4H-Pyrrolo[3,2-C]pyridin-4-one compounds

Abstract

Compounds of formula (I), methods for their preparation and their use as medicines. [Formula 1] TIFF2022532850000205.tif105133

Description

[Technical Field]

[0001] Application field of the invention The present invention relates to substituted 4H-pyrrolo[3,2-c]pyridin-4-one compounds, methods for their preparation and their use. [Background technology]

[0002] Background of the Invention The epidermal growth factor receptor (EGFR or EGF receptor) receptor tyrosine kinase family consists of four members: EGFR (Erbb1, Her1), ERBB2 (Her2), ERBB3 (Her3), and ERBB4 (Her4). EGFR mediates activation of MAPK and PI3K signaling pathways, thereby regulating cell proliferation, differentiation, migration, and survival (Pao et al., 2010). EGFR gene amplification, overexpression, and mutations are frequently observed in various cancer indications and are associated with poor prognosis (Gridelli et al., 2015).

[0003] In lung adenocarcinoma, EGFR mutations are prevalent in approximately 15% of Western patients and up to 50% of East Asian patients (Paez et al., 2004). These mutations typically occur in one of four exons, exons 18–21, in the kinase domain of EGFR (Paez et al., 2004). The most common activating mutations in EGFR are a point mutation in exon 21 substituting arginine for leucine (L858R) and a small in-frame deletion in exon 19 (del 19 / del746–750) that removes four amino acids (Pao et al., 2010). The FDA-approved inhibitors gefitinib, erlotinib, and afatinib targeting mutations in EGFR exons 18, 19, and 21 are effective in patients, but responses are often short-lived (Mok et al., 2009; Sequist et al., 2013). Resistance frequently develops in these patients in response to the acquisition of a second mutation, T790M (Pao et al., 2005). Second-generation inhibitors, such as afatinib, irreversibly target this mutation but remain potent inhibitors of wild-type EGFR, resulting in dose-limiting toxicity and a lack of efficacy in patients. Osimertinib, a third-generation irreversible inhibitor, maximizes activity against T790M while minimizing activity against wild-type EGFR, making it effective in patients with T790M mutations and currently the standard of care for T790M-positive patients (Mok et al., 2017). Osimertinib has also been approved as first-line treatment for patients with EGFR exon 19 or 21 mutations (Soria et al., 2018).

[0004] However, patients also acquire resistance to irreversible third-generation EGFR inhibitors, such as osimertinib. One of the major osimertinib resistance mechanisms identified is the mutation of cysteine ​​to serine at position 797, resulting in the loss of the covalently interacting cysteine ​​and loss of sensitivity to irreversible EGFR inhibitors, at which point patients who progress are currently left with limited treatment options (Thress et al., 2015; Oxnard et al., 2018). Such C797S mutations can also occur in the absence of T790M mutations, even when osimertinib is used as first-line treatment (Ramilingham et al., 2018a; Ramilingham et al., 2018b). Novel targeted therapies that can specifically address EGFR-C797S acquired resistance mutations would be highly beneficial for these patients.

[0005] In contrast, small in-frame insertions in EGFR exon 20, with the exception of A763_Y764insFQEA, are resistant to all clinically approved EGFR inhibitors at achievable doses in lung cancer patients, constituting an unmet medical need ( Yasuda et al., 2013 ).

[0006] Patients with EGFR exon 20 insertions, such as V769_D770insASV, D770_N771insSVD, D770_N771insNPG, N771_P772insH, H773_V774insH, H773_V774insNPH, and V774_C775insHV, exhibit significantly lower response rates to all currently approved EGFR-targeted therapies, resulting in significantly reduced progression-free survival and overall survival (Chen et al., 2016). This has been shown for first-generation inhibitors erlotinib and gefitinib, as well as the second-generation inhibitor afatinib (Chen et al., 2016; Yang et al., 2015).

[0007] Therefore, the standard of care for patients with EGFR exon 20 insertions is currently chemotherapy.

[0008] The same resistance profile has been observed for exon 20 insertion mutations in ERBB2 (e.g., ERBB2 A775_G776insYVMA, which has the highest prevalence), another member of the EGF receptor family ( Arcila et al., 2012 ), and some of the rarer EGFR mutations, such as L681Q ( Chiu et al., 2015 ).

[0009] Several irreversible EGFR exon 20 inhibitors are currently in clinical trials for the treatment of patients with EGFR exon 20 insertions: osimertinib, originally approved for the treatment of patients with T790M-mutant NSCLC (Floc'h et al., 2018); poziotinib (HM-781-36B), an unapproved pan-Hertz inhibitor targeting EGFR, Her2 / neu, and Her4 (Robichaux et al., 2018); and TAK-788 (AP32788) (Doebele et al., ASCO 2018). Initial clinical data have been published for poziotinib and TAK-788. Both compounds demonstrate clear clinical efficacy in patients with EGFR exon 20 insertions. However, major adverse events mediated by inhibition of wild-type EGFR have been reported in both clinical trials, which may limit their clinical utility.

[0010] More recently, new preclinical data have been published for two additional compounds showing activity against EGFR exon 20 insertions: TAS6417 (TCP-064) and compound 1a (Hasako et al., 2018; Jang et al., 2018). Clinical results for these two compounds are not yet available. [Prior art documents] [Non-patent literature]

[0011] [Non-Patent Document 1] Arcila et al., 2012: Arcila et al., https: / / www.ncbi.nlm.nih.gov / pubmed / 227614692012 Sep 15;18(18):4910-8 [Non-Patent Document 1] Chen et al., 2016:Chen et al., Onco Targets Ther. 2016 Jul 8;9:4181-6 [Non-patent document 2] Chiu et al., 2015: Chiu et al., J Thorac Oncol.2015;10:793-799 [Non-patent document 3] Doebele et al., 2018: Doebele et al., Poster 338, presented at the 54th Annual Meeting of the American Society of Clinical Oncology, June 1–5, 2018, Chicago, IL. [Non-patent document 4] Floc´h et al., 2018:Floc´h et al., Mol Cancer Ther.2018 May 17(5):885-896 [Non-patent document 5] Hasako et al., 2018: Hasako et al., Mol Cancer Ther.2018 Aug;17(8):1648-1658 [Non-patent document 6] Jang et al., 2018: Jang et al., Angew Chem Int Ed Engl. 2018 Sep 3;57(36):11629-11633 [Non-Patent Document 7] Mok et al., 2009: Mok et al., N Engl J Med.2009 Sep 3;361(10):947-57 [Non-patent document 8] Mok et al., 2017: Mok et al., N Engl J Med.2017 Feb 16;376(7):629-640 [Non-Patent Document 9] Oxnard et al., 2013: Oxnard et al., J Thorac Oncol. 2013 Feb;8(2):179-184 [Non-Patent Document 10] Oxnard et al., 2018: Oxnard et al., JAMA Oncol. 2018;4(11):1527-1534 [Non-Patent Document 11] Paez et al., 2004:Paez et al., Science.2004 Jun 4;304(5676):1497-500 [Non-Patent Document 12] Pao et al., 2005: Pao et al., PLoS Med. 2005 Mar;2(3):e73 [Non-Patent Document 13] Pao et al., 2010: Pao and Chmielecki, Nat Rev Cancer.2010 Nov;10(11):760-74 [Non-Patent Document 14] Ramalingam et al., 2018a: Ramalingam et al., J Clin Oncol.2018 Mar 20;36(9):841-849. [Non-Patent Document 15] Ramalingam et al., 2018b: Ramalingam et al., ESMO 2018;Annals Oncol.2018 Oct:29(Suppl 8) [Non-Patent Document 16] Robichaux et al., 2018:Robichaux et al., Nat Med.2018 May;24(5):638-646 [Non-Patent Document 17] Sequist et al., 2013: Sequist et al., J Clin Oncol. 2013 Sep 20;31(27):3327-34 [Non-Patent Document 18] Soria et al., 2018: Soria et al., N Engl J Med.2018 Jan 11;378(2):113-125. [Non-Patent Document 19] Thress et al., 2015:Thress et al., Nat Med.2015 Jun;21(6):560-562. [Non-Patent Document 20] Yang et al., 2015: Yang et al., Lancet Oncol.2015 Jul;16(7):830-8 [Non-Patent Document 21] Yasuda et al., 2013: Yasuda, Sci Transl Med.2013 Dec 18;5(216):216ra177 Summary of the Invention

[0012] In summary, mutant EGFR is a promising drug target for cancer treatment. In particular, patients who exhibit primary resistance to approved anti-EGFR therapies due to EGFR exon 20 insertions currently have few treatment options, and there is a great need for novel, alternative, and / or improved therapeutic agents to provide these patients with effective and tolerable treatments (Oxnard et al., 2013). Therefore, potent inhibitors of mutant EGFR, especially those harboring exon 20 insertion mutations that exhibit improved selectivity over wild-type EGFR, would be valuable compounds to complement treatment options either as single agents or in combination with other drugs.

[0013] The present invention provides compounds that inhibit mutant EGFR, in the presence or absence of the C797S mutation, specifically EGFR containing one or more exon 20 insertion mutations, L858R mutations, or small in-frame deletions of exon 19. These compounds further have reduced activity relative to wild-type EGFR.

[0014] The compounds of the present invention have been found to have surprising and advantageous properties.

[0015] In particular, the compounds of the present invention surprisingly inhibit mutant EGFR carrying exon 20 insertion mutations, particularly with an IC of less than 5 nM. 50These compounds were found to effectively inhibit mutant EGFR carrying the D770_N771ins SVD exon 20 insertion. Furthermore, these compounds were further found to exhibit differentiation potency of less than 1 μM in EGFR V769_D770insASV, D770_N771insSVD, D770_N771insNPG, N771_P772insH, or H773_V774insNPH exon 20 insertions, including the BA / F3 cell line. Furthermore, the compounds described herein are active in the BA / F3 cell line carrying D770_N771insSVD C797S. Additionally, the compounds described herein potently inhibit the growth of BA / F3 cell lines harboring EGFR activating mutations with or without the C797S acquired resistance mutation (EGFR E746_A750del, L858R, E746_A750del C797S, L858R C797S), a rare EGFR mutation (EGFR L681Q) or the ERBB2 exon 20 insertion A775_G776insYVMA.

[0016] Surprisingly, these compounds show at least 5-fold selectivity in anti-proliferation assays over the EGFR D770_N771ins SVD exon 20 insertion, including BA / F3 cell line, and wild-type EGFR, including BA / F3 cells, and therefore may be used for the treatment or prevention of diseases of uncontrolled cell proliferation, growth and / or survival, inappropriate cellular immune response, or uncontrolled cell proliferation, diseases involving proliferation and / or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response mediated by mutant EGFR with exon 20 insertion mutations and / or diseases that reduce (or block) proliferation in cells with EGFR exon 20 insertion mutations, such as hematological tumors, solid tumors, and / or metastases thereof, e.g., leukemia and myelodysplastic syndromes, malignant lymphomas, head and neck tumors, including brain tumors and brain metastases, thoracic tumors, including non-small cell and small cell lung tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors, including kidney tumors, bladder tumors, and prostate tumors, skin tumors, and sarcomas, and / or metastases thereof. DETAILED DESCRIPTION OF THE INVENTION

[0017] According to a first aspect, the present invention provides a compound of formula (I) [ka]

[0018] [During the ceremony, R 1 represents methyl, ethyl, trifluoromethyl, 2,2-difluoroethyl, cyano, chloro, bromo, methoxy or difluoromethoxy; R 2 represents hydrogen, methyl, ethyl, fluoro, chloro or bromo; R 3 represents hydrogen or fluoro; R 4 represents hydrogen or methyl; R 5 represents independently for each occurrence hydrogen, trifluoromethyl, or C1-C3 alkyl; R 5 is attached to any carbon atom of the ring; R 6 represents independently for each occurrence hydrogen, C1-C3-alkyl or C1-C3-haloalkyl; R 7 represents C1-C3-alkyl or C2-C3-haloalkyl; R 8 represents C1-C3-alkyl or C2-C3-haloalkyl; X is NR 7 or represents O; Y is NR 8 or represents O; m represents 0, 1, 2 or 3; n represents 0 or 1. or an N-oxide, salt, or tautomer of said compound, or a salt of said N-oxide or tautomer. In some embodiments, at least two R 5 The groups are geminal (ie, attached to the same carbon atom).

[0019] In a second aspect, the present invention provides a compound of formula (I) above: R 1 represents methyl, ethyl, chloro, methoxy or difluoromethoxy; R 2 represents methyl, ethyl, fluoro or chloro; R 3 represents hydrogen or fluoro; R 4 represents hydrogen or methyl; R 5 represents hydrogen, methyl or trifluoromethyl, R 5 is attached to any carbon atom of the ring; R 6 represents hydrogen, methyl or trifluoromethyl; R 7 represents C1-C2-alkyl or C2-C3-fluoroalkyl; R 8 represents C1-C2-alkyl or C2-C3-fluoroalkyl; X is NR 7 or represents O; Y is NR 8 or represents O; m represents 0, 1 or 2; n represents 0 or 1; or an N-oxide, salt or tautomer of said compound, or a salt of said N-oxide or tautomer.

[0020] In a third aspect, the present invention provides a compound of formula (I) above: R 1 represents methyl, ethyl, chloro or methoxy; R 2 represents fluoro or chloro; R 3 represents hydrogen or fluoro; R 4 represents hydrogen; R 5 represents hydrogen or methyl, and R 5 is attached to any carbon atom of the ring; R 6 represents hydrogen; R 7 represents methyl; R 8 represents methyl, 2,2,2-trifluoroethyl or 2,2-difluoroethyl; X is NR 7 or represents O; Y is NR 8 or represents O; m represents 0, 1, or 2; n represents 0 or 1; or an N-oxide, salt or tautomer of said compound, or a salt of said N-oxide or tautomer.

[0021] In a fourth aspect, the present invention relates to compounds of formula (I) above, selected from the group consisting of: 3-(3-chloro-2-methoxyanilino)-2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{[(2R)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2R)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(2,3-Dichloroanilino)-2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(2,3-Dichloroanilino)-2-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(2,3-Dichloroanilino)-2-(3-{[(2R)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methylanilino)-2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-fluoro-2-methoxyanilino)-2-{3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-fluoro-2-methoxyanilino)-2-(3-{[(2R)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-fluoro-2-methoxyanilino)-2-(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-{3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{[(2R)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-5-fluoro-2-methoxyanilino)-2-(3-{[4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-5-fluoro-2-methoxyanilino)-2-(3-{[1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-Fluoro-2-methoxyanilino)-2-(3-{[(3S)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{[(3S)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2S)-4-(2,2-difluoroethyl)morpholin-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-fluoro-2-methoxyanilino)-2-(3-{[(2S)-4-(2,2,2-trifluoroethyl)morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-{3-[2-(4-dioxan-2-yl)ethoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{2-[(2R)-1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{2-[(2S)-1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-5-fluoro-2-methoxyanilino)-2-(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-5-fluoro-2-methoxyanilino)-2-(3-{[(2S)-4-(2,2,2-trifluoroethyl)morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-ethylanilino)-2-{3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-{3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{[(2R)-5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{[(2S)-5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2R)-5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2S)-5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{2-[(2R)-1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{2-[(2S)-1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-fluoro-2-methoxyanilino)-2-(3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-{3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-3-(3-fluoro-2-methylanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2S)-5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methylanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-[2-(2,2-difluoroethyl)-3-fluoroanilino]-2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-[2-(2,2-difluoroethyl)-3-fluoroanilino]-2-(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methylanilino)-2-(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methylanilino)-2-(3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methylanilino)-2-{3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methylanilino)-2-(3-{[(2S)-5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methylanilino)-2-(3-{[(2R)-5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-3-(3-fluoro-2-methylanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methylanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2R)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methylanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methylanilino)-2-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methylanilino)-2-(3-{[(2R)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-ethylanilino)-2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-ethylanilino)-2-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-ethylanilino)-2-(3-{[(2R)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-ethylanilino)-2-(3-{[(2R)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-ethylanilino)-2-(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{1-[1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{(1S)-1-[(2S)-1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{(1S)-1-[(2R)-1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{(1R)-1-[(2S)-1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{(1R)-1-[(2R)-1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-fluoro-2-methylanilino)-2-{3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-fluoro-2-methylanilino)-2-(3-{[(2R)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-fluoro-2-methylanilino)-2-(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3-fluoroanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2R)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3-fluoroanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3-fluoroanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3-fluoroanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2R)-5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3-fluoroanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2S)-5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3-fluoroanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-[3-({1-[4-methylmorpholin-2-yl]ethyl}oxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-[3-({(1R)-1-[(2R)-4-methylmorpholin-2-yl]ethyl}oxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-[3-({(1S)-1-[(2S)-4-methylmorpholin-2-yl]ethyl}oxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-[3-({(1R)-1-[(2S)-4-methylmorpholin-2-yl]ethyl}oxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-[3-({(1S)-1-[(2R)-4-methylmorpholin-2-yl]ethyl}oxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one.

[0022] A further aspect of the present invention relates to compounds of formula (I) present as their salts.

[0023] It is to be understood that the present invention relates to any subcombination within any embodiment or aspect of the invention of compounds of general formula (I) above.

[0024] Even more particularly, the present invention encompasses compounds of general formula (I) disclosed in the Examples section of the text below.

[0025] According to another aspect, the present invention encompasses a method of preparing a compound of the present invention, said method comprising the steps described in the Experimental Section herein.

[0026] Another embodiment of the present invention is the compounds disclosed in the claims, or the disclosed analogs of the exemplified compounds, and subcombinations thereof.

[0027] definition It should be understood that the embodiments disclosed herein are not intended to be understood as separate, unrelated embodiments. Features discussed in one embodiment or aspect of the present invention are also intended to be disclosed in relation to other embodiments or aspects of the present invention set forth herein. In one instance, if a particular feature is not disclosed in one embodiment or aspect of the present invention but is disclosed in another embodiment or aspect, those skilled in the art will understand that this does not necessarily mean that the feature is not intended to be disclosed in the other embodiment or aspect of the present invention. Those skilled in the art will understand that the gist of the present application is to disclose the same features for other embodiments or aspects of the present invention, but only for the sake of clarity and to keep the length of this specification manageable. For example, it should be understood that all aspects, embodiments, pharmaceutical compositions, combinations, uses, and / or methods of the present invention defined herein for compounds of Formula (I) also relate to more specific embodiments of compounds of Formula (I), such as, but not limited to, compounds of Formula (Ia), and vice versa.

[0028] Furthermore, it should be understood that the contents of documents referred to herein are incorporated by reference in their entirety, for example, for enabling purposes, i.e., where the details of which are set out in said documents are discussed. This approach helps keep the length of this specification manageable.

[0029] As described herein, optionally substituted components may be substituted one or more times, independently of each other, at any available position, unless otherwise specified. When any variable occurs more than once in any component, each definition is independent. For example, in any complex of formula (I), R 1 , R 1a , R 1b , R 1c , R 2 , R 3 and / or R 4 occurs multiple times, R 1 , R 1a , R 1b , R 1c , R 2 , R 3 and R 4 Each definition is independent.

[0030] When a component is composed of multiple moieties, for example C1-C4-alkoxy-C2-C4-alkyl, the possible position of substitution can be any of these moieties at any suitable position. A hyphen at the beginning or end of a component indicates the point of attachment to the rest of the molecule. When a ring is substituted, the substituent can be at any suitable position on the ring, including, if appropriate, on a ring nitrogen atom.

[0031] As used herein, the term "comprising" includes "consisting of."

[0032] Whenever reference is made in the description to "as mentioned above" or "mentioned above" or "supra", it refers to any of the disclosures made in the specification on any of the preceding pages.

[0033] Whenever reference is made in the description to "as mentioned herein," "described herein," "provided herein," or "as mentioned in the present text," or "stated herein," it refers to any of the disclosures made within this specification, either in the preceding or following pages.

[0034] "Suitable" in the sense of the present invention means chemically possible by methods within the knowledge of a person skilled in the art.

[0035] Terms referred to herein may have the following meanings: The terms "halogen atom", "halo-" or "Hal-" shall be understood to mean a fluorine, chlorine, bromine or iodine atom.

[0036] The term "C1-C6-alkyl" should be understood to mean a linear or branched, saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5, or 6 carbon atoms, such as, for example, a methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neo-pentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl group, or an isomer thereof. In particular, the radicals have 1, 2, 3 or 4 carbon atoms ("C1-C4-alkyl"), such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl radicals, and more particularly have 1, 2 or 3 carbon atoms ("C1-C3-alkyl"), such as methyl, ethyl, n-propyl or isopropyl radicals.

[0037] The term "C1-C4-haloalkyl" should be understood to mean a linear or branched, saturated, monovalent hydrocarbon radical, wherein the term "C1-C4-alkyl" is defined above, and wherein one or more hydrogen atoms are replaced by identical or different halogen atoms, i.e., one halogen atom is independent of the other halogen atoms. In particular, said halogen atoms are F. Said C1-C4-haloalkyl radicals are, for example, -CF3, -CHF2, -CH2F, -CF2CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CF3, or -CH(CH2F)2.

[0038] The term "C2-C3-fluoroalkyl" should be understood to mean a linear or branched, saturated, monovalent hydrocarbon radical, as the term "C2-C3-alkyl" is defined above, in which one or more hydrogen atoms have been replaced by fluorine atoms. The C2-C3-fluoroalkyl radical is, for example, -CF2CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CF3, or -CH(CH2F)2.

[0039] The term "C1-C4-alkoxy" is a linear or branched, saturated monovalent hydrocarbon radical of the formula -O-alkyl, the term "alkyl" being understood to mean as defined above, such as a methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy or sec-butoxy radical, or an isomer thereof.

[0040] Unless otherwise defined, the term "5- to 6-membered heterocycloalkyl" or "5- to 6-membered heterocyclic ring" should be understood to mean a saturated, monovalent, monocyclic hydrocarbon ring containing 4 or 5 carbon atoms and one heteroatom-containing group selected from O and NR, where R represents a hydrogen atom, a C-C-alkyl or a C-C-haloalkyl group, and said heterocycloalkyl group can be bonded to the rest of the molecule via any one of the carbon atoms.

[0041] In particular, but without limitation, said heterocycloalkyl may be a five-membered ring, such as tetrahydrofuranyl, pyrazolidinyl, or a six-membered ring, such as tetrahydropyranyl, piperidinyl.

[0042] The term "C1-C6" as used herein, for example in the context of the definition of "C1-C6-alkyl" or "C1-C6-haloalkyl", is to be understood as meaning that the alkyl group has a finite number of carbon atoms from 1 to 6, i.e., 1, 2, 3, 4, 5, or 6 carbon atoms, and further it is to be understood that said term "C1-C6" is to be interpreted as any subrange contained therein, for example, C1-C6, C2-C6, C3-C6, C1-C2, C1-C3, in particular C1-C2, C1-C3, C1-C4.

[0043] The term "C1-C4" as used herein, for example in the context of the definitions of "C1-C4-alkyl", "C1-C4-haloalkyl", "C1-C4-alkoxy" or "C1-C4-haloalkoxy", is to be understood as meaning that the alkyl group has a finite number of carbon atoms from 1 to 4, i.e. 1, 2, 3 or 4 carbon atoms, and further it is to be understood that said term "C1-C4" is to be interpreted as any subrange contained therein, for example C1-C4, C2-C4, C3-C4, C1-C2, C1-C3, more particularly C1-C2, in the case of "C1-C6-haloalkyl" or "C1-C4-haloalkoxy".

[0044] Furthermore, the term "C3-C6" as used herein, for example, as used in the context of the definition of "C3-C6-cycloalkyl", should be understood to mean that the cycloalkyl group has a finite number of carbon atoms from 3 to 6, i.e., 3, 4, 5 or 6 carbon atoms. Furthermore, the term "C3-C6" should be understood to be interpreted as, for example, any subrange contained therein, such as C3-C6, C4-C5, C3-C5, C3-C4, C4-C6, C5-C6, in particular C3-C6.

[0045] The term "substituted" means that one or more hydrogens on a designated atom are replaced with a selection from the indicated group, provided that the replacement does not exceed the normal valence of the designated atom under the existing circumstances, and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0046] The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties.

[0047] Ring system substituent means a substituent attached to an aromatic or non-aromatic ring system which, for example, replaces an available hydrogen on the ring system.

[0048] As used herein, the term "one or more", for example in the definition of substituents of compounds of the general formula of the invention, is understood to mean "one, two, three, four, five, etc., particularly one, two, three or four, more particularly one, two or three, even more particularly one or two".

[0049] Compounds of general formula (I) may exist as isotopic variations. Thus, the present invention includes one or more isotopic variations of compounds of general formula (I), particularly deuterium-containing compounds of general formula (I).

[0050] The term "isotopic variant" of a compound or reagent is defined as a compound that exhibits an unnatural proportion of one or more isotopes that constitute such compound.

[0051] The term "isotopic variant of a compound of general formula (I)" is defined as a compound of general formula (I) that exhibits unnatural proportions of one or more isotopes that constitute such compound.

[0052] The expression "unnatural proportion" should be understood to mean that the proportion of such isotope is higher than the natural abundance, and the natural abundance of an isotope as applied in this context is described in "Isotopic Compositions of Elements 1997", Pure Appl. Chem., 70(1), 217-235, 1998. Such isotopes include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, for example, 2 H (deuterium), 3 H (tritium), 11 C. 13 C. 14 C. 15 N, 17 O. 18 O. 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I and 131 I.

[0053] For the treatment and / or prevention of the disorders identified herein, isotopic variants of compounds of general formula (I) in one embodiment contain deuterium ("deuterium-containing compounds of general formula (I)"). 3 H or 14 Isotopic variations of compounds of general formula (I) incorporating one or more radioactive isotopes, such as C, are useful, for example, in drug and / or substrate tissue distribution studies. These isotopes are particularly preferred for their ease of incorporation and detectability. 18 F or 11 Positron-emitting isotopes such as C may be incorporated into the compounds of general formula (I). These isotopic variants of the compounds of general formula (I) are useful for in vivo imaging applications. Deuterium-containing and 13C-containing compounds can be used for mass spectrometry analysis (HJ Leis et al., Curr. Org. Chem., 1998, 2, 131) in the context of preclinical or clinical trials.

[0054] Isotopic variants of compounds of general formula (I) can generally be prepared by methods known to those skilled in the art (e.g., those described in the schemes and / or examples herein) by substituting an isotopic variant of the reagent, in one embodiment, a deuterium-containing reagent. Depending on the desired site of deuteration, deuterium from DO can be incorporated directly into the compound or into a reagent useful for synthesizing such a compound (Esaki et al., Tetrahedron, 2006, 62, 10954; Esaki et al., Chem. Eur. J., 2007, 13, 4052). Deuterium gas is also a useful reagent for incorporating deuterium into molecules. Catalytic deuteration of olefinic bonds (H.J. Leis et al., Curr. Org. Chem., 1998, 2, 131; J.R. Morandi et al., J. Org. Chem., 1969, 34(6), 1889) and acetylenic bonds (H.H. Han, J. Am. Chem. Soc., 1952, 74(12), 3018; S. Chandrasekhar et al., Tetrahedron, 2011, 52, 3865) are rapid routes for deuterium incorporation. Metal catalysts (i.e., Pd, Pt, and Rh) in the presence of deuterium gas can be used to directly exchange hydrogen for deuterium in hydrocarbon-containing functional groups (J.G. Atkinson et al., U.S. Pat. No. 3,966,781). Various deuterated reagents and synthetic building blocks are commercially available from companies such as C / D / N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc., Princeton, NJ, USA.Further information on the state of the art regarding deuterium-hydrogen exchange can be found, for example, in Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990; R.P. Hanzlik et al., Biochem. Biophys. Res. Commun. 160, 844, 1989; P.J. Reider et al., J. Org. Chem. 52, 3326-3334, 1987; M. Jarman et al., Carcinogenesis 16(4), 683-688, 1993; J. Atzrodt et al., Angew. Chem., Int. Ed. 2007, 46, 7744; K. Matoishi et al., J. Chem. Soc. Chem. Commun. 2000, 1519-1520; K. Kassahun et al., WO2012 / 112363.

[0055] The term "deuterium-containing compound of general formula (I)" is defined as a compound of general formula (I) in which one or more hydrogen atoms are replaced with one or more deuterium atoms, and the abundance of deuterium at each deuteration position of the compound of general formula (I) is greater than the natural abundance of deuterium (about 0.015%). In particular, in a deuterium-containing compound of general formula (I), the abundance of deuterium at each deuteration position of the compound of general formula (I) is greater than 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80%, and in one embodiment, greater than 90%, 95%, 96%, or 97%, and in another embodiment, greater than 98% or 99% at that position. It is understood that the abundance of deuterium at each deuteration position is independent of the abundance of deuterium at other deuteration positions.

[0056] The selective incorporation of one or more deuterium atoms into a compound of general formula (I) can alter the physicochemical properties (e.g., acidity [A. Streitwieser et al., J. Am. Chem. Soc., 1963, 85, 2759; C.L. Perrin et al., J. Am. Chem. Soc., 2007, 129, 4490], basicity [C.L. Perrin et al., J. Am. Chem. Soc., 2003, 125, 15008; C.L. Perrin in Advances in Physical Organic Chemistry, 44, 144; C.L. Perrin et al., J. Am. Chem. Soc., 2005, 127, 9641], lipophilicity [B. Testa et al., Int. J. Pharm., 1984, 19(3), 271]) and / or metabolic profile of the molecule, and can alter the ratio of metabolites to parent compounds or the amount of metabolites formed. Such changes can provide certain therapeutic benefits and may therefore be desirable in some situations. A decrease in the rate of metabolism and metabolic switching (changing the ratio of metabolites) has been reported (DJ Kushner et al., Can. J. Physiol. Pharmacol., 1999, 77, 79; AEMutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). These changes in exposure to parent drugs and metabolites can have important consequences for the pharmacodynamics, tolerability, and efficacy of deuterium-containing compounds of general formula (I). In some cases, deuterium substitution reduces or eliminates the formation of undesirable or toxic metabolites and enhances the formation of desirable metabolites (e.g., Nevirapine: AM Sharma et al., Chem. Res. Toxicol., 2013, 26, 410; Uetrecht et al., Chemical Research in Toxicology, 2008, 21, 9, 1862; Efavirenz: AEMutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). In other cases, the primary effect of deuteration is to decrease the rate of systemic clearance, thereby increasing the biological half-life of the compound.Potential clinical benefits would include the ability to maintain similar systemic exposure with reduced peak levels and increased trough levels. This may result in fewer side effects and enhanced efficacy, depending on the pharmacokinetic / pharmacodynamic relationship of the specific compound. Indiplon (AJ Morales et al., Abstract 285, The Journal of Clinical Oncology, Vol. 15, No. 15, 2015). th North American Meeting of the International Society of Xenobiotics, San Diego, CA, October 12-16, 2008), ML-337 (C.J. Wenthur et al., J.Med.Chem., 2013, 56, 5208), and odanacatib (K. Kassahun et al., WO2012 / 112363) are examples of this deuteration effect. Additional cases have been reported in which a decrease in metabolic rate results in increased drug exposure without altering the rate of systemic clearance (e.g., rofecoxib: F. Schneider et al., Arzneim.Forsch.Drug.Res., 2006, 56, 295; telaprevir: F. Maltais et al., J.Med.Chem., 2009, 52, 7993). Deuterated drugs that exhibit this effect may have reduced dosage requirements (e.g., fewer administrations or lower doses to achieve the desired effect) and / or may produce a lower metabolite burden.

[0057] The compound of general formula (I) may have multiple potential attack sites for metabolism. To optimize the above effects on physicochemical properties and metabolic profile, a deuterium-containing compound of general formula (I) with one or more specific patterns of deuterium-hydrogen exchange can be selected. In particular, the deuterium atoms of the deuterium-containing compound of general formula (I) are bonded to carbon atoms and / or to the cytochrome P of the compound of general formula (I), for example. 450 It is located in a position that is an attack site for metabolic enzymes such as

[0058] When plural forms of words such as compounds, salts, polymorphs, hydrates, solvates, etc. are used herein, this is understood to also mean a single compound, salt, polymorph, isomer, hydrate, solvate, etc.

[0059] By "stable compound" or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0060] The compounds of the present invention may contain one or more asymmetric centers, depending on the location and nature of the various substituents desired. The asymmetric carbon atoms may be in the (R) or (S) configuration, resulting in a racemic mixture in the case of a single asymmetric center, and a diastereomeric mixture in the case of multiple asymmetric centers. In certain instances, asymmetry may also exist due to restricted rotation around a given bond, for example, the central bond adjacent to the two substituted aromatic rings of a particular compound.

[0061] Substituents on a ring may also be present in either the cis or trans form, and all such configurations (including enantiomers and diastereomers) are intended to be included within the scope of the present invention.

[0062] Preferred compounds are those that produce the more desirable biological activity. Also included within the scope of the present invention are separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of the present invention. Purification and separation of such materials can be accomplished by standard techniques known in the art.

[0063] Optical isomers can be obtained by resolving racemic mixtures according to conventional processes, for example, by the formation of diastereomeric salts or covalent diastereomers using optically active acids or bases. Examples of suitable acids are tartaric acid, diacetyltartaric acid, ditoluoyltartaric acid, and camphorsulfonic acid. Diastereomeric mixtures can be separated into their individual diastereomers based on their physical and / or chemical differences by methods known in the art, such as chromatography or fractional crystallization. The optically active base or acid is then liberated from the separated diastereomeric salts. Different methods for the separation of optical isomers include the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivatization, optimally selected to maximize the separation of the enantiomers. Suitable chiral HPLC columns are manufactured by Daicel (e.g., Chiracel OD and Chiracel OJ, among many others), and are all routinely selectable. Enzymatic separations, with or without derivatization, are also useful. The optically active compounds of this invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.

[0064] For the purpose of limiting different types of isomers to one another, see IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).

[0065] The present invention includes all possible stereoisomers of the compounds of the present invention, either as a single stereoisomer or as any mixture of said stereoisomers, e.g., as R- or S-isomers, or E- or Z-isomers, in any ratio. Isolation of a single stereoisomer of a compound of the present invention, e.g., a single enantiomer or a single diastereomer, can be achieved by any suitable state-of-the-art method, such as, for example, chromatography, in particular chiral chromatography.

[0066] Furthermore, the compounds of the present invention may exist as tautomers. For example, any compound of the present invention containing a pyrazole moiety as a heteroaryl group can exist as, for example, a 1H tautomer, or a 2H tautomer, or a mixture of any amounts of the two tautomers, or a triazole moiety can exist as, for example, a 1H tautomer, a 2H tautomer, or a 4H tautomer, or a mixture of any amounts of the 1H, 2H, and 4H tautomers: [ka]

[0067] The present invention includes all possible tautomers of the compounds of the present invention, either as single tautomers or as any mixture of said tautomers, in any proportion.

[0068] Additionally, compounds of the present invention can exist as N-oxides, which are defined in that at least one nitrogen of a compound of the present invention is oxidized, and the present invention encompasses all such possible N-oxides.

[0069] The present invention also relates to useful forms, metabolites, hydrates, solvates, prodrugs, salts, particularly pharmaceutically acceptable salts, and coprecipitates, etc., of the compounds as disclosed herein.

[0070] The compounds of the present invention can exist as hydrates or solvates, where the compounds of the present invention contain polar solvents, particularly water, methanol or ethanol, for example, as structural elements of the crystal lattice of the compounds. The amount of polar solvent, particularly water, can be in a stoichiometric or non-stoichiometric ratio. In the case of stoichiometric solvates, for example, hydrates, hemi-, semi-, mono-, sesqui-, di-, tri-, tetra-, penta-, etc., can be solvates or hydrates, respectively. The present invention includes all such hydrates or solvates.

[0071] Furthermore, the compounds of the present invention can exist in free form, for example as a free base, or as a free acid, or as a zwitterion, or can exist in the form of a salt, which can be either an organic or inorganic addition salt, in particular any pharmaceutically acceptable organic or inorganic addition salt conventionally used in pharmacy.

[0072] The term "pharmaceutically acceptable salts" refers to relatively non-toxic, inorganic or organic acid addition salts of compounds of the present invention. See, e.g., S. M. Berge et al., "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19.

[0073] Suitable pharmaceutically acceptable salts of the compounds of the present invention can be, for example, acid addition salts of compounds of the present invention having a nitrogen atom in the chain or ring, e.g., sufficiently basic, for example, acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, bisulfuric acid, phosphoric acid or nitric acid, or acid addition salts with formic acid, acetic acid, acetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)-benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthonic acid, nicotinic acid, pamoic acid, pectic acid, persulfate, 3-phenyl Acid addition salts with organic acids such as propionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, paratoluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid, and thiocyanic acid.

[0074] Further suitable pharmaceutically acceptable salts of compounds of the invention that are sufficiently acidic are alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, ammonium salts, or salts with organic bases that provide physiologically acceptable cations, such as N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, dicyclohexylamine, 1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-aminomethane, aminopropanediol, sovak's base, 1-amino-2,3,4-butanetriol. Additionally, basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides, e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates, such as dimethyl, diethyl, and dibutyl sulfates; and diamyl sulfate, long chain halides, such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; and aralkyl halides, such as benzyl and phenethyl bromide.

[0075] Those skilled in the art will further recognize that acid addition salts of the claimed compounds can be prepared via any of a number of known methods by reacting the compounds with the appropriate inorganic or organic acid. Alternatively, alkali and alkaline earth metal salts of acidic compounds of the invention are prepared via a variety of known methods by reacting the compounds of the invention with the appropriate base.

[0076] The present invention includes all possible salts of the compounds of the present invention, either as single salts or as any mixture of said salts, in any proportion.

[0077] When compounds are referred to herein, particularly in the experimental part, for the synthesis of intermediates and examples of the present invention, as salt forms with corresponding bases or acids, the exact stoichiometry of said salt forms obtained by the respective preparation and / or purification process is in most cases unknown.

[0078] Unless otherwise specified, for example, "hydrochloride", "trifluoroacetate", "sodium salt", or "xHCl", "xCF3COOH", "xNa + A suffix to a chemical name or structural formula such as "" should be understood to simply refer to the salt form and not to a stoichiometric specification.

[0079] This also applies if the synthetic intermediates or example compounds or salts thereof are obtained by the described preparation and / or purification processes as solvates, such as hydrates, of unknown stoichiometry (if defined).

[0080] Salts include water-insoluble salts and particularly water-soluble salts.

[0081] Furthermore, derivatives of the compound of formula (I) and their salts (bioprecursors or prodrugs) that are converted to the compound of formula (I) or its salt in a biological system are encompassed by the present invention. The biological system is, for example, a mammalian organism, particularly a human subject. The bioprecursors are, for example, converted to the compound of formula (I) or its salt by metabolic processes.

[0082] As used herein, the term "in vivo hydrolyzable ester" is understood to mean an in vivo hydrolyzable ester of a compound of the present invention containing a carboxy or hydroxy group, for example, a pharmaceutically acceptable ester that is hydrolyzed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically acceptable esters for carboxy include, for example, alkyl, cycloalkyl, and optionally substituted phenylalkyl, particularly benzyl ester, C-C alkoxymethyl ester, for example, methoxymethyl, C-C alkanoyloxymethyl ester, for example, pivaloyloxymethyl, phthalidyl ester, C-C cycloalkoxycarbonyloxy-C-C alkyl ester, for example, 1-cyclohexylcarbonyloxyethyl, 1,3-dioxolen-2-onylmethyl ester, for example, 5-methyl-1,3-dioxolen-2-onylmethyl, and C-C alkoxycarbonyloxyethyl ester, for example, 1-methoxycarbonyloxyethyl, and may be formed at any carboxy group in the compound of the present invention.

[0083] In vivo hydrolyzable esters of the compounds of the present invention containing a hydroxy group include inorganic esters such as phosphate esters and [α]-acyloxyalkyl ethers, as well as related compounds that yield the parent hydroxy group as a result of in vivo hydrolysis of the ester decomposition. Examples of [α]-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. The in vivo hydrolyzable ester-forming groups selected for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (yielding alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (yielding carbamates), dialkylaminoacetyl, and carboxyacetyl. The present invention encompasses all such esters.

[0084] Furthermore, the present invention includes all possible crystalline forms or polymorphs of the compounds of the present invention, either as a single polymorph or as a mixture of two or more polymorphs, in any proportion.

[0085] In the context of the properties of the compounds of the present invention, the term "pharmacokinetic profile" refers to one single parameter or a combination thereof, including pharmacodynamic parameters such as permeability, bioavailability, exposure, and duration, or the magnitude of pharmacological effect, as measured in appropriate experiments. A compound with an improved pharmacokinetic profile can, for example, be used at a lower dose to achieve the same effect, can achieve a longer duration of action, or can achieve a combination of both effects.

[0086] The term "combination" as used herein is used as known to those skilled in the art and may exist as a fixed combination, a loose combination, or a kit-of-parts.

