Substituted imidazopyridinyl compounds useful as inhibitors of TLR9

Abstract

Formula (I): TIFF2025508426000128.tif35153 (where X, Y, Q, G, R1, and R 5a Disclosed are compounds of the formula: (wherein R is as defined herein) or salts thereof. Also disclosed are methods of using such compounds as inhibitors of TLR9, and pharmaceutical compositions comprising such 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 / 311,612, filed February 18, 2022, and to U.S. Provisional Application No. 63 / 379,340, filed October 13, 2022, each of which is incorporated by reference in its entirety herein. [Background technology]

[0002] The present invention relates generally to substituted imidazopyridinyl compounds useful as inhibitors of signal transduction via Toll-like receptor 9 (TLR9). The present invention provides substituted imidazopyridinyl compounds, compositions comprising the compounds, and methods of using them. The present invention further relates to pharmaceutical compositions comprising at least one compound according to the present invention, useful for treating conditions involving modulation of TLR9 (e.g., fibrosis), and methods of inhibiting the activity of TLR9 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, which can reside on the cell surface or, in the case of TLR7, 8 and 9, endolysosomes. TLR9 recognizes unmethylated single-stranded DNA with cytosine-phosphate-guanine (CpG) motifs, commonly found in bacterial DNA and mitochondrial DNA (mtDNA). TLR9 may contribute to fibrosis by promoting inflammation through MyD88-dependent signaling pathways that ultimately involve 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 progression (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, it has been observed that TLR9 expression is elevated in human and murine nonalcoholic steatohepatitis (NASH) (Clin. Sci. 2017, 131(16), 2145), and that hepatocyte mitochondrial DNA promotes NASH via TLR9 activation (J. Clin. Inv. 2016, 126(3), 859). Therefore, it is predicted that TLR9 inhibitors / antagonists will be effective as novel therapeutic agents for treating fibrosis.

[0005] Inhibition of TLR9 has been shown to improve the progression of 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, pages251-255(2012)), and hypertension (McCarthy et al. Cardiovascular Research, 2015, Pages 119-130).

[0006] There is a need for compounds useful as inhibitors of TLR9, and further, there is a need for compounds useful as inhibitors of TLR9 that have selectivity for TLR9 over TLR7 or TLR8.

[0007] Considering the conditions that may benefit from treatment involving modulation of Toll-like receptors, it is apparent 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] Applicants have discovered useful compounds that have activity as TLR9 inhibitors, and further compounds that have activity as TLR9 inhibitors that are selective for TLR9 over TLR7 or TLR8. These compounds are provided as useful pharmaceutical agents with desirable stability, bioavailability, therapeutic index, and toxicity values ​​that are critical to their druggability.

[0009] SUMMARY OF THE PRESENTINVENTION The present invention relates to novel substituted imidazopyridinyl 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 values ​​that are critical to their druggability.

[0010] The present invention provides compounds of formula (I) or a stereoisomer, N-oxide, tautomer, pharma- ceutically 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 pharma- ceutically acceptable carrier and at least one compound of the invention, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0012] The present invention also provides a method of 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, pharma-ceutically 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, pharma-ceutically 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 the compounds of formula (I), or salts, solvates, and prodrugs thereof.

[0015] The present invention also provides processes and intermediates for the synthesis of 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 compound of formula (I), or a salt, solvate, and prodrug thereof, for the manufacture of a medicament for the treatment or prevention of a condition associated with Toll-like receptor 9 (e.g., fibrosis, an autoimmune disease, or an inflammatory disease).

[0018] The compounds of formula (I) and compositions comprising the 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 progression of diseases or disorders in various treatment sites, such as fibrosis including nonalcoholic steatohepatitis (NASH), nonalcoholic 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 which follows. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] The first aspect of the present invention is a compound of formula (I): [ka] [In the formula, One of X and Y is N, the other of X and Y is CR 5b and; G is (i) F, Cl, Br, C 1-2 Alkoxy, C 1-2 Fluoroalkoxy, C 3-4 Cycloalkyl, -C(O)NR y R y , -S(O)2CH3, -S(O)2(phenyl), -S(O)2NR x R x , and -S(O)(NH)NR x R x phenyl substituted with 1 to 3 substituents independently selected from (ii) [ka] ; (iii) [ka] ; (iv) [ka] ; (v) [ka] [ka] [ka] or (vi) [ka] is a 10-membered heterocycle selected from the group consisting of: Q is piperidinyl, phenyl, tetrahydropyridinyl, pyridinyl, or azabicyclo[3.2.1]octanyl, each of which is -L-R4 and 0 to 2 R 4bReplaced with; L is a bond, -(CR x R x ) 1-2 - or -C(O)(CR x R x ) 0-2 - and; R1 is hydrogen, C 1-3 Alkyl, C 1-2 Fluoroalkyl, or C 3-4 is cycloalkyl; Each R2 is independently halogen, -CN, -OH, -NO2, C 1-4 Alkyl, C 1-2 Fluoroalkyl, C 1-2 Cyanoalkyl, C 1-3 Hydroxyalkyl, C 1-3 Aminoalkyl, -O(CH2) 1-2 OH, -(CH2) 0-4 O(C 1-4 Alkyl), C 1-3 Fluoroalkoxy, -O(CH2) 1-2 O.C.(O)(C 1-3 alkyl), -O(CH2) 1-2 NR x R x , -C(O)O(C 1-3 alkyl), -(CH2) 0-2 C(O)NR y R y , -C(O)NR x (C 1-5 Hydroxyalkyl), -C(O)NR x (C 2-6 Alkoxyalkyl), -C(O)NR x (C 3-6 Cycloalkyl), -NR y R y , -NR y (C 1-3 Fluoroalkyl), -NR y (C 1-4 Hydroxyalkyl), -NR x CH2(phenyl), -NR x S(O)2(C 3-6 Cycloalkyl), -NR x C(O)(C 1-3 alkyl), -NRx CH2(C 3-6 Cycloalkyl), -S(O)2(C 1-3 alkyl), -S(O)2N(C 1-3 alkyl)2, -S(O)(NH)N(C 1-3 alkyl)2, -(CH2) 0-2 (C 3-6 Cycloalkyl), -(CH2) 0-2 (phenyl), morpholinyl, dioxothiomorpholinyl, dimethylpyrazolyl, methylpiperidinyl, methylpiperazinyl, amino-oxadiazolyl, imidazolyl, triazolyl, or -C(O)(thiazolyl); R 2a is C 1-6 Alkyl, C 1-3 Fluoroalkyl, C 1-6 Hydroxyalkyl, C 1-3 Aminoalkyl, -(CH2) 0-4 O(C 1-3 Alkyl), C 3-6 Cycloalkyl, -(CH2) 1-3 C(O)NR x R x , -CH2(C 3-6 cycloalkyl), -CH2(phenyl), tetrahydrofuranyl, tetrahydropyranyl, or phenyl; Each R 2b are independently hydrogen, halogen, -CN, -NR x R x , C 1-6 Alkyl, C 1-3 Fluoroalkyl, C 1-3 Hydroxyalkyl, C 1-3 Fluoroalkoxy, -(CH2) 0-2 O(C 1-3 alkyl), -(CH2) 0-3 C(O)NR x R x , -(CH2) 1-3 (C 3-6 Cycloalkyl), -C(O)O(C 1-3 alkyl), -C(O)NR x (C 1-3 alkyl), -CR x =CR x Rx , or -CR x =CH(C 3-6 cycloalkyl); R 2c is R 2a or R 2b and; R 2d is R 2a or R 2b Here, R 2c and R 2d One of them is R 2a and R 2c and R 2d The other is R 2b and; R4 is, (i)-N(CH3)2; (ii) pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, azepanyl, azaspiro[3.3]heptanyl, octahydrocyclopenta[c]pyrrolyl, diazaspiro[3.3]heptanyl, azabicyclo[3.2.1]octanyl, or hexahydropyrrolo[3,4-c]pyrrolyl, each of which has 0 to 2 R 4a or (iii) [ka] and; Each R 4a is independently C 1-6 Alkyl, C 1-3 Fluoroalkyl, C 1-4 Hydroxyalkyl, -(CH2) 1-3 OCH3, C 3-6 Cycloalkyl, -(CH2) 1-3 (C 3-6 Cycloalkyl), -(CH2) 1-3 (Oxetanyl), -(CH2) 1-3 (morpholinyl), -C(O)(C 1-4 alkyl), -C(O)(C 3-6 cycloalkyl), -C(O)(phenyl), -C(O)CH2(C 3-6 cycloalkyl), -C(O)CH2(phenyl), -C(O)O(C 1-4alkyl), -NR y R y , -NR x (C 3-6 cycloalkyl), azetidinyl, oxetanyl, tetrahydropyranyl, pyrrolidinyl, phenyl, morpholinyl, or piperidinyl (substituted with 0-2 substituents selected from -OH or -CH3); R 4b is F, Cl, -CN, or -CH3; Each R 4c is independently C 1-6 Alkyl, C 1-3 Fluoroalkyl, -CH2(C 3-6 cycloalkyl), -C(O)(C 1-4 alkyl), -C(O)(phenyl), -C(O)CH2(phenyl), -C(O)OCH2CH3, or C 3-6 is cycloalkyl; R 5a are hydrogen, F, Cl, C 1-2 Alkyl, C 1-2 fluoroalkyl, or cyclopropyl; R 5b are hydrogen, F, Cl, C 1-2 Alkyl, C 1-2 fluoroalkyl, or cyclopropyl; Each R x are independently hydrogen or -CH3; Each R y are independently hydrogen or C 1-6 is alkyl; m is 0, 1, or 2; n is 0, 1, or 2; p is 0, 1, 2, 3, or 4; and Q is 1 or 2. or a salt thereof.

[0021] A second aspect of the present invention relates to a compound of formula (I): [ka] [In the formula, One of X and Y is N and the other of X and Y is CR 5b and; G is (i) F, Cl, Br, C 1-2 Alkoxy, C 1-2 Fluoroalkoxy, C 3-4 Cycloalkyl, -C(O)NR y R y , -S(O)2CH3, -S(O)2(phenyl), -S(O)2NR x R x , and -S(O)(NH)NR x R x phenyl substituted with 1 to 3 substituents independently selected from (ii) [ka] ; (iii) [ka] ; (iv) [ka] ; (v) [ka] [ka] [ka] or (vi) [ka] is a 10-membered heterocycle selected from the group consisting of: Q is piperidinyl, phenyl, tetrahydropyridinyl, pyridinyl, or azabicyclo[3.2.1]octanyl, each of which is -L-R4 and 0 to 2 R4b Replaced with; L is a bond, -(CR x R x ) 1-2 - or -C(O)(CR x R x ) 0-2 - and; R1 is hydrogen, C 1-3 Alkyl, C 1-2 Fluoroalkyl, or C 3-4 is cycloalkyl; Each R2 is independently halogen, -CN, -OH, -NO2, C 1-4 Alkyl, C 1-2 Fluoroalkyl, C 1-2 Cyanoalkyl, C 1-3 Hydroxyalkyl, C 1-3 Aminoalkyl, -O(CH2) 1-2 OH, -(CH2) 0-4 O(C 1-4 Alkyl), C 1-3 Fluoroalkoxy, -O(CH2) 1-2 O.C.(O)(C 1-3 alkyl), -O(CH2) 1-2 NR x R x , -C(O)O(C 1-3 alkyl), -(CH2) 0-2 C(O)NR y R y , -C(O)NR x (C 1-5 Hydroxyalkyl), -C(O)NR x (C 2-6 Alkoxyalkyl), -C(O)NR x (C 3-6 Cycloalkyl), -NR y R y , -NR y (C 1-3 Fluoroalkyl), -NR y (C 1-4 Hydroxyalkyl), -NR x CH2(phenyl), -NR x S(O)2(C 3-6 Cycloalkyl), -NR x C(O)(C 1-3alkyl), -NR x CH2(C 3-6 Cycloalkyl), -S(O)2(C 1-3 alkyl), -S(O)2N(C 1-3 alkyl)2, -S(O)(NH)N(C 1-3 alkyl)2, -(CH2) 0-2 (C 3-6 Cycloalkyl), -(CH2) 0-2 (phenyl), morpholinyl, dioxothiomorpholinyl, dimethylpyrazolyl, methylpiperidinyl, methylpiperazinyl, amino-oxadiazolyl, imidazolyl, triazolyl, or -C(O)(thiazolyl); R 2a is C 1-6 Alkyl, C 1-3 Fluoroalkyl, C 1-6 Hydroxyalkyl, C 1-3 Aminoalkyl, -(CH2) 0-4 O(C 1-3 Alkyl), C 3-6 Cycloalkyl, -(CH2) 1-3 C(O)NR x R x , -CH2(C 3-6 cycloalkyl), -CH2(phenyl), tetrahydrofuranyl, tetrahydropyranyl, or phenyl; Each R 2b are independently hydrogen, halogen, -CN, -NR x R x , C 1-6 Alkyl, C 1-3 Fluoroalkyl, C 1-3 Hydroxyalkyl, C 1-3 Fluoroalkoxy, -(CH2) 0-2 O(C 1-3 alkyl), -(CH2) 0-3 C(O)NR x R x , -(CH2) 1-3 (C 3-6 Cycloalkyl), -C(O)O(C 1-3 alkyl), -C(O)NR x (C 1-3 alkyl), -CR x =CRx R x , or -CR x =CH(C 3-6 cycloalkyl); R 2c is R 2a or R 2b and; R 2d is R 2a or R 2b Here, R 2c and R 2d One of them is R 2a and R 2c and R 2d The other is R 2b and; R4 is (i)-N(CH3)2; (ii) pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, azepanyl, azaspiro[3.3]heptanyl, octahydrocyclopenta[c]pyrrolyl, diazaspiro[3.3]heptanyl, azabicyclo[3.2.1]octanyl, or hexahydropyrrolo[3,4-c]pyrrolyl, each of which has 0 to 2 R 4a or (iii) [ka] and; Each R 4a is independently C 1-6 Alkyl, C 1-3 Fluoroalkyl, C 3-6 Cycloalkyl, -CH2(C 3-6 cycloalkyl), -C(O)(C 1-4 alkyl), -C(O)(C 3-6 cycloalkyl), -C(O)(phenyl), -C(O)CH2(C 3-6 cycloalkyl), -C(O)CH2(phenyl), or -C(O)O(C 1-4 alkyl); R 4b is F, Cl, -CN, or -CH3; Each R 4c is independently C 1-6Alkyl, C 1-3 Fluoroalkyl, -CH2(C 3-6 cycloalkyl), -C(O)(C 1-4 alkyl), -C(O)(phenyl), -C(O)CH2(phenyl), -C(O)OCH2CH3, or C 3-6 is cycloalkyl; R 5a are hydrogen, F, Cl, C 1-2 Alkyl, C 1-2 fluoroalkyl, or cyclopropyl; R 5b are hydrogen, F, Cl, C 1-2 Alkyl, C 1-2 fluoroalkyl, or cyclopropyl; Each R x are independently hydrogen or -CH3; Each R y are independently hydrogen or C 1-6 is alkyl; m is 0, 1, or 2; n is 0, 1, or 2; p is 0, 1, 2, 3, or 4; and Q is 1 or 2. or a salt thereof.

[0022] In certain embodiments, X is CR 5b and Y is N. The compound of this embodiment has the formula (Ia): [ka] It has the structure:

[0023] In certain embodiments, X is N and Y is CR 5b The compound of this embodiment has the formula (Ib): [ka] It has the structure:

[0024] In one embodiment, G is F, Cl, Br, C 1-2 Alkoxy, C 1-2 Fluoroalkoxy, C 3-4 Cycloalkyl, -C(O)NR y R y , -S(O)2CH3, -S(O)2(phenyl), -S(O)2NR x R x , and -S(O)(NH)NR x R x Compounds of formula (I), or salts thereof, are provided in which G is phenyl substituted with 1-3 substituents independently selected from: -OCH3, -S(O)2CH3, -S(O)2N(CH3)2, and -S(O)(NH)N(CH3)2. Also included in this embodiment are compounds in which G is phenyl substituted with 1-2 substituents independently selected from: -OCH3, -S(O)2CH3, -S(O)2N(CH3)2, and -S(O)(NH)N(CH3)2. Also included in this embodiment are compounds in which G is phenyl substituted with 1-2 substituents independently selected from: -OCH3, and -S(O)2CH3. Additionally included in this embodiment are compounds in which G is [ka] Compounds in which:

[0025] In certain embodiments, wherein G is: [ka] or a salt thereof. Within this embodiment are compounds where each R2 is independently F, Cl, Br, -CN, -OH, -CH3, -CH2CH3, -CF3, -CH2OH, -C(CH3)2OH, -CH2NH2, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCH2CH2OCH3, -OCH2CH2N(CH3)2, -OCHF2, -C(O)OCH3, -C(O)NH2, -C(O)NH(CH2CH3), -C(O)(thiazolyl), -NH2, -NH(CH3), -NH(CH2CH3), -N(CH3)2, -NHC(O)CH3, -NHC(O)C(CH3)3, -NH(CH2-cyclopropyl), cyclopropyl, methylpiperidinyl, methylpiperazinyl, amino-oxadiazolyl, imidazolyl, or triazolyl. Also included in this embodiment are compounds where each R2 is independently F, Cl, -CN, -CH3, -OCH3, -NH2, or cyclopropyl. Additionally included in this embodiment are compounds where p is 2; one R2 is -CH3; and the other R2 is F, Cl, -CN, -CH3, -OCH3, -NH2, or cyclopropyl.

[0026] In certain embodiments, wherein G is: [ka] [ka] [ka] [ka] or a salt thereof, wherein R is a 9-membered heterocycle selected from the group consisting of:

[0027] In this embodiment, G is The compound is TIFF2025508426000028.tif32153.

