Substitutive heteroaryl compounds useful as TLR9 inhibitors

Abstract

Disclosed are compounds of formula (I) and (II): JPEG2023539136000114.jpg32103, or a salt thereof, wherein X, Y, Q1, Q2, G, R1, and R3 are defined herein. Also disclosed are methods of using such compounds as inhibitors of TLR9 and pharmaceutical compositions containing such compounds. These compounds are useful for treating, preventing, or slowing fibrotic diseases.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Application 63 / 067,389, filed on 19 August 2020, which is incorporated herein by reference in its entirety.

[0002] explanation The present invention relates to substituted heteroaryl compounds that are generally useful as inhibitors of signal transduction mediated by Toll-like receptor 9 (TLR9). Provided herein are substituted heteroaryl compounds, compositions comprising such compounds, and methods of use thereof. The present invention further relates to pharmaceutical compositions comprising at least one of the compounds of the present invention that are useful for treating conditions associated with TLR9 modulation, such as inflammatory and autoimmune diseases, and to methods for inhibiting TLR9 activity in mammals.

[0003] Toll-like receptors (TLRs) are transmembrane proteins capable of initiating inflammatory responses through the recognition of pattern-associated molecular patterns (PAMPs) or microorganism-associated molecular patterns (MAMPs). Ten human TLRs have been identified and may be present on the cell surface or, in the case of TLR7, 8, and 9, in endolysosomes. TLR9 recognizes unmethylated single-stranded DNA containing the cytosine-phosphate-guanine (CpG) motif, typically found in bacterial and mitochondrial DNA (mtDNA). TLR9 may contribute to fibrosis by promoting inflammation via the MyD88-dependent signaling pathway, which ultimately mediates the activation of several cytokines, including 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] TLR9 levels are higher in lung biopsy specimens from patients with rapidly progressing IPF than in healthy individuals or those with stable IPF progression (Sci. Transl. Med. 2010, 2(57):57ra82). Circulating mtDNA, a ligand for TLR9, has recently been identified as a prognostic biomarker based on the mechanism of action of IPF (Am J. Resp. and Crit. Care Med. 2017, 196(12), 1502). Furthermore, TLR9 is upregulated in human and mouse non-alcoholic steatohepatitis (NASH) (Clin. Sci. 2017, 131 (16), 2145), while hepatocyte mitochondrial DNA has been observed to induce NASH via TLR9 activation (J. Clin. Inv. 2016, 126 (3), 859). Therefore, TLR9 inhibitors / antagonists are expected to be effective as novel therapeutic agents for the treatment of fibrotic diseases.

[0005] TLR9 inhibition has been shown to treat fibrous diseases including idiopathic pulmonary fibrosis (Trujillo et al. Sci. Transl. Med. 2010, 2(57):57ra82; Yoshizaki et al. Ann Rheum Dis. 2016 Oct; 75(10):1858-65), non-alcoholic steatohepatitis (Garcia-Martinez et al. J Clin Invest 2016, 126: 859-864; Gabele et al. Biochem Biophys Res Commun. 2008;376:271-276), liver injury (Shaker et al. Biochem Pharmacol. 2016. 112:90-101; Hoeque et al. J. Immun. 2013, 190:4297-304), and scleroderma (systemic sclerosis or SSc) (Yoshizaki et al. Ann Rheum Dis. 2016 Oct;75(10):1858-65); and it is recognized as a potential route for treating heart failure (Oka et al. Nature 485, pages 251-255 (2012)) and hypertension (McCarthy et al. Cardiovascular Research, 2015, Pages 119-130). [Overview of the project] [Problems that the invention aims to solve]

[0006] There is a continuing demand for compounds useful as TLR9 inhibitors. Furthermore, there is a continuing demand for compounds useful as TLR9 inhibitors that have greater selectivity than TLR7 or TLR8.

[0007] From the perspective of conditions that can be benefited by treatments involving modulation of Toll-like receptors, it is clear that novel compounds capable of inhibiting TLR9 and methods of using these compounds will bring therapeutic benefits to a wide variety of patients.

[0008] The applicant has discovered potent compounds exhibiting activity as TLR9 inhibitors. Furthermore, the applicant has discovered compounds that are active as TLR9 inhibitors and exhibit selectivity exceeding that of TLR7 or TLR8. These compounds are provided to be useful as pharmaceuticals possessing desirable stability, bioavailability, therapeutic index, and toxicity values, which are important for druggability. [Means for solving the problem]

[0009] Summary of the Invention This invention relates to a novel class of substituted heteroaryl compounds that have been found to be effective inhibitors of TLR9-mediated signaling. These compounds are provided to be useful as pharmaceuticals possessing desirable stability, bioavailability, therapeutic index, and toxicity values ​​that are important for druggability.

[0010] The present invention provides a compound of formula (I) or its stereoisomers, N-oxides, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs that are useful as inhibitors of signal transduction mediated by Toll-like receptor 9 and are useful for the treatment of fibrotic diseases.

[0011] The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one of the compound of the present invention or its stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs.

[0012] The present invention also provides a method for inhibiting Toll-like receptor 9, comprising administering to a host requiring such treatment at least one of the compounds of the present invention or its stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs in a therapeutically effective amount.

[0013] The present invention also provides a method for treating a fibrous disease, comprising administering to a host in need of such treatment at least one of the compounds of the present invention or its stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs in a therapeutically effective amount.

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

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

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

[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 pharmaceuticals for the treatment or prevention of Toll-like receptor 9-related conditions such as allergic diseases, autoimmune diseases, inflammatory diseases, and proliferative diseases.

[0018] Compounds of formula (I) and compositions containing compounds of formula (I) may be used to treat, prevent or cure various Toll-like receptor 9-related conditions. Pharmaceutical compositions containing these compounds are useful for treating, preventing or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as allergic diseases, autoimmune diseases, inflammatory diseases, and proliferative disorders.

[0019] These and other features of the present invention will be presented in an expanded form as the disclosure continues.

[0020] Detailed description A first aspect of the present invention is a combination of at least one formula (I) or formula (II): [ka] [During the ceremony, One of X and Y is N, and the other of X and Y is CR5; One of Q1 and Q2 is A and the other of Q1 and Q2 is R5; 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 and -S(O)(NH)NR x R x phenyl substituted with 1 to 3 substituents independently selected from; (ii)

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0021] A second aspect of the present invention is at least one formula (I) or formula (II): [ka] [During the ceremony, One of X and Y is N, and the other of X and Y is CR5; One of Q1 and Q2 is A, and the other of Q1 and Q2 is R5; G is: (i) F, Cl, Br, C 1-2 Alkoxy, C 1-2 Fluoroalkoxy, C 3-4Cycloalkyl-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 compounds substituted with 1 to 3 substituents independently selected from the above; (ii) [ka] (iii) [ka] (iv) [ka] (v) [ka] [ka] [ka] A nine-membered heterocyclic ring selected from; or (vi) [ka] A 10-membered heterocyclic ring selected from and; A is piperidinyl, phenyl, pyridinyl, pyrimidinyl, 6-azabicyclo[3.2.1]octanyl, or azabicyclo[3.2.1]octanyl, each consisting of -L-R4 and 0-1 R 4b It has been replaced with; L is a bond, -CR x R x -or -C(O)(CR x R x ) 0-2 -and; R1 is hydrogen, C 1-3 Alkyl, C 1-2Fluoroalkyl or C 3-4 It is a cycloalkyl; Each R2 independently produces Halo, -CN, -OH, -NO2, and 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, -(CH2) 1-4 O(C 1-3 Alkyl), -O(CH2) 1-2 OC(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), -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, methylpiperizinyl, 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 It is cycloalkyl, -CH2(phenyl), tetrahydrofuranyl, tetrahydropyranyl, or phenyl; Each R 2b These are independently hydrogen, halo, -CN, and -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 R x or -CR x =CH(C 3-6 It is a cycloalkyl group; R 2c is R 2a or R 2b and; R 2dis R 2a or R 2b And; however, R 2c and R 2d One of them is R 2a And R 2c and R 2d The other is R 2b and; R3 is hydrogen, F, Cl, C 1-3 Alkyl, C 1-2 Fluoroalkyl or C 3-4 It is a cycloalkyl; R4 is: (i)-N(CH3)2; (ii) pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, azaspiro[3.3]heptanyl or azabicyclo[3.2.1]octanyl, each substituted with pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, azaspiro[3.3]heptanyl or azabicyclo[3.2.1]octanyl; or (iii) [ka] and; Each R 4a C is independent 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) is; R 4b is F, Cl, or -CH3; Each R 4c C is independent 1-6 Alkyl, C 1-3 Fluoroalkyl, -CH2(C 3-6 Cycloalkyl), -C(O)(C 1-4Alkyl), -C(O)(phenyl), -C(O)CH2(phenyl), -C(O)OCH2CH3 or C 3-6 It is a cycloalkyl; Each R5 independently contains hydrogen, F, Cl, and C. 1-2 Alkyl, C 1-2 It is fluoroalkyl or cyclopropyl; R 5a is hydrogen, C 1-2 Alkyl, C 1-2 It is fluoroalkyl or cyclopropyl; Each R x It is independently hydrogen or -CH3; Each R y These are independently hydrogen or C 1-6 It 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 either 1 or 2. The present invention provides compounds or salts thereof.

[0022] In one embodiment, a compound of formula (I) or its stereoisomers, tautomers, solvates, or salts are provided.

[0023] In one embodiment, a compound of formula (II) or its stereoisomers, tautomers, solvates, or salts are provided.

[0024] In one embodiment, a compound of formula (I) or a salt thereof, or a stereoisomer, tautomer, solvate or salt thereof, is provided, where X is N and Y is CR5. The compound of this embodiment is of formula (Ia): [ka] It has the structure of [the object].

[0025] In one embodiment, a compound of formula (I) or its stereoisomers, tautomers, solvates, or salts is provided, where X is CR5 and Y is N. The compound of this embodiment is of formula (Ib): [ka] It has the structure of [the object].

[0026] In one embodiment, a compound of formula (I) or its stereoisomers, tautomers, solvates, or salts is provided, where X is N; Y is CR5; Q1 is A; and Q2 is R5. The compound of this embodiment is of formula (Ia-1): [ka] It has the structure of [the object].

[0027] In one embodiment, a compound of formula (I) or its stereoisomers, tautomers, solvates, or salts is provided, where X is N; Y is CR5; Q1 is R5; and Q2 is A. The compound of this embodiment is of formula (Ia-2): [ka] It has the structure of [the object].

[0028] In one embodiment, a compound of formula (I) or a salt thereof is provided, where X is CR5; Y is N; Q1 is A; and Q2 is R5. The compound of this embodiment is of formula (Ib-1): [ka] It has the structure of [the object].

[0029] In one embodiment, a compound of formula (I) or a salt thereof or a stereoisomer, tautomer, solvate or salt thereof is provided, where X is CR5; Y is N; Q1 is R5; and Q2 is A. The compound of this embodiment is of formula (Ib-2): [ka] It has the structure of [the object].

[0030] In one embodiment, a compound of formula (II) or its stereoisomers, tautomers, solvates, or salts is provided, where Q1 is A and Q2 is R5. The compound of this embodiment is of formula (IIa): [ka] It has the structure of [the object].

[0031] In one embodiment, a compound of formula (II) or its stereoisomers, tautomers, solvates, or salts is provided, where Q1 is R5 and Q2 is A. The compound of this embodiment is of formula (IIb): [ka] It has the structure of [the object].

[0032] In one embodiment, 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 and -S(O)(NH)NR x R x A compound of formula (I) or formula (II) or its stereoisomers, tautomers, solvates, or salts is provided, wherein G is a phenyl compound substituted with 1 to 3 substituents independently selected from F, -CN, -OCH3, -S(O)2CH3, -S(O)2(cyclopropyl) or -S(O)2N(CH3)2. Also included in this embodiment is a compound in which G is a phenyl compound substituted with 1 to 2 substituents independently selected from F, -CN, -OCH3, -S(O)2CH3, -S(O)2(cyclopropyl) or -S(O)2N(CH3)2. [ka] It is a compound.

[0033] In one embodiment, a compound of formula (I) or formula (II) or a stereoisomer, tautomer, solvate, or salt thereof is provided, where G is a phenyl compound 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. Included in this embodiment are compounds where G is a phenyl compound substituted with 1 to 2 substituents independently selected from F, -OCH3, and -S(O)2CH3. Also included in this embodiment are compounds where G is [ka] It is a compound.

[0034] In one example, G [ka] A compound of formula (I) or formula (II) or its stereoisomers, tautomers, solvates, or salts is provided. Included in this embodiment are compounds in which 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, methylpiperizinyl, methylpiperazinyl, amino-oxadiazolyl, imidazolyl, or triazolyl. Also included in this embodiment are compounds in which each R2 is independently F, Cl, -CN, -CH3, -OCH3, -NH2, or cyclopropyl. Furthermore, included in this embodiment are compounds in which p is 2; one R2 is -CH3; and the other R2 is F, Cl, -CN, -CH3, -OCH3, -NH2, or cyclopropyl.

[0035] In one example, G [ka] [ka] [ka] A compound of formula (I) or formula (II) or its stereoisomers, tautomers, solvates, or salts is provided, which is a nine-membered heterocyclic ring selected from the above.

[0036] This embodiment includes G is [ka] It is a compound.

[0037] In one example, G [ka] A compound of formula (I) or formula (II) or its stereoisomers, tautomers, solvates, or salts is provided, which is a 10-membered heterocyclic ring selected from the above.

[0038] This embodiment includes G is [ka] It is a compound.

[0039] In one example, G (i) Phenyls substituted with one or two substituents independently selected from F, -CN, -OCH3, -S(O)2CH3, -S(O)2(cyclopropyl), or -S(O)2N(CH3)2; (ii) [ka] (iii) [ka] (iv) [ka] A compound of formula (I) or formula (II) or its stereoisomers, tautomers, solvates, or salts is provided. Included in this embodiment are compounds in which each R2 is independently Cl, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2CN, -OCH3, -CH2OCH3, or -CH2CH2S(O)2CH3.

[0040] In one example, G (i) Phenyls substituted with one or two substituents independently selected from F, -OCH3, -S(O)2CH3, -S(O)2N(CH3)2, and -S(O)(NH)N(CH3)2; (ii) [ka] (iii) [ka] (iv) [ka] A compound of formula (I) or formula (II) or its stereoisomers, tautomers, solvates, or salts is provided.

[0041] This embodiment includes compounds in which each R2 is independently Cl, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2CN, -OCH3, -CH2OCH3, or -CH2CH2S(O)2CH3.

[0042] In one embodiment, a compound of formula (I) or formula (II) or its stereoisomers, tautomers, solvates, or salts is provided, where p is 0, 1, 2, or 3. Included in this embodiment are compounds where p is 1 or 2.

[0043] In one embodiment, A is piperidinyl, phenyl, pyridinyl, pyrimidinyl, 6-azabicyclo[3.2.1]octanyl, or azabicyclo[3.2.1]octanyl, each consisting of -L-R4 and 0-1 R 4b Substituting with, the compounds of formula (I) or formula (II) or their stereoisomers, tautomers, solvates or salts are provided. Included in this embodiment are those in which A is -L-R4 and 0-1 R 4b The compound is a piperidinyl, phenyl, or pyridinyl compound substituted with . Also included in this embodiment are compounds in which A is -L-R4 and 0 to 1 R 4b The compound is a piperidinyl or phenyl compound substituted with . Furthermore, this embodiment includes a compound in which A is -L-R4 and 0-1 R 4bIt is a compound that is substituted with phenyl or pyridinyl.

[0044] In one embodiment, A is piperidinyl, phenyl, pyridinyl, or pyrimidinyl, and each has -L-R4 and 0-1 R 4b A compound of formula (I) or formula (II) or its stereoisomers, tautomers, solvates or salts is provided, in which A is substituted with and L is bonded or -C(O)-. Included in this embodiment are A which is -L-R4 and 0-1 R 4b It is a compound that is a phenyl or pyridinyl compound substituted with L, and L is a bond.

[0045] In one embodiment, L is used for concatenation, -CR x R x -or -C(O)(CR x R x ) 0-1 A compound of formula (I) or formula (II) or its stereoisomers, tautomers, solvates, or salts is provided. Included in this embodiment are a compound of formula (I) or formula (II) where L is bonded, -CH2- or -C(O)(CH2) 0-1 - is a compound. Also included in this embodiment is L is -CR x R x -or -C(O)(CR x R x ) 0-1 - is a compound. Furthermore, this embodiment includes a compound in which L is -C(O)CH2-.

[0046] In one embodiment, a compound of formula (I) or formula (II) or its stereoisomers, tautomers, solvates, or salts is provided, wherein L is bonded to -CH2- or -C(O)-.