[0087] The term "fixed combination" in the present invention is used as known to those skilled in the art and is defined as a combination in which the first active ingredient and the second active ingredient are present together in one unit dose or single entity. One example of a "fixed combination" is a pharmaceutical composition in which the first active ingredient and the second active ingredient are present in admixture for simultaneous administration, such as in a formulation. Another example of a "fixed combination" is a pharmaceutical combination in which the first active ingredient and the second active ingredient are present in one unit, not in admixture.

[0088] A "non-fixed combination" or "kit-of-parts" as used herein is used as known to those skilled in the art and is defined as a combination in which the first active ingredient and the second active ingredient are present in two or more units. An example of a non-fixed combination or kit-of-parts is a combination in which the first active ingredient and the second active ingredient are present separately. The components of a non-fixed combination or kit-of-parts may be administered separately, sequentially, simultaneously, concurrently, or chronologically staggered. Any such combination of a compound of formula (I) of the present invention with an anti-cancer agent as defined below is an embodiment of the present invention.

[0089] The term "(chemotherapeutic) anti-cancer agent" refers to any agent that reduces the survival or proliferation of cancer cells, including, but not limited to: 131I-chTNT, abarelix, abiraterone, aclarubicin, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alemtuzumab, alendronate, alitretinoin, altretamine, amifostine, aminoglutethimide, hexylaminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anetholedithiourethion, angiotensin II, antithrombin III, aprepitant, arcitumomab, aruglavin, arsenic trioxide, asparaginase, axiticin Nib, azacitidine, basiliximab, belotecan, bendamustine, belinstat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib, calcium folinate, calcium levofolinate, capecitabine, capromab, carboplatin, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, ceritinib, cetuximab, chlorambucil, chlormadib Non, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronate, clofarabine, copanlisib, crisantaspase, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, docetaxel, dolasetron, doxif Luridin, doxorubicin, doxorubicin + estrone, dronabinol, eculizumab, edrecolomab, elliptinium acetate, eltrombopag, endostatin, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine,Fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoterate meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, glucarpidase, glutoxim, GM-CSF, goserelin, granisetron, granulocyte colony-stimulating factor, histamine dihydrochloride, histrelin, hydroxycarbamide, I-125 seed, lansoprazole, ibandronate, ibritumomab Tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate, interferon alpha, interferon beta, interferon gamma, iobitridol, iobenguane (123I), iomeprol, ipilimumab, irinotecan, itraconazole, ixabepilone, lanreotide , Lapatinib, Iasocholine, Lenalidomide, Lenograstim, Lentinan, Letrozole, Leuprorelin, Levamisole, Levonorgestrel, Levothyroxine sodium, Lisuride, Lobaplatin, Lomustine, Lonidamine, Masoprocol, Medroxyprogesterone, Megestrol, Melarsoprol, Melphalan, Mepitiostane, Mercaptopurine, Mesna, Methadone, methotrexate, methoxsalen, methyl aminolevulinate, methylprednisolone, methyltestosterone, metyrosine, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphine hydrochloride, morphine sulfate, nabilone, nabiximols, nafa Relin, naloxone + pentazocine, naltrexone, nartograstim, nedaplatin, nelarabine, neridronic acid, nivolumab pentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, omacetaxine mepesuccinate, omeprazole,Ondansetron, oprelvekin, orgotein, orilotimod, osimertinib, oxaliplatin, oxycodone, oxymetholone, ozogamicin, p53 gene therapy, paclitaxel, palifermin, palladium-103 seed, palonosetron, pamidronate, panitumumab, pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alfa-2b, pemetrexed, pentazocine, pentostatin, Puromycin, perflubutane, perfosfamide, pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, poliglusum, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium, poziotinib, pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium-223 chloride, radtipine Nib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib, regorafenib, risedronate, etidronate rhenium-186, rituximab, romidepsin, romiplostim, romurtide, roniciclib, samarium (153Sm) lexidronam, sargramostim, satumomab, secretin, sipuleucel-T, sizofiran, sobuzoxane, glycidazole sodium, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin, tamibarote tamoxifen, tapentadol, tasonermin, teceleukin, technetium (99mTc) nofetumomab merpentane, 99mTc-HYNIC-[Tyr3]-octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, human thyrotropin alpha, thioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, tramadol,Trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, varatinib, valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin.

[0090] "Epidermal growth factor receptor (EGFR) polypeptide" refers to a polypeptide having at least about 95% amino acid sequence identity to the sequence provided in UniProt Accession No. P00533-1, or a fragment thereof. In some embodiments, the EGFR fragment binds to an EGFR ligand and / or has kinase activity. Mutant EGFR polypeptides include, for example, those having an insertion between amino acids V769 and D770, or between D770 and N771. In other embodiments, the amino acid sequence identity is 96, 97, 98, 99, or 100% to UniProt Accession No. P00533-1.

[0091] An exemplary full-length sequence of human EGFR, with V769, D770, and N771 in bold, is provided in UniProt accession number P00533-1 and is reproduced below: 10 20 30 40 50 MRPSGTAGAA LLALLAALCP ASRALEEKKV CQGTSNKLTQ LGTFEDHFLS 60 70 80 90 100 LQRMFNNCEV VLGNLEITYV QRNYDLSFLK TIQEVAGYVL IALNTVERIP 110 120 130 140 150 LENLQIIRGN MYYENSYALA VLSNYDANKT GLKELPMRNL QEILHGAVRF 160 170 180 190 200 SNNPALCNVE SIQWRDIVSS DFLSNMSMDF QNHLGSCQKC DPSCPNGSCW 210 220 230 240 250 GAGEENCQKL TKIICAQQCS GRCRGKSPSD CCHNQCAAGC TGPRESDCLV 260 270 280 290 300 CRKFRDEATC KDTCPPLMLY NPTTYQMDVN PEGKYSFGAT CVKKCPRNYV 310 320 330 340 350 VTDHGSCVRA CGADSYEMEE DGVRKCKKCE GPCRKVCNGI GIGEFKDSLS 360 370 380 390 400 INATNIKHFK NCTSISGDLH ILPVAFRGDS FTHTPPLDPQ ELDILKTVKE 410 420 430 440 450 ITGFLLIQAW PENRTDLHAF ENLEIIRGRT KQHGQFSLAV VSLNITSLGL 460 470 480 490 500 RSLKEISDGD VIISGNKNLC YANTINWKKL FGTSGQKTKI ISNRGENSCK 510 520 530 540 550 ATGQVCHALC SPEGCWGPEP RDCVSCRNVS RGRECVDKCN LLEGEPREFV 560 570 580 590 600 ENSECIQCHP ECLPQAMNIT CTGRGPDNCI QCAHYIDGPH CVKTCPAGVM 610 620 630 640 650 GENNTLVWKY ADAGHVCHLC HPNCTYGCTG PGLEGCPTNG PKIPSIATGM 660 670 680 690 700 VGALLLLLVV ALGIGLFMRR RHIVRKRTLR RLLQERELVE PLTPSGEAPN 710 720 730 740 750 QALLRILKET EFKKIKVLGS GAFGTVYKGL WIPEGEKVKI PVAIKELREA 760 770 780 790 800 TSPKANKEIL DEAYVMASVD NPHVCRLLGI CLTSTVQLIT QLMPFGCLLD 810 820 830 840 850 YVREHKDNIG SQYLLNWCVQ IAKGMNYLED RRLVHRDLAA RNVLVKTPQH 860 870 880 890 900 VKITDFGLAK LLGAEEKEYH AEGGKVPIKW MALESILHRI YTHQSDVWSY 910 920 930 940 950 GVTVWELMTF GSKPYDGIPA SEISSILEKG ERLPQPPICT IDVYMIMVKC 960 970 980 990 1000 WMIDADSRPK FRELIIEFSK MARDPQRYLV IQGDERMHLP SPTDSNFYRA 1010 1020 1030 1040 1050 LMDEEDMDDV VDADEYLIPQ QGFFSSPSTS RTPLLSSLSA TSNNSTVACI 1060 1070 1080 1090 1100 DRNGLQSCPI KEDSFLQRYS SDPTGALTED SIDDTFLPVP EYINQSVPKR 1110 1120 1130 1140 1150 PAGSVQNPVY HNQPLNPAPS RDPHYQDPHS TAVGNPEYLN TVQPTCVNST 1160 1170 1180 1190 1200 FDSPAHWAQK GSHQISLDNP DYQQDFFPKE AKPNGIFKGS TAENAEYLRV 1210 APQSSEFIGA An exemplary polynucleotide encoding EGFR is provided in NCBI Reference Sequence: NM_001346897.1, which is reproduced below: 1 gtccgggcag cccccggcgc agcgcggccg cagcagcctc cgccccccgc acggtgtgag 61 cgcccgacgc ggccgaggcg gccggagtcc cgagctagcc ccggcggccg ccgccgccca 121 gaccggacga caggccacct cgtcggcgtc cgcccgagtc cccgcctcgc cgccaacgcc 181 acaaccaccg cgcacggccc cctgactccg tccagtattg atcgggag ccggagcgag 241 ctcttcgggg agcagcgatg cgaccctccg ggacggccgg ggcagcgctc ctggcgctgc 301 tggctgcgct ctgcccggcg agtcgggctc tggaggaaaa gaaagtttgc caaggcacga 361 gtaacaagct cacgcagttg ggcacttttg aagatcattt tctcagcctc cagaggatgt 421 tcaataactg tgaggtggtc cttgggaatt tggaaattac ctatgtgcag aggaattatg 481 atctttcctt cttaaagacc atccaggagg tggctggtta tgtcctcatt gccctcaaca 541 cagtggagcg aattccttg gaaaacctgc agatcatcag aggaatatg tactacgaaa 601 attcctatgc cttagcagtc ttactact atgatgcaa taaaaccgga ctgaggagc 661 tgcccatgag aaatttacag ggccaaagt gtgatccaag ctgtcccaat gggagctgct 721 gggtgcagg agaggagaac tgccagaac tgaccaaat catctgtgcc cagcagtgct 781 ccggcgctg ccgtggcaag tcccagtg actgctgcca caaccagtgt gctgcaggct 841 gcacaggccc ccgggagc gactgcctgg tctgccgcaa attccgagac gaagccacgt 901 gcaggacac ctgccccca ctcatgctct acacccac cacgtaccag atggatgtga 961 accccgaggg caatacagc tttggtgcca cctgcgtgaa gaagtgtccc cgtaattatg 1021 tggtgacaga tcacggctcg tgcgtccgag cctgtggggc cgacagctat gagatggagg 1081 aagacggcgt ccgcaagtgt aagaagtgcg aagggccttg ccgcaagtg tgtaacggaa 1141 taggtattgg tgaatttaaa gactcactct ccataaatgc tacgaatatt aaacactca 1201 aaaactgcac ctccatcagt ggggatctcc acatctgcc ggtggcattt agggtgact 1261 ccttcacaca tactcctcct ctggatccac aggaactgga tattctgaaa accgtaaagg 1321 aaatcacagg gtttttgctg attcaggctt ggcctgaaaa caggacggac ctccatgcct 1381 1441 tcgtcagcct gaacataaca tccttgggat tacgctccct caaggagata agtgatggag 1501 1561 tgtttgggac ctccggtcag aaaaccaaaa ttataagcaa cagaggtgaa aacagctgca 1621 aggccacagg ccaggtctgc catgccttgt gctcccccga gggctgctgg ggcccggagc 1681 ccagggactg cgtctcttgc cggaatgtca gccgaggcag ggaatgcgtg gacaagtgca 1741 accttctgga gggtgagcca agggagtttg tggagaactc tgagtgcata cagtgccacc 1801 cagagtgcct gcctcaggcc atgaacatca cctgcacagg acgggggacca gacaactgta 1861 tccagtgtgc ccactacatt gacggccccc actgcgtcaa gacctgcccg gcaggagtca 1921 tgggagaaaa caacaccctg gtctggagagt acgcagacgc cggccatgtg tgccacctgt 1981 gccatccaaa ctgcacctac ggatgcactg ggccaggtct tgaaggctgt ccaacgaatg 2041 ggcctaagat cccgtccatc gccactggga tggtggggc cctcctcttg ctgctggtgg 2101 tggccctggg gatcggcctc ttcatgcgaa ggcgccacat cgttcggaag cgcacgctgc 2161 ggaggctgct gcaggagagg gagcttgtgg agcctcttac acccagtgga gaagctccca 2221 accaagctct cttgaggatc ttgaaggaaa ctgaattcaa aaagatcaaa gtgctgggct 2281 ccggtgcgtt cggcacggtg tataagggac tctggatccc agaaggtgag aaagttaaaa 2341 ttcccgtcgc tatcaaggaa ttagagaag caacatctcc gaagccaac aaggaaatcc 2401 tcgatgaagc ctacgtgatg gccagcgtgg acaaccccca cgtgtgccgc ctgctgggca 2461 tctgcctcac ctccaccgtg cagctcatca cgcagctcat gcccttcggc tgcctcctgg 2521 actatgtccg ggaacaaa gaatattg gctcccagta cctgctcaac tggtgtgtgc 2581 agatcgcaaa gggcatgaac tacttggagg accgtcgctt ggtgcaccgc gacctggcag 2641 ccaggaacgt actggtgaaa acaccgcagc atgtcaagat cacagatttt gggctggcca 2701 aactgctggg tgcggaagag aaagaatacc atgcagaagg aggcaaagtg cctatcaagt 2761 ggatggcatt ggaatcaatt ttacacagaa tctataccca ccagagtgat gtctggagct 2821 acggggtgac tgtttgggag ttgatgacct ttggatccaa gccatatgac ggaatccctg 2881 ccagcgagat ctcctccatc ctggagaaag gagaacgcct ccctcagcca cccatatgta 2941 ccatcgatgt ctacatgatc atggtcaagt gctggatgat agacgcagat agtcgcccaa 3001 agttccgtga gttgatcatc gaattctcca aaatggcccg agacccccag cgctaccttg 3061 tcattcaggg ggatgaaaga atgcatttgc caagtcctac agactccaac ttctaccgtg 3121 ccctgatgga tgaagaagac atggacgacg tggtggatgc cgacgagtac ctcatcccac 3181 agcagggctt cttcagcagc ccctccacgt cacggactcc cctcctgagc tctctgagtg 3241 caaccagcaa caattccacc gtggcttgca ttgatagaaa tgggctgcaa agctgtccca 3301 tcaaggaaga cagcttcttg cagcgataca gctcagaccc cacaggcgcc ttgactgagg 3361 acagcataga cgacaccttc ctcccagtgc ctggtgagtg gcttgtctgg aaacagtcct 3421 gctcctcaac ctcctcgacc cactcagcag cagccagtct ccagtgtcca agccaggtgc 3481 tccctccagc atctccagag ggggaaacag tggcagattt gcagacacag tgaagggcgt 3541 aaggagcaga taaacacatg accgagcctg cacaagctct ttgttgtgtc tggttgtttg 3601 ctgtacctct gttgtaagaa tgaatctgca aaatttctag cttatgaagc aaatcacgga 3661 catacacatc tgtgtgtgtg agtgttcatg atgtgtgtac atctgtgtat gtgtgtgtgt 3721 gtatgtgtgt gtttgtgaca gatttgatcc ctgttctctc tgctggctct atcttgacct 3781 gtgaaacgta tatttaacta attaaatatt agttaatatt aataaatttt aagctttatc 3841 cagaaaaaaa aaaaaaaaa The intermediates used in the synthesis of the compounds of claims 1 to 4 described below, as well as their use for the synthesis of the compounds of claims 1 to 4, are further aspects of the present invention. Preferred intermediates are the intermediate examples disclosed below.

[0092] General Procedure The compounds according to the present invention can be prepared according to the following Schemes 1 to 4.

[0093] The schemes and procedures described below are illustrative of the synthetic routes to the compounds of general formula (I) of the present invention, but are not intended to be limiting. It is clear to those skilled in the art that the order of the transformations illustrated in the schemes can be modified in various ways. Therefore, the order of the transformations illustrated in the schemes is not intended to be limiting. Furthermore, any substitution R 1 , R 2 , R 3 , R 4 , R 5 , R 6 The interconversion of PG and PG can be achieved before or after the exemplified transformations. These modifications can be the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, methylation, substitution, or other reactions known to those skilled in the art. These transformations include transformations that introduce functional groups that allow further interconversion of substituents. Suitable protecting groups and their introduction and cleavage are well known to those skilled in the art. Specific examples are described in the following paragraphs.

[0094] Scheme 1 : [ka]

[0095] Scheme 1: Route for the preparation of compounds of general formula (I), where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, Y, m and n have the meanings given in general formula (I), and PG can be hydrogen or a suitable protecting group, such as tert-butoxycarbonyl (Boc).

[0096] Compounds of Formulas 1, 2, and 4 are either commercially available or can be prepared according to procedures available in the public domain, as will be appreciated by those skilled in the art. Specific examples are described in the following paragraphs.

[0097] A suitably substituted piperazine-2,4-diones of general formula (compounds of formula 1), such as 2,4-piperazinion, can be reacted with a suitably substituted isothiocyanate (compounds of formula 2), such as 3-fluorophenylisothiocyanate, in a suitable solvent system, such as acetonitrile, in the presence of a suitable base, such as triethylamine or DBU, at temperatures ranging from −78° C. to +100° C.; in some embodiments, the reaction is carried out at 0° C. or +100° C. to give compounds of general formula (3). Similar reactions have been reported in the literature (D.E. Worrall, J. Am. Chem. Soc., 1940, 62, 675).

[0098] The intermediate of general formula (3) can be converted to an intermediate of general formula (5) by reacting with a suitable amine (compound of general formula 4), for example, 4-(aminomethyl)pyridine, in a suitable solvent system, for example, ethanol and ethyl acetate, at a temperature between room temperature and the boiling point of the respective solvent, in some embodiments, the reaction is carried out at the boiling point of the respective solvent, whereby water formed in the reaction is removed from the reaction by methods known to those skilled in the art, for example, azeotropic removal of water (Dean-Stark conditions) or using molecular sieves, to provide the intermediate of general formula (5).

[0099] The intermediates of general formula (3) and general formula (5), in which PG represents a protecting group, can be converted to intermediates in which PG represents a hydrogen atom using standard deprotection conditions known to those skilled in the art. When PG is a protecting group, such as tert-butoxycarbonyl (Boc), the deprotection can be carried out using an acid, such as hydrochloric acid and trifluoroacetic acid, in a suitable solvent system, such as dichloromethane and dioxane, at a temperature between 0°C and the boiling point of the respective solvent; in one embodiment, the reaction is carried out at room temperature to provide compounds of general formula (3) and intermediates of general formula (5), in which PG is a hydrogen atom.

[0100] The intermediate of general formula (5) is reacted with a base and / or an oxidizing reagent, in one embodiment an oxidizing agent such as hydrogen peroxide or SIBX (stabilized iodoxybenzoic acid), in a suitable solvent system, such as methanol, at a temperature ranging from −30° C. to the boiling point of the respective solvent, in one embodiment the reaction is carried out at the boiling point of the respective solvent, to provide a compound of general formula (I). Optionally, these types of reactions can be carried out using an additive such as an acid or a base, for example, but not limited to, acetic acid or trifluoroacetic acid, and triethylamine or diisopropylethylamine.

[0101] Intermediates of general formula (5) can be converted to compounds of general formula (I) by thermally heating them in a suitable solvent at elevated temperatures (which can be above the boiling point of the solvent, for example, from room temperature to +250°C). These reactions can optionally be carried out in a vessel capable of increasing pressure, such as an autoclave. Intermediates of general formula (5) can also be converted to compounds of general formula (I) by thermally heating them in a suitable solvent, such as, but not limited to, DMF, DMA, EtOH, MeOH, NMP, at elevated temperatures, for example, from room temperature to +150°C, in the presence of a metal catalyst, such as, for example, palladium on activated carbon. Optionally, these types of reactions can be carried out using an additive, such as an acid or base, for example, acetic acid or trifluoroacetic acid (but not limited to), and triethylamine or diisopropylethylamine (but not limited to), to obtain compounds of general formula (I).

[0102] Scheme 2 : [ka]

[0103] Scheme 2: Method for preparing compounds of general formula (4), where R 4 , R 5 , R 6 , X, Y, m and n have the meanings given in general formula (I).

[0104] Compounds of general formula (6) can be converted to compounds of general formula (7) by treatment with a suitable nucleophile, such as an amine, alcohol, metal alkoxide, azide, thiol, or metal thiolate, under basic, neutral, acidic, or catalytic conditions, in one embodiment, under basic conditions in a suitable solvent, or with a solvent such as DMF or tetrahydrofuran (THF) as the nucleophile, at a temperature ranging from -78°C to the boiling point of the respective solvent, and in one embodiment, the reaction is carried out at a temperature ranging from -10°C to the boiling point of the respective solvent, to give compounds of general formula (7). Such substitution reactions have been previously reported (Clark et al., J. Med. Chem., 2008, 51, 6631-6634; Guo et al., Tetrahedron Letts., 2013, 54, 3233-3237; Watterson et al., J.Med.Chem., 2007, 50, 3730-3742; Bellale et al., J.Med.Chem., 2014, 57, 6572-6582; Klimesova et al., Eur.J.Med.Chem., 1996, 31, 389-395; Leroy et al., Synth.Commun., 1997, 27, 2905-2916; LaMattina et al., J.Org.Chem., 1981, 46, 4179-4182; Beugelmans et al., Tetrahedron, 1983, 39, 4153-4162).

[0105] Compounds of general formula (7) can be reduced by many methods known to those skilled in the art using a number of different reagents and reaction conditions; such methods and reagents can be carried out, for example, using metal hydrides such as lithium aluminum hydride in THF (Bullock et al., J. Am. Chem. Soc., 1956, 78, 490; Wang et al., J. Org. Chem., 2006, 71, 4021-3160), or using zinc in acetic acid (Rabe, Chem. Ber., 1913, 46, 1024), or using diborane (De Munno et al., Heterocycles, 1996, 43, 1893-1900), or catalytic hydrogenation methods, for example, using hydrogen and palladium on carbon under acidic conditions (Stokker et al., J. Med. Chem., 1981, 24, 115-117; Bertini et al., J. Med. Chem., 2005, 48, 664-670), or using hydrogen and nickel under basic conditions (Walpole et al., J. Med. Chem., 1993, 36, 2362-2372; Kuramochi et al., Bioorg. Med. Chem., 2005, 13, 4022-4036), can be used to convert to compounds of formula (4).

[0106] Scheme 3: [ka]

[0107] Scheme 3: Method for the preparation of compounds of general formula 2, where R 1a R in the general formula (I) means methoxy and difluoromethoxy. 1 The synthesis of compounds 9 and 10 involves alkoxy substitution of the phenyl ring. However, the synthesis of product 2 containing an isothiocyanate (i.e., 10→2 or 11→2) involves the synthesis of compound 10, which is similar to the synthesis of compound 10, but does not involve the synthesis of compound 11, which is similar to the synthesis of compound 10, but does involve the synthesis of compound 11, which is similar to the synthesis of compound 10, which is similar to 1 It is generally based on

[0108] Compounds of general formula (8) can be converted to compounds of general formula (9) using a variety of methods known to those skilled in the art. Such conversions can be, for example, alkylating the phenolic alcohol with an alkylating agent, such as an alkyl halide or alkyl sulfonate, where the alkyl group can optionally contain a fluoride or alkoxy group. Alkylation reactions using these various methods are known to those skilled in the art: i) K2CO3 in solvents such as DMF, acetone, DMFA (see the teachings of Muro et al., J. Med. Chem., 2009, 52, 7974 and WO2009 / 20990A1); ii) KOH in EtOH (see the teachings of Macias et al., J. Agric. Food. Chem., 2006, 54, 9843); iii) Mitsunobu reaction (see the teachings of US2006 / 122168A1 and EP2151431A1), giving intermediates of general formula (9).

[0109] Compounds of general formula (9) can be converted to compounds of general formula (10) by reduction methods, which are known to those skilled in the art. These reductions can be carried out using i) hydrogen gas and a catalyst (see the teachings of Chan et al., J. Am. Chem. Soc., 2011, 133, 2989 for Pd / C as a catalyst; see the teachings of Niemann et al., J. Am. Chem. Soc., 1941, 63, 2204 for platinum; see the teachings of US 2009 / 253767 A1 for Raney-nickel); ii) iron and ammonium chloride (see the teachings of Sweeney et al., Bioorg. Med. Chem. Lett., 2008, 18, 4348); iii) sodium dithionite (see the teachings of Chong et al., J. Med. Chem., 2012, 55, 10601); iv) zinc and ammonium chloride (see the teachings of WO 2010 / 42699 A1) to give intermediates of general formula (10).

[0110] Compounds of general formula (10) can be converted to compounds of general formula (2) by using reagents such as, for example, thiophosgene, carbon disulfide, 1,1"-thiocarbonyldi-2(1H)-pyridone, or 1,1'-thiocarbonyldiimidazole; in one embodiment, thiophosgene, under basic conditions, for example, in dichloromethane, chloroform, acetone, or a biphasic mixture, for example, dichloromethane, chloroform, and aqueous basic solution; in another embodiment, dichloromethane and saturated aqueous sodium bicarbonate or sodium carbonate; at temperatures ranging from -78°C to the boiling point of the respective solvent; in another embodiment, the reaction is carried out at 0°C to room temperature, to provide compounds of general formula (2). Such conversion reactions have been previously reported (Harris et al., J. Med. Chem., 2005, 48, 1610; Degorce et al., Tetrahedron Lett., 2011, 52, 6719; WO2016 / 91845A1; Fairhurst et al., Org. Lett., 2005, 7, 4697; Chaskar et al., Synth. Commun., 2008, 38, 16940; US2004 / 122237A1).

[0111] Scheme 4 : [ka]

[0112] Scheme 4: Route for the preparation of compounds of general formula (I), where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, Y, m and n have the meanings given in general formula (I), and PG represents hydrogen or a suitable protecting group such as, for example, tert-butoxycarbonyl (Boc).

[0113] Compounds similar to compounds of general formula 12 are known to those skilled in the art and their synthesis has been reported in the literature (see the teachings of Voss et al., WO2015 / 22073A1; Hart et al., WO2016 / 100166A1; Anderson et al., J. Med. Chem., 2007, 50, 2647; Vanotti et al., J. Med. Chem., 2008, 51, 487).

[0114] Compounds of general formula (12) can be converted to compounds of general formula (13) using standard bromination methods known to those skilled in the art (WO 2016 / 100166 A1). Such bromination can be carried out, for example, using a brominating agent such as N-bromosuccinimide in a suitable solvent such as DMF at a temperature ranging from −78° C. to the boiling point of the solvent; in one embodiment, the temperature range is from 0° C. to RT.

[0115] Intermediates of general formula (13) can be reacted with an appropriate aniline, such as 2-difluoromethoxyaniline, in the presence of a base, such as lithium bis(trimethylsilyl)amide (LHMDS), in the presence of a catalyst, such as 2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl (tBuBrettPhos), and in the presence of a pre-catalyst, such as a palladium pre-catalyst, or in another embodiment, in the presence of chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (BrettPhos-PreCat MTBE ether adduct), in a suitable solvent system, such as tetrahydrofuran (THF), at a temperature range of 0°C to 200°C. In one embodiment, the reaction is carried out at 80° C. to give a compound of general formula (I). Similar transformations have been carried out and reported (WO2015 / 193339A1).

[0116] Scheme 5: [ka]

[0117] Scheme 5: Route for the preparation of compounds of general formula (I), where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, Y, m and n have the meanings given in general formula (I), and PG represents a suitable protecting group such as, for example, tert-butoxycarbonyl (Boc).

[0118] Compounds similar to those of general formula (14) can be prepared according to the procedure described in Scheme 1, using 4-(aminomethyl)-3-hydroxypyridine instead of intermediate (4). The intermediate of general formula (14) can be converted to compounds of general formula (I) using a suitable alcohol, such as oxetan-3-ylmethanol, under Mitsunobu conditions (see Oyo Mitsunobu, Synthesis, 1981, pp. 1-28, or Tsunoda et al., Tetrahedron Lett., 1994, 35, 5081), in the presence of (tributylphosphoranylidene)acetonitrile or triphenylphosphine and diisopropyl azodicarboxylate in a suitable solvent system, such as dioxane or THF, at a temperature between room temperature and the boiling point of the respective solvent.

[0119] It is known to those skilled in the art that when multiple reactive centers are present on a starting compound or intermediate compound, it may be necessary to temporarily block one or more reactive centers with a protecting group in order to allow the reaction to proceed specifically at the desired reactive center.

[0120] The compounds of the present invention can be isolated and purified in a manner known per se, for example, by vacuum distillation of the solvent and recrystallization of the resulting residue from a suitable solvent, or by one of the usual purification methods, such as chromatography on a suitable support material. Furthermore, reverse-phase preparative HPLC may be applied. Compounds of the present invention having sufficiently basic or acidic functionality can be converted into salts, such as trifluoroacetate or formate salts in the case of sufficiently basic compounds, or ammonium salts in the case of sufficiently acidic compounds. These types of salts can be converted into their free base or free acid forms, respectively, by various methods known to those skilled in the art, or can be used as salts in subsequent biological assays. Furthermore, the drying process during isolation of the compounds of the present invention may not completely remove traces of cosolvents, particularly formic acid or trifluoroacetic acid, to form solvates or inclusion complexes. Those skilled in the art will recognize which solvates or inclusion complexes are acceptable for use in subsequent biological assays. It is to be understood that the particular form (e.g., salt, free base, free acid, solvate, inclusion complex) of a compound of the invention isolated and described herein is not necessarily the only form in which said compound can be applied in a biological assay to determine a specific biological activity.

[0121] Salts of compounds of formula (I) according to the present invention can be obtained by dissolving the free compound in a suitable solvent (e.g., a ketone such as acetone, methyl ethyl ketone, or methyl isobutyl ketone; an ether such as diethyl ether, tetrahydrofuran, or dioxane; a chlorinated hydrocarbon such as methylene chloride or chloroform; or a low molecular weight aliphatic alcohol such as methanol, ethanol, or isopropanol) containing the desired acid or base or to which the desired acid or base is then added. The acids or bases can be used in the preparation of the salt in equimolar or different ratios, depending on whether a monobasic or polybasic acid or base is involved and which salt is desired. The salt can be obtained by filtering, reprecipitating, precipitating with a non-solvent for the salt, or by evaporating the solvent. The obtained salt can be converted into the free compound, which can then be converted into a salt. In this way, pharmaceutically unacceptable salts, for example, obtainable as process products in industrial-scale production, can be converted into pharmaceutically acceptable salts by processes known to those skilled in the art. Particularly preferred are hydrochloride salts and the methods used in the Examples section.

[0122] Pure diastereomers and pure enantiomers of the compounds and salts according to the invention can be obtained, for example, by asymmetric synthesis, by using chiral starting compounds in the synthesis or by resolving the enantiomeric and diastereomeric mixtures obtained in the synthesis.

[0123] Enantiomeric and diastereomeric mixtures can be resolved into pure enantiomers and pure diastereomers by methods known to those skilled in the art. In one embodiment, diastereomeric mixtures are separated by crystallization, particularly fractional crystallization, or chromatography. Enantiomeric mixtures can be separated, for example, by forming diastereomers using a chiral auxiliary, resolving the resulting diastereomers, and removing the chiral auxiliary. For example, chiral acids can be used as chiral auxiliary to separate enantiomeric bases, such as mandelic acid, and chiral bases can be used to separate enantiomeric acids by forming diastereomeric salts. Furthermore, diastereomeric derivatives, such as diastereomeric esters, can be formed from enantiomeric mixtures of alcohols or acids using chiral acids or chiral alcohols, respectively, as chiral auxiliary. Furthermore, diastereomeric complexes or diastereomeric clathrates can be used to separate enantiomeric mixtures. Alternatively, enantiomeric mixtures can be resolved using chiral separation columns in chromatography. Another suitable method for isolating enantiomers is enzymatic separation.

[0124] One preferred embodiment of the present invention is a process for preparing the compounds of claims 1 to 4 according to the examples, as well as intermediates used in their preparation.

[0125] Optionally, the compounds of formula (I) can be converted into their salts, or optionally, the salts of the compounds of formula (I) can be converted into the free compounds. The corresponding processes are conventional for those skilled in the art.

[0126] commercial utility As described above, the compounds of the present invention effectively inhibit mutant EGFR in cells (e.g., cancer cells) contacted with the compounds, thereby inducing cell death (e.g., apoptosis), and therefore, are useful in treating diseases of uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, or diseases involving uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, or in particular diseases in which uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses are mediated by mutant EGFR, such as benign and malignant tumors, more particularly, for example, hematological tumors, solid tumors, and / or their metastases, leukemia and myelodysplastic syndromes, malignant lymphomas. It has surprisingly been found that the compounds of the present invention may be used in the treatment or prevention of tumors of the head and neck, including brain tumors and brain metastases, thoracic tumors, including non-small cell and small cell lung tumors, gastrointestinal tumors, endocrine tumors, breast tumors and other gynecological tumors, urinary tumors, including kidney, tumors of the bladder and prostate, skin tumors, sarcomas, and / or metastases thereof, in particular tumors of the breast, bladder, bone, brain, central and peripheral nervous system, cervix, colon, endocrine glands (e.g., thyroid and adrenal cortex), endocrine tumors, endometrium, esophagus, gastrointestinal tumors, germ cell, kidney, liver, lung, larynx and hypopharynx, mesothelioma, hematological tumors, solid tumors, and / or metastases of the ovaries, pancreas, prostate, rectum, kidney, small intestine, soft tissue, stomach, skin, testes, ureters, vagina and vulva, as well as primary tumors in said organs and corresponding secondary tumors in distant organs ("tumor metastases"). Hematological tumors can be exemplified by, for example, aggressive and indolent forms of leukemia and lymphoma, i.e., non-Hodgkin's disease, chronic and acute myeloid leukemia (CML / AML), acute lymphoblastic leukemia (ALL), Hodgkin's disease, multiple myeloma, and T-cell lymphoma, as well as myelodysplastic syndromes, plasma cell neoplasms, paraneoplastic syndromes, and cancer of unknown primary site, and AIDS-related malignancies.

[0127] A further aspect of the present invention is the use of a compound of formula (I) for the treatment of lung cancer, in particular lung cancer harboring mutant EGFR with exon 20 insertion mutations, more particularly lung cancer harboring V769_770ins ASV and / or D770_N771ins SVD exon 20 insertions, and / or metastases thereof, which comprises administering an effective amount of a compound of formula (I).

[0128] A further aspect of the invention is the use of compounds according to formula (I) for the treatment of lung cancer, in particular lung cancer harboring mutant EGFR with an in-frame deletion in exon 19 (such as EGFR E746_A750del) or a point mutation in exon 21 (e.g., L858R), and / or metastases thereof.

[0129] A further aspect of the invention is the use of a compound according to formula (I) for the treatment of lung cancer, in particular lung cancer with mutant EGFR carrying a D770_N771insSVD C797S, E746_A750del C797S, or L858R C797S acquired resistance mutation, and / or metastases thereof.

[0130] A further aspect of the invention is the use of compounds according to formula (I) for the treatment of lung cancer, in particular lung cancer with mutant ERBB2 having an exon 20 insertion mutation (such as ERBB2 A775_G776insYVMA), and / or metastases thereof.

[0131] Thus, according to one aspect, the present invention relates to a compound of general formula I as described and defined herein, or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer, in particular a pharmaceutically acceptable salt thereof, or a mixture thereof, for use in the treatment or prevention of a disease, in particular for use in the treatment of a disease.

[0132] Therefore, another particular aspect of the present invention is the use of a compound of general formula I above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or salt thereof, in particular a pharmaceutically acceptable salt thereof, or a mixture thereof, for the prevention or treatment of hyperproliferative disorders or disorders responsive to the induction of cell death, i.e. apoptosis.

[0133] "Hyperproliferative disease" refers to a disease, such as cancer, that is associated with inappropriately high levels of cell division, inappropriately low levels of apoptosis, or both. In the context of the present invention, and particularly in the context of an "inappropriate cellular immune response, or an inappropriate cellular inflammatory response," the term "inappropriate," as used herein, should generally be understood to mean a response that is less or more than normal and that is associated with, causes, or results in the pathology of the disease.

[0134] In a particular embodiment, the use is in the treatment or prevention of disease, particularly in the treatment where the disease is a hematological tumor, a solid tumor and / or metastasis thereof.

[0135] Another aspect is the use of compounds of formula (I) for the prevention and / or treatment of lung cancer, in particular lung cancer with mutant EGFR having exon 20 insertion mutations, more particularly lung cancer with V769_770ins ASV and / or D770_N771ins SVD exon 20 insertions, and / or metastasis thereof, the treatment of which is particularly preferred.

[0136] Another aspect of the present invention is the use of a compound of Formula (I) as described herein or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture thereof, in the manufacture of a medicament for treating or preventing a disease, wherein such disease is a hyperproliferative disorder or a disorder responsive to induction of cell death (e.g., apoptosis). In one embodiment, the disease is a hematological tumor, a solid tumor, and / or metastasis thereof. In another embodiment, the disease is lung cancer, particularly lung cancer with a mutant EGFR having an exon 20 insertion mutation, in particular lung cancer containing the V769_770ins ASV and / or D770_N771ins SVD exon 20 insertion, and / or metastasis thereof.

[0137] Methods of Treating Hyperproliferative Disorders The present invention relates to methods of using compounds of the present invention and compositions thereof to treat hyperproliferative disorders in mammals. The compounds can be used to inhibit, block, reduce, decrease, etc., cell growth and / or cell division, and / or cause cell death (e.g., apoptosis). The methods involve administering to a mammal (including a human) in need thereof an amount of a compound of the present invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate, or ester thereof, which is effective to treat the disorder. Hyperproliferative disorders include, but are not limited to, psoriasis, keloids, and other hyperplasias affecting the skin, benign prostatic hyperplasia (BPH), solid tumors, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, and parathyroid, and their distant metastases. These disorders also include lymphomas, sarcomas, and leukemias.

[0138] Examples of breast cancer include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.

[0139] Examples of cancers of the respiratory tract include, but are not limited to, small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.

[0140] Examples of brain tumors include, but are not limited to, brain stem and hypothalamic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor.

[0141] Tumors of the male reproductive organs include, but are not limited to, prostate and testicular cancer. Tumors of the female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as uterine sarcoma.

[0142] Tumors of the digestive tract include, but are not limited to, anal cancer, colon cancer, colorectal cancer, esophageal cancer, gallbladder cancer, gastric cancer, pancreatic cancer, rectal cancer, small intestine cancer, and salivary gland cancer.

[0143] Tumors of the urinary tract include, but are not limited to, bladder cancer, penile cancer, kidney cancer, renal pelvis cancer, ureter cancer, urethral cancer, and human papillary renal carcinoma.

[0144] Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.

[0145] Examples of liver cancer include, but are not limited to, hepatocellular carcinoma (with or without fibrolamellar atypia), cholangiocarcinoma (intrahepatic cholangiocarcinoma), and mixed hepatocellular-biliary carcinoma.

[0146] Skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, inverting sinonasal papilloma, inverting sinonasal papilloma-associated sinonasal squamous cell carcinoma, Merkel cell skin cancer, and non-melanoma skin cancer.

[0147] Head and neck cancers include, but are not limited to, laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, inverted sinonasal papilloma, inverted sinonasal papilloma-associated sinonasal squamous cell carcinoma, lip and oral cavity cancer, and squamous cell carcinoma. Lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt's lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.

[0148] Sarcomas include, but are not limited to, sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.

[0149] Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.

[0150] These disorders are well characterized in humans, but also exist in other mammals with similar etiologies and can be treated by administering the pharmaceutical compositions of the present invention.

[0151] The terms "treating" or "treatment" as used throughout this document are used conventionally as the management or care of a subject with the intent to eradicate, alleviate, reduce, relieve, ameliorate, ameliorate, etc. the state of a disease or disorder, e.g., cancer.

[0152] The present invention relates to a method of treating cancer in a subject, the method comprising administering to the subject an effective amount of a compound of general formula (I) as defined herein.

[0153] The present invention relates to a method of treating cancer in a subject, wherein the cancer is resistant or has acquired resistance to anti-EGF receptor therapy, the method comprising administering to the subject an effective amount of a compound of general formula (I) as defined herein.

[0154] The present invention relates to a method of enhancing the efficacy of anti-EGF receptor therapy, comprising administering to a subject the anti-EGF receptor therapy in combination with a compound of general formula (I) as defined herein.

[0155] In a further embodiment, the present invention relates to a method of treating cancer in a subject, wherein the cancer is selected from the group consisting of leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumors, breast tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urinary tumors, skin tumors, and sarcoma, the method comprising administering to the subject an effective amount of a compound of general formula (I) as defined herein.

[0156] In a further embodiment, the present invention relates to a method of treating cancer in a subject, wherein the cancer is selected from the group consisting of inverting sinonasal papilloma or inverting sinonasal papilloma-associated sinonasal squamous cell carcinoma, the method comprising administering to the subject an effective amount of a compound of general formula (I) as defined herein.

[0157] In a further embodiment, the present invention relates to a method of treating cancer in a subject, wherein the tumour of the breast is non-small cell lung cancer, the method comprising administering to the subject an effective amount of a compound of general formula (I) as defined herein.

