EA037358B1 - New substituted cyanoindoline derivatives as nik inhibitors - Google Patents

Abstract

The invention relates to pharmaceutical agents useful for therapy and/or prophylaxis in a mammal, and in particular to inhibitors of NF-B-inducing kinase (NIK - also known as MAP3K14) useful for treating diseases such as cancer, inflammatory disorders, metabolic disorders and autoimmune disorders. The invention also provides pharmaceutical compositions comprising such compounds, and the use of such compounds or pharmaceutical compositions for the prevention or treatment of diseases mediated by NF-B-inducing kinase (NIK) such as cancer, B-cell neoplasia and haematological malignancy.

Description

The technical field to which the invention relates

The present invention relates to pharmaceutical agents used for the therapy and / or prophylaxis of diseases in mammals, and in particular to inhibitors of signaling-induced NF-kB kinase (NIK - also known as MAPZK14), suitable for the treatment of diseases such as cancer ( in particular, B-cell malignant tumors, including leukemia, lymphomas and myelomas), inflammatory diseases, metabolic disorders including obesity and diabetes, and autoimmune diseases. This invention also relates to pharmaceutical compositions containing such compounds and to the use of such compounds or pharmaceutical compositions for the prevention or treatment of diseases such as cancer, inflammatory diseases, metabolic disorders, including obesity and diabetes, and autoimmune diseases.

Background Art

The present invention relates to pharmaceutical agents used for therapy and / or prophylaxis in mammals and, in particular, to inhibitors of NF-KB-inducible kinase (NIK - also known as MAP3K14), suitable for the treatment of diseases such as cancer and inflammatory diseases. Nuclear factor kappaB (NF-kB) is a transcription factor that regulates the expression of various genes involved in the immune response, cell proliferation, adhesion, apoptosis, and oncogenesis (carcinogenesis). NF-kB-dependent transcriptional activation tightly regulates the signaling pathway through sequential events, including phosphorylation and degradation of proteins. NIK is a serine / threonine kinase that regulates the NF-kB signaling pathway. There are two NF-kB signaling pathways, canonical and non-canonical. NIK is required for a noncanonical signaling pathway where it phosphorylates IKKa, leading to partial proteolysis of p100; releasing p52, which then heterodimerizes with RelB, translocates into the nucleus and mediates gene expression. The non-canonical signaling pathway is activated by only a small number of ligands such as CD40 ligands, B cell activating factor (BAFF), lymphotoxin receptor β ligands, and TNF-like weak apoptosis factor (TWEAK), and it has been shown that NIK is required to activate the signaling pathway by these ligands. Due to its key role, NIK expression is tightly regulated.

Under normal non-stimulated conditions, the amount of NIK protein is very small, this is due to its interaction with a number of factors associated with the TNF receptor (TRAF2 and TRAF3), which are ubiquitin ligases and lead to the destruction of NIK. It is believed that when a noncanonical signaling pathway is stimulated by ligands, the activated receptors compete for TRAFs, dissociating TRAF-NIK complexes and thereby increasing the number of NIKs (Thu and Richmond, Cytokine Growth F.R. 2010, 21, 213-226).

Studies have shown that blocking the NF-κB signaling pathway in cancer cells can stop cell proliferation, their death, and make them more susceptible to the action of other anticancer therapeutic agents. The role of NIK in the pathogenesis of both hematological malignant neoplasms and solid tumors has been shown.

The NF-kB signaling pathway is dysregulated in multiple myelomas due to a number of different genetic abnormalities that lead to the involvement of canonical and non-canonical signaling 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). Samples from patients with myeloma are often characterized by increased levels of NIK activity. This may be due to chromosomal amplification, translocations (which result in NIK proteins that have lost TRAF binding domains), mutations (in the TRAF binding domain of NIK), or loss of TRAF functional mutations. Researchers have shown that myeloma cell lines may be dependent on NIK for proliferation; in these cell lines, if NIK activity is reduced either by shRNA or by inhibition of the compound, this leads to disruption of the NF-kB signaling pathway and induction of cell death (Annuziata 2007).

Likewise, mutations in TRAF and elevated NIK levels have also been found in samples from patients with Hodgkin's lymphoma (HL). As in the previous case, the proliferation of cell lines selected from patients with HL is sensitive to inhibition of NIK function by both shRNA and compounds (Ranuncolo et al. Blood First Edition Paper, 2012, DOI 10.1182 / blood2012-01-405951).

NIK levels are also increased in T cells of adult leukemia patients (ATL) and NIK shRNA targeting reduced ATL 1 N growth in vivo (Saitoh et al. Blood 2008, 111, 5118-5129).

It has been shown that the API2-MALT1 fusion oncoprotein formed by repeated t (11; 18) (q21; q21) translocations in mucosal lymphoid tissue (MALT) induces proteolytic degradation of NF-kB-inducing kinase (NIK) in arginine residue 325 NIK disruption generates a C-terminal NIK fragment that retains kinase activity and is resistant to proteasomal degradation (due to loss of the TRAF-binding site). The presence of this processed NIK results in a constitutive non-canonical NF-kB signaling pathway, improved B-cell adhesion

- 1 037358 and resistance to apoptosis. Thus, the use of NIK inhibitors may represent a new approach to the treatment of difficult to treat t (11; 18) -positive MALT lymphoma (Rosebeck et al. Science 2011, 331, 468-472).

NIK aberrantly accumulates in diffuse large diffuse B-cell lymphoma (DLBCL) cells due to constitutive activation of B-cell activation factor (BAFF) when interacting with an autochthonous (ubiquitous) B-lymphocyte stimulator ligand (BLyS). NIK accumulation in human DLBCL cell lines and in patient tumor samples means that constitutive activation of NIK kinase is likely a key signaling mechanism involved in abnormal proliferation of lymphoma tumor cells. Growth studies showed that the use of shRNA to inhibit the expression of the NIK kinase protein in GCB- and ABC-like DLBCL cells inhibited the growth of 1 N lymphoma cells in vitro; NIK-induced activation of the NFKB signaling pathway is implicitly implicated in DLBCL cell proliferation (Pham et al. Blood 2011, 117, 200-210).

Recently, the loss of functional mutations in TRAF3 has been characterized in human and canine DLBCL cells (Bushell et al., Blood 2015, 125, 999-1005).

Similar mutations in the non-canonical NFkB signaling pathway (TRAF2, TRAF3, NIK, BIRC3) have also been found in ibrutinib-resistant lymphoma cell lines from the mantle zone (Rahal et al., Nat Med 2014, 1, 87-92).

As mentioned, the role of NIK in tumor cell proliferation is not limited to hematological cells, there is evidence that the level of the NIK protein is stabilized in some pancreatic cells and, as seen in the proliferation of blood cells, these pancreatic cancer cells are susceptible to siRNA NIK treatment ( Nishina et al Biochem Bioph Res Co. 2009, 388, 96-101). Constitutive activation of the NF-kB signaling pathway is preferentially involved in the proliferation of basal-like subtype breast cancer cells, including increased levels of the NIK protein in specific lines (Yamamoto et al. Cancer Sci. 2010, 101, 2391-2397). The tissue matrix method in analyzing the expression of NIK in melanoma tissues revealed that there was a statistically significant increase in NIK expression when compared with benign tissue. Moreover, shRNA technology was used to knock down NIK, the resulting NIK-depleted melanoma cell lines were characterized by reduced proliferation, enhanced apoptosis, delayed cell cycle progression, and decreased tumor growth in a mouse xenograft model (Thu et al. Oncogene 2012, 31 (20) , 2580-92). A wealth of data has shown that NF-κB is often constitutively activated in tissue samples and cell lines of non-small cell lung cancer. NIK depletion in mRNA-induced apoptosis influenced the efficiency of anchorage-free growth of NSCLC cells.

In addition, studies have shown that NF-κB regulates the expression of many genes involved in inflammation, and that the NF-κB signaling pathway is persistently active in many inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, sepsis, and other diseases. Thus, pharmaceutical agents capable of inhibiting NIK while interrupting the NF-kB signaling pathway may have a therapeutic advantage in the treatment of diseases and disorders in which there is an excessive activation of the NF-kB signaling pathway.

Dysregulated NF-κB activity is associated with inflammation and colon cancer, and NLRP12-deficient mice have been shown to be highly susceptible to colon cancer caused by or associated with colitis. In this context, studies have shown that NLRP12 functions as a negative regulator of the NF-kB signaling pathway in its interaction and regulation of NIK and TRAF3 and as a checkpoint of critical signaling pathways associated with inflammation and tumor associated with inflammation (Allen et al. Immunity 2012 , 36, 742-754).

Tumor necrosis factor (TNF) -a is secreted in response to the stimulating effect of inflammation in diseases such as rheumatoid arthritis and inflammatory bowel disease. In a number of experiments with epithelial cells of the colon and with embryonic fibroblasts, TNF-α mediates both apoptosis and inflammation by stimulating the inflammatory cascade along the noncanonical signaling pathway of NF-kB activation, leading to increased nuclear RelB and p52. TNF-α induced ubiquitination of TRAFs, which interacts with NIK, resulting in 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), and NIK has been shown to play a key role in worsening disease following infection with the non-typed gram-negative bacteria Hemophilus influenza (Shuto et al. PNAS 2001, 98, 8774-8779) ... Likewise, cigarette smoke (CS) contains numerous reactive oxygen / nitrogen compounds, reactive aldehydes and quinones, which are considered one of the most important causes of the pathogenesis of chronic inflammatory lung diseases such as COPD and lung cancer. Elevated levels of NIK and p-IKKa were observed in the peripheral lungs of smokers and COPD patients. In addition, it has been shown that endogenous NIK is recruited to the promoter sites of proinflammatory genes to induce 2037358 stranslational histone modification, while modifying gene expression profiles in response to CS or TNFa (Chung et al. PLoS ONE 2011, 6 (8) : e23488.doi: 10.1371 / journal.pone.0023488). ShRNA screening was used in a 1 N vitro model of oxidative stress-induced cell death (as a COPD model) to investigate a drug-amenable human shRNA genomic library to identify genes that modulate the cellular response to stress. NIK was one of the genes identified in this screening as a potential novel therapeutic agent targeting the modulation of epithelial apoptosis in chronic lung diseases (Wixted et al. Toxicol. 1 N Vitro 2010, 24, 310-318).

Patients with diabetes may be concerned about a number of additional manifestations associated with inflammation. One of these manifestations is cardiovascular disease, it has been shown that there are increased levels of p-NIK, p-IKK-a / e and p-IKB-a in the tissues of the diabetic aorta (Bitar et al. Life Sci. 2010, 86, 844-853). Similarly, NIK has been shown to regulate the pro-inflammatory responses of renal proximal tubular epithelial cells through a TRAF3-mediated mechanism. This demonstrates the role of activation of the non-canonical NF-kB signaling pathway in modulating diabetes-induced inflammation in renal tubular epithelial cells (Zhao et al. Exp. Diabetes Res. 2011, 1-9). The same group of researchers showed that NIK plays a critical role in activating the non-canonical NF-KB signaling pathway that induces skeletal muscle insulin resistance 1 N vitro, suggesting that NIK may 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-kB is an important component of both the autoimmune system and bone destruction in rheumatoid arthritis (RA). Mice lacking a functional NIK lack peripheral lymph nodes, defective B and T cells, and an impaired NF-kB receptor activator for ligand-stimulated osteoclastogenesis. Aya et al. (J. Clin. Invest. 2005, 115, 1848-1854) investigated the role of NIK in mouse models of inflammatory arthritis using Nik - / - mice. The serum transfusion arthritis model was initiated with pre-formed antibodies and required only intact neutrophil and complement systems in recipients. While Nik - / - mice had inflammation equivalent to that of Nik + / + control mice, they had 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. In addition, transfer of Nik + / + splenocytes or Rag2 - / - T cells to mice conferred susceptibility to AIA, while transfer of Nik - / - cells did not. Nik - / - mice were also resistant to the genetic spontaneous form of arthritis generated in mice expressing both the KRN T cell receptor and H-2g7. The same group of researchers used transgenic mice with Ocellular NIK expression with its missing binding domain TRAF3 (NT3) to show that constitutive NIK activation induces increased osteoclastogenesis and bone resorption under basal conditions and in response to inflammatory stimuli (Yang et al. PLoS ONE 2010, e15383.doi: 10.1371 / journal.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 NIK levels in T cells may have therapeutic implications. Reducing NIK activity in T cells can significantly improve autoimmune responses and allogeneic immune responses, such as GVHD (graft versus host reaction), and graft rejection without disrupting the immune system, as canonical NF-kB activation inhibitors do.

WO 2003030909 describes the preparation of 2- and 4-aminopyridines N-substituted with a bicyclic ring for use as kinase inhibitors in the treatment of cancer.

WO 2002079197 discloses 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 relates to new compounds of formula (I)

their tautomers and stereoisomeric forms, where R ¹ denotes C _1-4 αalkyl;

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R ² is C _1-6 alkyl or C _1-6 alkyl substituted with one R ⁵ ;

Y is CR ⁴ or N;

R ⁴ is hydrogen or halogen;

R ⁵ is halogen, Het ^3a , —NR ^6a R ^6b or —OR ⁷ ;

R ^6a is hydrogen or C _1-4 alkyl;

R ^6b is hydrogen, C1-4alkyl, C3-6cycloalkyl; -C (= O) -C1-4alkyl; -C (= O) -Het ⁴ ; -S (= O) 2-C _1-4 alkyl; —C (= O) —C _1-4 alkyl substituted with one substituent selected from the group consisting of —OH and —NR ^16a R ^16b ; or C _1-4 alkyl substituted with one substituent selected from the group consisting of —OH and —S (= O) ₂ —C _1-4 alkyl;

R ⁷ denotes hydrogen, C1-4 alkyl, -C1-4alkyl-NR ^8a R ^8b , -C (= O) -R ⁹ , -S (= O) 2-OH, -P (= O) ₂ -OH, - (C = O) -CH (NH ₂ ) -C _1-4 alkyl-Ar ¹ or -C _1-4 alkyl-Het ^3b ;

R ^8a is hydrogen or C _1-4 alkyl;

R ^8b is hydrogen, C _1-4 alkyl or C _3-6 cycloalkyl;

R ⁹ is C _1-6 alkyl or C _1-6 alkyl substituted with one substituent selected from the group consisting of —NH ₂ , —COOH and Het ⁶ ;

R ^16a and R ^16b are each independently hydrogen, C _1-4 alkyl or C _3-6 cycloalkyl;

R ³ is phenyl optionally substituted with one, two or three substituents, each of which is independently selected from the group consisting of halogen; cyano; C1-6alkyl; -O-C1-4alkyl; -C (= O) -R ¹⁰ ; -S (= O) 2 -C _1-4 alkyl; -S (= O) (= NR ^20a ) -C1-4alkyl; -O-C1-4alkyl substituted with one, two, three halogen atoms; -O-C1-4alkyl-K / ² ; C3-6cycloalkyl; —O — C _3-6 cycloalkyl; Het ^1a ; -O-Het ^1b ; R ¹⁸ ; R ²¹ ; -P (= O) - (C1-4alkyl) 2; -NH-C (= O) -C1-4alkyl; -NH-C (= O) -Het ^1g ; -NR ^17a R ^17b ; C1-4alkyl substituted with one, two, three halogen atoms; C1-4alkyl substituted with one, two, three substituents —OH; C _1-4 alkyl substituted with one R ¹³ ; C1-4alkyl substituted with one R ¹⁸ ; C2-6 alkenyl; C _2-6 alkenyl substituted with one R ¹³ ; C _2-6 alkynyl and C _2-6 alkynyl substituted with one R ¹³ ;

R ¹⁰ is —OH, —O — C _1-4 alkyl, —NR ^11a R ^11b, or Het ² ;

R ¹⁸ denotes a 5-membered aromatic ring containing one, two or three N atoms; wherein said 5-membered aromatic ring may be optionally substituted with one substituent selected from the group consisting of C _1-4 alkyl and C _3-6 cycloalkyl;

R ²¹ is 3,6-dihydro-2H-pyran-4-yl or 1,2,3,6-tetrahydro-4-pyridinyl, where 1,2,3,6tetrahydro-4-pyridinyl may be optionally substituted at the N atom C _1-4 alkyl or C _3-6 cycloalkyl;

Het ^1a , Het ^1c and Het ^1d each independently represent a 4-7 membered monocyclic saturated heterocyclic radical containing one or two heteroatoms independently selected from O, S, S (= O) _p and N; or a 6-11 membered bicyclic saturated heterocyclic radical including fused, spiro and bridging rings containing one, two or three heteroatoms independently selected from O, S, S (= O) p and N;

wherein said 4-7-membered monocyclic saturated heterocyclic radical or said 6-11-membered bicyclic saturated heterocyclic radical may be optionally substituted, where possible, on one, two or three ring atoms with N substituents, each of which is independently selected from the group consisting of C _1-4 alkyl, C _3-6 cycloalkyl and C _1-4 alkyl substituted with one substituent selected from the group consisting of —OH and —C _1-4 alkyl; and said 4-7 membered monocyclic saturated heterocyclyl or said 6-11 membered bicyclic saturated heterocyclyl may be optionally substituted at one, two or three ring C atoms with one or two substituents, each independently selected from the group consisting of -OH , halogen, C _1-4 alkyl, cyano, -C (= O) -C _1-4 alkyl, -O-C _1-4 alkyl, -NH ₂ , -NH (C _1-4 alkyl) and -N ( _C1-4 alkyl) ₂ ;

Het ^1b , Het ^1e , Het ^1g , Het ⁴ , Het ⁷ and Het ⁸ each independently represent a 4-7 membered monocyclic saturated heterocyclic radical attached to the remainder of the molecule of a compound of formula (I) through any available ring carbon atom, wherein said Het ^1b , Het ^1e , Het ^1g , Het ⁴ , Het ⁷ and Het ⁸ contain one or two heteroatoms, each independently selected from O, S, S (= O) _p and N; and said 4-7 membered monocyclic saturated heterocyclic radical may be optionally substituted, where possible, on one or two ring atoms with N substituents, each independently selected from the group consisting of C _1-4 alkyl, C _3-6 cycloalkyl and C _1-4 alkyl substituted with one substituent selected from the group consisting of —OH and —OC _1-4 alkyl; and said 4-7 membered monocyclic saturated heterocyclic radical may be optionally substituted at one, two or three C ring atoms with one or two substituents, each independently selected from the group consisting of —OH, halogen, C _1-4 alkyl, cyano, —C (= O) —C _1-4 alkyl, —O — C _1-4 alkyl, —NH ₂ , —NH (C _1-4 alkyl) and —N (C _1-4 alkyl) ₂ ;

