4h-pyrrolo[3,2-c]pyridin-4-one compounds

Abstract

Compounds of formula (I), processes for their preparation and their use as pharmaceuticals.

Description

Invention Field

[0001] This invention relates to substituted 4H-pyrrolo[3,2-c]pyridine-4-one compounds, their preparation methods, and their uses. Background of the Invention

[0002] 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 the activation of the 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 the four exons (exons 18–21) of the EGFR kinase domain (Paez et al., 2004). The most common activating mutations in EGFR are point mutations in exon 21 (replacing leucine with arginine (L858R)) and small-frame deletions in exon 19 (del19 / del746–750) that remove four amino acids (Pao et al., 2010). FDA-approved inhibitors targeting EGFR exon 18, 19, and 21 mutations, such as gefitinib, erlotinib, and afatinib, are effective in patients, but responses are generally not durable (Mok et al., 2009; Sequist et al., 2013). These patients often develop resistance upon acquiring a second mutation, T790M (Pao et al., 2005). Second-generation inhibitors, such as afatinib, irreversibly target this mutation but remain effective inhibitors of wild-type EGFR, leading to dose-limiting toxicities and lack of efficacy in patients. Third-generation irreversible inhibitors, osimertinib, maximize activity against T790M while minimizing activity against wild-type EGFR, are effective in patients with T790M mutations and are currently the standard of care for T790M-positive patients (Mok et al., 2017). Osimertinib has also been approved as first-line therapy for patients with EGFR exon 19 or 21 mutations (Soria et al., 2018).

[0004] However, patients can also develop resistance to irreversible third-generation EGFR inhibitors, such as osimertinib. One of the main identified mechanisms of osimertinib resistance is a mutation at position 797 cysteine ​​to serine, resulting in the loss of covalent interaction between the cysteine ​​and the EGFR inhibitor, leading to irreversible EGFR inhibitor desensitization. Patients at this stage currently have limited treatment options (Thress et al., 2015; Oxnard et al., 2018). Such C797S mutations can also occur when osimertinib is used as first-line therapy in the absence of the T790M mutation (Ramalingham et al., 2018a; Ramalingham et al., 2018b). A novel targeted therapy specifically addressing EGFR-C797S acquired resistance mutations would be highly beneficial for these patients.

[0005] In contrast, except for A763_Y764insFQEA, the in-frame insertion of EGFR exon 20 is resistant to all clinically approved EGFR inhibitors at doses achievable in lung cancer patients and represents unmet medical needs (Yasuda et al., 2013).

[0006] Patients with EGFR exon 20 insertions (e.g., V769_D770insASV, D770_N771insSVD, D770_N771insNPG, N771_P772insH, H773_V774insH, H773_V774insNPH, V774_C775insHV) have shown particularly low 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 confirmed with first-generation inhibitors erlotinib and gefitinib, as well as second-generation inhibitor afatinib (Chen et al., 2016; Yang et al., 2015).

[0007] Therefore, the current standard treatment for patients with EGFR exon 20 insertion is chemotherapy.

[0008] The same resistance was also observed in exon 20 insertion mutations in another member of the EGF receptor family (Arcila et al., 2012) of ERBB2 (e.g., ERBB2A775_G776insYVMA, which has the highest prevalence) and some uncommon EGFR mutations such as L681Q (Chiu et al., 2015).

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

[0010] Recently, new preclinical data for two other compounds have been published, showing activity against EGFR exon 20 insertion: TAS6417 (TCP-064) and compound 1a (Hasako et al., 2018; Jang et al., 2018). Clinical results are not yet available for either of these compounds.

[0011] In summary, mutant EGFR is a promising drug target for cancer treatment. In particular, due to EGFR exon 20 insertions, patients with primary resistance to approved anti-EGFR therapies have had very limited treatment options to date, and there is a great need for new alternative and / or improved therapies to provide effective and well-tolerated treatments for these patients (Oxnard et al., 2013). Therefore, effective inhibitors of mutant EGFR, especially those with exon 20 insertion mutations, exhibit higher selectivity compared to wild-type EGFR and represent valuable compounds that can be used as monotherapy or in combination with other drugs to complement treatment options. Invention Overview

[0013] This invention provides compounds that inhibit mutant EGFRs (particularly EGFRs containing one or more exon 20 insertion mutations, L858R mutations, or in-small-frame deletions of exon 19) with or without the C797S mutation. Furthermore, these compounds exhibit reduced activity against wild-type EGFR.

[0014] It has now been discovered that the compounds of the present invention possess surprising and advantageous properties.

[0015] In particular, it has been surprisingly found that the compounds of the present invention effectively inhibit mutant EGFRs with exon 20 insertion mutations, especially those mutant EGFRs carrying the D770_N771ins SVD exon 20 insertion, with an IC50 value of 1.5%.50 Less than 5 nM. Furthermore, these compounds have been found to exhibit cellular potency below 1 μM in BA / F3 cell lines carrying exon 20 insertions of EGFR V769_D770insASV, D770_N771insSVD, D770_N771insNPG, N771_P772insH, or H773_V774insNPH. Additionally, the compounds described herein are active in BA / F3 cell lines carrying D770_N771insSVD C797S. Furthermore, the compounds described in this article effectively inhibit the proliferation of BA / F3 cell lines carrying EGFR activating mutations (with or without C797S acquired resistance mutations (EGFR E746_A750del, L858R, E746_A750del C797S, L858R C797S), uncommon EGFR mutations (EGFR L681Q), or ERBB2 exon 20 insertion A775_G776insYVMA).

[0016] Surprisingly, these compounds also showed at least 5-fold selectivity in anti-proliferation assays of BA / F3 cell lines carrying EGFR D770_N771ins SVD exon 20 insertions compared to BA / F3 cells carrying wild-type EGFR, and therefore could be used to treat or prevent diseases with uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune responses or inappropriate cellular inflammatory responses, or diseases accompanied by uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune responses or inappropriate cellular inflammatory responses, wherein the uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune responses or inappropriate cellular inflammatory responses... The answer is mediated by mutated EGFR with exon 20 insertion mutations, and / or reduces (or blocks) the proliferation of cells carrying EGFR exon 20 insertion mutations, such as hematologic malignancies, solid tumors and / or their metastases, such as leukemia and myelodysplastic syndromes, malignant lymphomas, head and neck tumors including brain tumors and brain metastases, thoracic tumors including non-small cell lung tumors and small cell lung tumors, gastrointestinal tumors, endocrine tumors, breast tumors and other gynecological tumors, urinary system tumors including kidney tumors, bladder tumors and prostate tumors, skin tumors and sarcomas, and / or their metastases. Summary of the Invention

[0017] According to a first aspect, the present invention relates to compounds of formula (I), or N-oxides, salts, or tautomers of said compounds, or salts of said N-oxides or tautomers.

[0018]

[0019] in:

[0020] R 1 Represents methyl, ethyl, trifluoromethyl, 2,2-difluoroethyl, cyano, chlorine, bromine, methoxy, or difluoromethoxy;

[0021] R 2 Represents hydrogen, methyl, ethyl, fluorine, chlorine, or bromine;

[0022] R 3 Represents hydrogen or fluorine;

[0023] R 4 Represents hydrogen or methyl;

[0024] R 5 Each time it appears, it independently represents hydrogen, trifluoromethyl, or C1-C3 alkyl, R 5 It can bond with any carbon atom in the ring;

[0025] R 6 Each time it appears, it independently represents hydrogen, C1-C3-alkyl, or C1-C3-haloalkyl;

[0026] R 7 Represents C1-C3-alkyl or C2-C3-haloalkyl;

[0027] R 8 Represents C1-C3-alkyl or C2-C3-haloalkyl;

[0028] X represents NR 7 Or O;

[0029] Y represents NR 8 Or O;

[0030] m represents 0, 1, 2, or 3;

[0031] n represents 0 or 1.

[0032] In some implementations, at least two R 5 The group is a twin group (i.e., connected to the same carbon atom).

[0033] In a second aspect, the present invention relates to compounds of formula (I) as described above, or N-oxides, salts, or tautomers of said compounds, or salts of said N-oxides or tautomers.

[0034] in:

[0035] R 1 Represents methyl, ethyl, chloro, methoxy, or difluoromethoxy;

[0036] R 2 Represents methyl, ethyl, fluorine, or chlorine;

[0037] R 3 Represents hydrogen or fluorine;

[0038] R 4 Represents hydrogen or methyl;

[0039] R 5 Represents hydrogen, methyl, or trifluoromethyl, R 5 It can bond with any carbon atom in the ring;

[0040] R 6 Represents hydrogen, methyl, or trifluoromethyl;

[0041] R 7 Represents C1-C2-alkyl or C2-C3-fluoroalkyl;

[0042] R 8 Represents C1-C2-alkyl or C2-C3-fluoroalkyl;

[0043] X represents NR 7 Or O;

[0044] Y represents NR 8 Or O;

[0045] m represents 0, 1, or 2;

[0046] n represents 0 or 1.

[0047] In a third aspect, the present invention relates to compounds of formula (I) as described above, or N-oxides, salts, or tautomers of said compounds, or salts of said N-oxides or tautomers.

[0048] in:

[0049] R 1 Represents methyl, ethyl, chloro, or methoxy;

[0050] R 2 Represents fluorine or chlorine;

[0051] R 3 Represents hydrogen or fluorine;

[0052] R 4 Represents hydrogen;

[0053] R 5 R represents hydrogen or methyl. 5 It can bond with any carbon atom in the ring;

[0054] R 6 Represents hydrogen;

[0055] R 7 Represents methyl;

[0056] R 8 Represents methyl, 2,2,2-trifluoroethyl, or 2,2-difluoroethyl;

[0057] X represents NR 7 Or O;

[0058] Y represents NR 8 Or O;

[0059] m represents 0, 1, or 2;

[0060] n represents 0 or 1.

[0061] In a fourth aspect, the present invention relates to compounds of formula (I) as described above, selected from:

[0062] 3-(3-chloro-2-methoxyaniline)-2-{3-[(1,4-dioxane-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0063] 3-(3-chloro-2-methoxyaniline)-2-(3-{[(2S)-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0064] 3-(3-chloro-2-methoxyaniline)-2-(3-{[(2R)-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0065] 2-{3-[(1,4-dioxane-2-yl)methoxy]pyridin-4-yl}-3-(3-fluoro-2-methoxyaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0066] 2-(3-{[(2S)-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0067] 2-(3-{[(2R)-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0068] 3-(2,3-dichloroanilino)-2-{3-[(1,4-dioxane-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0069] 3-(2,3-dichloroanilino)-2-(3-{[(2S)-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0070] 3-(2,3-dichloroanilino)-2-(3-{[(2R)-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0071] 3-(3-chloro-2-methylaniline)-2-{3-[(1,4-dioxane-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0072] 3-(3-chloro-2-methoxyaniline)-2-(3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0073] 3-(3-fluoro-2-methoxyaniline)-2-{3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0074] 3-(3-fluoro-2-methoxyaniline)-2-(3-{[(2R)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0075] 3-(3-fluoro-2-methoxyaniline)-2-(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0076] 3-(3-chloro-2-methoxyaniline)-2-{3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0077] 3-(3-chloro-2-methoxyaniline)-2-(3-{[(2R)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0078] 3-(3-chloro-2-methoxyaniline)-2-(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0079] 3-(3-chloro-5-fluoro-2-methoxyaniline)-2-(3-{[4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0080] 3-(3-chloro-5-fluoro-2-methoxyaniline)-2-(3-{[1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0081] 3-(3-fluoro-2-methoxyaniline)-2-(3-{[(3S)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0082] 3-(3-chloro-2-methoxyaniline)-2-(3-{[(3S)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0083] 2-(3-{[(2S)-4-(2,2-difluoroethyl)morpholin-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0084] 3-(3-fluoro-2-methoxyaniline)-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

[0085] 3-(3-chloro-2-methoxyaniline)-2-{3-[2-(4-dioxane-2-yl)ethoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0086] 3-(3-chloro-2-methoxyanilino)-2-(3-{2-[(2R)-1,4-dioxane-2-yl]ethoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0087] 3-(3-chloro-2-methoxyaniline)-2-(3-{2-[(2S)-1,4-dioxane-2-yl]ethoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0088] 3-(3-chloro-5-fluoro-2-methoxyaniline)-2-(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0089] 3-(3-chloro-5-fluoro-2-methoxyaniline)-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

[0090] 3-(3-chloro-2-ethylanilino)-2-{3-[(4-methylmorpholino-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0091] 3-(3-chloro-2-methoxyaniline)-2-{3-[(5,5-dimethyl-1,4-dioxane-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0092] 3-(3-chloro-2-methoxyaniline)-2-(3-{[(2R)-5,5-dimethyl-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0093] 3-(3-chloro-2-methoxyaniline)-2-(3-{[(2S)-5,5-dimethyl-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0094] 2-(3-{[(2R)-5,5-dimethyl-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0095] 2-(3-{[(2S)-5,5-dimethyl-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0096] 2-(3-{2-[(2R)-1,4-dioxane-2-yl]ethoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0097] 2-(3-{2-[(2S)-1,4-dioxane-2-yl]ethoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0098] 3-(3-fluoro-2-methoxyaniline)-2-(3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0099] 2-{3-[(5,5-dimethyl-1,4-dioxane-2-yl)methoxy]pyridin-4-yl}-3-(3-fluoro-2-methylaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0100] 2-(3-{[(2S)-5,5-dimethyl-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methylaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0101] 3-[2-(2,2-difluoroethyl)-3-fluoroaniline]-2-{3-[(1,4-dioxane-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0102] 3-[2-(2,2-difluoroethyl)-3-fluoroaniline]-2-(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0103] 3-(3-chloro-2-methylaniline)-2-(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0104] 3-(3-chloro-2-methylaniline)-2-(3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0105] 3-(3-chloro-2-methylaniline)-2-{3-[(5,5-dimethyl-1,4-dioxane-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0106] 3-(3-chloro-2-methylaniline)-2-(3-{[(2S)-5,5-dimethyl-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0107] 3-(3-chloro-2-methylaniline)-2-(3-{[(2R)-5,5-dimethyl-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0108] 2-{3-[(1,4-dioxane-2-yl)methoxy]pyridin-4-yl}-3-(3-fluoro-2-methylaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0109] 2-(3-{[(2S)-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methylaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0110] 2-(3-{[(2R)-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methylaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0111] 3-(3-chloro-2-methylaniline)-2-(3-{[(2S)-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0112] 3-(3-chloro-2-methylaniline)-2-(3-{[(2R)-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0113] 3-(3-chloro-2-ethylanilino)-2-{3-[(1,4-dioxane-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0114] 3-(3-chloro-2-ethylanilino)-2-(3-{[(2S)-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0115] 3-(3-chloro-2-ethylanilino)-2-(3-{[(2R)-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0116] 3-(3-chloro-2-ethylanilino)-2-(3-{[(2R)-4-methylmorpholino-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0117] 3-(3-chloro-2-ethylanilino)-2-(3-{[(2S)-4-methylmorpholino-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0118] 3-(3-chloro-2-methoxyanilino)-2-(3-{1-[1,4-dioxane-2-yl]ethoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0119] 3-(3-chloro-2-methoxyaniline)-2-(3-{(1S)-1-[(2S)-1,4-dioxane-2-yl]ethoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0120] 3-(3-chloro-2-methoxyaniline)-2-(3-{(1S)-1-[(2R)-1,4-dioxane-2-yl]ethoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0121] 3-(3-chloro-2-methoxyaniline)-2-(3-{(1R)-1-[(2S)-1,4-dioxane-2-yl]ethoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0122] 3-(3-chloro-2-methoxyaniline)-2-(3-{(1R)-1-[(2R)-1,4-dioxane-2-yl]ethoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0123] 3-(3-fluoro-2-methylaniline)-2-{3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0124] 3-(3-fluoro-2-methylaniline)-2-(3-{[(2R)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0125] 3-(3-fluoro-2-methylaniline)-2-(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0126] 2-(3-{[1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3-fluoroaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0127] 2-(3-{[(2R)-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3-fluoroaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0128] 2-(3-{[(2S)-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3-fluoroaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0129] 2-(3-{[5,5-dimethyl-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3-fluoroaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0130] 2-(3-{[(2R)-5,5-dimethyl-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3-fluoroaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0131] 2-(3-{[(2S)-5,5-dimethyl-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3-fluoroaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0132] 3-(3-chloro-2-methoxyanilino)-2-[3-({1-[4-methylmorpholino-2-yl]ethyl}oxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0133] 3-(3-chloro-2-methoxyaniline)-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

[0134] 3-(3-chloro-2-methoxyaniline)-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

[0135] 3-(3-chloro-2-methoxyaniline)-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

[0136] 3-(3-chloro-2-methoxyaniline)-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.

[0137] Another aspect of the invention relates to compounds of formula (I), which exist in the form of their salts.

[0138] It should be understood that this invention relates to any embodiment or aspect of the invention of compounds of the above general formula (I) and any sub-combination thereof.

[0139] More specifically, the present invention covers compounds of general formula (I) disclosed in the following embodiment section of this text.

[0140] According to another aspect, the present invention covers a method for preparing the compounds of the present invention, the method comprising the steps described in the experimental section herein.

[0141] Another embodiment of the present invention is an analogue of the compound disclosed in the claims or the disclosed example compounds, and sub-combinations thereof.

[0142] definition

[0143] It should be understood that the embodiments disclosed herein are not intended to be construed as single, unrelated embodiments. Features discussed in connection with one embodiment or aspect of the invention are intended to be disclosed also in connection with other embodiments or aspects of the invention shown herein. If, in one instance, a particular feature is not disclosed with one embodiment or aspect of the invention but is disclosed with another embodiment or aspect, those skilled in the art will understand that this does not necessarily mean that the feature will not be disclosed with the other embodiments or aspects of the invention. Those skilled in the art will understand that the purpose of this application is to disclose the features also with respect to other embodiments or aspects of the invention, but this is only for 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 invention relating to compounds of formula (I) as defined herein also relate to more specific embodiments of compounds of formula (I), such as, but not limited to, compounds of formula (Ia), and vice versa.

[0144] It should also be understood that the contents of the documents cited herein are incorporated in their entirety by reference, for example, for enabling purposes, i.e., when a method is discussed, for example, whose details are described in the document. This approach helps to make the length of this specification manageable.

[0145] Unless otherwise stated, as described herein, optionally substituted components may be substituted one or more times independently of each other in any possible position. Each definition is independent when any variable appears more than once in any component. For example, when R... 1 R 1a R 1b R 1c R 2 R 3 and / or R 4 When R appears more than once in any compound of formula (I), 1 R 1aR 1b R 1c R 2 R 3 and R 4 Each customization is independent.

[0146] When a component consists of more than one part, such as C1-C4-alkoxy-C2-C4-alkyl, the possible positions of the substituents can be at any suitable position in any of these parts. A hyphen at the beginning or end of the component indicates the connection point with the remainder of the molecule. When the ring is substituted, the substituents can be at any suitable position on the ring, and if appropriate, on the nitrogen atom of the ring.

[0147] When used in this specification, the term "comprising" includes "consisting of".

[0148] If the description uses the phrases "as stated above" or "as above," it refers to any disclosure made on any of the aforementioned pages within this specification.

[0149] If the description uses the terms "as stated herein", "as described herein", "as provided herein", or "as stated in this text" or "as specified herein", it refers to any disclosure made on any of the foregoing or subsequent pages of this specification.

[0150] In the context of this invention, "suitable" means chemically capable of being prepared by methods within the knowledge of a person skilled in the art.

[0151] The terms used in this text may have the following meanings:

[0152] The terms “halogen atom,” “halogen-”, or “halogen-” should be understood to refer to fluorine, chlorine, bromine, or iodine atoms.

[0153] The term “C1-C6-alkyl” should be understood to mean a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 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 or their isomers. In particular, the group has 1, 2, 3 or 4 carbon atoms (“C1-C4-alkyl”), such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, and more particularly, the group has 1, 2 or 3 carbon atoms (“C1-C3-alkyl”), such as methyl, ethyl, n-propyl or isopropyl.

[0154] The term "C1-C4-haloalkyl" should be understood to refer to a straight-chain or branched saturated monovalent hydrocarbon group, wherein the term "C1-C4-alkyl" is defined as above, and wherein one or more hydrogen atoms are replaced by the same or different halogen atoms (i.e., one halogen atom is independent of another halogen atom). In particular, the halogen atom is F. The C1-C4-haloalkyl is, for example, -CF3, -CHF2, -CH2F, -CF2CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CF3, or -CH(CH2F)2.

[0155] The term "C2-C3-fluoroalkyl" should be understood to refer to a straight-chain or branched saturated monovalent hydrocarbon group, wherein the term "C2-C3-alkyl" is as defined above, and one or more hydrogen atoms are replaced by fluorine atoms. The C2-C3-fluoroalkyl group is, for example, -CF2CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CF3, or -CH(CH2F)2.

[0156] The term “C1-C4-alkoxy” should be understood as a straight-chain or branched saturated monovalent hydrocarbon group representing the formula -O-alkyl, wherein the term “alkyl” is as defined above, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, or sec-butoxy, or isomers thereof.

[0157] Unless otherwise defined, the terms “5-to-6-membered heterocyclic alkyl” or “5-to-6-membered heterocycle” shall be understood to mean a saturated monovalent monocyclic hydrocarbon ring containing 4 or 5 carbon atoms and a heteroatom-containing group selected from O and NR, wherein R represents a hydrogen atom, a C1-C3-alkyl or a C1-C3-haloalkyl, and the heterocyclic alkyl can be attached to the rest of the molecule by any one of the carbon atoms.

[0158] Specifically, but not limited to, the heterocyclic alkyl group may be a five-membered ring such as tetrahydrofuranyl or pyrazolyl, or a six-membered ring such as tetrahydropyranyl or piperidinyl.

[0159] As used throughout this document, the term "C1-C6," for example, in the context of the definitions of "C1-C6-alkyl" or "C1-C6-haloalkyl," should be understood to mean an alkyl group having a limited number of carbon atoms from 1 to 6, i.e., 1, 2, 3, 4, 5, or 6 carbon atoms. It should be further understood that the term "C1-C6" should be interpreted as any subrange contained therein, such as C1-C6, C2-C6, C3-C6, C1-C2, C1-C3, and especially C1-C2, C1-C3, C1-C4.

[0160] As used throughout this document, the term "C1-C4" as used, for example in the context of the definitions of "C1-C4-alkyl," "C1-C4-haloalkyl," "C1-C4-alkoxy," or "C1-C4-haloalkoxy," should be understood to mean an alkyl group having a limited number of carbon atoms, i.e., 1, 2, 3, or 4 carbon atoms. It should be further understood that the term "C1-C4" should be interpreted as any subrange contained therein, such as C1-C4, C2-C4, C3-C4, C1-C2, C1-C3, especially C1-C2, C1-C3, C1-C4, and, in the case of "C1-C6-haloalkyl" or "C1-C4-haloalkoxy," even more particularly C1-C2.

[0161] Furthermore, as used herein, and throughout this document, for example in the context of the definition of “C3-C6-cycloalkyl,” the term “C3-C6” should be understood to mean a cycloalkyl group having a limited number of carbon atoms, i.e., 3, 4, 5, or 6 carbon atoms. It should be further understood that the term “C3-C6” should be interpreted as any subrange contained herein, such as C3-C6, C4-C5, C3-C5, C3-C4, C4-C6, C5-C6; particularly C3-C6.

[0162] The term "substituted" refers to the selective replacement of one or more hydrogen atoms of a specified atom by a designated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound.

[0163] The term "optionally substituted" refers to being optionally substituted by a specific group, radical, or partial group.

[0164] Substituents in a ring system refer to substituents that are connected to an aromatic or non-aromatic ring system, for example, the substituents replacing hydrogen available in the ring system.

[0165] The term “one or more” as used herein, for example in the definition of substituents in the general formula compounds of this invention, should be understood to mean “1, 2, 3, 4 or 5, especially 1, 2, 3 or 4, more particularly 1, 2 or 3, and even more particularly 1 or 2”.

[0166] Compounds of general formula (I) can exist in the form of isotopic variants. The present invention therefore includes one or more isotopic variants of compounds of general formula (I), particularly deuterium-containing compounds of general formula (I).

[0167] The term "isotope variant" for a compound or reagent is defined as a compound that exhibits one or more isotopes that constitute the compound in a non-natural proportion.

[0168] The term “isotopic variant of a compound of general formula (I)” is defined as a compound of general formula (I) that exhibits one or more isotopes constituting the compound in non-natural proportions.

[0169] The phrase "non-natural proportion" should be understood as indicating that the proportion of such isotopes is higher than their natural abundance. The natural abundance of isotopes applicable in this context is described in "Isotopic Compositions of the Elements 1997", Pure Appl. Chem., 70(1), 217-235, 1998. Examples of 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.

[0170] Regarding the treatment and / or prevention of the conditions specified herein, isotopic variants of compounds of general formula (I) in one embodiment contain deuterium (“compounds of general formula (I) containing deuterium”). This includes one or more radioactive isotopes, such as… 3 H or 14 Isotopic variants of compounds of general formula (I) C can be used, for example, in studies of drug and / or substrate tissue distribution. These isotopes are particularly preferred due to their ease of incorporation and detectability. Positron emission isotopes, for example... 18 F or 11 C can be incorporated into compounds of general formula (I). These isotopic variants of compounds of general formula (I) can be used for in vivo imaging applications. Deuterium-containing and... 13 Compounds of general formula (I) of C can be used for mass spectrometry analysis in preclinical or clinical research contexts (HJ Leiis et al., Curr. Org. Chem., 1998, 2, 131).

[0171] Isotopic variants of compounds of general formula (I) can typically be prepared by methods known to those skilled in the art (e.g., those described in the schemes and / or examples herein) by replacing the reagent with an isotopic variant of the reagent (in one embodiment, a deuterium-containing reagent). Depending on the desired deuteration position, in some cases, deuterium derived from D₂O can be directly incorporated into the compound or into a reagent that can be used to synthesize such compounds (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 the molecule. Catalytic deuteration of alkene bonds (HJ Leiis et al., Curr. Org. Chem., 1998, 2, 131; J. R. Morandi et al., J. Org. Chem., 1969, 34(6), 1889) and alkynes (NH Khan, J. Am. Chem. Soc., 1952, 74(12), 3018; S. Chandrasekhar et al., Tetrahedron, 2011, 52, 3865) is a rapid pathway for the incorporation of deuterium. Metal catalysts (i.e., Pd, Pt, and Rh) in the presence of deuterium can be used to directly replace hydrogen with deuterium in functionalized hydrocarbons (J. G. Atkinson et al., US Patent 3966781). A wide variety of deuterating agents 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 CombiPhosCatalysts, Inc., Princeton, NJ, USA. Further information on existing techniques for deuterium-hydrogen exchange is given in, for example, 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.

[0172] 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 by one or more deuterium atoms and in which the abundance of deuterium at each deuteration position of the compound of general formula (I) is higher than the natural abundance of deuterium (which is about 0.015%). In particular, in compounds of deuterium-containing 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%, in one embodiment greater than 90%, 95%, 96%, or 97%, and in other embodiments greater than 98% or 99% at said position. It should be understood that the abundance of deuterium at each deuteration position is independent of the abundance of deuterium at other deuteration positions.

