EA046642B1 - 4H-PYRROLO[3,2-c]PYRIDIN-4-ONE COMPOUNDS - Google Patents

Description

The invention relates to substituted 4H-pyrrolo[3,2-c]pyridin-4-one compounds, a method for their preparation and options for their use.

Prerequisites for creating the invention

The epidermal growth factor receptor (EGFR or EGF receptor) family of tyrosine kinases consists of 4 members: EGFR (Erbb1, Her1), ERBB2 (Her2), ERBB3 (Her3) and ERBB4 (Her4). EGFR mediates the activation of MAPK and PI3K signaling pathways and thereby regulates cell proliferation, differentiation, migration and survival (Pao et al., 2010). EGFR gene amplification, overexpression, and mutations are frequently observed in various features of malignancy and are associated with poor prognosis (Gridelli et al., 2015).

In lung adenocarcinoma, EGFR mutations are common in approximately 15% of Western patients and up to 50% of East Asian patients (Paez et al., 2004). These mutations typically occur in one of four exons—exons 18–21—of the EGFR kinase domain (Paez et al., 2004). The most common activating mutations in EGFR are a point mutation in exon 21, resulting in a leucine to arginine substitution (L858R), and a small in-frame deletion in exon 19, which results in the deletion of four amino acids (del19/del746-750) (Pao et al. ., 2010). The US Food and Drug Administration-approved inhibitors gefitinib, erlotinib, and afatinib, which target mutations in EGFR exons 18, 19, and 21, are effective in patients, but response is often short-lived (Mok et al., 2009; Sequist et al., 2013). Resistance in these patients often occurs in response to the acquisition of a second mutation, T790M (Pao et al., 2005). Second-generation inhibitors such as afatinib irreversibly target this mutation but are still potent inhibitors of wild-type EGFR, resulting in dose-limiting toxicity and lack of efficacy in patients. An irreversible third-generation inhibitor, osimertinib, which maximizes activity against T790M while minimizing activity against wild-type EGFR, is effective in T790M mutant patients and is currently the standard treatment for T790M-positive patients (Mok et al., 2017). Osimertinib is also approved as first-line therapy for patients with EGFR exon 19 or 21 mutations (Soria et al., 2018).

However, patients also develop resistance to third-generation irreversible EGFR inhibitors such as osimertinib. One of the main identified mechanisms of resistance to osimertinib is the occurrence of a mutation of cysteine at position 797, which consists of its replacement with serine, which leads to the loss of covalently interacting cysteine and loss of sensitivity to irreversible EGFR inhibitors, after which only limited treatment options are currently available to progressing patients (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). New targeted therapies that can specifically target the acquired resistance mutation EGFR-C797S will be of great benefit to these patients.

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

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

Thus, the standard treatment for patients with EGFR exon 20 insertions is currently chemotherapy.

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

Several irreversible inhibitors are currently in clinical trials for the treatment of patients with an EGFR exon 20 insertion: osimertinib, initially approved for the treatment of patients with T790M mutant NSCLC (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). Among them, the first clinical data were published for poziotinib and TAK-788. Both compounds clearly demonstrate clinical efficacy in patients with an EGFR exon 20 insertion. However, serious adverse events mediated by wild-type EGFR inhibition were reported in both clinical trials, and these adverse events

- 1 046642 These phenomena may limit clinical applicability.

More recently, new preclinical data have been published for two additional compounds demonstrating activity against EGFR with an exon 20 insertion: TAS6417 (TCP-064) and compound 1a (Hasako et al., 2018; Jang et al., 2018). Clinical results are not yet available for these two compounds.

Thus, the EGFR mutant is a promising drug target for the treatment of malignancies. In particular, patients with primary resistance due to insertions in EGFR exon 20 to approved EGFR-targeting therapies currently have few treatment options, and there is a great need for new alternative and/or improved therapeutics to provide such patients with effective and well-tolerated therapies (Oxnard et al., 2013). Thus, potent inhibitors of mutant EGFR, particularly mutant EGFR with insertion mutations in exon 20, that exhibit improved selectivity over wild-type EGFR are valuable compounds that should complement therapeutic treatment options either as stand-alone agents or in combination with other drugs.

Summary of the invention

The present invention provides compounds that inhibit mutant EGFR; specifically, EGFR comprising one or more insertion mutations in exon 20, the L858R mutation, or a small in-frame deletion in exon 19, in the presence or absence of the C797S mutation. These compounds furthermore have reduced activity against wild-type EGFR.

The compounds of the present invention have been found to have unexpected and advantageous properties.

In particular, it was unexpectedly found that the compounds of the present invention effectively inhibit the EGFR mutant with insertion mutations in exon 20, in particular the D770_N771ins SVD insertion in exon 20 with an IC ₅₀ below 5 nM. Moreover, it was unexpectedly found that these compounds additionally exhibit cellular activity below 1 μM in BA/F3 cell lines anchoring EGFR with V769_D770insASV, D770_N771insSVD, D770_N771insNPG, N771_P772insH or H773_V774insNPH insertions in exon 20. connections for this application are active in BA/F3 cell lines anchoring D770_N771insSVD C797S. In addition, the compounds described herein effectively inhibit the proliferation of BA/F3 cell lines carrying activating EGFR mutations with or without acquired resistance C797S mutations (EGFR E746_A750del, L858R, E746_A750del C797S, L858R C797S), uncommon EGFR mutations (EGFR L681Q), or ERBB2 insertion in exon 20 A775_G776insYVMA.

Surprisingly, these compounds additionally exhibit at least 5-fold selectivity in an antiproliferative assay with EGFR-anchored BA/F3 cell lines with a D770_N771ins SVD insertion in exon 20 compared to wild-type EGFR-anchored BA/F3 cells, and therefore their may 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 that are accompanied by uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, mediated by the EGFR insertion mutant in exon 20, and/or reducing (or blocking) the proliferation of cells harboring EGFR insertion mutations in exon 20, for example, such as hematological tumors, solid tumors, and /or their metastases, for example, leukemia and myelodysplastic syndrome, malignant lymphomas, head and neck tumors, including brain tumors and brain metastases, chest tumors, including non-small cell and small cell lung tumors, gastrointestinal tumors, endocrine tumors, breast tumors and other gynecological tumors, urological tumors, including renal tumors, bladder and prostate tumors, skin tumors and sarcomas, and/or metastases thereof.

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Description of the invention

According to a first aspect, the invention relates to a compound of formula (I)

(I) in which R ¹ represents methyl, ethyl, trifluoromethyl, 2,2-difluoroethyl, cyano, chlorine, bromine, methoxy or difluoromethoxy;

R ² is hydrogen, methyl, ethyl, fluorine, chlorine or bromine;

R ³ represents hydrogen or fluorine;

R ⁴ represents hydrogen or methyl;

R ⁵ is independently in each case hydrogen, trifluoromethyl or ^-^-alkyl, wherein

R ⁵ is attached to any carbon atom of the ring;

R ⁶ is independently in each case hydrogen, ^-^-alkyl or C ₁ -C ₃ -haloalkyl;

R ⁷ represents C ₁ -C ₃ -αalkyl or ^-^-haloalkyl;

R ⁸ represents C ₁ -C ₃ -alkyl or ^-^-haloalkyl;

X represents NR or O;

Y represents NR ⁸ or O;

m represents 0, 1, 2 or 3;

n is 0 or 1;

or an N-oxide, salt or tautomer of said compound, or a salt of said N-oxide or tautomer.

In some embodiments, at least two R ⁵ groups are geminal groups (ie, groups attached to the same carbon atom).

In a second aspect, the invention relates to a compound of formula (I) as described above, wherein

R ¹ is methyl, ethyl, chlorine, methoxy or difluoromethoxy;

R ² is methyl, ethyl, fluorine or chlorine;

R ³ represents hydrogen or fluorine;

R ⁴ represents hydrogen or methyl;

R ⁵ represents hydrogen, methyl or trifluoromethyl, and

R ⁵ is attached to any carbon atom of the ring;

R ⁶ is hydrogen, methyl or trifluoromethyl;

R ⁷ represents C ₁ -C ₂ -alkyl or C ₂ -C ₃ -fluoroalkyl;

R ⁸ represents C ₁ -C ₂ -alkyl or C ₂ -C ₃ -fluoroalkyl;

X represents NR ⁷ or O;

Y represents NR ⁸ or O;

m represents 0, 1 or 2;

n is 0 or 1;

or an N-oxide, salt or tautomer of said compound, or a salt of said N-oxide or tautomer.

In a third aspect, the invention relates to a compound of formula (I) as described above, wherein

R ¹ is methyl, ethyl, chlorine or methoxy;

R ² represents fluorine or chlorine;

R ³ represents hydrogen or fluorine;

R ⁴ represents hydrogen;

R ⁵ represents hydrogen or methyl, and

R ⁵ is attached to any carbon atom of the ring;

R ⁶ represents hydrogen;

R ⁷ represents methyl;

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R ⁸ is 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 is 0 or 1;

or an N-oxide, salt or tautomer of said compound, or a salt of said N-oxide or tautomer.

In a fourth aspect, the invention relates to a compound of formula (I) as described above, which is selected from the group consisting of:

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

3-(3-chloro-2-methoxyanilino)-2-(3-{[(25)-1,4-dioxan-2yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro- 4/7-pyrrolo[3,2-c]pyridin-4-one

3-(3-chloro-2-methoxyanilino)-2-(3-{[(27?)-1,4-dioxan-2yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro -4/7-pyrrolo[3,2-c]pyridin-4-one

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

2-(3-{[(25)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2methoxyanilino)-1,5,6,7-tetrahydro- 4/7-pyrrolo[3,2-c]pyridin-4-one

2-(3-{[(27?)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2methoxyanilino)-1,5,6,7-tetrahydro -4/7-pyrrolo[3,2-c]pyridin-4-one

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

3-(2,3-dichloroanilino)-2-(3-{[(25)-1,4-dioxan-2-yl]methoxy}pyridin-4yl)-1,5,6,7-tetrahydro-477- pyrrolo[3,2-c]pyridin-4-one

3-(2,3-dichloroanilino)-2-(3-{[(27?)-1,4-dioxan-2-yl]methoxy}pyridin-4yl)-1,5,6,7-tetrahydro-4R -pyrrolo[3,2-c]pyridin-4-one

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

3-(3-chloro-2-methoxyanilino)-2-(3-{[(37?)-4-methylmorpholin-3yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4 /7-pyrrolo[3,2-c]pyridin-4-one

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

3-(3-fluoro-2-methoxyanilino)-2-(3-{[(27?)-4-methylmorpholin-2yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4R -pyrrolo[3,2-c]pyridin-4-one

3-(3-fluoro-2-methoxyanilino)-2-(3-{[(25)-4-methylmorpholin-2yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H- pyrrolo[3,2-c]pyridin-4-one

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

3-(3-chloro-2-methoxyanilino)-2-(3-{[(27?)-4-methylmorpholin-2yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4 /7-pyrrolo[3,2-c]pyridin-4-one

3-(3-chloro-2-methoxyanilino)-2-(3-{[(25)-4-methylmorpholin-2yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4R- pyrrolo[3,2-c]pyridin-4-one

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3-(3-chloro-5-fluoro-2-methoxyanilino)-2-(3-{[4-methylmorph olin-2yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-477 -pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-5-fluoro-2-methoxyanilino)-2-(3-{[1,4-dioxan-2yl]methoxy}pyridin-4 -yl)-1,5,6,7-tetrahydro-4R-pyrrolo[3,2-c]pyridin-4-one 3-(3-fluoro-2-methoxyanilino)-2-(3-{[(35 ')-4-methylmorpholin-3yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4/7-pyrrolo[3,2-c]pyridin-4-one 3-(3 -chloro-2-methoxyanilino)-2-(3-{[(35)-4-methylmorpholin-3yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-477-pyrrolo[3, 2-c]pyridin-4-one 2-(3-{ [(25)-4-(2,2-difluoroethyl)morpholin-2-yl]methoxy}pyridin-4-yl)-3-(3fluoro-2 -methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

3-(3-fluoro-2-methoxyanilino)-2-(3-{[(25)-4-(2,2,2-trifluoroethyl)morpholin-2yl]methoxy}pyrid in-4-yl)-1, 5,6,7-tetrahydro-4//-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-{3-[2-(4-dioxane- 2-yl)ethoxy]pyridin-4yl}-1,5,6,7-tetrahydro-477-pyrrolo[3,2-c]pyridin-4-one

3-(3-chloro-2-methoxyanilino)-2-(3-{2-[(2K)-1,4-dioxan-2yl]ethoxy}pyridin-4-yl)-1,5,6,7- tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{2-[(25)-1,4-dioxan-2yl] ethoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4R-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-5-fluoro-2-methoxyanilino)- 2-(3-{[(25)-4-methylmorpholin-2yl] methoxy} pyridine in-4-yl)-1,5,6,7-tetrahydro-4//-pyrrolo[3,2-c]pyridine -4-one 3-(3-chloro-5-fluoro-2-methoxyanilino)-2-(3-{ [(25)-4-(2,2,2trifluoroethyl)morpholin-2-yl]methoxy}pyridin- 4-yl)-1,5,6,7-tetrahydro-4/7pyrrolo[3,2-c]pyridin-4-one

3-(3-chloro-2-ethylanilino)-2-{3-[(4-methylmorpholin-2-yl)methoxy]pyridin4-yl}-1,5,6,7-tetrahydro-4R-pyrrolo[3, 2-c]pyridin-4-one

3-(3-chloro-2-methoxyanilino)-2-{3-[(5,5-dimethyl-1,4-dioxan-2yl)methoxy]pyridin-4-yl}-1,5,6,7- tetrahydro-4//-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{[(27?)-5,5-dimethyl-1 ,4-dioxan-2yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2- methoxyanilino)-2-(3-{[(25)-5,5-dimethyl-1,4-dioxan-2yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4R-pyrrolo [3,2-c]pyridin-4-one 2-(3-{[(2K)-5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3- (3fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(25)-5,5-dimethyl- 1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(3fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4/7-pyrrolo[3,2-c ]pyridin-4-one 2-(3-{2-[(27?)-1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)-3-(3-fluoro-2methoxyanilino)-1 ,5,6,7-tetrahydro-4/7-pyrrolo[3,2-c]pyridin-4-one 2-(3-{2-[(25)-1,4-dioxan-2-yl]ethoxy }pyridin-4-yl)-3-(3-fluoro-2methoxyanilino)-1,5,6,7-tetrahydro-4R-pyrrolo[3,2-c]pyridin-4-one 3-(3-fluoro- 2-methoxyanilino)-2-(3-{[(37?)-4-methylmorpholin-3yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4R-pyrrolo[3,2- c]pyridin-4-one

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2-{3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridin-4-yl)-3-(3-fluoro-2methylanilino)-1,5,6,7- tetrahydro-4R-pyrrolo[3,2-c]pyridin-4-one

2-(3-{ [(25)-5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(3fluoro-2-methylanilino)-1,5, 6,7-tetrahydro-4R-pyrrolo[3,2-c]pyridin-4-one

3-[2-(2,2-difluoroethyl)-3-fluoroanilino]-2-{3-[(1,4-dioxan-2yl)methoxy]pyridin-4-yl}-1,5,6,7- tetrahydro-4/7-pyrrolo[3,2-c]pyridin-4-one 3-[2-(2,2-difluoroethyl)-3-fluoroanilino]-2-(3-{[(25)-4- methylmorpholin-2yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4/7-pyrrolo[3,2-c]pyridin-4-one

3-(3-chloro-2-methylanilino)-2-(3-{[(25)-4-methylmorpholin-2yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4/ 7-pyrrolo[3,2-c]pyridin-4-one

3-(3-chloro-2-methylanilino)-2-(3-{[(37?)-4-methylmorpholin-3yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4 /7-pyrrolo[3,2-c]pyridin-4-one

3-(3-chloro-2-methylanilino)-2-{3-[(5,5-dimethyl-1,4-dioxan-2yl)methoxy]pyridin-4-yl)-1,5,6,7- tetrahydro-4R-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methylanilino)-2-(3-{[(25)-5,5-dimethyl-1,4- dioxan-2yl]methoxy)pyridin-4-yl)-1,5,6,7-tetrahydro-4R-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methylanilino)- 2-(3-{[(27?)-5,5-dimethyl-1,4-dioxan-2yl]methoxy)pyridin-4-yl)-1,5,6,7-tetrahydro-4R-pyrrolo[3 ,2-c]pyridin-4-one

2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl)-3-(3-fluoro-2methylanilino)-1,5,6,7-tetrahydro-4R-pyrrolo[ 3,2-c]pyridin-4-one

2-(3-{[(25)-1,4-dioxan-2-yl]methoxy)pyridin-4-yl)-3-(3-fluoro-2methylanilino)-1,5,6,7-tetrahydro- 4/7-pyrrolo[3,2-c]pyridin-4-one

2-(3-{ [(27?)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2methylanilino)-1,5,6,7-tetrahydro -4/7-pyrrolo[3,2-c]pyridin-4-one

3-(3-chloro-2-methylanilino)-2-(3-{[(25)-1,4-dioxan-2-yl]methoxy)pyridin4-yl)-1,5,6,7-tetrahydro- 4R-pyrrolo[3,2-c]pyridin-4-one

3-(3-chloro-2-methylanilino)-2-(3-{[(27?)-1,4-dioxan-2-yl]methoxy)pyridin4-yl)-1,5,6,7-tetrahydro -4/7-pyrrolo[3,2-c]pyridin-4-one

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

3-(3-chloro-2-ethylanilino)-2-(3-{[(25)-1,4-dioxan-2-yl]methoxy)pyridin-4yl)-1,5,6,7-tetrahydro- 4/7-pyrrolo[3,2-c]pyridin-4-one

3-(3-chloro-2-ethylanilino)-2-(3-{[(27?)-1,4-dioxan-2-yl]methoxy)pyridin-4 yl)-1,5,6,7 -tetrahydro-4R-pyrrolo[3,2-c]pyridin-4-one

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3-(3-chloro-2-ethylanilino)-2-(3-{[(27?)-4-methylmorpholin-2yl]methoxy} pyridin-4-yl)-1,5,6,7-tetrahydro-4R -pyrrolo[3,2-c]pyridin-4-one

3-(3-chloro-2-ethylanilino)-2-(3-{[(25)-4-methylmorpholin-2yl]methoxy} pyridin-4-yl)-1,5,6,7-tetrahydro-4R- pyrrolo[3,2-c]pyridin-4-one

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

3-(3-chloro-2-methoxyanilino)-2-(3-{(1Х)-1-[(25')-1,4-dioxan-2yl]ethoxy}pyridin-4-yl)-1,5 ,6,7-tetrahydro-4/7-pyrrolo[3,2-c]pyridin-4-one

3-(3-chloro-2-methoxyanilino)-2-(3-{(1Х)-1-[(27?)-1,4-dioxan-2yl]ethoxy}pyridin-4-yl)-1,5 ,6,7-tetrahydro-4/7-pyrrolo[3,2-c]pyridin-4-one

3-(3-chloro-2-methoxyanilino)-2-(3-{(17?)-1-[(25)-1,4-dioxan-2yl]ethoxy}pyridin-4-yl)-1,5 ,6,7-tetrahydro-4/7-pyrrolo[3,2-c]pyridin-4-one

3-(3-chloro-2-methoxyanilino)-2-(3-{(17?)-1-[(27?)-1,4-dioxan-2yl]ethoxy}pyridin-4-yl)-1, 5,6,7-tetrahydro-4/7-pyrrolo[3,2-c]pyridin-4-one

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

3-(3-fluoro-2-methylanilino)-2-(3-{[(27?)-4-methylmorpholin-2yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4 /7-pyrrolo[3,2-c]pyridin-4-one

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

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

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

2-(3-{[(28)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3fluoroanilino)-1,5,6,7-tetrahydro- 4H-pyrrolo[3,2-c]pyridin-4-one

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

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

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

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

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

3-(3-chloro-2-methoxyanilino)-2-[3-({(18)-1-[(28)-4-methylmorpholin-2yl]ethyl}oxy)pyridin-4-yl]-1,5 ,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

3-(3-chloro-2-methoxyanilino)-2-[3-({(1К)-1-[(28)-4-methylmorpholin-2yl]ethyl}oxy)pyridin-4-yl]-1,5 ,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

3-(3-chloro-2-methoxyanilino)-2-[3-({(18)-1-[(2K)-4-methylmorpholin-2yl]ethyl }oxy)pyridin-4-yl]-1,5 ,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4one.

A further aspect of the invention relates to compounds of formula (I) which are presented in the form of salts thereof.

It should be understood that the present invention relates to any subcombination within any of the embodiments or aspects of the present invention of compounds of general formula (I) as defined above.

Even more specifically, the present invention covers compounds of general formula (I), which are disclosed in the Examples section of this text below.

In accordance with another aspect, the present invention covers methods for preparing the compounds of the present invention, which include the steps as described in the Experimental section of this description.

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Another embodiment of the invention is the compounds disclosed in the Claims or disclosed analogues of the exemplified compounds and subcombinations thereof.

Definitions.

It should be understood that the embodiments disclosed herein should not be understood as separate embodiments that are not related to each other. The features discussed in 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 disclosed in another embodiment or aspect of the invention rather than in another, one skilled in the art will appreciate that this does not necessarily mean that said feature is not intended to be disclosed in said other embodiment or aspect of the invention. One skilled in the art will appreciate that the intent of the present application is to disclose this feature also for another embodiment or aspect of the invention, but only for purposes of clarity and to keep the present description within reasonable scope. For example, it should be understood that all aspects, embodiments, pharmaceutical compositions, combinations, uses and/or methods of the present invention defined herein for compounds of formula (I) also apply to more specific embodiments of compounds of formula (I), such such as, but not limited to, compounds of formula (Ia), and vice versa.

In addition, it should be understood that the contents of documents that are referred to in this application are incorporated by reference in their entirety, for example, for purposes of providing continuity of experience, such as in the case of a discussion of a method, the details of which are described in the specified document. This approach allows us to keep the present description within a reasonable scope.

Structural moieties that are optionally substituted as defined herein may be substituted, unless otherwise indicated, one or more times independently of each other in any possible position. When any variable occurs more than once in any structural component, each definition is independent. For example, when R ¹ , R ^1a , R ^1b , R ^1c , R ² , R ³ and/or R ⁴ occur more than once in any compound of formula (I), each definition of R ¹ , R ^1a , R ^1b , R ^1c , R ² , R ³ and R ⁴ are independent.

If the structural moiety consists of more than one moiety, such as G-G-alkoxyG-G-alkyl, the possible substituent may be present on any of these moieties in any suitable position. A hyphen at the beginning or end of a structural component indicates where it joins the rest of the molecule. If the ring is substituted, the substituent may be at any suitable position on the ring, as well as on a nitrogen atom of the ring if appropriate.

The term including (containing), when used in the description, covers consisting of.

If within the scope of the description the expression as mentioned above or referred to above as above is used, it refers to any of the disclosures made within the scope of the description on any of the preceding pages.

When used within the specification, the expression as mentioned in this application, described in this application, provided in this application, or as mentioned herein, or stated in this application, refers to any of the disclosures made within the specification on any of the preceding or subsequent pages.

Suitable in the sense of the invention means chemically capable of being obtained by methods within the knowledge of a person skilled in the art.

The terms, as mentioned in this text, may have the following meanings:

The term halogen atom, halogen- or Hal- should be understood to mean a fluorine, chlorine, bromine or iodine atom.

The term GG-alkyl should be understood to mean a linear or branched, saturated, monovalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms, for example, 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, 4methylpentyl, 3-methylpentyl, 2-methylpentyl, 1 -methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2dimethylbutyl, or an isomer thereof. In particular, said group has 1, 2, 3 or 4 carbon atoms (C ₁ -C ₄ alkyl), for example, means a methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl group, more particularly 1, 2 or 3 carbon atoms (GG-alkyl), for example, means a methyl, ethyl, n-propyl or isopropyl group.

The term GG-haloalkyl should be understood to mean a linear or branched, saturated, monovalent hydrocarbon group, where the term GG-alkyl is defined above, and in which one or more hydrogen atoms are replaced by halogen atoms, either identically or differently, i.e. one halogen atom is independent of the other. In particular, said halogen atom means F. Said GG-haloalkyl group means, for example, -CF ₃ , -CHF ₂ , -CH ₂ F, -CF ₂ CF ₃ , -CH ₂ CH ₂ F,

- 8 046642

-CH2CHF2, -CH2CF3, -CH2CH2CF3 or -CH(CH2F)2.

The term C ₂ -C ₃ -fluoroalkyl should be understood to mean a linear or branched, saturated, monovalent hydrocarbon group, where the term O-O-alkyl is defined above, and in which one or more hydrogen atoms are replaced by a fluorine atom. Said O-O-fluoroalkyl group means, for example, -CF ₂ CF ₃ , -CH ₂ CH ₂ F , -CH ₂ CHF ₂ , -CH ₂ CF ₃ , -CH ₂ CH ₂ CF ₃ or -CH(CH ₂ F ) ₂ .

The term C.'i-C-1-alkoxy should be understood to mean a linear or branched, saturated, monovalent, hydrocarbon group of the formula -O-alkyl, where the term alkyl is defined above, for example, a methoxy, ethoxy, n-propoxy, isopropoxy, n- group butoxy, isobutoxy, t-butoxy or sec-butoxy, or an isomer thereof.

Unless otherwise defined, the term 5-6 membered heterocycloalkyl or 5-6 membered heterocyclic ring should be understood to mean a saturated, monovalent, monocyclic hydrocarbon ring that contains 4 or 5 carbon atoms and one heteroatom-containing group selected from O and NR, where R is a hydrogen atom, a Cj-C.'3-alkyl or a C1-C3-haloalkyl group, said heterocycloalkyl group may be attached to the rest of the molecule through any of the carbon atoms.

In particular, without limitation, said heterocycloalkyl may be, for example, a 5-membered ring such as tetrahydrofuranyl, pyrazolidinyl, or a 6-membered ring such as tetrahydropyranyl, piperidinyl.

The term C ₁ -C ₆ used throughout the text, for example, in the context of the definition of C ₁ -C ₆ -alkyl or O-O-haloalkyl, should be understood to mean an alkyl group having a finite number of carbon atoms from 1 to 6, i.e. e. 1, 2, 3, 4, 5 or 6 carbon atoms. In addition, it should be understood that the term C1-C6 should be interpreted as any sub-range contained therein, for example, C ₁ -C ₆ , C ₂ -C ₆ , C ₃ -C ₆ , C ₁ -C ₂ , C ₁ - C ₃ , in particular C ₁ -C ₂ , C ₁ -C ₃ , C ₁ -C ₄ .

The term C ₁ -C ₄ used throughout the text, for example, in the context of the definition of O-O-alkyl, O-O-haloalkyl, O-O-alkoxy or O-O-haloalkoxy, should be understood to mean an alkyl group having the terminal the number of carbon atoms is from 1 to 4, i.e. 1, 2, 3 or 4 carbon atoms. In addition, it should be understood that the term C ₁ -C ₄ should be interpreted as any subrange contained therein, for example, C ₁ -C ₄ , C ₂ -C ₄ , C ₃ -C ₄ , C ₁ -C ₂ , C ₁ -C ₃ , in particular C ₁ -C ₂ , C ₁ -C ₃ , C ₁ C ₄ , and in the case of O-O-haloalkyl or O-O-haloalkoxy even more specifically C ₁ -C ₂ .

Moreover, the term C3-C6 used throughout the text, for example in the context of the definition of C ₃ C.'6-cycloalkyl, should be understood to mean a cycloalkyl group having a finite number of carbon atoms from 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms. In addition, it should be understood that the term C3-C6 should be interpreted as any sub-range contained therein, for example, C3-C6, C4-C5, C3-C5, C3-C4, C4-C6, C5-C6; in particular C3-C6.

The term substituted means that one or more hydrogen atoms on the designated atom are replaced by substituents selected from the indicated group, provided that the normal valency of the designated atom under existing circumstances is not exceeded and that the substitution results in a stable compound. Only such combinations of substituents and/or variables are allowed that lead to stable compounds.

The term optionally substituted means optional substitution with specified groups, radicals or moieties.

A ring system substituent means a substituent attached to an aromatic or non-aromatic ring system that, for example, replaces an available hydrogen on such ring system.

As used herein, the term one or more, for example in the definition of substituents of compounds of the general formulas of the present invention, is understood to mean one, two, three, four, five, etc., in particular one, two, three or four, more specifically one, two or three, even more specifically one or two.

Compounds of general formula (I) may exist as isotopic variants. Thus, the invention includes one or more isotopic variants of the compounds of general formula (I), in particular deuterium-containing compounds of general formula (I).

The term isotopic variant of a compound or reagent is defined as a compound that exhibits a non-naturally occurring relative abundance of one or more of the isotopes that make up the compound.

The term isotopic variant of a compound of general formula (I) is defined as a compound of general formula (I) exhibiting a non-naturally occurring relative abundance of one or more isotopes that constitute such compound.

The expression non-natural relative abundance should be understood to mean the relative abundance of such an isotope, which is higher than its abundance in nature. Information regarding the natural abundances of isotopes mentioned 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, azo

- 9 046642 ta, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as ² H (deuterium), ³ H (tritium), 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, respectively.

With respect to the treatment and/or prevention of the disorders described in this application, isotopic variants of the compounds of general formula (I) in one embodiment contain deuterium (deuterium-containing compounds of general formula (I)). Isotopic variants of compounds of general formula (I) into which one or more radioactive isotopes such as ³ H or ¹⁴ C have been included are useful, for example, for studying drug and/or substrate tissue distribution. These isotopes are particularly preferred due to their ease of inclusion and detectability. Positron-active isotopes such as ¹⁸ F or ¹¹ C may also be included in the compound of general formula (I). Such isotopic variants of the compounds of general formula (I) are useful for in vivo imaging applications. Deuterium-containing and ¹³ C-containing compounds of general formula (I) can be used in mass spectrometric analyzes (H. J. Leis et al., Curr. Org. Chem., 1998, 2, 131) in the context of preclinical or clinical studies.

Isotopic variants of compounds of general formula (I) can generally be prepared by methods known to one skilled in the art, such as those described in the diagrams and/or examples herein, by replacing the reagent with an isotopic variant of said reagent, and in one embodiment, to a reagent containing deuterium. Depending on the desired deuteration sites, in some cases deuterium from D ₂ O can be introduced either directly into compounds or into reagents that are useful for the synthesis of such compounds (Esaki et al., Tetrahedron, 2006, 62, 10954; Esaki and al., Chem. Eur., 2007, 13, 4052). Deuterium gas is also a useful reagent for introducing deuterium into molecules. A rapid route for introducing deuterium is the catalytic deuteration of olefin bonds (H. J. Leis et al., Curr. Org. Chem., 1998, 2, 131; J. R. Morandi et al., J. Org. Chem., 1969, 34 (6), 1889) and acetylene bonds (NH Khan, J. Am. Chem. Soc., 1952, 74 (12), 3018; S. Chandrasekhar et al., Tetrahedron, 2011, 52, 3865). Metal catalysts (ie, Pd, Pt, and Rh) in the presence of deuterium gas can be used to directly exchange hydrogen for deuterium in functional groups containing hydrocarbon moieties (JG Atkinson et al., US Pat. No. 3,966,781). A variety of deuterated reagents and building blocks for synthesis are commercially available from companies such as C/D/N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc., Princeton, NJ, USA. Additional information on the prior art regarding the exchange of hydrogen for deuterium is given, for example, in the following documents: 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.

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 where the relative content of deuterium at each deuterated position of such compound of general formula (I ) is higher than the natural abundance of deuterium, which is approximately 0.015%. In particular, in a deuterium-containing compound of general formula (I), the relative content of deuterium at each deuterated position of such 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, said position(s) have a deuterium content greater than 98% or 99%. It should be understood that the relative deuterium content at each deuterated position is independent of the relative deuterium content at the other deuterated position(s).

Selective introduction of one or more deuterium atoms into a compound of general formula (I) can change physicochemical properties (such as, for example, acidity [A. Streitwieser et al., J. Am. Chem. Soc., 1963, 85, 2759; C. L. Perrin, et al., J. Am. Soc., 2007, 129, 4490], basicity [C. L. Perrin, et al., J. Am. Soc., 2003, 125, 15008; Advances in Physical Organic Chemistry, 44, 144; C. L. Perrin et al., J. Am. Soc., 2005, 127, 9641], lipophilicity [B. Testa et al., Int. J. Pharm., 1984 19(3), 271]) and/or the metabolic profile of the molecule, and may lead to changes in the ratio of the amounts of parent compound to metabolites or the amounts of metabolites formed. Such changes may lead to certain therapeutic benefits and may therefore be preferable in some circumstances. A decrease in metabolic rate and a metabolic switch in which the ratio of metabolites was changed has been reported (D. J. Kushner et al., Can. J. Physiol. Pharmacol., 1999, 77, 79; A. E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). These changes in the exposure of the parent drug and metabolites may have important consequences regarding the pharmacodynamics, tolerability and efficacy of the deuterium-containing compound of general formula (I). In some cases, deuterium substitution reduces or eliminates the formation of an unwanted or toxic metabolite and increases the formation of the target metabolite (eg, Nevirapine: A. M. Sharma et al., Chem. Res. Toxicol., 2013, 26, 410; Uetrecht et al., Chemical

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Research in Toxicology, 2008, 21, 9, 1862; Efavirenz: A. E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). In other cases, the main effect of deuteration is a decrease in the rate of systemic clearance. As a result, the biological half-life of the compound increases. Potential clinical benefits will include the ability to maintain similar systemic exposure with reduced peak levels and increased trough levels. This may result in reduced side effects and increased efficacy, depending on the pharmacokinetic/pharmacodynamic profile of the particular compound. Examples for this effect of deuterium are the preparations indiplon (A. J. Morales et al., Abstract 285, 15th North American Conference of the International Society for the Study of Xenobiotics, San Diego, California, October 12-16, 2008), ML-337 (C. J. Wenthur et al., J. Med. Chem., 2013, 56, 5208) and odanacatib (K. Kassahun et al., WO2012/112363). Other cases have also been reported in which decreased metabolic rates lead to increased drug exposure without changing the rate of systemic clearance (eg, rofecoxib: F. Schneider et al., Arzneim. Forsch. Drug. Res., 2006, 56, 295; Telaprevir : F. Maltais et al., J. Med. Chem., 2009, 52, 7993). Deuterated drugs exhibiting this effect may have reduced dosing requirements (eg, fewer doses or a lower dose to achieve the desired effect) and/or may result in reduced metabolic loads.

A compound of general formula (I) may have several potential sites of attack for metabolism. To optimize the above-described effects on physicochemical properties and metabolic profile, deuterium-containing compounds of general formula (I) that have a specific exchange pattern of one or more deuterium-hydrogen atoms can be selected. In particular, the deuterium atom(s) of the deuterium-containing compound(s) of general formula (I) are attached to a carbon atom and/or are located at those positions of such compound(s) of general formula (I) that are sites of attack for metabolizing enzymes such as , for example, cytochrome P ₄₅₀ .

If the plural form is used herein for the words compounds, salts, polymorphs, hydrates, solvates, or the like, then this is also to be understood as one compound, salt, polymorph, isomer, hydrate, solvate, or the like.

The expression stable compound or stable structure means a compound that is stable enough to withstand isolation to an acceptable degree of purity from a reaction mixture and preparation from it into an effective therapeutic agent.

The compounds of the present invention may contain one or more asymmetric centers, depending on the location and nature of the various substituents desired. Asymmetric carbon atoms can be in the (R) or (S) configuration, leading to racemic mixtures in the case of a single asymmetric center, and diastereomeric mixtures in the case of multiple asymmetric centers. In some cases, asymmetry may also be present due to limited rotation around a given bond, for example, a central bond adjacent to two substituted aromatic rings of the specified compounds.

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

Preferred compounds are those that produce the more desirable biological activity. Isolated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of this invention are also included within the scope of the present invention. Purification and separation of such substances can be accomplished using standard methods known in the art.

Optical isomers can be prepared by resolving racemic mixtures according to conventional methods, for example by forming diastereomeric salts using an optically active acid or base, or by forming covalent diastereomers. Examples of suitable acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereoisomers based on their physical and/or chemical differences using methods known in the art, such as chromatography or fractional crystallization. The optically active bases or acids are then released from the separated diastereomeric salts. Another method for separating optical isomers involves the use of chiral chromatography (eg, chiral HPLC columns), with or without conventional derivatization optimally selected to maximize enantiomer separation. Suitable chiral HPLC columns are produced by Diacel, for example Chiracel OD and Chiracel OJ, among many others commonly selected. Enzymatic separation methods, with or without derivatization, are also suitable. The optically active compounds of the present invention can also be prepared by chiral synthesis using optically active starting materials.

In order to distinguish between the different types of isomers, reference is made to the IUPAC rules, section E (Pure Appl Chem 45, 11-30, 1976).

The present invention includes all possible stereoisomers of the compounds of the present invention

- 11 046642 in the form of individual stereoisomers or in the form of any mixture of said stereoisomers, for example, R or S-isomers, or E- or Z-isomers, in any ratio. Isolation of a single stereoisomer, for example a single enantiomer or a single diastereomer, of a compound of the present invention can be achieved using any suitable prior art method, such as, for example, chromatography, especially chiral chromatography.

Moreover, the compounds of the present invention may exist as tautomers. For example, any compound of the present invention that contains a pyrazole moiety as a heteroaryl group, for example, may exist as a 1H tautomer or a 2H tautomer, or even a mixture of any amounts of two tautomers, or a triazole moiety, for example, may exist as a 1H tautomer, 2H tautomer or 4H tautomer, or even mixtures of any amounts of the indicated 1H, 2H and 4H tautomers, namely:

The present invention includes all possible tautomers of the compounds of the present invention, either as individual tautomers or as any mixture of said tautomers, in any ratio.

Moreover, the compounds of the present invention may exist as N-oxides, which are defined by the fact that at least one nitrogen atom of the compounds of the present invention is oxidized. The present invention includes all such possible N-oxides.

The present invention also relates to useful forms of the compounds disclosed herein, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and co-precipitation products.

The compounds of the present invention may exist as a hydrate or as a solvate, where the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol, for example, as a lattice building block of the compounds. The amount of polar solvents, in particular water, can be in a stoichiometric or non-stoichiometric ratio. In the case of stoichiometric solvates, for example, hydrate, hemi- (half-), mono-, sesqui-, di-, tri-, tetra-, penta-, etc. are possible. solvates or hydrates, respectively. The present invention includes all such hydrates or solvates.

Moreover, the compounds of the present invention may exist in a free form, for example, as a free base or as a free acid, or as a zwitterion, or may exist as a salt. Said salt may be any salt, either organic or inorganic addition salt, in particular any pharmaceutically acceptable organic or inorganic addition salt commonly used in the pharmaceutical industry.

The term pharmaceutically acceptable salt refers to a relatively non-toxic addition salt of an inorganic or organic acid to a compound of the present invention. For example, see S. M. Berge, et al. Pharmaceutical Salts J. Pharm. Sci. 1977, 66, 1-19.

A suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid addition salt of a compound of the present invention bearing a nitrogen atom, for example, in a chain or ring that is sufficiently basic, such as an addition salt with an inorganic acid, such as e.g. , hydrochloric, hydrobromic, hydroiodic, sulfuric, beading, phosphoric or nitric acid, or with an organic acid such as, for example, formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4hydroxybenzoyl)benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy2-naphthoic, nicotinic, pamoic, pectic, suprasulfuric, 3-phenylpropionic, picric, pivalic, 2-hydroxyethanesulfonic, itaconic, sulfamic, trifluoromethanesulfonic, dodec ilsulfur , ethanesulfonic, benzenesulfonic, para-toluenesulfonic, methanesulfonic, 2-naphthalene sulfonic, naphthalene disulfonic, camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic, ascorbic, , glucoheptane, glycerophosphoric, aspartic, sulfosalicylic, hemisulfuric or thiocyanic acid.

Moreover, another suitable pharmaceutically acceptable salt of the compound of the present invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base , which produces a physiologically acceptable cation, for example, the salt with N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, dicyclohexylamine, 1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, trishydroxymethylaminomethane, aminopropanediol, Sovak's base, 1-amino-2, 3,4-butanetriol. Additionally, groups containing basic nitrogen can be quaternized with reagents such as

- 12 046642 lower alkyl halides, such as methyl, ethyl, propyl and butyl chlorides, -bromides and -iodides; dialkyl sulfates like dimethyl, diethyl and dibutyl sulfate; and diamyl sulfates; long-chain halides such as decyl-, lauryl-, myristyl- and stearyl chlorides, -bromides and -iodides, aralkyl halides like benzyl and phenethyl bromides, and others.

Those skilled in the art will further appreciate that 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 number of known methods. Alternatively, the alkali and alkaline earth metal salts of the acidic compounds of the invention are prepared by reacting the compounds of the invention with a suitable base using a variety of known methods.

The present invention includes all possible salts of the compounds of the present invention in the form of individual salts, or in the form of any mixture of these salts, in any ratio.

In the present text, in particular in the experimental section, in the case of the synthesis of intermediates and examples of the present invention, when the compound is mentioned in the form of a salt form with the corresponding base or acid, the exact stoichiometric composition of the said salt form obtained using the corresponding method of preparation and/or cleaning is, in most cases, unknown.

Unless otherwise indicated, suffixes to chemical names or structural formulas such as hydrochloride, trifluoroacetate, sodium salt, or xHCl, xCF3COOH, xNa ⁺ , for example, should not be understood as a stoichiometric characteristic, but solely as an indication of the salt form.

This similarly applies to cases in which synthetic intermediates or illustrative compounds or salts thereof have been prepared, using the preparation and/or purification methods described, as solvates such as hydrates of (if of a certain type) unknown stoichiometric composition.

Salts include water-insoluble salts and, in particular, water-soluble salts.

Moreover, derivatives of compounds of formula (I) and salts thereof that are converted into a compound of formula (I) or a salt thereof in a biological system (bioprecursors or prodrugs) are also covered by the present invention. Said biological system is, for example, a mammalian organism, in particular a human. The bioprecursor, for example, is converted into the compound of formula (I) or a salt thereof through metabolic processes.

As used herein, the term in vivo hydrolyzable ester is understood to mean the in vivo hydrolyzable ester of a compound of the present invention containing a carboxyl or hydroxyl group, for example, a pharmaceutically acceptable ester that is hydrolyzed in a human or animal body to produce the parent acid or alcohol Suitable pharmaceutically acceptable esters in the case of a carboxyl group include, for example, alkyl, cycloalkyl and optionally substituted phenylalkyl, in particular benzyl esters, C ₁ -C ₆ alkoxymethyl esters, for example methoxymethyl, C ₁ -C ₆ alkanoyloxymethyl esters esters, for example pivaloyloxymethyl, phthalidyl esters, C ₃ -C ₈ -cycloalkoxycarbonyloxy-C ₁ -C ₆ -alkyl esters, for example 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters, for example 5methyl-1,3-dioxolen-2-onylmethyl; and C ₁ -C ₆ -alkoxycarbonyloxyethyl esters, for example, 1-methoxycarbonyloxyethyl, and can be formed involving any carboxyl group in the compounds of this invention.

The in vivo hydrolyzable esters of the hydroxyl group-containing compound of the present invention include inorganic esters such as phosphoric acid esters, and [alpha]-acyloxyalkyl esters and related compounds which, upon in vivo hydrolysis of the ester group, are cleaved to yield the parent hydroxyl group. groups. Examples of [alpha]-acyloxyalkyl ethers include acetoxymethoxy and 2,2dimethylpropionyloxymethoxy. The list of selectable groups forming an in vivo hydrolyzable ester in the case of hydroxy includes alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates) , dialkylaminoacetyl and carboxyacetyl. The present invention covers all such esters.

Moreover, the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as a single polymorph or as a mixture of more than one polymorph, in any ratio.

In the context of the properties of the compounds of the present invention, the term pharmacokinetic profile means a single parameter or combination of parameters, including permeability, bioavailability, exposure and pharmacodynamic parameters, such as duration or magnitude of pharmacological action, measured in a suitable experiment. Compounds with an improved pharmacokinetic profile, for example, can be used at lower doses to achieve the same effect, or allow for a longer duration of action, or allow for a combination

- 13 046642 both effects.

The term combination in the present invention is used as is known to those skilled in the art and may be presented as a fixed combination, a non-fixed combination, or a set of components.

The term fixed combination in the present invention is used as known to those skilled in the art and is defined as a combination in which said first active ingredient and said second active ingredient are present together in one unit dosage form or in the form of a single unit. One example of a fixed combination is a pharmaceutical composition in which said first active ingredient and said second active ingredient are present in a mixture for simultaneous administration, such as in a formulation. Another example of a fixed combination is a pharmaceutical combination in which said first active ingredient and said second active ingredient are present in one unit in an unmixed state.

The term non-fixed combination or set of components in the present invention is used as known to those skilled in the art and is defined as a combination in which said first active component and said second active component are present in more than one unit. One example of a non-fixed combination or set of components is a combination in which said first active component and said second active component are present separately. Components of a non-fixed combination or set of components can be introduced separately, sequentially, simultaneously, in parallel or chronologically offset. Any such combination of a compound of formula (I) of the present invention with an antitumor agent as defined below is one embodiment of the invention.

The term (chemotherapeutic) anticancer agents refers to any agent that reduces the survival or proliferation of cancer cells and includes, but is not limited to: 131I-chTNT, abarelix, abiraterone, aclarubicin, adotrastuzumab emtansine, afatinib, aflibercept, aldesleukin, alemtuzumab, alendronic acid , alitretinoin, altretamine, amifostine, aminoglutethimide, hexyl aminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithioletion, angiotensin II, antithrombin III, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, azacitidine, basiliximab, belotecan, bendamustine, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib, calcium folinate, calcium levofolinate, capecitabine, capromab, carboplatin, carfilzomib, carmofur, carmustine, ab, celecoxib, celmoleukin , ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, copanlisib, crisantaspas, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, dabrafenib, ib, daunorubicin, decitabine, degarelix , denileukin diftitox, denosumab, depreotide, deslorelin, dexrazoxane, dibrospidium chloride, dihydrogalactitol, diclofenac, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, eculizumab, edrecolomab, eliptinium acetate, eltrombopag, , enocitabine, enzalutamide, epirubicin, epithiostanol, epoetin alpha, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid a, formstan, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoteric acid - meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, glucarpidas, glutoxim, GM-CSF, goserelin, granisetron, granulocyte colony-stimulating factor, histamine chloride, histrelin, hydroxyurea, I-125 grains, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indysetron, incadronic acid, ingenol mebulate, interferon alpha, interferon beta, interferon gamma, iobene, guan ( 123I), iomeprol, ipilimumab, irinotecan, itraconazole, ixabepilone, lanreotide, lapatinib, yasocholine, lenalidomide, lenograstim, lentinan, letrozole, leuprorelin, levamisol, levonorgrestel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, masoprocol, progesterone, megestrol, melarsoprol, melphalan, mepithiostane, mercaptopurine, mesna, methadone, methotrexate, methoxalen, methylaminolevulinate, methylprednisolone, methyltestosterone, metyrosine, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitoxant, ron, mogamulizumab, molgramostim, mopidamole, morphine hydrochloride , morphine sulfate, nabilone, nabiximolz, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, nedaplatin, nelarabine, neridronic acid, nivolumabpentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nitracrine, nivolumab, obinutuzumab, octreotide, mumab, omacetaxine mepesucinate, - epoetin beta (methoxy PEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alfa-2K pemetrec

- 14 046642 sed, pentazocine, pentostatin, peplomycin, perflubutan, perfosfamide, pertuzumab, picibanil, pilocarpine, pyrarubicin, pixantrone, plerixafor, plicamycin, polyglusam, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, b, sodium porfimer, posiotinib, pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumumab, radium-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicas, razoxane, refametinib, regorafenib, edronic acid, rhenium etidronate -186, rituximab, romidepsin, romiplostim, romurtide, roniciclib, samarium (153Sm) lexidronam, sargramostim, satumomab, secretin, sipuleucel-T, sisofiran, sobuzoxan, sodium glycididazole, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin, ibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium (99mTc) nofetumomab-merpentane, 99mTc-HYNIC-[Tyr3]-octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, fasin, thyrotropin alpha, thioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, valatinib, , valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin.

By epidermal growth factor receptor (EGFR) polypeptide is meant a polypeptide having an amino acid sequence identity to the sequence presented in UniProt accession number P00533-1, or a fragment thereof, that is at least about 95%. In some embodiments, the EGFR moiety binds an EFGR ligand and/or has kinase activity. EGFR mutant polypeptides include polypeptides having an insertion between, for example, amino acids V769 and D770 or between D770 and N771. In other embodiments, the amino acid sequence identity to UniProt accession number P00533-1 is 96%, 97%, 98%, 99%, or 100%.

An exemplary full-length sequence of human EGFR, with V769, D770 and N771 in bold, is provided in UniProt accession number P00533-1, which is reproduced below:

10 20 thirty 40 50 MRPSGTAGAA LLALLAALCP ASRALEEKKV CQGTSNKLTQ LGTFEDHFLS 60 70 80 90 100 LQRMFNNCEV VLGNLEITYV QRNYDLSFLK TIQEVAGYVL IALNTVERIP 110 120 130 140 150 LENLQIIRGN MYYENSYALA VLSNYDANKT GLKELPMRNNL QEILHGAVRF 160 170 180 190 200 SNNPALCNVE SIQWRDIVSS DFLSNMSMDF QNHLGSCQKC DPSCPNGSCW 210 220 230 240 250 GAGEENCQKL TKIICAQQCS GRCRGKSPSD CCHNQCAAGC TGPRESDCLV 260 270 280 290 300 CRKFRDEATC KDTCPPLMLY NPTTYQMDVN PEGKYSFGAT CVKKCPRNYV

- 15 046642

310 320 330 340 350 VTDHGSCVRA CGADSYEMEE DGVRKCKKCE GPCRKVCNGI GIGEFKDSLS 360 370 380 390 400 INATNIKHFK NCTSISGDLH ILPVAFRGDS FTHTPPLDPQ ELDILKTVKE 410 420 430 440 450 ITGFLLIQAW PENRTDLHAF ENLEIIRGRT KQHGQFSLAV VSLNITSLGL 460 470 480 490 500 RSLKEISDGD VIISGNKNLC YANTINWKKL FGTSGQKTKI ISNRGENSCK 510 520 530 540 550 ATGQVCHALC SPEGCWGPEP RDCVSCRNVS RGRECVDKCN LLEGEPREFV 560 570 580 590 600 ENSECIQCHP ECLPQAMNIT CTGRGPDNCI QCAHYIDGPH CVKTCPAGVM 610 620 630 640 650 GENNTLVWKY ADAGHVCHLC HPNCTYGCTG PGLEGCPTNG PKIPSIATGM 660 670 680 690 700 VGALLLLLW ALGIGLFMRR RHIVRKRTLR RLLQERELVE PLTPSGEAPN 710 720 730 740 750 QALLRILKET EFKKIKVLGS GAFGTVYKGL WIPEGEKVKI PVAIKELREA 760 770 780 790 800 TSPKANKEIL DEAYVMASVD NPHVCRLLGI CLTSTVQLIT QLMPFGCLLD 810 820 830 840 850 YVREHKDNIG SQYLLNWCVQ IAKGMNYLED RRLVHRDLAA RNVLVKTPQH 860 870 880 890 900 VKITDFGLAK LLGAEEKEYH AEGGKVPIKW MALESILHRI YTHQSDVWSY 910 920 930 940 950 GVTVWELMTF GSKPYDGIPA SEISSILEKG ERLPQPPICT IDVYMIMVKC 960 970 980 990 1000 WMIDADSRPK FRELIIEFSK MARDPQRYLV IQGDERMHLP SPTDSNFYRA 1010 1020 1030 1040 1050 LMDEEDMDDV VDADEYLIPQ QGFSSPSTS RTPLLSSLSA TSNNSTVAC 1060 1070 1080 1090 1100 DRNGLQSCPI KEDSFLQRYS SDPTGALTED SIDDTFLPVP EYINQSVPKR 1110 1120 ISO 1140 1150 PAGSVQNPVY HNQPLNPAPS RDPHYQDPHS TAVGNPEYLN TVQPTCVNST 1160 1170 1180 1190 1200 FDSPAHWAQK GSHQISLDNP DYQQDFFPKE AKPNGIFKGS TAENAYLRV 1210 APQSSEFIGA

An exemplary polynucleotide encoding EGFR is provided by NCBI reference sequence NM_001346897.1, which is reproduced below:

- 16 046642 gtccggggcag cccccggcgc agcgcggccg cagcagcctc cgccccccgc acggtgtgag 61 cgcccgacgc ggccgaggcg gccggagtcc cgagctagcc ccggcggccg ccgccgccca 121 gaccggacga caggccacct cgtcggcgtc cg cccgagtc cccgcctcgc cgccaacgcc

181 acaaccaccg cgcacggccc cctgactccg tccagtattg atcggggagag ccggagcgag

241 ctcttcgggg agcagcgatg cgaccctccg ggacggccgg ggcagcgctc ctggcgctgc

301 tggctgcgct ctgcccggcg agtcgggctc tggaggaaaa gaaagtttgc caaggcacga

361 gtaacaagct cacgcagttg ggcacttttg aagatcattt tctcagcctc cagaggatgt

421 tcaataactg tgaggtggtc cttgggaatt tggaaattac ctatgtgcag aggaattatg

481 atctttcctt cttaaagacc atccaggagg tggctggtta tgtcctcatt gccctcaaca

541 cagtggagcg aattcctttg gaaaacctgc agatcatcag aggaaatatg tactacgaaa

601 attcctatgc cttagcagtc ttatctaact atgatgcaaa taaaaccgga ctgaaggagc

661 tgcccatgag aaatttacag ggccaaaagt gtgatccaag ctgtcccaat gggagctgct

721 ggggtgcagg agaggagaac tgccagaaac tgaccaaaat catctgtgcc cagcagtgct

781 ccgggcgctg ccgtggcaag tcccccagtg actgctgcca caaccagtgt gctgcaggct

841 gcacaggccc ccgggagagc gactgcctgg tctgccgcaa attccgagac gaagccacgt

901 gcaaggacac ctgcccccca ctcatgctct acaaccccac cacgtaccag atggatgtga

961 accccgaggg caaatacagc tttggtgcca cctgcgtgaa gaagtgtccc cgtaattatg

1021 tggtgacaga tcacggctcg tgcgtccgag cctgtggggc cgacagctat gagatggagg

1081 aagacggcgt ccgcaagtgt aagaagtgcg aagggccttg ccgcaaagtg tgtaacggaa

1141 taggtattgg tgaatttaaa gactcactct ccataaatgc tacgaatatt aaacacttca

1201 aaaactgcac ctccatcagt ggcgatctcc acatcctgcc ggtggcattt aggggtgact

1261 ccttcacaca tactcctcct ctggatccac aggaactgga tattctgaaa accgtaaagg

1321 aaatcacagg gtttttgctg attcaggctt ggcctgaaaa caggacggac ctccatgcct

1381 ttgagaacct agaaatcata cgcggcagga ccaagcaaca tggtcagttt tctcttgcag

1441 tcgtcagcct gaacataaca tccttgggat tacgctccct caaggagata agtgatggag

1501 atgtgataat ttcaggaaac aaaaatttgt gctatgcaaa tacaataaac tggaaaaaac

1561 tgtttgggac ctccggtcag aaaaccaaaa ttataagcaa cagaggtgaa aacagctgca

1621 aggccacagg ccaggtctgc catgccttgt gctcccccga gggctgctgg ggcccggagc

1681 ccaggactg cgtctcttgc cggaatgtca gccgaggcag ggaatgcgtg gacaagtgca

1741 accttctgga gggtgagcca agggagtttg tggagaactc tgagtgcata cagtgccacc

1801 cagagtgcct gcctcaggcc atgaacatca cctgcacagg acggggacca gacaactgta

1861 tccagtgtgc ccactacatt gacggccccc actgcgtcaa gacctgcccg gcaggagtca

1921 tggggagaaaa caacaccctg gtctggaagt acgcagacgc cggccatgtg tgccacctgt

1981 gccatccaaa ctgcacctac ggatgcactg ggccaggtct tgaaggctgt ccaacgaatg

2041 ggcctaagat cccgtccatc gccactggga tggtggggggc cctcctcttg ctgctggtgg

2101 tggccctggg gatcggcctc ttcatgcgaa ggcgccacat cgttcggaag cgcacgctgc

- 17 046642

2161 ggaggctgct gcaggagagg gagcttgtgg agcctcttac acccagtgga gaagctccca 2221 accaagctct cttgaggatc ttgaaggaaa ctgaattcaa aaagatcaaa gtgctgggct 2281 ccggtgcgtt cggcacggtg tataagggac tctggatccc agaaggt gag aaagttaaaa 2341 ttcccgtcgc tatcaaggaa ttaagagaag caacatctcc gaaagccaac aaggaaatcc 2401 tcgatgaagc ctacgtgatg gccagcgtgg acaaccccca cgtgtgccgc ctgctgggca 2461 tctgcctcac ctccaccgtg cagctcatca cgcagctcat gcccttcggc tgcctcctgg 2521 actatgtccg ggaacacaaa gacaatattg gctcccagta cctgctcaac tggtgtgtgc 2581 agatcgcaaa gggcatgaac tacttggagg accgtcgctt ggtgcaccgc gacctggcag 2641 ccaggaacgt actggtgaaa acaccgcagc atgtcaagat cacagatttt gggctggcca 2701 aactgctggg tgcggaagag aaagaatacc atgcagaagg aggcaaagtg cctatcaag t 2761 ggatggcatt ggaatcaatt ttacacagaa tctataccca ccagagtgat gtctggagct 2821 acggggtgac tgtttgggag ttgatgacct ttggatccaa gccatatgac ggaatccctg 2881 ccagcgagat ctcctccatc ctggagaaag gagaacgcct ccctcagcca cc catatgta 2941 ccatcgatgt ctacatgatc atggtcaagt gctggatgat agacgcagat agtcgcccaa 3001 agttccgtga gttgatcatc gaattctcca aaatggcccg agacccccag cgctaccttg 3061 tcattcaggg ggatgaaaga atgcatttgc caagtcctac agactccaac ttctaccgtg 3121 ccctgatgga tgaagaagac atggacgacg tggtggatgc cgacgagtac ctcatcccac 3181 a gcagggctt cttcagcagc ccctccacgt cacggactcc cctcctgagc tctctgagtg 3241 caaccagcaa caattccacc gtggcttgca ttgatagaaa tgggctgcaa agctgtccca 3301 tcaaggaaga cagcttcttg cagcgataca gctcagaccc cacaggcgcc ttgactgagg 3361 acagcataga cgacaccttc ctcccagtgc ctggtgagtg gcttgtctgg aaacagtcct 3421 gctcctcaac ctcctcgacc cactcagcag cagccagtct ccagtgtcca agccaggtgc 3481 tccctccagc atctccagag ggggaaacag tggcagattt gcagacacag tgaagggcgt 3541 aaggagcaga taaacacatg accgagcctg cacaagctct ttgttgtgtc tggttgtttg 3601 ct gtacctct gttgtaagaa tgaatctgca aaatttctag cttatgaagc aaatcacgga 3661 catacacatc tgtgtgtgtg agtgttcatg atgtgtgtac atctgtgtat gtgtgtgtgt 3721 gtatgtgtgt gtttgtgaca gatttgatcc ctgtt ctctc tgctggctct atcttgacct 3781 gtgaaacgta tatttaacta attaaatatt agttaatatt aataaatttt aagctttatc 3841 cagaaaaaaa aaaaaaaaa

The intermediates used for the synthesis of the compounds of claims 1-4, as described below, as well as their use for the synthesis of the compounds of claims 1-4, constitute one additional aspect of the present invention. Preferred intermediates are Examples of intermediates are disclosed below.