[0158] In a further embodiment, the present invention relates to a method of treating cancer in a subject, wherein the cancer is lung cancer, in particular lung cancer with a mutant EGFR having an in-frame deletion in exon 19 (e.g., EGFR E746_A750del), or a point mutation in exon 21 (e.g., L858R), and / or metastasis thereof, the method comprising administering to the subject an effective amount of a compound of general formula (I) as defined herein.

[0159] In a further embodiment, the present invention relates to a method of treating cancer in a subject, wherein the cancer is lung cancer, in particular lung cancer with mutant EGFR carrying a D770_N771insSVD C797S, E746_A750del C797S, or L858R C797S acquired resistance mutation, and / or metastases thereof, the method comprising administering to the subject an effective amount of a compound of general formula (I) as defined herein.

[0160] In a further embodiment, the present invention relates to a method of treating cancer in a subject, wherein the cancer is lung cancer, in particular lung cancer with a mutant ERBB2 having an exon 20 insertion mutation (such as ERBB2 A775_G776insYVMA), and / or metastasis thereof, the method comprising administering to the subject an effective amount of a compound of general formula (I) as defined herein.

[0161] The present disclosure also relates to a method for selecting a patient for cancer treatment with a compound of general formula (I), comprising detecting the presence of a mutation in exon 20 of a gene encoding an EGF receptor in a biological sample from the subject, thereby determining that the patient should be treated with the compound. In some embodiments, the EGFR contains a D770_N771insSVD C797S, E746_A750del C797S, or L858R C797S acquired resistance mutation, and / or a translocation thereof. In some embodiments, the method for selecting a patient for cancer treatment with a compound of general formula (I) can include detecting the presence of an in-frame deletion in exon 19 or a point mutation in exon 21 of a gene encoding an EGF receptor in a biological sample from the subject, thereby determining that the patient should be treated with the compound. For example, the in-frame deletion in exon 19 can be EGFR E746_A750del, or the point mutation in exon 21 can be L858R. In some embodiments, a method for selecting a patient for cancer treatment with a compound of general formula (I) can include detecting the presence of a mutation in exon 20 of the gene encoding ERBB2 in a biological sample from the subject, thereby determining that the patient should be treated with the compound. In some embodiments, the ERBB2 contains an ERBB2 A775 or _G776insYVMA insertion mutation, and / or a transposition thereof. Furthermore, a method for treating a patient with cancer can include administering a compound of general formula (I) to the subject (e.g., in combination with anti-EGF receptor therapy), and the subject is selected for treatment by detecting the presence of a mutation in EGFR in the subject's biological sample. Detecting the presence of a mutation in exon 20 is within the skill of one of ordinary skill in the art. In some embodiments, detection of mutations (e.g., mutations in exon 20 of EGFR or the gene encoding EGFR) can be performed by sequencing (e.g., Sanger, next-generation sequencing), or by a method selected from the group consisting of immunoblotting, mass spectrometry, immunoprecipitation quantitative PCR, Northern blot, microarray, enzyme-linked immunosorbent assay (ELISA), in situ hybridization, and combinations thereof.

[0162] Methods for treating kinase disorders The present invention also provides methods for treating disorders associated with aberrant mitogenic extracellular kinase activity, including, but not limited to, stroke, heart failure, hepatomegaly, cardiac hypertrophy, diabetes, Alzheimer's disease, cystic fibrosis, conditions of xenograft rejection, septic shock, or asthma.

[0163] Effective amounts of the compounds of the invention can be used to treat such disorders, including those diseases (e.g., cancer) mentioned in the Background section above. Nevertheless, such cancers and other diseases can be treated with the compounds of the invention regardless of the mechanism of action and / or the relationship between the kinase and the disorder.

[0164] The term "aberrant kinase activity" or "aberrant tyrosine kinase activity" includes any abnormal expression or activity of the kinase-encoding gene or the polypeptide it encodes. Examples of such abnormal activity include, but are not limited to, overexpression of the gene or polypeptide; gene amplification; mutations that result in constitutively active or hyperactive kinase activity; gene mutations, deletions, substitutions, additions, etc.

[0165] The present invention also provides a method for inhibiting kinase activity, particularly mitogenic extracellular kinases, comprising administering an effective amount of a compound of the present invention (including salts, polymorphs, metabolites, hydrates, solvates, prodrugs (e.g., esters), and diastereoisomeric forms thereof). Kinase activity can be inhibited in cells (e.g., in vitro), or in the cells of a mammalian subject, particularly a human patient in need of treatment.

[0166] Methods for treating angiogenic disorders The present invention also provides methods for treating disorders and diseases associated with excessive and / or aberrant angiogenesis.

[0167] Inappropriate and ectopic angiogenesis can be harmful to an organism. Many pathological conditions are associated with the growth of extraneous blood vessels. These include, for example, diabetic retinopathy, ischemic retinal vein occlusion, and retinopathy of prematurity [Aiello et al., New Engl. J. Med. 1994, 331, 1480; Peer et al., Lab. Invest. 1995, 72, 638], age-related macular degeneration [AMD; Lopez et al., Invest. Opthalmol. Vis. Sci. 1996, 37, 855], neovascular glaucoma, psoriasis, retrolental fibroplasia, angiofibroma, inflammation, rheumatoid arthritis (RA), restenosis, in-stent restenosis, and vascular graft restenosis. Furthermore, the increased blood supply associated with cancerous and neoplastic tissues promotes proliferation, leading to rapid tumor growth and metastasis. Furthermore, the growth of new blood and lymphatic vessels in tumors provides an escape route for rebel cells, promoting metastasis and the spread of cancer. Thus, the compounds of the present invention can be utilized to treat and / or prevent any of the above-mentioned angiogenic disorders, for example, by inhibiting and / or reducing angiogenesis; by inhibiting, blocking, reducing, decreasing, etc., endothelial cell proliferation or other types involved in angiogenesis, and by inducing cell death (e.g., apoptosis of such cell types).

[0168] In various embodiments, the disease of the method is a hematological tumor, a solid tumor and / or metastasis thereof.

[0169] The compounds of the present invention may in particular be used in therapy and prophylaxis, i.e. prophylaxis, in particular in the treatment of tumor growth and metastasis, in particular in solid tumors of all indications and stages, with or without prior treatment of tumor growth.

[0170] Pharmaceutical Compositions of the Compounds of the Invention The present invention also relates to pharmaceutical compositions containing one or more compounds of the present invention. These compositions can be used to achieve a desired pharmacological effect by administration to a patient in need thereof. A patient, for the purposes of this invention, is a mammal, including a human, in need of treatment for a particular condition, disorder, or disease.

[0171] Accordingly, the present invention includes pharmaceutical compositions that are comprised of a pharmaceutically acceptable carrier or adjuvant and a pharmaceutically effective amount of a compound, or salt thereof, of the present invention.

[0172] Another aspect of the present invention is a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula (I) and pharmaceutically acceptable adjuvants for the treatment of the above-mentioned diseases, in particular for the treatment of hematological tumors, solid tumors and / or metastases thereof.

[0173] A pharmaceutically acceptable carrier or adjuvant may be a carrier that is non-toxic and harmless to a patient at a concentration consistent with the effective activity of the active ingredient, so that any side effects attributable to the carrier do not impair the beneficial effects of the active ingredient. Carriers and adjuvants are any type of additive that aids in making the composition suitable for administration.

[0174] A pharmaceutically effective amount of a compound may be that amount that produces the result or has the intended effect on the particular condition being treated.

[0175] The compounds of the present invention may be administered orally, parenterally, topically, nasally, ocularly, otically, sublingually, rectally, vaginally, etc. using any effective conventional unit dosage form, including immediate-release, delayed-release, and sustained-release preparations, together with pharmaceutically acceptable carriers or adjuvants known in the art.

[0176] For oral administration, the compounds can be formulated into solid or liquid preparations, such as capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, which can be prepared according to methods known in the art for the manufacture of pharmaceutical compositions. The solid unit dosage form can be a capsule, which can be of the ordinary hard- or soft-shelled gelatin type, containing adjuvants, such as surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and corn starch.

[0177] In another embodiment, the compounds of the present invention may be compressed into tablets with conventional tablet bases such as lactose, sucrose, and corn starch, in combination with binders such as acacia, corn starch, or gelatin, disintegrants such as potato starch, alginic acid, corn starch, and guar gum, tragacanth gum, and acacia to aid in the breakup and dissolution of the tablet after administration, lubricants such as talc, stearic acid, or magnesium, calcium, or zinc stearate to improve the flow of the tablet granulation and prevent the tablet material from sticking to the tablet dies and punch surfaces, and dyes, colorings, and flavorings such as peppermint, oil of wintergreen, or cherry flavoring to improve the appearance and patient acceptance of the tablet. Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols, e.g., ethanol, benzyl alcohol, and polyethylene alcohol, with or without pharmaceutically acceptable surfactants, suspending agents, or emulsifying agents. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit, for instance, tablets, pills, or capsules may be coated with shellac, sugar or both.

[0178] Dispersible powder and granule are suitable for preparing aqueous suspension.They provide the active ingredient in the mixture with dispersing agent or wetting agent, suspending agent and one or more preservatives.Suitable dispersing agent or wetting agent and suspending agent are exemplified by those already mentioned above.In addition, other additives, such as the above-mentioned sweetener, flavoring agent and coloring agent, may also be present.

[0179] The pharmaceutical compositions of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, such as liquid paraffin, or a mixture of vegetable oils. Suitable emulsifiers may be (1) natural gums, such as gum acacia and gum tragacanth, (2) natural phospholipids, such as soybean and lecithin, (3) esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, or (4) condensation products of ethylene oxide with such partial esters, such as polyoxyethylenesorbitan monooleate. The emulsion may also contain sweeteners and flavoring agents.

[0180] Oily suspension can be prepared by suspending active ingredient in vegetable oil, such as peanut oil, olive oil, sesame oil or coconut oil, or mineral oil, such as liquid paraffin.Oily suspension can contain thickening agent, such as beeswax, hard paraffin or cetyl alcohol.Suspension can also contain one or more preservatives, such as ethyl p-hydroxybenzoate or n-propyl p-hydroxybenzoate; one or more coloring agents; one or more flavoring agents and one or more sweeteners, such as sucrose or saccharin.

[0181] Syrups and elixirs can be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent and preservative, such as methyl and propylparabens, and flavoring and coloring agents.

[0182] The compounds of the present invention may also be administered parenterally, i.e., subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or intraperitoneally, as an injectable dose of the compound in a physiologically acceptable diluent and pharmaceutical carrier which may be a sterile liquid or mixture of liquids, such as water, saline, aqueous dextrose and related sugar solutions, alcohols such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethyl-1,1-dioxolane-4-methanol, ethers such as poly(ethylene glycol) 400, oils, fatty acids, fatty acid esters, or fatty acid glycerides, or acetylated fatty acid glycerides, with or without pharmaceutically acceptable surfactants, such as soaps or detergents, suspending agents, such as pectin, carbomer, methiccellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agents and other pharmaceutical adjuvants.

[0183] The oils that can be used in the parenteral formulations of the present invention include oils of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petroleum and mineral oil.Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid.Suitable fatty acid esters include, for example, ethyl oleate and isopropyl myristate. Suitable soaps include alkali metal, ammonium, and triethanolamine salts of fatty acids, and suitable surfactants include cationic surfactants such as dimethyldialkylammonium halides, alkylpyridinium halides, and alkylamine acetates; anionic surfactants such as alkyl, aryl, and olefin sulfonates, alkyl sulfates, olefin sulfates, ether and monoglyceride sulfates, and sulfosuccinates; nonionic surfactants such as fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene-oxypropylene) or ethylene oxide or propylene oxide copolymers; and amphoteric surfactants such as quaternary ammonium salts of alkyl β-aminopropionates and 2-alkylimidazolines, and mixtures thereof.

[0184] The parenteral compositions of the present invention generally contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffering agents may also be advantageously used. To minimize or eliminate injection site irritation, such compositions may, in one embodiment, contain a nonionic surfactant having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The amount of surfactant in such formulations, in one embodiment, ranges from about 5% to about 15% by weight. The surfactant may be a single component having the above HLB or a mixture of two or more components having the desired HLB.

[0185] Examples of surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, e.g., sorbitan monooleate, and high molecular weight adducts of ethylene oxide with a hydrophobic base formed by the condensation of propylene oxide with propylene glycol.

[0186] The pharmaceutical composition can be in the form of a sterile injectable aqueous suspension.This suspension can be prepared according to known methods using suitable dispersing or wetting agents and suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; natural phospholipids such as lecithin, condensation products of alkylene oxides and fatty acids, such as polyoxyethylene stearate, condensation products of ethylene oxide and long-chain aliphatic alcohols, such as heptadecaethyleneoxycetanol, condensation products of ethylene oxide and partial esters derived from fatty acids and hexitols, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol anhydrides, such as polyoxyethylene sorbitan monooleate.

[0187] Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents. Diluents and solvents that can be used include, for example, water, Ringer's solution, isotonic sodium chloride solution, and isotonic glucose solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil, including synthetic monoglycerides or diglycerides, can be used. In addition, fatty acids, such as oleic acid, can be used to prepare injectables.

[0188] The compositions of the present invention may also be administered in the form of suppositories for rectal administration of drugs. These compositions can be prepared by mixing the drug with a suitable non-irritating additive that is solid at room temperature but liquid at rectal temperature, and therefore melts in the rectum to release the drug. Such materials include, for example, cocoa butter and polyethylene glycol.

[0189] Controlled release formulations for parenteral administration include liposomal, polymeric microsphere and polymeric gel formulations known in the art.

[0190] It may be desirable or necessary to introduce pharmaceutical compositions into patients via mechanical delivery.The construction and use of mechanical delivery devices for drug delivery are well known in the art.Direct administration techniques, such as direct administration of drugs to the brain, usually involve placing a drug delivery catheter into the patient's ventricular system to bypass the blood-brain barrier.One such implantable delivery system used to transport drugs to specific anatomical regions of the body is described in U.S. Patent No. 5,011,472 (issued April 30, 1991).

[0191] The compositions of the present invention may also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired. Conventional procedures for preparing such compositions in appropriate dosage forms may be utilized.

[0192] Such ingredients and procedures include those described in the following references, each of which is incorporated herein by reference: Powell, MF et al., "Compendium of Excipients for Parenteral Formulations," PDA Journal of Pharmaceutical Science & Technology 1998, 52(5), 238-311; Strickley, RG, "Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States (1999) - Part-1," PDA Journal of Pharmaceutical Science & Technology 1999, 53(6), 324-349; and Nema, S et al., "Excipients and Their Use in Injectable Products," PDA Journal of Pharmaceutical Science & Technology 1997, 51(4), 166-171.

[0193] Commonly used pharmaceutical ingredients that can be suitably used to formulate a composition for its intended route of administration include: Acidifying Agent (Examples include, but are not limited to, acetic acid, citric acid, fumaric acid, hydrochloric acid, and nitric acid); Alkalizing agents (Examples include, but are not limited to, ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine); Adsorbent (examples include, but are not limited to, powdered cellulose and activated charcoal); aerosol propellants (e.g., including but not limited to carbon dioxide, CCl2F2, F2ClC-CClF2, and CClF3); Air displacement agent(examples include, but are not limited to, nitrogen and argon); antifungal preservative (Examples include, but are not limited to, benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate); antimicrobial preservatives (examples include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate, and thimerosal); antioxidants (Examples include, but are not limited to, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite); bonding material (Examples include, but are not limited to, block polymers, natural and synthetic rubbers, polyacrylates, polyurethanes, silicones, polysiloxanes, and styrene-butadiene copolymers); buffer (Examples include, but are not limited to, potassium metaphosphate, dipotassium phosphate, sodium acetate, sodium citrate anhydrous, and sodium citrate dihydrate); Transport Agent (Examples include, but are not limited to, acacia syrup, aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection, and bacteriostatic water for injection); chelating agents (examples include, but are not limited to, edetate disodium and edetic acid); coloring agent(Examples include, but are not limited to, FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel, and ferric oxide red); Clarifying agent (Examples include, but are not limited to, bentonite); emulsifier (Examples include, but are not limited to, acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate); Encapsulating Agent (examples include, but are not limited to, gelatin and cellulose acetate phthalate); Flavoring agents (Examples include, but are not limited to, anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil, and vanillin); moisturizer (examples include, but are not limited to, glycerol, propylene glycol, and sorbitol); Levigating agents (examples include, but are not limited to, mineral oil and glycerin); oils (examples include, but are not limited to, arachis oil, mineral oil, olive oil, peanut oil, sesame oil, and vegetable oil); Ointment base (Examples include, but are not limited to, lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment, and rose water ointment); Penetration enhancers (transdermal delivery) (examples include, but are not limited to, monohydroxy or polyhydroxy alcohols, monohydric or polyhydric alcohols, saturated or unsaturated fatty alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives, cephalins, terpenes, amides, ethers, ketones and ureas); plasticizer(examples include, but are not limited to, diethyl phthalate and glycerol); solvent (Examples include, but are not limited to, ethanol, corn oil, cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection, and sterile water for irrigation); hardener (Examples include, but are not limited to, cetyl alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl alcohol, white wax, and yellow wax); suppository base (Examples include, but are not limited to, cocoa butter and polyethylene glycols (mixtures)); surfactants (examples include, but are not limited to, benzalkonium chloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium lauryl sulfate, and sorbitan monopalmitate); Suspension (examples include, but are not limited to, agar, bentonite, carbomer, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, kaolin, methylcellulose, tragacanth, and veegum); sweeteners (examples include, but are not limited to, aspartame, dextrose, glycerol, mannitol, propylene glycol, sodium saccharin, sorbitol, and sucrose); Tablet anti-adhesion agent (examples include, but are not limited to, magnesium stearate and talc); tablet binders (Examples include, but are not limited to, acacia, alginate, sodium carboxymethylcellulose, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinylpyrrolidone, and pregelatinized starch); Tablet and capsule diluents (examples include, but are not limited to, dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol, and starch); tablet coating agents (Examples include, but are not limited to, liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, ethyl cellulose, cellulose acetate phthalate, and shellac); Direct compression tablet excipient (Examples include, but are not limited to, dibasic calcium phosphate); Tablet disintegrants (examples include, but are not limited to, alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrilin potassium, cross-linked polyvinylpyrrolidone, sodium alginate, sodium starch glycolate, and starch); Tablet lubricants (examples include, but are not limited to, colloidal silica, corn starch, and talc); Tablet lubricants (examples include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, stearic acid, and zinc stearate); Tablet / capsule opacifier (Examples include, but are not limited to, titanium dioxide); Tablet abrasives (examples include, but are not limited to, carnuba wax and white wax); thickener (examples include, but are not limited to, beeswax, cetyl alcohol, and paraffin); Isotonic agent (examples include, but are not limited to, dextrose and sodium chloride); Viscosity enhancer(examples include, but are not limited to, alginic acid, bentonite, carbomer, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, sodium alginate, and tragacanth); and Wetting agent (Examples include, but are not limited to, heptadecaethyleneoxycetanol, lecithin, sorbitol monooleate, polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).

[0194] The pharmaceutical compositions according to the present invention can be exemplified as follows: Sterile intravenous (iv) solution A 5 mg / ml solution of the desired compound of the invention can be made using sterile injectable water, pH adjusted as necessary. For administration, this solution is diluted to 1-2 mg / ml with sterile 5% dextrose and administered as an intravenous infusion over approximately 60 minutes.

[0195] Lyophilized powder for intravenous administration A sterile preparation can be prepared using (i) 100-1000 mg of the desired compound of the invention as a lyophilized powder, (ii) 32-327 mg / ml sodium citrate, and (iii) 300-3000 mg dextran 40. The formulation is reconstituted with sterile injectable saline or 5% dextrose to a concentration of 10-20 mg / ml, which is further diluted to 0.2-0.4 mg / ml with saline or 5% dextrose and administered either by intravenous bolus or intravenous infusion over 15-60 minutes.

[0196] Intramuscular suspension For intramuscular injection, the following solutions or suspensions can be prepared: 50 mg / ml of the desired water-insoluble compound of the invention 5mg / ml sodium carboxymethylcellulose 4mg / ml TWEEN 80 9mg / ml sodium chloride 9mg / ml benzyl alcohol hard-shell capsulesA number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose, and 6 mg of magnesium stearate.

[0197] soft gelatin capsules A mixture of the active ingredient in a digestible oil such as soybean oil, cottonseed oil, or olive oil is prepared and then injected into molten gelatin using a positive displacement pump to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin, and sorbitol to prepare a water-miscible medicine mix.

[0198] tablet A number of tablets are prepared by conventional procedures so that each dosage unit contains 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch, and 98.8 mg of lactose. Suitable aqueous and non-aqueous coatings can be applied to increase palatability, improve elegance and stability, or delay absorption.

[0199] immediate-release tablets / capsules These are solid oral dosage forms manufactured by conventional and novel methods. These units are taken orally without water for immediate dissolution and delivery of the drug. The active ingredient is mixed in a liquid containing ingredients such as sugar, gelatin, pectin, and sweeteners. These liquids are solidified into solid tablets or caplets by freeze-drying and solid-phase extraction techniques. The drug compound may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent ingredients to produce a porous matrix intended for immediate release without the need for water.

[0200] Dosage and Administration Based on the standard experimental techniques known to evaluate compounds useful for the treatment of hyperproliferative and angiogenic disorders, by standard toxicity tests and by standard pharmacological assays for determining the treatment of the above-identified conditions in mammals, and by comparing these results with the results of known drugs used to treat these conditions, the effective dosage of the compound of the present invention can be easily determined for the treatment of each desired indication.The amount of active ingredient administered in the treatment of one of these conditions can vary widely according to such considerations as the specific compound and dosage unit used, the mode of administration, the duration of treatment, the age and sex of the patient being treated, and the nature and severity of the condition being treated.

[0201] The total amount of active ingredient administered generally ranges from about 0.001 mg / kg to about 200 mg / kg body weight per day, and in particular embodiments, from about 0.01 mg / kg to about 20 mg / kg body weight per day. Clinically useful dosing schedules may range from one to three times daily to once every four weeks. Additionally, a "drug holiday" during which the patient is not administered the drug for a period of time may be beneficial to the overall balance of pharmacological activity and tolerability. A unit dose may contain from about 0.5 mg to about 1500 mg of active ingredient and may be administered one or more times per day or less than once per day. The average daily dose for administration by injection, including intravenous, intramuscular, subcutaneous, and parenteral injections, and for use with infusion techniques, is, in other embodiments, 0.01 to 200 mg / kg of total body weight. In certain embodiments, the average daily rectal dosing regimen is 0.01 to 200 mg / kg of total body weight. In another embodiment, the average daily vaginal dosage regimen is 0.01 to 200 mg / kg of total body weight. In yet another embodiment, the average daily topical dosage regimen is 0.1 to 200 mg administered between 1 and 4 times daily. In another embodiment, the transdermal concentration is that required to maintain a daily dose of 0.01 to 200 mg / kg. In another embodiment, the average daily inhalation dosage regimen is 0.01 to 100 mg / kg of total body weight.

[0202] Of course, the specific initial and continued dosing regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the particular compound used, the age and general condition of the patient, the time of administration, the route of administration, the rate of excretion of the drug, the combination of drugs, etc. The desired mode of treatment and frequency of administration of the compounds of the invention or pharmaceutically acceptable salts or esters thereof, or compositions thereof, can be ascertained by one skilled in the art using conventional therapeutic trials.

[0203] Combination therapy The compounds of the present invention can be administered as a single pharmaceutical agent or in combination with one or more other pharmaceutical agents, and the combination does not cause unacceptable side effects. These combined pharmaceutical agents can be, for example, other drugs with antiproliferative effects for the treatment of hematological tumors, solid tumors and / or their metastases, and / or drugs for the treatment of undesirable side effects. The present invention also relates to such combinations.

[0204] Other anti-hyperproliferative agents suitable for use with the compositions of the present invention include, but are not limited to, compounds recognized for use in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (9th ed.), edited by Molinoff et al., published by McGraw-Hill, pp. 1225-1287 (1996) (incorporated herein by reference), particularly anti-cancer agents (chemotherapeutic agents) as defined above. Combinations may optionally be loose combinations or fixed-dose combinations.

[0205] Methods for testing for particular pharmacological or pharmaceutical properties are well known to those skilled in the art.

[0206] The test experiments described herein serve to illustrate the invention, and the invention is not limited to the examples given.

[0207] As will be understood by those skilled in the art, the present invention is not limited to the particular embodiments described herein, but encompasses all variations of said embodiments that are within the spirit and scope of the present invention as defined by the appended claims.

[0208] The following examples illustrate the invention in more detail without limiting it in any way. Further compounds according to the invention, the preparation of which is not explicitly described, can be prepared in an analogous manner.

[0209] The compounds and salts thereof mentioned in the examples represent preferred embodiments of the invention, as well as claims encompassing all subcombinations of residues of compounds of formula (I) disclosed by the specific examples.

[0210] The term "according to" in the experimental section is used to mean that the procedure referred to should be used "analogously to". [Example]

[0211] Experimental section Chemical names were generated using ACD / Name software from ACD / Labs. In some cases, the commonly accepted name of a commercially available reagent was used in place of the ACD / Name-generated name.

[0212] Table 1 below lists the abbreviations used in this paragraph and in the Examples section unless explained in the text. Other abbreviations have their customary meanings to those skilled in the art.

[0213] Table 1: Abbreviations [Table 1] TIFF0007641913000009.tif121150

[0214] Other abbreviations have their customary meanings to those skilled in the art.

[0215] Various aspects of the invention described in this application are illustrated by the following examples, which are not meant to limit the invention in any way.

[0216] The test experiments described herein serve to illustrate the invention, and the invention is not limited to the experiments given.

[0217] Experimental section - General section All reagents whose synthesis is not described in the experimental section are either commercially available, are known compounds, or can be formed from known compounds by known methods by those skilled in the art.

[0218] The compounds and intermediates produced according to the methods of the present invention may require purification. Purification of organic compounds is well known to those skilled in the art, and there may be several ways to purify the same compound. In some cases, purification may not be necessary. In some cases, compounds can be purified by crystallization. In some cases, impurities can be removed by trituration with an appropriate solvent. In some cases, compounds can be purified by chromatography, particularly flash column chromatography, using, for example, a Biotage automated purification system (SP4® or Isolera Four®) and a Biotage SNAP cartridge KP-Sil® or KP-NH® in combination with an eluent (e.g., a gradient of hexane / ethyl acetate or DCM / methanol). In flash column chromatography, unmodified ("normal") silica gel can be used, as well as amino-functionalized silica gel. In the experimental section, when referring to flash column chromatography or flash chromatography without specifying the stationary phase, normal silica gel was used.

[0219] In some cases, compounds can be purified by preparative HPLC using, for example, a Waters automated purifier equipped with a diode array detector and / or an online electrospray ionization mass spectrometer in combination with a suitable pre-packed reverse-phase column and eluent (e.g., a gradient of water and acetonitrile, which may contain additives such as trifluoroacetic acid, formic acid, or aqueous ammonia).

[0220] In some cases, the purification methods described above can provide compounds of the present invention having sufficiently basic or acidic functionalities in the form of a salt, such as a trifluoroacetate or formate salt in the case of a sufficiently basic compound of the present invention, or an ammonium salt in the case of a sufficiently acidic compound of the present invention. This type of salt can be converted to its free base or free acid form, respectively, by various methods known to those skilled in the art, or can be used as a salt in subsequent biological assays. It should be understood that the specific form (e.g., salt, free base, etc.) of a compound of the present invention isolated and described herein is not necessarily the only form in which the compound can be applied to biological assays to determine specific biological activity.

[0221] Analytical LC-MS method : Method 1: Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7 μm, 50 × 2.1 mm; Eluent A: water + 0.1% by volume formic acid (99%), Eluent B: acetonitrile; Gradient: 0–1.6 min, 1–99% B, 1.6–2.0 min, 99% B; Flow rate: 0.8 ml / min; Temperature: 60 °C; DAD scan: 210–400 nm.

[0222] Method 2: Apparatus: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7 μm, 50 × 2.1 mm; Eluent A: water + 0.2% (v / v) aqueous ammonia (32%), Eluent B: acetonitrile; Gradient: 0–1.6 min, 1–99% B, 1.6–2.0 min, 99% B; Flow rate: 0.8 ml / min; Temperature: 60 °C; DAD scan: 210–400 nm.

[0223] Method 3: Apparatus: Waters Acquity UPLC H-Class system; Column: Acquity CSH C18 1.7 μm 2.1 × 50 mm; Eluent A: water + 0.1% formic acid (volume), Eluent B: acetonitrile, Eluent C: 2% ammonia (28%) in water (volume), Eluent D: 2% formic acid (volume) in water; Gradient: 0–1.2 min, 2–95% B and A and 5% D throughout, 1.2–1.4 min, 95% B; Flow rate: 0.8 ml / min; Temperature: 40°C; PDA: 215–350 nm.

[0224] Method 4: Apparatus: Waters Acquity UPLC H-Class system; Column: XBridge BECH C18 2.5 μm 2.1 × 50 mm; Eluent A: water + 0.1% (v / v) formic acid, Eluent B: acetonitrile, Eluent C: 2% (v / v) ammonia in water (28%), Eluent D: 2% (v / v) formic acid in water; Gradient: 0–1.2 min, 2–95% B and A and 5% C throughout, 1.2–1.4 min, 95% B; Flow rate: 0.8 ml / min; Temperature: 40°C; PDA: 215–350 nm.

[0225] Method 5: MS instrument: SHIMADZU LCMS-2020; HPLC instrument: LabSolution Version 5.72; Column: Kinetex@5um EVO C18 30×2.1mm; Eluent A: 0.0375% TFA (v / v) in water; Eluent B: 0.01875% TFA in acetonitrile; Gradient: 0.0 min 0% B → 3.00 min 60% B → 3.50 min 60% B → 3.51 min 0% B → 4.00 min 0% B; Flow rate: 0.8 mL / mix; Oven temperature: 50°C; UV detection: 220 nm & 254 nm.

[0226] Method 6: Instrument: Agilent 1290 UPLCMS 6230 TOF; Column: BEH C18 1.7 μm, 50x2.1 mm; Eluent A: water + 0.05% formic acid (99%); Eluent B: acetonitrile + 0.05% formic acid (99%); Gradient: 0-1.7 2-90% B; 1.7-2.0 90% B; Flow rate: 1.2 ml / min; Temperature: 60 °C; DAD scan: 190-400 nm.

[0227] Preparative LC-MS method : Method 7: Apparatus: Waters Autopurification MS SingleQuad; Column: Waters XBrigde C18 5μ 100x30mm; Eluent A: water + 0.2% (v / v) aqueous ammonia (32%), Eluent B: acetonitrile; Gradient: 0-5.5 min, 5-100% B; Flow rate: 70 ml / min; Temperature: 25°C; DAD scan: 210-400 nm.

[0228] Method 8: Apparatus: Waters Autopurification MS SingleQuad; Column: Waters XBrigde C18 5μ 50x50mm; Eluent A: water + 0.1% by volume formic acid, Eluent B: methanol; Gradient: 0-0.50 min, 20% B; Flow rate: 50-100 ml / min, 0.50-8.00 min, 20-60% B; Flow rate: 100 ml / min, Temperature: 25°C; DAD scan: 210-400 nm.

[0229] Method 9: Equipment: Labomatic HD-5000, pump head HDK-280, gradient module NDB-1000, fraction collector Labomatic Labocol Vario 2000, Knauer UV detector Azura UVD 2.1S, Prepcon 5 software. Column: Chromatorex C18 10 μM 120 x 30 mm; Eluent A: water + 0.1% formic acid; Eluent B: acetonitrile; Gradient: given in intermediates and examples, flow rate 150 mL / min, temperature 25 °C; UV 220 nm.

[0230] Method 10: Equipment: Labomatic HD-5000, pump head HDK-280, gradient module NDB-1000, fraction collector Labomatic Labocol Vario 2000, Knauer UV detector Azura UVD 2.1S, Prepcon 5 software. Column: Chromatorex C18 10 μM 120 x 30 mm; Eluent A: 0.1% ammonia in water; Eluent B: acetonitrile; Gradient: given in intermediates and examples, speed 150 mL / min, temperature 25 °C; UV 250 nm.

[0231] Method 11: Equipment: Labomatic HD-5000, pump head HDK-280, gradient module NDB-1000, fraction collector Labomatic Labocol Vario 2000, Knauer UV detector Azura UVD 2.1S, Prepcon 5 software. Column: Chromatorex C18 10 μM 300 x 50 mm; Eluent A: 0.1% ammonia in water; Eluent B: acetonitrile; Gradiene: given in intermediates and examples, flow rate 250 mL / min, temperature 25 °C; UV 250 nm.

[0232] NMR spectrum: Given in the following paragraphs 1 The multiplicity of proton signals in H NMR spectra reflects the observed signal morphology and does not take into account any higher-order signal phenomena. As a rule, chemical shift data refer to the center of the signal in question. In the case of broad multiplets, a range is specified. Signals obscured by solvent or water are either tentatively assigned or not listed. Strongly broadened signals (e.g., caused by rapid rotation of molecular moieties or by proton exchange) are also tentatively assigned (often called broad multiplets or broad singlets) or not listed.

[0233] of selected compounds 1 H-NMR data is 1 The peaks are listed in the form of a H-NMR peak list, where for each signal peak, a δ value in ppm is given, followed by the signal intensity reported in parentheses. δ value-signal intensity pairs from different peaks are separated by commas. Thus, the peak list is: δ1 (intensity 1), δ2 (intensity 2), ..., δ i (strength i ), …, δ n (strength n ) in the general form

[0234] The intensity of a sharp signal correlates with the signal's height (cm) in the printed NMR spectrum. When compared to other signals, this data can be correlated with the actual ratio of signal intensities. For broad signals, two or more peaks, or signal centers, are shown along with their relative intensities compared to the most intense signal displayed in the spectrum. 1 The H-NMR peak list is a classic 1 It is similar to a H-NMR reading and therefore usually includes all peaks listed in a classical NMR interpretation. 1 Similar to a H-NMR printout, the peak list includes solvent signals, signals originating from stereoisomers of a particular target compound, impurity peaks,13 The peaks of the target compound may show C satellite peaks and / or spinning side bands. The peaks of the stereoisomers and / or impurities are typically shown at lower intensities (e.g., >90% purity) compared to the peaks of the target compound. Such stereoisomers and / or impurities are typical for a particular manufacturing process, and therefore, their peaks can be useful for identifying the reproduction of the manufacturing process based on "by-product fingerprints." The peaks of the target compound can be isolated by known methods (MestReC, ACD simulations, or using empirically evaluated expectation values), optionally using additional intensity filters, and such behavior is consistent with classical 1 This is similar to peak picking in H-NMR interpretation. A detailed description of reporting NMR data in the form of a peak list can be found in the publication "Citation of NMR Peaklist Data within Patent Applications" (see http: / / www.researchdisclosure.com / searching-disclosures, Research Disclosure Database Number 605005, 2014, 01 August 2014). In the peak picking routine, the parameter "MinimumHeight" can be adjusted between 1% and 4%, as described in Research Disclosure Database Number 605005. However, depending on the chemical structure and / or concentration of the compound being measured, it is reasonable to set the parameter "MinimumHeight" to <1%.

[0235] Synthesis of intermediate 1 compound Intermediate 1-1 3-[(1,4-dioxan-2-yl)methoxy]pyridine-4-carbonitrile [ka]

[0236] 3-Chloropyridine-4-carbonitrile (CAS 68325-15-5, 1.40 g, 10.1 mmol) and (1,4-dioxan-2-yl)methanol (CAS 143669-41-4, 1.31 g, 11.1 mmol) were dissolved in THF (45 ml). Potassium tert-butoxide (1.03 g, 9.14 mmol) was added, and the mixture was stirred at 0 °C for 1 h. The reaction mixture was slowly diluted with saturated ammonium chloride solution and extracted with EtOAc (3x). The organic phase was washed with brine, filtered through a water-repellent filter, concentrated under reduced pressure, and purified by flash chromatography (silica, hexane / EtOAc gradient 0-100%; EtOAc / EtOH gradient 0-35%) to give 1.18 g of the title compound (53% yield).

[0237] 1 H-NMR (400MHz, DMSO-d6): δ [ppm]= 8.72 (s, 1H), 8.23 ​​- 8.46 (m, 1H), 7.68 - 7.86 (m, 1H), 4.32 (d, 2H), 3.40 - 3.99 (m, 7H). LC-MS (Method 2): R t = 0.77 min; MS (ESIpos): m / z = 221 [M+H] + Intermediate 1-2 3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridine-4-carbonitrile [ka]

[0238] To a solution of [(3S)-4-methylmorpholin-3-yl]methanol (CAS 1620510-50-0, 1.00 g, 7.62 mmol) in THF (20 mL) at 0 °C, sodium hydride (366 mg, 9.15 mmol, 60% purity) was slowly added. The reaction mixture was stirred for 3 h at RT, and then 3-chloropyridine-4-carbonitrile (CAS 68325-15-5, 1.06 g, 7.62 mmol) in THF (10 mL) was added, and the mixture was stirred overnight. The reaction mixture was quenched with 1N HCl until pH = 7. The suspension was filtered through hydrophobic filter paper, and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography (basic silica, hexane / EtOAc gradient 0 to 100%) to give 355 mg of the title compound (20% yield).

[0239] 1 H-NMR (400MHz, DMSO-d6): δ [ppm]= 8.75 (s, 1H), 8.40 (d, 1H), 7.78 (d, 1H), 4.44 (dd, 1H), 4.23 (dd, 1H), 3.87 (dd, 1H), 3.71 (dt, 1H), 3.50 (td, 1H), 3.35 - 3.41 (m, 1H), 2.65 - 2.71 (m, 1H), 2.45 - 2.49 (m, 1H), 2.29 - 2.35 (m, 3H), 2.24 (ddd, 1H). LC-MS (Method 2): R t = 0.72 min; MS (ESIpos): m / z = 234.2 [M+H] + Intermediate 1-3 3-{[4-methylmorpholin-2-yl]methoxy}pyridine-4-carbonitrile [ka]

[0240] Using 3-chloropyridine-4-carbonitrile (CAS 68325-15-5, 764 mg, 5.51 mmol) and [4-methylmorpholin-2-yl]methanol (CAS 40987-46-0, 940 mg, 7.17 mmol) as starting materials, 836 mg of the title compound (90% purity, 59% yield) was prepared using a method similar to that described for Intermediate 1-1.

[0241] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm]= 1.893 (0.97), 1.920 (1.44), 1.947 (1.07), 1.954 (0.50), 1.962 (0.54), 1.983 (1.01), 1.991 (1.03), 2.011 (0.58), 2.019 (0.52), 2.197 (16.00), 2.518 (0.41), 2.589 (0.80), 2.593 (0.82), 2.617 (0.73), 2.621 (0.74), 2.766 (0.66), 2.770 (0.95), 2.794 (0.63), 2.798 (0.89), 3.513 (0.60), 3.520 (0.73), 3.541 (1.36), 3.547 (1.39), 3.570 (0.80), 3.575 (0.67), 3.793 (0.74), 3.796 (1.10), 3.801 (1.12), 3.805 (0.92), 3.808 (0.85), 3.814 (0.79), 3.821 (1.18), 3.826 (1.18), 3.833 (1.27), 3.839 (0.66), 4.316 (5.03), 4.329 (4.72), 7.772 (2.40), 7.774 (2.63), 7.785 (2.49), 8.381 (3.41), 8.393 (3.28), 8.714 (4.32). LC-MS (Method 2): R t = 0.70 min; MS (ESIpos): m / z = 234.2 [M+H] + Intermediate 1-4 3-{[(3S)-4-Methylmorpholin-3-yl]methoxy}pyridine-4-carbonitrile [ka]

[0242] Using 3-chloropyridine-4-carbonitrile (CAS 68325-15-5, 1.00 g, 7.24 mmol) and [(3R)-4-methylmorpholin-3-yl]methanol (1.00 g, 95% purity, 7.24 mmol; CAS 1620510-51-1) as starting materials, 823 mg of the title compound (99% purity, 48% yield) was prepared using a method similar to that described for intermediate 1-2.