[0173] The selective incorporation of one or more deuterium atoms into compounds of general formula (I) can alter the physicochemical properties of the molecule (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 characteristics, and can lead to changes in the ratio of the parent compound to the metabolite or the amount of metabolite formed. These changes can lead to certain therapeutic benefits and may therefore be preferred in some cases. Decreased metabolic rate and metabolic switching resulting from altered metabolite ratios have been reported (DJ Kushner et al., Can. J. Physiol. Pharmacol., 1999, 77, 79; AEMutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). These changes involving the parent drug and metabolites can have significant effects on the pharmacokinetics, tolerability, and potency of deuterium-containing compounds of general formula (I). In some cases, deuteration reduces or eliminates the formation of undesirable or toxic metabolites and increases the formation of desired metabolites (e.g., Nevirapine: AMSharma 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 reduce systemic clearance. This results in an increased biological half-life of the compound. Potential clinical benefits include the ability to maintain similar systemic exposure while reducing peak levels and increasing trough levels. This may lead to lower side effects and enhanced efficacy, depending on the specific compound's pharmacokinetic / pharmacodynamic relationship. Indipram (AJ Morales et al., Abstract 285, The 15) thExamples of this deuterium effect include the North American Meeting of the International Society of Xenobiotics, San Diego, CA, October 12-16, 2008; ML-337 (CJ Wenthhur et al., J. Med. Chem., 2013, 56, 5208); and Odanacatib (K. Kassahun et al., WO2012 / 112363). Other examples have also been reported where a reduced metabolic rate leads to increased drug exposure without altering systemic clearance (e.g., rofecoxib: F. Schneider et al., Arzneim. Forsch. Drug. Res., 2006, 56, 295; teclarevir: F. Maltais et al., J. Med. Chem., 2009, 52, 7993). Deuterated drugs exhibiting this effect may have reduced dosing requirements (e.g., fewer dosing frequencies or lower doses to achieve the desired effect) and / or produce lower metabolite loads.

[0174] Compounds of general formula (I) can possess multiple potential sites for metabolic attack. To optimize the aforementioned effects on physicochemical properties and metabolic characteristics, deuterium-containing compounds of general formula (I) with one or more deuterium-hydrogen exchange patterns can be selected. In particular, the deuterium atom in the deuterium-containing compound of general formula (I) may be attached to a carbon atom and / or located in those compounds of general formula (I) that are metabolic enzymes such as cytochrome P. 450 The location of the attack site.

[0175] When the plural forms of words such as compound, salt, polymorph, hydrate, and solvate are used in this article, they should be understood to also represent the singular compound, salt, polymorph, isomer, hydrate, and solvate.

[0176] "Stable compound" or "stable structure" refers to a compound that is robust enough to withstand separation from the reaction mixture to a useful purity and formulation into an effective therapeutic agent.

[0177] The compounds of the present invention may contain one or more asymmetric centers, depending on the position and nature of the various substituents desired. The asymmetric carbon atom may exist in (R) or (S) configurations, yielding racemic mixtures with one asymmetric center and diastereomeric mixtures with multiple asymmetric centers. In some cases, asymmetry may also exist due to hindered rotation around a particular bond, for example, where the central bond connects two substituted aromatic rings of a particular compound.

[0178] The substituents on the ring may also be present in cis or trans form. It is intended that all such configurations (including enantiomers and diastereomers) are included within the scope of this invention.

[0179] Preferred compounds are those that produce the more desired biological activity. Isolated, pure, or partially purified isomers and stereoisomers, or racemic mixtures or diastereomer mixtures of the compounds of this invention, are included within the scope of this invention. Purification and isolation of such substances can be achieved using standard techniques known in the art.

[0180] Optical isomers can be obtained by resolving racemic mixtures using conventional methods, such as by forming diastereomer salts using optically active acids or bases, or by forming covalent diastereomers. Examples of suitable acids are tartaric acid, diacetyltartaric acid, benzoyltartaric acid, and camphorsulfonic acid. Mixtures of diastereomers 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. An optically active base or acid is then released from the separated diastereomer salts. A different method for separating optical isomers involves using chiral chromatography (e.g., chiral HPLC columns) with or without conventional derivatization, which can be optimally selected to maximize the separation of enantiomers. Suitable chiral HPLC columns are manufactured by Daicel, such as Chiracel OD and Chiracel OJ, all of which are routinely used. Enzymatic separation can also be used with or without derivatization. Similarly, the optically active compounds of the present invention can be obtained by chiral synthesis using optically active raw materials.

[0181] To distinguish between different types of isomers, IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976) is referenced.

[0182] This invention includes all possible stereoisomers of the compounds of this invention, which are either single stereoisomers or any mixtures of said stereoisomers (e.g., R- or S-isomers or E- or Z-isomers) in any ratio. The separation of single stereoisomers, such as single enantiomers or single diastereomers, of the compounds of this invention can be achieved by any suitable prior art method, such as chromatography, particularly chiral chromatography.

[0183] Furthermore, the compounds of the present invention can exist in tautomer form. For example, any compound of the present invention containing a pyrazole moiety as a heteroaryl group can exist, for example, in the form of a 1H tautomer or a 2H tautomer, or even in any amount of a mixture of the two tautomers; or any compound of the present invention containing a triazole moiety can exist, for example, in the form of a 1H tautomer, a 2H tautomer, or a 4H tautomer, or even in any amount of a mixture of the 1H, 2H, and 4H tautomers, i.e.:

[0184]

[0185] This invention includes all possible tautomers of the compounds of this invention, in the form of a single tautomer or any mixture of said tautomers in any proportion.

[0186] Furthermore, the compounds of the present invention may exist in the form of N-oxides, which are defined as compounds in which at least one nitrogen atom is oxidized. The present invention includes all such possible N-oxides.

[0187] The present invention also relates to useful forms of compounds as disclosed herein, such as metabolites, hydrates, solvates, prodrugs, salts, especially pharmaceutically acceptable salts, and coprecipitates.

[0188] The compounds of the present invention can exist in the form of hydrates or solvates, wherein the compounds of the present invention contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, can be stoichiometric or non-stoichiometric. In the case of stoichiometric solvates, such as hydrates, they may be hemi-solvates or hydrates, (semi-)solvates or hydrates, monosolvates or hydrates, sesquisolvates or hydrates, disolvates or hydrates, trisolvates or hydrates, tetrasolvates or hydrates, pentasolvates or hydrates, etc. The present invention includes all such hydrates or solvates.

[0189] Furthermore, the compounds of the present invention can exist in a free form, such as as a free base or free acid or zwitterion, or as a salt. The salt can be any salt, which can be an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt commonly used in pharmaceutical science.

[0190] The term "pharmaceutical-acceptable salt" refers to a relatively non-toxic inorganic or organic acid addition salt of the compounds of the present invention. See, for example, SMBerge et al., "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19.

[0191] Suitable pharmaceutically acceptable salts of the compounds of the present invention can be, for example, acid addition salts of the compounds of the present invention that carry nitrogen atoms in the chain or ring and have sufficient basicity, such as acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, bisulfuric acid, phosphoric acid, or nitric acid, or acid addition salts formed with organic acids such as formic acid, acetic acid, acetoacetic 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, and digluconic acid. (acid), 3-hydroxy-2-naphthylcarboxylic acid, nicotinic acid, pyruvic acid, pectinic acid, persulfate, 3-phenylpropionic acid, picric acid, tervamolonic acid, 2-hydroxyethanesulfonic acid, itaconic acid, aminosulfonic acid, trifluoromethanesulfonic acid, dodecyl sulfate, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic 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, glucohepanoic acid, glycerophosphate, aspartic acid, sulfosalicylic acid, hemisulfuric acid, or thiocyanate.

[0192] Alternatively, another suitable pharmaceutically acceptable salt of the compounds of the present invention having sufficient acidity is an alkali metal salt such as a sodium or potassium salt, an alkaline earth metal salt such as a calcium or magnesium salt, an ammonium salt, or a salt formed with an organic base that provides a physiologically acceptable cation, such as a salt formed with N-methylglucosamine, dimethylglucosamine, ethylglucosamine, lysine, dicyclohexylamine, 1,6-hexanediamine, ethanolamine, glucosamine, sarcosine, serine, trihydroxymethylaminomethane, aminopropylene glycol, Sovak base, 1-amino-2,3,4-butanetriol. In addition, basic nitrogen-containing groups can be quaternized with the following reagents: lower alkyl halides, such as chlorides, bromides, and iodides of methyl, ethyl, propyl, and butyl; dialkyl sulfates, such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and dipentyl sulfate; long-chain halides, such as chlorides, bromides, and iodides of decyl, lauryl, myristyl, and stearyl; and aralkyl halides, such as bromides of benzyl and phenethyl.

[0193] Those skilled in the art will also recognize that the acid addition salts of the claimed compounds can be prepared by reacting the compounds with a suitable inorganic or organic acid using any of a variety of known methods. Alternatively, the alkali metal and alkaline earth metal salts of the acidic compounds of the present invention can be prepared by reacting the compounds of the present invention with a suitable base using various known methods.

[0194] This invention includes all possible salts of the compounds of this invention, which may be a single salt or any mixture of said salts in any proportion.

[0195] In this text, particularly in the Examples section, when the compounds are mentioned as salts of the corresponding bases or acids, the exact stoichiometric composition of the salts obtained by the various preparation and / or purification methods is unknown in most cases when referring to the intermediates and examples of the invention.

[0196] Unless otherwise specified, suffixes in chemical names or structural formulas such as "hydrochloride", "trifluoroacetate", "sodium salt" or "x HCl", "x CF3COOH", "x Na" are not considered part of the chemical name or structural formula. + "It should not be understood as a stoichiometric specification, but simply as a salt form."

[0197] This is similarly applicable to cases where a solvate, such as a hydrated synthetic intermediate or an example compound or its salt, having an unknown stoichiometric composition (if defined) has been obtained by the described preparation and / or purification methods.

[0198] The salts include water-insoluble salts and, in particular, water-soluble salts.

[0199] Furthermore, this invention covers derivatives (biological precursors or prodrugs) of formula (I) compounds or their salts that are converted into formula (I) compounds or their salts in biological systems. The biological system is, for example, a mammalian organism, particularly a human subject. The biological precursor is converted into formula (I) compounds or their salts, for example, through metabolic processes.

[0200] The term “in vivo hydrolyzable ester” as used herein should be understood to mean an in vivo hydrolyzable ester of the compounds of the present invention containing a carboxyl or hydroxyl group, such as a pharmaceutically acceptable ester that can be hydrolyzed in the human or animal body to produce a parent acid or alcohol. Pharmaceutically acceptable esters suitable for the carboxyl group include, for example, alkyl esters, cycloalkyl esters and optionally substituted phenylalkyl esters, particularly benzyl esters, C1-C6 alkoxymethyl esters such as methoxymethyl esters, C1-C6 alkyloxymethyl esters such as pivaloyloxymethyl esters, phthaloyl esters, C3-C8 cycloalkoxy-carbonyloxy-C1-C6 alkyl esters such as 1-cyclohexylcarbonyloxyethyl ester; 1,3-dioxolen-2-oneylmethyl ester, such as 5-methyl-1,3-dioxolen-2-oneylmethyl ester; and C1-C6-alkoxycarbonyloxyethyl esters, such as 1-methoxycarbonyloxyethyl ester, and said esters may be formed on any carboxyl group of the compounds of the present invention.

[0201] The in vivo hydrolyzable esters comprising the compounds of the present invention include inorganic esters (e.g., phosphate esters), [α]acyloxyalkyl ethers, and related compounds that cleave to yield the parent hydroxyl group upon in vivo hydrolysis of the ester. Examples of [α]acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. Choice of groups for forming the in vivo hydrolyzable esters with the hydroxyl group includes alkylyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, alkoxycarbonyl (to yield alkyl carbonates), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to yield carbamates), dialkylaminoacetyl and carboxyacetyl. The present invention includes all such esters.

[0202] Furthermore, the present invention includes all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.

[0203] In the context of the properties of the compounds of this invention, the term "pharmacokinetic profile" refers to a single parameter or combination thereof as measured in suitable experiments, including permeability, bioavailability, exposure, and pharmacodynamic parameters such as duration of action or magnitude of pharmacological effect. Compounds with improved pharmacokinetic profiles can, for example, achieve the same effect at lower doses, achieve a longer duration of action, or a combination of both.

[0204] In this invention, the term "combination" is used as is known to those skilled in the art and can exist as a fixed combination, a non-fixed combination, or a kit-of-part.

[0205] In this invention, "fixed combination" is used as is 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 a unit dose or a single entity. An example of a "fixed combination" is a pharmaceutical composition in which the first active ingredient and the second active ingredient are present in a mixture for simultaneous administration, for example, 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 a single unit but not in a mixture.

[0206] In this invention, a non-fixed combination or "kit" 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 more than one unit. An example of a non-fixed combination or kit 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 may be administered separately, sequentially, simultaneously, concurrently, or in a staggered chronological order. Any such combination of the compound of formula (I) of this invention with the anticancer agent described below is an embodiment of this invention.

[0207] The term "(chemotherapy) anticancer agent" refers to any agent that reduces the survival or proliferation of cancer cells, and includes, but is not limited to, 131I-chTNT, abaricicliz, abiraterone, arubib, ado-trastuzumab emtansine, afatinib, aflibercept, interleukin, alenzusab, alendronate, retinoic acid, hexamethylmelamine, amifostine, aminoglutethimide, hexyl aminolevulinate, arubib, acridine, anastrozole, acesulfame K, and anethole. dithiolethione), angiotensin II, antithrombin III, aprepitant, acimomab, arglabin, arsenic trioxide, asparaginase, axitinib, azacitidine, baliximab, belotecone, bendamustine, belistat, bevacizumab, besalotine, bicalutamide, bisensitol, bleomycin, bortezomib, busherin, bosutinib, brentuximab Vedotin, Busulfan, Cabazitaxel, Cabozantinib, Leucovorin, Leucovorin, Capecitabine, Carolomumab, Carboplatin, Carfilzomib, Carmoflu, Carmustine, Caputoxumab, Celecoxib, Cimointerleukin, Ceritinib, Cetuximab, Chlordigesterone, Nitrogen Mustard, Sidofovir, Cinacalcet, Cisplatin, Cladribine, Clodronate, Clofarabine, Copanlisib, Crisantaspase, Cyclophosphamide, Cyproterone Acid, Cytarabine, Dacarbazine, Actinomycin D, Dabepoetin Alpha, Darafenib, Dasatinib, Dassatinib, Daunorubicin, Decitabine, Degarelix, DenileukinDiftitox, Denosumab, Deprothiopeptide, Delorelin, Dexazosin, Spirochloride dibromodiphenyltrimethylammonium, Didehydroepiandrosterone, Diclofenac, Docetaxel, Dolastron, Deoxyfluorouridine, Doxorubicin, Doxorubicin + Estrone, Drowanediol, Eculizumab, Eculizumab, Elimethicone, Eltrombopag, Endostatin, Enoxabin, Enzalutamide, Epirubicin, Cyclothrosine, Eberberine afa, Ephedracin, Zetaepine, Etaplatin, Eribulin, Erlotinib, Esomeprazole, Estradiol, Estrolimustine, Etoposide, Everolimus, Exemestane, Fazodazole, Fentanyl, Filgrastim, Fluoromethyltestosterone, Fluorouracil, Fluoride Darabine, Fluorouracil, Flutamide, Leucovorin, Formestane, Forsapidem, Formustine, Fulvestrant, Gadoxetine, Gadoxetine, Gadoxetine Meglumine, Gadoxetine, Gadoxetine, Gallium Nitrate, Garnierix, Gefitinib, Gemcitabine, Gemtuzumab, Carboxypeptidase, Glucooxim, GM-CSF, Goserelin, Granisetron, Granulocyte Colony-Stimulating Factor, Histamine Dihydrochloride, Histamine Relin, Hydroxyurea, I-125 Seed, Lansoprazole, Ibandronic Acid, Teimimozab, Ibrutinib, Idarubicin, Ifosfamide, Imatinib, Imiquimod, Inprofen, Pyridisetron, Incardronic Acid, Ingenol mebutate), α-interferon, β-interferon, γ-interferon, iodine, iodobenzylguanidine (123I), iodomeprazole, ipilimumab, irinotecan, itraconazole, ixaspirin, lanreotide, lapatinib, lasocholine, lenalidomide, letrozole, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, ergot ethionide, lobaplatin, lomustine, chlorpheniramine, masorofol, medroxyprogesterone acetate, melarisol, melphalan, meandrolone, mercaptopurine, guanosine sodium, methadone, methotrexate, methoxsalen, methyl levonorgestrel, methylprednisolone, methyltestosterone, methyltyrosine, mivamineptide, mitefocin, m iriplatin, dibromomannitol, mitotoxin, dibromo-eugenol, mitomycin, mitotoxin, mitotoxantrone, mogamulizumab, morasilidine, mopadrolol, morphine hydrochloride, morphine sulfate, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, natosine, nedaplatin, nerabine, neridonic acid, nivolumab penetreotide, nilotinib, nilumet, nimoprazole, nimotuzumab, nimustine, diammoniazoline, nivolumab, obinutuzumab, octreotide, ocfamumab, omacetaxelMepesuccinate), omeprazole, ondansetron, interleukin, orgotein, olimotoxin, osimertinib, oxaliplatin, oxycodone, hydroxymethylnidine, ozogarnicine, p53 gene therapy, paclitaxel, parivmin, palladium-103 seed, palonosetron, pamidronate, panitumumab, pantoprazole, pazopanib, pegaspargase, PEG-betaepoetin (methoxyPEG-betaepoetin) Pembrolizumab, Pefepristone, Pegylated interferon alpha-2b, Pemetrexed, Pentazocine, Pentostatin, Pelomycin, Perfluorobutane, Pephosamide, Pertuzumab, Hemolytic streptococcal preparations, Pilucarpine, Pirarubicin, Pixifen, Plexafor, Pucarimycin, Polyglucosamine, Estradiol polyphosphate, Polyvinylpyrrolidone + Sodium hyaluronate, Polysaccharide-K, Pomalidomide, Panatinib, Porphyrin sodium, Pozidinib, Pralatrexate, Prednimustine Prednisone, Procarbazine, Procodazole, Propranolol, Quinolotide, Rabeprazole, Racotumomab, Radium-223 Chloride, Radoltinib, Raloxifene, Raltitrexed, Ramosetron, Ramucirumab, Ramustin, Raburicase, Razoxen, Refametinib, Regorafenib, Rizedronate, Rhenium-186 etidronate, Rituximab, Romidixin, Romidipyridamole, Romotide, Ron icielib, samarium (153Sm)lexidronam, saxaglastine, satumomab, secretin, ciprofloxacin T, cizonan, sobuzosen, sodium glycididazole, sorafenib, stanozolol, streptozocin, sunitinib, tarapofen, tamibarbitine, tamoxifen, tapentathol, tasonamin, texici-interleukin, technetium (99mTc)nofetumomab Merpentan, 99mTc-HYNIC-[Tyr3]-octreotide, tegafur, tegafur + gemcimethin + oteracil, temopofol, temozolomide, tamsulosin, teniposide, testosterone, tetrophosphine, thalidomide, thiotepa, thymosin alpha, thioguanine, tocilizumab, topotecan, toremifene, tosimomab, trabectedin, tramadol, trastuzumab, trastuzumab-metaneconjugate (trastuzumab)Emtansine), Treosulfan, Retinoic acid, Trifluorouridine + Tipiracil, Tralostan, Triptorelin, Trametinib, Trafenisol, Thrombopoietin, Tryptophan, Ubenimex, Vatalanib, Penrubicin, Vandetanib, Vaportide, Vemurafenib, Vincristine, Vincristine, Vindesine, Vinflunine, Vinorelbine, Vimodeil, Volindegaard, Volindegaard, Vorindulgazole, Yttrium-90 glass microspheres, Nettostatin, Nettostatin ester, Zoledronic acid, Zorubicin.

[0208] "Epidermal growth factor receptor (EGFR) polypeptide" refers to a polypeptide having at least about 95% amino acid sequence identity with the sequence or fragment thereof provided in UniProt accession number P00533-1. In some embodiments, the EGFR fragment binds to an EFGR ligand and / or has kinase activity. Mutant EGFR polypeptides include those with an insertion, for example, between amino acids V769 and D770 or between D770 and N771. In other embodiments, the amino acid sequence identity with UniProt accession number P00533-1 is 96, 97, 98, 99, or 100%.

[0209] UniProt accession number P00533-1 provides an exemplary full-length human EGFR sequence, with V769, D770, and N771 indicated in bold, as copied below:

[0210]

[0211]

[0212] The NCBI reference sequence NM_001346897.1 provides an example polynucleotide encoding EGFR, which is replicated as follows:

[0213]

[0214]

[0215]

[0216] The intermediates used in the synthesis of the compounds of claims 1-4, as described below, and their use in the synthesis of the compounds of claims 1-4, constitute another aspect of the invention. Preferred intermediates are those described in the examples below.

[0217] General methods

[0218] The compounds of the present invention can be prepared according to the following schemes 1 to 4.

[0219] The schemes and methods described below illustrate the synthetic route for compounds of general formula (I) of the present invention, and are not intended to limit it. Those skilled in the art will understand that the transformation sequences exemplified in the schemes can be modified in various ways. Therefore, the transformation sequences exemplified in the schemes are not intended to limit it. Furthermore, any substituent R... 1 R 2 R 3 R 4 R 5 R 6 The interconversion of PG can be performed before and / or after the exemplified conversion reactions. These modifications can be, for example, the introduction of protecting groups, the cleavage of protecting groups, the reduction or oxidation of functional groups, halogenation, metallization, substitution, or other reactions known to those skilled in the art. These conversions include those that introduce functionality that allows for further interconversion of the substituents. Suitable protecting groups, and their introduction and cleavage, are well known to those skilled in the art. Specific examples are described in subsequent paragraphs.

[0220] Option 1:

[0221]

[0222] Scheme 1: Route for preparing 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 by general formula (I), and PG can be hydrogen or optionally a suitable protecting group, such as tert-butoxycarbonyl (Boc).

[0223] As will be understood by those skilled in the art, the compounds of formulas 1, 2, and 4 are commercially available or can be prepared using methods available in the public domain. Specific examples are described in the following paragraphs.

[0224] At temperatures ranging from -78°C to +100°C, appropriately substituted piperidine-2,4-diones of the general formula (compounds of formula 1), such as piperidine-2,4-dione, can be reacted with appropriately substituted isothiocyanates (compounds of formula 2), such as 3-fluorophenyl isothiocyanate, in a suitable solvent system, such as acetonitrile, in the presence of a suitable base, such as triethylamine or DBU. In some embodiments, the reaction is carried out at 0°C or +100°C to provide compounds of general formula (3). Similar reactions have been carried out in the literature (DE Worrall, J. Am. Chem. Soc., 1940, 62, 675).

[0225] The intermediate of general formula (3) can be converted into the intermediate of general formula (5) by reacting with a suitable amine (a compound of general formula 4) such as 4-(aminomethyl)pyridine in a suitable solvent system such as ethanol and ethyl acetate at a temperature from room temperature to the boiling point of each solvent. In some embodiments, the reaction is carried out at the boiling point of each solvent, thereby removing the water formed in the reaction from the reaction by methods known to those skilled in the art, such as azeotropic dehydration (Dean-Stark conditions) or by using molecular sieves to provide the intermediate of general formula (5).

[0226] Using standard deprotection conditions known to those skilled in the art, intermediates of general formula (3) where PG represents a protecting group and intermediates of general formula (5) can be converted to intermediates where PG represents a hydrogen atom. When PG is a protecting group such as tert-butoxycarbonyl (Boc), 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 from 0°C to the boiling point of each solvent. In one embodiment, the reaction is carried out at room temperature to provide a compound of general formula (3) and an intermediate of general formula (5), wherein PG is a hydrogen atom.

[0227] The intermediate of general formula (5) is reacted with a base and / or an oxidizing agent (an oxidizing agent in one embodiment) such as hydrogen peroxide or SIBX (stable iodobenzoic acid) in a suitable solvent system such as methanol at a temperature from -30°C to the boiling point of each solvent. In one embodiment, the reaction is carried out at the boiling point of each solvent to provide the intermediate of general formula (I). Optionally, these types of reactions can be carried out with additives, such as acids or bases, such as acetic acid or trifluoroacetic acid (not limiting) and triethylamine or diisopropylethylamine (not limiting).

[0228] Intermediates of formula (5) can be converted to compounds of formula (I) by heating them in a suitable solvent at elevated temperatures, which can be above the boiling point of the solvent, for example, room temperature to +250°C. These reactions can optionally be carried out in a vessel, thereby increasing the pressure, for example, in an autoclave. Intermediates of formula (5) can also be converted to compounds of formula (I) by heating in a suitable solvent, such as DMF, DMA, EtOH, MeOH, or NMP (not limiting), in the presence of a metal catalyst (e.g., palladium / activated carbon) at elevated temperatures, for example, room temperature to +150°C. Optionally, these types of reactions can be carried out with additives, such as acids or bases, such as acetic acid or trifluoroacetic acid (not limiting) and triethylamine or diisopropylethylamine (not limiting), to provide compounds of formula (I).

[0229] Option 2:

[0230]

[0231] Scheme 2: Route for preparing compounds of general formula (4), wherein R 4 R 5 R 6 X, Y, m and n have the meanings given by the general formula (I).

[0232] 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 (basic conditions in one embodiment), in a suitable solvent or using a nucleophile such as DMF or tetrahydrofuran (THF), within a temperature range of -78°C to the boiling point of the corresponding solvent. In one embodiment, the reaction is carried out at -10°C to the boiling point of the corresponding solvent to provide 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).

[0233] Compounds of general formula (7) can be converted to compounds of general formula (4) by many reduction methods known to those skilled in the art, using many different reagents and reaction conditions; such methods and reagents can use 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 zinc in acetic acid (Rabe, Chem. Ber., 1913, 46, 1024), or diborane (De Munno et al., Heterocycles, 1996, 43, 1893-1900), or catalytic hydrogenation methods, such as 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), and using hydrogen and nickel under alkaline conditions (Walpole et al., J. Med. Chem., 1993, 36, 2362-2372; Kuramochi et al., Bioorg. Med. Chem., 2005, 13, 4022-4036).

[0234] Option 3:

[0235]

[0236] Scheme 3: Route for preparing compounds of general formula 2, where R 1a Representing methyl or difluoromethyl, corresponding to R in general formula (I) having the meanings of methoxy and difluoromethoxy. 1 The synthesis of compounds 9 and 10 involves alkoxy substitution of the benzene ring. However, the isothiocyanate-containing product 2 and its synthesis (i.e., 10→2 or 11→2) are related to the R of general formula (I). 1 The functional group is universal.

[0237] Compounds of general formula (8) can be converted to compounds of general formula (9) using various methods known to those skilled in the art. Such conversion can be, for example, alkylation of phenolic alcohols with an alkylating agent, such as an alkyl halide or alkyl sulfonate, wherein these alkyl groups may optionally contain fluorine or alkoxy groups. These alkylation reactions are known to those skilled in the art and use a variety of methods: i) K2CO3 in solvents such as DMF, acetone, or 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) the Mitsunobu reaction (see the teachings of US2006 / 122168A1 and EP2151431A1) to provide intermediates of general formula (9).

[0238] Compounds of general formula (9) can be converted into compounds of general formula (10) by reduction methods known to those skilled in the art. These reductions can be carried out using the following substances: i) hydrogen and a catalyst (for Pd / C as a catalyst, see the teachings of Chan et al., J. Am. Chem. Soc., 2011, 133, 2989; for platinum as a catalyst, see the teachings of Niemann et al., J. Am. Chem. Soc., 1941, 63, 2204; for Raney nickel as a catalyst, see the teachings of US2009 / 253767A1); 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 WO2010 / 42699A1) to provide an intermediate of general formula (10).

[0239] The compound of general formula (10) can be converted to a compound of general formula (2) by using reagents such as phosgene, carbon disulfide, 1,1”-thiocarbonylbis-2(1H)-pyridone or 1,1′-thiocarbonyldiimidazole (in one embodiment, phosgene), under alkaline conditions, in a suitable solvent such as dichloromethane, chloroform, acetone or a two-phase mixture (e.g., dichloromethane, chloroform and an alkaline aqueous solution) (in another embodiment, dichloromethane and a saturated aqueous solution of sodium bicarbonate or sodium carbonate), in a temperature range 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 a compound of general formula (2). This conversion reaction has 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).

[0240] Option 4:

[0241]

[0242] Scheme 4: Route for preparing 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 for general formula (I), and PG represents hydrogen or a suitable protecting group, such as tert-butyloxycarbonyl (Boc).