- 4 037358

Het ² represents a heterocyclic radical of formula (b-1)

(b-1) is an N-linked 4-7 membered monocyclic saturated heterocyclic radical optionally containing one additional heteroatom selected from O, S, S (= O) p and N, or an N-linked 6-11 membered bicyclic saturated heterocyclic radical, including fused, spiro-fused and bridged rings, optionally containing one or two heteroatoms, each of which is independently selected from O, S, S (= O) p and N;

where in the case where (b-1) contains one or two additional N atoms, said one or two N atoms may be optionally substituted by substituents, each of which is independently selected from the group consisting of Cl _-4 alkyl, C _3-6 cycloalkyl and Het ⁷ ; and wherein (b-1) may optionally be substituted at one, two or three ring carbon atoms with one or two substituents each independently selected from the group consisting of halogen, -OH, cyano, C1 _-4 alkyl, -O- C1 _-4 alkyl, -NH _2, -NH (Cl _-4 alkyl), -N (Cl _-4 alkyl) ₂ and C _1-4 alkyl-OH;

R ^11b is hydrogen; Het ^1e ; C1-4alkyl; -C1-4alkyl-Het ⁵ ; -C1-4alkyl-Het ⁸ ; C _1-4 alkyl substituted with one, two or three substituents each independently selected from the group consisting of halogen, —OH, and —O — C _1-4 alkyl; C _3-6 cycloalkyl or C _3-6 cycloalkyl substituted with one, two or three substituents, each independently selected from the group consisting of halogen, —OH, and —OC _1-4 alkyl;

R ¹³ is —O — C1-4 alkyl, —C (= O) NR ^15a R ^15b , —NR ^19a R ^19b , C3-6 cycloalkyl, Het ^1d or —C (= O) —Het ^1f ;

R ¹² denotes -OH, -O-C ^ alkyl, -NR ^14a R ^14b , -C (= O) NR ^14c R ^14d , -S (= O) 2-C1-4 alkyl, -S (= O) (= NR ^20b ) —C 1-4 alkyl, C _3-6 cycloalkyl, Ar ² or Het ^1c ;

Ar ¹ is phenyl optionally substituted with one hydroxyl group;

Ar ² is phenyl optionally substituted with one C _1-4 alkyl;

Het ^3a , Het ^3b , Het ⁵ , Het ⁶ and Het ^1f each independently represent a heterocyclic radical of formula (c-1)

(c-1) is an N-linked 4-7 membered monocyclic saturated heterocyclic radical optionally containing one additional heteroatom selected from O, S, S (= O) _p and N;

moreover, when (c-1) contains one additional N atom, said additional N atom may be optionally substituted with C1-4 alkyl or C3-6 cycloalkyl; and (c-1) may optionally be substituted on one or two of the C ring atoms with one or two substituents each independently selected from the group consisting of halogen, C _1-4 alkyl, or C _3-6 cycloalkyl;

^{R 11a, R1 4a, R1 4c} , R1 5a, R1 7a and R ^19a, each independently represent hydrogen or C _1-4 alkul;

R ^14b , R ^14d , R ^15b , R ^17b and R ^19b are each independently hydrogen, C _1-4 alkyl; C _3-6 cycloalkyl; -C (= O) -C _1-4 alkyl; C _1-4 alkyl substituted with one substituent selected from the group consisting of halogen, —OH, and —O — C _1-4 alkyl; -C (= O) -C _1-4 alkyl substituted with one substituent selected from the group consisting of halogen, -OH and -O-C _1-4 alkyl, or -S (= O) ₂ -C _1-4 alkyl ;

R ^20a and R ^20b each independently represent hydrogen, C _1-4 alkyl; C _3-6 cycloalkyl or C _1-4 alkyl substituted with one substituent selected from the group consisting of —OH and —O — C _1-4 alkyl;

p is 1 or 2;

and a pharmaceutically acceptable addition salt or solvate 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 solvate thereof, and a pharmaceutically acceptable carrier or excipient.

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

In a specific embodiment, this invention relates to a compound of formula (I), a pharmaceutically acceptable addition salt thereof or a solvate thereof for use in the treatment or prevention of hematological malignancies or solid tumors (solid cancer).

In a specific embodiment, said hematologic malignancy is selected from the group consisting of multiple myeloma, Hodgkin's lymphoma, T-cell leukemia, and bladder carcinoma.

The present invention also relates to the use of a compound of formula (I), a pharmaceutically acceptable addition salt thereof or a solvate thereof in combination with an additional pharmaceutical agent for use in the treatment or prevention of cancer, inflammatory diseases, autoimmune diseases and metabolic disorders such as diabetes or obesity.

In addition, the present invention relates to a method for preparing a pharmaceutical composition according to the invention, characterized in that a pharmaceutically acceptable carrier is thoroughly mixed with a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable addition salt thereof or a solvate thereof.

This invention also relates to a product containing a compound of formula (I), a pharmaceutically acceptable addition salt or 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 diseases, autoimmune diseases and metabolic disorders such as diabetes or obesity.

In addition, this invention relates to a method for the treatment or prevention of a cell proliferative disease in a warm-blooded animal, which comprises administering to said animal an effective amount of a compound of formula (I), a pharmaceutically acceptable addition salt or a solvate thereof, or a pharmaceutical composition or combination as defined in this application.

Certain compounds of the invention can be metabolized to give the more active 1 N vivo form (prodrug).

Detailed description of the invention

The term halo or halogen as used in this application means fluorine, chlorine, bromine and iodine.

The prefix Cx _-y (where x and y are integers) as used herein refers to the number of carbon atoms in a given group. Thus, C1 _-6 alkyl group contains from 1 to 6 carbon atoms, C _3-6 cycloalkyl group contains from 3 to 6 carbon atoms, etc.

The term C _1-4 alkyl used in this application to indicate a group or part of a group means a linear or branched saturated hydrocarbon radical used in this application having from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl , n-butyl, sec-butyl, tert-butyl and the like.

The term _1-6 alkyl, as used herein to indicate a group or part of a group, means a linear or branched saturated hydrocarbon radical used in this application having from 1 to 6 carbon atoms, such as the groups defined for C _1-4 alkyl, and n-pentyl, nhexyl, 2-methylbutyl and the like.

The term C _2-6 alkenyl, as used herein to indicate a group or part of a group, means a linear or branched hydrocarbon radical used in this application having from 2 to 6 carbon atoms and containing a carbon-carbon double bond, such as, without limitation , ethenyl, propenyl, butenyl, pentenyl, 1-propen-2-yl, hexenyl and the like.

The term C _2-6 alkynyl, as used herein to indicate a group or part of a group, means a linear or branched hydrocarbon radical used in this application having from 2 to 6 carbon atoms and containing a carbon-carbon triple bond.

The term C _3-6 cycloalkyl as used herein to indicate a group or part of a group means a linear or branched saturated hydrocarbon radical used in this application having from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In general, wherever the term substituted is used in this application, it means, unless otherwise indicated or indicated by the context, that one or more hydrogen atoms, in particular from 1 to 4 hydrogen atoms, more preferably from 1 to 3 atoms hydrogen, even more preferably 1 or 2 hydrogen atoms, even more preferably 1 hydrogen atom, at the atom or radical indicated in the expression with the word substituted are substituted by the selected indicated group, provided that the normal valence is not exceeded and that the substitution leads to a chemically stable a compound, that is, a compound that is strong enough to withstand isolation from the reaction mixture to an acceptable degree of purity and production of a therapeutic agent therefrom.

Combinations of substituents and / or variables are only permitted if such combinations lead to chemically stable compounds. The term “stable compound” means that the compound is strong enough to withstand isolation from the reaction mixture to an acceptable degree of purity and production of a therapeutic agent therefrom.

A person skilled in the art knows that the term optionally substituted means that an atom or radical indicated in an expression containing the term optionally substituted may or may not be substituted (meaning substituted or unsubstituted, respectively).

When a moiety contains two or more substituents, they can, where possible and unless otherwise indicated or indicated by the context, substitute hydrogen atoms on the same atom, or they can replace hydrogen atoms on different atoms of this moiety.

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It is clear to those skilled in the art that unless otherwise indicated or indicated by the context, a substituent on a heterocyclic group may substitute for a hydrogen atom on a ring carbon atom or on a ring heteroatom (for example, a hydrogen atom on a nitrogen atom may be replaced with a substituent), for example, in saturated heterocyclic groups or in 5-membered aromatic rings as defined in the definition of R ¹⁸ .

C (O) or C (= O) represents a carbonyl group.

S (= O) ₂ or SO2 represents a sulfonyl group.

It is clear to the specialist that -S (= O) (= NR ^20a ) -C _1-4 α-alkyl corresponds to the formula o and ---- S — C- | _ ₄ alkyl% ^20а

In the context of this invention, the term saturated means fully saturated2 ', unless otherwise indicated.

Het ^1a , Het ^1c and Het ^1d can be attached to the remainder of the molecule of the compound of formula (I) through any available ring carbon or nitrogen atom, as appropriate, unless otherwise indicated.

A 5-membered aromatic ring containing one, two or three N atoms, as defined in the definition of R ¹⁸ , can be attached to the remainder of the molecule of formula (I) through any available ring carbon or nitrogen atom as appropriate, unless otherwise indicated ...

It is understood that in the case where a saturated cyclic group is substituted on two ring carbon atoms by one substituent, in both moieties bonded to carbon atoms, the substituents are in the saturated cyclic group (one substituent on each carbon atom).

It is understood that in the case where a saturated cyclic group is substituted on two ring carbon atoms by two substituents, in four moieties bonded to carbon atoms, the substituents are in the saturated cyclic group (two substituents on each carbon atom).

It is understood that in the case where a saturated cyclic group is substituted at three ring carbon atoms by two substituents, in six moieties bonded to carbon atoms, the substituents are in the saturated cyclic group (two substituents at each carbon atom).

It is understood that in the case where a saturated cyclic group is substituted on two ring atoms with N substituents, the two substituents bonded to the nitrogen atom are in the saturated cyclic group (one substituent for each N atom).

It is clear that a saturated cyclic group may, where possible, be substituted on both carbon and nitrogen atoms, unless otherwise indicated or otherwise indicated by the context.

In the context of the present invention, bicyclic saturated heterocyclic groups include fused, spiro-fused and bridged saturated heterocycles.

Fused bicyclic groups are two rings that contain two common atoms and a bond between those atoms.

Bicyclic spiro compounds are two rings linked at one atom.

Bridging bicyclic groups are two rings that contain more than two atoms in common.

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

etc.

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

etc.

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

etc.

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One skilled in the art will appreciate that the definitions of Het ^1a , Het ^1c and Het ^1d also include Attached bicycles attached to the remainder of the molecule of a compound of formula (I) through any available ring carbon atom.

It will be appreciated that in accordance with any of the options, the exemplary bicyclic saturated heterocyclic groups described above may optionally be substituted, where possible, at carbon atoms and / or nitrogen atoms.

Non-limiting examples of 4-7 membered monocyclic saturated heterocyclic groups containing one or two heteroatoms, each independently selected from O, S, S (= O) p and N (as defined in the definition of Het ^1a , Het ^1c and Het ^1d ) are shown below

etc.

In accordance with any of the options, each of these groups may be optionally substituted, where possible, at carbon and / or nitrogen atoms.

Non-limiting examples of 4-7 membered monocyclic saturated heterocyclic groups attached to the rest of the molecule of formula (I) through any available ring carbon atom (C-attached) and containing one or two heteroatoms, each of which is independently selected from O, S, S (= O) _p and N (as defined in the definition of Het ^1b , Het ^1e , Het ^1g , Het ⁴ , Het ⁷ and Het ⁸ ) are shown below

etc.

In accordance with any of the options, each of these groups can be optionally substituted, where possible, at carbon and / or nitrogen atoms.

Non-limiting examples of 4-7 membered monocyclic saturated heterocyclic groups optionally containing one additional heteroatom selected from O, S, S (= O) _p and N (as defined in the definition of (b-1) and (c-1)), shown below

etc.

In accordance with any of the options, each of these groups may be optionally substituted, where possible, at carbon and / or nitrogen atoms

Non-limiting examples of 5-membered aromatic rings containing one, two or three N atoms as defined in the definition of R ¹⁸ are shown below.

etc.

In accordance with any of the options, each of these groups can be optionally substituted, where possible, at carbon and / or nitrogen atoms.

When substituents are represented by chemical structures, means the bond by which they are attached to the rest of the molecule of the compound of formula (I).

Lines (such as ---) connecting to ring systems indicate that a bond can connect a substituent to any of the suitable ring atoms.

When any variable occurs more than once in any structural component, each of its definitions is independent.

- 8 037358

When any variable occurs more than once in any formula (for example, in formula (I)), each of its definitions is independent.

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

The term therapeutically effective amount as used in this application means that the amount of active compound or pharmaceutical agent that elicits a biological or medical response in the tissue system in an animal or human that is the subject of medical attention of a researcher, veterinarian, physician or clinician, results in relief or relief of symptoms of the disease or disorder being treated.

The term composition encompasses a product containing specific ingredients in specific amounts, as well as any product that is obtained directly or indirectly by combining specific ingredients in specific amounts.

The term treatment, as used in this application, refers to all processes where there can be a slowdown, interruption, arrest or cessation of the development of the disease, but does not necessarily indicate the complete disappearance of all symptoms.

The term compound (s) according to (this) invention or compound (s) for (this) invention as used in this application means that it includes compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates.

As used in this application, any chemical formula with bonds shown only as a solid line and not in the form of wedge-shaped or dotted lines, or otherwise shown as having a particular configuration (e.g., R, S) around one or more atoms, means any possible a stereoisomer or a mixture of two or more stereoisomers.

Earlier and hereinafter in this application, the term compound (s) of formula (I) means that it includes the tautomers of this compound and its stereoisomeric forms.

The terms stereoisomers, stereoisomeric forms or stereochemically isomeric forms above and below are used interchangeably in this application.

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

Enantiomers are stereoisomers, which are mirror images of each other that are not aligned in space. A 1: 1 mixture of a pair of enantiomers is a racemate or racemic mixture.

Atropisomers (or atropisomers) are stereoisomers that have a particular spatial configuration resulting from limited rotation around a simple bond due to large steric hindrances. All atropisomeric forms of the compounds of formula (I) are included within the scope of this invention.

Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, that is, they are not mirror images.

If the compound contains a double bond, the substituents can be in the E- or Z-configuration.

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

Therefore, the present invention includes enantiomers, atropisomers, diastereomers, racemates, E-isomers, Z-isomers, cis-isomers, trans-isomers, or mixtures thereof, where possible from a chemical point of view.

The meaning of all these terms, ie enantiomers, atropisomers, diastereomers, racemates, Eisomers, Z-isomers, cis-isomers, trans-isomers, or mixtures thereof, are well known to those skilled in the art.

The absolute configuration is indicated according to the CahnIngold-Prelog system. The configuration at an asymmetric atom is denoted either R or S. Separated stereoisomers, the absolute configuration of which is not known, can be denoted (+) or (-) depending on the direction in which they rotate the plane of polarization of the light. For example, separated enantiomers, the absolute configuration of which is not known, may be designated (+) or (-) depending on the direction in which they rotate the plane of polarization of the light.

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

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Some of the compounds of formula (I) may also exist in their tautomeric forms. Such forms, if they may exist, although not explicitly indicated in formula (I) above, are included within the scope of this invention. Thus, one compound can exist in both stereoisomeric and tautomeric forms.

Pharmaceutically acceptable addition salts include acid addition salts and base addition salts. Such salts can be prepared by conventional means, for example, by reacting the free acid or free base with one or more equivalents of the corresponding acid or base, optionally in a solvent medium or in an environment in which the salt is insoluble, followed by removal of said solvent or said medium with using standard methods (e.g. vacuum, freeze drying or filtration). Salts can also be prepared by exchanging a counterion of a compound of the invention in salt form with another counterion, for example using a suitable ion exchange resin.

The pharmaceutically acceptable addition salts mentioned above or below in this application include the salts of a therapeutically active non-toxic acid and base which the compounds of formula (I) and their solvates are capable of forming.

Suitable acids include, for example, inorganic acids such as hydrohalic acids, for example hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids, such as, for example, acetic, propane, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic acid, ethanesulfonic acid benzenesulfonic acid, p-toluenesulfonic acid, cyclamic, salicylic, p-aminosalicylic, pamic and the like acids. Salt forms can be converted by treatment with an appropriate base to the free base.

The compounds of formula (I) and their acidic proton-containing solvates can be converted into their non-toxic metal or amine addition salt by treatment with appropriate organic and inorganic bases.

Suitable base addition salts include, for example, ammonium salts, alkali and alkaline earth metal salts, for example, lithium, sodium, potassium, magnesium, calcium and the like, salts with organic bases, for example, primary, secondary and tertiary amines such as methylamine , ethylamine, propylamine, isopropylamine, four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropydinolamine, pyrrolidine; benzathine, N-methyl-D-glucamine, hydrabamine salts and salts with amino acids such as, for example, arginine, lysine and the like. Such a salt form can be converted to a free acidic form by treatment with an acid.

The term solvate refers to the forms of addition of solvents as well as their salts which the compounds of formula (I) are capable of forming. Examples of such forms of solvent addition are, for example, hydrates, alcoholates and the like.

The compounds of the invention obtained by the methods described below can be synthesized as mixtures of enantiomers, in particular specific racemic mixtures of enantiomers, which can be separated from one another using the following known resolution methods. The method for separating the enantiomeric forms of the compounds of formula (I) and their pharmaceutically acceptable salts and solvates 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 corresponding starting materials, provided that the reaction proceeds stereospecifically. It is preferred, if a particular stereoisomer is desired, to synthesize said compound by stereospecific methods of preparation. These methods use predominantly enantiomerically pure starting materials.

The present invention also encompasses isotopically labeled compounds of the invention that are identical to those described herein, but with one or more atoms replaced by an atom having an atomic mass or mass number other than the atomic mass or mass number normally found in nature.

All isotopes and mixtures of isotopes of any particular atom or element specified in this application are within the scope of this invention, they can be of natural origin or obtained by synthetic methods, or common in nature or in isotopically enriched form. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as ² H, ³ H, C. ¹³ C, ¹⁴ C, ¹³ N , ¹⁵ O, ¹⁷ O, ¹⁸ O, ³² P, ³³ P, ³⁵ S, ¹⁸ F, ³⁶ Cl, ¹²² I, ¹²³ I, ¹²⁵ I, ¹³¹ I, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br and ⁸² Br. Preferably, the radioactive isotope is selected from the group consisting of ² H, ³ H, 11C and ¹⁸ F. More preferably, the radioactive isotope is ² H. In particular, deuterated compounds are included within the scope of the present invention.

