Irreversible mutegfr inhibitors

Abstract

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

Description

[0001] Irreversible mutEGFR Inhibitors

[0002] STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED

[0003] RESEARCH

[0004] 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.

[0005] Field of application of the invention

[0006] The present invention covers 6,7-dihydropyrazolo[1 ,5-a]pyrazin derivatives of formula (I) as described and defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds, and 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.

[0007] BACKGROUND OF THE INVENTION

[0008] The present invention covers 6,7-dihydropyrazolo[1 ,5-a]pyrazin derivatives of formula (I) which inhibit EGFR.

[0009] The Epidermal Growth Factor Receptor (EGFR or EGF-receptor) receptor tyrosine kinase family consists of 4 members: EGFR (Erbbl , Herl), 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).

[0010] 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.

[0011] Several irreversible EGFR inhibitors are published in CN 110857292, IN 201821027709, GN 110698461 , WO 2020001351 , WO 2020001350, WO 2019233459, CN 110407852, CN 110357863, WO 2019070167, W020061470. WO2019 / 081486 describes 4H-Pyrrolo[3,2- c]pyridine-4-one derivatives.

[0012] 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).

[0013] 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).

[0014] Patients with EGFR exon20 insertions, such as V769__D770insASV, D770__N771insSVD, D770__N771insNPG, N771_P772insH, H773. V774insH, H773__V774insNPH,

[0015] 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).

[0016] 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).

[0017] 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).

[0018] 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.

[0019] SUMMARY OF THE INVENTION

[0020] 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.

[0021] It has now been found that the compounds of the present invention have surprising and advantageous properties.

[0022] 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__N771 insSVD, D770_N771insNPG, N771_P772insH, or H773_V774insNPH exon 20 insertion harboring BA / F3 cell lines.

[0023] Surprisingly, the here described compounds retain high cellular activity in BA / F3 cell lines harboring D770_N771insSVD and the T790M mutation.

[0024] 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).

[0025] 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_A750dei) 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

[0026] In accordance with a first aspect, the invention relates to compounds of formula (I), in which: represents a group selected from the group:

[0027] R3represents -(CO)-R11, “(CO)-C=C-R12, -(SO2)-CH=CH2, or oxirane-2-carbonyl;

[0028] R4arepresents a hydrogen atom, fluoro, or methyl; R4brepresents a hydrogen atom, fluoro, or methyl;

[0029] R4crepresents a hydrogen atom, fluoro, or methyl; R4drepresents a hydrogen atom, fluoro, or methyl;

[0030] R4erepresents a hydrogen atom, fluoro, or methyl;

[0031] R4irepresents a hydrogen atom, fluoro, methyl, C1-C2-hydroxyalkyl, -(CO)-NR19R20, or

[0032] -CH2~(CO)-NR19R20;

[0033] R53represents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1-

[0034] C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1-

[0035] C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1-

[0036] C3-alkyl, hydroxy, cyano, fluoro, chloro, or bromo;

[0037] R5brepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1-

[0038] C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1-

[0039] C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1-

[0040] C3-alkyl, cyano, fluoro, chloro, or bromo;

[0041] R5crepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1-

[0042] C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1-

[0043] C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1-

[0044] C3-alkyl, trifluoromethylsulfanyl, cyano, fluoro, chloro, or bromo;

[0045] R5drepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1-

[0046] C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1-

[0047] C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1-

[0048] C3-alkyl, cyano, fluoro, chloro, or bromo;

[0049] R5erepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1-

[0050] C3-haloalkyl, O-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, CrCa-alkoxy-C1-

[0051] C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyQzamino-C1-

[0052] C3-alkyl, cyano, fluoro, chloro, or bromo;

[0053] R6arepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1-

[0054] C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1-

[0055] C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo;

[0056] 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-alkylJzamino-C1-

[0057] C3-aikyi, or cyano;

[0058] R6crepresents a hydrogen atom, amino, C1-C3-alkyl, Cz-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;

[0059] R6cirepresents 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- Ca-aikyi, or cyano;

[0060] R73represents a hydrogen atom, amino, C1-C3-alkyl, C3-C3-alkenyl, Cz-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;

[0061] 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-alkyQzamino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo;

[0062] 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;

[0063] 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;

[0064] R83represents 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;

[0065] 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-alkylJzamino-C1- C3-aikyi, cyano, fluoro, chloro, or bromo;

[0066] R8crepresents a hydrogen atom, amino, C1-C3-alkyl, Cz-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, O-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;

[0067] R8cirepresents 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;

[0068] R8erepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, Cz-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;

[0069] R9arepresents a hydrogen atom, amino, Ci-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-alkyQzamino-C1- C3-alkyl, C2-C2-cycloalkyl, cyano, fluoro, chloro, or bromo;

[0070] R9brepresents a hydrogen atom, amino, C1-C3-alkyl, Cz-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;

[0071] RSCrepresent8 ahydrOgen 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-aikyi, C1-C3-alkylamino-C1-C3-alkyl, (C1- C3-alkyl)2amino-C1-C3-alkyl, cyano, anilino, pyridin-2-yl-amino, or C2-Ce- cycloalkylformamido;

[0072] 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-alkylamino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo; R,Oarepresents a hydrogen atom, amino, C1-C3-alkyl, Cz-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, O-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-alkyQzamino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo;

[0073] Riot, represents 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;

[0074] RIOC representsahydrOgenatomormethyl;

[0075] Riod representsahydrogen atom, fluoro, or methyl;

[0076] R" represents ~-CH2-CsCH, -C(R14)-R15, or

[0077] R!2represents a hydrogen atom, methyl, -CH2-NR!9R20, or a group selected from the group:

[0078] R14represents =CHR1S;

[0079] R15represents a hydrogen atom, C1-C3-alkyl, fluoro, dimethylamino-methyl, or morpholino-methyl;

[0080] R16represents a hydrogen atom, methyl, chloro, C1-Cj-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy-C1-C3-alkyl, -CH2-NR17a-CR17bR17GR17d, or a group selected from the group: represents a hydrogen atom, methyl, or ethyl; R17brepresents a hydrogen atom or methyl;

[0081] R17crepresents a hydrogen atom or methyl;

[0082] R!7drepresents a hydrogen atom, methyl, hydroxymethyl, or methoxymethyl;

[0083] R!8represents a hydrogen atom or methyl;

[0084] R19represents a hydrogen atom or methyl;

[0085] R20represents a hydrogen atom, CrCU-alkyl, or tert-butoxycarbonyl;

[0086] R21represents a hydrogen atom or methyl;

[0087] R22represents a hydrogen atom or fluoro;

[0088] R23represents a hydrogen atom or fluoro;

[0089] R24represents a hydrogen atom or fluoro;

[0090] R25represents a hydrogen atom, fluoro, or chloro;

[0091] R26represents a hydrogen atom or fluoro;

[0092] R27arepresents a hydrogen atom or fluoro;

[0093] R27brepresents a hydrogen atom or fluoro;

[0094] R28arepresents a hydrogen atom or fluoro;

[0095] R28O represents a hydrogen atom or fluoro;

[0096] R29represents a hydrogen atom or methoxy;

[0097] R3O representsahydrOgenatomormethoxy; 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.

[0098] In a second aspect, the invention relates to compounds of formula (I) as described supra, wherein: represents a group selected from the group: R2represents a group selected from the group:

[0099] R3 represents -(COJ-R11, ~(CO)-C=C-R12, -(SOsJ-CH-CHb, or oxirane-2-carbonyl;

[0100] R4arepresents a hydrogen atom, or methyl;

[0101] R4brepresents a hydrogen atom; R4crepresents a hydrogen atom, or methyl;

[0102] R4drepresents a hydrogen atom;

[0103] R4erepresents a hydrogen atom, or methyl;

[0104] R4irepresents a hydrogen atom, methyl, C1-Cz-hydroxyalkyl, -~(CO)-NR19R20, or -CH2~(CO)-NR19R20; R53represents a hydrogen atom, methyl, hydroxymethyl, methoxy, hydroxy, fluoro, or chloro;

[0105] R5brepresents a hydrogen atom, C1-C2-alkyl, trifluoromethyl, hydroxymethyl, methoxy, cyano, fluoro, or chloro; R5crepresents a hydrogen atom, C1-C2-alkyl, ethinyl, C1-haloalkyl, C1-C2-alkoxy, C1- haloalkoxy, trifluoromethylsulfanyl, cyano, fluoro, or chloro;

[0106] R5drepresents a hydrogen atom, or chloro;

[0107] R5erepresents a hydrogen atom;

[0108] R73represents a hydrogen atom;

[0109] R7brepresents a hydrogen atom;

[0110] R7crepresents trifluoromethyl;

[0111] R7drepresents a hydrogen atom;

[0112] R83represents a hydrogen atom, or fluoro;

[0113] R8b representsahydrogen atom, or fluoro;

[0114] R8crepresents a hydrogen atom, methoxy, trifluoromethyl, fluoro, or chloro;

[0115] R8drepresents a hydrogen atom;

[0116] R8erepresents a hydrogen atom;

[0117] R9arepresents a hydrogen atom, , , ;

[0118] R9brepresents a hydrogen atom;

[0119] R9crepresents a hydrogen atom, amino, methoxy, methyl-amino, anilino, or cyclopropylformamido;

[0120] R9drepresents a hydrogen atom, methyl, methoxy, or cyclopropyl;

[0121] R10arepresents a hydrogen atom, or fluoro;

[0122] R10brepresents a hydrogen atom;

[0123] R10crepresents a hydrogen atom or methyl;

[0124] R10drepresents a hydrogen atom, fluoro, or methyl; represents ~C(R14)-R15, or R12represents a hydrogen atom, methyl, -CH2-NR19R20, or a group selected from the group:

[0125] R!4represents ~CHR!6;

[0126] R15represents a hydrogen atom, methyl, fluoro, dimethylamino-methyl, or morpholino- methyl;

[0127] R!6represents a hydrogen atom, methyl, chloro, C1-haloalkyl, hydroxymethyl, methoxymethyl, -CH2-NR17a-CR17bR17cR17d, or a group selected from the group:

[0128] R17arepresents a hydrogen atom, methyl, or ethyl;

[0129] R17!)represents a hydrogen atom or methyl;

[0130] R17crepresents a hydrogen atom or methyl;

[0131] R17drepresents a hydrogen atom, methyl, hydroxymethyl, or methoxymethyl;

[0132] R18represents a hydrogen atom;

[0133] R19represents a hydrogen atom or methyl;

[0134] R20represents a hydrogen atom, methyl, or tert-butoxycarbonyl;

[0135] R2!represents a hydrogen atom or methyl;

[0136] R22represents a hydrogen atom or fluoro;

[0137] R23represents a hydrogen atom or fluoro;

[0138] R24represents a hydrogen atom or fluoro;

[0139] R25represents a hydrogen atom, fluoro, or chloro; R26represents a hydrogen atom or fluoro;

[0140] R27arepresents a hydrogen atom or fluoro;

[0141] R27brepresents a hydrogen atom or fluoro; p28a represents a hydrogen atom or fluoro; R28brepresents a hydrogen atom or fluoro;

[0142] R29represents a hydrogen atom or methoxy;

[0143] R30represents a hydrogen atom or methoxy; 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.

[0144] In a third aspect, the invention relates to compounds of formula (I) as described supra, wherein:

[0145] R1represents a group selected from the group: wherein4indicates the point of attachment of said group with the rest of the molecule; R2represents a group selected from the group: wherein4indicates the point of attachment of said group with the rest of the molecule;

[0146] R3represents -(CO)-R11, -(CO)-CsC-R12, -(SC^J-CH-CHs, or oxirane-2-carbonyl;

[0147] R43represents a hydrogen atom, fluoro, or methyl;

[0148] R4brepresents a hydrogen atom, fluoro, or methyl;

[0149] R4crepresents a hydrogen atom, fluoro, or methyl;

[0150] R4drepresents a hydrogen atom, fluoro, or methyl;

[0151] R4erepresents a hydrogen atom, fluoro, or methyl;

[0152] R4frepresents a hydrogen atom, fluoro, methyl, C1-Ca-hydroxyalkyl, -(CO)-NR19R20, or -CH2-(CO)-NR19R20;

[0153] R5arepresents 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;

[0154] R5brepresents 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-alkylamino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo;

[0155] 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-Cs-alkyl, (C1-C3-alkyQzamino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo;

[0156] R5cirepresents a hydrogen atom, amino, C1-Cs-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-alkylJzamino-C1- C3-aikyi, cyano, fluoro, chloro, or bromo;

[0157] R5erepresents a hydrogen atom, amino, C1-C3-alkyl, Cz-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, chtoro, or bromo;

[0158] 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- Ca-aikyi, cyano, fluoro, chtoro, or bromo;

[0159] R5brepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, Cz-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;

[0160] 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-alkyQzamino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo;

[0161] 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;

[0162] 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;

[0163] 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;

[0164] 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-alkylJzamino-C1- C3-aikyi, or cyano;

[0165] R7drepresents a hydrogen atom, amino, C1-C3-alkyl, Cz-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;

[0166] 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- Ca-aikyi, cyano, fluoro, chloro, or bromo;

[0167] R8brepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, Cz-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;

[0168] 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-alkyQzamino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo;

[0169] 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;

[0170] 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;

[0171] R93represents 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-alkylamino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo;

[0172] R9brepresents 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-alkylJzamino-C1- C3-aikyi, or cyano;

[0173] R9crepresents a hydrogen atom, amino, C1-C3-alkyl, Cz-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, O-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, anilino, pyridin-2-ylamino, or C2-Ce-cycloalkylformamido;

[0174] R9cirepresents 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- Ca-aikyi, cyano, fluoro, chtoro, or bromo; pioa representsahydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, Cz-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-aikyi, cyano, fluoro, chloro, or bromo;

[0175] R10brepresents a hydrogen atom, amino, Ci-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-alkyQzamino-C1- C3-alkyl, or cyano;

[0176] R10crepresents a hydrogen atom or methyl;

[0177] Riodrepresen|s ahydrogen atom or methyl;

[0178] R11represents -CHa-CsCH, or -C(R14)-R15;

[0179] R12represents a hydrogen atom or methyl;

[0180] R!4represents =CH2, =CH-CH3, or =CH-CH2-N(CH3)-CHR16R17;

[0181] R15represents a hydrogen atom, C1-C3-alkyl, or fluoro;

[0182] R15represents a hydrogen atom or methyl;

[0183] R17represents a hydrogen atom or methyl;

[0184] R18represents a hydrogen atom or methyl;

[0185] R19represents a hydrogen atom or methyl; R20represents a hydrogen atom or methyl; 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.

[0186] In a fourth aspect, the invention relates to compounds of formula (I) as described supra, wherein:

[0187] R1represents a group selected from the group: wherein * indicates the point of attachment of said group with the rest of the molecule;

[0188] R2represents a group selected from the group: wherein * indicates the point of attachment of said group with the rest of the molecule;

[0189] R3represents -(CO)-R11, “(CO)-C=C-R12, “(SOzJ-CH^CHa, or oxirane-2-carbonyl;

[0190] R5crepresenfs ahydrogen atom, fluoro, or chloro;

[0191] R5d representsahydrogen atom, methyl, fluoro, or methoxy;

[0192] R9crepresents a hydrogen atom, amino, methoxy, aniline, or cyclopropylformamido;

[0193] R9cirepresents a hydrogen atom or methoxy;

[0194] R11represents “C(R14)“R15;

[0195] R12represents a hydrogen atom or methyl; R14represents =CH2, =CH-CH3, or =CH-CH2-N(CH3)-CHR16R17;

[0196] R15represents a hydrogen atom, methyl, or fluoro;

[0197] R!6represents a hydrogen atom or methyl;

[0198] R!7represents a hydrogen atom or methyl; 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.

[0199] In a fifth aspect, the invention relates to compounds of formula (I) as described supra, which is selected from the group consisting of:

[0200] 1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2-en- 1-one,

[0201] 1-[2-(4-chloro-3-methylphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one,

[0202] 1-[2-(4-chlorophenyi)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yi]prop-2- en-1-one,

[0203] 1-[2-(3-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2-en-

[0204] 1-one,

[0205] 1-[2-(3-methoxyphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2- en-1-one,

[0206] N-{4-[2-(4-fluorophenyl)-5-{(2E)-4-[methyl(propan-2-yl)amino]but-2-enoyl}-4, 5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl]pyridin-2-yl}cyclopropanecarboxamide,

[0207] N-{4-[2-(4-fluorophenyl)-5-(prop-2-enoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3- yl]pyridin-2-yl}cyclopropanecarboxamide,

[0208] N-(4-{5-[(2E)-4-(dimethylamino)but-2-enoyl]-2-(4-fluorophenyl)-4, 5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl}pyridin-2-yl)cyclopropanecarboxamide,

[0209] N-{4-[2-(4-fluorophenyl)-5-(oxirane-2-carbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3- yl]pyridin-2-yl}cyclopropanecarboxamide,

[0210] 1-[3-(2-aminopyridin-4-yl)-2-(4-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one, 1-[2-(4-fluorophenyl)-3-(2-methoxypyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one,

[0211] 1-[2-(4-fluorophenyl)-3-(3-methoxypyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one,

[0212] 1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2-yn-

[0213] 1-one,

[0214] 5-(ethenesulfonyl)-2-(4-fluorophenyi)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1 ,5- a]pyrazine,

[0215] (2E)-4-(dimethylamino)-1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yi]but-2-en-1-one,

[0216] 1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6!7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]but-2-yn-

[0217] 1-one,

[0218] 2-fluoro-1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl]prop-2-en-1 -one,

[0219] (2E)-1-[2-(4-fluorophenyi)-3-(pyridin-4-yi)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-

[0220] [methyl(propan-2-yl)amino]but-2-en-1-one,

[0221] 1-[2-(4-fluoroanilino)-3-(pyridin-4~yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin~5(4H)-yl]prop-2-en-

[0222] 1-one,

[0223] 1-[3-(2-anilinopyridin-4-yl)-2-(4-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one,

[0224] (2E)-1-[3-(2-anilinopyridin-4-yl)-2-(4-fluorophenyO-6,7-dihydropyrazolo[1 ,5-a]pyrazin-

[0225] 5(4H)-yl]"4"(dimethytamino)but-2"en"1-one,

[0226] 142“(4-fluorophenyl)-3-(1 H-pyrrolo[2i3-b]pyridin-4-yQ-6,7-dihydropyrazoto[1 ,5-a]pyrazin-

[0227] 5(4H)-yl]prop-2-eri"1"One,

[0228] (2E)-1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yi]but-

[0229] 2-en-1-one,

[0230] 1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6!7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-2- methylprop-2-en- l-one.

[0231] (2E)-1-[2-(4-chloro-3-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-

[0232] 5(4H)-yl]-4-(dimethylamino)but-2-en-1-one (2E)-1-[2-(4-chloro-2-fluorophenyl)-3-(pyridin-4-yi)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-

[0233] 5(4H)-yl]-4-(dimethyiamino)but-2-en-1-one

[0234] (2E)-1-[2-(3-chloro-4-methoxyphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-

[0235] 5(4H)-yi]-4-(dimethylamino)but-2-en-1-one

[0236] (2E)-4-(dimethy!amino)-1-[2-(2-methoxyphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]but-2-en-1-one

[0237] (2E)-1-[2-(3,4-dichiorophenyl)-3-(pyridin-4-yi)-6,7-dihydropyrazoio[1,5-a]pyrazin-5(4H)-yl]-

[0238] 4-(dimethylamino)but-2-en-1-one

[0239] (2E)-4-(dimethylamino)-1-[2-(4-methoxyphenyl)-3-(pyridin-4-yi)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yi]but-2-en-1-one

[0240] (2E)-4-(dimethylamino)-1-[2-(3-fluoro-4-methoxyphenyl)-3-(pyridin-4-yl)-6!7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]but-2-en-1-one formic acid - (2E)-1-[2-(4-ch!oro-3-ethylphenyl)-3-(pyridin-4-yl)-6!7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yi]-4-(dimethylamino)but-2-en-1-one

[0241] 4-{5-[(2E)-4-(dimethylamino)but-2-enoyl]-3-(pyridin-4-yl)-4,5l6,7-tetrahydropyrazolo[1,5- a]pyrazin-2-yl}benzonitrile

[0242] (2E)-4-(dimethylamino)-1-[3-(pyridin-4-yi)-2-[4-(trifluoromethyl)phenyl]-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]but-2-en-1-one

[0243] (2E)-1-{2-[4-chloro-2-(hydroxymethyl)phenyl]-3-(pyridin-4-yi)-6,7-dihydropyrazoio[1,5- a]pyrazin-5(4H)-yl}-4-(dimethyiamino)but-2-en~1-one

[0244] 1-[2-(4-ch!oro-3-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl]prop-2-en-1”One

[0245] 1-[2-(4-ch!oro-2-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl]prop-2-en-1”One

[0246] 1-[2-(3-chloro-4-methoxyphenyl)-3-(pyridjn-4-yl)-6,7-djhydropyrazoio[1,5-a]pyrazjn-5(4H)- yl]prop-2-en-1-one

[0247] 1-[2-(2-methoxyphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2- en-1-one

[0248] 1-[2-(3!4-dichloropheny!)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-

[0249] 2-en-1-one 1-[2-(4-methoxyphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazoio[1,5-a]pyrazin-5(4H)-yl]prop-2- en-1-one

[0250] 1-[2-(3-fluoro-4-methoxyphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one

[0251] 4-[5-acryloyl-3-(pyridin-4-y!)-4,5,6,7-tetrahydropyrazolo[1 ,5-a]pyrazin-2-yl]benzonitrile

[0252] 1-[3-(pyridin-4-yl)-2-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one

[0253] 3-[3-(3-methyl-1H-pyrroio[2,3-b]pyridin-4-yl)-5-(prop-2-enoyl)-4, 5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile

[0254] 1-[2-(3-fluoro-4-methoxyphenyl)-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one

[0255] 1-[2-(4-methoxyphenyl)-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-6!7-dihydropyrazolo[1!5- a]pyrazin-5(4H)-y!]prop-2-en-1-one

[0256] 1-[3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-y!)-2-[4-(trifluoromethyl)phenyl]-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one

[0257] 1-[2-(4-chloro-2-fluorophenyl)-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-6>7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop~2-en-1-one

[0258] 1-[2-(4-chloro-2~fluorophenyl)~3-(3-methylpyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-

[0259] 5(4H)-yl]prop-2-en-1-one

[0260] 1-[2-(4-chioro-2-fluorophenyl)-3-(5-fluoro-1H-pyrroio[2,3-b]pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one

[0261] 1-[2-(4-ch!oro-2-fluorophenyl)-3-(3-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one

[0262] 1-[2-(4-ch!oro-2-fluorophenyl)-3-[2-(methylamino)pyridin-4-yl]-6,7-dihydropyrazo!o[1,5- a]pyrazin-5(4H)-yl]prop-2-en~1-one

[0263] 1-[3-(2-methyi-1 H-pyrrolo[2,3-b]pyridin-4-yl)-2-[4-(trifluoromethyl)phenyl]-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one

[0264] 1-[3-(3-cyciopropylpyridin-4-yl)-2-[4-(trifluoromethyl)phenyi]-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-y!]prop-2-en-1-one

[0265] 1-[3-(2,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-[4-(trifluoromethyl)phenyl]-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one (2E)-1-[2-(4-chloro-2-fluorophenyl)-3-(3-methyi-1H-pyrrolo[2,3-b]pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(dimethyiamino)but-2-en-1-one

[0266] (2E)-4-(dimethyiamino)-1-[3-(3-methyi-1 H-pyrrolo[2,3-b]pyridin-4-yl)-2-[4-

[0267] (trifluoromethyl)phenyl]-6!7-dihydropyrazolo[1!5-a]pyrazin-5(4H)-yl]but-2-en-1-one

[0268] (2E)-4-(dimethylamino)-1-[2-(3-fluoro-4-methoxyphenyl)-3-(3-methyl-1 H-pyrroto[2,3- b]pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]but-2-en-1-one

[0269] (2E)-4-(dimethyiamino)-1-[2-(4-methoxyphenyl)-3-(3-methyl-1 H-pyrroio[2,3-b]pyridin-4-yl)-

[0270] 6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]but-2-en-1-one

[0271] 3-{5-[(2E)-4-(dimethyiamino)but-2-enoyl]-3-(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-

[0272] 4,5,6l7-tetrahydropyrazoio[1,5-a]pyrazin-2-yi}benzonitriie

[0273] 2-[(dimethylamino)methyl]-1-[2-(4-fluorophenyl)-3-(pyridin-4-yi)-6,7-dihydropyrazoio[1,5- a]pyrazin-5(4H)-y!]prop-2-en-1-one

[0274] (2E)-1-[2-(4-fluoropheny!)-3-(pyridin-4-y!)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-

[0275] (morphoiin-4-yl)but-2-en-1-one

[0276] 1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1!5-a]pyrazin-5(4H)-yl]-2-

[0277] [(morpholin-4-yl)methyl]prop-2-en-1-one

[0278] 4-(dimethylamino)-1-[2-(4-fluorophenyl)-3-(pyridin~4~yl)~6,7-dihydropyrazolo[1 ,5-a]pyrazin- 5(4H)-yl]but-2-yn-1-one

[0279] (2E)-1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4- methoxybut-2-en- 1 -one

[0280] (2E)-4,4,4-trifluoro-1-[2-(4-fluorophenyO-3-(pyridin-4-yO-6,7“dihydropyrazolo[1 ,5-a]pyrazin- 5(4H)-yl]but-2-en-1-one

[0281] 1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-

[0282] (morpholin-4-yl)but-2-yn-1-one

[0283] (2E)-4-(diethylamino)-1-[2-(4-fluorophenyi)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yi]but-2-en-1-one

[0284] (2E)-1-[2-(4-fluorophenyi)-3-(pyridin-4-yi)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yi]-4- hydroxybut-2-en-1-one

[0285] (2E)-4-[ethyl(methyl)amino]-1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yi]but-2-en-1-one 1-[2-(4-chloro-2-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-

[0286] 4-(dimethylamino)but-2-yn-1-one

[0287] (2E)-1-[2-(4-chloro-2-fluorophenyl)-3-(pyridin-4-yi)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-

[0288] 5(4H)-yl]-4-fluorobut-2-en-1-one

[0289] (2E)-1-[2-(4-chloro-2-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-

[0290] 5(4H)-yl]-4,4-difluorobut-2-en-1-one

[0291] (2E)-3-chloro-1-[2-(4-chloro-2-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]prop-2-en~1-one

[0292] [2-(4-chloro-2-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl](1- methyl-2,5-dihydro-1 H-pyrrol-3-yl)methanone

[0293] (2E)-4-(azetidin-1-yi)-1-[2-(4-chloro-2-fiuorophenyl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]but-2-en-1-one

[0294] (2E)-4-fluoro-1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6!7-dihydropyrazolo[1!5-a]pyrazin-

[0295] 5(4H)-yl]but-2-en-1-one

[0296] (2E)-1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-

[0297] (pyrroiidin-1-yl)but-2-en-1-one

[0298] (2E)-1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-

[0299] (methylamino)but-2-en-1-one

[0300] (2E)-4-(ethylamino)-1-[2-(4-fluorophenyi)-3-(pyridin-4-yi)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)~yl]but-2-en~1-one

[0301] (2E)-1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(4- methylpiperazin-1-yl)but-2-en-1-one

[0302] (2E)-1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-

[0303] [(3S)-3-methoxypyrrolidin-1-yl]but-2-en-1-one

[0304] (2E)-4-(3,3-difluoroazetidin-1-yl)-1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]but-2-en-1-one

[0305] 1-[2-(4-chloro-2-fluorophenyi)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yi]- 4-(morpholin-4-yl)but-2-yn-1-one tert-butyl (2RS)-2-{3-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-

[0306] 5(4H)-yl]-3-oxoprop-1-yn-1-yl}pyrrolidine-1 -carboxylate 1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-3-[(2RS)- pyrrolidin-2-yl]prop-2-yn-1-one

[0307] 3-(1-aminocyclopropyl)-1-[2-(4-fluorophenyi)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]prop-2-yn-1-one tert-butyl {4-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl]"4"Oxobut"2-yn-1-yl}carbamate

[0308] 4-amino-1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl]but-2-yn-1-one

[0309] 1-[2-(4-chloro-2-fluoroanilino)-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one

[0310] 1-[2-(3-fluoro-4-methoxyaniiino)-3-(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one

[0311] 1-[3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-2-[4-(trifluoromethyl)anilino]-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one

[0312] 1-[2-(4-chloro-2-fluoroanilino)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one

[0313] 1-[2-(3-fluoro-4-methoxyanilino)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one

[0314] 1-[3-(pyridin-4-yQ-2-[4-(trifluoromethyl)anilino]-6!7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one

[0315] (2E)-4-(dimethylamino)-142-(4-fluorophenyl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]but-2-en-1-one

[0316] (2E)"4-(dimethylamino)-1-[2-(2-fluoro-4-methylphenyl)-3-(1 H-pyrrolo[2,3-b]pyridin"4-yl)-

[0317] 6!7-dihydropyrazolo[1,5-a]pyrazjn-5(4H)-yl]but-2-en-1-one

[0318] 3-[(6R)-5-[(2E)-4-(dimethylamino)but-2-enoyi]-6-methyl-3-(pyridin-4-yl)-4, 5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile

[0319] 3-[(6S)-5-[(2E)-4-(dimethylamino)but-2-enoyl]-6-methyl-3-(pyridin-4-yi)-4, 5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile

[0320] 1-[2-(2-fluoro-4-methylphenyl)-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one (2E)-1-[2-(4-chloro-2-fluorophenyl)-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(dimethyiamino)but-2-en-1-one

[0321] 1-[2-(4-chioro-2-fluorophenyl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one

[0322] 1-[2-(4-fluoro-1-benzofuran-7-yl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one

[0323] 1-[2-(4-fluoronaphthaien-1-yl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one

[0324] 1-[2-(1-benzofuran-7-yl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2- en-1-one

[0325] 1-[2-(3-methyi-1 H-indol-6-yl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one

[0326] 1-[2-(3-fluoronaphthalen-2-y!)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl]prop”2-en-1-one

[0327] 1-[2-(6-fluoro-1-benzofuran-5-yl)-3-(pyridin-4-yl)-6!7-dihydropyrazolo[1!5-a]pyrazin-5(4H)- yl]prop-2-en-1-one

[0328] 1-[2-(1-fluoronaphthalen-2-yl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl]prop-2-en-1~one

[0329] 1-[2-(2-hydroxy-4-methylphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yHprop-2-en-l-one

[0330] 1-[2-(2-fluoro-4-methylphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one

[0331] 142“(7"fluoro-1 H-indob6-yl)-3-(pyridin-4-yO-6i7-dihydropyrazoto[1 ,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one