[0047] In one embodiment, L is bonded, -CH2- or -C(O)(CH2) 0-2- There is provided a compound of formula (I) or a compound of formula (II) or a stereoisomer, tautomer, solvate or salt thereof. Included in this embodiment are compounds wherein L is -CH2-. Also included in this embodiment are compounds wherein L is -C(O)(CH2) 0-2 - There is provided a compound wherein L is -C(O)(CH2)-

[0048] In certain embodiments, there is provided a compound of formula (I) or a compound of formula (II) or a stereoisomer, tautomer, solvate or salt thereof, wherein L is a bond.

[0049] In certain embodiments, there is provided a compound of formula (I) or a compound of formula (II) or a stereoisomer, tautomer, solvate or salt thereof, wherein L is -CH2-.

[0050] In certain embodiments, there is provided a compound of formula (I) or a compound of formula (II) or a stereoisomer, tautomer, solvate or salt thereof, wherein L is -C(O)-.

[0051] In certain embodiments, there is provided a compound of formula (I) or a stereoisomer, tautomer, solvate or salt thereof, wherein R4 is -N(CH3)2.

[0052] In certain embodiments, R4 is (i) piperidinyl, piperazinyl, pyridinyl, azabicyclo[3.2.1]octanyl or diazabicyclo[3.2.1]octanyl each substituted with 0 to 1 R 4a and 0 to 2 -CH3; or (ii)

Chemical formula

[0053] In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, solvate or salt thereof, wherein each R4 is pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, azaspiro[3.3]heptanyl or azabicyclo[3.2.1]octanyl substituted with pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, azaspiro[3.3]heptanyl or azabicyclo[3.2.1]octanyl.

[0054] In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, solvate or salt thereof, wherein R4 is pyrrolidinyl, piperidinyl, piperazinyl or pyridinyl each substituted with 0 to 2 R 4a This embodiment includes compounds wherein R4 is piperidinyl, piperazinyl or pyridinyl. This embodiment also includes compounds wherein R4 is piperidinyl or piperazinyl. Further, this embodiment includes compounds wherein R4 is piperazinyl substituted with 0 or 1 R 4a .

[0055] In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, solvate or salt thereof, wherein R4 is

Chemical formula

[0056] In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, solvate or salt thereof, wherein R4 is pyrrolidinyl, piperidinyl, piperazinyl or pyridinyl each substituted with 0 to 2 R 4a ; or

Chemical formula

[0057] In one embodiment, R4 [ka] A compound of formula (I) or its stereoisomers, tautomers, solvates, or salts is provided.

[0058] One reason, R 4b A compound of formula (I) or its stereoisomers, tautomers, solvates, or salts is provided, wherein R is F or Cl. This embodiment includes R 4b It is a compound in which F is present.

[0059] One way of doing this is for each R 4c 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 A compound of formula (I) that is cycloalkyl is provided, or its stereoisomers, tautomers, solvates, or salts. Included in this embodiment are each R 4c 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 It is a cycloalkyl compound.

[0060] In one embodiment, R1 is hydrogen, C 1-3 Alkyl, -CHF2, -CF3 or C 3-4A compound of formula (I) or formula (II) or its stereoisomers, tautomers, solvates, or salts is provided, which is a cycloalkyl compound. Included in this embodiment are compounds in which R1 is hydrogen, -CH3, -CH2CH3, -CHF2, -CF3, or cyclopropyl. Also included in this embodiment are compounds in which R1 is hydrogen or -CH3.

[0061] In one embodiment, each R2 independently contains F, Cl, -CN, -OH, and 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), C 3-6 Cycloalkyl, -NR x R x ,-(CH2) 0-2 C(O)NR x R x -CH2(C 3-6 A compound of formula (I) or formula (II) or its stereoisomers, tautomers, solvates, or salts is provided, where R2 is cycloalkyl, -CH2(phenyl), or phenyl. Included in this embodiment are compounds where each R2 is independently Cl, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2CN, -OCH3, -CH2OCH3, or -CH2CH2S(O)2CH3. Also included in this embodiment are compounds where each R2 is independently Cl, -CH3, -CH2OH, or -OCH3.

[0062] One reason, R 2a C 1-4 Alkyl, C 1-2 Fluoroalkyl, C 1-4 Hydroxyalkyl, -(CH2) 1-3 O CH3, C 3-6 Cycloalkyl, -CH2C(O)NR x R x -CH2(C 3-6It is cycloalkyl, -CH2(phenyl), tetrahydrofuranyl or phenyl; and each R 2b These are independently H, F, Cl, -CN, and -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 3-6 A compound of formula (I) or formula (II) or its stereoisomers, tautomers, solvates, or salts is provided, which is a cycloalkyl compound. Also included in this embodiment is R 2a is -CH3; and each R 2b It is a compound in which each of the elements is independently H, Cl, or -CH3.

[0063] In one instance, R3 is hydrogen, F, Cl, C 1-3 Alkyl, -CHF2, -CF3 or C 3-4 A compound of formula (I) or formula (II) or its stereoisomers, tautomers, solvates, or salts is provided, which is a cycloalkyl compound. Included in this embodiment are compounds where R3 is hydrogen, F, -CH3, -CH2CH3, alkyl, -CHF2, -CF3, or cyclopropyl. Also included are compounds where R3 is hydrogen or -CH3. Furthermore, included are compounds where R3 is hydrogen.

[0064] In one embodiment, compounds of formula (I) or their stereoisomers, tautomers, solvates, or salts are provided, where each R5 is independently hydrogen, F, Cl, -CH3, or cyclopropyl. Included in this embodiment are compounds where each R5 is independently hydrogen, -CH3, or cyclopropyl. Also included are compounds where each R5 is hydrogen or -CH3.

[0065] One reason, R 5a is hydrogen, C 1-2 Compounds of formula (II) or their stereoisomers, tautomers, solvates, or salts are provided, wherein the compound is alkyl, -CHF2, -CF3, or cyclopropyl. Included in this embodiment are compounds in which hydrogen, -CH3, -CHF2, -CF3, or cyclopropyl is phenyl.

[0066] In one embodiment, R1 is hydrogen or -CH3; each R5 is hydrogen; G is a phenyl compound substituted with 1-2 substituents independently selected from F, -CN, -OCH3, -S(O)2CH3, -S(O)2(cyclopropyl) or -S(O)2N(CH3)2; A is a piperidinyl, phenyl, or pyridinyl compound each substituted with -L-R4; L is a bond, -CH2- or -C(O)-; R3 is hydrogen; R4 is (i) each 0-1 R 4a and piperidinyl, piperazinyl, pyridinyl, azabicyclo[3.2.1]octanyl or diazabicyclo[3.2.1]octanyl substituted with 0 to 2 -CH3 groups; or (ii) [ka] And; R 4a A compound of formula (I) or its stereoisomers, tautomers, solvates or salts is provided, where R5 is -OH, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2C(CH3)2OH, -CH2CH2C(CH3)2OH, -CH2(cyclopropyl) or cyclopropyl; and each R5 is hydrogen or -CH3.

[0067] In one embodiment, R1 is hydrogen or -CH3; each R5 is hydrogen; G is phenyl substituted with one or two substituents independently selected from F, -OCH3 or -S(O)2CH3; A is phenyl or pyridinyl each substituted with -L-R4; L is a bond or -C(O)-; R3 is hydrogen; R4 is piperazinyl substituted with 0 or 1 R 4a which is piperazinyl substituted with 4a -CH(CH3)2, -CH2CH(CH3)2, -CH2C(CH3)2OH, -CH2CH2C(CH3)2OH or -CH2(cyclopropyl); and each R5 is hydrogen or -CH3, there is provided a compound of formula (I) or a stereoisomer, tautomer, solvate or salt thereof. Included in this embodiment are compounds wherein X is N and Y is CH. Also included in this embodiment are compounds wherein X is CH and Y is N.

[0068] In one embodiment, X is N(CH3); Y is CH; Q1 is hydrogen; Q2 is A; A is phenyl; L is a bond; R1 is hydrogen; R3 is hydrogen; R4 is piperazinyl; and R 4a which is -CH(CH3)2 or -CH2CH(CH3)2, there is provided a compound of formula (II) or a stereoisomer, tautomer, solvate or salt thereof.

[0069] One embodiment provides a compound of formula (I) or its stereoisomers, tautomers, solvates, or salts, wherein the compound is: 2-(3,4-dimethoxyphenyl)-6-(4-(4-isopropylpiperazine-1-yl)phenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine(1); 6-(4-(4-isopropylpiperazine-1-yl)phenyl)-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine(2); 1-(4-(4-(2-(3,4-dimethoxyphenyl (4-( 4-(cyclopropylmethyl)piperazine-1-yl)phenyl)-2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine(8); 2-(3,4-dimethoxyphenyl)-6-(6-(4-isopropylpiperazine-1-yl)pyridine-3-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridine(9); 2-(3-fluoro-4-methoxyphenyl)-6-(4-(4-isopropylpiperazine-1-yl)phenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine(10 );6-(4-(4-isopropylpiperazine-1-yl)phenyl)-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine(11);4-(4-(4-(2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-6-yl)phenyl)piperazine-1-yl)-2-methylbutan-2-ol(12);2-(3,4-dimethoxyphenyl)-1-methyl-6-(4-(piperazine-1-yl)phenyl)-1H-pyrrolo[3,2-b]pyridine(13);6-(4-(4-isobutylpiperazine-1-yl)phenyl)-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine(14); 6-(4-(4-isobutylpiperazine-1-yl)phenyl)-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine(15); 2-methyl-1-(4-(4-(1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine-6- It is (yl)phenyl)piperazine-1-yl)propan-2-ol (15);-methyl-4-(4-(4-(1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine-6-yl)phenyl)piperazine-1-yl)butan-2-ol (16); or 6-(4-(4-isopropylpiperazine-1-yl)phenyl)-1-methyl-2-(3-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine (18).

[0070] One embodiment provides a compound of formula (I) or its stereoisomers, tautomers, solvates, or salts, where the compound is 2-(3,4-dimethoxyphenyl)-6-(4-(4-isopropylpiperazin-1-yl)phenyl)-1-methyl-1H-pyrrolo[2,3-b]pyridine(7).

[0071] One embodiment provides a compound of formula (I) or its stereoisomers, tautomers, solvates, or salts, wherein the compound is: 6-(4-(4-isopropylpiperazin-1-yl)phenyl)-4-methyl-2-(4-(methylsulfonyl)phenyl)-4H-pyrrolo[3,2-b]pyridine(3); or 6-(4-(4-isobutylpiperazin-1-yl)phenyl)-4-methyl-2-(4-(methylsulfonyl)phenyl)-4H-pyrrolo[3,2-b]pyridine(17).

[0072] One embodiment is a TLR9 IC with a minimum thickness of ≤0.6 μM. 50 The present invention provides a compound of formula (I) having a value.

[0073] One embodiment is a TLR9 IC with a mass of ≤0.1 μM. 50 The present invention provides a compound of formula (I) having a value.

[0074] One embodiment is a TLR9 IC with a mass of ≤0.05 μM. 50 The present invention provides a compound of formula (I) having a value.

[0075] One embodiment is a TLR9 IC with a mass of ≤0.025 μM. 50 The present invention provides a compound of formula (I) having a value.

[0076] One embodiment is a TLR9 IC with a mass of ≤0.015 μM. 50 The present invention provides a compound of formula (I) having a value.

[0077] One embodiment is a TLR9 IC with a mass of ≤0.01 μM. 50 The present invention provides a compound of formula (I) having a value.

[0078] In other embodiments, the present invention provides a composition comprising at least one of the compound of the present invention or its stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates.

[0079] In other embodiments, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one of the compound of the present invention or its stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates.

[0080] In other embodiments, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one of the compound of the present invention or its stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates in a therapeutically effective amount.

[0081] In another embodiment, the present invention provides a method for producing the compound of the present invention.

[0082] In another embodiment, the present invention provides intermediates for the production of the compounds of the present invention.

[0083] In another embodiment, the present invention provides the pharmaceutical composition defined above, further comprising one or more additional therapeutic agents.

[0084] definition The features and advantages of the present invention will be more readily understood by those skilled in the art by reading the following detailed description. For reasons of clarity, it will be recognized that certain features of the present invention described above and below in other embodiments may be combined to form a single embodiment. Conversely, for reasons of brevity, various features of the present invention described in a single embodiment may also be combined to form subordinate combinations thereof. Embodiments identified herein as examples or preferred are intended to be descriptive and not restrictive.

[0085] Unless otherwise specified, singular expressions can include plurals. For example, "aru" (ある) can refer to one or more than one.

[0086] The term "compound" as used herein 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).

[0087] Unless otherwise specified, any heteroatom whose valence is not satisfied is assumed to have a hydrogen atom to make its valence dependent.

[0088] The definitions set forth herein supersede any definitions set forth in any patent, patent application and / or patent application publication incorporated herein by reference.

[0089] The definitions of various terms used to describe this invention are listed below. These definitions apply insofar as the terms are used herein, individually or as part of a larger framework (unless otherwise defined in specific cases).

[0090] Throughout this specification, the groups and their substituents may be selected by those skilled in the art to provide stable moieties and compounds.

[0091] In accordance with the conventions used in this field, [ka] In the structural formulas presented herein, is used to represent a bond that is a bonding point of the moiety or substituent to the core or main chain structure.

[0092] The terms "halo" and "halogen" used here refer to F, Cl, Br, and I.

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

[0094] The term "amino" refers to the group -NH2.

[0095] The term "oxo" refers to the base element = oxygen (O).

[0096] The term "alkyl" as used herein refers to saturated aliphatic hydrocarbon groups, both branched and linear, that contain, for example, 1 to 12 carbon atoms, 1 to 6 carbon atoms, and 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and 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 subscript number follows the symbol "C", the subscript more specifically specifies the number of carbon atoms that a particular group may contain. For example, "C 1-6 "Alkyl" refers to linear and branched alkyl groups having 1 to 6 carbon atoms.

[0097] The term "fluoroalkyl" as used herein is intended to include both branched and linear saturated aliphatic hydrocarbon groups substituted with one or more fluorine atoms. For example, "C 1-4The term "fluoroalkyl" is intended 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.

[0098] The term "hydroxyalkyl" includes both branched and linear saturated alkyl groups substituted with one or more hydroxyl groups. For example, "hydroxyalkyl" includes -CH2OH, -CH2CH2OH, and C 1-4 Contains hydroxyalkyl.

[0099] The term "aminoalkyl" includes both branched and linear saturated alkyl groups substituted with one or more amine groups. For example, "aminoalkyl" includes -CH2NH2, -CH2CH2NH2, and C 1-4 Contains aminoalkyl compounds.

[0100] The term "cyanoalkyl" includes both branched and linear saturated alkyl groups substituted with one or more cyano groups. For example, "aminoalkyl" includes -CH2CN, -CH2CH2CN, and C 1-4 Contains cyanoalkyl.

[0101] The term "alkoxy" used here refers to an alkyl group bonded to the parent molecule via an oxygen atom, such as a methoxy group (-OCH3). For example, "C 1-3 "Alkoxy" refers to an alkoxy group having 1 to 3 carbon atoms.

[0102] The terms "fluoroalkoxy" and "-O (fluoroalkyl)" refer to fluoroalkyl groups defined as being bonded via an oxygen bond (-O-). For example, "C 1-4 "Fluoroalkoxy" is intended to include C1, C2, C3, and C4 fluoroalkoxy groups.

[0103] The term "alkoxyalkyl" used here refers to an alkoxy group in which an alkyl group is bonded via its oxygen atom, and the alkyl group is bonded to the parent molecule via a carbon atom, such as a methoxymethyl group (-CH2OCH3). For example, "C 2-4 "Alkoxyalkyl" refers to alkoxyalkyl groups having 2 to 4 carbon atoms, such as -CH2OCH3, -CH2CH2OCH3, -CH2OCH2CH3, and -CH2CH2OCH2CH3.

[0104] The term "cycloalkyl" as used herein refers to a group derived from a non-aromatic monocyclic or polycyclic hydrocarbon molecule by a single hydrogen atom from a saturated ring carbon atom. Typical examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl. When a number follows the symbol "C," the subscript more specifically defines the number of carbon atoms that a particular cycloalkyl group may contain. For example, "C 3-6 A "cycloalkyl" refers to a cycloalkyl group having 3 to 6 carbon atoms.

[0105] The term "pharmaceutically acceptable" here refers to a compound, substance, composition, and / or dosage form that, within the bounds of sound medical judgment, is suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic response, or other problems or complications, given a reasonable benefit / risk ratio.

[0106] The compounds of formula (I) and formula (II) may be provided as amorphous solids or crystalline solids. To provide the compounds of formula (I) and formula (II) as amorphous solids, lyophilization may be used.

