Heteroaromatic derivatives as NIK inhibitors

FIELD OF THE INVENTION

The present invention relates to pharmaceutical agents useful for therapy and/or prophylaxis in a mammal, and in particular to inhibitors of NF-κB-inducing kinase (NIK—also known as MAP3K14) useful for treating diseases such as cancer (in particular B-cell malignancies including leukemias, lymphomas and myeloma), inflammatory disorders, metabolic disorders including obesity and diabetes, and autoimmune disorders. The invention is also directed to pharmaceutical compositions comprising such compounds, and to the use of such compounds or pharmaceutical compositions for the prevention or treatment of diseases such as cancer, inflammatory disorders, metabolic disorders including obesity and diabetes, and autoimmune disorders.

BACKGROUND OF THE INVENTION

The present invention relates to pharmaceutical agents useful for therapy and/or prophylaxis in a mammal, and in particular to inhibitors of NF-κB-inducing kinase (NIK—also known as MAP3K14) useful for treating diseases such as cancer and inflammatory disorders. Nuclear factor-kappa B (NF-κB) is a transcription factor regulating the expression of various genes involved in the immune response, cell proliferation, adhesion, apoptosis, and carcinogenesis. NF-κB dependent transcriptional activation is a tightly controlled signaling pathway, through sequential events including phosphorylation and protein degradation. NIK is a serine/threonine kinase which regulates NF-κB pathway activation. There are two NF-κB signaling pathways, the canonical and the non-canonical. NIK is indispensable for the non-canonical signaling pathway where it phosphorylates IKKα, leading to the partial proteolysis of p100; liberating p52 which then heterodimerizes with RelB, translocates to the nucleus and mediates gene expression. The non-canonical pathway is activated by only a handful of ligands such as CD40 ligands, B-cell activating factor (BAFF), lymphotoxin β receptor ligands and TNF-related weak inducer of apoptosis (TWEAK) and NIK has been shown to be required for activation of the pathway by these ligands. Because of its key role, NIK expression is tightly regulated. Under normal non-stimulated conditions NIK protein levels are very low, this is due to its interaction with a range of TNF receptor associated factors (TRAF2 and TRAF3), which are ubiquitin ligases and result in degradation of NIK. It is believed that when the non-canonical pathway is stimulated by ligands, the activated receptors now compete for TRAFs, dissociating the TRAF-NIK complexes and thereby increasing the levels of NIK. (Thu and Richmond, Cytokine Growth F. R. 2010, 21, 213-226)

Research has shown that blocking the NF-κB signaling pathway in cancer cells can cause cells to stop proliferating, to die and to become more sensitive to the action of other anti-cancer therapies. A role for NIK has been shown in the pathogenesis of both hematological malignancies and solid tumours.

The NF-κB pathway is dysregulated in multiple myeloma due to a range of diverse genetic abnormalities that lead to the engagement of the canonical and non-canonical pathways (Annuziata et al. Cancer Cell 2007, 12, 115-130; Keats et al. Cancer Cell 2007, 12, 131-144; Demchenko et al. Blood 2010, 115, 3541-3552). Myeloma patient samples frequently have increased levels of NIK activity. This can be due to chromosomal amplification, translocations (that result in NIK proteins that have lost TRAF binding domains), mutations (in the TRAF binding domain of NIK) or TRAF loss of function mutations. Researchers have shown that myeloma cell lines can be dependent on NIK for proliferation; in these cell lines if NIK activity is reduced by either shRNA or compound inhibition, this leads to a failure in NF-κB signaling and the induction of cell death (Annuziata 2007).

In a similar manner, mutations in TRAF and increased levels of NIK have also been seen in samples from Hodgkin lymphoma (HL) patients. Once again proliferation of cell lines derived from HL patients is susceptible to inhibition of NIK function by both shRNA and compounds (Ranuncolo et al. Blood First Edition Paper, 2012, DOI 10.1182/blood-2012-01-405951).

NIK levels are also enhanced in adult T cell leukemia (ATL) cells and targeting NIK with shRNA reduced ATL growth in vivo (Saitoh et al. Blood 2008, 111, 5118-5129). It has been demonstrated that the API2-MALT 1 fusion oncoprotein created by the recurrent translocation t(11; 18)(q21; q21) in mucosa-associated lymphoid tissue (MALT) lymphoma induces proteolytic cleavage of NF-κB-inducing kinase (NIK) at arginine 325. NIK cleavage generates a C-terminal NIK fragment that retains kinase activity and is resistant to proteasomal degradation (due to loss of TRAF binding region). The presence of this truncated NIK leads to constitutive non-canonical NF-κB signaling, enhanced B cell adhesion, and apoptosis resistance. Thus NIK inhibitors could represent a new treatment approach for refractory t(11; 18)-positive MALT lymphoma (Rosebeck et al. Science 2011, 331, 468-472).

NIK aberrantly accumulates in diffuse large B-cell lymphoma (DLBCL) cells due to constitutive activation of B-cell activation factor (BAFF) through interaction with autochthonous B-lymphocyte stimulator (BLyS) ligand. NIK accumulation in human DLBCL cell lines and patient tumor samples suggested that constitutive NIK kinase activation is likely to be a key signaling mechanism involved in abnormal lymphoma tumor cell proliferation. Growth assays showed that using shRNA to inhibit NIK kinase protein expression in GCB- and ABC-like DLBCL cells decreased lymphoma cell growth in vitro, implicating NIK-induced NF-κB pathway activation as having a significant role in DLBCL proliferation (Pham et al. Blood 2011, 117, 200-210). More recently, also loss-of-function mutations in TRAF3 have been characterized in human and canine DLBCL (Bushell et al., Blood 2015, 125, 999-1005).

Recently, similar mutations in the non-canonical NFkB signaling pathway (TRAF2, TRAF3, NIK, BIRC3) were found in ibrutinib-refractory mantle cell lymphoma cell lines (Rahal et al., Nat Med 2014, 1, 87-92).

As mentioned a role of NIK in tumour cell proliferation is not restricted to hematological cells, there are reports that NIK protein levels are stabilised in some pancreatic cancer cell lines and as seen in blood cells proliferation of these pancreatic cancer lines are susceptible to NIK siRNA treatment (Nishina et al. Biochem. Bioph. Res. Co. 2009, 388, 96-101). Constitutive activation of NF-κB, is preferentially involved in the proliferation of basal-like subtype breast cancer cell lines, including elevated NIK protein levels in specific lines (Yamamoto et al. Cancer Sci. 2010, 101, 2391-2397). In melanoma tumours, tissue microarray analysis of NIK expression revealed that there was a statistically significant elevation in NIK expression when compared with benign tissue. Moreover, shRNA techniques were used to knock-down NIK, the resultant NIK-depleted melanoma cell lines exhibited decreased proliferation, increased apoptosis, delayed cell cycle progression and reduced tumor growth in a mouse xenograft model (Thu et al. Oncogene 2012, 31(20), 2580-92). A wealth of evidence showed that NF-κB is often constitutively activated in non-small cell lung cancer tissue specimens and cell lines. Depletion of NIK by RNAi induced apoptosis and affected efficiency of anchorage-independent NSCLC cell growth.

In addition research has shown that NF-κB controls the expression of many genes involved in inflammation and that NF-κB signaling is found to be chronically active in many inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease, sepsis and others. Thus pharmaceutical agents capable of inhibiting NIK and thereby reducing NF-κB signaling pathway can have a therapeutic benefit for the treatment of diseases and disorders for which over-activation of NF-κB signaling is observed.

Dysregulated NF-κB activity is associated with colonic inflammation and cancer, and it has been shown that Nlrp12 deficient mice were highly susceptible to colitis and colitis-associated colon cancer. In this context work showed that NLRP12 functions as a negative regulator of the NF-κB pathway through its interaction and regulation of NIK and TRAF3, and as a checkpoint of critical pathways associated with inflammation and inflammation-associated tumorigenesis (Allen et al. Immunity 2012, 36, 742-754).

Tumor necrosis factor (TNF)-α, is secreted in response to inflammatory stimuli in diseases such as rheumatoid arthritis and inflammatory bowel disease. In a series of experiments in colonic epithelial cells and mouse embryonic fibroblasts, TNF-α mediates both apoptosis and inflammation, stimulating an inflammatory cascade through the non-canonical pathway of NF-κB activation, leading to increased nuclear RelB and p52. TNF-α induced the ubiquitination of TRAFs, which interacts with NIK, leading to increased levels of phospho-NIK (Bhattacharyya et al. J Biol. Chem. 2011, 285, 39511-39522).

Inflammatory responses are a key component of chronic obstructive pulmonary disease (COPD) as such it has been shown that NIK plays a key role in exacerbating the disease following infection with the Gram-negative bacterium nontypeable Hemophilus influenza (Shuto et al. PNAS 2001, 98, 8774-8779). Likewise cigarette smoke (CS) contains numerous reactive oxygen/nitrogen species, reactive aldehydes, and quinones, which are considered to be some of the most important causes of the pathogenesis of chronic inflammatory lung diseases, such as COPD and lung cancer. Increased levels of NIK and p-IKKα have been observed in peripheral lungs of smokers and patients with COPD. In addition it has been shown that endogenous NIK is recruited to promoter sites of pro-inflammatory genes to induce post-translational modification of histones, thereby modifying gene expression profiles, in response to CS or TNFα (Chung et al. PLoS ONE 2011, 6(8): e23488. doi:10.1371/joumal.pone.0023488). A shRNA screen was used in an in vitro model of oxidative stress induced cell death (as a model of COPD) to interrogate a human drugable genome siRNA library in order to identify genes that modulate the cellular response to stress. NIK was one of the genes identified in this screen as a potential new therapeutic target to modulate epithelial apoptosis in chronic lung diseases (Wixted et al. Toxicol. In Vitro 2010, 24, 310-318).

Diabetic individuals can be troubled by a range of additional manifestations associated with inflammation. One such complication is cardiovascular disease and it has been shown that there are elevated levels of p-NIK, p-IKK-α/β and p-IκB-α in diabetic aortic tissues (Bitar et al. Life Sci. 2010, 86, 844-853). In a similar manner, NIK has been shown to regulate proinflammatory responses of renal proximal tubular epithelial cells via mechanisms involving TRAF3. This suggests a role for NF-κB noncanonical pathway activation in modulating diabetes-induced inflammation in renal tubular epithelium (Zhao et al. Exp. Diabetes Res. 2011, 1-9. doi: 10.1155/2011/192564). The same group has shown that NIK plays a critical role in noncanonical NF-κB pathway activation, induced skeletal muscle insulin resistance in vitro, suggesting that NIK could be an important therapeutic target for the treatment of insulin resistance associated with inflammation in obesity and type 2 diabetes (Choudhary et al. Endocrinology 2011, 152, 3622-3627).

NF-κB is an important component of both autoimmunity and bone destruction in rheumatoid arthritis (RA). Mice lacking functional NIK have no peripheral lymph nodes, defective B and T cells, and impaired receptor activator of NF-κB ligand-stimulated osteoclastogenesis. Aya et al. (J. Clin. Invest. 2005, 115, 1848-1854) investigated the role of NIK in murine models of inflammatory arthritis using Nik−/− mice. The serum transfer arthritis model was initiated by preformed antibodies and required only intact neutrophil and complement systems in recipients. While Nik−/− mice had inflammation equivalent to that of Nik+/+ controls, they showed significantly less periarticular osteoclastogenesis and less bone erosion. In contrast, Nik−/− mice were completely resistant to antigen-induced arthritis (AIA), which requires intact antigen presentation and lymphocyte function but not lymph nodes. Additionally, transfer of Nik+/+ splenocytes or T cells to Rag2−/− mice conferred susceptibility to AIA, while transfer of Nik−/− cells did not. Nik−/− mice were also resistant to a genetic, spontaneous form of arthritis, generated in mice expressing both the KRN T cell receptor and H-2 g7. The same group used transgenic mice with OC-lineage expression of NIK lacking its TRAF3 binding domain (NT3), to demonstrate that constitutive activation of NIK drives enhanced osteoclastogenesis and bone resorption, both in basal conditions and in response to inflammatory stimuli (Yang et al. PLoS ONE 2010, 5(11): e15383. doi:10.1371/joumal.pone.0015383). Thus this group concluded that NIK is important in the immune and bone-destructive components of inflammatory arthritis and represents a possible therapeutic target for these diseases.

It has also been hypothesized that manipulating levels of NIK in T cells may have therapeutic value. Decreasing NIK activity in T cells might significantly ameliorate autoimmune responses and alloresponses, like GVHD (Graft Versus Host Disease) and transplant rejection, without crippling the immune system as severely as do inhibitors of canonical NF-κB activation.

WO2003030909 describes the preparation of 2- and 4-aminopyrimidines N-substituted by a bicyclic ring for use as kinase inhibitors in the treatment of cancer.

WO2002079197 describes 4-aryl-substituted 2-pyrimidinamines and 2-pyridinamines, useful as inhibitors of c-Jun N-terminal kinases (JNK) and other protein kinases.

DESCRIPTION OF THE INVENTION

The present invention concerns novel compounds of Formula (I):

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tautomers and stereoisomeric forms thereof, wherein

R¹represents C_1-4alkyl;

R²represents C_1-6alkyl, C_1-6alkyl substituted with one R⁵, or C_1-6alkyl substituted with one, two or three fluoro atoms;

Y represents CR⁴or N;

R⁴represents hydrogen or halo;

R⁵represents Het^3a, —NR^6aR^6b, or —OR⁷;

R^6arepresents hydrogen or C_1-4alkyl;

R^6brepresents hydrogen; C_1-4alkyl; C_3-6cycloalkyl; —C(═O)—C_1-4alkyl; —C(═O)—Het⁴; —S(═O)₂—C_1-4alkyl; —C(═O)—C_1-4alkyl substituted with one substituent selected from the group consisting of —OH and —NR^16aR^6b; or C_1-4alkyl substituted with one substituent selected from the group consisting of —OH and —S(═O)₂—C_1-4alkyl;

R⁷represents hydrogen, C_1-4alkyl, —C_1-4akyl-NR^8aR^8b, —C(═O)—R⁹, —S(═O)₂—OH, —P(═O)₂—OH, —(C═O)—CH(NH₂)—C_1-4alkyl-Ar¹, or —C_1-4alkyl-Het^3b;

R^8arepresents hydrogen or C_1-4alkyl;

R^8brepresents hydrogen, C_1-4alkyl, or C_3-6cycloalkyl;

R⁹represents C_1-6alkyl, or C_1-6alkyl substituted with one substituent selected from the group consisting of —NH₂, —COOH, and Het⁶;

R^16aand R^16beach independently represents hydrogen, C_1-4alkyl or C_3-6cycloalkyl;

R³represents a 5-membered heteroaromatic ring containing one, two or three heteroatoms each independently selected from O, S, and N;

wherein said 5-membered heteroaromatic ring may optionally be substituted, where possible, on one ring N-atom with a substituent selected from the group consisting of C_1-6alkyl; C_3-6cycloalkyl; Het^1a; R¹⁸; R²¹; C_1-4alkyl substituted with one, two or three halo atoms; C_1-5alkyl substituted with one, two or three —OH substituents; C_1-6alkyl substituted with one R¹³; —C₄alkyl-O—C_1-4alkyl substituted with one or two —OH substituents; C_1-4alkyl substituted with one R¹⁸; C_2-6alkenyl; and C_2-6alkenyl substituted with one R¹³; provided that when Het^1aor R¹⁸are directly attached to the N-atom of the 5-membered heteroaromatic ring, said Het^1aor R¹⁸are attached to the N-atom via a ring carbon atom; and

wherein said 5-membered heteroaromatic ring may optionally be substituted on the ring carbon atoms with in total one or two substituents each independently selected from the group consisting of halo; cyano; C_1-6alkyl; —O—C_1-4alkyl; —C(═O)—R¹⁰; —S(═O)₂—C_1-4alkyl; —S(═O)(═N—R^20a)—C_1-4alkyl; —O—C_1-4alkyl substituted with one, two or three halo atoms; —O—C_1-4alkyl-R¹²; C_3-6cycloalkyl; —O—C_3-6cycloalkyl; Het^1a; —O-Het^1b; R¹⁸; R²¹; —P(═O)—(C_1-4alkyl)₂; —NH—C(═O)—C_1-4alkyl; —NH—C(═O)—Het^1g; —NR^17aR^17b; C_1-4alkyl substituted with one, two or three halo atoms; C_1-4alkyl substituted with one, two or three —OH substituents; C_1-6alkyl substituted with one R¹³; C_1-4alkyl substituted with one R¹⁸; C_2-6alkenyl; and C_2-6alkenyl substituted with one R¹³;

R¹⁰represents —OH, —O—C_1-4alkyl, —NR^11aR^11bor Het²;

R¹⁸represents a 5-membered aromatic ring containing one, two or three N-atoms; wherein said 5-membered aromatic ring may optionally be substituted with one substituent selected from the group consisting of C_1-4alkyl and C_3-6cycloalkyl;

R²¹represents 3,6-dihydro-2H-pyran-4-yl or 1,2,3,6-tetrahydro-4-pyridinyl, wherein 1,2,3,6-tetrahydro-4-pyridinyl may optionally be substituted on the N-atom with C_1-4alkyl or C_3-6cycloalkyl;

Het^1a, Het^1cand Het^1deach independently represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O, S, S(═O)_pand N; or a 6- to 11-membered bicyclic saturated heterocyclyl, including fused, spiro and bridged cycles, containing one, two or three heteroatoms each independently selected from O, S, S(═O)_pand N;

wherein said 4- to 7-membered monocyclic saturated heterocyclyl or said 6- to 11-membered bicyclic saturated heterocyclyl may optionally be substituted, where possible, on one, two or three ring N-atoms with a substituent each independently selected from the group consisting of C_1-4alkyl, C_3-6cycloalkyl, C_1-4alkyl substituted with one, two or three halo atoms, and C_1-4alkyl substituted with one substituent selected from the group consisting of —OH, —C(═O)—OH, —C(═O)—NR^22aR^22band —O—C_1-4alkyl; and

wherein said 4- to 7-membered monocyclic saturated heterocyclyl or said 6- to 11-membered bicyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of —OH, oxo, halo, C_1-4alkyl, cyano, —C(═O)—C_1-4alkyl, —O—C_1-4alkyl, —NH₂, —NH(C_1-4alkyl), and —N(C_1-4alkyl)₂;

Het^1b, Het^1e, Het^1gand Het⁴each independently represents a 4- to 7-membered monocyclic saturated heterocyclyl, attached to the remainder of the molecule of Formula (I) through any available ring carbon atom, said Het^1b, Het^1e, Het^1gand Het⁴containing one or two heteroatoms each independently selected from O, S, S(═O)_pand N;

wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with a substituent each independently selected from the group consisting of C_1-4alkyl, C_3-6cycloalkyl, and C_1-4alkyl substituted with one substituent selected from the group consisting of —OH and —O—C_1-4alkyl; and

wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of —OH, halo, C_1-4alkyl, cyano, —C(═O)—C_1-4alkyl, —O—C_1-4alkyl, —NH₂, —NH(C_1-4alkyl), and —N(C_1-4alkyl)₂;

Het²represents a heterocyclyl of formula (b-1):

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(b-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional heteroatom selected from O, S, S(═O)_pand N, or a N-linked 6- to 11-membered bicyclic saturated heterocyclyl, including fused, spiro and bridged cycles, optionally containing one or two additional heteroatoms each independently selected from O, S, S(═O)_pand N;

wherein in case (b-1) contains one or two additional N-atoms, said one or two N-atoms may optionally be substituted with C_1-4alkyl; and

R^11brepresents hydrogen; Het^1e; C_1-4alkyl; C_1-4alkyl-Het; C_1-4alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C_1-4alkyl; C_3-6cycloalkyl; or C_3-6cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C_1-4alkyl;

R¹³represents —O—C_1-4alkyl, —C(═O)OH, —C(═O)NR^15aR^15b, —NR^19aR^19b, C_3-6cycloalkyl, Het^1d, Het⁷, —S(═O)₂—C_1-4alkyl, —S(═O)(═N—R^20c)—C_1-4alkyl, or —C(═O)—Het^1f;

R¹²represents —OH, —O—C_1-4alkyl, —NR^14aR^14b, —C(═O)NR^14cR^14d, —S(═O)₂—C_1-4alkyl, —S(═O)(═N—R^20b)—C_1-4alkyl, C_3-6cycloalkyl, Ar², or Het^1e;

Ar¹represents phenyl optionally substituted with one hydroxy;

Ar²represents phenyl optionally substituted with one C_1-4alkyl;

Het^3a, Het^3b, Het⁵, Het⁶and Het^1feach independently represents a heterocyclyl of formula (c-1):

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(c-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional heteroatom selected from O, S, S(═O)_pand N; wherein in case (c-1) contains one additional N-atom, said additional N-atom may optionally be substituted with C_1-4alkyl or C_3-6cycloalkyl; and

wherein (c-1) may optionally be substituted on one or two ring C-atoms atoms with one or two substituents each independently selected from the group consisting of halo, C_1-4alkyl, and C_3-6cycloalkyl;

Het⁷represents 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridinyl;

R^11a, R^14a, R^14c, R^15a, R^17a, R^19aand R^22aeach independently represents hydrogen, C_1-4alkyl, or C_3-6cycloalkyl;

R^14b, R^14d, R^15b, R^17b, R^19band R^22beach independently represents hydrogen; C_1-4alkyl; C_3-6cycloalkyl; or C_1-4alkyl substituted with one substituent selected from the group consisting of halo, —OH and —O—C_1-4alkyl;

R^20a, R^20band R^20ceach independently represents hydrogen; C_1-4alkyl; C_3-6cycloalkyl; or

C_1-4alkyl substituted with one substituent selected from the group consisting of —OH and —O—C_1-4alkyl;

p represents 1 or 2;

and the pharmaceutically acceptable addition salts, and the solvates thereof.

The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), a pharmaceutically acceptable addition salt, or a solvate thereof, and a pharmaceutically acceptable carrier or excipient.

Additionally, the invention relates to a compound of Formula (I), a pharmaceutically acceptable addition salt, or a solvate thereof, for use as a medicament, and to a compound of Formula (I), a pharmaceutically acceptable addition salt, or a solvate thereof, for use in the treatment or in the prevention of cancer, inflammatory disorders, autoimmune disorders, and metabolic disorders such as diabetes and obesity.

In a particular embodiment, the invention relates to a compound of Formula (I), a pharmaceutically acceptable addition salt, or a solvate thereof, for use in the treatment or in the prevention of a haematological malignancy or solid tumour.

In a specific embodiment said haematological malignancy is selected from the group consisting of multiple myeloma, Hodgkin lymphoma, T-cell leukaemia, mucosa-associated lymphoid tissue lymphoma, diffuse large B-cell lymphoma and mantle cell lymphoma. In another specific embodiment of the present invention, the solid tumour is selected from the group consisting of pancreatic cancer, breast cancer, melanoma and non-small cell lung cancer.

The invention also relates to the use of a compound of Formula (I), a pharmaceutically acceptable addition salt, or a solvate thereof, in combination with an additional pharmaceutical agent for use in the treatment or prevention of cancer, inflammatory disorders, autoimmune disorders, and metabolic disorders such as diabetes and obesity. Furthermore, the invention relates to a process for preparing a pharmaceutical composition according to the invention, characterized in that a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound of Formula (I), a pharmaceutically acceptable addition salt, or a solvate thereof.

The invention also relates to a product comprising a compound of Formula (I), a pharmaceutically acceptable addition salt, or a solvate thereof, and an additional pharmaceutical agent, as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of cancer, inflammatory disorders, autoimmune disorders, and metabolic disorders such as diabetes and obesity.

Additionally, the invention relates to a method of treating or preventing a cell proliferative disease in a warm-blooded animal which comprises administering to the said animal an effective amount of a compound of Formula (I), a pharmaceutically acceptable addition salt, or a solvate thereof, as defined herein, or a pharmaceutical composition or combination as defined herein.

Some of the compounds of the present invention may undergo metabolism to a more active form in vivo (prodrugs).

DETAILED DESCRIPTION OF THE INVENTION

The term ‘halo’ or ‘halogen’ as used herein represents fluoro, chloro, bromo and iodo.

The prefix ‘C_x-y’ (where x and y are integers) as used herein refers to the number of carbon atoms in a given group. Thus, a C_1-6alkyl group contains from 1 to 6 carbon atoms, a C_3-6cycloalkyl group contains from 3 to 6 carbon atoms, and so on.

The term ‘C_1-4alkyl’ as used herein as a group or part of a group represents a straight or branched chain saturated hydrocarbon radical having from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl and the like.

The term ‘C_1-6alkyl’ as used herein as a group or part of a group represents a straight or branched chain saturated hydrocarbon radical having from 1 to 6 carbon atoms such as the groups defined for C_1-4alkyl and n-pentyl, n-hexyl, 2-methylbutyl and the like.

The term “C_2-6alkenyl” as used herein as a group or part of a group represents a straight or branched chain hydrocarbon group containing from 2 to 6 carbon atoms and containing a carbon carbon double bond such as, but not limited to, ethenyl, propenyl, butenyl, pentenyl, 1-propen-2-yl, hexenyl and the like.

The term ‘C_3-6cycloalkyl’ as used herein as a group or part of a group represents cyclic saturated hydrocarbon radicals having from 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In general, whenever the term “substituted” is used in the present invention, it is meant, unless otherwise is indicated or is clear from the context, to indicate that one or more hydrogens, in particular from 1 to 4 hydrogens, more in particular from 1 to 3 hydrogens, preferably 1 or 2 hydrogens, more preferably 1 hydrogen, on the atom or radical indicated in the expression using “substituted” are replaced with a selection from the indicated group, provided that the normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent.

Combinations of substituents and/or variables are permissible only if such combinations result in chemically stable compounds. “Stable compound” is meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent.

The skilled person will understand that the term “optionally substituted” means that the atom or radical indicated in the expression using “optionally substituted” may or may not be substituted (this means substituted or unsubstituted respectively).

When two or more substituents are present on a moiety they may, where possible and unless otherwise is indicated or is clear from the context, replace hydrogens on the same atom or they may replace hydrogen atoms on different atoms in the moiety.

It will be clear for the skilled person that, unless otherwise is indicated or is clear from the context, a substituent on a heterocyclyl group may replace any hydrogen atom on a ring carbon atom or on a ring heteroatom (e.g. a hydrogen on a nitrogen atom may be replaced by a substituent), for example in saturated heterocyclyl groups or 5-membered aromatic rings as used in the definition of R^is.

C(O) or C(═O) represents a carbonyl moiety.

S(═O)₂or SO₂represents a sulfonyl moiety.

“oxo” means custom character for example piperidine substituted with oxo in position 2 is represented by the following structure:

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The skilled person will understand that —S(═O)(═N—R^20a)—C_1-4alkyl corresponds with

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Within the context of this invention ‘saturated’ means ‘fully saturated’, if not otherwise specified.

Het^1a, Het^1cand Het^1d, may be attached to the remainder of the molecule of Formula (I) through any available ring carbon or nitrogen atom as appropriate, if not otherwise specified.

The 5-membered aromatic ring containing one, two or three N-atoms as referred to in the definition of R¹⁸, may be attached to the remainder of the molecule of Formula (I) through any available ring carbon or nitrogen atom as, if not otherwise specified.

It will be clear that in case a saturated cyclic moiety is substituted on two ring carbon atoms with one substituent, in total two carbon-linked substituents are present on the saturated cyclic moiety (one substituent on each carbon atom).

It will be clear that in case a saturated cyclic moiety is substituted on two ring carbon atoms with two substituents, in total four carbon-linked substituents are present on the saturated cyclic moiety (two substituents on each carbon atom).

It will be clear that in case a saturated cyclic moiety is substituted on three ring carbon atoms with two substituents, in total six carbon-linked substituents are present on the saturated cyclic moiety (two substituents on each carbon atom).

It will be clear that in case a saturated cyclic moiety is substituted on two ring N-atoms with a substituent, in total two N-linked substituents are present on the saturated cyclic moiety (a substituent on each N-atom).

It will be clear that a saturated cyclic moiety may, where possible, have substituents on both carbon and N-atoms, unless otherwise is indicated or is clear from the context.

Within the context of this invention, bicyclic saturated heterocyclyl groups include fused, spiro and bridged saturated heterocycles.

Fused bicyclic groups are two cycles that share two atoms and the bond between these atoms.

Spiro bicyclic groups are two cycles that are joined at a single atom.

Bridged bicyclic groups are two cycles that share more than two atoms.

Examples of N-linked 6- to 11-membered fused bicyclic saturated heterocyclyl groups, include, but are not limited to,

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and the like.

Examples of N-linked 6- to 11-membered spiro bicyclic saturated heterocyclyl groups, include, but are not limited to

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and the like.

Examples of N-linked 6- to 11-membered bridged bicyclic saturated heterocyclyl groups, include, but are not limited to

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and the like.

The skilled person will realize that the definition of Het^1a, Het^1cand Het^1dalso includes C-linked bicycles (attached to the remainder of the molecule of Formula (I) through any available ring carbon atom).

It should be understood that the exemplified bicyclic saturated heterocyclyl groups referred to above may optionally be substituted, where possible, on carbon and/or nitrogen atoms according to any of the embodiments.

Non-limiting examples of 4- to 7-membered monocyclic saturated heterocyclyl moieties containing one or two heteroatoms each independently selected from O, S, S(═O)_pand N (as in the definition of Het^1a, Het^1c, and Het^1d) are shown below:

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and the like.

Each of which may optionally be substituted, where possible, on carbon and/or nitrogen atoms according to any of the embodiments.

Non-limiting examples of 4- to 7-membered monocyclic saturated heterocyclyl moieties, attached to the remainder of the molecule of Formula (I) through any available ring carbon atom (C-linked), and containing one or two heteroatoms each independently selected from O, S, S(═O)_pand N (as in the definition of Het^1b, Het^1e, Het^1gand Het⁴) are shown below:

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and the like.

Each of which may optionally be substituted, where possible, on carbon and/or nitrogen atoms according to any of the embodiments.

Non-limiting examples of N-linked 4- to 7-membered monocyclic saturated heterocyclyl moieties optionally containing one additional heteroatom selected from O, S, S(═O), and N (as in the definition of (b-1) and (c-1)) are shown below:

embedded image

and the like.

Each of which may optionally be substituted, where possible, on carbon and/or nitrogen atoms according to any of the embodiments.

Non-limiting examples of 5-membered aromatic ring containing one, two or three N-atoms as referred to in the definition of R⁸are shown below:

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and the like.

Each of which may optionally be substituted, where possible, on carbon and/or nitrogen atoms according to any of the embodiments.

Non-limiting examples of 5-membered heteroaromatic ring containing one, two or three heteroatoms each independently selected from O, S, and N (as in the definition of R³) are shown below:

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and the like.

Each of which may optionally be substituted, where possible, on carbon atoms and/or one nitrogen atom according to any of the embodiments.

The skilled person will understand that R³is attached to the remainder of the molecule of Formula (I) (—NH— moiety) via a ring carbon atom.

Whenever substituents are represented by chemical structure, “ - - - ” represents the bond of attachment to the remainder of the molecule of Formula (I).

Lines (such as “ - - - ”) drawn into ring systems indicate that the bond may be attached to any of the suitable ring atoms.

When any variable occurs more than one time in any constituent, each definition is independent.

When any variable occurs more than one time in any formula (e.g. Formula (I)), each definition is independent.

The term “subject” as used herein, refers to an animal, preferably a mammal (e.g. cat, dog, primate or human), more preferably a human, who is or has been the object of treatment, observation or experiment.

The term “therapeutically effective amount” as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medicinal doctor or other clinician, which includes alleviation or reversal of the symptoms of the disease or disorder being treated.

The term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

The term “treatment”, as used herein, is intended to refer to all processes wherein there may be a slowing, interrupting, arresting or stopping of the progression of a disease, but does not necessarily indicate a total elimination of all symptoms.

The term “compound(s) of the (present) invention” or “compound(s) according to the (present) invention” as used herein, is meant to include the compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof.

As used herein, any chemical formula with bonds shown only as solid lines and not as solid wedged or hashed wedged bonds, or otherwise indicated as having a particular configuration (e.g. R, S) around one or more atoms, contemplates each possible stereoisomer, or mixture of two or more stereoisomers.

Hereinbefore and hereinafter, the term “compound(s) of Formula (I)” is meant to include the tautomers thereof and the stereoisomeric forms thereof.

The terms “stereoisomers”, “stereoisomeric forms” or “stereochemically isomeric forms” hereinbefore or hereinafter are used interchangeably.

The invention includes all stereoisomers of the compounds of the invention either as a pure stereoisomer or as a mixture of two or more stereoisomers.

Enantiomers are stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemate or racemic mixture.

Atropisomers (or atropoisomers) are stereoisomers which have a particular spatial configuration, resulting from a restricted rotation about a single bond, due to large steric hindrance. All atropisomeric forms of the compounds of Formula (I) are intended to be included within the scope of the present invention.

Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e. they are not related as mirror images. If a compound contains a double bond, the substituents may be in the E or the Z configuration.

Substituents on bivalent cyclic saturated or partially saturated radicals may have either the cis- or trans-configuration; for example if a compound contains a disubstituted cycloalkyl group, the substituents may be in the cis or trans configuration.

Therefore, the invention includes enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, whenever chemically possible.

The meaning of all those terms, i.e. enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof are known to the skilled person.

The absolute configuration is specified according to the Cahn-Ingold-Prelog system.

The configuration at an asymmetric atom is specified by either R or S. Resolved stereoisomers whose absolute configuration is not known can be designated by (+) or (−) depending on the direction in which they rotate plane polarized light. For instance, resolved enantiomers whose absolute configuration is not known can be designated by (+) or (−) depending on the direction in which they rotate plane polarized light.

When a specific stereoisomer is identified, this means that said stereoisomer is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, in particular less than 2% and most preferably less than 1%, of the other stereoisomers. Thus, when a compound of Formula (I) is for instance specified as (R), this means that the compound is substantially free of the (S) isomer; when a compound of Formula (I) is for instance specified as E, this means that the compound is substantially free of the Z isomer; when a compound of Formula (I) is for instance specified as cis, this means that the compound is substantially free of the trans isomer.

Some of the compounds according to Formula (I) may also exist in their tautomeric form. Such forms in so far as they may exist, although not explicitly indicated in the above Formula (I) are intended to be included within the scope of the present invention. It follows that a single compound may exist in both stereoisomeric and tautomeric form.

Pharmaceutically-acceptable addition salts include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.

The pharmaceutically acceptable addition salts as mentioned hereinabove or hereinafter are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds of Formula (I) and solvates thereof, are able to form.

Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids. Conversely said salt forms can be converted by treatment with an appropriate base into the free base form.

The compounds of Formula (I) and solvates thereof containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases.

Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline; the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely the salt form can be converted by treatment with acid into the free acid form.

The term solvate comprises the solvent addition forms as well as the salts thereof, which the compounds of Formula (I) are able to form. Examples of such solvent addition forms are e.g. hydrates, alcoholates and the like.

The compounds of the invention as prepared in the processes described below may be synthesized in the form of mixtures of enantiomers, in particular racemic mixtures of enantiomers, that can be separated from one another following art-known resolution procedures. A manner of separating the enantiomeric forms of the compounds of Formula (I), and pharmaceutically acceptable addition salts, and solvates thereof, involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said compound would be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.

The present invention also embraces isotopically-labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature).

All isotopes and isotopic mixtures of any particular atom or element as specified herein are contemplated within the scope of the compounds of the invention, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, ³³P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²²I, ¹²³I, ¹²⁵I, ¹³¹I, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br and ⁸²Br. Preferably, the radioactive isotope is selected from the group of ²H, ³H, ¹¹C and ¹⁸F. More preferably, the radioactive isotope is ²H. In particular, deuterated compounds are intended to be included within the scope of the present invention.

Certain isotopically-labeled compounds of the present invention (e.g., those labeled with ³H and ¹⁴C) are useful in compound and for substrate tissue distribution assays.

Tritiated (³H) and carbon-14 (¹⁴C) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Positron emitting isotopes such as ¹⁵O, ¹³N, C and ¹⁸F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy.

The present invention relates in particular to compounds of Formula (I) as defined herein, tautomers and stereoisomeric forms thereof, wherein

R¹represents C_1-4alkyl;

R²represents C_1-6alkyl, or C_1-6alkyl substituted with one R⁵; Y represents CR⁴;

R⁴represents hydrogen or halo;

R⁵represents Het^3a, —NR^6aR^6b, or —OR⁷;

R^6arepresents hydrogen or C_1-4alkyl;

R^6brepresents hydrogen; C_1-4alkyl; C_3-6cycloalkyl; —C(═O)—C_1-4alkyl; —C(═O)—Het⁴;

—S(═O)₂—C_1-4alkyl; —C(═O)—C_1-4alkyl substituted with one substituent selected from the group consisting of —OH and —NR^6aR^16b; or C_1-4alkyl substituted with one substituent selected from the group consisting of —OH and —S(═O)₂—C_1-4alkyl;

R⁷represents hydrogen, C_1-4alkyl, —C_1-4alkyl-NR^8aR^8b, —C(═O)—R⁹, —S(═O)₂—OH, —P(═O)₂—OH, —(C═O)—CH(NH₂)—C_1-4alkyl-Ar¹, or —C₄alkyl-Het^3b;

R^8arepresents hydrogen or C_1-4alkyl;

R^8brepresents hydrogen, C_1-4alkyl, or C_3-6cycloalkyl;

R⁹represents C_1-6alkyl, or C_1-6alkyl substituted with one substituent selected from the group consisting of —NH₂, —COOH, and Het⁶;

R^16aand R^16beach independently represents hydrogen, C_1-4alkyl or C_3-6cycloalkyl;

R³represents a 5-membered heteroaromatic ring containing one, two or three heteroatoms each independently selected from O, S, and N;

wherein said 5-membered heteroaromatic ring may optionally be substituted, where possible, on one ring N-atom with a substituent selected from the group consisting of C_1-6alkyl; C_3-6cycloalkyl; Het^1a; R¹⁸; R²¹; C_1-4alkyl substituted with one, two or three halo atoms; C_1-4alkyl substituted with one, two or three —OH substituents; C_1-6alkyl substituted with one R¹³; C_1-4alkyl substituted with one R¹⁸; C_2-6alkenyl; and C_2-6alkenyl substituted with one R¹³; provided that when Het^1aor R¹⁸are directly attached to the N-atom of the 5-membered heteroaromatic ring, said Het^1aor R¹⁸are attached to the N-atom via a ring carbon atom; and

wherein said 5-membered heteroaromatic ring may optionally be substituted on the ring carbon atoms with in total one or two substituents each independently selected from the group consisting of halo; cyano; C_1-6alkyl; —O—C_1-4alkyl; —C(═O)—R¹⁰; —S(═O)₂—C_1-4alkyl; —S(═O)(═N—R^20a)—C_1-4alkyl; —O—C_1-4alkyl substituted with one, two or three halo atoms; —O—C_1-4alkyl-R¹²; C_3-6cycloalkyl; —O—C_3-6cycloalkyl; Het^1a; —O-Het^1b; R¹⁸; R²¹; —P(═O)—(C_1-4alkyl)₂; —NH—C(═O)—C_1-4alkyl; —NH—C(═O)—Het^1g; —NR^17aR^17b; C_1-4alkyl substituted with one, two or three halo atoms; C_1-4alkyl substituted with one, two or three —OH substituents; C_1-6alkyl substituted with one R¹³; C_1-4allyl substituted with one R¹⁸; C_2-6alkenyl; and C_2-6alkenyl substituted with one R¹³;

R¹⁰represents —OH, —O—C_1-4alkyl, —NR^11aR^11bor Het²;

R²¹represents 3,6-dihydro-2H-pyran-4-yl or 1,2,3,6-tetrahydro-4-pyridinyl, wherein 1,2,3,6-tetrahydro-4-pyridinyl may optionally be substituted on the N-atom with C_1-4alkyl or C_3-6cycloalkyl;

Het^1b, Het^1c, Het^1gand Het⁴each independently represents a 4- to 7-membered monocyclic saturated heterocyclyl, attached to the remainder of the molecule of Formula (I) through any available ring carbon atom, said Het^1b, Het^1e, Het^1gand Het⁴containing one or two heteroatoms each independently selected from O, S, S(═O)_pand N;

Het²represents a heterocyclyl of formula (b-1):

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wherein in case (b-1) contains one or two additional N-atoms, said one or two N-atoms may optionally be substituted with C_1-4alkyl; and

R^11brepresents hydrogen; Het^1e; C_1-4alkyl; C_1-4alkyl-Het⁵; C_1-4alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C_1-4alkyl; C_3-6cycloalkyl; or C_3-6cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C_1-4alkyl;

R¹³represents —O—C_1-4alkyl, —C(═O)OH, —C(═O)NR^1aR^5b, —NR^19aR^19b, C_3-6cycloalkyl, Het^1d, —S(═O)₂—C_1-4alkyl, —S(═O)(═N—R^20c)—C_1-4alkyl, or —C(═O)—Het^f;

R¹²represents —OH, —O—C_1-4alkyl, —NR^14aR^14b, —C(═O)NR^14cR^14d, —S(═O)₂—C₄alkyl, —S(═O)(═N—R^20b)—C_1-4alkyl, C_3-6cycloalkyl, Ar², or Het^1e;

Ar¹represents phenyl optionally substituted with one hydroxy;

Ar²represents phenyl optionally substituted with one C_1-4alkyl;

Het^3a, Het^3b, Het⁵, Het⁶and Het^1feach independently represents a heterocyclyl of formula (c-1):

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R^11a, R^14a, R^14c, R^15a, R^17a, R^19aand R^22aeach independently represents hydrogen, C_1-4alkyl, or C_3-6cycloalkyl;

R^20a, R^20band R^20ceach independently represents hydrogen; C_1-4alkyl; C_3-6cycloalkyl; or C_1-4alkyl substituted with one substituent selected from the group consisting of —OH and —O—C_1-4alkyl;

p represents 1 or 2;

and the pharmaceutically acceptable addition salts, and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, tautomers and stereoisomeric forms thereof, wherein

R¹represents C_1-4alkyl;

R²represents C_1-6alkyl substituted with one R⁵;

Y represents CR⁴or N;

R⁴represents hydrogen or halo;

R⁵represents Het^3a, —NR^6aR^6b, or —OR⁷;

R^6arepresents hydrogen or C_1-4alkyl;

R^6brepresents hydrogen; or C_1-4alkyl substituted with one —OH substituent;

R⁷represents hydrogen or —C(═O)—R⁹;

R⁹represents C_1-6alkyl;

R³represents a 5-membered heteroaromatic ring containing one, two or three heteroatoms each independently selected from O, S, and N;

wherein said 5-membered heteroaromatic ring may optionally be substituted, where possible, on one ring N-atom with a substituent selected from the group consisting of C_1-6alkyl; C_3-6cycloalkyl; Het^1a; C_1-4alkyl substituted with one, two or three halo atoms; C_1-5alkyl substituted with one, two or three —OH substituents; C_1-6alkyl substituted with one R¹³; —C_1-4alkyl-O—C_1-4alkyl substituted with one or two —OH substituents; C_1-4alkyl substituted with one R¹⁸; and C_2-6alkenyl; provided that when Het^1ais directly attached to the N-atom of the 5-membered heteroaromatic ring, said Het^1ais attached to the N-atom via a ring carbon atom; and

R¹⁰represents —NR^11aR^11bor Het²;

Het^1a, Het^1cand Het^1deach independently represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O, S, S(═O)_pand N; or a 6- to 11-membered bicyclic saturated heterocyclyl, including fused cycles, containing one, two or three heteroatoms each independently selected from O and N;

wherein said 4- to 7-membered monocyclic saturated heterocyclyl or said 6- to 11-membered bicyclic saturated heterocyclyl may optionally be substituted, where possible, on one, two or three ring N-atoms with a substituent each independently selected from the group consisting of C_1-4alkyl, C_1-4alkyl substituted with one, two or three halo atoms, and C_1-4alkyl substituted with one substituent selected from the group consisting of —C(═O)—OH, —C(═O)—NR^22aR^22band —O—C_1-4alkyl; and

Het^1band Het^1eeach independently represents a 4- to 7-membered monocyclic saturated heterocyclyl, attached to the remainder of the molecule of Formula (I) through any available ring carbon atom, said Het^band Het^1econtaining one or two O-atoms;

Het²represents a heterocyclyl of formula (b-1):

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(b-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional N-atom;

wherein in case (b-1) contains one additional N-atom, said N-atom may optionally be substituted with C_1-4alkyl;

R^11brepresents Het^1e; C_1-4alkyl; or C_3-6cycloalkyl;

R¹³represents —O—C_1-4alkyl, —C(═O)OH, —C(═O)NR^1aR^15b, —NR^19aR^19b, C_3-6cycloalkyl, Het^1d, Het⁷, —S(═O)₂—C_1-4alkyl, or —C(═O)—Het^1f;

R¹²represents —O—C_1-4alkyl or Het^1c;

Het^3aand Het^1feach independently represents a heterocyclyl of formula (c-1):

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(c-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional N-atom;

wherein in case (c-1) contains one additional N-atom, said additional N-atom may optionally be substituted with C_3-6cycloalkyl; and

wherein (c-1) may optionally be substituted on one or two ring C-atoms atoms with one or two halo substituents;

Het⁷represents 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridinyl;

R^11a, R^15a, R^19aand R^22aeach independently represents hydrogen,

C_1-4alkyl, or C_3-6cycloalkyl;

R^15b, R^19band R^22beach independently represents C_1-4alkyl or C_3-6cycloalkyl;

p represents 2;

and the pharmaceutically acceptable addition salts, and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, tautomers and stereoisomeric forms thereof, wherein

R¹represents C_1-4alkyl;

R²represents C_1-6alkyl, or C_1-6alkyl substituted with one R⁵;