General techniques.

The compounds according to the invention can be prepared according to the following Schemes 1-4.

The schemes and procedures described below illustrate the routes for the synthesis of compounds of general formula (I) of the invention and are not intended to limit its scope. It will be apparent to one skilled in the art that the order of transformations exemplified in the diagrams can be modified in various ways. As a result, the order of transformations given as an example in the diagrams is not intended to limit the scope. In addition, interconversion of any of the substituents, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and PG, can be successfully accomplished before and/or after the exemplary transformations. These modifications may be the introduction of protecting groups, deprotection, reduction or oxidation of functional groups, halogenation, metalation, substitution or other reactions known to one skilled in the art. These transformations include those reactions that introduce functions that allow additional interconversion of substituents. Suitable protecting groups and their introduction and removal are well known to one skilled in the art. Specific examples are described in the following paragraphs.

- 18 046642

Scheme 1

Scheme 1. Route for the preparation of compounds of general formula (I), where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , X, Y, m and n have the meanings given for the general formula (I), and PG can mean hydrogen or, optionally, a suitable protecting group, for example tert-butoxycarbonyl (Boc).

The compounds of formulas 1, 2 and 4 are either commercially available or can be prepared according to procedures available from public sources as understood by one skilled in the art. Specific examples are described in the following paragraphs.

Suitably substituted piperidine-2,4-diones of the general formula (compound of formula 1), such as, for example, 2,4-piperidinedione, can be reacted with a suitably substituted isothiocyanate (compound of formula 2), such as, for example, 3- fluorophenyl isothiocyanate, in a suitable solvent system, such as, for example, acetonitrile, in the presence of a suitable base, such as, for example, triethylamine or DBU, at temperatures ranging from -78°C to +100°C, and in some embodiments, the reaction is carried out at 0°C or +100°C, obtaining a product of general formula (3). Carrying out similar reactions is described in the literature (D. E. Worrall, J. Am. Chem. Soc., 1940, 62, 675).

Intermediates of general formula (3) can be converted into intermediates of general formula (5) by reaction with a suitable amine (compounds of general formula 4), such as, for example, 4-(aminomethyl)pyridine, in a suitable solvent system, such as, for example , ethanol and ethyl acetate, at temperatures ranging from room temperature to the boiling point of the respective solvents, and in some embodiments, the reaction is carried out at the boiling point of the respective solvents, during which time the water formed as a result of the reaction is removed from the reaction mixture by methods known to those skilled in the art. the art, such as, for example, azeotropic removal of water (Dean-Stark conditions) or the use of molecular sieves, to obtain a product of general formula (5).

Intermediates of general formula (3) and intermediates of general formula (5) in which PG represents a protecting group can be converted into intermediates in which PG represents a hydrogen atom using standard deprotection conditions known to those skilled in the art technology. When PG denotes a protecting group, such as, for example, tert-butoxycarbonyl (Boc), deprotection can be carried out using acids, such as, for example, hydrochloric acid and trifluoroacetic acid, in a suitable solvent system, such as, for example, dichloromethane and dioxane , at a temperature from 0°C to the boiling point of the corresponding solvents, and in one embodiment, the reaction is carried out at room temperature, to obtain compounds of general formula (3) and intermediate compounds of general formula (5), where PG denotes a hydrogen atom.

Intermediates of general formula (5) are reacted with a base and/or an oxidizing agent, in one embodiment with an oxidizing agent such as, for example, hydrogen peroxide or SIBX (stabilized iodoxybenzoic acid), in a suitable solvent system, such as, for example, methanol, at temperatures ranging from -30°C to boiling temperature

- 19 046642 reaction of the corresponding solvent, and in one embodiment, the reaction is carried out at the boiling point of the corresponding solvent, to obtain compounds of general formula (I). Optionally, such reactions can be carried out with an additive such as, for example, an acid or a base, such as, but not limited to, acetic acid or trifluoroacetic acid, and (but not limited to) triethylamine or diisopropylethylamine.

Intermediates of general formula (5) can be converted into compounds of general formula (I) by thermally heating them in a suitable solvent at elevated temperatures, which may be above the boiling point of said solvent, such as in the range from RT to +250°C. These reactions may not necessarily be carried out in a vessel whereby the pressure may be increased, such as in an autoclave. Intermediates of general formula (5) can also be converted to compounds of general formula (I) by thermal heating in the presence of a metal catalyst such as, for example, palladium on activated carbon, in a suitable solvent such as, for example, DMF, DMA, EtOH, MeOH, NMP (but not limited to), at elevated temperatures, such as from RT to +150°C. Optionally, such reactions can be carried out with an additive such as, for example, an acid or a base, such as, but not limited to, acetic acid or trifluoroacetic acid, and (but not limited to) triethylamine or diisopropylethylamine, to produce compounds of general formula (I ).

Scheme 2

LG

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

Compounds of general formula (6) can be converted to compounds of general formula (7) by treatment with a suitable nucleophile, such as, for example, amines, alcohols, metal alkoxides, azides, thiols or metal thiolates, under basic, neutral, acidic, catalytic conditions, under in one embodiment, in a basic environment, in a suitable solvent, or using a nucleophile as a solvent, such as, for example, DMF, tetrahydrofuran (THF), at temperatures ranging from -78°C to the boiling point of the appropriate solvent, in one embodiment implementation of the reaction is carried out in the range from -10°C to the boiling point of the appropriate solvent, obtaining a product of general formula (7). Such displacement reactions have been reported previously (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; J. Med. Chem., 2014, 57, 6572 - 6582; 31, 389 - 395; Leroy et al., Synth. Commun., 1997, 27, 2905 2916; LaMattina et al., J. Org. Chem., 1981, 46, 4179 - 4182; 1983, 39, 4153 4162).

Compounds of general formula (7) can be converted to compounds of general formula (4) using a variety of reduction methods known to those skilled in the art, using a variety of different reagents and reaction conditions; such reduction methods involve the use of reagents such as metal hydrides, such as, for example, 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 the use of catalytic hydrogenation conditions, for example, hydrogen and palladium on carbon in an acidic environment (Stokker et al., J. Med. Chem., 1981, 24, 115 - 117; Bertini et al., J. Med. Chem. ., 2005, 48, 664 - 670), hydrogen and nickel in a basic environment (Walpole et al., J. Med. Chem., 1993, 36, 2362 2372, Kuramochi et al., Bioorg. Med. Chem., 2005 , 13, 4022 - 4036.)

- 20 046642

Scheme 3

Scheme 3. Method for preparing compounds of general formula 2, where R ^1a represents methyl or difluoromethyl, corresponding to R ¹ in general formula (I) with the meaning of methoxy and difluoromethoxy. The synthesis of compounds 9 and 10 involves alkoxy substitution on the phenyl ring. However, product 2 containing an isothiocyanate group and its synthesis (i.e. 10^2 or 11^2) are common to R ¹ groups according to general formula (I).

Compounds of general formula (8) can be converted into compounds of general formula (9) using various methods known to those skilled in the art. Such transformations may be, for example, the alkylation of phenol alcohol with alkylating reagents, such as, for example, alkyl halides, alkyl sulfonates, where these alkyl groups may optionally contain fluorine atoms, alkoxy groups. Such alkylation reactions are known to those skilled in the art and involve the use of a number of methods: i) K ₂ CO ₃ in a solvent such as DMF, acetone, DMF (see Muro et al., J. Med. Chem., 2009, 52 , 7974 and WO2009/20990 A1); ii) KOH in EtOH (see Macias et al., J. Agric. Food Chem., 2006, 54, 9843); iii) Mitsunobu reaction (see procedure US2006/122168 A1 and EP2151431 A1), yielding intermediates of general formula (9).

Compounds of general formula (9) can be converted to compounds of general formula (10) using reduction methods known to those skilled in the art. Such reduction reactions can be carried out using: i) hydrogen gas and a catalyst (for Pd/C as a catalyst, see the method of Chan et al., J. Am. Chem. Soc., 2011, 133, 2989; for platinum, see the method Niemann et al., J. Am. Chem Soc., 1941, 63, 2204; for Raney nickel see method US2009/253767 A1); ii) iron and ammonium chloride (see Sweeney et al., Bioorg. Med. Chem. Lett., 2008, 18, 4348); iii) sodium dithionite (see Chong et al., J. Med. Chem., 2012, 55, 10601); iv) zinc and ammonium chloride (see procedure WO2010/42699 A1), to obtain intermediate compounds of general formula (10).

Compounds of general formula (10) can be converted into compounds of general formula (2) using reagents such as, for example, thiophosgene, carbon disulfide, 1,1-thiocarbonyldi-2(III)-pyridone or 1,1'-thiocarbonyldiimidazole, in in one embodiment, thiophosgene, in a basic medium, in a suitable solvent, such as, for example, dichloromethane, chloroform, acetone, or two-phase mixtures, such as, for example, dichloromethane, chloroform with an aqueous basic solution, in another embodiment, dichloromethane with aqueous a saturated solution of sodium hydrogencarbonate or sodium carbonate, at temperatures ranging from -78°C to the boiling point of the appropriate solvent, in another embodiment the reaction is carried out at temperatures ranging from 0°C to room temperature, to obtain compounds of general formula (2) . Such reactions have been reported previously (Harris et al., J. Med. Chem., 2005, 48, 1610; Degorce et al., Tetrahedron Lett., 2011, 52, 6719; WO2016/91845 A1; Fairhurst et al., Org Lett., 2005, 7, 4697; Chaskar et al., Synth. Comraun, 2008, 38, 16940;

- 21 046642

Scheme 4

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

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

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 reactions can be carried out using a bromination reagent, such as, for example, N-bromosuccinimide, in a suitable solvent, such as, for example, DMF, at temperatures ranging from -78°C to the boiling point of said solvent, in one embodiment the temperature is maintained in the range from 0°C to RT.

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

are the values given for general formula (I), and PG is hydrogen or a suitable protecting group, for example tert-butoxycarbonyl (Boc).

Compounds similar to those of general formula (14) can be prepared according to the procedure described in Scheme 1 using 4-(aminomethyl)-3-hydroxypyridine in place of intermediate (4). Intermediates of general formula (14) can be converted to compounds of general formula (I) by reaction with a suitable alcohol under Mitsunobu reaction conditions (Oyo Mitsunobu method, Synthesis, 1981, 1-28 or Tsunoda et al., Tetrahedron Lett., 1994, 35 , 5081), such as, for example, oxetan-3-ylmethanol, in the presence of (tributylphosphoranilidene)acetonitrile or triphenylphosphine

- 22 046642 together with diisopropyl azodicarboxylate in a suitable solvent system, such as, for example, dioxane or THF, at temperatures ranging from room temperature to the boiling point of the respective solvents.

One skilled in the art will recognize that if a number of reaction sites are present on a parent or intermediate compound, it may be necessary to temporarily block one or more reaction sites with protecting groups in order to allow the reaction to occur specifically at the desired reaction site.

The compounds according to the invention are isolated and purified in a manner known per se, for example by distilling the solvent in vacuo and recrystallizing the resulting residue from a suitable solvent or introducing it into one of the usual purification methods, such as chromatography on a suitable support material. In addition, reverse phase preparative HPLC can be used. Compounds of the present invention that are sufficiently basic or acidic in function may result in the formation of a salt, such as, in the case of a compound of the present invention, which is sufficiently basic, such as trifluoroacetate or formate, or, in the case of a compound of the present invention, which is sufficiently acidic , for example, ammonium salt. Salts of this type can be converted into either the free base form or the free acid form, respectively, by various methods known to one skilled in the art, or the compounds can be used as salts in subsequent biological assays. In addition, the drying process during isolation of the compounds of the present invention may not completely remove traces of co-solvents, particularly such as formic acid or trifluoroacetic acid, to produce solvates or inclusion complexes. One skilled in the art will determine which solvates or inclusion complexes are acceptable for use in subsequent biological assays. It should be understood that the particular form (e.g., salt, free base, free acid, solvate, inclusion complex) of the compound of the present invention as isolated and described herein is not necessarily the only form in which the compound can be used in a biological assay with for the purpose of quantitative determination of specific biological activity.

Salts of the compounds of formula (I) according to the invention can be prepared by dissolving the free compound in a suitable solvent (for example, a ketone such as acetone, methyl ethyl ketone or methyl isobutyl ketone, an ether such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol such as methanol, ethanol or isopropanol) which contains the desired acid or base, or to which the desired acid or base is added later. The acid or base in preparing the salt can be used, depending on whether the mono- or poly-acidic acid or -acid base is of interest, and depending on which salt is required, either in an equimolar ratio or in a different ratio. Salts are obtained by filtration, reprecipitation, precipitation with a salt precipitant, or by evaporation of the solvent. The resulting salts can be converted into free compounds, which in turn can be converted into salts. Thus, pharmaceutically unacceptable salts that may be obtained, for example, as a product of a production process carried out on an industrial scale, can be converted into pharmaceutically acceptable salts using methods known to one skilled in the art. Particularly preferred are the hydrochlorides and the method used in the Examples section.

Pure diastereoisomers and pure enantiomers of the compounds and salts according to the invention can be obtained, for example, by asymmetric synthesis, by using chiral starting compounds in the synthesis, and by separating enantiomeric and diastereoisomeric mixtures obtained in the synthesis.

Enantiomeric and diastereoisomeric mixtures can be separated into pure enantiomers and pure diastereoisomers using methods known to one skilled in the art. In one embodiment, diastereomeric mixtures are separated using crystallization, in particular fractional crystallization, or chromatography. Enantiomeric mixtures can be separated, for example, by forming diastereoisomers with a chiral auxiliary agent, separating the resulting diastereoisomers, and removing the chiral auxiliary agent. As chiral auxiliaries, for example, chiral acids such as, for example, mandelic acid can be used to resolve enantiomeric bases, and chiral bases can be used to resolve enantiomeric acids by forming diastereomeric salts. In addition, diastereomeric derivatives, such as diastereomeric esters, can be formed from enantiomeric mixtures of alcohols or enantiomeric mixtures of acids, respectively, using chiral acids or chiral alcohols as chiral auxiliaries, respectively. In addition, diastereomeric complexes or diastereomeric clathrates can be used to separate enantiomeric mixtures. Alternatively, enantiomeric mixtures can be separated by chromatography using chiral separation columns. Another approach

- 23 046642 The current method for isolating enantiomers is enzymatic separation.

One preferred aspect of the invention is the method for preparing the compounds of claims 1-4 in accordance with the examples, as well as the intermediate compounds used for their preparation.

Optionally, the compounds of formula (I) can be converted into their salts, or, optionally, salts of the compounds of formula (I) can be converted into the free compounds. Appropriate methods are common to one skilled in the art.

Commercial value.

As mentioned above, it has surprisingly been found that the compounds of the present invention effectively inhibit mutant EGFR in a cell (eg, a tumor cell) that comes into contact with the compound, thereby inducing cell death (eg, apoptosis), and therefore can be used for the treatment or prevention of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, or diseases that are accompanied by uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, in particular where uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses are mediated by an EGFR mutant, such as, for example, benign and malignant neoplasia, more particularly hematological tumors, solid tumors, and/or their metastases, for example, leukemia and myelodysplastic syndrome, malignant lymphomas, head and neck tumors, including brain tumors and brain metastases, chest tumors, including non-small cell and small cell lung tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors, including renal tumors, bladder and prostate tumors, skin tumors and sarcomas, and/or metastases thereof, in particular hematological tumors, solid tumors, and/or metastases thereof , such as tumors of the breast, bladder, bone, brain, central and peripheral nervous system, cervix, colon, endocrine glands (eg, thyroid and adrenal cortex), endocrine tumors, endometrial tumors, esophageal tumors, gastrointestinal tumors , tumors of germ cells, kidney, liver, lung, larynx and hypopharynx, mesothelioma, tumors of the ovary, pancreas, prostate, rectum, renal tumors, tumors of the small intestine, soft tissue, stomach, skin, male gonads, ureter, vagina and vulva, as well as malignant neoplasia, including primary tumors in these organs and corresponding secondary tumors in distant organs (tumor metastases). Examples of hematological tumors include, for example, 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. Also included are myelodysplastic syndromes, plasma cell neoplasia, paraneoplastic syndromes, and types of cancer of unknown primary site, as well as AIDS-associated malignancies.

A further aspect of the invention is the use of compounds according to formula (I) for the treatment of lung cancer, in particular lung cancer anchoring an EGFR insertion mutation in exon 20, more particularly lung cancer anchoring V769_770ins ASV and/or D770_N771ins SVD insertions in exon 20, and/or metastases thereof, comprising administering an effective amount of a compound of formula (I).

A further aspect of the invention is the use of compounds according to formula (I) for the treatment of lung cancer, in particular lung cancer anchoring an EGFR-anchoring mutant with in-frame deletions in exon 19 (such as EGFR E746_A750del) or point mutations in exon 21 (for example, L858R), and/or its metastases.

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

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

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

Thus, another specific aspect of the present invention is the use of a compound of general formula I described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate thereof.

- 24 046642 that or a salt, especially a pharmaceutically acceptable salt thereof, or a mixture thereof, for the prevention or treatment of a hyperproliferative disorder or a disorder responsive to the induction of cell death, i.e. apoptosis.

By hyperproliferative disease is meant a disease, such as a malignancy, associated with inappropriately high levels of cell division, inappropriately low levels of apoptosis, or both. The term inappropriate in the context of the present invention, in particular in the context of the expressions inappropriate cellular immune responses, or inappropriate cellular inflammatory responses as used herein, should be generally understood to mean a response that is less than or greater than normal, and which is associated with, is responsible for, or leads to the pathology of these diseases.

In certain embodiments, the use is for the treatment or prevention of diseases, in particular, treatment where the diseases are hematological tumors, solid tumors and/or metastases thereof.

Another aspect is the use of a compound of formula (I) for the prevention and/or treatment of lung cancer, in particular lung cancer anchoring an EGFR insertion mutation in exon 20, more particularly lung cancer anchoring V769_770ins ASV and/or D770_N771ins SVD insertions in exon 20, and/or its metastases, is especially preferred for its treatment.

Another aspect of the present invention is the use of a compound of formula (I) or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, in particular a pharmaceutically acceptable salt thereof, or a mixture thereof, as described herein, for the manufacture of a medicament for treating or preventing a disease, where the disease is a hyperproliferative disorder or a disorder that responds to the induction of cell death, such as apoptosis. In one embodiment, the disease is a hematologic tumor, a solid tumor, and/or metastases thereof. In another embodiment, the disease is a lung cancer, particularly a lung cancer anchoring an EGFR anchoring mutant with insertion mutations in exon 20, more specifically a lung cancer anchoring V769_770ins ASV and/or D770_N771ins SVD insertions in exon 20, and/or metastases thereof.

Method for treating hyperproliferative disorders.

The present invention relates to a method of using the compounds of the present invention and their compositions for the treatment of hyperproliferative disorders in mammals. The compounds can be used to inhibit, block, reduce, reduce, etc. cell proliferation and/or cell division, and/or production of cell death, such as apoptosis. This method involves administering to a mammal in need thereof, including a human, an amount of a compound of the present invention or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof; etc., which is effective for treating the disorder. Hyperproliferative disorders include, but are not limited to, psoriasis, keloids and other hyperplasias affecting the skin, benign prostatic hyperplasia (BPH), solid tumors such as cancer of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eyes, liver, skin, head and neck, thyroid gland, parathyroid gland and their distant metastases. Such disorders also include lymphomas, sarcomas, and leukemias.

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.

Examples of types of respiratory tract cancer include, but are not limited to, small cell and non-small cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.

Examples of types of brain cancer include, but are not limited to, brainstem and hypophthalmic glioma, cerebellar and brain astrocytoma, medulloblastoma, ependymoma, and neuroectodermal and pineal tumors.

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

Tumors of the digestive tract 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.

Urinary tract tumors include, but are not limited to, bladder, penile, kidney, renal pelvis, ureter, urethra, and human papillary renal cancer.

Ocular cancer types include, but are not limited to, intraocular melanoma and retinoblastoma.

- 25 046642

Examples of types of liver cancer include, but are not limited to, hepatocellular carcinoma (liver cell carcinoma with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.

Types of skin cancer include, but are not limited to, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, sinonasal inverted papilloma, sinonasal squamous cell carcinoma associated with sinonasal inverted papilloma, Merkel cell skin cancer, and nonmelanoma skin cancer.

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

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

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

These disorders have been well characterized in humans, but also exist with similar etiologies in other mammals, and can be treated by administration of the pharmaceutical compositions of the present invention.

The term treat or treat as used throughout this document is used conventionally, for example, to mean the management or care of a patient for the purpose of controlling, alleviating, reducing, relieving, ameliorating, etc., a disease or disorder such as carcinoma.

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

The present invention relates to a method of treating cancer in a subject where the cancer is resistant or has become resistant to anti-EGF receptor antibody therapy, which comprises administering to the subject an effective amount of a compound of general formula (I) as defined herein.

The present invention relates to a method of increasing the effectiveness of anti-EGF receptor antibody therapy, which comprises administering anti-EGF receptor antibody therapy to a subject in combination with a compound of general formula (I) as defined herein.

In a further embodiment, the present invention provides a method of treating a cancer in a subject, wherein the cancer is selected from the group consisting of leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumors, chest tumors, gastrointestinal tumors, endocrine tumors, breast tumors and other gynecological tumors, urological tumors, skin tumors and sarcomas, which comprises administering to a subject an effective amount of a compound of general formula (I) as defined herein.

In a further embodiment, the present invention provides a method of treating a cancer in a subject, wherein the cancer is selected from the group consisting of sinonasal inverted papilloma or sinonasal squamous cell carcinoma associated with sinonasal inverted papilloma, which comprises administering to the subject an effective amount of a compound of general formula (I) , as defined herein.

In a further embodiment, the present invention provides a method of treating cancer in a subject wherein the chest tumor is non-small cell lung cancer, which comprises administering to the subject an effective amount of a compound of general formula (I) as defined herein.

In a further embodiment, the present invention provides a method of treating a cancer in a subject, wherein the cancer is a lung cancer, in particular a lung cancer with an EGFR anchoring mutant with in-frame deletions in exon 19 (such as EGFR E746_A750del) or point mutations in exon 21 (eg, L858R), and/or metastases thereof, which comprises administering to the subject an effective amount of a compound of general formula (I) as defined herein.

In a further embodiment, the present invention provides a method for treating a cancer in a subject, wherein the cancer is a lung cancer, in particular an EGFR anchoring mutant lung cancer with an acquired resistance mutation D770_N771insSVD C797S, E746_A750del C797S or L858R C797S, and/or metastases thereof , which

- 26 046642 involves administering to a subject an effective amount of a compound of general formula (I) as defined herein.

In a further embodiment, the present invention provides a method for treating a cancer in a subject, wherein the cancer is a lung cancer, in particular a lung cancer with an ERBB2 anchoring mutant with insertion mutations in exon 20 (such as ERBB2 A775_G776insYVMA) and/or metastases thereof, which comprises administering to a subject an effective amount of a compound of general formula (I) as defined herein.

The present disclosure also relates to a method of selecting a patient for treatment of a cancer with a compound of general formula (I), comprising detecting a mutation in exon 20 of a gene encoding an EGF receptor in a biological sample of the subject, thereby determining that the patient should be treated with the compound. In some embodiments, EGFR includes aD770_N771insSVD C797S, E746_A750del C797S, or L858R C797S acquired resistance mutation. In some embodiments, a method of selecting a patient for treatment of a cancer with a compound of general formula (I) may include detecting the presence of in-frame deletions in exon 19 or point mutations in exon 21 of a gene encoding an EGF receptor in a biological sample of the subject, thereby determining that the patient should be treated with the indicated compound. For example, an in-frame deletion in exon 19 may be EGFR E746_A750del, or a point mutation in exon 21 may be L858R. In some embodiments, a method of selecting a patient for treatment of a cancer with a compound of general formula (I) may include detecting a mutation in exon 20 of the gene encoding ERBB2 in a biological sample of the subject, thereby determining that the patient should be treated with the compound. In some embodiments, ERBB2 includes an ERBB2 A775 or_G776insYVMA insertion mutation. Moreover, methods of treating a patient with a cancer may involve administering to the subject a compound of general formula (I) (eg, in combination with anti-EGF receptor antibody therapy), wherein the subject for therapy is selected by detecting a mutation in EGFR in a biological sample of the subject. Detection of a mutation in exon 20 is within the skill of the person skilled in the art.

In some embodiments, detection of a mutation (e.g., in EGFR, or a mutation in exon 20 of the gene encoding EGFR) can be performed using sequencing (e.g., Sanger sequencing, next-generation sequencing) or a method selected from the group consisting of immunoblotting, mass spectrometry, immunoprecipitation and quantitative PCR, Northern blot, microarray analysis, enzyme-linked immunosorbent assay (ELISA), in situ hybridization and combinations thereof.

Methods for treating kinase disorders.

The present invention also provides methods for treating disorders associated with aberrant mitogenic extracellular kinase activity, including, but not limited to, stroke, heart failure, hepatomegaly, cardiomegaly, diabetes, Alzheimer's disease, fibrocystic degeneration, xenograft rejection symptoms, septic shock, or asthma. .

Effective amounts of the compounds of the present invention can be used to treat such disorders, including diseases (eg, cancer) that are mentioned in the Background section above. However, such cancers and other diseases can be treated with the compounds of the present invention, regardless of the mechanism of action and/or the relationship between the kinase and the disorder.

The phrase aberrant kinase activity or aberrant tyrosine kinase activity includes any abnormal expression or activity of a gene encoding a kinase or the polypeptide it encodes. Examples of such aberrant activity include, but are not limited to, overexpression of a gene or polypeptide; gene amplification; mutations that produce constitutively active or hyperactive kinase activity; gene mutations, deletions, substitutions, additions, etc.

The present invention also provides methods for inhibiting kinase activity, especially mitogenic extracellular kinase, comprising administering an effective amount of a compound of the present invention, including salts, polymorphs, metabolites, hydrates, solvates, prodrugs (eg, esters), and diastereoisomeric forms thereof. Kinase activity may be inhibited in cells (eg, in vitro), or in cells of a mammalian subject, especially a human patient, who is in need of treatment.

Methods for treating angiogenic disorders.

The present invention also provides methods for treating disorders and diseases associated with excessive and/or pathological angiogenesis.

Inappropriate and biased expression of angiogenesis can be harmful to the body. Many pathological conditions are associated with the growth of extraneous blood vessels. These include, for example, diabetic retinopathy, ischemic retinal vein occlusion and juvenile retinopathy [Aiello et al. New Engl. J. Med. 1994, 331, 1480; Peer et al. Lab. Invest. 1995, 72, 638], age ma

- 27 046642 cular degeneration [AMD; see Lopez et al. Invest. Optthalmol. Vis. Sci. 1996, 37, 855], neovascular glaucoma, psoriasis, retrolental fibroplasia, angiofibroma, inflammation, rheumatoid arthritis (RA), restenosis, in-stent restenosis, vascular graft restenosis, etc. In addition, the increased blood supply associated with malignant and neoplastic tissue promotes growth, leading to rapid tumor spread and metastasis. In addition, the growth of new blood and lymphatic vessels in the tumor provides an escape route for rogue cells, promoting metastasis and subsequent spread of the cancer. Thus, the compounds of the present invention can be used for the treatment and/or prevention of any of the above-mentioned angiogenesis disorders, for example, by inhibiting and/or reducing the formation of blood vessels; by inhibiting, blocking, reducing, reducing, etc. proliferation of endothelial cells or other cell types involved in angiogenesis, as well as causing cell death, such as apoptosis of such cell types.

In various embodiments, the diseases of this method are hematological tumors, solid tumors and/or metastases thereof.

The compounds of the present invention can be used in particular for therapy and prevention, i.e. prophylaxis, in particular for the therapy of tumor growth and metastases, in particular in the case of solid tumors of all indications and stages with or without prior treatment(s) tumor growth.

Pharmaceutical compositions of compounds according to the invention.

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

Thus, the present invention includes pharmaceutical compositions that consist of a pharmaceutically acceptable carrier or excipient and a pharmaceutically effective amount of a compound of the present invention or a salt thereof.

Another aspect of the invention is a pharmaceutical composition containing a pharmaceutically effective amount of a compound of formula (I) and a pharmaceutically acceptable adjuvant for the treatment of the above-mentioned disease, in particular for the treatment of hematological tumors, solid tumors and/or metastases thereof.

The pharmaceutically acceptable carrier or excipient may be a carrier that is non-toxic and harmless to the patient at concentrations consistent with the effective activity of the active ingredient so that any side effects attributable to the carrier do not interfere with the beneficial effects of the active ingredient. Carriers and auxiliaries are all kinds of additives that help the composition to be suitable for administration.

A pharmaceutically effective amount of a compound may be that amount that produces a result or a desired effect on the particular condition being treated.

The compounds of the present invention can be administered with pharmaceutically acceptable carriers or excipients well known in the art, using any effective conventional dosage unit forms, including immediate, sustained and time-controlled release formulations, orally, parenterally, topically, nasally, ophthalmically, optically , sublingual, rectal, vaginal, etc.

For oral administration, the compounds may be formulated into solid or liquid preparations such as capsules, pills, tablets, lozenges, lozenges, melts, powders, solutions, suspensions or emulsions, which may be prepared according to methods known in the art. areas for the production of pharmaceutical compositions. Solid unit dosage forms may be a capsule, which may be a standard gelatin type with a hard or soft shell, containing excipients, for example, surfactants, lubricants, and excipients such as lactose, sucrose, calcium phosphate and corn starch.

In another embodiment, the compounds of this invention may be tabletted with conventional tablet bases such as lactose, sucrose and corn starch, in combination with binders such as gum arabic, corn starch or gelatin, disintegrants designed to promote disintegration and dissolution of the tablet after administration, such as potato starch, alginic acid, corn starch and guar gum, gum tragacanth, gum acacia, lubricants intended to improve fluidity when granulating tablets and to prevent adhesion of the tablet substance to the surfaces of the tablet press and punches, such as, for example talc, stearic acid or magnesium, calcium or zinc stearate, dyes, coloring agents and flavoring agents

- 28 046642 agents, such as peppermint oil, wintergreen oil or cherry flavoring, intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient. Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols, for example ethanol, benzyl alcohol and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent. . Various other substances may be present as coatings or to otherwise modify the physical form of the dosage unit. For example, tablets, pills, or capsules may be coated with shellac, sugar, or both.

Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are illustrated by those already mentioned above. Additional excipients may also be present, such as the sweetening, flavoring and coloring agents described above.

The pharmaceutical compositions of this invention may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils. Suitable emulsifying agents may be (1) natural gums such as gum arabic and gum tragacanth, (2) natural phosphatides such as soybean phosphatides and lecithin, (3) esters or partial esters derived from fatty acids and hexitol anhydrides. , for example, sorbitan monooleate, (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. Emulsions may also contain sweetening and flavoring agents.

Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil, such as, for example, peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil, such as liquid paraffin. Oily suspensions may contain a thickening agent such as, for example, beeswax, paraffin wax or cetyl alcohol. Suspensions may also contain one or more preservatives, for example, ethyl or n-propyl phydroxybenzoate; one or more coloring agents; one or more flavoring agents; and one or more sweeteners such as sucrose or saccharin.

Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerin, propylene glycol, sorbitol or sucrose. Such formulations may also contain an anti-irritant and a preservative such as methyl and propyl parabens and flavoring and coloring agents.

The compounds of this invention can also be administered parenterally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly or intraperitoneally, as injectable dosages of the compound in, for example, a physiologically acceptable diluent with a pharmaceutical carrier, which may be a sterile liquid or mixture of liquids such such as water, saline, aqueous solutions of dextrose and related sugars, alcohol such as ethanol, isopropanol or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerin ketals such as 2,2-dimethyl-1,1-dioxolane-4- methanol, ethers such as poly(ethylene glycol) 400, oil, fatty acid, fatty acid ester or fatty acid glyceride, or acetylated fatty acid glyceride, with the addition of a pharmaceutically acceptable surfactant such as soap or detergent, suspending agent , such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose or carboxymethylcellulose, or emulsifying agents and other pharmaceutical adjuvants, or without them.

Examples of oils that can be used in the parenteral compositions of the present invention are those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petroleum jelly 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 myristate. Suitable soaps include fatty acid alkali metal salts, ammonium and triethanolamine, and suitable detergents include cationic detergents, for example, dimethyldialkylammonium halides, alkylpyridinium halides and alkylamine acetates; anionic detergents, for example alkyl, aryl and olefin sulfonates, alkyl, olefin, ether and monoglyceride sulfates and sulfosuccinates; nonionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene-oxypropylene)s or copolymers of ethylene oxide or propylene oxide; and amphoteric detergents, for example, alkyl beta-aminopropionates and quaternary ammonium salts of 2-alkylimidazoline, and mixtures.

Parenteral compositions of this invention will typically contain from about 0.5% to about 25% by weight of active ingredient in solution. Preservatives and buffers may also be advantageously used. To minimize or eliminate irritation in the area

- 29 046642 sections, such compositions may contain a nonionic surfactant having, in one embodiment, a hydrophilic-lipophilic balance (HLB) of from about 12 to about 17. The amount of surfactant in such a composition in one embodiment ranges from about 5% to about 15 wt.%. The surfactant may be a single component having the aforementioned HLB, or may be a mixture of two or more components having the desired HLB.

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

The pharmaceutical compositions may be in the form of sterile injectable aqueous suspensions. Such suspensions can be formulated according to known methods using suitable dispersing or wetting agents and suspending agents, such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic; dispersing or wetting agents, which may be a natural phosphatide, such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadecaethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived from a fatty acid acid and hexitol, such as polyoxyethylene sorbitan monooleate, or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and hexitol anhydride, such as polyoxyethylene sorbitan monooleate.

The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Diluents and solvents that can be used are, for example, water, Ringer's solution, isotonic sodium chloride solutions and isotonic glucose solutions. In addition, sterile fixed oils are traditionally used as solvents or suspending media. Any soft, non-volatile oil, including synthetic mono- or diglycerides, can be used for this purpose. In addition, fatty acids such as oleic acid can be used in the preparation of injectable forms.

The composition in accordance with the present invention can also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at normal temperatures but becomes liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such substances are, for example, cocoa butter and polyethylene glycol.

Controlled-release formulations for parenteral administration include liposomal formulations, polymer microsphere formulations, and polymeric gel formulations, which are known in the art.

It may be desirable or necessary to administer the pharmaceutical composition to a patient via a mechanical delivery device. The design and use of mechanical delivery devices for delivering pharmaceuticals are well known in the art. Direct methods for administration, such as administering a drug directly to the brain, typically involve placing a catheter to deliver the drug into the patient's ventricular system to bypass the blood-brain barrier. One such implantable delivery system used to transport agents to specific anatomical sites in the body is described in U.S. Patent No. 5,011,472, published April 30, 1991.

The compositions of the present invention may also contain other conventional pharmaceutically acceptable components, generally referred to as carriers or diluents, as needed or desired. Conventional techniques for preparing such compositions in suitable dosage forms can be used.

Such components and techniques include those described in the following references, each of which is incorporated herein by reference: Powell, M.F. et al., Compendium of Excipients for Parenteral Formulations PDA Journal of Pharmaceutical Science & Technology 1998, 52(5), 238-311; Strickley, R.G Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States (1999) - part 1 PDA Journal of Pharmaceutical Science & Technology 1999, 53(6), 324-349; and Nema, S. et al., Excipients and Their Use in Injectable Products PDA Journal of Pharmaceutical Science & Technology 1997, 51(4), 166171.

Commonly used pharmaceutical components which may be used to formulate the composition for its intended route of administration include:

acidifying agents (examples include, but are not limited to, acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid);

- 30 046642 alkalizing agents (examples include, but are not limited to, ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine);

adsorbents (examples include, but are not limited to, powdered cellulose and activated charcoal);

aerosol propellants (examples include, but are not limited to, carbon dioxide, CC^, F2ClC-CClF2 and CCIF3);

air displacement agents (examples include, but are not limited to, nitrogen and argon);

antifungal preservatives (examples include, but are not limited to, benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate);

antibacterial preservatives (examples include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal);

antioxidants (examples include, but are not limited to, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphoric acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite);

binders (examples include, but are not limited to, block polymers, natural and synthetic rubbers, polyacrylates, polyurethanes, silicones, polysiloxanes and butadiene styrene copolymers);

buffering agents (examples include, but are not limited to, metapotassium phosphate, dipotassium phosphate, sodium acetate, anhydrous sodium citrate and sodium citrate dihydrate);

carriers (examples include, but are not limited to, gum arabic syrup, aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride for injections and bacteriostatic water for injections);

chelating agents (examples include, but are not limited to, disodium edetate and edetic acid);

dyes (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 );

brightening agents (examples include, but are not limited to, bentonite);

emulsifying agents (examples include, but are not limited to, gum acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate);

encapsulating agents (examples include, but are not limited to, gelatin and cellulose acetate phthalate);

flavorings (examples include, but are not limited to, anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin);

humectants (examples include, but are not limited to, glycerin, propylene glycol and sorbitol);

elutrients (examples include, but are not limited to, mineral oil and glycerin);

oils (examples include, but are not limited to, peanut oil, mineral oil, olive oil, peanut butter, sesame oil and vegetable oil);

ointment bases (examples include, but are not limited to, lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment, and rosewater ointment);

permeation enhancers (transdermal delivery) (examples include, but are not limited to, monohydroxy or polyhydroxy alcohols, mono- or polyvalent alcohols, saturated or unsaturated fatty alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives, cephalin, terpenes, amides, ethers, ketones and ureas);

plasticizers (examples include, but are not limited to, diethyl phthalate and glycerin);

solvents (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 water for irrigation);

hardening agents (examples include, but are not limited to, cetyl alcohol, cetyl esters, wax, microcrystalline wax, paraffin, stearyl

- 31 046642 alcohol, white wax and yellow wax);

suppository bases (examples include, but are not limited to, cocoa butter and polyethylene glycols (mixtures));

surfactants (examples include, but are not limited to, benzalkonium chloride, nonoxynol 10, oxoxynol 9, polysorbate 80, sodium lauryl sulfate and sorbitan monopalmitate);

suspending agents (examples include, but are not limited to, agar, bentonite, carbomers, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, kaolin, methylcellulose, tragacanth and vigum);

sweeteners (examples include, but are not limited to, aspartame, dextrose, glycerin, mannitol, propylene glycol, sodium saccharin, sorbitol and sucrose);

tablet release agents (examples include, but are not limited to, magnesium stearate and talc);

tablet binders (examples include, but are not limited to, gum acacia, alginic acid, sodium carboxymethylcellulose, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinylpyrrolidone and pregelatinized starch);

tablet and capsule diluents (examples include, but are not limited to, dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol and starch);

tablet coating agents (examples include, but are not limited to, liquid glucose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, cellulose acetate phthalate, and shellac);

direct compression tablet fillers (examples include, but are not limited to, dibasic calcium phosphate);

tablet disintegrants (examples include, but are not limited to, alginic acid, calcium carboxymethylcellulose, microcrystalline cellulose, polacrillin potassium, cross-linked polyvinylpyrrolidone, sodium alginate, sodium starch glycolate and starch);

tablet glidants (examples include, but are not limited to, colloidal silica gel, corn starch and talc);

tablet lubricants (examples include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc stearate);

opaque agents for tablets/capsules (examples include, but are not limited to, titanium dioxide);

tablet polishes (examples include, but are not limited to, carnauba wax and white wax);

thickeners (examples include, but are not limited to, wax, cetyl alcohol and paraffin);

tonicity agents (examples include, but are not limited to, dextrose and sodium chloride);

viscosity-increasing agents (examples include, but are not limited to, alginic acid, bentonite, carbomers, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, sodium alginate and tragacanth); and wetting agents (examples include, but are not limited to, heptadecaethyleneoxycetanol, lecithins, sorbitol monooleate, polyoxyethylene sorbitol monooleate and polyoxyethylene stearate).

Pharmaceutical compositions in accordance with the present invention can be illustrated as follows:

Sterile IV Solution: A 5 mg/ml solution of the desired compound of this invention can be prepared using sterile water for injection and pH adjustments made if necessary. The solution is diluted to a concentration of 1-2 mg/ml with sterile 5% dextrose and administered as an IV infusion over approximately 60 minutes.

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

Intramuscular suspension: The following solution or suspension can be prepared for intramuscular injection:

- 32 046642 mg/ml of the desired, water-insoluble compound of the present invention;

mg/ml sodium carboxymethylcellulose;

mg/ml TWIN 80;

mg/ml sodium chloride;

mg/ml benzyl alcohol.

Hard shell capsules: Large quantities of capsules are prepared by filling standard double hard gelatin capsules with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.

Soft Gelatin Capsules: Mix the active ingredient in a digestible oil such as soybean oil, cottonseed oil, or olive oil and inject it with a positive displacement pump into softened gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to produce a water-miscible drug mixture.

Tablets: A large number of tablets are prepared in accordance with conventional methods so that the dosage unit is 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 may be applied to enhance palatability, improve elegance and stability, or delay absorption.

Immediate release tablets/capsules: These are solid oral dosage forms prepared through standard and novel methods. These units are taken orally without water to immediately dissolve and deliver the drug. The active ingredient is mixed in a liquid containing an ingredient such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze-drying and solid state extraction methods. Drug compounds can be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to form porous matrices designed for immediate release without the need for water.

Dose and administration.

Based on standard laboratory methods known to evaluate compounds useful for the treatment of hyperproliferative disorders and angiogenic disorders, using standard toxicity tests and standard pharmacological assays to determine treatment parameters for the conditions identified above in mammals, and by comparing these results with those of known drugs that are used to treat these conditions, the effective dosage of the compounds of the present invention for the treatment of each desired indication can be readily determined. The amount of active ingredient to be administered in the treatment of one of these conditions may vary widely according to factors considered such as the particular compound and dosage unit used, the route of administration, the period of treatment, the age and sex of the patient being treated, and the nature and extent of the condition being treated. treatment.

The total amount of active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and, in certain embodiments, from about 0.01 mg/kg to about 20 mg/kg body weight per day. day. Clinically useful dosing regimens will range from dosing once to three times daily to dosing once every four weeks. In addition, drug breaks, where the patient is not dosed with the drug for a certain period of time, may be beneficial for the overall balance between pharmacological action and tolerability. A dosage unit may contain from about 0.5 mg to about 1500 mg of active ingredient, and may be administered once or more times per day or less than once per day. The average daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and the use of infusion techniques, in other embodiments will range from 0.01 to 200 mg/kg total body weight. The average daily rectal dosage regimen in certain embodiments will range from 0.01 to 200 mg/kg total body weight. The average daily vaginal dosing regimen in other embodiments will range from 0.01 to 200 mg/kg total body weight. The average daily topical dosage regimen in the following embodiments will range from 0.1 to 200 mg, administered one to four times daily. The transdermal concentration in other embodiments will be that required to maintain a daily dose of 0.01 to 200 mg/kg. The average daily inhalation dosage regimen in other embodiments will range from 0.01 to 100 mg/kg total body weight.

Of course, the specific initial and ongoing dosage regimen for each patient will vary depending on the nature and severity of the condition as determined by the treating physician, the potency of the particular compound used, the age and general condition of the patient, time of administration, route of administration, rate of elimination of the drug from the body, combination

- 33 046642 tions of medicines, etc. The desired treatment method and the number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester thereof or composition thereof can be determined by those skilled in the art using routine treatment tests.

Methods of combination therapy.

The compounds of this invention can be administered as a single pharmaceutical agent or in combination with one or more other pharmaceutical agents, where the combination does not cause unacceptable side effects. Said combination pharmaceutical agents may be other agents having an antiproliferative effect, such as, for example, those intended for the treatment of hematological tumors, solid tumors and/or their metastases, and/or agents for the treatment of unwanted side effects. The present invention also relates to such combinations.

Other antihyperproliferative agents suitable for use with the composition of the invention include, but are not limited to, those compounds recognized for use in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (ninth edition), editor Molinoff et al., publ. . McGraw-Hill, pages 1225-1287, (1996), which are thus incorporated herein by reference, particularly the (chemotherapeutic) antineoplastic agents defined above. The combination, depending on the specific case, may be a non-fixed combination or a fixed dose combination.

Methods for testing a particular pharmacological or pharmaceutical property are well known to those skilled in the art.

The exemplary test experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given.

As will be appreciated by those skilled in the art, the invention is not limited to the specific embodiments described herein, but embraces all modifications thereof that fall within the spirit and scope of the invention as defined in the appended claims.

The following examples illustrate the invention in more detail, without limiting it. Further compounds according to the invention, the preparation of which is not described in detail, can be prepared in a similar manner.

The compounds which are mentioned in the examples and their salts represent preferred embodiments of the invention, as well as the claims covering all subcombinations of residues of the compound of formula (I) as disclosed by the specific examples.

The term in accordance with within the experimental section is used in the sense that the mentioned technique should be used in a similar way.

Experimental section

Chemical names were generated using ACD/Name software from ACD/Labs. In some cases, the common names of commercially available reagents were used instead of the names generated by ACD/Name.

In the next table. 1 lists the abbreviations used in this paragraph and in the Examples section because they are not explained in the main text. Other abbreviations have meanings substantially common to one skilled in the art.

- 34 046642

Table 1 Abbreviations

Reduction ACN AcOH bg d DAD DAST DBU DXM dd DIPEA DMA DMAP DMF DMSO EDC.HC1 ESI EtOAc EtOH 4 HC1 HPLC LC-MS m MeCN MeOH min MC MTBE MWD Meaning Acetonitrile Acetic acid Broad signal (NMR) Doublet (NMR) Diode array detector Diethylaminosulfur trifluoride 1,8-Diazabicyclo(5.4.0)undec-7-ene Dichloromethane Doublet of doublets (NMR) Diisopropylethylamine N,N-dimethyl acetamide 4-Dimethylaminopyridine N,N-dimethylformamide Dimethyl sulfoxide Hydrochloride salt of X-(3-dimethylaminopropyl)-X'ethylcarbodiimide Electrospray ionization Ethyl acetate Ethanol Watch) Hydrogen chloride, hydrochloric acid High performance liquid chromatography Liquid chromatography - mass spectrometry Multiplet (NMR) Acetonitrile Methanol Minute(s) Mass spectrometry Methyl-ot/?eot-butyl ether Multi-wave detector NMR Nuclear Magnetic Resonance Spectroscopy: chemical shifts (δ) are given in ppm. Chemical shifts were corrected by setting the DMSO signal to 2.50 ppm unless otherwise noted. q Quartet (NMR) KT Room temperature _Rt , Rt Hold Time s Singlet (NMR) sat. Saturated SFH Supercritical fluid chromatography t triplet (NMR) td doublet triplet (NMR) TEA Triethylamine TFU Trifluoroacetic acid THF Tetrahydrofuran δ Chemical shift

Other abbreviations have meanings substantially common to one skilled in the art.

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

The exemplary test experiments described in this application serve to illustrate the present invention and the invention is not limited to the examples given.

Experimental section - general part

All reagents for which synthesis is not described in the experimental section are either commercially available, are known compounds, or can be prepared by known methods from known compounds by one skilled in the art.

Compounds and intermediates prepared in accordance with the methods of the invention may require purification. The purification of organic compounds is well known to one skilled in the art, and there may be multiple purification routes for the same compound. In some cases, cleaning may not be necessary. In some cases, compounds can be purified by crystallization. In some cases, impurities can be removed by rubbing using a suitable solvent.

In some cases, compounds can be purified by chromatography, in particular flash column chromatography, using, for example, pre-filled silica gel cartridges, such as Biotage SNAP KP-Sil® or KP-NH® cartridges in combination with the Biotage Automatic Purification System (SP4 ® or Isolera Four®) and eluents such as hexane/ethyl acetate or DCM/methanol gradients. When performing flash column chromatography, you can use non-modify

- 35 046642 zirovanny (regular) silica gel, as well as amino-phase functionalized silica gel. If the experimental section refers to flash column chromatography or to flash chromatography without specifying a stationary phase, regular silica gel was used

In some cases, compounds can be purified by preparative HPLC using, for example, a Waters autopurifier equipped with a diode array detector and/or a real-time electrospray ionization mass spectrometer in combination with a suitable prefilled reversed-phase column, and eluents such as gradients of water and acetonitrile, which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.

In some cases, purification methods as described above can provide compounds of the present invention that have a sufficiently basic or acidic function, in the form of a salt, such as, in the case of a compound of the present invention, which is sufficiently basic, for example, trifluoroacetate or formate, or , in the case of a compound of the present invention which is sufficiently acidic, for example an ammonium salt. A salt of this type can be converted into either the free base form or the free acid form, respectively, by various methods known to one skilled in the art, or the compound can be used as salts in subsequent biological assays. It should be understood that the particular form (e.g., salt, free base, etc.) of a compound of the present invention isolated and described herein is not necessarily the only form in which the compound may be used in a biological assay to quantify a specific biological activity.

Analytical LC-MS methods.

Method 1.

Instrument: Waters Acquity UPLCMS SingleQuad; column: Acquity UPLC BEH C18 1.7 µm, 50x2.1 mm; eluent A: water + 0.1 vol.% formic acid (99%), eluent B: acetonitrile; gradient: 0-1.6 min. 199% B, 1.6-2.0 min. 99% B; flow 0.8 ml/min; temperature: 60°C; DMD scanning: 210-400 nm.

Method 2.

Instrument: Waters Acquity UPLCMS SingleQuad; column: Acquity UPLC BEH C18 1.7 µm, 50x2.1 mm; eluent A: water + 0.2 vol.% aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0-1.6 min. 1-99% B, 1.6-2.0 min. 99% B; flow 0.8 ml/min; temperature: 60°C; DMD scanning: 210-400 nm.

Method 3.

Device: Waters Acquity UPLC H-Class system; column: Acquity CSH C18 1.7 µm 2.1x50 mm; eluent A: water + 0.1 vol.% formic acid, eluent B: acetonitrile, eluent C: 2 vol.% ammonia (28%) in water, eluent D: 2 vol.% formic acid in water; gradient: 0-1.2 min 2-95% B with A and 5% D at all stages, 1.2-1.4 min. 95% B; flow 0.8 ml/min; temperature: 40°C; FDMD: 215-350 nm.

Method 4.

Device: Waters Acquity UPLC H-Class system; Column: XBridge BEH C18 2.5 µm 2.1x50 mm; eluent A: water + 0.1 vol.% formic acid, eluent B: acetonitrile, eluent C: 2 vol.% ammonia (28%) in water, eluent D: 2 vol.% formic acid in water; gradient: 0-1.2 min 2-95% B with A and 5% C at all stages, 1.2-1.4 min 95% B; flow 0.8 ml/min; temperature: 40°C; FDMD: 215-350 nm.

Method 5.

MS device: SHIMADZU LCMS-2020; HPLC instrument: LabSolution Version 5.72; Column: Kinetex@5 µm EVO C18 30x2.1 mm; eluent A: 0.0375% TFA in water (v/v), eluent B: 0.01875% TFA in acetonitrile: gradient: 0.0 min 0% B ^ 3.00 min 60% B ^ 3.50 min 60% B ^ 3.51 min 0% B ^ 4.00 min 0% B; flow rate: 0.8 ml/min; thermostat temperature: 50°C; UV detection: 220 nm & 254 nm.

Method 6.

Instrument: Agilent 1290 UPLCMS 6230 TOF; column: BEH C 18 1.7 µm, 50x2.1 mm; eluent A: water + 0.05% formic acid (99%); eluent B: acetonitrile + 0.05% formic acid (99%); gradient: 0-1.7 2-90% B, 1.7-2.0 90% B; flow: 1.2 ml/min; temperature: 60°C; DMD scanning: 190-400 nm.

Preparative LC-MS methods:

Method 7.

Device: Waters Autopurification MS SingleQuad; Column: Waters XBrigde C18 5 µm 100x30 mm; eluent A: water + 0.2 vol.% aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0-5.5 min. 5-100% B; flow 70 ml/min; temperature: 25°C; DMD scanning: 210-400 nm.

Method 8.

Device: Waters Autopurification MS SingleQuad; Column: Waters XBrigde C18 5 µm 50x50 mm; eluent A: water + 0.1 vol.% formic acid, eluent B: methanol; gradient: 0-0.50 min. 20% B; flow 50 100 ml/min, 0.50-8.00 min. 20 -60% B; flow 100 ml/min, temperature: 25°C; DMD scanning: 210-400 nm.

Method 9.

Device: Labomatic HD-5000, pump head HDK-280, gradient module NDB-1000, fraction separator Labomatic Labocol Vario 2000, Knauer UV detector Azura UVD 2.1S, software

- 36 046642

Prepcon 5. Column: Chromatorex C18 10 µm 120x30 mm; eluent A: water + 0.1% formic acid; eluent B: acetonitrile; gradient: given for intermediates and examples, flow rate 150 ml/min, temperature 25°C; UV 220 nm.

Method 10.

Instrument: Labomatic HD-5000, pump head HDK-280, gradient module NDB-1000, fraction separator Labomatic Labocol Vario 2000, Knauer UV detector Azura UVD 2.1S, Prepcon 5 software. Column: Chromatorex C18 10 µm 120x30 mm; eluent A: 0.1% ammonia in water; eluent B: acetonitrile; gradient: given for intermediates and examples, flow rate 150 ml/min, temperature 25°C; UV 250 nm.

Method 11.

Instrument: Labomatic HD-5000, pump head HDK-280, gradient module NDB-1000, fraction separator Labomatic Labocol Vario 2000, Knauer UV detector Azura UVD 2.1S, Prepcon 5 software. Column: Chromatorex C18 10 µm 300x50 mm; eluent A: 0.1% ammonia in water; eluent B: acetonitrile; gradient: given for intermediates and examples, flow rate 250 ml/min, temperature 25°C; UV 250 nm.

NMR spectra.

The proton signal multiplicities in the 1H NMR spectra given in the following paragraphs reflect the observed signal shape and do not take into account any manifestations of a higher order signal. Typically, chemical shift data is relative to the center of the signal in question. In the case of wide multiplets, the interval is indicated. Signals hidden by solvent or water are either tentatively assigned or not listed. Highly extended signals—for example, those caused by rapid rotation of molecular fragments or proton exchange—are also either assigned tentatively (often called a broad multiplet or broad singlet) or are not shown.

¹ H-NMR data of selected compounds are listed in the form of ¹ H-NMR peak lists. In them, for each signal peak, the value 5 in ppm is first given, and then the signal intensity value is indicated in parentheses. Pairs value 5 - signal intensity from different peaks are separated by commas. Thus, the list of peaks is described by the following general form: δ1 (intensity^, δ ₂ (intensity^), ..., δ ₁ (intensity^, ..., δ _Ώ (intensity^).