[0243] 1H-NMR (400 MHz, DMSO-d6): δ [ppm]= 2.211 (0.52), 2.219 (0.64), 2.236 (0.66), 2.240 (0.68), 2.245 (0.68), 2.249 (0.72), 2.266 (0.69), 2.274 (0.63), 2.306 (16.00), 2.472 (0.48), 2.475 (0.50), 2.518 (1.22), 2.522 (0.71), 2.658 (0.56), 2.664 (1.27), 2.671 (0.67), 2.687 (0.47), 2.694 (0.96), 2.701 (0.47), 3.356 (1.17), 3.378 (1.16), 3.384 (1.30), 3.406 (1.20), 3.472 (0.50), 3.478 (0.58), 3.499 (0.80), 3.506 (0.81), 3.525 (0.71), 3.532 (0.61), 3.685 (0.44), 3.692 (0.86), 3.698 (0.45), 3.720 (0.66), 3.856 (0.80), 3.864 (0.81), 3.884 (0.73), 3.892 (0.72), 4.209 (1.03), 4.223 (1.01), 4.234 (1.29), 4.249 (1.23), 4.417 (1.25), 4.429 (1.28), 4.443 (1.03), 4.454 (0.99), 7.778 (2.39), 7.780 (2.38), 7.790 (2.45), 7.792 (2.50), 8.391 (3.23), 8.403 (3.11), 8.745 (3.91). LC-MS (Method 2): Rt = 0.70 min; MS (ESIpos): m / z = 234 [M+H] + Intermediate 1-5 tert-Butyl (2S)-2-{[(4-cyanopyridin-3-yl)oxy]methyl}morpholine-4-carboxylate [ka]

[0244] Using 3-chloropyridine-4-carbonitrile (CAS 68325-15-5, 2.55 g, 18.4 mmol) and tert-butyl (2S)-2-(hydroxymethyl)morpholine-4-carboxylate (CAS 135065-76-8, 4.00 g, 18.4 mmol) as starting materials, 4.82 g (90% purity, 74% yield) of the title compound was prepared using a method similar to that described for Intermediate 1-1.

[0245] 1 H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.41 (s, 9H), 2.72 - 3.05 (m, 2H), 3.46 (br d, 1H), 3.67 - 3.82 (m, 2H), 3.82 - 3.88 (m, 1H), 4.00 (s, 1H), 4.37 (br d, 2H), 7.79 (d, 1H), 8.40 (d, 1H), 8.73 (s, 1H). LC-MS (Method 2): R t = 1.06 min; MS (ESIpos): m / z = 320 [M+H] + Intermediate 1-6 3-[2-(1,4-dioxan-2-yl)ethoxy]pyridine-4-carbonitrile [ka]

[0246] Using 3-chloropyridine-4-carbonitrile (CAS 68325-15-5, 2.10 g, 15.1 mmol) and 2-(1,4-dioxan-2-yl)ethan-1-ol (CAS 151720-04-6, 2.00 g, 15.1 mmol) as starting materials, 2.89 g (99% purity, 81% yield) of the title compound was prepared using a method similar to that described for Intermediate 1-2.

[0247] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.754 (0.63), 1.768 (1.37), 1.774 (0.82), 1.781 (0.98), 1.790 (2.18), 1.803 (3.39), 1.810 (2.10), 1.817 (1.93), 1.824 (3.23), 1.838 (2.78), 1.855 (2.41), 1.867 (2.45), 1.869 (2.40), 1.874 (2.53), 1.886 (2.23), 1.902 (0.99), 1.910 (0.87), 1.922 (0.67), 2.326 (0.72), 2.668 (0.69), 3.223 (4.26), 3.247 (5.57), 3.250 (5.62), 3.276 (5.26), 3.428 (1.77), 3.434 (1.89), 3.455 (4.59), 3.462 (4.80), 3.483 (3.76), 3.489 (3.97), 3.530 (3.36), 3.535 (3.38), 3.558 (4.71), 3.564 (5.40), 3.585 (1.93), 3.592 (3.08), 3.626 (4.58), 3.631 (4.33), 3.654 (3.70), 3.659 (4.02), 3.668 (1.98), 3.673 (1.97), 3.680 (2.77), 3.687 (2.85), 3.693 (2.89), 3.706 (6.98), 3.712 (6.06), 3.724 (1.75), 3.735 (3.40), 3.759 (4.77), 3.766 (4.02), 3.788 (4.04), 3.794 (3.73), 4.315 (0.93), 4.329 (1.18), 4.339 (3.54), 4.354 (6.92), 4.359 (5.21), 4.370 (6.49), 4.384 (3.79), 4.392 (1.47), 4.408 (0.68), 7.778 (9.22), 7.790 (9.58), 8.380 (10.88), 8.392 (10.45), 8.698 (16.00). LC-MS (Method 6): Rt = 0.64 min; MS (ESIpos): m / z = 235 [M+H] + Intermediate 1-7 3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridine-4-carbonitrile [ka]

[0248] Using 3-chloropyridine-4-carbonitrile (CAS 68325-15-5, 948 mg, 6.84 mmol) and (5,5-dimethyl-1,4-dioxan-2-yl)methanol (1.00 g, 6.84 mmol; CAS 54321-57-2) as starting materials, 1.31 g (95% purity, 73% yield) of the title compound was prepared using a method similar to that described for intermediate 1-2.

[0249] 1H-NMR (400 MHz, DMSO-d6): δ [ppm]= 1.014 (0.69), 1.048 (16.00), 1.172 (0.55), 1.200 (0.51), 1.263 (13.01), 1.987 (0.92), 2.518 (0.62), 2.523 (0.43), 3.313 (1.67), 3.340 (2.27), 3.342 (2.21), 3.542 (2.95), 3.570 (2.39), 3.604 (1.50), 3.627 (1.97), 3.734 (1.24), 3.760 (3.08), 3.781 (2.25), 3.787 (2.73), 3.791 (1.58), 3.796 (0.77), 3.802 (0.63), 4.356 (3.63), 4.365 (4.41), 7.780 (3.42), 7.792 (3.63), 8.387 (4.49), 8.399 (4.29), 8.715 (5.54). LC-MS (Method 6): Rt = 0.75 min; MS (ESIpos): m / z = 249 [M+H]+ Intermediate 1-8 3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridine-4-carbonitrile [ka]

[0250] Using 3-chloropyridine-4-carbonitrile (CAS 68325-15-5, 1.00 g, 7.22 mmol) and [(2R)-1,4-dioxan-2-yl]methanol (CAS 406913-88-0, 938 mg, 7.94 mmol) as starting materials, 490 mg of the title compound (95% purity, 29% yield) was prepared using a method similar to that described for Intermediate 1-1.

[0251] Optical rotation: [α] D = - 1.68° + / - 0.35° (c = 7 mg / ml, methanol) 1 H-NMR (400 MHz, DMSO-d6): δ ppm= 3.41 - 3.53 (m, 2 H), 3.59 - 3.72 (m, 2 H), 3.75 - 3.81 (m, 1 H), 3.82 - 3.87 (m, 1 H), 3.87 - 3.95 (m, 1 H), 4.27 - 4.37 (m, 2 H), 7.77 - 7.80 (m, 1 H), 8.38 - 8.41 (m, 1 H), 8.71 - 8.73 (m, 1 H). Intermediate 1-9 tert-Butyl (3R)-3-{[(4-cyanopyridin-3-yl)oxy]methyl}morpholine-4-carboxylate [ka]

[0252] To a solution of tert-butyl (3S)-3-(hydroxymethyl)morpholine-4-carboxylate (4.30 g, 19.8 mmol) in THF (28 mL) at 0 °C, sodium hydride (1.55 g, 55% purity, 35.6 mmol) was slowly added. The reaction mixture was stirred for 1 h. 3-Fluoropyridine-4-carbonitrile (CAS 113770-88-0, 2.42 g, 19.8 mmol) in THF (14 mL) was added, and the mixture was stirred at 0 °C for 4 h. The reaction mixture was quenched with 2N HCl until pH = 6-7 and extracted with EE. The organic layer was filtered through a water-repellent filter paper and concentrated under reduced pressure. The residue was purified by flash chromatography (silica, DCM / EtOH gradient 0-7%) to give 4 g of the title compound (70% yield).

[0253] LC-MS (Method 6): R t = 0.95 min; MS (ESIpos): m / z = 264 [M+H] + Intermediate 1-10 tert-Butyl (2R)-2-{[(4-cyanopyridin-3-yl)oxy]methyl}morpholine-4-carboxylate [ka]

[0254] Using 3-chloropyridine-4-carbonitrile (CAS 68325-15-5, 3.25 g, 23.5 mmol) and tert-butyl (2R)-2-(hydroxymethyl)morpholine-4-carboxylate (CAS 135065-71-3, 5.10 g, 23.5 mmol) as starting materials, 6.92 g (90% purity, 83% yield) of the title compound was prepared using a method similar to that described for Intermediate 1-1.

[0255] 1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.41 (s, 9H), 2.73 - 3.00 (m, 2H), 3.39 - 3.50 (m, 1H), 3.75 (m, 2H), 3.82 - 3.89 (m, 1H), 3.95 - 4.00 (m, 1H), 4.37 (br d, 2H), 7.79 (d, 1H), 8.40 (d, 1H), 8.73 (s, 1H). LC-MS (Method 2): R t = 1.04 min; MS (ESIpos): m / z = 320 [M+H] + Intermediate 1-11 3-[(1S)-1-(1,4-dioxan-2-yl)ethoxy]pyridine-4-carbonitrile [ka]

[0256] Using 3-fluoropyridine-4-carbonitrile (878 mg, 7.19 mmol) and (1S)-1-[1,4-dioxan-2-yl]ethan-1-ol (CAS 1372875-59-6, 950 mg, 7.19 mmol) as starting materials, 1.68 g (95% purity, 95% yield) of the title compound was prepared using a method similar to that described for intermediate 1-9.

[0257] 1H-NMR (400 MHz, DMSO- d6): δ ppm= 0.988 (0.85), 1.004 (0.92), 1.056 (0.59), 1.071 (0.60), 1.154 (4.47), 1.166 (0.63), 1.172 (9.29), 1.189 (4.59), 1.276 (12.44), 1.292 (12.55), 1.325 (11.08), 1.341 (11.16), 1.987 (16.00), 2.518 (1.63), 2.522 (1.05), 3.300 (0.46), 3.396 (1.81), 3.421 (2.99), 3.424 (2.99), 3.429 (1.78), 3.450 (5.06), 3.457 (3.42), 3.472 (1.97), 3.478 (1.62), 3.485 (2.38), 3.497 (2.19), 3.500 (1.91), 3.525 (2.26), 3.552 (1.16), 3.559 (1.31), 3.582 (2.48), 3.588 (2.91), 3.611 (1.70), 3.616 (2.62), 3.638 (4.15), 3.642 (3.63), 3.664 (3.89), 3.671 (4.01), 3.676 (1.93), 3.683 (1.76), 3.685 (1.80), 3.689 (1.79), 3.695 (1.76), 3.701 (1.17), 3.704 (1.27), 3.707 (1.26), 3.710 (1.28), 3.744 (1.82), 3.750 (3.32), 3.757 (1.01), 3.778 (3.94), 3.784 (2.19), 3.807 (1.47), 3.813 (1.33), 3.906 (1.40), 3.912 (1.35), 3.935 (1.24), 3.941 (1.18), 3.999 (1.24), 4.016 (3.72), 4.034 (3.66), 4.052 (1.20), 4.804 (0.41), 4.821 (1.95), 4.836 (3.43), 4.852 (2.64), 4.864 (1.34), 7.755 (3.58), 7.757 (3.60), 7.769 (4.33), 7.771 (3.80), 7.783 (3.28), 7.785 (3.20), 8.351 (4.95), 8.363 (4.90), 8.368 (4.48), 8.380 (4.17), 8.749 (6.40), 8.772 (5.46). LC-MS (Method 6): R t = 0.64 min; MS (ESIpos): m / z = 235 [M+H] + Intermediate 1-12 3-{(1R)-1-[1,4-dioxan-2-yl]ethoxy}pyridine-4-carbonitrile [ka]

[0258] Using 3-fluoropyridine-4-carbonitrile (905 mg, 7.42 mmol) and (1R)-1-[1,4-dioxan-2-yl]ethan-1-ol (CAS 1372881-98-5, 980 mg, 7.42 mmol) as starting materials, 1.39 g (95% purity, 76% yield) of the title compound was prepared using a method similar to that described for intermediate 1-9.

[0259] 1H-NMR (400 MHz, DMSO- d6): δ ppm= 1.274 (0.82), 1.289 (0.87), 1.322 (16.00), 1.337 (15.97), 1.984 (0.48), 2.331 (0.56), 2.673 (0.57), 3.427 (2.95), 3.448 (3.45), 3.455 (3.30), 3.471 (3.27), 3.482 (2.59), 3.496 (3.79), 3.499 (3.36), 3.524 (3.41), 3.580 (1.59), 3.586 (1.80), 3.609 (2.32), 3.615 (2.92), 3.636 (5.12), 3.662 (3.60), 3.668 (3.70), 3.680 (2.08), 3.687 (1.49), 3.693 (1.53), 3.698 (1.52), 3.704 (1.41), 3.746 (3.19), 3.754 (1.74), 3.775 (2.26), 3.903 (2.52), 3.909 (2.44), 3.932 (2.24), 3.937 (2.13), 4.818 (0.65), 4.833 (2.08), 4.845 (2.30), 4.849 (2.22), 4.861 (2.00), 4.876 (0.57), 7.766 (5.15), 7.778 (5.29), 8.348 (0.42), 8.365 (6.23), 8.377 (6.01), 8.743 (0.51), 8.765 (9.13). LC-MS (Method 6): R t = 0.67 min; MS (ESIpos): m / z = 235 [M+H] + Intermediate 1-71 3-[1-(4-methylmorpholin-2-yl)ethoxy]isonicotinonitrile [ka]

[0260] Using 3-fluoropyridine-4-carbonitrile (824 mg, 6.75 mmol) and 1-(4-methylmorpholin-2-yl)ethanol (980 mg, 6.75 mmol, CAS 1540922-49-3) as starting materials, a method similar to that described for intermediate 1-9 was used to prepare 817 mg of the title compound (99% purity, 48% yield) after column chromatography using a Biotage Isolera.

[0261] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.285 (4.44), 1.300 (4.47), 1.318 (5.38), 1.333 (5.31), 1.848 (0.57), 1.874 (0.94), 1.901 (0.63), 1.927 (0.93), 1.933 (0.66), 1.953 (2.04), 1.961 (1.23), 1.981 (1.32), 1.990 (0.60), 2.188 (16.00), 2.518 (1.33), 2.522 (0.90), 2.572 (0.89), 2.600 (0.79), 2.718 (0.54), 2.746 (0.52), 2.839 (0.64), 2.867 (0.60), 3.485 (0.78), 3.488 (0.66), 3.491 (0.85), 3.516 (1.00), 3.522 (0.92), 3.544 (0.48), 3.550 (0.42), 3.562 (0.44), 3.568 (0.54), 3.573 (0.73), 3.578 (0.77), 3.587 (0.81), 3.593 (0.83), 3.598 (0.85), 3.604 (0.71), 3.772 (0.51), 3.777 (0.56), 3.781 (0.78), 3.786 (0.61), 3.789 (0.59), 3.794 (0.56), 3.800 (0.46), 3.805 (0.46), 3.809 (0.64), 3.814 (0.50), 3.817 (0.45), 4.818 (0.60), 4.833 (0.97), 4.848 (0.79), 4.858 (0.65), 4.862 (0.67), 4.874 (0.57), 7.746 (1.41), 7.760 (2.88), 7.772 (1.71), 8.341 (1.93), 8.355 (2.69), 8.368 (2.12), 8.745 (2.34), 8.766 (2.68). LC-MS (Method 6): R t = 0.32 min; MS (ESIpos): m / z = 248 [M+H] + Synthesis of intermediate 2 compound Intermediate 2-1 1-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methanamine [ka]

[0262] An autoclave was charged with 3-[(1,4-dioxan-2-yl)methoxy]pyridine-4-carbonitrile (Intermediate 1-1, 1.17 g, 5.34 mmol), ammonia (19 ml, 7.0 M in methanol, 850 mmol), and Raney nickel (CAS 7440-02-0, 783 mg, 50% wet), and the mixture was stirred at RT under a hydrogen atmosphere of 25 bar for 22 h. The mixture was filtered through a pad of Celite, eluting with methanol, and the combined filtrate was concentrated under reduced pressure. The residue was used directly in the next step without further purification (1.13 g, 94% yield).

[0263] 1 H-NMR (400MHz, DMSO-d6): δ [ppm]= 8.24 (s, 1H), 8.17 (d, 1H), 7.38 (d, 1H), 4.09 (d, 2H), 3.73 - 3.91 (m, 3H), 3.59 - 3.73 (m, 4H), 3.46 - 3.52 (m, 2H), 3.39 - 3.45 (m, 2H). 2.06 (br., 2H). LC-MS (Method 2): R t = 0.54 min; MS (ESIpos): m / z = 225 [M+H] + Intermediate 2-2 1-(3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)methanamine [ka]

[0264] Using 3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridine-4-carbonitrile (Intermediate 1-2, 355 mg, 1.52 mmol) as the starting material, 350 mg of the title compound was prepared (89% yield) using a method similar to that described for Intermediate 2-1.

[0265] 1 H-NMR (400MHz, DMSO-d6): δ [ppm]= 8.24 - 8.31 (m, 1H), 8.17 (d, 1H), 7.39 (d, 1H), 4.18 - 4.27 (m, 1H), 4.00 (dd, 1H), 3.86 (dd, 1H), 3.63 - 3.75 (m, 3H), 3.42 - 3.55 (m, 1H), 3.36 - 3.41 (m, 1H), 2.67 (dq, 1H), 2.40 - 2.47 (m, 1H), 2.19 - 2.31 (m, 4H), 1.63 - 2.19 (m, 2H). Intermediate 2-3 1-(3-{[4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)methanamine [ka]

[0266] Using 3-{[4-methylmorpholin-2-yl]methoxy}pyridine-4-carbonitrile (Intermediate 1-3, 836 mg, 3.58 mmol) as the starting material, 860 mg of the title compound (90% purity, 91% yield) was prepared using a method similar to that described for Intermediate 2-1.

[0267] 1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.68 - 1.84 (br s, 2H), 1.85 - 1.94 (t, 1H), 1.94 - 2.05 (td, 1H), 2.19 (s, 3H), 2.57 - 2.64 (d, 1H), 2.73 - 2.83 (d, 1H), 3.46 - 3.63 (t, 1H), 3.63 - 3.73 (s, 2H), 3.73 - 3.86 (m, 3H), 4.10 (br d, 2H), 7.34 - 7.44 (d, 1H), 8.10 - 8.20 (d, 1H), 8.21 - 8.30 (s, 1H). LC-MS (method 2): R t = 0.56 min; MS (ESIpos): m / z = 238 [M+H] + Intermediate 2-4 1-(3-{[(3S)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)methanamine [ka]

[0268] Using 3-{[(3S)-4-methylmorpholin-3-yl]methoxy}pyridine-4-carbonitrile (Intermediate 1-4, 823 mg, 3.53 mmol) as the starting material, 798 mg of the title compound (90% purity, 86% yield) was prepared using a method similar to that described for Intermediate 2-1.

[0269] 1H-NMR (400 MHz, DMSO-d6): δ [ppm]= 1.865 (0.49), 2.199 (0.64), 2.210 (1.08), 2.228 (0.99), 2.233 (0.96), 2.236 (0.96), 2.254 (0.85), 2.263 (0.81), 2.269 (0.55), 2.284 (16.00), 2.327 (0.53), 2.430 (0.78), 2.439 (0.81), 2.447 (0.65), 2.518 (2.11), 2.523 (1.42), 2.649 (0.75), 2.654 (1.38), 2.660 (0.91), 2.669 (0.65), 2.674 (0.60), 2.678 (0.83), 2.684 (1.22), 2.690 (0.66), 3.361 (1.52), 3.365 (1.53), 3.388 (1.10), 3.469 (0.59), 3.474 (0.65), 3.496 (1.15), 3.502 (1.16), 3.523 (0.75), 3.528 (0.68), 3.683 (2.49), 3.690 (2.42), 3.712 (0.79), 3.719 (1.11), 3.846 (1.01), 3.853 (1.04), 3.873 (0.94), 3.880 (0.91), 3.982 (0.79), 3.997 (0.86), 4.007 (1.03), 4.021 (0.96), 4.215 (1.01), 4.226 (1.09), 4.240 (0.86), 4.250 (0.84), 7.379 (0.99), 7.389 (1.01), 8.168 (1.06), 8.179 (1.11), 8.259 (1.53). Intermediate 2-5 tert-Butyl (2S)-2-{[4-(aminomethyl)pyridin-3-yl]oxy}methyl)morpholine-4-carboxylate [ka]

[0270] Using tert-butyl (2S)-2-{[(4-cyanopyridin-3-yl)oxy]methyl}morpholine-4-carboxylate (Intermediate 1-5, 5.75 g, 18.0 mmol) as the starting material, 6.00 g (95% purity, 98% yield) of the title compound was prepared using a method similar to that described for Intermediate 2-1.

[0271] 1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.41 (s, 9H), 3.16 (s, 2H), 3.39 - 3.49 (m, 2H), 3.66 - 3.79 (m, 5H), 3.79 - 3.98 (m, 3H), 4.07 - 4.20 (m, 3H), 7.39 (d, 1H), 8.19 (d, 1H), 8.27 (s, 1H). LC-MS (method 2): R t = 0.84 min; MS (ESIpos): m / z = 324 [M+H] + Intermediate 2-6 1-{3-[2-(1,4-dioxan-2-yl)ethoxy]pyridin-4-yl}methanamine [ka]

[0272] The title compound, 2.22 g (90% purity, 68% yield), was prepared using a method similar to that described for Intermediate 2-1, starting with 3-[2-(1,4-dioxan-2-yl)ethoxy]pyridine-4-carbonitrile (Intermediate 1-6, 2.89 g, 12.3 mmol).

[0273] 1H-NMR (400 MHz, DMSO-d6): δ [ppm]= 1.536 (0.40), 1.729 (1.99), 1.751 (3.41), 1.765 (5.01), 1.785 (6.00), 1.804 (5.59), 1.817 (5.34), 1.834 (4.06), 1.852 (2.92), 1.870 (2.15), 2.326 (1.02), 2.669 (1.04), 3.159 (0.53), 3.208 (5.54), 3.235 (8.67), 3.261 (7.11), 3.424 (3.46), 3.430 (3.63), 3.451 (7.09), 3.457 (7.51), 3.479 (5.43), 3.485 (5.78), 3.528 (4.90), 3.534 (5.03), 3.557 (6.69), 3.563 (7.65), 3.584 (3.06), 3.590 (4.57), 3.622 (8.16), 3.653 (8.66), 3.688 (14.98), 3.697 (16.00), 3.731 (13.03), 3.759 (6.36), 4.136 (7.05), 4.152 (13.01), 4.167 (8.38), 7.385 (5.36), 7.394 (5.58), 8.163 (5.21), 8.172 (5.56), 8.224 (7.44). Intermediate 2-7 1-{3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methanamine [ka]

[0274] Using 3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridine-4-carbonitrile (Intermediate 1-7, 1.30 g, 5.24 mmol) as the starting material, 1.26 g of the title compound (90% purity, 86% yield) was prepared using a method similar to that described for Intermediate 2-1.

[0275] 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.014 (0.96), 1.049 (16.00), 1.201 (0.72), 1.262 (13.58), 1.751 (0.48), 2.518 (2.17), 2.523 (1.47), 3.308 (2.76), 3.539 (2.43), 3.567 (1.99), 3.601 (1.13), 3.623 (1.75), 3.694 (1.97), 3.720 (2.07), 3.746 (2.38), 3.783 (0.46), 4.128 (3.01), 4.136 (2.80), 7.386 (0.85), 8.181 (0.83), 8.237 (0.96). Intermediate 2-8 1-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)methanamine [ka]

[0276] Using 3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridine-4-carbonitrile (Intermediate 1-8, 1.24 g, 5.63 mmol) as the starting material, 1.56 g of the title compound (80% purity, 99% yield) was prepared using a method similar to that described for Intermediate 2-1.

[0277] 1H-NMR (400 MHz, DMSO-d6): δ [ppm]= 1.232 (0.52), 1.845 (1.06), 2.518 (2.37), 2.523 (1.54), 3.159 (14.24), 3.171 (14.33), 3.376 (0.69), 3.379 (0.65), 3.404 (2.41), 3.419 (0.41), 3.428 (3.79), 3.431 (3.86), 3.439 (0.59), 3.447 (0.69), 3.455 (2.71), 3.465 (1.97), 3.474 (0.57), 3.486 (2.71), 3.493 (2.97), 3.508 (1.01), 3.520 (2.61), 3.592 (0.45), 3.601 (1.92), 3.608 (2.10), 3.630 (2.77), 3.636 (3.65), 3.659 (5.73), 3.661 (5.45), 3.683 (16.00), 3.700 (1.95), 3.754 (3.49), 3.762 (2.18), 3.784 (2.51), 3.794 (0.57), 3.812 (0.61), 3.823 (2.48), 3.829 (3.16), 3.842 (0.81), 3.849 (2.07), 3.856 (6.45), 3.868 (1.93), 3.874 (1.37), 3.880 (1.69), 3.887 (1.30), 3.892 (1.13), 3.899 (0.89), 4.087 (11.44), 4.099 (10.46), 4.111 (2.62), 4.125 (1.15), 7.380 (4.02), 7.391 (4.11), 7.411 (0.67), 7.423 (0.67), 8.168 (6.28), 8.179 (6.26), 8.184 (1.58), 8.196 (1.02), 8.230 (10.21), 8.274 (1.76). Intermediate 2-9 tert-Butyl (3R)-3-({[4-(aminomethyl)pyridin-3-yl]oxy}methyl)morpholine-4-carboxylate [ka]

[0278] Using tert-butyl (3R)-3-{[(4-cyanopyridin-3-yl)oxy]methyl}morpholine-4-carboxylate (Intermediate 1-9, 4.00 g, 12.5 mmol) as the starting material, 3.65 g of the title compound was prepared (86% yield) using a method similar to that described for Intermediate 2-1.

[0279] 1H-NMR (400 MHz, DMSO-d6): δ [ppm]= 1.038 (0.41), 1.055 (0.77), 1.073 (0.44), 1.363 (10.92), 1.754 (6.47), 2.200 (1.02), 2.325 (1.05), 2.330 (1.42), 2.334 (1.05), 2.521 (5.72), 2.526 (3.72), 2.667 (0.88), 2.672 (1.22), 2.676 (0.89), 3.057 (1.02), 3.068 (1.10), 3.087 (1.65), 3.090 (1.62), 3.097 (1.89), 3.101 (1.73), 3.120 (2.21), 3.130 (2.39), 3.168 (16.00), 3.210 (1.86), 3.235 (0.59), 3.240 (1.07), 3.258 (1.25), 3.265 (1.40), 3.286 (1.75), 3.294 (2.07), 3.316 (3.15), 3.365 (3.67), 3.372 (3.73), 3.395 (1.88), 3.402 (1.68), 3.462 (1.41), 3.470 (1.43), 3.503 (3.53), 3.534 (2.78), 3.682 (7.14), 3.764 (1.68), 3.774 (1.81), 3.792 (3.17), 3.802 (2.81), 3.820 (1.93), 3.855 (0.89), 3.859 (1.19), 3.865 (1.80), 3.869 (2.32), 3.873 (3.62), 3.882 (2.64), 3.886 (3.02), 3.889 (2.79), 3.893 (4.31), 3.899 (3.39), 3.902 (2.87), 3.927 (2.09), 4.111 (1.76), 4.227 (3.64), 4.303 (0.96), 4.315 (1.37), 4.329 (3.71), 4.331 (3.43), 4.338 (1.95), 4.345 (2.50), 7.401 (2.60), 8.192 (2.81), 8.337 (2.91). LC-MS (Method 1): R t = 0.49 min; MS (ESIpos): m / z = 324 [M+H] + Intermediate 2-10 tert-Butyl (2R)-2-({[4-(aminomethyl)pyridin-3-yl]oxy}methyl)morpholine-4-carboxylate [ka]

[0280] Using tert-butyl (2R)-2-{[(4-cyanopyridin-3-yl)oxy]methyl}morpholine-4-carboxylate (Intermediate 1-10, 6.92 g, 21.7 mmol) as the starting material, 6.95 g of the title compound was prepared using a method similar to that described for Intermediate 2-1 (purity 90%, yield 89%).

[0281] 1 H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.41 (s, 9H), 2.70 - 3.01 (m, 2H), 3.17 (d, 3H), 3.41 - 3.52 (m, 1H), 3.63 - 3.70 (m, 2H), 3.70 - 3.81 (m, 2H), 3.82 - 4.00 (m, 2H), 4.08 - 4.18 (m, 3H), 7.39 (d, 1H), 8.18 (d, 1H), 8.25 (s, 1H). LC-MS (Method 2): R t = 0.84 min; MS (ESIpos): m / z = 324 [M+H] + Intermediate 2-11 1-{3-[(1S)-1-(1,4-dioxan-2-yl)ethoxy]pyridin-4-yl}methanamine [ka]

[0282] Using 3-[(1S)-1-(1,4-dioxan-2-yl)ethoxy]pyridine-4-carbonitrile (Intermediate 1-11, 1.68 g, 7.17 mmol) as the starting material, 1.49 g of the title compound (90% purity, 78% yield) was prepared using a method similar to that described for Intermediate 2-1. LC-MS (Method 6): R t = 0.2 min; MS (ESIpos): m / z = 239 [M+H] + 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.990 (0.87), 1.006 (0.89), 1.058 (0.73), 1.073 (0.73), 1.165 (0.76), 1.216 (15.68), 1.232 (16.00), 1.256 (14.15), 1.272 (13.96), 1.755 (9.46), 1.917 (0.88), 3.240 (0.43), 3.265 (0.46), 3.276 (0.41), 3.293 (0.54), 3.302 (0.81), 3.325 (0.68), 3.338 (0.50), 3.350 (0.56), 3.371 (0.56), 3.378 (0.58), 3.400 (2.78), 3.412 (2.79), 3.426 (5.84), 3.438 (5.24), 3.453 (6.52), 3.459 (6.28), 3.466 (5.96), 3.479 (2.46), 3.486 (3.26), 3.493 (2.78), 3.521 (0.49), 3.529 (0.67), 3.535 (0.58), 3.564 (2.05), 3.572 (2.72), 3.580 (2.41), 3.600 (6.11), 3.609 (5.52), 3.617 (4.09), 3.634 (11.25), 3.637 (11.05), 3.756 (8.08), 3.785 (6.75), 3.889 (2.49), 3.894 (2.48), 3.917 (2.26), 3.922 (2.16), 4.540 (1.04), 4.555 (3.05), 4.569 (4.27), 4.580 (2.83), 4.584 (2.84), 7.369 (3.21), 7.379 (4.91), 8.135 (3.33), 8.146 (5.23), 8.157 (3.20), 8.261 (4.69), 8.275 (4.23). Intermediate 2-12 1-{3-[(1R)-1-(1,4-dioxan-2-yl)ethoxy]pyridin-4-yl}methanamine [ka]

[0283] Using 3-{(1R)-1-[1,4-dioxan-2-yl]ethoxy}pyridine-4-carbonitrile (Intermediate 1-12, 1.39 g, 5.93 mmol) as the starting material, 1.36 g of the title compound (95% purity, 91% yield) was prepared using a method similar to that described for Intermediate 2-1.

[0284] 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.216 (0.81), 1.232 (0.99), 1.255 (15.91), 1.271 (16.00), 1.753 (0.71), 3.290 (0.44), 3.399 (0.54), 3.412 (2.42), 3.424 (0.71), 3.437 (3.81), 3.440 (3.42), 3.453 (0.77), 3.459 (2.72), 3.465 (5.00), 3.485 (1.48), 3.494 (2.02), 3.573 (1.45), 3.580 (1.70), 3.598 (2.00), 3.603 (3.43), 3.609 (3.84), 3.616 (2.24), 3.622 (2.04), 3.628 (1.97), 3.634 (4.41), 3.638 (4.68), 3.645 (2.04), 3.662 (5.32), 3.672 (6.05), 3.713 (0.63), 3.757 (2.28), 3.764 (2.39), 3.787 (1.75), 3.790 (1.84), 3.887 (2.14), 3.894 (2.12), 3.916 (1.94), 3.922 (1.85), 4.535 (0.53), 4.550 (1.85), 4.564 (2.15), 4.566 (2.17), 4.579 (1.80), 4.595 (0.50), 7.381 (3.18), 7.393 (3.14), 8.144 (4.36), 8.156 (4.13), 8.257 (0.50), 8.272 (6.58). LC-MS (Method 6): R t = 0.21 min; MS (ESIpos): m / z = 239 [M+H] + Intermediate 2-71 1-{3-[1-(4-methylmorpholin-2-yl)ethoxy]pyridin-4-yl}methanamine [ka]

[0285] Using 3-({1-[4-methylmorpholin-2-yl]ethyl}oxy)pyridine-4-carbonitrile (Intermediate 1-71, 815 mg, 3.30 mmol) as the starting material, 810 mg of the title compound (99% purity, 97% yield) was prepared using a method similar to that described for Intermediate 2-1.

[0286] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.227 (3.82), 1.242 (3.97), 1.254 (4.80), 1.270 (4.60), 1.850 (1.08), 1.862 (1.12), 1.876 (1.43), 1.888 (1.42), 1.903 (0.90), 1.915 (1.07), 1.928 (0.67), 1.937 (0.65), 1.945 (0.81), 1.957 (1.14), 1.965 (0.95), 1.973 (0.53), 1.985 (0.64), 1.993 (0.48), 2.152 (0.51), 2.183 (16.00), 2.332 (0.45), 2.518 (2.14), 2.522 (1.29), 2.575 (1.38), 2.602 (1.24), 2.673 (0.44), 2.692 (0.68), 2.720 (0.63), 2.834 (0.79), 2.862 (0.75), 3.475 (0.48), 3.480 (0.56), 3.487 (0.60), 3.504 (1.27), 3.508 (1.56), 3.514 (1.44), 3.536 (1.04), 3.542 (1.01), 3.563 (0.49), 3.568 (0.50), 3.575 (0.48), 3.588 (0.47), 3.667 (1.61), 3.793 (1.27), 3.821 (1.05), 4.561 (0.97), 7.374 (1.24), 8.138 (1.27), 8.267 (1.31). LC-MS (Method 6): R t = 0.11 min; MS (ESIpos): m / z = 252 [M+H] + Synthesis of intermediate 3 compound Intermediate 3-1 1-Chloro-3-isothiocyanato-2-methoxybenzene [ka]

[0287] 3-Chloro-2-methoxyaniline (CAS 51114-68-2, 8.4 ml, 63 mmol) was dissolved in DCM (100 ml) and saturated sodium bicarbonate solution (100 ml) was added. To the ice-cooled mixture, thiophosgene (5.4 ml, 70 mmol) was slowly added. The reaction was stirred at 0°C for 2 hours. The DCM layer was separated at room temperature and washed with saturated sodium bicarbonate solution. Filtration through a hydrophobic filter and concentration under reduced pressure gave the title compound (12.97 g, 100% yield), which was used directly in the next step.

[0288] 1 H-NMR (400MHz, DMSO-d6): δ [ppm]= 7.51 (dd, 1H), 7.35 (dd, 1H), 7.20 (t, 1H), 3.85 - 3.91 (m, 3H). Intermediate 3-4 1-Fluoro-3-isothiocyanato-2-methoxybenzene [ka]

[0289] Using a method similar to that described for intermediate 3-1; 6.24 g of the title compound was prepared (96% yield) using 3-fluoro-2-methoxyaniline (CAS 437-83-2, 5.00 g, 35.4 mmol) as the starting material.

[0290] 1 H-NMR (400MHz, DMSO-d6): δ [ppm]= 7.32 (m, 1H), 7.10 - 7.19 (m, 2H), 3.96 (d, 3H). Intermediate 3-18 1-chloro-5-fluoro-3-isothiocyanato-2-methoxybenzene [ka]

[0291] Using 3-chloro-5-fluoro-2-methoxyaniline (1.00 g, 5.70 mmol) as the starting material, 1.17 g of the title compound was prepared using a method similar to that described for Intermediate 3-1 (95% purity, 90% yield).

[0292] 1H NMR (400 MHz, DMSO-d6): δ [ppm]= 3.86 (s, 3H) 7.38 (dd, 1H) 7.58 (dd, 1H). Intermediate 3-29 1-chloro-2-ethyl-3-isothiocyanatobenzene [ka]

[0293] Using 3-chloro-2-ethylaniline (5.00 g, 85% purity, 27.3 mmol) as the starting material, 6.29 g of the title compound (85% purity, 99% yield) was prepared using a method similar to that described for intermediate 3-1.

[0294] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm]= 1.009 (7.50), 1.027 (16.00), 1.046 (7.55), 1.090 (0.44), 1.109 (0.89), 1.128 (0.44), 2.590 (2.26), 2.608 (6.71), 2.627 (6.58), 2.646 (2.00), 5.199 (6.39), 6.533 (4.44), 6.539 (4.27), 6.553 (5.20), 6.559 (4.97), 6.821 (3.47), 6.841 (5.70), 6.861 (2.75), 7.056 (0.43), 7.060 (0.52). Intermediate 3-65 2-Ethyl-1-fluoro-3-isothiocyanatobenzene [ka]

[0295] Using a method similar to that described for intermediate 3-1; 2-ethyl-3-fluoroaniline (2.50 g, 18.0 mmol, CAS 1139437-61-8) was used as the starting material to prepare 3.0 g of the title compound (90% purity, 83% yield).

[0296] 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.108 (7.13), 1.127 (16.00), 1.146 (7.13), 2.462 (0.95), 2.483 (1.27), 2.517 (0.79), 2.522 (0.48), 2.637 (0.95), 2.641 (1.11), 2.655 (3.17), 2.659 (3.17), 2.674 (3.17), 2.678 (3.17), 2.693 (0.95), 2.697 (0.95), 3.461 (0.48), 3.477 (0.63), 3.484 (0.63), 3.506 (1.11), 3.528 (2.06), 3.537 (2.69), 3.625 (3.01), 3.648 (1.11), 3.663 (0.63), 3.669 (0.63), 7.185 (1.11), 7.189 (1.11), 7.205 (1.58), 7.209 (2.53), 7.212 (1.27), 7.229 (1.43), 7.233 (1.74), 7.243 (1.27), 7.246 (1.43), 7.263 (3.80), 7.266 (2.38), 7.282 (2.53), 7.296 (2.38), 7.301 (2.38), 7.317 (2.53), 7.322 (0.79), 7.337 (0.79). Synthesis of intermediate 4 compound Intermediate 4-1 tert-Butyl 5-[(3-chloro-2-methoxyphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate [ka]

[0297] To an ice-cold solution of 1-chloro-3-isothiocyanato-2-methoxybenzene (Intermediate 3-1, 4.00 g, 20.0 mmol) and tert-butyl 2,4-dioxopiperidine-1-carboxylate (CAS 845267-78-9, 4.27 g, 20.0 mmol) in acetonitrile (92 mL) was added DBU (4.5 mL, 30 mmol) dropwise. The reaction was stirred at room temperature overnight. To the reaction mixture was added ice water (200 mL) and concentrated HCl (2 mL). The mixture was stirred for 20 minutes and extracted with DCM. The organic phase was filtered over a water-repellent filter, concentrated under reduced pressure, and purified by flash chromatography (silica, hexane / EtOAc gradient 0-50%) to give 6.54 g of the title compound (71% yield).

[0298] 1 H-NMR (400MHz, DMSO-d6): δ [ppm]= 13.36 (br s, 1H), 7.73 (d, 1H), 7.47 (dd, 1H), 7.22 (t, 1H), 3.76 - 3.82 (m, 5H), 2.88 (t, 2H), 1.48 (s, 9H). LC-MS (Method 1): R t = 1.49 min; MS (ESIpos): m / z = 413.1 [M+H] + Intermediate 4-4 tert-Butyl 5-[(3-fluoro-2-methoxyphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate [ka]

[0299] Using tert-butyl 2,4-dioxopiperidine-1-carboxylate (CAS 845267-78-9, 7.26 g, 34.1 mmol) and 1-fluoro-3-isothiocyanato-2-methoxybenzene (Intermediate 3-4, 6.24 g, 34.1 mmol) as starting materials, a method similar to that described for Intermediate 4-1 was used to prepare 9.49 g of the title compound (67% yield) after stirring the product in MeOH, filtering, and drying the precipitate in vacuo.

[0300] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm]= 13.37 (br s, 1H), 7.58 (br d, 1H), 7.23 - 7.30 (m, 1H), 7.09 - 7.21 (m, 1H), 4.10 (br s, 1H), 3.78 (t, 2H), 3.17 (s, 3H), 2.88 (br t, 2H), 1.48 (s, 9H). LC-MS (Method 2): R t = 0.66 min; MS (ESIpos): m / z = 397.3 [M+H] + Intermediate 4-7 tert-Butyl 5-[(2,3-dichlorophenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate [ka]

[0301] 1,2-Dichloro-3-isothiocyanatobenzene (CAS 6590-97-2, 5.00 g, 24.5 mmol) and tert-butyl 2,4-dioxopiperidine-1-carboxylate (CAS 845267-78-9, 5.22 g, 24.5 mmol) were dissolved in acetonitrile (55 ml), DBU (5.5 ml, 37 mmol) was carefully added at 0 °C under an argon atmosphere, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with HCl (200 ml, 1N in water) and stirred at room temperature for 30 minutes. The resulting solid was filtered off, the filter cake was washed with water, and dried in a vacuum oven at 50 °C overnight to give 9.40 g of the title compound (92% yield).