Y represents CR⁴;

R⁴represents hydrogen or halo;

- R⁵represents Het^3a, —NR^6aR^6b, or —OR⁷;

R^6arepresents hydrogen or C_1-4alkyl;

R^6brepresents hydrogen; C_1-4alkyl; C_3-6cycloalkyl; —C(═O)—C_1-4alkyl; —C(═O)—C_1-4alkyl substituted with one substituent selected from the group consisting of —OH and —NR^16aR^16b; or C_1-4alkyl substituted with one —OH substituent;

R⁷represents hydrogen, C_1-4alkyl, —C_1-4alkyl-NR^8aR^b, or —C(═O)—R⁹;

R^8arepresents hydrogen or C_1-4alkyl;

R^8brepresents hydrogen, C_1-4alkyl, or C_3-6cycloalkyl;

R⁹represents C_1-6alkyl, or C_1-6alkyl substituted with one substituent selected from the group consisting of —NH₂, and —COOH;

R^16aand R^16beach independently represents hydrogen, C_1-4alkyl or C_3-6cycloalkyl;

R³represents a 5-membered heteroaromatic ring containing one, two or three heteroatoms each independently selected from O, S, and N;

wherein said 5-membered heteroaromatic ring may optionally be substituted, where possible, on one ring N-atom with a substituent selected from the group consisting of C_1-6alkyl; C_3-6cycloalkyl; Het^1a; R¹⁸; C_1-4alkyl substituted with one, two or three halo atoms; C_1-4alkyl substituted with one, two or three —OH substituents; C_1-6alkyl substituted with one R¹³; C_1-4alkyl substituted with one R¹⁸; C_2-6alkenyl; and C_2-6alkenyl substituted with one R¹³; provided that when Het^1aor R¹⁸are directly attached to the N-atom of the 5-membered heteroaromatic ring, said Het^1aor R¹⁸are attached to the N-atom via a ring carbon atom; and

wherein said 5-membered heteroaromatic ring may optionally be substituted on the ring carbon atoms with in total one or two substituents each independently selected from the group consisting of halo; cyano; C_1-6alkyl; —O—C_1-4alkyl; —C(═O)—R¹⁰; —O—C_1-4alkyl substituted with one, two or three halo atoms; —O—C_1-4alkyl-R¹²; C_3-6cycloalkyl; —O—C_3-6cycloalkyl; Het a; —O-Het^1b; R¹⁸; —P(═O)—(C_1-4alkyl)₂; —NH—C(═O)—C_1-4alkyl; —NH—C(═O)—Het^1g; —NR^17aR^17b; C_1-4alkyl substituted with one, two or three halo atoms; C_1-4alkyl substituted with one, two or three —OH substituents; C_1-6alkyl substituted with one R¹³; C_1-4alkyl substituted with one R¹⁸; C_2-6alkenyl; and C_2-6alkenyl substituted with one R¹³;

R¹⁰represents —OH, —O—C_1-4alkyl, —NR^11aR^11bor Het²;

Het^1a, and Het^1deach independently represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O, S, S(═O)_pand N;

wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one, two or three ring N-atoms with a substituent each independently selected from the group consisting of C_1-4alkyl, C_3-6cycloalkyl, C_1-4alkyl substituted with one, two or three halo atoms, and C_1-4alkyl substituted with one substituent selected from the group consisting of —OH, —C(═O)—OH, —C(═O)—NR^22aR^22band —O—C_1-4alkyl; and

wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of —OH, oxo, halo, C_1-4alkyl, cyano, —C(═O)—C_1-4alkyl, —O—C_1-4alkyl, —NH₂, —NH(C_1-4alkyl), and —N(C_1-4alkyl)₂;

Het²represents a heterocyclyl of formula (b-1):

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(b-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional heteroatom selected from O, S, S(═O)_pand N; wherein in case (b-1) contains one additional N-atom, said N-atom may optionally be substituted with C_1-4alkyl; and

R^11brepresents hydrogen; Het^1e; C_1-4alkyl; C_1-4alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C_1-4alkyl; C_3-6cycloalkyl; or C_3-6cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C_1-4alkyl;

R¹³represents —O—C_1-4alkyl, —C(═O)OH, —C(═O)NR^1aR^15b, —NR^19aR^19b, C_3-6cycloalkyl, Het^1d, —S(═O)₂—C_1-4alkyl, or —C(═O)—Het^f;

R¹²represents —OH, —O—C_1-4alkyl, —NR^14aR^14b, —C(═O)NR^14cR^14d, —S(═O)₂—C_1-4alkyl, C_3-6cycloalkyl;

Het^3a, and Het^1feach independently represents a heterocyclyl of formula (c-1):

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R^11a, R^14a, R^14c, R^15a, R^17a, R^19aand R^22aeach independently represents hydrogen, C_1-4alkyl, or C_3-6cycloalkyl;

p represents 1 or 2;

and the pharmaceutically acceptable addition salts, and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, tautomers and stereoisomeric forms thereof, wherein

R¹represents C_1-4alkyl;

R²represents C_1-6alkyl substituted with one R⁵;

Y represents CR⁴;

R⁴represents hydrogen or halo;

R⁵represents Het^3a, —NR^6aR^6b, or —OR⁷;

R^6arepresents C_1-4alkyl;

R^6brepresents C_1-4alkyl substituted with one —OH substituent;

R⁷represents hydrogen, or —C(═O)—R⁹;

R⁹represents C_1-6alkyl;

R³represents a 5-membered heteroaromatic ring containing two or three heteroatoms each independently selected from O, S, and N;

wherein said 5-membered heteroaromatic ring may optionally be substituted, where possible, on one ring N-atom with a substituent selected from the group consisting of C_1-6alkyl; Het^1a; C_1-4alkyl substituted with one, two or three halo atoms; C_1-4alkyl substituted with one, two or three —OH substituents; C_1-6alkyl substituted with one R¹³; C_1-4alkyl substituted with one R¹⁸; and C_2-6alkenyl; provided that when Het^1ais directly attached to the N-atom of the 5-membered heteroaromatic ring, said Het¹a is attached to the N-atom via a ring carbon atom; and

R¹⁰represents —NR^11aR^11bor Het²;

R¹⁸represents a 5-membered aromatic ring containing one, two or three N-atoms; wherein said 5-membered aromatic ring may optionally be substituted with one C_1-4alkyl;

Het^1a, and Het^1deach independently represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O, S, S(═O)_pand N;

wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one ring N-atom with a substituent each independently selected from the group consisting of C_1-4alkyl, C_1-4alkyl substituted with one, two or three halo atoms, and C_1-4alkyl substituted with one substituent selected from the group consisting of —C(═O)—NR^22aR^22band —O—C_1-4alkyl; and

Het^1erepresents a 4- to 7-membered monocyclic saturated heterocyclyl, attached to the remainder of the molecule of Formula (I) through any available ring carbon atom, said Het^1econtaining one or two O-atoms;

Het²represents 1-piperidinyl;

R^11brepresents Het^1e; C_1-4alkyl; C_3-6cycloalkyl;

R¹³represents —O—C_1-4alkyl, —C(═O)OH, —C(═O)NR^5aR^15b, —NR^19aR^19b, C_3-6cycloalkyl, Het^1d, —S(═O)₂—C_1-4alkyl, or —C(═O)—Het^1f;

Het^3a, and Het^1feach independently represents a heterocyclyl of formula (c-1):

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(c-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional N-atom;

wherein in case (c-1) contains one additional N-atom, said additional N-atom may optionally be substituted with C_3-6cycloalkyl; and

wherein (c-1) may optionally be substituted on one or two ring C-atoms atoms with one or two halo substituents;

R^11a, R^15a, R^19aand R^22aeach independently represents hydrogen, C_1-4alkyl, or C_3-6cycloalkyl;

R^15b, R^19band R^22beach independently represents C_1-4alkyl; or C_3-6cycloalkyl; p represents 2;

and the pharmaceutically acceptable addition salts, and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, tautomers and stereoisomeric forms thereof, wherein

R¹represents C_1-4alkyl;

R²represents C_1-6alkyl substituted with one R⁵;

Y represents CR⁴;

R⁴represents hydrogen or halo;

R⁵represents Het^3a, —NR^6aR^6b, or —OR⁷;

R^6arepresents C_1-4alkyl;

R^6brepresents C_1-4alkyl substituted with one —OH substituent;

R⁷represents hydrogen, or —C(═O)—R⁹;

R⁹represents C_1-6alkyl;

R³represents a 5-membered heteroaromatic ring containing two or three heteroatoms each independently selected from O, S, and N;

wherein said 5-membered heteroaromatic ring may optionally be substituted, where possible, on one ring N-atom with a substituent selected from the group consisting of C_1-6alkyl; Het^1a; C_1-4alkyl substituted with one, two or three halo atoms; C_1-5alkyl substituted with one, two or three —OH substituents; C_1-6alkyl substituted with one R¹³; C_1-4alkyl substituted with one R¹⁸; and C_2-6alkenyl; provided that when Het^1ais directly attached to the N-atom of the 5-membered heteroaromatic ring, said Het^1ais attached to the N-atom via a ring carbon atom; and

R¹⁰represents —NR^11aR^11bor Het²;

R¹⁸represents a 5-membered aromatic ring containing one, two or three N-atoms; wherein said 5-membered aromatic ring may optionally be substituted with one C_1-4alkyl;

Het^1a, and Het^1deach independently represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O, S, S(═O)_pand N;

Het²represents 1-piperidinyl;

Het⁷represents 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridinyl;

R^11brepresents Het^1e; C_1-4alkyl; C_3-6cycloalkyl;

R¹³represents —O—C_1-4alkyl, —C(═O)OH, —C(═O)NR^15aR^15b, —NR^19aR^19b, C_3-6cycloalkyl, Het^1d, Het⁷, —S(═O)₂—C_1-4alkyl, or —C(═O)—Het^1f;

Het^3a, and Het^1feach independently represents a heterocyclyl of formula (c-1):

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(c-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional N-atom;

wherein in case (c-1) contains one additional N-atom, said additional N-atom may optionally be substituted with C_3-6cycloalkyl; and

wherein (c-1) may optionally be substituted on one or two ring C-atoms atoms with one or two halo substituents;

R^11a, R^15a, R^19aand R^22aeach independently represents hydrogen, C_1-4alkyl, or C_3-6cycloalkyl;

R^15b, R^19band R^22beach independently represents C_1-4alkyl; or C_3-6cycloalkyl; p represents 2;

and the pharmaceutically acceptable addition salts, and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, tautomers and stereoisomeric forms thereof, wherein

R¹represents C_1-4alkyl;

R²represents C_1-6alkyl substituted with one, two or three fluoro atoms;

Y represents CR⁴;

R⁴represents hydrogen or halo;

R³represents a 5-membered heteroaromatic ring containing two or three heteroatoms each independently selected from O, S, and N;

wherein said 5-membered heteroaromatic ring may optionally be substituted, where possible, on one ring N-atom with a substituent selected from the group consisting of C_1-6alkyl; Het^1a; C_1-4alkyl substituted with one, two or three halo atoms; C_1-5alkyl substituted with one, two or three —OH substituents; C_1-6alkyl substituted with one R¹³; C_1-4alkyl substituted with one R¹⁸; and C_2-6alkenyl; provided that when Het^1ais directly attached to the N-atom of the 5-membered heteroaromatic ring, said Het^1ais attached to the N-atom via a ring carbon atom; and

R¹⁰represents —NR^11aR^11bor Het²;

R¹⁸represents a 5-membered aromatic ring containing one, two or three N-atoms; wherein said 5-membered aromatic ring may optionally be substituted with one C_1-4alkyl;

Het^1a, and Het^1deach independently represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O, S, S(═O)_pand N;

Het²represents 1-piperidinyl;

Het⁷represents 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridinyl;

R^11brepresents Het^1e; C_1-4alkyl; C_3-6cycloalkyl;

R¹³represents —O—C_1-4alkyl, —C(═O)OH, —C(═O)NR^15aR^15b, —NR^19aR^19b, C_3-6cycloalkyl, Het^1d, Het⁷, —S(═O)₂—C_1-4alkyl, or —C(═O)—Het^f;

Het^3a, and Het^1feach independently represents a heterocyclyl of formula (c-1):

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(c-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional N-atom;

wherein in case (c-1) contains one additional N-atom, said additional N-atom may optionally be substituted with C_3-6cycloalkyl; and

wherein (c-1) may optionally be substituted on one or two ring C-atoms atoms with one or two halo substituents;

R^11a, R^15a, R^19aand R^22aeach independently represents hydrogen, C_1-4alkyl, or C_3-6cycloalkyl;

R^15b, R^19band R^22beach independently represents C_1-4alkyl; or C_3-6cycloalkyl; p represents 2;

and the pharmaceutically acceptable addition salts, and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, tautomers and stereoisomeric forms thereof, wherein

R¹represents C_1-4alkyl;

R²represents C_1-6alkyl substituted with one R⁵;

Y represents CR⁴;

R⁴represents hydrogen;

R⁵represents —OR⁷;

R⁷represents hydrogen, or —C(═O)—R⁹;

R⁹represents C_1-6alkyl;

R³represents a 5-membered heteroaromatic ring containing two or three heteroatoms each independently selected from S, and N;

R¹⁰represents —NR^11aR^11b;

R¹⁸represents a 5-membered aromatic ring containing two N-atoms; wherein said 5-membered aromatic ring may optionally be substituted with one C_1-4alkyl;

Het^1drepresents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or O-atom;

R^11brepresents C_1-4alkyl or C_3-6cycloalkyl;

R¹³represents —O—C_1-4alkyl, —C(═O)NR^15aR^15b, or Het^1d;

R^11aand R^15aeach independently represents hydrogen or C_1-4alkyl;

R^15brepresents C_3-6cycloalkyl;

and the pharmaceutically acceptable addition salts, and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, tautomers and stereoisomeric forms thereof, wherein

R¹represents C_1-4alkyl;

R²represents C_1-6alkyl substituted with one R⁵;

Y represents CR⁴;

R⁴represents hydrogen;

R⁵represents —OR⁷;

R⁷represents hydrogen, or —C(═O)—R⁹;

R⁹represents C_1-6alkyl;

R³represents a 5-membered heteroaromatic ring containing two or three heteroatoms each independently selected from S, and N;

R¹⁰represents —NR^11aR^11b;

R¹⁸represents a 5-membered aromatic ring containing two N-atoms; wherein said 5-membered aromatic ring may optionally be substituted with one C_1-4alkyl;

Het⁷represents 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridinyl;

R^11brepresents C_1-4alkyl or C_3-6cycloalkyl;

R¹³represents Het⁷;

and the pharmaceutically acceptable addition salts, and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, tautomers and stereoisomeric forms thereof, wherein

R¹represents C_1-4alkyl;

R²represents C_1-6alkyl substituted with one R⁵;

Y represents N;

R⁴represents hydrogen;

R⁵represents —OR⁷;

R⁷represents hydrogen, or —C(═O)—R⁹;

R⁹represents C_1-6alkyl;

R³represents a 5-membered heteroaromatic ring containing two or three heteroatoms each independently selected from S, and N;

R¹⁰represents —NR^11aR^11b;

R¹⁸represents a 5-membered aromatic ring containing two N-atoms; wherein said 5-membered aromatic ring may optionally be substituted with one C_1-4alkyl;

Het^1drepresents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or O-atom;

R^11brepresents C_1-4alkyl or C_3-6cycloalkyl;

R¹³represents —O—C_1-4alkyl, —C(═O)NR^15aR^15b, or Het^1d;

R^11aand R^15aeach independently represents hydrogen or C_1-4alkyl;

R^15brepresents C_3-6cycloalkyl;

and the pharmaceutically acceptable addition salts, and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, tautomers and stereoisomeric forms thereof, wherein

R¹represents methyl;

R²represents methyl substituted with one R⁵;

Y represents CR⁴;

R⁴represents hydrogen;

R⁵represents —OR⁷;

R⁷represents hydrogen;

R³represents pyrazolyl optionally substituted on one ring N-atom with a substituent selected from the group consisting of C_1-6alkyl; C_1-4alkyl substituted with one, two or three halo atoms; C_1-6alkyl substituted with one R¹³; and C_1-4alkyl substituted with one R¹⁸; and

R¹⁰represents —NR^11aR^11b; R¹⁸represents

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Het^1drepresents tetrahydrofuranyl;

R^11brepresents C_1-4alkyl or C_3-6cycloalkyl;

R¹³represents —O—C_1-4alkyl, —C(═O)NR^15aR^15b, or Het^1d;

R^11aand R^15aeach independently represents hydrogen or C_1-4alkyl;

R^15brepresents C_3-6cycloalkyl;

and the pharmaceutically acceptable addition salts, and the solvates thereof.

Another embodiment of the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments wherein one or more of the following restrictions apply:

(a) R²represents C_1-6alkyl substituted with one R⁵;

(b) R^6arepresents C_1-4alkyl;

(d) R⁷represents hydrogen, or —C(═O)—R⁹;

(e) R⁹represents C_1-6alkyl;

(f) R³represents a 5-membered heteroaromatic ring containing two or three heteroatoms each independently selected from O, S, and N;

wherein said 5-membered heteroaromatic ring may optionally be substituted, where possible, on one ring N-atom with a substituent selected from the group consisting of C_1-6alkyl; Het¹a; C_1-4alkyl substituted with one, two or three halo atoms; C_1-4alkyl substituted with one, two or three —OH substituents; C_1-6alkyl substituted with one R¹³; C_1-4alkyl substituted with one R¹⁸; and C_2-6alkenyl; provided that when Het¹a is directly attached to the N-atom of the 5-membered heteroaromatic ring, said Het^1ais attached to the N-atom via a ring carbon atom; and

(g) R¹⁰represents —NR^11aR^11bor Het²;

(h) R¹⁸represents a 5-membered aromatic ring containing one, two or three N-atoms; wherein said 5-membered aromatic ring may optionally be substituted with one C_1-4alkyl;

(i) Het^1a, and Het¹-d each independently represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O, S, S(═O)_pand N;

(j) Het^1erepresents a 4- to 7-membered monocyclic saturated heterocyclyl, attached to the remainder of the molecule of Formula (I) through any available ring carbon atom, said Het^1econtaining one or two O-atoms;

(k) Het²represents 1-piperidinyl;

(l) R^1brepresents Het^1e; C_1-4alkyl; C_3-6cycloalkyl;

(m) R¹³represents —O—C_1-4alkyl, —C(═O)OH, —C(═O)NR^15aR^15b, —NR^19aR^19bC_3-6cycloalkyl, Het^1d, —S(═O)₂—C_1-4alkyl, or —C(═O)—Het^f;

(n) Het^3a, and Het^1feach independently represents a heterocyclyl of formula (c-1):

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(c-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional N-atom;

wherein in case (c-1) contains one additional N-atom, said additional N-atom may optionally be substituted with C_3-6cycloalkyl; and

wherein (c-1) may optionally be substituted on one or two ring C-atoms atoms with one or two halo substituents;

(o) R^11a, R^15a, R^19aand R^22aeach independently represents hydrogen, C_1-4alkyl, or C_3-6cycloalkyl;

(p) R^15b, R^19band R^22beach independently represents C_1-4alkyl; or C_3-6cycloalkyl; (q) p represents 2.

(a) R²represents C_1-6alkyl substituted with one R⁵;

(b) R^6arepresents C_1-4alkyl;

(d) R⁷represents hydrogen, or —C(═O)—R⁹;

(e) R⁹represents C_1-6alkyl;

(f) R³represents a 5-membered heteroaromatic ring containing two or three heteroatoms each independently selected from O, S, and N;

wherein said 5-membered heteroaromatic ring may optionally be substituted, where possible, on one ring N-atom with a substituent selected from the group consisting of C_1-6alkyl; Het^1a; C_1-4alkyl substituted with one, two or three halo atoms; C_1-5alkyl substituted with one, two or three —OH substituents; C_1-6alkyl substituted with one R¹³; C_1-4alkyl substituted with one R¹⁸; and C_2-6alkenyl; provided that when Het^1ais directly attached to the N-atom of the 5-membered heteroaromatic ring, said Het a is attached to the N-atom via a ring carbon atom; and

(g) R¹⁰represents —NR^11aR^11bor Het²;

(h) R¹⁸represents a 5-membered aromatic ring containing one, two or three N-atoms; wherein said 5-membered aromatic ring may optionally be substituted with one C_1-4alkyl;

(i) Het^1a, and Het^1deach independently represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O, S, S(═O)_pand N;

(k) Het²represents 1-piperidinyl;

(l) R^11brepresents Het^1e; C_1-4alkyl; C_3-6cycloalkyl;

(m) R¹³represents —O—C_1-4alkyl, —C(═O)OH, —C(═O)NR^5aR^15b, —NR^19aR^19b, C_3-6cycloalkyl, Het^1d, —S(═O)₂—C_1-4alkyl, or —C(═O)—Het^f;

(n) Het^3a, and Het^1feach independently represents a heterocyclyl of formula (c-1):

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(c-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional N-atom;

wherein in case (c-1) contains one additional N-atom, said additional N-atom may optionally be substituted with C_3-6cycloalkyl; and

wherein (c-1) may optionally be substituted on one or two ring C-atoms atoms with one or two halo substituents;

(o) R^11a, R^15a, R^19aand R^22aeach independently represents hydrogen, C_1-4alkyl, or C_3-6cycloalkyl;

(p) R^15b, R^19band R^22beach independently represents C_1-4alkyl; or C_3-6cycloalkyl; (q) p represents 2.

(a) R²represents C_1-6alkyl substituted with one R⁵;

(b) R⁴represents hydrogen;

(d) R⁷represents hydrogen, or —C(═O)—R⁹;

(e) R⁹represents C_1-6alkyl;

(f) R³represents a 5-membered heteroaromatic ring containing two or three heteroatoms each independently selected from S, and N;

(g) R¹⁰represents —NR^11aR^11b;

(h) R¹⁸represents a 5-membered aromatic ring containing two N-atoms; wherein said 5-membered aromatic ring may optionally be substituted with one C_1-4alkyl;

(i) Het^1drepresents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or O-atom;

(j) R^11brepresents C_1-4alkyl or C_3-6cycloalkyl;

(k) R¹³represents —O—C_1-4alkyl, —C(═O)NR^15aR^15b, or Het^1d;

(l) R^11aand R^15aeach independently represents hydrogen or C_1-4alkyl;

(m) R^15brepresents C_3-6cycloalkyl.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R^6brepresents hydrogen; C_1-4alkyl; C_3-6cycloalkyl; —C(═O)—C_1-4alkyl; —C(═O)—C_1-4alkyl substituted with one substituent selected from the group consisting of —OH and —NR^16aR^6b; or C_1-4alkyl substituted with one —OH substituent;

R⁷represents hydrogen, C_1-4alkyl, —C_1-4alkyl-NR^8aR^8b, or —C(═O)—R⁹;

R⁹represents C_1-6alkyl, or C_1-6alkyl substituted with one substituent selected from the group consisting of —NH₂, and —COOH;

R³represents a 5-membered heteroaromatic ring containing one, two or three heteroatoms each independently selected from O, S, and N;

wherein said 5-membered heteroaromatic ring may optionally be substituted, where possible, on one ring N-atom with a substituent selected from the group consisting of C_1-6alkyl; C_3-6cycloalkyl; Het^1a; R¹⁸; C_1-4alkyl substituted with one, two or three halo atoms; C_1-4alkyl substituted with one, two or three —OH substituents; C_1-6alkyl substituted with one R¹³; C_1-4alkyl substituted with one R¹⁸; C_2-6alkenyl; and C_2-6alkenyl substituted with one R¹³; provided that when Het^1aor R¹⁸are directly attached to the N-atom of the 5-membered heteroaromatic ring, said Het a or R¹⁸are attached to the N-atom via a ring carbon atom; and

wherein said 5-membered heteroaromatic ring may optionally be substituted on the ring carbon atoms with in total one or two substituents each independently selected from the group consisting of halo; cyano; C_1-6alkyl; —O—C_1-4alkyl; —C(═O)—R¹⁰; —O—C_1-4alkyl substituted with one, two or three halo atoms; —O—C_1-4alkyl-R¹²; C_3-6cycloalkyl; —O—C_3-6cycloalkyl; Het^1a; —O-Het^1b; R¹⁸; —P(═O)—(C_1-4alkyl)₂; —NH—C(═O)—C_1-4alkyl; —NH—C(═O)—Het^1g; —NR^17aR^17b; C_1-4alkyl substituted with one, two or three halo atoms; C_1-4alkyl substituted with one, two or three —OH substituents; C_1-6alkyl substituted with one R¹³; C_1-4alkyl substituted with one R¹⁸; C_2-6alkenyl; and C_2-6alkenyl substituted with one R¹³;

Het^1a, and Het^1deach independently represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O, S, S(═O)_pand N;

wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of —OH, oxo, halo, C_1-4alkyl, cyano, —C(═O)—C_1-4alkyl, —O—C_1-4alkyl, —NH₂, —NH(C_1-4alkyl), and —N(C_1-4alkyl)₂;

Het^1b, Het^1e, and Het^1geach independently represents a 4- to 7-membered monocyclic saturated heterocyclyl, attached to the remainder of the molecule of Formula (I) through any available ring carbon atom, said Het^1b, Het^1e, and Het^1gcontaining one or two heteroatoms each independently selected from O, S, S(═O)_pand N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with a substituent each independently selected from the group consisting of C_1-4alkyl, C_3-6cycloalkyl, and C_1-4alkyl substituted with one substituent selected from the group consisting of —OH and —O—C_1-4alkyl; and

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wherein (b-1) may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of halo, —OH, cyano, C_1-4alkyl, —O—C_1-4alkyl, —NH₂, —NH(C_1-4alkyl), —N(C_1-4alkyl)₂, and C_1-4alkyl-OH; R^11brepresents hydrogen; Het^1e; C_1-4alkyl; C_1-4alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C_1-4alkyl; C_3-6cycloalkyl; or C_3-6cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C_1-4alkyl;

R¹³represents —O—C_1-4alkyl, —C(═O)OH, —C(═O)NR^15aR^15b, —NR^19aR^19b, C_3-6cycloalkyl, Het^1d, —S(═O)₂—C_1-4alkyl, or —C(═O)—Het^f;

R¹²represents —OH, —O—C_1-4alkyl, —NR^4aR^14b, —C(═O)NR^14cR^14d, —S(═O)₂—C₄alkyl, C_3-6cycloalkyl;

Het^3a, and Het^1feach independently represents a heterocyclyl of formula (c-1):

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R²represents C_1-6alkyl substituted with one R⁵;

R⁴represents hydrogen;

R⁵represents —OR⁷;

R⁷represents hydrogen, or —C(═O)—R⁹;

R⁹represents C_1-6alkyl;

R³represents a 5-membered heteroaromatic ring containing two or three heteroatoms each independently selected from S, and N;

R¹⁰represents —NR^11aR^11b;

R¹⁸represents a 5-membered aromatic ring containing two N-atoms; wherein said 5-membered aromatic ring may optionally be substituted with one C_1-4alkyl; Het^1drepresents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or O-atom;

R^11brepresents C_1-4alkyl or C_3-6cycloalkyl;

R¹³represents —O—C_1-4alkyl, —C(═O)NR^15aR^15b, or Het^1d;

R^11aand R^15aeach independently represents hydrogen or C_1-4alkyl;

R^15brepresents C_3-6cycloalkyl.

In an embodiment, the present invention relates to a subgroup of Formula (I), hereby named compounds of Formula (I′):

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wherein R¹represents C_1-4alkyl;

R²represents C_1-6alkyl substituted with one R⁵;

in particular wherein R¹represents C_1-4alkyl;

R²represents C_1-6alkyl substituted with one R⁵;

R⁵represents —OR⁷;

more in particular wherein R¹represents C_1-4alkyl;

R²represents C_1-6alkyl substituted with one R⁵;

R⁵represents —OR⁷;

R⁷represents hydrogen;

and wherein all other variables are defined according to any of the other embodiments.

R¹represents methyl;

R²represents methyl or —CH₂—OH.

R⁷represents hydrogen.

R⁵represents —OR⁷; and

R⁷represents hydrogen.

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each optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

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each substituted on the NH with C_1-4alkyl.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het^1a, Het^1cand Het^1deach independently represents morpholinyl, piperidinyl, pyrrolidinyl, oxetanyl, azetidinyl, piperazinyl, tetrahydro-2H-pyranyl, tetrahydrofuranyl, or hexahydro-1,4-oxazepinyl,

each optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het^1a, Het^1cand Het^1drepresent morpholinyl, in particular 1-morpholinyl, optionally substituted where possible on carbon and/or nitrogen atoms according to any of the other embodiments.

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each optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het^1b, Het^1e, Het^1gand Het⁴each independently represents morpholinyl, piperidinyl, pyrrolidinyl, oxetanyl, azetidinyl, piperazinyl, tetrahydro-2H-pyranyl, tetrahydrofuranyl, or hexahydro-1,4-oxazepinyl, attached to the remainder of the molecule of Formula (I) through any available ring carbon atom,

each optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het^1b, Het^1e, Het^1gand Het⁴each independently represents piperidinyl, tetrahydro-2H-pyranyl, or pyrrolidinyl, attached to the remainder of the molecule of Formula (I) through any available ring carbon atom,

each optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

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each optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

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optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

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each optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

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each optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

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each optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

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each optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

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each optionally substituted according to any of the other embodiments.

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each optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

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each optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het^1a, Het^1cand Het^1deach independently represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O, S, S(═O)_pand N;

wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of —OH, oxo, halo, C_1-4alkyl, cyano, —C(═O)—C_1-4alkyl, —O—C_1-4alkyl, —NH₂, —NH(C_1-4alkyl), and —N(C_1-4alkyl)₂;

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Het^1arepresents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O, S, S(═O)_pand N; or a 6- to 11-membered bicyclic saturated heterocyclyl, including fused, spiro and bridged cycles, containing one, two or three heteroatoms each independently selected from O, S, S(═O)_pand N;

Het^1cand Het^1deach independently represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O, S, S(═O)_pand N; or in case Het¹C and Het^1dare attached to the remainder of the molecule of Formula (I) through an N-atom, Het^1cand Het^1dmay also represent a N-linked 6- to 11-membered bicyclic saturated heterocyclyl, including fused, spiro and bridged cycles, optionally containing one or two additional heteroatoms each independently selected from O, S, S(═O)_pand N;

wherein said 4- to 7-membered monocyclic saturated heterocyclyl or said N-linked 6- to 11-membered bicyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with a substituent each independently selected from the group consisting of C_1-4alkyl, C_3-6cycloalkyl, C_1-4alkyl substituted with one, two or three halo atoms, and C_1-4alkyl substituted with one substituent selected from the group consisting of —OH, —C(═O)—OH, —C(═O)—NR^22aR^22band —O—C_1-4alkyl; and wherein said 4- to 7-membered monocyclic saturated heterocyclyl or said N-linked 6- to 11-membered bicyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of —OH, oxo, halo, C_1-4alkyl, cyano, —C(═O)—C_1-4alkyl, —O—C_1-4alkyl, —NH₂, —NH(C_1-4alkyl), and —N(C_1-4alkyl)₂.

R³represents a 5-membered heteroaromatic ring selected from the following structures

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each optionally substituted according to any of the other embodiments (on the carbon and/or nitrogen atoms).

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R³represents pyrazolyl optionally substituted on one ring N-atom with a substituent selected from the group consisting of C_1-6alkyl; C_3-6cycloalkyl; Het^1a; R¹⁸; R²¹; C_1-4alkyl substituted with one, two or three halo atoms; C_1-4alkyl substituted with one, two or three —OH substituents; C_1-6alkyl substituted with one R¹³; C_1-4alkyl substituted with one R¹⁸; C_2-6alkenyl; and C_2-6alkenyl substituted with one R¹³; provided that when Het^1aor R¹⁸are directly attached to the N-atom of the 5-membered heteroaromatic ring, said Het^1aor R¹⁸are attached to the N-atom via a ring carbon atom; and

R³represents pyrazolyl optionally substituted on one ring N-atom with a substituent selected from the group consisting of C_1-6alkyl; C_3-6cycloalkyl; Het^1a; R¹⁸; R²¹; C_1-4alkyl substituted with one, two or three halo atoms; C_1-6alkyl substituted with one, two or three —OH substituents; C_1-6alkyl substituted with one R¹³; —C_1-4alkyl-O—C_1-4alkyl substituted with one or two —OH substituents; C_1-4alkyl substituted with one R¹⁸; C_2-6alkenyl; and C_2-6alkenyl substituted with one R¹³; provided that when Het^1aor R¹⁸are directly attached to the N-atom of the 5-membered heteroaromatic ring, said Het^1aor R¹⁸are attached to the N-atom via a ring carbon atom; and

wherein said 5-membered heteroaromatic ring may optionally be substituted on the ring carbon atoms with in total one or two substituents each independently selected from the group consisting of halo; cyano; C_1-6alkyl; —O—C_1-4alkyl; —C(═O)—R¹⁰; —S(═O)₂—C_1-4alkyl; —S(═O)(═N—R^20a)—C_1-4alkyl; —O—C_1-4alkyl substituted with one, two or three halo atoms; —O—C_1-4alkyl-R¹²; C_3-6cycloalkyl; —O—C_3-6cycloalkyl; Het^1a; —O-Het^1b; R¹; R²¹; —P(═O)—(C_1-4alkyl)₂; —NH—C(═O)—C_1-4alkyl; —NH—C(═O)—Het^1g; —NR^17aR^17b; C_1-4alkyl substituted with one, two or three halo atoms; C_1-4alkyl substituted with one, two or three —OH substituents; C_1-6alkyl substituted with one R¹³; C_1-4alkyl substituted with one R¹⁸; C_2-6alkenyl; and C_2-6alkenyl substituted with one R¹³.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R¹³represents —O—C_1-4alkyl, —C(═O)NR^15aR^15b, —NR^19aR^19b, C_3-6cycloalkyl, Het^1d, —S(═O)₂—C_1-4alkyl, —S(═O)(═N—R^20c)—C_1-4alkyl, or —C(═O)—Het^1f.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R¹³represents —O—C_1-4alkyl, —C(═O)NR^15aR^15b, —NR^19aR^19b, C_3-6cycloalkyl, Het^1d, Het⁷, —S(═O)₂—C_1-4alkyl, —S(═O)(═N—R^20c)—C_1-4alkyl, or —C(═O)—Het^1f.

R¹⁸represents

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In an embodiment, the present invention relates to a subgroup of Formula (I), hereby named compounds of Formula (I-x), and the pharmaceutically acceptable addition salts, and the solvates thereof:

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wherein all variables are defined according to any of the other embodiments.

In an embodiment, the present invention relates to a subgroup of Formula (I), hereby named compounds of Formula (I-y), and the pharmaceutically acceptable addition salts, and the solvates thereof:

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wherein all variables are defined according to any of the other embodiments.

In an embodiment, the present invention relates to a subgroup of Formula (I), hereby named compounds of Formula (I″), and the pharmaceutically acceptable addition salts, and the solvates thereof:

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wherein all variables are defined according to any of the other embodiments.

In an embodiment, the present invention relates to a subgroup of Formula (I) as defined in the general reaction schemes.

In an embodiment the compound of Formula (I) is selected from the group consisting of compounds 19, 42, 49, 107, 113, 114, 118, 120, 132, 145, 156, 164, 183 and 177, tautomers and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof.

In an embodiment the compound of Formula (I) is selected from the group consisting of compounds 19, 42, 49, 107, 113, 114, 118, 120, 132, 145, 156, 164, 183 and 177.

In an embodiment the compound of Formula (I) is selected from the group consisting of any of the exemplified compounds,

tautomers and stereoisomeric forms thereof,

and the free bases, the pharmaceutically acceptable addition salts, and the solvates thereof.

All possible combinations of the above-indicated embodiments are considered to be embraced within the scope of this invention.

Methods for the Preparation of Compounds of Formula (I)

In this section, as in all other sections unless the context indicates otherwise, references to Formula (I) also include all other sub-groups and examples thereof as defined herein.

The general preparation of some typical examples of the compounds of Formula (I) is described hereunder and in the specific examples, and are generally prepared from starting materials which are either commercially available or prepared by standard synthetic processes commonly used by those skilled in the art. The following schemes are only meant to represent examples of the invention and are in no way meant to be a limit of the invention.

Alternatively, compounds of the present invention may also be prepared by analogous reaction protocols as described in the general schemes below, combined with standard synthetic processes commonly used by those skilled in the art of organic chemistry.

The skilled person will realise that functionalization reactions illustrated in the Schemes below for compounds of Formula (I) wherein Y is CR⁴, may also be carried out for compounds wherein Y is N. The skilled person will realise this applies, for example and without limitation, to steps 3 and 4 of scheme 2 and scheme 20.

The skilled person will realize that in the reactions described in the Schemes, although this is not always explicitly shown, it may be necessary to protect reactive functional groups (for example hydroxy, amino, or carboxy groups) where these are desired in the final product, to avoid their unwanted participation in the reactions. For example in Scheme 6, the NH moiety on the pyrimidinyl or the cyanoindoline moiety can be protected with a t-butoxycarbonyl protecting group. In general, conventional protecting groups can be used in accordance with standard practice. The protecting groups may be removed at a convenient subsequent stage using methods known from the art. This is illustrated in the specific examples.

The skilled person will realize that in the reactions described in the Schemes, it may be advisable or necessary to perform the reaction under an inert atmosphere, such as for example under N₂-gas atmosphere.

It will be apparent for the skilled person that it may be necessary to cool the reaction mixture before reaction work-up (refers to the series of manipulations required to isolate and purify the product(s) of a chemical reaction such as for example quenching, column chromatography, extraction).

The skilled person will realize that heating the reaction mixture under stirring may enhance the reaction outcome. In some reactions microwave heating may be used instead of conventional heating to shorten the overall reaction time.

The skilled person will realize that another sequence of the chemical reactions shown in the Schemes below, may also result in the desired compound of formula (I).

The skilled person will realize that intermediates and final compounds shown in the schemes below may be further functionalized according to methods well-known by the person skilled in the art.

It will be clear for a skilled person that in case a variable in a specific general scheme is not defined, the variable is defined according to the scope of the present invention, or as defined in any one of the other general schemes.

In general, compounds of Formula (I) wherein R²is R^2abeing C_1-6alkyl, and wherein all the other variables are defined according to the scope of the present invention, hereby named compounds of Formula (Ia), can be prepared according to the following reaction Scheme 1. In Scheme 1 halo¹is defined as Cl, Br or I; and PG¹represents a suitable protecting group, such as for example tert-(butoxycarbonyl). All other variables in Scheme 1 are defined according to the scope of the present invention.

In Scheme 1, the following reaction conditions apply:

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The skilled person will understand that the reactions described in Scheme 1 will also be applicable starting from an intermediate of formula (III-a) (as described in Scheme 23).

In general, compounds of Formula (I) wherein R²is R^2abeing C_1-6alkyl, a-1 is a 5-membered heteroaromatic ring containing one, two or three heteroatoms each independently selected from O, S, and N, substituted with —C(═O)—R¹⁰and additionally optionally substituted with other substituents according to the scope of the present invention, and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (Ib), can be prepared according to the following reaction Scheme 2. In Scheme 2, halo¹is defined as Cl, Br or I; PG¹represents a suitable protecting group, such as for example tert-(butoxycarbonyl). All other variables in Scheme 2 are defined as before or according to the scope of the present invention.

In Scheme 2, the following reaction conditions apply:

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In general, compounds of Formula (I) wherein R²is R^2bbeing C_1-6alkyl substituted with one OH, and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (Ic), can be prepared according to the following reaction Scheme 3. In Scheme 3 halo¹is defined as Cl, Br or I; PG¹represents a suitable protecting group, such as for example tert-(butoxycarbonyl) and PG²represents a suitable protecting group, such as for example tert-butyl-dimethylsilyl. All other variables in Scheme 3 are defined as before or according to the scope of the present invention.

In Scheme 3, the following reaction conditions apply:

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In general, compounds of Formula (I) wherein R²is R^2bbeing C_1-6alkyl substituted with one OH, R³is 5-membered heteroaromatic ring containing one, two or three heteroatoms each independently selected from O, S, and N, substituted with —C(═O)—R¹⁰and additionally optionally substituted with other substituents according to the scope of the present invention, and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (Id), can be prepared according to the following reaction Scheme 4. In Scheme 4, halo¹is defined as Cl, Br or I; PG¹represents a suitable protecting group, such as for example tert-(butoxycarbonyl) and PG²represents a suitable protecting group, such as for example tert-butyl-dimethylsilyl. All other variables in Scheme 4 are defined as before or according to the scope of the present invention.

In Scheme 4, the following reaction conditions apply:

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In general, compounds of Formula (I) wherein R²is R^2cbeing C_1-6alkyl substituted with one Het^3aor —NR^6aR^6b, wherein R^6bis R^6ba being H, C_1-4alkyl and C_3-6cycloalkyl and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (Ie) and Formula (If), can be prepared according to the following reaction Scheme 5. In Scheme 5 PG¹represents a suitable protecting group, such as for example tert-(butoxycarbonyl). All other variables in Scheme 5 are defined according to the scope of the present invention.

In Scheme 5, the following reaction conditions apply:

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In general, compounds of Formula (I) wherein R²is C_1-6alkyl substituted with one OR^7a, R^7abeing —C(═O)—R⁹or —(C═O)—CH(NH₂)—C_1-4alkyl-Art), and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (Ig), can be prepared according to the following reaction Scheme 6. In Scheme 6 PG³represents a suitable protecting group, such as for example a tert-(butoxycarbonyl), a tert-butyl or a benzyl. All other variables in Scheme 6 are defined according to the scope of the present invention.

In Scheme 6, the following reaction conditions apply:

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In general, compounds of Formula (I) wherein R²is C_1-6alkyl substituted with one OR^7b, R^7bbeing C_1-4alkyl, and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (Ih), can be prepared according to the following reaction Scheme 7. In Scheme 7 halo¹is defined as Cl, Br or I; PG¹represents a suitable protecting group, such as for example tert-(butoxycarbonyl) and PG²represents a suitable protecting group, such as for example tert-butyl-dimethylsilyl; W represents a leaving group, such as for example a methane sulfonate or toluene sulfonate or an halogen (Cl, Br or I). All other variables in Scheme 7 are defined as before or according to the scope of the present invention.

In Scheme 7, the following reaction conditions apply:

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In general, compounds of Formula (I) wherein R²is C_1-6alkyl substituted with one OR^7c, R^7cbeing C_1-4alkyl-NR^8aR^8bor C_1-4alkyl-Het^3b, and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (Ii) and Formula (Ij), can be prepared according to the following reaction Scheme 8. In Scheme 8 halo¹is defined as Cl, Br or I; PG¹represents a suitable protecting group, such as for example tert-(butoxycarbonyl); W¹represents a leaving group, such as for example a methane sulfonate or toluene sulfonate or an halogen (Cl, Br or I); W²represents a leaving group, such as for example a mesyl or a tosyl. All other variables in Scheme 8 are defined as before or according to the scope of the present invention.

In Scheme 8, the following reaction conditions apply:

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In general, intermediates of Formula (II) and (III) wherein R²is R^2abeing C_1-6alkyl, and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (II) and (III), can be prepared according to the following reaction Scheme 9. In Scheme 9 halo¹is defined as Cl, Br, I; halo²is defined as Cl, Br, I; PG¹represents a suitable protecting group, such as for example tert-(butoxycarbonyl), W¹represents a leaving group, such as for example a methane sulfonate or toluene sulfonate or an halogen (Cl, Br or I). All other variables in Scheme 9 are defined as before or according to the scope of the present invention.

In Scheme 9, the following reaction conditions apply:

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In general, intermediates of Formula (XII) and (XIII) wherein R²is R^2bbeing C_1-6alkyl substituted with one OH, and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (XII) and (XIII), can be prepared according to the following reaction Scheme 10. In Scheme 10 halo¹is defined as Cl, Br, I; halo²is defined as Cl, Br, I; PG¹represents a suitable protecting group, such as for example tert-(butoxycarbonyl) and PG²represents a suitable protecting group, such as for example tert-butyl-dimethylsilyl; W¹represents a leaving group, such as for example a methane sulfonate or toluene sulfonate or an halogen (Cl, Br or I). All other variables in Scheme 10 are defined as before or according to the scope of the present invention.

In Scheme 10, the following reaction conditions apply:

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In general, compounds of Formula (I) wherein R²is as shown in the scheme 11, and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (Ik) can be prepared according to the following reaction Scheme 11. In Scheme 11 PG¹represents a suitable protecting group, such as for example tert-(butoxycarbonyl). All other variables in Scheme 11 are defined as before or according to the scope of the present invention.

In Scheme 11, the following reaction conditions apply:

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In general, compounds of Formula (I) wherein R²is as shown in the scheme 12, and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (Il) can be prepared according to the following reaction Scheme 12. In Scheme 12 PG¹represents a suitable protecting group, such as for example tert-(butoxycarbonyl). All other variables in Scheme 12 are defined as before or according to the scope of the present invention.

In Scheme 12, the following reaction conditions apply:

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In general, compounds of Formula (I) wherein R²is as shown in the scheme 13 and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (Im) can be prepared according to the following reaction Scheme 13. In Scheme 13 PG¹represents a suitable protecting group, such as for example tert-(butoxycarbonyl). All other variables in Scheme 13 are defined as before or according to the scope of the present invention.

In Scheme 13, the following reaction conditions apply:

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In general, compounds of Formula (I) wherein R²is being C_1-6alkyl substituted with one Het^3aor —NR^6aR^6b, wherein R^6ais being H, R is being —C(═O)—C_1-4alkyl; —C(═O)-Het⁴; —S(═O)₂—C_1-4alkyl and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (In), Formula (Io) and Formula (Ip), can be prepared according to the following reaction Scheme 14. In Scheme 14, PG¹represents a suitable protecting group, such as for example tert-(butoxycarbonyl). All other variables in Scheme 14 are defined as before or according to the scope of the present invention.