The intensity of the sharp signal correlates with the height (in cm) of the signal in the printed version of the NMR spectrum. When compared with other signals, these data can be compared with actual signal intensity ratios. In the case of broad signals, multiple peaks, or the center of the signal, are shown along with their relative intensity compared to the most intense signal shown in the spectrum. The ¹ H-NMR peak listing is similar to the classical ¹ H-NMR representation of the data, and thus typically contains all the peaks listed in the classical NMR interpretation. Moreover, like classic printed ¹ H-NMR versions, peak lists can display solvent signals, signals derived from stereoisomers of a particular target compound, impurity peaks, ¹³ C satellite peaks, and/or rotational side bands. Stereoisomer peaks and/or impurity peaks typically appear at lower intensities compared to peaks of the target compound (eg, >90% purity). Such stereoisomers and/or impurities may be typical of a particular production method, and therefore their peaks can help identify the reproduction of a given production method based on by-product fingerprints. An expert who calculates target compound peaks using known methods (MestReC, ACD modeling, or using empirically estimated expected values) can, if necessary, highlight target compound peaks, optionally using additional intensity filters. Such an operation would be similar to peak selection in the classical interpretation of ¹ H-NMR. A detailed description of the presentation of NMR data in the form of peak lists can be found in the publication Citation of NMR Peaklist Data within Patent Applications (see http://www.researchdisclosure.com/searching-disclosures, Research Disclosure Database Number 605005, 2014, August 01, 2014 .). In a typical peak picking operation, as described in Research Disclosure Database Number 605005, the Minimum Height parameter can be set between 1 and 4%. However, depending on the chemical structure and/or depending on the concentration of the analyte, it may be prudent to set the Minimum Height to <1%.

Syntheses of intermediates 1.

Intermediate connection 1-1.

3-[(1,4-dioxan-2-yl)methoxy]pyridine-4-carbonitrile

3-Chloropyridin-4-carbonitrile (CAS 68325-15-5, 1.40 g, 10.1 mmol) and (1,4-dioxan-2-yl)methanol (CAS 143669-41-4, 1.31 g, 11.1 mmol) were dissolved in THF (45 ml). Potassium tert-butoxide (1.03 g,

- 37 046642

9.14 mmol), and the mixture was stirred for 1 hour at 0°C. The reaction mixture was slowly diluted into sat. ammonium chloride solution and extracted with EtOAc (3x). The organic phase was washed with brine and filtered through a hydrophobic filter, concentrated under reduced pressure and purified by flash chromatography (silica gel, hexane/EtOAc, gradient 0-100%; EtOAc/EtOH, gradient 0-35%) to give 1.18 g of the title compound (53% yield).

¹ H-NMR (400 MHz, DMSO-de): δ [ppm] = 8.72 (s, 1H), 8.23 - 8.46 (m, 1H), 7.68 - 7.86 (m, 1H), 4.32 (d, 2H), 3.40 - 3.99 (m, 7H).

LC-MS (method 2): Rt = 0.77 min; MS (ESI positive): m/z = 221 [M+H]+.

Intermediate 1-2.

3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridine-4-carbonitrile CH ₃

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

¹ H-NMR (400 MHz, DMSO^ ₆ ): δ [ppm] = 8.75 (s, 1H), 8.40 (d, 1H), 7.78 (d, 1H), 4.44 (dd, 1H), 4.23 (dd, 1H), 3.87 (dd, 1H), 3.71 (dt, 1H), 3.50 (td, 1H), 3.35 -3.41 (m, 1H), 2.65 - 2.71 (m, 1H), 2.45 - 2.49 (m , 1H), 2.29 - 2.35 (m, 3H), 2.24 (ddd, 1H).

LC-MS (method 2): R _t = 0.72 min; MS (ESI positive): m/z = 234.2 [M+H] ⁺ .

Intermediate 1-3.

3-{[4-methylmorpholin-2-yl]methoxy}pyridin-4-carbonitrile

Using a method similar to that described for intermediate 1-1, with 3-chloropyridin4-carbonitrile (CAS 68325-15-5, 764 mg, 5.51 mmol) and [4-methylmorpholin-2-yl]methanol (CAS 40987-46-0 , 940 mg, 7.17 mmol) as starting materials to obtain 836 mg (purity 90%, yield 59%) of the title compound.

¹ H-NMR (400 MHz, DMSO^ ₆ ): δ [ppm] = 1.893 (0.97), 1.920 (1.44), 1.947 (1.07), 1.954 (0.50), 1.962 (0.54), 1.983 (1.01) , 1.991 (1.03), 2.011 (0.58), 2.019 (0.52), 2.197 (16.00), 2.518 (0.41), 2.589 (0.80), 2.593 (0.82), 2.617 (0.73), 2.621 (0.74), 2.766 (0.66) , 2.770 (0.95), 2.794 (0.63), 2.798 (0.89), 3.513 (0.60), 3.520 (0.73), 3.541 (1.36), 3.547 (1.39), 3.570 (0.80), 3.575 (0.67), 3.793 (0.74) , 3.796 (1.10), 3.801 (1.12),3.805 (0.92), 3.808 (0.85), 3.814 (0.79), 3.821 (1.18), 3.826 (1.18), 3.833 (1.27), 3.839 (0.66), 4.316 (5.03) ,4.329 (4.72), 7.772 (2.40), 7.774 (2.63), 7.785 (2.49), 8.381 (3.41), 8.393 (3.28), 8.714 (4.32).

LC-MS (method 2): Rt = 0.70 min; MS (ESI positive): m/z = 234.2 [M+H] ⁺ .

Intermediate 1-4.

3-{[^)-4-methylmorpholin-3-yl]methoxy}pyridin-4-carbonitrile

Using a method similar to that described for intermediate 1-2, with 3-chloropyridin4-carbonitrile (CAS 68325-15-5, 1.00 g, 7.24 mmol) and [(3R)-4-methylmorpholin-3-yl]methanol (1.00 g , purity 95%, 7.24 mmol; CAS 1620510-51-1) as starting materials, 823 mg (purity 99%, yield 48%) of the title compound were obtained.

¹ H-NMR (400 MHz, DMSO-de): δ [ppm] = 2.211 (0.52), 2.219 (0.64), 2.236 (0.66), 2.240 (0.68), 2.245 (0.68), 2.249 (0.72) , 2.266 (0.69), 2.274 (θ.63), 2.306 (16.00), 2.472 (0.48), 2.475 (0.50), 2.518 (1.22), 2.522 (0.71), 2.658 (0.56), 2.664 (1.27), 2.671 ( 0.67), 2.687 (0.47), 2.694 (0.96), 2.701 (0.47), 3.356 (1.17), 3.378 (1.16), 3.384 (1.30), 3.406 (1.20), 3.472 (0.50), 3.478 (0.58), 3.499 ( 0.80), 3.506 (0.81), 3.525 (0.71), 3.532

- 38 046642 (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 (1.0 3 ), 4.223 (1.01), 4.234 (1.29), 4.249 (1.23), 4.417 (1.25), 4.429 (1.28), 4.443 (1.03), 4.454 (0.99), 7.778 (2.39), 7.780 (2.38), 7.790 (2.45 ), 7.792 (2.50), 8.391 (3.23), 8.403 (3.11), 8.745 (3.91).

LC-MS (method 2): Rt = 0.70 min; MS (ESI positive): m/z = 234 [M+H]+.

Intermediate 1-5.

tert-butyl DO)-2-{[(4-cyanopyridin-3-yl)oxy]methyl}morpholine-4-carboxylate

Using a method similar to that described for intermediate 1-1, with 3-chloropyridine 4-carbonitrile (CAS 68325-15-5, 2.55 g, 18.4 mmol) and tert-butyl DO)-2-(hydroxymethyl)morpholine-4carboxylate (CAS 135065 -76-8, 4.00 g, 18.4 mmol) as starting materials, giving 4.82 g (purity

90%, yield 74%) of the title compound.

¹ H-NMR (400 MHz, DMSO^): δ [ppm] = 1.41 (s, 9H), 2.72 - 3.05 (m, 2H), 3.46 (br d, 1H), 3.67 - 3.82 (m, 2H), 3.82 - 3.88 (m, 1H), 4.00 (s, 1H), 4.37 (br d, 2H), 7.79 (d, 1H), 8.40 (d, 1H), 8.73 (s, 1H).

LC-MS (method 2): R _t = 1.06 min; MS (ESI positive): m/z = 320 [M+H] ⁺

Intermediate 1-6.

3-[2-(1,4-dioxan-2-yl)ethoxy]pyridine-4-carbonitrile N

Using a method similar to that described for intermediate 1-2, with 3-chloropyridin4-carbonitrile (CAS 68325-15-5, 2.10 g, 15.1 mmol) and 2-(1,4-dioxan-2-yl)ethane-1- ol (CAS 15172004-6, 2.00 g, 15.1 mmol) as starting materials gave 2.89 g (purity 99%, yield 81%) of the title compound.

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

LC-MS (method 6): Rt = 0.64 min; MS (ESI positive): m/z = 235 [M+H] ⁺ .

Intermediate 1-7.

3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridine-4-carbonitrile

Using a method similar to that described for intermediate 1-2, with 3-chloropyridin4-carbonitrile (CAS 68325-15-5, 948 mg, 6.84 mmol) and (5,5-dimethyl-1,4-dioxan-2-yl) methanol (1.00 g, 6.84 mmol; CAS 54321-57-2) as starting materials gave 1.31 g (95% purity, 73% yield) of the title compound.

1H-NMR (400 MHz, DMSO): δ [ppm] = 1.014 (0.69), 1.048 (16.00), 1.172 (0.55), 1.200 (0.51), 1.263 (13.01), 1.987 (0.92), 2.518 ( 0.62), 2.523 (0.43), 3.313 (1.67), 3.340 (2.27), 3.342 (2.21), 3.542 (2.95), 3.570 (2.39), 3.604 (1.50), 3.627 (1.97), 3.734 (1.24), 3.760 ( 3.08), 3.781 (2.25), 3.787 (2.73), 3.791 (1.58), 3.796 (0.77), 3.802 (0.63), 4.356 (3.63), 4.365 (4.41), 7.780 (3.42), 7.792 (3.63), 8.387 ( 4.49), 8.399 (4.29), 8.715 (5.54).

LC-MS (method 6): Rt = 0.75 min; MS (ESI positive): m/z = 249 [M+H] ⁺ .

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Intermediate 1-8.

3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridine-4-carbonitrile

Using a method similar to that described for intermediate 1-1, with 3-chloropyridin4-carbonitrile (CAS 68325-15-5, 1.00 g, 7.22 mmol) and [(2R)-1,4-dioxan-2-yl]methanol ( CAS40691388-0, 938 mg, 7.94 mmol) as starting materials gave 490 mg (95% purity, 29% yield) of the title compound.

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

¹ H-NMR (400 MHz, DMSO^b): δ ppm = 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).

Intermediate 1-9.

tert-butyl (3R)-3-{[(4-cyanopyridin-3-yl)oxy]methyl} morpholine-4-carboxylate

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

LC-MS (method 6): R _t = 0.95 min; MS (ESI positive): m/z = 264 [M+H]+.

Intermediate 1-10.

tert-butyl (2R)-2-{[(4-cyanopyridin-3-ul)oxy]methyl}morpholine-4-carboxylate

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

¹ H-NMR (400 MHz, DMSO-a ₆ ): δ [ppm] = 1.41 (s, 9H), 2.73 - 3.00 (m, 2H), 3.39 - 3.50 (m, 1H), 3.75 (m , 2H), 3.82 - 3.89 (m, 1H), 3.95 - 4.00 (m, 1H), 4.37 (br d, 2H), 7.79 (d, 1H), 8.40 (d, 1H), 8.73 (s, 1H) .

LC-MS (method 2): R _t = 1.04 min; MS (ESI positive): m/z = 320 [M+H]+.

Intermediate 1-11.

3-[(^)-1-(1,4-dioxan-2-yl)ethoxy]pyridine-4-carbonitrile

Using a method similar to that described for intermediate 1-9, with 3-fluoropyridin4-carbonitrile (878 mg, 7.19 mmol) and (^)-1-[1,4-dioxan-2-yl]ethan-1-ol (CAS 1372875-59-6, 950 mg, 7.19 mmol) as starting materials, 1.68 g (purity 95%, yield 95%) of the title compound were obtained.

- 40 046642

Ή-NMR (400 MHz, DMSO-06): δ ppm= 0.988 (0.85), 1.004 (0.92), 1.056 (0.59), 1.071 (0.60), 1.154 (4.47), 1.166 (0.63), 1.172 ( 9.29), 1.189 (4.59), 1.276 (12.44), 1.292 (12.55), 1.325 (11.08), 1.341 (11.16), 1.987 (16.00), 2.518 (1.63), 2.522 (1.05), 3.300 (0.46), 96 ( 1.81), 3.421 (2.99), 3.424 (2.99), 3.429 (1.78), 3.450 (5.06), 3.457 (3.42), 3.472 (1.97), 3.478 (1.62), 3.485 (2.38), 3.497 (2.19), 3.500 ( 1.91), 3.525 (2.26), 3.552 (1.16), 3.559 (1.31), 3.582 (2.48), 3.588 (2.91), 3.611 (1.70), 3.616 (2.62), 3.638 (4.15), 3.642 (3.63), 3.664 ( 3.89), 3.671 (4.01), 3.676 (1.93), 3.683 (1.76), 3.685 (1.80), 3.689 (1.79), 3.695 (1.76), 3.701 (1.17), 3.704 (1.27), 3.707 (1.26), 3.710 ( 1.28), 3.744 (1.82), 3.750 (3.32), 3.757 (1.01), 3.778 (3.94), 3.784 (2.19), 3.807 (1.47), 3.813 (1.33), 3.906 (1.40), 3.912 (1.35), 3.935 ( 1.24), 3.941 (1.18), 3.999 (1.24), 4.016 (3.72), 4.034 (3.66), 4.052 (1.20), 4.804 (0.41), 4.821 (1.95), 4.836 (3.43), 4.852 (2.64), 4.864 ( 1.34), 7.755 (3.58),7.757 (3.60), 7.769 (4.33), 7.771 (3.80), 7.783 (3.28), 7.785 (3.20), 8.351 (4.95), 8.363 (4.90), 8.368 (4.48),8.380 ( 4.17), 8.749 (6.40), 8.772 (5.46).

LC-MS (method 6): Rt = 0.64 min; MS (ESI positive): m/z = 235 [M+H]+.

Intermediate 1-12.

3-{(1 R)-1-[1,4-dioxan-2-yl]ethoxy} pyridine-4-carbonitrile

N

Using a method similar to that described for intermediate 1-9, with 3-fluoropyridin4-carbonitrile (905 mg, 7.42 mmol) and (^)-1-[1,4-dioxan-2-yl]ethan-1-ol (CAS 1372881-98-5, 980 mg, 7.42 mmol) as starting materials gave 1.39 g (purity 95%, yield 76%) of the title compound.

Ή-NMR (400 MHz, DMSO-06): δ ppm = 1.274 (0.82), 1.289 (0.87), 1.322 (16.00), 1.337 (15.97), 1.984 (0.48), 2.331 (0.56), 2.673 (0.57 ), 3.427 (2.95), 3.448 (3.45), 3.455 (3.30), 3.471 (3.27), 3.482 (2.59), 3.496 (3.79), 3.499 (3.36), 3.524 (3.41), 3.580 (1.59), 3.586 (1.80 ), 3.609 (2.32), 3.615 (2.92), 3.636 (5.12), 3.662 (3.60), 3.668 (3.70), 3.680 (2.08), 3.687 (1.49), 3.693 (1.53), 3.698 (1.52), 3.704 (1.41 ), 3.746 (3.19),3.754 (1.74), 3.775 (2.26), 3.903 (2.52), 3.909 (2.44), 3.932 (2.24), 3.937 (2.13), 4.818 (0.65), 4.833 (2.08),4.845 (2.30 ), 4.849 (2.22), 4.861 (2.00), 4.876 (0.57), 7.766 (5.15), 7.778 (5.29), 8.348 (0.42), 8.365 (6.23), 8.377 (6.01), 8.743 (0.51), 8.765 (9.13 ).

LC-MS (method 6): Rt = 0.67 min; MS (ESI positive): m/z = 235 [M+H]+.

Intermediate 1-71.

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

Using a method similar to that described for intermediate 1-9, with 3-fluoropyridine4-carbonitrile (824 mg, 6.75 mmol) and 1-(4-methylmorpholin-2-yl)ethanol (980 mg, 6.75 mmol, CAS 1540922-49- 3) As starting materials, 817 mg (purity 99%, yield 48%) of the title compound was obtained after column chromatography using Biotage Isolera.

Ή-NMR (400 MHz, DMSO-06) δ [ppm]: 1.285 (4.44), 1.300 (4.47), 1.318 (5.38), 1.333 (5.31), 1.848 (0.57), 1.874 (0.94), 1.901 (0.63), 1.927 (0.93), 1.933 (0.66), 1.953 (2.04), 1.961 (1.23), 1.981 (1.32), 1.990 (0.60), 2.188 (16.00), 2.518 (1.33), 2.522 (0.90), 2.572 (0.89), 2.600 (0.79), 2.718 (0.54), 2.746 (0.52), 2.839 (0.64), 2.867 (0.60), 3.485 (0.78), 3.488 (0.66), 3.491 (0.85), 3.516 (1.00), 3.522 (0.92), 3.544 (0.48), 3.550 (0.42), 3.562 (0.44), 3.568 (0.54), 3.573 (0.73), 3.578 (0.77), 3.587 (0.81), 3.593 (0.83), 3.598 (0.85), 3.604 (0.71), 3.772 (0.51), 3.777 (0.56), 3.781 (0.78), 3.786 (0.61), 3.789 (0.59), 3.794 (0.56), 3.800 (0.46), 3.805 (0.46), 3.809 (0.64), 3.814 (0.50), 3.817 (0.45), 4.818 (0.60), 4.833 (0.97), 4.848 (0.79), 4.858 (0.65), 4.862 (0.67), 4.874 (0.57), 7.746 (1.41), 7.760 (2.88), 7.772 (1.71), 8.341 (1.93), 8.355 (2.69), 8.368 (2.12), 8.745 (2.34), 8.766 (2.68).

LC-MS (method 6): Rt = 0.32 min; MS (ESI positive): m/z = 248 [M+H]+.

Syntheses of intermediates 2.

Intermediate 2-1.

1-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methanamine

3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-carbonitrile (intermediate compound 1-1, 1.17 g, 5.34 mmol), ammonia (19 ml, 7.0 M in methanol, 850 mmol) and Raney nickel (CAS 7440-02-0, 783 mg, 50% hum.), and the mixture was stirred under a hydrogen atmosphere at 25 bar at RT for 22 hours. The mixture was filtered through a celite pad, eluted with methanol and the combined filtrates were concentrated under reduced pressure. The residue was used directly in the next step without further purification (1.13 g, 94% yield).

¹ H-NMR (400 MHz, DMSO-ds): δ [ppm] = 8.24 (s, 1H), 8.17 (d, 1H), 7.38 (d, 1H), 4.09 (d, 2H), 3.73 3.91 (m, 3H), 3.59 - 3.73 (m, 4H), 3.46 - 3.52 (m, 2H), 3.39 - 3.45 (m, 2H). 2.06 (br., 2H).

LC-MS (method 2): Rt = 0.54 min; MS (ESI positive): m/z = 225 [M+H]+.

Intermediate connection 2-2.

1-(3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)methanamine CH ₃ (Tv SG NH ₂

Using a method similar to that described for intermediate 2-1, with 3-{[(3R)-4methylmorpholin-3-yl]methoxy}pyridin-4-carbonitrile (intermediate 1-2, 355 mg, 1.52 mmol) as starting material substances, 350 mg (yield 89%) of the title compound were obtained.

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

Intermediate connection 2-3.

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

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

1H-NMR (400 MHz, DMSO^): δ [ppm] = 1.68 - 1.84 (br s, 2H), 1.85 - 1.94 (t, 1H), 1.94 - 2.05 (td, 1H), 2.19 (s , 3H), 2.57 - 2.64 (d, 1H), 2.73 - 2.83 (d, 1H), 3.46 -3.63 (t, 1H), 3.63 - 3.73 (s, 2H), 3.73 - 3.86 (m, 3H), 4.10 (br d, 2H), 7.34 - 7.44 (d, 1H), 8.10 - 8.20 (d, 1H), 8.21 - 8.30 (s, 1H).

LC-MS (method 2): Rt = 0.56 min; MS (ESI positive): m/z = 238 [M+H] ⁺ .

Intermediate 2-4.

1-(3-{[^)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)methanamine

Using a method similar to that described for intermediate 2-1, with 3-{[(3S)-4methylmorpholin-3-yl]methoxy}pyridin-4-carbonitrile (intermediate 1-4, 823 mg, 3.53 mmol) as starting material substances, 798 mg (purity 90%, yield 86%) of the title compound were obtained.

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

- 42 046642

Intermediate 2-5.

tert-butyl (2S)-2-({[4-(aminomethyl)pyridin-3-yl]oxy}methyl)morpholine-4-carboxylate

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

¹ H-NMR (400 MHz, DMSO): δ [ppm] = 1.41 (s, 9H), 3.16 (s, 2H), 3.39 - 3.49 (m, 2H), 3.66 - 3.79 (m, 5H) , 3.79 - 3.98 (m, 3H), 4.07 - 4.20 (m, 3H), 7.39 (d, 1H), 8.19 (d, 1H), 8.27 (s, 1H).

LC-MS (method 2): Rt = 0.84 min; MS (ESI positive): m/z = 324 [M+H]+.

Intermediate 2-6.

1-{3-[2-(1,4-dioxan-2-yl)ethoxy]pyridin-4-yl}methanamine

Using a method similar to that described for intermediate 2-1, with 3-[2-(1,4dioxan-2-yl)ethoxy]pyridin-4-carbonitrile (intermediate 1-6, 2.89 g, 12.3 mmol) as starting material substances, we obtained 2.22 g (purity 90%, yield 68%) of the title compound.

¹ H-NMR (400 MHz, DMSO-d^: δ [ppm] = 1.536 (0.40), 1.729 (1.99), 1.751 (3.41), 1.765 (5.01), 1.785 (6.00), 1.804 (5.59) , 1.817 (5.34), 1.834 (4.06), 1.852 (2.92), 1.870 (2.15), 2.326 (1.02), 2.669 (1.04), 3.159 (0.53), 3.208 (5.54), 3.235 (8.67), 3.261 (7.11) , 3.424 (3.46), 3.430 (3.63), 3.451 (7.09), 3.457 (7.51), 3.479 (5.43), 3.485 (5.78), 3.528 (4.90), 3.534 (5.03), 3.557 (6.69), 3.563 (7.65) , 3.584 (3.06), 3.590 (4.57), 3.622 (8.16), 3.653 (8.66), 3.688 (14.98), 3.697 (16.00), 3.731 (13.03), 3.759 (6.36), 4.136 (7.05), 4.152 (13.0 1) ,4.167 (8.38), 7.385 (5.36), 7.394 (5.58), 8.163 (5.21), 8.172 (5.56), 8.224 (7.44).

Intermediate 2-7.

1-{3-[(5,5 - dimethyl-1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methanamine

Using a method similar to that described for intermediate 2-1, with 3-[(5,5-dimethyl1,4-dioxan-2-yl)methoxy]pyridin-4-carbonitrile (intermediate 1-7, 1.30 g, 5.24 mmol ) as starting material gave 1.26 g (purity 90%, yield 86%) of the title compound.

1H-NMR (400 MHz, DMSO^) δ [ppm]: 1.014 (0.96), 1.049 (16.00), 1.201 (0.72), 1.262 (13.58), 1.751 (0.48), 2.518 (2.17), 2.523 ( 1.47), 3.308 (2.76), 3.539 (2.43), 3.567 (1.99), 3.601 (1.13), 3.623 (1.75), 3.694 (1.97), 3.720 (2.07), 3.746 (2.38), 3.783 (0.46), 4.128 ( 3.01), 4.136 (2.80), 7.386 (0.85), 8.181 (0.83), 8.237 (0.96).

Intermediate 2-8.

1-(3-{[(2S}-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)methanamine

Using a method similar to that described for intermediate 2-1, with 3-{[(2S)-1,4dioxan-2-yl]methoxy}pyridin-4-carbonitrile (intermediate 1-8, 1.24 g, 5.63 mmol) in as starting material, 1.56 g (80% purity, 99% yield) of the title compound were obtained.

1H-NMR (400 MHz, DMSO^): δ [ppm] = 1.232 (0.52), 1.845 (1.06), 2.518 (2.37), 2.523 (1.54), 3.159 (14.24), 3.171 (14.33), 3.376 (0.69), 3.379 (0.65), 3.404 (2.41), 3.419 (0.41), 3.428 (3.79), 3.431 (3.86), 3.439 (0.59), 3.447 (0.69), 3.455 (2.71), 3.465 (1.97), 3.474 (0.57), 3.486 (2.71), 3.493 (2.97), 3.508 (1.01), 3.520 (2.61), 3.592 (0.45), 3.601 (1.92), 3.608 (2.10), 3.630 (2.77), 3.636 (3.65), 3.659 (5.73), 3.661 (5.45), 3.683

- 43 046642 (16.00), 3.700 (1.95), 3.754 (3.49), 3.762 (2.18), 3.784 (2.51), 3.794 (0.57), 3.812 (0.61), 3.823 (2.48), 3.829 (3.16), 3.842 (0. 81 ), 3.849 (2.07), 3.856 (6.45), 3.868 (1.93), 3.874 (1.37), 3.880 (1.69), 3.887 (1.30), 3.892 (1.13), 3.899 (0.89), 4.087 (11.44), 4.099 (10.46 ), 4.111 (2.62), 4.125 (1.15), 7.380 (4.02), 7.391 (4.11), 7.411 (0.67), 7.423 (0.67), 8.168 (6.28), 8.179 (6.26), 8.184 (1.58), 8.196 (1.02 ), 8.230 (10.21), 8.274 (1.76).

Intermediate 2-9.

tert-butyl (3R)-3-({[4-(aminomethyl)pyridin-3-yl]oxy}methyl)morpholine-4-carboxylate

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

¹ H-NMR (400 MHz, DMSO-dg): δ [ppm] = 1.038 (0.41), 1.055 (0.77), 1.073 (0.44), 1.363 (10.92), 1.754 (6.47), 2.200 (1.02) , 2.325 (1.05), 2.330 (1.42), 2.334 (1.05), 2.521 (5.72), 2.526 (3.72), 2.667 (0.88), 2.672 (1.22), 2.676 (0.89), 3.057 (1.02), 3.068 (1.10) , 3.087 (1.65), 3.090 (1.62), 3.097 (1.89), 3.101 (1.73),3.120 (2.21), 3.130 (2.39), 3.168 (16.00), 3.210 (1.86), 3.235 (0.59), 3.240 (1.07) , 3.258 (1.25), 3.265 (1.40),3.286 (1.75), 3.294 (2.07), 3.316 (3.15), (1.43), 3.503 (3.53), 3.534 (2.78), (1.93), 3.855 (0.89), 3.859 (1.19), (2.79), 3.893 (4.31), 3.899 (3.39),

3.365

3.682

3.865

3.902 (3.67), 3.372 (3.73), 3.395 (7.14), 3.764 (1.68), 3.774 (1.80), 3.869 (2.32), 3.873 (2.87), 3.927 (2.09), 4.111 (1.88), 3.402 (1.68), 3.462 (1.41), 3.470 (1.81), 3.792 (3.17), 3.802 (2.81), 3.820 (3.62), 3.882 (2.64), 3.886 (3.02), 3.889 (1.76), 4.227 (3.64), 4.303 (0.96), 4.315 (1.37), 4.329 (3.71), 4.331 (3.43), 4.338 (1.95), 4.345 (2.50), 7.401 (2.60), 8.192 (2.81), 8.337 (2.91). LC-MS (method 1): Rt = 0.49 min; MS (ESI positive): m/z = 324 [M+H]+.

Intermediate 2-10.

tert-butyl (2R)-2-({[4-(aminomethyl)pyridin-3-yl]oxy}methyl)morpholine-4-carboxylate

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

¹ H-NMR (400 MHz, DMSO-dg): δ [ppm] = 1.41 (s, 9H), 2.70 - 3.01 (m, 2H), 3.17 (d, 3H), 3.41 - 3.52 (m, 1H), 3.63 - 3.70 (m, 2H), 3.70 - 3.81 (m, 2H), 3.82 - 4.00 (m, 2H), 4.08 - 4.18 (m, 3H), 7.39 (d, 1H), 8.18 (d, 1H), 8.25 (s, 1H).

LC-MS (method 2): Rt = 0.84 min; MS (ESI positive): m/z = 324 [M+H]+.

Intermediate 2-11.

1-{3-[(1S)-1-(1,4-dioxan-2-yl)ethoxy]pyridin-4-yl}methanamine

Using a method similar to that described for intermediate 2-1, with 3-[(1S)-1-(1,4dioxan-2-yl)ethoxy]pyridin-4-carbonitrile (intermediate 1-11, 1.68 g, 7.17 mmol ) as starting material gave 1.49 g (purity 90%, yield 78%) of the title compound.

LC-MS (method 6): Rt = 0.2 min; MS (ESI positive): m/z = 239 [M+H]+.

¹ H-NMR (400 MHz, DMSO-dg) 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

- 44 046642 (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 (2.78 ), 3.412 (2.79), 3.426 (5.84), 3.438 (5.24), 3.453 (6.52), 3.459 (6.28), 3.466 (5.96), 3.479 (2.46), 3.486 (3.26), 3.493 (2.78), 3.521 (0.49 ), 3.529 (0.67), 3.535 (0.58), 3.564 (2.05), 3.572 (2.72), 3.580 (2.41), 3.600 (6.11), 3.609 (5.52), 3.617 (4.09), 3.634 (11.25), 3.637 (11.05 ), 3.756 (8.08), 3.785 (6.75),3.889 (2.49), 3.894 (2.48), 3.917 (2.26), 3.922 (2.16), 4.540 (1.04), 4.555 (3.05), 4.569 (4.27), 4.580 (2.83 ),4.584 (2.84), 7.369 (3.21), 7.379 (4.91), 8.135 (3.33), 8.146 (5.23), 8.157 (3.20), 8.261 (4.69), 8.275 (4.23).

Intermediate connection 2-12.

1-{3-[(^)-1-(1,4-dioxan-2-yl)ethoxy]pyridin-4-yl}methanamine

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

1H-NMR (400 MHz, DMSO-de) δ [ppm]: 1.216 (0.81), 1.232 (0.99), 1.255 (15.91), 1.271 (16.00), 1.753 (0.71), 3.290 (0.44), 3.399 (0.54), 3.412 (2.42), 3.424 (0.71), 3.437 (3.81), 3.440 (3.42), 3.453 (0.77), 3.459 (2.72), 3.465 (5.00), 3.485 (1.48), 3.494 (2.02), 3.573 (1.45), 3.580 (1.70), 3.598 (2.00), 3.603 (3.43), 3.609 (3.84), 3.616 (2.24), 3.622 (2.04), 3.628 (1.97), 3.634 (4.41), 3.638 (4.68), 3.645 (2.04), 3.662 (5.32),3.672 (6.05), 3.713 (0.63), 3.757 (2.28), 3.764 (2.39), 3.787 (1.75), 3.790 (1.84), 3.887 (2.14), 3.894 (2.12),3.916 (1.94), 3.922 (1.85), 4.535 (0.53), 4.550 (1.85), 4.564 (2.15), 4.566 (2.17), 4.579 (1.80), 4.595 (0.50), 7.381 (3.18), 7.393 (3.14), 8.144 (4.36), 8.156 (4.13), 8.257 (0.50), 8.272 (6.58).

LC-MS (method 6): Rt = 0.21 min; MS (ESI positive): m/z = 239 [M+H]+.

Intermediate 2-71.

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

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

¹ H-NMR (400 MHz, DMSO-de) δ [ppm]: 1.227 (3.82), 1.242 (3.97), 1.254 (4.80), 1.270 (4.60), 1.850 (1.08), 1.862 (1.12), 1.876 (1.43), 1.888 (1.42), 1.903 (0.90), 1.915 (1.07), 1.928 (0.67), 1.937 (0.65), 1.945 (0.81), 1.957 (1.14), 1.965 (0.95), 1.973 (0.53), 1.985 (0.64), 1.993 (0.48), 2.152 (0.51), 2.183 (16.00), 2.332 (0.45), 2.518 (2.14), 2.522 (1.29), 2.575 (1.38), 2.602 (1.24), 2.673 (0.44), 2.692 (0.68), 2.720 (0.63), 2.834 (0.79), 2.862 (0.75), 3.475 (0.48), 3.480 (0.56), 3.487 (0.60), 3.504 (1.27), 3.508 (1.56), 3.514 (1.44), 3.536 (1.04), 3.542 (1.01), 3.563 (0.49), 3.568 (0.50), 3.575 (0.48), 3.588 (0.47), 3.667 (1.61), 3.793 (1.27), 3.821 (1.05), 4.561 (0.97), 7.374 (1.24), 8.138 (1.27), 8.267 (1.31).

LC-MS (method 6): R _t = 0.11 min; MS (ESI positive): m/z = 252 [M+H]+.

Syntheses of intermediates 3.

Intermediate 3-1.

1-chloro-3-isothiocyanato-2-methoxybenzene

3-chloro-2-methoxyaniline (CAS 51114-68-2, 8.4 ml, 63 mmol) was dissolved in DCM (100 ml) and added sat. sodium bicarbonate solution (100 ml). Thiophosgene (5.4 mL, 70 mmol) was slowly added to the ice-cooled mixture. The reaction mixture was stirred at 0°C for 2 hours. At RT, the DCM layer was separated and washed with sat. sodium bicarbonate solution, filtered through a hydrophobic filter and concentrated under reduced pressure to obtain the title compound (12.97 g, 100% yield), which was directly used in the next step.

¹ H-NMR (400 MHz, DMSO-de): δ [ppm] = 7.51 (dd, 1H), 7.35 (dd, 1H), 7.20 (t, 1H), 3.85 - 3.91 (m, 3H) .

- 45 046642

Intermediate 3-4.

1-fluoro-3-isothiocyanato-2-methoxybenzene

Using a method similar to that described for intermediate 3-1, with 3-fluoro-2methoxyaniline (CAS 437-83-2, 5.00 g, 35.4 mmol) as the starting material, 6.24 g (96% yield) of the title compound were obtained.

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

Intermediate 3-18.

1-chloro-5-fluoro-3-isothiocyanato-2-methoxybenzene

Using a method similar to that described for intermediate 3-1, with 3-chloro-5-fluoro2-methoxyaniline (1.00 g, 5.70 mmol) as starting material, 1.17 g (95% purity, 90% yield) of the title compound were obtained .

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

Intermediate 3-29.

-chloro-2-ethyl-3-isothiocyanatobenzene

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

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

Intermediate 3-65.

2-ethyl-1-fluoro-3-isothiocyanatobenzene

Using a similar method to that described for intermediate 3-1, with 2-ethyl-3fluoroaniline (2.50 g, 18.0 mmol, CAS 1139437-61-8) as the starting material, 3.0 g (90% purity, 83% yield) of the title were obtained in the connection header.

¹ H-NMR (400 MHz, DMSO-de) δ [ppm]: 1.108 (7.13), 1.127 (16.00), 1.146 (7.13), 2.462 (0.95), 2.483 (1.27), 2.517 (0.79), 2.522 (0.48), 2.637 (0.95), 2.641 (1.11), 2.655 (3.17), 2.659 (3.17), 2.674 (3.17), 2.678 (3.17), 2.693 (0.95), 2.697 (0.95), 3.461 (0.48), 3.477 (0.63), 3.484 (0.63), 3.506 (1.11), 3.528 (2.06), 3.537 (2.69), 3.625 (3.01), 3.648 (1.11), 3.663 (0.63), 3.669 (0.63), 7.185 (1.11), 7.189 (1.11), 7.205 (1.58),7.209 (2.53), 7.212 (1.27), 7.229 (1.43), 7.233 (1.74), 7.243 (1.27), 7.246 (1.43), 7.263 (3.80), 7.266 (2.38), 7.282 (2.53), 7.296 (2.38), 7.301 (2.38), 7.317 (2.53), 7.322 (0.79), 7.337 (0.79).

Syntheses of intermediates 4.

Intermediate 4-1.

tert-butyl 5-[(3-chloro-2-methoxyphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine1 (2H)-carboxylate

To an ice-cooled solution of 1-chloro-3-isothiocyanato-2-methoxybenzene (intermediate with

- 46 046642 unit 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) were added dropwise DBU (4.5 ml, 30 mmol). The reaction mixture was stirred at RT overnight. Ice water (200 ml) was added to the reaction mixture and conc. HCl (2 ml). The mixture was stirred for 20 minutes. and extracted with DCM. The organic phase was filtered through a hydrophobic filter, concentrated under reduced pressure and purified by flash chromatography (silica gel, hexane/EtOAc, 0-50% gradient) to give 6.54 g of the title compound (71% yield).

¹ H-NMR (400 MHz, DMSO-de): δ [ppm] = 13.36 (br s, 1H), 7.73 (d, 1H), 7.47 (dd, 1H), 7.22 (t, 1H), 3.76 3.82 (m, 5H), 2.88 (t, 2H), 1.48 (s, 9H).

LC-MS (method 1): Rt = 1.49 min; MS (ESI positive): m/z = 413.1 [M+H] ⁺ .

Intermediate connection 4-4.

tert-butyl 5-[(3-fluoro-2-methoxyphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-(2H)-carboxylate

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

¹ H-NMR (400 MHz, DMSO-de): 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).

LC-MS (method 2): Rt = 0.66 min; MS (ESI positive): m/z = 397.3 [M+H]+.

Intermediate 4-7.

tert-butyl 5-[(2,3-dichlorophenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)carboxylate

1,2-Dichloro-3-isothiocyanatobenzene (CAS 6590-97-2, 5.00 g, 24.5 mmol) and tert-butyl 2,4dioxopiperidine-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 argon, and the mixture was stirred overnight at RT. The reaction mixture was diluted with HCl (200 ml, 1 N in water) and stirred for 30 min. with CT. The resulting solid was filtered, the filter cake was washed with water and dried at 50°C in a vacuum oven overnight to obtain 9.40 g of the title compound (92% yield).

1H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.467 (16.00), 1.484 (0.56), 1.622 (0.34), 1.644 (0.25), 1.661 (0.20), 1.674 (0.17), 1.898 (0.19), 1.913 (0.31), 1.927 (0.19), 2.075 (0.20), 2.327 (0.18), 2.518 (0.60), 2.523 (0.39), 2.621 (0.30), 2.647 (0.32), 2.665 (0.24), 2.669 (0.29), 2.673 (0.25), 3.249 (0.25), 3.459 (0.23), 3.473 (0.39), 3.487 (0.22), 3.538 (0.28), 3.561 (0.29), 3.727 (0.50), 7.357 (0.17), 7.377 (0.36), 7.383 (0.28), 7.397 (0.28), 7.544 (0.27), 7.547 (0.33), 7.560 (0.29), 7.564 (0.31), 7.568 (0.25), 7.580 (0.18).

LC-MS (method 2): Rt = 0.70 min; MS (ESI positive): m/z = 416 [MH] ^- .

Intermediate 4-10.

tert-butyl 5-[(3-chloro-2-methylphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)carboxylate

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

¹ H-NMR (400 MHz, DMSO-d^: δ [ppm] = 15.73 (s, 1H), 12.77 (br s, 1H), 7.45 (d, 1H), 7.30 (t, 1H), 7.19

- 47 046642 (d, 1H), 3.78 (t, 2H), 2.85 (t, 2H), 2.20 (s, 3H), 1.48 (s, 9H).

LC-MS (method 2): R _t = 0.72 min; MS (ESI positive): m/z = 397.3 [M+H]+.

Intermediate 4-18.

tert-butyl

- [(3-chloro-5-fluoro-2-methoxyphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6 dihydropyridine-1 (2H)-carboxylate

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

'H-NMR (400 MHz, DMSO-ds): δ [ppm] = 1.154 (0.88), 1.172 (1.70), 1.189 (0.80), 1.484 (16.00), 1.987 (3.28), 2.518 (0.89) , 2.522 (0.61), 2.883 (0.73), 2.899 (0.40), 3.359 (0.69), 3.644 (4.46), 3.760 (7.94), 3.774 (0.44), 3.782 (1.03), 3.798 (0.53), 4.017 (0.69) , 4.035 (0.69), 6.400 (0.60), 6.405 (0.53), 6.427 (1.00), 7.498 (0.41).

LC-MS (method 2): R _t = 0.73 min; MS (ESI positive): m/z = 431 [M+H] ⁺ .

Intermediate 4-29.

tert-butyl 5-[(3-chloro-2-ethylphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)carboxylate

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

¹ H-NMR (400 MHz, DMSO-d^: δ [ppm] = 1.063 (0.89), 1.082 (2.14), 1.100 (0.95), 1.362 (0.65), 1.478 (16.00), 1.486 (1.29) , 2.518 (0.64), 2.523 (0.44), 2.631 (0.70), 2.650 (0.69), 2.850 (0.41), 2.866 (0.78), 2.883 (0.43), 3.775 (0.51), 3.791 (0.90), 3.807 (0.46) , 7.212 (0.46), 7.214 (0.44), 7.232 (0.62), 7.234 (0.61), 7.293 (0.62), 7.313 (1.08), 7.332 (0.53), 7.440 (0.61), 7.443 (0.62), 7.460 (0.49) , 7.463 (0.45).

Intermediate 4-38.

tert-butyl 5-[(3-fluoro-2-methylphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)carboxylate

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

1H-NMR (400 MHz, DMSO^): δ [ppm] = 1.479 (16.00), 2.084 (2.80), 2.088 (2.74), 2.834 (0.58), 2.850 (1.12), 2.866 (0.61), 3.768 (0.64), 3.784 (1.16), 3.800 (0.59), 7.073 (0.61), 7.093 (0.71), 7.186 (0.59), 7.299 (0.45), 7.316 (0.42).

- 48 046642

Intermediate 4-40.

tert-butyl 5-{[2-(2,2-difluoroethyl)-3-fluorophenyl]carbamothioyl}-4-hydroxy-6-oxo-3,6dihydropyridine-1 (2H)-carboxylate

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

¹ H-NMR (400 MHz, DMSO-a ₆ ): δ [ppm] = 1.471 (16.00), 2.518 (0.65), 2.523 (0.43), 2.788 (0.47), 2.804 (0.87), 2.820 (0.50 ), 3.166 (3.72), 3.754 (0.60), 3.770 (1.08), 3.786 (0.57), 7.149 (0.62), 7.169 (0.70), 7.271 (0.58), 7.446 (0.46), 7.462 (0.43).

Intermediate 4-65.

tert-butyl 5-[(2-ethyl-3-fluorophenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)carboxylate

CH ₃ O O S ^H3C < 1 1 1 1 L ^CH ₃

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

¹ H-NMR (400 MHz, DMSOC) δ [ppm]: 1.066 (1.02), 1.085 (2.41), 1.104 (1.06), 1.477 (16.00), 1.486 (1.04), 2.074 (0.65), 2.518 ( 1.12), 2.522 (0.92), 2.538 (0.61), 2.858 (0.69), 3.771 (0.55), 3.787 (0.98), 3.803 (0.50), 7.092 (0.50), 7.112 (0.55), 7.186 (0.45), 7.311 ( 0.44), 7.327 (0.41). LC-MS (method 2): R _t = 0.72 min; MS (ESI positive): m/z = 395 [M+H]+.

Syntheses of intermediates 5.

Intermediate 5-1.

N(3-chloro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

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

¹ H-NMR (400 MHz, DMSO-a6): δ [ppm] = 16.45 (d, 1H), 14.69 (s, 1H), 14.33 (s, 1H), 9.37 (br s, 1H), 8.18 (br s, 1H), 7.76 - 7.87 (m, 1H), 7.37 - 7.45 (m, 1H), 7.15 - 7.23 (m, 1H), 3.73 - 3.76 (m, 3H), 3.43 (td, 1H) , 3.27 - 3.32 (m, 1H), 2.79 (t, 1H), 2.59-2.69 (m, 1H).

LC-MS (method 1): R _t = 1.19 min; MS (ESI positive): m/z = 313 [M+H] ⁺ .

Intermediate 5-4.

^(3-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using a method similar to that described for intermediate 5-1, with tert-butyl 5[(3-fluoro-2-methoxyphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate

- 49 046642 (intermediate 4-4, 9.49 g, 23.9 mmol) as starting material, 6.98 g (yield 89%) of the title compound was obtained after 15 min of stirring and used in the following steps without further purification.

¹ H-NMR (400 MHz, DMSO^): δ [ppm] = 16.48 (d, 1H), 14.63 (s, 0.5H), 14.28 (s, 0.5H), 9.34 (br s, 0.5H ), 8.16 (br s, 0.5H), 7.65 (t, 1H), 6.97 - 7.37 (m, 2H), 3.79 -3.85 (m, 3H), 3.35 - 3.46 (m, 1H), 3.26 - 3.32 (m , 1H), 2.78 (t, 1H), 2.63 (t, 1H).

LC-MS (method 2): Rt = 0.46 min; MS (ESI positive): m/z = 297.1 [M+H]+.

Intermediate 5-7.

N(2,3-dichlorophenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

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

1H-NMR (400 MHz, DMSO^): 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), .352 (5.82), 16.503 (1.11).

LC-MS (method 2): R _t = 0.55 min; MS (ESI positive): m/z = 316 [MH] ^- .

Intermediate 5-10.

N(3-chloro-2-methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

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

1H-NMR (400 MHz, DMSO^): δ [ppm] = 16.42 (d, 1H), 14.01 - 14.37 (m, 1H), 8.14 - 9.40 (m, 1H), 7.43 (br t, 1H ), 7.16 - 7.32 (m, 2H), 3.42 - 3.48 (m, 1H), 3.26 -3.34 (m, 1H), 2.78 (t, 1H), 2.60 - 2.68 (m, 1H), 2.12 2.21 (m, 3H).

LC-MS (method 2): R _t = 0.60 min; MS (ESI positive): m/z = 297.4 [M+H] ⁺ .

Intermediate 5-18.

No.(3-chloro-5-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

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

1H-NMR (400 MHz, DMSO^): δ [ppm] = 2.61 - 2.70 (m, 1H), 2.80 (m, 1H), 3.25 - 3.32 (m, 1H), 3.38 3.47 (m, 1H ), 3.74 (s, 3H), 7.39 - 7.62 (m, 1H), 7.83 - 8.02 (m, 1H), 8.20 - 8.33 (s, 0.5H), 9.33 - 9.57 (s, 0.5H), 14.53 (s, 0.5H), 14.93 (s, 0.5H), 16.29 (s, 0.5H), 16.36 (s, 0.5H).

LC-MS (method 2): Rt = 0.57 min; MS (ESI negative): m/z = 329 [MH] ^- .

- 50 046642

Intermediate 5-29.

N(3-chloro-2-ethylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

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

¹ H-NMR (400 MHz, DMSO-06): δ [ppm] = 1.048 (7.06), 1.067 (16.00), 1.086 (7.43), 1.107 (1.58), 1.124 (1.32), 1.143 (0.50) , 1.154 (1.34), 1.172 (2.43), 1.190 (1.24), 1.232 (0.50), 1.988 (4.56), 2.318 (0.47), 2.323 (1.05), 2.327 (1.56), 2.332 (1.11), 2.336 (0.47) , 2.518 (5.61), 2.523 (4.03), 2.581 (2.03), 2.600 (6.41), 2.619 (6.62), 2.642 (4.59), 2.661 (2.69), 2.669 (1.90), 2.673 (1.27), 2.678 (0.58) , 2.771 (2.35), 2.789 (4.82),2.807 (2.58), 3.287 (1.61), 3.294 (1.79), 3.305 (3.11), 3.312 (3.14), 3.323 (2.06), 3.330 (2.35), 3.415 (1.53) ,3.422 (1.66), 3.433 (2.56), 3.441 (2.45), 3.452 (1.40), 3.459 (1.24), 4.017 (1.03), 4.035 (1.00), 7.166 (0.95), 7.176 (0.58), 7.179 (0.58) , 7.248 (0.71), 7.259 (6.30), 7.268 (3.58), 7.275 (4.43), 7.287 (7.20), 7.294 (3.90), 7.303 (3.56), 7.324 (0.87), 7.392 (1.85), 7.400 (1.37) , 7.407 (1.85), 7.415 (1.74), 7.419 (2.40), 7.426 (1.77), 7.436 (1.77), 7.443 (1.45), 8.174 (1.77), 9.335 (1.42), 14.111 (2.98), 14.452 (2.74) , 16.428 (7.88), 16.441 (7.38).

LC-MS (method 6): Rt = 1.28 min; MS (ESI positive): m/z = 311 [M+H]+.

Intermediate 5-38.

N(3-fluoro-2-methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

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

¹ H-NMR (400 MHz, DMSO-06): δ [ppm] = 1.172 (0.55), 1.987 (1.05), 2.063 (16.00), 2.518 (1.49), 2.523 (1.01), 2.612 (1.94) , 2.631 (3.67), 2.649 (2.11), 2.761 (1.99), 2.779 (4.22), 2.798 (2.26), 3.280 (1.36), 3.287 (1.47), 3.298 (2.58), 3.305 (2.57), 3.315 (1.39) , 3.322 (1.33), 3.410 (1.40), 3.417 (1.48), 3.428 (2.27), 3.435 (2.22), 3.446 (1.27), 3.454 (1.15), 7.112 (1.56), 7.119 (0.96), 7.132 (2.25) , 7.141 (3.30), 7.161 (2.66),7.168 (2.15), 7.192 (1.12), 7.243 (0.73), 7.262 (1.15), 7.272 (0.99), 7.279 (1.25), 7.292 (1.27), 7.308 (1.21) ,7.328 (0.45), 8.150 (1.43), 9.317 (1.16), 14.003 (2.32), 14.321 (2.05), 16.439 (5.35), 16.468 (4.62).

LC-MS (method 2): Rt = 0.47 min; MS (ESI positive): m/z = 281 [M+H]+.

Intermediate 5-40.

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

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

¹ H-NMR (400 MHz, DMSO-06): δ [ppm] = 1.145 (0.50), 1.154 (1.98), 1.172 (3.87), 1.190 (1.88), 1.441 (0.60), 1.987 (7.01) 2.323 (1.39), 2.327 (1.98), 2.332 (1.39), 2.518 (8.20), 2.523 (5.52), 2.617 (6.21), 2.635 (11.74), 2.653 (7.04), 2.665 (3.21), 2.669 (3.14) , 2.673 (2.21), 2.769 (5.92), 2.786 (10.81), 2.803 (6.18), 3.059 (7.57), 3.067 (7.93), 3.104 (15.40), 3.111 (15.40), 3.148 (7.93), 3.307 (9.3 6) 3.434 (8.96), 4.000 (0.56), 4.017 (1.65), 4.035 (1.65), 4.053 (0.53), 6.057 (3.27), 6.067 (6.55), 6.077 (2.98), 6.198 (6.18), 6.208 (13.09) , 6.217 (6.12), 6.339 (2.81), 6.348 (6.12), 6.358 (3.01), 7.165 (5.62), 7.185 (7.24), 7.207 (6.64), 7.227 (8.53), 7.242 (9.39), 7.265 (9.26) , 7.288 (3.31), 7.393 (2.38), 7.413 (5.55), 7.430 (6.51), 7.459 (4.53), 7.479 (1.45), 8.152 (5.29), 9.352 (4.96), 14.013 (9.02), 14.389 (7.90 ) , 16.346 (15.47), 16.353 (16.00).

LC-MS (method 2): Rt = 0.48 min; MS (ESI positive): m/z = 331.1 [M+H]+.

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Intermediate 5-65.

N(2-ethyl-3-fluorophenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

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

Ή-NMR (400 MHz, DMSO-d^delta [ppm]: 1.052 (6.61), 1.071 (16.00), 1.089 (6.75), 1.116 (0.56), 1.224 (4.60), 1.734 (1.58), 2.326 (0.43), 2.472 (1.56), 2.518 (2.10), 2.523 (1.69), 2.647 (0.85), 2.659 (0.85), 2.664 (0.98), 2.668 (1.03), 2.673 (0.80), 2.782 (0.89), 3.423 (0.82), 4.037 (0.62), 7.160 (2.35), 7.288 (0.98), 8.170 (0.48), 14.073 (0.46), 14.414 (0.52).

LC-MS (method 6): Rt = 1.18 min; MS (ESI positive): m/z = 295 [M+H]+.

Syntheses of intermediates 6.

Intermediate 6-1.

No.(3-chloro-2-methoxyphenyl)-4-[({3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2-oxo1,2,5 ,6-tetrahydropyridine-3-carbothioamide

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

Ή-NMR (400 MHz, DMSO-d^: δ [ppm] = 14.79 (s, 1H), 13.69 (t, 1H), 8.39 (s, 1H), 8.24 (d, 1H), 7.81 ( dd, 1H), 7.73 (s, 1H), 7.26 - 7.33 (m, 2H), 7.11 (t, 1H), 4.67 (d, 2H), 4.16 (t, 2H), 3.84 - 3.95 (m, 2H) , 3.74 3.79 (m, 1H), 3.71 (s, 3H), 3.59 -3.70 (m, 2H), 3.45 - 3.54 (m, 2H), 3.11 - 3.20 (m, 2H), 2.78 (t, 2H).

LC-MS (method 2): Rt = 1.07 min; MS (ESI positive): m/z = 519.2 [M+H]+.

Intermediate 6-2.

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

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

Ή-NMR (400 MHz, DMSO-b6): δ [ppm] = 2.78 (t, 2H), 3.16 (td, 2H), 3.40 -3.54 (m, 3H), 3.59 - 3.69 (m, 2H ), 3.71 (s, 3H), 3.73 - 3.79 (m, 1H), 3.83 - 3.95 (m, 2H), 4.16 (t, 2H), 4.67 (d, 2H), 7.11 (t, 1H), 7.27 - 7.33 (m, 2H), 7.73 (br s, 1H), 7.81 (dd, 1H), 8.24 (d, 1H), 8.39 (s, 1H), 13.69 (s, 1H), 14.79 (s, 1H).

LC-MS (method 2): Rt = 1.09 min; MS (ESI positive): m/z = 519 [M+H]+.

Intermediate 6-4.

4-[({3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methyl)amino]X-(3-fluoro-2-methoxyphenyl)-2-oxo1,2,5 ,6-tetrahydropyridine-3-carbothioamide

- 52 046642

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

¹ H-NMR (400 MHz, DMSO^ ₆ ): δ [ppm] = 14.74 (s, 1H), 13.70 (br t, 1H), 8.39 (s, 1H), 8.24 (d, 1H), 7.64 7.73 (m, 2H), 7.30 (d, 1H), 7.02 - 7.14 (m, 2H), 4.67 (d, 2H), 4.13 - 4.21 (m, 2H), 3.84 - 3.95 (m, 2H), 3.59 3.77 (m, 4H), 3.40 - 3.53 (m, 2H), 3.13 - 3.22 (m, 2H), 2.68 - 2.80 (m, 2H), 1.59 (br s, 1H), 0.93 - 1.39 (m, 1H) .

LC-MS (method 2): R _t = 1.01 min; MC (ESI positive): m/z = 503 [M+H]+.

Intermediate 6-7.

N(2,3-dichlorophenyl)-4-[({3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methyl)amino)]-2-oxo1,2,5, 6-tetrahydropyridine-3-carbothioamide

C.I.

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

¹ H-NMR (400 MHz, DMSO-06): δ [ppm] = 14.90 (s, 1h), 13.66 (t, 1H), 8.39 (s, 1H), 8.24 (d, 1H), 7.75 (br s, 1H), 7.55 (dd, 1H), 7.51 (dd, 1H), 7.28 - 7.38 (m, 3H), 4.68 (d, 3H), 4.14 - 4.21 (m, 2H), 3.87 - 3.90 ( m, 1H),

3.72 - 3.76 (m, 1H), 3.64 - 3.67 (m, 1H), 3.58 - 3.63 (m, 1H), 3.35 - 3.53 (m, 3H), 2.79 (t, 2H).

LC-MS (method 2): Rt = 1.08 min; MS (ESI positive): m/z = 523 [M+H]+.

Intermediate 6-10.

№(3-chloro-2-methylphenyl)-4-[({3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2-oxo1,2,5 ,6-tetrahydropyridine-3-carbothioamide

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

1H-NMR (400 MHz, DMSO-06): δ [ppm] = 14.54 (s, 1H), 13.64 (br t, 1H), 8.38 (s, 1H), 8.24 (d, 1H), 7.69 (br s, 1H), 7.28 - 7.37 (m, 2H), 7.13 - 7.26 (m, 2H), 4.65 (d, 2H), 4.14 - 4.20 (m, 2H), 3.74 - 3.88 (m, 3H), 3.63 3.71 (m, 2H), 3.42 - 3.53 (m, 2H), 3.14 - 3.31 (m, 2H), 2.77 (t, 2H), 2.16 (s, 3H).

LC-MS (method 2): Rt = 1.09 min; MS (ESI positive): m/z = 501 [M+H]+.

- 53 046642

Intermediate 6-11.

