Pyrazolopiperazine compounds

Abstract

The present invention relates to 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine compounds of formula (I) to methods of preparing said compounds, intermediate compounds useful for preparing said compounds, to pharmaceutical compositions, to combinations comprising said compounds, and to the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular cancer, as a sole agent or in combination with other active ingredients.

Description

[0001] PYRAZOLOPIPERAZINE COMPOUNDS STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH This invention was made with government support under Grant Nos. R01CA116020 and 5P01CA154303 awarded by the National Institutes of Health. The government has certain rights in the invention. Field of application of the invention The present invention relates to 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine compounds of formula (I) as described and defined herein, to methods of preparing said compounds, intermediate compounds useful for preparing said compounds, to pharmaceutical compositions, to combinations comprising said compounds, and to the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular cancer, as a sole agent or in combination with other active ingredients. BACKGROUND OF THE INVENTION The present invention covers 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine compounds of formula (I) which inhibit EGFR. The Epidermal Growth Factor Receptor (EGFR or EGF- receptor) receptor tyrosine kinase family consists of 4 members: EGFR (Erbb1, Her1), ERBB2 (Her2), ERBB3 (Her3), and ERBB4 (Her4). EGFR mediates 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 cancer indications and are associated with a poor prognosis (Gridelli et al., 2015). In lung adenocarcinoma, mutations of EGFR are prevalent in approximately 15% of Western patients and up to 50% of East Asian patients (Paez et al., 2004). These mutations typically occur in one of four exons, exons 18-21, in the kinase domain of EGFR (Paez et al., 2004). The most common activating mutations in EGFR are a point mutation in exon 21, substituting an arginine for a leucine (L858R), and a small in-frame deletion in exon 19 that removes four amino acids (del 19 / del746-750) (Pao et al., 2010). The FDA-approved inhibitors gefitinib, erlotinib, and afatinib, targeting mutations in exons 18, 19, and 21 of EGFR, are effective in patients, but the response is often not durable (Mok et al., 2009; Sequist et al., 2013). Resistance frequently occurs in these patients in response to acquisition of a second mutation, T790M (Pao et al., 2005). Second generation inhibitors, e.g. afatinib, irreversibly target this mutation, but are still potent inhibitors of wild-type EGFR, leading to dose-limiting toxicity and lack of efficacy in patients. Several irreversible EGFR inhibitors are published in CN 110857292, IN 201821027709, CN 110698461, WO 2020001351, WO 2020001350, WO 2019233459, CN 110407852, CN 110357863, WO 2019070167, WO20061470. WO2019 / 081486 describes 4H-Pyrrolo[3,2- c]pyridine-4-one derivatives. A third-generation irreversible inhibitor, osimertinib, that maximizes activity towards T790M while minimizing activity towards 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 a front-line therapy for patients with mutations of EGFR exons 19 or 21 (Soria et al., 2018). By contrast, and with the exception of A763_Y764insFQEA, small in-frame insertions of EGFR exon20 are resistant to the classical EGFR inhibitors at doses achievable in lung cancer patients and comprise an unmet medical need (Yasuda et. al., 2013). Patients with EGFR exon20 insertions, such as V769_D770insASV, D770_N771insSVD, D770_N771insNPG, N771_P772insH, H773_V774insH, H773_V774insNPH, V774_C775insHV show particular low response rates to EGFR-targeted therapies, resulting in 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 for the second-generation inhibitor afatinib (Chen et al., 2016; Yang et al., 2015). The same resistance profile has been observed for exon20 insertion mutations in ERBB2 (e.g. ERBB2 A775_G776insYVMA with the highest prevalence), another member of the EGF-receptor family (Arcila et al., 2012) and some of the uncommon EGFR mutations like L681Q (Chiu et al., 2015). The standard of care for EGFR exon20 insertion patients is currently chemotherapy. However, amivantamab and mobocertinib received accelerated approval for 2ndline treatment post chemotherapy recently, and several other inhibitors are currently in clinical trials for the treatment of EGFR exon20 insertion mutation positive lung cancer patients (Friedlaender et al., 2022). About 40% of patients with advanced EGFR mutant NSCLC develop brain metastases over the course of their disease (Rangachari et al., 2015). The 1stand 2ndgeneration EGFR inhibitors show only limited brain permeability. The 3rdgeneration EGFR inhibitor Osimertinib shows clearly improved CNS activity and is currently the preferred treatment option for patients with classical activating EGFR mutations and brain metastasis (Reungwetwattana et al., 2018). However, Osimertinib has only limited activity on EGFR exon20 insertion mutations. Furthermore, the recently approved bispecific antibody amivantamab and also mobocertinib show only limited blood-brain-barrier permeability. So there still remains a high unmet medical need especially for lung cancer patients carrying EGFR exon20 insertion mutations and brain metastasis. In summary, mutant EGFR is a promising drug target for cancer therapy. In particular, patients with primary resistance to approved anti-EGFR therapies, due to EGFR exon20 insertions and with brain metastases, have only few treatment options to date and there is a great need for novel alternative and / or improved therapeutics to provide these patients with an efficacious, well-tolerable therapy. Therefore, potent inhibitors of mutant EGFR, particularly of mutant EGFR with exon20 insertion mutations that show improved permeability of the blood-brain-barrier and CNS activity, represent valuable compounds that should complement therapeutic options either as single agents or in combination with other drugs. SUMMARY OF THE INVENTION The invention provides compounds that inhibit a mutant EGFR; specifically, an EGFR comprising one or more exon 20 insertion mutations, an L858R mutation, or a small in- frame deletion of exon 19, in the presence or absence of a T790M mutation and show brain permeability. It has now been found that the compounds of the present invention have surprising and advantageous properties. In particular, said compounds of the present invention have surprisingly been found to effectively inhibit mutant ERBB2 and or mutant EGFR with exon 20 insertion mutations. In addition, said compounds are active in certain point mutations of EGFR and ERBB2. In particular, said compounds of the present invention have surprisingly been found to effectively inhibit mutant EGFR with exon 20 insertion mutations, particularly those harboring a D770_N771ins SVD exon 20 insertion. Furthermore it has been found that these compounds additionally show high cellular potency in EGFR V769_D770insASV, D770_N771insSVD, D770_N771insNPG, N771_P772insH, or H773_V774insNPH exon 20 insertion harboring BA / F3 cell lines. Surprisingly, the here described compounds retain high cellular activity in BA / F3 cell lines harboring D770_N771insSVD and the T790M mutation. In addition, the here described compounds potently inhibit proliferation of BA / F3 cell lines carrying EGFR activating mutations with or without T790M acquired resistance mutations (EGFR E746_A750del, L858R, E746_A750del T790M, L858R T790M). Furthermore, the here described compounds show strong potency in BA / F3 cell lines harboring ERBB2 exon 20 insertion mutations (e.g. ERBB2 A775_G776insYVMA and ERBB2 G776delinsVC) and ERBB2 point mutations (e.g. ERBB2 S310F, ERBB2 L755S, ERBB2 V777L), Based on the described properties the here described compounds can therefore be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses or diseases which are accompanied with uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses mediated by mutant EGFR with exon 20 insertion mutations, a L858R mutation, or a small in-frame deletion of exon 19 (e.g. EGFR E746_A750del) in the presence or absence of a T790M mutation and / or reduce (or block) proliferation in cells harboring EGFR with exon 20 insertion mutations, a L858R mutation, or a small in-frame deletion of exon 19 (e.g. EGFR E746_A750del) in the presence or absence of a T790M mutation, for example, haematological tumours, solid tumours, and / or metastases thereof, e.g. leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non- small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and / or metastases thereof. Description of the invention In accordance with a first aspect, the invention relates to compounds of formula (I), in which: in which: R1represents a group selected from the group: , R2represents a group selected from the group: R3represents –(CO)-R11, −(CO)-C≡C-R12, –(CO)-O-C1-C4-alkyl, −(SO2)-CH=CH2, -CH2-CN, or oxirane-2-carbonyl; R4arepresents a hydrogen atom, fluoro, methyl, or R4g; R4brepresents a hydrogen atom, fluoro, or methyl; R4crepresents a hydrogen atom, fluoro, methyl, or R4g; R4drepresents a hydrogen atom, fluoro, or methyl; R4erepresents a hydrogen atom, fluoro, methyl, phenyl, , or ; R4frepresents a hydrogen atom, fluoro, or methyl; R4grepresents C2-C4-alkyl, C1-C3-haloalkyl, C1-C3-hydroxyalkyl, C3-C6-cycloalkyl, benzyl, or ; on the conditions that : x when R4arepresents a hydrogen atom, and R4brepresents a hydrogen atom, fluoro or methyl, then R4cis R4gand R4drepresents a hydrogen atom, fluoro, or methyl, and x when R4crepresents a hydrogen atom, and R4drepresents a hydrogen atom, fluoro or methyl, then R4ais R4gand R4brepresents a hydrogen atom, fluoro, or methyl; R5arepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkyl-S(=O)-, C1-C3-alkyl-S(=O)2-, C1-C3- alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1-C3-alkyl, amino-C1-C3-alkyl, C1-C3- alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1-C3-alkyl, hydroxy, cyano, fluoro, chloro, or bromo; R5brepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C3- C6-cycloalkyl, C1-C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1-C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3- alkyl)2amino-C1-C3-alkyl, –(CO)-NR19R20, hydroxy, cyano, fluoro, chloro, bromo, or ; R5crepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, trifluoromethylsulfanyl, cyano, fluoro, chloro, or bromo; R5drepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo; R5erepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo; R6arepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo; R6brepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, or cyano; R6crepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo; R6drepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, or cyano; R7arepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, or cyano; R7brepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo; R7crepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, or cyano; R7drepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, or cyano; R8arepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo; R8brepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo; R8crepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo; R8drepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo; R8erepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo; R9arepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, C3-C6-cycloalkyl, cyano, fluoro, chloro, or bromo; R9brepresents a hydrogen atom, amino, C1-C3-alkylamino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1-C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1-C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3- alkyl)2amino-C1-C3-alkyl, or cyano; R9crepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, C1-C3-alkyl-amino, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1- C3-alkyl)2amino-C1-C3-alkyl, cyano, anilino, phenylamino substituted with a hydrogen atom or methoxy, pyridin-2-ylamino substituted with R13, or C3-C6- cycloalkylformamido; R9drepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo; R10arepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo; R10brepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, or cyano; R10crepresents a hydrogen atom or methyl; R10drepresents a hydrogen atom, fluoro, or methyl; R11represents C1-C3-alkyl, −CH2-C≡CH, −C(R14)-R15, -CH2−C(R14)-R15, or a group selected from the group: ; R12represents a hydrogen atom, methyl, -CH2-NR19R20, , or ; 13 R represents a hydrogen atom, C1-C3-alkoxy-C1-C3-alkoxy, or ; R14represents =CHR16; R15represents a hydrogen atom, C1-C3-alkyl, fluoro, cyano, dimethylamino-methyl, or morpholino-methyl; R16represents a hydrogen atom, chloro, C1-C4-alkyl, C1-C3-haloalkyl, C1-C3-alkoxy, C1- C3-hydroxyalkyl, C1-C3-alkoxy-C1-C3-alkyl, trifluoromethylsulfanyl, –CH2-NR19R20, – (CO)-NR19R20, -CH2-NR17a-CHR17bR17c, or a group selected from the group: R17arepresents a hydrogen atom, methyl, or ethyl; R17brepresents a hydrogen atom, methyl, or methoxymethyl; R17crepresents a hydrogen atom or methyl; R18represents a hydrogen atom or methyl; R19represents a hydrogen atom, methyl, or ethyl; R20represents a hydrogen atom, C1-C4-alkyl, phenyl, C1-C3-haloalkyl, or tert- butoxycarbonyl; or R19and R20, together with the N-atom to which they are attached, form a group; R21represents a hydrogen atom or methyl; R22represents a hydrogen atom or fluoro; R23represents a hydrogen atom or fluoro; R24represents a hydrogen atom or fluoro; R25represents a hydrogen atom, fluoro, or chloro; R26represents a hydrogen atom or fluoro; R27arepresents a hydrogen atom or fluoro; R27brepresents a hydrogen atom or fluoro; R28arepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, hydroxy, cyano, fluoro, chloro, or bromo; R28brepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, –(CO)-NR19R20, cyano, fluoro, chloro, or bromo; R28crepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, trifluoromethylsulfanyl, cyano, fluoro, chloro, or bromo; R28drepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo; R28erepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo; R29represents a hydrogen atom or -COOH; R30arepresents a hydrogen atom or fluoro; R30brepresents a hydrogen atom or fluoro; R31represents a hydrogen atom or methoxy; R32represents a hydrogen atom or methoxy; R33arepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo; R33brepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo; R33crepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo; R33drepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo; R33erepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo; wherein * indicates the point of attachment of said group with the rest of the molecule; or an N-oxide, a salt, a tautomer, a rotamer, or a stereoisomer of said compound, or a salt of said N-oxide, tautomer, rotamer, or stereoisomer. In a second aspect, the invention relates to compounds of formula (I) as described supra, wherein: R1represents a group selected from the group: R2represents a group selected from the group: R3represents –(CO)-R11; R4arepresents a hydrogen atom or R4g; R4brepresents a hydrogen atom; R4crepresents a hydrogen atom or R4g; R4drepresents a hydrogen atom; R4erepresents a hydrogen atom, phenyl, , or ; R4frepresents a hydrogen atom; R4grepresents C2-C4-alkyl, C1-C3-haloalkyl, C1-C3-hydroxyalkyl, C3-C6-cycloalkyl, benzyl, or ; wherein one of R4aor R4crepresents R4g; R5arepresents C1-C3-alkyl, C1-C3-alkyl-S(=O)-, C1-C3-alkyl-S(=O)2-, cyano, or fluoro; R5brepresents C1-C3-alkyl, C2-C3-alkinyl, C3-C6-cycloalkyl, C1-C3-haloalkyl, C1-C3- hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1-C3-alkyl, hydroxy, cyano, fluoro, or chloro; R5crepresents C1-C3-alkyl, C1-C3-alkoxy, cyano, fluoro, or chloro; R5drepresents cyano; R5erepresents a hydrogen atom; R9arepresents a hydrogen atom; R9brepresents a hydrogen atom or C1-C3-alkylamino; R9crepresents a hydrogen atom; R9drepresents a hydrogen atom; R10arepresents a hydrogen atom; R10brepresents a hydrogen atom; R10crepresents a hydrogen atom; R10drepresents a hydrogen atom; R11represents −C(R14)-R15; R14represents =CHR16; R15represents a hydrogen atom; R16represents a hydrogen atom or –CH2-NR19R20; R19represents methyl or ethyl; R20represents C1-C4-alkyl, phenyl, C1-C3-haloalkyl; or R19and R20, together with the N-atom to which they are attached, form a group; R21represents a hydrogen atom; R22represents a hydrogen atom; R23represents a hydrogen atom; R33arepresents a hydrogen atom or chloro; R33brepresents a hydrogen atom; R33crepresents a hydrogen atom or chloro; R33drepresents a hydrogen atom; R33erepresents a hydrogen atom; wherein * indicates the point of attachment of said group with the rest of the molecule; or an N-oxide, a salt, a tautomer, a rotamer, or a stereoisomer of said compound, or a salt of said N-oxide, tautomer, rotamer, or stereoisomer. In a third aspect, the invention relates to compounds of formula (I) as described supra, wherein: R1represents a group selected from the group: R2represents a group selected from the group: 4-pyridyl R3represents –(CO)-R11; R4arepresents a hydrogen atom or R4g; R4brepresents a hydrogen atom; R4crepresents a hydrogen atom or R4g; R4drepresents a hydrogen atom; R4erepresents a hydrogen atom, phenyl, ; R4frepresents a hydrogen atom; R4grepresents ethyl, 2-propyl, 2-methylpropyl, tert-butyl, trifluoromethyl, 1,1,1- trifluoroethyl, 1,1,1-trifluoropropyl-, 2-hydroxy-2-methylethyl-, cyclopropyl, cyclobutyl, 2-oxetanyl, benzyl, or wherein one of R4aor R4crepresents R4g; R5arepresents methyl, C1-C3-alkyl-S(=O)-, C1-C3-alkyl-S(=O)2-, cyano, or fluoro; R5brepresents methyl, ethyl, 2-propyl, ethynyl, cyclopropyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl-, hydroxymethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methoxymethyl-, hydroxy, cyano, fluoro, or chloro; R5crepresents methyl, methoxy, cyano, fluoro, or chloro; R5drepresents cyano; R5erepresents a hydrogen atom; R10arepresents a hydrogen atom; R10brepresents a hydrogen atom; R10crepresents a hydrogen atom; R10drepresents a hydrogen atom; R11represents −C(R14)-R15; R14represents =CHR16; R15represents a hydrogen atom; R16represents a hydrogen atom or –CH2-NR19R20; R19represents methyl or ethyl; R20represents methyl, tert-butyl, phenyl, 1,1,1-trifluoropropyl-; or R19and R20, together with the N-atom to which they are attached, form a group; R21represents a hydrogen atom; R22represents a hydrogen atom; R23represents a hydrogen atom; R33arepresents a hydrogen atom or chloro; R33brepresents a hydrogen atom; R33crepresents a hydrogen atom or chloro; R33drepresents a hydrogen atom; R33erepresents a hydrogen atom; wherein * indicates the point of attachment of said group with the rest of the molecule; or an N-oxide, a salt, a tautomer, a rotamer, or a stereoisomer of said compound, or a salt of said N-oxide, tautomer, rotamer, or stereoisomer. In an embodiment, the invention relates to compounds of formula (I) as described supra, wherein: R1represents a group selected from the group: R5arepresents methyl, C1-C3-alkyl-S(=O)-, C1-C3-alkyl-S(=O)2-, cyano, or fluoro; R5brepresents methyl, ethyl, 2-propyl, ethynyl, cyclopropyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl-, hydroxymethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methoxymethyl-, hydroxy, cyano, fluoro, or chloro; R5crepresents methyl, methoxy, cyano, fluoro, or chloro; R5drepresents cyano; R5erepresents a hydrogen atom; R21represents a hydrogen atom; R22represents a hydrogen atom; and R23represents a hydrogen atom; wherein * indicates the point of attachment of said group with the rest of the molecule; or an N-oxide, a salt, a tautomer, a rotamer, or a stereoisomer of said compound, or a salt of said N-oxide, tautomer, rotamer, or stereoisomer. In an embodiment, the invention relates to compounds of formula (I) as described supra, wherein: R2represents a group selected from the group: 4-pyridyl R10arepresents a hydrogen atom; R10brepresents a hydrogen atom; R10crepresents a hydrogen atom; and R10drepresents a hydrogen atom; wherein * indicates the point of attachment of said group with the rest of the molecule; or an N-oxide, a salt, a tautomer, a rotamer, or a stereoisomer of said compound, or a salt of said N-oxide, tautomer, rotamer, or stereoisomer. In an embodiment, the invention relates to compounds of formula (I) as described supra, wherein: R3represents –(CO)-R11; R11represents −C(R14)-R15; R14represents =CHR16; R15represents a hydrogen atom; R16represents a hydrogen atom or –CH2-NR19R20; R19represents methyl or ethyl; R20represents methyl, tert-butyl, phenyl, 1,1,1-trifluoropropyl-; or R19and R20, together with the N-atom to which they are attached, form a group; wherein * indicates the point of attachment of said group with the rest of the molecule; or an N-oxide, a salt, a tautomer, a rotamer, or a stereoisomer of said compound, or a salt of said N-oxide, tautomer, rotamer, or stereoisomer. In an embodiment, the invention relates to compounds of formula (I) as described supra, wherein: R4arepresents a hydrogen atom or R4g; R4brepresents a hydrogen atom; R4crepresents a hydrogen atom or R4g; R4drepresents a hydrogen atom; R4erepresents a hydrogen atom, phenyl, , or ; R4frepresents a hydrogen atom; R4grepresents ethyl, 2-propyl, 2-methylpropyl, tert-butyl, trifluoromethyl, 1,1,1- trifluoroethyl, 1,1,1-trifluoropropyl-, 2-hydroxy-2-methylethyl-, cyclopropyl, cyclobutyl, 2-oxetanyl, benzyl, or wherein one of R4aor R4crepresents R4g; R33arepresents a hydrogen atom or chloro; R33brepresents a hydrogen atom; R33crepresents a hydrogen atom or chloro; R33drepresents a hydrogen atom; R33erepresents a hydrogen atom; wherein * indicates the point of attachment of said group with the rest of the molecule; or an N-oxide, a salt, a tautomer, a rotamer, or a stereoisomer of said compound, or a salt of said N-oxide, tautomer, rotamer, or stereoisomer. In an embodiment, the invention relates to compounds of formula (I) as described supra, wherein: R4arepresents a hydrogen atom or R4g; R4grepresents ethyl, 2-propyl, 2-methylpropyl, tert-butyl, trifluoromethyl, 1,1,1- trifluoroethyl, 1,1,1-trifluoropropyl-, 2-hydroxy-2-methylethyl-, cyclopropyl, cyclobutyl, 2-oxetanyl, benzyl, or R33arepresents a hydrogen atom or chloro; R33brepresents a hydrogen atom; R33crepresents a hydrogen atom or chloro; R33drepresents a hydrogen atom; R33erepresents a hydrogen atom; wherein * indicates the point of attachment of said group with the rest of the molecule; or an N-oxide, a salt, a tautomer, a rotamer, or a stereoisomer of said compound, or a salt of said N-oxide, tautomer, rotamer, or stereoisomer. In an embodiment, the invention relates to compounds of formula (I) as described supra, wherein: R4brepresents a hydrogen atom; or an N-oxide, a salt, a tautomer, a rotamer, or a stereoisomer of said compound, or a salt of said N-oxide, tautomer, rotamer, or stereoisomer. In an embodiment, the invention relates to compounds of formula (I) as described supra, wherein: R4crepresents a hydrogen atom or R4g; R4grepresents ethyl, 2-propyl, 2-methylpropyl, tert-butyl, trifluoromethyl, 1,1,1- trifluoroethyl, 1,1,1-trifluoropropyl-, 2-hydroxy-2-methylethyl-, cyclopropyl, cyclobutyl, 2-oxetanyl, benzyl, or R33arepresents a hydrogen atom or chloro; R33brepresents a hydrogen atom; R33crepresents a hydrogen atom or chloro; R33drepresents a hydrogen atom; R33erepresents a hydrogen atom; wherein * indicates the point of attachment of said group with the rest of the molecule; or an N-oxide, a salt, a tautomer, a rotamer, or a stereoisomer of said compound, or a salt of said N-oxide, tautomer, rotamer, or stereoisomer. In an embodiment, the invention relates to compounds of formula (I) as described supra, wherein: R4drepresents a hydrogen atom; or an N-oxide, a salt, a tautomer, a rotamer, or a stereoisomer of said compound, or a salt of said N-oxide, tautomer, rotamer, or stereoisomer. In an embodiment, the invention relates to compounds of formula (I) as described supra, wherein: R4erepresents a hydrogen atom, phenyl, ; wherein * indicates the point of attachment of said group with the rest of the molecule; or an N-oxide, a salt, a tautomer, a rotamer, or a stereoisomer of said compound, or a salt of said N-oxide, tautomer, rotamer, or stereoisomer. In an embodiment, the invention relates to compounds of formula (I) as described supra, wherein: R4frepresents a hydrogen atom; or an N-oxide, a salt, a tautomer, a rotamer, or a stereoisomer of said compound, or a salt of said N-oxide, tautomer, rotamer, or stereoisomer. In an embodiment, the invention relates to compounds of formula (I) as described supra, wherein: R4grepresents ethyl, 2-propyl, 2-methylpropyl, tert-butyl, trifluoromethyl, 1,1,1- trifluoroethyl, 1,1,1-trifluoropropyl-, 2-hydroxy-2-methylethyl-, cyclopropyl, cyclobutyl, 2-oxetanyl, benzyl, or R33arepresents a hydrogen atom or chloro; R33brepresents a hydrogen atom; R33crepresents a hydrogen atom or chloro; R33drepresents a hydrogen atom; R33erepresents a hydrogen atom; wherein * indicates the point of attachment of said group with the rest of the molecule; or an N-oxide, a salt, a tautomer, a rotamer, or a stereoisomer of said compound, or a salt of said N-oxide, tautomer, rotamer, or stereoisomer. In a fourth aspect, the invention relates to compounds of formula (I) as described supra, which is selected from the group consisting of: 1-[2-(4-chloro-2-fluorophenyl)-4-(2,4-dichlorophenyl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one (isomer 1) 1-[2-(4-chloro-2-fluorophenyl)-4-ethyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin- 5(4H)-yl]prop-2-en-1-one (isomer 2) 1-[2-(4-chloro-2-fluorophenyl)-4-phenyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin- 5(4H)-yl]prop-2-en-1-one (isomer 1) 1-[2-(4-chloro-2-fluorophenyl)-4-phenyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin- 5(4H)-yl]prop-2-en-1-one (isomer 2) 1-(7RS)-[2-(4-chloro-2-fluorophenyl)-7-phenyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one 1-[2-(4-chloro-2-fluorophenyl)-7-phenyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin- 5(4H)-yl]prop-2-en-1-one (isomer 1) 1-[2-(4-chloro-2-fluorophenyl)-7-phenyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin- 5(4H)-yl]prop-2-en-1-one (isomer 2) 1-[(7RS)-2-(4-chloro-2-fluorophenyl)-7-(2-chlorophenyl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo [1,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one 1-[2-(4-chloro-2-fluorophenyl)-7-(2-chlorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one (isomer1) 1-[2-(4-chloro-2-fluorophenyl)-7-(2-chlorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one (isomer 2) 1-[2-(4-chloro-2-fluorophenyl)-7-(2,4-dichlorophenyl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one (isomer 1) 1-[2-(4-chloro-2-fluorophenyl)-7-(2,4-dichlorophenyl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one (isomer 2) 1-[(6RS)-2-(4-chlorophenyl)-6-(oxetan-3-yl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one 3-[(6RS)-6-(oxetan-3-yl)-5-(prop-2-enoyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-2-yl]benzonitrile (2E)-1-[(6RS)-2-(4-chlorophenyl)-6-(oxetan-3-yl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one 3-[(6RS)-6-(2-hydroxypropan-2-yl)-5-(prop-2-enoyl)-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile 3-[(6S)-5-[(2E)-4-(dimethylamino)but-2-enoyl]-6-(2-methylpropyl)-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile formic acid 3-[(6S)-5-[(2E)-4-(dimethylamino)but-2-enoyl]-3-(pyridin-4-yl)-6-(3,3,3- trifluoropropyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile (1: 1) 3-[(6S)-6-benzyl-5-[(2E)-4-(dimethylamino)but-2-enoyl]-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile formic acid 3-[(6R)-6-benzyl-5-[(2E)-4-(dimethylamino)but-2-enoyl]-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile (1: 1) 3-[(6R)-6-tert-butyl-5-[(2E)-4-(dimethylamino)but-2-enoyl]-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile 3-[(6S)-6-(2-methylpropyl)-5-(prop-2-enoyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-2-yl]benzonitrile 3-[(6S)-6-cyclobutyl-5-(prop-2-enoyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-2-yl]benzonitrile 3-[(6S)-5-(prop-2-enoyl)-3-(pyridin-4-yl)-6-(3,3,3-trifluoropropyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile 3-[(6S)-6-benzyl-5-(prop-2-enoyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin- 2-yl]benzonitrile 3-[(6S)-6-tert-butyl-5-(prop-2-enoyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-2-yl]benzonitrile 3-[(6R)-6-cyclobutyl-5-(prop-2-enoyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-2-yl]benzonitrile 3-[(6R)-5-(prop-2-enoyl)-3-(pyridin-4-yl)-6-(3,3,3-trifluoropropyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile 3-[(6R)-6-benzyl-5-(prop-2-enoyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin- 2-yl]benzonitrile 3-[(6R)-6-tert-butyl-5-(prop-2-enoyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-2-yl]benzonitrile formic acid 3-[(6S)-5-{(2E)-4-[tert-butyl(methyl)amino]but-2-enoyl}-6-cyclobutyl-3-(pyridin- 4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile (1: 1) formic acid 3-[(6S)-5-{(2E)-4-[tert-butyl(methyl)amino]but-2-enoyl}-3-(pyridin-4-yl)-6-(3,3,3- trifluoropropyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile (1 / 1) 3-[(6S)-6-tert-butyl-5-{(2E)-4-[tert-butyl(methyl)amino]but-2-enoyl}-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile formic acid 3-[(6R)-5-{(2E)-4-[tert-butyl(methyl)amino]but-2-enoyl}-6-cyclobutyl-3-(pyridin- 4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile (1: 1) 3-[(6R)-6-benzyl-5-{(2E)-4-[tert-butyl(methyl)amino]but-2-enoyl}-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile 3-[(6R)-6-tert-butyl-5-{(2E)-4-[tert-butyl(methyl)amino]but-2-enoyl}-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile formic acid 3-[(6S)-6-cyclobutyl-5-[(2E)-4-(2,2-dimethylpyrrolidin-1-yl)but-2-enoyl]-3- (pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile (1: 1) formic acid 3-[(6S)-5-[(2E)-4-(2,2-dimethylpyrrolidin-1-yl)but-2-enoyl]-3-(pyridin-4-yl)-6- (3,3,3-trifluoropropyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile (1: 1) formic acid 3-[(6R)-6-cyclobutyl-5-[(2E)-4-(2,2-dimethylpyrrolidin-1-yl)but-2-enoyl]-3- (pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile (1 / 1) 1-[(6R*)-2-(4-chloro-2-fluorophenyl)-6-ethyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one - enantiomer 1 3-[(6R*)-6-ethyl-5-(prop-2-enoyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin- 2-yl]benzonitrile - enantiomer 1 3-[(6R*)-6-ethyl-5-(prop-2-enoyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin- 2-yl]benzonitrile - enantiomer 2 1-[(6R*)-2-(4-chlorophenyl)-6-ethyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin- 5(4H)-yl]prop-2-en-1-one - enantiomer 1 3-[(6R)-6-cyclopropyl-5-[(2E)-4-(dimethylamino)but-2-enoyl]-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile 3-[(6S)-6-cyclopropyl-5-[(2E)-4-(dimethylamino)but-2-enoyl]-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile 1-[(6RS)-2-(4-Chlor-2-fluorphenyl)-6-ethyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]prop-2-en-1-on 1-[(6RS)-6-Ethyl-2-(4-methoxyphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin- 5(4H)-yl]prop-2-en-1-on 1-[(6RS)-2-(4-chloro-2-fluorophenyl)-6-ethyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one 1-[(6RS)-6-ethyl-2-(3-fluoro-4-methoxyphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one 3-[(6RS)-6-ethyl-5-(prop-2-enoyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin- 2-yl]benzonitrile 1-[(6RS)-2-(3-chlorophenyl)-6-cyclopropyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one 3-[(6RS)-6-(propan-2-yl)-5-(prop-2-enoyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-2-yl]benzonitrile (2E)-1-[(6RS)-2-(3-chlorophenyl)-6-cyclopropyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one 1-[(6R)-2-(4-chloro-2-fluorophenyl)-3-(pyridin-4-yl)-6-(2,2,2-trifluoroethyl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one (2E)-1-[(6RS)-2-(3-chlorophenyl)-6-cyclopropyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-1-[(6R)-6-cyclopropyl-2-(3-ethynylphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-1-[(6S)-6-cyclopropyl-2-(1H-indol-6-yl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-1-[(6S)-2-(1-benzothiophen-5-yl)-6-cyclopropyl-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-1-[(6RS)-6-cyclopropyl-2-[3-(hydroxymethyl)phenyl]-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-1-[(6RS)-2-(4-chloro-2-fluorophenyl)-6-ethyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-4-(dimethylamino)-1-[(6RS)-2-[3-(hydroxymethyl)phenyl]-6-(propan-2-yl)-3-(pyridin-4- yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]but-2-en-1-one (2E)-1-[(6S)-6-cyclopropyl-2-(3-hydroxyphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one 5-[(6RS)-6-cyclopropyl-5-[(2E)-4-(dimethylamino)but-2-enoyl]-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]-2-fluorobenzonitrile 3-[(6RS)-6-cyclopropyl-5-[(2E)-4-(dimethylamino)but-2-enoyl]-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile (2E)-1-[(6S)-2-(2,1,3-benzoxadiazol-5-yl)-6-cyclopropyl-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one 3-[(6RS)-6-cyclopropyl-5-[(2E)-4-(dimethylamino)but-2-enoyl]-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]-4-fluorobenzonitrile 3-[(6S)-6-cyclopropyl-5-[(2E)-4-(dimethylamino)but-2-enoyl]-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]-2-methylbenzonitrile 5-[(6S)-6-cyclopropyl-5-[(2E)-4-(dimethylamino)but-2-enoyl]-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]-2-methylbenzonitrile (2E)-1-[(6S)-6-cyclopropyl-2-[3-(methanesulfonyl)phenyl]-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-1-[(6S)-6-cyclopropyl-2-[3-(methanesulfinyl)phenyl]-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one 3-[(6S)-6-cyclopropyl-5-[(2E)-4-(dimethylamino)but-2-enoyl]-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]-5-methylbenzonitrile 3-[(6S)-6-cyclopropyl-5-[(2E)-4-(dimethylamino)but-2-enoyl]-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]-4-methylbenzonitrile (2E)-1-[(6S)-2-(1-benzothiophen-5-yl)-6-cyclopropyl-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(2,2-dimethylpyrrolidin-1-yl)but-2-en-1-one (2E)-1-[(6S)-2-(2,1,3-benzoxadiazol-5-yl)-6-cyclopropyl-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(2,2-dimethylpyrrolidin-1-yl)but-2-en-1-one 3-[(6S)-6-cyclopropyl-5-[(2E)-4-(2,2-dimethylpyrrolidin-1-yl)but-2-enoyl]-3-(pyridin-4-yl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile 3-[(6S)-6-cyclopropyl-5-[(2E)-4-(2,2-dimethylpyrrolidin-1-yl)but-2-enoyl]-3-(pyridin-4-yl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]-2-methylbenzonitrile 5-[(6S)-6-cyclopropyl-5-[(2E)-4-(2,2-dimethylpyrrolidin-1-yl)but-2-enoyl]-3-(pyridin-4-yl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]-2-methylbenzonitrile 3-[(6S)-6-cyclopropyl-5-{(2E)-4-[methyl(3,3,3-trifluoropropyl)amino]but-2-enoyl}-3-(pyridin- 4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile 5-[(6S)-5-{(2E)-4-[tert-butyl(methyl)amino]but-2-enoyl}-6-cyclopropyl-3-(pyridin-4-yl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]-2-methylbenzonitrile 3-[(6S)-5-{(2E)-4-[tert-butyl(ethyl)amino]but-2-enoyl}-6-cyclopropyl-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile 5-[(6S)-5-{(2E)-4-[tert-butyl(ethyl)amino]but-2-enoyl}-6-cyclopropyl-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]-2-methylbenzonitrile 3-[(6S)-6-cyclopropyl-5-{(2E)-4-[methyl(phenyl)amino]but-2-enoyl}-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile (2E)-1-[(6S)-6-cyclopropyl-2-(3-cyclopropylphenyl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-1-[(6R)-6-cyclopropyl-2-(3-cyclopropylphenyl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-1-[(6S)-6-cyclopropyl-2-(3-ethylphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-1-[(6R)-6-cyclopropyl-2-(3-ethylphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one 3-[(6S)-5-{(2E)-4-[tert-butyl(methyl)amino]but-2-enoyl}-6-cyclopropyl-3-(pyridin-4-yl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile (2E)-1-[(6S)-6-cyclopropyl-2-(3-ethynylphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-1-[(6S)-6-cyclopropyl-2-[3-(difluoromethyl)phenyl]-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-1-[(6S)-6-cyclopropyl-2-[3-(difluoromethoxy)phenyl]-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one 2-[(6S)-6-cyclopropyl-5-[(2E)-4-(dimethylamino)but-2-enoyl]-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile (2E)-1-[(6S)-6-cyclopropyl-3-(pyridin-4-yl)-2-[3-(2,2,2-trifluoroethyl)phenyl]-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-1-[(6S)-2-(4-chloro-3-ethylphenyl)-6-cyclopropyl-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-4-[tert-butyl(methyl)amino]-1-[(6S)-6-cyclopropyl-3-(pyridin-4-yl)-2-[3- (trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]but-2-en-1-one N-(4-{(6S)-2-(3-cyanophenyl)-6-cyclopropyl-5-[(2E)-4-(dimethylamino)but-2-enoyl]-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl}pyridin-2-yl)cyclopropanecarboxamide 3-{(6S)-6-cyclopropyl-5-[(2E)-4-(dimethylamino)but-2-enoyl]-3-[2-(methylamino)pyridin-4- yl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl}benzonitrile 2-chloro-5-[(6S)-6-cyclopropyl-5-[(2E)-4-(dimethylamino)but-2-enoyl]-3-(pyridin-4-yl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile (2E)-1-[(6S)-2-[4-chloro-3-(trifluoromethyl)phenyl]-6-cyclopropyl-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-4-[tert-butyl(methyl)amino]-1-[(6S)-2-[4-chloro-3-(trifluoromethyl)phenyl]-6- cyclopropyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]but-2-en-1-one (2E)-1-[(6S)-6-cyclopropyl-2-(3-methoxyphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-1-[(6S)-6-cyclopropyl-2-(3-ethoxyphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-1-[(6S)-6-cyclopropyl-2-(3-ethoxyphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-1-[(6S)-2-(4-chloro-3-methoxyphenyl)-6-cyclopropyl-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-1-[(6S)-6-cyclopropyl-2-[3-(1H-pyrazol-3-yl)phenyl]-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-1-[(6S)-6-cyclopropyl-2-[3-(difluoromethyl)-4-fluorophenyl]-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-1-[(6S)-6-cyclopropyl-2-[3-(propan-2-yl)phenyl]-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-4-[tert-butyl(methyl)amino]-1-[(6S)-6-cyclopropyl-2-[3-(difluoromethoxy)phenyl]-3- (pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]but-2-en-1-one (2E)-4-[tert-butyl(methyl)amino]-1-[(6S)-6-cyclopropyl-3-(pyridin-4-yl)-2-[3- (trifluoromethoxy)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]but-2-en-1-one (2E)-1-[(6S)-2-(1-benzofuran-7-yl)-6-cyclopropyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-1-[(6S)-6-cyclopropyl-2-[4-fluoro-3-(trifluoromethyl)phenyl]-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one 1-[(6SR)-2-(4-chloro-2-fluorophenyl)-3-(pyridin-4-yl)-6-(trifluoromethyl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one and 1-[(6SR)-2-(4-methoxyphenyl)-3-(pyridin-4-yl)-6-(trifluoromethyl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one; or an N-oxide, a salt, a tautomer, a rotamer, or a stereoisomer of said compound, or a salt of said N-oxide, tautomer, rotamer, or stereoisomer. A further aspect of the invention relates to compounds of formula (I), which are present as their salts, such as pharmaceutically acceptable salts. It is to be understood that the present invention relates to any sub-combination within any embodiment or aspect of the present invention of compounds of formula (I), supra. More particularly still, the present invention covers compounds of formula (I) which are disclosed in the Example section of this text, infra. In accordance with another aspect, the present invention covers methods of preparing compounds of the present invention, said methods comprising the steps as described in the Experimental Section herein. Another embodiment of the invention are compounds according as disclosed in the Claims section or disclosed analogs of the exemplified compounds and subcombinations thereof. Definitions It is to be understood that embodiments disclosed herein are not meant to be understood as