[0243] Compounds similar to general formula 12 are known to those skilled in the art, and their synthetic methods have been reported in the literature (see the teachings of Voss et al., WO2015 / 22073A1; Hart et al., WO2016 / 100166 A1; Anderson et al., J. Med. Chem., 2007, 50, 2647; Vanotti et al., J. Med. Chem., 2008, 51, 487).

[0244] 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 (WO2016 / 100166 A1). Such bromination can be carried out using a brominating agent, such as N-bromosuccinimide, in a suitable solvent, such as DMF, at a temperature range of -78°C to the boiling point of the solvent, and in one embodiment, this temperature range is 0°C to RT.

[0245] In the presence of a base such as lithium bis(trimethylsilyl)aminoide (LHMDS), a catalyst such as a suitable ligand (in one embodiment 2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl (tBuBrettPhos)), and a precatalyst such as a palladium precatalyst (in another embodiment [2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) chloride (BrettPhos-PreCat MTBE ether adduct)), in a suitable solvent system such as tetrahydrofuran (THF), at a temperature range of 0°C to 200°C, the intermediate of general formula (13) can be reacted with a suitable aniline such as 2-difluoromethoxyaniline. In one embodiment, the reaction is carried out at 80 °C to provide a compound of general formula (I). Similar transformations have been performed and reported (WO2015 / 193339A1).

[0246] Option 5:

[0247]

[0248] Scheme 5: Route for preparing 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 for general formula (I), and PG represents hydrogen or a suitable protecting group, such as tert-butyloxycarbonyl (Boc).

[0249] When 4-(aminomethyl)-3-hydroxypyridine is used instead of intermediate (4), compounds similar to general formula (14) can be prepared according to the operation described in Scheme 1. The intermediate of general formula (14) can be reacted with a suitable alcohol to convert it into a compound of general formula (I) under Mitsunobu conditions (the teachings of Oyo Mitsunobu, Synthesis, 1981, 1-28 or Tsunoda et al., Tetrahedron Lett., 1994, 35, 5081), for example, under oxetane-3-ylmethanol, in the presence of (tributylphosphine)acetonitrile or triphenylphosphine and diisopropyl azodicarbonate, in a suitable solvent system such as dioxane or THF, at a temperature between room temperature and the boiling point of each solvent.

[0250] Those skilled in the art will know that if there are many reaction sites in a starting or intermediate compound, it may be necessary to temporarily block one or more reaction sites by a protecting group in order to allow the reaction to proceed specifically at the desired reaction site.

[0251] The compounds of the present invention can be isolated and purified in a manner known per se, for example by removing the solvent in a vacuum and recrystallizing the residue from a suitable solvent, or by subjecting it to one of the usual purification methods, such as chromatography on a suitable support material. Alternatively, reversed-phase preparative HPLC can be applied. Compounds of the present invention having sufficient basic or acidic functionality can lead to the formation of salts, for example, in the case of sufficiently basic compounds of the present invention, such as trifluoroacetate or formate salts, or in the case of sufficiently acidic compounds of the present invention, such as ammonium salts. Such salts can be converted to their free base or free acid forms, respectively, by various methods known to those skilled in the art, or used as salts for subsequent biological assays. Furthermore, the drying process during the isolation of the compounds of the present invention may not completely remove trace amounts of co-solvents, particularly formic acid or trifluoroacetic acid, in order to obtain 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 should be understood that the specific forms (e.g., salts, free bases, free acids, solvates, inclusion complexes) of the compounds of the present invention as described and isolated herein are not necessarily the only forms, and said compounds can be used in biological assays to quantify specific biological activities.

[0252] Salts of compounds of formula (I) of the present invention can be obtained by dissolving the free compound in a suitable solvent (e.g., ketones such as acetone, methyl ethyl ketone, or methyl isobutyl ketone; ethers such as diethyl ether, tetrahydrofuran, or dioxane; chlorinated hydrocarbons such as dichloromethane or chloroform; or low molecular weight aliphatic alcohols such as methanol, ethanol, or isopropanol), said solvent containing a desired acid or base, or by adding the desired acid or base thereto. The acid or base can be used for salt preparation, depending on whether a mono- or poly-acid or base is considered, and depending on which salt is desired, in an equimolar ratio or a different ratio. Salts are obtained by filtration, reprecipitation, precipitation with a non-solvent of the salt, or by evaporation of the solvent. The obtained salt can be converted back to the free compound, and in turn, the free compound can be converted back to the salt. In this way, pharmaceutically unacceptable salts that can be obtained as process products in industrial-scale preparations can be converted into pharmaceutically acceptable salts by methods known to those skilled in the art. Hydrochloride salts and the methods used in the Examples section are particularly preferred.

[0253] The pure diastereomers and pure enantiomers of the compounds and salts of the present invention can be obtained, for example, by asymmetric synthesis, by using a chiral starting compound in synthesis, or by separating a mixture of enantiomers and diastereomers obtained in the synthesis.

[0254] A mixture of enantiomers and diastereomers can be separated into pure enantiomers and pure diastereomers by methods known to those skilled in the art. In one embodiment, a mixture of diastereomers is separated by crystallization (particularly fractional crystallization) or chromatography. A mixture of enantiomers can be separated, for example, by forming diastereomers with a chiral auxiliary agent, resolving the obtained diastereomers, and removing the chiral auxiliary agent. As chiral auxiliaries, for example, chiral acids can be used 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 a mixture of enantiomers of alcohols or acids, respectively, using chiral acids or chiral alcohols as chiral auxiliaries. Additionally, diastereomeric complexes or diastereomeric inclusion complexes can be used to separate mixtures of enantiomers. Alternatively, a chiral separation column in chromatography can be used to separate mixtures of enantiomers. Another suitable method for separating enantiomers is enzymatic separation.

[0255] A preferred aspect of the present invention is a method for preparing the compounds of claims 1-4 according to the embodiments, and intermediates for the preparation thereof.

[0256] Optionally, compounds of formula (I) can be converted into their salts, or alternatively, salts of compounds of formula (I) can be converted into free compounds. The corresponding methods are conventional to those skilled in the art.

[0257] Commercial use

[0258] As mentioned above, it has been surprisingly found that the compounds of the present invention effectively inhibit mutant EGFR in cells (e.g., cancer cells) in contact with the compounds, thereby inducing cell death (e.g., apoptosis), and can therefore be used to treat or prevent diseases of uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune responses or inappropriate cellular inflammatory responses, or diseases accompanied by uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune responses or inappropriate cellular inflammatory responses, particularly where said uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune responses or inappropriate cellular inflammatory responses are mediated by mutant EGFR, such as the formation of benign and malignant tumors, more specifically, hematologic malignancies, solid tumors and / or their metastases, such as leukemia and myelodysplastic syndromes, malignant lymphomas, including brain tumors and brain metastases. Head and neck tumors, thoracic tumors including non-small cell lung tumors and small cell lung tumors, gastrointestinal tumors, endocrine tumors, breast tumors and other gynecological tumors, urinary system tumors including kidney tumors, bladder tumors and prostate tumors, skin tumors and sarcomas, and / or their metastases, especially hematologic malignancies, solid tumors, and / or metastases 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 cells, kidney, liver, lung, larynx and hypopharynx, mesothelioma, ovary, pancreas, prostate, rectum, kidney, small intestine, soft tissue, stomach, skin, testis, ureter, vagina and vulva, as well as malignant tumor formation, including primary tumors in the said organs and corresponding secondary tumors in distant organs (“tumor metastases”). Hematologic malignancies can be exemplified by aggressive and indolent forms of leukemia and lymphoma, namely non-Hodgkin's disease, chronic and acute myeloid leukemia (CML / AML), acute lymphoblastic leukemia (ALL), Hodgkin's disease, multiple myeloma, and T-cell lymphoma. They also include myelodysplastic syndromes, plasmacytoma formation, paraneoplastic syndromes, cancers of unknown primary origin, and AIDS-related malignancies.

[0259] Another aspect of the invention is the use of the compound of formula (I) in the treatment of lung cancer, particularly lung cancer carrying mutated EGFR with exon 20 insertion mutations, more particularly lung cancer carrying exon 20 insertions of V769_770ins ASV and / or D770_N771ins SVD, and / or its metastases, including administering an effective amount of the compound of formula (I).

[0260] Another aspect of the invention is the use of the compound according to formula (I) in the treatment of lung cancer, particularly lung cancer carrying mutated EGFR with an in-frame deletion of exon 19 (e.g., EGFR E746_A750del) or a point mutation of exon 21 (e.g., L858R), and / or its metastases.

[0261] Another aspect of the invention is the use of the compound according to formula (I) in the treatment of lung cancer, particularly lung cancer carrying mutated EGFR with acquired resistance mutations of D770_N771msSVD C797S, E746_A750del C797S or L858R C797S, and / or its metastases.

[0262] Another aspect of the invention is the use of the compound according to formula (I) in the treatment of lung cancer, particularly lung cancer carrying mutated ERBB2 with exon 20 insertion mutations (e.g., ERBB2A775_G776insYVMA), and / or its metastases.

[0263] According to one aspect of the invention, the present invention relates to compounds of general formula I as described and defined herein, or N-oxides, salts, tautomers or stereoisomers of said compounds, or salts of said N-oxides, tautomers or stereoisomers, particularly pharmaceutically acceptable salts thereof, or mixtures thereof, for the treatment or prevention of diseases, particularly for the treatment of diseases.

[0264] Therefore, another specific aspect of the invention is the use of compounds of general formula I as described above, or their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, especially pharmaceutically acceptable salts, or mixtures thereof, for the prevention or treatment of hyperproliferative disorders or disorders that induce cell death, such as apoptosis.

[0265] "Proliferative disorders"

[0266] This refers to a disease associated with inappropriate high levels of cell division, inappropriate low levels of cell apoptosis, or both, such as cancer. As used herein, in the context of this invention, and particularly in the context of “inappropriate cellular immune response or inappropriate cellular inflammatory response,” the term “inappropriate” should be understood to generally mean a response that is weaker or stronger than a normal response and that is related to, causes, or contributes to the pathology of the disease.

[0267] In a specific implementation, the use is for the treatment or prevention of a disease, particularly the treatment of a hematologic malignancy, a solid tumor, and / or its metastatic tumors.

[0268] On the other hand, the use of the compound of formula (I) in the prevention and / or treatment of lung cancer, particularly lung cancer carrying mutated EGFR with exon 20 insertion mutations, more particularly lung cancer carrying exon 20 insertions of V769_770ins ASV and / or D770_N771ins SVD, and / or its metastases, is especially preferred for its treatment.

[0269] Another aspect of the invention is the use of compounds of formula (I) as described herein, or their stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts, particularly pharmaceutically acceptable salts thereof, or mixtures thereof, in the preparation of medicaments for treating or preventing diseases, said diseases being hyperproliferative conditions or conditions responding to induced cell death, such as apoptosis. In one embodiment, said disease is a hematologic malignancy, a solid tumor, and / or its metastases. In another embodiment, said disease is lung cancer, particularly lung cancer carrying a mutant EGFR with an exon 20 insertion mutation, more particularly lung cancer carrying exon 20 insertions of V769_770ins ASV and / or D770_N771ins SVD, and / or its metastases.

[0270] Methods for treating proliferative disorders

[0271] This invention relates to a method for treating hyperproliferative disorders in mammals using compounds and compositions thereof. The compounds can be used to inhibit, block, reduce, or decrease cell proliferation and / or cell division, and / or induce cell death, such as apoptosis. This method involves administering to a mammal, including humans, a measured amount of a compound of the invention that is effective in treating the disorder, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate, or ester thereof. Hyperproliferative disorders include, but are not limited to, psoriasis, keloids and other skin hyperplasia, benign prostatic hyperplasia (BPH), solid tumors such as breast cancer, respiratory cancer, brain cancer, reproductive organ cancer, digestive tract cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer, and their distant metastases. These diseases also include lymphoma, sarcoma, and leukemia.

[0272] 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.

[0273] Examples of respiratory cancers include, but are not limited to, small cell lung cancer and non-small cell lung cancer, as well as bronchial adenoma and pleural pulmonary blastoma.

[0274] Examples of brain cancer include, but are not limited to, brainstem and hypothalamic gliomas, cerebellar and cerebral astrocytomas, medulloblastomas, ependymomas, neuroectodermal tumors, and pineal tumors.

[0275] Tumors of the male reproductive organs include, but are not limited to, prostate cancer and testicular cancer. Tumors of the female reproductive organs include, but are not limited to, endometrial cancer, cervical cancer, ovarian cancer, vaginal cancer, vulvar cancer, and uterine sarcoma.

[0276] Digestive tract tumors include, but are not limited to, anal cancer, colon cancer, colorectal cancer, esophageal cancer, gallbladder cancer, stomach cancer, pancreatic cancer, rectal cancer, small bowel cancer, and salivary gland cancer.

[0277] Urinary tract tumors include, but are not limited to, bladder cancer, penile cancer, kidney cancer, renal pelvis cancer, ureter cancer, urethral cancer, and human papillary renal cell carcinoma.

[0278] Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.

[0279] Examples of liver cancer include, but are not limited to, hepatocellular carcinoma (with or without fibrolamellar variation), cholangiocarcinoma (intrahepatic cholangiocarcinoma), and mixed hepatocellular cholangiocarcinoma.

[0280] Skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, inverted papilloma of the nasal cavity and sinuses, inverted papilloma of the nasal cavity and sinuses associated with squamous cell carcinoma of the nasal cavity and sinuses, Merkel cell skin cancer, and non-melanoma skin cancers.

[0281] Head and neck cancers include, but are not limited to, laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, inverted papilloma of the nasal cavity and sinuses, related squamous cell carcinoma of the nasal cavity and sinuses, lip cancer, oral 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 central nervous system lymphoma.

[0282] Sarcomas include, but are not limited to, soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.

[0283] Leukemia includes, but is not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and hairy cell leukemia.

[0284] These conditions 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.

[0285] The use of the term "treating" or "treatment" throughout this document is conventional, such as for managing or caring for an individual for the purpose of resisting, alleviating, reducing, relieving, or improving a disease or condition such as cancer.

[0286] This invention relates to a method for 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.

[0287] This invention relates to a method of treating a subject with cancer, wherein the cancer has 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.

[0288] This invention relates to a method for enhancing the efficacy of anti-EGF receptor therapy, the method comprising administering to a subject an anti-EGF receptor therapy in combination with a compound of general formula (I) as defined herein.

[0289] In another embodiment, the present invention relates to a method of treating a subject with cancer, wherein the cancer is selected from leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumors, thoracic tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urinary system tumors, skin tumors and sarcomas, the method comprising administering to the subject an effective amount of a compound of general formula (I) as defined herein.

[0290] In another embodiment, the present invention relates to a method of treating a subject with cancer, wherein the cancer is selected from nasal and paranasal sinus inverted papillary tumors or nasal and paranasal sinus squamous cell carcinomas associated with nasal and paranasal sinus inverted papillary tumors, the method comprising administering to the subject an effective amount of a compound of general formula (I) as defined herein.

[0291] In another embodiment, the present invention relates to a method of treating a subject with cancer, wherein the thoracic tumor 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.

[0292] In another embodiment, the present invention relates to a method of treating a subject with cancer, wherein the cancer is lung cancer, particularly lung cancer carrying a mutated EGFR with an in-frame deletion of exon 19 (e.g., EGFR E746_A750del) or a point mutation of exon 21 (e.g., L858R), and / or its metastases, the method comprising administering to the subject an effective amount of a compound of general formula (I) as defined herein.

[0293] In another embodiment, the present invention relates to a method of treating a subject with cancer, wherein the cancer is lung cancer, particularly lung cancer carrying a mutant EGFR having an acquired resistance mutation of D770_N771insSVD C797S, E746_A750del C797S or L858R C797S, and / or its metastases, the method comprising administering to the subject an effective amount of a compound of general formula (I) as defined herein.

[0294] In another embodiment, the present invention relates to a method of treating a subject with cancer, wherein the cancer is lung cancer, particularly lung cancer carrying a mutated ERBB2 with an exon 20 insertion mutation (e.g., ERBB2 A775_G776insYVMA), and / or its metastases, the method comprising administering to the subject an effective amount of a compound of general formula (I) as defined herein.

[0295] This disclosure also relates to a method for selecting a patient to be treated with a compound of formula (I) for cancer treatment, the method comprising detecting the presence of a mutation in exon 20 of a gene encoding an EGF receptor in a subject's biological sample to determine that the patient should be treated with the compound. In some embodiments, EGFR includes acquired resistance mutations of D770_N771insSVD C797S, E746_A750delC797S, or L858R C797S, and / or their metastases. In some embodiments, the method for selecting a patient to be treated with a compound of formula (I) for cancer treatment may 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 subject's biological sample to determine that the patient should be treated with the compound. For example, an in-frame deletion in exon 19 might be EGFR E746_A750del, or a point mutation in exon 21 might be L858R. In some embodiments, methods for selecting a patient to be treated with a compound of formula (I) may include detecting the presence of a mutation in exon 20 of the gene encoding ERBB2 in a subject's biological sample, thereby determining that the patient should be treated with said compound. In some embodiments, ERBB2 comprises an ERBB2 A775 or _G776insYVMA insertion mutation, and / or its metastases. Furthermore, methods for treating a patient with cancer may include administering a compound of formula (I) to a subject (e.g., in combination with an anti-EGF receptor therapy), wherein the subject is selected for treatment by detecting the presence of an EGFR mutation in the subject's biological sample. Detecting the presence of a mutation in exon 20 is within the skill of those skilled in the art.

[0296] In some implementations, the detection of mutations (e.g., mutations in EGFR or in exon 20 of the gene encoding EGFR) can be performed by sequencing (e.g., Sanger, Next Generation Sequencing) or by methods selected from immunoblotting, mass spectrometry, immunoprecipitation quantitative PCR, Northern blotting, microarrays, enzyme-linked immunosorbent assay (ELISA), in situ hybridization, and combinations thereof.

[0297] Treatment of kinase disorders

[0298] The present invention also provides methods for treating conditions associated with abnormal extracellular mitogen kinase activity, including but not limited to stroke, heart failure, hepatomegaly, cardiomegaly, diabetes, Alzheimer's disease, cystic fibrosis, symptoms of xenograft rejection, septic shock, or asthma.

[0299] Effective amounts of the compounds of the present invention can be used to treat such conditions, including those mentioned in the background section above (e.g., cancer). However, the compounds of the present invention can be used to treat such cancers and other diseases, regardless of the mechanism of action and / or the relationship between the kinase and the condition.

[0300] The phrase “abnormal kinase activity” or “abnormal tyrosine kinase activity” includes any abnormal expression or activity of the gene encoding the kinase or the polypeptide encoded by it. Examples of such abnormal activity include, but are not limited to, overexpression of the gene or polypeptide; gene amplification; mutations that produce constitutive or extreme kinase activity; gene mutations, deletions, substitutions, additions, etc.

[0301] The present invention also provides a method for inhibiting kinase activity, particularly mitogen extracellular kinase activity, the method comprising administering an effective amount of the compound of the present invention, including its salts, polymorphs, metabolites, hydrates, solvates, prodrugs (e.g., esters), and their diastereomers. Kinase activity can be inhibited in cells (e.g., in vitro) or in the cells of mammalian individuals, particularly human patients requiring treatment.

[0302] Methods for treating angiogenesis disorders

[0303] The present invention also provides methods for treating conditions and diseases associated with excessive and / or abnormal angiogenesis.

[0304] Inappropriate and abnormal expression of angiogenesis can be detrimental to organisms. 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; see Lopez et al., Invest. Opththalmol. Vis. Sci. 1996, 37, 855], neovascular glaucoma, psoriasis, retrolental fibrosis, angiofibroma, inflammation, rheumatoid arthritis (RA), restenosis, in-stent restenosis, and graft restenosis. Furthermore, increased blood supply associated with cancerous and tumor tissue promotes growth, leading to rapid tumor enlargement and metastasis. Furthermore, the growth of new blood vessels and lymphatic vessels in tumors provides a pathway for renegade cells to leave, promoting metastasis and leading to cancer spread. Therefore, the compounds of the present invention can be used to treat and / or prevent any of the aforementioned angiogenesis disorders, for example by inhibiting and / or reducing angiogenesis; by inhibiting, blocking, reducing, or decreasing endothelial cell proliferation or other types associated with angiogenesis; and by inducing cell death, such as apoptosis, in these cells.

[0305] In several implementations, the disease in the method is a hematologic malignancy, a solid tumor, and / or its metastatic tumor.

[0306] The compounds of the present invention are particularly useful for the treatment and prevention (i.e., prevention), especially for the treatment of tumor growth and metastasis, particularly for solid tumors of all indications and stages, whether or not they have received pre-treatment for said tumor growth.

[0307] Pharmaceutical compositions of the compounds of the present invention

[0308] This invention also relates to pharmaceutical compositions comprising 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. For the purposes of this invention, a patient is a mammal, including humans, requiring treatment for a specific symptom, disorder, or disease.

[0309] Therefore, the present invention includes pharmaceutical compositions comprising a pharmaceutically acceptable carrier or adjuvant and a pharmaceutically effective amount of the compound of the present invention or a salt thereof.

[0310] Another aspect of the invention is a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula (I) and a pharmaceutically acceptable adjuvant, for treating the diseases mentioned above, particularly for treating hematologic malignancies, solid tumors and / or their metastases.

[0311] Pharmaceutically acceptable carriers or adjuvants are those that are non-toxic and harmless to patients at concentrations consistent with the effective activity of the active ingredient, such that any side effects caused by the carrier do not negate the beneficial effects of the active ingredient. Carriers and adjuvants are all types of additives that facilitate the administration of the composition.

[0312] The pharmaceutically effective amount of a compound can be the amount that produces a result or the expected effect on a specific condition being treated.

[0313] The compounds of the present invention can be administered, together with pharmaceutically acceptable carriers or adjuvants known in the art, in any effective conventional dosage unit form, including immediate-release, sustained-release, and time-release formulations, via oral, parenteral, topical, nasal, ophthalmological, optical, sublingual, rectal, or vaginal administration.

[0314] For oral administration, the compound can be formulated as a solid or liquid dosage form, such as capsules, pills, tablets, troche, lozenges, melts, powders, solutions, suspensions, or emulsions, and can be prepared according to methods known in the art for preparing pharmaceutical compositions. Solid unit dosage forms can be capsules, which can be of the common hard-shell or soft-shell gelatin type, containing adjuvants such as surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.

[0315] In another embodiment, the compounds of the present invention may be compressed together with conventional tablet matrices (e.g., lactose, sucrose, and corn starch) and combined with the following substances to form tablets: binders, such as gum arabic, corn starch, or gelatin; disintegrants for assisting in the breakdown and dissolution of the tablets after administration, such as potato starch, alginate, corn starch, guar gum, tragacanth gum, and gum arabic; lubricants for improving the flowability of the tablets during granulation and preventing tablet material from adhering to the surfaces of the tablet mold and punch, such as talc, stearic acid, or magnesium stearate, calcium stearate, or zinc stearate; and dyes, colorants, and flavorings for improving the sensory properties of the tablets and making them more acceptable to patients, such as peppermint oil, wintergreen oil, or cherry flavoring. Suitable excipients for oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols (e.g., ethanol, benzyl alcohol, and polyvinyl alcohol), with or without pharmaceutically acceptable surfactants, suspending agents, or emulsifiers. Various other substances may be present as coatings or in physical forms for changing dosage units. For example, tablets, pills, or capsules can be coated with shellac, sugar, or both.

[0316] Dispersible powders and granules are suitable for preparing aqueous suspensions. They provide an active ingredient that can be mixed with dispersants or wetting agents, suspending agents, and one or more preservatives. Examples of suitable dispersants or wetting agents and suspending agents are those mentioned above. Other excipients may also be present, such as the sweeteners, flavoring agents, and coloring agents described above.

[0317] 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) naturally occurring gums, such as gum arabic and tragacanth gum, (2) naturally occurring phospholipids, such as soybean phospholipids and lecithin, (3) esters or metaesters derived from fatty acids and hexitan anhydrides, such as sorbitan monooleate, and (4) condensation products of said metaesters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavoring agents.

[0318] Oily suspensions can be formulated by suspending the active ingredient in vegetable oils such as peanut oil, olive oil, sesame oil, or coconut oil, or in mineral oils such as liquid paraffin. The oily suspension may contain a thickener, such as beeswax, solid paraffin, or cetyl alcohol. The suspension may also contain one or more preservatives, such as ethylparaben or n-propylparaben; one or more colorants; one or more flavoring agents; and one or more sweeteners, such as sucrose or saccharin.

[0319] Syrups and elixirs can be formulated using sweeteners such as glycerin, propylene glycol, sorbitol, or sucrose. These formulations may also contain modifiers and preservatives (such as methylparaben and propylparaben), as well as flavoring agents and coloring agents.

[0320] The compounds of the present invention can also be administered parenterally, i.e., subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or intraperitoneally, at injectable doses, for example in a physiologically acceptable diluent having a drug carrier, which can be a sterile liquid or mixture of liquids, such as water, saline, dextran aqueous solution and associated sugar solution, alcohols such as ethanol, isopropanol or cetyl alcohol, diols 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, methylcellulose, hydroxypropyl methylcellulose or carboxymethylcellulose, or emulsifiers and other pharmaceutical excipients.

[0321] Examples of oils that can be used in the parenteral preparations of this invention are those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum oil, and mineral oil. Suitable fatty acids include oleic acid, stearic acid, isostearic acid, and myristic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristicate. Suitable soaps include alkali metal salts, ammonium salts, and triethanolamine salts of fatty acids; suitable detergents include cationic detergents such as dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents such as alkyl sulfonates, aryl sulfonates, and olefin sulfonates, alkyl sulfates and alkyl sulfosuccinates, olefin sulfates and olefin sulfosuccinates, ether sulfates and ether sulfosuccinates, and monoglyceride sulfates and monoglyceride sulfosuccinates; nonionic detergents such as fatty amine oxides, fatty acid alkanolamides, and poly(ethylene oxide-propylene oxide) or ethylene oxide copolymers or propylene oxide copolymers; and amphoteric detergents such as alkyl-β-aminopropionates and 2-alkylimidazoline quaternary ammonium salts, as well as mixtures thereof.

[0322] The parenteral compositions of the present invention typically contain about 0.5 to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be advantageously used. To minimize or eliminate irritation to the injection site, such compositions may contain a nonionic surfactant having a hydrophilic-lipophilic balance (HLB) of about 12 to about 17 in one embodiment. The amount of surfactant in such formulations is about 5 to about 15% by weight in one embodiment. The surfactant may be a single component having the above HLB, or a mixture of two or more components having the desired HLB.

[0323] Examples of surfactants used in parenteral preparations include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate, and high molecular weight adducts of ethylene oxide with a hydrophobic matrix formed by the condensation of propylene oxide and propylene glycol.

[0324] The pharmaceutical composition may be in the form of a sterile aqueous suspension for injection. Such suspensions may be formulated using known methods using the following substances: suitable dispersants or wetting agents and suspending agents, such as sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum arabic; the dispersants or wetting agents may be naturally occurring phospholipids such as lecithin, condensation products of alkyl esters and fatty acids such as polyoxyethylene stearate, condensation products of ethylene oxide and long-chain fatty alcohols such as heptadecaethyleneoxycetyl alcohol, condensation products of ethylene oxide and esters derived from fatty acids and hexitols such as polyoxyethylene sorbitan monooleate, or condensation products of ethylene oxide and esters derived from fatty acids and hexitols such as polyoxyethylene sorbitan monooleate.

[0325] Sterile injectable formulations can also be sterile injectable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents. Suitable diluents and solvents include, for example, water, Ringer's solution, isotonic sodium chloride solution, and isotonic glucose solution. Furthermore, sterile, non-volatile oils are routinely used as solvents or suspension media. For this purpose, any mild, non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids such as oleic acid can be used in the preparation of injectables.