[0332] 1-[2-(4-chloro-2-methylphenyl)~3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one

[0333] 1-[2-(2!4-dichlorophenyl)-3-(pyridin~4-yl)~6,7-dihydropyrazoto[1 ,5-a]pyrazin-5(4H)-yl]prop-

[0334] 2-en-1-one

[0335] 1"[2-(4-chlorO"2-methoxypheny0-3-(pyridin-4-y0-6,7-dihydropyrazoto[1 ,5-a]pyrazin-5(4H) yl]prop”2-en-1-one 2-chloro-5-[5-(prop-2-enoyl)-3-(pyridin-4-yi)-4,5,6!7-tetrahydropyrazolo[1,5-a]pyrazin-2- yl]benzonitrile

[0336] 2-fluoro-5-[5-(prop-2-enoyi)-3-(pyridin-4-yi)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2- yl]benzonitrile

[0337] 1-[(6R)-2-[2-fluoro-4-(trifluoromethyl)phenyl]-6-methyl-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one

[0338] 2-fluoro-3-[5-(prop-2-enoyl)-3-(pyridin-4-yi)-4,5,6,7-tetrahydropyrazolo[1 ,5-a]pyrazin-2- yl]benzonitrile

[0339] 1-{2-[3-(hydroxymethyl)phenyl]-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)- yl}prop-2-en-1-one

[0340] 1-[(6S)-2-(4-chlorophenyl)-6-methyl-3-(pyridin-4-yi)-6,7-dihydropyrazoio[1,5-a]pyrazin-

[0341] 5(4H)-yl]prop-2-en-1-one

[0342] 1-[(6R)-2-(4-chlorophenyl)-6-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1!5-a]pyrazin-

[0343] 5(4H)-yl]prop-2-en-1-one

[0344] 1-[(6S)-2-[2-fluoro-4-(trifluoromethyl)phenyl]-6-methyi-3-(pyridin-4-yi)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one

[0345] 3-[(6R)-6-methyl-5-(prop-2-enoyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-2-yl]benzonitrile

[0346] 3-[(6S)-6-methyl-5-(prop~2~enoyl)-3-(pyridin-4-yQ-4,5,6,7-tetrahydropyrazoto[1 ,5-a]pyrazin-

[0347] 2-yi]benzonitnle

[0348] 1-{2-[4-(difluoromethoxy)phenyl]-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1!5-a]pyrazin-5(4H)- yQprop-2-en-l-one

[0349] 143"(pyridin-4-yQ-2"[4-(trifluoromethoxy)phenyO-6,7-dihydropyrazoto[1i5-a]pyrazin-5(4H)- yl]prop-2-en-1-one

[0350] 1-[2-(4-ethoxyphenyl)-3-(pyndin-4-yl)-6,7-dihydropyrazolo[1:5-a]pyrazin-5(4H)-yl]prop-2- en-1-one

[0351] 1-{2-[4-(difluoromethyl)phenyl]-3-(pyridin-4-yi)-6,7-dihydropyrazoio[1,5-a]pyrazin-5(4H)- yl}prop-2-en-1-one

[0352] 1-[2-(5-chloro-2-fluoropheny!)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl]prop”2-en-1-one 1-[2-(3-chlorophenyi)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yi]prop-2- en-1-one

[0353] 1-{2-[3-fluoro-4-(trifluoromethyl)phenyl]-3-(pyridin-4-yl)-6,7-dihydropyrazoio[1l5-a]pyrazin-

[0354] 5(4H)-yl}prop-2-en-1-one

[0355] 1-{2-[2-fluoro-4-(trifluoromethyl)phenyl]-3-(pyridin-4-yl)-6!7-dihydropyrazolo[1!5-a]pyrazin-

[0356] 5(4H)-yl}prop-2-en-1-one

[0357] 1-[2-(2-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2-en-

[0358] 1-one

[0359] 1-[2-(2-chlorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2- en-1-one

[0360] 1-[2-(4-methyiphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yi]prop-2- en-1-one

[0361] 1-[2-(3-methy!phenyl)-3-(pyridin-4-yl)-67-dihydropyrazolo[1,5-a]pyrazin-5(4H)-y!]prop-2- en-1-one

[0362] 1-[2-(4-ethylphenyl)-3-(pyridin-4-yi)-6,7-dihydropyrazoio[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-

[0363] 1-one

[0364] 3-[5-(prop-2-enoyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazoio[1,5-a]pyrazin-2- yl]benzonitrile

[0365] 1-[2-(2-fluoro-4-methoxyphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one

[0366] 1-[3"(pyridin-4-yl)-2-{4-[(trifluoromethyl)su^anynphenyQ-6,7-dihydropyrazoto[1 ,5-a]pyrazin- 5(4H)-yl]prop-2-en~1"One

[0367] (2E)"1-{2-[4-(difluoromethoxy)phenyl]-3-(pyridin-4-yQ-6,7“dihydropyrazolo[1 ,5"a]pyrazin"

[0368] 5(4H)-yl}-4-(dimethylamino)but-2-en-1-one

[0369] (2E)-4-(dimethylamino)-1-[3-(pyridin-4-yl)-2-[4-(trifluoromethoxy)phenyl]-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]but-2-en-1-one

[0370] (2E)-4-(dimethylamino)-1-[2-(4-ethynylphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-y!]but-2-en-1-one

[0371] (2E)-4-(dimethylamino)-1-[2-(4-ethoxyphenyl)-3-(pyridin-4-yl)-6!7-dihydropyrazolo[1!5- a]pyrazin-5(4H)-yi]but-2-en-1-one (2E)-1-{2-[4-(difluoromethyl)phenyl]-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-

[0372] 5(4H)-yl}-4-(dimethylamino)but-2-en-1-one

[0373] (2E)-1-[2-(5-chloro-2-fluorophenyl)-3-(pyridin-4-yi)-6,7-dihydropyrazoio[1 ,5-a]pyrazin-

[0374] 5(4H)-yl]-4-(dimethylamino)but-2-en-1-one

[0375] (2E)-1-[2-(3-chlorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-

[0376] (dimethylamino)but-2-en-1 -one

[0377] (2E)-4-(dimethyiamino)-1-{2-[3-fluoro-4-(trifluoromethyl)phenyl]-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl}but-2-en-1-one

[0378] (2E)-4-(dimethylamino)-1-{2-[2-fluoro-4-(trifluoromethyl)phenyl]-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl}but-2-en-1-one

[0379] (2E)-4-(dimethylamino)-1-[2-(2-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-y!]but-2-en-1-one

[0380] (2E)-1-[2-(2-chlorophenyl)-3-(pyridin-4-yl)-6!7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-

[0381] (dimethylamino)but-2-en-1"One

[0382] (2E)-4-(dimethylamino)-1-[2-(3-methoxyphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazoio[1,5- a]pyrazin-5(4H)-yl]but-2-en-1-one

[0383] (2E)-4-(dimethylamino)-1-[2-(4-methylphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]but-2-en-1-one

[0384] (2E)-4-(dimethyiamino)-1-[2-(3-methyiphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)~yl]but-2-en~1-one

[0385] (2E)-4-(dimethy!amino)-1-[2-(4-ethylphenyl)-3-(pyridin-4-y!)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]but-2-en-1-one

[0386] 3-{5-[(2E)-4-(dimethylamino)but-2-enoyl]-3-(pyridin-4-yl)-4,5!6,7-tetrahydropyrazolo[1,5- a]pyrazin-2-yl}benzonitrile

[0387] (2E)-4-(dimethylamino)-1-[2-(2-fluoro-4-methoxyphenyl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]but-2-en-1-one

[0388] (2E)-4-(dimethylamino)-1-[3-(pyridin-4-yl)-2-{4-[(trifluoromethyl)suifanyl]phenyl}-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]but-2-en-1-one

[0389] (2E)-4-(azetidin-1-yl)-1-[2-(4-chlorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yi]but-2-en-1-one (2E)-1-[2-(4-chlorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4- (piperidin-1-yl)but-2-en-1-one

[0390] (2E)-1-[2-(4-chlorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-

[0391] (4-methylpiperazin-1 -yl)but-2-en- 1 -one

[0392] (E)-1-(2-(4-chlorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-y!)-4- morpholinobut-2-en-1-one

[0393] (2E)-1-[2-(4-chlorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-

[0394] [isopropyl(methyl)amino]but-2-en-1-one

[0395] (2E)-4-(tert-butylamino)-1-[2-(4-chlorophenyi)-3-(pyridin-4-yl)-6l7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yi]but-2-en-1-one

[0396] (2E)-1-[2-(4-chiorophenyl)-3-(pyridin-4-yi)-6,7-dihydropyrazoio[1,5-a]pyrazin-5(4H)-yl]-4-

[0397] (4-methoxypiperidin-1-yl)but-2-en-1-one

[0398] (2E)-1-[2-(4-chlorophenyl)-3-(pyridin-4-yl)-6!7-dihydropyrazolo[1!5-a]pyrazin-5(4H)-yl]-4-

[0399] [(2-methoxyethyl)(methyl)amino]but-2-en-1-one

[0400] (2E)-1 -[2-(4-chlorophenyi)-3-(pyridin-4-yi)-6,7-dihydropyrazoio[1 ,5-a]pyrazin- 5(4H)-yi]-4-[(2-hydroxyethyl)(methyi)amino]but-2-en-1 -one

[0401] (2E)-1 -[2-(4-chlorophenyi)-3-(pyridin-4-yl)-6l7-dihydropyrazoio[1 ,5-a]pyrazin-

[0402] 5(4H)-yi]-4-(pyrrolidin-1 -yl)but-2-en-1 -one

[0403] (2E)-1-[2-(4-chiorophenyl)-3-(pyridin-4-yi)-6,7-dihydropyrazoio[1,5-a]pyrazin-5(4H)-yl]-4-

[0404] (3-fluoroazetidin- 1 -yl) but-2-en- 1 -one

[0405] 1-[2-(4-fiuorophenyl)-3-(3-methyi-1H-pyrrolo[2,3-b]pyridin-4-yi)-6,7-dihydropyrazoio[1,5- a]pyrazin-5(4H)-y!]prop-2-en-1-one

[0406] 1"(2"(2"fluoro-4-(trifluoromethyl)phenyl)-3-(3-methyb1 H-pyrroto[2,3"b]pyridin-4-yO-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl)prop-2-en-1-one

[0407] 1-[2-(4-chlorophenyl)-3-(3-methyl-1 H-pyrrolo[2J3-b]pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one

[0408] 1-[2-(3-chloro-2-fluorophenyl)-3-(3-methyl-1 H-pyrrolo[2!3-b]pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one

[0409] 1-[2-(3-chiorophenyl)-3-(3-methyi-1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one 1-(3-(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(3-(trifluoromethyl)phenyl)-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl)prop-2-en-1-one

[0410] 1-[2-(2-chiorophenyl)-3-(3-methyi-1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one

[0411] 1-[2-(5-ch!oro-2-fluorophenyl)-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one

[0412] 1-[2-(2-fluoro-1-benzothiophen-6-yl)-3-(3-methyl-1 H-pyrroio[2,3-b]pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one

[0413] 4-[3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-5-(prop-2-enoyl)-4, 5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile

[0414] (2E)-1-[2-(4-chlorophenyl)-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yi)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one

[0415] (2E)-1-[2-(3-chlorophenyl)-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one

[0416] (E)-4-(dimethylamino)-1-(3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-2-(3-

[0417] (trifluoromethyl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)but-2-en-1-one

[0418] (2E)-1-[2-(1-benzofuran-7-yl)-3-(3-methyi-1 H-pyrrolo[2,3-b]pyridin-4-yl) -6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-4-(dimethyiamino)but-2-en-1-one formic acid

[0419] (2E)-4-(dimethyiamino)-1-[2-(2-fluoro-1-benzothiophen-6-yi)-3-(3-methyl-1H-pyrrolo[2,3- b]pyridin-4-yi)-6,7-dihydropyrazoio[1 ,5-a]pyrazin-5(4H)-yl]but-2-en-1-one

[0420] 1-[3-(pyridin-4-yi)-2-[6-(trifiuoromethyi)pyridin-3-yl]-6,7-dihydropyrazoio[1 ,5-a]pyrazin-

[0421] 5(4H)-yl]prop-2-en-1-one

[0422] 1-[2-phenyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one

[0423] 1-[2-(4-ch!oro-3-ethylphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazo!o[1,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one

[0424] 1-{2-[4-chloro-2-(hydroxymethyl)phenyl]-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-

[0425] 5(4H)-yi}prop-2-en-1-one

[0426] 1-[2-(1-benzothiophen-5-yl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one

[0427] 1-[2-(1 H-indol-5-yl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-

[0428] 1-one 1-[2-(1-benzofuran-5-yl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2- en-1-one

[0429] 1-[2-(1H-indoi-6-yi)-3-(pyridin-4-yi)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yi]prop-2-en- 1-one

[0430] (2E)-1-[2-(1-benzothiophen-5-yl)-3-(pyridin-4-y!)-6,7-dihydropyrazo!o[1,5-a]pyrazin-5(4H)- yl]-4-(dimethylamino)but-2-en-1-one

[0431] (2E)-4-(dimethyiamino)-1-[2-(1 H-indol-5-yl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]but-2-en-1-one

[0432] (2E)-1-[2-(1H-benzotriazol-6-yi)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)- yl]-4-(dimethylamino)but-2-en-1-one

[0433] (2E)-1-[2-(1-benzofuran-5-yl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-

[0434] 4-(dimethylamino)but-2-en-1-one

[0435] (2E)-4-(dimethylamino)-1-[2-(1 H-indol-6-y!)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yi]but-2-en-1-one rac-(R,E)-4-(dimethylamino)-1-(2-(4-fluorophenyl)-7-(hydroxymethyl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)but-2-en-1-one

[0436] (7RS)-5-[(2E)-4-(dimethylamino)but-2-enoyl]-2-(4-fluorophenyl)-3-(pyridin-4-yl)-4, 5,6,7- tetrahydropyrazolo[1 ,5-a]pyrazine-7-carboxamide

[0437] 1-[(7RS)-2-(4-fluorophenyl)-7-(hydroxymethyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one

[0438] (7RS)-5-acry!oyl-2-(4-fluorophenyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1 ,5- a]pyrazine-7-carboxamide

[0439] 5-acryloyl-2-(4-fluorophenyl)-N-methyl-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1 ,5- a]pyrazine-7-carboxamide

[0440] 5-acryloyl-2-(4-fluorophenyl)-N,N-dimethyi-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-7-carboxamide

[0441] 1-[2-(4-fluorophenyl)-7,7-dimethyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1!5-a]pyrazin-

[0442] 5(4H)-yl]prop-2-en-1-one

[0443] 1-[2-(4-chloro-3-methylphenyl)-7,7-dimethyb3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yi]prop-2-en-1-one 1-[2-(4-chlorophenyi)-7,7-dimethyi-3-(pyridin-4-yi)-6,7-dihydropyrazolo[1,5-a]pyrazin-

[0444] 5(4H)-yl]prop-2-en-1-one

[0445] 1-[2-(4-fluorophenyl)-6,6-dimethyi-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-

[0446] 5(4H)-yl]prop-2-en-1-one

[0447] 1-[2-(4-ch!orophenyl)-6!6-dimethyl-3-(pyridin-4-yl)-6,7-dihydropyrazo!o[1,5-a]pyrazin-

[0448] 5(4H)-yl]prop-2-en-1-one

[0449] 1-[2-(4-chioro-3-methylphenyi)-6!6-dimethyl-3-(pyridin-4-yi)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]prop-2-en~1-one

[0450] (2E)-4-(dimethylamino)-1-[2-(4-fluorophenyl)-7,7-dimethyl-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]but-2-en-1-one

[0451] (2E)-1-[2-(4-chtoro-3-methylphenyl)-7,7-dimethyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1l5- a]pyrazin-5(4H)-y!]-4-(dimethylamino)but-2-en-1-one

[0452] 1-[(2E)-4-(dimethylamino)but-2-enoyl]-3'-pheny!-2'-(pyridin-4-yl)-5',6'- dihydrospiro[piperidine-4!7'-pyrrolo[3,2-c]pyridin]-4'(1'H)-one

[0453] (2E)-4-(dimethylamino)-1-[2-(4-fluorophenyl)-6,6-dimethyl-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]but-2-en-1-one

[0454] (2E)-1-[2-(4-chlorophenyl)-6,6-dimethyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1:5-a]pyrazin-

[0455] 5(4H)-yl]-4-(dimethyhmino)but~2~en-1-one

[0456] (2E)-1-[2-(4-chloro-3-methylphenyl)-6,6-dimethyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one rac-(R,E)-4-(dimethylamino)-1-(2-(4-fluorophenyl)-7-(2-hydroxyethyl)-3-(pyridin-4-y!)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)but-2-en-1-one

[0457] 2-[(7RS)-5-[(2E)-4-(dimethylamino)but-2-enoyl]-2-(4-fluorophenyl)-3-(pyridin-4-y!)-4, 5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-7-yl]acetamide

[0458] 2-[(7RS)-5-[(2E)-4-(dimethylamino)but-2-enoyl]-2-(4-fluorophenyl)-3-(pyridin-4-yl)-4, 5,6,7- tetrahydropyrazolo[1 ,5-a]pyrazin-7-yl]-N-methyhcetamide

[0459] 2-[(7RS)-5-[(2E)-4-(dimethylamino)but-2-enoyl]-2-(4-fluorophenyl)-3-(pyridin-4-yl)-4, 5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-7-yl]-N!N-dimethylacetamide

[0460] 1-(2-(4-fluorophenyl)-7-(2-hydroxyethyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-

[0461] 5(4H)-yl)prop-2-en-1-one 2-(5-acryioyl-2-(4-fluorophenyl)-3-(pyridin-4-yl)-4,5,6l7-tetrahydropyrazolo[1 ,5-a]pyrazin-7- yQacetamide

[0462] 2-(5-acryioyl-2-(4-fluorophenyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1 ,5-a]pyrazin-7- yl)-N-methylacetamide

[0463] 2-(5-acryloyl-2-(4-fluorophenyl)-3-(pyridin-4-yl)-4,5!6,7-tetrahydropyrazolo[1 ,5-a]pyrazin-7- yl)-N,N"dimethylacetamide

[0464] 1-(2-(4-chloro-2-fluorophenyl)-6-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-

[0465] 5(4H)-yl)prop-2-en-1-one

[0466] 1-[(6RS)-2-(4-methoxyphenyl)-6-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-

[0467] 5(4H)-yl]prop-2-en-1-one

[0468] 1-[(RS)-2-(2-fluoro-1-benzothiophen-6-yi)-6-methyl-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one

[0469] 1-[(6RS)-2-[2-fluoro-4-(trifluoromethy!)phenyl]-6-methyl-3-(pyridin-4-yl)-6!7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one

[0470] 1-[(RS)-2-(2-fluoro-4-methoxyphenyl)-6-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1!5- a]pyrazin-5(4H)-yl]prop-2-en-1-one

[0471] 1-[(RS)-6-methyl-2-(naphthaien-2-yl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-

[0472] 5(4H)-yl]prop-2-en-1-one

[0473] 1-[(RS)-2-(2-chloro-1-benzothiophen-6-yl)-6-methyl-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one

[0474] 1-[(6RS)-2-(1-benzothiophen-6-yl)-6-methy!-3-(pyridin-4-y!)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]prop-2”en-1-one

[0475] (2E)-1-[(RS)-2-(4-chloro-2-fluoropheny!)-6-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]-4-(dimethylamino)but"2"en-1-one

[0476] (2E)-1-[(RS)-2-(1-benzothiophen-6-yl)-6-methyi-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yi]-4-(dimethylamino)but-2-en-1-one

[0477] 1-[(RS)-2-(4-chioro-2-fluorophenyl)-6-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-y!]-2-fluoroprop-2-en-1-one

[0478] 1-[(RS)4241“benzothiophen-6-yQ-6-methyl~3-(pyridin-4-yl)-6y-dihydropyrazolo[1 ,5- a]pyrazin~5(4H)-yl]-2"fluoroprop-2-en"1"One 1-[(RS)-2-(4-fluorophenyl)-4-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazoio[1,5-a]pyrazin-

[0479] 5(4H)-yl]prop-2-en-1-one

[0480] 1-[(RS)-2-(4-chloro-2-fluorophenyi)-4-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one

[0481] 1-[(RS)-2-(4-methoxyphenyl)-4-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-

[0482] 5(4H)-yl]prop-2-en-1-one

[0483] 1-[(RS)42-(1-benzothiophen-5-yl)-4-methyl-3-(pyridin-4-yl)-67-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]prop-2-en~1-one

[0484] 1-[(RS)-2-(1 H-indoi-6-yl)-4-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-

[0485] 5(4H)-yl]prop-2-en-1-one

[0486] (2E)-1-[(RS)-2-(4-chloro-2-fluorophenyl)-4-methyi-3-(pyridin-4-yi)-6,7-dihydropyrazoio[1 ,5- a]pyrazin-5(4H)-y!]-4-(dimethylamino)but-2-en-1-one

[0487] (2E)-1-[(6S)-2-(4-chlorophenyl)-6-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yi]-4-(dimethylamino)but-2-en-1-one

[0488] (2E)-1-[(6R)-2-(4-chlorophenyl)-6-methyl-3-(pyridin-4-yl)-6!7-dihydropyrazoio[1 ,5- a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one

[0489] 1-(4-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(4-(trifluoromethyl)phenyl)-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl)prop-2-en-1-one

[0490] 1-[(6S)-6-methyl-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yi)-2-[4-(trifiuoromethyl)phenyl]-

[0491] 6!7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one

[0492] 1-(2-(4-fluorophenyl)-4-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl)prop"2-en-1-one

[0493] 1-(2-(4-fluorophenyl)-4-methyl-3-(3-methy!-1 H-pyrrolo[2!3-b]pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)prop-2-en-1-one

[0494] 1-[(6S)-2-(4-fluorophenyi)-6-methyl-3-(3-methyl-1H-pyrrolo[2l3-b]pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one

[0495] 4-(dimethylamino)-1-[4-methyl-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)-2-[4-

[0496] (trifluoromethyl)phenyl]-6!7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]but-2-en-1-one

[0497] 4-(dimethylamino)-1-(4-methyl-3-(3-methy!-1 H-pyrrolo[2,3-b]pyridin-4-y!)-2-(4-

[0498] (trifluoromethyl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)but-2-en-1-one (2E)-4-(dimethylamino)-1-[(6S)-6-methyl-3-(3-methyl-1H-pyrroio[2,3-b]pyridin-4-yl)-2-[4-

[0499] (trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1l5-a]pyrazin-5(4H)-yl]but-2-en-1-one

[0500] 4-(dimethylamino)-1-[2-(4-fluorophenyl)-4-methyl-3-(1 H-pyrroio[2,3-b]pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]but-2-en-1-one

[0501] (E)-4-(dimethylamino)-1-(2-(4-fluorophenyl)-4-methyl-3-(3-methyl-1H-pyrrolo[2,3-b]pyridin-

[0502] 4-yl)-6!7-dihydropyrazolo[1!5-a]pyrazin-5(4H)-yl)but-2-en-1-one

[0503] (2E)"4"(dimethylamino)-1”[(6S)-2-(4-fluorophenyl)-6-methyl"3-(3-methyl"1 H"pyrroto[2,3" b]pyridin-4-yi)-6,7-dihydropyrazoio[1,5-a]pyrazin-5(4H)-yl]but-2-en-1-one

[0504] 1-(4-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(4-(trifluoromethyi)phenyl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)prop-2-en-1-one

[0505] 1-(4-methyl-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yi)-2-(4-(trifluoromethyl)phenyl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)prop-2-en-1-one

[0506] 1-[(6R)-6-methyl-3-(3-methy!-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-[4-(trif!uoromethyl)phenyl]-

[0507] 6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one

[0508] 1-(2-(4-fluorophenyl)-4-methyl-3-(1H-pyrroio[2,3-b]pyridin-4-yl)-6,7-dihydropyrazolo[1!5- a]pyrazin-5(4H)-yl)prop-2-en-1-one

[0509] 1-(2-(4-fluorophenyl)-4-methyl-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-6:7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl)prop-2-en-1-one

[0510] 1-[(6R)-2-(4-fluorophenyl)-6-methyl-3-(3-methyl-1H-pyrroio[2,3-b]pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one

[0511] (E)-4-(dimethylamino)-1-(4-methyl-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)-2-(4-

[0512] (trifluoromethyl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)but-2-en-1-one

[0513] (E)-4-(dimethylamino)-1-(4-methyl-3-(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(4-

[0514] (trifluoromethyl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)but-2-en-1-one

[0515] (2E)-4-(dimethylamino)-1-[(6R)-6-methyl-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-2-[4-

[0516] (trifluoromethyl)phenyi]-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]but-2-en-1-one

[0517] (E)-4-(dimethylamino)-1-(2-(4-fluorophenyi)-4-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)but-2-en-1-one

[0518] (E)-4-(dimethylamino)-1-(2-(4-fluoropheny!)-4-methyl-3-(3-methyl-1H-pyrrolo[2!3-b]pyridin-

[0519] 4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)but-2-en-1-one (2E)-4-(dimethylamino)-1-[(6R)-2-(4-fluorophenyl)-6-methyi-3-(3-methyl-1H-pyrrolo[2,3- b]pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]but-2-en-1-one

[0520] 1-[(6S)-2-(4-chloro-2-fluorophenyl)-6-methyi-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one

[0521] 1-[(6R)-2-(4-ch!oro-2-fluorophenyl)-6-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one

[0522] 1-[2-anilino-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one

[0523] (2E)-1-[2-anilino-3-(pyridin-4-yi)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yi]-4-

[0524] (dimethylamino)but-2-en-1-one

[0525] 1-[2-(4-methoxyphenyl)-7-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one

[0526] 1-[(6S)-2-(1-benzothiophen-5-yl)-6-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-y!]prop-2-en-1-one

[0527] 1-[(6R)-2-(1-benzothiophen-5-y!)-6-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one

[0528] 1-[2-(4-chloro-2-fluorophenyi)-4-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-

[0529] 5(4H)-yl]prop~2-en-1-one

[0530] 1-[(7RS)-2-(1-benzothiophen-5-yl)-7-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one

[0531] 1-[(7RS)-2-(4-chlorophenyi)-7-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-

[0532] 5(4H)-yl]prop-2-en-1-one

[0533] 1-[2-(4-ch!oro-2-fluorophenyl)-7-methyl-3-(pyridin-4-yl)-6!7-dihydropyrazolo[1!5-a]pyrazin-

[0534] 5(4H)-yl]prop-2-en-1-one

[0535] 3-[(6S)-6-methyl-3-(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-(prop-2-enoyl)-4!5,6,7- tetrahydropyrazolo[1 ,5-a]pyrazin-2-yl]benzonitrile

[0536] 3-[(6R)-6-methyi-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-5-(prop-2-enoyl)-4, 5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile

[0537] (2E)-1-[(2-(4-chloro-2-fluorophenyl)-4-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-y!]-4-(dimethylamino)but-2-en-1-one

[0538] (2E)-1-[2-(4-chloro-2-fluorophenyl)-7-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yi]-4-(dimethylamino)but-2-en-1-one 3-[(6S)-5-[(2E)-4-(dimethylamino)but-2-enoyl]-6-methyl-3-(3-methyl-1 H-pyrrolo[2,3- b]pyndin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile

[0539] 3-[(6R)-5-[(2E)-4-(dimethylamino)but-2-enoyl]-6-methyl-3-(3-methyl-1 H-pyrrolo[2,3- b]pyridin-4-yl)-4,5,6!7-tetrahydropyrazolo[1!5-a]pyrazin-2-yl]benzonitrile

[0540] 1-[(6R)-2-(4-chloro-2-fluorophenyl)-4,6-dimethyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one

[0541] 1-[(6S)-2-(4-chloro-2-fluorophenyl)-4!6-dimethyl-3-(pyridin-4-yl)-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,

[0542] A further aspect of the invention relates to compounds of formula (I), which are present as their salts, such as pharmaceutically acceptable salts.

[0543] 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.

[0544] More particularly still, the present invention covers compounds of formula (I) which are disclosed in the Example section of this text, infra.

[0545] 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.

[0546] Another embodiment of the invention are compounds according as disclosed in the Claims section or disclosed analogs of the exemplified compounds and subcombinations thereof.

[0547] Definitions

[0548] 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 (la) and vice-versa, for example.

[0549] 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.

[0550] The term “comprising” when used in the specification includes “consisting of”.

[0551] 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.

[0552] 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.

[0553] 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.

[0554] “Suitable” within the sense of the invention means chemically possible to be made by methods within the knowledge of a skilled person.

[0555] The terms as mentioned in the present text may have the following meanings: The term “C2-C2-cycloalkyl” means a saturated, monovalent, monocyclic hydrocarbon ring which contains 3, 4, 5, or 6 carbon atoms. Said C2-Ce-cycloalkyl group is for example, a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group.

[0556] Further, as used herein, the term “C2-Cs”, as used throughout this text, e.g. in the context of the definition of “C2-Ce-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 “Ca-Ce” is to be interpreted as any sub-range comprised therein, e.g. C2-Ce , C4-C5 , C3-C5 , C3-C4 , C^Cs, C2-Cs; particularly C2-Cs.

[0557] 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.

[0558] 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”.

[0559] 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).

[0560] 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.

[0561] 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.

[0562] 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, 18Q, 32p, 33p, 33g, 34g, 35g, 36g, 18p, 36Q| 82gr, !23|, 124^, 125|, 129| 131^, respectively.

[0563] 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 or "C 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.

[0564] 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.

[0565] 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).

[0566] 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.

[0567] 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 exchangers) 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.

[0568] 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.

[0569] 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.

[0570] 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.

[0571] 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.

[0572] 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.

[0573] 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).

[0574] 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 Appt. 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.

[0575] Figure 1: Atropisomerism examples of compounds of general formula (I)

[0576] Several related compounds with the related type of atropisomerlsm 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 a / ., J. Med. Chem. 2011 , 54, 7005-7022.

[0577] 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.

[0578] 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.

[0579] 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 1 H 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 1 H tautomer, a 2H tautomer, or a 4H tautomer, or even a mixture in any amount of said 1 H, 2H and 4H tautomers, namely :

[0580] 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.

[0581] 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.

[0582] 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.

[0583] 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.

[0584] The present invention includes all such hydrates or solvates.

[0585] 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.

[0586] 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 a / . “Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19.

[0587] 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.

[0588] 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.

[0589] 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.

[0590] 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.

[0591] 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.

[0592] Unless specified otherwise, suffixes to chemical names or structural formulae such as "hydrochloride", "trifluoroacetate", "sodium salt", or "x HCI", "x CF3COOH", "x Na+", for example, are to be understood as not a stoichiometric specification, but solely as a salt form.