Certain isotopically labeled compounds of the invention (eg labeled with ³ H and ¹⁴ C) are suitable for use in assays of compound distribution in substrate tissues. The isotopes labeled with tritium ( ³ H) and carbon-14 ( ¹⁴ C) are useful because of their ease of preparation and detection. In addition, substitution with heavy isotopes such as deuterium (i.e., ² H) may provide some therapeutic benefits resulting from greater metabolic stability (e.g., increased vivo 1 N elimination half-life or reduced dosing requirements) and therefore in some circumstances may be preferable. Positron active isotopes such as ¹⁵ O, ¹³ N, 11C and ¹⁸ F are useful in positron emission tomography (PET) to investigate substrate receptor occupancy.

The present invention relates, in particular, to the compounds of formula (I) specified in this application, their tautomers and stereoisomeric forms, where R ¹ denotes C _1-4 alkyl;

R ² is C _1-6 alkyl or C _1-6 alkyl substituted with one R ⁵ ;

Y is CR ⁴ ;

R ⁴ is hydrogen or halogen;

R ⁵ is Het ^3a , —NR ^6a R ^6b or —OR ⁷ ;

R ^6a is hydrogen or C _1-4 alkyl;

R ^6b is hydrogen, C1-4alkyl, C3-6cycloalkyl; -C (= O) -C1-4alkyl; -C (= O) -Het ⁴ ; -S (= O) 2 -C _1-4 alkyl; —C (= O) —C _1-4 alkyl substituted with one substituent selected from the group consisting of —OH and —NR ^16a R ^16b ; or C _1-4 alkyl substituted with one substituent selected from the group consisting of —OH and —S (= O) ₂ —C _1-4 alkyl;

R ⁷ denotes hydrogen, C1-4 alkyl, -C1-4alkyl-NR ^8a R ^8b , -C (= O) -R ⁹ , -S (= O) 2-OH, -P (= O) ₂ -OH, - (C = O) -CH (NH ₂ ) -C _1-4 alkyl-Ar ¹ or -C _1-4 alkyl-Het ^3b ;

R ^8a is hydrogen or C _1-4 alkyl;

R ^8b is hydrogen, C _1-4 alkyl or C _3-6 cycloalkyl;

R ⁹ is C _1-6 alkyl or C _1-6 alkyl substituted with one substituent selected from the group consisting of —NH ₂ , —COOH and Het ⁶ ;

R ^16a and R ^16b are each independently hydrogen, C _1-4 alkyl or C _3-6 cycloalkyl;

R ³ is phenyl optionally substituted with one, two or three substituents, each of which is independently selected from the group consisting of halogen; cyano; C1-6alkyl; -O-C1-4alkyl; -C (= O) -R ¹⁰ ; -S (= O) 2 -C _1-4 alkyl; -S (= O) (= NR ^20a ) -C1-4alkyl; —O — C1-4 alkyl substituted with one, two or three halogen atoms; -O-C1-4alkyl-K ¹² ; C3-6cycloalkyl; —O — C _3-6 cycloalkyl; Het ^1a ; -O-Het ^1b ; R ¹⁸ ; R ²¹ ; -P (= O) - (C1-4alkyl) 2; -NH-C (= O) -C1-4alkyl; -NH-C (= O) -Het ^1g ; -NR ^17a R ^17b ; C1-4 alkyl substituted with one, two or three halogen atoms; C _1-4 alkyl substituted with one, two or three —OH groups; C _1-4 alkyl substituted with one R ¹³ ; C1-4alkyl substituted with one R ¹⁸ ; C2-6 alkenyl; C _2-6 alkenyl substituted with one R ¹³ ;

R ¹⁰ is —OH, —O — C _1-4 alkyl, —NR ^11a R ^11b, or Het ² ;

R ¹⁸ denotes a 5-membered aromatic ring containing one, two or three N atoms; wherein said 5-membered aromatic ring may be optionally substituted with one substituent selected from the group consisting of C _1-4 alkyl and C _3-6 cycloalkyl;

R ²¹ is 3,6-dihydro-2H-pyran-4-yl or 1,2,3,6-tetrahydro-4-pyridinyl, where 1,2,3,6tetrahydro-4-pyridinyl may optionally be substituted at NC _1-4 alkyl or C _3-6 cycloalkyl;

Het ^1a , Het ^1c and Het ^1d each independently represent a 4-7 membered monocyclic saturated heterocyclic radical containing one or two heteroatoms, each independently selected from O, S, S (= O) _p and N; or a 6-11 membered bicyclic saturated heterocyclic radical including fused, spiro fused and bridged rings containing one, two or three heteroatoms, each independently selected from O, S, S (= O) p and N;

wherein said 4-7 membered monocyclic saturated heterocyclic radical or said 6-11 membered bicyclic saturated heterocyclic radical may optionally be substituted, where possible, on one, two or three ring nitrogen atoms with substituents, each of which is independently selected from the group consisting of C _1-4 alkyl, C _3-6 cycloalkyl and C1 ₄ alkyl substituted with one substituent selected from the group consisting of —OH and C _1-4 alkyl; and wherein said 4-7 membered monocyclic saturated heterocyclic radical or said 6-11 membered bicyclic saturated heterocyclic radical may optionally be substituted on one, two or three C ring atoms with one or two substituents, each of which is independently selected from the group consisting of from —OH, halogen, C _1-4 alkyl, cyano, —C (= O) —C _1-4 alkyl, —O — C _1-4 alkyl, —NH ₂ , —NH (C _1-4 alkyl) and -N ( _C1-4 alkyl) ₂ ;

Het ^1b , Het ^1c , Het ^1g and Het ⁴ each independently represent a 4-7 membered monocyclic saturated heterocyclic radical attached to the remainder of the molecule of a compound of formula (I) through any available ring carbon atom, said Het ^1b , Het ^1c , Het ^1g and Het ⁴ contain one or two heteroatoms, each of which is independently selected from O, S, S (= O) _p and N;

and where said 4-7 membered monocyclic saturated heterocyclic radical may

- 11 037358 be optionally substituted, where possible, on one or two ring atoms with N substituents, each of which is independently selected from the group consisting of C _1-4 alkyl, C _3-6 cycloalkyl and

C _1-4 alkyl, C _1-4 alkyl substituted with one substituent selected from the group consisting of —OH and

-OC _1-4 alkyl; and wherein said 4-7 membered monocyclic saturated heterocyclic radical may be optionally substituted on one, two or three C ring atoms with one or two substituents, each independently selected from the group consisting of —OH, halogen, C _1-4 alkyl , cyano, —C (= O) —C _1-4 alkyl, —O — C _1-4 alkyl, —NH2, —NH (C _1-4 alkyl) and —N (C _1-4 alkyl) ₂ ;

Het ² represents a heterocyclic radical of formula (b-1)

(b-1) is an N-linked 4-7 membered monocyclic saturated heterocyclic radical optionally containing one additional heteroatom selected from O, S, S (= O) p and N, or an N-linked 6-11 membered bicyclic saturated heterocyclic radical including fused, spiro-fused and bridged rings, optionally containing one or two additional heteroatoms, each independently selected from O, S, S (= O) p and N;

where in the case where (b-1) contains one or two additional N atoms, said one or two N atoms may be optionally substituted with C _1-4 alkyl, and where (b-1) may be optionally substituted on one, two or three C ring atoms with one or two substituents, each of which is independently selected from the group consisting of halogen, -OH, cyano, C _1-4 alkyl, -O-C _1-4 alkyl, -NH2, -NH (C _{1- 4} alkyl), —N (C _1-4 alkyl) ₂ and C _1-4 alkyl-OH;

R ^11b is hydrogen; Het ^1e ; C1-4alkyl; -C1-4alkyl-Het ⁵ ; C1-4alkyl substituted with one, two or three substituents each independently selected from the group consisting of halogen, —OH, and —O — C _1-4 alkyl; C _3-6 cycloalkyl; or C _3-6 cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halogen, —OH, and —O — C1-4 alkyl;

R ¹³ is —O — C1-4 alkyl, —C (= O) NR ^15a R ^15b , —NR ^19a R ^19b , C3-6 cycloalkyl, Het ^1d or —C (= O) —Het ^1f ;

R ¹² is —OH, —O — C ^ alkyl, —NR ^14a R ^14b , —C (= O) NR ^14c R ^14d , —S (= O) 2-C1-4 alkyl,

-S (= O) (= NR ^20b ) -C _1-4 alkyl, C _3-6 cycloalkyl, Ar ² or Het ^1c ;

Ar ¹ is phenyl optionally substituted with one hydroxyl group;

Ar ² is phenyl optionally substituted with one C _1-4 alkyl;

Het ^3a , Het ^3b , Het ⁵ , Het ⁶ and Het ^1f are each independently a heterocyclyl of formula (c-1)

(c-1) is an N-linked 4-7 membered monocyclic saturated heterocyclic radical optionally containing one additional heteroatom selected from O, S, S (= O) p and N;

moreover, when (c-1) contains one additional N atom, said additional N atom may be optionally substituted with C _1-4 alkyl or C _3-6 cycloalkyl; and (c-1) may optionally be substituted on one or two of the C ring atoms with one or two substituents each independently selected from the group consisting of halogen, C _1-4 alkyl, or C _3-6 cycloalkyl;

R ^11a , R ^14a , R ^14c , R ^15a , R ^17a and R ^19a are each independently hydrogen or C _1-4 alkyl;

R ^14b , R ^14d , R ^15b , R ^17b and R ^19b are each independently hydrogen; C _1-4 alkyl; C _3-6 cycloalkyl; or C _1-4 alkyl substituted with one substituent selected from the group consisting of halogen, —OH, and —O — C _1-4 alkyl;

R ^20a and R ^20b are each independently hydrogen, C _1-4 alkyl; C _3-6 cycloalkyl or C _1-4 alkyl substituted with one substituent selected from the group consisting of —OH and —O — C1-4 alkyl;

p is 1 or 2;

and their pharmaceutically acceptable addition salts and their solvates.

The present invention relates, in particular, to the compounds of formula (I) described in this application, their tautomers and stereoisomeric forms, where R ¹ denotes C _1-4 alkyl;

R ² is C _1-6 alkyl or C _1-6 alkyl substituted with one R ⁵ ;

Y is CR ⁴ or N;

R ⁴ is hydrogen or halogen;

R ⁵ is halogen, Het ^3a , —NR ^6a R ^6b or —OR ⁷ ;

R ^6a is hydrogen or C _1-4 alkyl;

R ^6b is hydrogen, C1-4alkyl, C3-6cycloalkyl; -C (= O) -C1-4alkyl; -S (= O) 2-C1-4 alkyl; —C (= O) —C1-4alkyl substituted with one substituent selected from the group consisting of —OH and —NR ^16a R ^16b ; or C1-4alkyl substituted with one substituent selected from the group consisting of —OH and

- 12 037358

-S (= O) ₂ -C _1-4 alkyl;

R ⁷ denotes hydrogen, C1-4 alkyl, -C1-4alkyl-NR ^8a R ^8b , -C (= O) -R ⁹ , -S (= O) 2-OH, -P (= O) ₂ -OH,

- (C = O) -CH (PN ₂ ) -C _1-4 alkyl-Ar1 or -C _1-4 alkyl-Het ^3b ;

R ^8a is hydrogen or C _1-4 alkyl;

R ^8b is hydrogen, C _1-4 alkyl or C _3-6 cycloalkyl;

R ⁹ is C _1-4 alkyl or C _1-4 alkyl substituted with one substituent selected from the group consisting of —NH2, —COOH and Het ⁶ ;

R ^16a and R ^16b are each independently hydrogen, C _1-4 alkyl or C _3-6 cycloalkyl;

R ³ is phenyl optionally substituted with one, two or three substituents, each of which is independently selected from the group consisting of halogen; cyano; C1-6alkyl; -O-C1-4alkyl; -C (= O) -R ¹⁰ ; -S (= O) 2 -C _1-4 alkyl; -S (= O) (= NR ^20a ) -C1-4alkyl; -O-C1-4alkyl, -C (= O) -R ¹⁰ ; -S (= O) 2-C _1-4 alkyl; -S (= O) (= NR ^20a ) -C1-4alkyl; —O — C1-4 alkyl substituted with one, two or three halogen atoms; -O-C1-4alkyl-I ¹² ; C3-6 cycloalkyl; -O-C _3-6 -cycloalkyl; Het ^1a ; -O-Het ^1b ; R ¹⁸ ; R ²¹ ; -P (= O) - (C1-4alkyl) 2; -NH-C (= O) -C1-4alkyl; -NH-C (= O) -Het ^1g ; -NR ^17a R ^17b ; C1-4alkyl substituted with one, two, three halogen atoms; C _1-4 alkyl substituted with one, two, three -OH groups; C _1-4 alkyl substituted with one R ¹³ ; C1-4alkyl substituted with one R ¹⁸ ; C2-6 alkenyl; C _2-6 alkenyl substituted with one R ¹³ ; C _2-6 alkynyl and C _2-6 alkynyl substituted with one R ¹³ ;

R ¹⁰ is —OH, —O — C _1-4 alkyl, —NR ^11a R ^11b, or Het ² ;

R ¹⁸ is 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 _1-4 alkyl and C _3-6 cycloalkyl ;

R ²¹ is 3,6-dihydro-2H-pyran-4-yl or 1,2,3,6-tetrahydro-4-pyridinyl, while 1,2,3,6tetrahydro-4-pyridinyl may be substituted at the NC atom _1-4 alkyl or C _3-6 cycloalkyl;

Het ^1a , Het ^1c and Het ^1d each independently represent a 4-7 membered monocyclic heterocyclic group containing one or two heteroatoms, each independently selected from O, S, S (= O) p and N;

wherein said 4-7 membered monocyclic heterocyclic group may optionally be substituted, where possible, on one or two ring atoms with N substituents, each independently selected from the group consisting of C _1-4 alkyl, C _3-6 cycloalkyl ; and C _1-4 alkyl substituted with one substituent selected from the group consisting of —OH and —O — C _1-4 alkyl;

and wherein said 4-7 membered monocyclic heterocyclic group may optionally be substituted on one, two or three C ring atoms with one or two substituents, each independently selected from the group consisting of —OH, halogen, C _1-4 alkyl , cyano, —C (= O) —C _1-4 alkyl, —O — C _1-4 alkyl, —NH2, —NH (C _1-4 alkyl) and —N (C _1-4 alkyl) ₂ ;

Het ^1b , Het ^1e , Het ^1g , Het ⁷ and Het ⁸ each independently represent a 4-7 membered monocyclic saturated heterocyclic radical attached to the remainder of the molecule of a compound of formula (I) through any available ring carbon atom, said Het ^1b , Het ^1e , Het ^1g , Het ⁷ and Het ⁸ contain one or two heteroatoms, each independently selected from O, S, S (= O) _p and N;

and said 4-7 membered monocyclic saturated heterocyclic radical may be optionally substituted, where possible, on one or two ring atoms with N substituents, each independently selected from the group consisting of C _1-4 alkyl, C _3-6 cycloalkyl and C _1-4 alkyl substituted with one substituent selected from the group consisting of —OH and —OC _1-4 alkyl;

and said 4-7 membered monocyclic saturated heterocyclic radical may be optionally substituted at one, two or three C ring atoms with one or two substituents, each independently selected from the group consisting of —OH, halogen, C _1-4 alkyl, cyano, —C (= O) —C _1-4 alkyl, —O — C _1-4 alkyl, —NH2, —NH (C _1-4 alkyl) and —N (C _1-4 alkyl) ₂ ;

Het ² represents a heterocyclic radical of formula (b-1)

(b-1) is an N-linked 4-7 membered monocyclic saturated heterocyclic radical optionally containing one additional heteroatom selected from O, S, S (= O) _p and N, or an N-linked 6-11 membered bicyclic saturated heterocyclic radical, including fused, spiro-fused and bridged rings, optionally containing one or two additional heteroatoms, each of which is independently selected from O, S, S (= O) p and N;

where in the case where (b-1) contains one or two additional N atoms, said one or two N atoms may be optionally substituted by substituents, each of which is independently selected from the group consisting of C _1-4 alkyl, C _3-6 cycloalkyl and Het ⁷ ; and wherein (b-1) may be optionally substituted on one, two or three C ring atoms with one or two substituents, each independently selected from the group consisting of halogen, —OH, cyano, C _1-4 alkyl, —O —C _1-4 alkyl, —NH2, —NH (C _1-4 alkyl), —N (C _1-4 alkyl) _2, and C _1-4 alkyl-OH;

- 13 037358

R ^11b is hydrogen; Het ^1e ; C1-4alkyl; -C1-4alkyl-Het ⁵ ; -C1-4alkyl-Het ⁸ ; C _1-4 alkyl substituted with one, two or three substituents each independently selected from the group consisting of halogen, —OH, and —O — C _1-4 alkyl; C _3-6 cycloalkyl; or C _3-6 cycloalkyl substituted with one, two or three substituents, each of which is independently selected from the group consisting of halogen, —OH and

—O — C _1-4 alkyl;

R ¹³ is —O — C1-4 alkyl, —C (= O) NR ^15a R ^15b , —NR ^19a R ^19b , C3-6 cycloalkyl, Het ^1d or —C (= O) —Het ^1f ;

R ¹² is —OH, —O — C1-4 alkyl, —NR ^14a R ^14b , —C (= O) NR ^14c R ^14d , —S (= O) 2 — C _1-4 alkyl,

-S (= O) (= NR ^20b ) -C _1-4 alkyl, C _3-6 cycloalkyl, Ar ² or Het ^1c ;

Ar ¹ is phenyl optionally substituted with one hydroxyl group;

Ar ² is phenyl optionally substituted with one C _1-4 alkyl;

Het ^3a , Het ^3b , Het ⁵ , Het ⁶ and Het ^1f each independently represent a heterocyclic radical of formula (c-1)

(c-1) is an N-linked 4-7 membered monocyclic saturated heterocyclic radical optionally containing one additional heteroatom selected from O, S, S (= O) p and N; moreover, when (c-1) contains one additional N atom, said additional N atom may be optionally substituted with C _1-4 alkyl or C _3-6 cycloalkyl;

and where (c-1) may optionally be substituted on one or two of the C ring atoms with one or two substituents, each of which is independently selected from the group consisting of halogen, C _1-4 alkyl, or C _3-6 cycloalkyl;

R ^11a , R ^14a , r ^i4c , R ^15a , R ^17a and R ^19a are each independently hydrogen or C _1-4 alkyl;

R ^14b , R ^14d , R ^15b , R ^17b and R ^19b are each independently hydrogen, C _1-4 alkyl; C _3-6 cycloalkyl; -C (= O) -C _1-4 alkyl; C _1-4 alkyl substituted with one substituent selected from the group consisting of halogen, —OH, and —O — C _1-4 alkyl; -C (= O) -C _1-4 alkyl substituted with one substituent selected from the group consisting of halogen, -OH and -O-C _1-4 alkyl, or -S (= O) ₂ -C _1-4 alkyl ;

R ^20a and R ^20b each independently represent hydrogen, C _1-4 alkyl; C _3-6 cycloalkyl or C _1-4 alkyl substituted with one substituent selected from the group consisting of —OH and —O — C _1-4 alkyl;

p is 1 or 2;

and their pharmaceutically acceptable addition salts and solvates.