[0326] The compositions of the present invention can also be administered in the form of suppositories for rectal administration of medicines. These compositions can be prepared by mixing the medicine with a suitable, non-irritating excipient that is solid at room temperature but liquid at rectal temperature and thus melts in the rectum to release the medicine. Examples of such substances are cocoa butter and polyethylene glycol.

[0327] Controlled-release formulations for parenteral administration include liposome microspheres, polymer microspheres, and polymer gel formulations known in the art.

[0328] The pharmaceutical composition may need to be delivered to a patient via a mechanical delivery device, or may be necessary. The construction and use of mechanical delivery devices for delivering pharmaceuticals are well known in the art. Direct drug delivery techniques, such as administering drugs directly to the brain, typically involve placing a drug delivery catheter into the patient's ventricular system to bypass the blood-brain barrier. One such implantable delivery system for delivering pharmaceuticals to specific anatomical regions of the body is described in U.S. Patent No. 5,011,472, issued April 30, 1991.

[0329] The compositions of the present invention may also, if necessary or as needed, contain other conventional pharmaceutically acceptable formulation ingredients, commonly referred to as carriers or diluents. Conventional methods for preparing such compositions into suitable dosage forms can be used.

[0330] Such ingredients and methods include those described in the following references, all of which are 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 Iniectable Products” PDA Journal of Pharmaceutical Science & Technology 1997, 51(4), 166-171.

[0331] Common pharmaceutical ingredients that can be used, when appropriate, to formulate the composition for its intended route of administration include:

[0332] Acidifier (Examples include, but are not limited to, acetic acid, citric acid, fumaric acid, hydrochloric acid, and nitric acid);

[0333] Alkalizing agent (Examples include, but are not limited to, ammonia, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, and trolamine.)

[0334] Adsorbent (Examples include, but are not limited to, powdered cellulose and activated carbon);

[0335] aerosol spray (Examples include, but are not limited to, carbon dioxide, CCl₂F₂, F₂ClC-CClF₂, and CClF₃);

[0336] Air replacement agent (air displacement agents) (examples include, but are not limited to, nitrogen and argon);

[0337] Antifungal preservatives(Examples include, but are not limited to, benzoic acid, butyl paraben, ethyl paraben, methyl paraben, propyl paraben, and sodium benzoate);

[0338] Antimicrobial preservatives (Examples include, but are not limited to, benzalkonium chloride, benzyl chloride, benzyl alcohol, hexadecylpyridine chloride, chloro-tert-butanol, phenol, phenylethanol, phenylmercuric nitrate, and thimerosal.)

[0339] antioxidants (Examples include, but are not limited to, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphite, thioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, and sodium metabisulfite).

[0340] Adhesive material (Examples include, but are not limited to, block polymers, natural and synthetic rubbers, polyacrylates, polyurethanes, silicones, polysiloxanes, and styrene-butadiene copolymers);

[0341] buffer (Examples include, but are not limited to, potassium metaphosphate, dipotassium hydrogen phosphate, sodium acetate, anhydrous sodium citrate, and sodium citrate dihydrate);

[0342] carrier (Examples include, but are not limited to, gum arabic syrup, flavoring syrup, flavoring elixir, cherry syrup, cocoa syrup, orange peel syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, antibacterial sodium chloride injection and antibacterial water for injection);

[0343] Chelating agents (Examples include, but are not limited to, disodium edetate and edetate);

[0344] Colorant (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 Iron Oxide Red);

[0345] Clarifying agent (Examples include, but are not limited to, bentonite);

[0346] emulsifier (Examples include, but are not limited to, gum arabic, polysitropol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, and polyoxyethylene 50 monostearate);

[0347] Encapsulation agents (Examples include, but are not limited to, gelatin and cellulose acetate phthalate);

[0348] spices (Examples include, but are not limited to, anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil, and vanillin);

[0349] wetting agent (Examples include, but are not limited to, glycerol, propylene glycol, and sorbitol);

[0350] abrasive (Examples include, but are not limited to, mineral oil and glycerin);

[0351] Oil (Examples include, but are not limited to, peanut oil, mineral oil, olive oil, sesame oil, and vegetable oil);

[0352] 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);

[0353] Penetration enhancer (Transdermal delivery) (Examples include, but are not limited to, monohydroxy or polyhydroxy alcohols, monovalent or polyvalent 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);

[0354] plasticizer (Examples include, but are not limited to, diethyl phthalate and glycerin);

[0355] solvent (Examples include, but are not limited to, ethanol, corn oil, cottonseed oil, glycerin, isopropanol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection, and sterile rinsing water);

[0356] hardener (Examples include, but are not limited to, cetyl alcohol, hexadecyl ester wax, microcrystalline wax, paraffin, stearyl alcohol, white wax, and yellow wax);

[0357] Suppository base (Examples include, but are not limited to, cocoa butter and polyethylene glycol (mixtures));

[0358] surfactants (Examples include, but are not limited to, benzalkonium chloride, nonylphenol polyether 10, octylphenol polyether 9, polysorbate 80, sodium dodecyl sulfate, and sorbitan monopalmitate);

[0359] Suspending agent(Examples include, but are not limited to, agar, bentonite, carbomer, sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, kaolin, methyl cellulose, tragacanth gum, and magnesium aluminum silicate);

[0360] sweeteners (Examples include, but are not limited to, aspartame, dextran, glycerol, mannitol, propylene glycol, sodium saccharin, sorbitol, and sucrose);

[0361] Tablet anti-adhesion agent (Examples include, but are not limited to, magnesium stearate and talc);

[0362] Tablet binders (Examples include, but are not limited to, gum arabic, alginate, sodium carboxymethyl cellulose, compressible sugar, ethyl cellulose, gelatin, liquid glucose, methyl cellulose, non-crosslinked polyvinylpyrrolidone, and pregelatinized starch);

[0363] Tablet and capsule diluent (Examples include, but are not limited to, dicalcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol, and starch);

[0364] Tablet coating (Examples include, but are not limited to, liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, cellulose acetate phthalate, and shellac);

[0365] Direct compression excipients for tablets (Examples include, but are not limited to, calcium hydrogen phosphate);

[0366] Tablet disintegrants (Examples include, but are not limited to, alginate, calcium carboxymethyl cellulose, microcrystalline cellulose, polacrillin potassium, cross-linked polyvinylpyrrolidone, sodium alginate, sodium glycolate starch, and starch);

[0367] Tablet Flow Aid (Examples include, but are not limited to, colloidal silica, corn starch, and talc);

[0368] Tablet Lubricant (Examples include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, stearic acid, and zinc stearate);

[0369] Tablet / Capsule Opacity Agent (Examples include, but are not limited to, titanium dioxide);

[0370] Tablet polishing agent (Examples include, but are not limited to, carnauba wax and beeswax);

[0371] Thickener(Examples include, but are not limited to, beeswax, cetyl alcohol, and paraffin);

[0372] tension agent (Examples include, but are not limited to, dextrose and sodium chloride);

[0373] Viscosity enhancer (Examples include, but are not limited to, alginate, bentonite, carbomer, sodium carboxymethyl cellulose, methyl cellulose, polyvinylpyrrolidone, sodium alginate, and tragacanth gum); and

[0374] wetting agent (Examples include, but are not limited to, heptadecaethoxycetyl alcohol, lecithin, sorbitol monooleate, polyoxyethylene sorbitol monooleate and polyoxyethylene stearate).

[0375] Examples of the pharmaceutical compositions of the present invention are as follows:

[0376] sterile IV solution A 5 mg / mL solution of the desired compound of the present invention can be prepared using sterile water for injection, with pH adjusted if necessary. The solution is diluted to 1-2 mg / mL with sterile 5% dextran for administration, and administered via intravenous infusion over approximately 60 minutes.

[0377] Lyophilized powder for intravenous administration A sterile formulation can be prepared using (i) the desired compound of the invention in lyophilized powder form (100-1000 mg), (ii) sodium citrate at a concentration of 32-327 mg / mL, and (iii) dextran 40 at a concentration of 300-3000 mg. The formulation is reconstituted to a concentration of 10-20 mg / mL with sterile saline for injection or 5% dextran, and then further diluted to 0.2-0.4 mg / mL with saline or 5% dextran, and administered via IV bolus or IV infusion over 15-60 minutes.

[0378] Intramuscular injection suspension The following solutions or suspensions can be prepared for intramuscular injection:

[0379] 50 mg / mL of the desired water-insoluble compound of the present invention

[0380] 5 mg / mL sodium carboxymethyl cellulose

[0381] 4mg / mL TWEEN 80

[0382] 9mg / ml sodium chloride

[0383] 9 mg / ml benzyl alcohol

[0384] Hard-shell capsules:Large quantities of unit capsules were prepared by filling standard two-piece hard galantine capsules with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose, and 6 mg of magnesium stearate.

[0385] 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 injected into molten gelatin using a volumetric pump to form a soft gelatin capsule 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 pharmaceutical mixture.

[0386] tablet: Large quantities of tablets are prepared using conventional methods, with each dosage unit containing 100 mg of the active ingredient, 0.2 mg of colloidal silica, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch, and 98.8 mg of lactose. Appropriate aqueous and non-aqueous coatings can be used to increase palatability, improve appearance and stability, or delay absorption.

[0387] Immediate-release tablets / capsules These are solid oral dosage forms prepared using conventional and novel methods. These units are taken orally without water, enabling immediate dissolution and delivery of the drug. The active ingredient is mixed in a liquid containing components such as sugars, gelatin, pectin, and sweeteners. These liquids are solidified into solid tablets or capsules using freeze-drying and solid-state extraction techniques. Drug compounds can be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to prepare a porous matrix for immediate release under water-free conditions.

[0388] Dosage and administration

[0389] Based on standard laboratory techniques known for evaluating compounds that can be used to treat hyperproliferative disorders and angiogenesis disorders, the effective dose of the compound of the present invention for each desired indication can be readily determined by standard toxicity tests and standard pharmacological assays for determining treatment of the aforementioned disorders in mammals, and by comparing these results with those of known drugs used to treat these disorders. The amount of active ingredient administered in the treatment of one of these disorders can vary considerably depending on considerations such as the specific compound and dosage unit used, the route of administration, the duration of treatment, the age and sex of the patient being treated, and the nature and severity of the disorder being treated.

[0390] The total amount of the active ingredient to be administered is generally from about 0.001 mg / kg to about 200 mg / kg body weight / day, and in certain embodiments, from about 0.01 mg / kg to about 20 mg / kg body weight / day. Clinically available dosing regimens range from once to three times daily to once every four weeks. Furthermore, a "withdrawal period" (where the patient is not given the drug for a period of time) may be advantageous for the overall balance between pharmacological efficacy and tolerability. A unit dose may contain from about 0.5 mg to about 1500 mg of the active ingredient and may be administered once or more daily, or less than once daily. In other embodiments, the average daily dose administered by injection, including intravenous, intramuscular, subcutaneous, and parenteral administration, as well as by infusion techniques, is 0.01-200 mg / kg body weight. In certain embodiments, the average daily rectal dosing regimen is 0.01-200 mg / kg body weight. In other embodiments, the average daily vaginal dosing regimen is 0.01-200 mg / kg body weight. In other embodiments, the average daily local dosage regimen is 0.1-200 mg administered once to four times daily. In other embodiments, the transdermal concentration is the concentration required to maintain a daily dose of 0.01-200 mg / kg. In other embodiments, the average daily inhalation dosage regimen is 0.01-100 mg / kg of total body weight.

[0391] Of course, the specific starting and maintenance dose regimens for each patient will vary depending on factors such as the nature and severity of the disease condition as determined by the clinical diagnostic physician, the activity of the specific compound used, the patient's age and overall health, the timing of administration, the route of administration, the rate of drug excretion, and the combination of drugs. The desired mode of treatment and dosage of the compounds of the present invention or their pharmaceutically acceptable salts, esters, or compositions can be determined by those skilled in the art using conventional therapeutic testing.

[0392] Combination therapy

[0393] The compounds of the present invention can be administered as a single agent or in combination with one or more other agents, wherein such combination does not cause unacceptable adverse effects. Those combined agents may be other agents with antiproliferative effects, such as those for treating hematologic malignancies, solid tumors, and / or their metastases, and / or agents for treating undesirable side effects. The present invention also relates to such combinations.

[0394] Other antiproliferative agents suitable for use with the compositions of the present invention include, but are not limited to, those compounds recognized for the treatment of neoplastic diseases as described in Goodman and Gilman's *The Pharmacological Basis of Therapeutics (Ninth Edition)*, edited by Molinoff et al., McGraw-Hill, pp. 1225-1287, (1996) (which is incorporated herein by reference), particularly (chemotherapeutic) anticancer agents as defined above. Depending on the circumstances, the combination may be a non-fixed combination or a fixed-dose combination.

[0395] The methods for testing specific pharmacological or pharmaceutical properties are known to those skilled in the art.

[0396] The test experiments described in this article are used to illustrate the present invention, and the present invention is not limited to the provided embodiments.

[0397] Those skilled in the art will understand that the present invention is not limited to the specific embodiments described herein, but covers all modifications of the embodiments described within the spirit and scope of the invention as defined in the appended claims.

[0398] The following examples illustrate the invention in more detail, but are not limiting. Other compounds of the invention not explicitly described can be prepared in a similar manner.

[0399] The compounds and their salts mentioned in the examples represent preferred embodiments of the invention and all sub-combinations of residues of compounds of formula (I) as disclosed in the specific embodiments.

[0400] The term "according to" in the experimental section is used in a meaning similar to that of the method referred to.

[0401] Experimental Section

[0402] Use ACD / Labs' ACD / Name software to generate chemical names. In some cases, use a generally accepted name of a commercially available reagent instead of the name generated by ACD / Name.

[0403] Table 1 below lists the abbreviations used in this paragraph and the Examples section, unless they are explained in the text. Other abbreviations have the meanings commonly understood by those skilled in the art.

[0404] Table 1: Abbreviations

[0405]

[0406]

[0407]

[0408] Other abbreviations have meanings that are generally understood by those skilled in the art.

[0409] The various aspects of the invention described in this application are illustrated by the following embodiments and are not intended to limit the invention in any way.

[0410] The test experiments described in this document are for illustrative purposes only, and the invention is not limited to the given embodiments.

[0411] Experimental Section - General Procedures

[0412] All reagents not described in the experimental section are commercially available products, or are known compounds, or can be formed by those skilled in the art from known compounds using known methods.

[0413] Compounds and intermediates prepared according to the method of the present invention may require purification. Purification of organic compounds is well known to those skilled in the art, and several methods for purifying the same compound may exist. In some cases, purification may not be necessary. In some cases, the compound may be purified by crystallization. In some cases, impurities may be removed by stirring with a suitable solvent. In some cases, the compound may be purified by chromatography, particularly rapid column chromatography, using, for example, a pre-packed silica column, such as a Biotage SNAP column. or With Biotage automatic purification system ( or Isolera Combined use of various methods, including eluents such as hexane / ethyl acetate or DCM / methanol gradient solutions. In rapid column chromatography, unmodified (“conventional”) silica gel and amino-phase functionalized silica gel can be used. If rapid column chromatography or rapid chromatography is mentioned in the experimental section without specifying a stationary phase, conventional silica gel is used.

[0414] In some cases, the compound can be purified by preparative HPLC using, for example, a Waters automated purification system equipped with a diode array detector and / or an online electrospray ionization mass spectrometer, with a suitable pre-packed reversed-phase column and a gradient solution of eluents such as water and acetonitrile, which may contain additives such as trifluoroacetic acid, formic acid, or ammonia.

[0415] In some cases, the purification methods described above can provide those of the present invention in salt form with sufficient basic or acidic functionality, for example, in the case of sufficiently basic compounds of the present invention, such as trifluoroacetate or formate salts, or in the case of sufficiently acidic compounds of the present invention, such as ammonium salts. Salts of this type can be converted to their free base or free acid forms, respectively, by various methods known to those skilled in the art, or used as salts in subsequent biological assays. It should be understood that the specific form (e.g., salt, free base, etc.) of the compounds of the present invention isolated as described herein is not necessarily the only form, and said compounds can be used in biological assays to quantify specific biological activities.

[0416] Analysis using LC-MS method:

[0417] Method 1:

[0418] Instruments: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7μm, 50x2.1mm; Eluent A: Water + 0.1 vol% 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℃; DAD scan: 210–400 nm.

[0419] Method 2:

[0420] Instruments: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7μm, 50x2.1mm; Eluent A: Water + 0.2 v / v ammonia solution (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℃; DAD scan: 210–400 nm.

[0421] Method 3:

[0422] Instrumentation: Waters Acquity UPLC H-Class system; Column: Acquity CSH C18 1.7μm 2.1x50mm; Eluent A: Water + 0.1 vol% formic acid, Eluent B: Acetonitrile, Eluent C: 2 vol% aqueous ammonia solution (28%), Eluent D: 2 vol% aqueous formic acid solution; Gradient: 0-1.2 min 2-95% B solution containing A, 5% D, 1.2-1.4 min 95% B; Flow rate: 0.8 ml / min; Temperature: 40℃; PDA: 215-350 nm.

[0423] Method 4:

[0424] Instrumentation: Waters Acquity UPLC H-Class system; Column: XBridge BEH C18 2.5μm 2.1x 50mm; Eluent A: Water + 0.1 vol% formic acid, Eluent B: Acetonitrile, Eluent C: 2 vol% aqueous ammonia solution (28%), Eluent D: 2 vol% aqueous formic acid solution; Gradient: 0-1.2 min 2-95% B solution containing A, 5% C, 1.2-1.4 min 95% B; Flow rate: 0.8 ml / min; Temperature: 40℃; PDA: 215-350 nm.

[0425] Method 5:

[0426] MS instrument: SHIMADZU LCMS-2020; HPLC instrument: LabSolution Version 5.72; Column: Kinetex@5um EVO C18 30 x 2.1mm; Eluent A: 0.0375% TFA aqueous solution (v / v), Eluent B: 0.01875% TFA in acetonitrile solution; Gradient: 0.0min 0%B→3.00min 60%B→3.50min 60%B→3.51min 0%B→4.00min 0%B; Flow rate: 0.8mL / mix; Oven temperature: 50℃; UV detection: 220nm & 254nm.

[0427] Method 6:

[0428] Instrument: Agilent 1290 UPLCMS 6230 TOF; BEH C18 1.7μm, 50x2.1mm; Eluent A: Wasser + 0.05% (99%); Eluent B: Acetonitrile + 0.05% (99%); Gradient: 0-1.7 2-90%B, 1.7-2.0 90%B; Fluss 1.2 ml / min; Temperature: 60℃; DAD scan: 190-400 nm.

[0429] Preparation of LC-MS method:

[0430] Method 7:

[0431] Instrumentation: Waters Autopurification MS SingleQuad; Column: Waters XBrigde C18 5μm 100x30mm; Eluent A: Water + 0.2% v / v ammonia solution (32%), Eluent B: Acetonitrile; Gradient: 0-5.5 min, 5-100% B; Flow rate: 70 ml / min; Temperature: 25℃; DAD scan: 210-400 nm

[0432] Method 8:

[0433] Instrument: Waters Autopurification MS SingleQuad; Column: Waters XBrigde C18 5μm 50x50mm; Eluent A: Water + 0.1 vol% formic acid, Eluent B: Methanol; Gradient: 0-0.50 min. 20% B; Flow rate 50 to 100 ml / min, 0.50-8.00 min. 20-60% B; Flow rate 100 ml / min; Temperature: 25℃; DAD scan: 210-400 nm

[0434] Method 9:

[0435] Instrumentation: 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 10μM 120x30mm; Eluent A: Water + 0.1% formic acid; Eluent B: Acetonitrile; Gradient: For intermediates and examples, flow rate 150mL / min, temperature 25℃; UV 220nm

[0436] Method 10:

[0437] Instrumentation: 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 10μM 120x30mm; Eluent A: 0.1% aqueous ammonia solution; Eluent B: acetonitrile; Gradient: used for intermediates and examples; Flow rate: 150mL / min; Temperature: 25℃; UV 250nm

[0438] Method 11:

[0439] Instrumentation: Labomatic HD-5000, pump head HDK-280, gradient module NDB-1000, fraction collector Labomatic Laboeol Vario 2000, Knauer UV detector Azura UVD 2.1S, Prepcon 5 software. Column: Chromatorex C18 10μM 300x50mm; Eluent A: 0.1% aqueous ammonia solution; Eluent B: Acetonitrile; Gradient: for intermediates and examples, flow rate 250mL / min, temperature 25℃; UV 250nm

[0440] NMR spectroscopy:

[0441] The following paragraphs give 1 The multiplicity of the proton signal in 1H NMR spectroscopy reflects the observed signal form without considering any higher-order signal phenomena. Typically, chemical shift data refers to the center of the relevant signal. In the case of broad multiplets, a range is specified. Signals hidden by solvent or water are temporarily specified or not listed. Strong broad signals (e.g., caused by rapid rotation of molecular moieties or proton exchange) are also temporarily specified (often referred to as broad multiplets or broad singlets) or not shown.

[0442] The selected compound 1 H-NMR data with 1 The peaks are listed in the form of a H-NMR peak list. For each signal peak, the δ value is given in ppm, and the signal intensity is reported in parentheses. δ value-signal intensity pairs from different peaks are separated by commas. Therefore, the peak list is described in a general form: δ1 (intensity 1), δ2 (intensity 2), ..., δ... i (strength i ),......,δ n (strength n ).

[0443] The intensity of a sharp signal is related to the height of the signal (in centimeters) in the printed NMR spectrum. This data can be correlated with the actual ratio of signal intensity compared to other signals. In the case of a broad signal, multiple peaks or signal centers and their relative intensities are shown compared to the strongest signal displayed in the spectrum. 1 The H-NMR peak list is similar to the classic one. 1 H-NMR readings, therefore, typically contain all the peaks listed in the classical NMR interpretation. Furthermore, similar to classical... 1 H-NMR printing readings and peak lists can display solvent signals, signals from stereoisomers derived from specific target compounds, impurity peaks, etc. 13 C-satellite peaks and / or spinning sidebands. The peaks of stereoisomers and / or impurities typically exhibit lower intensities than those of the target compound (e.g., purity > 90%). These stereoisomers and / or impurities may be typical for a particular manufacturing process, and therefore their peak values ​​may aid in identifying the reproducibility of the manufacturing process based on a "byproduct fingerprint." Experts who calculate the target compound peaks using known methods (MestReC, ACD simulation, or expected values ​​assessed empirically) may optionally use additional intensity filters to separate the target compound peaks as needed. This operation is similar to classical... 1 Peak picking in H-NMR interpretation. Detailed instructions for reporting NMR data in peak list form can be found in the publication "Citation of NMR Peaklist Data within Patent Applications" (cf. http: / / www.researchdisclosure.com / searching-disclosures, Research Disclosure Database Number 605005, 2014, 01 Aug 2014). In the peak picking procedure, as described in Research Disclosure Database Number 605005, the parameter "minimum height" can be adjusted between 1% and 4%. However, depending on the chemical structure and / or the concentration of the analyte, setting the parameter "minimum height" to <1% may be reasonable.

[0444] Synthesis of intermediate 1 compound

[0445] Intermediate 1-1

[0446] 3-[(1,4-dioxane-2-yl)methoxy]pyridine-4-carboxynitrile

[0447]

[0448] 3-chloropyridine-4-carboxynitrile (CAS) 68325-15-5 (1.40 g, 10.1 mmol) and (1,4-dioxane-2-yl)methanol (CAS 1,4-dioxane-2-yl)methanol 143669-41-4 1.31 g (11.1 mmol) was 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 hour. The reaction mixture was slowly diluted with a saturated ammonium chloride solution and extracted with EtOAc (3x). The organic phase was washed with brine, filtered through a waterproof filter, concentrated under reduced pressure, and purified by rapid chromatography (silica gel, hexane / EtOAc gradient 0-100%; EtOAc / EtOH gradient 0-35%) to give 1.18 g of the title compound (53% yield).

[0449] 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).

[0450] LC-MS (Method 2): R t =0.77min; MS (ESIpos): m / z=221[M+H] +

[0451] Intermediate 1-2

[0452] 3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridine-4-carboxynitrile

[0453]

[0454] Sodium hydride (366 mg, 9.15 mmol, 60% purity) was slowly added to a 20 mL THF solution of [(3S)-4-methylmorpholino-3-yl]methanol (CAS 1620510-50-0, 1.00 g, 7.62 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 3 hours. 3-chloropyridin-4-carboxynitrile (CAS 1620510-50-0, 1.00 g, 7.62 mmol) was then added. 68325-15-5A 10 mL solution of THF (1.06 g, 7.62 mmol) was added and the mixture was stirred overnight. The reaction mixture was quenched with 1 N 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 rapid chromatography (basic silica gel, hexane / EtOAc gradient 0-100%) to give 355 mg of the title compound (20% yield).

[0455] 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).

[0456] LC-MS (Method 2): R t =0.72min; MS(ESIpos): m / z=234.2[M+H] +

[0457] Intermediate 1-3

[0458] 3-{[4-methylmorpholin-2-yl]methoxy}pyridine-4-carboxynitrile

[0459]

[0460] Using a similar method as described in Intermediate 1-1, 3-chloropyridin-4-carboxynitrile (CAS 68325-15-5, 764 mg, 5.51 mmol) and [4-methylmorpholino-2-yl]methanol (CAS 40987-46-0, 940 mg, 7.17 mmol) were used as starting materials to prepare 836 mg (90% purity, 59% yield) of the title compound.

[0461] 1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.893 (0.97), 1.920 (1.44), 1.947 (1.07), 1.9 54(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), 3.5 20 (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 0.18), 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).

[0462] LC-MS (Method 2): R t =0.70min; MS(ESIpos): m / z=234.2[M+H] +

[0463] Intermediate 1-4

[0464] 3-{[(3S)-4-methylmorpholin-3-yl]methoxy}pyridine-4-carboxynitrile

[0465]

[0466] Using a similar method as described in Intermediates 1-2, 3-chloropyridin-4-carboxynitrile (CAS 68325-15-5, 1.00 g, 7.24 mmol) and [(3R)-4-methylmorpholino-3-yl]methanol (1.00 g, 95% purity, 7.24 mmol; CAS 1620510-51-1) were used as starting materials to prepare 823 mg (99% purity, 48% yield) of the title compound.

[0467] 1H-NMR (400MHz, DMSO-d6): δ[ppm]=2.211(0.52), 2.219(0.64), 2.236(0.66), 2.240(0.68), 2.24 5(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(0.5) 8), 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), 4.22 3 (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).

[0468] LC-MS (Method 2): R t =0.70min; MS (ESIpos): m / z=234[M+H] +

[0469] Intermediate 1-5

[0470] (2S)-2-{[(4-cyanopyridin-3-yl)oxy]methyl}morpholine-4-carboxylic acid tert-butyl ester

[0471]

[0472] Using a similar method as described in Intermediate 1-1, 3-chloropyridin-4-carboxynitrile (CAS 68325-15-5, 2.55 g, 18.4 mmol) and (2S)-2-(hydroxymethyl)morpholine-4-carboxylic acid tert-butyl ester (CAS 135065-76-8, 4.00 g, 18.4 mmol) were used as starting materials to prepare 4.82 g (90% purity, 74% yield) of the title compound.

[0473] 1 H-NMR (400MHz, DMSO-d6): 6 [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).

[0474] LC-MS (Method 2): R t =1.06min; MS(ESIpos): m / z=320[M+H] +

[0475] Intermediate 1-6

[0476] 3-[2-(1,4-dioxane-2-yl)ethoxy]pyridine-4-carboxynitrile

[0477]

[0478] Using a similar method as described in Intermediates 1-2, 2.89 g (99% purity, 81% yield) of the title compound was prepared from 3-chloropyridin-4-carboxynitrile (CAS 68325-15-5, 2.10 g, 15.1 mmol) and 2-(1,4-dioxane-2-yl)ethanol-1-ol (CAS 151720-04-6, 2.00 g, 15.1 mmol) as starting materials.

[0479] 1H-NMR (400MHz, 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), 1.81 0(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).