[0593] 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.

[0594] The salts include water-insoluble and, particularly, water-soluble salts.

[0595] 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.

[0596] 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-C3 alkoxymethyl esters, e.g. methoxy methyl, C1- Ce alkanoyloxymethyl esters, e.g. pivaloyloxymethyl, phthalidyl esters, C2-Cs cycloalkoxy- carbonyloxy-C1-C3 alkyl esters, e.g. 1 -cyclohexylcarbonyloxyethyl, 1,3-dioxolen-2- onylmethyl esters, e.g. 5-methyl-1,3-dioxolen-2-onylmethyl, and C1-C3- alkoxycarbonyloxyethyl esters, e.g. 1 -methoxycarbonyloxyethyl, and may be formed at any carboxy group in the compounds of this invention.

[0597] An in vivo hydrolysable ester of a compound of the present invention containing a hydroxy group includes inorganic esters such as phosphate esters and [alphaj-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 [alphaj-acyloxyalkyl ethers include acetoxym ethoxy 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.

[0598] 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.

[0599] 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.

[0600] 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.

[0601] 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.

[0602] 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

[0603] 1311-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, 1-125 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 (1231), iomeprol, ipilimumab, irinotecan, Itraconazole, ixabepilone, lanreotide, lapatinib, lasocholine, 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, oxymethoIone, 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.

[0604] 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.

[0605] An exemplary full length sequence of human EGFR, which indicates V769, D770, and N771 in bold, is provided at Uni Prof Accession No. P00533-1 , which is reproduced below:

[0606] 80

[0607] LQRMFNNCEV QRNYDLSFLK T IQEVAGYVL 1ALNTVERIP

[0608] 150

[0609] LENLQI IRGN LKELPMRNL QEILHGAVRF

[0610] 160 170 180 190 200

[0611] ;NHLC :w

[0612] 21 220 2 240 250

[0613] 270 280 290 CRKFRDEATC KDTCPPLMLY NPTTYQMDVN PEGKYSFGAT CVKKCPRNYV

[0614] 310 320 330 340 350

[0615] VTDHGSCVRA CGADSYEMEE DGVRKCKKCE GPCRKVCNGI GIGEFKDSLS

[0616] 360 370 380 390 400

[0617] INATNIKHFK NCTSISGDLH ILPVAFRGDS FTHTPPLDPQ ELDILKTVKE

[0618] 410 420 430 440 450

[0619] ITGFLLIQAW P E N R T D L H A t ’ ENLEIIRGRT KQHGQFSLAV VSLNITSLGL

[0620] 460 470 480 4 90 500

[0621] RSLKE ISDGD VI I SGNKNLC YANT INWKKL FGTSGQKTKI ISNRGENSCK 520 530 540 550

[0622] ATGQVCHALC SPEGCWGPEP RDC57SCB.NVS RGRECVDKCN LLEGEPRE FV

[0623] 560 570 580 5 90 600

[0624] ENSECIQCHP ECLPQAMNIT CTGRGPDNCI QCAHY 1DGPH CVKTCPAGVM

[0625] 610 620 630 640 650

[0626] GENNTLVWKY ADAGHVCHLC HPNCTYGCTG PGLEGCPTNG PKI PSIATGF1

[0627] 660 670 680 690 700

[0628] V GALLLLLVV ALGIGLFMRR RHIVRKRTLR RLLQERELVE PLTPSGEAPN

[0629] 71 0 720 730 740 750

[0630] QALLRILKET E FKKIKVLGS GAFGTVYKGL WI PEGEKVKI PVAIKELREA

[0631] ' 60 770 780 7 90 800

[0632] TSPKANKEIL DEAYVMASVD NPHVCRLLGI CLTSTVQLIT QLMPFGCLLD

[0633] 810 820 830 840 850

[0634] YVREHKDNIG SQYLLNWCVQ IAKGMNYLED RRLVHRDLAA RNVLVKTPQH

[0635] 860 870 880 8 90 900

[0636] VKITDFGLAK LLGAEEKEYH AEGGKVPI KW MALES ILHRI YTHQSDVWSY

[0637] 910 920 930 940 950

[0638] G V'lVWELMT F GSKPYDGI PA SE ISSILEKG ERLPQPPICT IDVYMIMVKC

[0639] 960 970 980 990 1000

[0640] WMIDADSRPK FRELI IEFSK FIARD PQ RY LV IQGDERMHLP SPTDSNFYRA

[0641] 1010 1020 1030 1040 1050

[0642] LMDEEDMDDV VDADEYLI PQ QGFFSSPSTS RTPLLSSLSA TSNNSTVACI

[0643] 1060 1070 1080 1090 1100

[0644] DRNGLQSCPI KEDSFLQRYS SDPTGALTED S I DDT FL P VP EY INQSVPKR

[0645] 1110 1120 1130 1140 1150

[0646] PAGSVQNPVY HNQ PLN PAPS RDPHYQDPHS TAVGNPEYLN TVQPTCVNST

[0647] 1160 1170 1180 1190 1200 FDSPAHWAQK GSHQISLDNP DYQQDFFPKE AKPNGI TAENAEYLRV

[0648] 1210

[0649] APQSSEFIGA

[0650] 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:

[0651] 1 gtccgggcag cccccggcgc agcgcggccg cagcagcctc cgccccccgc aeggtgtgag

[0652] 61 cgcccgacgc ggccgaggcg gccggagtcc cgagctagcc ccggcggccg ccgccgccca gaccggacga caggccacct cgtcggcgtc cgcccgagtc cccgcctcgc cgccaacgcc

[0653] 181 acaaccaccg cgcacggccc cctgactccg tccagtattg atcgggagag c eg gage gag

[0654] 241 ctcttcgggg ageagegatg cgaccctccg ggaeggeegg ggcagcgctc ctggcgctgc

[0655] 301 tggetgeget ctgcccggcg agtcgggctc tggaggaaaa gaaagtttgc caaggcacga

[0656] 361 gtaacaagct cacgcagttg ggcacttttg aagatcattt tctcagcctc cagaggatgt

[0657] 421 teaataaetg tgaggtggtc. cttgggaatt tggaaattac ctatgtgcag aggaattatg

[0658] 481 atctttcctt cttaaagacc atccaggagg tggctggtta tgtcctcatt gccctcaaca

[0659] 541 cagtggagcg aattcctttg gaaaacctgc agatcatcag aggaaatatg t.actdcgaaa

[0660] 601 attcctatgc cttagcagtc ttatctaact atgatgeaaa taaaaccgga etgaaggage

[0661] 661 tgcccatgag aaatttacag ggccaaaagt gtgatccaag ctgtcccaat gggagetget

[0662] 721 ggggtgcagg agaggagaac tgccagaaac tgaccaaaat catctgtgcc cagcagtgct 781 ccgggcgctg ccgtggcaag tcccccagtg actgctgcca caaccagtgt gctgcaggct

[0663] 841 gcacaggccc ccgggagagc gactgcctgg tctgccgcaa attccgagac gaagccacgt

[0664] 901 gcaaggacac ctgcccccca ctcatgctct acaaccccac cacgtaccag atggatgtga

[0665] 961 accccgaggg caaatacagc tttggtgcca cctgcgtgaa gaagtgtccc

[0666] / .gtaattatg tggtgacaga tcacggctcg tgcgtccgag cctgtggggc cgacagctat gagatggagg

[0667] 1081 aagacggcgt ccgcaagtgt aagaagtgcg aagggccttg ccgcaaagtg tgtaacggaa

[0668] 1141 taggtattgg tgaatttaaa gactcactct ccataaatgc tacgaatatt aaacacttca

[0669] 1201 aaaactgcac ctccatcagt ggcgatctcc acatcctgcc ggtggcattt aggggtgact

[0670] 1261 ccttcacaca tactcctcct ctggatccac aggaactgga tattctgaaa accgtaaagg

[0671] 1321 aaatcacagg gtttttgctg attcaggctt ggcctgaaaa caggacggac ctccatgcct

[0672] 1381 ttgagaacct agaaatcata cgcggcagga ccaagcaaca tggtcagttt tctcttgcag

[0673] 1441 tcgtcagcct gaacataaca tccttgggat tacgctccct caaggagata agtgatggag

[0674] 1501 atgtgataat ttcaggaaac aaaaatttgt gctatgcaaa tacaataaac c cr cj a. a a a 8. a. c

[0675] 15 (51 tgtttgggac ctccggtcag aaaaccaaaa ttataagcaa cagaggtgaa aacagctgca

[0676] 1621 aggccacagg ccaggtctgc catgccttgt gctcccccga gggctgctgg ggcccggagc

[0677] 1681 ccagggactg cgtctcttgc cggaatgtca gccgaggcag ggaatgcgtg gacaagtgca

[0678] 1 / 41 accttctgga gggtgagcca agggagtttg tggagaactc tgagtgcata

[0679] / .agtgccacc

[0680] 180 cagagtgcct gcctcaggcc atgaacatca cctgcacagg acggggacca 18 (51 tccagtgtgc ccactacatt gacggccccc actgcgtcae i gacctgcccg gcaggagtca

[0681] 1921 tgggagaaaa caacaccctg gtctggaagt acgcagacgc : cggccatgtg tgccacctgt

[0682] 1981 gccatccaaa ctgcacctac ggatgcactg ggccaggtct ; tgaaggctgt ccaacgaatg

[0683] 204 1 ggcctaagat cccgtccatc gccactggga tggtgggggc : cctcctcttg ctgctggtgg

[0684] 2101 tggccctggg gatcggcctc ttcatgcgaa ggcgccacat : cgttcggaag cgcacgctgc

[0685] 2161 ggaggctgct gcaggagagg gagcttgtgg agcctcttac ; acccagtgga gaagctccca

[0686] 2221 accaagctct cttgaggatc ttgaaggaaa ctgaattcae 3 clcLclQa C Cclcia gtgctgggct

[0687] 2281 ccggtgcgtt cggcacggtg tataagggac tctggatccc : agaaggtgag aaagttaaaa

[0688] 2341 ttcccgtcgc tatcaaggaa ttaagagaag caacatctcc ?• g a a a g c c a a c a a g g a a a t c c

[0689] 2401 tcgatgaagc ctacgtgatg gccagcgtgg acaaccccce i cgtgtgccgc ctgctgggca

[0690] 2461 tctgcctcac ctccaccgtg cagctcatca cgcagctcat : gcccttcggc tgcctcctgg

[0691] 2521 actatgtccg ggaacacaaa gacaatattg gctcccagte it c c t g ct ca a c tggtgtgtgc

[0692] 2581 agatcgcaaa gggcatgaac tacttggagg accgtcgctt i ggtgcaccgc gacctggcag

[0693] 2 641 ccaggaacgt actggtgaaa acaccgcagc atgtcaagat ; cacagatttt gggctggcca

[0694] 270 1 aactgctggg tgcggaagag aaagaatacc atgcagaagc i aggcaaagtg cctatcaagt

[0695] 2761 ggatggcatt ggaatcaatt ttacacagaa tctataccce i ccacjagrgat gtctggagct

[0696] 282 1 acggggtgac tgtttgggag ttgatgacct ttggatcca; i gccatatgac ggaat ccctg

[0697] 2881 ccagcgagat ctcctccatc ctggagaaag gagaacgcct : ccctcagcca cccatatata 2941 ccatcgatgt ctacatgatc atggtcaagt gctggatgat agacgcagat agtcgcccaa

[0698] 3001 agttccgtga gttgatcatc gaattctcca aaatggcccg agacccccag cgctaccttg

[0699] 3061 tcattcaggg ggatgaaaga atgcatttgc caagtcctac agactccaac t c t a c c g g

[0700] 3121 ccctgatgga tgaagaagac atggacgacg tggtggatgc cgacgagtac ctcatcccac

[0701] 3181 agcagggctt cttcagcagc ccctccacgt cacggactcc cctcctgagc tctctgagtg a 24 J_ c a a c c. a g c a a caiat tccacc gtgc^cLtgca iaLgatagaaa tgggctgcaa agctgtccca

[0702] 3301 tcaaggaaga cagcttcttg cagcgataca gctcagaccc cacaggcgcc ttgactgagg

[0703] 3361 acagcataga cgacaccttc ctcccagtgc ctggtgagtg gcttgtctgg aaacagtcct

[0704] 3421 gctcctcaac ctcctcgacc cactcagcag cagccagtct ccagtgtcca agccaggtgc

[0705] 3481 tccctccagc atctccagag ggggaaacag tggcagattt gcagacacag tgaagggcgt

[0706] 3541 aaggagcaga taaacacatg accgagcctg cacaagctct ttgttgtgtc tggttgtttg

[0707] 3601 ctgtacctct gttgtaagaa tgaatctgca aaatttctag cttatgaagc a a a t c a c g g a

[0708] 3661 catacacatc tgtgtgtgtg agtgttcatg atgtgtgtac atctgtgtat gtgtgtgtgt

[0709] 3721 gtatgtgtgt gtttgtgaca gatttgatcc ctgttctctc tgctggctct atcttgacct a / 81 grcjaaacgta t at 11 aacca attaaatatt agctaatatc a a t aa a t a 11 aagctttatc

[0710] 3841 cagaaaaaaa

[0711] 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.

[0712] 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.

[0713] General Procedures

[0714] The compounds according to the invention can be prepared according to the following schemes 1 - 6.

[0715] The schemes and procedures described below illustrate synthetic routes to the compounds of formula (I) of the invention and are not intended to be limiting. It is obvious to the person skilled in the art that the order of transformations as exemplified in the schemes can be modified in various ways. The order of transformations exemplified in the schemes is therefore not intended to be limiting. In addition, interconversion of any of the substituents R1, R2, R3, R4(e.g., R4a, R4b, R4c, R4d, R4e, R4f), R5(e.g., R5a, R5b, R5c, R5d, R5e), R5(e.g., R6a, R6b, R6c, R6d), R7(e.g., R7a, R7b, R7c, R7d), R8(e.g., R8a, R8b, R8c, R8d, R8e), R9(e.g., R9a, R9b, R9C, p9dj an(j pgcanijgachieved before and / or after the exemplified transformations. These modifications can be such as the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to the person skilled in the art. These transformations include those which introduce a functionality which allows for further interconversion of substituents. Appropriate protecting groups and their introduction and cleavage are well- known to the person skilled in the art. Specific examples are described in the subsequent paragraphs.

[0716]

[0717] Scheme 1: Route for the preparation of compounds of formula (I), wherein R1, R2, R3, R4a, R4b, R4G, 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 (Boo), and LG, is a suitable leaving group such as a halide or sulfonate as known to one skilled in the art. Compounds of the formula 1 can be converted to compounds of the formula 2 by reacting for example suitable boronic acids in a Suzuki-type reaction. 2 can be converted to compounds of the formula 3 by halogenation reactions e.g. brominations, with reagents such as N- Bromsuccinimid (NBS) in solvents such as DMF or acetonitrile in a temperature range from -30°C to the boiling point of the respective solvent. Compounds of formula 3 can be converted to compounds of the type 4 with suitable boronic acids in a Suzuki-type reaction. Compounds of type 5 can be prepared from compounds of the formula 4 by deprotection reactions known to those skilled in the art. Compounds of the formula 5 can be converted to compounds of the formula (I) 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 or T4P. Additionally, following the introduction of a substituent at position R3, further synthetic manipulations could be carried out at this position. For instance, elimination of hydrogen chloride, could be used to form an alkene, or transformations such as alkylation’s may be undertaken to introduce additional substituents such as alkylamines. Furthermore, the sequence shown here may be altered, for instance formula type 1 , could be halogenated, affording a halogenated intermediate, which through a sequence of selective cross coupling reactions could also be used to generate compounds of type 4, as obvious to one skilled in the art.

[0718] Scheme 2: Route for the preparation of compounds of formula (18), wherein R2, R3, R4a, R4b, R4c, R4d, R4e, R4fR8a, R8b, R8c, R8d, R8e, and R18have the meaning as given for formula (I) and PG can be hydrogen or optionally a suitable protecting group, e.g tert- butoxycarbonyl (Boc). X represents a halogen, preferably Cl, Br or I. Compounds of the formula 13 can be converted to compounds of the formula 14 using various methods which are known to those skilled in the art. These transformations include Buchwald-Hartwig- or Ullmann- reactions with suitable anilins. Compounds of the formula 14 can be converted to compounds of the formula 15 by reactions to introduce halogen known to a person skilled in the art. Introduction of Br is preferred by using N-Bromosuccinimide (NBS) in solvents such as DMF or acetonitrile in a temperature range from -30°C to the boiling point of the respective solvent. Compounds of the formular 15 can be converted to compounds of the formula 16 by reacting for example suitable boronic acids in a Suzuki-type reaction. In cases in which PG represents a protecting group such as tert-butoxycarbonyl compounds of the formula 17 can be prepared from compounds of the formula 16 by deprotection reactions 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 17 can be converted to compounds of the formula 18 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, EDO -HOBt or T3P. Additionally, following the introduction of a substituent at position R3, further synthetic manipulations could be carried out at this position. For instance, elimination of hydrogen chloride, could be used to form an alkene, or transformations such as alkylation’s may be undertaken to introduce additional substituents such as alkylamines.

[0719] Scheme 3: Route for the preparation of compounds of formula 28, 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. Compounds of the formula 19 can be converted to compounds of the formula 20 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). 20 can be converted to compounds of the formula 21 by reduction, with reagents such as sodium borohydride. 21 can be converted to compounds of the type 22 by reaction with for instance mesyl chloride, to convert the corresponding alcohol into a suitable leaving group (LG). 22 can be converted to compounds of the type 23 by treatment with a suitable base such as sodium hydride. 23 can be converted to compounds of the type 24 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 24 can be converted to compounds of the formula 25 by reacting for example suitable boronic acids in a Suzuki-type reaction. 25 can be converted to compounds like 26 by reacting for example suitable boronic acids in a Suzuki-type reaction. In cases in which PG represents a protecting group such as tert-butoxycarbonyl, compounds of the formula 27 can be prepared from compounds of the formula 26 by deprotection reactions 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 27 can be converted to compounds of the formula 28 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. Additional transformations on the groups R4a, R4!5, R4c, R4d, R4eand R4fmay be undertaken at suitable stages in the sequence described above, for instance cleavage of protecting groups, reductions or oxidations, and further manipulations such as amide formation, as known to one skilled in the art. Furthermore, the sequence shown here may be altered, for instance formula type 23, 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 26, as obvious to one skilled in the art.

[0720]

[0721] Scheme 4: Route for the preparation of compounds of formula (I), wherein atom and R1, R2, R3, R4a, R4!5, R4c, R4d, R4e, and R4fhave the meaning as given for formuia (I) and PG can be hydrogen or optionally a suitable protecting group, e.g. tert-butoxycarbonyl (Boc). A compound of type 29 (here described as a ethyl ester, but not limited to specifically this ester), could be converted to formula 30 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 31. 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 32, 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 33. Deprotection generates an imine of formula 34, 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 35. Analogously to Scheme 3, 35 can be converted to compounds of the type 40 by the described transformations.

[0722]

[0723] Scheme 5: Route for the preparation of compounds of formula (I), wherein R43, R4bare 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 41 (here described as a methyl ester, but not limited to specifically this ester), could be converted to formula 42 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 43, which can be cyclized to formula 44, by for instance treatment with a base such as triethyiamine. Conversion of formula 44 to formula 45 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. Reduction of the lactam with a suitable reagent, such as but not limited to borane dimethyl sulfide, yields formula 46, which can, but not must be suitably protected, as for instance a carbamate, yielding formula type 47. Analogously to Scheme 1, 47 can be converted to compounds of the type 51 by the described transformations.

[0724]

[0725] Scheme 6: Route for the preparation of compounds of formula (I), wherein 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) or benzyl, as preferable as known to one skilled in the art. Compounds of formula type 52 may be prepared by the approaches described in Schemes 1-5, as obvious to one skilled in the art. Deprotection of, for instance a benzyl protecting group, using for instance dihydrogen with a suitable catalyst such as palladium, in a suitable solvent, can be performed, yielding compounds of type 53. Oxidation of the corresponding alcohol, using for instance a suitable oxidant, such as for instance Dess-Martin periodane, can be used to produce formula type 54, which can be further oxidized, with for instance sodium chlorite, to the corresponding acid of formula 55. Amide coupling, using for instance HATU and a suitable amine, can be used to produce formula type 56. Deprotection, yielding formula 57, and further transformations, analogously to Schemes 1 - 5 can be used to produce compounds of formula type 58. Additionally, the order of the sequence could be altered, with for instance formula type 53, could be deprotected, and directly used to produce compounds of formula 58, as known to one skilled in the art.

[0726] 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.

[0727] 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.

[0728] 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.

[0729] 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.

[0730] 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 auxiliary agent, resolving the diastereomers obtained and removing the chiral auxiliary agent. As chiral auxiliary 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 auxiliary 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.

[0731] 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.

[0732] 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.

[0733] 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.

[0734] Commercial utility

[0735] 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.

[0736] 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).

[0737] 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__N771 insSVD C797S, E746_A750del C797S, or L858R C797S acquired resistance mutation, and / or metastases thereof.

[0738] 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.

[0739] 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.

[0740] 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.

[0741] 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.

[0742] 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__N771 ins SVD exon 20 insertions, and / or metastases thereof, especially preferred for the treatment thereof.

[0743] 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 ceil 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.

[0744] Method of treating hyper-proliferative disorders

[0745] 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.

[0746] 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.

[0747] 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.

[0748] 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.

[0749] 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.

[0750] Tumours of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers.

[0751] Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.

[0752] 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.

[0753] 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.

[0754] 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.

[0755] 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.

[0756] 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.

[0757] 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.

[0758] 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.

[0759] 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.

[0760] 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.

[0761] 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.

[0762] 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.

[0763] 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.

[0764] 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.

[0765] 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.

[0766] 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.

[0767] 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.

[0768] 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).

[0769] 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.

[0770] Methods of treating kinase disorders

[0771] 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.

[0772] 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.

[0773] 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.

[0774] Methods of treating angiogenic disorders

[0775] The present invention also provides methods of treating disorders and diseases associated with excessive and / or abnormal angiogenesis.

[0776] 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.

[0777] In various embodiments, the diseases of said method are haematological tumours, solid tumour and / or metastases thereof.

[0778] 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.

[0779] Pharmaceutical compositions of the compounds of the invention

[0780] 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.

[0781] 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.

[0782] 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.

[0783] 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.

[0784] 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.

[0785] 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.

[0786] 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.

[0787] 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.

[0788] 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.

[0789] 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.

[0790] 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.

[0791] 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.

[0792] 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~ oxypropylenejs 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.

[0793] 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.

[0794] 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.

[0795] 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.

[0796] 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.

[0797] 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.

[0798] Controlled release formulations for parenteral administration include liposomal, polymeric microsphere and polymeric gel formulations that are known in the art.

[0799] 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.

[0800] 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.

[0801] Such ingredients and procedures include those described in the following references, each of which is incorporated herein by reference: Powell, M.F. etal., "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.

[0802] 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 (examples include but are not limited to carbon dioxide, CCI2F2, F2CIC-

[0803] CCIF2 and CCIF3); air di (examples include but are not limited to nitrogen and argon);

[0804] (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 di hydrate); 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, carboxymethyicelluiose 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, carboxymethyicelluiose 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 disir (examples include but are not limited to alginic acid, carboxymethyicelluiose 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, com starch and talc); tablet lubricants (examples include but are not limited to calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc stearate); luants (examples include but are not limited to titanium dioxide); tablet ;nts (examples include but are not limited to carnuba wax and white wax); (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).

[0805] Pharmaceutical compositions according to the present invention can be illustrated as follows:

[0806] 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.

[0807] 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.

[0808] Intramuscular suspension: The following solution or suspension can be prepared, for intramuscular injection:

[0809] 50 mg / ml of the desired, water-insoluble compound of this invention

[0810] 5 mg / ml sodium carboxymethylcellulose

[0811] 4 mg / ml TWEEN 80

[0812] 9 mg / ml sodium chloride

[0813] 9 mg / ml benzyl alcohol

[0814] 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.

[0815] 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.

[0816] 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.

[0817] 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.

[0818] Dose and administration

[0819] 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.

[0820] 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.

[0821] 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.

[0822] Combination Therapies

[0823] 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.

[0824] 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 a / ., 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.

[0825] Methods of testing for a particular pharmacological or pharmaceutical property are well known to persons skilled in the art.

[0826] The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given.

[0827] 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.

[0828] 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.

[0829] 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.

[0830] The term “according to” within the experimental section is used in the sense that the procedure referred to is to be used “analogously to”.

[0831] EXPERIMENTAL SECTION

[0832] 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.

[0833] 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 perse to the skilled person.

[0834] Other abbreviations have their meanings customary perse to the skilled person.

[0835] 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.

[0836] The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given.

[0837] EXPERIMENTAL SECTION - GENERAL PART

[0838] 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.

[0839] 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.

[0840] 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.

[0841] Analytical LC-MS Methods:

[0842] Method 1

[0843] Instrument: Agilent 1290 UPLCMS 6230 TOP; column: BEH C 18 1.7 μm, 50x2.1 mm; Eluent A: water + 0.05 % formic acid (99%); Eluent B: acetonitrile + 0.05 % formic acid (99%); gradient: 0-1.7 2-90% B, 1.7-2.0 90% B; flow 1.2 ml / min; temperature: 60°C; DAD scan: 190-400 nm.

[0844] Method 2:

[0845] Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7 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.

[0846] Method 3:

[0847] Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1. / 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.

[0848] Method 4:

[0849] System MS: Thermo Scientific FT-MS; System UHPLC+: Thermo Scientific UltiMate 3000; Column: Waters, HSST3, 2.1 x 75 mm, C18 1.8 μm; Eluent A: 1 I Water + 0.01% Formic acid; Eluent B: 1 I Acetonitrile + 0.01 % Formic acid; Gradient: 0.0 min 10% B ■■■■> 2.5 min 95% B — > 3.5 min 95% B; Oven: 50°C; Flow: 0.90 ml / min; UV-Detection: 210 nm / Optimum integration Path 210-300 nm

[0850] Method 9:

[0851] System MS: Thermo Scientific FT-MS; System UHPLC+: Thermo Scientific Vanquish; Column: Waters, HSST3, 2.1 x 75 mm, C18 1.8 μm; Eluent A: 1 I Water + 0.01% Formic acid; Eluent B: 1 I Acetonitrile + 0.01 % Formic acid; Gradient: 0.0 min 10% B ■■■■> 2.5 min 95% B —► 3.5 min 95% B; Oven: 50°C; Flow: 0.90 ml / min; UV-Detection: 210 nm

[0852] Method 10:

[0853] Instrument: Knauer P2.1 L, Knauer UV detector Azura UVD 2.1S, Prepcon 5 software. Column: Chromatorex C18 10 μm, 125 mm x 30 mm; eluent A: water, eluent B: acetonitrile; gradient: 0-5 min 20% B; 5-18 min 20%-90% B, 18-25 min 90% B; column temperaure: rt; flow rate: 50 mL / min; UV detection: 210 nm.

[0854] Method 11 :

[0855] Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Chromolith@Flash RP-18E 25- 2 MM; eluent A: water + 0.0375 voi% 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.

[0856] Method 12:

[0857] Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex EVO C18 2.1*30 mm,

[0858] 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

[0859] 6 254 nm.

[0860] Method 13:

[0861] Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex EVO C18 2.1*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.

[0862] Method 14:

[0863] 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.

[0864] Method 15:

[0865] Instrument: Agilent 1100\G1956A SingleQuad; Column: Kinetex@ 5um EVO C18 30*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.

[0866] Method 16:

[0867] 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.

[0868] Method 17:

[0869] Instrument: Agilent 1100\G1956A SingleQuad; Column: Kinetex@ 5 μm EVO C18 30*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.

[0870] Method 18:

[0871] Instrument: Agilent 1200\G6110A SingleQuad; Column: XBridge C18 2.1*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.

[0872] Method 19:

[0873] Instrument: Agilent 1200\G6110A SingleQuad; Column: XBridge C18 2.1*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 20:

[0874] Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex EVO C18 2.1*30 mm,

[0875] 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

[0876] 6 254 nm.

[0877] Method 21 :

[0878] Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex EVO C18 2.1*30 mm,

[0879] 5 μm; eluent A: water + 0.025 vol% ammonium hydroxide, eluent B: acetonitrile; gradient: 0-1.2 min, 0-60% B, 12-1.6 min, 60% B; flow 10 ml / min; temperature: 40 °C; PDA: 220 nm

[0880] 6 254 nm.

[0881] Method 22:

[0882] Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex EVO C18 2.1*30 mm, 5um; eluent A: water + 0.025 vol% ammonium hydroxide, eluent B: acetonitrile; gradient: 0- 0.8 min, 5-95% B, 0.8-12 min, 95% B; flow 15 ml / min; temperature: 40 °C; PDA: 220 nm & 254 nm.

[0883] Method 23:

[0884] Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex EVO C18 2.1*30 mm,

[0885] 5 pm; eluent A: water + 0.025 vol% ammonium hydroxide, eluent B: acetonitrile; gradient: 0-0.8 min, 0-60% B, 0.8-12 min, 60% B; flow 15 ml / min; temperature: 40 °C; PDA: 220 nm

[0886] 6 254 nm.

[0887] Method 24:

[0888] Instrument: Waters Acquity UPLCMS SingleQuad; Colum: Acquity UPLC BEH C18 1.7 50x2.1mm; eluent A: water + 0.2 vol % aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 16-2.0 min 99% B; flow 0.8 ml / min; temperature: 60 °C; DAD scan: 210-400 nm

[0889] Preparative LC-MS Methods:

[0890] Method 5:

[0891] Instrument: Knauer P2.1 L, Knauer UV detector Azura UVD 2.1S, Prepcon 5 software. Column: Chromatorex C18 10 μm, 125 mm x 30 mm; eluent A: water, eluent B: acetonitrile; gradient: 0-5 min 20% B; 5-18 min 20%-90% B, 18-25 min 90% B; column temperaure: rt; flow rate: 50 mL / min; UV detection: 210 nm. Method 7:

[0892] Instrument: Waters Autopurification MS SingleQuad; Column: Waters XBrigde C18 5p 100x30mm; eluent A: water + 0.2 vol. % aqueous ammonia (32 %), eluent B: acetonitrile; gradient: 0-5.5 min. 5-100 % B; flow 70 ml / min; temperature: 25 °C; DAD scan: 210-400 nm

[0893] Method 8:

[0894] Instrument: Waters Autopurification MS SingleQuad; Column: Waters XBrigde C18 5p 50x50mm; eluent A: water + 0.1 vol% formic acid, eluent B: methanol; gradient: 0-0.50 min. 20 % B; flow 50 to 100 ml / min, 0.50-8.00 min. 20 - 60% B; flow 100 ml / min, temperature: 25 °C; DAD scan: 210-400 nm

[0895] Method 9:

[0896] Instrument: Labomatic HD-5000, pump head HDK-280, gradient module NDB-1000, fraction collector Labomatic Labocol Vario 2000, Knauer UV detector Azura UVD 2.1S, Prepcon 5 software. Column: Chromatorex C18 10pM 120x30 mm; Eluent A: water + 0.1% formic acid; Eluent B: acetonitrile; gradient: given for intermediates and examples, rate 150 mL / min, temperature 25°C.; UV 220 nm

[0897] Method 10 :

[0898] Instrument: Labomatic HD-5000, pump head HDK-280, gradient module NDB-1000, fraction collector Labomatic Labocol Vario 2000, Knauer UV detector Azura UVD 2.1S, Prepcon 5 software. Column: Chromatorex C18 10pM 120x30 mm; Eluent A: 0.1 % ammonia in water; Eluent B: acetonitrile; gradient: given for intermediates and examples, rate 150 mL / min, temperature 25°C.; UV 220 nm

[0899] NMR Spectra:

[0900] 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.