[0028] In certain embodiments, wherein G is: [ka] or a salt thereof, wherein R is a 10-membered heterocycle selected from the group consisting of:

[0029] In this embodiment, G is [ka] Compounds in which:

[0030] In certain embodiments, wherein G is: (i) phenyl substituted with 1 to 2 substituents independently selected from F, -OCH3, -S(O)2CH3, -S(O)2N(CH3)2, and -S(O)(NH)N(CH3)2; (ii) [ka] or (iii) [ka] or a salt thereof. Within this embodiment are compounds where each R2 is independently Cl, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2CN, -OCH3, -CH2OCH3, or -CH2CH2S(O)2CH3.

[0031] In certain embodiments, wherein G is: (i) F, Cl, Br, -CN, C 1-2 Alkoxy, C 1-2 Fluoroalkoxy, C 3-4 Cycloalkyl, -C(O)NR y R y , -S(O)2CH3, -S(O)2(phenyl), -S(O)2(cyclopropyl), -S(O)2NR x R x , -S(O)(NH)NRx R x -, and -NHS(O)2CH3; (ii) [ka] or (iii) [ka] or a salt thereof. Within this embodiment are compounds where each R2 is independently Cl, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2CN, -OCH3, or -CH2OCH3.

[0032] In certain embodiments, wherein G is: (i) phenyl substituted with -S(O)2CH3 or phenyl substituted with two -OCH3; (ii) [ka] ;or (iii) [ka] or a salt thereof. Within this embodiment are compounds where each R2 is independently -CH3 or -OCH3. Also within this embodiment are compounds where G is [ka] Also included are compounds in which:

[0033] In one embodiment, a compound of formula (I) or a salt thereof is provided, wherein G is phenyl substituted with -S(O)2CH3 or phenyl substituted with two -OCH3. This embodiment includes compounds in which G is [ka] Compounds in which:

[0034] In certain embodiments, wherein G is: [ka] or a salt thereof. Within this embodiment are compounds where each R2 is -CH3. Also within this embodiment are compounds where G is [ka] Also included are compounds in which:

[0035] In certain embodiments, wherein G is: [ka] or a salt thereof. Within this embodiment are compounds where each R2 is independently -CH3 or -OCH3. Also within this embodiment are compounds where G is [ka] Also included are compounds in which:

[0036] In certain embodiments, Q is piperidinyl, phenyl, pyridinyl, or tetrahydropyridinyl, each of which is -L-R and 0 to 1 R 4b In this embodiment, Q is piperidinyl, phenyl, or tetrahydropyridinyl, each of which is selected from -L-R4 and 0-1 R 4b The present invention includes compounds substituted with

[0037] In certain embodiments, Q is piperidinyl, phenyl, or pyridinyl, each of which is -L-R4 and 0 to 1 R 4b or a salt thereof.

[0038] In certain embodiments, Q is piperidinyl or phenyl, each of which is -L-R and 0 to 1 R 4b or a salt thereof. Within this embodiment are compounds wherein Q is piperidinyl or phenyl, each substituted with -L-R4.

[0039] In one embodiment, Q is piperidinyl, -L-R and 0 to 1 R 4b or a salt thereof. Within this embodiment are compounds where Q is piperidinyl and substituted with -L-R4.

[0040] In one embodiment, Q is phenyl, -L-R and 0 to 1 R 4b or a salt thereof. Within this embodiment are compounds where Q is phenyl and substituted with -L-R4.

[0041] In one embodiment, Q is pyridinyl, -L-R and 0 to 1 R 4b or a salt thereof. Within this embodiment are compounds where Q is pyridinyl and is substituted with -L-R4.

[0042] In one embodiment, Q is tetrahydropyridinyl, -L-R and 0 to 1 R 4b or a salt thereof. Within this embodiment are compounds where Q is tetrahydropyridinyl and substituted with -L-R4.

[0043] In certain embodiments, R is hydrogen, C 1-3 Alkyl, -CHF2, -CF3, or C 3-4 The present invention provides a compound of formula (I) or a salt thereof, wherein R is hydrogen, C 1-2Included in this embodiment are compounds where R1 is hydrogen, -CH3, or cyclopropyl.

[0044] In certain embodiments, there is provided a compound of formula (I) or a salt thereof, wherein R 1 is hydrogen.

[0045] In one embodiment, R is C 1-3 Alkyl, C 1-2 Fluoroalkyl, or C 3-4 The present invention provides a compound of formula (I) or a salt thereof, wherein R is cycloalkyl. 1-3 Alkyl, -CHF2, -CF3, or C 3-4 Also included within this embodiment are compounds where R1 is -CH3 or cyclopropyl. Additionally included within this embodiment are compounds where R1 is -CH3.

[0046] In certain embodiments, compounds of formula (I) or salts thereof are provided, wherein p is 0, 1, 2, or 3. Within this embodiment, compounds are included where p is 1 or 2.

[0047] In certain embodiments, L is a bond, -(CR x R x ) 1-2 - or -C(O)(CR x R x ) 0-1 In one embodiment, L is a bond, -CH2- or -C(O)(CH2) 0-1 Also included in this embodiment are compounds in which L is -CR x R x -or-C(O)(CR x R x ) 0-1 Also included within this embodiment are compounds where L is -. Additionally included within this embodiment are compounds where L is -C(O)CH2-.

[0048] In certain embodiments, L is a bond or -(CR x R x ) 1-2 - or a salt thereof. In this embodiment, L is a bond or -CR x R x -Compounds in which:

[0049] In certain embodiments, L is a bond or -(CH) 1-2 or a salt thereof. Within this embodiment are compounds wherein L is a bond or -CH2-.

[0050] In certain embodiments, L is a bond, -CH2-, or -C(O)(CH2), 0-1 The present invention provides a compound of formula (I) or a salt thereof, wherein L is -. Within this embodiment, compounds are provided where L is -CH2-.

[0051] In certain embodiments, L is -C(O)(CH) 0-2 or a salt thereof. In this embodiment, L is -C(O)(CH2) 0-1 Also included in this embodiment are compounds where L is -C(O)(CH2) 1-2 Also included are compounds in which -.

[0052] In certain embodiments, there is provided a compound of Formula (I) or a salt thereof, wherein L is a bond.

[0053] In certain embodiments, L is -(CR x R x ) 1-2 - or a salt thereof. In this embodiment, L is -CR x R x -Compounds in which:

[0054] In certain embodiments, L is -(CH) 1-2or a salt thereof. Within this embodiment are compounds wherein L is -CH2-.

[0055] In certain embodiments, there is provided a compound of formula (I) or a salt thereof, wherein L is -C(O)-.

[0056] In certain embodiments, there is provided a compound of formula (I) or a salt thereof, wherein L is -C(O)CH2-.

[0057] In certain embodiments, there is provided a compound of formula (I) or a salt thereof, wherein L is -C(O)CH2CH2-.

[0058] In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein R4 is -N(CH3)2.

[0059] In certain embodiments, R4 is pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, azepanyl, azaspiro[3.3]heptanyl, octahydrocyclopenta[c]pyrrolyl, diazaspiro[3.3]heptanyl, azabicyclo[3.2.1]octanyl, or hexahydropyrrolo[3,4-c]pyrrolyl, each of which is selected from 0 to 2 R 4a In one embodiment, R4 is pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, azepanyl, azaspiro[3.3]heptanyl, octahydrocyclopenta[c]pyrrolyl, diazaspiro[3.3]heptanyl, azabicyclo[3.2.1]octanyl, or hexahydropyrrolo[3,4-c]pyrrolyl, each of which is substituted with 0 to 1 R 4a The present invention includes compounds substituted with

[0060] In certain embodiments, R4 is piperidinyl, piperazinyl, octahydrocyclopenta[c]pyrrolyl, diazaspiro[3.3]heptanyl, or azabicyclo[3.2.1]octanyl, each of which is zero or one R 4aIn this embodiment, R4 is piperidinyl or piperazinyl, each of which is 0 to 1 R 4a The present invention includes compounds substituted with

[0061] In certain embodiments, R is piperidinyl and 0 or 1 R 4a or a salt thereof.

[0062] In certain embodiments, R is piperazinyl and 0 or 1 R 4a or a salt thereof.

[0063] In certain embodiments, R4 is octahydrocyclopenta[c]pyrrolyl and 0 or 1 R 4a or a salt thereof.

[0064] In certain embodiments, R is diazaspiro[3.3]heptanyl and 0 or 1 R 4a or a salt thereof.

[0065] In certain embodiments, R4 is azabicyclo[3.2.1]octanyl and 0 or 1 R 4a or a salt thereof.

[0066] In certain embodiments, R4 is [ka] or a salt thereof. Included within this embodiment are compounds where n is 1 or 2. Also included within this embodiment are compounds where n is 1. Additionally included within this embodiment are compounds where n is 2.

[0067] In certain embodiments, each R4a is independently -CH3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2C(CH3)2OH, -CH2CH2OCH3, -C(O)CH(CH3)2, cyclopropyl, cyclobutyl, -CH2(cyclopropyl), -CH2(cyclobutyl), -CH2(oxetanyl), -CH2CH2(morpholinyl), -CH2CH2CH2(morpholinyl), -N(CH3)2, -N(CH3)(CH2CH3), -N(CH3)(cyclopropyl), azetidinyl, oxetanyl, tetrahydropyranyl, pyrrolidinyl, phenyl, morpholinyl, or piperidinyl (substituted with 0-2 substituents selected from -OH or -CH3), or a salt thereof. 4a is -CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2C(CH3)2OH, -CH2CH2OCH3, -CH2(cyclopropyl), -CH2CH2(morpholinyl), -CH2CH2CH2(morpholinyl), cyclopropyl, cyclobutyl, pyrrolidinyl, oxetanyl, tetrahydropyranyl, or morpholinyl.

[0068] In certain embodiments, each R 4a is independently -CH3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2C(CH3)2OH, -CH2CH2OCH3, -C(O)CH(CH3)2, cyclopropyl, cyclobutyl, -CH2(cyclopropyl), -CH2(cyclobutyl), -CH2(oxetanyl), -N(CH3)2, -N(CH3)(CH2CH3), -N(CH3)(cyclopropyl), azetidinyl, oxetanyl, tetrahydropyranyl, pyrrolidinyl, phenyl, or piperidinyl (substituted with 0-2 substituents selected from -OH or -CH3), or a salt thereof. 4aare independently -CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2C(CH3)2OH, -CH2CH2OCH3, -CH2(cyclopropyl), cyclopropyl, cyclobutyl, pyrrolidinyl, oxetanyl, or tetrahydropyranyl.

[0069] In certain embodiments, in formula R 4b is F, -CN, or -CH3. 4b is F. Also included in this embodiment are compounds in which R 4b Also included are compounds where is -CH3.

[0070] In certain embodiments, each R 4c But independently, C 1-4 Alkyl, C 1-2 Fluoroalkyl, -CH2(C 3-6 cycloalkyl), -C(O)(C 1-3 alkyl), -C(O)(phenyl), -C(O)CH2(phenyl), -C(O)OCH2CH3, or C 3-6 The present invention provides a compound of formula (I) or a salt thereof, wherein each R 4c But independently, C 1-3 Alkyl, C 1-2 Fluoroalkyl, -CH2(C 3-4 cycloalkyl), -C(O)(C 1-2 alkyl), -C(O)(phenyl), -C(O)CH2(phenyl), -C(O)OCH2CH3, or C 3-4 Included are compounds which are cycloalkyl.

[0071] In certain embodiments, each R2 is independently F, Cl, -CN, -OH, C 1-3 Alkyl, C 1-2 Fluoroalkyl, C 1-2 Cyanoalkyl, C 1-3 Hydroxyalkyl, C 1-2 Aminoalkyl, -(CH2) 0-2 O(C 1-3 Alkyl), C3-6 Cycloalkyl, -NR x R x , -(CH2) 0-2 C(O)NR x R x , -CH2(C 3-6 The present invention provides a compound of formula (I) or a salt thereof, wherein R2 is independently Cl, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2CN, -OCH3, -CH2OCH3, or -CH2CH2S(O)2CH3. Also provided in this embodiment are compounds in which each R2 is independently Cl, -CH3, -CH2OH, or -OCH3.

[0072] In certain embodiments, in formula R 2a But, C 1-4 Alkyl, C 1-2 Fluoroalkyl, C 1-4 Hydroxyalkyl, -(CH2) 1-3 OCH3, C 3-6 Cycloalkyl, -CHC(O)NR x R x , -CH2(C 3-6 cycloalkyl), -CH2(phenyl), tetrahydrofuranyl, or phenyl; and each R 2b are independently H, F, Cl, -CN, -NR x R x , C 1-6 Alkyl, C 1-2 Fluoroalkyl, C 1-3 Hydroxyalkyl, -(CH2) 0-2 O(C 1-2 alkyl), -(CH2) 0-2 C(O)NR x R x , -(CH2) 1-3 (cyclopropyl), -C(O)O(C 1-2 alkyl), -C(O)NR x (C 1-3 alkyl), -CR x =CH2, or -CH=CH(C 3-6Also provided in this embodiment is a compound of formula (I) or a salt thereof, wherein R 2a is -CH3; and each R 2b Also included are compounds where are independently H, Cl, or -CH3.

[0073] In certain embodiments, in formula R 5a is hydrogen, F, Cl, -CH, -CHF, -CHF, -CF, or cyclopropyl. 5a is hydrogen, F, -CH3, -CF3, or cyclopropyl. Also included in this embodiment are compounds where R 5a Also included are compounds in which is hydrogen, -CH3, or -CF3.

[0074] In certain embodiments, in formula R 5a is -CH3, or a salt thereof.

[0075] In certain embodiments, in formula R 5a is hydrogen, or a salt thereof.

[0076] In certain embodiments, in formula R 5b is hydrogen, F, Cl, -CH, -CHF, -CHF, -CF, or cyclopropyl. 5b is hydrogen, F, -CH3, or -CF3. Also included in this embodiment are compounds where R 5b Also included are compounds in which is hydrogen or -CH3.

[0077] In certain embodiments, in formula R 5b is hydrogen, or a salt thereof.

[0078] In certain embodiments, in formula R 5b is -CH3, or a salt thereof.

[0079] In certain embodiments, in formula R 5a is hydrogen; and R 5b is hydrogen, or a salt thereof.

[0080] In certain embodiments, in formula R 5a is hydrogen; and R 5b is hydrogen or -CH3, or a salt thereof.

[0081] In one embodiment, in the formula: G, (i) phenyl substituted with -S(O)2CH3; (ii) phenyl substituted with two -OCH3; or (iii) [ka] and; Q is phenyl or piperidinyl, each substituted with -L-R4; L is a bond or -CH2-; R1 is hydrogen, -CH3, or cyclopropyl; R4 is piperidinyl, piperazinyl, octahydrocyclopenta[c]pyrrolyl, diazaspiro[3.3]heptanyl, or azabicyclo[3.2.1]octanyl, each of which may contain zero or one R 4a Replaced with; R 4a is -CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2C(CH3)2OH, -CH2CH2OCH3, -CH2(cyclopropyl), -CH2CH2(morpholinyl), -CH2CH2CH2(morpholinyl), cyclopropyl, cyclobutyl, pyrrolidinyl, oxetanyl, tetrahydropyranyl, or morpholinyl; R 5a is hydrogen; and R 5b is hydrogen or -CH3, or a salt thereof.

[0082] In one embodiment, in the formula: G is F, Cl, Br, -CN, C 1-2 Alkoxy, C 1-2 Fluoroalkoxy, C 3-4 Cycloalkyl, -C(O)NR y R y , -S(O)2CH3, -S(O)2(phenyl), -S(O)2(cyclopropyl), -S(O)2NR x R x , -S(O)(NH)NR x R x -, and -NHS(O)2CH3; L is a bond, -CH2-, or -CH2CH2-; Q is piperidinyl, phenyl, tetrahydropyridinyl, or pyridinyl, each of which is -L-R4 and 0 to 1 R 4b Replaced with; R1 is hydrogen, C 1-3 Alkyl, -CHF2, -CF3, or C 3-4 is cycloalkyl; each R2 is independently Cl, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2CN, -OCH3, or -CH2OCH3; R4 is pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, octahydrocyclopenta[c]pyrrolyl, azaspiro[3.3]heptanyl, diazaspiro[3.3]heptanyl, azabicyclo[3.2.1]octanyl, or hexahydropyrrolo[3,4-c]pyrrolyl, each of which is 0 to 1 R 4a Replaced with; R 4ais -CH3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2C(CH3)2OH, -CH2CH2OCH3, -C(O)CH(CH3)2, cyclopropyl, cyclobutyl, -CH2(cyclopropyl), -CH2(cyclobutyl), -CH2(oxetanyl), -N(CH3)2, -N(CH3)(CH2CH3), -N(CH3)(cyclopropyl), azetidinyl, oxetanyl, tetrahydropyranyl, pyrrolidinyl, phenyl, or piperidinyl (substituted with 0-2 substituents selected from -OH or -CH3); R 4b is F, -CN, or -CH3; R 5a is hydrogen, -CH3, -CF3, or cyclopropyl; and R 5b is hydrogen, -CH3, or -CF3, or a salt thereof.

[0083] In one embodiment, in the formula: G, (i) phenyl substituted with -S(O)2CH3; (ii) phenyl substituted with two -OCH3; or (iii) [ka] and; Q is phenyl or piperidinyl, each substituted with -L-R4; L is a bond or -CH2-; R1 is hydrogen, -CH3, or cyclopropyl; R4 is piperidinyl, piperazinyl, octahydrocyclopenta[c]pyrrolyl, diazaspiro[3.3]heptanyl, or azabicyclo[3.2.1]octanyl, each of which may contain zero or one R 4a Replaced with; R 4ais -CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2C(CH3)2OH, -CH2CH2OCH3, -CH2(cyclopropyl), -CH2CH2(morpholinyl), -CH2CH2CH2(morpholinyl), cyclopropyl, cyclobutyl, pyrrolidinyl, oxetanyl, tetrahydropyranyl, or morpholinyl; R 5a is hydrogen; and R 5b is hydrogen or -CH3, or a salt thereof.