[0302] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm]= 1.467 (16.00), 1.484 (0.56), 1.622 (0.34), 1.644 (0.25), 1.661 (0.20), 1.674 (0.17), 1.898 (0.19), 1.913 (0.31), 1.927 (0.19), 2.075 (0.20), 2.327 (0.18), 2.518 (0.60), 2.523 (0.39), 2.621 (0.30), 2.647 (0.32), 2.665 (0.24), 2.669 (0.29), 2.673 (0.25), 3.249 (0.25), 3.459 (0.23), 3.473 (0.39), 3.487 (0.22), 3.538 (0.28), 3.561 (0.29), 3.727 (0.50), 7.357 (0.17), 7.377 (0.36), 7.383 (0.28), 7.397 (0.28), 7.544 (0.27), 7.547 (0.33), 7.560 (0.29), 7.564 (0.31), 7.568 (0.25), 7.580 (0.18). LC-MS (method 2): R t = 0.70 min; MS (ESIpos): m / z = 416 [MH] - Intermediate 4-10 tert-Butyl 5-[(3-chloro-2-methylphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate [ka]

[0303] Following the method described for intermediate 4-1; using 1-chloro-3-isothiocyanato-2-methylbenzene (CAS 19241-35-1; 2.50 g, 13.6 mmol) and tert-butyl 2,4-dioxopiperidine-1-carboxylate (CAS 845267-78-9, 2.9 g, 13.6 mmol) as starting materials, 4.68 g of the title compound was prepared (78% yield) after adding HCl, filtering, and drying the precipitate in vacuo.

[0304] 1 H-NMR (400MHz, DMSO-d6): δ [ppm]= 15.73 (s, 1H), 12.77 (br s, 1H), 7.45 (d, 1H), 7.30 (t, 1H), 7.19 (d, 1H), 3.78 (t, 2H), 2.85 (t, 2H), 2.20 (s, 3H), 1.48 (s, 9H). LC-MS (Method 2): R t = 0.72 min; MS (ESIpos): m / z = 397.3 [M+H] + Intermediate 4-18 tert-Butyl 5-[(3-chloro-5-fluoro-2-methoxyphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate [ka]

[0305] Using tert-butyl 2,4-dioxopiperidine-1-carboxylate (CAS 845267-78-9, 1.15 g, 5.38 mmol) and 1-chloro-5-fluoro-3-isothiocyanato-2-methoxybenzene (Intermediate 3-18, 1.17 g, 5.38 mmol) as starting materials, 1.42 g of the title compound was prepared using a method similar to that described for Intermediate 4-1 (75% purity, 46% yield).

[0306] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm]= 1.154 (0.88), 1.172 (1.70), 1.189 (0.80), 1.484 (16.00), 1.987 (3.28), 2.518 (0.89), 2.522 (0.61), 2.883 (0.73), 2.899 (0.40), 3.359 (0.69), 3.644 (4.46), 3.760 (7.94), 3.774 (0.44), 3.782 (1.03), 3.798 (0.53), 4.017 (0.69), 4.035 (0.69), 6.400 (0.60), 6.405 (0.53), 6.427 (1.00), 7.498 (0.41). LC-MS (Method 2): R t = 0.73 min; MS (ESIpos): m / z = 431 [M+H] + Intermediate 4-29 tert-Butyl 5-[(3-chloro-2-ethylphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate [ka]

[0307] Using tert-butyl 2,4-dioxopiperidine-1-carboxylate (CAS 845267-78-9, 5.77 g, 27.0 mmol) and 2-chloro-1-ethyl-3-isothiocyanatobenzene (Intermediate 3-29, 6.29 g, 85% purity, 27.0 mmol) as starting materials, 6.35 g of the title compound was prepared (85% purity, 49% yield) using a method similar to that described for Intermediate 4-1.

[0308] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm]= 1.063 (0.89), 1.082 (2.14), 1.100 (0.95), 1.362 (0.65), 1.478 (16.00), 1.486 (1.29), 2.518 (0.64), 2.523 (0.44), 2.631 (0.70), 2.650 (0.69), 2.850 (0.41), 2.866 (0.78), 2.883 (0.43), 3.775 (0.51), 3.791 (0.90), 3.807 (0.46), 7.212 (0.46), 7.214 (0.44), 7.232 (0.62), 7.234 (0.61), 7.293 (0.62), 7.313 (1.08), 7.332 (0.53), 7.440 (0.61), 7.443 (0.62), 7.460 (0.49), 7.463 (0.45). Intermediate 4-38 tert-Butyl 5-[(3-fluoro-2-methylphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate [ka]

[0309] Using tert-butyl 2,4-dioxopiperidine-1-carboxylate (CAS 845267-78-9, 8.19 g, 38.4 mmol) and 1-fluoro-3-isothiocyanato-2-methylbenzene (CAS 363179-58-2, 6.42 g, 38.4 mmol) as starting materials, a method similar to that described for intermediate 4-1 was used to prepare 11.1 g of the title compound (purity 95%, yield 72%) after stirring the product in MeOH, filtering, and drying the precipitate in vacuo.

[0310] 1 H-NMR (400 MHz, DMSO- d6): δ [ppm]= 1.479 (16.00), 2.084 (2.80), 2.088 (2.74), 2.834 (0.58), 2.850 (1.12), 2.866 (0.61), 3.768 (0.64), 3.784 (1.16), 3.800 (0.59), 7.073 (0.61), 7.093 (0.71), 7.186 (0.59), 7.299 (0.45), 7.316 (0.42). Intermediate 4-40 tert-Butyl 5-{[2-(2,2-difluoroethyl)-3-fluorophenyl]carbamothioyl}-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate [ka]

[0311] Using tert-butyl 2,4-dioxopiperidine-1-carboxylate (CAS 845267-78-9, 7.85 g, 36.8 mmol) and 2-(2,2-difluoroethyl)-1-fluoro-3-isothiocyanatobenzene (CAS 2311902-79-9, 8.00 g, 36.8 mmol) as starting materials, the title compound 12.1 g was prepared using a method similar to that described for intermediate 4-1 (purity 95%, yield 72%).

[0312] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm]= 1.471 (16.00), 2.518 (0.65), 2.523 (0.43), 2.788 (0.47), 2.804 (0.87), 2.820 (0.50), 3.166 (3.72), 3.754 (0.60), 3.770 (1.08), 3.786 (0.57), 7.149 (0.62), 7.169 (0.70), 7.271 (0.58), 7.446 (0.46), 7.462 (0.43). Intermediate 4-65 tert-Butyl 5-[(2-ethyl-3-fluorophenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate [ka]

[0313] Using tert-butyl 2,4-dioxopiperidine-1-carboxylate (CAS 845267-78-9, 7.85 g, 36.8 mmol) and 2-ethyl-1-fluoro-3-isothiocyanatobenzene (Intermediate 3-65, 3.00 g, 16.6 mmol) as starting materials, 5.46 g of the title compound was prepared using a method similar to that described for Intermediate 4-1 (purity 95%, yield 79%).

[0314] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.066 (1.02), 1.085 (2.41), 1.104 (1.06), 1.477 (16.00), 1.486 (1.04), 2.074 (0.65), 2.518 (1.12), 2.522 (0.92), 2.538 (0.61), 2.858 (0.69), 3.771 (0.55), 3.787 (0.98), 3.803 (0.50), 7.092 (0.50), 7.112 (0.55), 7.186 (0.45), 7.311 (0.44), 7.327 (0.41).LC-MS (method 2): R t = 0.72 min; MS (ESIpos): m / z = 395 [M+H] + Synthesis of intermediate 5 compound Intermediate 5-1 N-(3-chloro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide [ka]

[0315] To a solution of tert-butyl 5-[(3-chloro-2-methoxyphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate (Intermediate 4-1, 6.54 g, 15.8 mmol) in dichloromethane (94 mL) was added TFA (12 mL, 160 mmol), and the mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in EtOAc and washed with sodium bicarbonate solution and brine. The organic layer was filtered through a hydrophobic filter, and the filtrate was evaporated to dryness. The residue was purified by flash chromatography (silica, hexane / EtOAc gradient 20 to 100%) to give 4.06 g of the title compound (78% yield).

[0316] 1H-NMR (400 MHz, DMSO-d6): δ [ppm]= 16.45 (d, 1H), 14.69 (s, 1H), 14.33 (s, 1H), 9.37 (br s, 1H), 8.18 (br s, 1H), 7.76 - 7.87 (m, 1H), 7.37 - 7.45 (m, 1H), 7.15 - 7.23 (m, 1H), 3.73 - 3.76 (m, 3H), 3.43 (td, 1H), 3.27 - 3.32 (m, 1H), 2.79 (t, 1H), 2.59 - 2.69 (m, 1H). LC-MS (Method 1): R t = 1.19 min; MS (ESIpos): m / z = 313 [M+H] + Intermediate 5-4 N-(3-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide [ka]

[0317] Using tert-butyl 5-[(3-fluoro-2-methoxyphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate (Intermediate 4-4, 9.49 g, 23.9 mmol) as the starting material, after stirring for 15 minutes, 6.98 g of the title compound was prepared using a method similar to that described for Intermediate 5-1 (89% yield), which was used in the next step without further purification.

[0318] 1H-NMR (400 MHz, DMSO-d6): δ [ppm]= 16.48 (d, 1H), 14.63 (s, 0.5H), 14.28 (s, 0.5H), 9.34 (br s, 0.5H), 8.16 (br s, 0.5H), 7.65 (t, 1H), 6.97 - 7.37 (m, 2H), 3.79 - 3.85 (m, 3H), 3.35 - 3.46 (m, 1H), 3.26 - 3.32 (m, 1H), 2.78 (t, 1H), 2.63 (t, 1H). LC-MS (Method 2): R t = 0.46 min; MS (ESIpos): m / z = 297.1 [M+H] + Intermediate 5-7 N-(2,3-dichlorophenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide [ka]

[0319] Using a method similar to that described for Intermediate 5-1 using tert-butyl 5-[(2,3-dichlorophenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate (Intermediate 4-7, 9.40 g, 22.5 mmol) as the starting material, 5.71 g of the title compound was prepared (62% yield) after stirring overnight.

[0320] 1H-NMR (400 MHz, DMSO-d6): δ [ppm]= 1.018 (1.18), 1.050 (1.33), 1.072 (0.81), 1.102 (0.59), 1.132 (0.81), 1.154 (1.84), 1.172 (3.17), 1.189 (1.84), 1.199 (0.88), 1.231 (1.92), 1.259 (1.40), 1.486 (0.66), 1.593 (1.33), 1.626 (1.18), 1.695 (1.25), 1.727 (1.18), 1.907 (2.14), 1.987 (5.97), 2.322 (3.17), 2.326 (4.28), 2.331 (3.17), 2.518 (15.85), 2.522 (9.44), 2.638 (11.06), 2.664 (7.82), 2.669 (7.52), 2.673 (5.53), 2.798 (8.11), 3.436 (9.81), 4.017 (1.18), 4.035 (1.11), 5.560 (1.33), 5.579 (1.25), 7.392 (4.42), 7.410 (10.03), 7.430 (9.22), 7.565 (12.24), 7.585 (16.00), 7.605 (9.51), 8.134 (0.74), 8.197 (4.35), 9.418 (3.91), 14.273 (6.93), 14.665 (6.64), 16.114 (1.03), 16.295 (9.95), 16.352 (5.82), 16.503 (1.11). LC-MS (Method 2): R t = 0.55 min; MS (ESIpos): m / z = 316 [MH] - . Intermediates 5-10 N-(3-chloro-2-methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide [ka]

[0321] Using a method similar to that described for Intermediate 5-1 with tert-butyl 5-[(3-chloro-2-methylphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate (Intermediate 4-10, 4.67 g, 11.8 mmol) as the starting material, 3.54 g of the title compound was prepared after 3 hours (91% yield), which was used in the next step without further purification.

[0322] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm]= 16.42 (d, 1H), 14.01 - 14.37 (m, 1H), 8.14 - 9.40 (m, 1H), 7.43 (br t, 1H), 7.16 - 7.32 (m, 2H), 3.42 - 3.48 (m, 1H), 3.26 - 3.34 (m, 1H), 2.78 (t, 1H), 2.60 - 2.68 (m, 1H), 2.12 - 2.21 (m, 3H). LC-MS (Method 2): R t = 0.60 min; MS (ESIpos): m / z = 297.4 [M+H] + . Intermediate 5-18 N-(3-chloro-5-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide [ka]

[0323] Using tert-butyl 5-[(3-chloro-5-fluoro-2-methoxyphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate (Intermediate 4-18, 1.42 g, 3.30 mmol) as the starting material, 690 mg of the title compound was prepared (purity 95%, yield 60%) using a method similar to that described for Intermediate 5-1.

[0324] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm]= 2.61 - 2.70 (m, 1H), 2.80 (m, 1H), 3.25 - 3.32 (m, 1H), 3.38 - 3.47 (m, 1H), 3.74 (s, 3H), 7.39 - 7.62 (m, 1H), 7.83 - 8.02 (m, 1H), 8.20 - 8.33 (s, 0,5H), 9.33 - 9.57 (s, 0,5H), 14.53 (s, 0,5H), 14.93 (s, 0,5H), 16.29 (s, 0,5H), 16.36 (s, 0,5H). LC-MS (Method 2): R t = 0.57 min; MS (ESIneg): m / z = 329 [MH] - . Intermediate 5-29 N-(3-chloro-2-ethylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide [ka]

[0325] Using tert-butyl 5-[(3-chloro-2-ethylphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate (Intermediate 4-29, 2.35 g, 75% purity, 4.29 mmol) as the starting material, 1.22 g of the title compound was prepared (95% purity, 87% yield) using a method similar to that described for Intermediate 5-1.

[0326] 1H-NMR (400 MHz, DMSO-d6): δ [ppm]= 1.048 (7.06), 1.067 (16.00), 1.086 (7.43), 1.107 (1.58), 1.124 (1.32), 1.143 (0.50), 1.154 (1.34), 1.172 (2.43), 1.190 (1.24), 1.232 (0.50), 1.988 (4.56), 2.318 (0.47), 2.323 (1.05), 2.327 (1.56), 2.332 (1.11), 2.336 (0.47), 2.518 (5.61), 2.523 (4.03), 2.581 (2.03), 2.600 (6.41), 2.619 (6.62), 2.642 (4.59), 2.661 (2.69), 2.669 (1.90), 2.673 (1.27), 2.678 (0.58), 2.771 (2.35), 2.789 (4.82), 2.807 (2.58), 3.287 (1.61), 3.294 (1.79), 3.305 (3.11), 3.312 (3.14), 3.323 (2.06), 3.330 (2.35), 3.415 (1.53), 3.422 (1.66), 3.433 (2.56), 3.441 (2.45), 3.452 (1.40), 3.459 (1.24), 4.017 (1.03), 4.035 (1.00), 7.166 (0.95), 7.176 (0.58), 7.179 (0.58), 7.248 (0.71), 7.259 (6.30), 7.268 (3.58), 7.275 (4.43), 7.287 (7.20), 7.294 (3.90), 7.303 (3.56), 7.324 (0.87), 7.392 (1.85), 7.400 (1.37), 7.407 (1.85), 7.415 (1.74), 7.419 (2.40), 7.426 (1.77), 7.436 (1.77), 7.443 (1.45), 8.174 (1.77), 9.335 (1.42), 14.111 (2.98), 14.452 (2.74), 16.428 (7.88), 16.441 (7.38). LC-MS (Method 6): Rt = 1.28 min; MS (ESIpos): m / z = 311 [M+H] + . Intermediate 5-38 N-(3-fluoro-2-methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide [ka]

[0327] Using a method similar to that described for Intermediate 5-1, with tert-butyl 5-[(3-fluoro-2-methylphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate (Intermediate 4-38, 11.1 g, 29.1 mmol) as the starting material, after stirring for 15 minutes, 7.25 g of the title compound was prepared (84% yield), which was used in the next step without further purification.

[0328] 1H-NMR (400 MHz, DMSO- d6): δ [ppm]= 1.172 (0.55), 1.987 (1.05), 2.063 (16.00), 2.518 (1.49), 2.523 (1.01), 2.612 (1.94), 2.631 (3.67), 2.649 (2.11), 2.761 (1.99), 2.779 (4.22), 2.798 (2.26), 3.280 (1.36), 3.287 (1.47), 3.298 (2.58), 3.305 (2.57), 3.315 (1.39), 3.322 (1.33), 3.410 (1.40), 3.417 (1.48), 3.428 (2.27), 3.435 (2.22), 3.446 (1.27), 3.454 (1.15), 7.112 (1.56), 7.119 (0.96), 7.132 (2.25), 7.141 (3.30), 7.161 (2.66), 7.168 (2.15), 7.192 (1.12), 7.243 (0.73), 7.262 (1.15), 7.272 (0.99), 7.279 (1.25), 7.292 (1.27), 7.308 (1.21), 7.328 (0.45), 8.150 (1.43), 9.317 (1.16), 14.003 (2.32), 14.321 (2.05), 16.439 (5.35), 16.468 (4.62). LC-MS (Method 2): R t = 0.47 min; MS (ESIpos): m / z = 281 [M+H] + . Intermediate 5-40 N-[2-(2,2-difluoroethyl)-3-fluorophenyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide [ka]

[0329] Using tert-butyl 5-{[2-(2,2-difluoroethyl)-3-fluorophenyl]carbamothioyl}-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate (Intermediate 4-40, 12.1 g, 28.0 mmol) as the starting material, 8.81 g of the title compound was prepared using a method similar to that described for Intermediate 5-1 (purity 95%, yield 90%).

[0330] 1H-NMR (400 MHz, DMSO-d6): δ [ppm]= 1.145 (0.50), 1.154 (1.98), 1.172 (3.87), 1.190 (1.88), 1.441 (0.60), 1.987 (7.01), 2.323 (1.39), 2.327 (1.98), 2.332 (1.39), 2.518 (8.20), 2.523 (5.52), 2.617 (6.21), 2.635 (11.74), 2.653 (7.04), 2.665 (3.21), 2.669 (3.14), 2.673 (2.21), 2.769 (5.92), 2.786 (10.81), 2.803 (6.18), 3.059 (7.57), 3.067 (7.93), 3.104 (15.40), 3.111 (15.40), 3.148 (7.93), 3.307 (9.36), 3.434 (8.96), 4.000 (0.56), 4.017 (1.65), 4.035 (1.65), 4.053 (0.53), 6.057 (3.27), 6.067 (6.55), 6.077 (2.98), 6.198 (6.18), 6.208 (13.09), 6.217 (6.12), 6.339 (2.81), 6.348 (6.12), 6.358 (3.01), 7.165 (5.62), 7.185 (7.24), 7.207 (6.64), 7.227 (8.53), 7.242 (9.39), 7.265 (9.26), 7.288 (3.31), 7.393 (2.38), 7.413 (5.55), 7.430 (6.51), 7.459 (4.53), 7.479 (1.45), 8.152 (5.29), 9.352 (4.96), 14.013 (9.02), 14.389 (7.90), 16.346 (15.47), 16.353 (16.00). LC-MS (Method 2): R t = 0.48 min; MS (ESIpos): m / z = 331.1 [M+H] + . Intermediate 5-65 N-(2-ethyl-3-fluorophenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide [ka]

[0331] Using tert-butyl 5-[(2-ethyl-3-fluorophenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate (Intermediate 4-65, 5.46 g, 71% purity, 9.83 mmol) as the starting material, 4.0 g of the title compound was prepared (70% purity, 97% yield) using a method similar to that described for Intermediate 5-1.

[0332] 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.052 (6.61), 1.071 (16.00), 1.089 (6.75), 1.116 (0.56), 1.224 (4.60), 1.734 (1.58), 2.326 (0.43), 2.472 (1.56), 2.518 (2.10), 2.523 (1.69), 2.647 (0.85), 2.659 (0.85), 2.664 (0.98), 2.668 (1.03), 2.673 (0.80), 2.782 (0.89), 3.423 (0.82), 4.037 (0.62), 7.160 (2.35), 7.288 (0.98), 8.170 (0.48), 14.073 (0.46), 14.414 (0.52). LC-MS (Method 6): R t = 1.18 min; MS (ESIpos): m / z = 295 [M+H] + . Synthesis of intermediate 6 compound Intermediate 6-1 N-(3-chloro-2-methoxyphenyl)-4-[({3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide [ka]

[0333] A mixture of N-(3-chloro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 5-1, 498 mg, 1.59 mmol) and 1-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methanamine (Intermediate 2-1, 0.5 g, 2.23 mmol) was stirred at 120° C. for 4 hours. The reaction mixture was purified by flash chromatography (silica, DCM / EtOH gradient 0–30%) to give 325 mg of the title compound (39% yield).

[0334] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm]= 14.79 (s, 1H), 13.69 (t, 1H), 8.39 (s, 1H), 8.24 (d, 1H), 7.81 (dd, 1H), 7.73 (s, 1H), 7.26 - 7.33 (m, 2H), 7.11 (t, 1H), 4.67 (d, 2H), 4.16 (t, 2H), 3.84 - 3.95 (m, 2H), 3.74 - 3.79 (m, 1H), 3.71 (s, 3H), 3.59 - 3.70 (m, 2H), 3.45 - 3.54 (m, 2H), 3.11 - 3.20 (m, 2H), 2.78 (t, 2H). LC-MS (method 2): R t = 1.07 min; MS (ESIpos): m / z = 519.2 [M+H] + . Intermediate 6-2 N-(3-chloro-2-methoxyphenyl)-4-{[(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide [ka]

[0335] A mixture of N-(3-chloro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 5-1, 866 mg, 2.77 mmol) and 1-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)methanamine (Intermediate 2-8, 776 mg, 80% purity, 2.77 mmol) in ACN (22 mL) was treated with N,O-bis(trimethylsilyl)acetamide (2.05 mL, 8.6 mmol, CAS 10416-59-8) and stirred at 80 °C for 4 h. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography (silica, DCM / EtOH gradient 0-20%) to give 1.23 g of the title compound (95% purity, 81% yield).

[0336] 1 H-NMR (400MHz, DMSO-d6): δ [ppm]= 2.78 (t, 2H), 3.16 (td, 2H), 3.40 - 3.54 (m, 3H), 3.59 - 3.69 (m, 2H), 3.71 (s, 3H), 3.73 - 3.79 (m, 1H), 3.83 - 3.95 (m, 2H), 4.16 (t, 2H), 4.67 (d, 2H), 7.11 (t, 1H), 7.27 - 7.33 (m, 2H), 7.73 (br s, 1H), 7.81 (dd, 1H), 8.24 (d, 1H), 8.39 (s, 1H), 13.69 (s, 1H), 14.79 (s, 1H). LC-MS (Method 2): R t= 1.09 min; MS (ESIpos): m / z = 519 [M+H] + Intermediate 6-4 4-[({3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methyl)amino]-N-(3-fluoro-2-methoxyphenyl)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide [ka]

[0337] Using N-(3-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 5-4, 179 mg, 604 μmol) and 1-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methanamine (Intermediate 2-1, 190 mg, 845 μmol) as starting materials, 120 mg of the title compound was prepared (34% yield) after heating for 2 hours and purification by flash chromatography (amino-phase silica, DCM / EtOH gradient 0-10%) using a method similar to that described for Intermediate 6-1.

[0338] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm]= 14.74 (s, 1H), 13.70 (br t, 1H), 8.39 (s, 1H), 8.24 (d, 1H), 7.64 - 7.73 (m, 2H), 7.30 (d, 1H), 7.02 - 7.14 (m, 2H), 4.67 (d, 2H), 4.13 - 4.21 (m, 2H), 3.84 - 3.95 (m, 2H), 3.59 - 3.77 (m, 4H), 3.40 - 3.53 (m, 2H), 3.13 - 3.22 (m, 2H), 2.68 - 2.80 (m, 2H), 1.59 (br s, 1H), 0.93 - 1.39 (m, 1H). LC-MS (Method 2): R t= 1.01 min; MS (ESIpos): m / z = 503 [M+H] + . Intermediate 6-7 N-(2,3-Dichlorophenyl)-4-[({3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide [ka]

[0339] Using a method similar to that described for Intermediate 6-1, N-(2,3-dichlorophenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 5-7, 160 mg, 504 μmol) and 1-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methanamine (Intermediate 2-1, 158 mg, 706 μmol), 110 mg of the title compound was prepared (35% yield) after heating for 2 hours and purification by flash chromatography (amino-phase silica, DCM / EtOH gradient 0-10%).

[0340] 1 H-NMR (400MHz, DMSO-d6): δ [ppm]= 14.90 (s, 1H), 13.66 (t, 1H), 8.39 (s, 1H), 8.24 (d, 1H), 7.75 (br s, 1H), 7.55 (dd, 1H), 7.51 (dd, 1H), 7.28 - 7.38 (m, 3H), 4.68 (d, 3H), 4.14 - 4.21 (m, 2H), 3.87 - 3.90 (m, 1H), 3.72 - 3.76 (m, 1H), 3.64 - 3.67 (m, 1H), 3.58 - 3.63 (m, 1H), 3.35 - 3.53 (m, 3H), 2.79 (t, 2H). LC-MS (Method 2): R t= 1.08 min; MS (ESIpos): m / z = 523 [M+H] + . Intermediates 6-10 N-(3-chloro-2-methylphenyl)-4-[({3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methyl)-amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide [ka]

[0341] Using a method similar to that described for Intermediate 6-1; starting from N-(3-chloro-2-methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 5-10, 189 mg, 637 μmol) and 1-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methanamine (Intermediate 2-1, 200 mg, 892 μmol); after heating for 2 hours and purification by flash chromatography (amino-phase silica, DCM / EtOH gradient 0-10%), 180 mg of the title compound was prepared (56% yield).

[0342] 1 H-NMR (400MHz, DMSO-d6): δ [ppm]= 14.54 (s, 1H), 13.64 (br t, 1H), 8.38 (s, 1H), 8.24 (d, 1H), 7.69 (br s, 1H), 7.28 - 7.37 (m, 2H), 7.13 - 7.26 (m, 2H), 4.65 (d, 2H), 4.14 - 4.20 (m, 2H), 3.74 - 3.88 (m, 3H), 3.63 - 3.71 (m, 2H), 3.42 - 3.53 (m, 2H), 3.14 - 3.31 (m, 2H), 2.77 (t, 2H), 2.16 (s, 3H). LC-MS (Method 2): R t= 1.09 min; MS (ESIpos): m / z = 501 [M+H] + . Intermediate 6-11 N-(3-chloro-2-methoxyphenyl)-4-{[(3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide [ka]

[0343] Using N-(3-chloro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 5-1, 142 mg, 407 μmol) and 1-(3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)methanamine (Intermediate 2-2, 116 mg, 489 μmol) as starting materials, a similar method as described in Intermediate 6-1 was used; heating for 3 hours and purification by preparative HPLC (Method 10, gradient: 0.00-0.50 min 30% B, 0.50-6.00 min 30-70% B) gave 85.6 mg of the title compound (36% yield).

[0344] 1H-NMR (400 MHz, DMSO-d6): δ [ppm]= 14.79 (s, 1H), 13.67 (br t, 1H), 8.41 (s, 1H), 8.24 (d, 1H), 7.81 (dd, 1H), 7.73 (br s, 1H), 7.28 - 7.33 (m, 2H), 7.11 (t, 1H), 4.67 (br d, 2H), 4.31 (dd, 1H), 4.05 (dd, 1H), 3.90 (dd, 1H), 3.67 - 3.73 (m, 4H), 3.50 (td, 1H), 3.34 - 3.40 (m, 1H), 3.13 - 3.21 (m, 2H), 2.79 (t, 2H), 2.63 - 2.70 (m, 1H), 2.19 - 2.33 (m, 4H), 1.46 - 1.76 (m, 1H). LC-MS (Method 2): R t = 1.08 min; MS (ESIpos): m / z = 532.5 [M+H] + Intermediate 6-12 N-(3-fluoro-2-methoxyphenyl)-4-(((3-hydroxypyridin-4-yl)methyl)amino)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide [ka]

[0345] A mixture of 4-(aminomethyl)pyridin-3-ol (CAS 20485-35-2, 75 g, 0.604 mol) and N-(3-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 5-4, 150 g, 0.506 mol) in DMA (1.2 L) was stirred at 120 °C under nitrogen for 2.5 h. The mixture was concentrated in vacuo to remove most of the solvent. The dark brown solution was slowly added to EtOAc (8 L) with stirring. The resulting mixture was washed with water (2.5 L) and brine (2.5 L × 2). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was slurried with EtOAc (300 mL) and filtered. The filter cake was dried in vacuo to give the title compound (87 g, 47% yield) as a yellow solid.

[0346] 1 H NMR (400 MHz, DMSO-d6): δ [ppm]= 14.73 (s, 1H), 13.69 (t, 1H), 10.28 (s, 1H), 8.21-8.13 (m, 2H), 7.67-7.66 (m, 2H), 7.10 (br.s, 1H), 7.09-7.04 (m, 2H), 4.61 (d, 2H), 3.79 (s, 3H), 3.16 (t, 2H), 2.77 (t, 2H). Intermediate 6-15 N-(3-chloro-2-methoxyphenyl)-4-[({3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide [ka]

[0347] Using N-(3-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 5-4, 100 mg, 320 μmol) and 1-(3-{[4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)methanamine (Intermediate 2-3, 114 mg, 480 μmol) as starting materials, 74.3 mg (80% purity, 35% yield) of the title compound was prepared using a method similar to that described for Intermediate 6-1 after heating for 4 hours and purification by flash chromatography (aminophase silica, DCM / EtOH gradient 0-10%).

[0348] 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.880 (0.45), 2.176 (4.07), 2.186 (0.73), 2.191 (0.45), 2.518 (1.66), 2.523 (1.13), 2.787 (0.65), 2.799 (0.61), 3.162 (0.56), 3.169 (0.54), 3.533 (0.46), 3.539 (0.45), 3.711 (9.24), 3.819 (0.47), 3.823 (0.40), 4.149 (0.65), 4.161 (1.12), 4.176 (0.61), 4.655 (0.80), 4.670 (0.82), 5.759 (16.00), 7.086 (0.63), 7.107 (1.27), 7.127 (0.73), 7.283 (0.77), 7.287 (0.81), 7.302 (0.77), 7.306 (1.39), 7.318 (0.80), 7.723 (0.53), 7.803 (0.59), 7.806 (0.60), 7.823 (0.57), 7.827 (0.53), 8.234 (1.27), 8.246 (1.26), 8.392 (1.87), 14.791 (1.01). LC-MS (Method 2): R t = 0.84 min; MS (ESIpos): m / z = 532 [M+H] + Intermediate 6-18 N-(3-chloro-5-fluoro-2-methoxyphenyl)-4-[({3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide [ka]

[0349] Using N-(3-chloro-5-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 5-18, 100 mg, 302 μmol) and 1-(3-{[4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)methanamine (Intermediate 2-3, 108 mg, 453 μmol) as starting materials, a method similar to that described for Intermediate 6-1 was used to prepare 166 mg (70% purity, 70% yield) of the title compound after purification by flash chromatography (amino-phase silica, DCM / EtOH gradient 0-10%).

[0350] 1H-NMR (400 MHz, DMSO-d6): δ [ppm]= 1.881 (0.59), 1.908 (0.51), 1.984 (0.51), 1.991 (0.55), 2.174 (5.75), 2.185 (0.88), 2.191 (2.53), 2.518 (2.46), 2.523 (1.65), 2.581 (0.55), 2.609 (0.49), 2.785 (0.52), 2.798 (0.96), 2.815 (0.60), 3.096 (0.44), 3.161 (0.55), 3.168 (0.51), 3.387 (0.97), 3.535 (0.57), 3.542 (0.68), 3.700 (7.75), 3.786 (0.69), 3.791 (0.73), 3.795 (0.71), 3.810 (0.63), 3.815 (0.70), 3.823 (0.75), 4.115 (0.52), 4.119 (0.55), 4.128 (0.53), 4.154 (0.77), 4.166 (0.94), 4.181 (0.60), 4.672 (0.76), 4.687 (0.77), 5.759 (16.00), 7.267 (0.58), 7.275 (0.65), 7.287 (0.58), 7.295 (0.63), 7.313 (0.77), 7.325 (0.74), 7.792 (0.49), 8.046 (0.50), 8.053 (0.50), 8.073 (0.47), 8.080 (0.47), 8.238 (1.20), 8.250 (1.12), 8.267 (0.55), 8.279 (0.66), 8.399 (1.72), 15.080 (0.94). LC-MS (Method 2): R t = 1.11 min; MS (ESIpos): m / z = 550 [M+H] + Intermediate 6-19 N-(3-chloro-5-fluoro-2-methoxyphenyl)-4-[({3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide [ka]

[0351] Using N-(3-chloro-5-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 5-18, 100 mg, 302 μmol) and 1-(3-{[1,4-dioxan-2-yl]methoxy}pyridin-4-yl)methanamine (Intermediate 2-1, 94.9 mg, 423 μmol) as starting materials, a method similar to that described for Intermediate 6-1 was used to prepare 160 mg of the title compound (90% purity, 89% yield) after purification by flash chromatography (silica, DCM / EtOH gradient 0-30%).

[0352] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.821 (0.41), 0.904 (0.45), 1.035 (8.84), 1.052 (16.00), 1.070 (9.56), 1.154 (1.90), 1.172 (3.66), 1.189 (1.72), 1.987 (6.85), 2.518 (1.36), 2.522 (0.92), 2.790 (0.61), 3.157 (0.42), 3.404 (1.39), 3.417 (1.49), 3.421 (4.01), 3.434 (4.35), 3.439 (4.40), 3.452 (4.43), 3.457 (1.21), 3.461 (0.53), 3.469 (1.28), 3.501 (0.40), 3.652 (0.66), 3.655 (0.65), 3.702 (7.42), 3.750 (0.43), 3.785 (0.67), 3.788 (0.43), 3.890 (0.58), 3.999 (0.46), 4.017 (1.36), 4.035 (1.39), 4.053 (0.47), 4.156 (0.56), 4.165 (0.77), 4.179 (0.54), 4.343 (2.52), 4.356 (4.91), 4.368 (2.35), 4.683 (0.68), 4.697 (0.68), 7.272 (0.48), 7.280 (0.60), 7.293 (0.51), 7.300 (0.64), 7.305 (0.63), 7.317 (0.62), 7.800 (0.42), 8.032 (0.40), 8.040 (0.42), 8.059 (0.41), 8.066 (0.40), 8.242 (0.98), 8.254 (0.94), 8.394 (1.43), 15.078 (0.82). LC-MS (Method 2): R t = 1.14 min; MS (ESIpos): m / z = 537 [M+H] + Intermediate 6-20 N-(3-Fluoro-2-methoxyphenyl)-4-{[(3-{[(3S)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide [ka]

[0353] Using N-(3-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 5-4, 200 mg, 675 μmol) and 1-(3-{[(3S)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)methanamine (Intermediate 2-4, 208 mg, 877 μmol) as starting materials, a method similar to that described for Intermediate 6-1 was used to prepare 105 mg of the title compound (99% purity, 30% yield) after heating for 3 hours and purification by preparative HPLC (Method 10, gradient: 0.00-0.50 min, 15% B, 0.50-6.00 min, 15% B-55% B).

[0354] 1H-NMR (400 MHz, DMSO-d6): δ [ppm]= 2.195 (0.50), 2.203 (0.62), 2.221 (0.73), 2.224 (0.80), 2.229 (0.79), 2.232 (0.77), 2.250 (0.69), 2.258 (0.63), 2.287 (16.00), 2.322 (0.48), 2.326 (0.65), 2.331 (0.46), 2.518 (2.86), 2.522 (1.80), 2.645 (0.60), 2.651 (1.24), 2.658 (0.75), 2.664 (0.58), 2.668 (0.75), 2.673 (0.96), 2.680 (1.16), 2.687 (0.56), 2.760 (1.14), 2.776 (2.31), 2.793 (1.34), 3.134 (0.86), 3.142 (0.98), 3.152 (1.59), 3.158 (1.51), 3.167 (0.87), 3.175 (0.73), 3.347 (1.31), 3.371 (1.26), 3.375 (1.37), 3.398 (1.19), 3.473 (0.50), 3.480 (0.60), 3.501 (0.98), 3.507 (0.98), 3.527 (0.72), 3.533 (0.60), 3.677 (0.56), 3.683 (1.07), 3.690 (0.58), 3.704 (0.46), 3.711 (0.82), 3.718 (0.41), 3.780 (13.85), 3.783 (13.72), 3.884 (0.99), 3.892 (0.99), 3.912 (0.89), 3.920 (0.88), 4.029 (0.98), 4.044 (1.01), 4.054 (1.17), 4.070 (1.12), 4.291 (1.18), 4.302 (1.21), 4.317 (1.03), 4.327 (0.97), 4.658 (1.87), 4.674 (1.89), 7.044 (0.58), 7.049 (1.31), 7.065 (1.59), 7.069 (2.63), 7.075 (1.64), 7.085 (1.41), 7.090 (0.58), 7.096 (1.44), 7.101 (1.44), 7.117 (0.56), 7.122 (0.41), 7.296 (2.20), 7.308 (2.24), 7.653 (1.44), 7.658 (0.89), 7.670 (1.15), 7.676 (0.86), 7.704 (1.58), 8.236 (3.27), 8.247 (3.17), 8.411 (4.92), 13.661 (0.56), 13.676 (1.10), 13.690 (0.53), 14.736 (2.92). LC-MS (Method 6): Rt = 0.62 min; MS (ESIpos): m / z = 516 [M+H] + Intermediate 6-21 N-(3-chloro-2-methoxyphenyl)-4-{[(3-{[(3S)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide [ka]

[0355] Starting from N-(3-chloro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 5-1, 200 mg, 639 μmol) and 1-(3-{[(3S)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)methanamine (Intermediate 2-4, 197 mg, 831 μmol), a method similar to that described for Intermediate 6-1 was used to prepare 102 mg (99% pure, 30% yield) of the title compound after heating at 120° C. for 3 hours and purification by preparative HPLC (Method 10, gradient: 0.00-0.50 min 15% B, 0.50-6.00 min 15-55% B).

[0356] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.288 (3.78), 2.327 (0.47), 2.518 (1.87), 2.523 (1.27), 2.651 (0.43), 2.665 (0.45), 2.669 (0.59), 2.673 (0.55), 2.679 (0.47), 2.769 (0.69), 2.786 (1.40), 2.803 (0.81), 3.141 (0.53), 3.148 (0.61), 3.157 (0.97), 3.164 (0.93), 3.174 (0.53), 3.181 (0.44), 3.346 (0.55), 3.372 (0.52), 3.506 (0.45), 3.684 (0.50), 3.712 (16.00), 3.883 (0.44), 3.891 (0.53), 3.912 (0.42), 4.293 (0.54), 4.304 (0.56), 4.319 (0.47), 4.329 (0.44), 4.663 (1.08), 4.679 (1.10), 7.088 (1.04), 7.108 (2.24), 7.128 (1.28), 7.285 (1.42), 7.289 (1.49), 7.301 (1.47), 7.305 (1.46), 7.309 (1.44), 7.312 (1.47), 7.726 (0.92), 7.794 (1.07), 7.797 (1.08), 7.814 (1.02), 7.818 (0.96), 8.238 (1.81), 8.250 (1.65), 8.413 (3.11), 13.667 (0.68), 14.787 (1.82). LC-MS (Method 6): Rt = 0.68 min; MS (ESIpos): m / z = 532 [M+H] + Intermediate 6-22 tert-Butyl (2S)-2-[({4-[({5-[(3-fluoro-2-methoxyphenyl)carbamothioyl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}amino)methyl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate [ka]

[0357] Starting from N-(3-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 5-4, 1.00 g, 3.37 mmol) and tert-butyl (2S)-2-({[4-(aminomethyl)pyridin-3-yl]oxy}methyl)morpholine-4-carboxylate (Intermediate 2-5, 1.53 g, 4.72 mmol), using a method similar to that described for Intermediate 6-1; after heating for 6 hours and purification by flash chromatography (silica, DCM / EtOH gradient 0-20%), 1.43 g of the title compound (70% purity, 49% yield) was prepared.

[0358] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm]= 1.035 (6.69), 1.052 (16.00), 1.070 (7.70), 1.394 (4.63), 1.401 (2.39), 1.405 (3.46), 2.331 (0.41), 2.518 (1.92), 2.523 (1.41), 2.673 (0.42), 3.404 (1.10), 3.417 (1.21), 3.422 (3.66), 3.435 (3.78), 3.440 (3.26), 3.452 (3.33), 3.457 (1.19), 3.469 (1.18), 3.780 (2.11), 3.782 (2.08), 3.797 (0.42), 3.857 (0.84), 3.860 (0.83), 4.219 (0.41), 4.231 (0.42), 4.344 (2.52), 4.356 (4.87), 4.369 (2.35), 8.241 (0.54), 8.253 (0.53), 8.402 (0.81), 14.735 (0.40). LC-MS (Method 2): R t= 1.19 min; MS (ESIpos): m / z = 602 [M+H] + Intermediate 6-24 N-(3-chloro-2-methoxyphenyl)-4-[({3-[2-(1,4-dioxan-2-yl)ethoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide [ka]

[0359] Starting from N-(3-chloro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 5-1, 200 mg, 639 μmol) and 1-(3-{2-[1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)methanamine (Intermediate 2-6, 198 mg, 831 μmol), a method similar to that described for Intermediate 6-1 was used to prepare 110 mg (96% pure, 31% yield) of the title compound after heating at 130° C. for 3 hours and purification by preparative HPLC (Method 10, gradient: 0.00-0.50 min 15% B, 0.50-6.00 min 15-55% B).