In Scheme 14, the following reaction conditions apply:

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In general, compounds of Formula (I) wherein R²is being C_1-6alkyl substituted with one Het^3aor —NR^6aR^6b, wherein R^6ais being C_1-4alkyl, R^6bis being —C(═O)—C_1-4alkyl; —C(═O)—Het⁴; —S(═O)₂—C_1-4alkyl and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (Iq), Formula (Ir) and Formula (Is), can be prepared according to the following reaction Scheme 15. In Scheme 15, PG¹represents a suitable protecting group, such as for example tert-(butoxycarbonyl). All other variables in Scheme 15 are defined as before or according to the scope of the present invention.

In Scheme 15, the following reaction conditions apply:

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In general, compounds of Formula (I) wherein R²is C_1-6alkyl substituted with one OR^7d, R^7dbeing —S(═O)₂—OH or —P(═O)—(OH)₂, and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (It) and Formula (Iu), can be prepared according to the following reaction Scheme 16. All other variables in Scheme 16 are defined as before or according to the scope of the present invention. In Scheme 16, the following reaction conditions apply:

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In general, compounds of Formula (I) wherein R²is R^2abeing C_1-6alkyl, R³is restricted to a-2 being a pyrazolyl substituted on one ring N-atom with a group consisting of C_1-4alkyl substituted with —C(═O)NR^15aR^1bor —C(═O)—Het^1f, and additionally optionally substituted with other substituents according to the scope of the present invention, and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (Iv), can be prepared according to the following reaction Scheme 17. In Scheme 17, PG¹represents a suitable protecting group, such as for example tert-(butoxycarbonyl). All other variables in Scheme 17 are defined as before or according to the scope of the present invention.

In Scheme 17, the following reaction conditions apply:

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In general, compounds of Formula (I) wherein R²is R^2bbeing C_1-6alkyl substituted with one OH, R³is restricted to a-2 being a pyrazolyl substituted on one ring N-atom with a group consisting of C_1-4alkyl substituted with —C(═O)NR^15aR^15bor —C(═O)—Het^1fand additionally optionally substituted with other substituents according to the scope of the present invention, and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (Ix), can be prepared according to the following reaction Scheme 18. In Scheme 18, PG¹represents a suitable protecting group, such as for example tert-(butoxycarbonyl) and PG²represents a suitable protecting group, such as for example tert-butyl-dimethylsilyl. All other variables in Scheme 18 are defined according to the scope of the present invention. In Scheme 18, the following reaction conditions apply:

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In general, intermediates of Formula (XII) wherein all the variables are as defined according to the scope of the present invention or as defined before, can be prepared according to the following reaction Scheme 19. All other variables in Scheme 19 are as defined before.

In Scheme 19, the following reaction conditions apply:

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In general, compounds of Formula (I) wherein R²is R^2dbeing C_1-6alkyl substituted one fluorine, Y is CR⁴, and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (Iz), can be prepared according to the following reaction Scheme 18.

In Scheme 20, the following reaction conditions apply:

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In general, compounds of Formula (I) wherein R²is R^2bbeing C_1-6alkyl substituted with one OH, Y is N, and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (Iz), can be prepared according to the following reaction Scheme 21. In Scheme 21, halo¹is defined as Cl, Br or I; PG¹represents a suitable protecting group, such as for example tert-(butoxycarbonyl) and PG²represents a suitable protecting group, such as for example tert-butyl-dimethylsilyl. All other variables in Scheme 21 are defined according to the scope of the present invention.

In Scheme 21, the following reaction conditions apply:

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In general, compounds of Formula (I) wherein R²is R^2bbeing C_1-6alkyl substituted with one OH, Y is CR⁴, and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (Ic), can be prepared according to the following reaction Scheme 22. All other variables in Scheme 22 are defined according to the scope of the present invention or as above.

In Scheme 22, the following reaction conditions apply:

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Intermediate of Formula (IIIa) wherein R²is R^2ebeing C_1-6alkyl or C_1-6alkyl substituted with one, two or three fluoro atoms, and wherein all the other variables are defined according to the scope of the present invention, can be prepared according to the following reaction All other variables in Scheme 23 are defined according to the scope of the present invention.

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In general, compounds of Formula (I) wherein R²is R^2cbeing C_1-6alkyl substituted with NH₂and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (If-a), can be prepared according to the following reaction Scheme 24. In Scheme 24, PG¹represents a suitable protecting group, such as for example tert-(butoxycarbonyl). All other variables in Scheme 24 are defined according to the scope of the present invention.

In Scheme 24, the following reaction conditions apply:

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In general, intermediate of formula C wherein all the variables are as defined according to the scope of the present invention or as defined above can be prepared according to the following reaction Scheme 25.

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It will be appreciated that where appropriate functional groups exist, compounds of various formulae or any intermediates used in their preparation may be further derivatised by one or more standard synthetic methods employing condensation, substitution, oxidation, reduction, or cleavage reactions. Particular substitution approaches include conventional alkylation, arylation, heteroarylation, acylation, sulfonylation, halogenation, nitration, formylation and coupling procedures.

The compounds of Formula (I) may be synthesized in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of Formula (I) containing a basic nitrogen atom may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of Formula (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.

In the preparation of compounds of the present invention, protection of remote functionality (e.g., primary or secondary amine) of intermediates may be necessary. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. Suitable amino-protecting groups (NH-Pg) include acetyl, trifluoroacetyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection is readily determined by one skilled in the art. For a general description of protecting groups and their use, see T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 4th ed., Wiley, Hoboken, N.J., 2007.

Pharmacology

It has been found that the compounds of the present invention inhibit NF-κB-inducing kinase (NIK—also known as MAP3K14). Some of the compounds of the present invention may undergo metabolism to a more active form in vivo (prodrugs). Therefore the compounds according to the invention and the pharmaceutical compositions comprising such compounds may be useful for treating or preventing diseases such as cancer, inflammatory disorders, metabolic disorders including obesity and diabetes, and autoimmune disorders. In particular, the compounds according to the present invention and the pharmaceutical compositions thereof may be useful in the treatment of a haematological malignancy or solid tumour. In a specific embodiment said haematological malignancy is selected from the group consisting of multiple myeloma, non-Hodgkin's lymphoma, Hodgkin lymphoma, T-cell leukaemia, mucosa-associated lymphoid tissue lymphoma, diffuse large B-cell lymphoma and mantle cell lymphoma, in a particular embodiment mantle cell lymphoma. In another specific embodiment of the present invention, the solid tumour is selected from the group consisting of pancreatic cancer, breast cancer, melanoma and non-small cell lung cancer.

Examples of cancers which may be treated (or inhibited) include, but are not limited to, a carcinoma, for example a carcinoma of the bladder, breast, colon (e.g. colorectal carcinomas such as colon adenocarcinoma and colon adenoma), kidney, urothelial, uterus, epidermis, liver, lung (for example adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas, squamous lung cancer), oesophagus, head and neck, gall bladder, ovary, pancreas (e.g. exocrine pancreatic carcinoma), stomach, gastrointestinal (also known as gastric) cancer (e.g. gastrointestinal stromal tumours), cervix, endometrium, thyroid, prostate, or skin (for example squamous cell carcinoma or dermatofibrosarcoma protuberans); pituitary cancer, a hematopoietic tumour of lymphoid lineage, for example leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, B-cell lymphoma (e.g. diffuse large B-cell lymphoma, mantle cell lymphoma), T-cell leukaemia/lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, or Burkett's lymphoma; a hematopoietic tumour of myeloid lineage, for example leukemias, acute and chronic myelogenous leukemias, chronic myelomonocytic leukemia (CMML), myeloproliferative disorder, myeloproliferative syndrome, myelodysplastic syndrome, or promyelocytic leukemia; multiple myeloma; thyroid follicular cancer; hepatocellular cancer, a tumour of mesenchymal origin (e.g. Ewing's sarcoma), for example fibrosarcoma or rhabdomyosarcoma; a tumour of the central or peripheral nervous system, for example astrocytoma, neuroblastoma, glioma (such as glioblastoma multiforme) or schwannoma; melanoma; seminoma; teratocarcinoma; osteosarcoma; xeroderma pigmentosum; keratoctanthoma; thyroid follicular cancer; or Kaposi's sarcoma.

Particular examples of cancers which may be treated (or inhibited) include B-cell malignancies, such as multiple myeloma, hodgkins lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma or chronic lymphocytic leukemia, with mutations in the non-canonical NFkB signalling pathway (eg in NIK (MAP3K14), TRAF3, TRAF2, BIRC2 or BIRC3 genes).

Hence, the invention relates to compounds of Formula (I), the tautomers and the stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof, for use as a medicament.

The invention also relates to the use of a compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable addition salt, or a solvate thereof, or a pharmaceutical composition according to the invention, for the manufacture of a medicament.

The present invention also relates to a compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable addition salt, or a solvate thereof, or a pharmaceutical composition according to the invention, for use in the treatment, prevention, amelioration, control or reduction of the risk of disorders associated with NF-κB-inducing kinase dysfunction in a mammal, including a human, the treatment or prevention of which is affected or facilitated by inhibition of NF-κB-inducing kinase.

Also, the present invention relates to the use of a compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable addition salt, or a solvate thereof, or a pharmaceutical composition according to the invention, for the manufacture of a medicament for treating, preventing, ameliorating, controlling or reducing the risk of disorders associated with NF-κB-inducing kinase dysfunction in a mammal, including a human, the treatment or prevention of which is affected or facilitated by inhibition of NF-κB-inducing kinase.

The invention also relates to a compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable addition salt, or a solvate thereof, for use in the treatment or prevention of any one of the diseases mentioned hereinbefore. The invention also relates to a compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable addition salt, or a solvate thereof, for use in treating or preventing any one of the diseases mentioned hereinbefore.

The invention also relates to the use of a compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable addition salt, or a solvate thereof, for the manufacture of a medicament for the treatment or prevention of any one of the disease conditions mentioned hereinbefore.

The compounds of the present invention can be administered to mammals, preferably humans, for the treatment or prevention of any one of the diseases mentioned hereinbefore.

In view of the utility of the compounds of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable addition salt, or a solvate thereof, there is provided a method of treating warm-blooded animals, including humans, suffering from any one of the diseases mentioned hereinbefore.

Said method comprises the administration, i.e. the systemic or topical administration, preferably oral administration, of a therapeutically effective amount of a compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable addition salt, or a solvate thereof, to warm-blooded animals, including humans.

Therefore, the invention also relates to a method for the treatment of any one of the diseases mentioned hereinbefore comprising administering a therapeutically effective amount of compound according to the invention to a patient in need thereof.

One skilled in the art will recognize that a therapeutically effective amount of the compounds of the present invention is the amount sufficient to have therapeutic activity and that this amount varies inter alias, depending on the type of disease, the concentration of the compound in the therapeutic formulation, and the condition of the patient. Generally, the amount of a compound of the present invention to be administered as a therapeutic agent for treating the disorders referred to herein will be determined on a case by case by an attending physician.

Those of skill in the treatment of such diseases could determine the effective therapeutic daily amount from the test results presented hereinafter. An effective therapeutic daily amount would be from about 0.005 mg/kg to 50 mg/kg, in particular 0.01 mg/kg to 50 mg/kg body weight, more in particular from 0.01 mg/kg to 25 mg/kg body weight, preferably from about 0.01 mg/kg to about 15 mg/kg, more preferably from about 0.01 mg/kg to about 10 mg/kg, even more preferably from about 0.01 mg/kg to about 1 mg/kg, most preferably from about 0.05 mg/kg to about 1 mg/kg body weight. A particular effective therapeutic daily amount might be from about 10 mg/kg body weight to 40 mg/kg body weight. A particular effective therapeutic daily amount might be 1 mg/kg body weight, 2 mg/kg body weight, 4 mg/kg body weight, or 8 mg/kg body weight. The amount of a compound according to the present invention, also referred to here as the active ingredient, which is required to achieve a therapeutically effect may vary on case-by-case basis, for example with the particular compound, the route of administration, the age and condition of the recipient, and the particular disorder or disease being treated. A method of treatment may also include administering the active ingredient on a regimen of between one and four intakes per day. In these methods of treatment the compounds according to the invention are preferably formulated prior to administration. As described herein below, suitable pharmaceutical formulations are prepared by known procedures using well known and readily available ingredients.

The present invention also provides compositions for preventing or treating the disorders referred to herein. Said compositions comprising a therapeutically effective amount of a compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable addition salt, or a solvate thereof, and a pharmaceutically acceptable carrier or diluent.

While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical composition. Accordingly, the present invention further provides a pharmaceutical composition comprising a compound according to the present invention, together with a pharmaceutically acceptable carrier or diluent. The carrier or diluent must be “acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.

The pharmaceutical compositions of this invention may be prepared by any methods well known in the art of pharmacy, for example, using methods such as those described in Gennaro et al. Remington's Pharmaceutical Sciences (18^thed., Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical preparations and their Manufacture). A therapeutically effective amount of the particular compound, in base form or addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for systemic administration such as oral, percutaneous or parenteral administration; or topical administration such as via inhalation, a nose spray, eye drops or via a cream, gel, shampoo or the like. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions: or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on or as an ointment.

It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.

The present compounds can be used for systemic administration such as oral, percutaneous or parenteral administration; or topical administration such as via inhalation, a nose spray, eye drops or via a cream, gel, shampoo or the like. The compounds are preferably orally administered. The exact dosage and frequency of administration depends on the particular compound of Formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention.

The compounds of the present invention may be administered alone or in combination with one or more additional therapeutic agents. Combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound according to the present invention and one or more additional therapeutic agents, as well as administration of the compound according to the present invention and each additional therapeutic agent in its own separate pharmaceutical dosage formulation. For example, a compound according to the present invention and a therapeutic agent may be administered to the patient together in a single oral dosage composition such as a tablet or capsule, or each agent may be administered in separate oral dosage formulations.

Therefore, an embodiment of the present invention relates to a product containing as first active ingredient a compound according to the invention and as further active ingredient one or more medicinal agent, more particularly, with one or more anticancer agent or adjuvant, as a combined preparation for simultaneous, separate or sequential use in the treatment of patients suffering from cancer.

Accordingly, for the treatment of the conditions mentioned hereinbefore, the compounds of the invention may be advantageously employed in combination with one or more other medicinal agents (also referred to as therapeutic agents), more particularly, with other anti-cancer agents or adjuvants in cancer therapy. Examples of anti-cancer agents or adjuvants (supporting agents in the therapy) include but are not limited to:

- platinum coordination compounds for example cisplatin optionally combined with amifostine, carboplatin or oxaliplatin;
- taxane compounds for example paclitaxel, paclitaxel protein bound particles (Abraxane™) or docetaxel;
- topoisomerase I inhibitors such as camptothecin compounds for example irinotecan, SN-38, topotecan, topotecan hcl;
- topoisomerase II inhibitors such as anti-tumour epipodophyllotoxins or podophyllotoxin derivatives for example etoposide, etoposide phosphate or teniposide;
- anti-tumour vinca alkaloids for example vinblastine, vincristine or vinorelbine;
- anti-tumour nucleoside derivatives for example 5-fluorouracil, leucovorin, gemcitabine, gemcitabine hcl, capecitabine, cladribine, fludarabine, nelarabine;
- alkylating agents such as nitrogen mustard or nitrosourea for example cyclophosphamide, chlorambucil, carmustine, thiotepa, mephalan (melphalan), lomustine, altretamine, busulfan, dacarbazine, estramustine, ifosfamide optionally in combination with mesna, pipobroman, procarbazine, streptozocin, temozolomide, uracil;
- anti-tumour anthracycline derivatives for example daunorubicin, doxorubicin optionally in combination with dexrazoxane, doxil, idarubicin, mitoxantrone, epirubicin, epirubicin hcl, valrubicin;
- molecules that target the IGF-1 receptor for example picropodophilin;
- tetracarcin derivatives for example tetrocarcin A;
- glucocorticoiden for example prednisone;
- antibodies for example trastuzumab (HER2 antibody), rituximab (CD20 antibody), gemtuzumab, gemtuzumab ozogamicin, cetuximab, pertuzumab, bevacizumab, alemtuzumab, eculizumab, ibritumomab tiuxetan, nofetumomab, panitumumab, tositumomab, CNTO 328;
- estrogen receptor antagonists or selective estrogen receptor modulators or inhibitors of estrogen synthesis for example tamoxifen, fulvestrant, toremifene, droloxifene, faslodex, raloxifene or letrozole;
- aromatase inhibitors such as exemestane, anastrozole, letrazole, testolactone and vorozole;
- differentiating agents such as retinoids, vitamin D or retinoic acid and retinoic acid metabolism blocking agents (RAMBA) for example accutane;
- DNA methyl transferase inhibitors for example azacytidine or decitabine;
- antifolates for example pemetrexed disodium;
- antibiotics for example antinomycin D, bleomycin, mitomycin C, dactinomycin, carminomycin, daunomycin, levamisole, plicamycin, mithramycin;
- antimetabolites for example clofarabine, aminopterin, cytosine arabinoside or methotrexate, azacytidine, cytarabine, floxuridine, pentostatin, thioguanine;
- apoptosis inducing agents and antiangiogenic agents such as Bcl-2 inhibitors for example YC 137, BH 312, ABT 737, gossypol, HA 14-1, TW 37 or decanoic acid;
- tubuline-binding agents for example combrestatin, colchicines or nocodazole;
- kinase inhibitors (e.g. EGFR (epithelial growth factor receptor) inhibitors, MTKI (multi target kinase inhibitors), mTOR inhibitors) for example flavoperidol, imatinib mesylate, erlotinib, gefitinib, dasatinib, lapatinib, lapatinib ditosylate, sorafenib, sunitinib, sunitinib maleate, temsirolimus;
- farnesyltransferase inhibitors for example tipifamib;
- histone deacetylase (HDAC) inhibitors for example sodium butyrate, suberoylanilide hydroxamic acid (SAHA), depsipeptide (FR 901228), NVP-LAQ824, R306465, quisinostat, trichostatin A, vorinostat;
- Inhibitors of the ubiquitin-proteasome pathway for example PS-341, Velcade (MLN-341) or bortezomib;
- Yondelis;
- Telomerase inhibitors for example telomestatin;
- Matrix metalloproteinase inhibitors for example batimastat, marimastat, prinostat or metastat;
- Recombinant interleukins for example aldesleukin, denileukin diftitox, interferon alfa 2a, interferon alfa 2b, peginterferon alfa 2b;
- MAPK inhibitors;
- Retinoids for example alitretinoin, bexarotene, tretinoin;
- Arsenic trioxide;
- Asparaginase;
- Steroids for example dromostanolone propionate, megestrol acetate, nandrolone (decanoate, phenpropionate), dexamethasone;
- Gonadotropin releasing hormone agonists or antagonists for example abarelix, goserelin acetate, histrelin acetate, leuprolide acetate;
- Thalidomide, lenalidomide;
- Mercaptopurine, mitotane, pamidronate, pegademase, pegaspargase, rasburicase;
- BH3 mimetics for example ABT-199;
- MEK inhibitors for example PD98059, AZD6244, CI-1040;
- colony-stimulating factor analogs for example filgrastim, pegfilgrastim, sargramostim; erythropoietin or analogues thereof (e.g. darbepoetin alfa); interleukin 11; oprelvekin; zoledronate, zoledronic acid; fentanyl; bisphosphonate; palifermin;
- a steroidal cytochrome P450 17alpha-hydroxylase-17,20-lyase inhibitor (CYP17), e.g. abiraterone, abiraterone acetate.

The one or more other medicinal agents and the compound according to the present invention may be administered simultaneously (e.g. in separate or unitary compositions) or sequentially in either order. In the latter case, the two or more compounds will be administered within a period and in an amount and manner that is sufficient to ensure that an advantageous or synergistic effect is achieved. It will be appreciated that the preferred method and order of administration and the respective dosage amounts and regimes for each component of the combination will depend on the particular other medicinal agent and compound of the present invention being administered, their route of administration, the particular tumour being treated and the particular host being treated. The optimum method and order of administration and the dosage amounts and regime can be readily determined by those skilled in the art using conventional methods and in view of the information set out herein.

The weight ratio of the compound according to the present invention and the one or more other anticancer agent(s) when given as a combination may be determined by the person skilled in the art. Said ratio and the exact dosage and frequency of administration depends on the particular compound according to the invention and the other anticancer agent(s) used, the particular condition being treated, the severity of the condition being treated, the age, weight, gender, diet, time of administration and general physical condition of the particular patient, the mode of administration as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that the effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. A particular weight ratio for the present compound of Formula (I) and another anticancer agent may range from 1/10 to 10/1, more in particular from 1/5 to 5/1, even more in particular from 1/3 to 3/1.

The platinum coordination compound is advantageously administered in a dosage of 1 to 500 mg per square meter (mg/m²) of body surface area, for example 50 to 400 mg/m², particularly for cisplatin in a dosage of about 75 mg/m²and for carboplatin in about 300 mg/m²per course of treatment.

The taxane compound is advantageously administered in a dosage of 50 to 400 mg per square meter (mg/m²) of body surface area, for example 75 to 250 mg/m², particularly for paclitaxel in a dosage of about 175 to 250 mg/m²and for docetaxel in about 75 to 150 mg/m²per course of treatment.

The camptothecin compound is advantageously administered in a dosage of 0.1 to 400 mg per square meter (mg/m²) of body surface area, for example 1 to 300 mg/m², particularly for irinotecan in a dosage of about 100 to 350 mg/m²and for topotecan in about 1 to 2 mg/m²per course of treatment.

The anti-tumour podophyllotoxin derivative is advantageously administered in a dosage of 30 to 300 mg per square meter (mg/m²) of body surface area, for example 50 to 250 mg/m², particularly for etoposide in a dosage of about 35 to 100 mg/m²and for teniposide in about 50 to 250 mg/m²per course of treatment.

The anti-tumour vinca alkaloid is advantageously administered in a dosage of 2 to 30 mg per square meter (mg/m²) of body surface area, particularly for vinblastine in a dosage of about 3 to 12 mg/m², for vincristine in a dosage of about 1 to 2 mg/m², and for vinorelbine in dosage of about 10 to 30 mg/m²per course of treatment.

The anti-tumour nucleoside derivative is advantageously administered in a dosage of 200 to 2500 mg per square meter (mg/m²) of body surface area, for example 700 to 1500 mg/m², particularly for 5-FU in a dosage of 200 to 500 mg/m², for gemcitabine in a dosage of about 800 to 1200 mg/m²and for capecitabine in about 1000 to 2500 mg/m²per course of treatment.

The alkylating agents such as nitrogen mustard or nitrosourea is advantageously administered in a dosage of 100 to 500 mg per square meter (mg/m²) of body surface area, for example 120 to 200 mg/m², particularly for cyclophosphamide in a dosage of about 100 to 500 mg/m², for chlorambucil in a dosage of about 0.1 to 0.2 mg/kg, for carmustine in a dosage of about 150 to 200 mg/m², and for lomustine in a dosage of about 100 to 150 mg/m²per course of treatment.

The anti-tumour anthracycline derivative is advantageously administered in a dosage of 10 to 75 mg per square meter (mg/m²) of body surface area, for example 15 to 60 mg/m², particularly for doxorubicin in a dosage of about 40 to 75 mg/m², for daunorubicin in a dosage of about 25 to 45 mg/m², and for idarubicin in a dosage of about 10 to 15 mg/m²per course of treatment.

The antiestrogen agent is advantageously administered in a dosage of about 1 to 100 mg daily depending on the particular agent and the condition being treated. Tamoxifen is advantageously administered orally in a dosage of 5 to 50 mg, preferably 10 to 20 mg twice a day, continuing the therapy for sufficient time to achieve and maintain a therapeutic effect. Toremifene is advantageously administered orally in a dosage of about 60 mg once a day, continuing the therapy for sufficient time to achieve and maintain a therapeutic effect. Anastrozole is advantageously administered orally in a dosage of about 1 mg once a day. Droloxifene is advantageously administered orally in a dosage of about 20-100 mg once a day. Raloxifene is advantageously administered orally in a dosage of about 60 mg once a day. Exemestane is advantageously administered orally in a dosage of about 25 mg once a day.

Antibodies are advantageously administered in a dosage of about 1 to 5 mg per square meter (mg/m²) of body surface area, or as known in the art, if different. Trastuzumab is advantageously administered in a dosage of 1 to 5 mg per square meter (mg/m²) of body surface area, particularly 2 to 4 mg/m²per course of treatment.

These dosages may be administered for example once, twice or more per course of treatment, which may be repeated for example every 7, 14, 21 or 28 days.

The following examples further illustrate the present invention.

EXAMPLES

Several methods for preparing the compounds of this invention are illustrated in the following examples. All starting materials were obtained from commercial suppliers and used without further purification, or alternatively, can be easily prepared by a skilled person according to well-known methods.

When a stereocenter is indicated with ‘RS’ this means that a racemic mixture was obtained.

For intermediates that were used in a next reaction step as a crude or as a partially purified intermediate, theoretical mol amounts are indicated in the reaction protocols described below.

Hereinafter, the terms: ‘ACN’ means acetonitrile, ‘AcOH’ means acetic acid, ‘Ar’ means argon, ‘BINAP’ means 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, ‘BOC’ means tert-butyloxycarbonyl, ‘Boc₂O’ means di-tert-butyl dicarbonate, ‘Celite®’ means diatomaceous earth, ‘Cu(OTf)₂’ means Copper(II) triflate, ‘DCM’ means dichloromethane, ‘DIPEA’ means diisopropylethylamine, ‘h’ means hours(s), ‘min’ means minute(s), ‘Int.’ means intermediate; ‘aq.’ Means aqueous; ‘DMAP’ means dimethylaminopyridine, ‘DMF’ means dimethylformamide, ‘DIBAL-H’ means diisobutylaluminium hydride, ‘EDC hydrochloride’ means 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, ‘Et₂O’ means diethylether, ‘Et’ means ethyl, ‘Me’ means methyl, ‘EtOAc’ or ‘AcOEt’ means ethyl acetate, ‘HPLC’ means High-performance Liquid Chromatography, ‘iPrOH’ means isopropyl alcohol, ‘HATU’ means 1-[bis(dimethylamino)methylene]-1H-[1,2,3]triazolo[4,5-b]pyridin-1-ium 3-oxide hexafluorophosphate, ‘HFIP’ means hexafluoroisopropanol, ‘HOBT’ means 1-Hydroxy-1H-benzotriazole, ‘MsCl’ means methanesulfonyl chloride, ‘LC/MS’ means Liquid Chromatography/Mass Spectrometry, ‘Me-THF’ means methyl-tetrahydrofuran, ‘MeOH’ means methanol, ‘EtOH’ means ethanol, ‘NBS’ means N-bromosuccinimide, ‘NCS’ means N-chlorosuccinimide, ‘NMR’ means Nuclear Magnetic Resonance, ‘Pd/C 10%’ means palladium on carbon loading 10%, ‘Pd(OAc)₂’ means palladium (II) acetate, ‘Pd(PPh₃)₄’ means tetrakis(triphenylphosphine)palladium (0), ‘Pd(dppf)Cl₂’ means [1,1′-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II), ‘rt’ or ‘RT’ means room temperature, ‘SFC’ means supercritical fluid chromatography, ‘ee’ means enantiomeric excess, ‘TBAF’ means tetrabutylammonium fluoride, ‘TBDMS’ or ‘SMDBT’ means tert-butyldimethylsilyl, ‘TEA’ means triethylamine, ‘TFA’ means trifluoroacetic acid, ‘THF’ means tetrahydrofuran, ‘CV’ means column volumes, ‘Quant.’ means quantitative, ‘equiv.’ means equivalent(s), ‘M.P.’ or ‘m.p.’ means melting point, ‘OR’ means optical rotation, ‘SFC’ means supercritical fluid chromatography, ‘DIPE’ means diisopropyl ethylether, ‘RaNi’ means Raney Nickel, ‘NaHCO₃’ means sodium hydrogenocarbonate, ‘BRETTPHOS’ means 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′, 4′, 6′-triisopropyl-1,1′-biphenyl, ‘DMSO’ means dimethylsulfoxide, ‘NaBH₃(OAc)₃’ means sodium triacetoxyborohydride, ‘DMA-DMF’ means N,N-dimethylformamidedimethylacetal, ‘v/v’ means volume/volume percent, ‘T’ means temperature, ‘TLC’ means thin layer chromatography, ‘iPrNH₂’ means isopropylamine, ‘2nd generation Xphos precatalyst’ means (chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)).

It is well known to one skilled in the art that protecting groups such as TBDMS can routinely be removed with TBAF in a variety of solvents such as for example THF. Similarly, conditions for removal of BOC protecting groups are well known to one skilled in the art, commonly including for example TFA in a solvent such as for example DCM, or HCl in a solvent such as for example dioxane.

The skilled person will realize that in some cases where an organic layer was obtained at the end of an experimental protocol, it was necessary to dry the organic layer with a typical drying agent such as for example MgSO₄, or by azeotropic distillation, and to evaporate the solvent before using the product as a starting material in the next reaction step.

A. Preparation of the Intermediates
Example A1
Preparation of Intermediate 1

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To a solution of 2,4-dibromo-6-cyanoaniline (200.00 g, 724.82 mmol) and DMAP (17.71 g, 144.96 mmol) in DCM (3 L), Boc₂O (474.58 g, 2.17 mol) was added and the reaction mixture was stirred at 45° C. for 4 h. The crude mixture was successively washed with saturated NaHCO₃(2×1 L) and brine (2×1 L), dried over MgSO₄, filtered and concentrated under vacuum to give 323 g of intermediate 1 (56% yield, yellow solid, 86% purity evaluated by LC/MS). The product was used in the next step without any further purification.

Preparation of Intermediate 2

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A mixture of intermediate 1 (620.00 g, 1.30 mol) and K₂CO₃(539.02 g, 3.90 mol) in MeOH (6 L) was stirred at 65° C. for 3 h. The reaction mixture was cooled to 25° C. filtered and concentrated under vacuum. Then, the residue was dissolved in EtOAc (4 L) and the organic layer was washed with brine (2 L), dried over MgSO₄, and filtered. The filtrate was evaporated under vacuum to 1/8 solvent, filtered to collect the solid and dried under reduced pressure to give 300 g of intermediate 2 (60% yield, yellow solid). The product was used in the next step without any further purification.

Preparation of Intermediate 3

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Intermediate 2 (100.00 g, 265.93 mmol), 2-(((tert-butyl-dimethyl-silanyl)oxy) methyl) prop-2-en-1-ol (80.72 g, 398.90 mmol) and tributylphosphane (107.61 g, 531.86 mmol) were dissolved in THF (2 L) and cooled to 0° C. A solution of (NE)-N-(piperidine-1-carbonylimino) piperidine-1-carboxamide (147.61 g, 585.05 mmol) in THF (50 mL) was added dropwise under N₂and stirred at 0° C. for 1 h, then 25° C. for 12 h. The resulting mixture was triturated with petroleum ether (3 L), filtered and concentrated under vacuum. Then, the residue was dissolved in EtOAc (6 L), washed successively with water (2×2 L) and brine (2×2 L), dried over MgSO₄, filtered and concentrated under vacuum. Three reactions (each 100 g) were carried out in parallel. The resulting residues were purified by column chromatography on silica gel (SiO₂, mobile phase: petroleum ether/EtOAc, 10:1). The desired fractions were collected and the solvent was concentrated to dryness under vacuum to give 350 g of intermediate 3 (78% yield, yellow oil).

Preparation of Intermediate 3a

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Triethylamine (196.3 mL; 1.408 mol) was added to a solution of 2-(((tert-butyl-dimethyl-silanyl)oxy) methyl) prop-2-en-1-ol (114 g, 563.3 mmol) in DCM (IL) at 0° C. Methanesulfonylchloride (56.0 mL; 704.2 mmol) was added slowly to the mixture and this mixture was stirred for 2 h at 0° C. The reaction was quenched with saturated aqueous solution of NaHCO₃(100 ml) and extracted with DCM (500 ml*2). The organic layer was dried over MgSO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (Petroleum ether/ethyl acetate from 0/100 to 5/1) to give 50 g (32%; light yellow oil) of intermediate 3a.

Alternative Preparation of Intermediate 3a

A solution of 1,3-Hydroxy-2-methylenepropane (100 g) in dry THF (200 mL) was added dropwise at 0° C. to a suspension of sodium hydride (0.95 eq.) in dry THF (600 mL). After 30 min a solution of tert-butyldimethylsilylchloride (0.95 eq.) in dry THF (200 mL) was added dropwise to the mixture. After approximately 18 hours at 0-5° C. the reaction was complete by GC and water (500 mL) was added slowly keeping the temperature between 0-5° C. After phase separation, the aqueous layer was back-extracted with ethyl acetate (500 mL) and the combined organic layers were washed with water (500 mL). The organic phase was concentrated to a residue which was azeotropically dried by co-evaporation with THF affording 252.7 g of the crude monoTBDMS-protected diol. A portion of the crude monoTBDMS-protected diol (152.4 g) was dissolved in dry dichloromethane (610 mL) and triethylamine (1.4 eq.) was added. The mixture was then stirred at 0° C. for 30 min and methanesulfonic anhydride (1.2 eq.) was added as a solution in dichloromethane (950 mL) and the mixture was stirred for 1 h between −5 and 5° C. An additional aliquot of methanesulfonic anhydride (0.1 eq.) and triethylamine (0.2 eq.) were added and, after 1 additional hour, water (500 mL) was added. After phase separation, the organic layer was washed twice with water (500 mL) and concentrated to a residue, which was re-diluted with THF and partially concentrated to obtain a solution of intermediate 3a (311.1 g, 57 weight % intermediate 3a in the solution).

Alternative Preparation of Intermediate 3

Intermediate 2 (140 g; 372.3 mmol) was dissolved in acetonitrile (1.3 L). Intermediate 3a (104.4 g; 372.3 mmol), potassium carbonate (128.6 g; 930.7 mmol), and sodium iodide (5.58 g; 37.2 mmol) were added. The mixture was stirred at 80° C. for 12 h, cooled and concentrated under reduced pressure. The residue was dissolved in water (1 L) and extracted with ethyl acetate (1 L×2). The combined organic phase was washed with brine (1 L), dried over Na₂SO₄and filtered. The filtrate was concentrated under vacuum to give a crude product. The residue was purified by silica gel chromatography (Petroleum ether/ethyl acetate from 100/0 to 40/1) to give 180 g (86%; clear oil) of intermediate 3.

Preparation of Intermediate 4 and intermediate 4′

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A suspension of intermediate 3 (120.00 g, 214.14 mmol), sodium acetate (45.67 g, 556.76 mmol), sodium formate (37.86 g, 556.76 mmol), Pd(OAc)₂(4.81 g, 21.41 mmol) and tetraethylammonium chloride (44.35 g, 267.67 mmol) in DMF (1.26 L) was degassed under vacuum, purged with Ar three times, and stirred at 85° C. for 2 h. The resulting mixture was filtered through a pad of Celite® and the solid was washed with DCM (2 L). The filtrate was concentrated under vacuum. The residue was dissolved in ethyl acetate (4 L), washed successively with water (2×2 L) and brine (2×2 L), dried over MgSO₄, filtered and concentrated under vacuum. Then, the residue was purified by column chromatography on silica gel (SiO₂, mobile phase: petroleum ether/EtOAc, 15:1). The desired fractions were collected and the solvent was concentrated to dryness under vacuum to give a mixture of intermediates 5 and 5′. Three reactions (each on 100-120 g of intermediate 3) were carried out in parallel which gave in total 160 g of a mixture of intermediates 4 and 4′ (38:62).

Alternative Preparation of Intermediate 4

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To a mixture of intermediates 4 and 4′ in CH₃CN (1.60 L), 1-bromopyrrolidine-2,5-dione (212.20 g, 1.19 mol) was added and stirred at 40° C. for 16 h. The solvent was removed by evaporation under reduced pressure. The residue was dissolved in ethyl acetate (2 L), washed successively with NaHCO₃(2×1 L) and brine (2×1 L), dried over MgSO₄and filtered. The filtrate was evaporated under vacuum and purified by column chromatography on silica gel (SiO₂, mobile phase: petroleum ether/EtOAc, 50:1). The desired fractions were collected and the solvent was concentrated to dryness under vacuum to give 110.00 g of intermediate 4 (56% yield, yellow oil, 97% purity evaluated by LC/MS).

Alternative Preparation A of Intermediate 4′

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To a solution of intermediate 3 (295.00 g, 473.70 mmol), sodium acetate (101.05 g, 1.23 mol), sodium formate dihydrate (128.15 g, 1.23 mol) and [1,1′-bis(diphenylphosphino) ferrocene] palladium, (II) chloride complex with dichloromethane (19.34 g, 23.70 mmol) in DMF (2 L), tetra-N-butylammonium chloride (164.60 g, 592.20 mmol) was added under N₂at rt. The reaction mixture was stirred overnight at 60° C., then, filtered through a pad of Celite® and the solid was washed with DCM (400 mL). The filtrate was concentrated under vacuum. The resulting residue was dissolved in EtOAc (4 L) and the organic layer was washed successively with water (2 L) and brine (2 L), dried over Na₂SO₄, filtered and concentrated to give the crude product as black oil. This residue was purified by column chromatography on silica gel (SiO₂, mobile phase: petroleum ether/EtOAc, gradient from 100:0 to 10:1). The desired fractions were collected and the solvent was concentrated to dryness under vacuum to give 155 g of intermediate 4′ (70% yield, yellow oil).

Alternative Preparation B of Intermediate 4′

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Intermediate 242 (50.0 g) was dissolved in DMF (250 mL). Sodium formate dehydrate (2.6 eq.), sodium acetate (2.6 eq.), tetraethylammonium chloride (1.25 eq.) and palladium acetate (0.05 eq.) were added. The mixture was degassed with nitrogen (3 times) and was then warmed at 45-50° C. until complete conversion (typically 24 hours monitored by HPLC). Water (350 mL) was then added followed by heptane (350 mL). The mixture was filtered and, after phase separation, the aqueous layer was extracted with heptane (350 mL). The combined organic layers were washed with water (250 mL) and then filtered on a diatomite pad (25 g; diatomaceous earth). The filtrate was concentrated to 100-150 mL, cooled to −10 to −5° C. for 2 hours and filtered to afford 37.6 g of intermediate 4′. An additional amount of intermediate 4′ could be recovered by filtering the mother liquors on a silica gel pad to remove impurities, and subsequently cool down the filtrate to −10° C. to crystallize out an additional amount of intermediate 4′.

Preparation of Intermediate 4′R

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Intermediates 4′R was obtained from a chiral chromatography separation of intermediate 4′ (column CHIRALPAK IC 5 cm*25 cm; mobile phase: hexane/EtOH:80/20; Flow rate: 60.0 mL/min; Wavelength: UV 254 nm; Temperature: 35° C.).

Preparation of Intermediate 4R and intermediate 4S

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Intermediate 4 (500 g) was purified via Normal Phase Chiral separation (Stationary phase: Daicel Chiralpak IC 2000 gram 10 microhm, mobile phase: heptane/EtOH, Isocratic 80% heptane, 20% EtOH). The fractions containing the products were mixed and concentrated to afford 266 g of intermediate 4R (53% yield, ee>98%) and 225 g of intermediate 4S (45% yield, ee>98%).

Alternatively, intermediate 4 (10 g) was purified by chiral SFC (Stationary phase: CHIRALPAK IC 5 m 250×30 mm, mobile phase: 85% CO₂, 15% iPrOH). The pure fractions were collected and evaporated to dryness yielding 4.3 g of intermediate 4R (43% yield, ee=100%) and 4.5 g of intermediate 4S (45% yield, ee=100%).

Alternative Preparation of Intermediate 4R

To a solution of intermediate 4′R (10.0 g) in ACN (100 mL) 1,3-dibromo-5,5-dimethylhydantoin (0.75 eq.) was added and the mixture was stirred at 20° C. for 24-28 hours, monitoring the conversion by HPLC. After complete conversion, aqueous 5% NaHCO₃was added (250 mL) and the mixture was stirred for 30 minutes. Toluene (250 mL) was then added and, after 30 min stirring at room temperature, the mixture was allowed to settle and the layers were separated. The organic layer was washed twice with water (100 mL) and used directly in the next step (conversion 99.6%).

Example A2
Preparation of Intermediate 5

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To a solution of intermediate 4 (127.00 g, 234.70 mmol) in 1,4-dioxane (1.2 L), bis(pinacolato)diboron (74.50 g, 293.40 mmol) and potassium acetate (69.11 g, 704.24 mmol) were added. Then, [1,1′-bis(diphenylphosphino) ferrocene] palladium, (II) chloride (8.59 g, 11.74 mmol) was added and stirred for 4 h at 85° C. under N₂atmosphere. The mixture was cooled, partitioned between EtOAc (2 L) and water (500 mL) and filtered through a pad of Celite®. The organic and aqueous layers were separated. The organic layer was washed successively with water (300 mL), brine (300 mL), dried over Na₂SO₄and concentrated under vacuum. The residue was dissolved in a mixture of DCM/EtOAc (90:10, 600 mL), filtered through a plug of flash silica gel, washed with DCM/EtOAc (90:10, 3 L). The filtrate was evaporated to give 125 g of crude intermediate 5 (brown oil) which was directly engaged in the next step.

Preparation of Intermediate 5R

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To a solution of intermediate 4R (20.00 g, 41.50 mmol) in 1,4-dioxane (200 mL), bis(pinacolato)diboron (13.20 g, 51.90 mmol) and potassium acetate (12.20 g, 124.60 mmol) were added. Then, [1,1′-bis(diphenylphosphino) ferrocene] palladium, (II) chloride complex with dichloromethane (1.70 g, 2.08 mmol) was added and stirred for 4 h at 85° C. under N₂. The mixture was cooled, partitioned between EtOAc (200 mL) and water (100 mL), and filtered through a pad of Celite®. The organic and aqueous layers were separated. The organic layer was washed successively with water (100 mL), brine (100 mL), dried over Na₂SO₄, and concentrated under vacuum. The residue was dissolved in a mixture of DCM/EtOAc (90:10, 200 mL), filtered through a plug of flash silica gel and washed with a mixture of DCM/EtOAc (90:10, 1 L). The filtrate was evaporated to give 25 g of crude intermediate 5R (brown oil) which was directly engaged in the next step.

Preparation of Intermediate 6

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A solution of intermediate 5 (160.00 g, 302.70 mmol) in 1,4-dioxane (1.2 L) was treated with a solution of NaHCO₃(76.30 g, 908.10 mmol) in water (400 mL). Then, 2,4-dichloropyrimidine (67.64 g, 545.06 mmol) and Pd(PPh₃)₄(17.50 g, 15.13 mmol) were added under N₂. The reaction mixture was stirred at 80° C. under N₂. The mixture was cooled, partitioned between EtOAc (2 L) and water (800 mL), and the mixture was filtered through a pad of Celite®. The organic and aqueous layers were separated. The organic layer was washed successively with water (800 mL) and brine (500 mL), dried over Na₂SO₄and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (SiO₂, mobile phase: petroleum ether/EtOAc, gradient from 100:0 to 10:1). The desired fractions were collected and the solvent was concentrated to dryness under vacuum to give 100 g of intermediate 6 (71% yield in 2 steps, yellow solid).

Preparation of Intermediate 6R and intermediate 6S

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Intermediate 6 (52.00 g) was purified by chiral SFC (stationary phase: CHIRALPAK IC 5 m 250×30 mm, mobile phase: 60% CO₂, 40% MeOH). The desired fractions were collected and the solvent was concentrated to dryness under vacuum to give 25 g of intermediate 6R (48% yield) and 25.1 g of intermediate 6S (48% yield).

Intermediate 6R (50.10 g) was further purified by chiral SFC (stationary phase: CHIRALPAK IA 5 m 250*20 mm, mobile phase: 87.5% CO₂, 12.5% MeOH). The pure fractions were mixed and the solvent was evaporated to afford 49.10 g of intermediate 6R.

Alternative Preparation A of Intermediate 6R

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A solution of intermediate 5R (25.00 g, 41.90 mmol) in 1,4-dioxane (1.2 L) was treated with a solution of NaHCO₃(10.50 g, 125.72 mmol) in water (80 mL). Then, 2,4-dichloropyrimidine (9.36 g, 62.86 mmol) and Pd(PPh₃)₄(2.42 g, 2.09 mmol) were added under N₂. The reaction mixture was stirred at 80° C. under N₂. The mixture was cooled, partitioned between EtOAc (300 mL) and water (100 mL), and filtered through a pad of Celite®. The organic layer was washed with water (100 mL), brine (100 mL), dried over Na₂SO₄and concentrated under vacuum. The resulting residue was combined with 3 other batches coming from reactions performed on 25 g of intermediate 5R. The residue was purified by flash column chromatography on silica gel (SiO₂, mobile phase: petroleum ether/EtOAc, gradient from 100:0 to 10:1). The desired fractions were collected and the solvent was concentrated to dryness under vacuum to give 63 g of intermediate 6R (70% yield over 2 steps, yellow solid).

Alternative Preparation B of Intermediate 6R

To a solution of intermediate 4R (50.0 g) in toluene (400 mL) was added bis(pinacolato)diboron (1.3 eq.), potassium acetate (3.0 eq.) and Pd(dppf)Cl₂(0.05 eq.). The mixture was degassed 3 times with nitrogen and heated to 90° C. for 12-14 hours. Subsequently, the mixture was cooled to room temperature and filtered on a celite pad which was washed with toluene (150 mL). The filtrate was washed with water (250 mL) and was then filtered on a silica pad (10 g) to afford a toluene solution containing 49 g of intermediate 5R. To this solution was added 2,4-dichloropyrimidine (1.5 eq.), NaHCO₃(3.0 eq.), water (25 mL) and Pd(PPh₃)₄(0.05 eq.). After degassing three times with nitrogen, the mixture was stirred at 90° C. monitoring the conversion by HPLC. After complete conversion (24-48 hours), the mixture was cooled to room temperature, filtered on a celite pad and washed with water (250 mL). To the organic layer was added silica thiol scavenging resin (10 g) and the mixture was stirred at 90° C. for 3 hours, then cooled to room temperature and filtered. The solvent was switched completely to isopropanol by repeated distillation until about 100 mL of isopropanol solution remained. The solution was warmed to 50° C. and 250 mL of methanol were added. After stirring at 50° C. for 4 hours, the mixture was cooled to 0° C. in 4 h, held at the same temperature for 16 hours and finally filtered to obtain 26 g of intermediate 6R.