[0084] In one embodiment, in the formula: G, (i) phenyl substituted with -S(O)2CH3; or (ii) phenyl substituted with two -OCH3; Q is phenyl or piperidinyl, each substituted with -L-R4; L is a bond or -CH2-; R1 is hydrogen, -CH3, or cyclopropyl; R4 is piperidinyl, piperazinyl, octahydrocyclopenta[c]pyrrolyl, diazaspiro[3.3]heptanyl, or azabicyclo[3.2.1]octanyl, each of which may contain zero or one R 4a Replaced with; R 4a is -CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2C(CH3)2OH, -CH2CH2OCH3, -CH2(cyclopropyl), cyclopropyl, cyclobutyl, pyrrolidinyl, oxetanyl, or tetrahydropyranyl; R 5a is hydrogen; and R 5b is hydrogen or -CH3, or a salt thereof.

[0085] In one embodiment, the compound is 5-(4-((6-cyclobutyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)phenyl)-3-cyclopropyl-7-methyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine (1); 3-cyclopropyl-7-methyl-2-(4-(methylsulfonyl)phenyl)-5-(4-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)phenyl)-3H-imidazo[4,5-b]pyridine (2); 3-cyclopropyl-5-(4-((6-isopropyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)phenyl)-7-methyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine (3); 3-Cyclopropyl-5-(4-((6-isobutyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)phenyl)-7-methyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine (4); 3-Cyclopropyl-7-methyl-2-(4-(methylsulfonyl)phenyl)-5-(4-((6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)phenyl)-3H-imidazo[4,5-b]pyridine (5); 3-Cyclopropyl-7-methyl-2-(4-(methylsulfonyl)phenyl)-5-(4-((6-(oxetan-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)phenyl)-3H-imidazo[4,5-b]pyridine (6); 5-(4-(4-isopropylpiperazin-1-yl)phenyl)-3,7-dimethyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine (7); 5-(4-(4-isobutylpiperazin-1-yl)phenyl)-3,7-dimethyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine (8); 3-Cyclopropyl-7-methyl-5-(4-(1-methylpiperidin-4-yl)phenyl)-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine (9);2-(3,4-dimethoxyphenyl)-5-(4-(4-isopropylpiperazin-1-yl)phenyl)-3,7-dimethyl-3H-imidazo[4,5-b]pyridine (10); 5-(1'-isopropyl-[1,4'-bipiperidine]-4-yl)-3-methyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine (17); 5-(1'-isobutyl-[1,4'-bipiperidine]-4-yl)-3-methyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine (18); 5-(1'-cyclopropyl-[1,4'-bipiperidine]-4-yl)-3-methyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine (19); 5-(1'-isopropyl-[1,4'-bipiperidine]-4-yl)-3,7-dimethyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine (20); 5-(1'-isobutyl-[1,4'-bipiperidine]-4-yl)-3,7-dimethyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine (21); 1-(4-(3,7-dimethyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridin-5-yl)-[1,4'-bipiperidine]-1'-yl)-2-methylpropan-2-ol (22); 5-(1'-(cyclopropylmethyl)-[1,4'-bipiperidine]-4-yl)-3,7-dimethyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine (23); 5-(1'-cyclobutyl-[1,4'-bipiperidine]-4-yl)-3,7-dimethyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine (24); 3,7-dimethyl-2-(4-(methylsulfonyl)phenyl)-5-(1'-(tetrahydro-2H-pyran-4-yl)-[1,4'-bipiperidine]-4-yl)-3H-imidazo[4,5-b]pyridine (25); 5-(1-(8-isopropyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-3,7-dimethyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine (26-27);5-(1-(8-isobutyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-3,7-dimethyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine (28-29); 5-(1-(8-(cyclopropylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-3,7-dimethyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine (30-31); 5-(1-(8-cyclobutyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-3,7-dimethyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine (32-33); 3,7-dimethyl-2-(4-(methylsulfonyl)phenyl)-5-(1-(8-(tetrahydro-2H-pyran-4-yl)-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-3H-imidazo[4,5-b]pyridine (34-35); 2-(3,4-dimethoxyphenyl)-5-(1-(2-isopropyloctahydrocyclopenta[c]pyrrol-5-yl)piperidin-4-yl)-3,7-dimethyl-3H-imidazo[4,5-b]pyridine (36); 2-(3,4-dimethoxyphenyl)-5-(1-(2-isobutyloctahydrocyclopenta[c]pyrrol-5-yl)piperidin-4-yl)-3,7-dimethyl-3H-imidazo[4,5-b]pyridine (37); 5-(1-(2-(cyclopropylmethyl)octahydrocyclopenta[c]pyrrol-5-yl)piperidin-4-yl)-2-(3,4-dimethoxyphenyl)-3,7-dimethyl-3H-imidazo[4,5-b]pyridine (38); 5-(1-(2-cyclobutyloctahydrocyclopenta[c]pyrrol-5-yl)piperidin-4-yl)-2-(3,4-dimethoxyphenyl)-3,7-dimethyl-3H-imidazo[4,5-b]pyridine (39); 2-(3,4-dimethoxyphenyl)-3,7-dimethyl-5-(1-(2-(tetrahydro-2H-pyran-4-yl)octahydrocyclopenta[c]pyrrol-5-yl)piperidin-4-yl)-3H-imidazo[4,5-b]pyridine (40);2-(3,4-dimethoxyphenyl)-5-(1-((3aR,5s,6aS)-2-(2-methoxyethyl)octahydrocyclopenta[c]pyrrol-5-yl)piperidin-4-yl)-3,7-dimethyl-3H-imidazo[4,5-b]pyridine (41); 5-(1-((3aR,5s,6aS)-2-cyclobutyloctahydrocyclopenta[c]pyrrol-5-yl)piperidin-4-yl)-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3,7-dimethyl-3H-imidazo[4,5-b]pyridine (42); 5-(1-((3aR,5s,6aS)-2-(cyclopropylmethyl)octahydrocyclopenta[c]pyrrol-5-yl)piperidin-4-yl)-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3,7-dimethyl-3H-imidazo[4,5-b]pyridine (43); 2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3,7-dimethyl-5-(1-((3aR,5s,6aS)-2-(tetrahydro-2H-pyran-4-yl)octahydrocyclopenta[c]pyrrol-5-yl)piperidin-4-yl)-3H-imidazo[4,5-b]pyridine (44); 5-(4-(4-isopropylpiperazin-1-yl)phenyl)-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3,7-dimethyl-3H-imidazo[4,5-b]pyridine (45); 2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(1-((3aR,5s,6aS)-2-(2-methoxyethyl)octahydrocyclopenta[c]pyrrol-5-yl)piperidin-4-yl)-3,7-dimethyl-3H-imidazo[4,5-b]pyridine (46); 4-(1-(4-(3-cyclopropyl-7-methyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridin-5-yl)benzyl)piperidin-4-yl)morpholine (47); 2-(3,4-dimethoxyphenyl)-5-(4-(4-isopropylpiperazin-1-yl)phenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (52);5-(4-(4-isopropylpiperazin-1-yl)phenyl)-3-methyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine (53); 3-cyclopropyl-5-(4-(4-isopropylpiperazin-1-yl)phenyl)-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine (54); 3-cyclopropyl-2-(3,4-dimethoxyphenyl)-5-(4-(4-isopropylpiperazin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridine (55); 4-(3-(4-(4-(3-cyclopropyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)piperazin-1-yl)propyl)morpholine (56); 4-(2-(4-(4-(3-cyclopropyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)piperazin-1-yl)ethyl)morpholine (57); 2-(3,4-dimethoxyphenyl)-5-(4-(2-isopropyl-2,7-diazaspiro[3.5]non-7-yl)phenyl)-3,7-dimethyl-3H-imidazo[4,5-b]pyridine (58); 2-(3,4-dimethoxyphenyl)-5-(4-(6-isopropyl-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-3,7-dimethyl-3H-imidazo[4,5-b]pyridine (59); 2-(3,4-dimethoxyphenyl)-5-(4-(2-isobutyl-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)-3,7-dimethyl-3H-imidazo[4,5-b]pyridine (60); 5-(4-(2-isopropyl-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)-3-methyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine (61); 5-(4-(2-isobutyl-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)-3-methyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine (62);2-Methyl-1-(7-(4-(3-methyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)-2,7-diazaspiro[3.5]nonan-2-yl)propan-2-ol (63); 2-(3,4-dimethoxyphenyl)-5-(4-(6-isobutyl-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-3,7-dimethyl-3H-imidazo[4,5-b]pyridine (64); The present invention provides a compound of formula (I) or a salt thereof, which is 5-(4-(6-isopropyl-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-3-methyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine (65); or 5-(4-(6-isobutyl-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-3-methyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine (66).

[0086] In one embodiment, the compound is 2-(3,4-dimethoxyphenyl)-6-(1'-isopropyl-[1,4'-bipiperidine]-4-yl)-1H-imidazo[4,5-b]pyridine (11); 2-(3,4-dimethoxyphenyl)-6-(1'-isobutyl-[1,4'-bipiperidine]-4-yl)-1H-imidazo[4,5-b]pyridine (12); 6-(1'-cyclopropyl-[1,4'-bipiperidine]-4-yl)-2-(3,4-dimethoxyphenyl)-1H-imidazo[4,5-b]pyridine (13); 6-(1'-isopropyl-[1,4'-bipiperidine]-4-yl)-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-imidazo[4,5-b]pyridine (14); 6-(1'-isobutyl-[1,4'-bipiperidine]-4-yl)-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-imidazo[4,5-b]pyridine (15); 6-(1'-cyclopropyl-[1,4'-bipiperidine]-4-yl)-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-imidazo[4,5-b]pyridine (16); 2-(3,4-dimethoxyphenyl)-6-(4-(4-isopropylpiperazin-1-yl)phenyl)-1-methyl-1H-imidazo[4,5-b]pyridine (48); The present invention provides a compound of formula (I) or a salt thereof, which is 6-(4-(4-isopropylpiperazin-1-yl)phenyl)-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-imidazo[4,5-b]pyridine (49); 1-cyclopropyl-2-(3,4-dimethoxyphenyl)-6-(4-(4-isopropylpiperazin-1-yl)phenyl)-1H-imidazo[4,5-b]pyridine (50); or 1-cyclopropyl-6-(4-(4-isopropylpiperazin-1-yl)phenyl)-2-(4-(methylsulfonyl)phenyl)-1H-imidazo[4,5-b]pyridine (51).

[0087] In one embodiment, the TLR9 IC 50 The compound of formula (I) has a value of ≦0.6 μM.

[0088] In one embodiment, the TLR9 IC 50The compound of formula (I) has a value of ≦0.1 μM.

[0089] In one embodiment, the TLR9 IC 50 The present invention provides compounds of formula (I) having a value of ≦0.05 μM.

[0090] In one embodiment, the TLR9 IC 50 The present invention provides compounds of formula (I) having a value of ≦0.025 μM.

[0091] In one embodiment, the TLR9 IC 50 The compound of formula (I) has a value of ≦0.015 μM.

[0092] In one embodiment, the TLR9 IC 50 The compound of formula (I) has a value of ≦0.01 μM.

[0093] In another embodiment, the present invention provides a composition comprising at least one compound of the present invention, or a stereoisomer, tautomer, or pharma- ceutically acceptable salt or solvate thereof.

[0094] In another embodiment, the present invention provides pharmaceutical compositions comprising a pharma- ceutically acceptable carrier and at least one compound of the present invention or a stereoisomer, tautomer, or pharma- ceutically acceptable salt or solvate thereof.

[0095] In another embodiment, the present invention provides pharmaceutical compositions comprising a pharma- ceutically acceptable carrier and a therapeutically effective amount of at least one compound of the present invention or a stereoisomer, tautomer, or pharma- ceutically acceptable salt or solvate thereof.

[0096] In another embodiment, the present invention provides a method of making a compound of the present invention.

[0097] In another embodiment, the present invention provides intermediates for making the compounds of the present invention.

[0098] In another embodiment, the present invention provides a pharmaceutical composition as defined above further comprising one or more additional therapeutic agents.

[0099] (definition) The features and advantages of the present invention may 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 present 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 present invention that are described in a single embodiment for brevity may also be combined to form subcombinations thereof. The embodiments identified herein as exemplary or preferred are intended to be illustrative and not limiting.

[0100] Unless otherwise specified 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."

[0101] 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).

[0102] Unless otherwise specified, any heteroatom with unsatisfied valences is assumed to have sufficient hydrogen atoms to satisfy the valences.

[0103] The definitions set forth herein take precedence over definitions set forth in any patents, patent applications, and / or published patent applications incorporated herein by reference.

[0104] 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 (unless otherwise limited in specific instances) or as part of a larger group.

[0105] Throughout the specification, groups and substituents may be chosen by one skilled in the art to provide stable moieties and compounds.

[0106] 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 moiety or substituent to a core or backbone structure.

[0107] The terms "halo" and "halogen" as used herein refer to F, Cl, Br, and I.

[0108] The term "cyano" refers to the group --CN.

[0109] The term "amino" refers to the group -NH2.

[0110] The term "oxo" refers to the group =O.

[0111] 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 in 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.

[0112] 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, 1-4 "Fluoroalkyl" is meant to include C1, C2, C3, and C4 alkyl groups substituted with one or more fluorine atoms. Representative examples of fluoroalkyl groups include, but are not limited to, -CF3 and -CH2CF3.

[0113] The term "cycloalkyl" as used herein 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 contain. For example, "C3-C6 cycloalkyl" refers to a cycloalkyl group having from 3 to 6 carbon atoms.

[0114] As used herein, the phrase "pharmacologically acceptable" refers to compounds, substances, compositions, and / or dosage forms that are suitable, within the scope of ordinary medical judgment, for contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, and which are consistent with a reasonable benefit / risk ratio.

[0115] Compounds of formula (I) may form salts, which are also within the scope of the present invention. Unless otherwise specified, reference to a compound of the invention is understood to include reference to one or more salts thereof. The term "salt" refers to acid and / or base salts formed with inorganic and / or organic acids and bases. In addition, the term "salt" may include zwitterions (internal salts), for example, when a compound of formula (I) has both a basic moiety (e.g., an amine or a pyridine or imidazole ring) and an acidic moiety (e.g., a carboxylic acid). Pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable) salts are preferred, for example, acceptable metal salts and amine salts, in which the cation does not significantly contribute to the toxicity or biological activity of the salt. However, other salts may also be useful, for example, in isolation or purification steps that may be used in the preparation process, and therefore other salts are considered to be within the scope of the present invention. Salts of compounds of formula (I) may be formed, for example, by reacting a compound of formula (I) with a certain amount of acid or base (e.g., one equivalent) and then precipitating the salt in a solvent, for example, or from an aqueous solution, followed by lyophilization. Suitable salts are listed in Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton, PA (1990), the contents of which are incorporated herein by reference.

[0116] Examples of acid addition salts include acetates (e.g., salts prepared from acetic acid or trihaloacetic acids (e.g., trifluoroacetic acid)), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, hydrogen sulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (prepared from hydrochloric acid), hydrobromides (prepared from hydrogen bromide), and the like. ), hydroiodide, maleate (prepared from maleic acid), 2-hydroxyethanesulfonate, lactate, methanesulfonate (prepared from methanesulfonic acid), 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate (e.g., prepared from sulfuric acid), sulfonate (e.g., those described herein), tartrate, thiocyanate, toluenesulfonate (e.g., tosylate), undecanoate, and the like.

[0117] Examples of base salts include ammonium salts, alkali metal salts (e.g., sodium, lithium, and potassium salts), alkaline earth metal salts (e.g., calcium and magnesium salts), barium, zinc, and aluminum salts, salts with organic bases (e.g., organic amines (e.g., trialkylamines such as triethylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine, N,N'-dibenzylethylene-diamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamine), or similar pharma- ceutically acceptable salts. and amino acid salts (e.g., arginine, lysine). Basic nitrogen-containing groups may be quaternized with reagents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.

[0118] 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.

[0119] In addition, solvates (e.g., hydrates) of the compounds of formula (I) should be considered 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.

[0120] 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).

[0121] In addition, the compounds of formula (I) may be prepared, isolated, purified, and obtained as compositions containing 99% or greater of the compound of formula (I) ("substantially pure"), which are then used or formulated as described herein. Such "substantially pure" compounds of formula (I) are also considered herein to be part of the invention.

[0122] 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 and formulation into an efficacious therapeutic agent. The present invention is intended to embody stable compounds.

[0123] "Therapeutically effective amount" is intended to include an amount of a compound of the invention alone, or in combination with the claimed compounds, or in combination with other active ingredients, that is effective to act as an inhibitor of TLR9 or to treat or prevent a fibrotic disease or disorder, or a disorder associated with bile acid dysregulation (e.g., fibrosis).

[0124] 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 susceptible to the condition, 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.

[0125] The compounds of the present invention are intended to include 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 of skill in the art, or by methods analogous to those described herein, substituting the appropriate isotopically labeled reagent for the non-labeled reagent used elsewhere. For example, methyl (-CH3) also includes deuterated methyl groups (e.g., -CD3).

[0126] (Usefulness) The compounds of the present invention are effective in inhibiting the TLR9 receptor.

[0127] Certain embodiments provide a method of treating a disease, disorder, or condition associated with dysregulation of bile acids 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, pharma-ceutically acceptable salt, or solvate thereof.

[0128] 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, pharma- ceutically acceptable salt, or solvate thereof.

[0129] One embodiment provides a method for treating a disease, disorder, or condition, comprising administering to a patient in need of treatment 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.

[0130] 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, or a pharma- ceutically acceptable salt or solvate thereof.

[0131] In some embodiments, the disease, disorder, or condition is associated with impaired function of TLR9 and includes fibrosis, cancer, an inflammatory disease, a metabolic disease, or a cholestatic disease.

[0132] In some embodiments, the disease, disorder, or condition is associated with fibrosis, including fibrosis of the liver, bile duct, kidney, heart, skin, eye, and pancreas.

[0133] In other embodiments, the disease, disorder, or condition is associated with a cell proliferation 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 a 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, testis, or thyroid. In other embodiments, the cancer is a carcinoma of the epithelium, a non-epithelium, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, or seminoma.