[0360] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.792 (0.45), 1.812 (0.43), 1.838 (0.40), 1.850 (0.42), 2.518 (1.13), 2.523 (0.78), 2.763 (0.87), 2.771 (0.86), 2.780 (0.52), 2.786 (0.47), 3.140 (0.51), 3.148 (0.57), 3.156 (0.97), 3.164 (0.96), 3.173 (0.50), 3.181 (0.43), 3.197 (0.60), 3.224 (0.94), 3.227 (0.95), 3.253 (0.64), 3.445 (0.75), 3.452 (0.83), 3.471 (0.48), 3.480 (0.60), 3.545 (0.45), 3.551 (0.53), 3.573 (0.70), 3.580 (0.81), 3.605 (0.86), 3.611 (1.14), 3.617 (0.53), 3.638 (0.55), 3.644 (0.47), 3.689 (0.92), 3.697 (1.10), 3.712 (16.00), 3.718 (2.12), 3.744 (0.88), 3.749 (0.65), 4.203 (0.84), 4.219 (1.35), 4.232 (0.58), 4.238 (0.56), 4.656 (1.44), 4.670 (1.43), 7.089 (1.01), 7.110 (2.16), 7.130 (1.25), 7.286 (1.37), 7.289 (1.46), 7.306 (2.13), 7.310 (1.42), 7.317 (1.10), 7.726 (0.93), 7.802 (1.03), 7.806 (1.05), 7.823 (0.99), 7.826 (0.93), 8.225 (1.23), 8.237 (1.18), 8.373 (1.98), 13.695 (0.65), 14.792 (1.75). LC-MS (Method 6): Rt = 0.90 min; MS (ESIpos): m / z = 533 [M+H] + Intermediate 6-27 tert-Butyl (2S)-2-[({4-[({5-[(3-chloro-5-fluoro-2-methoxyphenyl)carbamothioyl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}amino)methyl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate [ka]

[0361] Starting from N-(3-chloro-5-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 5-18, 225 mg, 680 μmol) and tert-butyl (2S)-2-({[4-(aminomethyl)pyridin-3-yl]oxy}morpholine-4-carboxylate (Intermediate 2-5, 308 mg, 952 μmol), a method similar to that described for Intermediate 6-1 was used to prepare 150 mg of the title compound (80% pure, 28% yield) after 6 hours of heating and purification by flash chromatography (silica, DCM / EtOH gradient 0-20%).

[0362] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.035 (2.70), 1.052 (5.86), 1.070 (3.02), 1.232 (0.46), 1.389 (16.00), 1.405 (6.16), 1.419 (1.21), 2.331 (0.75), 2.430 (0.47), 2.447 (0.51), 2.518 (3.46), 2.523 (2.53), 2.673 (0.75), 2.772 (0.61), 2.789 (1.14), 2.805 (0.74), 3.137 (0.46), 3.145 (0.53), 3.154 (0.79), 3.161 (0.75), 3.405 (0.58), 3.417 (0.72), 3.422 (1.54), 3.435 (1.70), 3.440 (1.70), 3.445 (0.63), 3.452 (1.56), 3.457 (0.61), 3.469 (0.63), 3.655 (0.79), 3.699 (12.68), 3.719 (0.53), 3.732 (0.75), 3.738 (0.84), 3.757 (0.49), 3.764 (0.44), 3.787 (2.07), 3.821 (0.49), 3.842 (0.93), 3.870 (0.40), 4.225 (1.58), 4.237 (1.60), 4.344 (0.84), 4.357 (1.63), 4.370 (0.82), 4.681 (1.14), 4.696 (1.11), 5.759 (0.75), 7.267 (0.93), 7.275 (1.12), 7.287 (0.96), 7.295 (1.05), 7.311 (0.79), 7.323 (0.79), 7.799 (0.77), 8.031 (0.67), 8.038 (0.68), 8.057 (0.67), 8.065 (0.63), 8.245 (1.81), 8.257 (1.63), 8.290 (0.54), 8.410 (2.60), 13.671 (0.58), 15.074 (1.58). LC-MS (Method 2): R t= 1.30 min; MS (ESIpos): m / z = 636 [M+H] + Intermediate 6-29 N-(3-chloro-2-ethylphenyl)-4-[({3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide [ka]

[0363] Starting from N-(3-chloro-2-ethylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 5-29, 300 mg, 965 μmol) and 1-(3-{[4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)methanamine (Intermediate 2-3, 321 mg, 1.35 mmol), a similar method as described for Intermediate 6-1 was used to prepare 300 mg of the title compound (80% pure, 47% yield) after heating for 6 hours and purification by flash chromatography (silica, DCM / EtOH gradient 0-20%).

[0364] 1H-NMR (400 MHz, DMSO-d6): δ [ppm]= 0.798 (0.84), 0.814 (0.93), 0.821 (0.93), 0.840 (0.43), 0.886 (0.53), 0.904 (1.07), 0.922 (0.50), 1.035 (9.51), 1.052 (16.00), 1.066 (1.09), 1.070 (9.08), 1.073 (1.50), 1.232 (0.45), 1.874 (0.59), 1.901 (0.47), 1.907 (0.59), 1.983 (0.41), 1.990 (0.52), 2.178 (5.56), 2.195 (1.38), 2.202 (0.47), 2.331 (0.74), 2.518 (3.86), 2.522 (2.50), 2.580 (0.57), 2.591 (1.05), 2.610 (1.21), 2.673 (0.95), 2.784 (0.95), 2.817 (0.50), 3.162 (0.41), 3.172 (0.69), 3.179 (0.65), 3.404 (1.33), 3.417 (1.38), 3.421 (3.41), 3.434 (3.43), 3.439 (3.91), 3.452 (4.01), 3.457 (1.15), 3.469 (1.19), 3.529 (0.57), 3.535 (0.57), 3.735 (0.55), 3.784 (0.47), 3.788 (0.47), 3.792 (0.47), 3.812 (0.64), 3.816 (0.62), 4.111 (0.41), 4.123 (0.48), 4.138 (0.83), 4.149 (0.83), 4.154 (0.88), 4.168 (0.74), 4.343 (2.64), 4.356 (5.06), 4.368 (2.39), 4.636 (0.93), 4.651 (0.93), 7.205 (1.50), 7.208 (1.38), 7.218 (2.69), 7.296 (1.02), 7.305 (1.02), 7.308 (1.05), 7.315 (1.17), 7.327 (0.55), 7.701 (0.64), 8.228 (1.50), 8.240 (1.38), 8.282 (0.47), 8.385 (2.07), 13.654 (0.43), 14.636 (1.17). LC-MS (Method 2): R t = 1.14 min; MS (ESIpos): m / z = 530 [M+H] + Intermediate 6-30 N-(3-chloro-2-methoxyphenyl)-4-[({3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide [ka]

[0365] Starting from N-(3-chloro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 5-1, 200 mg, 639 μmol) and 1-{3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methanamine (Intermediate 2-7, 210 mg, 831 μmol), a method similar to that described for Intermediate 6-1 was used to prepare 55.0 mg (98% pure, 15% yield) of the title compound after heating at 130 °C for 3 hours and purification by preparative HPLC (Method 10, gradient: 0.00-0.50 min 15% B, 0.50-6.00 min 15%-55% B).

[0366] 1H-NMR (400 MHz, DMSO-d6): δ [ppm]= 1.042 (9.29), 1.249 (8.31), 2.518 (2.85), 2.523 (1.83), 2.752 (0.79), 2.768 (1.57), 2.785 (0.95), 3.147 (0.74), 3.156 (1.18), 3.164 (1.13), 3.299 (1.11), 3.533 (1.90), 3.562 (1.50), 3.628 (0.50), 3.648 (1.21), 3.658 (1.28), 3.667 (1.26), 3.691 (1.55), 3.713 (16.00), 3.720 (1.14), 3.795 (0.51), 3.806 (0.64), 3.817 (0.52), 4.154 (0.42), 4.164 (0.43), 4.180 (1.25), 4.191 (1.23), 4.198 (1.31), 4.212 (1.18), 4.225 (0.43), 4.663 (1.86), 4.678 (1.86), 7.088 (1.13), 7.108 (2.42), 7.128 (1.39), 7.286 (1.58), 7.290 (1.68), 7.305 (2.17), 7.310 (1.58), 7.316 (1.59), 7.729 (1.16), 7.799 (1.26), 7.803 (1.27), 7.819 (1.18), 7.823 (1.14), 8.241 (1.91), 8.253 (1.81), 8.397 (3.02), 13.669 (0.43), 13.683 (0.81), 14.792 (2.17). LC-MS (method 6): Rt = 1.04 min; MS (ESIpos): m / z = 547 [M+H] + Intermediate 6-33 4-[({3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methyl)amino]-N-(3-fluoro-2-methoxyphenyl)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide [ka]

[0367] Using a method similar to that described for Intermediate 6-1; starting from N-(3-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 5-1, 200 mg, 675 μmol) and 1-{3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methanamine (Intermediate 2-7, 221 mg, 877 μmol), 130 mg of the title compound (96% purity, 35% yield) was prepared after heating at 130 °C for 2 h and purification by preparative HPLC (Method 10, gradient: 0.00-0.50 min 15% B, 0.50-6.00 min 15-55% B).

[0368] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.043 (15.59), 1.251 (13.74), 2.518 (2.60), 2.523 (1.78), 2.742 (1.25), 2.759 (2.52), 2.775 (1.52), 3.134 (1.00), 3.142 (1.15), 3.152 (1.86), 3.158 (1.79), 3.167 (1.02), 3.175 (0.86), 3.300 (1.91), 3.535 (3.14), 3.563 (2.56), 3.622 (0.60), 3.630 (0.81), 3.650 (1.97), 3.659 (2.07), 3.668 (2.14), 3.692 (2.45), 3.722 (1.19), 3.782 (15.81), 3.785 (16.00), 3.796 (0.91), 3.808 (1.03), 3.819 (0.82), 3.832 (0.62), 4.155 (0.57), 4.165 (0.61), 4.181 (1.80), 4.192 (1.83), 4.198 (1.91), 4.212 (1.68), 4.225 (0.61), 4.238 (0.55), 4.658 (2.20), 4.672 (2.17), 7.029 (0.54), 7.045 (0.69), 7.050 (1.65), 7.065 (1.84), 7.069 (2.29), 7.071 (2.14), 7.077 (2.06), 7.085 (1.65), 7.093 (0.69), 7.098 (1.72), 7.103 (1.74), 7.119 (0.69), 7.124 (0.54), 7.307 (0.94), 7.317 (0.99), 7.657 (1.74), 7.662 (1.08), 7.676 (1.36), 7.681 (1.03), 7.708 (1.84), 8.254 (0.72), 8.404 (0.81), 13.678 (0.65), 13.693 (1.25), 13.707 (0.60), 14.741 (3.47). LC-MS (Method 6): Rt = 0.94 min; MS (ESIpos): m / z = 531 [M+H] + Intermediate 6-35 4-{[(3-{2-{[1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)methyl]amino}-N-(3-fluoro-2-methoxyphenyl)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide [ka]

[0369] Using a method similar to that described for Intermediate 6-1; starting from N-(3-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 5-4, 200 mg, 675 μmol) and 1-(3-{2-[1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)methanamine (Intermediate 2-6, 209 mg, 877 μmol), 137 mg of the title compound (purity 96%, yield 38%) was prepared.

[0370] LC-MS (Method 6): Rt = 0.83 min; MS (ESIpos): m / z = 517 [M+H] + 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.757 (0.42), 1.778 (0.61), 1.793 (0.89), 1.813 (0.86), 1.822 (0.55), 1.826 (0.49), 1.833 (0.54), 1.840 (0.80), 1.852 (0.85), 1.857 (0.64), 1.868 (0.60), 2.518 (2.52), 2.523 (1.61), 2.674 (0.45), 2.735 (0.74), 2.752 (1.68), 2.761 (1.69), 2.769 (1.02), 2.777 (0.89), 3.134 (1.00), 3.142 (1.11), 3.151 (1.92), 3.159 (1.89), 3.168 (0.98), 3.175 (0.85), 3.198 (1.19), 3.224 (1.91), 3.228 (1.91), 3.254 (1.24), 3.421 (0.47), 3.425 (0.68), 3.446 (1.52), 3.453 (1.67), 3.472 (0.99), 3.481 (1.19), 3.545 (0.92), 3.552 (1.09), 3.574 (1.39), 3.580 (1.60), 3.606 (1.73), 3.612 (2.26), 3.618 (1.04), 3.639 (1.07), 3.645 (0.93), 3.690 (1.77), 3.697 (2.11), 3.709 (0.79), 3.719 (3.54), 3.728 (1.41), 3.735 (0.73), 3.744 (1.71), 3.751 (1.33), 3.782 (15.79), 3.784 (16.00), 4.203 (1.78), 4.219 (2.73), 4.232 (1.20), 4.237 (1.18), 4.653 (2.89), 4.667 (2.88), 7.030 (0.49), 7.046 (0.68), 7.051 (1.63), 7.067 (1.82), 7.070 (3.31), 7.077 (2.11), 7.086 (1.65), 7.092 (0.71), 7.098 (1.72), 7.103 (1.73), 7.119 (0.68), 7.124 (0.52), 7.303 (1.99), 7.314 (2.03), 7.660 (1.68), 7.665 (1.06), 7.677 (1.35), 7.683 (1.07), 7.703 (1.84), 8.226 (1.84), 8.237 (1.79), 8.373 (2.98), 13.689 (0.64), 13.704 (1.28), 13.718 (0.60), 14.740 (3.42). Intermediate 6-37 N-(3-fluoro-2-methoxyphenyl)-4-{[(3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide [ka]

[0371] Starting from N-(3-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 5-4, 200 mg, 675 μmol) and 1-(3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)methanamine (Intermediate 2-2, 224 mg, 945 μmol), a method similar to that described for Intermediate 6-1 was used to prepare 134 mg (38% yield) of the title compound after heating at 124 °C for 1 h and purification by preparative HPLC (Method 10, gradient: 0.00-0.50 min 15% B, 0.50-6.00 min 15-55% B).

[0372] 1H-NMR (400 MHz, DMSO-d6): δ [ppm]= 2.205 (0.86), 2.226 (1.57), 2.254 (1.23), 2.290 (15.27), 2.327 (1.28), 2.654 (2.07), 2.681 (1.95), 2.762 (2.11), 2.779 (3.81), 2.795 (2.41), 3.155 (3.13), 3.374 (3.80), 3.401 (2.16), 3.482 (0.97), 3.504 (1.80), 3.531 (1.16), 3.686 (1.75), 3.714 (1.51), 3.784 (16.00), 3.888 (1.65), 3.916 (1.59), 4.031 (1.27), 4.047 (1.48), 4.057 (1.61), 4.073 (1.47), 4.294 (1.53), 4.304 (1.57), 4.320 (1.45), 4.328 (1.29), 4.661 (3.52), 4.675 (3.54), 7.031 (0.48), 7.052 (1.50), 7.070 (3.26), 7.087 (1.82), 7.099 (1.95), 7.122 (0.79), 7.299 (2.83), 7.311 (2.84), 7.655 (2.12), 7.672 (2.11), 7.706 (2.52), 8.239 (3.08), 8.250 (2.98), 8.414 (5.21), 13.678 (1.85), 14.738 (3.80). LC-MS (Method 6): R t = 0.64 min; MS (ESIpos): m / z = 516 [M+H] + Intermediate 6-38 4-[[3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]-4-pyridyl]methylamino]-N-(3-fluoro-2-methyl-phenyl)-6-oxo-2,3-dihydro-1H-pyridine-5-carbothioamide [ka]

[0373] Starting from N-(3-fluoro-2-methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 5-38, 350 mg, 1.25 mmol) and 1-{3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methanamine (Intermediate 2-7, 315 mg, 1.25 mmol), a similar method as described for Intermediate 6-1 was used to prepare 192 mg (27% yield) of the title compound after heating at 120 °C for 3 hours and purification by preparative HPLC (Method 11, gradient: 0.00-2.00 min 30% B, 2.00-14.00 min 30-70% B).

[0374] 1H-NMR (400 MHz, DMSO-d6): δ [ppm]= 1.046 (16.00), 1.253 (14.02), 2.045 (8.35), 2.050 (8.21), 2.063 (1.09), 2.521 (2.37), 2.525 (1.62), 2.741 (1.29), 2.757 (2.61), 2.774 (1.60), 3.145 (1.01), 3.152 (1.15), 3.161 (1.90), 3.168 (1.80), 3.178 (0.99), 3.185 (0.85), 3.298 (1.92), 3.534 (3.17), 3.562 (2.60), 3.617 (0.65), 3.626 (0.83), 3.647 (2.00), 3.656 (2.10), 3.666 (2.13), 3.690 (2.57), 3.719 (1.29), 3.780 (0.43), 3.793 (0.82), 3.803 (1.04), 3.814 (0.83), 3.828 (0.60), 4.148 (0.72), 4.159 (0.78), 4.174 (2.17), 4.186 (2.01), 4.194 (2.14), 4.208 (2.03), 4.220 (0.76), 4.234 (0.69), 4.647 (3.08), 4.662 (3.06), 7.040 (0.87), 7.061 (1.78), 7.074 (1.74), 7.085 (1.37), 7.094 (2.40), 7.189 (0.89), 7.208 (1.38), 7.225 (1.30), 7.244 (0.54), 7.295 (2.49), 7.307 (2.52), 7.686 (1.77), 8.237 (2.54), 8.249 (2.42), 8.393 (3.97), 13.662 (1.07), 14.520 (2.54). LC-MS (Method 6): R t = 0.98 min; MS (ESIpos): m / z = 515 [M+H] + Intermediate 6-40 N-[2-(2,2-difluoroethyl)-3-fluoro-phenyl]-4-[[3-(1,4-dioxan-2-ylmethoxy)-4-pyridyl]methylamino]-6-oxo-2,3-dihydro-1H-pyridine-5-carbothioamide [ka]

[0375] Starting from N-[2-(2,2-difluoroethyl)-3-fluorophenyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 5-40, 100 mg, 303 μmol) and 1-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methanamine (Intermediate 2-1, 95.0 mg, 424 μmol), 19.5 mg (10% yield) of the title compound was prepared after purification by flash chromatography (silica, DCM / EtOH gradient 0-10%) using a method similar to that described for Intermediate 6-1.

[0376] LC-MS (Method 2): R t = 1.07 min; MS (ESIpos): m / z = 537 [M+H] + Intermediate 6-41 tert-Butyl (2S)-2-{[(4-{[(5-{[2-(2,2-difluoroethyl)-3-fluorophenyl]carbamothioyl}-6-oxo-1,2,3,6-tetrahydropyridin-4-yl)amino]methyl}pyridin-3-yl)oxy]methyl}morpholine-4-carboxylate [ka]

[0377] A mixture of N-[2-(2,2-difluoroethyl)-3-fluorophenyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 5-40, 200 mg, 605 μmol) and tert-butyl (2S)-2-({[4-(aminomethyl)pyridin-3-yl]oxy}morpholine-4-carboxylate (Intermediate 2-5, 274 mg, 848 μmol) in ACN (2.5 ml) was treated with N,O-bis-(trimethylsilyl)acetamide (111 μl, 0.6 mmol, CAS The reaction was treated with N,O-bis-(trimethylsilyl)acetamide (111 μl, 0.6 mmol) and stirred at 80° C. for 5 hours. The reaction was treated with another equivalent of N,O-bis-(trimethylsilyl)acetamide (111 μl, 0.6 mmol) and stirred at 80° C. overnight. The reaction mixture was diluted with DCM and purified by flash chromatography (silica, DCM / EtOH gradient 0-20%) to give 255 mg (45% yield) of the title compound.

[0378] LC-MS (Method 2): R t = 1.25 min; MS (ESIpos): m / z = 636 [M+H] + Intermediate 6-42 tert-Butyl (2S)-2-[({4-[({5-[(3-chloro-2-methylphenyl)carbamothioyl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}amino)methyl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate [ka]

[0379] Starting from N-(3-chloro-2-methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 5-10, 350 mg, 1.18 mmol) and tert-butyl (2S)-2-({[4-(aminomethyl)pyridin-3-yl]oxy}methyl)morpholine-4-carboxylate (Intermediate 2-5, 381 mg, 1.18 mmol), a similar method as described for Intermediate 6-1 was used; heating for 3 h was followed by preparative HPLC (Method 11, gradient: 0.00-1.00 min 30% B, 1.00-12.74 min 30-68.9% B, 12.74-14.19 min 68.9% B, 14.19-14.45 min 68.9% B). After purification with 68.9-70% B), 208 mg of the title compound was prepared (purity 99%, yield 29%).

[0380] 1H-NMR (400 MHz, DMSO-d6): δ [ppm]= 1.396 (16.00), 2.077 (0.96), 2.158 (7.73), 2.520 (2.53), 2.525 (1.63), 2.542 (0.50), 2.747 (0.68), 2.763 (1.35), 2.780 (0.85), 3.146 (0.53), 3.153 (0.62), 3.162 (0.99), 3.169 (0.96), 3.434 (0.57), 3.441 (0.60), 3.710 (0.46), 3.723 (0.54), 3.730 (0.70), 3.737 (0.68), 3.749 (0.56), 3.756 (0.45), 3.837 (0.42), 4.213 (1.89), 4.225 (1.86), 4.648 (1.39), 4.663 (1.40), 7.153 (0.57), 7.170 (1.15), 7.196 (0.92), 7.216 (1.36), 7.236 (0.59), 7.294 (0.89), 7.306 (0.92), 7.326 (1.13), 7.329 (1.10), 7.346 (0.85), 7.349 (0.79), 7.691 (0.91), 8.237 (2.11), 8.249 (1.94), 8.399 (3.05), 13.653 (0.59), 14.540 (1.38). LC-MS (Method 6): Rt = 1.17 min; MS (ESIpos): m / z = 602 [M+H] + Intermediate 6-43 tert-Butyl (3R)-3-[({4-[({5-[(3-chloro-2-methylphenyl)carbamothioyl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}amino)methyl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate [ka]

[0381] Starting from N-(3-chloro-2-methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 5-10, 350 mg, 1.18 mmol) and tert-butyl (3R)-3-({[4-(aminomethyl)pyridin-3-yl]oxy}methyl)morpholine-4-carboxylate (Intermediate 2-9, 381 mg, 1.18 mmol), a similar method as described for Intermediate 6-1 was used; heating for 3 h was followed by preparative HPLC (Method 11, gradient: 0.00-1.00 min 30% B, 1.00-12.74 min 30-68.9% B, 12.74-14.19 min 68.9 B, 14.19-14.45 min). After purification with 68.9-70% B), 184 mg of the title compound was prepared (purity 99%, yield 26%).

[0382] 1H-NMR (400 MHz, DMSO-d6): δ [ppm]= 1.339 (2.92), 2.087 (1.31), 2.161 (16.00), 2.521 (1.63), 2.525 (1.08), 2.676 (0.52), 2.708 (0.66), 2.725 (1.74), 2.742 (1.82), 2.757 (0.75), 3.140 (1.42), 3.147 (1.59), 3.156 (2.44), 3.163 (2.41), 3.319 (0.58), 3.365 (1.06), 3.372 (1.25), 3.395 (0.56), 3.402 (0.54), 3.478 (0.92), 3.507 (1.00), 3.651 (0.51), 3.797 (0.72), 3.821 (0.64), 3.957 (0.67), 3.985 (0.59), 4.236 (1.53), 4.415 (0.46), 4.441 (0.83), 4.625 (2.12), 4.639 (2.15), 7.160 (1.07), 7.178 (2.26), 7.200 (2.08), 7.220 (3.03), 7.239 (1.27), 7.291 (1.19), 7.301 (1.19), 7.329 (2.50), 7.332 (2.34), 7.349 (1.83), 7.352 (1.71), 7.691 (1.99), 8.240 (3.22), 8.252 (3.11), 8.489 (2.72), 13.669 (0.94), 14.536 (3.05). LC-MS (Method 6): Rt = 1.17 min; MS (ESIpos): m / z = 602 [M+H] + Intermediate 6-44 N-(3-chloro-2-methyl-phenyl)-4-[[3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]-4-pyridyl]methylamino]-6-oxo-2,3-dihydro-1H-pyridine-5-carbothioamide [ka]

[0383] Starting from N-(3-chloro-2-methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 5-10, 200 mg, 674 μmol) and 1-{3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methanamine (Intermediate 2-7, 200 mg, 85% purity, 674 μmol), 328 mg of the title compound was prepared (97% purity, 89% yield) using a method similar to that described for Intermediate 6-41.

[0384] 1H-NMR (400 MHz, DMSO-d6): δ [ppm]= 1.047 (14.25), 1.253 (12.85), 2.077 (16.00), 2.162 (14.45), 2.520 (1.87), 2.525 (1.19), 2.742 (1.21), 2.759 (2.44), 2.775 (1.45), 3.147 (0.98), 3.154 (1.11), 3.163 (1.80), 3.170 (1.74), 3.180 (0.98), 3.186 (0.82), 3.297 (1.66), 3.327 (2.92), 3.533 (2.87), 3.561 (2.30), 3.617 (0.55), 3.626 (0.77), 3.646 (1.84), 3.655 (1.96), 3.664 (1.91), 3.689 (2.20), 3.718 (1.12), 3.791 (0.79), 3.802 (0.97), 3.812 (0.78), 3.826 (0.56), 4.147 (0.62), 4.158 (0.66), 4.173 (1.85), 4.184 (1.77), 4.193 (1.88), 4.206 (1.73), 4.220 (0.66), 4.233 (0.60), 4.644 (2.79), 4.659 (2.74), 7.158 (1.13), 7.175 (2.37), 7.200 (1.72), 7.220 (2.58), 7.239 (1.09), 7.298 (1.31), 7.310 (1.39), 7.328 (2.08), 7.332 (2.01), 7.348 (1.56), 7.351 (1.42), 7.689 (1.69), 8.245 (0.80), 8.399 (1.03), 13.621 (0.57), 13.635 (1.07), 14.542 (2.54). LC-MS (Method 6): Rt = 1.06 min; MS (ESIpos): m / z = 531 [M+H] + Intermediate 6-47 4-[[3-(1,4-dioxan-2-ylmethoxy)-4-pyridyl]methylamino]-N-(3-fluoro-2-methyl-phenyl)-6-oxo-2,3-dihydro-1H-pyridine-5-carbothioamide [ka]

[0385] Starting from N-(3-fluoro-2-methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 5-38, 300 mg, 1.07 mmol) and 1-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methanamine (Intermediate 2-1, 240 mg, 1.07 mmol), using a method similar to that described for Intermediate 6-41, 156.3 mg of the title compound was prepared (purity 93%, yield 71%).

[0386] 1H-NMR (400 MHz, DMSO-d6): δ [ppm]= 0.000 (0.70), 1.998 (0.55), 2.033 (16.00), 2.038 (15.45), 2.064 (3.23), 2.508 (3.78), 2.513 (2.36), 2.737 (2.61), 2.754 (5.23), 2.771 (2.96), 3.142 (2.39), 3.151 (3.71), 3.158 (3.53), 3.168 (2.07), 3.393 (2.34), 3.418 (3.51), 3.421 (3.41), 3.446 (3.16), 3.461 (1.34), 3.482 (2.56), 3.488 (2.76), 3.506 (1.42), 3.516 (2.71), 3.579 (1.64), 3.585 (1.94), 3.608 (2.49), 3.614 (2.79), 3.641 (5.03), 3.670 (1.97), 3.735 (2.71), 3.744 (2.66), 3.769 (2.09), 3.837 (2.39), 3.844 (2.81), 3.871 (4.35), 3.883 (1.72), 3.890 (1.32), 3.895 (1.57), 3.902 (1.32), 3.907 (1.44), 3.914 (1.14), 3.926 (0.62), 4.108 (0.85), 4.120 (0.95), 4.134 (3.73), 4.145 (6.69), 4.158 (3.48), 4.171 (0.87), 4.184 (0.75), 4.624 (4.75), 4.639 (4.68), 7.028 (1.64), 7.050 (3.46), 7.062 (3.48), 7.073 (2.79), 7.081 (4.60), 7.179 (1.62), 7.198 (2.71), 7.215 (2.51), 7.235 (1.00), 7.333 (1.12), 7.676 (3.41), 8.321 (0.42), 13.651 (2.04), 14.509 (4.80). LC-MS (Method 6): Rt = 0.85 min; MS (ESIpos): m / z = 487 [M+H] + Intermediate 6-50 N-(3-chloro-2-methyl-phenyl)-4-[[3-(1,4-dioxan-2-ylmethoxy)-4-pyridyl]methylamino]-6-oxo-2,3-dihydro-1H-pyridine-5-carbothioamide [ka]

[0387] Starting from N-(3-chloro-2-methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 5-10, 200 mg, 674 μmol) and 1-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methanamine (Intermediate 2-1, 151 mg, 674 μmol), using a method similar to that described for Intermediate 6-41, 150.0 mg of the title compound was prepared (purity 96%, yield 42%).

[0388] 1H-NMR (400 MHz, DMSO-d6): δ [ppm]= 2.077 (1.64), 2.162 (16.00), 2.520 (2.60), 2.525 (1.64), 2.751 (1.41), 2.768 (2.82), 2.784 (1.63), 3.156 (1.22), 3.165 (1.94), 3.172 (1.87), 3.404 (1.32), 3.429 (1.94), 3.432 (1.93), 3.457 (1.81), 3.472 (0.72), 3.493 (1.40), 3.500 (1.50), 3.518 (0.79), 3.528 (1.45), 3.591 (0.91), 3.597 (1.05), 3.619 (1.35), 3.626 (1.54), 3.650 (2.14), 3.653 (2.65), 3.660 (0.95), 3.682 (1.04), 3.748 (1.44), 3.756 (1.54), 3.781 (1.16), 3.849 (1.30), 3.855 (1.59), 3.883 (2.54), 3.894 (0.99), 3.901 (0.68), 3.906 (0.89), 3.913 (0.76), 3.918 (0.79), 3.925 (0.62), 3.930 (0.51), 4.118 (0.55), 4.129 (0.59), 4.144 (2.26), 4.155 (4.42), 4.168 (2.30), 4.181 (0.52), 4.194 (0.48), 4.648 (3.19), 4.663 (3.19), 7.159 (1.24), 7.176 (2.55), 7.203 (1.84), 7.222 (2.83), 7.242 (1.22), 7.290 (2.72), 7.302 (2.78), 7.330 (2.22), 7.333 (2.19), 7.349 (1.69), 7.353 (1.54), 7.691 (1.83), 8.233 (4.07), 8.245 (3.96), 8.383 (6.40), 13.623 (0.61), 13.637 (1.14), 14.544 (2.74). LC-MS (Method 6): Rt = 0.94 min; MS (ESIpos): m / z = 503 [M+H] + Intermediate 6-52 N-(3-chloro-2-ethyl-phenyl)-4-[[3-(1,4-dioxan-2-ylmethoxy)-4-pyridyl]methylamino]-6-oxo-2,3-dihydro-1H-pyridine-5-carbothioamide [ka]

[0389] Using a method similar to that described for Intermediate 6-41, starting with N-(3-chloro-2-ethylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 5-29, 150 mg, 483 μmol) and 1-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methanamine (Intermediate 2-1, 108 mg, 483 μmol), 150.0 mg of the title compound was prepared (90% purity, 54% yield) using flash chromatography (silica, DCM / EtOH gradient 1-13%).

[0390] 1H-NMR (400 MHz, DMSO-d6): δ ppm= 1.01 - 1.11 (m, 4 H), 2.56 - 2.65 (m, 2 H), 2.73 - 2.81 (m, 2 H), 3.12 - 3.22 (m, 2 H), 3.39 - 3.54 (m, 3 H), 3.58 - 3.69 (m, 2 H), 3.73 - 3.80 (m, 1 H), 3.88 (s, 2 H), 4.09 - 4.23 (m, 2 H), 4.11 - 4.15 (m, 1 H), 4.57 - 4.71 (m, 2 H), 7.16 - 7.25 (m, 2 H), 7.28 - 7.36 (m, 2 H), 7.32 (s, 1 H), 7.66 - 7.75 (m, 1 H), 8.07 - 8.11 (m, 1 H), 8.21 - 8.26 (m, 1 H), 8.33 - 8.43 (m, 1 H), 13.60 - 13.70 (m, 1 H), 14.59 - 14.67 (m, 1 H). LC-MS (Method 2): R t = 1.15 min; MS (ESIpos): m / z = 517 [M+H] + Intermediate 6-53 N-(3-chloro-2-ethylphenyl)-4-{[(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide [ka]

[0391] Using a method similar to that described for Intermediate 6-41, starting with N-(3-chloro-2-ethylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 5-29, 210 mg, 676 μmol) and 1-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)methanamine (Intermediate 2-8, 185 mg, 90% purity, 743 μmol), 320.0 mg of the title compound was prepared (86% yield) using flash chromatography (silica, DCM / EtOH gradient 1-15%).

[0392] 1H-NMR (400 MHz, DMSO-d6): δ [ppm]= 1.036 (8.39), 1.040 (4.03), 1.053 (16.00), 1.059 (9.01), 1.071 (8.71), 1.078 (3.84), 2.066 (0.41), 2.518 (1.19), 2.523 (0.81), 2.577 (0.95), 2.596 (2.98), 2.614 (2.87), 2.632 (0.86), 2.757 (1.69), 2.774 (3.38), 2.790 (1.92), 3.152 (1.31), 3.159 (1.49), 3.169 (2.36), 3.174 (2.23), 3.185 (1.26), 3.403 (1.67), 3.405 (1.77), 3.418 (1.45), 3.423 (4.19), 3.427 (2.48), 3.430 (2.54), 3.435 (4.26), 3.440 (3.60), 3.453 (4.76), 3.457 (2.12), 3.470 (1.96), 3.492 (1.59), 3.498 (1.73), 3.516 (0.85), 3.526 (1.70), 3.589 (1.03), 3.594 (1.21), 3.617 (1.57), 3.623 (1.85), 3.651 (3.24), 3.679 (1.31), 3.745 (1.75), 3.754 (1.70), 3.779 (2.03), 3.847 (1.59), 3.853 (1.84), 3.880 (2.81), 3.893 (1.13), 3.900 (0.84), 3.905 (1.04), 3.912 (0.89), 3.917 (0.95), 3.924 (0.75), 3.929 (0.59), 3.936 (0.44), 4.116 (0.64), 4.127 (0.69), 4.142 (2.65), 4.154 (5.01), 4.167 (2.53), 4.180 (0.60), 4.193 (0.55), 4.343 (2.64), 4.356 (5.10), 4.369 (2.52), 4.647 (3.70), 4.662 (3.66), 7.209 (5.05), 7.211 (4.85), 7.222 (8.23), 7.231 (0.55), 7.293 (2.86), 7.307 (4.24), 7.319 (3.43), 7.331 (1.67), 7.706 (2.31), 8.234 (3.16), 8.246 (3.01), 8.383 (5.19), 13.642 (0.84), 13.657 (1.55), 13.672 (0.72), 14.639 (4.11). LC-MS (Method 2): R t = 1.17 min; MS (ESIpos): m / z = 517 [M+H] + Intermediate 6-55 tert-Butyl (2R)-2-[({4-[({5-[(3-chloro-2-ethylphenyl)carbamothioyl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}amino)methyl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate [ka]

[0393] Starting from N-(3-chloro-2-ethylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 5-29, 300 mg, 965 μmol) and tert-butyl (2R)-2-({[4-(aminomethyl)pyridin-3-yl]oxy}methyl)morpholine-4-carboxylate (Intermediate 2-10, 312 mg, 965 μmol), using a method similar to that described for Intermediate 6-41; 476.0 mg of the title compound was prepared (purity 95%, yield 76%) using flash chromatography (silica, DCM / EtOH gradient 1-10%).

[0394] 1H-NMR (400 MHz, DMSO-d6): δ [ppm]= 1.036 (1.51), 1.055 (3.57), 1.073 (1.55), 1.393 (16.00), 2.518 (1.71), 2.523 (1.10), 2.590 (1.19), 2.609 (1.16), 2.751 (0.68), 2.769 (1.33), 2.785 (0.84), 3.165 (0.96), 3.171 (0.92), 3.431 (0.55), 3.438 (0.59), 3.729 (0.71), 3.749 (0.48), 3.756 (0.41), 3.835 (0.41), 4.210 (1.81), 4.222 (1.76), 4.646 (1.35), 4.662 (1.35), 5.758 (7.84), 7.202 (2.06), 7.214 (2.99), 7.296 (1.00), 7.304 (1.58), 7.316 (1.60), 7.328 (0.75), 7.703 (0.94), 8.236 (1.90), 8.248 (1.81), 8.398 (2.84), 13.671 (0.64), 14.632 (1.67). LC-MS (Method 2): R t = 1.32 min; MS (ESIpos): m / z = 616 [M+H] + Intermediate 6-56 tert-Butyl (2S)-2-[({4-[({5-[(3-chloro-2-ethylphenyl)carbamothioyl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}amino)methyl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate [ka]

[0395] Starting from N-(3-chloro-2-ethylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 5-29, 300 mg, 965 μmol) and tert-butyl (2S)-2-({[4-(aminomethyl)pyridin-3-yl]oxy}methyl)morpholine-4-carboxylate (Intermediate 2-5, 312 mg, 965 μmol), using a method similar to that described for Intermediate 6-41; after purification by flash chromatography (silica, DCM / EtOH gradient 1-10%), 479.0 mg of the title compound was prepared (purity 95%, yield 77%).

[0396] 1 H-NMR (400MHz, DMSO-d6): δ [ppm]= 14.55 - 14.67 (m, 1H), 13.60 - 13.72 (m, 1H), 8.40 (s, 1H), 8.24 (d, 1H), 7.70 (br s, 1H), 7.16 - 7.36 (m, 4H), 5.70 - 5.80 (m, 1H), 5.66 - 5.81 (m, 1H), 4.59 - 4.73 (m, 2H), 4.12 - 4.27 (m, 2H), 3.80 - 3.99 (m, 2H), 3.65 - 3.78 (m, 2H), 3.37 - 3.50 (m, 1H), 3.10 - 3.22 (m, 2H), 2.70 - 2.99 (m, 4H), 2.55 - 2.64 (m, 2H), 1.30 - 1.46 (m, 9H), 1.01 - 1.12 (m, 3H). LC-MS (Method 2): R t = 1.32 min; MS (ESIpos): m / z = 616 [M+H] + Intermediate 6-57 N-(3-chloro-2-methoxyphenyl)-4-([{3-[(1S)-1-(1,4-dioxan-2-yl)ethoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide [ka]

[0397] Starting from N-(3-chloro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 5-1, 300 mg, 959 μmol) and 1-{3-[(1S)-1-(1,4-dioxan-2-yl)ethoxy]pyridin-4-yl}methanamine (Intermediate 2-11, 251 mg, 1.06 mmol), a method similar to that described for Intermediate 6-41 was used to prepare 384 mg of the title compound as a mixture of diastereomers (purity 99%, yield 74%).

[0398] 1H-NMR (400 MHz, DMSO-d6): δ [ppm]= 0.064 (0.95), 1.239 (2.82), 1.255 (2.83), 1.279 (2.06), 1.295 (2.09), 2.518 (1.11), 2.523 (0.82), 2.761 (0.76), 2.777 (0.86), 3.141 (0.52), 3.148 (0.60), 3.157 (1.00), 3.164 (0.99), 3.181 (0.43), 3.417 (0.87), 3.443 (0.88), 3.455 (0.44), 3.462 (0.47), 3.470 (0.68), 3.476 (0.41), 3.591 (0.40), 3.597 (0.65), 3.620 (0.88), 3.632 (0.76), 3.639 (0.41), 3.647 (0.54), 3.653 (0.56), 3.672 (0.40), 3.678 (0.44), 3.711 (16.00), 3.732 (0.56), 3.766 (0.89), 3.772 (0.52), 3.794 (0.57), 4.651 (1.27), 4.665 (1.31), 4.682 (0.58), 7.090 (0.70), 7.110 (1.53), 7.131 (0.88), 7.287 (1.67), 7.289 (1.87), 7.300 (1.26), 7.305 (1.12), 7.309 (1.02), 7.314 (0.67), 7.726 (0.98), 7.791 (0.95), 7.794 (0.96), 7.811 (0.90), 7.815 (0.85), 8.198 (1.34), 8.211 (1.99), 8.223 (0.91), 8.416 (1.88), 8.432 (1.35), 13.666 (0.43), 13.675 (0.50), 14.790 (1.61). LC-MS (Method 6): R t = 0.96 points and R t = 0.98 min; MS (ESIpos): m / z = 533.2 [M+H] + Intermediate 6-60 N-(3-chloro-2-methoxyphenyl)-4-{[(3-{(1R)-1-[1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide [ka]

[0399] Starting from N-(3-chloro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 5-1, 300 mg, 959 μmol) and 1-{3-[(1R)-1-(1,4-dioxan-2-yl)ethoxy]pyridin-4-yl}methanamine (Intermediate 2-12, 251 mg, 1.06 mmol), 346 mg of the title compound was prepared (99% purity, 67% yield) using a method similar to that described for Intermediate 6-41.