[0480] LC-MS (Method 6): Rt = 0.64 min; MS (ESIpos): m / z = 235 [M+H] +

[0481] Intermediates 1-7

[0482] 3-[(5,5-dimethyl-1,4-dioxane-2-yl)methoxy]pyridine-4-carboxynitrile

[0483]

[0484] Using a similar method as described in Intermediates 1-2, 1.31 g (95% purity, 73% yield) of the title compound was prepared from 3-chloropyridin-4-carboxynitrile (CAS 68325-15-5, 948 mg, 6.84 mmol) and (5,5-dimethyl-1,4-dioxane-2-yl)methanol (1.00 g, 6.84 mmol; CAS 54321-57-2) as starting materials.

[0485] 1 H-NMR (400MHz, DMSO-d6): δ[ppm]=1.014(0.69), 1.048(16.00), 1.172(0.55), 1.200(0.51), 1.263(13.01), 1.9 87(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).

[0486] LC-MS (Method 6): Rt = 0.75 min; MS (ESIpos): m / z = 249 [M+H] +

[0487] Intermediate 1-8

[0488] 3-{[(2S)-1,4-dioxane-2-yl]methoxy}pyridine-4-carboxynitrile

[0489]

[0490] Using a similar method as described in Intermediate 1-1, 3-chloropyridin-4-carboxynitrile (CAS 68325-15-5, 1.00 g, 7.22 mmol) and [(2R)-1,4-dioxane-2-yl]methanol (CAS 406913-88-0, 938 mg, 7.94 mmol) were used as starting materials to prepare 490 mg (95% purity, 29% yield) of the title compound.

[0491] Optical rotation: [α] D = -1.68° + / - 0.35° (c = 7 mg / ml, methanol)

[0492] 1 H-NMR (400MHz, DMSO-d6): δppm=3.41-3.53(m, 2H), 3.59-3.72(m, 2H), 3.75-3.81(m, 1H), 3.82-3.87( m, 1H), 3.87-3.95 (m, 1H), 4.27-4.37 (m, 2H), 7.77-7.80 (m, 1H), 8.38-8.41 (m, 1H), 8.71-8.73 (m, 1H).

[0493] Intermediates 1-9

[0494] (3R)-3-{[(4-cyanopyridin-3-yl)oxy]methyl}morpholine-4-carboxylic acid tert-butyl ester

[0495]

[0496] Sodium hydride (1.55 g, 55% purity, 35.6 mmol) was slowly added to a THF (28 ml) solution of (3S)-3-(hydroxymethyl)morpholine-4-carboxylic acid tert-butyl ester (4.30 g, 19.8 mmol). The reaction mixture was stirred for 1 hour. A THF (14 ml) solution of 3-fluoropyridine-4-carboxynitrile (CAS 113770-88-0, 2.42 g, 19.8 mmol) was added, and the mixture was stirred at 0 °C for 4 hours. The reaction mixture was quenched with 2N HCl until pH 6–7 and extracted with EE. The organic layer was filtered through waterproof filter paper and concentrated under reduced pressure. The residue was purified by rapid chromatography (silica gel, DCM / EtOH gradient 0–7%) to give 4 g of the title compound (70% yield).

[0497] LC-MS (Method 6): R t =0.95min; MS (ESIpos): m / z=264[M+H] +

[0498] Intermediate 1-10

[0499] (2R)-2-{[(4-cyanopyridin-3-yl)oxy]methyl}morpholine-4-carboxylic acid tert-butyl ester

[0500]

[0501] Using a similar method as described in Intermediate 1-1, 3-chloropyridin-4-carboxynitrile (CAS 68325-15-5, 3.25 g, 23.5 mmol) and (2R)-2-(hydroxymethyl)morpholine-4-carboxylic acid tert-butyl ester (CAS 135065-71-3, 5.10 g, 23.5 mmol) were used as starting materials to prepare 6.92 g (90% purity, 83% yield) of the title compound.

[0502] 1 H-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).

[0503] LC-MS (Method 2): R t =1.04min; MS (ESIpos): m / z=320[M+H] +

[0504] Intermediate 1-11

[0505] 3-[(1S)-1-(1,4-dioxane-2-yl)ethoxy]pyridine-4-carboxynitrile

[0506]

[0507] Using a similar method as described in intermediates 1-9, 3-fluoropyridine-4-carboxynitrile (878 mg, 7.19 mmol) and (1S)-1-[1,4-dioxane-2-yl]ethane-1-ol (CAS 1372875-59-6, 950 mg, 7.19 mmol) were used as starting materials to prepare 1.68 g (95% purity, 95% yield) of the title compound.

[0508] 1H-NMR(400MHz,DMSO-d6):δppm=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).

[0509] LC-MS (Method 6): R t =0.64min; MS (ESIpos): m / z=235[M+H] +

[0510] Intermediate 1-12

[0511] 3-{(1R)-1-[1,4-dioxane-2-yl]ethoxy}pyridine-4-carboxynitrile

[0512]

[0513] Using a similar method as described in intermediates 1-9, 3-fluoropyridine-4-carboxynitrile (905 mg, 7.42 mmol) and (1R)-1-[1,4-dioxane-2-yl]ethane-1-ol (CAS 1372881-98-5, 980 mg, 7.42 mmol) were used as starting materials to prepare 1.39 g (95% purity, 76% yield) of the title compound.

[0514] 1H-NMR (400MHz, DMSO-d6): δppm=1.274(0.82), 1.289(0.87), 1.322(16.00), 1.337(15.9 7), 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), 3.6 80 (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 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).

[0515] LC-MS (Method 6): R t =0.67min; MS (ESIpos): m / z=235[M+H] +

[0516] Intermediate 1-71

[0517] 3-[1-(4-methylmorpholin-2-yl)ethoxy]isonicotinonitrile

[0518]

[0519] Using a similar method to that described in intermediates 1-9, the title compound was prepared in 817 mg (99% purity, 48% yield) using 3-fluoropyridine-4-carboxynitrile (824 mg, 6.75 mmol) and 1-(4-methylmorpholino-2-yl)ethanol (980 mg, 6.75 mmol, CAS 1540922-49-3) as starting materials by column chromatography using Biotage Isolera.

[0520] 1 H-NMR (400MHz, 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(0.4 4), 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).

[0521] LC-MS (Method 6): R t =0.32min; MS (ESIpos): m / z=248[M+H] +

[0522] Synthesis of intermediate 2 compound

[0523] Intermediate 2-1

[0524] 1-{3-[(1,4-dioxane-2-yl)methoxy]pyridin-4-yl}methylamine

[0525]

[0526] 3-[(1,4-dioxane-2-yl)methoxy]pyridine-4-carboxynitrile (intermediate 1-1, 1.17 g, 5.34 mmol), ammonia solution (19 mL, 7.0 M methanol solution, 850 mmol), and Raney nickel (CAS 7440-02-0, 783 mg, 50% wet) were charged into a high-pressure reactor, and the mixture was stirred at room temperature under a hydrogen atmosphere of 25 bar for 22 hours. The mixture was filtered through a diatomaceous earth pad, eluted with methanol, and the combined filtrates were concentrated under reduced pressure. The residue was used directly for the next step without further purification (1.13 g, 94% yield).

[0527] 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).

[0528] LC-MS (Method 2): R t =0.54min; MS (ESIpos): m / z=225[M+H] +

[0529] Intermediate 2-2

[0530] 1-(3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)methylamine

[0531]

[0532] Using a similar method as described in Intermediate 2-1, 3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridine-4-carboxynitrile (Intermediate 1-2, 355 mg, 1.52 mmol) was used as the starting material to prepare 350 mg of the title compound (89% yield).

[0533] 1H-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).

[0534] Intermediate 2-3

[0535] 1-(3-{[4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)methylamine

[0536]

[0537] Using a similar method as described in Intermediate 2-1, 860 mg (90% purity, 91% yield) of the title compound was prepared from 3-{[4-methylmorpholin-2-yl]methoxy}pyridine-4-carboxynitrile (Intermediate 1-3, 836 mg, 3.58 mmol) as the starting material.

[0538] 1 H-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).

[0539] LC-MS (Method 2): R t =0.56min; MS (ESIpos): m / z=238[M+H] +

[0540] Intermediate 2-4

[0541] 1-(3-{[(3S)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)methylamine

[0542]

[0543] Using a similar method as described in Intermediate 2-1, 798 mg (90% purity, 86% yield) of the title compound was prepared from 3-{[(3S)-4-methylmorpholino-3-yl]methoxy}pyridine-4-carboxynitrile (Intermediate 1-4, 823 mg, 3.53 mmol) as the starting material.

[0544] 1 H-NMR (400MHz, 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 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(1.5) 3), 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).

[0545] Intermediate 2-5

[0546] (2S)-2-({[4-(aminomethyl)pyridin-3-yl]oxy}methyl)morpholine-4-carboxylic acid tert-butyl ester

[0547]

[0548] Using a similar method as described in Intermediate 2-1, tert-butyl morpholine-4-carboxylate (Intermediate 1-5, 5.75 g, 18.0 mmol) was used as the starting material to prepare 6.00 g (95% purity, 98% yield) of the title compound.

[0549] 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).

[0550] LC-MS (Method 2): R t =0.84min; MS (ESIpos): m / z=324[M+H] +

[0551] Intermediate 2-6

[0552] 1-{3-[2-(1,4-dioxane-2-yl)ethoxy]pyridin-4-yl}methylamine

[0553]

[0554] Using a similar method as described in Intermediate 2-1, 2.22 g (90% purity, 68% yield) of the title compound was prepared from 3-[2-(1,4-dioxane-2-yl)ethoxy]pyridine-4-carboxylonitrile (Intermediate 1-6, 2.89 g, 12.3 mmol) as the starting material.

[0555] 1H-NMR (400MHz, 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(2.9 2), 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).

[0556] Intermediate 2-7

[0557] 1-{3-[(5,5-dimethyl-1,4-dioxane-2-yl)methoxy]pyridin-4-yl}methylamine

[0558]

[0559] Using a similar method as described in Intermediate 2-1, 1.26 g (90% purity, 86% yield) of the title compound was prepared from 3-[(5,5-dimethyl-1,4-dioxane-2-yl)methoxy]pyridine-4-carboxylonitrile (Intermediate 1-7, 1.30 g, 5.24 mmol) as the starting material.

[0560] 1H-NMR (400MHz, 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), 3.5 67 (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).

[0561] Intermediate 2-8

[0562] 1-(3-{[(2S)-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)methylamine

[0563]

[0564] Using a similar method as described in Intermediate 2-1, 1.56 g (80% purity, 99% yield) of the title compound was prepared from 3-{[(2S)-1,4-dioxane-2-yl]methoxy}pyridine-4-carboxynitrile (Intermediate 1-8, 1.24 g, 5.63 mmol) as the starting material.

[0565] 1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.232 (0.52), 1.845 (1.06), 2.518 (2.37), 2.523 (1.54), 3.159 (14.24), 3.17 1(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(16.0) 0), 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).

[0566] Intermediate 2-9

[0567] (3R)-3-({[4-(aminomethyl)pyridin-3-yl]oxy}methyl)morpholine-4-carboxylic acid tert-butyl ester

[0568]

[0569] Using a similar method as described in Intermediate 2-1, tert-butyl morpholine-4-carboxylate (Intermediate 1-9, 4.00 g, 12.5 mmol) was used as the starting material to prepare 3.65 g of the title compound (86% yield).

[0570] 1 H-NMR (400MHz, 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), 2.3 25(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), 3.88 2(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).

[0571] LC-MS (Method 1): R t =0.49min; MS (ESIpos): m / z=324[M+H] +

[0572] Intermediate 2-10

[0573] (2R)-2-({[4-(aminomethyl)pyridin-3-yl]oxy}methyl)morpholine-4-carboxylic acid tert-butyl ester

[0574]

[0575] Using a similar method as described in Intermediate 2-1, tert-butyl morpholino-4-carboxylate (Intermediate 1-10, 6.92 g, 21.7 mmol) was used as the starting material to prepare 6.95 g of the title compound (90% purity, 89% yield).

[0576] 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).

[0577] LC-MS (Method 2): R t =0.84min; MS (ESIpos): m / z=324[M+H] +

[0578] Intermediate 2-11

[0579] 1-{3-[(1S)-1-(1,4-dioxane-2-yl)ethoxy]pyridin-4-yl}methylamine

[0580]

[0581] Using a similar method as described in Intermediate 2-1, 1.49 g (90% purity, 78% yield) of the title compound was prepared from 3-[(1S)-1-(1,4-dioxane-2-yl)ethoxy]pyridine-4-carboxylonitrile (Intermediate 1-11, 1.68 g, 7.17 mmol) as the starting material.

[0582] LC-MS (Method 6): R t =0.2min; MS (ESIpos): m / z=239[M+H] +

[0583] 1 H-NMR (400MHz, 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(2.4 6), 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), 3.8 89(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).

[0584] Intermediate 2-12

[0585] 1-{3-[(1R)-1-(1,4-dioxane-2-yl)ethoxy]pyridin-4-yl}methylamine

[0586]

[0587] Using a similar method as described in Intermediate 2-1, 1.39 g (5.93 mmol) of the title compound was prepared from 3-{(1R)-1-[1,4-dioxane-2-yl]ethoxy}pyridine-4-carboxylonitrile (Intermediate 1-12, 1.39 g, 5.93 mmol) as the starting material.

[0588] 1 H-NMR (400MHz, 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 0.42), 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(1.9) 7), 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).

[0589] LC-MS (Method 6): R t =0.21min; MS (ESIpos): m / z=239[M+H] +

[0590] Intermediate 2-71

[0591] 1-{3-[1-(4-methylmorpholin-2-yl)ethoxy]pyridin-4-yl}methylamine

[0592]

[0593] Using a similar method as described in Intermediate 2-1, 810 mg (99% purity, 97% yield) of the title compound was prepared from 3-({1-[4-methylmorpholin-2-yl]ethyl}oxy)pyridine-4-carboxylonitrile (Intermediate 1-71, 815 mg, 3.30 mmol) as the starting material.

[0594] 1H-NMR (400MHz, 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), 2.5 75 (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).

[0595] LC-MS (Method 6): R t =0.11min; MS (ESIpos): m / z=252[M+H] +

[0596] Synthesis of intermediate 3 compound

[0597] Intermediate 3-1

[0598] 1-Chloro-3-isothiocyano-2-methoxybenzene

[0599]

[0600] 3-Chloro-2-methoxyaniline (CAS) 51114-68-2 8.4 ml (63 mmol) was dissolved in DCM (100 ml), and a saturated sodium bicarbonate solution (100 ml) was added. Phosgene (5.4 ml, 70 mmol) was slowly added to the chilled mixture. The reaction was stirred at 0 °C for 2 hours. The DCM layer was separated at room temperature, washed with a saturated sodium bicarbonate solution, filtered through a hydrophobic filter, and concentrated under reduced pressure to give the title compound (12.97 g, 100% yield), which was used directly in the next step.

[0601] 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).

[0602] Intermediate 3-4

[0603] 1-Fluoro-3-isothiocyano-2-methoxybenzene

[0604]

[0605] Using a method similar to that described in intermediate 3-1, 3-fluoro-2-methoxyaniline (CAS) was employed. 437-83-2 Using 5.00 g (35.4 mmol) as starting material, 6.24 g of the title compound (96% yield) was prepared.

[0606] 1 H-NMR (400MHz, DMSO-d6): δ [ppm] = 7.32 (m, 1H), 7.10-7.19 (m, 2H), 3.96 (d, 3H).

[0607] Intermediate 3-18

[0608] 1-Chloro-5-fluoro-3-isothiocyano-2-methoxybenzene

[0609]

[0610] Using a similar method as described in Intermediate 3-1, 1.17 g of the title compound (95% purity, 90% yield) was prepared from 3-chloro-5-fluoro-2-methoxyaniline (1.00 g, 5.70 mmol) as the starting material.

[0611] 1H NMR (400MHz, DMSO-d6): δ [ppm] = 3.86 (s, 3H) 7.38 (dd, 1H) 7.58 (dd, 1H).

[0612] Intermediate 3-29

[0613] 1-Chloro-2-ethyl-3-isothiocyanobenzene

[0614]

[0615] Using a similar method as described in Intermediate 3-1, 6.29 g of the title compound (85% purity, 99% yield) was prepared from 3-chloro-2-ethylaniline (5.00 g, 85% purity, 27.3 mmol) as the starting material.

[0616] 1 H-NMR (400MHz, 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(6.5 8), 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).

[0617] Intermediate 3-65

[0618] 2-Ethyl-1-fluoro-3-isothiocyanobenzene

[0619]

[0620] Using a similar method as described in Intermediate 3-1, 3.0 g of the title compound (90% purity, 83% yield) was prepared from 2-ethyl-3-fluoroaniline (2.50 g, 18.0 mmol, CAS1139437-61-8) as the starting material.

[0621] 1H-NMR (400MHz, 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(2.0) 6), 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).

[0622] Synthesis of intermediate 4 compound

[0623] Intermediate 4-1

[0624] 5-[(3-chloro-2-methoxyphenyl)thiocarbamoyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[0625]

[0626] DBU (4.5 mL, 30 mmol) was added dropwise to an ice-cold solution of 1-chloro-3-isothiocyano-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). The reaction mixture was stirred overnight at room temperature. Ice water (200 mL) and concentrated HCl (2 mL) were added to the reaction mixture. The mixture was stirred for 20 min and extracted with DCM. The organic phase was filtered through a waterproof filter, concentrated under reduced pressure, and purified by rapid chromatography (silica gel, hexane / EtOAc gradient 0–50%) to give 6.54 g of the title compound (71% yield).

[0627] 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).

[0628] LC-MS (Method 1): R t =1.49min; MS(ESIpos): m / z=413.1[M+H] +

[0629] Intermediate 4-4

[0630] 5-[(3-fluoro-2-methoxyphenyl)thiocarbamoyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[0631]

[0632] Using a similar method as described in Intermediate 4-1, tert-butyl 2,4-dioxopiperidine-1-carboxylate (CAS845267-78-9, 7.26 g, 34.1 mmol) and 1-fluoro-3-isothiocyano-2-methoxybenzene (Intermediate 3-4, 6.24 g, 34.1 mmol) were used as starting materials; the product was stirred in MeOH, filtered, and the precipitate was dried under vacuum to prepare 9.49 g of the title compound (67% yield).

[0633] 1H-NMR (400MHz 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 (brt, 2H), 1.48 (s, 9H).

[0634] LC-MS (Method 2): R t =0.66min; MS(ESIpos): m / z=397.3[M+H] +

[0635] Intermediate 4-7

[0636] 5-[(2,3-dichlorophenyl)thiocarbamoyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[0637]

[0638] 1,2-Dichloro-3-isothiocyanobenzene (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 overnight at room temperature. The reaction mixture was diluted with HCl (200 mL, 1 N aqueous solution) and stirred at room temperature for 30 minutes. The resulting solid was filtered off, the filter cake was washed with water, and dried overnight in a vacuum oven at 50 °C to give 9.40 g of the title compound (92% yield).

[0639] 1H-NMR (400MHz, 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), 2.6 69(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).

[0640] LC-MS (Method 2): R t =0.70min; MS(ESIpos): m / z=416[MH] -

[0641] Intermediate 4-10

[0642] 5-[(3-chloro-2-methylphenyl)thiocarbamoyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[0643]

[0644] According to the method described in intermediate 4-1; using 1-chloro-3-isothiocyano-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; HCl was added, the mixture was filtered, and the precipitate was dried under vacuum to prepare 4.68 g of the title compound (78% yield).

[0645] 1H-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).

[0646] LC-MS (Method 2): R t =0.72min; MS(ESIpos): m / z=397.3[M+H] +

[0647] Intermediate 4-18

[0648] 5-[(3-chloro-5-fluoro-2-methoxyphenyl)thiocarbamoyl]4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[0649]

[0650] Using a similar method as described in Intermediate 4-1, tert-butyl 2,4-dioxopiperidine-1-carboxylate (CAS845267-78-9, 1.15 g, 5.38 mmol) and 1-chloro-5-fluoro-3-isothiocyano-2-methoxybenzene (Intermediate 3-18, 1.17 g, 5.38 mmol) as starting materials, 1.42 g of the title compound (75% purity, 46% yield) was prepared.

[0651] 1 H-NMR (400MHz, 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), 3.3 59 (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).

[0652] LC-MS (Method 2): R t =0.73min; MS (ESIpos): m / z=431[M+H] +

[0653] Intermediate 4-29

[0654] 5-[(3-chloro-2-ethylphenyl)thiocarbamoyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[0655]

[0656] Using a similar method as described in Intermediate 4-1, tert-butyl 2,4-dioxopiperidin-1-carboxylate (CAS845267-78-9, 5.77 g, 27.0 mmol) and 2-chloro-1-ethyl-3-isothiocyanobenzene (Intermediate 3-29, 6.29 g, 85% purity, 27.0 mmol) as starting materials, 6.35 g of the title compound (85% purity, 49% yield) was prepared.

[0657] 1 H-NMR (400MHz, 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), 2.8 83(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).

[0658] Intermediate 4-38

[0659] 5-[(3-fluoro-2-methylphenyl)thiocarbamoyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[0660]

[0661] Using a similar method as described in Intermediate 4-1, tert-butyl 2,4-dioxopiperidine-1-carboxylate (CAS 845267-78-9, 8.19 g, 38.4 mmol) and 1-fluoro-3-isothiocyano-2-methylbenzene (CAS 363179-58-2, 6.42 g, 38.4 mmol) were used as starting materials; the product was stirred in MeOH, filtered, and the precipitate was dried under vacuum to prepare 11.1 g of the title compound (95% purity, 72% yield).

[0662] 1 H-NMR (400MHz, 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 (0.6 1), 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).

[0663] Intermediate 4-40

[0664] 5-{[2-(2,2-difluoroethyl)-3-fluorophenyl]thiocarbamoyl}-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[0665]

[0666] Using a similar method as described in Intermediate 4-1, 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-isothiocyanobenzene (CAS 2311902-79-9, 8.00 g, 36.8 mmol) as starting materials, 12.1 g of the title compound (95% purity, 72% yield) was prepared.

[0667] 1H-NMR (400MHz, 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), 3.1 66(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).

[0668] Intermediate 4-65

[0669] 5-[(2-ethyl-3-fluorophenyl)thiocarbamoyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[0670]

[0671] Using a similar method as described in Intermediate 4-1, tert-butyl 2,4-dioxopiperidin-1-carboxylate (CAS845267-78-9, 7.85 g, 36.8 mmol) and 2-ethyl-1-fluoro-3-isothiocyanobenzene (Intermediate 3-65, 3.00 g, 16.6 mmol) as starting materials, 5.46 g of the title compound (95% purity, 79% yield) was prepared.

[0672] 1 ¹H-NMR (400MHz, 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 =0.72min; MS (ESIpos): m / z=395[M+H] +

[0673] Synthesis of intermediate 5 compound

[0674] Intermediate 5-1

[0675] N-(3-chloro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide

[0676]

[0677] TFA (12 mL, 160 mmol) was added to a solution of tert-butyl 5-[(3-chloro-2-methoxyphenyl)thiocarbamoyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate (intermediate 4-1, 6.54 g, 15.8 mmol) in dichloromethane (94 mL), 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 saturated sodium bicarbonate solution and brine. The organic layer was filtered through a hydrophobic filter, and the filtrate was dried to dryness. The residue was purified by rapid chromatography (silica gel, hexane / EtOAc gradient 20-100%) to give 4.06 g of the title compound (78% yield).

[0678] 1 H-NMR (400MHz, 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), 3.73-3.7 6(m, 3H), 3.43(td, 1H), 3.27-3.32(m, 1H), 2.79(t, 1H), 2.59-2.69(m, 1H).

[0679] LC-MS (Method 1): R t =1.19min; MS (ESIpos): m / z=313[M+H] +

[0680] Intermediate 5-4

[0681] N-(3-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide

[0682]

[0683] Using a similar method as described in Intermediate 5-1, tert-butyl 5-[(3-fluoro-2-methoxyphenyl)thiocarbamoyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate (Intermediate 4-4, 9.49 g, 23.9 mmol) was used as the starting material, and after stirring for 15 minutes, 6.98 g of the title compound (89% yield) was prepared and could be used for the next step without further purification.

[0684] 1 H-NMR (400MHz, 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).

[0685] LC-MS (Method 2): R t =0.46min; MS(ESIpos): m / z=297.1[M+H] +

[0686] Intermediate 5-7

[0687] N-(2,3-dichlorophenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide

[0688]

[0689] Using a similar method as described in Intermediate 5-1, tert-butyl 5-[(2,3-dichlorophenyl)thiocarbamoyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate (Intermediate 4-7, 9.40 g, 22.5 mmol) was used as the starting material; after stirring overnight, 5.71 g of the title compound (62% yield) was obtained.

[0690] 1H-NMR (400MHz, 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).

[0691] LC-MS (Method 2): R t =0.55min; MS(ESIpos): m / z=316[MH] - .

[0692] Intermediate 5-10

[0693] N-(3-chloro-2-methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide

[0694]

[0695] Using a similar method as described in Intermediate 5-1, with 5-[(3-chloro-2-methylphenyl)thiocarbamoyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (Intermediate 4-10, 4.67 g, 11.8 mmol) as the starting material, 3.54 g of the title compound (91% yield) was prepared after 3 hours and could be used in the next step without further purification.

[0696] 1 H-NMR (400MHz, 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).

[0697] LC-MS (Method 2): R t =0.60min; MS(ESIpos): m / z=297.4[M+H] + .

[0698] Intermediate 5-18

[0699] N-(3-chloro-5-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide

[0700]

[0701] Using a similar method as described in Intermediate 5-1, tert-butyl 5-[(3-chloro-5-fluoro-2-methoxyphenyl)thiocarbamoyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate (Intermediate 4-18, 1.42 g, 3.30 mmol) was used as the starting material to prepare 690 mg of the title compound (95% purity, 60% yield).

[0702] 1H-NMR (400MHz, 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).

[0703] LC-MS (Method 2): R t =0.57min; MS(ESIneg): m / z=329[MH] - .

[0704] Intermediate 5-29

[0705] N-(3-chloro-2-ethylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide

[0706]

[0707] Using a similar method as described in Intermediate 5-1, tert-butyl 5-[(3-chloro-2-ethylphenyl)thiocarbamoyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate (Intermediate 4-29, 2.35 g, 75% purity, 4.29 mmol) was used as the starting material to prepare 1.22 g of the title compound (95% purity, 87% yield).

[0708] 1H-NMR (400MHz, 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), 1.15 4(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).

[0709] LC-MS (Method 6): Rt = 1.28 min; MS (ESIpos): m / z = 311 [M+H] + .

[0710] Intermediate 5-38

[0711] N-(3-fluoro-2-methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide

[0712]

[0713] Using a similar method as described in Intermediate 5-1, tert-butyl 5-[(3-fluoro-2-methylphenyl)thiocarbamoyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate (Intermediate 4-38, 11.1 g, 29.1 mmol) was used as the starting material, and 7.25 g of the title compound (84% yield) was prepared after stirring for 15 minutes. It could be used in the next step without further purification.

[0714] 1 H-NMR (400MHz, 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).

[0715] LC-MS (Method 2): R t =0.47min; MS (ESIpos): m / z=281[M+H] + .

[0716] Intermediate 5-40

[0717] N-[2-(2,2-difluoroethyl)-3-fluorophenyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide

[0718]

[0719] Using a similar method as described in Intermediate 5-1, tert-butyl 5-{[2-(2,2-difluoroethyl)-3-fluorophenyl]thiocarbamoyl}-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate (Intermediate 4-40, 12.1 g, 28.0 mmol) was used as the starting material to prepare 8.81 g of the title compound (95% purity, 90% yield).

[0720] 1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.145 (0.50), 1.154 (1.98), 1.172 (3.87), 1.190 (1.88), 1.441 (0.60), 1.9 87(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).

[0721] LC-MS (Method 2): R t =0.48min; MS(ESIpos): m / z=331.1[M+H] + .