The present invention relates, in particular, to compounds of formula (I) given in this application, their tautomers and stereoisomeric forms, where R ¹ denotes C _1-4 alkyl;

R ² is C _1-6 alkyl or C _1-6 alkyl substituted with one R ⁵ ;

Y is CR ⁴ ;

R ⁴ is hydrogen or halogen;

R ⁵ is Het ^3a , —NR ^6a R ^6b or —OR ⁷ ;

R ^6a is hydrogen or C _1-4 alkyl;

R ^6b is hydrogen, C1-4alkyl, C3-6cycloalkyl; -C (= O) -C1-4alkyl; -S (= O) 2-C1-4 alkyl; —C (= O) —C1-4alkyl substituted with one substituent selected from the group consisting of —OH and —NR ^16a R ^16b ; or C1-4alkyl substituted with one substituent selected from the group consisting of —OH and —S (= O) ₂ —C _1-4 alkyl;

R ⁷ denotes hydrogen, C1-4 alkyl, -C1-4alkyl-NR ^8a R ^8b , -C (= O) -R ⁹ , -S (= O) 2-OH, -P (= O) ₂ -OH, - (C = O) -CH (NH ₂ ) -C _1-4 alkyl-Ar ¹ or —C _1-4 alkyl-Het ^3b ;

R ^8a is hydrogen or C _1-4 alkyl;

R ^8b is hydrogen, C _1-4 alkyl or C _3-6 cycloalkyl;

R ⁹ is C _1-4 alkyl or C _1-4 alkyl substituted with one substituent selected from the group consisting of —NH2, —COOH and Het ⁶ ;

R ^16a and R ^16b are each independently hydrogen, C _1-4 alkyl or C _3-6 cycloalkyl;

R ³ is phenyl optionally substituted with one, two or three substituents, each of which is independently selected from the group consisting of halogen; cyano; C1-6alkyl; -O-C1-4alkyl; -C (= O) -R ¹⁰ ; -S (= O) 2-C _1-4 alkyl; -S (= O) (= NR ^20a ) -C1-4alkyl; —O — C1-4 alkyl substituted with one, two or three halogen atoms; -O-C1-4alkyl-R ¹² ; C3-6cycloalkyl; —O — C _3-6 cycloalkyl; Het ^1a ; -O-Het ^1b ; R ¹⁸ ; R ²¹ ; -P (= O) - (C1-4alkyl) 2; -NH-C (= O) -C1-4alkyl; -NH-C (= O) -Het ^1g ; -NR ^17a R ^17b ; C1-4alkyl substituted with one, two or three halogen atoms; C1-4alkyl substituted with one, two or three —OH groups; C _1-4 alkyl substituted with one R ¹³ ; C1-4alkyl substituted with one R ¹⁸ ; C2-6 alkenyl and C _2-6 alkenyl substituted with one R ¹³ ;

R ¹⁰ is —OH, —O — C _1-4 alkyl, —NR ^11a R ^11b, or Het ² ;

R ¹⁸ denotes a 5-membered aromatic ring containing one, two or three N atoms; moreover, the specified 5-membered aromatic ring may be optionally substituted with one substituent selected from the group consisting of C _1-4 alkyl and C _3-6 cycloalkyl;

- 14 037358

R ²¹ is 3,6-dihydro-2H-pyran-4-yl or 1,2,3,6-tetrahydro-4-pyridinyl, while 1,2,3,6tetrahydro-4-pyridinyl may optionally be substituted at N C _1-4 alkyl or C _3-6 cycloalkyl;

Het ^1a , Het ^1c and Het ^1d each independently represent a 4-7 membered monocyclic heterocyclic group containing one or two heteroatoms, each independently selected from O, S, S (= O) p and N;

wherein said 4-7 membered monocyclic saturated heterocyclic radical may be optionally substituted, where possible, on one or two ring atoms with N substituents, each independently selected from the group consisting of C _1-4 alkyl, C _3-6 cycloalkyl and C _1-4 alkyl substituted with one substituent selected from the group consisting of —OH and —O — C _1-4 alkyl;

and wherein the 4-7 membered monocyclic saturated heterocyclic radical may be optionally substituted at one, two or three C ring atoms with one or two substituents, each independently selected from the group consisting of —OH, halogen, C _1-4 alkyl , cyano, —C (= O) —C _1-4 alkyl, —O — C _1-4 alkyl, —NH ₂ , —NH (C _1-4 alkyl) and —N (C _1-4 alkyl) ₂ ;

Het ^1b , Het ^1e and Het ^1g each independently represent a 4-7 membered monocyclic saturated heterocyclic radical attached to the remainder of the molecule of a compound of formula (I) through any available ring carbon atom, said Het ^1b , Het ^1e and Het ^1g contain one or two heteroatoms, each of which is independently selected from O, S, S (= O) _p and N;

and said 4-7 membered monocyclic saturated heterocyclic radical may be optionally substituted, where possible, on one or two ring atoms with N substituents, each independently selected from the group consisting of C _1-4 alkyl, C _3-6 cycloalkyl and C _1-4 alkyl, C _1-4 alkyl substituted with one substituent selected from the group consisting of —OH and —OC _1-4 alkyl; and wherein said 4-7 membered monocyclic saturated heterocyclic radical may be optionally substituted on one, two or three C ring atoms with one or two substituents, each independently selected from the group consisting of —OH, halogen, C _1-4 alkyl , cyano, —C (= O) —C _1-4 alkyl, —O — C _1-4 alkyl, —NH ₂ , —NH (C _1-4 alkyl) and —N (C _1-4 alkyl) ₂ ;

Het ² represents a heterocyclic radical of formula (b-1)

(b-1) is an N-linked 4-7 membered monocyclic saturated heterocyclic radical optionally containing one additional heteroatom selected from O, S, S (= O) _p and N, or an N-linked 6-11 membered bicyclic saturated heterocyclic radical including fused, spiro-fused and bridged rings and optionally containing one or two additional heteroatoms, each independently selected from O, S, S (= O) _p and N; and where in the case where (b-1) contains one or two additional N atoms, said one or two N atoms may be optionally substituted with C _1-4 alkyl;

where (b-1) may be optionally substituted on one, two or three ring C atoms with one or two substituents, each of which is independently selected from the group consisting of halogen, -OH, cyano, C _1-4 alkyl, -O- C _1-4 alkyl, —NH ₂ , —NH (C _1-4 alkyl), —N (C _1-4 alkyl) _2, and C _1-4 alkyl-OH;

R ^11b is hydrogen; Het ^1e ; C1-4alkyl; -C1-4alkyl-Het ⁵ ; C1-4alkyl substituted with one, two or three substituents each independently selected from the group consisting of halogen, —OH, and —O — C _1-4 alkyl; C _3-6 cycloalkyl or C _3-6 cycloalkyl substituted with one, two or three substituents, each independently selected from the group consisting of halogen, —OH, and C _1-4 alkyl;

R ¹³ is —O — C1-4 alkyl, —C (= O) NR ^15a R ^15b , —NR ^19a R ^19b , C3-6 cycloalkyl, Het ^1d or —C (= O) —Het ^1f ;

R ¹² is —OH, —O — C1-4 alkyl, —NR ^14a R ^14b , —C (= O) NR ^14c R ^14d , —S (= O) 2 — C _1-4 alkyl,

-S (= O) (= NR ^20b ) -C _1-4 alkyl, C _3-6 cycloalkyl, Ar ² or Het ^1c ;

Ar ¹ is phenyl optionally substituted with one hydroxyl group;

Ar ² is phenyl optionally substituted with one C _1-4 alkyl;

Het ^3a , Het ^3b , Het ⁵ , Het ⁶ and Het ^1f each independently represent a heterocyclic group of formula (c-1)

(c-1) is an N-linked 4-7 membered monocyclic saturated heterocyclic radical optionally containing one additional heteroatom selected from O, S, S (= O) _p and N; moreover, when (c-1) contains one additional N atom, said additional N atom may be optionally substituted with C _1-4 alkyl or C _3-6 cycloalkyl;

and where (c-1) may be optionally substituted on one or two of the C ring atoms with one or two substituents, each independently selected from the group consisting of halogen,

- 15 037358

C _1-4 alkyl or C _3-6 cycloalkyl;

R ^11a , R ^14a , R ^14c , R ^15a , R ^17a and R ^19a are each independently hydrogen or C _1-4 alkyl;

R ^14b , R ^14d , R ^15b , R ^17b and R ^19b are each independently hydrogen, C _1-4 alkyl; C _3-6 cycloalkyl or

C _1-4 alkyl substituted with one substituent selected from the group consisting of halogen, —OH, and

—O — C _1-4 alkyl;

R ^20a and R ^20b each independently represent hydrogen, C _1-4 alkyl; C _3-6 cycloalkyl or C _1-4 alkyl substituted with one substituent selected from the group consisting of —OH and —O — C _1-4 alkyl;

p is 1 or 2;

and their pharmaceutically acceptable addition salts and their solvates.

The present invention relates, in particular, to compounds of formula (I) given in this application, their tautomers and stereoisomeric forms, where R ¹ denotes C _1-4 alkyl;

R ² is C _1-6 alkyl or C _1-6 alkyl substituted with one R ⁵ ;

Y is CR ⁴ or N;

R ⁴ is hydrogen or halogen;

R ⁵ is halogen, Het ^3a , —NR ^6a R ^6b or —OR ⁷ ;

R ^6a is hydrogen or C _1-4 alkyl;

R ^6b is hydrogen, C1-4alkyl, C3-6cycloalkyl; -C (= O) -C1-4alkyl; -C (= O) -Het ⁴ ; -S (= O) 2-C _1-4 alkyl; —C (= O) —C _1-4 alkyl substituted with one substituent selected from the group consisting of —OH and —NR ^16a R ^16b ; or C _1-4 alkyl substituted with one substituent selected from the group consisting of —OH and —S (= O) ₂ —C _1-4 alkyl;

R ⁷ denotes hydrogen, C1-4 alkyl, -C1-4alkyl-NR ^8a R ^8b , -C (= O) -R ⁹ , -S (= O) 2-OH, -P (= O) ₂ -OH, - (C = O) -CH (NH ₂ ) -C _1-4 alkyl-Ar ¹ or C _1-4 alkyl-Het ^3b ;

R ^8a is hydrogen or C _1-4 alkyl;

R ^8b is hydrogen, C _1-4 alkyl or C _3-6 cycloalkyl;

R ⁹ is C _1-4 alkyl or C _1-4 alkyl substituted with one substituent selected from the group consisting of —NH ₂ , —COOH and Het ⁶ ;

R ^16a and R ^16b are each independently hydrogen, C _1-4 alkyl or C _3-6 cycloalkyl;

R ³ is phenyl optionally substituted with one, two or three substituents, each of which is independently selected from the group consisting of halogen; cyano; C1-6alkyl; -O-C1-4alkyl; -C (= O) -R ¹⁰ ; -S (= O) 2 -C _1-4 alkyl; -S (= O) (= NR ^20a ) -C1-4alkyl; —O — C1-4 alkyl substituted with one, two or three halogen atoms; -O-C1-4alkyl-R ¹² ; C3-6cycloalkyl; —O — C _3-6 cycloalkyl; Het ^1a ; -O-Het ^1b ; R ¹⁸ ; R ²¹ ; -P (= O) - (C1-4alkyl) 2; -NH-C (= O) -C1-4alkyl; -NH-C (= O) -Het ^1g ; -NR ^17a R ^17b ; C1-4alkyl substituted with one, two or three halogen atoms; C1-4alkyl substituted with one, two or three —OH groups; C1-4alkyl substituted with one R ¹³ ; C1-4alkyl substituted with one R ¹⁸ ; C2-6 alkynyl and C2-6 alkynyl substituted with one R ¹³ ;

R ¹⁰ is —OH, —OC _1-4 alkyl, —NR ^11a R ^11b or Het ² ;

R ¹⁸ denotes 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 _1-4 alkyl and C _3-6 cycloalkyl;

R ²¹ is 3,6-dihydro-2H-pyran-4-yl or 1,2,3,6-tetrahydro-4-pyridinyl, while 1,2,3,6tetrahydro-4-pyridinyl may be optionally substituted at NC _1-4 alkyl or C 3-6 cycloalkyl;

Het ^1a , Het ^1c and Het ^1d each independently represent a 4-7 membered monocyclic saturated heterocyclic radical containing one or two heteroatoms, each independently selected from O, S, S (= O) _p and N; or a 6-11 membered bicyclic saturated heterocyclic radical including fused, spiro fused and bridged rings containing one, two or three heteroatoms, each independently selected from O, S, S (= O) p and N; O, S, S (= O) p and N;

wherein said 4-7-membered monocyclic saturated heterocyclic radical or 611-membered bicyclic saturated heterocyclic radical may optionally be substituted, where possible, on one, two or three ring atoms with N substituents, each of which is independently selected from the group consisting of C _1-4 alkyl, C _3-6 cycloalkyl; and C _1-4 alkyl substituted with one substituent selected from the group consisting of —OH and —OC _1-4 alkyl; and wherein said 4-7 membered monocyclic saturated heterocyclic radical or 611 membered bicyclic saturated heterocyclic radical may optionally be substituted on one, two or three C ring atoms with one substituent independently selected from the group consisting of —OH, halogen, C _1-4 alkyl, cyano, —C (= O) —C _1-4 alkyl, —O — C _1-4 alkyl, —NH ₂ , —NH (C _1-4 alkyl) and —N (C _{1- 4} alkyl) ₂ ;

Het ^1b , Het ^1e , Het ^1g , Het ⁴ , Het ⁷ and Het ⁸ each independently represent a 4-7 membered monocyclic saturated heterocyclic radical attached to the remainder of the molecule of a compound of formula (I) through any available ring carbon atom, wherein said Het ^1b , Het ^1e , Het ^1g , Het ⁴ , Het ⁷ and Het ⁸ contain one or two heteroatoms, each of which is independently selected from O, S, S (= O) _p and

- 16 037358

N;

wherein said 4-7 membered monocyclic saturated heterocyclic radical may be optionally substituted, where possible, on one or two ring atoms with an N substituent, each independently selected from the group consisting of C _1-4 alkyl, C _3-6 cycloalkyl and C _1-4 alkyl substituted with one substituent selected from the group consisting of —OH and —O — C _1-4 alkyl;

and wherein said 4-7 membered monocyclic saturated heterocyclic radical may be optionally substituted at one, two or three C ring atoms with one substituent, each independently selected from the group consisting of —OH, halogen, C _1-4 alkyl, cyano , —C (= O) —C _1-4 alkyl, —O — C _1-4 alkyl, —NH2, —NH (C _1-4 alkyl) and —N (C _1-4 alkyl) ₂ ;

Het ² represents a heterocyclic radical of formula (b-1)

(b-1) is an N-linked 4-7 membered monocyclic saturated heterocyclic radical optionally containing one additional heteroatom selected from O, S, S (= O) p and N, or an N-linked 6-11 membered bicyclic saturated heterocyclyl, including fused, spiro-fused and bridged rings, optionally containing one or two additional heteroatoms, each independently selected from O, S, S (= O) _p and N;

where in case (b-1) contains one or two additional N heteroatoms, said one or two N atoms may be optionally substituted with a substituent independently selected from the group consisting of C _1-4 alkyl, C _3-6 cycloalkyl and Het ⁷ ; and wherein (b-1) may be optionally substituted on one, two or three C ring atoms with one substituent independently selected from the group consisting of halogen, —OH, cyano, C _1-4 alkyl, —O — C _{1- 4} alkyl, —NH2, —NH (C _1-4 alkyl), —N (C _1-4 alkyl) and C _1-4 alkyl-OH;

R ^11b is hydrogen; Het ^1e ; C1-4alkyl; -C1-4alkyl-Het ⁵ ; -C1-4alkyl-Het ⁸ ; C _1-4 alkyl substituted with one, two or three substituents each independently selected from the group consisting of halogen, —OH, and —O — C _1-4 alkyl; C _3-6 cycloalkyl or C _3-6 cycloalkyl substituted with one, two or three substituents, each independently selected from the group consisting of halogen, —OH, and —O — C _1-4 alkyl;

R ¹³ is —O — C1-4 alkyl, —C (= O) NR ^15a R ^15b , —NR ^19a R ^19b , C3-6 cycloalkyl, Het ^1d or —C (= O) —Het ^1f ;

R ¹² is —OH, —O — C1-4 alkyl, —NR ^14a R ^14b , —C (= O) NR ^14c R ^14d , —S (= O) 2 — OC _1-4 alkyl,

-S (= O) (= NR ^20b ) -O-C _1-4 alkyl, C _3-6 cycloalkyl, Ar ² or Het ^1c ;

Ar ¹ is phenyl optionally substituted with one hydroxyl group;

Ar ² represents phenyl optionally substituted with one C1 _-4 alkyl;

Het ^3a , Het ^3b , Het ⁵ , Het ⁶ and Het ^1f each independently represent a heterocyclic radical of formula (c-1)

(c-1) is an N-linked 4-7 membered monocyclic saturated heterocyclic radical optionally containing one additional heteroatom selected from O, S, S (= O) p and N;

moreover, when (c-1) contains one additional N atom, said additional N atom may be optionally substituted with C1-4 alkyl or C3-6 cycloalkyl;

and (c-1) may optionally be substituted at one or two ring carbon atoms with one substituent, each independently selected from the group consisting of halogen, C1 _-4 alkyl or C3-6 cycloalkyl;

R ^11a , R1 ^4a , R1 ^4c , R1 ^5a , R1 ^7a and R ^19a are each independently hydrogen or _C1-4 alkyl;

R ^14b , R ^14d , R ^15b , R ^17b and R ^19b are each independently hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl; -C (= O) -C _1-4 alkyl; C _1-4 alkyl substituted with one substituent selected from the group consisting of halogen, —OH, and —O — C _1-4 alkyl; -C (= O) -C _1-4 alkyl substituted with one substituent selected from the group consisting of halogen, -OH and -O-C _1-4 alkyl, or -S (= O) ₂ -C _1-4 alkyl ;

R ^20a and R ^20b are each independently hydrogen; C _1-4 alkyl; C _3-6 cycloalkyl or C _1-4 alkyl substituted with one substituent selected from the group consisting of —OH and —O — C _1-4 alkyl;

p is 1 or 2;

and to their pharmaceutically acceptable addition salts and solvates.

