared, for example, by mixing at least one compound of formula (I) with at least one inert solid diluent (eg, calcium carbonate, calcium phosphate, and kaolin).

[0115] Soft gelatin capsules can be prepared, for example, by mixing at least one compound of formula (I) with at least one water-soluble carrier (e.g., polyethylene glycol) and at least one oil medium (e.g., peanut oil, liquid paraffin, and olive oil).

[0116] Aqueous suspensions can be prepared, for example, by mixing at least one compound of formula (I) with at least one additive suitable for the preparation of aqueous suspensions. Examples of additives suitable for the preparation of aqueous suspensions include, but are not limited to, suspending agents (e.g., sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, alginic acid, polyvinylpyrrolidone, tragacanth gum, and gum arabic), dispersing or wetting agents (e.g., naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide and fatty acids and and partial esters derived from hexitols (e.g., polyoxyethylene sorbitol monooleate), and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene sorbitan monooleate). The aqueous suspension may also contain at least one preservative (e.g., ethyl p-hydroxybenzoate and n-propyl p-hydroxybenzoate), at least one coloring agent, at least one flavoring agent, and / or at least one sweetening agent (e.g., but not limited to, sucrose, saccharin, and aspartame).

[0117] Oily suspensions can be prepared, for example, by suspending at least one compound of formula (I) in either a vegetable oil (e.g., peanut oil, olive oil, sesame oil, and coconut oil) or a mineral oil (e.g., liquid paraffin). Oily suspensions can also contain at least one thickening agent (e.g., beeswax, hard paraffin, and cetyl alcohol). To provide an oily suspension that is easy to drink, at least one sweetener as described above and / or at least one flavoring agent can be added to the oily suspension. Oily suspensions can further contain at least one preservative, including, but not limited to, an antioxidant (e.g., butylhydroxyanisole and α-tocopherol).

[0118] Dispersible powders and granules can be prepared, for example, by mixing at least one compound of formula (I) with at least one dispersant and / or wetting agent, at least one suspending agent, and / or at least one preservative. Suitable dispersants, wetting agents, and suspending agents have already been described above. Examples of preservatives include, but are not limited to, antioxidants (e.g., ascorbic acid). Furthermore, dispersible powders and granules can also contain at least one additive (e.g., but not limited to, sweeteners, flavoring agents, and coloring agents).

[0119] Emulsions of at least one compound of formula (I) can be prepared, for example, as oil-in-water emulsions. The oil phase of emulsions containing a compound of formula (I) can be composed of known ingredients in a known manner. The oil phase can be provided by, but is not limited to, vegetable oils (e.g., olive oil and peanut oil), mineral oils (e.g., liquid paraffin), and mixtures thereof. The oil phase can include only an emulsifier, or a mixture of at least one emulsifier and a fat or oil, or both a fat and an oil. Suitable emulsifiers include, but are not limited to, naturally occurring phosphatides (e.g., soybean lecithin), esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate), and condensation products of partial esters with ethylene oxide (e.g., polyoxyethylene sorbitan monooleate). Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier, which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier, with or without a stabilizer, makes up the so-called emulsifying wax, and the wax, together with the oil and fat, forms the oily dispersed phase of the cream, making up the so-called emulsifying ointment base. The emulsion may also contain sweeteners, flavorings, preservatives, and / or antioxidants. Suitable emulsifiers and emulsion stabilizers for use in the formulations of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate, alone or in combination with wax; or other materials known in the art.

[0120] In addition, the compound of formula (I) can be delivered, for example, intravenously, subcutaneously, and / or intramuscularly via any pharmaceutically acceptable and suitable injection form. Examples of injection forms include, but are not limited to, sterile aqueous solutions containing acceptable vehicles and solvents (e.g., water, Ringer's solution, and isotonic sodium chloride solution), sterile oil-in-water microemulsions, and aqueous or oily suspensions.

[0121] Preparations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules by using one or more carriers or diluents described for use in oral preparations, or by using other suitable dispersing or wetting agents and suspending agents. The compound may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride solution, tragacanth gum, and / or various buffer solutions. Other adjuvants and administration methods are well known and widely known in the pharmaceutical field. The active ingredient may also be administered by injection in a composition with a suitable carrier (e.g., saline, dextrose, or water), or cyclodextrin (i.e., Captisol), solubilizing cosolvent (i.e., propylene glycol), or solubilizing micelle (i.e., Tween 80).

[0122] Alternatively, a sterile injectable preparation may be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent (e.g., a solution in 1,3-butanediol). Among the acceptable vehicles and solvents that may be used, water, Ringer's solution, and isotonic sodium chloride solution are used. Furthermore, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any sterile, fixed oil may be used, including synthetic monoglycerides or diglycerides. Furthermore, fatty acids such as oleic acid are used in injectable preparations.

[0123] Sterile injectable oil-in-water microemulsions can be prepared, for example, by 1) dissolving at least one compound of formula (I) in an oil phase (e.g., a mixture of soybean oil and lecithin), 2) combining the oil phase containing formula (I) with a mixture of water and glycerol, and 3) treating the combination to form a microemulsion.

[0124] Sterile aqueous suspensions or sterile oily suspensions can be prepared according to methods known to those skilled in the art. For example, sterile aqueous solutions or sterile aqueous suspensions can be prepared using non-toxic, parenterally acceptable diluents or solvents (e.g., 1,3-butanediol), and sterile oily suspensions can be prepared using non-toxic, acceptable solvents or suspension media (e.g., sterile fixed oils (e.g., synthetic monoglycerides or diglycerides) and fatty acids (e.g., oleic acid).