[0107] It should be further understood that solvates (e.g., hydrates) of the compounds of formulas (I) and (II) are also within the scope of the present invention. The term “solvate” means the physical association of the compounds of formulas (I) and (II) with one or more organic or inorganic solvent molecules. This physical association includes hydrogen bonding. In some cases, the solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. “Solvate” encompasses both liquid phase and separable solvates. Examples of solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvate, and ethyl acetate solvate. Methods of solvation are known in the art.

[0108] Various forms of prodrugs are well known in this field and are described in Rautio, J. et al., Nature Review Drug Discovery, 17, 559-587 (2018).

[0109] Furthermore, the compounds of formula (I) and formula (II) can be isolated and purified to obtain a composition containing 99% or more by weight of the compound of formula (I) and formula (II) ("substantially pure"), respectively, following their preparation, which is then used or formulated as described herein. Such "substantially pure" compounds of formula (I) and "substantially pure" compounds of formula (II) are also intended herein as part of the present invention.

[0110] A “stable compound” and a “stable structure” refer to a compound that is robust enough to be isolated from a reaction mixture at a useful purity and remain present for formulation into an effective therapeutic agent. This invention aims to embody a stable compound.

[0111] "Therapeutic dose" is intended to include the amount of the compound of the present invention alone, or a combination of the compounds of the present invention, or a combination of the compounds of the present invention with other active ingredients, that is effective in acting as an inhibitor of TLR9 or in treating or preventing fibrotic diseases or disorders such as pathological fibrosis, or disorders associated with bile acid dysregulation.

[0112] As used herein, “to treat” or “to treat” encompasses the treatment of disease conditions in mammals, particularly humans, and includes (a) preventing the onset of a disease condition in a mammal, in particular when such mammal is predisposed to the disease condition but has not yet been diagnosed as having it; (b) stopping the disease condition, i.e., halting its progression; and / or (c) alleviating the disease condition, i.e., regressing it.

[0113] The compounds of the present invention are intended to contain all isotopes of the atoms present in the compound. Isotopes include atoms that have the same atomic number but different mass numbers. As a general example, but not limited to, hydrogen isotopes include deuterium (D) and tritium (T). Carbon isotopes include 13 C and 14 Contains C. The isotope-labeled compounds of the present invention can be prepared by conventional techniques generally known to those skilled in the art or by methods similar to those described herein, using appropriate isotope-labeled reactants in place of unlabeled reactants used elsewhere. For example, methyl (-CH3) also includes deuterated methyl groups such as -CD3.

[0114] usefulness The compounds of the present invention are useful for inhibiting TLR9 receptors.

[0115] One embodiment provides a method for treating a disease, disorder, or condition associated with bile acid dysregulation in a patient requiring treatment, comprising administering to the patient a therapeutically effective amount of the compound of the present invention or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0116] One embodiment provides a method for treating a disease, disorder, or condition associated with TLR9 receptor activity in a patient requiring treatment, comprising administering a therapeutically effective amount of the compound of the present invention or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof to the patient.

[0117] One embodiment provides a method for treating a disease, disorder, or condition, comprising administering to a patient in need of such treatment, a therapeutically effective amount of at least one of the compounds of the present invention, alone or, optionally, in combination with other compounds of the present invention and / or at least one other type of therapeutic agent.

[0118] One embodiment provides a method for inducing a TLR9 receptor antagonistic effect in a patient, comprising administering to the patient a therapeutically effective amount of the compound of the present invention or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0119] In one embodiment, the disease, disorder, or condition is associated with TLR9 dysfunction and includes pathological fibrosis, cancer, inflammatory disorders, metabolic or cholestatic disorders.

[0120] In one embodiment, the disease, disorder, or condition is associated with fibrosis and includes hepatic, bile duct, kidney, heart, skin, eye, and pancreatic fibrosis.

[0121] In other embodiments, the disease, disorder, or condition is associated with a cell proliferation disorder such as cancer. In some embodiments, cancer includes solid tumor growth or tumors. In other embodiments, cancer includes tumor metastasis. In some embodiments, cancer is of the liver, gallbladder, small intestine, large intestine, kidney, prostate, bladder, blood, bone, brain, breast, central nervous system, cervix, colon, endometrium, esophagus, genitals, urogenital tract, head, larynx, lungs, muscle tissue, neck, oral or nasal mucosa, ovaries, pancreas, skin, spleen, stomach, testes, or thyroid gland. In other embodiments, cancer is carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, or seminomasm.

[0122] Examples of diseases, disorders, or conditions associated with FXR activity that can be prevented, regulated, or treated by the present invention include, but are not limited to, transplantation, fibrotic disorders (e.g., hepatic fibrosis, renal fibrosis), inflammatory disorders (e.g., acute hepatitis, chronic hepatitis, non-alcoholic steatohepatitis (NASH), irritable bowel syndrome (IBS), inflammatory bowel disease (IBD)), and cell proliferation disorders (e.g., cancer, myeloma, fibroma, hepatocellular carcinoma, colorectal cancer, prostate cancer, leukemia, Kaposi's sarcoma, solid tumors).

[0123] The compounds of the present invention are suitable for preventing or treating fibrous disorders, inflammatory disorders, and cell proliferation disorders, including non-alcoholic fatty liver disease (NAFLD), alcoholic 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, hepatic hypofunction, hepatic blood flow disorders, nephropathy, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), pancreatic secretory disorders, benign prostatic hyperplasia, neurogenic bladder disease, diabetic nephropathy, focal segmental glomerulosclerosis, IgA nephropathy, drug or transplant-induced nephropathy, autoimmune nephropathy, lupus nephritis, hepatic fibrosis, renal fibrosis, chronic kidney disease (CKD), diabetic kidney disease (DKD), dermatofibrosis, keloids, systemic sclerosis, scleroderma, virus-induced fibrosis, and idiopathic pulmonary fibrosis (I). PF), interstitial lung disease, nonspecific interstitial pneumonia (NSIP), usual interstitial pneumonia (UIP), radiation-induced fibrosis, familial pulmonary fibrosis, airway fibrosis, chronic obstructive pulmonary disease (COPD), spinal cord tumor, herniated disc, spinal stenosis, heart failure, cardiac fibrosis, vascular fibrosis, perivascular fibrosis, foot and mouth disease, cancer, myeloma, fibroma, hepatocellular carcinoma, colorectal cancer, prostate cancer, leukemia, chronic lymphocytic leukemia, Kaposi's sarcoma, Solid tumors, cerebral infarction, cerebral hemorrhage, neuropathic pain, peripheral neuropathy, age-related macular degeneration (AMD), glaucoma, ocular fibrosis, corneal scarring, diabetic retinopathy, proliferative vitreoretinopathy (PVR), scarring pemphigoid, glaucoma filtration surgery scars, Crohn's disease or systemic lupus erythematosus; keloid formation resulting from abnormal wound healing; organ transplantation, myelofibrosis and fibrosis occurring after uterine fibroids, etc. In one embodiment, the present invention provides a method for treating a fibrous disorder, an inflammatory disorder or a cell proliferation disorder, comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention, alone or, optionally, in combination with other compounds of the present invention and / or at least one other type of therapeutic agent.

[0124] In another embodiment, the present invention provides compounds for use in therapeutic purposes.

[0125] In other embodiments, the present invention provides compounds for use in the treatment of fibrotic disorders, inflammatory disorders, or cell proliferation disorders.

[0126] In other embodiments, the present invention also provides the use of the compounds of the present invention for the manufacture of pharmaceuticals for the treatment of fibrotic disorders, inflammatory disorders, or cell proliferation disorders.

[0127] In other embodiments, the present invention provides a method for treating a fibrotic disorder, an inflammatory disorder, or a cell proliferation disorder, comprising administering therapeutically effective amounts of a first and second therapeutic agent to a patient in need thereof, wherein the first therapeutic agent is a compound of the present invention.

[0128] In other embodiments, the present invention provides combination formulations of the compounds of the present invention and additional therapeutic agents for simultaneous, separate, or sequential use in treatment.

[0129] In other embodiments, the present invention provides combination formulations of the compounds and additional therapeutic agents for simultaneous, separate, or sequential use in the treatment of fibrotic disorders, inflammatory disorders, or cell proliferation disorders.

[0130] The compounds of the present invention may be used in combination with one or more additional therapeutic agents, such as antifibrotic and / or anti-inflammatory therapeutic agents.

[0131] In one embodiment, the additional therapeutic agent used in the combination pharmaceutical composition, combination method, or combination use is selected from one or more, preferably one to three, of the following therapeutic agents: a TGFβ receptor inhibitor (e.g., garnicertib), a TGFβ synthesis inhibitor (e.g., pirfenidone), a vascular endothelial growth factor (VEGF) inhibitor, a platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) receptor kinase (e.g., nintedanib), and a humanized anti-α Vβ6 integrin monoclonal antibodies (e.g., 3G9), recombinant human pentraxin-2, recombinant human serum amyloid-P, recombinant human antibodies against TGFβ-1, -2 and -3, endothelin receptor antagonists (e.g., macitentan), interferon gamma, c-Jun amino-terminal kinase (JNK) inhibitors (e.g., 4-[[9-[(3S)-tetrahydro-3-furanyl]-8-[(2,4,6-trifluorophenyl)amino]-9H-purine-2 -ylamino]-trans-cyclohexanol, 3-pentylbenzeneacetic acid (PBI-4050), manganese(III)-containing tetrasubstituted porphyrin derivatives, eotaxin-2 targeting monoclonal antibodies, interleukin-13 (IL-13) antibodies (e.g., lebrikizumab, tralokinumab), bispecific antibodies targeting interleukin-4 (IL-4) and interleukin-13 (IL-13), NK1 tachykinin receptor agonists (e.g., Sar 9 Met(O2) 11-Substance P), Syntredekinbesdotox, derived from human recombinant DNA, IgG1 kappa monoclonal antibody and fully human IgG1 kappa antibody against binding growth factors, CC-chemokine ligand 2 selective (e.g., carrumab, CCX140), antioxidant (e.g., N-acetylcysteine), phosphodiesterase 5 (PDE5) inhibitor (e.g., sildenafil), agents for treating obstructive airway diseases, e.g., muscarinic antagonists (e.g., tiotropium, iprabromide) Tropium, adrenaline β2 agonists (e.g., salbutamol, salmeterol), corticosteroids (e.g., triamcinolone, dexamethasone, fluticasone), immunosuppressants (e.g., tacrolimus, rapamycin, pimecrolimus), and therapeutic agents useful in treating fibrotic conditions, such as hepatic, biliary, and renal fibrosis, non-alcoholic fatty liver disease (NALFD), non-alcoholic steatohepatitis (NASH), cardiac fibrosis, idiopathic pulmonary fibrosis (IPF), and systemic sclerosis. Useful therapeutic agents for treating such fibrous conditions include FXR agonists (e.g., OCA, GS-9674, and LJN452), LOXL2 inhibitors (e.g., simtuzumab), LPA1 antagonists (e.g., BMS-986020 and SAR100842), PPAR modulators (e.g., ellafibranor, pioglitazone, and saroglitazal, IVA337), SSAO / VAP-1 inhibitors (e.g., PXS-4728A and SZE5302), and ASK-1 inhibitors (e.g., GS-4997). This includes, but is not limited to, ceroncertib, ACC inhibitors (e.g., CP-640186 and NDI-010976 or GS-0976), FGF21 mimetics (e.g., LY2405319 and BMS-986036), caspase inhibitors (e.g., emricasan), NOX4 inhibitors (e.g., GKT137831), MGAT2 inhibitors (e.g., BMS-963272), αV integrin inhibitors (e.g., abituzumab), and bile acid / fatty acid conjugates (e.g., alamcol).The FXR agonists of various embodiments of the present invention include one or more therapeutic agents, such as CCR2 / 5 inhibitors (e.g., senicliviroc), Ga lectin-3 inhibitors (e.g., TD-139, GR-MD-02), leukotriene receptor antagonists (e.g., tiperkast, montelukast), SGLT2 inhibitors (e.g., dapagliflozin, remogliflozin), GLP-1 receptor agonists (e.g., liraglutide and semaglutide), F Combinations with AK 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., halofdinone), FPR2 agonists (e.g., ZK-994), and THR agonists (e.g., MGL:3196) may also be used. In other embodiments, the additional therapeutic agent used in the combination pharmaceutical composition, combination method, or combination use is selected from one or more, preferably one to three, oncological immunotherapy agents, such as alemtuzumab, atezolizumab, ipilimumab, nivolumab, ofatumumab, pembrolizumab, and rituximab.

[0132] When the terms “TLR9-related condition” or “TLR9-related disease or disorder” are used herein, they are intended to encompass, to the same extent as all of the conditions specified above, and any other conditions affected by TLR9 inhibition.

[0133] The other therapeutic agents described above may be used in combination with the compound of the present invention, for example, in amounts described in the Physicians' Desk Reference (PDR) or determined by those skilled in the art. In the method of the present invention, such other therapeutic agents may be administered before, simultaneously with, or after the administration of the compound of the present invention. The present invention also provides pharmaceutical compositions capable of treating TLR9-related conditions.

[0134] The compositions of the present invention may include other therapeutic agents as described above and can be formulated using techniques well known in the field of pharmaceutical formulation, for example, using conventional solid or liquid media or diluents and pharmaceutical additives of a type suitable for the desired method of administration (e.g., additives, binders, preservatives, stabilizers, flavoring agents, etc.).

[0135] Accordingly, the present invention further comprises compositions comprising one or more compounds of formula (I) and a pharmaceutically acceptable carrier.

[0136] A “pharmaceutically acceptable carrier” means a medium generally accepted in the art for the delivery of biological agents to animals, particularly mammals. A pharmaceutically acceptable carrier depends on several factors, which are well within the rights of those skilled in the art. These include, but are not limited to, the type and nature of the agent being formulated; the target to which the drug-containing composition is administered; the intended route of administration of the composition; and the targeted therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers may contain several different components and additives in addition to the agent, and such additional components may be included in the formulation for a variety of reasons well known to those skilled in the art, such as agent stabilizers, binders, etc. Descriptions relating to a suitable pharmaceutically acceptable carrier and its selection can be found in a variety of readily available sources, such as Remington's Pharmaceutical Sciences, 17th Edition (1985), which is incorporated herein by reference in whole.

[0137] The compound of formula (I) may be administered by any means suitable for the condition being treated, depending on the need for site-specific treatment or the amount of compound of formula (I) to be delivered.

[0138] The compound of formula (II) may be administered by any means suitable for the condition being treated, depending on the need for site-specific treatment or the amount of the compound of formula (II) to be delivered.

[0139] Also included within the scope of the present invention are pharmaceutical compositions comprising a compound of formula (I) and / or a compound of formula (II) and one or more non-toxic, pharmaceutically acceptable carriers and / or diluents and / or adjuvants (collectively referred to here as “carrier” substances) and, optionally, other active ingredients. The compounds of formula (I) and formula (II) can be administered by any suitable route, preferably in the form of a pharmaceutical composition suitable for such route, and in doses effective for the intended treatment. The compounds and compositions of the present invention can be administered, for example, orally, mucosally or intravascularly, intravenously, intraperitoneally, subcutaneously, intramuscularly and intrasternally, in dose-unit formulations comprising conventionally pharmaceutically acceptable carriers, adjuvants and media. For example, a pharmaceutical carrier may comprise a mixture of mannitol or lactose and microcrystalline cellulose. The mixture may comprise additional components such as lubricants, such as magnesium stearate and disintegrants such as 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 intravenous infusion.

[0140] For oral administration, the pharmaceutical composition may be in the form of, for example, tablets, capsules, liquid capsules, suspensions, or liquids. The pharmaceutical composition is preferably manufactured in the form of dosage units containing a specific amount of the active ingredient. For example, the pharmaceutical composition may be provided as tablets or capsules containing an amount of the active ingredient ranging from about 0.1 to 1000 mg, preferably about 0.25 to 250 mg, and more preferably about 0.5 to 100 mg. An appropriate daily dose for humans or other mammals can be determined using routine methods, although this may vary considerably depending on the patient's condition and other factors.

[0141] Any pharmaceutical composition intended herein may be delivered orally, for example, via any acceptable and suitable oral formulation. Examples of oral formulations include, but are not limited to, tablets, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs. Pharmaceutical compositions intended for oral administration may be manufactured by any method known in the art for the manufacture of pharmaceutical compositions intended for oral administration. To provide pharmaceutically acceptable formulations, the pharmaceutical compositions of the present invention may contain at least one agent selected from sweeteners, flavoring agents, colorants, lubricants, antioxidants, and preservatives.