[0722] Intermediate 5-65

[0723] N-(2-ethyl-3-fluorophenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide

[0724]

[0725] Using a similar method as described in Intermediate 5-1, tert-butyl 5-[(2-ethyl-3-fluorophenyl)thiocarbamoyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate (Intermediate 4-65, 5.46 g, 71% purity, 9.83 mmol) was used as the starting material to prepare 4.0 g of the title compound (70% purity, 97% yield).

[0726] 1 H-NMR (400MHz, DMSO-d6) δ [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),2.64 7 (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).

[0727] LC-MS (Method 6): R t =1.18min; MS(ESIpos): m / z=295[M+H] + .

[0728] Synthesis of intermediate 6 compound

[0729] Intermediate 6-1

[0730] N-(3-chloro-2-methoxyphenyl)-4-[({3-[(1,4-dioxane-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide

[0731]

[0732] A mixture of N-(3-chloro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (intermediate 5-1, 498 mg, 1.59 mmol) and 1-{3-[(1,4-dioxane-2-yl)methoxy]pyridine-4-yl}methylamine (intermediate 2-1, 0.5 g, 2.23 mmol) was stirred at 120 °C for 4 hours. The reaction mixture was purified by rapid chromatography (silica gel, DCM / EtOH gradient 0-30%) to give 325 mg of the title compound (39% yield).

[0733] 1 H-NMR (400MHz, 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).

[0734] LC-MS (Method 2): R t =1.07min; MS(ESIpos): m / z=519.2[M+H] + .

[0735] Intermediate 6-2

[0736] N-(3-chloro-2-methoxyphenyl)-4-{[(3-{[(2S)-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide

[0737]

[0738] A mixture of N-(3-chloro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (intermediate 5-1, 866 mg, 2.77 mmol) and 1-(3-{[(2S)-1,4-dioxane-2-yl]methoxy}pyridine-4-yl)methylamine (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 rapid chromatography (silica gel, DCM / EtOH gradient 0-20%) to give 1.23 g (95% purity, 81% yield) of the title compound.

[0739] 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).

[0740] LC-MS (Method 2): R t =1.09min; MS (ESIpos): m / z=519[M+H] +

[0741] Intermediate 6-4

[0742] 4-[({3-[(1,4-dioxane-2-yl)methoxy]pyridin-4-yl}methyl)amino]-N-(3-fluoro-2-methoxyphenyl)-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide

[0743]

[0744] Using a similar method as described in Intermediate 6-1, N-(3-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (Intermediate 5-4, 179 mg, 604 μmol) and 1-{3-[(1,4-dioxane-2-yl)methoxy]pyridine-4-yl}methylamine (Intermediate 2-1, 190 mg, 845 μmol) were used as starting materials; after heating for 2 hours and purification by rapid chromatography (amino-phase silica gel, DCM / EtOH gradient 0-10%), 120 mg of the title compound (34% yield) was prepared.

[0745] 1 H-NMR (400MHz, 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).

[0746] LC-MS (Method 2): R t =1.01min; MS (ESIpos): m / z=503[M+H] + .

[0747] Intermediate 6-7

[0748] N-(2,3-dichlorophenyl)-4-[({3-[(1,4-dioxane-2-yl)methoxy]pyridin-4-yl}methyl)amino)]-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide

[0749]

[0750] Using a similar method as described in Intermediate 6-1, starting materials were N-(2,3-dichlorophenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (intermediate 5-7, 160 mg, 504 μmol) and 1-{3-[(1,4-dioxane-2-yl)methoxy]pyridine-4-yl}methylamine (intermediate 2-1, 158 mg, 706 μmol); after heating for 2 hours and purification by rapid chromatography (amino-phase silica gel, DCM / EtOH gradient 0-10%), 110 mg of the title compound (35% yield) was prepared.

[0751] 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).

[0752] LC-MS (Method 2): R t =1.08min; MS(ESIpos): m / z=523[M+H] + .

[0753] Intermediate 6-10

[0754] N-(3-chloro-2-methylphenyl)-4-[({3-[(1,4-dioxane-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide

[0755]

[0756] Using a similar method as described in Intermediate 6-1, N-(3-chloro-2-methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (intermediate 5-10, 189 mg, 637 μmol) and 1-{3-[(1,4-dioxane-2-yl)methoxy]pyridine-4-yl}methylamine (intermediate 2-1, 200 mg, 892 μmol) were used as starting materials; after heating for 2 hours and purification by rapid chromatography (amino-phase silica gel, DCM / EtOH gradient 0-10%), 180 mg of the title compound (56% yield) was prepared.

[0757] 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).

[0758] LC-MS (Method 2): R t =1.09min; MS(ESIpos): m / z=501[M+H] + .

[0759] Intermediate 6-11

[0760] 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-thiocarboxamide

[0761]

[0762] Using a similar method as described in Intermediate 6-1, starting materials N-(3-chloro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (Intermediate 5-1, 142 mg, 407 μmol) and 1-(3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridine-4-yl)methylamine (Intermediate 2-2, 116 mg, 489 μmol) were used; after 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), 85.6 mg of the title compound (36% yield) was prepared.

[0763] 1 H-NMR (400MHz, 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).

[0764] LC-MS (Method 2): R t =1.08min; MS(ESIpos): m / z=532.5[M+H] +

[0765] Intermediate 6-12

[0766] N-(3-fluoro-2-methoxyphenyl)-4-(((3-hydroxypyridin-4-yl)methyl)amino)-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide

[0767]

[0768] Under a nitrogen atmosphere, a mixture of 4-(aminomethyl)pyridine-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-thiocarboxamide (intermediate 5-4, 150 g, 0.506 mol) in DMA (1.2 L) was stirred at 120 °C for 2.5 h. The mixture was concentrated under vacuum to remove most of the solvent. A 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 x 2). The organic phase was dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was slurried with EtOAc (300 mL) and filtered. The filter cake was dried under vacuum to give the title compound (87 g, 47% yield) as a yellow solid.

[0769] 1 H NMR (400MHz, 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).

[0770] Intermediate 6-15

[0771] 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-thiocarboxamide

[0772]

[0773] Using a similar method as described in Intermediate 6-1, N-(3-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (intermediate 5-4, 100 mg, 320 μmol) and 1-(3-{[4-methylmorpholin-2-yl]methoxy}pyridine-4-yl)methylamine (intermediate 2-3, 114 mg, 480 μmol) were used as starting materials; the mixture was heated for 4 hours and purified by rapid chromatography (amino-phase silica gel, DCM / EtOH gradient 0-10%) to prepare 74.3 mg (80% purity, 35% yield) of the title compound.

[0774] 1H-NMR (400MHz, 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 (0.6 1), 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).

[0775] LC-MS (Method 2): R t =0.84min; MS (ESIpos): m / z=532[M+H] +

[0776] Intermediate 6-18

[0777] 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-thiocarboxamide

[0778]

[0779] Using a similar method as described in Intermediate 6-1, the title compound was prepared using N-(3-chloro-5-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (intermediate 5-18, 100 mg, 302 μmol) and 1-(3-{[4-methylmorpholin-2-yl]methoxy}pyridine-4-yl)methylamine (intermediate 2-3, 108 mg, 453 μmol) as starting materials; after purification by rapid chromatography (amino-phase silica gel, DCM / EtOH gradient 0-10%), 166 mg (70% purity, 70% yield) was obtained.

[0780] 1 H-NMR (400MHz, 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), 3.81 5 (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).

[0781] LC-MS (Method 2): R t=1.11min; MS(ESIpos): m / z=550[M+H] +

[0782] Intermediate 6-19

[0783] N-(3-chloro-5-fluoro-2-methoxyphenyl)-4-[({3-[(1,4-dioxane-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide

[0784]

[0785] Using a similar method as described in Intermediate 6-1, the title compound was prepared in 160 mg (90% purity, 89% yield) using N-(3-chloro-5-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (intermediate 5-18, 100 mg, 302 μmol) and 1-(3-{[1,4-dioxane-2-yl]methoxy}pyridine-4-yl)methylamine (intermediate 2-1, 94.9 mg, 423 μmol) as starting materials and purified by rapid chromatography (silica gel, DCM / EtOH gradient 0-30%).

[0786] 1H-NMR (400MHz, 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), 3.78 5 (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).

[0787] LC-MS (Method 2): R t =1.14min; MS(ESIpos): m / z=537[M+H] +

[0788] Intermediate 6-20

[0789] 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-thiocarboxamide

[0790]

[0791] Using a similar method as described in Intermediate 6-1, starting materials N-(3-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (intermediate 5-4, 200 mg, 675 μmol) and 1-(3-{[(3S)-4-methylmorpholin-3-yl]methoxy}pyridine-4-yl)methylamine (intermediate 2-4, 208 mg, 877 μmol) were heated for 3 hours and purified by preparative HPLC (Method 10, gradient: 0.00–0.50 min 15% B, 0.50–6.00 min 15–55% B) to prepare 105 mg (99% purity, 30% yield) of the title compound.

[0792] 1H-NMR(400MHz,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).

[0793] LC-MS (Method 6): Rt = 0.62 min; MS (ESIpos): m / z = 516 [M+H] +

[0794] Intermediate 6-21

[0795] 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-thiocarboxamide

[0796]

[0797] Using a similar method as described in Intermediate 6-1, starting materials N-(3-chloro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (Intermediate 5-1, 200 mg, 639 μmol) and 1-(3-{[(3S)-4-methylmorpholin-3-yl]methoxy}pyridine-4-yl)methylamine (Intermediate 2-4, 197 mg, 831 μmol) were heated at 120 °C for 3 hours and purified by preparative HPLC (Method 10, gradient: 0.00–0.50 min 15% B, 0.50–6.00 min 15–55% B) to prepare 102 mg (99% purity, 30% yield) of the title compound.

[0798] 1H-NMR (400MHz, DMSO-d6) δ [ppm]: 2.288 (3.78), 2.327 (0.47), 2.518 (1.87), 2.523 (1.27), 2.65 1(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), 3.89 1 (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 (1.4) 7), 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).

[0799] LC-MS (Method 6): Rt = 0.68 min; MS (ESIpos): m / z = 532 [M+H] +

[0800] Intermediate 6-22

[0801] (2S)-2-[({4-[({5-[(3-fluoro-2-methoxyphenyl)thiocarbamoyl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}amino)methyl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylic acid tert-butyl ester

[0802]

[0803] Using a similar method as described in Intermediate 6-1, N-(3-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (Intermediate 5-4, 1.00 g, 3.37 mmol) and (2S)-2-({[4-(aminomethyl)pyridin-3-yl]oxy}methyl)morpholine-4-carboxylic acid tert-butyl ester (Intermediate 2-5, 1.53 g, 4.72 mmol) were used as starting materials; the mixture was heated for 6 hours and purified by rapid chromatography (silica gel, DCM / EtOH gradient 0-20%) to prepare 1.43 g (70% purity, 49% yield) of the title compound.

[0804] 1 H-NMR (400MHz, 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(3.2 6), 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).

[0805] LC-MS (Method 2): R t =1.19min; MS (ESIpos): m / z=602[M+H] +

[0806] Intermediate 6-24

[0807] N-(3-chloro-2-methoxyphenyl)-4-[({3-[2-(1,4-dioxane-2-yl)ethoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide

[0808]

[0809] Using a similar method as described in Intermediate 6-1, starting materials N-(3-chloro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (Intermediate 5-1, 200 mg, 639 μmol) and 1-(3-{2-[1,4-dioxane-2-yl]ethoxy}pyridine-4-yl)methylamine (Intermediate 2-6, 198 mg, 831 μmol) were heated at 130 °C for 3 hours and purified by preparative HPLC (Method 10, gradient: 0.00–0.50 min 15% B, 0.50–6.00 min 15–55% B) to prepare 110 mg (96% purity, 31% yield) of the title compound.

[0810] 1H-NMR (400MHz, 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(2.1) 6), 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).

[0811] LC-MS (Method 6): Rt = 0.90 min; MS (ESIpos): m / z = 533 [M+H] +

[0812] Intermediate 6-27

[0813] (2S)-2-[({4-[({5-[(3-chloro-5-fluoro-2-methoxyphenyl)thiocarbamoyl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}amino)methyl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylic acid tert-butyl ester

[0814]

[0815] Using a similar method as described in Intermediate 6-1, N-(3-chloro-5-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (Intermediate 5-18, 225 mg, 680 μmol) and (2S)-2-({[4-(aminomethyl)pyridin-3-yl]oxy}methyl)morpholine-4-carboxylic acid tert-butyl ester (Intermediate 2-5, 308 mg, 952 μmol) were used as starting materials; the mixture was heated for 6 hours and purified by rapid chromatography (silica gel, DCM / EtOH gradient 0-20%) to prepare 150 mg (80% purity, 28% yield) of the title compound.

[0816] 1H-NMR (400MHz, 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), 3.71 9 (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), 7.2 67 (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).

[0817] LC-MS (Method 2): R t =1.30min; MS(ESIpos): m / z=636[M+H] +

[0818] Intermediate 6-29

[0819] 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-thiocarboxamide

[0820]

[0821] Using a similar method as described in Intermediate 6-1, N-(3-chloro-2-ethylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (intermediate 5-29, 300 mg, 965 μmol) and 1-(3-{[4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)methylamine (intermediate 2-3, 321 mg, 1.35 mmol) were used as starting materials; the mixture was heated for 6 hours and purified by rapid chromatography (silica gel, DCM / EtOH gradient 0-20%) to prepare 300 mg (80% purity, 47% yield) of the title compound.

[0822] 1H-NMR (400MHz, 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), 1.0 35(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), 3.43 4(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(2.6) 4), 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).

[0823] LC-MS (Method 2): R t=1.14min; MS(ESIpos): m / z=530[M+H] +

[0824] Intermediate 6-30

[0825] N-(3-chloro-2-methoxyphenyl)-4-[({3-[(5,5-dimethyl-1,4-dioxane-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide

[0826]

[0827] Using a similar method as described in Intermediate 6-1, starting materials were N-(3-chloro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (Intermediate 5-1, 200 mg, 639 μmol) and 1-{3-[(5,5-dimethyl-1,4-dioxane-2-yl)methoxy]pyridine-4-yl}methylamine (Intermediate 2-7, 210 mg, 831 μmol); the mixture was heated at 130 °C for 3 h and purified by preparative HPLC (Method 10, gradient: 0.00–0.50 min 15% B, 0.50–6.00 min 15–55% B) to obtain 55.0 mg (98% purity, 15% yield) of the title compound.

[0828] 1H-NMR (400MHz, DMSO-d6): δ[ppm]=1.042(9.29), 1.249(8.31), 2.518(2.85), 2.523(1.83), 2.7 52(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), 4.16 4 (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 (2.1 7), 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).

[0829] LC-MS (Method 6): Rt = 1.04 min; MS (ESIpos): m / z = 547 [M+H] +

[0830] Intermediate 6-33

[0831] 4-[({3-[(5,5-dimethyl-1,4-dioxane-2-yl)methoxy]pyridin-4-yl}methyl)amino]-N-(3-fluoro-2-methoxyphenyl)-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide]

[0832]

[0833] Using a similar method as described in Intermediate 6-1, starting materials N-(3-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (Intermediate 5-1, 200 mg, 675 μmol) and 1-{3-[(5,5-dimethyl-1,4-dioxane-2-yl)methoxy]pyridine-4-yl}methylamine (Intermediate 2-7, 221 mg, 877 μmol) were heated at 130 °C for 2 hours and purified by preparative HPLC (Method 10, gradient: 0.00–0.50 min 15% B, 0.50–6.00 min 15–55% B) to prepare 130 mg (96% purity, 35% yield) of the title compound.

[0834] 1H-NMR (400MHz, 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), 4.18 1 (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), 7.09 8 (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).

[0835] LC-MS (Method 6): Rt = 0.94 min; MS (ESIpos): m / z = 531 [M+H] +

[0836] Intermediate 6-35

[0837] 4-{[(3-{2-[1,4-dioxane-2-yl]ethoxy}pyridin-4-yl)methyl]amino}-N-(3-fluoro-2-methoxyphenyl)-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide

[0838]

[0839] Using a similar method as described in Intermediate 6-1, the title compound was prepared in 137 mg (96% purity, 38% yield) using N-(3-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (intermediate 5-4, 200 mg, 675 μmol) and 1-(3-{2-[1,4-dioxane-2-yl]ethoxy}pyridine-4-yl)methylamine (intermediate 2-6, 209 mg, 877 μmol) as starting materials.

[0840] LC-MS (Method 6): Rt = 0.83 min; MS (ESIpos): m / z = 517 [M+H] +

[0841] 1H-NMR(400MHz,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).

[0842] Intermediate 6-37

[0843] 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-thiocarboxamide

[0844]

[0845] Using a similar method as described in Intermediate 6-1, starting materials were N-(3-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (Intermediate 5-4, 200 mg, 675 μmol) and 1-(3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridine-4-yl)methylamine (Intermediate 2-2, 224 mg, 945 μmol); after heating at 124 °C for 1 hour and purification by preparative HPLC (Method 10, gradient: 0.00–0.50 min 15% B, 0.50–6.00 min 15–55% B), 134 mg of the title compound (38% yield) was obtained.

[0846] 1H-NMR (400MHz, 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), 4.0 47(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).

[0847] LC-MS (Method 6): R t =0.64min; MS(ESIpos): m / z=516[M+H] +

[0848] Intermediate 6-38

[0849] 4-[[3-[(5,5-dimethyl-1,4-dioxane-2-yl)methoxy]-4-pyridyl]methylamino]-N-(3-fluoro-2-methyl-phenyl)-6-oxo-2,3-dihydro-1H-pyridine-5-thiocarboxamide]

[0850]

[0851] Using a similar method as described in Intermediate 6-1, starting materials were N-(3-fluoro-2-methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (intermediate 5-38, 350 mg, 1.25 mmol) and 1-{3-[(5,5-dimethyl-1,4-dioxane-2-yl)methoxy]pyridine-4-yl}methylamine (intermediate 2-7, 315 mg, 1.25 mmol); the mixture was heated at 120 °C for 3 h and purified by preparative HPLC (Method 11, gradient: 0.00–2.00 min 30% B, 2.00–14.00 min 30–70% B) to obtain 192 mg of the title compound (27% yield).

[0852] 1H-NMR (400MHz, 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 0.90), 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(0.8 2), 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).

[0853] LC-MS (Method 6): R t =0.98min; MS (ESIpos): m / z=515[M+H] +

[0854] Intermediate 6-40

[0855] N-[2-(2,2-difluoroethyl)-3-fluoro-phenyl]-4-[[3-(1,4-dioxane-2-ylmethoxy)-4-pyridinyl]methylamino]-6-oxo-2,3-dihydro-1H-pyridine-5-thiocarboxamide

[0856]

[0857] Using a similar method as described in Intermediate 6-1, N-[2-(2,2-difluoroethyl)-3-fluorophenyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (Intermediate 5-40, 100 mg, 303 μmol) and 1-{3-[(1,4-dioxane-2-yl)methoxy]pyridine-4-yl}methylamine (Intermediate 2-1, 95.0 mg, 424 μmol) were used as starting materials; after purification by rapid chromatography (silica gel, DCM / EtOH gradient 0-10%), 19.5 mg of the title compound (10% yield) was prepared.

[0858] LC-MS (Method 2): R t =1.07min; MS(ESIpos): m / z=537[M+H] +

[0859] Intermediate 6-41

[0860] (2S)-2-{[(4-{[(5-{[2-(2,2-difluoroethyl)-3-fluorophenyl]thiocarbamoyl}-6-oxo-1,2,3,6-tetrahydropyridin-4-yl)amino]methyl}pyridin-3-yl)oxy]methyl}tert-butyl morpholino-4-carboxylate

[0861]

[0862] A mixture of N-[2-(2,2-difluoroethyl)-3-fluorophenyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (intermediate 5-40, 200 mg, 605 μmol) and (2S)-2-({[4-(aminomethyl)pyridin-3-yl]oxy}methyl)morpholine-4-carboxylic acid tert-butyl ester (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 10416-59-8) and stirred at 80 °C for 5 hours. The reaction was then treated with another equal volume (111 μl, 0.6 mmol) of N,O-bis-(trimethylsilyl)acetamide and stirred overnight at 80 °C. The reaction mixture was diluted in DCM and purified by rapid chromatography (silica gel, DCM / EtOH gradient 0-20%) to give 255 mg (45% yield) of the title compound.

[0863] LC-MS (Method 2): R t =1.25min; MS(ESIpos): m / z=636[M+H]+

[0864] Intermediate 6-42

[0865] (2S)-2-[({4-[({5-[(3-chloro-2-methylphenyl)thiocarbamoyl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}amino)methyl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylic acid tert-butyl ester

[0866]

[0867] Using a similar method as described in Intermediate 6-1, N-(3-chloro-2-methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (intermediate 5-10, 350 mg, 1.18 mmol) and (2S)-2-({[4-(aminomethyl)pyridin-3-yl]oxy}methyl)morpholine-4-carboxylic acid tert-butyl ester (intermediate 2-5, 381 mg, 1.18 mmol) were used as starting materials; the mixture was heated for 3 hours and analyzed by preparative HPLC (Method 11, 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 (68.9-70% B), 208 mg of the title compound (99% purity, 29% yield) was obtained.

[0868] 1H-NMR (400MHz, 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), 3.75 6 (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 (0.8 9), 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).

[0869] LC-MS (Method 6): Rt = 1.17 min; MS (ESIpos): m / z = 602 [M+H] +

[0870] Intermediate 6-43

[0871] (3R)-3-[({4-[({5-[(3-chloro-2-methylphenyl)thiocarbamoyl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}amino)methyl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylic acid tert-butyl ester

[0872]

[0873] Using a similar method as described in Intermediate 6-1, N-(3-chloro-2-methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (intermediate 5-10, 350 mg, 1.18 mmol) and (3R)-3-({[4-(aminomethyl)pyridin-3-yl]oxy}methyl)morpholine-4-carboxylic acid tert-butyl ester (intermediate 2-9, 381 mg, 1.18 mmol) were used as starting materials; the mixture was heated for 3 hours and analyzed by preparative HPLC (Method 11, 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 (68.9-70% B), 184 mg of the title compound (99% purity, 26% yield) was obtained.

[0874] 1 H-NMR (400MHz, 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).

[0875] LC-MS (Method 6): Rt = 1.17 min; MS (ESIpos): m / z = 602 [M+H] +

[0876] Intermediate 6-44

[0877] N-(3-chloro-2-methyl-phenyl)-4-[[3-[(5,5-dimethyl-1,4-dioxane-2-yl)methoxy]-4-pyridyl]methylamino]-6-oxo-2,3-dihydro-1H-pyridine-5-thiocarboxamide

[0878]

[0879] Using a similar method as described in intermediates 6-41, N-(3-chloro-2-methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (intermediates 5-10, 200 mg, 674 μmol) and 1-{3-[(5,5-dimethyl-1,4-dioxane-2-yl)methoxy]pyridine-4-yl}methylamine (intermediates 2-7, 200 mg, 85% purity, 674 μmol) were used as starting materials to prepare 328 mg of the title compound (97% purity, 89% yield).

[0880] 1H-NMR (400MHz, DMSO-d6): δ[ppm]=1.047(14.25), 1.253(12.85), 2.077(16.00), 2.162(14.45), 2.520(1.8 7), 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), 3.1 70 (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), 3.8 02 (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), 7.2 00(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).

[0881] LC-MS (Method 6): Rt = 1.06 min; MS (ESIpos): m / z = 531 [M+H] +

[0882] Intermediate 6-47

[0883] 4-[[3-(1,4-dioxane-2-ylmethoxy)-4-pyridyl]methylamino]-N-(3-fluoro-2-methyl-phenyl)-6-oxo-2,3-dihydro-1H-pyridine-5-thiocarboxamide

[0884]

[0885] Using a similar method as described in intermediates 6-41, with N-(3-fluoro-2-methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (intermediate 5-38, 300 mg, 1.07 mmol) and 1-{3-[(1,4-dioxane-2-yl)methoxy]pyridine-4-yl}methylamine (intermediate 2-1, 240 mg, 1.07 mmol) as starting materials, 156.3 mg of the title compound (93% purity, 71% yield) was prepared.

[0886] 1H-NMR (400MHz, 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), 3.39 3 (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), 3.7 69(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).

[0887] LC-MS (Method 6): Rt = 0.85 min; MS (ESIpos): m / z = 487 [M+H] +

[0888] Intermediate 6-50

[0889] N-(3-chloro-2-methyl-phenyl)-4-[[3-(1,4-dioxane-2-ylmethoxy)-4-pyridinyl]methylamino]-6-oxo-2,3-dihydro-1H-pyridine-5-thiocarboxamide

[0890]

[0891] Using a similar method as described in intermediates 6-41, N-(3-chloro-2-methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (intermediate 5-10, 200 mg, 674 μmol) and 1-{3-[(1,4-dioxane-2-yl)methoxy]pyridine-4-yl}methylamine (intermediate 2-1, 151 mg, 674 μmol) were used as starting materials to prepare 150.0 mg of the title compound (96% purity, 42% yield).

[0892] 1H-NMR (400MHz, 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), 3.88 3(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(1.2) 4), 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).

[0893] LC-MS (Method 6): Rt = 0.94 min; MS (ESIpos): m / z = 503 [M+H] +

[0894] Intermediate 6-52

[0895] N-(3-chloro-2-ethyl-phenyl)-4-[[3-(1,4-dioxane-2-ylmethoxy)-4-pyridinyl]methylamino]-6-oxo-2,3-dihydro-1H-pyridine-5-thiocarboxamide

[0896]

[0897] Using a similar method as described in intermediates 6-41, N-(3-chloro-2-ethylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (intermediate 5-29, 150 mg, 483 μmol) and 1-{3-[(1,4-dioxane-2-yl)methoxy]pyridine-4-yl}methylamine (intermediate 2-1, 108 mg, 483 μmol) were used as starting materials; the title compound (90% purity, 54% yield) was prepared by purification using rapid chromatography (silica gel, DCM / EtOH gradient 1-13%).

[0898] 1 H-NMR (400MHz, DMSO-d6): δppm=1.01-1.11(m, 4H), 2.56-2.65(m, 2H), 2.73-2.81(m, 2H), 3.12-3.22( m, 2H), 3.39-3.54 (m, 3H), 3.58-3.69 (m, 2H), 3.73-3.80 (m, 1H), 3.88 (s, 2H), 4.09-4.23 (m, 2H), 4.11 -4.15(m, 1H), 4.57-4.71(m, 2H), 7.16-7.25(m, 2H), 7.28-7.36(m, 2H), 7.32(s, 1H), 7.66-7.75(m, 1H ), 8.07-8.11(m, 1H), 8.21-8.26(m, 1H), 8.33-8.43(m, 1H), 13.60-13.70(m, 1H), 14.59-14.67(m, 1H).

[0899] LC-MS (Method 2): R t =1.15min; MS (ESIpos): m / z=517[M+H] +

[0900] Intermediate 6-53

[0901] N-(3-chloro-2-ethylphenyl)-4-{[(3-{[(2S)-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide

[0902]

[0903] Using a similar method as described in intermediates 6-41, N-(3-chloro-2-ethylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (intermediate 5-29, 210 mg, 676 μmol) and 1-(3-{[(2S)-1,4-dioxane-2-yl]methoxy}pyridine-4-yl)methylamine (intermediate 2-8, 185 mg, 90% purity, 743 μmol) were used as starting materials; the title compound was prepared in 320.0 mg (86% yield) by purification using rapid chromatography (silica gel, DCM / EtOH gradient 1-15%).

[0904] 1H-NMR(400MHz,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).