individual embodiments which would not relate to one another. Features discussed with one embodiment or aspect of the invention are meant to be disclosed also in connection with other embodiments or aspects of the invention shown herein. If, in one case, a specific feature is not disclosed with one embodiment or aspect of the invention, but with another, the skilled person would understand that does not necessarily mean that said feature is not meant to be disclosed with said other embodiment or aspect of the invention. The skilled person would understand that it is the gist of this application to disclose said feature also for the other embodiment or aspect of the invention, but that just for purposes of clarity and to keep the length of this specification manageable. For example, it is to be understood that all aspects, embodiments, pharmaceutical compositions, combinations, uses and / or methods of the present invention defined herein for the compounds of formula (I) also relate to more specific embodiments of the compounds of formula (I), such as, but not limited to, the compounds of formula (Ia) and vice-versa, for example. It is further to be understood that the content of the documents referred to herein is incorporated by reference in their entirety, namely when e.g. a method is discussed details of which are described in said document. This approach serves to keep the length of this specification manageable. The term “comprising” when used in the specification includes “consisting of”. If it is referred to “as mentioned above” or “mentioned above”, “supra” within the description it is referred to any of the disclosures made within the specification in any of the preceding pages. If it is referred to “as mentioned herein”, “described herein”, “provided herein,” or “as mentioned in the present text,” or “stated herein” within the description it is referred to any of the disclosures made within the specification in any of the preceding or subsequent pages. By "subject" is meant a mammal, including, but not limited to, a human or non-human mammal, such as a bovine, equine, canine, ovine, or feline. “Suitable” within the sense of the invention means chemically possible to be made by methods within the knowledge of a skilled person. The terms as mentioned in the present text may have the following meanings: The term “C3-C6-cycloalkyl” means a saturated, monovalent, monocyclic hydrocarbon ring which contains 3, 4, 5, or 6 carbon atoms. Said C3-C6-cycloalkyl group is for example, a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group. Further, as used herein, the term “C3-C6”, as used throughout this text, e.g. in the context of the definition of “C3-C6-cycloalkyl”, is to be understood as meaning a cycloalkyl group having a finite number of carbon atoms of 3 to 6, i.e.3, 4, 5 or 6 carbon atoms. It is to be understood further that said term “C3-C6” is to be interpreted as any sub-range comprised therein, e.g. C3-C6 ,C4-C5 ,C3-C5 ,C3-C4, C4-C6, C5-C6;particularly C3-C6. The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. As used herein, the term “one or more”, e.g. in the definition of the substituents of the compounds of the formulae of the present invention, is understood as meaning “one, two, three, four, five, etc. particularly one, two, three or four, more particularly one, two or three, even more particularly one or two”. The compounds of formula (I) may exist as isotopic variants. The invention therefore includes one or more isotopic variant(s) of the compounds of formula (I), particularly deuterium-containing compounds of formula (I). The term “isotopic variant” of a compound or a reagent is defined as a compound exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound. The term “isotopic variant of the compound of formula (I)” is defined as a compound of formula (I) exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound. The expression “unnatural proportion” is to be understood as meaning a proportion of such isotope which is higher than its natural abundance. The natural abundances of isotopes to be applied in this context are described in “Isotopic Compositions of the Elements 1997”, Pure Appl. Chem., 70(1), 217-235, 1998. Examples of such isotopes include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as2H (deuterium),3H (tritium),11C,13C,14C,15N,17O,18O,32P,33P,33S,34S,35S,36S,18F,36Cl,82Br,123I,124I,125I,129I and131I, respectively. With respect to the treatment and / or prophylaxis of the disorders specified herein the isotopic variant(s) of the compounds of formula (I) in one embodiment contain deuterium (“deuterium-containing compounds of formula (I)”). Isotopic variants of the compounds of formula (I) in which one or more radioactive isotopes, such as3H or14C, are incorporated are useful e.g. in drug and / or substrate tissue distribution studies. These isotopes are particularly preferred for the ease of their incorporation and detectability. Positron emitting isotopes such as18F or11C may be incorporated into a compound of formula (I). These isotopic variants of the compounds of formula (I) are useful for in vivo imaging applications. Deuterium-containing and13C-containing compounds of formula (I) can be used in mass spectrometry analyses (H. J. Leis et al., Curr. Org. Chem., 1998, 2, 131) in the context of preclinical or clinical studies. Isotopic variants of the compounds of formula (I) can generally be prepared by methods known to a person skilled in the art, such as those described in the schemes and / or examples herein, by substituting a reagent for an isotopic variant of said reagent, in one embodiment for a deuterium-containing reagent. Depending on the desired sites of deuteration, in some cases deuterium from D2O can be incorporated either directly into the compounds or into reagents that are useful for synthesizing such compounds (Esaki et al., Tetrahedron, 2006, 62, 10954; Esaki et al., Chem. Eur. J., 2007, 13, 4052). Deuterium gas is also a useful reagent for incorporating deuterium into molecules. Catalytic deuteration of olefinic bonds (H. J. Leis et al., Curr. Org. Chem., 1998, 2, 131; J. R. Morandi et al., J. Org. Chem., 1969, 34 (6), 1889) and acetylenic bonds (N. H. Khan, J. Am. Chem. Soc., 1952, 74 (12), 3018; S. Chandrasekhar et al., Tetrahedron, 2011, 52, 3865) is a rapid route for incorporation of deuterium. Metal catalysts (i.e. Pd, Pt, and Rh) in the presence of deuterium gas can be used to directly exchange deuterium for hydrogen in functional groups containing hydrocarbons (J. G. Atkinson et al., US Patent 3966781). A variety of deuterated reagents and synthetic building blocks are commercially available from companies such as for example C / D / N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc., Princeton, NJ, USA. Further information on the state of the art with respect to deuterium-hydrogen exchange is given for example in Hanzlik et al., J. Org. Chem.55, 3992-3997, 1990; R. P. Hanzlik et al., Biochem. Biophys. Res. Commun.160, 844, 1989; P. J. Reider et al., J. Org. Chem.52, 3326-3334, 1987; M. Jarman et al., Carcinogenesis 16(4), 683-688, 1993; J. Atzrodt et al., Angew. Chem., Int. Ed.2007, 46, 7744; K. Matoishi et al., J. Chem. Soc, Chem. Commun.2000, 1519−1520; K. Kassahun et al., WO2012 / 112363. The term “deuterium-containing compound of formula (I)” is defined as a compound of formula (I), in which one or more hydrogen atom(s) is / are replaced by one or more deuterium atom(s) and in which the abundance of deuterium at each deuterated position of the compound of formula (I) is higher than the natural abundance of deuterium, which is about 0.015%. Particularly, in a deuterium-containing compound of formula (I) the abundance of deuterium at each deuterated position of the compound of formula (I) is higher than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, in one embodiment higher than 90%, 95%, 96% or 97%, in other embodiments higher than 98% or 99% at said position(s). It is understood that the abundance of deuterium at each deuterated position is independent of the abundance of deuterium at other deuterated position(s). The selective incorporation of one or more deuterium atom(s) into a compound of formula (I) may alter the 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. Chem. Soc., 2007, 129, 4490], basicity [C. L. Perrin, et al., J. Am. Chem. Soc., 2003, 125, 15008; C. L. Perrin in Advances in Physical Organic Chemistry, 44, 144; C. L. Perrin et al., J. Am. Chem. Soc., 2005, 127, 9641], lipophilicity [B. Testa et al., Int. J. Pharm., 1984, 19(3), 271]) and / or the metabolic profile of the molecule and may result in changes in the ratio of parent compound to metabolites or in the amounts of metabolites formed. Such changes may result in certain therapeutic advantages and hence may be preferred in some circumstances. Reduced rates of metabolism and metabolic switching, where the ratio of metabolites is changed, have 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 to parent drug and metabolites can have important consequences with respect to the pharmacodynamics, tolerability and efficacy of a deuterium-containing compound of formula (I). In some cases deuterium substitution reduces or eliminates the formation of an undesired or toxic metabolite and enhances the formation of a desired metabolite (e.g. Nevirapine: A. M. Sharma et al., Chem. Res.Toxicol., 2013, 26, 410; Uetrecht et al., Chemical Research in Toxicology, 2008, 21, 9, 1862; Efavirenz: A. E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). In other cases the major effect of deuteration is to reduce the rate of systemic clearance. As a result, the biological half-life of the compound is increased. The potential clinical benefits would include the ability to maintain similar systemic exposure with decreased peak levels and increased trough levels. This could result in lower side effects and enhanced efficacy, depending on the particular compound’s pharmacokinetic / pharmacodynamic relationship. Indiplon (A. J. Morales et al., Abstract 285, The 15thNorth American Meeting of the International Society of Xenobiotics, San Diego, CA, October 12-16, 2008), ML-337 (C. J. Wenthur et al., J. Med. Chem., 2013, 56, 5208), and Odanacatib (K. Kassahun et al., WO2012 / 112363) are examples for this deuterium effect. Still other cases have been reported in which reduced rates of metabolism result in an increase in exposure of the drug without changing the rate of systemic clearance (e.g. Rofecoxib: F. Schneider et al., Arzneim. Forsch. Drug. Res., 2006, 56, 295; Telaprevir: F. Maltais et al., J. Med. Chem., 2009, 52, 7993). Deuterated drugs showing this effect may have reduced dosing requirements (e.g. lower number of doses or lower dosage to achieve the desired effect) and / or may produce lower metabolite loads. A compound of formula (I) may have multiple potential sites of attack for metabolism. To optimize the above-described effects on physicochemical properties and metabolic profile, deuterium-containing compounds of formula (I) having a certain pattern of one or more deuterium-hydrogen exchange(s) can be selected. Particularly, the deuterium atom(s) of deuterium- containing compound(s) of formula (I) is / are attached to a carbon atom and / or is / are located at those positions of the compound of formula (I), which are sites of attack for metabolizing enzymes such as e.g. cytochrome P450. Where the plural form of the word compounds, salts, polymorphs, hydrates, solvates and the like, is used herein, this is taken to mean also a single compound, salt, polymorph, isomer, hydrate, solvate or the like. By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. The compounds of this invention may contain one or more asymmetric centre, depending upon the location and nature of the various substituents desired. Asymmetric carbon atoms may be present in the (R) or (S) configuration, resulting in racemic mixtures in the case of a single asymmetric centre, and diastereomeric mixtures in the case of multiple asymmetric centres. In certain instances, asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds. Substituents on a ring may also be present in either cis or trans form. It is intended that all such configurations (including enantiomers and diastereomers), are included within the scope of the present invention. Typically, compounds of the present disclosure are those which produce the more desirable biological activity. Separated, 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. The purification and the separation of such materials can be accomplished by standard techniques known in the art. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers. Examples of appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and / or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation. The optically active bases or acids are then liberated from the separated diastereomeric salts. A different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers. Suitable chiral HPLC columns are manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ among many others, all routinely selectable. Enzymatic separations, with or without derivatisation, are also useful. The optically active compounds of this invention can likewise be obtained by chiral syntheses utilizing optically active starting materials. In order to limit different types of isomers from each other reference is made to 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 as single stereoisomers, or as any mixture of said stereoisomers, e.g. R- or S- isomers, or E- or Z-isomers, in any ratio. Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention may be achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example. In certain compounds of the present invention, optionally asymmetry may be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds. Particularly, dependent on the sterical demands of the substituents in position R1, R4a, R4b, R10a, and R10d, compounds of the present invention can exist as atropisomers, as shown in Figure 1. Atropisomers represent a subclass of conformers which arise from restricted rotation around a single bond. The conformers (called atropisomers) can be isolated as separated species (IUPAC Gold book, http: / / goldbook.iupac.org / A00511.html; Pure and Appl. Chem., 2009, 68, 2193- 2222). This induced chirality belongs to the axial type of chirality. Hence, compounds featuring said atropisomerism and an additional asymmetric centre can exist as diasteromeric mixtures as described supra. Figure 1: Atropisomerism examples of compounds of general formula (I) Several related compounds with the related type of atropisomerism have been already described as observed in the literature (G. Bringmann et al., Chem. Rev., 2011, 111, 563- 639). For examples of atropisomers in drug discovery, see the mini-review from J. Clayden, S. R. Laplante et al.: Angew. Chem. Int. Ed.2009, 48, 6398-6401 and also: S. R. LaPlante, P. J. Edwards et al., J. Med. Chem.2011, 54, 7005-7022. Further, the compounds of the present invention may optionally contain one or more asymmetric centres, depending upon the location and nature of the various substituents desired. It is possible that one or more asymmetric carbon atoms are present in the (R) or (S) configuration, which can result in racemic mixtures in the case of a single asymmetric centre, and in diastereomeric mixtures in the case of multiple elements of asymmetry, such as axial chirality and asymmetric centres. Preferred compounds are those which produce the more desirable biological activity. Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of the present invention are also included within the scope of the present invention. The purification and the separation of such materials can be accomplished by standard techniques known in the art,examples of which can be found in the experimental section. If the atropisomers were separated, said atropisomers are being referred to as “atrop 1” (for atropisomer 1) and “atrop 2” (for atropisomer 2), subsequent to the respective compound name. Names without any such indication but still naming a compound showing atropisomerism is to be understood to include both atropisomers which were not separated. Further, the compounds of the present invention may exist as tautomers. For example, any compound of the present invention which contains a pyrazole moiety as a heteroaryl group for example can exist as a 1H tautomer, or a 2H tautomer, or even a mixture in any amount of the two tautomers, or a triazole moiety for example can exist as a 1H tautomer, a 2H tautomer, or a 4H tautomer, or even a mixture in any amount of said 1H, 2H and 4H tautomers, namely : 1H-tautomer 2H-tautomer 4H-tautomer . The present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio. Further, the compounds of the present invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised. The present invention includes all such possible N-oxides. The present invention also relates to useful forms of the compounds as disclosed herein, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and co-precipitates. The compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example as structural element of the crystal lattice of the compounds. The amount of polar solvents, in particular water, may exist in a stoichiometric or non- stoichiometric ratio. In the case of stoichiometric solvates, e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, are possible. The present invention includes all such hydrates or solvates. Further, the compounds of the present invention can exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or can exist in the form of a salt. Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, customarily used in pharmacy. The term “pharmaceutically acceptable salt" refers to a relatively non-toxic, inorganic or organic acid addition salt of 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, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, bisulfuric, phosphoric or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic, pamoic, pectinic, persulfuric, 3-phenylpropionic, picric, pivalic, 2-hydroxyethanesulfonate, itaconic, sulfamic, trifluoromethanesulfonic, dodecylsulfuric, ethansulfonic, benzenesulfonic, para- toluenesulfonic, methansulfonic, 2-naphthalenesulfonic, naphthalinedisulfonic, camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic, mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic, sulfosalicylic, hemisulfuric or thiocyanic acid, for example. Further, another suitably pharmaceutically acceptable salt of a 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 affords a physiologically acceptable cation, for example a salt with N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, dicyclohexylamine, 1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-aminomethane, aminopropandiol, sovak-base, 1-amino-2,3,4- butantriol. Additionally, basic nitrogen containing groups may be quaternised with such agents as 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 strearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others. Those skilled in the art will further recognise that acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts of acidic compounds of the invention are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods. The present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio. In the present text, in particular in the Experimental Section, for the synthesis of intermediates and of examples of the present invention, when a compound is mentioned as a salt form with the corresponding base or acid, the exact stoichiometric composition of said salt form, as obtained by the respective preparation and / or purification process, is, in most cases, unknown. Unless specified otherwise, suffixes to chemical names or structural formulae such as "hydrochloride", "trifluoroacetate", "sodium salt", or "x HCl", "x CF3COOH", "x Na+", for example, are to be understood as not a stoichiometric specification, but solely as a salt form. This applies analogously to cases in which synthesis intermediates or example compounds or salts thereof have been obtained, by the preparation and / or purification processes described, as solvates, such as hydrates with (if defined) unknown stoichiometric composition. The salts include water-insoluble and, particularly, water-soluble salts. Furthermore, derivatives of the compounds of formula (I) and the salts thereof which are converted into a compound of formula (I) or a salt thereof in a biological system (bioprecursors or pro-drugs) are covered by the invention. Said biological system is e.g. a mammalian organism, particularly a human subject. The bioprecursor is, for example, converted into the compound of formula (I) or a salt thereof by metabolic processes. As used herein, the term “in vivo hydrolysable ester” is understood as meaning an in vivo hydrolysable ester of a compound of the present invention containing a carboxy or hydroxy group, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically acceptable esters for carboxy include for example alkyl, cycloalkyl and optionally substituted phenylalkyl, in particular benzyl esters, C1-C6alkoxymethyl esters, e.g. methoxymethyl, C1- C6alkanoyloxymethyl esters, e.g. pivaloyloxymethyl, phthalidyl esters, C3-C8cycloalkoxy- carbonyloxy-C1-C6alkyl esters, e.g. 1-cyclohexylcarbonyloxyethyl, 1,3-dioxolen-2- onylmethyl esters, e.g. 5-methyl-1,3-dioxolen-2-onylmethyl, and C1-C6- alkoxycarbonyloxyethyl esters, e.g.1-methoxycarbonyloxyethyl, and may be formed at any carboxy group in the compounds of this invention. An in vivo hydrolysable ester of a compound of the present invention containing a hydroxy group includes inorganic esters such as phosphate esters and [alpha]-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group. Examples of [alpha]-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of in vivo hydrolysable ester forming groups for hydroxy include 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. Furthermore, the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorphs, or as a mixture of more than one polymorphs, in any ratio. In the context of the properties of the compounds of the present invention the term “pharmacokinetic profile” means one single parameter or a combination thereof including permeability, bioavailability, exposure, and pharmacodynamic parameters such as duration, or magnitude of pharmacological effect, as measured in a suitable experiment. Compounds with improved pharmacokinetic profiles can, for example, be used in lower doses to achieve the same effect, may achieve a longer duration of action, or a may achieve a combination of both effects. The term “combination” in the present invention is used as known to persons skilled in the art and may be present as a fixed combination, a non-fixed combination or kit-of-parts. A “fixed combination” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein the said first active ingredient and the said second active ingredient are present together in one unit dosage or in a single entity. One example of a “fixed combination” is a pharmaceutical composition wherein the said first active ingredient and the said second active ingredient are present in admixture for simultaneous administration, such as in a formulation. Another example of a “fixed combination” is a pharmaceutical combination wherein the said first active ingredient and the said second active ingredient are present in one unit without being in admixture. A non-fixed combination or “kit-of-parts” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein the said first active ingredient and the said second active ingredient are present in more than one unit. One example of a non-fixed combination or kit-of-parts is a combination wherein the said first active ingredient and the said second active ingredient are present separately. The components of the non-fixed combination or kit-of-parts may be administered separately, sequentially, simultaneously, concurrently or chronologically staggered. Any such combination of a compound of formula (I) of the present invention with an anti-cancer agent as defined below is an embodiment of the invention. The term “(chemotherapeutic) anti-cancer agents” relates to any agent that reduces the survival or proliferation of a cancer cell, and includes but is not limited to 131I-chTNT, abarelix, abiraterone, aclarubicin, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alemtuzumab, Alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, Hexyl aminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, angiotensin II, antithrombin III, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, axitinib, 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, catumaxomab, celecoxib, celmoleukin, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, copanlisib, crisantaspase, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, eculizumab, edrecolomab, elliptinium acetate, eltrombopag, endostatin, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, Glucarpidase, glutoxim, GM-CSF, goserelin, granisetron, granulocyte colony stimulating factor, histamine dihydrochloride, histrelin, hydroxycarbamide, I-125 seeds, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate, interferon alfa, interferon beta, interferon gamma, iobitridol, iobenguane (123I), iomeprol, ipilimumab, irinotecan, Itraconazole, ixabepilone, lanreotide, lapatinib, Iasocholine, lenalidomide, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone, methyltestosterone, metirosine, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphine hydrochloride, morphine sulfate, nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, nedaplatin, nelarabine, neridronic acid, nivolumabpentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, omacetaxine mepesuccinate, omeprazole, ondansetron, oprelvekin, orgotein, orilotimod, osimertinib, oxaliplatin, oxycodone, oxymetholone, ozogamicine, p53 gene therapy, paclitaxel, palifermin, palladium-103 seed, palonosetron, pamidronic acid, panitumumab, pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alfa-2b, pemetrexed, pentazocine, pentostatin, peplomycin, Perflubutane, perfosfamide, Pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium, poziotinib, pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib, regorafenib, risedronic acid, rhenium-186 etidronate, rituximab, romidepsin, romiplostim, romurtide, roniciclib, samarium (153Sm) lexidronam, sargramostim, satumomab, secretin, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin, tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium (99mTc) nofetumomab merpentan, 99mTc-HYNIC-[Tyr3]-octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa, tioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, 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 at least about 95% amino acid sequence identity to the sequence provided at UniProt Accession No. P00533-1 or a fragment thereof. In some embodiments, the EGFR fragment binds an EFGR ligand and / or has kinase activity. Mutant EGFR polypeptides include those having an insertion between, for example, amino acids V769 and D770 or between D770 and N771. In other embodiments, the amino acid sequence identity is 96, 97, 98, 99, or 100% to UniProt Accession No. P00533-1. An exemplary full length sequence of human EGFR, which indicates V769, D770, and N771 in bold, is provided at UniProt Accession No. P00533-1, which is reproduced below: 10 20 30 40 50 MRPSGTAGAA LLALLAALCP ASRALEEKKV CQGTSNKLTQ LGTFEDHFLS 60 70 80 90 100 LQRMFNNCEV VLGNLEITYV QRNYDLSFLK TIQEVAGYVL IALNTVERIP 110 120 130 140 150 LENLQIIRGN MYYENSYALA VLSNYDANKT GLKELPMRNL QEILHGAVRF 160 170 180 190 200 SNNPALCNVE SIQWRDIVSS DFLSNMSMDF QNHLGSCQKC DPSCPNGSCW 210 220 230 240 250 GAGEENCQKL TKIICAQQCS GRCRGKSPSD CCHNQCAAGC TGPRESDCLV 260 270 280 290 300 CRKFRDEATC KDTCPPLMLY NPTTYQMDVN PEGKYSFGAT CVKKCPRNYV 310 320 330 340 350 VTDHGSCVRA CGADSYEMEE DGVRKCKKCE GPCRKVCNGI GIGEFKDSLS 360 370 380 390 400 INATNIKHFK NCTSISGDLH ILPVAFRGDS FTHTPPLDPQ ELDILKTVKE 410 420 430 440 450 ITGFLLIQAW PENRTDLHAF ENLEIIRGRT KQHGQFSLAV VSLNITSLGL 460 470 480 490 500 RSLKEISDGD VIISGNKNLC YANTINWKKL FGTSGQKTKI ISNRGENSCK 510 520 530 540 550 ATGQVCHALC SPEGCWGPEP RDCVSCRNVS RGRECVDKCN LLEGEPREFV 560 570 580 590 600 ENSECIQCHP ECLPQAMNIT CTGRGPDNCI QCAHYIDGPH CVKTCPAGVM 610 620 630 640 650 GENNTLVWKY ADAGHVCHLC HPNCTYGCTG PGLEGCPTNG PKIPSIATGM 660 670 680 690 700 VGALLLLLVV ALGIGLFMRR RHIVRKRTLR RLLQERELVE PLTPSGEAPN 710 720 730 740 750 QALLRILKET EFKKIKVLGS GAFGTVYKGL WIPEGEKVKI PVAIKELREA 760 770 780 790 800 TSPKANKEIL DEAYVMASVD NPHVCRLLGI CLTSTVQLIT QLMPFGCLLD 810 820 830 840 850 YVREHKDNIG SQYLLNWCVQ IAKGMNYLED RRLVHRDLAA RNVLVKTPQH 860 870 880 890 900 VKITDFGLAK LLGAEEKEYH AEGGKVPIKW MALESILHRI YTHQSDVWSY 910 920 930 940 950 GVTVWELMTF GSKPYDGIPA SEISSILEKG ERLPQPPICT IDVYMIMVKC 960 970 980 990 1000 WMIDADSRPK FRELIIEFSK MARDPQRYLV IQGDERMHLP SPTDSNFYRA 1010 1020 1030 1040 1050 LMDEEDMDDV VDADEYLIPQ QGFFSSPSTS RTPLLSSLSA TSNNSTVACI 1060 1070 1080 1090 1100 DRNGLQSCPI KEDSFLQRYS SDPTGALTED SIDDTFLPVP EYINQSVPKR 1110 1120 1130 1140 1150 PAGSVQNPVY HNQPLNPAPS RDPHYQDPHS TAVGNPEYLN TVQPTCVNST 1160 1170 1180 1190 1200 FDSPAHWAQK GSHQISLDNP DYQQDFFPKE AKPNGIFKGS TAENAEYLRV 1210 APQSSEFIGA By “Epidermal Growth Factor Receptor (EGFR) Polynucleotide” is meant a nucleic acid molecule encoding an EGFR polypeptide or fragment thereof. An exemplary polynucleotide encoding EGFR is provided at NCBI Reference Sequence: NM_001346897.1, which is reproduced below: 1 gtccgggcag cccccggcgc agcgcggccg cagcagcctc cgccccccgc acggtgtgag 61 cgcccgacgc ggccgaggcg gccggagtcc cgagctagcc ccggcggccg ccgccgccca 121 gaccggacga caggccacct cgtcggcgtc cgcccgagtc cccgcctcgc cgccaacgcc 181 acaaccaccg cgcacggccc cctgactccg tccagtattg atcgggagag 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 ccagggactg 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 tgggagaaaa caacaccctg gtctggaagt acgcagacgc cggccatgtg tgccacctgt 1981 gccatccaaa ctgcacctac ggatgcactg ggccaggtct tgaaggctgt ccaacgaatg 2041 ggcctaagat cccgtccatc gccactggga tggtgggggc cctcctcttg ctgctggtgg 2101 tggccctggg gatcggcctc ttcatgcgaa ggcgccacat cgttcggaag cgcacgctgc 2161 ggaggctgct gcaggagagg gagcttgtgg agcctcttac acccagtgga gaagctccca 2221 accaagctct cttgaggatc ttgaaggaaa ctgaattcaa aaagatcaaa gtgctgggct 2281 ccggtgcgtt cggcacggtg tataagggac tctggatccc agaaggtgag aaagttaaaa 2341 ttcccgtcgc tatcaaggaa 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 cctatcaagt 2761 ggatggcatt ggaatcaatt ttacacagaa tctataccca ccagagtgat gtctggagct 2821 acggggtgac tgtttgggag ttgatgacct ttggatccaa gccatatgac ggaatccctg 2881 ccagcgagat ctcctccatc ctggagaaag gagaacgcct ccctcagcca cccatatgta 2941 ccatcgatgt ctacatgatc atggtcaagt gctggatgat agacgcagat agtcgcccaa 3001 agttccgtga gttgatcatc gaattctcca aaatggcccg agacccccag cgctaccttg 3061 tcattcaggg ggatgaaaga atgcatttgc caagtcctac agactccaac ttctaccgtg 3121 ccctgatgga tgaagaagac atggacgacg tggtggatgc cgacgagtac ctcatcccac 3181 agcagggctt cttcagcagc ccctccacgt cacggactcc cctcctgagc tctctgagtg 3241 caaccagcaa caattccacc gtggcttgca ttgatagaaa tgggctgcaa agctgtccca 3301 tcaaggaaga cagcttcttg cagcgataca gctcagaccc cacaggcgcc ttgactgagg 3361 acagcataga cgacaccttc ctcccagtgc ctggtgagtg gcttgtctgg aaacagtcct 3421 gctcctcaac ctcctcgacc cactcagcag cagccagtct ccagtgtcca agccaggtgc 3481 tccctccagc atctccagag ggggaaacag tggcagattt gcagacacag tgaagggcgt 3541 aaggagcaga taaacacatg accgagcctg cacaagctct ttgttgtgtc tggttgtttg 3601 ctgtacctct gttgtaagaa tgaatctgca aaatttctag cttatgaagc aaatcacgga 3661 catacacatc tgtgtgtgtg agtgttcatg atgtgtgtac atctgtgtat gtgtgtgtgt 3721 gtatgtgtgt gtttgtgaca gatttgatcc ctgttctctc tgctggctct atcttgacct 3781 gtgaaacgta tatttaacta attaaatatt agttaatatt aataaatttt aagctttatc 3841 cagaaaaaaa aaaaaaaaa By "fragment" is meant a portion of a polypeptide or nucleic acid molecule. This portion contains, preferably, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the entire length of the reference nucleic acid molecule or polypeptide. A fragment may contain 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 nucleotides or amino acids. 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, are one further aspect of the present invention. Preferred intermediates are the Intermediate Examples as disclosed below. General Procedures Scheme 1: Scheme 1: Route for the preparation of compounds of formula (I), wherein R4aand R4bare defined as hydrogen atoms, and R1, R2, R3, R4c, R4d, R4e, and R4fhave the meaning as given for formula (I) and PG can be hydrogen or optionally a suitable protecting group, e.g. tert- butoxycarbonyl (Boc), and LG, is a suitable leaving group such as a halide or sulfonate as known to one skilled in the art. For simplicity the starting material 1, has been depicted as a ethyl ester, however other esters, such as a methyl ester could also be utilized the sequence shown here. Compounds of the formula 1 can be converted to compounds of the formula 2 using various methods include alkylation with various electrophiles such as halides, or with groups such as mesyl or tosyl, or by direct reaction of alcohols in the presence of triphenylphosphine with azo compounds (Mitsonubu type reactions).2 can be converted to compounds of the formula 3 by reduction, with reagents such as sodium borohydride or lithium aluminium hydride in a suitable solvent. Formula 3 can be converted to compounds of the type 4 by reaction with, for instance mesyl chloride, to convert the corresponding alcohol into a suitable leaving group (LG). Additionally, chlorination with a reagent such as thionyl chloride, could be used to produce a compound of type 4 where the LG is chlorine. Formula 4 can be converted to compounds of the type 5 by treatment with a suitable base such as sodium hydride or potassium carbonate, at a temperature between the freezing point and boiling point of a suitable solvent such as but not limited to, DMF, THF or acetonitrile, as governed by the reactivity and nature of the leaving group, as known to one skilled in the art. Formula 5 can be converted to compounds of the type 6 with reagents such as N-iodosuccinimide in a suitable solvent such as DCE, DMF or MeCN in a temperature range from -30°C to the boiling point of the respective solvent. Compounds of the formular 6 can be converted to compounds of the formula 7 by reacting for example suitable boronic acids in a Suzuki-type reaction, using for instance, DPPF ligated palladium dichloride, in the presence of a base such as sodium carbonate and a suitable solvent system such as dioxane and water. Forumla 7 can be converted to compounds of nature 8 by reacting for example, suitable boronic acids in a Suzuki-type reaction, performed at a suitable temperature (generally between RT and 110ºC), as known to one skilled in the art. For instance, DPPF ligated palladium dichloride, in the presence of a base such as sodium carbonate and a suitable solvent system such as dioxane and water at 110ºC in the presence of a boronic acid or ester produces compounds of formula 8. In cases in which PG represents a protecting group such as tert-butoxycarbonyl, compounds of the formula 9 can be prepared from compounds of the formula 8 by deprotection reactions, using for instance HCl in various solvents such as DCM, EtOAc or dioxane, as known to those skilled in the art (or as generally described in the chemical literature such as in Greens Protecting Group in Organic Chemistry). Compounds of the formula 9 can be converted to compounds of the formula 10 using various methods. Depending on the nature of R3corresponding acid chlorides, sulfonylchlorides or other electrophiles can be used under basic conditions in a suitable solvent. If carboxylic acids are employed the corresponding reaction can be facilitated by the use coupling reagents such as HATU, EDC -HOBt or T3P from -30°C to the boiling point of the respective solvent. Additional transformations on the groups R4a, R4b, R4c, R4d, R4eand R4fmay also be undertaken at suitable stages in the sequence described above, for instance cleavage of protecting groups, reductions or oxidations, and further manipulations, as known to one skilled in the art. Furthermore, the sequence shown here may be altered, for instance formula type 5, could be subjected to an arylation reaction replacing the here depicted bromide, and then subsequently halogenated, and duly subjected to a second arylation reaction, affording compounds of formula type 8, as obvious to one skilled in the art. Scheme 2: 19202122(I) Scheme 2: Route for the preparation of compounds of formula (I), wherein R4aand R4bare defined as hydrogen atoms, and R1, R2, R3, R4c, R4d, R4e, and R4fhave the meaning as given for formula (I) and PG can be hydrogen or optionally a suitable protecting group, e.g. tert- butoxycarbonyl (Boc), and LG, is a suitable leaving group such as a halide or sulfonate as known to one skilled in the art. For simplicity the starting material 11, has been depicted as a methyl ester, however other esters such as a ethyl, could also be utilized the sequence shown here. Compound 11 could be, but not must be, suitably protected, for instance using a protecting group such as SEM. For instance a reagent like [2- (chloromethoxy)ethyl](trimethyl)silane, with a base such as sodium hydride in a solvent such as THF, at a suitable reaction temperature, as known to those skilled in the art (or as generally described in the chemical literature such as in Greens Protecting Group in Organic Chemistry). Compounds of formular 12 can be converted to compounds of the formula 13 by reacting for example suitable boronic acids, in the presence of a suitable catalyst, ligand, base and solvent system, in a Suzuki-type reaction. For instance, DPPF ligated palladium dichloride, in the presence of a sodium carbonate, in a mixture of water and 1,4 dioxane, and a bronic acid or ester, at a reaction temperature between RT and 110ºC could be used to produce compounds of type 13. If required, deprotection of compound type 13, can be performed. For instance if the protection group used is SEM, exposed to an acid such as TFA in a solvent system such as DCM, could yield compounds of type 14. Halogenation of 14, using for instance a reagent such as NIS, in a solvent such as DMF, at a suitable temperature such as 50ºC, produces compound of type 15. Exposure of compounds of type 15 to Suzuki type of reaction conditions, using for instance caesium fluoride or sodium carbonate, with DPPF ligated palladium dichloride, in a mixture of water and 1,4 dioxane, and the presence of a boronic acid or ester, at a reaction temperature of for instance 110ºC, yield formula 16, as known to one skilled in the art. Analagously to Scheme 1, alkylation of 16, using various methods include with various electrophiles such as halides, or with groups such as mesyl or tosyl, or by direct reaction of alcohols in the presence of triphenylphosphine with azo compounds (Mitsonubu type reactions) furnish compounds of formula 17, which can in turn be reduced by a suitable reagent, such as lithium aliminium hydride in a solvent such as THF, at a suitable temperature such as -30ºC to yield compounds of formula 18. Formula 18, can be converted to compounds of the type 19 by reaction with, for instance mesyl chloride, to convert the corresponding alcohol into a suitable leaving group (LG), or chlorination with a reagent such as thionyl chloride, could be used to produce a compound of type 4 where the LG is chlorine. Cyclisation of formula type 19, using for instance a suitable base such as sodium hydride, in a solvent such as but not limited to for instance THF, at a temperature such as 25ºC, yields type 20, as known to one skilled in the art. In cases in which PG represents a protecting group such as tert- butoxycarbonyl, compounds of the formula 21 can be prepared from compounds of the formula 20 by deprotection reactions, using for instance HCl in various solvents such as DCM, EtOAc or dioxane, as known to those skilled in the art (or as generally described in the chemical literature such as in Greens Protecting Group in Organic Chemistry). Compounds of the formula 9 can be converted to compounds of the formula 10 using various methods, analogously to Scheme 1 (in the transformations of type 9 to 10), depending on the nature of R3, as known to one skilled in the art. Scheme 3:

[0002] Scheme 3: Route for the preparation of compounds of formula (I), wherein atom and R1, R2, R3, R4a, R4b, R4c, R4d, R4e, and R4fhave the meaning as given for formula (I) and PG can be hydrogen or optionally a suitable protecting group, e.g. tert-butoxycarbonyl (Boc). A compound of type 23 (here described as a ethyl ester, but not limited to specifically this ester), could be converted to formula 24 using various methods include alkylation with various electrophiles such as halides, or with groups such as mesyl or tosyl, or by direct reaction of alcohols in the presence of triphenylphosphine with azo compounds (Mitsonubu type reactions). Base or acid catalyzed hydrolysis of the ester produces compounds of formula type 25. Formation of a so called Weinreb-amide by reaction of the corresponding acid with the corresponding amine, facilitated by an amide coupling reagent such as HATU, generates formula 26, which when reacted with a suitable organometallic reagent, for instance a Grignard or alkyl lithium species, as known to one skilled in the art, can be used to generate formula type 27. Deprotection generates an imine of formula 28, which in turn may be reduced with a suitable hydride source such as sodium cyanoborohydride, or subjected to further transformations, as known to one skilled in the art to generate formula type 29. Analogously to Scheme 1 and 2, formula type 29 can be converted to formula of type 34 by an iodination reaction, two sequential Suzuki reactions, cleavage of the protecting group (if required) and final amide formation, as known to one skilled in the art and governed by the nature of the R1, R2, R3, R4a, R4b, R4c, R4d, R4e, and R4fgroups. Scheme 4: 47 (I) Scheme 4: Route for the preparation of compounds of formula (I), wherein atom and R1, R2, R3, R4a, R4b, R4c, R4d, R4e, and R4fhave the meaning as given for formula (I) and PG can be hydrogen or optionally a suitable protecting group, e.g. tert-butoxycarbonyl (Boc). Analagous to Scheme 3, compounds of type 35 can be converted to compounds of type 38, as known to one skilled in the art, through a sequential alkylation, hydrolysis of the ester, amide formation sequence. Formula 38, can be converted to 39, by exposure to so called Suzuki type of reaction conditions, using for instance, sodium carbonate as a suitable base, with DPPF ligated palladium dichloride, in a mixture of water and 1,4 dioxane, and a suitable boronic acid or ester, at a reaction temperature of for instance 90ºC, to produce compounds of type 39. Reaction of formula 39, with a suitable organometallic reagent, for instance an aryl lithium species, in a solvent such as THF, at a temperature of for instance -50ºC, can be used to generate formula type 40 as known to one skilled in the art. Deprotection of for instance a BOC group using TFA in DCM, generates an imine of formula 41, which in turn may be reduced with a suitable hydride source such as sodium cyanoborohydride in a solvent such as methanol in the presence of acetic acid, producing formula type 42. If required, the free amine may be protected with, for instance a BOC group using di-tert-butyl carbonate in a suitable solvent such as DCM in the presence of a base such as triethylamine, yielding formula 43 (or as generally described in the chemical literature such as in Greens Protecting Group in Organic Chemistry). Formular 43 can be halogenated using a reagent such as NIS in a solvent such as DMF at a temperature such as 50ºC (to produce formula type 44). Formula type 44 may then be converted to formula 47, using the aforementioned sequences described in Scheme 1-3, by two sequential arylation reactions, for example two Suzuki reactions, deprotection, if required, and finally amide formation, generating formula type 47, as known to one skilled in the art, depending on the nature of the groups R1, R2, R3, R4a, R4b, R4c, R4d, R4e, and R4fpresent. Scheme 5: Scheme 5: Route for the preparation of compounds of formula (I), wherein R4a, are hydrogen atoms, and R1, R2, R3, R4c, R4d, R4e, and R4fhave the meaning as given for formula (I) and PG can be hydrogen or optionally a suitable protecting group, e.g. tert- butoxycarbonyl (Boc). A compound of type 48 (here described as a methyl ester, but not limited to specifically this ester), could be converted to formula 49 using various methods include alkylation with various electrophiles such as halides, or with groups such as mesyl or tosyl, or by direct reaction of alcohols in the presence of triphenylphosphine with azo compounds (Mitsonubu type reactions). Removal of the protecting group (PG), by for instance treatment with hydrochloric acid (when the protecting group is BOC), yields a compound of formula 50, which can be cyclized to formula 51, by for instance treatment with a base such as triethylamine in a suitable solvent such as methanol, or using sodium carbonate in dioxane. Conversion of formula 51 to formula 52 using a so called Suyuki reaction, an known to one skilled in the art, can be accomplished by reaction with for instance a boronic acid in the presence of a suitable catalyst such as palladium ligated by a ligand such as DPPF, a suitable base such as sodium carbonate and solvent system such as water and dioxane at a suitable reaction temperature (between RT and 110ºC). Reduction of the lactam with a suitable reagent, such as but not limited to borane dimethyl sulfide, yields formula 53, which can, but not must be suitably protected, as for instance a carbamate, yielding formula type 54. Analogously to Scheme 1-4, 54 can be converted to compounds of the type 58 by a sequence of halogenation, Suzuki reaction, deprotection and amide formation, as known to one skilled in the art and depending on the exact natureof the groups R1, R2, R3, R4a, R4b, R4c, R4d, R4e, and R4f.It is known to the person skilled in the art that, if there are a number of reactive centers on a starting or intermediate compound, it may be necessary to block one or more reactive centers temporarily by protective groups in order to allow a reaction to proceed specifically at the desired reaction center. The compounds according to the invention are isolated and purified in a manner known per se, e.g. by distilling off the solvent in vacuo and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as chromatography on a suitable support material. Furthermore, reverse phase preparative HPLC may be applied. The compounds of the present invention which possess a sufficiently basic or acidic functionality, may result as a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example. Salts of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. Additionally, the drying process during the isolation of the compounds of the present invention may not fully remove traces of cosolvents, especially such as formic acid or trifluoroacetic acid, to give solvates or inclusion complexes. The person skilled in the art will recognise which solvates or inclusion complexes are acceptable to be used in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base, free acid, solvate, inclusion complex) of a compound of the present invention as isolated and described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity. Salts of the compounds of formula (I) according to the invention can be obtained by dissolving the free compound in a suitable solvent (for example a ketone such as acetone, methylethylketone or methylisobutylketone, 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 then added. The acid or base can be employed in salt preparation, depending on whether a mono- or polybasic acid or base is concerned and depending on which salt is desired, in an equimolar ratio or one differing therefrom. The salts are obtained by filtering, reprecipitating, precipitating with a non-solvent for the salt or by evaporating the solvent. Salts obtained can be converted into the free compounds which, in turn, can be converted into salts. In this manner, pharmaceutically unacceptable salts, which can be obtained, for example, as process products in the manufacturing on an industrial scale, can be converted into pharmaceutically acceptable salts by processes known to the person skilled in the art. Especially preferred are hydrochlorides and the process used in the example section. Pure diastereomers and pure enantiomers of the compounds and salts according to the invention can be obtained e.g. by asymmetric synthesis, by using chiral starting compounds in synthesis or by splitting up enantiomeric and diasteriomeric mixtures obtained in synthesis. Enantiomeric and diastereomeric mixtures can be split up into the pure enantiomers and pure diastereomers by methods known to the person skilled in the art. In one embodiment, diastereomeric mixtures are separated by crystallization, in particular fractional crystallization, or chromatography. Enantiomeric mixtures can be separated e.g. by forming diastereomers with a chiral auxillary agent, resolving the diastereomers obtained and removing the chiral auxillary agent. As chiral auxillary agents, for example, chiral acids can be used to separate enantiomeric bases such as e.g. mandelic acid and chiral bases can be used to separate enantiomeric acids by formation of diastereomeric salts. Furthermore, 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, respectively, as chiral auxillary agents. Additionally, diastereomeric complexes or diastereomeric clathrates may be used for separating enantiomeric mixtures. Alternatively, enantiomeric mixtures can be split up using chiral separating columns in chromatography. Another suitable method for the isolation of enantiomers is the enzymatic separation. Compounds featuring atropisomerism and an additional asymmetric centre can exist as diasteromeric mixtures and can be split up into the pure enantiomers and pure diastereomers as described supra. In certain compounds of the present invention, optionally asymmetry may be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds. Atropisomers represent a subclass of conformers which arise from restricted rotation around a single bond. The conformers (called atropisomers) can be isolated as separated species (IUPAC Gold book, http: / / goldbook.iupac.org / A00511.html; Pure and Appl. Chem., 2009, 68, 2193-2222). This induced chirality belongs to the axial type of chirality. Hence, compounds featuring said atropisomerism and an additional asymmetric centre can exist as diasteromeric mixtures as described supra. Several related compounds with the related type of atropisomerism have been already described as observed in the literature (G. Bringmann et al., Chem. Rev., 2011, 111, 563- 639). For examples of atropisomers in drug discovery, see the mini-review from J. Clayden, S. R. Laplante et al.: Angew. Chem. Int. Ed.2009, 48, 6398-6401 and also: S. R. LaPlante, P. J. Edwards et al., J. Med. Chem.2011, 54, 7005-7022. It is known to the person skilled in the art that, if there are a number of reactive centers on a starting or intermediate compound, it may be necessary to block one or more reactive centers temporarily by protective groups in order to allow a reaction to proceed specifically at the desired reaction center. The compounds according to the invention are isolated and purified in a manner known per se, e.g. by distilling off the solvent in vacuo and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as chromatography on a suitable support material. Furthermore, reverse phase preparative HPLC may be applied. The compounds of the present invention which possess a sufficiently basic or acidic functionality, may result as a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example. Salts of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. Additionally, the drying process during the isolation of the compounds of the present invention may not fully remove traces of cosolvents, especially such as formic acid or trifluoroacetic acid, to give solvates or inclusion complexes. The person skilled in the art will recognise which solvates or inclusion complexes are acceptable to be used in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base, free acid, solvate, inclusion complex) of a compound of the present invention as isolated and described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity. Salts of the compounds of formula (I) according to the invention can be obtained by dissolving the free compound in a suitable solvent (for example a ketone such as acetone, methylethylketone or methylisobutylketone, 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 then added. The acid or base can be employed in salt preparation, depending on whether a mono- or polybasic acid or base is concerned and depending on which salt is desired, in an equimolar ratio or one differing therefrom. The salts are obtained by filtering, reprecipitating, precipitating with a non-solvent for the salt or by evaporating the solvent. Salts obtained can be converted into the free compounds which, in turn, can be converted into salts. In this manner, pharmaceutically unacceptable salts, which can be obtained, for example, as process products in the manufacturing on an industrial scale, can be converted into pharmaceutically acceptable salts by processes known to the person skilled in the art. Especially preferred are hydrochlorides and the process used in the example section. Pure diastereomers and pure enantiomers of the compounds and salts according to the invention can be obtained e.g. by asymmetric synthesis, by using chiral starting compounds in synthesis or by splitting up enantiomeric and diasteriomeric mixtures obtained in synthesis. Enantiomeric and diastereomeric mixtures can be split up into the pure enantiomers and pure diastereomers by methods known to the person skilled in the art. In one embodiment, diastereomeric mixtures are separated by crystallization, in particular fractional crystallization, or chromatography. Enantiomeric mixtures can be separated e.g. by forming diastereomers with a chiral auxillary agent, resolving the diastereomers obtained and removing the chiral auxillary agent. As chiral auxillary agents, for example, chiral acids can be used to separate enantiomeric bases such as e.g. mandelic acid and chiral bases can be used to separate enantiomeric acids by formation of diastereomeric salts. Furthermore, 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, respectively, as chiral auxillary agents. Additionally, diastereomeric complexes or diastereomeric clathrates may be used for separating enantiomeric mixtures. Alternatively, enantiomeric mixtures can be split up using chiral separating columns in chromatography. Another suitable method for the isolation of enantiomers is the enzymatic separation. Compounds featuring atropisomerism and an additional asymmetric centre can exist as diasteromeric mixtures and can be split up into the pure enantiomers and pure diastereomers as described supra. One preferred aspect of the invention is the process for the preparation of the compounds of claims 1-4 according to the examples as well as the intermediates used for their preparation. Optionally, compounds of the formula (I) can be converted into their salts, or, optionally, salts of the compounds of the formula (I) can be converted into the free compounds. Corresponding processes are customary for the skilled person. Commercial utility As mentioned supra, the compounds of the present invention have surprisingly been found to effectively inhibit mutant EGFR in a cell (e.g., a cancer cell) contacted with the compound, thereby inducing cell death (e.g., apoptosis) and may therefore be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, or diseases which are accompanied with uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses is mediated by mutant EGFR, such as, for example, benign and malignant neoplasia, more specifically haematological tumours, solid tumours, and / or metastases thereof, e.g. leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and / or metastases thereof, especially haematological tumours, solid tumours, and / or metastases of breast, bladder, bone, brain, central and peripheral nervous system, cervix, colon, endocrine glands (e.g., thyroid and adrenal cortex), endocrine tumours, endometrium, esophagus, gastrointestinal tumours, germ cells, kidney, liver, lung, larynx and hypopharynx, mesothelioma, ovary, pancreas, prostate, rectum, renal, small intestine, soft tissue, stomach, skin, testis, ureter, vagina and vulva as well as malignant neoplasias including primary tumours in said organs and corresponding secondary tumours in distant organs (“tumour metastases”). Haematological tumours can, e.g., be exemplified by aggressive and indolent forms of leukemia and lymphoma, namely non-Hodgkins disease, chronic and acute myeloid leukemia (CML / AML), acute lymphoblastic leukemia (ALL), Hodgkins disease, multiple myeloma and T-cell lymphoma. Also included are myelodysplastic syndrome, plasma cell neoplasia, paraneoplastic syndromes, and cancers of unknown primary site, as well as AIDS related malignancies. A further aspect of the invention is the use of the compounds according to formula (I) for the treatment of lung cancer, particularly lung cancer harboring mutant EGFR with exon 20 insertion mutations, more particularly lung cancer harboring V769_770ins ASV and / or D770_N771ins SVD exon 20 insertions, and / or metastases thereof, comprising administering an effective amount of a compound of formula (I). A further aspect of the invention is the use of the compounds according to formula (I) for the treatment of lung cancer, particularly lung cancer harboring a mutant EGFR with in- frame deletions in exon 19 (such as EGFR E746_A750del) or point mutations in exon 21 (e.g. L858R), and / or metastases thereof. A further aspect of the invention is the use of the compounds according to formula (I) for the treatment of lung cancer, particularly lung cancer harboring a mutant EGFR with a D770_N771insSVD C797S, E746_A750del C797S, or L858R C797S acquired resistance mutation, and / or metastases thereof. A further aspect of the invention is the use of the compounds according to formula (I) for the treatment of lung cancer, particularly lung cancer harboring a mutant ERBB2 with exon 20 insertion mutations (such as ERBB2 A775_G776insYVMA), and / or metastases thereof. In accordance with an aspect of the present invention therefore the invention relates to a compound of formula I, or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer particularly a pharmaceutically acceptable salt thereof, or a mixture of same, as described and defined herein, for use in the treatment or prophylaxis of a disease, especially for use in the treatment of a disease. Another particular aspect of the present invention is therefore the use of a compound of formula I, described supra, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, for the prophylaxis or treatment of hyperproliferative disorders or disorders responsive to induction of cell death, i.e., apoptosis. By “hyperproliferative disease” is meant a disease, such as cancer, associated with inappropriately high levels of cell division, inappropriately low levels of apoptosis, or both. The term “inappropriate” within the context of the present invention, in particular in the context of “inappropriate cellular immune responses, or inappropriate cellular inflammatory responses”, as used herein, is to be understood as generally meaning a response, which is less than, or greater than normal, and which is associated with, responsible for, or results in, the pathology of said diseases. In particular embodiments, the use is in the treatment or prophylaxis of diseases, especially the treatment, wherein the diseases are haematological tumours, solid tumours and / or metastases thereof. Another aspect is the use of a compound of formula (I) for the prophylaxis and / or treatment of lung cancer, particularly lung cancer harboring mutant EGFR with exon 20 insertion mutations, more particularly lung cancer harboring V769_770ins ASV and / or D770_N771ins SVD exon 20 insertions, and / or metastases thereof, especially preferred for the treatment thereof. Another aspect of the present invention is the use of a compound of formula (I) or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, as described herein, in the manufacture of a medicament for the treatment or prophylaxis of a disease, wherein such disease is a hyperproliferative disorder or a disorder responsive to induction of cell death e.g., apoptosis. In an embodiment the disease is a haematological tumour, a solid tumour and / or metastases thereof. In another embodiment the disease is lung cancer, particularly lung cancer harboring mutant EGFR with exon 20 insertion mutations, more particularly lung cancer harboring V769_770ins ASV and / or D770_N771ins SVD exon 20 insertions, and / or metastases thereof. Method of treating hyper-proliferative disorders The present invention relates to a method for using the compounds of the present invention and compositions thereof, to treat mammalian hyper-proliferative disorders. Compounds can be utilized to inhibit, block, reduce, decrease, etc., cell proliferation and / or cell division, and / or produce cell death e.g. apoptosis. This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof; etc. which is effective to treat the disorder. Hyper-proliferative disorders include but are not limited, e.g., psoriasis, keloids, and other hyperplasias affecting the skin, benign prostate hyperplasia (BPH), solid tumours, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include lymphomas, sarcomas, and leukaemias. 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 cancers of the respiratory tract include, but are not limited to small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma. Examples of brain cancers include, but are not limited to brain stem and hypothalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumour. Tumours of the male reproductive organs include, but are not limited to prostate and testicular cancer. Tumours of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus. Tumours of the digestive tract include, but are not limited to anal, colon, colorectal, oesophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers. Tumours of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers. Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma. Examples of liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma. Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi’s sarcoma, malignant melanoma, inverted sinonasal papilloma, inverted sinonasal papilloma- associated sinonasal squamous cell carcinoma, Merkel cell skin cancer, and non- melanoma skin cancer. Head-and-neck cancers include, but are not limited to laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, inverted sinonasal papilloma, inverted sinonasal papilloma-associated sinonasal squamous cell carcinoma, lip and oral cavity cancer and squamous cell. Lymphomas include, but are not limited to AIDS-related lymphoma, non- Hodgkin’s lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin’s disease, and lymphoma of the central nervous system. Sarcomas include, but are not limited to sarcoma of the soft tissue, 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 a similar etiology in other mammals, and can be treated by administering pharmaceutical compositions of the present invention. The term “treating” or “treatment” as stated throughout this document is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of, etc., of a disease or disorder, such as a carcinoma. The present invention relates to a method of treating cancer in a subject, the method comprising administering to the subject an effective amount of a compound of formula (I) as defined herein. The present invention relates to a method of treating cancer in a subject, wherein the cancer is or has acquired resistance to an anti-EGF receptor therapy, the method comprising administering to the subject an effective amount of a compound of formula (I) as defined herein. The present invention relates to a method of enhancing the efficacy of an anti-EGF-receptor therapy, the method comprising administering to the subject an anti-EGF receptor therapy in combination with a a compound of formula (I) as defined herein. In a further embodiment, the present invention relates to a method of treating cancer in a subject, wherein the cancer is selected from the group consisting of leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumours, tumours of the thorax, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours, skin tumours, and sarcomas, the method comprising administering to the subject an effective amount of a compound of formula (I) as defined herein. In a further embodiment, the present invention relates to a method of treating cancer in a subject, wherein the cancer is selected from the group consisting of inverted sinonasal papilloma or inverted sinonasal papilloma associated sinanonasal squamous cell carcinoma, the method comprising administering to the subject an effective amount of a compound of formula (I) as defined herein. In a further embodiment, the present invention relates to a method of treating cancer in a subject, wherein the tumour of the thorax is non-small cell lung cancer, the method comprising administering to the subject an effective amount of a compound of formula (I) as defined herein. In a further embodiment, the present invention relates to a method of treating cancer in a subject, wherein the cancer is lung cancer, particularly lung cancer harboring a mutant EGFR with in-frame deletions in exon 19 (such as EGFR E746_A750del) or point mutations in exon 21 (e.g. L858R), and / or metastases thereof, the method comprising administering to the subject an effective amount of a compound of formula (I) as defined herein. In a further embodiment, the present invention relates to a a method of treating cancer in a subject, wherein the cancer is lung cancer, particularly lung cancer harboring a mutant EGFR with a D770_N771insSVD C797S, E746_A750del C797S, or L858R C797S acquired resistance mutation, and / or metastases thereof, the method comprising administering to the subject an effective amount of a compound of formula (I) as defined herein. In a further embodiment, the present invention relates to a a method of treating cancer in a subject, wherein the cancer is lung cancer, particularly lung cancer harboring a mutant ERBB2 with exon 20 insertion mutations (such as ERBB2 A775_G776insYVMA), and / or metastases thereof, the method comprising administering to the subject an effective amount of a compound of formula (I) as defined herein. The present disclosure is also related to method of selecting a patient for cancer treatment with a compound of formula (I) comprising detecting the presence of a mutation in exon 20 of the gene encoding the EGF-receptor in a biological sample of the subject, thereby determining that the patient should be treated with said compound. In some embodiments, the EGFR comprises aD770_N771insSVD C797S, E746_A750del C797S, or L858R C797S acquired resistance mutation, and / or metastases thereof. In some embodiments, the method of selecting a patient for cancer treatment with a compound of formula (I) may comprise detecting the presence of in-frame deletions in exon 19 or point mutations in exon 21 of the gene encoding EGF-receptor in a biological sample of the subject, thereby determining that the patient should be treated with said compound. For example, the in- frame deletion in exon 19 may be EGFR E746_A750del or the point mutation in exon 21 may be L858R. In some embodiments, the method of selecting a patient for cancer treatment with a compound of formula (I) may comprise detecting the presence of 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 said compound. In some embodiments, the ERBB2 comprises an ERBB2 A775 or_G776insYVMA insertion mutation, and / or metastases thereof. Furthermore, methods of treating a patient with cancer may comprise administering to the subject a compound of formula (I) (e.g., in combination with anti-EGF receptor therapy), wherein the subject is selected for therapy by detecting the presence of a mutation in EGFR in a biological sample of the subject. In some embodiments, the method may comprise obtaining a biological sample from a subject and detecting a mutation in exon 19, 20, or 21 of the gene encoding EGF-receptor in the biological sample obtained from the subject. Detection of the presence of a mutation in exon 20 is within the skill of one of the art. In embodiments, the disclosure provides a method of treating a selected subject, the method comprising administering to the selected subject a compound described herein, wherein the subject is selected by detecting a mutant EGFR comprising an in-frame deletion in exon 19 (e.g., EGFR E746_A750del) or a point mutations in exon 21 (e.g. L858R). In some embodiments, the detection of a mutation (e.g., in an EGFR or a mutaton in exon 20 of the gene encoding EGFR) may be performed by sequencing (e.g., Sanger, Next Generation Sequencing) or a method selected from the group consisting of immunoblotting, mass spectrometry, immunoprecipitation quantitative PCR, Northern Blot, microarray, enzyme-linked immunosorbent assay (ELISA), in situ hybridization, and combinations thereof. Methods of treating kinase disorders The present invention also provides methods for the treatment of disorders associated with aberrant mitogen extracellular kinase activity, including, but not limited to stroke, heart failure, hepatomegaly, cardiomegaly, diabetes, Alzheimer's disease, cystic fibrosis, symptoms of xenograft rejections, septic shock or asthma. Effective amounts of compounds of the present invention can be used to treat such disorders, including those diseases (e.g., cancer) mentioned in the Background section above. Nonetheless, such cancers and other diseases can be treated with 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 the gene encoding the kinase or of the polypeptide it encodes. Examples of such aberrant activity, include, but are not limited to, over-expression of the gene or polypeptide; gene amplification; mutations which produce constitutively- active or hyperactive kinase activity; gene mutations, deletions, substitutions, additions, etc. The present invention also provides for methods of inhibiting kinase activity, especially of mitogen extracellular kinase, comprising administering an effective amount of a compound of the present invention, including salts, polymorphs, metabolites, hydrates, solvates, prodrugs (e.g.: esters) thereof, and diastereoisomeric forms thereof. Kinase activity can be inhibited in cells (e.g., in vitro), or in the cells of a mammalian subject, especially a human patient in need of treatment. Methods of treating angiogenic disorders The present invention also provides methods of treating disorders and diseases associated with excessive and / or abnormal angiogenesis. Inappropriate and ectopic expression of angiogenesis can be deleterious to an organism. A number of pathological conditions are associated with the growth of extraneous blood vessels. These include, e.g., diabetic retinopathy, ischemic retinal-vein occlusion, and retinopathy of prematurity [Aiello et al. New Engl. J. Med.1994, 331, 1480; Peer et al. Lab. Invest.1995, 72, 638], age-related macular degeneration [AMD; see, Lopez et al. Invest. Opththalmol. Vis. Sci. 1996, 37, 855], neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma, inflammation, rheumatoid arthritis (RA), restenosis, in-stent restenosis, vascular graft restenosis, etc. In addition, the increased blood supply associated with cancerous and neoplastic tissue, encourages growth, leading to rapid tumour enlargement and metastasis. Moreover, the growth of new blood and lymph vessels in a tumour provides an escape route for renegade cells, encouraging metastasis and the consequence spread of the cancer. Thus, compounds of the present invention can be utilized to treat and / or prevent any of the aforementioned angiogenesis disorders, e.g., by inhibiting and / or reducing blood vessel formation; by inhibiting, blocking, reducing, decreasing, etc. endothelial cell proliferation or other types involved in angiogenesis, as well as causing cell death e.g. apoptosis of such cell types. In various embodiments, the diseases of said method are haematological tumours, solid tumour and / or metastases thereof. The compounds of the present invention can be used in particular in therapy and prevention i.e. prophylaxis, especially in therapy of tumour growth and metastases, especially in solid tumours of all indications and stages with or without pre-treatment of the tumour growth. Pharmaceutical compositions of the compounds of the invention This invention also relates to pharmaceutical compositions containing one or more compounds of the present invention. These compositions can be utilised to achieve the desired pharmacological effect by administration to a patient in need thereof. A patient, for the purpose of this invention, is a mammal, including a human, in need of treatment for the particular condition, disorder, or disease. Therefore, the present invention includes pharmaceutical compositions that are comprised of a pharmaceutically acceptable carrier or auxiliary and a pharmaceutically effective amount of a compound, or salt thereof, of the present invention. Another aspect of the invention is a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula (I) and a pharmaceutically acceptable auxiliary for the treatment of a disease mentioned supra, especially for the treatment of haematological tumours, solid tumours and / or metastases thereof. A pharmaceutically acceptable carrier or auxiliary may be a carrier that is non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient. Carriers and auxiliaries are all kinds of additives assisting to the composition to be suitable for administration. A pharmaceutically effective amount of compound may be that amount which produces a result or exerts the intended influence on the particular condition being treated. The compounds of the present invention can be administered with pharmaceutically- acceptable carriers or auxiliaries well known in the art using any effective conventional dosage unit forms, including immediate, slow and timed release preparations, orally, parenterally, topically, nasally, ophthalmically, optically, sublingually, rectally, vaginally, and the like. For oral administration, the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions. The solid unit dosage forms can be a capsule that can be of the ordinary hard- or soft-shelled gelatine type containing auxiliaries, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch. In another embodiment, the compounds of this invention may be tableted with conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders such as acacia, corn starch or gelatine, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration, such as potato starch, alginic acid, corn starch, and guar gum, gum tragacanth, acacia, lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example talc, stearic acid, or magnesium, calcium or zinc stearate, dyes, colouring agents, and flavouring agents such as peppermint, oil of wintergreen, or cherry flavouring, 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 materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or capsules may be coated with shellac, sugar or both. 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 exemplified by those already mentioned above. Additional excipients, for example those sweetening, flavouring and colouring agents described above, may also be present. The pharmaceutical compositions of this invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils. Suitable emulsifying agents may be (1) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soy bean 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. The emulsions may also contain sweetening and flavouring agents. Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol. The suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate; one or more colouring agents; one or more flavouring agents; and one or more sweetening agents such as sucrose or saccharin. Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavouring and colouring agents. The compounds of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or interperitoneally, as injectable dosages of the compound in, for example, a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethyl-1,1-dioxolane-4-methanol, ethers such as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty acid glyceride, or an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable surfactant such as a soap or a detergent, suspending agent such as pectin, carbomers, methycellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agent and other pharmaceutical adjuvants. Illustrative of oils which can be used in the parenteral formulations of this invention are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum 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, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene- oxypropylene)s or ethylene oxide or propylene oxide copolymers; and amphoteric detergents, for example, alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammonium salts, as well as mixtures. The parenteral compositions of this invention will typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimise or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile-lipophile balance (HLB) in one embodiment of from about 12 to about 17. The quantity of surfactant in such formulation in one embodiment ranges from about 5% to about 15% by weight. The surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB. Illustrative of surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol. The pharmaceutical compositions may be in the form of sterile injectable aqueous suspensions. Such suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally occurring 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, heptadeca- ethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, for example 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 may be employed are, for example, water, Ringer’s solution, isotonic sodium chloride solutions and isotonic glucose solutions. In addition, sterile fixed oils are conventionally employed as solvents or suspending media. For this purpose, any bland, fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables. A composition of the invention may 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-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are, for example, cocoa butter and polyethylene glycol. Controlled release formulations for parenteral administration include liposomal, polymeric microsphere and polymeric gel formulations that are known in the art. It may be desirable or necessary to introduce the pharmaceutical composition to the patient via a mechanical delivery device. The construction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art. Direct techniques for administration, for example, administering a drug directly to the brain usually involve placement of a drug delivery catheter into the patient’s ventricular system to bypass the blood-brain barrier. One such implantable delivery system, used for the transport of agents to specific anatomical regions of the body, is described in US Patent No.5,011,472, issued April 30, 1991. The compositions of the invention can also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired. Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized. Such ingredients and procedures 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), 166-171. Commonly used pharmaceutical ingredients that can be used as appropriate 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); alkalinizing 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, CCl2F2, F2ClC- CClF2and CClF3); 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); antimicrobial preservatives (examples include but are not limited to benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal); antioxidants (examples include but are not limited to ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite); binding materials (examples include but are not limited to block polymers, natural and synthetic rubber, polyacrylates, polyurethanes, silicones, polysiloxanes and styrene- butadiene copolymers); buffering agents (examples include but are not limited to potassium metaphosphate, dipotassium phosphate, sodium acetate, sodium citrate anhydrous and sodium citrate dihydrate); carrying agents (examples include but are not limited to acacia syrup, aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection and bacteriostatic water for injection); chelating agents (examples include but are not limited to edetate disodium and edetic acid); colourants (examples include but are not limited to FD&C Red No.3, FD&C Red No. 20, FD&C Yellow No.6, FD&C Blue No.2, D&C Green No.5, D&C Orange No.5, D&C Red No.8, caramel and ferric oxide red); clarifying agents (examples include but are not limited to bentonite); emulsifying agents (examples include but are not limited to 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); flavourants (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 glycerol, propylene glycol and sorbitol); levigating agents (examples include but are not limited to mineral oil and glycerin); oils (examples include but are not limited to arachis oil, mineral oil, olive oil, peanut oil, sesame oil and vegetable oil); ointment bases (examples include but are not limited to lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment, and rose water ointment); penetration enhancers (transdermal delivery) (examples include but are not limited to monohydroxy or polyhydroxy alcohols, 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 glycerol); solvents (examples include but are not limited to ethanol, corn oil, cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection and sterile water for irrigation); stiffening agents (examples include but are not limited to cetyl alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl 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, oxtoxynol 9, polysorbate 80, sodium lauryl sulfate and sorbitan mono-palmitate); suspending agents (examples include but are not limited to agar, bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, kaolin, methylcellulose, tragacanth and veegum); sweetening agents (examples include but are not limited to aspartame, dextrose, glycerol, mannitol, propylene glycol, saccharin sodium, sorbitol and sucrose); tablet anti-adherents (examples include but are not limited to magnesium stearate and talc); tablet binders (examples include but are not limited to acacia, alginic acid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinyl pyrrolidone, and pregelatinized starch); tablet and capsule diluents (examples include but are not limited to dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol and starch); tablet coating agents (examples include but are not limited to liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, cellulose acetate phthalate and shellac); tablet direct compression excipients (examples include but are not limited to dibasic calcium phosphate); tablet disintegrants (examples include but are not limited to alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrillin potassium, cross- linked polyvinylpyrrolidone, sodium alginate, sodium starch glycollate and starch); tablet glidants (examples include but are not limited to colloidal silica, corn starch and talc); tablet lubricants (examples include but are not limited to calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc stearate); tablet / capsule opaquants (examples include but are not limited to titanium dioxide); tablet polishing agents (examples include but are not limited to carnuba wax and white wax); thickening agents (examples include but are not limited to beeswax, 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, carboxymethylcellulose sodium, methylcellulose, polyvinyl pyrrolidone, sodium alginate and tragacanth); and wetting agents (examples include but are not limited to heptadecaethylene oxycetanol, lecithins, sorbitol monooleate, polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate). Pharmaceutical compositions according to the present invention can be illustrated as follows: Sterile i.v. solution: A 5 mg / ml solution of the desired compound of this invention can be made using sterile, injectable water, and the pH is adjusted if necessary. The solution is diluted for administration to 1 – 2 mg / ml with sterile 5% dextrose and is administered as an i.v. infusion over about 60 minutes. Lyophilised powder for i.v. administration: A sterile preparation can be prepared with (i) 100 - 1000 mg of the desired compound of this invention as a lyophilised powder, (ii) 32- 327 mg / ml sodium citrate, and (iii) 300 – 3000 mg Dextran 40. The formulation is reconstituted with sterile, injectable saline or dextrose 5% to a concentration of 10 to 20 mg / ml, which is further diluted with saline or dextrose 5% to 0.2 – 0.4 mg / ml, and is administered either IV bolus or by IV infusion over 15 – 60 minutes. Intramuscular suspension: The following solution or suspension can be prepared, for intramuscular injection: 50 mg / ml of the desired, water-insoluble compound of this invention 5 mg / ml sodium carboxymethylcellulose 4 mg / ml TWEEN 80 9 mg / ml sodium chloride 9 mg / ml benzyl alcohol Hard Shell Capsules: A large number of unit capsules are prepared by filling standard two- piece hard galantine capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate. Soft Gelatin Capsules: A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into molten 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 prepare a water miscible medicine mix. Tablets: A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 mg of active ingredient, 0.2 mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg. of starch, and 98.8 mg of lactose. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption. Immediate Release Tablets / Capsules: These are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication. The active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques. The drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water. Dose and administration Based upon standard laboratory techniques known to evaluate compounds useful for the treatment of hyper-proliferative disorders and angiogenic disorders, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication. The amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated. The total amount of the 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 particular embodiments from about 0.01 mg / kg to about 20 mg / kg body weight per day. Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing. In addition, "drug holidays" in which a patient is not dosed with a drug for a certain period of time, may be beneficial to the overall balance between pharmacological effect and tolerability. A unit dosage may contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day. The average daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will in other embodiments be from 0.01 to 200 mg / kg of total body weight. The average daily rectal dosage regimen will in particular embodiments be from 0.01 to 200 mg / kg of total body weight. The average daily vaginal dosage regimen will in other embodiments be from 0.01 to 200 mg / kg of total body weight. The average daily topical dosage regimen will in still other embodiments be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will in other embodiments be that required to maintain a daily dose of from 0.01 to 200 mg / kg. The average daily inhalation dosage regimen will in other embodiments be from 0.01 to 100 mg / kg of total body weight. Of course the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests. Combination Therapies The compounds of this invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects. Those combined pharmaceutical agents can be other agents having antiproliferative effects such as for example for the treatment of haematological tumours, solid tumours and / or metastases thereof and / or agents for the treatment of undesired side effects. The present invention relates also to such combinations. Other anti-hyper-proliferative agents suitable for use with the composition of the invention include but are not limited to those compounds acknowledged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., publ. by McGraw-Hill, pages 1225-1287, (1996), which is hereby incorporated by reference, especially (chemotherapeutic) anti- cancer agents as defined supra. The combination can be a non-fixed combination or a fixed- dose combination as the case may be. Methods of testing for a particular pharmacological or pharmaceutical property are well known to persons skilled in the art. The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given. As will be appreciated by persons skilled in the art, the invention is not limited to the particular embodiments described herein, but covers all modifications of said embodiments that are within the spirit and scope of the invention as defined by the appended claims. The following examples illustrate the invention in greater detail, without restricting it. Further compounds according to the invention, of which the preparation is not explicitly described, can be prepared in an analogous way. The compounds, which are mentioned in the examples and the salts thereof represent preferred embodiments of the invention as well as a claim covering all subcombinations of the residues of the compound of formula (I) as disclosed by the specific examples. The term “according to” within the experimental section is used in the sense that the procedure referred to is to be used “analogously to”. EXPERIMENTAL SECTION Chemical names were generated using the ACD / Name software from ACD / Labs. In some cases generally accepted names of commercially available reagents were used in place of ACD / Name generated names. The following table 1 lists the abbreviations used in this paragraph and in the Examples section as far as they are not explained within the text body. Other abbreviations have their meanings customary per se to the skilled person. Table 1: Abbreviations Other abbreviations have their meanings customary per se to the skilled person. The various aspects of the invention described in this application are illustrated by the following examples which are not meant to limit the invention in any way. The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given. EXPERIMENTAL SECTION - GENERAL PART All reagents, for which the synthesis is not described in the experimental part, are either commercially available, or are known compounds or may be formed from known compounds by known methods by a person skilled in the art. The compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be removed by trituration using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g. Biotage SNAP cartridges KP-Sil®or KP-NH®in combination with a Biotage autopurifier system (SP4®or Isolera Four®) and eluents such as gradients of hexane / ethyl acetate or DCM / methanol. In flash column chromatography, unmodified (“regular”) silica gel may be used as well as aminophase functionalized silica gel. If reference is made to flash column chromatography or to flash chromatography in the experimental section without specification of a stationary phase, regular silica gel was used. In some cases, the compounds may be purified by preparative HPLC using for example a Waters autopurifier equipped with a diode array detector and / or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse 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 those compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example. A salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base etc.) of a compound of the present invention as isolated and as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity. Analytical LC-MS Methods: Method 1 Instrument: Agilent 1290 UPLCMS 6230 TOF; column: BEH C 181.7 μm, 50x2.1mm; Eluent A: water + 0.05 % formic acid (99%); Eluent B: acetonitrile + 0.05 % formic acid (99%); gradient: 0-1.72-90% B, 1.7-2.090% B; flow 1.2 ml / min; temperature: 60°C; DAD scan: 190-400 nm. Method 2: Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C181.7 μm, 50x2.1mm; 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; DAD scan: 210-400 nm. Method 3: Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C181.7 μm, 50x2.1mm; eluent A: water + 0.1 vol % formic acid (99%), eluent B: MeCN; gradient: 0-1.6min 1-99% B, 1.6-2.0min 99% B; flow 0.8 ml / min; temperature: 60°C; DAD scan: 210- 400 nm. Method 4: Instrument: Waters Acquity UPLCMS SingleQuad; Colum: Acquity UPLC BEH C181.7 50x2.1mm; 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; DAD scan: 210-400 nm Method A:0-60AB, Shimadzu Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Chromolith@Flash RP-18E 25- 2 MM; eluent A: water + 0.0375 vol% trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol% trifluoroacetic acid; gradient: 0-0.8 min 0-60% B, 0.8-1.2 min 60% B; flow 1.5 ml / min; temperature: 50 °C; PDA: 220 nm & 254 nm. Method B:0-60AB, Agilent Instrument: Agilent 1100\G1956A SingleQuad; Column: Kinetex@ 5um EVO C1830*2.1 mm; eluent A: water + 0.0375 vol% trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol% trifluoroacetic acid; gradient: 0-0.8 min 0-60% B, 0.8-1.2 min 60% B; flow 1.5 ml / min; temperature: 50 °C; PDA: 220 nm & 254 nm. Method C:5-95AB, Shimadzu Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Chromolith@Flash RP-18E 25- 2 MM; eluent A: water + 0.0375 vol% trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol% trifluoroacetic acid; gradient: 0-0.8 min, 5-95% B, 0.8-1.2 min 95% B; flow 1.5 ml / min; temperature: 50 °C; PDA: 220 nm & 254 nm. Method D:5-95AB, Agilent Instrument: Agilent 1100\G1956A SingleQuad; Column: Kinetex@ 5 μm EVO C1830*2.1 mm; eluent A: water + 0.0375 vol% trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol% trifluoroacetic acid; gradient: 0-0.8 min 5-95% B, 0.8-1.2 min 95% B; flow 1.5 ml / min; temperature: 50 °C; PDA: 220 nm & 254 nm. Method E:10-80CD, Agilent Instrument: Agilent 1200\G6110A SingleQuad; Column: XBridge C182.1*50 mm, 5 μm; eluent A: water + 0.025 vol% ammonium hydroxide, eluent B: acetonitrile; gradient: 0-1.2 min 10-80% B, 1.2-1.6 min 80% B; flow 1.2 ml / min; temperature: 40 °C; DAD: 220 nm & 254 nm. Method F:0-60CD, Agilent Instrument: Agilent 1200\G6110A SingleQuad; Column: XBridge C182.1*50 mm, 5 μm; eluent A: water + 0.025 vol% ammonium hydroxide, eluent B: acetonitrile; gradient: 0-1.2 min 0-60% B, 1.2-1.6 min 60% B; flow 1.0 ml / min; temperature: 40 °C; DAD: 220 nm & 254 nm. Method G:5-95CD, Shimadzu Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex EVO C182.1*30 mm, 5 μm; eluent A: water + 0.025 vol% ammonium hydroxide, eluent B: acetonitrile; gradient: 0-0.8 min, 5-95% B, 0.8-1.2 min 95% B; flow 1.5 ml / min; temperature: 40 °C; PDA: 220 nm & 254 nm. Method H:0-60CD, Shimadzu Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex EVO C182.1*30 mm, 5 μm; eluent A: water + 0.025 vol% ammonium hydroxide, eluent B: acetonitrile; gradient: 0-1.2 min, 0-60% B, 1.2-1.6 min, 60% B; flow 1.0 ml / min; temperature: 40 °C; PDA: 220 nm & 254 nm. Method I:5-95CD, Shimadzu Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex EVO C182.1*30 mm, 5um; eluent A: water + 0.025 vol% ammonium hydroxide, eluent B: acetonitrile; gradient: 0-0.8 min, 5-95% B, 0.8-1.2 min, 95% B; flow 1.5 ml / min; temperature: 40 °C; PDA: 220 nm & 254 nm. Method J:0-60CD, Shimadzu Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex EVO C182.1*30 mm, 5 μm; eluent A: water + 0.025 vol% ammonium hydroxide, eluent B: acetonitrile; gradient: 0-0.8 min, 0-60% B, 0.8-1.2 min, 60% B; flow 1.5 ml / min; temperature: 40 °C; PDA: 220 nm & 254 nm. NMR Spectra: The multiplicities of proton signals in1H NMR spectra given in the following paragraphs reflect the observed signal form and do not take into account any higher-order signal phenomena. As a rule, the chemical shift data refers to the center of the signal in question. In the case of wide multiplets, a range is specified. Signals hidden by solvent or water were either assigned tentatively or are not listed. Strongly broadened signals - e.g. caused by rapid rotation of molecular moieties or by interchanging protons - have also been assigned tentatively (often referred to as a broad multiplet or broad singlet) or are not shown. The1H-NMR data of selected compounds are listed in the form of1H-NMR peaklists. Therein, for each signal peak the δ value in ppm is given, followed by the signal intensity, reported in round brackets. The δ value-signal intensity pairs from different peaks are separated by commas. Therefore, a peaklist is described by the general form: δ1(intensity1), δ2(intensity2), ... , δi(intensityi), ... , δn(intensityn). The intensity of a sharp signal correlates with the height (in cm) of the signal in a printed NMR spectrum. When compared with other signals, this data can be correlated to the real ratios of the signal intensities. In the case of broad signals, more than one peak, or the center of the signal along with their relative intensity, compared to the most intense signal displayed in the spectrum, are shown. A1H-NMR peaklist is similar to a classical1H-NMR readout, and thus usually contains all the peaks listed in a classical NMR interpretation. Moreover, similar to classical1H-NMR printouts, peaklists can show solvent signals, signals derived from stereoisomers of the particular target compound, peaks of impurities,13C satellite peaks, and / or spinning sidebands. The peaks of stereoisomers, and / or peaks of impurities are typically displayed with a lower intensity compared to the peaks of the target compound (e.g., with a purity of >90%). Such stereoisomers and / or impurities may be typical for the particular manufacturing process, and therefore their peaks may help to identify a reproduction of the manufacturing process on the basis of "by-product fingerprints". An expert who calculates the peaks of the target compound by known methods (MestReC, ACD simulation, or by use of empirically evaluated expectation values), can isolate the peaks of the target compound as required, optionally using additional intensity filters. Such an operation would be similar to peak-picking in classical1H-NMR interpretation. A detailed description of the reporting of NMR data in the form of peaklists can be found in the publication "Citation of NMR Peaklist Data within Patent Applications" (cf. http: / / www.researchdisclosure.com / searching-disclosures, Research Disclosure Database Number 605005, 2014, 01 Aug 2014). In the peak picking routine, as described in the Research Disclosure Database Number 605005, the parameter "MinimumHeight" can be adjusted between 1% and 4%. However, depending on the chemical structure and / or depending on the concentration of the measured compound it may be reasonable to set the parameter "MinimumHeight" <1%. Synthesis of Intermediate Compounds Intermediate 1 ethyl 3-bromo-1-{2-[(tert-butoxycarbonyl)amino]-2-cyclopropylethyl}-1H-pyrazole-5- carboxylate^ A mixture of tert-butyl (1-cyclopropyl-2-hydroxyethyl)carbamate (115 g, 571 mmol, 1.00 eq CAS-RN:[1279821-50-9]), ethyl 3-bromo-1H-pyrazole-5-carboxylate (100 g, 457 mmol, 0.80 eq, CAS-RN:[1886994-07-5])), DIAD (277 g, 1.37 mol, 266 mL, 2.40 eq), PPh3(357 g, 1.37 mol, 2.40 eq) in THF (1.15 L) was degassed and purged with N2for 3 times, and then the mixture was stirred at 25°C for 1 hr under an atmosphere of nitrogen. The mixture was washed with H2O (100 mL), and extracted with EtOAc (50.0 mL x 3), the combined phase was washed with brine (50.0 mL), dried over Na2SO4, filtered and concentrated under reduce pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 20: 1 to 5: 1), Petroleum ether: Ethyl acetate = 5: 1, P1: Rf = 0.70 yielding the title compound (148 g, 351 mmol, 61.4% yield, 95.4% purity) was obtained as a white solid. ^ LC-MS (Method 3): Rt = 1.38 min; MS (ESI+): m / z = 402.2 [M+H+]+¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.185 (0.46), 0.197 (0.40), 0.379 (0.44), 0.388 (0.41), 0.399 (0.40), 1.172 (1.20), 1.190 (0.52), 1.277 (16.00), 1.296 (3.88), 1.314 (1.78), 1.987 (1.13), 4.261 (0.50), 4.271 (0.78), 4.288 (1.51), 4.294 (1.43), 4.305 (1.51), 4.312 (1.04), 4.323 (0.51), 4.730 (0.44), 4.742 (0.44), 6.898 (0.62), 6.921 (0.61), 6.953 (2.30).^ Intermediate 2 tert-butyl {2-[3-bromo-5-(hydroxymethyl)-1H-pyrazol-1-yl]-1-cyclopropylethyl}carbamate^ To a solution of compound ethyl 3-bromo-1-{2-[(tert-butoxycarbonyl)amino]-2- cyclopropylethyl}-1H-pyrazole-5-carboxylate (128 g, 318 mmol, 1.00 eq, Intermediate 1) in THF (1.28 L) was added LiAlH4(2.50 M, 140 mL, 1.10 eq) at 0 °C, The mixture was stirred at 25 °C for 2 hrs. The reaction was quenched with H2O (13.3 mL), aqueous 15% NaOH (13.3 mL) and H2O (39.9 mL) under N2in portions, then the mixture was diluted with EtOAc (1000 mL), and dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate=10: 1 to 2: 1), Petroleum ether: Ethyl acetate = 2: 1, P1: Rf= 0.25, to yield the title compound (91.0 g, 217 mmol, 68.2% yield, 85.9% purity) was obtained as a yellow oil. LC-MS (Method 3): Rt = 1.06 min; MS (ESI+): m / z = 360.1 [M+H+]+¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.034 (0.41), 0.197 (0.50), 0.210 (0.50), 0.323 (0.83), 0.341 (0.88), 0.820 (0.62), 0.829 (0.47), 0.841 (0.60), 1.052 (0.48), 1.154 (3.08), 1.172 (6.13), 1.190 (2.87), 1.263 (0.70), 1.270 (0.68), 1.321 (16.00), 1.988 (10.18), 2.518 (0.85), 2.523 (0.56), 3.210 (0.49), 3.999 (0.73), 4.017 (2.17), 4.035 (2.12), 4.053 (0.89), 4.091 (0.69), 4.110 (0.66), 4.146 (0.68), 4.161 (0.65), 4.485 (1.78), 5.390 (1.02), 6.230 (4.34), 6.861 (0.70), 6.883 (0.68).^ Intermediate 3 [5-bromo-2-[2-(tert-butoxycarbonylamino)-2-cyclopropyl-ethyl]pyrazol-3-yl]methyl 4- methylbenzenesulfonate ^ A mixture of tert-butyl {2-[3-bromo-5-(hydroxymethyl)-1H-pyrazol-1-yl]-1- cyclopropylethyl}carbamate (85.0 g, 203 mmol, 1.00 eq, Intermediate 2), TosCl (34.8 g, 182 mmol, 0.90 eq), TEA (41.0 g, 405 mmol, 56.4 mL, 2.00 eq) in DCM (850 mL) was degassed and purged with N23 times, and then the mixture was stirred at 25 °C for 12 hrs under N2atmosphere. Petroleum ether: Ethyl acetate = 2:1, P1: Rf= 0.60. The mixture was diluted with DCM (1.00 L), and then washed with H2O (1.00 L), the combined layers was washed with aqueous NaHCO3(1.00 L), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 20: 1 to 5: 1), Petroleum ether: Ethyl acetate = 2: 1, P1: Rf= 0.60. Compound 4 (41.0 g, 73.7mmol, 36.4% yield, 92.5% purity) was obtained as a white solid, which was used directly in the following step. Intermediate 4 tert-butyl-2-bromo-6-cyclopropyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate^ To a solution of [5-bromo-2-[2-(tert-butoxycarbonylamino)-2-cyclopropyl-ethyl]pyrazol-3- yl]methyl 4-methylbenzenesulfonate (36.0 g, 64.7 mmol, 1.00 eq), NaI (9.70 g, 64.7 mmol, 1.00 eq) in THF (360 mL) was added NaH (3.88 g, 97.1 mmol, 60.0% purity, 1.50 eq). The mixture was stirred at 25 °C for 2 hrs. The mixture was poured into aqueous NH4Cl (300 mL) at 0 ^ under N2, and extracted with EtOAc (300 mL x 3), and washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduce pressure to give a residue. The residue was used for next step without purification yielding the crude title compound (36.0 g, crude) as a yellow solid. LC-MS (Method 3): Rt= 1.31 min; MS (ESI+): m / z = 342.2^[M+H+]+^ Intermediate 5 tert-butyl-2-bromo-6-cyclopropyl-3-iodo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate^ To a solution of tert-butyl-2-bromo-6-cyclopropyl-6,7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxylate (40.0 g, 117 mmol, 1.00 eq, Intermediate 4) in ACN (360 mL) was added NIS (78.9 g, 351 mmol, 3.00 eq) and AcOH (42.1 g, 701 mmol, 40.2 mL, 6.00 eq). The mixture was stirred at 25 °C for 2 hrs. The mixture was adjust pH to 7 with aqueous NaHCO3(500 mL), and then the organic phase was washed with aqueous Na2SO3(500 mL), then washed with brine (300 mL), dried over Na2SO4, filtered and concentrated. The crude product was triturated with MeOH (40.0 mL) at 25 °C for 30 min, yielding the title compound (39.5 g, crude) as a white solid.^ LC-MS (Method 3): Rt= 1.47 min; MS (ESI+): m / z = 468.2^[M+H+]+^ ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.353 (0.44), 0.361 (0.59), 0.373 (0.48), 0.454 (0.63), 0.475 (0.67), 1.434 (16.00), 1.987 (0.46), 4.169 (0.89), 4.172 (0.89), 4.182 (0.71), 4.193 (0.71), 4.660 (0.96), 4.703 (0.80).^ Intermediate 6 tert-butyl (6S)-2-bromo-6-cyclopropyl-3-iodo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate^ tert-butyl-2-bromo-6-cyclopropyl-3-iodo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (Intermediate 5) was purified by prep-HPLC (column: DAICEL CHIRALPAK IK (250mm * 50 mm, 10 um); mobile phase: [CO2-i-PrOH (0.100% NH3H2O)]; B%: 35.0%, isocratic elution method). Yielding the title compound (8.20 g, 16.7 mmol, 48.9% yield, 95.4% purity) as a white solid. LC-MS (Method 3): Rt= 1.47 min; MS (ESI+): m / z = 468.2^[M+H+]+SFC Analytical Method: Column:Chiralpak IK-350*4.6mm I.D.,3um, Mobile phase:Phase A for CO2,and Phase B for IPA(0.05%DEA); Gradient elution:IPA(0.05%DEA) in CO2 from 5% to 40%, Flow rate:3mL / min;Detector:PDA; Column Temp:35C;Back Pressure:100Bar Rt: 1.114 minutes ¹H-NMR (400 MHz, CDCl3) δ, 4.89 (d, J = 15.2 Hz, 1H), 4.26 - 4.18 (m, 3H), 3.88 (s, 1H), 1.50 (s, 9H), 0.95 - 0.90 (m, 1H), 0.63 - 0.47 (m, 3H), 0.38 - 0.32 (m, 1H)^ Specific Optical Rotation: –58.8 ° (c = 1.0174 g / 100mL, Methanol) Intermediate 7 tert-butyl (6R)-2-bromo-6-cyclopropyl-3-iodo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate^ tert-butyl-2-bromo-6-cyclopropyl-3-iodo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (Intermediate 5) was purified by prep-HPLC (column: DAICEL CHIRALPAK IK (250mm * 50 mm, 10 um); mobile phase: [CO2-i-PrOH (0.100% NH3H2O)]; B%: 35.0%, isocratic elution method). Yielding the title compound (5.90 g, 12.4 mmol, 36.3% yield, 98.3% purity) as a white solid. LC-MS (Method 3): Rt= 1.47 min; MS (ESI+): m / z = 468.2^[M+H+]+SFC Analytical Method: Column:Chiralpak IK-350*4.6mm I.D.,3um, Mobile phase:Phase A for CO2,and Phase B for IPA(0.05%DEA); Gradient elution:IPA(0.05%DEA) in CO2 from 5% to 40%, Flow rate:3mL / min;Detector:PDA; Column Temp:35C;Back Pressure:100Bar Rt: 1.358 minutes ¹H-NMR (400 MHz, CDCl3) δ, 4.89 (d, J = 15.2 Hz, 1H), 4.26 - 4.18 (m, 3H), 3.88 (s, 1H), 1.50 (s, 9H), 0.95 - 0.90 (m, 1H), 0.63 - 0.47 (m, 3H), 0.38 - 0.32 (m, 1H)^ Specific Optical Rotation: +59.7 ° (c = 0.8340 g / 100mL, Methanol) Intermediate 8 tert-butyl (2-{3-(4-chloro-2-fluorophenyl)-5-[methoxy(methyl)carbamoyl]-1H-pyrazol-1- yl}ethyl)carbamate^ To a solution of tert-butyl (2-{3-bromo-5-[methoxy(methyl)carbamoyl]-1H-pyrazol-1- yl}ethyl)carbamate (2.00 g, 5.30 mmol, CAS-RN:[2758660-53-4]) and (4-chloro-2- fluorophenyl)boronic acid (1.02 g, 5.83 mmol) in 1,4-dioxane (60 ml) and water (20 ml) were added sodium carbonate (0.843 g, 7.95 mmol) and (1,1'- bis(diphenylphosphino)ferrocene)palladium(II) dichloride (388 mg, 0.530 mmol, CAS-RN: [72287-26-4]), the reaction mixture was stirred at 90 °C under nitrogen atmosphere for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phase was cocentrated in vacuo to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 50: 1 to 3: 1) to give tert-butyl (2-{3-(4-chloro-2-fluorophenyl)-5-[methoxy(methyl)carbamoyl]-1H- pyrazol-1-yl}ethyl)carbamate (2.00 g, 4.69 mmol, 88% yield) as a yellow solid. LCMS (Method C): Rt= 0.977 min; MS (ESIpos): m / z = 371.1 [M+H]+. Intermediate 9 tert-butyl {2-[3-(4-chloro-2-fluorophenyl)-5-(2,4-dichlorobenzoyl)-1H-pyrazol-1- yl]ethyl}carbamate^ To a solution of 2,4-dichloro-1-iodobenzene (6.39 g, 23.4 mmol, CAS-RN:[29898-32-6]) in tetrahydrofuran (100 ml) was added butyllithium (2.50 M in tetrahydrofuran, 9.37 ml, 23.4 mmol) at -50 °C under nitrogen atmosphere. After the addtion, the mixture was stirred at - 50 °C for 0.5 hour. A solution of tert-butyl (2-{3-(4-chloro-2-fluorophenyl)-5- [methoxy(methyl)carbamoyl]-1H-pyrazol-1-yl}ethyl)carbamate (2.00 g, 4.69 mmol, Intermediate 8) in tetrahydrofuran (50 ml) was added into the reaction mixture. The reaction mixture was stirred at -50 °C for another 2 hours. The reaction mixture was quenched by slowly adding water. The mixture was extrated with ethyl acetate. The combined organic phase was cocentrated in vacuo to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 100: 1 to 5: 1) to give tert- butyl {2-[3-(4-chloro-2-fluorophenyl)-5-(2,4-dichlorobenzoyl)-1H-pyrazol-1- yl]ethyl}carbamate (1.20 g, 2.34 mmol, 50% yield) as a yellow oil. LCMS (Method C): Rt= 1.167 min; MS (ESIpos): m / z = 456.0 [M+H]+. Intermediate 10 2-(4-chloro-2-fluorophenyl)-4-(2,4-dichlorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine^ To a solution of tert-butyl {2-[3-(4-chloro-2-fluorophenyl)-5-(2,4-dichlorobenzoyl)-1H- pyrazol-1-yl]ethyl}carbamate (1.20 g, 2.34 mmol, Intermediate 9) in dichloromethane (60 ml) was added trifluoroacetic acid (20 ml). The reaction mixture was stirred at 20 °C for 16 hours. The solvent was removed in vacuo to give crude 2-(4-chloro-2-fluorophenyl)-4-(2,4- dichlorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine (0.90 g, 2.28 mmol, 97% yield) as a yellow solid. LCMS (Method C): Rt= 1.094 min; MS (ESIpos): m / z = 396.0 [M+H]+.Intermediate 11 2-(4-chloro-2-fluorophenyl)-4-(2,4-dichlorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine^ To a solution of 2-(4-chloro-2-fluorophenyl)-4-(2,4-dichlorophenyl)-6,7-dihydropyrazolo[1,5- a]pyrazine (1.00 g, 2.53 mmol, Intermediate 10) in methanol (20 ml) was added sodium cyanoborohydride (318 mg, 5.07 mmol) at 0 °C. Then AcOH (152 mg, 2.53 mmol) was added into the reaction mixture. The reaction mixture was allowed to warm to 20 °C and stirred for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phase was washed with sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate and filitered. The filtrate was concentrated in vacuo to give a crude 2-(4-chloro-2-fluorophenyl)-4-(2,4-dichlorophenyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (1.00 g, 2.52 mmol, 99% yield) as a yellow solid. LCMS (Method C): Rt= 0.894 min; MS (ESIpos): m / z = 398.0 [M+H]+. Intermediate 12 tert-butyl 2-(4-chloro-2-fluorophenyl)-4-(2,4-dichlorophenyl)-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate^ To a solution of 2-(4-chloro-2-fluorophenyl)-4-(2,4-dichlorophenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine (1.00 g, 2.52 mmol, Intermediate 11) in dicloromethane (30 ml) was added triethylamine (510 mg, 5.04 mmol). Then di-tert-butyl carbonate (659 mg, 3.78 mmol) was added. The reaction mixture was stirred at 20 °C for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phase was concentrated in vacuo to give a residue. The residue was purified by column chromatography on silica gel (petrolem ether: ethyl acetate = 100: 1 to 4: 1) to give tert-butyl 2-(4-chloro-2-fluorophenyl)-4-(2,4-dichlorophenyl)-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate (1.30 g, 2.62 mmol, 104% yield) as a yellow solid. LCMS (Method C): Rt= 1.243 min; MS (ESIpos): m / z = 496.1 [M+H]+.Intermediate 13 tert-butyl 2-(4-chloro-2-fluorophenyl)-4-(2,4-dichlorophenyl)-3-iodo-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate^ To a solution of tert-butyl 2-(4-chloro-2-fluorophenyl)-4-(2,4-dichlorophenyl)-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (1.30 g, 2.62 mmol, Intermediate 12) in N,N-dimethylformamide (30 ml) was added 1-iodopyrrolidine-2,5-dione (2.94 g, 13.1 mmol, CAS-RN: [516-12-1]). The reaction mixture was heated to 50 °C and stirred for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phase was washed with sodium sulfite solution and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a crude tert-butyl 2-(4-chloro-2-fluorophenyl)-4-(2,4-dichlorophenyl)-3-iodo-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate (1.60 g, 2.57 mmol, 98% yield) as a yellow solid. LCMS (Method C): Rt= 1.240 min; MS (ESIpos): m / z = 624.0 [M+H]+.Intermediate 14 tert-butyl 2-(4-chloro-2-fluorophenyl)-4-(2,4-dichlorophenyl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate^