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

Using a method similar to that described for intermediate 6-1, with N-(3-χλορ-2methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-1 , 142 mg, 407 µmol) and 1-(3-{[(3R)-4-methylmoρφolin-3-yl]methoxy}pipidin-4yl)methanamine (intermediate 2-2, 116 mg, 489 µmol) as starting materials substances, 85.6 mg (yield 36%) of the title compound was obtained after heating for 3 hours and purification using preparative HPLC (method 10, gradient: 0.00 - 0.50 min 30% B, 0.50 - 6.00 min 30 70% B).

¹ H-NMR (400 MHz, DMSO-66): δ [ppm] = 14.79 (s, 1H), 13.67 (br t, 1H), 8.41 (s, 1H), 8.24 (d, 1H), 7.81 (dd, 1H), 7.73 (br s, 1H), 7.28 - 7.33 (m, 2H), 7.11 (t, 1H), 4.67 (br d, 2H), 4.31 (dd, 1H), 4.05 (dd, 1H), 3.90 (dd, 1H), 3.67 - 3.73 (m, 4H), 3.50 (td, 1H), 3.34 - 3.40 (m, 1H), 3.13 - 3.21 (m, 2H), 2.79 (t, 2H) , 2.63 - 2.70 (m, 1H), 2.19 - 2.33 (m, 4H), 1.46 - 1.76 (m, 1H).

LC-MS (method 2): R _t = 1.08 min; MS (ESI positive): m/z = 532.5 [M+H]+.

Intermediate 6-12.

N(3-fluoro-2-methoxyphenyl)-4-(((3-hydroxypyridin-4-yl)methyl)amino)-2-oxo-1,2,5,6tetrahydropyridine-3-carbothioamide

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

1H-NMR (400 MHz, DMSOO: δ [ppm] = 14.73 (s, 1H), 13.69 (t, 1H), 10.28 (s, 1H), 8.21-8.13 (m, 2H), 7.67-7.66 (m, 2H), 7.10 (br.s, 1H), 7.09-7.04 (m, 2H), 4.61 (d, 2H), 3.79 (s, 3H), 3.16 (t, 2H), 2.77 (t, 2H ).

Intermediate 6-15.

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

Using a method similar to that described for intermediate 6-1, with N-(3-φτορ-2methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-4 , 100 mg, 320 µmol) and 1-(3-{[4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)methanamine

- 54 046642 (intermediate 2-3, 114 mg, 480 µmol) as starting materials, 74.3 mg (80% purity, 35% yield) of the title compound were obtained after heating for 4 hours and purification by flash chromatography (amino phase silica gel, DCM/EtOH, gradient 0-10%).

1H-NMR (400 MHz, DMSO-06) δ [ppm]: 1.880 (0.45), 2.176 (4.07), 2.186 (0.73), 2.191 (0.45), 2.518 (1.66), 2.523 (1.13), 2.787 (0.65), 2.799 (0.61), 3.162 (0.56), 3.169 (0.54), 3.533 (0.46), 3.539 (0.45), 3.711 (9.24), 3.819 (0.47), 3.823 (0.40), 4.149 (0.65), 4.161 (1.12), 4.176 (0.61), 4.655 (0.80), 4.670 (0.82),5.759 (16.00), 7.086 (0.63), 7.107 (1.27), 7.127 (0.73), 7.283 (0.77), 7.287 (0.81), 7.302 (0.77), 7.306 (1.39),7.318 (0.80), 7.723 (0.53), 7.803 (0.59), 7.806 (0.60), 7.823 (0.57), 7.827 (0.53), 8.234 (1.27), 8.246 (1.26),8.392 (1.87), 14.791 (1.01).

LC-MS (method 2): Rt = 0.84 min; MS (ESI positive): m/z = 532 [M+H]+.

Intermediate 6-18.

^(3-chloro-5-fluoro-2-methoxyphenyl)-4-[({3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4yl}methyl)amino]-2-oxo-1,2 ,5,6-tetrahydropyridine-3-carbothioamide

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

¹ H-NMR (400 MHz, DMSO-a ₆ ): δ [ppm] = 1.881 (0.59), 1.908 (0.51), 1.984 (0.51), 1.991 (0.55), 2.174 (5.75), 2.185 (0.88 ), 2.191 (2.53), 2.518 (2.46), 2.523 (1.65), 2.581 (0.55), 2.609 (0.49), 2.785 (0.52), 2.798 (0.96), 2.815 (0.60), 3.096 (0.44), 3.161 (0.55 ), 3.168 (0.51), 3.387 (0.97), 3.535 (0.57), 3.542 (0.68), 3.700 (7.75), 3.786 (0.69), 3.791 (0.73), 3.795 (0.71), 3.810 (0.63), 3.815 (0.70 ), 3.823 (0.75), 4.115 (0.52),4.119 (0.55), 4.128 (0.53), 4.154 (0.77), 4.166 (0.94), 4.181 (0.60), 4.672 (0.76), 4.687 (0.77), 5.759 (16.00 ), 7.267 (0.58), 7.275 (0.65), 7.287 (0.58), 7.295 (0.63), 7.313 (0.77), 7.325 (0.74), 7.792 (0.49), 8.046 (0.50), 8.053 (0.50), 8.073 (0.47 ), 8.080 (0.47), 8.238 (1.20), 8.250 (1.12), 8.267 (0.55), 8.279 (0.66), 8.399 (1.72), 15.080 (0.94).

LC-MS (method 2): Rt = 1.11 min; MS (ESI positive): m/z = 550 [M+H] ⁺ .

Intermediate 6-19.

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

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

1H-NMR (400 MHz, DMSO-de) δ [ppm]: 0.821 (0.41), 0.904 (0.45), 1.035 (8.84), 1.052 (16.00), 1.070 (9.56), 1.154 (1.90), 1.172 (3.66), 1.189 (1.72), 1.987 (6.85), 2.518 (1.36), 2.522 (0.92), 2.790 (0.61), 3.157 (0.42), 3.404 (1.39), 3.417 (1.49), 3.421 (4.01), 3.434 (4.35), 3.439 (4.40), 3.452 (4.43), 3.457 (1.21), 3.461 (0.53), 3.469 (1.28), 3.501 (0.40), 3.652 (0.66), 3.655 (0.65), 3.702 (7.42), 3.750 (0.43), 3.785 (0.67),3.788 (0.43), 3.890 (0.58), 3.999 (0.46), 4.017 (1.36), 4.035 (1.39), 4.053 (0.47), 4.156 (0.56), 4.165 (0.77),4.179 (0.54), 4.343 (2.52), 4.356 (4.91), 4.368 (2.35), 4.683 (0.68), 4.697 (0.68), 7.272 (0.48), 7.280 (0.60),7.293

- 55 046642 (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 (0.9 8 ), 8.254 (0.94), 8.394 (1.43), 15.078 (0.82).

LC-MS (method 2): R _t = 1.14 min; MS (ESI positive): m/z = 537 [M+H]+.

Intermediate 6-20.

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

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

¹ H-NMR (400 MHz, DMSO-66): δ [ppm] = 2.195 (0.50), 2.203 (0.62), 2.221 (0.73), 2.224 (0.80), 2.229 (0.79), 2.232 (0.77) , 2.250 (0.69), 2.258 (0.63), 2.287 (16.00), 2.322 (0.48), 2.326 (0.65), 2.331 (0.46), 2.518 (2.86), 2.522 (1.80), 2.645 (0.60), 2.651 (1.24) , 2.658 (0.75), 2.664 (0.58), 2.668 (0.75), 2.673 (0.96), 2.680 (1.16), 2.687 (0.56), 2.760 (1.14), 2.776 (2.31), 2.793 (1.34), 3.134 (0.86) , 3.142 (0.98), 3.152 (1.59),3.158 (1.51), 3.167 (0.87), 3.175 (0.73), 3.347 (1.31), 3.371 (1.26), 3.375 (1.37), 3.398 (1.19), 3.473 (0.50) ,3.480 (0.60), 3.501 (0.98), 3.507 (0.98), 3.527 (0.72), 3.533 (0.60), 3.677 (0.56), 3.683 (1.07), 3.690 (0.58), 3.704 (0.46), 3.711 (0.82) , 3.718 (0.41), 3.780 (13.85), 3.783 (13.72), 3.884 (0.99), 3.892 (0.99), 3.912 (0.89), 3.920 (0.88), 4.029 (0.98), 4.044 (1.01), 4.054 (1.17 ) , 4.070 (1.12), 4.291 (1.18), 4.302 (1.21), 4.317 (1.03),4.327 (0.97), 4.658 (1.87), 4.674 (1.89), 7.044 (0.58), 7.049 (1.31), 7.065 (1.59) , 7.069 (2.63), 7.075 (1.64),7.085 (1.41), 7.090 (0.58), 7.096 (1.44), 7.101 (1.44), 7.117 (0.56), 7.122 (0.41), 7.296 (2.20), 7.308 (2.24) , 7.653 (1.44), 7.658 (0.89), 7.670 (1.15), 7.676 (0.86), 7.704 (1.58), 8.236 (3.27), 8.247 (3.17), 8.411 (4.92), 13.661 (0.56), 13.676 (1.10) , 13.690 (0.53), 14.736 (2.92).

LC-MS (method 6): R _t = 0.62 min; MS (ESI positive): m/z = 516 [M+H]+.

Intermediate 6-21.

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

Using a method similar to that described for intermediate 6-1, with N-(3-χλορ-2methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-1 , 200 mg, 639 µmol) and 1-(3-{[^)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)methanamine (intermediate 2-4, 197 mg, 831 µmol) as starting materials, 102 mg (purity 99%, yield 30%) of the title compound were obtained after heating for 3 hours at 120°C and purification by preparative HPLC (method 10, gradient: 0.00 - 0.50 min 15% B, 0.50 - 6.00 min 15 - 55% B).

¹ H-NMR (400 MHz, DMSO-66) δ [ppm]: 2.288 (3.78), 2.327 (0.47), 2.518 (1.87), 2.523 (1.27), 2.651 (0.43), 2.665 (0.45), 2.669 (0.59), 2.673 (0.55), 2.679 (0.47), 2.769 (0.69), 2.786 (1.40), 2.803 (0.81), 3.141 (0.53), 3.148 (0.61), 3.157 (0.97), 3.164 (0.93), 3.174 (0.53), 3.181 (0.44), 3.346 (0.55), 3.372 (0.52), 3.506 (0.45), 3.684 (0.50), 3.712 (16.00), 3.883 (0.44), 3.891 (0.53), 3.912 (0.42), 4.293 (0.54), 4.304 (0.56), 4.319 (0.47), 4.329 (0.44), 4.663 (1.08), 4.679 (1.10), 7.088 (1.04), 7.108 (2.24), 7.128 (1.28), 7.285 (1.42), 7.289 (1.49), 7.301 (1.47), 7.305 (1.46), 7.309 (1.44), 7.312 (1.47), 7.726 (0.92), 7.794 (1.07), 7.797 (1.08), 7.814

- 56 046642 (1.02), 7.818 (0.96), 8.238 (1.81), 8.250 (1.65), 8.413 (3.11), 13.667 (0.68), 14.787 (1.82).

LC-MS (method 6): R _t = 0.68 min; MS (ESI positive): m/z = 532 [M+H]+.

Intermediate 6-22.

tert-butyl DO)-2-[({4-[({5-[(3-fluoro-2-methoxyphenyl)carbamothioyl]-6-oxo-1,2,3,6tetrahydropyridin-4-yl}amino)methyl ]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate

Using a method similar to that described for intermediate 6-1, with N(3-fluoro-2methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-4, 1.00 g, 3.37 mmol) and tert-butyl (2S)-2-({[4-(aminomethyl)pyridin-3yl]oxy}methyl)morpholine-4-carboxylate (intermediate 2-5, 1.53 g, 4.72 mmol) As starting materials, 1.43 g (purity 70%, yield 49%) of the title compound were obtained after heating for 6 h and purification by flash chromatography (silica gel, DCM/EtOH, gradient 0-20%).

¹ H-NMR (400 MHz, DMSO-06): δ [ppm] = 1.035 (6.69), 1.052 (16.00), 1.070 (7.70), 1.394 (4.63), 1.401 (2.39), 1.405 (3.46) , 2.331 (0.41), 2.518 (1.92), 2.523 (1.41), 2.673 (0.42), 3.404 (1.10), 3.417 (1.21), 3.422 (3.66), 3.435 (3.78), 3.440 (3.26), 3.452 (3.33) , 3.457 (1.19), 3.469 (1.18), 3.780 (2.11), 3.782 (2.08), 3.797 (0.42), 3.857 (0.84), 3.860 (0.83), 4.219 (0.41), 4.231 (0.42), 4.344 (2.52) , 4.356 (4.87), 4.369 (2.35), 8.241 (0.54), 8.253 (0.53), 8.402 (0.81), 14.735 (0.40).

LC-MS (method 2): Rt = 1.19 min; MS (ESI positive): m/z = 602 [M+H] ⁺ .

Intermediate 6-24.

N(3-chloro-2-methoxyphenyl)-4-[({3-[2-(1,4-dioxan-2-yl)ethoxy]pyridin-4-yl}methyl)amino]-2-oxo1,2 ,5,6-tetrahydropyridine-3-carbothioamide

Using a method similar to that described for intermediate 6-1, with N-(3-χλορ-2methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-1 , 200 mg, 639 µmol) and 1-(3-{2-[1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)methanamine (intermediate 2-6, 198 mg, 831 µmol) in as starting materials, 110 mg (purity 96%, yield

31%) of the title compound was obtained after heating for 3 hours at 130°C and purification using preparative HPLC (method 10, gradient: 0.00 - 0.50 min 15% B, 0.50 - 6.00 min 15 - 55% B).

¹ H-NMR (400 MHz, DMSO-06) δ [ppm]: 1.792 (0.45), 1.812 (0.43), 1.838 (0.40), 1.850 (0.42), 2.518 (1.13), 2.523 (0.78), 2.763 (0.87), 2.771 (0.86), 2.780 (0.52), 2.786 (0.47), 3.140 (0.51), 3.148 (0.57), 3.156 (0.97), 3.164 (0.96), 3.173 (0.50), 3.181 (0.43), 3.197 (0.60), 3.224 (0.94), 3.227 (0.95), 3.253 (0.64), 3.445 (0.75), 3.452 (0.83), 3.471 (0.48), 3.480 (0.60), 3.545 (0.45), 3.551 (0.53), 3.573 (0.70), 3.580 (0.81), 3.605 (0.86), 3.611 (1.14), 3.617 (0.53), 3.638 (0.55), 3.644 (0.47), 3.689 (0.92), 3.697 (1.10), 3.712 (16.00), 3.718 (2.12), 3.744 (0.88), 3.749 (0.65), 4.203 (0.84), 4.219 (1.35), 4.232 (0.58), 4.238 (0.56), 4.656 (1.44), 4.670 (1.43), 7.089 (1.01), 7.110 (2.16), 7.130 (1.25), 7.286 (1.37), 7.289 (1.46), 7.306 (2.13), 7.310 (1.42),7.317 (1.10), 7.726 (0.93), 7.802 (1.03), 7.806 (1.05), 7.823 (0.99), 7.826 (0.93), 8.225 (1.23), 8.237 (1.18), 8.373 (1.98), 13.695 (0.65), 14.792 (1.75).

LC-MS (method 6): R _t = 0.90 min; MS (ESI positive): m/z = 533 [M+H] ⁺ .

Intermediate 6-27.

tert-butyl (28)-2-[({4-[({5-[(3-chloro-5-fluoro-2-methoxyphenyl)carbamothioyl]-6-oxo-1,2,3,6

- 57 046642 tetrahydropyridin-4-yl}amino)methyl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate

Using a method similar to that described for intermediate 6-1, with N-(3-χλορ-5fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate compound 5-18, 225 mg, 680 µmol) and tert-butyl ^)-2-({[4-(aminomethyl)pyridin-3yl]oxy}methyl)morpholine-4-carboxylate (intermediate 2-5, 308 mg , 952 µmol) as starting materials, 150 mg (80% purity, 28% yield) of the title compound were obtained after heating for 6 h and purification by flash chromatography (silica gel, DCM/EtOH, 0-20% gradient ).

¹ H-NMR (400 MHz, DMSO-a ₆ ) δ [ppm]: 1.035 (2.70), 1.052 (5.86), 1.070 (3.02), 1.232 (0.46), 1.389 (16.00), 1.405 (6.16) , 1.419 (1.21), 2.331 (0.75), 2.430 (0.47), 2.447 (0.51), 2.518 (3.46), 2.523 (2.53), 2.673 (0.75), 2.772 (0.61), 2.789 (1.14), 2.805 (0.74) , 3.137 (0.46), 3.145 (0.53), 3.154 (0.79), 3.161 (0.75), 3.405 (0.58), 3.417 (0.72), 3.422 (1.54), 3.435 (1.70), 3.440 (1.70), 3.445 (0.63) , 3.452 (1.56), 3.457 (0.61),3.469 (0.63), 3.655 (0.79), 3.699 (12.68), 3.719 (0.53), 3.732 (0.75), 3.738 (0.84), 3.757 (0.49), 3.764 (0.44) , 3.787 (2.07), 3.821 (0.49), 3.842 (0.93), 3.870 (0.40), 4.225 (1.58), 4.237 (1.60), 4.344 (0.84), 4.357 (1.63), 4.370 (0.82), 4.681 (1.14) , 4.696 (1.11), 5.759 (0.75), 7.267 (0.93), 7.275 (1.12), 7.287 (0.96), 7.295 (1.05), 7.311 (0.79), 7.323 (0.79), 7.799 (0.77), 8.031 (0.67) , 8.038 (0.68), 8.057 (0.67), 8.065 (0.63), 8.245 (1.81), 8.257 (1.63), 8.290 (0.54), 8.410 (2.60), 13.671 (0.58), 15.074 (1.58).

LC-MS (method 2): R _t = 1.30 min; MS (ESI positive): m/z = 636 [M+H]+.

Intermediate 6-29.

N(3-chloro-2-ethylphenyl)-4-[({3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2oxo-1,2,5,6 -tetrahydropyridine-3-carbothioamide n

Using a method similar to that described for intermediate 6-1, with N-(3-χλορ-2ethylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-29 , 300 mg, 965 µmol) and 1-(3-{[4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)methanamine (intermediate 2-3, 321 mg, 1.35 mmol) as starting materials, 300 mg (80% purity, 47% yield) of the title compound were obtained after heating for 6 h and purification by flash chromatography (silica gel, DCM/EtOH, 0-20% gradient).

¹ H-NMR (400 MHz, DMSO-a ₆ ): δ [ppm] = 0.798 (0.84), 0.814 (0.93), 0.821 (0.93), 0.840 (0.43), 0.886 (0.53), 0.904 (1.07 ), 0.922 (0.50), 1.035 (9.51), 1.052 (16.00), 1.066 (1.09), 1.070 (9.08), 1.073 (1.50), 1.232 (0.45), 1.874 (0.59), 1.901 (0.47), 1.907 (0.59 ), 1.983 (0.41), 1.990 (0.52), 2.178 (5.56), 2.195 (1.38), 2.202 (0.47), 2.331 (0.74), 2.518 (3.86), 2.522 (2.50), 2.580 (0.57), 2.591 (1.05 ), 2.610 (1.21), 2.673 (0.95), 2.784 (0.95), 2.817 (0.50), 3.162 (0.41), 3.172 (0.69), 3.179 (0.65), 3.404 (1.33), 3.417 (1.38), 3.421 (3.41 ),3.434 (3.43), 3.439 (3.91), 3.452 (4.01), 3.457 (1.15), 3.469 (1.19), 3.529 (0.57), 3.535 (0.57), 3.735 (0.55), 3.784 (0.47), 3.788 (0.47 ), 3.792 (0.47), 3.812 (0.64), 3.816 (0.62), 4.111 (0.41), 4.123 (0.48), 4.138 (0.83), 4.149 (0.83), 4.154 (0.88), 4.168 (0.74), 4.343 (2.64 ), 4.356 (5.06), 4.368 (2.39), 4.636 (0.93), 4.651 (0.93),7.205 (1.50), 7.208 (1.38), 7.218 (2.69), 7.296 (1.02), 7.305 (1.02), 7.308 (1.05 ), 7.315 (1.17), 7.327 (0.55), 7.701 (0.64), 8.228 (1.50), 8.240 (1.38), 8.282 (0.47), 8.385 (2.07), 13.654 (0.43), 14.636 (1.17).

LC-MS (method 2): R _t = 1.14 min; MS (ESI positive): m/z = 530 [M+H] ⁺ .

Intermediate 6-30.

No.(3-chloro-2-methoxyphenyl)-4-[({3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridin-4yl}methyl)amino]-2-oxo -1,2,5,6-tetrahydropyridine-3-carbothioamide

- 58 046642

Using a method similar to that described for intermediate 6-1, with N-(3-χΛορ-2methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-1 , 200 mg, 639 µmol) and 1-{3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridin-4yl}methanamine (intermediate 2-7, 210 mg, 831 µmol ) as starting materials, 55.0 mg (purity 98%, yield 15%) of the title compound was obtained after heating for 3 h at 130°C and purification by preparative HPLC (method 10, gradient: 0.00 - 0.50 min 15% B, 0.50 - 6.00 min 15 - 55% B).

¹ H-NMR (400 MHz, DMSO-66): δ [ppm] = 1.042 (9.29), 1.249 (8.31), 2.518 (2.85), 2.523 (1.83), 2.752 (0.79), 2.768 (1.57) , 2.785 (0.95), 3.147 (0.74), 3.156 (1.18), 3.164 (1.13), 3.299 (1.11), 3.533 (1.90), 3.562 (1.50), 3.628 (0.50), 3.648 (1.21), 3.658 (1.28) , 3.667 (1.26), 3.691 (1.55), 3.713 (16.00), 3.720 (1.14), 3.795 (0.51), 3.806 (0.64), 3.817 (0.52), 4.154 (0.42), 4.164 (0.43), 4.180 (1.25) , 4.191 (1.23), 4.198 (1.31),4.212 (1.18), 4.225 (0.43), 4.663 (1.86), 4.678 (1.86), 7.088 (1.13), 7.108 (2.42), 7.128 (1.39), 7.286 (1.58) ,7.290 (1.68), 7.305 (2.17), 7.310 (1.58), 7.316 (1.59), 7.729 (1.16), 7.799 (1.26), 7.803 (1.27), 7.819 (1.18), 7.823 (1.14), 8.241 (1.91) , 8.253 (1.81), 8.397 (3.02), 13.669 (0.43), 13.683 (0.81), 14.792 (2.17).

LC-MS (method 6): Rt = 1.04 min; MS (ESI positive): m/z = 547 [M+H]+.

Intermediate 6-33.

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

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

¹ H-NMR (400 MHz, DMSO-66) δ [ppm]: 1.043 (15.59), 1.251 (13.74), 2.518 (2.60), 2.523 (1.78), 2.742 (1.25), 2.759 (2.52), 2.775 (1.52), 3.134 (1.00), 3.142 (1.15), 3.152 (1.86), 3.158 (1.79), 3.167 (1.02), 3.175 (0.86), 3.300 (1.91), 3.535 (3.14), 3.563 (2.56), 3.622 (0.60), 3.630 (0.81), 3.650 (1.97), 3.659 (2.07), 3.668 (2.14), 3.692 (2.45), 3.722 (1.19), 3.782 (15.81), 3.785 (16.00), 3.796 (0.91), 3.808 (1.03), 3.819 (0.82), 3.832 (0.62), 4.155 (0.57), 4.165 (0.61), 4.181 (1.80), 4.192 (1.83), 4.198 (1.91), 4.212 (1.68), 4.225 (0.61), 4.238 (0.55), 4.658 (2.20), 4.672 (2.17), 7.029 (0.54), 7.045 (0.69), 7.050 (1.65), 7.065 (1.84), 7.069 (2.29), 7.071 (2.14), 7.077 (2.06), 7.085 (1.65), 7.093 (0.69), 7.098 (1.72), 7.103 (1.74), 7.119 (0.69), 7.124 (0.54), 7.307 (0.94), 7.317 (0.99), 7.657 (1.74), 7.662 (1.08), 7.676 (1.36), 7.681 (1.03), 7.708 (1.84), 8.254 (0.72), 8.404 (0.81), 13.678 (0.65), 13.693 (1.25), 13.707 (0.60), 14.741 (3.47).

LC-MS (method 6): Rt = 0.94 min; MS (ESI positive): m/z = 531 [M+H] ⁺ .

Intermediate 6-35.

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

- 59 046642

Using a method similar to that described for intermediate 6-1, with N-(3-φτορ-2methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-4 , 200 mg, 675 µmol) and 1-(3-{2-[1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)methanamine (intermediate 2-6, 209 mg, 877 µmol) in as starting materials, 137 mg was obtained (purity

96%, yield 38%) of the title compound.

LC-MS (method 6): Rt = 0.83 min; MS (ESI positive): m/z = 517 [M+H]+.

¹ H-NMR (400 MHz, DMSO-06) δ [ppm]: 1.757 (0.42), 1.778 (0.61), 1.793 (0.89), 1.813 (0.86), 1.822 (0.55), 1.826 (0.49), 1.833 (0.54), 1.840 (0.80), 1.852 (0.85), 1.857 (0.64), 1.868 (0.60), 2.518 (2.52), 2.523 (1.61), 2.674 (0.45), 2.735 (0.74), 2.752 (1.68), 2.761 (1.69), 2.769 (1.02), 2.777 (0.89), 3.134 (1.00), 3.142 (1.11), 3.151 (1.92), 3.159 (1.89), 3.168 (0.98), 3.175 (0.85), 3.198 (1.19), 3.224 (1.91), 3.228 (1.91),3.254 (1.24), 3.421 (0.47), 3.425 (0.68), 3.446 (1.52), 3.453 (1.67), 3.472 (0.99), 3.481 (1.19), 3.545 (0.92), 3.552 (1.09), 3.574 (1.39), 3.580 (1.60), 3.606 (1.73), 3.612 (2.26), 3.618 (1.04), 3.639 (1.07), 3.645 (0.93), 3.690 (1.77), 3.697 (2.11), 3.709 (0.79), 3.719 (3.54), 3.728 (1.41), 3.735 (0.73), 3.744 (1.71), 3.751 (1.33), 3.782 (15.79), 3.784 (16.00), 4.203 (1.78), 4.219 (2.73), 4.232 (1.20), 4.237 (1.18), 4.653 (2.89), 4.667 (2.88), 7.030 (0.49), 7.046 (0.68), 7.051 (1.63), 7.067 (1.82), 7.070 (3.31), 7.077 (2.11), 7.086 (1.65), 7.092 (0.71), 7.098 (1.72), 7.103 (1.73), 7.119 (0.68), 7.124 (0.52), 7.303 (1.99), 7.314 (2.03), 7.660 (1.68), 7.665 (1.06), 7.677 (1.35), 7.683 (1.07), 7.703 (1.84), 8.226 (1.84), 8.237 (1.79), 8.373 (2.98), 13.689 (0.64), 13.704 (1.28), 13.718 (0.60), 14.740 (3.42 ).

Intermediate 6-37.

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

Using a method similar to that described for intermediate 6-1, with N(3-fluoro-2methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-4, 200 mg, 675 µmol) and 1-(3-{[(3R)-4-methylmoρφolin-3-yl]methoxy}pipidin-4yl)methanamine (intermediate 2-2, 224 mg, 945 µmol) as starting materials , 134 mg (yield 38%) of the title compound were obtained after heating for 1 hour at 124°C and purification by preparative HPLC (method 10, gradient: 0.00 - 0.50 min 15% B, 0.50 - 6.00 min 15 -55 % B).

¹ H-NMR (400 MHz, DMSO-b6): δ [ppm] = 2.205 (0.86), 2.226 (1.57), 2.254 (1.23), 2.290 (15.27), 2.327 (1.28), 2.654 (2.07) , 2.681 (1.95), 2.762 (2.11), 2.779 (3.81), 2.795 (2.41), 3.155 (3.13), 3.374 (3.80), 3.401 (2.16), 3.482 (0.97), 3.504 (1.80), 3.531 (1.16) , 3.686 (1.75), 3.714 (1.51), 3.784 (16.00), 3.888 (1.65), 3.916 (1.59), 4.031 (1.27), 4.047 (1.48), 4.057 (1.61), 4.073 (1.47), 4.294 (1.53) , 4.304 (1.57), 4.320 (1.45),4.328 (1.29), 4.661 (3.52), 4.675 (3.54), 7.031 (0.48), 7.052 (1.50), 7.070 (3.26), 7.087 (1.82), 7.099 (1.95) ,7.122 (0.79), 7.299 (2.83), 7.311 (2.84), 7.655 (2.12), 7.672 (2.11), 7.706 (2.52), 8.239 (3.08), 8.250 (2.98), 8.414 (5.21), 13.678 (1.85) , 14.738 (3.80).

LC-MS (method 6): Rt = 0.64 min; MS (ESI positive): m/z = 516 [M+H]+.

Intermediate 6-38.

4-[[3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]-4-pyridyl]methylamino]-N-(3-fluoro-2-methylphenyl)-6oxo-2, 3-dihydro-1H-pyridine-5-carbothioamide

- 60 046642

Using a method similar to that described for intermediate 6-1, with N-(3-φτορ-2methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-38 , 350 mg, 1.25 mmol) and 1-{3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridin-4yl}methanamine (intermediate 2-7, 315 mg, 1.25 mmol ) as starting materials, 192 mg (27% yield) of the title compound were obtained after heating for 3 h at 120°C and purification by preparative HPLC (Method 11, gradient: 0.00 - 2.00 min 30% B, 2.00 - 14.00 min 30 - 70% B).

¹ H-NMR (400 MHz, DMSO-b6): δ [ppm] = 1.046 (16.00), 1.253 (14.02), 2.045 (8.35), 2.050 (8.21), 2.063 (1.09), 2.521 (2.37) , 2.525 (1.62), 2.741 (1.29), 2.757 (2.61), 2.774 (1.60), 3.145 (1.01), 3.152 (1.15), 3.161 (1.90), 3.168 (1.80), 3.178 (0.99), 3.185 (0.85) , 3.298 (1.92), 3.534 (3.17), 3.562 (2.60), 3.617 (0.65), 3.626 (0.83), 3.647 (2.00), 3.656 (2.10), 3.666 (2.13), 3.690 (2.57), 3.719 (1.29) , 3.780 (0.43), 3.793 (0.82),3.803 (1.04), 3.814 (0.83), 3.828 (0.60), 4.148 (0.72), 4.159 (0.78), 4.174 (2.17), 4.186 (2.01), 4.194 (2.14) ,4.208 (2.03), 4.220 (0.76), 4.234 (0.69), 4.647 (3.08), 4.662 (3.06), 7.040 (0.87), 7.061 (1.78), 7.074 (1.74), 7.085 (1.37), 7.094 (2.40) , 7.189 (0.89), 7.208 (1.38), 7.225 (1.30), 7.244 (0.54), 7.295 (2.49), 7.307 (2.52),7.686 (1.77), 8.237 (2.54), 8.249 (2.42), 8.393 (3.97) , 13.662 (1.07), 14.520 (2.54).

LC-MS (method 6): Rt = 0.98 min; MS (ESI positive): m/z = 515 [M+H]+.

Intermediate 6-40.

No.[2-(2,2-difluoroethyl)-3-fluorophenyl]-4-[[3-(1,4-dioxan-2-ylmethoxy)-4-pyridyl]methylamino]-6oxo-2,3-dihydro- 1 H-pypidine-5-cabotioamide

Using a method similar to that described for intermediate 6-1, with N-[2-(2,2difluoroethyl)-3-fluorophenyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-40, 100 mg, 303 µmol) and 1-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4yl}methanamine (intermediate 2-1, 95.0 mg, 424 µmol ) as starting materials, 19.5 mg (10% yield) of the title compound were obtained after purification by flash chromatography (silica gel, DCM/EtOH, 0-10% gradient).

LC-MS (method 2): Rt = 1.07 min; MS (ESI positive): m/z = 537 [M+H] ⁺ .

Intermediate 6-41.

tert-butyl ^)-2-{[(4-{[(5-{[2-(2,2-difluoroethyl)-3-fluorophenyl]carbamothioyl}-6-oxo-1,2,3,6tetrahydropyridine-4 -yl)amino]methyl}pyridin-3-yl)oxy]methyl}morpholine-4-carboxylate

- 61 046642

Mixture

No.[2-(2,2-difluoroethyl)-3-fluorophenyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3 carbothioamide (intermediate 5-40, 200 mg, 605 µmol) and tert-butyl (2S)-2-({[4(aminomethyl)pyridin-3-yl]oxy}methyl)morpholine-4-carboxylate (intermediate 2-5, 274 mg, 848 µmol) in ACN (2.5 ml ) were treated with HO-bis-(trimethylsilyl)acetamide (111 μl, 0.6 mmol, CAS 10416-59-8) and stirred at 80°C for 5 h. The reaction mixture was treated with another equivalent (111 μl, 0.6 mmol) HO-bis -(trimethylsilyl)acetamide and stirred at 80°C overnight. The reaction mixture was diluted with DCM and purified by flash chromatography (silica gel, DCM/EtOH, 0-20% gradient) to give 255 mg of the title compound (45% yield).

LC-MS (method 2): R _t = 1.25 min; MS (ESI positive): m/z = 636 [M+H]+.

Intermediate 6-42.

tert-butyl

^)-2-[({4-[({5-[(3-chloro-2-methylphenyl)carbamothioyl]-6-oxo-1,2,3,6 tetrahydropyridin-4-yl}amino)methyl]pyridine -3-yl}oxy)methyl]morpholine-4-carboxylate

Using a method similar to that described for intermediate 6-1, with N(3-chloro-2methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-10, 350 mg, 1.18 mmol) and tert-butyl DO)-2-({[4-(aminomethyl)pyridin-3yl]oxy}methyl)morpholine-4-carboxylate (intermediate 2-5, 381 mg, 1.18 mmol) in As starting materials, 208 mg (99% purity, 29% yield) of the title compound were obtained after heating for 3 h and purification 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 68.9 - 70% B).

'H-NMR (400 MHz, DMSO-^): 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 (0.96), 3.434 (0.57), 3.441 (0.60), 3.710 (0.46), 3.723 (0.54), 3.730 (0.45), 3.837 (0.42) , 4.213 (1.89), 4.225 (1.86), 4.648 (1.39),4.663 (0.92), 7.216 (1.36), 7.236 (0.59), 7.294 (0.89), 7.306 (0.92), 7.326 (0.53), 3.153 (0.62) , 3.162 (0.99), 3.169 (0.70), 3.737 (0.68), 3.749 (0.56), 3.756 (1.40), 7.153 (0.57), 7.170 (1.15), 7.196 (1.13), 7.329 (1.10), 7.346 (0.85) , 7.349 (0.79), 7.691 (0.91), 8.237 (2.11), 8.249 (1.94), 8.399 (3.05), 13.653 (0.59), 14.540 (1.38).

LC-MS (method 6): R _t = 1.17 min; MS (ESI positive): m/z = 602 [M+H] ⁺ .

Intermediate 6-43.

tert-butyl (3R)-3-[({4-[({5-[(3-chloro-2-methylphenyl)carbamothioyl]-6-oxo-1,2,3,6tetrahydropyridin-4-yl}amino) methyl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate

- 62 046642

Using a method similar to that described for intermediate 6-1, with N-(3-χλορ-2methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-10 , 350 mg, 1.18 mmol) and tert-butyl (3R)-3-({[4-(aminomethyl)pyridin-3yl]oxy}methyl)morpholine-4-carboxylate (intermediate 2-9, 381 mg, 1.18 mmol ) as starting materials, 184 mg (99% purity, 26% yield) of the title compound were obtained after heating for 3 h and purification 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 68.9 - 70% B).

'I-NMR (400 MHz, DMSO-d,.): 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), (2.44), 3.163 (2.41), 3.319 (0.58), (1.00), 3.651 (0.51), 3.797 (0.72), (0.83), 4.625 (2.12), 4.639 (2.15), (1.19), 7.301 (1.19), 7.329 (2.50),

2.725

3.365

3.821

7.160

7.332 (1.74), 2.742 (1.82), 2.757 (0.75), 3.140 (1.42), 3.147 (1.59), 3.156 (1.06), 3.372 (1.25), 3.395 (0.56), 3.402 (0.54), 3.478 (0.92), 3.507 (0.64), 3.957 (0.67), 3.985 (0.59), 4.236 (1.53), 4.415 (0.46), 4.441 (1.07), 7.178 (2.26), 7.200 (2.08), 7.220 (3.03), 7.239 (1.27), 7.291 (2.34), 7.349 (1.83), 7.352 (1.71), 7.691 (1.99), 8.240 (3.22), 8.252 (3.11), 8.489 (2.72), 13.669 (0.94), 14.536 (3.05).

LC-MS (method 6): Rt = 1.17 min; MS (ESI positive): m/z = 602 [M+H]+.

Intermediate 6-44.

No.(3-chloro-2-methylphenyl)-4-[[3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]-4-pyridyl]methylamino]-6oxo-2,3 -dihydro-1H-pyridine-5-carbothio amide

Using a method similar to that described for intermediate 6-41, with N-(3-χλορ-2methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-10 , 200 mg, 674 µmol) and 1-{3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridin-4yl}methanamine (intermediate 2-7, 200 mg, purity 85 %, 674 µmol) as starting materials, 328 mg of the title compound were obtained (purity 97%, yield 89%).

¹ H-NMR (400 MHz, DMSO-06): δ [ppm] = 1.047 (14.25), 1.253 (12.85), 2.077 (16.00), 2.162 (14.45), 2.520 (1.87), 2.525 (1.19) , 2.742 (1.21), 2.759 (2.44), 2.775 (1.45), 3.147 (0.98), 3.154 (1.11), 3.163 (1.80),

3.170 (1.74), 3.180 (0.98), 3.186 (0.82), 3.297 (1.66), 3.327 (2.92), 3.533 (2.87), 3.561 (2.30), 3.617 (0.55),

3.626 (0.77), 3.646 (1.84), 3.655 (1.96), 3.664 (1.91), 3.689 (2.20), 3.718 (1.12), 3.791 (0.79), 3.802 (0.97),

3.812 (0.78), 3.826 (0.56), 4.147 (0.62), 4.158 (0.66), 4.173 (1.85), 4.184 (1.77), 4.193 (1.88), 4.206 (1.73),

4.220 (0.66), 4.233 (0.60), 4.644 (2.79), 4.659 (2.74), 7.158 (1.13), 7.175 (2.37), 7.200 (1.72), 7.220 (2.58),

7.239 (1.09), 7.298 (1.31), 7.310 (1.39), 7.328 (2.08), 7.332 (2.01), 7.348 (1.56), 7.351 (1.42), 7.689 (1.69),

8.245 (0.80), 8.399 (1.03), 13.621 (0.57), 13.635 (1.07), 14.542 (2.54).

LC-MS (method 6): Rt = 1.06 min; MS (ESI positive): m/z = 531 [M+H]+.

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Intermediate 6-47.

4-[[3-(1,4-dioxan-2-ylmethoxy)-4-pyridyl]methylamino]-N-(3-fluoro-2-methylphenyl)-6-oxo-2,3dihydro-1H-pyridine-5 -carbothioamide

Using a method similar to that described for intermediate 6-41, with X-(3-fluoro-2methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-38 , 300 mg, 1.07 mmol) and 1-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methanamine (intermediate 2-1, 240 mg, 1.07 mmol) as starting materials substances, we obtained 156.3 mg (purity 93%, yield 71%) of the title compound.

¹ H-NMR (400 MHz, DMSO-06): δ [ppm] = 0.000 (0.70), 1.998 (0.55), 2.033 (16.00), 2.038 (15.45), 2.064 (3.23), 2.508 (3.78) , 2.513 (2.36), 2.737 (2.61), 2.754 (5.23), 2.771 (2.96), 3.142 (2.39), 3.151 (3.71), 3.158 (3.53), 3.168 (2.07), 3.393 (2.34), 3.418 (3.51) , 3.421 (3.41), 3.446 (3.16), 3.461 (1.34), 3.482 (2.56), 3.488 (2.76), 3.506 (1.42), 3.516 (2.71), 3.579 (1.64), 3.585 (1.94), 3.608 (2.49) , 3.614 (2.79), 3.641 (5.03),3.670 (1.97), 3.735 (2.71), 3.744 (2.66), 3.769 (2.09), 3.837 (2.39), 3.844 (2.81), 3.871 (4.35), 3.883 (1.72) ,3.890 (1.32), 3.895 (1.57), 3.902 (1.32), 3.907 (1.44), 3.914 (1.14), 3.926 (0.62), 4.108 (0.85), 4.120 (0.95), 4.134 (3.73), 4.145 (6.69) , 4.158 (3.48), 4.171 (0.87), 4.184 (0.75), 4.624 (4.75), 4.639 (4.68), 7.028 (1.64),7.050 (3.46), 7.062 (3.48), 7.073 (2.79), 7.081 (4.60) , 7.179 (1.62), 7.198 (2.71), 7.215 (2.51), 7.235 (1.00), 7.333 (1.12), 7.676 (3.41), 8.321 (0.42), 13.651 (2.04), 14.509 (4.80).

LC-MS (method 6): Rt = 0.85 min; MS (ESI positive): m/z = 487 [M+H]+.

Intermediate 6-50.

X-(3-chloro-2-methylphenyl)-4-[[3-(1,4-dioxan-2-ylmethoxy)-4-pyridyl]methylamino]-6-oxo-2,3dihydro-III-pyridine-5 -carbothioamide

C.I.

Using a similar method to that described for intermediate 6-41, with X-(3-chloro-2methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-10 , 200 mg, 674 µmol) and 1-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methanamine (intermediate 2-1, 151 mg, 674 µmol) as starting materials substances, we obtained 150.0 mg (purity 96%, yield 42%) of the title compound.

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

LC-MS (method 6): Rt = 0.94 min; MS (ESI positive): m/z = 503 [M+H] ⁺ .

Intermediate 6-52.

X-(3-chloro-2-ethylphenyl)-4-[[3-(1,4-dioxan-2-ylmethoxy)-4-pyridyl]methylamino]-6-oxo-2,3dihydro-1H-pyridin-5 -carbothioamide

- 64 046642

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

1H-NMR (400 MHz, DMSO-06): δ ppm= 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).

LC-MS (method 2): R _t = 1.15 min; MS (ESI positive): m/z = 517 [M+H]+.

Intermediate 6-53.

N-(3-chloro-2-ethylphenyl)-4-{[(3-{ [(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)methyl] amino }-2oxo- 1,2,5,6-tetrahydropyridine-3-carbothioamide CH ₃ ci

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

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

LC-MS (method 2): Rt = 1.17 min; MS (ESI positive): m/z = 517 [M+H] ⁺ .

Intermediate 6-55.

tert-butyl (2R)-2-[({4-[({5-[(3-χloρ-2-ethylphenyl)cabamothioyl]-6-oxo-1,2,3,6-tetahydropypidin4-yl}amino) methyl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate

- 65 046642

Using a method similar to that described for intermediate 6-41, with N-(3-χλορ-2ethylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-29 , 300 mg, 965 µmol) and tert-butyl (2R)-2-({[4-(aminomethyl)pipidin-3yl]oxy}methyl)morpholine-4-carboxylate (intermediate 2-10, 312 mg, 965 µmol ) as starting materials, 476.0 mg (95% purity, 76% yield) of the title compound was obtained using flash chromatography (silica gel, DCM/EtOH, 1-10% gradient).

Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 1.036 (1.51), 1.055 (3.57), 1.073 (1.55), 1.393 (16.00), 2.518 (1.71), 2.523 (1.10), 2.590 (1.19), 2.609 (1.16), 2.751 (0.68), 2.769 (1.33), 2.785 (0.84), 3.165 (0.96), 3.171 (0.92), 3.431 (0.55), 3.438 (0.59), 3.729 (0.71), 3.749 (0.48), 3.756 (0.41), 3.835 (0.41), 4.210 (1.81), 4.222 (1.76), 4.646 (1.35), 4.662 (1.35), 5.758 (7.84), 7.202 (2.06), 7.214 (2.99), 7.296 (1.00), 7.304 (1.58), 7.316 (1.60), 7.328 (0.75), 7.703 (0.94), 8.236 (1.90), 8.248 (1.81), 8.398 (2.84), 13.671 (0.64), 14.632 (1.67).

LC-MS (method 2): Rt = 1.32 min; MS (ESI positive): m/z = 616 [M+H]+.

Intermediate 6-56.

tert-butyl ^)-2-[({4-[({5-[(3-chloro-2-ethylphenyl)carbamothioyl]-6-oxo-1,2,3,6-tetrahydropyridin4-yl}amino)methyl ]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate

Using a method similar to that described for intermediate 6-41, with N-(3-χλορ-2ethylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-29 , 300 mg, 965 µmol) and tert-butyl^)-2-({[4-(aminomethyl)pyridin-3-yl]oxy}methyl)morpholine-4-carboxylate (intermediate 2-5, 312 mg, 965 µmol) as starting materials, 479.0 mg (95% purity, 77% yield) of the title compound was obtained after purification by flash chromatography (silica gel, DCM/EtOH, 1-10% gradient).

Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 14.55 - 14.67 (m, 1H), 13.60 - 13.72 (m, 1H), 8.40 (s, 1H), 8.24 (d, 1H ), 7.70 (br s, 1H), 7.16 - 7.36 (m, 4H), 5.70 - 5.80 (m, 1H), 5.66 - 5.81 (m, 1H), 4.59 - 4.73 (m, 2H), 4.12 4.27 (m , 2H), 3.80 - 3.99 (m, 2H), 3.65 - 3.78 (m, 2H), 3.37 - 3.50 (m, 1H), 3.10 - 3.22 (m, 2H), 2.70 - 2.99 (m, 4H), 2.55 - 2.64 (m, 2H), 1.30 - 1.46 (m, 9H), 1.01-1.12 (m, 3H).

LC-MS (method 2): Rt = 1.32 min; MS (ESI positive): m/z = 616 [M+H]+.

Intermediate 6-57.

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

Using a method similar to that described for intermediate 6-41, with N-(3-χΛορ-2methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-1 , 300 mg, 959 µmol) and 1-{3-[(^)-1-(1,4-dioxan-2-yl)ethoxy]pyridin-4-yl}methanamine (intermediate 2-11, 251 mg, 1.06 mmol) as starting materials, 384 mg (purity 99%, yield 74%) of the title compound were obtained as a mixture of diastereoisomers.

Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 0.064 (0.95), 1.239 (2.82), 1.255 (2.83), 1.279 (2.06), 1.295 (2.09), 2.518 (1.11), 2.523 (0.82), 2.761 (0.76), 2.777 (0.86), 3.141 (0.52), 3.148 (0.60), 3.157 (1.00), 3.164 (0.99), 3.181 (0.43), 3.417 (0.87), 3.443 (0.88), 3.455 (0.44), 3.462 (0.47), 3.470 (0.68), 3.476 (0.41), 3.591 (0.40), 3.597 (0.65), 3.620 (0.88), 3.632 (0.76), 3.639 (0.41), 3.647 (0.54), 3.653 (0.56), 3.672 (0.40), 3.678 (0.44), 3.711 (16.00), 3.732 (0.56), 3.766 (0.89), 3.772 (0.52), 3.794 (0.57), 4.651 (1.27), 4.665 (1.31), 4.682 (0.58), 7.090 (0.70), 7.110 (1.53), 7.131 (0.88), 7.287 (1.67), 7.289 (1.87), 7.300 (1.26), 7.305 (1.12), 7.309

- 66 046642 (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 (0.9 1 ), 8.416 (1.88), 8.432 (1.35), 13.666 (0.43), 13.675 (0.50), 14.790 (1.61).

LC-MS (method 6): Rt = 0.96 min and Rt = 0.98 min; MS (ESI positive): m/z = 533.2 [M+H]+. Intermediate 6-60.

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

Using a method similar to that described for intermediate 6-41, with N-(3-χλορ-2methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-1 , 300 mg, 959 µmol) and 1-{3-[(^)-1-(1,4-dioxan-2-yl)ethoxy]pyridin-4-yl}methanamine (intermediate 2-12, 251 mg, 1.06 mmol) as starting materials gave 346 mg (purity 99%, yield 67%) of the title compound.

¹ H-NMR (400 MHz, DMSO-a ₆ ): δ [ppm] = 1.278 (5.25), 1.294 (5.21), 2.073 (0.98), 2.331 (0.40), 2.518 (2.02), 2.522 (1.36 ), 2.673 (0.42), 2.749 (0.74), 2.765 (0.56), 2.775 (0.83), 2.792 (0.42), 3.140 (0.62), 3.147 (0.73), 3.156 (1.17), 3.164 (1.16), 3.417 (0.81 ), 3.441 (1.16), 3.445 (1.15), 3.469 (1.68), 3.475 (0.85), 3.503 (0.74), 3.570 (0.47), 3.576 (0.55), 3.598 (0.72), 3.604 (0.82), 3.631 (1.87 ), 3.638 (0.97), 3.646 (0.63), 3.652 (0.78), 3.657 (1.02), 3.663 (0.93), 3.670 (0.52), 3.677 (0.47), 3.710 (16.00), 3.758 (0.87), 3.767 (0.74 ),3.790 (0.67), 3.920 (0.78), 3.926 (0.76), 3.949 (0.72), 3.955 (0.66), 4.646 (1.57), 4.653 (1.48), 4.662 (1.63), 4.682 (0.73), 7.092 (1.08 ), 7.112 (2.33), 7.133 (1.33), 7.287 (1.60), 7.290 (1.60), 7.302 (1.73), 7.306 (1.61),7.310 (1.69), 7.314 (1.68), 7.725 (1.16), 7.791 (1.23 ), 7.794 (1.22), 7.811 (1.17), 7.814 (1.08), 8.210 (2.42), 8.222 (2.24), 8.430 (3.36), 13.651 (0.41), 13.665 (0.79), 14.786 (2.12).

LC-MS (method 6): Rt = 0.96 min; MS (ESI positive): m/z = 533 [M+H]+.

Intermediate 6-62.

N(3-fluoro-2-methylphenyl)-4-{[(3-{[^)-4-methylmorpholin-2-yl]methoxy}pyridin-4yl)methyl]amino}-2-oxo-1,2, 5,6-tetrahydropyridine-3-carbothioamide

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

¹ H-NMR (400 MHz, DMSO-a ₆ ): δ [ppm] = 1.035 (0.65), 1.053 (1.08), 1.070 (0.68), 1.848 (1.00), 1.876 (1.47), 1.901 (1.11 ), 1.953 (0.45), 1.962 (0.59), 1.982 (1.04), 1.990 (1.08), 2.010 (0.69), 2.019 (0.57), 2.040 (7.36), 2.044 (6.91), 2.177 (16.00), 2.518 (1.64 ), 2.522 (1.10), 2.578 (0.88), 2.607 (0.81), 2.756 (0.84), 2.770 (1.72), 2.789 (2.10), 2.817 (1.02), 3.149 (0.83), 3.156 (0.97), 3.166 (1.67 ), 3.173 (1.63), 3.182 (0.94), 3.318 (0.50), 3.501 (0.55), 3.507 (0.70), 3.529 (1.25), 3.535 (1.29), 3.557 (0.76), 3.563 (0.62), 3.784 (0.93 ),3.788 (0.90), 3.791 (0.76), 3.812 (1.29), 3.815 (1.26), 3.829 (0.63), 3.837 (0.57), 4.112 (0.53), 4.124 (0.56), 4.138 (1.82), 4.150 (1.97 ), 4.154 (2.08), 4.168 (1.68), 4.180 (0.56), 4.194 (0.52), 4.636 (2.30), 4.651 (2.34), 7.034 (0.71), 7.055 (1.49), 7.070 (1.47), 7.079 (1.12 ), 7.089 (1.98), 7.185 (0.72), 7.204 (1.19), 7.221 (1.13),7.241 (0.44), 7.295 (2.26), 7.306 (2.30), 7.679 (1.46), 8.227 (3.76), 8.239 (3.55 ), 8.383 (5.45), 13.662 (0.88), 14.516 (2.06).

LC-MS (method 6): Rt = 0.62 min; MS (ESI positive): m/z = 500 [M+H]+.

- 67 046642

Intermediate 6-65.

4-{[(3-{[1,4-dioxan-2-yl]methoxy}pyridin-4-yl)methyl] amino } -N(2-ethyl-3-fluorophenyl)-2-oxo1,2,5 ,6-tetrahydropyridine-3-carbothioamide

Using a method similar to that described for intermediate 6-41, with N-(2-ύγηλ-3fluorophenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (300 mg, 1.02 mmol ) and 1(3-{[1,4-dioxan-2-yl]methoxy}pyridin-4-yl)methanamine (229 mg, 1.02 mmol) as starting materials, 218 mg (purity 90%, yield 38%) The title compound was obtained after evaporating the solvent, filtering and washing the solid with ACN.

¹ H-NMR (400 MHz, DMSO^) δ [ppm]: 0.057 (1.12), 1.042 (7.32), 1.061 (16.00), 1.080 (7.29), 1.231 (0.88), 1.751 (0.58), 2.074 (6.86), 2.522 (5.66), 2.753 (3.09), 2.770 (6.11), 2.787 (3.52), 3.156 (2.86), 3.166 (4.42), 3.172 (4.30), 3.181 (2.51), 3.402 (2.65), 3.427 (3.92), 3.430 (3.92), 3.455 (3.70), 3.471 (1.62), 3.491 (2.84), 3.498 (3.08), 3.516 (1.51), 3.526 (2.87), 3.589 (1.80), 3.594 (1.99), 3.617 (2.79), 3.623 (3.19),3.650 (5.74), 3.679 (2.35), 3.745 (3.17), 3.754 (3.06), 3.778 (2.46), 3.846 (2.80), 3.853 (3.24), 3.881 (4.78),3.893 (1.98), 3.900 (1.58), 3.905 (1.80), 3.911 (1.59), 3.918 (1.69), 3.925 (1.36), 3.936 (0.73), 4.117 (1.01), 4.129 (1.14), 4.143 (4.20), 4.155 (7.71), 4.168 (3.95), 4.181 (1.08), 4.194 (0.91), 4.632 (5.48), 4.646 (5.40), 7.029 (2.23), 7.051 (3.97), 7.074 (2.84), 7.091 (3.92), 7.110 (5.33), 7.191 (2.31), 7.207 (2.86), 7.211 (3.55),7.228 (3.42), 7.248 (1.35), 7.351 (1.30), 7.701 (4.14), 8.329 (0.48), 8.476 (0.42), 13.662 (1.51), 13.676 (2.76), 13.691 (1.37), 14.588 (6.37).

LC-MS (method 6): Rt = 0.92 min; MS (ESI positive): m/z = 501 [M+H]+.

Intermediate 6-68.

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

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

¹ H-NMR (400 MHz, DMSO^) 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 (1.79), 3.688 (2.07), 3.718 (1.01), 3.778 (0.65), 4.156 (0.71), 4.172 (1.96), 4.182 (3.11), 4.658 (3.10), 7.029 (0.86), 7.050 (1.52), 7.225 (1.39), 7.245 (0.52), 7.295 (2.19), 3.615 (0.45), 3.789 (1.95), 4.191 (1.63), 7.074 (2.40), 7.306 (0.59), 3.624 (0.91), 3.801 (2.02), 4.205 (1.12), 7.091 (2.41), 7.700 (0.79), 3.644 (1.91), 3.653 (2.05), 3.664 (1.07), 3.812 (0.86), 3.824 (0.63), 4.145 (1.76), 4.218 (0.69), 4.231 (0.59), 4.644 (1.71), 7.111 (2.37), 7.189 (0.89), 7.208 (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), 7 (3.04).

LC-MS (method 6): Rt = 1.03 min; MS (ESI positive): m/z = 529 [M+H]+.

Intermediate 6-71.

N-(3-chloro-2-methoxyphenyl)-4-({[3-({1-[4-methylmorpholin-2-yl]ethyl}oxy)pyridin-4yl]methyl}amino)-2-oxo-1 ,2,5,6-tetrahydropyridine-3-carbothioamide

- 68 046642

Using a method similar to that described for intermediate 6-41, with N-(3-χΛορ-2methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-1 , 300 mg, 959 µmol) and 1-[3-({1-[4-methylmorpholin-2-yl]ethyl}oxy)pyridin-4-yl]methanamine (intermediate 2-71, 265 mg, 1.06 mmol) As starting materials, 360 mg (purity 93%, yield 62%) of the title compound was obtained after purification by column chromatography.

¹ H-NMR (400 MHz, DMSO-06) δ [ppm]: 1.014 (0.69), 1.044 (16.00), 1.061 (7.08), 1.080 (3.30), 1.172 (0.52), 1.200 (0.60), 1.251 (13.22), 1.987 (0.87), 2.745 (1.36), 2.761 (2.65), 2.779 (1.61), 3.164 (2.11), 3.170 (2.09), 3.295 (1.79), 3.532 (2.73), 3.560 (2.19), 3.615 (0.59), 3.624 (0.79), 3.644 (1.91), 3.653 (2.05), 3.664 (1.79), 3.688 (2.07), 3.718 (1.01), 3.778 (0.45), 3.789 (0.91), 3.801 (1.07), 3.812 (0.86), 3.824 (0.63),4.145 (0.65), 4.156 (0.71), 4.172 (1.96), 4.182 (1.95), 4.191 (2.02), 4.205 (1.76), 4.218 (0.69), 4.231 (0.59), 4.644 (3.11), 4.658 (3.10), 7.029 (0.86), 7.050 (1.63), 7.074 (1.12), 7.091 (1.71), 7.111 (2.37), 7.189 (0.89), 7.208 (1.52), 7.225 (1.39), 7.245 (0.52), 7.295 (2.40), 7.306 (2.41), 7.700 (1.92), 8.235 (3.11), 8.247 (2.98), 8.389 (5.24), 13.661 (0.71), 13.675 (1.32), 13.688 (0.68), 14.587 (3.04).