Preparation of Intermediate 29

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To a solution of intermediate 7 (1.50 g, 2.91 mmol) in DCM (30 mL), TFA (7 mL, 91.50 mmol) was added at 0-5° C. and stirred at 0-5° C. for 1 h, then rt for 1 h. The crude product was poured in a mixture of crushed ice and a saturated aqueous solution of NaHCO₃. After extraction with DCM (twice), the organic layers were combined, washed with a saturated solution of NaHCO₃, dried over MgSO₄and concentrated under vacuum. The residue was purified by column chromatography on silica gel (Irregular SiOH, 40 m, mobile phase: NH₄OH/MeOH/DCM, gradient from 0% NH₄OH, 0% MeOH, 100% DCM to 0.1% NH₄OH, 2% MeOH, 98% DCM). The desired fractions were collected and the solvent was concentrated to dryness under vacuum to give 524 mg of intermediate 7 (65% yield).

Example A3
Preparation of Intermediate 305

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In a three neck round bottom flask, SiO₂(35-70 m) (200 g) was added to a solution of intermediate 6R (45.00 g, 87.36 mmol) in toluene (640 mL) at rt. The reaction mixture was reflux (bath temperature 125° C.) for 6 h under mechanical agitation. Then, SiO₂(35-70 m) was filtered off, washed successively with THF and EtOAc, and the filtrate was evaporated to dryness to give 37.2 g of crude intermediate 305 which was directly engaged in the next steps.

Alternative Preparation of Intermediate 305

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TFA (135 mL, 1.76 mol) was added dropwise at −10° C. (over 50 min) to a solution of intermediate 6R (20.00 g, 38.82 mmol) in DCM (550 mL). The reaction mixture was stirred below 0° C. for 15 min more, then poured in a mixture of crushed ice and a saturated aqueous solution of K₂CO₃. After extraction with DCM (twice), the organic layers were combined, washed with an aqueous solution of K₂CO₃, dried over MgSO₄and evaporated to dryness. The residue (17.40 g) was purified by chromatography on silica gel (irregular SiOH, 80 g, mobile phase: NH₄OH/MeOH/DCM, gradient from 0% NH₄OH, 0% MeOH, 100% DCM to 0.2% NH₄OH, 2% MeOH, 98% DCM). The desired fractions were collected and the solvent was concentrated to dryness under vacuum to give 12.1 g of intermediate 305 (75% yield).

Example A4
Preparation of Intermediate 436

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To a solution of intermediate 5 (3.89 g, 4.92 mmol), 5-fluoro-2,4-dichloropyrimidine (1.07 g, 6.40 mmol) and Cs₂CO₃(4.81 g, 14.80 mmol) in 1,4-dioxane (25 mL) and distilled water (2.5 mL), Pd(PPh₃)₄(0.28 g, 0.25 mmol) was added and the reaction mixture was heated overnight at 95° C. The mixture was poured into ice and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO₄, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (240 g, 15-40 μm, mobile phase: heptane/EtOAc, gradient from 1:0 to 0:1). The pure fractions were mixed and the solvent was evaporated to give 1.92 g of intermediate 436 (73% yield).

The intermediates in the Table below were prepared by using an analogous starting from the respective starting materials.

Intermediate

Mass
Yield

number
Structure
(mg)
(%)

Intermediate 439

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1820
83

Example A5
Preparation of Intermediate 7

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A mixture of intermediate 6 (2.00 g, 3.88 mmol), 1-methyl-1H-pyrazol-3-amine (565.60 mg, 5.82 mmol) and Cs₂CO₃(3.79 g, 11.65 mmol) in 1,4-dioxane (40 mL) was purged with N₂. Then Pd(OAc)₂(87.17 mg, 0.39 mmol) and BINAP (241.76 mg, 0.39 mmol) were added. The mixture was purged with N₂and stirred at 95° C. for 18 h. An extraction was performed with EtOAc and water. The organic layer was washed with brine, dried and evaporated to give 2.96 g of intermediate 7 (quant. yield, 75% purity based on LC/MS, brown foam) and used as it in the next step.

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Int. number
Structure
Mass (mg)
Yield (%)

Intermediate 9

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574 brown solid
Quant.

Intermediate 11

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865 (66% purity based on LC/MS) brown solid
Quant.

Intermediate 13

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650 (86% purity based on LC/MS) brown solid
Quant.

Intermediate 16

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350 230 (contaminated by impurities)
56 37

Intermediate 19

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280
44

Intermediate 21

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304 yellow foam
53

Intermediate 23

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272
44

Intermediate 25

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311 (78% purity based on LC/MS)
49

Intermediate 27

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498 (62% purity based on LC/MS)
48

Intermediate 36

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477 viscous oil
78 with T = 90° C.

Intermediate 38

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482
82

Intermediate 45

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208 orange solid
56 with T = 90° C.

Intermediate 46

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2000 (84% purity based on LC/MS) orange foam
Quant.

Intermediate 50

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505 (80% purity based on NMR)
—

Intermediate 65

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100
27

Intermediate 97

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365 brown oil
Quant.

Intermediate 99

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5530 (85% purity based on LC/MS)
90 with T = 110° C.

Intermediate 116

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24300 (75% purity based on LC/MS) 11100
43 20 T = 120° C.

Intermediate 184′ (mixture of 2 diastereoisomers)

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560 (58% purity based on LC/MS)
45 T = 120° C.

Intermediate 197

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397 orange powder
74 with T = 90° C.

Intermediate 221

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3300
69 T = 120° C.

Intermediate 226

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2800
68 T = 120° C.

Intermediate 234

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445
65 T = 120° C.

Intermediate 237

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2990
49 T = 120° C.

Intermediate 243

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5111
62 T = 120° C.

Intermediate 248

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4150 (86% purity based on LC/MS)
58 T = 120° C.

Intermediate 277

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2300 (64% purity based on LC/MS)
61 T = 120° C.

Intermediate 280

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730 (92% purity based on LC/MS)
27 T = 120° C.

Intermediate 290

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4510 (92% purity based on LC/MS)
61 T = 90° C.

Intermediate 301

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1310 (81% purity based on LC/MS) brown foam
Quant. T = 90° C.

Intermediate 309

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881 brown residue
76 T = 90° C.

Intermediate 313

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760 yellow oil
94 T = 90° C.

Intermediate 317

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765 (84% purity based on LC/MS) brown oil
63 T = 90° C.

Intermediate 321

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301 brown oil
56 T = 90° C.

Intermediate 325

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534 yellow residue
84 T = 90° C.

Intermediate 329

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578
73 T = 120° C.

Intermediate 333

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244 yellow foam
51 T = 90° C.

Intermediate 339

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178 pale yellow foam
29 T = 85° C.

Intermediate 343

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370
40 T = 120° C.

Intermediate 347

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615
77 T = 120° C.

Intermediate 360

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250 yellow oil
68 T = 90° C.

Intermediate 364

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578
71 T = 120° C.

Intermediate 368

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475 yellow residue
42 T = 90° C.

Mixture of Intermediate 372 and intermediate 373

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400 (85% purity based on LC/MS) Ratio 372/373: 56/44
37 T = 120° C.

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Intermediate 377

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3600
87 T = 120° C.

Intermediate 381

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175 pale yellow solid
35 T = 90° C.

Intermediate 384

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600 (82% purity based on LC/MS)
65 T = 120° C.

Intermediate 388

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398
62 T = 120° C.

Intermediate 402

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430 yellow solid
49 T = 90° C.

Intermediate 421

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348
50 T = 90° C.

Intermediate 425

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320
51 T = 120° C.

Intermediate 429

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520
65 T = 120° C.

Intermediate 432

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300
37 T = 120° C.

Intermediate 442

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276 (90% purity based on LC/MS) foam
Quant. T = 100° C.

Intermediate 444

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412 yellow foam
89 T = 100° C.

Intermediate 446

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280
50 T = 100° C.

Intermediate 448

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700 (59% purity based on LC/MS) black foam
Quant.

Intermediate 450

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465 yellow solid
90 T = 100° C.

Intermediate 458

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790
88 T = 90° C.

Intermediate 462

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376
53 T = 90° C.

Intermediate 466

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435 pale yellow foam
80 T = 90° C.

Intermediate 477

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452 white foam
75 T = 90° C.

Intermediate 481

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580 yellow solid
54 T = 90° C.

Intermediate 485

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377
50 T = 120° C.

Intermediate 501

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674 brown residue
53 T = 90° C.

Intermediate 552

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833
25 T = 90° C.

Intermediate 697

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200
52 T = 85° C. 48 h

Intermediate 723

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290
82 T = 100° C. 2 h

Intermediate 736

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80
21

Intermediate 744

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4450
85 Schlenk 120° C. for 90 min

Example A6
Preparation of Intermediate 33

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Intermediate 6 (500.00 mg, 0.971 mmol), 1-(1-methyl-4-piperidyl)pyraol-4-amine (279.93 mg, 1.55 mmol), Pd(OAc)₂(21.79 mg, 97.06 μmol), BINAP (60.44 mg, 97.06 mol) and Cs₂CO₃(948.76 mg, 2.91 mmol) in 1,4-dioxane (19.87 mL, 232.95 mmol) in a sealed tube were stirred at 120° C. using one single mode microwave (Biotage Initiator EXP 60® with a power output ranging from 0 to 400 W for 30 min). The reaction mixture was poured onto water and DCM, filtered over Celite®. The filtrate was decanted and the organic layer was dried over MgSO₄, filtered and evaporated. The residue was purified by column chromatography on silica gel (Irregular SiOH, 40 m, mobile phase: gradient from 100% DCM to 97% DCM, 3% MeOH, 0.1% NH₄OH). The pure fractions were combined and the solvent was evaporated to give 375 mg of intermediate 33 (yield 59%).

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials. For the synthesis of these intermediates, a one single mode microwave was used (Biotage Initiator EXP 60® with a power output ranging from 0 to 400 W for 30 min or alternatively an Anton Parr monowave 300® with a power output ranging from 0 to 850 W for 30 min).

Int. number
Structure
Mass (mg)
Yield (%)

Intermediate 40

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500
83

Intermediate 42

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474
75

Intermediate 48

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450 (88% purity based on LC/MS)
68

Intermediate 54

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220
36

Intermediate 58

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516
84

Intermediate 60

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585
Quant.

Intermediate 63

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305
45

Intermediate 68

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369
60

Intermediate 71

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212
30

Intermediate 73

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610 (93% purity based on LC/MS)
95

Intermediate 75

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468
77

Intermediate 77

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229
39

Intermediate 79

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460
78

Intermediate 81 (mixture of 2 distereoisomers)

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411 (91% purity based on LC/MS)
61

Intermediate 85

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386
54

Intermediate 87

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410
72

Intermediate 89

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410
64

Intermediate 91

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130 (88% purity based on LC/MS)
20

Intermediate 93

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650
99

Intermediate 95

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544
91

Intermediate 95

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260
44

Intermediate 104

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440 (70% purity based on LC/MS)
59

Intermediate 106

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537 (92% purity based on LC/MS)
86

Intermediate 108

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2300 (62% purity based on LC/MS)
47

Intermediate 110

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980
80

Intermediate 112

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229
39

Intermediate 119

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287
42

Intermediate 122

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1000
78

Intermediate 124

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653
—

Intermediate 126

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1310
Quant.

Intermediate 128

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370
60

Intermediate 130

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325
53

Intermediate 132

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1130
92

Intermediate 136

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540 (88% purity based on LC/MS)
72

Intermediate 139

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395
53

Intermediate 143

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600
92

Intermediate 146

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227
35

Intermediate 148

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300
46

Intermediate 150

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586
91

Intermediate 152

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320
21

Intermediate 154

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107
16

Intermediate 157

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410
94

Intermediate 160

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618
96

Intermediate 164

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830
63

Intermediate 167

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814
62

Intermediate 168

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350 (47% purity based on LC/MS)
31

Intermediate 172

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545 (63% purity based on LC/MS)
91

Intermediate 174

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275
25

Intermediate 178

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375 (76% purity based on LC/MS)
25

Intermediate 180

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455 (44% purity based on LC/MS)
31

Intermediate 193 Mixture of 2 diastereoisomers

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680
53

Intermediate 201 Mixture of 2 diastereoisomers

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1170 (66% purity based on LC/MS)
52

Intermediate 203

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365
63

Intermediate 215

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288
55

Intermediate 217

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380 (89% purity based on LC/MS)
63

Intermediate 230 Mixture of 2 diastereoisomers

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1050 (77% purity based on LC/MS)
80

Intermediate 257

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75
15

Intermediate 259

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195
38

mixture of Intermediate 265 and intermediate 266

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340
62

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Intermediate 271

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880
98

Intermediate 294

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790
61

Intermediate 297

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430 (75% purity based on LC/MS)
50

Intermediate 353

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245
39

Intermediate 356

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290
63

Intermediate 392

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630
51

Intermediate 396

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1050 brown residue
71

Intermediate 411

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135
31

Intermediate 415

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711
88

Intermediate 437

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382
86

Intermediate 440

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335
75

Intermediate 454

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266 (73% purity based on LC/MS)
85

Intermediate 473

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517
61

Intermediate 493

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900 (78% purity based on LC/MS)
98

Intermediate 497

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120
64

Intermediate 510

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343
59

Intermediate 515

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675
Quant.

Intermediate 519

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565
77

Intermediate 523

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247
34

Intermediate 527

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270
34

Intermediate 531

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258
25

Intermediate 535

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170
50

Intermediate 539

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479
64

Intermediate 543

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870
Quant.

Intermediate 547

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368
53

Intermediate 570

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3800
81

Intermediate 571

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235
59

Intermediate 575

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215
41

Intermediate 586

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142
62

Intermediate 589

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170 (80% purity based on LC/MS)
66

Intermediate 593

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810
83

Intermediate 599

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680 (86% purity based on LC/MS)
100

Intermediate 603

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440
66

Intermediate 608

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350
63

Intermediate 614

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280
43

Intermediate 618

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293
89

Intermediate 622

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230
31

Intermediate 626

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80
16

Intermediate 630

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720
90

Intermediate 638

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233 (92% purity based on LC/MS)
87

Intermediate 648

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819 (53% purity based on LC/MS)
100

Intermediate 653

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182 (72% purity based on LC/MS)
93

Intermediate 660

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540
83

Intermediate 664

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420
68

Intermediate 670

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240 (85% purity based on LC/MS)
17

Intermediate 676

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510
75

Intermediate 682

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816 (81% purity based on LC/MS)
90

Intermediate 688

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227
76

Intermediate 690

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600
70

Intermediate 694

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440
76

Intermediate 705

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405
47

Intermediate 710

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180
18

Intermediate 716

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103
24

Intermediate 719

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550
100

Intermediate 727

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266
53

Intermediate 765

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260 (74% purity based on LC/MS)
92

Example A7
Preparation of Intermediate 306

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In a sealed tube, a solution of intermediate 305 (350.00 mg, 0.84 mmol), intermediate 304 (275.12 mg, 1.52 mmol) and Cs₂CO₃(686.90 mg, 2.11 mmol) in dry Me-THF (8.40 mL) was purged with N₂. Pd(OAc)₂(18.90 mg, 84.30 μmol) and BINAP (52.50 mg, 84.30 μmol) were added. The mixture was purged with N₂and heated at 85° C. for 3 h. After cooling down to rt, the mixture was filtered over a pad of Celite®. The cake was washed with EtOAc and the filtrate was evaporated in vacuo. The residue (752 mg, brown oil) was purified by column chromatography on silica gel (irregular SiOH, 15-40 m, 30 g, mobile phase: DCM/EtOAc, gradient from 100:0 to 50:50). The pure fractions were combined and evaporated to dryness to give 387 mg of intermediate 306 as an orange oil used as it in the next step.

Int. number
Structure
Mass (mg)
Yield (%)

Intermediate 470

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323
71

Intermediate 505

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364
38 with T = 90° C.

Intermediate 581

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244 2410 (crude)
With T = 120° C. 26 25

Intermediate 643

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4000
54

Example A8
Preparation of Intermediate 343

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In a sealed tube, a mixture of intermediate 6 (0.30 g, 0.58 mmol), 5-methyl-1,3,4-oxadiazol-2-ylamine (63.50 mg, 0.64 mmol) and Cs₂CO₃(569.00 mg, 1.75 mmol) in THF (6 mL) was purged with N₂. Then, chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl] palladium (II) (47.00 mg, 58.20 μmol) and BRETTPHOS (31.00 mg, 58.20 μmol) were added. The mixture was purged with N₂and stirred at 95° C. for 5 h 30 min. Further chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl] palladium (II) (47.00 mg, 58.20 μmol) and BRETTPHOS (31.00 mg, 58.20 μmol) were added and the mixture was purged again with N₂and stirred at 95° C. for 20 h. The reaction mixture was diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO₄, filtered and the solvent was removed under reduced pressure to give intermediate 343 as a brown solid used as it in the next step.

Int. number
Structure
Mass (mg)
Yield (%)

Intermediate 31

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259
41 with T = 90° C.

Example A9
Preparation of Intermediate 8

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A mixture of intermediate 7 (2.96 g, 3.86 mmol) in a mixture of TFA (7 mL) and DCM (40 mL) was stirred at rt for 1 h and 20 min. The mixture was basified with a saturated aqueous solution of NaHCO₃. An extraction was performed with DCM. The organic layer was washed with brine, dried over MgSO₄, evaporated and purified by column chromatography on silica gel (irregular SiOH 15-40 m, 120 g, liquid injection with DCM, mobile phase: heptane/EtOAc, gradient from 100:0 to 0:100 in 15 CV). The fractions containing the product were combined and concentrated under vacuum to give 1.09 g of intermediate 8 (59% yield, white solid).

Int. number
Structure
Mass (mg)
Yield (%)

Intermediate 14

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165 yellow solid
36 Procedure with DCM/TFA (5:1, v/v)

Intermediate 22

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143 yellow solid
57 Procedure with DCM/TFA (6.5:1, v/v)

Intermediate 34

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370
— Procedure with DCM/TFA (4:1, v/v)

Mixture of Intermediate 37 and compound 14

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430 (64% purity based on LC/MS; int. 37/ comp. 14 34/66)
— Procedure with DCM/TFA (5:2, v/v)

Intermediate 41

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385 (72% purity based on LC/MS)
92 Procedure with DCM/TFA (5:1, v/v)

Intermediate 43

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333
83 Procedure with DCM/TFA (4:1, v/v)

Intermediate 47

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350 white solid
25 Procedure with DCM/TFA (5:1, v/v)

Intermediate 49

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264 (88% purity based on LC/MS)
62 Procedure with DCM/TFA (4:1, v/v)

Intermediate 51

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256 yellow solid
82 Procedure with DCM/TFA (3:1, v/v)

Intermediate 55

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107
56 Procedure with DCM/TFA (6:1, v/v)

Intermediate 59

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343 (87% purity based on LC/MS)
79 Procedure with DCM/TFA (5:1, v/v)

Intermediate 61

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291
63

Intermediate 64

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123
47 Procedure with DCM/TFA (5:2, v/v)

Intermediate 69

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225
74

Intermediate 72

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112
61 Procedure with DCM/TFA (7:1, v/v)

Intermediate 74

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350 (82% purity based on LC/MS)
74 Procedure with DCM/TFA (4:1, v/v)

Intermediate 76

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100
27 Procedure with DCM/TFA (4:1, v/v)

Intermediate 78

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112
24

Intermediate 80

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270
73 Procedure with DCM/TFA (4:1, v/v)

Intermediate 82

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177
50 Procedure with DCM/TFA (4:1, v/v)

Intermediate 86

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237
71

Intermediate 88

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108
32 Procedure with DCM/TFA (5:1, v/v)

Intermediate 90

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160 (86% purity based on LC/MS)
46 Procedure with DCM/TFA (4:1, v/v)

Intermediate 91

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210 (47% purity based on LC/MS)
— Procedure with DCM/TFA (4:1, v/v)

Intermediate 94

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419 (82% purity based on LC/MS)
76 Procedure with DCM/TFA (4:1, v/v)

Intermediate 96

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300 (73% purity based on LC/MS)
66 Procedure with DCM/TFA (4:1, v/v)

Intermediate 98

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132 yellow oil
48 Procedure with DCM/TFA (9:2, v/v)

Intermediate 100

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2720
58 Procedure with DCM/TFA (9:2, v/v)

Intermediate 102

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220
Quant. Procedure with DCM/TFA (4:1, v/v)

Intermediate 105

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210
81 Procedure with DCM/TFA (4:1, v/v)

Intermediate 107

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349
77 Procedure with DCM/TFA (7:1, v/v)

Intermediate 109

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1240 (80% purity based on LC/MS)
64 Procedure with DCM/TFA (4:1, v/v)

Intermediate 111

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761
92 Procedure with DCM/TFA (4:1, v/v)

Intermediate 113

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146
76 Procedure with DCM/TFA (7:1, v/v)

Intermediate 117

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24000
80 Procedure with DCM/TFA (4:1, v/v)

Intermediate 120

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118
48 Procedure with DCM/TFA (5:1, v/v)

Intermediate 123

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810
95 Procedure with DCM/TFA (4:1, v/v)

Intermediate 125

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273
50 Procedure with DCM/TFA (8:1, v/v)

Intermediate 127

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676
63 Procedure with DCM/TFA (4:1, v/v)

Intermediate 129

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171
55 Procedure with DCM/TFA (4:1, v/v)

Intermediate 131

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72 (71% purity based on LC/MS)
26

Intermediate 133

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634 89% purity based on LC/MS)
67 Procedure with DCM/TFA (4:1, v/v)

Intermediate 137

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370
91 Procedure with DCM/TFA (4:1, v/v)

Intermediate 140

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227
67 Procedure with DCM/TFA (4:1, v/v)

Intermediate 144

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296 (64% purity based on LC/MS)
58 Procedure with DCM/TFA (4:1, v/v)

Intermediate 147

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218
54 Procedure with DCM/TFA (4:1, v/v)

Intermediate 149

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169
66 Procedure with DCM/TFA (4:1, v/v)

Intermediate 151

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354
71 Procedure with DCM/TFA (4:1, v/v)

Intermediate 153

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179
66 Procedure with DCM/TFA (13:2, v/v)

Intermediate 155

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65
71 Procedure with DCM/TFA (8:1, v/v)

Intermediate 158

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250
71 Procedure with DCM/TFA (9:1, v/v)

Intermediate 161

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376
72 Procedure with DCM/TFA (4:1, v/v)

Intermediate 165

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47
58 Procedure with DCM/TFA (4:1, v/v)

Intermediate 167

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505
73 Procedure with DCM/TFA (4:1, v/v)

Intermediate 169

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110 (74% purity based on LC/MS)
27 Procedure with DCM/TFA (4:1, v/v)

Intermediate 173

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195 (88% purity based on LC/MS)
43

Intermediate 175

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140
60 Procedure with DCM/TFA (4:1, v/v)

Intermediate 179

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205
64 Procedure with DCM/TFA (4:1, v/v)

Intermediate 181

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190
49 Procedure with DCM/TFA (4:1, v/v)

Intermediate 185 mixture of 2 diastereoisomers

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260
55 Procedure with DCM/TFA (4:1, v/v)

Intermediate 188

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150 yellow oil
41 Procedure with DCM/TFA (5:1, v/v)

Intermediate 190

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122 yellow oil
82 Procedure with DCM/TFA (5:1, v/v)

Intermediate 194 Mixture of 2 disatereomers

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219
38 Procedure with DCM/TFA (4:1, v/v)

Intermediate 198

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269 yellow oil
81 Procedure with DCM/TFA (10:1, v/v)

Intermediate 202

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730 (69% purity based on LC/MS)
77 Procedure with DCM/TFA (4:1, v/v)

Intermediate 204

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155
46 Procedure with DCM/TFA (5:1, v/v)

Intermediate 206

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173 yellow oil
77 Procedure with DCM/TFA (5:1, v/v)

Intermediate 208

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182 yellow oil
75 Procedure with DCM/TFA (5:1, v/v)

Intermediate 210

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130 yellow oil
60 Procedure with DCM/TFA (5:1, v/v)

Intermediate 216

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169
69 Procedure with DCM/TFA (7:1, v/v)

Intermediate 218

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242
75 Procedure with DCM/TFA (12:1, v/v)

Intermediate 222

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2000
72 Procedure with DCM/TFA (4:1, v/v)

Intermediate 227

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1050
44 Procedure with DCM/TFA (4:1, v/v)

Intermediate 231

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531
59 Procedure with DCM/TFA (4:1, v/v)

Intermediate 235

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254
68 Procedure with DCM/TFA (5:1, v/v)

Intermediate 238

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1530
61 Procedure with DCM/TFA (6:1, v/v)

Intermediate 244

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2830
66 Procedure with DCM/TFA (4:1, v/v)

Intermediate 249

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2050
59 Procedure with DCM/TFA (7:2, v/v)

Intermediate 258

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30
47 Procedure with DCM/TFA (8:1, v/v)

Intermediate 260

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52
32 Procedure with DCM/TFA (8:1, v/v)

mixture of Intermediate 267 and intermediate 268

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189
65 Procedure with DCM/TFA (8:1, v/v)

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Intermediate 278

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710 (30% purity based on LC/MS)
56 Procedure with DCM/TFA (4:1, v/v)

Intermediate 281

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1073 (60% purity based on LC/MS)
— Procedure with DCM/TFA (4:1, v/v)

Intermediate 291

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2860 (75% purity based on LC/MS) yellow solid
75 Procedure with DCM/TFA (10:1, v/v)

Intermediate 295

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308
46 Procedure with DCM/TFA (4:1, v/v)

Intermediate 310

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530
71 Procedure with DCM/TFA (5:1, v/v)

Intermediate 314

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425 yellow oil
66 Procedure with DCM/TFA (10:1, v/v)

Intermediate 318

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511 orange oil
78 Procedure with DCM/TFA (5:1, v/v)

Intermediate 322

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119 yellow oil
47 Procedure with DCM/TFA (5:1, v/v)

Intermediate 326

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243 (85% purity based on LC/MS) white solid
55 Procedure with DCM/TFA (10:1, v/v)

Intermediate 334

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209 orange foam
Quant. Procedure with DCM/TFA (10:1, v/v)

Intermediate 340

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114 pale yellow solid
75 Procedure with DCM/TFA (10:1, v/v)

Intermediate 354

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168
81 Procedure with DCM/TFA (7:1, v/v)

Intermediate 357

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116
47 Procedure with DCM/TFA (6:1, v/v)

Intermediate 361

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160 yellow residue
75 Procedure with DCM/TFA (6:1, v/v)

Intermediate 369

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293 yellow residue
72 Procedure with DCM/TFA (10:1, v/v)

Intermediate 382

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86 white solid
58 Procedure with DCM/TFA (10:1, v/v)

Intermediate 397

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582 (65% purity based on LC/MS) yellow residue
68 (over 2 steps) Procedure with DCM/TFA (5:1, v/v)

Intermediate 403

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284 yellow residue
76 Procedure with DCM/TFA (10:1, v/v)

Intermediate 406

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170 yellow solid
48 Procedure with DCM/TFA (4:1, v/v)

Intermediate 422

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210
70 Procedure with DCM/TFA (5:1, v/v)

Intermediate 438

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390
Quant. Procedure with DCM/TFA (9:1, v/v)

Intermediate 441

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396
Quant.

Intermediate 443

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138 yellow solid
60 Procedure with DCM/TFA (10:1, v/v)

Intermediate 445

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245 foam
72 Procedure with DCM/TFA (10:1, v/v)

Intermediate 447

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220 orange solid
95 Procedure with DCM/TFA (10:1, v/v)

Intermediate 449

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195 white solid
56 Procedure with DCM/TFA (7:1, v/v)

Intermediate 451

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394
Quant. Procedure with DCM/TFA (10:1, v/v)

Intermediate 459

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454
68 Procedure with DCM/TFA (10:1, v/v)

Intermediate 463

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243 yellow residue
74 Procedure with DCM/TFA (10:1, v/v)

Intermediate 467

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233 white foam
63 Procedure with DCM/TFA (10:1, v/v)

Intermediate 482

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400 yellow residue
81 Procedure with DCM/TFA (5:1, v/v)

Intermediate 498

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75
73 Procedure with DCM/TFA (5:1, v/v)

Intermediate 502

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310
54 Procedure with DCM/TFA (5:1, v/v)

Intermediate 520

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277
58 Procedure with DCM/TFA (7:1, v/v)

Intermediate 740

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62 (80% purity based on LC/MS)
quant Procedure with DCM/TFA (9:1, v/v) 5° C. for 1 h

Example A10
Preparation of Intermediate 10

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A mixture of intermediate 9 (335.00 mg, 0.58 mmol) and TBAF (1M in THF) (0.64 mL, 0.64 mmol) in THF (5 mL) was stirred at rt for 1 h. An extraction was performed with EtOAc and water. The organic layer was washed with brine, dried over MgSO₄and evaporated to give 355 mg of intermediate 10 (quant. yield, yellow solid) which was used as it for the next step.

The intermediates in the Table below were prepared by using an analogous starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Int. number
Structure
Mass (mg)
Yield (%)

Intermediate 12

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950 (48% purity based on LC/MS) yellow solid
99

From intermediate 11

Intermediate 17

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161
56 Procedure with 1.2 equiv. of TBAF

From intermediate 16

Intermediate 20

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180
78 Procedure with 1.2 equiv. of TBAF

From intermediate 19

Intermediate 24

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171
77 Procedure with 1.9 equiv. of TBAF

From intermediate 23

Intermediate 26

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252
99 Procedure with 1.9 equiv. of TBAF

From intermediate 25

Intermediate 28

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219
53 Procedure with 1.2 equiv. of TBAF

From intermediate 27

Intermediate 32

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246 brown oil
— Procedure with 2.2 equiv. of TBAF

From intermediate 31

Intermediate 39

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170
44 Procedure with 1.9 equiv. of TBAF

From intermediate 39

Intermediate 66

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74
90 Procedure with 1.9 equiv. of TBAF

From intermediate 65

Intermediate 272

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618
76 Procedure with 1.5 equiv of TBAF

From intermediate 271

Intermediate 302

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680 (80% purity based on ¹H NMR)
62 Procedure with 1.7 equiv of TBAF

From intermediate 301

Intermediate 435

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270
Quant.

From intermediate 435

Intermediate 549

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569 yellow powder
85 Procedure with 2 equiv. of TBAF

From intermediate 552

Intermediate 553

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544 yellow powder
85 Procedure with 2 equiv. of TBAF

From intermediate 46

Intermediate 728

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165
73

From intermediate 727

Example A11
Preparation of Intermediate 30

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In a sealed glassware, a mixture of intermediate 29 (400.00 mg, 0.96 mmol), 2-(2-dimethylaminoethyl)-5-methyl-2H-pyrazole-3-ylamine (178.37 mg, 1.06 mmol) and Cs₂CO₃(942.10 mg, 2.89 mmol) in dry 1,4-dioxane (20 mL) was purged with N₂. Then, Pd(OAc)₂(21.64 mg, 96.40 mol) and BINAP (60.00 mg, 96.40 μmol) were added. The mixture was purged with N₂and stirred at 95° C. for 2 h. The crude was combined with another batch (from 245 mg of intermediate 29) and an extraction was performed with EtOAc and water. The layers were separated and the organic layer was dried over MgSO₄, filtered and evaporated under reduced pressure. The residue (958 mg) was purified by column chromatography on silica gel (irregular SiOH 15-40 m, 80 g, dry loading on Celite®, mobile phase: DCM/(MeOH(+aq. 5% NH₃)) gradient from 100:0 to 90:10). The fractions containing the product were combined and concentrated to dryness to give 600 mg of intermediate 30 (quant. yield, brown solid) which was used as it in the next step.

Int. number
Structure
Mass (mg)
Yield (%)

Intermediate 35

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255 yellow oil
72 with T = 100° C.

From intermediate 29 and 1,5-

dimethy1-1H-pyrazol-3-ylamine

Intermediate 749

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340
54 μw, 120° C., 30 min

From intermediate 305 and 748

Intermediate 753

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3380
40 120° C., 60 min

From intermediate 305 and 752

Intermediate 761

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112
59 μw, 120° C., 30 min

From intermediate 305 and 760

Example A12
Preparation of Intermediate 186

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In a sealed glassware, a mixture of intermediate 6R (2.00 g, 3.88 mmol), ethyl-(5-amino-3-methyl-1H-pyrazol-1-yl)acetate hydrochloride (938.20 mg, 4.27 mmol) and Cs₂CO₃(5.10 g, 15.50 mmol) in dry 1,4-dioxane (80 mL) was purged with N₂. Then, Pd(OAc)₂(87.20 mg, 0.39 mmol) and BINAP (241.80 mg, 0.39 mmol) were added. The mixture was purged with N₂and stirred at 90° C. for 3 h. Then, lithium hydroxide monohydrate (244.40 mg, 5.82 mmol) and distilled water (11 mL) were added at room temperature for 2 h. The reaction mixture was combined with another batch (from 4 g of intermediate 6R) and the mixture was evaporated under reduced pressure to give a crude. The crude was purified by column chromatography on silica gel (irregular SiOH 15-40 μm, dry load on celiteR, mobile phase: DCM/(MeOH(+10% aq. AcOH)), gradient from 100:0 to 90:10). The fractions containing the product were combined and evaporated to dryness to give 5.98 g of intermediate 186 (81% yield, over 2 steps, brown solid).

Preparation of Intermediate 187

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In a sealed tube, intermediate 186 (500.00 mg, 0.79 mmol) and N-isopropylmethylamine (0.14 mL, 1.34 mmol) were diluted in dry DMF (10 mL). Then, HATU (0.81 g, 2.13 mmol) and DIPEA (0.34 mL, 1.97 mmol) were added and the mixture was stirred at rt for 17 h. The reaction mixture was evaporated under reduced pressure and an extraction was performed with EtOAc. The organic layer was washed with brine and the layers were separated. The organic layer was dried over MgSO₄, filtered and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (irregular SiOH, 15-40 m, 30 g, dry load on Celite®, mobile phase: DCM/(MeOH(+10% aq. AcOH)), gradient from 100:0 to 90:10). The fractions containing the product were combined and evaporated to dryness to give 504 mg of intermediate 187 (93% yield, yellow residue).

Int. number
Structure
Mass (mg)
Yield (%)

Intermediate 189

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173
31

From intermediate 186 and

dicyclopropylamine hydrochloride

Intermediate 205

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260 brown residue
58

From intermediate 186 and 3,3-

difluoroazetidine hydrochloride

Intermediate 207

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285 brown oil
66

From int. 186 and pyrrolidine

Intermediate 209

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255 yellow oil
59

From intermediate 186 and N-

methylcyclopropanamine

Example A13
Preparation of Intermediate 298

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SiO₂(35-70 μm, 1.1 g) was added to a solution of intermediate 298 (400.00 mg, 0.45 mmol) in toluene (3.63 mL, 34.17 mmol) at rt. The resulting mixture was stirred at reflux for 2 h. After cooling down to rt, the reaction mixture was evaporated. The residue was purified by column chromatography on silica gel (Irregular SiOH, 40 m, 40 g, deposited solid, mobile phase gradient from 100% DCM to 96% DCM, 4% MeOH, 0.4% NH₄OH). The pure fractions were combined and the solvent was evaporated to give 275 mg of intermediate 298 (Quant. yield).

Int. number
Structure
Mass (mg)
Yield (%)

Intermediate 330

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420
85

From intermediate 329

Intermediate 340

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260
82

From intermediate 339

Intermediate 348

embedded image

530
Quant.

From intermediate 347

Intermediate 365

embedded image

420
84

From intermediate 364

Intermediate 373

embedded image

280 (51% purity based on LC/MS)
82

From intermediate 372

Intermediate 378

embedded image

1620 (83% purity based on LC/MS)
53

From intermediate 377

Intermediate 385

embedded image

517 (85% purity based on LC/MS)
Quant.

From intermediate 384

Intermediate 389

embedded image

337
Quant.

From intermediate 388

Intermediate 393

embedded image

313
59

From intermediate 392

Intermediate 412

embedded image

107
91

From intermediate 411

Intermediate 416

embedded image

452
73

From intermediate 415

Intermediate 426

embedded image

260
95

From intermediate 425

Intermediate 430

embedded image

445
Quant.

From intermediate 429

Intermediate 434

embedded image

260
Quant.

From intermediate 432

Intermediate 455

embedded image

162 (30% purity based on LC/MS)
72

From intermediate 454

Intermediate 474

embedded image

450
Quant.

From intermediate 473

Intermediate 478

embedded image

271
71

From intermediate 477

Intermediate 486

embedded image

290
90

From intermediate 485

Intermediate 494

embedded image

664 (74% purity based on LC/MS)
85

From intermediate 493

Intermediate 511

embedded image

279
93

From intermediate 510

Intermediate 516

embedded image

403 (100% purity based on LC/MS)
70

From intermediate 515

Intermediate 524

embedded image

263
84

From intermediate 523

Intermediate 528

embedded image

210
90

From intermediate 527

Intermediate 532

embedded image

135
60

From intermediate 531

Intermediate 536

embedded image

121 (45% purity based on LC/MS)
81

From intermediate 535

Intermediate 540

embedded image

432 (57% purity based on LC/MS)
Quant.

From intermediate 539

Intermediate 544 (mixture of 2 distereoisomers)

embedded image

684
92

From intermediate 543

Intermediate 548

embedded image

253
80

From intermediate 547

Intermediate 572

embedded image

3150
Quant.

From intermediate 570

Intermediate 573

embedded image

214
Quant.

From intermediate 571

Intermediate 574

embedded image

166
90

From intermediate 575

Intermediate 587

embedded image

110
89 Reflux 2 h

From intermediate 586

Intermediate 590

embedded image

120 (80% purity based on LC/MS)
82 Reflux 2 h

From intermediate 589

Intermediate 594

embedded image

620
91

From intermediate 593

Intermediate 600

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580
100 Reflux 4 h

From intermediate 599

Intermediate 649

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642 (90% purity based on LCMS)
92 Reflux 3 h

From intermediate 648

Intermediate 604

embedded image

375
100 Reflux 4 h

From intermediate 603

Intermediate 609

embedded image

370
100 Reflux 2 h

From intermediate 608

Intermediate 615

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224
95 Reflux 2 h

From intermediate 614

Intermediate 619

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251
100 Reflux 2 h

From intermediate 618

Intermediate 623

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202
100

From intermediate 622

Intermediate 627

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68
100 Reflux 4 h

From intermediate 626

Intermediate 631

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620
Quant Reflux 4 h

From intermediate 630

Intermediate 639

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175
88 Reflux 1 h 30 mins

From intermediate 638

Intermediate 655

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118
86 90° C. 2 days

From intermediate 654

Intermediate 661

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410
89 Reflux (120° C.) 4 h

From intermediate 660

Intermediate 665

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420
68 Reflux 12 h

From intermediate 664

Intermediate 671

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220 (84% purity based on LC/MS)
88 With T = 120° C. 5 h

From intermediate 670

Intermediate 677

embedded image

510
75 Reflux 4 h

From intermediate 676

Intermediate 683

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605
87 With T = 120° C. 4 h

From intermediate 682

Intermediate 689

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86
45 With T = 120° C. 3 h

From intermediate 688

Intermediate 691

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231
45 With T = 120° C. 2 h

From intermediate 690

Intermediate 695

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380
82 Reflux 4 h

From intermediate 694

Intermediate 698

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172
100 Reflux 4 h

From intermediate 697

Intermediate 706

embedded image

300
87 Reflux 2 h

From intermediate 705

Intermediate 711

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154
100 With T = 120° C. 1 h 30 mins

From intermediate 710

Intermediate 717

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83
94 With T = 120° C. 4 h

From intermediate 716

Intermediate 720

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550
100 With T = 120° C. 3 h 20 mins

From intermediate 719

Intermediate 724

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170
68 With T = 90° C. 5 h

From intermediate 723

Intermediate 737

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45 (91% purity based on LC/MS)
66 With T = 90° C. 2 days

From intermediate 736

Intermediate 745

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4450
100

From intermediate 744

Intermediate 766

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113 LCMS pure at 68%
51

From intermediate 765

Example A14
Preparation of Intermediate 550

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In a dry 25 ml 3 neck round bottom flask, DCM (0.3 mL) was charged and cooled to −78° C., oxalyl chloride (0.92 mL, 1.85 mmol) was added followed by DMSO (0.26 mL, 3.70 mmol). After 1 h, a solution of intermediate 549 (0.57 g, 1.23 mmol) in solution in DCM (1.5 mL) was added dropwise. The mixture was stirred for 1 h at −78° C., before DIPEA (1.27 mL, 7.40 mmol) was added. Stirring was continued and then the mixture was allowed to warm to rt over 5 h. A diluted solution of NH₄Cl was added and the aqueous layer was extracted twice with DCM and the combined layers were dried over MgSO₄. After filtration and removal of the solvent in vacuo, 669 mg of intermediate 550 (Quant. yield, orange solid) were obtained and directly used in the next steps without any further treatment.

The intermediates in the Table below were prepared by using an analogous starting from the respective starting materials.

Int. number
Structure
Mass (mg)
Yield (%)

Intermediate 554

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608 yellow solid
Quant.

Preparation of Intermediate 551

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A solution of intermediate 550 (0.30 g, 0.65 mmol), 2-[[(1,1-dimethylethyl) dimethylsilyl]oxy]-N-methyl-ethanamine (0.74 mg, 3.92 mmol), AcOH (224 μl, 3.92 mmol) and NaBH(OAc)₃(1.38 g, 6.53 mmol) in dichloroethane (13.2 ml) was stirred at rt overnight. A saturated solution of NaHCO₃was added and the aqueous layer was extracted with DCM. The organic layer was dried over MgSO₄and evaporated to dryness. The residue (1240 mg, yellow oil) was purified by column chromatography on silica gel (irregular SiOH, 40 g, mobile phase: heptane/EtOAc, gradient from 100:0 to 50:50). The fractions containing the product were combined and evaporated to dryness to provide 152 mg of intermediate 551 (37% yield, yellow oil).

The intermediates in the Table below were prepared by using an analogous starting from the respective starting materials.

Int. number
Structure
Mass (mg)
Yield (%)

Intermediate 555

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93 colorless oil
23

Intermediate 556

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295 (57% purity based on LC/MS) yellow oil
79

Intermediate 557

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201 (57% purity based on LC/MS) yellow oil
59

Example A15
Preparation of Intermediate 15 and intermediate 15′

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Methylhydrazine (1.14 mL, 21.77 mmol) was added to a stirred solution of 3-methyl-β-oxo-3-oxetanepropanetrile (2.33 g, 16.74 mmol) and TEA (3.23 mL, 23.24 mmol) in toluene (12.22 mL, 115.03 mmol) at rt and stirred at 90° C. for 1 h. The reaction mixture was purified by column chromatography on silica gel (Irregular SiOH 40 μm, mobile phase: DCM/MeOH/NH₄OH, gradient from 100% DCM to 95% DCM, 5% MeOH, 0.1% NH₄OH. The residue (1.37 g) was purified by achiral SFC (Stationary phase: CHIRALCEL OJ-H, 5 μm, 250×20 mm, mobile phase: 90% CO₂, 10% MeOH) providing 355 mg of intermediate 15′ (13% yield) and 966 mg of intermediate 15 (35% yield).

The intermediates in the Table below were prepared by using an analogous starting from the respective starting materials.

Int. number
Structure
Mass (mg)
Yield (%)

Intermediate 18

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310
26

Example A16
Preparation of Intermediate 44

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In sealed glassware, dimethylamine (1.64 mL, 3.28 mmol) and triazabicyclo[4.4.0]des-5-ene (TBD) (62.02 mg, 0.44 mmol) were added to a solution of ((5-amino-3-methyl-pyrazol-1-yl)-acetic acid ethyl ester (200.00 mg, 1.09 mmol) in dry toluene (19.5 mL). The reaction mixture was stirred at 50° C. for 17 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (irregular SiOH, 15-40 μm, 40 g, liquid loading, mobile phase: DCM/(MeOH(+5% aq NH₃)), gradient from 100:0 to 90:10). The fractions containing the product were combined and evaporated to dryness to give 102 mg of intermediate 44 (51% yield, yellow oil).

Example A17
Preparation of Intermediate 52 and intermediate 52′

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A mixture of 1-methyl-3-nitro-1H-pyrazole-5-carboxylic acid (400.00 mg, 2.34 mmol) and 1-methyl-2-nitro-1H-pyrazole-4-carboxylic acid, 4,4-difluoropiperidine (440.00 mg, 2.79 mmol), HATU (1.25 g, 3.29 mmol) in DCM (10 mL) and DIPEA (2.10 mL, 12.19 mmol) was stirred at rt for a weekend. Water was added and this mixture was extracted with DCM. The organic layer was decanted with Chromabond®, the solvent was evaporated until dryness. The residue (773 mg) was purified by column chromatography on silica gel (Stationary phase: irregular bare silica 40 g, mobile phase: 70% heptane, 30% EtOAc). The pure fractions were collected and the solvent was evaporated until dryness to give 270 mg of intermediate 52′ (42% yield) and 244 mg of intermediate 52 (38% yield). These intermediates were used as it in the next step.

The intermediates in the Table below were prepared by using an analogous starting from the respective starting materials.

