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EP-4200297-B1 - IMIDAZO[1,2-A]PYRIDINE AND [1,2,4]TRIAZOLO[1,5-A]PYRIDINE DERIVATIVES AS TLR9 INHIBITORS FOR THE TREATMENT OF FIBROSIS

EP4200297B1EP 4200297 B1EP4200297 B1EP 4200297B1EP-4200297-B1

Inventors

  • YOON, DAVID S.
  • REGUEIRO-REN, ALICIA
  • DEGNAN, ANDREW P.
  • WU, GANG

Dates

Publication Date
20260513
Application Date
20210818

Claims (12)

  1. A compound of Formula (II): or stereoisomers, tautomer, solvates or salts thereof, wherein: X is N or CR 3 ; one of Q 1 and Q 2 is A and the other of Q 1 and Q 2 is R 5 ; G is phenyl substituted with 1 to 3 substituents independently selected from -S(O) 2 CH 3 , -S(O) 2 (phenyl), -S(O) 2 NR x R x , and -S(O)(NH)NR x R x ; A is cyclohexyl, piperidinyl, phenyl, pyridinyl, pyrimidinyl, 6-azabicyclo[3.2.1]octanyl, or azabicyclo[3.2.1]octanyl, each substituted with -L-R 4 and zero to 1 R 4b ; L is a bond, -CR x R x - or -C(O)(CR x R x ) 0-2 -; R 3 is hydrogen, F, Cl, C 1-3 alkyl, C 1-2 fluoroalkyl, or C 3-4 cycloalkyl; R 4 is: (i) -N(CH 3 ) 2 ; (ii) pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, pyridinyl, azaspiro[3.3]heptanyl, azabicyclo[3.2.1]octanyl, or diazabicyclo[3.2.1]octanyl, each substituted with zero to 2 R 4a ; or each R 4a is independently C 1-6 alkyl, C 1-3 fluoroalkyl, -(CH 2 ) 0-2 O(C 1-2 alkyl), C 3-6 cycloalkyl, -CH 2 (C 3-6 cycloalkyl), -C(O)(C 1-4 alkyl), -C(O)(C 3-6 cycloalkyl), -C(O)(phenyl), -C(O)CH 2 (C 3-6 cycloalkyl), -C(O)CH 2 (phenyl), -C(O)O(C 1-4 alkyl), oxetanyl, tetrahydrofuran, or tetrahydropyranyl; R 4b is F, Cl, or -CH 3 ; each R 4c is independently C 1-6 alkyl, C 1-3 fluoroalkyl, -CH 2 (C 3-6 cycloalkyl), -C(O)(C 1-4 alkyl), -C(O)(phenyl), -C(O)CH 2 (phenyl), -C(O)OCH 2 CH 3 , or C 3-6 cycloalkyl; each R 5 is independently hydrogen, F, Cl, C 1-3 alkyl, C 1-2 fluoroalkyl, or C 3-4 cycloalkyl; each R x is independently hydrogen or -CH 3 ; m is zero, 1, or 2; n is zero, 1, or 2; and q is 1 or 2.
  2. The compound according to claim 1 or stereoisomers, tautomer, solvates or salts thereof, wherein G is phenyl substituted with -S(O) 2 CH 3 , -S(O) 2 (phenyl), -S(O) 2 NR x R x , or -S(O)(NH)NR x R x .
  3. The compound according to claim 1 or stereoisomers, tautomer, solvates or salts thereof, wherein X is CR 3 .
  4. The compound according to claim 1 or stereoisomers, tautomer, solvates or salts thereof, wherein X is N.
  5. The compound according to claim 1 or stereoisomers, tautomer, solvates or salts thereof, wherein: G is phenyl substituted with 1 to 2 substituents selected from -S(O) 2 CH 3 ; A is cyclohexyl, piperidinyl, phenyl, or 6-azabicyclo[3.2.1]octanyl, each substituted with -L-R 4 ; L is a bond; R 3 is hydrogen; R 4 is piperidinyl, piperazinyl, azepanyl, azaspiro[3.3]heptanyl, azabicyclo[3.2.1]octanyl, or diazabicyclo[3.2.1]octanyl, each substituted with R 4a ; R 4a is -CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH 2 OCH 3 , -C(O)CH(CH 3 ) 2 , -C(O)(cyclopropyl), -CH 2 (cyclopropyl), -CH 2 (cyclobutyl), cyclopropyl, cyclobutyl, oxetanyl, or tetrahydropyranyl; and each R 5 is hydrogen, F, or -CH 3 .
  6. The compound according to claim 1 or stereoisomers, tautomer, solvates or salts thereof, wherein G is