[0901] The1H-NMR data of selected compounds are listed in the form of1H-NMR peaklists. Therein, for each signal peak the 6 value in ppm is given, followed by the signal intensity, reported in round brackets. The 0 value-signal intensity pairs from different peaks are separated by commas. Therefore, a peaklist is described by the general form: 61 (intensityi), 82 (intensitya), ... , 0: (intensity,), ... , 0R(intensity,,).

[0902] 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 classical 'H-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%. of Intermediate

[0903] Intermediate 1 tert-butyl 3-bromo-2-(4-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate tert-Butyl 2-(4-fluorophenyl)-6,7-dihydropyrazolo[1 ,5-a]pyrazine-5(4H)-carboxylate (1.00 g, 3.15 mmol; CAS-RN: [1773507-35-9]) was added to a reaction vessel along with DCM (15 ml), it was cooled to 0°C and 1 -bromopyrrolidine-2, 5-dione (561 mg, 3.15 mmol; CAS- RN: [128-08-5]) was added. The mixture was stirred at rt over the weekend. Additional 1- bromopyrrolidine-2, 5-dione (110mg) was added and the mixture stirred for an additional 2 hours. Saturated NaHCOs solution (aqueous, 20 mL) and water (5 mL) were added, the layers separated and the aqueous layer extracted twice with DCM (total 2 x 20 mL), the combined organic layers were dried over NaaSO, filtered and concentrated under reduced pressure yielding the title compound (1.4 g, 113% yield, containing some minor impurities).

[0904] LC-MS (Method 1): Rt= 1.46 min; MS (ESIpos): m / z = 396.1 [M+H]+

[0905] 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.45 (s, 9 H) 3.86 (m, 2 H) 4.15 (m, 2 H) 4.52 (s, 2 H) 7.31 (m, 2 H) 7.84 (m, 2 H)

[0906] Intermediate 2 tert-butyl 2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate tert-butyl 3-bromo-2-(4-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (738 mg, 1.86 mmol, Intermediate 1), 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (458 mg, 2.23 mmol, CAS-RN:[ 181219-01-2]), Pd(dppf)Ch DCM complex (126 mg, 155 μmol; CAS-RN:[95464-05-4]) and potassium carbonate (772 mg, 5.59 mmol; CAS-RN: [584-08-7]) were added to a microwave reaction vessel, the reaction vessel flushed with nitrogen and sealed. Degassed THE (20 ml) and water (2.5 ml) were added and the mixture heated at 110°C for 1 hour in a microwave, ethyl acetate (100 ml) was added, and the organic phase was then washed with NaHCCh solution (aqueous, saturated), dried over sodium sulfate, and concentrated under reduced presssure. The residue was dissolved residue in ca 5 ml ethyl acetate and filtered through a 2g silica column, and washed with additional ethyl acetate (5 ml), and the combined fractions concentrated under reduced pressure yielding the title compound (800 mg, 90 % purity, 98 % yield).

[0907] LC-MS (Method 3): Rt= 0.95 min; MS (ESIpos): m / z = 396.1 [M+H]+

[0908] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41 (s, 9 H) 3.89 (m, 2 H) 4.21 (m, 2 H) 4.66 (s, 2 H) 7.14 (d, J=5.00 Hz, 2 H) 7.19 (m, J=8.19 Hz, 2 H) 7.37 (m, 2 H) 8.53 (m, 2 H)

[0909] Intermediate 3

[0910] 2-(4-fluorophenyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1 ,5-a]pyrazine tert-Butyl 2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (512 mg, 1.30 mmol, Intermediate 2) was added to a reaction vessel, followed by DCM (3.8 ml) and then the dropwise addition of trifluoroacetic acid (1.5 ml, 19 mmol; CAS-RN:[76-05-1]). The mixture was stirred at rt for 1.5 hours, under nitrogen. The mixture was concentrated under reduced pressure. DCM (50 ml) was added and the mixture stirred with NaHCOs (saturated, aqueous, 30 ml), the layers separated, the aqueous layer was extracted with DCM (30 ml), the combined layers dried over sodium sulfate and concentrated under reduced pressure. Further purification by silica gel column chromatography (Biotage Sfar Silica HC D, 25g), Eluent: DCM / Ethanol from 100 / 0 to 0 / 100 over 20 min, with a flowrate of 60 mL / min fractions yielded the title compound (372 mg, 97 % yield).

[0911] LC-MS (Method 3): R(= 0.50 min; MS (ESIpos): m / z = 295.1 [M+H]+

[0912] 1H NMR (400 MHz, DMSO-d6) 5 ppm 3.22 - 3.32 (m, 2 H) 4.09 (s, 2 H) 4.15 (m, 2 H) 7.11 (dd, 2 H) 7.14 - 7.24 (m, 2 H) 7.37 (m, 2 H) 8.50 (dd, 2 H)

[0913] Intermediate 4 trifluoroacetic acid — 2-(4-fluorophenyi)-3-(pyridin-4-yl)-4, 5,6,7- tetrahydropyrazolo[1,5-a]pyrazine (1 / 1) tert-butyl 2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (550 mg, 1 .39 mmol) was added to a reaction vessel, followed by DCM (11 ml) and then the dropwise addition of trifluoroacetic acid (1.1 ml, 14 mmol; CAS-RN; [76-05-1]). The mixture was stirred at 40°C for 4 hours. The reaction mixture was concentrated under reduced pressure to yield the title compound which was used without further purification in the next reaction.

[0914] LC-MS (Method 1): Rt= 0.32 min; MS (ESIpos): m / z = 295.1 [M+H]+

[0915] 1 H-NMR (400 MHz, DMSO-d6) delta [ppm]: 0.068 (0.73), 1.066 (13.41), 1.107 (1.61), 1.156 (3.07), 1.232 (0.68), 1.256 (0.48), 1.427 (0.43), 1.532 (16.00), 2.518 (8.70), 2.523 (5.60),

[0916] 2.562 (0.65), 2.728 (1.11), 2.888 (1.36), 3.739 (1.86), 3.754 (3.24), 3.769 (1.91), 4.337

[0917] (0.93), 4.352 (1.29), 4.366 (0.91), 4.442 (2.56), 4.457 (4.16), 4.471 (3.61), 4.610 (7.08),

[0918] 4.964 (1.02), 5.758 (1.08), 6.692 (1.76), 7.224 (3.75), 7.246 (8.07), 7.268 (4.52), 7.400

[0919] (3.61), 7.405 (1.74), 7.414 (4.08), 7.423 (3.66), 7.436 (6.40), 7.450 (3.95), 7.537 (0.43),

[0920] 7.547 (1.03), 7.565 (1.16), 7.573 (1.01), 7.595 (1.38), 7.612 (1.16), 7.622 (1.41), 7.641

[0921] (0.83), 7.803 (0.86), 7.816 (0.95), 7.825 (0.93), 7.839 (0.82), 8.711 (5.05), 8.727 (4.77),

[0922] 9.613 (0.51).

[0923] Intermediate 5 tert-butyl 2-(4-chloro-3-methylphenyl)-6,7-dihydropyrazolo[1 ,5-a]pyrazine-5(4H)- carboxylate tert-butyl 2-bromo-6,7-dihydropyrazolo[1 ,5-a]pyrazine-5(4H)-carboxylate (160 mg, 529 μmol, CAS-RN: [1250998-21-0]) and 2-(4-chioro-3-methylphenyl)-4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolane (174 mg, 688 μmol) were added to DMF (4.2 ml) and then a solution of potassium carbonate (790 pl, 2.0 M, 1.6 mmol; CAS-RN :[584-08-7]) was added in a microwave reaction vessel. The reaction vessel was flushed with nitrogen and tetrakis(triphenylphosphin)palladium(0) (612 mg, 52.9 μmol; CAS-RN:[14221-01-3]) was added. The sealed vessel was heated at 110°C for 30 min in a microwave, ethyl acetate and water was added. After extraction 2x with ethyl acetate the combined organic phases were dried with an water-repellent filter and concentrated under reduced presssure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane 0- 20%) yielding the title compound 126 mg (93 % purity, 64 % yield).

[0924] LC-MS (Method 1): Rt= 1.4 min; MS (ESIpos): m / z = 348.1 [M+H]+

[0925] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.441 (16.00), 2.359 (3.58), 3.834 (0.64), 3.848 (0.44), 4.117 (0.52), 4.132 (0.76), 4.145 (0.43), 4.623 (0.81), 6.596 (1.32), 7.402 (0.79), 7.423 (0.97), 7.753 (0.62), 7.757 (0.58).

[0926] Intermediate 6 tert-butyl 3-bromo-2-(4-chloro-3-methylphenyl)-6,7-dihydropyrazolo[1,5-a]pyrazme- 5(4H)-carboxylate tert-butyl 2-(4-chloro-3-methylphenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (125 mg, 359 μmol, Intermediate 5) was added to a reaction vessel along with DCM (5 ml), it was cooled to 0°C and 1-bromopyrrolidine-2, 5-dione (67.2 mg, 377 μmol) was added. The mixture was stirred at Rtfor 1 hour. Saturated NaHCOs solution and water were added, the layers separated and the aqueous layer extracted twice with DCM, the combined organic layers were dried over a water-repellent filter and concentrated under reduced pressure yielding the title compound (176 mg, 100% yield, 87% purity).

[0927] LC-MS (Method 1): Rt= 1.6 min; MS (ESIpos): m / z = 427.9 [M+H]+

[0928] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.451 (16.00), 1.461 (1.79), 2.382 (4.33), 2.518 (1.41), 2.523 (0.97), 2.563 (2.94), 3.856 (0.69), 3.870 (0.46), 4.144 (0.57), 4.158 (0.85), 4.171 (0.48), 4.519 (1.42), 5.759 (4.36), 7.500 (0.87), 7.520 (1.09), 7.657 (0.52), 7.663 (0.53), 7.683 (0.41), 7.780 (0.78), 7.784 (0.70).

[0929] Intermediate 7 tert-butyl 2-(4-chloro-3-methyllphenyl)-3-(pyridiin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate tert-butyl 3-bromo-2-(4-chloro-3-methylphenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (170 mg, 398 μmol, Intermediate 6) were added to a mixture of THF (4.2 ml) and water (530pl) in a microwave reaction vessel. The reaction vessel flushed with nitrogen and 4-(4,4,5,5-tetramethyl-1,3l2-dioxaborolan-2-yl)pyridine (114 mg, 558 μmol), potassium carbonate (165 mg, 1.20 mmol; CAS-RN: [584-08-7]) and dichloro[1,1'- bis(dialkyl / diarylphosphino)ferrocene]palladium(ll) (9.76 mg, 12.0 μmol; CAS- RN: [95464- 05-4]) were added. The sealed vessel was heated at 110°C for 1 hour in a microwave, ethyl acetate and water was added. After extraction 2x with ethyl acetate the combined organic phases were dried with an water-repellent filter and concentrated under reduced presssure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane 0-50%) yielding the title compound 102 mg (90 % purity, 54 % yield).

[0930] LC-MS (Method 1): Rt= 1.0 min; MS (ESIpos): m / z = 425.1 [M+H]+

[0931] 1H-NMR (400 MHz, DMSO-d6) 5 [ppm]: 1.066 (0.84), 1.084 (0.53), 1.154 (2.45), 1.172 (5.31), 1.190 (2.63), 1.259 (0.72), 1.414 (15.06), 1.463 (0.84), 1.987 (8.81), 2.291 (16.00), 2.322 (1.44), 2.326 (1.05), 2.332 (0.72), 2.518 (4.92), 2.522 (3.39), 2.562 (0.49), 2.664

[0932] (0.68), 2.668 (0.90), 2.673 (0.67), 3.878 (1.47), 3.891 (2.64), 3.905 (1.78), 3.999 (0.59),

[0933] 4.017 (1.74), 4.035 (1.70), 4.053 (0.57), 4.199 (1.97), 4.213 (3.09), 4.226 (1.75), 4.662

[0934] (5.12), 7.062 (1.01), 7.082 (1.15), 7.149 (6.68), 7.153 (3.90), 7.160 (3.97), 7.164 (6.82),

[0935] 7.181 (0.42), 7.354 (3.90), 7.374 (3.37), 7.416 (2.76), 7.420 (2.68), 8.536 (6.51), 8.540

[0936] (3.84), 8.547 (3.92), 8.551 (6.40), 8.559 (0.44), 8.563 (0.51).

[0937] Intermediate 8 trifluoroacetic acid— 2-(4-chloro-3-methylphenyl)-3-(pyridin-4-yl)-4, 5,6,7- tetrahydropyrazolo[1,5~a]pyrazine (1 / 1)

[0938] tert-butyl 2-(4-chloro-3-methylphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxylate (100 mg, 235 μmol, Intermediate 7) was added to a reaction vessel, followed by DCM (1.8 ml) and then the dropwise addition of trifluoroacetic acid (180 pl, 2.4 mmol; CAS-RN:[76-05-1]). The mixture was stirred at Rtfor 2 hours. After the addion of further 150pl TFA and stirring for an additional 1 hour the mixture was concentrated under reduced pressure to yield the title compound which was used without further purification in the next reaction.

[0939] LC-MS (Method 2): Rt= 1.01 min; MS (ESIpos): m / z = 325.2 [M+H]+

[0940] Intermediate 9 tert-butyl 2-(4-chlorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazme-5(4H)-carboxylate tert-butyl 2-bromo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (160 mg, 529 μmol, CAS-RN: [1250998-21-0]) and 2-(4-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (164 mg, 688 μmol) were added to DMF (4.2 ml) and then a solution of potassium carbonate (790 pl, 2.0 M, 1.6 mmol; CAS-RN: [584-08-7]) was added in a microwave reaction vessel. The reaction vessel was flushed with nitrogen and tetrakis(triphenylphosphin)palladium(0): (61.2 mg, 52.9 μmol; CAS-RN:[14221-01-3]) was added. The sealed vessel was heated at 110°C for 30 min in a microwave, ethyl acetate and water was added. After extraction 2x with ethyl acetate the combined organic phases were dried with an water-repellent filter and concentrated under reduced presssure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane 0- 20%) yielding the title compound 132 mg (90 % purity, 67 % yield).

[0941] LC-MS (Method 1): Rt= 1.3 min; MS (ESIpos): m / z = 334.1 [M+H]+1H-NMR (400 MHz, DMS0-d6) δ [ppm]: 1.441 (16.00), 1.448 (0.99), 2.518 (0.58), 2.523 (0.41), 3.833 (0.64), 3.847 (0.45), 4.123 (0.53), 4.137 (0.75), 4.151 (0.43), 4.625 (0.77), 6.615 (1.40), 7.436 (1.42), 7.440 (0.43), 7.452 (0.50), 7.457 (1.71), 7.764 (1.73), 7.769 (0.51), 7.781 (0.47), 7.786 (1.42), 8.173 (0.53).

[0942] Intermediate 10 tert-butyl 3-bromo-2-(4-chlorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate tert-butyl 2-(4-chlorophenyl)-6,7-dihydropyrazolo[1 ,5-a]pyrazine~5(4H)-carboxylate (130 mg, 389 μmol, Intermediate 9) was added to a reaction vessel along with DCM (2 ml), it was cooled to 0°C and 1-bromopyrrolidine-2, 5-dione (72.8 mg, 409 μmoi) was added. The mixture was stirred at rt for 1 hour. Saturated NaHCOs solution and water were added, the layers separated and the aqueous layer extracted twice with DCM, the combined organic layers were dried over a water-repellent filter and concentrated under reduced pressure yielding the title compound (177 mg, 99% yield, 90% purity).

[0943] LC-MS (Method 1): Rt= 1.5 min; MS (ESIpos): m / z = 413.9 [M+H]+

[0944] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.451 (16.00), 2.518 (0.50), 2.563 (2.94), 3.843 (0.40), 3.856 (0.70), 3.870 (0.48), 4.149 (0.59), 4.163 (0.84), 4.176 (0.49), 4.522 (1.43), 5.759 (3.29), 7.528 (1.78), 7.533 (0.57), 7.545 (0.66), 7.550 (2.19), 7.827 (2.18), 7.832 (0.63), 7.844 (0.58), 7.849 (1.68).

[0945] Intermediate 11 tert-butyl 2-(4-chiorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxyiate tert-butyl 3-bromo-2-(4-chlorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (170 mg, 412 μmol, Intermediate 10) were added to a mixture of THF (4.3 ml) and water (500pl) in a microwave reaction vessel. The reaction vessel flushed with nitrogen and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (118 mg, 577 μmol), potassium carbonate (171 mg, 1.24 mmol; CAS-RN: [584-08-7]) and dichloro[1,T- bis(dialkyl / diarylphosphino)ferrocene]palladium(ll) (27.9 mg, 34.2 μmol; CAS-RN: [95464- 05-4]) were added. The sealed vessel was heated at 110°C for 1 hour in a microwave, ethyl acetate and water was added. After extraction 2x with ethyl acetate the combined organic phases were dried with an water-repellent filter and concentrated under reduced presssure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane 0-80%) yielding the title compound 96.4 mg (90 % purity, 51 % yield).

[0946] LC-MS (Method 1): Rt= 0.9 min; MS (ESIpos): m / z = 411.1 [M+H]+

[0947] 1H-NMR (400 MHz, DMSO-d6) 5 [ppm]: 1.066 (16.00), 1.414 (3.36), 3.892 (0.60), 3.905 (0.40), 3.940 (2.85), 4.205 (0.45), 4.219 (0.69), 4.662 (1.16), 7.151 (1.48), 7.155 (0.91), 7.162 (0.92), 7.167 (1.48), 7.343 (0.72), 7.364 (1.29), 7.412 (2.03), 7.417 (0.51), 7.433 (1.08), 8.541 (1.60), 8.545 (0.88), 8.552 (0.89), 8.557 (1.50).

[0948] Intermediate 12 trifluoroacetic acid-—2-(4-chlorophenyl)-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1 ,5~a]pyrazine (1 / 1) tert-butyl 2-(4-chlorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (93.0 mg, 226 μmol, Intermediate 11) was added to a reaction vessel, followed by DCM (1.7 ml) and then the dropwise addition of trifluoroacetic acid (170 pl, 2.3 mmol; CAS-RN:[76-05-1]). The mixture was stirred at rt for 2 hours. After the addion of further 150pl TFA and stirring for an additional 1 hour the mixture was concentrated under reduced pressure to yield the title compound which was used without further purification in the next reaction.

[0949] LC-MS (Method 2): Rt= 0.94 min; MS (ESIpos): m / z = 311.2 [M+H]+

[0950] Intermediate 13 tert-butyl 2-(3-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazme-5(4H)-carboxylate tert-butyl 2-bromo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (200 mg, 662 μmol, CAS-RN: [1250998-21-0]) and 2-(3-fluorophenyl)-4,4,5,5-tetramethyi-1,3,2- dioxaborolane (191 mg, 860 μmol) were added to DMF (8.4 ml) and then a solution of potassium carbonate (990 pl, 2.0 M, 2.0 mmol; CAS-RN: [584-08-7]) was added in a microwave reaction vessel. The reaction vessel was flushed with nitrogen and tetrakis(triphenylphosphin)palladium(0) (76.5 mg, 66.2 μmol; CAS-RN:[14221-01-3]) was added. The sealed vessel was heated at 110°C for 30 min in a microwave, ethyl acetate and water was added. After extraction 2x with ethyl acetate the combined organic phases were dried with an water-repellent filter and concentrated under reduced presssure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane 0- 16%) yielding the title compound 195 mg (95 % purity, 88 % yield).

[0951] LC-MS (Method 1): Rt= 1.3 mln; MS (ESIpos): m / z = 318.1[M+H]+

[0952] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.066 (0.67), 1.430 (0.45), 1.442 (16.00), 2.518 (0.41), 3.837 (0.66), 3.852 (0.45), 4.133 (0.56), 4.147 (0.79), 4.160 (0.46), 4.629 (0.82), 6.656 (1.38), 7.426 (0.41), 7.442 (0.41), 7.595 (0.40), 7.597 (0.53), 7.618 (0.41).

[0953] Intermediate 14 tert-butyl 3"bromo-2-(3-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-S(4H)" carboxylate tert-butyl 2-(3-fluorophenyl)-6,7-dihydropyrazolo[1 ,5-a]pyrazine-5(4H)-carboxylate (190 mg, 599 μmol, Intermediate 13) was added to a reaction vessel along with DCM (2 ml), it was cooled to 0°C and 1-bromopyrrolidine-2, 5-dione (72.8 mg, 409 μmol) was added. The mixture was stirred at rt for 2 hour. Saturated NaHCOs solution and water were added, the layers separated and the aqueous layer extracted twice with DCM, the combined organic layers were dried over a water-repellent filter and concentrated under reduced pressure yielding the title compound (306 mg, 99% yield, 77% purity). LC-MS (Method 1): Rt= 1.4 min; MS (ESIpos): m / z = 396 [M+H]+

[0954] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.065 (1.22), 1.154 (0.66), 1.172 (1.37), 1.190 (0.70), 1.443 (1.59), 1.453 (16.00), 1.987 (2.42), 2.518 (0.60), 2.523 (0.42), 2.563 (11.27), 3.847 (0.44), 3.861 (0.72), 3.874 (0.49), 4.017 (0.55), 4.035 (0.55), 4.158 (0.64), 4.172 (0.89), 4.186 (0.51), 4.528 (1.46), 7.517 (0.50), 7.533 (0.50), 7.554 (0.47), 7.677 (0.52), 7.679 (0.65), 7.683 (0.48), 7.697 (0.41), 7.700 (0.51).

[0955] Intermediate 15 tert-butyl 2-(3-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-

[0956] 5(4H)-carboxylate tert-butyl 3-bromo-2-(3-fluorophenyi)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (250 mg, 77 % purity, 486 μmol, Intermediate 14) were added to a mixture of THF (4.5 ml) and water (450pl) in a microwave reaction vessel. The reaction vessel flushed with nitrogen and 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (130 mg, 632 μmol), potassium carbonate (201 mg, 1.46 mmol; CAS-RN:[584-08-7]) and dichloro[1,1'- bis(dialkyl / diarylphosphino)ferrocene]palladium(ll) (32.9 mg, 40.3 μmol; CAS- RN: [95464- 05-4]) were added. The sealed vessel was heated at 110°C for 1 hour in a microwave, ethyl acetate and water was added. After extraction 2x with ethyl acetate the combined organic phases were dried with an water-repellent filter and concentrated under reduced presssure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane 0-90%) yielding the title compound 176 mg (85 % purity, 78 % yield).

[0957] LC-MS (Method 1): Rt= 0.9 min; MS (ESIpos): m / z = 395.1 [M+H]+

[0958] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.066 (16.00), 1.154 (0.63), 1.172 (1.33), 1.190 (0.67), 1.416 (1.21), 1.987 (2.32), 3.938 (2.35), 4.017 (0.46), 4.034 (0.44), 4.658 (0.42), 7.168 (0.52), 7.183 (0.42), 8.551 (0.44), 8.567 (0.41).

[0959] Intermediate 16 trifluoroacetic acid — 2-(3-fluorophenyi)-3-(pyridin-4-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine (1 / 1 )

[0960] tert-butyl 2-(3-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (175 mg, 444 μmol, Intermediate 15) was added to a reaction vessel, followed by DCM (3.4 ml) and then the dropwise addition of trifluoroacetic acid (340 pl, 4.4 mmol; CAS-RN: [76-05-1]). The mixture was stirred at rt for 3 hours. The solution was concentrated under reduced pressure to yield the title compound which was used without further purification in the next reaction.

[0961] LC-MS (Method 2): Rt= 0.85 min; MS (ESIpos): m / z = 295.3 [M+H]+

[0962] Intermediate 17 tert-butyl 2-(3-methoxyphenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-S(4H)- carboxylate tert-butyl 2-bromo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (250 mg, 827 μmol; CAS-RN:[1250998-21-0]) and 2-(3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (252 mg, 1.08 mmol) were added to DMF (10 ml) and then a solution of potassium carbonate (1.2 ml, 2.0 M, 2.5 mmol; CAS-RN:[584-08-7]) was added in a microwave reaction vessel. The reaction vessel was flushed with nitrogen and tetrakis(trlphenylphosphln)palladium(0) (95.6 mg, 82.7 μmol; CAS-RN:[14221-01-3]) was added. The sealed vessel was heated at 110°C for 30 min in a microwave, ethyl acetate and water was added. After extraction 2x with ethyl acetate the combined organic phases were dried with an water-repellent filter and concentrated under reduced presssure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane 0- 25%) yielding the title compound 220 mg (90 % purity, 73 % yield).

[0963] LC-MS (Method 1): Rt= 1.2 min; MS (ESIpos): m / z = 330.1 [M+H]+1H-NMR (400 MHz, DMS0-d6) δ [ppm]: 1.066 (16.00), 1.156 (2.29), 1.426 (2.20), 1.430 (0.92), 1.442 (12.90), 2.518 (0.54), 2.729 (1.37), 2.888 (1.54), 3.677 (0.67), 3.784 (5.90), 3.833 (0.53), 3.938 (3.00), 4.123 (0.43), 4.138 (0.62), 4.623 (0.61), 6.593 (1.12), 7.295 (1.05), 7.301 (0.47), 7.303 (0.45), 7.314 (0.62), 7.317 (0.59), 7.321 (0.75), 7.324 (0.42).

[0964] Intermediate 18 tert-butyl 3-bromo-2-(3-methoxyphenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate tert-butyl 2-(3-methoxyphenyl)-6,7-dihydropyrazolo[1 ,5-a]pyrazine-5(4H)-carboxylate (213 mg, 90 % purity, 582 μmol, Intermediate 17) was added to a reaction vessel along with DCM (2 ml), it was cooled to 0°C and 1-bromopyrrolidine-2, 5-dione (104 mg, 582 μmol) was added. The mixture was stirred at rt for 2 hour. Saturated NaHCOs solution and water were added, the layers separated and the aqueous layer extracted twice with DCM, the combined organic layers were dried over a water-repellent filter and concentrated under reduced pressure yielding the title compound 290 mg (59 % purity, 72 % yield).

[0965] LC-MS (Method 1): R(= 1.4 min; MS (ESIpos): m / z = 410 [M+H]+

[0966] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.066 (7.46), 1.154 (0.75), 1.172 (1.39), 1.190 (0.71), 1.425 (3.34), 1.429 (1.32), 1.443 (3.22), 1.453 (16.00), 1.987 (2.51), 2.518 (0.40),

[0967] 2.563 (9.14), 3.765 (0.89), 3.784 (1.53), 3.792 (7.79), 3.843 (0.50), 3.856 (0.78), 3.870

[0968] (0.51), 3.939 (1.14), 4.017 (0.57), 4.035 (0.58), 4.148 (0.68), 4.162 (0.92), 4.174 (0.51),

[0969] 4.521 (1.44), 6.959 (0.44), 6.972 (0.41), 6.977 (0.43), 6.978 (0.48), 6.983 (0.40), 7.336

[0970] (0.69), 7.339 (0.81), 7.343 (0.67), 7.344 (0.64), 7.375 (0.97), 7.393 (1.45), 7.397 (1.19),

[0971] 7.400 (0.71). intermediate 19 tert-butyl 2-(3-methoxyphenyi)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxylate

[0972] tert-butyl 3-bromo-2-(3-methoxyphenyl)-6,7-dihydropyrazolo[1 ,5-a]pyrazine-5(4H)- carboxylate (210 mg, 514 μmol, Intermediate 18) were added to a mixture of THF (5.4 ml) and water (540pl) in a microwave reaction vessel. The reaction vessel flushed with nitrogen and 4-(4,4,5!5-tetramethyl-1,3!2-dioxaborolan-2-yl)pyridine (137 mg, 669 μmol), potassium carbonate (213 mg, 1.54 mmol; CAS-RN: [584-08-7]) and dichloro[1 , 1 bis(dialkyl / diarylphosphino)ferrocene]palladium(ll) (34.9 mg, 42.7 μmol; CAS-RN: [95464- 05-4]) were added. The sealed vessel was heated at 110°C for 1 hour in a microwave, ethyl acetate and water was added. After extraction 2x with ethyl acetate the combined organic phases were dried with an water-repellent filter and concentrated under reduced presssure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane 0-90%) yielding the title compound 129 mg (85 % purity, 52 % yield).

[0973] LC-MS (Method 1): Rt= 0.8 min; MS (ESIpos): m / z = 407.1 [M+H]+

[0974] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (4.11), 1.172 (9.37), 1.190 (4.86), 1.416 (4.35), 1.435 (0.94), 1.987 (16.00), 2.518 (0.72), 2.523 (0.50), 3.667 (8.47), 3.878 (0.45),

[0975] 3.891 (0.79), 3.905 (0.51), 3.999 (1.06), 4.017 (3.13), 4.035 (3.20), 4.053 (1.05), 4.203

[0976] (0.60), 4.217 (0.92), 4.230 (0.51), 4.655 (1.51), 5.758 (7.65), 6.875 (0.54), 6.879 (0.58),

[0977] 6.882 (0.40), 6.886 (1.04), 6.889 (1.25), 6.892 (1.09), 6.896 (1.58), 6.902 (1.04), 6.906

[0978] (0.56), 7.155 (1.87), 7.159 (1.04), 7.166 (1.05), 7.170 (1.88), 7.226 (0.53), 7.246 (0.62),

[0979] 7.250 (0.48), 7.268 (0.43), 7.544 (0.43), 7.547 (0.57), 7.549 (0.55), 7.555 (0.48), 7.558

[0980] (0.41), 7.565 (0.68), 7.566 (0.52), 7.572 (0.57), 7.574 (0.47), 7.591 (0.44), 7.596 (0.83),

[0981] 7.613 (0.70), 7.615 (0.62), 7.622 (0.75), 7.625 (0.87), 7.630 (0.44), 7.642 (0.47), 7.645

[0982] (0.45), 8.531 (1.92), 8.535 (1.04), 8.542 (1.06), 8.546 (1.83).