Int. number
Structure
Mass (mg)
Yield (%)

Intermediate 62 + intermediate 62′

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295 (intermediate 62) 530 (intermediate 62′)
40 71

Intermediate 83

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520
Quant.

Preparation of Intermediate 53

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Intermediate 52 (0.24 g, 0.88 mmol) was hydrogenated at rt in MeOH (6 mL) with Pd/C (10 wt. %, 50.00 mg, 0.05 mmol) as a catalyst at atmospheric pressure. After overnight, the catalyst was filtered through a pad of Celite® and the solvent was evaporated until dryness to give 210 mg of intermediate 53 (98% yield) used as it in the next step.

Int. number
Structure
Mass (mg)
Yield (%)

Intermediate 63

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265
Quant. Procedure with a mixture of MeOH/EtOAc (3:1, v/v) as solvent

Intermediate 70

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251
Quant.

Intermediate 84

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32
72 Procedure with a mixture of MeOH/EtOAc (5:2, v/v) as solvent

Intermediate 118

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524
Quant.

Mixture of intermediate 177/intermediate 177′

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640 mixture of intermediates 177 and 177′
43 under 3 bars of H₂

Intermediate 196

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2140 orange solid
99

Intermediate 214

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160
23 Procedure with a mixture of MeOH/EtOAc (5:3, v/v) as solvent

Intermediate 233

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297
Quant. Procedure with a mixture of MeOH/EtOAc (2:1, v/v) as solvent

Intermediate 236

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1950
Quant. Procedure with a mixture of MeOH/EtOAc (3:1, v/v) as solvent

Intermediate 242

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1000
73

Intermediate 247

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1610
97 Procedure with a mixture of MeOH/EtOAc (2:1, v/v)

Mixture of Intermediate 255/ Intermediate 256

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200 (mixture of intermediate 255 and intermediate 256, 50:34)
98 Procedure with a mixture of MeOH/EtOAc (3:2, v/v) as solvent

Mixture of Intermediate 263/ Intermediate 264

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200
50 Procedure with a mixture of MeOH/EtOAc (3:2, v/v) as solvent

Intermediate 270

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338
Quant. Procedure with a mixture of MeOH/EtOAc (5:2, v/v) as solvent

Intermediate 304

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2000 off-white solid
73 Procedure with EtOH as solvent

Intermediate 328

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700
Quant. Procedure with a mixture of MeOH/EtOAc (3:1, v/v) as solvent

Intermediate 342

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407
77 Procedure with a mixture of MeOH/EtOAc (3:1, v/v) as solvent

Intermediate 346

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360
Quant. Procedure with a mixture of MeOH/EtOAc (3:1, v/v) as solvent

Intermediate 352

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220
Quant. Procedure with a mixture of MeOH/EtOAc (3:1, v/v) as solvent

Intermediate 355

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160
Quant. Procedure with a mixture of MeOH/EtOAc (2:1, v/v) as solvent

Intermediate 363

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380
Quant. Procedure with a mixture of MeOH/EtOAc (3:1, v/v) as solvent

Intermediate 383

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490
71 Procedure with a mixture of MeOH/EtOAc (3:1, v/v) as solvent

Intermediate 387

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270
Quant. Procedure with a mixture of MeOH/EtOAc (3:1, v/v) as solvent

Intermediate 391

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720
Quant. with a mixture of MeOH/EtOAc (5:4, v/v) as solvent

Intermediate 410

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187
Quant. Procedure with a mixture of MeOH/EtOAc (3:2, v/v) as solvent

Intermediate 414

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440
95 Procedure with a mixture of MeOH/EtOAc (2:1, v/v) as solvent

Intermediate 424

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495
88

Intermediate 428

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700
98

Intermediate 431

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760
Quant.

Intermediate 469

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287
92 Procedure with EtOH as solvent

Intermediate 472

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440
93 Procedure with a mixture of MeOH/EtOAc (2:1, v/v) as solvent

Intermediate 484

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940
Quant.

Intermediate 492

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370
Quant. Procedure with a mixture of MeOH/EtOAc (2:1, v/v) as solvent

Intermediate 509

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260
34 Procedure with a mixture of MeOH/EtOAc (2:1, v/v) as solvent

Intermediate 514

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293
96 Procedure with a mixture of MeOH/EtOAc (5:2, v/v) as solvent

Intermediate 518

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750
Quant. Procedure with a mixture of MeOH/EtOAc (2:1, v/v) as solvent

Intermediate 522

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243
Quant. Procedure with a mixture of MeOH/EtOAc (2:1, v/v) as solvent

Intermediate 526

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310
93 Procedure with a mixture of MeOH/EtOAc (2:1, v/v) as solvent

Intermediate 530

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430
Quant. Procedure with a mixture of MeOH/EtOAc (2:1, v/v) as solvent

Intermediate 534

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148
86 Procedure with a mixture of MeOH/EtOAc (2:1, v/v) as solvent

Intermediate 538

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523
92 Procedure with a mixture of MeOH/EtOAc (2:1, v/v) as solvent

Intermediate 542

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377
47 Procedure with a mixture of MeOH/EtOAc (2:1, v/v) as solvent

Intermediate 546

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532
88 Procedure with a mixture of MeOH/EtOAc (2:1, v/v) as solvent

Intermediate 585

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97
38

Intermediate 588

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100
99

Intermediate 592

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266
83

Intermediate 598

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340
95

Intermediate 602

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305
100

Intermediate 621

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330
84

Intermediate 625

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199
100

Intermediate 629

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312
91

Intermediate 637

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135
74

Intermediate 642

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3960
100

Intermediate 647

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562
96

Intermediate 652

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65
90

Intermediate 659

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249
100

Intermediate 667

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308
Quant.

Intermediate 669

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1010
100

Intermediate 675

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665
100

Intermediate 681

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430
100

Intermediate 687

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115
100

Intermediate 693

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220
63

Intermediate 704

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290
84

Intermediate 709

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283
96

Intermediate 715

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165
80

Intermediate 718

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252
94

Intermediate 726

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687
93

Intermediate 743

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1440 1380
51 Procedure with a mixture of ⁱPrOH/THF (2:1, v/v) as solvent, 1.5 bars H₂, 2days OR 49 With MeOH as solvent, atmospheric pressure H₂, 18 h

Intermediate 748

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307
86 Procedure with a mixture of AcOEt/EtOH (4:1, v/v) as solvent, atmospheric pressure H₂, 12 h

Intermediate 752

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4150
quant Procedure with a mixture of MeOH/AcOEt (4:1, v/v) as solvent, atmospheric pressure H₂, 1 h 30

Intermediate 764

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120
20

Example A18
Preparation of Intermediate 56 and intermediate 56′

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Bromo-3-methoxypropane (1.20 mL, 10.51 mmol) was added at rt to a mixture of 5-nitro-1H-pyrazole (1.00 g, 8.84 mmol), K₂CO₃(2.35 g, 17.00 mmol) in DMF (10 mL). This reaction was stirred in a sealed tube at 120° C. using one single mode microwave (Biotage Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 min. Then, water was added and this mixture was extracted twice with EtOAc. The organic layers were mixed, dried over MgSO₄, filtered and the solvent was evaporated until dryness. The residue was purified by column chromatography on silica gel (Irregular SiOH, 40 μm, 80 g, mobile phase: gradient from 70% heptane, 29% EtOAc, 1% MeOH (+10% NH₄OH) to 40% heptane, 52% EtOAc, 8% MeOH (+10% NH₄OH)). The pure fractions were collected and the solvent was evaporated until dryness to give 1.39 g of intermediate 56 (85% yield) and 267 mg of intermediate 56′ (16% yield). These intermediates were used as it in the next step.

Int. number
Structure
Mass (mg)
Yield (%)

Intermediate 114

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20400 (intermediate 114)
22 without microwave activation

Intermediate 134 + intermediate 134′

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880 (intermediate 134) 493 (intermediate 134′)
24 14 without microwave activation

Intermediate 141 + intermediate 141′

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2240 (intermediate 141) 2140 (intermediate 141′)
25 24

Intermediate 162 + intermediate 162′

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1280 (intermediate 162) 3900 (intermediate 162′)
12 37

Intermediate 170

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435 (intermediate 170)
17

Mixture of Intermediate 176 + intermediate 176′

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1190 (mixture of intermediates 176 and 176′ (44:56))
67

Intermediate 191

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1300 (intermediate 191)
24

Intermediate 199

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750
11 without microwave activation

Intermediate 219

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1770 (intermediate 219)
24

Intermediate 223

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2300
32 without microwave activation

Intermediate 228

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1670 (intermediate 228)
27

Intermediate 275 + Intermediate 275′

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1050 (intermediate 275) 1900 (intermediate 275′)
24 43

Intermediate 292 + Intermediate 292′

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1270 (intermediate 292) 1730 (intermediate 292′)
24 32

Intermediate 370

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336
14

Intermediate 506

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4810
23

Intermediate 513

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356 (intermediate 513)
37 without microwave activation and T = 80° C.

Intermediate 650

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83
17 RT overnight

Intermediate 651

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391
80 RT overnight

Intermediate 656

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4400
44 without microwave activation T = 120° C., 2 h

Intermediate 708

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335
14 without microwave activation T = 120° C., 2 h 20

Intermediate 713

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235
18 without microwave activation T = 120° C., 2 h 20

Intermediate 714

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305
24 without microwave activation T = 120° C., 2 h 20

Intermediate 633

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675
80 rt, overnight

Intermediate 731

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1220
63

Intermediate 750 + 751

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3600 3850
32 120° C., 1 h 40 34

Example A19
Preparation of Intermediate 57

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Intermediate 56 (1.30 g, 7.02 mmol) was hydrogenated in MeOH (25 mL) with RaNi (1.00 g, 17.04 mmol) as a catalyst in a pressure vessel reactor with 3 bars of H₂at rt for 2 h. The reaction was filtered over Celite® and the solvent was evaporated until dryness to give 1.03 g of intermediate 57 (95% yield) used as it in the next step.

Int. number
Structure
Mass (mg)
Yield (%)

Intermediate 67

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220
Quant.

Intermediate 115

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16200
95

Intermediate 135

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760
Quant.

Intermediate 138

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390
92

Intermediate 142

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1960
Quant.

Intermediate 145

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1930
Quant.

intermediate 163

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1000
90

intermediate 166

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3300
98

intermediate 184

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850
Quant.

intermediate 192

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1100
Quant.

intermediate 200

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650
Quant.

intermediate 220

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1400
98

intermediate 229

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1530
Quant.

intermediate 276

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890
96

intermediate 279

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1700
Quant.

intermediate 293

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1100
Quant.

intermediate 296

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1400
96

intermediate 371

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350
84

intermediate 607

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120
70

intermediate 613

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176
72

intermediate 617

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105
89

Example A20
Preparation of Intermediate 103

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In a sealed glassware, (2-ethoxyethyl)-hydrazine (1.70 g, 9.60 mmol) was added to a solution of 3-aminocrotononitrile (394.12 mg, 4.80 mmol) in a mixture of AcOH (6.3 mL) and EtOH (20.8 mL). The mixture was stirred at 90° C. for 17 h. Water was added and the aqueous layer was extracted with Et₂O. The aqueous layer was basified with K₂CO₃powder and extracted twice with DCM. The combined organic layers were dried over MgSO₄, filtered and evaporated. The residue (400 mg) was purified by column chromatography on silica gel (Irregular SiOH, 40 m, mobile phase DCM/MeOH/NH₄OH, gradient from 100% DCM to 95% DCM, 5% MeOH, 0.1% NH₄OH). The pure fractions were combined and the solvent was evaporated to give 194 mg of intermediate 103 (24% yield).

Example A21
Preparation of Intermediate 121

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3-aminocrotononitrile (1.91 g, 23.27 mmol) and [(tetrahydro-2-furanyl)methyl]-hydrazine (4.40 g, 23.27 mmol) in EtOH (7.8 mL) were stirred at reflux for 5 h. EtOH was evaporated. The residue was taken up into water, extracted with Et₂O twice, basified with K₂CO₃powder and extracted with DCM. The organic layer was dried over MgSO₄, filtered and evaporated. The residue was purified by column chromatography on silica gel (stationary phase: irregular SiOH 15-40 μm, 80 g, mobile phase: DCM/MeOH/NH₄OH, gradient from 100% DCM to 97% DCM, 3% MeOH, 0.1% NH₄OH). The fractions containing the product were combined and evaporated to dryness to give 1.6 g of intermediate 121 (38% yield).

The intermediates in the Table below were prepared by using an analogous starting from the respective starting materials.

Int. number
Structure
Mass (mg)
Yield (%)

Intermediate 156

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209
28

Intermediate 159

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260
25

Intermediate 239 + intermediate 239′

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3730 (intermediate 239) 2230 (intermediate 239′)
22 13

Example A22
Preparation of Intermediate 171

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A mixture of intermediate 170 (430.00 mg, 2.57 mmol), NH₄Cl (550.36 mg, 10.29 mmol) and Iron powder (718.31 mg, 12.86 mmol) in a mixture of EtOH (9.82 mL) and distilled water (3.93 mL) was heated at 75° C. for 2 h. The reaction mixture was cooled to rt, poured onto a mixture of 10% aqueous K₂CO₃and DCM, then filtered through a pad of Celite®. The organic layer was decanted, washed with brine, dried over MgSO₄, filtered and evaporated to dryness to give 331 mg of intermediate 171 (94% yield, 81% purity based on LC/MS).

Int. number
Structure
Mass (mg)
Yield (%)

Intermediate 225

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1460
Quant.

Intermediate 308

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505 off-white solid
81 with T = 85° C.

Intermediate 324

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284 colorless oil
67 with T = 85° C.

Intermediate 332

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209 colorless oil
70 with T = 85° C.

Intermediate 420

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559 brown residue
90 with T = 85° C.

Intermediate 461

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600
86 with T = 85° C.

Intermediate 496

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95 (86% purity based on LC/MS) colorless oil
61 with T = 85° C.

Intermediate 500

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462
69 with T = 85° C.

Intermediate 504

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930 (79% purity based on LC/MS) colorless oil
81 with T = 85° C.

Intermediate 722

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130
77 with T = 70° C., 30 min

Intermediate 735

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120
77 with T = 70° C., 30 min

Example A23
Preparation of Intermediate 182 and intermediate 182′

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A mixture of 5-methyl-3-nitro-1H-pyrazole (7.00 g, 55.07 mmol) (+/−)-propylene oxide (7.71 mL, 110.15 mmol) in EtOH (64.31 mL) in a sealed tube was stirred at 140° C. for 4 h. The solvent was evaporated and the residue was purified by column chromatography on silica gel (stationary phase: irregular SiOH, 15-40 m, 120 g, mobile phase: heptane/EtOAc, gradient from 80:20 to 50:50). The fractions containing the product were combined to give 2.5 g of intermediate 182 (25% yield) and 7.5 g of intermediate 182′ (74% yield).

Preparation of Intermediate 183

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Intermediate 182 (1.00 g, 5.40 mmol) and iodomethane (504.26 μL, 8.10 mmol) in THF (10 mL) were added at 0° C. under N₂. Then, NaH (60% dispersion in mineral oil) (259.18 mg, 6.48 mmol) was added and the resulting mixture was stirred at rt for 4 h, poured out onto water, extracted with EtOAc, dried over MgSO₄, filtered and evaporated. The residue was purified by column chromatography on silica gel (stationary phase: irregular SiOH, 15-40 μm 40 g, mobile phase: heptane/EtOAc, gradient from 80:20 to 60:40). The fractions containing the product were combined and evaporated to dryness to give 1.01 g of intermediate 183 (94% yield).

Example A24
Preparation of Intermediate 195

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To a solution of 3-methyl-5-nitro-1H-pyrazole (2.46 g, 19.40 mmol) and 1-methyl-4-piperidinemethanol (5.00 g, 38.70 mmol) in dry Me-THF (190 mL). Di-tert-butyl azodicarboxylate (8.91 g, 38.70 mmol) and PPh₃(10.20 g, 38.70 mmol) were added. The solution was heated at 55° C. over the weekend. The reaction mixture was diluted with EtOAc and water. The organic layer was separated and the aqueous layer was extracted thrice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO₄, filtered and concentrated. The residue (yellow oil) was purified by column chromatography on silica gel (Irregular SiOH, 15-40 m, 330 g, liquid loading in DCM, mobile phase: DCM/MeOH, gradient from 100:0 to 90:10). The fractions containing the product were combined and evaporated to dryness to give 2.36 g of intermediate 195 (51% yield, yellow oil).

Int. number
Structure
Mass (mg)
Yield (%)

Intermediate 288

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4360 yellow oil
63 with T = rt

Intermediate 307

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780 yellow oil
65 with T = rt

Intermediate 311

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780 colourless oil
62 with T = rt

Intermediate 315

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759 yellow oil
60 with T = rt

Intermediate 319

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718 yellow oil
71 with T = rt

Intermediate 323

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484 white solid
31 with T = rt

Intermediate 331

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847 white solid
27 with T = rt

Intermediate 358

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274
16 with T = rt

Intermediate 366

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1240 colorless oil
74 colorless oil with T = rt

Intermediate 379 + intermediate 379′

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1040 (intermediate 379) colorless oil 426 (intermediate 379′) yellow oil
66 27 with T = rt

Intermediate 394 + intermediate 394′

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1560 (intermediate 394) colorless oil 730 (intermediate 394′) colorless oil
93 43 with T = rt

Intermediate 398

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10600 yellow oil
75 with T = rt

Intermediate 479

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706 yellow oil
49 with T = rt

Intermediate 495

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174 yellow oil
13 with T = rt

Intermediate 499

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761 yellow oil
55 with T = rt

Intermediate 503

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1450 off-white solid
92 with T = rt

Example A25
Preparation of Intermediate 211 and intermediate 212

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MsCl (0.36 mL, 4.65 mmol) was added slowly at 0° C. to a solution of 1-methyl-4-nitro-1H-pyrazole-3-methanol (0.62 g, 3.95 mmol) in a mixture of DCM (8 mL) and TEA (1 mL, 7.194 mmol). This reaction was stirred for 2 h at rt. Then, water and an aqueous solution of HCl 3N was added. The aqueous layer was extracted twice with DCM. The organic layer was decanted and the solvent was evaporated until dryness to give 526 mg of a mixture of intermediate 211 and 212 (50:50) which was used directly as it in the next step.

The intermediates in the Table below were prepared by using an analogous starting from the respective starting materials.

Mass
Yield

Int. number
Structure
(mg)
(%)

Intermediate 490

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800
86

Intermediate 702

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500
100

Example A26
Preparation of Intermediate 213

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NaH (60% dispersed in mineral oil) (0.61 g, 15.38 mmol) was added at rt to a solution of pyrrolidinone (1.10 mL, 14.26 mmol) in DMF (35 mL). After 5 min at rt, a mixture of intermediate 211 and 212 (1.83 g, 7.78 mmol) was added and stirred at rt overnight. Then, water and an aqueous solution of NH₄Cl 10% were added and this mixture was extracted twice with EtOAc. The organic layer was decanted and the solvent was evaporated until dryness to give 810 mg of intermediate 213 (46% yield) used as it for the next step.

Example A27
Preparation of Intermediate 224

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Intermediate 223 (2.30 g, 10.17 mmol) and CH₃CN (15.93 mL, 0.30 mol) in POCl₃(3.78 mL, mL, 40.67 mmol) in a sealed tube were stirred at 140° C. using one single mode microwave (Biotage Initiator EXP 60) with a power output ranging from 0 to 400 W for 5 min. The resulting mixture was poured out onto ice and water, extracted with DCM, dried over MgSO₄, filtered and evaporated. The residue was purified by column chromatography on silica gel (stationary phase: irregular SiOH, 15-40 m, 80 g, liquid injection, mobile phase: heptane/EtOAc 90:10). The pure fractions were combined and the solvent was evaporated to give 1.71 g of intermediate 224 (81% yield).

Example A28
Preparation of Intermediate 232 and intermediate 232′

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In a sealed tube, 2-(tributylphosphoranylidene)-acetonitrile (7.30 g, 30.25 mmol) was added to a solution of 5-Methyl-3-nitro-1H-pyrazole (2.00 g, 15.74 mmol) and 2-cyclopropylethanol (2.04 g, 23.68 mmol) in toluene (70 mL). The mixture was heated at 60° C. for 19 h. After cooling down to rt, the mixture was diluted with EtOAc and water. The organic layer was decanted and the solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel (Irregular SiOH, 20-45 m, 40 g, mobile phase: heptane/EtOAc, gradient from 60:40 EtOAc to 50:50). The pure fractions were combined and the solvent was evaporated until dryness to give 2.10 g of intermediate 232′ (68% yield) and 330 mg of intermediate 232 (11% yield).

Example A29
Preparation of Intermediate 240

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LiOH (1.40 g, 58.46 mmol) was added to a mixture of intermediate 239 (3.73 g, 19.01 mmol) at rt in a mixture of EtOH (20.00 mL), distilled water (20.00 mL) and 1,4-dioxane (20.00 mL). This reaction was stirred at 40° C. for 3 h then at rt 2 nights. The reaction was poured onto water and Et₂O. The organic layer was decanted and the aqueous layer was acidified by an aqueous solution of HCl 3N until pH=4. The aqueous layer was extracted twice with EtOAc and the organic layer was decanted and evaporated until dryness to give 3.71 g of intermediate 240 (quant. yield) used as it in the next step.

The intermediates in the Table below were prepared by using an analogous starting from the respective starting materials.

Int. number
Structure
Mass (mg)
Yield (%)

Intermediate 245

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1600
77

Preparation of Intermediate 241

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This reaction has been made twice from 1 g of intermediate 240. At rt, diphenyl phosphoryl azide (2.40 mL, 11.16 mmol) followed by benzyl alcohol (2.40 mL, 23.19 mmol) was added to a mixture of intermediate 240 (1.00 g, 5.49 mmol) and TEA (1.60 mL, 11.51 mmol). This reaction was stirred under microwave 160° C. using one single mode microwave (Biotage Initiator EXP 60) with a power output ranging from 0 to 400 W for 15 min. The reaction was cooled down to rt. These reactions were combined with another batch (from 860 mg of intermediate 240) and the solvent was evaporated until dryness. This residue was purified by column chromatography on silica gel (stationary phase: irregular SiOH, 15-40 μm, 120 g, mobile phase: heptane/EtOAc, gradient from 80:20 to 60:40). The pure fractions were collected and the solvent was evaporated until dryness to give 2.58 g of intermediate 241 (57% over 3 batches) which was directly used as it in the next step.

The intermediates in the Table below were prepared by using an analogous starting from the respective starting materials.

Int. number
Structure
Mass (mg)
Yield (%)

Intermediate 246

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3.1
Quant.

Example A30
Preparation of Intermediate 250

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At −78° C. under N₂, BuLi (1.6 M in hexane) (8.30 mL, 13.28 mmol) was added over 15 min to a solution of 1-(-2-tetrahydropyranyl)-1H-pyrazole (2.00 g, 13.14 mmol) in THF (20.00 mL). This reaction was stirred at −78° C. for 30 min. 1-bromo-3-methylbutane (1.80 mL, 14.40 mmol) was added dropwise over 10 min to this mixture. After 3 h at −78° C., the reaction mixture was warmed to rt overnight then quenched with water and few drops of an aqueous solution of HCl 3N was added. This mixture was extracted twice with EtOAc and once with DCM. The organic layers were combined and the solvent was evaporated until dryness. The residue was purified by column chromatography on silica gel (stationary phase: irregular SiOH, 15-40 μm, 40 g, mobile phase gradient from: 95% heptane, 5% MeOH to 75% heptane, 25% EtOAc). The pure fractions were collected and the solvent was evaporated until dryness to give: 1.23 g of intermediate 250 (42% yield) (and 60 mg of intermediate 251).

Preparation of Intermediate 251

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At 0° C., HCl (37% in H₂O) (2.50 mL, 29.94 mmol) was added to a mixture of intermediate 250 (1.23 g, 5.53 mmol) in EtOH (55 mL). This reaction was stirred at rt for 5 h. The solvent was evaporated until dryness. This crude was basified by an aqueous solution of NaHCO₃until pH=8. This mixture was extracted twice with Et₂O and the organic layer was decanted and the solvent was evaporated until dryness to give 625 mg of intermediate 251 (82% yield) which was directly used as it in the next step. Alternative preparation of intermediate 251: 5-methyl-1-hexyne (10 mL, 76.11 mmol) and (trimethylsilyl)diazomethane (38.06 mL, 2 M, 76.11 mmol) in a sealed glassware were stirred at 135° C. for 2 h then at 100° C. for 12 h. The volatiles were evaporated. The residue was performed by column chromatography on silica gel (stationary phase: irregular SiOH, 15-40 μm, 80 g, mobile phase: gradient from 80% heptane, 20% EtOAc to 60% heptane, 40% EtOAc). The fractions containing the product were combined and evaporated to dryness to give 3.2 g of intermediate 251 (30% yield).

Int. number
Structure
Mass (mg)
Yield (%)

Intermediate 678

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4000
53 135° C. 4 hours

Intermediate 684

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8400
quant 135° C. 4 hours

Preparation of Intermediate 252

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HNO₃(65%) (6.50 mL, 142.35 mmol) was added dropwise to a solution of intermediate 251 (0.62 g, 4.49 mmol) in H₂SO₄(6.50 mL, 122.00 mmol) at 0° C. and the reaction was stirred at 0° C. for 3 h and 40 min. HNO₃(65%) (1.50 mL, 32.85 mmol) was added and this reaction was stirred at 0° C. for 2 h. At 0° C., the reaction was poured out onto ice and water, extracted twice with EtOAc and the combined organic layers were washed with saturated NaHCO₃aqueous solution. The organic layer was dried over MgSO₄, filtered and evaporated until dryness to give 764 mg of intermediate 252 (93% yield) which was directly used as it in the next step.

Int. number
Structure
Mass (mg)
Yield (%)

Intermediate 679

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1410
25

Intermediate 685

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4410
37

Preparation of Intermediate 261, 262, 253 and 254

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A mixture of intermediate 252 (0.76 g, 4.17 mmol), K₂CO₃(1.10 g, 7.96 mmol) and 2-bromo-N,N-dimethylethylamine hydrobromide (1.13 g, 4.61 mmol) in DMF (8 mL) was stirred in a sealed tube at 120° C. using one single mode microwave (Biotage Initiator EXP 60) with a power output ranging from 0 to 400 W for 60 min. [fixed hold time]. This reaction was performed at 150° C. for 15 min then K₂CO₃added 150° C. for 70 min. Water was added and this mixture was extracted twice with EtOAc. The organic layer was decanted and the solvent was evaporated until dryness. This residue was purified by column chromatography on silica gel (Irregular SiOH, 40 m, 40 g, mobile phase: heptane/EtOAc, gradient from 80:20 to 60:40). The pure fractions were collected and the solvent was evaporated until dryness to give 240 mg of a mixture of intermediates 253 & 254 (29% yield) used as it in the next step. This purification was performed with 95% DCM, 5% MeOH (+10% NH₄OH) to 85% DCM, 15% MeOH (+10% NH₄OH). The pure fractions were collected and the solvent was evaporated until dryness to give 450 mg of a mixture of intermediates 261 & 262 (42% yield) directly used as it in the next step and a mixture of intermediates 253 & 254 also directly used in the next step.

Example A31
Preparation of Intermediate 269

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A mixture of 2-isopropyl-5-nitro-2H-pyrazole-3-carboxylic acid (0.64 g, 3.21 mmol), HATU (1.70 g, 4.47 mmol), DIPEA (1.50 mL, 8.70 mmol) and methylamaine (2M in THF) (3.20 mL, 3.40 mmol) in Me-THF (6.50 mmol) was stirred at 70° C. for overnight. The reaction was cooled down to rt. Water was added and this mixture was extracted twice with DCM. The organic layer was decanted and dried over MgSO₄, filtered then the solvent was evaporated until dryness. The residue (1 g) was purified by column chromatography on silica gel (Irregular SiOH, 20-45 m, 40 g, mobile phase: 60% heptane, 40% EtOAc). The pure fractions were collected and the solvent was evaporated until dryness to give 385 mg of intermediate 269 (56% yield).

Int. number
structure
Mass (mg)
Yield (%)

Intermediate 635

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10300
39 DCM RT, overnight

Intermediate 636

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4900
18 DCM RT, overnight

Example A33
Preparation of Intermediate 289

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A mixture of intermediate 288 (3.69 g, 18.12 mmol), Zinc (11.85 g, 181.21 mmol) and AcOH (10.37 mL, 181.21 mmol) in MeOH (86 mL) was stirred at rt for 1 h. The mixture was filtered over a pad of Celite® and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with EtOAc and water. The aqueous layer was basified with solid K₂CO₃and the layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgSO₄, filtered and the solvent was removed under reduced pressure to give 3.44 g of intermediate 289 as a yellow residue (92% yield) directly used as it in the next step.

Int. number
Structure
Mass (mg)
Yield (%)

Intermediate 312

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360 yellow solid
53

Intermediate 316

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553 colorless oil
84 with T = 85° C.

Intermediate 320

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227 yellow oil
46 with T = 85° C.

Intermediate 359

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205 yellow solid
85

Intermediate 367

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888 yellow solid
65

Intermediate 380

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226 pale yellow solid
25

Intermediate 395

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1010 yellow oil
74

Intermediate 401

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625 yellow oil
—

Intermediate 696

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106
10

Example A34
Preparation of Intermediate 299

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A mixture of 3-cyano-2-oxo-propanoic acid ethyl ester (4.00 g, 22.30 mmol), 3-methylbutyl-hydrazine (2.28 g, 22.32 mmol) and HCl (37% in H₂O) (5.50 mL, 65.90 mmol) in EtOH (80 mL) was stirred at 60° C. for 18 h. The mixture was evaporated and an extraction was performed with NaOH (3N) and Et₂O. The organic layer was dried over MgSO₄, evaporated. The resulting residue was purified by column chromatography on silica gel (stationary phase: irregular SiOH, 15-40 μm, 120 g, mobile phase heptane/EtOAc, gradient from 100:0 to 40:60). The fractions containing the product were combined and evaporated to dryness to give 1.36 g of intermediate 299 (27% yield, yellow solid).

The intermediates in the Table below were prepared by using an analogous starting from the respective starting materials.

Int. number
Structure
Mass (mg)
Yield (%)

Intermediate 456

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723
31

Intermediate 464

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397
33

Intermediate 475

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879 (80% purity based on LC/MS) pale yellow solid
25

Preparation of Intermediate 300

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At 0° C., LiAlH₄(230.00 mg, 6.06 mmol) was added slowly to a solution of intermediate 299 (1.36 g, 6.04 mmol) in Et₂O (60 mL). The mixture was stirred at rt for 18 h. Further, LiAlH₄(230.00 mg, 6.06 mmol) was added and the mixture was stirred at rt for 2 h. The mixture was placed at 0° C., water (0.5 mL), NaOH (3N, 0.5 mL) and water (1.5 mL) were successively added. The resulting mixture was stirred at rt for 20 min. MgSO₄was added and the mixture was stirred at rt for 1 h. The mixture was filtered and the filtrate was evaporated. The resulting residue was purified by column chromatography on silica gel (irregular SiOH, 15-40 m, 120 g, liquid loading with DCM, mobile phase heptane/EtOAc, gradient from 100:0 to 0:100 in 10 CV then EtOAc/MeOH gradient from 100:0 to 80:20 in 5 CV). The fractions containing the product were combined and evaporated to dryness to give 720 mg of intermediate 300 (65% yield, white solid).

Int. number
Structure
Mass (mg)
Yield (%)

Intermediate 457

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400 (84% purity based on LC/MS)
69 with THF as solvent

Intermediate 465

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243
56 with THF as solvent

Intermediate 476

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500
72 with THF as solvent

Example A35
Preparation of Intermediate 303

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The reaction was performed in 2 batches. In a sealed tube, cyanomethylenetributyl phosphorane (9.28 mL, 35.40 mmol) was added to a solution of 3-methyl-5-nitro-1H-pyrazole (1.50 g, 11.80 mmol) and 3-hydroxymethyl-3-methyloxethane (3.53 mL, 35.40 mmol) in toluene (100 mL). The solution was heated at 60° C. for 18 h. The 2 batches were combined and the solvent was evaporated in vacuo. The residue (black oil) was purified by column chromatography on silica gel (irregular SiOH, 15-40 m, 330 g, liquid loading on DCM, mobile phase: heptane/EtOAc, gradient from 90:10 to 50:50). The fractions containing the product were combined and evaporated to dryness to give 3.95 g of intermediate 303 (79% yield, orange oil) directly used as it in the next step.

Int. number
Structure
Mass (mg)
Yield (%)

Intermediate 327

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750
24

Intermediate 341 + intermediate 341′

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590 (intermediate 341) 900 (intermediate 341′)
19 30

Intermediate 345

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407
13

Intermediate 362

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540
17

Intermediate 374

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2900
32

Intermediate 386

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324 (intermediate 386)
21

Intermediate 390

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856
41

Intermediate 407

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11100
75

Intermediate 417

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10600 yellow oil
75 with T = rt

Intermediate 423

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640 (intermediate 423)
38 with T = 90° C.

Intermediate 427 + intermediate 427′

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817 (intermediate 427) 870 (intermediate 427′)
22 23 with T = 50° C.

Intermediate 468

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361
92

Intermediate 483

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1050
63 with T = 90° C.

Intermediate 488

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3320
47

Intermediate 517 + intermediate 517′

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832 (intermediate 517) 405 (intermediate 517′)
63 31 with T = 90° C.

Intermediate 533

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192 (80% purity based on LC/MS)
22 Procedure with Me-THF

Intermediate 537

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647
11 with T = 90° C.

Intermediate 541

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911
76

Intermediate 583

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720
19 Procedure with Me-THF 8 h

Intermediate 583

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282
6 60° C., 6 h

Intermediate 591

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372
50 110° C. μw 30 min

Intermediate 605

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1660
17 110° C. μw 30 min

Intermediate 601

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350
68 110° C. μw 30 min

Intermediate 656

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700
51 60° C., 36 h

Intermediate 688

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1100
67 90° C., 5 h

Intermediate 680

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490
50 60° C., 19 h

Intermediate 686

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600
38 60° C., 19 h

Intermediate 692

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390
52 RT, 18 h

Intermediate 699

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680
31 110° C. μw 30 min

Intermediate 700

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1200
55 110° C. μw 30 min

Intermediate 742

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6700
79 60° C., 12 h

Intermediate 747

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470
48 60° C., 12 h

Example A36
Preparation of Intermediate 335

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A mixture of 5-bromo-1H-pyrazol-3-amine (790.00 mg, 4.88 mmol) and N,N-dimethyl formamide dimethyl acetal (1.17 mL, 8.78 mmol) in MeOH (12 mL) was refluxed for 2 h. The mixture was evaporated in vacuo. The residual gum was triturated in Et₂O and filtered on a glass-frit to give 617 mg of intermediate 335 (58%, off-white solid). The filtrate was evaporated in vacuo and the residue (380 mg, orange oil) was purified by column chromatography on silica gel (irregular SiOH, 15-40 μm, 10 g, dry loading on Celite®, mobile phase gradient: from heptane 80%, EtOAc 18%, MeOH 2% to heptane 30%, EtOAc 63%, EtOAc 7%). The fractions containing the product were combined and evaporated to dryness to give additional 253 mg of intermediate 335 (24%, white solid).

Preparation of Intermediate 336

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To a solution of intermediate 335 (899.00 mg, 4.14 mmol) and 1-iodo-2-methylpropane (0.71 mL, 6.21 mmol) in DMF (42 mL), Cs₂CO₃(2.70 g, 8.28 mmol) was added and stirred at rt overnight. Further 1-iodo-2-methylpropane (0.24 mL, 2.07 mmol) and Cs₂CO₃(1.35 g, 4.14 mmol) were added and the mixture was stirred at rt for 1 h. EtOAc was added and the mixture was filtered off. The filtrate was evaporated in vacuo and the residual crude was taken-up in EtOAc and water. The organic layer was washed thrice with brine, dried over MgSO₄, filtered off and evaporated in vacuo. The residue (1.09 g, pale yellow liquid) was purified by column chromatography on silica gel (irregular SiOH, 15-40 m, 50 g, dry loading on Celite®, mobile phase gradient: from heptane 90%, EtOAc 9%, MeOH 1% to heptane 60%, EtOAc 36%, MeOH 4%). The fractions containing the product were combined and evaporated to dryness to give 707 mg of intermediate 336 (62% yield, colorless liquid).

Preparation of Intermediate 337

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In a sealed tube, a mixture of intermediate 336 (707.00 mg, 2.59 mmol), dimethylphosphine oxide (0.24 g, 2.85 mmol) and K₃PO₄(0.60 g, 2.85 mmol) in DMF was purged with N₂. Pd(OAc)₂(58.10 mg, 0.26 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (149.70 mg, 0.26 mmol) were added. The mixture was purged with N₂and stirred at 130° C. overnight. The mixture was warmed to rt and filtered on a pad of Celite®. The cake was washed with EtOAc and the filtrate was evaporated in vacuo. The residue (920 mg, red oil) was purified by column chromatography on silica gel (irregular SiOH, 15-40 μm, 50 g, dry loading on Celite®, mobile phase: DCM/MeOH, gradient from 100:0 to 95:5). The fractions containing the product were combined and evaporated to dryness to give 330 mg of intermediate 337 (47% yield, reddish solid).

Preparation of Intermediate 338

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In a sealed tube, to a solution of intermediate 337 (330.00 mg, 1.22 mmol) in EtOH (6 mL) was added HCl (3M in cyclopentyl methyl ether) (6.10 mL, 18.30 mmol). The mixture was stirred at 90° C. overnight. The mixture was evaporated in vacuo to give 501 mg of intermediate 338 (Quant. yield, 77% purity based on NMR, yellow gum).

Example A37
Preparation of Intermediate 349: and intermediate 349′

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A mixture of 3-methyl-4-nitro-1H-pyrazole (1.36 g, 10.71 mmol), tert-butyl-4-iodopiperidine-1-carboxylate (10.00 g, 32.14 mmol) and K₂CO₃(2.96 g, 21.42 mmol) in DMF (16.6 mL) was stirred at reflux for 24 h. The reaction mixture was diluted with EtOAc and water and the layers were separated. The organic layer was washed with brine, dried over MgSO₄, filtered and was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (irregular SiOH 40 m, 80 g, mobile phase: heptane/DCM, gradient from 50:50 to 0:100). The pure fractions were combined and the solvent was evaporated to give a mixture of intermediate 349 and intermediate 349′ (540.00 mg, 16% yield).

Preparation of Intermediate 350 and intermediate 350′

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At 0° C., HCl (4M in dioxane) (15.00 mL, 60.00 mmol) was added to a solution of a mixture of intermediates 349 and 349′ (0.54 g, 1.74 mmol) in 1,4-dioxane (4 mL). The reaction was stirred at rt overnight. The solvent was evaporated until dryness. The residue was taken up into DCM and basified with a 10% aqueous solution of K₂CO₃. The organic layer was dried over MgSO₄, filtered and the solvent was evaporated until dryness. The residue (817 mg) was purified by column chromatography on silica gel (stationary phase: irregular SiOH, 15-40 μm, 40 g, mobile phase: 98% DCM, 2% MeOH (+10% NH₄OH) to 95% DCM, 5% MeOH (+10% NH₄OH)). The pure fractions were collected and the solvent was evaporated until dryness to give 0.480 g of a mixture of intermediates 350 and 350′ used as it for the next step.

The intermediates in the Table below were prepared by using an analogous starting from the respective starting materials.

Int. number
Structure
Mass (mg)
Yield (%)

Intermediate 408

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6550
85

Preparation of Intermediate 351 and intermediate 351′

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A mixture of intermediates 350 and 350′ (0.48 g, 2.28 mmol), formaldehyde (0.21 mL, 2.80 mmol) in MeOH (2.70 mL) and AcOH (0.32 mL, 5.59 mmol) was stirred for 10 min. Then, sodium cyanoborohydride (0.17 g, 2.75 mmol) was added. The reaction was stirred at rt over the weekend. DCM and a 10% solution of K₂CO₃were added. The organic layer was washed with water, dried over MgSO₄, filtered and evaporated. The residue (538 mg) was purified by achiral SFC (Stationary phase: CHIRALPAK IC 5 μm 250×20 mm, mobile phase: 75% CO₂, 25% MeOH). The pure fractions were collected and the solvent was evaporated until dryness to give: 248 mg of intermediate 351 (49% yield) and 184 mg of intermediate 351′ (36% yield).

Example A38
Preparation of Intermediate 375

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To a solution of intermediate 374 (4.30 g, 19.18 mmol) in DMF (95.9 mL, 0.2 M) at rt was added SOCl₂(2.09 mL, 28.77 mmol) and the resulting solution was stirred at rt overnight. Then, EtOAc was added and the reaction mixture was washed with saturated aqueous sodium bicarbonate solution and water. The combined organic layers were dried over Na₂SO₄, filtered and concentrated. The residue (3.1 g) was purified by column chromatography on silica gel (irregular SiOH, 40 μm, 120 g, mobile phase: heptane/EtOAc, gradient from 90:10 to 60:40). The pure fractions were combined and the solvent was evaporated to give 2.11 g of intermediate 375 (53% yield).

Preparation of Intermediate 376

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To a solution of intermediate 375 (2.11 g, 10.23 mmol) in a mixture of 1,4-dioxane (30 mL) and distilled water (6 mL), were added iron powder (5.71 g, 102.33 mmol) and iron (II) sulfate heptahydrate (6.22 g, 40.93 mmol). The resulting solution was heated to reflux for 12 h. The reaction mixture was filtered over a pad of Celite®. DCM was added and the organic layer was decanted, dried over MgSO₄, filtered and evaporated. DCM was added. The insoluble was filtered and dried with DIPE to give 1.21 g of intermediate 376 (67% yield).

The intermediates in the Table below were prepared by using an analogous starting from the respective starting materials.

Int. number
Structure
Mass (mg)
Yield (%)

Intermediate 453

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100
22

Intermediate 480

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540 yellow oil
95

Example A39
Preparation of Intermediate 399

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To a solution of intermediate 398 (1.00 g, 2.90 mmol) in DCM (25 mL), TFA (2.50 mL, 32.70 mmol) was added and the reaction mixture was stirred at rt for 16 h. The solvent was removed under reduced pressure. The residue (1.66 g, yellow oil) was triturated with Et₂O to give a white solid. The solid was filtered on a glass frit, washed with Et₂O to give 820 mg of intermediate 399 (79% yield, white solid, TFA salt).

Int. number
Structure
Mass (mg)
Yield (%)

Intermediate 418

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2820
90

Intermediate 507

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4880
Quant. Procedure with T = 0-5° C. and with DCM/TFA (4:1, v/v)

Preparation of Intermediate 400

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In a sealed tube, a solution of intermediate 399 (1.00 g, 2.79 mmol) in CH₃CN (14 mL) was treated with 1-(4-methylbenzenesulfonate)-2-fluoro-ethanol (0.70 g, 3.21 mmol) and Cs₂CO₃(2.73 g, 8.36 mmol). The reaction mixture was stirred at 80° C. for 70 h. The crude was diluted with water and a saturated aqueous solution of NaHCO₃and extracted with EtOAc. The organic layer was dried over MgSO₄, filtered and evaporated in vacuo to give 790 mg of intermediate 400 (97% yield, yellow oil).

The intermediates in the Table below were prepared by using an analogous starting from the respective starting materials.

Int. number
Structure
Mass (mg)
Yield (%)

Intermediate 460

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790
87

Example A40
Preparation of Intermediate 409

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In a sealed tube a mixture of intermediate 408 (0.50 g, 2.23 mmol), 2-chloro-N,N-dimethylacetamide (0.25 mL, 2.43 mmol) and DIPEA (0.95 mL, 5.51 mmol) in DMF (15 mL) was stirred at 80° C. for overnight. The reaction was cooled down to rt. Water was added and this mixture was extracted twice with EtOAc and twice with DCM. These organic layers were combined and the solvent was evaporated until dryness. The residue was purified by column chromatography on silica gel (irregular SiOH, 40 μm, 40 g, mobile phase gradient from 98% DCM, 2% MeOH (+10% NH₄OH) to 94% DCM, 6% MeOH (+10% NH₄OH)). The pure fractions were collected and the solvent was evaporated until dryness to give 189 mg of intermediate 409 (27% yield) used directly as it in the next step.

Int. number
Structure
Mass (mg)
Yield (%)

Intermediate 413

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537
79 under microwave activation with T = 70° C.

Intermediate 419

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710 (70% purity based on LC/MS)
84

Intermediate 471

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530
84

Intermediate 508

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840 (61% purity based on LC/MS)
91 under microwave activation with T = 70° C.

Intermediate 529

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122
15

Intermediate 545

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683
81

Intermediate 725

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824
89

Example A41
Preparation of Intermediate 452

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Intermediate 211 (0.729 g, 3.10 mmol), morpholine (540.15 mg, 6.20 mmol) and TEA (1.29 mL, 9.30 mmol) in CH₃CN (8.10 mL, 155.00 mmol) were stirred at 60° C. for 1 h. The solvent was evaporated. The residue was purified by column chromatography on silica gel (stationary phase: irregular SiOH, 15-40 μm, 80 g, mobile phase: gradient from 100% DCM to 98% DCM, 2% MeOH, 0.1% NH₄OH). The fractions were combined and evaporated to dryness to give 520 mg of intermediate 452 (74% yield).

The intermediates in the Table below were prepared by using an analogous starting from the respective starting materials.

Int. number
Structure
Mass (mg)
Yield (%)

Intermediate 491

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450
Quant.