The present invention relates, in particular, to compounds of formula (I) given in this application, their tautomers and stereoisomeric forms, where R ¹ denotes C _1-4 alkyl;

R ² is C _1-6 alkyl or C _1-6 alkyl substituted with one R ⁵ ;

Y is CR ⁴ ;

R ⁴ is hydrogen or halogen;

- 17 037358

R ⁵ is Het ^3a , —NR ^6a R ^6b or —OR ⁷ ;

R ^6a is hydrogen or C _1-4 alkyl;

R ^6b is hydrogen or C1-4 alkyl; C3-6cycloalkyl; -C (= O) -C1-4alkyl; -C (= O) -Het ⁴ ; -S (= O) 2-C _1-4 alkyl; —C (= O) —C _1-4 alkyl substituted with one substituent selected from the group thereof consisting of —OH and —NR ^16a R ^16b ; or C _1-4 alkyl substituted with one substituent selected from the group consisting of OH and —S (= O) ₂ —C _1-4 alkyl;

R ⁷ denotes hydrogen, C1-4 alkyl, -C1-4alkyl-NR ^8a R ^8b , -C (= O) -R ⁹ , -S (= O) 2-OH, -P (= O) ₂ -OH, - (C = O) -CH (NH ₂ ) -C _1-4 alkyl-Ar ¹ or —C _1-4 alkyl-Het ^3b ;

R ^8a is hydrogen or C _1-4 alkyl;

R ^8b is hydrogen, C _1-4 alkyl or C _3-6 cycloalkyl;

R ⁹ is C _1-4 alkyl, or C _1-4 alkyl substituted with one substituent selected from the group thereof consisting of —NH2, —COOH and Het ⁶ ;

R ^16a and R ^16b are each independently hydrogen, C _1-4 alkyl or C _3-6 cycloalkyl;

R ³ is phenyl optionally substituted with one, two or three substituents, each of which is independently selected from the group consisting of halogen; cyano; C1-6alkyl; -O-C1-4alkyl; -C (= O) -R ¹⁰ ; -S (= O) 2-C _1-4 alkyl; -S (= O) (= NR ^20a ) -C1-4alkyl; —O — C1-4 alkyl substituted with one, two or three halogen atoms; -O-C1-4alkyl-K? ² ; C3-6cycloalkyl; —O — C _3-6 cycloalkyl; Het ^1a ; -O-Het ^1b ; R ¹⁸ ; R ²¹ ; -P (= O) - (C1-4alkyl) 2; -NH-C (= O) -C1-4alkyl; -NH-C (= O) -Het ^1g ; -NR ^17a R ^17b ; C1-4alkyl substituted with one, two or three halogen atoms; C _1-4 alkyl substituted with one, two or three —OH groups; C _1-4 alkyl substituted with one R ¹³ ; C1-4alkyl substituted with one R ¹⁸ ; C2-6 alkenyl and C _2-6 alkenyl substituted with one R ¹³ ;

R ¹⁰ is —OH, —O — C _1-4 alkyl, —NR ^11a R ^11b, or Het ² ;

R ¹⁸ denotes a 5-membered aromatic ring containing one, two or three N atoms; moreover, the specified 5-membered aromatic ring may be optionally substituted with one substituent selected from the group consisting of C _1-4 alkyl and C _3-6 cycloalkyl;

R ²¹ is 3,6-dihydro-2H-pyran-4-yl or 1,2,3,6-tetrahydro-4-pyridinyl, while 1,2,3,6tetrahydro-4-pyridinyl may optionally be substituted at NC _1-4 alkyl or C _3-6 cycloalkyl;

Het ^1a , Het ^1c and Het ^1d each independently represent a 4-7 membered monocyclic saturated heterocyclic radical containing one or two heteroatoms, each independently selected from O, S, S (= O) _p and N; or a 6-11 membered bicyclic saturated heterocyclic radical including fused, spiro fused and bridged rings containing one, two or three heteroatoms, each independently selected from O, S, S (= O) p and N; O, S, S (= O) p and N;

wherein said 4-7-membered monocyclic saturated heterocyclic radical or 6-11-membered bicyclic saturated heterocyclic radical may optionally be substituted, where possible, on one, two or three ring atoms with N substituents, each of which is independently selected from the group, consisting of C1-4 alkyl, C3-6 cycloalkyl and C1-4 alkyl substituted with one substituent selected from the group consisting of —OH and —OC _1-4 alkyl;

and wherein said 4-7 membered monocyclic saturated heterocyclic radical or 6-11 membered bicyclic saturated heterocyclic radical may optionally be substituted on one, two or three ring atoms by N with a substituent independently selected from the group consisting of —OH and - O-C _1-4 alkyl; and wherein said 4-7 membered monocyclic heterocyclic radical or 6-11 membered bicyclic saturated heterocyclic radical may be optionally substituted on one, two or three ring atoms C with one substituent independently selected from the group consisting of -OH, halogen, C _1-4 alkyl, cyano, -C (= O) -C _1-4 alkyl, -O-C _1-4 alkyl, -NH2, -NH (C _1-4 alkyl) and -N (C _1-4 alkyl ) ₂ ;

Het ^1b , Het ^1e , Het ^1g and Het ⁴ each independently represent a 4-7 membered monocyclic saturated heterocyclic radical attached to the remainder of the molecule of a compound of formula (I) through any available ring carbon atom, wherein said Het ^1b , Het ^1e , Het ^1g and Het ⁴ contain one or two heteroatoms, each independently selected from O, S, S (= O) _p and N;

wherein said 4-7 membered monocyclic saturated heterocyclic radical may be optionally substituted, where possible, on one or two N atoms with a substituent independently selected from the group consisting of C _1-4 alkyl, C _3-6 cycloalkyl and C _{1- 4} alkyl substituted with one substituent selected from the group consisting of —OH and —O — C1-4 alkyl;

and wherein said 4-7 membered monocyclic saturated heterocyclic radical may be optionally substituted on one, two or three C ring atoms with one substituent independently selected from the group consisting of —OH, halogen, C _1-4 alkyl, cyano, —C (= O) —C _1-4 alkyl, —OC _1-4 alkyl, —NH2, —NH (C _1-4 alkyl) and —N (C _1-4 alkyl) ₂ ;

- 18 037358

Het ² represents a heterocyclic group of formula (b-1)

(b-1) is an N-linked 4-7 membered monocyclic saturated heterocyclic radical optionally containing one additional heteroatom selected from O, S, S (= O) p and N, or an N-linked 6-11 membered bicyclic saturated heterocyclyl, including fused, spiro-fused and bridged rings, optionally containing one or two additional heteroatoms, each independently selected from O, S, S (= O) p and N;

where in the case where (b-1) contains one or two additional N atoms, said one or two N atoms may be optionally substituted with C _1-4 alkyl; and where (b-1) may be optionally substituted at one, two or three C atoms with one substituent independently selected from the group consisting of halogen, -OH, cyano, -C (= O) -Cl _-4 alkyl, -O —C1 _-4 alkyl, —NH2, —NH (Cl _-4 alkyl), —N (Cl _-4 alkyl) ₂ and C1 _-4 alkyl-OH;

R ^11b is hydrogen; Het ^1e ; C1-4alkyl; C1-4alkyl-Het ⁵ ; C1-4 alkyl substituted with one, two or three substituents each independently selected from the group consisting of halogen, —OH, and —O — C _1-4 alkyl; C _3-6 cycloalkyl or C _3-6 cycloalkyl substituted with one, two or three substituents, each independently selected from the group consisting of halogen, —OH, and —O — C _1-4 alkyl;

R ¹³ is —O — C1-4 alkyl, —C (= O) NR ^15a R ^15b , —NR ^19a R ^19b , C3-6 cycloalkyl, Het ^1d or —C (= O) —Het ^1f ;

R ¹² is —OH, —O — C1-4 alkyl, —NR ^14a R ^14b , —C (= O) NR ^14c R ^14d , —S (= O) 2 — OC _1-4 alkyl,

-S (= O) (= NR ^20b ) -OC _1-4 alkyl, C _3-6 cycloalkyl, Ar ² or Het ^1c ;

Ar ¹ is phenyl optionally substituted with one hydroxyl group;

Ar ² is phenyl optionally substituted with one C _1-4 alkyl;

Het ^3a , Het ^3b , Het ⁵ , Het ⁶ and Het ^1f each independently represent a heterocyclic radical of formula (c-1)

(c-1) is an N-linked 4-7 membered monocyclic saturated heterocyclic radical optionally containing one additional heteroatom selected from O, S, S (= O) p and N;

moreover, when (c-1) contains one additional N atom, said additional N atom may be optionally substituted with C _1-4 alkyl or C _3-6 cycloalkyl; and (c-1) may optionally be substituted on one or two of the C ring atoms with one substituent independently selected from the group consisting of halogen, C _1-4 alkyl, or C _3-6 cycloalkyl;

R ^11a , R1 ^4a , R1 ^4c , R1 ^5a , R1 ^7a and R ^19a are each independently hydrogen or _C1-4 alkyl;

R ^14b , R ^14d , R ^15b , R ^17b and R ^19b are each independently hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, or C _1-4 alkyl substituted with one substituent selected from the group consisting of halogen , —OH and —O — C _1-4 alkyl;

R ^20a and R ^20b are each independently hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, or C _1-4 alkyl substituted with one substituent selected from the group consisting of —OH and —O — C _1-4 alkyl;

p is 1 or 2;

and their pharmaceutically acceptable addition salts or their solvates.

The present invention relates, in particular, to compounds of formula (I) given in this application, their tautomers and stereoisomeric forms, where R ¹ denotes C _1-4 alkyl;

R ² is C _1-6 alkyl or C _1-4 alkyl substituted with one R ⁵ ;

Y is CR ⁴ or N;

R ⁴ is hydrogen or halogen;

R ⁵ is halogen, —NR ^6a R ^6b or —OR ⁷ ;

R ^6a is hydrogen or C _1-4 alkyl;

R ^6b is hydrogen; C1-4alkyl; C3-6cycloalkyl; -C (= O) -C1-4alkyl; -S (= O) 2-C1-4alkyl; —C (= O) —C1-4alkyl substituted with one substituent selected from the group consisting of —OH and —NR ^16a R ^16b ; or C1-4alkyl substituted with one substituent selected from the group consisting of the group consisting of —OH and —S (= O) ₂ —C _1-4 alkyl;

R ⁷ is hydrogen; C1-4alkyl, C1-4alkyl-NR ^8a R ^8b , -C (= O) -R ⁹ , -S (= O) 2-OH, -P (= O) ₂ -OH or - (C = O) - CH (NH2) -C1-4alkyl-Ar ¹ ;

R ^8a is hydrogen or C _1-4 alkyl;

R ^8b is hydrogen, C _1-4 alkyl or C _3-6 cycloalkyl;

R ⁹ is C _1-4 alkyl or C _1-4 alkyl substituted with one substituent selected from the group consisting of —NH ₂ and —COOH;

R ^16a and R ^16b are each independently hydrogen, C _1-4 alkyl or C _3-6 cycloalkyl;

R ³ denotes phenyl, optionally substituted with one, two or three substituents, each

- 19,037358 of which is independently selected from the group consisting of halogen; cyano; _C1-6 alkyl; -C (= O) -R ¹⁰ ; -S (= O) 2-C1-4alkyl; -S (= O) (= NR ^20a ) -C1-4alkyl; -OC _1-4 alkyl substituted with one, two or three halogen atoms; -O-C _1-4 alkyl-K ¹² ; C3-6cycloalkyl; -O-C3-6cycloalkyl; -P (= O) - (C1-4alkyl) 2; -NH-C (= O) -C1-4alkyl; -NR ^17a R ^17b ; C1-4 alkyl substituted with one, two or three halogen atoms; C _1-4 alkyl substituted with one, two or three —OH groups; C _1-4 alkyl substituted with one R ¹³ ; C _2-6 alkynyl and C _2-6 alkynyl substituted with one R ¹³ ;

R ¹⁰ is —OH, —O — C _1-4 alkyl or —NR ^11a R ^11b ;

R ^11b is hydrogen; C _1-4 alkyl; C _1-4 alkyl substituted with one, two or three substituents each independently selected from the group consisting of halogen, —OH, and —O — C _1-4 alkyl; C3-6 cycloalkyl or C3-6 cycloalkyl substituted with one, two or three substituents, each independently selected from the group consisting of halogen, —OH, and —O — C _1-4 alkyl;

R ¹³ is —O — C1-4 alkyl, —C (= O) NR ^15a R ^15b , —NR ^19a R ^19b or C3-6 cycloalkyl,

R ¹² means -OH, -O-C ^ alkyl, -NR ^14a R ^14b , -C (= O) NR ^14c R ^14d , -S (= O) 2-O-C1-4 alkyl, -S (= O) (= NR ^20b ) O — C _1-4 alkyl, C _3-6 cycloalkyl or Ar ² ;

Ar ¹ is phenyl optionally substituted with one hydroxyl group;

Ar ² is phenyl optionally substituted with one C _1-4 alkyl;

R ^11a , R1 ^4a , R1 ^4c , R1 ^5a , R1 ^7a and R1 ^9a are each independently hydrogen or _C1-4 alkyl;

R ^14b , R ^14d , R ^15b , R ^17b and R ^19b are each independently hydrogen; C _1-4 alkyl; C _3-6 cycloalkyl; -C (= O) -C _1-4 alkyl; C _1-4 alkyl substituted with one substituent selected from the group consisting of halogen, —OH, and —O — C _1-4 alkyl; —C (= O) —C _1-4 alkyl substituted with one substituent selected from the group consisting of halogen, —OH, and —C (= O) —C _1-4 alkyl; or —S (= O) ₂ —C _1-4 alkyl;

R ^20a and R ^20b are each independently hydrogen; C _1-4 alkyl; C _3-6 cycloalkyl or C _1-4 alkyl substituted with one substituent selected from the group consisting of —OH and —O — C _1-4 alkyl;

and their pharmaceutically acceptable addition salts and solvates.

The present invention relates, in particular, to compounds of formula (I) given in this application, their tautomers and stereoisomeric forms, where R ¹ denotes C _1-4 alkyl;

R ² is C _1-6 alkyl or C _1-6 alkyl substituted with one R ⁵ ; Y is CR ⁴ ; R ⁴ is hydrogen or halogen;

R ⁵ is —NR ^6a R ^6b or —OR ⁷ ;

R ^6a is hydrogen or C _1-4 alkyl;

R ^6b is hydrogen, C1-4 alkyl; C3-6cycloalkyl; -C (= O) -C1-4alkyl; -S (= O) 2-C1-4 alkyl; —C (= O) —C1-4alkyl substituted with one substituent selected from the group consisting of —OH and —NR ^16a R ^16b ; or C1-4 alkyl substituted with one substituent selected from the group consisting of —OH and S (= O) ₂ —C _1-4 alkyl;

R ⁷ denotes hydrogen, C1-4 alkyl, -C1-4alkyl-NR ^8a R ^8b , -C (= O) -R ⁹ , -S (= O) 2-OH, -P (= O) ₂ -OH or - (C = O) -CH (NH2) -C1-4alkyl-Ar ¹ ;

R ^8a is hydrogen or C _1-4 alkyl;

R ^8b is hydrogen, C _1-4 alkyl or C _3-6 cycloalkyl;

R ⁹ is C _1-4 alkyl or C _1-4 alkyl substituted with one substituent selected from the group consisting of —NH ₂ and —COOH;

R ^16a and R ^16b are each independently hydrogen, C _1-4 alkyl or C _3-6 cycloalkyl;

R ³ is phenyl optionally substituted with one, two or three substituents, each of which is independently selected from the group consisting of halogen; cyano; C1-6alkyl; -O-C1-4alkyl; -C (= O) -R ¹⁰ ; -S (= O) 2-C _1-4 alkyl; -S (= O) (= NR ^20a ) -C1-4alkyl; —O — C1-4 alkyl substituted with one, two or three halogen atoms; -O-C1-4alkyl-K ¹² ; C3-6cycloalkyl; —O — C _3-6 cycloalkyl; -P (= O) - (C1. ₄ alkyl) ₂ ; -NH-C (= O) -C _1-4 alkyl; -NR ^17a R ^17b ; C1-4alkyl substituted with one, two or three halogen atoms; C1-4alkyl substituted with one, two or three —OH groups; C1-4 alkyl substituted with one R ¹³ ; C2-6 alkenyl and C _2-6 alkenyl substituted with one R ¹³ ;

R ¹⁰ is —OH, —O — C _1-4 alkyl or —NR ^11a R ^11b ;

R ^11b is hydrogen; C _1-4 alkyl; C _1-4 alkyl substituted with one, two or three substituents each independently selected from halogen, —OH, and —O — C _1-4 alkyl; C _3-6 cycloalkyl or C _3-6 cycloalkyl substituted with one, two or three substituents, each independently selected from the group consisting of halogen, —OH, and —O — C _1-4 alkyl;

R ¹³ is -O-C1-4alkyl, -C (= O) NR ^15a R ^15b , -NR ^19a R ^19b or C3-6 cycloalkyl,

R ¹² denotes -OH, -O-C ^ alkyl, -NR ^14a R ^14b , -C (= O) NR ^14c R ^14d , -S (= O) 2-C1-4 alkyl,

-S (= O) (= NR ^20b ) -C _1-4 alkyl, C _3-6 cycloalkyl or Ar ² ;

Ar ¹ is phenyl optionally substituted with one hydroxyl group;

Ar ² is phenyl optionally substituted with one C _1-4 alkyl;

R ^11a , R ^14a , r ^i4c , R ^15a , R ^17a and R ^19a are each independently hydrogen or C _1-4 alkyl;

R ^14b , R ^14d , R ^15b , R ^17b and R ^19b are each independently hydrogen, C _1-4 alkyl; C _3-6 cycloalkyl or C _1-4 alkyl substituted with one substituent selected from the group consisting of halogen, —OH, and —OC _1-4 alkyl;

- 20 037358

R ^20a and R ^20b each independently represent hydrogen, C _1-4 alkyl; C _3-6 cycloalkyl or C _1-4 alkyl substituted with one substituent selected from the group consisting of —OH and —OC _1-4 alkyl;

and their pharmaceutically acceptable salts and solvates.

