1h-pyrrolo[3,2-c]pyridine and 1h-pyrrolo[2,3-c]pyridine derivatives as tlr9 inhibitors for the treatment of fibrosis

Abstract

The present invention relates to 1H-pyrrolo[3,2-c]pyridine and 1H-pyrrolo[2,3-c]pyridine derivatives of formula (I): or a salt thereof. These compounds are TLR9 compounds suitable for use in the treatment, prevention or slowing of a fibrotic disease, such as liver fibrosis, kidney fibrosis, biliary fibrosis or pancreatic fibrosis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic nephropathy, primary sclerosing cholangitis (PSC) or primary biliary cirrhosis (PBC), or idiopathic pulmonary fibrosis (IPF).

Description

[0001] Cross-referencing

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 067,465, filed on August 19, 2020, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention generally relates to substituted heteroaryl compounds suitable as inhibitors of Toll-like receptor 9 (TLR9) signaling. This document provides substituted heteroaryl compounds, compositions comprising such compounds, and methods of using them. The invention further relates to pharmaceutical compositions containing at least one compound according to the invention, which can be used to treat or prevent fibrotic diseases and other diseases, conditions, and illnesses indicating a need for TLR9 inhibitors. Background Technology

[0004] Toll-like receptors (TLRs) are transmembrane proteins that can trigger an inflammatory response upon recognition of pathogen-associated molecular patterns (PAMPs) or microbe-associated molecular patterns (MAMPs). A total of 10 human TLRs have been identified, which may be located on the cell surface or, in the case of TLR7, TLR8, and TLR9, in lysosomes. TLR9 recognizes unmethylated single-stranded DNA containing the cytosine-phosphate-guanine (CpG) motif, which is commonly found in bacterial and mitochondrial DNA (mtDNA). TLR9 can promote inflammation via the MyD88-dependent signaling pathway, ultimately mediating the activation of IL-6, IFN-α, IL-1β, TNF-α, and other cytokines, thereby promoting fibrosis. (Barton GM, Kagan JC (2009) Nat. Rev. Immunol. 9(8), 535-42; Li X, Jiang S, Tapping RI (2010), Cytokine 49(1), 1-9).

[0005] TLR9 levels in lung biopsies from patients with rapidly progressing idiopathic pulmonary fibrosis (IPF) were higher than in healthy individuals or those with stable IPF progression (Sci. Transl. Med. 2010, 2(57): 57ra82). Recently, circulating mtDNA, a ligand of TLR9, has been identified as a mechanism-based prognostic biomarker for IPF (Am J. Resp. and Crit. Care Med. 2017, 196(12), 1502). Furthermore, TLR9 upregulation has been observed in human and murine nonalcoholic steatosis hepatitis (NASH) (Clin. Sci. 2017, 131(16), 2145), and NASH is caused by activation of hepatocyte mitochondrial DNA via TLR9 (J. Clin. Inv. 2016, 126(3), 859). Therefore, TLR9 inhibitors / antagonists are predicted to have potential efficacy as novel therapeutic agents for fibrotic diseases.

[0006] TLR9 inhibition has been recognized as a potential therapeutic approach for fibrotic diseases, including idiopathic pulmonary fibrosis (Trujillo et al. Sci. Transl. Med. 2010, 2(57): 57ra82; Yoshizaki et al. Ann Rheum Dis. 2016 Oct; 75(10): 1858-65), non-alcoholic steatotic hepatitis (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) (Yo ... Rheum Dis. October 2016; 75(10):1858-65); and heart failure (Oka et al. Nature 485, pp. 251-255 (2012)) and hypertension (McCarthy et al. Cardiovascular Research, 2015, pp. 119-130).

[0007] There is still a need for compounds suitable as TLR9 inhibitors. Additionally, there is still a need for compounds suitable as TLR9 inhibitors selective for TLR7 or TLR8.

[0008] Given the potential for patients to benefit from treatments involving the modulation of Toll-like receptors, novel compounds capable of inhibiting TLR9 and methods of using these compounds could obviously provide substantial therapeutic benefits to a wide range of patients.

[0009] The applicant has discovered effective compounds with activity as TLR9 inhibitors. Furthermore, the applicant has discovered compounds with activity as TLR9 inhibitors and selectivity for TLR7 or TLR8. These compounds are suitable as pharmaceutical products possessing the required stability, bioavailability, therapeutic index, and toxicity values ​​that are essential to their pharmaceutical usability. Summary of the Invention

[0010] This invention relates to a novel class of substituted heteroaryl compounds, which have been found to be effective inhibitors of TLR9 signaling. These compounds are suitable as pharmaceutical products having the required stability, bioavailability, therapeutic index, and toxicity levels that are crucial to their pharmaceutical usability.

[0011] This invention provides a compound of formula (I) suitable for use as an inhibitor of TLR9 signaling and for the treatment of fibrotic diseases, or a stereoisomer, N-oxide, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof.

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

[0013] The present invention also provides a method for inhibiting Toll-like receptor 9, comprising administering to a subject requiring this treatment a therapeutically effective amount of at least one of the compounds of the present invention or its stereoisomers, tautomers, pharmaceutically acceptable salts, solvates or prodrugs.

[0014] The present invention also provides a method for treating fibrotic diseases, comprising administering to a subject requiring such treatment a therapeutically effective amount of at least one of the compounds of the present invention or its stereoisomers, tautomers, pharmaceutically acceptable salts, solvates or prodrugs.

[0015] The present invention also provides a method for treating diseases or conditions associated with TLR9 activity, the method comprising administering to a mammal in need at least one compound of formula (I) or a salt thereof, a solvate thereof, and a prodrug.

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

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

[0018] The present invention also provides the use of at least one compound of formula (I) or its salts, solvates and prodrugs for the manufacture of medicaments for the treatment or prevention of TLR9-related conditions, such as fibrotic diseases, allergic diseases, autoimmune diseases and inflammatory diseases.

[0019] Compounds of formula (I) and compositions comprising compounds of formula (I) may be used to treat, prevent, or cure various TLR9-related conditions. Pharmaceutical compositions comprising these compounds are suitable for treating, preventing, or slowing the progression of diseases or conditions in a variety of therapeutic areas, such as fibrotic diseases, allergic diseases, autoimmune diseases, and inflammatory diseases.

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

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

[0022]

[0023] Or its stereoisomers, tautomers, solvates or salts, wherein:

[0024] One of X and Y is N, and the other of X and Y is CA;

[0025] One of Q1 and Q2 is G, and the other of Q1 and Q2 is R3;

[0026] G is:

[0027] (i) A phenyl group substituted with one to three independent substituents selected from the following: -OCH3, -S(O)2CH3, -S(O)2N(CH3)2, -S(O)2(cyclopropyl) and -S(O)(NH)N(CH3)2;

[0028] (ii)

[0029] (iii)

[0030] (iv) Selected from the following 9-membered heterocycles:

[0031]

[0032]

[0033]

[0034]

[0035] and or

[0036] (v) Selected from the following 10-membered heterocycles:

[0037]

[0038] and

[0039] A is piperidinyl, phenyl, pyridinyl, pyrimidinyl, 6-azabicyclo[3.2.1]octyl or azabicyclo[3.2.1]octyl, each after -L-R4 and zero to two R's. 4b replace;

[0040] L represents the bond, -CR x R x -or-C(O)(CR) x R x ) 0-2 -;

[0041] R1 is hydrogen, C 1-3 Alkyl, C 1-2 fluoroalkyl or C 3-4 cycloalkyl;

[0042] Each R2 group is independently a halogen, -CN, -OH, -NO2, or C group. 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 group), -O(CH2) 1-2 OC(O)(C 1-3 Alkyl group), -O(CH2) 1-2 NR x R x -C(O)O(C 1-3 Alkyl group), -(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 3-6cycloalkyl), -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 group 2, -(CH2) 0-2 (C 3-6 cycloalkyl), -(CH2) 0-2 (phenyl), morpholino, dioxothiomorpholino, dimethylpyrazolyl, methylpiperidinyl, methylpiperazinyl, amino-oxadiazolyl, imidazolyl, triazolyl or -C(O)(thiazolyl);

[0043] R 2a C 1-6 Alkyl, C 1-3 fluoroalkyl, C 1-6 Hydroxyalkyl, C 1-3 Aminoalkyl, -(CH2) 0-4 O(C 1-3 Alkyl), C 3-6 Cycloalkyl, -(CH2) 1-3 C(O)NR x R x -CH2(C 3-6 Cycloalkyl), -CH2(phenyl), tetrahydrofuranyl, tetrahydropyranyl or phenyl;

[0044] Each R 2b Independently H, halogen, -CN, -NR x R x C 1-6 Alkyl, C 1-3 fluoroalkyl, C 1-3 Hydroxyalkyl, C 1-3 Fluoroalkoxy, -(CH2) 0-2 O(C 1-3 Alkyl group), -(CH2) 0-3 C(O)NR x R x -(CH2) 1-3 (C3-6 cycloalkyl), -C(O)O(C 1-3 Alkyl), -C(O)NR x (C 1-3 alkyl), -CR x =CR x R x or -CR x =CH(C 3-6 cycloalkyl);

[0045] R 2c For R 2a Or R 2b ;

[0046] R 2d For R 2a Or R 2b The constraint is R. 2c and R 2d One of them is R 2a And R 2c and R 2d The other one is R 2b ;

[0047] R3 represents hydrogen, F, and C. 1-3 Alkyl or C 3-4 cycloalkyl;

[0048] R4 is:

[0049] (i)-N(CH3)2;

[0050] (ii) Morpholinyl, pyrrolylyl, piperidinyl, piperazinyl, pyridinyl, dioxothiomorpholinyl, azaspiro[3.3]heptyl, azabicyclo[3.2.1]octyl, diazabicyclo[2.2.2]octyl or diazabicyclo[3.2.1]octyl, each via zero to four R 4a Replace; or

[0051] (iii

[0052] Each R 4a Independently -OH, C 1-6 Alkyl, C 1-3 fluoroalkyl, C 3-6 cycloalkyl, -CH2(C 3-6 cycloalkyl), -C(O)(C 1-4 Alkyl), -C(O)(C 3-6 cycloalkyl), -C(O)(phenyl), -C(O)CH2(C 3-6 cycloalkyl), -C(O)CH2(phenyl) or -C(O)O(C 1-4 alkyl);

[0053] Each R 4b Independently, it can be F, Cl, or -CH3;

[0054] Each R 4c Independently -OH, C 1-6 Alkyl, C 1-3 fluoroalkyl, -CH2(C 3-6 cycloalkyl), -C(O)(C 1-4 Alkyl), -C(O) (phenyl), -C(O)CH2 (phenyl), -C(O)OCH2CH3 or C 3-6 cycloalkyl;

[0055] Each R5 is independently hydrogen, F, Cl, or C. 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkyl, cyclopropyl, or morpholino;

[0056] Each R x Independently H or -CH3;

[0057] Each R y Independently H or C 1-6 alkyl;

[0058] m is zero, 1, or 2;

[0059] n is zero, 1, or 2; and

[0060] p can be zero, 1, 2, 3, or 4.

[0061] A second aspect of the invention provides at least one compound of formula (I):

[0062]

[0063] Or its salt, wherein:

[0064] One of X and Y is N, and the other of X and Y is CA;

[0065] One of Q1 and Q2 is G, and the other of Q1 and Q2 is R3;

[0066] G is:

[0067] (i) A phenyl group substituted with one or two independent substituents selected from the following: -OCH3, -S(O)2CH3, -S(O)2N(CH3)2 and -S(O)(NH)N(CH3)2;

[0068] (ii)

[0069] (iii)

[0070] (iv) Selected from the following 9-membered heterocycles:

[0071]

[0072]

[0073]

[0074]

[0075] and or

[0076] (v) Selected from the following 10-membered heterocycles:

[0077]

[0078] and

[0079] A is piperidinyl, phenyl, pyridinyl, pyrimidinyl, 6-azabicyclo[3.2.1]octyl or azabicyclo[3.2.1]octyl, each after -L-R4 and zero to one R. 4b replace;

[0080] L represents the bond, -CR x R x -or-C(O)(CR) x R x ) 0-2 -;

[0081] R1 is hydrogen, C 1-3 Alkyl, C 1-2 fluoroalkyl or C 3-4 cycloalkyl;

[0082] Each R2 group is independently a halogen, -CN, -OH, -NO2, or C group. 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 group), -O(CH2) 1-2 OC(O)(C 1-3 Alkyl group), -O(CH2) 1-2 NRx R x -C(O)O(C 1-3 Alkyl group), -(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 group 2, -(CH2) 0-2 (C 3-6 cycloalkyl), -(CH2) 0-2 (phenyl), morpholino, dioxothiomorpholino, dimethylpyrazolyl, methylpiperidinyl, methylpiperazinyl, amino-oxadiazolyl, imidazolyl, triazolyl or -C(O)(thiazolyl);

[0083] R 2a C 1-6 Alkyl, C 1-3 fluoroalkyl, C 1-6 Hydroxyalkyl, C 1-3 Aminoalkyl, -(CH2) 0-4 O(C 1-3 Alkyl), C 3-6 Cycloalkyl, -(CH2) 1-3 C(O)NR x R x -CH2(C 3-6 Cycloalkyl), -CH2(phenyl), tetrahydrofuranyl, tetrahydropyranyl or phenyl;

[0084] Each R 2bIndependently H, halogen, -CN, -NR x R x C 1-6 Alkyl, C 1-3 fluoroalkyl, C 1-3 Hydroxyalkyl, C 1-3 Fluoroalkoxy, -(CH2) 0-2 O(C 1-3 Alkyl group), -(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 cycloalkyl);

[0085] R 2c For R 2a or R 2b ;

[0086] R 2d For R 2a or R 2b The constraint is R. 2c and R 2d One of them is R 2a And R 2c and R 2d The other one is R 2b ;

[0087] R3 represents hydrogen, F, and C. 1-3 Alkyl or C 3-4 cycloalkyl;

[0088] R4 is:

[0089] (i)-N(CH3)2;

[0090] (ii) pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, azaspiro[3.3]heptyl or azabicyclo[3.2.1]octyl, each via zero to two R 4a Replace; or

[0091] (iii)

[0092] Each R 4a Independently for C 1-6 Alkyl, C 1-3fluoroalkyl, 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 (C1-4 alkyl);

[0093] R 4b It can be F, Cl, or -CH3;

[0094] Each R 4c Independently for C 1-6 Alkyl, C 1-3 fluoroalkyl, -CH2(C 3-6 cycloalkyl), -C(O)(C 1-4 Alkyl), -C(O) (phenyl), -C(O)CH2 (phenyl), -C(O)OCH2CH3 or C 3-6 cycloalkyl;

[0095] Each R5 is independently hydrogen, F, Cl, or C. 1-2 Alkyl or cyclopropyl;

[0096] Each R x Independently H or -CH3;

[0097] Each R y Independently H or C 1-6 alkyl;

[0098] m is zero, 1, or 2;

[0099] n is zero, 1, or 2; and

[0100] p can be zero, 1, 2, 3, or 4.

[0101] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein X is CA and Y is N. The compound of this embodiment has the structure of formula (II):

[0102]

[0103] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein X is CA and Y is N; and Q1 is G and Q2 is R3. The compound of this embodiment has the structure of formula (IIa):

[0104]

[0105] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein X is CA and Y is N; and Q1 is R3 and Q2 is G. The compound of this embodiment has the structure of formula (IIb):

[0106]

[0107] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein X is N and Y is CA. The compound of this embodiment has the structure of formula (III):

[0108]

[0109] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein X is N and Y is CA; and Q1 is G and Q2 is R3. The compound of this embodiment has the structure of formula (IIIa):

[0110]

[0111] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein X is N and Y is CA; and Q1 is R3 and Q2 is G. The compound of this embodiment has the structure of formula (IIIb):

[0112]

[0113] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein G is a phenyl group substituted with 1 to 3 independently selected substituents: -OCH3, -S(O)2CH3, -S(O)2N(CH3)2, -S(O)2(cyclopropyl), and -S(O)(NH)N(CH3)2. This embodiment includes compounds in which G is a phenyl group substituted with 1 to 2 independently selected substituents: -OCH3, -S(O)2CH3, -S(O)2N(CH3)2, and -S(O)2(cyclopropyl). This embodiment also includes compounds in which G is:

[0114]

[0115] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein G is a phenyl group substituted with one or two independently selected substituents: -OCH3, -S(O)2CH3, -S(O)2N(CH3)2, and -S(O)(NH)N(CH3)2. This embodiment includes compounds in which G is a phenyl group substituted with one or two independently selected substituents: -OCH3 and -S(O)2CH3. This embodiment also includes compounds in which G is:

[0116] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein G is... This embodiment includes the following compounds, wherein each R2 is independently F, Cl, Br, -CN, -OH, -CH3, -CH2CH3, -CF3, -CH2OH, -C(CH3)2OH, -CH2NH2, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCH2CH2OCH3, -OCH2CH2N(CH3)2, -OCHF2, -C(O)OCH3, -C(O)NH2, -C(O)NH(CH2CH3), -C(O)(thiazolyl), -NH2, -NH(CH3), -NH(CH2CH3), -N(CH3)2, -NHC(O)CH3, -NHC(O)C(CH3)3, -NH(CH2-cyclopropyl), cyclopropyl, methylpiperidinyl, methylpiperazinyl, amino-oxadiazolyl, imidazolyl, or triazolyl. This embodiment also includes compounds in which each R2 is independently F, Cl, -CN, -CH3, -OCH3, -NH2, or cyclopropyl. Additionally, this embodiment includes compounds in which p is 2; one R2 is -CH3; and the other R2 is F, Cl, -CN, -CH3, -OCH3, -NH2, or cyclopropyl.

[0117] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein G is a 9-membered heterocycle selected from:

[0118]

[0119]

[0120]

[0121] and

[0122] This implementation scheme includes the following compounds, wherein G is:

[0123]

[0124] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein G is a 10-membered heterocycle selected from:

[0125]

[0126] and

[0127] This implementation scheme includes the following compounds, wherein G is:

[0128]

[0129] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein G is:

[0130] (i) A phenyl group substituted with one or two independent substituents selected from the following: -OCH3, -S(O)2CH3, -S(O)2N(CH3)2 and -S(O)2 (cyclopropyl);

[0131] (ii)

[0132] (iii or

[0133] (iv

[0134] This embodiment includes compounds in which each R2 is independently Cl, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2CN, -OCH3, -CH2OCH3 or -CH2CH2S(O)2CH3.

[0135] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein G is:

[0136] (i) A phenyl group substituted with one or two independent substituents selected from the following: -OCH3, -S(O)2CH3, -S(O)2N(CH3)2 and -S(O)(NH)N(CH3)2;

[0137] (ii)

[0138] (iii) or

[0139] (iv

[0140] This embodiment includes compounds in which each R2 is independently Cl, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2CN, -OCH3, -CH2OCH3 or -CH2CH2S(O)2CH3.

[0141] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein p is zero, 1, 2, or 3. This embodiment includes compounds wherein p is 1 or 2.

[0142] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein A is piperidinyl, phenyl, pyridinyl, pyrimidinyl, 6-azabicyclo[3.2.1]octyl or azabicyclo[3.2.1]octyl, each having a -L-R4 derivative and zero to two R derivatives. 4b replace.

[0143] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein A is piperidinyl, phenyl, pyridinyl, pyrimidinyl, 6-azabicyclo[3.2.1]octyl or azabicyclo[3.2.1]octyl, each having a -L-R4 derivative and zero to one R... 4b replace.

[0144] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein A is piperidinyl, phenyl, or pyridinyl, each having an R-L-R4 and zero to two R-terms. 4b Substitution. This embodiment includes compounds in which A is piperidinyl or phenyl, each via -L-R4 and zero to one R... 4b Substitution. This embodiment also includes compounds in which A is phenyl or pyridyl, each via a -L-R4 and zero to one R... 4b replace.

[0145] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein A is piperidinyl, phenyl, or pyridinyl, each having an R-L-R4 and zero to one R-... 4b Substitution. This embodiment includes compounds in which A is piperidinyl or phenyl, each via -L-R4 and zero to one R... 4b Substitution. This embodiment also includes compounds in which A is phenyl or pyridyl, each via a -L-R4 and zero to one R... 4b replace.

[0146] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein A is piperidinyl, phenyl, pyridinyl, or pyrimidinyl, each having an R-L-R4 and zero to two R-terms. 4b Substitution; and L is a bond. This embodiment includes compounds in which A is piperidinyl, phenyl, or pyridinyl, each via -L-R4 and zero to one R 4b Replacement; and L is a bond.

[0147] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein A is piperidinyl, phenyl, pyridinyl, or pyrimidinyl, each having a -L-R4 derivative and zero to one R... 4b Substitution; and L is a bond. This embodiment includes compounds in which A is piperidinyl, phenyl, or pyridinyl, each via -L-R4 and zero to one R 4b Replacement; and L is a bond.

[0148] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate or salt thereof is provided, wherein L is a bond.

[0149] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein L is -CR x R x This embodiment includes the following compound, wherein L is -CH2-.

[0150] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein L is -C(O)(CR x R x ) 0-2 This embodiment includes the following compound, where L is -C(O)(CH2). 0-2 This embodiment also includes compounds in which L is -C(O)(CH2). 0-1 Additionally, this embodiment includes compounds in which L is -C(O)-.

[0151] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein L is -CR x R x -or-C(O)(CR) x R x ) 0-2 This embodiment includes the following compound, where L is -CR x R x -or-C(O)(CR)x R x ) 0-1 This embodiment also includes compounds in which L is -CR x R x - or -C(O)-. Additionally, this embodiment includes compounds wherein each R x It is hydrogen.

[0152] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein L is a bond, -CH2-, or -C(O)(CH2). 0-2 - This embodiment includes compounds in which L is a bond or -C(O)-.

[0153] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate or salt thereof is provided, wherein R4 is -N(CH3)2.

[0154] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein R4 is morpholino, pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, dioxothiomorpholino, azaspiro[3.3]heptyl, azabicyclo[3.2.1]octyl, diazabicyclo[2.2.2]octyl, or diazabicyclo[3.2.1]octyl, each having zero to four R4 groups. 4a replace.

[0155] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein R4 is morpholino, pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, dioxothiomorpholino, azabicyclo[3.2.1]octyl, diazabicyclo[2.2.2]octyl, or diazabicyclo[3.2.1]octyl, each having zero to four R4 groups. 4a replace.

[0156] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein R4 is pyrrolidinyl, piperidinyl, piperazinyl, or pyridinyl, each having zero to four R4 groups. 4a replace.

[0157] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein R4 is pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, azaspiro[3.3]heptyl, or azabicyclo[3.2.1]octyl, each having zero to two R4 groups. 4a replace.

[0158] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein R4 is pyrrolidinyl, piperidinyl, piperazinyl, or pyridinyl, each having zero to two R4 groups. 4a Substitution. This embodiment includes compounds in which R4 is piperidinyl, piperazineyl, or pyridinyl. This embodiment also includes compounds in which R4 is piperidinyl or piperazineyl.

[0159] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein R4 is This embodiment includes the following compounds, where n is 1 or 2. This embodiment also includes the following compounds, where n is 1. Additionally, this embodiment includes the following compounds, where n is 2.

[0160] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein R4 is pyrrolidinyl, piperidinyl, piperazinyl, or pyridinyl, each having zero to two R4 groups. 4a Replace; or

[0161] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein R4 is pyrrolidinyl, piperidinyl, piperazinyl, or pyridinyl, each having zero to two R4 groups. 4a Replace; or This embodiment includes compounds in which R4 is pyrrolidinyl, piperidinyl, piperazineyl, or pyridinyl, each having zero to two R... 4a Replace; or

[0162] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein each R 4a Independently -OH, C 1-6 Alkyl, C 1-3 fluoroalkyl, C 3-6 cycloalkyl, -CH2(C 3-6 cycloalkyl), -C(O)(C 1-4 Alkyl), -C(O)(C 3-6 cycloalkyl), -C(O)(phenyl), -C(O)CH2(C 3-6 cycloalkyl), -C(O)CH2(phenyl) or -C(O)O(C 1-4 alkyl).

[0163] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein each R 4aIndependently -OH, C 1-6 Alkyl, C 1-3 fluoroalkyl, -CH2(C 3-6 cycloalkyl), -C(O)(C 1-4 Alkyl), -C(O) (phenyl), -C(O)CH2 (phenyl), -C(O)OCH2CH3 or C 3-6 Cycloalkyl.

[0164] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein each R 4a Independently, it can be -OH, -CH3, -CHCH3, -CH(CH3)2, -CH2CH(CH3)2, -C(CH3)3, -CH2C(CH3)3, -CH2CH2C(CH3)3, -CF3, -CH2CH2OH, -CH2CH2CH2OH, -CH2C(CH3)2OH, -CH2CH2C(CH3)2OH, -CH2CH2OCH3, -CH2(cyclopropyl), -C(O)CH3, -C(O)CH(CH3)2, -C(O)CH2CH3, -C(O)(phenyl), -C(O)CH2(phenyl), -C(O)OCH2CH3, -C(O)O(phenyl), cyclopropyl, cyclobutyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, -(CH2) 1-2 (Bromophenyl) or -(CH2) 1-2 (Iodophenyl).

[0165] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein each R 4a Independently, it can be -OH, -CH3, -CHCH3, -CH(CH3)2, -CH2CH(CH3)2, -C(CH3)3, -CF3, -CH2CH2OH, -CH2CH2CH2OH, -CH2C(CH3)2OH, -CH2CH2C(CH3)2OH, -CH2CH2OCH3, -CH2(cyclopropyl), -C(O)CH3, -C(O)(phenyl), -C(O)OCH2CH3, cyclopropyl, cyclobutyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, -(CH2) 1-2 (Bromophenyl) or -(CH2) 1-2 (Iodophenyl).

[0166] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein each R 4b Independently, it is F or -CH3. This embodiment includes the following compounds, wherein each R is... 4bIt is -CH3.

[0167] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein R 4b It is F or Cl. This embodiment includes the following compounds, wherein R is F or Cl. 4b It is F.

[0168] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein A is a compound with -L-R4 and zero to two R groups. 4b Substituted phenyl groups. This embodiment includes the following compounds, wherein each R... 4b It is F.

[0169] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein each R 4c Independently for 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 Cycloalkyl. This embodiment also includes compounds wherein each R... 4c Independently for 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 Cycloalkyl.

[0170] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein R1 is hydrogen, C 1-2 Alkyl, -CH2F, -CHF2, -CF3 or C 3-4 Cycloalkyl. This embodiment includes compounds in which R1 is hydrogen, -CH3, -CF3, or cyclopropyl. This embodiment also includes compounds in which R1 is hydrogen or -CH3.

[0171] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein R1 is hydrogen, C 1-2Alkyl, -CH2F, -CHF2, -CF3, or cyclopropyl. This embodiment includes compounds in which R1 is hydrogen, -CH3, -CHF2, or cyclopropyl. This embodiment also includes compounds in which R1 is hydrogen. This embodiment includes compounds in which R1 is -CH3, -CHF2, or cyclopropyl.

[0172] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein each R2 is independently F, Cl, -CN, -OH, C. 1-3 Alkyl, C 1-2 fluoroalkyl, C 1-2 Cyanoalkyl, C 1-3 Hydroxyalkyl, C 1-2 Aminoalkyl, -(CH2) 0-2 O(C 1-3 Alkyl), C 3-6 cycloalkyl, -NR x R x -(CH2) 0-2 C(O)NR x R x -CH2(C 3-6 Cycloalkyl), -CH2(phenyl), or phenyl. This embodiment includes compounds wherein each R2 is independently Cl, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2CN, -OCH3, -CH2OCH3, or -CH2CH2S(O)2CH3. This embodiment also includes compounds wherein each R2 is independently Cl, -CH3, -CH2OH, or -OCH3.