Intermediate 521

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275
49

Intermediate 525
From Intermediate 490 and 1-methyl
390
91

piperazine

Intermediate 703
From intermediate 702 and 1-methyl
396
98

piperazone

Example A42
Preparation of Intermediate 487

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SOCl₂(4.62 mL, 63.66 mmol) was added dropwise over 5 min approximately to a solution of 4-Nitro-1H-pyrazole-3-carboxylic acid (5.00 g, 31.83 mmol) in MeOH (50 mL) at 0° C. The resulting clear solution was stirred at 0° C. for 30 min, followed by rt for 16 h. Solvent was evaporated under reduced pressure to obtain 5.4 of intermediate 487 (99% yield, white solid).

Int. number
Structure
Mass (mg)
Yield (%)

Intermediate 730

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4800
99 Reflux, 5 h

Example A43
Preparation of Intermediate 489

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To a solution of intermediate 488 (2.26 g, 9.45 mmol) in dry DCM (25.4 mL) was added dropwise diisobutylaluminium hydride (3.62 mL, 20.31 mmol) at −50° C. The reaction mixture was stirred at −50° C. for 3 h then at rt for 2 h. The mixture was acidified at 0° C. with a 3N aqueous solution of HCl and diluted with Et₂O. The organic layer was separated, washed with a 1N aqueous solution of HCl, then twice with brine, dried over MgSO₄and evaporated in vacuo. The residue (2.17 g) was purified by column chromatography on silica gel (irregular SiOH, 40 m, 40 g, mobile phase: heptane/EtOAc, gradient from 100:0 to 60:40). The pure fractions were combined and the solvent was evaporated to give 536 mg of intermediate 489 (27% yield).

Int. number
Structure
Mass (mg)
Yield (%)

Intermediate 701

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266
25 −20° C. 18 h, then 0° C. 2 h

Example A44
Preparation of Intermediate 512

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At 0° C., oxalyl chloride (9.5 mL, 19.00 mmol) was added to a solution of 5-nitro-1H-pyrazole-3-carboxylic acid (1.50 g, 9.55 mmol) in a mixture of DCM (30 mL) and Me-THF (0.85 mL). Then, one drop of DMF was added at 0° C. and this mixture was stirred at rt for 3 h. The solvent was evaporated until dryness. This product was taken up into DCM (45 mL) and a mixture of cyclopropylamine (13 mL), DCM (3 mL) and pyridine (1.50 mL) was added over a period of 10 min. This reaction was stirred over the weekend at rt. This mixture was concentrated in vacuo and purified by column chromatography on silica gel (irregular SiOH, 20-45 m, 80 g, mobile phase gradient from: 100% DCM to 90% DCM, 10% MeOH (+10% NH₄OH)). The fractions containing the product were combined and the solvent was evaporated until dryness. The residue (1.80 g) was purified by column chromatography on silica gel (irregular SiOH, 20-45 m, 24 g, mobile phase: heptane/EtOAc, gradient from 70:30 to 50:50). The pure fractions were collected and the solvent was evaporated until dryness to give 1.30 g of intermediate 512 (69% yield).

Example A45
Preparation of Intermediate 558

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A mixture of intermediate 186 in dioxane (18 mL) was stirred with lithium hydroxide monohydrate (55 mg, 1.31 mmol) and distilled water (2.5 mL) at rt for 2 h. Then, TFA (3.0 mL, 39.3 mmol) was added and the mixture was stirred at rt for 30 min. The reaction mixture was evaporated under reduced pressure and a dry load on Celite® was prepared. The residue was purified by column chromatography on silica gel (irregular SiOH, 15-40 μm, 30 g, dry load on Celite®, mobile phase gradient: from DCM 100% to DCM 90%, MeOH (+AcOH 10%) 10%). The fractions containing the product were combined and evaporated to dryness to give 697 mg of intermediate 558 (67% purity based on LC/MS) as a yellow residue used as it in the next step.

Preparation of Intermediate 559

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In a sealed tube, intermediate 558 (434.00 mg, 0.84 mmol) and piperidine (99.20 μL, 1.00 mmol) were diluted in dry DMF (10.6 mL). Then, HATU (698.90 mg, 1.84 mmol) and DIPEA (0.36 mL, 2.09 mmol) were added and the mixture was stirred at 70° C. for 17 h. The reaction mixture was evaporated under reduced pressure and purified by column chromatography on silica gel (irregular SiOH, 40 g, dry load on Celite®, mobile phase gradient: from DCM 100% to DCM 90%, MeOH (+aq. NH₃5%) 10%). The fractions containing the product were combined and evaporated to dryness. The residue (512 mg, yellow residue) was triturated in Et₂O and the solid was filtered on a glass frit to give two batches of intermediate 559 (batch 1, 85 mg, 17% yield, yellow solid; batch 2, 90 mg, 18% yield, yellow residue) directly used as it in the next step.

Example A 46
Preparation of Intermediate 560

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DMA-DMF (10.00 mL; 74.69 mmol) was added dropwise to methyl 5-methoxy-3-oxopentanoate (10.00 mL; 68.68 mmol) in DCM (50.00 mL) at room temperature. This reaction was stirred at room temperature for overnight. The solvent was evaporated until dryness to give 15.54 g of intermediate 560 (quantitative) directly used in the next step without any further treatment.

The intermediates in the table below were prepared by using an analogous method starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Int. number
Structure
Mass (mg)
Yield (%)

Intermediate 755

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820
97 Neat, rt, overnight

Preparation of Intermediate 561

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Hydrazine monohydrate (8.00 mL; 164.73 mmol) was added to a solution of intermediate 560 (15.54 g; 72.19 mmol) in EtOH (230 mL). This reaction was stirred at reflux for 6 hours (T=95° C.) then cooled down to room temperature. The solvent was evaporated until dryness. The crude was purified by silica gel chromatography (Irregular SiOH 15-40 m 220 g, mobile phase gradient from: 80% Heptane, 20% EtOAc to 45% Heptane, 55% EtOAc). The pure fractions were collected and the solvent was evaporated until dryness to give 2 fractions of intermediate 561: Fraction A: 3.54 g (27% yield); Fraction B: 7.34 g (55% yield).

These two fractions were directly used in the next step without any further treatment.

Int. number
Structure
Mass (mg)
Yield (%)

Intermediate 756

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438
62 95° C., 2 h then rt, overnight

Preparation of Intermediate 562 and intermediate 563

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In a sealed tube, 2-(tributylphosphoranylidene)acetonitrile (8.70 mL; 33.16 mmol) was added to a solution of intermediate 561 (3.40 g; 18.46 mmol) and 2,2-difluoroethanol (1.40 mL; 22.11 mmol) in toluene (50.00 mL). This reaction was heated at 70° C. overnight. The reaction was cooled down to room temperature. Water was added and this mixture was extracted twice with EtOAc. The organic layer was decanted and the solvent was evaporated until dryness. This crude was purified by silica gel chromatography (Irregular SiOH 15-40 μm 120 g GraceResolv, mobile phase gradient from: 80% Heptane, 20% EtOAc to 60% Heptane, 40% EtOAc). The pure fractions were collected and the solvent was evaporated until dryness to give 3.26 g of impure intermediate 563 and 1.47 g of impure intermediate 562.

Impure intermediate 563 (3.26 g) was repurified by silica gel chromatography (Irregular SiOH 15-40 m 80 g, mobile phase Gradient from: 90% Heptane, 10% EtOAc to 60% Heptane, 40% EtOAc). The fractions containing the product were collected and the solvent was evaporated until dryness to give 1.2 g (26%) of intermediate 563 and 1 g (22%) of intermediate 562.

Impure intermediate 562 (1.47 g) was repurified by silica gel chromatography (Irregular SiOH 15-40 m 80 g GraceResolv, mobile phase Gradient from: 90% Heptane, 10% EtOAc to 60% Heptane, 40% EtOAc). The pure fractions were collected and the solvent was evaporated until dryness to give 0.53 g (11%) of intermediate 562.

In total 1.53 g of intermediate 562 were obtained.

Int. number
Structure
Mass (mg)
Yield (%)

Intermediate 757

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395
69

Preparation of Intermediate 564

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Lithium hydroxide 98% (0.33 g; 13.49 mmol) was added to a solution of intermediate 562 (1.53 g; 6.16 mmol) in ethanol (9.00 mL), water (9.00 mL) and 1,4-dioxane (9.00 mL). The reaction was stirred for 60 minutes at 95° C., then was cooled down to room temperature. Water was added and the mixture was acidified with an aqueous solution of HCl 3N. The aqueous layer was extracted twice with EtOAc. The organic layers were mixed, dried over MgSO₄, filtered and the solvent was evaporated until dryness to give 1.41 g of intermediate 564 (98% yield) which was directly engaged in the next step without any further treatment The intermediates in the table below were prepared by using an analogous method starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Int. number
Structure
Mass (mg)
Yield (%)

Intermediate 565

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273
91 45° C. for 3 hours then, room temperature overnight

Intermediate 758

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234
quant

Preparation of Intermediate 566

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A mixture of intermediate 564 (1.42 g; 6.06 mmol), diphenylphosphoryl azide (2.40 mL), triethylamine (1.6 mL; 11.51 mmol) and benzyl alcohol (2.4 mL; 23.19) was stirred at 160° C. using one single mode microwave (Biotage Initiator EXP 60)® with a power output ranging from 0 to [400 W] for 15 minutes. The reaction was cooled down to room temperature and the solvent was evaporated until dryness. The crude was purified by silica gel chromatography (Irregular SiOH 20-45 m 80 g, mobile phase Gradient from: 90% Heptane, 10% EtOAc to 50% Heptane, 50% EtOAc). The pure fractions were collected and the solvent was evaporated until dryness to give:

Fraction A: 0.92 g of intermediate 566 (45% yield)

Fraction B: 0.88 g of impure intermediate 566. Fraction B was repurified by silica gel chromatography (Irregular SiOH, 20-45 m, 40 g, mobile phase gradient from: 90%

Heptane, 10% EtOAc to 50% Heptane, 50% EtOAc). The pure fractions were collected and the solvent was evaporated until dryness to give:

Fraction C: 0.64 g of intermediate 566 (31% yield).

Fraction A and fraction C were combined to give 1.56 g of intermediate 566 (76% yield) which was directly used in the next step.

Inter-

mediate

Mass
Yield

number
Structure
(mg)
(%)

Inter- mediate 567

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285
72

Inter- mediate 759

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200
61 Anton Parr μw

Preparation of Intermediate 568

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Intermediate 566 (1.56 g; 4.60 mmol) was hydrogenated at room temperature in MeOH (25.00 mL) and EtOAc (20.00 mL) with Pd/C 10% (0.330 g; 0.31 mmol) as a catalyst for 2 hours at atmospheric pressure. The catalyst was filtered over Celite® and the solvent was evaporated until dryness to give 916 mg of intermediate 568 (97% yield) directly used in the next step.

Intermediate

Mass
Yield

number
Structure
(mg)
(%)

Intermediate 569

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156
91

Intermediate 576

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187
53

Intermediate 580

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4340
100

Example A48
Preparation of Intermediate 577

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At 0° C. oxalyl chloride (2M in DCM) (70 mL; 140 mmol) was added slowly to mixture of 5-nitro-3-pyrazolecaboxilic acid (14.50 g, 92.31 mmol) and dimethylformamide (0.200 mL, 2.58 mmol) in DCM (100 mL). The reaction mixture was stirred at room temperature overnight. The precipitate was filtered and the filtrate was evaporated until dryness to give 7.5 g (47%) of intermediate 577 directly used in the next steps without any further purification.

Preparation of Intermediate 578

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Intermediate 577 (7.52 g; 42.84 mmol) was dissolved in THF (110.00 mL) at room temperature. Then a solution of methylamine (2M in THF) (28.00 mL; 56.00 mmol) in THF (20.00 mL) and trimethylamine (17.00 mL; 122.30 mmol) was added slowly (temperature increased). This reaction mixture was stirred for 4 hours at room temperature, then poured onto a mixture of a 10% aqueous solution of NH₄Cl and EtOAc (100 mL). The aqueous layer was extracted three times with EtOAc (3*200 mL). The organic layers were combined and the solvent was evaporated.

The crude residue was taken up with DCM and triturated. The precipitate was filtered and dried until dryness to give 825 mg (11%) of intermediate 578.

The filtrate was purified via silica gel chromatography (Gradient: 98% DCM, 2% MeOH, 0.2% NH₄OH to 93% DCM, 7% MeOH, 0.7% NH₄OH).

The desired fractions were collected and the solvent was evaporated to give 0.126 g of intermediate 578 (impure).

The aqueous layer was acidified until pH 5 with a 10% aqueous solution of HCl and was extracted twice with EtOAc (2*200 mL). The organic layers were mixed and the solvent was evaporated to give 3.46 g (47%) of intermediate 578.

A total of 4.28 g (59%) of intermediate 578 was obtained and directly used in the next reaction step without further purification.

Preparation of Intermediate 579 and intermediate 269

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In sealed tube, a mixture of intermediate 578 (4.28 g; 25.16 mmol), potassium carbonate (6.81 g; 50.03 mmol) and 2-iodopropane (3.00 mL) in DMF (50 mL) was stirred at 120° C. for 2 hours and 20 minutes. Additional 2-iodopropane (1.00 mL; 10.00 mmol) was added and this reaction was stirred for 2 more hours at 120° C. The mixture was poured onto a mixture of water and a saturated solution of NH₄Cl. Then, this mixture was extracted three times with DCM. The organic layer were mixed and the solvent was evaporated until dryness.

The residue (6.34 g) was purified via silica gel chromatography (Stationary phase: irregular SiOH 40 m 330 g, Mobile phase: Gradient from 70% heptane, 30% EtOAc to 60% heptane, 40% EtOAc). The pure fractions were collected and the solvent was evaporated until dryness to give:

- 1.30 g (24%) of intermediate 269
- 2.50 g (47%) of intermediate 579 which was combined with another batch of 2.42 g, coming from another reaction, and engaged in the next reaction step.

Example A49
Preparation of Intermediate 582

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To a suspension of 4-nitro-3-pyrazole carboxylic acid (6 g, 38.196 mmol) and DMF (73.938 μL, 0.944 g/mL, 0.955 mmol) in DCM (48.93 mL) at 0° C. was added dropwise a solution of oxalyl chloride 2M in DCM (36 mL, 2 M, 72 mmol) and the reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in 20 mL of DCM and 1-methylpiperazine (6.355 mL, 0.903 g/mL, 57.294 mmol) was added slowly at 0° C. The reaction mixture was then allowed to warm to rt and stirred at rt overnight. DCM was removed in vacuo and the resulting slurry was diluted with DCM and a little MeOH. The insoluble residue was filtered off to give 5 g (54%) of intermediate 582.

The filtrate was concentrated in vacuo and purified by Normal phase flash chromatography (Irregular SiOH 40 m 40 g GRACE). Mobile phase 98% DCM, 2% MeOH, 0.2% NH₄OH to 90% DCM, 10% MeOH, 1% NH₄OH. The pure fractions were combined and the solvent was evaporated to give a further 2.7 g (30%) of intermediate 582.

Example A50
Preparation of Intermediate 584

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Borane tetrahydrofuran complex, 1.0M in THF (8.30 mL; 1 M, 8.31 mmol) was added dropwise over 1 h to a stirred suspension of intermediate 583 (630 mg, 2.08 mmol) in THF (4.40 mL, 0.886 g/mL, 54.01 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 h and then at rt overnight. Then H₂O was added (2.077 mL), and the mixture extracted with DCM. The organic layers were decanted, dried over MgSO₄, filtered and evaporated. The crude product was purified by Normal phase flash chromatography (Irregular SiOH 40 m 80 g GRACE). Mobile phase 100% DCM to 90% DCM, 10% MeOH, 1% NH₄OH. The pure fractions were combined and the solvent was evaporated to give 337 mg of material. This material was further purified by Normal phase flash chromatography (Irregular SiOH 40 μm 40 g GRACE). Mobile phase 80% Heptane, 20% AcOEt to 40% Heptane, 50% AcOEt, 10% MeOH, 0.1% NH₄OH. The pure fractions were combined in 2 batches and the solvent was evaporated to give respectively 113 mg (19%) of intermediate 584 (19%) and 120 mg of intermediate 584 (20%).

Example A51
Preparation of Intermediate 632, intermediate 633 and intermediate 634

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A mixture of intermediate 730 (800 mg, 4.68 mmol), cyclopentyl bromide (0.600 mL, 5.60 mmol) and K₂CO₃(1.25 g, 9.04 mmol) in DMF (5.50 mL) was stirred in a sealed tube at 120° C. using one single mode microwave (Biotage Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 min. [fixed hold time]. The reaction was cooled down to room temperature. The mixture was poured out onto water and DCM. The mixture was decanted and the solvent was evaporated until dryness. The crude was purified by Normal phase flash chromatography (Irregular SiOH 15-40 m 40 g GraceResolv®). Mobile phase 90% Heptane, 10% AcOEt to 60% Heptane, 40% AcOEt. The pure fractions were combined and the solvent was evaporated to give 142 mg (10%) of intermediate 634 and 670 mg of a mixture of the intermediates (60%), which was used directly in the next step.

Alternative Preparation of Intermediate 633

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Cyclopentyl iodide (0.608 ml; 5.26 mmol) was added to a solution of intermediate 730 (600 mg; 3.506 mmol) in DMF (12 ml) under N₂atmosphere. The mixture was stirred at rt for 15 minutes and K₂CO₃(969.2 mg; 7.013 mmol) was added. The reaction was stirred at rt for overnight. The reaction mixture was diluted with ice water (5 mL). The precipitate was filtered off and washed with water and dried in vacuo. The product was taken forward directly in the next step.

Preparation of Intermediate 640 and intermediate 641

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Lithium hydroxide monohydrate (5.80 g; 137.94 mmol) and water (35.4 mL) were added to a solution of the mixture of intermediates 632, 633 and 634 (30 g; 125.40 mmol) in THF (430 mL) and MeOH (430 mL). The reaction mixture was stirred at rt for overnight. The volume of the solution was reduced in vacuo and the solution was poured onto an aqueous solution HCl 3N (500 mL). The resultant precipitate was filtered, washed with aqueous solution of HCl 1M and dissolved in DCM (400 mL). The organic layer was dried over MgSO₄, filtered and the solvent was evaporated to give 25.16 g of a mixture of the intermediates 640 and 641. The product (675 mg; 80%) was used without purification for the next step.

Alternative Preparation of Intermediate 641

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Intermediate 633 (650 mg; 2.717 mmol) was dissolved in a mixture of MeOH (7 ml) and THF (7 ml). To this solution, was added H₂O (0.5 ml) and Lithium hydroxide monohydrate (125.4 mg; 2.989 mmol) and the mixture was stirred until the starting material had disappeared on the TLC. The solution was concentrated in vacuo, the residue was then dissolved in H₂O and acidified with 1M HCl (aq). The resultant precipitate was filtered, washed with aq. 1M HCl and dried in vacuo. The product (250 mg; 41%) was taken forward directly in the next step.

Preparation of Intermediate 721

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Intermediate 641 (210 mg, 0.933 mmol) was dissolved in DCM (10 mL) and TEA (0.26 mL, 1.865 mmol) was added. To the stirred solution, pyrrolidine (0.156 mL, 1.865 mmol), EDC hydrochloride (357.5 mg, 1.865 mmol) and HOBT (285.6 mg, 1.865 mmol) were added. The resulting suspension was stirred at rt overnight. The reaction mixture was quenched by addition of water (10 ml). The organic layer was washed with brine and the layers were separated. The organic layer was dried over MgSO₄, filtered and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (irregular SiOH, 15-40 μm, mobile phase: Heptane/EtOAc 50:50). The fractions containing the product were combined and evaporated to dryness to give 210 mg of intermediate 721 (81% yield).

Example A52

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Preparation of Intermediate 595 and 596

Cyanomethylenetributylphosphorane (19.769 mL, 0.92 g/mL, 75.354 mmol) was added to a solution of intermediate 487 (7 g, 40.909 mmol) and 2,2-difluoroethanol, 97% (4.68 g, 57.034 mmol) in toluene (195.641 mL, 0.867 g/mL, 1840.895 mmol) in a sealed tube. The reaction mixture was stirred at 110° C. using one single mode microwave (Masterwave BTR Anton Paar) with a power output ranging from 0 to 1700 W for 30 min. [fixed hold time]. The reaction mixture was diluted with EtOAc washed with a solution 10% of K₂CO₃(aq), water and a solution of saturated NaCl. The layers were separated and the organic layer was dried over MgSO₄, filtered and the solvent was removed under reduced pressure. The crude was purified by Normal phase flash chromatography (Irregular SiOH 40 m 330 g GRACE). Mobile phase 90% Heptane, 10% AcOEt to 40% Heptane, 60% AcOEt. The pure fractions were combined and the solvent was evaporated to give 1.77 g of pre-purified intermediate 596 (18%) and 2.9 g of pre-purified intermediate 595 (30%).

The 1.77 g was further purified by Normal phase flash chromatography (Irregular SiOH 40 μm 80 g GRACE). Mobile phase 80% DCM, 20% Heptane to 99% DCM, 1% MeOH, 0.1% NH₄₀OH. The pure fractions were combined and the solvent was evaporated to give 1 μg of intermediate 596 (11%).

The 2.9 g was further purified by Normal phase flash chromatography (Irregular SiOH 40 μm 120 g GRACE). Mobile phase 80% DCM, 20% Heptane to 99% DCM, 1% MeOH, 0.1% NH₄OH. The pure fractions were combined and the solvent was evaporated to give 1.66 g of intermediate 595 (17%).

Mass
Yield

Int. number
structure
(mg)
(%)

Mixture of Intermediates 644 + 645

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1270
40

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Example A53
Preparation of Intermediate 597

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Intermediate 595 (0.6 g, 2.55 mmol) in methyl amine 40% in THF (6.40 mL, 2 M, 12.76 mmol) and ⁱPrOH (3.90 mL, 0.785 g/mL, 51.03 mmol) in a sealed tube were stirred at 120° C. using one single mode microwave (Biotage Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 min. [fixed hold time]. The volatiles were evaporated. The crude residue was purified via preparative LC (Stationary phase: irregular SiOH 15-40 μm 40 g GraceResolv®, Mobile phase: gradient from 100% DCM to 97% DCM, 3% MeOH (2% NH₄OH))

The pure fractions were collected and the solvent was evaporated until dryness to give intermediate 597 (418 mg, 70%)

Mass
Yield

Int. number
structure
(mg)
(%)

Intermediate 606

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192
34

Intermediate 612

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293
59

Intermediate 616

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136
22 Procedure in MeOH 80° C. 10 min

Intermediate 635

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210
31

Intermediate 636

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131
20

Intermediate 646

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670
53

Intermediate 666

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359
99 Neat Procedure in methyl- amine RT 30 min

Example A54
Preparation of Intermediate 654

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A mixture of intermediate 653 and methylamine solution (33 wt % in EtOH) was stirred at rt for 1 h. The volatiles were removed under reduced pressure, without heating, to afford intermediate 654 (161 mg, 88%). The material was used directly in the next step.

Example A55
Preparation of Intermediate 620

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A solution of 4-nitro-3-pyrazole carboxylic acid (5 g, 31.83 mmol), iodomethane (3.963 mL, 2.28 g/mL, 63.66 mmol) and K₂CO₃(8.798 g, 63.66 mmol) in DMF (60 mL) was stirred rt overnight. Ethyl acetate and water were added to the mixture. The organic layer was dried over MgSO₄, filtered and concentrated. A purification was performed via preparative LC (Stationary phase: irregular SiOH 15-40 μm 220 g grace, Mobile phase: gradient from 90% Heptane, 10% AcOEt to 40% Heptane, 60% AcOEt. The pure fractions were combined and the solvent was evaporated to give 1.43 g of intermediate 610 (24%) and 2.5 g of intermediate 611 (42%).

Example A56
Preparation of Intermediate 620

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KO^tBu (938 mg, 8.36 mmol) was added to a stirred solution of 5-chloro-1-methyl-4-nitro-1H-pyrazole (900 mg, 5.57 mmol) and cyclopropanol (970.713 mg, 16.713 mmol) in MeCN (7.27 mL) at rt. Addition was done portionwise. The mixture was stirred at rt for 3 hours. Water was added and the mixture acidified with 3N HCl(aq). The reaction mixture was extracted with DCM, dried over MgSO₄, filtered and evaporated. A purification was performed via preparative LC (Stationary phase: irregular SiOH 15-40 μm 80 g GraceResolv®, Mobile phase: gradient from 100% DCM to 98% DCM, 2% MeOH, 0.1% NH₄OH) to afford intermediate 620 (470 mg, yield 46%).

Mass

Int. number
structure
(mg)
Yield (%)

Intermediate 624

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235
19 140° C. 20 min

Intermediate 628

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407
58 Procedure in ⁱPrOH, reflux, 12 h

Intermediate 741

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3300
65

Example A57
Preparation of Intermediate 657

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Lithium bis(trimethylsilyl)amide (3.713 mL, 1 M, 3.713 mmol) was added dropwise to a stirred solution of intermediate 656 (700 mg, 3.094 mmol) in THF (9.282 mL, 0.886 g/mL, 114.055 mmol) at −70° C. under nitrogen. The reaction mixture was stirred at −70° C. for 2 hours then hexachloroethane (878.997 mg, 3.713 mmol) in THF (1.856 mL, 0.886 g/mL, 22.811 mmol) was added dropwise. The resulting mixture was allowed to stir at rt and stirred for 1 hour. A diluted solution of NH₄Cl was added and the aqueous layer was extracted with DCM and the combined layers were dried over MgSO₄. After filtration and removal of the solvent in vacuo, 550 mg of intermediate 657 (68%. yield) were obtained and directly used in the next steps without any further treatment.

Preparation of Intermediate 658

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Intermediate 657 (420 mg, 1.611 mmol) in ⁱPrOH (2.965 mL, 0.785 g/mL, 38.726 mmol) in a sealed tube were stirred at 165° C. using one single mode microwave (Biotage Initiator EXP 60) with a power output ranging from 0 to 400 W for 10 min. [fixed hold time]. Sodium Isopropoxide (396.724 mg, 4.834 mmol) was added. Then the resulting mixture was stirred at 165° C. using one single mode microwave (Biotage Initiator EXP 60) with a power output ranging from 0 to 400 W for 5 min. [fixed hold time]. The reaction mixture was poured onto water and an extraction was performed with DCM. The organic layer was washed with brine and the layers were separated. The organic layer was dried over MgSO₄, filtered and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (irregular SiOH, 15-40 m, 40 g, GraceResolv®), mobile phase: DCM/(MeOH(+10% aq. NH₄OH)), gradient from 100:0 to 96:4). The fractions containing the product were combined and evaporated to dryness to give 285 mg of intermediate 658 (79% yield).

Example A58
Preparation of Intermediate 662

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Intermediate 657 (990 mg, 3.798 mmol) was stirred in ⁱPrOH for 20 minutes at 165° C. in a sealed tube. ⁱPrOH was evaporated to give the nitro pre-cursor to the targeted amino pyrazole. The residue was taken up into MeOH (18.045 mL, 0.791 g/mL, 445.47 mmol). AcOH (2.143 mL, 1.049 g/mL, 37.432 mmol) then zinc (2.483 g, 37.978 mmol) were added and the reaction mixture was stirred at rt for 1 hour.

The resulting mixture was filtered on a pad of Celite® and the solvent was concentrated under reduced pressure. A diluted solution of 10% K₂CO₃(aq) was added and the aqueous layer was extracted with DCM and the combined layers were dried over MgSO₄. After filtration and removal of the solvent in vacuo, 437 mg of intermediate 662 (50%) were obtained and directly used in the next steps without any further treatment.

Preparation of Intermediate 663

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Intermediate 662 (384 mg, 1.665 mmol) and hexahydro-1H-furo[3,4-C]pyrrole (470.891 mg, 4.161 mmol) in ⁱPrOH (3.063 mL, 0.785 g/mL, 40.009 mmol) in a sealed tube were stirred at 165° C. using one single mode microwave (Biotage Initiator EXP 60) with a power output ranging from 0 to 400 W for 10 min. [fixed hold time]. The residue was purified by column chromatography on silica gel (irregular SiOH 15-40 m, 40 g GraceResolv®, mobile phase: DCM/(MeOH(+2% aq. NH₄OH)), gradient from 100:0 to 90:10). The fractions containing the product were combined and evaporated to dryness to give 371 mg of intermediate 663 (73% yield).

Example A59
Preparation of Intermediate 672

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Methyl alpha-chloroacrylate (25 g, 1.189 g/mL, 207.408 mmol) in THF (70 mL) and methylhydrazine (22.083 mL, 0.86 g/mL, 412.217 mmol) in THF (70 mL) were added dropwise at the same rate to THF (10 mL) at rt. The reaction mixture was stirred at rt for 16 h then was heated at 50° C. for 1 hour. The resulting mixture was diluted with water. The aqueous layer was extracted with EtOAc (4×) and the layers were separated. The organic layer was dried over MgSO₄, filtered and the solvent was removed under reduced pressure to give 15.7 g intermediate 672 (77%, yield) which was used directly for the next step>yligny_4508_1

Preparation of Intermediate 673

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H₂SO₄(39.369 mL, 1.84 g/mL, 738.569 mmol) was cooled down to −5° C. Intermediate 672 (3 g, 30.58 mmol) was added and the solution was stirred for 15 minutes at 0° C. HNO₃(43.306 mL, 1.38 g/mL, 948.406 mmol) was added dropwise. The reaction was stirred at 0-5° C. for 2 hours. The reaction mixture was poured out onto ice and water, stirred for 20 min and the precipitate was filtered off and dried, affording intermediate 673 (2.3 g, yield 52.6%).

Preparation of Intermediate 674

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Cyanomethylenetributyl phosphorane (3.483 mL, 0.92 g/mL, 13.277 mmol) was added to a solution of intermediate 673 (1 g, 6.988 mmol) and 4-(2-hydroxyethyl)morpholine (1.273 mL, 1.08 g/mL, 10.482 mmol) in toluene (30.449 mL) at rt. The mixture was stirred at rt for 18 hours. The solvent was evaporated and the residue was purified by preparative LC (Irregular SiOH 20-45 m 40 g GraceResolv®, mobile phase Gradient from 80% Heptane, 20% AcOEt to 40% Heptane, 50% AcOEt, 10% MeOH (2% NH₄OH)). The pure fractions were combined and the solvent was evaporated to afford intermediate 674 (1.52 g, yield 84.9%).

Example A60
Preparation of Intermediate 707

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Intermediate 577 (2.00 g; 11.39 mmol) was dissolved in THF (30.00 mL). Then a solution of pyrrolidine (15.00 mL; 13.00 mmol), triethylamine (4.50 mL; 32.37 mmol) in THF (10.00 mL) was added slowly to this mixture and the reaction was stirred overnight at room temperature. Water was added and this mixture was extracted twice with EtOAc. The organic layer was decanted and the solvent was evaporated until dryness to give 1.10 g (46%) of intermediate 707. The aqueous layer was acidified with 3N HCl(aq) and extracted twice with EtOAc. The organic layer was decanted and the solvent was evaporated until dryness to give a further 0.90 g (38%) of intermediate 707. The two fractions were combined to give 2.00 g (84%) of intermediate 707 which was used directly in the next step.

Intermediate

Mass
Yield

number
Structure
(mg)
(%)

Intermediate 712

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2140
89 Procedure in Et₃N, THF RT, o/n

Example A61
Preparation of Intermediate 729

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A mixture of intermediate 728 (0.165 g; 0.26 mmol), SiO₂35-70 m (0.500 g) in toluene (4.00 mL) was stirred at 120° C. for 2 hours. The reaction was cooled down to room temperature. SiO₂was filtered off and washed four times with a mixture of EtOAc/MeOH (85%/15%). The solvent was evaporated until dryness. The crude was purified by preparative LC (Irregular SiOH 20-45 m 40 g GraceResolv®, mobile phase: 98% DCM, 2% MeOH to 94% DCM 6% MeOH). The pure fractions were collected and the solvent was evaporated until dryness to afford intermediate 729 (0.066 g; 48%) which was used directly for the next step.

Example A62
Preparation of Intermediate 732

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A solution of intermediate 731 (1.22 g, 6.59 mmol) in dry DCM (30 mL) was cooled to −78° C. The reaction mixture was purged with N₂, then DIBAL-H (1M solution in DCM) (7.25 mL, 7.249 mmol) was added dropwise. The resulting mixture was stirred at −78° C. for 1.5 h. A saturated NH₄Cl solution (1 mL) was added, followed by 1 M HCl (1 mL). The mixture was extracted with DCM. The organic layer was washed with brine and the layers were separated. The organic layer was dried over MgSO₄, filtered and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (irregular SiOH, 15-40 μm, mobile phase: Heptane/EtOAc 70:30). The fractions containing the product were combined and evaporated to dryness to give intermediate 732 (530 mg; 52% yield).

Preparation of Intermediate 733

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To a solution of SnAP reagent (2-[(tributylstannyl)methoxy]-ethanamine) (0.995 mL, 3.417 mmol) in DCM (15 mL) at rt was added intermediate 732 (530 mg, 3.417 mmol) and Molecular Sieves 4A (100 mg/mmol, 341 mg). The resulting suspension was stirred at rt for 2 hours, filtered and concentrated under reduced pressure to afford the imine. Separately, 2,6-lutidine (0.398 mmol, 3.417 mmol) was added in one portion to a suspension of HFIP (10 mL) and Cu(OTf)₂(1.236 g, 3.417 mmol). A solution of the imine in DCM (6 mL) was added in one portion and the resulting mixture was stirred at rt overnight. The reaction was quenched by addition of 10% aq NH₄OH (5 ML) and was extracted with DCM. The organic layer was washed with brine and the layers were separated. The organic layer was dried over MgSO₄, filtered and the solvent was removed under reduced pressure to give. The crude was purified by column chromatography on silica gel (irregular SiOH 15-40 m, mobile phase: DCM/(MeOH), gradient from 100:0 to 98:2). The fractions containing the product were combined and evaporated to dryness to give 270 mg of intermediate 733 (37% yield).

Preparation of Intermediate 734

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To a solution of intermediate 733 (250 mg, 1.178 mmol) in MeOH (10 mL) were added formaldehyde (0.191 mL, 2.356 mmol) and then formic acid (0.444 μL, 0.0118 mmol). The reaction mixture was stirred at rt 1 hour. Then, sodium triacetoxyborohydride (312.1 mg, 1.473 mmol) was added and the reaction mixture was stirred for 1 hour. Then, the reaction mixture was carefully quenched by addition of saturated NaHCO₃(aq) (2 mL). The organic layer was washed with brine and the layers were separated. The organic layer was dried over MgSO₄, filtered and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (irregular SiOH, 15-40 μm, mobile phase: EtOAc 100%). The fractions containing the product were combined and evaporated to dryness to give 180 mg of intermediate 734 (68% yield).

Example A63
Preparation of Intermediate 738

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DIPEA (0.385 mL; 2.24 mmol) was added to a solution of 1-methyl-1H-pyrazol-3-amine (0.159 mL; 2 mmol) and 2,4-dichloro, 1,3,5-triazine (0.3 g; 2 mmol) in acetone (9 mL) at 0° C. The reaction mixture was allowed to warm up to rt, was purged with N₂and was stirred for 3 h. A diluted solution of NH₄Cl was added and the aqueous layer was extracted twice with EtOAc and the combined layers were dried over MgSO₄. After filtration and removal of the solvent in vacuo, 660 mg of intermediate 738 (quantitative recovery, purity 57%) were obtained and used directly in the next step without any further treatment.

Preparation of Intermediate 739

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To a solution of intermediate 5 (0.6 g; 0.772 mmol), intermediate 738 (0.285 g; 0.772 mmol) and cesium carbonate (0.755 g; 2.32 mmol) in 1,4-dioxane (3.9 mL) and distilled water (0.4 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.045 g; 0.0386 mmol). The reaction mixture was heated at 95° C. overnight. The reaction mixture was poured into ice and extracted with EtOAc. The organic layer was washed with brine and the layers were separated. The organic layer was dried over MgSO₄, filtered and the solvent was removed under reduced pressure. The crude residue was purified by column chromatography on silica gel (irregular SiOH, 15-40 m, 40 g, mobile phase: Heptane/EtOAc gradient from 100:0 to 0:100). The fractions containing the product were combined and evaporated to dryness to give 60 mg of intermediate 739 (13% yield).

Example A64

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Preparation of Intermediate 746

At 0° C. and under nitrogen flux, NaH (60% dispersion in mineral oil) (0.510 g; 12.8 mmol) was added portionwise to a solution of cyclopropanol (0.64 mL, 12.74 mmol) in Me-THF (24 mL). The reaction was stirred at room temperature for 10 minutes.

At −78° C., the above described suspension was added dropwise to a solution of 1,4-dinitro-1H-pyrazole (3.00 g; 18.98 mmol) in Me-THF (6.50 mL, 64.9 mmol). The reaction mixture was stirred at −78° C. for 1 h then allowed to stir at rt for 5 hours. The reaction mixture was poured out onto water, made acidic with 3N HCl(aq), extracted with DCM, dried over MgSO₄, filtered and evaporated. The crude was purified via preparative LC (Stationary phase irregular SiOH 15-40 m 24 g GraceResolv®, Mobile phase: gradient from 80% Heptane, 20% EtOAc to 40% heptane, 60% EtOAc). The pure fractions were collected and the solvent was evaporated to give 466 mg of intermediate 746 (22%).

Example A65
Preparation of Intermediate 754

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NaH (60% dispersion in mineral oil) (0.340 g; 8.5 mmol) was added to a solution of dimethyl carbonate (0.83 mL; 9.85 mmol) in 1,4-dioxane (4.00 mL) The mixture was heated at 90° C. and 1-(tetrahydro-2H-pyran-4-yl) ethanone (0.5 g; 3.90 mmol) in 1,4-dioxane (1.00 mL) was added to the suspension. The reaction mixture was stirred at reflux for 3 hours. Water was added and few drops of an aqueous solution of 3N HCl.

The mixture was extracted twice with ethylic ether. The organic layer was decanted and the solvent was evaporated until dryness to give 0.65 g of intermediate 754 (89%).

Example A66
Preparation of Intermediate 762

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In a sealed tube, 4-nitro-1H-pyrazole (1.9 g, 16.5 mmol), (R)-glycidyl methyl ether (1.6 g, 18.2 mmol) and K₂CO₃(3.4 g, 24.8 mmol) in DMF (17.9 mL, 231 mmol) were stirred at 130° C. using one single mode microwave (Masterwave BTR Anton Paar) with a power output ranging from 0 to 1700 W for 5 min. [fixed hold time]. The reaction mixture was poured out onto water, made acidic with 3N HCl(aq), extracted twice with AcOEt and the combined organic layers were washed with water, dried over MgSO₄, filtered and evaporated. The residue was purified by Normal phase on (Irregular SiOH 40 μm 40 g GraceResolv®). Mobile phase gradient from 80% heptane, 20% AcOEt to 60% heptane, 40% AcOEt. The pure fractions were combined and the solvent was evaporated to give 1.52 g of intermediate 762 (46%).

Preparation of Intermediate 763

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Lithium bis(trimethylsilyl)amide (1M in THF) (18 mL, 1 M, 18 mmol) was added dropwise to a stirred solution of intermediate E5 (1.5 g, 7.5 mmol) in THF (22 mL) at −70° C. under nitrogen. The reactive mixture was stirred at −70° C. for 1 hour and hexachloroethane (2.1 g, 8.9 mmol) in THF (4.5 mL) was added dropwise. The reactive mixture was allowed to stir at rt for 2 h. Water and 3N HCl(aq) were added and the solution was extracted with DCM. The organic layer was dried over MgSO₄, filtered and evaporated. The crude residue was purified via silica gel chromatography (Stationary phase: irregular SiOH 15-40 μm, 80 g, mobile phase: gradient from 80% heptane, 20% AcOEt to 60% heptane, 40% AcOEt) to give 700 mg of intermediate 763 (47% yield).

Example A67
Preparation of Intermediate 767

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A solution of intermediate 4S (3.85 g; 8 mmol) in dry THF (50 mL) was treated with TBAF (1M in THF) (9 mL; 9 mmol) and allowed to stir at room temperature. The reaction mixture was stirred for 30 min, diluted with EtOAc and washed with brine (3×). The organic layer was dried over MgSO₄, filtered, concentrated, and dried overnight under high-vacuum to yield 3.36 g of intermediate 767 (greater than quantitative recovery, pure at 67%).

Preparation of Intermediate 768

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A solution of intermediate 767 (3.36 g; 6.12 mmol) and DIPEA (3 mL; 17.4 mmol) in CH₂Cl₂(50 mL) was cooled down to 0° C. and treated with mesyl chloride (1 mL; 12.9 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. The volatiles were evaporated. The residue was redissolved in CH₂Cl₂and purified via Flash column chromatography (330 g SiO₂, 25-75% EtOAc/Hex over 5 Column Volumes). The desired fractions were combined, concentrated, and dried under high-vac to yield 2.56 g of intermediate 768 (93% yield, 92% purity) as a pale yellow/off-white solid.

Preparation of Intermediate 769 and 769′

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A heterogeneous solution of intermediate 768 (2.48 g; 5.13 mmol) and sodium azide (0.74 g; 11.2 mmol) in dry DMF (20 mL) was heated overnight at 115° C. while stirring under N₂. The reaction mixture was cooled to room temperature, diluted with EtOAc and washed with water followed by brine (2×). The organic layer was dried (MgSO₄), filtered, concentrated, and dried under high-vacuum to give 1.68 g of a mixture of intermediate 769 and intermediate 769′ (in a ratio of 3/1).

Preparation of Intermediate 770 and 770′

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A homogeneous solution of the mixture of intermediate 769 and intermediate 769′ (1.68 g; 4.3 mmol) in dry THF (25 mL) was treated with triphenylphosphine (1.68 g; 6.4 mmol) and allowed to stir overnight at room temperature. Next day, Water (5 mL; 277 mmol) was added and the reaction mixture was stirred at 50° C. for 18 hours. Next day, the reaction mixture was cooled down to room temperature, diluted with EtOAc and washed with brine (3×). The organic layer was dried (MgSO₄), filtered, concentrated, and dried under high-vacuum. The crude residue was re-dissolved in a minimal amount of CH₂Cl₂and purified via Flash Column Chromatography (120 g SiO₂, 0-10% 2N NH₃/MeOH/EtOAc over 10 Column Volumes, flushing with MeOH). The desired fractions were combined, concentrated, and dried under high-vacuum to give 2.03 g of intermediate 770 (129%, pure at 38%) and 0.38 g of intermediate 770′ (32%).

Preparation of Intermediate 771

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A homogeneous solution of intermediate 770 (2.03 g, 2.1 mmol) in CH₂Cl₂(20 mL) was treated with di-tert-butyl dicarbonate (1 mL; 4.7 mmol) at room temperature. The reaction mixture was stirred for 1 hour. The volatiles were evaporated. The residue was re-dissolved in a minimal amount of CH₂Cl₂and purified via Flash Column Chromatography (40 g SiO₂, 0-50% EtOAc/Hex over 10 Column Volumes). The desired fractions were combined, concentrated, and dried under high-vacuum to yield 1 g of intermediate 771 (quant, based on purity of starting material) as a white solid.

Preparation of Intermediate 772

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In a 20 mL vial, intermediate 771 (0.395 g; 0.847 mmol), bis(pinacolato)diboron (0.326 g; 1.284 mmol), potassium acetate (0.262 g; 2.67 mmol) and 2nd generation Xphos precatalyst (chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl) [2-(2′-amino-1,1′-biphenyl)]palladium(II)) (0.035 g; 0.0445 mmol) together with a stirbar were added and the vessel capped. The atmosphere was evacuated and purged with N₂(3×) and then the vial was charged with dry, freshly degassed 1,4-dioxane (5 ml). Heating was started directly at 80° C. After 30 min, the reaction mixture had turned heterogeneous black and HPLC indicated complete consumption of intermediate 771. The filtrate was concentrated and dried under high-vacuum to yield crude intermediate 772 as a dark yellow oil. The material used directly in the next step (quantitative conversion assumed).

The intermediate in the table below was prepared by using an analogous 6 step sequence as applied for intermediate 772, but starting from the enantiomeric starting material, 4R.

Inter-

mediate

Yield

number
Structure
Mass (mg)
(%)

Inter- mediate 773

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218 (used without further purification)

Example A68
Preparation of Intermediate 774

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1-Methyl-1H-pyrazol-3-amine (70.0 g, 721 mmol) and 2-(methylthio)pyrimidin-4(3H)-one (63.0 g, 443 mmol) were added to a 250 mL round-bottomed flask. The resulting mixture was then stirred and heated at 180° C. for 2 hours before a yellow solid was formed. The resulting mixture was cooled to room-temperature. The residue was triturated with ethanol (300 mL), filtered, to afford intermediate 774 (80 g, 94.3%) as a white solid, which was used in the next step without further purification.

Preparation of Intermediate 775

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Intermediate 774 (80.0 g, 418 mmol) and phosphoryl trichloride (256.6 g, 1674 mmol) were added to a 500 mL flask. The reaction mixture was stirred at 100° C. for 2 hours. After cooling to r.t., the mixture was concentrated to dryness under reduced pressure. The residue was redissolved in dichloromethane (500 mL) and H₂O (500 mL), neutralised cautiously with saturated aqueous NaHCO₃to pH=7.0. The mixture was extracted with dichloromethane (500 mL×3). The combined organic extracts were dried over anhydrous Na₂SO₄, filtered and concentrated to dryness under reduced pressure to afford intermediate 775 (81 g, 89%) as a yellow solid.