The present invention relates, in particular, to the compounds of formula (I) described in this application, their tautomers and stereoisomeric forms, where R ¹ denotes C _1-4 alkyl;

R ² is C _1-6 alkyl or C _1-6 alkyl substituted with one R ⁵ ;

Y is CR ⁴ or N;

R ⁴ is hydrogen or halogen;

R ⁵ is —NR ^6a R ^6b or —OR ⁷ ;

R ^6a is hydrogen;

R ^6b is —C (= O) —C _1-4 alkyl or —S (= O) ₂ —C _1-4 alkyl;

R ⁷ denotes hydrogen, -C1-4alkyl-NR ^8a R ^8b , -C (= O) -R ⁹ , -S (= O) 2-OH or - (C = O) -CH (NH ₂ ) -C _{1 -4} alkylAr ¹ ;

R ^8a is hydrogen;

R ^8b is C _3-6 cycloalkyl;

R ⁹ is C _1-6 alkyl or C _1-6 alkyl substituted with one substituent selected from the group consisting of —NH ₂ , —COOH and Het ⁶ ;

R ³ is phenyl optionally substituted with one, two or three substituents, each of which is independently selected from the group consisting of halogen; cyano; C1-6alkyl; -O-C1-4alkyl; -C (= O) -R ¹⁰ ; -S (= O) 2-C _1-4 alkyl; -O-C _1-4 alkyl-K? ² ; C3-6cycloalkyl; -O-C3-6cycloalkyl; Het ^1a ; -O-Het ^1b ; R ¹⁸ ; -P (= O) - (C1-4alkyl) ₂ ; -NH-C (= O) -C _1-4 alkyl; -NH-C (= O) -Het ^1g ; -NR ^17a R ^17b ; C1-4alkyl substituted with one, two or three halogen atoms; C1-4alkyl substituted with one, two or three —OH groups; C1-4 alkyl substituted with one R ¹³ ; C2-6 alkenyl substituted with one R ¹³ ; and C _2-6 alkynyl substituted with one R ¹³ ;

R ¹⁰ is —OH, —O — C _1-4 alkyl, —NR ^11a R ^11b, or Het ² ;

R ¹⁸ denotes a 5-membered aromatic ring containing one, two or three N atoms; wherein said 5-membered aromatic ring may be optionally substituted with one substituent selected from the group consisting of C _1-4 alkyl;

Het ^1a , Het ^1c and Het ^1d each independently represent a 4-7 membered monocyclic saturated heterocyclic radical containing one or two heteroatoms, each independently selected from O and N;

wherein said 4-7 membered monocyclic saturated heterocyclic radical may optionally be substituted at one, two or three C ring atoms with one or two substituents, each of which is independently selected from the group consisting of —OH, halogen, C _1-4 alkyl , —O — C _1-4 alkyl and —N (C _1-4 alkyl) ₂ ;

Het ^1b , Het ^1e , Het ^1g , Het ⁷ and Het ⁸ each independently represent a 4-7 membered monocyclic saturated heterocyclic radical attached to the remainder of the molecule of a compound of formula (I) through any available ring carbon atom, said Het ^1b , Het ^1e , Het ^1g , Het ⁷ and Het ⁸ contain one or two heteroatoms, each independently selected from O and N;

wherein said 4-7 membered monocyclic saturated heterocyclic radical may be optionally substituted, where possible, on one or two ring atoms with N with a substituent independently selected from the group consisting of C _1-4 alkyl and C _3-6 cycloalkyl;

and said 4-7 membered monocyclic saturated heterocyclic radical may be optionally substituted, where possible, on one, two or three C ring atoms with one or two substituents, each independently selected from the group consisting of —OH and halogen;

Het ² represents a heterocyclic radical of formula (b-1)

(b-1) is an N-linked 4-7 membered monocyclic saturated heterocyclic radical, optionally containing one additional heteroatom selected from O and N, or an N-linked 6-11 membered bicyclic saturated heterocyclic radical including fused, spiro-fused and bridging rings optionally containing one or two additional N atoms;

where in the case where (b-1) contains one or two additional N atoms, said one or two N atoms may be optionally substituted with a substituent, each of which is independently selected from the group consisting of C _1-4 alkyl, C _3-6 cycloalkyl and Het ⁷ ; and wherein (b-1) may be optionally substituted on one, two or three C ring atoms with one or two substituents, each independently selected from the group consisting of —OH, cyano, C _1-4 alkyl, and C _1-4 alkyl-OH;

R ^11b is Het ^1e ; C1-4alkyl; -C1-4alkyl-Het ⁵ ; -C1-4alkyl-Het ⁸ , _C1-4 alkyl substituted with one,

- 21 037358 with two or three OH groups; or C _3-6 cycloalkyl substituted with one, two or three substituents, each independently selected from the group consisting of halogen and —OH;

R ¹³ is —O — C1-4 alkyl, —C (═O) NR ^15a R ^15b , —NR ^19a R ^19b , C3-6 cycloalkyl, Het ^1d or —C (= O) —Het ^1f ;

R ¹² is —OH, —O — C1-4 alkyl, —NR ^14a R ^14b , —C (= O) NR ^14c R ^14d , —S (= O) 2 — C _1-4 alkyl, C _3-6 cycloalkyl,

Ar ² or Het ^1c ;

Ar ¹ is phenyl;

Ar ² is phenyl optionally substituted with one C _1-4 alkyl;

Het ⁵ , Het ⁶ and Het ^1f each independently represent a heterocyclic radical of formula (c-1)

(c-1) is an N-linked 4-7 membered monocyclic saturated heterocyclic radical optionally containing one additional heteroatom selected from O and N; where in the case where (c-1) contains one additional N atom, the specified additional N atom may be optionally substituted with C _1-4 alkyl;

R ^11a , R ^14a , R ^14c , R ^15a , R ^17a and R ^19a are each independently hydrogen or C _1-4 alkyl;

R ^14b , R ^14d , R ^15b , R ^17b and R ^19b are each independently hydrogen; C _1-4 alkyl; C _3-6 cycloalkyl; -C (= O) -C _1-4 alkyl; C _1-4 alkyl substituted with one substituent selected from the group consisting of —OH and —O — C _1-4 alkyl; or —S (= O) ₂ —C _1-4 alkyl;

and their pharmaceutically acceptable addition salts and their solvates.

The present invention relates, in particular, to the compounds of formula (I) described in this application, their tautomers and stereoisomeric forms, where R ¹ denotes C _1-4 alkyl;

R ² is C _1-6 alkyl or C _1-6 alkyl substituted with one R ⁵ ;

Y is CR ⁴ ; R ⁴ is hydrogen or halogen;

R ⁵ is —NR ^6a R ^6b or —OR ⁷ ;

R ^6a is hydrogen;

R ^6b is —C (= O) —C _1-4 alkyl or —S (= O) ₂ —C _1-4 alkyl;

R ⁷ is hydrogen, —C (= O) —R ⁹ , —S (= O) ₂ —OH or - (C = O) —CH (NH ₂ ) —C _1-4 alkyl-Ar ¹ ;

R ⁹ is C _1-4 alkyl or C _1-4 alkyl substituted with one substituent selected from the group consisting of —NH ₂ , —COOH and Het ⁶ ;

R ³ is phenyl optionally substituted with one, two or three substituents, each of which is independently selected from the group consisting of halogen; cyano; C1-6alkyl; -O-C1-4alkyl; -C (= O) -R ¹⁰ ; -S (= O) 2-C _1-4 alkyl; -O-C _1-4 alkyl-K ¹² ; C3-6cycloalkyl; -O-C3-6cycloalkyl; Het ^1a ; -O-Het ^1b ; R ¹⁸ ; -P (= O) - (C1-4alkyl) ₂ ; -NH-C (= O) -C _1-4 alkyl; -NH-C (= O) -Het ^1g ; C _1-4 alkyl substituted with one, two or three halogen atoms; C1-4alkyl substituted with one, two or three —OH groups; and C _1-4 alkyl substituted with one R ¹³ ;

R ¹⁰ is —OH, —O — C _1-4 alkyl, —NR ^11a R ^11b, or Het ² ;

R ¹⁸ denotes a 5-membered aromatic ring containing one, two or three N atoms; wherein said 5-membered aromatic ring may be optionally substituted with one substituent selected from the group consisting of C _1-4 alkyl;

Het ^1a , Het ^1c and Het ^1d each independently represent a 4-7 membered monocyclic saturated heterocyclic radical containing one or two heteroatoms, each independently selected from O and N;

wherein said 4- to 7-membered monocyclic saturated heterocyclic radical may be optionally substituted, where possible, on one, two or three ring N atoms with a substituent independently selected from the group consisting of C1-4alkyl, C3-6cycloalkyl and C1- 4alkyl substituted with one —O — C1-4 alkyl;

and wherein the 4-7 membered monocyclic saturated heterocyclic radical may be optionally substituted at one, two or three C ring atoms with one or two substituents, each independently selected from the group consisting of —OH, halogen, C _1-4 alkyl, —O — C _1-4 alkyl and —N (C _1-4 alkyl) ₂ ;

Het ^1b , Het ^1e and Het ^1g each independently represent a 4-7 membered monocyclic saturated heterocyclic radical attached to the remainder of the molecule of a compound of formula (I) through any available ring carbon atom, said Het ^1b , Het ^1e and Het ^1g contain one or two heteroatoms, each independently selected from O and N;

wherein said 4-7 membered monocyclic saturated heterocyclic radical may be optionally substituted, where possible, on one or two ring atoms with N with a substituent independently selected from the group consisting of C _1-4 alkyl and C _3-6 cycloalkyl;

and said 4-7 membered monocyclic saturated heterocyclic radical may optionally be substituted at one, two or three C ring atoms with one or two —OH substituents;

- 22 037358

Het ² represents a heterocyclic radical of formula (b-1)

(b-1) is an N-linked 4-7 membered monocyclic saturated heterocyclic radical, optionally containing one additional heteroatom selected from O and N, or an N-linked 6-11 membered bicyclic saturated heterocyclic radical including fused, spiro-fused and bridging rings optionally containing one or two additional N atoms;

where in the case where (b-1) contains one or two additional N atoms, said one or two N atoms may be optionally substituted with C _1-4 alkyl; and wherein (b-1) may optionally be substituted at one, two or three ring carbon atoms with one or two substituents each independently selected from the group consisting of -OH, cyano and C1 _-4 alkyl-OH;

R ^11b is Het ^1e ; Cl-4alkyl; -Cl-4alkyl-Het ⁵ ; Cl-4alkyl substituted with one, two or three OH groups; or C _3-6 cycloalkyl substituted with one, two or three substituents, each independently selected from the group consisting of halogen and —OH;

R ¹³ is —O — C1-4 alkyl, —C (= O) NR ^15a R ^15b , —NR ^19a R ^19b , C3-6 cycloalkyl, Het ^1d , or —C (= O) —Het ^1f ;

R ¹² is —OH, —O — C1-4 alkyl, —NR ^14a R ^14b , —C (= O) NR ^14c R ^14d , —S (= O) 2 — C _1-4 alkyl, C _3-6 cycloalkyl, Ar ² or Het ^1c ;

Ar ¹ is phenyl;

Ar ² is phenyl optionally substituted with one C _1-4 alkyl;

Het ⁵ , Het ⁶ and Het ^1f each independently represent a heterocyclic radical of formula (c-1)

(c-1) is an N-linked 4-7 membered monocyclic saturated heterocyclic radical optionally containing one additional heteroatom selected from O and N;

where in the case where (c-1) contains one additional N atom, the specified additional N atom may be optionally substituted with C _1-4 alkyl;

R ^11a , R ^14a , R ^14c , R ^15a and d R ^19a are each independently hydrogen or C _1-4 alkyl;

R ^14b , R ^14d , R ^15b and R ^19b are each independently hydrogen, C _1-4 alkyl; C _3-6 cycloalkyl or C _1-4 alkyl substituted with one —O — C _1-4 alkyl;

and their pharmaceutically acceptable addition salts and their solvates.

The present invention relates, in particular, to the compounds of formula (I) described in this application, their tautomers and stereoisomeric forms, where R ¹ denotes C _1-4 alkyl;

R ² is C _1-6 alkyl or C _1-6 alkyl substituted with one R ⁵ ;

Y is CR ⁴ ;

R ⁴ is hydrogen or halogen;

R ⁵ is -OR ⁷ ;

R ⁷ denotes hydrogen or-C (= O) -B ⁹ ;

R ⁹ is C _1-4 alkyl;

R ³ is phenyl optionally substituted with one, two or three substituents, each of which is independently selected from the group consisting of halogen; cyano; C1-6alkyl; -O-C1-4alkyl; -C (= O) -R ¹⁰ ; -S (= O) 2-C _1-4 alkyl; -O-C _1-4 alkyl-K? ² ; C3-6cycloalkyl; -O-C3-6cycloalkyl; Het ^1a ; -O-Het ^1b ; R ¹⁸ ; -P (= O) - (C1-4alkyl) ₂ ; -NH-C (= O) -C _1-4 alkyl; -NH-C (= O) -Het ^1g ; C _1-4 alkyl substituted with one, two or three halogen atoms; C _1-4 alkyl substituted with one, two or three —OH groups; and C _1-4 alkyl substituted with one R ¹³ ;

R ¹⁰ is —O — C _1-4 alkyl, —NR ^11a R ^11b or Het ² ;

Het ^1a , Het ^1c and Het ^1d each independently represent a 4-7 membered monocyclic saturated heterocyclic radical containing one or two heteroatoms, each independently selected from O and N;

wherein said 4-7 membered monocyclic saturated heterocyclic radical may be optionally substituted, where possible, on one, two or three ring atoms with N with a substituent independently selected from the group consisting of C _1-4 alkyl, C _3-6 cycloalkyl and C1-4alkyl substituted with one —O — C1-4alkyl;

and wherein said 4-7 membered monocyclic saturated heterocyclic radical may be optionally substituted at one, two or three C ring atoms with one or two substituents, each independently selected from the group consisting of —OH, C _1-4 alkyl, - O — C _1-4 alkyl and —N (C _1-4 alkyl) ₂ ;

Het ^1b , Het ^1e and Het ^1g each independently represent a 4-7 membered monocyclic saturated

23 037358 heterocyclic radical attached to the rest of the molecule of the compound of formula (I) through any available ring carbon atom, wherein said Het ^1b , Het ^1e and Het ^1g contain one or two heteroatoms, each of which is independently selected from O and N;

wherein said 4-7 membered monocyclic saturated heterocyclic radical may be optionally substituted, where possible, on one or two ring atoms with N with a substituent independently selected from the group consisting of C _1-4 alkyl and C _3-6 cycloalkyl;

and said 4-7 membered monocyclic saturated heterocyclic radical may optionally be substituted at one, two or three C ring atoms with one or two —OH substituents;

Het ² represents a heterocyclic radical of formula (b-1)

(b-1) is an N-attached 4-7 membered monocyclic saturated heterocyclic radical, optionally containing one additional N atom, or an N-attached 6-11 membered bicyclic saturated heterocyclic radical, including fused, spiro fused and bridged rings, optionally containing one or two additional N atoms;

where in the case where (b-1) contains one or two additional N atoms, said one or two N atoms may be optionally substituted with C _1-4 alkyl; and where (b-1) may be optionally substituted on one, two or three C ring atoms with one or two substituents, each independently selected from the group consisting of —OH, cyano, and C _1-4 alkyl-OH;

R ^14b , R ^14d , R ^15b and R ^19b are each independently hydrogen, C _1-4 alkyl; C _3-6 cycloalkyl or C _1-4 alkyl substituted with one —O — C _1-4 alkyl;

R ^11b is Het ^1e ; C _1-4 alkyl; C _1-4 alkyl substituted with one, two or three OH groups; or C3-6cycloalkyl substituted with one, two or three substituents, each independently selected from the group consisting of halogen and —OH;

R ¹³ is —O — C1-4 alkyl, —C (= O) NR ^15a R ^15b , C3-6 cycloalkyl, Het ^1d or —C (= O) —Het ^1f ;

R ¹² is —OH, —O — C1-4 alkyl, —NR ^14a R ^14b , —C (= O) NR ^14c R ^14d , —S (= O) 2 — C _1-4 alkyl, C _3-6 cycloalkyl, Ar ² or Het ^1c ;

Ar ¹ is phenyl;

Ar ² is phenyl optionally substituted with one C _1-4 alkyl;

Het ^1f represents a heterocyclic radical of formula (c-1)

(c-1) is an N-linked 4-7 membered monocyclic saturated heterocyclic radical optionally containing one additional heteroatom selected from O and N;

where in the case where (c-1) contains one additional N atom, the specified additional N atom may be optionally substituted with C _1-4 alkyl;

R ^11a , R ^14a , r ^14c and R ^15a are each independently hydrogen or C _1-4 alkyl;

R ^14b , R ^14d , R ^15b and R ^19b are each independently hydrogen, C _1-4 alkyl or C _3-6 cycloalkyl;

and their pharmaceutically acceptable addition salts and their solvates.