[0400] 1H-NMR (400 MHz, DMSO- d6): δ [ppm]= 1.278 (5.25), 1.294 (5.21), 2.073 (0.98), 2.331 (0.40), 2.518 (2.02), 2.522 (1.36), 2.673 (0.42), 2.749 (0.74), 2.765 (0.56), 2.775 (0.83), 2.792 (0.42), 3.140 (0.62), 3.147 (0.73), 3.156 (1.17), 3.164 (1.16), 3.417 (0.81), 3.441 (1.16), 3.445 (1.15), 3.469 (1.68), 3.475 (0.85), 3.503 (0.74), 3.570 (0.47), 3.576 (0.55), 3.598 (0.72), 3.604 (0.82), 3.631 (1.87), 3.638 (0.97), 3.646 (0.63), 3.652 (0.78), 3.657 (1.02), 3.663 (0.93), 3.670 (0.52), 3.677 (0.47), 3.710 (16.00), 3.758 (0.87), 3.767 (0.74), 3.790 (0.67), 3.920 (0.78), 3.926 (0.76), 3.949 (0.72), 3.955 (0.66), 4.646 (1.57), 4.653 (1.48), 4.662 (1.63), 4.682 (0.73), 7.092 (1.08), 7.112 (2.33), 7.133 (1.33), 7.287 (1.60), 7.290 (1.60), 7.302 (1.73), 7.306 (1.61), 7.310 (1.69), 7.314 (1.68), 7.725 (1.16), 7.791 (1.23), 7.794 (1.22), 7.811 (1.17), 7.814 (1.08), 8.210 (2.42), 8.222 (2.24), 8.430 (3.36), 13.651 (0.41), 13.665 (0.79), 14.786 (2.12). LC-MS (Method 6): R t= 0.96 min; MS (ESIpos): m / z = 533 [M+H] + Intermediate 6-62 N-(3-Fluoro-2-methylphenyl)-4-{[(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide [ka]

[0401] Starting from N-(3-fluoro-2-methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 5-38, 197 mg, 704 μmol) and 1-(3-{[-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)methanamine (Intermediate 2-3, 167 mg, 704 μmol), a method similar to that described for Intermediate 6-41 was used; after purification by reverse-phase HPLC (basic), 170 mg of the title compound was prepared (purity 93%, yield 45%).

[0402] 1H-NMR (400 MHz, DMSO- d6): δ [ppm]= 1.035 (0.65), 1.053 (1.08), 1.070 (0.68), 1.848 (1.00), 1.876 (1.47), 1.901 (1.11), 1.953 (0.45), 1.962 (0.59), 1.982 (1.04), 1.990 (1.08), 2.010 (0.69), 2.019 (0.57), 2.040 (7.36), 2.044 (6.91), 2.177 (16.00), 2.518 (1.64), 2.522 (1.10), 2.578 (0.88), 2.607 (0.81), 2.756 (0.84), 2.770 (1.72), 2.789 (2.10), 2.817 (1.02), 3.149 (0.83), 3.156 (0.97), 3.166 (1.67), 3.173 (1.63), 3.182 (0.94), 3.318 (0.50), 3.501 (0.55), 3.507 (0.70), 3.529 (1.25), 3.535 (1.29), 3.557 (0.76), 3.563 (0.62), 3.784 (0.93), 3.788 (0.90), 3.791 (0.76), 3.812 (1.29), 3.815 (1.26), 3.829 (0.63), 3.837 (0.57), 4.112 (0.53), 4.124 (0.56), 4.138 (1.82), 4.150 (1.97), 4.154 (2.08), 4.168 (1.68), 4.180 (0.56), 4.194 (0.52), 4.636 (2.30), 4.651 (2.34), 7.034 (0.71), 7.055 (1.49), 7.070 (1.47), 7.079 (1.12), 7.089 (1.98), 7.185 (0.72), 7.204 (1.19), 7.221 (1.13), 7.241 (0.44), 7.295 (2.26), 7.306 (2.30), 7.679 (1.46), 8.227 (3.76), 8.239 (3.55), 8.383 (5.45), 13.662 (0.88), 14.516 (2.06). LC-MS (Method 6): R t = 0.62 min; MS (ESIpos): m / z = 500 [M+H] + Intermediate 6-65 4-{[(3-{[1,4-dioxan-2-yl]methoxy}pyridin-4-yl)methyl]amino}-N-(2-ethyl-3-fluorophenyl)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide [ka]

[0403] Starting from N-(2-ethyl-3-fluorophenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (300 mg, 1.02 mmol) and 1-(3-{[1,4-dioxan-2-yl]methoxy}pyridin-4-yl)methanamine (229 mg, 1.02 mmol), a method similar to that described for intermediate 6-41 was used; after evaporating the solvent, filtering, and washing the solid with ACN, 218 mg of the title compound was prepared (purity 90%, yield 38%).

[0404] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.057 (1.12), 1.042 (7.32), 1.061 (16.00), 1.080 (7.29), 1.231 (0.88), 1.751 (0.58), 2.074 (6.86), 2.522 (5.66), 2.753 (3.09), 2.770 (6.11), 2.787 (3.52), 3.156 (2.86), 3.166 (4.42), 3.172 (4.30), 3.181 (2.51), 3.402 (2.65), 3.427 (3.92), 3.430 (3.92), 3.455 (3.70), 3.471 (1.62), 3.491 (2.84), 3.498 (3.08), 3.516 (1.51), 3.526 (2.87), 3.589 (1.80), 3.594 (1.99), 3.617 (2.79), 3.623 (3.19), 3.650 (5.74), 3.679 (2.35), 3.745 (3.17), 3.754 (3.06), 3.778 (2.46), 3.846 (2.80), 3.853 (3.24), 3.881 (4.78), 3.893 (1.98), 3.900 (1.58), 3.905 (1.80), 3.911 (1.59), 3.918 (1.69), 3.925 (1.36), 3.936 (0.73), 4.117 (1.01), 4.129 (1.14), 4.143 (4.20), 4.155 (7.71), 4.168 (3.95), 4.181 (1.08), 4.194 (0.91), 4.632 (5.48), 4.646 (5.40), 7.029 (2.23), 7.051 (3.97), 7.074 (2.84), 7.091 (3.92), 7.110 (5.33), 7.191 (2.31), 7.207 (2.86), 7.211 (3.55), 7.228 (3.42), 7.248 (1.35), 7.351 (1.30), 7.701 (4.14), 8.329 (0.48), 8.476 (0.42), 13.662 (1.51), 13.676 (2.76), 13.691 (1.37), 14.588 (6.37). LC-MS (Method 6): R t = 0.92 min; MS (ESIpos): m / z = 501 [M+H] + Intermediate 6-68 4-{[(3-{[5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)methyl]amino}-N-(2-ethyl-3-fluorophenyl)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide [ka]

[0405] Starting from N-(2-ethyl-3-fluorophenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (300 mg, 1.02 mmol) and 1-(3-{[5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)methanamine (257 mg, 1.02 mmol), a method similar to that described for intermediate 6-41 was used; after purification by column chromatography, 360 mg of the title compound was prepared (purity 93%, yield 62%).

[0406] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.014 (0.69), 1.044 (16.00), 1.061 (7.08), 1.080 (3.30), 1.172 (0.52), 1.200 (0.60), 1.251 (13.22), 1.987 (0.87), 2.745 (1.36), 2.761 (2.65), 2.779 (1.61), 3.164 (2.11), 3.170 (2.09), 3.295 (1.79), 3.532 (2.73), 3.560 (2.19), 3.615 (0.59), 3.624 (0.79), 3.644 (1.91), 3.653 (2.05), 3.664 (1.79), 3.688 (2.07), 3.718 (1.01), 3.778 (0.45), 3.789 (0.91), 3.801 (1.07), 3.812 (0.86), 3.824 (0.63), 4.145 (0.65), 4.156 (0.71), 4.172 (1.96), 4.182 (1.95), 4.191 (2.02), 4.205 (1.76), 4.218 (0.69), 4.231 (0.59), 4.644 (3.11), 4.658 (3.10), 7.029 (0.86), 7.050 (1.63), 7.074 (1.12), 7.091 (1.71), 7.111 (2.37), 7.189 (0.89), 7.208 (1.52), 7.225 (1.39), 7.245 (0.52), 7.295 (2.40), 7.306 (2.41), 7.700 (1.92), 8.235 (3.11), 8.247 (2.98), 8.389 (5.24), 13.661 (0.71), 13.675 (1.32), 13.688 (0.68), 14.587 (3.04). LC-MS (Method 6): R t = 1.03 min; MS (ESIpos): m / z = 529 [M+H] + Intermediate 6-71 N-(3-chloro-2-methoxyphenyl)-4-({[3-({1-[4-methylmorpholin-2-yl]ethyl}oxy)pyridin-4-yl]methyl}amino)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide [ka]

[0407] Starting from N-(3-chloro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 5-1, 300 mg, 959 μmol) and 1-[3-({1-[4-methylmorpholin-2-yl]ethyl}oxy)pyridin-4-yl]methanamine (Intermediate 2-71, 265 mg, 1.06 mmol), a method similar to that described for Intermediate 6-41 was used; after purification by column chromatography, 360 mg of the title compound was prepared (purity 93%, yield 62%).

[0408] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.014 (0.69), 1.044 (16.00), 1.061 (7.08), 1.080 (3.30), 1.172 (0.52), 1.200 (0.60), 1.251 (13.22), 1.987 (0.87), 2.745 (1.36), 2.761 (2.65), 2.779 (1.61), 3.164 (2.11), 3.170 (2.09), 3.295 (1.79), 3.532 (2.73), 3.560 (2.19), 3.615 (0.59), 3.624 (0.79), 3.644 (1.91), 3.653 (2.05), 3.664 (1.79), 3.688 (2.07), 3.718 (1.01), 3.778 (0.45), 3.789 (0.91), 3.801 (1.07), 3.812 (0.86), 3.824 (0.63), 4.145 (0.65), 4.156 (0.71), 4.172 (1.96), 4.182 (1.95), 4.191 (2.02), 4.205 (1.76), 4.218 (0.69), 4.231 (0.59), 4.644 (3.11), 4.658 (3.10), 7.029 (0.86), 7.050 (1.63), 7.074 (1.12), 7.091 (1.71), 7.111 (2.37), 7.189 (0.89), 7.208 (1.52), 7.225 (1.39), 7.245 (0.52), 7.295 (2.40), 7.306 (2.41), 7.700 (1.92), 8.235 (3.11), 8.247 (2.98), 8.389 (5.24), 13.661 (0.71), 13.675 (1.32), 13.688 (0.68), 14.587 (3.04). LC-MS (Method 6): R t = 1.03 min; MS (ESIpos): m / z = 529 [M+H] + Intermediate 12 3-((3-fluoro-2-methoxyphenyl)amino)-2-(3-hydroxypyridin-4-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one [ka]

[0409] To a suspension of N-(3-fluoro-2-methoxyphenyl)-4-(((3-hydroxypyridin-4-yl)methyl)amino)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 6-12, 41 g, 101.88 mmol) in MeOH (410 mL) was added TFA (0.75 mL, 10.13 mmol), followed by hydrogen peroxide (18 mL, 30% in water). The mixture was heated to 60° C. and stirred for 16 hours. Additional TFA (6.8 mL, 91.84 mmol) and hydrogen peroxide (1.5 mL, 30% in water) were added. The suspension was stirred at 60° C. for an additional 3 hours. The mixture was cooled to room temperature and left overnight. The suspension was combined with a second batch produced in a similar manner. The combined suspension was filtered, and the cake was washed with water (250 mL) and MeOH (150 mL), then slurried in MeOH (150 mL). The suspension was filtered. The cake was washed with MeOH (75 mL) and dried in vacuo to give the title compound (25.4 g, 33.8% yield) as a yellow solid.

[0410] 1 H NMR (400 MHz, DMSO-d6): δ = 11.45 (s, 1H), 8.18 (s, 1H), 7.98 (d, 1H), 7.39 (d, 1H), 7.18 (s, 1H), 6.67 (t, 1H), 6.54 (t, 1H), 6.04 (d, 1H), 3.92 (s, 3H), 3.40 (t, 2H), 2.90 (t, 2H). LC-MS (Method 5): R t = 1.851 min; m / z = 369.0 (M +H) + Intermediate 22-1 tert-Butyl (2S)-2-[({4-[3-(3-fluoro-2-methoxyanilino)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate [ka]

[0411] Starting from tert-butyl (2S)-2-[({4-[({5-[(3-fluoro-2-methoxyphenyl)carbamothioyl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}amino)methyl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate (Intermediate 6-22, 1.43 g, 2.38 mmol), using a method similar to that described for Example 1; after purification by flash chromatography (silica, DCM / EtOH gradient 0-10%), 572 mg of the title compound (80% purity, 34% yield) was prepared.

[0412] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.035 (0.86), 1.053 (1.99), 1.071 (0.88), 1.380 (0.83), 1.401 (6.79), 1.409 (16.00), 2.518 (1.63), 2.523 (1.18), 2.842 (0.65), 2.859 (1.16), 2.877 (0.76), 3.178 (0.95), 3.301 (0.60), 3.398 (0.50), 3.404 (0.61), 3.415 (0.94), 3.418 (0.82), 3.422 (1.10), 3.435 (0.77), 3.440 (0.72), 3.452 (0.50), 3.553 (0.42), 3.560 (0.43), 3.750 (0.64), 3.760 (0.40), 3.851 (0.50), 3.858 (0.40), 3.873 (0.46), 3.906 (6.63), 3.936 (0.57), 3.939 (0.59), 3.950 (0.46), 4.343 (0.56), 4.356 (0.65), 5.759 (1.09), 5.993 (0.75), 6.013 (0.76), 6.485 (0.50), 6.489 (0.49), 6.492 (0.42), 6.513 (0.45), 6.516 (0.42), 6.627 (0.54), 6.642 (0.52), 7.147 (0.86), 7.280 (1.09), 7.293 (1.13), 7.509 (0.98), 8.025 (1.38), 8.038 (1.27), 8.401 (2.10), 11.020 (0.61). LC-MS (Method 2): R t = 1.12 min; MS (ESIpos): m / z = 568 [M+H] + Intermediate 22-2 3-(3-fluoro-2-methoxyanilino)-2-(3-{[(2S)-morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one [ka]

[0413] Tert-butyl (2S)-2-[({4-[3-(3-fluoro-2-methoxyanilino)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate (Intermediate 22-1, 572 mg, 1.01 mmol) was dissolved in dichloromethane (7.2 mL) and TFA (780 μL, 10 mmol) was added. The mixture was stirred at room temperature for 2 hours. The mixture was evaporated and purified by flash chromatography (amino-phase silica, DCM / EtOH gradient 0-20%) to give 352 mg of the title compound (95% purity, 71% yield).

[0414] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm]= 2.53 - 2.78 (m, 4H), 2.80 - 2.90 (m, 3H), 3.38 - 3.47 (m, 3H), 3.55 - 3.66 (m, 1H), 3.83 - 3.90 (m, 1H), 3.91 - 3.95 (s, 3H), 4.07 - 4.16 (m, 1H), 4.29 - 4.39 (m, 1H), 6.01 (d, 1H), 6.44 - 6.56 (m, 1H), 6.65 (dt, 1H), 7.17 (s, 1H), 7.29 (d, 1H), 7.53 (s, 1H), 8.01 (d, 1H), 8.39 (s, 1H), 11.10 (s, 1H). LC-MS (Method 2): R t = 0.84 min; MS (ESIpos): m / z = 468 [M+H] + Intermediate 27-1 tert-Butyl (2S)-2-[({4-[3-(3-chloro-5-fluoro-2-methoxyanilino)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate [ka]

[0415] Starting from tert-butyl (2S)-2-[({4-[({5-[(3-chloro-5-fluoro-2-methoxyphenyl)carbamothioyl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}amino)methyl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate (Intermediate 6-27, 150 mg, 236 μmol), 73.5 mg of the title compound (90% purity, 47% yield) was prepared using a method similar to that described for Example 1.

[0416] 1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.40 (s, 9H), 2.52 - 2.53 (m, 2H), 2.70 - 3.03 (m, 1H), 2.87 (br t, 2H), 3.42 (td, 2H), 3.46 - 3.61 (m, 1H), 3.71 - 3.79 (m, 1H), 3.82 (s, 4H), 3.93 (br d, 1H), 4.20 (m, 1H), 4.27 - 4.33 (dd, 1H), 5.85 (dd, 1H), 6.55 (dd, 1H), 7.11 (s, 1H), 7.32 (d, 1H), 7.60 (s, 1H), 8.10 (d, 1H), 8.44 (s, 1H), 11.17 (s, 1H). LC-MS (Method 2): R t = 1.19 min; MS (ESIpos): m / z = 602 [M+H] + Intermediate 27-2 3-(3-chloro-5-fluoro-2-methoxyanilino)-2-(3-{[(2S)-morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one [ka]

[0417] Starting from tert-butyl (2S)-2-[({4-[3-(3-chloro-5-fluoro-2-methoxyanilino)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate (Intermediate 27-1, 73.0 mg, 121 μmol), a method similar to that described for Intermediate 22-2 was used; after purification by flash chromatography (amino-phase silica, DCM / EtOH gradient 0-15%), 56.3 mg of the title compound (95% purity, 88% yield) was prepared.

[0418] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm]= 2.51 - 2.58 (m, 2H), 2.61 - 2.75 (m, 2H), 2.77 - 2.94 (m, 3H), 3.38 - 3.48 (m, 1H), 3.56 (td, 1H), 3.76 - 3.92 (m, 2H), 3.84 (s, 3H), 4.10 (dd, 1H), 4.29 (dd, 1H), 5.85 (dd, 1H), 6.57 (dd, 1H), 7.13 (s, 1H), 7.32 (d, 1H), 7.64 (d, 1H), 8.09 (d, 1H), 8.43 (s, 1H), 11.22 (s, 1H). LC-MS (Method 2): R t = 0.93 min; MS (ESIpos): m / z = 502 [M+H] + . Intermediate 41-1 tert-Butyl (2S)-2-{[(4-{3-[2-(2,2-difluoroethyl)-3-fluoroanilino]-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl}pyridin-3-yl)oxy]methyl}morpholine-4-carboxylate [ka]

[0419] Starting from tert-butyl (2S)-2-{[(4-{[(5-{[2-(2,2-difluoroethyl)-3-fluorophenyl]carbamothioyl}-6-oxo-1,2,3,6-tetrahydropyridin-4-yl)amino]methyl}pyridin-3-yl)oxy]methyl}morpholine-4-carboxylate (Intermediate 6-41, 266 mg, 418 μmol), using a method similar to that described for Example 1; after purification by preparative HPLC (Method 10, gradient: 0.00-0.50 min 30% B, 0.50-6.00 min 30-70% B), 33.0 mg of the title compound (purity 65%, yield 9%) was prepared.

[0420] LC-MS (Method 2): R t = 1.16 min; MS (ESIneg): m / z = 600 [MH] - Intermediate 41-2 3-[2-(2,2-difluoroethyl)-3-fluoroanilino]-2-(3-{[(2S)-morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one [ka]

[0421] Starting from tert-butyl (2S)-2-{[(4-{3-[2-(2,2-difluoroethyl)-3-fluoroanilino]-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl}pyridin-3-yl)oxy]methyl}morpholine-4-carboxylate (Intermediate 41-1, 33.0 mg, 54.9 μmol), a method similar to that described for Intermediate 22-2 was used; after purification by flash chromatography (amino-phase silica, DCM / EtOH gradient 0-10%), 22.0 mg of the title compound (purity 65%, yield 52%) was prepared.

[0422] LC-MS (Method 2): R t = 0.92 min; MS (ESIneg): m / z = 500 [MH] - Intermediate 42-1 tert-Butyl (2S)-2-[({4-[3-(3-chloro-2-methylanilino)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate [ka]

[0423] Starting from tert-butyl (2S)-2-[({4-[({5-[(3-chloro-2-methylphenyl)carbamothioyl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}amino)methyl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate (Intermediate 6-42, 207 mg, 344 μmol), using a method similar to that described for Example 1; after purification by preparative HPLC (Method 9, gradient: 0.00-0.50 min 15% B, 0.50-4.65 min 15-44.9% B, 4.65-5.94 min 44.9% B, 5.94-7.29 min 44.9-55% B), 27.8 mg of the title compound (90% purity, 13% yield) was prepared.

[0424] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm]= 1.414 (16.00), 2.349 (5.99), 2.520 (0.82), 2.525 (0.50), 2.853 (0.68), 2.870 (1.29), 2.887 (0.75), 3.405 (0.49), 3.410 (0.53), 3.422 (0.95), 3.428 (0.93), 3.439 (0.48), 3.445 (0.43), 3.554 (0.43), 3.560 (0.45), 4.294 (0.43), 4.304 (0.45), 6.191 (0.69), 6.195 (0.66), 6.211 (0.71), 6.214 (0.69), 6.719 (0.48), 6.735 (1.31), 6.738 (1.11), 6.747 (0.85), 6.767 (0.82), 7.175 (0.83), 7.232 (0.92), 7.245 (0.92), 7.351 (0.48), 7.998 (1.24), 8.010 (1.16), 8.378 (1.84), 11.016 (0.78). LC-MS (Method 6): Rt = 0.92 min; MS (ESIpos): m / z = 568 [M+H] + Intermediate 42-2 3-(3-chloro-2-methylanilino)-2-(3-{[(2S)-morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one [ka]

[0425] Starting from tert-butyl (2S)-2-[({4-[3-(3-chloro-2-methylanilino)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate (Intermediate 42-1, 30.0 mg, 52.8 μmol), 19.0 mg of the title compound (92% purity, 71% yield) was prepared after filtration through an SCX-2 column (MeOH wash, followed by elution with 1 M ammonia in MeOH) using a method similar to that described for Intermediate 22-2.

[0426] 1H-NMR (400 MHz, DMSO-d6): δ [ppm]= 1.235 (1.09), 2.334 (1.58), 2.338 (0.84), 2.362 (16.00), 2.520 (7.24), 2.525 (4.55), 2.545 (1.21), 2.570 (1.33), 2.575 (1.40), 2.601 (1.20), 2.676 (1.83), 2.680 (1.06), 2.705 (1.02), 2.713 (0.99), 2.732 (1.01), 2.740 (0.93), 2.758 (1.50), 2.787 (0.62), 2.846 (1.74), 2.863 (4.52), 2.880 (2.07), 2.894 (1.12), 3.300 (4.30), 3.410 (1.44), 3.416 (1.55), 3.427 (2.54), 3.433 (2.52), 3.445 (1.29), 3.585 (0.65), 3.593 (0.77), 3.612 (1.20), 3.620 (1.22), 3.640 (0.69), 3.646 (0.62), 3.851 (0.59), 3.868 (0.92), 3.875 (0.91), 3.902 (1.40), 3.930 (1.00), 4.073 (1.20), 4.090 (1.18), 4.098 (1.63), 4.116 (1.39), 4.274 (1.41), 4.282 (1.45), 4.299 (1.18), 4.307 (1.08), 5.528 (0.41), 6.196 (1.85), 6.200 (1.81), 6.215 (2.00), 6.219 (1.86), 6.726 (1.04), 6.730 (1.33), 6.746 (3.44), 6.750 (2.92), 6.761 (2.53), 6.780 (2.58), 6.800 (0.88), 7.192 (2.31), 7.231 (3.82), 7.244 (3.92), 7.364 (4.42), 7.980 (4.81), 7.993 (4.51), 8.370 (6.73), 8.397 (0.45), 11.102 (2.40). LC-MS (Method 6): Rt = 0.52 min; MS (ESIpos): m / z = 468 [M+H] + Intermediate 43-1 tert-Butyl (3R)-3-[({4-[3-(3-chloro-2-methylanilino)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate [ka]

[0427] Starting from tert-butyl (3R)-3-[({4-[({5-[(3-chloro-2-methylphenyl)carbamothioyl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}amino)methyl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate (180 mg, 299 μmol), a method similar to that described for Example 1 was used; after purification by preparative HPLC (Method 9, gradient: 0.00-0.50 min 15% B, 0.50-4.23 min 15-41.9% B, 4.23-5.60 min 41.9% B, 5.60-7.37 min 41.9-55% B), 35.1 mg (90% purity, 19% yield) of the title compound was prepared.

[0428] 1H-NMR (400 MHz, DMSO-d6): δ [ppm]= 1.344 (16.00), 2.357 (14.22), 2.520 (2.49), 2.525 (1.70), 2.891 (0.42), 2.923 (1.43), 3.384 (1.03), 3.405 (2.12), 3.412 (2.73), 3.417 (2.74), 3.435 (1.48), 3.555 (0.76), 3.577 (0.85), 3.680 (1.24), 3.709 (1.06), 3.840 (1.02), 3.860 (0.92), 3.952 (1.42), 3.982 (1.23), 4.301 (0.62), 6.161 (1.64), 6.165 (1.44), 6.179 (1.77), 6.184 (1.67), 6.725 (0.94), 6.740 (3.11), 6.745 (3.77), 6.765 (1.40), 6.785 (0.46), 7.187 (1.94), 7.309 (2.75), 7.322 (2.75), 7.351 (4.78), 7.971 (1.97), 7.983 (1.88), 8.445 (5.01), 11.063 (1.60). LC-MS (Method 6): R t = 0.92 min; MS (ESIpos): m / z = 568 [M+H] + Intermediate 43-2 3-(3-chloro-2-methylanilino)-2-(3-{[(3R)-morpholin-3-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one [ka]

[0429] Starting from tert-butyl (3R)-3-[({4-[3-(3-chloro-2-methylanilino)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate (Intermediate 43-1, 30.0 mg, 52.8 μmol), 25.3 mg (purity 97%, yield 99%) of the title compound was prepared after filtration through an SCX-2 column (MeOH wash, followed by elution with 1 M ammonia in MeOH) using a method similar to that described for Intermediate 22-2.

[0430] 1H-NMR (400 MHz, DMSO-d6): δ [ppm]= 1.235 (0.47), 2.334 (1.10), 2.338 (0.53), 2.367 (16.00), 2.383 (0.45), 2.520 (5.15), 2.525 (3.36), 2.676 (1.09), 2.680 (0.50), 2.825 (1.81), 2.842 (3.79), 2.860 (2.41), 2.888 (0.56), 2.945 (0.90), 2.976 (0.54), 3.155 (0.67), 3.371 (1.08), 3.398 (1.36), 3.416 (2.04), 3.426 (3.16), 3.433 (2.75), 3.444 (2.06), 3.450 (1.95), 3.471 (0.57), 3.720 (1.01), 3.747 (0.86), 3.794 (1.03), 3.816 (0.90), 4.192 (0.59), 4.208 (0.66), 4.218 (1.25), 4.232 (1.21), 4.252 (1.38), 4.261 (1.46), 4.277 (0.69), 4.286 (0.59), 6.222 (1.82), 6.225 (1.83), 6.241 (1.98), 6.245 (1.89), 6.731 (1.15), 6.735 (1.43), 6.751 (3.26), 6.754 (2.74), 6.769 (2.24), 6.790 (2.51), 6.809 (0.87), 7.172 (2.36), 7.217 (2.75), 7.230 (2.77), 7.391 (4.55), 7.941 (1.75), 7.953 (1.66), 8.359 (2.93), 12.612 (0.40). LC-MS (Method 6): R t = 0.53 min; MS (ESIpos): m / z = 468 [M+H] + Intermediate 55-1 tert-Butyl (2R)-2-[({4-[3-(3-chloro-2-ethylanilino)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate [ka]

[0431] Starting from tert-butyl (2R)-2-[({4-[({5-[(3-chloro-2-ethylphenyl)carbamothioyl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}amino)methyl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate (Intermediate 6-55, 473 mg, 768 μmol), using a method similar to that described for Example 1; preparative HPLC (Method 10, gradient: 0.00-0.50 min 10% B, 0.50-11.05 min 10-34.4% B, 11.05-12.46 min 34.4% B, 12.46-24.12 min 34.4-60% B), followed by flash chromatography (silica, DCM / EtOH gradient After subjecting the mixture to 100°C / 100°C (0-12%), 57.0 mg of the title compound (purity 95%, yield 12%) was prepared.

[0432] LC-MS (Method 2): R t = 1.26 min; MS (ESIpos): m / z = 582 [M+H] + Intermediate 55-2 3-(3-chloro-2-ethylanilino)-2-(3-{[(2R)-morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one [ka]

[0433] Starting from tert-butyl (2R)-2-[({4-[3-(3-chloro-2-ethylanilino)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate (Intermediate 55-1, 70.4 mg, 121 μmol), a method similar to that described for Intermediate 22-2 was used; after purification by flash chromatography (silica, DCM / EtOH+triethylamine gradient 1-40%), 58.0 mg of the title compound (95% purity, 95% yield) was prepared.

[0434] 1 H-NMR (400MHz, DMSO-d6): δ [ppm]= 10.96 - 11.17 (m, 1H), 8.36 (s, 1H), 7.69 - 8.02 (m, 1H), 7.37 - 7.51 (m, 1H), 7.19 (s, 2H), 6.65 - 6.86 (m, 2H), 6.15 - 6.24 (m, 1H), 6.12 - 6.31 (m, 1H), 4.26 - 4.36 (m, 1H), 4.06 - 4.14 (m, 1H), 3.85 - 3.96 (m, 2H), 3.58 - 3.67 (m, 1H), 3.40 - 3.46 (m, 2H), 3.35 - 3.39 (m, 1H), 2.69 - 2.96 (m, 7H), 2.56 - 2.64 (m, 1H), 1.19 - 1.27 (m, 6H). LC-MS (Method 2): R t = 0.99 min; MS (ESIneg): m / z = 480 [MH] - Intermediate 56-1 tert-Butyl (2S)-2-[({4-[3-(3-chloro-2-ethylanilino)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate [ka]

[0435] Starting from tert-butyl (2S)-2-[({4-[({5-[(3-chloro-2-ethylphenyl)carbamothioyl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}amino)methyl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate (Intermediate 6-56, 476 mg, 772 μmol), using a method similar to that described for Example 1; preparative HPLC (Method 10, gradient: 0.00-0.50 min 20% B, 0.50-12.99 min 20-40% B, 12.99-15.46 min 40% B, 15.46-24.12 min 40-55% B), followed by flash chromatography (silica, DCM / EtOH gradient After subjecting the mixture to 100°C / 100°C (0-12%), 68.0 mg of the title compound was prepared (purity 95%, yield 14%).

[0436] LC-MS (method 2): R t = 1.26 min; MS (ESIpos): m / z = 582 [M+H] + Intermediate 56-2 3-(3-chloro-2-ethylanilino)-2-(3-{[(2S)-morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one [ka]

[0437] Starting from tert-butyl (2S)-2-[({4-[3-(3-chloro-2-ethylanilino)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate (Intermediate 56-1, 70.4 mg, 121 μmol), a method similar to that described for Intermediate 22-2 was used; after purification by flash chromatography (amino-phase silica, DCM / EtOH gradient 1-35%), 46.9 mg of the title compound (95% purity, 78% yield) was prepared.

[0438] 1 H-NMR (400MHz, DMSO-d6): δ [ppm]= 11.09 (s, 1H), 8.36 (s, 1H), 7.96 (d, 1H), 7.46 (s, 1H), 7.19 (d, 2H), 6.68 - 6.84 (m, 2H), 6.23 (dd, 1H), 4.24 - 4.34 (m, 1H), 4.03 - 4.16 (m, 1H), 3.82 - 3.96 (m, 2H), 3.57 - 3.65 (m, 1H), 3.39 - 3.48 (m, 2H), 2.82 - 2.94 (m, 5H), 2.64 - 2.79 (m, 2H), 2.54 - 2.60 (m, 1H), 1.23 (t, 3H). LC-MS (Method 2): R t = 0.99 min; MS (ESIneg): m / z = 480 [MH] - Example Example 1 3-(3-chloro-2-methoxyanilino)-2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one [ka]

[0439] To a suspension of N-(3-chloro-2-methoxyphenyl)-4-[({3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 6-1, 140 mg, 240 μmol) in MeOH (2.7 mL), TFA (42 μL, 540 μmol) was added, followed by aqueous hydrogen peroxide (94 μL, 35% purity, 1.08 mmol), and the mixture was heated at 50° C. for 17 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC (Method 10, gradient: 0.00–0.50 min 15% B, 0.50–6.00 min 15–55% B) to give 70 mg of the title compound (51% yield).

[0440] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm]= 2.86 (t, 2H), 3.37 - 3.57 (m, 4H), 3.70 - 3.90 (m, 4H), 3.88 (s, 3H), 3.92 - 4.08 (m, 1H), 4.10 - 4.20 (m, 1H), 4.28 (dd, 1H), 6.15 (t, 1H), 6.68 (d, 2H), 7.16 (br s, 1H), 7.28 (d, 1H), 7.52 (s, 1H), 8.04 (d, 1H), 8.39 (s, 1H), 11.07 (s, 1H). LC-MS (Method 2): R t = 0.98 min; MS (ESIpos): m / z = 485 [M+H] + Example 2 3-(3-chloro-2-methoxyanilino)-2-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (stereoisomer 1) [ka]

[0441] The title compound from Example 1 (140 mg) was separated into enantiomers by preparative chiral HPLC to give the title compound (Enantiomer 1, 27 mg with Rt = 14.0-17.0 min) and Enantiomer 2 (R t = 25 mg in 20.0 to 24.8 minutes, see Example 3).

[0442] Preparative Chiral HPLC Method: Apparatus: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000; Column: Cellulose SB 5μ, 250 × 30 mm; Eluent A: hexane + 0.1% (v / v) diethylamine (99%); Eluent B: 2-propanol; Isocratic: 50% A + 50% B; Flow rate: 50 ml / min; UV: 254 nm.

[0443] Analytical Chiral HPLC Method: Apparatus: Agilent HPLC 1260; Column: Cellulose SB 3μ, 100 × 4.6 mm; Eluent A: hexane + 0.1% by volume diethylamine (99%); Eluent B: 2-propanol; Isocratic: 50% A + 50% B, flow rate 1.4 ml / min; Temperature: 25 °C; UV: 254 nm.

[0444] Analytical Chiral HPLC:R t =4.49 minutes.

[0445] Optical rotation: [α] D =1.7°+ / -0.98°(c=3.6mg / 2ml, methanol) Enantioselective synthesis confirmed the title compound as 3-(3-chloro-2-methoxyanilino)-2-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one. The title compound (872 mg, 95% purity, 72% yield) was prepared in analogy to Example 1 using N-(3-chloro-2-methoxyphenyl)-4-{[(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 6-2, 1.23 g, 2.36 mmol) as the starting material, followed by purification by preparative HPLC (Method 10, gradient: 0.00–0.50 min 15% B, 0.50–6.00 min 15–55% B).

[0446] 1 H-NMR (400MHz, DMSO-d6): δ [ppm]= 2.86 (t, 2H), 3.38 - 3.47 (m, 3H), 3.53 (td, 1H), 3.69 - 3.78 (m, 2H), 3.83 (dd, 1H), 3.88 (s, 3H), 3.90 (m, 1H), 3.98 - 4.08 (m, 1H), 4.12 - 4.18 (m, 1H), 4.28 (dd, 1H), 6.12 - 6.17 (quin, 1H), 6.66 - 6.71 (m, 2H), 7.16 (s, 1H), 7.28 (d, 1H), 7.52 (s, 1H), 8.04 (d, 1H), 8.39 (s, 1H), 11.07 (s, 1H). Analytical Chiral HPLC:R t =4.46 minutes.

[0447] Optical rotation: [α] D =-12.5°+ / -0.52°(c=5.6mg / ml, chloroform) Example 3 3-(3-chloro-2-methoxyanilino)-2-(3-{[(2R)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (stereoisomer 2) [ka]

[0448] For the preparation of the racemic title compound, see Example 1. Separation of the enantiomers by preparative chiral HPLC (see Example 2) gave 25 mg of the title compound (R t =20.0~24.8 minutes).

[0449] Analytical chiral HPLC (see Example 2 for method): t =6.56 minutes.

[0450] Optical rotation: [α] D =-3.0°+ / -1.03°(c=3.2mg / 2ml, methanol) Optical rotation: [α] D =22.8°+ / -6.1°(c=6.3mg / ml, chloroform) Example 4 2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one [ka]

[0451] In a manner analogous to Example 1, 25.7 mg (21% yield) of the title compound was prepared using 4-[({3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methyl)amino]-N-(3-fluoro-2-methoxyphenyl)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 6-4, 120 mg, 239 μmol) after heating for 25 hours and purification by preparative HPLC (Method 10, gradient: 0.00-0.50 min 15% B, 0.50-6.00 min 15-55% B).

[0452] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm]= 2.86 (t, 2H), 3.37 - 3.57 (m, 4H), 3.66 - 3.89 (m, 4H), 3.91 (s, 3H), 3.98 - 4.09 (m, 1H), 4.09 - 4.20 (m, 1H), 4.28 (dd, 1H), 6.00 (d, 1H), 6.45 - 6.54 (m, 1H), 6.64 (m, 1H), 7.16 (br s, 1H), 7.29 (d, 1H), 7.53 (s, 1H), 8.04 (d, 1H), 8.39 (s, 1H), 11.05 (s, 1H). LC-MS (Method 2): R t = 0.92 min; MS (ESIpos): m / z = 469 [M+H] + Example 5 2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (stereoisomer 1) [ka]

[0453] The title compound from Example 4 (26 mg) was separated into enantiomers by preparative chiral HPLC to give the title compound (Enantiomer 1, 11 mg, Rt = 8.2–9.1 min, 10% yield) and enantiomer 2 (12 mg, R t =9.7 to 10.7 minutes, see Example 6).

[0454] Preparative Chiral HPLC Method: Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000; Column: Cellulose SB 5μ, 250 × 30 mm; Eluent A: MTBE + 0.1% (v / v) diethylamine (99%); Eluent B: acetonitrile; Gradient: 2 to 60% B in 20 min; Flow rate: 50 ml / min; UV: 280 nm Analytical Chiral HPLC Method: Apparatus: Agilent HPLC 1260; Column: Cellulose SB 3μ, 100 × 4.6 mm; Eluent A: MTBE + 0.1% (v / v) diethylamine (99%); Eluent B: acetonitrile; Gradient: 2 to 60% B in 7 min, flow rate: 1.4 ml / min; Temperature: 25°C; UV: 280 nm Analytical Chiral HPLC:R t =4.34 minutes.

[0455] Optical rotation: [α] D =-0.5°+ / -0.87°(c=7.5mg / 2ml, methanol) Example 6 2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (stereoisomer 2) [ka]

[0456] For the preparation of the racemic title compound, see Example 4. Separation of the enantiomers by preparative chiral HPLC (method see Example 5) gave 12 mg of the title compound (R t = 9.7-10.7 min, yield 11%).

[0457] Analytical chiral HPLC (see Example 5 for method): t =5.11 minutes.

[0458] Optical rotation: [α] D =-0.1°+ / -0.89°(c=6.3mg / 3ml, methanol) Example 7 3-(2,3-Dichloroanilino)-2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one [ka]

[0459] Analogously to Example 1, N-(2,3-dichlorophenyl)-4-[({3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 6-7, 110 mg, 210 μmol) was used to prepare 34.6 mg (32% yield) of the title compound after heating for 25 hours and purification by preparative HPLC (Method 10, gradient: 0.00-0.50 min 15% B, 0.50-6.00 min 15-55% B).

[0460] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm]= 2.86 (br t, 2H), 3.35 - 3.45 (m, 3H), 3.47 - 3.56 (m, 1H), 3.65 - 3.75 (m, 2H), 3.75 - 3.88 (m, 2H), 3.93 - 4.04 (m, 1H), 4.06 - 4.20 (m, 2H), 6.27 (dd, 1H), 6.83 - 6.91 (m, 2H), 7.17 (br s, 1H), 7.26 (d, 1H), 7.66 (s, 1H), 8.08 (d, 1H), 8.38 (s, 1H), 11.21 (s, 1H). LC-MS (Method 2): R t = 1.01 min; MS (ESIpos): m / z = 489 [M+H] + Example 8 3-(2,3-Dichloroanilino)-2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (stereoisomer 1) [ka]

[0461] The title compound from Example 7 (27 mg) was separated into its enantiomers by preparative chiral HPLC to give the title compound (Enantiomer 1, 10 mg) and Enantiomer 2 (12 mg, see Example 9).