[0905] LC-MS (Method 2): R t =1.17min; MS (ESIpos): m / z=517[M+H] +

[0906] Intermediate 6-55

[0907] (2R)-2-[({4-[({5-[(3-chloro-2-ethylphenyl)thiocarbamoyl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}amino)methyl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylic acid tert-butyl ester

[0908]

[0909] Using a similar method as described in intermediates 6-41, N-(3-chloro-2-ethylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (intermediate 5-29, 300 mg, 965 μmol) and (2R)-2-({[4-(aminomethyl)pyridin-3-yl]oxy}methyl)morpholine-4-carboxylic acid tert-butyl ester (intermediate 2-10, 312 mg, 965 μmol) were used as starting materials; the title compound (95% purity, 76% yield) was prepared to 476.0 mg by purification using rapid chromatography (silica gel, DCM / EtOH gradient 1-10%).

[0910] 1H-NMR (400MHz, 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).

[0911] LC-MS (Method 2): R t =1.32min; MS(ESIpos): m / z=616[M+H] +

[0912] Intermediate 6-56

[0913] (2S)-2-[({4-[({5-[(3-chloro-2-ethylphenyl)thiocarbamoyl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}amino)methyl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylic acid tert-butyl ester

[0914]

[0915] Using a similar method as described in intermediates 6-41, N-(3-chloro-2-ethylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (intermediate 5-29, 300 mg, 965 μmol) and (2S)-2-({[4-(aminomethyl)pyridin-3-yl]oxy}methyl)morpholine-4-carboxylic acid tert-butyl ester (intermediate 2-5, 312 mg, 965 μmol) were used as starting materials; after purification by rapid chromatography (silica gel, DCM / EtOH gradient 1-10%), 479.0 mg of the title compound (95% purity, 77% yield) was prepared.

[0916] 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).

[0917] LC-MS (Method 2): R t =1.32min; MS(ESIpos): m / z=616[M+H] +

[0918] Intermediate 6-57

[0919] N-(3-chloro-2-methoxyphenyl)-4-([{3-[(1S)-1-(1,4-dioxane-2-yl)ethoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide

[0920]

[0921] Using a similar method as described in intermediates 6-41, N-(3-chloro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (intermediate 5-1, 300 mg, 959 μmol) and 1-{3-[(1S)-1-(1,4-dioxane-2-yl)ethoxy]pyridine-4-yl}methylamine (intermediate 2-11, 251 mg, 1.06 mmol) were used as starting materials to prepare 384 mg of the title compound (99% purity, 74% yield), a mixture of diastereomers.

[0922] 1H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.064 (0.95), 1.239 (2.82), 1.255 (2.83), 1.279 (2.06), 1.295 (2.09), 2.5 18(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(1.1 2), 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).

[0923] LC-MS (Method 6): R t =0.96min and R t =0.98min; MS(ESIpos): m / z=533.2[M+H] +

[0924] Intermediate 6-60

[0925] N-(3-chloro-2-methoxyphenyl)-4-{[(3-{(1R)-1-[1,4-dioxane-2-yl]ethoxy}pyridin-4-yl)methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide

[0926]

[0927] Using a similar method as described in intermediates 6-41, N-(3-chloro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (intermediate 5-1, 300 mg, 959 μmol) and 1-{3-[(1R)-1-(1,4-dioxane-2-yl)ethoxy]pyridine-4-yl}methylamine (intermediate 2-12, 251 mg, 1.06 mmol) were used as starting materials to prepare 346 mg (99% purity, 67% yield) of the title compound.

[0928] 1H-NMR (400MHz, 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), 7.2 87(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).

[0929] LC-MS (Method 6): R t =0.96min; MS (ESIpos): m / z=533[M+H] +

[0930] Intermediate 6-62

[0931] 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-thiocarboxamide

[0932]

[0933] Using a similar method as described in intermediates 6-41, N-(3-fluoro-2-methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (intermediate 5-38, 197 mg, 704 μmol) and 1-(3-{[-4-methylmorpholin-2-yl]methoxy}pyridine-4-yl)methylamine (intermediate 2-3, 167 mg, 704 μmol) were used as starting materials; after purification by reversed-phase HPLC (basic), 170 mg of the title compound (93% purity, 45% yield) was prepared.

[0934] 1H-NMR (400MHz, 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), 3.55 7 (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), 4.6 51(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).

[0935] LC-MS (Method 6): R t =0.62min; MS(ESIpos): m / z=500[M+H] +

[0936] Intermediate 6-65

[0937] 4-{[(3-{[1,4-dioxane-2-yl]methoxy}pyridin-4-yl)methyl]amino}-N-(2-ethyl-3-fluorophenyl)-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide

[0938]

[0939] Using a similar method as described in intermediates 6-41, N-(2-ethyl-3-fluorophenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (300 mg, 1.02 mmol) and 1-(3-{[1,4-dioxane-2-yl]methoxy}pyridine-4-yl)methylamine (229 mg, 1.02 mmol) were used as starting materials; the solvent was evaporated, the solid was filtered, and washed with ACN to prepare 218 mg of the title compound (90% purity, 38% yield).

[0940] 1H-NMR (400MHz, 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(2.6 5), 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).

[0941] LC-MS (Method 6): R t =0.92min; MS (ESIpos): m / z=501[M+H] +

[0942] Intermediate 6-68

[0943] 4-{[(3-{[5,5-dimethyl-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)methyl]amino}-N-(2-ethyl-3-fluorophenyl)-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide

[0944]

[0945] Using a similar method as described in intermediates 6-41, N-(2-ethyl-3-fluorophenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (300 mg, 1.02 mmol) and 1-(3-{[5,5-dimethyl-1,4-dioxane-2-yl]methoxy}pyridine-4-yl)methylamine (257 mg, 1.02 mmol) were used as starting materials; after purification by column chromatography, 360 mg of the title compound (93% purity, 62% yield) was prepared.

[0946] 1H-NMR (400MHz, 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), 7.11 1 (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).

[0947] LC-MS (Method 6): R t =1.03min; MS (ESIpos): m / z=529[M+H] +

[0948] Intermediate 6-71

[0949] 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-thiocarboxamide

[0950]

[0951] Using a similar method as described in intermediates 6-41, N-(3-chloro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (intermediate 5-1, 300 mg, 959 μmol) and 1-[3-({1-[4-methylmorpholin-2-yl]ethyl}oxy)pyridine-4-yl]methylamine (intermediate 2-71, 265 mg, 1.06 mmol) were used as starting materials; after purification by column chromatography, 360 mg of the title compound (93% purity, 62% yield) was prepared.

[0952] 1 H-NMR (400MHz, 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), 7.11 1 (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).

[0953] LC-MS (Method 6): R t =1.03min; MS (ESIpos): m / z=529[M+H] +

[0954] Intermediate 12

[0955] 3-((3-fluoro-2-methoxyphenyl)amino)-2-(3-hydroxypyridin-4-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one

[0956]

[0957] TFA (0.75 mL, 10.13 mmol) was added to a MeOH suspension of N-(3-fluoro-2-methoxyphenyl)-4-(((3-hydroxypyridin-4-yl)methyl)amino)-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (intermediate 6-12, 41 g, 101.88 mmol) (410 mL), followed by hydrogen peroxide (18 mL, 30% aqueous solution). 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% aqueous solution) were added. The suspension was stirred again at 60 °C for 3 hours. The mixture was cooled to room temperature and left overnight. The suspension was then mixed with a second batch prepared similarly. The combined suspension was filtered, and the filter cake was washed with water (250 mL) and MeOH (150 mL), and then slurried in MeOH (150 mL). The suspension was filtered. The filter cake was washed with MeOH (75 mL) and dried under vacuum to give the title compound (25.4 g, 33.8% yield) as a yellow solid.

[0958] 1 H NMR (400MHz, 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).

[0959] LC-MS (Method 5): R t =1.851min; m / z=369.0(M+H) +

[0960] Intermediate 22-1

[0961] (2S)-2-[({4-[3-(3-fluoro-2-methoxyaniline)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylic acid tert-butyl ester

[0962]

[0963] Using a similar method as described in Example 1, tert-butyl morpholine-4-carboxylate (intermediate 6-22, 1.43 g, 2.38 mmol) was used as the starting material; after purification by rapid chromatography (silica gel, DCM / EtOH gradient 0-10%), 572 mg (80% purity, 34% yield) of the title compound was prepared.

[0964] 1H-NMR (400MHz, 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).

[0965] LC-MS (Method 2): R t =1.12min; MS(ESIpos): m / z=568[M+H] +

[0966] Intermediate 22-2

[0967] 3-(3-fluoro-2-methoxyaniline)-2-(3-{[(2S)-morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0968]

[0969] (2S)-2-[({4-[3-(3-fluoro-2-methoxyaniline)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylic acid tert-butyl ester (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 rapid chromatography (amino phase silica gel, DCM / EtOH gradient 0-20%) to give 352 mg (95% purity, 71% yield) of the title compound.

[0970] 1 H-NMR (400MHz, 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).

[0971] LC-MS (Method 2): R t =0.84min; MS (ESIpos): m / z=468[M+H] +

[0972] Intermediate 27-1

[0973] (2S)-2-[({4-[3-(3-chloro-5-fluoro-2-methoxyaniline)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylic acid tert-butyl ester

[0974]

[0975] Using a similar method as described in Example 1, 73.5 mg (90% purity, 47% yield) of the title compound was prepared from (2S)-2-[({4-[({5-[(3-chloro-5-fluoro-2-methoxyphenyl)thiocarbamoyl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}amino)methyl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylic acid tert-butyl ester (intermediate 6-27, 150 mg, 236 μmol) as the starting material.

[0976] 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).

[0977] LC-MS (Method 2): R t =1.19min; MS (ESIpos): m / z=602[M+H] +

[0978] Intermediate 27-2

[0979] 3-(3-chloro-5-fluoro-2-methoxyaniline)-2-(3-{[(2S)-morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0980]

[0981] Using a similar method as described in Intermediate 22-2, the title compound was prepared in 56.3 mg (95% purity, 88% yield) using (2S)-2-[({4-[3-(3-chloro-5-fluoro-2-methoxyaniline)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylic acid tert-butyl ester (Intermediate 27-1, 73.0 mg, 121 μmol) as the starting material, followed by purification by rapid chromatography (amino phase silica gel, DCM / EtOH gradient 0-15%).

[0982] 1 H-NMR (400MHz, 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).

[0983] LC-MS (Method 2): R t =0.93min; MS (ESIpos): m / z=502[M+H] + .

[0984] Intermediate 41-1

[0985] (2S)-2-{[(4-{3-[2-(2,2-difluoroethyl)-3-fluoroaniline]-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl}pyridin-3-yl)oxy]methyl}morpholine-4-carboxylic acid tert-butyl ester

[0986]

[0987] Using a similar method as described in Example 1, tert-butyl morpholine-4-carboxylate (intermediate 6-41, 266 mg, 418 μmol) was prepared from (2S)-2-{[(4-{[(5-{[2-(2,2-difluoroethyl)-3-fluorophenyl]thiocarbamoyl}-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) as the starting material; 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 (65% purity, 9% yield) of the title compound was obtained.

[0988] LC-MS (Method 2): R t =1.16min; MS(ESIneg): m / z=600[MH] -

[0989] Intermediate 41-2

[0990] 3-[2-(2,2-difluoroethyl)-3-fluoroaniline]-2-(3-{[(2S)-morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0991]

[0992] Using a similar method as described in Intermediate 22-2, the title compound was prepared from (2S)-2-{[(4-{3-[2-(2,2-difluoroethyl)-3-fluoroaniline]-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl}pyridin-3-yl)oxy]methyl}morpholine-4-carboxylic acid tert-butyl ester (Intermediate 41-1, 33.0 mg, 54.9 μmol) as the starting material; after purification by rapid chromatography (amino phase silica gel, DCM / EtOH gradient 0-10%), 22.0 mg (65% purity, 52% yield) was obtained.

[0993] LC-MS (Method 2): R t =0.92min; MS(ESIneg): m / z=500[MH] -

[0994] Intermediate 42-1

[0995] (2S)-2-[({4-[3-(3-chloro-2-methylaniline)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylic acid tert-butyl ester

[0996]

[0997] Using a similar method as described in Example 1, the title compound was prepared in 27.8 mg (90% purity, 13% yield) using (2S)-2-[({4-[({5-[(3-chloro-2-methylphenyl)thiocarbamoyl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}amino)methyl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylic acid tert-butyl ester (intermediate 6-42, 207 mg, 344 μmol) as the starting material; 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).

[0998] 1H-NMR (400MHz, 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(0.4 3), 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).

[0999] LC-MS (Method 6): Rt = 0.92 min; MS (ESIpos): m / z = 568 [M+H] +

[1000] Intermediate 42-2

[1001] 3-(3-chloro-2-methylaniline)-2-(3-{[(2S)-morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[1002]

[1003] Using a similar method as described in Intermediate 22-2, the title compound was prepared in 19.0 mg (92% purity, 71% yield) using (2S)-2-[({4-[3-(3-chloro-2-methylaniline)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylic acid tert-butyl ester (intermediate 42-1, 30.0 mg, 52.8 μmol) as the starting material, after filtration through an SCX-2 column (washed with MeOH, then eluted with 1M ammonia in MeOH solution).

[1004] 1H-NMR (400MHz, 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), 2.5 45(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(0.6 9), 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).

[1005] LC-MS (Method 6): Rt = 0.52 min; MS (ESIpos): m / z = 468 [M+H] +

[1006] Intermediate 43-1

[1007] (3R)-3-[({4-[3-(3-chloro-2-methylaniline)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylic acid tert-butyl ester

[1008]

[1009] Using a similar method as described in Example 1, tert-butyl morpholine-4-carboxylate (180 mg, 299 μmol) was used as the starting material. The title compound was prepared in 35.1 mg (90% purity, 19% yield) 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).

[1010] 1 H-NMR (400MHz, 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), 3.40 5(2.12), 3.412(2.73), 3.417(2.74), 3.435(1.48), 3.555(0.76), 3.5 77(0.85), 3.680(1.24), 3.709(1.06), 3.840(1.02), 3.860(0.92), 3.9 52 (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).

[1011] LC-MS (Method 6): R t=0.92min; MS (ESIpos): m / z=568[M+H] +

[1012] Intermediate 43-2

[1013] 3-(3-chloro-2-methylaniline)-2-(3-{[(3R)-morpholin-3-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[1014]

[1015] Using a similar method as described in Intermediate 22-2, the title compound was prepared in 25.3 mg (97% purity, 99% yield) using (3R)-3-[({4-[3-(3-chloro-2-methylaniline)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylic acid tert-butyl ester (intermediate 43-1, 30.0 mg, 52.8 μmol) as the starting material, after filtration through an SCX-2 column (washed with MeOH, then eluted with 1M ammonia in MeOH solution).

[1016] 1H-NMR (400MHz, 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), 3.7 94 (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).

[1017] LC-MS (Method 6): R t =0.53min; MS (ESIpos): m / z=468[M+H] +

[1018] Intermediate 55-1

[1019] (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-carboxylic acid tert-butyl ester

[1020]

[1021] Using a method similar to that described in Example 1, (2R)-2-[({4-[({5-[(3-chloro-2-ethylphenyl)thiocarbamoyl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}amino)methyl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylic acid tert-butyl ester (intermediate 6-55, 473 mg, 768 μmol) was used as the starting material; preparative HPLC was performed (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) The title compound was purified by 34.4-60% B and then purified by rapid chromatography (silica gel, DCM / EtOH gradient 0-12%) to prepare 57.0 mg (95% purity, 12% yield).

[1022] LC-MS (Method 2): R t =1.26min; MS(ESIpos): m / z=582[M+H] +

[1023] Intermediate 55-2

[1024] 3-(3-chloro-2-ethylanilino)-2-(3-{[(2R)-morpholino-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[1025]

[1026] Using a similar method as described in Intermediate 22-2, the title compound was prepared from 58.0 mg (95% purity, 95% yield) using (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-carboxylic acid tert-butyl ester (intermediate 55-1, 70.4 mg, 121 μmol) as the starting material, followed by purification by rapid chromatography (silica gel, DCM / EtOH + triethylamine gradient 1-40%).

[1027] 1H-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, 1 H), 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).

[1028] LC-MS (Method 2): R t =0.99min; MS(ESIneg): m / z=480[MH] -

[1029] Intermediate 56-1

[1030] (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-carboxylic acid tert-butyl ester

[1031]

[1032] Using a method similar to that described in Example 1, tert-butyl morpholine-4-carboxylate (intermediate 6-56, 476 mg, 772 μmol) was used as the starting material; the reaction was performed by 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). The title compound was purified by 40-55% B) and then purified by rapid chromatography (silica gel, DCM / EtOH gradient 0-12%) to prepare 68.0 mg (95% purity, 14% yield).

[1033] LC-MS (Method 2): R t =1.26min; MS(ESIpos): m / z=582[M+H] +

[1034] Intermediate 56-2

[1035] 3-(3-chloro-2-ethylanilino)-2-(3-{[(2S)-morpholino-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[1036]

[1037] Using a similar method as described in Intermediate 22-2, the title compound was prepared from (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-carboxylic acid tert-butyl ester (Intermediate 56-1, 70.4 mg, 121 μmol) as the starting material; after purification by rapid chromatography (amino-phase silica gel, DCM / EtOH gradient 1-35%), 46.9 mg (95% purity, 78% yield) was obtained.

[1038] 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, 1 H), 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).

[1039] LC-MS (Method 2): R t =0.99min; MS(ESIneg): m / z=480[MH] - Example

[1040] Example 1

[1041] 3-(3-chloro-2-methoxyaniline)-2-{3-[(1,4-dioxane-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[1042]

[1043] TFA (42 μl, 540 μmol) was added to a suspension of N-(3-chloro-2-methoxyphenyl)-4-[({3-[(1,4-dioxane-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (intermediate 6-1, 140 mg, 240 μmol) in MeOH (2.7 mL), followed by the addition of aqueous hydrogen peroxide solution (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).

[1044] 1 H-NMR (400MHz, 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).

[1045] LC-MS (Method 2): R t =0.98min; MS (ESIpos): m / z=485[M+H] +

[1046] Example 2

[1047] 3-(3-chloro-2-methoxyaniline)-2-(3-{[(2S)-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (stereoisomer 1)

[1048]

[1049] The title compound (140 mg) from Example 1 was separated into enantiomers by preparative chiral HPLC to obtain the title compound (enantiomer 1, 27 mg, at Rt = 14.0–17.0 min) and enantiomer 2 (25 mg, at Rt = 14.0–17.0 min). t=20.0-24.8 min, see Example 3).

[1050] Preparative chiral HPLC methods :

[1051] Instruments: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000; Column: Cellulose SB 5μ, 250x30mm; Eluent A: Hexane + 0.1 vol% diethylamine (99%); Eluent B: 2-propanol; Isocratic: 50% A + 50% B; Flow rate: 50 ml / min; UV: 254 nm.

[1052] Analytical chiral HPLC methods :

[1053] Instrument: Agilent HPLC1260; Column: Cellulose SB 3μm, 100x4.6mm; Eluent A: Hexane + 0.1 vol% diethylamine (99%); Eluent B: 2-propanol; Constant solvent: 50% A + 50% B, flow rate 1.4 ml / min; Temperature: 25℃; UV: 254 nm

[1054] Analytical chiral HPLC: R t = 4.49 min.

[1055] Optical rotation: [α] D =1.7° + / -0.98° (c = 3.6 mg / 2 ml, methanol)

[1056] Enantioselective synthesis confirmed that the title compound is 3-(3-chloro-2-methoxyaniline)-2-(3-{[(2S)-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one. Following a similar approach to Example 1, the title compound was prepared in 872 mg (95% purity, 72% yield) using N-(3-chloro-2-methoxyphenyl)-4-{[(3-{[(2S)-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (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).

[1057] 1H-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).

[1058] Analytical chiral HPLC: R t = 4.46 min.

[1059] Optical rotation: [α] D = -12.5° + / - 0.52° (c = 5.6 mg / ml, chloroform)

[1060] Example 3

[1061] 3-(3-chloro-2-methoxyaniline)-2-(3-{[(2R)-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (stereoisomer 2)

[1062]

[1063] The preparation of the racemic title compound is described in Example 1. Enantiomers were separated by preparative chiral HPLC (method described in Example 2) to obtain 25 mg of the title compound (in R...). t = 20.0-24.8 min (when).

[1064] Analytical chiral HPLC (method see Example 2): R t = 6.56 min.

[1065] Optical rotation: [α] D = -3.0° + / - 1.03° (c = 3.2 mg / 2 ml, methanol)

[1066] Optical rotation: [α] D =22.8° + / -6.1° (c = 6.3 mg / ml, chloroform)

[1067] Example 4

[1068] 2-{3-[(1,4-dioxane-2-yl)methoxy]pyridin-4-yl}-3-(3-fluoro-2-methoxyaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[1069]

[1070] Following a similar procedure to Example 1, 25.7 mg of the title compound (21% yield) was prepared by heating 4-[({3-[(1,4-dioxane-2-yl)methoxy]pyridin-4-yl}methyl)amino]-N-(3-fluoro-2-methoxyphenyl)-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (intermediate 6-4, 120 mg, 239 μmol) for 25 hours, followed by purification by preparative HPLC (Method 10, gradient: 0.00-0.50 min 15% B, 0.50-6.00 min 15-55% B).

[1071] 1 H-NMR (400MHz, DMSO-d6): δ [ppm] = 2.86 (t, 2H), 3.37-3.57 (m, 4H), 3.66-3.89 (m, 4H), 3.91 (s, 3H), 3.9 8-4.09(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).

[1072] LC-MS (Method 2): R t =0.92min; MS (ESIpos): m / z=469[M+H] +

[1073] Example 5

[1074] 2-{3-[(1,4-dioxane-2-yl)methoxy]pyridin-4-yl}-3-(3-fluoro-2-methoxyaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (stereoisomer 1)

[1075]

[1076] The title compound (26 mg) from Example 4 was separated into enantiomers by preparative chiral HPLC to obtain the title compound (enantiomer 1, 11 mg, in R...t =8.2-9.1 min, 10% yield) and enantiomer 2 (12 mg, at R t = 9.7-10.7 min, see Example 6).

[1077] Preparative chiral HPLC methods :

[1078] Instruments: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000; Column: Cellulose SB 5μ, 250x30mm; Eluent A: MTBE + 0.1 vol% diethylamine (99%); Eluent B: Acetonitrile; Gradient: 2-60% B, 20 min; Flow rate: 50 ml / min; UV: 280 nm

[1079] Analytical chiral HPLC methods :

[1080] Instrument: Agilent HPLC1260; Column: Cellulose SB 3μm, 100x4.6mm; Eluent A: MTBE + 0.1 v / v diethylamine (99%); Eluent B: Acetonitrile; Gradient: 2-60% B, 7 min, flow rate 1.4 ml / min; Temperature: 25℃; UV: 280 nm

[1081] Analytical chiral HPLC: R t = 4.34 min.

[1082] Optical rotation: [α] D = -0.5° + / -0.87° (c = 7.5 mg / 2 ml, methanol)

[1083] Example 6

[1084] 2-{3-[(1,4-dioxane-2-yl)methoxy]pyridin-4-yl}-3-(3-fluoro-2-methoxyaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (stereoisomer 2)

[1085]

[1086] The preparation of the racemic title compound is described in Example 4. Enantiomers were separated by preparative chiral HPLC (method described in Example 5) to obtain 12 mg of the title compound (in R...). t =11% yield at 9.7-10.7 min.

[1087] Analytical chiral HPLC (method see Example 5): R t= 5.11 min.

[1088] Optical rotation: [α] D = -0.1° + / -0.89° (c = 6.3 mg / 3 ml, methanol)

[1089] Example 7

[1090] 3-(2,3-dichloroanilino)-2-{3-[(1,4-dioxane-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[1091]

[1092] Following a similar procedure to Example 1, 34.6 mg of the title compound (32% yield) was prepared by heating N-(2,3-dichlorophenyl)-4-[({3-[(1,4-dioxane-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (intermediate 6-7, 110 mg, 210 μmol) for 25 hours, followed by purification by preparative HPLC (Method 10, gradient: 0.00-0.50 min 15% B, 0.50-6.00 min 15-55% B).

[1093] 1 H-NMR (400MHz, 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).

[1094] LC-MS (Method 2): R t =1.01min; MS(ESIpos): m / z=489[M+H] +

[1095] Example 8

[1096] 3-(2,3-dichloroanilino)-2-{3-[(1,4-dioxane-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (stereoisomer 1)

[1097]

[1098] The title compound (27 mg) from Example 7 was separated into enantiomers by preparative chiral HPLC to obtain the title compound (enantiomer 1, 10 mg) and enantiomer 2 (12 mg, see Example 9).

[1099] Preparative chiral HPLC methods :

[1100] Instruments: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000; Column: Cellulose SB 5μ, 250x30mm; Eluent A: MTBE + 0.1 vol% diethylamine (99%); Eluent B: Acetonitrile; Gradient: 2-60% B, 20 min; Flow rate: 50 ml / min; UV: 280 nm

[1101] Analytical chiral HPLC methods :

[1102] Instrument: Agilent HPLC 1260; Column: Cellulose SB 3μm, 100x4.6mm; Eluent A: MTBE + 0.1 v / v diethylamine (99%); Eluent B: Acetonitrile; Gradient: 2-60% B, 7 min, flow rate 1.4 ml / min; Temperature: 25℃; UV: 280 nm

[1103] Analytical chiral HPLC: R t = 5.11 min.

[1104] Optical rotation: [α] D =1.4° + / -0.69° (c = 5.8 mg / 2 ml, methanol)

[1105] Example 9

[1106] 3-(2,3-dichloroanilino)-2-{3-[(1,4-dioxane-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (stereoisomer 2)

[1107]

[1108] The preparation of the racemic title compound is described in Example 7. Enantiomers were separated by preparative chiral HPLC (method described in Example 8) to obtain 12 mg of the title compound.

[1109] Analytical chiral HPLC (method see Example 8): R t = 6.74 min.

[1110] Optical rotation: [α] D = -14.9° + / - 3.16° (c = 5.6 mg / ml, methanol)

[1111] Example 10

[1112] 3-(3-chloro-2-methylaniline)-2-{3-[(1,4-dioxane-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[1113]

[1114] Following a similar procedure to Example 1, 12.1 mg of the title compound (7% yield) was prepared by heating N-(3-chloro-2-methylphenyl)-4-[({3-[(1,4-dioxane-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (intermediate 6-10, 180 mg, 358 μmol) for 25 hours, followed by purification by preparative HPLC (Method 10, gradient: 0.00-0.50 min 15% B, 0.50-6.00 min 15-55% B).

[1115] 1 H-NMR (400MHz, 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).

[1116] LC-MS (Method 2): R t =1.02min; MS (ESIpos): m / z=469[M+H]+

[1117] Example 11

[1118] 3-(3-chloro-2-methoxyaniline)-2-(3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[1119]

[1120] Following a similar procedure to Example 1, 11 mg of the title compound (15% yield) was prepared by heating 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-thiocarboxamide (intermediate 6-11, 82 mg, 139 μmol) for 17 hours and then purified by preparative HPLC (Method 10, gradient: 0.00-0.50 min 15% B, 0.50-6.00 min 15-55% B).

[1121] 1 H-NMR (400MHz, DMSO-d6): δ [ppm] = 11.51-12.57 (m, 1H), 8.40 (br s, 1H), 8.04 (brs, 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).

[1122] LC-MS (Method 6): R t =0.55min; MS(ESIpos): m / z=498.2[M+H] +

[1123] Optical rotation: [α] D = -82.0° + / - 0.41° (c = 5.8 mg / ml, methanol)

[1124] Example 12

[1125] 3-(3-fluoro-2-methoxyaniline)-2-{3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[1126]

[1127] 3-(3-fluoro-2-methoxyaniline)-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. Then, (tributylphosphanylidene)acetonitrile (384 μl, 1.5 mmol, CAS 157141-27-0) and (4-methylmorpholino-2-yl)methanol (CAS 157141-27-0) were added. 40987-46-0 The mixture was prepared by stirring at 50°C for 30 hours (80.0 mg, 610 μmol). The mixture was concentrated under reduced pressure and a saturated sodium bicarbonate solution was added. The mixture was extracted with DCM. The organic phase was filtered through a waterproof 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 of the title compound (8% yield).