[0134] Examples of diseases, disorders, or conditions associated with TLR9 activity that may be prevented, modulated, or treated in accordance with the present invention include, but are not limited to, transplant disorders, fibrosis (e.g., liver fibrosis, renal 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).

[0135] 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, hepatic hematopoiesis, and hepatic stenosis. Blood flow disorder, nephropathy, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), pancreatic secretory abnormality, benign prostatic hyperplasia, neurogenic bladder, diabetic nephropathy, focal segmental glomerulosclerosis, IgA nephropathy, drug-induced or transplant-induced nephropathy, autoimmune nephropathy, lupus nephritis, hepatic fibrosis, renal fibrosis, chronic kidney disease (CKD), diabetic kidney disease (DKD), skin fibrosis, keloid, systemic sclerosis, scleroderma, viral fibrosis, idiopathic Interstitial pneumonia (IPF), interstitial pneumonia, non-specific 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, colon cancer, prostate cancer, leukemia, chronic lymphocytic leukemia In one embodiment, the present invention provides a method for treating a fibrotic disease, an inflammatory disease, or a cell proliferation 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.

[0136] In another embodiment, the present invention provides a compound of the present invention for use in therapy.

[0137] 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.

[0138] 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.

[0139] In another embodiment, the invention provides a method of treating a fibrotic disease, an inflammatory disease, or a 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 invention.

[0140] 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.

[0141] 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.

[0142] The compounds of the invention may be used in combination with other therapeutic agents, such as one or more anti-fibrotic and / or anti-inflammatory agents.

[0143] In certain embodiments, the additional therapeutic agent used in the combination pharmaceutical composition or combination method or combination is selected from the group consisting of: TGFβ receptor inhibitors (e.g., galunisertib), TGFβ synthesis inhibitors (e.g., pirfenidone), vascular endothelial growth factor (VEGF) inhibitors, platelet-derived growth factor (PDGF) inhibitors and fibroblast growth factor (FGF) receptor kinase inhibitors (e.g., nintedanib), 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 gamma, 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., substance P ([Sar 9 , Met(O2) 11]), syntredekin vesudotox, human recombinant DNA-derived IgG1κ monoclonal antibodies against connective tissue growth factor, and CC chemokine ligand 2-selective fully human IgG1κ antibodies (e.g., carlumab, CCX140), antioxidants (e.g., N-acetylcysteine), phosphodiesterase 5 (PDE5) inhibitors (e.g., sildenafil), agents for treating airway obstructive diseases (e.g., muscarinic antagonists (e.g., tiotropium, ipratropium bromide)), adrenergic β2 agonists (e.g., The therapeutic agent is selected from one or more, preferably one to three, of therapeutic agents effective in treating fibrotic conditions (e.g., hepatic 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 complexes (e.g., aramchol).The TLR9 inhibitors of various embodiments of the present invention may be administered in combination with one or more therapeutic agents (e.g., 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), FA ...cenicriviroc), galectin 3 inhibitors (e.g., cenicriviroc), galectin 3 inhibitors (e.g., cenicriviroc), galectin 3 inhibitors (e.g., cenicriviroc), galectin 3 inhibitors (e. It may 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 combination pharmaceutical composition or 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).

[0144] The terms "TLR9-associated condition" or "TLR9-associated disease or disorder" as used herein are meant to encompass all of the above-mentioned conditions, as well as any other condition that is affected by TLR9 inhibition, such as those that recur over time.

[0145] The above-mentioned other therapeutic agents, when used in combination with the compounds of the present invention, may be used, for example, in amounts as described in the US Pharmacopoeia (PDR) or in amounts as determined by one skilled in the art. In the methods of the present invention, the other therapeutic agents may be administered before, simultaneously, 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.

[0146] 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, for example, using conventional solid or liquid vehicles or diluents, as well as pharmaceutical excipients (e.g., additives, binders, preservatives, stabilizers, flavoring agents, and the like) of a type appropriate to the desired method of administration.

[0147] Therefore, the present invention further includes compositions comprising one or more compounds of formula (I) and a pharma- ceutically acceptable carrier.

[0148] "Pharmaceutically acceptable carrier" refers to a medium 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 one of ordinary skill 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 a variety of solid and semi-solid dosage forms. Such carriers can contain many different components and additives in addition to the active agent, and such added components are included in the formulation for a variety of reasons (e.g., stabilization of the active agent, binders, etc., known to those of ordinary skill in the art). Descriptions of suitable pharmacopoeia acceptable carriers and the factors involved in selecting them 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.

[0149] 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 amount of treatment required per site or the amount of compound of formula (I) to be delivered.

[0150] The present invention also includes a class of pharmaceutical compositions comprising a compound of formula (I) and one or more non-toxic, pharma- ceutically acceptable carriers and / or diluents and / or adjuvants (substances 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 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 pharma-ceutically acceptable carriers, adjuvants, and vehicles. For example, pharmaceutical carriers may include mixtures of mannitol or lactose and microcrystalline cellulose. The mixtures may include additional ingredients, such as lubricants (e.g., magnesium stearate) and disintegrants (e.g., crospovidone). The carrier mixture may be filled into gelatin capsules or compressed into tablets. The pharmaceutical composition may be administered, for example, in oral dosage form or as an infusion.

[0151] 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 with 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 to be administered to a human or other mammal may vary widely depending on the patient's condition and other factors, but can be determined using routine methods.

[0152] Any pharmaceutical composition discussed herein may be orally administered, for example, by any suitable acceptable oral agent. Examples of oral agents 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 may 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 may include at least one substance selected from sweeteners, flavoring agents, coloring agents, demulcents, antioxidants, and preservatives.

[0153] Tablets can be prepared, for example, by mixing at least one compound of formula (I) with at least one non-toxic pharma- ceutically acceptable additive suitable for tablet preparation. 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), binding agents (e.g., starch, gelatin, polyvinylpyrrolidone, and gum arabic), and lubricants (e.g., magnesium stearate, stearic acid, and talc). In addition, 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 digestive tract, thus prolonging the effect of the active ingredient for a longer period of time. Examples of water-soluble taste-masking materials include, but are not limited to, hydroxypropyl methylcellulose and hydroxypropyl cellulose. Examples of time delay materials include, but are not limited to, ethyl cellulose and cellulose acetate butyrate.

[0154] Hard gelatin capsules may be prepared, for example, by mixing at least one compound of formula (I) with at least one inert solid diluent, such as calcium carbonate, calcium phosphate, and kaolin.

[0155] 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).

[0156] Aqueous suspensions may 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, gum tragacanth, and gum arabic), dispersing or wetting agents (e.g., naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with fatty acids and Examples of suitable condensation products include condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (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).

[0157] Oily suspensions can be prepared, for example, by suspending at least one compound of formula (I) in either vegetable oil (e.g., peanut oil, olive oil, sesame oil, and coconut oil) or mineral oil (e.g., liquid paraffin). Oily suspensions can also include at least one thickening agent (e.g., beeswax, hard paraffin, and cetyl alcohol). To provide a palatable oily suspension, at least one sweetener already described above and / or at least one flavoring agent can be added to the oily suspension. Oily suspensions can further include at least one preservative, including but not limited to, for example, an antioxidant (e.g., butylated hydroxyanisole, and alpha-tocopherol).

[0158] Dispersible powders and granules can be prepared, for example, by mixing at least one compound of formula (I) with at least one dispersing agent and / or wetting agent, at least one suspending agent, and / or at least one preservative. Suitable dispersing agents, wetting agents, and suspending agents have already been described above. Examples of preservatives include, but are not limited to, antioxidants (e.g., ascorbic acid). In addition, dispersible powders and granules can also include at least one excipient (e.g., but are not limited to, sweeteners, flavoring agents, and coloring agents).

[0159] The emulsion of at least one compound of formula (I) may be prepared, for example, as an oil-in-water emulsion. The oil phase of the emulsion containing the compound of formula (I) may be composed of known ingredients in a known manner. The oil phase may be provided, for example, but not limited to, vegetable oils (e.g., olive oil and peanut oil), mineral oils (e.g., liquid paraffin), and mixtures thereof. The oil phase may include only an emulsifier, but may also include 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 and ethylene oxide (e.g., polyoxyethylene sorbitan monooleate). Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier, with or without stabilizer, makes up the so-called emulsifying wax, and the wax, with oil and fat, makes up the so-called emulsifying ointment base, which forms the oily dispersed phase of the cream.The emulsion may also include sweeteners, flavorings, preservatives, and / or antioxidants.Emulsifiers and emulsion stabilizers suitable 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 with wax; or other materials known in the art.

[0160] In addition, the compound of formula (I) can be delivered, for example, intravenously, subcutaneously, and / or intramuscularly, via any medicamentously 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.

[0161] 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 preparations for oral administration, 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 methods of administration are 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).

[0162] A sterile injectable preparation may also 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 are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any sterile fixed oil may be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are used as injectable preparations.

[0163] 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.

[0164] Sterile aqueous suspension or sterile oily suspension can be prepared according to a method known to those skilled in the art. For example, sterile aqueous solution or sterile aqueous suspension can be prepared using a non-toxic, parenterally acceptable diluent or solvent (e.g., 1,3-butanediol), and sterile oily suspension can be prepared using a non-toxic, acceptable solvent or suspension medium (e.g., sterile fixed oil (e.g., synthetic monoglyceride or diglyceride), and fatty acid (e.g., oleic acid).

[0165] Pharmaceutically acceptable carriers, adjuvants, and vehicles that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) (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., phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes (e.g., protamine sulfate, Salts, 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 (e.g., hydroxyalkyl cyclodextrins, including 2- and 3-hydroxypropyl cyclodextrin, or other solubilizing derivatives)) may also be effectively used to enhance the delivery of the compounds of the formulae described herein.

[0166] The pharma- ceutical active compounds of the present invention can be processed according to conventional pharmaceutical methods to prepare medicaments for administration to patients (e.g., humans and other mammals). The pharmaceutical compositions can be subjected to conventional pharmaceutical operations (e.g., sterilization) and / or can contain conventional adjuvants (e.g., preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc.). Tablets and pills can additionally be prepared with enteric coatings. Such compositions can also contain adjuvants (e.g., wetting agents, sweeteners, flavoring agents, and aromatic agents).

[0167] The amount of compound administered to treat a condition using the compounds and / or compositions of the present invention, and the dosing schedule will depend on a variety of factors, such as age, weight, sex, the condition of the patient, the type of disease, the severity of the disease, the route and frequency of administration, and the specific compound utilized. Thus, the dosing schedule 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 between about 0.0025 to about 50 mg / kg body weight, and most preferably between about 0.005 to 10 mg / kg body weight, may be appropriate. The daily dose may be administered 1 to 4 times a day. Other dosing schedules include weekly and biday cycles.

[0168] 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 phosphoric acid and sulfate, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.Such capsules or tablets can include controlled release formulations, and can be provided with active compound dispersed in hydroxypropylmethylcellulose.

[0169] The pharmaceutical compositions of the present invention include at least one compound of formula (I) and optional additives selected from pharma- ceutically acceptable carriers, adjuvants, and vehicles. Another composition of the present invention includes a compound of formula (I) as described herein, or a prodrug thereof, and a pharma- ceutically acceptable carrier, adjuvant, or vehicle.

[0170] The present invention also encompasses an article of manufacture. As used herein, article of manufacture is intended to include, but is not limited to, kits and packages. The 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, comprising a compound of the present invention or a pharma- ceutically acceptable salt form thereof, and (c) a package insert that describes that the pharmaceutical composition can be used to treat cardiovascular disorders, diuresis, and / or natriuresis. In other embodiments, the package insert describes 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 within or outside the second container. Located within the first and second containers means that each container holds the item within its area.

[0171] The first container is a container used to hold a 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 containers used in manufacturing, holding, storing, or distributing pharmaceutical formulations.

[0172] 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, stapler, or other attachment methods, or can be present in the second container without being attached to the first container by physical means. 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, stapler, or other attachment methods. Alternatively, the package insert can be in close proximity to or in contact with the outside of the second container without being physically attached.

[0173] A package insert is a label, tag, marker, or other written paper that provides information related to the pharmaceutical composition placed in the first container. The information provided is usually determined by a regulatory agency (e.g., the U.S. Food and Drug Administration) governing the geographic area in which the product is sold. Preferably, the package insert specifically provides the indication that 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-backed paper or plastic) on which the desired information is placed (e.g., printed or affixed).

[0174] (Manufacturing method) The compounds of the present invention can be prepared by many 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 thereto that will be appreciated by those skilled in the art. Preferred methods include, but are not limited to, the following methods:

[0175] The reactions and techniques described in this section are carried out in solvents suitable for the reagents and materials used and are appropriate for the transformations effected. It is also understood that in the description of the synthetic methods described below, all reaction conditions presented (including the choice of solvent, reaction atmosphere, reaction temperature, experimental time and work-up method) are selected to be standard conditions for the reaction, which should be readily recognized by those skilled in the art. It is understood by those skilled in the art of organic synthesis that the functional groups present on the various parts of the molecule must be compatible with the reagents and reactions shown. Such limitations of the 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 a decision to change the order of synthetic steps or to select a particular reaction sequence differently in order to obtain the desired compound of the 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 be used to protect reactive functional groups contained in the compounds described in the invention. For those skilled in the art, an authoritative reference describing many protecting group options is Protective Groups in Organic Synthesis, Fifth Edition, by Greene et al., Wiley and Sons (2014).

[0176] [ka] Scheme 1 describes one possible synthetic route to compounds of formula IA or IB, which are one of formula I. In this scheme, [halogen] refers to any halogen that one skilled in the art would deem appropriate for the intended transformation. Compound 1a is reacted with aldehyde 1b by heating in a suitable solvent (e.g., EtOH, MeOH, DMSO, NMP) in the presence of sodium metabisulfite to give compound 1c. Depending on the nature of the substituent R1, it may be deemed necessary to first reduce the nitro group of compound 1a. The reduction is carried out using a typical nitro reducing agent (e.g., iron powder, tin chloride dihydrate, hydrogenation catalyst), followed by cyclization by heating with aldehyde 1b in the presence of sodium metabisulfite in a suitable solvent (e.g., NMP, DMSO, EtOH) to give compound 1c. Compound 1c is reacted with the appropriate boronic ester or boronic acid using standard Suzuki coupling conditions to give compounds of formula IA and IB.

[0177] (Example) The compounds of the present invention and intermediates used in the preparation of the compounds of the present invention can be prepared using the methods shown 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 are meant to illustrate how the compounds of the present invention can be prepared. The starting materials and reagents used in these examples are generally commercially available or reported in the chemical literature, or may be prepared by using steps described in the chemical literature, unless the preparation method is described herein. The present invention is further defined in the following examples, which should be understood to be given by way of illustration only. From the above discussion and examples, one skilled in the art can 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. As a result, the present invention is not limited by the examples described below, but rather is defined by the claims appended hereto.

[0178] 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).

[0179] Chemical names were determined using ChemDraw Professional, version 20.1.0.110 (PerkinElmer Informatics, Inc.). The following abbreviations are used: [Table 1]

[0180] (Manufacturing) All commercially purchased reagents were used without further purification unless otherwise noted. All reactions involving air- or moisture-sensitive reagents were carried out under an inert atmosphere. Proton magnetic resonance spectra were primarily recorded on Bruker Avance 400 or 500 MHz spectrometers.

[0181] Analytical LC / MS method Method 1: Column: Waters Acquity BEH C18, 2.1x50mm, particle size: 1.7μm; Mobile phase A: 5:95 MeCN:0.05% TFA in water; Mobile phase B: 95:5 MeCN:0.05% TFA in water; Temperature: 50°C; Gradient: 0%B to 100%B over 3 min, then 100%B for 0.50 min; Flow rate: 1mL / min; Detection: MS and UV (220, 254nm). Method 2: Column: XBridge C18, 2.1mm x 50mm, particle size: 1.7μm; Mobile phase A: MeCN / H2O (5:95, containing 10mM NH4OAc); Mobile phase B: MeCN / H2O (95:5, containing 10mM NH4OAc); Temperature: 50°C; Gradient: 0~100%B (0.0~3.0 min), 100%B (3.0~3.5 min); Flow rate: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI+ ) Method 3: Column: XBridge C18, 2.1 mm x 50 mm, particle size: 1.7 μm; Mobile phase A: MeCN / H2O (5:95, containing 0.05% TFA); Mobile phase B: MeCN / H2O (95:5, containing 0.05% TFA); Temperature: 50 °C; Gradient: 0-100% B (0.0-3.0 min), 100% B (3.0-3.5 min); Flow rate: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + ) Method 4: Column: HALO C18, 3.0x30mm, particle size: 2.7μm; Mobile phase A: 0.05% TFA in water; Mobile phase B: MeCN (containing 0.05% TFA); Temperature: 40°C; Gradient: 5% B to 100% B over 1.3 min, then 100% B for 0.50 min; Flow rate: 1.5mL / min; Detection: MS and UV (254 / 220nm). Method 5: Column: HALO C18, 3.0x30mm, particle size: 2.7μm; Mobile phase A: 0.05% TFA in water; Mobile phase B: MeCN (containing 0.05% TFA); Temperature: 40°C; Gradient: 5%B to 50%B over 2 min, then 5%B to 50%B over 0.4 min, then 100%B for 0.40 min; Flow rate: 1.5mL / min; Detection: MS and UV (254 / 220nm). Method 6: Column: Waters Acquity BEH C18, 2.1x50mm, particle size: 1.7μm; Mobile phase A: 5:95 MeCN:10mM NH4OAc in water; Mobile phase B: 95:5 MeCN:10mM NH4OAc in water; Temperature: 50°C; Gradient: 0%B to 100%B over 3 min, then 100%B for 0.50 min; Flow rate: 1mL / min; Detection: MS and UV (220, 254nm).