[0125] Pharmaceutically acceptable carriers, adjuvants, and vehicles that can 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) (e.g., d-α-tocopherol polyethylene glycol 1000 succinate), surfactants used in pharmaceutical dosage forms (e.g., Tween, polyethoxylated castor oil (e.g., CREMOPHOR surfactants (BASF), or other similar polymeric delivery matrices), serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphate, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids), water, salts, or electrolytes (e.g., protamine sulfate, PEG-100, PEG-1000), and the like. Examples of suitable cyclodextrins include hydroxypropyl methylcellulose, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin. Cyclodextrins (e.g., α-, β-, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkyl cyclodextrins, including 2- and 3-hydroxypropyl cyclodextrin, or other solubilizing derivatives) may also be effectively used to enhance delivery of the compounds of the formulae described herein.

[0126] The pharmaceutically active compounds of the present invention can be processed according to conventional pharmaceutical methods to produce medicaments for administration to patients (e.g., humans and other mammals). The pharmaceutical compositions may be subjected to conventional pharmaceutical operations (e.g., sterilization) and / or may contain conventional adjuvants (e.g., preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc.). Tablets and pills may further be prepared with enteric coatings. Such compositions may also contain adjuvants (e.g., wetting agents, sweeteners, flavoring agents, and perfumes).

[0127] The amount of compound and dosage regimen administered to treat a condition using the compounds and / or compositions of the present invention depend on various factors, such as age, weight, sex, the patient's condition, the type of disease, the severity of the disease, the route and frequency of administration, and the particular compound used. Therefore, dosage regimens may vary widely but can be routinely determined using standard methods. A daily dose of about 0.001 to 100 mg / kg body weight, preferably about 0.0025 to about 50 mg / kg body weight, and most preferably about 0.005 to 10 mg / kg body weight, may be appropriate. The daily dose may be administered one to four times daily. Other dosage regimens include weekly and biday cycles.

[0128] For treatment, the active compound of the present invention is usually combined with one or more adjuvants suitable for intended administration route.When administered orally, the compound can be mixed with lactose, sucrose, starch powder, cellulose ester of alkanoic acid, cellulose alkyl ester, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphate and sulfate, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol, and then tableted or encapsulated for suitable administration.Such capsules or tablets can also contain controlled-release formulations, and can also be provided by dispersing the active compound in hydroxypropylmethylcellulose.

[0129] Pharmaceutical compositions of the present invention include at least one compound of formula (I) and optional additives selected from pharmaceutically acceptable carriers, adjuvants, and vehicles. Another composition of the present invention includes a compound of formula (I) described herein, or a prodrug thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0130] The present invention also encompasses articles of manufacture. As used herein, the term "article of manufacture" is intended to include, but is not limited to, kits and packages. An article of manufacture of the present invention includes (a) a first container, (b) a pharmaceutical composition contained within the first container (wherein the composition includes a first therapeutic agent, the first therapeutic agent comprising a compound of the present invention or a pharmaceutically acceptable salt form thereof), and (c) a package insert stating that the pharmaceutical composition can be used to treat cardiovascular disorders, diuresis, and / or natriuresis. In other embodiments, the package insert states that the pharmaceutical composition can be used in combination with a second therapeutic agent (as defined above) to treat cardiovascular disorders, diuresis, and / or natriuresis. The article of manufacture may further include (d) a second container (wherein components (a) and (b) are contained within the second container and component (c) is located inside or outside the second container). "Located in the first and second containers" means that each container holds the item within its area.

[0131] The first container is a container used to hold the pharmaceutical composition. This container may be for manufacturing, storage, distribution, and / or individual / bulk sales. The first container is intended to include bottles, jars, vials, flasks, syringes, tubes (e.g., for creams), or any other container used in manufacturing, holding, storing, or distributing pharmaceutical formulations.

[0132] The second container is for holding the first container and, optionally, the package insert. Examples of the second container include, but are not limited to, boxes (e.g., cardboard or plastic), wooden boxes, corrugated boxes, bags (e.g., paper or plastic bags), pouches, and cloth bags. The package insert can be physically attached to the first container by tape, glue, staples, or other methods, or can be present in the second container without being physically attached to the first container. Alternatively, the package insert is located on the outside of the second container. When located on the outside of the second container, the package insert is preferably physically attached by tape, glue, staples, or other methods. Alternatively, the package insert can be close to or in contact with the outside of the second container without being physically attached.

[0133] A package insert is a label, tag, marker, or other written form that provides information related to the pharmaceutical composition placed in the first container. The information provided is typically determined by a regulatory agency (e.g., the U.S. Food and Drug Administration) governing the region in which the product will be sold. Preferably, the package insert specifically describes the indications for which the pharmaceutical composition is approved. The package insert may be made of any material that allows a person to read the information contained therein or thereon. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive paper, or plastic) onto which the desired information can be placed (e.g., printed or affixed).

[0134] (Manufacturing method) The compounds of the present invention can be prepared by a number of methods known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized by the following methods using synthetic methods known in the art of organic synthetic chemistry, or by analogous synthetic methods appreciated by those skilled in the art. Preferred methods include, but are not limited to, the following methods:

[0135] The reactions and techniques described in this section are carried out in solvents appropriate to the reagents and materials used and are suitable for the transformations being effected. It is also understood that in describing the synthetic methods set forth below, all proposed reaction conditions (including solvent selection, reaction atmosphere, reaction temperature, experimental time, and workup method) have been selected to be standard conditions for the reactions, and should be readily recognized by those skilled in the art. Those skilled in the art of organic synthesis will understand that functional groups present on various portions of the molecule must be compatible with the reagents and reactions shown. Such limitations on substituents compatible with the reaction conditions will be readily apparent to those skilled in the art, and alternative methods must be used. The reactions may sometimes require the determination to alter the order of synthetic steps or to select a different course of action for certain reactions to obtain the desired compounds of the present invention. It is also recognized that another important consideration in planning any synthetic route in this field is the selection of appropriate protecting groups to protect reactive functional groups contained in the compounds described herein. For those skilled in the art, an authoritative reference describing many protecting group options is Greene et al.: Protective Groups in Organic Synthesis, Third Edition, Wiley and Sons (1999). [Example]