[0142] Tablets may be manufactured, for example, by mixing at least one compound of formula (I) and / or formula (II) with at least one non-toxic, pharmaceutically acceptable additive suitable for the manufacture of tablets. Examples of additives include, but are not limited to, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate; granulating and disintegrating agents such as microcrystalline cellulose, sodium croscarmellose, corn starch, and alginic acid; binders such as starch, gelatin, polyvinylpyrrolidone, and acacia; and lubricants such as magnesium stearate, stearic acid, and talc. Furthermore, even if tablets are not coated, they may be coated by known techniques that mask the bad taste of unpleasant-tasting drugs or delay the disintegration and absorption of the active ingredient in the gastrointestinal tract, thereby prolonging the effect of the active ingredient. Examples of water-soluble taste-masking substances include, but are not limited to, hydroxypropyl methylcellulose and hydroxypropyl cellulose. Examples of time-delaying substances include, but are not limited to, ethylcellulose and cellulose butyrate acetate.

[0143] Hard gelatin capsules can be prepared, for example, by a mixture of at least one compound of formula (I) and / or formula (II) and at least one inert solid diluent, such as calcium carbonate; calcium phosphate; and kaolin.

[0144] Soft gelatin capsules can be manufactured, for example, by mixing at least one compound of formula (I) and / or formula (II), at least one water-soluble carrier, such as polyethylene glycol; and at least one oil medium, such as peanut oil, liquid paraffin, and olive oil.

[0145] Aqueous suspensions can be prepared, for example, by mixing at least one compound of formula (I) and / or formula (II) with at least one additive suitable for the preparation of an aqueous suspension. Examples of additives suitable for the preparation of aqueous suspensions include, but are not limited to, suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, alginic acid, polyvinylpyrrolidone, tragacanth gum, and acacia gum; dispersing or wetting agents such as naturally occurring phosphatides such as lecithin; condensation products of alkylene oxides and fatty acids such as polyoxyethylene stearate; condensation products of ethylene oxides and long-chain aliphatic alcohols such as heptadecaethylene-oxycetanol; condensation products of ethylene oxides and partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate; and condensation products of ethylene oxides and partial esters derived from fatty acids and hexitol anhydrides such as polyethylene sorbitan monooleate. The aqueous suspension may also contain at least one preservative, e.g., ethyl and n-propyl p-hydroxybenzoate; at least one coloring agent; at least one flavoring agent; and / or at least one sweetener, e.g., sucrose, saccharin, and aspartame.

[0146] An oily suspension can be prepared, for example, by suspending at least one compound of formula (I) and / or formula (II) in a vegetable oil, such as peanut oil; olive oil; sesame oil; and coconut oil; or a mineral oil, such as liquid paraffin. The oily suspension may also contain at least one thickening agent, such as beeswax; hard paraffin; and cetyl alcohol. To provide a drinkable oily suspension, at least one of the sweeteners and / or at least one flavoring agent already described above may be added to the oily suspension. The oily suspension may further contain at least one preservative, such as antioxidants, such as butylated hydroxyanisole and alpha-tocopherol, but not limited to these.

[0147] Dispersible powders and granules may be prepared, for example, by mixing at least one compound of formula (I) and / or formula (II) with at least one dispersing 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 such as ascorbic acid. Furthermore, dispersible powders and granules may also include at least one additive, including, but not limited to, sweeteners; flavoring agents; and coloring agents.

[0148] Emulsions of at least one compound of formula (I) and / or formula (II) can be prepared, for example, as an oil-in-water emulsion. The oil phase of an emulsion containing a compound of formula (I) and / or formula (II) may consist of known components in a known manner. The oil phase may, but is not limited, be provided by, for example, vegetable oils, e.g., olive oil and peanut oil; mineral oils, e.g., liquid paraffin; and mixtures thereof. The phase may contain only emulsifiers, but may contain at least one emulsifier and a fat or oil or a mixture of both fat and oil. Suitable emulsifiers include, but are not limited to, naturally occurring phosphatides, e.g., soy 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 preferable to include both oil and fat. In summary, emulsifiers used in combination with or without stabilizers form so-called emulsifying waxes, which, together with oils and fats, form so-called emulsifying ointment bases, which form the oily dispersion phase of cream formulations. Emulsions may also contain 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, either alone or in combination with waxes or other substances well known in the art.

[0149] Compounds of formula (I) and / or formula (II) may also be delivered intravenously, subcutaneously, and / or intramuscularly, for example, via any pharmaceutically acceptable and suitable injectable form. Examples of injectable forms include, but are not limited to, sterile aqueous solutions containing acceptable media and solvents, such as water, Ringer's solution, and isotonic sodium chloride solution; sterile oil-in-water microemulsions; and aqueous or oily suspensions.

[0150] Non-enteral formulations 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 using one or more of the carriers or diluents described for use in oral formulations, or other suitable dispersing or wetting and suspending agents. The compound can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum, and / or various buffers. Other adjuvants and administration methods are well and extensively known in the pharmaceutical field. The active ingredient may also be administered by injection as a composition with a suitable carrier containing saline, dextrose, or water, or using cyclodextrin (i.e., captisol), co-solubilization (i.e., propylene glycol), or micelle solubilization (i.e., Tween 80).

[0151] Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic, non-enterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable media and solvents include, among others, water, Ringer's solution, and isotonic sodium chloride solutions. Furthermore, sterile, fixative oils may be conventionally used as solvents or suspension media. For this purpose, any non-irritating fixative oil, including synthetic mono- or diglycerides, may be used. In addition, fatty acids such as oleic acid are useful in the manufacture of injectable preparations.

[0152] A sterile oil-in-water microemulsion for injection may be produced, for example, by 1) dissolving at least one compound of formula (I) and / or formula (II) in an oil phase, for example, a mixture of soybean oil and lecithin; 2) combining the oil phase containing formula (I) and / or formula (II) with a mixture of water and glycerol; and 3) processing the combination to form a microemulsion.

[0153] Sterile aqueous or oily suspensions can be prepared by methods already known in the art. For example, a sterile aqueous solution or suspension can be prepared using a non-toxic, non-enterally acceptable diluent or solvent, such as 1,3-butanediol; and a sterile oily suspension can be prepared using a sterile, non-toxic, acceptable solvent or suspension medium, such as a sterile fixative oil, such as a synthetic mono or diglyceride; and a fatty acid, such as oleic acid.

[0154] pharmaceutically acceptable carriers, adjuvants, and media that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, self-emulsifying drug delivery systems (SEDDS) such as alumina, aluminum stearate, lecithin, d-alpha-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical administration forms such as tweene, polyethoxylated castor oil, such as Cremofor surfactant (BASF) or other similar polymer delivery matrices, serum proteins such as human serum albumin, buffers such as phosphoric acid, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylic acid, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin fat. Cyclodextrins, such as alpha-, beta-, and gamma-cyclodextrins, or chemically modified derivatives, such as hydroxyalkylcyclodextrins or other solubilizing derivatives including 2- and 3-hydroxypropyl-cyclodextrins, may also be advantageously used to enhance the delivery of compounds of the formulas described herein.

[0155] The pharmaceutically active compounds of the present invention may be processed by conventional compounding methods for producing drugs for administration to patients, including humans and other mammals. The pharmaceutical compositions may be subjected to conventional pharmaceutical procedures such as sterilization and / or may contain conventional adjuvants such as preservatives, stabilizers, humectants, emulsifiers, and buffers. Tablets and pills may be further coated with enteric coating. Such compositions may also contain adjuvants such as humectants, sweeteners, flavorings, and fragrances.

[0156] The amount of compound administered and the dosage regimen for treating a disease condition with the compounds and / or compositions of the present invention depend on a variety of factors, including the subject's age, weight, sex, medical condition, disease type, disease severity, route and frequency of administration, and the specific compound used. Therefore, dosage regimens can vary widely but can be determined routinely using standard methods. A daily dose of about 0.001 to 100 mg / kg body weight, preferably about 0.0025 to about 50 mg / kg body weight and most preferably about 0.005 to 10 mg / kg body weight may be appropriate. The daily dose may be administered 1 to 4 times a day. Other dosing schedules include once a week and once every two days.

[0157] For therapeutic purposes, the active compound of the present invention is combined with one or more adjuvants suitable for the usual route of administration. For oral administration, the compound is mixed with lactose, sucrose, starch powder, cellulose esters of alkanates, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric acid and sulfate, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone and / or polyvinyl alcohol, and then compressed into tablets or encapsulated for convenient administration. Such capsules or tablets may include controlled-release formulations, such as those provided as a dispersion of the active compound in hydroxypropyl methylcellulose.

[0158] The pharmaceutical compositions of the present invention comprise at least one compound of formula (I) and optionally an additional agent selected from any pharmaceutically acceptable carrier, adjuvant, and medium. Another composition of the present invention comprises one of the compounds of formula (I) described herein or its prodrug and a pharmaceutically acceptable carrier, adjuvant, or medium.

[0159] The pharmaceutical compositions of the present invention comprise at least one compound of formula (II) and optionally an additional agent selected from any pharmaceutically acceptable carrier, adjuvant, and medium. Another composition of the present invention comprises one of the compounds of formula (II) described herein or its prodrug and a pharmaceutically acceptable carrier, adjuvant, or medium.

[0160] The present invention also includes products. Products as used herein are intended to include, but are not limited to, kits and packaging. Products of the present invention include (a) a first container; (b) a pharmaceutical composition placed in the first container (wherein the composition comprises a first therapeutic agent comprising the compound of the present invention or a pharmaceutically acceptable salt form thereof); and (c) a statement of instructions that the pharmaceutical composition can be used for the treatment of cardiovascular disorders, diuresis, and / or natriuresis. In other embodiments, the statement of instructions may include instructions that the pharmaceutical composition can be used in combination with a second therapeutic agent (as defined above) for the treatment of cardiovascular disorders, diuresis, and / or natriuresis. Products may further include (d) a second container in which elements (a) and (b) are placed inside the second container and element (c) is placed inside or outside the second container. Placement inside the first and second containers means that each container contains the articles within its boundaries.

[0161] The first container is a container used to hold pharmaceutical compositions. This container is for manufacturing, storage, transport, and / or individual / bulk sales. The first container is intended to include bottles, jars, vials, flasks, syringes, tubes (e.g., for cream formulations) or any other containers used for the manufacture, holding, storage, or dispensing of pharmaceuticals.

[0162] The second container is used to hold the first container and, optionally, accompanying documentation. Examples of the second container include, but are not limited to, boxes (e.g., cardboard or plastic), crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks. The accompanying documentation may be physically attached to the outside of the first container by tape, glue, staples, or other means of attachment, or it may be placed inside the second container without any means of attachment to the first container. Alternatively, the accompanying documentation may be placed outside the second container. When placed outside the second container, it is preferable that the accompanying documentation is physically attached by tape, glue, staples, or other means of attachment. Alternatively, it may be placed adjacent to or in contact with the outside of the second container without physical attachment.

[0163] The package insert is a label, tag, marker, or other document that contains information about the pharmaceutical composition placed in the first container. The information contained herein is usually determined by the regulatory authority governing the region where the product is sold (e.g., the U.S. Food and Drug Administration). Preferably, the package insert describes the indication for which the pharmaceutical composition is specifically approved. The package insert may be manufactured from any material on which the information contained herein can be read. Preferably, the package insert is from a printable material (e.g., paper, plastic, cardboard, foil, adhesive paper, or plastic) on which the desired information is recorded (e.g., printed or applied).

[0164] Manufacturing method The compounds of the present invention can be produced by several methods well known to those skilled in the art of organic synthesis. The compounds of the present invention can also be synthesized by combining them with synthetic methods known in the field of synthetic organic chemistry, using the methods described below or variations thereof recognized by those skilled in the art. Preferred methods include, but are not limited to, those described below.

[0165] The reactions and techniques described in this section are carried out in solvents suitable for the reactants and substances used and for the transformations to be performed. Furthermore, in the descriptions of the synthetic methods below, it is understood that all proposed reaction conditions, including the selection of solvent, reaction atmosphere, reaction temperature, experimental time, and workup method, are selected to be standard conditions for the reaction, readily apparent to those skilled in the art. It is recognized to those skilled in the field of organic synthesis that the functional groups present in each part of the molecule must be compatible with the proposed reactants and reaction. Such restrictions on substituents that must be compatible with the reaction conditions are readily apparent to those skilled in the art, where an alternative method is used. This may require judgment to change the order of the synthetic steps or to select a particular method scheme rather than another in order to obtain the desired compound of the present invention. Another major concern in planning any synthetic route in this art is the wise selection of protecting groups to be used to protect the reactive functional groups present in the compounds described herein. An authoritative description for skilled practitioners of many options is Greene et al. (Protective Groups in Organic Synthesis, Third Edition, Wiley and Sons (1999)).

[0166] Scheme 1 [ka] Scheme 1 describes the synthesis of compounds of formulas (I) and (I'). 1b can be obtained by the reaction of 1a with methanesulfonyl chloride, followed by hydrolysis with a base such as sodium hydroxide. 1d can be obtained by cyclization of 1b and alkyne 1c in the presence of copper(I) iodide with a palladium catalyst such as bis(triphenylphosphine)palladium(II) chloride, and 1e can be obtained by alkylation. Compounds of formula (I) or precursors of (I) can be obtained by Suzuki coupling of 1e with boronic acid ester 1f. Similarly, 1h can be obtained by Suzuki coupling of 1e with boronic acid ester 1g, which can be converted to compounds of formula (I') by hydrogenation, deprotection, and further modification.

[0167] Scheme 2 [ka] Scheme 2 presents compounds of formulas (II) and (II'). 1bj can be obtained by the reaction of 1i with methanesulfonyl chloride, followed by hydrolysis with a base such as sodium hydroxide. 1k can be obtained by cyclization of 1j and alkyne 1c in the presence of copper(I) iodide with a palladium catalyst such as bis(triphenylphosphine)palladium(II), and 1l can be obtained by alkylation. 1l can be obtained by Suzuki coupling of boronic acid ester 1f to obtain compounds of formula (II) or precursors of (II). Similarly, 1m can be obtained by Suzuki coupling of 1l and boronic acid ester 1g, which can be converted to compounds of formula (II') by hydrogenation, deprotection, and further modification. [Examples]

[0168] The compounds of the present invention and intermediates used in the production of these compounds can be produced using the methods and related methods shown in the following examples. The methods and conditions used in these examples, and the actual compounds produced in these examples, are intended to illustrate methods for producing the compounds of the present invention, not to be limiting. The starting materials and reactants used in these examples can, if not produced by the methods described herein, be commercially available or described in the chemical literature or produced by methods described in the chemical literature. The present invention is further defined in the following examples. It should be understood that the examples are provided for illustrative purposes only. From the above description and examples, those skilled in the art can elucidate the essential features of the present invention and make various modifications and alterations to adapt the invention to various uses and conditions without departing from its spirit and scope. As a result, the present invention is not limited by the following explanatory examples, but rather by the appended claims.

[0169] In the examples shown, the term "concentrated to dryness" generally refers to drying a solution in an organic solvent with sodium sulfate or magnesium sulfate, followed by filtration to remove the solvent from the filtrate (generally under reduced pressure and at a temperature suitable for the stability of the substance being concentrated to dryness).

[0170] Column chromatography was performed using an Isco medium-pressure chromatography apparatus (Teledyne Corporation) with pre-filled silica gel cartridges eluted with the indicated solvent or solvent mixture. Preparative high-performance liquid chromatography (HPLC) was performed using a reversed-phase column (Waters Sunfire C) of a size appropriate for the amount of substance to be separated. 18 Waters Xbridge C 18 , PHENOMENEX(R) Axia C 18 The procedure is carried out using YMC S5 ODS, etc., and generally, elution is performed with a gradient increasing the concentration of methanol or acetonitrile in water, also containing 0.05% or 0.1% trifluoroacetic acid or 10 mM ammonium acetate, at a flow rate appropriate for the column size and the separation to be achieved. Chemical names were determined using ChemDraw Ultra, version 9.0.5 (CambridgeSoft). The following abbreviations were used: ACN Acetonitrile aq. Water-based BOP Benzotriazole-1-yloxytris-(dimethylamino)-phosphonium hexafluorophosphate Saturated sodium chloride solution DMF (N,N-dimethylformamide) DMSO (Dimethyl Sulfoxide) DPPF 1,1'-bis(diphenylphosphino)ferrocene Et3N triethylamine HCl ethyl acetate g grams h time HPLC (High-Performance Liquid Chromatography) LCMS Liquid Chromatography-Mass Spectrometry MeI methyl iodide MeOH methanol Pd(PPh3)2Cl2 bis(triphenylphosphine)palladium(II) dichloride petroleum ether t-BuOK potassium tertiary butoxide TBAF Tetrabutylammonium Fluoride TFA (Trifluoroacetic Acid) THF (Tetrahydrofuran)

[0171] manufacturing All reactants purchased from suppliers were used without further purification unless otherwise specified. All reactions involving air or moisture-sensitive reactants were carried out under an inert atmosphere. Proton magnetic resonance spectra were recorded using a Bruker Avance 400 or JEOL Eclipse 500 spectrometer. LC-MS analysis was performed using a Waters Acquity UPLC system connected to a Waters TUV and SQ mass detector (column: BEH C18 2.1×50mm; mobile phase A: water containing 0.05% TFA; mobile phase B: acetonitrile containing 0.05% TFA; gradient: 2-98% B over 1.6 minutes; flow rate: 0.8 mL / min); HPLC analysis was recorded using a Shimadzu LC10-AT HPLC system connected to an SPD-10AV UV detector (column: YMC S5 Combiscreen ODS 4.6×50mm; mobile phase A: 5:95 acetonitrile: water containing 0.1% TFA; mobile phase B: 95:5 acetonitrile: water containing 0.1% TFA; gradient: 0-100% B over 40 minutes, then held at 100% B for 1 minute; flow rate: 1 mL / min); preparative HPLC purification was performed using an SPD 20 The experiment was performed using a Shimadzu LC-8 preparative HPLC system connected to a UV detector. Detailed conditions are described in the experimental procedure section.

