Substituted pyrrole carbosamides, methods for their preparation and their use as kinase inhibitors - Patents.com

Abstract

The present invention relates to certain substituted pyrrole compounds that modulate the activity of cycle 7-related protein kinase (Cdc7). The compounds of the present invention are therefore useful in the treatment of diseases associated with dysregulated kinase activity, such as cancer, cell proliferation disorders, viral infections, immune disorders, neurodegenerative disorders, cardiovascular disorders and bone-related disorders. The invention also provides methods for making these compounds, pharmaceutical compositions containing these compounds, and methods of treating diseases using pharmaceutical compositions containing these compounds. TIFF2024513040000320.tif58166

Description

[Technical Field]

[0001] This invention relates to certain substituted pyrrole compounds that regulate the activity of protein kinases. Accordingly, the compounds of this invention are useful in treating diseases associated with dysregulated kinase activity, such as cancer, proliferative disorders, viral infections, immune disorders, neurodegenerative disorders, cardiovascular diseases, and bone-related diseases.

[0002] The present invention also provides methods for producing these compounds, pharmaceutical compositions containing these compounds, and methods for treating diseases using pharmaceutical compositions containing these compounds. [Background technology]

[0003] Protein kinase (PK) dysfunction is a prominent feature of many diseases. The majority of oncogenes and proto-oncogenes involved in human cancer encode PKs. Increased PK activity is also associated with many non-malignant diseases. For general literature on PK dysfunction or dysregulation, see, for example, Current Opinion in Chemical Biology 1999, 3, 459–465.

[0004] Among several protein kinases known in this field to be involved in the proliferation of cancer cells is period 7-related protein kinase (Cdc7), a crucial cell cycle protein required for DNA replication by catalyzing MCM helicase activation at the DNA replication origin. Cdc7 kinase and its regulatory subunit Dbf4 are overexpressed in many tumors, and overexpression is correlated with poor prognosis and tumor progression. Cdc7 is also involved in mediating the processing of stalled replication forks after replication stress or damage has been resolved, and in DNA repair over damage (see Montagnoli A. et al., EMBO Journal, 2002, Vol. 21, No.12, 3171; Montagnoli A. et al., Cancer Research 2004, Vol. 64, October 1, 7110; Hou Y. et al., Mol Oncol 2012, Vol. 29, 3498; Day TA et al, 2010, J Cell Biol Vol. 191, 953).

[0005] Pyrrole carboxamide derivatives are known in the art as protein kinase inhibitors. For example, WO2009 / 040399 reports pyrimidinyl-pyrrole derivatives useful for treating diseases associated with dysregulated protein kinase activity, particularly the polo-like kinase (PLK) family; WO2013 / 014039 and WO2014 / 019908 disclose pyrimidinyl-pyrrole derivatives with Janus kinase (JAK) and Src inhibitory activity; and WO2007 / 110344 claims a pyrimidinyl-pyrrole compound with inhibitory activity against Cdc7 protein kinase activity.

[0006] Drug metabolism and pharmacokinetics (DMPK) are primarily relevant to safety assessment in the drug discovery and development process. To increase the chances of a candidate drug becoming a successful treatment, it must possess sufficient efficacy against the target protein, in addition to an acceptable safety profile. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] International Publication No. 2009 / 040399 [Patent Document 2] International Publication No. 2013 / 014039 [Patent Document 3] International Publication No. 2014 / 019908 [Patent Document 4] International Publication No. 2007 / 110344 [Non-patent literature]

[0008] [Non-Patent Document 1] Current Opinion in Chemical Biology 1999, 3, 459-465 [Non-Patent Document 2] Montagnoli A. et al., EMBO Journal, 2002, Vol. 21, No.12, 3171 [Non-Patent Document 3] Montagnoli A. et al., Cancer Research 2004, Vol. 64, October 1, 7110 [Non-Patent Document 4] Hou Y. et al., Mol Oncol 2012, Vol. 29, 3498 [Non-Patent Document 5] Day TA et al, 2010, J Cell Biol Vol. 191, 953 [Overview of the project] [Problems that the invention aims to solve]

[0009] Considering the above, there is a strong need for the development of Cdc7 inhibitors for the treatment of cancer and other diseases. The inventors have now identified a novel pyrrole carboxamide compound with inhibitory activity against Cdc7 protein kinase. The compound of the present invention is a potent inhibitor of Cdc7 kinase and, remarkably, exhibits improved metabolic stability compared to compounds of the same chemical class disclosed in the prior art. These improved properties are described in more detail in the "Experimental Section" below.

[0010] Due to the important role of PK, particularly Cdc7, in regulating cell proliferation, these pyrrole carboxamide derivatives are especially useful not only in the treatment of cancer but also in the treatment of various cell proliferation disorders and immune-related disorders. [Means for solving the problem]

[0011] Therefore, the first object of the present invention is to provide a substituted pyrrole carboxamide compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

[0012] [ka] During the ceremony, R1 is

[0013] [ka] A heteroaryl group selected from the group consisting of; Ra, Rb, and Rc are independently hydrogen, a substituted or possibly substituted linear or branched (C1-C6) alkyl group, or a substituted or possibly substituted linear or branched (C2-C6) alkenyl group; R2 is a substituted aryl ring or substituted heteroaryl ring having 1 to up to 3 substituents selected from halogen, nitro, amino, (C1-C6)alkylamino, aminocarbonyl, optionally substituted linear or branched (C1-C6)alkyl, optionally substituted linear or branched (C1-C6)alkoxy, optionally substituted linear or branched polyfluorinated (C1-C6)alkyl, and optionally substituted linear or branched polyfluorinated (C1-C6)alkoxy; However, 2,5-disubstituted phenyl groups are excluded; R3 is hydrogen, an optionally substituted linear or branched (C1-C4) alkyl group, an optionally substituted (C3-C6) cycloalkyl group, or an optionally substituted (C5-C6) heterocyclic group; R4 is hydrogen, a substituted or possibly substituted linear or branched (C1-C6) alkyl group, or a substituted or possibly substituted linear or branched (C2-C6) alkenyl group; R5 is hydrogen, a halogen, or a linear or branched (C1-C3) alkyl group which may be substituted.

[0014] The preferred compounds of formula (I) are: R1 is a heteroaryl group that may be substituted by a selection from groups (A), (B), (C), (D), and (E); Ra, Rb, and Rc are independently linear or branched (C1-C6) alkyl groups, which may be hydrogenated or substituted; R2 is 2,4-disubstituted phenyl, 4,6-disubstituted pyridine-3-yl, 2,6-disubstituted pyridine-3-yl, or 3,5-disubstituted pyridine-2-yl; This is a compound in which R3, R4, and R5 are as defined above.

[0015] A more preferred compound of formula (I) is: R2 is a 2,4-disubstituted phenyl compound; R3 is a linear or branched (C1-C4) alkyl chain, which may be hydrogen or substituted; R5 is hydrogen; This is a compound in which R1 and R4 are as defined above.

[0016] A more preferred compound of formula (I) is: R4 is hydrogen; This is a compound in which R1, R2, R3, and R5 are as defined above.

[0017] Preferred specific compounds of formula (I) or pharmaceutically acceptable salts thereof are the compounds listed below: 2-(3-chloro-2-fluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide (compound 1); 2-(4-chloro-2-fluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide (compound 2); 2-(2-chloro-4-fluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide (compound 3); 2-(2,4-difluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide (compound 4); 2-[2-chloro-4-(trifluoromethyl)phenyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide (compound 5); 2-(2,3-difluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide (compound 6); 2-(2,3-dichlorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide (compound 7); 2-[4-methyl-2-(trifluoromethyl)phenyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide (compound 8); 2-(2-chloro-4-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide (compound 9); 2-(2,3-difluoro-4-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide (compound 10); 2-[2-methyl-4-(trifluoromethyl)phenyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide (compound 11); 2-(2-fluoro-3-methoxyphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide (compound 12); 2-(2-chloro-3-fluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide (compound 13); 2-(2-fluoro-3-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrrole-3-carb tree Samide (compound 14); 2-[2-methyl-3-(trifluoromethyl)phenyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide (compound 15); 2-[4-Methoxy-2-(trifluoromethyl)phenyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide (compound 16); 2-[2-chloro-4-(difluoromethoxy)phenyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb treeSamide (compound 17); 2-(3,4-dichlorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide (compound 18); 2-(3,4-difluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide (compound 19); 2-(3-ethoxy-2-fluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide (compound 20); 2-(4-methyl-3-nitrophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide (compound 21); 2-(3-carbamoyl-4-fluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide (compound 22); 2-(2-fluoro-4-methylphenyl)-N-[2-(pyrrolidin-1-yl)ethyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide (compound 23); N-[2-(dimethylamino)ethyl]-2-(2-fluoro-4-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide (compound 24); 2-(2-fluoro-4-methylphenyl)-N-[2-(morpholine-4-yl)ethyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide (compound 25); N-[(1S,2R)-2-aminocyclohexyl]-2-(2-fluoro-4-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide (compound 26); 2-(2-fluoro-4-methylphenyl)-N-(furan-2-ylmethyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide (compound 27); N-(fluoroethyl)-2-(2-fluoro-4-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide (compound 28); 2-(2-fluoro-4-methylphenyl)-N-[2-(methylamino)ethyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide (compound 29); 2-(2-fluoro-4-methylphenyl)-N-(1-methylpiperidine-4-yl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide (compound 30); 2-(dibenzo[b,d]thiophene-4-yl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carbol tree Samide (compound 31); 2-(4-methylnaphthalene-1-yl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carbol tree Samide (compound 32); 2-(3-fluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrrole-3-carb tree Samide (compound 33); 5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-2-[4-(trifluoromethoxy)phenyl]-1H-pyrrole-3-carb tree Samide (compound 34); 2-(1-benzothiophen-3-yl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide (compound 35); 2-(2,3-dihydro-1,4-benzodioxin-6-yl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carbol tree Samide (compound 36); 2-(4-fluoro-2-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide (compound 37); 2-(2-fluoro-4-methylphenyl)-4-iodo-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide (compound 38); 4-Bromo-2-(2-fluoro-4-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide (compound 39); 4-Ethyl-2-(2-fluoro-4-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide (compound 40); 2-(2-fluoro-4-methylphenyl)-4-(propan-2-yl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide (compound 41); 5-(6-aminopyrimidine-4-yl)-2-(2,4-dichlorophenyl)-1H-pyrrole-3-carb tree Samide (compound 42); 2-(2,4-dichlorophenyl)-5-(1H-pyrazole-4-yl)-1H-pyrrole-3-carb tree Samide (compound 43); 2-(2,4-dichlorophenyl)-5-(3-methyl-1H-pyrazole-4-yl)-1H-pyrrole-3-carb tree Samide (compound 44); 5-(2-amino-1,3-thiazole-4-yl)-2-(2,4-dichlorophenyl)-1H-pyrrole-3-carb tree Samide (compound 45); 2-(2,4-dichlorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide (compound 46); 2-(2,4-dichlorophenyl)-5-(1H-pyrazolo[3,4-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide (compound 47); 2-(2,4-dichlorophenyl)-5-[3-(trifluoromethyl)-1H-pyrazole-4-yl]-1H-pyrrole-3-carb tree Samide (compound 48); 2-(2-fluoro-4-methylphenyl)-5-(1H-pyrazole-4-yl)-1H-pyrrole-3-carb tree Samide (compound 49); 5-(3,5-dimethyl-1H-pyrazole-4-yl)-2-(2-fluoro-4-methylphenyl)-1H-pyrrole-3-carb tree Samide (compound 50); 2-(2-fluoro-4-methylphenyl)-5-(1-methyl-1H-pyrazole-4-yl)-1H-pyrrole-3-carb tree Samide (compound 51); 2-(2-fluoro-4-methylphenyl)-5-(3-methyl-1H-pyrazole-4-yl)-1H-pyrrole-3-carb tree Samide (compound 52); 2-(2-fluoro-4-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide (compound 53); 2-(2,4-dichlorophenyl)-1-(2-hydroxyethyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide (compound 54); 2-(2,4-dichlorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-(3,3,3-trifluoropropyl)-1H-pyrrole-3-carb tree Samide (compound 55); 2-(2,4-dichlorophenyl)-1-methyl-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide (compound 56); and 2-(2,4-dichlorophenyl)-1-ethyl-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide (compound 57) That is the case. [Modes for carrying out the invention]

[0018] Where a stereocenter or another form of chiral center is present in the compounds of the present invention, all forms of such optical isomers, such as enantiomers and diastereomers, are incorporated herein. Compounds containing a stereocenter can be used as a racemic mixture, an enantiomer-rich mixture, or the racemic mixture can be separated using known techniques, and individual enantiomers can be used. Such procedures include standard chromatographic techniques, such as chromatography using a chiral stationary phase, or crystallization. A general method for separating compounds containing one or more chiral centers is reported, for example, in Jacques, Jean; Collet, Andre; Wilen, Samuel H., - Enantiomers, Racemates, and Resolutions, John Wiley & Sons Inc., New York (NY), 1981.

[0019] When a compound has an unsaturated carbon-carbon double bond, both cis (Z) and trans (E) isomers are included within the scope of the present invention.

[0020] If a compound can exist as a keto-enol tautomer or other tautomer, each tautomer type is assumed to be included in the present invention, regardless of whether it exists in equilibrium or primarily in one form.

[0021] pharmaceutically acceptable salts of the compound of formula (I) include salts with inorganic or organic acids, such as nitric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, lactic acid, oxalic acid, fumaric acid, malonic acid, malic acid, maleic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, isethionic acid, and salicylic acid.

[0022] pharmaceutically acceptable salts of the compound of formula (I) also include salts with inorganic or organic bases, such as alkalis or alkaline earth metals, particularly hydroxides, carbonates or bicarbonates of sodium, potassium, calcium, ammonium or magnesium, and acyclic or cyclic amines.

[0023] A further object of the present invention is a compound of formula (I) in which one or more hydrogen atoms are replaced by one or more deuterium atoms.

[0024] The term "(C1-C6) alkyl" refers to an aliphatic (C1-C6) hydrocarbon chain containing only carbon-carbon single bonds, which can be linear or branched. Typical examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, and n-hexyl.

[0025] The term "(C3-C6) cycloalkyl," unless otherwise specified, refers to a 3- to 6-membered all-carbon monocyclic ring that may contain one or more double bonds but does not have a fully conjugated π-electron system.

[0026] Examples of (C3-C6) cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexanyl, cyclohexenyl, and cyclohexadienyl.

[0027] The term "(C5-C6) heterocycle" refers to a 5- to 6-membered saturated or partially unsaturated carbon ring in which one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen, and sulfur. Non-restrictive examples of heterocycle groups include, for example, pyranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolidinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyridinyl, 1,3-dioxolanyl, piperidinyl, piperazinyl, and morpholinyl. The heterocycle may be further condensed or linked to aromatic and non-aromatic carbon rings or heterocycles.

[0028] The term "(C2-C6) alkenyl" refers to an aliphatic straight or branched (C2-C6) hydrocarbon chain containing at least one carbon-carbon double bond. Representative examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, and 1- or 2-butenyl.

[0029] The term "aryl" refers to monocyclic, bicyclic, or polycyclic carbocyclic hydrocarbons having a 1- to 4-ring system, which may be further linked to one another by condensation or single bonds, where at least one of the carbocyclic rings is "aromatic," and the term "aromatic" refers to a fully conjugated π-electron bonding system. Non-limiting examples of such aryl groups include phenyl, α- or β-naphthyl, α- or β-tetrahydronaphthalenyl, biphenyl, and indanyl groups.

[0030] The term "heteroaryl" refers to an aromatic heterocycle, typically a 5-6 membered heterocycle having 1-3 heteroatoms selected from N, O, or S; the heteroaryl ring may be further fused or linked to aromatic and non-aromatic carbocyclic and heterocycles. Non-exclusive examples of such heteroaryl groups include, for example, pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, indolyl, imidazolyl, thiazolyl, isothiazolyl, pyrrolyl, furanil, oxazolyl, isoxazolyl, pyrazolyl, thiophenyl, thiadiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, indazolyl, sinnolinyl, benzo[1,3]dioxolyl, benzo[1,4]dioxynyl, benzothiazolyl, benzothiophenyl, benzofuranil, isoindolinyl, benzimidazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, 1,2,3-triazolyl, 1-phenyl-1,2,3-triazolyl, 2,3-dihydroindolyl, 2,3-dihydrobenzofuranil, 2,3-dihydrobenzothiophenyl, benzopyranil, 2,3-dihydrobenzoxazinyl, and 2,3-dihydroquinoxalinyl.

[0031] The term "halogen" refers to fluoro, chloro, bromo, or iodine.

[0032] The terms "polyfluorinated (C1-C6) alkyl" or "polyfluorinated (C1-C6) alkoxy" refer to either the (C1-C6) alkyl or (C1-C6) alkoxy groups defined above, which are substituted with multiple fluorine atoms, such as trifluoromethyl, trifluoroethyl, 1,1,1,3,3,3-hexafluoropropyl, or trifluoromethoxy.

[0033] The term "hydroxy(C1-C6)alkyl" refers to any of the above-defined (C1-C6) alkyl groups having a hydroxyl group, such as hydroxymethyl, 2-hydroxyethyl, or 3-hydroxypropyl.

[0034] According to the present invention, unless otherwise specified, R1, R2, R3, R4, R5, Ra, Rb, and Rc are independently hydroxyl, (C1-C6)alkoxyhydroxy(C1-C6)alkyl, halogen, nitro, oxo group (=O), cyano, (C1-C6)alkyl, polyfluorinated(C1-C6)alkyl, polyfluorinated(C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, aryl(C1-C6)alkyl, (C1-C6)alkylaryl, aryl(C1-C6)alkoxy, heteroaryl, heteroaryl (C1-C6)alkyl, (C1-C6)alkyl heteroaryl, heterocycle, heterocycle (C1-C6)alkyl, (C1-C6)alkyl heterocycle, (C1-C6)alkyl heterocycle (C1-C6)alkyl, tri(C1-C6)alkylsilyl, (C3-C7)cycloalkyl, aryloxy, heterocycle oxy, methylenedioxy, (C1-C6)alkylcarbonyloxy, arylcarbonyloxy, di(C1-C6)alkylamino heterocycle (C1-C6)alkyl, (C3-C7)cycloalkenyloxy, heterocycle carbonyloxy, (C1-C6) Alkylideneaminooxy, carboxy, (C1-C6)alkoxycarbonyl, aryloxycarbonyl, (C3-C7)cycloalkyloxycarbonyl, nitro, amino, heterocyclic (C1-C6)alkoxycarbonylamino, ureido, (C1-C6)alkylamino, amino(C1-C6)alkyl, di(C1-C6)alkylamino, arylamino, diarylamino, heterocyclic amino, formylamino, (C1-C6)alkylcarbonylamino, arylcarbonylamino, heterocyclic carbonylamino, aminocarbonyl, (C1-C6) Alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, arylaminocarbonyl (C1-C6)alkyl, (C3-C7)cycloalkylaminocarbonyl, heterocyclicaminocarbonyl, (C1-C6)alkoxycarbonylamino, hydroxyaminocarbonyl, (C1-C6)alkoxyimino, (C1-C6)alkylsulfonylamino, arylsulfonylamino, heterocyclicsulfonylamino, formyl, (C1-C6)alkylcarbonyl, arylcarbonyl,(C3-C7)cycloalkylcarbonyl, heterocyclic carbonyl, heterocyclic carbonyl, (C1-C6)alkyl, (C1-C6)alkylsulfonyl, polyfluorinated (C1-C6)alkylsulfonyl, arylsulfonyl, aminosulfonyl, (C1-C6)alkylaminosulfonyl, di(C1-C6)alkylaminosulfonyl, arylaminosulfonyl, heterocyclic aminosulfonyl, arylthio, (C1-C6)alkylthio may be substituted at any of the available positions by one or more groups selected from, for example, 1 to 6 groups; then, where appropriate, each of the above substituents may be further substituted by one or more of the above groups.

[0035] From all of the above, it will be obvious to those skilled in the art that a group whose name is a compound name such as "arylamino" should be interpreted conventionally by the part derived from an amino group substituted with, for example, aryl (aryl is as defined above).

[0036] Similarly, any of the terms, for example, (C1-C6)alkylthio, (C1-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxycarbonylamino, heterocyclic carbonyl, heterocyclic carbonylamino, and (C3-C7)cycloalkyloxycarbonyl, include groups in which the (C1-C6)alkyl, (C1-C6)alkoxy, aryl, (C3-C7)cycloalkyl, and heterocyclic portions are as defined above.

[0037] The present invention also provides a method for producing the compound of general formula (I) defined above, using the reaction pathway and synthesis diagram described below, with respect to the techniques available in the art and readily available starting materials. The following examples describe the production of a predetermined embodiment of the present invention, but as will be obvious to those skilled in the art, the following production examples can be readily adapted to produce other embodiments of the present invention. For example, by modifications obvious to those skilled in the art, such as appropriately protecting interfering groups, suitably substituting reagents with others known in the art, or making routine changes to the reaction conditions, it is possible to synthesize compounds of the present invention that are not exemplified. Alternatively, other reactions described herein or other reactions known in the art can be adapted to produce other compounds of the present invention.

[0038] The compounds of the present invention can be prepared from readily available starting materials using the following general methods and procedures. Unless otherwise specified, the starting materials are known compounds, or may be prepared from known compounds according to well-known procedures. Naturally, where typical or preferred processing conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure) are described, different processing conditions may also be used unless otherwise stated. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art through routine optimization procedures.

[0039] The compound of general formula (I) defined above can be prepared according to the general synthesis process described below in Figures A, B, and C.

[0040] R1 is a heteroaryl selected from the group of formulas (A), (B), (C), (D), and (E); and R2 is a halogen, nitro, amino, (C1-C6)alkylamino, aminocarbonyl, optionally substituted linear or branched (C1-C6)alkyl, optionally substituted linear or branched (C1-C6)alkoxy, optionally substituted linear or branched polyfluorinated (C1-C6)alkyl, and optionally substituted linear or branched polyfluorinated (C1-C6)alkoxy. The compound of formula (I), which is a substituted aryl ring or substituted heteroaryl ring having 1 to up to 3 selected substituents; R3 is H, an optionally substituted linear or branched (C1-C4) alkyl chain, an optionally substituted (C3-C6) cycloalkyl group, or an optionally substituted (C5-C6) heterocyclic group; R4 is hydrogen, and R5 is hydrogen, a halogen, or an optionally substituted linear or branched (C1-C3) alkyl group, can be prepared according to Figure A below.

[0041] Diagram A

[0042] [ka]

[0043] Therefore, the process predicts the following steps:

[0044] Step 1) Compound of formula (II):

[0045] [ka] [In the formula, R5 is hydrogen or a linear or branched (C1-C3) alkyl which may be substituted, and X is a halogen.] A suitable organoboronic acid derivative of formula (III):

[0046] [ka] A step of metal-catalyzed coupling reaction with [wherein R1 is a heteroaryl group of formula (A), (B), (C), (D), or (E)]; Step 2) The compound of formula (IV) obtained:

[0047] [ka] [R1 and R5 are as defined in step 1.] are halogenated to form compound (V):

[0048] [ka] The process of obtaining [wherein R1 and R5 are as defined in step 1, and X is a halogen]; Step 3) A compound of formula (V) is used to a suitable organic boronic acid derivative of formula (VI):

[0049] [ka] [wherein R2 is a substituted aryl or substituted heteroaryl ring having 1 to up to 3 substituents selected from halogen, nitro, amino, (C1-C6)alkylamino, aminocarbonyl, optionally substituted linear or branched (C1-C6)alkyl, optionally substituted linear or branched (C1-C6)alkoxy, optionally substituted linear or branched polyfluorinated (C1-C6)alkyl, and optionally substituted linear or branched polyfluorinated (C1-C6)alkoxy.] is reacted with a metal-catalyzed coupling reaction to form the compound of formula (VII):

[0050] [ka] The process of obtaining [wherein R1 and R5 are as defined in process 1, and R2 is as defined in process 3]; Conversion 1) The compound of formula (VII) obtained from step 3, in which R5 is hydrogen, can be converted to the compound of formula (VII) in which R5 is halogen (X) according to the conditions already reported in step 2 above.

[0051] [ka]

[0052] Step 4) Protect the compound of formula (VII) obtained from Step 3 or Transformation 1 [wherein R1 and R2 are as defined in Steps 1 and 3, respectively, and R5 is hydrogen, a halogen, or an optionally substituted linear or branched (C1-C3) alkyl] by a reaction with a suitable protecting group to obtain the carboxylic acid ester of formula (VIII):

[0053] [ka] The process of obtaining [wherein R1, R2, and R5 are as defined above, and PG is a protecting group such as trimethylsilylethoxymethyl (SEM), tert-butyloxycarbonyl (BOC), or benzenesulfonyl]; Step 5) Hydrolyze the carboxylic acid ester of formula (VIII) under basic conditions to obtain the carboxylic acid of formula (IX):

[0054] [ka] The process of obtaining [wherein R1, R2, R5, and PG are as defined in process 4]; Step 6) The intermediate of formula (IX) is converted into an amine derivative of formula (X):

[0055] [ka] A process of amidation by reaction with [wherein R3 is hydrogen, an optionally substituted linear or branched (C1-C4) alkyl chain, an optionally substituted (C3-C6) cycloalkyl group, or an optionally substituted (C5-C6) heterocyclic group]; Step 7) The compound of formula (XI) obtained:

[0056] [ka] [In the formula, R1, R2, R5 and PG are as defined in step 5, and R3 is as defined in step 6.] is deprotected to obtain the compound of formula (I):

[0057] [ka] The process of obtaining [R1, R2, R3, and R5 are as defined above, and R4 is hydrogen]; or An intermediate compound of formula (VIII) in which R5 is a halogen can be converted to an intermediate of formula (XI) in which R5 is a linear or branched C1-C3 alkyl chain, according to diagram A1 below.

[0058] Diagram A1

[0059] [ka]

[0060] Therefore, this process predicts the following steps:

[0061] Compounds of transformation 2) formula (VIII):

[0062] [ka] [wherein R1 and R2 are as defined in step 1.] is converted to a compound of formula (VIII), which is a linear or branched (C1-C3) alkenyl chain in which R5 may be substituted, according to conditions known in the art for the palladium-catalyzed reaction already reported in step 3 of Figure A; then, compound (VIII) is reacted under the conditions reported in steps 5 and 6 of Figure A to obtain compound (XIa), in which R1, R2 and R5 are as defined above; Transformation 3) Compound of the resulting formula (XIa):

[0063] [ka] Convert [wherein R5 is as defined above] to a compound of formula (XI) which is a linear or branched (C1-C3) alkyl group in which R5 may be substituted, according to the reduction / hydrogenation of the double bond known in the art.

[0064] Alternatively, the compound of formula (I) [R1 is an optionally substituted heteroaryl group of formulas (A), (B), (C), (D), or (E); R2 is a substituted aryl or substituted heteroaryl ring having 1 to up to 3 substituents; R3 and R4 are hydrogen, and R5 is hydrogen or an optionally substituted linear or branched (C1-C3) alkyl] can be prepared according to the following diagram B.

[0065] Diagram B

[0066] [ka]

[0067] Therefore, this process predicts the following steps.

[0068] Step 8) Compound of formula (XII):

[0069] [ka] A step to protect [wherein R2 is a substituted aryl or substituted heteroaryl ring having 1 to up to 3 substituents, and R5 is hydrogen or an optionally substituted linear or branched (C1-C3) alkyl]; Step 9) The compound of formula (XIII) obtained:

[0070] [ka] [In the formula, R2 and R5 are as defined in step 8, and PG is a protecting group such as SEM, BOC, or benzenesulfonyl.] The step of halogenating [the product]; Step 10) The compound of formula (XIV) obtained:

[0071] [ka] [In the formula, R2, R5, and PG are as defined in step 9, and X is a halogen.] Equation (III):

[0072] [ka] A step of reacting a suitable organoboronic acid derivative of [wherein R1 is a heteroaryl group of formula (A), (B), (C), (D), or (E)] with a metal-catalyzed coupling reaction; Step 11) The compound of formula (XV) obtained:

[0073] [ka] A step of hydrolyzing [wherein R1, R2, R5, and PG are as defined above in step 10] to produce the corresponding amide intermediate of the following formula (XVI);

[0074] [ka]

[0075] Step 12) Deprotect the compound of formula (XVI) to obtain the compound of formula (I):

[0076] [ka] The process of obtaining [wherein R1, R2, and R5 are as defined above, and R3 and R4 are hydrogen].

[0077] Alternatively, a compound of formula (I) [R1 is a heteroaryl group of formula (A), (B), (C), (D), or (E); R2 is a substituted aryl or substituted heteroaryl ring having 1 to up to 3 substituents; R3 is hydrogen, R4 is hydrogen, an optionally substituted linear or branched (C1-C6) alkyl or an optionally substituted linear or branched (C2-C6) alkenyl; and R5 is hydrogen or an optionally substituted linear or branched (C1-C4) alkyl chain] can be prepared according to diagram C below.

[0078] Diagram C

[0079] [ka]

[0080] Therefore, the process predicts the following steps.

[0081] Step 13) Derivative of formula (XII):

[0082] [ka] [In the formula, R2 is a substituted aryl or substituted heteroaryl ring having 1 to up to 3 substituents, and R5 is hydrogen or an optionally substituted linear or branched (C1-C3) alkyl.] is converted to a halo derivative of formula (XVII) in the presence of a base or by the addition of a metal catalyst:

[0083] [ka] A step of reacting with [wherein R4 is a linear or branched C1-C6 alkyl group which may be substituted, or a linear or branched C2-C6 alkenyl group which may be substituted, and X is a halogen]; Step 14) The compound of formula (XVIII) obtained:

[0084] [ka] [In the formula, R2, R4, and R5 are as defined in step 13.] A step of halogenating [the substance]; Step 15) The compound of formula (XIX) obtained:

[0085] [ka] [In the formula, X is a halogen, and R2, R3, and R4 are as defined above.] Replace with a suitable organoboronic acid derivative of the following formula (III):

[0086] [ka] A step of metal-catalyzed coupling reaction with [wherein R1 is a heteroaryl group of (A), (B), (C), (D), or (E)]; Step 16) Intermediate of the obtained formula (XX):

[0087] [ka] Hydrolyzing yields the compound of formula (I):

[0088] [ka] The process of obtaining [wherein R1, R2, R4, and R5 are as defined above, and R3 is hydrogen.].

[0089] According to step 1 of diagram A, a metal-catalyzed coupling reaction between the compound of formula (II) and the organic boronic acid derivative of general formula (III) can be carried out by various methods to obtain the compound of formula (IV). Preferably, the compound of formula (IV) can be produced from the intermediate of formula (II) by Pd-catalyzed Suzuki-Miyaura coupling. Transition metal-catalyzed coupling between (hetero)aryl halides and (hetero)arylboronic acids or boronic acid esters is well known to those skilled in the art, see reference: a) Miyaura, Norio; Suzuki, Akira (1979). Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds” See Chemical Reviews 95(7):2457-2483; b) Suzuki, A. In Metal-Catalyzed Cross-Coupling Reactions, Diederich, F., and Stang, PJ, Eds.; Wiley-VCH: New York, 1998, pp.49-97. In the so-called Suzuki-Miyaura reaction, the coupling reaction between (hetero)arylboronic acid or boronic acid ester and (hetero)aryl halogens is typically induced by palladium complexes. Phosphine-palladium complexes such as [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) are used in this reaction, but bis(triphenylphosphin)palladium(II) chloride and tetrakis(triphenylphosphin)palladium(O) may also be used. Bases such as potassium phosphate, sodium carbonate, cesium carbonate, potassium carbonate, potassium t-butoxide, tetramethylammonium hydroxide, and triethylamine can be added, and tetrahydrofuran, dioxane, N,N-dimethylformamide, ethanol, toluene, water, or mixtures thereof can be used as reaction solvents. Typically, the temperature ranges from room temperature to 150°C. Conventional heating can be used in combination with microwave irradiation. The reaction time ranges from approximately 30 minutes to approximately 96 hours. Various Pd catalyst / base / solvent combinations that allow for fine-tuning of reaction conditions to introduce other functional groups with a broad aggregation on both coupling partners are described in the literature.

[0090] According to step 2 of Figure A, the compound of formula (V) can be obtained by halogenating the compound of formula (IV) under a variety of methods and experimental conditions known in the art. Preferably, this reaction is carried out in the presence of N-bromosuccinimide, N-iodosuccinimide, N-chlorosuccinimide, bromine, iodine, hydrobromic acid / hydrogen peroxide, in a suitable solvent such as acetonitrile, methanol, tetrahydrofuran, N,N-dimethylformamide, dioxane, dimethyl sulfoxide, acetic acid, water, or a mixture thereof, at a temperature ranging from about 0°C to reflux, for a period ranging from about 1 hour to about 96 hours.

[0091] According to step 3 of Figure A, the acquisition of compound (VII) by a metal-catalyzed coupling reaction between compound (V) and an organoboronic acid derivative of general formula (VI) can be achieved by the various methods already described in step 1 of Figure A.