[0136] (Example) The compounds of the present invention and intermediates used in preparing the compounds of the present invention can be prepared using the methods set forth in the following examples and related methods. The methods and conditions used in these examples, and the actual compounds prepared in these examples, are not meant to be limiting but rather to illustrate how the compounds of the present invention can be prepared. The starting materials and reagents used in these examples, unless their preparation is described herein, are generally commercially available or are reported in the chemical literature or may be prepared using processes described in the chemical literature. The present invention is further defined in the following examples, which should be understood as being given by way of illustration only. From the above discussion and examples, one skilled in the art will be able to ascertain the essential features of the present invention and can make changes and modifications to adapt the present invention to a wide range of conditions and applications without departing from the spirit and scope of the invention. Consequently, the present invention is not limited by the examples set forth below, but rather is defined by the claims appended hereto.

[0137] In the described examples, the phrase "dried and concentrated" generally refers to drying a solution in an organic solvent with either sodium sulfate or magnesium sulfate, followed by filtration and removal of the solvent from the filtrate (generally under reduced pressure at a temperature appropriate for the stability of the material being prepared).

[0138] Chemical names were determined using ChemDraw Professional, version 20.1.0.110 (PerkinElmer Informatics, Inc.). The following abbreviations are used:

[0139] [Table 1]

[0140] General scheme for the synthesis of piperazinyl quinolones [ka] Step 1. General Procedure for Preparing Compound 1 To a glass vial was added 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 G (0.1 equiv.), and 3M KPO (3.0 equiv.). The vial was sparged with N and a vent needle. 1,4-Dioxane (0.2 M) was then added, and the mixture was heated to 90 °C for 1 h. The mixture was loaded onto a pre-column of Celite and subjected to flash column chromatography using DCM / MeOH as the eluent. The product-containing fractions were combined and concentrated under reduced pressure to give compound 1.

[0141] Synthesis of 4-amino-4'-(4-isopropylpiperazin-1-yl)-[1,1'-biphenyl]-3-carbaldehyde: [ka] To a 40 mL vial was added 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 G (0.26 g, 0.32 mmol), and 3M KPO (3.2 mL, 9.7 mmol). The vial was sparged with N and a vent needle. 1,4-Dioxane (11 mL) was then added, and the mixture was heated to 90 °C for 1 h. The mixture was loaded onto a Celite pre-column and subjected to flash column chromatography using DCM / MeOH as the eluent. The product-containing fractions were combined and concentrated under reduced pressure to give 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: Found Mass: 324.2 (MH+ ); Retention time: 1.1 minutes. Analysis method 4 m / z 324.2 (MH + );Holding time: 1.30 minutes. 1 H NMR(500MHz, chloroform-d)δ9.94(s, 1H), 7.66(d, J = 2.2Hz, 1H), 7.55(dd, J = 8.5, 2.2Hz, 1H), 7.45(d, J = 8.7Hz, 2H), 6.99 (d, J = 8.9Hz, 2H), 6.71 (d, J = 8.6Hz, 1H), 6.09 (br s, 2H), 3.28-3.21 (m, 4H), 2.74-2.67 (m, 5H), 1.10 (d, J = 6.5Hz, 6H).

[0142] Step 2. General procedure for producing R1-substituted quinolones (compound 2): To a 4 mL vial was added 4-amino-4'-(4-isopropylpiperazin-1-yl)-[1,1'-biphenyl]-3-carbaldehyde (1.0 equiv.), a solution of T3P in 50% DMF (1.5 equiv.), a phenylacetic acid derivative (1.0 equiv.), DIPEA (2.0 equiv.), and DMF (0.2 M). The mixture was heated to 90 °C for 16 h. The mixture was then filtered through a 0.45 μm syringe filter and purified by preparative HPLC. The product-containing fractions were combined and concentrated by centrifugal evaporation to give the R 1 The substituted quinolone (compound 2) was obtained.

[0143] General scheme for the synthesis of N-alkylated quinolones (5) and O-alkylated quinolines (6) [ka] Step 1. General procedure for producing 6-bromoquinolones (3): To a glass vial was added 2-amino-5-bromobenzaldehyde (1.0 equiv.), phenylacetic acid derivative (1.0 equiv.), a 50% DMF solution of T3P (1.5 equiv.), DIPEA (2.0 equiv.), and DMF (0.2 M). The mixture was heated to 65-90°C for 16 hours. The mixture was diluted with at least 50 mL of water to precipitate a solid. The solid was collected by filtration to give 6-bromoquinolones (3).

[0144] Synthesis example of 6-bromoquinolone (3): Synthesis of 6-bromo-3-(4-nitrophenyl)quinolin-2(1H)-one: [ka] To a 10 mL glass vial was added 2-amino-5-bromobenzaldehyde (500 mg, 2.5 mmol), 2-(4-nitrophenyl)acetic acid (450 mg, 2.5 mmol), a 50% DMF solution of T3P (2.2 mL, 3.8 mmol), DIPEA (0.9 mL, 5.0 mmol), and DMF (12 mL). The mixture was heated to 65° C. for 16 hours. The mixture was diluted with at least 50 mL of water to precipitate a solid. The solid was collected by filtration to give 6-bromo-3-(4-nitrophenyl)quinolin-2(1H)-one (810 mg, 2.3 mmol, 94% yield). 1 H NMR (500MHz, DMSO-d6)δ8.36-8.29 (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).