[0003] To a solution of tert-butyl 2-(4-chloro-2-fluorophenyl)-4-(2,4-dichlorophenyl)-3-iodo-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (1.60 g, 2.57 mmol, Intermediate 13) and pyridin-4-ylboronic acid (632 mg, 5.14 mmol) in 1,4-dioxane (50 ml) and water (10 ml) were added sodium carbonate (545 mg, 5.14 mmol) and (1,1'- bis(diphenylphosphino)ferrocene)palladium(II) dichloride (188 mg, 257 mmol, CAS-RN: [72287-26-4]). The reaction mixture was stirred at 90 °C for 16 hours under nitrogen atmophere. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phase was concentrated in vacuo to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 100: 1 to 2: 1) to give tert-butyl 2-(4-chloro-2-fluorophenyl)-4-(2,4-dichlorophenyl)-3-(pyridin-4-yl)- 6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (600 mg, 1.05 mmol, 41% yield) as a yellow solid. LCMS (Method C): Rt= 0.936 min; MS (ESIpos): m / z = 575.2 [M+H]+. Intermediate 15 2-(4-chloro-2-fluorophenyl)-4-(2,4-dichlorophenyl)-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine hydrochloride (1:1)^ To a solution of tert-butyl 2-(4-chloro-2-fluorophenyl)-4-(2,4-dichlorophenyl)-3-(pyridin-4- yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (600 mg, 1.05 mmol, Intermediate 14) in ethyl acetate (10 ml) was added hydrochloric acid (4.00 M in ethyl acetate, 5 ml). The reaction mixture was stirred at 20 °C for 1 hour. The solvent was removed in vacuo to give a crude 2-(4-chloro-2-fluorophenyl)-4-(2,4-dichlorophenyl)-3- (pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo [1,5-a]pyrazine hydrochloride (1: 1) (530 mg, 1.04 mmol, 99% yield) as a light yellow solid. LCMS (Method C): Rt= 0.768 min; MS (ESIpos): m / z = 475.0 [M+H]+. Intermediate 16 tert-butyl [2-(5-benzoyl-3-bromo-1H-pyrazol-1-yl)ethyl]carbamate^ To a solution of tert-butyl (2-{3-bromo-5-[methoxy(methyl)carbamoyl]-1H-pyrazol-1- yl}ethyl)carbamate (3.00 g, 7.95 mmol, CAS-RN:[2758660-53-4]) in tetrahydrofuran (150 ml) was added phenylmagnesium bromide (3.00 M in tetrahydrofuran, 13.3ml, 39.8 mmol) at 0 °C. The reaction mixture was stirre at 0°C for 2 hours. The reaction mixture was quenchend by adding ammonium chloride solution and extracted with ethyl acetate. The combined organic phase was concentrated in vacuo to give a crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 100: 1 to 4: 1) to give tert-butyl [2-(5-benzoyl-3-bromo-1H-pyrazol-1-yl)ethyl]carbamate (3.10 g, 7.86 mmol, 99% yield) as a white solid. LCMS (Method C): Rt= 1.004 min; MS (ESIpos): m / z = 338.0 [M-56+H]+.Intermediate 17 2-bromo-4-phenyl-6,7-dihydropyrazolo[1,5-a]pyrazine^ To a solution of tert-butyl [2-(5-benzoyl-3-bromo-1H-pyrazol-1-yl)ethyl]carbamate (3.10 g, 7.86 mmol, Intermediate 16) in dichloromethane (60 ml) was added trifluoroacetic acid (20 ml). The reaction mixture was stirred at 20 °C for 3 hours. The solvent was removed in vacuo to give a residue. The residue was dissolved in ethyl acetate. The organic phase was washed with sodium hydrogen carbonate solution and brine. Then the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a crude 2- bromo-4-phenyl-6,7-dihydropyrazolo[1,5-a]pyrazine (2.10 g, 7.60 mmol, 97% yield) as a white solid. LCMS (Method C): Rt= 0.680 min; MS (ESIpos): m / z = 276.0 [M+H]+.Intermediate 18 2-bromo-4-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine^ To a solution of 2-bromo-4-phenyl-6,7-dihydropyrazolo[1,5-a]pyrazine (2.10 g, 7.60 mmol, Intermediate 17) in methanol (30 ml) was added sodium cyanoborohydride (956 mg, 15.2 mmol) and acetic acid (457 mg, 7.60 mmol) at 0 °C, the reaction mixture was then stirred at 20 °C for 2 hours. The solvent was removed in vacuo to give a residue, which was then dissolved with water and ethyl acetate, the organic phase was washed with brine and dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo to give a crude 2-bromo-4-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (2.10 g, 7.55 mmol, 99% yield) as a white solid. LCMS (Method C): Rt= 0.354 min; MS (ESIpos): m / z = 280.0 [M+H]+.Intermediate 19 tert-butyl 2-bromo-4-phenyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate^ To a solution of 2-bromo-4-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (2.10 g, 7.55 mmol, Intermediate 18) in dichloromethane (50 ml) were added triethylamine (1.53 g, 15.1 mmol) and di-tert-butyl carbonate (1.97 g, 11.3 mmol). The reaction mixture was stirred at 20 °C for 16 hours. The solvent was removed in vacuo to give crude tert-butyl 2-bromo-4- phenyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (2.80 g, 7.40 mmol, 98% yield) as a yellow oil. LCMS (Method C): Rt= 1.019 min; MS (ESIpos): m / z = 378.1 [M+H]+. Intermediate 20 tert-butyl 2-bromo-3-iodo-4-phenyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate^ To a solution of tert-butyl 2-bromo-4-phenyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (2.80 g, 7.40 mmol, Intermediate 19) in N,N-dimethylformamide (50 ml) was added 1-iodopyrrolidine-2,5-dione (2.50 g, 11.1 mmol, CAS-RN: [516-12-1]). The reaction mixture was stirred at 45 °C for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phase was washed with sodium sulfite solution and brine. Then the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a crude tert-butyl 2-bromo-3-iodo-4-phenyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (3.70 g, 7.34 mmol, 99% yield) as an off- white solid. LCMS (Method C): Rt= 0.979 min; MS (ESIpos): m / z = 523.0 [M+H]+. Intermediate 21 tert-butyl 2-bromo-4-phenyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate^ To a soloution of tert-butyl2-bromo-3-iodo-4-phenyl-6,7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxylate (3.70 g, 7.34 mmol, Intermediate 20) and pyridin-4-ylboronic acid (0.902 g, 7.34 mmol) in 1,4-dioxane (60 ml) and water (20 ml) were added (1,1'- bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.537 g, 0.734 mmol, CAS-RN: [72287-26-4]) and sodium carbonate (1.17 g, 11.0 mmol). The reaction mixture was stirred at 80 °C for 16 hours under nitrogen atmophere. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phase was concentrated in vacuo to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 50: 1 to 3: 1) to give tert-butyl 2-bromo-4-phenyl-3-(pyridin- 4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (2.30 g, 5.05 mmol, 69% yield) as a yellow solid. LCMS (Method C): Rt= 0.541 min; MS (ESIpos): m / z = 457.2 [M+H]+.Intermediate 22 tert-butyl 2-(4-chloro-2-fluorophenyl)-4-phenyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate^ To a solution of tert-butyl 2-bromo-4-phenyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate (2.30 g, 5.05 mmol, Intermediate 21) and (4-chloro-2- fluorophenyl)boronic acid (1.06 g, 6.06 mmol) in 1,4-dioxane (40 ml) and water (10 ml) were added bis(diphenylphosphino)ferrocene)palladium(II) dichloride (370 mg, 0.505 mmol, CAS-RN: [72287-26-4]) and sodium carbonate (803 mg, 7.58 mmol). The reaction mixture was stirred at 90 °C for 16 hours under nitrogen atmosphere. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phase was concentrated in vacuo to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 100: 1 to 3: 1) to give tert- butyl 2-(4-chloro-2-fluorophenyl)-4-phenyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate (2.20 g, 4.36 mmol, 86% yield) as a yellow solid. LCMS (Method C): Rt= 0.874 min; MS (ESIpos): m / z = 505.2 [M+H]+.Intermediate 23 2-(4-chloro-2-fluorophenyl)-4-phenyl-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine hydrochloride (1:1)^ To a solution of tert-butyl 2-(4-chloro-2-fluorophenyl)-4-phenyl-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (2.20 g, 4.36 mmol, Intermediate 22) in ethyl acetate (50 ml) was added hydrochloric acid (4.00 M in ethyl acetate, 30 ml). The reaction mixture was stirred at 20 °C for 1 hour. The solvent was removed in vacuo to give a crude 2-(4-chloro-2-fluorophenyl)-4-phenyl-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine hydrochloride (1: 1) (1.90 g, 4.31 mmol, 99% yield) as a light yellow solid. LCMS (Method C): Rt= 0.692 min; MS (ESIpos): m / z = 405.1 [M+H]+. Intermediate 24 1-[2-(4-chloro-2-fluorophenyl)-4-phenyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin- 5(4H)-yl]prop-2-en-1-one^ To a solution of 2-(4-chloro-2-fluorophenyl)-4-phenyl-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine hydrochloride (1: 1) (500 mg, 1.13 mmol, Intermediate 23) in dichloromethane (50 ml) was added triethylamine (344 mg, 3.40 mmol) at 0 °C. Then acryloyl chloride (154 mg, 1.70 mmol) was added. The reaction mixture was stirred at 0 °C for 1 hour. The solvent was removed in vacuo to give a residue. The residue was purified by preparative HPLC [Instrument: GX-A; Column: Waters Xbridge 150*25 mm* 5 μm; eluent A: water (0.2% ammonium hydroxide), eluent B: acetonitrile; gradient: 0-10 min 15-45% B; flow 25 ml / min; temperature: RT; Detector: UV 220 / 254 nm] to give 1-[2-(4-chloro-2- fluorophenyl)-4-phenyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2- en-1-one (320 mg, 0.697 mmol, 62% yield) as a white solid. LCMS (Method C): Rt= 0.824 min; MS (ESIpos): m / z = 459.1 [M+H]+. Intermediate 25 tert-butyl (2-oxo-2-phenylethyl)carbamate^ To a solution of 2-amino-1-phenylethan-1-one—hydrogen chloride (1^^ 1) (2.00 g, 11.7 mmol, CAS-RN: [5468-37-1]) in tetrahydrofuran (10 ml) and water (30 ml) were added sodium hydrogen carbonate (2.94 g, 35.0 mmol) and di-tert-butyl dicarbonate (5.09 g, 23.3 mmol) at 25 °C for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phase was concentrated in vacuo to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 50: 1 to 2: 1) to give tert-butyl (2-oxo-2-phenylethyl)carbamate (2.60 g, 11.1 mmol, 94.8% yield) as an off-white solid. Intermediate 26 tert-butyl [2-hydroxy-2-phenylethyl]carbamate^