[0092] According to step 4, the compound of formula (VII) can be converted to the compound of formula (VIII) by a variety of methods and experimental conditions widely known in the art for the protection of the secondary amino group. Preferably, the reaction is carried out by treatment with an excess of (trimethylsilyl)ethoxymethyl chloride in a suitable solvent such as tetrahydrofuran or dichloromethane in the presence of a base such as sodium hydride. Typically, the reaction is carried out at a temperature ranging from 0°C to reflux for about 30 minutes to about 96 hours. The benzenesulfonyl group can be introduced by reacting benzenesulfonyl chloride with a solvent such as dichloromethane or acetonitrile in the presence of a proton scavenger such as triethylamine or N,N-diisopropylethylamine at a temperature ranging from room temperature to reflux. The tert-butoxycarbonyl (Boc) group can be introduced by treatment with excess di-tert-butyl dicarbonate in a solvent such as tetrahydrofuran, dioxane, or dichloromethane in the presence of a base such as sodium bicarbonate, triethylamine, or N,N-diisopropylethylamine, at temperatures ranging from room temperature to reflux.

[0093] According to step 5 of Figure A, the hydrolysis of the carboxylic acid ester of formula (VIII) to the carboxylic acid of formula (IX) can be achieved in various ways. Preferably, this reaction is carried out in a suitable solvent such as methanol, ethanol, 1,4-dioxane, or tetrahydrofuran, in the presence of a suitable base such as sodium hydroxide, potassium hydroxide, or lithium hydroxide·H2O / tetrahydrofuran. Typically, the reaction is carried out at a temperature ranging from room temperature to 150°C for a time ranging from about 1 hour to about 96 hours. It is also possible to use conventional heating in combination with microwave irradiation.

[0094] According to step 6 of Figure A, the conversion of the carboxylic acid of formula (IX) to the carboxamide of formula (XI) can be achieved by various methods and experimental conditions widely known in the art of carboxamide production. For example, the compound of formula (IX) can be reacted with the ammonium salt of 1-hydroxybenzotriazole or amine NH2R3(X) in the presence of O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, or hydroxybenzotriazole, dicyclohexylcarbodiimide, diisopropylcarbodiimide, or 1-ethyl-3-(3′-dimethylamino)carbodiimide hydrochloride. Preferably, this reaction is carried out in a suitable solvent such as tetrahydrofuran, dichloromethane, toluene, dioxane, N,N-dimethylformamide, or N,N-dimethylacetamide, in the presence of a proton scavenger such as triethylamine or N,N-diisopropylethylamine, at a temperature in the range of 0°C to reflux, for a period of about 30 minutes to about 96 hours. Alternatively, the compound of formula (IX) can be converted to its corresponding acyl chloride in the presence of thionyl chloride or oxalyl chloride, in a suitable solvent such as toluene, dichloromethane, chloroform, diethyl ether, tetrahydrofuran, or dioxane, at a temperature in the range of about -10°C to reflux, for a period of about 1 hour to about 96 hours. The asyl chloride can be isolated by distillation of the solvent and further reacted with a 33% ammonium hydroxide solution or amine NH2R3(X) in a suitable solvent such as toluene, dichloromethane, chloroform, diethyl ether, tetrahydrofuran, or dioxane for a period of about 1 to 96 hours at temperatures ranging from about -10°C to reflux.

[0095] According to step 7 of Figure A, the removal of the protecting group PG on the pyrrole ring of the compound of formula (XI) can be carried out according to a procedure known in the art. Depending on the protecting group selected, the following conditions can be used: 2-(trimethylsilyl)ethoxymethyl (SEM) can be removed at or below room temperature in a solvent such as tetrahydrofuran or dichloromethane using tetra-n-butylammonium fluoride, pyridine hydrogen fluoride, or trifluoroacetic acid; the benzenesulfonyl (Bs) group can be removed at temperatures ranging from room temperature to reflux in a solvent such as methanol, tetrahydrofuran or dioxane using potassium hydroxide, sodium hydroxide, potassium carbonate, or lithium hydroxide; and tert-butoxycarbonyl (Boc) can be removed at temperatures ranging from room temperature to 130°C in the presence of trifluoroacetic acid in dichloromethane, or by sodium carbonate in dimethoxyethane or N,N-dimethylformamide.

[0096] According to step 8 of diagram B, the conversion of the compound of general formula (XII) to the compound of formula (XIII) can be achieved by the reaction already described in step 4 of diagram A.

[0097] According to step 9 of diagram B, the acquisition of compound (XIV) by halogenation of compound (XIII) can be carried out according to the method described above in step 2 of diagram A.

[0098] According to step 10 of Figure B, the acquisition of compound (XV) by metal-catalyzed coupling reaction of compound (XIV) with an organoboronic acid derivative of general formula (III) can be achieved by the various methods already described in step 1 of Figure A.

[0099] According to step 11 of Figure B, the hydrolysis of the compound of formula (XV) to the compound of formula (XVI) can be carried out in a variety of ways, following conventional methods for converting cyano groups to amides. Preferably, this reaction is carried out in a suitable solvent such as methanol, ethanol, n-butanol, 1,4-dioxane, toluene, water, or a mixture thereof, in the presence of a suitable acid or base, such as sulfuric acid, hydrochloric acid, methanesulfonic acid, indium chloride, sodium hydroxide or potassium hydroxide, sodium carbonate or potassium carbonate, or a suitable reagent such as hydrogen peroxide, sodium perborate or acetaldehyde. Typically, the reaction is carried out at a temperature ranging from room temperature to reflux, for a period ranging from about 1 hour to about 96 hours.

[0100] According to step 12 in Figure B, the acquisition of compound (I) by removing the protecting group PG on the pyrrole ring of compound (XVI) can be carried out according to the method described above in step 7 in Figure A.

[0101] According to step 13 of Figure C, the acquisition of compound (XVIII) by reaction of compound (XII) with the halo derivative of general formula (XVII) can be carried out in the presence of a base such as sodium hydride, and tetrahydrofuran or dioxane can be used as the reaction medium. Typically, the temperature is in the range of 5°C to reflux. The reaction period is in the range of approximately 30 minutes to approximately 24 hours. Alternatively, the acquisition of compound (Ic) by metal-catalyzed coupling reaction of compound (XIV) with the halo derivative of general formula (V) can be achieved in the presence of tris(dibenzylideneacetone)dipalladium and tri-tert-butylphosphine. Bases such as sodium carbonate, cesium carbonate, and potassium carbonate may be added, and tetrahydrofuran, dioxane, N,N-dimethylformamide, and toluene may be used as reaction mediums. Typically, the temperature is in the range of room temperature to 150°C. A combination of conventional heating and microwave irradiation is also possible. The reaction time is in the range of approximately 30 minutes to approximately 24 hours.

[0102] According to step 14 in Figure C, the acquisition of compound (XIX) by halogenation of compound (XVIII) can be carried out according to the method described above in step 2 in Figure A.

[0103] According to step 15 of Figure C, the acquisition of compound (XX) by a metal-catalyzed coupling reaction of compound (XIX) with an organoboronic acid derivative of general formula (III) can be achieved by the various methods already described in step 1 of Figure A.

[0104] According to step 16 of Figure C, the hydrolysis of the compound of formula (XX) to the compound of formula (I) can be carried out in step 11 of Figure B according to the method described above.

[0105] The conversion of the compound of formula (VII) to the compound of formula (VII) can be carried out in different ways and under different experimental conditions, according to the conversion described in conversion 1). Preferably, it is carried out in a manner similar to that reported for step 2 of Figure A.

[0106] According to the conversion described in conversion 2), the derivatization of the compound of formula (VIII) to the compound of formula (VIII) can be achieved by the various methods already described in step 3 of Figure A.

[0107] According to the conversion described in conversion 3), the conversion of the compound of formula (XIa) to the compound of formula (XI) can be achieved by various methods and experimental conditions widely known in the art for the reduction of double bonds. Preferably, this reaction is carried out in a suitable solvent such as methanol, ethanol, toluene, or tetrahydrofuran, in the presence of a suitable catalyst such as palladium carbon (10%), palladium acetate, or a rhodium catalyst. Typically, the reaction is carried out at a temperature ranging from room temperature to 150°C for a period of time ranging from about 1 hour to about 96 hours.

[0108] From all of the above, it will be apparent to those skilled in the art that compounds of formula (I) having a functional group that can be further derivatized to another functional group by working in accordance with methods well known in the art are within the scope of the present invention.

[0109] When preparing compounds of general formula (I) according to the above-described modifications of the process, any functional groups in the starting materials, reagents, or intermediates that could cause undesirable side reactions must be adequately protected in accordance with the prior art (see, for example, Green, Theodora W. and Wuts, Peter GM-Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons Inc., New York (NY), 1999). Similarly, the conversion of these latter liberated groups into deprotected compounds can be carried out according to known procedures.

[0110] Any compound of the general formula can be further converted into other compounds of the same general formula according to methods known in the literature, as reported in the experimental section.

[0111] According to any variation of the method for producing the compound of formula (I), the starting materials and any other reactants are known or readily produced by known methods.

[0112] The compound of formula (XII) can be prepared according to the method described in WO2009133170A1.

[0113] Compounds of formulas (II), (III), (VI), (X), and (XVII) are commercially available.

[0114] The final compound can be isolated and purified using conventional procedures, such as chromatography and / or crystallization and salt formation.

[0115] The compound of general formula (I) as defined above can be converted into a pharmaceutically acceptable salt. The compound of general formula (I) as defined above, or a pharmaceutically acceptable salt thereof, can then be formulated together with a pharmaceutically acceptable carrier or diluent to provide a pharmaceutical composition.

[0116] The synthesis of compounds of general formula (I) by the above-described synthesis process can be carried out stepwise, thereby isolating each intermediate and purifying them as needed using standard purification techniques such as column chromatography before proceeding with the subsequent reaction. Alternatively, two or more steps in the synthesis sequence can be carried out in a so-called "one-pot" procedure known in the art, thereby isolating and purifying only the compounds obtained from two or more steps.

[0117] The present invention also provides a method for treating a disease caused by and / or associated with dysregulation of Cdc7 kinase activity, comprising administering an effective amount of a compound of formula (I) as defined above to a mammal, preferably a human, that is in need of treatment.

[0118] Furthermore, the present invention provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in a method for treating a disease caused and / or associated with dysregulated Cdk7 kinase activity, which comprises administering an effective amount of the compound of formula (I) as defined above to a mammal, preferably a human, that is in need of treatment.

[0119] Furthermore, the present invention provides the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, in the manufacture of a drug for treating diseases caused and / or associated with dysregulated Cdc7 kinase activity.

[0120] Preferably, the disease is selected from the group consisting of cancer, cell proliferation disorders, and immune-related disorders. More preferably, the disease is cancer.

[0121] According to the most preferred embodiment of the present invention, the cancers include cancers such as bladder cancer, breast cancer, kidney cancer, liver cancer, colon cancer, lung cancer such as small cell lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, prostate cancer, head and neck cancer, and skin cancer such as squamous cell carcinoma; and hematopoietic tumors of the lymphatic system such as leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, angioimmunoblastic T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, mantle cell lymphoma, and Burkitt lymphoma. The group is selected from the following: ulcers; hematopoietic malignancies of the myeloid cell lineage, such as acute and chronic myeloid leukemia, myelodysplastic syndrome and promyelocytic leukemia; mesenchymal cell-derived tumors, such as fibrosarcoma and rhabdomyosarcoma; central and peripheral nervous system tumors, such as glioma, glioblastoma, glioblastoma multiforme, astrocytoma, oligodendroglioma, paraglioma, neuroblastoma and peripheral nervous system tumors; and other tumors, such as melanoma, seminomas, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoxanthoma, papillary thyroid carcinoma and medullary thyroid carcinoma, Kaposi's sarcoma, chondrosarcoma, cholangiocarcinoma, and head and neck tumors.

[0122] Other desirable diseases caused and / or associated with dysregulated Cdc7 kinase activity include, for example, benign prostatic hyperplasia, familial adenomatous neoplasia, polyposis, neurofibromatosis, psoriasis, vascular smooth muscle cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis, and proliferative disorders such as postoperative stenosis and restenosis.

[0123] Further preferred diseases caused and / or associated with dysregulated Cdc7 kinase activity include transplant rejection, skin diseases such as psoriasis, allergies, asthma, and immune-related disorders such as (but not limited to) autoimmune-mediated diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Crohn's disease, and amyotrophic lateral sclerosis.

[0124] Furthermore, the present invention provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in methods of treating mammals requiring treatment in combination with radiotherapy or in combination with chemotherapy, targeted therapy or immunotherapy.

[0125] In one embodiment, chemotherapy and / or targeted therapy comprises at least one cell proliferation inhibitor or cytotoxic agent.

[0126] Cell proliferation inhibitors or cytotoxic agents include, but are not limited to, antibiotics, alkylating agents, antimetabolites, hormones, immunotherapies, interferon-type agents, cyclooxygenase inhibitors (e.g., COX-2 inhibitors), matrix metalloproteinase inhibitors, telomerase inhibitors, tyrosine kinase inhibitors, anti-growth factor receptors, anti-HER2 agents, anti-EGFR agents, anti-angiogenic agents (e.g., angiogenesis inhibitors), farnesyltransferase inhibitors, ras-raf signaling pathway inhibitors, cell cycle inhibitors, CDK inhibitors, tubulin conjugates, topoisomerase I inhibitors, topoisomerase II inhibitors, aromatase inhibitors, kinesin inhibitors, therapeutic monoclonal antibodies, mTOR inhibitors, histone deacetylase inhibitors, platinum, and hypoxia response inhibitors. Immunotherapy agents include PD-1 antagonists and antibodies that specifically bind to PD-1 or PD-L1.

[0127] When formulated as a fixed dose, such a combination formulation utilizes the compound of the present invention within the following dose range and another pharmaceutically active agent within the permissible dose range.

[0128] If the combination formulation is inappropriate, the compound of formula (I) may be sequentially used in combination with a known anticancer agent.

[0129] The compound of formula (I) of the present invention, suitable for administration to mammals (e.g., humans), can be administered via the usual route, and the dose level will vary depending on the patient's age, weight and condition, and route of administration.

[0130] For example, an appropriate dose for oral administration of the compound of formula (I) may be approximately 10 to 1000 mg per dose, 1 to 5 times a day. The compound of the present invention can be administered in various dosage forms, such as tablets, capsules, sugar-coated tablets, film-coated tablets, solutions, or suspensions, or rectally in the form of suppositories, or parenterally, for example, via intramuscular routes, intravenous and / or intrathecal and / or intraspinal injection or infusion.

[0131] Pharmaceutical compositions containing the compound of the present invention are typically manufactured according to conventional methods and administered in an appropriate pharmaceutical form.

[0132] For example, the solid oral form may contain, along with the active compound, diluents (e.g., lactose, dextrose, saccharose, sucrose, cellulose, corn starch, or potato starch); lubricants (e.g., silica, talc, stearic acid, magnesium stearate, calcium stearate, and / or polyethylene glycol); binders (e.g., starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose, or polyvinylpyrrolidone); disintegrants (e.g., starch, alginic acid, alginates, or sodium starch glycolate); effervescent mixtures; colorants; sweeteners; wetting agents (e.g., lecithin, polysorbates, lauryl sulfates); and generally, pharmacologically inert, non-toxic substances used in pharmaceutical formulations. These pharmaceutical formulations can be manufactured as known, for example, by mixing, granulation, tableting, sugar coating, or film coating.

[0133] Examples of orally administered dispersions include syrups, emulsions, and suspensions.

[0134] For example, the syrup may contain saccharose or saccharose and glycerin and / or mannitol and sorbitol as a carrier.

[0135] The suspensions and emulsions may contain natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol as examples of carriers. The suspension or solution for intramuscular injection may contain, along with the active compound, a pharmaceutically acceptable carrier, such as sterile water, olive oil, ethyl oleate, glycols (e.g., propylene glycol), and optionally, an appropriate amount of lidocaine hydrochloride.

[0136] Intravenous injection or infusion solutions may contain sterile water as a carrier, preferably sterile isotonic saline solution, or may contain propylene glycol as a carrier.

[0137] The suppository may contain a pharmaceutically acceptable carrier along with the active compound, such as cocoa butter, polyethylene glycol, polyoxyethylene sorbitan fatty acid ester surfactant, or lecithin.

[0138] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, carrier, or diluent.

[0139] The present invention further provides a pharmaceutical composition of a compound of formula (I) comprising one or more chemotherapeutic agents.

[0140] Furthermore, the present invention provides an in vitro method for inhibiting Cdc7 protein activity, comprising contacting the protein with an effective amount of the compound of formula (I) defined above.

[0141] Furthermore, the present invention provides a product comprising a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof, and one or more chemotherapeutic agents, as a combination formulation for simultaneous, separate, or sequential use in anticancer therapy.

[0142] Finally, the present invention provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

[0143] Experiment Section The abbreviations and shortened forms used herein have the following meanings:

[0144] g: grams mg: milligrams ›: milliliter μL: microliter mM: millimoles mmol: millimoles μM (micromolar concentration) MHz (megahertz) h: time Hz (Hertz) mm (millimeters) min (minutes) μm (micron) M (molar concentration) BSA: Bovine serum albumin DTT: Dithiothreitol NADPH: Nicotinamide adenine dinucleotide phosphate Rt retention time 2-HG:2-hydroxyglutaric acid KOtBu (potassium tert-butoxide) rt (room temperature) TEA (triethylamine) DMAP (4-dimethylaminopyridine) DME (1,2-dimethoxyethane) TFA (trifluoroacetic acid) Na2SO4 (sodium sulfate) AcOH (acetic acid) ESI (electrospray ionization) Na2CO3 (sodium carbonate) K2CO3 (potassium carbonate) Cs2CO3 (cesium carbonate) K3PO4 (potassium phosphate) LiOH (Lithium Hydroxide) NaOH (Sodium Hydroxide) KOH (potassium hydroxide) p-TsOH (p-toluenesulfonic acid) Depositphotos (ethyl acetate) LiHMDS (lithium bis(trimethylsilyl)amide) NMP (N-methyl-2-pyrrolidone) NaH (sodium hydride) DMA (N,N-dimethylacetamide) KH (potassium hydride) DMF (N,N-dimethylformamide) DCM (dichloromethane) DIPEA(N,N-diisopropyl-N-ethylamine)Hexa(hexane) THF (tetrahydrofuran) DMSO (dimethyl sulfoxide) MeOH (methanol) ACN (acetonitrile) EtOH (ethanol) Bn (benzyl) -OMs (mesirate) -OTs (tosirate) HOBT (N-hydroxybenzotriazole) DCC (1,3-dicyclohexylcarbodiimide) NMR: Nuclear magnetic resonance MS: Mass spectrometry m / z: mass / charge ratio; LC: liquid chromatography MgCl2: Magnesium Chloride EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) TBTU (N,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uronium-tetrafluoroborate) RP-HPLC (Reverse-phase high-performance liquid chromatography) Biochemical assay The inhibitory activity of the estimated Cdc7 inhibitor and the efficacy of the selected compound are determined by the method described below.

[0145] ADPGlo assay method The biochemical activity of the compounds was determined by incubation with specific enzymes and substrates, followed by quantification of ADP products. The compounds were serially diluted four-fold from 10 to 0.0006 μM. In the pre-incubation step, the enzyme was added to the inhibitor solution, and the mixture was incubated at room temperature (rt) for 30 minutes. If the enzyme was already present in the pre-incubation step, the substrate and ATP were added; if there was no pre-incubation step, the substrate, ATP, and enzyme were added to initiate the reaction. The concentrations of ATP, substrate, and reaction buffer are as described above. The assay was performed in a robotic manner using 384-well plates. Each 384-well plate contained Z' and several reference wells used for signal vs. background evaluation (total enzyme activity vs. enzyme completely inhibited by the specific inhibitor). After the incubation time, the reaction was stopped by adding an equal volume of ADPGlo reagent 1 (Promega), and all unreacted ATP was removed. After 60 minutes, an equal volume of ADPGlo reagent 2 (Promega) was added to convert ADP in ATP, and then ATP was converted by light using a luciferase reaction. After 15 minutes at room temperature, the luminescence signal was read using a plate reader.

[0146] The data obtained from both assay methods were analyzed using the 4-parameter logistic equation for IC. 50 The analysis was performed using an in-house customized version of the SW software "Assay Explorer," which provides sigmoid fitting of 8 dilution curves to determine the optimal ratio.

[0147]

number

[0148] All raw data regarding plate dilution, distribution, assay type, target, and inhibition is tracked via barcode scanning and stored in an Oracle DB.

[0149] The biochemical activity of the compounds of the present invention obtained by the method reported above is summarized in Table 1 below.

[0150] Table 1

[0151] [Table 1] TIFF2022207404000037.tif228170 TIFF2022207404000038.tif226170

[0152] As summarized in Table 1, the compounds of the present invention exhibit remarkable activity against cell cycle 7-related protein kinase (Cdc7).

[0153] Metabolic Stability Assay The involvement of aldehyde oxidase in the metabolism of the test substance was determined by comparing intrinsic clearance values ​​in the presence and absence of hydralazine hydrochloride, an aldehyde oxidase inhibitor. The objective of the study was to evaluate in vitro intrinsic clearance, metabolic stability against aldehyde oxidase (AO) activity, and the metabolism of the test substance in human liver cytosol. Intrinsic clearance was determined using a half-life approach by measuring substrate disappearance during a 60-minute incubation with human liver cytosol. Incubation was performed at a concentration of 1 μM. A starting concentration of 1 μM was assumed to be much lower than Km. HPLC-MS / MS was used to detect compounds remaining after incubation. To measure intrinsic clearance, samples were analyzed by online high-performance liquid chromatography (HPLC) with a mass spectrometer (MS). To measure the aldehyde oxidase activity of the cytosol (i.e., positive control), phthalazine was incubated with human liver cytosol in the presence and absence of an aldehyde oxidase inhibitor. On the day of incubation, the compound was dissolved in DMSO at a concentration of 10 mM. Portions of this solution were added to the test system to a final concentration of 1. The percentage of DMSO in the final incubation solution was 0.1%.

[0154] Subdivision samples of the test material were added to human liver cytosol (protein content 1 mg / mL) in Dulbecco's buffer (pH 7.4, 37°C) to a final concentration of 1 μM. Incubation was performed in a 48-well plate under shaking. At incubation times of 0, 5, 10, 20, 30, and 60 minutes, 50 μL of the subdivision sample from the incubation solution was sampled and added to 80 μL of ice-cold acetonitrile and 20 μL of 1 μM warfarin in acetonitrile solution (injection control), and centrifuged at 2500 rpm for 20 minutes. The supernatant was immediately analyzed by LC-MS / MS.

[0155] The test samples were incubated in parallel in double-row conditions at 37°C for 60 minutes at a concentration of 1 M in Dulbecco's buffer (pH 7.4) in the presence of 10 μM hydralazine hydrochloride (aldehyde oxidase inhibitor).

[0156] The chemical stability of the test samples was checked in parallel by incubating them alone in Dulbecco's buffer (pH 7.4) at a concentration of 1 M at 37°C for 60 minutes (negative control).

[0157] Intrinsic clearance (CLint) was calculated using a half-life approach. Half-life and CLint were determined from the residual concentration (area count) at various sampling points using LC-MS / MS. The slope of the plot of the natural logarithmic area of ​​the residual compound against time was calculated using linear regression analysis and converted to half-life (t1 / 2). CLint was expressed as μL / min / mg protein according to the following formula.

[0158]

number

[0159] Formation of phthalazine metabolites Phthalazone was determined from concentrations at different sampling points using HPLC-MS / MS. The slope was calculated by plotting the metabolite concentration against time, and the maximum value was converted to the metabolite production rate expressed as pmol / min / mg.

[0160] Table 2 below reports the metabolic stability results of the compound of the present invention compared with Reference Compound A and Reference Compound B, which have been identified as the closest prior art.

[0161] [ka]

[0162] Reference compound A and reference compound B correspond to compounds (53) and (55) of international PCT application WO2007 / 110344, respectively.

[0163] Table 2

[0164] [Table 2] TIFF2022207404000042.tif222170 TIFF2022207404000043.tif45170

[0165] As shown in Table 2, both reference compound A and reference compound B exhibited low metabolic stability when incubated in human liver cytosol, with short half-lives (T1 / 1 = 14.8 minutes and 154 minutes, respectively) and low percentages of the compound remaining after 60 minutes of incubation (40% and 70%, respectively). Surprisingly, the compounds of the present invention were found to exhibit significantly better metabolic stability than conventional compounds under the same experimental conditions.

[0166] In particular, this new compound exhibits an extended half-life (225 minutes), an increased percentage of residual compounds (up to 85% in the worst case), and a decreased intrinsic clearance value. Therefore, it is superior to conventional reference compounds in terms of DMPK properties, making it highly likely to become a candidate drug for a new drug.

[0167] Preparation of the compound of formula (I) For reference to any specific compound of formula (I) of the present invention, which may also be in the form of a pharmaceutically acceptable salt, see the Experimental Section and the Claims. Referring to the following examples, the compounds of the present invention were synthesized using the methods described herein or other methods known in the art.

[0168] The following examples are provided for the purpose of better illustrating the present invention, but the present invention is not limited in any way to them.

[0169] Where used herein, the symbols and conventions used in processes, diagrams, and examples are consistent with those used in modern scientific literature, such as the Journal of the American Chemical Society or the Journal of Biological Chemistry.

[0170] The compound names are IUPAC names generated using ACD names (by Advanced Chemistry Development, Inc.).

[0171] Unless otherwise stated, all materials, including anhydrous solvents such as DMF, THF, and DCM, were obtained from commercial suppliers at the highest grade and used without further purification. All reactions involving air-sensitive or moisture-sensitive compounds were carried out under a nitrogen or argon atmosphere.

[0172] General purification and analytical methods Flash chromatography was performed using silica gel (Merck grade 9395, 60A).

[0173] The HPLC system consisted of a Waters mod. ZQ 2000 single quadrupole mass spectrometer equipped with a Waters 996 PDA detector and an electrospray (ESI) ion source. Instrument control, data acquisition, and data processing were provided by Empower 2 and MassLynx 4.1 software.

[0174] HPLC was performed using a YMC-Triart C18 (4.6 × 50 mm, 3 μm) column at 25°C with a flow rate of 1.2 mL / min. Mobile phase B was ammonium acetate 5 mM pH=5.2 buffer and acetonitrile (95:5), and mobile phase C was H2O / acetonitrile (5:95). The gradient was increased from 10 to 90% C over 5 minutes, then rapidly increased to 100% C over 0.1 minutes. The injection volume was 10 μL. The mass spectrometer operated in both cation and anion modes, with a capillary voltage of 3.5 kV (ES). + ) and 2.8kV(ES - The cone voltage was set to 14V (ES). + ) and 28V (ES - The source temperature was 120°C. A full scan mass range of 100-800 AMU was set.

[0175] The preparative HPLC system consisted of a Shimadzu HPLC system equipped with an SCL-8A system controller, two LC-8A pumps, an SPD-6AUV spectrophotometer, and a manual Rheodyne injection system. Data acquisition (analog signals) and data processing were provided by Empower 2 software. Purification was performed at 25°C at a flow rate of 15 mL / min using a Waters X-Terra MS RP18 (150 × 30 mm, 10 μm) column. Mobile phase A was a 0.1% TFA solution in water / acetonitrile (95:5), or mobile phase A was a 0.05% NH3 solution in water / acetonitrile (95:5) and mobile phase B was H2O / acetonitrile (5:95). The gradient was raised from 10% to 90% B in 15 minutes, then rapidly increased to 100% B in 0.1 minutes. The injection volume was a maximum of 500 μL.

[0176] 1 1H-NMR spectra were acquired on a Varian INOVA 400 spectrometer operating at 400.5 MHz, equipped with a 5 mm 1 1H{ 15 N- 31 P} z-axis PFG indirect detection probe, and on a Varian INOVA 500 spectrometer operating at 499.7 MHz, equipped with a 5 mm 1 1H{ 13 C- 15 N} triple resonance indirect detection probe at a constant temperature of 28°C. Chemical shifts were referenced relative to the residual solvent signal (for DMSO-d6: 1 2.50 ppm for 1H). Data are reported as follows: chemical shift (δ), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br.s = broad singlet, dd = doublet of doublets, ddd = doublet of doublets of doublets, m = multiplet), coupling constant (J, Hz), number of protons.

[0177] As previously reported (M. Colombo, F R Sirtori, V. Rizzo, Rapid Commun Mass Spectrom 2004, 18(4), 511-517), positive ESI high-resolution mass spectra (HRMS) were acquired on a Q-Tof Ultima (Waters, Manchester, UK) mass spectrometer directly connected to an Agilent 1100 micro-HPLC system (Palo Alto, US).

Examples

[0178] Example A Process 1 Methyl 5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyrrole-3-carboxylate (IV)

[0179]

Chemical Formula

[0180] In the reactor under an argon atmosphere, methyl 5-bromo-1H-pyrrole-3-carboxylate (1 equivalent, 5 g, 24.51 mmol), 1-(phenylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (1 equivalent, 9.41 g, 24.51 mmol), Na2CO3 (3 equivalents, 7.79 g, 73.53 mmol), degassed 1,4-dioxane (25 mL), and degassed distilled water (6.25 mL) were added. After 3 cycles of vacuum / argon, the [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with the catalyst dichloromethane (0.1 equivalent, 2 g, 2.45 mmol) was added. After three cycles of vacuum / argon chromatography, the reaction mixture was heated at T=100°C for 30 minutes. Distilled water was added, and the product was extracted with AcOEt (three times). The organic layer was washed with distilled water and brine, dehydrated with anhydrous Na2SO4, and removed by distillation to dryness. The crude product was purified by flash chromatography (DCM / acetone 95 / 5 to 9 / 1) to obtain the title compound (solid, 4.58 g, Y=49%).

[0181] 1 H NMR (500MHz, DMSO-d6) dppm3.75 (s, 3H) 7.14 (s, 1H) 7.16 (d, J=4.12Hz, 1H) 7.52 (d, J=5.19Hz, 1H) 7.60-7.65 (m, 2 H)7.70(s, 1H)7.71-7.75(m, 1H)7.97(d, J=4.27Hz, 1H)8.09-8.16(m, 2H)8.35(d, J=5.19Hz, 1H)12.30(brs, 1H). LCMS:m / z382[M+H] + HRMS(ESI)C 19 H 15 N3O4S[M+H] + Calculated value: 382.0856, measured value: 382.0855.

[0182] Process 2 Methyl 2-bromo-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1H-pyrrole-3-carboxylate (V)

[0183] [ka]

[0184] To a solution of methyl 5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1H-pyrrole-3-carboxylate (1 equivalent, 4 g, 10.499 mmol) in MeOH (410 mL) and THF (205 mL), 0.33 equivalents of N-bromosuccinimide (566.3 mg, 3.18 mmol) were added at T=0°C. The reaction mixture was stirred at T=0°C for 30 minutes, and then 0.33 equivalents of N-bromosuccinimide (566.3 mg, 3.18 mmol) were added. The reaction mixture was stirred at T=0°C for 30 minutes, and then the final portion of N-bromosuccinimide (0.33 equivalents, 566.3 mg, 3.18 mmol) was added. The reaction mixture was stirred at T=0°C for 1 hour and 30 minutes. Distilled water was added, and the product was extracted three times with AcOEt. The organic layer was washed with brine, dehydrated with anhydrous Na2SO4, and removed by distillation to dryness. The crude product was purified by flash chromatography (DCM / acetone 99 / 1-9 / 1) to obtain the title compound (white solid, 3.62 g, Y=75%).

[0185] 1 H NMR (500MHz, DMSO-d6) dppm3.76 (s, 3H) 7.10 (d, J=4.12Hz, 1H) 7.15 (s, 1H) 7.53 (d, J=5.19Hz, 1H) 7.60-7. 66(m, 2H)7.70-7.75(m, 1H)7.97(d, J=4.12Hz, 1H)8.11-8.15(m, 2H)8.36(d, J=5.19Hz, 1H)12.93(s, 1H). LCMS:m / z459[M+H] + HRMS(ESI)C 19 H 14 BrN3O4S[M+H] + Calculated value: 459.9961, measured value: 459.996.

[0186] Process 3 Methyl-2-(3-chloro-2-fluorophenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1H-pyrrole-3-carboxylate[(VII)]

[0187] [ka]

[0188] In the reactor under an argon atmosphere, methyl 2-bromo-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1H-pyrrole-3-carboxylate (1 equivalent, 150 mg, 0.33 mmol), (3-chloro-2-fluorophenyl)boronic acid (1.2 equivalents, 68 mg, 0.39 mmol), Na2CO3 (3 equivalents, 103.7 mg, 0.978 mmol), degassed 1,4-dioxane (4 mL), and degassed distilled water (1 mL) were added. After 3 cycles of vacuum / argon, the [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with the catalyst dichloromethane (0.1 equivalent, 26.6 mg, 0.033 mmol) was added. After three cycles of vacuum / argon chromatography, the reaction mixture was heated at T=100°C for 2 hours and 30 minutes. Distilled water was added, and the product was extracted with AcOEt (three times). The organic layer was washed with distilled water and brine, dehydrated with anhydrous Na2SO4, and removed by distillation to dryness. The crude product was purified by flash chromatography (DCM / acetone 98 / 2) to obtain the title compound (solid, 115 mg, Y=69%).