[0173] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein R 2a C 1-4 Alkyl, C 1-2 fluoroalkyl, C 1-4 Hydroxyalkyl, -(CH2) 1-3 OCH3, C 3-6 Cycloalkyl, -CH2C(O)NR x R x -CH2(C 3-6 cycloalkyl), -CH2(phenyl), tetrahydrofuran or phenyl; and each R 2b Independently H, F, Cl, -CN, -NR x R x C 1-6 Alkyl, C 1-2 fluoroalkyl, C 1-3 Hydroxyalkyl, -(CH2) 0-2O(C 1-2 Alkyl group), -(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 (Cycloalkyl). This embodiment also includes compounds in which R 2a It is -CH3; and each R 2b It can be H, Cl, or -CH3 independently.

[0174] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein R3 is hydrogen, F, or C. 1-3 Alkyl or C 3-4 Cycloalkyl. This embodiment includes compounds in which R3 is hydrogen, F, or C. 1-2 Alkyl or cyclopropyl. This embodiment also includes compounds in which R3 is hydrogen, F, -CH3, or cyclopropyl.

[0175] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein R3 is hydrogen, C 1-2 Alkyl or C 3-4 Cycloalkyl. This embodiment includes compounds in which R3 is hydrogen, C 1-2 Alkyl or cyclopropyl. This embodiment also includes compounds in which R3 is hydrogen or -CH3.

[0176] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate or salt thereof is provided, wherein each R5 is independently hydrogen, F, Cl, C. 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-2 Alkoxy, cyclopropyl, or morpholino. This embodiment includes compounds in which each R5 is independently hydrogen, -CH3, -C(CH3)2OH, -OCH3, or morpholino.

[0177] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein each R5 is independently hydrogen, F, Cl, -CH3, or cyclopropyl. This embodiment includes compounds wherein each R5 is independently hydrogen, -CH3, or cyclopropyl. It also includes compounds wherein each R5 is hydrogen or -CH3.

[0178] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein: G is a phenyl group substituted with one to two independently selected substituents: -OCH3, -S(O)2CH3, -S(O)2N(CH3)2, and -S(O)2 (cyclopropyl); A is piperidinyl, phenyl, or pyridinyl, each substituted with -L-R4 and zero to two R groups. 4b Substitution; L is a bond, -CH2-, -C(O)-, -C(O)CH2- or -C(O)CH2CH2-; R1 is hydrogen, -CH3, -CHF2 or cyclopropyl; R3 is hydrogen, F, -CH3 or cyclopropyl; R4 is (i)-N(CH3)2; or (ii) is pyrrolidinyl, piperidinyl, piperazinyl or pyridinyl, each via zero to four R... 4a Replace; each R 4a Independently for C 1-6 Alkyl, C 1-3 fluoroalkyl, -CH2(C 3-6 cycloalkyl), -C(O)(C 1-4 Alkyl), -C(O) (phenyl), -C(O)CH2 (phenyl), -C(O)OCH2CH3 or C 3-6 cycloalkyl; each R 4b Independently F, Cl, or -CH3; each R 4c Independently for C 1-6 Alkyl, C 1-3 fluoroalkyl, -CH2(C 3-6 cycloalkyl), -C(O)(C 1-4 Alkyl), -C(O) (phenyl), -C(O)CH2 (phenyl), -C(O)OCH2CH3 or C 3-6 Cycloalkyl; each R5 is independently hydrogen, F, Cl, C. 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-2 Alkoxy, cyclopropyl, or morpholino; m is zero, 1, or 2; and n is zero, 1, or 2.

[0179] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein: G is a phenyl group substituted with one to two independently selected substituents: -OCH3, -S(O)2CH3, -S(O)2N(CH3)2, and -S(O)2 (cyclopropyl); A is piperidinyl, phenyl, or pyridinyl, each substituted with -L-R4 and zero to two R groups. 4bSubstitution; L is a bond, -CH2-, -C(O)-, -C(O)CH2- or -C(O)CH2CH2-; R1 is hydrogen or -CH3; R3 is hydrogen, F, -CH3 or cyclopropyl; R4 is: (i) -N(CH3)2; or (ii) pyrrolidinyl, piperidinyl, piperazineyl or pyridinyl, each via zero to four R... 4a Replace; each R 4a Independently, it can be -OH, -CH3, -CHCH3, -CH(CH3)2, -CH2CH(CH3)2, -C(CH3)3, -CH2C(CH3)3, -CH2CH2C(CH3)3, -CF3, -CH2CH2OH, -CH2CH2CH2OH, -CH2C(CH3)2OH, -CH2CH2C(CH3)2OH, -CH2CH2OCH3, -CH2(cyclopropyl), -C(O)CH3, -C(O)CH(CH3)2, -C(O)CH2CH3, -C(O)(phenyl), -C(O)CH2(phenyl), -C(O)OCH2CH3, -C(O)O(phenyl), cyclopropyl, cyclobutyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, -(CH2) 1-2 (Bromophenyl) or -(CH2) 1-2 (Iodophenyl); each R 4b It is F; and each R5 is independently hydrogen, -CH3, -C(CH3)2OH, -OCH3 or morpholino.

[0180] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein:

[0181] G is:

[0182] (i) A phenyl group substituted with one or two independent substituents selected from the following: -OCH3, -S(O)2CH3, -S(O)2N(CH3)2 and -S(O)(NH)N(CH3)2;

[0183] (ii)

[0184] (iii) or

[0185] (iv)

[0186] A is piperidinyl, phenyl, pyridinyl, or pyrimidinyl, each with -L-R4 and zero to one R. 4b replace;

[0187] L represents the bond, -CR x R x -or-C(O)(CR) xR x ) 0-2 -;

[0188] R1 is hydrogen, C 1-3 Alkyl, C 1-2 fluoroalkyl or C 3-4 cycloalkyl;

[0189] Each R2 is independently F, Cl, -CN, -OH, or C. 1-3 Alkyl, C 1-2 fluoroalkyl, C 1-2 Cyanoalkyl, C 1-3 Hydroxyalkyl, C1-2 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 Cycloalkyl), -CH2(phenyl) or phenyl;

[0190] R 2a C 1-4 Alkyl, C 1-2 fluoroalkyl, C 1-4 Hydroxyalkyl, -(CH2) 1-3 OCH3, C 3-6 Cycloalkyl, -CH2C(O)NR x R x -CH2(C 3-6 cycloalkyl), -CH2(phenyl), tetrahydrofuran or phenyl;

[0191] Each R 2b Independently H, F, Cl, -CN, -NR x R x C 1-6 Alkyl, C 1-2 fluoroalkyl, C 1-3 Hydroxyalkyl, -(CH2) 0-2 O(C 1-2 Alkyl group), -(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 cycloalkyl);

[0192] R3 is hydrogen, C 1-3 Alkyl or C 3-4 cycloalkyl;

[0193] R4 is

[0194] (i)-N(CH3)2;

[0195] (ii) pyrrolidinyl, piperidinyl, piperazinyl or pyridinyl, each with zero to two R... 4a Replace; or

[0196] (iii)

[0197] Each R 4a Independently for C 1-6 Alkyl, C 1-3 fluoroalkyl, C 3-6 cycloalkyl, -CH2(C 3-6 cycloalkyl), -C(O)(C 1-4 Alkyl), -C(O)(C 3-6 cycloalkyl), -C(O)(phenyl), -C(O)CH2(C 3-6 Cycloalkyl), -C(O)CH2 (phenyl) or -C(O)O (C1-4 alkyl);

[0198] R 4b It can be F, Cl, or -CH3;

[0199] Each R 4c Independently for C 1-6 Alkyl, C 1-3 fluoroalkyl, -CH2(C 3-6 cycloalkyl), -C(O)(C 1-4 Alkyl), -C(O) (phenyl), -C(O)CH2 (phenyl), -C(O)OCH2CH3 or C 3-6 cycloalkyl;

[0200] Each R5 is independently hydrogen, F, Cl, or C. 1-2 Alkyl or cyclopropyl;

[0201] Each R x Independently H or -CH3;

[0202] Each R y Independently H or C 1-6 alkyl;

[0203] m is zero, 1, or 2;

[0204] n is zero, 1, or 2; and

[0205] p can be zero, 1, 2, 3, or 4.

[0206] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein: G is a phenyl substituted with one to two independently selected substituents: -OCH3 and -S(O)2CH3; A is piperidinyl, phenyl, or pyridinyl, each substituted with -L-R4 and zero to one R... 4b Substitution; L is a bond, -CH2-, -C(O)-, -C(O)CH2- or -C(O)CH2CH2-; R1 is hydrogen or -CH3; R3 is hydrogen or -CH3; R4 is: (i) -N(CH3)2; or (ii) pyrrolidinyl, piperidinyl, piperazineyl or pyridinyl, each via zero to two R... 4a Replace; R 4a Independently for C 1-6 Alkyl, C 1-3 fluoroalkyl, -CH2(C 3-6 cycloalkyl), -C(O)(C 1-4 Alkyl), -C(O) (phenyl), -C(O)CH2 (phenyl), -C(O)OCH2CH3 or C 3-6 cycloalkyl; R 4b For F, Cl, or -CH3; R 4c C 1-6 Alkyl, C 1-3 fluoroalkyl, -CH2(C 3-6 cycloalkyl), -C(O)(C 1-4 Alkyl), -C(O) (phenyl), -C(O)CH2 (phenyl), -C(O)OCH2CH3 or C 3-6 Cycloalkyl; each R5 is independently hydrogen, F, Cl or C. 1-2 Alkyl; m is zero, 1, or 2; and n is zero, 1, or 2.

[0207] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein: G is a phenyl substituted with one to two independently selected substituents: -OCH3 and -S(O)2CH3; A is piperidinyl, phenyl, or pyridinyl, each substituted with -L-R4 and zero to one R... 4b Substitution; L is a bond, -CH2-, -C(O)-, -C(O)CH2- or -C(O)CH2CH2-; R1 is hydrogen or -CH3; R3 is hydrogen or -CH3; R4 is: (i) -N(CH3)2; or (ii) pyrrolidinyl, piperidinyl, piperazineyl or pyridinyl, each via zero to two R... 4a Replace; R 4aIndependently, it is -CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2C(CH3)3, -CH2CH2C(CH3)3, -CF3, -CH2(cyclopropyl), -C(O)CH3, -C(O)CH(CH3)2, -C(O)CH2CH3, -C(O)(phenyl), -C(O)CH2(phenyl), -C(O)OCH2CH3, cyclopropyl, or cyclobutyl; R 4b It is F; and each R5 is independently hydrogen or -CH3.

[0208] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein X is CA; Y is N; Q1 is G; Q2 is R3; G is a phenyl substituted with two substituents selected from -OCH3; A is piperidinyl or phenyl, each substituted with -L-R4; R1 is hydrogen or -CH3; R3 is -CH3; L is a bond, -C(O)-, -C(O)CH2-, or -C(O)CH2CH2-; R4 is: (i) -N(CH3)2; or (ii) pyrrolidinyl, piperidinyl, piperazinyl, or pyridinyl, each substituted with zero to two R4 groups. 4a Replace; R 4a It is independently -CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2C(CH3)3, -C(O)CH(CH3)2, -C(O)(phenyl), -C(O)CH2(phenyl) or cyclopropyl; and each R5 is hydrogen.

[0209] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein X is CA; Y is N; Q1 is R3; Q2 is G; G is a phenyl substituted with two substituents selected from -OCH3; A is piperidinyl or phenyl, each substituted with -L-R4; L is a bond; R1 is -CH3; R3 is -CH3; R4 is piperidinyl or piperazine, each substituted with R 4a Replace; R 4a It is independently -CH(CH3)2 or -CH2CH(CH3)2; and each R5 is hydrogen.

[0210] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein X is N; Y is CA; Q1 is R3; Q2 is G; G is a phenyl substituted with one to two independently selected substituents: -OCH3 and -S(O)2CH3; A is piperidinyl or phenyl, each substituted with -L-R4 and zero to one R 4b Substitution; L is a bond, -CH2- or -C(O)CH2-; R1 is -CH3; R3 is hydrogen; R4 is piperidinyl, piperazinyl or pyridinyl, each via zero to two R...4a Replace; R 4a Independently, it is -CH3, -CH(CH3)2, -CH2CH(CH3)2, -CF3, -CH2 (cyclopropyl), -C(O)CH3, -C(O) (phenyl), -C(O)OCH2CH3 or cyclobutyl; R 4b It is F; and each R5 is independently hydrogen or -CH3.

[0211] One embodiment provides a compound of formula (I) or a stereoisomer, tautomer, solvate or salt thereof, wherein the compound is: 2-(3,4-dimethoxyphenyl)-5-(4-(4-isopropylpiperazin-1-yl)phenyl)-3-methyl-1H-pyrrolo[2,3-c]pyridine (1); or 2-(3,4-dimethoxyphenyl)-5-(1'-isobutyl-[1,4'-dipiperidine]-4-yl)-1,3-dimethyl-1H-pyrrolo[2,3-c]pyridine (13).

[0212] One embodiment provides a compound of formula (I) or a salt thereof, wherein the compound is: 2-(3,4-dimethoxyphenyl)-5-(4-(4-isopropylpiperazin-1-yl)phenyl)-3-methyl-1H-pyrrolo[2,3-c]pyridine (2); 1-(4-(4-(3-(3,4-dimethoxyphenyl)-1,2-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)phenyl)piperazin-1-yl)-2-methylprop-2-ol (3); 4-(3-(3,4-dimethoxyphenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-[1,4'-dipiperidine]-1'-carboxylic acid methyl ester (4); (1-cyclopropylpiperidine) -4-yl)(4-(3-(3,4-dimethoxyphenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidin-1-yl) methyl ketone (5); 3-(3,4-dimethoxyphenyl)-5-(1-(2,6-dimethylpyridin-4-yl)piperidin-4-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridine (6); (4-(3-(3,4-dimethoxyphenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-[1,4'-dipiperidin]-1'-yl)(phenyl) methyl ketone (14); 1-(4-(3-(3,4-dimethoxyphenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine) 1-(4-(3-(3,4-dimethoxyphenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidin-1-yl)-2-(piperidin-1-yl)ethyl-1-one (16); 3-(3,4-dimethoxyphenyl)-5-(1'-isobutyl-[1,4'-dipiperidin]-4-yl)-1,2-dimethyl-1H-pyrrolo[2,3-c]pyridine (17); 1-(4-(3-(3,4-dimethoxyphenyl)-1,2-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-[1,4'-dipiperidine] (18) (4-(3-(3,4-dimethoxyphenyl)-1,2-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-[1,4'-dipiperidine]-1'-yl)(phenyl) methyl ketone (19); ethyl 4-(3-(3,4-dimethoxyphenyl)-1,2-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-[1,4'-dipiperidine]-1'-carboxylic acid (20); 1-(4-(3-(3,4-dimethoxyphenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidine-1-yl)-2-(pyrrolidin-1-yl)ethyl-1-one (21);1-(4-(3-(3,4-dimethoxyphenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidin-1-yl)-2-(dimethylamino)aceto-1-one (22); 1-(4-(3-(3,4-dimethoxyphenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidin-1-yl)-3-(pyrrolidine-1-yl)prop-1-one (2 3); 3-(3,4-dimethoxyphenyl)-5-(4-(4-isopropylpiperazin-1-yl)phenyl)-1,2-dimethyl-1H-pyrrolo[2,3-c]pyridine (32); or 4-(4-(4-(3-(3,4-dimethoxyphenyl)-1,2-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)phenyl)piperazin-1-yl)-2-methylbut-2-ol (33).

[0213] One embodiment provides a compound of formula (I) or a stereoisomer, tautomer, solvate or salt thereof, wherein the compound is: ethyl 4-(2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-[1,4'-dipiperidine]-1'-carboxylate (7); ethyl 2-(3,4-dimethoxyphenyl)-1-methyl-6-(1-((6-methylpyridin-3-yl)methyl)piperidine-4-yl)-1H-pyrrolo[3,2-c]pyridine (8); 6-(4-(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)-2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-c]pyridine (9); 6- (4-(4-cyclobutylpiperazin-1-yl)phenyl)-2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-c]pyridine (10); 6-(4-(4-isopropylpiperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (11); 6-(3-fluoro-4-(4-isopropylpiperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (12); 2-(3,4-dimethoxyphenyl)-6-(4-(4-isopropylpiperazin-1-yl)phenyl)-1-methyl-1H-pyrrolo[3,2-c]pyridine 2-c]pyridine (24); 1-(4-(2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)piperidin-1-yl)-2-(piperidin-1-yl)ethyl-1-one (25); (4-(2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-[1,4'-dipiperidin]-1'-yl)(phenyl) methyl ketone (26); 2-(3,4-dimethoxyphenyl)-1-methyl-6-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[3,2-c]pyridine (27); 2-(3,4-dimethoxyphenyl)-1-methyl-6-(1-((6- (trifluoromethyl)pyridin-3-yl)methyl)piperidin-4-yl)-1H-pyrrolo[3,2-c]pyridine (28); (4-(4-(2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)phenyl)piperazin-1-yl)(phenyl)methyl ketone (29); 1-(4-(4-(2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)phenyl)piperazin-1-yl)ethyl-1-one (30); 2-(3,4-dimethoxyphenyl)-6-(6-(4-isopropylpiperazin-1-yl)pyridin-3-yl)-1-methyl-1H-pyrrolo[3,2-c]pyridine (31);6-(4-(4-isobutylpiperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (34); 1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-6-(4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)-1H-pyrrolo[3,2-c]pyridine (35); 3-(4-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)phenyl)piperazin-1-yl)prop-1-ol (36); 1,4-dimethyl-2-(4-(methylsulfonyl)phenyl) 6-(4-(4-(tetrahydrofuran-3-yl)piperazin-1-yl)phenyl)-1H-pyrrolo[3,2-c]pyridine (37); 6-(4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (38); 6-(4-(4-isopropylpiperazin-1-yl)phenyl)-1,4-dimethyl-2-(3-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (39); 6-(4-(4-isobutylpiperazin-1-yl)phenyl)-1,4-dimethyl-2-(3-(methanesulfonyl)phenyl)-1H- Pyrrolo[3,2-c]pyridine (40); 3-(4-(4-(1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)phenyl)piperidin-1-yl)prop-1-ol (41); 2-(4-(cyclopropylsulfonyl)phenyl)-6-(4-(4-isopropylpiperazin-1-yl)phenyl)-1,4-dimethyl-1H-pyrrolo[3,2-c]pyridine (42); 6-(2,5-difluoro-4-(piperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (43); 1-(4-(4-(1,4- Dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzyl)piperazin-1-yl)-2-methylprop-2-ol (44); 3-((1R,4R)-5-(4-(1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzyl)-2,5-diazabicyclo[2.2.2]oct-2-yl)-2,2-dimethylprop-1-ol (45); 2-(4-(cyclopropylsulfonyl)phenyl)-6-(4-(4-isobutylpiperazin-1-yl)phenyl)-1,4-dimethyl-1H-pyrrolo[3,2-c]pyridine (46);3-(4-(4-(2-(4-(cyclopropylsulfonyl)phenyl)-1,4-dimethyl-1H-pyrrolo[3,2-c]pyridin-6-yl)phenyl)piperazin-1-yl)prop-1-ol (47); 2-(4-(cyclopropylsulfonyl)phenyl)-6-(4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)-1,4-dimethyl-1H-pyrrolo[3,2-c]pyridine (48); 4-(6-(4-(4-isopropylpiperazin-1-yl)phenyl)-1,4-dimethyl-1H-pyrrolo[3,2-c]pyridin-2-yl)-N,N-dimethylbenzenesulfonamide (49); 4-(1,4-dimethyl-6-(4-(4-) (oxacyclobut-3-yl)piperazin-1-yl)phenyl)-1H-pyrrolo[3,2-c]pyridin-2-yl)-N,N-dimethylbenzenesulfonamide (50); 4-(6-(4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)-1,4-dimethyl-1H-pyrrolo[3,2-c]pyridin-2-yl)-N,N-dimethylbenzenesulfonamide (51); 4-(1,4-dimethyl-6-(4-(4-(tetrahydrofuran-3-yl)piperazin-1-yl)phenyl)-1H-pyrrolo[3,2-c]pyridin-2-yl)-N,N-dimethylbenzenesulfonamide (52); 6-(4-(4-isobutylpiperazin-1-yl)phenyl)-1-methyl -2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (53); 6-(4-(4-isopropylpiperazin-1-yl)phenyl)-1-methyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (54); 3-(4-(4-(1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-2,3-difluorophenyl)piperazin-1-yl)prop-1-ol (55); 3-(4-(4-(1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-2,5 -difluorophenyl)piperazin-1-yl)prop-1-ol (56); 6-(4-((4-isobutylpiperazin-1-yl)methyl)phenyl)-1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (57); 3-(4-(4-(1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzyl)piperazin-1-yl)prop-1-ol (58); 1-(4-(1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzyl)-4-methylpiperidin-4-ol (59);4-(4-(4-(1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzyl)piperazin-1-yl)-2-methylbut-2-ol (60); 4-((1S,4S)-5-(4-(1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzyl)-2,5-diazabicyclo[2.2.2]oct-2-yl)-2-methylbut-2-ol (61); 6-(4-(4-cyclopropylpiperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (62); 6- (4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)-1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (63); 6-(4-(8-isopropyl-3,8-diazabicyclo[3.2.1]oct-3-yl)phenyl)-1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (64); 6-(3-fluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)-1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (65); 6-(3-fluoro-4-(4- (2-Methoxyethyl)piperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (66); 6-(3-(4-isopropylpiperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (67); 6-(3-(4-cyclopropylpiperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (68); 2-(4-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine-6-yl)- 2-Fluorophenyl)piperazin-1-yl)ethyl-1-ol (69); 6-(3-fluoro-4-(4-(tetrahydrofuran-3-yl)piperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (70); 6-(3-fluoro-4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (71); 6-(3-fluoro-4-(4-isobutylpiperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (72);6-(4-(8-isobutyl-3,8-diazabicyclo[3.2.1]oct-3-yl)phenyl)-1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (73); 6-(4-(8-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)phenyl)-1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (74); 6-(3-fluoro-4-(8-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)phenyl)-1,4-dimethyl-2-(4-(methanesulfonyl)phenyl) 3-(3-(4-(1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)phenyl)-3,8-diazabicyclo[3.2.1]oct-8-yl)prop-1-ol (76); 3-(3-(4-(1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-2-fluorophenyl)-3,8-diazabicyclo[3.2.1]oct-8-yl)prop-1-ol (77); 6-(2,5-difluoro-4-(8-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]oct-8-yl)prop-1-ol Bicyclic [3.2.1]oct-3-yl)phenyl)-1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (78); 3-(3-(4-(1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-2,5-difluorophenyl)-3,8-diazabicyclic [3.2.1]oct-8-yl)prop-1-ol (79-80); 6-(2,5-difluoro-4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (78); 3-(3-(4-(1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine ... ]Pyridine (81); 6-(2,3-difluoro-4-(4-isobutylpiperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (82); 6-(2,3-difluoro-4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (83); 6-(3,5-difluoro-4-(4-isobutylpiperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (84);4-(4-(1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)phenyl)thiomorpholine 1,1-dioxide (85); 4-(4-(1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)phenyl)morpholine (86); 1-cyclopropyl-4-(4-(1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)phenyl)piperidin-4-ol (87); 4-(4-(1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl) 6-(3,5-difluoro-4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (89); 4-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-2-fluorophenyl)-1-isobutylpiperidine-4-ol (90); (1R,3r,5S)-3-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-2-fluorophenyl)-8-isobutylpiperidine-4-ol Butyl-8-azabicyclo[3.2.1]oct-3-ol (91); 4-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-2-fluorophenyl)-1-(2-methoxyethyl)piperidin-4-ol (92); 1-cyclopropyl-4-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-2-fluorophenyl)piperidin-4-ol (93); 4-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-2,5-difluorophenyl)-1-isobutylpiperidin-4 - Alcohol (94); 4-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-2,5-difluorophenyl)-1-(2-methoxyethyl)piperidine-4-ol (95); 1-cyclopropyl-4-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-2,5-difluorophenyl)piperidine-4-ol (96); 6-(2,5-difluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (97);6-(3,5-difluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)-1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (98); 6-(2,3-difluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)-1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (99); (1R,3r,5S)-3-(4-(1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-2-fluorophenyl)-8-isopropyl 8-azabicyclo[3.2.1]oct-3-ol (100); (1R,3r,5S)-3-(4-(1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-2-fluorophenyl)-8-ethyl-8-azabicyclo[3.2.1]oct-3-ol (101); (1R,3r,5S)-3-(4-(1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-2-fluorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-3-ol (102); (1R,3r,5S)-3-(4-(1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-2-fluorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-3-ol (102); (1R,3r,5S)-3-(4-(1, 4-Dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-3-fluorophenyl)-8-isopropyl-8-azabicyclo[3.2.1]oct-3-ol (103); 1-(tert-butyl)-4-(4-(1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-2-fluorophenyl)piperidin-4-ol (104); (R)-4-(4-(1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-2-fluorophenyl)-1-isopropyl-2,2-dimethylpiperidin-4-ol (10) 5); (S)-4-(4-(1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-2-fluorophenyl)-1-isopropyl-2,2-dimethylpiperidin-4-ol (106); 4-(4-(1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-2-fluorophenyl)-1-isopropylpiperidin-4-ol (107); 1-(tert-butyl)-4-(4-(1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-3-fluorophenyl)piperidin-4-ol (108);4-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-3-fluorophenyl)-1-isopropylpiperidin-4-ol (109); 6-(4-(4-(4-iodophenylethyl)piperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (110); 6-(4-(4-(4-bromophenylethyl)piperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (111); 6-(4-(4-(4-iodophenylmethyl)piperazin-1-yl)phenyl)-1 ,4-Dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (112); 6-(4-(4-(4-bromophenylmethyl)piperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (113); 6-(1-(8-isobutyl-8-azabicyclo[3.2.1]oct-3-yl)piperidin-4-yl)-1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (114); 4-(4-(4-(3-fluoro-1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine c]pyridin-6-yl)benzyl)piperazin-1-yl)-2-methylbut-2-ol (115); 4-[4-[[4-[1-cyclopropyl-4-methyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridin-6-yl]phenyl]methyl]piperazin-1-yl]-2-methyl-but-2-ol (116); 4-[4-[[4-[1-(difluoromethyl)-4-methyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridin-6-yl]phenyl]methyl]piperazin-1-yl]-2-methyl-but-2-ol (117); 2-[6-[4-(4-isopropylpiperazin-1-yl)phenyl]-1-methyl-2-(4-methylsulfonylphenyl)pyrrolo[ 3,2-c]pyridin-4-yl]prop-2-ol (118); 6-[4-(4-isopropylpiperazin-1-yl)phenyl]-4-methoxy-1-methyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridine (119); 4-[6-[4-(4-isopropylpiperazin-1-yl)phenyl]-1-methyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridin-4-yl]morpholine (120); 1-[3-[[4-[1-cyclopropyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridin-6-yl]phenyl]methyl]-3,8-diazabicyclo[3.2.1]oct-8-yl]-2-methyl-prop-2-ol (121);1-(4-(4-(3-fluoro-1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzyl)piperazin-1-yl)-2-methylprop-2-ol (122); 1-(4-(4-(1-cyclopropyl-4-methyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzyl)piperazin-1-yl)-2-methylprop-2-ol (123); 1-(4-(4-(1-(difluoromethyl)) -4-Methyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzyl)piperazin-1-yl)-2-methylprop-2-ol (124); 2-(6-(4-((4-isopropylpiperazin-1-yl)methyl)phenyl)-1-methyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-4-yl)prop-2-ol (125); 6-(4-((4-isopropylpiperazin-1-yl)methyl)phenyl)-4-methoxy-1- Methyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (126); 4-(6-(4-((4-isopropylpiperazin-1-yl)methyl)phenyl)-1-methyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-4-yl)morpholine (127); 1-(4-(4-(1-cyclopropyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzyl)piperazin-1-yl)-2-methyl 4-(4-(4-(1-cyclopropyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzyl)piperazin-1-yl)-2-methylbut-2-ol (129); or 1-(8-(4-(1-cyclopropyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-methylprop-2-ol (130).