[0182] Preparative HPLC method Preparative method A: Column: XBridge C18, 200mm x 19mm, particle size: 5μm; Mobile phase A: 5:95 MeCN:NH4OAc in water; Mobile phase B: 95:5 MeCN:NH4OAc in water; Gradient: Elute with B (in a ratio that depends on the substrate) over 20 min, then 100% B for 0 min; Flow rate: 20mL / min; Column temperature: 25℃ Fractions were collected as determined by MS and UV signals. Fractions containing the desired product were combined and dried in a centrifugal evaporator. Preparative method B: Column: XBridge C18, 200mm x 19mm, particle size: 5μm; Mobile phase A: 5:95 MeCN:water (containing 0.05% TFA); Mobile phase B: 95:5 MeCN:water (containing 0.05% TFA); Gradient: elution with B (in a ratio that varies with the substrate) over 20 min, followed by 100% B for 0 min; Flow rate: 20mL / min; Column temperature: 25°C. Fractions were collected based on the MS signal, and the fractions containing the desired product were combined and dried in a centrifugal evaporator. Prep Method C: Column: Phenomenex AXIA 5u C18, 30x100mm; Mobile Phase A: 90%H2O / 10%MeOH-10mM NH4OAc; Mobile Phase B: 10%H2O / 90%MeOH-10mM NH4OAc; Method: 100%A:0%B to 0%A:100%B; Detection: 220nM; Gradient: 10min Prep Method D: Column: Phenomenex AXIA 5u C18, 30x100mm; Mobile Phase A: 90%H2O / 10%MeCN / 0.1%TFA; Mobile Phase B: 10%H2O / 90%MeCN / 0.1%TFA; Method: 100%A:0%B to 0%A:100%B; Detection: 220nM; Gradient: 10min. Preparative Method E: Column: SunFire Prep C18 OBD column, 19x150mm, 5μm 10nm; Mobile phase A: water (0.05% TFA), Mobile phase B: MeCN; Flow rate: 25mL / min; Gradient: 5%B to 15%B over 6.8min; Wavelength: 254nm; Column temperature: 25℃ Fractions were collected as determined by MS and UV signals. Pure fractions were combined and concentrated under reduced pressure to remove the organic solvent. The remaining aqueous solution was lyophilized to give the final product. Preparative Method F: Column: XBridge Prep C18 OBD column, 19x150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: MeCN; Flow rate: 20mL / min; Gradient: 30%B to 50%B over 4.5min; Wavelength: 254 / 210nm; Column temperature: 25℃ Fractions were collected as determined by MS and UV signals. Pure fractions were combined and concentrated under reduced pressure to remove the organic solvent. The remaining aqueous solution was lyophilized to give the final product.

[0183] Example 1 5-(4-((6-cyclobutyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)phenyl)-3-cyclopropyl-7-methyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine [ka]

[0184] Step A. Preparation of Intermediate 1A: 6-chloro-N-cyclopropyl-4-methyl-3-nitropyridin-2-amine [ka] To a round bottom flask (500 mL) were added 2,6-dichloro-4-methyl-3-nitropyridine (5.0 g, 24 mmol), DIEA (13 mL, 73 mmol), THF (200 mL), followed by cyclopropylamine (1.7 mL, 24 mmol) and the mixture was stirred under N2 atmosphere. After 18 h, the solvent was concentrated and the resulting residue was purified by flash column chromatography (120 g silica gel cartridge; A=Hex, B=EtOAc; gradient: 30 min; 0% B to 100% B; flow rate=80 mL / min). The product fractions were combined, concentrated and dried under vacuum to give the title compound (2.9 g, 13 mmol, 54% yield) as a yellow solid. Analytical LC / MS (Method 1): Observed mass: 228.0; Retention time: 2.037 min; 1 H NMR (500MHz, methanol-d4) δ 6.65(s, 1H), 2.91(s, 1H), 2.46(s, 3H), 0.85(dd, J=7.0, 1.6Hz, 2H), 0.66-0.49(m, 2H)

[0185] Step B. Preparation of Intermediate 1B: 6-chloro-N2-cyclopropyl-4-methylpyridine-2,3-diamine [ka] To a pear-shaped flask (200 mL) was added Intermediate 1A (2.0 g, 8.8 mmol), ammonium chloride (2.4 g, 44 mmol), iron powder (2.5 g, 44 mmol), EtOH (10 mL), and water (10 mL), and the mixture was stirred at 80 °C. After 18 h, the reaction mixture was cooled, filtered, the filter cake was washed with MeOH, and the volatiles were concentrated from the filtrate. The resulting suspension was diluted with water (100 mL) and extracted with EtOAc (2x50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The resulting residue was purified by flash column chromatography (120 g silica gel cartridge; A=Hex, B=EtOAc; gradient: 30 min; 0% B to 100% B; flow rate=80 mL / min). The product fractions were combined, concentrated and dried under vacuum to give the title compound (1.0 g, 5.2 mmol, 59% yield) as a pale yellow solid. Analytical LC / MS (Method 1): Observed mass: 197.9; Retention time: 1.133 min; 1 H NMR (500 MHz, methanol-d4) δ 6.42(s, 1H), 2.85-2.73(m, 1H), 2.11(s, 3H), 0.76(br d, J=5.0Hz, 2H), 0.57-0.47(m, 2H)

[0186] Step C. Preparation of Intermediate 1C: 5-chloro-3-cyclopropyl-7-methyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine [ka] A pear-shaped flask (200 mL) was charged with Intermediate 1B (1.0 g, 5.2 mmol) and NMP (60 mL). To this mixture was added sodium pyrosulfite (1.5 g, 7.7 mmol), followed by 4-(methylsulfonyl)benzaldehyde (1.0 g, 5.7 mmol) and stirred at 70 °C under N2 atmosphere. After 18 h, the mixture was cooled, diluted with water (250 mL) and extracted with EtOAc (2x100 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash column chromatography (120 g silica gel cartridge; A=DCM, B=MeOH; gradient: 30 min; 0% B to 15% B; flow rate=80 mL / min). The product fractions were combined, concentrated and dried under vacuum to give the title compound (0.85 g, 2.3 mmol, 44% yield) as a pale yellow solid. Analytical LC / MS (Method 1): Observed mass: 361.9; Retention time: 1.592 min; 1 H NMR (500MHz, methanol-d4) δ 8.32-8.26(m, 2H), 8.21-8.17(m, 2H), 7.29-7.21(m, 1H), 3.77-3.67(m, 1H), 3.25(s, 3H), 2.68(d, J=0.7Hz, 3H), 1.22-1.15(m, 2H), 0.85-0.76(m, 2H)

[0187] Step D. Preparation of Intermediate 1D: 4-(3-cyclopropyl-7-methyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridin-5-yl)benzaldehyde [ka] A round bottom flask (250 mL) was charged with Intermediate 1C (0.85 g, 2.3 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (0.60 g, 2.6 mmol), 1,4-dioxane (20 mL), and potassium phosphate tribasic (1.5 g, 7.1 mmol) dissolved in water (5 mL). The mixture was purged with N2, XPhos Pd G3 (0.099 g, 0.12 mmol) was added, the vessel was purged again, and the reaction was heated and stirred at 80 °C. After 18 h, the mixture was cooled, diluted with water (150 mL), and extracted with EtOAc (2x75 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The resulting residue was purified by flash column chromatography (80 g silica gel cartridge; A=Hex, B=EtOAc; gradient: 30 min; 0% B to 100% B; flow rate=60 mL / min). The product fractions were combined, concentrated and dried under vacuum to give the title compound (0.89 g, 2.1 mmol, 88% yield) as a pale yellow solid. Analytical LC / MS (Method 1): Observed mass: 432.0; Retention time: 1.677 min (gradient 3 min); 1 H NMR (500MHz, DMSO-d6) δ 10.10(s, 1H), 8.55-8.50(m, 1H), 8.44(d, J=8.3Hz, 2H), 8.37(s, 2H), 8.14(d, J=8.6Hz, 2H), 8.06(d, J=8.5Hz, 2H), 3.94-3.80(m, 1H), 3.35(s, 3H), 2.72-2.67(m, 3H), 1.26-1.14(m, 2H), 0.99-0.83(m, 2H)

[0188] Step E. Preparation of Intermediate 1E: 5-(4-((2,6-diazaspiro[3.3]heptan-2-yl)methyl)phenyl)-3-cyclopropyl-7-methyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine diTFA salt [ka] To a vial (40 mL) was added Intermediate 1D (0.40 g, 0.93 mmol), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate oxalate (0.80 g, 2.8 mmol), AcOH (0.058 mL, 1.0 mmol), magnesium sulfate (1.7 g, 14 mmol), and DMF (10 mL). The reaction mixture was stirred for 20 min, then sodium triacetoxyborohydride (0.98 g, 4.6 mmol) was added. After stirring for 18 h, the mixture was diluted with 10% IPA / CHCl3 (100 mL) and filtered. The filtrate was partitioned into KOH solution (10% saturated aqueous NaCl solution, 50 mL) and the layers were separated. The aqueous layer was extracted with 10% IPA / CHCl3 (50 mL) and the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The resulting residue was purified by flash column chromatography (80 g silica gel cartridge; A=DCM, B=MeOH; gradient: 30 min; 0%B to 20%B; flow rate=60 mL / min). The product fractions were combined and concentrated. The resulting intermediate was dissolved in MeOH (10 mL), TFA (1.4 mL, 19 mmol) was added and the reaction mixture was stirred at 45° C. After 2 h, the solvent was concentrated and the resulting residue was co-concentrated with toluene (2×) and the product was dried in vacuum to give the title compound (480 mg, 0.65 mmol, 70% yield) as a pale yellow solid. Analytical LC / MS (Method 1): Observed mass: 514.1; Retention time: 1.051 min; 1 H NMR (500MHz, methanol-d4) δ 8.34-8.30(m, 4H), 8.22(d, J=8.6Hz, 2H), 7.84-7.81(m, 1H), 7.63-7.60(m, 2H), 4.48-4.44(m, 6H), 4.39-4.33(m, 4H), 3.86-3.75(m, 1H), 3.27(s, 3H), 2.79-2.75(m, 3H), 1.29-1.18(m, 2H), 1.01-0.90(m, 2H)

[0189] Step F. Preparation of Example 1 To a vial (40 mL) was added Intermediate 1E (96 mg, 0.13 mmol), cyclobutanone (45 mg, 0.65 mmol), AcOH (8.2 μL, 0.14 mmol), magnesium sulfate (230 mg, 1.9 mmol), and DMF (2 mL). The mixture was stirred for 20 min, then sodium triacetoxyborohydride (140 mg, 0.65 mmol) was added, the vial was capped, and the mixture was stirred. After 18 h, the reaction was diluted with 10% IPA / CHCl3 (40 mL) and filtered. The filtrate was partitioned into a KOH solution (20 mL of 10% saturated aqueous NaCl solids) and the layers were separated. The aqueous layer was extracted with 10% IPA / CHCl3 (10 mL) and the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The crude material was purified by preparative HPLC (Method A) to give the title compound (44 mg, 0.077 mmol, 59% yield). Analytical LC / MS (Method 2): Observed mass: 568.20; Retention time: 1.53 min; Analytical LC / MS (Method 3): Observed mass: 568.20; Retention time: 1.14 min; 1 H NMR (500MHz, DMSO-d6) δ 8.36(br d, J=8.2Hz, 2H), 8.12(br dd, J=8.1, 4.1Hz, 4H), 7.77(s, 1H), 7.38(br d, J=7.9Hz, 2H), 3.88-3.80(m, 1H), 3.61-3.54(m, 1H), 3.37-3.30(m, 1H), 3.24-3.21(m, 2H), 3.16(s, 3H), 3.05-2.96(m, 1H), 2.91-2.86(m, 1H), 2.66(s, 3H), 2.51(br s, 3H), 1.91(s, 2H), 1.88-1.78(m, 2H), 1.74-1.51(m, 4H), 1.25-1.13(m, 2H), 0.86(br s, 2H)

[0190] Example 14 6-(1'-isopropyl-[1,4'-bipiperidine]-4-yl)-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-imidazo[4,5-b]pyridine [ka]

[0191] Step A. Preparation of Intermediate 14A: 5-Bromo-N-methyl-2-nitro-pyridin-3-amine [ka] To a solution of 5-bromo-3-fluoro-2-nitro-pyridine (5 g, 22.63 mmol) in dry THF (70 mL) was added methylamine solution (2 M in THF, 33.94 mL, 67.88 mmol). After stirring at 50 °C for 18 h, the mixture was cooled, the solvent was concentrated and the resulting crude product was purified by silica gel column chromatography (eluent = hexane / EtOAc = 0-70%) to give the title compound (5.2 g, 22.4 mmol, 99% yield) as a yellow solid. Analytical LC / MS (Method 4): Observed mass: 232.0 / 234.0; Retention time: 0.836 min.

[0192] Step B. Preparation of Intermediate 14B: 6-Bromo-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-imidazo[4,5-b]pyridine [ka] A mixture of intermediate 14A (2 g, 8.62 mmol), 4-methylsulfonylbenzaldehyde (3.2 g, 17.24 mmol), Na2S2O4 (4.5 g, 25.86 mmol) in ethanol (30 mL) and water (15 mL) was stirred at 90 °C under N2 atmosphere. After 36 h, the reaction mixture was cooled and the resulting mixture was diluted with water (500 mL) and extracted with EtOAc (3x300 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated and the resulting residue was purified by silica gel column chromatography (eluent = hexane / EtOAc = 0-100%) to give the title compound (850 mg, 2.32 mmol, 27% yield) as a yellow solid. Analytical LC / MS (Method 4): Observed mass: 366.2 / 368.2; Retention time: 0.654 min.

[0193] Step C. Preparation of Intermediate 14C: tert-butyl 4-(1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-imidazo[4,5-b]pyridin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate [ka] A mixture of intermediate 14B (830 mg, 2.27 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (1.05 g, 3.4 mmol), K2CO3 (625 mg, 4.53 mmol) and Pd(PPh3)4 (200 mg, 0.24 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was degassed with nitrogen (3x) and stirred at 90° C. After 18 h, the reaction mixture was cooled, diluted with water (100 mL) and extracted with EtOAc (3x80 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent = hexane / EtOAc = 0-100%) to give the title compound (850 mg, 1.81 mmol, 80% yield) as a yellow solid. Analytical LC / MS (Method 4): Observed mass: 469.2; Retention time: 0.910 min.

[0194] Step D. Preparation of Intermediate 14D: 1-Methyl-2-(4-(methylsulfonyl)phenyl)-6-(piperidin-4-yl)-1H-imidazo[4,5-b]pyridine HCl salt [ka] To a solution of intermediate 14C (830 mg, 1.77 mmol) in DMF (50 mL) and DCM (10 mL) was added AcOH (1 mL) and the solution was evacuated and replaced with nitrogen (3x). To this solution was added Pd / C (0.2 g), the mixture was evacuated and purged with nitrogen, and the mixture was stirred under a hydrogen atmosphere. After 3 days, the catalyst was filtered and the filtrate was concentrated. The resulting residue was dissolved in DCM (10 mL) and a solution of HCl (2M in EtOAc, 5 mL) was added and the suspension was stirred. After 2 h, the resulting precipitate was collected by vacuum filtration and washed with DCM. The resulting product was dried under vacuum to give the title compound (crude, 330 mg) as a pale yellow solid. Analytical LC / MS (Method 4): Observed mass: 371.2; Retention time: 0.551 min.

[0195] Step F. Preparation of Example 14 To a solution of intermediate 14D (60 mg, 0.15 mmol) in methanol (1 mL) was added TEA (0.06 mL, 0.44 mmol), NaBH3CN (31 mg, 0.49 mmol), ZnCl2 solution (2 M in THF, 0.09 mL, 0.18 mmol) and 1-isopropylpiperidin-4-one (69 mg, 0.49 mmol). The suspension was stirred at 60° C. After 20 h, the reaction mixture was cooled, the solution was concentrated and the crude product was purified by preparative HPLC (Method E) to give the title compound (14.6 mg, 0.029 mmol, 20% yield) as a white solid. Analytical LC / MS (Method 5): Purity: 99.3%; Observed mass: 496.2; Retention time: 0.553 min; 1 H NMR (400MHz, DMSO-d6) δ 10.22(s, 1H), 9.65(s, 1H), 8.46(s, 1H), 8.23-8.13(m, 4H), 8.07-8.01(m, 1H), 3.98(s, 3H), 3.70-3.47(m, 6H), 3.34(s, 3H), 3.28-3.01(m, 5H), 2.41-2.33(m, 2H), 2.25-1.96(m, 6H), 1.33-1.24(m, 6H)

[0196] Example 17 5-(1'-isopropyl-[1,4'-bipiperidine]-4-yl)-3-methyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine [ka]

[0197] Step A. Preparation of 5-chloro-3-methyl-2-(4-methylsulfonylphenyl)imidazo[4,5-b]pyridine [ka] To a vial (40 mL) were added 6-chloro-N-methyl-3-nitro-pyridin-2-amine (0.5 g, 2.67 mmol), 4-(methylsulfonyl)benzaldehyde (0.491 g, 2.67 mmol), sodium hyposulfite (0.928 g, 5.33 mmol), followed by DMSO (15 mL) and the mixture was stirred at 80° C. After 24 h, the resulting mixture was cooled, diluted with water (200 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash column chromatography (120 g silica gel cartridge; A=DCM, B=MeOH; gradient: 30 min; 0% B to 20% B; flow rate=85 mL / min). The product fractions were combined, concentrated and dried under vacuum to give the title compound (0.73 g, 2.269 mmol, 85% yield) as a tan solid. Analytical LC / MS (Method 1): Observed mass: 321.8; Retention time: 1.366 min; 1 H NMR (500 MHz, methanol-d4) δ 8.24-8.20 (m, 2H), 8.19-8.14 (m, 2H), 8.13-8.09 (m, 1H), 7.46-7.38 (m, 1H), 4.02-3.99 (m, 3H), 3.26-3.23 (m, 3H).