LC-MS (method 6): Rt = 1.03 min; MS (ESI positive): m/z = 529 [M+H]+.

Intermediate connection 12.

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

F

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

^1H NMR (400 MHz, DMSO-06): δ = 11.45 (s, 1H), 8.18 (s, 1H), 7.98 (d, 1H), 7.39 (d, 1H), 7.18 (s, 1H), 6.67 (t, 1H), 6.54 (t, 1H), 6.04 (d, 1H), 3.92 (s, 3H), 3.40 (t, 2H), 2.90 (t, 2H).

LC-MS (method 5): Rt =1.851 min; m/z = 369.0 (M +H)+.

Intermediate 22-1.

tert-butyl ^)-2-[({4-[3-(3-fluoro-2-methoxyanilino)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2c]pipidin- 2-yl]pipidin-3-yl}oxy)methyl]mopholin-4-caboxylate

- 69 046642

Using a method similar to that described for Example 1, with tert-butyl (2S)-2-|([4-|({5-|(3-(|)Top-2methoxyphenyl)carbamothioyl]-6-oxo-1,2 ,3,6-tetrahydropyridin-4-yl}amino)methyl]pyridin-3yl}oxy)methyl]morpholine-4-carboxylate (intermediate 6-22, 1.43 g, 2.38 mmol) as starting material, 572 mg (purity 80%, 34% yield) of the title compound was obtained after purification by flash chromatography (silica gel, DCM/EtOH, 0-10% gradient).

1H-NMR (400 MHz, DMSO-66) 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 (0.50), 3.553 (0.42), 3.560 (0.43), 3.750 (0.64), 3.760 (6.63), 3.936 (0.57), 3.939 (0.59), 3.950 (0.46), 4.343 (0.76), 6.485 (0.50), 6.489 (0.49), 6.492 (0.42),6.513 (0.82), 3.422 (1.10), 3.435 (0.77), (0.40), 3.851 (0.50), 3.858 (0.40), (0.56), 4.356 (0.65), 5.759 (1.09 ), (0.45), 6.516 (0.42), 6.627 (0.54),

3.440 (0.72), 3.452

3.873 (0.46), 3.906

5.993 (0.75), 6.013

6.642 (0.52), 7.147 (0.86), 7.280 (1.09), 7.293 (1.13), 7.509 (0.98), 8.025 (1.38), 8.038 (1.27), 8.401 (2.10), 11.020 (0.61). LC-MS (method 2): R _t = 1.12 min; MS (ESI positive): m/z = 568 [M+H]+.

Intermediate 22-2.

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

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

1H-NMR (400 MHz, DMSO-66): δ [ppm] = 2.53 - 2.78 (m, 4H), 2.80 - 2.90 (m, 3H), 3.38 - 3.47 (m, 3H), 3.55 - 3.66 (m, 1H), 3.83 - 3.90 (m, 1H), 3.91 - 3.95 (s, 3H), 4.07 - 4.16 (m, 1H), 4.29 - 4.39 (m, 1H), 6.01 (d, 1H), 6.44 - 6.56 (m, 1H), 6.65 (dt, 1H), 7.17 (s, 1H), 7.29 (d, 1H), 7.53 (s, 1H), 8.01 (d, 1H), 8.39 (s, 1H), 11.10 (s, 1H).

LC-MS (method 2): Rt = 0.84 min; MS (ESI positive): m/z = 468 [M+H]+.

Intermediate 27-1.

tert-butyl DO)-2-[({4-[3-(3-chloro-5-fluoro-2-methoxyanilino)-4-oxo-4,5,6,7-tetrahydro-1Hpyrrolo[3,2- c]pyridin-2-yl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate

- 70 046642

Using a method similar to that described for Example 1, with tert-butyl ^)-2-[({4-[({5-[(3-chloro-5fluoro-2-methoxyphenyl)carbamothioyl]-6-oxo-1,2 ,3,6-tetrahydropyridin-4-yl}amino)methyl]pyridin-3yl}oxy)methyl]morpholine-4-carboxylate (intermediate 6-27, 150 mg, 236 μmol) as starting material, yielded 73.5 mg ( purity 90%, yield 47%) of the title compound.

¹ H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.40 (s, 9H), 2.52 - 2.53 (m, 2H), 2.70 - 3.03 (m, 1H), 2.87 (br t , 2H), 3.42 (td, 2H), 3.46 - 3.61 (m, 1H), 3.71 - 3.79 (m, 1H), 3.82 (s, 4H), 3.93 (br d, 1H), 4.20 (m, 1H) , 4.27 4.33 (dd, 1H), 5.85 (dd, 1H), 6.55 (dd, 1H), 7.11 (s, 1H), 7.32 (d, 1H), 7.60 (s, 1H), 8.10 (d, 1H) , 8.44 (s, 1H), 11.17 (s, 1H).

LC-MS (method 2): Rt = 1.19 min; MS (ESI positive): m/z = 602 [M+H] ⁺ .

Intermediate 27-2.

3-(3-chloro-5-fluoro-2-methoxyanilino)-2-(3-{[^)-morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7tetrag 'hydro -411-i shrrolo[3,2-c]pyridin-4-one

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

¹ H-NMR (400 MHz, DMSO-a ₆ ): δ [ppm] = 2.51 - 2.58 (m, 2H), 2.61 - 2.75 (m, 2H), 2.77 - 2.94 (m, 3H), 3.38 - 3.48 (m, 1H), 3.56 (td, 1H), 3.76 - 3.92 (m, 2H), 3.84 (s, 3H), 4.10 (dd, 1H), 4.29 (dd, 1H), 5.85 (dd, 1H ), 6.57 (dd, 1H), 7.13 (s, 1H), 7.32 (d, 1H), 7.64 (d, 1H), 8.09 (d, 1H), 8.43 (s, 1H), 11.22 (s, 1H) .

LC-MS (method 2): R _t = 0.93 min; MS (ESI positive): m/z = 502 [M+H]+.

Intermediate 41-1.

tert-butyl

^)-2-{[(4-{3-[2-(2,2-difluoroethyl)-3-fluoroanilino]-4-oxo-4,5,6,7-tetrahydro-1H pyrrolo[3,2- c]pyridin-2-yl}pyridin-3-yl)oxy]methyl}morpholine-4-carboxylate

Using a method similar to that described for Example 1, with tert-butyl (2S)-2-{[(4-{[(5-{ [2-(2,2

- 71 046642 difluoroethyl)-3-fluorophenyl]carbamothioyl}-6-oxo-1,2,3,6-tetrahydropyridin-4yl)amino]methyl}pyridin-3-yl)oxy]methyl}morpholine-4-carboxylate (intermediate compound 641, 266 mg, 418 µmol) as starting material, 33.0 mg (65% purity, 9% yield) of the title compound was obtained after purification by preparative HPLC (Method 10, gradient: 0.00-0.50 min 30% B, 0.50-6.00 min 30-70% B).

LC-MS (method 2): Rt = 1.16 min; MS (ESI negative): m/z = 600 [MH] ^- .

Intermediate 41-2.

3-[2-(2,2-difluoroethyl)-3-fluoroanilino]-2-(3-{[DO)-morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7tetrahydro ^H-pyrrolo^D-Dpyridin^-one

Using a method similar to that described for intermediate 22-2, with tert-butyl (2S)-2-{[(4-{3-[2-(2,2-difluoroethyl)-3-fluoroanilino]-4-oxo- 4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin2-yl}pyridin-3-yl)oxy]methyl}morpholine-4-carboxylate (intermediate 41-1, 33.0 mg, 54.9 µmol) as starting material, 22.0 mg (65% purity, 52% yield) of the title compound was obtained after purification by flash chromatography (amino phase silica gel, DCM/EtOH, 0-10% gradient).

LC-MS (method 2): R _t = 0.92 min; MS (ESI negative): m/z = 500 [MH] ^- .

Intermediate 42-1.

tert-butyl

DO)-2-[({4-[3-(3-chloro-2-methylanilino)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-

c] pyridin-2-yl] pyridin-Zyl } oxy) methyl] morpholine-4-carboxylate

Using a method similar to that described for Example 1, with tert-butyl (2S)-2-[({4-[({5-[(3-chloro-2methylphenyl)carbamothioyl]-6-oxo-1,2,3, 6-tetrahydropyridin-4-yl} amino)methyl]pyridin-3 yl}oxy)methyl]morpholine-4-carboxylate (intermediate 6-42, 207 mg, 344 µmol) as starting material, 27.8 mg (90% purity , yield 13%) of the title compound was obtained after purification using 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).

¹ H-NMR (400 MHz, DMSO-d..): 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 (0.43), 3.554 (0.43), 3.560 (0.45), 4.294 (0.43), 4.304 (0.45), 6.191 ( 0.69),6.195 (0.69), 6.719 (0.48), 6.735 (1.31), 6.738 (1.11), 6.747 (0.85), 6.767 (0.82),7.175 (0.93), 3.439 (0.48), 3.445 (0.66), 6.211 ( 0.71), 6.214 (0.83), 7.232 (0.92), 7.245 (0.92), 7.351 (0.48), 7.998 (1.24), 8.010 (1.16), 8.378 (1.84), 11.016 (0.78).

LC-MS (method 6): Rt = 0.92 min; MS (ESI positive): m/z = 568 [M+H]+.

Intermediate 42-2.

3-(3-chloro-2-methylanilino)-2-(3-{[DO)-morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro4H-pyrrolo [3 ,2-c]pyridin-4-one

- 72 046642 ci

Using a method similar to that described for intermediate 22-2, with tert-butyl^)-2-[({4-[3-(3-chloro-2-methylanilino)-4-oxo-4,5,6,7 -tetrahydro-III-pyrrolo[3,2-c]pyridin-2yl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate (intermediate 42-1, 30.0 mg, 52.8 µmol) as starting material, 19.0 mg (purity 92%, yield 71%) of the title compound was obtained after filtration through an SCX-2 column (washing with MeOH followed by elution with 1 M ammonia in MeOH).

1H-NMR (400 MHz, DMSO-06): δ [ppm] = 1.235 (1.09), 2.334 (1.58), 2.338 (0.84), 2.362 (16.00), 2.520 (7.24), 2.525 (4.55), 2.545 (1.21), 2.570 (1.33), 2.575 (1.40), 2.601 (1.20), 2.676 (1.83), 2.680 (1.06), 2.705 (1.02), 2.713 (0.99), 2.732 (1.01), 2.740 (0.93), 2.758 (1.50), 2.787 (0.62), 2.846 (1.74), 2.863 (4.52), 2.880 (2.07), 2.894 (1.12), 3.300 (4.30), 3.410 (1.44), 3.416 (1.55), 3.427 (2.54), 3.433 (2.52), 3.445 (1.29), 3.585 (0.65), 3.593 (0.77), 3.612 (1.20), 3.620 (1.22), 3.640 (0.69), 3.646 (0.62), 3.851 (0.59), 3.868 (0.92), 3.875 (0.91), 3.902 (1.40), 3.930 (1.00), 4.073 (1.20), 4.090 (1.18), 4.098 (1.63), 4.116 (1.39), 4.274 (1.41), 4.282 (1.45), 4.299 (1.18), 4.307 (1.08), 5.528 (0.41), 6.196 (1.85), 6.200 (1.81), 6.215 (2.00), 6.219 (1.86), 6.726 (1.04), 6.730 (1.33), 6.746 (3.44), 6.750 (2.92), 6.761 (2.53), 6.780 (2.58), 6.800 (0.88), 7.192 (2.31),7.231 (3.82), 7.244 (3.92), 7.364 (4.42), 7.980 (4.81), 7.993 (4.51), 8.370 (6.73), 8.397 (0.45), 11.102 (2.40).

LC-MS (method 6): Rt = 0.52 min; MS (ESI positive): m/z = 468 [M+H]+.

Intermediate 43-1.

tert-butyl (3R)-3-[({4-[3-(3-chloro-2-methylanilino)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2c]pyridine -2-yl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate CI

Using a method similar to that described for Example 1, with tert-butyl (3R)-3-[({4-[({5-[(3-xtop-2methylphenyl)carbamothioyl]-6-oxo-1,2,3, 6-tetrahydropyridin-4-yl}amino)methyl]pyridin-3yl}oxy)methyl]morpholine-4-carboxylate (180 mg, 299 µmol) as starting material, 35.1 mg (purity 90%, yield 19%) indicated in The title compounds were obtained after purification using 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 ).

¹ H-NMR (400 MHz, DMSO-06): δ [ppm] = 1.344 (16.00), 2.357 (14.22), 2.520 (2.49), 2.525 (1.70), 2.891 (0.42), 2.923 (1.43) , 3.384 (1.03), 3.405 (2.12), 3.412 (2.73), 3.417 (2.74), 3.435 (1.48), 3.555 (0.76), 3.577 (0.85), 3.680 (1.24), 3.709 (1.06), 3.840 (1.02) , 3.860 (0.92), 3.952 (1.42), 3.982 (1.23), 4.301 (0.62), 6.161 (1.64), 6.165 (1.44), 6.179 (1.77), 6.184 (1.67), 6.725 (0.94), 6.740 (3.11) , 6.745 (3.77), 6.765 (1.40),6.785 (0.46), 7.187 (1.94), 7.309 (2.75), 7.322 (2.75), 7.351 (4.78), 7.971 (1.97), 7.983 (1.88), 8.445 (5.01) , 11.063 (1.60).

LC-MS (method 6): Rt = 0.92 min; MS (ESI positive): m/z = 568 [M+H] ⁺ .

Intermediate 43-2.

-(3-chloro-2-methylanilino)-2-(3 - {[(3R)-morpholin-3-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro4H-pyrrolo[3 ,2-c]pyridin-4-one

- 73 046642

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

¹ H-NMR (400 MHz, DMSO-bb): δ [ppm] = 1.235 (0.47), 2.334 (1.10), 2.338 (0.53), 2.367 (16.00), 2.383 (0.45), 2.520 (5.15) , 2.525 (3.36), 2.676 (1.09), 2.680 (0.50), 2.825 (1.81), 2.842 (3.79), 2.860 (2.41), 2.888 (0.56), 2.945 (0.90), 2.976 (0.54), 3.155 (0.67) , 3.371 (1.08), 3.398 (1.36), 3.416 (2.04), 3.426 (3.16), 3.433 (2.75), 3.444 (2.06), 3.450 (1.95), 3.471 (0.57), 3.720 (1.01), 3.747 (0.86) , 3.794 (1.03), 3.816 (0.90),4.192 (0.59), 4.208 (0.66), 4.218 (1.25), 4.232 (1.21), 4.252 (1.38), 4.261 (1.46), 4.277 (0.69), 4.286 (0.59) ,6.222 (1.82), 6.225 (1.83), 6.241 (1.98), 6.245 (1.89), 6.731 (1.15), 6.735 (1.43), 6.751 (3.26), 6.754 (2.74), 6.769 (2.24), 6.790 (2.51) , 6.809 (0.87), 7.172 (2.36), 7.217 (2.75), 7.230 (2.77), 7.391 (4.55), 7.941 (1.75), 7.953 (1.66), 8.359 (2.93), 12.612 (0.40).

LC-MS (method 6): R _t = 0.53 min; MS (ESI positive): m/z = 468 [M+H]+.

Intermediate 55-1.

tert-butyl (2R)-2-[({4-[3-(3-chloro-2-ethylanilino)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2c]pyridine -2-yl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate

Using a method similar to that described for Example 1, with tert-butyl ^R^-^^-^^-^-xrop^ethylphenyl)carbamothioyl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl} amino)methyl]pyridin-3yl}oxy)methyl]morpholine-4-carboxylate (intermediate 6-55, 473 mg, 768 μmol) as starting material; 57.0 mg (purity 95%, yield 12%) of the title compound was obtained after purification by preparative HPLC (method 10, gradient: 0.00-0.50 min 10% B, 0.5011.05 min 10-34.4% B, 11.05 - 12.46 min 34.4% B, 12.46 - 24.12 min 34.4 - 60% B) followed by flash chromatography (silica gel, DCM/EtOH, gradient 0-12%).

LC-MS (method 2): R _t = 1.26 min; MS (ESI positive): m/z = 582 [M+H] ⁺ .

Intermediate 55-2.

3-(3-chloro-2-ethylanilino)-2-(3-{[(2R)-morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro4H-pyrrolo [ 3,2-c]pyridin-4-one

Using a method similar to that described for intermediate 22-2, with tert-butyl (2R)-2-[({4-[3-(3-chloro-2-ethylanilino)-4-oxo-4,5,6, 7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2yl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate (intermediate 55-1, 70.4 mg, 121 µmol) as starting material , 58.0 mg (purity 95%, yield 95%) indicated in the title with

- 74,046,642 units were obtained after purification by flash chromatography (silica gel, DCM/EtOH + triethylamine, gradient 1-40%).

1H-NMR (400 MHz, DMSO^ ₆ ): δ [ppm] = 10.96 - 11.17 (m, 1H), 8.36 (s, 1H), 7.69 - 8.02 (m, 1H), 7.37 7.51 (m, 1H), 7.19 (s, 2H), 6.65 - 6.86 (m, 2H), 6.15 - 6.24 (m, 1H), 6.12 - 6.31 (m, 1H), 4.26 - 4.36 (m, 1H), 4.06 - 4.14 ( m, 1H), 3.85 - 3.96 (m, 2H), 3.58 - 3.67 (m, 1H), 3.40 - 3.46 (m, 2H), 3.35 - 3.39 (m, 1H), 2.69 2.96 (m, 7H), 2.56 - 2.64 (m, 1H), 1.19-1.27 (m, 6H).

LC-MS (method 2): R _t = 0.99 min; MS (ESI negative): m/z = 480 [MH] ^- .

Intermediate 56-1.

tert-butyl ^)-2-[({4-[3-(3-chloro-2-ethylanilino)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2c]pyridin- 2-yl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate

Using a method similar to that described for Example 1, with tert-butyl (2S)-2-[({4-[({5-[(3-xtop-2ethylphenyl)carbamothioyl]-6-oxo-1,2,3, 6-tetrahydropyridin-4-yl}amino)methyl]pyridin-3yl}oxy)methyl]morpholine-4-carboxylate (intermediate 6-56, 476 mg, 772 µmol) as starting material, 68.0 mg (95% purity, 14% yield of the title compound was obtained after purification by preparative HPLC (method 10, gradient: 0.00-0.50 min 20% B, 0.5012.99 min 20-40% B, 12.99 - 15.46 min 40% B, 15.46 - 24.12 min 40 - 55% B) followed by flash chromatography (silica gel, DCM/EtOH, gradient 0-12%).

LC-MS (method 2): Rt = 1.26 min; MS (ESI positive): m/z = 582 [M+H]+.

Intermediate 56-2.

3-(3-chloro-2-ethylanilino)-2-(3-{[^)-morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro4H-pyrrolo [3 ,2-c]pyridin-4-one

Using a method similar to that described for intermediate 22-2, with tert-butyl (2S)-2-[({4-[3-(3-chloro-2-ethylanilino)-4-oxo-4,5,6, 7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2yl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate (intermediate 56-1, 70.4 mg, 121 µmol) as starting material 46.9 mg (95% purity, 78% yield) of the title compound were obtained after purification by flash chromatography (silica amino acid, DCM/EtOH, 1-35% gradient).

1H-NMR (400 MHz, DMSO^ ₆ ): δ [ppm] = 11.09 (s, 1H), 8.36 (s, 1H), 7.96 (d, 1H), 7.46 (s, 1H), 7.19 ( d, 2H), 6.68 - 6.84 (m, 2H), 6.23 (dd, 1H), 4.24 - 4.34 (m, 1H), 4.03 - 4.16 (m, 1H), 3.82 - 3.96 (m, 2H), 3.57 - 3.65 (m, 1H), 3.39 - 3.48 (m, 2H), 2.82 - 2.94 (m, 5H), 2.64 - 2.79 (m, 2H), 2.54 - 2.60 (m, 1H), 1.23 (t, 3H).

LC-MS (method 2): R _t = 0.99 min; MS (ESI negative): m/z = 480 [MH] ^- .

- 75 046642

Examples

Example 1.

3-(3-chloro-2-methoxyanilino)-2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro4H-pyrrolo [ 3,2-c]pyridin-4-one

suspensions of ^-(3-chloro-2-methoxyphenyl)-4-[({3-[(1,4-dioxan-2-yl)methoxy]pyridin-4 yl}methyl)amino]-2-oxo-1, 2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 6-1, 140 mg, 240 µmol) in MeOH (2.7 ml) was added with TFA (42 µl, 540 µmol) followed by aqueous hydrogen peroxide (94 µl, purity 35%, 1.08 mmol), and the mixture was heated at 50°C for 17 hours. The reaction mixture was allowed to cool to RT and concentrated under reduced pressure. The residue was purified by preparative HPLC (Method 10, gradient: 0.00-0.50 min 15% B, 0.506.00 min 15-55% B) to give 70 mg of the title compound (51% yield).

¹ H-NMR (400 MHz, DMSO-de): δ [ppm] = 2.86 (t, 2H), 3.37 - 3.57 (m, 4H), 3.70 - 3.90 (m, 4H), 3.88 (s, 3H), 3.92 - 4.08 (m, 1H), 4.10 - 4.20 (m, 1H), 4.28 (dd, 1H), 6.15 (t, 1H), 6.68 (d, 2H), 7.16 (br s, 1H), 7.28 (d, 1H), 7.52 (s, 1H), 8.04 (d, 1H), 8.39 (s, 1H), 11.07 (s, 1H).

LC-MS (method 2): R _t = 0.98 min; MS (ESI positive): m/z = 485 [M+H] ⁺ .

Example 2.

3-(3-chloro-2-methoxyanilino)-2-(3-{[^)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7tetrahydro^H -pyrroloP^-^pyridin^-one (stereoisomer 1)

The title compound 1 (140 mg) was resolved into enantiomers using preparative chiral HPLC to give the title compound (enantiomer 1, 27 mg at R _t = 14.0 - 17.0 min) and enantiomer 2 (25 mg at R _t = 20.0 - 24.8 min, see example 3).

Preparative chiral HPLC method.

Device: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000; column: Cellulose SB 5 μ, 250x30 mm; eluent A: hexane + 0.1 vol.% diethylamine (99%); eluent B: 2-propanol; isocratic mode: 50% A + 50% B; flow 50 ml/min; UV: 254 nm.

Analytical chiral HPLC method.

Instrument: Agilent HPLC 1260; column: Cellulose SB 3 μ, 100x4.6 mm; eluent A: hexane + 0.1 vol.% diethylamine (99%); eluent B: 2-propanol; isocratic mode: 50% A + 50% B, flow 1.4 ml/min; temperature: 25°C; UV: 254 nm.

Analytical chiral HPLC: R _t = 4.49 min.

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

Enantioselective synthesis confirmed that the title compound is 3-(3-chloro-2-methoxyanilino)-2-(3-{[^)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl )-1,5,6,7-tetrahydro4H-pyrrolo[3,2-c]pyridin-4-one. 872 mg (purity 95%, yield 72%) of the title compound were prepared by analogy with Example 1 using Na(3-chloro-2-methoxyphenyl)-4-{[(3-{[^)-1,4- dioxan-2yl]methoxy}pyridin-4-yl)methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 6-2, 1.23 g, 2.36 mmol) as starting material substances followed by purification using preparative HPLC (method 10, gradient: 0.00-0.50 min 15% B, 0.50-6.00 min 15-55% B).

'H-NMR (400 MHz, DMSO-de,): 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).

- 76 046642

Analytical chiral HPLC: R _t = 4.46 min.

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

Example 3.

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

For the preparation of the title racemic compound, see Example 1. Separation of enantiomers by preparative chiral HPLC (method see Example 2) resulted in 25 mg of the title compound (at R _t = 20.0 - 24.8 min).

Analytical chiral HPLC (method see example 2): Rt = 6.56 min.

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

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

Example 4.

2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro4H-pyrrolo[ 3,2-c]pyridin-4-one

By analogy with example 1 4-[({3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methyl)amino]-N-(3fluoro-2-methoxyphenyl)-2-oxo -1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 6-4, 120 mg, 239 µmol) was used for preparation after heating for 25 hours and purification by preparative HPLC (method 10, gradient: 0.00- 0.50 min 15% B, 0.50-6.00 min 15-55% B) 25.7 mg (yield 21%) of the title compound.

¹ H-NMR (400 MHz, DMSO-66): δ [ppm] = 2.86 (t, 2H), 3.37 - 3.57 (m, 4H), 3.66 - 3.89 (m, 4H), 3.91 (s, 3H), 3.98 - 4.09 (m, 1H), 4.09 - 4.20 (m, 1H), 4.28 (dd, 1H), 6.00 (d, 1H), 6.45 - 6.54 (m, 1H), 6.64 (m, 1H) , 7.16 (br s, 1H), 7.29 (d, 1H), 7.53 (s, 1H), 8.04 (d, 1H), 8.39 (s, 1H), 11.05 (s, 1H).

LC-MS (method 2): Rt = 0.92 min; MS (ESI positive): m/z = 469 [M+H] ⁺ .

Example 5.

2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro4H-pyrrolo[ 3,2-c]pyridin-4-one (stereoisomer 1)

The title compound of Example 4 (26 mg) was resolved into enantiomers by preparative chiral HPLC to give the title compound (enantiomer 1, 11 mg, 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).

Preparative chiral HPLC method.

Device: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000; column: Cellulose SB 5 μ, 250x30 mm; eluent A: MTBE + 0.1 vol.% diethylamine (99%); eluent B: acetonitrile; gradient: 260% B for 20 min; flow 50 ml/min; UV: 280 nm.

- 77 046642

Analytical chiral HPLC method.

Instrument: Agilent HPLC 1260; column: Cellulose SB 3 μ, 100x4.6 mm; eluent A: MTBE + 0.1 vol.% diethylamine (99%); eluent B: acetonitrile; gradient: 2-60% B for 7 min, flow 1.4 ml/min; temperature: 25°C; UV: 280 nm.

Analytical chiral HPLC: R _t = 4.34 min.

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

Example 6.

2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro4H-pyrrolo[ 3,2-c]pyridin-4-one (stereoisomer 2)

For the preparation of the title racemic compound, see Example 4. Separation of enantiomers using preparative chiral HPLC (method see Example 5) resulted in 12 mg of the title compound (at R _t = 9.7 - 10.7 min, 11% yield).

Analytical chiral HPLC (method see example 5): R _t = 5.11 min.

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

Example 7.

-(2,3-dichloroanilino)-2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrag 'hydro-411pyrrolo[3 ,2-c]pyridin-4-one

By analogy with example 1 No. (2,3-dichlorophenyl)-4-[({3-[(1,4-dioxan-2-yl)methoxy]pyridin-4yl}methyl)amino]-2-oxo-1, 2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 6-7, 110 mg, 210 µmol) was used for preparation after heating for 25 hours and purification by preparative HPLC (method 10, gradient: 0.00-0.50 min 15 % B, 0.50-6.00 min 15-55% B) 34.6 mg (yield 32%) of the title compound.

1H-NMR (400 MHz, DMSO-06): δ [ppm] = 2.86 (br t, 2H), 3.35 - 3.45 (m, 3H), 3.47 - 3.56 (m, 1H), 3.65 3.75 (m , 2H), 3.75 - 3.88 (m, 2H), 3.93 - 4.04 (m, 1H), 4.06 - 4.20 (m, 2H), 6.27 (dd, 1H), 6.83 - 6.91 (m, 2H), 7.17 (br s, 1H), 7.26 (d, 1H), 7.66 (s, 1H), 8.08 (d, 1H), 8.38 (s, 1H), 11.21 (s, 1H).

LC-MS (method 2): Rt = 1.01 min; MS (ESI positive): m/z = 489 [M+H] ⁺ .

Example 8.

-(2,3-dichloroanilino)-2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4Hpyrrolo[3,2 -c]pyridin-4-one (stereoisomer 1)

The title compound of Example 7 (27 mg) was resolved into enantiomers by preparative chiral HPLC to give the title compound (enantiomer 1, 10 mg) and enantiomer 2 (12 mg, see Example 9).

- 78 046642

Preparative chiral HPLC method.

Device: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000; column: Cellulose SB 5 μ, 250x30 mm; eluent A: MTBE + 0.1 vol.% diethylamine (99%); eluent B: acetonitrile; gradient: 260% B for 20 min; flow 50 ml/min; UV: 280 nm.

Analytical chiral HPLC method.

Instrument: Agilent HPLC 1260; column: Cellulose SB 3 μ, 100x4.6 mm; eluent A: MTBE + 0.1 vol.% diethylamine (99%); eluent B: acetonitrile; gradient: 2-60% B for 7 min, flow 1.4 ml/min; temperature: 25°C; UV: 280 nm.

Analytical chiral HPLC: R _t = 5.11 min.

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

Example 9.

3-(2,3-dichloroanilino)-2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4Hpyrrolo[3, 2-c]pyridin-4-one (stereoisomer 2)

For the preparation of the title racemic compound, see Example 7. Separation of the enantiomers by preparative chiral HPLC (method see Example 8) provided 12 mg of the title compound.

Analytical chiral HPLC (method see example 8): R _t = 6.74 min.

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

Example 10.

3-(3-chloro-2-methylanilino)-2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4Hpyrrolo [ 3,2-c]pyridin-4-one

By analogy with example 1 No(3-chloro-2-methylphenyl)-4-[({3-[(1,4-dioxan-2-yl)methoxy]pyridin-4yl}methyl)amino]-2-oxo- 1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 6-10, 180 mg, 358 µmol) was used for preparation after heating for 25 hours and purification by preparative HPLC (method 10, gradient: 0.00-0.50 min 15% B, 0.50-6.00 min 15-55% B) 12.1 mg (yield 7%) of the title compound.

¹ H-NMR (400 MHz, DMSO-d^: δ [ppm] = 2.35 (s, 3H), 2.86 (br t, 2H), 3.37 -3.47 (m, 3H), 3.55 (br dd, 1H), 3.67 - 3.85 (m, 3H), 3.89 (br d, 1H), 4.01 (br dd, 1H), 4.08 - 4.18 (m, 1H), 4.24 (dd, 1H), 6.20 (d, 1H) , 6.71 - 6.80 (m, 2H), 7.19 (br s, 1H), 7.24 (d, 1H), 7.37 (s, 1H), 8.01 (d, 1H), 8.37 (s, 1H), 11.05 (s, 1H).

LC-MS (method 2): R _t = 1.02 min; MS (ESI positive): m/z = 469 [M+H] ⁺ .

Example 11.

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

- 79 046642

By analogy with example 1 N-(3-chloro-2-methoxyphenyl)-4-{[(3-{[(3R)-4-methylmorpholin-3yl]methoxy}pyridin-4-yl)methyl]amino}-2 -Oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 6-11, 82 mg, 139 µmol) was used for preparation after heating for 17 hours and purification by preparative HPLC (method 10, gradient: 0.00-0.50 min 15% B, 0.50-6.00 min 15-55% B) 11 mg (15% yield) of the title compound.

¹ H-NMR (400 MHz, DMSO-06): δ [ppm] = 11.51 - 12.57 (m, 1H), 8.40 (br s, 1H), 8.04 (br s, 1H), 7.62 (br s , 1H), 7.32 (d, 1H), 7.19 (br s, 1H), 6.71 (br d, 2H), 6.15 (dd, 1H), 4.40 (br s, 2H), 3.90 (s, 4H), 3.85 (br s, 1H), 3.60 (br d, 3H), 3.40 -3.51 (m, 3H), 3.01 (br s, 1H), 2.74 - 2.96 (m, 3H), 2.22 - 2.43 (m, 2H).

LC-MS (method 6): R _t = 0.55 min; MS (ESI positive): m/z = 498.2 [M+H]+.

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

Example 12.

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

-(3-Fluoro-2-methoxyanilino)-2-(3-hydroxypyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2c]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-methylmorpholin-2-yl)methanol (CAS 40987-46-0, 80.0 mg, 610 µmol) were added and the mixture was stirred at 50°C for 30 hours. The mixture was concentrated under reduced pressure and saturated was added. sodium bicarbonate solution. The mixture was extracted with DCM. The organic phase was filtered through a hydrophobic 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 (yield 8%).

¹ H-NMR (400 MHz, DMSO-d^: δ [ppm] = 11.05 (s, 1H), 8.40 (s, 1H), 8.02 (d, 1H), 7.52 (s, 1H), 7.29 (d, 1H), 7.16 (s, 1H), 6.64 (td, 1H), 6.50 (ddd, 1H), 6.01 (d, 1H), 4.34 (dd, 1H), 4.15 (dd, 1H), 3.88 - 4.00 (m, 5H), 3.67 (td, 1H), 3.37 - 3.47 (m, 2H), 2.85 (t, 2H), 2.77 (br d, 1H), 2.66 - 2.70 (m, 1H), 2.20 (s , 3H), 2.04 (td, 1H), 1.91 (t, 1H).

LC-MS (method 2): R _t = 0.92 min; MS (ESI positive): m/z = 482.3 [M+H] ⁺ .

Example 13.

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

The title compound of Example 12 (19 mg) was resolved into enantiomers by preparative chiral HPLC to give the title compound (enantiomer 1, 6 mg, Rt = 6.7 - 8.7 min, 3% yield) and enantiomer 2 (7 mg, at R _t = 8.9 - 11.9 min, see example 14).

Preparative chiral HPLC method.

Instrument: PrepCon Labomatic HPLC; column: Chiralcel OD-H 5 μm, 250x20; eluent A: acetonitrile + 0.1 vol.% diethylamine (99%); eluent B: ethanol; isocratic mode: 93% A + 7% B; flow 20 ml/min; temperature: 25°C; UV: 254 nm.

Analytical chiral HPLC method.

Device: Waters Alliance 2695; column: Chiralcel OD-H 5 μm, 100x4.6; eluent A: ethanol + 0.1 vol.% diethylamine (99%); eluent B: ethanol; isocratic mode: 90% A + 10% B, flow 1.4 ml/min; temperature: 25°C; UV: 254 nm.

Analytical chiral HPLC: R _t = 2.91 min.

- 80 046642 ¹ H-NMR (400 MHz, DMSO-a ₆ ): δ [ppm] = 11.05 (s, 1H), 8.40 (s, 1H), 8.02 (d, 1H), 7.53 (s, 1H), 7.29 (d, 1H), 7.16 (s, 1H), 6.64 (td, 1H), 6.50 (t, 1H), 6.01 (d, 1H), 4.34 (dd, 1H), 4.15 (dd, 1H ), 3.89 - 3.99 (m, 5H), 3.67 (td, 1H), 3.38 - 3.46 (m, 2H), 2.85 (t, 2H), 2.77 (br d, 1H), 2.61 - 2.71 (m, 1H) , 2.20 (s, 3H), 1.98 - 2.16 (m, 1H), 1.91 (t, 1H).

Example 14.

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

For the preparation of the title racemic compound, see Example 12. Enantiomer resolution using preparative chiral HPLC (method see Example 13) provided 7 mg of the title compound (at Rt = 8.9 - 11.9 min, 3% yield).

Analytical chiral HPLC (method see example 13): Rt = 3.70 min.

'H-NMR (400 MHz, DMSO-de): δ [ppm] = 11.05 (s, 1H), 8.40 (s, 1H), 8.02 (br d, 1H), 7.53 (s, 1H), 7.29 (d, 1H), 7.16 (br s, 1H), 6.59 - 6.70 (m, 1H), 6.50 (br t, 1H), 6.01 (br d, 1H), 4.34 (br dd, 1H), 4.15 ( br dd, 1H), 3.86 - 4.00 (m, 5H), 3.60 - 3.74 (m, 1H), 3.40 - 3.48 (m, 2H), 2.85 (br t, 2H), 2.77 (br d, 1H), 2.63 - 2.70 (m, 1H), 2.20 (s, 3H), 1.99 - 2.09 (m, 1H), 1.91 (br t, 1H).

Example 15.

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

By analogy with example 1

N-(3-chloro-2-methoxyphenyl)-4-[({3-[(4-methylmorpholin-2 yl)methoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5 ,6-tetrahydropyridine-3-carbothioamide (intermediate 6-15, 74.0 mg, 139 µmol) was used for preparation after heating for 18 hours and purification by preparative HPLC (method 10, gradient: 0.00-0.50 min 15% B, 0.50-6.00 min 15-55% B) 24.1 mg (purity 90%, yield 31%) of the title compound.

¹ H-NMR (400 MHz, DMSO-06): δ [ppm] = 1.86 - 1.95 (t, 1H), 2.00 - 2.09 (td, 1H), 2.20 (s, 3H), 2.66 (br d , 1H), 2.73 - 2.81 (br d, 1H), 2.86 (t, 2H), 3.42 (td, 2H), 3.61 - 3.73 (td, 1H), 3.88 (s, 3H), 3.91 - 4.02 (m, 2H), 4.16 (dd, 1H), 4.33 (dd, 1H), 6.15 (t, 1H), 6.69 (d, 2H), 7.16 (s, 1H), 7.28 (d, 1H), 7.53 (s, 1H ), 8.03 (d, 1H), 8.40 (s, 1H), 11.07 (s, 1H).

LC-MS (method 2): Rt = 0.97 min; MS (ESI positive): m/z = 498 [M+H]+.

Example 16.

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

The title compound of Example 15 (24.1 mg) was separated into enantiomers using pre

- 81 046642 parative chiral HPLC to obtain the title compound (enantiomer 1, 8 mg, at _Rt = 17.4 - 21.8, yield 11%) and enantiomer 2 (7 mg, at Rt = 12.5 - 14.5 min, see example 17 ).

Preparative chiral HPLC method.

Instrument: PrepCon Labomatic HPLC; column: Chiralpak IF 5 microns, 250x30; eluent A: hexane + 0.1 vol.% diethylamine; eluent B: ethanol + 0.1 vol.% diethylamine; isocratic mode: 50% A + 50% B; flow: 40 ml/min; temperature: 25°C; UV: 280 nm.

Analytical chiral HPLC method.

Device: Waters Alliance 2695; column: Chiralpak IF 3 microns, 100x4.6; eluent A: hexane + 0.1 vol.% diethylamine; eluent B: ethanol; isocratic mode: 50% A + 50% B; flow: 1.4 ml/min; temperature: 25°C; UV: 280 nm.

Analytical chiral HPLC: Rt = 4.55 min.

¹ H-NMR (400 MHz, DMSO-b ₆ ): 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), (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), (1.87), 11.066 (1.70).

Example 17.

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

For the preparation of the title racemic compound, see Example 15. Separation

6.692

8.402 enantiomers by preparative chiral HPLC (method see example 16) resulted in 7 mg of the title compound (at R _t = 12.5 - 14.5 min).

Analytical chiral HPLC (method see example 16): R _t = 2.93 min.

Example 18.

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

Using a method similar to that described for Example 1, with 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-3carbothioamide (intermediate 6-18, 166 mg, 302 µmol) as starting material, 13.0 mg (purity 95%, yield 8%) indicated in The title compounds were obtained after purification by preparative HPLC (method 10, gradient: 0.00 - 0.50 min 15% B, 0.50 - 6.00 min 15 - 55% B).

¹ H-NMR (400 MHz, DMSO-66): δ [ppm] = 1.88 (t, 1H), 1.93 - 2.05 (dt, 1H), 2.19 (s, 3H), 2.60 - 2.66 (d, 1H), 2.70 - 2.77 (d, 1H), 2.86 (t, 2H), 3.37 - 3.48 (m, 2H), 3.56 - 3.68 (m, 1H), 3.83 (s, 3H), 3.90 (br d, 2H ), 4.15 (m, 1H), 4.27 (dd, 1H), 5.85 (dd, 1H), 6.56 (dd, 1H), 7.13 (s, 1H), 7.33 (d, 1H), 7.64 (s, 1H) , 8.10 (d, 1H), 8.43 (s, 1H), 11.18 (s, 1H).

LC-MS (method 2): R _t = 1.00 min; MS (ESI positive): m/z = 516 [M+H] ⁺ .

- 82 046642

Example 19.

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

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

1H-NMR (400 MHz, DMSOSH ₆ ): 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 (brd, 1H), 8.42 (s, 1H), 11.19 (s, 1H).

LC-MS (method 2): Rt = 1.01 min; MS (ESI positive): m/z = 503 [M+H] ⁺ .

Example 20.

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

Using a method similar to that described for Example 1, with \-(3-fluoro-2-\1ethoxyphenyl)-4-[[(3{[^)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl) methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine3-carbothioamide (intermediate 6-20, 102 mg, 197 µmol) as starting material, 27.9 mg (90% purity, 26% yield) of the above The title compounds were obtained after purification by preparative HPLC (method 10, gradient: 0.00 - 0.50 min 10% B, 0.50 - 6.00 min 10 - 50% B).

LC-MS (method 6): Rt = 0.51 min; MS (ESI positive): m/z = 482 [M+H]+. 'H-NMR (400 MHz, DMSO^) δ [ppm]: 2.274 (13.29), 2.304 (1.76), 2.318 (0.88), 2.434 (0.91), 2.449 (5.99), 2.523 (4.32), 2.775 (0.79), 2.908 (1.13), 2.938 (0.58), 3.459 (0.55), 3.546 (0.43), 2.454 (0.88), 2.458 (1.03), 2.463 (1.43), 2.468 (0.40), 2.798 (0.70), 2.815 (1.49), 2.822 (0.88),2.832 (1.00), 3.294 (0.43), 3.406 (0.64), 3.423 (1.46),3.429 (1.13), 3.573 (1.76), 3.589 (1.13), 3.594 (1.22), 3.600 (0.55), 2.404 (1.37), 2.473 (0.91), 2.841 (1.19), 3.438 (1.28), 3.618 (0.46), (1.55), (1.16), (1.37), (0.61),

2.426

2.518

2.858

3.453

3.816 (0.94), 3.840 (1.83), 3.847 (1.95), 3.868 (2.71), 4.414 (0.46), 6.011 (1.89), 6.031 (1.19), 6.545 (0.94), 6.562 (1.19), 6.565 (0.82), 6.711 (0.67), 7.176 (2.07), 7.310 (1.06), (1.89), (1.06), (3.71),

3.875 (0.97), 3.938 (16.00), 3.951 (2.07), 4.374 (1.67), 4.386

6.514 (1.03), 6.518 (0.97), 6.535 (1.28), 6.539 (1.34),

6.655 (0.97), 6.670 (1.03), 6.675 (1.70), 6.691 (1.55),

7.323 (3.68), 7.514 (0.43), 7.527 (0.52), 7.533 (0.58),

6.541

6.696

7.601 (4.56), 7.977 (5.29), 7.990 (4.50), 8.067 (0.61), 8.080 (0.55), 8.358 (6.27), 8.439 (0.73), 12.011 (2.13).

Example 21.

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

- 83 046642

Using a method similar to that described for Example 1, with N(3-chloro-2-methoxyphenyl)-4-{[(3{[(3 S)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl) methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine3-carbothioamide (intermediate 6-21, 99.5 mg, 187 µmol) as starting material, 4.70 mg (98% purity, 5%) of the above The title compounds were obtained after purification by preparative HPLC (method 10, gradient: 0.00 - 0.50 min 10% B, 0.50 - 6.00 min 10 - 50% B).

¹ H-NMR (400 MHz, DMSO-b ₆ ): δ [ppm] = 1.232 (0.45), 2.276 (9.36), 2.426 (0.63), 2.434 (0.67), 2.456 (0.51), 2.464 (0.76 ), 2.472 (0.79), 2.518 (1.95), 2.523 (1.26), 2.539 (9.95), 2.806 (0.54), 2.823 (1.37), 2.841 (1.19), 2.860 (0.60), 2.910 (0.85), 2.940 (0.76 ), 3.408 (0.49), 3.425 (1.12), 3.431 (0.95), 3.441 (1.04), 3.454 (0.49), 3.460 (0.44), 3.544 (0.71), 3.572 (1.31), 3.588 (0.84), 3.594 (0.92 ), 3.599 (0.96), 3.617 (0.47), 3.817 (0.72), 3.841 (1.23), 3.847 (1.34), 3.868 (0.69), 3.875 (0.63), 3.912 (16.00), 3.924 (0.49), 4.376 (1.24 ), 4.387 (2.11), 6.151 (1.35), 6.162 (2.22), 6.175 (1.39), 6.718 (3.50), 6.720 (3.93), 6.731 (4.23), 7.179 (1.54), 7.299 (2.18), 7.312 (2.21 ), 7.614 (3.34), 7.983 (1.76), 7.995 (1.68), 8.362 (2.68), 12.027 (1.61).

LC-MS (method 6): Rt = 0.54 min; MS (ESI positive): m/z = 498 [M+H]+.

Example 22.

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

F ^NC 9

3-(3-Fluoro-2-methoxyanilino)-2-(3-{[DO)-morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7tetrahydro-4H-pyrrolo[3 ,2-c]pyridin-4-one (intermediate 22, 50.0 mg, 107 µmol) was dissolved in DMF (1.6 ml), triethylamine (89 µl, 640 µmol) and 2,2difluoroethyl trifluoromethanesulfonate (64 µl, 480 µmol) were added. and the mixture was stirred for 1 hour at RT. 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 obtain 11.3 mg (purity 90%, yield 18%) of the title compound.

¹ H-NMR (400 MHz, DMSO-66): δ [ppm] = 2.24 (t, 1H), 2.34 - 2.40 (dd, 1H), 2.78 (m, 1H), 2.78 - 2.81 (m, 1H), 2.83 (m, 1H), 2.85 - 2.90 (t, 2H), 2.90 - 2.97 (d, 1H), 3.38 - 3.47 (m, 2H), 3.68 (dt, 1H), 3.89 - 3.92 (s, 3H), 3.92 - 4.03 (m, 2H), 4.17 (dd, 1H), 4.29 (dd, 1H), 5.97 - 6.02 (d, 1H), 6.02 - 6.34 (tt, 1H), 6.47 - 6.54 (m, 1H), 6.64 (td, 1H), 7.16 (s, 1H), 7.29 (d, 1H), 7.54 (s, 1H), 8.02 (d, 1H), 8.40 (s, 1H), 11.03 (s, 1H ).

LC-MS (method 2): Rt = 1.04 min; MS (ESI positive): m/z = 532 [M+H] ⁺ .

Example 23.

3-(3-fluoro-2-methoxyanilino)-2-(3-{[^)-4-(2,2,2-trifluoroethyl)morpholin-2-yl]methoxy}pyridin-4yl)-1,5, 6,7-tetrahydro-4H-pyrrolo[3,2-c]pyrigin-4-one

F F

Using a method similar to that described for Example 22, with 3-(3-fluoro-2-methoxyanilino)-2-(3{[(2S)-morpholin-2-yl]methoxy}pyridin-4-yl)-1,5 ,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (intermediate 22, 35.0 mg, 74.9 µmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (CAS 6226-25-1, 16 µl, 110 µmol) as starting materials, 11.9 mg (purity 95%, yield 27%) of the title compound were obtained after preparative HPLC (method 10, gradient: 0.00 - 0.50 min 30% B, 0.50 - 6.00 min 30 - 70% B).

¹ H-NMR (400 MHz, DMSO^): 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

- 84 046642 (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 (16.0 0 ), 3.934 (1.11), 3.966 (1.11), 3.983 (0.72), 3.999 (0.75), 4.008 (0.65), 4.157 (1.04), 4.174 (1.00), 4.183 (1.51), 4.199 (1.22), 4.277 (1.40 ), 4.286 (1.36), 4.303 (1.04), 4.312 (0.86), 5.989 (1.94),6.010 (1.97), 6.472 (0.86), 6.475 (0.86), 6.493 (1.26), 6.497 (1.26), 6.502 (0.93 ), 6.520 (1.18), 6.523 (1.04),6.611 (0.90), 6.626 (1.04), 6.632 (1.54), 6.647 (1.51), 6.652 (0.75), 6.668 (0.65), 7.161 (2.22), 7.278 (3.52 ),7.291 (3.55), 7.535 (4.77), 8.018 (4.38), 8.030 (4.02), 8.391 (6.17), 11.018 (2.48).

LC-MS (method 2): Rt = 1.09 min; MS (ESI positive): m/z = 550 [M+H]+.

Example 24.

3-(3-chloro-2-methoxyanilino)-2-{3-[2-(4-dioxan-2-yl)ethoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4HpyPPROlo[ 3,2-c]pyridin-4-one

Using a method similar to that described for Example 1, with N(3-chloro-2-methoxyphenyl)-4-[({3-[2(1,4-dioxan-2-yl)ethoxy]pyridin-4-yl}methyl )amino]-2-oxo-1,2,5,6-tetrahydropyridine-3carbothioamide (intermediate 6-24, 105 mg, 197 µmol) as starting material, 43.5 mg (purity 95%, yield 42%) indicated in The title compounds were obtained after preparative HPLC (method 7).

¹ H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.817 (0.39), 1.834 (1.18), 1.849 (1.57), 1.861 (1.08), 1.876 (0.49), 2.518 (3.04) , 2.522 (2.06), 2.673 (0.59), 2.833 (0.88), 2.846 (1.87), 2.863 (0.98), 3.204 (0.88), 3.231 (1.47), 3.260 (1.08), 3.312 (1.28), 3.396 (1.67) , 3.408 (2.16), 3.413 (2.16), 3.426 (1.28), 3.456 (1.18), 3.462 (1.08), 3.484 (0.98), 3.490 (0.98), 3.521 (0.79), 3.525 (0.88), 3.549 (1.08) , 3.554 (1.18), 3.582 (0.69),3.625 (1.28), 3.648 (1.37), 3.668 (2.45), 3.678 (0.98), 3.693 (1.37), 3.716 (1.28), 3.745 (0.98), 3.858 (16.00) , 4.226 (1.37), 4.241 (2.94), 4.257 (1.37), 6.103 (1.47), 6.115 (2.06), 6.127 (1.47), 6.640 (5.60), 6.650 (3.63), 7.108 (1.77), 7.287 (2.65) , 7.299 (2.75), 7.458 (3.93), 8.020 (3.04), 8.033 (2.85), 8.350 (4.32), 11.191 (1.96).

LC-MS (method 6): Rt = 0.68 min; MS (ESI positive): m/z = 499 [M+H]+.

Example 25.

3-(3-chloro-2-methoxyanilino)-2-{3-[2-(4-dioxan-2-yl)ethoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4Hpyrrolo[ 3,2-c]pyridin-4-one (stereoisomer 1)

The title compound of Example 24 (40 mg) was resolved into enantiomers by preparative chiral HPLC to give the title compound (enantiomer 1, 18.0 mg, Rt = 18.8 - 21.3 min, 96% purity) and enantiomer 2 (17 mg, at Rt = 21.7 - 24.5 min, see example 26).

Preparative chiral HPLC method.

Instrument: PrepCon Labomatic HPLC; column: YMC Cellulose SB 5 μ, 250x30; eluent A: methyl tert-butyl ether + 0.1 vol.% diethylamine; eluent B: acetonitrile + 0.1 vol.% diethylamine; gradient: 0-20 min 2-60% B; flow: 40 ml/min; temperature: 25°C; UV: 280 nm.

Analytical chiral HPLC method.

Device: Waters Alliance 2695; column: YMC Cellulose SB 3 μ, 100x4.6; eluent A: methyl tert-butyl ether + 0.1 vol.% diethylamine; eluent B: acetonitrile; gradient: 0-7 min 2-60% B; flow: 1.4 ml/min; temperature: 25°C; UV: 280 nm.

Analytical chiral HPLC: Rt = 4.94 min.

Optical rotation: [a]D = -1.6° +/- 1.63° (c = 2.8 mg/ml in methanol).

¹ H-NMR (400 MHz, DMSO-06) δ [ppm] = 1.835 (1.01), 1.851 (1.31), 1.862 (0.93), 1.877 (0.41), 2.518

- 85 046642 (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 (1.30), 3.235 (1.27 (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).

Example 26.

3-(3-chloro-2-methoxyanilino)-2-{3-[2-(4-dioxan-2-yl)ethoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4Hpyrrolo[ 3,2-c]pyridin-4-one (stereoisomer 2)

For the preparation of the title racemic compound, see Example 24. Separation of enantiomers by preparative chiral HPLC (method see Example 25) provided 25 mg of the title compound (at R _t = 21.7 - 24.5 min, 19% yield).

Analytical chiral HPLC (method see example 25): R _t = 5.49 min.

Optical rotation: [a]D = 2.5° +/- 1.93° (c = 2.7 mg/ml in methanol).

Example 27.

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

3-(3-Chloro-5-fluoro-2-methoxyanilino)-2-(3-{[^)-morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7tetrahydro-4H -pyrrolo[3,2-c]pyridin-4-one (intermediate 27, 24.0 mg, 47.8 µmol) was dissolved in methanol (650 µl), formaldehyde (7.2 µl, 37% purity, 96 µmol) and acetic acid ( 2.7 µl, 48 µmol), and the mixture was stirred for 15 min at RT. Sodium triacetoxyborohydride (15.2 mg, 71.7 µmol) was added and the mixture was stirred for 1 h at RT. The mixture was diluted with methanol, filtered through an SCX column and washed with methanol and ammonia (7 M in methanol). 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 obtain 17.3 mg (95% purity, 61% yield) of the title compound in form of its formate salt.

LC-MS (method 2): R _t = 1.01 min; MS (ESI positive): m/z = 516 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO^6) 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).

3-(3-chloro-5-fluoro-2-methoxyanilino)-2-[3-[[^)-4-methylmorpholin-4-ium-2-yl]methoxy]-4pyridyl]-1,5,6 formate ,7-tetrahydropyrrolo ^^-^pyridin^-one was dissolved in DCM and washed with saturated aqueous NaHCO ₃ and brine to obtain 9.00 mg (purity 90%, yield 33%) of the title compound as the free base.

1H-NMR (400 MHz, DMSO^): 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).

Example 28.

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

- 86 046642

Using a method similar to that described for Example 22, with 3-(3-chloro-5-fluoro-2-methoxyanilino)2-(3-{[^)-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-trifluoroethyltrifluoromethanesulfonate (CAS 6226-25- 1, 11 µl, 75 µmol) as starting materials, 15.1 mg (purity 95%, yield 49%) of the title compound were obtained after preparative HPLC (method 10, gradient: 0.00 - 0.50 min 30% B, 0.50 - 6.00 min 30 - 70% B).

¹ H-NMR (400 MHz, DMSOL6): 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).

LC-MS (method 2): R _t = 1.19 min; MS (ESI positive): m/z = 584 [M+H]+.

Example 29.

-(3-chloro-2-ethylanilino)-2-{ 3 - [(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl }-1,5,6,7 -tetrahydro4H-pyrrolo[3,2 -c]pyridin-4-one

Using a method similar to that described for Example 1, with N(3-chloro-2-ethylphenyl)-4-[({3-[(4methylmorpholin-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2 -oxo-1,2,5,6-tetrahydropyridine-3carbothioamide (intermediate 6-29, 300 mg, 566 µmol) as starting material, 3.00 mg (85% purity, 1% yield) of the title compound was obtained after preparative HPLC (method 10, gradient: 0.00 - 0.50 min 30% B, 0.50 - 6.00 min 30 - 70% B).

¹ H-NMR (400 MHz, DMSO-d^: 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).

LC-MS (method 2): R _t = 1.07 min; MS (ESI positive): m/z = 496 [M+H] ⁺ .

Example 30.

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

Using a method similar to that described for Example 1, with N(3-chloro-2-methoxyphenyl)-4-[({3[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridin-4 -yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine3-carbothioamide (intermediate 6-30, 55.0 mg, 101 µmol) as starting material, 28.00 mg (purity 98%, yield 53 %) of the title compound was obtained after purification using preparative HPLC (method 10, gradient: 0.00 - 0.50 min 30% B, 0.50 - 6.00 min 30 - 70% B).

¹ H-NMR (400 MHz, DMSO-d^: 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 (16.00) , 3.894 (0.49), 3.902 (0.53), 3.910

- 87 046642 (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 (o .76), 4.330 (0.67), 6.143 (1.4θ), 6.155 (1.71), 6.167 (1.4θ), 6.653 (θ.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).

LC-MS (method 6): Rt = 0.80 min; MS (ESI positive): m/z = 513 [M+H] ⁺ .

Example 31.

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

The title compound of Example 30 (26.3 mg) was resolved into enantiomers by preparative chiral HPLC to give the title compound (enantiomer 1, 11.00 mg, at Rt = 10.7 - 13.4 min) and enantiomer 2 (10 mg, at Rt = 14.0 - 19.9 min, see example 32).

Preparative chiral HPLC method.

Instrument: PrepCon Labomatic HPLC; column: Chiralcel OD-H 5 μm, 250x20; eluent A: hexane + 0.1 vol.% diethylamine; eluent B: ethanol + 0.1 vol.% diethylamine; isocratic mode: 70% A + 30% B; flow: 20 ml/min; temperature: 25°C; UV: 280 nm.