[0462] Preparative Chiral HPLC Method: Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000; Column: Cellulose SB 5μ, 250 × 30 mm; Eluent A: MTBE + 0.1% (v / v) diethylamine (99%); Eluent B: acetonitrile; Gradient: 2 to 60% B in 20 min; Flow rate: 50 ml / min; UV: 280 nm Analytical Chiral HPLC Method: Apparatus: Agilent HPLC 1260; Column: Cellulose SB 3μ, 100 × 4.6 mm; Eluent A: MTBE + 0.1% (v / v) diethylamine (99%); Eluent B: acetonitrile; Gradient: 2 to 60% B in 7 min, flow rate: 1.4 ml / min; Temperature: 25°C; UV: 280 nm Analytical Chiral HPLC:R t =5.11 minutes.

[0463] Optical rotation: [α] D =1.4°+ / -0.69°(c=5.8mg / 2ml, methanol) Example 9 3-(2,3-Dichloroanilino)-2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (stereoisomer 2) [ka]

[0464] For the preparation of the racemic title compound see Example 7. Separation of the enantiomers by preparative chiral HPLC (method see Example 8) afforded 12 mg of the title compound.

[0465] Analytical chiral HPLC (see Example 8 for method): t =6.74 minutes.

[0466] Optical rotation: [α] D =-14.9°+ / -3.16°(c=5.6mg / ml, methanol) Example 10 3-(3-chloro-2-methylanilino)-2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one [ka]

[0467] Analogously to Example 1, N-(3-chloro-2-methylphenyl)-4-[({3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 6-10, 180 mg, 358 μmol) was used to prepare 12.1 mg (7% yield) of the title compound after heating for 25 hours and purification by preparative HPLC (Method 10, gradient: 0.00-0.50 min 15% B, 0.50-6.00 min 15-55% B).

[0468] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm]= 2.35 (s, 3H), 2.86 (br t, 2H), 3.37 - 3.47 (m, 3H), 3.55 (br dd, 1H), 3.67 - 3.85 (m, 3H), 3.89 (br d, 1H), 4.01 (br dd, 1H), 4.08 - 4.18 (m, 1H), 4.24 (dd, 1H), 6.20 (d, 1H), 6.71 - 6.80 (m, 2H), 7.19 (br s, 1H), 7.24 (d, 1H), 7.37 (s, 1H), 8.01 (d, 1H), 8.37 (s, 1H), 11.05 (s, 1H). LC-MS (Method 2): R t = 1.02 min; MS (ESIpos): m / z = 469 [M+H] + Example 11 3-(3-chloro-2-methoxyanilino)-2-(3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one [ka]

[0469] As in Example 1, 11 mg (15% yield) of the title compound was prepared using N-(3-chloro-2-methoxyphenyl)-4-{[(3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 6-11, 82 mg, 139 μmol) after heating for 17 hours and purification by preparative HPLC (Method 10, gradient: 0.00-0.50 min 15% B, 0.50-6.00 min 15-55% B).

[0470] 1H-NMR (400 MHz, DMSO-d6): δ [ppm]= 11.51 - 12.57 (m, 1H), 8.40 (br s, 1H), 8.04 (br s, 1H), 7.62 (br s, 1H), 7.32 (d, 1H), 7.19 (br s, 1H), 6.71 (br d, 2H), 6.15 (dd, 1H), 4.40 (br s, 2H), 3.90 (s, 4H), 3.85 (br s, 1H), 3.60 (br d, 3H), 3.40 - 3.51 (m, 3H), 3.01 (br s, 1H), 2.74 - 2.96 (m, 3H), 2.22 - 2.43 (m, 2H). LC-MS (Method 6): R t = 0.55 min; MS (ESIpos): m / z = 498.2 [M+H] + Optical rotation: [α] D =-82.0°+ / -0.41°(c=5.8mg / ml, methanol) Example 12 3-(3-fluoro-2-methoxyanilino)-2-{3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one [ka]

[0471] 3-(3-Fluoro-2-methoxyanilino)-2-(3-hydroxypyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (Intermediate 12, 150 mg, 407 μmol) was dissolved in dioxane (4.8 ml). The reaction mixture was degassed with argon. Next, (tributylphosphanylidene)acetonitrile (384 μl, 1.5 mmol, CAS 157141-27-0) and (4-methylmorpholin-2-yl)methanol (CAS 40987-46-0, 80.0 mg, 610 μmol) were added, and the mixture was stirred at 50 °C for 30 hours. The mixture was concentrated under reduced pressure, and saturated sodium bicarbonate solution was added. The mixture was extracted with DCM. The organic phase was filtered through a water-repellent filter, concentrated under reduced pressure, and purified by preparative HPLC (Method 10, gradient: 0.00-0.50 min 1% B, 0.50-27.40 min 1-50% B) to give 16.2 mg (8% yield) of the title compound.

[0472] 1 H-NMR (400MHz, DMSO-d6): δ [ppm]= 11.05 (s, 1H), 8.40 (s, 1H), 8.02 (d, 1H), 7.52 (s, 1H), 7.29 (d, 1H), 7.16 (s, 1H), 6.64 (td, 1H), 6.50 (ddd, 1H), 6.01 (d, 1H), 4.34 (dd, 1H), 4.15 (dd, 1H), 3.88 - 4.00 (m, 5H), 3.67 (td, 1H), 3.37 - 3.47 (m, 2H), 2.85 (t, 2H), 2.77 (br d, 1H), 2.66 - 2.70 (m, 1H), 2.20 (s, 3H), 2.04 (td, 1H), 1.91 (t, 1H). LC-MS (Method 2): R t = 0.92 min; MS (ESIpos): m / z = 482.3 [M+H] + Example 13 3-(3-Fluoro-2-methoxyanilino)-2-{3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (stereoisomer 1) [ka]

[0473] The title compound from Example 12 (19 mg) was separated into enantiomers by preparative chiral HPLC to give the title compound (enantiomer 1, 6 mg, R t = 6.7–8.7 min, 3% yield) and enantiomer 2 (7 mg, R t =8.9 to 11.9 minutes, see Example 14).

[0474] Preparative Chiral HPLC Method: Apparatus: PrepCon Labomatic HPLC; Column: Chiralcel OD-H 5μ, 250 × 20; Eluent A: acetonitrile + 0.1% (v / v) diethylamine (99%); Eluent B: ethanol; Isocratic: 93% A + 7% B; Flow rate: 20 ml / min; Temperature: 25°C; UV: 254 nm Analytical Chiral HPLC Method: Apparatus: Waters Alliance 2695; Column: Chiralcel OD-H 5μ, 100 × 4.6; Eluent A: ethanol + 0.1% (v / v) diethylamine (99%); Eluent B: ethanol; Isocratic: 90% A + 10% B, Flow rate: 1.4 ml / min; Temperature: 25°C; UV: 254 nm Analytical Chiral HPLC:R t =2.91 minutes.

[0475] 1H-NMR (400MHz, DMSO-d6): δ [ppm]= 11.05 (s, 1H), 8.40 (s, 1H), 8.02 (d, 1H), 7.53 (s, 1H), 7.29 (d, 1H), 7.16 (s, 1H), 6.64 (td, 1H), 6.50 (t, 1H), 6.01 (d, 1H), 4.34 (dd, 1H), 4.15 (dd, 1H), 3.89 - 3.99 (m, 5H), 3.67 (td, 1H), 3.38 - 3.46 (m, 2H), 2.85 (t, 2H), 2.77 (br d, 1H), 2.61 - 2.71 (m, 1H), 2.20 (s, 3H), 1.98 - 2.16 (m, 1H), 1.91 (t, 1H). Example 14 3-(3-Fluoro-2-methoxyanilino)-2-{3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (stereoisomer 2) [ka]

[0476] For the preparation of the racemic title compound, see Example 12. Separation of the enantiomers by preparative chiral HPLC (method see Example 13) gave 7 mg of the title compound (R t = 8.9-11.9 min, yield 3%).

[0477] Analytical chiral HPLC (see Example 13 for method): t =3.70 minutes.

[0478] 1H-NMR (400 MHz, DMSO-d6): δ [ppm]= 11.05 (s, 1H), 8.40 (s, 1H), 8.02 (br d, 1H), 7.53 (s, 1H), 7.29 (d, 1H), 7.16 (br s, 1H), 6.59 - 6.70 (m, 1H), 6.50 (br t, 1H), 6.01 (br d, 1H), 4.34 (br dd, 1H), 4.15 (br dd, 1H), 3.86 - 4.00 (m, 5H), 3.60 - 3.74 (m, 1H), 3.40 - 3.48 (m, 2H), 2.85 (br t, 2H), 2.77 (br d, 1H), 2.63 - 2.70 (m, 1H), 2.20 (s, 3H), 1.99 - 2.09 (m, 1H), 1.91 (br t, 1H). Example 15 3-(3-chloro-2-methoxyanilino)-2-{3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one [ka]

[0479] As in Example 1, N-(3-chloro-2-methoxyphenyl)-4-[({3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 6-15, 74.0 mg, 139 μmol) was heated for 18 hours and purified by preparative HPLC (Method 10, gradient: 0.00 to 0.50 min 15% B, 0.50 to 6.00 min 15 to 55% B) to prepare 24.1 mg of the title compound (purity 90%, yield 31%).

[0480] 1H-NMR (400 MHz, DMSO-d6): δ [ppm]= 1.86 - 1.95 (t, 1H), 2.00 - 2.09 (td, 1H), 2.20 (s, 3H), 2.66 (br d, 1H), 2.73 - 2.81 (br d, 1H), 2.86 (t, 2H), 3.42 (td, 2H), 3.61 - 3.73 (td, 1H), 3.88 (s, 3H), 3.91 - 4.02 (m, 2H), 4.16 (dd, 1H), 4.33 (dd, 1H), 6.15 (t, 1H), 6.69 (d, 2H), 7.16 (s, 1H), 7.28 (d, 1H), 7.53 (s, 1H), 8.03 (d, 1H), 8.40 (s, 1H), 11.07 (s, 1H). LC-MS (Method 2): R t = 0.97 min; MS (ESIpos): m / z = 498 [M+H] + Example 16 3-(3-chloro-2-methoxyanilino)-2-(3-{[4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (stereoisomer 1) [ka]

[0481] The title compound from Example 15 (24.1 mg) was separated into enantiomers by preparative chiral HPLC to give the title compound (enantiomer 1, 8 mg, R t = 17.4-21.8, yield 11%) and enantiomer 2 (7 mg, R t = 12.5 to 14.5 minutes, see Example 17).

[0482] Preparative Chiral HPLC Method: Apparatus: PrepCon Labomatic HPLC; Column: Chiralpak IF 5μ, 250x30; Eluent A: hexane + 0.1% (v / v) diethylamine; Eluent B: ethanol + 0.1% (v / v) diethylamine; Isocratic: 50% A + 50% B; Flow rate: 40 ml / min; Temperature: 25°C; UV: 280 nm Analytical Chiral HPLC Method: Apparatus: Waters Alliance 2695; Column: Chiralpak IF 3μ, 100x4.6; Eluent A: hexane + 0.1% (v / v) diethylamine; Eluent B: ethanol; Isocratic: 50% A + 50% B; Flow rate: 1.4 ml / min; Temperature: 25°C; UV: 280 nm Analytical Chiral HPLC:R t =4.55 minutes.

[0483] 1H-NMR (400 MHz, DMSO-d6): δ [ppm]= 1.232 (1.95), 1.259 (0.49), 1.888 (0.59), 1.914 (1.04), 1.941 (0.65), 2.016 (0.40), 2.037 (0.73), 2.045 (0.70), 2.065 (0.49), 2.206 (9.36), 2.327 (0.42), 2.518 (1.60), 2.523 (1.15), 2.540 (16.00), 2.646 (0.75), 2.670 (0.96), 2.673 (0.98), 2.758 (0.81), 2.787 (0.77), 2.841 (1.13), 2.858 (2.36), 2.876 (1.27), 3.405 (0.89), 3.410 (0.98), 3.422 (1.69), 3.428 (1.67), 3.439 (0.85), 3.445 (0.77), 3.638 (0.41), 3.644 (0.49), 3.666 (0.89), 3.672 (0.89), 3.694 (0.54), 3.700 (0.52), 3.883 (15.90), 3.933 (0.86), 3.952 (0.89), 3.960 (1.15), 3.976 (0.47), 3.983 (0.40), 4.137 (0.82), 4.154 (0.74), 4.163 (1.02), 4.179 (0.84), 4.315 (0.97), 4.324 (1.01), 4.341 (0.80), 4.349 (0.72), 6.139 (1.35), 6.151 (2.23), 6.163 (1.38), 6.681 (4.49), 6.692 (3.40), 6.694 (3.35), 7.163 (1.58), 7.274 (1.81), 7.287 (1.83), 7.533 (3.41), 8.021 (1.20), 8.034 (1.14), 8.402 (1.87), 11.066 (1.70). Example 17 3-(3-chloro-2-methoxyanilino)-2-(3-{[4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (stereoisomer 2) [ka]

[0484] For the preparation of the racemic title compound, see Example 15. Separation of the enantiomers by preparative chiral HPLC (method see Example 16) affords 7 mg of the title compound (R t =12.5~14.5 minutes).

[0485] Analytical chiral HPLC (see Example 16 for method): t =2.93 minutes.

[0486] Example 18 3-(3-chloro-5-fluoro-2-methoxyanilino)-2-(3-{[4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one [ka]

[0487] Starting from N-(3-chloro-5-fluoro-2-methoxyphenyl)-4-[({3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 6-18, 166 mg, 302 μmol), using a method similar to that described for Example 1; after purification by preparative HPLC (Method 10, gradient: 0.00-0.50 min 15% B, 0.50-6.00 min 15-55% B), 13.0 mg of the title compound (95% purity, 8% yield) was prepared.

[0488] 1H-NMR (400 MHz, DMSO-d6): δ [ppm]= 1.88 (t, 1H), 1.93 - 2.05 (dt, 1H), 2.19 (s, 3H), 2.60 - 2.66 (d, 1H), 2.70 - 2.77 (d, 1H), 2.86 (t, 2H), 3.37 - 3.48 (m, 2H), 3.56 - 3.68 (m, 1H), 3.83 (s, 3H), 3.90 (br d, 2H), 4.15 (m, 1H), 4.27 (dd, 1H), 5.85 (dd, 1H), 6.56 (dd, 1H), 7.13 (s, 1H), 7.33 (d, 1H), 7.64 (s, 1H), 8.10 (d, 1H), 8.43 (s, 1H), 11.18 (s, 1H). LC-MS (Method 2): R t = 1.00 min; MS (ESIpos): m / z = 516 [M+H] + Example 19 3-(3-chloro-5-fluoro-2-methoxyanilino)-2-(3-{[1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one [ka]

[0489] Using a method similar to that described for Example 1, N-(3-chloro-5-fluoro-2-methoxyphenyl)-4-[({3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 6-19, 160 mg, 298 μmol), 3.90 mg (90% purity, 2% yield) of the title compound was prepared after purification by preparative HPLC (Method 10, gradient: 0.00-0.50 min 15% B, 0.50-6.00 min 15-55% B).

[0490] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm]= 2.86 (t, 2H), 3.37 - 3.45 (m, 3H), 3.47 - 3.61 (m, 1H), 3.62 - 3.77 (m, 3H), 3.77 - 3.87 (m, 6H), 3.94 - 4.01 (m, 1H), 4.07 - 4.20 (m, 1H), 4.24 (dd, 1H), 5.85 (dd, 1H), 6.56 (dd, 1H), 7.13 (s, 1H), 7.33 (d, 1H), 7.60 - 7.66 (d, 1H), 8.11 (br d, 1H), 8.42 (s, 1H), 11.19 (s, 1H). LC-MS (Method 2): R t = 1.01 min; MS (ESIpos): m / z = 503 [M+H] + Example 20 3-(3-Fluoro-2-methoxyanilino)-2-(3-{[(3S)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one [ka]

[0491] Starting from N-(3-fluoro-2-methoxyphenyl)-4-{[(3-{[(3S)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 6-20, 102 mg, 197 μmol), a method similar to that described for Example 1 was used to prepare 27.9 mg (90% purity, 26% yield) of the title compound after purification by preparative HPLC (Method 10, gradient: 0.00-0.50 min 10% B, 0.50-6.00 min 10-50% B).

[0492] LC-MS (Method 6): Rt = 0.51 min; MS (ESIpos): m / z = 482 [M+H] + 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.274 (13.29), 2.304 (1.76), 2.318 (0.55), 2.404 (0.46), 2.426 (0.88), 2.434 (0.91), 2.449 (0.43), 2.454 (0.88), 2.458 (1.03), 2.463 (1.43), 2.468 (1.37), 2.473 (1.55), 2.518 (5.99), 2.523 (4.32), 2.775 (0.40), 2.798 (0.70), 2.815 (1.49), 2.822 (0.88), 2.832 (0.91), 2.841 (1.16), 2.858 (0.79), 2.908 (1.13), 2.938 (1.00), 3.294 (0.43), 3.406 (0.64), 3.423 (1.46), 3.429 (1.19), 3.438 (1.37), 3.453 (0.58), 3.459 (0.55), 3.546 (1.13), 3.573 (1.76), 3.589 (1.13), 3.594 (1.22), 3.600 (1.28), 3.618 (0.61), 3.816 (0.94), 3.840 (1.83), 3.847 (1.95), 3.868 (1.06), 3.875 (0.97), 3.938 (16.00), 3.951 (2.07), 4.374 (1.67), 4.386 (2.71), 4.414 (0.46), 6.011 (1.89), 6.031 (1.89), 6.514 (1.03), 6.518 (0.97), 6.535 (1.28), 6.539 (1.34), 6.541 (1.19), 6.545 (0.94), 6.562 (1.19), 6.565 (1.06), 6.655 (0.97), 6.670 (1.03), 6.675 (1.70), 6.691 (1.55), 6.696 (0.82), 6.711 (0.67), 7.176 (2.07), 7.310 (3.71), 7.323 (3.68), 7.514 (0.43), 7.527 (0.52), 7.533 (0.58), 7.601 (4.56), 7.977 (5.29), 7.990 (4.50), 8.067 (0.61), 8.080 (0.55), 8.358 (6.27), 8.439 (0.73), 12.011 (2.13). Example 21 3-(3-chloro-2-methoxyanilino)-2-(3-{[(3S)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one [ka]

[0493] Starting from N-(3-chloro-2-methoxyphenyl)-4-{[(3-{[(3S)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 6-21, 99.5 mg, 187 μmol), using a method similar to that described for Example 1; after purification by preparative HPLC (Method 10, gradient: 0.00-0.50 min 10% B, 0.50-6.00 min 10-50% B), 4.70 mg of the title compound (98% purity, 5% yield) was prepared.

[0494] 1H-NMR (400 MHz, DMSO-d6): δ [ppm]= 1.232 (0.45), 2.276 (9.36), 2.426 (0.63), 2.434 (0.67), 2.456 (0.51), 2.464 (0.76), 2.472 (0.79), 2.518 (1.95), 2.523 (1.26), 2.539 (9.95), 2.806 (0.54), 2.823 (1.37), 2.841 (1.19), 2.860 (0.60), 2.910 (0.85), 2.940 (0.76), 3.408 (0.49), 3.425 (1.12), 3.431 (0.95), 3.441 (1.04), 3.454 (0.49), 3.460 (0.44), 3.544 (0.71), 3.572 (1.31), 3.588 (0.84), 3.594 (0.92), 3.599 (0.96), 3.617 (0.47), 3.817 (0.72), 3.841 (1.23), 3.847 (1.34), 3.868 (0.69), 3.875 (0.63), 3.912 (16.00), 3.924 (0.49), 4.376 (1.24), 4.387 (2.11), 6.151 (1.35), 6.162 (2.22), 6.175 (1.39), 6.718 (3.50), 6.720 (3.93), 6.731 (4.23), 7.179 (1.54), 7.299 (2.18), 7.312 (2.21), 7.614 (3.34), 7.983 (1.76), 7.995 (1.68), 8.362 (2.68), 12.027 (1.61). LC-MS (Method 6): Rt = 0.54 min; MS (ESIpos): m / z = 498 [M+H] + Example 22 2-(3-{[(2S)-4-(2,2-difluoroethyl)morpholin-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one [ka]

[0495] 3-(3-Fluoro-2-methoxyanilino)-2-(3-{[(2S)-morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (Intermediate 22, 50.0 mg, 107 μmol) was solubilized in DMF (1.6 mL). Triethylamine (89 μL, 640 μmol) and 2,2-difluoroethyl trifluoromethanesulfonate (64 μL, 480 μmol) were added, and the mixture was stirred at RT for 1 h. The mixture was purified by preparative HPLC (Method 10, gradient: 0.00–0.50 min 15% B, 0.50–6.00 min 15–55% B) to give 11.3 mg of the target compound (90% purity, 18% yield).

[0496] 1 H-NMR (400MHz, DMSO-d6): δ [ppm]= 2.24 (t, 1H), 2.34 - 2.40 (dd, 1H), 2.78 (m, 1H), 2.78 - 2.81 (m, 1H), 2.83 (m, 1H), 2.85 - 2.90 (t, 2H), 2.90 - 2.97 (d, 1H), 3.38 - 3.47 (m, 2H), 3.68 (dt, 1H), 3.89 - 3.92 (s, 3H), 3.92 - 4.03 (m, 2H), 4.17 (dd, 1H), 4.29 (dd, 1H), 5.97 - 6.02 (d, 1H), 6.02 - 6.34 (tt, 1H), 6.47 - 6.54 (m, 1H), 6.64 (td, 1H), 7.16 (s, 1H), 7.29 (d, 1H), 7.54 (s, 1H), 8.02 (d, 1H), 8.40 (s, 1H), 11.03 (s, 1H). LC-MS (Method 2): R t = 1.04 min; MS (ESIpos): m / z = 532 [M+H] + Example 23 3-(3-fluoro-2-methoxyanilino)-2-(3-{[(2S)-4-(2,2,2-trifluoroethyl)morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one [ka]

[0497] Starting from 3-(3-fluoro-2-methoxyanilino)-2-(3-{[(2S)-morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (Intermediate 22, 35.0 mg, 74.9 μmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (CAS 6226-25-1, 16 μl, 110 μmol), a method similar to that described for Example 22 was used; after purification by preparative HPLC (Method 10, gradient: 0.00-0.50 min 30% B, 0.50-6.00 min 30-70% B), 11.9 mg of the title compound (95% purity, 27% yield) was prepared.

[0498] 1H-NMR (400 MHz, DMSO-d6): δ [ppm]= 1.231 (0.47), 1.264 (0.47), 2.326 (2.22), 2.331 (1.58), 2.359 (0.93), 2.387 (1.69), 2.414 (1.15), 2.518 (7.61), 2.522 (5.31), 2.668 (2.30), 2.673 (1.58), 2.805 (1.18), 2.836 (2.55), 2.853 (3.44), 2.870 (1.79), 2.936 (1.26), 2.964 (1.11), 3.196 (0.54), 3.205 (0.61), 3.221 (1.54), 3.230 (1.58), 3.247 (1.51), 3.255 (1.47), 3.271 (0.61), 3.281 (0.54), 3.400 (1.26), 3.406 (1.33), 3.417 (2.37), 3.423 (2.26), 3.434 (1.15), 3.440 (1.08), 3.654 (0.54), 3.660 (0.65), 3.674 (0.72), 3.683 (1.18), 3.688 (1.15), 3.711 (0.68), 3.912 (16.00), 3.934 (1.11), 3.966 (1.11), 3.983 (0.72), 3.999 (0.75), 4.008 (0.65), 4.157 (1.04), 4.174 (1.00), 4.183 (1.51), 4.199 (1.22), 4.277 (1.40), 4.286 (1.36), 4.303 (1.04), 4.312 (0.86), 5.989 (1.94), 6.010 (1.97), 6.472 (0.86), 6.475 (0.86), 6.493 (1.26), 6.497 (1.26), 6.502 (0.93), 6.520 (1.18), 6.523 (1.04), 6.611 (0.90), 6.626 (1.04), 6.632 (1.54), 6.647 (1.51), 6.652 (0.75), 6.668 (0.65), 7.161 (2.22), 7.278 (3.52), 7.291 (3.55), 7.535 (4.77), 8.018 (4.38), 8.030 (4.02), 8.391 (6.17), 11.018 (2.48). LC-MS (Method 2): R t = 1.09 min; MS (ESIpos): m / z = 550 [M+H] + Example 24 3-(3-chloro-2-methoxyanilino)-2-{3-[2-(4-dioxan-2-yl)ethoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one [ka]

[0499] Starting from N-(3-chloro-2-methoxyphenyl)-4-[({3-[2-(1,4-dioxan-2-yl)ethoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (Intermediate 6-24, 105 mg, 197 μmol), using a method similar to that described for Example 1; after preparative HPLC (Method 7), 43.5 mg (purity 95%, yield 42%) of the title compound was prepared.

[0500] 1H-NMR (400 MHz, DMSO-d6): δ [ppm]= 1.817 (0.39), 1.834 (1.18), 1.849 (1.57), 1.861 (1.08), 1.876 (0.49), 2.518 (3.04), 2.522 (2.06), 2.673 (0.59), 2.833 (0.88), 2.846 (1.87), 2.863 (0.98), 3.204 (0.88), 3.231 (1.47), 3.260 (1.08), 3.312 (1.28), 3.396 (1.67), 3.408 (2.16), 3.413 (2.16), 3.426 (1.28), 3.456 (1.18), 3.462 (1.08), 3.484 (0.98), 3.490 (0.98), 3.521 (0.79), 3.525 (0.88), 3.549 (1.08), 3.554 (1.18), 3.582 (0.69), 3.625 (1.28), 3.648 (1.37), 3.668 (2.45), 3.678 (0.98), 3.693 (1.37), 3.716 (1.28), 3.745 (0.98), 3.858 (16.00), 4.226 (1.37), 4.241 (2.94), 4.257 (1.37), 6.103 (1.47), 6.115 (2.06), 6.127 (1.47), 6.640 (5.60), 6.650 (3.63), 7.108 (1.77), 7.287 (2.65), 7.299 (2.75), 7.458 (3.93), 8.020 (3.04), 8.033 (2.85), 8.350 (4.32), 11.191 (1.96). LC-MS (Method 6): Rt = 0.68 min; MS (ESIpos): m / z = 499 [M+H] + Example 25 3-(3-chloro-2-methoxyanilino)-2-{3-[2-(4-dioxan-2-yl)ethoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (stereoisomer 1) [ka]

[0501] The title compound from Example 24 (40 mg) was separated into enantiomers by preparative chiral HPLC to give the title compound (Enantiomer 1, 18.0 mg, R t = 18.8–21.3 min, 96% purity and enantiomer 2 (17 mg, R t = 21.7 to 24.5 minutes, see Example 26).

[0502] Preparative Chiral HPLC Method: Apparatus: PrepCon Labomatic HPLC; Column: YMC Cellulose SB 5μ, 250x30; Eluent A: methyl tert-butyl ether + 0.1% (v / v) diethylamine; Eluent B: acetonitrile + 0.1% (v / v) diethylamine; Gradient: 0-20 min, 2-60% B; Flow rate: 40 ml / min; Temperature: 25°C; UV: 280 nm Analytical Chiral HPLC Method: Apparatus: Waters Alliance 2695; Column: YMC Cellulose SB 3μ, 100 x 4.6; Eluent A: methyl tert-butyl ether + 0.1% (v / v) diethylamine; Eluent B: acetonitrile; Gradient: 0-7 mi...

Claims

1. Formula (I) 【Chemistry 1】 [In the ceremony: R1 represents methyl, ethyl, trifluoromethyl, 2,2-difluoroethyl, cyano, chloro, bromo, methoxy or difluoromethoxy; R2 represents hydrogen, methyl, ethyl, fluoro, chloro or bromo; R3 represents hydrogen or fluoro; R4 represents hydrogen or methyl; R5, independently for each occurrence, represents hydrogen, trifluoromethyl, or C1-C3 alkyl, R5 being attached to any carbon atom of the ring; R6, independently for each occurrence, represents hydrogen, C1-C3-alkyl or C1-C3-haloalkyl; R7 represents C1-C3-alkyl or C2-C3-haloalkyl; R8 represents C1-C3-alkyl or C2-C3-haloalkyl; X represents NR7 or O; Y represents NR8 or O; m represents 0, 1, 2 or 3; n represents 0 or 1; or an N-oxide, salt or tautomer of said compound, or a salt of said N-oxide or tautomer.

2. R1 represents methyl, ethyl, chloro, methoxy or difluoromethoxy; R2 represents methyl, ethyl, fluoro or chloro; R3 represents hydrogen or fluoro; R4 represents hydrogen or methyl; R5 represents hydrogen, methyl or trifluoromethyl, R5 being attached to any carbon atom of the ring; R6 represents hydrogen, methyl or trifluoromethyl; R7 represents C1-C2-alkyl or C2-C3-fluoroalkyl; R8 represents C1-C2-alkyl or C2-C3-fluoroalkyl; X represents NR7 or O; Y represents NR8 or O; m represents 0, 1 or 2; 2. A compound of formula (I) according to claim 1, wherein n represents 0 or 1; or an N-oxide, salt or tautomer of said compound, or a salt of said N-oxide or tautomer.

3. R1 represents methyl, ethyl, chloro or methoxy; R2 represents fluoro or chloro; R3 represents hydrogen or fluoro; R4 represents hydrogen; R5 represents hydrogen or methyl, R5 being attached to any carbon atom of the ring; R6 represents hydrogen; R7 represents methyl; R8 represents methyl, 2,2,2-trifluoroethyl or 2,2-difluoroethyl; X represents NR7 or O; Y represents NR8 or O; m represents 0, 1, or 2; 3. A compound of formula (I) according to claim 1 or 2, wherein n represents 0 or 1; or an N-oxide, salt or tautomer of said compound, or a salt of said N-oxide or tautomer.

4. A compound of formula (I) according to any one of claims 1 to 3, selected from the group consisting of: 3-(3-chloro-2-methoxyanilino)-2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{[(2R)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2R)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(2,3-dichloroanilino)-2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(2,3-dichloroanilino)-2-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(2,3-dichloroanilino)-2-(3-{[(2R)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methylanilino)-2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-fluoro-2-methoxyanilino)-2-{3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-fluoro-2-methoxyanilino)-2-(3-{[(2R)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-fluoro-2-methoxyanilino)-2-(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-{3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{[(2R)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-5-fluoro-2-methoxyanilino)-2-(3-{[4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-5-fluoro-2-methoxyanilino)-2-(3-{[1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-fluoro-2-methoxyanilino)-2-(3-{[(3S)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{[(3S)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2S)-4-(2,2-difluoroethyl)morpholin-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-fluoro-2-methoxyanilino)-2-(3-{[(2S)-4-(2,2,2-trifluoroethyl)morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-{3-[2-(4-dioxan-2-yl)ethoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{2-[(2R)-1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{2-[(2S)-1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-5-fluoro-2-methoxyanilino)-2-(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-5-fluoro-2-methoxyanilino)-2-(3-{[(2S)-4-(2,2,2-trifluoroethyl)morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-ethylanilino)-2-{3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-{3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{[(2R)-5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{[(2S)-5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2R)-5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2S)-5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{2-[(2R)-1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{2-[(2S)-1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-fluoro-2-methoxyanilino)-2-(3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-{3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-3-(3-fluoro-2-methylanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2S)-5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methylanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-[2-(2,2-difluoroethyl)-3-fluoroanilino]-2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-[2-(2,2-difluoroethyl)-3-fluoroanilino]-2-(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methylanilino)-2-(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methylanilino)-2-(3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methylanilino)-2-{3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methylanilino)-2-(3-{[(2S)-5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methylanilino)-2-(3-{[(2R)-5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-3-(3-fluoro-2-methylanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methylanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2R)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methylanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methylanilino)-2-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methylanilino)-2-(3-{[(2R)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-ethylanilino)-2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-ethylanilino)-2-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-ethylanilino)-2-(3-{[(2R)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-ethylanilino)-2-(3-{[(2R)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-ethylanilino)-2-(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{1-[1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{(1S)-1-[(2S)-1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{(1S)-1-[(2R)-1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{(1R)-1-[(2S)-1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{(1R)-1-[(2R)-1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-fluoro-2-methylanilino)-2-{3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-fluoro-2-methylanilino)-2-(3-{[(2R)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-fluoro-2-methylanilino)-2-(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3-fluoroanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2R)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3-fluoroanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3-fluoroanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3-fluoroanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2R)-5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3-fluoroanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2S)-5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3-fluoroanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-[3-({1-[4-methylmorpholin-2-yl]ethyl}oxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-[3-({(1R)-1-[(2R)-4-methylmorpholin-2-yl]ethyl}oxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-[3-({(1S)-1-[(2S)-4-methylmorpholin-2-yl]ethyl}oxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-[3-({(1R)-1-[(2S)-4-methylmorpholin-2-yl]ethyl}oxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-[3-({(1S)-1-[(2R)-4-methylmorpholin-2-yl]ethyl}oxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one.

5. Use of a compound of general formula (I) according to any of claims 1 to 4 for the manufacture of a medicament for the treatment or prevention of a disease.

6. Use of compounds of general formula (I) according to claim 5, wherein said diseases are hyperproliferative diseases and / or disorders responsive to the induction of cell death.

7. 7. Use of compounds of general formula (I) according to claim 6, wherein said hyperproliferative diseases and / or disorders responsive to the induction of cell death are hematological tumors, solid tumors and / or metastases thereof.

8. 8. The use of a compound of formula (I) according to claim 7, wherein said tumor has a mutant EGFR and / or a metastasis thereof.

9. 8. The use of a compound of formula (I) according to claim 7, wherein said tumor is a lung cancer and / or a metastasis thereof.

10. 10. The use of a compound of formula (I) according to claim 9, wherein the tumor is a lung cancer with a mutant EGFR having an exon 20 insertion mutation.

11. 8. The use of a compound of formula (I) according to claim 7, wherein the tumor is a lung cancer with a mutant EGFR with an in-frame deletion in exon 19 or a point mutation in exon 21.

12. 12. The use of a compound of formula (I) according to claim 11, wherein the in-frame deletion in exon 19 is EGFR E746_A750del.

13. 12. The use of a compound of formula (I) according to claim 11, wherein the point mutation in exon 21 is L858R.

14. 8. The use of a compound of formula (I) according to claim 7, wherein the tumor is a lung cancer with a mutant EGFR with D770_N771insSVD C797S, E746_A750del C797S, or L858R C797S acquired resistance mutation, and / or a metastasis thereof.

15. 8. The use of a compound of formula (I) according to claim 7, wherein the tumor is a lung cancer with a mutant ERBB2 having an exon 20 insertion mutation and / or a metastasis thereof.

16. 16. The use of a compound of formula (I) according to claim 15, wherein the mutant ERBB2 having an exon 20 insertion mutation is ERBB2 A775_G776insYVMA.

17. A pharmaceutical composition comprising at least one compound of general formula (I) according to any of claims 1 to 4, together with at least one pharma- ceutically acceptable adjuvant.

18. The composition according to claim 17 for the treatment of hematological tumors, solid tumors and / or their metastases.

19. A combination drug comprising one or more first active ingredients selected from the compounds of general formula (I) according to any one of claims 1 to 4, and one or more second active ingredients selected from chemotherapeutic anticancer agents and target-specific anticancer agents.

20. A pharmaceutical composition for use in a method for inhibiting EGF receptor kinase activity in cancer cells, said pharmaceutical composition comprising a compound of general formula (I) as defined in any one of claims 1 to 4, said method comprising contacting cancer cells with said compound of general formula (I).

21. 21. The pharmaceutical composition of claim 20, wherein the cancer cell is in vitro or in vivo.

22. A pharmaceutical composition for use in a method of reducing survival or inducing death in cancer cells, said pharmaceutical composition comprising a compound of general formula (I) as defined in any of claims 1 to 4, said method comprising contacting a cancer cell containing a mutation in the EGF receptor with said compound of general formula (I).

23. The pharmaceutical composition according to any one of claims 20 to 22, wherein the cancer cells contain an EGF receptor containing a mutation in exon 20.

24. 24. The pharmaceutical composition of any one of claims 20 to 23, wherein the cancer cells are derived from a cancer selected from the group consisting of leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumor, gastrointestinal tumor, endocrine tumor, breast tumor, urinary tumor, skin tumor, and sarcoma.

25. 25. The pharmaceutical composition of claim 24, wherein the cancer cells are from a cancer selected from the group consisting of inverting sinonasal papilloma or inverting sinonasal papilloma-associated sinonasal squamous cell carcinoma.

26. A pharmaceutical composition for use in a method of treating cancer in a subject, said pharmaceutical composition comprising a compound of general formula (I) as defined in any one of claims 1 to 4, said method comprising administering to the subject an effective amount of said compound of general formula (I).

27. A pharmaceutical composition for use in a method of treating cancer in a subject, said pharmaceutical composition comprising a compound of general formula (I) as defined in any one of claims 1 to 4, said cancer being resistant or having acquired resistance to anti-EGF receptor therapy, said method comprising administering to the subject an effective amount of said compound of general formula (I).

28. A pharmaceutical composition for use in a method for enhancing the efficacy of an anti-EGF receptor therapy, said pharmaceutical composition comprising a compound of general formula (I) as defined in any one of claims 1 to 4, said method comprising administering to a subject an anti-EGF receptor therapy in combination with said compound of general formula (I).

29. 28. The pharmaceutical composition of claim 26 or 27, wherein the cancer is selected from the group consisting of leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumor, breast tumor, gastrointestinal tumor, endocrine tumor, breast tumor, urinary tract tumor, skin tumor, and sarcoma.

30. 30. The pharmaceutical composition of claim 29, wherein the cancer is selected from the group consisting of inverting sinonasal papilloma or inverting sinonasal papilloma-associated sinonasal squamous cell carcinoma.

31. 30. The pharmaceutical composition of claim 29, wherein the breast tumor is non-small cell lung cancer.

32. The pharmaceutical composition of any one of claims 20 to 27 and 29 to 31, wherein the cancer cells comprise a mutation in the EGF receptor.

33. 33. The pharmaceutical composition of claim 32, wherein the EGF receptor comprises a mutation in exon 20.

34. 34. The pharmaceutical composition of claim 33, wherein the EGF receptor comprises an insertion in exon 20.

35. 35. The pharmaceutical composition of claim 34, wherein the EGF receptor comprises an insertion between amino acids V769 and D770 and / or between D770 and N771.

36. 36. The pharmaceutical composition of claim 35, wherein the insertion is an ASV and / or SVD insertion.

37. 35. The pharmaceutical composition of claim 34, wherein the EGF receptor comprises an ASV insertion between amino acids V769 and D770 and / or an SVD insertion between amino acids D770 and N771.

38. A method for aiding in the selection of patients for cancer treatment with a compound of general formula (I) according to any of claims 1 to 4, said method comprising detecting the presence of a mutation in exon 20 of the EGF receptor in a biological sample of a subject, the presence of said mutation indicating that the patient should be treated with said compound.

39. A pharmaceutical composition for use in a method for treating a cancer patient, said pharmaceutical composition comprising a compound of general formula (I) as defined in any one of claims 1 to 4, said method comprising administering to a subject an anti-EGF receptor therapy in combination with said compound of general formula (I), wherein the subject is selected for treatment by detecting the presence of a mutation in exon 20 of the EGF receptor in a biological sample of the subject.

40. 40. The pharmaceutical composition of claim 39, wherein the EGF receptor comprises an insertion in exon 20.

41. 41. The pharmaceutical composition of claim 40, wherein the EGF receptor comprises an insertion between amino acids V769 and D770 and / or between amino acids D770 and N771.

42. 42. The pharmaceutical composition of claim 41, wherein the insertion is an ASV and / or SVD insertion.

43. 41. The pharmaceutical composition of claim 40, wherein the EGF receptor comprises an ASV insertion between amino acids V769 and D770 and / or an SVD insertion between amino acids D770 and N771.

44. 40. The pharmaceutical composition according to any one of claims 20, 22 and 39, wherein the cancer is lung cancer and / or metastases thereof.

45. 45. The pharmaceutical composition of claim 44, wherein the lung cancer is a lung cancer with a mutant EGFR with an in-frame deletion in exon 19 or a point mutation in exon 21 and / or a metastasis thereof.

46. 46. ​​The pharmaceutical composition of claim 45, wherein the in-frame deletion in exon 19 is EGFR E746_A750del.

47. 46. ​​The pharmaceutical composition of claim 45, wherein the point mutation in exon 21 is L858R.

48. 40. The pharmaceutical composition of any one of claims 20, 22 and 39, wherein the cancer is a lung cancer with a mutant EGFR with a D770_N771insSVD C797S, E746_A750del C797S, or L858R C797S acquired resistance mutation, and / or a metastasis thereof.

49. 40. The pharmaceutical composition of any one of claims 20, 22 and 39, wherein the cancer is lung cancer with a mutant ERBB2 having an exon 20 insertion mutation and / or a metastasis thereof.

50. 50. The pharmaceutical composition of claim 49, wherein the mutant ERBB2 having an exon 20 insertion mutation is ERBB2 A775_G776insYVMA.

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