[0172] Example 1 2-(3,4-dimethoxyphenyl)-6-(4-(4-isopropylpiperazine-1-yl)phenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine [ka] Step 1. N-(2,5-dibromopyridine-3-yl)-N-(methylsulfonyl)methanesulfonamide [ka] At 0°C, a solution of 2,5-dibromopyridine-3-amine (3.0 g, 11.91 mmol) and triethylamine (8.30 mL, 59.5 mmol) in dichloromethane (40 mL) was added over 10 minutes to a solution of methanesulfonyl chloride (4.61 mL, 59.5 mmol) in dichloromethane (40 mL). The mixture was stirred at room temperature for 24 hours. The mixture was diluted with dichloromethane (80 mL), washed with water (2 × 30 mL) and brine (30 mL), and dried over anhydrous MgSO4. The product, N-(2,5-dibromopyridine-3-yl)-N-(methylsulfonyl)methanesulfonamide (3.69 g, 9.04 mmol, 76% yield), was isolated as a white solid by ISCO chromatography (220 g silica gel, 10-50% ethyl acetate / hexane). LCMS (M+H) + = 406.9. 1 H NMR (500 MHz, DMSO-d6) δ 8.74 (d, J=2.2 Hz, 1H), 8.64 (d, J=2.5 Hz, 1H), 3.68 (s, 6H)

[0173] Step 2. N-(2,5-dibromopyridine-3-yl)methanesulfonamide [ka] At room temperature, 16 ml of 10% sodium hydroxide (44.0 mmol) was added over 3 minutes to a 16 mL solution of N-(2,5-dibromopyridine-3-yl)-N-(methylsulfonyl)methanesulfonamide (3.68 g, 9.02 mmol) in tetrahydrofuran. The mixture was stirred at room temperature for 15 hours and then concentrated under reduced pressure to approximately 10 mL. The residue was diluted with water (5 mL) and neutralized with concentrated hydrochloric acid to pH 6-7. The precipitated product, N-(2,5-dibromopyridine-3-yl)methanesulfonamide (2.79 g, 8.45 mmol, 94% yield), was collected as a white solid by suction filtration and dried under reduced pressure at 50°C. LCMS (M+H) + = 328.9. 1 H NMR (500 MHz, DMSO-d6) δ 9.85 (br s, 1H), 8.42 (d, J=2.2 Hz, 1H), 8.04 (d, J=2.2 Hz, 1H), 3.19 (s, 3H)

[0174] Step 3. 6-Bromo-2-(3,4-dimethoxyphenyl)-1H-pyrrolo[3,2-b]pyridine [ka] A mixture of N-(2,5-dibromopyridine-3-yl)methanesulfonamide (1.00 g, 3.03 mmol), 4-ethynyl-1,2-dimethoxybenzene (0.614 g, 3.79 mmol), bis(triphenylphosphine)palladium(II) chloride (0.128 g, 0.182 mmol), and copper(I) iodide (0.035 g, 0.182 mmol) in DMF (12 mL) was degassed and heated in a sealed vial at 100 °C for 15 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate (50 mL) and filtered through Celite. The filtrate was further diluted with ethyl acetate (150 mL), washed with water (3 × 40 mL) and brine (40 mL), and dried over anhydrous MgSO4. After removing the solvent under reduced pressure, the residue was subjected to ISCO chromatography (80 g silica gel, solid-packed, 0-5% methanol / dichloromethane). The product was purified by preparative HPLC (column: Phenomenex Luna AXIA 5u C18 30.0×100; Solvent A: 90% H2O~10% methanol-0.1% TFA; Solvent B: 10% methanol~90% H2O 0.1% TFA; Flow rate: 40 mL / min; Gradient time: 12 min; Starting %B: 15; Final %B: 100). The collected fractions were combined, concentrated under reduced pressure, basicized to pH 10 with saturated NaHCO3 solution, and extracted with dichloromethane (3×50 mL). The combined extract was dried over anhydrous MgSO4. Solvent removal under reduced pressure yielded 6-bromo-2-(3,4-dimethoxyphenyl)-1H-pyrrolo[3,2-b]pyridine (178 mg, 0.534 mmol, 17.63% yield) as a white solid. LCMS (M+H) + = 333.4. 1 H NMR (500 MHz, DMSO-d6) δ 8.33 (d, J=1.9 Hz, 1H), 7.90 (d, J=1.4 Hz, 1H), 7.56-7.47 (m, 2H), 7.09 (d, J=8.3 Hz, 1H), 7.04 (s, 1H), 3.89 (s, 3H), 3.83 (s, 3H)

[0175] Step 4. 6-Bromo-2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine [ka] At 0°C, sodium hydride (60% dispersion) (51.0 mg, 1.276 mmol) was added all at once to a solution of 6-bromo-2-(3,4-dimethoxyphenyl)-1H-pyrrolo[3,2-b]pyridine (170 mg, 0.510 mmol) and iodomethane (181 mg, 1.276 mmol) in DMF (5 mL). The mixture was stirred at room temperature for 1 hour. The reaction was stopped with acetic acid (0.5 mL). The reaction mixture was diluted with ethyl acetate (150 mL) and washed with 1N K2HPO4 solution (2 × 35 mL), water (2 × 35 mL), and brine (35 mL). The organic solution was then dried over anhydrous MgSO4. The product, 6-bromo-2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine (75 mg, 0.216 mmol, 42.3% yield), was isolated as a white solid by ISCO chromatography (40 g silica gel, 10-50% ethyl acetate). LC-MS (M+H) + = 347.9

[0176] Step 5. 2-(3,4-dimethoxyphenyl)-6-(4-(4-isopropylpiperazine-1-yl)phenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine 1,4-Dioxane (1.2 mL) contains 6-bromo-2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine (35 mg, 0.101 mmol), 1-isopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (46.6 mg, 0.141 mmol), (2-dicyclohexyl A mixture of xylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (XPhos-Pd-G3) (8.53 mg, 10.08 μmol) and tripotassium phosphate (0.176 mL, 0.353 mmol) was degassed and heated in a sealed vial at 85°C for 15 hours. After cooling to room temperature, the reaction mixture was diluted with methanol, filtered through an Acrodisc, and injected into a preparative HPLC (column: Phenomenex Luna AXIA 5u C18 21.2×100; Solvent A: 90%H2O~10%Methanol-0.1%TFA; Solvent B: 10%Methanol~90%H2O 0.1%TFA; Flow rate: 20 mL / min; Gradient time: 15 min; Starting %B: 14; Final %B: 100). The collected fractions were concentrated under reduced pressure, basicized with 1N NaOH solution, and extracted with dichloromethane (4×40 mL). The combined extracts were dried over anhydrous Na2SO4. By removing the solvent under reduced pressure, the product, 2-(3,4-dimethoxyphenyl)-6-(4-(4-isopropylpiperazin-1-yl)phenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine (34.5 mg, 0.073 mmol, 72.0% yield), was obtained as a pale yellow solid. LC-MS (M+H) + = 471.2. 1H NMR (500 MHz, chloroform-d) δ 8.73 (d, J=1.4 Hz, 1H), 7.76 (s, 1H), 7.62 (d, J=8.8 Hz, 2H), 7.12 (dd, J=8.3, 1.7 Hz, 1H), 7.10-7.06 (m, 3H), 7.03 (d, J=8.3 Hz, 1H), 6.75 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H), 3.81 (s, 3H), 3.35-3.28 (m, 4H), 2.80-2.73 (m, 5H), 1.14 (d, J=6.6Hz, 6H)

[0177] Example 2 6-(4-(4-isopropylpiperazine-1-yl)phenyl)-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine [ka] Step 1. 6-Bromo-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine [ka] A mixture of N-(2,5-dibromopyridine-3-yl)methanesulfonamide (0.48 g, 1.455 mmol), 1-ethynyl-4-(methylsulfonyl)benzene (0.328 g, 1.818 mmol), bis(triphenylphosphine)palladium(II) chloride (0.061 g, 0.087 mmol), and copper(I) iodide (0.017 g, 0.087 mmol) in DMF (5 mL) was degassed and heated in a sealed vial at 100 °C for 15 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate (50 mL) and filtered through Celite. The filtrate was further diluted with ethyl acetate (150 mL), washed with water (3 × 40 mL) and brine (40 mL), and dried over anhydrous MgSO4. After removing the solvent under reduced pressure, the residue was subjected to ISCO chromatography (80g silica gel, solid packing, 0-5% methanol / dichloromethane). The product (0.275g) was purified by preparative HPLC (column: Phenomenex Luna AXIA 5u C18 30.0×100. Solvent A: 90%H2O~10% methanol-0.1% TFA; Solvent B: 10% methanol~90% H2O 0.1% TFA. Flow rate: 40 mL / min. Gradient time: 12 min. Starting %B: 15; Final %B: 100). The collected fractions were combined, concentrated under reduced pressure, basicized to pH 10 with saturated NaHCO3 solution, and extracted with dichloromethane (3×50 mL). The combined extract was dried over anhydrous MgSO4. The solvent was removed under reduced pressure to obtain 6-bromo-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine (119 mg, 0.339 mmol, 23.29% yield) as a white solid. LC-MS (M+H) + = 351.1. 1 H NMR (500 MHz, DMSO-d6) δ 12.21 (s, 1H), 8.43 (d, J=2.2 Hz, 1H), 8.24-8.18 (m, 2H), 8.08-8.03 (m, 2H), 8.02 (dd, J=1.9, 0.8 Hz, 1H), 7.34 (s, 1H), 3.28 (s, 3H)

[0178] Step 2. 6-Bromo-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine and 6-Bromo-4-methyl-2-(4-(methylsulfonyl)phenyl)-4H-pyrrolo[3,2-b]pyridine [ka] At 0°C, 129 mg (3.23 mmol) of sodium hydride (60% oil dispersion) was added all at once to a 10 mL solution of 6-bromo-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine and iodomethane (459 mg, 3.23 mmol) in DMF. The mixture was stirred at room temperature for 1 hour. The reaction was stopped with acetic acid (0.370 mL, 6.46 mmol). The mixture was concentrated under reduced pressure to a volume of approximately 5 mL. The residue was diluted with methanol (10 mL) and injected in multiple steps into a preparative HPLC (column: Phenomenex Luna AXIA 5u C18 30.0 × 100. Solvent A: 90% H2O ~ 10% methanol - 0.1% TFA; Solvent B: 10% methanol ~ 90% H2O 0.1% TFA. Flow rate: 40 mL / min. Gradient time: 12 min. Start %B: 12; Final %B: 100). The fractions containing the same product were combined, concentrated under reduced pressure, basicized with saturated NaHCO3 solution, and extracted with dichloromethane (4 × 30 mL). The combined extracts were dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to obtain 6-bromo-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine (154 mg, 0.422 mmol, 32.6% yield) and 6-bromo-4-methyl-2-(4-(methylsulfonyl)phenyl)-4H-pyrrolo[3,2-b]pyridine (64 mg, 0.175 mmol, 13.56% yield). Both products were bright yellow solids. 6-Bromo-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine:LCMS (M+H) + = 365.0. 1¹H NMR (500 MHz, acetonitrile-d3) δ 8.50 (d, J=1.9 Hz, 1H), 8.11-8.06 (m, 3H), 7.90-7.84 (m, 2H), 6.85 (d, J=0.6 Hz, 1H), 3.79 (s, 3H), 3.16 (s, 3H) 6-Bromo-4-methyl-2-(4-(methylsulfonyl)phenyl)-4H-pyrrolo[3,2-b]pyridine:LCMS (M+H) + = 365.1. 1 ¹H NMR (500 MHz, acetonitrile-d3) δ 8.42-8.37 (m, 2H), 8.25 (s, 1H), 8.05 (d, J=1.3 Hz, 1H), 8.02-7.98 (m, 2H), 7.09 (d, J=0.6 Hz, 1H), 4.19 (s, 3H), 3.12 (s, 3H)

[0179] Step 3. 6-(4-(4-isopropylpiperazine-1-yl)phenyl)-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine 1,4-Dioxane (0.8 mL) contains 6-bromo-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine (21 mg, 0.057 mmol), 1-isopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (26.6 mg, 0.080 mmol), (2-disic A mixture of lohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (XPhos-Pd-G3) (4.87 mg, 5.75 μmol) and tripotassium phosphate (0.101 mL, 0.201 mmol) was degassed and heated in a sealed vial at 85°C for 15 hours. After cooling to room temperature, the reaction mixture was diluted with methanol, filtered through an Acrodisc, and injected into a preparative HPLC (column: Phenomenex Luna AXIA 5u C18 21.2×100; Solvent A: 90%H2O~10%Methanol-0.1%TFA; Solvent B: 10%Methanol~90%H2O 0.1%TFA; Flow rate: 20 mL / min; Gradient time: 15 min; Starting %B: 14; Final %B: 100). The collected fractions were concentrated under reduced pressure, basicized with 1N NaOH solution, and extracted with dichloromethane (4×40 mL). The combined extracts were dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to obtain 6-(4-(4-isopropylpiperazin-1-yl)phenyl)-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine (14 mg, 0.028 mmol, 49.3% yield) as a pale yellow solid. LC-MS (M+H) + = 489.5. 1H NMR (500 MHz, DMSO-d6) δ 8.71 (d, J=1.9 Hz, 1H), 8.18 (d, J=1.1 Hz, 1H), 8.09 (d, J=8.3 Hz, 2H), 7.97 (d, J=8.5 Hz, 2H), 7.70 (d, J=8.8 Hz, 2H), 7.07 (d, J=8.8 Hz, 2H), 6.90 (s, 1H), 3.90 (s, 3H), 3.30 (m, 3H), 3.24-3.18 (m, 4H), 2.70 (dt, J=13.1, 6.4 Hz, 1H), 2.64-2.59 (m, 4H), 1.03 (d, J = 6.6 Hz, 6H)

[0180] Example 3 6-(4-(4-isopropylpiperazine-1-yl)phenyl)-4-methyl-2-(4-(methylsulfonyl)phenyl)-4H-pyrrolo[3,2-b]pyridine [ka] 1,4-Dioxane (0.8 mL) containing 6-bromo-4-methyl-2-(4-(methylsulfonyl)phenyl)-4H-pyrrolo[3,2-b]pyridine (Step 2 of Example 2) (22 mg, 0.060 mmol), 1-isopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (26.9 mg, 0.081 mmol), ( A mixture of 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (XPhos-Pd-G3) (5.10 mg, 6.02 μmol) and tripotassium phosphate (0.105 mL, 0.211 mmol) was degassed and heated in a sealed vial at 85°C for 15 hours. After cooling to room temperature, the reaction mixture was diluted with methanol, filtered through an Acrodisc, and injected into a preparative HPLC (column: Phenomenex Luna AXIA 5u C18 21.2×100; Solvent A: 90%H2O~10%Methanol-0.1%TFA; Solvent B: 10%Methanol~90%H2O 0.1%TFA; Flow rate: 20 mL / min; Gradient time: 15 min; Starting %B: 10; Final %B: 100). The collected fractions were concentrated under reduced pressure, basicized with 1N NaOH, and extracted with dichloromethane (4×40 mL). The combined extracts were dried over anhydrous Na2SO4. By removing the solvent under reduced pressure, the product, 6-(4-(4-isopropylpiperazin-1-yl)phenyl)-4-methyl-2-(4-(methylsulfonyl)phenyl)-4H-pyrrolo[3,2-b]pyridine (12 mg, 0.024 mmol, 40.0% yield), was obtained as a pale yellow solid. LC-MS (M+H) + = 489.4. 1H NMR (500 MHz, DMSO-d6) δ 8.45 (d, J=0.9 Hz, 1H), 8.40 (d, J=8.5 Hz, 2H), 8.36 (s, 1H), 7.98 (d, J=8.5 Hz, 2H), 7.65 (d, J=8.8 Hz, 2H), 7.16 (s, 1H), 7.07 (d, J=8.8 Hz, 2H), 4.28 (s, 3H), 3.26 (s, 3H), 3.23-3.17 (m, 4H), 2.70 (quin, J=6.5 Hz, 1H), 2.63-2.58 (m, 4H), 1.03 (d, J=6.6 Hz, 6H)