Example A69
Preparation of Intermediate 776

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In a 25 mL round bottomed flask were added intermediate 773 (0.218 g; 0.425 mmol), intermediate 775 (0.189 g; 0.902 mmol), potassium phosphate (tribasic) (0.482 g; 2.203 mmol), 2nd generation Xphos precatalyst (chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)) (0.022 g; 0.028 mmol) together with a stirbar. The vessel was sealed and the atmosphere evacuated and purged with N₂(3×). The vessel was then charged with freshly degassed solvents: dioxane (5 mL) and de-ionized H₂O (1 mL). Heating was started directly at 80° C. After 1 hour 30 min the reaction was cooled to room temp, diluted with EtOAc, and washed with de-ionized H₂O (3×). The organic layer was dried (MgSO₄), filtered, concentrated, and dried under high-vacuum to yield a dark yellow oil. The crude material was dissolved in a minimal amount of CH₂Cl₂and purified via Flash Column Chromatography (40 g, 0-100% EtOAc/CH₂Cl₂over 10 Column Volumes). The desired fractions were combined, concentrated, and dried under high-vacuum to yield 172 mg of intermediate 776 (63% yield; 88% purity) as a yellow solid.

The intermediate in the table below was prepared by using an analogous method starting from the respective R enantiomer, intermediate 772. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Intermediate

Mass
Yield

number
Structure
(mg)
(%)

Intermediate 777

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240
95

Example A70
Preparation of Intermediate 778 and 778′

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Methanesulfonyl chloride (6.683 mL, 1.48 g/mL, 86.338 mmol) was added to a solution of 3-methoxy-3-methylbutanol (5 g, 42.31 mmol) and Et₃N (17.661 mL, 0.728 g/mL, 127.059 mmol) in DCM (477.33 mL, 1.326 g/mL, 7452.28 mmol) at rt and the reaction mixture was stirred for 18 h. Water was added. The organic layer was separated, washed with 1N HCl(aq) then with brine before drying over MgSO₄. The organic layer was filtered and evaporated to afford a mixture on intermediate 778 and 778′ (10.3 g, quantitative yield) that was used directly in the next step.

Example A71
Preparation of Intermediate 779

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To a solution of 2-Amino-3-bromobenzonitrile (30.0 g) in THF (240 mL) was added sodium tert-butoxide (1.1 eq.) and the mixture was stirred at −5 to 50° C. for 1 hour. A solution of intermediate 3a in THF (85.0 g) was then added dropwise and the mixture was stirred for 2-4 hours monitoring the conversion by HPLC. Water (210 mL) was then added dropwise and the mixture was concentrated to remove most of THF. Heptane (300 mL) was then added and the mixture was stirred for 30 min. After phase separation, the organic layer was washed with water (210 mL), concentrated to 2-3 volumes and filtered through a pad of silica gel (60 g), washing the pad with heptane (300 mL), affording 63.3 g of intermediate 779.

Preparation of Intermediate 780

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To a solution of intermediate 779 (50.0 g) in dry THF (500 mL) was added dimethylaminopyridine (0.5 eq.) and the temperature was adjusted to 65-70° C. Di-tert-butyldicarbonate (2.2 eq.) was then added and the mixture was stirred for 2 hours (monitoring by HPLC). Water (350 mL) was added and the mixture was concentrated to 350-400 mL. Heptane (500 mL) was added and the pH was adjusted by addition of 20% aqueous AcOH to 4-6. The layers were separated and water (350 mL) was added. After pH adjustment to 7-8 with aqueous 8% NaHCO₃, the layers were separated and the organic layer was washed with water (350 mL) and concentrated to afford 64 g (quantitative) of intermediate 780.

B. Preparation of the Final Compounds
Example B 1

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Preparation of Compound 1

A mixture of intermediate 8 (1.09 g, 2.29 mmol) and TBAF (1M in THF) (2.50 mL, 2.50 mmol) in Me-THF (20 mL) was stirred at rt for 18 h. The reaction mixture was directly purified by column chromatography on silica gel (irregular SiOH 15-40 m, 120 g, liquid injection with a mixture of Me-THF/DCM, mobile phase: DCM/(MeOH(10% aq NH₃)), gradient from 100:0 to 90:10 in 10 CV). The fractions containing the product were combined and concentrated under vacuum to give 650 mg of compound 1 (78% yield, yellow solid). 255 mg of compound 1 was solubilized in a mixture of CH₃CN/H₂O (1:1) and freeze-dried overnight then dried at 50° C. under reduced pressure to give 255 mg of compound 1 (31%, yellow fluffy solid).

Preparation of Compound 19

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A mixture of intermediate 47 (0.35 g, 0.74 mmol) and TBAF (1M in THF) (0.80 mL, 0.80 mmol) in THF (6 mL) was stirred at rt for 18 h. The reaction mixture was directly (without evaporation) purified by column chromatography on silica gel (irregular SiOH, 15-40 m, 120 g, liquid injection (THF/DCM), mobile phase gradient: DCM/(MeOH(10% aq. NH₃)) from 100:0 to 90:10 in 15 CV). The fractions containing the product were combined and evaporated to dryness to give 231 mg of compound 19 (87% yield, yellow solid).

Preparation of Compound 42

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At rt, intermediate 100 (7.60 mL, 7.60 mmol) was added to a solution of TBAF (1M in THF) (2.72 g, 5.10 mmol) in Me-THF (50 mL) and stirred at rt overnight. Water was added and this mixture was extracted twice with EtOAc. The organic layer was decanted and the solvent was evaporated until dryness. The residue was taken up into EtOH and this precipitate was triturated and filtered. The product was dried until dryness to give 1.27 g of compound 42 (56% yield).

Preparation of Compound 49

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This reaction was done twice on the same quantities of intermediate 117 (12 g, 21.91 mmol). A mixture of intermediate 117 (12.00 g, 21.9 mmol) and TBAF (1M in THF) (48.19 mL, 48.19 mmol) in Me-THF (231.5 mL) was stirred at rt for 12 h. The reaction mixtures were mixed and diluted with EtOAc and water and the layers were separated. The organic layer was washed with brine, dried over MgSO₄, filtered and was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (irregular SiOH, 40 m, 330 g mobile phase from 99% DCM, 1% MeOH, 0.1% NH₄OH to 97% DCM, 3% MeOH, 0.3% NH₄OH). The pure fractions were combined and the solvent was evaporated. The residue (12.900 g) was crystallized with CH₃CN to give 11.565 g of compound 49 (60% yield). M.P=164° C. (K).

Preparation of Compound 107

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To a solution of intermediate 291 (2.86 g, 5.18 mmol) in Me-THF (60 mL) was added TBAF (1M in THF) (5.95 mL, 5.95 mmol) and the mixture was stirred at rt overnight and combined with another batch (from 270 mg of intermediate 291). The residue was purified by column chromatography on silica gel (irregular SiOH, 15-40 m, 120 g, dry load on Celite®, mobile phase: DCM/MeOH (aq. NH₃5%), gradient from 100:0 to 90:10). The fractions containing the product were combined and evaporated to dryness. The residue (1480 mg) was taken up with water, triturated and sonicated at 45° C. for 1 h. The mixture was then filtered on a glass frit and the resulting solid was then washed twice with Et₂O, collected and dried under reduced pressure at 50° C. for 16 h to give 1.23 g of compound 107 (54% yield, white solid).

Preparation of Compound 113

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A mixture of intermediate 314 (425.00 mg, 0.73 mmol) and TBAF (1M in THF) (0.81 mL, 0.81 mmol) in dry Me-THF (10 mL) was stirred at rt for 17 h. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over MgSO₄, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (irregular SiOH, 15-40 m, 24 g, liquid injection in DCM, mobile phase: DCM/iPrOH, gradient from 100:0 to 90:10). The fractions containing the product were combined and evaporated to dryness. The residue (247 mg, yellow solid) was dried at 50° C. under reduced pressure for 17 h to give 205 mg of a yellow powder. This residue was dried again at 50° C. under reduced pressure for 72 h. Then, it was solubilized in MeOH (1 mL), extended with water (8 mL) and freeze-dried to afford 164 mg of compound 113 (48% yield, white fluffy solid).

Preparation of Compound 114

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A mixture of intermediate 318 (511.00 mg, 0.88 mmol) and TBAF (1M in THF) (0.97 mL, 0.97 mmol) in Me-THF (12.5 mL) was stirred at rt for 17 h. The reaction mixture was diluted with DCM and washed with water. The organic layer was dried over MgSO₄, filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (irregular SiOH, 15-40 m, 24 g, liquid injection in DCM, mobile phase: DCM/MeOH, gradient from 100:0 to 90:10). The fractions containing the product were combined and evaporated to dryness. The residue (275 mg, yellow oil) was purified by reverse phase (stationary phase: X-Bridge-C18, 10 m, 30×150 mm, mobile phase gradient: from 65% aq. NH₄HCO₃(0.2%), 35% CH₃CN to 25% aq. NH₄HCO₃(0.2%), 75% CH₃CN). The fractions containing the product were combined and evaporated to dryness. The residue (173 mg, pale yellow residue) was solubilized in MeOH (1 mL), extended with water (8 mL) and freeze-dried to afford 153 mg of compound 114 (37% yield, white fluffy solid).

Preparation of Compound 118

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A solution of intermediate 334 (209.00 mg, 0.34 mmol) in Me-THF (4 mL) was treated with TBAF (1M in THF) (0.38 mL, 0.38 mmol) and stirred at rt for 17 h. Celite® was added and the crude mixture was evaporated in vacuo to give a dry load which was purified by column chromatography on silica gel (irregular SiOH, 15-40 m, 40 g, mobile phase gradient: from DCM 98%, MeOH (+5% aq. NH₃) 2% to DCM 90%, MeOH (+5% aq. NH₃) 10%). The fractions containing the product were combined and evaporated to dryness. The residue was recrystallized from EtOH. After cooling down to rt, the mixture was filtered on a glass frit and the solid was washed with Et₂O, collected and dried in vacuo. This residue (102 mg, white solid) was warmed in EtOH (mainly insoluble) and sonicated during 15 min. The mixture was evaporated in vacuo to give a solid which was dried in vacuo to afford 90 mg of compound 118 (53% yield, off-white solid).

Preparation of Compound 120

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A mixture of intermediate 344 (260.00 mg, 0.41 mmol) and TBAF (1M in THF) (0.62 mL, 0.62 mmol) in Me-THF (6.7 mL) was stirred for 12 h. The resulting mixture was directly purified (injection of the solution) by column chromatography on silica gel (stationary phase: irregular SiOH, 15-40 μm, 80 g, mobile phase: gradient from 100% DCM to 91% DCM, 9% MeOH, 0.1% NH₄OH). The fractions containing the product were combined and the solvent was evaporated. The residue was crystallized from CH₃CN to give 143 mg of compound 120 (67% yield).

Preparation of Compound 132

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A mixture of intermediate 393 (582.00 mg, 0.98 mmol) and TBAF (1M in THF) (1.07 mL, 1.07 mmol) in Me-THF (14 mL) was stirred at rt for 17 h. The reaction mixture was diluted with DCM and washed with water. The organic layer was dried over MgSO₄, filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (irregular SiOH, 15-40 m, 40 g, liquid injection in DCM, mobile phase gradient: from DCM 100% to 90%, MeOH (+aq. NH₃5%) 10%). The fractions containing the product were combined and evaporated to dryness. The residue (318 mg, brown residue) was purified by reverse phase (stationary phase: YMC-actus Triart-C18, 10 m, 30×150 mm, mobile phase gradient: from 75% aq. NH₄HCO₃(0.2%), 25% CH₃CN to 35% aq. NH₄HCO₃(0.2%), 65% CH₃CN). The fractions containing the product were combined and evaporated to dryness. The residue (275 mg, yellow oil) was solubilized in MeOH (1 mL), extended with water (8 mL) and freeze-dried to afford 246 mg of compound 132 (52% yield, white fluffy solid).

Preparation of Compound 145

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A solution of intermediate 443 (138.00 mg, 0.28 mmol) in Me-THF (5 mL) was treated with TBAF (1M in THF) (0.308 mL, 0.31 mmol) and stirred at rt for 17 h. Celite® was added and the crude mixture was evaporated in vacuo. The residue was purified by column chromatography on silica gel (irregular SiOH, 15-40 m, 40 g, mobile phase gradient: from DCM 98%, MeOH (+5% aq. NH₃) 2% to DCM 90%, MeOH (+5% aq. NH3) 10%). The fractions containing the product were combined and evaporated to dryness. The solid was recrystallized from EtOH. After cooling down to rt, the superrnatent was removed with a pipette. The solid was triturated in Et₂O. The supernatent was removed with a pipette and the solid was dried in vacuo to afford 53 mg of compound 145 (50% yield, pale yellow solid).

Preparation of Compound 156

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A mixture of intermediate 478 (271.00 mg, 0.51 mmol) and TBAF (1 M in THF) (1.00 mL, 1 mmol) in Me-THF (7 mL) was stirred at rt for 4 h. The reaction mixture was concentrated then directly purified by column chromatography on silica gel (irregular SiOH, 15-40 μm, 120 g, liquid injection (Me-THF/DCM), mobile phase gradient: DCM/(MeOH/10% aq. NH₃) from 100:0 to 90:10 in 10 CV). The fractions containing the product were combined and evaporated to dryness to give 192 mg of compound 156 (90% yield, white solid).

Preparation of Compound 164

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TBAF (1M in THF) (1.00 mL, 1.00 mmol) was added to a solution of intermediate 516 (0.40 g, 0.69 mmol) in Me-THF (5 mL) and this reaction was stirred overnight at rt. This mixture was poured onto water and a 10% aqueous solution of K₂CO₃. This mixture was extracted twice with EtOAc. The organic layer was decanted and the solvent was evaporated until dryness. The residue was purified by column chromatography on silica gel (irregular SiOH, 45 μm, 40 g, mobile phase gradient from: 98% DCM, 2% MeOH (+10% NH₄OH) to 92% DCM, 8% MeOH (+10% NH₄OH)). The pure fractions were collected and the solvent was evaporated until dryness. The residue was taken up into CH₃CN, triturated and the precipitate was filtered and dried until dryness to give: 224 mg of compound 164 (69% yield).

Preparation of Compound 180

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At room temperature, TBAF (1M in THF) (9.00 mL; 9.00 mmol) was added to a solution of intermediate 572 (3.15 g; 5.40 mmol) in THF (50 mL). This reaction was stirred at room temperature for 1 hour. Water and a 10% aqueous solution of K₂CO₃were added and this mixture was extracted twice with EtOAc. The organic layer was mixed, dried over MgSO₄, filtered and the solvent was evaporated until dryness. The crude was purified by silica gel chromatography (Irregular SiOH 15-40 m 120 g, mobile phase Gradient from: 99% DCM, 1% MeOH, 0.1% NH₄OH to 93% DCM, 7% MeOH, 0.7% NH₄OH). The pure fractions were collected and the solvent was evaporated until dryness to give 1.71 g of compound 180 (67% yield). This quantity of compound 180 was mixed with 510 mg of another batch (obtained from a reaction performed on 710 mg of intermediate 572), taken up into a small amount of ACN, totally dissolved with a hot bath (60° C.) and then, triturated. The solution was cooled to room temperature and a crystalline product appeared after 1 night. This solid was triturated, filtered, washed once with cold ACN and dried until dryness (1 h and 20 min) under vacuum (70° C.) to give 1.22 g of fraction A of compound 180 (MP: 131° C., DSC).

The filtrate was evaporated until dryness and the resulting product was taken up into ACN, totally dissolved, and triturated (initiating crystallization with some crystal coming from fraction A). After several minutes the product crystallized. A small amount of cold isopropylic ether was added and this cristal product was filtered, washed once with cold isopropylic ether then dried until dryness (70° C. under vacuum) to give after 40 minutes 0.67 g of fraction B of compound 180. Fraction B was taken up into ACN, totally solubilized with a hot bath (60° C.) then cooled to room temperature overnight. The cristal product was filtered, washed once with cold isopropylic ether and dried until dryness (70° C. under vacuum) to give 501 mg of fraction B of compound 180 (MP: 150° C., DSC).

Preparation of Compound 183

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TBAF (1M in THF) (8.00 mL 8.00 mmol) was added slowly to a solution of intermediate 581 (2.44 g; 4.35 mmol) in tetrahydrofurane (40.00 mL) This reaction was stirred at room temperature for 3 hours and 40 minutes and was purified (without treatment) by silica gel chromatography (Irregular SiOH 15-40 m 220 g, mobile phase Gradient from: 100% DCM to 93% DCM, 7% MeOH, 0.7% NH₄OH). The pure fractions were collected and the solvent was evaporated until dryness to give 1.7 g (88%) of compound 183.

This material was combined with another batch (1.74 g) of compound 183 obtained from a reaction performed on 2.41 g of intermediate 581 to give 3.44 g of compound 183 which were totally dissolved in ACN (57 mL) and MeOH (34 mL) at 90° C.

This solution was cooled down to room temperature and let for crystallization overnight. The precipitate was filtered and dried C under vacuum until dryness at 900 during 3 hours to give 1.25 g (36%) of compound 183. M.P.=256° C. (DSC).

The filtrate was evaporated until dryness and the residue (1.72 g) was dissolved totally in MeOH (38 mL) at 70° C. (bath oil). The solution was cooled down to room temperature overnight. The precipitate was filtered and dried for 2 hours and 30 minutes at 90° C. under vacuum to give 0.77 g (22%) of compound 183 (not crystalline). This material (0.77 g) was dissolved in a mixture of ACN (12 mL) and MeOH (7 mL) at 95° C. (bath oil). The solution was cooled down to room temperature and let for crystallization overnight. The precipitate was filtered to give 303 mg (9%) of compound 183. M.P.=255° C. (DSC).

The compounds in the Table below were prepared by using an analogous method than the one used for the preparation of compound 1 starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Compound number
Structure
Mass (mg)
Yield (%)

Compound 4

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99
79 Procedure with 1.1 equiv. of TBAF

Compound 7

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74 white solid
67 Procedure with 1.1 equiv. of TBAF

Compound 11

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128 off-white solid
19 Procedure with 2.2 equiv. of TBAF

Compound 12

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70
28 Procedure with 3 equiv. of TBAF

Compound 13

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67 pale yellow solid
34 Procedure with 1.1 equiv. of TBAF

Compound 14

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34 off-white solid
10 Procedure with 1.3 equiv. of TBAF

Compound 16

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161
54 Procedure with 1.9 equiv. of TBAF

Compound 17

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140
53 Procedure with 2 equiv. of TBAF

Compound 18

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72 yellow solid
43 Procedure with 2.2 equiv. of TBAF

Compound 20

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174
97 Procedure with 1.5 equiv. of TBAF

Compound 21

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45 pale yellow solid
23 Procedure with 1.1 equiv. of TBAF

Compound 22

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37
42 Procedure with 1.5 equiv. of TBAF

Compound 23

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89
33 Procedure with 1.5 equiv. of TBAF

Compound 24

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107
48 Procedure with 1.5 equiv. of TBAF

Compound 25

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62
62 Procedure with 1.5 equiv. of TBAF

Compound 27

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114
65 Procedure with 1.7 equiv. of TBAF

Compound 28

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42
46 Procedure with 1.5 equiv. of TBAF

Compound 29

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123
45 Procedure with 1.5 equiv. of TBAF

Compound 30

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12
37 Procedure with 1.5 equiv. of TBAF

Compound 31

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45
52 Procedure with 1.5 equiv. of TBAF

Compound 32

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94
45 Procedure with 1.1 equiv. of TBAF

Compound 33 (obtained as a mixture of 2 diastereoisomers)

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69
48 Procedure with 1.5 equiv. of TBAF

Compound 34

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1250
63 Procedure with 1.1 equiv. of TBAF

Compound 35

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55
28 Procedure with 1.5 equiv. of TBAF

Compound 36

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27
33 Procedure with 1.5 equiv. of TBAF

Compound 37

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59
44 Procedure with 1.1 equiv. of TBAF

Compound 38

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43
26 Procedure with 1.1 equiv. of TBAF

Compound 39

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186
55 Procedure with 1.1 equiv. of TBAF

Compound 40

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160
69 Procedure with 1.1 equiv. of TBAF

Compound 41

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44 orange solid
43 Procedure with 1.1 equiv. of TBAF

Compound 43

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128
75 Procedure with 1.5 equiv. of TBAF

Compound 44

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45
27 Procedure with 1.5 equiv. of TBAF

Compound 45

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185
67 Procedure with 1.5 equiv. of TBAF

Compound 46

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490
38 Procedure with 1.5 equiv. of TBAF

Compound 47

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243
41 Procedure with 2.2 equiv. of TBAF

Compound 48

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51
45 Procedure with 1.5 equiv. of TBAF

Compound 50

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35
37 Procedure with 1.5 equiv. of TBAF

Compound 51

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100
16 Procedure with 1.5 equiv. of TBAF

Compound 52

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97
15 Procedure with 1.5 equiv. of TBAF

Compound 53

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145
68 Procedure with 1.5 equiv. of TBAF

Compound 54

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153
32 Procedure with 2.2 equiv. of TBAF

Compound 55

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54
40 Procedure with 2.2 equiv. of TBAF

Compound 56

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9
16 Procedure with 1 equiv. of TBAF

Compound 57

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150
30 Procedure with 1.5 equiv. of TBAF

Compound 58

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150
51 Procedure with 1.5 equiv. of TBAF

Compound 59

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130
71 Procedure with 1.5 equiv. of TBAF

Compound 60

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81
34 Procedure with 2.2 equiv. of TBAF

Compound 61

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113
65 Procedure with 2.2 equiv. of TBAF

Compound 62

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58
43 Procedure with 2.2 equiv. of TBAF

Compound 63

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131
46 Procedure with 2.2 equiv. of TBAF

Compound 64

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71
50 Procedure with 1.5 equiv. of TBAF

Compound 65

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25
48 Procedure with 1.5 equiv. of TBAF

Compound 66

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111 white foam
55 Procedure with 1.5 equiv. of TBAF

Compound 67

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203
68 Procedure with 1.6 equiv. of TBAF

Compound 68

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78
24 Procedure with 2.2 equiv. of TBAF

Compound 69

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77
24 Procedure with 2.2 equiv. of TBAF

Compound 70

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95
28 Procedure with 2.2 equiv. of TBAF

Compound 71

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106
31 Procedure with 2.2 equiv. of TBAF

Compound 72

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31
35 Procedure with 1.5 equiv. of TBAF

Compound 73

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59
39 Procedure with 1.5 equiv. of TBAF

Compound 74

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65
58 Procedure with 1.5 equiv. of TBAF

Compound 75

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92
56 Procedure with 1.5 equiv. of TBAF

Compound 76

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42
29 Procedure with 1.5 equiv. of TBAF

Compound 77

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57
28 Procedure with 1.5 equiv. of TBAF

Compound 78

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58
28 Procedure with 1.5 equiv. of TBAF

Compound 79

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58
48 Procedure with 1.1 equiv. of TBAF

Compound 80

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52
52 Procedure with 1.1 equiv. of TBAF

Compound 81

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58
33 Procedure with 2.2 equiv. of TBAF

Compound 82

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55
32 Procedure with 2.2 equiv. of TBAF

Compound 83

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77 orange powder
36 Procedure with 1.1 equiv. of TBAF

Compound 84

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66
11 Procedure with 1.5 equiv. of TBAF

Compound 85

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66
11 Procedure with 1.5 equiv. of TBAF

Compound 86

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110
90 Procedure with 1.8 equiv. of TBAF

Compound 87

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26 pink solid
19 Procedure with 1.1 equiv. of TBAF

Compound 88

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105 beige solid
72 Procedure with 1.1 equiv. of TBAF

Compound 89

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85 pink solid
63 Procedure with 1.1 equiv. of TBAF

Compound 90

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49
36 Procedure with 1.5 equiv. of TBAF

Compound 91

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68
35 Procedure with 1.5 equiv. of TBAF

Compound 92

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1230
78 Procedure with 1.5 equiv. of TBAF

Compound 93

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321
38 Procedure with 1.5 equiv. of TBAF

Compound 94 (obtained as a mixture of 2 diastereoisomers)

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60
17 Procedure with 2.2 equiv. of TBAF

Compound 95

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124
62 Procedure with 1.5 equiv. of TBAF

Compound 96

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813
67 Procedure with 1.6 equiv. of TBAF

Compound 97

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1500
68 Procedure with 1.5 equiv. of TBAF

Compound 98

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1000
62 Procedure with 1.6 equiv. of TBAF

Compound 99

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15
63 Procedure with 1.6 equiv. of TBAF

Compound 100

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36
88 Procedure with 2.5 equiv. of TBAF

Compound 101

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50
32 Procedure with 1.7 equiv of TBAF

Compound 102

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20
13 Procedure with 1.7 equiv of TBAF

Compound 104

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327
57 Procedure with 2.2 equiv. of TBAF

Compound 105

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312
36 Procedure with 2.2 equiv. of TBAF

Compound 108

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137
56 Procedure with 2.2 equiv. of TBAF

Compound 109

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103
54 Procedure with 2.2 equiv. of TBAF

Compound 111

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127
34 (over 2 steps) Procedure with 1 equiv. of TBAF

Compound 112

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218
51 Procedure with 1.1 equiv. of TBAF

Compound 115

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12 off-white solid
13 Procedure with 1.1 equiv. of TBAF

Compound 116

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112 off-white solid
57 Procedure 1.1 equiv. of TBAF

Compound 117

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205
60 Procedure with 1.5 equiv. of TBAF

Compound 119

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40 white fluffy solid
43 Procedure with 1.1 equiv. of TBAF

Compound 121

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85
20 Procedure with 1.5 equiv. of TBAF

Compound 122

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106
79 Procedure with 1.5 equiv. of TBAF

Compound 123

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19
20 Procedure with 1.5 equiv. of TBAF

Compound 124

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56 white fluffy solid
43 Procedure with 1.1 equiv. of TBAF

Compound 125

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114
33 Procedure with 2 equiv. of TBAF

Compound 126

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85 white fluffy solid
36 Procedure with 1.1 equiv. of TBAF

Compound 127

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75
33 Procedure with 2 equiv. of TBAF

Compound 128

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592
46 Procedure with 2 equiv. of TBAF

Compound 129

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61 white solid
88 Procedure with 2 equiv. of TBAF

Compound 130

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246
58 Procedure with 2 equiv. of TBAF

Compound 131

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144
53 Procedure with 2 equiv. of TBAF

Compound 133

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246 white fluffy solid
52 Procedure with 1.1 equiv. of TBAF

Compound 134

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134 yellow solid
57 Procedure with 1.1 equiv. of TBAF

Compound 135

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88 yellow fluffy solid
62 with 2.2 equiv. of TBAF

Compound 136

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50
57 Procedure with 1.5 equiv. of TBAF

Compound 137

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210
56 Procedure with 1.6 equiv. of TBAF

Compound 138

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114 white fluffy solid
66 Procedure with 1.1 equiv. of TBAF

Compound 139

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152
73 Procedure with 2 equiv. of TBAF

Compound 140

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271
76 Procedure with 2 equiv. of TBAF

Compound 141

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163
79 Procedure with 2 equiv. of TBAF

Compound 143

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78
32 Procedure with 1.5 equiv. of TBAF

Compound 144

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130
61 Procedure with 1.5 equiv. of TBAF

Compound 146

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138 pinkish solid
73 Procedure with 1.1 equiv. of TBAF

Compound 147

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17 off-white solid
10 Procedure with 1.7 equiv. of TBAF and a mixture of DCM/THF (3:2, v/v) as solvent

Compound 148

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73 yellow solid
48 Procedure with 1.8 equiv. of TBAF

Compound 149

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172 off-white solid
54 Procedure with 1.1 equiv. of TBAF

Compound 150

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53
41 Procedure with 2 equiv. of TBAF

Compound 151

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274
76 Procedure with 2 equiv. of TBAF

Compound 152

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157
78 Procedure with 1.1 equiv. of TBAF

Compound 153

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176 white solid
95 Procedure with 2.1 equiv. of TBAF

Compound 154

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164 off-white solid
45 (over 2 steps) Procedure with 1.1 equiv. of TBAF

Compound 155

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70
19 Procedure with 1.5 equiv. of TBAF

Compound 156

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47
15 Procedure with 1.1 equiv. of TBAF

Compound 157

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172
74 Procedure with 2.5 equiv. of TBAF

Compound 158

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179
33 Procedure with 2 equiv. of TBAF

Compound 160

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29 yellow fluffy solid
47 Procedure with 1.1 equiv. of TBAF

Compound 161

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132 white solid
53 Procedure with 2.1 equiv. of TBAF

Compound 162

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70 white fluffy- solid
24 Procedure with 1.1 equiv. of TBAF

Compound 163

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64
27 Procedure with 2 equiv. of TBAF

Compound 165

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154
69 Procedure with 1.5 equiv. of TBAF

Compound 166

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137
65 Procedure with 2 equiv. of TBAF

Compound 167

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84
49 Procedure with 2 equiv. of TBAF

Compound 168

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27
25 Procedure with 2 equiv. of TBAF

Compound 169

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21
21 Procedure with 2 equiv. of TBAF

Compound 170

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119
34 Procedure with 2 equiv. of TBAF

Compound 171 (obtained as a mixture of 2 diastereoisomers)

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274
49 Procedure with 1.5 equiv. of TBAF

Compound 172

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37
18 Procedure with 1.5 equiv. of TBAF

Compound 181

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106
61

Compound 182

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72
54 Procedure with 1.5 eq. of TBAF

Compound 184

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68
75 Procedure with 2 eq of TBAF Me—THF 3 h

Compound 185

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63
64 Procedure with 2 eq. of TBAF

Compound 186

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228
47 Procedure with 2 eq. of TBAF

Compound 187

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740
63 Procedure with 2 eq. of TBAF

Compound 188

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70
23 Procedure with 2 eq. of TBAF

Compound 189

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140
46 Procedure with 2 eq. of TBAF Me—THF 12 h

Compound 190

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114
65 Procedure with 2 eq. of TBAF

Compound 191

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119
60 Procedure with 2 eq of TBAF Me—THF 4 h

Compound 192

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90
57 Procedure with 2 eq of TBAF Me—THF 12 h

Compound 193

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22
41 Procedure with 2 eq of TBAF Me—THF 8 h

Compound 194

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217
44 Procedure with 2 eq of TBAF Me—THF 8 h

Compound 195

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73
51 Procedure with 1.6 eq of TBAF THF 2 h

Compound 196

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1850
55 Procedure with 2 eq of TBAF THF

Compound 197

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166
32 Procedure with 1.54 eq of TBAF Me—THF

Compound 198

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55
58 Procedure with 1.2 eq of TBAF Me—THF 18 h

Compound 199

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114
35 Procedure with 2 eq of TBAF Me—THF 8 h

Compound 200

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75
26 Procedure with 2 eq of TBAF Me—THF 2 h

Compound 202

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45
25 Procedure with 1.55 eq of TBAF THF 5 h

Compound 203

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164
53 Procedure with 2 eq of TBAF Me—THF 4 h

Compound 204

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328
68 Procedure with 1.5 eq of TBAF THF 12 h

Compound 205

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30
44 Procedure with 1.51 eq of TBAF Me—THF 12 h

Compound 206

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96
52 Procedure with 1.5 eq of TBAF THF 5 h

Compound 207

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129
41 Procedure with 2 eq of TBAF Me—THF 8 h

Compound 208

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21
15 Procedure with 2 eq of TBAF Me—THF 8 h

Compound 209

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159
66 Procedure with 2 eq. of TBAF

Compound 210

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104
83 Procedure with 1.6 eq of TBAF THF 12 h

Compound 211

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25
37 Procedure with 1.45 eq of TBAF THF 12 h

Compound 212

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176
54 Procedure with 1.5 eq of TBAF THF 2 h

Compound 213

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87
63 Procedure with 1.2 eq of TBAF Me—THF 3 h

Compound 215

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23
64 Procedure with 1.2 eq of TBAF Me—THF 3 h

Compound 216

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17
35 Procedure with 1.43 eq of TBAF THF 18 h

Compound 217

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2100
64 Procedure with 2 eq TBAF

Compound 218

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65 28
27 11 Procedure with 1.5 eq TBAF

Compound 219

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2400
69 Procedure with 2 eq TBAF

Compound 220

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37
41 Procedure with 1.6 eq TBAF

Compound 221

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36
40 Procedure with 2 eq TBAF

Example B2
Preparation of Compound 2

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A mixture of intermediate 10 (268.00 mg, 0.58 mmol) in a mixture of TFA (2 mL) and DCM (5 mL) was stirred at rt for 1 h. The mixture was basified with saturated aqueous solution of NaHCO₃. An extraction was performed with DCM. The organic layer was washed with brine, dried over MgSO₄, evaporated and purified by column chromatography on silica gel (irregular SiOH 15-40 m, 120 g, liquid injection with DCM, mobile phase: DCM/(MeOH(10% aq. NH₃)), gradient from 100:0 to 90:10 in 15 CV). The fractions containing the product were combined and concentrated to give 70 mg of compound 2 (33% yield over 3 steps, white solid).

Preparation of Compound 103

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At 0° C., TFA (1.73 mL; 22.61 mmol) was added dropwise to a mixture of intermediate 272 (0.618 g; 1.13 mmol) in DCM (10.00 mL). This reaction was stirred for 1 hour at 0° C. Water and a 10% aqueous solution of K₂CO₃were added. This mixture was extracted twice with DCM. The organic layer was decanted and the solvent was evaporated until dryness. The crude was purified (solid deposit) by silica gel chromatography (Irregular SiOH 20-45 m 40 g, mobile phase: gradient from 98% DCM, 2% MeOH to 92% DCM, 8% MeOH (+10% NH₄OH)). The fractions containing the product were collected and the solvent was evaporated until dryness. The product was taken up into ethylic ether and the precipitate was filtered to give 140 mg of compound 103 (23% yield)

The compounds in the Table below were prepared by using an analogous procedure than the one used for the preparation of compound 2 or 103 starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Compound number
Structure
Mass (mg)
Yield (%)

Compound 3

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130 white solid
36% (over 3 step) Procedure with DCM/TFA (8:3, v/v)

Compound 5

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66
41 Procedure with DCM/TFA (4:1, v/v)

Compound 6

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54
37 Procedure with DCM/TFA (4:1, v/v)

Compound 7

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53
38 Procedure with DCM/TFA (5:1, v/v)

Compound 9

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65
32 Procedure with DCM/TFA (6:1, v/v)

Compound 10

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69
39 Procedure with DCM/TFA (4:1, v/v)

Compound 11

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18
9 Procedure with DCM/TFA (5:2, v/v)

Compound 15

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15
11 Procedure with DCM/TFA (5:1, v/v)

Compound 26

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8
13 Procedure with DCM/TFA (6:1, v/v)

Compound 110

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200
45 Procedure with DCM/TFA (10:1, v/v)

Compound 142

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17
8 Procedure with DCM/TFA (5:1, v/v)

Example B3
Preparation of Compound 173

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HCl (3M in H₂O) (0.80 mL, 2.40 mmol) was added to a solution of intermediate 551 (152.00 mg, 0.24 mmol) in MeOH (3.7 mL) and the reaction mixture was stirred at reflux overnight. The reaction mixture was cooled to rt, poured onto a 10% aqueous solution of K₂CO₃and extracted with DCM. The organic layer was decanted, dried over MgSO₄, filtered and evaporated to dryness. The residue (75 mg, orange powder) was purified by column chromatography on silica gel (irregular SiOH, 12 g, mobile phase: gradient from 0% NH₄OH, 0% MeOH, 100% DCM to 0.8% NH₄OH, 8% MeOH, 92% DCM). The fractions containing the product were collected and evaporated to dryness. The residue (39 mg) was taken up with Et₂O to provide 15 mg of compound 173 (yellow powder).

The compounds in the Table below were prepared by using an analogous starting from the respective starting materials.

Compound number
Structure
Mass (mg)
Yield (%)

Compound 174

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21 yellow oil
34

Example B4
Preparation of Compound 176

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TFA (0.40 mL, 5.29 mmol) was added at 5° C. to a solution of intermediate 557 (201.00 mg, 0.35 mmol) in DCM (3.84 mL). The reaction mixture was stirred at 5° C. for 1 h and 30 min. The residue was diluted with DCM and poured onto a 10% aqueous solution of K₂CO₃, dried over MgSO₄, filtered, evaporated to dryness (500 m, yellow powder) and purified by column chromatography on silica gel (irregular SiOH, 24 g, mobile phase: gradient from 100% DCM to 90% DCM, 10% MeOH, 1% NH₄OH). The fractions containing the product were collected and evaporated to dryness. The residue (151 mg, light yellow powder) was purified by reverse phase (stationary phase: X-Bridge-C18, 5 m, 30×150 mm, mobile phase: gradient from 75% NH₄HCO₃0.2%, 25% CH₃CN to 35% NH₄HCO₃0.2%, 65% CH₃CN). The fractions containing the product were combined and evaporated. The residue (31 mg, colorless oil) was taken up with Et₂O to provide 27 mg of compound 176 (16% yield, white powder).

The compounds in the Table below were prepared by using an analogous starting from the respective starting materials.

Compound number
Structure
Mass (mg)
Yield (%)

Compound 175

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57 white powder
23

Example B5
Preparation of Compound 179

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In a sealed tube, a mixture of intermediate 559 (90.00 mg, 153 μmol) and TFA (583.00 μL, 7.62 mmol) in dry DCM (3 mL) was stirred at rt for 1 h. The reaction mixture was diluted with DCM and basified with a saturated aqueous solution of NaHCO₃. The layers were separated and the organic layer was combined with another batch (from 75 mg of intermediate 559), dried over MgSO₄, filtered and the solvent was removed under reduced pressure. The residue (155 mg, yellow residue) was purified by column chromatography on silica gel (irregular SiOH, 15-40 μm, 10 g, liquid injection in DCM, mobile phase gradient: from DCM 100% to DCM 90%, MeOH (+aq. NH₃5%) 10%). The fractions containing the product were combined and evaporated to dryness. The residue (55 mg, yellow oil) was triturated in EtOH and the solvent was removed under reduced pressure. The residue (48 mg, yellow solid) was dried 17 h at 50° C. under reduced pressure to give 36 mg of compound 179 (26% yield, yellow powder).

Example B6
Preparation of Compound 214

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Lithium hydroxide monohydrate (0.011 g; 0.26 mmol) was added slowly to a mixture of intermediate 729 (0.066 g; 0.12 mmol) in H₂O (0.250 mL) and 1,4-dioxane (0.500 mL). The reaction was stirred at 100° C. for 1 hour then room temperature overnight. Water was added and this mixture was acidified with an aqueous solution of HCl 3N. This mixture was extracted twice with EtOAc. The solvent was evaporated until dryness to give: 86 mg of crude product. Purification was performed via Reverse phase (Stationary phase: YMC-actus Triart-C18 10 μm 30*150 mm, Mobile phase: Gradient from 85% H₂O, 15% ACN to 45% H₂O, 55% ACN). The pure fractions were collected and the solvent was evaporated until dryness. The product was taken up into ACN/Water (2 mL/5 mL) and freeze-dried overnight to afford compound 214 (10 mg, 16%).

Example B7
Preparation of Compound 201

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A mixture of intermediate 6R (415.5 mg; 0.81 mmol) and intermediate 667 (252 mg; 1.21 mmol) in 1,4-dioxane (4.40 mL) was added p-toluensulfonic acid monohydrate (236 mg; 1.37 mmol). The resulting mixture was stirred at 95° C. for 15 h. Then the reaction was quenched with a solution of 10% K₂CO₃(aq), and extracted with a mixture of DCM-MeOH 9:1. The crude was purified using a silica gel column (DCM:MeOH 90:10) to afford compound 201 (60 mg, 16%).

Example B8
Preparation of Compound 222

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To a homogeneous solution of intermediate 776 (0.172 g; 0.27 mmol) in dry toluene (10 ml) was added SiO₂(0.5 g; 40-63 μm) and the reaction heated at reflux (˜120° C.) overnight (16 h). The reaction mixture was cooled to room temp and filtered through celite, rinsing the SiO₂with THF followed by CH₂Cl₂. The filtrate was concentrated to dryness, redissolved in MeOH, and purified via acidic prep-HPLC (Shimadzu pumps with Gilson fraction collector, DAD. Column: Inertsil ODS-3 (5 uM, 30×50 mm). Mobile phase: A=0.05% TFA in H₂O, B=0.05% TFA in CH₃CN. Gradient: 5% B for 1 min to 95% B over 12 min, held at 95% B for 2 min. Flow: 80 mL/min. Run time: 15 min). Desired fractions were combined, frozen, and lyophilized to yield 23.6 mg (18% yield) of compound 222 as a yellow solid TFA salt.

The compound in the table below was prepared by using an analogous method starting from the respective R enantiomer, intermediate 777. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Compound number
Structure
Mass (mg)
Yield (%)

Compound 223

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47
33

Example C1
Preparation of Compound 177

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A mixture of compound 49 (50.00 mg, 0.11 mmol), AcOH (6.60 μL, 0.11 mmol), HATU (57.01 mg, 0.15 mmol), DIPEA (70.50 μL, 0.40 mmol) in DMF (2 mL) was stirred 12 h at rt. Water and DCM were added. The mixture was extracted with DCM. The organic layer was washed with brine, dried over MgSO₄, filtered and the solvent was evaporated. The residue (690 mg) was purified by column chromatography on silica gel (irregular SiOH, 40 m, 40 g, mobile phase 100% DCM to 98% DCM, 2% MeOH, 0.2% NH₄OH). The pure fractions were combined and the solvent was evaporated. The residue (237 mg) was purified again by column chromatography on silica gel (irregular SiOH, 40 μm, 40 g, mobile phase 100% DCM to 99% DCM, 1% MeOH, 0.1% NH₄OH). The pure fractions were combined and the solvent was evaporated. The residue (185 mg) was freeze-dried with CH₃CN and water. The residue (169 mg) was further purified by reverse phase (Stationary phase: X-Bridge-C18, 10 m, 30×150 mm, mobile phase: gradient from 75% H₂O, 25% CH₃CN to 35% H₂O, 65% CH₃CN). The fractions containing the product were combined and evaporated to dryness. The residue (122 mg) was freeze-dried with CH₃CN and water to give 101 mg of compound 177 (18% yield). M.P.=70° C. (K, gum).

The intermediates in the Table below were prepared by using an analogous starting from the respective starting materials.

Compound number
Structure
Mass (mg)
Yield (%)

Compound 178

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45
24

Analytical Part

LCMS (Liquid Chromatography/Mass Spectrometry)

The High Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array (DAD) or a UV detector and a column as specified in the respective methods. If necessary, additional detectors were included (see table of methods below).

Flow from the column was brought to the Mass Spectrometer (MS) which was configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time . . . ) in order to obtain ions allowing the identification of the compound's nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software. Compounds are described by their experimental retention times (R_t) and ions. If not specified differently in the table of data, the reported molecular ion corresponds to the [M+H]⁺ (protonated molecule) and/or [M−H]⁻ (deprotonated molecule). In case the compound was not directly ionizable the type of adduct is specified (i.e. [M+NH₄]⁺, [M+HCOO]⁻, etc. . . . ). For molecules with multiple isotopic patterns (Br, Cl.), the reported value is the one obtained for the lowest isotope mass. All results were obtained with experimental uncertainties that are commonly associated with the method used. Hereinafter, “SQD” means Single Quadrupole Detector, “RT” room temperature, “BEH” bridged ethylsiloxane/silica hybrid, “HSS” High Strength Silica, “DAD” Diode Array Detector.

Table: LCMS Method codes (Flow expressed in mL/min; column temperature (T) in ° C.; Run time in minutes).

Method

Flow
Run

code
Instrument
Column
Mobile phase
gradient
Column T
time

Method
Waters: Acquity
Waters:
A: 95%
84.2% A for
0.343
6.2

1
UPLC ® - DAD
BEH C18
CH₃COONH₄
0.49 min, to 10.5%
40

and Quattro
(1.7 μm,
7 mM/5%
A in 2.18 min, held

Micro ™
2.1 × 100
CH₃CN, B:
for 1.94 min, back

mm)
CH₃CN
to 84.2% A in

0.73 min, held for

0.73 min.

Method
Waters:
Waters:
A: 95%
From 84.2% A to
0.343
6.1

2
Acquity
BEH
CH₃COONH₄
10.5% A in 2.18
40

UPLC ® H -
C18
7 mM/5%
min, held for

Class -
(1.7 μm,
CH₃CN, B:
1.94 min, back to

DAD and
2.1 × 10
CH₃CN
84.2% A in

SQD 2
0 mm)

0.73 min, held for

0.73 min.

Method
Agilent
ACE
A: 0.05%
1% B to 99% B
1.5
3.5

3
1260 Series -
EXCEL
TFA in
over 2.5 min, held
50

DAD
3 C18-
H₂O, B:
at 99% for

VL+ and
AR
100%
0.5 min, then back

Agilent
(3 uM,
CH₃CN
to 10% B over

G6120B
3.0 ×

0.5 min

ESI-SQD
50 mm)

Quadrupole

LC/MS

Method
Agilent
YMC-
A: 0.1%
From 95% A to
2.6
6.2

4
1100 HPLC
pack
HCOOH in
5% A in 4.8 min,
35

DAD
ODS-
H₂O
held for 1.0 min,

LC/MS
AQ
B: CH₃CN
to 95% A in 0.2

G1956A
C18

min.

(50 ×

4.6

mm, 3

μm)

Method
Agilent
YMC-
A: 0.1%
From 94.51% A
2.6
6.0

5
1290
pack
HCOOH in
to 5% A in 4.8
35

Infinity
ODS-
water
min, held for 1.0

DAD TOF-
AQ
B: CH₃CN
min, to 95% A in

LC/MS
C18 (3

0.2 min

G6224A
μm,

4.6 × 50

mm)

NMR

The NMR experiments were carried out using a Bruker Avance 500 III using internal deuterium lock and equipped with reverse triple-resonance (¹H, ¹³C, ¹⁵N TXI) probe head or using a Bruker Avance DRX 400 spectrometer at ambient temperature, using internal deuterium lock and equipped with reverse double-resonance (¹H, ¹³C, SEI) probe head with z gradients and operating at 400 MHz for the proton and 100 MHz for carbon. Chemical shifts (δ) are reported in parts per million (ppm). J value are expressed in Hertz (Hz).