[0145] Step 2. General procedure for producing N-alkylated bromoquinolones (4): To a glass vial was added 6-bromoquinolone (3) (1.0 equiv.), alkyl halide (3.0 equiv.), carbonate base (3.0 equiv.), and DMF (0.2 M). The mixture was heated to 70°C for 10 minutes to 1 hour. The mixture was diluted with 5 volumes of distilled water to precipitate a solid. The solid was collected by filtration to give a mixture of N- and O-alkylated products.

[0146] Synthesis example of N-alkylated bromoquinolone (4): Synthesis of 6-bromo-1-methyl-3-(4-nitrophenyl)quinolin-2(1H)-one: [ka] To a 20 mL glass vial were added 6-bromo-3-(4-nitrophenyl)quinolin-2(1H)-one (390 mg, 1.1 mmol), iodomethane (0.2 mL, 3.4 mmol), cesium carbonate (1.1 g, 3.4 mmol), and DMF (5.7 mL). The mixture was heated to 70°C for 10 minutes. The mixture was diluted with 5 volumes of distilled water to precipitate a solid. The solid was collected by filtration to give a mixture of 6-bromo-1-methyl-3-(4-nitrophenyl)quinolin-2(1H)-one (409 mg, 1.1 mmol, 100% yield) (Analysis Method 1: Found Mass: 358.8 (MH + ); retention time: 1.09 min) and 6-bromo-2-methoxy-3-(4-nitrophenyl)quinoline (Analysis Method 2: Measured mass: 358.8 (MH + ); retention time: 1.18 minutes).

[0147] Step 3. General procedure for producing compound 5 To a glass vial was added arylboronic ester (1.1 equiv.), bromoquinolone (1.0 equiv.), XPhos Pd G2 (0.1 equiv.), and 3M K3PO4 (3.0 equiv.). The mixture was sparged with N2 and a vent needle for 5 min. Dioxane (0.2 M) was added, and the mixture was heated to 90 °C for 20 min to 1 h. The crude reaction mixture was subjected to normal-phase flash column chromatography. Product-containing fractions were combined and concentrated under reduced pressure to give the Suzuki coupling adduct.

[0148] Synthesis example of compound 5: Synthesis of 6-(4-(4-isopropylpiperazin-1-yl)phenyl)-1-methyl-3-(4-nitrophenyl)quinolin-2(1H)-one: (Example 1) [ka] To a 4 mL glass vial was added 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 G (43 mg, 0.055 mmol), and 3M KPO (0.55 mL, 1.6 mmol). The mixture was sparged with N and a vent needle and heated to 90 °C for 20 min. The crude reaction mixture was subjected to flash column chromatography using DCM / MeOH as eluent. The product-containing fractions were combined and concentrated under reduced pressure to give 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: Found Mass: 483.3 (MH + ); Retention time: 0.848 minutes.

[0149] General reduction scheme of nitroarenes to anilines [ka] To a thick-walled round-bottom flask equipped with a magnetic stirrer was added nitroarene (1 equiv.), aqueous Pd / C (0.1 equiv.), and ethanol (0.2 M) under a N atmosphere. The flask was evacuated to vacuum and backfilled with N three times, after which the flask was evacuated to vacuum and backfilled with H (50 psi) and stirred at 23 °C for 1 h. The reaction mixture was filtered through Celite and concentrated under reduced pressure to give the aniline.

[0150] General scheme for preparing amide derivative 7 [ka] To a glass vial equipped with a magnetic stirrer, carboxylic acid (1.5 equiv.), HATU (1.5 equiv.), DMF (0.2 M), and DIPEA (2 equiv.) were added, and the mixture was stirred for 2 min at 23 °C. An aniline compound (1 equiv.) was added, and the mixture was stirred for 1 h at 23 °C. The mixture was purified by preparative reverse-phase HPLC to give carboxamide 7.

[0151] General scheme for amide derivative 9 [ka]

[0152] Step 1. General procedure for producing benzoic acid (8): To a glass vial was added benzoate (1.0 equiv.), 1 M aqueous lithium hydroxide (1.5 equiv.), and THF / water / MeOH (1 / 1 / 5, 0.1 M). The reaction mixture was heated to 80 °C for 1 h. The reaction mixture was dried by centrifugal evaporation to give benzoic acid 8 as the lithium salt, which was used directly in the amide bond coupling step.

[0153] Step 2. General procedure for generating amide derivatives (9): To a glass vial equipped with a magnetic stirrer was added the carboxylic acid (1.0 equiv.), a 50% DMF solution of T3P (2.0 equiv.), DMF (0.1 M), and DIPEA (3 equiv.). The mixture was stirred at 23 °C for 2 min. Aniline (1.2 equiv.) was added, and the mixture was stirred at 23 °C for 1 h. The mixture was purified by preparative reverse-phase HPLC to give carboxamide 9.

[0154] General scheme for aniline derivatives 11 [ka] Step 1. General procedure for producing bromobenzene 10: To a glass vial was added 2-aminoaldehyde (1.0 equiv.), 2-(4-bromophenyl)acetic acid (1.2 equiv.), a 50% DMF solution of T3P (1.5 equiv.), DIPEA (4.0 equiv.), and DMF (0.2 M). The mixture was heated to 150 °C in a microwave for 1 h. The reaction mixture was quenched with 5 volumes of 10% saturated LiCl and extracted with 3 equal volumes of EtOAc or DCM + 5% MeOH. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give bromobenzene 10.

[0155] Step 2. General procedure for generating aniline derivatives 11: 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) were added to a glass vial equipped with a magnetic stirrer. The mixture was sparged with N2 and a vent needle for 5 min. Si-thiol resin (0.5 equiv., 1.0 mmol / g) was added and stirred at 23 °C for 30 min, then passed through a 0.45 μm syringe filter. The mixture was purified by preparative reverse-phase HPLC to give the aniline derivative 11.