  7. The compound according to claim 1 or stereoisomers, tautomer, solvates or salts thereof, wherein said compound is: 6-(1'-cyclopropyl-[1,4'-bipiperidin]-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl) imidazo[1,2-a]pyridine (7); 6-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl) imidazo[1,2-a]pyridine (8); 6-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl) imidazo[1,2-a]pyridine (9); 6-(1-(8-isopropyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (62-63); 7-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-5-methyl-2-(4-(methylsulfonyl)phenyl) imidazo[1,2-a]pyridine (66); 8-fluoro-6-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-2-(4-(methylsulfonyl)phenyl) imidazo[1,2-a]pyridine (67); 8-fluoro-6-(1-(8-isopropyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (68-69); 7-fluoro-6-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-2-(4-(methylsulfonyl)phenyl) imidazo[1,2-a]pyridine (70); 8-fluoro-6-(1-(1-isopropylazepan-4-yl)piperidin-4-yl)-2-(4-(methylsulfonyl) phenyl)imidazo[1,2-a]pyridine (71-72); 5-fluoro-6-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-2-(4-(methylsulfonyl)phenyl) imidazo[1,2-a]pyridine (73); 8-fluoro-7-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-2-(4-(methylsulfonyl)phenyl) imidazo[1,2-a]pyridine (74); 6-(1-(8-cyclobutyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (83-84); 6-(1-(8-isobutyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (85-86); 6-(1-(8-(cyclopropylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (87-88); 6-(1-(8-(cyclobutylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (89-90); 6-(1'-cyclobutyl-[1,4'-bipiperidin]-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl) imidazo[1,2-a]pyridine (91); 6-(1'-(cyclopropylmethyl)-[1,4'-bipiperidin]-4-yl)-8-methyl-2-(4-(methylsulfonyl) phenyl)imidazo[1,2-a]pyridine (92); 6-(1'-(cyclobutylmethyl)-[1,4'-bipiperidin]-4-yl)-8-methyl-2-(4-(methylsulfonyl) phenyl)imidazo[1,2-a]pyridine (93); 6-(4-(4-isobutylpiperazin-1-yl)phenyl)-8-methyl-2-(4-(methylsulfonyl)phenyl) imidazo[1,2-a]pyridine (99); 6-(4-(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (100); 6-(4-(4-(cyclobutylmethyl)piperazin-1-yl)phenyl)-8-methyl-2-(4-(methylsulfonyl) phenyl)imidazo[1,2-a]pyridine (101); 6-(4-(4-cyclobutylpiperazin-1-yl)phenyl)-8-methyl-2-(4-(methylsulfonyl)phenyl) imidazo[1,2-a]pyridine (102); 8-methyl-2-(4-(methylsulfonyl)phenyl)-6-(4-(4-(oxetan-3-yl)piperazin-1-yl) phenyl)imidazo[1,2-a]pyridine (103); 8-methyl-2-(4-(methylsulfonyl)phenyl)-6-(4-(4-(tetrahydro-2H-pyran-4-yl) piperazin-1-yl)phenyl)imidazo[1,2-a]pyridine (104); 6-(4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)-8-methyl-2-(4-(methylsulfonyl) phenyl)imidazo[1,2-a]pyridine (105); 7-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-5-methyl-2-(4-(methylsulfonyl)phenyl) imidazo[1,2-a]pyridine (106); 8-fluoro-6-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-2-(4-(methylsulfonyl)phenyl) imidazo[1,2-a]pyridine (107); 6-(1'-cyclopropyl-[1,4'-bipiperidin]-4-yl)-8-fluoro-2-(4-(methylsulfonyl)phenyl) imidazo[1,2-a]pyridine (108); 6-(1'-(cyclopropylmethyl)-[1,4'-bipiperidin]-4-yl)-8-fluoro-2-(4-(methylsulfonyl) phenyl)imidazo[1,2-a]pyridine (109); 6-(1'-cyclobutyl-[1,4'-bipiperidin]-4-yl)-8-fluoro-2-(4-(methylsulfonyl)phenyl) imidazo[1,2-a]pyridine (110); 8-fluoro-2-(4-(methylsulfonyl)phenyl)-6-(1'-(oxetan-3-yl)-[1,4'-bipiperidin]-4-yl) imidazo[1,2-a]pyridine (111); 8-fluoro-2-(4-(methylsulfonyl)phenyl)-6-(1'-(tetrahydro-2H-pyran-4-yl)-[1,4'-bipiperidin]-4-yl)imidazo[1,2-a]pyridine (112); 8-fluoro-6-(1-(8-isobutyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (113-114); 6-(1-(8-(cyclopropylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-8-fluoro-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (115-116); 6-(1-(8-cyclobutyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-8-fluoro-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (117); 