[0004] To a solution of tert-butyl (2-oxo-2-phenylethyl)carbamate (2.60 g, 11.1 mmol, Intermediate 25) in methanol (30 ml) was added sodium tetrahydroborate (836 mg, 22.1 mmol, CAS-RN: [16940-66-2]) at 0°C. The reaction mixture was stirred at 20 °C for 4 hours. The reaction mixture was quenched by adding ammonium chloride solution. The mixture was poured into water and extracted with ethyl acetate. The combined organic phase was concentrated in vacuo to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 50: 1 to 1: 1) to give tert-butyl [2-hydroxy-2- phenylethyl]carbamate (2.60 g, 11.0 mmol, 99% yield) as a white solid. Intermediate 27 methyl 3-bromo-1-{2-[(tert-butoxycarbonyl)amino]-1-phenylethyl}-1H-pyrazole-5- carboxylate^ To a solution of methyl 3-bromo-1H-pyrazole-5-carboxylate (2.16 g, 10.5 mmol) and tert- butyl [2-hydroxy-2-phenylethyl]carbamate (2.50 g, 10.5 mmol, Intermediate 26) in tetrahydrofuran (50 ml) was added triphenylphosphine (5.53 g, 21.1 mmol) and diisopropyl azodicarboxylate (4.26 g, 21.1 mmol, CAS-RN: [2446-83-5]) at 0 °C. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 4: 1 to 1: 1) to give methyl 3-bromo-1-{2-[(tert-butoxycarbonyl)amino]-1-phenylethyl}-1H- pyrazole-5-carboxylate (3.60 g, 8.48 mmol, 81% yield) as a yellow oil. LC-MS (Method C): Rt= 0.954 min; MS (ESIpos): m / z = 324.0 [M-99]+. Intermediate 28 tert-butyl {2-[3-bromo-5-(hydroxymethyl)-1H-pyrazol-1-yl]-2-phenylethyl}carbamate^ To a solution of methyl 3-bromo-1-{2-[(tert-butoxycarbonyl)amino]-1-phenylethyl}-1H- pyrazole-5-carboxylate (3.60 g, 8.48 mmol, Intermediate 27) in ethanol (50 ml) was added sodium tetrahydroborate (642 mg, 17.0 mmol, CAS-RN: [16940-66-2]) at 0 °C. The reaction mixture was stirred at 40 °C for 16 hours. The reaction mixture was quenched by adding ammonium chloride solution. The mixture was poured into water. During this period, white precipitate was formed. The suspension was filtered. The filter cake collected, washed with water and dried in vacuo to give a crude tert-butyl {2-[3-bromo-5-(hydroxymethyl)-1H- pyrazol-1-yl]-2-phenylethyl}carbamate (2.90 g, 7.32 mmol, 86% yield) as a yellow oil. Intermediate 29 [5-bromo-2-[2-(tert-butoxycarbonylamino)-1-phenyl-ethyl]pyrazol-3-yl]methyl-triethyl- ammonium methanesulfonate To a solution of tert-butyl {2-[3-bromo-5-(hydroxymethyl)-1H-pyrazol-1-yl]-2- phenylethyl}carbamate (2.40 g, 6.06 mmol, Intermediate 28) in dichloromethane (50 ml) were added triethylamine (4.2 ml, 30 mmol) and methanesulfonic anhydride (2.11 g, 12.1 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 16 hours. The solvent was removed under reduced pressure to give a crude [5-bromo-2-[2-(tert- butoxycarbonylamino)-1-phenyl-ethyl]pyrazol-3-yl]methyl-triethyl-ammonium methanesulfonate (720 mg, 1.25 mmol, 99% yield) as a brown oil. LC-MS (Method C): Rt= 0.520 min; MS (ESIpos): m / z = 481.2 [M-95]+. Intermediate 30 tert-butyl-2-bromo-7-phenyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate^ To a solution of [5-bromo-2-[2-(tert-butoxycarbonylamino)-1-phenyl-ethyl]pyrazol-3- yl]methyl-triethyl-ammonium methanesulfonate (450 mg, 1.19 mmol, Intermediate 29) in tetrahydrofuran (10 ml) and N,N-dimethylformamide (20 ml) was added sodium hydride (730 mg, 60 % purity, 30.4 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 50: 1 to 10: 1) to give tert- butyl 2-bromo-7-phenyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (450 mg, 1.19 mmol, 95% yield) as a yellow solid. LC-MS (Method C): Rt= 1.013 min; MS (ESIpos): m / z = 378.1 [M+H]+. Intermediate 31 tert-butyl 2-(4-chloro-2-fluorophenyl)-7-phenyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate^

[0005] To a solution of tert-butyl 2-bromo-7-phenyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (250 mg, 0.661 mmol, Intermediate 30) and (4-chloro-2-fluorophenyl)boronic acid (115 mg, 0.661 mmol) in 1,4-dioxane (5.0 ml) and water (1.0 ml) were added sodium carbonate (105 mg, 0.991 mmol) and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (48.4 mg, 0.066 mmol, CAS-RN: [72287-26-4]) at 25 °C under nitrogen atmosphere. The reaction mixture was stirred at 90 °C for 16 hours under nitrogen atmophere. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography on silica gel (petroelum ether: etheyl acetate = 100: 1 to 10: 1) to give tert- butyl 2-(4-chloro-2-fluorophenyl)-7-phenyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (370 mg, 0.86 mmol, 73% yield) as a white solid. LC-MS (Method C): Rt= 0.747 min; MS (ESIpos): m / z = 428.2 [M+H]+. Intermediate 32 tert-butyl 2-(4-chloro-2-fluorophenyl)-3-iodo-7-phenyl-6,7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxylate^ To a solution of tert-butyl-2-(4-chloro-2-fluorophenyl)-7-phenyl-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate (370 mg, 0.865 mmol, Intermediate 31) in N,N- dimethylformamide (5 ml) was added 1-iodopyrrolidine-2,5-dione (214 mg, 0.952 mmol, CAS-RN: [516-12-1]). The reaction mixture was stirred at 25 °C for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phase was concentrated in vacuo to give a crude. The crdue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 100: 1 to 2: 1) to give tert- butyl 2-(4-chloro-2-fluorophenyl)-3-iodo-7-phenyl-6,7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxylate (290 mg, 0.520 mmol, 64% yield) as a yellow solid. LC-MS (Method C): Rt= 0.768 min; MS (ESIpos): m / z = 554.0 [M+H]+. Intermediate 33 tert-butyl 2-(4-chloro-2-fluorophenyl)-7-phenyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate^ To a solution of tert-butyl 2-(4-chloro-2-fluorophenyl)-3-iodo-7-phenyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (160 mg, 0.289 mmol, Intermediate 32) and pyridin-4-ylboronic acid (71.0 mg, 0.578 mmol) in 1,4-dioxane (3 ml) and water (0.5 ml) were added (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (21.1 mg, 0.029 mmol, CAS-RN: [72287-26-4]) and potassium carbonate (61.2 mg, 0.578 mmol). The reaction mixture was stirred at 90 °C under nitrogen atmosphere for 16 hours. The reaction mixture was poured into water. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 20: 1 to 1: 1) to give tert- butyl 2-(4-chloro-2-fluorophenyl)-7-phenyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate (230 mg, 0.460 mmol, 97% yield) as a white solid. LC-MS (Method C): Rt= 0.902 min; MS (ESIpos): m / z = 505.2 [M+H]+. Intermediate 34 2-(4-chloro-2-fluorophenyl)-7-phenyl-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine—hydrogen chloride (1: 1)^

[0006] To a solution of tert-butyl 2-(4-chloro-2-fluorophenyl)-7-phenyl-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (230 mg, 0.460 mmol, Intermediate 33) in ethyl acetate (5 ml) was added hydrochloric acid (4.00 M in ethyl acetate, 5 ml). The reaction mixture was stirred at 20 °C for 1 hour. The solvent was removed in vacuo to give a crude 2-(4-chloro-2-fluorophenyl)-7-phenyl-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine—hydrogen chloride (1: 1) (200 mg, 0.450 mmol, 99% yield) as a yellow solid. LC-MS (Method C): Rt= 0.458 min; MS (ESIpos): m / z = 405.1 [M+H]+. Intermediate 35 tert-butyl [2-(2-chlorophenyl)-2-oxoethyl]carbamate^ To a solution of 2-amino-1-(2-chlorophenyl)ethan-1-one—hydrogen chloride (1: 1) (4.00 g, 19.4 mmol, CAS-RN:[ 16442-79-8]) in methanol (40 ml) and water (40 ml) were added sodium hydrogen carbonate (4.08 g, 48.5 mmol) and di-tert-butyl dicarbonate (6.7 ml, 29 mmol). The mixture was stirred at 20 °C for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 10: 1 to 2: 1) to give tert-butyl [2-(2-chlorophenyl)-2-oxoethyl]carbamate (4.20 g, 15.6 mmol, 80% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ [ppm] = 7.65-7.60 (m, 1H), 7.58-7.50 (m, 2H), 7.49-7.42 (m, 1H), 7.29 (t, J = 5.6 Hz, 1H), 4.27-4.15 (m, 2H), 1.40-1.31 (m, 8H) Intermediate 36 tert-butyl [2-(2-chlorophenyl)-2-hydroxyethyl]carbamate^ To a solution of tert-butyl [2-(2-chlorophenyl)-2-oxoethyl]carbamate (4.20 g, 15.6 mmol, Intermediate 35) in methanol (50 ml) was added sodium tetrahydroborate (1.18 g, 31.1 mmol, CAS-RN: [16940-66-2]) at 0°C. The reaction mixture was stirred at 20 °C for 4 hours. The reaction mixture was quenched by adding ammonium chloride solution. The mixture was poured into water and extracted with ethyl acetate. The combined organic phase was concentrated in vacuo to give a crude.The crude was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 50: 1 to 1: 1) to give tert-butyl [2-(2- chlorophenyl)-2-hydroxyethyl]carbamate (4.30 g, 15.8 mmol, 102% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ [ppm] = 7.56-7.54 (dd, J = 7.6, 1.2 Hz, 1H), 7.40-7.31 (m, 2H), 7.31-7.22 (m, 1H), 5.01-4.92 (m, 1H), 3.17-3.12 (td, J = 13.2, 5.2 Hz, 1H), 3.07-3.02 (td, J = 13.2, 6.8 Hz, 1H), 1.39-1.26 (m, 9H). Intermediate 37 methyl 3-bromo-1-[2-[(tert-butoxycarbonyl)amino]-1-(2-chlorophenyl)ethyl]-1H-pyrazole-5- carboxylate^ To a solution of tert-butyl [2-(2-chlorophenyl)-2-hydroxyethyl]carbamate (4.30 g, 15.8 mmol, Intermediate 36) and methyl 3-bromo-1H-pyrazole-5-carboxylate (3.24 g, 15.8 mmol) in tetrahydrofuran (93 ml) were added triphenylphosphine (12.5 g, 47.5 mmol) and diisopropyl azodicarboxylate (9.60 g, 47.5 mmol, CAS-RN: [2446-83-5]) at 0 °C. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 20: 1 to 3: 1) to give methyl 3-bromo-1-[2-[(tert-butoxycarbonyl)amino]-1-(2- chlorophenyl)ethyl]-1H-pyrazole-5-carboxylate (5.60 g, 12.2 mmol, 77% yield) as a pink oil. Intermediate 38 tert-butyl [2-[3-bromo-5-(hydroxymethyl)-1H-pyrazol-1-yl]-2-(2- chlorophenyl)ethyl]carbamate ^ To a solution of methyl 3-bromo-1-[2-[(tert-butoxycarbonyl)amino]-1-(2-chlorophenyl)ethyl]- 1H-pyrazole-5-carboxylate (5.40 g, 11.8 mmol, Intermediate 37) in methanol (98 ml) was added sodium tetrahydroborate (4.45 g, 118 mmol, CAS-RN: [16940-66-2]) at 0 °C. The reaction mixture was stirred at 20°C for 4 hours. The reaction mixture was quenched by adding ammonium chloride solution. The mixture was poured into water. During this period, white precipitate was formed. The suspension was filtered. The filter cake was collected, washed with water and dried in vacuo to give a crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 20: 1 to 2: 1) to give tert-butyl [2-[3-bromo-5-(hydroxymethyl)-1H-pyrazol-1-yl]-2-(2- chlorophenyl)ethyl]carbamate (3.90 g, 9.05 mmol, 76.9% yield) as a colorless oil. LC-MS (Method C): Rt= 0.618 min; MS (ESIpos): m / z = 330.0 [M-100]+. Intermediate 39 [5-bromo-2-[2-(tert-butoxycarbonylamino)-1-(2-chlorophenyl)ethyl]pyrazol-3-yl]methyl- triethyl-ammonium methanesulfonate

[0007] To a solution of tert-butyl [2-[3-bromo-5-(hydroxymethyl)-1H-pyrazol-1-yl]-2-(2- chlorophenyl)ethyl]carbamate (3.40 g, 7.89 mmol, Intermediate 38) in dichloromethane (50 ml) were added triethylamine (5.5 ml, 39 mmol) and methanesulfonic anhydride (2.75 g, 15.8 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 16 hours. The solvent was evaporated under reduced pressure to give [5-bromo-2-[2-(tert- butoxycarbonylamino)-1-(2-chlorophenyl)ethyl]pyrazol-3-yl]methyl-triethyl-ammonium methanesulfonate (4.70 g, 7.70 mmol, 97.6% yield) as a brown solid. LC-MS (Method C): Rt= 0.509 min; MS (ESIpos): m / z = 515.1 [M-95]+. Intermediate 40 tert-butyl 2-bromo-7-(2-chlorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate^ To a solution of [5-bromo-2-[2-(tert-butoxycarbonylamino)-1-(2-chlorophenyl)ethyl]pyrazol- 3-yl]methyl-triethyl-ammonium methanesulfonate (4.70 g, 7.70 mmol, Intermediate 39) in tetrahydrofuran (30 ml) and N,N-dimethylformamide (60 ml) was added sodium hydriide (3.08 g, 60 % purity, 77.0 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 16 hours. The mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate= 100: 1 to 10: 1) to give tert- butyl 2-bromo-7-(2-chlorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (2.10 g, 5.08 mmol, 66% yield) as a yellow gum. LC-MS (Method C): Rt= 0.985 min; MS (ESIpos): m / z = 414.1 [M+H]+. Intermediate 41 tert-butyl 2-(4-chloro-2-fluorophenyl)-7-(2-chlorophenyl)-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate^ To a solution of tert-butyl 2-bromo-7-(2-chlorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxylate (2.10 g, 5.09 mmol, Intermediate 40) and (4-chloro-2- fluorophenyl)boronic acid (932 mg, 5.34 mmol) in 1,4-dioxane (40 ml) and water (8 ml) were added sodium carbonate (1.08 g, 10.2 mmol) and (1,1'- bis(diphenylphosphino)ferrocene)palladium(II) dichloride (372 mg, 0.509 mmol, CAS-RN: [72287-26-4]). The reaction mixture was stirred at 90 °C under nitrogen atmophere for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 10: 1 to 1: 1) to give tert- butyl 2-(4-chloro-2-fluorophenyl)-7-(2-chlorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxylate (2.20 g, 4.76 mmol, 94% yield) as a white solid. LC-MS (Method C): Rt= 0.795 min; MS (ESIpos): m / z = 462.1 [M+H]+. Intermediate 42 tert-butyl 2-(4-chloro-2-fluorophenyl)-7-(2-chlorophenyl)-3-iodo-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate^ ^ To a solution of tert-butyl 2-(4-chloro-2-fluorophenyl)-7-(2-chlorophenyl)-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (2.20 g, 4.76 mmol, Intermediate 41) in N,N-dimethylformamide (52 ml) were added 1-iodopyrrolidine-2,5-dione (2.14 g, 9.52 mmol, CAS-RN: [516-12-1]). The reaction mixture was stirred at 40 °C for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined orgainc phase was washed with sodium sulfite solution and brine. Then the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a crude tert-butyl 2-(4-chloro-2-fluorophenyl)-7-(2-chlorophenyl)-3-iodo-6,7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxylate (2.40 g, 4.08 mmol, 86% yield) as a yellow solid. LC-MS (Method C): Rt= 1.211 min; MS (ESIpos): m / z = 588.0[M+H]+. Intermediate 43 tert-butyl 2-(4-chloro-2-fluorophenyl)-7-(2-chlorophenyl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate^ To a solution of tert-butyl 2-(4-chloro-2-fluorophenyl)-7-(2-chlorophenyl)-3-iodo-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (800 mg, 1.36 mmol, Intermediate 42) and pyridin-4-ylboronic acid (167 mg, 1.36 mmol) in 1,4-dioxane (15 ml) and water (3.0 ml) were added (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (99.5 mg, 0.136 mmol, CAS-RN: [72287-26-4]) and potassium carbonate (288 mg, 2.72 mmol). The reaction mixture was stirred at 90 °C under nitrogen atmosphere for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 20: 1 to 1: 1) to give tert-butyl 2-(4-chloro-2-fluorophenyl)- 7-(2-chlorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (480 mg, 0.890 mmol, 65% yield) as a white solid. LC-MS (Method C): Rt= 0.857 min; MS (ESIpos): m / z = 539.1 [M+H]+. Intermediate 44 2-(4-chloro-2-fluorophenyl)-7-(2-chlorophenyl)-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine—hydrogen chloride (1: 1)^ To a solution of tert-butyl 2-(4-chloro-2-fluorophenyl)-7-(2-chlorophenyl)-3-(pyridin-4-yl)- 6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (480 mg, 0.890 mmol, Intermediate 43) in ethyl acetate (20 ml) was added hydrochloric acid (4.00 M in ethyl acetate, 4.4 ml, 18.0 mmol). The reaction mixture was stirred at 20 °C for 1 hour. The solvent was removed in vacuo to give a crude 2-(4-chloro-2-fluorophenyl)-7-(2-chlorophenyl)-3-(pyridin-4-yl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine—hydrogen chloride (1: 1) (420 mg, 0.880 mmol, 99% yield) as a yellow solid. LC-MS (Method C): Rt= 0.773 min; MS (ESIpos): m / z = 439.1 [M+H]+. Intermediate 45 tert-butyl [2-(2,4-dichlorophenyl)-2-oxoethyl]carbamate^ To a solution of 2,4-dichloro-1-iodobenzene (10.0 g, 36.6 mmol, CAS-RN:[29898-32-6]) in tetrahydrofuran (200 ml) was added n-butyllithium (2.5 M in hexane, 29 ml, 72.5 mmol) at - 60 °C under nitrogen atmosphere. The mixture was stirred for 0.5 hour. Then a solution of tert-butyl {2-[methoxy(methyl)amino]-2-oxoethyl}carbamate (8.00 g, 36.6 mmol, CAS- RN:[121505-93-9]) in tetrahydrofuran (20 ml) was added at -60 °C. The reaction mixture was stirred at -60 °C for another 2 hours. The reaction mixture was quenched with saturated ammonium chloride aqueous solution and the mixture was extracted with ethyl acetate. The combined organic phase was concentrated in vacuum to give tert-butyl [2-(2,4- dichlorophenyl)-2-oxoethyl]carbamate (11.0 g, 36.2 mmol, 99% yield) as a yellow solid. LC-MS (Method C): Rt= 0.957 min; MS (ESIpos): m / z = 204.0 [M-99]+. Intermediate 46 tert-butyl [2-(2,4-dichlorophenyl)-2-hydroxyethyl]carbamate^ To a solution of tert-butyl [2-(2,4-dichlorophenyl)-2-oxoethyl]carbamate (11.0 g, 36.2 mmol, Intermediate 45) in methanol (240 ml) was added sodium tetrahydroborate (6.84 g, 181 mmol, CAS-RN: [16940-66-2]) at 0° C. The resulting solution was stirred at 20° C for 2 hours. The reaction mixture was quenched by slowly additon of water. The mixture was extracted with ethyl acetate. The combined organic phase was concentrated in vacuum to give a residue. The residue was purified by reversed phase MPLC [Spherical C18 (20-45 μm, 100 Å), eluent A: acetonitrile, eluent B: water (0.5% formic acid); gradient: 0-15 min 35- 80% B; flow 100 ml / min; Detector: UV 220 / 254 nm] to give tert-butyl [2-(2,4-dichlorophenyl)- 2-hydroxyethyl]carbamate (2.00 g, 6.53 mmol, 18% yield) as a brown oil. LC-MS (Method C): Rt= 0.933 min; MS (ESIpos): m / z = 232.0 [M-73]+. Intermediate 47 methyl 3-bromo-1-[2-[(tert-butoxycarbonyl)amino]-1-(2,4-dichlorophenyl)ethyl]-1H- pyrazole-5-carboxylate^

[0008] To a solution of tert-butyl [2-(2,4-dichlorophenyl)-2-hydroxyethyl]carbamate (2.00 g, 6.53 mmol, Intermediate 46) and methyl 3-bromo-1H-pyrazole-5-carboxylate (1.34 g, 6.53 mmol) in tetrahydrofuran (40 ml) were added triphenylphosphine (3.43 g, 13.1 mmol) and diisopropyl azodicarboxylate (2.64 g, 13.1 mmol, CAS-RN: [2446-83-5]) at 20 °C. The mixture was stirred at 20 °C for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were concentrated in vacuum to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1: 0 to 5: 1) to give methyl 3-bromo-1-[2-[(tert-butoxycarbonyl)amino]- 1-(2,4-dichlorophenyl)ethyl]-1H-pyrazole-5-carboxylate (1.90 g, 3.85 mmol, 59% yield) as a yellow oil. LC-MS (Method C): Rt= 1.070 min; MS (ESIpos): m / z = 494.0 [M+2+H]+. Intermediate 48 tert-butyl [2-[3-bromo-5-(hydroxymethyl)-1H-pyrazol-1-yl]-2-(2,4- dichlorophenyl)ethyl]carbamate^ To a solution of methyl 3-bromo-1-[2-[(tert-butoxycarbonyl)amino]-1-(2,4- dichlorophenyl)ethyl]-1H-pyrazole-5-carboxylate (1.90 g, 3.85 mmol, Intermediate 47) in methanol (40 ml) was added sodium tetrahydroborate (437 mg, 11.6 mmol, CAS-RN: [16940-66-2]) at 20 °C. The reaction mixture was stirred at 20 °C for 2 hours. The reaction mixture was quenched by slowly addition of water. The mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give tert-butyl [2-[3-bromo-5-(hydroxymethyl)-1H-pyrazol-1- yl]-2-(2,4-dichlorophenyl)ethyl]carbamate (1.60 g, 3.44 mmol, 89% yield) as a colorless solid. LC-MS (Method C): Rt= 1.016 min; MS (ESIpos): m / z = 410.0 [M-56+2+H]+. Intermediate 49 {3-bromo-1-[2-[(tert-butoxycarbonyl)amino]-1-(2,4-dichlorophenyl)ethyl]-1H-pyrazol-5- yl}methyl methanesulfonate^ To a solution of tert-butyl [2-[3-bromo-5-(hydroxymethyl)-1H-pyrazol-1-yl]-2-(2,4- dichlorophenyl)ethyl]carbamate (1.50 g, 3.22 mmol, Intermediate 48) and triethylamine (1.8 ml, 13 mmol) in dichloromethane (40 ml) was added methanesulfonic anhydride (1.12 g, 6.45 mmol) at 20 °C. The reaction mixture was sirred at 20 °C for 16 hours. The reaction mixture was concentrated in vacuum to give {3-bromo-1-[2-[(tert-butoxycarbonyl)amino]-1- (2,4-dichlorophenyl)ethyl]-1H-pyrazol-5-yl}methyl methanesulfonate (1.70 g, 3.13 mmol, 97% yield) as a brown oil. LC-MS (Method C): Rt= 1.042 min; MS (ESIpos): m / z = 487.9 [M-56+2+1]+. Intermediate 50 tert-butyl 2-bromo-7-(2,4-dichlorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate^ To a mixture of {3-bromo-1-[2-[(tert-butoxycarbonyl)amino]-1-(2,4-dichlorophenyl)ethyl]- 1H-pyrazol-5-yl}methyl methanesulfonate (1.70 g, 3.13 mmol, Intermediate 49) in tetrahydrofuran (14 ml) and N,N-dimethylformamide (28 ml) was added a solution of sodium hydride (1.00 g, 60 % purity, 25.0 mmol) in tetrahydrofuran (5 ml) at 0 °C. The resulting mixture was stirred at 20 °C for 16 hours. The reaction mixture was quenched with slowly addition of water. The mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuum to give a crude product. The crude product was purified by column chromatography silica gel (petroleum ether: ethyl acetate = 1: 0 to 9: 1) to give tert-butyl 2- bromo-7-(2,4-dichlorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (450 mg, 1.01 mmol, 32% yield) as a yellow solid. LC-MS (Method C): Rt= 1.077 min; MS (ESIpos): m / z = 448.1 [M+2+1]+. Intermediate 51 tert-butyl 2-(4-chloro-2-fluorophenyl)-7-(2,4-dichlorophenyl)-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate^ To a solution of tert-butyl 2-bromo-7-(2,4-dichlorophenyl)-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate (400 mg, 0.895 mmol, Intermediate 50) and (4-chloro-2- fluorophenyl)boronic acid (234 mg, 1.34 mmol) in 1,4-dioxane (10 ml) and water (2 ml) were added sodium carbonate (190 mg, 1.79 mmol) and (1,1'- bis(diphenylphosphino)ferrocene)palladium(II) dichloride (65.5 mg, 0.090 mmol, CAS-RN: [72287-26-4]) at 20 °C. The mixture was degassed and purge with nitrogen for three times. The mixture was stirred at 90 °C for 16 hours. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1: 0 to 9: 1) to give tert-butyl 2-(4-chloro-2-fluorophenyl)- 7-(2,4-dichlorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (420 mg, 0.845 mmol, 95% yield) as a brown solid. LC-MS (Method C): Rt= 1.178 min; MS (ESIpos): m / z = 498.1 [M+2+H]+. Intermediate 52 tert-butyl 2-(4-chloro-2-fluorophenyl)-7-(2,4-dichlorophenyl)-3-iodo-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate^ To a solution of tert-butyl 2-(4-chloro-2-fluorophenyl)-7-(2,4-dichlorophenyl)-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (370 mg, 0.745 mmol, Intermediate 51) in N,N-dimethylformamide (12 ml) was added N-iodosuccinimide (1.34 g, 5.96 mmol) at 20 °C. The reaction mixture was stirred at 45 °C for 48 hours. The reaction mixture was quenched by saturated sodium sulfite aqueous solution. The mixture was extracted with ethyl acetate. The combined organic layers were concentrated in vacuo to give tert-butyl 2- (4-chloro-2-fluorophenyl)-7-(2,4-dichlorophenyl)-3-iodo-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate (450 mg, 0.723 mmol, 97% yield) as a brown solid. LC-MS (Method C): Rt= 1.126 min; MS (ESIpos): m / z = 624.0 [M+2+1]+. Intermediate 53 tert-butyl 2-(4-chloro-2-fluorophenyl)-7-(2,4-dichlorophenyl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate^