[0983] Intermediate 20 trifluoroacetic acid — 2-(3-methoxyphenyl)-3-(pyridin-4-yi)-4, 5,6,7- tetrahydropyrazolo[1,5-a]pyrazine (1 / 1)

[0984] tert-butyl 2-(3-methoxyphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (130 mg, 320 μmol, Intermediate 19) was added to a reaction vessel, followed by DCM (2.5 ml) and then the dropwise addition of trifluoroacetic acid (250 pl, 3.2 mmol; CAS-RN:[76-05-1]). The mixture was stirred at rt for 3 hours. The solution was concentrated under reduced pressure to yield the title compound which was used without further purification in the next reaction.

[0985] LC-MS (Method 2): Rt= 0.82 min; MS (ESIpos): m / z = 307.2 [M+H]+

[0986] Intermediate 21 tert-butyl 3-{2-[(cyclopropanecarbonyl)amino]pyridin-4-yl}-2-(4-fluorophenyl)-6,7- dihydropyrazolo[1 ,5-a]pyrazine-5(4H)-carboxylate tert-Butyl 3-bromo-2-(4-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (100 mg, 252 μmol, Intermediate 1), N-[4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridin-2-yl]cyclopropanecarboxamide (80.0 mg, 278 μmoi, CAS- RN:[1286230-87-2]), THF (2.7 ml), potassium carbonate (105 mg, 757 μmol; CAS-RN:[584- 08-7]) and water (330 pl) were added to a microwave vessel. After degassing the mixture, Pd(dppf)Cl2 DCM complex (17.1 mg, 20.9 μmol; CAS- RN: [95464-05-4]) was added and the vessel was sealed under nitrogen. The mixture was stirred at 110°C for 1h in a microwave, ethyl acetate (25 ml) was added, and the mixture was washed with water, NaHCOs solution and saturated sodium chloride solution (each 20 mL), the organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure yielding the crude title compound (118 mg). LC-MS (Method 3): Rt= 1.23 min; MS (ESIpos): m / z = 478.3 [M+H]+

[0987] Intermediate 22

[0988] N-{4-[2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl]pyridin-2- yljcyclopropanecarboxamide

[0989] To a solution of tert-butyl 3-{2-[(cyclopropanecarbonyl)amino]pyridin-4-yl}-2-(4- fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (118 mg, 247 μmol, Intermediate 21) in DCM (2.1 ml) was added TFA (620 pl, 4.0 M, 2.5 mmol; CAS-RN:[76- 05-1]) under nitrogen. The mixture was stirred at rt for 3h. The precipitate was filtered yielding the crude title compound as the TFA salt. (93.3 mg). The free base can be obtained by basic aqueous workup with extraction into ethyl acetate.

[0990] LC-MS (Method 3): Rt= 0.70 min; MS (ESIpos): m / z = 378.2 [M+H]+

[0991] Intermediate 23 tert-butyl 3-{2-[(tert-butoxycarbonyl)amino]pyridin-4-yl}-2-(4-fluorophenyl)-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate tert-butyl 3-bromo-2-(4-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (110 mg, 278 μmol, Intermediate 1), tert-butyl [4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridin-2-yl]carbamate (107 mg, 333 μmol, CAS-RN:[1095708-32-9]), (18.8 mg, 23.0 μmol; CAS-RN: [95464-05-4]) and Pd(dppf)CI2DCM complex (115 mg, 833 μmol; CAS- RN: [584-08-7]) were added to a microwave reaction vessel, the vessel was flushed with nitrogen and sealed. Degassed THF (2.9 ml) and water (370 pl) were added and the mixture heated at 110°C for 1 hour in a microwave, ethyl acetate (100 ml) was added, and the mixture washed with NaHCOs solution (aqueous, saturated), the organic phase dried over sodium sulfate, filtered, and concentrated under reduced presssure. The residue was dissolved in ethyl acetate (ca 5 ml ) and filtered through a 2g silica column, and the column washed with an additional ethyl acetate (5 ml). The combined organic phases were concentrated under reduced pressure yielding the crude title compound (140 mg).

[0992] LC-MS (Method 3): Rt= 1.41 min; MS (ESIpos): m / z = 510 [M+H]+

[0993] Intermediate 24

[0994] 4-[2-(4-fluorophenyl)-4,5!6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl]pyridin-2-amine tert-Butyl 3-{2-[(tert-butoxycarbonyl)amino]pyridin-4-yl}-2-(4-fluorophenyl)-6,7-dihydro- pyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (135 mg, 265 μmol, Intermediate 23) was added to a reaction vessel, followed by DCM (5.0 ml) and then the dropwise addition of trifluoroacetic acid (310 pl, 4.0 mmol; CAS-RN:[76-05-1]) and the mixture stirred at rt overnight. Additional trifluoroacetic acid (100 pl) was added and the mixture was stirred for a further 2 hours. DCM (50 ml) was added followed by NaHCCh (saturated, aquesous 30 ml), the layer were separated, and the aqueous layer extracted with DCM (30 ml), the combined organic layers dried over sodium sulfate and concentrated under reduced pressure yielding the crude title compound (70.0 mg).

[0995] LC-MS (Method 3): Rt= 0.48 min; MS (ESIpos): m / z = 309 [M+H]+

[0996] Intermediate 25 tert-butyl 2-(4-fluorophenyl)-3-(2-methoxypyridin-4-yi)-6,7-dihydropyrazoio[1 ,5-a]pyrazine- 5(4H)-carboxylate

[0997] tert-butyl 3-bromo-2-(4-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (100 mg, 252 μmol, Intermediate 1), (2-methoxypyridin-4-yl)boronic add (42.5 mg, 278 μmol, CAS-RN:[ 762262-09-9]), potassium carbonate (105 mg, 757 μmol; CAS- RN: [584-08-7]) and degassed THF (2.7 ml) and water (330 pl) were added to a microwave vessel. Pd(dppf)Cb DCM complex (17.1 mg, 20.9 μmol; CAS-RN: [95464-05-4]) was added and the vessel was sealed under nitrogen. The mixture was stirred at 110°C for 1h in a microwave reactor, ethyl acetate (25 ml) was added, and the mixture was washed with water, NaHCCh solution and saturrated sodium chloride solution (each 20 mL), the organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure, yielding the crude title compound (126 mg).

[0998] LC-MS (Method 3): Rt= 1.38 min; MS (ESIpos): m / z = 425.3 [M+H]+

[0999] Intermediate 26

[1000] 2-(4-fluorophenyl)-3-(2-methoxypyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine

[1001] To a solution of tert-butyl 2-(4-fluorophenyl)-3-(2-methoxypyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazine-5(4H)-carboxylate (101 mg, 239 μmol, Intermediate 25) in DCM (2.0 ml) and added TFA (280 pl, 3.6 mmol; CAS-RN:[76-05-1]) under nitrogen. The mixture was stirred at rt for 3h. The mixture was then dilluted with DCM (15 ml) and sodium carbonate (aqueous, saturated, 15 ml), the layers seperated and the aqueous layer extracted with DCM (20 ml). The combined organic layers were dried over sodium sulfate, filtered and concentraded under reduced pressure, yielding the crude title compound(98.7 mg). LC-MS (Method 3): Rt= 0.71 min; MS (ESipos): m / z = 325.1 [M+H]+

[1002] Intermediate 27 tert-butyl 2-(4-fluorophenyl)-3-(3-methoxypyridin-4-yl)-6!7-dihydropyrazolo[1 ,5-a]pyrazine-

[1003] 5(4H)-carboxylate tert-butyl 3-bromo-2-(4-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (100 mg, 252 μmol, Intermediate 1), 3-methoxy-4-(4,4,5,5-tetramethyl-1!3,2- dioxaborolan-2-yl)pyridine (65.3 mg, 278 μmol, CAS-RN:[1243312-43-7]), were added to a reaction vessel, followed by THF (2.7 ml), (105 mg, 757 μmol; CAS-RN: [584-08-7]) and water (330 pl). After degassing the mixture Pd(dppf)Ch DCM complex (17.1 mg, 20.9 μmol; CAS-RN: [95464-05-4]) was added and the vessel was sealed under nitrogen. The mixture was stirred at 110°C for 1h in a microwave. Added ethyl acetate (25 ml), then washed with water, NaHCOs solution and satur rated sodium chloride solution each 20 mL, dried organic phase over sodium sulfate, concentrated under reduced pressure yielding the crude title compound (146 mg).

[1004] LC-MS (Method 3): Rt= 1.04 min; MS (ESipos): m / z = 425.3 [M+H]+

[1005] Intermediate 28

[1006] 2-(4-fluorophenyl)-3-(3-methoxypyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine

[1007] To a mixture of tert-butyl 2-(4-fluorophenyl)-3-(3-methoxypyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazine-5(4H)-carboxylate (101 mg, 239 μmol, Intermediate 27) in DCM (2.0 ml) was added TFA (280 pl, 3.6 mmol; CAS-RN:[76-05-1]) under nitrogen. The mixture was stirred at rt for 3h. The mixture was dilluted with DCM (15 mL) and sat. sodium carbonate (15 mL) was added, the layers separated and the aqueous phase was extracted with DCM (2 x 20 ml), the combined organic phases dried over sodium sulfate, filtered and concentrated under reduced pressure yielding the crude title compound (95.0 mg).

[1008] LC-MS (Method 3): Rt= 0.55 min; MS (ESIpos): m / z = 325.2 [M+H]+

[1009] Intermediate 29 tert-butyl 2-(4-fluoroanilino)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate

[1010] To a solution of tert-butyl 2-amino-6,7-dihydropyrazolo[1 ,5-a]pyrazine-5(4H)-carboxylate (228 mg, 957 μmol, CAS-RN: [1209487-56-8]) in 2 ml of 1,4-dioxane 1-bromo-4- fluorobenzene (335 mg, 1.91 mmol) was added. The resulting mixture was purged with argon for 5 min. Potassium carbonate (264 mg, 1.91 mmol; CAS-RN:[584-08-7]), Tris- (dibenzylidenacetone)dipalladium (35.0 mg, 38.3 μmol) and Xphos (18.2 mg, 38.3 μmol; CAS-RN: [564483- 18-7]) were added and the mixture was heated to 100 °C for 18 h. After cooling to rt, 2 ml of water were added. The mixture was diluted with 5 ml of ethyl acetate and filtered through a pad of celite. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane 0-90%) yielding 135 mg (99 % purity, 42 % yield) of the title compound.

[1011] LC-MS (Method 4): Rt= 1.91 min; MS (ESIpos): m / z = 333.2 [M+H]+

[1012] 1H-NMR (600 MHz, DMSO-d6) 5 ppm 1.42 (s, 9 H) 3.74 - 3.85 (m, 2 H) 3.90 - 3.99 (m, 2 H) 4.53 (br s, 2 H) 5.65 (s, 1 H) 6.96 - 7.06 (m, 2 H) 7.31 - 7.40 (m, 2 H) 8.45 (s, 1 H).

[1013] Intermediate 30 tert-butyl 3-bromo-2-(4-fluoroanilino)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate

[1014]

[1015] To a solution of tert-butyl 2-(4-fluoroanilino)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (135 mg, 406 μmol, Intermediate 29) in 2 ml DCM 1-bromopyrrolidine-2,5- dione (72.3 mg, 406 μmol; CAS-RN:[128-08-5]) was added at 0°C in one portion. The ice bath was removed and the stirred mixture was allowed to warm to rt. After 30 min NaHCOs (saturated, aqueous, 1 ml) and DCM (5 ml) were added. The mixture was dried with an water-repellent filter and concentrated under reduced presssure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane 0-90%) yielding 108 mg (94 % purity, 61 % yield) of the title compound.

[1016] LC-MS (Method 4): R(= 2.22 min; MS (ESIpos): m / z = 411 [M+H]+

[1017] 1H NMR (600 MHz, DMSO-cfe) δ ppm 1.44 (s, 9 H) 3.78 - 3.86 (m, 2 H) 3.95 - 4.03 (m, 2 H) 4.45 (br s, 2 H) 6.97 - 7.06 (m, 2 H) 7.39 - 7.47 (m, 2 H) 7.95 (s, 1 H)

[1018] Intermediate 31 tert-butyl 2-(4-fluoroanilino)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate

[1019] In a microwave reaction vessel, tert-butyl 3-bromo-2-(4-fluoroanilino)-6,7- dihydropyrazolo[1 ,5-a]pyrazine-5(4H)-carboxylate (78.0 mg, 190 μmo, Intermediate 30) und pyridin-4-ylboronic acid (25.6 mg, 209 μmol) were dissolved in 1 ,4-dioxane (2 ml) and were flushed with Argon. With stirring, PdCI2(PCy3)2 (14.0 mg, 19.0 μmol; CAS- RN: [29934- 17-6]) and aqueous sodium carbonate solution (460 pl, 2.0 M, 910 μmol) were added, the vial was sealed and the misture was heated at 150°C for 30 min in a microwave. After cooling to rt, ethyl acetate and water was added and the mixture was filtered through a pad of celite. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by reverse phase preparative HPLC (Method 5) yielding 17.0 mg (97 % purity, 21 % yield) of the desired product.

[1020] LC-MS (Method 4): Rt= 1.36 min; MS (ESIneg): m / z = 408 [M-H]'

[1021] 1H NMR (600 MHz, DMSO-d6) 0 ppm 1.42 (br s, 9 H) 3.83 - 3.91 (m, 2 H) 4.01 - 4.11 (m, 2 H) 4.69 (br s, 2 H) 6.91 - 7.02 (m, 2 H) 7.17 - 7.26 (m, 2 H) 7.31 - 7.38 (m, 2 H) 8.02 (s, 1 H) 8.51 - 8.57 (m, 2 H)

[1022] Intermediate 32

[1023] N-(4-fluorophenyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1 ,5-a]pyrazin-2-amine

[1024] To a solution of tert-butyl 2-(4-fluoroanilino)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazine-5(4H)-carboxylate (16.0 mg, 39.1 μmol, Intermediate 31) in DCM (4 ml) (30 pl, 390 μmol) TFA was added. The mixture was stirred at rt for 18 h. An additional amount of (30 pl, 390 μmol) TFA was added and stirring at rt was continued for 24 h. DCM (5 ml) was added followed by NaHCOs (saturated, aqueous 1 ml). The mixture was dried with an water- repellent filter and concentrated under reduced presssure. The crude product 6.30 mg (73 % purity, 38 % yield) was used without further purification.

[1025] LC-MS (Method 4): R(= 0.45 min; MS (ESIpos): m / z = 310 [M+H]+

[1026] 1H NMR (600 MHz, DMSO-cfe) 0 ppm 3.11 - 3.19 (m, 2 H) 3.90 - 3.94 (m, 2 H) 3.98 (br s, 2 H) 6.90 - 7.03 (m, 2 H) 7.13 - 7.23 (m, 2 H) 7.28 - 7.37 (m, 2 H) 7.94 (s, 1 H) 8.45 - 8.53 (m, 2 H)

[1027] Intermediate 33 tert-butyl 3-(2-anilinopyr!d!n-4-yl)-2-(4-fluorophenyl)-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate tert-butyl 3-bromo-2-(4-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (200 mg, 505 μmol, Intermediate 1) were added to a mixture of THF (5.3 ml) and water (690 pl) in a microwave reaction vessel. The reaction vessel flushed with nitrogen and N-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (164 mg, 555 μmol), potassium carbonate (209 mg, 1.51 mmol; CAS-RN:[584-08-7]) and dichloro[1 , T- bis(dialkyl / diarylphosphino)ferrocene]palladium(ll) (34.2 mg, 41.9 μmol; CAS-RN: [95464- 05-4]) were added. The sealed vessel was heated at 110°C for 1 hour in a microwave, ethyl acetate and water was added and the mixture neutralized using 1M acid acid. After extraction 2x with ethyl acetate the combined organic phases were dried with an water- repellent filter and concentrated under reduced presssure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate 0-20%) yielding the title compound 109 mg (93 % purity, 41 % yield).

[1028] LC-MS (Method 1): Rt= 1.06 min; MS (ESIpos): m / z = 486.1 [M+H]+

[1029] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.066 (16.00), 1.154 (1.07), 1.172 (2.00), 1.190 (0.94), 1.423 (1.73), 1.988 (3.68), 2.518 (0.96), 2.523 (0.64), 3.939 (2.57), 4.017 (0.73), 4.035 (0.73), 4.651 (0.96), 7.194 (0.48), 7.197 (0.52), 7.215 (0.69), 7.220 (0.92), 7.234 (0.46), 7.242 (0.48).

[1030] Intermediate 34 trifluoroacetic acid — 4-[2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazm- 3-yl]-N-phenylpyridm-2-amine (1 / 1) tert-butyl 3-(2-anilinopyridin-4-yl)-2-(4-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxylate (105 mg, 216 μmol, Intermediate 33) was added to a reaction vessel, followed by DCM (2.0 ml) and then the dropwise addition of trifluoroacetic acid (170 pi, 2.2 mmol; CAS-RN:[76-05-1]). The mixture was stirred at rt for 5 hours. The solution was concentrated under reduced pressure to yield 84 mg (95 % purity, 74 % yield) of the title crude product which was used without further purification in the next reaction.

[1031] LC-MS (Method 2): Rt= 1.10 min; MS (ESIpos): m / z = 386.5 [M+H]+

[1032] Intermediate 35 tert-butyl 2-(4-fluorophenyl)-3-(1 H-pyrrolo[2,3-b]pyridin-4--yl)-6,7- dihydropyrazolo[1,5-a]pyrazme-5(4H)-carboxylate tert-butyl 3-bromo-2-(4-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (148 mg, 373 μmol, Intermediate 1) were added to a mixture of THF (3.9 ml) and water (510 pl) in a microwave reaction vessel. The reaction vessel flushed with nitrogen and 1 H-pyrrolo[2,3-b]pyridin-4-ylboronic acid (96.8 mg, 598 μmol), potassium carbonate (155 mg, 1.12 mmol; CAS-RN:[584-08-7]) and dichloro[1 ,T-bis(dialkyl / diarylphosphino)- ferrocene]palladium(ll) (25.3 mg, 31 μmol; CAS- RN: [95464-05-4]) were added. The sealed vessel was heated at 110°C for 1 hour in a microwave, ethyl acetate and water was added and the mixture neutralized using 1M acid acid. After extraction 2x with ethyl acetate the combined organic phases were dried with an water-repellent filter and concentrated under reduced presssure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate 0-100%) yielding the title compound 45 mg (28 % yield).

[1033] LC-MS (Method 2): R(= 1.22 min; MS (ESIpos): m / z = 435 [M+H]+

[1034] Intermediate 36 trifluoroacetic acid — 2-(4-fluorophenyi)-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)-4, 5,6,7- tetrahydropyrazolo[1,5-a]pyrazine (1 / 1 )

[1035] tert-butyl 2-(4-fluorophenyl)-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]- pyrazine-5(4H)-carboxylate (85.0 mg, 196 μmol, Intermediate 35) was added to a reaction vessel, followed by DCM (2.0 ml) and then the dropwise addition of trifluoroacetic acid (150 pl, 2.0 mmol; CAS-RN:[76-05-1]). The mixture was stirred at rt for 3 hours. The solution was concentrated under reduced pressure to yield 65.0 mg (90 % purity, 67 % yield) of the title crude product which was used without further purification in the next reaction.

[1036] LC-MS (Method 2): R(= 0.85 min; MS (ESIpos): m / z = 334.3 [M+H]+

[1037] Intermediate 37 ethyl 3-bromo-1-{2-[(tert-butoxycarbonyl)amino]ethyl}-1 H-pyrazole-5-carboxylate

[1038] To a solution of ethyl 5-bromo-1 H-pyrazole-3-carboxylate (10.0 g, 45.7 mmol CAS-RN: [1392208-46-6), tert-butyl (2-hydroxyethyl)carbamate (7.36 g, 45.7 mmol) and triphenylphosphine (23.9 g, 91.3 mmol) in tetra hydrofuran (80 ml) was added diisopropyl azodicarboxylate (18.5 g, 91.3 mmol) at 20 °C. The resulting mixture was stirred at 20 °C for 10 h. The reaction solution was concentrated in vacuo to give ethyl 3-bromo-1-{2-[(tert- butoxycarbonyl)amino]ethyl}-1H-pyrazole-5-carboxylate (16.0 g, 44.2 mmol, 97% yield) as a yellow oil.

[1039] LC-MS (Method 11): Rt = 0.842 min; MS (ESIpos): m / z = 262.0 [(M-100)+H]+, 306.0 [(M- 55)+H]+.

[1040] Intermediate 38 tert-butyl (2-(3-bromo-5-(hydroxymethyl)-1 H-pyrazol-1-yl)ethyl)carbamate

[1041] To a solution of ethyl 3-bromo-1-{2-[(tert-butoxycarbonyl)amino]ethyl}-1 H-pyrazole-5- carboxylate (16.0 g, 44.2 mmol, Intermediate 37) in ethanol (400 ml) was added sodium tetrahydroborate (5.01 g, 133 mmol) in batches under 0 °C. After the addtion, the reaction mixture was allowed to warm to 20 °C and stirred for 12 hours. The reaction mixture was quenched with slowly adding water, and then concentrated under vacuo to give a crude. The crude was triturated with ethanol, filtered and the filtrate was concentrated 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 tert-butyl (2-(3-bromo-5-(hydroxymethyl)-1 H-pyrazol-1- yl)ethyl)carbamate (14.0 g, 43.7 mmol, 99% yield) as a yellow solid.

[1042] LC-MS (Method 11): Rt = 0.503 min; MS (ESIpos): m / z = 320.2 [M+H]+.

[1043] Intermediate 39 ethyl 1-(2-aminoethyl)-3-bromO"1 H-pyrazole-5-carboxylate

[1044] To a solution of ethyl 3-bromo-1-{2-[(tert-butoxycarbonyl)amino]ethyl}-1 H-pyrazole-5- carboxylate (13.0 g, 35.9 mmol, Intermediate 37) in ethyl acetate (43 ml) was added hydrochloric acid (4 M in ethyl acetate, 27 ml, 110 mmol;) at 20 °C. The mixture was stirred at 20 °C for 1 hour. The reaction mixture was filtered and the solid cake was collected to give a crude product. The crude product was diluted with water and the resulting mixture was filtered. The filtrate was basified with saturated sodium bicarbinate aqueous solution and then extracted with ethyl acetate. The combined organic layers were wahsed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound as a white solid (8.6 g, 91% yield).

[1045] Intermediate 40

[1046] 2-bromo-6,7-dihydropyrazolo[1 ,5-a]pyrazin-4(5H)-one

[1047] To a solution of ethyl 1-(2-aminoethyl)-3-bromo-1 H-pyrazole-5-carboxylate (8.60 g, 32.8 mmol, Intermediate 39) in methanol (150 ml) was added triethylamine (13.7 ml, 98.4 mmol) at 20 °C. The mixtrue was stirred at 50 °C for 12 hours. The reaction mixture was concentrated in vacuo to give 2-bromo-6,7-dihydropyrazolo[1 ,5-a]pyrazin-4(5H)-one (7 g, 32.4 mmol, 99% yield) as a white solid.

[1048] LC-MS (Method 11): Rt = 0.224 min; MS (ESipos): m / z = 216.0 [M+H]+

[1049] Intermediate 41

[1050] 2-(4-chloro-3-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

[1051] To a mixture of 2-bromo-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (450 mg, 2.08 mmol, Intermediate 40) and (4-chloro-3-fluorophenyl)boronic acid (710 mg, 4.07 mmol) in 1 ,4- dioxane (10 ml) and water (3 ml) were added dichloro[1 ,1- bis(diphenylphosphino)ferrocene]palladium(ll) (270 mg, 0.370 mmol) and sodium carbonate (784 mg, 7.40 mmol) at 20 °C. The resulting mixture was stirred at 90 °C for 12 hours under nitrogen atmosphere. 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 2-(4-chloro-3- fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (950 mg, 3.57 mmol, 96% yield) as a brown solid.

[1052] LC-MS (Method 11): Rt = 0.856 min; MS (ESIpos): m / z = 266.0 [M+H]+

[1053] Intermediate 42

[1054] 2-(4-chloro-3-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1 ,5-a]pyrazine

[1055] To a solution of 2-(4-chloro-3-fluorophenyl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-4(5H)-one (950 mg, 3.57 mmol, Intermediate 41) in tetrahydrofuran (20 ml) was added borane dimethyl sulfide complex (10 ml, 10 M in tetra hydrofuran) at 20 °C and the resulting solution was stirred at 65 °C for 12 hours. The reaction was quenched with methanol and the resulting solution was concentrated in vacuo to give 2-(4-chloro-3-fluorophenyl)-4, 5,6,7- tetrahydropyrazolo[1,5-a]pyrazine (850 mg, 3.37 mmol, 94% yield) as a black oil.

[1056] LC-MS (Method 11): Rt = 0.657 min; MS (ESIpos): m / z = 252.0 [M+H]+

[1057] Intermediate 43 tert-butyl 2-(4-chloro-3-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate

[1058] To a solution of 2-(4-chloro-3-fiuorophenyl)-4,5,6,7-tetrahydropyrazolo[1 ,5-a]pyrazine (850 mg, 3.37 mmol, Intermediate 42) in dichloromethane (10 ml) were added trimethylamine (1.4 ml, 10.1 mmol), 4-(dimethylamino)pyridine (41.0 mg, 0.337 mmol) and di-tert-butyl dicarbonate (1.5 ml, 6.75 mmol) at 20 °C. The resulting mixture was stirred at 20 °C for 4 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 tert-butyl 2-(4-chloro-3-fiuorophenyl)-6,7- dihydropyrazolo[1 ,5-a]pyrazine-5(4H)-carboxylate (1000 mg, 2.84 mmol, 84% yield) as a brown solid.

[1059] LC-MS (Method 11): Rt = 1.029 min; MS (ESIpos): m / z = 352.1 [M+H]+

[1060] Intermediate 44 tert-butyl 2-(4-chloro-3-fluorophenyl)-3-iodo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate

[1061] To a solution of tert-butyl 2-(4-chloro-3-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxylate (100 mg, 2.84 mmol, Intermediate 43) in dichloromethane (10 ml) was added N-iodosuccinimide (703 mg, 3.12 mmol) at 20 °C. The reaction mixture was stirred at 43 °C for 3 hours. The reaction mixture was poured into sodium sulfite aqueous solution 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 tert-butyl 2- (4-chloro-3-fluorophenyl)-3-iodo-6,7-dihydropyrazolo[1 ,5-a]pyrazine-5(4H)-carboxylate (1.10 g, 2.30 mmol, 81% yield) as a black solid.

[1062] LC-MS (Method 11): Rt = 1.106 min; MS (ESIpos): m / z = 478.0 [M+H]+.

[1063] Intermediate 45 tert-butyl 2-(4-chloro-3-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-

[1064] 5(4H)-carboxylate To a mixture of tert-butyl 2-(4-chloro-3-fluorophenyl)-3-iodo-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate (1100 mg, 2.30 mmol, Intermediate 44) and pyridin-4- ylboronic acid (283 mg, 2.30 mmol) in 1 ,4-dioxane (50 ml) and water (10 ml) were added dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium(ll) (153 mg, 0.209 mmol) and sodium carbonate (444 mg, 4.18 mmol) at 20 °C. The resulting mixture was stirred at 80 °C for 12 hours under nitrogen atmosphere. 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 crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1 : 1) to give tert-butyl 2-(4-chloro-3-fluorophenyl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazine-5(4H)-carboxylate (511 mg, 1.19 mmol, 56% yield) as a gray solid.

[1065] LC-MS (Method 11): Rt = 0.857 min; MS (ESIpos): m / z = 429.1 [M+H]+.

[1066] Intermediate 46

[1067] 2-(4-chloro-3-fluorophenyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine hydrochloride (1 :1)

[1068] T oa solution of tert-butyl 2-(4-chloro-3-fluorophenyl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazine-5(4H)-carboxylate (511 mg, 1.19 mmol, Intermediate 45) in ethyl acetate (10 ml) was added hydrochloric acid (1.4 ml, 4 M in ethyl acetate) at 20 °C. The resulting mixture was stirred at 20 °C for 2 hours. The reaction mixture was filtered and the solid cake was collected to give 2-(4-chloro-3-fluorophenyl)-3-(pyridin-4-yl)-4, 5,6,7- tetrahydropyrazolo[1,5-a]pyrazine hydrochloride (1 :1) (390 mg, 1.06 mmol, 89% yield) as a yellow solid.

[1069] LC-MS (Method 11): Rt = 0.495 min; MS (ESIpos): m / z = 329.1 [M+H]+

[1070] Intermediate 47

[1071] 2-(4-chloro-2-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

[1072] To a solution of 2-bromo-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (600 mg, 2.78 mmol, Intermediate 40) and (4-chloro-2-fluorophenyl)boronic acid (533 mg, 3.06 mmol) in 1 ,4- dioxane (10 ml) and water (2 ml) were added sodium carbonate (589 mg, 5.55 mmol) and (1,T-bis(diphenylphosphino)ferrocene)palladium(ll) dichloride (203 mg, 278 μmol) at 20 °C. The mixture was degassed with nitrogen and stirred at 90 °C for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. Combined extracts were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under vacuum to give 2-(4-chioro-2-fluorophenyl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-4(5H)-one (500 mg, 1.88 mmol, 68% yield) as a brown solid.

[1073] LC-MS (Method 11): Rt = 0.752 min; MS (ESIpos): m / z = 266.0 [M+H]+.

[1074] Intermediate 48

[1075] 2-(4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1 ,5-a]pyrazine

[1076] To a solution of 2-(4-chl oro-2-fluorophenyl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-4(5H)-one (500 mg, 1.88 mmol, Intermediate 47) in tetrahydrofuran (20 ml) was added borane tetrahydrofuran complex (11 ml, 11 mmol, 1 .0 M in tetrahydrofuran) dropwise via syringe at 0 °C under nitrogen atmosphere. The mixture was stirred at 65 °C for 12 hours. The reaction mixture was quenched with methanol and the mixture was concentrated under vacuum to give 2-(4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (470 mg, 1.87 mmol, 99% yield) as a black gum.