[0156] Procedure for producing 3-(4-hydroxyphenyl)-6-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2-dihydroquinolin-2-one: (Example 2) [ka] To a glass vial equipped with a magnetic stirrer was added 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 Pd G3 (5.1 mg, 6.0 μmol), and dioxane (1 mL). The mixture was sparged with N2 and a vent needle for 5 minutes. The mixture was heated at 90 °C for 3 hours. The mixture was concentrated by centrifugal evaporation and purified by preparative reverse-phase HPLC (Preparative Method 1) to give 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%; Found Mass: 440.2 (MH + ); Retention time: 1.2 min. Analysis Method 6: Purity: 100%; Measured mass: 440.0 (MH + ); Retention time: 1.58 minutes. 1 H NMR(500MHz, DMSO-d6) δ 11.87(s, 1H), 9.64(s, 1H), 8.04(s, 1H), 7.94(s, 1H), 7.74(dd, J = 8.5, 1.7Hz, 1H), 7.63(d, J = 8.6Hz, 2H), 7.60 (br d, J = 8.5Hz, 2H), 7.36 (d, J = 8.5Hz, 1H), 7.07 (br d, J = 8.2Hz, 2H), 6.82 (d, J = 8.5Hz, 2H), 3.28-2.88 (m, 8H), 1.18 (br d, J = 2.7Hz, 7H).

[0157] General scheme for the synthesis of C4-alkylated intermediate 15 [ka] Step 1. General procedure for generating ketone 13: To a glass vial equipped with a magnetic stirrer was added 2-amino-5-bromobenzonitrile (1.0 equiv.) and THF (0.5 M). The mixture was cooled to 0 °C. Next, a 1.0 M Grignard solution in THF (3.0 equiv.) was added dropwise, and the solution was stirred at 0 °C for 20 min before warming to 23 °C for 16 h. The reaction solution was quenched with 6 M hydrochloric acid (5.0 equiv.). The solution was stirred for 1 h, neutralized with 1 N NaOH, and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give ketone 13.

[0158] Synthesis of ketone 13: Synthesis of 1-(2-amino-5-bromophenyl)propan-1-one: [ka] To a 20 mL glass vial equipped with a magnetic stirrer was added 2-amino-5-bromobenzonitrile (2.1 g, 10.5 mmol) and THF (21 mL). The mixture was cooled to 0° C. Then, a 1.0 M Grignard solution in THF (32 mL, 31.5 mmol) was added dropwise, and the solution was stirred at 0° C. for 20 minutes before warming to 23° C. for 16 hours. The reaction solution was quenched with 6 M hydrochloric acid (8.8 mL, 53 mmol). The solution was stirred for 1 hour, neutralized with 1 N NaOH (100 mL), and extracted with EtOAc (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 1-(2-amino-5-bromophenyl)propan-1-one (2.35 g, 10.3 mmol, 98% yield). Analytical Method 1: Found Mass: 229.8 (MH + ); Retention time: 0.967 minutes. 1H NMR (500MHz, chloroform-d)δ7.84 (d, J = 2.2Hz, 1H), 7.32 (dd, J = 8.8, 2.3Hz, 1H), 6.56 (d, J = 8.9Hz, 1H), 6.29 (br s, 2H), 2.95 (q, J = 7.2Hz, 2H), 1.21 (t, J = 7.3Hz, 3H).

[0159] Step 2. General procedure for generating ketoamide 14: To a glass vial equipped with a magnetic stirrer was added 13 (1.0 equiv.), EDCI (2.0 equiv.), phenylacetic acid (2.0 equiv.), DIPEA (3.0 equiv.), and DCM (0.2 M). The mixture was stirred at 23 °C for 2 h. The reaction mixture was subjected to flash column chromatography, and the product-containing fractions were concentrated under reduced pressure to give ketoamide 14.

[0160] Synthesis of ketoamide 14: Synthesis of N-(4-bromo-2-propionylphenyl)-2-(4-(methylsulfonyl)phenyl)acetamide: [ka] To a 40 mL glass vial equipped with a magnetic stirrer was added 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). The mixture was stirred at 23 °C for 2 h. The reaction mixture was subjected to flash column chromatography, and the product-containing fractions were concentrated under reduced pressure to give N-(4-bromo-2-propionylphenyl)-2-(4-(methylsulfonyl)phenyl)acetamide (560 mg, 1.3 mmol, 60% yield). Analytical Method 1: Found Mass: 425.9 (MH + ); Retention time: 0.940 minutes.

[0161] Step 3. General procedure for producing quinolone 15: To a glass vial equipped with a magnetic stirrer was added ketoamide 14 (1.0 equiv) and EtOH (0.2 M). The mixture was cooled to 0 °C. To the stirred mixture was added 60% sodium hydride (3.0 equiv), and after 5 min the mixture was stirred at 23 °C for 1 h. The solvent was evaporated under a stream of N2 gas, and water (5 vol) was added to dissolve the residual sodium ethoxide. The solid precipitate was filtered through a sintered glass funnel and air-dried to recover quinolone 15.

[0162] Synthesis example of quinolone 14: Synthesis of 6-bromo-4-ethyl-3-(4-(methylsulfonyl)phenyl)quinolin-2(1H)-one: [ka] To a 20 mL glass vial equipped with a magnetic stirrer was added N-(4-bromo-2-propionylphenyl)-2-(4-(methylsulfonyl)phenyl)acetamide (558 mg, 1.3 mmol) and EtOH (6.6 mL). The reaction mixture was cooled to 0 °C. To the stirred mixture was added 60% sodium hydride (158 mg, 4.0 mmol) 5 min later, and the mixture was stirred at 23 °C for 1 h. The solvent was evaporated under a stream of N2 gas, and water (33 mL) was added to dissolve the residual sodium ethoxide. The solid precipitate was filtered through a sintered glass funnel and air-dried to recover 6-bromo-4-ethyl-3-(4-(methylsulfonyl)phenyl)quinolin-2(1H)-one (480 mg, 1.2 mmol, 90% yield). Analytical Method 3: Found Mass: 407.8 (MH + ); Retention time: 1.712 minutes.