[0189] 1 H NMR (500MHz, DMSO-d6) dppm3.66 (s, 3H) 7.17 (d, J=4.27Hz, 1H) 7.23 (s, 1H) 7.34 (t, J=7.85Hz, 1H) 7.53-7.60 (m, 2H) 7.61-7. 66(m, 2H)7.67-7.71(m, 1H)7.71-7.76(m, 1H)8.00(d, J=4.12Hz, 1H)8.12-8.15(m, 2H)8.37(d, J=5.19Hz, 1H)12.49(s, 1H). LCMS:m / z510[M+H] +HRMS(ESI)C 25 H 17 ClFN3O4S[M+H] + Calculated value: 510.0685, measured value: 510.0681.

[0190] The following compounds were obtained by performing the same procedure except for using suitably substituted starting materials.

[0191] Methyl-2-(2-fluoro-4-methylphenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1H-pyrrole-3-carboxylate(VII)

[0192] [ka] 1 H NMR (500MHz, DMSO-d6) dppm 2.39 (s, 3H) 3.63 (s, 3H) 7.08-7.17 (m, 3H) 7.20 (d, J=1.37Hz, 1H) 7.44 (t, J=7.78Hz, 1H) 7.58 (d, J=5.19H) z, 1H) 7.63 (t, J = 1.00Hz, 2H) 7.73 (t, J = 1.00Hz, 1H) 7.98 (d, J = 4.12Hz, 1H) 8.11-8.17 (m, 2H) 8.35 (d, J = 5.19Hz, 1H) 12.32 (brs, 1H). LCMS:m / z490[M+H] + HRMS(ESI)C 26 H 20 FN3O4S[M+H] + Calculated value: 490.1232, measured value: 490.1209.

[0193] Methyl-2-(4-chloro-2-fluorophenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1H-pyrrole-3-carboxylate(VII)

[0194] [ka] 1H NMR (500MHz, DMSO-d6) dppm3.65 (s, 3H) 7.16 (d, J=4.12Hz, 1H) 7.22 (d, J=2.59Hz, 1H) 7.42 (dd, J=8.31, 2.06Hz, 1H) 7.55-7.59 (m, 2H) 7.6 1-7.67(m, 3H)7.72(d, J=7.47Hz, 1H)7.99(d, J=4.12Hz, 1H)8.14(dd, J=8.46, 1.14Hz, 2H)8.37(d, J=5.19Hz, 1H)12.43(d, J=1.52Hz, 1H). LCMS:m / z510[M+H] + HRMS(ESI)C 25 H 17 ClFN3O4S[M+H] + Calculated value: 510.0685, measured value: 510.067.

[0195] Methyl-2-(2-chloro-4-fluorophenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1H-pyrrole-3-carboxylate(VII)

[0196] [ka] 1 H NMR (500MHz, DMSO-d6) dppm3.61 (s, 3H) 7.16-7.19 (m, 1H) 7.22 (d, J=2.75Hz, 1H) 7.33 (td, J=8.54, 2.59Hz, 1H) 7.56 (d, J=5.19Hz) , 1H)7.58-7.67(m, 4H)7.71-7.75(m, 1H)7.99(d, J=4.12Hz, 1H)8.10-8.16(m, 2H)8.35(d, J=5.18Hz, 1H)12.42(d, J=1.98Hz, 1H). LCMS:m / z510[M+H] + HRMS(ESI)C 25 H 17 ClFN3O4S[M+H] + Calculated value: 510.0685, measured value: 510.0689.

[0197] Methyl-2-(2,4-difluorophenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1H-pyrrole-3-carboxylate(VII)

[0198] [ka] 1 H NMR (500MHz, DMSO-d6) dppm3.65 (s, 3H) 7.17 (d, J=4.12Hz, 1H) 7.19-7.25 (m, 2H) 7.39 (td, J=9.84, 2.29Hz, 1H) 7.58 (d, J=5.19H) z, 1H)7.61-7.67(m, 3H)7.71-7.75(m, 1H)7.99(d, J=4.12Hz, 1H)8.14(d, J=7.47Hz, 2H)8.37(d, J=5.19Hz, 1H)12.41(brs, 1H). LCMS:m / z494[M+H] + HRMS(ESI)C 25 H 17 F2N3O4S[M+H] + Calculated value: 494.0981, measured value: 494.0977.

[0199] Methyl-2-[2-chloro-4-(trifluoromethyl)phenyl]-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1H-pyrrole-3-carboxylate(VII)

[0200] [ka] 1 H NMR (500MHz, DMSO-d6) dppm3.62 (s, 3H) 7.19 (d, J=3.78Hz, 1H) 7.24 (s, 1H) 7.55 (d, J=5.25Hz, 1H) 7.60-7.67 (m, 2H) 7.71-7. 75(m, 1H)7.77-7.85(m, 2H)7.99(d, J=3.78Hz, 1H)8.01(s, 1H)8.13(d, J=7.69Hz, 2H)8.36(d, J=5.13Hz, 1H)12.48(brs, 1H). LCMS:m / z560[M+H]+ HRMS(ESI)C 26 H 17 ClF3N3O4S[M+H] + Calculated value: 560.0653, measured value: 560.0656.

[0201] Methyl-2-(2,3-difluorophenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1H-pyrrole-3-carboxylate(VII)

[0202] [ka] 1 H NMR (500MHz, DMSO-d6) dppm3.66 (s, 3H) 7.17 (d, J=4.12Hz, 1H) 7.23 (d, J=1.22Hz, 1H) 7.33 (dd, J=7.78, 5.03Hz, 1H) 7.39-7.44 (m, 1H) 7.51-7.57 (m, 1H) )7.59(d, J=5.34Hz, 1H)7.61-7.67(m, 2H)7.71-7.76(m, 1H)8.00(d, J=4.1 2Hz, 1H)8.14(dd, J=8.46, 1.14Hz, 2H)8.38(d, J=5.19Hz, 1H)12.49(s, 1H). LCMS:m / z494[M+H] + HRMS(ESI)C 25 H 17 F2N3O4S[M+H] + Calculated value: 494.0981, measured value: 494.0981.

[0203] Methyl-2-(2,3-dichlorophenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1H-pyrrole-3-carboxylate(VII)

[0204] [ka] 1H NMR (500MHz, DMSO-d6) dppm3.62 (s, 3H) 7.18 (d, J=4.27Hz, 1H) 7.22 (s, 1H) 7.43-7.48 (m, 1H) 7.50-7.53 (m, 1H) 7.55 (d, J=5. 19Hz, 1H)7.60-7.67(m, 2H)7.70-7.78(m, 2H)7.99(d, J=4.12Hz, 1H)8.11-8.16(m, 2H)8.36(d, J=5.19Hz, 1H)12.47(s, 1H). LCMS:m / z526[M+H] + HRMS(ESI)C 25 H 17 Cl2N3O4S[M+H] + Calculated value: 526.039, measured value: 526.0383.

[0205] Methyl-2-[4-methyl-2-(trifluoromethyl)phenyl]-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1H-pyrrole-3-carboxylate(VII)

[0206] [ka] 1 H NMR (500MHz, DMSO-d6) dppm2.47(s, 3H)3.54(s, 3H)7.16(d, J=4.12Hz, 1H)7.19(d, J=2.75Hz, 1H)7.44(d, J=7.78Hz, 1H)7.52(d, J=5.34Hz, 1H)7.55(d, J=7.63Hz, 1H)7.60-7.65(m, 2H)7.68(s, 1H)7.70-7.75(m, 1H)7.98(d, J=4. 12Hz, 1H)8.10-8.14(m, 2H)8.33(d, J=5.19Hz, 1H)12.39(d, J=2.14Hz, 1H). LCMS:m / z540[M+H] + HRMS(ESI)C 27 H 20 F3N3O4S[M+H] + Calculated value: 540.1199, measured value: 540.1193.

[0207] Methyl-2-(2-chloro-4-methylphenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1H-pyrrole-3-carboxylate(VII)

[0208] [ka] 1 H NMR (500MHz, DMSO-d6) dppm 2.38 (s, 3H) 3.60 (s, 3H) 7.16 (d, J=4.12Hz, 1H) 7.20 (d, J=2.90Hz, 1H) 7.24 (dd, J=7.78, 0.76Hz, 1H) 7.39 (s, 2H) 7.5 6(d, J=5.19Hz, 1H) 7.61-7.66(m, 2H) 7.71-7.76(m, 1H) 7.98(d, J=4.12H z, 1H) 8.10-8.16 (m, 2H) 8.34 (d, J=5.34Hz, 1H) 12.34 (d, J=2.29Hz, 1H). LCMS:m / z506[M+H] + HRMS(ESI)C 26 H 20 ClN3O4S[M+H] + Calculated value: 506.0936, measured value: 506.0938.

[0209] Methyl-2-(2,3-difluoro-4-methylphenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1H-pyrrole-3-carboxylate(VII)

[0210] [ka] 1H NMR (500MHz, DMSO-d6) dppm2.36 (d, J=1.53Hz, 3H) 3.66 (s, 3H) 7.16 (d, J=4. 12Hz, 1H)7.18-7.21(m, 1H)7.22(d, J=2.75Hz, 1H)7.27-7.32(m, 1H)7.59(d , J=5.34Hz, 1H)7.62-7.67(m, 2H)7.70-7.76(m, 1H)7.99(d, J=4.12Hz, 1H)8 .14(dd, J=8.46, 1.14Hz, 2H)8.37(d, J=5.18Hz, 1H)12.43(d, J=2.14Hz, 1H). LCMS:m / z508[M+H] + HRMS(ESI)C 26 H 19 F2N3O4S[M+H] + Calculated value: 508.1137, measured value: 508.1132.

[0211] Methyl-2-[2-methyl-4-(trifluoromethyl)phenyl]-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1H-pyrrole-3-carboxylate(VII)

[0212] [ka] 1 H NMR (500MHz, DMSO-d6) dppm2.25 (s, 3H) 3.62 (s, 3H) 7.18 (d, J=4.27Hz, 1H) 7.25 (s, 1H) 7.52-7.58 (m, 2H) 7.63 (t, J=7. 93Hz, 3H)7.69-7.76(m, 2H)7.99(d, J=4.12Hz, 1H)8.13(dd, J=8.54, 1.07Hz, 2H)8.34(d, J=5.19Hz, 1H)12.36(s, 1H). LCMS:m / z540[M+H] + HRMS(ESI)C 27 H 20 F3N3O4S[M+H] + Calculated value: 540.12, measured value: 540.1207.

[0213] Methyl-2-(2-fluoro-3-methoxyphenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1H-pyrrole-3-carboxylate(VII)

[0214] [ka] 1 H NMR (500MHz, DMSO-d6) dppm3.64 (s, 3H) 3.88 (s, 3H) 7.10 (td, J=6.83, 1.75Hz, 1H) 7.16 (d, J=4.12Hz, 1H) 7.18-7.30 (m, 3H) 7.59 (d, J=5.1 9Hz, 1H)7.60-7.67(m, 2H)7.71-7.77(m, 1H)7.98(d, J=4.12Hz, 1H)8.13(dd, J=8.46, 0.99Hz, 2H)8.36(d, J=5.19Hz, 1H)12.39(brs, 1H). LCMS:m / z506[M+H] + HRMS(ESI)C 26 H 20 FN3O5S[M+H] + Calculated value: 506.1181, measured value: 506.1177.

[0215] Methyl-2-(2-chloro-3-fluorophenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1H-pyrrole-3-carboxylate(VII)

[0216] [ka] 11H NMR (500 MHz, DMSO-d6) δ ppm 3.61 (s, 3H) 7.17 (d, J=4.12 Hz, 1H) 7.22 (s, 1H) 7.39 (d, J=7.02 Hz, 1H) 7.44-7.50 (m, 1H) 7.50-7.54 (m, 1H) 7.55 (d, J=5.19 Hz, 1H) 7.60-7.66 (m, 2H) 7.70-7.75 (m, 1H) 7.99 (d, J=4.12 Hz, 1H) 8.12 (dd, J=8.46, 1.14 Hz, 2H) 8.35 (d, J=5.34 Hz, 1H) 12.48 (br s, 1H). LCMS: m / z 510 [M+H] + . HRMS (ESI) C 25 H 17 ClFN3O4S[M+H] + calculated value: 510.0685, found value: 510.0686.

[0217] methyl 2-(2-fluoro-3-methylphenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyrrole-3-carboxylate (VII)

[0218]

Chemical Formula

[0219] Methyl-2-[2-methyl-3-(trifluoromethyl)phenyl]-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1H-pyrrole-3-carboxylate(VII)

[0220] [ka] 1 H NMR (500MHz, DMSO-d6) dppm2.25 (s, 3H) 3.61 (s, 3H) 7.17-7.20 (m, 1H) 7.24-7.26 (m, 1H) 7.44-7.51 (m, 1H) 7.55-7.58 (m, 1H) 7.60 -7.67 (m, 3H) 7.70-7.75 (m, 1H) 7.78-7.82 (m, 1H) 7.98-8.00 (m, 1H) 8.10-8.15 (m, 2H) 8.31-8.36 (m, 1H) 12.38 (d, J=2.29Hz, 1H). LCMS:m / z540[M+H] + HRMS(ESI)C 27 H 20 F3N3O4S[M+H] + Calculated value: 540.11994, measured value: 540.1203.

[0221] Methyl-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1H-pyrrole-3-carboxylate(VII)

[0222] [ka] 1H NMR (500MHz, DMSO-d6) dppm3.55 (s, 3H) 3.90 (s, 3H) 7.15 (d, J=4.12Hz, 1H) 7.1 9(d, J=2.75Hz, 1H)7.30(dd, J=8.46, 2.52Hz, 1H)7.33(d, J=2.59Hz, 1H)7.47-7 .50(m, 1H) 7.52(d, J=5.19Hz, 1H) 7.61-7.66(m, 2H) 7.71-7.75(m, 1H) 7.98(d, J =4.12Hz, 1H)8.09-8.14(m, 2H)8.33(d, J=5.34Hz, 1H)12.37(d, J=2.29Hz, 1H). LCMS:m / z556[M+H] + HRMS(ESI)C 27 H 20 F3N3O5S[M+H] + Calculated value: 556.1149, measured value: 556.1144.

[0223] Methyl-2-[2-chloro-4-(difluoromethoxy)phenyl]-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1H-pyrrole-3-carboxylate(VII)

[0224] [ka] 1 H NMR (500MHz, DMSO-d6)dppm3.94(s, 3H)7.18(d, J=4.12Hz, 1H)7.22(d, J=2.75Hz, 1H)7.27(dd, J=8.35, 2.52Hz, 1H)7.48(d, J=2.59Hz, 1H)7. 55-7.56(m, 1H)7.63-7.65(m, 2H)7.71-7.74(m, 1H)7.98(d, J=4.10Hz, 1H)8.12-8.14(m, 2H)8.35(d, J=5.31Hz, 1H)12.42(d, J=2.24Hz, 1H). LCMS:m / z558[M+H] + HRMS(ESI)C 26 H 18 ClF2N3O5S[M+H] + Calculated value: 558.0697, measured value: 558.0714.

[0225] Methyl-2-(3,4-dichlorophenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1H-pyrrole-3-carboxylate(VII)

[0226] [ka] 1 H NMR (500MHz, DMSO-d6) dppm3.71 (s, 3H) 7.15 (d, J=4.12Hz, 1H) 7.21 (d, J=2.59Hz, 1H) 7.61-7.66 (m, 3H) 7.66-7.70 (m, 1H)7.71-7.76(m, 2H)7.94-8.02(m, 2H)8.14(dd, J=8.39, 1.07Hz, 2H)8.39(d, J=5.19Hz, 1H)12.32(d, J=1.98Hz, 1H). LCMS:m / z526[M+H] + HRMS(ESI)C 25 H 17 Cl2N3O4S[M+H] + Calculated value: 526.039, measured value: 526.0387.

[0227] Methyl-2-(3,4-difluorophenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1H-pyrrole-3-carboxylate(VII)

[0228] [ka] 1 H NMR (500MHz, DMSO-d6) dppm3.70 (s, 3H) 7.15 (d, J=4.12Hz, 1H) 7.20 (s, 1H) 7.53-7.57 (m, 1H) 7.62-7.67 (m, 3H)7 .70-7.76(m, 1H)7.77-7.84(m, 1H)7.99(d, J=4.12Hz, 1H)8.12-8.16(m, 2H)8.38(d, J=5.19Hz, 1H)12.27(s, 1H). LCMS:m / z494[M+H] + HRMS(ESI)C25 H 17 F2N3O4S[M+H] + Calculated value: 494.0981, measured value: 494.0982.

[0229] Methyl-2-(3-ethoxy-2-fluorophenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1H-pyrrole-3-carboxylate(VII)

[0230] [ka] 1 H NMR (500MHz, DMSO-d6) dppm 1.37 (t, J=6.94Hz, 1H) 3.65 (s, 3H) 4.15 (q, J=6.91Hz, 1 H)7.08(td, J=6.90, 1.60Hz, 1H)7.16(d, J=4.27Hz, 1H)7.17-7.22(m, 2H)7.22-7.27 (m, 1H)7.59(d, J=5.19Hz, 1H)7.61-7.67(m, 2H)7.70-7.76(m, 1H)7.99(d, J=4.12H z, 1H) 8.13 (dd, J=8.39, 1.07Hz, 2H) 8.36 (d, J=5.19Hz, 1H) 12.38 (d, J=2.14Hz, 1H). LCMS:m / z520[M+H] + HRMS(ESI)C 27 H 22 FN3O5S[M+H] + Calculated value: 520.1337, measured value: 520.1335.

[0231] Methyl-2-(4-methyl-3-nitrophenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1H-pyrrole-3-carboxylate(VII)

[0232] [ka] 1H NMR (500MHz, DMSO-d6) dppm2.58(s, 3H)3.69-3.72(m, 3H)7.16(d, J=4.12Hz, 1H)7.23(s, 1H)7.57-7.68(m, 4H)7.70-7.77(m, 1H)7 .94(dd, J=7.93, 1.83Hz, 1H)8.00(d, J=4.12Hz, 1H)8.12-8.18(m, 2H)8.32(d, J=1.68Hz, 1H)8.39(d, J=5.18Hz, 1H)12.36(s, 1H). LCMS:m / z517[M+H] + HRMS(ESI)C 26 H 20 N4O6S[M+H] + Calculated value: 517.1177, measured value: 517.118.

[0233] Methyl-2-(4-cyano-3-fluorophenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1H-pyrrole-3-carboxylate(VII)

[0234] [ka] 1 H NMR (500MHz, DMSO-d6) dppm3.70 (s, 3H) 7.17 (d, J=4.12Hz, 1H) 7.21 (d, J=2.75Hz, 1H) 7.61-7.69 (m, 4H) 7.72-7.77 (m, 1H) )8.00(d, J=4.12Hz, 1H)8.06-8.18(m, 3H)8.27(dd, J=6.18, 2.36Hz, 1H)8.39(d, J=5.19Hz, 1H)12.35(d, J=2.14Hz, 1H). LCMS:m / z501[M+H] + HRMS(ESI)C 26 H 17 FN4O4S[M+H] + Calculated value: 501.1028, measured value: 501.102.

[0235] Methyl-2-(dibenzo[b,d]thiophen-4-yl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1H-pyrrole-3-carboxylate(VII)

[0236] [ka] 1 H NMR (500MHz, DMSO-d6) dppm3.51-3.60(m, 3H)7.23(d, J=4.27Hz, 1H)7.31(d, J=2.59Hz, 1H)7.51-7.56(m, 2H)7.59-7.68(m, 5H)7.69-7.77(m, 1H)7.94-8.05(m, 2H)8.09-8.17(m, 2H)8.37(d, J=5.19Hz, 1H)8.40-8.51(m, 2H)12.60(d, J=2.14Hz, 1H). LCMS:m / z564[M+H] + HRMS(ESI)C 31 H 21 N3O4S2[M+H] + Calculated value: 564.1046, measured value: 564.1054.

[0237] Methyl-2-(4-methylnaphthalene-1-yl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1H-pyrrole-3-carboxylate(VII)

[0238] [ka] 1 H NMR (500MHz, DMSO-d6) dppm2.74 (s, 3H) 3.49 (s, 3H) 7.21 (d, J=4.27Hz, 1H) 7.32 (d, J=2.90Hz, 1H) 7.42-7.52 (m, 3H) 7.55 -7.68 (m, 5H) 7.71-7.78 (m, 1H) 7.99 (d, J=4.12Hz, 1H) 8.07-8.17 (m, 3H) 8.33 (d, J=5.19Hz, 1H) 12.44 (d, J=2.14Hz, 1H). LCMS:m / z522[M+H] + HRMS(ESI)C30 H 23 N3O4S[M+H] + Calculated value: 522.1482, measured value: 522.1477.

[0239] Methyl 2-(3-fluorophenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1H-pyrrole-3-carboxylate(VII)

[0240] [ka] 1 H NMR (500MHz, DMSO-d6) dppm3.70 (s, 3H) 7.15 (d, J=4.27Hz, 1H) 7.21 (d, J=2.75Hz, 1H) 7.23-7.30 (m, 1H) 7.44-7.56 (m, 3H) 7.6 0-7.68(m, 3H) 7.73(d, J=7.47Hz, 1H) 7.99(d, J=4.27Hz, 1H) 8.04-8.17(m, 2H) 8.37(d, J=5.34Hz, 1H) 12.26(d, J=2.14Hz, 1H). LCMS:m / z476[M+H] + HRMS(ESI)C 25 H 18 FN3O4S[M+H] + Calculated value: 476.1075, measured value: 476.1072.

[0241] Methyl 5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-2-[4-(trifluoromethoxy)phenyl]-1H-pyrrole-3-carboxylate(VII)

[0242] [ka] 1H NMR (500MHz, DMSO-d6) dppm3.69(s, 3H) 7.16(d, J=4.12Hz, 1H) 7.21(d, J=2.75Hz, 1H) 7.47(d, J=8.08Hz, 2H) 7.57-7.67( m, 3H) 7.70-7.76 (m, 1H) 7.77-7.84 (m, 2H) 7.99 (s, 1H) 8.07-8.18 (m, 2H) 8.37 (d, J=5.19Hz, 1H) 12.28 (d, J=2.29Hz, 1H). LCMS:m / z542[M+H] + HRMS(ESI)C 26 H 18 F3N3O5S[M+H] + Calculated value: 542.0992, measured value: 542.0999.

[0243] Methyl 2-(1-benzothiophen-3-yl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1H-pyrrole-3-carboxylate(VII)

[0244] [ka] 1 H NMR (500MHz, DMSO-d6)dppm3.57(s, 3H)7.20(d, J=4.12Hz, 1H)7.29(d, J=2.59Hz, 1H)7.37-7.45(m, 2H)7.57(m, J=1.98Hz, 1H)7.64(m, J=5.19Hz, 3H)7 .73(tt, J=7.50, 1.40Hz, 1H)8.00(m, J=4.12Hz, 2H)8.07(m, J=1.83Hz, 1H)8 .14(m, J=8.46, 1.14Hz, 2H)8.36(d, J=5.34Hz, 1H)12.45(d, J=1.83Hz, 1H). LCMS:m / z514[M+H] + HRMS(ESI)C 27 H 19 N3O4S2[M+H] + Calculated value: 514.089, measured value: 514.0878.

[0245] Methyl 2-(2,3-dihydro-1,4-benzodioxin-6-yl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1H-pyrrole-3-carboxylate(VII)

[0246] [ka] 1 H NMR (500MHz, DMSO-d6) dppm3.68(s, 3H)4.22-4.35(m, 4H)6.93(d, J=8.39Hz, 1H)7.12(d, J=4.12Hz, 1H)7.13-7.18(m, 2H)7.20(d, J=2. 14Hz, 1H)7.58-7.68(m, 3H)7.69-7.76(m, 1H)7.97(d, J=4.12Hz, 1H)8.13(dd, J=8.46, 0.99Hz, 2H)8.34(d, J=5.19Hz, 1H)12.06(s, 1H). LCMS:m / z516[M+H] + HRMS(ESI)C 27 H 21 N3O6S[M+H] + Calculated value: 516.1224, measured value: 516.1206.

[0247] Methyl 2-(4-fluoro-2-methylphenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1H-pyrrole-3-carboxylate(VII)

[0248] [ka] 1H NMR (500MHz, DMSO-d6) dppm2.16 (s, 1H) 3.61 (s, 3H) 7.10 (td, J=8.50, 2.67Hz, 1H) 7.16 (d, J=4.12Hz, 1H) 7.18-7.22 (m, 2H) 7.36 (dd, J=8.39, 6.10 Hz, 1H)7.57(d, J=5.19Hz, 1H)7.61-7.65(m, 2H)7.70-7.75(m, 1H)7.97(d , J=4.12Hz, 1H)8.11-8.13(m, 2H)8.33(d, J=5.19Hz, 1H)12.26(brs, 1H). LCMS:m / z490[M+H] + HRMS(ESI)C 26 H 20 FN3O4S[M+H] + Calculated value: 490.1232, measured value: 490.1224.

[0249] Conversion 1 Methyl 2-(2-fluoro-4-methylphenyl)-4-iodo-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1H-pyrrole-3-carboxylate(VII)

[0250] [ka]

[0251] To a solution of methyl-2-(2-fluoro-4-methylphenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1H-pyrrole-3-carboxylate (1 equivalent, 200 mg, 0.40 mmol) in DMF (2 mL), N-iodosuccinimide (1.15 equivalents, 106 mg, 0.47 mmol) was added. The reaction mixture was stirred at room temperature for 15 hours. Ice and distilled water were added, and precipitate formation was observed. The solid was filtered and washed three times with distilled water (and three times with Et2O) to obtain the title compound (beige solid, 960 mg, Y = quantitative %).

[0252] 1H NMR (500MHz, DMSO-d6) dppm2.36 (s, 3H) 3.58 (s, 3H) 6.84 (d, J=3.81Hz, 1H) 7.05-7.16 (m, 2H) 7.45 (t, J=8.01Hz, 1H) 7.48-7.5 3(m, 1H)7.60-7.69(m, 2H)7.70-7.77(m, 1H)8.00(d, J=4.12Hz, 1H)8.10-8.21(m, 2H)8.46(d, J=4.88Hz, 1H)12.49(brs, 1H). LCMS:m / z616[M+H] + HRMS(ESI)C 26 H 19 FIN3O4S[M+H] + Calculated value: 616.0198, measured value: 616.0182.

[0253] Methyl 2-(2-fluoro-4-methylphenyl)-4-bromo-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1H-pyrrole-3-carboxylate(VII)

[0254] [ka]

[0255] A solution of methyl-2-(2-fluoro-4-methylphenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1H-pyrrole-3-carboxylate (1 equivalent, 300 mg, 0.61 mmol) was added to MeOH (24.4 mL) and THF (6.1 mL) at T=0°C. 0.33 equivalents of N-bromosuccinimide (36 mg, 0.3 mmol) were added. The reaction mixture was stirred at T=0°C for 30 minutes, and then another 0.33 equivalents of N-bromosuccinimide (36 mg, 0.3 mmol) were added. The reaction mixture was stirred at T=0°C for 30 minutes, and then the final N-bromosuccinimide (0.33 equivalents, 36 mg, 0.3 mmol) was added. The reaction mixture was stirred at T=0°C for 1 hour and 30 minutes. Distilled water was added, and the product was extracted three times with AcOEt. The organic layer was washed with brine, dehydrated with anhydrous Na2SO4, and removed by distillation to dryness. The crude product was purified by flash chromatography (hexane / AcOEt6 / 4) to obtain the title compound (white solid, 188 mg, Y=54%).

[0256] LCMS:m / z568[M+H] + HRMS(ESI)C 26 H 19 BrFN3O4S[M+H] + Calculated value: 568.0336, measured value: 568.0331.

[0257] Process 4 Methyl-2-(3-chloro-2-fluorophenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate(VIII)

[0258] [ka]

[0259] To a solution of methyl 2-(3-chloro-2-fluorophenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1H-pyrrole-3-carboxylate (1 equivalent, 100 mg, 0.196 mmol) in anhydrous THF (1 mL), 60% NaH mineral oil (1.7 equivalents, 13.4 mg, 0.33 mmol) was added at T=0°C. The reaction mixture was stirred at T=0°C for 20 minutes, and SEMCl (1.8 equivalents, 63 μL, 0.35 mmol) was added. After 10 minutes at T=0°C, the reaction mixture was warmed to room temperature and stirred for 3 hours. Distilled water was added, and the product was extracted with AcOEt. The organic layer was washed with distilled water and brine, dehydrated with anhydrous Na2SO4, and removed by distillation to dryness. The crude product was purified by flash chromatography (hexane / AcOEt85 / 15-7 / 3) to obtain the title compound (solid, 118 mg, Y=94%).

[0260] 1 H NMR (500MHz, DMSO-d6) dppm-0.34--0.21(m, 9H) 0.40-0.59(m, 2H) 2.89-2.98(m, 2H)3.62(s, 3H)4.96-5.21(m, 2H)6.90(d, J=4.12Hz, 1H)6.92(s, 1H)7.36(t, J=7. 93Hz, 1H) 7.50(d, J=5.03Hz, 1H) 7.52-7.56(m, 1H) 7.62-7.68(m, 2H) 7.71-7.77(m , 2H)8.01(d, J=3.97Hz, 1H)8.17(dd, J=8.46, 1.14Hz, 2H)8.45(d, J=5.03Hz, 1H). LCMS:m / z640[M+H] + HRMS(ESI)C 31 H 31 ClFN3O5SSi[M+H] + Calculated value: 640.1499, measured value: 640.149.

[0261] The following compounds were obtained by performing the same procedure except for using suitably substituted starting materials.

[0262] Methyl-2-(2-fluoro-4-methylphenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate(VIII)

[0263] [ka] 1 H NMR (500MHz, DMSO-d6) dppm-0.33--0.26(m, 9H) 0.47(t, J=8.31Hz, 1H) 2.40(s , 3H)2.93(q, J=8.29Hz, 1H)3.60(s, 3H)4.98-5.18(m, 2H)6.87-6.94(m, 2H)7. 11-7.19 (m, 2H) 7.36-7.41 (m, 1H) 7.51 (d, J=5.19Hz, 1H) 7.62-7.68 (m, 2H) 7.7 1-7.79 (m, 1H) 8.00 (d, J=4.12Hz, 1H) 8.13-8.22 (m, 2H) 8.44 (d, J=5.03Hz, 1H). LCMS:m / z620[M+H] + HRMS(ESI)C 31 H 31 ClFN3O5SSi[M+H] + Calculated value: 620.2045, measured value: 620.2047.

[0264] Methyl-2-(4-chloro-2-fluorophenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate(VIII)

[0265] [ka] 1H NMR (500MHz, DMSO-d6) dppm-0.30--0.28 (m, 9H) 0.44-0.50 (m, 2H) 2.91-2.97 (m, 2H) )3.59-3.64(m, 3H)5.00-5.18(m, 2H)6.89(d, J=4.12Hz, 1H)6.91(s, 1H)7.44(dd, J= 8.24, 1.98Hz, 1H) 7.47-7.51 (m, 1H) 7.57-7.62 (m, 2H) 7.63-7.67 (m, 2H) 7.73-7.77 (m, 1H)8.01(d, J=3.97Hz, 1H)8.17(dd, J=8.46, 1.14Hz, 2H)8.45(d, J=5.19Hz, 1H). LCMS:m / z640[M+H] + HRMS(ESI)C 31 H 31 ClFN3O5SSi[M+H] + Calculated value: 640.1499, measured value: 640.1.

[0266] Methyl-2-(2-chloro-4-fluorophenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate(VIII)

[0267] [ka] 1H NMR (500MHz, DMSO-d6) dppm-0.31--0.27(m, 9H) 0.47(dd, J=9.38, 6.94Hz, 2H) 2.93(dd, J=9.23, 7.5 5Hz, 2H) 3.59(s, 3H) 4.93(d, J=11.13Hz, 1H) 5.10(d, J=11.13Hz, 1H) 6.86(d, J=4.12Hz, 1H) 6.89(s, 1H)7.36(td, J=8.46, 2.59Hz, 1H)7.48(d, J=5.19Hz, 1H)7.60(dd, J=8.62, 6.18Hz, 1H)7.62-7.68(m , 3H)7.71-7.77(m, 1H)8.01(d, J=4.12Hz, 1H)8.16(dd, J=8.46, 1.14Hz, 2H)8.44(d, J=5.03Hz, 1H). LCMS:m / z640[M+H] + HRMS(ESI)C 31 H 31 ClFN3O5SSi[M+H] + Calculated value: 640.1499, measured value: 640.1491.

[0268] Methyl-2-(2,4-difluorophenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate(VIII)

[0269] [ka] LCMS:m / z624[M+H] + HRMS(ESI)C 31 H 31 F2N3O5SSi[M+H] + Calculated value: 624.1795, measured value: 624.1788.