[0214] One implementation provides a TLR9 IC 50 Compounds of formula (I) with a value ≤ 0.6 μM.

[0215] One implementation provides a TLR9 IC 50 Compounds of formula (I) with a value ≤ 0.1 μM.

[0216] One implementation provides a TLR9 IC 50 Compounds of formula (I) with a value ≤0.05 μM.

[0217] One implementation provides a TLR9 IC 50Compounds of formula (I) with a value ≤ 0.025 μM.

[0218] One implementation provides a TLR9 IC 50 Compounds of formula (I) with a value ≤ 0.015 μM.

[0219] One implementation provides a TLR9 IC 50 Compounds of formula (I) with a value ≤ 0.01 μM.

[0220] In another embodiment, the present invention provides a composition comprising at least one of the compounds of the present invention or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0221] In another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound of the present invention or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0222] In another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0223] In another embodiment, the present invention provides a method for preparing the compound of the present invention.

[0224] In another embodiment, the present invention provides an intermediate for preparing the compound of the present invention.

[0225] In another embodiment, the present invention provides a pharmaceutical composition as defined above, which further comprises one or more other therapeutic agents.

[0226] definition

[0227] Those skilled in the art will more readily understand the features and advantages of the present invention after reading the following detailed description. It should be understood that certain features of the invention described above and below in separate embodiments for clarity can also be combined to form a single embodiment. Conversely, various features of the invention described in single embodiments for brevity can also be combined to form sub-combinations. The embodiments identified herein as illustrative or preferred are intended to be explanatory rather than restrictive.

[0228] Unless otherwise specified herein, references to the singular may also include the plural. For example, “a (and an)” may refer to one or more.

[0229] As used herein, the term “compound” refers to at least one compound. For example, a compound of formula (I) includes one compound of formula (I) and two or more compounds of formula (I).

[0230] Unless otherwise indicated, it is assumed that any heteroatom with an unsaturated valence has enough hydrogen atoms to saturate the valence.

[0231] The definitions set forth herein take precedence over those set forth in any patent, patent application and / or patent application publication incorporated herein by reference.

[0232] The following lists definitions of various terms used to describe the invention. When a term is used individually throughout the specification or as part of a larger group, these definitions apply to the term (unless it is otherwise limited in specific circumstances).

[0233] Throughout this specification, those skilled in the art can select groups and their substituents to obtain stable moieties and compounds.

[0234] According to the conventions used in this field,

[0235]

[0236] In the structural formula of this paper, the bonds are used to describe the connection points between the parts or substituents and the core or main chain structure.

[0237] As used in this article, the terms “halogen” and “halogen” refer to F, Cl, Br and I.

[0238] The term "cyano" refers to the -CN group.

[0239] The term "amino" refers to the -NH2 group.

[0240] The term "oxo" refers to the =O group.

[0241] As used herein, the term "alkyl" refers to a branched or straight-chain saturated aliphatic hydrocarbon group containing, for example, 1 to 12 carbon atoms, 1 to 6 carbon atoms, and 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, dibutyl, and tert-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl. When a number appears in subscript form after the symbol "C", the subscript more specifically defines the number of carbon atoms that a particular group may contain. For example, "C..." 1-6 "Alkyl" refers to straight-chain and branched alkyl groups having one to six carbon atoms.

[0242] As used herein, the term "fluoroalkyl" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups substituted with one or more fluorine atoms. For example, "C 1-4 "Fluoroalkyl" is intended to include 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.

[0243] The term "hydroxyalkyl" includes branched and straight-chain saturated alkyl groups substituted with one or more hydroxyl groups. For example, "hydroxyalkyl" includes -CH2OH, -CH2CH2OH, and C... 1-4 Hydroxyalkyl.

[0244] The term "aminoalkyl" includes branched and straight-chain saturated alkyl groups substituted with one or more amino groups. For example, "aminoalkyl" includes -CH2NH2, -CH2CH2NH2, and C... 1-4 Aminoalkyl.

[0245] The term "cyanoalkyl" includes branched and straight-chain saturated alkyl groups substituted with one or more cyano groups. For example, "cyanoalkyl" includes -CH2CN, -CH2CH2CN, and C... 1-4 Cyanoalkyl.

[0246] As used herein, the term "alkoxy" refers to an alkyl group, such as a methoxy group (-OCH3), which is attached to the parent molecule via an oxygen atom. For example, "C 1-3 "Alkoxy" refers to an alkoxy group having one to three carbon atoms.

[0247] The terms "fluoroalkoxy" and "-O (fluoroalkyl)" refer to fluoroalkyl groups as defined above, linked via an oxygen bond (-O-). For example, "C 1-4 "Fluoroalkoxy" is intended to include C1, C2, C3, and C4 fluoroalkoxy groups.

[0248] As used herein, the term "alkoxyalkyl" refers to an alkoxy group linked via its oxygen atom to an alkyl group, which in turn is linked via a carbon atom to a parent molecule moiety, such as methoxymethyl (-CH2OCH3). For example, "C..." 2-4 "Alkoxyalkyl" refers to alkoxyalkyl groups having two to four carbon atoms, such as -CH2OCH3, -CH2CH2OCH3, -CH2OCH2CH3 and -CH2CH2OCH2CH3.

[0249] As used herein, the term "cycloalkyl" refers to a group derived from a non-aromatic monocyclic or polycyclic hydrocarbon molecule by removing a hydrogen atom from a self-saturated ring carbon atom. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl. When a number appears in subscript form after 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 "Cycloalkyl" refers to a cycloalkyl group having three to six carbon atoms.

[0250] The phrase “pharmaceutically acceptable” is used in this article to refer to compounds, materials, compositions, and / or dosage forms that, within the bounds of reasonable medical judgment, are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and whose benefits / risks are commensurate with a reasonable ratio.

[0251] Compounds of formula (I) may be provided in amorphous or crystalline solid form. Compounds of formula (I) in amorphous solid form may be provided by lyophilization.

[0252] It should be further understood that solvates (e.g., hydrates) of compounds of formula (I) are also within the scope of this invention. The term "solvate" means the physical association of a compound of formula (I) with one or more solvent molecules (organic or inorganic). This physical association includes hydrogen bonding. In some cases, such as when one or more solvent molecules are incorporated into the lattice of a crystalline solid, the solvate can be separated. "Solvate" encompasses both the solution phase and the separable solvate. Exemplary solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates, and ethyl acetate solvates. Solvation methods are known in the art.

[0253] Various forms of prodrugs are well known in the art and described in Rautio, J. et al., Nature Review Drug Discovery, 17, 559-587 (2018).

[0254] Furthermore, the compounds of formula (I) can be isolated and purified after preparation to obtain compositions containing 99% by weight of the compounds of formula (I) (“substantially pure”), which are then used or formulated as described herein. Such “substantially pure” compounds of formula (I) are also contemplated herein as part of the present invention.

[0255] "Stable compound" and "stable structure" mean a compound that is sufficiently robust to withstand separation from the reaction mixture to a suitable purity and formulation into an effective therapeutic agent. This invention is intended to include stable compounds.

[0256] "Therapeutic effective amount" is intended to include the amount of a single compound of the invention that is effective as a TLR9 inhibitor or effective in treating or preventing conditions associated with fibrotic diseases or symptoms (bile acid dysregulation), such as pathological fibrosis, or the amount of a combination of the claimed compounds or the amount of a compound of the invention combined with other active ingredients.

[0257] As used herein, “treating” encompasses treating a disease state in mammals, particularly humans, and includes: (a) preventing the development of the disease state in mammals, especially when such mammals are susceptible to the disease state but have not yet been diagnosed with it; (b) suppressing the disease state, i.e., halting its development; and / or (c) alleviating the disease state, i.e., promoting its remission.

[0258] The compounds of this invention are intended to include all isotopes of the atoms appearing in the compounds of this invention. Isotopes include atoms with the same number of atoms but different mass numbers. As a general example, but not limitingly, isotopes of hydrogen include deuterium (D) and tritium (T). Isotopes of carbon include... 13 C and 14 C. The isotope-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described herein, using a suitable isotope-labeling reagent instead of the originally used unlabeled reagent. For example, methyl (-CH3) also includes deuterated methyl groups, such as -CD3.

[0259] practicality

[0260] The compounds of this invention are suitable for inhibiting TLR9 receptors.

[0261] One embodiment provides a method for treating a patient in need of such treatment with a disease, condition, or illness related to bile acid dysregulation, the method 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.

[0262] One embodiment provides a method for treating a patient in need of such treatment with a disease, symptom, or condition related to the activity of the TLR9 receptor, 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.

[0263] One embodiment provides a method for treating a disease, symptom, or condition, comprising administering a therapeutically effective amount of at least one of the compounds of the invention, alone or optionally in combination with another compound of the invention and / or at least one other type of therapeutic agent, to a patient in need of such treatment.

[0264] One embodiment provides a method for inducing TLR9 receptor agonism 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.

[0265] In some implementations, diseases, conditions, or illnesses are associated with TLR9 dysfunction, including pathological fibrosis, cancer, inflammatory conditions, metabolic or cholestatic conditions.

[0266] In some implementations, diseases, symptoms, or conditions are associated with fibrosis, including liver fibrosis, gallbladder fibrosis, kidney fibrosis, heart fibrosis, skin fibrosis, eye fibrosis, and pancreatic fibrosis.

[0267] In other embodiments, the disease, symptom, or condition is associated with a proliferative cytokine disorder, such as cancer. In some embodiments, cancer includes solid tumor growth or neoplasm formation. In other embodiments, cancer includes tumor metastasis. In some embodiments, cancer is cancer of the liver, gallbladder, small intestine, large intestine, kidney, prostate, bladder, blood, bone, brain, breast, central nervous system, cervix, colon, endometrium, esophagus, reproductive organs, genitourinary tract, head, larynx, lungs, muscle tissue, neck, oral or nasal mucosa, ovary, pancreas, skin, spleen, stomach, testis, or thyroid. In other embodiments, cancer is carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, or seminoma.

[0268] Examples of diseases, conditions, or illnesses related to FXR activity that can be prevented, modulated, or treated according to the present invention include, but are not limited to, transplantation injections, fibrotic conditions (e.g., liver fibrosis, kidney fibrosis), inflammatory conditions (e.g., acute hepatitis, chronic hepatitis, non-alcoholic steatosis (NASH), irritable bowel syndrome (IBS), inflammatory bowel disease (IBD)), and proliferative conditions (e.g., cancer, myeloma, fibroma, hepatocellular carcinoma, colorectal cancer, prostate cancer, leukemia, Kaposi's sarcoma, solid tumors).

[0269] The fibrotic, inflammatory, and proliferative conditions suitable for prevention or treatment by the compounds of this invention include, but are not limited to, non-alcoholic fatty liver disease (NAFLD), alcoholic or non-alcoholic steatosis (NASH), acute hepatitis, chronic hepatitis, cirrhosis, primary biliary cirrhosis, primary sclerosing cholangitis, drug-induced hepatitis, biliary cirrhosis, portal hypertension, aplastic disorders, hepatic insufficiency, hepatic blood loss disorders, nephropathy, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), pancreatic secretory disorders, benign prostatic hyperplasia, neuropathic bladder disease, diabetic nephropathy, focal segmental glomerulosclerosis, IgA nephropathy, drug- or transplant-induced nephropathy, autoimmune nephropathy, lupus nephritis with liver fibrosis, renal fibrosis, chronic kidney disease (CKD), diabetic nephropathy (DKD), skin fibrosis, keloids, and systemic sclerosis. Scleroderma, Viral Fibrosis, Idiopathic Pulmonary Fibrosis (IPF), 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 Tumors, Intervertebral Disc Herniation, Spinal Stenosis, Heart Failure, Cardiac Fibrosis, Vascular Fibrosis, Perivascular Fibrosis, Foot-and-Mouth Disease, Cancer, Myeloma, Fibroma, Hepatocellular Carcinoma, Colorectal Cancer, Prostate Cancer, Leukemia, Chronic Lymphocytic Leukemia, Kaposi's Sarcoma, Solid Tumors, Cerebral Infarction, Cerebral Hemorrhage, Neuropathic Pain, Peripheral Neuropathy, Age-Related Macular Degeneration (AMD), Glaucoma, Ocular Fibrosis, Corneal Scarring, Diabetic Retinopathy, Proliferative Vitreoretinopathy (PVR), Cicatricial Pemphigoid, Glaucoma Fibrosis Surgical Scar, Crohn's Disease Diseases such as systemic lupus erythematosus; keloid formation due to abnormal wound healing; fibrosis, myelofibrosis, and fibroids following organ transplantation. In one embodiment, the present invention provides a method for treating fibrotic conditions, inflammatory conditions, or proliferative conditions, comprising administering, alone or optionally in combination with another compound of the present invention and / or at least one other type of therapeutic agent, a therapeutically effective amount of at least one compound of the present invention to a patient in need of such treatment.

[0270] In another embodiment, the present invention provides a compound of the present invention for use in a therapeutic therapy.

[0271] In another embodiment, the present invention provides a compound of the invention for use in a therapy for treating fibrotic, inflammatory, or proliferative conditions.

[0272] In another embodiment, the present invention also provides the use of the compounds of the present invention for manufacturing medicaments for treating fibrotic conditions, inflammatory conditions, or proliferative conditions.

[0273] In another embodiment, the present invention provides a method for treating fibrotic conditions, inflammatory conditions, or proliferative conditions, comprising administering therapeutically effective amounts of a first and a second therapeutic agent to a patient in need, wherein the first therapeutic agent is a compound of the present invention.

[0274] In another embodiment, the present invention provides a combination formulation of the compound of the present invention used simultaneously, separately, or sequentially in a therapy with other therapeutic agents.

[0275] In another embodiment, the present invention provides a combination formulation of the compound of the present invention with other therapeutic agents for simultaneous, separate or sequential use in treating fibrotic conditions, inflammatory conditions or proliferative conditions.

[0276] The compounds of the present invention can be used in combination with other therapeutic agents, such as one or more antifibrotic and / or anti-inflammatory therapeutic agents.

[0277] In one embodiment, the other therapeutic agent used in combination with the pharmaceutical composition or method of combination or for combination use is selected from one or more (preferably one to three) of the following therapeutic agents: TGFβ receptor inhibitors (e.g., galunisertib); TGFβ synthesis inhibitors (e.g., pirfenidone); inhibitors of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) receptor kinases (e.g., nintedanib); humanized anti-α V β6 integrin monoclonal antibodies (e.g., 3G9); recombinant human pentameric protein-2; recombinant human serum amyloid protein P; recombinant human antibodies against TGFβ-1, TGFβ-2, and TGFβ-3; endothelin receptor antagonists (e.g., macitentan); interferon-γ; c-Jun N-terminal kinase (JNK) inhibitors (e.g., 4-[[9-[(3S)-tetrahydro-3-furanyl]-8-[(2,4,6-trifluorophenyl)amino]-9H-purine- 2-[2-yl]amino]-trans-cyclohexanol; 3-pentylphenylacetic acid (PBI-4050); tetrasubstituted porphyrin derivatives containing manganese(III); monoclonal antibodies targeting eosin-2; interleukin-13 (IL-13) antibodies (e.g., lebrikizumab, tralokinumab); bispecific antibodies targeting interleukin-4 (IL-4) and interleukin-13 (IL-13); NK1 tachykinin receptor agonists (e.g., Sar 9 Met(O2) 11-Substance P); Cintredekin Besudotox; recombinant human DNA-derived IgG1κ monoclonal antibodies against connective tissue growth factor; and all-human IgG1κ antibodies selective for CC-chemokine ligand 2 (e.g., carlumab, CCX140); antioxidants (e.g., N-acetylcysteine); phosphodiesterase 5 (PDE5) inhibitors (e.g., sildenafil); agents for the treatment of obstructive airway diseases, such as muscarinic antagonists (e.g., tiotropium, ipatropium bromide). bromide; β2 adrenergic agonists (e.g., salbutamol, salmeterol); corticosteroids (e.g., triamcinolone, dexamethasone, fluticasone); immunosuppressants (e.g., tacrolimus, rapamycin, pimecrolimus); and agents indicated for the treatment of fibrotic conditions (such as liver fibrosis, biliary fibrosis, and renal fibrosis), non-alcoholic fatty liver disease (NALFD), non-alcoholic steatohepatitis (NASH), cardiac fibrosis, idiopathic pulmonary fibrosis (IPF), and systemic sclerosis. Suitable treatments for these fibrotic conditions include, but are not limited to, FXR agonists (e.g., OCA, GS-9674, and LJN452); LOXL2 inhibitors (e.g., simtuzumab); LPA1 antagonists (e.g., BMS-986020 and SAR 100842); PPAR modulators (e.g., elafibrinor, pioglitazone, saroglitazar, and IVA337); SSAO / VAP-1 inhibitors (e.g., PXS-4728A and SZE5302); ASK-1 inhibitors (e.g., GS-4997 or selonsertib); and ACC inhibitors (e.g., CP-640186 and NDI-0). 10976 or GS-0976); FGF21 mimics (e.g. LY2405319 and BMS-986036); apoptosis protease inhibitors (e.g. emricasan); NOX4 inhibitors (e.g. GKT137831); MGAT2 inhibitors (e.g. BMS-963272); αV integrin inhibitors (e.g. abituzumab); and bile acid / fatty acid conjugates (e.g., aramchol).The FXR agonists of various embodiments of the present invention can also be used in combination with one or more therapeutic agents, such as CCR2 / 5 inhibitors (e.g., cenicriviroc); galactoglobin-3 inhibitors (e.g., TD-139, GR-MD-02); leukotriene receptor antagonists (e.g., tipelukast, montelukast); SGLT2 inhibitors (e.g., dapagliflozin, remogliflozin); and GLP-1 receptor agonists. (e.g., liraglutide and semaglutide); FAK inhibitors (e.g., GSK-2256098); CB1 inverse agonists (e.g., JD-5037); CB2 agonists (e.g., APD-371 and JBT-101); autotaxin inhibitors (e.g., GLPG1690); prolyl tRNA synthetase inhibitors (e.g., halofugenone); FPR2 agonists (e.g., ZK-994); and THR agonists (e.g., MGL:3196). In another embodiment, the other therapeutic agents used in the combination of the pharmaceutical composition or combination method or combination use are selected from one or more (preferably one to three) of immuno-oncology agents, such as alemtuzumab, atezolizumab, ipilimumab, nivolumab, offatumumab, pembrolizumab, and rituximab.

[0278] When the terms “TLR9-related condition” or “TLR9-related disease or symptom” are used in this article, each is intended to encompass all the conditions identified above, as repeated in detail, as well as any other conditions affected by TLR9 inhibition.

[0279] When used in combination with the compounds of the present invention, the other therapeutic agents described above may be used, for example, in amounts indicated in the Physicians' Desk Reference (PDR) or otherwise determined by those skilled in the art. In the methods of the present invention, such other therapeutic agents may be administered before, simultaneously with, or after the application of the compounds of the present invention. The present invention also provides pharmaceutical compositions capable of treating conditions associated with TLR9.

[0280] The compositions of the present invention may contain other therapeutic agents as described above, and may be formulated, for example, according to techniques known in pharmaceutical formulation techniques by employing conventional solid or liquid mediators or diluents and a class of pharmaceutical additives suitable for the desired mode of administration.

[0281] Therefore, the present invention further includes compositions comprising one or more compounds of formula (I) and pharmaceutically acceptable carriers.

[0282] "Pharmaceutically acceptable carriers" are generally accepted media used in techniques for delivering bioactive agents to animals, particularly mammals. Pharmaceutically acceptable carriers are formulated based on several factors known to a person skilled in the art. These factors include, but are not limited to: the type and nature of the active agent being formulated; the individual to whom the composition containing the agent will be 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 various solid and semi-solid dosage forms. In addition to the active agent, such carriers may also include a variety of different components and additives, which are included in the formulation for various reasons well known to a person skilled in the art (e.g., to stabilize the active agent, binder, etc.). Descriptions of suitable pharmaceutically acceptable carriers and the factors involved in their selection can be found in various readily available sources, such as Remington: The Science and Practice of Pharmacy, 22nd edition (2013).

[0283] The compound according to formula (I) may be administered by any means suitable for the condition to be treated, depending on the need for targeted treatment or the amount of the compound of formula (I) to be delivered.

[0284] Compounds of formula (I) may be administered via any suitable route, preferably in the form of a pharmaceutical composition suitable for this route and at a dose effective for the intended treatment. The compounds and compositions of the present invention may be administered, for example, in dosage form containing pharmaceutically acceptable conventional carriers, adjuvants, and mediators, via oral, mucosal, or non-enteric routes (including intravascular, intravenous, intraperitoneal, subcutaneous, intramuscular, and intrasternal administration). For example, the pharmaceutical carrier may contain a mixture of mannitol or lactose with microcrystalline cellulose. The mixture may contain additional components, such as lubricants, for example magnesium stearate; and disintegrants, such as crospovidone. The carrier mixture may be filled into gelatin capsules or compressed into tablets. The pharmaceutical compositions may be administered, for example, in oral dosage forms or infusion forms.

[0285] 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 prepared in a dosage unit containing a specific amount of the active ingredient. For example, the pharmaceutical composition may be provided in the form of tablets or capsules containing an amount of the active ingredient in the range of about 0.1 to 1000 mg, preferably about 0.25 to 250 mg, and more preferably about 0.5 to 100 mg. Suitable daily doses for human or other mammals can vary widely depending on the patient's condition and other factors, but can be determined using conventional methods.

[0286] Any pharmaceutical composition considered herein may be delivered orally, for example, via any acceptable and suitable oral formulation. Exemplary oral formulations include, but are not limited to, tablets, sugar-coated 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 prepared according to any method known in the art for manufacturing pharmaceutical compositions intended for oral administration. To provide a pharmaceutically palatable formulation, pharmaceutical compositions according to the invention may contain at least one agent selected from sweeteners, flavoring agents, coloring agents, modifiers, antioxidants, and preservatives.

[0287] Tablets can be prepared, for example, by blending at least one compound of formula (I) with at least one pharmaceutically acceptable, non-toxic excipient suitable for the manufacture of tablets. Exemplary excipients include, but are not limited to, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate; granulating agents and disintegrants such as microcrystalline cellulose, croscarmellose sodium, corn starch, and alginic acid; binders such as starch, gelatin, polyvinylpyrrolidone, and gum arabic; and lubricants such as magnesium stearate, stearic acid, and talc. Additionally, tablets may be uncoated or coated using known techniques to mask unpleasant tastes of the drug or to delay the disintegration and absorption of the active ingredient in the gastrointestinal tract, thereby maintaining the action of the active ingredient for a longer period. Exemplary water-soluble taste-masking materials include, but are not limited to, hydroxypropyl-methylcellulose and hydroxypropyl-cellulose. Exemplary time-delaying materials include, but are not limited to, ethylcellulose and cellulose acetate butyrate.

[0288] Hard gelatin capsules can be prepared, for example, by mixing at least one compound of formula (I) with at least one inert solid diluent, such as calcium carbonate, calcium phosphate and kaolin.

[0289] Soft gelatin capsules can be prepared, for example, by mixing at least one compound of formula (I) with at least one water-soluble carrier (such as polyethylene glycol) and at least one oily medium (such as peanut oil, liquid paraffin and olive oil).

[0290] Aqueous suspensions can be prepared, for example, by blending at least one compound of formula (I) with at least one excipient suitable for making aqueous suspensions. Excipients suitable for making aqueous suspensions include, but are not limited to, suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, alginic acid, polyvinylpyrrolidone, tragacanth gum, and gum arabic; dispersants or wetting agents such as naturally occurring phospholipids, such as lecithin; condensation products of alkyl epoxides and fatty acids, such as polyoxyethylene stearate; condensation products of ethylene oxides and long-chain aliphatic alcohols, such as heptadecanyl ethyl-oxyhexadecyl alcohol; condensation products of ethylene oxides and esters derived from fatty acids and hexitols, such as polyoxyethylene sorbitan monooleate; and condensation products of ethylene oxides and esters derived from fatty acids and hexitols, such as polyoxyethylene sorbitan monooleate. Aqueous suspensions may also contain at least one preservative, such as ethylparaben and n-propylparaben; at least one colorant; at least one flavoring agent; and / or at least one sweetener, including but not limited to sucrose, saccharin and aspartame.

[0291] Oily suspensions can be prepared, for example, by suspending at least one compound of formula (I) in vegetable oils (such as peanut oil, olive oil, sesame oil, and coconut oil) or mineral oils (such as liquid paraffin). Oily suspensions may also contain at least one thickener, such as beeswax, hard paraffin, and cetyl alcohol. To provide a palatable oily suspension, at least one sweetener and / or at least one flavoring agent described above may be added to the oily suspension. Oily suspensions may additionally contain at least one preservative, including but not limited to, antioxidants such as butylated hydroxyanisole and α-tocopherol.

[0292] Dispersible powders and granules can be prepared, for example, by blending at least one compound of formula (I) with at least one dispersant and / or wetting agent, at least one suspending agent and / or at least one preservative. Suitable dispersants, wetting agents and suspending agents have been described above. Exemplary preservatives include, but are not limited to, antioxidants such as ascorbic acid. In addition, dispersible powders and granules may also contain at least one excipient, including but not limited to, sweeteners, flavoring agents and coloring agents.

[0293] An emulsion of at least one compound of formula (I) can be prepared, for example, as an oil-in-water emulsion. The oil phase of an emulsion containing a compound of formula (I) can be composed of known ingredients in a known manner. The oil phase can be provided by (but is not limited to) the following: for example, vegetable oils, such as olive oil and peanut oil; mineral oils, such as liquid paraffin; and mixtures thereof. Although the phase may contain only an emulsifier, it may also 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 phospholipids, such as soybean lecithin; esters or metaesters derived from fatty acids and hexadiol anhydrides, such as sorbitan monooleate; and condensation products of metaesters and ethylene oxide, such as polyoxyethylene sorbitan monooleate. Preferably, hydrophilic emulsifiers are included together with lipophilic emulsifiers that act as stabilizers. Both oils and fats are also preferred. In summary, the emulsifier, with or without a stabilizer, constitutes a so-called emulsified wax, which, together with oils and fats, constitutes a so-called emulsified ointment base, forming the oily dispersed phase of the ointment formulation. The emulsion may also contain sweeteners, flavoring agents, preservatives, and / or antioxidants. Suitable emulsifiers and emulsion stabilizers for use in the formulations of this invention include Tween 60, Span 80, cetearyl alcohol, myristicin, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate alone or containing wax, or other substances well known in the art.

[0294] Compounds of formula (I) may also be delivered intravenously, subcutaneously, and / or intramuscularly, for example, via any pharmaceutically acceptable and suitable injectable form. Exemplary injectable forms include, but are not limited to, sterile aqueous solutions containing, for example, acceptable mediators and solvents such as water, Ringer's solution, and isotonic sodium chloride solution; sterile oil-in-water microemulsions; and aqueous or oil suspensions.

[0295] Formulations intended for non-enteral administration may be in the form of aqueous or non-aqueous isotonic sterile injectable solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules using one or more of the carriers or diluents mentioned for oral administration formulations, or by using other suitable dispersants or wetting agents and suspending agents. The compounds may be soluble in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum, and / or various buffer solutions. Other adjuvants and administration methods are well known in pharmaceutical technology. The active ingredient may also be administered by injection in the form of a composition containing a suitable carrier (including physiological saline, dextran, or water) or containing cyclodextrin (i.e., Captisol), co-solvent solubilization (i.e., propylene glycol), or microcellular solubilization (i.e., Tween 80).

[0296] Sterile injectable formulations can also be sterile injectable solutions or suspensions in non-toxic, non-enteric, acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable mediators and solvents may include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, non-volatile oils are routinely used as solvents or suspension media. For this purpose, any mild, non-volatile oil may be used, including synthetic monoglycerides or diglycerides. Furthermore, fatty acids such as oleic acid can be used in the preparation of injectable formulations.

[0297] Sterile injectable oil-in-water microemulsions can be prepared, for example, by: 1) dissolving at least one compound of formula (I) in an oil phase, such as a mixture of soybean oil and lecithin; 2) combining the oil-containing compound of formula (I) with a mixture of water and glycerol; and 3) treating the combination to form a microemulsion.