6-(1-(8-cyclobutyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-8-fluoro-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (118); 8-fluoro-2-(4-(methylsulfonyl)phenyl)-6-(1-(8-(oxetan-3-yl)-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)imidazo[1,2-a]pyridine (119-120); 8-fluoro-2-(4-(methylsulfonyl)phenyl)-6-(1-(8-(tetrahydro-2H-pyran-4-yl)-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)imidazo[1,2-a]pyridine (121-122); 7-fluoro-6-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-2-(4-(methylsulfonyl)phenyl) imidazo[1,2-a]pyridine (123); 6-(1'-cyclopropyl-[1,4'-bipiperidin]-4-yl)-7-fluoro-2-(4-(methylsulfonyl)phenyl) imidazo[1,2-a]pyridine (124); 8-fluoro-6-(1-(1-isobutylazepan-4-yl)piperidin-4-yl)-2-(4-(methylsulfonyl)phenyl) imidazo[1,2-a]pyridine (125-126); 6-(1-(1-(cyclopropylmethyl)azepan-4-yl)piperidin-4-yl)-8-fluoro-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (127-128); 8-fluoro-2-(4-(methylsulfonyl)phenyl)-6-(1-(1-(tetrahydro-2H-pyran-4-yl)azepan-4-yl)piperidin-4-yl)imidazo[1,2-a]pyridine (129-130); 5-fluoro-6-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-2-(4-(methylsulfonyl)phenyl) imidazo[1,2-a]pyridine (131); 8-fluoro-7-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-2-(4-(methylsulfonyl)phenyl) imidazo[1,2-a]pyridine (132); 8-fluoro-2-(4-(methylsulfonyl)phenyl)-7-(1'-(tetrahydro-2H-pyran-4-yl)-[1,4'-bipiperidin]-4-yl)imidazo[1,2-a]pyridine (133); 6-(4-(4-isopropylpiperazin-1-yl)phenyl)-8-methyl-2-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine (147); 6-(4-(8-isopropyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)-8-methyl-2-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine (153); 6-(8-(1-cyclopropylpiperidin-4-yl)-8-azabicyclo[3.2.1]octan-3-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine (159); 6-(8-(1-isopropylpiperidin-4-yl)-8-azabicyclo[3.2.1]octan-3-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine (160); 6-(1'-cyclopropyl-[1,4'-bipiperidin]-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine (161); 6-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine (162); 6-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine (163); or 6-(4-(4-isopropylpiperazin-1-yl)phenyl)-2-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine (167).
  8. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 7 or stereoisomers, tautomer, solvates or pharmaceutically-acceptable salts thereof; and a pharmaceutically acceptable carrier.
  9. A compound according to any one of claims 1 to 7 or stereoisomers, tautomers, solvates or pharmaceutically-acceptable salts thereof, or a pharmaceutical composition according to claim 8, for use in treating pathological fibrosis.
  10. The compound or stereoisomers, tautomers, solvates or a pharmaceutically-acceptable salt thereof, or pharmaceutically-acceptable salts thereof, or the pharmaceutical composition, for use according to claim 9 wherein said pathological fibrosis is liver fibrosis, renal fibrosis, biliary fibrosis, or pancreatic fibrosis.
  11. A compound according to any one of claims 1 to 7 or stereoisomers, tautomers, solvates or pharmaceutically-acceptable salts thereof, or a pharmaceutical composition according to claim 8, for use in treating nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis (PSC), or primary biliary cirrhosis (PBC).
  12. A compound according to any one of claims 1 to 7 or stereoisomers, tautomers, solvates or pharmaceutically-acceptable salts thereof, or a pharmaceutical composition according to claim 8, for use in treating idiopathic pulmonary fibrosis (IPF).