[0198] Step B. Preparation of Example 17 Example 17 was prepared according to the methods described anywhere herein using the appropriate starting materials, reagents and conditions. Analytical LC / MS (Method 5): Purity: 98.8%; Observed mass: 496.1; Retention time: 0.584 min; 1 H NMR (300MHz, DMSO-d6) δ 8.26-8.01(m, 5H), 7.26(d, J=8.4Hz, 1H), 3.96(s, 3H), 3.32(s, 3H), 3.04-2.94(m, 2H), 2.87-2.59(m, 4H), 2.38-2.00(m, 5H), 1.96-1.66(m, 6H), 1.51-1.33(m, 2H), 0.95(d, J=6.5Hz, 6H)

[0199] Example 20 5-(1'-isopropyl-[1,4'-bipiperidine]-4-yl)-3,7-dimethyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine [ka]

[0200] Step A. Preparation of Intermediate 20A: 6-Chloro-N,4-dimethyl-3-nitro-pyridin-2-amine [ka] To a solution of 2,6-dichloro-4-methyl-3-nitro-pyridine (1 g, 4.83 mmol) in THF (1 mL) was added methylamine solution (2 M in THF, 4.8 mL, 9.66 mmol) and DIEA (1.87 g, 14.49 mmol). After stirring for 18 h, the mixture was concentrated and the resulting crude product was purified by silica gel chromatography (eluent = petroleum ether:DCM = 2:1) to give the title compound (450 mg, 46% yield) as a yellow solid. Analytical LC / MS (Method 4): Observed mass: 202 / 204; Retention time: 1.072 min; 1H NMR (300MHz, DMSO-d6) δ 7.95(d, J=5.0Hz, 1H), 6.72(s, 1H), 2.89(d, J=4.6Hz, 3H), 2.38(s, 3H)

[0201] Step B. Preparation of Intermediate 20B: 5-chloro-3,7-dimethyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine [ka] To a stirred solution of intermediate 20A (440 mg, 2.18 mmol) in ethanol (5 mL) and water (2.5 mL) was added 4-methylsulfonylbenzaldehyde (804.1 mg, 4.36 mmol) and Na2S2O4 (759.5 mg, 4.36 mmol). After stirring at 90 °C for 18 h, the mixture was cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (2x50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting crude was purified by silica gel chromatography (eluent = petroleum ether:ethyl acetate = 1:1) to give the title compound (470 mg, 64% yield) as a yellow solid. Analytical LC / MS (Method 4): Observed mass: 336.1 / 338.1; Retention time: 0.919 min; 1 H NMR (300MHz, DMSO-d6) δ 8.27-8.08(m, 4H), 7.31(s, 1H), 3.92(s, 3H), 2.63(s, 3H), 2.53(s, 3H)

[0202] Step C. Preparation of Intermediate 20C: tert-butyl 4-(3,7-dimethyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate [ka] To a solution of intermediate 20B (460 mg, 1.37 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (847.1 mg, 2.74 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added K3PO4 (872.3 mg, 4.11 mmol) and Pd(dppf)Cl2 (100.1 mg, 0.14 mmol). The resulting solution was degassed with nitrogen (3x) and stirred at 90 °C. After 18 h, the resulting mixture was cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (2x50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude residue obtained was purified by silica gel chromatography (eluent = ethyl acetate) to give the title compound (480 mg, 73% yield) as a white solid. Analytical LC / MS (Method 4): Observed mass: 483.1; Retention time: 1.051 min; 1 H NMR (300MHz, DMSO-d6) δ 8.23(d, J=8.3Hz, 2H), 8.13(d, J=8.2Hz, 2H), 7.43(s, 1H), 6.74(s, 1H), 4.10(s, 2H), 3.97(s, 3H), 3.59 (t, J=5.5Hz, 2H), 2.70(s, 2H), 2.63(s, 3H), 2.53(s, 3H), 1.45(s, 9H)

[0203] Step D. Preparation of Intermediate 20D: tert-butyl 4-(3,7-dimethyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidine-1-carboxylate [ka] A solution of intermediate 20C (470 mg, 0.97 mmol) in methanol (3 mL) and DCM (1 mL) was degassed with nitrogen (3x) and to this mixture was added Pd / C (100 mg). The reaction vessel was evacuated and filled with nitrogen (3x) and then filled with hydrogen (1 atm). After stirring for 3 h, the resulting mixture was filtered and the filtrate was concentrated in vacuo. The crude material was purified by silica gel chromatography (eluent = ethyl acetate) to give the title compound (400 mg, 85% yield) as a white solid. Analytical LC / MS (Method 4): Observed mass: 485.3; Retention time: 1.005 min; 1 H NMR (300MHz, DMSO-d6) δ 8.21(d, J=8.3Hz, 2H), 8.13(d, J=8.2Hz, 2H), 7.12(s, 1H), 4.19-3.99(m, 2H), 3.94(s, 3H), 3.06-2.72(m, 3H), 2.60(s, 3H), 2.51(s, 3H), 1.95-1.81(m, 2H), 1.78-1.59(m, 2H), 1.44(s, 9H)

[0204] Step E. Preparation of 3,7-dimethyl-2-(4-(methylsulfonyl)phenyl)-5-(piperidin-4-yl)-3H-imidazo[4,5-b]pyridine [ka] To a pear-shaped flask (200 mL) was added Intermediate 20D (1.9 g, 3.92 mmol), MeOH (20 mL), and HCl solution (4 M in dioxane, 20 mL) and the mixture was stirred. After 15 min, the solvent was concentrated and the resulting residue was dissolved in MeOH (100 mL) and to this solution was added ion exchange resin (Dowex 550A, 30 g, previously washed alternately with DCM and MeOH). After 5 min, the resin was filtered and the filtrate was concentrated. The product was dried under vacuum to give the title compound (1.37 g, 3.56 mmol, 91% yield) as a tan solid. Analytical LC / MS (Method 1): Observed mass: 385.1; Retention time: 0.923 min; 1H NMR (400MHz, methanol-d4) δ 8.21(s, 2H), 8.19-8.10(m, 2H), 7.15(s, 1H), 4.02-3.98(m, 3H), 3.50-3.43(m, 1H), 2.87-2.84(m, 3H), 2.72-2.68(m, 3H), 2.44-2.33(m, 2H), 2.10-2.03(m, 2H), 2.02-1.88(m, 4H)

[0205] Step F. Preparation of Example 20 To a stirred solution of intermediate 20E (80 mg, 0.21 mmol) in DCM (5 mL) was added 1-isopropylpiperidin-4-one (146.9 mg, 1.04 mmol) and acetic acid (0.1 mL). After stirring for 20 min, NaBH(OAc)3 (308.8 mg, 1.46 mmol) was added and the mixture was stirred. After 20 h, the resulting mixture was concentrated, diluted with water (100 mL) and extracted with ethyl acetate (3x30 mL). The combined organic layers were dried over Na2SO4 and concentrated to give the crude product which was purified by preparative HPLC (Method F) to give the title compound (47.5 mg, 0.0945 mmol, 45% yield) as a white solid. Analytical LC / MS (Method 5): Purity: 99.5%; Observed mass: 510.4; Retention time: 0.635 min; 1 H NMR (300MHz, DMSO-d6) δ 8.21(d, J=8.4Hz, 2H), 8.13(d, J=8.8Hz, 2H), 7.14(s, 1H), 3.98(s, 3H), 3.24(s, 3H), 3.16(d, J=11.4Hz, 2H), 3.05(d, J=11.4Hz, 2H), 2.91-2.80(m, 1H), 2.80-2.69(m, 1H), 2.68(s, 3H), 2.50-2.34(m, 3H), 2.30-2.19(m, 2H), 2.11-1.94(m, 6H), 1.74-1.57(m, 2H), 1.11(d, J=6.5Hz, 6H)

[0206] Examples 26 and 27 5-(1-(8-isopropyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-3,7-dimethyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine [ka]

[0207] Step A. Preparation of Intermediate 26A: 5-(1-(8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-3,7-dimethyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine diHCl salt [ka] A round bottom flask (250 mL) was charged with intermediate 20E (1 g, 2.60 mmol), DCE (10 mL), 1,4-dioxane (10 mL), and tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (2.344 g, 10.40 mmol), followed by titanium(IV) isopropoxide (3.85 mL, 13.00 mmol), and the mixture was stirred at 40° C. under N2 atmosphere. After 18 h, the mixture was cooled to room temperature, and then sodium triacetoxyborohydride (2.205 g, 10.40 mmol) was added. After stirring for 1.5 h, the reaction mixture was filtered and partitioned between KOH solution (150 mL of 10% saturated aqueous NaCl solids) and 10% IPA / chloroform (150 mL). The layers were separated, the aqueous layer was extracted with 10% IPA / chloroform (75 mL), and the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The resulting residue was purified by flash column chromatography (120 g silica gel cartridge; A=DCM, B=MeOH; gradient: 30 min; 0%B to 30%B; flow rate=80 mL / min). The product-containing fractions were combined and concentrated. The resulting residue was dissolved in MeOH (20 mL) and HCl solution (4M in dioxane, 20 mL) and stirred. After 30 min, the solvent was concentrated, the resulting residue was co-concentrated with toluene (2x), and the product was dried in vacuo to give the title compound (1 g, 1.765 mmol, 68% yield, mixture of isomers) as a pale yellow solid. Analytical LC / MS (Method 1): Observed mass: 494.1; Retention time: 0.888; 1 H NMR (500MHz, methanol-d4) δ 8.39-8.35(m, 2H), 8.28-8.24(m, 2H), 7.61-7.58(m, 1H), 4.31-4.27(m, 1H), 4.26-4.18(m, 2H), 4.15(s, 3H), 3.90-3.80(m, 3H), 3.40-3.34(m, 2H), 3.29(s, 4H), 2.99-2.91(m, 1H), 2.79(s, 3H), 2.49-2.32(m, 6H), 2.27-2.06(m, 4H)

[0208] Step B. Examples 26 and 27 To a vial (40 mL) was added Intermediate 26A (200 mg, 0.353 mmol), propan-2-one (103 mg, 1.765 mmol), AcOH (0.022 mL, 0.388 mmol), magnesium sulfate (637 mg, 5.29 mmol), and DMF (2 mL). The mixture was stirred for 20 min, then sodium triacetoxyborohydride (374 mg, 1.765 mmol) was added. After stirring for 18 h, the mixture was diluted with 10% IPA / CHCl3 (40 mL) and filtered. The filtrate was partitioned with KOH solution (10% saturated aqueous NaCl solution, 20 mL) and the layers were separated. The aqueous layer was extracted with 10% IPA / CHCl3 (10 mL) and the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The crude material was purified by preparative LC / MS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: acetonitrile:aqueous NHOAc=5:95; mobile phase B: acetonitrile:aqueous NHOAc=95:5; gradient: 7% B for 0 min, 7-52% B over 23 min, then 100% B for 0 min; flow rate: 20 mL / min; column temperature: 25 °C). Fractions were collected as determined by MS and UV signals. Fractions containing the desired products were combined and dried in a centrifugal evaporator.

[0209] The first eluting isomer was isolated as Example 26 (86 mg, 0.16 mmol, 46% yield). Analytical LC / MS (Method 2): Purity: 100%; Observed mass: 536.40; Retention time: 1.13 min; LC / MS (Method 3): Purity: 100%; Observed mass: 536.20; Retention time: 1.0 min; 1H NMR (500MHz, DMSO-d6) δ 8.22-8.17(m, 2H), 8.15-8.08(m, 2H), 7.09(s, 1H), 3.95-3.91(m, 2H), 3.33-3.28(m, 2H), 3.04-2.98(m, 2H), 2.84-2.76(m, 1H), 2.76-2.69(m, 1H), 2.69-2.61(m, 1H), 2.60-2.58(m, 2H), 2.57-2.54(m, 3H), 2.25-2.15(m, 2H), 1.92-1.75(m, 8H), 1.73-1.63(m, 2H), 1.60-1.53(m, 2H), 1.52-1.45(m, 2H), 1.07-0.98(m, 6H) The second eluting isomer was isolated as Example 27 (73 mg, 0.136 mmol, 39% yield). Analytical LC / MS (Method 2): Purity: 100%; Observed mass: 536.40; Retention time: 1.34 min; Analytical LC / MS (Method 3): Purity: 100%; Observed mass: 536.20; Retention time: 0.99 min; 1 H NMR (500MHz, DMSO-d6) δ 8.24-8.17(m, 2H), 8.13-8.12(m, 2H), 7.11(s, 1H), 3.94(s, 3H), 3.69-3.60(m, 1H), 3.58-3.42(m, 2H), 3.31(s, 3H), 2.92-2.69(m, 3H), 2.61-2.58(m, 3H), 2.41-2.31(m, 2H), 2.07-1.92(m, 7H), 1.88-1.78(m, 6H), 1.11(br d, J=6.1Hz, 6H)

[0210] Example 36 2-(3,4-Dimethoxyphenyl)-5-(1-((3aR,5s,6aS)-2-isopropyloctahydrocyclopenta[c]pyrrol-5-yl)piperidin-4-yl)-3,7-dimethyl-3H-imidazo[4,5-b]pyridine [ka]

[0211] Step A. Preparation of Intermediate 36A: 5-chloro-2-(3,4-dimethoxyphenyl)-3,7-dimethyl-3H-imidazo[4,5-b]pyridine [ka] To a pear-shaped flask (100 mL) was added Intermediate 20A (1.4 g, 6.94 mmol), EtOH (27.8 mL), sodium hyposulfite (3.63 g, 20.83 mmol), followed by 3,4-dimethoxybenzaldehyde (1.154 g, 6.94 mmol) and the mixture was stirred at 70° C. After 18 h, the resulting mixture was cooled to room temperature and the precipitated product was collected by vacuum filtration, washed with ether and dried under reduced pressure to give the title compound (2.08 g, 6.55 mmol, 94% yield) as a pale yellow solid. Analytical LC / MS (Method 1): Observed mass: 317.9; Retention time: 1.380 min; 1 H NMR (500MHz, DMSO-d6) δ 7.49-7.42(m, 2H), 7.25-7.23(m, 1H), 7.19-7.15(m, 1H), 3.89-3.86(m, 9H), 2.62-2.60(m, 3H)

[0212] Step B. Preparation of Intermediate 36B: tert-butyl 4-(2-(3,4-dimethoxyphenyl)-3,7-dimethyl-3H-imidazo[4,5-b]pyridin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate [ka] A round bottom flask (250 mL) was charged with Intermediate 36A (1.48 g, 4.66 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.584 g, 5.12 mmol), Pd(dppf)Cl2·DCM (0.190 g, 0.233 mmol), followed by potassium phosphate tribasic (3.46 g, 16.30 mmol) dissolved in water (8 mL). The vessel was flushed with N2 and the mixture was stirred at 85 °C. After 18 h, the mixture was cooled, diluted with water (200 mL), and extracted with EtOAc (2x100 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The resulting residue was purified by flash column chromatography (120 g silica gel cartridge; A=Hex, B=EtOAc; gradient: 30 min; 0% B to 100% B; flow rate=80 mL / min). The product fractions were combined, concentrated, and dried under vacuum to give the title compound (0.67 g, 1.442 mmol, 31% yield) as a pale yellow solid. Analytical LC / MS (Method 1): Observed mass: 465.2; Retention time: 1.662 min; 1 H NMR (500MHz, methanol-d4) δ 7.47(s, 1H), 7.45-7.42(m, 1H), 7.38(s, 1H), 7.20(s, 1H), 6.73-6.61(m, 1H), 4.20-4.13(m, 2H), 3.98-3.94(m, 9H), 3.75-3.66(m, 2H), 2.83-2.76(m, 2H), 2.70-2.66(m, 3H), 1.53(s, 9H)

[0213] Step C. Preparation of Intermediate 36C: 2-(3,4-dimethoxyphenyl)-3,7-dimethyl-5-(piperidin-4-yl)-3H-imidazo[4,5-b]pyridine HCl salt [ka] To a round bottom flask (250 mL) was added Intermediate 36B (0.67 g, 1.442 mmol), DCM (7 mL), MeOH (7 mL), and Pd / C (5 wt% on carbon, wet type, 0.307 g, 0.144 mmol). The vessel was evacuated and purged with N2, and a hydrogen balloon was attached and stirred. After 18 h, the catalyst was filtered and to the filtrate was added HCl solution (4 M in dioxane, 15 mL). After stirring for 2 h, the solvent was concentrated and the resulting residue was concentrated with toluene and the product was dried under vacuum to give the title compound (0.6 g, 1.489 mmol, 100% yield) as a pale yellow solid. Analytical LC / MS (Method 1): Observed mass: 367.0; Retention time: 0.945 min; 1 H NMR (500MHz, methanol-d4) δ 7.63-7.58(m, 1H), 7.55-7.52(m, 1H), 7.49(s, 1H), 7.33(d, J=8.5Hz, 1H), 4.16-4.11(m, 3H), 4.03-3.98(m, 6H), 3.71-3.66(m, 1H), 3.62-3.57(m, 2H), 3.28-3.19(m, 2H), 2.76(s, 3H), 2.32-2.16(m, 4H)