[0298] Sterile aqueous or oily suspensions can be prepared according to methods known in the art. For example, sterile aqueous solutions or suspensions can be prepared using non-enteric acceptable non-toxic diluents or solvents, such as 1,3-butanediol; and sterile oily suspensions can be prepared using acceptable sterile, non-toxic solvents or suspension media, such as sterile non-volatile oils (e.g., synthetic monoglycerides or diglycerides) and fatty acids (such as oleic acid).

[0299] Pharmaceutically acceptable carriers, adjuvants, and mediators that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; self-emulsifying drug delivery systems (SEDDS), such as d-α-tocopherol polyethylene glycol 1000 succinate; surfactants for pharmaceutical dosage forms, such as Tween, polyethoxylated castor oil (such as CREMOPHOR surfactant (BASF)) or other similar polymeric delivery matrices; serum proteins, such as human serum albumin; buffering substances, such as phosphates; glycine; sorbic acid; potassium sorbate; mixtures of saturated vegetable fatty acid metaglycerides; 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 carboxymethyl cellulose; polyacrylates; waxes; polyethylene-polyoxypropylene block polymers; polyethylene glycol; and lanolin. Cyclodextrins (such as α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin) or chemically modified derivatives (such as hydroxyalkyl cyclodextrins, including 2-hydroxypropyl-cyclodextrin and 3-hydroxypropyl-cyclodextrin) or other dissolved derivatives may also be advantageously used to enhance the delivery of compounds of the formulas described herein.

[0300] The pharmaceutically active compounds of the present invention can be processed according to conventional pharmaceutical methods to produce pharmaceutical preparations for administration to patients, including humans and other mammals. The pharmaceutical compositions may undergo conventional pharmaceutical processes such as sterilization and / or may contain conventional adjuvants, such as preservatives, stabilizers, humectants, emulsifiers, buffers, etc. Tablets and pills may be additionally prepared with enteric coatings. Such compositions may also contain adjuvants such as humectants, sweeteners, flavoring agents, and aromatizers.

[0301] The amount of compound applied and the dosing regimen for treating disease conditions with the compounds and / or compositions of the present invention depend on a variety of factors, including an individual's age, weight, sex, medical condition; disease type; disease severity; route and frequency of administration; and the specific compound used. Therefore, dosing regimens can vary widely, but can be routinely determined using standard methods. A daily dose of about 0.001 to 100 mg per kilogram of body weight, preferably between about 0.0025 and about 50 mg per kilogram of body weight, and optimally between about 0.005 and 10 mg per kilogram of body weight, is appropriate. The daily dose can be administered one to four times daily. Other dosing schedules include cycles of weekly and every two days.

[0302] For therapeutic purposes, the active compounds of the present invention are generally combined with one or more adjuvants suitable for the specified route of administration. For oral administration, the compounds may be blended with lactose, sucrose, starch powder, cellulose esters of alkyl cellulose, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric acid and sulfuric acid, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol, and subsequently tableted or encapsulated for convenient administration. These capsules or tablets may contain a controlled-release formulation, such as a dispersion of the active compound in hydroxypropyl methylcellulose.

[0303] The pharmaceutical compositions of the present invention comprise at least one compound of formula (I) and optionally include additional agents selected from pharmaceutically acceptable carriers, adjuvants, and mediators. Alternative compositions of the present invention comprise a compound of formula (I) as described herein, or a prodrug thereof, and a pharmaceutically acceptable carrier, adjuvant, or mediator.

[0304] This invention also covers an article of manufacture. As used herein, the article of manufacture is intended to include, but is not limited to, kits and packaging. The article of manufacture of this invention comprises: (a) a first container; (b) a pharmaceutical composition located within the first container, wherein the composition comprises a first therapeutic agent comprising a compound of the present invention or a pharmaceutically acceptable salt thereof; and (c) a product information label stating that the pharmaceutical composition can be used to treat cardiovascular disease, polyuria, and / or nauria. In another embodiment, the product information label states that the pharmaceutical composition can be used in combination with a second therapeutic agent for treating cardiovascular disease, polyuria, and / or nauria (as defined above). The article of manufacture may further comprise: (d) a second container, wherein components (a) and (b) are located within the second container, and component (c) is located inside or outside the second container. Located within the first and second containers means that each container contains the article within its boundaries.

[0305] The first container is a vessel for containing a pharmaceutical composition. This container may be used for manufacturing, storing, transporting, and / or selling individually or in whole. The first container is intended to encompass bottles, jars, vials, flasks, syringes, tubes (e.g. for cream formulations), or any other container used for manufacturing, containing, storing, or dispensing pharmaceutical products.

[0306] The second container is a container for holding the first container and optionally, any accompanying instruction leaflets. 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), sachets, and large bags. The instruction leaflets may be physically attached to the outside of the first container by tape, glue, U-straps, or another attachment method, or they may remain inside the second container without being physically attached to the first container. Alternatively, the instruction leaflets may be located on the outside of the second container. When located on the outside of the second container, the instruction leaflets are preferably physically attached by tape, glue, U-straps, or another attachment method. Alternatively, they may be adjacent to or in contact with the outside of the second container but not physically attached.

[0307] A drug instruction leaflet is a label, tag, mark, or other written piece of paper that describes information relating to the drug composition located within a first container. The information described will generally be determined by the regulatory agency in the region where the product is regulated. Preferably, the drug instruction leaflet specifically describes the indications for which the drug composition has been approved. The drug instruction leaflet can be made of any material from which an individual can read the information contained therein. Preferably, the drug instruction leaflet is a printable material (e.g., paper, plastic, cardboard, foil, adhesive-backed paper, or plastic) on which the desired information has been formed (e.g., printed or coated).

[0308] Preparation method

[0309] The compounds of the present invention can be prepared in a variety of ways well known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, as well as synthetic methods known in organic synthetic chemistry or variations thereof as understood by those skilled in the art. Preferred methods include, but are not limited to, those described below.

[0310] The reactions and techniques described in this section are carried out in solvents suitable for the reagents and materials used and for the transformations achieved. Furthermore, in the description of the synthetic methods described below, it should be understood that all proposed reaction conditions (including solvent selection, reaction atmosphere, reaction temperature, experimental duration, and processing procedures) are chosen as standard conditions for the reaction that will be readily recognized by those skilled in the art. Those skilled in the art of organic synthesis will understand that the functional groups present on various parts of the molecule must be compatible with the proposed reagents and reactions. These limitations on substituents compatible with the reaction conditions will be apparent to those skilled in the art, thus necessitating the use of alternative methods. Sometimes, judgments will be required to modify the order of synthetic steps or to choose a particular methodological flow over another to obtain the desired compounds of the present invention. It will also be recognized that another major consideration in the planning of any synthetic route in the art is the careful selection of protecting groups used to protect the reactive functional groups present in the compounds described in this invention. Authoritative descriptions of various alternative methods to trained practitioners are provided by Greene et al. (Protective Groups in Organic Synthesis, 3rd Edition, Wiley and Sons (1999)).

[0311] Process 1

[0312]

[0313] Procedure 1 describes the synthesis of compounds of formulas (I) and (I'). Cyclization of 1a and alkyne 1b in the presence of a palladium catalyst such as bis(triphenylphosphine)palladium chloride (II) and copper iodide (I) yields 1c and 1d. N-alkylation of 1c yields 1e. Suzuki coupling of 1e with borate 1f yields compound (I) or a precursor of (I). Similarly, suzuki coupling of 1e with borate 1g yields 1h, which can be converted to compound (I') by hydrogenation, deprotection, and further modification.

[0314] Process 2

[0315]

[0316] Procedure 2 describes the synthesis of compounds of formula (II) and (II'). N-alkylation of 1d, obtained from the cyclization of 1a and alkyne 1b in procedure 1, yields 1f. Coupling 1f with 1g of borate ester to yield a compound of formula (II) or a precursor of (II). Similarly, coupling 1f with 1h of borate ester to yield 1i, which can be converted into a compound of formula (II') by hydrogenation, deprotection, and further modification.

[0317] Example

[0318] The compounds of the present invention and the intermediates used to prepare the compounds of the present invention can be prepared using the procedures and related procedures shown in the following examples. The methods and conditions used in these examples and the actual compounds prepared in these examples are not intended to be limiting, but rather to demonstrate how the compounds of the present invention can be prepared. When not prepared by the procedures described herein, the starting materials and reagents used in these examples are generally commercially available or reported in the chemical literature or can be prepared using procedures described in the chemical literature. The present invention is further defined in the following examples. It should be understood that the examples are provided by way of illustration only. Based on the foregoing discussion and examples, those skilled in the art can determine the essential features of the invention, and various changes and modifications can be made to adapt the invention to various uses and conditions without departing from its spirit and scope. Therefore, the present invention is not limited to the illustrative examples set forth below, but is defined by the appended claims.

[0319] In the given examples, the phrase "drying and concentrating" generally refers to drying a solution in an organic solvent with sodium sulfate or magnesium sulfate, followed by filtration from the filtrate and removal of the solvent (generally under reduced pressure and at a temperature suitable for the stability of the material).

[0320] Use ChemDraw Ultra, version 16.0.1.4 (CambridgeSoft) to determine the chemical name. Use the following abbreviations:

[0321] aq. Aqueous solution

[0322] BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl

[0323] BOP Benzotriazine-1-yloxytri-(dimethylamino)-phosphoric acid

[0324] n-BuLi n-Butyllithium

[0325] Salt water saturated sodium chloride aqueous solution

[0326] Chloramine-T sodium chloride (4-methylbenzene-1-sulfonyl)aminoide

[0327] Cu(OAc)₂ Copper acetate(II)

[0328] DCE dichloroethane

[0329] DCM dichloromethane

[0330] DIEA (Diisopropylethylamine)

[0331] DMF N,N-dimethylformamide

[0332] DMSO (dimethyl sulfoxide)

[0333] dppf 1,1'-bis(diphenylphosphine)ferrocene

[0334] EtOAc (ethyl acetate)

[0335] EtOH (ethanol)

[0336] g gram

[0337] h hours

[0338] HPLC (High Performance Liquid Chromatography)

[0339] KOAc potassium acetate

[0340] LCMS (Liquid Chromatography-Mass Spectrometry)

[0341] MeI iodomethane

[0342] MeOH (methanol)

[0343] NaBH(OAc)3 sodium triacetoxyborohydride

[0344] Sodium tert-butoxide (NaOtBu)

[0345] NH4OAc ammonium acetate

[0346] Pd2(dba)3 tris-(diphenylmethyleneacetone)dipalladium

[0347] PdCl2(dppf) [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride

[0348] Pd(PPh3)4 tetra(triphenylphosphine)palladium

[0349] petroleum ether

[0350] t-BuOH tert-butanol

[0351] t-BuOK potassium tert-butoxide

[0352] TEA Triethylamine

[0353] TFA (trifluoroacetic acid)

[0354] THF Tetrahydrofuran

[0355] XPhos-Pd-G3(2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonate

[0356] preparation

[0357] Unless otherwise specified, all reagents purchased from commercial sources were used without further purification. All reactions involving air-sensitive or moisture-sensitive reagents were carried out under an inert atmosphere. Proton magnetic resonance spectra were recorded on a Bruker 400 or JEOL Eclipse500 spectrometer. LCMS analysis was performed on a WatersAcquity UPLC system coupled with a Waters TUV and SQ mass detector (column: BEH C18 2.1×50 mm; mobile phase A: water, containing 0.05% TFA; mobile phase B: acetonitrile, containing 0.05% TFA; gradient: 2-98% B for 1.6 min; flow rate: 0.8 mL / min); HPLC analysis was performed on a Shimadzu LC10-AT HPLC system coupled with an SPD-10AVUV detector (column: YMC S5 Combiscreen ODS 4.6×50 mm; 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 for 40 min, followed by a 1 min hold at 100% B; flow rate: 1 mL / min); HPLC analysis was performed on a Shimadzu LC10-AT HPLC system coupled with an SPD-20UV detector. Preparative HPLC purification was performed using an LC-8 preparative HPLC system. Detailed conditions are described in the experimental procedure.

[0358] Example 1

[0359] 2-(3,4-Dimethoxyphenyl)-5-(4-(4-isopropylpiperazin-1-yl)phenyl)-3-methyl-1H-pyrrolo[2,3-c]pyridine

[0360]

[0361] Step 1.1,2-Dimethoxy-4-(prop-1-yn-1-yl)benzene

[0362]

[0363] A solution of 4-ethynyl-1,2-dimethoxybenzene (2.0 g, 12.33 mmol) in THF (70 mL) was added to n-butyllithium / hexane (1.6 M, 15.41 mL, 24.66 mmol) at -10 °C for 15 min. The mixture was stirred at -10 °C for 45 min, followed by the addition of MeI (1.735 mL, 27.7 mmol) over 3 min. The mixture was then stirred at room temperature for 1 h. The reaction mixture was quenched with a saturated ammonium chloride solution (70 mL). The reaction mixture was concentrated to approximately 100 mL under vacuum and extracted with dichloromethane (3 × 60 mL). The combined extracts were dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was subjected to ISCO chromatography (200 g silica gel, 0-10% ethyl acetate / hexane) to give 1,2-dimethoxy-4-(prop-1-yn-1-yl)benzene as a white solid (1.65 g, 9.36 mmol, 76% yield). LCMS (M+H) + =177.0.

[0364] Step 2. 6-Chloro-4-iodopyridine-3-amine

[0365]

[0366] TFA (30 mL) was added to a solution of (6-chloro-4-iodopyridin-3-yl)carbamate (1.939 g, 5.47 mmol) in dichloromethane (30 mL) for 3 min at 0 °C. The resulting solution was stirred at 0 °C for 30 min, followed by stirring at room temperature for 1.5 h. The mixture was concentrated to almost dryness. 1 N K₂HPO₄ (30 mL) was added to the residue, and the mixture was extracted with dichloromethane (4 × 40 mL). The combined extracts were dried over anhydrous MgSO₄. The solvent was removed under vacuum to give 6-chloro-4-iodopyridin-3-amine (1.356 g, 5.33 mmol, 97% yield) as a pale yellow solid. LCMS (M+H) + =254.8.

[0367] Step 3.5-Chloro-2-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrrolo[2,3-c]pyridine and 5-chloro-3-(3,4-dimethoxyphenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine

[0368]

[0369] A mixture of 6-chloro-4-iodopyridin-3-amine (1.90 g, 7.47 mmol), 1,2-dimethoxy-4-(prop-1-yn-1-yl)benzene (1.513 g, 8.59 mmol), lithium chloride (0.317 g, 7.47 mmol), sodium carbonate (3.96 g, 37.3 mmol), and PdCl2(dppf)-CH2Cl2- adduct (0.366 g, 0.448 mmol) in DMF (25 mL) was degassed and heated at 100 °C in a sealed vial for 16 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate (100 mL) and filtered through diatomaceous earth. The filtrate was further diluted with ethyl acetate (200 mL), washed with water (3 × 50 mL) and brine (50 mL), and dried over anhydrous MgSO4. After removing the solvent under vacuum, the residue was subjected to ISCO chromatography (220 g silica gel, solid-supported, 0-4% methanol / dichloromethane) to give a mixture of the two isomers (1.62 g). The isomer mixture was then separated by SFC (instrument: Berger MG II (CTR-L409-PSFC1, column: Chiralpak AD-H, 21×250 mm, 5 μm, mobile phase: 30% methanol / 70% CO2, flow conditions: 45 mL / min, 150 bar, 40 °C) to give 5-chloro-2-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrrolo[2,3-c]pyridine (0.866 g, 2.86 mmol, 38.3% yield) and 5-chloro-3-(3,4-dimethoxyphenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine (0.408 g, 1.348 mmol, 18.05% yield). Both isomers were separated as beige solids.

[0370] 5-Chloro-2-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrrolo[2,3-c]pyridine: LCMS(M+H) + =303.2. 1 HNMR(500MHz,DMSO-d6)δ11.76(br s,1H),8.46(s,1H),7.58(s,1H),7.32-7.26(m,2H),7.14(d,J=8.0Hz,1H),3.87(s,3H),3.84(s,3H),2.39(s,3H).

[0371] 5-Chloro-3-(3,4-dimethoxyphenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine: LCMS(M+H) + =303.2. 1HNMR(500MHz,DMSO-d6)δ11.84(br s,1H),8.46(s,1H),7.44(s,1H),7.07(d,J=8.0Hz,1H),7.03-6.95(m,2H),3.82(s,3H),3.81(s,3H),2.52(br s,3H).

[0372] Step 4

[0373] A mixture of 5-chloro-2-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrrolo[2,3-c]pyridine (20 mg, 0.066 mmol), 1-isopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)phenyl)piperazine (26.2 mg, 0.079 mmol), (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonateXPhos-Pd-G3 (5.59 mg, 6.61 μmol) and tripotassium phosphate (0.116 mL, 0.231 mmol) in 1,4-dioxane (0.8 mL) was degassed and heated at 80 °C in a closed vial for 12 h. After cooling to room temperature, the reaction mixture was diluted with methanol, filtered through an acrodisc syringe filter, and injected into a preparative HPLC system (column: Phenomenex Luna AXIA 5u C182 1.2 × 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, initial %B: 10; final %B: 100). The correct eluent was concentrated under vacuum, alkalized with 1N NaOH solution, and extracted with dichloromethane (4 × 40 mL). The combined extracts were dried over anhydrous Na2SO4. Solvent removal under vacuum yielded 2-(3,4-dimethoxyphenyl)-5-(4-(4-isopropylpiperazin-1-yl)phenyl)-3-methyl-1H-pyrrolo[2,3-c]pyridine as a pale solid (14.6 mg, 0.030 mmol, 46.0% yield). LCMS (M+H) + =471.5. 1H NMR (500MHz, DMSO-d6) δ11.48(s,1H),8.70(d,J=1.1Hz,1H),8.00(d,J=9.1Hz ,2H),7.93(s,1H),7.31(d,J=1.9Hz,1H),7.30-7.27(m,1H),7.14(d,J=8.5Hz, 1H),7.00(d,J=9.1Hz,2H),3.88(s,3H),3.84(s,3H),3.21-3.17(m,4H),2.70( dt,J=13.1,6.4Hz,1H),2.63-2.59(m,4H),2.46(s,3H),1.03(d,J=6.6Hz,6H).

[0374] Example 2

[0375] 2-(3,4-Dimethoxyphenyl)-5-(4-(4-isopropylpiperazin-1-yl)phenyl)-3-methyl-1H-pyrrolo[2,3-c]pyridine

[0376]

[0377] A mixture of 5-chloro-3-(3,4-dimethoxyphenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine (20 mg, 0.066 mmol), 1-isopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)phenyl)piperazine (26.2 mg, 0.079 mmol), (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonateXPhos-Pd-G3 (5.59 mg, 6.61 μmol) and tripotassium phosphate (0.116 mL, 0.231 mmol) in 1,4-dioxane (0.8 mL) was degassed in a closed vial at 80 °C and heated for 12 h. Additional 1-isopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)phenyl)piperazine (26.2 mg, 0.079 mmol) and (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonateXPhos-Pd-G3 (5.59 mg, 6.61 μmol) were added. The mixture was degassed and heated at 105 °C for 3 h. After cooling to room temperature, the reaction mixture was diluted with methanol, filtered through a syringe filter, and injected into a preparative HPLC system (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, initial %B: 8; final %B: 100). The correct eluent was concentrated under vacuum, alkalized with 1N NaOH solution, and extracted with dichloromethane (4 × 40 mL). The combined extracts were dried over anhydrous Na2SO4. Solvent removal under vacuum yielded 3-(3,4-dimethoxyphenyl)-5-(4-(4-isopropylpiperazin-1-yl)phenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine as a pale solid (11 mg, 0.023 mmol, 34.7% yield). LCMS (M+H) + =471.5. 1H NMR (500MHz, methanol-d4) δ8.61(d,J=0.8Hz,1H),7.80(d,J=0.8Hz,1H),7.76(d,J=8.8Hz,2H),7.14-7.11(m,1H),7.10(d,J=1.9Hz ,1H),7.09-7.05(m,3H),3.92(s,3H),3.91(s,3H),3.30-3.27(m,4H),2.80-2.72(m,5H),2.57(s,3H),1.16(d,J=6.6Hz,6H).

[0378] Example 3

[0379] 1-(4-(4-(3-(3,4-dimethoxyphenyl)-1,2-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)phenyl)piperazin-1-yl)-2-methylprop-2-ol

[0380]

[0381] Step 1.5-Chloro-3-(3,4-dimethoxyphenyl)-1,2-dimethyl-1H-pyrrolo[2,3-c]pyridine

[0382]

[0383] Sodium hydride (60% oil dispersion) (159 mg, 3.96 mmol) was added in a single addition to a solution of 5-chloro-3-(3,4-dimethoxyphenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine (400 mg, 1.321 mmol) and iodomethane (375 mg, 2.64 mmol) in DMF (6 mL). The mixture was stirred at room temperature for 1 h, then quenched with acetic acid (0.378 mL, 6.61 mmol) and concentrated and dried under vacuum. The residue was diluted with ethyl acetate (150 mL) and washed successively with 1 N K₂HPO₄ solution (25 mL), water (25 mL), and brine (25 mL). The organic solution was dried over anhydrous MgSO₄. The product 5-chloro-3-(3,4-dimethoxyphenyl)-1,2-dimethyl-1H-pyrrolo[2,3-c]pyridine (357 mg, 1.127 mmol, 85% yield) was separated as a white solid by ISCO chromatography (40 g silica gel, solid-supported, 35-100% ethyl acetate / hexane). LCMS (M+H) + =317.1. 1HNMR(500MHz,DMSO-d6)δ8.67(s,1H),7.42(s,1H),7.09(d,J=8.3Hz,1H),6.99-6.92(m,2H),3.85(s,3H),3.82(s,3H),3.81(s,3H),2.52(br s,3H).

[0384] Step 2.2-Methyl-1-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)phenyl)piperazin-1-yl)prop-2-ol

[0385]

[0386] A mixture of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)phenyl)piperazine (150 mg, 0.520 mmol) and potassium carbonate (108 mg, 0.781 mmol) in MeOH (2 mL) was added in a single batch of 0.2 mL DMF containing 2,2-dimethylethylene oxide (56.3 mg, 0.781 mmol). The mixture was stirred at room temperature for 28 h, diluted with ethyl acetate (10 mL), and filtered through diatomaceous earth. The filtrate was diluted with ethyl acetate (60 mL), washed continuously 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-dioxolane-2-yl)phenyl)piperazin-1-yl)prop-2-ol (113 mg, 0.314 mmol, 60.3% yield) was separated as a white solid by ISCO chromatography (24 g silica gel, solid-supported, 1-10% ethyl acetate / hexane). LCMS (M+H) + =361.3. 1 ¹H 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).

[0387] Step 3

[0388] A mixture of 5-chloro-3-(3,4-dimethoxyphenyl)-1,2-dimethyl-1H-pyrrolo[2,3-c]pyridine (30 mg, 0.095 mmol), 1-isopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)phenyl)piperazine (42.2 mg, 0.128 mmol), (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonateXPhos-Pd-G3 (8.02 mg, 9.47 μmol) and tripotassium phosphate (0.166 mL, 0.331 mmol) in 1,4-dioxane (1 mL) was degassed and heated at 85 °C in a closed vial for 15 h. After cooling to room temperature, the reaction mixture was diluted with methanol, filtered through a syringe filter, and injected into a preparative HPLC system (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, initial %B: 15; final %B: 100). The correct eluent was concentrated under vacuum, alkalized with 1N NaOH solution, and extracted with dichloromethane (4 × 40 mL). The combined extracts were dried over anhydrous Na2SO4. Solvent removal under vacuum yielded 3-(3,4-dimethoxyphenyl)-5-(4-(4-isopropylpiperazin-1-yl)phenyl)-1,2-dimethyl-1H-pyrrolo[2,3-c]pyridine as a white solid (21.8 mg, 0.045 mmol, 47.0% yield). LCMS (M+H) + =485.1. 1 H NMR (500MHz, chloroform-d) δ8.77(s,1H),7.93(d,J=8.5Hz,2H),7.87(s,1H),7.05-7.00(m,5H),3.99(s,3H),3 .95(s,3H),3.87(s,3H),3.33-3.26(m,4H),2.79-2.69(m,6H),2.54(s,3H),1.13(s,3H),1.12(s,3H).

[0389] Example 4

[0390] 4-(3-(3,4-dimethoxyphenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-[1,4'-dipiperidine]-1'-carboxylic acid methyl ester

[0391]

[0392] Step 1. Benzyl 4-(3-(3,4-dimethoxyphenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid

[0393]

[0394] A mixture of 5-chloro-3-(3,4-dimethoxyphenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine (408 mg, 1.348 mmol), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid methyl ester (555 mg, 1.617 mmol), (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonate XPhos-Pd-G3 (114 mg, 0.135 mmol) and tripotassium phosphate (2.358 mL, 4.72 mmol) in 1,4-dioxane (14 mL) was degassed and heated at 80 °C in a closed vial for 16 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (20 mL) and filtered through diatomaceous earth. The filtrate was further diluted with ethyl acetate (120 mL), washed continuously with water (2 × 30 mL) and brine (30 mL), and dried over anhydrous MgSO4. The product 4-(3-(3,4-dimethoxyphenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid methyl ester (414 mg, 0.856 mmol, 63.5% yield) was separated as a beige solid by ISCO chromatography (80 g silica gel, solid-supported, 3-12% methanol / dichloromethane). LCMS (M+H) + =484.4. 1 H NMR (500MHz, DMSO-d6) δ11.60(s,1H),8.63(d,J=0.8Hz,1H),7.55(s,1H),7.42-7.30(m,5H),7.08(d,J=8.3Hz,1H),7.04-6.98(m,2H),6.60(br s,1H),5.13(s,2H),4.18-4.06(m,2H),3.82(s,6H),3.69-3.60(m,2H),2.63(br d,J=1.4Hz,2H),2.50(s,3H).

[0395] Step 2.3-(3,4-dimethoxyphenyl)-2-methyl-5-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridine

[0396]

[0397] A mixture of 4-(3-(3,4-dimethoxyphenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid methyl ester (260 mg, 0.538 mmol) and 10% Pd / C (114 mg, 0.108 mmol) in MeOH (30 mL) and THF (10 mL) was stirred at room temperature under H2 supplied by a hydrogen bladder for 5 h. The mixture was diluted with dichloromethane (10 mL) and filtered through diatomaceous earth. The filtrate was concentrated to dryness under vacuum to give 3-(3,4-dimethoxyphenyl)-2-methyl-5-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridine (187 mg, 0.532 mmol, 99% yield) as a slightly yellow solid. LCMS(M+H) + =352.4.

[0398] Step 3

[0399] Sodium triacetoxyborohydride (60.3 mg, 0.285 mmol) was added in a single batch to a solution of 3-(3,4-dimethoxyphenyl)-2-methyl-5-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridine (20 mg, 0.057 mmol), methyl 4-oxopiridine-1-carboxylic acid (53.1 mg, 0.228 mmol), magnesium sulfate (137 mg, 1.138 mmol), and acetic acid (0.049 mL, 0.854 mmol) in 1.2 mL of DMF. The mixture was stirred at room temperature for 2.5 days (weekend). The non-homogeneous mixture was diluted with ethyl acetate (10 mL) and filtered through diatomaceous earth. The filtrate was concentrated under vacuum. The residue was diluted with methanol and injected into a preparative HPLC system (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, initial %B: 16; final %B: 100). The correct eluent was concentrated under vacuum, alkalized with 2N NaOH solution, and extracted with dichloromethane (4 × 30 mL). The combined extracts were dried over anhydrous Na2SO4. Solvent removal under vacuum yielded methyl 4-(3-(3,4-dimethoxyphenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-[1,4'-dipiperidine]-1'-carboxylic acid as a white solid (11.5 mg, 0.020 mmol, 35.2% yield). LCMS (M+H) + =569.4.1 H NMR(500MHz,chloroform-d)δ8.67(s,1H),8.20(br s,1H),7.43(s,1H),7.40-7.37(m,4H),7.34(dq,J=8.6,4.2Hz,1H),7.03-6.99(m,3H),5.15(s,2H),4.27(br s,2H),3.98(s,3H),3.95(s,3H),3.07(br d,J=11.3Hz,2H),2.88-2.76(m,3H),2.57(s,3H),2.54-2.47(m,1H),2.36(br t,J=11.1Hz,2H),2.06(br d,J=10.7Hz,2H),1.92-1.80(m,4H),1.57-1.49(m,2H).