Description

The present invention generally relates to substituted bicyclic compounds useful as inhibitors of signaling through Toll-like receptor 9 (TLR9). Provided herein are substituted bicyclic compounds, compositions comprising such compounds, and said compounds for use in methods of medical treatment. The invention further pertains to pharmaceutical compositions containing at least one compound according to the invention that are useful for the treatment of conditions related to TLR9 modulation, such as inflammatory and autoimmune diseases, and methods of inhibiting the activity of TLR9 in a mammal. Toll-like receptors (TLRs) are transmembrane proteins having the ability to initiate an inflammatory response upon recognition of pattern-associated molecular patterns (PAMPs) or microbe-associated molecular patterns (MAMPs). A total of 10 human TLRs have been identified and can be located in the cell surface or, as in the case of TLR7, 8 and 9, in the endolysosomes. TLR9 recognizes unmethylated single-stranded DNA containing cytosine-phosphate-guanine (CpG) motifs that are typically found in bacterial and mitochondrial DNA (mtDNA). TLR9 may contribute to fibrogenesis by promoting inflammation via the MyD88-dependent signalling pathway that ultimately mediates activation of IL-6, IFN-α, IL-1β, and TNF-α among others cytokines. (Barton GM, Kagan JC (2009) Nat. Rev. Immunol. 9(8), 535-42; Li X, Jiang S, Tapping RI (2010), Cytokine 49(1), 1-9). TLR9 levels are higher in lung biopsies of rapid idiopathic pulmonary fibrosis (IPF) progressors than in the healthy or stable IPF progressors (Sci. Transl. Med. 2010, 2(57):57ra82). Circulating mtDNA, the ligand for TLR9 has recently been identified as a mechanism-based prognostic biomarker of IPF (Am J. Resp. and Crit. Care Med. 2017, 196(12), 1502). In addition, it has been observed that TLR9 is up-regulated in human and murine non-alcoholic steatohepatitis (NASH) (Clin. Sci. 2017, 131(16), 2145), while hepatocyte mitochondrial DNA drives NASH via activation of TLR9 (J. Clin. Inv. 2016, 126(3), 859. Accordingly, inhibitors/antagonists of TLR9 are predicted to have efficacy as novel therapeutic agents to treat fibrotic diseases. TLR9 inhibition has been recognized as a potential route to therapies for fibrotic diseases including idiopathic pulmonary fibrosis (Trujillo et al. Sci. Transl. Med. 2010, 2(57):57ra82; Yoshizaki et al. Ann Rheum Dis. 2016 Oct; 75(10):1858-65), non-alcoholic steatohepatitis (Garcia-Martinez et al. J Clin Invest 2016, 126: 859-864; Gabele et al. Biochem Biophys Res Commun. 2008;376:271-276), hepatic 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). Imidazopyridine and triazolopyridine containing compounds are described in, e.g., International patent publications WO 2017/058503 A1 and WO 2018/165112 A1, each of which provides bicyclic compounds that can act as inhibitors of histone methyltransferase SUV39H2. Lesuisse et al. Bioorg Med Chem Lett. 2019, 29:929-932 describe imidazopyridine compounds as agonists of the nuclear receptor Nurr1/NOT. Methods for the sulfenylation of imidazopyridines are described by Le Bescont et al. Eur J Org Chem. 2020, 14:2101-2109. None of the aforementioned documents describes imidazopyridine or triazolopyridine derivatives as presently claimed. There remains a need for compounds useful as inhibitors of TLR9. Additionally, there remains a need for compounds useful as inhibitors of TLR9 that have selectivity over TLR7 or TLR8. In view of the conditions that may benefit by treatment involving modulation of Toll-like receptors, it is immediately apparent that new compounds capable of inhibiting TLR9 and methods of using these compounds could provide substantial therapeutic benefits to a wide variety of patients. Applicants have found potent compounds that have activity as TLR9 inhibitors. Further, applicants have found compounds that have activity as TLR9 inhibitors and are selective over TLR7 or TLR8. These compounds are provided to be useful as pharmaceuticals with desirable stability, bioavailability, therapeutic index, and toxicity values that are important to their drugability. SUMMARY The present disclosure relates to a new class of substituted bicyclic compounds found to be effective inhibitors of signaling through TLR9. These compounds are provided to be useful as pharmaceuticals with desirable stability, bioavailability, therapeutic index, and toxicity values that are important to their drugability. The present disclosure relates to compounds of Formula (I) that are useful as inhibitors of signaling through Toll-like receptor 9 and are useful for the treatment of fibrotic diseases, or stereoisomers, N-oxides, tautom