[0214] Step D. Preparation of Intermediate 36D: 2-(3,4-dimethoxyphenyl)-3,7-dimethyl-5-(1-(octahydrocyclopenta[c]pyrrol-5-yl)piperidin-4-yl)-3H-imidazo[4,5-b]pyridine diHCl salt [ka] To a vial (40 mL) was added Intermediate 36C (0.6 g, 1.489 mmol), tert-butyl 5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1.006 g, 4.47 mmol), AcOH (0.094 mL, 1.638 mmol), magnesium sulfate (2.69 g, 22.34 mmol), and DMF (30 mL), the mixture was stirred for 20 min, and then sodium triacetoxyborohydride (1.578 g, 7.45 mmol) was added. After stirring for 18 h, the mixture was diluted with 10% IPA / CHCl3 (150 mL) and filtered. The filtrate was partitioned into KOH solution (10% saturated aqueous NaCl solution, 75 mL), and the layers were separated. The aqueous layer was extracted with 10% IPA / CHCl3 (50 mL) and the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash column chromatography (80 g silica gel cartridge; A=DCM, B=MeOH; gradient: 30 min; 0%B to 20%B; flow rate=60 mL / min). The product fractions were combined and concentrated. The resulting residue was dissolved in MeOH (10 mL) and HCl solution (4M in dioxane, 10 mL). After stirring for 1 h, the solvent was concentrated and the resulting residue was concentrated with toluene and the product was dried in vacuum to give the title compound (0.65 g, 1.185 mmol, 80% yield) as an off-white solid. Analytical LC / MS (Method 1): Observed mass: 476.2; Retention time: 0.908 min; 1 H NMR (500MHz, methanol-d4) δ 7.63-7.60(m, 1H), 7.57-7.51(m, 2H), 7.35-7.33(m, 1H), 4.16(s, 3H), 4.00(d, J=6.2Hz, 6H), 3.87-3.78(m, 2H), 3.49-3.38(m, 4H), 3.29-3.20(m, 2H), 3.07-3.02(m, 2H), 2.76(s, 3H), 2.73-2.71(m, 2H), 2.66-2.58(m, 2H), 2.50-2.38(m, 2H), 2.34-2.26(m, 2H), 1.98-1.87(m, 2H)

[0215] Step E. Preparation of Example 36 To a vial (40 mL) was added Intermediate 36D (80 mg, 0.146 mmol), propan-2-one (42.4 mg, 0.729 mmol), AcOH (9.18 μL, 0.160 mmol), magnesium sulfate (263 mg, 2.188 mmol), and DMF (2 mL), and the mixture was stirred for 20 min, followed by the addition of sodium triacetoxyborohydride (155 mg, 0.729 mmol). After stirring for 18 h, the resulting mixture was diluted with 10% IPA / CHCl3 (40 mL) and filtered. The filtrate was partitioned with KOH solution (10% saturated aqueous NaCl solution, 20 mL) and the layers were separated. The aqueous layer was extracted with 10% IPA / CHCl3 (10 mL), and the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The resulting crude product was purified by preparative HPLC (Method A) to give the title compound (50.6 mg, 0.0978 mmol, 67% yield). Analytical LC / MS (Method 2): Purity: 100%; Observed mass: 518.5; Retention time: 1.53 min; (Method 3): Purity: 100%; Observed mass: 518.4; Retention time: 1.09 min; 1 H NMR (500MHz, DMSO-d6) δ 7.29-7.19(m, 2H), 6.98-6.92(m, 1H), 6.86-6.79(m, 1H), 3.70-3.68(m, 2H), 3.67-3.64(m, 3H), 2.96-2.86(m, 1H), 2.56-2.41(m, 3H), 2.39-2.33(m, 6H), 2.28-2.19(m, 3H), 2.18-2.10(m, 1H), 2.08-1.99(m, 2H), 1.97-1.81(m, 4H), 1.73-1.69(m, 2H), 1.68-1.61(m, 4H), 1.11-0.98(m, 2H), 0.88-0.80(m, 6H)

[0216] Example 42 5-(1-((3aR,5s,6aS)-2-Cyclobutyloctahydrocyclopenta[c]pyrrol-5-yl)piperidin-4-yl)-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3,7-dimethyl-3H-imidazo[4,5-b]pyridine [ka]

[0217] Step A. Preparation of Intermediate 42A: 5-chloro-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3,7-dimethyl-3H-imidazo[4,5-b]pyridine [ka] To a pear-shaped flask (100 mL) was added Intermediate 20A (1.75 g, 8.68 mmol), EtOH (34.7 mL), sodium hyposulfite (4.53 g, 26.0 mmol), followed by 8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-carbaldehyde (1.538 g, 8.68 mmol), and the mixture was stirred at 70° C. After 18 h, the resulting mixture was cooled to room temperature and the precipitated product was collected by vacuum filtration, washed with ether, and dried under reduced pressure to give the title compound (2.84 g, 8.64 mmol, 100% yield) as a pale yellow solid. Analytical LC / MS (Method 1): Observed mass: 328.9; Retention time: 1.385 min; 1 H NMR (500MHz, DMSO-d6) δ 9.15-9.11(m, 1H), 8.62-8.58(m, 1H), 7.51-7.47(m, 1H), 7.36-7.29(m, 1H), 4.10(s, 3H), 3.96(s, 3H), 2.67-2.64(m, 3H)

[0218] Step B. Preparation of Intermediate 42B: 2-(8-Methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3,7-dimethyl-5-(1-(octahydrocyclopenta[c]pyrrol-5-yl)piperidin-4-yl)-3H-imidazo[4,5-b]pyridine diHCl salt [ka] Intermediate 42B was prepared according to the methods described anywhere herein using the appropriate starting materials, reagents and conditions. Analytical LC / MS (Method 1): Observed mass: 487.2; Retention time: 0.920 min; 1 H NMR (500MHz, methanol-d4) δ 9.20-9.16(m, 1H), 8.63(s, 1H), 7.60-7.52(m, 2H), 4.24-4.22(m, 3H), 4.20-4.18(m, 3H), 3.86-3.80(m, 2H), 3.48-3.35(m, 5H), 3.31-3.22(m, 2H), 3.11-2.96(m, 3H), 2.82-2.76(m, 3H), 2.68-2.58(m, 2H), 2.50-2.40(m, 2H), 2.36-2.28(m, 2H), 1.99-1.89(m, 2H)

[0219] Step C. Preparation of Example 42 Example 42 was prepared according to the methods described anywhere herein using the appropriate starting materials, reagents and conditions. Analytical LC / MS (Method 2): Purity: 98.3%; Observed mass: 541.4; Retention time: 1.34 min; (Method 3): Purity: 100%; Observed mass: 541.2; Retention time: 0.99 min; 1H NMR (500MHz, DMSO-d6) δ 9.15-9.08(m, 1H), 8.59(s, 1H), 7.53-7.46(m, 1H), 7.13-7.08(m, 1H), 4.10(s, 3H), 3.98(s, 3H), 2.65-2.60(m, 4H), 2.55-2.52(m, 9H), 2.21-2.08(m, 4H), 2.07-1.80(m, 10H), 1.78-1.61(m, 3H)

[0220] Example 59 2-(3,4-dimethoxyphenyl)-5-(4-(2-isopropyl-2,7-diazaspiro[3.5]non-7-yl)phenyl)-3,7-dimethyl-3H-imidazo[4,5-b]pyridine [ka]

[0221] Step A. Preparation of Intermediate 59A: tert-butyl 7-(4-bromophenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate [ka] A round bottom flask (250 mL) was charged with tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (4 g, 17.67 mmol), 1,4-dibromobenzene (6.25 g, 26.5 mmol), rac-BINAP (1.101 g, 1.767 mmol), sodium tert-butoxide (2.72 g, 28.3 mmol), followed by toluene (100 mL). The mixture was purged and replaced with N2, then Pd2(dba)3 (0.809 g, 0.884 mmol) was added. The vessel was purged with N2 and stirred at 100 °C. After 18 h, the reaction mixture was cooled, diluted with water (200 mL), and extracted with EtOAc (2x100 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The resulting residue was purified by flash column chromatography (220 g silica gel cartridge; A=Hex, B=EtOAc; gradient: 30 min; 0% B to 100% B; flow rate=100 mL / min). The product fractions were combined, concentrated, and dried under vacuum to give the title compound (5.7 g, 14.95 mmol, 85% yield) as a tan solid. Analytical LC / MS (Method 1): Observed mass: 383.0; Retention time: 1.826 min; 1 H NMR (400MHz, methanol-d4) δ 7.39-7.24(m, 2H), 6.90(d, J=9.0Hz, 2H), 3.77-3.63(m, 4H), 3.21-3.08(m, 4H), 1.95-1.80(m, 4H), 1.46(s, 9H)

[0222] Step B. Preparation of Intermediate 59B: tert-butyl 7-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate [ka] A round bottom flask (250 mL) was charged with Intermediate 59A (5.7 g, 14.95 mmol), potassium acetate (2.93 g, 29.9 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (7.59 g, 29.9 mmol), and 1,4-dioxane (150 mL). The vessel was evacuated and purged with N2, Pd(dppf)Cl2·DCM (1.221 g, 1.495 mmol) was added, the vessel was purged again, and the mixture was stirred at 100 °C. After 18 h, the mixture was cooled, diluted with water (200 mL), and extracted with EtOAc (2x100 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The resulting residue was purified by flash column chromatography (120 g silica gel cartridge; A=Hex, B=EtOAc; gradient: 30 min; 0% B to 100% B; flow rate=85 mL / min). The product fractions were combined, concentrated, and dried under vacuum to give the title compound (4.1 g, 9.57 mmol, 64% yield) as a tan solid. Analytical LC / MS (Method 1): Observed mass: 429.1; Retention time: 1.968 min; 1 H NMR (400MHz, methanol-d4) δ 7.61(d, J=8.7Hz, 2H), 6.94(d, J=8.7Hz, 2H), 3.75-3.63(m, 4H), 3.29-3.20(m, 4H), 1.97-1.83(m, 4H), 1.50-1.46(m, 9H), 1.34(s, 12H)

[0223] Step C. Preparation of intermediate 59C: 5-(4-(2,7-diazaspiro[3.5]nonan-7-yl)phenyl)-2-(3,4-dimethoxyphenyl)-3,7-dimethyl-3H-imidazo[4,5-b]pyridine diHCl salt [ka] To a vial (40 mL) was added Intermediate 36A (0.26 g, 0.818 mmol), Intermediate 59B (0.456 g, 1.064 mmol), potassium phosphate tribasic (0.347 g, 1.636 mmol), 1,4-dioxane (10 mL), and water (2 mL). The vessel was purged with N2, then XPhos Pd G3 (0.021 g, 0.025 mmol) was added, the vessel was purged again, and stirred at 85 °C. After 18 h, the mixture was cooled, diluted with water (100 mL), and extracted with EtOAc (2x50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The resulting residue was purified by flash column chromatography (80 g silica gel cartridge; A=DCM, B=MeOH; gradient: 30 min; 0%B to 20%B; flow rate=60 mL / min). The product fractions were combined and concentrated. The resulting residue was dissolved in MeOH (10 mL) and HCl solution (4M in dioxane, 10 mL). After stirring for 2 h, the solvent was concentrated and the resulting residue was co-concentrated with toluene (2x) and the product was dried in vacuo to give the title compound (140 mg, 0.252 mmol, 31% yield) as a tan solid. Analytical LC / MS (Method 1): Observed mass: 484.2; Retention time: 1.052 min.

[0224] Step D. Preparation of Example 59 To a vial (40 mL) was added intermediate 59C (70 mg, 0.126 mmol), MgSO4 (76 mg, 0.629 mmol), DMF (5 mL), AcOH (7.20 μL, 0.126 mmol), followed by propan-2-one (36.5 mg, 0.629 mmol). After stirring for 10 min, sodium triacetoxyborohydride (133 mg, 0.629 mmol) was added and the vial was capped and stirred. After 18 h, the mixture was diluted with 10% IPA / CHCl3 (40 mL), filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Method D) and the pure fractions were combined and concentrated. The residue was partitioned between 10% IPA / CHCl3 (20 mL) and KOH solution (20 mL of 10% saturated aqueous solid NaCl). The layers were separated, the aqueous layer was extracted with 10% IPA / CHCl3 (10 mL), and the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The resulting product was dried in vacuo to give the title compound (35.13 mg, 0.066 mmol, 53% yield) as an off-white solid. Analytical LC / MS (Method 1): Purity: 99%; Observed mass: 526.2; Retention time: 1.123 min; Analytical LC / MS (Method 6): Purity: 99%; Observed mass: 526.2; Retention time: 1.459 min; 1 H NMR (500MHz, DMSO-d6) δ 8.07-7.98(m, 2H), 7.64-7.61(m, 1H), 7.48(s, 2H), 7.19-7.14(m, 1H), 7.06-6.99(m, 2H), 3.98-3.93(m, 3H), 3.91-3.84(m, 6H), 3.25-3.18(m, 4H), 3.08-2.87(m, 3H), 2.66-2.62(m, 3H), 1.83-1.70(m, 4H), 0.97-0.79(m, 6H)(two protons are unclear)

[0225] Example 60 2-(3,4-dimethoxyphenyl)-5-(4-(6-isopropyl-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-3,7-dimethyl-3H-imidazo[4,5-b]pyridine [ka]

[0226] Step A. Preparation of Intermediate 60A: tert-butyl 6-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate [ka] A round bottom flask (500 mL) was charged with tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate oxalate (6 g, 20.81 mmol), 1,4-dibromobenzene (7.36 g, 31.2 mmol), rac-BINAP (1.296 g, 2.081 mmol), sodium tert-butoxide (5.20 g, 54.1 mmol), followed by toluene (100 mL). The mixture was purged and replaced with N2, then Pd2(dba)3 (0.953 g, 1.041 mmol) was added. The vessel was purged with N2 and stirred at 100 °C. After 18 h, the reaction mixture was cooled, diluted with water (300 mL) and extracted with EtOAc (2x150 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash column chromatography (220 g silica gel cartridge; A=Hex, B=EtOAc; gradient: 30 min; 0% B to 100% B; flow rate=100 mL / min). The product fractions were combined, concentrated, and dried under vacuum to give the title compound (5.0 g, 14.15 mmol, 68% yield) as a tan solid. Analytical LC / MS (Method 1): Observed mass: 352.9; Retention time: 2.180 min; 1 H NMR (500MHz, methanol-d4) δ 7.32-7.24(m, 2H), 6.41(d, J=8.9Hz, 2H), 4.85(s, 4H), 3.99-3.91(m, 4H), 1.46(s, 9H)

[0227] Step B. Preparation of Intermediate 60B: tert-butyl 6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate [ka] A round bottom flask (500 mL) was charged with Intermediate 60A (5.0 g, 14.15 mmol), potassium acetate (2.78 g, 28.3 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (7.19 g, 28.3 mmol), and 1,4-dioxane (200 mL). The vessel was evacuated and purged with N2, Pd(dppf)Cl2·DCM (1.156 g, 1.415 mmol) was added, the vessel was purged again, and the mixture was stirred at 100 °C. After 18 h, the mixture was cooled, diluted with water (200 mL), and extracted with EtOAc (2x100 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The resulting residue was purified by flash column chromatography (120 g silica gel cartridge; A=Hex, B=EtOAc; gradient: 30 min; 0% B to 100% B; flow rate=80 mL / min). The product fractions were combined, concentrated, and dried under vacuum to give the title compound (4.06 g, 10.14 mmol, 72% yield) as a tan solid. Analytical LC / MS (Method 1): Observed mass: 401.0; Retention time: 2.297 min; 1 H NMR (500MHz, methanol-d4) δ 7.63-7.52(m, 2H), 6.50-6.42(m, 2H), 4.24-4.09(m, 4H), 4.00(s, 4H), 1.48-1.43(m, 9H), 1.36-1.31(m, 12H)

[0228] Step C. Preparation of Intermediate 60C: 5-(4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-2-(3,4-dimethoxyphenyl)-3,7-dimethyl-3H-imidazo[4,5-b]pyridine diTFA salt [ka] To a vial (40 mL) was added Intermediate 36A (0.26 g, 0.818 mmol), Intermediate 60B (0.491 g, 1.227 mmol), potassium phosphate tribasic (0.347 g, 1.636 mmol), 1,4-dioxane (10 mL), and water (2 mL). The vessel was purged with N2, then XPhos Pd G3 (0.021 g, 0.025 mmol) was added, the vessel was purged again, and stirred at 85 °C. After 18 h, the resulting mixture was cooled, diluted with water (100 mL), and extracted with EtOAc (2x50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The resulting crude mixture was purified by flash column chromatography (80 g silica gel cartridge; A=DCM, B=MeOH; gradient: 30 min; 0%B to 20%B; flow rate=60 mL / min). The product fractions were combined and concentrated. The resulting residue was dissolved in MeOH (10 mL) and HCl solution (4M in dioxane, 10 mL). After stirring for 2 h, the solvent was concentrated and the resulting residue was co-concentrated with toluene (2x) and the product was dried in vacuum to give the title compound (90 mg, 0.132 mmol, 16% yield) as a tan solid. Analytical LC / MS (Method 1): Observed mass: 456.1; Retention time: 1.067 min; 1 H NMR (500MHz, methanol-d4) δ 8.16-8.06(m, 2H), 7.94-7.87(m, 1H), 7.64-7.57(m, 1H), 7.56-7.51(m, 1H), 7.37-7.29(m, 1H), 6.69-6.59(m, 2H), 4.39-4.32(m, 4H), 4.17(s, 7H), 4.03-3.98(m, 6H), 2.82-2.73(m, 3H)

[0229] Step D. Preparation of Example 60 To a vial (40 mL) was added intermediate 60C (45 mg, 0.066 mmol), MgSO4 (39.6 mg, 0.329 mmol), DMF (5 mL), AcOH (3.77 μL, 0.066 mmol), followed by propan-2-one (19.12 mg, 0.329 mmol). After stirring for 10 min, sodium triacetoxyborohydride (69.8 mg, 0.329 mmol) was added and the vial was capped and stirred. After 18 h, the mixture was diluted with 10% IPA / CHCl3 (40 mL), filtered, and the filtrate was concentrated. The resulting residue was purified by preparative HPLC (Method D) and the product fractions were combined. The volatiles were evaporated and the resulting aqueous solution was partitioned between 10% IPA / CHCl3 (20 mL) and KOH solution (20 mL of 10% saturated aqueous solid NaCl). The layers were separated, the aqueous layer was extracted with 10% IPA / CHCl3 (10 mL), and the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The product was dried in vacuo to give the title compound (21.57 mg, 0.043 mmol, 65% yield) as a light tan solid. Analytical LC / MS (Method 1): Purity: 99%; Observed Mass: 498.2; Retention Time: 1.138 min; (Method 6): Purity 99%, Observed Mass: 498.2; Retention Time: 1.432 min; 1 H NMR (500MHz, DMSO-d6) δ 8.06-7.99(m, 2H), 7.62-7.58(m, 1H), 7.48(s, 2H), 7.20-7.13(m, 1H), 6.52(d, J=8.7Hz, 2H), 3.97-3.91(m, 7H), 3.88(d, J=2.6Hz, 6H), 3.30-3.28(m, 1H), 3.26-3.22(m, 4H), 2.67-2.60(m, 3H), 0.88-0.82(m, 6H)

[0230] The following examples were prepared according to the procedures described anywhere 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

[0231] Biological assays The pharmacological properties of the compounds of the invention may be confirmed by a number of biological assays. The following biological assays have been carried out with the compounds of the invention.