[1077] LC-MS (Method 11): Rt = 0.808 min; MS (ESIpos): m / z = 252.1 [M+H]+

[1078] Intermediate 49 tert-butyl 2-(4-chloro-2-fluorophenyl)-6,7-dihydropyrazoio[1,5-a]pyrazine-5(4H)- carboxylate

[1079] To a solution of 2-(4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1 ,5-a]pyrazine (470 mg, 1.87 mmol, Intermediate 48) in dichloromethane (20 ml) were added di-tert-butyl dicarbonate (22.8 mg, 187 μmol), triethylamine (780 pl, 5.6 mmol) and 4- (dimethylamino)pyridine (22.8 mg, 187 μmol) at 20 °C. The mixture was stirred at 20 °C for 2 hours. The reaction mixture was concentrated under vacuum to give a crude product and the crude product product was purified by silica gel column chromatography (petroleum ether: ethyl aceate = 1: 0 to 3: 1) to give tert-butyl 2-(4-chloro-2-fluorophenyl)-6,7- dihydropyrazolo[1 ,5-a]pyrazine-5(4H)-carboxylate (500 mg, 1.42 mmol, 76% yield) as a yellow solid.

[1080] LC-MS (Method 11): Rt = 0.929 min; MS (ESIpos): m / z = 352.1 [M+H]+

[1081] Intermediate 50 tert-butyl 2-(4-chloro-2-fluorophenyl)-3-iodo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate

[1082] To a solution of tert-butyl 2-(4-chloro-2-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxylate (500 mg, 1.42 mmol, Intermediate 49) in dichloromethane (10 ml) and methanol (2.5 ml) was added 1 -iodopyrrolidine-2, 5-dione (640 mg, 2.84 mmol) in partions at 20 °C and the reaction mixture was stirred at 43 °C for 16 hours. The reaction mixture was quenched with saturated sodium sulfite aqueous solution and the resulting mixture was extracted with ethyl acetate. Combined extracts were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under vacuum to give tert-butyl 2-(4-chloro-2- fluorophenyl)-3-iodo-6,7-dihydropyrazolo[1 ,5-a]pyrazine-5(4H)-carboxylate (500 mg, 1.05 mmol, 74% yield) as a yellow oil.

[1083] LC-MS (Method 11): Rt = 1.105 min; MS (ESIpos): m / z = 478.1 [M+H]+ Intermediate 51 tert-butyl 2-(4-chloro-2-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-

[1084] 5(4H)-carboxylate

[1085] To a solution of tert-butyl 2-(4-chloro-2-fluorophenyl)-3-iodo-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate (480 mg, 1.00 mmol, Intermediate 50) and pyridin-4-ylboronic acid (247 mg, 2.01 mmol) in 1,4-dioxane (9 ml) and water (2 ml) were added sodium carbonate (213 mg, 2.01 mmol) and (1,T-bis(diphenylphosphino)ferrocene)palladium(ll) dichloride (60.7 mg, 100 μmol) at 20 °C. The mixture was degassed with nitrogen and stirred at 80 °C for 16 hours. The reaction mixture was concentrated under vacuum to give a crude product product and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl aceate = 1: O to 1 : 1) to give tert-butyl 2-(4-chloro-2-fluorophenyl)-3- (pyridin-4~yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazine~5(4H)-carboxylate (270 mg, 630 μmol, 63% yield) as a yellow oil.

[1086] LC-MS (Method 11): Rt = 0.841 min; MS (ESIpos): m / z = 429.2 [M+H]+

[1087] Intermediate 52

[1088] 2-(4-chloro-2-fluorophenyl)-3-(pyridin-4-yl)-4,5,6!7-tetrahydropyrazolo[1 ,5-a]pyrazine hydrogen chloride

[1089] To a solution of hydrochloric acid (459 mg, 12.6 mmol) in ethyl aceate (10 ml) was added tert-butyl 2-(4-chloro-2-fluorophenyl)-3-(pyridin-4-yl)-6!7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxylate (270 mg, 630 μmol, Intermediate 51) at 20 °C and the reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under vacuum to give 2-(4-chloro-2-fluorophenyl)-3-(pyridin-4-yl)-4,5,6!7-tetrahydropyrazolo[1 ,5-a]pyrazine hydrogen chloride (220 mg, 602 μmol, 96% yield) as a yellow solid.

[1090] LC-MS (Method 14): Rt = 0.641 min; MS (ESipos): m / z = 329.1 [M+H]+

[1091] Intermediate 53

[1092] 2-(3-chloro-4-methoxyphenyl)-6,7-dihydropyrazolo[1l5-a]pyrazin-4(5H)-one

[1093] To a mixture of 2-bromo-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (800 mg, 3.70 mmol, Intermediate 40) and (3-chloro-4-methoxyphenyl)boronic acid (759 mg, 4.07 mmol) in 1,4- dioxane (10 ml) and water (3 ml) were added dichloro[1 ,1-bis(diphenylphosphino)- ferrocene]palladium(ll) (270 mg, 0.370 mmol) and sodium carbonate (784 mg, 7.40 mmol) at 20 °C. The mixture was stirred at 90 °C for 12 hours under nitrogen atmosphere. 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 2-(3-chloro-4-methoxyphenyl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-4(5H)-one (1.00 g, 3.60 mmol, 97% yield) as a gray solid.

[1094] LC-MS (Method 11): Rt = 0.819 min; MS (ESipos): m / z = 278.0 [M+H]+

[1095] Intermediate 54

[1096] 2-(3-chloro-4-methoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine

[1097] To a solution of 2-(3-chloro-4-methoxyphenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)- one (1000 mg, 3.60 mmol, Intermediate 53) in tetra hydrofuran (20 ml) was added borane dimethyl sulfide complex (10 ml, 10 M in tetrahydrofuran) at 20 °C and the resulting solution was stirred at 65 °C for 12 hours. The reaction was quenched with methanol and the resulting solution was concentrated in vacuo to give 2-(3-chloro-4-methoxyphenyl)-4, 5,6,7- tetrahydropyrazolo[1 ,5-a]pyrazine (900 mg, 3.41 mmol, 94% yield) as a black oil.

[1098] LC-MS (Method 11): Rt = 0.565 min; MS (ESIpos); m / z = 264.0 [M+H]+

[1099] Intermediate 55 tert-butyl 2-(3-chloro-4-methoxyphenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate

[1100] To a solution of 2-(4-chloro-3-fluorophenyl)-4!5,6,7-tetrahydropyrazolo[1 ,5-a]pyrazine (900mg, 3.41 mmol, Intermediate 54) in dichloromethane (10 ml) were added trimethylamine (1.4 ml, 10.2 mmol), 4-(dimethylamino)pyridine (42.0 mg, 0.341 mmol) and di-tert-butyl dicarbonate (1.5 ml, 6.82 mmol) at 20 °C. The resulting mixture was stirred at 20 °C for 2 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 tert-butyl 2-(3-chloro-4-methoxyphenyl)-6,7- dihydropyrazolo[1 ,5-a]pyrazine-5(4H)-carboxylate (1.10 g, 3.02 mmol, 88% yield) as a black oil.

[1101] LC-MS (Method 11): Rt = 0.992 min; MS (ESIpos): m / z = 364.1 [M+H]+

[1102] Intermediate 56 tert-butyl 2-(3-chloro-4-methoxyphenyl)-3-iodo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate To a solution of tert-butyl 2-(3-chloro-4-methoxyphenyl)-6,7-dihydropyrazolo[1 ,5- a]pyrazine-5(4H)-carboxylate (1100 mg, 3.02 mmol, Intermediate 55) in dichloromethane (10 ml) was added N-iodosuccinimide (1360 mg, 6.04 mmol) at 20 °C. The reaction mixture was stirred at 20 °C for 12 hours. The reaction mixture was poured into sodium sulfite aqueous solution 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 tert-butyl 2-(3-chloro-4-methoxyphenyl)-3-iodo-6,7-dihydropyrazolo[1 ,5-a]pyrazine- 5(4H)-carboxylate (1.20 g, 2.45 mmol, 81% yield) as a black gum.

[1103] LC-MS (Method 11): Rt = 1.064 min; MS (ESIpos): m / z = 490.0 [M+H]+

[1104] Intermediate 57 tert-butyl 2-(3-chloro-4-methoxyphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazine-5(4H)-carboxyiate

[1105] To a mixture of tert-butyl 2-(3-chloro-4-methoxyphenyl)-3-iodo-6,7-dihydropyrazolo[1 ,5- a]pyrazine-5(4H)-carboxylate (1.10 g, 2.24 mmol, Intermediate 56) and pyridin-4-ylboronic acid (304 mg, 2.47 mmol) in 1 ,4-dioxane (66 ml) and water (22 ml) were added dichloro[1 , 1- bis(diphenylphosphino)ferrocene]palladium(ll) (164 mg, 0.224 mmol) and sodium carbonate (476 mg, 4.47 mmol) at 20 °C. The resulting mixture was stirred at 80 °C for 12 hours under nitrogen atmosphere. 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 crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1 : 1) to give tert-butyl 2-(3-chloro-4-methoxyphenyl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazine-5(4H)-carboxylate (780 mg, 1.76 mmol, 78% yield) as a brown solid.

[1106] LC-MS (Method 11): Rt = 0.857 min; MS (ESIpos): m / z = 429.1 [M+H]+

[1107] Intermediate 58 2-(3-chloro-4-methoxyphenyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine hydrochloride (1 :1)

[1108] T oa solution of tert-butyl 2-(3-chloro-4-methoxyphenyi)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazine-5(4H)-carboxylate (780 mg, 1.76 mmol, Intermediate 57) in ethyl acetate (55 ml) was added hydrochloric acid (2.2 ml, 4 M in ethyl acetate) at 20 °C. The resulting mixture was stirred at 20 °C for 1 hour. The reaction mixture was filtered and the solid cake was collected to give 2-(3-chloro-4-methoxyphenyi)-3-(pyridin-4-yl)-4, 5,6,7- tetrahydropyrazolo[1,5-a]pyrazine hydrochloride (1 :1) (650 mg, 1.72 mmol, 97% yield) as a yellow solid.

[1109] LC-MS (Method 11): Rt = 0.840 min; MS (ESIpos): m / z = 341.1 [M+H]+

[1110] Intermediate 59

[1111] 2-(2-methoxyphenyl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-4(5H)-one

[1112] To a solution of 2-bromo-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (600 mg, 2.78 mmol, Intermediate 40) and (2-methoxyphenyl)boronic acid (464 mg, 3.06 mmol) in 1 ,4-dioxane (10 ml) and water (2 ml) were added sodium carbonate (589 mg, 5.55 mmol) and (1,T- bis(diphenylphosphino)ferrocene)palladium(ll) dichloride (203 mg, 278 μmol) at 20 °C. The mixture was degassed with nitrogen and then stirred at 90 °C for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. Combined extracts were dried over anhydrous sodium sulfate and concentrated under vacuum to give 2-(2- methoxyphenyl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-4(5H)-one (600 mg, 2.47 mmol, 89% yield) as a brown solid.

[1113] LC-MS (Method 16): Rt= 0.680 min; MS (ESIpos): m / z = 244.1 [M+H]+. Intermediate 60

[1114] 2-(2-methoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1 ,5-a]pyrazine

[1115] To a solution of 2-(2-methoxyphenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (600 mg, 2.47 mmol, Intermediate 59) in tetra hydrofuran (30 ml) was added dropwise borane tetrahydrofuran complex (15 ml, 1.0 M, 15 mmol) via syringe at 0 °C under a nitrogen atmosphere. The mixture was then stirred at 65 °C for 12 hours. The reaction was quenched with methanol and the resulting mixture was concentrated under vacuum to give 2-(2- methoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (565 mg, 2.46 mmol, 100% yield) as a black gum.

[1116] LC-MS (Method 11): Rt = 0.736 min; MS (ESIpos): m / z = 230.2 [M+H]+

[1117] Intermediate 61 tert-butyl 2-(2-methoxyphenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate

[1118] To a solution of 2-(2-methoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (565 mg, 2.46 mmol, Intermediate 60) in dichloromethane (20 ml) were added di-tert-butyl dicarbonate (1.08 g, 4.93 mmol), triethylamine (1.0 ml, 7.4 mmol) and 4- (Dimethylamino)pyridine (30.1 mg, 246 μmol) at 20 °C. The resulting mixture was stirred at 20 °C for 2 hours. The reaction mixture was concentrated under vacuum to give a crude product and the crude product product was purified by silica gel column chromatography (petroleum ether: ethyl aceate = 1: 0 to 3: 1) to give tert-butyl 2-(2-methoxyphenyl)-6,7- dihydropyrazolo[1 ,5-a]pyrazine-5(4H)-carboxylate (700 mg, 2.13 mmol, 86% yield) as a yellow oil.

[1119] LC-MS (Method 11): Rt = 0.846 min; MS (ESIpos): m / z = 330.2 [M+H]+

[1120] Intermediate 62 tert-butyl 3-iodo-2-(2-methoxyphenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate

[1121] To a solution of tert-butyl 2-(2-rnethoxyphenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (700 mg, 2.13 mmol, Intermediate 61) in dichloromethane (10 ml) and methanol (2.5 ml) was added 1-iodopyrrolidine-2,5-dione (956 mg, 4.25 mmol) in portions at 20 °C and the reaction mixture was stirred at 43 °C for 16 hours. The reaction was quenched with saturated sodium sulfite aqueous solution and the resulting mixture was extracted with ethyl acetate. Combined extracts were dried over anhydrous sodium sulfate and concentrated under vacuum to give tert-butyl 3-iodo-2-(2-methoxyphenyl)-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate (800 mg, 1.76 mmol, 83% yield) as a yellow oil.

[1122] LC-MS (Method 11): Rt = 1.021 min; MS (ESIpos): m / z = 456.1 [M+H]+.

[1123] Intermediate 63 tert-butyl 2-(2-methoxyphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazine-5(4H)- carboxylate

[1124] To a solution of tert-butyl 3-iodo-2-(2-methoxyphenyl)-6,7-dihydropyrazolo[1 ,5-a]pyrazine- 5(4H)-carboxylate (780 mg, 1.71 mmol, Intermediate 62) and pyridin-4-ylboronic acid (421 mg, 3.43 mmol) in 1,4-dioxane (8 ml) and water (2 ml) were added sodium carbonate (363 mg, 3.43 mmol) and (1,T-bis(diphenylphosphino)ferrocene)palladium(ll) dichloride (125 mg, 171 μmol) at 20 °C. The mixture was degassed with nitrogen and stirred at 80 °C for 16 hours. The reaction mixture was concentrated under vacuum to give a crude product and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl aceate = 1: 0 to 0: 1) to give tert-butyl 2-(2-methoxyphenyl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (300 mg, 738 μmol, 43% yield) as a yellow oil.

[1125] LC-MS (Methodi 1): Rt = 0.810 min; MS (ESIpos): m / z = 407.3 [M+H]+.

[1126] Intermedjate 64

[1127] 2-(2-methoxyphenyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1!5-a]pyrazine hydrogen chloride

[1128] To a solution of hydrochloric acid (538 mg, 14.8 mmol) in ethyl aceate (10 ml) was added tert-butyl 2-(2-methoxyphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (300 mg, 738 μmol, Intermediate 63) at 20 °C and the reaction mixture was stirred at 20 °C for 1 hour. The insolubles were collected by filtration to give 2-(2- methoxyphenyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine hydrogen chloride (240 mg, 700 pmol, 95% yield) as a brown solid.

[1129] LC-MS (Method 14): Rt = 0.126 min; MS (ESIpos): m / z = 307.1 [M+H]+

[1130] Intermediate 65

[1131] N-[(3-bromo-1-{2-[(tert-butoxycarbonyl)amino]ethyl}-1H-pyrazol-5-yl)methyl]-N,N- diethylethanaminium methanesulfonate

[1132] To a solution of tert-butyl {2-[3-bromo-5-(hydroxymethyl)-1H-pyrazol-1-yl]ethyl}carbamate (14.0 g, 43.7 mmol, Intermediate 38) and methanesulfonic anhydride (17.4 g, 99.9 mmol) in dichloromethane (160 ml) was added triethyl amine (14 ml, 99.9 mmol) at 20 °C. The resulting mixture was stirred at 20 °C for 16 hours. The reaction mixture was concentrated in vacuo to give N-[(3-bromo-1-{2-[(tert-butoxycarbonyl)amino]ethyl}-1 H-pyrazol-5- yl)methyl]-N,N-diethylethanaminium methanesulfonate (24.0 g, 48.1 mmol, 96% yield) as a pale brown oil.

[1133] LC-MS (Method 11): Rt = 0.710 min; MS (ESIpos): m / z = 403.2 [M+H]+.

[1134] Intermediate 66 tert-butyl 2-bromo-6,7-dihydropyrazolo[1 ,5-a]pyrazine-5(4H)-carboxylate

[1135] To a mixture of N-[(3-bromo-1-{2-[(tert-butoxycarbonyl)amino]ethyl}-1 H-pyrazol"5- yl)methyl]-N,N-diethylethanaminium methanesulfonate (24.0 g, 48.1 mmol, Intermediate 65) in tetrahydrofuran (80 ml) and N.N-dimethylformamide (80 ml) was added a solution of sodium hydride (3.8 g, 60% purity, 96.1 mmol) in tetrahydrofuran (20 ml) at 0 °C. The resulting mixture was stirred at 20 °C for 2 hours. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give tert-butyl 2- bromo-6,7-dihydropyrazolo[1 ,5-a]pyrazine-5(4H)-carboxylate (14 g, 46.3 mmol, 96% yield) as a brown oil.

[1136] LC-MS (Method 11): Rt = 0.910 min; MS (ESIpos): m / z = 302.0 [M+H]+.

[1137] Intermediate 67 tert-butyl 2-bromo-3-iodo-6,7-dihydropyrazolo[1 ,5-a]pyrazine-5(4H)-carboxylate

[1138] To a solution of tert-butyl 2-bromo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (14 g, 46.3 mmol, Intermediate 66) in dichloromethane (100 ml) and methanol (50 ml) was added 1-iodopyrrolidine-2, 5-dione (15.6 g, 69.5 mmol) at 20 °C. The resulting mixture was stirred at 43 °C for 12 hour. The reaction mixture was poured into saturated sodium sulfite aqueous solution 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 give tert-butyl 2-bromo-3-iodo-6,7- dihydropyrazolo[1 ,5-a]pyrazine-5(4H)-carboxylate (10.5 g, 24.5 mmol, 53% yield) as a yellow oil.

[1139] LC-MS (Method 11): Rt = 0.684 min; MS (ESIpos): m / z = 428.0 [M+H]+.

[1140] 1 H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.090 (0.49), 1.107 (0.47), 1.133 (0.45), 1.155 (0.59), 1.173 (0.97), 1.191 (0.97), 1.219 (0.69), 1.235 (0.62), 1.907 (0.45), 1.987 (0.49), 2.564 (3.35), 2.670 (0.43), 2.751 (0.44), 3.058 (4.69), 3.071 (8.34), 3.085 (5.15), 3.686 (16.00), 3.751 (0.56), 3.914 (4.88), 3.928 (8.30), 3.941 (4.61).

[1141] Intermediate 68 tert-butyl 2-bromo-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazine-5(4H)-carboxylate

[1142] To a mixture of tert-butyl 2-bromo-3-iodo-6,7-dihydropyrazolo[1 ,5-a]pyrazine-5(4H)- carboxylate (8.50 g, 19.9 mmol, Intermediate 67) and pyridin-4-ylboronic acid (2.44 g, 19.9 mmol) in 1 ,4-dioxane (85 ml) and water (26 ml) were added dichloro[1 , 1- bis(diphenylphosphino)ferrocene]palladium(ll) (1.45 g, 1.99 mmol) and sodium carbonate (4.21 g, 39.7 mmol) at 20 °C. The mixture was stirred at 80 °C for 12 hours under nitrogen atmosphere. 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 = 2: 1 to 1: 1) to give tert-butyl 2-bromo-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (5.8 g, 15.3 mmol, 77% yield) as a yellow solid. LC-MS (Method 11): Rt = 0.460 min; MS (ESIpos): m / z ~ 379.1 [M+H]+.

[1143] 1H NMR (400 MHz, DMSO-d6) 0 [ppm] = 8.81-8.52 (m, 2H), 7.56-7.23 (m, 2H), 4.70 (s, 2H), 4.16 (t, J = 5.4 Hz, 2H), 3.86 (t, J - 5.4 Hz, 2H), 1.41 (s, 9H).

[1144] Intermediate 69 tert-butyl 2-(3,4-dichlorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate

[1145] To a solution of tert- butyl 2-bromo-3-(pyridin-4-yl)-6!7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxylate (300 mg, 0.791 mmol, Intermediate 68) and (3,4-dichlorophenyl)boronic acid (196 mg, 1.02 mm!) in 1,4-dioxane (8 ml) and water (2 ml) were added sodium carbonate (167 mg, 1.58 mmol) and dichloro[1,1- bis(diphenylphosphino)ferrocene]palladium(ll) (57.8 mg, 0.0791 mmol) at 20 °C. The mixture was degassed with nitrogen and then stirred at 90 °C for 16 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 the filtrate was concentrated in vacuo to give tert-butyl 2-(3,4-dichlorophenyl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazine-5(4H)-carboxylate (270 mg, 0.606 mmol, 76% yield) as a yellow solid.

[1146] LC-MS (Method 11): Rt = 0.565 min; MS (ESIpos): m / z = 445.1 [M+H]+.

[1147] Intermediate 70

[1148] 2-(3,4-dichlorophenyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1 ,5-a]pyrazine

[1149]

[1150] To a solution of tert-butyl 2-(3,4-dichiorophenyl)-3-(pyridin-4-yi)-6,7-dihydropyrazolo[1 ,5- a]pyrazine-5(4H)-carboxylate (272 mg, 0.610 mmol, Intermediate 69) in ethyl acetate (3 ml) was added hydrochloric acid (5 ml, 4 M in ethyl acetate) at 20 °C. The mixture was stirred at 20 °C for 1 hour. The reaction mixture was filtered and the solid cake was collected to give 2-(3,4-dichlorophenyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine(200 mg, 0.579 mmol, 94% yield) as a brown solid.

[1151] LC-MS (Method 11): Rt = 0.416 min; MS (ESIpos): m / z = 345.0 [M+H]+

[1152] Intermediate 71

[1153] 2-(4-methoxyphenyl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-4(5H)-one

[1154] To a mixture of 2-bromo-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (450 mg, 2.08 mmol, Intermediate 40) and (4-methoxyphenyl)boronic acid (348 mg, 2.29 mmol) in 1 ,4-dioxane (14 ml) and water (4 ml) were added dichloro[1,1- bis(diphenylphosphino)ferrocene]palladium(ll) (152 mg, 0.208 mmol) and sodium carbonate (442 mg, 4.17 mmol) at 20 °C. The resulting mixture was stirred at 90 °C for 12 hours under nitrogen atmosphere. 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 = 0: 1) to give 2-(4-methoxyphenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (390 mg, 1.60 mmol, 77% yield) as a white solid.

[1155] LC-MS (Method 12): Rt = 0.675 min; MS (ESIpos): m / z = 244.0 [M+H]+

[1156] Intermediate 72

[1157] 2-(4-methoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine

[1158] To a solution of 2-(4-methoxyphenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (390 mg, 1.60 mmol, Intermediate 71) in tetrahydrofuran (10 ml) was added borane dimethyl sulfide complex (0.5 ml, 10 M in tetra hydrofuran) at 20 °C and the resulting solution was stirred at 60 °C for 16 hours. The reaction was quenched with methanol and the resulting solution was concentrated in vacuo to give 2-(4-methoxyphenyl)-4, 5,6,7- tetrahydropyrazolo[1,5-a]pyrazine (350 mg, 1.53 mmol, 95% yield) as a white solid.

[1159] LC-MS (Method 12): Rt = 0.723 min; MS (ESIpos): m / z = 230.0 [M+H]f.

[1160] Intermediate 73 tert-butyl 2-(4-methoxyphenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate

[1161] To a solution of 2-(4-methoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1 ,5-a]pyrazine (350 mg, 1.53 mmol, Intermediate 72) in dichloromethane (5 ml) were added trimethylamine (0.4 ml, 3.05 mmol), 4-(dimethylarnino)pyridine (18.6 mg, 0.153 mmol) and di-tert-butyl dicarbonate (0.7 ml, 3.05 mmol) at 20 °C. The resulting mixture was stirred at 20 °C for 4 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 tert-butyl 2-(4-methoxyphenyl)-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate (450 mg, 1.37 mmol, 89% yield) as a pale yellow oil.

[1162] LC-MS (Method 12): Rt = 0.947 min; MS (ESIpos): m / z = 330.3 [M+H]f.

[1163] Intermediate 74 tert-butyl 3-iodo-2-(4-methoxyphenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate

[1164] To a solution of tert-butyl 2-(4-methoxyphenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (450 mg, 1.37 mmol, Intermediate 73) in dichloromethane (5 ml) was added N- iodosuccinimide (922 mg, 4.10 mmol) at 20 °C. The reaction mixture was stirred at 20 °C for 2 hours. The reaction mixture was poured into sodium sulfite aqueous solution 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 tert-butyl 3-iodo- 2-(4-methoxyphenyl)-6,7~dihydropyrazolo[1 ,5-a]pyrazine-5(4H)-carboxylate (450 mg, 0.988 mmol, 72% yield) as a pale yellow solid.

[1165] LC-MS (Method 12): Rt = 1.019 min; MS (ESIpos): m / z = 456.2 [M+H]+

[1166] Intermediate 75 tert-butyl 2-(4-methoxyphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate

[1167]

[1168] To a mixture of tert-butyl 3-iodo-2-(4-methoxyphenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxylate (350 mg, 0.769 mmol, Intermediate 74) and pyridin-4-ylboronic acid (113 mg, 0.922 mmol) in 1 ,4-dioxane (14 ml) and water (4 ml) were added dichloro[1 , 1 - bis(diphenylphosphino)ferrocene]palladium(ll) (56.2 mg, 0.0769 mmol) and sodium carbonate (163 mg, 1.54 mmol) at 20 °C. The resulting mixture was stirred at 80 °C for 12 hours under nitrogen atmosphere. The reaction mixture was poured into water and extracted with ethyl acetate. The combiend organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 2: 1 to 0: 1) to give tert-butyl 2-(4-methoxyphenyl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazine-5(4H)-carboxylate (160 mg, 0.394 mmol, 51 % yield) as a brown solid.

[1169] LC-MS (Method 12): Rt = 0.717 min; MS (ESIpos): m / z = 407.3 [M+H]+Intermediate 76

[1170] 2-(4-methoxyphenyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine hydrochloride (1 :1)

[1171] T oa solution of tert-butyl 2-(4-methoxyphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazine-5(4H)-carboxylate (160 mg, 0.394 mmol, intermediate 75) in ethyl acetate (9 ml) was added hydrochloric acid (0.5 ml, 4 M in ethyl acetate) at 20 °C. The resulting mixture was stirred at 20 °C for 2 hours. The reaction mixture was filtered and the solid cake was collected to give 2-(4-methoxyphenyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1 ,5- a]pyrazine hydrochloride (1 :1) (120 mg, 0.350 mmol, 89% yield) as a yellow solid.

[1172] Intermediate 77

[1173] 2-(3-fluoro-4-methoxyphenyl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-4(5H)-one

[1174] To a mixture of 2-bromo-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (600 mg, 2.78 mmol, Intermediate 40) and (3-fluoro-4-methoxyphenyl)boronic acid (520 mg, 3.06 mmol) in 1 ,4- dioxane (6 ml) and water (2 ml) were added dichloro[1 , 1 - bis(diphenylphosphino)ferrocene]palladium(ll) (203 mg, 0.278 mmol) and sodium carbonate (589 mg, 5.55 mmol). The resulting mixture was stirred at 90 °C for 12 hours under nitrogen atmosphere. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were wahsed 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 = 0: 1) to give 2-(3-fluoro-4-methoxyphenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (120 mg, 0.459 mmol, 17% yield) as a white solid.

[1175] LC-MS (Method 11): Rt = 0.801 min; MS (ESIpos): m / z = 262.1 [M+H]+

[1176] Intermediate 78

[1177] 2-(3-fluoro-4-methoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine To a solution of 2-(3-fluoro-4-methoxyphenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (120 mg, 0,459 mmol, Intermediate 77) in tetra hydrofuran (5 ml) was added borane tetrahydrofuran complex (1.4 ml, 1 M in tetrahydrofuran) at 20 °C. The mixture was stirred at 65 °C for 12 hours. The reaction was quenched with methanol and the resulting mixture was concentrated in vacuo to give 2-(3-fluoro-4-methoxyphenyl)-4, 5,6,7- tetrahydropyrazolo[1 ,5-a]pyrazine (110 mg, 0.445 mmol, 97% yield) as a black oil.

[1178] LC-MS (Method 11): Rt = 0.837 min; MS (ESIpos): m / z = 248.1 [M+H]+

[1179] Intermediate 79 tert-butyl 2-(3-fluoro-4-methoxyphenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate

[1180] To a solution of 2-(3-fluoro-4-methoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (110 mg, 0.445 mmol, Intermediate 78) and di-tert-butyl dicarbonate (194 mg, 0.900 mmol) in dichloromethane (5 ml) were added trimethylamine (0.2 ml) and 4- (dimethylamino)pyridine (5.44 mg, 0.0445 mmol) at 20 °C. The resulting mixture was stirred at 20 °C for 1 hour. 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 vcuo to give tert-butyl 2-(3-fluoro-4- methoxyphenyl)-6,7-dihydropyrazolo[1 ,5-a)pyrazine-5(4H)-carboxylate (130 mg, 0.374 mmol, 84% yield) as a pale brown solid.

[1181] LC-MS (Method 11): Rt ~ 0.878 min; MS (ESIpos): m / z = 348.2 [M+H]+

[1182] Intermediate 80 tert-butyl 2-(3-fluoro-4-methoxyphenyl)-3-iodo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)~ carboxylate

[1183] To a solution of tert-butyl 2-(3-fluoro-4-methoxyphenyl)-6,7-dihydropyrazolo[1 ,5-a]pyrazine- 5(4H)-carboxylate (130 mg, 0.374 mmol, Intermediate 79) in dichloromethane (10 ml) and methanol (3 ml) was added N-iodosuccinimide (92.0 mg, 0.412 mmol) at 20 °C. The mixture was stirred at 43 °C for 12 hours. The reaction mixture was poured into saturated sodium sulfite aqueous solution 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 tert-butyl 2-(3-fluoro-4-methoxyphenyl)-3-iodo-6,7-dihydropyrazolo[1 ,5-a]pyrazine- 5(4H)-carboxylate (150 mg, 0.317 mmol, 85% yield) as a brown solid.