Analytical chiral HPLC method.

Device: Waters Alliance 2695; column: Chiralcel OD-H 5 μm, 100x4.6; eluent A: hexane + 0.1 vol.% diethylamine; eluent B: ethanol; isocratic mode: 70% A + 30% B; flow: 1.4 ml/min; temperature: 25°C; UV: 280 nm.

Analytical chiral HPLC: Rt = 6.72 min.

Example 32.

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

For the preparation of the title racemic compound, see Example 30. Separation of enantiomers by preparative chiral HPLC (method see Example 31) yielded 10 mg of the title compound (at Rt = 14.0 - 19.9 min).

Analytical chiral HPLC (method see example 31): Rt = 10.04 min.

Example 33.

2-(3-{[5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyanilino)-1,5,6, 7tetrahydro^^pyrrolo[3,2-c]pyridin-4-one

Using a method similar to that described for Example 1, with 4-{[(3-{[5,5-dimethyl-1,4-dioxan-2yl]methoxy}pyridin-4-yl)methyl]amino}-M-(3 -fluoro-2-methoxyphenyl)-2-oxo-1,2,5,6-tetrahydropyridine

- 88 046642

With 3-carbothioamide (intermediate 6-33, 125 mg, 236 µmol) as starting material, 15.00 mg (80% purity, 10% yield) of the title compound was obtained after preparative HPLC (Method 7).

Ή-NMR (400 MHz, DMSO-b6) δ [ppm]: 1.068 (15.53), 1.236 (15.37), 2.517 (2.98), 2.522 (2.00), 2.817 (1.52), 2.834 (3.10), 2.851 (1.65), 2.903 (0.47), 2.921 (0.89), 2.936 (0.48), 3.402 (2.87), 3.408 (2.55), 3.415 (2.29), 3.431 (3.39), 3.580 (0.97), 3.588 (1.12), 3.609 (2.52), 3.618 (2.17), 3.633 (3.03), 3.651 (2.10), 3.661 (2.34), 3.677 (2.32), 3.706 (1.26), 3.900 (16.00), 3.917 (5.39), 3.933 (0.80), 3.942 (0.71), 4.147 (1.18), 4.163 (1.12), 4.173 (1.56), 4.189 (1.34), 4.294 (1.63), 4.302 (1.37), 4.320 (1.26), 4.329 (0.93), 4.769 (0.55), 4.780 (0.55), 4.787 (0.58), 4.797 (0.52), 5.696 (0.85), 5.759 (1.92), 5.985 (0.55), 6.000 (1.88), 6.020 (1.84), 6.455 (0.97), 6.476 (1.43), 6.479 (1.49), 6.503 (1.30), 6.597 (0.86), 6.612 (1.11), 6.618 (1.49), 6.625 (0.60), 6.633 (1.47), 6.638 (0.71), 6.653 (0.62), 7.141 (2.11), 7.277 (3.15), 7.289 (3.21), 7.297 (1.00), 7.479 (4.43), 7.531 (1.26), 8.030 (3.74), 8.042 (3.54), 8.399 (6.35), 11.053 (2.30), 11.085 (0.73).

LC-MS (method 6): Rt = 0.71 min; MS (ESI positive): m/z = 497 [M+H]+.

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

The title compound of Example 33 (15.0 mg) was resolved into enantiomers by preparative chiral HPLC to give the title compound (enantiomer 1, 5.00 mg, Rt = 10.9 - 13.1 min, 32% yield) and enantiomer 2 (4 mg, at Rt = 13.5 - 18.3 min, see example 34).

Preparative chiral HPLC method.

Instrument: PrepCon Labomatic HPLC; column: Chiralcel OD-H 5 μm, 250x20; eluent A: hexane + 0.1 vol.% diethylamine; eluent B: ethanol; isocratic mode: 70% A + 30% B; flow: 20 ml/min; temperature: 25°C; UV: 280 nm.

Analytical chiral HPLC method.

Device: Waters Alliance 2695; column: Chiralcel OD-H 5 μm, 100x4.6; eluent A: hexane + 0.1 vol.% diethylamine; eluent B: ethanol; isocratic mode: 70% A + 30% B; flow: 1.4 ml/min; temperature: 25°C; UV: 280 nm.

Analytical chiral HPLC: Rt = 6.58 min.

Optical rotation: [a] _D = 2.6° +/- 1.66° (c = 2.3 mg/ml in methanol).

Example 34.

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

For the preparation of the title racemic compound, see Example 33. Enantiomer resolution using preparative chiral HPLC (method see Example 33) provided 4 mg of the title compound (at Rt = 13.5 - 18.3 min, 24% yield).

Analytical chiral HPLC (method see example 33): Rt = 9.21 min.

Ή-NMR (400 MHz, DMSO-a ₆ ) δ [ppm]: 1.046 (0.67), 1.068 (13.52), 1.108 (0.86), 1.185 (0.55), 1.236 (13.07), 1.259 (0.64), 2.084 (0.44), 2.331 (0.49), 2.518 (2.88), 2.523 (1.93), 2.673 (0.47), 2.817 (1.52), 2.834 (3.11), 2.851 (1.67), 3.403 (2.57), 3.409 (2.57), 3.416 (2.39), 3.431 (2.89), 3.581 (0.83), 3.589 (0.95), 3.611 (1.68), 3.618 (1.66), 3.633 (2.61), 3.652 (1.72), 3.661 (2.23), 3.678 (1.86), 3.707 (1.00), 3.901 (16.00), 3.917 (1.07), 3.926 (0.91), 3.934 (0.65), 3.943 (0.58), 4.148 (1.01), 4.165 (0.96), 4.174 (1.36), 4.190 (1.18), 4.294 (1.36), 4.303 (1.36), 4.320 (1.03), 4.329 (0.91), 6.000 (1.83), 6.021 (1.91), 6.455 (0.83), 6.459 (0.87), 6.476 (1.19), 6.480 (1.27), 6.486 (0.94), 6.503 (1.10), 6.506 (1.01), 6.597 (0.86), 6.612 (1.01), 6.618 (1.47), 6.633

- 89 046642 (1.44), 6.638 (0.75), 6.654 (0.61), 7.141 (2.15), 7.277 (2.70), 7.290 (2.68), 7.479 (4.53), 8.030 (2.67), 8.043 (2.48), 8.400 (4.0 7 ), 11.054 (2.33).

Example 35.

2-(3-{2-[1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro4H- pyrrolo[3,2-c]pyridin-4-one (stereoisomer 1) CH ₃ o

Using a method similar to that described for Example 1, with 4-{[(3-{2-[1,4-dioxan-2yl]ethoxy}pyridin-4-yl)methyl]amino}-X-(3-fluoro-2 -methoxyphenyl)-2-oxo-1,2,5,6-tetrahydropyridine-3carbothioamide (intermediate 6-35, 130 mg, 252 µmol) as starting material, 30.0 mg (purity 90%, yield 22%) indicated in The title racemic compound was obtained after preparative HPLC (method 7).

¹ H-NMR (400 MHz, DMSO-b6): δ [ppm] = 1.229 (0.48), 1.827 (0.71), 1.843 (1.74), 1.859 (2.06), 1.869 (1.50), 1.885 (0.63) , 2.331 (0.40), 2.517 (2.30), 2.522 (1.50), 2.539 (4.51), 2.669 (0.55), 2.673 (0.48), 2.831 (1.19), 2.842 (2.22), 2.848 (2.06), 2.858 (1.19) , 2.865 (1.11), 3.162 (1.27), 3.174 (0.71), 3.207 (1.35), 3.233 (2.14), 3.236 (2.14), 3.262 (1.58), 3.406 (4.44), 3.412 (3.88), 3.428 (2.22) , 3.456 (1.90), 3.462 (1.82),3.484 (1.50), 3.490 (1.50), 3.522 (1.27), 3.527 (1.35), 3.550 (1.66), 3.556 (1.90), 3.578 (0.95), 3.583 (1.27) ,3.624 (2.22), 3.651 (2.14), 3.671 (3.25), 3.681 (1.50), 3.695 (2.22), 3.700 (1.98), 3.716 (2.06), 3.721 (1.98), 3.728 (1.35), 3.745 (1.50) , 3.780 (0.71), 3.862 (0.95), 3.889 (16.00), 3.906 (1.19), 4.074 (0.71), 4.222 (2.14), 4.238 (3.96), 4.253 (1.82), 4.754 (0.55), 5.960 (1.98) , 5.981 (1.98), 6.430 (0.95), 6.433 (0.95), 6.451 (1.43),6.455 (1.43), 6.461 (0.95), 6.478 (1.19), 6.482 (1.11), 6.572 (0.95), 6.587 (1.11) , 6.593 (1.58), 6.608 (1.58),6.613 (0.79), 6.628 (0.63), 7.108 (2.30), 7.292 (2.77), 7.305 (2.77), 7.455 (4.67), 8.017 (2.61), 8.030 (2.46) ,8.344 (4.04), 11.175 (2.46).

LC-MS (method 6): Rt = 0.63 min; MS (ESI positive): m/z = 483 [M+H]+.

Racemic 2-(3-{2-[1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyanilino)1,5,6,7-tetrahydro- 4H-pyrrolo[3,2-c]pyridin-4-one (25.0 mg) was resolved into enantiomers by preparative chiral HPLC to give the title compound (enantiomer 1, 12.00 mg, Rt = 15.1 - 17.0 min) and enantiomer 2 (4 mg, at Rt = 19.8 - 26.8 min, see example 36).

Preparative chiral HPLC method.

Instrument: PrepCon Labomatic HPLC; column: Chiralpak IF 5 microns, 250x30; eluent A: hexane + 0.1 vol.% diethylamine; eluent B: ethanol + 0.1 vol.% diethylamine; isocratic mode: 70% A + 30% B; flow: 50 ml/min; temperature: 25°C; UV: 280 nm.

Analytical chiral HPLC method.

Device: Waters Alliance 2695; column: Chiralpak IF 3 microns, 100x4.6; eluent A: hexane + 0.1 vol.% diethylamine; eluent B: ethanol; isocratic mode: 70% A + 30% B; flow: 1.4 ml/min; temperature: 25°C; UV: 280 nm.

Analytical chiral HPLC: Rt = 4.68 min.

Optical rotation: [a]D = -12.9° +/- 1.72° (c = 1.4 mg/ml in methanol).

Example 36.

2-(3-{2-[1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro4H- pyrrolo[3,2-c]pyridin-4-one (stereoisomer 2)

For the preparation of the title racemic compound, see Example 35. Resolution of the enantiomers using preparative chiral HPLC (see Example 35 for method) yielded 4

- 90 046642 mg of the title compound (at R _t = 19.8 - 26.8 min).

Analytical chiral HPLC (method see example 35): R _t = 6.58 min.

Optical rotation: [a]D = -21.4° +/- 1.94° (c = 1.3 mg/ml in methanol).

Example 37.

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

Using a method similar to that described for Example 1, with N(3-fluoro-2-methoxyphenyl)-4-{[(3{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)methyl ]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 6-37, 130 mg, 252 µmol) as starting material, 35.00 mg (purity 92%, yield 27%) indicated in The title compounds were obtained after preparative HPLC (method 7).

¹ H-NMR (400 MHz, DMSO-66): δ [ppm] = 2.277 (13.00), 2.292 (1.54), 2.307 (0.96), 2.324 (0.70), 2.329 (0.89), 2.334 (0.66) , 2.407 (0.69), 2.428 (1.27), 2.435 (1.36), 2.520 (2.98), 2.525 (1.88), 2.667 (0.63), 2.671 (0.83), 2.676 (0.62), 2.777 (0.67), 2.801 (0.82) , 2.818 (1.61), 2.825 (0.99), 2.835 (1.02), 2.844 (1.23), 2.860 (0.82), 2.911 (1.23), 2.940 (1.09), 3.388 (0.53), 3.408 (0.96), 3.425 (1.66) , 3.431 (1.41), 3.441 (1.54),3.455 (0.69), 3.548 (1.12), 3.576 (1.89), 3.592 (1.35), 3.597 (1.35), 3.602 (1.33), 3.621 (0.70), 3.626 (0.70) ,3.783 (1.37), 3.785 (1.33), 3.818 (1.11), 3.843 (1.97), 3.849 (2.06), 3.870 (1.11), 3.878 (0.99), 3.941 (16.00), 3.954 (1.12), 4.078 (0.56) , 4.349 (0.43), 4.358 (0.42), 4.376 (1.85), 4.388 (2.91), 4.416 (0.47), 6.013 (1.90), 6.034 (1.91), 6.516 (0.95), 6.520 (0.92), 6.537 (1.27) , 6.541 (1.33), 6.547 (0.95), 6.564 (1.12), 6.568 (1.03),6.657 (0.94), 6.672 (1.04), 6.678 (1.61), 6.693 (1.51), 6.698 (0.80), 6.714 (0.65) , 7.180 (2.21), 7.313 (3.72), 7.325 (3.57), 7.605 (4.51), 7.980 (4.40), 7.993 (4.17), 8.360 (6.21), 8.414 (0.59), 12.014 (2.24).

LC-MS (method 6): Rt = 0.51 min; MS (ESI positive): m/z = 482 [M+H]+.

Example 38.

2-[3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]-4-pyridyl]-3-(3-fluoro-2-methylanilino)-1,5,6,7tetrahydropyrrolo [3,2-c]pyridin-4-one

Using a method similar to that described for Example 1, with 4-[[3-[(5,5-dimethyl-1,4-dioxan-2yl)methoxy]-4-pyridyl]methylamino]-N-(3-fluoro-2 -methylphenyl)-6-oxo-2,3-dihydro-1H-pyridine-5 carbothioamide (intermediate 6-38, 190 mg, 369 µmol) as starting material, 30.2 mg (purity 98%, yield 17%) The title compound was obtained after preparative HPLC (method 10, gradient: 0.00 - 0.50 min 15% B, 0.50 - 5.59 min 15 - 51.7% B, 5.59 - 5.88 min 51.7% B, 5.88 - 5.93 min 51.7 -52.1% B, 5.93 - 5.95 min 52.1% B, 5.95 - 6.32 min 52.1-55% B).

¹ H-NMR (400 MHz, DMSO-66): δ [ppm] = 1.073 (16.00), 1.243 (14.37), 2.177 (9.43), 2.180 (9.37), 2.520 (3.20), 2.525 (2.30) , 2.542 (0.63), 2.826 (1.74), 2.843 (3.73), 2.861 (2.01), 3.406 (3.15), 3.417 (2.63), 3.424 (2.71), 3.434 (3.36), 3.569 (0.91), 3.577 (1.10) , 3.598 (1.87), 3.607 (1.84), 3.643 (4.40), 3.671 (4.37), 3.699 (1.24), 3.881 (0.69), 3.890 (0.81), 3.898 (1.03), 3.907 (0.94), 3.915 (0.67) , 3.923 (0.65), 4.121 (1.26),4.137 (1.17), 4.147 (1.71), 4.163 (1.45), 4.265 (1.62), 4.274 (1.65), 4.291 (1.24), 4.300 (1.11), 6.059 (2.34) ,6.080 (2.42), 6.427 (1.06), 6.449 (1.94), 6.470 (1.21), 6.721 (0.73), 6.742 (1.51), 6.759 (1.47), 6.779 (0.63), 7.168 (2.42), 7.232 (4.19) , 7.244 (4.24), 7.308 (4.82), 7.997 (5.22), 8.009 (4.80), 8.373 (6.80), 11.029 (2.61).

LC-MS (method 6): R _t = 0.74 min; MS (ESI positive): m/z = 481 [M+H]+.

Example 39.

2-[3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]-4-pyridyl]-3-(3-fluoro-2-methylanilino)-1,5,6,7

- 91 046642 tetrahydropyrrolo[3,2-c]pyridin-4-one (stereoisomer 1)

The title compound of Example 38 (30.2 mg) was resolved into enantiomers by preparative chiral HPLC to give the title compound (enantiomer 1, 10.00 mg, R _t = 30.4 - 36.0 min, 5% yield) and enantiomer 2 (9 mg, R _t = 45.9 - 51.7 min).

Preparative chiral HPLC method: NPB

Instrument: PrepCon Labomatic HPLC; column: Chiralpak IF 5 microns, 250x30; eluent A: hexane + 0.1 vol.% diethylamine; eluent B: ethanol + 0.1 vol.% diethylamine; isocratic mode: 90% A + 10% B; flow: 50 ml/min; temperature: 25°C; UV: 254 nm.

Analytical chiral HPLC method: NPB

Device: Waters Alliance 2695; column: Chiralpak IF 3 microns, 100x4.6; eluent A: hexane + 0.1 vol.% diethylamine; eluent B: ethanol; isocratic mode: 90% A + 10% B; flow: 1.4 ml/min; temperature: 25°C; UV: 254 nm.

Analytical chiral HPLC: R _t = 11.60 min.

Optical rotation: [a]D = - 6.4° +/- 0.47° (c = 6.2 mg/ml in DMSO).

1H-NMR (400 MHz, DMSO-de): δ [ppm] = 0.700 (5.10), 0.744 (1.84), 0.764 (1.85), 0.836 (0.93), 0.854 (1.20), 1.073 (15.11), 1.152 (5.69), 1.235 (8.54), 1.243 (16.00), 1.296 (2.78), 1.350 (0.95), 1.378 (0.62), 1.672 (0.88), 2.179 (9.59), 2.525 (2.28), 2.827 (1.75), 2.844 (3.61),2.861 (2.72), 3.434 (3.38), 3.570 (0.86), 3.578 (1.00), 3.599 (1.76),3.607 (1.09), 3.882 (0.67), 3.890 (0.80), 3.899 (1.00), 3.907 (0.92),3.915 (1.06), 4.147 (1.50), 4.164 (1.30), 4.267 (1.44), 4.275 (1.48),4.292 (2.31), 6.428 (1.04), 6.450 (1.90), 6.472 (1.17), 6.722 (0.70),6.742 (0.44), 7.170 (2.40), 7.201 (0.51), 7.222 (0.55), 7.234 (1.95),7.246 (1.08), 8.375 (1.57), 11.031 (2.61).

(1.95), 3.407 (3.22), 3.418 (2.68), 3.424 (1.71), 3.644 (4.10), 3.671 (4.05), 3.700 (0.66), 3.924 (0.61), 4.121 (1.09), 4.138 (1.11), 4.301 (1.01), 6.060 (2.24), 6.080 (1.49), 6.759 (1.45), 6.780 (0.58), 6.959 (1.95), 7.309 (4.47), 7.999 (1.12), 8.010

Example 40.

3-[2-(2,2-difluoroethyl)-3-fluoroanilino]-2-[3-(1,4-dioxan-2-ylmethoxy)-4-pyridyl]-1,5,6,7tetrahydropyrroloRD-^pyridine ^-he

Using a method similar to that described for Example 1, with N[2-(2,2-difluoroethyl)-3-fluorophenyl]4-{[(3-{[1,4-dioxan-2-yl]methoxy}pyridin-4 -yl)methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3carbothioamide (intermediate 6-40, 19.5 mg, 36.3 µmol) as starting material, 3.80 mg (purity 92%, yield 19 %) of the title compound was obtained after purification using preparative HPLC (method 10, gradient: 0.00 - 0.50 min 30% B, 0.50 - 6.00 min 30 - 70% B).

1H-NMR (400 MHz, DMSO): δ [ppm] = 2.86 (t, 2H), 3.22 - 3.30 (m, 1H), 3.39 - 3.48 (m, 3H), 3.50 3.58 (td, 1H) , 3.67 - 3.93 (m, 5H), 3.97 - 4.06 (m, 1H), 4.09 - 4.18 (m, 1H), 4.25 - 4.31 (dd, 1H), 6.07 - 6.17 (d, 1H), 6.29 - 6.63 ( q, 2H), 6.83 - 6.94 (m, 1H), 7.10 (s, 1H), 7.34 (s, 1H), 7.37 (d, 2H), 8.00 (d, 1H), 8.38 (s, 1H), 11.07 (s, 1H).

LC-MS (method 2): R _t = 0.99 min; MS (ESI positive): m/z = 503 [M+H] ⁺ .

Example 41.

3-[2-(2,2-difluoroethyl)-3-fluoroanilino]-2-(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)^^D-tetrahydro ^H-pyrroloRD-Dpyridin^-one

- 92 046642

3-[2-(2,2-difluoroethyl)-3-fluoroanilino]-2-(3-{[^)-morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7tetrahydro -4H-pyrrolo[3,2-c]pyridin-4-one (intermediate 41, 22.0 mg, 43.9 µmol) was suspended in MeOH and formaldehyde (6.6 µl, 37% purity, solution in water, 88 µmol) and acetic acid were added acid (2.5 µl, 44 µmol). The reaction mixture was stirred for 15 minutes at room temperature. Sodium triacetoxyborohydride (13.9 mg, 65.8 µmol) was added and the mixture was stirred for 1 hour at room temperature. The mixture was filtered through an SCX column and washed with MeOH and ammonia (7M in MeOH). The ammonia filtrate was evaporated 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 8.8 mg (90% purity, 35% yield) of the title compound .

¹ H-NMR (400 MHz, DMSO-66): δ [ppm] = 2.07 (m, 3H), 2.22 (s, 3H), 2.63 -2.83 (m, 2H), 2.86 (t, 2H) , 3.27 - 3.31 (m, 1H), 3.35 - 3.38 (m, 1H), 3.42 (td, 2H), 3.68 (td, 1H), 3.91 - 4.00 (m, 2H), 4.12 - 4.19 (dd, 1H) , 4.33 (dd, 1H), 6.13 (d, 1H), 6.29 - 6.64 (m, 1H), 6.89 (q, 1H), 7.07 - 7.14 (m, 1H), 7.33 - 7.40 (t, 2H), 7.99 (d, 1H), 8.39 (s, 1H), 11.07 (s, 1H).

LC-MS (method 2): R _t = 0.98 min; MS (ESI positive): m/z = 516 [M+H]+.

Example 42.

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

Using a method similar to that described for Example 41, with 3-(3-chloro-2-methylanilino)-2-(3{[(2S)-morpholin-2-yl]methoxy}pyridin-4-yl)-1,5 ,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (intermediate 42, 18.0 mg, 38.5 µmol) as starting material, 10.9 mg (purity 94%, yield 55%) of the above The title compounds were obtained after purification by preparative HPLC (method 10, gradient: 0.00 - 0.50 min 15% B, 0.50 - 6.00 min 15-55% B).

¹ H-NMR (400 MHz, DMSO-^): δ [ppm] = 1.234 (0.45), 1.874 (1.12), 1.901 (1.88), 1.928 (1.19), 2.006 (0.51), 2.015 (0.63) , 2.035 (1.18), 2.043 (1.18), 2.064 (0.68), 2.072 (0.56), 2.207 (15.79), 2.324 (0.67), 2.329 (0.91), 2.334 (0.71), 2.338 (0.45), 2.357 (16.00 ) , 2.374 (1.16), 2.520 (2.98), 2.525 (1.85), 2.647 (1.22), 2.671 (1.61), 2.676 (1.69), 2.736 (1.32), 2.764 (1.23), 2.847 (1.67), 2.865 (3.57) , 2.882 (1.86), 3.411 (1.24),3.417 (1.33), 3.428 (2.40), 3.434 (2.36), 3.445 (1.17), 3.451 (1.06), 3.639 (0.62), 3.645 (0.95), 3.667 (1.35) ,3.672 (1.38), 3.695 (0.78), 3.701 (0.66), 3.937 (1.97), 3.960 (1.51), 4.111 (1.22), 4.128 (1.10), 4.137 (1.63), (1.36), 4.253 (1.46), 4.262 (1.52), 4.279 (1.14), 4.287 (1.03), 6.190 (1.81), 6.194 (1.78), 6.209 (1.99), (1.81), 6.722 (0.90), 6.726 (1.25), 6.742 (3.67), 6.746 (2.96), 6.753 (2.81), 6.773 (2.59), 6.792 (0.84), (2.30), 7.232 (3.39), 7.244 (3.38), 7.377 (4.48), 7.990 (3.43), 8.003 (3.19), 8.370 ( 5.23), 11.051 (2.53).

LC-MS (method 6): Rt = 0.52 min; MS (ESI positive): m/z = 482 [M+H]+.

Example 43.

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

4.153

6.213

7.190

- 93 046642

Using a method similar to that described for Example 41, with 3-(3-chloro-2-methylanilino)-2-(3{[(3R)-morpholin-3-yl]methoxy}pyridin-4-yl)-1,5 ,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (30.0 mg, 64.1 µmol) as starting material, 7.0 mg (purity 94%, yield 21%) of the title compound were obtained after purification using preparative HPLC (method 10, gradient: 0.00 - 0.50 min 15% B, 0.50 - 6.00 min 15 - 55% B).

¹ H-NMR (400 MHz, DMSO-ds): δ [ppm] = -0.002 (3.00), 0.879 (0.57), 2.085 (5.27), 2.272 (14.21), 2.318 (0.47), 2.382 (16.00 ), 2.397 (1.43), 2.423 (1.05), 2.431 (1.10), 2.460 (1.63), 2.518 (5.17), 2.523 (3.38), 2.660 (0.46), 2.810 (0.81), 2.828 (2.27), 2.845 (1.96 ), 2.864 (0.87), 2.909 (1.32), 2.938 (1.64), 3.435 (1.37), 3.444 (1.50), 3.464 (0.63), 3.540 (1.08), 3.568 (2.41), 3.595 (1.11), 3.844 (2.09 ), 3.864 (1.06), 3.872 (0.93), 4.357 (1.94), 4.368 (3.51),4.395 (1.85), 6.228 (1.98), 6.232 (1.91), 6.756 (1.10), 6.760 (1.40), 6.776 (3.46 ),6.779 (2.75), 6.833 (0.95), 7.200 (2.25), 7.250 (3.55), 7.263 (3.70), 7.431 (4.31), 7.946 (5.51), 12.003 (2.32).

3.428

3.818

6.212

6.813

8.338 (1.16), 3.411 (0.70), (2.18), 3.620 (0.70), (0.46), 6.209 (1.79), (2.93), 6.793 (2.52), (3.93), 7.958 (3.66),

LC-MS (method 6): Rt = 0.57 min; MS (ESI positive): m/z = 512 [M+H]+.

Example 44.

3-(3-chloro-2-methylanilino)-2-[3 -[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]-4-pyridyl]-1,5,6,7tetrahydropyrroloPP -^pyridin-4-one

By analogy with example 1, N(3-chloro-2-methylphenyl)-4-[[3-[(5,5-dimethyl-1,4-dioxan-2yl)methoxy]-4-pyridyl]methylamino]-6 -Oxo-2,3-dihydro-N-pyridine-5-carbothioamide (intermediate 6-44, 320 mg, 603 µmol) was used for preparation after stirring for 2 h at room temperature and purification by preparative HPLC (Method 10 , gradient: 0.00-0.50 min 15% B, 0.50-5.92 min 15-54.2% B, 5.92 - 7.34 min 54.2% B, 7.34 -7.42 min 54.2 - 55% B) 32 mg (purity 98%, yield 10%) specified in the connection header.

¹ H-NMR (400 MHz, DMSO-a ₆ ): δ [ppm] = 1.072 (14.59), 1.241 (13.05), 2.325 (0.47), 2.329 (0.73), 2.344 (16.00), 2.520 (1.82 ), 2.525 (1.27), 2.671 (0.54), 2.828 (1.59), 2.845 (3.40), 2.862 (1.80), 3.402 (2.68), 3.417 (2.39), 3.423 (2.57), 3.431 (2.75), 3.565 (0.87 ), 3.574 (1.01), 3.595 (1.70), 3.603 (4.15), 3.697 (1.17), 3.872 (0.64), 3.880 (0.75), 3.888 (0.95), 3.897 (0.88), 3.905 (1.12), 4.139 (1.05 ), 4.149 (1.54), 4.165 (1.34), 4.254 (1.47), 4.263 (1.52),4.281 (1.81), 6.199 (1.76), 6.215 (1.97), 6.218 (1.81), 6.705 (0.97), 6.709 (1.30 ), 6.725 (2.56), 6.757 (2.50), 6.778 (0.82), 7.165 (2.26), 7.230 (3.85), 7.243 (3.87), 7.323 (4.69), 8.374 (6.56), 11.049 (2.45).

(1.65), (0.63), (1.10), (3.57), (4.45), (3.45), (0.58), (0.98), (2.82), (5.13),

3.640

3.914

4.289

6.729

8.004

3.668

4.122

6.196

6.738

8.016

LC-MS (method 6): Rt = 0.79 min; MS (ESI positive): m/z = 497 [M+H]+.

Example 45.

3-(3-chloro-2-methylanilino)-2-[3 -[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]-4-pyridyl]-1,5,6,7tetrahydropyrroloPP -^pyridin^-one (stereoisomer 1)

- 94 046642

The title compound of Example 44 (32.0 mg) was resolved into enantiomers by preparative chiral HPLC to give the title compound (enantiomer 1, 15.50 mg, Rt = 12.1 - 14.2 min) and enantiomer 2 (12.6 mg, Rt = 14.5 - 19.0 min, see example 46).

Preparative chiral HPLC method: POB

Instrument: PrepCon Labomatic HPLC; column: Chiralcel OD-H 5 μm, 250x20; eluent A: ethanol + 0.1 vol.% diethylamine; eluent B: methanol; isocratic mode: 70% A + 30% B; flow: 10 ml/min; temperature: 25°C; UV: 280 nm.

Analytical chiral HPLC method: POB

Device: Waters Alliance 2695; column: Chiralcel OD-H 5 μm, 100x4.6; eluent A: ethanol + 0.1 vol.% diethylamine; eluent B: methanol; isocratic mode: 70% A + 30% B; flow: 1.4 ml/min; temperature: 25°C; UV: 280 nm.

Analytical chiral HPLC: R _t = 3.52 min.

Optical rotation: [a] _D = 30.31° +/- 1.05° (c = 2.7 mg/ml in chloroform).

¹ H-NMR (400 MHz, DMSO-66): δ [ppm] = 1.050 (0.51), 1.070 (14.54), 1.119 (0.40), 1.137 (0.77), 1.155 (0.80), 1.190 (0.47) , 1.239 (13.63), 2.085 (0.73), 2.318 (0.77), 2.323 (1.71), 2.327 (2.48), 2.332 (2.11), 2.342 (16.00), 2.518 (7.25), 2.523 (5.03), 2.660 (0.73 ) , 2.665 (1.64), 2.669 (2.30), 2.673 (1.60), 2.679 (0.73), 2.825 (1.60), 2.842 (3.43), 2.859 (1.86), 3.306 (0.95), 3.399 (2.77), 3.415 (2.44) , 3.421 (2.59), 3.429 (2.84), 3.563 (0.87), 3.572 (1.02), 3.592 (1.71), 3.601 (1.68), 3.638 (3.46), 3.665 (4.15), 3.695 (1.17), 3.869 (0.77) ,3.878 (0.77), 3.886 (0.95), 3.894 (0.87), 3.903 (0.62), 3.911 (0.58), 4.120 (1.13), 4.137 (1.06), 4.147 (1.53), 4.163 (1.31), 4.252 (1.46) , 4.261 (1.53), 4.278 (1.09), 4.287 (0.98), 6.193 (1.82), 6.197 (1.75), 6.212 (1.93),6.216 (1.82), 6.703 (0.98), 6.707 (1.28), 6.723 (3.50) , 6.727 (2.81), 6.736 (2.59), 6.756 (2.51), 6.775 (0.84),7.162 (2.22), 7.228 (3.64), 7.241 (3.64), 7.321 (4.48), 8.002 (4.30), 8.014 (4.01) , 8.372 (5.94), 11.046 (2.48).

LC-MS (method 6): R _t = 0.80 min; MS (ESI positive): m/z = 497 [M+H]+.

Example 46.

3-(3-chloro-2-methylanilino)-2-[3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]-4-pyridyl]-1,5,6,7tetrahydropyrrolo ^^-^pyridinL-one (stereoisomer 2)

For the preparation of the title racemic compound, see Example 44. Separation of enantiomers by preparative chiral HPLC (method see Example 45) yielded 12.6 mg of the title compound (R _t = 14.5 - 19.0 min).

Analytical chiral HPLC (method see example 45): R _t = 4.43 min.

Optical rotation: [a] _D = - 26.44° +/- 1.41° (c = 2.9 mg/ml in chloroform).

¹ H-NMR (400 MHz, DMSO-66): δ [ppm] = 0.748 (0.44), 0.764 (0.44), 1.053 (0.52), 1.070 (14.81), 1.154 (1.45), 1.239 (13.86) , 2.085 (1.85), 2.318 (0.46), 2.323 (0.99), 2.327 (1.45), 2.332 (1.39), 2.342 (16.00), 2.518 (4.03), 2.523 (2.82), 2.540 (0.54), 2.665 (0.89) , 2.669 (1.25), 2.673 (0.85), 2.825 (1.61), 2.843 (3.39), 2.859 (1.81), 3.399 (2.78), 3.415 (2.48), 3.421 (2.64), 3.429 (2.88), 3.563 (0.83) , 3.572 (0.99), 3.593 (1.69),3.601 (1.67), 3.638 (3.49), 3.665 (4.15), 3.695 (1.15), 3.869 (0.83), 3.878 (0.77), 3.886 (0.95), 3.895 (0.89) ,3.903 (0.64), 3.912 (0.58), 4.120 (1.09), 4.137 (1.03), 4.147 (1.53), 4.163 (1.33), 4.252 (1.45), 4.261 (1.51), 4.278 (1.09), 4.287 (0.97) , 6.193 (1.77), 6.197 (1.75), 6.212 (1.97), 6.216 (1.85), 6.703 (0.95), 6.707 (1.27),6.723 (3.51), 6.727 (2.82), 6.736 (2.58), 6.756 (2.54) , 6.775 (0.85), 7.162 (2.26), 7.228 (3.10), 7.241 (3.12), 7.321 (4.45), 8.002 (2.54), 8.015 (2.36), 8.372 (3.89), 11.046 (2.46).

- 95 046642

LC-MS (method 6): Rt = 0.80 min; MS (ESI positive): m/z = 497 [M+H]+.

Example 47.

2-[3-(1,4-dioxan-2-ylmethoxy)-4-pyridyl]-3-(3-fluoro-2-methylanilino)-1,5,6,7tetrahydropyrrolo[3,2-c]pyridin- 4-he

By analogy with example 1 4-[[3-(1,4-dioxan-2-ylmethoxy)-4-pyridyl]methylamino]-M-(3-fluoro-2methylphenyl)-6-oxo-2,3-dihydro- N-pyridine-5-carbothioamide (intermediate 6-47, 399 mg, 820 µmol) was used for preparation after stirring overnight at 60°C and purification by preparative HPLC (method 9, gradient: 0.00-0.50 min 15% B, 0.50-6.00 min 15-55% B) 135 mg (purity 97%, yield 35%) of the title compound.

¹ H-NMR (400 MHz, DMSO-b6) δ [ppm]: 1.154 (4.20), 1.172 (8.22), 1.189 (3.94), 1.987 (16.00), 2.185 (2.36), 2.189 (2.36), 2.518 (0.75), 2.522 (0.47), 2.843 (0.44), 2.860 (0.94), 2.877 (0.50), 3.398 (0.42), 3.425 (1.01), 3.451 (0.56), 3.709 (0.44), 3.740 (0.57), 3.999 (1.26), 4.017 (3.61), 4.035 (3.57), 4.053 (1.15), 4.125 (0.48), 4.230 (0.43), 4.239 (0.42), 5.758 (0.88), 6.052 (0.58), 6.072 (0.60), 6.459 (0.48), 7.186 (0.59), 7.234 (1.00), 7.247 (1.01), 7.345 (1.17), 7.990 (1.32), 8.002 (1.20), 8.361 (1.76), 11.030 (0.60).

LC-MS (method 6): Rt = 0.65 min; MS (ESI positive): m/z = 453 [M+H]+.

Example 48.

2-[3-(1,4-dioxan-2-ylmethoxy)-4-pyridyl]-3-(3-fluoro-2-methylanilino)-1,5,6,7tetrahydropyrrolo^D-^pyridinL-one (stereoisomer 1)

The title compound of Example 47 (15.0 mg) was resolved into enantiomers by preparative chiral HPLC to give the title compound (enantiomer 1, 3.0 mg, R _t = 5.5 - 6.2 min) and enantiomer 2 (2.0 mg, R _t = 9.0 - 9.9 min, see example 49).

Preparative chiral HPLC method: MTBE

Instrument: PrepCon Labomatic HPLC; column: YMC Cellulose SB 5 μ, 250x30; eluent A: methyl tert-butyl ether + 0.1 vol.% diethylamine; eluent B: acetonitrile; isocratic mode: 55% B+45% A; flow: 80 ml/min; temperature: 25°C; UV: 280 nm.

Analytical chiral HPLC method: MTBE

Device: Waters Alliance 2695; column: YMC Cellulose SB 3 μ, 100x4.6; eluent A: methyl tert-butyl ether + 0.2 vol.% diethylamine; eluent B: acetonitrile; isocratic mode: 50% A + 50% B; flow: 1.4 ml/min; temperature: 25°C; UV: 280 nm.

Analytical chiral HPLC: R _t = 2.90 min.

Optical rotation: [a]D = - 19.1° +/- 1.65° (c = 2.19 mg/ml in chloroform).

¹ H-NMR (400 MHz, DMSO-b6): δ [ppm] = -0.008 (0.55), 0.000 (16.00), 0.008 (0.53), 0.700 (0.57), 0.752 (0.76), 0.770 (0.76 ), 1.140 (1.18), 1.160 (2.36), 1.234 (1.64), 1.296 (0.42), 2.189 (11.55), 2.191 (11.53), 2.521 (2.85), 2.525 (1.90), 2.846 (2.15), 2.863 (4.59 ), 2.880 (2.42), 3.401 (1.96), 3.410 (1.71), 3.417 (1.88), 3.428 (4.95), 3.444 (1.64), 3.454 (2.68), 3.505 (0.67), 3.510 (0.82), 3.532 (1.56 ), 3.539 (1.58), 3.560 (1.14), 3.569 (1.03), 3.712 (2.13), 3.721 (1.35), 3.743 (2.76), 3.750 (1.24), 3.771 (1.14), 3.778 (0.84), 3.800 (1.69 ),3.806 (1.85), 3.829 (1.52), 3.835 (1.54), 3.885 (1.66), 3.912 (1.22), 3.992 (0.42), 4.001 (0.68), 4.008 (1.01), 4.017 (1.14), 4.025 (1.10 ), 4.033 (0.93), 4.042 (0.78), 4.049 (0.53), 4.103 (1.71), 4.119 (1.24), 4.129 (2.26), 4.145 (1.73), 4.233 (2.09), 4.243 (2.05), 4.259 (1.54 ), 4.269 (1.33), 6.056 (2.82), 6.076 (2.91), 6.440 (1.29),6.463 (2.36), 6.484 (1.46), 6.734 (0.89), 6.754 (1.85), 6.771 (1.77), 6.792 (0.72 ), 7.187 (2.91), 7.237 (3.80), 7.250 (3.82), 7.348 (5.65), 7.994 (2.64), 8.006 (2.47), 8.365 (4.17), 11.029 (3.12).

LC-MS (method 6): R _t = 0.66 min; MS (ESI positive): m/z = 453 [M+H]+.

Example 49.

2-[3-(1,4-dioxan-2-ylmethoxy)-4-pyridyl]-3-(3-fluoro-2-methylanilino)-1,5,6,7- 96 046642 tetrahydropyrrolo[3,2- c]pyridin-4-one (stereoisomer 2)

For the preparation of the title racemic compound, see Example 47. Separation of enantiomers by preparative chiral HPLC (method see Example 48) provided 2.0 mg of the title compound (Rt = 9.0 - 9.9 min).

Analytical chiral HPLC (method see example 48): Rt = 4.67 min.

Optical rotation: [a]D = 24.3° +/- 7.66° (c = 1.29 mg/ml in chloroform).

¹ H-NMR (400 MHz, DMSO-06) δ [ppm]: -0.008 (0.54), 0.000 (16.00), 0.008 (0.54), 0.700 (0.74), 0.752 (0.54), 0.771 (0.57) , 0.854 (0.52), 1.139 (0.91), 1.160 (1.70), 1.234 (2.19), 1.296 (0.52), 2.087 (0.66), 2.189 (11.26), 2.191 (11.28), 2.521 (4.55), 2.525 (3.00 ) , 2.846 (2.09), 2.863 (4.47), 2.880 (2.36), 3.401 (1.99), 3.410 (1.67), 3.417 (1.87), 3.428 (4.87), 3.444 (1.65), 3.454 (1.55), 3.560 (1.13) , 3.569 (1.03), 3.712 (2.09),3.721 (0.81), 3.800 (1.67), 3.806 (1.77), 3.829 (1.50),3.835 (0.66), 4.009 (0.98), 4.017 (1.11), 4.025 (1.08) ,4.033 (1.20), 4.129 (2.19), 4.145 (1.72), 4.233 (2.04),4.243 (2.85), 6.440 (1.25), 6.463 (2.31), 6.484 (1.45), 6.734 (2.65), 3.505 (0.69) , 3.510 (0.84), 3.532 (1.52),3.539 (1.35), 3.744 (2.70), 3.750 (1.23), 3.771 (1.16),3.778 (1.52), 3.885 (1.62), 3.912 (1.20), 3.992 (0.42) ,4.001 (0.91), 4.042 (0.76), 4.049 (0.54), 4.103 (1.70),4.119 (2.04), 4.259 (1.52), 4.269 (1.33), 6.055 (2.75),6.076 (0.86), 6.754 (1.79) , 6.772 (1.72), 6.792 (0.74),7.187 (2.83), 7.237 (3.37), 7.250 (3.42), 7.349 (5.43), 7.994 (2.24), 8.007 (2.14), 8.365 (3.56), 11.030 (3.02) .

Example 50.

3-(3-chloro-2-methylanilino)-2-(3-{[DO)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro4H -pyrrolo[3,2-c]pyridin-4-one

Using a method similar to that described for Example 1, with N(3-chloro-2-methylphenyl)-4-[[3-(1,4dioxan-2-ylmethoxy)-4-pyridyl]methylamino]-6-oxo-2, With 3-dihydro-N-pyridine-5-carbothioamide (intermediate 6-50, 150 mg, 298 µmol) as starting material, 35.0 mg (25% yield) of the title racemic compound was obtained after preparative HPLC (Method 10, gradient : 0.00-0.50 min 15% B, 0.50-6.00 min 15-55% B).

LC-MS (method 6): Rt = 0.71 min; MS (ESI positive): m/z = 469 [M+H] ⁺ .

Racemic 3 -(3 -chloro-2-methylanilino)-2-[3 -(1,4-dioxan-2-ylmethoxy)-4-pyridyl]-1,5,6,7tetrahydropyrrolo^D-^pyridin^-one (35.0 mg) was resolved into enantiomers by preparative chiral HPLC to give the title compound (enantiomer 1, 12.5 mg, Rt = 14.3 - 16.6 min) and enantiomer 2 (13.4 mg, Rt = 21.1 - 25.3 min, see Example 51) .

Preparative chiral HPLC method: MTBE

Instrument: PrepCon Labomatic HPLC; column: YMC Cellulose SB 5 μ, 250x30; eluent A: methyl tert-butyl ether + 0.1 vol.% diethylamine; eluent B: ethanol; gradient; flow: 40 ml/min; temperature: 25°C; UV: 254 nm.

Analytical chiral HPLC method: MTBE

Device: Waters Alliance 2695; column: YMC Cellulose SB 3 μ, 100x4.6; eluent A: methyl tert-butyl ether + 0.1 vol.% diethylamine; eluent B: ethanol; gradient; flow: 1.4 ml/min; temperature: 25°C; UV: 254 nm.

Analytical chiral HPLC: Rt = 3.23 min.

Optical rotation: [a]D = -20.5° +/- 1.23° (c = 2.7 mg/ml in chloroform).

¹ H-NMR (400 MHz, DMSO-66): δ [ppm] = 1.234 (0.41), 2.338 (0.44), 2.355 (16.00), 2.520 (2.76), 2.524 (1.87), 2.847 (1.60) , 2.864 (3.40), 2.882 (1.80), 3.398 (1.50), 3.410 (1.20), 3.416 (1.35), 3.427 (3.93), 3.432 (2.41), 3.444 (1.16), 3.451 (2.30), 3.502 (0.46) , 3.508 (0.60), 3.530 (1.13), 3.537 (1.16), 3.558 (0.85), 3.566 (0.78), 3.711 (1.87), 3.718 (1.04), 3.740 (2.36), 3.768 (0.89), 3.775 (0.60) , 3.796 (1.27), 3.802 (1.36), 3.825 (1.15), 3.831 (1.16), 3.883 (1.23), 3.909 (0.88), 3.994 (0.48), 4.001 (0.77), 4.009 (0.80), 4.018 (0.79) ,4.025

- 97 046642 (0.69), 4.033 (0.55), 4.104 (1.32), 4.120 (0.96), 4.130 (1.76), 4.146 (1.34), 4.223 (1.59), 4.232 (1.56), 4.249 (1.15), 4.258 (1.00 ), 6.190 (1.73), 6.194 (1.69), 6.210 (2.01), 6.213 (1.79), 6.718 (0.97), 6.722 (1.27),6.738 (3.59), 6.742 (2.81), 6.751 (2.54), 6.771 (2.47 ), 6.790 (0.80), 7.184 (2.17), 7.234 (3.49), 7.247 (3.51), 7.364 (4.36), 7.999 (3.35), 8.012 (3.08), 8.365 (4.78), 11.044 (2.32).

LC-MS (method 6): Rt = 0.70 min; MS (ESI positive): m/z = 469 [M+H]+.

Enantioselective synthesis starting from 1-(3-{|(2S)-1,4-dioxan-2-yl|methoxy}11iridin-4yl)methanamine (intermediate 2-8) confirmed that the title compound is a 3- (3-chloro-2-methylanilino)-2-(3-{[DO)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)1,5,6,7-tetrahydro-4H- pyrrolo[3,2-c]pyridin-4-one.

Example 51.

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

For the preparation of the title racemic compound, see Example 50. Separation of enantiomers by preparative chiral HPLC (method see Example 50) yielded 13.4 mg of the title compound (Rt = 21.1 - 25.3 min).

Analytical chiral HPLC (method see example 50): Rt = 5.22 min.

Optical rotation: [a]D = 20.4° +/- 1.23° (c = 2.69 mg/ml in chloroform).

1H-NMR (400 MHz, DMSO-a ₆ ): δ [ppm] = 1.173 (0.44), 1.234 (0.51), 2.355 (16.00), 2.521 (2.29), 2.525 (1.50), 2.848 (1.58) , 2.865 (3.44), 2.882 (1.83), 3.346 (0.44), 3.399 (1.49), 3.410 (1.19), 3.416 (1.34), 3.428 (3.98), 3.432 (2.45), 3.444 (1.19), 3.452 (2.35) , 3.503 (0.46), 3.508 (0.62), 3.531 (1.13), 3.538 (1.20), 3.558 (0.84), 3.567 (0.81), 3.711 (1.90), 3.718 (1.09), 3.740 (2.39), 3.768 (0.88) , 3.775 (0.62), 3.797 (1.26), 3.803 (1.39), 3.825 (1.14), 3.832 (1.17), 3.883 (1.25), 3.910 (0.90), 3.995 (0.49), 4.001 (0.76), 4.010 (0.82) ,4.018 (0.79), 4.026 (0.71), 4.035 (0.56), 4.042 (0.40), 4.104 (1.30), 4.121 (0.95), 4.130 (1.77), 4.147 (1.36), 4.224 (1.60), 4.233 (1.58) , 4.250 (1.15), 4.259 (0.99), 6.191 (1.74), 6.195 (1.73), 6.210 (1.96), 6.214 (1.81),6.719 (0.94), 6.723 (1.27), 6.738 (3.57), 6.743 (2.82) , 6.752 (2.56), 6.771 (2.49), 6.791 (0.81), 7.185 (2.19),7.235 (3.09), 7.248 (3.12), 7.365 (4.33), 8.000 (2.48), 8.013 (2.34), 8.366 (3.75) , 11.045 (2.33).

LC-MS (method 6): Rt = 0.70 min; MS (ESI positive): m/z = 469 [M+H] ⁺ .

Example 52.

-(3-chloro-2-ethylanilino)-2-[3 -(1,4-dioxan-2-ylmethoxy)-4-pyridyl]-1,5,6,7tetrahydropyrrolo[3,2-c]pyridin-4 -He

By analogy with example 1, N(3-chloro-2-ethylphenyl)-4-[[3-(1,4-dioxan-2-ylmethoxy)-4pyridyl]methylamino]-6-oxo-2,3-dihydro- 1H-pyridine-5-carbothioamide (intermediate 652, 150 mg, 290 µmol) was used to prepare after stirring for 4 h at 60°C and purification by preparative HPLC (method 10, gradient: 0.00-0.50 min 10% B , 0.50-8.06 min 10-20% B, 8.06-9.02 min 20% B, 9.02-24.12 min 20-50% B, 24.12-27.44 min 50% B) 23.2 mg (purity 95%, yield 16%) indicated in connection header.

'I-NMR (400 MHz, DMSO): δ ppm= 1.23 (t, 3H), 2.86 (s, 4H), 3.38 - 3.46 (m, 4H), 3.49 - 3.58 (m, 1H), 3.68 - 3.78 (m, 2H), 3.78 - 3.85 (m, 1I), 3.86 - 3.92 (m, 1H), 3.98 - 4.06 (m, 1I), 4.09 - 4.17 (m, 1I), 4.21 - 4.28 (m, 1H), 6.22 (dd, 1H), 6.67 - 6.78 (m, 2H), 7.20 (d, 2H), 7.45 (s, 1H), 7.98 (d, 1H), 8.32 - 8.39 (m, 1H).

LC-MS (method 2): R, = 1.08 min; MS (ESI positive): m/z = 483 [M+H] ⁺ .

Example 53.

3-(3-chloro-2-ethylanilino)-2-(3-{[DO)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro4H -pyrrolo[3,2-c]pyridin-4-one

- 98 046642

The title compound of Example 52 (23.2 mg) was resolved into enantiomers by preparative chiral HPLC to give the title compound (enantiomer 1, 6.0 mg, Rt = 6.6 - 7.-3 min) and enantiomer 2 (5.0 mg, Rt = 10.7 - 11.6 min, see example 54).

Preparative chiral HPLC method: MTBE

Instrument: PrepCon Labomatic HPLC; column: YMC Cellulose SB 5 μ, 250x30; eluent A: methyl tert-butyl ether + 0.1 vol.% diethylamine; eluent B: acetonitrile; isocratic mode: 50% A + 50% B; flow: 60 ml/min; temperature: 25°C; UV: 254 nm.

Analytical chiral HPLC method: MTBE

Device: Waters Alliance 2695; column: YMC Cellulose SB 3 μ, 100x4.6; eluent A: methyl tert-butyl ether + 0.1 vol.% diethylamine; eluent B: acetonitrile; isocratic mode: 50% A + 50% B; flow: 1.4 ml/min; temperature: 25°C; UV: 254 nm.

Analytical chiral HPLC: Rt = 2.40 min.

¹ H-NMR (400 MHz, DMSO-b ₆ ): δ [ppm] = 1.23 (t, 3H), 2.81 - 2.91 (m, 4H), 3.40 -3.45 (m, 3H), 3.53 (dt , 1H), 3.69 - 3.79 (m, 2H), 3.79 - 3.85 (m, 1H), 3.86 - 3.93 (m, 1H), 3.99 - 4.06 (m, 1H), 4.12 (dd, 1H), 4.24 (dd , 1H), 6.23 (dd, 1H), 6.69 - 6.78 (m, 2H), 7.15 - 7.23 (m, 2H), 7.43 - 7.47 (m, 1H), 7.98 (d, 1H) 8.36 (s, 1H) , 11.03 (br s, 1H).

Enantioselective synthesis confirmed that the title compound was 3-(3-chloro-2-ethylanilino)-2-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4- yl)-1,5,6,7-tetrahydro-4Hpyrrolo[3,2-c]pyridin-4-one. By analogy with example 1, the title compound (25 mg, 7.6% yield) was prepared using N(3-chloro-2-ethylphenyl)-4-{[(3-{[DO)-1,4-dioxane- 2-yl]methoxy}pyridin-4yl)methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 6-53, 320 mg, 0.62 mmol) as starting material with subsequent purification using preparative HPLC (method 10, gradient: 0.00-0.50 min 5% B, 0.50-7.99 min 5-60% B, 7.99-11.20 min 60% B).

¹ H-NMR (400 MHz, DMSO-06): δ [ppm] = 11.03 (s, 1H), 8.36 (s, 1H), 7.98 (d, 1H), 7.43 - 7.49 (m, 1H) , 7.15 - 7.24 (m, 2H), 6.68 - 6.80 (m, 2H), 6.14 - 6.28 (m, 1H), 4.21 - 4.33 (m, 1H), 4.10 - 4.17 (m, 1H), 4.00 4.05 (m , 1H), 3.70 - 3.92 (m, 4H), 3.51 - 3.59 (m, 1H), 3.39 - 3.47 (m, 3H), 2.81 - 2.90 (m, 4H), 1.23 (t, 3H).

Example 54.

3-(3-chloro-2-ethylanilino)-2-(3-{[(2R)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7- tetrahydro4H-pyrrolo[3,2-c]pyridin-4-one

For the preparation of the title racemic compound, see Example 52. Enantiomer resolution using preparative chiral HPLC (method see Example 53) yielded 5.0 mg of the title compound (Rt = 10.7 - 11.6 min).

Analytical chiral HPLC (method see example 53): Rt = 3.22 min.

¹ H-NMR (400 MHz, DMSO): δ [ppm] = 1.14 - 1.34 (m, 6H), 2.81 - 2.91 (m, 4H), 3.38 - 3.48 (m, 3H), 3.55 (dd, 1H), 3.69 - 3.85 (m, 3H), 3.85 - 3.93 (m, 1H), 3.99 - 4.06 (m, 1H), 4.09 - 4.17 (m, 1H), 4.25 (dd, 1H), 6.23 (dd, 1H), 6.69 - 6.79 (m, 2H), 7.14 - 7.23 (m, 2H), 7.39 - 7.49 (m, 1H), 7.91 - 8.04 (m, 1H), 8.31 - 8.40 (m, 1H), 10.97 - 11.12 (m, 1H).

- 99 046642

Example 55.

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

Using a method similar to that described for Example 41, with 3-(3-chloro-2-ethylanilino)-2-(3{[(2R)-morpholin-2-yl]methoxy}pyridin-4-yl)-1,5 ,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (intermediate 55, 58.0 mg, 120 µmol) as starting material, 27.5 mg (purity 95%, yield 44%) of the above The title compounds were obtained after purification by preparative HPLC (method 10, gradient: 0.00 - 0.50 min 30% B, 0.50 - 7.00 min 30 - 70% B).

Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 1.23 (t, 3H), 1.90 (t, 1H), 1.99 - 2.09 (td, 1H), 2.21 (s, 3H), 2.63 - 2.71 (d, 1H), 2.73 - 2.78 (d, 1H), 2.78 - 2.89 (m, 4H), 3.40 - 3.47 (td, 2H), 3.67 (td, 1H), 3.92 - 3.98 (m, 2H ), 4.14 (dd, 1H), 4.27 (dd, 1H), 6.23 (dd, 1H), 6.71 - 6.78 (m, 2H), 7.16 - 7.21 (m, 2H), 7.46 (s, 1H), 7.97 ( d, 1H), 8.36 (s, 1H), 11.04 (s, 1H).

LC-MS (method 2): Rt = 1.10 min; MS (ESI positive): m/z = 496 [M+H]+.

Example 56.

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

Using a method similar to that described for Example 41, with 3-(3-chloro-2-ethylanilino)-2-(3-{[^)morpholin-2-yl]methoxy}pyridin-4-yl)-1,5, 6,7-Tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (intermediate 56, 68.0 mg, 141 µmol) as starting material, 37.8 mg (purity 95%, yield 51%) indicated in The title compounds were obtained after purification by preparative HPLC (method 10, gradient: 0.00 - 0.50 min 30% B, 0.50 - 7.00 min 30 - 70% B).

Ή-NMR (400 MHz, DMSO-06): δ [ppm] = 1.23 (t, 3H), 1.90 (t, 1H), 2.00 - 2.08 (td, 1H), 2.21 (s, 3H), 2.63 - 2.72 (d, 1H), 2.72 - 2.81 (d, 1H), 2.81 - 2.90 (m, 4H), 3.44 (td, 2H), 3.67 (td, 1H), 3.91 - 3.99 (m, 2H), 4.13 (dd, 1H), 4.29 (dd, 1H), 6.23 (dd, 1H), 6.71 - 6.78 (m, 2H), 7.16 - 7.21 (m, 2H), 7.46 (s, 1H), 7.97 (d, 1H), 8.36 (s, 1H), 11.04 (s, 1H).

LC-MS (method 2): R _t = 1.10 min; MS (ESI positive): m/z = 496 [M+H]+.

Example 57.