Compound 19: ¹H NMR (400 MHz, DMSO-d₆): δ 9.56 (s, 1H), 8.36 (d, J=5.6 Hz, 1H), 8.08 (d, J=1.0 Hz, 1H), 7.98 (d, J=1.0H, 1H), 7.57 (d, J=2.0 Hz, 1H), 7.36 (s, 1H), 7.25 (d, J=5.0 Hz, 1H), 6.60 (d, J=2.0 Hz, 1H), 5.00 (t, J=5.3 Hz, 1H), 3.75 (s, 3H), 3.68 (d, J=10.1 Hz, 1H), 3.41-3.47 (m, 1H) 3.34-3.40 (m, 1H), 3.28 (m, 1H, partially obscured by solvent peak), 1.28 (s, 3H)

Compound 42: ¹H NMR (500 MHz, DMSO-d₆): δ 9.17 (s, 1H), 8.38 (d, J=5.4 Hz, 1H), 8.07 (d, J=1.6 Hz, 1H), 7.97 (d, J=1.6 Hz, 1H), 7.42 (s, 1H), 7.35 (d, J=5.4 Hz, 1H), 6.14 (s, 1H), 5.02 (t, J=5.4 Hz, 1H), 4.13 (t, J=5.6 Hz, 2H), 3.67 (d, J=9.8 Hz, 1H), 3.63 (t, J=9.8 Hz, 2H), 3.40-3.46 (m, 1H) 3.35-3.40 (m, 1H), 3.30 (d, J=9.8 Hz, 1H), 3.22 (s, 3H), 2.13 (s, 3H), 1.27 (s, 3H)

Compound 145: ¹H NMR (500 MHz, DMSO-d₆): δ 11.51 (br s, 1H), 8.53 (d, J=5.4 Hz, 1H), 8.23 (d, J=1.6 Hz, 1H), 8.15 (s, 1H), 7.45-7.53 (m, 2H), 6.71 (s, 1H), 5.02 (t, J=5.2 Hz, 1H), 3.70 (d, J=9.8 Hz, 1H), 3.43-3.49 (m, 1H) 3.37-3.42 (m, 1H), 3.31 (m, 1H, partially obscured by solvent peak), 2.26 (s, 3H), 1.30 (s, 3H)

Compound 49: ¹H NMR (500 MHz, DMSO-d₆): δ 9.14 (s, 1H), 8.36 (d, J=5.4 Hz, 1H), 8.06 (d, J=1.9 Hz, 1H), 7.95 (d, J=1.3 Hz, 1H), 7.39 (s, 1H), 7.32 (d, J=5.4 Hz, 1H), 6.07 (s, 1H), 4.99 (t, J=5.4 Hz, 1H), 3.98 (t, J=7.1 Hz, 2H), 3.67 (d, J=9.5 Hz, 1H), 3.40-3.45 (m, 1H) 3.34-3.39 (m, 1H) 3.31 (m, 1H, partially obscured by solvent peak), 3.27 (t, J=6.3 Hz, 2H), 3.16 (s, 3H), 2.13 (s, 3H), 1.92 (q, J=6.6 Hz, 2H), 1.27 (s, 3H)

Compound 107: ¹H NMR (400 MHz, DMSO-d₆): δ 9.54 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.07 (s, 1H), 7.93 (s, 1H), 7.41 (s, 1H), 7.38 (d, J=5.0 Hz, 1H), 6.40 (s, 1H), 4.98 (t, J=5.0 Hz, 1H), 3.87 (d, J=7.6 Hz, 2H), 3.69 (br d, J=10.1 Hz, 1H), 3.40-3.48 (m, 1H) 3.33-3.39 (m, 1H), 3.29 (m, 1H, partially obscured by solvent peak), 2.04-2.18 (m, 1H), 1.27 (s, 3H), 0.81 (d, J=6.6 Hz, 6H)

Compound 113: ¹H NMR (400 MHz, DMSO-d₆): δ 9.41 (s, 1H), 8.43 (d, J=5.6 Hz, 1H), 8.07 (s, 1H), 7.95 (s, 1H), 7.40-7.42 (m, 2H), 6.46 (s, 1H), 4.96 (t, J=5.3 Hz, 1H), 4.24-4.12 (m, 3H), 3.78-3.60 (m, 3H), 3.34-3.47 (m, 2H), 3.31 (m, 1H, partially obscured by solvent peak), 1.94-1.88 (m, 1H), 1.81-1.74 (m, 2H), 1.67-1.57 (m, 1H), 1.28 (s, 3H)

Compound 114: ¹H NMR (400 MHz, DMSO-d₆): δ 9.44 (s, 1H), 8.43 (d, J=5.0 Hz, 1H), 8.07 (d, J=2.0 Hz, 1H), 7.95 (d, J=1.5 Hz, 1H), 7.45-7.38 (m, 2H), 6.46 (s, 1H), 4.99 (t, J=5.0 Hz, 1H), 4.24-4.10 (m, 3H), 3.83-3.53 (m, 3H), 3.34-3.47 (m, 2H), 3.30 (m, 1H, partially obscured by solvent peak), 1.98-1.84 (m, 1H), 1.82-1.77 (m, 2H), 1.67-1.57 (m, 1H), 1.28 (s, 3H)

Compound 118: ¹H NMR (500 MHz, DMSO-d₆): δ 9.84 (s, 1H), 8.39 (d, J=5.4 Hz, 1H), 8.09 (d, J=1.6 Hz, 1H), 7.99 (d, J=1.3 Hz, 1H), 7.41 (s, 1H), 7.32 (d, J=5.4 Hz, 1H), 6.80 (s, 1H), 5.13 (s, 2H), 5.02 (s, 1H), 3.68 (d, J=9.7 Hz, 1H), 3.47-3.29 (m, 3H, partially obscured by solvent peak), 2.90-2.86 (m, 1H), 2.83 (s, 3H), 1.29 (m, 3H), 0.83-0.95 (s, 4H)

Compound 120: ¹H NMR (500 MHz, DMSO-d₆): δ 8.53 (s, 1H), 8.26 (d, J=5.0 Hz, 1H), 8.00 (s, 1H), 7.88 (s, 1H), 7.61-7.50 (m, 2H), 7.33 (s, 1H), 7.15 (d, J=5.0 Hz, 1H), 6.85 (s, 1H), 5.31 (s, 2H), 5.03 (t, J=5.4 Hz, 1H), 3.66 (d, J=9.5 Hz, 1H), 3.60 (s, 3H), 3.33-3.44 (m, 2H), 3.27 (d, J=9.5 Hz, 1H), 2.67 (t, J=8.2 Hz, 2H), 1.52-1.44 (m, 1H), 1.28-1.21 (m, 5H), 0.79 (d, J=6.6 Hz, 6H)

Compound 132: ¹H NMR (500 MHz, DMSO-d₆): δ 8.77 (s, 1H), 8.34 (d, J=5.4 Hz, 1H), 8.10-7.93 (m, 3H), 7.35 (s, 1H), 7.21 (d, J=5.4 Hz, 1H), 6.32 (tt, J=55.1, 3.7 Hz, 1H), 5.01 (t, J=5.4 Hz, 1H), 4.49 (td, J=15.0, 3.8 Hz, 2H), 3.67 (d, J=9.8 Hz, 1H), 3.35-3.35 (m, 2H), 3.29 (d, J=9.5 Hz, 1H), 2.17 (s, 3H), 1.28 (s, 3H)

Compound 156: ¹H NMR (400 MHz, DMSO-d₆): δ 9.15 (s, 1H), 8.34 (d, J=5.0 Hz, 1H), 8.05 (d, J=1.0 Hz, 1H), 7.93 (s, 1H), 7.38 (s, 1H), 7.32 (d, J=5.6 Hz, 1H), 6.14 (s, 1H), 4.98 (t, J=5.3 Hz, 1H), 4.93 (t, J=5.8 Hz, 1H), 4.49 (q, J=6.4 Hz, 1H), 4.37 (d, J=6.1 Hz, 2H), 3.68 (d, J=10.1 Hz, 1H), 3.32-3.46 (m, 2H), 3.28 (m, 1H, partially obscured by solvent peak), 1.31 (d, J=6.6 Hz, 6H), 1.26 (s, 3H)

Compound 164: ¹H NMR (500 MHz, DMSO-d₆): δ 9.75 (s, 1H), 8.52 (d, J=4.1 Hz, 1H), 8.37 (d, J=5.4 Hz, 1H), 8.10 (s, 1H), 7.98 (s, 1H), 7.38 (s, 1H), 7.29 (d, J=5.4 Hz, 1H), 7.12 (s, 1H), 5.41 (q, J=6.6 Hz, 1H), 4.98 (t, J=5.4 Hz, 1H), 3.70 (d, J=10.1 Hz, 1H), 3.34-3.48 (m, 2H), 3.29 (d, J=9.8 Hz, 1H), 2.78-2.85 (m, 1H), 1.38 (dd, J=6.6, 2.2 Hz, 6H), 1.28 (s, 3H), 0.70-0.64 (m, 2H), 0.63-0.58 (m, 2H)

Compound 177: ¹H NMR (500 MHz, DMSO-d₆): δ 9.16 (s, 1H), 8.38 (d, J=5.4 Hz, 1H), 8.11 (d, J=1.3 Hz, 1H), 8.04 (d, J=1.3 Hz, 1H), 7.51 (s, 1H), 7.35 (d, J=5.4 Hz, 1H), 6.07 (s, 1H), 4.12 (d, J=10.7 Hz, 1H), 4.04 (d, J=11.0 Hz, 1H), 3.98 (t, J=7.1 Hz, 2H), 3.63 (d, J=10.1 Hz, 1H), 3.40 (d, J=10.1 Hz, 1H), 3.26 (t, J=6.1 Hz, 2H), 3.15 (s, 3H), 2.13 (s, 3H), 1.98 (s, 3H), 1.91 (q, J=6.6 Hz, 2H), 1.34 (s, 3H)

Compound 103: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.76 (s, 1H) 8.42 (q, J=4.4 Hz, 1H) 8.38 (d, J=5.4 Hz, 1H) 8.11 (d, J=1.9 Hz, 1H) 8.01 (d, J=1.6 Hz, 1H) 7.37 (s, 1H) 7.29 (d, J=5.4 Hz, 1H) 7.17 (s, 1H) 5.43 (quin, J=6.6 Hz, 1H) 5.00 (t, J=5.5 Hz, 1H) 3.70 (d, J=9.1 Hz, 1H) 3.42-3.48 (m, 1H) 3.35-3.40 (m, 1H) 3.29 (d, J=9.5 Hz, 1H) 2.75 (d, J=4.7 Hz, 3H) 1.38 (dd, J=6.6, 0.9 Hz, 6H) 1.28 (s, 3H)

Compound 180 (fraction B): ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.78 (s, 1H) 8.35 (d, J=5.0 Hz, 1H) 8.06 (br s, 2H) 7.96 (s, 1H) 7.37 (s, 1H) 7.23 (d, J=5.4 Hz, 1H) 6.09-6.48 (m, 1H) 5.02 (br t, J=5.0 Hz, 1H) 4.40-4.65 (m, 2H) 3.67 (br d, J=10.1 Hz, 1H) 3.57 (t, J=6.9 Hz, 2H) 3.41-3.48 (m, 1H) 3.35-3.41 (m, 1H) 3.29 (br d, J=10.1 Hz, 1H) 3.27 (s, 3H) 2.87 (br t, J=6.9 Hz, 2H) 1.28 (s, 3H)

Compound 183: ¹H NMR (500 MHz, DMSO-d₆) δ 9.35 (s, 1H), 8.38 (d, J=5.4 Hz, 1H), 8.05 (s, 1H), 7.94 (s, 1H), 7.88 (q, J=4.4 Hz, 1H), 7.42 (s, 1H), 7.36 (d, J=5.4 Hz, 1H), 6.58 (s, 1H), 5.00 (t, J=5.2 Hz, 1H), 4.57-4.66 (m, 1H), 3.68 (d, J=9.8 Hz, 1H), 3.40-3.46 (m, 1H), 3.34-3.38 (m, 1H), 3.29 (br d, J=10.1 Hz, 1H), 2.76 (d, J=4.7 Hz, 3H), 1.38 (d, J=6.6 Hz, 6H), 1.26 (s, 3H)

Optical Rotation is measured with a polarimeter such as e.g. 341 Perkin Elmer, an Autopol IV automatic polarimeter (Rodolph research analytical) or a P-2000 (Jasco).

Specific rotation(OR): [α]^θ_λ=(100*α)/(c*1)

α (measured rotation) is the angle through which plane polarized light is rotated by a solution of c (mass concentration) and 1 (path length). Concentration is in grams per 100 mL; path length is in decimeters and is 1.000 decimeter.

θ is the temperature (° C.) and a the wavelength of the light used.

Unless otherwise indicated, temperature is 20° C., and the sodium D line is used (589 nanometer).

Or Data:

Solvent: DMF (unless otherwise indicated); temperature: 20° C. (unless otherwise indicated); wavelength: 589 nm (unless otherwise indicated); ‘Conc.’ means concentration of the sample in grams per 100 mL; ‘OR’ means optical rotation (specific rotation); ‘N°’ means compound number

Concentration

N°
OR (°)
(g/100 mL)

19
+19.82
0.202

31
−15.60
0.250

34
−19.41
0.232

37
+7.92
0.240

38
+9.52
0.210

39
+14.78
0.230

40
+17.14
0.210

41
+16.92
0.260

42
+11.20
0.250

43
+17.58
0.330

44
+12.96
0.270

45
+14.07
0.270

46
+14.21
0.218

47
−17.24
0.273

48
+16.94
0.310

49
+16.06
0.330

51
−11.00
0.264

52
+39.24
0.273

53
+31.17
0.231

54
−17.59
0.290

55
+14.83
0.290

57
−12.54
0.311

58
+15.29
0.340

59
+13.93
0.280

60
+13.87
0.310

61
+12.69
0.260

62
+14.80
0.250

63
+13.70
0.270

64
+4.46
0.269

65
+21.20
0.250

66
+16.45
0.274

67
+16.45
0.310

72
+10.88
0.340

73
+15.52
0.290

74
+4.62
0.238

75
+4.14
0.290

76
+14.62
0.260

79
+13.79
0.290

80
+10.40
0.250

83
+9.60
0.271

86
+19.66
0.290

87
+8.93
0.280

88
+12.50
0.280

89
+14.00
0.250

90
−4.52
0.310

91
+13.64
0.330

92
+14.07
0.270

93
+15.15
0.330

94
+48.33
0.300

95
+10.00
0.290

96
+8.30
0.253

97
−6.71
0.298

98
+11.48
0.248

101
+20.5
0.317

103
+9.00
0.300

104
+10.65
0.310

105
+31.90
0.210

107
+20.69
0.242

108
+12.52
0.192

109
+10.43
0.192

110
+14.40
0.250

111
+13.29
0.241

112
+17.42
0.258

113
+21.50
0.200

114
−7.86
0.242

115
+16.89
0.225

116
+14.71
0.258

117
+11.08
0.217

118
+14.48
0.242

119
−29.77
0.215

120
+4.80
0.250

122
−9.60
0.250

123
+18.58
0.258

124
+16.14
0.242

125
+14.83
0.283

126
+12.86
0.233

127
+11.46
0.148

128
+16.55
0.242

129
+20.80
0.250

130
+5.45
0.275

131
+14.48
0.242

132
+6.43
0.233

133
+15.31
0.242

134
+19.29
0.233

135
+11.67
0.300

136
+11.63
0.215

137
+9.55
0.262

138
+11.11
0.225

142
+24.22
0.244

145
+27.81
0.241

146
+8.85
0.260

147
+16.09
0.230

148
+29.33
0.150

149
+30.38
0.260

150
+22.91
0.183

151
+16.40
0.250

152
+11.58
0.242

153
+16.73
0.275

154
+15.74
0.235

155
+9.34
0.289

156
+13.82
0.275

157
+17.20
0.250

159
+17.50
0.200

160
+15.60
0.250

161
+18.08
0.260

162
+11.11
0.270

163
+8.50
0.200

164
+26.07
0.280

165
+18.48
0.330

166
+32.69
0.260

167
+9.62
0.260

168
+7.20
0.250

169
+9.58
0.240

170
+8.33
0.300

172
+9.06
0.309

173
−13.95
0.251

174
+18.48
0.233

175
−30.99
0.284

176
+39.18
0.268

177
+35.99
0.192

178
+29.12
0.364

179
+12.59
0.270

180
+8.26
0.363

181
+12.99
0.254

182
+14.52
0.31

183
+10.71
0.252

184
+11.72
0.290

185
+11.11
0.270

186
+10.91
0.330

187
+12.17
0.230

188
+9.58
0.240

189
+11.74
0.230

190
+15.71
0.210

192
+13.6
0.250

194
+16.94
0.366

195
+4.72
0.254

196
+8.97
0.290

197
+13.15
0.251

198
+18.60
0.07 (MeOH

@ 23° C.)

199
+7.17
0.279

200
+10.29
0.272

201
+4.2
0.1 (MeOH @

23° C.)

203
+4.36
0.390

204
+4.68
0.278

205
+30.0
0.220

206
+11.63
0.301

207
+5.18
0.251

208
+7.39
0.230

209
+13.48
0.230

210
+9.35
0.278

211
+5.65
0.230

212
+7.27
0.289

213
+12.4
0.06 (MeOH

@ 23° C.)

217
+7.69
0.260

218
+5.81
0.241

219
+11.55
0.251

220
+9.13
0.230

Melting Point (DSC, MP50, or K)

For a number of compounds, melting points (MP) were determined with a DSC1 (Mettler-Toledo) (indicated with DSC in the analytical table). Melting points were measured with a temperature gradient of 10° C./minute. Maximum temperature was 350° C. Values are peak values.”

For a number of compounds, melting points were obtained with a Kofler hot bench, consisting of a heated plate with linear temperature gradient, a sliding pointer and a temperature scale in degrees Celsius (indicated with K in the analytical table).

For a number of compounds, melting points were obtained with a Mettler Toledo MP50 apparatus (indicated with MP50 in the analytical table). Melting points were measured with a temperature gradient of 10° C. per minute starting from 50° C. (waiting time 10 seconds) to a maximum value of 300° C.

Table: N° means compound number; MP means melting point (° C.); R_tmeans retention time (min)

MP
MP

LC/MS

N°
(° C.)
method
Rt
[M + H]⁺
Method

1
212
DSC
2.15
362
1

2
208
DSC
2.08
362
1

3
232
DSC
2.15
376
1

4
252
DSC
2.10
362
1

5
—
—
2.14
432
1

6
>260
K
2.74
444
1

7
227
DSC
2.04
376
2

8
—
—
2.37
418
2

9
—
—
1.91
434
2

10
—
—
2.17
448
2

11
206
DSC
2.14
433
1

12
203
K
1.66
445
2

13
260
DSC
1.97
375
2

14
—
—
2.01
420
1

15
—
—
2.33
390
1

16
—
—
2.21
406
1

17
—
—
2.00
433
1

18
—
—
2.08
447
1

19
199
DSC
2.15
362
1

20
215
DSC
2.45
390
1

21
233
DSC
2.02
348
1

22
—
—
2.40
509
1

23
—
—
2.30
420
1

24
—
—
2.28
390
1

25
—
—
2.05
489
1

26
—
—
2.18
432
1

27
—
—
2.24
420
1

28
—
—
2.39
509
1

29
150
K
2.42
402
1

(gum)

30
—
—
2.25
412
1

31
—
—
2.45
390
1

32
163
K
2.19
396
1

33
250
K
2.33
480
1

34
200
DSC
2.14
362
1

35
<260
K
2.35
517
1

36
—
—
2.04
376
1

37
>260
K
1.94
445
1

38
249
K
1.90
445
1

39
170
K
2.13
461
1

40
221
K
2.45
402
1

41
208
DSC
2.34
396
1

42
—
—
2.30
420
1

43
240
K
2.44
396
1

44
—
—
2.41
434
1

45
—
—
2.03
433
1

46
166
K
2.18
420
1

47
174
K
2.18
420
1

48
—
—
2.38
390
1

49
162
DSC
2.34
767
1

50
—
—
2.14
489
1

51
192
K
2.47
446
1

52
173
K
2.46
446
1

53
260
K
2.33
419
1

54
159
K
2.32
434
1

55
200
K
2.50
418
1

56
—
—
1.95
419
1

57
—
—
2.29
420
1

58
228
K
2.60
462
1

59
—
—
2.45
462
1

60
>260
K
2.39
460
1

61
138
K
2.24
460
1

(gum)

62
192
K
2.00
459
1

63
>250
K
2.21
446
1

64
—
—
2.58
430
1

65
—
—
2.07
468
1

66
—
—
2.32
490
1

67
—
—
2.17
446
1

68
142
K
2.64
460
1

(gum)

69
138
K
2.65
460
1

(gum)

70
214
K
2.63
460
1

71
150
K
2.63
460
1

(gum)

72
167
K
2.17
446
1

(gum)

73
—
—
2.32
402
1

74
191
K
2.20
446
1

75
203
K
2.24
460
1

76
134
K
2.21
460
1

(gum)

77
123
K
2.44
434
1

(gum)

78
117
K
2.44
434
1

(gum)

79
—
—
2.31
475
1

80
304
DSC
2.35
499
1

81
124
K
2.22
446
1

(gum)

82
140
K
2.22
446

(gum)

83
—
—
2.00
473
1

84
140
K
2.28
462
1

(gum)

85
141
K
2.28
462
1

(gum)

86
152
K
2.03
433
1

(gum)

87
—
—
2.26
495
1

88
—
—
2.19
473
1

89
—
—
2.25
473
1

90
118
K
2.00
459
1

(gum)

91
—
—
2.40
474
1

92
—
—
2.08
420
1

93
—
—
2.89
443
1

94
—
—
2.33
460
1

95
222
DSC
2.74
430
1

96
182
DSC
2.54
430
1

97
—
—
2.52
418
1

98
248
DSC
2.48
418
1

99
—
—
2.61
432
1

100
—
—
2.66
432
1

101
—
—
2.49
489
1

102
—
—
2.44
489
1

103
—
—
2.08
447
1

104
—
—
2.74
490
1

105
150
K
2.80
490
1

107
202
DSC
2.80
438
1

108
186
K
2.21
448
1

109
230
K
2.30
448
1

110
—
—
2.31
448
1

111
227
DSC
2.24
446
1

112
190
DSC
2.62
454
1

113
—
—
2.75
466
1

114
—
—
2.74
466
1

115
202
DSC
2.81
450
1

116
277
DSC
2.23
467
1

117
206
K
2.43
512
1

118
238
DSC
2.46
493
1

119
—
—
2.16
480
1

120
189
K
2.37
512
1

121
189
K
2.63
518
1

122
—
—
1.97
459
1

123
—
—
1.93
459
1

124
—
—
2.19
493
1

125
194
K
2.52
531
1

126
—
—
2.54
482
1

127
178
K
2.37
462
1

128
184
K
2.76
441
1

129
—
—
2.48
466
1

130
226
K
2.51
512
1

131
139
K
2.15
491
1

(gum)

132
—
—
2.30
426
1

133
—
—
2.54
482
1

134
—
—
2.45
525
1

135
—
—
1.69
420
1

136
—
—
2.07
544
1

137
—
—
2.64
541
1

138
—
—
2.29
537
1

139
—
—
2.21
475
1

140
—
—
2.03
473
1

141
129
K
2.04
473
1

(gum)

142
—
—
1.89
364
1

143
>250
K
2.31
380
1

144
>250
K
2.31
380
1

145
—
—
2.40
379
1

146
222
DSC
2.43
379
1

147
—
—
2.10
363
1

148
285
DSC
2.55
393
1

149
—
—
2.14
450
1

150
>260
K
2.21
461
1

151
227
DSC
2.19
434
1

152
257
DSC
2.93
561
1

153
199
DSC
1.98
436
1

154
—
—
2.24
460
1

155
197
DSC
2.07
517
1

156
219
DSC
2.05
420
1

157
—
—
2.18
479
1

158
141
K
2.21
475
1

(gum)

159
183
K
2.63
515
1

160
—
—
2.36
511
1

161
243
DSC
2.18
479
1

162
211
DSC
2.49
466
1

163
191
K
3.17
597
1

164
262
DSC
2.50
473
1

165
—
—
2.35
475
1

166
245
K
1.96
474
1

167
165
K
2.33
528
1

168
126
K
2.21
559
1

169
147
K
2.95
579
1

(gum)

170
177
K
2.08
475
1

171
—
—
2.12
487
1

172
—
—
1.95
503
1

173
110
K
2.22
419
1

(gum)

174
110
K
2.22
419
1

(gum)

175
260
K
2.67
470
1

176
264
K
2.67
470
1

177
70
K
2.63
476
1

(gum)

178
—
—
2.28
515
1

179
—
—
2.34
487
1

180
131
DSC
2.43
470
1

170
DSC

181
182
DSC
2.41
470
1

182
271
DSC
2.23
475
1

183
255-
DSC
2.24
447
1

256

184
148
K
2.38
538
1

(gum)

185
154
K
2.00
524
2

(gum)

186
240
K
2.36
426
1

187
267
DSC
2.47
469
1

188
107
K
2.74
470
1

(gum)

189
238
K
2.81
509
1

190
250
K
2.03
419
1

191
192
K
2.15
459
1

192
204
K
2.27
418
1

193
128
K
1.98
434
1

(gum)

194
250
K
2.34
420
1

195
292
DSC
2.47
473
2

196
217
DSC
2.49
473
1

197
304
DSC
2.33
469
1

198
158
MP50
2.86
473
4

199
226
K
2.25
461
1

200
138
K
2.06
572
1

(gum)

201
290
MP50
2.32
473
5

202
158
K
2.12
496
1

(gum)

203
112
K
2.15
491
1

(gum)

204
—
—
2.60
454
1

205
—
—
2.53
452
1

206
212
DSC
2.11
447
1

207
126
K
2.45
519
1

208
129
K
2.25
495
1

(gum)

209
254
K
1.78
474
2

210
179
DSC
2.54
487
1

211

2.44
487
1

212
275
DSC
2.53
487
1

213
299
MP50
2.08
513
4

214
—
—
1.88
517
1

215
230
MP50
1.99
461
4

216
—
—
2.06
363
1

217
156
DSC
2.46
486
1

218
183
DSC
2.56
468
1

219
173
DSC
2.37
461
1

220
—
—
2.36
496
1

221
—
—
2.03
466
1

222
—
—
1.61
361
3

223
—
—
1.61
361
3

SFC-MS Method

The SFC measurement was performed using an Analytical Supercritical fluid chromatography (SFC) system composed by a binary pump for delivering carbon dioxide (CO₂) and modifier, an autosampler, a column oven, a diode array detector equipped with a high-pressure flow cell standing up to 400 bars. If configured with a Mass Spectrometer (MS) the flow from the column was brought to the (MS). It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time . . . ) in order to obtain ions allowing the identification of the compound's nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software.

Table: Analytical SFC-MS Methods (flow expressed in mL/min; column temperature (T) expressed in ° C.; run time expressed in minutes, backpressure (BPR) expressed in bars.

Flow
Run time

Method
column
mobile phase
gradient
Col T
BPR

Method 1
Chiralpak ® AD-H
A: CO₂
30% B
3
7

column (5 μm, 150 ×
B: iPrOH
hold 7 min,
35
100

4.6 mm)
(0.3% iPrNH₂)

Method 2
Chiralcel ® OJ-H
A: CO₂
40% B
3
7

column (5 μm, 150 ×
B: MeOH
hold 7 min,
35
100

4.6 mm)
(0.3% iPrNH₂)

Method 3
Chiralpak ® AD-3
A: CO₂
30% B
3.5
3

column (3 μm, 100 ×
B: EtOH (0.3%
hold 3 min,
35
103

4.6 mm)

iPrNH₂)

Method 4
Chiralcel ® OJ-H
A: CO₂
15% B
3.5
6

column (5 μm, 150 ×
B: MeOH
hold 6 min,
35
103

4.6 mm)
(0.3% iPrNH₂)

Method 5
Chiralpak ® AD-3
A: CO₂
40% B
3.5
3

column (3 μm, 100 ×
B: EtOH (0.3%
hold 3 min,
35
103

4.6 mm)

iPrNH₂)

Method 6
Chiralpak ® AD-3
A: CO₂
35% B
3.5
3

column (3 μm, 100 ×
B: iPrOH
hold 3 min,
35
103

4.6 mm)
(0.3% iPrNH₂)

Method 7
Chiralpak ® IC3
A: CO₂
35% B
3.5
3

column (3 μm, 100 ×
B: iPrOH
hold 3 min,
35
103

4.6 mm)
(0.3% iPrNH₂)

Method 8
Lux cellulose 4
A: CO₂
40% B
3.5
3

column (3 μm, 100 ×
B: EtOH (0.3%
hold 3 min,
35
103

4.6 mm)

iPrNH₂)

Table: Analytical SFC data (R_tmeans retention time (in minutes), [M+H]⁺ means the protonated mass of the compound, method refers to the method used for SFC-MS analysis of enantiomerically pure compounds; N° means compound number).

Chiral

purity UV

N°
Rt
[M + H]⁺
Area %
Method

68
2.96
460
100
1

69
3.54
460
99.10
1

70
4.16
460
100
2

71
2.31
460
100
2

77
1.01
434
100
3

78
1.14
434
99.12
3

81
2.31
446
99.39
4

82
2.70
446
98.12
4

84
1.00
462
100
5

85
1.56
462
100
5

121
0.99
518
97.2
6

139
1.69
475
100
7

140
1.52
473
100
8

141
2.05
473
98.63
8

158
2.31
475
100
7

Pharmacological Part

Biological Assay a

Inhibition of auto-phosphorylation of recombinant human NF-kappaB-inducing kinase (NIK/MAP3K14) activity (AlphaScreen®)

NIK/MAP3K14 auto-phosphorylation activity was measured using the AlphaScreen® (αscreen) format (Perkin Elmer). All compounds tested were dissolved in dimethyl sulfoxide (DMSO) and further dilutions were made in assay buffer. Final DMSO concentration was 1% (v/v) in assays. Assay buffer was 50 mM Tris pH 7.5 containing 1 mM EGTA (ethylene glycol tetraacetic acid), 1 mM DTT (dithiothreitol), 0.1 mM Na₃VO₄, 5 mM MgCl₂, 0.01% Tween® 20. Assays were carried out in 384 well Alphaplates (Perkin Elmer). Incubations consisted of compound, 25 microM Adenosine-5′-triphosphate (ATP), and 0.2 nM NIK/MAP3K14. Incubations were initiated by addition of GST-tagged NIK/MAP3K14 enzyme, carried out for 1 h at 25° C. and terminated by addition of stop buffer containing anti-phospho-IKK Ser176/180 antibody. Protein A Acceptor and Glutathione-Donor beads were added before reading using an EnVision® Multilabel Plate Reader (Perkin Elmer). Signal obtained in the wells containing blank samples was subtracted from all other wells and IC₅₀'s were determined by fitting a sigmoidal curve to % inhibition of control versus Log₁₀compound concentration.

Biological assay B

Effect of compounds on P-IKKα levels in L363 (NIK translocated multiple myeloma) cells

All compounds tested were dissolved in DMSO and further dilutions were made in culture medium. Final DMSO concentration was 1% (v/v) in cell assays. The human L363 cells (ATCC) were cultured in RPMI 1640 medium supplemented with GlutaMax and 10% fetal calf serum (PAA). Cells were routinely maintained at densities of 0.2×10⁶cells per ml-1×10⁶cells per ml at 37° C. in a humidified 5% CO₂atmosphere. Cells were passaged twice a week splitting back to obtain the low density. Cells were seeded in 96 well plates (Nunc 167008) at 2×10⁶per ml media in a volume of 75 μl per well plus 25 μl 1 μg/ml recombinant human B-cell activating factor (BAFF/BLyS/TNFSF13B). Seeded cells were incubated at 37° C. in a humidified 5% CO₂atmosphere for 24 hr. Drugs and/or solvents were added (20 μl) to a final volume of 120 μl. Following 2 hr treatment plates were removed from the incubator and cell lysis was achieved by the addition of 30 μl 5× lysis buffer followed by shaking on a plate shaker at 4° C. for 10 min. At the end of this incubation lysed cells were centrifuged at 800×g for 20 min at 4° C. and the lysate was assessed for P-IKKα levels by sandwich immuno-assay carried out in anti-rabbit antibody coated Mesoscale plates. Within an experiment, the results for each treatment were the mean of 2 replicate wells. For initial screening purposes, compounds were tested using an 8 point dilution curve (serial 1:3 dilutions). For each experiment, controls (containing MG132 and BAFF but no test drug) and a blank incubation (containing MG132 and BAFF and 10 μM ADS125117, a test concentration known to give full inhibition) were run in parallel. The blank incubation value was subtracted from all control and sample values. To determine the IC₅₀a sigmoidal curve was fitted to the plot of % inhibition of control P-IKKα levels versus Log₁₀compound concentration.

Biological assay C

Determination of antiproliferative activity on JJN-3 (NIK translocated) and KMS12-BM (NIK WT) multiple myeloma cells

All compounds tested were dissolved in DMSO and further dilutions were made in culture medium. Final DMSO concentration was 0.3% (v/v) in cell proliferation assays. Viability was assessed using CellTiter-Glo cell viability assay kit (Promega). The human JJN-3 and KMS12-BM cells (DSMZ) were cultured in RPMI 1640 medium supplemented with 2 mM L-glutamine, and 10% fetal calf serum (PAA). Cells were routinely kept as suspension cells at 37° C. in a humidified 5% CO₂atmosphere. Cells were passaged at a seeding density of 0.2×10⁶/ml twice a week. Cells were seeded in black tissue culture treated 96-well plates (Perkin Elmer). Densities used for plating ranged from 15000 (JJN3) to 20000 (KMS12BM) cells per well in a total volume of 135 μl medium. Drugs and/or solvents were added (15 μl) to a final volume of 150 μl. Following 96 hr of treatment, plates were removed from the incubator and allowed to equilibrate to room temperature for approx 10 min. 75 μl CellTiter-Glo reagent was added to each well that was then covered (Perkin Elmer Topseal) and shaken on plate shaker for 10 min. Luminescence was measured on a HTS Topcount (Perkin Elmer). Within an experiment, the results for each treatment were the mean of 2 replicate wells. For initial screening purposes, compounds were tested using a 9 point dilution curve (serial 1:3 dilutions). For each experiment, controls (containing no drug) and a blank incubation (containing cells read at the time of compound addition) were run in parallel. The blank value was subtracted from all control and sample values. For each sample, the mean value for cell growth (in relative light units) was expressed as a percentage of the mean value for cell growth of the control.

Data for the compounds of the invention in the above assays are provided in Table A (the values in Table are averaged values over all measurements on all batches of a compound). (‘n.c.’ means not calculated)

TABLE A

Auto-
Inhibition

phosphorylation
of
KMS-12
JJN-3

inhibition of
pIKKα_L-
Proliferation
Proliferation

Com-
NIK
363
inhibition
inhibition

pound
(IC50 (nM))
(IC50 (nM))
(IC50 (nM))
(IC50 (nM))

1
4.0
n.c.
2434
250

2
6.9
n.c.
794
141

3
4.2
n.c.
~1230
407

4
2.5
n.c.
162
~55

5
5.4
n.c.
>10000
708

6
7.6
n.c.
>10000
347

7
3.2
2
~1738
112

8
5.5
n.c.
7943
129

9
5.1
n.c.
>10000
832

10
13
n.c.
>10000
724

11
21
n.c.
3702
576

12
3.6
n.c.
~213.8
~45

13
3.4
n.c.
~2512
162

14
7.1
n.c.
~7244
234

15
5.4
n.c.
437
191

16
2.8
n.c.
7079
525

17
10
n.c.
4169
4365

18
11
n.c.
>10000
1862

19
2.2
n.c.
2717
163

20
3.4
n.c.
2512
229

21
2.9
n.c.
1023
813

22
18
n.c.
>10000
2344

23
4.9
n.c.
3890
295

24
10
n.c.
>10000
646

25
8.1
n.c.
1514
1905

26
10
n.c.
~2951
457

27
13
n.c.
~4571
389

28
~17
n.c.
>10000
2570

29
4.4
n.c.
1445
~603

30
3.2
n.c.
~170
47

31
14
n.c.
>10000
589

32
27
n.c.
>10000
7762

33
9.1
n.c.
~6166
1259

34
10
n.c.
~10000
1175

35
7.9
4
>10000
209

36
2.6
n.c.
7586
174

37
2.0
n.c.
182
162

38
47
n.c.
3890
3981

39
32
n.c.
>10000
1445

40
2.2
n.c.
562
295

41
2.1
n.c.
~479
78

42
4.2
68
5976
398

43
2.6
n.c.
933
234

44
4.5
n.c.
8710
324

45
7.6
n.c.
4169
1318

46
6.6
n.c.
2399
158

47
44
n.c.
>10000
1549

48
5.1
n.c.
263
89

49
4.0
11
2089
134

50
3.8
n.c.
>10000
316

51
4.1
n.c.
~1905
~59

52
6.9
n.c.
>10000
115

53
3.5
n.c.
~5012
851

54
11
n.c.
>10000
525

55
4.4
n.c.
~2041.74
59

56
3.1
n.c.
~1412.54
~363

57
28
n.c.
>10000
~933

58
1.5
n.c.
468
69

59
5.0
n.c.
1950
68

60
2.0
5
~501.19
72

61
4.4
n.c.
355
162

62
23
n.c.
269
204

63
9.8
n.c.
6310
692

64
1.9
n.c.
3236
240

65
10
n.c.
>10000
~1412

66
13
n.c.
>10000
324

67
1.6
n.c.
912
141

68
5.3
n.c.
>10000
38

69
5.8
n.c.
>10000
78

70
3.8
6
1862
209

71
2.8
4
813
102

72
2.9
3
724
102

73
1.9
2
1318
195

74
3.0
n.c.
~3890
324

75
13
n.c.
~6026
2089

76
1.2
2
741
141

77
13
n.c.
1585
309

78
9.8
n.c.
9120
457

79
8.3
n.c.
>10000
2239

80
3.9
n.c.
6166
1096

81
4.3
11
851
195

82
~5.0
13
380
182

83
10
514
148
111

84
11
11
>10000
437

85
9.8
31
~4898
380

86
2.6
15
~3715
871

87
~6.5
34
>10000
3236

88
6.8
9
>10000
2138

89
3.7
~85
>10000
427

90
5.7
n.c.
5129
1549

91
5.5
13
>10000
324

92
3.5
7
1514
~224

93
11
37
457
182

94
5.6
7
4169
178

95
1.6
4
871
100

96
1.6
12
3802
76

97
2.0
2
>10000
309

98
2.0
5
>10000
1023

99
2.9
3
9772
288

100
2.1
~15
>10000
54

101
6.0
234
5248
1513

102
2.2
12
~6457
112

103
2.6
4
3020
71

104
3.4
15
>10000
117

105
5.5
20
>10000
447

107
3.8
9
1349
55

108
4.1
14
~3162
~724

109
3.6
11
468
50

110
3.0
4
2042
138

111
9.3
~331
5129
355

112
2.9
13
8913
69

113
6.2
42
3020
69

114
6.0
30
1072
151

115
4.6
10
4266
62

116
9.3
269
n.c.
n.c.

117
6.0
11
>10000
269

118
4.0
33
>10000
447

119
9.6
43
>10000
3162

120
~29
3
5012
126

121
5.0
25
>10000
282

122
6.8
1023
~1660
479

123
1.6
20
~447
195

124
6.8
219
832
49

125
3.5
1
>10000
120

126
4.8
170
>10000
468

127
2.0
25
>10000
617

128
3.7
~41
1905
417

129
3.8
28
2042
251

130
6.0
115
>10000
1000

131
5.9
166
>10000
224

132
1.0
2
~1862
58

133
6.9
65
6607
389

134
4.8
107
2239
47

135
5.1
229
>10000
>10000

136
7.2
562
>10000
724

137
6.3
36
>10000
676

138
8.3
178
2570
44

139
13
182
>10000
1122

140
8.3
145
6457
174

141
42
813
>10000
79

142
42
n.c.
~9772
>10000

143
1.3
n.c.
204
~81

144
2.0
n.c.
44
36

145
1.5
n.c.
~3388
71

146
1.3
n.c.
589
102

147
9.6
n.c.
~5012
~436

148
0.8
n.c.
282
93

149
0.7
8
~741
50

150
15
170
>10000
2399

151
2.0
13
7079
871

152
17
135
7943
646

153
4.3
28
>10000
1445

154
4.9
15
2291
646

155
9.3
126
>10000
59

156
3.6
14
~7244
1259

157
12
182
141
45

158
10
123
>10000
339

159
10
91
>10000
1514

160
3.6
34
~5012
69

161
4.3
83
2239
204

162
7.2
35
2630
832

163
12
5
>10000
309

164
2.6
<0.66
4677
132

165
8.5
48
>10000
1622

166
13
151
>10000
37

167
13
62
>10000
83

168
2.3
3
7586
631

169
3.9
16
~7079
389

170
2.2
7
~1778
417

171
6.2
1445
n.c.
n.c.

172
4.6
~10000
n.c.
n.c.

173
162
n.c.
~6310
6026

174
35
n.c.
3162
1549

175
n.c.
n.c.
>10000
4074

176
32
76
~3311.31
65

177
10
28
>10000
81

178
20
141
2344
98

179
6.2
n.c.
~10000
832

180
4.7
2
~6719
46

181
3.3
11
~9120
87

182
1.7
1
1380
151

183
22
35
~9772
1412

184
5.4
17
>10000
224

185
6.0
20
>10000
91

186
6.5
3
617
151

187
7.2
11
>10000
~1380

188
2.9
4
~8128
138

189
17.0
51
n.c.
n.c.

190
11.7
110
n.c.
n.c.

191
107
4467
n.c.
n.c.

192
8.1
6
>10000
91

193
25.1
91
n.c.
n.c.

194
3.1
29
>10000
407

195
4.9
1
>10000
158

196
8.3
36
5248
554

197
2.1
4
~2239
204

198
6.8
20
>10000
112

199
3.5
25
>10000
1905

200
5.9
20
>10000
3548

201
3.4
2
>10000
100

202
7.2
1950
n.c.
n.c.

203
4.0
25
>10000
339

204
1.1
2
~6026
16

205
2.2
1
~4898
5

206
2.9
31
n.c.
n.c.

207
15.5
93
n.c.
n.c.

208
2.0
4
~4786
48

209
28.2
141
n.c.
n.c.

210
6.3
71
>10000
1585

211
14.8
204
n.c.
n.c.

212
11.7
98
>10000
257

213
5.6
27
>10000
95

214
18.6
2630
n.c.
n.c.

215
168
3490
n.c.
n.c.

216
7.8
n.c.
2630
537

217
4.6
11
~7623
154

218
2.8
7
~7431
38

219
9.5
100
n.c.
214

220
5.6
11
>10000
195

221
14.8
~105
>10000
2291

222
12.0
15
n.c.
n.c.

223
224
269
n.c.
n.c.

Prophetic Composition Examples

“Active ingredient” (a.i.) as used throughout these examples relates to a compound of Formula (I), including any tautomer or stereoisomeric form thereof, or a pharmaceutically acceptable addition salt, or a solvate thereof; in particular to any one of the exemplified compounds.

Typical examples of recipes for the formulation of the invention are as follows:

1. Tablets

Active ingredient
5 to 50
mg

Di-calcium phosphate
20
mg

Lactose
30
mg

Talcum
10
mg

Magnesium stearate
5
mg

Potato starch
ad 200
mg

2. Suspension

An aqueous suspension is prepared for oral administration so that each milliliter contains 1 to 5 mg of active ingredient, 50 mg of sodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg of sorbitol and water ad 1 ml.

3. Injectable

A parenteral composition is prepared by stirring 1.5% (weight/volume) of active ingredient in 0.9% NaCl solution or in 10% by volume propylene glycol in water.

4. Ointment

Active ingredient
5 to 1000
mg

Stearyl alcohol
3
g

Lanoline
5
g

White petroleum
15
g

Water
ad 100
g

In this Example, active ingredient can be replaced with the same amount of any of the compounds according to the present invention, in particular by the same amount of any of the exemplified compounds.

Number	Date	Country
2003511378	Mar 2003	JP
2014510794	May 2014	JP
WO 2001025220	Apr 2001	WO
WO-0160816	Aug 2001	WO
WO-0164643	Sep 2001	WO
WO-02079197	Oct 2002	WO
WO-02102313	Dec 2002	WO
WO-03030909	Apr 2003	WO
WO-2009158011	Dec 2009	WO
WO-2009158571	Dec 2009	WO
WO-2010042337	Apr 2010	WO
WO-2011022440	Feb 2011	WO
WO-2011153553	Dec 2011	WO
WO-2012016217	Feb 2012	WO
WO 2012142329	Oct 2012	WO
WO-2014174021	Oct 2014	WO
WO-2015030847	Mar 2015	WO
WO-2015044267	Apr 2015	WO
WO-2015044269	Apr 2015	WO
WO-2015154039	Oct 2015	WO
WO-2015176135	Nov 2015	WO
WO-2016022645	Feb 2016	WO
WO 2016049211	Mar 2016	WO
WO-2017114510	Jul 2017	WO
WO-2017125530	Jul 2017	WO
WO-2017125534	Jul 2017	WO
WO-2017161028	Sep 2017	WO
WO-2018002217	Jan 2018	WO
WO-2018002219	Jan 2018	WO

Heteroaromatic derivatives as NIK inhibitors

Information

Patent Number

Date Filed

Date Issued

Inventors

Original Assignees

Examiners

CPC

Field of Search

CPC

International Classifications

Abstract

Description

Claims

Priority Claims (1)

PCT Information

US Referenced Citations (1)

Foreign Referenced Citations (29)

Non-Patent Literature Citations (42)

Related Publications (1)