[0232] 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 with five binding sites for NF-κB and AP-1. Cells were seeded (15000 cells / well) in 384-well plates (Greiner) pre-dispensed with test compounds in DMSO by ECHO, with concentrations ranging from 0.85 nM to 50 μM for the final dose response. After pre-treatment with compounds for 60 min in a 37°C incubator, cells were then stimulated with TLR7 ligand (final concentration 2.5 μM), TLR8 ligand (final concentration 14.25 μM R848) or TLR9 ligand (final concentration 200 nM ODN2006) to activate NF-κB and AP-1, which induces SEAP production. After 22 h of incubation (37 °C, 5% CO2), SEAP levels were determined using HEK-Blue staining according to the manufacturer's specifications. TM Detection reagent (Invivogen) and cell culture medium allowing detection of SEAP were added and inhibition was determined by the % reduction in HEK-Blue signal present in wells treated with agonist plus DMSO alone compared to wells treated with a known inhibitor. [Table 29] [Table 30]

Claims

1. Formula (I): 【change】 [In the formula, One of X and Y is N, the other of X and Y is CR 5b and; G is (i) F, Cl, Br, C 1-2 Alkoxy, C 1-2 Fluoroalkoxy, C 3-4 Cycloalkyl, -C(O)NR y R y , -S(O) 2 CH 3 , -S(O) 2 (phenyl), -S(O) 2 NR x R x , and -S(O)(NH)NR x R x phenyl substituted with 1 to 3 substituents independently selected from: (ii) 【Chemistry 1】 ; (iii) 【Chemistry 2】 ; (iv) 【Transformation 3】 ; (v) 【Chemistry 4】 【Transformation 5】 【Transformation 6】 or a 9-membered heterocycle selected from the group consisting of (vi) 【Transformation 7】 is a 10-membered heterocycle selected from the group consisting of: Q is piperidinyl, phenyl, tetrahydropyridinyl, pyridinyl, or azabicyclo[3.2.1]octanyl, each of which is -LR 4 and 0 to 2 R 4b is replaced by; L is a bond, -(CR x R x ) 1-2 - or -C(O)(CR x R x ) 0-2 - and; R 1 is hydrogen, C 1-3 Alkyl, C 1-2 Fluoroalkyl, or C 3-4 is cycloalkyl; Each R 2 are independently halogen, -CN, -OH, -NO 2 , C 1-4 Alkyl, C 1-2 Fluoroalkyl, C 1-2 Cyanoalkyl, C 1-3 Hydroxyalkyl, C 1-3 Aminoalkyl, -O(CH 2 ) 1-2 OH, -(CH 2 ) 0-4 O(C 1-4 alkyl), C 1-3 Fluoroalkoxy, -O(CH 2 ) 1-2 OC(O)(C 1-3 alkyl), -O(CH 2 ) 1-2 NR x R x , -C(O)O(C 1-3 alkyl), -(CH 2 ) 0-2 C(O)NR y R y , -C(O)NR x (C 1-5 hydroxyalkyl), -C(O)NR x (C 2-6 Alkoxyalkyl), -C(O)NR x (C 3-6 cycloalkyl), -NR y R y , -NR y (C 1-3 Fluoroalkyl), -NR y (C 1-4 hydroxyalkyl), -NR x CH 2 (phenyl), -NR x S(O) 2 (C 3-6 cycloalkyl), -NR x C(O)(C 1-3 alkyl), -NR x CH 2 (C 3-6 cycloalkyl), -S(O) 2 (C 1-3 alkyl), -S(O) 2 N(C 1-3 alkyl) 2 , -S(O)(NH)N(C 1-3 alkyl) 2 , -(CH 2 ) 0-2 (C 3-6 cycloalkyl), -(CH 2 ) 0-2 (phenyl), morpholinyl, dioxothiomorpholinyl, dimethylpyrazolyl, methylpiperidinyl, methylpiperazinyl, amino-oxadiazolyl, imidazolyl, triazolyl, or —C(O)(thiazolyl); R 2a is C 1-6 Alkyl, C 1-3 Fluoroalkyl, C 1-6 Hydroxyalkyl, C 1-3 Aminoalkyl, -(CH 2 ) 0-4 O(C 1-3 alkyl), C 3-6 Cycloalkyl, -(CH 2 ) 1-3 C(O)NR x R x , -CH 2 (C 3-6 cycloalkyl), -CH 2 (phenyl), tetrahydrofuranyl, tetrahydropyranyl, or phenyl; Each R 2b are independently hydrogen, halogen, -CN, -NR x R x , C 1-6 Alkyl, C 1-3 Fluoroalkyl, C 1-3 Hydroxyalkyl, C 1-3 Fluoroalkoxy, -(CH 2 ) 0-2 O(C 1-3 alkyl), -(CH 2 ) 0-3 C(O)NR x R x , -(CH 2 ) 1-3 (C 3-6 cycloalkyl), -C(O)O(C 1-3 alkyl), -C(O)NR x (C 1-3 alkyl), -CR x =CR x R x , or -CR x =CH(C 3-6 cycloalkyl); R 2c is R 2a or R 2b and; R 2d is R 2a or R 2b However, here R 2c and R 2d One of them is R 2a and R 2c and R 2d The other is R 2b and; R 4 teeth, (i)-N(CH 3 ) 2 ; (ii) pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, azepanyl, azaspiro[3.3]heptanyl, octahydrocyclopenta[c]pyrrolyl, diazaspiro[3.3]heptanyl, azabicyclo[3.2.1]octanyl, or hexahydropyrrolo[3,4-c]pyrrolyl, each of which is 0 to 2 R 4a is replaced by; or (iii) 【Transformation 8】 and; Each R 4a independently C 1-6 Alkyl, C 1-3 Fluoroalkyl, C 1-4 Hydroxyalkyl, -(CH 2 ) 1-3 OCH 3 , C 3-6 Cycloalkyl, -(CH 2 ) 1-3 (C 3-6 cycloalkyl), -(CH 2 ) 1-3 (oxetanyl), -(CH 2 ) 1-3 (morpholinyl), -C(O)(C 1-4 alkyl), -C(O)(C 3-6 -C(O)(cycloalkyl), -C(O)(phenyl), -C(O)CH 2 (C 3-6 cycloalkyl), -C(O)CH 2 (phenyl), -C(O)O(C 1-4 alkyl), -NR y R y , -NR x (C 3-6 cycloalkyl), azetidinyl, oxetanyl, tetrahydropyranyl, pyrrolidinyl, phenyl, morpholinyl, or piperidinyl (-OH or -CH 3 substituted with 0 to 2 substituents selected from: R 4b is F, Cl, -CN, or -CH 3 and; Each R 4c 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 is cycloalkyl; R 5a are hydrogen, F, Cl, C 1-2 Alkyl, C 1-2 fluoroalkyl, or cyclopropyl; R 5b are hydrogen, F, Cl, C 1-2 Alkyl, C 1-2 fluoroalkyl, or cyclopropyl; Each R x are independently hydrogen or -CH 3 and; Each R y are independently hydrogen or C 1-6 is alkyl; m is 0, 1, or 2; n is 0, 1, or 2; p is 0, 1, 2, 3, or 4; and Q is 1 or 2. or a salt thereof.

2. During the ceremony, G is F, Cl, Br, -CN, C 1-2 Alkoxy, C 1-2 Fluoroalkoxy, C 3-4 Cycloalkyl, -C(O)NR y R y , -S(O) 2 CH 3 , -S(O) 2 (phenyl), -S(O) 2 (cyclopropyl), -S(O) 2 NR x R x , -S(O)(NH)NR x R x , and -NHS(O) 2 CH 3 is phenyl substituted with 1 to 3 substituents independently selected from L is a bond, -CH 2 -, or -CH 2 CH 2 - and; Q is piperidinyl, phenyl, tetrahydropyridinyl, or pyridinyl, each of which is -LR 4 and 0 to 1 R 4b is replaced by; R 1 But hydrogen, C 1-3 Alkyl, -CHF 2 , -CF 3 , or C 3-4 is cycloalkyl; Each R 2 are independently Cl, -CH 3 , -CH 2 CH 3 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CN, -OCH 3 , or -CH 2 OCH 3 and; R 4 is pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, azaspiro[3.3]heptanyl, octahydrocyclopenta[c]pyrrolyl, diazaspiro[3.3]heptanyl, azabicyclo[3.2.1]octanyl, or hexahydropyrrolo[3,4-c]pyrrolyl, each of which contains 0 to 1 R 4a is replaced by; R 4a But -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , -CH 2 C(CH 3 ) 2 OH, -CH 2 CH 2 OCH 3 , -C(O)CH(CH 3 ) 2 , cyclopropyl, cyclobutyl, -CH 2 (cyclopropyl), -CH 2 (cyclobutyl), -CH 2 (oxetanyl), -CH 2 CH 2 (morpholinyl), -CH 2 CH 2 CH 2 (morpholinyl), -N(CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ), -N(CH 3 ) (cyclopropyl), azetidinyl, oxetanyl, tetrahydropyranyl, pyrrolidinyl, phenyl, morpholinyl, or piperidinyl (-OH or -CH 3 substituted with 0 to 2 substituents selected from: R 4b is F, -CN, or -CH 3 and; R 5a is hydrogen, -CH 3 , -CF 3 or cyclopropyl; and R 5b is hydrogen, -CH 3 , or -CF 3 That is, 2. The compound of claim 1 having the structure of formula (I) or a salt thereof:

3. During the ceremony, G, (i)-S(O) 2 CH 3 phenyl substituted with; (ii) two -OCH 3 phenyl substituted with; or (iii) 【Chemistry 9】 and; Q is phenyl or piperidinyl, and each is -LR 4 is replaced by; L is a bond or -CH 2 - and; R 1 is hydrogen, -CH 3 or cyclopropyl; R 4 is piperidinyl, piperazinyl, octahydrocyclopenta[c]pyrrolyl, diazaspiro[3.3]heptanyl, or azabicyclo[3.2.1]octanyl, each of which contains zero or one R 4a is replaced by; R 4a But -CH 3 , -CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , -CH 2 C(CH 3 ) 2 OH, -CH 2 CH 2 OCH 3 , -CH 2 (cyclopropyl), -CH 2 CH 2 (morpholinyl), -CH 2 CH 2 CH 2 (morpholinyl), cyclopropyl, cyclobutyl, pyrrolidinyl, oxetanyl, tetrahydropyranyl, or morpholinyl; R 5a is hydrogen; and R 5b is hydrogen or -CH 3 That is, 2. The compound of claim 1 having the structure of formula (I) or a salt thereof:

4. Formula (Ia): 【Chemistry 10】 2. A compound of formula (I) according to claim 1, having the structure: or a salt thereof.

5. Formula (Ib): 【Chemistry 11】 2. A compound of formula (I) according to claim 1, having the structure: or a salt thereof.

6. In the formula, G is 【Chemistry 12】 2. The compound according to claim 1, having the structure of formula (I), or a salt thereof:

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

8. In the formula, L is -(CR x R x ) 1-2 2. The compound of claim 1, having the structure of formula (I), or a salt thereof, wherein:

9. The compound is 5-(4-((6-cyclobutyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)phenyl)-3-cyclopropyl-7-methyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine (1); 3-cyclopropyl-7-methyl-2-(4-(methylsulfonyl)phenyl)-5-(4-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)phenyl)-3H-imidazo[4,5-b]pyridine (2); 3-cyclopropyl-5-(4-((6-isopropyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)phenyl)-7-methyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine (3); 3-cyclopropyl-5-(4-((6-isobutyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)phenyl)-7-methyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine (4); 3-cyclopropyl-7-methyl-2-(4-(methylsulfonyl)phenyl)-5-(4-((6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)phenyl)-3H-imidazo[4,5-b]pyridine (5); 3-cyclopropyl-7-methyl-2-(4-(methylsulfonyl)phenyl)-5-(4-((6-(oxetan-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)phenyl)-3H-imidazo[4,5-b]pyridine (6); 5-(4-(4-isopropylpiperazin-1-yl)phenyl)-3,7-dimethyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine (7); 5-(4-(4-isobutylpiperazin-1-yl)phenyl)-3,7-dimethyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine (8); 3-cyclopropyl-7-methyl-5-(4-(1-methylpiperidin-4-yl)phenyl)-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine (9); 2-(3,4-dimethoxyphenyl)-5-(4-(4-isopropylpiperazin-1-yl)phenyl)-3,7-dimethyl-3H-imidazo[4,5-b]pyridine (10); 2-(3,4-Dimethoxyphenyl)-6-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-1H-imidazo[4,5-b]pyridine (11); 2-(3,4-dimethoxyphenyl)-6-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-1H-imidazo[4,5-b]pyridine (12); 6-(1'-cyclopropyl-[1,4'-bipiperidin]-4-yl)-2-(3,4-dimethoxyphenyl)-1H-imidazo[4,5-b]pyridine (13); 6-(1'-Isopropyl-[1,4'-bipiperidin]-4-yl)-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-imidazo[4,5-b]pyridine (14); 6-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-imidazo[4,5-b]pyridine (15); 6-(1'-cyclopropyl-[1,4'-bipiperidin]-4-yl)-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-imidazo[4,5-b]pyridine (16); 5-(1'-Isopropyl-[1,4'-bipiperidin]-4-yl)-3-methyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine (17); 5-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-3-methyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine (18); 5-(1'-cyclopropyl-[1,4'-bipiperidin]-4-yl)-3-methyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine (19); 5-(1'-Isopropyl-[1,4'-bipiperidin]-4-yl)-3,7-dimethyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine (20); 5-(1'-Isobutyl-[1,4'-bipiperidin]-4-yl)-3,7-dimethyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine (21); 1-(4-(3,7-dimethyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridin-5-yl)-[1,4'-bipiperidin]-1'-yl)-2-methylpropan-2-ol (22); 5-(1'-(cyclopropylmethyl)-[1,4'-bipiperidin]-4-yl)-3,7-dimethyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine (23); 5-(1'-cyclobutyl-[1,4'-bipiperidin]-4-yl)-3,7-dimethyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine (24); 3,7-dimethyl-2-(4-(methylsulfonyl)phenyl)-5-(1'-(tetrahydro-2H-pyran-4-yl)-[1,4'-bipiperidin]-4-yl)-3H-imidazo[4,5-b]pyridine (25); 5-(1-(8-isopropyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-3,7-dimethyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine (26-27); 5-(1-(8-isobutyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-3,7-dimethyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine (28-29); 5-(1-(8-(cyclopropylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-3,7-dimethyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine (30-31); 5-(1-(8-cyclobutyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-3,7-dimethyl-2-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine (32-33); 3,7-dimethyl-2-(4-(methylsulfonyl)phenyl)-5-(1-(8-(tetrahydro-2H-pyran-4-yl)-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-3H-imidazo[4,5-b]pyridine (34-35); 2-(3,4-Dimethoxyphenyl)-5-(1-(2-isopropyloctahydrocyclopenta[c]pyrrol-5-yl)piperidin-4-yl)-3,7-dimethyl-3H-imidazo[4,5-b]pyridine (36); 2-(3,4-dimethoxyphenyl)-5-(1-(2-isobutyloctahydrocyclopenta[c]pyrrol-5-yl)piperidin-4-yl)-3,7-dimethyl-3H-imidazo[4,5-b]pyridine (37); 5-(1-(2-(cyclopropylmethyl)octahydrocyclopenta[c]pyrrol-5-yl)piperidin-4-yl)-2-(3,4-dimethoxyphenyl)-3,7-dimethyl-3H-imidazo[4,5-b]pyridine (38); 5-(1-(2-cyclobutyloctahydrocyclopenta[c]pyrrol-5-yl)piperidin-4-yl)-2-(3,4-dimethoxyphenyl)-3,7-dimethyl-3H-imidazo[4,5-b]pyridine (39); 2-(3,4-dimethoxyphenyl)-3,7-dimethyl-5-(1-(2-(tetrahydro-2H-pyran-4-yl)octahydrocyclopenta[c]pyrrol-5-yl)piperidin-4-yl)-3H-imidazo[4,5-b]pyridine (40); or 2-(3,4-Dimethoxyphenyl)-5-(1-((3aR,5s,6aS)-2-(2-methoxyethyl)octahydrocyclopenta[c]pyrrol-5-yl)piperidin-4-yl)-3,7-dimethyl-3H-imidazo[4,5-b]pyridine (41) 2. The compound according to claim 1, wherein:

10. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 9 and a pharmaceutically acceptable carrier or diluent.

11. A pharmaceutical composition comprising a compound or salt thereof according to any one of claims 1 to 9 for use in therapy.

12. A pharmaceutical composition comprising a compound or a salt thereof according to any one of claims 1 to 9 for the treatment of an inflammatory disease, an autoimmune disease, or cancer.

13. Use of a compound or salt thereof according to any one of claims 1 to 9 in the manufacture of a medicament for the treatment of an inflammatory disease, an autoimmune disease, or cancer.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof for the treatment of pathological fibrosis.

15. 15. The pharmaceutical composition of claim 14, wherein the pathological fibrosis is liver fibrosis, kidney fibrosis, bile duct fibrosis, or pancreatic fibrosis.

16. 10. A pharmaceutical composition comprising the compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof for treating non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic nephropathy, primary sclerosing cholangitis (PSC), or primary biliary cirrhosis (PBC).

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof for treating idiopathic pulmonary fibrosis (IPF).