[0163] General scheme for the synthesis of bispiperidine compound 18 [ka]

[0164] Step 1. General procedure for producing compound 16: Compound 15 (1.0 equiv.), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.5 equiv.), XPhos Pd G (0.1 equiv.), 3M KPO (3.0 equiv.), and dioxane (0.2 M) were added to a glass vial equipped with a magnetic stirrer. The reaction mixture was heated to 90 °C under N for 2 h. The reaction mixture was subjected to flash column chromatography, and the product-containing fractions were pooled and concentrated under reduced pressure.

[0165] Synthesis 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: [ka] To an 8 mL glass vial equipped with a magnetic stirrer was added 6-bromo-4-ethyl-3-(4-(methylsulfonyl)phenyl)quinolin-2(1H)-one (135 mg, 0.33 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (154 mg, 0.50 mmol), XPhos Pd G2 (26 mg, 0.033 mmol), 3M K3PO4 (0.33 mL, 1.0 mmol), and dioxane (1.6 mL). The reaction mixture was heated to 90 °C under N2 for 2 h. The reaction mixture was subjected to flash column chromatography, and the product-containing fractions were pooled and concentrated under reduced pressure to give the title compound (108 mg, 0.21 mmol, 64% yield). Analysis method 1: Measured mass: 509.1 (MH + ); Retention time: 0.958 minutes.

[0166] Step 2. General procedure for producing compound 17: To a thick-walled round-bottom flask equipped with a magnetic stirrer was added compound 16 (1.0 equiv.), aqueous Pd / C (0.1 equiv.), and ethanol (minimum amount to dissolve the residue). The flask was evacuated to vacuum and backfilled with N2 three times. The flask was then evacuated to vacuum and backfilled with H2 (50 psi) three times 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 4 M hydrochloric acid / dioxane (0.2 M) and stirred at 23 °C for 1 h, followed by concentration under reduced pressure to give compound 17 as the hydrochloride salt.

[0167] Synthesis example of compound 17: Synthesis of 4-ethyl-3-(4-(methylsulfonyl)phenyl)-6-(piperidin-4-yl)quinolin-2(1H)-one: [ka] To a 250 mL thick-walled round-bottom flask equipped with a magnetic stirrer was added tert-butyl 4-(4-ethyl-3-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydroquinolin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (108 mg, 0.21 mmol), aqueous Pd / C (71 mg, 0.033 mmol), and ethanol (10 mL). The flask was evacuated to vacuum and backfilled with N three times. The flask was then evacuated to vacuum and backfilled with H (50 psi) three times 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 4 M HCl / dioxane (1.5 mL) and stirred at 23 °C for 1 h before being concentrated under reduced pressure. This material was further purified by reverse-phase preparative HPLC (Preparation Method 2) to give the title compound as the hydrochloride salt (1.6 mg, 0.0039 mmol, 1% yield). Analytical Method 5: Purity: 100%; Found Mass: 411.0 (MH + Retention time: 1.02 min; Analysis Method 6: Purity: 100%; Measured mass: 411.0 (MH + ); Retention time: 1.02 minutes.

[0168] Step 3. General procedure for producing compound 18: To a glass vial equipped with a magnetic stirrer was added compound 17 (1.0 equiv.) as the HCl salt, 1-isopropylpiperidin-4-one (10 equiv.), MgSO (10 equiv.), and 10 / 1 DMF / AcOH (0.1 M). The reaction mixture was stirred at 60 °C for 15 min, followed by the addition of NaCNBH (10 equiv.). The reaction mixture was stirred at 60 °C for 72 h. The reaction was quenched with 1 M NaOH (20 vol.), and the reaction mixture was extracted with DCM (20 vol.). The organic layer was concentrated under reduced pressure, and the residue was dissolved in DMF and subjected to preparative reverse-phase HPLC. The product-containing fractions were concentrated by centrifugal evaporation to give compound 18.

[0169] Synthesis example of compound 18: Synthesis of 4-ethyl-6-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-3-(4-(methylsulfonyl)phenyl)quinolin-2(1H)-one: [ka] Compound 17 (28 mg, 0.063 mmol) as the HCl salt, 1-isopropylpiperidin-4-one (88 mg, 0.63 mmol), MgSO (75 mg, 0.63 mmol), and 10 / 1 DMF / AcOH (0.6 mL / 0.06 mL) were added to a glass vial equipped with a magnetic stirrer. The reaction mixture was stirred at 60°C for 15 minutes, after which NaCNBH (39 mg) was added. The reaction mixture was stirred at 60°C for 72 hours. The reaction was quenched with 1M 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 preparative reverse-phase HPLC (Preparative Method 1). The product-containing fractions were concentrated by centrifugal evaporation to give the title compound (5.2 mg, 0.0097 mmol, 15% yield). Analysis Method 5: Purity: 100%; Measured Mass: 536.3 (MH +Retention time: 0.94 min; Analysis Method 6: Purity: 100%; Measured mass: 536.5 (MH + ); Retention time: 1.12 minutes. 1 H NMR (500MHz, DMSO-d6) δ 11.84 (br s, 1H), 7.99 (d, J = 8.0Hz, 2H), 7.62 (s, 1H), 7.50 (d, J = 7.9Hz, 2H), 7.45 (br d, J = 8.8Hz, 1H), 7.30 (d, J = 8.5Hz, 1H), 3.28 (s, 3H), 3.04-2.95 (m, 2H), 2.89 (br dd, J = 5.1, 1.9Hz, 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 (br t, J = 7.4Hz, 3H), 0.98 (br d, J = 6.5Hz, 6H).