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

Microwave solution

N-(3-chloro-2-methoxyphenyl)-4-([{ 3-[(1S)-1-(1,4-dioxan-2 yl)ethoxy]pyridin-4-yl}methyl)amino]-2 -oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 6-57, 380 mg, 713 µmol) in methanol (1.5 ml) was treated with TFA (55 µl, 710 µmol) followed by hydrogen peroxide ( 9.2 µl, 0.106 mmol), heated to 60°C and

- 100 046642 was stirred for 16 hours. The reaction mixture was concentrated to dryness under reduced pressure, dissolved in DMSO and purified using preparative HPLC (method 10, gradient: 0.00-0.50 min 15% B, 0.50-5.00 min 15-50% B, 5.00-8.00 min 50% B) to obtain, after freeze-drying, the target product (174 mg, 44% yield) as a mixture of two stereoisomers.

¹ H-NMR (400 MHz, DMSO-0b): δ [ppm] = 1.176 (0.47), 1.192 (0.46), 1.245 (3.61), 1.261 (3.63), 1.326 (5.41), 1.342 (5.34) , 2.074 (0.90), 2.518 (2.00), 2.523 (1.30), 2.832 (0.58), 2.853 (1.78), 2.871 (2.29), 2.889 (1.20), 3.374 (0.58), 3.402 (1.93), 3.412 (1.77) , 3.419 (2.47), 3.427 (2.74), 3.435 (1.67), 3.442 (1.31), 3.455 (1.30), 3.464 (0.88), 3.485 (1.04), 3.493 (0.81), 3.500 (0.81), 3.522 (0.58) , 3.614 (0.42), 3.643 (1.28),3.650 (1.69), 3.669 (0.97), 3.699 (1.00), 3.725 (1.81), 3.734 (0.89), 3.748 (1.07), 3.754 (0.91), 3.768 (0.44) ,3.777 (0.54), 3.783 (0.42), 3.806 (1.65), 3.813 (2.16), 3.823 (1.17), 3.836 (1.62), 3.843 (1.75), 3.850 (1.00), 3.863 (9.50), 3.890 (16.00) , 3.919 (0.92), 3.948 (0.61), 4.068 (2.33), 4.626 (0.70), 4.630 (0.86), 4.643 (1.15), 4.653 (0.66), 4.658 (0.86), 6.133 (0.95), 6.143 (2.18) , 6.148 (0.96), 6.151 (1.32), 6.158 (1.98), 6.167 (1.48),6.638 (1.70), 6.643 (2.02), 6.653 (3.46), 6.678 (0.58), 6.690 (6.05), 6.699 (2.71) , 6.706 (2.31), 7.122 (0.98),7.161 (1.50), 7.264 (0.72), 7.285 (0.52), 7.294 (1.80), 7.299 (2.64), 7.307 (1.85), 7.312 (2.64), 7.440 (2.17) , 7.519 (3.36), 7.631 (0.44), 7.998 (3.33), 8.011 (3.08), 8.031 (2.20), 8.044 (1.98), 8.396 (4.10), 8.411 (2.66), 11.072 (1.20), 11.085 (1.69) .

LC-MS (method 6): Rt = 0.72 min; MS (ESI positive): m/z = 499 [M+H]+.

Example 58.

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

dn ₃

The title compound of Example 57 (170 mg) was separated into its stereoisomers by preparative chiral HPLC to give the title compound (stereoisomer 1, 58 mg, Rt = 16.2-18.8 min) and stereoisomer 2 (35 mg, Rt = 19.3-21.6 min, see example 60).

Preparative chiral HPLC method.

Instrument: PrepCon Labomatic HPLC; column: YMC Cellulose SC 5 μ, 250x30; eluent A: hexane + 0.1 vol.% diethylamine; eluent B: ethanol + 0.1 vol.% diethylamine; gradient: 0-15 min 20-30% B; flow: 40 ml/min; temperature: 25°C; UV: 254 nm.

Analytical chiral HPLC method.

Device: Waters Alliance 2695; column: YMC Cellulose SC 3 μ, 100x4.6; eluent A: hexane + 0.1 vol.% diethylamine; eluent B: ethanol; isocratic mode: 70% A + 30% B; flow: 1.4 ml/min; temperature: 25°C; UV: 254 nm.

Analytical chiral HPLC: Rt = 5.19 min.

¹ H-NMR (400 MHz, DMSO-66): δ [ppm] = 1.157 (0.42), 1.326 (5.83), 1.342 (5.94), 2.518 (2.45), 2.523 (1.64), 2.854 (1.00) , 2.872 (2.23), 2.889 (1.30), 3.159 (0.76), 3.172 (0.81), 3.403 (0.88), 3.409 (0.98), 3.420 (1.66), 3.427 (1.98), 3.435 (0.89), 3.456 (1.40) , 3.469 (0.49), 3.485 (1.09), 3.493 (0.89), 3.500 (0.89), 3.522 (0.63), 3.530 (0.42), 3.699 (1.04), 3.725 (1.77), 3.748 (1.00), 3.755 (0.79) , 3.777 (0.55), 3.783 (0.42),3.806 (1.16), 3.812 (1.76), 3.824 (0.88), 3.836 (1.39), 3.843 (1.20), 3.850 (0.51), 3.890 (16.00), 3.919 (1.02) , 3.948 (0.70), 4.631 (0.81), 4.646 (0.95), 4.659 (0.80), 6.143 (1.46), 6.151 (1.29), 6.159 (1.42), 6.167 (1.47), 6.679 (0.61), 6.691 (6.25) , 6.699 (2.81), 6.706 (2.43), 6.727 (0.42), 7.159 (1.65), 7.298 (2.69), 7.311 (2.69),7.518 (3.71), 7.998 (3.52), 8.010 (3.22), 8.395 (4.49) , 11.084 (1.82).

Optical rotation: [a]D = 30.21° +/- 0.60° (c = 1.0 g/100 ml chloroform).

LC-MS (method 6): Rt = 0.72 min; MS (ESI positive): m/z = 499 [M+H] ⁺ .

- 101 046642

Example 59.

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

The title compound of Example 57 (170 mg) was separated into its stereoisomers by preparative chiral HPLC to give the title compound stereoisomer 2 (35 mg, R _t = 19.3-21.6 min, see Example 58 for separation method).

Analytical chiral HPLC: R _t = 5.91 min.

1H-NMR (400 MHz, DMSO-a ₆ ): δ [ppm] = 0.798 (0.48), 0.815 (0.56), 0.822 (0.55), 0.905 (0.48), (0.46), 1.137 (0.84), 1.156 (0.69), 1.233 (1.00), 1.246 (6.21), 1.261 (6.32), 2.084 (0.60), 2.332 (0.57), (3.49), 2.522 (2.23), 2.673 (0.60), 2.833 (1.01), 2.850 (2.05), 2.867 (1.22), 3.308 (0.48), 3.373 (0.98), (2.29), 3.412 (2.05), 3.418 (2.16), 3.427 (2.02), 3.435 (1.84), 3.442 (0.62), 3.643 ( 2.17), 3.670 (1.14), 3.726 (0.62), 3.732 (0.73), 3.738 (0.63), 3.762 (0.57), 3.768 (0.57), 3.805 (1.25), 3.815 (1.51), 3.821 (1.08), 3.863 ( 16.00), 3.889 (0.74), 4.625 (0.83), 4.637 (0.87),4.641 (1.44), 6.147 (1.32), 6.157 (1.50), 6.639 (2.71), 6.643 (3.20),6.653

1.084

2.518

3.402

3.614

3.757

3.850

6.143

7.294 (1.19), 3.465 (0.79), 3.607 (0.46), (0.65), 3.744 (0.72), 3.751 (0.57), (1.12), 3.834 (1.01), 3.844 (1.36), (0.90), 4.653 (0.81 ), 6.133 (1.40), (5.57), 6.663 (0.45), 7.120 (1.71), (2.55), 7.307 (2.61), 7.438 (3.73), 8.031 (2.89), 8.043 (2.69), 8.411 (4.05), 11.071 (1.88).

Optical rotation: [a]D = 19.87° +/- 0.91° (c = 1.0 g/100 ml chloroform).

LC-MS (method 6): R _t = 0.72 min; MS (ESI positive): m/z = 499 [M+H] ⁺ .

Example 60.

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

Using a method similar to that described for Example 57, with N(3-chloro-2-methoxyphenyl)-4-{[(3 {(^)-1-[1,4-dioxan-2-yl]ethoxy}pyridin-4 -yl)methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3carbothioamide (intermediate 6-60, 340 mg, 638 µmol) as starting material, 76.0 mg (purity 99%, yield 24 %) of the title compound (stereoisomer 1, R _t = 18.7-22.0 min) was obtained after purification using preparative HPLC (method 10, gradient: 0.00-0.50 min 15% B, 0.50-5.00 min 15-50% B, 5.00 -8.00 min 50% B) followed by chiral prep. HPLC. Additionally, 7 mg of stereoisomer 2 (example 61) was isolated (R _t = 16.5-17.9 min).

Preparative chiral HPLC method.

Instrument: PrepCon Labomatic HPLC; column: YMC Cellulose SB 5 μ, 250x30; eluent A: hexane + 0.1 vol.% diethylamine; eluent B: ethanol + 0.1 vol.% diethylamine; isocratic mode: 80% A + 20% B; flow: 60 ml/min; temperature: 25°C; UV: 254 nm.

Analytical chiral HPLC method.

Device: Waters Alliance 2695; column: YMC Cellulose SB 3 μ, 100x4.6; eluent A: hexane + 0.1 vol.% diethylamine; eluent B: ethanol; isocratic mode: 80% A + 20% B; flow: 1.4 ml/min; temperature: 25°C; UV: 254 nm.

Analytical chiral HPLC: R _t = 6.96 min.

¹ H-NMR (400 MHz, DMSO-a ₆ ): δ [ppm] = 1.245 (5.93), 1.261 (5.97), 2.518 (0.96), 2.522 (0.61), 2.833 (0.89), 2.850 (1.81 ), 2.868 (1.07), 3.374 (0.88), 3.398 (1.92), 3.402 (2.05), 3.412 (1.84), 3.418 (1.88), 3.427 (1.81), 3.435 (1.62), 3.442 (1.07), 3.465 (0.71 ), 3.608 (0.45), 3.614 (0.62), 3.643 (2.07), 3.669 (1.04), 3.726 (0.57), 3.733 (0.70), 3.736 (0.65), 3.744 (0.69), 3.751 (0.53), 3.757 (0.58 ), 3.762 (0.53), 3.768 (0.55), 3.805 (1.12), 3.815 (1.32), 3.821 (0.99), 3.834 (0.89), 3.844 (1.24), 3.850 (0.97), 3.864 (16.00), 3.890 (0.81 ),4.068

- 102 046642 (0.46), 4.626 (0.76), 4.637 (0.80), 4.641 (0.83), 4.653 (0.76), 6.133 (1.41), 6.143 (1.51), 6.148 (1.26), 6.158 (1.48), 6.638 (2. 78 ), 6.643 (3.34), 6.653 (5.70), 6.663 (0.46), 7.122 (1.57), 7.294 (2.67), 7.307 (2.70), 7.440 (3.53), 8.031 (3.75), 8.044 (3.34), 8.411 (4.42 ), 11.072 (1.72).

LC-MS (method 6): R _t = 0.72 min; MS (ESI positive): m/z = 499 [M+H]+.

Example 61.

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

To obtain the title compound as a mixture of two diastereomers, see Example 60. Separation of the enantiomers using preparative chiral HPLC (method see Example 60) resulted in 7.0 mg of the title compound (R _t = 9.4 - 10.8 min).

Analytical chiral HPLC (method see example 60): R _t = 6.10 min.

Optical rotation: [a]D = -3.38° +/- 0.78° (c = 3.7 mg/ml, chloroform).

Example 62.

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

To a solution of N-(3-fluoro-2-methylphenyl)-4-{[(3-{ [4-methylmorpholin-2-yl]methoxy} pyridin-4yl)methyl]amino}-2-oxo-1,2, 5,6-Tetrahydropyridine-3-carbothioamide (intermediate 6-62, 110 mg, 220 µmol) in acetic acid (1.1 ml), aqueous hydrogen peroxide (45 µl, 30% purity, 440 µM) was added and the mixture was heated at 80°C for 2 hours. The reaction mixture was quenched with saturated sodium thiosulfate solution and the pH was adjusted to 7 by adding 4M aqueous sodium hydroxide solution. After adding DCM, the mixture was stirred for 15 min at RT. The phases were separated and the aqueous phase was extracted with DCM. The combined organic layers were dried using hydrophobic filter paper and concentrated under reduced pressure. The mixture was purified using Rev. HPLC (Method 10) gave 28 mg (purity 97%, yield 26%) of the title compound.

¹ H-NMR (400 MHz, DMSO-66): δ [ppm] = 1.877 (1.11), 1.904 (1.76), 1.931 (1.15), 2.007 (0.48), 2.016 (0.62), 2.036 (1.18) 2.044 (1.14), 2.064 (0.65), 2.074 (0.91), 2.188 (9.04), 2.191 (9.20), 2.204 (16.00), 2.326 (0.50), 2.518 (1.93), 2.522 (1.23), 2.647 (1.09) , 2.669 (1.06), 2.673 (1.34), 2.743 (1.21), 2.770 (1.13), 2.844 (1.64), 2.861 (3.54), 2.878 (1.85), 3.410 (1.18), 3.415 (1.29), 3.426 (2.35) , 3.432 (2.33), 3.443 (1.13),3.449 (1.04), 3.642 (0.55), 3.648 (0.70), 3.670 (1.28), 3.675 (1.30), 3.698 (0.76), 3.703 (0.63), 3.935 (1.65) ,3.942 (1.53), 3.951 (0.92), 3.962 (1.44), 3.967 (1.29), 4.109 (1.20), 4.126 (1.08), 4.135 (1.56), 4.151 (1.27), 4.276 (1.43), 4.285 (1.48) , 4.301 (1.18), 4.310 (1.07), 6.056 (2.20), 6.076 (2.25), 6.442 (1.00), 6.464 (1.83), 6.486 (1.13), 6.735 (0.68), 6.755 (1.42), 6.772 (1.36) , 6.793 (0.57), 7.188 (2.26), 7.230 (3.88), 7.242 (3.85), 7.346 (4.43), 7.979 (5.07), 7.991 (4.58), 8.368 (6.78), 11.029 (2.41).

LC-MS (method 6): R _t = 0.46 min; MS (ESI positive): m/z = 466 [M+H]+.

Example 63.

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

- 103 046642

The title compound of Example 62 (21 mg) was resolved into enantiomers by preparative chiral HPLC to give the title compound (stereoisomer 1, 7.0 mg, R _t = 7.1-8.1 min) and stereoisomer 2 (9.0 mg, R _t = 9.4 - 10.8 min, see example 64).

Preparative chiral HPLC method.

Instrument: PrepCon Labomatic HPLC; column: YMC Cellulose SB 5 μ, 250x30; eluent A: methyl tert-butyl ether + 0.1 vol.% diethylamine; eluent B: acetonitrile; isocratic mode: 50% A + 50% B; flow: 60 ml/min; temperature: 25°C; UV: 254 nm.

Analytical chiral HPLC method.

Device: Waters Alliance 2695; column: YMC Cellulose SB 3 μ, 100x4.6; eluent A: methyl tert-butyl ether + 0.1 vol.% diethylamine; eluent B: acetonitrile; isocratic mode: 50% A + 50% B; flow: 1.4 ml/min; temperature: 25°C; UV: 254 nm.

Analytical chiral HPLC: R _t = 2.60 min.

Optical rotation: [a]D = 21.60° +/- 1.04° (c = 1.0 g/100 ml chloroform).

¹ H-NMR (400 MHz, DMSO-66): δ [ppm] = 1.232 (0.89), 1.877 (1.15), 1.904 (1.74), 1.931 (1.14), 2.008 (0.48), 2.016 (0.62) , 2.036 (1.17), 2.044 (1.15), 2.064 (0.65), 2.073 (0.56), 2.188 (9.17), 2.191 (9.34), 2.204 (16.00), 2.322 (0.45), 2.327 (0.62), 2.332 (0.45) , 2.518 (2.49), 2.523 (1.54), 2.646 (1.12), 2.669 (1.21), 2.673 (1.46), 2.743 (1.23), 2.770 (1.15), 2.844 (1.60), 2.861 (3.42), 2.878 (1.82) , 3.410 (1.23), 3.415 (1.32), 3.426 (2.40), 3.432 (2.38), 3.444 (1.15), 3.449 (1.07), 3.641 (0.56), 3.648 (0.70), 3.670 (1.28), 3.675 (1.31) ,3.698 (0.76), 3.703 (0.61), 3.935 (1.67), 3.942 (1.57), 3.951 (0.95), 3.962 (1.45), 4.109 (1.14), 4.126 (1.03), 4.135 (1.51), 4.152 (1.21) , 4.276 (1.39), 4.285 (1.43), 4.301 (1.14), 4.310 (1.03), 6.056 (2.16), 6.076 (2.23), 6.442 (1.01), 6.464 (1.85), 6.486 (1.14), 6.735 (0.67) , 6.755 (1.42), 6.772 (1.37), 6.793 (0.56), 7.188 (2.29), 7.230 (3.04), 7.243 (3.00), 7.345 (4.40), 7.979 (3.05), 7.991 (2.83), 8.368 (4.67) , 11.030 (2.40).

LC-MS (method 6): R _t = 0.46 min; MS (ESI positive): m/z = 466 [M+H]+.

Example 64.

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

For the preparation of the title racemic compound, see Example 63. Separation of enantiomers by preparative chiral HPLC (method see Example 63) provided 9.0 mg of the title compound (R _t = 9.4 - 10.8 min).

Analytical chiral HPLC (method see example 63): R _t = 3.37 min.

Optical rotation: [a]D = - 20.75° +/- 1.29° (c = 1.0 g/100 ml in chloroform).

¹ H-NMR (400 MHz, DMSO-66): δ [ppm] = 1.232 (0.99), 1.877 (1.12), 1.904 (1.80), 1.931 (1.15), 2.008 (0.49), 2.016 (0.64) , 2.036 (1.17), 2.044 (1.15), 2.065 (0.66), 2.073 (0.57), 2.188 (9.36), 2.191 (9.48), 2.204 (16.00), 2.323 (0.47), 2.327 (0.62), 2.332 (0.47) , 2.518 (2.39), 2.522 (1.44), 2.647 (1.15), 2.669 (1.24), 2.673 (1.48), 2.743 (1.24), 2.770 (1.16), 2.844 (1.63), 2.861 (3.47), 2.878 (1.82) , 3.410 (1.27), 3.415 (1.36), 3.426 (2.43), 3.432 (2.39), 3.443 (1.17), 3.449 (1.07), 3.642 (0.56), 3.648 (0.70), 3.670 (1.30), 3.675 (1.30) ,3.698 (0.75), 3.703 (0.63), 3.935 (1.71), 3.942 (1.60), 3.962 (1.47), 4.109 (1.17), 4.126 (1.03), 4.135 (1.51), 4.152 (1.22), 4.276 (1.40) , 4.285 (1.45), 4.301 (1.13), 4.310 (1.03), 6.056 (2.19), 6.076 (2.26), 6.442 (1.05), 6.464 (1.87), 6.486 (1.15), 6.735 (0.70), 6.755 (1.43) , 6.772 (1.38), 6.793 (0.56), 7.188 (2.30), 7.230 (3.03),7.243

- 104 046642 (3.07), 7.346 (4.46), 7.979 (3.01), 7.992 (2.84), 8.368 (4.73), 11.030 (2.43).

LC-MS (method 6): Rt = 0.46 min; MS (ESI positive): m/z = 466 [M+H]+.

Example 65.

2-(3-{[1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3-fluoroanilino)-1,5,6,7-tetrahydro-4Hpyrrolo [ 3,2-c]pyridin-4-one

Using a method similar to that described for Example 62, with 4-{[(3-{[1,4-dioxan-2yl]methoxy}pyridin-4-yl)methyl]amino}-N-(2-ethyl-3-fluorophenyl )-2-oxo-1,2,5,6-tetrahydropyridine-3 carbothioamide (intermediate 6-65, 215 mg, 429 µmol) as starting material, 76.0 mg (purity 95%, yield 36%) stated in the title compounds were obtained after purification by preparative HPLC (basic medium).

¹ H-NMR (400 MHz, DMSO-b6) delta [ppm]: 1.097 (0.45), 1.206 (6.70), 1.225 (16.00), 1.244 (6.93),

2.322 (0.88), 2.327 (1.21), 2.332 (0.88), 2.518 (4.46), 2.522 (2.73), 2.664 (1.18), 2.669 (1.70), 2.673 (2.02),

2.697 (3.88), 2.715 (3.73), 2.732 (1.31), 2.847 (3.66), 2.864 (7.84), 2.881 (4.11), 3.404 (3.38), 3.415 (2.84),

3.420 (3.17), 3.432 (8.74), 3.437 (5.90), 3.449 (2.86), 3.457 (4.93), 3.506 (1.16), 3.511 (1.46), 3.533 (2.58),

3.540 (2.78), 3.562 (2.02), 3.570 (1.77), 3.711 (3.25), 3.719 (1.53), 3.726 (2.41), 3.738 (2.86), 3.749 (3.64),

3.756 (2.33), 3.777 (2.11), 3.783 (1.59), 3.804 (2.97), 3.810 (3.25), 3.833 (2.65), 3.839 (2.67), 3.887 (2.80),

3.915 (2.07), 4.005 (0.73), 4.013 (1.16), 4.021 (1.72), 4.029 (1.94), 4.036 (1.90), 4.045 (1.57), 4.054 (1.36),

4.061 (0.97), 4.106 (3.19), 4.123 (2.20), 4.132 (4.05), 4.149 (3.10), 4.246 (3.66), 4.255 (3.60), 4.272 (2.73),

4.281 (2.45), 6.084 (4.91), 6.104 (5.10), 6.433 (2.28), 6.454 (4.07), 6.476 (2.61), 6.720 (1.92), 6.741 (3.81),

6.758 (3.70), 6.778 (1.62), 7.180 (5.15), 7.199 (8.92), 7.212 (8.89), 7.427 (9.02), 7.964 (12.58), 7.976 (11.33), 8.358 (15.85), 11.012 (5.43 ).

LC-MS (method 6): Rt = 0.70 min; MS (ESI positive): m/z = 467 [M+H]+.

Example 66, example 67.

2-(3-{ [(2R)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3 -(2-ethyl-3-fluoroanilino)-1,5,6,7 - tetrahydro4H-pyrrolo[3,2-c]pyridin-4-one

2-(3-{[DO)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3-fluoroanilino)-1,5,6,7-tetrahydro4H -pyrrolo[3,2-c]pyridin-4-one

Example 66.

2-(3-{[1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3-fluoroanilino)-1,5,6,7-tetrahydro-4Hpyrrolo[ 3,2-c]pyridin-4-one (stereoisomer 1)

The title compound of Example 65 (74 mg) was resolved into enantiomers by preparative chiral HPLC to give the title compound (stereoisomer 1, 30 mg, R _t = 4.5-5.3 min) and stereoisomer 2 (31 mg, R t = 5.3- 6.2 min, see example 67).

Preparative chiral HPLC method.

Instrument: PrepCon Labomatic HPLC; column: YMC Cellulose SB 10 μ, 250x50; eluent A: methyl tert-butyl ether + 0.1 vol.% diethylamine; eluent B: methanol; isocratic mode: 90% A + 10% B; flow: 150 ml/min; temperature: 25°C; UV: 254 nm.

Analytical chiral HPLC method.

Device: Waters Alliance 2695; column: YMC Cellulose SB 3 μ, 100x4.6; eluent A: methyl tert-butyl ether + 0.1 vol.% diethylamine; eluent B: methanol; isocratic mode: 90% A + 10% B; flow: 1.4 ml/min; temperature: 25°C; UV: 254 nm.

Analytical chiral HPLC: Rt = 4.41 min.

Optical rotation: [a]D = -21.9° +/- 0.60° (c = 1.0 g/100 ml chloroform).

- 105 046642

1H-NMR (400 MHz, DMSO-06) δ [ppm]: 1.097 (0.44), 1.104 (0.61), 1.206 (6.68), 1.225 (16.00), 1.243 (7.03), 2.074 (3.21), 2.322 (1.00), 2.326 (1.39), 2.332 (1.01), 2.518 (6.14), 2.522 (3.75), 2.664 (1.33), 2.669 (1.92), 2.673 (2.17), 2.696 (3.92), 2.715 (3.83), 2.732 (1.29), 2.846 (3.62), 2.864 (7.78), 2.881 (4.15), 3.404 (3.29), 3.414 (2.85), 3.420 (3.24), 3.431 (8.73), 3.437 (6.06), 3.448 (2.90), 3.457 (4.88), 3.505 (1.14),3.511 (1.37), 3.533 (2.57), 3.540 (2.76), 3.562 (1.97), 3.570 (1.73), 3.711 (3.19), 3.719 (1.56), 3.726 (2.37),3.738 (2.90), 3.749 (3.58), 3.755 (2.31), 3.777 (1.96), 3.783 (1.46), 3.804 (2.93), 3.810 (3.13), 3.833 (2.59), 3.839 (2.71), 3.887 (2.80), 3.914 (2.06), 4.013 (1.15), 4.020 (1.68), 4.029 (1.97), 4.036 (1.90), 4.045 (1.59), 4.053 (1.40), 4.060 (0.95), 4.106 (3.06), 4.122 (2.09), 4.132 (3.85), 4.148 (2.90), 4.245 (3.58), 4.255 (3.47),4.271 (2.68), 4.280 (2.36), 6.083 (4.88), 6.104 (5.09), 6.433 (2.24), 6.454 (4.08), 6.476 (2.56), 6.720 (1.80),6.741 (3.65), 6.758 (3.54), 6.778 (1.53), 7.179 (5.11), 7.199 (8.20), 7.211 (8.15), 7.426 (8.99), 7.963 (9.54),7.976 (8.80), 8.357 (13.39), 11.012 (5.48).

LC-MS (method 6): R _t = 0.70 min; MS (ESI positive): m/z = 467 [M+H]+.

Example 67.

2-(3-{[1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3-fluoroanilino)-1 ^^D-tetra^dro^^ pyRRolo[ 3,2-c]pyridin-4-one (stereoisomer 2)

F

For the preparation of the title racemic compound, see Example 65. Separation of the enantiomers by preparative chiral HPLC (method see Example 66) provided 31 mg of the title compound.

Analytical chiral HPLC (method see example 63): R _t = 4.49 min.

Optical rotation: [a]D = 22.51° +/- 0.86° (c = 1.0 g/100 ml in chloroform).

¹ H-NMR (400 MHz, DMSO-06) δ [ppm]: 1.104 (0.57), 1.164 (0.90), 1.206 (6.89), 1.225 (16.00), 1.244 (7.18), 2.322 (0.60), 2.326 (0.81), 2.332 (0.59), 2.518 (3.44), 2.522 (2.12), 2.665 (0.84), 2.669 (1.32), 2.677 (1.68), 2.696 (3.95), 2.715 (3.83), 2.732 (1.33), 2.847 (3.68), 2.864 (7.81), 2.881 (4.16), 3.404 (3.21), 3.415 (2.88), 3.421 (3.23), 3.432 (8.92), 3.437 (6.02), 3.449 (2.91), 3.457 (4.87), 3.506 (1.11), 3.511 (1.37),3.533 (2.61), 3.540 (2.72), 3.562 (2.00), 3.570 (1.74), 3.712 (3.25), 3.719 (1.51), 3.726 (2.32), 3.738 (2.93), 3.749 (3.59), 3.756 (2.31), 3.777 (1.96), 3.784 (1.44), 3.804 (2.94), 3.810 (3.18), 3.833 (2.64), 3.839 (2.70), 3.887 (2.87), 3.915 (2.12), 4.005 (0.70), 4.014 (1.17), 4.020 (1.70), 4.029 (2.01), 4.037 (1.92), 4.045 (1.57), 4.053 (1.42), 4.060 (0.95), 4.106 (3.05), 4.123 (2.12), 4.132 (3.86), 4.148 (2.88), 4.246 (3.51), 4.255 (3.49), 4.271 (2.68), 4.281 (2.35), 6.084 (4.92), 6.105 (5.14), 6.433 (2.23), 6.454 (4.07), 6.476 (2.59), 6.720 (1.81),6.741 (3.64), 6.758 (3.58), 6.778 (1.55), 7.180 (5.16), 7.199 (7.86), 7.212 (7.80), 7.426 (9.02), 7.963 (7.86), 7.976 (7.32), 8.358 (12.12), 11.012 (5.54).

LC-MS (method 6): R _t = 0.70 min; MS (ESI positive): m/z = 467 [M+H]+.

Example 68.

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

F

Using a method similar to that described for Example 62, with 4-{[(3-{[5,5-dimethyl-1,4-dioxan-2yl]methoxy}pyridin-4-yl)methyl]amino}-M-(2 -ethyl-3-fluorophenyl)-2-oxo-1,2,5,6-tetrahydropyridine-3carbothioamide (intermediate 6-68, 350 mg, 662 µmol) as starting material, 82 mg (purity 85%, yield 21 %) of the title compound was obtained after purification by preparative HPLC (basic medium).

¹ H-NMR (400 MHz, DMSO-66) δ [ppm]: 1.051 (1.89), 1.073 (11.18), 1.171 (0.57), 1.182 (0.76), 1.197 (3.04), 1.216 (5.73), 1.234 (3.31), 1.243 (10.52), 2.326 (0.46), 2.518 (1.69), 2.522 (1.07), 2.539 (16.00), 2.669 (0.94), 2.673 (0.76), 2.688 (1.36), 2.706 (1.38), 2.828 (1.23), 2.845 (2.62), 2.862 (1.40), 3.412 (2.22), 3.422 (1.93), 3.428 (1.91), 3.440 (2.37), 3.574 (0.81), 3.582 (0.90), 3.604 (1.34), 3.612 (1.29), 3.629 (0.40),3.646

- 106 046642 (2.91), 3.674 (3.37), 3.703 (0.90), 3.896 (0.52), 3.903 (0.59), 3.912 (0.74), 3.920 (0.70), 3.929 (0.49), 3.938 (0.47), 4.129 (0.8 9 ), 4.146 (0.81), 4.155 (1.16), 4.172 (1.00), 4.284 (1.20), 4.292 (1.15), 4.310 (0.88),4.319 (0.81), 5.758 (2.21), 6.089 (1.68), 6.110 (1.75 ), 6.420 (0.77), 6.443 (1.38), 6.464 (0.88), 6.709 (0.64), 6.729 (1.28), 6.746 (1.24), 6.767 (0.55), 7.165 (1.72), 7.200 (2.88), 7.213 (2.92 ), 7.249 (0.48), 7.369 (0.47),7.382 (0.67), 7.392 (2.91), 7.972 (3.81), 7.985 (3.48), 8.067 (0.61), 8.080 (0.54), 8.372 (5.10), 8.439 (0.78 ), 11.018 (1.92).

LC-MS (method 6): Rt = 0.79 min; MS (ESI positive): m/z = 495 [M+H]+.

Example 69, example 70.

2-(3-{[(2R)-5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3-fluoroanilino)-1, 5,6,7tetrahydro^H-pyrrolo^D-^pyridin^-one;

2-(3-{[(28)-5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3-fluoroavilino)-1, 5,6,7tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one.

Example 69.

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

F

The title compound of Example 68 (32 mg) was resolved into enantiomers by preparative chiral HPLC to give the title compound (stereoisomer 1, 13 mg, Rt = 36.8-46.0 min) and stereoisomer 2 (10 mg, Rt = 21.9-26.4 min., see example 70)

Preparative chiral HPLC method.

Instrument: PrepCon Labomatic HPLC-4; column: Chiralcel OD-H 5 μm, 250x20; eluent A: hexane + 0.1 vol.% diethylamine; eluent B: 2-propanol; isocratic mode: 70% A + 30% B; flow: 10 ml/min; temperature: 25°C; UV: 254 nm.

Analytical chiral HPLC method.

Device: Thermo Fisher UltiMate 3000; column: Chiralcel OD-H 5 μm, 100x4.6; eluent A: hexane + 0.1 vol.% diethylamine; eluent B: 2-propanol; isocratic mode: 70% A + 30% B; flow: 1.4 ml/min; temperature: 25°C; UV: 254 nm.

Analytical chiral HPLC: Rt = 7.38 min.

Optical rotation: [a] _D = -24.42° +/- 0.72° (c = 1.0 g/100 ml chloroform).

¹ H-NMR (400 MHz, DMSO-66) δ [ppm]: 0.698 (1.11), 0.742 (0.61), 0.834 (0.47), 0.851 (0.63), 1.072 (16.00), 1.147 (1.48), 1.195 (4.00), 1.214 (8.27), 1.233 (6.80), 1.242 (15.37), 1.294 (0.70), 2.322 (0.63), 2.326 (0.85), 2.331 (0.63), 2.517 (3.89), 2.522 (2.40), 2.664 (1.17), 2.668 (1.54), 2.673 (1.19), 2.687 (1.95), 2.705 (1.86), 2.722 (0.66), 2.826 (1.78), 2.843 (3.74), 2.860 (2.02), 3.411 (3.06), 3.420 (2.79), 3.427 (2.73),3.440 (3.33), 3.573 (0.89), 3.581 (1.05), 3.603 (1.84), 3.611 (1.82), 3.646 (3.73), 3.674 (4.44), 3.703 (1.16), 3.893 (0.70), 3.901 (0.84), 3.910 (1.06), 3.918 (0.98), 3.926 (0.71), 3.935 (0.66), 4.126 (1.20), 4.143 (1.14), 4.152 (1.62), 4.169 (1.39), 4.281 (1.52), 4.290 (1.61), 4.307 (1.22), 4.316 (1.10), 6.088 (2.37), 6.108 (2.47), 6.417 (1.08), 6.440 (1.96), 6.461 (1.24), 6.707 (0.87), 6.728 (1.74), 6.745 (1.70), 6.765 (0.75), 7.159 (2.50), 7.197 (3.08), 7.209 (3.08), 7.378 (4.32), 7.967 (2.35), 7.980 (2.25), 8.368 (3.77), 11.014 (2.75).

LC-MS (method 6): Rt = 0.78 min; MS (ESI positive): m/z = 495 [M+H] ⁺ .

Example 70.

2-(3-{[5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3-fluoroanilino)-1,5,6, 7tetrahydro^H-pyrrolo^D-^pyridin^-one (stereoisomer 2)

F

WV ^Hs ^V _O CH ₃

For the preparation of the title racemic compound, see Example 68. Separation of enantiomers using preparative chiral HPLC (method see Example 69) resulted in 10

- 107 046642 mg of the title compound.

Analytical chiral HPLC (method see example 69): Rt = 5.50 min.

Optical rotation: [a]D = 33.52° +/- 1.07° (c = 1.0 g/100 ml in chloroform).

¹ H-NMR (400 MHz, DMSO-06) δ [ppm]: 0.852 (0.50), 1.072 (16.00), 1.147 (0.81), 1.195 (3.63), 1.214 (8.06), 1.233 (5.99), 1.242 (15.29), 2.322 (0.67), 2.326 (0.93), 2.331 (0.67), 2.518 (4.20), 2.522 (2.70), 2.664 (1.19), 2.668 (1.61), 2.673 (1.22), 2.687 (1.88), 2.705 (1.81), 2.722 (0.65), 2.826 (1.76), 2.843 (3.72), 2.860 (1.98), 3.411 (2.99), 3.420 (2.72), 3.427 (2.69), 3.440 (3.28), 3.573 (0.90), 3.582 (1.04), 3.603 (1.85), 3.611 (1.82), 3.646 (3.73), 3.674 (4.50), 3.703 (1.19), 3.893 (0.69), 3.901 (0.82), 3.910 (1.04), 3.918 (0.98), 3.927 (0.70), 3.935 (0.65), 4.126 (1.23), 4.143 (1.15), 4.152 (1.63), 4.169 (1.40), 4.281 (1.53), 4.290 (1.62), 4.307 (1.24), 4.316 (1.12), 6.088 (2.36), 6.108 (2.47), 6.419 (1.10), 6.440 (1.96), 6.461 (1.24), 6.707 (0.90), 6.728 (1.77), 6.744 (1.72), 6.765 (0.75), 7.159 (2.47), 7.196 (3.38), 7.209 (3.41), 7.378 (4.36), 7.967 (2.84), 7.980 (2.69), 8.368 (4.39), 11.014 (2.71).

LC-MS (method 6): Rt = 0.78 min; MS (ESI positive): m/z = 495 [M+H] ⁺ .

Example 71.

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

Using a method similar to that described for Example 62, with K-(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-3carbothioamide (intermediate 6-71, 420 mg, 769 µmol) as starting material, 139 mg (95% purity, 33% yield) The title compound was obtained after purification by preparative HPLC (basic medium).

¹ H-NMR (400 MHz, DMSO-06) δ [ppm]: 1.277 (4.27), 1.293 (4.32), 1.333 (0.47), 1.350 (0.67), 1.358 (4.99), 1.374 (4.94), 1.824 (0.55), 1.851 (0.91), 1.878 (0.61), 1.893 (0.74), 1.906 (0.40), 1.920 (1.17), 1.934 (0.70), 1.947 (0.76), 1.956 (0.54), 1.965 (0.55), 1.987 (0.64), 1.995 (0.65), 2.128 (0.82), 2.159 (7.74), 2.180 (8.74), 2.322 (0.51), 2.326 (0.68), 2.332 (0.49), 2.518 (2.39), 2.522 (1.49), 2.577 (0.56), 2.606 (0.54), 2.642 (0.72), 2.665 (0.85), 2.669 (1.29), 2.673 (1.01), 2.748 (1.31), 2.775 (1.22), 2.835 (0.82), 2.852 (2.10), 2.867 (2.15), 2.882 (1.06), 3.403 (1.26), 3.414 (1.72), 3.420 (2.29), 3.437 (1.06), 3.546 (0.63), 3.551 (0.64), 3.640 (0.42), 3.663 (1.06), 3.668 (1.07), 3.680 (0.51), 3.691 (0.88), 3.696 (0.73), 3.712 (0.46), 3.717 (0.51), 3.724 (0.46), 3.729 (0.51), 3.738 (0.48), 3.743 (0.44), 3.750 (0.47), 3.754 (0.43), 3.867 (12.16), 3.891 (16.00), 3.969 (0.62), 3.993 (0.54), 4.637 (0.80), 4.650 (1.17), 4.659 (0.74), 4.665 (1.09), 4.675 (0.61), 6.146 (2.23),6.155 (2.15), 6.162 (1.69), 6.170 (2.32), 6.642 (2.11), 6.647 (2.51), 6.657 (4.69), 6.667 (0.52), 6.672 (0.41), 6.680 (0.65), 6.692 (5.88), 6.701 (2.71), 6.709 (2.25), 7.122 (1.19), 7.160 (1.40), 7.290 (2.01), 7.300 (2.69), 7.303 (2.35), 7.313 (2.45), 7.426 (0.41), 7.435 (2.71), 7.520 (3.23), 7.989 (3.33), 8.002 (3.13), 8.019 (2.70), 8.031 (2.40), 8.402 (3.96), 8.421 (3.26), 11.070 (1.28), 11.110 (1.54).

LC-MS (method 6): Rt = 0.54 min; MS (ESI positive): m/z = 512 [M+H] ⁺ .

Example 72, example 73, example 74, example 75.

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

3-(3-chloro-2-methoxyanilino)-2-[3-({(^)-1-[^)-4-methylmorpholin-2-yl]ethyl}oxy)pyridin-4-yl]1.5 ,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one;

3-(3-chloro-2-methoxyanilino)-2-[3-({(^)-1-[^)-4-methylmorpholin-2-yl]ethyl}oxy)pyridin-4-yl]1.5 ,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one;

3-(3-chloro-2-methoxyanilino)-2-[3-({(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.

Example 72.

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

- 108 046642

The title compound of Example 71 (135 mg) was separated into four stereoisomers using preparative chiral HPLC. The title compound, stereoisomer 1 (20 mg, R _t = 6.8-7.6 min) was obtained along with stereoisomer 2 (27 mg, R _t = 9.6-10.9 min, see example 73), stereoisomer 3 (37 mg, see example 74) and stereoisomer 4 (37 mg, see example 75).

Preparative chiral HPLC method.

Instrument: PrepCon Labomatic HPLC 4; column: YMC Cellulose SB 10 μ, 250x50; eluent A: methyl tert-butyl ether + 0.1 vol.% diethylamine; eluent B: acetonitrile; isocratic mode: 80% A + 20% B; flow: 140 ml/min; temperature: 25°C; UV: 254 nm.

Analytical chiral HPLC method.

Device: Waters Alliance 2695; column: YMC Cellulose SB 3 μ, 100x4.6; eluent A: methyl tert-butyl ether + 0.1 vol.% diethylamine; eluent B: acetonitrile; isocratic mode: 80% A + 20% B; flow: 1.4 ml/min; temperature: 25°C; UV: 254 nm.

Analytical chiral HPLC: R _t = 3.85 min.

Optical rotation: [a]D = 16.84° +/- 0.40° (c = 1.0 g/100 ml chloroform).

¹ H-NMR (400 MHz, DMSO-b6) delta [ppm]: 1.137 (0.95), 1.159 (0.63), 1.232 (0.54), 1.277 (5.83), 1.293 (5.97), 1.826 (0.63), 1.853 (1.16), 1.880 (0.71), 1.907 (0.46), 1.928 (0.77), 1.935 (0.78), 1.956 (0.45), 2.160 (9.53), 2.326 (0.58), 2.522 (2.28), 2.579 (0.94), 2.608 (0.86), 2.665 (0.41), 2.669 (0.54), 2.673 (0.40), 2.748 (0.95), 2.776 (0.90), 2.835 (1.17), 2.852 (2.46), 2.869 (1.37), 3.402 (1.17), 3.413 (1.92), 3.419 (1.92), 3.431 (0.97), 3.523 (0.52), 3.545 (0.95), 3.551 (0.92), 3.573 (0.56), 3.660 (0.71), 3.670 (0.67), 3.690 (0.73), 3.866 (16.00), 3.891 (0.61), 4.649 (0.83), 4.659 (0.85), 4.664 (0.85), 4.675 (0.80), 5.758 (1.51), 6.145 (1.46), 6.155 (1.45), 6.159 (1.36), 6.169 (1.48), 6.643 (2.83), 6.647 (3.21), 6.657 (5.61), 6.667 (0.55), 7.123 (1.81), 7.291 (2.03), 7.303 (2.10), 7.435 (3.81), 8.018 (1.65), 8.031 (1.59), 8.420 (2.63), 11.071 (2.01).

LC-MS (method 6): Rt = 0.53 min; MS (ESI positive): m/z = 512 [M+H] ⁺ .

Example 73.

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

H ₃ C—N\__j

For the preparation of the title racemic compound, see Example 71. Resolution of the stereoisomers using preparative chiral HPLC (see Example 72 for method) provided 27 mg of the title compound, stereoisomer 2.

Analytical chiral HPLC (method see example 72): R _t = 5.24 min.

Optical rotation: [a]D = 16.84° +/- 0.40° (c = 1.0 g/100 ml in chloroform).

¹ H-NMR (400 MHz, DMSO-b6) delta [ppm]: 1.137 (0.95), 1.159 (0.63), 1.232 (0.54), 1.277 (5.83), 1.293 (5.97), 1.826 (0.63), 1.853 (1.16), 1.880 (0.71), 1.907 (0.46), 1.928 (0.77), 1.935 (0.78), 1.956 (0.45), 2.160 (9.53), 2.326 (0.58), 2.522 (2.28), 2.579 (0.94), 2.608 (0.86), 2.665 (0.41), 2.669 (0.54), 2.673 (0.40), 2.748 (0.95), 2.776 (0.90), 2.835 (1.17), 2.852 (2.46), 2.869 (1.37), 3.402 (1.17), 3.413 (1.92), 3.419 (1.92), 3.431 (0.97), 3.523 (0.52), 3.545 (0.95), 3.551 (0.92), 3.573 (0.56), 3.660 (0.71), 3.670 (0.67), 3.690 (0.73), 3.866 (16.00), 3.891 (0.61), 4.649 (0.83), 4.659 (0.85), 4.664 (0.85), 4.675 (0.80), 5.758 (1.51), 6.145 (1.46), 6.155 (1.45), 6.159 (1.36), 6.169 (1.48), 6.643 (2.83), 6.647 (3.21), 6.657 (5.61), 6.667 (0.55), 7.123 (1.81), 7.291 (2.03), 7.303 (2.10), 7.435 (3.81), 8.018 (1.65), 8.031 (1.59), 8.420 (2.63), 11.071 (2.01). LC-MS (method 6): R _t = 0.53 min; MS (ESI positive): m/z = 512 [M+H] ⁺ .

- 109 046642

Example 74.

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

To obtain the title racemic compound, see Example 71. To separate stereoisomer 3 from stereoisomer 4 (see Example 75), preparative chiral HPLC was first performed using the method described in Example 72. One fraction (R _t = 5.5-6.5 min. ) was further separated by another preparative chiral HPLC using the following method to obtain 37 mg of the title compound stereoisomer 3.

Preparative chiral HPLC method.

Device: Sepiatec: Prep SFC100; column: Chiralpak IG 5 mk 250x30 mm; eluent A: CO2; eluent B: 2 propanol + 0.4 vol.% diethylamine; isocratic mode: 40% B; flow: 100 ml/min; temperature: 40°C; BPR: 150 bar; UV: 254 nm.

Analytical chiral HPLC method.

Instrument: Agilent: 1260, Aurora SFC module; column: Chiralpak IG 5 µm 100x4.6 mm; eluent A: CO2; eluent B: 2-propanol + 0.4 vol.% diethylamine; isocratic mode: 40% B; flow: 4 ml/min; temperature: 37.5°C; BPR: 100 bar; UV: 254 nm.

Analytical chiral HPLC: Rt = 3.98 min.

Optical rotation: [a]D = 30.08° +/- 0.91° (c = 1.0 g/100 ml in chloroform).

¹ H-NMR (400 MHz, DMSO-06) delta [ppm]: 0.697 (0.90), 1.026 (1.27), 1.042 (1.28), 1.088 (0.45), 1.137 (0.56), 1.232 (1.77), 1.293 (0.50), 1.358 (5.47), 1.374 (5.50), 1.893 (0.68), 1.920 (1.22), 1.947 (0.76), 1.959 (1.07), 1.966 (0.44), 1.987 (0.74), 1.995 (0.74), 2.016 (0.44), 2.180 (9.88), 2.327 (0.45), 2.523 (1.85), 2.643 (0.83), 2.669 (1.19), 2.749 (0.84), 2.776 (0.82), 2.847 (0.81), 2.865 (1.90), 2.882 (1.25), 3.409 (0.92), 3.419 (1.42), 3.425 (1.62), 3.439 (0.79), 3.640 (0.45), 3.663 (0.82), 3.668 (0.85), 3.691 (0.49), 3.712 (0.49), 3.718 (0.58), 3.724 (0.55), 3.730 (0.61), 3.738 (0.58), 3.744 (0.54), 3.750 (0.58), 3.755 (0.50), 3.891 (16.00), 3.970 (0.75), 3.993 (0.66), 4.638 (0.75), 4.653 (0.92), 4.666 (0.75), 6.146 (1.43), 6.154 (1.30), 6.162 (1.45), 6.170 (1.48), 6.681 (0.60), 6.693 (6.14), 6.701 (2.75), 6.709 (2.40), 6.729 (0.44), 7.162 (1.65), 7.301 (1.65), 7.313 (1.71), 7.521 (3.68), 7.990 (1.16), 8.002 (1.10), 8.403 (1.76), 11.111 (1.82).

LC-MS (method 6): Rt = 0.53 min; MS (ESI positive): m/z = 512 [M+H]+.

Example 75.

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

To obtain the title racemic compound, see Example 71. To separate stereoisomer 3 (see Example 74) and stereoisomer 4 (Example 75), preparative chiral HPLC was first performed using the method described in Example 72. One fraction (Rt = 5.5- 6.5 min) was further separated by another preparative chiral HPLC (see Example 74 for method) to give 37 mg of the title compound stereoisomer 4.

Analytical chiral HPLC: Rt = 7.23 min.

Optical rotation: [a]D = -24.97° +/- 0.50° (c = 1.0 g/100 ml in chloroform).

¹ H-NMR (400 MHz, DMSO-06) delta [ppm]: 0.697 (2.05), 0.742 (1.32), 0.760 (1.30), 0.832 (0.55), 0.851 (0.74), 0.973 (0.66), 0.984 (0.67), 0.991 (0.96), 0.999 (0.64), 1.009 (0.72), 1.026 (0.75), 1.042 (0.77), 1.070 (0.82), 1.088 (1.27), 1.106 (1.27), 1.151 (4.27), 1.232 (4.01), 1.293 (1.22), 1.358 (5.91), 1.373 (6.07), 1.894

- 110 046642 (0.71), 1.921 (1.28), 1.948 (0.80), 1.959 (1.52), 1.988 (0.82), 1.995 (0.85), 2.017 (0.51), 2.181 (10.00), 2.322 (0.74), 2.326 (0 .99 ), 2.331 (0.74), 2.522 (4.96), 2.643 (0.98), 2.669 (1.77), 2.749 (0.99), 2.777 (0.93), 2.849 (0.99), 2.865 (2.18), 2.882 (1.43), 3.408 (1.14 ), 3.424 (1.91), 3.640 (0.51), 3.663 (0.93), 3.668 (0.95), 3.692 (0.56), 3.718 (0.67), 3.730 (0.69), 3.743 (0.64), 3.750 (0.64), 3.891 (16.00 ), 3.969 (0.87), 3.993 (0.79), 4.638 (0.82), 4.653 (1.03), 4.667 (0.80), 6.145 (1.44), 6.154 (1.38), 6.161 (1.41), 6.169 (1.51), 6.681 (0.63 ), 6.693 (5.87), 6.701 (2.92), 6.709 (2.49), 6.729 (0.47), 7.162 (1.85), 7.300 (1.91), 7.313 (1.96), 7.520 (3.80), 7.990 (1.46), 8.002 (1.40 ), 8.402 (2.29), 11.110 (1.99).

LC-MS (method 6): Rt = 0.53 min; MS (ESI positive): m/z = 512 [M+H]+.

Experimental section - biological analyzes

The pharmacological activity of the compounds according to the invention can be assessed using in vitro and/or in vivo assays known to one skilled in the art. The following examples describe the biological activity of the compounds according to the invention without limiting its scope in any way.

Examples - Compounds of the invention were tested in selected biological assays one or more times. In cases where testing is performed more than once, data are reported as either means or medians, where mean, also called the arithmetic mean, means the sum of the values obtained divided by the number of tests performed, and median means the median number of a group of values when ranked in ascending or descending order. If there is an odd number of values in a data set, the median is the middle value. If there is an even number of values in the data set, the median is the arithmetic mean of the two median values.

Examples were synthesized one or more times. When a synthesis was performed more than once, data from biological assays are means or medians calculated using datasets obtained from testing one or more synthesis batches.

The in vitro activity of the compounds of the present invention can be demonstrated in the following assays:

Expression and Purification of EGFR Proteins Used in Biochemical Kinase Activity Assays The various EGFR proteins used in biochemical kinase inhibition assays were produced in-house by expression in insect cells using a baculovirus system and subsequent purification as described in the following paragraphs.

Expressive designs:

cDNA molecules encoding different protein sequences from human EGFR (P00533) were optimized for expression in eukaryotic cells and synthesized using GeneArt Technology at Life Technologies.

These DNA sequences encoded the following sequences.

EGFR #1 design, amino acids R669 - A1210.

EGFR #2 construct, amino acids R669 - A1210 and insertion of the ASV amino acid sequence between V769 and D770.

EGFR #3 construct, amino acids R669 - A1210 and insertion of the SVD amino acid sequence between D770 and N771.

Additionally, all EGFR constructs #1 - #3 encoded: at the N-terminus a TEV (tobacco etch virus) protease cleavage site (DYDIPTTENLYFQG), at the C-terminus two stop codons and additionally 5' and 3' att-DNA sequences for cloning with using the Gateway system.

Each of the four EFGR constructs was subcloned using Gateway technology into the destination vector pD-Ins1. Vector pD-Ins1 is a baculovirus transfer vector (based on vector pVL1393, Pharmingen) that provides an N-terminal fusion of a GST tag to an integrated gene construct. The corresponding transfer vectors were named pD-Ins1_EGFR #1, pD-Ins1_EGFR #2, pD-Ins1_EGFR #3.

- 111 046642

Amino acid sequences of EGFR:

GST-EGFR #1 (Wild type)

MSPILGYWKIKGLVQPTRLLLEYLEEKYEEHLYERDEGDKWRNKKFELGL EFPNLPYIDGDVKLTQSMAIIRYIADKHNMLGGCPKERAEISMLEGAVLDIRYG VSRIAYSKDFETLKVDFLSKLPEMLKMFEDRLCHKTYLNGDHVTHPDFMLYDA LDVVLYMDPMCLDAFPKLVCFKKRIEAIPQIDK YLKSSKYIAWPLQGWQATFG GGDHPPKSDPITSLYKKAGSDYDIPTTTENLYFQGRRRHIVRKRTLRRLLQEREL VEPLTPSGEAPNQALLRILKETEFKKIKVLGSGAFGTVYKGLWIPEGEKVKIPVAI KELREATSPKANKEILDEAYVMASVDNPHVCRLLGICLTSTVQLITQLMPFGCLL DYVREHKD NIGSQYLLNWCVQIAKGMNYLEDRRLVHRDLAARNVLVKTPQHV KITDFGLAKLLGAEEKEYHAEGGKVPIKWMALESILHRIYTHQSDVWSYGVTV WELMTFGSKPYDGIPASEISSILEKGERLPQPPICTIDVYMIMVKCWMIDADSRP KFRELIIEFSKMARDPQRYLVIQGDERMHLPSPTDSNFYRALMEDDEMDDV VDA DEYLIPQQGFFSSPSTSRTPLLSSLSATSNNSTVACIDRNGLQSCPIKEDSFLQRYS SDPTGALTEDSIDDTFLPVPEYINQSVPKRPAGSVQNPVYHNQPLNPAPSRDPHY QDPHSTAVGNPEYLNTVQPTCVNSTFDSPAHWAQKGSHQISLDNPDYQQDFFP KEAKPNGIFKGSTAENAEYLRVAPQSSEFIGA

GST-EGFR #2 (ASV between V769 and D770)

MSPILGYWKIKGLVQPTRLLLEYLEEKYEEHLYERDEGDKWRNKKFELGL EFPNLPYIDGDVKLTQSMAIIRYIADKHNMLGGCPKERAEISMLEGAVLDIRYG VSRIAYSKDFETLKVDFLSKLPEMLKMFEDRLCHKTYLNGDHVTHPDFMLYDA LDVVLYMDPMCLDAFPKLVCFKKRIEAIPQIDK YLKSSKYIAWPLQGWQATFG GGDHPPKSDPITSLYKKAGSDYDIPTTTENLYFQGRRRHIVRKRTLRRLLQEREL VEPLTPSGEAPNQALLRILKETEFKKIKVLGSGAFGTVYKGLWIPEGEKVKIPVAI KELREATSPKANKEILDEAYVMASVASVDNPHVCRLLGICLTSTVQLITQLMPF GCLLDYVREHK DNIGSQYLLNWCVQIAKGMNYLEDRRLVHRDLAARNVLVKT PQHVKITDFGLAKLLGAEEKEYHAEGGKVPIKWMALESILHRIYTHQSDVWSY GVTVWELMTFGSKPYDGIPASEISSILEKGERLPQPPICTIDVYMIMVKCWMIDA D SRPKFRELIIEF SKM ARDPQR YL VIQ GDERMHLP SPTD SNF YRA LMDEEDMDD VVDADEYLIPQQGFFSSPSTSRTPLLSSLSATSNNSTVACIDRNGLQSCPIKEDSFL QRYSSDPTGALTEDSIDDTFLPVPEYINQSVPKRPAGSVQNPVYHNQPLNPAPSR DPHYQDPHSTAVGNPEYLNTVQPTCVNSTFDSPAHWAQKGSHQISLDNPDYQQ DFFPKEAKPNGIFKGSTAENAEYLRVAPQS SEFIGA

GST-EGFR #3 (SVD between D770 and N771)

MSPILGYWKIKGLVQPTRLLLEYLEEKYEEHLYERDEGDKWRNKKFELGL EFPNLPYIDGDVKLTQSMAIIRYIADKHNMLGGCPKERAEISMLEGAVLDIRYG VSRIAYSKDFETLKVDFLSKLPEMLKMFEDRLCHKTYLNGDHVTHPDFMLYDA LDVVLYMDPMCLDAFPKLVCFKKRIEAIPQIDK YLKSSKYIAWPLQGWQATFG GGDHPPKSDPITSLYKKAGSDYDIPTTTENLYFQGRRRHIVRKRTLRRLLQEREL VEPLTPSGEAPNQALLRILKETEFKKIKVLGSGAFGTVYKGLWIPEGEKVKIPVAI KELREATSPKANKEILDEAYVMASVDSVDNPHVCRLLGICLTSTVQLITQLMPF GCLLDYVREH KDNIGSQYLLNWCVQIAKGMNYLEDRRLVHRDLAARNVLVKT PQHVKITDFGLAKLLGAEEKEYHAEGGKVPIKWMALESILHRIYTHQSDVWSY GVTVWELMTFGSKPYDGIPASEISSILEKGERLPQPPICTIDVYMIMVKCWMIDA D SRPKFRELIIEF SKM ARDPQR YL VIQ GDERMHLP SPTD SNF Y RALMDEEDMDD VVDADEYLIPQQGFFSSPSTSRTPLLSSLSATSNNSTVACIDRNGLQSCPIKEDSFL

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QRYSSDPTGALTEDSIDDTFLPVPEYINQSVPKRPAGSVQNPVYHNQPLNPAPSR DPHYQDPHSTAVGNPEYLNTVQPTCVNSTFDSPAHWAQKGSHQISLDNPDYQQ DFFPKEAKPNGIFKGSTAENAEYLRVAPQSSEFIGA

Preparation of recombinant baculovirus.