[1184] LC-MS (Method 11): Rt = 1.034 min; MS (ESIpos): m / z = 474.2 [M+H]+

[1185] Intermediate 81 tert-butyl 2-(3-fluoro-4-methoxyphenyl)-3-(pyridin-4-yl)-6!7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxylate

[1186] To a solution of tert-butyl 2-bromo-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxylate (150 mg, 0.317 mmol, Intermediate 80) and (3-fluoro-4- methoxyphenyl)boronic acid (46.7 mg, 0.380 mmol) in 1,4-dioxane (6 ml) and water (2 ml) were added sodium carbonate (67.2 mg, 0.634 mmol) and dichloro[1 ,1 - bis(diphenylphosphino)ferrocene]palladium(ll) (23.2 mg, 0.0317 mmol) at 20 °C. The mixture was degassed with nitrogen and then stirred at 90 °C for 16 hours. The reaction mixture 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 purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1 : 1) to give tert-butyl 2-(3-fluoro-4-methoxyphenyl)-3- (pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (100 mg, 0.236 mmol, 74% yield) as a yellow solid.

[1187] LC-MS (Method 11): Rt = 0.819 min; MS (ESIpos): m / z = 425.3 [M+H]+

[1188] Intermediate 82

[1189] 2-(3-fluoro-4-methoxyphenyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine hydrochloride (1:1)

[1190] To a solution of tert-butyl 2-(3-fluoro-4-methoxyphenyl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (100 mg, 0.236 mmol, Intermediate 81) in ethyl acetate (5 ml) was added hydrochloric acid (0.3 ml, 4 M in ethyl acetate) at 20 °C. The mixture was stirred at 20 °C for 1 hour. The reaction mixture was filtered and the solid cake was collected to give 2-(3-fluoro-4-methoxyphenyl)-3-(pyridin-4-yl)-4, 5,6,7- tetrahydropyrazolo[1,5-a]pyrazine hydrochloride (1 :1) (60 mg, 0.166 mmol, 71% yield) as a yellow solid.

[1191] Intermediate 83 tert-butyl 2-(4-cyanophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate

[1192] To a solution of tert-butyl 2-bromo-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxylate (400 mg, 1.00 mmol, Intermediate 68) in 1,4-dioxane (4.0 ml) and water (1 ml) were added (4-cyanophenyl)boronic acid (177 mg, 1.20 mmol), sodium carbonate (212 mg, 2.00 mmol) and dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium(ll) (73 mg, 0.10 mmol) at 25 °C. The reaction mixture was stirred at 90 °C for 18 hours under nitrogen atmosphere. The mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography on silica gel (100-200 mesh, petroleum ether: ethyl acetate = 5: 1) to give tert-butyl 2-(4-cyanophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (310 mg, 87% purity, 54% yield) as a yellow solid.

[1193] LC-MS (Method 13): Rt = 0.524 min; MS (ESIpos): m / z = 402.3 [M+H]+

[1194] Intermediate 84

[1195] 4-[3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1 ,5-a]pyrazin-2-yl]benzonitrile — hydrogen chloride (1 / 1)

[1196] The reaction mixture of tert-butyl 2-(4-cyanophenyl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazine-5(4H)-carboxylate (350 mg, 845 μmol, Intermediate 83) in ethyl acetate (10 ml) was added hydrochloric acid (5 ml, 4 M in ethyl acetate) at 25 °C. The mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrared in vacuo to give 2-ethyl-4-[3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1 ,5-a]pyrazin-2-yl]benzonitrile hydrochloride (1 :1) (380 mg, 78% purity, 96% yield) as a yellow solid.

[1197] LC-MS (Method 13): Rt = 0.246 min; MS (ESIpos): m / z = 302.2 [M+H]+

[1198] Lntermediate 85

[1199] 2-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1 ,5-a]pyrazin-4(5H)-one

[1200] To a mixture of 2-bromo-6,7-dihydropyrazolo[1 ,5-a]pyrazin-4(5H)-one (600 mg, 2.78 mmol, Intermediate 40) and [4-(trifluoromethyl)phenyl]boronic acid (580 mg, 3.06 mmol) in 1,4- dioxane (6 ml) and water (2 ml) were added dichloro[1,1- bis(diphenylphosphino)ferrocene]palladium(ll) (203 mg, 0.278 mmol) and sodium carbonate (589 mg, 5.55 mmol) at 20 °C. The resulting mixture was stirred at 90 °C for 12 hours under nitrogen atmosphere. 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 = 0: 1) to give 2-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (220 mg, 0.782 mmol, 28% yield) as a white solid.

[1201] LC-MS (Method 11): Rt = 0.866 min; MS (ESIpos): m / z = 282.1 [M+H]+

[1202] Intermediate 86

[1203] 2-[4-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine

[1204] To a solution of 2-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (220 mg, 0.782 mmol, Intermediate 85) in tetrahydrofuran (3 ml) was added borane tetrahydrofuran complex (2 ml, 1 M in tetrahydrofuran) at 20 °C. The mixture was stirred at 65 °C for 12 hours. The reaction was quenched with methanol and the resulting mixture was concentrated in vacuo to give 2-[4-(trifluoromethyl)phenyl]-4, 5,6,7- tetrahydropyrazolo[1,5-a]pyrazine (200 mg, 0.748 mmol, 96% yield) as a black oil.

[1205] LC-MS (Method 11): Rt = 0.906 min; MS (ESIpos): m / z = 268.1 [M+H]+

[1206] Intermediate 87 tert-butyl 2-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate

[1207]

[1208] To a solution of 2-[4-(trifluoromethyl)phenyl]-4l5,6,7-tetrahydropyrazolo[1 ,5-a]pyrazine (200 mg, 0.748 mmol, Intermediate 86) and di-tert-butyl dicarbonate (0.344 ml, 1.50 mmol) in dichloromethane (5 ml) were added triethylamine (0.2 ml, 1.50 mmol) and 4- (dimethylamino)pyridine (9.14 mg, 0.0748 mmol) at 20 °C. The resulting mixture was stirred at 20 °C for 1 hour. 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 vcuo to give tert-butyl 2-[4- (trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1 ,5-a]pyrazine-5(4H)-carboxylate (250 mg, 0.681 mmol, 91% yield) as a pale brown solid.

[1209] LC-MS (Method 11): Rt = 0.936 min; MS (ESIpos): m / z = 368.2 [M+H]f.

[1210] Intermediate 88 tert-butyl 3-iodo-2-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate

[1211] To a solution of tert- butyl 2-[4-(trifluoromethyl)phenyl]-6!7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxyiate (250 mg, 0.681 mmol, Intermediate 87) in dichloromethane (5 ml) and methanol (5 ml) was added N-iodosuccinimide (322 mg, 1.43 mmol) at 20 °C. The mixture was stirred at 43 °C for 12 hours. The reaction mixture was poured into saturated sodium sulfite aqueous solution 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 tert-butyl 3-iodo-2-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxylate (300 mg, 0.608 mmol, 89% yield) as a brown solid. LC-MS (Method 11): Rt = 1.105 min; MS (ESIpos): m / z = 494.2 [M+H]+

[1212] Intermediate 89 tert-butyl 3-(pyridin-4-yl)-2-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1 ,5-a]pyrazine-

[1213] 5(4H)-carboxylate

[1214] To a solution of tert-butyl 3-iodo-2-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1 ,5- a]pyrazine-5(4H)-carboxylate (300 mg, 0.608 mmol, Intermediate 88) and pyridin-4- ylboronic acid (89.7 mg, 0.730 mmol) in 1,4-dioxane (6 ml) and water (3 ml) were added dichloro[1 ,1-bis(diphenylphosphino)ferrocene]palladium(ll) (44.5 mg, 0.0608 mmol) and sodium carbonate (129 mg, 1 .22 mmol) at 20 °C. The resulting mixture was stirred at 90 °C for 12 hours under nitrogen atmosphere. 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 = 3: 1) to give tert-butyl 3-(pyridin-4-yl)-2-[4-(trifluoromethyl)phenyl]-6,7- dihydropyrazolo[1 ,5-a]pyrazine-5(4H)-carboxylate (150 mg, 0.337 mmol, 55% yield) as a yellow gum.

[1215] LC-MS (Method 11): Rt = 0.848 min; MS (ESIpos): m / z = 445.3 [M+ H]+

[1216] Intermediate 90

[1217] 3-(pyridin-4-yl)-2-[4-(trifluoromethyl)phenyl]-4,5l6,7-tetrahydropyrazolo[1 ,5-a]pyrazine hydrochloride (1 :1) To a solution of tert-butyl 3-(pyridin-4-yl)-2-[4-(trifluoromethyl)phenyl]-6,7- dihydropyrazolo[1 ,5-a]pyrazine-5(4H)-carboxylate (150 mg, 0.337 mmol, Intermediate 89) in ethyl acetate (5 ml) was added hydrochloric acid (0.4 ml, 4 M in ethyl acetate) at 20 °C. The mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated in vacuo to give 3-(pyridin-4-yl)-2-[4-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydropyrazolo[1 ,5- a]pyrazine hydrochloride (1 :1) (100 mg, 0.263 mmol, 78% yield) as a gray solid.

[1218] Intermediate 91 tert-butyl 2-[4-chloro-2-(hydroxymethyl)phenyl]-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate

[1219] To a solution of tert-butyl 2-bromo-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxylate (450 mg, 1.13 mmol, Intermediate 68) in 1 ,4-dioxane (5.0 ml) and water (1.0 ml) were added [4-chloro-2-(hydroxymethyl)phenyl]boronic acid (252 mg, 1.35 mmol), sodium carbonate(239 mg, 2.25 mmol) and dichloro[1 , 1- bis(diphenylphosphino)ferrocene]palladium(ll) (82.5 mg, 113 μmol) at 25 °C. The reaction mixture was stirred at 90 °C for 18 hours under nitrogen atmosphere. The mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography on silica gel (100-200 mesh, petroleum ether: ethyl acetate = 5: 1) to give tert-butyl 2-[4-chloro-2- (hydroxymethyl)phenyl]-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (500 mg, 92% purity, 92% yield) as a yellow solid.

[1220] LC-MS (Method 11): Rt = 0.469 min; MS (ESIpos): m / z = 441.1 [M+H]+

[1221] Intermediate 92

[1222] {5-chloro-2-[3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]phenyl}methanol

[1223]

[1224] To a solution of tert-butyl 2-[4-chloro-2-(hydroxymethyl)phenyl]-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazine-5(4H)-carboxylate (460 mg, 991 μmol, Intermediate 91) in water (5) and dioxane (5 ml) was added sulfuric acid (1 ml) at 20 °C. The mixture was stirred at 90 °C for 18 hours. pH of the reaction mixture was adjusted with saturated sodium carbonate aqueous solution to pH = 7-8, then the residue was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give {5-chloro-2-[3-(pyridin-4-yl)-4, 5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl]phenyl}methanol (300 mg, 89% purity, 79% yield) as a pale yellow solid.

[1225] LC-MS (Method 11): Rt = 0.209 min; MS (ESIpos): m / z = 341.1 [M+H]+

[1226] Intermediate 93 tert-butyl 3-(2-chloropyridin-4-yl)-2-(4-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxylate

[1227] To a mixture of THF (21 ml) and water (2.6ml) was added tert-butyl 3-bromo-2-(4- fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (780 mg, 1.97 mmol, Intermediate 1) and then (2-chloropyridin-4-yl)boronic acid (341 mg, 2.17 mmol). After degassing of the solution with argon, potassium carbonate (816 mg, 5.91 mmol) and PdCI2(dppf).CH2Cl2 (133 mg, 163 μmol; CAS-RN:[95464-05-4]) was added under a flow of argon and the mixture was heated under stirring at 110 °C for 1 hour under nitrogen atmosphere in the microwave. The reaction mixture was poured into water and extracted 3x with ethyl acetate. The combined organic layers were filtered with a hydrophobic filter and concentrated in vacuo to give a crude product. The crude product was purified by column chromatography on silica gel to yield 410 mg (97 % purity, 47 % yield) of the desired product.

[1228] LC-MS (Method 1): Rt = 1 .35 min; MS (ESIpos): m / z = 429 [M+H]+

[1229] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.172 (0.58), 1.424 (16.00), 1.987 (1.07), 2.518 (1.91), 2.523 (1.28), 3.869 (1.10), 3.882 (1.93), 3.896 (1.25), 4.204 (1.45), 4.218 (2.23), 4.231 (1.23), 4.701 (4.06), 7.126 (1.53), 7.130 (1.56), 7.139 (1.54), 7.143 (1.60), 7.198 (2.12), 7.204 (0.76), 7.215 (0.97), 7.221 (4.53), 7.226 (0.93), 7.238 (0.87), 7.243 (2.78), 7.254 (3.32), 7.256 (3.03), 7.365 (2.04), 7.370 (0.96), 7.379 (2.28), 7.387 (1.87), 7.395 (0.75), 7.401 (1.56), 8.359 (2.31), 8.371 (2.23).

[1230] Intermediate 94 tert-butyl 2-bromo-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazine-5(4H)-carboxylate

[1231] A solution of tert-butyl 2-bromo-3-iodo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (1.66 g, 99 % purity, 3.83 mmol, Intermediate 67) and (3-methyl-1 H-pyrrolo[2,3- b]pyridin-4-yl)boronic acid (675 mg, 3.83 mmol, Intermediate 245) in 1,4-dioxane (17ml) and water (1.7ml) was degassed with argon for 15min, sodium carbonate (1.02 g, 9.59 mmol) and PdCI2(dppf) (281 mg, 383 μmoi; CAS-RN:[72287-26-4]) were added, degassed further for 5min and stirred at 80°C over night. The mixture was quenched with water and extracted twice with ethyl acetate. The organic phase was washed with brine, dried using a hydrophobic filter and concentrated in vacuo. The residue was purified by column chromatography to yield 686 mg (99 % purity, 41 % yield) of the desired product.

[1232] LC-MS (Method 1): Rt = 1.01 min; MS (ESIpos): m / z = 434 [M+H]+

[1233] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.065 (0.66), 1.154 (4.08), 1.171 (8.64), 1.189 (4.30), 1.373 (7.07), 1.425 (1.28), 1.891 (15.56), 1.893 (16.00), 1.987 (15.06), 2.518 (1.72), 2.522 (1.08), 3.941 (0.52), 3.998 (1.15), 4.016 (3.16), 4.034 (3.01), 4.052 (1.02), 4.172 (1.87), 4.185 (3.42), 4.198 (1.74), 4.346 (2.11), 6.809 (5.49), 6.821 (5.54), 7.264 (2.78), 8.200 (6.27), 8.212 (5.82), 11.502 (2.17). Intermediate 95 tert-butyl 2-bromo-3-(3-methylpyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazine-5(4H)- carboxylate

[1234] A solution of 2-bromo-3-iodo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (200 mg, 467 μmol, Intermediate 67) and (3-methylpyridin-4-yl)boronic acid (64.0 mg, 467 μmol) in 1,4-dioxane (2ml) and water (0.5ml) was degassed with argon for 15min, sodium carbonate (99.0 mg, 934 μmol) and PdCI2(dppf) (34.2 mg, 46.7 μmol; CAS-RN:[72287-26- 4]) were added, degassed further for 5min and stirred at 80°C for 16h. The mixture was quenched with water and extracted twice with ethyl acetate. The organic phase was washed with brine, dried using a hydrophobic filter and concentrated in vacuo. The residue was purified by column chromatography to yield 64.3 mg (95 % purity, 33 % yield) of the desired product.

[1235] LC-MS (Method 1): Rt = 0.78 min; MS (ESIpos): m / z = 329.9 [M+H]+.

[1236] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (1.43), 1.172 (2.90), 1.190 (1.45), 1.332

[1237] (1.16), 1.396 (14.65), 1.444 (0.84), 1.988 (5.33), 2.166 (16.00), 2.518 (4.91), 2.523 (2.99),

[1238] 3.842 (1.31), 3.855 (1.75), 3.999 (0.41), 4.017 (1.23), 4.035 (1.18), 4.053 (0.40), 4.151

[1239] (2.08), 4.165 (3.74), 4.178 (1.72), 4.344 (0.71), 4.431 (2.52), 4.472 (1.07), 7.177 (2.90),

[1240] 7.190 (2.98), 8.443 (2.92), 8.455 (2.88), 8.559 (4.62).

[1241] Intermediate 96 tert-butyl 2-bromo-3-(5-fluoro-1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazine-5(4H)-carboxylate

[1242]

[1243] A solution of 2-bromo-3-iodo-6,7-dihydropyrazoio[1,5-a]pyrazine-5(4H)-carboxylate (200 mg, 467 μmol, Intermediate 67) and 5-fluoro-4-(4!4,5!5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1 H-pyrrolo[2,3-b]pyridine (122 mg, 467 μmoi) in 1 ,4-dioxane (2ml) and water (0.6ml) was degassed with argon for 15min, sodium carbonate (99.0 mg, 934 μmol) and PdCI2(dppf) (34.2 mg, 46.7 μmol; CAS-RN:[72287-26-4]) were added, degassed further for 5min and stirred at 80°C for 13h. The mixture was quenched with water and extracted twice with ethyl acetate. The organic phase was washed with brine, dried using a hydrophobic filter and concentrated in vacuo. The residue was purified by column chromatography to yield 204 mg (70 % purity, 70 % yield) of the desired product.

[1244] LC-MS (Method 1): Rt = 1.04 min; MS (ESIpos): m / z = 437.9 [M+H]+

[1245] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.065 (15.47), 1.155 (3.15), 1.392 (1.28), 1.425 (3.52), 1.434 (4.48), 2.518 (0.72), 2.523 (0.44), 3.565 (16.00), 3.939 (2.64), 4.404 (0.57), 7.632 (0.42).

[1246] Intermediate 97 tert-butyl 2-bromo-3-(3-fluoro-1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazine-5(4H)-carboxylate

[1247] A solution of 2-bromo-3-iodo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (200 mg, 467 μmol, Intermediate 67) and 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1 H-pyrrolo[2,3-b]pyridine (122 mg, 467 μmol) in 1 ,4-dioxane (2ml) and water (0.6ml) was degassed with argon for 15min, sodium carbonate (99.0 mg, 934 μmol) and PdCI2(dppf) (34.2 mg, 46.7 μmol; CAS-RN: [72287-26-4]) were added, degassed further for 5min and stirred at 80°C for 13h. The mixture was quenched with water and extracted twice with ethyl acetate. The organic phase was washed with brine, dried using a hydrophobic filter and concentrated in vacuo. The residue was purified by column chromatography to yield 204 mg (75 % purity, 75 % yield) of the desired product.

[1248] LC-MS (Method 1): Rt = 1.03 min; MS (ESIpos): m / z = 435.9 [M+H]+

[1249] 1 H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.064 (16.00), 1.155 (4.12), 1.332 (0.20), 1.391 (1.91), 1.425 (4.46), 1.434 (3.08), 2.522 (0.73), 3.564 (9.88), 3.772 (0.20), 3.786 (0.34),

[1250] 3.799 (0.26), 3.941 (2.61), 4.043 (0.19), 4.057 (0.26), 4.070 (0.18), 4.091 (0.20), 4.190

[1251] (0.33), 4.203 (0.22), 4.404 (0.25), 4.469 (0.17), 4.491 (0.18), 4.559 (0.30), 6.279 (0.37),

[1252] 6.986 (0.47), 6.998 (0.47), 7.529 (0.37), 7.943 (0.30), 8.312 (0.36), 8.324 (0.34), 11.693

[1253] (0.18).

[1254] Intermediate 98 tert-butyl 2-bromo-3-[2-(methylamino)pyridin-4-yi]-6,7-dihydropyrazolo[1,5-a]pyrazine-

[1255] 5(4H)-carboxylate

[1256] A solution of 2-bromo-3-iodo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (200 mg, 467 μmol, Intermediate 67) and N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridin-2-amine (109 mg, 467 μmol; CAS-RN:[1350913-08-4]) in 1,4-dioxane (2ml) and water (0.6ml) was degassed with argon for 15min, sodium carbonate (99.0 mg, 934 μmol) and PdCI2(dppf) (34.2 mg, 46.7 μmol; CAS-RN: [72287-26-4]) were added, degassed further for 5min and stirred at 80°C for 13h. The mixture was quenched with water and extracted twice with ethyl acetate. The organic phase was washed with brine, dried using a hydrophobic filter and concentrated in vacuo. The residue was purified by column chromatography to yield 284 mg (67 % purity, 100 % yield) of the desired product.

[1257] LC-MS (Method 1): Rt = 0.72 min; MS (ESIpos): m / z = 409.91H-NMR (400 MHz, DMS0-d6) δ [ppm]: 1.064 (16.00), 1.154 (2.64), 1.408 (4.61), 1.424 (1.24), 1.434 (2.35), 2.770 (1.35), 2.782 (1.35), 3.564 (6.32), 3.843 (0.49), 3.939 (2.74), 4.129 (0.59), 4.638 (0.84), 6.438 (0.63), 8.014 (0.45), 8.028 (0.44).

[1258] Intermediate 99 tert-butyl 3-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-[4-(trifluoromethyl)phenyl]-6,7- dihydropyrazolo[1 ,5-a]pyrazine-5(4H)-carboxylate

[1259] A solution of tert-butyl 3-iodo-2-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate (150 mg, 304 μmol, Intermediate 88) and (2-methyl-1H- pyrrolo[2,3-b]pyridin-4-yl)boronic acid (53.5 mg, 304 μmol; CAS-RN:[1014614-07-3]) in 1 ,4- dioxane (2ml) and water (0.6ml) was degassed with argon for 15min, sodium carbonate (64.5 mg, 608 μmol) and PdCI2(dppf) (22.3 mg, 30.4 μmol; CAS-RN: [72287-26-4]) were added, degassed further for 5min and stirred at 80°C for 16h. The mixture was quenched with water and extracted twice with ethyl acetate. The organic phase was washed with brine, dried using a hydrophobic filter and concentrated in vacuo. The residue was purified by column chromatography to yield 90.5 mg (98 % purity, 59 % yield) of the desired product.

[1260] LC-MS (Method 1): Rt = 1.25 min; MS (ESIpos): m / z = 498 [M+H]+.

[1261] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (4.41), 1.172 (9.50), 1.190 (4.74), 1.396 (5.13), 1.988 (16.00), 2.313 (5.23), 2.327 (0.58), 2.518 (1.12), 2.523 (0.75), 2.669 (0.41), 3.920 (0.69), 3.999 (1.18), 4.017 (3.49), 4.034 (3.35), 4.053 (1.07), 4.263 (0.84), 4.277 (1.40), 4.290 (0.71), 4.466 (0.43), 6.767 (0.74), 6.779 (0.74), 7.505 (0.87), 7.525 (1.24), 7.596 (2.36), 7.617 (1.48), 8.077 (1.59), 8.089 (1.60), 11.609 (0.77).

[1262] Intermediate 100 tert-butyl 3-(3-cyclopropylpyridin-4-yl)-2-[4-(trifluoromethyl)phenyl]-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate

[1263]

[1264] A solution of 3-iodo-2-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1 ,5-a]pyrazine-5(4H)- carboxylate (150 mg, 304 μmol, Intermediate 88) and 3-cyclopropyl-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyridine (74.5 mg, 304 μmol; CAS-RN:[2096333~32-1]) in 1 ,4- dioxane (2ml) and water (0.6ml) was degassed with argon for 15min, sodium carbonate (64.5 mg, 608 μmol) and PdCI2(dppf) (22.3 mg, 30.4 μmol; CAS-RN: [72287-26-4]) were added, degassed further for 5min and stirred at 80°C for 16h. The mixture was quenched with water and extracted twice with ethyl acetate. The organic phase was washed with brine, dried using a hydrophobic filter and concentrated in vacuo. The residue was purified by column chromatography to yield 127 mg (98 % purity, 84 % yield).

[1265] LC-MS (Method 1): Rt = 1.19 min; MS (ESIpos): m / z = 485 [M+H]+

[1266] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.744 (0.47), 0.756 (0.41), 0.836 (0.44), 1.065 (15.68), 1.154 (4.04), 1.172 (8.08), 1.190 (4.15), 1.411 (7.45), 1.987 (16.00), 2.523 (0.76), 3.939 (1.34), 3.999 (1.35), 4.017 (3.76), 4.035 (3.70), 4.053 (1.21), 4.258 (0.86), 4.272 (1.57), 4.284 (0.87), 4.458 (0.74), 7.169 (1.12), 7.181 (1.12), 7.499 (1.57), 7.520 (1.92), 7.650 (2.14), 7.671 (1.62), 8.209 (1.81), 8.396 (1.58), 8.408 (1.51).

[1267] Intermediate 101 tert-butyl 2-(4-chloro-2-fluoroanilino)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate

[1268] Under argon tert-butyl 2-amino-6,7-dihydropyrazolo[1 ,5-a]pyrazine-5(4H)-carboxylate (500 mg, 2.10 mmol; CAS-RN:[1209487-56-8]) was dissolved in 1 ,4-dioxane (5ml), 1-bromo-4- chloro-2-fluorobenzene (879 mg, 4.20 mmol; CAS-RN: [1996-29-8]) was added and the mixture was degassed with argon for 5 min. Potassiumcarbonate (580 mg, 4.20 mmol), XPhos (40.0 mg, 83.9 μmol; CAS-RN: [564483- 18-7]) and Tris-

[1269] (dibenzylidenacetone)dipalladium (76.9 mg, 83.9 μmol; CAS-RN:[51364-51-3]) were added and heated to 100°C over night. Water was added to the reaction mixture, extracted twice into ethyl acetate, dried using a hydrophobic filter and evaporated in vacuo. The crude product was purified on 25g silica (eluent: hexane / ethyl acetate 0-40%) to yield 649 mg (97 % purity, 82 % yield) of the desired product.

[1270] LC-MS (Method 1): Rt = 1.36 min; MS (ESIpos): m / z = 367 [M+H]+

[1271] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.433 (16.00), 3.798 (0.69), 3.811 (0.46), 3.963 (0.57), 3.977 (0.83), 3.989 (0.41), 4.537 (0.79), 5.810 (1.66), 7.286 (0.60), 7.292 (0.56), 7.315 (0.57), 7.321 (0.56), 8.124 (0.49), 8.147 (0.69), 8.170 (0.46), 8.455 (0.61), 8.461 (0.59).

[1272] Intermediate 102 tert-butyl 3-bromo-2-(4-chlo...