[0170] General scheme for the synthesis of compound 19: [ka]

[0171] General procedure for producing compound 19: To a glass vial equipped with a magnetic stirrer was added compound 15 (1.0 equiv.), amine (1.2 equiv.), Pd2(dba)3 (0.1 equiv.), Xantphos (0.1 equiv.), NaOtBu (2.0 equiv.), and dioxane (0.2 M). The reaction mixture was sparged with N2 and a vent needle for 5 min and stirred at 90 °C under N2 for 1 h. The mixture was subjected to normal-phase flash column chromatography followed by preparative reverse-phase HPLC. The product-containing fractions were concentrated by centrifugal evaporation to give compound 19.

[0172] Synthesis 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) [ka] To an 8 mL glass vial equipped with a magnetic stirrer 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), Pd2(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 sparged with N2 and a vent needle for 5 min and stirred at 90 °C under N2 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 product-containing fractions were concentrated by centrifugal evaporation to give the title compound (5.8 mg, 0.011 mmol, 9% yield). Analytical Method 5: Purity: 100%; Found Mass: 531.1 (MH + Retention time: 1.30 min; Analysis method 6: Purity: 100%; Measured mass: 531.1 (MH + ); Retention time: 1.47 minutes. 1H NMR(500MHz, DMSO-d6)δ8.12(s, 1H), 8.02-7.98(m, 2H), 7.97-7.93(m, 2H), 7.91(s, 1H), 7.45(d, J = 9.1Hz, 1H), 7.32(d, J = 2.4Hz, 1H), 7.28(dd, J = 9.0, 2.5Hz, 1H), 7.03 (d, J = 8.9Hz, 2H), 6.89 (d, J = 8.9Hz, 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 = 6.5Hz, 6H).

[0173] The following examples were prepared according to the general procedures described herein using the appropriate starting materials, reagents and conditions. [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] Table 11 Table 12 Table 13 Table 14 Table 15 Table 16 Table 17 Table 18 Table 19 Table 20 Table 21

[0174] Table 22 Table 23 Table 24 Table 25 Table 26 Table 27 Table 28 Table 29 Table 30 Table 31 Table 32 Table 33 Table 34 Table 35 Table 36 Table 37 Table 38 [Table 39] [Table 40] [Table 41] [Table 42] [Table 43]

[0175] Analytical LC / MS method Method 1 (TFA, 1 min): Starting % B = 0, gradient over 1 min to final % B = 100; flow rate = 1.0 mL / min; wavelength = 254 nm; solvent A = 0.05% TFA / MeCN:HO (5:95); solvent B = 0.05% TFA / MeCN:HO (95:5); column = Acquity BEH C18 1.7 μm particle size; 2.1 x 50 mm; temperature = 50 °C. Method 2 (Ammonium acetate, 1 min): Starting % B = 0, gradient over 1 min to final % B = 100; flow rate = 1.0 mL / min; wavelength = 220 nm; Solvent A = 10 mM NHOAc / MeCN:HO (5:95); Solvent B = 10 mM NHOAc / MeCN:HO (95:5); Column = Acquity BEH C18 1.7 μm particle size; 2.1 x 50 mm; Temperature = 50 °C. Method 3 (TFA, 3 min): Starting % B = 0, gradient over 3 min to final % B = 100; flow rate = 1.0 mL / min; wavelength = 254 nm; solvent A = 0.05% TFA / MeCN:HO (5:95); solvent B = 0.05% TFA / MeCN:HO (95:5); column = Acquity BEH C18 1.7 μm particle size; 2.1 x 50 mm; temperature = 50 °C. Method 4 (Ammonium acetate, 3 min): Starting % B = 0, gradient over 3 min to final % B = 100; flow rate = 1.0 mL / min; wavelength = 254 nm; Solvent A = 10 mM NHOAc / MeCN:HO (5:95); Solvent B = 10 mM NHOAc / MeCN:HO (95:5); Column = Acquity BEH C18 1.7 μm particle size; 2.1 x 50 mm; Temperature = 50 °C. Method 5 (SCP TFA, 3 min): Starting % B = 0, gradient over 3 min to final % B = 100; flow rate = 1.0 mL / min; wavelength = 254 nm; solvent A = 0.05% TFA / MeCN:HO (5:95); solvent B = 0.05% TFA / MeCN:HO (95:5); column = XBridge C18 1.7 μm particle size; 2.1 x 50 mm; temperature = 50 °C. Method 6 (SCP Ammonium Acetate, 3 min): Starting % B = 0, gradient over 3 min to final % B = 100; flow rate = 1.0 mL / min; wavelength = 254 nm; Solvent A = 10 mM NHOAc / MeCN:HO (5:95); Solvent B = 10 mM NHOAc / MeCN:HO (95:5); Column = XBridge C18 1.7 μm particle size; 2.1 x 50 mm; Temperature = 50 °C.