[0400] Example 5

[0401] (1-Cyclopropylpiperidin-4-yl)(4-(3-(3,4-dimethoxyphenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidin-1-yl)methyl ketone

[0402]

[0403] A mixture of 3-(3,4-dimethoxyphenyl)-2-methyl-5-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridine (20 mg, 0.057 mmol), 1-cyclopropylpiperidin-4-carboxylic acid (11.56 mg, 0.068 mmol), hexafluorophosphate (benzotriazol-1-yloxy)triazine (dimethylamino)phosphonium (BOP) (37.8 mg, 0.085 mmol) and N,N-diisopropylethylamine (0.040 mL, 0.228 mmol) in DMF (1.2 mL) was stirred at room temperature for 2 h. The mixture was diluted with MeOH and injected into a preparative HPLC system (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, initial %B: 10; final %B: 100). The correct eluates were combined, concentrated under vacuum, alkalized with 2N NaOH solution, and extracted with dichloromethane (4 × 30 mL). The combined extracts were dried over anhydrous Na2SO4. Solvent removal under vacuum yielded a white solid (1-cyclopropylpiperidin-4-yl)(4-(3-(3,4-dimethoxyphenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidin-1-yl) methyl ketone (18 mg, 0.035 mmol, 61.7% yield). LCMS (M+H) + =503.2. 1 H NMR (500MHz, chloroform-d) δ8.68(d,J=0.8Hz,1H),8.34(br s,1H),7.37(s,1H),7.06-7.01(m,2H),6.99(d,J=1.4Hz,1H),4.83(br d,J=12.9Hz,1H),4.11-4.04(m,1H),3.98(s,3H),3.95(s,3H),3.19(br t,J=12.8Hz,1H),3.13-3.08(m,2H),3.02(tt,J=12.0,3.6Hz,1H),2.57(s,3H),2.56-2 .50(m,1H),2.23(td,J=11.8,2.5Hz,2H),2.13-1.98(m,2H),1.90-1.75(m,4H),1.71(br d,J=13.2Hz,2H),1.61-1.58(m,2H),0.47-0.42(m,4H).

[0404] Example 6

[0405] 3-(3,4-Dimethoxyphenyl)-5-(1-(2,6-dimethylpyridin-4-yl)piperidin-4-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridine

[0406]

[0407] A mixture of 3-(3,4-dimethoxyphenyl)-2-methyl-5-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridine (20 mg, 0.057 mmol), 4-chloro-2,6-dimethylpyridine (24.17 mg, 0.171 mmol), and N,N-diisopropylethylamine (0.040 mL, 0.228 mmol) in isopropanol (0.8 mL) was heated at 150 °C in a closed vial for 15 h. Solvent leakage was observed. The residue was diluted with methanol and injected into a preparative HPLC system (column: Phenomenex Luna AXIA 5u C182 1.2 × 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, initial %B: 13; final %B: 100). The correct eluates were combined, concentrated under vacuum, alkalized with 1N NaOH solution, and extracted with dichloromethane (3 × 35 mL). The combined extracts were dried over anhydrous Na2SO4. Solvent removal under vacuum yielded 3-(3,4-dimethoxyphenyl)-5-(1-(2,6-dimethylpyridin-4-yl)piperidin-4-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridine as a pale solid (17 mg, 0.036 mmol, 64.1% yield). LCMS (M+H) + =457.5. 1 H NMR (500MHz, chloroform-d) δ8.68 (d, J = 0.8Hz, 1H), 8.37 (br s, 1H), 7.38 (s, 1H), 7.05-6.98 (m, 3H), 6.46 (s, 2H), 4.04 (br d,J=12.9Hz,2H),3.98(s,3H),3.95(s,3H),3.06-2.96(m,3H),2.57(s,3H),2.45(s,6H),2.10(br d, J=11.6Hz, 2H), 1.92 (qd, J=12.6, 4.0Hz, 2H).

[0408] Example 7

[0409] 4-(2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-[1,4'-dipiperidine]-1'-carboxylic acid ethyl ester

[0410]

[0411] Step 1. N-(2-chloro-5-iodopyridin-4-yl)-N-(methylsulfonyl)methanesulfonamide

[0412]

[0413] A solution of 2-chloro-5-iodopyridin-4-amine (2.0 g, 7.86 mmol) and triethylamine (5.48 mL, 39.3 mmol) in dichloromethane (20 mL) was added to the solution at 0 °C for 30 min. The mixture was stirred at room temperature for 15 h. The mixture was diluted with dichloromethane (80 mL), washed continuously with water (2 × 30 mL) and brine (30 mL), and dried over anhydrous MgSO4. The product N-(2-chloro-5-iodopyridin-4-yl)-N-(methanesulfonyl)methanesulfonamide (2.35 g, 5.72 mmol, 72.8% yield) was separated as a white solid by ISCO chromatography (220 g silica gel, 15-50% ethyl acetate / hexane). LCMS (M+H) + =411.1. 1 ¹H NMR (500 MHz, chloroform-d) δ 8.91 (s, 1H), 7.39 (s, 1H), 3.59 (s, 6H).

[0414] Step 2. N-(2-chloro-5-iodopyridin-4-yl)methanesulfonamide

[0415]

[0416] A solution of N-(2-chloro-5-iodopyridin-4-yl)-N-(methanesulfonyl)methanesulfonamide (2.34 g, 5.70 mmol) in THF (10 mL) was added to a solution of 10% sodium hydroxide (10 mL, 27.5 mmol) at room temperature for 3 min. The mixture was stirred at room temperature for 14 h and then concentrated under vacuum to approximately 10 mL. The residue was diluted with water (5 mL) and neutralized to pH 6–7 with concentrated hydrochloric acid. The precipitate N-(2-chloro-5-iodopyridin-4-yl)methanesulfonamide (1.66 g, 4.99 mmol, 88% yield) was collected as a white solid by filtration and dried under vacuum at 50 °C. LCMS (M+H) + =333.0. 1 ¹H NMR (500MHz, chloroform-d) δ 8.62 (s, 1H), 7.58 (s, 1H), 7.09 (br s, 1H), 3.22 (s, 3H).

[0417] Step 3. 6-Chloro-2-(3,4-dimethoxyphenyl)-1H-pyrrolo[3,2-c]pyridine

[0418]

[0419] A mixture of N-(2-chloro-5-iodopyridin-4-yl)methanesulfonamide (120 mg, 0.361 mmol), 4-ethynyl-1,2-dimethoxybenzene (88 mg, 0.541 mmol), bis(triphenylphosphine)palladium(II) chloride (15.20 mg, 0.022 mmol), and copper(I) iodide (4.12 mg, 0.022 mmol) in DMF (1.5 mL) was degassed and heated at 100 °C in a sealed vial for 25 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (10 mL) and filtered through diatomaceous earth. The filtrate was concentrated under vacuum until almost dry. The residue was diluted with methanol and injected into a preparative HPLC system (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: 15 min, initial %B: 15; final %B: 100). The correct eluates were combined, concentrated under vacuum, alkalized with 1N K2HPO4 solution, and extracted with dichloromethane (3 × 40 mL). The combined extracts were dried over anhydrous Na2SO4. Solvent removal under vacuum yielded 6-chloro-2-(3,4-dimethoxyphenyl)-1H-pyrrolo[3,2-c]pyridine (53 mg, 0.184 mmol, 50.9% yield). LCMS (M+H) + =289.2. 1 H NMR (500MHz, chloroform-d) δ8.67(s,1H),8.66(br.s,1H),7.35(s,1H),7.24(dd,J=8.3,2.2Hz,1H),7.1 9(d,J=1.9Hz,1H), 6.99(d,J=8.3Hz,1H), 6.78(dd,J=1.9,0.8Hz,1H), 4.00(s,3H), 3.97(s,3H).

[0420] Step 4. 6-Chloro-2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-c]pyridine

[0421]

[0422] Sodium hydride (60% oil dispersion) (18.01 mg, 0.450 mmol) was added in a single step to a solution of 6-chloro-2-(3,4-dimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine (52 mg, 0.180 mmol) and iodomethane (63.9 mg, 0.450 mmol) in DMF (2 mL). The mixture was stirred at room temperature for 1 h, quenched with acetic acid (0.2 mL), diluted with methanol, and injected into a preparative HPLC system (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: 15 min, initial %B: 18; final %B: 100). The correct eluates were combined, concentrated under vacuum, alkalized with saturated NaHCO3 solution, and extracted with dichloromethane (3 × 35 mL). The combined extracts were dried over anhydrous Na2SO4. Solvent removal under vacuum yielded 6-chloro-2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-c]pyridine as a white solid (39 mg, 0.129 mmol, 71.5% yield). LCMS (M+H) + =303.2.

[0423] Step 5. Benzyl 4-(2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid

[0424]

[0425] A mixture of 6-chloro-2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridine (172 mg, 0.568 mmol), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid methyl ester (244 mg, 0.710 mmol), (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonateXPhos-Pd-G3 (48.1 mg, 0.057 mmol) and tripotassium phosphate (0.994 mL, 1.988 mmol) in 1,4-dioxane (6 mL) was degassed and heated at 85 °C in a closed vial for 11 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (20 mL) and filtered through diatomaceous earth. The filtrate was further diluted with ethyl acetate (120 mL), washed continuously with water (30 mL) and brine (30 mL), and dried over anhydrous MgSO4. The product methyl 4-(2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid (180 mg, 0.365 mmol, 64.2% yield) was separated as a white solid by ISCO chromatography (40 g silica gel, solid support, 45-80% ethyl acetate / hexane). LCMS (M+H) + =484.5. 1 H NMR (500MHz, chloroform-d) δ8.87 (d, J = 0.8Hz, 1H), 7.46-7.31 (m, 6H), 7.10-7.06 (m, 1H), 7.04-7.00 (m, 2H), 6.72 (br s,1H),6.60(s,1H),5.23(s,2H),4.29(q,J=2.6Hz,2H),3.98(s,3H),3.96(s,3H),3.85-3.80(m,2H),3.77(s,3H),2.80(br d,J=1.4Hz,2H).

[0426] Step 6.2-(3,4-dimethoxyphenyl)-1-methyl-6-(piperidin-4-yl)-1H-pyrrolo[3,2-c]pyridine

[0427]

[0428] A mixture of 4-(2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid methyl ester (177 mg, 0.366 mmol) and 10% Pd / C (78 mg, 0.073 mmol) in MeOH (21 mL) and THF (7 mL) was stirred at room temperature under H2 supplied by a hydrogen bladder for 13 h. The mixture was diluted with dichloromethane (10 mL) and filtered through diatomaceous earth. The filtrate was concentrated to dryness under vacuum to give 3-(3,4-dimethoxyphenyl)-1-methyl-6-(piperidin-4-yl)-1H-pyrrolo[3,2-c]pyridine (97 mg, 0.276 mmol, 75% yield) as a slightly yellow solid. LCMS(M+H) + =352.3.

[0429] Step 7

[0430] Sodium triacetoxyborohydride (54.3 mg, 0.256 mmol) was added in a single batch to a solution of 2-(3,4-dimethoxyphenyl)-1-methyl-6-(piperidin-4-yl)-1H-pyrrolo[3,2-c]pyridine (18 mg, 0.051 mmol), ethyl 4-oxopiridine-1-carboxylate (35.1 mg, 0.205 mmol), magnesium sulfate (123 mg, 1.024 mmol), and acetic acid (0.044 mL, 0.768 mmol) in 1.2 mL of DMF. The mixture was stirred at room temperature for 2.5 days (weekend). The heterogeneous mixture was diluted with ethyl acetate (10 mL) and filtered through diatomaceous earth. The filtrate was concentrated under vacuum. The residue was diluted with methanol and injected into a preparative HPLC system (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, initial %B: 12; final %B: 100). The correct eluent was concentrated under vacuum, alkalized with 1N NaOH solution, and extracted with dichloromethane (4 × 30 mL). The combined extracts were dried over anhydrous Na2SO4. Solvent removal under vacuum yielded ethyl 4-(2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-[1,4'-dipiperidine]-1'-carboxylate (5.3 mg, 10.25 μmol, 20.02% yield), a pale yellow solid. LCMS (M+H) + =507.5. 1H NMR (500MHz, chloroform-d) δ8.83(s,1H),7.16(s,1H),7.08-7.04(m,1H),7.02-6.99(m,2H),6.56(s, 1H),4.33-4.20(m,2H),4.16(q,J=7.2Hz,2H),3.98(s,3H),3.95(s,3H),3.72(s,3H),3.12(br d,J=10.2Hz,2H),2.94-2.86(m,1H),2.80(br t,J=11.4Hz,2H),2.55(br t,J=9.8Hz,1H),2.43(br t,J=11.0Hz,2H),2.14(br d,J=12.4Hz,2H),1.91(br d,J=12.1Hz,4H),1.60-1.51(m,2H),1.29(t,J=7.0Hz,3H).

[0431] Example 8

[0432] 2-(3,4-Dimethoxyphenyl)-1-methyl-6-(1-((6-methylpyridin-3-yl)methyl)piperidin-4-yl)-1H-pyrrolo[3,2-c]pyridine

[0433]

[0434] Sodium triacetoxyborohydride (54.3 mg, 0.256 mmol) was added to a solution of 2-(3,4-dimethoxyphenyl)-1-methyl-6-(piperidin-4-yl)-1H-pyrrolo[3,2-c]pyridine (25 mg, 0.057 mmol), 6-methylnicotinaldehyde (24.13 mg, 0.199 mmol), magnesium sulfate (137 mg, 1.138 mmol), and acetic acid (0.049 mL, 0.854 mmol) in 1.2 mL of DMF. The non-homogeneous mixture was stirred at room temperature for 23 h, diluted with ethyl acetate (10 mL), and filtered through diatomaceous earth. The filtrate was concentrated under vacuum. The residue was diluted with methanol and injected into a preparative HPLC system (column: Phenomenex LunaAXIA 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, initial %B: 9; final %B: 100). The correct eluent was concentrated under vacuum, alkalized with 2N NaOH solution, and extracted with dichloromethane (3 × 35 mL). The combined extracts were dried over anhydrous Na2SO4. Solvent removal under vacuum yielded 2-(3,4-dimethoxyphenyl)-1-methyl-6-(1-((6-methylpyridin-3-yl)methyl)piperidin-4-yl)-1H-pyrrolo[3,2-c]pyridine as a white solid (18.8 mg, 0.040 mmol, 70.9% yield). LCMS (M+H) + =457.5. 1 H NMR (500MHz, chloroform-d) δ8.84(s,1H),8.48(d,J=1.7Hz,1H),7.64(dd,J=8.0,2.2Hz,1H),7.19-7.11(m,2H),7.0 9-7.03(m,1H),7.03-6.99(m,2H),6.56(s,1H),3.98(s,3H),3.95(s,3H),3.73(s,3H),3.56(s,2H),3.06(br d,J=11.3Hz,2H),2.89(tt,J=12.1,3.6Hz,1H),2.58(s,3H),2.24-2.17(m,2H),2.06(br d,J=11.6Hz,2H),1.99-1.89(m,2H).

[0435] Example 9

[0436] 6-(4-(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)-2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-c]pyridine

[0437]

[0438] Step 1.1-(cyclopropylmethyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)phenyl)piperazine

[0439]

[0440] At 0 °C, a mixture of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)phenyl)piperazine (100 mg, 0.347 mmol) and potassium carbonate (71.9 mg, 0.520 mmol) in 1 mL of DMF was added in a single batch to DMF containing (bromomethyl)cyclopropane (73.2 mg, 0.520 mmol). The mixture was stirred at room temperature for 12 h, diluted with 10 mL of ethyl acetate, and filtered through diatomaceous earth. The filtrate was diluted with 60 mL of ethyl acetate, washed continuously with water (2 × 20 mL) and brine (20 mL), and dried over anhydrous MgSO4. The product 1-(cyclopropylmethyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)phenyl)piperazine (72 mg, 0.210 mmol, 60.6% yield) was separated as a white solid by ISCO chromatography (25 g silica gel, solid-supported, 40-80% ethyl acetate / hexane). LCMS (M+H) + =343.3. 1 H NMR (500MHz, chloroform-d) δ7.73(d,J=8.8Hz,2H),6.92(d,J=8.8Hz,2H),3.42-3.27(m,4H),2.80-2.59(m,4 H), 2.33 (d, J = 6.6Hz, 2H), 1.35 (s, 12H), 1.01-0.84 (m, 1H), 0.65-0.49 (m, 2H), 0.16 (d, J = 5.5Hz, 2H).

[0441] Step 2

[0442] A mixture of 6-chloro-2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-c]pyridine (18 mg, 0.059 mmol), 1-(cyclopropylmethyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)phenyl)piperazine (25.4 mg, 0.074 mmol), (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonateXPhos-Pd-G3 (5.03 mg, 5.95 μmol) and tripotassium phosphate (0.104 mL, 0.208 mmol) in 1,4-dioxane (0.8 mL) was degassed and heated at 80 °C in a closed vial for 15 h. After cooling to room temperature, the reaction mixture was diluted with methanol, filtered through a syringe filter, and injected into a preparative HPLC system (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, initial %B: 15; final %B: 100). The correct eluent was concentrated under vacuum, alkalized with 1N NaOH solution, and extracted with dichloromethane (4 × 40 mL). The combined extracts were dried over anhydrous Na2SO4. Solvent removal under vacuum yielded 6-(4-(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)-2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-c]pyridine as a white solid (9 mg, 0.018 mmol, 31.1% yield). LCMS (M+H) + =483.4. 1 H NMR (500MHz, chloroform-d) δ8.95 (s, 1H), 8.02 (d, J = 8.8Hz, 2H), 7.60 (s, 1H), 7.12-7.04 (m, 4H), 7.04-7.00 (m, 1H), 6.60 (s, 1H), 3.99 (s, 3H), 3.97 (s,3H),3.79(s,3H),3.37-3.33(m,4H),2.78-2.74(m,4H),2.37(d,J=6.6Hz,2H),1.01-0.91(m,1H),0.62-0.55(m,2H),0.21-0.16(m,2H).

[0443] Example 10

[0444] 6-(4-(4-cyclobutylpiperazin-1-yl)phenyl)-2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-c]pyridine

[0445]

[0446] Step 1.1-Cyclobutyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)phenyl)piperazine

[0447]

[0448] Sodium triacetoxyborohydride (496 mg, 2.342 mmol) was added in a single batch to a solution of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)phenyl)piperazine (150 mg, 0.520 mmol), cyclobutanone (128 mg, 1.822 mmol), magnesium sulfate (1253 mg, 10.41 mmol), and acetic acid (0.298 mL, 5.20 mmol) in 1.2 mL of DMF. The mixture was stirred at room temperature for 12 h. The non-homogeneous mixture was diluted with ethyl acetate (20 mL) and filtered through diatomaceous earth. The filtrate was further diluted with ethyl acetate (80 mL), washed continuously with saturated NaHCO3 solution (25 mL), water (2 × 25 mL), and brine (25 mL), and dried over anhydrous MgSO4. The product 1-cyclobutyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)phenyl)piperazine (108 mg, 0.316 mmol, 60.6% yield) was separated as a white solid by ISCO chromatography (24 g silica gel, solid-supported, 35-80% ethyl acetate / hexane). LCMS (M+H) + =343.2.

[0449] Step 2

[0450] A mixture of 6-chloro-2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-c]pyridine (20 mg, 0.066 mmol), 1-cyclobutyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)phenyl)piperazine (28.3 mg, 0.083 mmol), (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonateXPhos-Pd-G3 (5.59 mg, 6.61 μmol) and tripotassium phosphate (0.116 mL, 0.231 mmol) in 1,4-dioxane (0.8 mL) was degassed and heated at 85 °C in a closed vial for 15 h. After cooling to room temperature, the reaction mixture was diluted with methanol, filtered through a syringe filter, and injected into a preparative HPLC system (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, initial %B: 15; final %B: 100). The correct eluent was concentrated under vacuum, alkalized with 1N NaOH, and extracted with dichloromethane (4 × 40 mL). The combined extracts were dried over anhydrous Na2SO4. The solvent was removed under vacuum to give 6-(4-(4-cyclobutylpiperazin-1-yl)phenyl)-2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-c]pyridine as a pale yellow solid (14 mg, 0.028 mmol, 43.0% yield). 1 ¹H NMR (500MHz, chloroform-d) δ 8.95 (s, 1H), 8.02 (d, J = 8.8 Hz, 2H), 7.60 (s, 1H), 7.12–7.08 (m, 1H), 7.08–7.04 (m, 3H), 7.04–7.00 (m, 1H), 6.60 (s, 1H), 3.99 (s, 3H), 3.97 (s, 3H), 3.80 (s, 3H), 3.34–3.31 (m, 4H), 2.84 (quintet, J = 7.9 Hz, 1H), 2.57–2.53 (m, 4H), 2.15–2.08 (m, 2H), 2.02–1.93 (m, 2H), 1.82–1.71 (m, 2H).

[0451] Example 11

[0452] 6-(4-(4-isopropylpiperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine

[0453]

[0454] Step 1. 6-Chloro-3-iodo-2-methylpyridin-4-amine

[0455]

[0456] Silver sulfate (4.24 g, 13.61 mmol) was added in a single addition to a solution of 2-chloro-6-methylpyridin-4-amine (1.94 g, 13.61 mmol) in ethanol (55 mL) at room temperature, followed by the addition of iodine (3.64 g, 13.61 mmol). The mixture was stirred at room temperature for 16 h. Ethyl acetate (80 mL) and triethylamine (1.896 mL, 13.61 mmol) were added to the mixture. The mixture was stirred at room temperature for 10 min and then filtered through diatomaceous earth. The filtrate was concentrated under vacuum and the residue was subjected to ISCO chromatography (220 g silica gel, solid-supported, 20–80% ethyl acetate / hexane) to give 6-chloro-3-iodo-2-methylpyridin-4-amine (1.03 g, 3.84 mmol, 28.2% yield) and 2-chloro-3-iodo-6-methylpyridin-4-amine (1.05 g, 3.91 mmol, 28.7% yield). Both products were obtained as white solids.

[0457] 6-Chloro-3-iodo-2-methylpyridin-4-amine: LCMS(M+H) + =269.0. 1 ¹H NMR (400MHz, chloroform-d) δ 6.46 (s, 1H), 4.80 (br s, 2H), 2.68 (s, 3H).

[0458] 2-Chloro-3-iodo-6-methylpyridin-4-amine: LCMS(M+H) + =269.0. 1 ¹H NMR (400MHz, chloroform-d) δ 6.35 (s, 1H), 4.79 (br s, 2H), 2.38 (s, 3H).

[0459] Step 2. N-(6-chloro-3-iodo-2-methylpyridin-4-yl)-N-(methanesulfonyl)methanesulfonamide

[0460]

[0461] A solution of 6-chloro-3-iodo-2-methylpyridin-4-amine (1.56 g, 5.81 mmol) and triethylamine (4.05 mL, 29.1 mmol) in dichloromethane (25 mL) was added to the solution at 0 °C for 10 min. The mixture was stirred at room temperature for 18 h. The mixture was diluted with dichloromethane (150 mL), washed with water (2 × 40 mL) and brine (40 mL), and dried over anhydrous MgSO4. N-(6-chloro-3-iodo-2-methylpyridin-4-yl)-N-(methanesulfonyl)methanesulfonamide (1.91 g, 4.50 mmol, 77% yield) was separated as a white solid by ISCO chromatography (220 g silica gel, 10-50% ethyl acetate / hexane). 1 ¹H NMR (400MHz, chloroform-d) δ 7.17 (s, 1H), 3.60 (s, 6H), 2.89 (s, 3H).

[0462] Step 3. N-(6-chloro-3-iodo-2-methylpyridin-4-yl)methanesulfonamide

[0463]

[0464] A solution of N-(6-chloro-3-iodo-2-methylpyridin-4-yl)-N-(methanesulfonyl)methanesulfonamide (1.91 g, 4.50 mmol) in THF (10 mL) was added to a solution of N-(6-chloro-3-iodo-2-methylpyridin-4-yl)methanesulfonamide (1.91 g, 4.50 mmol) at room temperature for 3 min. The mixture was stirred at room temperature for 15 h and then concentrated under vacuum to approximately 10 mL. The residue was diluted with water (5 mL) and neutralized to pH 6–7 with concentrated hydrochloric acid. The precipitate N-(6-chloro-3-iodo-2-methylpyridin-4-yl)methanesulfonamide (1.10 g, 3.17 mmol, 70.6% yield) was collected by filtration as a white solid and dried under vacuum at 50 °C. LCMS(M+H) + =347.0.

[0465] Step 4. 6-Chloro-4-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine

[0466]

[0467] A mixture of N-(6-chloro-3-iodo-2-methylpyridin-4-yl)methanesulfonamide (0.500 g, 1.443 mmol), 1-ethynyl-4-(methanesulfonyl)benzene (0.325 g, 1.803 mmol), bis(triphenylphosphine)palladium(II) chloride (0.061 g, 0.087 mmol), and copper iodide(I) (0.016 g, 0.087 mmol) in DMF (6 mL) was degassed and heated at 100 °C in a sealed vial for 15 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (50 mL) and filtered through diatomaceous earth. The filtrate was further diluted with ethyl acetate (150 mL), washed continuously with water (3 × 40 mL) and brine (40 mL), and dried over anhydrous MgSO4. After removing the solvent under vacuum, the residue was subjected to ISCO chromatography (80 g silica gel, solid-supported, 0–5% methanol / dichloromethane). The product obtained (0.275 g) was further purified by preparative HPLC (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, initial %B: 11; final %B: 100). The correct eluents were combined, concentrated under vacuum, alkalized to pH 10 with saturated NaHCO3 solution, and extracted with dichloromethane (3 × 50 mL). The combined extracts were dried over anhydrous MgSO4. The solvent was removed under vacuum to give 6-chloro-4-methyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (0.210 g, 0.655 mmol, 45.4% yield) as a white solid. LCMS(M+H) + =321.2. 1 H NMR (400MHz, DMSO-d6) δ12.29(s,1H),8.16(d,J=8.6Hz,2H),8.04(d,J=8.6Hz,2H),7.40(d,J=0.8Hz,1H),7.27(s,1H),3.28(s,3H),2.67(s,3H).

[0468] Step 5. 6-Chloro-1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine

[0469]

[0470] Sodium hydride (60% oil dispersion) (63.9 mg, 1.598 mmol) was added in a single addition to a solution of 6-chloro-4-methyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (205 mg, 0.639 mmol) and iodomethane (227 mg, 1.598 mmol) in DMF (6 mL). The mixture was stirred at room temperature for 1 h. The reactants were quenched with acetic acid (0.183 mL, 3.20 mmol). The resulting mixture was concentrated to almost dryness under vacuum. The residue was diluted with ethyl acetate (120 mL), washed with saturated NaHCO3 solution (2 × 25 mL), and dried over anhydrous MgSO4. The product 6-chloro-1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (172 mg, 0.514 mmol, 80% yield) was separated as a white solid by ISCO chromatography (40 g silica gel, 0-6% methanol / dichloromethane). LCMS (M+H) + =335.2. 1 ¹H NMR (500MHz, acetonitrile-d³) δ 8.07 (d, J = 8.5Hz, 2H), 7.84 (d, J = 8.5Hz, 2H), 7.36 (s, 1H), 6.86 (d, J = 0.6Hz, 1H), 3.75 (s, 3H), 3.16 (s, 3H), 2.70 (s, 3H).