[0270] Methyl-2-[2-chloro-4-(trifluoromethyl)phenyl]-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate(VIII)

[0271] [ka] 1 H NMR (500MHz, DMSO-d6) dppm-0.32--0.30(m, 8H)0.40-0.48(m, 2H)2.87-2.95(m, 2H)3 .57-3.62(m, 3H)4.93-5.14(m, 2H)6.87(d, J=4.12Hz, 1H)6.92(s, 1H)7.45-7.51(m, 1H) )7.62-7.68(m, 2H)7.72-7.77(m, 1H)7.79-7.82(m, 1H)7.84-7.88(m, 1H)8.02(d, J=4. 12Hz, 1H) 8.05 (d, J=0.76Hz, 1H) 8.17 (dd, J=8.54, 1.07Hz, 2H) 8.46 (d, J=5.19Hz, 1H). LCMS:m / z690[M+H] + HRMS(ESI)C 32 H 31 ClF3N3O5SSi[M+H] + Calculated value: 690.1467, measured value: 690.1469.

[0272] Methyl-2-(2,3-difluorophenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate(VIII)

[0273] [ka] LCMS:m / z624[M+H] + HRMS(ESI)C 31 H 31 F2N3O5SSi[M+H] + Calculated value: 624.1795, measured value: 624.1791.

[0274] Methyl-2-(2,3-dichlorophenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate(VIII)

[0275] [ka] LCMS:m / z656[M+H] + HRMS(ESI)C 31 H 31 Cl2N3O5SSi[M+H] + Calculated value: 656.1204, measured value: 656.1207.

[0276] Methyl-2-[4-methyl-2-(trifluoromethyl)phenyl]-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate(VIII)

[0277] [ka] 1 H NMR (500MHz, DMSO-d6) dppm-0.33--0.29(m, 9H) 0.45(dd, J=9.23, 7.55Hz, 2H) 2.48(s, 3H) 2.90( dd, J=9.30, 7.47Hz, 2H)3.51-3.53(m, 3H)4.75(d, J=10.98Hz, 1H)5.07(d, J=10.98Hz, 1H)6.77(d , J=4.12Hz, 1H)6.85(s, 1H)7.39-7.45(m, 2H)7.58(d, J=7.93Hz, 1H)7.62-7.67(m, 2H)7.70(s, 1 H)7.72-7.76(m, 1H)8.01(d, J=3.97Hz, 1H)8.16(dd, J=8.62, 1.14Hz, 2H)8.44(d, J=5.03Hz, 1H). LCMS:m / z670[M+H] + HRMS(ESI)C 33 H 34F3N3O5SSi[M+H] + Calculated value: 670.2014, measured value: 670.2007.

[0278] Methyl-2-(2-chloro-4-methylphenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate(VIII)

[0279] [ka] LCMS:m / z636[M+H] + HRMS(ESI)C 32 H 34 ClN3O5SSi[M+H] + Calculated value: 636.1750, measured value: 636.1753.

[0280] Methyl-2-(2,3-difluoro-4-methylphenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate(VIII)

[0281] [ka] LCMS:m / z638[M+H] + HRMS(ESI)C 32 H 33 F2N3O5SSi[M+H] + Calculated value: 638.1951, measured value: 638.1956.

[0282] Methyl-2-[2-methyl-4-(trifluoromethyl)phenyl]-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate(VIII)

[0283] [ka] LCMS:m / z670[M+H] + HRMS(ESI)C 33 H 34 F3N3O5SSi[M+H] + Calculated value: 670.2013, measured value: 670.2017.

[0284] Methyl-2-(2-fluoro-3-methoxyphenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate(VIII)

[0285] [ka] LCMS:m / z636[M+H] + HRMS(ESI)C 32 H 34 FN3O6SSi[M+H] + Calculated value: 636.1994, measured value: 636.1993.

[0286] Methyl-2-(2-chloro-3-fluorophenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate(VIII)

[0287] [ka] LCMS:m / z640[M+H] + HRMS(ESI)C 31 H 31 ClFN3O5SSi[M+H] + Calculated value: 640.1499, measured value: 640.1495.

[0288] Methyl-2-(2-fluoro-3-methylphenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate(VIII)

[0289] [ka] LCMS:m / z620[M+H] + HRMS(ESI)C 32 H 34 FN3O5SSi[M+H] + Calculated value: 620.2045, measured value: 620.2039.

[0290] Methyl-2-[2-methyl-3-(trifluoromethyl)phenyl]-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate(VIII)

[0291] [ka] LCMS:m / z670[M+H] + HRMS(ESI)C 33 H 34 F3N3O5SSi[M+H] + Calculated value: 670.2013, measured value: 670.2008.

[0292] Methyl-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate(VIII)

[0293] [ka] LCMS:m / z686[M+H] +HRMS(ESI)C 33 H 34 F3N3O6SSi[M+H] + Calculated value: 686.1963, measured value: 686.1961.

[0294] Methyl-2-[2-chloro-4-(difluoromethoxy)phenyl]-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate(VIII)

[0295] [ka] 1 H NMR (500MHz, DMSO-d6) dppm-0.31--0.28(m, 9H) 0.44-0.49(m, 2H) 2.91-2.95(m, 2H) 3.59(s, 3H) 4.42-5.12(m, 2H) 6.85(d, J=3.85Hz, 1H )6.89(s, 1H)7.59(d, J=3.88Hz, 1H)7.63-7.66(m, 2H)7.73-7.76(m, 1H)8.01(d, J=4.22Hz, 1H)8.15-8.17(m, 2H)8.45(d, J=5.22Hz, 1H). LCMS:m / z688[M+H] + HRMS(ESI)C 32 H 32 ClF2N3O6SSi[M+H] + Calculated value: 688.1511, measured value: 688.1508.

[0296] Methyl-2-(3,4-dichlorophenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate(VIII)

[0297] [ka] 1H NMR(500MHz, DMSO-d6)dppm-0.27--0.24(m, 8H)0.47-0.57(m, 2H)2.97-3.04(m, 2H)3.62(s, 3H)5.05(s, 2H)6.89(s, 1H)6.93(d, J=3.97Hz, 1H )7.45-7.54(m, 2H)7.62-7.69(m, 2H)7.71-7.78(m, 2H)7.81(d, J=1.98Hz, 1H)8.01(d, J=4.12Hz, 1H)8.13-8.21(m, 2H)8.45(d, J=5.19Hz, 1H). LCMS:m / z656[M+H] + HRMS(ESI)C 31 H 31 Cl2N3O5SSi[M+H] + Calculated value: 656.1204, measured value: 656.1215.

[0298] Methyl-2-(3,4-difluorophenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate(VIII)

[0299] [ka] 1 H NMR(500MHz, DMSO-d6)dppm-0.28--0.26(m, 8H)0.48-0.56(m, 2H)2.96-3.03(m, 2H)3.61(s, 3H)5.06(s, 2H)6.88(s, 1H)6.92(d, J=4.12Hz, 1H)7.34-7.39(m, 1H)7.47-7.51(m, 1H)7.53-7.67(m, 4H)7.72-7.78(m, 1H)8.01(d, J=3.97Hz, 1H)8.14-8.21(m, 2H)8.45(d, J=5.03Hz, 1H). LCMS:m / z624[M+H] + HRMS(ESI)C 31 H 31 F2N3O5SSi[M+H] + Calculated value: 624.1795, measured value: 624.1816.

[0300] Methyl-2-(3-ethoxy-2-fluorophenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate(VIII)

[0301] [ka] 1 H NMR (500MHz, DMSO-d6) dppm-0.31--0.26(m, 9H) 0.47(t, J=8.31Hz, 2H) 1.37(t, J=7.02Hz, 1 H)2.87-3.02(m, 2H)3.61(s, 3H)4.04-4.22(m, 1H)4.98-5.18(m, 2H)6.84-6.94(m, 1H)6.97- 7.09(m, 2H)7.19-7.25(m, 1H)7.26-7.32(m, 1H)7.52(d, J=5.03Hz, 1H)7.62-7.68(m, 2H)7. 72-7.77(m, 1H)8.00(d, J=4.12Hz, 1H)8.17(dd, J=8.46, 1.14Hz, 2H)8.44(d, J=5.19Hz, 1H). LCMS:m / z650[M+H] + HRMS(ESI)C 33 H 36 FN3O6SSi[M+H] + Calculated value: 650.2151, measured value: 650.2164.

[0302] Methyl-2-(4-methyl-3-nitrophenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate(VIII)

[0303] [ka] 1H NMR (500MHz, DMSO-d6)dppm-0.28--0.25(m, 8H)0.52-0.58(m, 2H)2.60(s, 3H)2.98-3.05(m, 2H)3.62(s, 3H)5.04(s, 2H)6.91(s, 1H)6.93(d , J=4.12Hz, 1H) 7.51(d, J=5.03Hz, 1H) 7.59-7.69(m, 3H) 7.71-7.78(m, 2H) 8.01(d, J=4.12Hz, 1H) 8.14-8.24(m, 3H) 8.45(d, J=5.03Hz, 1H). LCMS:m / z647[M+H] + HRMS(ESI)C 32 H 34 N4O7SSi[M+H] + Calculated value: 647.1990, measured value: 647.2003.

[0304] Methyl-2-(4-cyano-3-fluorophenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate(VIII)

[0305] [ka] 1 H NMR (500MHz, DMSO-d6) dppm-0.28--0.24(m, 9H) 0.46-0.57(m, 2H) 2.92-3.04( m, 2H)3.62(s, 3H)5.05(s, 2H)6.90(s, 1H)6.92(d, J=4.12Hz, 1H)7.47(d, J=5.0 3Hz, 1H)7.62-7.71(m, 3H)7.72-7.77(m, 1H)7.87-7.97(m, 1H)8.02(d, J=4.12 Hz, 1H) 8.12 (dd, J=6.25, 2.14Hz, 1H) 8.15-8.20 (m, 2H) 8.46 (d, J=5.03Hz, 1H). LCMS:m / z631[M+H] + HRMS(ESI)C 32 H 31 FN4O5SSi[M+H] + Calculated value: 631.1841, measured value: 631.1846.

[0306] Methyl-2-(dibenzo[b,d]thiophen-4-yl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate(VIII)

[0307] [ka] LCMS:m / z694[M+H] + HRMS(ESI)C 37 H 35 N3O5S2Si[M+H] + Calculated value: 694.1860, measured value: 694.1863.

[0308] Methyl-2-(4-methylnaphthalene-1-yl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate(VIII)

[0309] [ka] 1 H NMR (500MHz, DMSO-d6) dppm-0.40--0.35 (m, 9H) 0.19-0.32 (m, 2H) 2.67-2.8 1 (m, 5H) 3.44 (s, 3H) 4.74-5.08 (m, 2H) 6.91-7.01 (m, 2H) 7.43-7.51 (m, 4H) 7 .53-7.61(m, 2H)7.62-7.71(m, 2H)7.73-7.78(m, 1H)8.02(d, J=4.12Hz, 1H) 8.10(d, J=8.39Hz, 1H)8.17(dd, J=8.46, 0.99Hz, 1H)8.44(d, J=5.03Hz, 1H). LCMS:m / z652[M+H] + HRMS(ESI)C 36 H 37 N3O5SSi[M+H] +Calculated value: 652.2296, measured value: 652.2303.

[0310] Methyl 2-(3-fluorophenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate(VIII)

[0311] [ka] 1 H NMR (500MHz, DMSO-d6)dppm-0.29--0.24(m, 9H)0.49-0.56(m, 2H)2.94-3.02(m, 2H)3.60(s, 3H)5.05(s, 2H)6.89(s, 1H)6.92(d, J=3.97Hz, 1H)7. 29-7.40 (m, 3H) 7.47-7.56 (m, 2H) 7.60-7.68 (m, 2H) 7.70-7.77 (m, 1H) 8.0 1(d, J=4.12Hz, 1H)8.17(dd, J=8.46, 1.14Hz, 2H)8.45(d, J=5.03Hz, 1H). LCMS:m / z606[M+H] + HRMS(ESI)C 31 H 32 FN3O5SSi[M+H] + Calculated value: 606.1889, measured value: 606.1885.

[0312] Methyl 5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-2-[4-(trifluoromethoxy)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate(VIII)

[0313] [ka] 1H NMR(500MHz, DMSO-d6)dppm-0.30--0.26(m, 9H)0.46-0.55(m, 2H)2.94-3.01(m, 2H)3.60(s, 3H)5.04(s, 2H)6.90(s, 1H)6.92(d, J=4.12H) z, 1H)7.44-7.53(m, 3H)7.61-7.68(m, 4H)7.71-7.78(m, 1H)8.01(d, J=4.12Hz, 1H)8.17(dd, J=8.46, 1.14Hz, 2H)8.45(d, J=5.03Hz, 1H). LCMS:m / z672[M+H] + HRMS(ESI)C 32 H 32 F3N3O6SSi[M+H] + Calculated value: 672.1806, measured value: 672.1808.

[0314] Methyl 2-(1-benzothiophen-3-yl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate(VIII)

[0315] [ka] 1 H NMR (500MHz, DMSO-d6) dppm-0.39--0.33(m, 9H)0.31-0.43(m, 2H)2.78-2.89(m, 2H)3.4 9(s, 3H)4.97(d, J=10.98Hz, 1H)5.21(d, J=10.98Hz, 1H)6.93(d, J=4.12Hz, 1H)6.99(s, 1H)7.33-7.45(m, 3H)7.56(d, J=5.03Hz, 1H)7.62-7.69(m, 2H)7.71-7.78(m, 1H)7.99(s , 1H)8.02(d, J=4.12Hz, 1H)8.04-8.12(m, 1H)8.14-8.22(m, 2H)8.45(d, J=5.19Hz, 1H). LCMS:m / z644[M+H] + HRMS(ESI)C 33 H 33 N3O5S2Si[M+H] +Calculated value: 644.1704, measured value: 644.17.

[0316] Methyl 2-(2,3-dihydro-1,4-benzodioxin-6-yl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate(VIII)

[0317] [ka] 1 H NMR (500MHz, DMSO-d6) dppm-0.25(s, 9H) 0.50-0.59(m, 2H) 2.98-3.07(m, 2H) 3.61(s , 3H)4.29(q, J=4.98Hz, 4H)5.04(s, 2H)6.86(s, 1H)6.91(d, J=4.12Hz, 1H)6.92-6.96 (m, 2H)7.00(m, J=1.22Hz, 1H)7.52(d, J=5.19Hz, 1H)7.61-7.67(m, 2H)7.74(m, J=7.4 7Hz, 1H) 7.99 (d, J=4.12Hz, 1H) 8.17 (dd, J=8.39, 1.07Hz, 2H) 8.43 (d, J=5.19Hz, 1H). LCMS:m / z646[M+H] + HRMS(ESI)C 33 H 35 N3O7SSi[M+H] + Calculated value: 646.2038, measured value: 646.2045.

[0318] Methyl 2-(4-fluoro-2-methylphenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate(VIII)

[0319] [ka] 1H NMR (500MHz, DMSO-d6) dppm-0.32--0.28(m, 9H)0.40-0.50(m, 2H)2.08(s, 3H)2.82-3.04 (m, 2H)3.57(s, 3H)4.79-5.05(m, 2H)6.84-6.92(m, 2H)7.12(d, J=2.59Hz, 1H)7.21(dd, J= 10.07, 2.59Hz, 1H) 7.33 (dd, J=8.46, 6.02Hz, 1H) 7.47-7.52 (m, 1H) 7.58-7.68 (m, 2H) 7.70 -7.77(m, 1H)8.00(d, J=3.97Hz, 1H)8.16(dd, J=8.46, 1.14Hz, 2H)8.43(d, J=5.19Hz, 1H). LCMS:m / z620[M+H] + HRMS(ESI)C 32 H 34 FN3O5SSi[M+H] + Calculated value: 620.2045, measured value: 620.2034.

[0320] Methyl-2-(2-fluoro-3-methylphenyl)-4-iodo-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate(VIII)

[0321] [ka] 1 H NMR (500MHz, DMSO-d6) dppm-0.30(s, 9H) 0.32(m, J=9.65, 9.65, 6.63Hz, 2H )2.38(s, 3H)2.67-2.86(m, 2H)3.53(s, 3H)4.58-5.07(m, 2H)6.37-6.81(m, 1H)7.09-7.19(m, 2H)7.39(d, J=5.03Hz, 2H)7.61-7.71(m, 2H)7.73-7.79( m, 1H) 8.02 (d, J=3.97Hz, 1H) 8.19 (d, J=7.47Hz, 2H) 8.51 (d, J=5.03Hz, 1H). LCMS:m / z746[M+H] + HRMS(ESI)C 33 H33 FIN3O5S[M+H] + Calculated value: 746.1012, measured value: 746.1024.

[0322] Methyl-2-(2-fluoro-3-methylphenyl)-4-bromo-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate(VIII)

[0323] [ka] 1 H NMR (500MHz, DMSO-d6) dppm-0.34--0.27(m, 9H) 0.26-0.41(m, 2H) 2.39(s, 3H)2.80(m, J=11.13, 11.13, 6.56Hz, 2H)3.55(s, 3H)4.68-5.18(m, 2H)6.47 -6.85 (m, 1H) 7.08-7.22 (m, 2H) 7.30-7.48 (m, 2H) 7.59-7.70 (m, 2H) 7.70-7 .82(m, 1H) 8.03(d, J=3.97Hz, 1H) 8.18-8.22(m, 2H) 8.51(d, J=5.03Hz, 1H). LCMS:m / z698[M+H] + HRMS(ESI)C 33 H 33 BrFN3O5S[M+H] + Calculated value: 698.1151, measured value: 698.1159.

[0324] Conversion 2 Methyl 4-ethenyl-2-(2-fluoro-4-methylphenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate(VIII)

[0325] [ka]

[0326] In the reactor under an argon atmosphere, methyl 2-(2-fluoro-4-methylphenyl)-4-iodo-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate (1 equivalent, 50 mg, 0.06 mmol), ethenylboronic acid (2 equivalents, 23 μL, 0.13 mmol), Na2CO3 (3 equivalents, 21.3 mg, 0.2 mmol), degassed 1,4-dioxane (1 mL), and degassed distilled water (0.25 mL) were added. After 3 cycles of vacuum / argon, the catalyst tetrakis(triphenylphosphine)-palladium(0) (0.1 equivalent, 7.7 mg, 0.006 mmol) was added. After three cycles of vacuum / argon chromatography, the reaction mixture was heated at T=100°C for 2 hours. Distilled water was added, and the product was extracted with AcOEt (three times). The organic layer was washed with distilled water and brine, dehydrated with anhydrous Na2SO4, and removed by distillation to dryness. The crude product was purified by flash chromatography (hexane / ethyl acetate 8 / 2) to obtain the title compound (white solid, 28 mg, Y=72%).

[0327] 1 H NMR (500MHz, DMSO-d6) dppm-0.32--0.28(m, 9H)0.27-0.37(m, 2H)2.36-2.40(m, 3H)2.7 7(td, J=10.29, 6.41Hz, 2H)3.50-3.54(m, 3H)4.64(d, J=17.54Hz, 1H)4.84(dd, J=11.44, 1.68Hz, 1H) 4.86-5.02 (m, 2H) 6.79 (brs, 2H) 7.08-7.18 (m, 2H) 7.28-7.47 (m, 2H) 7.60-7 .69(m, 2H)7.74(t, J=7.40Hz, 1H)7.93-8.04(m, 1H)8.11-8.22(m, 2H)8.45-8.53(m, 1H). LCMS:m / z645[M+H] + HRMS(ESI)C 34 H 36 FN3O5SSi[M+H] + Calculated value: 646.2202, measured value: 646.2194.

[0328] The following compounds were obtained by the same procedure, except that suitable substituted starting materials were used.

[0329] Methyl 2-(2-fluoro-4-methylphenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-4-(propa-1-en-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate 12((VIII)

[0330] [ka] 1 H NMR(500MHz, DMSO-d6)dppm-0.34--0.23(m, 9H)0.27-0.39(m, 2H)1.88(s, 3H)2 .38(s, 3H)2.74-2.81(m, 2H)3.49(s, 3H)4.44(d, J=1.37Hz, 1H)4.76(s, 3H)6.39 -6.76(m, 1H)7.07-7.17(m, 3H)7.32(d, J=4.88Hz, 1H)7.62-7.68(m, 2H)7.70-7 .80(m, 1H)7.95(d, J=4.12Hz, 1H)8.17(d, J=7.47Hz, 2H)8.42(d, J=5.03Hz, 1H). LCMS:m / z659[M+H] + HRMS(ESI)C 35 H 38 FN3O5SSi[M+H] + Calculated value: 660.2358, measured value: 660.2358.

[0331] Process 5 2-(3-chloro-2-fluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylic acid(IX)

[0332] [ka]

[0333] To a solution of methyl 2-(3-chloro-2-fluorophenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate (1 equivalent, 100 mg, 0.156 mmol) in dioxane (0.5 mL), a solution of 4 M NaOH (0.5 mL) was added. The reaction mixture was stirred at T=100°C for 4 hours. After cooling to room temperature, acetic acid was added to adjust the pH to 6. Distilled water was added, and the product was extracted three times with AcOEt. The organic layer was washed with brine, dehydrated with anhydrous Na2SO4, and removed by distillation to dryness. The crude product was used in the next step without further purification (white solid, 70 mg, Y=92%).

[0334] 1 H NMR(500MHz, DMSO-d6)dppm-0.24--0.18(m, 9H)0.46-0.58(m, 2H)2.90-3.02(m, 2H)5.04-5.21(m, 2H)6.53(dd, J=3.43, 1.91Hz, 1H)6.86(s, 1H)7.23(d, J=5.03Hz, 1H)7.35(t, J=7.85Hz, 1H)7.53-7.61(m, 2H)7.67-7.73(m, 1H)8.29(d, J=4.88Hz, 1H)11.86(brs, 1H)12.04(brs, 1H). LCMS:m / z486[M+H] + HRMS(ESI)C 24 H 25 ClFN3O3Si[M+H] + Calculated value: 486.1411, measured value: 486.1397.

[0335] The following compounds were obtained by performing the same procedure except for using suitably substituted starting materials.

[0336] 2-(4-chloro-2-fluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylic acid(IX)

[0337] [ka] 1 H NMR (500MHz, DMSO-d6)dppm-0.23--0.18(m, 9H)0.48-0.56(m, 2H)2.94-3.00(m, 2H)5.04-5.22(m, 2H)6.52(dd, J=3.43, 1.91Hz, 1H)6.85(s, 1H)7. 22(d. LCMS:m / z486[M+H] + HRMS(ESI)C 24 H 25 ClFN3O3Si[M+H] + Calculated value: 486.1411, measured value: 486.1417.

[0338] 2-(2-chloro-4-fluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylic acid(IX)

[0339] [ka] LCMS:m / z486[M+H] + HRMS(ESI)C 24 H 25 ClFN3O3Si[M+H] + Calculated value: 486.1411, measured value: 486.1408.

[0340] 2-(2,4-difluorophenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylic acid(IX)

[0341] [ka] LCMS:m / z470[M+H] + HRMS(ESI)C 24 H 25 F2N3O3Si[M+H] + Calculated value: 470.1706, measured value: 470.1711.

[0342] 2-[2-chloro-4-(trifluoromethyl)phenyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylic acid(IX)

[0343] [ka] 1 H NMR (500MHz, DMSO-d6) dppm-0.24--0.22 (m, 7H) 0.42-0.52 (m, 2H) 2.89-2.98 (m, 2H) 4.96-5.18 (m, 2H) 6.49 (dd, J=3.36, 1.83Hz , 1H)6.85(s, 1H)7.20(d, J=4.88Hz, 1H)7.56-7.59(m, 1H)7.80-7.87(m, 2H)8.03(s, 1H)8.29(d, J=4.88Hz, 1H)11.87(brs, 1H). LCMS:m / z536[M+H] + HRMS(ESI)C 25 H 25 ClF3N3O3Si[M+H] + Calculated value: 536.1379, measured value: 536.1384.

[0344] 2-(2,3-difluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylic acid(IX)

[0345] [ka] LCMS:m / z470[M+H] + HRMS(ESI)C 24H 25 F2N3O3Si[M+H] + Calculated value: 470.1706, measured value: 470.1701.

[0346] 2-(2,3-dichlorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylic acid(IX)

[0347] [ka] LCMS:m / z502[M+H] + HRMS(ESI)C 24 H 25 Cl2N3O3Si[M+H] + Calculated value: 502.1112, measured value: 502.1119.

[0348] 2-[4-methyl-2-(trifluoromethyl)phenyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylic acid (IX)

[0349] [ka] 1 H NMR (500MHz, DMSO-d6) dppm-0.25--0.19(m, 9H) 0.49(ddd, J=9.76, 7.02, 2.29H z, 2H) 2.47 (s, 3H) 2.86-2.99 (m, 2H) 4.76 (d, J=10.98Hz, 1H) 5.11 (d, J=10.98Hz, 1H)6.39(dd, J=3.36, 1.83Hz, 1H)6.79(s, 1H)7.16(d, J=5.03Hz, 1H)7.43(d, J=7 .78Hz, 1H)7.52-7.60(m, 2H)7.68(s, 1H)8.28(d, J=4.88Hz, 1H)11.85(brs, 1H). LCMS:m / z516[M+H] + HRMS(ESI)C 26 H 28F3N3O3Si[M+H] + Calculated value: 516.1925, measured value: 516.1931.

[0350] 2-(2-chloro-4-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylic acid(IX)

[0351] [ka] LCMS:m / z482[M+H] + HRMS(ESI)C 25 H 28 ClN3O3Si[M+H] + Calculated value: 482.1661, measured value: 482.1664.

[0352] 2-(2,3-difluoro-4-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylic acid(IX)

[0353] [ka] LCMS:m / z484[M+H] + HRMS(ESI)C 25 H 27 F2N3O3Si[M+H] + Calculated value: 484.1863, measured value: 484.1866.

[0354] 2-[2-methyl-4-(trifluoromethyl)phenyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylic acid(IX)

[0355] [ka] LCMS:m / z516[M+H]+ HRMS(ESI)C 26 H 28 F3N3O3Si[M+H] + Calculated value: 516.1925, measured value: 516.1927.

[0356] 2-(2-fluoro-3-methoxyphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylic acid(IX)

[0357] [ka] LCMS:m / z482[M+H] + HRMS(ESI)C 25 H 28 FN3O4Si[M+H] + Calculated value: 482.1906, measured value: 482.1904.

[0358] 2-(2-chloro-3-fluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylic acid(IX)

[0359] [ka] LCMS:m / z486[M+H] + HRMS(ESI)C 24 H 25 ClFN3O3Si[M+H] + Calculated value: 486.1411, measured value: 486.1409.

[0360] 2-(2-fluoro-3-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylic acid(IX)

[0361] [ka] LCMS:m / z466[M+H] + HRMS(ESI)C 25 H 28 FN3O3Si[M+H] + Calculated value: 466.1957, measured value: 466.1951.

[0362] 2-[2-methyl-3-(trifluoromethyl)phenyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylic acid (IX)

[0363] [ka] LCMS:m / z516[M+H] + HRMS(ESI)C 26 H 28 F3N3O3Si[M+H] + Calculated value: 516.1925, measured value: 516.1919.

[0364] 2-[4-Methoxy-2-(trifluoromethyl)phenyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylic acid (IX)

[0365] [ka] LCMS:m / z532[M+H] + HRMS(ESI)C 26 H 28 F3N3O4Si[M+H] + Calculated value: 532.1874, measured value: 532.1871.

[0366] 2-[2-chloro-4-(difluoromethoxy)phenyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylic acid (IX)

[0367] [ka] LCMS:m / z534[M+H] + HRMS(ESI)C 25 H 26 ClF2N3O4Si[M+H] + Calculated value: 534.1422, measured value: 534.1423.

[0368] 2-(3,4-dichlorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylic acid(IX)

[0369] [ka] LCMS:m / z502[M+H] + HRMS(ESI)C 24 H 25 Cl2N3O3Si[M+H] + Calculated value: 502.1115, measured value: 502.1121.

[0370] 2-(3,4-difluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylic acid(IX)

[0371] [ka] LCMS:m / z470[M+H] + HRMS(ESI)C 24 H 25 F2N3O3Si[M+H] + Calculated value: 470.1706, measured value: 470.1715.

[0372] 2-(3-ethoxy-2-fluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylic acid(IX)

[0373] [ka] 1 H NMR (500MHz, DMSO-d6) dppm-0.24--0.16(m, 9H) 0.48-0.58(m, 2H) 1.38(t, J=6.94Hz, 1H)2.87-3.08(m, 2H)4.04-4.25(m, 1H)4.95-5.23(m, 2H)6.52(d d, J=3.43, 1.91Hz, 1H)6.81-6.91(m, 1H)7.02-7.11(m, 1H)7.18-7.32(m, 3 H)7.55-7.61(m, 1H)8.28(d, J=4.88Hz, 1H)11.85(brs, 1H)11.95(brs, 1H). LCMS:m / z496[M+H] + HRMS(ESI)C 26 H 30 FN3O4Si[M+H] + Calculated value: 496.2063, measured value: 496.2069.

[0374] 2-(4-methyl-3-nitrophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylic acid(IX)

[0375] [ka] 1H NMR(500MHz, DMSO-d6)dppm-0.20--0.14(m, 2H)0.57-0.67(m, 1H)2.61(s, 1H)2.99-3.11(m, 1H)5.09(s, 1H)6.57(dd, J=3.36, 1.98Hz, 1H)6.88( s, 1H)7.26(d, J=5.03Hz, 1H)7.55-7.65(m, 1H)7.80(dd, J=7.85, 1.75Hz, 1H)8.18(d, J=1.68Hz, 1H)8.30(d, J=4.88Hz, 1H)11.60-12.24(m, 1H). LCMS:m / z493[M+H] + HRMS(ESI)C 25 H 28 N4O5Si[M+H] + Calculated value: 493.1902, measured value: 493.1903.

[0376] 2-(3-carboxy-4-fluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylic acid(IX)

[0377] [ka] LCMS:m / z496[M+H] + HRMS(ESI)C 25 H 26 FN3O5Si[M+H] + Calculated value: 496.1699, measured value: 496.1701.

[0378] 2-(2-fluoro-4-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylic acid(IX)

[0379] [ka] LCMS:m / z466[M+H] + HRMS(ESI)C 25 H 28FN3O3Si[M+H] + Calculated value: 466.1957, measured value: 466.1959.

[0380] 2-(dibenzo[b,d]thiophen-4-yl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylic acid(IX)

[0381] [ka] LCMS:m / z540[M+H] + HRMS(ESI)C 30 H 29 N3O3SSi[M+H] + Calculated value: 540.1772, measured value: 540.1775.

[0382] 2-(4-methylnaphthalene-1-yl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylic acid(IX)

[0383] [ka] LCMS:m / z498[M+H] + HRMS(ESI)C 29 H 31 N3O3Si[M+H] + Calculated value: 498.2207, measured value: 498.2209.

[0384] 2-(3-fluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylic acid(IX)

[0385] [ka] LCMS:m / z452[M+H] +HRMS(ESI)C 24 H 26 FN3O3Si[M+H] + Calculated value: 452.1800, measured value: 452.1811.

[0386] 5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-2-[4-(trifluoromethoxy)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylic acid(IX)

[0387] [ka] LCMS:m / z518[M+H] + HRMS(ESI)C 25 H 26 F3N3O4Si[M+H] + Calculated value: 518.1718, measured value: 518.1725.

[0388] 2-(1-benzothiophen-3-yl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylic acid(IX)

[0389] [ka] LCMS:m / z490[M+H] + HRMS(ESI)C 26 H 27 N3O3SSi[M+H] + Calculated value: 490.1615, measured value: 490.1624.

[0390] 2-(2,3-dihydro-1,4-benzodioxin-6-yl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylic acid(IX)

[0391] [ka] LCMS:m / z492[M+H] + HRMS(ESI)C 26 H 29 N3O5Si[M+H] + Calculated value: 492.1949, measured value: 492.1952.

[0392] 2-(4-fluoro-2-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylic acid(IX)

[0393] [ka] LCMS:m / z466[M+H] + HRMS(ESI)C 25 H 28 N3O3Si[M+H] + Calculated value: 466.1957, measured value: 466.1959.

[0394] 2-(2-fluoro-4-methylphenyl)-4-iodo-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylic acid(IX)

[0395] [ka] LCMS:m / z592[M+H] + HRMS(ESI)C 25 H 27 FIN3O3Si[M+H] + Calculated value: 592.0923, measured value: 592.0929.

[0396] 2-(2-fluoro-4-methylphenyl)-4-bromo-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylic acid(IX)

[0397] [ka] LCMS:m / z544[M+H] + HRMS(ESI)C 25 H 27 BrFN3O3Si[M+H] + Calculated value: 544.1062, measured value: 544.1067.

[0398] 4-Ethenyl-2-(2-fluoro-4-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylic acid (IX)

[0399] [ka] LCMS:m / z492[M+H] + HRMS(ESI)C 27 H 30 FN3O3Si[M+H] + Calculated value: 492.2113, measured value: 492.2114.

[0400] 2-(2-fluoro-4-methylphenyl)-4-(propa-1-en-2-yl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylic acid(IX)

[0401] [ka] LCMS:m / z506[M+H] + HRMS(ESI)C 28 H 32 FN3O3Si[M+H] + Calculated value: 506.2270, measured value: 506.2271.