[0009] To a solution of tert-butyl 2-(4-chloro-2-fluorophenyl)-7-(2,4-dichlorophenyl)-3-iodo-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (400 mg, 642 μmol, Intermediate 52) and pyridin-4-ylboronic acid (158 mg, 1.28 mmol) in 1,4-dioxane (10 ml) and water (2 ml) were added sodium carbonate (136 mg, 1.28 mmol) and (1,1'- bis(diphenylphosphino)ferrocene)palladium(II) dichloride (47.0 mg, 64.2 μmol, CAS-RN: [72287-26-4]) at 20 °C. The mixture was degassed and purged with nitrogen. The reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was concentrated in vacuo to give a residue and the residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1: 0 to 1: 1) to give tert-butyl 2-(4-chloro-2-fluorophenyl)- 7-(2,4-dichlorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (350 mg, 0.610 mmol, 95% yield) as a brown oil. LC-MS (Method C): Rt= 0.947 min; MS (ESIpos): m / z = 575.2 [M+2+H]+. Intermediate 54 2-(4-chloro-2-fluorophenyl)-7-(2,4-dichlorophenyl)-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine hydrogen chloride (1: 1)^ To a solution of tert-butyl 2-(4-chloro-2-fluorophenyl)-7-(2,4-dichlorophenyl)-3-(pyridin-4- yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (350 mg, 0.610 mmol, Intermediate 53) in ethyl acetate (1 ml) was added hydrochloric acid (4.00 M in ethyl acetate, 9 ml, 36.0 mmol) at 20 °C. The reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated in vacuum to give 2-(4-chloro-2-fluorophenyl)-7- (2,4-dichlorophenyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine hydrogen chloride (1: 1) (310 mg, 0.608 mmol, 100% yield) as a white solid. LC-MS (Method A): Rt= 0.976 min; MS (ESIpos): m / z = 475.1 [M+2+H]+. Intermediate 55 methyl {[(benzyloxy)carbonyl]amino}(oxetan-3-ylidene)acetate^ To a solution of methyl {[(benzyloxy)carbonyl]amino}(diethoxyphosphoryl)acetate (20.0 g, 55.7 mmol, CAS-RN:[114684-69-4]) in toluene (200 ml) was added 1,1,3,3- tetramethylguanidine (7.0 ml, 56.0 mmol) at -78 °C. The mixture was stirred at -78 °C for 30 minutes. Then a solution of oxetan-3-one (4.41 g, 61.2 mmol) in toluene was added to the above mixture at -78 °C. The mixture was stirred at 20 °C for 12 hours. The reaction mixture was filtered and the cake was triturated with petroleum ether. The suspension was filtered under reduced pressure. The filter cake was concentrated and dried under reduced pressure to give methyl {[(benzyloxy)carbonyl]amino}(oxetan-3-ylidene)acetate (20.0 g, crude) as a white solid.1H NMR (400 MHz, CDCl3) δ [ppm] = 7.41-7.34 (m, 5H), 6.78 (br s, 1H), 5.46 (br s, 2H), 5.43-5.38 (m, 2H), 5.12 (s, 2H), 3.80 (s, 3H).^ Intermediate 56 methyl amino(oxetan-3-yl)acetate^ To a solution of methyl {[(benzyloxy)carbonyl]amino}(oxetan-3-ylidene)acetate (15.0 g, 54.1 mmol, Intermediate 55) in a mixed solvent of dichloromethane (300 ml) and methanol (300 ml) was added palladium(II) hydroxide (760 mg, 5.41 mmol) at 20 °C under nitrogen atmosphere. The mixture was stirred at 20 °C for 16 hours under hydrogen atmosphere. The mixture was filtered. The filtrate was concentarted under reduced pressure to give methyl amino(oxetan-3-yl)acetate (13.0 g, 50% purity, 83% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ [ppm] = 4.77 (dd, J = 14.8, 7.2 Hz, 2H), 4.73-4.66 (m, 2H), 3.94 (d, J = 9.2 Hz, 1H), 3.86 (m, 2H), 3.73 (s, 3H), 3.36 (d, J = 7.6 Hz, 1H).^ Intermediate 57 methyl [(tert-butoxycarbonyl)amino](oxetan-3-yl)acetate^ To a solution of methyl amino(oxetan-3-yl)acetate (13.0 g, 89.6 mmol, Intermediate 56) in tetrahydrofuran (260 ml) was added di-tert-butyl decarbonate (25 ml, 110 mmol) and triethylamine (25 ml, 180 mmol). The mixture was stirred at 20 °C for 16 hours. The mixturte was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromagraphy (petroleum ether: ethyl acetate = 20: 1 to 1: 1) to give methyl [(tert-butoxycarbonyl)amino](oxetan-3-yl)acetate (10.0 g, 46 % yield) as a yellow oil.^1H NMR (400 MHz, DMSO-d6) δ [ppm] = 7.39 (d, J = 7.6 Hz, 1H), 4.63-4.50 (m, 2H), 4.45 - 4.30 (m, 3H), 3.61 (s, 3H), 3.27-3.17 (m, 1H), 1.43-1.35 (m, 9H).^ Intermediate 58 tert-butyl [2-hydroxy-1-(oxetan-3-yl)ethyl]carbamate^ To a solution of methyl [(tert-butoxycarbonyl)amino](oxetan-3-yl)acetate (9.00 g, 36.7 mmol, Intermediate 57) in tetrahydrofuran (180 ml) was added lithium borohydride (46 ml, 4.0 M in tetrahydrofuran, 180 mmol) at 0 °C. The mixture was stirred at 20 °C for 2 hours. The mixturte was quenched with water and extracted with ethyl acetate. The combined organic layers was dried over sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl [2-hydroxy-1-(oxetan-3-yl)ethyl]carbamate (7.00 g, 88% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ [ppm] = 6.67 (d, J = 8.8 Hz, 1H), 4.60 (t, J = 5.6 Hz, 1H), 4.57-4.46 (m, 2H), 4.45-4.31 (m, 2H), 3.75 (t, J = 5.6 Hz, 1H), 3.32-3.27 (m, 1H), 3.24-3.16 (m, 1H), 3.13-3.02 (m, 1H), 1.39 (s, 9H).^ Intermediate 59 methyl 3-bromo-1-[2-[(tert-butoxycarbonyl)amino]-2-(oxetan-3-yl)ethyl]-1H-pyrazole-5- carboxylate^ To a solution of methyl 3-bromo-1H-pyrazole-5-carboxylate (6.94 g, 33.8 mmol) in tetrahydrofuran (200 ml) were added triphenylphosphine (16.9 g, 64.4 mmol) and tert-butyl [2-hydroxy-1-(oxetan-3-yl)ethyl]carbamate (7.00 g, 32.2 mmol, Intermediate 58) at 20 °C. Then diisopropyl azodicarboxylate (13 ml, 64.4 mmol, CAS-RN: [2446-83-5]) was added into the above mixture at 0 °C. The reaction mixture was stirred at 50 °C for 16 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromagraphy (petroleum ether: ethyl acetate = 10: 1 to 1: 1) to give methyl 3-bromo-1-[2-[(tert-butoxycarbonyl)amino]-2-(oxetan-3-yl)ethyl]-1H- pyrazole-5-carboxylate (13.0 g, 95% yield) as a white solid. LC-MS (Method C): Rt = 0.570 min; MS (ESIpos): m / z = 406.0 [M+H]+. Intermediate 60 tert-butyl [2-[3-bromo-5-(hydroxymethyl)-1H-pyrazol-1-yl]-1-(oxetan-3-yl)ethyl]carbamate^ To a solution of methyl 3-bromo-1-[2-[(tert-butoxycarbonyl)amino]-2-(oxetan-3-yl)ethyl]-1H- pyrazole-5-carboxylate (13.0 g, 32.2 mmol, Intermediate 59) in tetrahydrofuran (260 ml) was added lithium borohydride (40 ml, 4.0 M in tetrahydrofuran, 160 mmol) at 0 °C. The mixture was stirred at 20 °C for 12 hours. The mixture was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl [2-[3-bromo-5-(hydroxymethyl)-1H-pyrazol-1-yl]-1- (oxetan-3-yl)ethyl]carbamate (10.0 g, 83% yield) as a white solid.^ LC-MS (Method C): Rt = 0.504 min; MS (ESIpos): m / z = 376.2 [M+H]+.^ Intermediate 61 [5-bromo-2-[2-(tert-butoxycarbonylamino)-2-(oxetan-3-yl)ethyl]pyrazol-3-yl]methyl-triethyl- ammonium methanesulfonate To a solution of tert-butyl [2-[3-bromo-5-(hydroxymethyl)-1H-pyrazol-1-yl]-1-(oxetan-3- yl)ethyl]carbamate (9.00 g, 23.9 mmol, Intermediate 60) in dichloromethane (220 ml) were added triethylamine (23 ml, 170 mmol) and methanesulfonic anhydride (8.33 g, 47.8 mmol) at 25 °C. The mixture was stirred at 25 °C for 12 hours. The reaction mixture was concentrated under reduced pressure at 20 °C to give [5-bromo-2-[2-(tert- butoxycarbonylamino)-2-(oxetan-3-yl)ethyl]pyrazol-3-yl]methyl-triethyl-ammonium methanesulfonate (20.0 g, crude) as a brown oil. LC-MS (Method C): Rt = 0.437 min; MS (ESIpos): m / z = 461.2 [M+H]+.^ Intermediate 62 tert-butyl 2-bromo-6-(oxetan-3-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate^ To a solution of [5-bromo-2-[2-(tert-butoxycarbonylamino)-2-(oxetan-3-yl)ethyl]pyrazol-3- yl]methyl-triethyl-ammonium methanesulfonate (20.0 g, 36.0 mmol, Intermediate 61) in a mixed solvent of N,N-dimethylformamide (200 ml) and tetrahydrofuran (600 ml) was added sodium hydride (28.8 g, 60 % purity, 720 mmol) in portions at 0 °C. The mixture was stirred at 20 °C for 12 hours. The mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and filtered and concentrated under reduced pressure to give tert-butyl 2-bromo-6-(oxetan-3-yl)-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (20.0 g, crude) as a brown oil.^ Intermediate 63 tert-butyl 2-bromo-3-iodo-6-(oxetan-3-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate^ To a solution of tert-butyl 2-bromo-6-(oxetan-3-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxylate (20.0 g, 55.8 mmol, Intermediate 64Intermediate 62) in a mixed solvent of dichloromethane (300 ml) and methanol (100 ml) was added N-iodosuccinimide (37.7 g, 167 mmol) at 20 °C. The resulting mixture was stirred at 43 °C for 12 hours. The mixture was quenched with saturated sodium sulfite solution, extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromagraphy (petroleum ether: ethyl acetate = 5: 1 to 1: 1) to give tert-butyl 2-bromo-3- iodo-6-(oxetan-3-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (10.0 g, 20.7 mmol, 37% yield) as a yellow solid.^ LC-MS (Method C): Rt = 0.620 min; MS (ESIpos): m / z = 486.0 [M+H]+.^ Intermediate 64 tert-butyl-2-bromo-6-(oxetan-3-yl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxylate^ To a solution of tert-butyl 2-bromo-3-iodo-6-(oxetan-3-yl)-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate (10.0 g, 20.7 mmol, Intermediate 63) and pyridin-4-ylboronic acid (10.2 g, 82.6 mmol) in a mixed solvent of 1,4-dioxane (200 ml) and water (50 ml) were added sodium carbonate (10.9 g, 103 mmol) and [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.51 g, 2.07 mmol) at 25 °C under nitrogen atmosphere. The reaction mixture was stirred at 60 °C for 16 hours under nitrogen atmosphere. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromagraphy (petroleum ether: ethyl acetate= 1: 1 to 0: 1) to give tert-butyl 2-bromo-6-(oxetan-3-yl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate (5.00 g, 56% yield) as a yellow solid. LC-MS (Method C): Rt = 0.628 min; MS (ESIpos): m / z = 437.0 [M+H]+. Intermediate 65 tert-butyl 2-(4-chlorophenyl)-6-(oxetan-3-yl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate^

[0010] To a solution of tert-butyl-2-bromo-6-(oxetan-3-yl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate (1.00 g, 2.30 mmol, Intermediate 66) and (4- chlorophenyl)boronic acid (1.08 g, 6.89 mmol) in 1,4-dioxane (25 ml) and water (10 ml) were added potassium carbonate (952 mg, 6.89 mmol) and [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (168 mg, 230 μmol) at 25 °C under nitrogen atmosphere. The reaction mixture was stirred at 80 °C under nitrogen atmosphere for 16 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromagraphy (petroleum ether: ethyl acetate = 1: 1 to 0: 1) to give tert-butyl 2-(4-chlorophenyl)-6-(oxetan-3-yl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (600 mg, 56% yield) as a yellow solid. LC-MS (Method C): Rt = 0.520 min; MS (ESIpos): m / z = 467.2 [M+H]+.^ Intermediate 66 2-(4-chlorophenyl)-6-(oxetan-3-yl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine^ To a solution of tert-butyl 2-(4-chlorophenyl)-6-(oxetan-3-yl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (600 mg, 1.28 mmol, Intermediate 65) in ethanol (5.0 ml) was added potassium hydroxide solution (5.0 ml, 10 M in water, 50 mmol). The mixture was stirred at 80 °C for 12 hours. The mixture was diluted with water and exracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC [Instrument: Gilson-281; Column: Phenomenex luna C18 150*25 mm* 5 μm; eluent A: water (0.225% ammonia hydroxide), eluent B: acetonitrile; gradient: 0-10 min 20-50% B; flow 25 ml / min; temperature: RT; Detector: UV 220 / 254 nm] to give 2-(4-chlorophenyl)-6-(oxetan-3-yl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine (200 mg, 0.545 mmol, 42% yield) as an off-white solid.^ LC-MS (Method C): Rt = 0.386 min; MS (ESIpos): m / z = 367.1 [M+H]+. Intermediate 67 tert-butyl 2-(3-chlorophenyl)-6-(oxetan-3-yl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate^ To a solution of tert-butyl 2-bromo-6-(oxetan-3-yl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate (1.00 g, 2.30 mmol, Intermediate 64) and (3- chlorophenyl)boronic acid (1.08 g, 6.89 mmol) in a mixed solvent of 1,4-dioxane (20 ml) and water (6.0 ml) were added potassium carbonate (952 mg, 6.89 mmol) and [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (168 mg, 0.230 mmol) at 25 °C under nitrogen atmosphere. The mixture was stirred at 80 °C for 12 hours under nitrogen atmosphere. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 0 to 1: 2) to give tert-butyl 2-(3-chlorophenyl)-6-(oxetan-3-yl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (840 mg, 1.80 mmol, 78% yield) as a yellow solid. LC-MS (Method G): Rt = 0.987 min; MS (ESIpos): m / z = 467.3 [M+H]+.^ Intermediate 68 2-(3-chlorophenyl)-6-(oxetan-3-yl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine^

[0011] To a solution of tert-butyl 2-(3-chlorophenyl)-6-(oxetan-3-yl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (840 mg, 1.80 mmol, Intermediate 67) in ethanol (10 ml) was added potassium hydroxide (10 ml, 10 M in water, 100 mmol) at 20 °C. The mixture was stirred at 80 °C for 16 hours. The mixture was extracted with ethyl acetate and dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed phase (0.5% ammonium hydroxide in water) to give 2-(3-chlorophenyl)-6-(oxetan-3-yl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine (500 mg, 76% yield) as a yellow solid. LC-MS (Method G): Rt = 0.857 min; MS (ESIpos): m / z = 367.1 [M+H]+. Intermediate 69 3-[6-(oxetan-3-yl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile^ To a solution of 2-(3-chlorophenyl)-6-(oxetan-3-yl)-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine (500 mg, 1.36 mmol, Intermediate 68) in acetonitrile (15 ml) was added zinc cyanide (128 mg, 1.09 mmol), nickel(II) chloride hexahydrate (32.4 mg, 136 mmol), 1,1'-bis(diphenylphosphino)ferrocene (151 mg, 0.273 mmol), 4- (dimethylamino)pyridine (333 mg, 2.73 mmol) and zinc (44.6 mg, 681 mmol) at 25 °C under nitrogen atmosphere. The mixture was stirred at 80 °C for 12 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The mixture was concentrated under reduced pressure to give a residue^ The residue was purified by preparative HPLC [Instrument: Gilson-281; Column: Phenomenex luna C18 150*25 mm* 10 μm; eluent A: water (0.225% ammonia hydroxide), eluent B: acetonitrile; gradient: 0-10 min 13-43% B; flow 25 ml / min; temperature: RT; Detector: UV 220 / 254 nm] to give 3-[6-(oxetan-3-yl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-2-yl]benzonitrile (300 mg, 0.839 mmol, 62% yield) as a white solid. LC-MS (Method G): Rt = 0.805 min; MS (ESIpos): m / z = 358.1 [M+H]+. Intermediate 70 3-tert-butyl 4-methyl 2,2-dimethyl-1,3-oxazolidine-3,4-dicarboxylate^ To a solution of methyl N-(tert-butoxycarbonyl)serinate (20.0 g, 91.2 mmol, CAS-RN: [69942-12-7]) and 4-toluenesulfonic acid monohydrate (2.60 g, 13.7 mmol) in dichloromethane (300 ml) was added 2,2-dimethoxypropane (47.5 g, 456 mmol), the mixture was stirred at 20 °C for 15 hours under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether: ethyl acetate = 1: 0 to 6: 1) to give tert-butyl 4-(2-hydroxypropan-2-yl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (20.0 g, 77.1 mmol, 85% yield) as a colorless oil.1H NMR (400 MHz, DMSO-d6) δ [ppm] = 4.42-4.37 (m, 1H), 4.16-4.13 (m, 1H), 3.96-3.93 (m, 1H), 3.68-3.66 (m, 3H), 1.54 (s, 3H), 1.44-1.34 (m, 12H). Intermediate 71 tert-butyl 4-(2-hydroxypropan-2-yl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate^ To a solution of 3-tert-butyl 4-methyl 2,2-dimethyl-1,3-oxazolidine-3,4-dicarboxylate (20.0 g, 77.1 mmol, Intermediate 70) in tetrahydrofuran (300 ml) was added bromo(methyl)magnesium (77 ml, 3.0 M in ethoxyethane, 230 mmol) at 0 °C under a nitrogen atmosphere over 0.5 hours, the mixture was stirred at 0 °C for 2 hours. The mixture was quenched with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a tert-butyl 4-[2- (benzyloxy)propan-2-yl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylat (19.0 g, 73.3 mmol, 95% yield) as a colorless oil.1H NMR (400 MHz, DMSO-d6) δ [ppm] = 4.67-4.42 (m, 1H), 4.02-3.92 (m, 1H), 3.87-3.68 (m, 2H), 1.51 (s, 3H), 1.50-1.42 (m, 12H), 1.08-1.03 (m, 6H). Intermediate 72 tert-butyl 4-[2-(benzyloxy)propan-2-yl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate To a solution of tert-butyl 4-(2-hydroxypropan-2-yl)-2,2-dimethyl-1,3-oxazolidine-3- carboxylate (6.00 g, 23.1 mmol,Intermediate 71) and (bromomethyl)benzene (19.8 g, 116 mmol) in N,N-dimethylformamide (120 ml) was added sodium hydride (2.3 g, 57.8 mmol, 60% purity in mineral oil) at 0 °C. The mixture was stirred at 20 °C for 15 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether: ethyl acetate = 1: 0 to 10: 1) to give tert-butyl 4-[2- (benzyloxy)propan-2-yl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (8.00 g, 22.9 mmol, 99% yield) as a colorless oil.1H NMR (400 MHz, DMSO-d6) δ [ppm] = 7.32-7.29 (m, 4H), 7.27-7.23 (m, 1H), 4.48-4.40 (q, J = 11.6 Hz, 2H), 4.07-4.04 (d, J = 14.4 Hz, 1H), 4.02-3.91 (m, 1H), 3.89-3.87 (m, 1H), 1.53 (s, 3H), 1.48-1.39 (m, 12H), 1.21 (s, 3H), 1.16 (s, 3H). Intermediate 73 tert-butyl [3-(benzyloxy)-1-hydroxy-3-methylbutan-2-yl]carbamate^ To a solution of tert-butyl 4-[2-(benzyloxy)propan-2-yl]-2,2-dimethyl-1,3-oxazolidine-3- carboxylate (8.00 g, 22.9 mmol,Intermediate 72) in methanol (100 ml) was addded 4- toluenesulfonic acid monohydrate (0.87 g, 4.58 mmol), the mixture was stirred at 20 °C for 15 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether: ethyl acetate = 1: 0 to 4: 1) to give tert-butyl [3-(benzyloxy)-1-hydroxy-3-methylbutan-2- yl]carbamate (4.00 g, 12.9 mmol, 56% yield) as a white solid. LC-MS (Method C): Rt= 0.943 min; MS (ESIpos): m / z = 210.1 [M-100+H]+.1H NMR (400 MHz, DMSO-d6) δ [ppm] = 7.32-7.27 (m, 6H), 6.51-6.48 (d, J = 9.2 Hz, 1H), 4.42-4.41 (d, J = 2.8 Hz, 2H), 4.39-4.37 (m, 1H), 3.70-3.63 (m, 2H), 3.37-3.34 (m, 1H), 1.39 (s, 9H), 1.16 (s, 3H), 1.12 (m, 3H). Intermediate 74 methyl 1-{3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyl}-3-bromo-1H- pyrazole-5-carboxylate^ To a solution of tert-butyl [3-(benzyloxy)-1-hydroxy-3-methylbutan-2-yl]carbamate (1.00 g, 3.23 mmol, Intermediate 73) and methyl 3-bromo-1H-pyrazole-5-carboxylate (0.60 g, 2.91 mmol) in tetrahydrofuran (20.0 ml) was added triphenylphosphine (1.70 g, 6.46 mmol) and diisopropyl azodicarboxylate (1.31 g, 6.46 mmol) at 0 °C. The mixture was stirred at 20 °C for 15 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether: ethyl acetate = 1: 0 to 7: 1) to give methyl 1-{3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyl}-3-bromo-1H- pyrazole-5-carboxylate (1.00 g, 2.01 mmol, 62% yield) as a colorless oil. LC-MS (Method C): Rt= 1.130 min; MS (ESIpos): m / z = 398.0 [M-100+2+H]+. Intermediate 75 tert-butyl {3-(benzyloxy)-1-[3-bromo-5-(hydroxymethyl)-1H-pyrazol-1-yl]-3-methylbutan-2- yl}carbamate^ To a solution of methyl 1-{3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyl}-3- bromo-1H-pyrazole-5-carboxylate (0.50 g, 1.01 mmol,Intermediate 74) in tetrahydrofuran (10.0 ml) was added lithium borohydride (1.26 ml, 5.04 mmol, 4 M in tetrahydrofuran) at 0 °C, the mixture was stirred at 20 °C for 15 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl {3-(benzyloxy)-1-[3-bromo-5-(hydroxymethyl)-1H-pyrazol-1-yl]-3-methylbutan-2- yl}carbamate (0.45 g, 0.96 mmol, 95% yield) as a colorless oil. LC-MS (Method C): Rt= 0.952 min; MS (ESIpos): m / z = 470.1 [M+H]+. Intermediate 76 [2-[3-benzyloxy-2-(tert-butoxycarbonylamino)-3-methyl-butyl]-5-bromo-pyrazol-3-yl]methyl- triethyl-ammonium methanesulfonate

[0012] To a solution of tert-butyl {3-(benzyloxy)-1-[3-bromo-5-(hydroxymethyl)-1H-pyrazol-1-yl]-3- methylbutan-2-yl}carbamate (450 mg, 0.96 mmol,Intermediate 75) in dichloromethane (9.0 ml) were added triethylamine (681 mg, 6.73 mmol) and methanesulfonic anhydride (335 mg, 1.92 mmol), the mixture was strred at 20 °C for 15 hours. The reaction mixture was concentrated under reduced pressure to give N-[(1-{3-(benzyloxy)-2-[(tert- butoxycarbonyl)amino]-3-methylbutyl}-3-bromo-1H-pyrazol-5-yl)methyl]-N,N- diethylethanaminium methanesulfonate (600 mg, 0.93 mmol, 96% yield) as a yellow oil. The crude product was used directly in the next step. Intermediate 77 tert-butyl 6-[2-(benzyloxy)propan-2-yl]-2-bromo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate^ To a solution of [2-[3-benzyloxy-2-(tert-butoxycarbonylamino)-3-methyl-butyl]-5-bromo- pyrazol-3-yl]methyl-triethyl-ammonium methanesulfonate (600 mg, 0.93 mmol, Intermediate 76) in tetrahydrofuran (12.0 ml) and N,N-dimethylformamide (4.0 ml) was added sodium hydride (370 mg, 9.26 mmol, 60% in mineral oil) at 0 °C, the mixture was stirred at 20 °C for 15 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1: 0 to 9: 1) to give tert-butyl 6-[2-(benzyloxy)propan-2-yl]-2-bromo-6,7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxylate (400 mg, 0.89 mmol, 96% yield) as a yellow oil. LC-MS (Method C): Rt= 1.054 min; MS (ESIpos): m / z = 452.2 [M+H]+. Intermediate 78 tert-butyl 6-[2-(benzyloxy)propan-2-yl]-2-bromo-3-iodo-6,7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxylate^ ^ To a solution of tert-butyl 6-[2-(benzyloxy)propan-2-yl]-2-bromo-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate (400 mg, 0.89 mmol, Intermediate 77) in dichloromethane (8.0 ml) and methanol (4.0 ml) was added N-iodosuccinimide (1.00 g, 4.44 mmol), the mixture was stirred at 45 °C for 48 hours. The reaction mixture was diluted with saturated sodium sulfite solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1: 0 to 9: 1) to give tert-butyl 6-[2-(benzyloxy)propan-2-yl]-2-bromo-3- iodo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (380 mg, 0.66 mmol, 74% yield) as a yellow solid. LC-MS (Method C): Rt= 1.120 min; MS (ESIpos): m / z = 576.1 [M+H]+. Intermediate 79 tert-butyl 6-[2-(benzyloxy)propan-2-yl]-2-bromo-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate^

[0013] To a solution of tert-butyl 6-[2-(benzyloxy)propan-2-yl]-2-bromo-3-iodo-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (300 mg, 0.52 mmol, Intermediate 78) and pyridin-4-ylboronic acid (64.0 mg, 0.52 mmol) in 1,4-dioxane (10.0 ml) and water (3.0 ml) were added sodium carbonate (276 mg, 2.60 mmol) and [1,1’- bis(diphenylphosphino)ferrocene] dichloropalladium(II) (38.1 mg, 52.1 μmol) under nitrogen atmosphere, the mixture was stirred at 60 °C for 15 hours under nitrogen atmosphere. The reaction solution was washed with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether: ethyl acetate = 7: 3 to 3: 2) to give tert- butyl 6-[2-(benzyloxy)propan-2-yl]-2-bromo-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate (230 mg, 0.44 mmol, 84% yield) as a yellow oil. LC-MS (Method C): Rt= 0.878 min; MS (ESIpos): m / z = 529.1 [M+H]+. Intermediate 80 tert-butyl 6-[2-(benzyloxy)propan-2-yl]-2-(3-cyanophenyl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate^ To a solution of tert-butyl 6-[2-(benzyloxy)propan-2-yl]-2-bromo-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (750 mg, 1.42 mmol, Intermediate 79) and (3-cyanophenyl)boronic acid (627 mg, 4.27 mmol) in 1,4-dioxane (75.0 ml) and water (15.0 ml) were added potassium carbonate (983 mg, 7.11 mmol) and [1,1’- bis(diphenylphosphino) ferrocene]dichloropalladium(II) (104 mg, 0.142 mmol), the mixture was stirred at 80 °C for 16 hours under nitrogen atmosphere. The reaction solution was washed with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether: ethyl acetate = 7: 3 to 1: 4) to give tert-butyl 6-[2-(benzyloxy)propan-2-yl]- 2-(3-cyanophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (400 mg, 0.73 mmol, 51% yield) as a yellow solid. LC-MS (Method C): Rt= 0.997 min; MS (ESIpos): m / z = 550.2 [M+H]+. Intermediate 81 3-[6-[2-(benzyloxy)propan-2-yl]-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2- yl]benzonitrile^ A solution of tert-butyl 6-[2-(benzyloxy)propan-2-yl]-2-(3-cyanophenyl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (400 mg, 0.728 mmol, Intermediate 80) in hydrogen chloride (5.0 ml, 4 M in ethyl acetate) was stirred at 20 °C for 1 hour. The solvent was evaporated under reduced pressure. The crude product of 3-[6-[2- (benzyloxy)propan-2-yl]-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2- yl]benzonitrile (320 mg, 0.71 mmol, 98% yield) was used directly in the next step. LC-MS (Method C): Rt= 0.756 min; MS (ESIpos): m / z = 450.2 [M+H]+. Intermediate 82 3-[6-(2-hydroxypropan-2-yl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2- yl]benzonitrile^ ^ To a solution of 3-[6-[2-(benzyloxy)propan-2-yl]-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile (320 mg, 0.712 mmol, Intermediate 81) in dichloromethane (32.0 ml) was added trifluoroacetic acid (32 ml, 420 mmol), the reaction mixture was stirred at 40 °C for 16 hour. The solvent was concentrated under reduced pressure. The residue was purified by flash reversed phase (acetonitrile / water, 0.05% ammonium hydroxide, 5%~15%) to give 3-[6-(2-hydroxypropan-2-yl)-3-(pyridin-4-yl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile (200 mg, 0.56 mmol, 78% yield) as a white solid. LC-MS (Method G): Rt= 0.784 min; MS (ESIpos): m / z = 360.1 [M+H]+. Intermediate 83 methyl 3-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5-carboxylate^ To a solution of methyl 3-bromo-1H-pyrazole-5-carboxylate (100 g, 488 mmol, CAS-RN:[ 1328893-17-9]) in tetrahydrofuran (1500 ml) was added sodium hydride (23.4 g, 585 mmol, 60% puirty) at 0 °C, the mixture was stirred at 0 °C for 1 hour, and then [2- (chloromethoxy)ethyl](trimethyl)silane (122 g, 732 mmol) was added, the reaction mixture was stirred at 0 °C for another 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate^ The combined organic layers were concentrated in vacuo to give a residue. The residue was purified by flash column on silica gel (petroleum ether: ethyl acetate = 100: 1 to 10: 1) to give methyl 3-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H- pyrazole-5-carboxylate (160 g, 477 mmol, 98% yield) as a yellow oil.^ Intermediate 84 methyl 3-(3-cyanophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5-carboxylate^ To a solution of methyl 3-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5- carboxylate (160 g, 477 mmol, Intermediate 83) and (3-cyanophenyl)boronic acid (70.1 g, 477 mmol) in dioxane (1000 ml) and water (300 ml) were added [1,1- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (17.5 g, 23.9 mmol) and sodium carbonate (101 g, 954 mmol), the reaction mixture was heated to 90 °C and stirred for 16 hours under nitrogen atomosphere. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phase was concentrated in vacuo to give a residue. The residue was purified by flash column on silica gel (petroleum ether: ethyl acetate = 1:0 to 5:1) to give methyl 3-(3-cyanophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}- 1H-pyrazole-5-carboxylate (132 g, 369 mmol, 77% yield) as a yellow solid. LC-MS (Method C): Rt= 1.147 min; MS (ESIpos): m / z = 358.1 [M+H]+. Intermediate 85 methyl 3-(3-cyanophenyl)-1H-pyrazole-5-carboxylate^ To a solution of methyl 3-(3-cyanophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole- 5-carboxylate (132 g, 369 mmol, Intermediate 84) in dichloromethane (1000 ml) was added trifluoroacetic acid (300 ml) at 25 °C, the mixture was stirred at 25 °C for 3 hours. The solvent was removed in vacuo to give methyl 3-(3-cyanophenyl)-1H-pyrazole-5-carboxylate (85.0 g, crude) as a yellow solid. LC-MS (Method C): Rt= 0.788 min; MS (ESIpos): m / z = 228.1 [M+H]+. Intermediate 86 methyl 3-(3-cyanophenyl)-4-iodo-1H-pyrazole-5-carboxylate^ To a solution of methyl 3-(3-cyanophenyl)-1H-pyrazole-5-carboxylate (85.0 g, 374 mmol, Intermediate 85) in N,N-dimethylformamide (800 ml) was added N-iodosuccinimide (126 g, 561 mmol), the mixture was heated to 50 °C and stirred for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with sodium sulfite solution and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by flash column on silica gel (petroleum ether: ethyl acetate = 50: 1 to 2: 1) to give methyl 3-(3-cyanophenyl)-4-iodo- 1H-pyrazole-5-carboxylate (130 g, 368 mmol, 98% yield) as an off-white solid. LC-MS (Method C): Rt= 0.494 min; MS (ESIpos): m / z = 353.9 [M+H]+. Intermediate 87 methyl 3-(3-cyanophenyl)-4-(pyridin-4-yl)-1H-pyrazole-5-carboxylate^ To a solution of methyl 3-(3-cyanophenyl)-4-iodo-1H-pyrazole-5-carboxylate (10.0 g, 28.3 mmol, Intermediate 86) and pyridin-4-ylboronic acid (10.4 g, 85.0 mmol) in 1,4-dioxane (300 ml) and water (80 ml) were added [1,1- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.07 g, 2.83 mmol) and caesium fluoride (8.60 g, 56.6 mmol), the mxiture was heated to 110 °C and stirred for 16 hours under nitrogen atmosphere. The reaction mixture was filtered and the filtrate was poured into water, extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was triturated with ethyl acetate. The suspensiom was filtered. The filter cake was collected and dired in vacuo to give methyl 3-(3-cyanophenyl)-4-(pyridin-4- yl)-1H-pyrazole-5-carboxylate (6.10 g, 20.0 mmol, 71% yield) as a brown solid.^ LC-MS (Method C): Rt= 0.373 min; MS (ESIpos): m / z = 305.0 [M+H]+. Intermediate 88 methyl 1-{(2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentyl}-3-(3-cyanophenyl)-4- (pyridin-4-yl)-1H-pyrazole-5-carboxylate^ To a solution of methyl 3-(3-cyanophenyl)-4-(pyridin-4-yl)-1H-pyrazole-5-carboxylate (3.30 g, 10.8 mmol, Intermediate 87) and tert-butyl [(2S)-1-hydroxy-4-methylpentan-2- yl]carbamate (2.59 g, 11.9 mol) in tetrahydrofuran (150 ml) were added triphenylphosphine (8.53 g, 32.5 mmol) and diisopropyl azodicarboxylate (6.58 g, 32.5 mmol, CAS-RN: [2446- 83-5]), the reaction mixture was heated to 60 °C and stirred for 3 hours. The solvent was removed in vacuo to give a residue. The residue was purified by reversed phase [Instrument: GX-A; Column: Waters Xbridge 450*45mm* 5μm; eluent A: water (0.2% FA), eluent B: acetonitrile; gradient: 0-10 min 15-50% B; flow 60 ml / min; temperature: RT; Detector: UV 220 / 254 nm] to give methyl 1-{(2S)-2-[(tert-butoxycarbonyl)amino]-4- methylpentyl}-3-(3-cyanophenyl)-4-(pyridin-4-yl)-1H-pyrazole-5-carboxylate (3.30 g, 6.55 mmol, 60% yield) as a yellow solid.^ LC-MS (Method G): Rt= 1.075 min; MS (ESIpos): m / z = 504.2 [M+H]+. Intermediate 89 tert-butyl {(2S)-1-[3-(3-cyanophenyl)-5-(hydroxymethyl)-4-(pyridin-4-yl)-1H-pyrazol-1-yl]-4- methylpentan-2-yl}carbamate^

[0014] To a solution of methyl 1-{(2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentyl}-3-(3- cyanophenyl)-4-(pyridin-4-yl)-1H-pyrazole-5-carboxylate (3.30 g, 6.55 mmol, Intermediate 88) in tetrahydrofuran (50 ml) was added lithium aluminum hydride (2.5 M in tetrahydrofuran, 3.1 ml, 7.9 mmol) at -30 °C, the reaction mixture was stirred at -30 °C for 1 hour. The reaction mixture was quenched by slowly adding water. The resulted solution was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue. The residue was purified by flash column on silica gel (petroleum ether: ethyl acetate= 20: 1 to 1: 3) to give tert-butyl {(2S)-1-[3-(3-cyanophenyl)-5-(hydroxymethyl)-4-(pyridin-4-yl)-1H- pyrazol-1-yl]-4-methylpentan-2-yl}carbamate (2.20 g, 4.63 mmol, 71% yiled) as a yellow solid. LC-MS (Method D): Rt= 0.733 min; MS (ESIpos): m / z = 476.2 [M+H]+. Intermediate 90 [1-{(2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentyl}-3-(3-cyanophenyl)-4-(pyridin-4-yl)- 1H-pyrazol-5-yl]methyl methanesulfonate^ To a solution of tert-butyl {(2S)-1-[3-(3-cyanophenyl)-5-(hydroxymethyl)-4-(pyridin-4-yl)-1H- pyrazol-1-yl]-4-methylpentan-2-yl}carbamate (2.20 g, 4.63 mmol, Intermediate 89) in dichloromethane (50 ml) was added triethylamine (2.81 g, 27.8 mmol) at 0 °C, and then methanesulfonic anhydride (2.42 g, 13.9 mmol) was added into the reaction mixture, the reaction mixture was warmed to 25 °C and stirred for 1 hour. The solvent was removed in vacuo to give [1-{(2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentyl}-3-(3-cyanophenyl)-4- (pyridin-4-yl)-1H-pyrazol-5-yl]methyl methanesulfonate (2.50 g, crude). LC-MS (Method C): Rt= 0.503 min; MS (ESIpos): m / z = 554.3 [M+H]+. Intermediate 91 tert-butyl (6S)-2-(3-cyanophenyl)-6-(2-methylpropyl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate^ To a solution of [1-{(2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentyl}-3-(3-cyanophenyl)- 4-(pyridin-4-yl)-1H-pyrazol-5-yl]methyl methanesulfonate (2.50 g, 4.52 mmol, Intermediate 90) in tetrahydrofuran (100 ml) was added sodium hydride (3.61 g, 90.3 mmol, 60% purity) at 0 °C, the reaction mixture was warmed to 25 °C and stirred for 1 hour. The reaction mixture was quenched by slowly adding water and extracted with ethyl acetate. The combined organic layers were concentrated to give a residue. The residue was purified by flash column on silica gel (petroleum ether: ethyl acetate = 100: 1 to 3: 1) to give tert-butyl (6S)-2-(3-cyanophenyl)-6-isobutyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxylate (500 mg, 1.09 mmol, 24% yield) as a yellow solid.^ LC-MS (Method C): Rt= 0.510 min; MS (ESIpos): m / z = 458.3 [M+H]+. Intermediate 92 3-[(6S)-6-(2-methylpropyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2- yl]benzonitrile hydrogen chloride (1: 1)^