[0471] Step 6

[0472] A mixture of 6-chloro-1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (40 mg, 0.119 mmol), 1-isopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)phenyl)piperazine (53.3 mg, 0.161 mmol), (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonateXPhos-Pd-G3 (10.11 mg, 0.012 μmol) and tripotassium phosphate (0.209 mL, 0.418 mmol) in 1,4-dioxane (1.5 mL) was degassed and heated at 85 °C in a closed vial for 18 h. After cooling to room temperature, the reaction mixture was diluted with methanol, filtered through a syringe filter, and injected into a preparative HPLC system (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: 15 min, initial %B: 10; final %B: 100). The correct eluent was concentrated under vacuum, alkalized with 1N NaOH, and extracted with dichloromethane (4 × 40 mL). The combined extracts were dried over anhydrous Na2SO4. Solvent removal under vacuum yielded 6-(4-(4-isopropylpiperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine as a pale yellow solid (41.6 mg, 0.081 mmol, 67.9% yield). LCMS (M+H) + =503.4. 1 H NMR (500MHz, chloroform-d) δ8.09(d,J=8.2Hz,2H),8.01(d,J=8.5Hz,2H),7.77(d,J=8.2Hz,2H),7.47(s,1H),7.06(d,J=8.8Hz ,2H),6.74(s,1H),3.83(s,3H),3.35-3.27(m,4H),3.16(s,3H),2.85(s,3H),2.81-2.71(m,5H),1.13(d,J=6.3Hz,6H).

[0473] Example 12

[0474] 6-(3-fluoro-4-(4-isopropylpiperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine

[0475]

[0476] Step 1.1-(2-fluoro-4-nitrophenyl)-4-isopropylpiperazine

[0477]

[0478] A mixture of 1,2-difluoro-4-nitrobenzene (0.90 g, 5.66 mmol), 1-isopropylpiperazine (0.834 g, 6.51 mmol), and potassium carbonate (0.938 g, 6.79 mmol) in DMF (35 mL) was stirred at room temperature for 24 h, and then concentrated under vacuum to almost dryness. The residue was diluted with ethyl acetate (160 mL), washed continuously with water (2 × 25 mL) and brine (25 mL), and dried over anhydrous MgSO4. The product 1-(2-fluoro-4-nitrophenyl)-4-isopropylpiperazine (1.36 g, 5.09 mmol, 90% yield), appearing as a yellow oil, was separated by ISCO chromatography (80 g silica gel, solid-supported, 1-5% methanol / dichloromethane). LCMS (M+H) + =268.2. 1 H NMR (500MHz, chloroform-d) δ8.00 (dd, J=8.7, 2.3Hz, 1H), 7.92 (dd, J=13.2, 2.8Hz, 1H), 6.93 (t, J=8.8Hz ,1H),3.38-3.32(m,4H),2.77(dt,J=13.1,6.5Hz,1H),2.74-2.70(m,4H),1.11(d,J=6.6Hz,6H).

[0479] Step 2.3-Fluoro-4-(4-isopropylpiperazin-1-yl)aniline

[0480]

[0481] A mixture of 1-(2-fluoro-4-nitrophenyl)-4-isopropylpiperazine (1.36 g, 5.09 mmol) and 10% Pd / C (0.35 g, 0.329 mmol) in MeOH (30 mL) and THF (10 mL) was stirred at room temperature under H2 supplied by an H2 gasbag for 2 h. The catalyst was removed by filtration through diatomaceous earth. The filtrate was concentrated to dryness under vacuum. The residue was dissolved in ethyl acetate (150 mL) and dried over anhydrous Na2SO4. The solvent was removed under vacuum to give 3-fluoro-4-(4-isopropylpiperazin-1-yl)aniline (1.20 g, 5.06 mmol, 99% yield) as a brown solid. LCMS (M+H) + =238.2. 1H NMR (500MHz, chloroform-d) δ6.84 (t, J = 8.9 Hz, 1H), 6.48-6.39 (m, 2H), 3.55 (br s, 2H), 3.07-3.00 (m, 4H), 2.78-2.69 (m, 5H), 1.11 (d, J = 6.6Hz, 6H).

[0482] Step 3.1-(4-bromo-2-fluorophenyl)-4-isopropylpiperazine

[0483]

[0484] Tert-butyl nitrite (0.551 mL, 4.64 mmol) was added to a mixture of 3-fluoro-4-(4-isopropylpiperazin-1-yl)aniline (0.55 g, 2.318 mmol) and copper(II) bromide (0.621 g, 2.78 mmol) in acetonitrile (15 mL) for 5 min at 0 °C. The mixture was stirred at 0 °C for 1.5 h and then at room temperature for 5.5 h. The mixture was diluted with ethyl acetate (15 mL) and filtered through diatomaceous earth. The filtrate was concentrated to dryness under vacuum. Water (10 mL) was added to the residue and the mixture was extracted with dichloromethane (4 × 40 mL). The combined extracts were dried over anhydrous Na₂SO₄. The product 1-(4-bromo-2-fluorophenyl)-4-isopropylpiperazine (94 mg, 0.312 mmol, 13.47% yield), appearing as a brown solid, was separated by ISCO chromatography (40 g silica gel, solid-supported, 0-5% methanol / dichloromethane). LCMS (M+H) + =301.1.

[0485] Step 4.1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)phenyl)-4-isopropylpiperazine

[0486]

[0487] A mixture of 1-(4-bromo-2-fluorophenyl)-4-isopropylpiperazine (94 mg, 0.312 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxolane) (119 mg, 0.468 mmol), PdCl2(dppf)-CH2Cl2 adduct (15.29 mg, 0.019 mmol), and potassium acetate (92 mg, 0.936 mmol) in 1,4-dioxane (3 mL) was heated at 110 °C for 20 h. The mixture was diluted with ethyl acetate (5 mL) and filtered through diatomaceous earth. The filtrate was concentrated under vacuum, and the residue was subjected to ISCO chromatography (24 g silica gel, solid-supported, 0-5% methanol / chloromethane) to give 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)phenyl)-4-isopropylpiperazine (39 mg, 0.112 mmol, 35.9% yield) as a white solid. LCMS (M+H) + =349.2. 1 H NMR (500MHz, chloroform-d) δ7.52(d,J=7.7Hz,1H),7.45(d,J=13.5Hz,1H),6.94(t,J=8.3H z,1H),3.24-3.18(m,4H),2.79-2.71(m,5H),1.35(s,12H),1.12(d,J=6.6Hz,6H).

[0488] Step 5

[0489] 6-chloro-1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (28 mg, 0.084 mmol), 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)phenyl)-4-isopropylpiperazine (37.9 mg, 0.109 mmol), (2-dicyclohexylphosphine-2'- The mixture of palladium(II)(2-(2'-amino-1,1'-biphenyl))methanesulfonate XPhos-Pd-G3 (7.08 mg, 8.36 μmol) and tripotassium phosphate (0.146 mL, 0.293 mmol) in 1,4-dioxane (1.5 mL) was degassed and heated in a closed vial at 85 °C for 18 h. After cooling to room temperature, the reaction mixture was diluted with methanol, filtered through a syringe filter, and injected into a preparative HPLC system (column: Phenomenex Luna AXIA 5u C1821.2×100, 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, initial %B: 11; final %B: 100). The correct eluent was concentrated under vacuum, alkalized with 1N NaOH, and extracted with dichloromethane (4 × 40 mL). The combined extracts were dried over anhydrous Na₂SO₄ and concentrated under vacuum to give 6-(3-fluoro-4-(4-isopropylpiperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (17 mg, 0.032 mmol, 38.7% yield) as a pale solid. LCMS (M+H) + =521.4. 1 H NMR (400MHz, chloroform-d) δ8.13-8.07(m,2H),7.86-7.79(m,2H),7.78-7.75(m,2 H),7.47(s,1H),7.07(t,J=8.8Hz,1H),6.75(s,1H),3.83(s,3H),3.22(br s, 4H), 3.16 (s, 3H), 2.85 (s, 3H), 2.81-2.75 (m, 5H), 1.14 (br d, J = 6.5Hz, 6H).

[0490] Examples 13 to 33 in Table 1 were prepared according to the synthetic routes described for the preparations of Examples 1 to 12.

[0491] Table 1

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503] Example 41

[0504] 3-(4-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)phenyl)piperidin-1-yl)prop-1-ol

[0505]

[0506] Step 1. 4-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)phenyl)piperidine-1-carboxylic acid tert-butyl ester

[0507]

[0508] 6-chloro-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (180 mg, 0.538 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxopentoboran-2-yl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (Example 11, step 5) (250 mg, 0.645 mmol), (2-dicyclohexyl) A mixture of phosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (XPhos-Pd-G3) (45.5 mg, 0.054 mmol) and tripotassium phosphate (0.941 mL, 1.882 mmol) in 1,4-dioxane (7 mL) was degassed and heated in a closed vial at 85 °C for 18 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (120 mL) and filtered through diatomaceous earth. The filtrate was washed with brine (25 mL) and dried over anhydrous MgSO4. The title intermediate (196 mg, 0.350 mmol, 65.1% yield) was separated as a beige solid by ISCO chromatography (40 g silica gel, 40–85% ethyl acetate / hexane). LCMS (M+H) + =560.4. 1 HNMR (400MHz, chloroform-d) δ8.07(d,J=8.6Hz,2H),8.00(d,J=8.4Hz,2H),7.75(d,J= 8.6Hz,2H),7.50(s,1H),7.32(d,J=8.2Hz,2H),6.73(d,J=0.8Hz,1H),4.26(br s,2H),3.82(s,3H),3.14(s,3H),2.89-2.65(m,3H),2.84(s,3H),1.87(br d,J=12.3Hz,2H),1.75-1.61(m,2H),1.50(s,9H).

[0509] Step 2.1,4-Dimethyl-2-(4-(methylsulfonyl)phenyl)-6-(4-(piperidin-4-yl)phenyl)-1H-pyrrolo[3,2-c]pyridine

[0510]

[0511] TFA (8 mL, 104 mmol) was added to a solution of tert-butyl 4-(4-(1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)phenyl)piperidin-1-carboxylate (194 mg, 0.347 mmol) in dichloromethane (8 mL) for 2 min at 0 °C. The mixture was stirred at 0 °C for 30 min and then concentrated to dryness under vacuum. The residue was neutralized with saturated NaHCO3 solution and extracted with dichloromethane (4 times). The combined extracts were dried over anhydrous Na2SO4. The solvent was removed under vacuum to give the title intermediate (168 mg, 0.366 mmol, 105% yield) as a beige solid. LCMS (M+H) + =460.4.

[0512] Step 3.3-(4-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)phenyl)piperidin-1-yl)prop-1-ol

[0513] A mixture of 1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-6-(4-(piperidin-4-yl)phenyl)-1H-pyrrolo[3,2-c]pyridine (30 mg, 0.065 mmol), 3-bromoprop-1-ol (18.14 mg, 0.131 mmol), and potassium carbonate (18.04 mg, 0.131 mmol) in DMF (0.5 mL) was stirred at room temperature for 36 h. The mixture was diluted with ethyl acetate (5 mL) and filtered through diatomaceous earth. The filtrate was concentrated to almost dryness under vacuum. The residue was diluted with MeOH and injected into a preparative HPLC. The correct eluates were combined, concentrated under vacuum, alkalized with saturated NaHCO3 solution, and extracted with dichloromethane (4 times). The combined extracts were dried over anhydrous Na2SO4. The solvent was removed under vacuum to give the title compound as a white solid (1.5 mg, 2.81 μmol, 4.31% yield). LCMS(M+H) + =518.5.

[0514] Example 42

[0515] 2-(4-(cyclopropylsulfonyl)phenyl)-6-(4-(4-isopropylpiperazin-1-yl)phenyl)-1,4-dimethyl-1H-pyrrolo[3,2-c]pyridine

[0516]

[0517] Step 1. ((4-(cyclopropylsulfonyl)phenyl)ethynyl)trimethylsilane

[0518]

[0519] A mixture of 1-bromo-4-(cyclopropylsulfonyl)benzene (1.0 g, 3.83 mmol), bis(triphenylphosphine)palladium(II) chloride (0.054 g, 0.077 mmol), copper(I) iodide (0.036 g, 0.191 mmol), and triethylamine (2.85 mL, 20.46 mmol) in DMF (3.8 mL) was prepared using N2O. 2鼓泡 After 5 min, ethynyltrimethylsilane (1.060 mL, 7.66 mmol) was added. The reaction flask was sealed and heated at 90 °C for 18 h. After cooling to room temperature, the mixture was diluted with EtOAc (300 mL), washed with water (100 mL), dried over Mg2SO4, and concentrated under vacuum. The residue was purified by ISCO chromatography (80 g silica gel, 0-60% hexane / EtOAc) to give the title intermediate (1.06 g, 3.81 mmol, 99% yield) as a light brown solid. 1 ¹H NMR (400MHz, chloroform-d) δ 7.63 (d, J = 8.4 Hz, 2H), 7.44–7.39 (m, 2H), 2.24 (tt, J = 8.0, 4.7 Hz, 1H), 1.18–1.11 (m, 2H), 0.88–0.79 (m, 2H), 0.07 (s, 9H).

[0520] Step 2.1 -(cyclopropylsulfonyl)-4-ethynylbenzene

[0521]

[0522] Potassium carbonate (52.0 mg, 0.376 mmol) was added to a mixture of ((4-(cyclopropylsulfonyl)phenyl)ethynyl)trimethylsilane (1.06 g, 3.81 mmol) and MeOH (50 mL). The reaction mixture was stirred at room temperature for 1.25 h. The solvent was removed under vacuum. The residue was diluted with dichloromethane (400 mL), washed with water (100 mL), and dried over MgSO4. The solvent was removed under vacuum to give the title intermediate (0.77 g, 3.73 mmol, 98% yield) as a pale brown solid. 1 ¹H NMR (400MHz, chloroform-d) δ 7.98–7.82 (m, 2H), 7.76–7.61 (m, 2H), 2.50 (tt, J = 8.0, 4.8 Hz, 1H), 1.63 (s, 1H), 1.49–1.34 (m, 2H), 1.18–1.02 (m, 2H).

[0523] Step 3.3-((4-(cyclopropylsulfonyl)phenyl)ethynyl)-2,6-dimethylpyridine-4-amine

[0524]

[0525] To a stirred solution of 6-chloro-3-iodo-2-methylpyridin-4-amine (Example 11, Step 1) (0.4 g, 1.490 mmol) in DMF (6 mL), 1-(cyclopropylsulfonyl)-4-ethynylbenzene (0.369 g, 1.79 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.105 g, 0.149 mmol), copper(I) iodide (0.028 g, 0.149 mmol), and triethylamine (0.623 mL, 4.47 mmol) were added. The resulting mixture was degassed with nitrogen and then heated at 100 °C for 2 h. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 80 mL). The combined extracts were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by ISCO chromatography (80 g silica gel, 0-5% MeOH / CH2Cl2) to a pale yellow solid, the title intermediate (267 mg, 0.770 mmol, 51.7% yield). LCMS (M+H) + =347.0.

[0526] Step 4. 6-Chloro-2-(4-(cyclopropylsulfonyl)phenyl)-4-methyl-1H-pyrrolo[3,2-c]pyridine

[0527]

[0528] Potassium tert-butoxide (259 mg, 2.309 mmol) was added in a single addition to a stirred solution of 6-chloro-3-((4-(cyclopropylsulfonyl)phenyl)ethynyl)-2-methylpyridin-4-amine (267 mg, 0.770 mmol) in DMF (2.9 mL). The mixture was stirred at 80 °C for 1 h. After cooling to room temperature, the mixture was diluted with water (80 mL) and extracted with EtOAc (3 × 60 mL). The combined extracts were washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. The residue was passed through a silica gel column with 1:1 EtOAc / petroleum ether as the eluent to give the title intermediate as a yellow solid (187 mg, 0.539 mmol, 70.0% yield). LCMS (M+H) + =346.7. 1¹H NMR (400MHz, chloroform-d) δ 9.65 (br s, 1H), 7.90–7.83 (m, 2H), 7.81–7.73 (m, 2H), 7.15 (s, 1H), 6.91 (d, J = 1.0 Hz, 1H), 2.67 (s, 3H), 2.44 (tt, J = 8.0, 4.8 Hz, 1H), 1.39–1.26 (m, 2H), 1.08–0.96 (m, 2H).

[0529] Step 5. 6-Chloro-2-(4-(cyclopropylsulfonyl)phenyl)-1,4-dimethyl-1H-pyrrolo[3,2-c]pyridine

[0530]

[0531] Sodium hydride (60% oil dispersion) (53.9 mg, 1.348 mmol) was added in a single addition to a solution of 6-chloro-2-(4-(cyclopropylsulfonyl)phenyl)-4-methyl-1H-pyrrolo[3,2-c]pyridine (187 mg, 0.539 mmol) and iodomethane (0.084 mL, 1.348 mmol) in DMF (6 mL) at 0 °C. The mixture was stirred at room temperature for 1 h and then quenched with acetic acid (0.154 mL, 2.70 mmol). The resulting mixture was concentrated under vacuum to almost dryness. The residue was diluted with ethyl acetate (120 mL), washed with saturated NaHCO3 solution (2 × 25 mL), dried over anhydrous MgSO4, and concentrated under vacuum. The residue was subjected to ISCO chromatography (24 g silica gel, 0-100% hexane / EtOAc) to give the title intermediate (136 mg, 0.378 mmol, 70%) as a beige solid. LCMS (M+H) + =361.0. 1 ¹H NMR (400MHz, chloroform-d) δ 7.95 (d, J = 8.2Hz, 2H), 7.63 (d, J = 8.2Hz, 2H), 7.10 (s, 1H), 6.62 (s, 1H), 3.66 (s, 3H), 2.66 (s, 3H), 2.46 (tt, J = 8.0, 4.7Hz, 1H), 1.39–1.31 (m, 2H), 1.07–0.99 (m, 2H).

[0532] Step 6.2-(4-(cyclopropylsulfonyl)phenyl)-6-(4-(4-isopropylpiperazin-1-yl)phenyl)-1,4-dimethyl-1H-pyrrolo[3,2-c]pyridine

[0533] A mixture of 6-chloro-2-(4-(cyclopropylsulfonyl)phenyl)-1,4-dimethyl-1H-pyrrolo[3,2-c]pyridine (25.4 mg, 0.070 mmol), 1-isopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)phenyl)piperazine (48 mg, 0.145 mmol), (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (XPhos-Pd-G3) (11 mg, 0.013 μmol) and tripotassium phosphate (0.123 mL, 0.246 mmol) in 1,4-dioxane (1.5 mL) was degassed and heated at 85 °C in a closed vial for 18 h. After cooling to room temperature, the reaction mixture was diluted with methanol, filtered through a syringe filter, and injected into a preparative HPLC system. The correct eluent was concentrated under vacuum, alkalized with 1N NaOH, and extracted with dichloromethane (3 × 40 mL). The combined extracts were dried over anhydrous Na₂SO₄. Solvent removal under vacuum yielded the title compound as a beige solid (9.01 mg, 0.016 mmol, 22.75% yield). LCMS (M+H) + =529.1. 1 ¹H NMR (400MHz, chloromethane-d) δ 7.93 (dd, J = 12.8, 8.7 Hz, 4H), 7.65 (d, J = 8.4 Hz, 2H), 7.37 (s, 1H), 6.96 (d, J = 9.0 Hz, 2H), 6.64 (s, 1H), 3.73 (s, 3H), 3.26–3.19 (m, 4H), 2.76 (s, 3H), 2.69–2.63 (m, 5H), 2.51–2.42 (m, 1H), 1.37–1.32 (m, 2H), 1.07–1.01 (m, 8H).

[0534] Example 43

[0535] 6-(2,5-Difluoro-4-(piperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine

[0536]

[0537] Step 1. 4-(4-bromo-2,5-difluorophenyl)piperazine-1-carboxylic acid tert-butyl ester

[0538]

[0539] At room temperature, a solution of piperazine-1-tert-butyl carboxylate (1.0 g, 5.37 mmol) in toluene (10 mL) was supplemented with 1-bromo-2,5-difluoro-4-iodobenzene (1.71 g, 5.37 mmol), NaOtBu (1.03 g, 10.74 mmol), BINAP (0.67 g, 1.07 mmol), and Pd2(dba)3 (0.49 g, 0.54 mmol). The resulting mixture was degassed three times with nitrogen and stirred overnight at 90 °C. The mixture was concentrated under reduced pressure, diluted with EtOAc (200 mL), washed with water (200 mL), and dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure, the residue was purified by silica gel column chromatography using petroleum ether / EtOAc (20 / 1) as eluent to give the title intermediate (1.6 g, 79% yield) as a yellow solid. LCMS (M+H) + =320.9.

[0540] Step 2.4-(2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester

[0541]

[0542] To a solution of tert-butyl piperazine-1-carboxylate (1.6 g, 4.24 mmol) in 1,4-dioxane (15 mL), bis(pinacolyl)diboron (2.15 g, 8.48 mmol), KOAc (1.25 g, 12.72 mmol), and PdCl2 (dppf) (0.31 g, 0.42 mmol) were added. The resulting mixture was degassed three times with nitrogen and stirred at 90 °C for 2 h. The mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography using petroleum ether / EtOAc (10 / 1) as eluent to give the title intermediate (1.522 g, 78% yield) as a brown solid. LCMS (M+H) + =425.4. 1 ¹H NMR (300MHz, chloroform-d) δ 7.50–7.29 (m, 1H), 6.69–6.43 (m, 1H), 3.64–3.55 (m, 4H), 3.15–3.05 (m, 4H), 1.48 (s, 9H), 1.23 (s, 12H).

[0543] Step 3.4-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-2,5-difluorophenyl)piperazine-1-carboxylic acid tert-butyl ester

[0544]

[0545] 6-chloro-1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (Example 11, step 5) (75 mg, 0.224 mmol), 4-(2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (119 mg, 0.280 mmol), (2-bicyclo[3,2-c]pyridine) was added to the pyridine solution. A mixture of hexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (XPhos-Pd-G3) (18.96 mg, 0.022 mmol) and tripotassium phosphate (0.392 mL, 0.784 mmol) in 1,4-dioxane (3 mL) was degassed and heated in a closed vial at 85 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (10 mL) and filtered through diatomaceous earth. The filtrate was diluted with ethyl acetate (50 mL), washed with brine (10 mL), and dried over anhydrous MgSO4. The title intermediate (87 mg, 0.146 mmol, 65.1% yield) was isolated by ISCO chromatography (40 g silica gel, 30–80% ethyl acetate / hexane). LCMS (M+H) + =597.4.

[0546] Step 4.6-(2,5-difluoro-4-(piperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine

[0547] TFA (2 mL, 26.0 mmol) was added to a solution of 4-(4-(1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-2,5-difluorophenyl)piperazine-1-carboxylic acid tert-butyl ester (87 mg, 0.146 mmol) in dichloromethane (2 mL) for 2 min at 0 °C. The mixture was stirred at 0 °C for 40 min and then concentrated to dryness under vacuum. The residue was neutralized with saturated NaHCO3 solution (10 mL) and extracted with dichloromethane (4 × 30 mL). The combined extracts were dried over anhydrous Na2SO4. The solvent was removed under vacuum to give the title product (55 mg, 0.107 mmol, 73.7% yield) as a pale yellow solid. LCMS (M+H) + =497.1. 1H NMR (400MHz, DMSO-d6) δ8.08(d,J=8.6Hz,2H),7.95(d,J=8.4Hz,2H),7.88(dd,J=1 4.5,7.4Hz,1H),7.77(s,1H),7.01-6.92(m,2H),3.84(s,3H),3.31(s,3H),3.09(br dd,J=5.9,3.5Hz,4H),2.99-2.91(m,4H),2.74(s,3H).

[0548] Example 44

[0549] 1-(4-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzyl)piperazin-1-yl)-2-methylprop-2-ol

[0550]

[0551] Step 1. 4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzaldehyde

[0552]

[0553] A mixture of 6-chloro-1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (Example 11, Step 5) (160 mg, 0.478 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)benzaldehyde (150 mg, 0.645 mmol), (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (XPhos-Pd-G3) (40.4 mg, 0.048 mmol) and tripotassium phosphate (0.836 mL, 1.673 mmol) in 1,4-dioxane (5 mL) was degassed and heated at 90 °C in a closed vial for 7.5 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (120 mL) and filtered through diatomaceous earth. The filtrate was washed with brine (25 mL) and dried over anhydrous MgSO4. The title intermediate (150 mg, 0.371 mmol, 78% yield) as a pale yellow solid was isolated by ISCO chromatography (40 g silica gel, 45–100% ethyl acetate / hexane). LCMS (M+H) + =405.0. 1H NMR (400MHz, DMSO-d6) δ10.07(s,1H),8.48(d,J=8.2Hz,2H),8.23(s,1H),8.09(d,J =8.4Hz,2H),8.06-7.95(m,4H),7.01(s,1H),3.93(s,3H),3.32(s,3H),2.78(s,3H).

[0554] Step 2.1-(4-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzyl)piperazin-1-yl)-2-methylprop-2-ol

[0555] Sodium triacetoxyborohydride (62.9 mg, 0.297 mmol) was added in a single batch to a mixture of 4-(1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzaldehyde (30 mg, 0.074 mmol), 2-methyl-1-(piperazin-1-yl)prop-2-ol (35.2 mg, 0.223 mmol), magnesium sulfate (179 mg, 1.483 mmol), and acetic acid (0.042 mL, 0.742 mmol) in 1.2 mL of DMF. The mixture was stirred at room temperature for 18 h. The non-homogeneous mixture was diluted with ethyl acetate (5 mL) and filtered through diatomaceous earth. The filtrate was concentrated to dryness under vacuum. The residue was dissolved in MeOH and injected into a preparative HPLC system. The correct eluates were combined, concentrated under vacuum, alkalized with 1N NaOH solution, and extracted with dichloromethane (4 × 35 mL). The combined extracts were dried over anhydrous Na₂SO₄. The solvent was removed under vacuum to give the title compound as a white solid (12.5 mg, 0.022 mmol, 30.2% yield). LCMS (M+H) + =547.3. 1 H NMR (500MHz, chloroform-d) δ8.10 (d, J = 8.5Hz, 2H), 8.04 (br d,J=7.9Hz,2H),7.80-7.75(m,2H),7.54(s,1H),7.50-7.43(m,2H),6.77(s,1H),3. 85(s,3H),3.72-3.56(m,2H),3.16(s,3H),2.87(s,3H),2.81-2.49(m,7H),2.37(br s,2H),1.19(br s,6H).

[0556] Example 45

[0557] 3-((1R,4R)-5-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzyl)-2,5-diazabicyclo[2.2.2]oct-2-yl)-2,2-dimethylprop-1-ol

[0558]

[0559] Step 1. (1R,4R)-5-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzyl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester

[0560]

[0561] Sodium triacetoxyborohydride (84 mg, 0.396 mmol) was added in a single batch to a mixture of 4-(1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzaldehyde (Example 44, Step 1) (40 mg, 0.099 mmol), (1R,4R)-2,5-diazabicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester (50.4 mg, 0.237 mmol), magnesium sulfate (238 mg, 1.978 mmol), and acetic acid (0.057 mL, 0.989 mmol) in DMF (2 mL). The mixture was stirred at room temperature for 24 h. The non-homogeneous mixture was diluted with ethyl acetate (5 mL) and filtered through diatomaceous earth. The filtrate was concentrated to dryness under vacuum. The residue was dissolved in ethyl acetate (60 mL), washed with saturated NaHCO3 solution (2 × 15 mL), and dried over anhydrous MgSO4. The title intermediate (36 mg, 0.060 mmol, 60.6% yield) was separated as a white solid by ISCO chromatography (24 g silica gel, solid-supported, 40–100% ethyl acetate / hexane). LCMS (M+H) + =601.5.