[0402] Process 6 2-(3-chloro-2-fluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbol tree Thamide (XI)

[0403] [ka]

[0404] To a solution of methyl 2-(3-chloro-2-fluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylic acid (1 equivalent, 70 mg, 0.144 mmol) in DMA (1 mL), DIPEA (6 equivalents, 143 μL, 0.87 mmol), TBTU (2 equivalents, 93 mg, 0.289 mmol), and HOBtNH3 (2 equivalents, 44 mg, 0.289 mmol) were added. The reaction mixture was stirred overnight at room temperature. Distilled water was added, and the product was extracted three times with AcOEt. The organic layer was washed with 0.5 M NaOH and brine, dehydrated with anhydrous Na2SO4, and removed by distillation to dryness. The crude product was purified by flash chromatography (DCM / acetone 7 / 3) to obtain the title compound (67 mg, Y=96%, including the solid). 1 H NMR (500MHz, DMSO-d6) dppm-0.21--0.18(m, 9H) 0.52-0.58(m, 2H) 2.95-3.02( m, 2H)5.01-5.19(m, 2H)6.67(dd, J=3.43, 1.91Hz, 1H)6.87(brs, 1H)7.08(s, 1 H)7.23(d, J=4.88Hz, 1H)7.30(t, J=7.93Hz, 1H)7.46-7.51(m, 1H)7.54(brs, 1 H)7.56-7.58(m, 1H)7.62-7.68(m, 1H)8.28(d, J=5.03Hz, 1H)11.82(brs, 1H). LCMS:m / z485[M+H] + HRMS(ESI)C 24 H 26 ClFN4O2Si[M+H] +Calculated value: 485.1571, measured value: 485.1555.

[0405] The following compounds were obtained by performing the same procedure except for using suitably substituted starting materials.

[0406] 2-(4-chloro-2-fluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbol tree Thamide (XI)

[0407] [ka] 1 H NMR (500MHz, DMSO-d6)dppm-0.23--0.16(m, 9H)0.50-0.59(m, 2H)2.94-3.04(m, 2H)4.96-5.17(m, 2H)6.65(dd, J=3.43, 1.91Hz, 1H)6. 86(brs, 1H)7.06(s, 1H)7.22(d, J=4.88Hz, 1H)7.38(dd, J=8.24, 1.83Hz, 1H)7.46-7.60(m, 4H)8.27(d, J=5.03Hz, 1H)11.82(brs, 1H). LCMS:m / z485[M+H] + HRMS(ESI)C 24 H 26 ClFN4O2Si[M+H] + Calculated value: 485.1571, measured value: 485.1567.

[0408] 2-(2-chloro-4-fluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbol tree Thamide (XI)

[0409] [ka] LCMS:m / z485[M+H] + HRMS(ESI)C 24 H26 ClFN4O2Si[M+H] + Calculated value: 485.1571, measured value: 485.1566.

[0410] 2-(2,4-difluorophenyl)-5-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbol tree Thamide (XI)

[0411] [ka] LCMS:m / z469[M+H] + HRMS(ESI)C 24 H 26 F2N4O2Si[M+H] + Calculated value: 469.1866, measured value: 469.1861.

[0412] 2-[2-chloro-4-(trifluoromethyl)phenyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbol tree Thamide (XI)

[0413] [ka] 1 H NMR (500MHz, DMSO-d6) dppm-0.24--0.20 (m, 9H) 0.45-0.55 (m, 0H) 2.90-2.96 (m, 2H)4.87-5.20(m, 2H)6.62(dd, J=3.43, 1.91Hz, 1H)6.87(brs, 1H)7.08(s, 1H)7.20(d, J=4.88Hz, 1H)7.54(brs, 1H)7.57-7.60(m, 1H)7.71-7.76(m, 1H) 7.77-7.82(m, 1H)7.97(d, J=0.92Hz, 1H)8.28(d, J=4.88Hz, 1H)11.84(s, 1H). LCMS:m / z535[M+H] + HRMS(ESI)C25 H 26 ClF3N4O2Si[M+H] + Calculated value: 535.1539, measured value: 535.1536.

[0414] 2-(2,3-difluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbol tree Thamide (XI)

[0415] [ka] LCMS:m / z469[M+H] + HRMS(ESI)C 24 H 26 F2N4O2Si[M+H] + Calculated value: 469.1866, measured value: 469.1862.

[0416] 2-(2,3-dichlorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbol tree Thamide (XI)

[0417] [ka] LCMS:m / z501[M+H] + HRMS(ESI)C 24 H 26 Cl2N4O2Si[M+H] + Calculated value: 501.1275, measured value: 501.1278.

[0418] 2-[4-methyl-2-(trifluoromethyl)phenyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbol tree Thamide (XI)

[0419] [ka] 1 H NMR (500MHz, DMSO-d6) dppm-0.23--0.19(m, 9H)0.46-0.57(m, 2H)2.46(s, 3H)2.83-3.0 2(m, 2H)4.71(d, J=10.83Hz, 1H)5.09(d, J=10.98Hz, 1H)6.52(dd, J=3.43, 1.91Hz, 1H)6. 73 (brs, 1H) 7.00 (s, 1H) 7.16 (d, J=4.88Hz, 1H) 7.24 (brs, 1H) 7.38 (d, J=7.93Hz, 1H) 7.5 3(d, J=7.93Hz, 1H)7.55-7.57(m, 1H)7.64(s, 1H)8.26(d, J=4.88Hz, 1H)11.81(brs, 1H). LCMS:m / z515[M+H] + HRMS(ESI)C 26 H 29 F3N4O2Si[M+H] + Calculated value: 515.2085, measured value: 515.2093.

[0420] 2-(2-chloro-4-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbol tree Thamide (XI)

[0421] [ka] LCMS:m / z481[M+H] + HRMS(ESI)C 25 H 29 ClN4O2Si[M+H] + Calculated value: 481.1821, measured value: 481.1825.

[0422] 2-(2,3-difluoro-4-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbol tree Thamide (XI)

[0423] [ka] LCMS:m / z483[M+H] + HRMS(ESI)C 25 H 28 F2N4O2Si[M+H] + Calculated value: 483.2022, measured value: 483.2025.

[0424] 2-[2-methyl-4-(trifluoromethyl)phenyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbol tree Thamide (XI)

[0425] [ka] 1 H NMR (500MHz, DMSO-d6) dppm-0.25--0.19 (m, 9H) 0.46-0.54 (m, 2H) 2.20 (s, 3H) 2.82-2.9 8(m, 2H)4.89(d, J=10.83Hz, 1H)5.01(d, J=10.83Hz, 1H)6.65(dd, J=3.43, 1.91Hz, 1H)6. 83(brs, 1H)7.08(s, 1H)7.21(d, J=5.03Hz, 1H)7.41(brs, 1H)7.51(d, J=7.78Hz, 1H)7.5 5-7.57(m, 1H)7.60(d, J=7.78Hz, 1H)7.67(s, 1H)8.27(d, J=4.88Hz, 1H)11.81(brs, 1H). LCMS:m / z515[M+H] + HRMS(ESI)C 26 H 29 F3N4O2Si[M+H] + Calculated value: 515.2085, measured value: 515.2084.

[0426] 2-(2-fluoro-3-methoxyphenyl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbol tree Thamide (XI)

[0427] [ka] 1 H NMR (500MHz, DMSO-d6)dppm-0.22--0.17(m, 9H)0.54(t, J=8.39Hz, 2H)2.92-3. 04 (m, 2H) 3.87 (s, 3H) 4.99-5.05 (m, 1H) 5.12-5.17 (m, 1H) 6.66 (dd, J=3.43, 1.9 1Hz, 1H) 6.81 (brs, 1H) 6.98-7.03 (m, 1H) 7.04 (s, 1H) 7.17-7.21 (m, 1H) 7.21-7. 27(m, 1H)7.38(brs, 1H)7.53-7.57(m, 1H)8.26(d, J=4.88Hz, 1H)11.80(s, 1H). LCMS:m / z481[M+H] + HRMS(ESI)C 25 H 29 FN4O3Si[M+H] + Calculated value: 481.2066, measured value: 481.2061.

[0428] 2-(2-chloro-3-fluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbol tree Thamide (XI)

[0429] [ka] 1H NMR (500MHz, DMSO-d6) dppm-0.24--0.17(m, 9H) 0.48-0.56(m, 2H) 2.90-3.00(m , 2H)4.96(d, J=11.13Hz, 1H)5.13(d, J=11.13Hz, 1H)6.62(dd, J=3.43, 1.91Hz, 1H)6.83(brs, 1H)7.07(s, 1H)7.21(d, J=4.88Hz, 1H)7.35(dd, J=7.47, 1.22Hz, 1H)7.42-7.53(m, 3H)7.55-7.59(m, 1H)8.27(d, J=5.03Hz, 1H)11.82(brs, 1H). LCMS:m / z485[M+H] + HRMS(ESI)C 24 H 26 ClFN4O2Si[M+H] + Calculated value: 485.1571, measured value: 485.1562.

[0430] 2-(2-fluoro-3-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbol tree Thamide (XI)

[0431] [ka] 1 H NMR (500MHz, DMSO-d6) dppm-0.21--0.17(m, 9H) 0.55(t, J=8.39Hz, 2H) 2.27(s, 3H) )2.95-3.04(m, 2H)4.97-5.04(m, 1H)5.12-5.17(m, 1H)6.66(dd, J=3.43, 1.91Hz, 1H) 6.79 (brs, 1H) 7.04 (s, 1H) 7.14-7.18 (m, 1H) 7.25 (d, J=5.03Hz, 1H) 7.28-7.32 (m, 1H) 7.33-7.41 (m, 2H) 7.55-7.57 (m, 1H) 8.26 (d, J=5.03Hz, 1H) 11.80 (brs, 1H). LCMS:m / z465[M+H] + HRMS(ESI)C 25 H 29 FN4O2Si[M+H]+ Calculated value: 465.2117, measured value: 465.2108.

[0432] 2-[2-methyl-3-(trifluoromethyl)phenyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbol tree Thamide (XI)

[0433] [ka] LCMS:m / z515[M+H] + HRMS(ESI)C 26 H 29 F3N4O2Si[M+H] + Calculated value: 515.2085, measured value: 515.2081.

[0434] 2-[4-Methoxy-2-(trifluoromethyl)phenyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbol tree Thamide (XI)

[0435] [ka] LCMS:m / z531[M+H] + HRMS(ESI)C 26 H 29 F3N4O3Si[M+H] + Calculated value: 531.2034, measured value: 531.2029.

[0436] 2-[2-chloro-4-(difluoromethoxy)phenyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carb tree Thamide (XI)

[0437] [ka] 1 H NMR (500MHz, DMSO-d6)dppm-0.22--0.19(m, 9H)0.48-0.55(m, 2H)2.91-3.00(m, 2H)4.91(d, J=10.98Hz, 1H)5.14(d, J=11.13Hz, 1H)6.61( dd. LCMS:m / z533[M+H] + HRMS(ESI)C 25 H 27 ClF2N4O3Si[M+H] + Calculated value: 533.1582, measured value: 533.1585.

[0438] 2-(3,4-dichlorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbol tree Thamide (XI)

[0439] [ka] 1 H NMR (500MHz, DMSO-d6) dppm-0.17-0.13 (m, 8H) 0.61-0.68 (m, 1H) 1.95 (s, 1H) 2.78 (s, 1) H)2.94(s, 1H)3.05-3.12(m, 1H)5.06(s, 1H)6.71(dd, J=3.36, 1.98Hz, 1H)6.93(brs, 1H )7.02(s, 1H)7.25(d, J=5.03Hz, 1H)7.46-7.50(m, 1H)7.51-7.54(m, 1H)7.56-7.58(m, 1 H)7.70(d, J=8.24Hz, 1H)7.76(d, J=1.98Hz, 1H)8.27(d, J=5.03Hz, 1H)11.82(brs, 1H). LCMS:m / z501[M+H] + HRMS(ESI)C 24 H 26Cl2N4O2Si[M+H] + Calculated value: 501.1275, measured value: 501.1282.

[0440] 2-(3,4-difluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbol tree Thamide (XI)

[0441] [ka] 1 H NMR(500MHz, DMSO-d6)dppm-0.18--0.13(m, 8H)0.58-0.66(m, 2H)3.03-3.11(m, 2H)5.07(s, 2H)6.69(dd, J=3.43, 1.91Hz, 1H)6.89( brs, 1H)7.00(s, 1H)7.25(d, J=4.88Hz, 1H)7.31-7.38(m, 1H)7.44(brs, 1H)7.48-7.60(m, 3H)8.27(d, J=4.88Hz, 1H)11.81(brs, 1H). LCMS:m / z469[M+H] + HRMS(ESI)C 24 H 26 F2N4O2Si[M+H] + Calculated value: 469.1866, measured value: 469.1864.

[0442] 2-(3-ethoxy-2-fluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbol tree Thamide (XI)

[0443] [ka] 1H NMR (500MHz, DMSO-d6)dppm-0.22--0.18(m, 8H)0.55(t, J=8.39Hz, 2H)1.34-1.40(m, 3H)4.12(quintet, J=7.40Hz, 2H)4.98-5.19(m, 2H)6.66(dd, J=3.3 6, 1.98Hz, 1H) 6.81 (brs, 1H) 6.96-7.02 (m, 1H) 7.04 (s, 1H) 7.13-7.29 (m, 3 H)7.37(brs, 1H)7.53-7.59(m, 1H)8.26(d, J=5.03Hz, 1H)11.80(brs, 1H). LCMS:m / z495[M+H] + HRMS(ESI)C 26 H 31 FN4O3Si[M+H] + Calculated value: 495.2222, measured value: 495.2216.

[0444] 2-(4-methyl-3-nitrophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbol tree Thamide (XI)

[0445] [ka] 1 H NMR(500MHz, DMSO-d6)dppm-0.22--0.09(m, 1H)0.57-0.73(m, 1H)2.59(s, 1H)3.06-3.14(m, 1H)5.05(s, 1H)6.72(dd, J=3.36, 1.98Hz, 1H)6.93(brs, 1H)7.05(s, 1H)7.27(d, J=5.03Hz, 1H)7.52-7.60(m, 1H)7.74(dd, J=7.85, 1.75Hz, 1H)8.15(d, J=1.68Hz, 1H)8.28(d, J=5.03Hz, 1H)11.82(brs, 1H). LCMS:m / z492[M+H] + HRMS(ESI)C 25 H 29 N5O4Si[M+H] + Calculated value: 492.2062, measured value: 492.2056.

[0446] 2-(3-carbamoyl-4-fluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carb tree Thamide (XI)

[0447] [ka] 1 H NMR (500MHz, DMSO-d6) dppm-0.13 (s, 9H) 0.63-0.75 (m, 2H) 3.03-3.16 (m, 2H) 5.00- 5.07(m, 2H)6.67-6.77(m, 1H)6.85-6.93(m, 1H)6.99-7.07(m, 1H)7.27-7.33(m, 1H) )7.33-7.40(m, 1H)7.41-7.48(m, 1H)7.56-7.60(m, 1H)7.61-7.66(m, 1H)7.68-7.7 3(m, 1H)7.74-7.79(m, 1H)7.82-7.87(m, 1H)8.26-8.31(m, 1H)11.66-11.98(m, 1H). LCMS:m / z494[M+H] + HRMS(ESI)C 25 H 28 FN5O3Si[M+H] + Calculated value: 494.2018, measured value: 494.2011.

[0448] 2-(2-fluoro-4-methylphenyl)-N-[2-(morpholine-4-yl)ethyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carb tree Thamide (XI)

[0449] [ka]

[0450] To a solution of 2-(2-fluoro-4-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylic acid (1 equivalent, 90 mg, 0.19 mmol) in DMA (1.5 mL), DIPEA (3 equivalents, 131 μL, 0.76 mmol), TBTU (2 equivalents, 118.5 mg, 0.38 mmol), and 2-(morpholin-1-yl)ethanamine (1.5 equivalents, 38 μL, 0.28 mmol) were added. The reaction mixture was stirred overnight at room temperature. Distilled water was added, and the product was extracted three times with AcOEt. The organic layer was washed with 0.5 M NaOH and brine, dehydrated with anhydrous Na2SO4, and removed by distillation to dryness. The crude product was purified by flash chromatography (DCM / MeOH9 / 1) to obtain the title compound (beige solid, 92 mg, Y=84%).

[0451] 1 H NMR (500MHz, DMSO-d6) dppm-0.24--0.17(m, 2H) 0.54(t, J=8.39Hz, 1H) 2.27-2.41(m, 2 H)2.90-3.04(m, 1H)3.19-3.28(m, 1H)3.52(t, J=4.50Hz, 1H)4.92-5.27(m, 1H)6.64(dd , J=3.43, 1.91Hz, 1H)6.99(s, 1H)7.07-7.15(m, 1H)7.24(d, J=4.88Hz, 1H)7.38(t, J=7. 85Hz, 1H)7.55-7.60(m, 1H)7.65(t, J=5.57Hz, 1H)8.26(d, J=5.03Hz, 1H)11.81(s, 1H). LCMS:m / z578[M+H] + HRMS(ESI)C 31 H40FN5O3Si[M+H] + Calculated value: 578.2957, measured value: 578.2952.

[0452] The following compounds were obtained by performing the same procedure except for using suitably substituted starting materials.

[0453] N-[2-(dimethylamino)ethyl]-2-(2-fluoro-4-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carb tree Thamide (XI)

[0454] [ka] 1 H NMR (500MHz, DMSO-d6) dppm-0.23--0.16(m, 9H) 0.54(t, J=8.39Hz, 1H) 2.10(s, 6H) 2.27(t , J=6.79Hz, 2H)2.39(s, 3H)2.90-3.04(m, 2H)3.13-3.24(m, 2H)4.94-5.23(m, 2H)6.64(dd, J=3.35, 1.98Hz, 1H)7.00(s, 1H)7.04-7.15(m, 2H)7.24(d, J=5.03Hz, 1H)7.36(t, J=7.85H z, 1H)7.57(t, J=2.97Hz, 1H)7.65(t, J=5.49Hz, 1H)8.26(d, J=4.88Hz, 1H)11.81(brs, 1H). LCMS:m / z536[M+H] + HRMS(ESI)C 29 H 38 FN5O2Si[M+H] + Calculated value: 536.2852, measured value: 536.2849.

[0455] 2-(2-fluoro-4-methylphenyl)-N-[2-(pyrrolidin-1-yl)ethyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carb tree Thamide (XI)

[0456] [ka] LCMS:m / z562[M+H] + HRMS(ESI)C 31 H 40 FN5O2Si[M+H]+ Calculated value: 562.3008, measured value: 562.3012.

[0457] tert-butyl-[(1R,2S)-2-({[2-(2-fluoro-4-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-yl]carbonyl}amino)cyclohexyl]carbamate(XI)

[0458] [ka] 1 H NMR (500MHz, DMSO-d6) dppm-0.21 (s, 9H) 0.52 (t, J=8.39Hz, 2H) 1.16-1.67 (m, 15 H)2.38(s, 3H)2.92-3.01(m, 2H)3.52-3.66(m, 1H)3.89(brs, 1H)4.92-5.26(m, 2 H)6.47-6.64(m, 2H)6.91(brs, 1H)7.11(d, J=10.22Hz, 3H)7.23(d, J=4.88Hz, 1H )7.35-7.48(m, 1H)7.56(t, J=2.97Hz, 1H)8.27(d, J=4.88Hz, 1H)11.82(brs, 1H). LCMS:m / z662[M+H] + HRMS(ESI)C 36 H 48 FN5O4Si[M+H] + Calculated value: 662.3533, measured value: 662.3553.

[0459] 2-(2-fluoro-4-methylphenyl)-N-(furan-2-ylmethyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carb tree Thamide (XI)

[0460] [ka] 1H NMR (500MHz, DMSO-d6) dppm-0.25--0.16 (m, 9H) 0.55 (t, J=8.31Hz, 2H) 2.37-2.41 (m, 3H) 2.95 -3.05(m, 2H) 4.27-4.39(m, 2H) 4.95-5.26(m, 2H) 6.18(dd, J=3.13, 0.69Hz, 1H) 6.37(dd, J=3.2 0, 1.83Hz, 1H)6.68(dd, J=3.36, 1.98Hz, 1H)7.04-7.14(m, 3H)7.25(d, J=5.03Hz, 1H)7.36(t, J=7.70Hz, 1H)7.52-7.59(m, 2H)8.26(d, J=4.88Hz, 1H)8.42(t, J=5.87Hz, 1H)11.81(brs, 1H). LCMS:m / z545[M+H] + HRMS(ESI)C 30 H 33 FN4O3Si[M+H] + Calculated value: 545.2379, measured value: 545.2383.

[0461] tert-butyl-[2-({[2-(2-fluoro-4-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-yl]carbonyl}amino)ethyl]methylcarbamate(XI)

[0462] [ka] 1H NMR (500MHz, DMSO-d6) dppm-0.24--0.18(m, 9H) 0.54(t, J=8.39Hz, 2H) 1.27-1.41(m , 9H)2.36-2.42(m, 3H)2.77(d, J=10.37Hz, 2H)2.89-3.05(m, 2H)3.14-3.29(m, 2H)4. 87-5.31(m, 2H)6.64(d, J=8.69Hz, 1H)6.97-7.12(m, 3H)7.24(d, J=4.88Hz, 1H)7.34( brs, 1H)7.57(t, J=2.82Hz, 1H)7.99(brs, 1H)8.26(d, J=5.03Hz, 1H)11.81(brs, 1H). LCMS:m / z622[M+H] + HRMS(ESI)C 33 H 44 FN5O4Si[M+H] + Calculated value: 622.322, measured value: 622.3234.

[0463] N-(2-fluoroethyl)-2-(2-fluoro-4-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbol tree Thamide (XI)

[0464] [ka] 1 H NMR (500MHz, DMSO-d6)dppm-0.21--0.17(m, 9H)0.55(t, J=8.39Hz, 2H)2.36-2.41(m, 3H)2 .95-3.05(m, 2H)3.38-3.47(m, 1H)4.39(t, J=5.19Hz, 1H)4.48(t, J=5.19Hz, 1H)4.89-5.28 (m, 2H)6.68(dd, J=3.43, 1.91Hz, 1H)7.05-7.13(m, 3H)7.26(d, J=4.88Hz, 1H)7.36(t, J=7 .63Hz, 1H)7.52-7.62(m, 1H)8.16(t, J=5.57Hz, 1H)8.26(d, J=5.03Hz, 1H)11.81(brs, 1H). LCMS:m / z511[M+H] +HRMS(ESI)C 27 H 32 F2N4O2Si[M+H] + Calculated value: 511.2336, measured value: 511.2336.

[0465] 2-(2-fluoro-4-methylphenyl)-N-(1-methylpiperidine-4-yl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbol tree Thamide (XI)

[0466] [ka] 1 H NMR (500MHz, DMSO-d6) dppm-0.28--0.14(m, 9H) 0.54(t, J=8.39Hz, 2H) 1.53(d, J=9.15Hz, 2 H)1.74(brs, 2H)2.15-2.35(m, 2H)2.38(s, 3H)2.74-3.05(m, 4H)3.65(brs, 1H)4.91-5.29( m, 2H)6.65(dd, J=3.36, 1.98Hz, 1H)7.05(s, 1H)7.07-7.12(m, 2H)7.24(d, J=4.88Hz, 1H)7. 37(t, J=7.78Hz, 1H)7.53-7.59(m, 1H)7.63(brs, 1H)8.26(d, J=4.88Hz, 1H)11.81(brs, 1H). LCMS:m / z562[M+H] + HRMS(ESI)C 31 H 40 FN5O2Si[M+H] + Calculated value: 562.3008, measured value: 562.2991.

[0467] 2-(dibenzo[b,d]thiophen-4-yl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbol tree Thamide (XI)

[0468] [ka] LCMS:m / z539[M+H] + HRMS(ESI)C 30 H 30 N4O2SSi[M+H] + Calculated value: 539.1932, measured value: 539.1938.

[0469] 2-(4-methylnaphthalene-1-yl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbol tree Thamide (XI)

[0470] [ka] 1 H NMR (500MHz, DMSO-d6)dppm-0.32--0.26(m, 9H)0.26-0.36(m, 2H)2.68-2.83(m, 5H)4.73-5.08(m, 2H)6.65-6.77(m, 2H)6.86-6.99(m, 1 H) 7.12(s, 1H) 7.28(d, J=5.03Hz, 1H) 7.43-7.54(m, 4H) 7.55-7.61(m, 2H) 8.09(d, J=8.39Hz, 1H) 8.26(d, J=5.03Hz, 1H) 11.81(brs, 1H). LCMS:m / z497[M+H] + HRMS(ESI)C 29 H 32 N4O2Si[M+H] + Calculated value: 497.2368, measured value: 497.2369.

[0471] 2-(3-fluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbol tree Thamide (XI)

[0472] [ka] 1H NMR (500MHz, DMSO-d6) dppm-0.20--0.12 (m, 9H) 0.57-0.67 (m, 2H) 3.01-3.10 (m, 2H) 5.06 (s, 2H) 6.70 (dd, J=3.43, 1.91Hz, 1H) 6.88 (brs, 1H) )6.99(s, 1H)7.22-7.30(m, 2H)7.30-7.36(m, 2H)7.39(brs, 1H)7.44-7.52(m, 1H)7.52-7.60(m, 1H)8.27(d, J=4.88Hz, 1H)11.80(brs, 1H). LCMS:m / z451[M+H] + HRMS(ESI)C 24 H 27 FN4O2Si[M+H] + Calculated value: 451.196, measured value: 451.1948.

[0473] 5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-2-[4-(trifluoromethoxy)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbol tree Thamide (XI)

[0474] [ka] 1 H NMR (500MHz, DMSO-d6) dppm-0.22--0.14 (m, 9H) 0.52-0.67 (m, 2H) 2.92-3.11 (m, 2H) 5.05 (s, 2H) 6.70 (dd, J=3.36, 1.98Hz, 1H) 6.82-6 .91(m, 1H)7.01(s, 1H)7.26(d, J=5.03Hz, 1H)7.43(m, 3H)7.53-7.58(m, 1H)7.59-7.66(m, 2H)8.27(d, J=4.88Hz, 1H)11.80(brs, 1H). LCMS:m / z517[M+H] + HRMS(ESI)C 25 H 27 F3N4O3Si[M+H] + Calculated value: 517.1878, measured value: 517.1857.

[0475] 2-(1-benzothiophen-3-yl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbol tree Thamide (XI)

[0476] [ka] 1 H NMR (500MHz, DMSO-d6) dppm-0.28--0.25 (m, 9H) 0.39-0.49 (m, 2H) 2.88 (dd, J=9.00, 7.78Hz, 2H )4.97(d, J=10.83Hz, 1H)5.22(d, J=10.83Hz, 1H)6.70(dd, J=3.43, 1.91Hz, 1H)6.78-6.86(m, 1 H)7.10(s, 1H)7.24(brs, 1H)7.29(d, J=5.03Hz, 1H)7.34-7.42(m, 2H)7.43-7.47(m, 1H)7.57(t , J=1.00Hz, 1H)7.93(s, 1H)8.04(m, J=7.09, 1.14Hz, 1H)8.27(d, J=5.03Hz, 1H)11.81(brs, 1H). LCMS:m / z489[M+H] + HRMS(ESI)C 26 H 28 N4O2SSi[M+H] + Calculated value: 489.1775, measured value: 489.1761.

[0477] 2-(2,3-dihydro-1,4-benzodioxin-6-yl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbol tree Thamide (XI)

[0478] [ka] 1H NMR(500MHz, DMSO-d6)dppm-0.17--0.12(m, 9H)0.61-0.70(m, 2H)3.03-3.13(m, 2H)4.21-4.34(m, 4H)5.04(s, 2H)6.68(dd, J=3.43, 1.91Hz, 1H)6.84 (brs, 1H)6.89-6.98(m, 3H)7.01(d, J=1.98Hz, 1H)7.06(brs, 1H)7.27(d, J =5.03Hz, 1H)7.54(t, J=1.00Hz, 1H)8.25(d, J=5.03Hz, 1H)11.77(brs, 1H). LCMS:m / z491[M+H] + HRMS(ESI)C 26 H 30 N4O4Si[M+H] + Calculated value: 491.2109, measured value: 491.2094.

[0479] 2-(4-fluoro-2-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbol tree Thamide (XI)

[0480] [ka] 1 H NMR(500MHz, DMSO-d6)dppm-0.22--0.19(m, 9H)0.54(t, J=8.39Hz, 2H)2.12(s, 3H)2.86-3 .01(m, 2H)4.88(d, J=10.83Hz, 1H)5.01(d, J=10.68Hz, 1H)6.63(dd, J=3.36, 1.98Hz, 1H)6. 79(brs, 1H)7.03(s, 1H)7.09(td, J=8.58, 2.82Hz, 1H)7.12-7.19(m, 2H)7.22(d, J=5.03Hz, 1H)7.32(dd, J=8.39, 6.10Hz, 1H)7.53-7.57(m, 1H)8.25(d, J=5.03Hz, 1H)11.79(brs, 1H). LCMS:m / z465[M+H] + HRMS(ESI)C 25 H 29FN4O2Si[M+H] + Calculated value: 465.2117, measured value: 465.2126.

[0481] 2-(2-fluoro-4-methylphenyl)-4-iodo-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carb tree Thamide (XI)

[0482] [ka] 1 H NMR (500MHz, DMSO-d6)dppm-0.27--0.23(m, 9H)0.36(t, J=7.70Hz, 2H)2.36-2.40(m, 3H)2.74-2.89(m, 2H)4.93(brs, 1H)6. 04-6.40 (m, 1H) 6.99 (d, J=4.88Hz, 2H) 7.07-7.21 (m, 3H) 7.43 (brs, 1H) 7.54-7.61 (m, 1H) 8.28-8.38 (m, 1H) 11.87 (brs, 1H). LCMS:m / z591[M+H] + HRMS(ESI)C 25 H 28 FIN4O2Si[M+H] + Calculated value: 591.1083, measured value: 591.1073.

[0483] 2-(2-fluoro-4-methylphenyl)-4-bromo-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carb tree Thamide (XI)

[0484] [ka] 1H NMR (500MHz, DMSO-d6) dppm-0.35--0.19(m, 9H) 0.37(t, J=7.78Hz, 2H) 2.38(s, 3H) 2.76-2.92(m, 2H) 4.90-5.23(m , 2H) 6.32 (brs, 1H) 6.84-7.25 (m, 4H) 7.43 (brs, 1H) 7.59 (t, J=2.97Hz, 1H) 8.33 (d, J=4.88Hz, 1H) 11.88 (brs, 1H). LCMS:m / z543[M+H] + HRMS(ESI)C 25 H 28 BrFN4O2Si[M+H] + Calculated value: 543.1222, measured value: 543.1221.

[0485] 4-Ethenyl-2-(2-fluoro-4-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbol tree Thamide (XIa)

[0486] [ka] 1 H NMR (500MHz, DMSO-d6) dppm-0.32--0.18 (m, 9H) 0.38 (brs, 2H) 2.33-2.42 (m, 3H) 2.72-2.91 (m, 2H) 4.90 (d, J=12.81Hz, 3H) 5.28 (d, J=17.69Hz) , 1H)6.22(brs, 1H)6.44(dd, J=17.77, 11.67Hz, 1H)7.01-7.29(m, 5H)7.44(t, J=7.85Hz, 1H)7.56(brs, 1H)8.26-8.39(m, 1H)11.84(brs, 1H). LCMS:m / z491[M+H] + HRMS(ESI)C 27 H 31 FN4O2Si[M+H] + Calculated value: 491.2273, measured value: 491.2267.

[0487] 2-(2-fluoro-4-methylphenyl)-4-(propa-1-en-2-yl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carb tree Thamide (XIa)

[0488] [ka] 1 H NMR (500MHz, DMSO-d6)dppm-0.23(s, 9H)0.38(t, J=8.31Hz, 2H)1.76(s, 3H)2.36-2.39(m, 3H)2.71-2.89(m, 2H)4.75(d, J=1.68Hz, 1H)4 .86(brs, 3H)6.22(brs, 1H)6.75(brs, 1H)6.93-7.06(m, 2H)7.07-7.17(m, 2H)7.37-7.66(m, 2H)8.25(d, J=4.88Hz, 1H)11.77(brs, 1H). LCMS:m / z505[M+H] + HRMS(ESI)C 28 H 33 FN4O2Si[M+H] + Calculated value: 505.243, measured value: 505.2415.

[0489] Conversion 3 2-(2-fluoro-4-methylphenyl)-4-(propan-2-yl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbol tree Thamide (XI)

[0490] [ka]

[0491] 2-(2-fluoro-4-methylphenyl)-4-(propa-1-en-2-yl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carb tree A solution of samide (1 equivalent, 50 mg, 0.1 mmol) in DCM / MeOH1 / 1 (2 mL) was pumped into an H-Cube(R) apparatus at a temperature of 60°C, a flow rate of 1 mL / min, and a pressure of 60 bar. The catalyst used was Pd / C10% packed in a CatCart(R). The product was isolated from 25 mL of the product solution and analyzed by HPLC. The solvent was removed, and the crude product was purified by flash chromatography (DCM / MeOH85 / 15) to obtain the title compound (white solid, 48 mg, Y=97%).