[0181] Example 4 1-(4-(4-(2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-6-yl)phenyl)piperazine-1-yl)-2-methylpropane-2-ol [ka] Step 1. 2-Methyl-1-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-yl)propan-2-ol [ka] At 0°C, a mixture of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (150 mg, 0.520 mmol) and potassium carbonate (108 mg, 0.781 mmol) in MeOH (2 mL) was suddenly added to a solution of 2,2-dimethyloxirane (56.3 mg, 0.781 mmol) in DMF (0.2 mL). The mixture was stirred at room temperature for 28 hours, diluted with ethyl acetate (10 mL), and filtered through Celite. The filtrate was diluted with ethyl acetate (60 mL), washed with water (2 × 20 mL) and brine (20 mL), and dried over anhydrous MgSO4. The product, 2-methyl-1-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-1-yl)propan-2-ol (113 mg, 0.314 mmol, 60.3% yield), was isolated as a white solid by ISCO chromatography (24 g silica gel, solid-packed, 1-10% ethyl acetate / hexane). LC-MS (M+H) + = 361.3. 1 H NMR (500 MHz, chloroform-d) δ 7.73 (d, J=8.8 Hz, 2H), 6.91 (d, J=8.5 Hz, 2H), 3.35-3.25 (m, 4H), 2.88-2.76 (m, 4H), 2.41 (s, 2H), 1.35 (s, 12H), 1.22 (s, 6H)

[0182] Step 2. 1-(4-(4-(2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-6-yl)phenyl)piperazine-1-yl)-2-methylpropane-2-ol 6-bromo-2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine (20 mg, 0.058 mmol), 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-yl)propan-2-ol (28.0 mg, 0.078 mmol), in 1,4-dioxane (0.8 mL), A mixture of (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (XPhos-Pd-G3) (4.88 mg, 5.76 μmol) and tripotassium phosphate (0.101 mL, 0.202 mmol) was degassed and heated in a sealed vial at 85°C for 15 hours. After cooling to room temperature, the reaction mixture was diluted with methanol, filtered through an Acrodisc, and injected into a preparative HPLC (column: Phenomenex Luna AXIA 5u C18 21.2×100; Solvent A: 90%H2O~10%Methanol-0.1%TFA; Solvent B: 10%Methanol~90%H2O 0.1%TFA; Flow rate: 20 mL / min; Gradient time: 15 min; Starting %B: 15; Final %B: 100). The collected fractions were concentrated under reduced pressure, basicized with 1N NaOH, and extracted with dichloromethane (4×40 mL). The combined extracts were dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to obtain 1-(4-(4-(2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-6-yl)phenyl)piperazin-1-yl)-2-methylpropan-2-ol (18 mg, 0.036 mmol, 61.8% yield) as a pale blue solid. LC-MS (M+H) + = 501.5. 1H NMR (500 MHz, chloroform-d) δ 8.73 (d, J=1.9 Hz, 1H), 7.76 (d, J=1.1 Hz, 1H), 7.62 (d, J=8.8 Hz, 2H), 7.13 (dd, J=8.3, 1.9 Hz, 1H), 7.10-7.05 (m, 3H), 7.03 (d, J=8.3 Hz, 1H), 6.75 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H), 3.82 (s, 3H), 3.33-3.28 (m, 4H), 2.90-2.85 (m, 4H), 2.45 (s, 2H), 1.24 (s, 6H)

[0183] Example 5 (4-(2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-6-yl)phenyl)(4-isopropylpiperazine-1-yl)methanone [ka] Step 1. (4-Isopropylpiperazine-1-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone [ka] A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (100 mg, 0.403 mmol), 1-isopropylpiperazine (64.6 mg, 0.504 mmol), benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (267 mg, 0.605 mmol), and N,N-diisopropylethylamine (0.282 mL, 1.612 mmol) in DMF (1 mL) was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate (50 mL), washed sequentially with water (3 × 15 mL) and brine (15 mL), and dried over anhydrous MgSO4. The product, (4-isopropylpiperazin-1-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone (92 mg, 0.257 mmol, 63.7% yield), was isolated as a white solid by ISCO chromatography (24 g silica gel, solid-packed, 0-8% methanol / dichloromethane). LC-MS (M+H) + = 359.1

[0184] Step 2. (4-(2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-6-yl)phenyl)(4-isopropylpiperazine-1-yl)methanone 1,4-Dioxane (0.8 mL) contains 6-bromo-2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine (15 mg, 0.043 mmol), (4-isopropylpiperazine-1-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone (19.35 mg, 0.054 mmol), (2- A mixture of dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (XPhos-Pd-G3) (3.66 mg, 4.32 μmol) and tripotassium phosphate (0.076 mL, 0.151 mmol) was degassed and heated in a sealed vial at 85°C for 15 hours. After cooling to room temperature, the reaction mixture was diluted with methanol, filtered through an Acrodisc, and injected into a preparative HPLC (column: Waters Symmetry Shield 5u 19×100 mm; Solvent A: 90% H2O~10% methanol-0.1% TFA; Solvent B: 10% methanol~90% H2O 0.1% TFA; Flow rate: 20 mL / min; Gradient time: 15 min; Starting %B: 14; Final %B: 100). The collected fractions were combined, concentrated under reduced pressure, basicized with 1N NaOH solution, and extracted with dichloromethane (4×35 mL). The combined extract was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to obtain (4-(2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-6-yl)phenyl)(4-isopropylpiperazine-1-yl)methanone (2.4 mg, 4.67 μmol, 10.81% yield) as a colorless film. LC-MS (M+H) + = 499.3. 1H NMR (500 MHz, chloroform-d) δ 8.76 (d, J=1.7 Hz, 1H), 7.81 (d, J=0.8 Hz, 1H), 7.74 (d, J=8.3 Hz, 2H), 7.57 (d, J=8.3 Hz, 2H), 7.14 (dd, J=8.1, 1.8 Hz, 1H), 7.09 (d, J=1.7 Hz, 1H), 7.04 (d, J=8.3 Hz, 1H), 6.78 (s, 1H), 4.00 (s, 3H), 3.98 (s, 3H), 3.91-3.85 (m, 2H), 3.84 (s, 3H), 3.56 (br s, 2H), 2.78 (dt, J=12.9, 6.4 Hz, 1H), 2.70-2.48 (m, 4H), 1.10 (d, J=6.6 Hz, 6H)

[0185] Example 6 6-(4-(4-isobutylpiperazine-1-yl)phenyl)-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine [ka] Step 1. 1-Isobutyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine [ka] At room temperature, sodium triacetoxyborohydride (2.366 g, 11.16 mmol) was added all at once to a 15 mL solution of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (0.715 g, 2.481 mmol), isobutyraldehyde (0.789 mL, 8.68 mmol), magnesium sulfate (5.97 g, 49.6 mmol), and acetic acid (1.420 mL, 24.81 mmol) in DMF (15 mL). The mixture was stirred at room temperature for 60 hours. The heterogeneous mixture was diluted with ethyl acetate (20 mL) and filtered through Celite. The filtrate was further diluted with ethyl acetate (80 mL), washed with saturated NaHCO3 solution (25 mL), water (2 × 25 mL), and brine (25 mL), and dried over anhydrous MgSO4. The product, 1-isobutyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (0.444 g, 1.290 mmol, 52.0% yield), was isolated as a white solid by ISCO chromatography (40 g silica gel, solid-packed, 0-5% methanol / dichloromethane). LC-MS (M+H) + = 345.3. 1 H NMR (500 MHz, chloroform-d) δ 7.72 (d, J=8.3 Hz, 2H), 6.91 (d, J=8.3 Hz, 2H), 3.37-3.20 (m, 4H), 2.65-2.49 (m, 4H), 2.15 (d, J=7.4 Hz, 2H), 1.84 (dt, J=13.5, 6.7 Hz, 1H), 1.35 (s, 12H), 0.95 (d, J=6.6 Hz, 6H)

[0186] Step 2. 6-(4-(4-isobutylpiperazine-1-yl)phenyl)-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine 1,4-Dioxane (1.5 mL) contains 6-bromo-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine (40 mg, 0.110 mmol), 1-isobutyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (52.8 mg, 0.153 mmol), (2-dicyclohexylphosphino-2',4',6'-triisopropyl- A mixture of 1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (XPhos-Pd-G3 (9.27 mg, 10.95 μmol) and tripotassium phosphate (0.192 mL, 0.383 mmol) was degassed and heated in a sealed vial at 85°C for 15 hours. After cooling to room temperature, the reaction mixture was diluted with methanol, filtered through an Acrodisc, and preparative HPLC (column: Phenomenex) was performed. Luna AXIA 5u C18 21.2×100. Solvent A: 90% H2O ~ 10% methanol - 0.1% TFA; Solvent B: 10% methanol ~ 90% H2O 0.1% TFA. Flow rate: 20 mL / min. Gradient time: 15 min. Injected into (starting %B: 11; final %B: 100). The collected fraction was concentrated under reduced pressure, basicized with 1N NaOH solution, and extracted with dichloromethane (4 × 40 mL). The combined extract was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to obtain 6-(4-(4-isobutylpiperazine-1-yl)phenyl)-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine (30 mg, 0.058 mmol, 53.4% ​​yield) as a pale yellow solid. LCMS (M+H) + = 503.4. 1H NMR (400 MHz, chloroform-d) δ 8.78 (d, J=1.8 Hz, 1H), 8.13-8.07 (m, 2H), 7.82-7.76 (m, 3H), 7.62 (d, J=8.6 Hz, 2H), 7.08 (d, J=8.8 Hz, 2H), 6.89 (s, 1H), 3.85 (s, 3H), 3.33-3.28 (m, 4H), 3.16 (s, 3H), 2.65-2.58 (m, 4H), 2.19 (d, J=7.4 Hz, 2H), 1.86 (dt, J=13.5, 6.7 Hz, 1H), 0.97 (d, J=6.7 Hz, 6H)

[0187] Example 7 2-(3,4-dimethoxyphenyl)-6-(4-(4-isopropylpiperazine-1-yl)phenyl)-1-methyl-1H-pyrrolo[2,3-b]pyridine [ka] Step 1. N-(6-chloro-3-iodopyridine-2-yl)-N-(methylsulfonyl)methanesulfonamide [ka] At 0°C, methanesulfonyl chloride (3.04 mL, 39.3 mmol) was added over 10 minutes to a pyridine (20 mL) solution of 6-chloro-3-iodopyridine-2-amine (2.0 g, 7.86 mmol). The mixture was stirred at room temperature for 36 hours. The mixture was diluted with dichloromethane (50 mL) and filtered through Celite. The filtrate was concentrated to dryness under reduced pressure. Ethyl acetate (180 mL) was added to the residue, and the mixture was filtered through Celite. The filtrate was washed sequentially with water (3 × 40 mL) and brine (40 mL) and dried over anhydrous MgSO4. The product, N-(6-chloro-3-iodopyridine-2-yl)-N-(methylsulfonyl)methanesulfonamide (1.89 g, 4.60 mmol, 58.6% yield), was isolated as a beige solid by ISCO chromatography (220 g silica gel, 10-50% ethyl acetate / hexane). LC-MS (M+H)+ = 410.9

[0188] Step 2. N-(6-chloro-3-iodopyridine-2-yl)methanesulfonamide [ka] At room temperature, 11 mL of 10% sodium hydroxide (11 mL, 30.3 mmol) was added over 3 minutes to a suspension of N-(6-chloro-3-iodopyridine-2-yl)-N-(methylsulfonyl)methanesulfonamide (1.89 g, 4.60 mmol) in THF (11 mL). The mixture was stirred at room temperature for 14 hours and then concentrated under reduced pressure to approximately 10 mL. The residue was diluted with water (10 mL) and neutralized with concentrated hydrochloric acid to pH 6-7. The precipitated product, N-(6-chloro-3-iodopyridine-2-yl)methanesulfonamide (1.46 g, 4.39 mmol, 95% yield), was collected as a beige solid by suction filtration and dried under reduced pressure at 50°C. LCMS (M+H) + = 332.8. 1 H NMR (500 MHz, DMSO-d6) δ 10.06 (br s, 1H), 8.28 (d, J=8.3 Hz, 1H), 7.08 (d, J=8.3 Hz, 1H), 3.34 (s, 3H)

[0189] Step 3. 6-Chloro-2-(3,4-dimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine [ka] A mixture of N-(6-chloro-3-iodopyridine-2-yl)methanesulfonamide (600 mg, 1.804 mmol), 4-ethynyl-1,2-dimethoxybenzene (439 mg, 2.71 mmol), bis(triphenylphosphine)palladium(II) chloride (76 mg, 0.108 mmol), and copper(I) iodide (20.62 mg, 0.108 mmol) in DMF (8 mL) was degassed and heated in a sealed vial at 100°C for 15 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate (30 mL) and filtered through Celite. The filtrate was concentrated to dryness under reduced pressure. The residue was diluted with ethyl acetate (150 mL), washed sequentially with water (2 × 30 mL) and brine (30 mL), and dried over anhydrous MgSO4. The product, 6-chloro-2-(3,4-dimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine (154 mg, 0.533 mmol, 29.6% yield), was isolated as a yellowish-brown solid by ISCO chromatography (80 g silica gel, 0-5% methanol / dichloromethane). LC-MS (M+H) + = 289.1. 1 H NMR (500 MHz, DMSO-d6) δ 12.30 (s, 1H), 7.95 (d, J=8.3 Hz, 1H), 7.52 (d, J=1.9 Hz, 1H), 7.48 (dd, J=8.4, 2.1 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H), 7.06 (d, J=8.3 Hz, 1H), 6.90 (d, J=1.9 Hz, 1H), 3.87 (s, 3H), 3.81 (s, 3H)

[0190] Step 4. 6-Chloro-2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[2,3-b]pyridine [ka] At 0°C, 52.6 mg (1.316 mmol) of sodium hydride (60% oil dispersion) was added all at once to a 5 mL solution of 6-chloro-2-(3,4-dimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine (152 mg, 0.526 mmol) and iodomethane (187 mg, 1.316 mmol) in DMF (5 mL). The mixture was stirred at room temperature for 1 hour. The reaction was stopped with acetic acid (0.5 mL). The mixture was diluted with ethyl acetate (150 mL). The resulting solution was successively washed with 1 N K2HPO4 solution (2 × 35 mL), water (2 × 35 mL), and brine (35 mL), and dried over anhydrous MgSO4. The product, 6-chloro-2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (175 mg, 0.578 mmol, 110% yield), was isolated as a yellowish-brown solid by ISCO chromatography (40 g silica gel, 10-50% ethyl acetate). LC-MS (M+H) + = 303.3

[0191] Step 5. 2-(3,4-dimethoxyphenyl)-6-(4-(4-isopropylpiperazine-1-yl)phenyl)-1-methyl-1H-pyrrolo[2,3-b]pyridine 1,4-Dioxane (1 mL) contains 6-chloro-2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (25 mg, 0.074 mmol), 1-isopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (30.7 mg, 0.093 mmol), (2-dicyclohex A mixture of sylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (XPhos-Pd-G3) (6.29 mg, 7.43 μmol) and tripotassium phosphate (0.130 mL, 0.260 mmol) was degassed and heated in a sealed vial at 80°C for 15 hours. After cooling to room temperature, the reaction mixture was diluted with methanol, filtered through an Acrodisc, and injected into a preparative HPLC (column: Phenomenex Luna AXIA 5u C18 21.2×100; Solvent A: 90%H2O~10%Methanol-0.1%TFA; Solvent B: 10%Methanol~90%H2O 0.1%TFA; Flow rate: 20 mL / min; Gradient time: 15 min; Starting %B: 22; Final %B: 100). The collected fractions were concentrated under reduced pressure, basicized with 1N NaOH solution, and extracted with dichloromethane (4×40 mL). The combined extracts were dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to obtain 2-(3,4-dimethoxyphenyl)-6-(4-(4-isopropylpiperazin-1-yl)phenyl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (19 mg, 0.040 mmol, 53.8% yield) as a pale blue solid. LC-MS (M+H) + = 471.4. 1H NMR (500 MHz, DMSO-d6) δ 8.06 (d, J=9.1 Hz, 2H), 7.95 (d, J=8.2 Hz, 1H), 7.62 (d, J=8.2 Hz, 1H), 7.24-7.19 (m, 2H), 7.12 (d, J=8.2 Hz, 1H), 7.04 (d, J=9.1 Hz, 2H), 6.56 (s, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 3.84 (s, 3H), 3.25-3.19 (m, 4H), 2.74-2.66 (m, 1H), 2.63-2.58 (m, 4H), 1.03 (d, J = 6.6 Hz, 6H)