[0176] Preparative HPLC purification method: Method 1 (SCP Ammonium Acetate): Column: XBridge C18, 19 mm x 200 mm, 5 μm particle size; Flow rate: 20 mL / min; Mobile phase A: 10 mM NHOAc / MeCN:HO (5:95); Mobile phase B: 10 mM NHOAc / MeCN:HO (95:5); Column temperature: 25 °C. Fraction collection was triggered by MS signal. Fractions containing the desired product were combined and dried by centrifugal evaporation. Method 2 (SCP TFA): Column: XBridge C18, 19 mm x 200 mm, 5 μm particle size; Flow rate: 20 mL / min; Column Mobile Phase A: 0.05% TFA / MeCN:HO (5:95); Mobile Phase B: 0.05% TFA / MeCN:HO (95:5); Column Temperature: 25 °C. Fraction collection was triggered by MS signal. Fractions containing the desired product were combined and dried by centrifugal evaporation. Method 3: Column: XBridge C18, 200 mm x 19 mm, 5 μm particle size; 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: 40% B for 0 min, 40–80% B for 20 min, then 100% B for 4 min; Flow rate: 20 mL / min; Column temperature: 25°C. Fraction collection was triggered by MS signal. Fractions containing the desired product were combined and dried by centrifugal evaporation. Method 4: The crude material was purified by preparative LC / MS using the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particle size; Mobile Phase A: 5:95 acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile Phase B: 95:5 acetonitrile:water (with 0.1% trifluoroacetic acid); Gradient: 32% B, hold at 0 min, 32–72% B over 20 min, then 100% B, hold for 4 min; Flow rate: 20 mL / min; Column temperature: 25°C. Fraction collection was triggered by the MS signal. Fractions containing the desired product were combined and dried by centrifugal evaporation. Method 5: Column: XBridge C18, 200 mm x 19 mm, 5 μm particle size; 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: 34% B held for 0 min, 34–84% B held for 20 min, then 100% B held for 4 min; Flow rate: 20 mL / min; Column temperature: 25°C. Fraction collection was triggered by UV signal. Fractions containing the desired product were combined and dried by centrifugal evaporation.

[0177] Biological assays The pharmacological properties of the compounds of this invention may be confirmed by a number of biological assays. The following exemplified biological assays have been carried out with the compounds of the invention.

[0178] TLR7 / 8 / 9 inhibition reporter assay HEK-Blue overexpressing human TLR7, TLR8, or TLR9 receptors TMCells (Invivogen) were used to screen for inhibitors of these receptors using an inducible SEAP (secreted placental alkaline phosphatase) reporter gene under the control of an IFN-β minimal promoter fused to five NF-κB and AP-1 binding sites. Briefly, cells were seeded into 384-well plates (Greiner) at 15,000 cells / well for TLR7, 20,000 cells / well for TLR8, and 25,000 cells / well for TLR9, and then treated with test compounds in DMSO over a final dose-response range of 0.05 nM to 50 μM. After pre-treatment with compounds for 30 min at room temperature, cells were stimulated with TLR7 ligand (gardiquimod at a final concentration of 7.5 μM), TLR8 ligand (R848 at a final concentration of 15.9 μM), or TLR9 ligand (ODN2006 at a final concentration of 5 nM) to activate NF-κB and AP-1, which induces SEAP production. After 22 h of incubation (37°C, 5% CO), SEAP levels were measured using HEK-Blue chromatin according to the manufacturer's specifications. TM Detection reagent (Invivogen) and cell culture medium enabling detection of SEAP were added. Inhibition was determined by the percent reduction in HEK-Blue signal present in wells treated with agonist plus DMSO alone compared to wells treated with a known inhibitor.

[0179] [Table 44] [Table 45] [Table 46] [Table 47]

Claims

1. Formula (I): 【Chemistry 1】 [In the formula, R 1 is phenyl, pyridinyl, pyrimidinyl, indolyl, indazolyl, or quinoxalinyl, each of which is represented by 0 to 5 R 1a is substituted with; Each R 1a are 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)(pyridinyl), -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 is hydroxyalkyl; L is a bond or -NH-; R 3 are R 3a phenyl or piperidinyl substituted with; R 3a is -CH 3 or a cyclic group selected from piperidinyl and piperazinyl, said cyclic group being 3b is substituted with; R 3b is C 1-3 alkyl or oxetanyl; R 4 is hydrogen or C 1-2 is alkyl; and Each R x are independently H or -CH 3 is] or a salt thereof.

2. Each R 1a are 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)(pyridinyl), -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 But R 3a phenyl or piperidinyl, each substituted with R 3a But -CH 3 or a cyclic group selected from piperidinyl and piperazinyl, said cyclic group being 3b is substituted with; R 3b But -CH 3 , -CH(CH 3 ) 3 or oxetanyl; and R 4 is hydrogen or -CH 2 CH 3 is] The compound according to claim 1 or a salt thereof.

3. R 1 However, 0 to 5 R 1a 2. The compound of claim 1, or a salt thereof, wherein R is phenyl, pyridinyl, or pyrimidinyl, each of which is substituted with R.

4. R 1 However, 0 to 5 R 1a 2. The compound of claim 1, or a salt thereof, wherein the phenyl is substituted with .

5. 2. The compound of claim 1, or a salt thereof, having the structure of formula (I), wherein L is a bond.

6. R 3 But 0 to 1 R 3a 2. The compound of claim 1 having the structure of formula (I), or a salt thereof, wherein R is phenyl substituted with R.

7. R 3a is a cyclic group selected from piperidinyl and piperazinyl, and said cyclic group is selected from zero or one R 3b 2. The compound of claim 1 having the structure of formula (I) or a salt thereof, wherein:

8. R 3 but, (i) piperidinyl or phenyl, each substituted with piperidinyl; or (ii) phenyl-substituted piperazinyl; 2. The compound of claim 1 having the structure of formula (I) or a salt thereof:

9. R 3 but, 【Chemistry 2】 2. The compound according to claim 1, having the structure of formula (I), or a salt thereof:

10. R 1 but, 【Transformation 3】 2. The compound according to claim 1, wherein:

11. 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), 2. The compound according to claim 1, wherein:

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

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

15. A compound or salt thereof according to any one of claims 1 to 11 or a pharmaceutical composition according to claim 10 for use in therapy.

16. 12. 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. 17. The compound for use according to claim 16, wherein the pathological fibrosis is liver fibrosis, kidney fibrosis, bile duct fibrosis or pancreatic fibrosis.

18. 12. The compound of 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. 12. 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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