[0562] Step 2. (1R,4R)-2-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzyl)-2,5-diazabicyclo[2.2.2]octane

[0563]

[0564] TFA (2 mL, 26.0 mmol) was added to a solution of (1R,4R)-5-(4-(1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzyl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester (36 mg, 0.060 mmol) in dichloromethane (2 mL) for 1 min at 0 °C. The mixture was stirred at 0 °C for 1.5 h and then concentrated to dryness under vacuum. A saturated NaHCO3 solution (6 mL) was added to the residue, and the mixture was extracted with dichloromethane (4 × 30 mL). The combined extracts were dried over anhydrous Na2SO4. The solvent was removed under vacuum to give the title intermediate (30 mg, 0.060 mmol, 100% yield) as a white solid. LCMS (M+H) + =501.2.

[0565] Step 3.3-((1R,4R)-5-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzyl)-2,5-diazabicyclo[2.2.2]oct-2-yl)-2,2-dimethylprop-1-ol

[0566] Sodium triacetoxyborohydride (57.1 mg, 0.270 mmol) was added in a single batch to a mixture of (1R,4R)-2-(4-(1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzyl)-2,5-diazabicyclo[2.2.2]octane (30 mg, 0.060 mmol), 3-hydroxy-2,2-dimethylpropionaldehyde (21.42 mg, 0.210 mmol), magnesium sulfate (144 mg, 1.198 mmol), and acetic acid (0.034 mL, 0.599 mmol) in DMF (1.2 mL). The mixture was stirred at room temperature for 24 h. The non-homogeneous mixture was diluted with ethyl acetate (5 mL) and filtered through diatomaceous earth. The filtrate was concentrated to dryness under vacuum. The residue was dissolved in MeOH and injected into a preparative HPLC system. The correct eluates were combined, concentrated under vacuum, alkalized with 1N NaOH solution, and extracted with dichloromethane (4 × 35 mL). The combined extracts were dried over anhydrous Na₂SO₄. The solvent was removed under vacuum to give the title product (5 mg, 8.35 μmol, 13.94% yield) as a white solid. LCMS (M+H) + =587.2. 11H NMR (400MHz, δ-d) 8.08(d,J=8.4Hz,2H), 8.02(br d,J=7.8Hz,2H), 7.78-7.72(m,2H), 7.52(s,3H), 6.74(d,J=0.8Hz,1H), 3.82(s,3H), 3.53(s,2H), 3.14(s,3H), 3.10-2.91(m,2H), 2.86-2.59(m,8H), 2.14-1.92(m,2H), 1.84-1.50(m,5H), 0.96(s,3H), 0.94(s,3H)

[0567]

[0568]

[0569]

[0570]

[0571]

[0572]

[0573]

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592] Example 115

[0593] 4-(4-(4-(3-fluoro-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzyl)piperazin-1-yl)-2-methylbut-2-ol

[0594]

[0595] Step 1. 6-Chloro-3-fluoro-1,4-dimethyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridine

[0596]

[0597] Selectfluor (158 mg, 0.45 mmol) was added to a stirred solution of 6-chloro-1,4-dimethyl-2-(4-methylsulfonylphenyl)-pyrrolo[3,2-c]pyridine (500 mg, 1.49 mmol) in DMF (6 mL). The reaction mixture was degassed three times with nitrogen and stirred overnight at room temperature. The crude mixture was purified by rapid HPLC (column: C18; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 40 mL / min; gradient: 5% B to 50% B over 30 min; wavelength: 254 / 210 nm) to give the title compound (120 mg, 23% yield) as a pale orange solid. 1 H NMR(400MHz, DMSO-d6)δ8.14-8.09(m,2H),7.90(d,J=8.2Hz,2H),7.67(d,J=2.5Hz,1H),3.71(s,3H),3.32(s,3H),2.72(s,3H).LCMS(M+H) + =601.5.

[0598] Step 2.4-[3-fluoro-1,4-dimethyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridin-6-yl]benzaldehyde

[0599]

[0600] To a stirred solution of 6-chloro-3-fluoro-1,4-dimethyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridine (120 mg, 0.34 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL), 4-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)benzaldehyde (158 mg, 0.68 mmol), K₂CO₃ (141 mg, 1.02 mmol), and Pd(PPh₃)₄ (39 mg, 0.03 mmol) were added. The resulting solution was stirred overnight at 90 °C under a nitrogen atmosphere, and the reaction was monitored by LCMS. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (DCM / methanol = 20 / 1) to give the title compound as a yellow solid (110 mg, 62.2% yield). 1 H NMR (400MHz, DMSO-d6) δ10.07(d,J=7.0Hz,1H),8.48(d,J=8.1Hz,2H),8.16-8.11(m,2H),8.03(d,J=8 .2Hz,2H),7.95(d,J=8.2Hz,2H),7.92-7.87(m,1H),3.85(s,3H),3.33(s,3H),2.85(s,3H).LCMS(M+H) + =423.2.

[0601] Step 3

[0602] To a solution of 4-[3-fluoro-1,4-dimethyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridin-6-yl]benzaldehyde (50 mg, 0.12 mmol) in DCM (5 mL), 2-methyl-4-piperazin-1-yl-but-2-ol (61 mg, 0.36 mmol) and acetic acid (0.01 mL) were added. After stirring at room temperature for 1 h, NaBH(OAc)3 (75 mg, 0.36 mmol) was added to the mixture. After stirring for 2 h, the mixture was diluted with water (50 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: XBridge Prep C18 OBD column, 19*150mm, 5μm; mobile phase A: water (10mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 20mL / min; gradient: 40%B to 50%B over 4.5min, 50%B; wavelength: 254 / 210nm; RT1 (min): 4.35) to give the title compound (15.8mg, 22.6% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.14(dd,J=14.7,8.0Hz,4H),8.02(s,1H),7.93(d,J=8.0Hz,2H),7.39(d,J=7.9Hz,2H),4.67(s, 1H), 3.81 (s, 3H), 3.51 (s, 2H), 2.82 (s, 3H), 2.50 (d, J = 1.8Hz, 2H), 2.60-2.41 (m, 8H), 1.51 (t, J = 7.3Hz, 2H), 1.09 (s, 6H). LCMS(M+H) + =579.2.

[0603] Example 116

[0604] 4-[4-[[4-[1-Cyclopropyl-4-methyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridin-6-yl]phenyl]methyl]piperazin-1-yl]-2-methyl-but-2-ol

[0605]

[0606] Step 1. 6-Chloro-1-cyclopropyl-4-methyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridine

[0607]

[0608] To a solution of 6-chloro-4-methyl-2-(4-methylsulfonylphenyl)-1H-pyrrolo[3,2-c]pyridine (200 mg, 0.62 mmol) in DCE (8 mL), Na₂CO₃ (198 mg, 1.87 mmol), cyclopropylboronic acid (161 mg, 1.87 mmol), Cu(OAc)₂ (148 mg, 0.94 mmol), and 2,2'-bipyridine (146 mg, 0.94 mmol) were added. The resulting solution was stirred at 60 °C. After 36 h, the mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over Na₂SO₄, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / EtOAc = 2:1) to give the title compound (140 mg, 56.6% yield) as a grayish-white solid. 1 H NMR(400MHz,DMSO-d6)δ8.05(s,4H),7.47(s,1H),6.99(s,1H),3.76(tt,J=7.2,3.9Hz, 1H), 3.32 (s, 3H), 2.65 (s, 3H), 1.06 (dt, J = 7.2, 3.6Hz, 2H), 0.56 (p, J = 5.2, 4.8Hz, 2H). LCMS(M+H) + =361.

[0609] Step 2.4-[1-Cyclopropyl-4-methyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridin-6-yl]benzaldehyde

[0610]

[0611] To a solution of 6-chloro-1-cyclopropyl-4-methyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridine (130 mg, 0.36 mmol) in 1,4-dioxane (4 mL) and water (0.8 mL), 4-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)benzaldehyde (167 mg, 0.72 mmol), K3PO4 (229 mg, 1.08 mmol), and Xphos-Pd-G3 (30 mg, 0.04 mmol) were added. The resulting solution was degassed three times with nitrogen and stirred at 90 °C. After 3 h, the mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over Na2SO4, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / EtOAc = 1:1). The crude product was purified by rapid HPLC (column: C18; mobile phase A: water (0.05%), mobile phase B: ACN; flow rate: 50 mL / min; gradient: 5% B to 27% B over 12 min; wavelength: 254 / 210 nm) to give the title compound (110 mg, 69.1% yield) as a pale yellow solid. LCMS (M+H) + =431.2.

[0612] Step 3

[0613] To a solution of 4-[1-cyclopropyl-4-methyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridin-6-yl]benzaldehyde (50 mg, 0.12 mmol) in DCM (4 mL), 2-methyl-4-piperazin-1-yl-but-2-ol (100 mg, 0.58 mmol) and acetic acid (0.01 mL) were added. After stirring at room temperature for 2 h, NaBH(OAc)3 (123 mg, 0.58 mmol) was added to the mixture. After stirring for 1 h, the mixture was diluted with water (50 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: XBridge Prep C18 OBD column, 19*150mm, 5μm; mobile phase A: water (10mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 20mL / min; gradient: 40%B to 65%B over 4.5min, 65%B; wavelength: 254 / 210nm) to give the title compound (16mg, 22.9% yield) as a white solid. 1H NMR (300MHz, methanol-d4) δ8.07(q,J=8.6Hz,4H),7.97-7.83(m,2H),7.79(s,1H),7.55-7.36(m,2H),6.91(s,1H),3.78-3.68(m,1H),3 .63(s,2H),3.22(s,3H),2.95-2.18(m,13H),1.69(t,J=7.4Hz,2H),1.22(s,6H),1.13(dd,J=7.4,5.6Hz,2H),0.72-0.58(m,2H). LCMS(M+H) + =587.2.

[0614] Example 117

[0615] 4-[4-[[4-[1-(difluoromethyl)-4-methyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridin-6-yl]phenyl]methyl]piperazin-1-yl]-2-methyl-but-2-ol

[0616]

[0617] Step 1. 6-Chloro-1-(difluoromethyl)-4-methyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridine

[0618]

[0619] NaH (30 mg, 1.25 mmol) was added to a stirred solution of 6-chloro-4-methyl-2-(4-methylsulfonylphenyl)-1H-pyrrolo[3,2-c]pyridine (200 mg, 0.62 mmol) in DMF (5 mL) at 0 °C. After stirring for 10 min at room temperature, a solution of sodium 2-chloro-2,2-difluoroacetate (190 mg, 1.25 mmol) in DMF (2 mL) was added to the mixture. The resulting solution was stirred for 10 min at room temperature and then stirred at 80 °C. After 1 h, the mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel rapid column chromatography (petroleum ether / EtOAc 3:2) to give the title compound (120 mg, 51.9% yield) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6) δ8.15-8.08(m,2H),8.08-7.75(m,3H),7.69(s,1H),7.21(s,1H),3.32(s,3H),2.70(s,3H). LCMS(M+H)+ =371.1.

[0620] Step 2.4-[1-(difluoromethyl)-4-methyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridin-6-yl]benzaldehyde

[0621]

[0622] To a stirred solution of 6-chloro-1-(difluoromethyl)-4-methyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridine (120 mg, 0.32 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL), K₂CO₃ (134 mg, 0.97 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxolaneborane-2-yl)benzaldehyde (150 mg, 0.65 mmol), and Pd(PPh₃)₄ (37 mg, 0.03 mmol) were added. The resulting solution was degassed three times with nitrogen and stirred at 90 °C under a nitrogen atmosphere. After 2 h, the reactants were concentrated under reduced pressure and purified by column chromatography (petroleum ether / EtOAc 3:2) to give the title compound (110 mg, 72.8% yield) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ10.09(s,1H),8.44-8.39(m,2H),8.30(s,1H),8.2 2-8.02(m,5H),7.94-7.89(m,2H),7.24(s,1H),3.33(s,3H),2.82(s,3H). LCMS(M+H) + =441.1.

[0623] Step 3

[0624] To a solution of 4-[1-(difluoromethyl)-4-methyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridin-6-yl]benzaldehyde (50 mg, 0.11 mmol) in DCM (4 mL), 2-methyl-4-piperazin-1-yl-but-2-ol (98 mg, 0.57 mmol) and acetic acid (0.01 mL) were added. After stirring at room temperature for 1 h, NaBH(OAc)3 (120 mg, 0.57 mmol) was added to the mixture. After stirring for 18 h, the mixture was diluted with water (50 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: XBridge Prep C18 OBD column, 19*150mm, 5μm; mobile phase A: water (10mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 20mL / min; gradient: 55%B to 80%B over 4.5min, 80%B; wavelength: 254 / 210nm) to give the title compound (20.5mg, 30.1% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.25-8.05(m,2H),8.00-7.51(m,6H),7.49(d,J=7.7Hz,2H),7.06 (s,1H),3.63(s,2H),3.22(s,3H),3.10-2.05(m,13H),1.69(t,J=7.4Hz,2H),1.22(s,6H). LCMS(M+H) + =597.2.

[0625] Example 118

[0626] 2-[6-[4-(4-isopropylpiperazin-1-yl)phenyl]-1-methyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridin-4-yl]prop-2-ol

[0627]

[0628] Step 1,2,6-Dichloro-3-iodopyridine-4-amine

[0629]

[0630] KOAc (602 mg, 6.13 mmol) and ICl (1.99 g, 12.27 mmol) were added to a solution of 2,6-dichloropyridin-4-amine (1 g, 6.13 mmol) in acetic acid (10 mL). The resulting solution was stirred at room temperature. After 4 days, water (15 mL) was added to the mixture, the slurry was filtered and dried under reduced pressure to give the title compound (1.6 g, 86% yield) as a light orange solid. 1 ¹H NMR (300 MHz, methanol-d⁴) δ 6.59 (s, ¹H). LCMS (M+H) + =288.9.

[0631] Step 2.2,6-Dichloro-3-[2-(4-methylsulfonamidophenyl)ethynyl]pyridine-4-amine

[0632]

[0633] A solution of 2,6-dichloro-3-iodopyridin-4-amine (600 mg, 2.08 mmol) in DMF (5 mL) was supplemented with 1-ethynyl-4-methylsulfonyl-benzene (450 mg, 2.49 mmol), Pd(PPh3)2Cl2 (145 mg, 0.21 mmol), CuI (40 mg, 0.21 mmol), and TEA (630 mg, 6.23 mmol). The resulting mixture was degassed three times with nitrogen and stirred at 90 °C. After 4 h, the mixture was diluted with ammonium chloride solution (60 mL) and extracted with EtOAc (3 × 60 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. LCMS (M+H) + =341.1.

[0634] Step 3,4,6-Dichloro-2-(4-methylsulfonylphenyl)-1H-pyrrolo[3,2-c]pyridine

[0635]

[0636] t-BuOK (466 mg, 4.15 mmol) was added to a stirred solution of 2,6-dichloro-3-[2-(4-methylsulfonylphenyl)ethynyl]pyridine-4-amine (708 mg, 2.07 mmol) in DMF (5 mL) at 0 °C. The resulting solution was stirred at 80 °C. After 1 h, the mixture was diluted with water (60 mL) and extracted with EtOAc (3 × 60 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was applied to a silica gel column with petroleum ether / EtOAc (1:1) as eluent to give the title compound (335 mg, 47.3% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ 12.78 (s, 1H), 8.26-8.19 (m, 2H), 8.09-8.03 (m, 2H), 7.51 (d, J = 0.9Hz, 1H), 7.35 (s, 1H), 3.29 (s, 3H). LCMS(M+H) + =340.9.

[0637] Step 4.4,6-Dichloro-1-methyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridine

[0638]

[0639] Cs₂CO₃ (640 mg, 1.96 mmol) and iodomethane (153 mg, 1.08 mmol) were added to a stirred solution of 4,6-dichloro-2-(4-methylsulfonylphenyl)-1H-pyrrolo[3,2-c]pyridine (335 mg, 0.98 mmol) in DMF (4 mL). The resulting solution was stirred at room temperature. After 1 h, the solid was filtered, the filtrate was concentrated under reduced pressure, and the crude residue was purified by rapid HPLC (column: C18; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 40 mL / min; gradient: 10% B to 60% B over 20 min; wavelength: 254 / 210 nm) to give the title compound (310 mg, 88.9% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ8.13-8.06 (m, 2H), 7.97 (d, J = 8.3Hz, 2H), 7.89 (s, 1H), 6.90 (s, 1H), 3.83 (s, 3H), 3.33 (s, 3H). LCMS(M+H) + =355.

[0640] Step 5. 6-Chloro-1-methyl-2-(4-methylsulfonylphenyl)-4-vinyl-pyrrolo[3,2-c]pyridine

[0641]

[0642] To a solution of 4,6-dichloro-1-methyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridine (310 mg, 0.87 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxolane (161 mg, 1.05 mmol), K₂CO₃ (361 mg, 2.62 mmol), and PdCl₂(dppf) (71 mg, 0.09 mmol) were added. The resulting mixture was degassed three times with nitrogen and stirred at 90 °C. Two hours later, the mixture was concentrated under reduced pressure and the crude product was purified by rapid HPLC (column: C18; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 40 mL / min; gradient: 5% B to 58% B over 30 min; wavelength: 254 / 210 nm) to give the title compound (190 mg, 62.8% yield) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6) δ8.09(d,J=8.1Hz,2H),7.95(d,J=8.1Hz,2H),7.68(s,1H),7.29-7.22(m,1H ), 7.19 (d, J = 3.7Hz, 1H), 6.43 (d, J = 17.2Hz, 1H), 5.65 (d, J = 10.8Hz, 1H), 3.81 (s, 3H), 3.32 (s, 3H). LCMS(M+H) + =347.

[0643] Step 6. 6-Chloro-1-methyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridine-4-carboxylic acid

[0644]

[0645] A solution of KMnO4 (168 mg, 1.07 mmol) in water (2 mL) was added dropwise to a stirred solution of 6-chloro-1-methyl-2-(4-methylsulfonylphenyl)-4-vinyl-pyrrolo[3,2-c]pyridine (185 mg, 0.53 mmol) in acetone (8 mL). The resulting solution was stirred at 0 °C. After 2 h, the mixture was concentrated under reduced pressure and purified by rapid HPLC (column: pC18; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 50 mL / min; gradient: 5% B to 40% B over 15 min; wavelength: 254 / 210 nm) to give the title compound (110 mg, 55.2% yield) as a pale yellow solid. 1H NMR (400MHz, DMSO-d6) δ13.35(s,1H),8.09(d,J=8.0Hz,2H),8.05(s,1H),7.98(d,J=8.0Hz,2H),7.22(s,1H),3.85(s,3H),3.32(s,3H). LCMS(M+H) + =365.

[0646] Step 7. Methyl 6-chloro-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine-4-carboxylate

[0647]

[0648] 20 drops of H₂SO₄ were added to a solution of 105 mg (0.29 mmol) of 6-chloro-1-methyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridine-4-carboxylic acid in methanol (5 mL). The resulting solution was stirred at 65 °C for 5 hours. The mixture was then concentrated under reduced pressure. The residue was partitioned into a saturated sodium bicarbonate solution and extracted with DCM (3 × 50 mL). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure to give the title compound (110 mg crude substance) as a red solid. LCMS (M+H) + =379.

[0649] Step 8.2-[6-chloro-1-methyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridin-4-yl]prop-2-ol

[0650]

[0651] A solution of methyl 6-chloro-1-methyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridine-4-carboxylate (50 mg, 0.13 mmol) in THF (1.5 mL) was degassed three times with nitrogen. Magnesium bromo(methyl) (3 M solution in diethyl ether) (1.5 mL, 0.4 mmol) was added to the solution at 0 °C. The resulting solution was stirred at 0 °C for 2 h. The reaction mixture was then quenched with ammonium chloride solution. The reaction mixture was diluted with water (30 mL) and extracted with DCM (3 × 30 mL). The combined organic layers were dried over Na₂SO₄, concentrated under reduced pressure, and applied to a silica gel column using petroleum ether / EtOAc (1:1) as eluent to give the title compound (25 mg, 47.6% yield) as a pale yellow solid. 1¹H NMR (300MHz, chloroform-d): δ 8.09 (d, J = 8.3Hz, 2H), 7.78–7.70 (m, 2H), 7.27 (s, 1H), 6.81 (d, J = 4.8Hz, 1H), 3.76 (s, 3H), 3.14 (s, 3H), 1.70 (s, 6H). LCMS (M+H) + =379.1.

[0652] Step 9

[0653] To a solution of 2-[6-chloro-1-methyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridin-4-yl]prop-2-ol (25 mg, 0.07 mmol) in 1,4-dioxane (1.5 mL) and water (0.3 mL), 1-isopropyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxolaneborane-2-yl)phenyl]piperazine (43 mg, 0.13 mmol), K3PO4 (42 mg, 0.2 mmol), and Xphos-Pd-G3 (6 mg, 0.01 mmol) were added. The resulting mixture was degassed three times with nitrogen and stirred at 90 °C. After 18 h, the mixture was concentrated under reduced pressure and the crude product was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3); mobile phase B: ACN; flow rate: 25 mL / min; gradient: 45% B to 75% B over 5.2 min, 75% B; wavelength: 210 nm) to give the title compound (13.6 mg, 37.3% yield) as a pale yellow solid. 1 H NMR (400MHz, chloroform-d) δ8.20-7.90(m,4H),7.75(d,J=8.4Hz,2H),7.55(s,1H),7.04(d,J=9.2Hz,2H),6.88-6.56 (m,2H),3.83(s,3H),3.50-3.30(m,4H),3.14(s,3H),2.90-2.67(m,5H),1.74(s,6H),1.14(d,J=6.4Hz,6H). LCMS(M+H) + =547.2.

[0654] Example 119

[0655] 6-[4-(4-isopropylpiperazin-1-yl)phenyl]-4-methoxy-1-methyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridine

[0656]

[0657] Step 1. 6-Chloro-3-iodo-2-methoxy-pyridine-4-amine

[0658]

[0659] Chloramine-T (1.07 g, 4.73 mmol) and NaI (709 mg, 4.73 mmol) were added to a stirred solution of 2-chloro-6-methoxy-pyridin-4-amine (500 mg, 3.15 mmol) in acetic acid (5 mL). The reaction mixture was stirred at room temperature for 18 h, followed by the addition of 2 M sodium hydroxide solution (60 mL) and ethyl acetate. The layers were partitioned, and the aqueous phase was extracted with ethyl acetate (3 × 60 mL). The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by rapid HPLC (column: C18; mobile phase A: water (10 mmol / L NH₄HCO₃); mobile phase B: ACN; flow rate: 40 mL / min; gradient: 5% B to 76% B over 23 min; wavelength: 254 / 210 nm) to give the title compound (470 mg, 51.6% yield) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ6.44(s,2H),6.36(s,1H),3.79(s,3H). LCMS(M+H) + =285.

[0660] Step 2. 6-Chloro-2-methoxy-3-[2-(4-methylsulfonylphenyl)ethynyl]pyridine-4-amine

[0661]

[0662] To a stirred solution of 6-chloro-3-iodo-2-methoxypyridine-4-amine (400 mg, 1.41 mmol) in DMF (5 mL), 1-ethynyl-4-methylsulfonyl-benzene (304 mg, 1.69 mmol), Pd(PPh3)2Cl2 (98 mg, 0.14 mmol), CuI (27 mg, 0.14 mmol), and TEA (427 mg, 4.22 mmol) were added. The resulting solution was degassed three times with nitrogen and stirred at 100 °C. After 3 h, the mixture was diluted with ammonium chloride solution (60 mL) and extracted with EtOAc (3 × 60 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. LCMS (M+H) + =337.1.

[0663] Step 3. 6-Chloro-4-methoxy-2-(4-methylsulfonylphenyl)-1H-pyrrolo[3,2-c]pyridine

[0664]

[0665] t-BuOK (315 mg, 2.81 mmol) was added to a stirred solution of 6-chloro-2-methoxy-3-[2-(4-methylsulfonylphenyl)ethynyl]pyridine-4-amine (crude substance) in DMF (5 mL) at 0 °C. The resulting solution was stirred at 80 °C. After 1 h, the mixture was diluted with water (60 mL) and extracted with EtOAc (3 × 60 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was applied to a silica gel column with petroleum ether / EtOAc (3:2) as eluent to give the title compound (160 mg, 32.3% yield) as a pale yellow solid. 1 H NMR (300MHz, DMSO-d6) δ12.35(s,1H),8.13(d,J=8.3Hz,2H),8.00(d,J=8.3Hz,2H),7.25(d,J=1.9Hz,1H),7.10(s,1H),4.00(s,3H),3.26(s,3H). LCMS(M+H) + =337.

[0666] Step 4. 6-Chloro-4-methoxy-1-methyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridine

[0667]

[0668] Cs₂CO₃ (310 mg, 0.95 mmol) and iodomethane (74 mg, 0.52 mmol) were added to a stirred solution of 6-chloro-4-methoxy-2-(4-methylsulfonylphenyl)-1H-pyrrolo[3,2-c]pyridine (160 mg, 0.48 mmol) in DMF (3 mL). The resulting solution was stirred at room temperature for 1 hour, then the mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. The crude product was applied to a silica gel column with petroleum ether / EtOAc (2:1) as eluent to give the title compound (160 mg, 96% yield) as a light orange solid. 1 H NMR (400MHz, DMSO-d6) δ 8.08-8.02 (m, 2H), 7.94-7.89 (m, 2H), 7.43 (d, J = 0.9Hz, 1H), 6.82 (d, J = 0.9Hz, 1H), 4.00 (s, 3H), 3.79 (s, 3H), 3.30 (s, 3H). LCMS(M+H) + =351.1.

[0669] Step 5

[0670] To a stirred solution of 6-chloro-4-methoxy-1-methyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridine (50 mg, 0.14 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL), K3PO4 (90 mg, 0.43 mmol), 1-isopropyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxolaneborane-2-yl)phenyl]piperazine (94 mg, 0.29 mmol), and Xphos-Pd-G3 (12 mg, 0.01 mmol) were added. The resulting mixture was degassed three times with nitrogen and stirred at 90 °C. Three days later, the mixture was concentrated under reduced pressure and the crude product was purified by preparative HPLC (column: XBridge Prep C18 OBD column, 19*150mm, 5μm; mobile phase A: water (10mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 20mL / min; gradient: 50%B to 70%B over 4.5min; wavelength: 254 / 210nm) to give the title compound (10mg, 13.2% yield) as a pale yellow solid. 1 H NMR (300MHz, chloroform-d) δ8.07(dd,J=8.7,3.2Hz,4H),7.73(d,J=8.0Hz,2H),7.31(s,1H),7.05(d,J=8.5Hz,2H),6. 76(s,1H),4.21(s,3H),3.82(s,3H),3.45-3.26(m,4H),3.15(s,3H),2.91-2.69(m,5H),1.17(d,J=6.5Hz,6H). LCMS(M+H) + =519.2.

[0671] Example 120

[0672] 4-[6-[4-(4-isopropylpiperazin-1-yl)phenyl]-1-methyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridin-4-yl]morpholine

[0673]

[0674] Step 1. 2-Chloro-6-(N-morpholino)-pyridine-4-amine

[0675]

[0676] DIEA (3.21 mL, 18.4 mmol) was added to a solution of 2,6-dichloropyridin-4-amine (1 g, 6.13 mmol) and morpholine (0.53 g, 6.13 mmol) in DMSO (10 mL). The resulting mixture was stirred at 90 °C. After 2 h, the mixture was cooled to room temperature, diluted with water (200 mL), and extracted with EtOAc (200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN and water (0.05% NH4HCO3), 10% ACN to 70% ACN gradient, for 20 min; detector, UV 254 nm, to give the title compound (0.81 g, 60.3% yield) as a white solid. 1 H NMR (300MHz, methanol-d6) δ6.05 (s, 2H), 5.97 (s, 1H), 5.76 (s, 1H), 3.66 (t, J = 4.8Hz, 4H), 3.27 (t, J = 4.9Hz, 4H). LCMS(M+H) + =213.9.