[0015] To a solution of tert-butyl (6S)-2-(3-cyanophenyl)-6-(2-methylpropyl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (500 mg, 1.09 mmol, Intermediate 91) in hydrochloric acid (2 M in 1,2-dioxane, 10 ml), the mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated in vacuo to give 3-[(6S)-6-(2-methylpropyl)-3- (pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile—hydrogen chloride (1: 1) (300 mg, crude) as a brown oil.^ LC-MS (Method C): Rt= 0.230 min; MS (ESIpos): m / z = 358.2 [M+H]+. Intermediate 93 N-(tert-butoxycarbonyl)-5,5,5-trifluoro-L-norvaline^ To a solution of 5,5,5-trifluoro-L-norvaline (1.90 g, 11.1 mmol, CAS-RN: [122565-28-0]) and di-tert-butyl dicarbonate (4.85 g, 22.2 mmol) in tetrahydrofuran (30 ml) and water (30 ml) was added potassium carbonate (6.14 g, 44.4 mmol) at 25 °C and the mixture was stirred at 25 °C for 16 hours. The pH of the reaction mixture was adjusted to 3 with hydrochloric acid solution (1 M). Then the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give N-(tert-butoxycarbonyl)-5,5,5-trifluoro-L-norvaline (3.00 g, crude). Intermediate 94 methyl N-(tert-butoxycarbonyl)-5,5,5-trifluoro-L-norvalinate^ A solution of N-(tert-butoxycarbonyl)-5,5,5-trifluoro-L-norvaline (1.10 g, 4.06 mmol, Intermediate 93), iodomethane (633 mg, 4.61 mmol) and sodium hydrogen carbonate (1.02 g, 12.2 mmol) in N,N-dimethylformamide (30 ml) was stirred at 20 °C for 6 hours. The reaction mixture was poured into water. The mixture was extracted with ethyl acetate. The combined organic layers were concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 0 to 5: 1) to give methyl N-(tert-butoxycarbonyl)-5,5,5-trifluoro-L-norvalinate (1.10 g, 3.86 mmol, 95% yield) as a pale yellow oil.1H NMR (400 MHz, CDCl3) δ [ppm] = 5.10 (d, J = 4.8 Hz, 1H), 4.37 (s, 1H), 3.78 (s, 3H), 2.28-2.07 (m, 3H), 1.94-1.80 (m, 1H), 1.46 (s, 9H). Intermediate 95 tert-butyl [(2S)-5,5,5-trifluoro-1-hydroxypentan-2-yl]carbamate^ To a solution of methyl N-(tert-butoxycarbonyl)-5,5,5-trifluoro-L-norvalinate (1.10 g, 3.86 mmol, Intermediate 94) in tetrahydrofuran (50 ml) was added lithium borohydride (2.9 ml, 4 M in tetrahydrofuran, 11.6 mmol) at 0 °C and the mixture was sitrred at 20 °C for 2 hours. The reaction mixture was quenched by water. The mixture was extracted with ethyl acetate. The combined organic layers were concentrated in vacuo to give tert-butyl [(2S)-5,5,5- trifluoro-1-hydroxypentan-2-yl]carbamate (990 mg, crude) as a white solid.1H NMR (400 MHz, CDCl3) δ [ppm] = 4.78 (d, J = 4.4 Hz, 1H), 3.75-3.55 (m, 3H), 2.35 (s, 1H), 2.28-2.10 (m, 2H), 1.87-1.66 (m, 2H), 1.45 (s, 9H). Intermediate 96 methyl 1-{(2S)-2-[(tert-butoxycarbonyl)amino]-5,5,5-trifluoropentyl}-3-(3-cyanophenyl)-4- (pyridin-4-yl)-1H-pyrazole-5-carboxylate^ To a solution of methyl 3-(3-cyanophenyl)-4-(pyridin-4-yl)-1H-pyrazole-5-carboxylate (1.07 g, 3.50 mmol, Intermediate 87) and tert-butyl [(2S)-5,5,5-trifluoro-1-hydroxypentan-2- yl]carbamate (900 mg, 3.50 mmol, Intermediate 95) in tetrahydrofuran (100 ml) were added diisopropyl azodicarboxylate (2.83 g, 14.0 mmol, CAS-RN: [2446-83-5]) and triphenylphosphine (3.67 g, 14.0 mmol) at 25 °C. The reaction mixture was sitrred at 60 °C for 16 hours. The reaction mixture was poured in water. The mixture was extracted with ethyl acetate. The combined organic layers were concentrated in vacuo to give a residue. The residue was purified by reversed phase [Column: Spherical C1820-45 μm 60Å, eluent A: water (0.5% ammonia hydroxide), eluent B: acetonitrile; gradient: 0-20 min 20%-70%B] to give methyl 1-{(2S)-2-[(tert-butoxycarbonyl)amino]-5,5,5-trifluoropentyl}-3-(3- cyanophenyl)-4-(pyridin-4-yl)-1H-pyrazole-5-carboxylate (1.80 g, 2.98 mmol, 90% yield, 85% yield) as a brown oil. LC-MS (Method G): Rt= 0.992 min; MS (ESIpos): m / z = 544.1 [M+H]+. Intermediate 97 tert-butyl {(2S)-1-[3-(3-cyanophenyl)-5-(hydroxymethyl)-4-(pyridin-4-yl)-1H-pyrazol-1-yl]- 5,5,5-trifluoropentan-2-yl}carbamate^

[0016] To a solution of methyl 1-{(2S)-2-[(tert-butoxycarbonyl)amino]-5,5,5-trifluoropentyl}-3-(3- cyanophenyl)-4-(pyridin-4-yl)-1H-pyrazole-5-carboxylate (1.60 g, 2.94 mmol, Intermediate 96) in tetrahydrofuran (100 ml) was added lithium aluminum hydride (2.4 ml, 2.5 M in tetrahydrofuran, 5.89 mmol) at -40°C under nitrogen atmosphere. The mixture was sitrred at -40 °C for 2 hours under nitrogen atmosphere. The reaction mixture was quenched by sodium sulfate decahydrate at -30 °C. The mixture was filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (petrodeum ether: ethyl acetate = 1: 0 to 1: 1) to give tert-butyl {(2S)-1-[3- (3-cyanophenyl)-5-(hydroxymethyl)-4-(pyridin-4-yl)-1H-pyrazol-1-yl]-5,5,5-trifluoropentan- 2-yl}carbamate (1.20 g, 2.33 mmol, 79% yield) as a pale yellow oil. LC-MS (Method C): Rt= 0.832 min; MS (ESIpos): m / z = 516.3 [M+H]+. Intermediate 98 tert-butyl {(2S)-1-[5-(chloromethyl)-3-(3-cyanophenyl)-4-(pyridin-4-yl)-1H-pyrazol-1-yl]- 5,5,5-trifluoropentan-2-yl}carbamate^ To a solution of tert-butyl {(2S)-1-[3-(3-cyanophenyl)-5-(hydroxymethyl)-4-(pyridin-4-yl)-1H- pyrazol-1-yl]-5,5,5-trifluoropentan-2-yl}carbamate (1.00 g, 19.4 mmol, Intermediate 97) in tetrahydrofuran (30 ml) was added thionyl chloride (0.28 ml, 3.88 mmol) at 25 °C. The mixture was sitrred at 25 °C for 1 hour. The reaction mixture was concentrated in vacuo to give tert-butyl {(2S)-1-[5-(chloromethyl)-3-(3-cyanophenyl)-4-(pyridin-4-yl)-1H-pyrazol-1- yl]-5,5,5-trifluoropentan-2-yl}carbamate (1.00 g, crude) as a white solid. LC-MS (Method C): Rt= 0.909 min; MS (ESIpos): m / z = 534.1 [M+H]+. Intermediate 99 3-{1-[(2S)-2-amino-5,5,5-trifluoropentyl]-5-(chloromethyl)-4-(pyridin-4-yl)-1H-pyrazol-3- yl}benzonitrile hydrochloride (1: 1)^ To a solution of tert-butyl {(2S)-1-[5-(chloromethyl)-3-(3-cyanophenyl)-4-(pyridin-4-yl)-1H- pyrazol-1-yl]-5,5,5-trifluoropentan-2-yl}carbamate (1.00 g, 1.87 mmol, Intermediate 98) in ethyl acetate (10 ml) was added hydrochloric acid (20 ml, 2 M in ethyl acetate, 40.0 mmol), the mixture was sitrred at 25 °C for 4 hours. The reaction mixture was concentrated in vacuo to give 3-{1-[(2S)-2-amino-5,5,5-trifluoropentyl]-5-(chloromethyl)-4-(pyridin-4-yl)-1H- pyrazol-3-yl}benzonitrile hydrochloride (1: 1) (850 mg, crude) as a pale yellow solid. LC-MS (Method C): Rt= 0.732 min; MS (ESIpos): m / z = 434.1 [M+H]+. Intermediate 100 3-[(6S)-3-(pyridin-4-yl)-6-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2- yl]benzonitrile^

[0017] A solution of 3-{1-[(2S)-2-amino-5,5,5-trifluoropentyl]-5-(chloromethyl)-4-(pyridin-4-yl)-1H- pyrazol-3-yl}benzonitrile (850 mg, 19.6 mmol, Intermediate 99) and potassium carbonate (1.35 g, 9.80 mmol) in acetonitrile (60 ml) and N,N-dimethylformamide (20 ml) was stirred at 25 °C for 16 hours. The reaction mixture was poured into water. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 3-[(6S)-3-(pyridin- 4-yl)-6-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile (700 mg, crude) as a brown oil. LC-MS (Method C): Rt= 0.682 min; MS (ESIpos): m / z = 398.1 [M+H]+. Intermediate 101 N-(tert-butoxycarbonyl)-5,5,5-trifluoro-D-norvaline To a solution of 5,5,5-trifluoro-D-norvaline (1.00 g, 5.84 mmol, CAS-RN:[ 122565-29-1]) and di-tert-butyl dicarbonate (2.7 ml, 12 mmol) in tetrahydrofuran (20 ml) and water (20 ml) was added potassium carbonate (3.23 g, 23.4 mmol) at 25 °C and the mixture was stirred at 25 °C for 16 hours. The pH of the reaction mixture was adjusted to 3 with hydrochloric acid solution (1 M). The mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give N- (tert-butoxycarbonyl)-5,5,5-trifluoro-D-norvaline (1.20 g, crude) as a yellow oil. LC-MS (Method G): Rt= 0.223 min; MS (ESIpos): m / z = 270.1 [M-H]-. Intermediate 102 methyl N-(tert-butoxycarbonyl)-5,5,5-trifluoro-D-norvalinate To a solution of N-(tert-butoxycarbonyl)-5,5,5-trifluoro-D-norvaline (1.00 g, 3.69 mmol, Intermediate 101) and sodium bicarbonate (929 mg, 11.1 mmol) in N,N-dimethylformamide (15 ml) was added stirred iodomethane (0.25 ml, 4.06 mmol) under nitrogen atmosphere at 20 °C. The mixture was stirred at 20 °C for 6 hours. The reaction solution was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (petroleum ether: ethyl aceate = 1: 0 to 3: 1) to give methyl N-(tert-butoxycarbonyl)-5,5,5-trifluoro-D- norvalinate (1.00 g, 3.51 mmol, 95% yield) as a yellow solid. LC-MS (Method C): Rt= 0.940 min; MS (ESIpos): m / z = 186.1 [M-100+H]+. Intermediate 103 tert-butyl [(2R)-5,5,5-trifluoro-1-hydroxypentan-2-yl]carbamate To a solution of methyl N-(tert-butoxycarbonyl)-5,5,5-trifluoro-D-norvalinate(1.00 g, 3.51 mmol, Intermediate 102) in tetrahydrofuran (15 ml) was added lithium borohydride (2.6 ml, 4.0 M in tetrahydrofuran, 11.0 mmol) at 0°C under nitrogen atmosphere. The mixture was sitrred at 20 °C for 2 hours. The reaction mixture was quenched by slow adding water. The mixture was extracted with ethyl acetate. The combined organic layers were concentrated in vacuo to give tert-butyl [(2R)-5,5,5-trifluoro-1-hydroxypentan-2-yl]carbamate (900 mg, crude) as a white solid. LC-MS (Method C): Rt= 0.964 min; MS (ESIpos): m / z = 158.2 [M-100+H]+. Intermediate 104 methyl 1-{(2R)-2-[(tert-butoxycarbonyl)amino]-5,5,5-trifluoropentyl}-3-(3-cyanophenyl)-4- (pyridin-4-yl)-1H-pyrazole-5-carboxylate To a solution of tert-butyl [(2R)-5,5,5-trifluoro-1-hydroxypentan-2-yl]carbamate (800 mg, 3.11 mmol, Intermediate 103) and methyl 3-(3-cyanophenyl)-4-(pyridin-4-yl)-1H-pyrazole- 5-carboxylate (946 mg, 3.11 mmol, Intermediate 87) in tetrahydrofuran (30 ml) were added diisopropyl azodicarboxylate (3.77 g, 18.7 mmol, CAS-RN: [2446-83-5]) and triphenylphosphine (4.89 g, 18.7 mmol) at 0 °C. The reaction mixture was sitrred at 60 °C for 16 hours. The reaction solution was poured into water. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by flash reversed phase (acetonitrile / water, 0.05% ammonium hydroxide, 45%~50%) to give methyl 1-{(2R)-2-[(tert-butoxycarbonyl)amino]-5,5,5-trifluoropentyl}-3-(3- cyanophenyl)-4-(pyridin-4-yl)-1H-pyrazole-5-carboxylate (1.20 g, 2.21 mmol, 71% yield) as a brown solid. LC-MS (Method G): Rt= 0.966 min; MS (ESIpos): m / z = 544.1 [M+H]+. Intermediate 105 tert-butyl {(2R)-1-[3-(3-cyanophenyl)-5-(hydroxymethyl)-4-(pyridin-4-yl)-1H-pyrazol-1-yl]- 5,5,5-trifluoropentan-2-yl}carbamate

[0018] To a solution of methyl 1-{(2R)-2-[(tert-butoxycarbonyl)amino]-5,5,5-trifluoropentyl}-3-(3- cyanophenyl)-4-(pyridin-4-yl)-1H-pyrazole-5-carboxylate (1.20 g, 2.21 mmol, Intermediate 104) in tetrahydrofuran (12 ml) was added lithium aluminum hydride (1.8 ml, 2.5 M in tetrahydrofuran, 4.40 mmol) at -40°C under nitrogen atmosphere. The mixture was sitrred at -40°C for 2 hours. The reaction mixture was quenched by adding sodium sulfate decahydrate at -30 °C. The suspension was collected by filtration, concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (petrodeum ether: ethyl acetate = 1: 0 to 1: 1) to give tert-butyl {(2R)-1-[3-(3-cyanophenyl)-5- (hydroxymethyl)-4-(pyridin-4-yl)-1H-pyrazol-1-yl]-5,5,5-trifluoropentan-2-yl}carbamate (400 mg, 0.780 mmol, 35% yield) as a pale yellow oil. LC-MS (Method C): Rt= 0.480 min; MS (ESIpos): m / z = 516.2 [M+H]+. Intermediate 106 tert-butyl {(2R)-1-[5-(chloromethyl)-3-(3-cyanophenyl)-4-(pyridin-4-yl)-1H-pyrazol-1-yl]- 5,5,5-trifluoropentan-2-yl}carbamate To a solution of tert-butyl {(2R)-1-[3-(3-cyanophenyl)-5-(hydroxymethyl)-4-(pyridin-4-yl)-1H- pyrazol-1-yl]-5,5,5-trifluoropentan-2-yl}carbamate (400 mg, 0.776 mmol, Intermediate 105) in dichloromethane (6.0 ml) was added thionyl chloride (0.11 ml, 1.6 mmol) at 25 °C. The mixture was sitrred at 25 °C for 1 hour. The reaction mixture was concentrated in vacuo to give tert-butyl {(2R)-1-[5-(chloromethyl)-3-(3-cyanophenyl)-4-(pyridin-4-yl)-1H-pyrazol-1- yl]-5,5,5-trifluoropentan-2-yl}carbamate (350 mg, crude) as a white solid. LC-MS (Method G): Rt= 1.078 min; MS (ESIpos): m / z = 534.2 [M+H]+. Intermediate 107 3-{1-[(2R)-2-amino-5,5,5-trifluoropentyl]-5-(chloromethyl)-4-(pyridin-4-yl)-1H-pyrazol-3- yl}benzonitrile hydrogen chloride (1: 1) To a solution of tert-butyl {(2R)-1-[5-(chloromethyl)-3-(3-cyanophenyl)-4-(pyridin-4-yl)-1H- pyrazol-1-yl]-5,5,5-trifluoropentan-2-yl}carbamate (350 mg, 0.655 mmol, Intermediate 106) in 1,4-dioxane (6.0 ml) was added hydrochloric acid (8.0 ml, 2 M in 1,4-dioxane, 16.0 mmol) and then the mixture was sitrred at 25 °C for 2 hours. The reaction mixture was concentrated in vacuo to give 3-{1-[(2R)-2-amino-5,5,5-trifluoropentyl]-5-(chloromethyl)-4-(pyridin-4-yl)- 1H-pyrazol-3-yl}benzonitrile hydrogen chloride (1: 1) (300 mg, crude) as a pale yellow solid. LC-MS (Method G): Rt = 0.916 min; MS (ESIpos): m / z = 434.1 [M+H]+. Intermediate 108 3-[(6R)-3-(pyridin-4-yl)-6-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2- yl]benzonitrile

[0019] A solution of 3-{1-[(2R)-2-amino-5,5,5-trifluoropentyl]-5-(chloromethyl)-4-(pyridin-4-yl)-1H- pyrazol-3-yl}benzonitrile hydrogen chloride (1: 1) (300 mg, 0.638 mmol, Intermediate 107) and potassium carbonate (441 mg, 3.19 mmol) in acetonitrile (9.0 ml) was added N,N- dimethylformamide (3.0 ml) at 25 °C, the mixture was stirred at 25 °C for 16 hours. The reaction mixture was poured into water. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 3-[(6R)-3-(pyridin-4-yl)-6-(3,3,3-trifluoropropyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile (200 mg, 0.500 mmol, 79% yiled) as a brown oil. LC-MS (Method G): Rt= 0.878 min; MS (ESIpos): m / z = 398.1 [M+H]+. Intermediate 109 methyl 1-{(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropyl}-3-(3-cyanophenyl)-4- (pyridin-4-yl)-1H-pyrazole-5-carboxylate^ To a solution of methyl 3-(3-cyanophenyl)-4-(pyridin-4-yl)-1H-pyrazole-5-carboxylate (3.00 g, 9.86 mmol, Intermediate 87) and tert-butyl [(2S)-1-hydroxy-3-phenylpropan-2- yl]carbamate (4.96 g, 19.7 mmol) in tetrahydrofuran (120 ml) was added triphenylphosphine (6.46 g, 24.6 mmol ) and diisopropyl azodicarboxylate (4.98 g, 24.6 mmol, CAS-RN: [2446- 83-5]), the reaction mixture was stirred at 60 °C for 16 hours under nitrogen atmosphere. The reaction solution was quenched by addition of water. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by flash reversed phase (acetonitrile / water, 0.05% ammonia hydroxide, 75%~100%) to give methyl 1-{(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropyl}-3-(3- cyanophenyl)-4-(pyridin-4-yl)-1H-pyrazole-5-carboxylate (2.40 g, 4.02 mmol, 41% yield) as a yellow oil. LC-MS (Method G): Rt= 1.075 min; MS (ESIpos): m / z = 538.2 [M+H]+. Intermediate 110 tert-butyl {(2S)-1-[3-(3-cyanophenyl)-5-(hydroxymethyl)-4-(pyridin-4-yl)-1H-pyrazol-1-yl]-3- phenylpropan-2-yl}carbamate^ To a solution of methyl 1-{(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropyl}-3-(3- cyanophenyl)-4-(pyridin-4-yl)-1H-pyrazole-5-carboxylate (2.40 g, 4.46 mmol, Intermediate 109) in tetrahydrofuran (160 ml) was added lithium aluminum hydride (2.1 ml, 2.5 M in tetrahydrofuran) at -30 °C. The reaction mixture was stirred at -30 °C for 1 hour. The reaction was then quenched by water. The resulting solution was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon oxide, petroleum ether: ethyl acetate = 3: 7 to 8: 9) to give tert-butyl {(2S)-1-[3-(3-cyanophenyl)-5-(hydroxymethyl)-4- (pyridin-4-yl)-1H-pyrazol-1-yl]-3-phenylpropan-2-yl}carbamate (1.50 g, 2.94 mmol, 66% yield) as a yellow oil.^ LC-MS (Method C): Rt= 0.830 min; MS (ESIpos): m / z = 510.2 [M+H]+. Intermediate 111 [1-{(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropyl}-3-(3-cyanophenyl)-4-(pyridin-4-yl)- 1H-pyrazol-5-yl]methyl methanesulfonate^ To a solution of tert-butyl {(2S)-1-[3-(3-cyanophenyl)-5-(hydroxymethyl)-4-(pyridin-4-yl)-1H- pyrazol-1-yl]-3-phenylpropan-2-yl}carbamate (200 mg, 0.392 mmol, Intermediate 110) in dichloromethane (6.0 ml) was added N,N-diisopropylethylamine (0.340 ml, 2.00 mmol) and methanesulfonic anhydride (205 mg, 1.18 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour. The solvent was evaporated under reduced pressure to give [1-{(2S)- 2-[(tert-butoxycarbonyl)amino]-3-phenylpropyl}-3-(3-cyanophenyl)-4-(pyridin-4-yl)-1H- pyrazol-5-yl]methyl methanesulfonate (200 mg, crude) as a brown oil.^ LC-MS (Method C): Rt= 0.880 min; MS (ESIpos): m / z = 588.2 [M+H]+. Intermediate 112 tert-butyl (6S)-6-benzyl-2-(3-cyanophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate^ To a solution of [1-{(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropyl}-3-(3-cyanophenyl)- 4-(pyridin-4-yl)-1H-pyrazol-5-yl]methyl methanesulfonate (200 mg, 0.340 mmol, Intermediate 111) in tetrahydrofuran (9.1 ml) was added sodium hydride (204 mg, 60% purity, 5.10 mmol ) at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours. The reaction was quenched by saturated ammonium chloride solution. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon oxide, petroleum ether: ethyl acetate = 7: 3 to 1:1) to give tert-butyl (6S)-6-benzyl-2-(3-cyanophenyl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (100 mg, 0.203 mmol, 60% yield) as a yellow solid. LC-MS (Method C): Rt= 0.858 min; MS (ESIpos): m / z = 492.2 [M+H]+. Intermediate 113 3-[(6S)-6-benzyl-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile^ A solution of tert-butyl (6S)-6-benzyl-2-(3-cyanophenyl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (110 mg, 0.224 mmol, Intermediate 112) in hydrochloric acid (2.0 M in ethyl acetate, 3.0 ml, 6.00 mmol) was stirred at 25 °C for 2 hours. The solvent was evaporated under reduced pressure to give a residue. The pH of the residue was adjusted with sodium bicarbonate solution to 7-8. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give 3-[(6S)-6-benzyl-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile (80 mg, crude) as a yellow solid. LC-MS (Method C): Rt= 0.602 min; MS (ESIpos): m / z = 392.1 [M+H]+. Intermediate 114 methyl 1-{(2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropyl}-3-(3-cyanophenyl)-4- (pyridin-4-yl)-1H-pyrazole-5-carboxylate

[0020] To a solution of methyl 3-(3-cyanophenyl)-4-(pyridin-4-yl)-1H-pyrazole-5-carboxylate (3.00 g, 9.86 mmol, Intermediate 87) and tert-butyl [(2R)-1-hydroxy-3-phenylpropan-2- yl]carbamate (6.19 g, 24.6 mmol) in tetrahydrofuran (150 ml) was added triphenylphosphine (6.46 g, 24.6 mmol) and diisopropyl azodicarboxylate (4.98 g, 24.6 mmol, CAS-RN: [2446- 83-5]), then the reaction mixture was stirred at 60 °C for 16 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by flash reversed phase (acetonitrile / water, 0.05% ammonium hydroxide, 45%~50%) to give methyl 1-{(2R)-2-[(tert- butoxycarbonyl)amino]-3-phenylpropyl}-3-(3-cyanophenyl)-4-(pyridin-4-yl)-1H-pyrazole-5- carboxylate (3.50 g, 6.51 mmol, 66% yield) as a brown solid. LC-MS (Method C): Rt = 0.916 min; MS (ESIpos): m / z = 538.2 [M+H]+. Intermediate 115 tert-butyl {(2R)-1-[3-(3-cyanophenyl)-5-(hydroxymethyl)-4-(pyridin-4-yl)-1H-pyrazol-1-yl]-3- phenylpropan-2-yl}carbamate To a solution of methyl 1-{(2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropyl}-3-(3- cyanophenyl)-4-(pyridin-4-yl)-1H-pyrazole-5-carboxylate (3.50 g, 6.51 mmol, Intermediate 114) in tetrahydrofuran (200 ml) was added lithium aluminum hydride (10 ml, 2.5 M in tetrahydrofuran, 26.0 mmol), the mixture was stirred at -30 °C under nitrogen atmosphere for 3 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford a residue. The residue was purified by column chromatography (silicon oxide, petroleum ether: ethyl acetate = 3: 7 to 8: 9) to give tert-butyl {(2R)-1-[3-(3-cyanophenyl)-5-(hydroxymethyl)-4-(pyridin-4-yl)-1H- pyrazol-1-yl]-3-phenylpropan-2-yl}carbamate (1.55 g, 3.04 mmol, 47% yield) as a yellow oil. LC-MS (Method G): Rt= 0.963 min; MS (ESIpos): m / z = 510.2 [M+H]+. Intermediate 116 tert-butyl {(2R)-1-[5-(chloromethyl)-3-(3-cyanophenyl)-4-(pyridin-4-yl)-1H-pyrazol-1-yl]-3- phenylpropan-2-yl}carbamate To a solution of tert-butyl {(2R)-1-[3-(3-cyanophenyl)-5-(hydroxymethyl)-4-(pyridin-4-yl)-1H- pyrazol-1-yl]-3-phenylpropan-2-yl}carbamate (350 mg, 0.687 mmol, Intermediate 115) in dichloromethane (4.7 ml) was added thionyl chloride (0.750 ml, 1.03 mmol) at 0 °C, then the mxiture was stirred at 20 °C for 1 hour. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford a residue. The residue was purified by column chromatography (silicon oxide, petroleum ether: ethyl acetate = 3: 7 to 8: 9) to give tert-butyl {(2R)-1-[5- (chloromethyl)-3-(3-cyanophenyl)-4-(pyridin-4-yl)-1H-pyrazol-1-yl]-3-phenylpropan-2- yl}carbamate (360 mg, 0.680 mmol, 99% yield) as a yellow oil. LC-MS (Method C): Rt = 0.895 min; MS (ESIpos): m / z = 528.2 [M+H]+. Intermediate 117 3-{1-[(2R)-2-amino-3-phenylpropyl]-5-(chloromethyl)-4-(pyridin-4-yl)-1H-pyrazol-3- yl}benzonitrile hydrogen chloride (1: 1) To a solution of tert-butyl {(2R)-1-[5-(chloromethyl)-3-(3-cyanophenyl)-4-(pyridin-4-yl)-1H- pyrazol-1-yl]-3-phenylpropan-2-yl}carbamate (360 mg, 0.682 mmol, Intermediate 116) in 1,4-dioxane (5.2 ml) was added hydrochloric acid (7.2 ml, 2 M in 1,4-dioxane, 14.4 mmol), the mixture was stirred at 25 °C for 1 hour. The reaction mixture was filtered. The filter cake was washed with ethyl acetate, collected and dried in vacuo to give 3-{1-[(2R)-2-amino-3- phenylpropyl]-5-(chloromethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl}benzonitrile hydrogen chloride (1: 1) (310 mg, crude) as a yellow solid. LC-MS (Method A): Rt= 0.847 min; MS (ESIpos): m / z = 428.2 [M+H]+. Intermediate 118 3-[(6R)-6-benzyl-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile To a solution of 3-{1-[(2R)-2-amino-3-phenylpropyl]-5-(chloromethyl)-4-(pyridin-4-yl)-1H- pyrazol-3-yl}benzonitrile (310 mg, 0.670 mmol, Intermediate 117) in N,N- dimethylformamide (2.0 ml) and acetonitrile (6.0 ml) was added potassium carbonate (500 mg, 3.62 mmol), the reaction mixture was stirred at 25 °C for 16 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 3-[(6R)-6-benzyl-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2- yl]benzonitrile (280 mg, crude) as a white solid. LC-MS (Method G): Rt= 0.950 min; MS (ESIpos): m / z = 392.2 [M+H]+. Intermediate 119 methyl 1-{(2R)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutyl}-3-(3-cyanophenyl)-4- (pyridin-4-yl)-1H-pyrazole-5-carboxylate^ To a solution of methyl 3-(3-cyanophenyl)-4-(pyridin-4-yl)-1H-pyrazole-5-carboxylate (3.00 g, 9.86 mmol, Intermediate 87) and tert-butyl [(2R)-1-hydroxy-3,3-dimethylbutan-2- yl]carbamate (3.21 g, 14.8 mmol) in tetrahydrofuran (80 ml) was added triphenylphosphine (7.76 g, 29.6 mmol) and di-tert-butyl azodicarboxylate (6.81 g, 29.6 mmol) at 25 °C. The mixture was stirred at 60 °C for 16 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by flash reversed phase (acetonitrile / water, 0.05% formic acid, 45%~50%) to give methyl 1-{(2R)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutyl}-3-(3- cyanophenyl)-4-(pyridin-4-yl)-1H-pyrazole-5-carboxylate (4.50 g, 8.94 mmol, 91% yield) as a brown oil. LC-MS (Method G): Rt= 1.064 min; MS (ESIpos): m / z = 504.3 [M+H]+. Intermediate 120 tert-butyl {(2R)-1-[3-(3-cyanophenyl)-5-(hydroxymethyl)-4-(pyridin-4-yl)-1H-pyrazol-1-yl]- 3,3-dimethylbutan-2-yl}carbamate^

[0021] To a solution of methyl 1-{(2R)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutyl}-3-(3- cyanophenyl)-4-(pyridin-4-yl)-1H-pyrazole-5-carboxylate (4.50 g, 8.94 mmol, Intermediate 119) in tetrahydrofuran (100 ml) was added lithium aluminum hydride (2.5 M in tetrahydrofuran, 11.0 ml, 27.0 mmol) at -30 °C. The mixture was stirred at -30 °C for 2 hours under nitrogen atmosphere. The mixture was quenched with sodium sulfate decahydrate. The suspension was filtered. The filter cake was washed with ethyl acetate. The filtrate was concentrated to give a residue. The residue was purified by column chromatography (silicon oxide, petroleum ether: ethyl acetate = 3: 7 to 0: 1) to give tert-butyl {(2R)-1-[3-(3- cyanophenyl)-5-(hydroxymethyl)-4-(pyridin-4-yl)-1H-pyrazol-1-yl]-3,3-dimethylbutan-2- yl}carbamate (2.20 g, 4.63 mmol, 53% yield) as a yellow oil. LC-MS (Method C): Rt= 0.820 min; MS (ESIpos): m / z = 476.3 [M+H]+. Intermediate 121 tert-butyl {(2R)-1-[5-(chloromethyl)-3-(3-cyanophenyl)-4-(pyridin-4-yl)-1H-pyrazol-1-yl]-3,3- dimethylbutan-2-yl}carbamate^ To a solution of tert-butyl {(2R)-1-[3-(3-cyanophenyl)-5-(hydroxymethyl)-4-(pyridin-4-yl)-1H- pyrazol-1-yl]-3,3-dimethylbutan-2-yl}carbamate (2.20 g, 4.63 mmol, Intermediate 120) in tetrahydrofuran (40 ml) was added thionyl chloride (0.670 ml, 9.30 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 16 hours. The mixture was evaporated under reduced pressure to give tert-butyl {(2R)-1-[5-(chloromethyl)-3-(3-cyanophenyl)-4-(pyridin- 4-yl)-1H-pyrazol-1-yl]-3,3-dimethylbutan-2-yl}carbamate (2.20 g, crude) as a brown oil. LC-MS (Method C): Rt= 0.865 min; MS (ESIpos): m / z = 494.3 [M+H]+. Intermediate 122 3-{1-[(2R)-2-amino-3,3-dimethylbutyl]-5-(chloromethyl)-4-(pyridin-4-yl)-1H-pyrazol-3- yl}benzonitrile^ A solution of tert-butyl {(2R)-1-[5-(chloromethyl)-3-(3-cyanophenyl)-4-(pyridin-4-yl)-1H- pyrazol-1-yl]-3,3-dimethylbutan-2-yl}carbamate (2.20 g, 4.45 mmol, Intermediate 121) in hydrogen chloride (2 M in ethyl acetate, 20.0 ml), the mixture was stirred at 25 °C for 2 hours. The mixture was evaporated under reduced pressure to give 3-{1-[(2R)-2-amino-3,3- dimethylbutyl]-5-(chloromethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl}benzonitrile (1.75 g, crude) as a yellow oil. LC-MS (Method C): Rt= 0.731 min; MS (ESIpos): m / z = 394.1 [M+H]+. Intermediate 123 3-[(6R)-6-tert-butyl-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2- yl]benzonitrile^ To a solution of 3-{1-[(2R)-2-amino-3,3-dimethylbutyl]-5-(chloromethyl)-4-(pyridin-4-yl)-1H- pyrazol-3-yl}benzonitrile (1.75 g, 4.44 mmol, Intermediate 122) in acetonitrile (15 ml) and N,N-dimethylformamide (5.0 ml) was added potassium carbonate (3.07 g, 22.2 mmol) at 25 °C, the mixture was stirred at 25 °C for 16 hours. The suspension was filtered. The filter cake was washed with ethyl acetate. The combined organic layers were concentrated under reduced pressure to give a residue. The residue was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 3-[(6R)-6-tert-butyl-3-(pyridin-4- yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile (1.50 g, crude) as a yellow oil. LC-MS (Method C): Rt= 0.615 min; MS (ESIpos): m / z = 358.2 [M+H]+. Intermediate 124 methyl 1-{(2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutyl}-3-(3-cyanophenyl)-4- (pyridin-4-yl)-1H-pyrazole-5-carboxylate^ To a solution of methyl 3-(3-cyanophenyl)-4-(pyridin-4-yl)-1H-pyrazole-5-carboxylate (3.00 g, 9.86 mmol, Intermediate 87) and tert-butyl [(2S)-1-hydroxy-3,3-dimethylbutan-2- yl]carbamate (3.21 g, 14.8 mmol) in tetrahydrofuran (80 ml) was added triphenylphosphine (7.76 g, 29.6 mmol) and di-tert-butyl azodicarboxylate (6.81 g, 29.6 mmol) at 25 °C. The mixture was stirred at 60°C for 16 hours. The reaction solution was washed with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the residue. The residue was purified by flash reversed phase (acetonitrile / water, 0.05% formic acid, 45%~50%) to give methyl 1-{(2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutyl}-3-(3- cyanophenyl)-4-(pyridin-4-yl)-1H-pyrazole-5-carboxylate (4.40 g, 7.94 mmol, 89% yield) as a brown oil.^ LC-MS (Method G): Rt= 1.082 min; MS (ESIpos): m / z = 504.2 [M+H]+. Intermediate 125 tert-butyl {(2S)-1-[3-(3-cyanophenyl)-5-(hydroxymethyl)-4-(pyridin-4-yl)-1H-pyrazol-1-yl]- 3,3-dimethylbutan-2-yl}carbamate^

[0022] To a solution of methyl 1-{(2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutyl}-3-(3- cyanophenyl)-4-(pyridin-4-yl)-1H-pyrazole-5-carboxylate (4.00 g, 7.94 mmol, Intermediate 124) in tetrahydrofuran (160 ml) was added lithium aluminum hydride (9.5 ml, 24.0 mmol, 2.5 M in tetrahydrofuran) at -30 °C for 2 hours under nitrogen atmosphere. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon oxide, petroleum ether: ethyl acetate = 3: 7 to 0: 1) to give tert-butyl {(2S)-1-[3-(3-cyanophenyl)-5- (hydroxymethyl)-4-(pyridin-4-yl)-1H-pyrazol-1-yl]-3,3-dimethylbutan-2-yl}carbamate (1.70 g, 3.57 mmol, 89% yield) as a yellow oil. LC-MS (Method C): Rt= 0.831 min; MS (ESIpos): m / z = 476.2 [M+H]+. Intermediate 126 3-{1-[(2S)-2-amino-3,3-dimethylbutyl]-5-(chloromethyl)-4-(pyridin-4-yl)-1H-pyrazol-3- To a solution of tert-butyl {(2S)-1-[3-(3-cyanophenyl)-5-(hydroxymethyl)-4-(pyridin-4-yl)-1H- pyrazol-1-yl]-3,3-dimethylbutan-2-yl}carbamate (1.70 g, 3.57 mmol, Intermediate 125) in tetrahydrofuran (54 ml) was added thionyl chloride (0.520 ml, 7.10 mmol) at 0 °C, the reaction mixture was stirred at 25 °C for 16 hours. The solvent was evaporated under reduced pressure to give a residue. The residue was redissolved in hydrochloric acid (1M in ethyl acetate, 20 ml) and stirred at 25 °C for 1 hour. Then the mixture was concentrated under reduced pressure to give 3-{1-[(2S)-2-amino-3,3-dimethylbutyl]-5-(chloromethyl)-4- (pyridin-4-yl)-1H-pyrazol-3-yl}benzonitrile (1.40 g, crude) as a brown oil. LC-MS (Method C): Rt= 0.700 min; MS (ESIpos): m / z = 394.2 [M+H]+. Intermediate 127 3-[(6S)-6-tert-butyl-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2- yl]benzonitrile^ To a solution of 3-{1-[(2S)-2-amino-3,3-dimethylbutyl]-5-(chloromethyl)-4-(pyridin-4-yl)-1H- pyrazol-3-yl}benzonitrile (1.40 g, 3.55 mmol, Intermediate 126) in acetonitrile (26 ml) and N,N-dimethylformamide (8.7 ml) was added potassium carbonate (2.46 g, 17.8 mmol), the reaction mixture was stirred at 25 °C for 16 hours. The suspension was filtered. The filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give a residue. The residue was washed with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 3-[(6S)-6-tert-butyl-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile (1.00 g, crude) as a yellow oil. LC-MS (Method C): Rt= 0.796 min; MS (ESIpos): m / z = 358.2 [M+H]+. Intermediate 128 tert-butyl [(1S)-1-cyclobutyl-2-hydroxyethyl]carbamate^ To a (2S)-[(tert-butoxycarbonyl)amino](cyclobutyl)acetic acid (2.00 g, 8.72 mmol, CAS-RN:[ 155905-77-4]) in tetrahydrofuran (50 ml) was added sodium dihydrido[bis(2- methoxyethanolato-kappao)]aluminate(1-) (10.1 g, 70 % purity, 35.0 mmol) at 0 °C, the mixture was stirred at 0 °C for 2 hours. The mixture was quenched by adding sodium sulfafe decahydrate slowly under nitrogen atmosphere. The mixture was filtered. The filtrate was concentrated under reduced pressure to give tert-butyl [(1S)-1-cyclobutyl-2- hydroxyethyl]carbamate (1.80 g, 96% yield) as a colorless oil. 1H), To a solution of methyl 3-(3-cyanophenyl)-4-(pyridin-4-yl)-1H-pyrazole-5-carboxylate (377 mg, 1.24 mmol, Intermediate 87) and tert-butyl [(1S)-1-cyclobutyl-2- hydroxyethyl]carbamate (400 mg, 1.86 mmol, Intermediate 128) in tetrahydrofuran (13 ml) was added triphenylphosphine (975 mg, 3.72 mmol) and di-tert-butyl azodicarboxylate (856 mg, 3.72 mmol) at 25 °C, then the mixture was stirred at 60°C for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (petroleum ether: ethyl acetate= 1:1) to give methyl 1-{(2S)-2- [(tert-butoxycarbonyl)amino]-2-cyclobutylethyl}-3-(3-cyanophenyl)-4-(pyridin-4-yl)-1H- pyrazole-5-carboxylate (300 mg 48% yield) as a yellow solid. LC-MS (Method G): Rt= 1.081 min; MS (ESIpos): m / z = 502.2 [M+H]+. Intermediate 130 tert-butyl {(1S)-2-[3-(3-cyanophenyl)-5-(hydroxymethyl)-...