[0192] The compounds in Examples 8-19 of Table 1 were prepared according to the synthesis routes described for the production of Examples 1-7. [Table 1] [Table 2]

[0193] [Table 3] [Table 4]

[0194] Example 19 2-methyl-4-(4-(4-(1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine-6-yl)benzyl)piperazine-1-yl)butan-2-ol [ka] Step 1. Benzyl 4-(3-hydroxy-3-methylbutyl)piperazine-1-carboxylate [ka] At 0°C, a mixture of benzylpiperazine-1-carboxylate (150 mg, 0.681 mmol) and potassium carbonate (188 mg, 1.362 mmol) in DMF (2 mL) was suddenly added to a solution of 4-bromo-2-methylbutan-2-ol (143 mg, 0.858 mmol) in DMF (0.2 mL). The mixture was stirred at room temperature for 60 hours, diluted with ethyl acetate (10 mL), and filtered through Celite. The filtrate was diluted with ethyl acetate (60 mL), washed with water (2 × 20 mL) and brine (20 mL), and dried over anhydrous MgSO4. The title intermediate (110 mg, 0.359 mmol, 52.7% yield) was isolated as a white solid by ISCO chromatography (24 g silica gel, solid-packed, 1-8% ethyl acetate / hexane). LCMS (M+H) + = 307.4. 1 ¹H NMR (400 MHz, chloroform-d) δ 7.39-7.29 (m, 5H), 5.13 (s, 2H), 3.55-3.48 (m, 4H), 2.68-2.60 (m, 2H), 2.49 (br s, 4H), 1.66-1.61 (m, 2H), 1.23 (s, 6H)

[0195] Step 2. 2-Methyl-4-(piperazine-1-yl)butan-2-ol [ka] A mixture of benzyl 4-(3-hydroxy-3-methylbutyl)piperazine-1-carboxylate (105 mg, 0.343 mmol) and 10% Pd / C (22.98 mg, 0.022 mmol) in MeOH (9 mL) and THF (3 mL) was stirred at room temperature for 3.5 hours under H2 supplied by an H2 balloon. The catalyst was removed by suction filtration through Celite. Solvent removal under reduced pressure yielded the title intermediate (56 mg, 0.325 mmol, 95% yield) as a white solid, which was used in the next step without further purification. LCMS (M+H) + = 173.2

[0196] Step 3. 6-Chloro-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine [ka] At room temperature, 1-ethynyl-4-methylsulfonylbenzene (6.0 g, 33.74 mmol), CuI (459 mg, 2.41 mmol), t-BuOK (5.4 g, 48.2 mmol), and Pd(PPh3)2Cl2 (500 mg, 0.43 mmol) were added simultaneously to a 50 mL DMF solution of 2-bromo-5-chloropyridine-3-amine (5.0 g, 24.1 mmol). The resulting mixture was degassed three times with nitrogen and stirred at 100°C for 3 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with brine, and dried over Na2SO4. After removing the solvent under reduced pressure, the residue was purified by silica flash chromatography using a 1:1 petroleum ether / ethyl acetate eluent to obtain the title intermediate (1.937 g, 5.8 mmol, 24% yield) as a yellow solid. LCMS (M+H) + = 307.1. 1 H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H), 8.37 (s, 1H), 8.20 (d, J = 8.4 Hz, 2H), 8.05 (d, J = 8.8 Hz, 2H), 7.89 (s, 1H), 7.35 (s, 1H), 3.28 (s, 3H)

[0197] Step 4. 6-Chloro-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine [ka] At room temperature, Cs2CO3 (8.52 g, 26.14 mmol) was gradually added to a solution of 6-chloro-2-(4-methylsulfonylphenyl)-1H-pyrrolo[3,2-b]pyridine (5.0 g, approximately 80% purity, 13.07 mmol) and MeI (2.03 g, 14.38 mmol) in DMF (60 mL). The resulting mixture was stirred at room temperature for 1 hour, then diluted with RINKAN (100 mL), washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography (column: XSelect CSH Prep C18 OBD column, 19 × 250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 50 mL / min; gradient: 25%B to 40%B over 15 minutes; UV detection at 254 / 210 nm) to obtain 6-chloro-1-methyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-b]pyridine (1.73 g, 5.22 mmol, 41.4% yield) as a grayish-white solid. LCMS (M+H) + = 321.1. 1 H NMR (300 MHz, DMSO-d6) δ 8.40 (s, 1H), 8.23 ​​(s, 1H), 8.09 (d, J = 6.9 Hz, 2H), 7.95 (d, J = 8.4 Hz, 2H), 6.92 (s, 1H), 3.83 (s, 3H), 3.29 (s, 3H)

[0198] Step 5. 4-(1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine-6-yl)benzaldehyde [ka] A mixture of 1,4-dioxane (10 mL), 6-chloro-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine (300 mg, 0.935 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (271 mg, 1.169 mmol), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (XPhos-Pd-G3) (79 mg, 0.094 mmol), and tripotassium phosphate (1.637 mL, 3.27 mmol) was degassed and heated in a sealed vial at 110°C for 8 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate (30 mL) and filtered through Celite. The filtrate was concentrated under reduced pressure and dried to dryness. The residue was dissolved in ethyl acetate (150 mL), washed with brine (25 mL), and dried over anhydrous MgSO4. The title intermediate (261 mg, 0.668 mmol, 71.5% yield) was isolated as a yellow solid by ISCO chromatography (40 g silica gel, solid packing, 40-100% ethyl acetate). LC-MS (M+H) + = 391.0. 1 H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.87 (d, J=2.0 Hz, 1H), 8.45 (d, J=1.4 Hz, 1H), 8.15-8.08 (m, 4H), 8.08-8.03 (m, 2H), 8.00 (d, J=8.4 Hz, 2H), 6.97 (s, 1H), 3.94 (s, 3H), 3.33 (s, 3H)

[0199] Step 6. 2-Methyl-4-(4-(4-(1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine-6-yl)benzyl)piperazine-1-yl)butan-2-ol At room temperature, sodium triacetoxyborohydride (87 mg, 0.410 mmol) was added all at once to a solution of 4-(1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine-6-yl)benzaldehyde (40 mg, 0.102 mmol), 2-methyl-4-(piperazine-1-yl)butan-2-ol (52.9 mg, 0.307 mmol), magnesium sulfate (247 mg, 2.049 mmol), and acetic acid (0.059 mL, 1.024 mmol) in DMF (1.2 mL). The mixture was stirred at room temperature for 18 hours. The heterogeneous mixture was diluted with ethyl acetate (5 mL) and filtered through Celite. The filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in MeOH and injected into a preparative HPLC. The collected fractions were combined, concentrated under reduced pressure, basicized with 1N NaOH solution, and extracted with dichloromethane (4 × 35 mL). The combined extract was dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure to obtain the title product (22.5 mg, 0.040 mmol, 39.4% yield) as a white solid. LC-MS (M+H) + = 547.2. 1 H NMR (400 MHz, chloroform-d) δ 8.80 (d, J=2.0 Hz, 1H), 8.15-8.09 (m, 2H), 7.87-7.84 (m, 1H), 7.82-7.76 (m, 2H), 7.67 (d, J=8.0 Hz, 2H), 7.48 (br d, J=6.7 Hz, 2H), 6.92 (d, J=0.8 Hz, 1H), 3.87 (s, 3H), 3.69 (br s, 2H), 3.16 (s, 3H), 3.01-2.61 (m, 6H), 1.97-1.50 (m, 6H), 1.27 (s, 6H)

[0200] Example 20 1-Methyl-2-(4-(methylsulfonyl)phenyl)-6-(4-(piperazin-1-yl)phenyl)-1H-pyrrolo[3,2-b]pyridine [ka] Step 1. Tert-butyl 4-(4-(1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine-6-yl)phenyl)piperazine-1-carboxylate [ka] 6-chloro-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine (Example 19, Step 4) (80 mg, 0.249 mmol) and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (121 mg, 0.312 mmol) in 1,4-dioxane (4 mL) A mixture of (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (XPhos-Pd-G3) (21.11 mg, 0.025 mmol) and tripotassium phosphate (0.436 mL, 0.873 mmol) was degassed and heated in a sealed vial at 110°C for 7 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate (60 mL), washed with brine (15 mL), and dried over anhydrous MgSO4. The title product (95 mg, 0.170 mmol, 68.3% yield) was isolated as a pale yellow solid by ISCO chromatography (40 g silica gel, 0-4% methanol / dichloromethane). LCMS (M+H) + = 547.2. 1 H NMR (400 MHz, chloroform-d) δ 8.76 (d, J=2.0 Hz, 1H), 8.09 (d, J=8.4 Hz, 2H), 7.80-7.74 (m, 3H), 7.61 (d, J=8.8 Hz, 2H), 7.06 (d, J=8.8 Hz, 2H), 6.88 (s, 1H), 3.83 (s, 3H), 3.66-3.59 (m, 4H), 3.26-3.18 (m, 4H), 3.14 (s, 3H), 1.50 (s, 9H)

[0201] Step 2. 1-Methyl-2-(4-(methylsulfonyl)phenyl)-6-(4-(piperazin-1-yl)phenyl)-1H-pyrrolo[3,2-b]pyridine At 0°C, tert-butyl 4-(4-(1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine-6-yl)phenyl)piperazine-1-carboxylate (90 mg, 0.165 mmol) was dissolved in dichloromethane (2 mL), to which TFA (2 mL) was added over 1 minute. The mixture was stirred at 0°C for 1 hour, then concentrated under reduced pressure to dryness. Saturated NaHCO3 solution was added to the residue. The mixture was extracted with dichloromethane (4 × 40 mL). The combined extracts were dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to obtain the title product (61 mg, 0.134 mmol, 81% yield) as a yellow solid. LCMS (M+H) + = 447.1. 1 H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J=2.0 Hz, 1H), 8.19 (d, J=1.2 Hz, 1H), 8.09 (d, J=8.4 Hz, 2H), 7.97 (d, J=8.4 Hz, 2H), 7.73 (d, J=8.8 Hz, 2H), 7.09 (d, J=9.0 Hz, 2H), 6.90 (s, 1H), 3.90 (s, 3H), 3.32 (s, 3H), 3.27-3.22 (m, 4H), 3.07-2.99 (m, 4H)

[0202] The following example compounds were prepared using appropriate starting materials, reactants, and conditions by the general method described herein. [Table 5] [Table 6]

[0203] [Table 7] [Table 8]

[0204] Example 37 2-(4-cyclopropylsulfonylphenyl)-1-methyl-6-[1-[rac-(1S,5R)-8-isobutyl-8-azabicyclo[3.2.1]octan-3-yl]-4-piperidyl]pyrrolo[3,2-b]pyridine [ka] Step 1. ((4-(cyclopropylsulfonyl)phenyl)ethynyl)trimethylsilane [ka] To a THF (20 mL) solution of 1-bromo-4-cyclopropylsulfonylbenzene (2.6 g, 9.96 mmol) and Et3N (4.16 mL, 29.87 mmol) while stirring, CuI (189.6 mg, 1 mmol), Pd(PPh3)2Cl2 (697.94 mg, 1 mmol), and ethinyl(trimethyl)silane (1.47 g, 14.93 mmol) were added at 0°C. The resulting solution was degassed three times with nitrogen and stirred under a nitrogen atmosphere at room temperature for 2 hours. The mixture was then concentrated and purified by column chromatography using petroleum ether / siRNA (2:1) as the eluent to obtain the title compound (1.7 g, 6.1 mmol, 61.3% yield) as a brown solid. LCMS (M+H) + = 279.1

[0205] Step 2. 1-(cyclopropylsulfonyl)-4-ethynylbenzene [ka] To a 20 mL solution of 2-(4-cyclopropylsulfonylphenyl)ethynyl-trimethyl-silane (1.7 g, 6.11 mmol) in THF (20 mL) while stirring, TBAF (1 M solution in THF) (2.44 mL, 2.44 mmol) was added. The resulting solution was stirred at room temperature under a nitrogen atmosphere for 10 minutes. The mixture was then concentrated and purified by column chromatography using petroleum ether / siRNA (2:1) as the eluent to obtain the title compound (720 mg, 3.49 mmol, 57.2% yield) as a yellow solid. 1 ¹H NMR (400 MHz, chloroform-d) δ 7.91-7.85 (m, 2H), 7.70-7.65 (m, 2H), 3.30 (s, 1H), 2.51-2.44 (m, 1H), 1.40-1.30 (m, 2H), 1.10-1.03 (m, 2H)

[0206] Step 3. 6-Chloro-2-(4-(cyclopropylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine [ka] To a 5 mL solution of 2-bromo-5-chloropyridine-3-amine (350 mg, 1.69 mmol) and 1-cyclopropylsulfonyl-4-ethynylbenzene (348 mg, 1.69 mmol) in DMF, CuI (32.1 mg, 0.17 mmol), Pd(PPh3)2Cl2 (118.2 mg, 0.17 mmol), and Et3N (0.71 mL, 5.06 mmol) were added while stirring. The resulting solution was degassed three times with nitrogen and stirred overnight at 90°C under a nitrogen atmosphere. The reaction was then stopped with water, and the mixture was extracted with  (3 × 30 mL). The organic layer was washed with NaCl solution, dried over Na2SO4, and concentrated. The crude product was dissolved in 5 mL of DMF, and t-BuOK (566.7 mg, 5.06 mmol) was added. The resulting solution was degassed three times with nitrogen and stirred overnight at 90°C. The reaction was then stopped with water, and the mixture was extracted with toluene (3 × 30 mL). The organic layer was washed with NaCl solution, dried over Na₂SO₄, and concentrated. The crude product was purified by column chromatography using petroleum ether / toluene (1:1) as the eluent to obtain the title compound (281 mg, 0.76 mmol, 63.8% yield) as a brown solid. LC-MS (M+H) + = 333.1

[0207] Step 4. 6-Chloro-2-(4-cyclopropylsulfonylphenyl)-1-methylpyrrolo[3,2-b]pyridine [ka] To a solution of 6-chloro-2-(4-cyclopropylsulfonylphenyl)-1H-pyrrolo[3,2-b]pyridine (350 mg, 1.05 mmol) in DMF (8 mL), CH3I (0.2 mL, 1.09 mmol) and Cs2CO3 (700 mg, 2.15 mmol) were added at room temperature. After stirring for 1 hour, the mixture was diluted with water, extracted with Âx (3 × 50 mL), washed with water (3 × 50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was then purified by silica gel chromatography to obtain the title compound (150 mg, 41.1% yield) as a bright yellow solid. LCMS (M+H) + = 347.1

[0208] Step 5. 2-(4-cyclopropylsulfonylphenyl)-1-methyl-6-(4-piperidyl)pyrrolo[3,2-b]pyridine [ka] A mixture of 6-chloro-2-(4-cyclopropylsulfonylphenyl)-1-methyl-pyrrolo[3,2-b]pyridine (140 mg, 0.4 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (190 mg, 0.61 mmol) in 1,4-dioxane (8 mL) was mixed with a solution of K3PO4 (260 mg, 1.23 mmol) in water (2 mL). Xphos Pd G3 (70 mg, 0.08 mmol) was added to the mixture. The resulting mixture was degassed three times with nitrogen and stirred overnight at 90°C. The mixture was then cooled, diluted with water (100 mL), and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with water (3 × 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography. The resulting intermediate was dissolved in MeOH (8 mL) and degassed three times with nitrogen. Pd / C (20 mg) was added to this mixture, and the reaction vessel was evacuated three times and backfilled with nitrogen, then backfilled with hydrogen (1 atm). After stirring for 3 hours, the catalyst was filtered, and the filtrate was concentrated. The residue was then dissolved in DCM (8 mL) and HCl (4 M solution in 1,4-dioxane) (2 mL). After 1 hour, the solvent was concentrated, and the product was dried under reduced pressure to obtain the title compound (70 mg crude) as a bright yellow solid. LCMS (M+H) + = 396.5