In separate approaches, each of the three transfer vectors was cotransfected in Sf9 cells with baculovirus DNA (Flashbac Gold DNA, Oxford Expression Technologies) using Fugene HD (Roche). After 5 days, the supernatant of transfected cells containing recombinant baculovirus encoding various EGFR proteins was used to further infect Sf9 cells to amplify the virus, and the virus titer was monitored by qPCR.

Expression of EGFR in Sf9 cells using a bioreactor.

Sf9 cells cultured (Insect-xpress medium, Lonza, 27°C) in a Wave bioreactor with a disposable culture bag were infected at a cell density of 106 cells/ml with one of the original recombinant baculoviruses at a multiplicity of infection of 1 and incubated for 48 hours. cells were collected by centrifugation and the cell mass was frozen at -80°C.

Purification of GST-EGFR fusion proteins.

Purification of GST-EGFR fusion proteins was successfully performed by affinity chromatography using Glutathion Sepharose 4B matrix (GE Healthcare Life Sciences).

Cells precipitated by centrifugation (from 4 L of cell culture) were resuspended in lysis buffer (50 mM HEPES pH 7.4, 150 mM NaCl, 5% glycerol, 1 mM _MgCl2 , 1 mM _MnCl2 , _0.5 mM _Na3VO4 ) and lysed by performing freeze-thaw cycle followed by incubation on ice for 60 min. The supernatant was centrifuged at 4000 x g for 30 min. at 4°C. The supernatant was then incubated with Glutathion Sepharose 4B matrix (in a glass bottle rotated for 16 hours at 4°C) to bind the GST EGFR fusion protein, washed with wash buffer and finally the bound protein was eluted using elution buffer (lysis buffer plus 25 mM glutathione) and shock-frozen with liquid nitrogen.

WT-EGFR kinase activity assay.

The inhibitory activity of the compounds of the present invention on wild-type epidermal growth factor receptor (EGFR) was quantified using a TR-FRET-based EGFR assay as described in the following paragraphs.

A recombinant fusion protein of N-terminal glutathione-transferase (GST) and a fragment of human EGFR (amino acids R669 to A1210), expressed in Sf9 insect cells and purified by glutathione-Sepharose affinity chromatography as described above, was used as the kinase. The biotinylated peptide biotin-Ahx-AEEEEYFELVAKKK (C-terminus in amide form), which can be purchased, for example, from Biosynthan GmbH (Berlin-Buch, Germany), was used as a substrate for the kinase reaction.

For the assay, 50 nL of a 100-fold concentrated solution of test compound in DMSO was pipetted into either a black low-volume 384-well microtiter plate or a black 1536-well microtiter plate (both Greiner Bio-One, Frickenhausen, Germany), and 2 μL of the solution was added EGFR in aqueous assay buffer [50 mM Hepes pH 7.0, 10 mM MgCl ₂ , 1 mM dithiothreitol, 0.5 mM EGTA, 0.3 mM activated sodium orthovanadate, 0.005% (wt/vol) bovine serum albumin, 0.005% (vol. /vol.) Tween-20], and the mixture was incubated for 15 min at 22°C to ensure pre-binding of the test compounds to the enzyme before the start of the kinase reaction. The kinase reaction was then started by adding 3 µl of adenosine triphosphate solution (ATP, 3.33 mM => final concentration in 5 µl assay volume was 2 mM) and substrate (1.67 µM => final conc. in 5 µl assay volume was 1 µM) into assay buffer and the resulting mixture was incubated for a reaction time of 30 min at 22°C. The concentration of EGFR was adjusted depending on the activity of the enzyme lot and was chosen as appropriate to ensure the assay was performed in a linear range, with a typical concentration being 7.6 pg/μl. The reaction was stopped by adding 3 μl of a solution of HTRF detection reagents (83.3 nM streptavidin-XL665 [Cisbio Bioassays, Caudol, France] and 1.67 nM PT66-Tb-cryptate, a terbium cryptate-labeled phosphotyrosine antibody from Cisbio Bioassays [PT66 Tb cryptate can also be replaced use PT66 Eu chelate from Perkin Elmer]) in aqueous EDTA solution (133.3 mM EDTA, 0.2% (w/v) bovine serum albumin in 50 mM HEPES pH 7.5).

The resulting mixture was incubated for 1 h at 22°C to allow binding of the biotinylated phosphorylated peptide to streptavidin-XL665 and PT66-Tb-cryptate. Subsequently, the amount of phosphorylated substrate was assessed by measuring the resonance energy transfer from PT66-Tb-cryptate to streptavidin-XL665. Thus, fluorescence emission at wavelengths 620 nm and 665 nm after excitation at 337 nm was measured in an HTRF reader such as Pherastar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of emission values at wavelengths of 665 nm and 622 nm was taken as a measure of the amount of phosphorylated substrate. Data were normalized (enzyme reaction without inhibitor =

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0% inhibition, all other assay components but no enzyme = 100% inhibition). Typically, test compounds were tested on the same microtiter plate at 11 different concentrations ranging from 20 µM to 0.07 nM (20 µM, 5.7 µM, 1.6 µM, 0.47 µM, 0.13 µM, 38 nM, 11 nM, 3.1 nM, 0.9 nM , 0.25 nM and 0.07 nM, dilution series prepared separately before analysis, based on the level of 100-fold concentrated solutions in DMSO by serial dilution, exact concentrations may vary depending on pipetting devices used) in duplicate values for each concentration, and IC ₅₀ was calculated using Genedata Screener™ software.

Analysis of the kinase activity of the EGFR exon 20 mutant (D770_N771insSVD).

The inhibitory activity of the compounds of the present invention on the epidermal growth factor receptor (EGFR) with an SVD amino acid sequence insertion between D770 and N771 was quantified using a TR-FRET-based kinase activity assay as described in the following paragraphs.

Recombinant fusion protein of N-terminal glutathione-transferase (GST) and a fragment of the human EGFR variant (amino acids R669 - A1210 with an insertion of the SVD amino acid sequence between D770 and N771 (EGFR ins SVD), expressed in Sf9 insect cells and purified using affinity chromatography with using glutathione-Sepharose as described above, was used as a kinase. The biotinylated peptide biotin-Ahx-AEEEEYFELVAKKK (C-terminus in amide form), which can be purchased, for example, from Biosynthan GmbH (Berlin) was used as a substrate for the kinase reaction. Buch, Germany).

For the assay, 50 nL of a 100-fold concentrated solution of test compound in DMSO was pipetted into either a black low-volume 384-well microtiter plate or a black 1536-well microtiter plate (both Greiner Bio-One, Frickenhausen, Germany), and 2 μL of the solution was added EGFR in aqueous assay buffer [50 mM Hepes pH 7.0, 10 mM MgCl ₂ , 1 mM dithiothreitol, 0.5 mM EGTA, 0.3 mM activated sodium orthovanadate, 0.005% (wt/vol) bovine serum albumin, 0.005% (vol. /vol.) Tween-20], and the mixture was incubated for 15 min at 22°C to ensure pre-binding of the test compounds to the enzyme before the start of the kinase reaction. The kinase reaction was then started by adding 3 µl of adenosine triphosphate solution (ATP, 3.33 mM => final concentration in 5 µl assay volume was 2 mM) and substrate (1.67 µM => final conc. in 5 µl assay volume was 1 µM) into assay buffer and the resulting mixture was incubated for a reaction time of 30 min at 22°C. The concentration of EGFR was adjusted depending on the activity of the enzyme lot and was chosen as appropriate to ensure the assay was performed in a linear range, with a typical concentration being 15 pg/μl. The reaction was stopped by adding 3 μl of a solution of HTRF detection reagents (83.3 nM streptavidin-^665 [Cisbio Bioassays, Caudol, France] and 1.67 nM PT66-Tb-cryptate, a terbium cryptate-labeled antiphosphotyrosine antibody from Cisbio Bioassays [replacing PT66 Tb cryptate also you can use PT66 Eu chelate from Perkin Elmer]) in aqueous EDTA solution (133.3 mM EDTA, 0.2% (w/v) bovine serum albumin in 50 mM HEPES pH 7.5).

The resulting mixture was incubated for 1 hour at 22°C to allow binding of the biotinylated phosphorylated peptide to stenmavidin-XL665 and PT66-Tb-cryptate. Subsequently, the amount of phosphorylated substrate was assessed by measuring the resonance energy transfer from PT66-Tb-cryptate to streptavidin-XL665. Thus, fluorescence emission at wavelengths 620 nm and 665 nm after excitation at 337 nm was measured in an HTRF reader such as Pherastar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of emission values at 665 nm and 622 nm was taken as a measure of the amount of phosphorylated substrate. Data were normalized (enzyme reaction without inhibitor = 0% inhibition, all other assay components but without enzyme = 100% inhibition). Typically, test compounds were tested on the same microtiter plate at 11 different concentrations ranging from 20 µM to 0.07 nM (20 µM, 5.7 µM, 1.6 µM, 0.47 µM, 0.13 µM, 38 nM, 11 nM, 3.1 nM, 0.9 nM , 0.25 nM and 0.07 nM, dilution series prepared separately before analysis, based on the level of 100-fold concentrated solutions in DMSO by serial dilution, exact concentrations may vary depending on pipetting devices used) in duplicate values for each concentration, and IC ₅₀ was calculated using Genedata Screener™ software.

Analysis of the kinase activity of the EGFR exon 20 mutant (V769_D770insASV).

The inhibitory activity of the compounds of the present invention on the epidermal growth factor receptor (EGFR) with an ASV amino acid sequence insertion between V769 and D770 was quantified using a TR-FRET-based kinase activity assay as described in the following paragraphs.

Recombinant fusion protein of N-terminal glutathione-transferase (GST) and a fragment of the human EGFR variant (amino acids R669 - A1210 with insertion of the ASV amino acid sequence

- 114 046642 between V769 and D770 (EGFR ins ASV), expressed in Sf9 insect cells and purified by affinity chromatography using glutathione-Sepharose as described above, was used as a kinase. The biotinylated peptide biotin-Ahx-AEEEEYFELVAKKK (C-terminus in amide form), which can be purchased, for example, from Biosynthan GmbH (Berlin-Buch, Germany), was used as a substrate for the kinase reaction.

For the assay, 50 nL of a 100-fold concentrated solution of test compound in DMSO was pipetted into either a black low-volume 384-well microtiter plate or a black 1536-well microtiter plate (both Greiner Bio-One, Frickenhausen, Germany), and 2 μL of the solution was added EGFR in aqueous assay buffer [50 mM Hepes pH 7.0, 10 mM MgCl ₂ , 1 mM dithiothreitol, 0.5 mM EGTA, 0.3 mM activated sodium orthovanadate, 0.005% (wt/vol) bovine serum albumin, 0.005% (vol. /vol.) Tween-20], and the mixture was incubated for 15 min at 22°C to ensure pre-binding of the test compounds to the enzyme before the start of the kinase reaction. The kinase reaction was then started by adding 3 µl of adenosine triphosphate solution (ATP, 3.33 mM => final concentration in 5 µl assay volume was 2 mM) and substrate (1.67 µM => final conc. in 5 µl assay volume was 1 µM) into assay buffer and the resulting mixture was incubated for a reaction time of 30 min at 22°C. The concentration of EGFR was adjusted depending on the activity of the enzyme lot and was chosen as appropriate to ensure the assay was performed in a linear range, with a typical concentration being 2.5 pg/μl. The reaction was stopped by adding 3 μl of a solution of HTRF detection reagents (83.3 nM streptavidin-XL665 [Cisbio Bioassays, Caudol, France] and 1.67 nM PT66-Tb-cryptate, terbium cryptate-labeled antiphosphotyrosine antibody from Cisbio Bioassays [PT66 Tb cryptate can also be replaced use PT66 Eu chelate from Perkin Elmer]) in aqueous EDTA solution (133.3 mM EDTA, 0.2% (w/v) bovine serum albumin in 50 mM HEPES pH 7.5).

The resulting mixture was incubated for 1 h at 22°C to allow binding of the biotinylated phosphorylated peptide to streptavidin-XL665 and PT66-Tb-cryptate. Subsequently, the amount of phosphorylated substrate was assessed by measuring the resonance energy transfer from PT66-Tb-cryptate to streptavidin-XL665. Thus, fluorescence emission at wavelengths 620 nm and 665 nm after excitation at 337 nm was measured in an HTRF reader such as Pherastar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of emission values at 665 nm and 622 nm was taken as a measure of the amount of phosphorylated substrate.

Data were normalized (enzyme reaction without inhibitor = 0% inhibition, all other assay components but without enzyme = 100% inhibition). Typically, test compounds were tested on the same microtiter plate at 11 different concentrations ranging from 20 µM to 0.07 nM (20 µM, 5.7 µM, 1.6 µM, 0.47 µM, 0.13 µM, 38 nM, 11 nM, 3.1 nM, 0.9 nM , 0.25 nM and 0.07 nM, dilution series prepared separately before analysis, based on the level of 100-fold concentrated solutions in DMSO by serial dilution, exact concentrations may vary depending on pipetting devices used) in duplicate values for each concentration, and IC ₅₀ values calculated using Genedata Screener™ software. In table Figure 2 shows the results of inhibition in a biochemical assay using an EGFR mutant.

table 2

Example No. Analysis of mutEGFR kinase activity (D770 N771insSVD) IC ₅₀ [mol/l] 1 1.59 E-10 2 < 7.25 E-11 7.79 E-11 7.87 E-11 9.12 E-11 1.65 E-10 2.00 E-10 3 1.37 E-10 4 2.56 E-10 5 < 7.25 E-11 8.51 E-11 1.12 E-10 1.14 E-10 1.20 E-10 1.24 E-10 1.36 E-10

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6 1.00 E-10 7 1.37 E-10 8 7.99 E-ll 9 8.91 E-ll 10 6.69 E-10 eleven 2.86 E-10 12 7.94 E-ll 13 1.39 E-10 14 1.30 E-10 15 1.51 E-10 16 2.28 E-10 17 1.56 E-10 18 1.47 E-10 19 1.13 E-10 20 8.72 E-ll 21 1.26 E-10 22 1.53 E-10 23 1.69 E-10 24 2.61 E-10 25 2.82 E-10 26 2.13 E-10 27 1.18 E-10 28 2.49 E-10 29 5.47 E-10 thirty 3.96 E-10 31 1.33 E-10 32 1.27 E-10 33 2.13 E-10 34 1.93 E-10 35 8.73 E-ll 36 1.14 E-10 37 4.00 E-10 38 1.19 E-10 39 3.04 E-10 40 1.15 E-10 41 2.91 E-10 42 1.55 E-10 43 2.25 E-10 44 1.50 E-10 45 4.92 E-10 46 4.33 E-10 47 < 7.25 E-ll 1.69 E-10 2.27 E-10 2.30 E-10 48 2.49 E-10 49 1.70 E-10 50 1.70 E-10 51 1.36 E-10 52 2.26 E-10 53 4.26 E-10 54 5.71 E-10

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55 2.57 E-10 56 2.58 E-10 57 2.69 E-10 58 1.70 E-10 2.15 E-10 < 2.54 E-10 3.64 E-10 59 2.35 E-10 60 3.05 E-10 61 9.35 E-10 62 2.37 E-10 63 2.65 E-10 64 1.87 E-10 65 1.36 E-10 66 1.82 E-10 67 2.17 E-10 68 2.67 E-10 69 2.33 E-10 70 1.68 E-10 71 4.05 E-10 72 1.41 E-9 73 1.12 E-9 74 6.61 E-10 75 4.99 E-9

Analysis of Bubl kinase activity at high ATP concentrations.

The inhibitory activity of the compounds of the present invention on Bub1 at high ATP concentration was quantified using the TR-FRET assay for Bub1 kinase activity at high ATP concentration, as described in the following paragraphs.

N-terminal His ₆ -tagged recombinant human Bub1 catalytic domain (amino acids 704-1085), expressed in insect cells (Hi5) and purified by Ni-NTA affinity chromatography and subsequent size exclusion chromatography, was used as the enzyme. The biotinylated peptide biotinAhx-VLLPKKSFAEPG - SEQ ID 5 (C-terminus in amide form), which can be purchased, for example, from Biosyntan (Berlin, Germany), was used as a substrate for the kinase reaction.

For the assay, 50 nL of a 100-fold concentrated solution of test compound in DMSO was pipetted into either a black low-volume 384-well microtiter plate or a black 1536-well microtiter plate (both Greiner Bio-One, Frickenhausen, Germany), and 3 μL of the solution was added adenosine triphosphate (ATP, 3.33 mM => final conc. in 5 µl assay volume was 2 mM) and substrate (1.67 µM => final conc. in 5 µl assay volume was 1 µM) in aqueous assay buffer [50 mM Tris /HCl pH 7.5, 10 mM magnesium chloride (MgCl ₂ ), 200 mM potassium chloride (KCl), 1.0 mM dithiothreitol (DTT), 0.1 mM sodium orthovanadate, 1% (v/v) glycerol, 0.01% (wt. /vol) bovine serum albumin (BSA), 0.005% (vol/vol) Triton X-100 (Sigma), and 1x EDTA-free complete protease inhibitor cocktail (Roche)]. The kinase reaction was then started by adding 2 μl of Bub1 solution in assay buffer, and the resulting mixture was incubated for a reaction time of 60 min at 22°C. The concentration of Bub1 was adjusted depending on the activity of the enzyme batch and was chosen to be appropriate to ensure the assay was performed in a linear range, with a typical concentration being approximately 200 ng/ml. The reaction was stopped by adding 3 μl of a solution of TR-FRET detection reagents (0.167 μM streptavidinXL665 [Cisbio Bioassays, Caudol, France] and 1.67 nM antiphosphoserine antibody [Merck Millipore, cat. # 35-002] and 0.67 nM LANCE EU-W1024 - labeled anti-mouse IgG antibody [Perkin-Elmer, product number AD0077; alternatively, terbium cryptate-labeled anti-mouse IgG antibody from Cisbio Bioassays]) in aqueous EDTA (83.3 mM EDTA, 0.2% (w/v) bovine serum albumin in 100 mM HEPES pH 7.5).

The resulting mixture was incubated for 1 h at 22°C to allow complex formation between the phosphorylated biotinylated peptide and the detection reagents. Subsequently, the amount of phosphorylated substrate was assessed by measuring the resonance energy transfer from Eu-chelate to streptavidin-XL. Thus, fluorescence emission at wavelengths 620 nm and 665 nm after excitation at 350 nm was measured in a TR-FRET reader, such as Pherastar or Pherastar FS (both from BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of emission values at 665 nm and 622 nm was taken as a measure of the amount of phosphorylated substrate. Data were normalized (enzyme reaction without inhibitor = 0% inhibition, all other assay components but without enzyme = 100% inhibition). Typically, test compounds were tested on the same microtiter plate at 11 different concentrations ranging from 20 µM to 0.7 nM (20 µM, 5.7 µM, 1.6 µM,

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0.47 µM, 0.13 µM, 38 nM, 11 nM, 3.1 nM, 0.9 nM, 0.25 nM and 0.07 nM, dilution series prepared separately before analysis, based on the level of 100-fold concentrated solutions in DMSO by serial dilution, exact concentrations may vary depending on the pipetting devices used) in duplicate values for each concentration, and IC ₅₀ values were calculated by 4-parameter fitting. In table Figure 3 shows the results of Bub1 inhibition in a kinase activity assay at high ATP concentrations.

Table 3

Example No. Bubl at high ATP concentration (2 mM) 1С ₅ о [mol/l] 1 3.36 E-6 2 6.04 E-6 3 3.33 E-6 4 1.13 E-5 5 1.29 E-5 6 6.31 E-6 7 1.06 E-5 8 7.88 E-6 9 4.23 E-6 10 1.78 E-6 eleven 4.33 E-6 12 > 2.00 E-5 13 > 2.00 E-5 14 > 2.00 E-5 15 > 2.00 E-5 16 > 2.00 E-5 17 > 2.00 E-5 18 > 2.00 E-5 19 1.14 E-5 20 9.53 E-6 21 3.79 E-6 22 > 2.00 E-5 23 > 2.00 E-5 24 1.94 E-6 25 > 2.00 E-5 26 1.08 E-6 27 >2.00 E-5 28 > 2.00 E-5 29 1.72 E-5 thirty > 2.00 E-5 33 > 2.00 E-5 34 > 2.00 E-5 35 > 2.00 E-5 36 2.82 E-6 37 1.90 E-5 38 > 5.71 E-6 39 > 2.00 E-5 40 8.62 E-6 41 > 2.00 E-5 42 > 2.00 E-5 43 2.41 E-6 45 > 5.71 E-6 46 1.30 E-5 47 5.01 E-6 48 1.22 E-5 49 3.93 E-6

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50 3.54 E-6 51 1.52 E-6 52 7.29 E-7 53 1.36 E-6 54 9.94 E-7 55 7.59 E-6 56 1.65 E-5 57 1.40 E-5 58 1.39 E-5 59 1.22 E-5 60 1.64 E-5 62 > 2.00 E-5 63 > 2.00 E-5 64 > 2.00 E-5 65 3.58 E-6 66 5.04 E-6 67 2.08 E-6 68 > 2.00 E-5 69 > 2.00 E-5 70 > 2.00 E-5 71 > 2.00 E-5 72 >2.00 E-5 73 > 2.00 E-5 74 > 2.00 E-5 75 > 2.00 E-5

The compounds of the present invention may also exhibit other beneficial properties, such as greater inhibition of exon 20 insertion mutant EGFR relative to wild-type EGFR, which may be useful in reducing the potential toxicity resulting from excessive inhibition of wild-type EGFR.

Description of cellular data (WT, insSVD).

293T cells from ATCC were transfected with pBABEpuro expression constructs for WT EGFR or EGFR-insSVD and pCL-Eco packaging vector using Fugene-6 transfection reagent from Promega. The plates were incubated at 37°C for 48 hours. Retrovirus was collected by filtering the supernatant medium through a 0.45 μm filter.

Ba/F3 cells purchased from DSMZ were grown in RPMI + 10% FBS + 10 ng/ml IL-3 and infected with filtered retroviral supernatant at a 1:2 dilution. Polybrene was added to a concentration of 8 μg/ml, the plates were rotated for 90 min, and incubated overnight at 37°C. At 24 h postinfection, 2 μg/ml puromycin was added to the infected cells, and the cells were grown continuously in the presence of puromycin and 10 ng/ml IL-3. The following stably expressing Ba/F3 cell lines were created: Ba/F3-EGFR-WT, Ba/F3-EGFR-insSVD, (Ba/F3 - vector control).

For cell survival assays, Ba/F3 cells were grown to a density of 1-2 million cells per ml, centrifuged and resuspended in IL-3-free medium, and replated at a concentration of 200,000-500,000 cells per ml. Cells ectopically expressing WT EGFR or EGFR-insSVD were seeded with 10 ng/ml Millipore Culture grade EGF. Cells ectopically expressing the empty pBABEpuro vector were seeded with 10 ng/ml IL-3.

After 2 days, cells were seeded in a volume of 50 μl in a 384-well plate at a concentration of 4000 cells per well for cells assayed in the absence of IL-3 and 2000 cells per well for cells assayed in the presence of IL-3. 100 nL of compound was added to each well using a 100 nL Pin Head device, and the plates were incubated at 37°C for 48 h.

Cell viability was measured by adding 20 μl of Cell Titer-Glo Luminescent Cell Viability Reagent diluted 1:3 in PBS. The plates were sealed with Perkin Elmer Top-Seal, inverted several times to mix, and immediately centrifuged at 1000 rpm for 2 min. The plates were incubated under low light conditions for 8–10 min and luminescence was measured. The IC ₅₀ values for the examples are shown in Table. 4.

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Table 4

Example No. BA/F3 (insSVD) IC50 |mol/l! BA/F3 (wild type) IC50 [mol/l] 1 9.80 E-9 3.66 E-7 2 7.12 E-9 2.92 E-7 3 2.28 E-8 7.55 E-7 4 1.95 E-8 4.52 E-7 5 9.73 E-9 2.62 E-7 6 5.03 E-8 7.85 E-7 7 1.80 E-8 2.92 E-7 8 8.18 E-9 1.21 E-7 9 3.27 E-8 3.03 E-7 10 1.11 E-8 4.96 E-7 eleven 1.87 E-8 7.01 E-7 12 2.28 E-8 5.74 E-7 13 1.57 E-7 1.52 E-6 14 1.05 E-8 3.87 E-7 15 1.53 E-8 4.26 E-7 16 1.26 E-7 1.05 E-6 17 9.53 E-9 2.31 E-7 18 2.79 E-8 5.79 E-7 19 2.91 E-8 5.32 E-7 20 8.25 E-9 3.13 E-7 21 8.49 E-9 3.41 E-7 22 4.19 E-8 5.44 E-7 23 7.10 E-8 6.48 E-7 24 3.46 E-8 4.44 E-7 25 1.83 E-8 3.49 E-7 26 8.99 E-8 8.39 E-7 27 1.69 E-8 5.02 E-7 28 1.26 E-7 1.24 E-6 29 3.36 E-8 6.21 E-7 thirty 1.93 E-8 4.07 E-7 33 1.02 E-7 5.57 E-7 34 1.20 E-8 2.04 E-7 35 2.15 E-8 2.61 E-7 36 6.81 E-8 8.45 E-7 37 3.57 E-8 3.48 E-7 38 2.93 E-8 4.19 E-7 39 4.40 E-8 6.30 E-7 40 1.19 E-7 8.67 E-7 41 7.75 E-8 6.95 E-7 42 1.98 E-8 5.96 E-7 43 6.05 E-8 1.25 E-6 44 2.57 E-8 45 1.11 E-7 1.64 E-6 46 1.01 E-8 3.76 E-7 47 4.16 E-8 7.15 E-7 48 1.88 E-8 3.79 E-7 49 5.36 E-8 7.85 E-7 50 8.82 E-9 3.61 E-7

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51 4.67 E-8 7.42 E-7 52 1.34 E-8 5.47 E-7 53 2.13 E-8 4.08 E-7 54 8.09 E-8 9.17 E-7 55 1.24 E-7 1.31 E-6 56 1.19 E-8 4.35 E-7 57 2.80 E-8 5.39 E-7 58 2.98 E-8 5.19 E-7 59 1.86 E-8 3.36 E-7 60 5.27 E-8 9.46 E-7 61 3.00 E-7 3.77 E-6 62 2.67 E-8 6.97 E-7 63 1.47 E-7 1.37 E-6 64 7.58 E-9 2.71 E-7 65 1.34 E-8 2.87 E-7 66 7.52 E-9 2.52 E-7 67 2.90 E-8 1.98 E-7 68 3.73 E-8 6.44 E-7 69 7.17 E-9 3.12 E-7 70 6.79 E-8 7.14 E-7 71 1.32 E-7 1.42 E-6 72 6.73E-8 9.57 E-7 73 7.80 E-8 1.28 E-6 74 5.11 E-8 8.28 E-7 75 5.71 E-7 3.90 E-6

Unlike the claimed compounds of this invention, the compounds claimed in the closest analogue of WO 2016/120196 do not exhibit the advantageous combination properties described above. This is shown in table. 5.

Table 5

WO 2016/120196 Example No. Analysis of mutEGFR kinase activity (D770 N771insSVD) IC50 [mol/l] BA/F3 (insSVD) IC50 [mol/l] BA/F3 (wild type) 1С ₅₀ [mol/l] 38 2.24 E-7 > 2.00 E-6 5.91 E-6 41 3.43 E-8 > 2.00 E-6 5.02 E-6 45 1.28 E-8 > 2.00 E-6 4.04 E-6

Description of cellular data (Ba/F3 cells overexpressing a non-insSVD EGFR mutant).

293T cells from ATCC were transfected with pBABEpuro expression constructs for the EGFR mutant (V769_D770insASV, D770_N771insNPG, N771_P772insH, H773_V774insNPH, E746_A750del, L858R, D770_N771insSVD C797S, 50del C797S, L858R C797S, L861Q) or ERBB2 mutant (A775_G776insYVMA) and pCL-Eco packaging vector using reagent for Fugene-6 transfection from Promega. The plates were incubated at 37°C for 48 hours. Retrovirus was collected by filtering the supernatant medium through a 0.45 μm filter.

Ba/F3 cells purchased from DSMZ were grown in RPMI + 10% FBS + 10 ng/ml IL-3 and infected with filtered retroviral supernatant at a 1:2 dilution. Polybrene was added to a concentration of 8 μg/ml, the plates were rotated for 90 min, and incubated overnight at 37°C. At 24 h postinfection, 2 μg/ml puromycin was added to the infected cells, and the cells were grown continuously in the presence of puromycin and 10 ng/ml IL-3. The following stably expressing Ba/F3 cell lines were created: Ba/F3-EGFR-V769_D770insASV, Ba/F3-EGFRD770_N771insNPG, Ba/F3-EGFR-N771_P772insH, Ba/F3-EGFR-H773_V774insNPH, Ba/F3-EGFRE746_A750del, Ba/F3 -EGFR-L858R, Ba/F3-EGFR-D770_N771insSVD C797S, Ba/F3-EGFR-E746_A750del C797S, Ba/F3-EGFR-L858R C797S, Ba/F3-EGFR L861Q and Ba/F3-ERBB2-A775_G776insYVMA (Ba/F3 vector control).

For cell survival assays, Ba/F3 cells were grown to a density of 1-2 million cells per ml, centrifuged and resuspended in IL-3-free medium, and replated at a concentration of 200,000-500,000 cells per ml. Cells ectopically expressing WT EGFR were seeded with 10 ng/ml Millipore Culture grade EGF, and Ba/F3 cells containing an EGFR mutant or an ERBB2 mutant were grown without EGF. Cells ectopically expressing the empty pBABEpuro vector were seeded with 10 ng/ml IL-3.

After 2 days, cells were seeded in a volume of 50 μl in a 384-well plate at a concentration of 4000 cells per well for cells assayed in the absence of IL-3 and 2000 cells per well for cells assayed in the presence of IL-3. 100 nL of compound was added to each well using a 100 nL Pin Head device, and the plates were incubated at 37°C for 48 h.

Cell survival was measured by adding 20 μl of Cell Titer-Glo Luminescent Cell Reagent

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Viability Reagent diluted 1:3 in PBS. The plates were sealed with Perkin Elmer Top-Seal, inverted several times to mix, and immediately centrifuged at 1000 rpm for 2 min. The plates were incubated under low light conditions for 8–10 min and luminescence was measured. The IC50 values for the examples are shown in Table. 6, 7, 8 and 9.

Description of cell data (PC9, EGFRexl9del cells).

PC9 cells were purchased from ATCC. 400 PC9 cells per well were seeded in growth medium (DMEM, 10% FCS) in a 384-well plate (CORNING #3571). The control plate for determining the zero time point was seeded on the same day. All plates were incubated overnight at 37°C. After 24 hours, a 7-step dilution of test compound was added using an HP Compound printer and incubated at 37°C for 72 hours. After 3 days, 30 μl/well of CTG solution (Promega Cell Titer Glo solution; cat. no.) was added to each well. G755B and G756B), the mixture was incubated for 30 minutes and the plate was read on a PheraStar instrument. Proliferation was calculated after subtracting luminescence values at time zero from day 4 values and comparing with untreated wells.

IC ₅₀ values were determined using a four-parameter fit. The IC ₅₀ values for the examples are shown in table. 9.

Description of cell data (HCC-827 cells, EGFRexl9del).

HCC-827 cells were purchased from ATCC. 400 HCC-829 cells per well were seeded in growth medium (RPMI1640, 10% FCS) in a 384-well plate (CORNING #3571). The control plate for determining the zero time point was seeded on the same day. All plates were incubated overnight at 37°C. After 24 hours, the test compound was added in a 7-step dilution using an HP Compound printer, and incubated at 37°C for 72 hours. After 3 days, 30 μl/well of CTG solution (Promega Cell Titer Glo solution; cat. No. G755B and G756B), the mixture was incubated for 30 minutes and the plate was read on a PheraStar instrument. Proliferation was calculated after subtracting luminescence values at time zero from day 4 values and comparing with untreated wells.

IC ₅₀ values were determined using a four-parameter fit. The IC ₅₀ values for the examples are shown in Table. 9.

Table 6 (insertion mutations in exon 20 of EGFR)

Example No. BA/F3 (insNPG) IC50 [mol/l] BA/F3 (ASV) 1С ₅₀ [mol/l] BA/F3 (EGFR N771_772 insH) IC50 [mol/l] BA/F3 (EGFR H773 774 insNPH) IC50 [mol/l] 2 4.44 E-9 4.66 E-9 7.48 E-9 2.82 E-8 5 2.63 E-8 2.87 E-8 1.15 E-8 7.93 E-8 8 1.16 E-8 9.62 E-9 4.91 E-9 2.31 E-8 14 1.25 E-8 1.64 E-8 7.60 E-9 6.58 E-8 20 1.47 E-8 1.17 E-8 6.59 E-9 5.67 E-8 21 5.65 E-9 7.78 E-9 4.22 E-9 2.76 E-8 32 9.38 E-9 1.32 E-8 1.10 E-8 4.73 E-8 42 1.20 E-8 1.41 E-8 6.01 E-9 4.85 E-8 46 1.43 E-8 1.17 E-8 5.77 E-9 3.89 E-8 48 4.24 E-8 4.18 E-8 1.76 E-8 1.42 E-7 50 1.13 E-8 1.04 E-8 7.42 E-9 4.03 E-8 56 6.96 E-9 1.41 E-8 7.36 E-9 4.89 E-8

Table 7 (classic activating and rare EGFR mutations)

Example No. BA/F3 (EGFR E746_A750del) IC50 [mol/l] BA/F3 (EGFR L858R) IC50 [mol/l] BA/F3 (EGFRL861Q) 1С ₅₀ [mol/l] 2 < 1.58 E-10 5.25 E-10 1.48 E-8 5 7.39 E-10 2.03 E-9 3.09 E-8 8 < 1.58 E-10 7.01 E-10 1.37 E-8 14 1.72 E-9 1.22 E-9 2.01 E-8 20 3.32 E-10 9.64 E-10 1.62 E-8 21 2.03 E-10 6.44 E-10 7.34 E-9 32 2.89 E-9 1.06 E-9 1.74 E-8 42 4.86 E-10 1.51 E-9 1.88 E-8 46 1.05 E-9 9.57 E-10 1.58 E-8 48 1.43 E-9 2.36 E-9 3.97 E-8 50 1.10 E-9 1.07 E-9 2.40 E-8 56 8.92 E-10 1.34 E-9 2.95 E-8

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Table 8 (limit of acquired resistance)

Example No. BA/F3 (EGFR 0770 N771 insSVD C797S) IC50 [mol/l] BA/F3 (EGFR E746 A750del C797S) IC50 [mol/l] BA/F3 (EGFR L858R C797S) IC50 [mol/l] 2 8.22 E-9 2.20 E-10 6.03 E-10 5 3.70 E-8 6.68 E-10 2.67 E-9 8 1.46 E-8 2.47 E-10 1.20 E-9 14 2.49 E-8 3.79 E-10 1.91 E-9 20 1.22 E-8 3.49 E-10 7.91 E-10 21 7.84 E-9 2.59 E-10 4.44 E-10 32 1.58 E-8 5.11 E-10 1.12 E-9 42 1.93 E-8 4.94 E-10 1.63 E-9 46 1.85 E-8 4.00 E-10 1.13 E-9 48 5.66 E-8 7.76 E-10 2.56 E-9 50 2.07 E-8 3.48 E-10 1.60 E-9 56 1.40 E-8 4.23 E-10 1.31 E-9

Table 9 (ERBB2, PC9, HCC-827 mutants)

Example No. BA/F3 (ERBB2 A775 G776 insYVMA) IC50 [mol/l] RS9 IC50 [mol/l] NSS-827 IC50 [mol/l] 2 8.31 E-9 6.73 E-10 < 3.00 E-9 5 3.18 E-8 1.94 E-9 < 3.00 E-9 8 1.31 E-8 7.38 E-10 < 3.00 E-9 14 1.36 E-8 2.12 E-9 < 3.00 E-9 20 2.35 E-8 2.68 E-9 < 3.00 E-9 21 1.34 E-8 1.16 E-9 < 3.00 E-9 32 1.67 E-8 1.70 E-9 < 3.00 E-9 42 1.32 E-8 4.03 E-9 < 3.00 E-9 46 1.10 E-8 2.89 E-9 < 3.00 E-9 48 3.98 E-8 3.40 E-9 < 3.00 E-9 50 1.03 E-8 6.82 E-9 < 3.00 E-9 56 1.35 E-8 1.74 E-9 < 3.00 E-9

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Claims (42)

1. Compound of formula (I) in which R ¹ represents methyl, ethyl, trifluoromethyl, 2,2-difluoroethyl, cyano, chlorine, bromine, methoxy or difluoromethoxy; R ² is hydrogen, methyl, ethyl, fluorine, chlorine or bromine; R ³ represents hydrogen or fluorine; R ⁴ represents hydrogen or methyl; R ⁵ is independently in each case hydrogen, trifluoromethyl or C ₁ -C ₃ -αalkyl, wherein R ⁵ is attached to any carbon atom of the ring; R ⁶ is independently in each case hydrogen, C1- _C3 alkyl or _C1 - _C3 haloalkyl; R ⁷ represents C _g C ₃ -alkyl or C ₂ -C ₃ -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 is 0 or 1; or an N-oxide, salt or tautomer of said compound, or a salt of said N-oxide or tautomer. 2. The compound of formula (I) according to claim 1, where R ¹ is methyl, ethyl, chlorine, methoxy or difluoromethoxy; R ² is methyl, ethyl, fluorine or chlorine; R ³ represents hydrogen or fluorine; R ⁴ represents hydrogen or methyl; R ⁵ represents hydrogen, methyl or trifluoromethyl, and R ⁵ is attached to any carbon atom of the ring; R ⁶ is 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 is 0 or 1; or an N-oxide, salt or tautomer of said compound, or a salt of said N-oxide or tautomer. 3. A compound of formula (I) according to claim 1 or 2, where R ¹ is methyl, ethyl, chlorine or methoxy; R ² represents fluorine or chlorine; R ³ represents hydrogen or fluorine; R ⁴ represents hydrogen; R ⁵ represents hydrogen or methyl, and R ⁵ is attached to any carbon atom of the ring; R ⁶ represents hydrogen; R ⁷ represents methyl; R ⁸ is 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 is 0 or 1; or an N-oxide, salt or tautomer of said compound, or a salt of said N-oxide or tautomer. - 136 046642 4. A compound of formula (I) according to any one of claims 1 to 3, which is selected from the group consisting of: 3 -(3-chloro-2-methoxyanilino)-2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro4H-pyPPROlo [ 3,2<]pyridin-4-one; 3-(3-chloro-2-methoxyanilino)-2-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7tetrahydro- 4H-pyrrolo ^^-^pyridinT-one; 3-(3-chloro-2-methoxyanilino)-2-(3-{[(2R)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7tetrahydro- 4H-pyrrolo ^^-^pyridinT-one; 2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro4H-pyrrolo [ 3,2<]pyridin-4-one; 2-(3-{[(28)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyanilino)-1,5,6,7tetrahydro- 4H-pyrrolo[3,2-c]pyridin-4-one; 2-(3-{[(2K)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyanilino)-1,5,6,7- tetrahydro-4H-pyrrolo ^^-^pyridinT-one; 3-(2,3-dichloroanilino)-2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4Hpyrrolo [3 D -DpyridinCh-she; 3-(2,3-dichloroanilino)-2-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro- 4Hpyrrolo [3 D-DpyridinH-one; 3-(2,3-dichloroanilino)-2-(3-{[(2R)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro- 4Hpyrrolo [3 D-DpyridinH-one; 3-(3-chloro-2-methylanilino)-2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4Hpyrrolo [ 3 D-DpyridinCh-ona; 3-(3-chloro-2-methoxyanilino)-2-(3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)-1,5,6,7tetrahydro-4H- pyrrolo ^^-^pyridinT-one; 3-(3-fluoro-2-methoxyanilino)-2-{3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}-1,5,6,7tetrahydro-4H-pyrrolo ^^- ^pyridinT-one; 3-(3-fluoro-2-methoxyanilino)-2-(3-{[(2R)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7tetrahydro-4H- pyrrolo ^^-^pyridinT-one; 3-(3-fluoro-2-methoxyanilino)-2-(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7tetrahydro-4H- pyrrolo ^^-^pyridinT-one; 3-(3-chloro-2-methoxyanilino)-2-{3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}-1,5,6,7tetrahydro-4H-pyrrolo[3, 2-c]pyridin-4-one; 3-(3-chloro-2-methoxyanilino)-2-(3-{[(2R)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7tetrahydro-4H- pyrrolo ^^-^pyridinT-one; 3-(3-chloro-2-methoxyanilino)-2-(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7tetrahydro-4H- pyrrolo ^^-^pyridinT-one; 3-(3-chloro-5-fluoro-2-methoxyanilino)-2-(3-{[4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7tetrahydro-4H- pyrrolo ^^-^pyridinT-one; 3-(3-chloro-5-fluoro-2-methoxyanilino)-2-(3-{[1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7tetrahydro- 4H-pyrrolo ^^-^pyridinT-one; 3-(3-fluoro-2-methoxyanilino)-2-(3-{[(3S)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)-1,5,6,7tetrahydro-4H- pyrrolo[3,2-c]pyridin-4-one; 3-(3-chloro-2-methoxyanilino)-2-(3-{[(3S)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)-1,5,6,7tetrahydro-4H- pyrrolo ^^-^pyridinT-one; 2-(3-{[(2S)-4-(2,2-difluoroethyl)morpholin-2-yl]methoxy}pyridin-4-yl)-3 -(3-fluoro-2methoxyanilino)-1,5,6 ,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 3-(3-fluoro-2-methoxyanilino)-2-(3-{ [(2S)-4-(2,2,2-trifluoroethyl)morpholin-2-yl]methoxy}pyridin-4yl)-1,5 ,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 3-(3-chloro-2-methoxyanilino)-2-{3-[2-(4-dioxan-2-yl)ethoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4Hpyrrolo [ 3 D-DpyridinCh-ona; 3-(3-chloro-2-methoxyanilino)-2-(3-{2-[(2R)-1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)-1,5,6, 7tetrahydro-4H-pyrrolo ^^-^pyridinT-one; 3-(3-chloro-2-methoxyanilino)-2-(3-{2-[^)-1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)-1,5,6,7tetrahydro -4H-pyrrolo ^^-^pyridinT-one; 3-(3-chloro-5-fluoro-2-methoxyanilino)-2-(3-{ [(2S)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)1,5,6,7 -tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 3-(3-chloro-5-fluoro-2-methoxyanilino)-2-(3-{[^)-4-(2,2,2-trifluoroethyl)morpholin-2yl]methoxy}pyridin-4-yl)- 1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 3 -(3-chloro-2-ethylanilino)-2-{3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro4H-pyrrolo [3, 2<]pyridin-4-one; 3-(3-chloro-2-methoxyanilino)-2-{3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6, 7tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 3-(3-chloro-2-methoxyanilino)-2-(3-{[(2R)-5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)- 137 046642 1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 3-(3-chloro-2-methoxyanilino)-2-(3-{[(2S)-5,5-dimethyl-1,4-dioxan-2-yl]memoxy}niridin-4-yl)1.5 ,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 2-(3-{[(2K)-5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3 -(3-fluoro-2-methoxyanilino)1.5 ,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 2-(3-{[(28)-5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyanilino)1.5 ,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 2-(3-{2-[(2R)-1,4-dioxan-2-yl]ethoxy}niridin-4-yl)-3-(3-fluoro-2-methoxyanilino)-1,5,6, 7tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 2-(3-{2-[(2S)-1,4-dioxan-2-yl]ethoxy}niridin-4-yl)-3-(3-fluoro-2-methoxyanilino)-1,5,6, 7tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 3-(3-fluoro-2-methoxyanilino)-2-(3-{[(3R)-4-methylmorpholin-3-yl]methoxy}niridin-4-yl)-1,5,6,7tetrahydro-4H- pyrrolo[3,2-c]pyridin-4-one; 2-{3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-3-(3-fluoro-2-methylanilino)-1,5,6, 7tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 2-(3-{[(28)-5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methylanilino)1.5 ,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 3-[2-(2,2-difluoroethyl)-3-fluoroanilino]-2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6, 7tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 3-[2-(2,2-difluoroethyl)-3-fluoroanilino]-2-(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}niridin-4-yl)1,5,6 ,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 3-(3-chloro-2-methylanilino)-2-(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}niridin-4-yl)-1,5,6,7tetrahydro-4H- pyrrolo[3,2-c]pyridin-4-one; 3-(3-chloro-2-methylanilino)-2-(3-{[(3R)-4-methylmorpholin-3-yl]methoxy}niridin-4-yl)-1,5,6,7tetrahydro-4H- pyrrolo[3,2-c]pyridin-4-one; 3-(3-chloro-2-methylanilino)-2-{3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6, 7tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 3-(3-chloro-2-methylanilino)-2-(3-{[(2S)-5,5-dimethyl-1,4-dioxan-2-yl]methoxy}niridin-4-yl)1.5 ,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 3-(3-chloro-2-methylanilino)-2-(3-{[(2R)-5,5-dimethyl-1,4-dioxan-2-yl]methoxy}niridin-4-yl)1.5 ,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-3-(3-fluoro-2-methylanilino)-1,5,6,7-tetrahydro-4Hpyrrolo [ 3,2-c]pyridin-4-one; 2-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}niridin-4-yl)-3-(3-fluoro-2-methylanilino)-1,5,6,7tetrahydro- 4H-pyrrolo[3,2-c]pyridin-4-one; 2-(3-{[(2K)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methylanilino)-1,5,6,7tetrahydro- 4H-pyrrolo[3,2-c]pyridin-4-one; 3-(3-chloro-2-methylanilino)-2-(3-{[^)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro4H -pyrrolo[3,2-c]pyridin-4-one; 3-(3-chloro-2-methylanilino)-2-(3-{[(2R)-1,4-dioxan-2-yl]methoxy}niridin-4-yl)-1,5,6,7tetrahydro- 4H-pyrrolo[3,2-c]pyridin-4-one; 3-(3-chloro-2-ethylanilino)-2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4Hpyrrolo [ 3,2-c]pyridin-4-one; 3-(3-chloro-2-ethylanilino)-2-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}niridin-4-yl)-1,5,6,7- tetrahydro4H-pyrrolo[3,2-c]pyridin-4-one; 3-(3-chloro-2-ethylanilino)-2-(3-{[(2R)-1,4-dioxan-2-yl]methoxy}niridin-4-yl)-1,5,6,7- tetrahydro4H-pyrrolo[3,2-c]pyridin-4-one; 3-(3-chloro-2-ethylanilino)-2-(3-{[(2R)-4-methylmorpholin-2-yl]methoxy}niridin-4-yl)-1,5,6,7tetrahydro-4H- pyrrolo[3,2-c]pyridin-4-one; 3-(3-chloro-2-ethylanilino)-2-(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}niridin-4-yl)-1,5,6,7tetrahydro-4H- pyrrolo[3,2-c]pyridin-4-one; 3-(3-chloro-2-methoxyanilino)-2-(3-{1-[1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)-1,5,6,7-tetrahydro4H- pyrrolo[3,2-c]pyridin-4-one; 3-(3-chloro-2-methoxyanilino)-2-(3-{(^)-1-|(2,5')-1,4-dioxan-2-yl|ethoxy;pyridin-4-yl) -1,5,6,7tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 3-(3-chloro-2-methoxyanilino)-2-(3-{(1S)-1-[(2R)-1,4-dioxan-2-yl]ethoxy}niridin-4-yl)-1, 5,6,7tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 3-(3-chloro-2-methoxyanilino)-2-(3-{(1R)-1-[(2S)-1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)-1, 5,6,7tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 3-(3-chloro-2-methoxyanilino)-2-(3-{(1R)-1-[(2R)-1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)-1, 5,6,7tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 3-(3-fluoro-2-methylanilino)-2-{3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}-1,5,6,7 - 138 046642 tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 3-(3-fluoro-2-methylanilino)-2-(3-{[(2R)-4-methylmorpholin-2-yl]methoxy}niridin-4-yl)-1,5,6,7tetrahydro-4H- pyrrolo[3,2-c]pyridin-4-one; 3-(3-fluoro-2-methylanilino)-2-(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}niridin-4-yl)-1,5,6,7tetrahydro-4H- pyrrolo[3,2-c]pyridin-4-one; 2-(3-{[1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3-fluoroanilino)-1,5,6,7-tetrahydro-4Hpyrrolo [ 3,2-c]pyridin-4-one; 2-(3-{[(2R)-1,4-dioxan-2-yl]methoxy}niridin-4-yl)-3-(2-ethyl-3-fluoroanilino)-1,5,6,7- tetrahydro4H-pyrrolo[3,2-c]pyridin-4-one; 2-(3-{[(28)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3-fluoroanilino)-1,5,6,7- ^those trahydro4H-pyrrolo[3,2-c]pyridin-4-one; 2-(3-{[5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3-fluoroanilino)-1,5,6, 7tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 2-(3-{[(2R)-5,5-dimethyl-1,4-dioxan-2-yl]methoxy}niridin-4-yl)-3 -(2-ethyl-3-fluoroanilino)-1, 5,6,7tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 2-(3-{[(25}-5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3 -(2-ethyl-3-fluoroanilino)-1, 5,6,7tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 3-(3-chloro-2-methoxyanilino)-2-[3-({1-[4-methylmorpholin-2-yl]ethyl}oxy)pyridin-4-yl]-1,5,6,7tetrahydro-4H -pyrrolo[3,2-c]pyridin-4-one; 3-(3-chloro-2-methoxyanilino)-2-[3-({(1R)-1-[(2R)-4-methylmorpholin-2-yl]ethyl}oxy)niridin-4-yl]1, 5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 3-(3-chloro-2-methoxyanilino)-2-|3-({(^)-1-|(2,5')-4-methylmorpholin-2-yl|ethyl}oxy)pyridin-4-yl |1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 3-(3-chloro-2-methoxyanilino)-2-[3-({(1R)-1-[(2S)-4-methylmorpholin-2-yl]ethyl}oxy)niridin-4-yl]1, 5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 3 -(3-chloro-2-methoxyanilino)-2-[3 -({(1 S)-1-[(2R)-4-methylmorpholin-2-yl]ethyl}oxy)pyridin-4-yl] 1 ,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one. 5. Use of a compound of general formula (I) according to any one of claims 1 to 4 for the treatment or prevention of hyperproliferative diseases and/or disorders that respond to the induction of cell death. 6. Use according to claim 5, wherein the hyperproliferative diseases and/or disorders that respond to the induction of cell death are hematological tumors, solid tumors and/or metastases thereof. 7. Use according to claim 6, wherein the tumor is an EGFR-anchoring mutant tumor. 8. The use of claim 7, wherein the EGFR anchoring mutant tumor is a lung cancer, an EGFR anchoring mutant with an insertion mutation in exon 20, with in-frame deletions in exon 19, or with point mutations in exon 21. 9. The use of claim 8, wherein the EGFR mutant with an insertion mutation in exon 20 is ERBB2 A775_G776insYVMA, the EGFR mutant with in-frame deletions in exon 19 is EGFR E746_A750del, and the EGFR mutant with point mutations in exon 21 is L858R. 10. Use according to claim 7, wherein the EGFR anchoring mutant tumor is an EGFR anchoring mutant lung cancer with an acquired resistance mutation D770_N771insSVD C797S, E746_A750del C797S or L858RC797S. 11. A pharmaceutical composition containing at least one compound of general formula (I) according to any one of claims 1 to 4, together with at least one pharmaceutically acceptable auxiliary agent. 12. Composition according to claim 11 for the treatment of hematological tumors, solid tumors and/or their metastases. 13. A combination for the treatment or prevention of hyperproliferative diseases and/or disorders that respond to the induction of cell death, containing one or more first active components selected from the compounds of general formula (I) according to any one of claims 1 to 4, and one or more second active components selected from chemotherapeutic anticancer agents and target-specific anticancer agents. 14. A method of inhibiting EGF receptor kinase activity in a tumor cell, which includes bringing the tumor cell into contact with a compound of general formula (I) according to any one of claims 1-4. 15. The method according to claim 14, where the tumor cell is an in vitro or in vivo cell. 16. A method for reducing the survival of a tumor cell or inducing the death of a tumor cell, which includes contacting a tumor cell containing a mutation in the EGF receptor with a compound of general formula (I) according to any one of claims 1 to 4. 17. The method according to any one of claims 14-16, where the EGF receptor contains a mutation in exon 20. 18. The method according to any one of claims 14-17, where the tumor cell comes from a malignant neoplasm selected from the group consisting of leukemia, myelodysplastic syndrome, malignancy - 139 046642 lymphoma, head and neck tumors, gastrointestinal tumors, endocrine tumors, breast tumors and other gynecological tumors, urological tumors, skin tumors and sarcoma. 19. The method of claim 18, wherein the tumor cell is derived from a malignancy selected from the group consisting of a sinonasal inverted papilloma or a sinonasal squamous cell carcinoma associated with a sinonasal inverted papilloma. 20. A method of treating cancer in a subject, which comprises administering to the subject an effective amount of a compound of general formula (I) according to any one of claims 1 to 4. 21. A method of treating a cancer in a subject where the cancer is resistant or has become resistant to anti-EGF receptor antibody therapy, which comprises administering to the subject an effective amount of a compound of general formula (I) according to any one of claims 1 to 4. 22. A method for increasing the effectiveness of antibody therapy against EGF receptors of a malignant neoplasm, which includes administering to a subject therapy with antibodies against EGF receptors in combination with a compound of general formula (I) according to any one of claims 1-4. 23. The method according to any one of claims 20-22, where the malignancy is selected from the group consisting of leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumors, chest tumors, gastrointestinal tumors, endocrine tumors, breast tumors and other gynecological tumors, urological tumors, skin tumors and sarcomas. 24. The method of claim 23, wherein the malignancy is selected from the group consisting of sinonasal inverted papilloma or sinonasal squamous cell carcinoma associated with sinonasal inverted papilloma. 25. The method of claim 23, wherein the chest tumor is non-small cell lung cancer. 26. The method according to any one of claims 14-25, wherein the EGF receptor contains a mutation. 27. The method according to claim 26, where the EGF receptor contains a mutation in exon 20. 28. The method according to claim 27, where the EGF receptor contains an insertion in exon 20. 29. The method according to claim 28, where the EGF receptor contains an insertion between amino acids V769-D770 and/or between D770-N771. 30. The method according to claim 29, where the insertion is an ASV and/or SVD insertion. 31. The method according to claim 28, where the EGF receptor contains an ASV insertion between amino acids V769-D770 and/or an SVD insertion between amino acids D770-N771. 32. A method of selecting a patient for treatment of a malignancy with a compound of general formula (I) according to any one of claims 1 to 4, which includes detecting a mutation in exon 20 of the EGF receptor in a biological sample of the subject, thereby determining that the patient should be treated with said compound. 33. A method of treating a patient with a malignant tumor, which includes subjecting the subject to therapy with antibodies against EGF receptors in combination with a compound of general formula (I) according to any one of claims 1 to 4, where the subject for therapy is selected by detecting a mutation in exon 20 of the EGF receptor in a biological sample subject. 34. The method according to claim 32 or 33, where the EGF receptor contains an insertion in exon 20. 35. The method according to claim 34, where the EGF receptor contains an insertion between amino acids V769-D770 and/or between amino acids D770-N771. 36. The method according to claim 35, where the insertion is an ASV and/or SVD insertion. 37. The method according to claim 34, where the EGF receptor contains an ASV insertion between amino acids V769-D770 and/or an SVD insertion between amino acids D770-N771. 38. The method according to any one of claims 14, 16, 22, 32 and 33, wherein the malignancy is lung cancer, in particular lung cancer, an EGFR anchoring mutant with in-frame deletions in exon 19 or point mutations in exon 21, and /or its metastases. 39. The method of claim 38, wherein the lung cancer EGFR anchoring mutant with in-frame deletions in exon 19 is EGFR E746_A750del or the point mutations in exon 21 is L858R. 40. The method according to any one of claims 14, 16, 22, 32 and 33, where the malignancy is lung cancer, in particular lung cancer, an EGFR anchoring mutant with an acquired resistance mutation D770_N771insSVD C797S, E746_A750del C797S or L858R C797S, and/or its metastases. 41. The method according to any one of claims 14, 16, 22, 32 and 33, wherein the malignancy is lung cancer, in particular lung cancer, ERBB2 anchoring mutant with insertion mutations in exon 20, and/or metastases thereof. 42. The method of claim 41, wherein the lung cancer anchoring mutant of ERBB2 with insertion mutations in exon 20 is ERBB2 A775_G776insYVMA.