Claims

CLAIMS 1. A compound of formula (I)in which: R1represents a group selected from the group: ,-CH2-CN, or oxirane-2-carbonyl; R4arepresents a hydrogen atom, fluoro, methyl, or R4g;R4brepresents a hydrogen atom, fluoro, or methyl; R4crepresents a hydrogen atom, fluoro, methyl, or R4g; R4drepresents a hydrogen atom, fluoro, or methyl; R4erepresents a hydrogen atom, fluoro, methyl, phenyl,, or; R4frepresents a hydrogen atom, fluoro, or methyl; R4grepresents C2-C4-alkyl, C1-C3-haloalkyl, C1-C3-hydroxyalkyl, C3-C6-cycloalkyl, benzyl, oron the conditions that : x when R4arepresents a hydrogen atom, and R4brepresents a hydrogen atom, fluoro or methyl, then R4cis R4gand R4drepresents a hydrogen atom, fluoro, or methyl, and x when R4crepresents a hydrogen atom, and R4drepresents a hydrogen atom, fluoro or methyl, then R4ais R4gand R4brepresents a hydrogen atom, fluoro, or methyl; R5arepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkyl-S(=O)-, C1-C3-alkyl-S(=O)2-, C1-C3- alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1-C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1-C3-alkyl, hydroxy, cyano, fluoro, chloro, or bromo; R5brepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C3- C6-cycloalkyl, C1-C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1-C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3- alkyl)2amino-C1-C3-alkyl, –(CO)-NR19R20, hydroxy, cyano, fluoro, chloro, bromo, or; R5crepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, trifluoromethylsulfanyl, cyano, fluoro, chloro, or bromo; R5drepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo; R5erepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo; R6arepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo; R6brepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, or cyano; R6crepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1-C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo; R6drepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, or cyano; R7arepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, or cyano; R7brepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo; R7crepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, or cyano; R7drepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, or cyano; R8arepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo; R8brepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo; R8crepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1-C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo; R8drepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo; R8erepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo; R9arepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, C3-C6-cycloalkyl, cyano, fluoro, chloro, or bromo; R9brepresents a hydrogen atom, amino, C1-C3-alkylamino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1-C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1-C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3- alkyl)2amino-C1-C3-alkyl, or cyano; R9crepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, C1-C3-alkyl-amino, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1- C3-alkyl)2amino-C1-C3-alkyl, cyano, anilino, phenylamino substituted with a hydrogen atom or methoxy, pyridin-2-ylamino substituted with R13, or C3-C6- cycloalkylformamido; R9drepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo; R10arepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo;R10brepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, or cyano; R10crepresents a hydrogen atom or methyl; R10drepresents a hydrogen atom, fluoro, or methyl; R11represents C1-C3-alkyl, −CH2-C≡CH, −C(R14)-R15, -CH2−C(R14)-R15, or a group selected from the group:, , , ; R12represents a hydrogen atom, methyl, -CH2-NR19R20,, or; 1R3represents a hydrogen atom, C1-C3-alkoxy-C1-C3-alkoxy, or ; R14represents =CHR16; R15represents a hydrogen atom, C1-C3-alkyl, fluoro, cyano, dimethylamino-methyl, or morpholino-methyl; R16represents a hydrogen atom, chloro, C1-C4-alkyl, C1-C3-haloalkyl, C1-C3-alkoxy, C1- C3-hydroxyalkyl, C1-C3-alkoxy-C1-C3-alkyl, trifluoromethylsulfanyl, –CH2-NR19R20, – (CO)-NR19R20, -CH2-NR17a-CHR17bR17c, or a group selected from the group:R17arepresents a hydrogen atom, methyl, or ethyl; R17brepresents a hydrogen atom, methyl, or methoxymethyl; R17crepresents a hydrogen atom or methyl; R18represents a hydrogen atom or methyl; R19represents a hydrogen atom, methyl, or ethyl; R20represents a hydrogen atom, C1-C4-alkyl, phenyl, C1-C3-haloalkyl, or tert- butoxycarbonyl; or R19and R20, together with the N-atom to which they are attached, form agroup; R21represents a hydrogen atom or methyl; R22represents a hydrogen atom or fluoro; R23represents a hydrogen atom or fluoro; R24represents a hydrogen atom or fluoro; R25represents a hydrogen atom, fluoro, or chloro; R26represents a hydrogen atom or fluoro; R27arepresents a hydrogen atom or fluoro; R27brepresents a hydrogen atom or fluoro; R28arepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, hydroxy, cyano, fluoro, chloro, or bromo; R28brepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1-C3-alkyl, –(CO)-NR19R20, cyano, fluoro, chloro, or bromo; R28crepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, trifluoromethylsulfanyl, cyano, fluoro, chloro, or bromo; R28drepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo; R28erepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo; R29represents a hydrogen atom or -COOH; R30arepresents a hydrogen atom or fluoro; R30brepresents a hydrogen atom or fluoro; R31represents a hydrogen atom or methoxy; R32represents a hydrogen atom or methoxy; R33arepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo; R33brepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo; R33crepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo;R33drepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo; R33erepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo; wherein * indicates the point of attachment of said group with the rest of the molecule; or an N-oxide, a salt, a tautomer, a rotamer, or a stereoisomer of said compound, or a salt of said N-oxide, tautomer, rotamer, or stereoisomer.

2. The compound of formula (I) according to claim 1, wherein: R1represents a group selected from the group:R2represents a group selected from the group:R3represents –(CO)-R11; R4arepresents a hydrogen atom or R4g; R4brepresents a hydrogen atom; R4crepresents a hydrogen atom or R4g; R4drepresents a hydrogen atom; R4erepresents a hydrogen atom, phenyl,, or; R4frepresents a hydrogen atom; R4grepresents C2-C4-alkyl, C1-C3-haloalkyl, C1-C3-hydroxyalkyl, C3-C6-cycloalkyl, benzyl, orwherein one of R4aor R4crepresents R4g; R5arepresents C1-C3-alkyl, C1-C3-alkyl-S(=O)-, C1-C3-alkyl-S(=O)2-, cyano, or fluoro; R5brepresents C1-C3-alkyl, C2-C3-alkinyl, C3-C6-cycloalkyl, C1-C3-haloalkyl, C1-C3- hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1-C3-alkyl, hydroxy, cyano, fluoro, or chloro; R5crepresents C1-C3-alkyl, C1-C3-alkoxy, cyano, fluoro, or chloro; R5drepresents cyano; R5erepresents a hydrogen atom; R9arepresents a hydrogen atom; R9brepresents a hydrogen atom or C1-C3-alkylamino; R9crepresents a hydrogen atom; R9drepresents a hydrogen atom; R10arepresents a hydrogen atom; R10brepresents a hydrogen atom;R10crepresents a hydrogen atom; R10drepresents a hydrogen atom; R11represents −C(R14)-R15; R14represents =CHR16; R15represents a hydrogen atom; R16represents a hydrogen atom or –CH2-NR19R20; R19represents methyl or ethyl; R20represents C1-C4-alkyl, phenyl, C1-C3-haloalkyl; or R19and R20, together with the N-atom to which they are attached, form agroup; R21represents a hydrogen atom; R22represents a hydrogen atom; R23represents a hydrogen atom; R33arepresents a hydrogen atom or chloro; R33brepresents a hydrogen atom; R33crepresents a hydrogen atom or chloro; R33drepresents a hydrogen atom; R33erepresents a hydrogen atom; wherein * indicates the point of attachment of said group with the rest of the molecule; or an N-oxide, a salt, a tautomer, a rotamer, or a stereoisomer of said compound, or a salt of said N-oxide, tautomer, rotamer, or stereoisomer.

3. The compound of formula (I) according to claim 1 or 2, wherein:R1represents a group selected from the group:R2represents a group selected from the group:4-pyridyl and , R3represents –(CO)-R11; R4arepresents a hydrogen atom or R4g; R4brepresents a hydrogen atom; R4crepresents a hydrogen atom or R4g; R4drepresents a hydrogen atom; R4erepresents a hydrogen atom, phenyl,, or; R4frepresents a hydrogen atom; R4grepresents ethyl, 2-propyl, 2-methylpropyl, tert-butyl, trifluoromethyl, 1,1,1- trifluoroethyl, 1,1,1-trifluoropropyl-, 2-hydroxy-2-methylethyl-, cyclopropyl, cyclobutyl, 2-oxetanyl, benzyl, orwherein one of R4aor R4crepresents R4g; R5arepresents methyl, C1-C3-alkyl-S(=O)-, C1-C3-alkyl-S(=O)2-, cyano, or fluoro; R5brepresents methyl, ethyl, 2-propyl, ethynyl, cyclopropyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl-, hydroxymethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methoxymethyl-, hydroxy, cyano, fluoro, or chloro; R5crepresents methyl, methoxy, cyano, fluoro, or chloro; R5drepresents cyano; R5erepresents a hydrogen atom; R10arepresents a hydrogen atom; R10brepresents a hydrogen atom; R10crepresents a hydrogen atom; R10drepresents a hydrogen atom; R11represents −C(R14)-R15; R14represents =CHR16; R15represents a hydrogen atom; R16represents a hydrogen atom or –CH2-NR19R20; R19represents methyl or ethyl; R20represents methyl, tert-butyl, phenyl, 1,1,1-trifluoropropyl-; or R19and R20, together with the N-atom to which they are attached, form agroup;R21represents a hydrogen atom; R22represents a hydrogen atom; R23represents a hydrogen atom; R33arepresents a hydrogen atom or chloro; R33brepresents a hydrogen atom; R33crepresents a hydrogen atom or chloro; R33drepresents a hydrogen atom; R33erepresents a hydrogen atom; wherein * indicates the point of attachment of said group with the rest of the molecule; or an N-oxide, a salt, a tautomer, a rotamer, or a stereoisomer of said compound, or a salt of said N-oxide, tautomer, rotamer, or stereoisomer.

4. The compound of formula (I) according to any of claims 1 to 3, which is selected from the group consisting of: 1-[2-(4-chloro-2-fluorophenyl)-4-(2,4-dichlorophenyl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one (isomer 1) 1-[2-(4-chloro-2-fluorophenyl)-4-ethyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin- 5(4H)-yl]prop-2-en-1-one (isomer 2) 1-[2-(4-chloro-2-fluorophenyl)-4-phenyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin- 5(4H)-yl]prop-2-en-1-one (isomer 1) 1-[2-(4-chloro-2-fluorophenyl)-4-phenyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin- 5(4H)-yl]prop-2-en-1-one (isomer 2) 1-(7RS)-[2-(4-chloro-2-fluorophenyl)-7-phenyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one 1-[2-(4-chloro-2-fluorophenyl)-7-phenyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin- 5(4H)-yl]prop-2-en-1-one (isomer 1) 1-[2-(4-chloro-2-fluorophenyl)-7-phenyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin- 5(4H)-yl]prop-2-en-1-one (isomer 2) 1-[(7RS)-2-(4-chloro-2-fluorophenyl)-7-(2-chlorophenyl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo [1,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[2-(4-chloro-2-fluorophenyl)-7-(2-chlorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one (isomer1) 1-[2-(4-chloro-2-fluorophenyl)-7-(2-chlorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one (isomer 2) 1-[2-(4-chloro-2-fluorophenyl)-7-(2,4-dichlorophenyl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one (isomer 1) 1-[2-(4-chloro-2-fluorophenyl)-7-(2,4-dichlorophenyl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one (isomer 2) 1-[(6RS)-2-(4-chlorophenyl)-6-(oxetan-3-yl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one 3-[(6RS)-6-(oxetan-3-yl)-5-(prop-2-enoyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-2-yl]benzonitrile (2E)-1-[(6RS)-2-(4-chlorophenyl)-6-(oxetan-3-yl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one 3-[(6RS)-6-(2-hydroxypropan-2-yl)-5-(prop-2-enoyl)-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile 3-[(6S)-5-[(2E)-4-(dimethylamino)but-2-enoyl]-6-(2-methylpropyl)-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile formic acid 3-[(6S)-5-[(2E)-4-(dimethylamino)but-2-enoyl]-3-(pyridin-4-yl)-6-(3,3,3- trifluoropropyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile (1: 1) 3-[(6S)-6-benzyl-5-[(2E)-4-(dimethylamino)but-2-enoyl]-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile formic acid 3-[(6R)-6-benzyl-5-[(2E)-4-(dimethylamino)but-2-enoyl]-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile (1: 1) 3-[(6R)-6-tert-butyl-5-[(2E)-4-(dimethylamino)but-2-enoyl]-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile 3-[(6S)-6-(2-methylpropyl)-5-(prop-2-enoyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-2-yl]benzonitrile 3-[(6S)-6-cyclobutyl-5-(prop-2-enoyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-2-yl]benzonitrile 3-[(6S)-5-(prop-2-enoyl)-3-(pyridin-4-yl)-6-(3,3,3-trifluoropropyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile3-[(6S)-6-benzyl-5-(prop-2-enoyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin- 2-yl]benzonitrile 3-[(6S)-6-tert-butyl-5-(prop-2-enoyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-2-yl]benzonitrile 3-[(6R)-6-cyclobutyl-5-(prop-2-enoyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-2-yl]benzonitrile 3-[(6R)-5-(prop-2-enoyl)-3-(pyridin-4-yl)-6-(3,3,3-trifluoropropyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile 3-[(6R)-6-benzyl-5-(prop-2-enoyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin- 2-yl]benzonitrile 3-[(6R)-6-tert-butyl-5-(prop-2-enoyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-2-yl]benzonitrile formic acid 3-[(6S)-5-{(2E)-4-[tert-butyl(methyl)amino]but-2-enoyl}-6-cyclobutyl-3-(pyridin- 4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile (1: 1) formic acid 3-[(6S)-5-{(2E)-4-[tert-butyl(methyl)amino]but-2-enoyl}-3-(pyridin-4-yl)-6-(3,3,3- trifluoropropyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile (1 / 1) 3-[(6S)-6-tert-butyl-5-{(2E)-4-[tert-butyl(methyl)amino]but-2-enoyl}-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile formic acid 3-[(6R)-5-{(2E)-4-[tert-butyl(methyl)amino]but-2-enoyl}-6-cyclobutyl-3-(pyridin- 4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile (1: 1) 3-[(6R)-6-benzyl-5-{(2E)-4-[tert-butyl(methyl)amino]but-2-enoyl}-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile 3-[(6R)-6-tert-butyl-5-{(2E)-4-[tert-butyl(methyl)amino]but-2-enoyl}-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile formic acid 3-[(6S)-6-cyclobutyl-5-[(2E)-4-(2,2-dimethylpyrrolidin-1-yl)but-2-enoyl]-3- (pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile (1: 1) formic acid 3-[(6S)-5-[(2E)-4-(2,2-dimethylpyrrolidin-1-yl)but-2-enoyl]-3-(pyridin-4-yl)-6- (3,3,3-trifluoropropyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile (1: 1) formic acid 3-[(6R)-6-cyclobutyl-5-[(2E)-4-(2,2-dimethylpyrrolidin-1-yl)but-2-enoyl]-3- (pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile (1 / 1) 1-[(6R*)-2-(4-chloro-2-fluorophenyl)-6-ethyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one - enantiomer 13-[(6R*)-6-ethyl-5-(prop-2-enoyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin- 2-yl]benzonitrile - enantiomer 1 3-[(6R*)-6-ethyl-5-(prop-2-enoyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin- 2-yl]benzonitrile - enantiomer 2 1-[(6R*)-2-(4-chlorophenyl)-6-ethyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin- 5(4H)-yl]prop-2-en-1-one - enantiomer 1 3-[(6R)-6-cyclopropyl-5-[(2E)-4-(dimethylamino)but-2-enoyl]-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile 3-[(6S)-6-cyclopropyl-5-[(2E)-4-(dimethylamino)but-2-enoyl]-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile 1-[(6RS)-2-(4-Chlor-2-fluorphenyl)-6-ethyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]prop-2-en-1-on 1-[(6RS)-6-Ethyl-2-(4-methoxyphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin- 5(4H)-yl]prop-2-en-1-on 1-[(6RS)-2-(4-chloro-2-fluorophenyl)-6-ethyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one 1-[(6RS)-6-ethyl-2-(3-fluoro-4-methoxyphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one 3-[(6RS)-6-ethyl-5-(prop-2-enoyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin- 2-yl]benzonitrile 1-[(6RS)-2-(3-chlorophenyl)-6-cyclopropyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one 3-[(6RS)-6-(propan-2-yl)-5-(prop-2-enoyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-2-yl]benzonitrile (2E)-1-[(6RS)-2-(3-chlorophenyl)-6-cyclopropyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one 1-[(6R)-2-(4-chloro-2-fluorophenyl)-3-(pyridin-4-yl)-6-(2,2,2-trifluoroethyl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one (2E)-1-[(6RS)-2-(3-chlorophenyl)-6-cyclopropyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-1-[(6R)-6-cyclopropyl-2-(3-ethynylphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one(2E)-1-[(6S)-6-cyclopropyl-2-(1H-indol-6-yl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-1-[(6S)-2-(1-benzothiophen-5-yl)-6-cyclopropyl-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-1-[(6RS)-6-cyclopropyl-2-[3-(hydroxymethyl)phenyl]-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-1-[(6RS)-2-(4-chloro-2-fluorophenyl)-6-ethyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-4-(dimethylamino)-1-[(6RS)-2-[3-(hydroxymethyl)phenyl]-6-(propan-2-yl)-3-(pyridin-4- yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]but-2-en-1-one (2E)-1-[(6S)-6-cyclopropyl-2-(3-hydroxyphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one 5-[(6RS)-6-cyclopropyl-5-[(2E)-4-(dimethylamino)but-2-enoyl]-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]-2-fluorobenzonitrile 3-[(6RS)-6-cyclopropyl-5-[(2E)-4-(dimethylamino)but-2-enoyl]-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile (2E)-1-[(6S)-2-(2,1,3-benzoxadiazol-5-yl)-6-cyclopropyl-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one 3-[(6RS)-6-cyclopropyl-5-[(2E)-4-(dimethylamino)but-2-enoyl]-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]-4-fluorobenzonitrile 3-[(6S)-6-cyclopropyl-5-[(2E)-4-(dimethylamino)but-2-enoyl]-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]-2-methylbenzonitrile 5-[(6S)-6-cyclopropyl-5-[(2E)-4-(dimethylamino)but-2-enoyl]-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]-2-methylbenzonitrile (2E)-1-[(6S)-6-cyclopropyl-2-[3-(methanesulfonyl)phenyl]-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-1-[(6S)-6-cyclopropyl-2-[3-(methanesulfinyl)phenyl]-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one 3-[(6S)-6-cyclopropyl-5-[(2E)-4-(dimethylamino)but-2-enoyl]-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]-5-methylbenzonitrile 3-[(6S)-6-cyclopropyl-5-[(2E)-4-(dimethylamino)but-2-enoyl]-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]-4-methylbenzonitrile(2E)-1-[(6S)-2-(1-benzothiophen-5-yl)-6-cyclopropyl-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(2,2-dimethylpyrrolidin-1-yl)but-2-en-1-one (2E)-1-[(6S)-2-(2,1,3-benzoxadiazol-5-yl)-6-cyclopropyl-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(2,2-dimethylpyrrolidin-1-yl)but-2-en-1-one 3-[(6S)-6-cyclopropyl-5-[(2E)-4-(2,2-dimethylpyrrolidin-1-yl)but-2-enoyl]-3-(pyridin-4-yl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile 3-[(6S)-6-cyclopropyl-5-[(2E)-4-(2,2-dimethylpyrrolidin-1-yl)but-2-enoyl]-3-(pyridin-4-yl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]-2-methylbenzonitrile 5-[(6S)-6-cyclopropyl-5-[(2E)-4-(2,2-dimethylpyrrolidin-1-yl)but-2-enoyl]-3-(pyridin-4-yl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]-2-methylbenzonitrile 3-[(6S)-6-cyclopropyl-5-{(2E)-4-[methyl(3,3,3-trifluoropropyl)amino]but-2-enoyl}-3-(pyridin- 4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile 5-[(6S)-5-{(2E)-4-[tert-butyl(methyl)amino]but-2-enoyl}-6-cyclopropyl-3-(pyridin-4-yl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]-2-methylbenzonitrile 3-[(6S)-5-{(2E)-4-[tert-butyl(ethyl)amino]but-2-enoyl}-6-cyclopropyl-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile 5-[(6S)-5-{(2E)-4-[tert-butyl(ethyl)amino]but-2-enoyl}-6-cyclopropyl-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]-2-methylbenzonitrile 3-[(6S)-6-cyclopropyl-5-{(2E)-4-[methyl(phenyl)amino]but-2-enoyl}-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile (2E)-1-[(6S)-6-cyclopropyl-2-(3-cyclopropylphenyl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-1-[(6R)-6-cyclopropyl-2-(3-cyclopropylphenyl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-1-[(6S)-6-cyclopropyl-2-(3-ethylphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-1-[(6R)-6-cyclopropyl-2-(3-ethylphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one 3-[(6S)-5-{(2E)-4-[tert-butyl(methyl)amino]but-2-enoyl}-6-cyclopropyl-3-(pyridin-4-yl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile (2E)-1-[(6S)-6-cyclopropyl-2-(3-ethynylphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one(2E)-1-[(6S)-6-cyclopropyl-2-[3-(difluoromethyl)phenyl]-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-1-[(6S)-6-cyclopropyl-2-[3-(difluoromethoxy)phenyl]-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one 2-[(6S)-6-cyclopropyl-5-[(2E)-4-(dimethylamino)but-2-enoyl]-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile (2E)-1-[(6S)-6-cyclopropyl-3-(pyridin-4-yl)-2-[3-(2,2,2-trifluoroethyl)phenyl]-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-1-[(6S)-2-(4-chloro-3-ethylphenyl)-6-cyclopropyl-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-4-[tert-butyl(methyl)amino]-1-[(6S)-6-cyclopropyl-3-(pyridin-4-yl)-2-[3- (trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]but-2-en-1-one N-(4-{(6S)-2-(3-cyanophenyl)-6-cyclopropyl-5-[(2E)-4-(dimethylamino)but-2-enoyl]-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl}pyridin-2-yl)cyclopropanecarboxamide 3-{(6S)-6-cyclopropyl-5-[(2E)-4-(dimethylamino)but-2-enoyl]-3-[2-(methylamino)pyridin-4- yl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl}benzonitrile 2-chloro-5-[(6S)-6-cyclopropyl-5-[(2E)-4-(dimethylamino)but-2-enoyl]-3-(pyridin-4-yl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile (2E)-1-[(6S)-2-[4-chloro-3-(trifluoromethyl)phenyl]-6-cyclopropyl-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-4-[tert-butyl(methyl)amino]-1-[(6S)-2-[4-chloro-3-(trifluoromethyl)phenyl]-6- cyclopropyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]but-2-en-1-one (2E)-1-[(6S)-6-cyclopropyl-2-(3-methoxyphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-1-[(6S)-6-cyclopropyl-2-(3-ethoxyphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-1-[(6S)-6-cyclopropyl-2-(3-ethoxyphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-1-[(6S)-2-(4-chloro-3-methoxyphenyl)-6-cyclopropyl-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-1-[(6S)-6-cyclopropyl-2-[3-(1H-pyrazol-3-yl)phenyl]-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one(2E)-1-[(6S)-6-cyclopropyl-2-[3-(difluoromethyl)-4-fluorophenyl]-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-1-[(6S)-6-cyclopropyl-2-[3-(propan-2-yl)phenyl]-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-4-[tert-butyl(methyl)amino]-1-[(6S)-6-cyclopropyl-2-[3-(difluoromethoxy)phenyl]-3- (pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]but-2-en-1-one (2E)-4-[tert-butyl(methyl)amino]-1-[(6S)-6-cyclopropyl-3-(pyridin-4-yl)-2-[3- (trifluoromethoxy)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]but-2-en-1-one (2E)-1-[(6S)-2-(1-benzofuran-7-yl)-6-cyclopropyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-1-[(6S)-6-cyclopropyl-2-[4-fluoro-3-(trifluoromethyl)phenyl]-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one 1-[(6SR)-2-(4-chloro-2-fluorophenyl)-3-(pyridin-4-yl)-6-(trifluoromethyl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one and 1-[(6SR)-2-(4-methoxyphenyl)-3-(pyridin-4-yl)-6-(trifluoromethyl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one, or an N-oxide, a salt, a tautomer, a rotamer, or a stereoisomer of said compound, or a salt of said N-oxide, tautomer, rotamer, or stereoisomer.

5. Use of a compound of formula (I) according to any of claims 1 to 4 for the treatment or prophylaxis of diseases.

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

7. Use of a compound of formula (I) according to claim 6, wherein the hyperproliferative diseases and / or disorders responsive to induction of cell death are haematological tumours, solid tumours and / or metastases thereof.

8. Use of a compound of formula (I) according to claim 7, wherein the tumour harbors a mutant EGFR and / or metastases thereof.

9. Use of a compound of formula (I) according to claim 7, wherein the tumour is lung cancer, particularly lung cancer harboring a mutant EGFR with exon 20 insertion mutation, and / or metastases thereof.

10. Use of a compound of formula (I) according to claim 7, wherein the tumour is lung cancer, particularly lung cancer harboring a mutant EGFR with in-frame deletions in exon 19 (such as EGFR E746_A750del) or point mutations in exon 21 (e.g. L858R), and / or metastases thereof.

11. Use of a compound of formula (I) according to claim 7, wherein the tumour is lung cancer, particularly lung cancer harboring a mutant EGFR with an exon 20 insertion and a T790M mutation, e.g. a D770_N771insSVD T790M mutation, and / or metastases thereof.

12. Use of a compound of formula (I) according to claim 7, wherein the tumour is lung cancer, particularly lung cancer harboring a mutant EGFR with inframe deletion in exon 19 such as E746_A750del and a T790M mutation, and / or metastases thereof.

13. Use of a compound of formula (I) according to claim 7, wherein the tumour is lung cancer, particularly lung cancer harboring a mutant EGFR with a point mutation in exon 21 such as L858R and a T790M mutation, and / or metastases thereof.

14. Use of a compound of formula (I) according to claim 7, wherein the tumour is lung cancer, particularly lung cancer harboring a mutant ERBB2 with exon 20 insertion mutations (such as ERBB2 A775_G776insYVMA), and / or metastases thereof.

15. Use of a compound of formula (I) according to claim 7, wherein the tumour is lung cancer, particularly lung cancer harboring a mutant ERBB2 with point mutations (such as ERBB2 S310F, ERBB2 L755S, ERBB2 V777L), and / or metastases thereof.

16. A pharmaceutical composition comprising at least one compound of formula (I) according to any of claims 1 to 4, together with at least one pharmaceutically acceptable auxiliary.

17. A composition according to claim 16 for the treatment of haematological tumours, solid tumours and / or metastases thereof.

18. A combination comprising one or more first active ingredients selected from a compound of formula (I) according to any of claims 1 to 4, and one or more second active ingredients selected from chemotherapeutic anti-cancer agents and target-specific anti-cancer agents.

19. A method of inhibiting EGF-receptor kinase activity in a cancer cell, the method comprising contacting the cancer cell with a compound of formula (I) according to any of claims 1 to 4.

20. The method of claim 19, wherein the cancer cell is in vitro or in vivo.

21. A method of reducing the survival of a cancer cell or inducing death in a cancer cell, the method comprising contacting a cancer cell comprising a mutation in an EGF-receptor with a compound of formula (I) according to any of claims 1 to 4.

22. The method of any one of claims 19 to 21, wherein the EGF-receptor comprises a mutation in exon 20.

23. The method of any one of claims 19 to 22, wherein the cancer cell is derived from a cancer selected from the group consisting of leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours, skin tumours, and sarcomas.

24. The method of claim 23, wherein the cancer cell is derived from a cancer selected from the group consisting of inverted sinonasal papilloma or inverted sinonasal papilloma associated sinanonasal squamous cell carcinoma.

25. A method of treating cancer in a subject, the method comprising administering to the subject an effective amount of a compound of formula (I) according to any of claims 1 to 4.

26. A method of treating cancer in a subject, wherein the cancer is or has acquired resistance to an anti-EGF receptor therapy, the method comprising administering to the subject an effective amount of a compound of formula (I) according to any of claims 1 to 4.

27. A method of enhancing the efficacy of an anti-EGF-receptor therapy for the treatment of cancer, the method comprising administering to the subject an anti-EGF receptor therapy in combination with a compound of formula (I) according to any of claims 1 to 4.

28. The method of any one of claims 25 to 27, wherein the cancer is selected from the group consisting of leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumours, tumours of the thorax, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours, skin tumours, and sarcomas.

29. The method of claim 28, wherein the cancer is selected from the group consisting of inverted sinonasal papilloma or inverted sinonasal papilloma associated sinanonasal squamous cell carcinoma.

30. The method of claim 28, wherein the tumour of the thorax is non-small cell lung cancer.

31. The method of any one of claims 19 to 30, wherein the EGF-receptor comprises a mutation.

32. The method of claim 31, wherein the EGF-receptor comprises a mutation in exon 20.

33. The method of claim 32, wherein the EGF-receptor comprises an insertion in exon 20.

34. The method of claim 33, wherein the EGF-receptor comprises an insertion between amino acids V769-D770 and / or between D770-N771.

35. The method of claim 34, wherein the insertion is an ASV and / or SVD insertion.

36. The method of claim 33, wherein the EGF-receptor comprising an ASV insertion between amino acids V769-D770 and / or a SVD insertion between amino acids D770-N771.

37. A method of selecting a patient for cancer treatment with a compound of formula (I) according to any of claims 1 to 4, the method comprising detecting the presence of 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.

38. A method for treating a patient with cancer, the method comprising administering to the subject an anti-EGF receptor therapy in combination with a compound of formula (I) according to any of claims 1 to 4, wherein the subject is selected for therapy by detecting the presence of a mutation in exon 20 of the EGF-receptor in a biological sample of the subject.

39. The method of claim 37 or 38, wherein the EGF-receptor comprises an insertion in exon 20.

40. The method of claim 39, wherein the EGF-receptor comprises an insertion between amino acids V769-D770 and / or between amino acids D770-N771.

41. The method of claim 40, wherein the insertion is an ASV and / or SVD insertion.

42. The method of claim 39, wherein the EGF-receptor comprising an ASV insertion between amino acids V769-D770 and / or a SVD insertion between amino acids D770-N771.

43. The method of any one of claims 19 to 21, 25 to 27, and 37 to 38, wherein the cancer is lung cancer, particularly lung cancer harboring a mutant EGFR with in-frame deletions in exon 19 (such as EGFR E746_A750del) or point mutations in exon 21 (e.g. L858R), and / or metastases thereof.

44. The method of any one of claims 19 to 21, 25 to 27, and 37 to 38, wherein the cancer is lung cancer, particularly lung cancer harboring a mutant EGFR with a D770_N771insSVD C797S, E746_A750del C797S, or L858R C797S acquired resistance mutation, and / or metastases thereof.

45. The method of any one of claims 19 to 21, 25 to 27, and 37 to 38, wherein the cancer is lung cancer, particularly lung cancer harboring a mutant ERBB2 with exon 20 insertion mutations (such as ERBB2 A775_G776insYVMA), and / or metastases thereof.

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