[0677] Step 2.6-Chloro-3-iodo-2-(N-morpholino)-pyridine-4-amine

[0678]

[0679] Ag₂SO₄ (1.17 g, 3.79 mmol) and I₂ (1.06 g, 4.17 mmol) were added to a stirred solution of 2-chloro-6-(N-morpholino)-pyridine-4-amine (810 mg, 3.79 mmol) in ethanol (10 mL) at 0 °C. The resulting solution was stirred for 18 h, then diluted with water (200 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. The crude product was applied to a silica gel column with petroleum ether / EtOAc (2:1) as eluent to give the title compound (900 mg, 69.9% yield) as a yellow solid. 1 H NMR (300MHz, methanol-d6) δ6.12 (s, 2H), 5.94 (s, 1H), 3.65 (t, J = 4.8 Hz, 4H), 3.26 (t, J = 4.9 Hz, 4H). LCMS(M+H) + =339.9.

[0680] Step 3. 6-Chloro-3-[2-(4-Methylsulfonylphenyl)ethynyl]-2-(N-morpholinyl)pyridine-4-amine

[0681]

[0682] To a stirred solution of 6-chloro-3-iodo-2-(N-morpholino)pyridin-4-amine (500 mg, 1.47 mmol) in DMF (5 mL), 1-ethynyl-4-methanesulfonyl-benzene (291.9 mg, 1.62 mmol), Pd(PPh3)2Cl2 (170.1 mg, 0.15 mmol), CuI (27.9 mg, 0.15 mmol), and TEA (0.77 mL, 4.42 mmol) were added. The resulting mixture was degassed three times with nitrogen and then stirred at 100 °C under a nitrogen atmosphere. After 2 h, the mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give the title compound (600 mg crude substance) as a brown solid. LCMS (M+H) + =392.1.

[0683] Step 4.4-[6-chloro-2-(4-methylsulfonylphenyl)-1H-pyrrolo[3,2-c]pyridin-4-yl]morpholine

[0684]

[0685] t-BuOK (436.3 mg, 3.83 mmol) was added to a stirred solution of 6-chloro-3-[2-(4-methylsulfonylphenyl)ethynyl]-2-(N-morpholinyl)pyridine-4-amine (500 mg, 1.28 mmol) in DMF (5 mL). The resulting mixture was degassed three times with nitrogen and then stirred under nitrogen at 80 °C. After 2 h, the mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was applied to a silica gel column with petroleum ether / EtOAc (1:1) as eluent to give the title compound (80 mg, 16% yield) as a yellow solid. LCMS (M+H) + =392.1.

[0686] Step 5.4-[6-chloro-1-methyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridin-4-yl]morpholine

[0687]

[0688] MeI (101.4 mg, 0.71 mmol) and Cs₂CO₃ (232.2 mg, 0.71 mmol) were added to a stirred solution of 4-[6-chloro-2-(4-methylsulfonylphenyl)-1H-pyrrolo[3,2-c]pyridin-4-yl]morpholine (140 mg, 0.36 mmol) in DMF (2 mL). The resulting solution was stirred at room temperature for 1 h, then the mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure to give the title compound (100 mg crude substance) as a yellow solid. LCMS (M+H) + =406.1.

[0689] Step 6

[0690] Xphos-Pd-G3 (14.5 mg, 0.02 mmol) and K2CO3 (71.4 mg, 0.52 mmol) were added to a solution of 4-[6-chloro-1-methyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridin-4-yl]morpholine (70 mg, 0.17 mmol) and 1-isopropyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)phenyl]piperazine (113.9 mg, 0.34 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was degassed three times with nitrogen and then stirred at 90 °C under nitrogen. Two hours later, the mixture was cooled to room temperature and purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel, mobile phase, ACN and water (0.05% TFA), 10% ACN to 70% ACN gradient over 20 min; detector, UV 254 nm. The product was purified by preparative HPLC (column: X Bridge Prep C18 OBD column, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 50% B to 65% B over 4.5 min, 65% B; wavelength: 254 / 210 nm) to give the title compound (35.6 mg, 35.5% yield) as a yellow solid. 1HNMR (400MHz, methanol-d6) δ8.14-7.82(m,6H),7.05(d,J=8.8Hz,2H),6.97(s,1H),6.75(s,1H),3.88-3.71(m,7H),3. 57-3.49(m,4H),3.29(s,3H),3.26-3.16(m,4H),2.78-2.66(m,1H),2.60(t,J=5.0Hz,4H),1.02(d,J=6.5Hz,6H). LCMS(M+H) + =574.2.

[0691] Example 121

[0692] 1-[3-[[4-[1-cyclopropyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridin-6-yl]phenyl]methyl]-3,8-diazabicyclo[3.2.1]oct-8-yl]-2-methyl-prop-2-ol

[0693]

[0694] Step 1. 8-(2-hydroxy-2-methyl-propyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester

[0695]

[0696] To a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (1 g, 4.71 mmol) in ethanol (20 mL), 1-chloro-2-methyl-prop-2-ol (1.53 g, 14.13 mmol) and DIEA (2.45 g, 18.84 mmol) were added. The resulting solution was stirred at 100 °C for 20 h, and then the reaction mixture was cooled to room temperature. The solvent was removed under reduced pressure, and the mixture was purified by silica gel column chromatography using petroleum ether / EtOAc (3:1) as eluent to give the title compound (780 mg, 58.2% yield) as a pale yellow oil. 1 H NMR (400MHz, DMSO-d6) δ3.99(s,1H),3.57(d,J=12.2Hz,1H),3.50(d,J=12.2Hz,1H),3.13(d,J=13.2Hz,2H),3.00(d,J =12.2Hz,1H),2.87(d,J=12.2Hz,1H),2.11(s,2H),1.80-1.72(m,2H),1.44(t,J=7.1Hz,2H),1.39(s,9H),1.08(s,6H). LCMS(M+H) + =285.3.

[0697] Step 2.1 - (3,8-diazabicyclo[3.2.1]oct-8-yl)-2-methyl-prop-2-ol

[0698]

[0699] 1,4-Dioxane (1.5 mL) containing 4 M HCl was added to a stirred solution of 780 mg (2.74 mmol) of 8-(2-hydroxy-2-methyl-propyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester in DCM (4 mL) and methanol (0.5 mL). The resulting solution was stirred at room temperature for 3 days, and then the mixture was concentrated under reduced pressure to give the title compound (600 mg crude substance) as a white solid. LCMS (M+H) + =185.2.

[0700] Step 3. 2-Chloro-5-[2-(4-methylsulfonylphenyl)ethynyl]pyridine-4-amine

[0701]

[0702] A solution of 2-chloro-5-iodopyridin-4-amine (2 g, 7.86 mmol) in DMF (20 mL) was supplemented with 1-ethynyl-4-methylsulfonyl-benzene (1.7 g, 9.43 mmol), Pd(PPh3)2Cl2 (550 mg, 0.79 mmol), CuI (150 mg, 0.79 mmol), and TEA (2.39 g, 23.58 mmol). The resulting solution was degassed three times with nitrogen and stirred at 100 °C. After 3 h, the mixture was diluted with ammonium chloride solution (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. LCMS (M+H) + =306.9.

[0703] Step 4. 6-Chloro-2-(4-methylsulfonylphenyl)-1H-pyrrolo[3,2-c]pyridine

[0704]

[0705] t-BuOK (2.63 g, 23.47 mmol) was added to a solution of 2-chloro-5-[2-(4-methylsulfonylphenyl)ethynyl]pyridine-4-amine (2.4 g, 7.82 mmol) in DMF (20 mL) at 0 °C. The resulting solution was stirred at 80 °C for 1 hour, then the mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was applied to a silica gel column with petroleum ether / EtOAc (1:4) as eluent to give the title compound (920 mg, 38.3% yield) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6) δ 12.38 (s, 1H), 8.70 (s, 1H), 8.16 (d, J = 8.3Hz, 2H), 8.04 (d, J = 8.3Hz, 2H), 7.44 (s, 1H), 7.32 (d, J = 1.9Hz, 1H), 3.27 (s, 3H). LCMS(M+H) + =306.9.

[0706] Step 5. 6-Chloro-1-cyclopropyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridine

[0707]

[0708] To a solution of 6-chloro-2-(4-methanesulfonylphenyl)-1H-pyrrolo[3,2-c]pyridine (500 mg, 1.63 mmol) in DCE (10 mL), Na₂CO₃ (518 mg, 4.89 mmol), cyclopropylboronic acid (420 mg, 4.89 mmol), Cu(OAc)₂ (388 mg, 2.44 mmol), and 2,2'-bipyridine (382 mg, 2.44 mmol) were added. The resulting solution was stirred at 60 °C for 3 days. The mixture was then diluted with water (60 mL) and extracted with DCM (3 × 60 mL). The combined organic layers were dried over Na2SO4, concentrated under reduced pressure, and purified by rapid-HPLC (column: C18; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 50 mL / min; gradient: 10% B to 48% B over 20 min, 254 / 210 nm) to give the title compound as a brown solid (230 mg, 40.7% yield). 1H NMR(300MHz,DMSO-d6)δ8.68(d,J=1.1Hz,1H),8.05(s,4H),7.65(s,1H),6.92(d,J=1.1Hz,1 H), 3.77 (dt, J = 6.9, 3.3Hz, 1H), 3.31 (s, 3H), 1.05 (dd, J = 7.4, 5.4Hz, 2H), 0.63-0.51 (m, 2H). LCMS(M+H) + =347.1.

[0709] Step 6.4-[1-Cyclopropyl-2-(4-Methylsulfonylphenyl)pyrrolo[3,2-c]pyridin-6-yl]benzaldehyde

[0710]

[0711] To a solution of 6-chloro-1-cyclopropyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridine (230 mg, 0.66 mmol) in 1,4-dioxane (4 mL) and water (0.8 mL), K3PO4 (422 mg, 1.99 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxolaneborane-2-yl)benzaldehyde (308 mg, 1.33 mmol), and Xphos-Pd-G3 (56 mg, 0.07 mmol) were added. The resulting solution was degassed three times with nitrogen and stirred at 90 °C for 1 h. The mixture was then diluted with water (50 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were dried over Na2SO4, concentrated under reduced pressure, and purified by rapid HPLC (column: C18 column; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 50 mL / min; gradient: 5% B to 31% B over 12 min; wavelength: 254 / 210 nm) to give the title compound (135 mg, 47.8% yield) as a pale yellow solid. 1 ¹H NMR (400MHz, methanol-d⁴) δ 9.15 (s, ¹H), 8.37 (s, ¹H), 8.19–8.15 (m, ³H), 8.13–8.08 (m, 2H), 8.00–7.95 (m, 2H), 7.76 (d, J = 8.1 Hz, 2H), 7.27 (s, ¹H), 3.90 (tt, J = 7.1, 3.8 Hz, ¹H), 3.23 (s, ³H), 1.27–1.20 (m, 2H), 0.83–0.77 (m, 2H). LCMS (M+H) + =417.2.

[0712] Step 7

[0713] To a solution of 4-[1-cyclopropyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridin-6-yl]benzaldehyde (50 mg, 0.12 mmol) in DCM (3 mL), 1-(3,8-diazabicyclo[3.2.1]oct-8-yl)-2-methyl-prop-2-ol (66 mg, 0.36 mmol) and acetic acid (0.01 mL) were added. After stirring at room temperature for 3 hours, NaBH(OAc)3 (76 mg, 0.36 mmol) was added to the mixture. The resulting solution was stirred at room temperature for 1 hour. The reaction mixture was then diluted with saturated sodium bicarbonate solution and extracted with DCM (3 × 50 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Kinetex EVO C18 column, 21.2*150, 5µm; mobile phase A: water (10mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 20mL / min; gradient: 40%B to 60%B over 5.5 min, 60%B; wavelength: 254 / 210nm) to obtain the title compound (8.6mg, 11.6% yield) as a grayish-white solid. 1 H NMR (300MHz, methanol-d4) δ8.85(s,1H),8.06(q,J=8.4Hz,4H),7.99-7.83(m,3H),7.46(d,J=7.9Hz,2H),6.89(s,1H),3.86-3.66(m,1H),3.55(s, 2H),3.30-3.11(m,5H),2.64(d,J=9.0Hz,2H),2.40(d,J=10.2Hz,2H), 2.28(s,2H),2.00-1.81(m,4H),1.25-1.11(m,8H),0.71-0.63(m,2H). LCMS(M+H) + =585.3.

[0714]

[0715]

[0716]

[0717]

[0718] Bioanalysis

[0719] The pharmacological properties of the compounds of the present invention can be confirmed by a variety of bioanalyses. The bioanalyses exemplified below have been performed on the compounds of the present invention.

[0720] TLR7 / 8 / 9 Suppression Report Subanalysis

[0721] HEK-Blue, which overexpresses human TLR7, TLR8, or TLR9 receptors TM Invivogen cells were used to screen for inhibitors of these receptors under the control of an IFN-β minimal promoter fused to five NF-κB and AP-1 binding sites, using an inducible SEAP (secreted embryonic alkaline phosphatase) reporter gene. In short, cells were seeded into Greiner 384-well discs (15,000 cells / well for TLR7; 20,000 cells / well for TLR8; and 25,000 cells / well for TLR9) and subsequently treated with DMSO containing the test compound to obtain a final dose-response concentration range from 0.05 nM to 50 μM. After pretreatment with the compound for 30 minutes at room temperature, cells were subsequently stimulated with TLR7 ligand (gardiquimod at a final concentration of 7.5 μM), TLR8 ligand (R848 at a final concentration of 15.9 μM), or TLR9 ligand (ODN2006 at a final concentration of 5 nM) to activate NF-κB and AP-1, which induce SEAP production. After incubation at 37 °C and 5% CO2 for 22 hours, cells were cultured in HEK-Blue cell culture medium, which allows for the detection of SEAP, according to the manufacturer's specifications. TM The SEAP content was determined using an assay reagent (Invivogen). The percentage of inhibition was measured as a percentage decrease compared to the HEK-Blue signal present in wells treated with only the agonist and DMSO, when compared to wells treated with known inhibitors.

[0722]

[0723]

[0724]

[0725]

[0726]

[0727] nd: Not measured.

Claims

1. A compound of formula (IIIb): ， Or its pharmaceutically acceptable salt, wherein: G is a phenyl group substituted with one or two independent substituents selected from the following: −OCH3, −S(O)2CH3, −S(O)2N(CH3)2 and −S(O)2 (cyclopropyl); A is either piperidinyl or phenyl, each with a -L-R4 group and zero to two R groups. 4b replace; L represents a bond, −CH2−, or −C(O)CH2−; R1 is −CH3; R3 is hydrogen, F, or cyclopropyl; R4 is morpholino, piperidino, piperazino, pyridino, dioxothiomorpholino, azabicyclo[3.2.1]octyl, diazabicyclo[2.2.2]octyl, or diazabicyclo[3.2.1]octyl, each with zero to four R4 groups. 4a Replace; or ； Each R 4a Independently, it can be −OH, −CH3, −CHCH3, −CH(CH3)2, −CH2CH(CH3)2, −C(CH3)3, −CF3, −CH2CH2OH, −CH2CH2CH2OH, −CH2C(CH3)2OH, −CH2CH2C(CH3)2OH, −CH2CH2OCH3, −CH2(cyclopropyl), −C(O)CH3, −C(O)(phenyl), −C(O)OCH2CH3, cyclopropyl, cyclobutyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, −(CH2) 1−2 (Bromophenyl) or −(CH2) 1−2 (Iodophenyl); Each R 4b It is F; and Each R5 group is independently hydrogen, −CH3, −C(CH3)2OH, −OCH3, or morpholino.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein: A is obtained by passing through −L−R4 and zero to 2 R. 4b Substituted phenyl groups.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein: L represents a bond or -CH2−.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein: R4 is piperidinyl, piperazinyl, or pyridinyl, each with zero to four R groups. 4a replace.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein: A is obtained by passing through −L−R4 and zero to 2 R. 4b Substituted phenyl; L is the key; and R4 is the result of zero to 4 R... 4a Substituted piperazine group.

6. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is: 4-(2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-[1,4'-dipiperidine]-1'-carboxylic acid ethyl ester (7); 2-(3,4-Dimethoxyphenyl)-1-methyl-6-(1-((6-methylpyridin-3-yl)methyl)piperidin-4-yl)-1H-pyrrolo[3,2-c]pyridine (8); 6-(4-(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)-2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-c]pyridine (9); 6-(4-(4-cyclobutylpiperazin-1-yl)phenyl)-2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-c]pyridine (10); 6-(4-(4-isopropylpiperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (11); 6-(3-fluoro-4-(4-isopropylpiperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (12); 2-(3,4-Dimethoxyphenyl)-6-(4-(4-isopropylpiperazin-1-yl)phenyl)-1-methyl-1H-pyrrolo[3,2-c]pyridine (24); 1-(4-(2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)piperidin-1-yl)-2-(piperidin-1-yl)ethyl-1-one (25); (4-(2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-[1,4'-dipiperidin]-1'-yl)(phenyl)methyl ketone (26); 2-(3,4-Dimethoxyphenyl)-1-methyl-6-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[3,2-c]pyridine (27); 2-(3,4-Dimethoxyphenyl)-1-methyl-6-(1-((6-(trifluoromethyl)pyridin-3-yl)methyl)piperidin-4-yl)-1H-pyrrolo[3,2-c]pyridine (28); (4-(4-(2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)phenyl)piperazin-1-yl)(phenyl)methyl ketone (29); 1-(4-(4-(2-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)phenyl)piperazin-1-yl)ethyl-1-one (30); 2-(3,4-Dimethoxyphenyl)-6-(6-(4-isopropylpiperazin-1-yl)pyridin-3-yl)-1-methyl-1H-pyrrolo[3,2-c]pyridine (31); 6-(4-(4-isobutylpiperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (34); 1,4-Dimethyl-2-(4-(methylsulfonyl)phenyl)-6-(4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)-1H-pyrrolo[3,2-c]pyridine (35); 3-(4-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)phenyl)piperazin-1-yl)prop-1-ol (36); 1,4-Dimethyl-2-(4-(methylsulfonyl)phenyl)-6-(4-(4-(tetrahydrofuran-3-yl)piperazin-1-yl)phenyl)-1H-pyrrolo[3,2-c]pyridine (37); 6-(4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (38); 6-(4-(4-isopropylpiperazin-1-yl)phenyl)-1,4-dimethyl-2-(3-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (39); 6-(4-(4-isobutylpiperazin-1-yl)phenyl)-1,4-dimethyl-2-(3-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (40); 3-(4-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)phenyl)piperidin-1-yl)prop-1-ol (41); 2-(4-(cyclopropylsulfonyl)phenyl)-6-(4-(4-isopropylpiperazin-1-yl)phenyl)-1,4-dimethyl-1H-pyrrolo[3,2-c]pyridine (42); 6-(2,5-difluoro-4-(piperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (43); 1-(4-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzyl)piperazin-1-yl)-2-methylprop-2-ol (44); 3-((1R,4R)-5-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzyl)-2,5-diazabicyclo[2.2.2]oct-2-yl)-2,2-dimethylprop-1-ol (45); 2-(4-(cyclopropylsulfonyl)phenyl)-6-(4-(4-isobutylpiperazin-1-yl)phenyl)-1,4-dimethyl-1H-pyrrolo[3,2-c]pyridine (46); 3-(4-(4-(2-(4-(cyclopropylsulfonyl)phenyl)-1,4-dimethyl-1H-pyrrolo[3,2-c]pyridin-6-yl)phenyl)piperazin-1-yl)prop-1-ol (47); 2-(4-(cyclopropylsulfonyl)phenyl)-6-(4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)-1,4-dimethyl-1H-pyrrolo[3,2-c]pyridine (48); 4-(6-(4-(4-isopropylpiperazin-1-yl)phenyl)-1,4-dimethyl-1H-pyrrolo[3,2-c]pyridin-2-yl)-N,N-dimethylbenzenesulfonamide (49); 4-(1,4-dimethyl-6-(4-(4-(oxacyclobut-3-yl)piperazin-1-yl)phenyl)-1H-pyrrolo[3,2-c]pyridin-2-yl)-N,N-dimethylbenzenesulfonamide (50); 4-(6-(4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)-1,4-dimethyl-1H-pyrrolo[3,2-c]pyridin-2-yl)-N,N-dimethylbenzenesulfonamide (51); 4-(1,4-dimethyl-6-(4-(4-(tetrahydrofuran-3-yl)piperazin-1-yl)phenyl)-1H-pyrrolo[3,2-c]pyridin-2-yl)-N,N-dimethylbenzenesulfonamide (52); 6-(4-(4-isobutylpiperazin-1-yl)phenyl)-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (53); 6-(4-(4-isopropylpiperazin-1-yl)phenyl)-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (54); 3-(4-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-2,3-difluorophenyl)piperazin-1-yl)prop-1-ol (55); 3-(4-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-2,5-difluorophenyl)piperazin-1-yl)prop-1-ol (56); 6-(4-((4-isobutylpiperazin-1-yl)methyl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (57); 3-(4-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzyl)piperazin-1-yl)prop-1-ol (58); 1-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzyl)-4-methylpiperidin-4-ol (59); 4-(4-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzyl)piperazin-1-yl)-2-methylbut-2-ol (60); 4-((1S,4S)-5-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzyl)-2,5-diazabicyclo[2.2.2]oct-2-yl)-2-methylbut-2-ol (61); 6-(4-(4-cyclopropylpiperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (62); 6-(4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (63); 6-(4-(8-isopropyl-3,8-diazabicyclo[3.2.1]oct-3-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (64); 6-(3-fluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (65); 6-(3-fluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (66); 6-(3-(4-isopropylpiperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (67); 6-(3-(4-cyclopropylpiperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (68); 2-(4-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-2-fluorophenyl)piperazin-1-yl)ethanol (69); 6-(3-fluoro-4-(4-(tetrahydrofuran-3-yl)piperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (70); 6-(3-fluoro-4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (71); 6-(3-fluoro-4-(4-isobutylpiperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (72); 6-(4-(8-isobutyl-3,8-diazabicyclo[3.2.1]oct-3-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (73); 6-(4-(8-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (74); 6-(3-fluoro-4-(8-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (75); 3-(3-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)phenyl)-3,8-diazabicyclo[3.2.1]oct-8-yl)prop-1-ol (76); 3-(3-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-2-fluorophenyl)-3,8-diazabicyclo[3.2.1]oct-8-yl)prop-1-ol (77); 6-(2,5-difluoro-4-(8-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (78); 3-(3-(4-(1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-2,5-difluorophenyl)-3,8-diazabicyclo[3.2.1]oct-8-yl)prop-1-ol (79-80); 6-(2,5-difluoro-4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (81); 6-(2,3-difluoro-4-(4-isobutylpiperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (82); 6-(2,3-difluoro-4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (83); 6-(3,5-difluoro-4-(4-isobutylpiperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (84); 4-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)phenyl)thiomorpholine 1,1-dioxide (85); 4-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)phenyl)morpholine (86); 1-Cyclopropyl-4-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)phenyl)piperidin-4-ol (87); 4-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)phenyl)-1-isopropylpiperidin-4-ol (88); 6-(3,5-difluoro-4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (89); 4-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-2-fluorophenyl)-1-isobutylpiperidin-4-ol (90); (1R,3r,5S)-3-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-2-fluorophenyl)-8-isobutyl-8-azabicyclo[3.2.1]oct-3-ol (91); 4-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-2-fluorophenyl)-1-(2-methoxyethyl)piperidin-4-ol (92); 1-Cyclopropyl-4-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-2-fluorophenyl)piperidin-4-ol (93); 4-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-2,5-difluorophenyl)-1-isobutylpiperidin-4-ol (94); 4-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-2,5-difluorophenyl)-1-(2-methoxyethyl)piperidin-4-ol (95); 1-Cyclopropyl-4-(4-(1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-2,5-difluorophenyl)piperidin-4-ol (96); 6-(2,5-difluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (97); 6-(3,5-difluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (98); 6-(2,3-difluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (99); (1R,3r,5S)-3-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-2-fluorophenyl)-8-isopropyl-8-azabicyclo[3.2.1]oct-3-ol(100); (1R,3r,5S)-3-(4-(1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-2-fluorophenyl)-8-ethyl-8-azabicyclo[3.2.1]oct-3-ol (101); (1R,3r,5S)-3-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-2-fluorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-3-ol (102); (1R,3r,5S)-3-(4-(1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-3-fluorophenyl)-8-isopropyl-8-azabicyclo[3.2.1]oct-3-ol (103); 1-(tert-butyl)-4-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-2-fluorophenyl)piperidin-4-ol (104); (R)-4-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-2-fluorophenyl)-1-isopropyl-2,2-dimethylpiperidin-4-ol (105); (S)-4-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-2-fluorophenyl)-1-isopropyl-2,2-dimethylpiperidin-4-ol (106); 4-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-2-fluorophenyl)-1-isopropylpiperidin-4-ol (107); 1-(tert-butyl)-4-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-3-fluorophenyl)piperidin-4-ol (108); 4-(4-(1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-3-fluorophenyl)-1-isopropylpiperidin-4-ol (109); 6-(4-(4-(4-iodophenylethyl)piperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (110); 6-(4-(4-(4-bromophenylethyl)piperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (111); 6-(4-(4-(4-iodobenzyl)piperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (112); 6-(4-(4-(4-bromophenylmethyl)piperazin-1-yl)phenyl)-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (113); 6-(1-(8-isobutyl-8-azabicyclo[3.2.1]oct-3-yl)piperidin-4-yl)-1,4-dimethyl-2-(4-(methanesulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (114); 4-(4-(4-(3-fluoro-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzyl)piperazin-1-yl)-2-methylbut-2-ol (115); 4-[4-[[4-[1-Cyclopropyl-4-methyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridin-6-yl]phenyl]methyl]piperazin-1-yl]-2-methyl-but-2-ol (116); 4-[4-[[4-[1-(difluoromethyl)-4-methyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridin-6-yl]phenyl]methyl]piperazin-1-yl]-2-methyl-but-2-ol (117); 2-[6-[4-(4-isopropylpiperazin-1-yl)phenyl]-1-methyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridin-4-yl]prop-2-ol (118); 6-[4-(4-isopropylpiperazin-1-yl)phenyl]-4-methoxy-1-methyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridine (119); 4-[6-[4-(4-isopropylpiperazin-1-yl)phenyl]-1-methyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridin-4-yl]morpholine (120); 1-[3-[[4-[1-cyclopropyl-2-(4-methylsulfonylphenyl)pyrrolo[3,2-c]pyridin-6-yl]phenyl]methyl]-3,8-diazabicyclo[3.2.1]oct-8-yl]-2-methyl-prop-2-ol (121); 1-(4-(4-(3-fluoro-1,4-dimethyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzyl)piperazin-1-yl)-2-methylprop-2-ol (122); 1-(4-(4-(1-cyclopropyl-4-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzyl)piperazin-1-yl)-2-methylprop-2-ol (123); 1-(4-(4-(1-(difluoromethyl)-4-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzyl)piperazin-1-yl)-2-methylprop-2-ol (124); 2-(6-(4-((4-isopropylpiperazin-1-yl)methyl)phenyl)-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-4-yl)prop-2-ol (125); 6-(4-((4-isopropylpiperazin-1-yl)methyl)phenyl)-4-methoxy-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (126); 4-(6-(4-((4-isopropylpiperazin-1-yl)methyl)phenyl)-1-methyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-4-yl)morpholine (127); 1-(4-(4-(1-cyclopropyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzyl)piperazin-1-yl)-2-methylprop-2-ol (128); 4-(4-(4-(1-cyclopropyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzyl)piperazin-1-yl)-2-methylbut-2-ol (129); or 1-(8-(4-(1-cyclopropyl-2-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-methylprop-2-ol (130).

7. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 6 or pharmaceutically acceptable salts thereof; and a pharmaceutically acceptable carrier.

8. Use of a compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 7 in the preparation of a medicament for treating pathological fibrosis.

9. The use according to claim 8, wherein the pathological fibrosis is liver fibrosis, kidney fibrosis, biliary fibrosis or pancreatic fibrosis.

10. Use of a compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 7 in the preparation of a medicament for treating non-alcoholic steatosis, non-alcoholic fatty liver disease, chronic kidney disease, diabetic nephropathy, primary sclerosing cholangitis, or primary biliary cirrhosis.

11. Use of a compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 7 in the preparation of a medicament for the treatment of idiopathic pulmonary fibrosis.

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