[0492] 1 H NMR (500MHz, DMSO-d6) dppm-0.23 (s, 9H) 0.29-0.40 (m, 2H) 1.12-1.22 (m, 6H) )2.36(s, 3H)2.75(brs, 2H)2.84(quintet, J=7.02Hz, 1H)4.64-5.02(m, 2H)6.19( brs, 1H)6.54-6.86(m, 1H)6.92(brs, 1H)6.99(d, J=4.88Hz, 1H)7.07-7.16(m , 2H)7.39(brs, 1H)7.51-7.57(m, 1H)8.29(d, J=4.73Hz, 1H)11.81(brs, 1H). LCMS:m / z507[M+H] + HRMS(ESI)C 28 H 35 FN4O2Si[M+H] + Calculated value: 507.2586, measured value: 507.2566.

[0493] The following compounds were obtained by the same procedure, except that suitable substituted starting materials were used.

[0494] 4-Ethyl-2-(2-fluoro-4-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbol treeThamide (XI)

[0495] [ka] 1 H NMR (500MHz, DMSO-d6) dppm - 0.24 (s, 9H) 0.37 (brs, 2H) 0.92 (t, J=7.40Hz, 3H) 2.37 (s, 4H) 2.70-2.91 (m, 2H) 4.87 (brs, 2H) 6.25 (brs, 1H) 6.64 (br s, 1H) 6.92 (brs, 1H) 7.03 (d, J=4.12Hz, 1H) 7.08-7.19 (m, 2H) 7.43 (t, J=7 .85Hz, 1H)7.53(t, J=2.90Hz, 1H)8.29(d, J=4.88Hz, 1H)11.80(brs, 1H). LCMS:m / z493[M+H] + HRMS(ESI)C 27 H 33 FN4O2Si[M+H] + Calculated value: 493.243, measured value: 493.2415.

[0496] Process 7 2-(3-chloro-2-fluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=3-chloro-2-fluorophenyl, R3=R4=R5=H] Compound 1

[0497] [ka]

[0498] 2-(3-chloro-2-fluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbol treeTo a solution of thamide (1 equivalent, 60 mg, 0.12 mmol) in DCM (2.6 mL), TFA (75 equivalents, 9.3 mmol, 711 μL) was added. The reaction mixture was stirred at room temperature for 5 hours. The solvent was removed under reduced pressure, and the crude product was treated three times with toluene. In the same reactor, 2-(3-chloro-2-fluorophenyl)-1-(hydroxymethyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carbone tree Thamide was dissolved in 95% EtOH (0.6 mL), and 30-32% ammonium hydroxide solution (0.3 mL) was added. The reaction mixture was stirred at room temperature for 2 hours, and precipitate formation was observed. The solid was filtered and rinsed three times with distilled water (CF3COO). - NH4 + The compound was washed three times with DCM / Et2O1 / 1 (to remove the residue) and then the title compound was obtained (pale yellow solid, 36 mg, Y=82%).

[0499] 1 1H NMR (500MHz, DMSO-d6) dppm 1 H NMR (500MHz, DMSO-d6) dppm6.84 (brs, 1H) 7.01 (dd, J=3.5, 2.0Hz, 1H) 7.28 (t, J=7.9Hz, 1H) 7.39 (d, J=5.2Hz, 1H) 7.43 (d, J=2.7Hz, 1 H)7.50-7.53(m, 1H)7.55-7.57(m, 1H)7.58-7.62(m, 1H)7.63(brs, 1H)8.20(d, J=5.0Hz, 1H)11.71(brs, 1H)12.03(d, J=1.8Hz, 1H). LCMS:m / z355[M+H] + HRMS(ESI)C 18 H 12 ClFN4O[M+H] + Calculated value: 355.0757, measured value: 355.0758.

[0500] The following compounds were obtained by performing the same procedure except for using suitably substituted starting materials.

[0501] 2-(4-chloro-2-fluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=4-chloro-2-fluorophenyl, R3=R4=R5=H] Compound 2

[0502] [ka] 1 H NMR (500MHz, DMSO-d6) dppm6.83 (brs, 1H) 7.00 (dd, J=3.5, 1.8Hz, 1H) 7.35 (dd, J=8.2, 2.0Hz, 1H) 7.38 (d, J=5.2Hz, 1H) 7.42 (d, J=2.6H) z, 1H)7.46-7.51(m, 1H)7.52-7.56(m, 1H)7.57-7.59(m, 1H)7.60(brs, 1H)8.20(d, J=5.0Hz, 1H)11.71(brs, 1H)11.98(d, J=2.0Hz, 1H). LCMS:m / z355[M+H] + HRMS(ESI)C 18 H 12 ClFN4O[M+H] + Calculated value: 355.0757, measured value: 355.0757.

[0503] 2-(2-chloro-4-fluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=2-chloro-4-fluorophenyl, R3=R4=R5=H] Compound 3

[0504] [ka] 1H NMR (500MHz, DMSO-d6) dppm6.76 (brs, 1H) 7.02 (dd, J=3.4, 1.9Hz, 1H) 7.28 (td, J=8.5, 2.7Hz, 1H) 7.37 (d, J=5 .2Hz, 1H)7.44(d, J=2.7Hz, 1H)7.49-7.57(m, 4H)8.17(d, J=5.0Hz, 1H)11.69(brs, 1H)11.96(d, J=2.1Hz, 1H). LCMS:m / z355[M+H] + HRMS(ESI)C 18 H 12 ClFN4O[M+H] + Calculated value: 355.0757, measured value: 355.0756.

[0505] 2-(2,4-difluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=2,4-difluorophenyl, R3=R4=R5=H] Compound 4

[0506] [ka] 1 H NMR (500MHz, DMSO-d6) dppm6.80 (brs, 1H) 7.01 (dd, J=3.6, 1.9Hz, 1H) 7.15 (td, J=8.5, 2.3Hz, 1H) 7.30 (td, J=9.8, 2.6Hz, 1H) 7.39 (d , J=5.2Hz, 1H)7.42(d, J=2.7Hz, 1H)7.53-7.56(m, 1H)7.56-7.62(m, 2H)8.19(d, J=5.0Hz, 1H)11.70(brs, 1H)11.96(d, J=1.8Hz, 1H). LCMS:m / z339[M+H] + HRMS(ESI)C 18 H 12 F2N4O[M+H] + Calculated value: 339.1052, measured value: 339.1048.

[0507] 2-[2-chloro-4-(trifluoromethyl)phenyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=2-chloro-4-(trifluoromethyl)phenyl, R3=R4=R5=H] Compound 5

[0508] [ka] 1 H NMR (500MHz, DMSO-d6) dppm6.80 (brs, 1H) 7.03 (dd, J=3.4, 1.8Hz, 1H) 7.36 (d, J=5.1Hz, 1H) 7.48 (d, J=2.4Hz, 1H)7 .54-7.57 (m, 1H) 7.61 (brs, 1H) 7.70-7.79 (m, 2H) 7.94 (s, 1H) 8.19 (d, J=5.0Hz, 1H) 11.69 (brs, 1H) 12.04 (brs, 1H). LCMS:m / z405[M+H] + HRMS(ESI)C 19 H 12 ClF3N4O[M+H] + Calculated value: 405.0725, measured value: 405.0724.

[0509] 2-(2,3-difluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=2,3-difluorophenyl, R3=R4=R5=H] compound 6

[0510] [ka] 1H NMR (500MHz, DMSO-d6) dppm6.81 (brs, 1H) 7.01 (dd, J=3.5, 1.8Hz, 1H) 7.21-7.30 (m, 1H) 7.33-7.4 9(m, 4H)7.55(t, J=3.1Hz, 1H)7.60(brs, 1H)8.20(d, J=5.0Hz, 1H)11.69(brs, 1H)12.01(brs, 1H). LCMS:m / z339[M+H] + HRMS(ESI)C 18 H 12 F2N4O[M+H] + Calculated value: 339.1052, measured value: 339.1046.

[0511] 2-(2,3-dichlorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=2,3-dichlorophenyl, R3=R4=R5=H] compound 7

[0512] [ka] 1 H NMR (500MHz, DMSO-d6) dppm6.78 (brs, 1H) 7.02 (dd, J=3.5, 2.0Hz, 1H) 7.36 (d, J=5.2Hz, 1H) 7.39-7.43 (m, 1H) 7.44-7.47 (m, 2H)7.54-7.56(m, 1H)7.57(brs, 1H)7.68(dd, J=7.9, 1.8Hz, 1H)8.18(d, J=5.2Hz, 1H)11.70(brs, 1H)12.01(d, J=1.8Hz, 1H). LCMS:m / z371[M+H] + HRMS(ESI)C 18 H 12 Cl2N4O[M+H] + Calculated value: 371.0461, measured value: 371.0463.

[0513] 2-[4-methyl-2-(trifluoromethyl)phenyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Thamide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=4-methyl-2-(trifluoromethyl)phenyl, R3=R4=R5=H] Compound 8

[0514] [ka] 1 H NMR (500MHz, DMSO-d6)dppm2.46(s, 3H)6.66(brs, 1H)7.01(dd, J=3.51, 1.83Hz, 1H)7.33(d, J=5.19Hz, 1H)7.39(d, J=7.78Hz, 2H)7. 42(d, J=2.75Hz, 1H)7.48-7.51(m, 1H)7.53-7.54(m, 1H)7.62(s, 1H)8.15(d, J=5.19Hz, 1H)11.67(brs, 1H)11.91(d, J=1.98Hz, 1H). LCMS:m / z385[M+H] + HRMS(ESI)C 20 H 15 F3N4O[M+H] + Calculated value: 385.1271, measured value: 385.1270.

[0515] 2-(2-chloro-4-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=2-chloro-4-methylphenyl, R3=R4=R5=H] compound 9

[0516] [ka] 1H NMR (500MHz, DMSO-d6) dppm2.35-2.40 (m, 3H) 6.68-6.78 (m, 1H) 7.01 (dd, J=3.5, 1.8Hz, 1H) 7.20 (dd, J=7.9, 0.8Hz, 1 H) 7.33-7.38 (m, 3H) 7.39-7.43 (m, 2H) 7.52-7.55 (m, 1H) 8.16 (d, J=5.2Hz, 1H) 11.67 (brs, 1H) 11.88 (d, J=1.8Hz, 1H). LCMS:m / z351[M+H] + HRMS(ESI)C 19 H 15 ClN4O[M+H] + Calculated value: 351.1007, measured value: 351.1008.

[0517] 2-(2,3-difluoro-4-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=2,3-difluoro-4-methylphenyl, R3=R4=R5=H] compound 10

[0518] [ka] 1 H NMR (500MHz, DMSO-d6) dppm2.32-2.36(m, 3H)6.82(brs, 1H)7.00(dd, J=3.4, 1.9Hz, 1H)7.12-7.16(m, 1H)7.22-7.26(m, 1H)7. 39(d, J=5.2Hz, 1H)7.41(d, J=2.6Hz, 1H)7.53-7.56(m, 1H)7.59(brs, 1H)8.20(d, J=5.2Hz, 1H)11.70(brs, 1H)11.97(brs, 1H). LCMS:m / z353[M+H] + HRMS(ESI)C 19 H 14 F2N4O[M+H] + Calculated value: 353.1209, measured value: 353.121.

[0519] 2-[2-methyl-4-(trifluoromethyl)phenyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Thamide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=2-methyl-4-(trifluoromethyl)phenyl, R3=R4=R5=H] Compound 11

[0520] [ka] 1 H NMR (500MHz, DMSO-d6) dppm2.28(s, 3H) 6.80(brs, 1H) 7.03(dd, J=3.5, 2.0Hz, 1H) 7.38(d, J=5.2Hz, 1H) 7.47-7.49( m, 1H) 7.50-7.53 (m, 1H) 7.53-7.60 (m, 3H) 7.66 (s, 1H) 8.17 (d, J=5.2Hz, 1H) 11.68 (brs, 1H) 11.90 (d, J=2.1Hz, 1H). LCMS:m / z385[M+H] + HRMS(ESI)C 20 H 15 F3N4O[M+H] + Calculated value: 385.1271, measured value: 385.127.

[0521] 2-(2-fluoro-3-methoxyphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=2-fluoro-3-methoxyphenyl, R3=R4=R5=H] Compound 12

[0522] [ka] 1H NMR (500MHz, DMSO-d6) dppm3.87 (s, 3H) 6.77 (brs, 1H) 7.00 (dd, J=3.5, 1.8Hz, 1H) 7.03-7.08 (m, 1H) 7.13-7.21 (m, 2H)7.37-7.41(m, 2H)7.51(brs, 1H)7.53-7.55(m, 1H)8.18(d, J=5.0Hz, 1H)11.68(brs, 1H)11.93(d, J=2.0Hz, 1H). LCMS:m / z351[M+H] + HRMS(ESI)C 19 H 15 FN4O2[M+H] + Calculated value: 351.1252, measured value: 351.1252.

[0523] 2-(2-chloro-3-fluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=2-chloro-3-fluorophenyl, R3=R4=R5=H] Compound 13

[0524] [ka] 1 H NMR (500MHz, DMSO-d6) dppm6.79 (brs, 1H) 7.03 (dd, J=3.4, 1.9Hz, 1H) 7.32-7.36 (m, 1H) 7.38 (d, J=5 .2Hz, 1H)7.41-7.48(m, 3H)7.53-7.62(m, 2H)8.18(d, J=5.2Hz, 1H)11.72(brs, 1H)12.02(brs, 1H). LCMS:m / z355[M+H] + HRMS(ESI)C 18 H 12 ClFN4O[M+H] + Calculated value: 355.0757, measured value: 355.0755.

[0525] 2-(2-fluoro-3-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrrole-3-carb treeThamide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=2-fluoro-3-methylphenyl, R3=R4=R5=H] Compound 14

[0526] [ka] 1 H NMR (500MHz, DMSO-d6) dppm2.28 (d, J=0.9Hz, 3H) 6.76 (brs, 1H) 7.00 (dd, J=3.4, 1.9Hz, 1H) 7.11-7.16 (m, 1H) 7.32 (dt, J= 19.9, 7.2Hz, 2H) 7.38-7.42 (m, 2H) 7.50 (brs, 0H) 7.53-7.56 (m, 1H) 8.18 (d, J=5.0Hz, 1H) 11.68 (brs, 1H) 11.90 (brs, 1H). LCMS:m / z335[M+H] + HRMS(ESI)C 19 H 15 FN4O[M+H] + Calculated value: 335.1303, measured value: 335.1299.

[0527] 2-[2-methyl-3-(trifluoromethyl)phenyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Thamide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=2-methyl-3-(trifluoromethyl)phenyl, R3=R4=R5=H] Compound 15

[0528] [ka] 1 H NMR (500MHz, DMSO-d6) ppm2.27 (s, 3H) 6.90 (brs, 1H) 7.33 (brs, 1H) 7.44-7.50 (m, 1H) 7.61 (d, J=7.47H) z, 1H) 7.69 (d, J=5.80Hz, 2H) 7.74-7.86 (m, 3H) 8.37 (d, J=6.10Hz, 1H) 12.34 (brs, 1H) 12.56 (brs, 1H). LCMS:m / z385[M+H] +HRMS(ESI)C 20 H 15 F3N4O[M+H] + Calculated value: 385.1271, measured value: 385.1276.

[0529] 2-[4-Methoxy-2-(trifluoromethyl)phenyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=4-methoxy-2-(trifluoromethyl)phenyl, R3=R4=R5=H] Compound 16

[0530] [ka] 1 H NMR (500MHz, DMSO-d6) dppm3.89 (s, 3H) 6.65 (brs, 1H) 7.01 (dd, J=3.43, 1.91Hz, 1H) 7.24-7.30 (m, 2H) 7.33 (d, J =5.03Hz, 2H)7.40-7.45(m, 2H)7.52-7.55(m, 1H)8.15(d, J=5.03Hz, 1H)11.66(brs, 1H)11.89(d, J=2.29Hz, 1H). LCMS:m / z401[M+H] + HRMS(ESI)C 20 H 15 F3N4O2[M+H] + Calculated value: 401.122, measured value: 401.1208.

[0531] 2-[2-chloro-4-(difluoromethoxy)phenyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=2-chloro-4-(difluoromethoxy)phenyl, R3=R4=R5=H] Compound 17

[0532] [ka] 1H NMR (500MHz, DMSO-d6) dppm3.89 (s, 3H) 6.65 (brs, 1H) 7.01 (dd, J=3.43, 1.91Hz, 1H) 7.24-7.30 (m, 2H) 7.33 (d, J =5.03Hz, 2H)7.40-7.45(m, 2H)7.52-7.55(m, 3H)8.15(d, J=5.03Hz, 1H)11.66(brs, 1H)11.89(d, J=2.29Hz, 1H). LCMS:m / z403[M+H] + HRMS(ESI)C 19 H 13 ClF2N4O2[M+H] + Calculated value: 403.07679, measured value: 403.0769.

[0533] 2-(3,4-dichlorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=3,4-dichlorophenyl, R3=R4=R5=H] Compound 18

[0534] [ka] 1 H NMR (500MHz, DMSO-d6) dppm6.92-7.04(m, 2H) 7.36(d, J=2.59Hz, 1H) 7.47(d, J=5.03Hz, 1H) 7.52-7.57(m, 1 H)7.64-7.75(m, 3H)8.00(d, J=1.98Hz, 1H)8.22(d, J=5.03Hz, 1H)11.71(brs, 1H)11.88(d, J=1.83Hz, 1H). LCMS:m / z371[M+H] + HRMS(ESI)C 18 H 12 Cl2N4O[M+H] + Calculated value: 371.0461, measured value: 371.0458.

[0535] 2-(3,4-difluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb treeSamide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=3,4-difluorophenyl, R3=R4=R5=H] Compound 19

[0536] [ka] 1 H NMR (500MHz, DMSO-d6) dppm6.88-7.03 (m, 2H) 7.35 (d, J=2.59Hz, 1H) 7.43-7.61 (m, 4H) 7.66 (brs, 1H)7.83(ddd, J=12.32, 8.12, 1.98Hz, 1H)8.21(d, J=5.03Hz, 1H)11.46-11.96(m, 2H). LCMS:m / z339[M+H] + HRMS(ESI)C 18 H 12 F2N4O[M+H] + Calculated value: 339.1052, measured value: 339.1049.

[0537] 2-(3-ethoxy-2-fluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=3-ethoxy-2-fluorophenyl, R3=R4=R5=H] compound 20

[0538] [ka] 1 H NMR (500MHz, DMSO-d6) dppm 1.38 (t, J=7.02Hz, 3H) 4.13 (q, J=7.02Hz, 2H) 6.77 (brs, 1H) 7.00 (dd, J=3.51, 1.98Hz, 1H )7.03-7.09(m, 1H)7.11-7.20(m, 2H)7.36-7.44(m, 2H)7.46-7.58(m, 2H)8.18(d, J=5.03Hz, 1H)11.36-12.12(m, 2H). LCMS:m / z365[M+H] + HRMS(ESI)C 20 H 17FN4O2[M+H] + Calculated value: 365.1409, measured value: 365.141.

[0539] 2-(4-methyl-3-nitrophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Thamide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=4-methyl-3-nitrophenyl, R3=R4=R5=H] Compound 21

[0540] [ka] 1 H NMR (500MHz, DMSO-d6) dppm2.57 (s, 3H) 6.96 (brs, 1H) 7.00 (brs, 1H) 7.39 (d, J=2.59Hz, 1H) 7.47 (d, J=5.19Hz, 1H) 7.50-7 .57(m, 2H)7.72(brs, 1H)7.97(dd, J=7.85, 1.75Hz, 1H)8.22(d, J=5.19Hz, 1H)8.37(d, J=1.83Hz, 1H)11.43-12.13(m, 2H). LCMS:m / z362[M+H] + HRMS(ESI)C 19 H 15 N5O3[M+H] + Calculated value: 362.1248, measured value: 362.1241.

[0541] 2-(3-carbamoyl-4-fluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=3-carbamoyl-4-fluorophenyl, R3=R4=R5=H] Compound 22

[0542] [ka] 1H NMR (500MHz, DMSO-d6) dppm6.87 (brs, 1H) 7.01 (dd, J=3.36, 1.83Hz, 1H) 7.31 (dd, J=10.37, 8.69Hz, 1H) 7.37 (d, J=2.44Hz, 1H) 7.41-7.51 (m, 1H) 7.52-7 .57(m, 1H)7.59-7.78(m, 1H)7.85(ddd, J=8.46, 4.88, 2.36Hz, 1H)7.96(dd, J=7.02, 2.29Hz, 1H) 8.21(d, J=5.19Hz, 1H) 11.71(brs, 1H) 11.84(brs, 1H). LCMS:m / z364[M+H] + HRMS(ESI)C 19 H 14 FN5O2[M+H] + Calculated value: 364.1205, measured value: 364.1204.

[0543] 2-(2-fluoro-4-methylphenyl)-N-[2-(pyrrolidin-1-yl)ethyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=2-fluoro-4-methylphenyl, R3=N-2-(pyrrolidine-1-yl)ethyl, R4=R5=H] Compound 23

[0544] [ka]

[0545] The compound was isolated as a TFA salt. 1H NMR (500MHz, DMSO-d6) dppm 1.78-1.91 (m, 2H) 1.93-2.06 (m, 2H) 2.37-2.40 (m, 3H) )2.97-3.10(m, 2H)3.23-3.31(m, 2H)3.47-3.55(m, 1H)3.56-3.65(m, 2H)6.94-6 .98(m, 1H)7.04-7.11(m, 2H)7.38-7.47(m, 3H)7.57-7.60(m, 1H)8.17-8.23(m, 1 H)8.24-8.31(m, 1H)9.25-9.63(m, 1H)11.67-11.83(m, 1H)11.99-12.09(m, 1H). LCMS:m / z432[M+H] + HRMS(ESI)C 25 H 26 FN5O[M+H] + Calculated value: 432.2194, measured value: 432.2197.

[0546] N-[2-(dimethylamino)ethyl]-2-(2-fluoro-4-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Thamide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=2-fluoro-4-methylphenyl, R3=N-2-(dimethylamino)ethyl, R4=R5=H] Compound 24

[0547] [ka]

[0548] The compound was isolated as a TFA salt. 1H NMR (500MHz, DMSO-d6) dppm 2.37-2.41 (m, 3H) 2.78-2.88 (m, 6H) 3.17-3.24 (m, 2H) 3.46-3.56 (m, 2H) 6.92-6.98 (m, 1H) 7.05-7 .13(m, 2H)7.38-7.46(m, 3H)7.55-7.61(m, 1H)8.13-8.24(m, 1H)8.25-8.32(m, 1H)11.59-11.85(m, 1H)11.95-12.12(m, 1H). LCMS:m / z406[M+H] + HRMS(ESI)C 23 H 24 FN5O[M+H] + Calculated value: 406.2038, measured value: 406.2036.

[0549] 2-(2-fluoro-4-methylphenyl)-N-[2-(morpholine-4-yl)ethyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=2-fluoro-4-methylphenyl, R3=N-2-(morpholine-4-yl)ethyl, R4=R5=H] Compound 25

[0550] [ka] 1 H NMR (500MHz, DMSO-d6) dppm2.37-2.39(m, 3H)2.9-4.02(m, 12H)6.95(dd, J=3.43, 1.91Hz, 1H)7.04 -7.12(m, 2H)7.32-7.47(m, 2H)7.57(t, J=2.82Hz, 1H)8.20(d, J=5.03Hz, 1H)11.47-12.21(m, 2H). LCMS:m / z448[M+H] + HRMS(ESI)C 25 H 26 FN5O2[M+H] + Calculated value: 448.2144, measured value: 448.2132.

[0551] N-[(1S,2R)-2-aminocyclohexyl]-2-(2-fluoro-4-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=2-fluoro-4-methylphenyl, R3=N-(1S,2R)-2-aminocyclohexyl, R4=R5=H] Compound 26

[0552] [ka]

[0553] The compound was isolated as a TFA salt. 1 H NMR (500MHz, DMSO-d6) dppm 1.30-1.45 (m, 2H) 1.48-1.78 (m, 6H) 2.38 (s, 3H) 4.23 (brs, 1H) 6.98 (dd, J=3.43, 1.91Hz, 1H) 7.06-7.15 (m, 2H) )7.40(d, J=5.19Hz, 1H)7.42-7.49(m, 3H)7.55-7.62(m, 1H)7.71(brs, 2H)8.21(d, J=5.19Hz, 1H)11.74(brs, 1H)11.98(d, J=2.14Hz, 1H). LCMS:m / z432[M+H] + HRMS(ESI)C 25 H 26 FN5O[M+H] + Calculated value: 432.2194, measured value: 432.2189.

[0554] 2-(2-fluoro-4-methylphenyl)-N-(furan-2-ylmethyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Thamide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=2-fluoro-4-methylphenyl, R3=N-(furan-2-ylmethyl), R4=R5=H] Compound 27

[0555] [ka] 1 H NMR (500MHz, DMSO-d6) dppm2.38 (s, 1H) 4.38 (d, J=5.80Hz, 1H) 6.20-6.25 (m, 1H) 6.39 (dd, J=3.13, 1.91Hz, 1H) 7.03 -7.11(m, 1H)7.37-7.47(m, 1H)7.55-7.60(m, 1H)8.22(d, J=5.34Hz, 1H)8.50(t, J=5.87Hz, 1H)11.64-12.14(m, 1H). LCMS:m / z415[M+H] + HRMS(ESI)C 24 H 19 FN4O2[M+H] + Calculated value: 415.1565, measured value: 415.1569.

[0556] N-(fluoroethyl)-2-(2-fluoro-4-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Thamide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=2-fluoro-4-methylphenyl, R3=N-(fluoroethyl), R4=R5=H] Compound 28

[0557] [ka] 1 H NMR (500MHz, DMSO-d6) dppm2.36-2.40 (m, 3H) 3.41-3.54 (m, 2H) 4.38-4.58 (m, 2H) 7.00 (dd, J=3.51, 1.83Hz, 1H) 7.04 -7.10 (m, 2H) 7.38-7.44 (m, 3H) 7.54-7.56 (m, 1H) 8.19 (d, J=5.19Hz, 1H) 8.24 (t, J=5.64Hz, 1H) 11.53-12.04 (m, 2H). LCMS:m / z381[M+H] + HRMS(ESI)C 21 H 18 F2N4O[M+H] + Calculated value: 381.1522, measured value: 381.1518.

[0558] 2-(2-fluoro-4-methylphenyl)-N-[2-(methylamino)ethyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=2-fluoro-4-methylphenyl, R3=N-(2-(methylamino)ethyl, R4=R5=H] Compound 29

[0559] [ka] 1 H NMR (500MHz, DMSO-d6) dppm2.37-2.40(m, 3H)2.58(s, 3H)3.04(t, J=5.95Hz, 2H)3.45(q, J=6.00Hz, 2H)6.96(dd, J=3.43, 1.91Hz, 1H)7 .04-7.11(m, 2H)7.37-7.46(m, 3H)7.55-7.60(m, 1H)8.20(d, J=5.03Hz, 1H)8.26(t, J=5.64Hz, 1H)8.33(brs, 1H)11.51-12.14(m, 2H). LCMS:m / z392[M+H] + HRMS(ESI)C 22 H 22 FN5O[M+H] + Calculated value: 392.1881, measured value: 392.1878.

[0560] 2-(2-fluoro-4-methylphenyl)-N-(1-methylpiperidine-4-yl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=2-fluoro-4-methylphenyl, R3=N-(1-methylpiperidine-4-yl), R4=R5=H] compound 30

[0561] [ka] 1H NMR (500MHz, DMSO-d6) dppm1.45-1.59 (m, 2H) 1.72 (d, J=10.37Hz, 2H) 1.90 (t, J =11.21Hz, 2H)2.15(s, 3H)2.35-2.39(m, 3H)2.74(d, J=11.13Hz, 2H)3.56-3.68 (m, 1H)7.00(dd, J=3.51, 1.98Hz, 1H)7.04-7.10(m, 2H)7.31-7.43(m, 3H)7.52- 7.58(m, 1H)7.70(d, J=7.93Hz, 1H)8.18(d, J=5.03Hz, 1H)11.53-12.01(m, 2H). LCMS:m / z432[M+H] + HRMS(ESI)C 25 H 26 FN5O[M+H] + Calculated value: 432.2194, measured value: 432.2186.

[0562] 2-(dibenzo[b,d]thiophene-4-yl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carbol tree Samide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=dibenzo[b,d]thiophene-4-yl, R3=R4=R5=H] compound 31

[0563] [ka] 1 H NMR (500MHz, DMSO-d6) dppm6.81 (brs, 1H) 7.07 (dd, J=3.51, 1.83Hz, 1H) 7.43 (d, J=5.19Hz, 1H) 7.46-7.55 (m, 3H) 7.56-7.58 (m, 1H)7.59-7.64(m, 1H)7.96-8.02(m, 1H)8.19(d, J=5.19Hz, 1H)8.36-8.46(m, 2H)11.71(brs, 1H)12.13(d, J=1.83Hz, 1H). LCMS:m / z409[M+H] + HRMS(ESI)C 24 H 16 N4OS[M+H] + Calculated value: 409.1118, measured value: 409.1119.

[0564] 2-(4-methylnaphthalene-1-yl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carbol tree Samide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=4-methylnaphthalene-1-yl, R3=R4=R5=H] compound 32

[0565] [ka] 1 H NMR (500MHz, DMSO-d6) dppm2.73 (s, 3H) 6.68 (brs, 1H) 7.05 (dd, J=3.43, 1.91Hz, 1H) 7.23 (brs, 1H) 7.40 (d, J=5.19Hz, 1H) 7.43-7.48 (m, 3H)7 .51(d, J=2.75Hz, 1H)7.54-7.61(m, 2H)7.66(d, J=8.24Hz, 1H)8.09(d, J=8.39Hz, 1H)8.14(d, J=5.03Hz, 1H)11.68(brs, 1H)11.98(brs, 1H). LCMS:m / z367[M+H] + HRMS(ESI)C 23 H 18 N4O[M+H] + Calculated value: 367.1554, measured value: 367.1545.

[0566] 2-(3-fluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrrole-3-carb tree Samide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=3-fluorophenyl, R3=R4=R5=H] compound 33

[0567] [ka] 1H NMR (500MHz, DMSO-d6) dppm6.92 (brs, 1H) 7.00 (dd, J=3.51, 1.83Hz, 1H) 7.14-7.23 (m, 1H) 7.34 (d, J=2.59Hz, 1 H)7.41-7.50(m, 1H)7.52-7.61(m, 3H)7.62-7.66(m, 1H)8.21(d, J=5.19Hz, 1H)11.70(brs, 1H)11.81(brs, 1H). LCMS:m / z321[M+H] + HRMS(ESI)C 18 H 13 FN4O[M+H] + Calculated value: 321.1146, measured value: 321.1143.

[0568] 5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-2-[4-(trifluoromethoxy)phenyl]-1H-pyrrole-3-carb tree Samide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=4-(trifluoromethoxy)phenyl, R3=R4=R5=H] Compound 34

[0569] [ka] 1 H NMR (500MHz, DMSO-d6) dppm6.89 (brs, 1H) 7.01 (dd, J=3.51, 1.83Hz, 1H) 7.37 (d, J=2.59Hz, 1H) 7.41 (d, J=8.24Hz, 1H) 7.46 (d, J =5.19Hz, 1H)7.51-7.57(m, 1H)7.64(brs, 1H)7.77-7.85(m, 1H)8.20(d, J=5.03Hz, 1H)11.69(brs, 1H)11.83(d, J=1.98Hz, 1H). LCMS:m / z387[M+H] + HRMS(ESI)C 19 H 13 F3N4O2[M+H] + Calculated value: 387.1064, measured value: 387.106.

[0570] 2-(1-benzothiophen-3-yl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=1-benzothiophen-3-yl, R3=R4=R5=H] compound 35

[0571] [ka] 1 H NMR (500MHz, DMSO-d6) dppm 6.79-6.82 (m, 1H) 7.03-7.05 (m, 1H) 7.37-7.41 (m, 1H) 7.43-7.45 (m, 1H) 7.47-7.49 (m, 1H) 7.54-7 .57(m, 1H)7.58-7.61(m, 1H)7.90-7.92(m, 1H)8.03-8.06(m, 1H)8.16-8.20(m, 1H)11.66-11.71(m, 1H)11.97-12.02(m, 1H). LCMS:m / z359[M+H] + HRMS(ESI)C 20 H 14 N4OS[M+H] + Calculated value: 359.0961, measured value: 359.0962.

[0572] 2-(2,3-dihydro-1,4-benzodioxin-6-yl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carbol tree Samide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=2,3-dihydro-1,4-benzodioxin-6-yl, R3=R4=R5=H] compound 36

[0573] [ka] 1H NMR (500MHz, DMSO-d6) dppm4.28 (s, 4H) 6.81 (brs, 1H) 6.88 (d, J=8.39Hz, 1H) 6.97 (dd, J=3.51, 1.83Hz, 1H) 7.18 (dd, J=8.39, 2.14Hz, 1H)7.24(d, J=2.14Hz, 1H)7.27(d, J=2.74Hz, 1H)7.46(d, J=5.19Hz, 1H)7.51-7.52(m, 1H)8.18(d, J=5.03Hz, 1H)11.58-11.67(m, 2H). LCMS:m / z361[M+H] + HRMS(ESI)C 20 H 16 N4O3[M+H] + Calculated value: 361.1295, measured value: 361.1295.