[1128] 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).

[1129] LC-MS (Method 2): R t =0.92min; MS(ESIpos): m / z=482.3[M+H] +

[1130] Example 13

[1131] 3-(3-fluoro-2-methoxyaniline)-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)

[1132]

[1133] The title compound (19 mg) from Example 12 was separated into enantiomers by preparative chiral HPLC to obtain the title compound (enantiomers 1.6 mg, R...). t = 6.7-8.7 min, 3% yield) and enantiomer 2 (7 mg, at R t =8.9-11.9 min, see Example 14).

[1134] Preparative chiral HPLC methods :

[1135] Instrument: PrepCon Labomatic HPLC; Column: Chiralcel OD-H 5μm, 250x20; Eluent A: Acetonitrile + 0.1 v / v diethylamine (99%); Eluent B: Ethanol; Constant solvent: 93% A + 7% B; Flow rate: 20 mL / min; Temperature: 25 °C; UV: 254 nm

[1136] Analytical chiral HPLC methods :

[1137] Instruments: Waters Alliance 2695; Column: Chiralcel OD-H 5μm, 100x4.6; Eluent A: Ethanol + 0.1 vol% diethylamine (99%); Eluent B: Ethanol; Constant solvent: 90% A + 10% B, flow rate 1.4 ml / min; Temperature: 25℃; UV: 254 nm

[1138] Analytical chiral HPLC: R t = 2.91 min.

[1139] 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).

[1140] Example 14

[1141] 3-(3-fluoro-2-methoxyaniline)-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)

[1142]

[1143] The preparation of the racemic title compound is described in Example 12. Enantiomers were separated by preparative chiral HPLC (method described in Example 13) to obtain 7 mg of the title compound (in R...). t =3% yield at 8.9-11.9 min.

[1144] Analytical chiral HPLC (method see Example 13): R t = 3.70 min.

[1145] 1 H-NMR (400MHz, 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 (brt, 2H), 2.77 (br d, 1H), 2.63-2.70 (m, 1H), 2.20 (s, 3H), 1.99-2.09 (m, 1H), 1.91 (brt, 1H).

[1146] Example 15

[1147] 3-(3-chloro-2-methoxyaniline)-2-{3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[1148]

[1149] Following a procedure similar to Example 1, the title compound was prepared in 24.1 mg (90% purity, 31% yield) by heating 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-thiocarboxamide (intermediate 6-15, 74.0 mg, 139 μmol) for 18 hours and then purified by preparative HPLC (Method 10, gradient: 0.00-0.50 min 15% B, 0.50-6.00 min 15-55% B).

[1150] 1 H-NMR (400MHz, 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).

[1151] LC-MS (Method 2): R t =0.97min; MS (ESIpos): m / z=498[M+H] +

[1152] Example 16

[1153] 3-(3-chloro-2-methoxyaniline)-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)

[1154]

[1155] The title compound (24.1 mg) from Example 15 was separated into enantiomers by preparative chiral HPLC to obtain the title compound (enantiomers 1.8 mg, in R... t =17.4-21.8, 11% yield) and enantiomer 2 (7 mg, at R t =12.5-14.5 min, see Example 17).

[1156] Preparative chiral HPLC methods :

[1157] Instrument: PrepCon Labomatic HPLC; Column: Chiralpak IF 5μm, 250x30; Eluent A: Hexane + 0.1 v / v diethylamine; Eluent B: Ethanol + 0.1 v / v diethylamine; Constant solvent: 50% A + 50% B; Flow rate: 40 mL / min; Temperature: 25 °C; UV: 280 nm

[1158] Analytical chiral HPLC methods :

[1159] Instrument: Waters Alliance 2695; Column: Chiralpak IF 3μ, 100x4.6; Eluent A: Hexane + 0.1 vol% diethylamine; Eluent B: Ethanol; Constant solvent: 50% A + 50% B; Flow rate: 1.4 ml / min; Temperature: 25℃; UV: 280 nm

[1160] Analytical chiral HPLC: R t = 4.55min.

[1161] 1H-NMR (400MHz, 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).

[1162] Example 17

[1163] 3-(3-chloro-2-methoxyaniline)-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)

[1164]

[1165] The preparation of the racemic title compound is described in Example 15. Enantiomers were separated by preparative chiral HPLC (method described in Example 16) to obtain 7 mg of the title compound (in R...). t =12.5-14.5 min).

[1166] Analytical chiral HPLC (method see Example 16): R t = 2.93 min.

[1167] Example 18

[1168] 3-(3-chloro-5-fluoro-2-methoxyaniline)-2-(3-{[4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[1169]

[1170] Using a similar method as described in Example 1, 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-thiocarboxamide (intermediate 6-18, 166 mg, 302 μmol) was used as the starting material; 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 (95% purity, 8% yield) of the title compound was prepared.

[1171] 1 H-NMR (400MHz, 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).

[1172] LC-MS (Method 2): R t =1.00min; MS(ESIpos): m / z=516[M+H] +

[1173] Example 19

[1174] 3-(3-chloro-5-fluoro-2-methoxyaniline)-2-(3-{[1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[1175]

[1176] Using a similar method as described in Example 1, N-(3-chloro-5-fluoro-2-methoxyphenyl)-4-[({3-[(1,4-dioxane-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (intermediate 6-19, 160 mg, 298 μmol) was used as the starting material; after purification by preparative HPLC (Method 10, gradient: 0.00-0.50 min 15% B, 0.50-6.00 min 15-55% B), 3.90 mg (90% purity, 2% yield) of the title compound was prepared.

[1177] 1 H-NMR (400MHz, 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).

[1178] LC-MS (Method 2): R t =1.01min; MS (ESIpos): m / z=503[M+H] +

[1179] Example 20

[1180] 3-(3-fluoro-2-methoxyaniline)-2-(3-{[(3S)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[1181]

[1182] Using a similar method as described in Example 1, 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-thiocarboxamide (intermediate 6-20, 102 mg, 197 μmol) was used as the starting material; after purification by preparative HPLC (Method 10, gradient: 0.00-0.50 min 10% B, 0.50-6.00 min 10-50% B), 27.9 mg (90% purity, 26% yield) of the title compound was prepared.

[1183] LC-MS (Method 6): R t =0.51min; MS (ESIpos): m / z=482[M+H] +

[1184] 1H-NMR (400MHz, 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), 2.45 4(0.88), 2.458(1.03), 2.463(1.43), 2.468(1.37), 2.473(1.55), 2.5 18(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).

[1185] Example 21

[1186] 3-(3-chloro-2-methoxyaniline)-2-(3-{[(3S)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[1187]

[1188] Using a similar method as described in Example 1, 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-thiocarboxamide (intermediate 6-21, 99.5 mg, 187 μmol) was used as the starting material; 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 (98% purity, 5% yield) of the title compound was prepared.

[1189] 1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.232 (0.45), 2.276 (9.36), 2.426 (0.63), 2.434 (0.67), 2.4 56(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), 3.58 8(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).

[1190] LC-MS (Method 6): R t =0.54min; MS (ESIpos): m / z=498[M+H] +

[1191] Example 22

[1192] 2-(3-{[(2S)-4-(2,2-difluoroethyl)morpholin-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[1193]

[1194] 3-(3-fluoro-2-methoxyaniline)-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 dissolved in DMF (1.6 mL), and triethylamine (89 μl, 640 μmol) and 2,2-difluoroethyl trifluoromethanesulfonic acid (64 μl, 480 μmol) were added. The mixture was stirred at room temperature for 1 hour. 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 (90% purity, 18% yield) of the target compound.

[1195] 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).

[1196] LC-MS (Method 2): R t =1.04min; MS (ESIpos): m / z=532[M+H] +

[1197] Example 23

[1198] 3-(3-fluoro-2-methoxyaniline)-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

[1199]

[1200] Using a similar method as described in Example 22, 3-(3-fluoro-2-methoxyaniline)-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) were used as starting materials; 11.9 mg (95% purity, 27% yield) of the title compound was prepared by preparative HPLC (Method 10, gradient: 0.00-0.50 min 30% B, 0.50-6.00 min 30-70% B).

[1201] 1H-NMR (400MHz, 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).

[1202] LC-MS (Method 2): R t=1.09min; MS (ESIpos): m / z=550[M+H] +

[1203] Example 24

[1204] 3-(3-chloro-2-methoxyaniline)-2-{3-[2-(4-dioxane-2-yl)ethoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[1205]

[1206] Using a similar method as described in Example 1, N-(3-chloro-2-methoxyphenyl)-4-[({3-[2-(1,4-dioxane-2-yl)ethoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (intermediate 6-24, 105 mg, 197 μmol) was used as the starting material; 43.5 mg (95% purity, 42% yield) of the title compound was prepared by preparative HPLC (Method 7).

[1207] 1H-NMR (400MHz9DMSO-d6): δ[ppm]=1.817(0.39), 1.834(1.18), 1.849(1.57), 1.861(1.08), 1.87 6(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).

[1208] LC-MS (Method 6): R t =0.68min; MS (ESIpos): m / z=499[M+H] +

[1209] Example 25

[1210] 3-(3-chloro-2-methoxyaniline)-2-{3-[2-(4-dioxane-2-yl)ethoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (stereoisomer 1)

[1211]

[1212] The title compound (40 mg) from Example 24 was separated into enantiomers by preparative chiral HPLC to obtain the title compound (enantiomer 1, 18.0 mg, in R... t =18.8-21.3 min, 96% purity) and enantiomer 2 (17 mg, at R t =21.7-24.5 min, see Example 26).

[1213] Preparative chiral HPLC methods :

[1214] Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SB 5μm, 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

[1215] Analytical chiral HPLC methods :

[1216] Instrument: Waters Alliance 2695; Column: YMC Cellulose SB 3μ, 100x4.6; Eluent A: Methyl tert-butyl ether + 0.1 vol% diethylamine; Eluent B: Acetonitrile; Gradient: 0-7 min 2-60% B; Flow rate: 1.4 ml / min; Temperature: 25℃; UV: 280 nm

[1217] Analytical chiral HPLC: R t = 4.94 min.

[1218] Optical rotation: [α] D = -1.6° + / -1.63° (c = 2.8 mg / ml in methanol)

[1219] 1H-NMR (400MHz, DMSO-d6) δ [ppm] = 1.835 (1.01), 1.851 (1.31), 1.862 (0.93), 1.877 (0.41), 2.518 (1.52), 2. 522(0.99), 2.834(0.77), 2.846(1.61), 2.852(1.47), 2.864(0.82), 2.869(0.80), 3.205(0.76), 3.231(1.3 0), 3.235(1.27), 3.261(0.85), 3.391(0.83), 3.397(0.91), 3.408(1.57), 3.415(1.62), 3.430(0.98), 3.457(0.99), 3.463(1.01), 3.485(0.84), 3.491(0.79), 3.522(0.72), 3.527(0.76), 3.551(0.96), 3.556(1.07) , 3.584(0.57), 3.624(1.00), 3.649(1.11), 3.654(1.11), 3.671(1.96), 3.680(0.81), 3.687(0.53), 3.695(1.23), 3.718(1.09), 3.723(1.01), 3.747(0.79), 3.859(16.00), 4.227(1.22), 4.242(2.58), 4.258(1.21) , 6.105(1.40), 6.118(1.81), 6.129(1.46), 6.641(5.45), 6.651(3.33), 6.654(3.12), 7.110(1.60), 7.288(2.35), 7.300(2.36), 7.306(0.49), 7.462(3.57), 8.023(2.38), 8.035(2.27), 8.353(3.43), 11.186(1.77).

[1220] Example 26

[1221] 3-(3-chloro-2-methoxyaniline)-2-{3-[2-(4-dioxane-2-yl)ethoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (stereoisomer 2)

[1222]

[1223] The preparation of the racemic title compound is described in Example 24. Enantiomers were separated by preparative chiral HPLC (method described in Example 25) to obtain 25 mg of the title compound (in R...). t =19% yield at 21.7-24.5 min.

[1224] Analytical chiral HPLC (method see Example 25): R t = 5.49 min.

[1225] Optical rotation: [α] D =2.5° + / -1.93° (c = 2.7 mg / ml in methanol)

[1226] Example 27

[1227] 3-(3-chloro-5-fluoro-2-methoxyaniline)-2-(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[1228]

[1229] 3-(3-chloro-5-fluoro-2-methoxyaniline)-2-(3-{[(2S)-morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (intermediate 27, 24.0 mg, 47.8 μmol) was dissolved in methanol (650 μl), and formaldehyde (7.2 μl, 37% purity, 96 μmol) and acetic acid (2.7 μl, 48 μmol) were added. The mixture was stirred at room temperature for 15 minutes. Sodium triacetoxyborohydride (15.2 mg, 71.7 μmol) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with methanol, filtered through an SCX column, and washed with methanol and ammonia solution (7 M methanol solution). The filtrate was evaporated and purified by preparative HPLC (Method 9, gradient: 0.00–0.50 min 15% B, 0.50–6.00 min 15–55% B) to give 17.3 mg (95% purity, 61% yield) of the title compound, its formate.

[1230] LC-MS (Method 2): R t =1.01min; MS (ESIpos): m / z=516[M+H] +

[1231] 1H-NMR (400MHz, DMSO-d6) δ [ppm]: 2.189 (13.49), 2.330 (5.06), 2.729 (5.60), 2.861 (7.86), 3.348 (16.00 ), 3.419(15.57), 3.624(4.81), 3.830(14.46), 3.908(6.49), 7.633(4.30), 8.098(4.59), 8.146(8.39).

[1232] The formate of 3-(3-chloro-5-fluoro-2-methoxy-aniline)-2-[3-[[(2S)-4-methylmorpholin-4-onth-2-yl]methoxy]-4-pyridinyl]-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one was dissolved in DCM and washed with saturated aqueous NaHCO3 solution and brine to give 9.00 mg (90% purity, 33% yield) of the target compound, which was its free base.

[1233] 1 H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.79-1.96 (t, 1H), 1.97-2.05 (td, 1H), 2.19 (s, 3H), 2.63 (br d, 1H), 2.71-2.82 (br d, 1H), 2.86 (t, 2H), 3.43 (td, 2H), 3.58-3.67 (m, 1H), 3.83 (s, 3H), 3.87-4.01 (m, 2H), 4.14 (dd, 1H), 4.29 (dd, 1H), 5.85(dd, 1H), 6.56(dd, 1H), 7.13(s, 1H), 7.33(d, 1H), 7.64(d, 1H), 8.07-8.12(d, 1H), 8.43(s, 1H), 11.18(s, 1H).

[1234] Example 28

[1235] 3-(3-chloro-5-fluoro-2-methoxyaniline)-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

[1236]

[1237] Using a similar method as described in Example 22, 3-(3-chloro-5-fluoro-2-methoxyaniline)-2-(3-{[(2S)-morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (intermediate 27, 25.0 mg, 49.8 μmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonic acid (CAS6226-25-1, 11 μl, 75 μmol) were used as starting materials; 15.1 mg (95% purity, 49% yield) of the title compound was prepared by preparative HPLC (Method 10, gradient: 0.00-0.50 min 30% B, 0.50-6.00 min 30-70% B).

[1238] 1 H-NMR (400MHz, DMSO-d6): δ [ppm] = 2.35 (t, 1H), 2.77-2.95 (m, 4H), 3.21 (dd, 2H), 3.42 (td, 2H), 3.60-3.69 (m, 1H), 3.83 (s, 3H), 3.88-4.01 ( m, 2H), 4.14-4.28 (m, 2H), 5.84 (dd, 1H), 6.56 (dd, 1H), 7.13 (s, 1H), 7.32 (d, 1H), 7.62-7.66 (m, 1H), 8.10 (d, 1H), 8.43 (s, 1H), 11.16 (s, 1H).

[1239] LC-MS (Method 2): R t =1.19min; MS (ESIpos): m / z=584[M+H] +

[1240] Example 29

[1241] 3-(3-chloro-2-ethylanilino)-2-{3-[(4-methylmorpholino-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[1242]

[1243] Using a similar method as described in Example 1, 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-thiocarboxamide (intermediate 6-29, 300 mg, 566 μmol) was used as the starting material; 3.00 mg (85% purity, 1% yield) of the title compound was prepared by preparative HPLC (Method 10, gradient: 0.00-0.50 min 30% B, 0.50-6.00 min 30-70% B).

[1244] 1 H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.851 (0.47), 1.210 (0.41), 1.230 (2.24), 1. 352(0.41), 2.206(1.49), 2.331(2.92), 2.336(1.36), 2.518(16.00), 2.522(10. 31), 2.539(1.02), 2.673(3.05), 2.678(1.42), 2.864(0.41), 6.728(0.41), 6.735(0.47), 7.188(0.47), 7.201(0.47), 7.962(0.54), 7.975(0.47), 8.365(0.68).

[1245] LC-MS (Method 2): R t =1.07min; MS (ESIpos): m / z=496[M+H] +

[1246] Example 30

[1247] 3-(3-chloro-2-methoxyaniline)-2-{3-[(5,5-dimethyl-1,4-dioxane-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[1248]

[1249] Using a similar method as described in Example 1, N-(3-chloro-2-methoxyphenyl)-4-[({3-[(5,5-dimethyl-1,4-dioxane-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-thiocarboxamide (intermediate 6-30, 55.0 mg, 101 μmol) was used as the starting material; after purification by preparative HPLC (Method 10, gradient: 0.00-0.50 min 30% B, 0.50-6.00 min 30-70% B), 28.00 mg (98% purity, 53% yield) of the title compound was prepared.

[1250] 1 H-NMR (400MHz, DMSO-d6): δ[ppm]=1.066(9.57), 1.234(8.81), 2.074(0.42), 2.326(1.06), 2.331(0 .74), 2.518(3.90), 2.522(2.65), 2.668(1.04), 2.673(0.76), 2.819(1.08), 2.837(2.21), 2.853(1. 18), 3.398(1.96), 3.409(1.62), 3.416(1.61), 3.427(2.05), 3.580(0.57), 3.588(0.65), 3.609(1.17), 3.618(1.13), 3.629(1.85), 3.654(1.43), 3.657(1.70), 3.679(1.32), 3.709(0.74), 3.868(16.0) 0), 3.894(0.49), 3.902(0.53), 3.910(0.64), 3.918(0.58), 3.927(0.42), 4.155(0.76), 4.171(0.72), 4.181(1.01), 4.198(0.88), 4.295(0.97), 4.304(0.99), 4.322(0.76), 4.330(0.67), 6.143(1.40) , 6.155(1.71), 6.167(1.40), 6.653(0.46), 6.663(5.26), 6.673(3.14), 6.676(2.88), 7.138(1.48), 7.270(2.51), 7.283(2.51), 7.475(3.39), 8.033(3.36), 8.045(2.98), 8.404(4.26), 11.073(1.66).

[1251] LC-MS (Method 6): Rt = 0.80 min; MS (ESIpos): m / z = 513 [M+H] +

[1252] Example 31

[1253] 3-(3-chloro-2-methoxyaniline)-2-{3-[(5,5-dimethyl-1,4-dioxane-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (stereoisomer 1)

[1254]

[1255] The title compound (26.3 mg) from Example 30 was separated into enantiomers by preparative chiral HPLC to obtain the title compound (enantiomer 1, 11.00 mg, at Rt = 10.7–13.4 min) and enantiomer 2 (10 mg, at Rt = 10.7–13.4 min). t =14.0-19.9 min, see Example 32).

[1256] Preparative chiral HPLC methods :

[1257] Instrument: PrepCon Labomatic HPLC; Column: Chiralcel OD-H 5μm, 250x20; Eluent A: Hexane + 0.1 v / v diethylamine; Eluent B: Ethanol + 0.1 v / v diethylamine; Constant solvent: 70% A + 30% B; Flow rate: 20 mL / min; Temperature: 25 °C; UV: 280 nm

[1258] Analytical chiral HPLC methods :

[1259] Instrument: Waters Alliance 2695; Column: Chiralcel OD-H 5μm, 100x4.6; Eluent A: Hexane + 0.1 vol% diethylamine; Eluent B: Ethanol; Constant solvent: 70% A + 30% B; Flow rate: 1.4 ml / min; Temperature: 25℃; UV: 280 nm

[1260] Analytical chiral HPLC: R t = 6.72 min.

[1261] Example 32

[1262] 3-(3-chloro-2-methoxyaniline)-2-{3-[(5,5-dimethyl-1,4-dioxane-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (stereoisomer 2)

[1263]

[1264] The preparation of the racemic title compound is described in Example 30. Enantiomers were separated by preparative chiral HPLC (m...

Claims

1. A pharmaceutical composition comprising a compound of formula (I), or a salt or tautomer of said compound, or a salt of said tautomer, and at least one pharmaceutically acceptable adjuvant, wherein said pharmaceutical composition is an oral formulation. in: R 1 Represents methyl, ethyl, trifluoromethyl, 2,2-difluoroethyl, cyano, chlorine, bromine, methoxy, or difluoromethoxy; R 2 Represents hydrogen, methyl, ethyl, fluorine, chlorine, or bromine; R 3 Represents hydrogen or fluorine; R 4 Represents hydrogen or methyl; R 5 Each time it appears, it independently represents hydrogen, trifluoromethyl, or C1-C3 alkyl, R 5 It can bond with any carbon atom in the ring; R 6 Each time it appears, it independently represents 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 represents NR 7 Or O; Y represents NR 8 Or O; m represents 0, 1, 2, or 3; n represents 0 or 1.

2. The pharmaceutical composition according to claim 1, wherein: R 1 Represents methyl, ethyl, chloro, methoxy, or difluoromethoxy; R 2 Represents methyl, ethyl, fluorine, or chlorine; R 3 Represents hydrogen or fluorine; R 4 Represents hydrogen or methyl; R 5 Represents hydrogen, methyl, or trifluoromethyl, R 5 It can bond with any carbon atom in 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 represents NR 7 Or O; Y represents NR 8 Or O; m represents 0, 1, or 2; n represents 0 or 1.

3. The pharmaceutical composition according to claim 1 or 2, wherein: R 1 Represents methyl, ethyl, chloro, or methoxy; R 2 Represents fluorine or chlorine; R 3 Represents hydrogen or fluorine; R 4 Represents hydrogen; R 5 R represents hydrogen or methyl. 5 It can bond with any carbon atom in the ring; R 6 Represents hydrogen; R 7 Represents methyl; R 8 Represents methyl, 2,2,2-trifluoroethyl, or 2,2-difluoroethyl; X represents NR 7 Or O; Y represents NR 8 Or O; m represents 0, 1, or 2; n represents 0 or 1.

4. A pharmaceutical composition comprising a compound, or a salt or tautomer of said compound, or a salt of said tautomer, and at least one pharmaceutically acceptable adjuvant, wherein said pharmaceutical composition is an oral formulation, and said compound is selected from: 3-(3-chloro-2-methoxyaniline)-2-{3-[(1,4-dioxane-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyaniline)-2-(3-{[(2S)-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyaniline)-2-(3-{[(2R)-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-{3-[(1,4-dioxane-2-yl)methoxy]pyridin-4-yl}-3-(3-fluoro-2-methoxyaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2S)-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2R)-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(2,3-dichloroanilino)-2-{3-[(1,4-dioxane-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-dioxane-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-dioxane-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methylaniline)-2-{3-[(1,4-dioxane-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyaniline)-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-methoxyaniline)-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-methoxyaniline)-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-methoxyaniline)-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-methoxyaniline)-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-methoxyaniline)-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-methoxyaniline)-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-methoxyaniline)-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-methoxyaniline)-2-(3-{[1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-fluoro-2-methoxyaniline)-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-methoxyaniline)-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-methoxyaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-fluoro-2-methoxyaniline)-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-dioxane-2-yl)ethoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyaniline)-2-(3-{2-[(2R)-1,4-dioxane-2-yl]ethoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyaniline)-2-(3-{2-[(2S)-1,4-dioxane-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-methoxyaniline)-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-methoxyaniline)-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-methylmorpholino-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyaniline)-2-{3-[(5,5-dimethyl-1,4-dioxane-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyaniline)-2-(3-{[(2R)-5,5-dimethyl-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyaniline)-2-(3-{[(2S)-5,5-dimethyl-1,4-dioxane-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-dioxane-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2S)-5,5-dimethyl-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{2-[(2R)-1,4-dioxane-2-yl]ethoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{2-[(2S)-1,4-dioxane-2-yl]ethoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-fluoro-2-methoxyaniline)-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-dioxane-2-yl)methoxy]pyridin-4-yl}-3-(3-fluoro-2-methylaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2S)-5,5-dimethyl-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methylaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-[2-(2,2-difluoroethyl)-3-fluoroaniline]-2-{3-[(1,4-dioxane-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-fluoroaniline]-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-methylaniline)-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-methylaniline)-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-methylaniline)-2-{3-[(5,5-dimethyl-1,4-dioxane-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methylaniline)-2-(3-{[(2S)-5,5-dimethyl-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methylaniline)-2-(3-{[(2R)-5,5-dimethyl-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-{3-[(1,4-dioxane-2-yl)methoxy]pyridin-4-yl}-3-(3-fluoro-2-methylaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2S)-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methylaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2R)-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methylaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methylaniline)-2-(3-{[(2S)-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methylaniline)-2-(3-{[(2R)-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-ethylaniline)-2-{3-[(1,4-dioxane-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-dioxane-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-dioxane-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-methylmorpholino-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-methylmorpholino-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-dioxane-2-yl]ethoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyaniline)-2-(3-{(1S)-1-[(2S)-1,4-dioxane-2-yl]ethoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyaniline)-2-(3-{(1S)-1-[(2R)-1,4-dioxane-2-yl]ethoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyaniline)-2-(3-{(1R)-1-[(2S)-1,4-dioxane-2-yl]ethoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyaniline)-2-(3-{(1R)-1-[(2R)-1,4-dioxane-2-yl]ethoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-fluoro-2-methylaniline)-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-methylaniline)-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-methylaniline)-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-dioxane-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3-fluoroaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2R)-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3-fluoroaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2S)-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3-fluoroaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[5,5-dimethyl-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3-fluoroaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2R)-5,5-dimethyl-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3-fluoroaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2S)-5,5-dimethyl-1,4-dioxane-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3-fluoroaniline)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyaniline)-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-methoxyaniline)-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-methoxyaniline)-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-methoxyaniline)-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-methoxyaniline)-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. A pharmaceutical composition comprising a compound of formula (I), or a salt or tautomer of said compound, or a salt of said tautomer, and at least one pharmaceutically acceptable adjuvant. in: R 1 Represents methyl, ethyl, 2,2-difluoroethyl, chloro, bromine, or methoxy; R 2 Represents fluorine, chlorine, or bromine; R 3 Represents hydrogen or fluorine; R 4 Represents hydrogen or methyl; R 5 Each time it appears, it independently represents either hydrogen or a C1-C3 alkyl group, R 5 It can bond with any carbon atom in the ring; R 6 Represents hydrogen; X represents O; Y represents O; m represents 0, 1, or 2; n represents 0 or 1.

6. The pharmaceutical composition according to claim 5, wherein: R 1 Represents methyl, ethyl, 2,2-difluoroethyl, chloro, bromine, or methoxy; R 2 Represents fluorine, chlorine, or bromine; R 3 Represents hydrogen or fluorine; R 4 Represents hydrogen or methyl; R 5 Each time it appears, it independently represents either hydrogen or methyl, R 5 It bonds to any carbon atom in the ring; R 6 Represents hydrogen; X represents O; Y represents O; m represents 0, 1, or 2; n represents 0 or 1.

7. The pharmaceutical composition according to claim 5, wherein: R 1 Represents methoxyl; R 2 Represents fluorine, chlorine, or bromine; R 3 Represents hydrogen or fluorine; R 4 Represents hydrogen or methyl; R 5 Each time it appears, it independently represents either hydrogen or methyl, R 5 It bonds to any carbon atom in the ring; R 6 Represents hydrogen; X represents O; Y represents O; m represents 0, 1, or 2; n represents 0 or 1.

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