[0209] Step 6. Example 37 NaBH3CN (320 mg, 5 mmol) was added to a THF solution of ZnCl2 (2 mL). The mixture was stirred at room temperature for 30 minutes. To this mixture, a methanol solution of 2-(4-cyclopropylsulfonylphenyl)-1-methyl-6-(4-piperidyl)pyrrolo[3,2-b]pyridine (100 mg, 0.25 mmol) and 8-isobutyl-8-azabicyclo[3.2.1]octan-3-one (600 mg, 3.31 mmol) was added. The resulting mixture was stirred at 60°C. After 18 hours, the solvent was concentrated, and the crude mixture was purified by reverse-phase chromatography flash and preparative HPLC (10 mmol / L NH4HCO3) and B:ACN (40%B to 50%B over 5.5 minutes); flow rate: 20 mL / min; detector: UV254 / 210 nm) to obtain the title compound (19.2 mg, 13.2% yield) as a grayish-white solid. 1 H NMR (400 MHz, methanol-d4) δ 8.31 (d, J = 1.8 Hz, 1H), 8.09-8.07 (m, 2H), 7.90-7.86 (m, 3H), 6.79 (s, 1H), 3.86 (s, 3H), 3.21 (d, J = 11.4 Hz, 2H), 2.81-2.75 (m, 2H), 2.71-2.61 (m, 1H), 2.33-2.26 (m, 4H), 2.05-1.75 (m, 13H), 1.72-1.63 (m, 2H), 1.32-1.29 (m, 2H), 1.15-1.12 (m, 2H), 0.97 (d, J = 6.6 Hz, 6H). LCMS (M+H) + = 561.2

[0210] Example 38 4-[6-[4-(4-isopropylpiperazine-1-yl)phenyl]-1-methyl-pyrrolo[3,2-b]pyridine-2-yl]-2-methoxy-benzonitrile [ka] Step 1. 2-Methoxy-4-(2-trimethylsilylethynyl)benzonitrile [ka] To a solution of 4-bromo-2-methoxybenzonitrile (1 g, 4.72 mmol) in THF (10 mL), ethynyl(trimethyl)silane (2.3 g, 23.58 mmol), TEA (3.3 mL, 23.58 mmol), Pd(pph3)2Cl2 (0.33 g, 0.47 mmol), and CuI (0.09 g, 0.47 mmol) were added. The resulting mixture was degassed three times with nitrogen and stirred at room temperature. After 2 hours, the mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica column chromatography using petroleum ether / ethyl acetate (10:1) as the eluent to obtain the title compound (1 g, 92.5% yield) as a yellow oil. LCMS (M+H) + = 230.2

[0211] Step 2. 4-Ethynyl-2-methoxy-benzonitrile [ka] To a methanol (10 mL) solution of 2-methoxy-4-(2-trimethylsilylethynyl)benzonitrile (1 g, 4.36 mmol), K2CO3 (1.2 g, 8.72 mmol) was added at 0°C. After stirring at room temperature for 5 minutes, the mixture was purified by silica column chromatography using petroleum ether / ethyl acetate (10:1) as the eluent to obtain the title compound (600 mg, 87.6% yield) as a yellow solid. LCMS (M+H) + = 158.2

[0212] Step 3. 4-(6-chloro-1H-pyrrolo[3,2-b]pyridine-2-yl)-2-methoxy-benzonitrile [ka] To a solution of 2-bromo-5-chloropyridine-3-amine (655 mg, 3.16 mmol) in DMF (5 mL), 4-ethynyl-2-methoxybenzonitrile (600 mg, 3.82 mmol), t-BuOK (855.1 mg, 7.64 mmol), CuI (72.5 mg, 0.38 mmol), and Pd(pph3)2Cl2 (267.6 mg, 0.38 mmol) were added. The resulting mixture was degassed three times with nitrogen and stirred at 100°C for 2 hours. The reaction product was then concentrated under reduced pressure, diluted with water (30 mL), and extracted with DCM (3 × 30 mL). The combined organic extract was washed with water (2 × 30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative flash filtration (column: SunFire Prep C18 OBD column, 19 × 150 mm 5 μm 10 nm; mobile phase A: water (0.05% NH4HCO3), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 60% B to 80% B over 5 minutes; 254 / 210 nm) to obtain the title compound (160 mg, 14.8% yield) as a yellow solid. LC-MS (M+H) + = 284

[0213] Step 4. 4-(6-chloro-1-methyl-pyrrolo[3,2-b]pyridine-2-yl)-2-methoxy-benzonitrile [ka] To a solution of 4-(6-chloro-1H-pyrrolo[3,2-b]pyridine-2-yl)-2-methoxybenzonitrile (160 mg, 0.56 mmol) and CH3I (0.13 mL, 0.68 mmol) in DMF (5 mL), Cs2CO3 (367.5 mg, 1.13 mmol) was added at 0°C. The mixture was stirred at room temperature for 1 hour. The resulting mixture was then diluted with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica column chromatography using ethyl acetate as the eluent to obtain the title compound (40 mg, 23.8% yield) as a yellow solid. LCMS (M+H) + = 298.1

[0214] Step 5. Example 38 To a solution of 4-(6-chloro-1-methyl-pyrrolo[3,2-b]pyridine-2-yl)-2-methoxybenzonitrile (30 mg, 0.1 mmol) and 1-isopropyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine (66.6 mg, 0.2 mmol) in 1,4-dioxane (2.5 mL) and water (0.5 mL), K3PO4 (64.2 mg, 0.3 mmol) and XPhos Pd G3 (8.5 mg, 0.01 mmol) were added. The resulting mixture was degassed three times with nitrogen and stirred at 90°C for 2 hours. The mixture was then cooled to room temperature, diluted with water, and extracted with ethyl acetate (3 ×). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by silica column chromatography using DCM / methanol (10:1) as the eluent to obtain the title compound (25.1 mg, 53.2%) as a yellow solid. 1 H NMR (300 MHz, chloroform-d) δ 8.76 (s, 1H), 7.77 (s, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.22-7.12 (m, 2H), 7.07 (d, J = LCMS (M+H) + = 466.2

[0215] The following example compounds were prepared using appropriate starting materials, reactants, and conditions by the general method described elsewhere here. [Table 9]

[0216] [Table 10]

[0217] Biological assays The pharmacological properties of the compounds of the present invention can be confirmed by several biological assays. The following exemplary biological assays have been performed with the compounds of the present invention.

[0218] TLR7 / 8 / 9 Inhibition Reporter Assay HEK-Blue overexpressing human TLR7, TLR8, or TLR9 receptors TM Using cells (Invivogen), inhibitors of these receptors were screened using inducible SEAP (secreted embryonic alkaline phosphatase) reporter genes fused to five NF-κB and AP-1 binding sites under the control of a minimal IFN-β promoter. Briefly, cells were seeded in Greiner 384-well plates (15,000 cells per well for TLR7, 20,000 cells for TLR8, and 25,000 cells for TLR9), then treated with DMSO solution of the compound to a final dose-response concentration ranging from 0.05 nM to 50 μM. After 30 minutes of pretreatment with the compound at room temperature, cells were stimulated with TLR7 ligand (gardikimod at a final concentration of 7.5 μM), TLR8 ligand (R848 at a final concentration of 15.9 μM), or TLR9 ligand (ODN2006 at a final concentration of 5 nM) to activate NF-κB and AP-1, which induce SEAP production. After incubation for 22 hours at 37°C and 5% CO2, the SEAP level was measured according to the manufacturer's specifications. HEK-Blue is a cell culture medium that enables SEAP detection. TM The detection reagent (Invivogen) is added to determine the result. Percent inhibition is determined as the percentage reduction in HEK-Blue signal present in wells treated with the agonist and DMSO alone, compared to wells treated with a known inhibitor.

[0219] [Table 11-1] [Table 11-2] nd: Not measured

Claims

1. Equation (Ia-2): 【Chemistry 1】 [During the ceremony, G is F, -CN, -OCH ３ , -S(O) ２ CH ３ , -S(O) ２ (Cyclopropyl) or -S(O) ２ N(CH ３ ) ２ A phenyl compound substituted with one or two substituents independently selected from; A is piperidinyl, phenyl, pyridinyl, pyrimidinyl, 6-azabicyclo[3.2.1]octanyl or azabicyclo[3.2.1]octanyl, each being -L-R ４ and 0 to 1 R ４ｂ and is substituted; L represents a bond, -CH ２ - or -C(O)-; R １ is hydrogen or -CH ３ And; R ３ is hydrogen; R ４ teeth: (i) piperidinyl, piperazinyl, pyridinyl, azabicyclo[3.2.1]octanyl, or diazabicyclo[3.2.1]octanyl, each containing 0 to 1 R ４ａ and 0 to 2 -CH ３ It is replaced by; or (ii) 【Chemistry 2】 And; R ４ａ -OH, -CH ３ ien-CH ２ CH ３ , -CH(CH ３ ) ２ ien-CH ２ CH(CH ３ ) ２ ien-CH ２ C(CH ３ ) ２ OH, -CH ２ CH ２ C(CH ３ ) ２ OH, -CH ２ (Cyclopropyl) or cyclopropyl; R 4b is F, Cl or -CH3; and Each R ５ is hydrogen or -CH ３ is] Compounds or salts thereof.

2. G is The compound according to claim 1 or a salt thereof.

3. G 【Transformation 3】 The compound according to claim 1 or a salt thereof.

4. R １ ga-CH ３ And; Each R ５ is hydrogen; G is -S(O) ２ CH ３ It is a phenyl that is substituted with; A is -L-R ４ It is a piperidinyl, phenyl, or pyridinyl substituted with; and R ４ but: (i) piperidinyl, piperazinyl, or pyridinyl, each containing 0 to 1 R ４ａ and 0 to 2 -CH ３ It is replaced by; or (ii) 【Chemistry 4】 That is, The compound according to claim 1 or a salt thereof.

5. G is F or -OCH ３ A phenyl compound substituted with one or two substituents independently selected from; A is piperidinyl or phenyl, and each is -L-R ４ It has been replaced with; L is bonded or -CH ２ - and; R ４ is piperazinyl or azabicyclo[3.2.1]octanyl, each containing 0 to 1 R ４ａ It is replaced by; and R ４ａ ga-CH ２ CH ３ , -CH(CH ３ ) ２ ien-CH ２ CH (CH ３ ) ２ ien-CH ２ C (CH ３ ) ２ OH, -CH ２ (Cyclopropyl), or is cyclopropyl The compound according to claim 1 or a salt thereof.

6. the below described: A compound according to claim 1 or a pharmaceutically acceptable salt thereof having the structure of the compound according to claim 1.

7. The following compounds or their salts: 2-(3,4-dimethoxyphenyl)-6-(4-(4-isopropylpiperazine-1-yl)phenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine(1); 6-(4-(4-isopropylpiperazine-1-yl)phenyl)-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine(2); 1-(4-(4-(2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-6-yl)phenyl)piperazine-1-yl)-2-methylpropan-2-ol(4); (4-(2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-6-yl)phenyl)(4-isopropylpiperazine-1-yl)methanone(5); 6-(4-(4-isobutylpiperazine-1-yl)phenyl)-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine(6); 6-(4-(4-(cyclopropylmethyl)piperazine-1-yl)phenyl)-2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine(8); 2-(3,4-dimethoxyphenyl)-6-(6-(4-isopropylpiperazine-1-yl)pyridine-3-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridine(9); 2-(3-fluoro-4-methoxyphenyl)-6-(4-(4-isopropylpiperazine-1-yl)phenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine(10); 6-(4-(4-isopropylpiperazine-1-yl)phenyl)-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine(11); 4-(4-(4-(2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-6-yl)phenyl)piperazine-1-yl)-2-methylbutan-2-ol(12); 2-(3,4-dimethoxyphenyl)-1-methyl-6-(4-(piperazine-1-yl)phenyl)-1H-pyrrolo[3,2-b]pyridine(13); 6-(4-(4-isobutylpiperazine-1-yl)phenyl)-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine(14); 2-methyl-1-(4-(4-(1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine-6-yl)phenyl)piperazine-1-yl)propan-2-ol(15); 2-methyl-4-(4-(4-(1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine-6-yl)phenyl)piperazine-1-yl)butan-2-ol(16); or 6-(4-(4-isobutylpiperazine-1-yl)phenyl)-4-methyl-2-(4-(methylsulfonyl)phenyl)-4H-pyrrolo[3,2-b]pyridine(18); 6-(4-(4-isopropylpiperazine-1-yl)phenyl)-1-methyl-2-(3-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine(19); 1-Methyl-2-(4-(methylsulfonyl)phenyl)-6-(4-(piperazine-1-yl)phenyl)-1H-pyrrolo[3,2-b]pyridine(20); 2-methyl-1-(4-(4-(1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine-6-yl)benzyl)piperazine-1-yl)propan-2-ol(21); 4-methyl-1-(4-(1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine-6-yl)benzyl)piperidine-4-ol(22); 6-(4-((4-isopropylpiperazine-1-yl)methyl)phenyl)-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine(23); 6-(4-((4-ethylpiperazine-1-yl)methyl)phenyl)-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine(25); 6-(4-(8-isopropyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine(26); 6-(4-(hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)phenyl)-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine(27); (R)-6-(4-(4-isopropyl-2-methylpiperazine-1-yl)phenyl)-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine(28); (S)-6-(4-(4-isopropyl-3-methylpiperazine-1-yl)phenyl)-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine(29); (S)-6-(4-(4-isopropyl-2-methylpiperazine-1-yl)phenyl)-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine(30); 6-(4-((2S,6S)-4-isopropyl-2,6-dimethylpiperazine-1-yl)phenyl)-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine(31); (R)-6-(4-(4-isopropyl-3-methylpiperazine-1-yl)phenyl)-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine(32); 6-(4-((2R,6S)-4-isopropyl-2,6-dimethylpiperazine-1-yl)phenyl)-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine(33); 6-(4-((3S,5R)-4-isopropyl-3,5-dimethylpiperazine-1-yl)phenyl)-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine(34); 6-(4-((3R,5R)-4-isopropyl-3,5-dimethylpiperazine-1-yl)phenyl)-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine(35); 6-(1-((1R,5S)-8-isobutyl-8-azabicyclo[3.2.1]octan-3-yl)piperidine-4-yl)-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine(36); 2-(4-cyclopropylsulfonylphenyl)-1-methyl-6-[1-[rac-(1S,5R)-8-isobutyl-8-azabicyclo[3.2.1]octan-3-yl]-4-piperidyl]pyrrolo[3,2-b]pyridine(37); 4-[6-[4-(4-isopropylpiperazine-1-yl)phenyl]-1-methyl-pyrrolo[3,2-b]pyridine-2-yl]-2-methoxy-benzonitrile(38); 5-(6-(4-(4-isopropylpiperazine-1-yl)phenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-2-yl)-2-methoxybenzonitrile(39); 3-(6-(4-(4-isopropylpiperazine-1-yl)phenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-2-yl)-N,N-dimethylbenzenesulfonamide (40); 2-(2-fluoro-4-(methylsulfonyl)phenyl)-6-(4-(4-isopropylpiperazine-1-yl)phenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine(41); 2-(2-fluoro-4-(methylsulfonyl)phenyl)-6-(4-(hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)phenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine(42); 2-(2-fluoro-4-(methylsulfonyl)phenyl)-6-(4-(8-isopropyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine(43); 3-(6-(4-(4-cyclopropylpiperazine-1-yl)phenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-2-yl)-N,N-dimethylbenzenesulfonamide (44); or 6-(4-(4-cyclopropylpiperazine-1-yl)phenyl)-2-(2-fluoro-4-(methylsulfonyl)phenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine(45).

8. 6-(4-(4-isopropylpiperazine-1-yl)phenyl)-4-methyl-2-(4-(methylsulfonyl)phenyl)-4H-pyrrolo[3,2-b]pyridine(3); or 6-(4-(4-isobutylpiperazine-1-yl)phenyl)-4-methyl-2-(4-(methylsulfonyl)phenyl)-4H-pyrrolo[3,2-b]pyridine(17) A compound or a salt thereof.

9. A pharmaceutical composition comprising one or more compounds from any of claims 1 to 8 and a pharmaceutically acceptable carrier or diluent.

10. A pharmaceutical composition comprising any compound of claims 1 to 8 or a pharmaceutically acceptable salt thereof, for treating pathological fibrosis.

11. The pharmaceutical composition according to claim 10, wherein the pathological fibrosis is hepatic fibrosis, renal fibrosis, cholangiofibrosis, or pancreatic fibrosis.

12. A pharmaceutical composition comprising any compound according to claims 1 to 8 or a pharmaceutically acceptable salt thereof, for the treatment of non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis (PSC), or primary biliary cirrhosis (PBC).

13. A pharmaceutical composition comprising any compound according to claims 1 to 8 or a pharmaceutically acceptable salt thereof, for the treatment of idiopathic pulmonary fibrosis (IPF).

Images