[0574] 2-(4-fluoro-2-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Thamide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=4-fluoro-2-methylphenyl, R3=R4=R5=H] Compound 37

[0575] [ka] 1 H NMR (500MHz, DMSO-d6) dppm2.20(s, 3H) 6.73(brs, 1H) 7.01(dd, J=3.51, 1.98Hz, 1H) 7.06(d, J=2.75Hz, 1H) 7.15(dd, J=10.22, 2.75Hz, 1H) 7.33(d d, J=8.46, 6.18Hz, 1H)7.36-7.40(m, 1H)7.43(d, J=2.59Hz, 1H)7.52-7. 54(m, 1H)8.15(d, J=5.19Hz, 1H)11.66(brs, 1H)11.81(d, J=1.98Hz, 1H). LCMS:m / z335[M+H] + HRMS(ESI)C 19 H 15 FN4O[M+H] + Calculated value: 335.1303, measured value: 335.13.

[0576] 2-(2-fluoro-4-methylphenyl)-4-iodo-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide(I)[R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=2-fluoro-4-methylphenyl, R3=R4=H, R5=iodine] Compound 38

[0577] [ka] 1 H NMR (500MHz, DMSO-d6) dppm2.35 (s, 3H) 6.54 (dd, J=3.43, 1.91Hz, 1H) 7.07 (d, J=7.78Hz, 1H) 7.11 (d, J=11.44Hz, 1H) 7.17 (brs, 1H) 7.23 (brs, 1H) 7.26 (d, J=5.03Hz, 1H) 7.42 (t, J=7.85Hz, 1H) 7.51-7.60 (m, 1H) 8.29 (d, J=5.03Hz, 1H) 11.78 (brs, 1H) 11.99 (s, 1H). LCMS:m / z461[M+H] + HRMS(ESI)C 19 H 14 FIN4O[M+H] + Calculated value: 461.0269, measured value: 461.0263.

[0578] 2-(2-fluoro-4-methylphenyl)-4-bromo-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Thamide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=2-fluoro-4-methylphenyl, R3=R4=H, R5=bromo] compound 39

[0579] [ka] 1H NMR (500MHz, DMSO-d6) dppm2.36 (s, 3H) 6.58 (dd, J=3.43, 1.91Hz, 1H) 7.08 (d, J=7.78Hz, 1H) 7.12 (d, J=11.44Hz, 1H) 7.23 (brs, 1H) 7.25(d, J=4.88Hz, 1H)7.28(brs, 1H)7.44(t, J=7.85Hz, 1H)7.53-7.58(m, 1H)8.28(d, J=5.03Hz, 1H)11.79(brs, 1H)12.00(s, 1H). LCMS:m / z413[M+H] + HRMS(ESI)C 19 H 14 FBrN4O[M+H] + Calculated value: 413.0408, measured value: 413.0407.

[0580] 4-Ethyl-2-(2-fluoro-4-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Thamide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=4-fluoro-2-methylphenyl, R3=R4=R5=ethyl] compound 40

[0581] [ka] 1 H NMR (500MHz, DMSO-d6) dppm1.05(t, J=7.40Hz, 3H)2.35(s, 3H)2.71(q, J=7.37Hz, 2H)6.51(dd, J=3.43, 1.91Hz, 1H)6.95( s, 2H) 7.02-7.11 (m, 3H) 7.44 (t, J=7.93Hz, 1H) 7.50 (t, J=1.00Hz, 1H) 8.24 (d, J=4.88Hz, 1H) 11.28 (s, 1H) 11.70 (brs, 1H). LCMS:m / z363[M+H] + HRMS(ESI)C 21 H 19 FN4O[M+H] + Calculated value: 363.1616, measured value: 363.1601.

[0582] 2-(2-fluoro-4-methylphenyl)-4-(propan-2-yl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=4-fluoro-2-methylphenyl, R3=R4=H, R5=propan-2-yl] compound 41

[0583] [ka] 1 H NMR (500MHz, DMSO-d6) dppm1.31 (d, J=7.02Hz, 6H) 2.34 (s, 3H) 3.10 (spt, J=7.00Hz, 1H) 6.51 (dd, J=3.36, 1.98Hz, 1H )6.89-7.14(m, 5H)7.39(t, J=7.93Hz, 1H)7.51(t, J=2.90Hz, 1H)8.24(d, J=4.88Hz, 1H)11.18(s, 1H)11.71(brs, 1H). LCMS:m / z377[M+H] + HRMS(ESI)C 22 H 21 FN4O[M+H] + Calculated value: 377.1772, measured value: 377.1767.

[0584] Example B Process 8 2-(2,4-dichlorophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbonitrile(XIII)

[0585] [ka]

[0586] To a solution of 2-(2,4-dichlorophenyl)-1H-pyrrole-3-carbonitrile (1 eq., 1.0 g, 4.22 mmol) in anhydrous THF (20 mL) at T = 0°C was added 60% NaH in mineral oil (1.7 eq., 287 mg, 7.17 mmol). The reaction mixture was stirred at T = 0°C for 20 min, then SEMCl (1.8 eq., 1.35 mL, 7.59 mmol) was added. After 10 min at T = 0°C, the reaction solution was warmed to room temperature and stirred for 3 hours. Distilled water was added, and the product was extracted with DCM. The organic layer was washed with distilled water and brine, dried over anhydrous Na₂SO₄, evaporated to dryness. The crude product was purified by flash chromatography (hexane / AcOEt 9 / 1) to give the title compound (pale yellow oil, 1.45 g, Y = 94%).

[0587] 1 ¹H NMR (500 MHz, DMSO-d₆) δ ppm -0.13--0.06 (m, 9H) 0.65-0.75 (m, 2H) 3.19-3.31 (m, 2H) 5.01-5.07 (m, 1H) 5.19-5.22 (m, 1H) 6.64-6.69 (m, 1H) 7.24-7.29 (m, 1H) 7.54-7.57 (m, 1H) 7.59-7.62 (m, 1H) 7.87-7.90 (m, 1H). LCMS: m / z 367 [M+H] + . HRMS (ESI) C 17 H 21 Cl₂N₂OSi [M+H] + calcd: 367.0795, found: 367.08.

[0588] The following compound was obtained in the same manner, except that 2-(2-fluoro-4-methylphenyl)-1H-pyrrole-3-carbonitrile was used as the starting material.

[0589] 2-(2-fluoro-4-methylphenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbonitrile (XIII)

[0590]

Chemical Structure

[0591] 2-(2,4-dichlorophenyl)-1-(phenylsulfonyl)-1H-pyrrole-3-carbonitrili(XIII)

[0592] [ka]

[0593] To a solution of 2-(2,4-dichlorophenyl)-1H-pyrrole-3-carbonitrile (1 equivalent, 1.0 g, 4.22 mmol) in anhydrous DMF (10 mL), 60% NaH mineral oil (1.3 equivalents, 219 mg, 5.49 mmol) was added at T=0°C. The reaction mixture was stirred at T=0°C for 20 minutes, and benzenesulfonyl chloride (1.2 equivalents, 0.64 mL, 5.06 mmol) was added. The reaction mixture was stirred at T=0°C for 2.5 hours. Distilled water was added at T=0°C, and the product was extracted with AcOEt. The organic layer was washed with distilled water and brine, dehydrated with anhydrous Na2SO4, and removed by distillation to dryness. The crude product was purified by flash chromatography (hexane / AcOEt9 / 1-hexane / AcOEt8 / 2) to obtain the title compound (white solid, 1.32 g, Y=83%).

[0594] 1¹H NMR (500 MHz, DMSO-d₆) δ ppm 6.96 (d, J=3.51 Hz, 1H), 7.37 (d, J=8.24 Hz, 1H), 7.58 (dd, J=8.24, 2.14 Hz, 1H), 7.60-7.66 (m, 4H), 7.78 (d, J=2.13 Hz, 1H), 7.81 (tt, J=5.85, 2.76 Hz, 1H), 7.85 (d, J=3.51 Hz, 1H). LCMS: m / z 378 [M+H] + . HRMS (ESI) C 17 H 11 Cl₂N₂O₂S [M+H] + calculated value: 378.9732, found value: 378.9744.

[0595] Process 9 5-bromo-2-(2,4-dichlorophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbonitrile (XIV)

[0596]

Chemical Formula

[0597] To a solution of 2-(2,4-dichlorophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbonitrile (1 equivalent, 1.44 g, 3.93 mmol) in MeOH (20 mL) and THF (10 mL) at T=0°C was added 0.5 equivalents of N-bromosuccinimide (349.5 mg, 1.96 mmol). The reaction mixture was stirred at T=0°C for 30 minutes, then 0.5 equivalents of N-bromosuccinimide (349.5 mg, 1.96 mmol) was added. The reaction solution was stirred at T=0°C for 1 hour and 30 minutes. Distilled water was added, and the product was extracted 3 times with AcOEt. The organic layer was washed with brine, dehydrated over anhydrous Na₂SO₄, evaporated to dryness. The crude product was purified by flash chromatography (hexane / AcOEt 95 / 5) to give the title compound (clear-pale yellow oil, 1.44 g, Y=82%).

[0598] 1H NMR (500MHz, DMSO-d6) dppm-0.15--0.06(m, 9H) 0.69(t, J=8.16Hz, 2H) 3.17-3.32(m, 2H) 5.06( d, J=11.44Hz, 1H) 5.21 (d, J=11.44Hz, 1H) 6.96 (s, 1H) 7.59-7.67 (m, 2H) 7.92 (d, J=1.98Hz, 1H). LCMS:m / z444[M+H] + HRMS(ESI)C 17 H 20 BrCl2N2OSi[M+H] + Calculated value: 444.99, measured value: 444.9915.

[0599] The following compounds were obtained by following the same procedure, except that 2-(2-fluoro-4-methylphenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbonitrile was used as the starting material.

[0600] 5-Bromo-2-(2-fluoro-4-methylphenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbonitrile(XIV)

[0601] [ka] 1 H NMR (500MHz, DMSO-d6) dppm-0.13--0.09(m, 9H) 0.63-0.71(m, 2H) 2.41(s, 3H) 3.17-3.27(m , 2H) 5.18 (brs, 2H) 6.89-6.97 (m, 1H) 7.16-7.23 (m, 1H) 7.25-7.32 (m, 1H) 7.39-7.45 (m, 1H). LCMS:m / z409[M+H] + HRMS(ESI)C 18 H 23 BrFN2OSi[M+H] + Calculated value: 409.0742, measured value: 409.0743.

[0602] 5-Bromo-2-(2,4-dichlorophenyl)-1-(phenylsulfonyl)-1H-pyrrole-3-carbonitrile(XIV)

[0603] [ka] LCMS:m / z454[M+H] + HRMS(ESI)C 17 H 10 BrCl2N2O2S[M+H] + Calculated value: 454.9018, measured value: 454.9125.

[0604] Step 10 2-(2,4-dichlorophenyl)-5-(1H-pyrazole-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbonitrile(XV)

[0605] [ka]

[0606] In the reactor under an argon atmosphere, 5-bromo-2-(2,4-dichlorophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbonitrile (1 equivalent, 100 mg, 0.22 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (1.5 equivalents, 99 mg, 0.34 mmol), Na2CO3 (3 equivalents, 71 mg, 0.67 mmol), degassed 1,4-dioxane (4 mL), and degassed distilled water (1 mL) were added. After 3 cycles of vacuum / argon, the catalyst [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1:1) (0.1 equivalents, 18 mg, 0.022 mmol) was added. After three cycles of vacuum / argon chromatography, the reaction mixture was heated at T=100°C for 2 hours. Distilled water was added, and the product was extracted with AcOEt (three times). The organic layer was washed with distilled water and brine, dehydrated with anhydrous Na2SO4, and removed by distillation to dryness. The crude product was purified by flash chromatography (DCM / MeOH98 / 2) to obtain the title compound (yellow solid, 43 mg, Y=45%).

[0607] 1 H NMR (401MHz, DMSO-d6) dppm-0.12(s, 9H) 0.65(t, J=8.30Hz, 2H) 1.28-1.28(m, 1H) 3.10-3.21(m, 2H) 4.99(d, J=11.35Hz, 1 H)5.21(d, J=11.35Hz, 1H)6.78(s, 1H)7.59-7.63(m, 1H)7.63-7.67(m, 1H)7.78(s, 1H)7.91(d, J=1.71Hz, 1H)8.02(s, 1H). LCMS:m / z433[M+H] + HRMS(ESI)C 20 H 23 Cl2N4OSi[M+H] + Calculated value: 433.1013, measured value: 433.1014.

[0608] The following compounds were obtained by performing the same procedure except for using suitably substituted starting materials.

[0609] 2-(2,4-dichlorophenyl)-5-(3-methyl-1H-pyrazole-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbonitrile(XV)

[0610] [ka] 1 H NMR (500MHz, DMSO-d6) dppm - 0.13 (s, 9H) 0.61 (t, J=8.31Hz, 2H) 2.15-2.29 (m, 3H) 3.07 (q, J=7.83Hz, 2H) 4.91 (d, J =11.29Hz, 1H)5.09(d, J=10.98Hz, 1H)6.61-6.72(m, 1H)7.57-7.68(m, 3H)7.84-7.96(m, 2H)12.72-12.97(m, 1H). LCMS:m / z447[M+H] + HRMS(ESI)C 21 H 25 Cl2N4OSi[M+H] + Calculated value: 447.1169, measured value: 447.1173.

[0611] 5-(2-amino-1,3-thiazole-4-yl)-2-(2,4-dichlorophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbonitrile(XV)

[0612] [ka] LCMS:m / z465[M+H] + HRMS(ESI)C 20 H 23 Cl2N4OSSi[M+H] + Calculated value: 465.0733, measured value: 465.0764.

[0613] 2-(2,4-dichlorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbonitrile(XV)

[0614] [ka] LCMS:m / z483[M+H] + HRMS(ESI)C 24 H 25 Cl2N4OSi[M+H] + Calculated value: 483.1169, measured value: 483.1185.

[0615] 2-(2,4-dichlorophenyl)-5-(1H-pyrazolo[3,4-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbonitrile(XV)

[0616] [ka] LCMS:m / z484[M+H] + HRMS(ESI)C 23 H 24 Cl2N5OSi[M+H] + Calculated value: 484.1122, measured value: 484.1157.

[0617] 2-(2,4-dichlorophenyl)-5-[3-(trifluoromethyl)-1H-pyrazole-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbonitrile(XV)

[0618] [ka] LCMS:m / z501[M+H] + HRMS(ESI)C 21 H 22 Cl2F3N4OSi[M+H] + Calculated value: 501.0887, measured value: 501.0894.

[0619] The following compounds were obtained by following the same procedure, except that 5-bromo-2-(2,4-dichlorophenyl)-1-(phenylsulfonyl)-1H-pyrrole-3-carbonitrile was used as the starting material.

[0620] 5-(6-aminopyrimidine-4-yl)-2-(2,4-dichlorophenyl)-1-(phenylsulfonyl)-1H-pyrrole-3-carbonitrile(XV)

[0621] [ka] 1 H NMR (500MHz, DMSO-d6) dppm6.60 (d, J=0.91Hz, 1H) 7.12 (s, 1H) 7.14 (brs, 1H) 7.41 (d, J=8.24Hz, 1H) 7.56 (dd, J=8.31, 2.06H z, 1H)7.58-7.63(m, 2H)7.76(dd, J=8.46, 0.99Hz, 2H)7.78(d, J=1.98Hz, 1H)7.80(t, J=7.50Hz, 0H)8.40(d, J=0.92Hz, 1H). LCMS:m / z470[M+H] + HRMS(ESI)C 21 H 14 Cl2N5O2S[M+H] + Calculated value: 470.0240, measured value: 470.0256.

[0622] The following compounds were obtained by following the same procedure, except that 5-bromo-2-(2-fluoro-4-methylphenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbonitrile was used as the starting material.

[0623] 2-(2-fluoro-4-methylphenyl)-5-(1H-pyrazole-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbonitrile(XV)

[0624] [ka] 1 H NMR(500MHz, DMSO-d6)dppm-0.15--0.12(m, 9H)0.59-0.69(m, 2H)2.41(s, 3H)3.09-3.19(m, 2H)5.14(brs, 2H)6.76( s, 1H) 7.22 (d, J = 8.24Hz, 1H) 7.29 (d, J = 10.83Hz, 1H) 7.43 (t, J = 7.85Hz, 1H) 7.77 (s, 1H) 8.01 (s, 1H) 13.14 (brs, 1H). LCMS:m / z397[M+H] + HRMS(ESI)C 21 H 26 FN4OSi[M+H] + Calculated value: 397.1855, measured value: 397.1857.

[0625] 5-(3,5-dimethyl-1H-pyrazole-4-yl)-2-(2-fluoro-4-methylphenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbonitrile(XV)

[0626] [ka] 1 H NMR (500MHz, DMSO-d6) dppm-0.16 (s, 9H) 0.46-0.58 (m, 2H) 2.02 (s, 3H) 2.10 (s, 3H) 2.41 (s, 3H) 2.86-3.00 (m, 2 H) 4.93(s, 2H) 6.56(s, 1H) 7.20(d, J=7.63Hz, 1H) 7.26(d, J=10.98Hz, 1H) 7.46(t, J=7.78Hz, 1H) 12.50(s, 1H). LCMS:m / z425[M+H] + HRMS(ESI)C 23 H 30 FN4OSi[M+H] + Calculated value: 425.2168, measured value: 425.2172.

[0627] 2-(2-fluoro-4-methylphenyl)-5-(1-methyl-1H-pyrazole-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbonitrile(XV)

[0628]

Chem.

[0629] 2-(2-Fluoro-4-methylphenyl)-5-(3-methyl-1H-pyrazol-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbonitrile (XV)

[0630]

Chem.

[0631] 2-(2-Fluoro-4-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbonitrile (XV)

[0632]

Chem.

[0633] Step 11 2-(2,4-dichlorophenyl)-5-(1H-pyrazole-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carb tree Samide (XVI)

[0634] [ka]

[0635] To a solution of 2-(2,4-dichlorophenyl)-5-(1H-pyrazole-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbonitrile (1 equivalent, 220 mg, 0.51 mmol) in toluene (7 mL), acetaldoxime (20 equivalents, 0.62 mL, 10.16 mmol) and InCl3 (0.1 equivalent, 11 mg, 0.051 mmol) were added. The reaction mixture was heated at T=100°C for 4 hours. Distilled water was added, and the product was extracted with AcOEt (3 times). The organic layer was washed with distilled water and brine, dehydrated with anhydrous Na2SO4, and removed by distillation to dryness. The crude product was purified by flash chromatography (DCM / MeOH95 / 5) to obtain the title compound (white solid, 106 g, Y=47%).

[0636] 1 H NMR (500MHz, DMSO-d6) dppm-0.14--0.10 (m, 8H) 0.59-0.69 (m, 2H) 3.05-3.17 (m, 2H) 4.81 (d, J=11.13Hz, 1H) 5.06 (d, J=11.29Hz, 1H) )6.71-6.76(m, 2H)7.18(brs, 1H)7.38-7.42(m, 1H)7.47-7.50(m, 2H)7.70(d, J=2.14Hz, 1H)7.92(d, J=4.27Hz, 1H)13.05(brs, 1H). LCMS:m / z451[M+H] + HRMS(ESI)C 20 H 25 Cl2N4O2Si[M+H] + Calculated value: 451.1119, measured value: 451.1119.

[0637] The following compounds were obtained by performing the same procedure except for using suitably substituted starting materials.

[0638] 2-(2,4-dichlorophenyl)-5-(3-methyl-1H-pyrazole-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carb tree Samide (XVI)

[0639] [ka] 1 H NMR (500MHz, DMSO-d6) dppm-0.22--0.04(m, 9H) 0.61(t, J=8.39Hz, 2H) 2.26(brs, 3H) 2.89-3.13(m, 2H) 4.73(d, J=10.98Hz, 1H) 4.95(d, J=10.98Hz, 1H)6.48-6.69(m, 1H)6.73(brs, 1H)7.22(brs, 1H)7.40(d, J=8.20Hz, 1H) 7.47(dd, J=8.20, 2.10Hz, 1H)7.68(d, J=2.14Hz, 1H)12.46-13.03(m, 1H). LCMS:m / z465[M+H] +HRMS(ESI)C 21 H 27 Cl2N4O2Si[M+H] + Calculated value: 465.1275, measured value: 465.1289.

[0640] 5-(2-amino-1,3-thiazole-4-yl)-2-(2,4-dichlorophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbonitrile(XVI)

[0641] [ka] LCMS:m / z483[M+H] + HRMS(ESI)C 20 H 24 Cl2N4O2SSi[M+H] + Calculated value: 483.0839, measured value: 483.0852.

[0642] 2-(2,4-dichlorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbol tree Samide (XVI)

[0643] [ka] LCMS:m / z501[M+H] + HRMS(ESI)C 24 H 27 Cl2N4O2Si[M+H] + Calculated value: 501.1275, measured value: 501.1268.

[0644] 2-(2,4-dichlorophenyl)-5-(1H-pyrazolo[3,4-b]pyridine-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbol tree Samide (XVI)

[0645] [ka] LCMS:m / z502[M+H] + HRMS(ESI)C 23 H 26 Cl2N5O2Si[M+H] + Calculated value: 502.1227, measured value: 502.1236.

[0646] 2-(2,4-dichlorophenyl)-5-[3-(trifluoromethyl)-1H-pyrazole-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carb tree Samide (XVI)

[0647] [ka] LCMS:m / z519[M+H] + HRMS(ESI)C 21 H 24 Cl2F3N4O2Si[M+H] + Calculated value: 519.0992, measured value: 519.0996.

[0648] 5-(6-aminopyrimidine-4-yl)-2-(2,4-dichlorophenyl)-1-(phenylsulfonyl)-1H-pyrrole-3-carb tree Samide (XVI)

[0649] [ka] LCMS:m / z488[M+H] + HRMS(ESI)C 21 H 16 Cl2N5O3S[M+H] + Calculated value: 488.0345, measured value: 488.0352.

[0650] 2-(2-fluoro-4-methylphenyl)-5-(1H-pyrazole-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carb tree Samide (XVI)

[0651] [ka] LCMS:m / z415[M+H] + HRMS(ESI)C 21 H 28 FN4O2Si[M+H] + Calculated value: 415.1960, measured value: 415.1975.

[0652] 5-(3,5-dimethyl-1H-pyrazole-4-yl)-2-(2-fluoro-4-methylphenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carb tree Samide (XVI)

[0653] [ka] 1 H NMR (500MHz, DMSO-d6) dppm-0.15 (s, 9H) 0.42-0.60 (m, 2H) 2.05 (brs, 6H) 2.36 (s, 3H) 2.89 (q, J=8.80Hz, 2H) 4.5 6-4.95 (m, 2H) 6.48 (s, 1H) 6.69 (brs, 1H) 7.02 (brs, 1H) 7.03-7.08 (m, 2H) 7.26 (t, J=7.85Hz, 1H) 12.38 (brs, 1H). LCMS:m / z443[M+H] + HRMS(ESI)C 23 H 32 FN4O2Si[M+H] + Calculated value: 443.2273, measured value: 443.2272.

[0654] 2-(2-fluoro-4-methylphenyl)-5-(1-methyl-1H-pyrazole-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carb tree Samide (XVI)

[0655] [ka] 1 H NMR(500MHz, DMSO-d6)dppm-0.12(s, 9H)0.64(t, J=8.31Hz, 2H)2.37(s, 3H)2.97-3.09(m, 1H)3.12(t, J=8.24Hz, 1H)3.88(s, 3H)4.80-4.98( m, 1H)4.98-5.18(m, 1H)6.68(s, 1H)6.70(brs, 1H)7.04(brs, 1H)7.05-7.11(m, 2H)7.23(t, J=7.85Hz, 1H)7.61(d, J=0.61Hz, 1H)7.86(s, 1H). LCMS:m / z429[M+H] + HRMS(ESI)C 22 H 30 FN4O2Si[M+H] + Calculated value: 429.2117, measured value: 429.2116.

[0656] 2-(2-fluoro-4-methylphenyl)-5-(3-methyl-1H-pyrazole-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carb tree Samide (XVI)

[0657] [ka] LCMS:m / z429[M+H] + HRMS(ESI)C 22 H 30 FN4O2Si[M+H] + Calculated value: 429.2117, measured value: 429.2116.

[0658] 2-(2-fluoro-4-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carbol tree Samide (XVI)

[0659] [ka] 1H NMR (500MHz, DMSO-d6)dppm-0.21--0.17(m, 9H)0.55(t, J=8.39Hz, 2H)2.38(s, 3H)2.87-3.10(m, 2H)4.95-5.22(m, 2H)6.66(brs, 0H)6 .80(brs, 1H)7.09(d, J=9.15Hz, 2H)7.24(d, J=5.03Hz, 1H)7.31-7.41(m, 2H)7.54-7.58(m, 1H)8.26(d, J=4.88Hz, 1H)11.80(brs, 1H). LCMS:m / z465[M+H] + HRMS(ESI)C 25 H 30 FN4O2Si[M+H] + Calculated value: 465.2117, measured value: 465.2132.

[0660] Step 12 5-(6-aminopyrimidine-4-yl)-2-(2,4-dichlorophenyl)-1H-pyrrole-3-carb tree Thamide [R1=6-aminopyrimidine-4-yl, R2=2,4-dichlorophenyl, R3=R4=R5=H] compound 42

[0661] [ka]

[0662] 5-(6-aminopyrimidine-4-yl)-2-(2,4-dichlorophenyl)-1-(phenylsulfonyl)-1H-pyrrole-3-carb tree To a solution of thamide (1 equivalent, 100 mg, 0.20 mmol) in THF (2.3 mL) and H2O (1.8 mL), LiOH (4 equivalents, 0.8 mmol, 33.5 mg) was added. The reaction mixture was stirred under reflux for 4 hours. The solvent was partially removed under reduced pressure, and HCl 2N was added to the mixture. The reaction mixture was stirred at room temperature for 30 minutes, and the title compound (white solid, 67 mg, Y=95%) was recovered by filtration.

[0663] 1H NMR (500MHz, DMSO-d6) dppm6.65 (s, 1H) 6.76 (brs, 1H) 6.91 (brs, 2H) 7.29 (s, 1H) 7 .35(brs, 1H)7.40-7.47(m, 2H)7.65(d, J=1.68Hz, 1H)8.34(s, 1H)12.09(brs, 1H). LCMS:m / z348[M+H] + HRMS(ESI)C 15 H 12 Cl2N5O[M+H] + Calculated value: 348.0414, measured value: 348.0424.

[0664] 2-(2,4-dichlorophenyl)-5-(1H-pyrazole-4-yl)-1H-pyrrole-3-carb tree Thamide [R1=1H-pyrazole-4-yl, R2=2,4-dichlorophenyl, R3=R4=R5=H] compound 43

[0665] [ka]

[0666] 2-(2,4-dichlorophenyl)-5-(1H-pyrazole-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carb tree To a solution of thamide (1 equivalent, 100 mg, 0.22 mmol) in DCM (4.9 mL), TFA (75 equivalents, 16.5 mmol, 1.26 mL) was added. The reaction mixture was stirred at room temperature for 5 hours. The solvent was removed under reduced pressure, and the crude product was treated three times with toluene. In the same reactor, 2-(2,4-dichlorophenyl)-1-(hydroxymethyl)-5-(1H-pyrazole-4-yl)-1H-pyrrole-3-carbone tree Samide was dissolved in 95% EtOH (8.5 mL), and 30-32% ammonium hydroxide solution (1.2 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the solid was boiled 5 times with distilled water (CF3COO). - NH4 +The compound was washed three times with DCM / Et2O1 / 1 (to remove the residue) to obtain the title compound (pale yellow solid, 31 mg, Y=44%).

[0667] 1 H NMR (500MHz, DMSO-d6) dppm6.65 (brs, 1H) 6.67 (d, J=2.6Hz, 1H) 7.09 (brs, 1H) 7.40-7.48 (m , 2H) 7.66 (dd, J=1.4, 0.8Hz, 1H) 7.73 (brs, 1H) 7.93 (brs, 1H) 11.46 (s, 1H) 12.84 (brs, 1H). LCMS:m / z321[M+H] + HRMS(ESI)C 14 H 11 Cl2N4O[M+H] + Calculated value: 321.0305, measured value: 321.0305.

[0668] The following compounds were obtained by performing the same procedure except for using suitably substituted starting materials.

[0669] 2-(2,4-dichlorophenyl)-5-(3-methyl-1H-pyrazole-4-yl)-1H-pyrrole-3-carb tree Thamide [R1=3-methyl-1H-pyrazole-4-yl, R2=2,4-dichlorophenyl, R3=R4=R5=H] Compound 44

[0670] [ka] 1 H NMR (500MHz, DMSO-d6) dppm 6.61 (brs, 1H) 6.64 (brs, 2H) 7.20 (brs, 1H) 7.44 (d, J=1.2Hz, 2H) 7.65 (s, 1H) 11.15-11.47 (m, 1H) 12.30-12.76 (m, 1H). LCMS:m / z335[M+H] + HRMS(ESI)C 15 H 13 Cl2N4O[M+H] + Calculated value: 335.0461, measured value: 335.0464.

[0671] 5-(2-amino-1,3-thiazole-4-yl)-2-(2,4-dichlorophenyl)-1H-pyrrole-3-carb tree Thamide [R1=2-amino-1,3-thiazole-4-yl, R2=2,4-dichlorophenyl, R3=R4=R5=H] Compound 45

[0672] [ka] 1 H NMR (500MHz, DMSO-d6) dppm6.70 (brs, 1H) 6.75 (s, 1H) 6.83 (d, J=2.59Hz, 1H) 7.19 ( brs, 1H)7.42-7.45(m, 1H)7.45-7.47(m, 1H)7.67(d, J=1.98Hz, 1H)11.70(brs, 1H). LCMS:m / z353[M+H] + HRMS(ESI)C 14 H 11 Cl2N4OS[M+H] + Calculated value: 353.0025, measured value: 353.0023.

[0673] 2-(2,4-dichlorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl, R2=2,4-dichlorophenyl, R3=R4=R5=H] Compound 46

[0674] [ka] 1 H NMR (500MHz, DMSO-d6) dppm6.78 (brs, 1H) 7.02 (dd, J=3.5, 1.8Hz, 1H) 7.36 (d, J=5.2Hz, 1H) 7.43-7.52 (m, 3H) 7.53 -7.59(m, 2H)7.70(d, J=2.0Hz, 1H)8.18(d, J=5.0Hz, 1H)9.50-9.51(m, 1H)11.69(brs, 1H)11.98(d, J=1.7Hz, 1H). LCMS:m / z371[M+H]+ HRMS(ESI)C 18 H 12 Cl2N4O[M+H] + Calculated value: 371.0461, measured value: 371.0462.

[0675] 2-(2,4-dichlorophenyl)-5-(1H-pyrazolo[3,4-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide [R1=1H-pyrazolo[3,4-b]pyridine-4-yl, R2=2,4-dichlorophenyl, R3=R4=R5=H] Compound 47

[0676] [ka] 1 H NMR (500MHz, DMSO-d6) dppm6.88 (brs, 1H) 7.46 (d, J=4.9Hz, 1H) 7.48-7.51 (m, 1H) 7.51-7.54 (m, 1H) 7.59 (brs, 1H) 7 .67(d, J=2.6Hz, 1H)7.72(d, J=2.0Hz, 1H)8.46(d, J=4.9Hz, 1H)8.67(d, J=1.1Hz, 1H)12.23(brs, 1H)13.68(s, 1H). LCMS:m / z372[M+H] + HRMS(ESI)C 17 H 12 Cl2N5O[M+H] + Calculated value: 372.0414, measured value: 372.0417.

[0677] 2-(2,4-dichlorophenyl)-5-[3-(trifluoromethyl)-1H-pyrazole-4-yl]-1H-pyrrole-3-carb tree Thamide [R1=3-(trifluoromethyl)-1H-pyrazole-4-yl, R2=2,4-dichlorophenyl, R3=R4=R5=H] Compound 48

[0678] [ka] 1H NMR (500MHz, DMSO-d6) dppm 6.68 (d, J = 1.7 Hz, 2H) 7.22 (brs, 1H) 7.41-7.50 (m, 2H) 7.67 (dd, J = 1.7, 0.6Hz, 1H) 8.15 (s, 1H) 11.53 (brs, 1H) 13.61 (brs, 1H). LCMS:m / z389[M+H] + HRMS(ESI)C 15 H 10 Cl2F3N4O[M+H] + Calculated value: 389.0178, measured value: 389.0184.