The present invention relates, in particular, to the compounds of formula (I) described in this application, their tautomers and stereoisomeric forms, where R ¹ denotes C _1-4 alkyl;

R ² is C _1-6 alkyl or C _1-6 alkyl substituted with one R ⁵ ;

Y is CR ⁴ ;

R ⁴ is hydrogen;

R ⁵ is —OR ⁷ ;

R ⁷ is hydrogen or —C (= O) —R ⁹ ;

R ⁹ is C _1-4 alkyl or C _1-4 alkyl substituted with one substituent —NH ₂ ;

R ³ is phenyl substituted with one, two or three substituents, each of which is independently selected from the group consisting of halogen; cyano; C1-6alkyl; -O-C1-4alkyl; -C (= O) -R ¹⁰ ; -S (= O) 2-C _1-4 alkyl; -O-C _1-4 alkyl-K ¹² ; -O-C3-6cycloalkyl; -O-Het ^1b ; -NH-C (= O) -C1-4alkyl; -NH-C (= O) -Het ^1g and C _1-4 alkyl substituted with one, two or three halogen atoms; C _1-4 alkyl substituted with one R ¹³ ;

R ¹⁰ is —NR ^11a R ^11b or Het ² ;

Het ^1g denotes a 4-7 membered monocyclic saturated heterocyclic radical attached to the remainder of the molecule of a compound of formula (I) through any available ring carbon atom, said Het ^1g containing one or two N atoms;

wherein said 4-7 membered monocyclic saturated heterocyclic radical may optionally be substituted, where possible, on one or two ring N atoms with a C _1-4 alkyl substituent;

Het ^1b denotes a 4-7 membered monocyclic saturated heterocyclic radical attached to the remainder of the molecule of the compound of formula (I) through any available ring carbon atom, said Het ^1b containing one or two N atoms; wherein said 4- to 7-membered saturated heterocyclic radical may be optionally substituted, where possible, at one or two ring NC atoms with _1-4 alkyl; and where the specified 4-7-membered saturated heterocyclic radical may be optionally substituted at the ring C atom with one halogen atom;

Het ² represents a heterocyclic radical of formula (b-1)

(b-1) is an N-linked 4-7 membered saturated heterocyclic radical;

wherein (b-1) may optionally be substituted at one C atom with one —OH group;

R ^11b is C _1-4 alkyl;

R ¹³ is —O — C _1-4 alkyl,

R ¹² is —O — C _1-4 alkyl;

R ^11a is hydrogen;

and to their pharmaceutically acceptable addition salts and their solvates.

The present invention relates, in particular, to compounds of formula (I) given in this application, their tautomers and stereoisomeric forms, where R ¹ denotes C _1-4 alkyl;

R ² is C _1-6 alkyl or C _1-6 alkyl substituted with one R ⁵ ;

Y is CR ⁴ ;

R ⁴ is hydrogen;

R ⁵ is —OR ⁷ ;

R ⁷ is hydrogen or —C (= O) —R ⁹ ;

R ⁹ is C _1-4 alkyl;

R ³ is phenyl substituted with one, two or three substituents, each of which is independently selected from the group consisting of halogen; cyano; C1-6alkyl; -O-C1-4alkyl; -C (= O) -R ¹⁰ ; -S (= O) 2-C _1-4 alkyl; —O — C _1-4 alkyl — I ¹² ; -NH-C (= O) -Het ^1g and C _1-4 alkyl substituted with one R ¹³ ;

R ¹⁰ is —NR ^11a R ^11b or Het ² ;

Het ^1g denotes a 4-7 membered monocyclic saturated heterocyclic radical attached to the remainder of the molecule of a compound of formula (I) through any available ring carbon atom, said Het ^1g containing one or two N atoms;

wherein said 4-7 membered monocyclic saturated heterocyclic radical may optionally be substituted, where possible, at one or two ring N atoms with a C _1-4 alkyl substituent;

Het ² represents a heterocyclic radical of formula (b-1)

(b-1) is an N-linked 4-7 membered monocyclic saturated heterocyclic radical;

where (b-1) may optionally be substituted at one C atom with one —OH group;

R ^11b is C _1-4 alkyl;

R ¹³ is —O — C _1-4 alkyl;

R ¹² is —O — C _1-4 alkyl;

R ^11a is hydrogen;

and to their pharmaceutically acceptable addition salts and their solvates.

The present invention relates, in particular, to compounds of formula (I) given in this application, their tautomers and stereoisomeric forms, where R ¹ denotes C _1-4 alkyl;

R ² is C _1-6 alkyl or C _1-6 alkyl substituted with one R ⁵ ;

Y is CR ⁴ ;

R ⁴ is hydrogen;

R ⁵ is —OR ⁷ ;

R ⁷ is hydrogen or —C (= O) —R ⁹ ;

R ⁹ is C _1-4 alkyl or C _1-4 alkyl substituted with one substituent —NH ₂ ,

R ³ is phenyl substituted with one, two or three substituents, each of which is independently selected from the group consisting of halogen; cyano; C1-6alkyl; -O-C1-4alkyl; -C (= O) -R ¹⁰ ; -S (= O) 2-C _1-4 alkyl; —O — C _1-4 alkyl — I ¹² ; —O — C _3-6 cycloalkyl and C _1-4 alkyl substituted with one R ¹³ ;

- 25 037358

R ¹⁰ is —NR ^11a R ^11b ;

R ^11b is C _1-4 alkyl;

R ¹³ represents —O — C _1-4 alkyl;

R ¹² is —O — C _1-4 alkyl;

R ^11a is hydrogen;

and to their pharmaceutically acceptable addition salts and their solvates.

The present invention relates, in particular, to the compounds of formula (I) described in this application, their tautomers and stereoisomeric forms, where R ¹ denotes C _1-4 alkyl;

R ² is C _1-6 alkyl or C _1-6 alkyl substituted with one R ⁵ ;

Y is CR ⁴ ;

R ⁴ is hydrogen;

R ⁵ is —OR ⁷ ;

R ⁷ is hydrogen or —C (= O) —R ⁹ ;

R ⁹ is C _1-4 alkyl;

R ³ is phenyl substituted with one, two or three substituents, each of which is independently selected from the group consisting of halogen; cyano; C1-6alkyl; -O-C1-4alkyl; -C (= O) -R ¹⁰ ; -S (= O) 2-C _1-4 alkyl; —O — C _1-4 alkyl — I ¹² ; —O — C _3-6 cycloalkyl and C _1-4 alkyl substituted with one R ¹³ ;

R ¹⁰ is —NR ^11a R ^11b ;

R ^11b is C _1-4 alkyl;

R ¹³ represents —O — C _1-4 alkyl;

R ¹² is —O — C _1-4 alkyl;

R ^11a is hydrogen;

and to their pharmaceutically acceptable addition salts and their solvates.

The present invention relates, in particular, to the compounds of formula (I) described in this application, their tautomers and stereoisomeric forms, where R ¹ denotes C _1-4 alkyl;

R ² is C _1-6 alkyl substituted with one R ⁵ ;

Y is CR ⁴ ;

R ⁴ is hydrogen;

R ⁵ is —OR ⁷ ;

R ⁷ is hydrogen or —C (= O) —R ⁹ ;

R ⁹ is C _1-4 alkyl; or C _1-4 alkyl; substituted with one substituent —NH ₂ ;

R ³ is phenyl substituted with one, two or three substituents, each of which is independently selected from the group consisting of halogen; cyano; C1-6alkyl; -O-C1-4alkyl; -C (= O) -R ¹⁰ ; -O-C3-6cycloalkyl and -O-Het ^1b ;

R ¹⁰ is —NR ^11a R ^11b ;

Het ^1b denotes a 4-7 membered monocyclic saturated heterocyclic radical attached to the remainder of the molecule of the compound of formula (I) through any available ring carbon atom, said Het ^1b containing one or two N atoms; wherein said 4- to 7-membered saturated heterocyclic radical may be optionally substituted, where possible, at one or two ring NC atoms with _1-4 alkyl; and where the specified 4-7-membered saturated heterocyclic radical may be optionally substituted at the ring C atom with one halogen atom;

R ^11b is C _1-4 alkyl;

R ^11a is hydrogen;

and to their pharmaceutically acceptable addition salts and their solvates.

The present invention relates, in particular, to compounds of formula (I) given in this application, their tautomers and stereoisomeric forms, where R ¹ denotes C _1-4 alkyl;

R ² is C _1-6 alkyl substituted with one R ⁵ ;

Y is CR ⁴ ;

R ⁴ is hydrogen;

R ⁵ is —OR ⁷ ;

R ⁷ is hydrogen;

R ³ is phenyl substituted with one, two or three substituents, each of which is independently selected from the group consisting of halogen; cyano; C1-6alkyl; -O-C1-4alkyl; -C (= O) -R ¹⁰ ; -S (= O) 2-C _1-4 alkyl; —O — C _1-4 alkyl — I ¹² ; -O-C3-6cycloalkyl and -O-Het ^1b ; NH-C (= O) -Het ^1g and C1-4 alkyl substituted with one R ¹³ ;

R ¹⁰ is —NR ^11a R ^11b ;

Het ^1b denotes a pyrrolidine ring attached to the remainder of the molecule of a compound of formula (I) through any available ring carbon atom, with the N atom being substituted with methyl and one

- 26 037358 ring C atom is replaced by one halogen atom;

Het ^1g is 4-piperidinyl and the N atom is substituted with methyl;

R ^11b is C _1-4 alkyl;

R ¹³ is —O — C _1-4 alkyl;

R ¹² is —O — C _1-4 alkyl;

R ^11a is hydrogen;

and to their pharmaceutically acceptable addition salts and their solvates.

The present invention relates, in particular, to compounds of formula (I) given in this application, their tautomers and stereoisomeric forms, where R ¹ denotes C _1-4 alkyl;

R ² is C _1-4 alkyl substituted with one R ⁵ ;

Y is CR ⁴ ;

R ⁴ is hydrogen;

R ⁵ is —OR ⁷ ;

R ⁷ is hydrogen;

R ³ is phenyl substituted with one, two or three substituents, each of which is independently selected from the group consisting of halogen; cyano; C1-6alkyl; -O-C1-4alkyl; -C (= O) -R ¹⁰ ; -S (= O) 2-C _1-4 alkyl; -O-C _1-4 alkyl-K ¹² ; -NH-C (= O) -Het ^1g and C _1-4 alkyl substituted with one R ¹³ ; in particular R ³ is phenyl substituted with one, two or three substituents, each of which is independently selected from the group consisting of halogen; cyano; C1-6alkyl; -O-C1-4alkyl; -C (= O) -R ¹⁰ ; -S (= O) 2-C _1-4 alkyl; —O — C _1-4 alkyl-K ¹² and C _1-4 alkyl substituted with one R ¹³ ;

R ¹⁰ is —NR ^11a R ^11b ;

Het ^1g is 4-piperidinyl and the N atom is substituted with methyl;

R ^11b is C _1-4 alkyl;

R ¹³ is —O — C _1-4 alkyl,

R ¹² is —O — C _1-4 alkyl;

R ^11a is hydrogen;

and to their pharmaceutically acceptable addition salts and their solvates.

The present invention relates, in particular, to compounds of formula (I) given in this application, their tautomers and stereoisomeric forms, where R ¹ denotes C _1-4 alkyl;

R ² is C _1-6 alkyl substituted with one R ⁵ ;

Y is CR ⁴ ;

R ⁴ is hydrogen;

R ⁵ is —OR ⁷ ;

R ⁷ is hydrogen or —C (= O) —R ⁹ ;

R ⁹ is C _1-4 alkyl or C _1-4 alkyl substituted with one substituent selected from the group consisting of —NH ₂ and —COOH,

R ³ is phenyl substituted with one, two or three substituents, each of which is independently selected from the group consisting of halogen; cyano and C _1-6 alkyl;

and to their pharmaceutically acceptable addition salts and their solvates.

The present invention relates, in particular, to compounds of formula (I) given in this application, their tautomers and stereoisomeric forms, where R ¹ denotes C1-4 alkyl; R ² is C1-6 alkyl substituted with one R ⁵ ;

Y is CR ⁴ ;

R ⁴ is hydrogen;

R ⁵ is —OR ⁷ ;

R ⁷ is hydrogen;

R ³ is phenyl substituted with one, two or three substituents, each of which is independently selected from the group consisting of halogen; cyano and C _1-6 alkyl;

and to their pharmaceutically acceptable addition salts and their solvates.

The present invention relates, in particular, to the compounds of formula (I) given in this application, their tautomers and stereoisomeric forms, where R ¹ denotes methyl;

R ² is methyl substituted with one R ⁵ ;

Y is CR ⁴ ;

R ⁴ is hydrogen;

R ⁵ is —OR ⁷ ;

R ⁷ is hydrogen or —C (= O) —R ⁹ ;

R ⁹ is C _1-4 alkyl substituted with one —NH ₂ group;

R ³ is phenyl substituted with one, two or three substituents, each of which is independently selected from the group consisting of cyano and C _1-6 alkyl;

- 27 037358 and their pharmaceutically acceptable addition salts and their solvates.

The present invention relates, in particular, to the compounds of formula (I) given in this application, their tautomers and stereoisomeric forms, where R ¹ denotes methyl;

R ² is methyl substituted with one R ⁵ ;

Y is CR ⁴ ;

R ⁴ is hydrogen;

R ⁵ is —OR ⁷ ;

R ⁷ is hydrogen;

R ³ denotes phenyl substituted with one, two or three substituents, each of which is independently selected from the group consisting of cyano and C _1-6 alkyl;

and to their pharmaceutically acceptable addition salts and their solvates.

In one embodiment, this invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and their solvates, or to any subgroup of these compounds described in any of the other embodiments, wherein R ⁵ is —NR ^6a R ^6b or —OR ⁷ ;

R ^6b is hydrogen; C1-4alkyl; C3-6cycloalkyl; -C (= O) -C1-4alkyl; -S (= O) 2-C1-4 alkyl; —C (= O) —C1-4alkyl substituted with one substituent selected from the group consisting of —OH and —NR ^16a R ^16b ; or C1-4alkyl substituted with one substituent selected from the group consisting of —OH and —S (= O) ₂ —C _1-4 alkyl;

R ⁷ is hydrogen; C1-4alkyl; -C1-4alkyl-NR ^8a R ^8b , -C (= O) -R ⁹ , -S (= O) 2-OH, -P (= O) ₂ -OH or - (C = O) -CH (NH2 ) -C1-4alkyl-Ar ¹ .

Another embodiment of the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and their solvates, or to any subgroup of these compounds described in any of the other embodiments, where Y is CR ⁴ or N, in particular where Y is CR ⁴ ; and where one or more of the following restrictions apply:

(a) R ⁵ is halogen, —NR ^6a R ^6b, or —OR ⁷ ; in particular R ⁵ is —NR ^6a R ^6b or —OR ⁷ ;

(b) R ^6a is hydrogen;

(c) R ^6b is —C (= O) —C _1-4 alkyl or —S (= O) ₂ —C _1-4 alkyl;

(d) R ⁷ is hydrogen, -C1-4alkyl-NR ^8a R ^8b , -C (= O) -R ⁹ , -S (= O) 2-OH or - (C = O) -CH (NH ₂ ) -C ₁ . ₄ αalkylAr ¹ ; in particular R ⁷ is hydrogen, —C (= O) —R ⁹ , —S (= O) ₂ —OH or - (C = O) —CH (NH ₂ ) —C _1-4 alkyl-Ar ¹ ;

(e) R ³ is phenyl optionally substituted with one, two or three substituents, each independently selected from the group consisting of halogen; cyano; C1-6alkyl; -O-C1-4alkyl; -C (= O) -R ¹⁰ ; -S (= O) 2-C _1-4 alkyl; —O — C _1-4 alkyl — I ¹² ; C3-6cycloalkyl; -O-C3-6cycloalkyl; Het ^1a ; -O-Het ^1b ; R ¹⁸ ; -P (= O) - (C1-4alkyl) ₂ ; -NH-C (= O) -C _1-4 alkyl; -NH-C (= O) -Het ^1g ; -NR ^17a R ^17b ; C1-4alkyl substituted with one, two or three halogen atoms; C1-4alkyl substituted with one, two or three —OH substituents; C1-4alkyl substituted with one R ¹³ ; C2-6 alkenyl substituted with one R ¹³ ; and C2-6 alkynyl substituted with one R ¹³ ; in particular R ³ is phenyl optionally substituted with one, two or three substituents, each of which is independently selected from the group consisting of halogen; cyano; C1-6alkyl; —O — C _1-4 alkyl; -C (= O) -R ¹⁰ ; -S (= O) 2-C1-4 alkyl; -O-C1-4alkyl-I ¹² ; C3-6cycloalkyl;

—O — C _3-6 cycloalkyl; Het ^1a ; -O-Het ^1b ; R ¹⁸ ; -P (= O) - (C1-4alkyl) 2; -NH-C (= O) -C1-4alkyl; -NH-C (= O) -Het ^1g ; -O-C1-4alkyl-R ¹² ; C3-6cycloalkyl; -O-C3-6cycloalkyl; Het ^1a ; -O-Het ^1b ; R ¹⁸ ; -P (= O) - (C1-4alkyl) ₂ ; -NH-C (= O) -C _1-4 alkyl; -NH-C (= O) -Het ^1g ; C _1-4 alkyl substituted with one, two or three halogen atoms; C _1-4 alkyl substituted with one, two or three —OH substituents; and C _1-4 alkyl substituted with one R ¹³ ;

(f) R ¹⁸ is a 5-membered aromatic ring containing one, two or three N atoms; wherein said 5-membered aromatic ring may be optionally substituted with one substituent selected from the group consisting of C _1-4 alkyl;

(g) Het ^1a , Het ^1c and Het ^1d each independently represent a 4-7 membered monocyclic saturated heterocyclic radical containing one or two heteroatoms, each independently selected from O and N; wherein said 4-7 membered monocyclic saturated heterocyclic radical may be optionally substituted, where possible, on one or two ring atoms with N with a substituent independently selected from the group consisting of C _1-4 alkyl, C _3-6 cycloalkyl and C _1-4 alkyl substituted with one —O — C _1-4 alkyl, and wherein said 4-7 membered monocyclic saturated heterocyclic radical may be optionally substituted on one, two or three C ring atoms with one or two substituents, each of which independently selected from the group consisting of —OH, halogen, C _1-4 alkyl, —O — C _1-4 alkyl, and —N (C _1-4 alkyl) ₂ ;

(h) Het ^1b , Het ^1e , Het ^1g , Het ⁷ and Het ⁸ each independently represent a 4-7 membered monocyclic saturated heterocyclic radical attached to the remainder of the molecule of the compound of formula (I) through any available ring carbon atom, wherein said Het ^1b , Het ^1e , Het ^1g , Het ⁷ and Het ⁸ contain one or two heteroatoms, each of which is independently selected from O and N;

where the 4-7 membered monocyclic saturated heterocyclic radical may be optionally substituted, where possible, on one or two ring N atoms with a substituent independently selected from the group consisting of C _1-4 alkyl and C _3-6 cycloalkyl ; and wherein said 4-7 membered monocyclic saturated heterocyclic radical may be optionally substituted at one, two or three C ring atoms with one or two substituents, each independently selected from the group consisting of —OH and halogen; in particular Het ^1b , Het ^1e and Het ^1g each denote a 4-7 membered monocyclic saturated heterocyclic radical attached to the remainder of the molecule of the compound of formula (I) through any available ring carbon atom, indicated by Het ^1b , Het ^1e and Het ^1g contain one or two heteroatoms, each of which is independently selected from O and N; wherein said 4- to 7-membered monocyclic saturated heterocyclic radical may be optionally substituted, where possible, on one or two ring atoms with an N substituent, each independently selected from the group consisting of C _1-4 alkyl and C _3-6 cycloalkyl; and wherein said 4-7 membered monocyclic saturated heterocyclic radical may optionally be substituted at one, two or three C ring atoms with one or two —OH groups;