Claims

Claims1. A compound of formula (I) in which:R1represents a group selected from the group:R2represents a group selected from the group:R3represents -(CO)-R11, -(CO)-C=C-R12, -(SO2)-CH=CH2, or oxirane-2-carbonyl;R4arepresents a hydrogen atom, fluoro, or methyl; R4brepresents a hydrogen atom, fluoro, or methyl;R4crepresents a hydrogen atom, fluoro, or methyl;R4drepresents a hydrogen atom, fluoro, or methyl;R4erepresents a hydrogen atom, fluoro, or methyl;R4frepresents a hydrogen atom, fluoro, methyl, C1-C2-hydroxyalkyl, -(CO)-NR19R20, or-CH2-(CO)-NR19R20;R5a represents 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-Cr 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, 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;R5crepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, Cr 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-Cr 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, Cr 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, Cr C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-CrC3-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-Cr 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, Cr C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-Cr C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-Cr C3-alkyl, or cyano;R7arepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, Cr C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-Cr C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-Cr C3-alkyl, or cyano;R7brepresents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, Cr C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-Cr C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-Cr 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-Cr 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-CrC3-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-Cr 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-Cr 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-Cr 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-Cr C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, C2-Ce-cycloalkyl, cyano, fluoro, chloro, or bromo;R9brepresents a hydrogen atom, amino, C1-C3-alkyl, Cs-C3-alkenyl, C2-C3-alkinyl, Cr 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-Cr C3-alkyl, C1-C3-alkyl-amino, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (Cr C3-alky^amino-C1-C3-alkyl, cyano, anilino, pyridin-2-yl-amino, or C2-Ce- cycloalkylformamido;R9d represents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, Cr 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, Cr C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-Cr C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo;RWb represents 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-Cr C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, or cyano;RWC represents a hydrogen atom or methyl;R10drepresents a hydrogen atom, fluoro, or methyl;R11represents -CH2-C=CH, -C(R14)-R15, orR12represents a hydrogen atom, methyl, -CH2-NR19R20, or a group selected from the group:R14represents =CHR16;R15represents a hydrogen atom, C1-C3-alkyl, fluoro, dimethylamino-methyl, or morpholino-methyl;R16represents a hydrogen atom, methyl, chloro, C1-C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy-C1-C3-alkyl, -CH2-NR17a-CR17bR17cR17d, or a group selected from the group:R17a represents a hydrogen atom, methyl, or ethyl;R17brepresents a hydrogen atom or methyl;R17crepresents a hydrogen atom or methyl;R17drepresents a hydrogen atom, methyl, hydroxymethyl, or methoxymethyl;R18represents a hydrogen atom or methyl;R19represents a hydrogen atom or methyl;R20represents a hydrogen atom, C1-C4-alkyl, or tert-butoxycarbonyl;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 or fluoro;R28brepresents a hydrogen atom or fluoro;R29represents a hydrogen atom or methoxy;R30represents a hydrogen atom or methoxy; 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, -(CO)-C=C-R12, -(SO2)-CH=CH2, or oxirane-2-carbonyl;R4arepresents a hydrogen atom, or methyl;R4brepresents a hydrogen atom; R4crepresents a hydrogen atom, or methyl;R4drepresents a hydrogen atom;R4erepresents a hydrogen atom, or methyl;R4frepresents a hydrogen atom, methyl, C1-Cz-hydroxyalkyl, -(CO)-NR19R20, or -CH2-(CO)-NR19R20; R5arepresents a hydrogen atom, methyl, hydroxymethyl, methoxy, hydroxy, fluoro, or chloro;R5brepresents a hydrogen atom, C1-C2-alkyl, trifluoromethyl, hydroxymethyl, methoxy, cyano, fluoro, or chloro;R5crepresents a hydrogen atom, C1-C2-alkyl, ethinyl, C1-haloalkyl, C1-C2-alkoxy, C1- haloalkoxy, trifluoromethylsulfanyl, cyano, fluoro, or chloro;R5drepresents a hydrogen atom, or chloro;R5erepresents a hydrogen atom;R7arepresents a hydrogen atom;R7brepresents a hydrogen atom;R7crepresents trifluoromethyl;R7drepresents a hydrogen atom;R8arepresents a hydrogen atom, or fluoro;R8brepresents a hydrogen atom, or fluoro;R8crepresents a hydrogen atom, methoxy, trifluoromethyl, fluoro, or chloro;R8drepresents a hydrogen atom;R8erepresents a hydrogen atom;R9arepresents a hydrogen atom;R9brepresents a hydrogen atom;R9crepresents a hydrogen atom, amino, methoxy, methyl-amino, aniline, or cyclopropylformamido;R9drepresents a hydrogen atom, methyl, methoxy, or cyclopropyl;RWa represents a hydrogen atom, or fluoro;R10brepresents a hydrogen atom;RWC represents a hydrogen atom or methyl;RIOT represents a hydrogen atom, fluoro, or methyl;R11R12represents a hydrogen atom, methyl, -CH2-NR19R20, or a group selected from the group:R14represents =CHR16;R15represents a hydrogen atom, methyl, fluoro, dimethylamino-methyl, or morpholino- methyl;R16represents a hydrogen atom, methyl, chloro, Crhaloalkyl, hydroxymethyl, methoxymethyl, -CH2-NR17a-CR17bR17cR17d, or a group selected from the group:R17arepresents a hydrogen atom, methyl, or ethyl;R17brepresents a hydrogen atom or methyl;R17crepresents a hydrogen atom or methyl;R17drepresents a hydrogen atom, methyl, hydroxymethyl, or methoxymethyl;R18represents a hydrogen atom;R19represents a hydrogen atom or methyl;R20represents a hydrogen atom, methyl, or tert-butoxycarbonyl;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 or fluoro;R28brepresents a hydrogen atom or fluoro;R29represents a hydrogen atom or methoxy;R30represents a hydrogen atom or methoxy; 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 any of claims 1 or 2, which is selected from the group consisting of:1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one,1-[2-(4-chloro-3-methylphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one,1-[2-(4-chlorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2- en-1-one,1-[2-(3-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one,1-[2-(3-methoxyphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2- en-1-one,N-{4-[2-(4-fluorophenyl)-5-{(2E)-4-[methyl(propan-2-yl)amino]but-2-enoyl}-4, 5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl]pyridin-2-yl}cyclopropanecarboxamide,N-{4-[2-(4-fluorophenyl)-5-(prop-2-enoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3- yl]pyridin-2-yl}cyclopropanecarboxamide,N-(4-{5-[(2E)-4-(dimethylamino)but-2-enoyl]-2-(4-fluorophenyl)-4, 5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl}pyridin-2-yl)cyclopropanecarboxamide,N-{4-[2-(4-fluorophenyl)-5-(oxirane-2-carbonyl)-4,5,6,7-tetrahydropyrazolo[1 ,5-a]pyrazin-3- yl]pyridin-2-yl}cyclopropanecarboxamide,1-[3-(2-aminopyridin-4-yl)-2-(4-fluorophenyl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one,1-[2-(4-fluorophenyl)-3-(2-methoxypyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one,1-[2-(4-fluorophenyl)-3-(3-methoxypyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one,1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-yn-1-one,5-(ethenesulfonyl)-2-(4-fluorophenyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1 ,5- a]pyrazine,(2E)-4-(dimethylamino)-1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]but-2-en-1-one,1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]but-2-yn-1-one,2-fluoro-1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one,(2E)-1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-4-[methyl(propan-2-yl)amino]but-2-en-1-one,1-[2-(4-fluoroanilino)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one,1-[3-(2-anilinopyridin-4-yl)-2-(4-fluorophenyl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one,(2E)-1-[3-(2-anilinopyridin-4-yl)-2-(4-fluorophenyl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one,1-[2-(4-fluorophenyl)-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one,(2E)-1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]but-2-en-1-one,1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-2- methylprop-2-en-1-one,(2E)-1-[2-(4-chloro-3-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one(2E)-1-[2-(4-chloro-2-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one(2E)-1-[2-(3-chloro-4-methoxyphenyl)-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-[2-(2-methoxyphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]but-2-en-1-one(2E)-1-[2-(3,4-dichlorophenyl)-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-[2-(4-methoxyphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]but-2-en-1-one(2E)-4-(dimethylamino)-1-[2-(3-fluoro-4-methoxyphenyl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]but-2-en-1-one formic acid - (2E)-1-[2-(4-chloro-3-ethylphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one4-{5-[(2E)-4-(dimethylamino)but-2-enoyl]-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-2-yl}benzonitrile(2E)-4-(dimethylamino)-1-[3-(pyridin-4-yl)-2-[4-(trifluoromethyl)phenyl]-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]but-2-en-1-one(2E)-1-{2-[4-chloro-2-(hydroxymethyl)phenyl]-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl}-4-(dimethylamino)but-2-en-1-one1-[2-(4-chloro-3-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one1-[2-(4-chloro-2-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one1-[2-(3-chloro-4-methoxyphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one1-[2-(2-methoxyphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2- en-1-one1-[2-(3,4-dichlorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[2-(4-methoxyphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2- en-1-one1-[2-(3-fluoro-4-methoxyphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one4-[5-acryloyl-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1 ,5-a]pyrazin-2-yl]benzonitrile1-[3-(pyridin-4-yl)-2-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one3-[3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-5-(prop-2-enoyl)-4, 5,6,7- tetrahydropyrazolo[1 ,5-a]pyrazin-2-yl]benzonitrile1-[2-(3-fluoro-4-methoxyphenyl)-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[2-(4-methoxyphenyl)-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-2-[4-(trifluoromethyl)phenyl]-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[2-(4-chloro-2-fluorophenyl)-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[2-(4-chloro-2-fluorophenyl)-3-(3-methylpyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[2-(4-chloro-2-fluorophenyl)-3-(5-fluoro-1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[2-(4-chloro-2-fluorophenyl)-3-(3-fluoro-1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[2-(4-chloro-2-fluorophenyl)-3-[2-(methylamino)pyridin-4-yl]-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[3-(2-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-2-[4-(trifluoromethyl)phenyl]-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[3-(3-cyclopropylpyridin-4-yl)-2-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[3-(2,3-dimethyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-2-[4-(trifluoromethyl)phenyl]-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one(2E)-1-[2-(4-chloro-2-fluorophenyl)-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one(2E)-4-(dimethylamino)-1-[3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-2-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]but-2-en-1-one(2E)-4-(dimethylamino)-1-[2-(3-fluoro-4-methoxyphenyl)-3-(3-methyl-1 H-pyrrolo[2,3- b]pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]but-2-en-1-one(2E)-4-(dimethylamino)-1-[2-(4-methoxyphenyl)-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-6.7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]but-2-en-1-one3-{5-[(2E)-4-(dimethylamino)but-2-enoyl]-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-4.5.6.7-tetrahydropyrazolo[1 ,5-a]pyrazin-2-yl}benzonitrile2-[(dimethylamino)methyl]-1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one(2E)-1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-4-(morpholin-4-yl)but-2-en-1-one1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazoto[1 ,5-a]pyrazin-5(4H)-yl]-2-[(morpholin-4-yl)methyl]prop-2-en-1-one4-(dimethylamino)-1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]but-2-yn-1-one(2E)-1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-4- methoxybut-2-en- 1 -one(2E)-4,4,4-trifluoro-1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]but-2-en-1-one1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-4-(morpholin-4-yl)but-2-yn-1-one(2E)-4-(diethylamino)-1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]but-2-en-1-one(2E)-1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-4- hydroxybut-2-en-1-one(2E)-4-[ethyl(methyl)amino]-1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]but-2-en-1-one1-[2-(4-chloro-2-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-yn-1-one(2E)-1-[2-(4-chloro-2-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-4-fluorobut-2-en-1-one(2E)-1-[2-(4-chloro-2-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-4,4-difluorobut-2-en-1-one(2E)-3-chloro-1-[2-(4-chloro-2-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one[2-(4-chloro-2-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl](1- methyl-2,5-dihydro-1 H-pyrrol-3-yl)methanone(2E)-4-(azetidin-1-yl)-1-[2-(4-chloro-2-fluorophenyl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]but-2-en-1-one(2E)-4-fluoro-1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]but-2-en-1-one(2E)-1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-4-(pyrrolidin-1-yl)but-2-en-1-one(2E)-1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-4-(methylamino)but-2-en-1-one(2E)-4-(ethylamino)-1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]but-2-en-1-one(2E)-1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-4-(4- methylpiperazin-1-yl)but-2-en-1-one(2E)-1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-4-[(3S)-3-methoxypyrrolidin-1-yl]but-2-en-1-one(2E)-4-(3,3-difluoroazetidin-1-yl)-1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]but-2-en-1-one1-[2-(4-chloro-2-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]- 4-(morpholin-4-yl)but-2-yn-1-one tert-butyl (2RS)-2-{3-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin- 5(4H)-yl]-3-oxoprop-1-yn-1-yl}pyrrolidine-1 -carboxylate1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-3-[(2RS)- pyrrolidin-2-yl]prop-2-yn-1-one3-(1-aminocyclopropyl)-1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]prop-2-yn-1-one tert-butyl {4-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)- yl]-4-oxobut-2-yn-1-yl}carbamate4-amino-1-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)- yl]but-2-yn-1-one1-[2-(4-chloro-2-fluoroanilino)-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[2-(3-fluoro-4-methoxyanilino)-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-2-[4-(trifluoromethyl)anilino]-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[2-(4-chloro-2-fluoroanilino)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one1-[2-(3-fluoro-4-methoxyanilino)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one1-[3-(pyridin-4-yl)-2-[4-(trifluoromethyl)anilino]-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one(2E)-4-(dimethylamino)-1-[2-(4-fluorophenyl)-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]but-2-en-1-one(2E)-4-(dimethylamino)-1-[2-(2-fluoro-4-methylphenyl)-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]but-2-en-1-one3-[(6R)-5-[(2E)-4-(dimethylamino)but-2-enoyl]-6-methyl-3-(pyridin-4-yl)-4, 5,6,7- tetrahydropyrazolo[1 ,5-a]pyrazin-2-yl]benzonitrile3-[(6S)-5-[(2E)-4-(dimethylamino)but-2-enoyl]-6-methyl-3-(pyridin-4-yl)-4, 5,6,7- tetrahydropyrazolo[1 ,5-a]pyrazin-2-yl]benzonitrile1-[2-(2-fluoro-4-methylphenyl)-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one(2E)-1-[2-(4-chloro-2-fluorophenyl)-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one1-[2-(4-chloro-2-fluorophenyl)-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[2-(4-fluoro-1-benzofuran-7-yl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one1-[2-(4-fluoronaphthalen-1-yl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one1-[2-(1-benzofuran-7-yl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2- en-1-one1-[2-(3-methyl-1 H-indol-6-yl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one1-[2-(3-fluoronaphthalen-2-yl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one1-[2-(6-fluoro-1-benzofuran-5-yl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one1-[2-(1-fluoronaphthalen-2-yl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one1-[2-(2-hydroxy-4-methylphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one1-[2-(2-fluoro-4-methylphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one1-[2-(7-fluoro-1 H-indol-6-yl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one1-[2-(4-chloro-2-methylphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one1-[2-(2,4-dichlorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[2-(4-chloro-2-methoxyphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one2-chloro-5-[5-(prop-2-enoyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1 ,5-a]pyrazin-2- yl]benzonitrile2-fluoro-5-[5-(prop-2-enoyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1 ,5-a]pyrazin-2- yl]benzonitrile1-[(6R)-2-[2-fluoro-4-(trifluoromethyl)phenyl]-6-methyl-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one2-fluoro-3-[5-(prop-2-enoyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1 ,5-a]pyrazin-2- yl]benzonitrile1-{2-[3-(hydroxymethyl)phenyl]-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)- yl}prop-2-en-1-one1-[(6S)-2-(4-chlorophenyl)-6-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[(6R)-2-(4-chlorophenyl)-6-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[(6S)-2-[2-fluoro-4-(trifluoromethyl)phenyl]-6-methyl-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one3-[(6R)-6-methyl-5-(prop-2-enoyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1 ,5- a]pyrazin-2-yl]benzonitrile3-[(6S)-6-methyl-5-(prop-2-enoyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1 ,5-a]pyrazin-2-yl]benzonitrile1-{2-[4-(difluoromethoxy)phenyl]-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)- yl}prop-2-en-1-one1-[3-(pyridin-4-yl)-2-[4-(trifluoromethoxy)phenyl]-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one1-[2-(4-ethoxyphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2- en-1-one1-{2-[4-(difluoromethyl)phenyl]-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl}prop-2-en-1-one1-[2-(5-chloro-2-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one1-[2-(3-chlorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2- en-1-one1-{2-[3-fluoro-4-(trifluoromethyl)phenyl]-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl}prop-2-en-1-one1-{2-[2-fluoro-4-(trifluoromethyl)phenyl]-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl}prop-2-en-1-one1-[2-(2-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[2-(2-chlorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2- en-1-one1-[2-(4-methylphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2- en-1-one1-[2-(3-methylphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2- en-1-one1-[2-(4-ethylphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one3-[5-(prop-2-enoyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2- yl]benzonitrile1-[2-(2-fluoro-4-methoxyphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one1-[3-(pyridin-4-yl)-2-{4-[(trifluoromethyl)sulfanyl]phenyl}-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one(2E)-1-{2-[4-(difluoromethoxy)phenyl]-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-[3-(pyridin-4-yl)-2-[4-(trifluoromethoxy)phenyl]-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]but-2-en-1-one(2E)-4-(dimethylamino)-1-[2-(4-ethynylphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]but-2-en-1-one(2E)-4-(dimethylamino)-1-[2-(4-ethoxyphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]but-2-en-1-one(2E)-1-{2-[4-(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-[2-(5-chloro-2-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one(2E)-1-[2-(3-chlorophenyl)-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-{2-[3-fluoro-4-(trifluoromethyl)phenyl]-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl}but-2-en-1-one(2E)-4-(dimethylamino)-1-{2-[2-fluoro-4-(trifluoromethyl)phenyl]-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl}but-2-en-1-one(2E)-4-(dimethylamino)-1-[2-(2-fluorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]but-2-en-1-one(2E)-1-[2-(2-chlorophenyl)-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-[2-(3-methoxyphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]but-2-en-1-one(2E)-4-(dimethylamino)-1-[2-(4-methylphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]but-2-en-1-one(2E)-4-(dimethylamino)-1-[2-(3-methylphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]but-2-en-1-one(2E)-4-(dimethylamino)-1-[2-(4-ethylphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]but-2-en-1-one3-{5-[(2E)-4-(dimethylamino)but-2-enoyl]-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-2-yl}benzonitrile(2E)-4-(dimethylamino)-1-[2-(2-fluoro-4-methoxyphenyl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]but-2-en-1-one(2E)-4-(dimethylamino)-1-[3-(pyridin-4-yl)-2-{4-[(trifluoromethyl)sulfanyl]phenyl}-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]but-2-en-1-one(2E)-4-(azetidin-1-yl)-1-[2-(4-chlorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]but-2-en-1-one(2E)-1-[2-(4-chlorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(piperidin-1-yl)but-2-en-1-one(2E)-1-[2-(4-chlorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(4-methylpiperazin-1 -yl)but-2-en- 1 -one(E)-1-(2-(4-chlorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)-4- morpholinobut-2-en-1-one(2E)-1-[2-(4-chlorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-[isopropyl(methyl)amino]but-2-en-1-one(2E)-4-(tert-butylamino)-1-[2-(4-chlorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]but-2-en-1-one(2E)-1-[2-(4-chlorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(4-methoxypiperidin-1-yl)but-2-en-1-one(2E)-1-[2-(4-chlorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-[(2-methoxyethyl)(methyl)amino]but-2-en-1-one(2E)-1 -[2-(4-chlorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-4-[(2-hydroxyethyl)(methyl)amino]but-2-en-1 -one(2E)-1 -[2-(4-chlorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H )-y l]-4-(pyrrol id in-1 -yl)but-2-en-1 -one(2E)-1-[2-(4-chlorophenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-4-(3-fluoroazetidin- 1 -yl)but-2-en- 1 -one1-[2-(4-fluorophenyl)-3-(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one1-(2-(2-fluoro-4-(trifluoromethyl)phenyl)-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl)prop-2-en-1-one1-[2-(4-chlorophenyl)-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[2-(3-chloro-2-fluorophenyl)-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[2-(3-chlorophenyl)-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one1-(3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-2-(3-(trifluoromethyl)phenyl)-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl)prop-2-en-1-one1-[2-(2-chlorophenyl)-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[2-(5-chloro-2-fluorophenyl)-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[2-(2-fluoro-1-benzothiophen-6-yl)-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one4-[3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-5-(prop-2-enoyl)-4, 5,6,7- tetrahydropyrazolo[1 ,5-a]pyrazin-2-yl]benzonitrile(2E)-1-[2-(4-chlorophenyl)-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one(2E)-1-[2-(3-chlorophenyl)-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one(E)-4-(dimethylamino)-1-(3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-2-(3-(trifluoromethyl)phenyl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl)but-2-en-1-one(2E)-1-[2-(1-benzofuran-7-yl)-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl) -6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one formic acid(2E)-4-(dimethylamino)-1-[2-(2-fluoro-1-benzothiophen-6-yl)-3-(3-methyl-1 H-pyrrolo[2,3- b]pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]but-2-en-1-one1-[3-(pyridin-4-yl)-2-[6-(trifluoromethyl)pyridin-3-yl]-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[2-phenyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[2-(4-chloro-3-ethylphenyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one1-{2-[4-chloro-2-(hydroxymethyl)phenyl]-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl}prop-2-en-1-one1-[2-(1-benzothiophen-5-yl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one1-[2-(1 H-indol-5-yl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[2-(1-benzofuran-5-yl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]prop-2- en-1-one1-[2-(1 H-indol-6-yl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one(2E)-1-[2-(1-benzothiophen-5-yl)-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-[2-(1H-indol-5-yl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]but-2-en-1-one(2E)-1-[2-(1H-benzotriazol-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-[2-(1-benzofuran-5-yl)-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-[2-(1 H-indol-6-yl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]but-2-en-1-one rac-(R,E)-4-(dimethylamino)-1-(2-(4-fluorophenyl)-7-(hydroxymethyl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)but-2-en-1-one(7RS)-5-[(2E)-4-(dimethylamino)but-2-enoyl]-2-(4-fluorophenyl)-3-(pyridin-4-yl)-4, 5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-7-carboxamide1-[(7RS)-2-(4-fluorophenyl)-7-(hydroxymethyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one(7RS)-5-acryloyl-2-(4-fluorophenyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1 ,5- a]pyrazine-7-carboxamide5-acryloyl-2-(4-fluorophenyl)-N-methyl-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1 ,5- a]pyrazine-7-carboxamide5-acryloyl-2-(4-fluorophenyl)-N,N-dimethyl-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-7-carboxamide1-[2-(4-fluorophenyl)-7,7-dimethyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[2-(4-chloro-3-methylphenyl)-7,7-dimethyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[2-(4-chlorophenyl)-7,7-dimethyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[2-(4-fluorophenyl)-6,6-dimethyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[2-(4-chlorophenyl)-6,6-dimethyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[2-(4-chloro-3-methylphenyl)-6,6-dimethyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one(2E)-4-(dimethylamino)-1-[2-(4-fluorophenyl)-7,7-dimethyl-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]but-2-en-1-one(2E)-1-[2-(4-chloro-3-methylphenyl)-7,7-dimethyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one1-[(2E)-4-(dimethylamino)but-2-enoyl]-3'-phenyl-2'-(pyridin-4-yl)-5',6'- dihydrospiro[piperidine-4,7'-pyrrolo[3,2-c]pyridin]-4'(TH)-one(2E)-4-(dimethylamino)-1-[2-(4-fluorophenyl)-6,6-dimethyl-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]but-2-en-1-one(2E)-1-[2-(4-chlorophenyl)-6,6-dimethyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one(2E)-1-[2-(4-chloro-3-methylphenyl)-6,6-dimethyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one rac-(R,E)-4-(dimethylamino)-1-(2-(4-fluorophenyl)-7-(2-hydroxyethyl)-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl)but-2-en-1-one2-[(7RS)-5-[(2E)-4-(dimethylamino)but-2-enoyl]-2-(4-fluorophenyl)-3-(pyridin-4-yl)-4, 5,6,7- tetrahydropyrazolo[1 ,5-a]pyrazin-7-yl]acetamide2-[(7RS)-5-[(2E)-4-(dimethylamino)but-2-enoyl]-2-(4-fluorophenyl)-3-(pyridin-4-yl)-4, 5,6,7- tetrahydropyrazolo[1 ,5-a]pyrazin-7-yl]-N-methylacetamide2-[(7RS)-5-[(2E)-4-(dimethylamino)but-2-enoyl]-2-(4-fluorophenyl)-3-(pyridin-4-yl)-4, 5,6,7- tetrahydropyrazolo[1 ,5-a]pyrazin-7-yl]-N,N-dimethylacetamide1-(2-(4-fluorophenyl)-7-(2-hydroxyethyl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl)prop-2-en-1-one2-(5-acryloyl-2-(4-fluorophenyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1 ,5-a]pyrazin-7- yl)acetamide2-(5-acryloyl-2-(4-fluorophenyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1 ,5-a]pyrazin-7- yl)-N-methylacetamide2-(5-acryloyl-2-(4-fluorophenyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1 ,5-a]pyrazin-7- yl)-N,N-dimethylacetamide1-(2-(4-chloro-2-fluorophenyl)-6-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl)prop-2-en-1-one1-[(6RS)-2-(4-methoxyphenyl)-6-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[(RS)-2-(2-fluoro-1-benzothiophen-6-yl)-6-methyl-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[(6RS)-2-[2-fluoro-4-(trifluoromethyl)phenyl]-6-methyl-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[(RS)-2-(2-fluoro-4-methoxyphenyl)-6-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[(RS)-6-methyl-2-(naphthalen-2-yl)-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[(RS)-2-(2-chloro-1-benzothiophen-6-yl)-6-methyl-3-(pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[(6RS)-2-(1-benzothiophen-6-yl)-6-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one(2E)-1-[(RS)-2-(4-chloro-2-fluorophenyl)-6-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one(2E)-1-[(RS)-2-(1-benzothiophen-6-yl)-6-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one1-[(RS)-2-(4-chloro-2-fluorophenyl)-6-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]-2-fluoroprop-2-en-1-one1-[(RS)-2-(1-benzothiophen-6-yl)-6-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]-2-fluoroprop-2-en-1-one1-[(RS)-2-(4-fluorophenyl)-4-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[(RS)-2-(4-chloro-2-fluorophenyl)-4-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[(RS)-2-(4-methoxyphenyl)-4-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[(RS)-2-(1-benzothiophen-5-yl)-4-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[(RS)-2-(1 H-indol-6-yl)-4-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one(2E)-1-[(RS)-2-(4-chloro-2-fluorophenyl)-4-methyl-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-chlorophenyl)-6-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one(2E)-1-[(6R)-2-(4-chlorophenyl)-6-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one1-(4-methyl-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)-2-(4-(trifluoromethyl)phenyl)-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl)prop-2-en-1-one1-[(6S)-6-methyl-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-2-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one1-(2-(4-fluorophenyl)-4-methyl-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl)prop-2-en-1-one1-(2-(4-fluorophenyl)-4-methyl-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl)prop-2-en-1-one1-[(6S)-2-(4-fluorophenyl)-6-methyl-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one4-(dimethylamino)-1-[4-methyl-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)-2-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]but-2-en-1-one4-(dimethylamino)-1-(4-methyl-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-2-(4-(trifluoromethyl)phenyl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl)but-2-en-1-one(2E)-4-(dimethylamino)-1-[(6S)-6-methyl-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-2-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]but-2-en-1-one4-(dimethylamino)-1-[2-(4-fluorophenyl)-4-methyl-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]but-2-en-1-one(E)-4-(dimethylamino)-1-(2-(4-fluorophenyl)-4-methyl-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl)but-2-en-1-one(2E)-4-(dimethylamino)-1-[(6S)-2-(4-fluorophenyl)-6-methyl-3-(3-methyl-1 H-pyrrolo[2,3- b]pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]but-2-en-1-one1-(4-methyl-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)-2-(4-(trifluoromethyl)phenyl)-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl)prop-2-en-1-one1-(4-methyl-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-2-(4-(trifluoromethyl)phenyl)-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl)prop-2-en-1-one1-[(6R)-6-methyl-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-2-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one1-(2-(4-fluorophenyl)-4-methyl-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl)prop-2-en-1-one1-(2-(4-fluorophenyl)-4-methyl-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl)prop-2-en-1-one1-[(6R)-2-(4-fluorophenyl)-6-methyl-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one(E)-4-(dimethylamino)-1-(4-methyl-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)-2-(4-(trifluoromethyl)phenyl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl)but-2-en-1-one(E)-4-(dimethylamino)-1-(4-methyl-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-2-(4-(trifluoromethyl)phenyl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl)but-2-en-1-one(2E)-4-(dimethylamino)-1-[(6R)-6-methyl-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-2-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]but-2-en-1-one(E)-4-(dimethylamino)-1-(2-(4-fluorophenyl)-4-methyl-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)-6,7- dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl)but-2-en-1-one(E)-4-(dimethylamino)-1-(2-(4-fluorophenyl)-4-methyl-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin- 4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl)but-2-en-1-one(2E)-4-(dimethylamino)-1-[(6R)-2-(4-fluorophenyl)-6-methyl-3-(3-methyl-1 H-pyrrolo[2,3- b]pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]but-2-en-1-one1-[(6S)-2-(4-chloro-2-fluorophenyl)-6-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[(6R)-2-(4-chloro-2-fluorophenyl)-6-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[2-anilino-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one(2E)-1-[2-anilino-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-4- (dimethylamino)but-2-en-1-one1-[2-(4-methoxyphenyl)-7-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)- yl]prop-2-en-1-one1-[(6S)-2-(1-benzothiophen-5-yl)-6-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[(6R)-2-(1-benzothiophen-5-yl)-6-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[2-(4-chloro-2-fluorophenyl)-4-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[(7RS)-2-(1-benzothiophen-5-yl)-7-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[(7RS)-2-(4-chlorophenyl)-7-methyl-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-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1 ,5-a]pyrazin-5(4H)-yl]prop-2-en-1-one3-[(6S)-6-methyl-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-5-(prop-2-enoyl)-4, 5,6,7- tetrahydropyrazolo[1 ,5-a]pyrazin-2-yl]benzonitrile3-[(6R)-6-methyl-3-(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-5-(prop-2-enoyl)-4, 5,6,7- tetrahydropyrazolo[1 ,5-a]pyrazin-2-yl]benzonitrile(2E)-1-[(2-(4-chloro-2-fluorophenyl)-4-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one(2E)-1-[2-(4-chloro-2-fluorophenyl)-7-methyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]-4-(dimethylamino)but-2-en-1-one3-[(6S)-5-[(2E)-4-(dimethylamino)but-2-enoyl]-6-methyl-3-(3-methyl-1 H-pyrrolo[2,3- b]pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1 ,5-a]pyrazin-2-yl]benzonitrile3-[(6R)-5-[(2E)-4-(dimethylamino)but-2-enoyl]-6-methyl-3-(3-methyl-1 H-pyrrolo[2,3- b]pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]benzonitrile1-[(6R)-2-(4-chloro-2-fluorophenyl)-4,6-dimethyl-3-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl]prop-2-en-1-one1-[(6S)-2-(4-chloro-2-fluorophenyl)-4,6-dimethyl-3-(pyridin-4-yl)-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.

4. Use of a compound of formula (I) according to any of claims 1 to 3 for the treatment or prophylaxis of diseases.

5. Use of a compound of formula (I) according to claim 4, wherein the diseases are hyperproliferative diseases and / or disorders responsive to induction of cell death.

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

7. Use of a compound of formula (I) according to claim 6, wherein the tumour harbors a mutant EGFR and / or metastases thereof.

8. Use of a compound of formula (I) according to claim 6, wherein the tumour is lung cancer, particularly lung cancer harboring a mutant EGFR with exon 20 insertion mutation, and / or metastases thereof.

9. Use of a compound of formula (I) according to claim 6, wherein the tumour is lung cancer, particularly lung cancer harboring a mutant EGFR with in-frame deletions in exon19 (such as EGFR E746_A750del) or point mutations in exon 21 (e.g. L858R), and / or metastases thereof.

10. Use of a compound of formula (I) according to claim 6, 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.

11. Use of a compound of formula (I) according to claim 6, 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.

12. Use of a compound of formula (I) according to claim 6, 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.

13. Use of a compound of formula (I) according to claim 6, 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.

14. A pharmaceutical composition comprising at least one compound of formula (I) according to any of claims 1 to 3, together with at least one pharmaceutically acceptable auxiliary.

15. A composition according to claim 14 for the treatment of haematological tumours, solid tumours and / or metastases thereof.

16. A combination comprising one or more first active ingredients selected from a compound of formula (I) according to any of claims 1 to 3, and one or more second active ingredients selected from chemotherapeutic anti-cancer agents and target-specific anti- cancer agents.

17. 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 3.

18. The method of claim 17, wherein the cancer cell is in vitro or in vivo.

19. 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 3.

20. The method of any one of claims 17 to 19, wherein the EGF-receptor comprises a mutation in exon 20.

21. The method of any one of claims 17 to 20, 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.

22. The method of claim 21 , 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.

23. 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 3.

24. 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 3.

25. 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 3.

26. The method of any one of claims 23 to 25, 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.

27. The method of claim 26, wherein the cancer is selected from the group consisting of inverted sinonasal papilloma or inverted sinonasal papilloma associated sinanonasal squamous cell carcinoma.

28. The method of claim 26, wherein the tumour of the thorax is non-small cell lung cancer.

29. The method of any one of claims 17 to 28, wherein the EGF-receptor comprises a mutation.

30. The method of claim 29, wherein the EGF-receptor comprises a mutation in exon 20.

31. The method of claim 30, wherein the EGF-receptor comprises an insertion in exon 20.

32. The method of claim 31, wherein the EGF-receptor comprises an insertion between amino acids V769-D770 and / or between D770-N771.

33. The method of claim 32, wherein the insertion is an ASV and / or SVD insertion.

34. The method of claim 31 , wherein the EGF-receptor comprising an ASV insertion between amino acids V769-D770 and / or a SVD insertion between amino acids D770- N771.

35. A method of selecting a patient for cancer treatment with a compound of formula (I) according to any of claims 1 to 3, 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.

36. 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 3, 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.

37. The method of claim 35 or 36, wherein the EGF-receptor comprises an insertion in exon 20.

38. The method of claim 37, wherein the EGF-receptor comprises an insertion between amino acids V769-D770 and / or between amino acids D770-N771.

39. The method of claim 38, wherein the insertion is an ASV and / or SVD insertion.

40. The method of claim 37, wherein the EGF-receptor comprising an ASV insertion between amino acids V769-D770 and / or a SVD insertion between amino acids D770- N771.

41. The method of any one of claims 17-19, 23-25, and 35-36, 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.

42. The method of any one of claims 17-19, 23-25, and 35-36, 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.

43. The method of any one of claims 17-19, 23-25, and 35-36, 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.

Images