[0679] 2-(2-fluoro-4-methylphenyl)-5-(1H-pyrazole-4-yl)-1H-pyrrole-3-carb tree Thamide [R1=1H-pyrazole-4-yl, R2=2-fluoro-4-methylphenyl, R3=R4=R5=H] compound 49

[0680] [ka] 1 H NMR (500MHz, DMSO-d6) dppm2.39 (s, 3H) 6.65 (brs, 1H) 6.66 (d, J=2.6Hz, 1H) 7.04 (brs, 1H) 7. 05-7.12 (m, 2H) 7.37 (t, J=7.9Hz, 1H) 7.78 (s, 1H) 7.98 (s, 1H) 11.38 (brs, 1H) 12.86 (brs, 1H). LCMS:m / z285[M+H] + HRMS(ESI)C 15 H 14 FN4O[M+H] + Calculated value: 285.1146, measured value: 285.1147.

[0681] 5-(3,5-dimethyl-1H-pyrazole-4-yl)-2-(2-fluoro-4-methylphenyl)-1H-pyrrole-3-carb tree Thamide [R1=3,5-dimethyl-1H-pyrazole-4-yl, R2=2-fluoro-4-methylphenyl, R3=R4=R5=H] Compound 50

[0682] [ka] 1 H NMR (500MHz, DMSO-d6) dppm2.20 (brs, 3H) 2.25 (brs, 3H) 2.34 (s, 3H) 6.43 (d, J=2.7Hz, 1H) 6.62 (b rs, 1H) 6.98-7.04 (m, 2H) 7.07 (brs, 1H) 7.35 (t, J=8.0Hz, 1H) 10.97 (d, J=2.0Hz, 1H) 12.24 (s, 1H). LCMS:m / z313[M+H] + HRMS(ESI)C 17 H 18 FN4O[M+H] + Calculated value: 313.1459, measured value: 313.1456.

[0683] 2-(2-fluoro-4-methylphenyl)-5-(1-methyl-1H-pyrazole-4-yl)-1H-pyrrole-3-carb tree Thamide [R1=1-methyl-1H-pyrazole-4-yl, R2=2-fluoro-4-methylphenyl, R3=R4=R5=H] Compound 51

[0684] [ka] 1 H NMR (500MHz, DMSO-d6) dppm2.35(s, 3H) 3.84(s, 3H) 6.60(d, J=2.7Hz, 1H) 6.63(brs, 1H) 7.01(brs, 1H) 7.03(d , J=7.0Hz, 1H)7.05(d, J=10.4Hz, 1H)7.33(t, J=7.9Hz, 1H)7.68(d, J=0.6Hz, 1H)7.88(s, 1H)11.37(brs, 1H). LCMS:m / z299[M+H] + HRMS(ESI)C 16 H 16 FN4O[M+H] + Calculated value: 299.1303, measured value: 299.1299.

[0685] 2-(2-fluoro-4-methylphenyl)-5-(3-methyl-1H-pyrazole-4-yl)-1H-pyrrole-3-carb tree Thamide [R1=3-methyl-1H-pyrazole-4-yl, R2=2-fluoro-4-methylphenyl, R3=R4=R5=H] Compound 52

[0686] [ka] 1 H NMR (500MHz, DMSO-d6) dppm2.35 (s, 6H) 6.51-6.68 (m, 2H) 7.00-7.07 (m, 2H) 7.10 ( brs, 1H) 7.33 (t, J=7.9Hz, 1H) 7.75 (brs, 1H) 11.23 (brs, 1H) 12.18-12.82 (m, 1H). LCMS:m / z299[M+H] + HRMS(ESI)C 16 H 16 FN4O[M+H] + Calculated value: 299.1303, measured value: 299.1299.

[0687] 2-(2-fluoro-4-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl), R2=2-fluoro-4-methylphenyl, R3=R4=R5=H] Compound 53

[0688] [ka] 1 H NMR (500MHz, DMSO-d6) dppm2.38 (s, 3H) 6.81 (brs, 1H) 7.02-7.15 (m, 3H) 7.38-7.44 (m, 1) H)7.47-7.57(m, 3H)7.63(t, J=2.90Hz, 1H)8.26(d, J=5.49Hz, 1H)11.89-12.15(m, 2H). LCMS:m / z335[M+H] + HRMS(ESI)C 19 H 16FN4O[M+H] + Calculated value: 335.1303, measured value: 335.1302.

[0689] Example C Step 13 1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-(2,4-dichlorophenyl)-1H-pyrrole-3-carbonitrile(XVIII)

[0690] [ka]

[0691] To a solution of 2-(2,4-dichlorophenyl)-1H-pyrrole-3-carbonitrile (1 equivalent, 300 mg, 1.27 mmol) in anhydrous THF (6 mL), 60% NaH mineral oil (1.8 equivalents, 92 mg, 2.29 mmol) was added at T=0°C. The reaction mixture was stirred at T=0°C for 20 minutes, and (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (XVII) (1.8 equivalents, 0.49 mL, 2.29 mmol) was added. After 10 minutes at T=0°C, the reaction mixture was warmed to room temperature and stirred for 6 hours. Distilled water was added, and the product was extracted with DCM. The organic layer was washed with distilled water and brine, dehydrated with anhydrous Na2SO4, and removed by distillation to dryness. The crude product was purified by flash chromatography (hexane / AcOEt9 / 1) to obtain the title compound (pale yellow oily substance, 336 mg, Y=67%).

[0692] 1 H NMR (500MHz, DMSO-d6) dppm-0.14--0.08(m, 6H) 0.73-0.80(m, 9H) 3.54-3.78(m, 3H) 3.89-3.97(m, 1H) 6.63(d, J =3.05Hz, 1H)7.14(d, J=3.05Hz, 1H)7.52(d, J=8.39Hz, 1H)7.63(dd, J=8.24, 2.14Hz, 1H)7.89(d, J=2.14Hz, 1H). LCMS:m / z395[M+H] + HRMS(ESI)C 19 H25 Cl2N2OSi[M+H] + Calculated value: 395.1108, measured value: 395.1110.

[0693] The following compounds were obtained by the same procedure, except that a starting material preferably substituted as intermediate (XVII) was used.

[0694] 2-(2,4-dichlorophenyl)-1-(3,3,3-trifluoropropyl)-1H-pyrrole-3-carbonitrile(XVIII)

[0695] [ka] LCMS:m / z333[M+H] + HRMS(ESI)C 14 H9Cl2F3N2[M+H] + Calculated value: 333.0168, measured value: 333.0172.

[0696] 2-(2,4-dichlorophenyl)-1-methyl-1H-pyrrole-3-carbonitrile(XVIII)

[0697] [ka] LCMS:m / z251[M+H] + HRMS(ESI)C 12 H8Cl2N2[M+H] + Calculated value: 251.0137, measured value: 251.0139.

[0698] 2-(2,4-dichlorophenyl)-1-ethyl-1H-pyrrole-3-carbonitrile(XVIII)

[0699] [ka] LCMS:m / z265[M+H] + HRMS(ESI)C 13 H 10 Cl2N2[M+H]+ Calculated value: 265.0294, measured value: 265.0297.

[0700] Step 14 5-Bromo-2-(2,4-dichlorophenyl)-1-(2-hydroxyethyl)-1H-pyrrole-3-carbonitrile(XIX)

[0701] [ka]

[0702] 1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-(2,4-dichlorophenyl)-1H-pyrrole-3-carbonitrile (1 equivalent, 330 mg, 0.84 mmol) was dissolved in MeOH (4 mL) and THF (2 mL) and 0.5 equivalents of N-bromosuccinimide (74.5 mg, 0.42 mmol) were added at T=0°C. The reaction mixture was stirred at T=0°C for 30 minutes and 0.5 equivalents of N-bromosuccinimide (74.5 mg, 0.42 mmol) were added. The reaction mixture was stirred at T=0°C for 1 hour and 30 minutes. Distilled water was added and the product was extracted three times with AcOEt. The organic layer was washed with brine, dehydrated with anhydrous Na2SO4, and removed by distillation to dryness. The crude product was purified by flash chromatography (hexane / AcOEt95 / 5) to obtain the title compound (clear to pale yellow oily substance, 360 mg, Y=48%).

[0703] LCMS:m / z358[M+H] + HRMS(ESI)C 13 H 10 BrCl2N2O[M+H] + Calculated value: 358.9348, measured value: 358.9352.

[0704] The following compounds were obtained by performing the same procedure except for using suitably substituted starting materials.

[0705] 5-Bromo-2-(2,4-dichlorophenyl)-1-(3,3,3-trifluoropropyl)-1H-pyrrole-3-carbonitrile(XIX)

[0706] [ka] LCMS:m / z410[M+H] + HRMS(ESI)C 14 H9BrCl2F3N2[M+H] + Calculated value: 410.9273, measured value: 410.9274.

[0707] 5-Bromo-2-(2,4-dichlorophenyl)-1-methyl-1H-pyrrole-3-carbonitrile(XIX)

[0708] [ka] LCMS:m / z328[M+H] + HRMS(ESI)C 12 H7BrCl2N2[M+H] + Calculated value: 328.9242, measured value: 328.9240.

[0709] 5-Bromo-2-(2,4-dichlorophenyl)-1-ethyl-1H-pyrrole-3-carbonitrile(XIX)

[0710] [ka] LCMS:m / z342[M+H] + HRMS(ESI)C 13 H9BrCl2N2[M+H] + Calculated value: 342.9399, measured value: 342.9398.

[0711] Step 15 2-(2,4-dichlorophenyl)-1-(2-hydroxyethyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carbonitrile(XX)

[0712] [ka]

[0713] In the reactor, under an argon atmosphere, 5-bromo-2-(2,4-dichlorophenyl)-1-(2-hydroxyethyl)-1H-pyrrole-3-carbonitrile (1 equivalent, 140 mg, 0.39 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (1.5 equivalents, 142 mg, 0.58 mmol), Na2CO3 (3 equivalents, 124 mg, 1.17 mmol), degassed 1,4-dioxane (4 mL), and degassed distilled water (1 mL) were added. After 3 cycles of vacuum / argon, the catalyst [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1:1) (0.1 equivalent, 32 mg, 0.039 mmol) was added. After three cycles of vacuum / argon chromatography, the reaction mixture was heated at T=100°C for 3 hours. Distilled water was added, and the product was extracted with AcOEt (three times). The organic layer was washed with distilled water and brine, dehydrated with anhydrous Na2SO4, and removed by distillation to dryness. The crude product was purified by flash chromatography (AcOEt) to obtain the title compound (yellow solid, 110 mg, Y=71%).

[0714] 1 H NMR (500MHz, DMSO-d6) dppm3.01 (quind, J=11.74, 11.74, 11.74, 11.74, 6.10Hz, 2H)3.77(dt, J=14.03, 6.86Hz, 1H)3.99-4.07(m, 1H)4.63(t, J=5.57Hz, 1H)6.42 -6.44(m, 1H)6.89(s, 1H)7.18(d, J=5.0Hz, 1H)7.59-7.61(m, 1H)7.67-7.69(m, 1 H)7.74-7.72(m, 1H)7.94(d, J=2.0Hz, 1H)8.30(d, J=5.0Hz, 1H)11.91(brs, 1H). LCMS:m / z397[M+H] + HRMS(ESI)C 20 H15 Cl2N4O[M+H] + Calculated value: 397.0618, measured value: 397.0623.

[0715] The following compounds were obtained by performing the same procedure except for using suitably substituted starting materials.

[0716] 2-(2,4-dichlorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-(3,3,3-trifluoropropyl)-1H-pyrrole-3-carbonitrile(XX)

[0717] [ka] LCMS:m / z449[M+H] + HRMS(ESI)C 21 H 14 Cl2F3N4[M+H] + Calculated value: 449.0542, measured value: 449.0541.

[0718] 2-(2,4-dichlorophenyl)-1-methyl-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carbonitrile(XX)

[0719] [ka] LCMS:m / z367[M+H] + HRMS(ESI)C 19 H 12 Cl2N4[M+H] + Calculated value: 367.0512, measured value: 367.0513.

[0720] 2-(2,4-dichlorophenyl)-1-ethyl-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carbonitrile(XX)

[0721] [ka] LCMS:m / z381[M+H] + HRMS(ESI)C 20 H 14 Cl2N4[M+H] + Calculated value: 381.0668, measured value: 381.0670.

[0722] Step 15 2-(2,4-dichlorophenyl)-1-(2-hydroxyethyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl), R2=2,4-dichlorophenyl, R3=R5=H, R4=2-hydroxyethyl,] Compound 54

[0723] [ka]

[0724] 2. To a solution of 2-(2,4-dichlorophenyl)-1-(2-hydroxyethyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carbonitrile (1 equivalent, 100 mg, 0.25 mmol) in toluene (3.6 mL), acetaldoxime (20 equivalents, 0.307 mL, 5.05 mmol) and InCl3 (0,1 equivalents, 5.6 mg, 0.025 mmol) were added. The reaction mixture was heated at T=100°C for 1 hour. Distilled water was added, and the product was extracted with AcOEt (3 times). The organic layer was washed with distilled water and brine, dehydrated with anhydrous Na2SO4, and removed by distillation to dryness. The crude product was purified by flash chromatography (DCM / EtOH95 / 5) to obtain the title compound (white solid, 21 mg, Y=20%).

[0725] 1H NMR (500MHz, DMSO-d6) dppm2.94-3.07(m, 2H)3.68(dt, J=14.2, 7.1Hz, 1H)3.88-3.97(m, 1H)6.53(dd, J=3.4, 1.8Hz, 1H)6.74(brs, 1H)6.93(s, 1H)7 .18(d, J=5.0Hz, 1H)7.33(brs, 1H)7.50-7.52(m, 1H)7.53-7.55(m, 1H)7.5 7-7.60 (m, 1H) 7.75 (d, J=2.0Hz, 1H) 8.30 (d, J=5.0Hz, 1H) 11.91 (brs, 1H). LCMS:m / z415[M+H] + HRMS(ESI)C 20 H 17 Cl2N4O2[M+H] + Calculated value: 415.0723, measured value: 415.0722.

[0726] The following compounds were obtained by performing the same procedure except for using suitably substituted starting materials.

[0727] 2-(2,4-dichlorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-(3,3,3-trifluoropropyl)-1H-pyrrole-3-carb tree Samide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl), R2=2,4-dichlorophenyl, R3=R5=H, R4=3,3,3-trifluoropropyl] compound 55

[0728] [ka] 1H NMR (500MHz, DMSO-d6) dppm1.99-2.17(m, 2H)3.88-3.97(m, 1H)4.11-4.20(m, 1H)6.51(dd, J=3.4, 1.9Hz, 1H)6.80(brs, 1H)6.97(s, 1 H)7.14(d, J=4.9Hz, 1H)7.39(brs, 1H)7.53-7.56(m, 1H)7.57-7.61(m, 2H)7.79(d, J=2.0Hz, 1H)8.30(d, J=4.9Hz, 1H)11.86(brs, 1H). LCMS:m / z467[M+H] + HRMS(ESI)C 21 H 16 Cl2F3N4O[M+H] + Calculated value: 467.0648, measured value: 467.0656.

[0729] 2-(2,4-dichlorophenyl)-1-methyl-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl), R2=2,4-dichlorophenyl, R3=R5=H, R4=methyl] Compound 56

[0730] [ka] 1 H NMR (500MHz, DMSO-d6) dppm3.30(s, 1H) 6.60(dd, J=3.43, 1.91Hz, 1H) 6.74(brs, 1H) 7.02(s, 1H) 7.11(d, J=4.88H) z, 1H) 7.38 (brs, 1H) 7.50-7.52 (m, 2H) 7.56 (t, J=1.00Hz, 1H) 7.76 (s, 1H) 8.27 (d, J=4.88Hz, 1H) 11.81 (brs, 1H). LCMS:m / z385[M+H] + HRMS(ESI)C 19 H 14 Cl2N4O[M+H] + Calculated value: 385.0618, measured value: 385.0616.

[0731] 2-(2,4-dichlorophenyl)-1-ethyl-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carb tree Samide [R1=1H-pyrrolo[2,3-b]pyridine-4-yl), R2=2,4-dichlorophenyl, R3=R5=H, R4=ethyl] Compound 57

[0732] [ka] 1 H NMR (500MHz, DMSO-d6) dppm 0.73 (t, J=7.17Hz, 3H) 3.61-3.90 (m, 2H) 6.51 (dd, J=3.36, 1.83Hz, 1H) 6.72 (brs, 1H) 6.93 (s, 1H)7.10(d, J=4.88Hz, 1H)7.32(brs, 1H)7.48-7.59(m, 3H)7.75(d, J=1.83Hz, 1H)8.28(d, J=5.03Hz, 1H)11.83(brs, 1H). LCMS:m / z399[M+H] + HRMS(ESI)C 20 H 16 Cl2N4O[M+H] + Calculated value: 399.0774, measured value: 399.0767.

Claims

1. A compound of the following formula or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 [In the formula, R1 is, 【Chemistry 2】 A heteroaryl group selected from the group consisting of; Ra, Rb, and Rc are independently hydrogen-substituted, linear, or branched (C) atoms. １ -C ６ ) alkyl or possibly substituted linear or branched (C ２ -C ６ ) is Alkenil; R2 is halogen, nitro, aminocarbonyl, optionally substituted linear or branched (C １ -C ６ )alkyl, optionally substituted linear or branched (C １ -C ６ )alkoxy, optionally substituted linear or branched polyfluorinated (C １ -C ６ )alkyl and optionally substituted linear or branched polyfluorinated (C １ -C ６ )alkoxy, which is a substituted phenyl ring or naphthyl ring having 1 to up to 3 substituents selected from; However, 2,5-disubstituted phenyl groups are excluded; R3 is a straight-chain or branched (C) which may be substituted with hydrogen. １ -C ４ ) Alkyl, may be substituted (C ３ -C ６ ) Cycloalkyl groups, or may be substituted (C ５ -C ６ ) is a heterocyclic group; R4 is a straight-chain or branched (C) which may be substituted with hydrogen. １ -C ６ ) alkyl or possibly substituted linear or branched (C ２ -C ６ ) is Alkenil; R5 is a linear or branched (C) which may be hydrogen, halogen, or substituted. １ -C ３ ) It is alkyl.

2. Ra, Rb, and Rc are independently linear or branched (C) which may be hydrogen or substituted. １ -C ６ ) is alkyl; A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 is a 2,4-disubstituted phenyl compound.

3. R2 is a 2,4-disubstituted phenyl compound; R3 may be hydrogen or substituted in a straight-chain or branched (C) １ -C ４ ) is an alkyl chain; A compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt thereof, wherein R5 is hydrogen.

4. A compound of formula (I) according to claim 3, or a pharmaceutically acceptable salt thereof, wherein R4 is hydrogen.

5. 2-(3-chloro-2-fluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 1); 2-(4-chloro-2-fluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 2); 2-(2-chloro-4-fluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 3); 2-(2,4-difluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 4); 2-[2-chloro-4-(trifluoromethyl)phenyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 5); 2-(2,3-difluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 6); 2-(2,3-dichlorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 7); 2-[4-methyl-2-(trifluoromethyl)phenyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 8); 2-(2-chloro-4-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 9); 2-(2,3-difluoro-4-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 10); 2-[2-methyl-4-(trifluoromethyl)phenyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 11); 2-(2-fluoro-3-methoxyphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 12); 2-(2-chloro-3-fluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 13); 2-(2-fluoro-3-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 14); 2-[2-methyl-3-(trifluoromethyl)phenyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 15); 2-[4-methoxy-2-(trifluoromethyl)phenyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 16); 2-[2-chloro-4-(difluoromethoxy)phenyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 17); 2-(3,4-dichlorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 18); 2-(3,4-difluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 19); 2-(3-ethoxy-2-fluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 20); 2-(4-methyl-3-nitrophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 21); 2-(3-carbamoyl-4-fluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 22); 2-(2-fluoro-4-methylphenyl)-N-[2-(pyrroridine-1-yl)ethyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 23); N-[2-(dimethylamino)ethyl]-2-(2-fluoro-4-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 24); 2-(2-fluoro-4-methylphenyl)-N-[2-(morpholine-4-yl)ethyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 25); N-[(1S,2R)-2-aminocyclohexyl]-2-(2-fluoro-4-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 26); 2-(2-fluoro-4-methylphenyl)-N-(furan-2-ylmethyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 27); N-(fluoroethyl)-2-(2-fluoro-4-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 28); 2-(2-fluoro-4-methylphenyl)-N-[2-(methylamino)ethyl]-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 29); 2-(2-fluoro-4-methylphenyl)-N-(1-methylpiperidine-4-yl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 30); 2-(dibenzo[b,d]thiophen-4-yl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 31); 2-(4-methylnaphthalene-1-yl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 32); 2-(3-fluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 33); 5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-2-[4-(trifluoromethoxy)phenyl]-1H-pyrrole-3-carboxamide (compound 34); 2-(2,3-dihydro-1,4-benzodioxin-6-yl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 36); 2-(4-fluoro-2-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 37); 2-(2-fluoro-4-methylphenyl)-4-iodo-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 38); 4-bromo-2-(2-fluoro-4-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 39); 4-ethyl-2-(2-fluoro-4-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 40); 2-(2-fluoro-4-methylphenyl)-4-(propan-2-yl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 41); 5-(6-aminopyrimidine-4-yl)-2-(2,4-dichlorophenyl)-1H-pyrrole-3-carboxamide (compound 42); 2-(2,4-dichlorophenyl)-5-(1H-pyrazole-4-yl)-1H-pyrrole-3-carboxamide (compound 43); 2-(2,4-dichlorophenyl)-5-(3-methyl-1H-pyrazole-4-yl)-1H-pyrrole-3-carboxamide (compound 44); 5-(2-amino-1,3-thiazole-4-yl)-2-(2,4-dichlorophenyl)-1H-pyrrole-3-carboxamide (compound 45); 2-(2,4-dichlorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 46); 2-(2,4-dichlorophenyl)-5-(1H-pyrazolo[3,4-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 47); 2-(2,4-dichlorophenyl)-5-[3-(trifluoromethyl)-1H-pyrazole-4-yl]-1H-pyrrole-3-carboxamide (compound 48); 2-(2-fluoro-4-methylphenyl)-5-(1H-pyrazole-4-yl)-1H-pyrrole-3-carboxamide (compound 49); 5-(3,5-dimethyl-1H-pyrazole-4-yl)-2-(2-fluoro-4-methylphenyl)-1H-pyrrole-3-carboxamide (compound 50); 2-(2-fluoro-4-methylphenyl)-5-(1-methyl-1H-pyrazole-4-yl)-1H-pyrrole-3-carboxamide (compound 51); 2-(2-fluoro-4-methylphenyl)-5-(3-methyl-1H-pyrazole-4-yl)-1H-pyrrole-3-carboxamide (compound 52); 2-(2-fluoro-4-methylphenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 53); 2-(2,4-dichlorophenyl)-1-(2-hydroxyethyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 54); 2-(2,4-dichlorophenyl)-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-(3,3,3-trifluoropropyl)-1H-pyrrole-3-carboxamide (compound 55); 2-(2,4-dichlorophenyl)-1-methyl-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 56); and 2-(2,4-dichlorophenyl)-1-ethyl-5-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrrole-3-carboxamide (compound 57) A compound selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

6. A method for producing a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof, comprising the following steps: Step 1) Compound of formula (II): 【Transformation 3】 [In the formula, R5 is hydrogen or a linear or branched (C) which may be substituted. １ -C ３ ) is alkyl, and X is a halogen. A suitable organoboronic acid derivative of formula (III): 【Chemistry 4】 [In the formula, R1 is as defined in claim 1.] A process involving a metal catalyst coupling reaction; Step 2) The compound of formula (IV) obtained: 【Transformation 5】 [R1 and R5 are as defined in step 1 above.] By halogenating it, the compound of formula (V) is obtained: 【Transformation 6】 [In the formula, R1 and R5 are as defined in step 1 above, and X is a halogen.] The process of obtaining; Step 3) A compound of formula (V) is used to obtain a suitable organic boronic acid derivative of formula (VI): 【Transformation 7】 [In the formula, R2 is as defined in claim 1.] It undergoes a metal-catalyzed coupling reaction to form the compound of formula (VII): 【Transformation 8】 [In the formula, R1 and R5 are as defined in step 1 above, and R2 is as defined in step 3.] The process of obtaining; The compound of formula (VII) obtained from step 3, in which R5 is hydrogen, is subjected to the following transformation 1) according to the conditions already reported in step 2: Conversion 1) 【Chemistry 9】 According to this, it can be converted to another compound of formula (VII) where R5 is a halogen (X); Step 4) Compound of formula (VII) obtained from Step 3 or conversion 1 [In the formula, R1 and R2 are as defined in steps 1 and 3 above, respectively, and R5 is hydrogen, halogen, or a linear or branched (C) which may be substituted. １ -C ３ ) It is alkyl. Protect it by reaction with a suitable protecting group to obtain the carboxylic acid ester of formula (VIII): 【Chemistry 10】 [In the formula, R1, R2, and R5 are as defined above, and PG is a protecting group selected from the group consisting of trimethylsilylethoxymethyl (SEM), tert-butyloxycarbonyl (BOC), and benzenesulfonyl.] The process of obtaining; Step 5) Hydrolyze the carboxylic acid ester of formula (VIII) under basic conditions to obtain the carboxylic acid of formula (IX): 【Chemistry 11】 [In the formula, R1, R2, R5, and PG are as defined in step 4 above.] The process of obtaining; Step 6) The intermediate of formula (IX) is an amine derivative of formula (X): 【Chemistry 12】 [In the formula, R3 is as defined in claim 1.] The process of amidation through a reaction with; Step 7) The compound of formula (XI) obtained: 【Chemistry 13】 [In the formula, R1, R2, R5, and PG are as defined in step 5 above, and R3 is as defined in step 6.] Deprotecting the compound of formula (I): 【Chemistry 14】 [R1, R2, and R3 are as defined in claim 1, and R4 is hydrogen.] The process of obtaining; or The intermediate compound of formula (VIII) where R5 is a halogen is subjected to the following transformation: Transformation 2) Compound of formula (VIII): 【Chemistry 15】 [In the formula, R1 and R2 are as defined in claim 1.] As reported in step 3, a linear or branched (C) may have R5 substituted by a palladium-catalyzed reaction. １ -C ３ ) Convert to a compound of formula (VIII) which is an alkenyl chain; The resulting compound (VIII): 【Chemistry 16】 Reacting the mixture under the conditions reported in steps 5 and 6 to obtain compound (XIa) in which R1, R2, and R5 are as defined above; Transformation 3) Compound of the obtained formula (XIa): 【Chemistry 17】 By reduction / hydrogenation of the double bond, a linear or branched (C) is formed where R1, R2 and R3 are as defined in claim 1, and R5 may be substituted. １ -C ３ ) Converting to a compound of formula (XI) which is alkyl; It can be transformed into an intermediate of formula (XI) according to a method including, or instead, Compound of formula (I) [In the formula, R1 and R2 are as defined in claim 1, R3 and R4 are hydrogen, and R5 is hydrogen or a linear or branched (C) which may be substituted. １ -C ３ ) It is alkyl. The following steps: Step 8) Compound of formula (XII): [Chemistry 18] [In the formula, R2 is as defined in claim 1, and R5 is hydrogen or a linear or branched (C) which may be substituted. １ -C ３ ) It is alkyl. A process to protect; Step 9) The compound of formula (XIII) obtained: 【Chemistry 19】 [In the formula, R2 and R5 are as defined in step 8 above, and PG is a protecting group selected from the group consisting of SEM, BOC, and benzenesulfonyl.] The process of halogenating; Step 10) The compound of formula (XIV) obtained: 【Chemistry 20】 [In the formula, R2, R5, and PG are as defined in step 9 above, and X is a halogen.] A suitable organoboronic acid derivative of formula (III): 【Chemistry 21】 [In the formula, R1 is as defined in claim 1.] A process involving a metal catalyst coupling reaction; Step 11) The compound of formula (XV) obtained: 【Chemistry 22】 [In the formula, R1, R2, R5, and PG are as defined in step 10 above.] A step of hydrolyzing to produce the corresponding amide intermediate of formula (XVI); 【Chemistry 23】 Step 12) Deprotect the compound of formula (XVI) to obtain the compound of formula (I): 【Chemistry 24】 [In the formula, R1 and R2 are as defined in claim 1, R3 and R4 are hydrogen, and R5 is as defined in step 8 above.] The process of obtaining It can be manufactured by a method including, instead, Compound of formula (I) [In the formula, R1, R2 and R4 are as defined in claim 1, R3 is hydrogen, and R5 is hydrogen or a linear or branched (C) which may be substituted. １ -C ４ ) It is an alkyl chain. The following steps: Step 13) Derivative of formula (XII): 【Chemistry 25】 [In the formula, R2 is as defined in claim 1, and R5 is hydrogen or a linear or branched (C) which may be substituted. １ -C ４ ) It is alkyl. In the presence of a base or by adding a metal catalyst, a halo derivative of formula (XVII) is obtained: 【Chemistry 26】 [In the formula, R4 is a linear or branched C which may be substituted.] １ -C ６ Alkyl, or optionally substituted, linear or branched carbon atoms ２ -C ６ The process involves reacting with an alkenyl, where X is a halogen; Step 14) The compound of formula (XVIII) obtained: 【Chemistry 27】 [In the formula, R2, R4, and R5 are as defined in step 13 above.] The process of halogenating; Step 15) The compound of formula (XIX) obtained: 【Chemistry 28】 [In the formula, X is a halogen, and R2, R3, and R4 are as defined in step 13 above.] A suitable organoboronic acid derivative of formula (III): 【Chemistry 29】 [In the formula, R1 is as defined in claim 1.] A process involving a metal catalyst coupling reaction; Step 16) Intermediate of the obtained formula (XX): 【Transformation 30】 Hydrolyzing yields the compound of formula (I): 【Chemistry 31】 [In the formula, R1 and R2 are as defined in claim 1, R3 is hydrogen, R4 is as defined in step 13, and R5 is hydrogen or a linear or branched (C) which may be substituted. １ -C ４ ) It is an alkyl chain. The process of obtaining A method that can be manufactured according to a method including the following.

7. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof, for treating mammals suffering from diseases caused by dysregulated Cdc7 activity.

8. The pharmaceutical composition according to claim 7, wherein the disease is selected from the group consisting of cancer and cell proliferation disorders.

9. Cancers selected from the group consisting of bladder cancer, breast cancer, kidney cancer, liver cancer, colon cancer, lung cancer including small cell lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, prostate cancer, head and neck cancer, and skin cancer including squamous cell carcinoma; hematopoietic tumors of the lymphatic system including leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, angioimmunoblastic T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, mantle cell lymphoma, and Burkitt lymphoma; acute and chronic myeloid leukemia, bone A pharmaceutical composition according to claim 8, selected from the group consisting of myeloid hematopoietic malignancies including myelodysplastic syndrome and promyelocytic leukemia; mesenchymal cell-derived tumors including fibrosarcoma and rhabdomyosarcoma; central and peripheral nervous system tumors including glioma, glioblastoma, glioblastoma multiforme, astrocytoma, oligodendroglioma, paraglioma, neuroblastoma and peripheral nervous system tumors; and other tumors, selected from the group consisting of thyroid cancer selected from the group consisting of melanoma, seminomas, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoxanthoma, papillary thyroid carcinoma and medullary thyroid carcinoma, Kaposi's sarcoma, chondrosarcoma, cholangiocarcinoma, and head and neck tumors.

10. The pharmaceutical composition according to claim 8, wherein the cell proliferation disorder is selected from the group consisting of benign prostatic hyperplasia, psoriasis, vascular smooth muscle cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis, and postoperative stenosis and restenosis.

11. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, carrier, or diluent.

12. The pharmaceutical composition according to claim 11, further comprising one or more chemotherapeutic agents.

13. An in vitro method for inhibiting Cdc7 kinase activity, comprising contacting the Cdc7 kinase with an effective amount of the compound of formula (I) as defined in claim 1.

14. A product or kit comprising a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof, and one or more chemotherapeutic agents, as a combination formulation for simultaneous, separate, or sequential use in anticancer therapy.

15. A compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

16. Use of a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical product for treating a disease caused by dysregulated Cdc7 kinase activity.

17. The use according to claim 16, wherein the disease is selected from the group consisting of cancer and cell proliferation disorders.

18. Cancers selected from the group consisting of bladder cancer, breast cancer, kidney cancer, liver cancer, colon cancer, lung cancer including small cell lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, prostate cancer, head and neck cancer, and skin cancer including squamous cell carcinoma; hematopoietic malignancies of the lymphatic system including leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, angioimmunoblastic T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, mantle cell lymphoma, and Burkitt lymphoma; acute and chronic myeloid leukemia, The use according to claim 17, selected from the group consisting of myelodysplastic syndrome and promyelocytic leukemia, hematopoietic tumors of the myeloid cell lineage; mesenchymal cell-derived tumors including fibrosarcoma and rhabdomyosarcoma; central and peripheral nervous system tumors including glioma, glioblastoma, glioblastoma multiforme, astrocytoma, oligodendroglioma, paraglioma, neuroblastoma and peripheral nervous system tumors; and other tumors including thyroid cancer selected from the group consisting of melanoma, seminomas, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoxanthoma, papillary thyroid carcinoma and medullary thyroid carcinoma, Kaposi's sarcoma, chondrosarcoma, cholangiocarcinoma, and head and neck tumors.

19. The use according to any one of claims 16 to 18, wherein the treatment is a combination of radiotherapy, targeted therapy, immunotherapy, or chemotherapy.

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