(i) Het ² is a heterocyclic radical of formula (b-1)

(b-1) is an N-linked 4-7 membered monocyclic saturated heterocyclic radical, optionally containing one additional heteroatom selected from O and N, or an N-linked 6-11 membered bicyclic saturated heterocyclic radical including fused, spiro-fused and bridging rings optionally containing one or two additional N atoms;

wherein when (b-1) comprises one or two additional N atom, said one or two N atom may be optionally substituted with a substituent independently selected from the group consisting of C1 _-4 alkyl, C _3-6 cycloalkyl and Het ^7; and where (b-1) may be optionally substituted on one, two or three ring C atoms with one or two substituents, each of which may be independently selected from the group consisting of —OH, cyano, C _1-4 alkyl and C _{1 -4} alkyl C _1-4 alkyl -OH;

in particular, Het ² denotes a heterocyclic radical of the formula (b-1)

(b-1) is an N-linked 4-7 membered monocyclic saturated heterocyclic radical optionally containing one additional N atom, or an N-linked 6-11 membered bicyclic saturated heterocyclic radical including fused, spiro fused and bridged rings, optionally containing one or two additional N atoms;

where when (b-1) contains one or two additional N atoms, said one or two N atoms may be optionally substituted with C _1-4 alkyl; and where (b-1) may optionally be substituted on one, two or three ring C atoms with one or two substituents, each of which may be independently selected from the group consisting of —OH, cyano, C _1-4 alkyl-OH;

(j) R ^11b is Het ^1e ; C1-4alkyl; -C1-4alkyl-Het ⁵ ; -C1-4alkyl-Het ⁸ , C1-4alkyl substituted with one, two or three OH groups; or C3-6cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halogen and —OH; in particular R ^11b is Het ^1e ; C1-4alkyl; -C _1-4 alkyl-Het ⁵ ; C _1-4 alkyl substituted with one, two or three OH groups; or C3-6cycloalkyl substituted with one, two or three substituents, each independently selected from the group consisting of halogen and —OH;

(k) R ¹³ is —O — C1-4 alkyl, —C (= O) NR ^15a R ^15b , —NR ^19a R ^19b , C3-6 cycloalkyl, Het ^1d or —C (= O) —Het ^1f ;

(1) R ¹² is —OH, —O — C1-4 alkyl, —NR ^14a R ^14b , —C (= O) NR ^14c R ^14d , —S (= O) 2-OC _1-4 alkyl, C _{3- 6} cycloalkyl, Ar ² or Het ^1c ;

(m) Ar ¹ is phenyl;

(n) Het ⁵ , Het ⁶ and Het ^1f each independently represent a heterocyclic radical of formula (c-1)

(c-1) is an N-linked 4-7 membered monocyclic saturated heterocyclic radical optionally containing one additional heteroatom selected from O and N; where in the case where (c-1) contains one additional N atom, the specified additional N atom may be optionally substituted with C _1-4 alkyl;

(o) R ^14b , R ^14d , R ^15b , R ^17b and R ^19b are each independently hydrogen; C _1-4 alkyl; C _3-6 cycloalkyl;

- 29 037358

-C (= O) -C1.4 alkyl; C1.4 alkyl substituted with one substituent selected from the group consisting of —OH and —O — C1.4 alkyl or —S (= O) ₂ —C ₁ . ₄ alkyl; in particular R ^14b , R ^14d , R ^15b and R ^19b are each independently hydrogen; C1. ₄ alkyl; C _3-6 cycloalkyl or C1. ₄ alkyl substituted with one-O-C1. _{4 by} alkyl.

Another embodiment of this invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and their solvates, or to any subgroup of these compounds described in any of the other embodiments, where Y is CR ⁴ or N, in particular when Y is CR ⁴ ; and where one or more of the following restrictions apply:

(a) R ⁴ is hydrogen;

(b) R ⁵ is —OR ⁷ ;

(c) R ⁷ is hydrogen or —C (= O) —R ⁹ ;

(d) R ⁹ is C _1-4 alkyl;

(e) R ³ is phenyl substituted with one, two or three substituents, each of which is independently selected from the group consisting of halogen; cyano, C1-6 alkyl; -O-C1-4alkyl; -C (= O) -R ¹⁰ ; -S (= O) 2-C _1-4 alkyl; —O — C _1-4 alkyl-R ¹² ; -NH-C (= O) -Het ^1g and C _1-4 alkyl substituted with one R ¹³ ;

(f) R ¹⁰ is —NR ^11a R ^nb or Het ² ;

(g) Het ^1g is a 4-7 membered monocyclic saturated heterocyclic radical attached to the remainder of the molecule of a compound of formula (I) through any available ring carbon atom, said Het ^1g containing one or two N atoms; wherein said 4-7 membered monocyclic saturated heterocyclic radical may optionally be substituted, where possible, at one or two ring N atoms with a C _1-4 alkyl substituent;

(h) Het ² is a heterocyclic radical of formula (b-1)

- (b-1) (b-1) denotes an N-linked 4-7 membered monocyclic saturated heterocyclic radical, where (b-1) may optionally be substituted at one C atom with one —OH group;

(i) R ^11b is C _1-4 alkyl;

(j) R ¹³ is —O — C _1-4 alkyl; (k) R ¹² is —O — C _1-4 alkyl;

(l) R ^11a is hydrogen.

In one embodiment, the present invention relates to a subgroup of compounds of formula (I), referred to herein as compounds of formula (I '), and pharmaceutically acceptable addition salts and their solvates

CN, .- .. JJ rj ^{n HN} Ύ R isomer wherein R1 is C _1-4 alkyl;

R ² is C _1-6 alkyl substituted with one R ⁵ substituent;

in particular, where R ¹ denotes C _1-4 alkyl;

R ² is C _1-6 alkyl substituted with one R ⁵ substituent;

R ⁵ is —OR ⁷ ;

in particular, where R ¹ denotes C _1-4 alkyl;

R ² is C _1-6 alkyl substituted with one R ⁵ substituent;

R ⁵ is —OR ⁷ ; R ⁷ is hydrogen;

and where all other variables are valid according to any of the other options.

In one embodiment, the present invention relates to a subgroup of compounds of formula (I), referred to herein as compounds of formula (I), and pharmaceutically acceptable addition salts and solvates thereof

where R ¹ means C _1-4 alkyl;

R ² is C _1-6 alkyl substituted with one R ⁵ substituent;

in particular, where R ¹ denotes C _1-4 alkyl;

R ² is C _1-6 alkyl substituted with one R ⁵ substituent;

- 30 037358

R ⁵ is —OR ⁷ ;

more preferably when R ¹ is C _1-4 alkyl;

R ² is C ₁ . ₆ αalkyl substituted with one R ⁵ substituent;

R ⁵ is —OR ⁷ ; R ⁷ is hydrogen;

and where all other variables are valid according to any of the other options.

In one embodiment, the present invention relates to a subgroup of compounds of formula (I) and their pharmaceutically acceptable addition salts and their solvates, or to any subgroup specified in any of the other embodiments, wherein R ¹ is methyl;

R ² is methyl or —CH2 — OH.

In one embodiment, the present invention relates to a subgroup of compounds of formula (I) and their pharmaceutically acceptable addition salts and their solvates, or to any subgroup specified in any of the other embodiments, wherein R ¹ is methyl; R ² is —CH ₂ —OH.

In one embodiment, the present invention relates to a subgroup of compounds of formula (I) and their pharmaceutically acceptable addition salts and their solvates, or to any subgroup specified in any of the other embodiments, wherein R ³ is phenyl which is substituted with one, two or three substituents according to any of the other options.

In one embodiment, the present invention relates to a subgroup of compounds of formula (I) and their pharmaceutically acceptable addition salts and their solvates, or to any subgroup specified in any of the other embodiments, wherein R ³ is phenyl optionally substituted with one, two or three substituents according to any of the other options, however, provided that these substituents are not selected from the group consisting of -S (= O) 2-C1-4alkyl; -S (= O) (= NR ^20a ) -C1-4alkyl and -P (= O) - ( _C1-4 alkyl) ₂ .

In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and their solvates, or any subgroup specified in any of the other embodiments, wherein R ⁴ is hydrogen or fluoro.

In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and their solvates, or any subgroup specified in any of the other embodiments, wherein R ⁴ is hydrogen.

In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and their solvates, or any subgroup specified in any of the other embodiments, wherein R ⁵ is —OR ⁷ ; and R ⁷ is hydrogen.

In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and their solvates, or any subgroup specified in any of the other embodiments, wherein R ⁹ is C _1-4 alkyl or C _1-4 alkyl substituted with one substituent selected from the group consisting of —NH ₂ , —COOH and Het ⁶ .

In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and their solvates, or any subgroup specified in any of the other embodiments, wherein R ^{18 is} attached to the remainder of the molecule of the compound of formula (I) through an atom carbon.

In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and their solvates, or any subgroup specified in any of the other embodiments, wherein R ¹⁸ is

or in particular

or

wherein each radical is optionally substituted at carbon and / or nitrogen atoms in accordance with any of the other options.

In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and their solvates, or any subgroup specified in any of the other embodiments, wherein R ¹⁸ is

- 31 037358

- - / k

Ό Q, u or

0 ^J NH in particular, Η Η

Ύ>, Ό or

-ο

V — Ν Η each of which is optionally substituted on the NH group with a C _1-4 alkyl substituent.

In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and their solvates, or to any subgroup specified in any of the other embodiments, wherein Het ^1a , Het ^1c and Het ^1d are each independently morpholinyl , piperidinyl, pyrrolidinyl, oxetanyl, azetidinyl, piperazinyl, tetrahydro-2H-pyranyl, tetrahydrofuranyl, or hexahydro-1,4-oxazepinyl, each of which is optionally substituted at carbon and / or nitrogen atoms according to any of the other options.

In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and their solvates, or to any subgroup specified in any of the other embodiments, wherein Het ^1a , Het ^1c and Het ^1d are each independently morpholinyl , piperidinyl, pyrrolidinyl, oxetanyl, azetidinyl, piperazinyl, tetrahydro-2H-pyranyl, or hexahydro1,4-oxazepinyl, each of which is optionally substituted at carbon and / or nitrogen atoms according to any of the other options.

In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and their solvates, or to any subgroup specified in any of the other embodiments, wherein Het ^1a , Het ^1c and Het ^1d are each independently ⁴ ΓΊ ⁴ ν-ι \ ^ν ^ \

Ι ^ ΝΗ, 1-6, l ^ o II / \ (__ _/ Ο

Ό □ ’Η, or

C ^ ^nh and each of which is optionally substituted at carbon and / or nitrogen atoms in accordance with any of the other options.

In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and their solvates, or to any subgroup specified in any of the other embodiments, wherein Het ^1a is kJ n kJ, n

or

C ^ NH _> each of which is optional according to any of the other options.

In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and their solvates, or any subgroup specified in any of the other embodiments, wherein Het ^1c is or b

each of which is optionally substituted at carbon and / or nitrogen atoms according to any

- 32 037358 from other options.

In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and their solvates, or any subgroup specified in any of the other embodiments, wherein Het ^1d is or

each of which is optionally substituted at carbon and / or nitrogen atoms in accordance with any of the other options.

In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and their solvates, or any subgroup specified in any of the other embodiments, where Het ^1b , Het ^1e , Het ^1g and Het ⁴ , each independently are morpholinyl, piperidinyl, pyrrolidinyl, oxetanyl, azetidinyl, piperazinyl, tetrahydro-2H-pyranyl, tetrahydrofuranyl or hexahydro-1,4-oxazepinyl, attached to the rest of the molecule of the compound of formula (I) through any available ring carbon atom, each of which optionally substituted at carbon and / or nitrogen atoms in accordance with any of the other options.

In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and their solvates, or any subgroup specified in any of the other embodiments, where Het ^1b , Het ^1e , Het ^1g and Het ⁴ , each independently are piperidinyl, tetrahydro-2H-pyranyl or pyrrolidinyl, attached to the remainder of the molecule of the compound of formula (I) through any available ring carbon atom, each of which is optionally substituted at carbon and / or nitrogen atoms in accordance with any of the other options.

In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and their solvates, or any subgroup specified in any of the other embodiments, where Het ^1b , Het ^1e , Het ^1g and Het ⁴ , each independently , denote

or

each of which is optionally substituted at carbon and / or nitrogen atoms in accordance with any of the other options.

In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and their solvates, or any subgroup specified in any of the other embodiments, wherein Het ^1g is

optionally substituted at carbon and / or nitrogen atoms in accordance with any of the other options.

In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and their solvates, or any subgroup specified in any of the other embodiments, wherein Het ^1e is

or

each of which is optionally substituted at carbon and / or nitrogen atoms in accordance with any of the other options.

In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and their solvates, or any subgroup specified in any of the other embodiments, wherein Het ^1b is

or

- 33 037358

each of which is optionally substituted at carbon and / or nitrogen atoms in accordance with any of the other options.

In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and their solvates, or any subgroup specified in any of the other embodiments, wherein Het ² is

or each of which is optionally substituted at carbon and / or nitrogen atoms in accordance with any of the other options.

In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and their solvates, or any subgroup specified in any of the other embodiments, wherein Het ^3a , Het ^3b , Het ⁵ , Het ⁶ and Het ^1f , each independently, denote

or

each of which is optionally substituted at carbon and / or nitrogen atoms in accordance with any of the other options.

In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and their solvates, or any subgroup specified in any of the other embodiments, wherein Het ⁴ is pyrrolidinyl, piperidinyl, tetrahydropyranyl, azetidinyl or 1.1 β-thiopyranyl dioxide; each of which is optionally substituted at carbon and / or nitrogen atoms in accordance with any of the other options.

In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and their solvates, or any subgroup specified in any of the other embodiments, wherein Het ⁵ is

or b, each of which is optionally substituted in accordance with any of the other options.

In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and their solvates, or to any subgroup specified in any of the other embodiments, wherein Het ⁶ is or

each of which is optionally substituted at carbon and / or nitrogen atoms in accordance with any of the other options.

In one embodiment, the present invention relates to those compounds of formula (I) and to their

34 037358 pharmaceutically acceptable addition salts and their solvates or any subgroup specified in any of the other embodiments, wherein Het ^1f is optionally substituted at carbon and / or nitrogen atoms according to any of the other embodiments.

In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and their solvates, or to any subgroup specified in any of the other embodiments, wherein Het ⁷ and Het ⁸ are each independently optionally substituted on atoms carbon in accordance with any of the other options.

In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and their solvates, or to any subgroup specified in any of the other embodiments, wherein Het ^1a , Het ^1c and Het ^1d are each independently 4 -7-membered monocyclic saturated heterocyclic radical containing one or two heteroatoms, each independently selected from O, S, S (= O) p and N;

wherein the 4-7 membered monocyclic saturated heterocyclic radical may be optionally substituted, where possible, on one or two ring atoms with an N substituent, each independently selected from the group consisting of C _1-4 alkyl, C _3-6 cycloalkyl and C _1-4 alkyl substituted with one substituent selected from the group consisting of —OH and —O — C _1-4 alkyl; and wherein said 4-7 membered monocyclic saturated heterocyclic radical may be optionally substituted at one, two or three ring carbon atoms with one or two substituents, each independently selected from the group consisting of —OH, halogen, C _1-4 alkyl , cyano, —C (= O) —C _1-4 alkyl, —O — C _1-4 alkyl, —NH2, —NH (C _1-4 alkyl) and —N (C _1-4 alkyl) ₂ .

In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and their solvates, or any subgroup specified in any of the other embodiments, wherein Het ² is a heterocyclic radical of formula (b-1) (b- 1) denotes an N-linked 4-7 membered monocyclic saturated heterocyclic radical, optionally containing one additional heteroatom selected from O, S, S (= O) _p and N;

where in the case where (b-1) contains one additional N atom, said N atom may be optionally substituted with C _1-4 alkyl; and wherein (b-1) may be optionally substituted on one, two or three C ring atoms with one or two substituents, each independently selected from the group consisting of halogen, —OH, cyano, C _1-4 alkyl, —O —C _1-4 alkyl, —NH2, —NH (C _1-4 alkyl), —N (C _1-4 alkyl) _2, and C _1-4 alkyl-OH.

In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and their solvates, or to any subgroup specified in any of the other embodiments, wherein Het ^1a is a 4-7 membered monocyclic saturated heterocyclic radical containing one or two heteroatoms, each of which is independently selected from O, S, S (= O) p and N; or a 611 membered bicyclic saturated heterocyclic radical including fused, spirocyclic and bridged rings containing one, two or three heteroatoms, each independently selected from O, S, S (= O) p and N;

wherein said 4-7 membered monocyclic saturated heterocyclic radical or said 6-11 membered bicyclic saturated heterocyclic radical may optionally be substituted, where possible, on one or two ring atoms with N substituents, each of which is independently selected from the group consisting of from C _1-4 alkyl, C _3-6 cycloalkyl and C _1-4 alkyl substituted with one substituent selected from the group consisting of —OH and —O — C 1-4 alkyl; and wherein said 4-7 membered monocyclic saturated heterocyclic radical or said 6-11 membered bicyclic saturated heterocyclic radical may optionally be substituted on one, two or three C ring atoms with one or two substituents, each of which is independently selected from the group consisting of from —OH, halogen, C _1-4 alkyl, cyano, —C (= O) —C _1-4 alkyl, —O — C _1-4 alkyl, —NH2, —NH (C _1-4 alkyl) and - N (C _1-4 alkyl) ₂ ;

Het ^1c and Het ^1d each independently represent a 4-7 membered monocyclic saturated heterocyclic radical containing one or two heteroatoms, each independently selected from O, S, S (= O) p and N; or in the case when Het ^1c and Het ^{1d are} attached to the rest of the molecule of the compound of formula (I) through the N atom, Het ^1c and Het ^1d can also represent an N-attached bicyclic saturated heterocyclic radical, including condensed, spirocyclic and bridging rings containing one or two additional heteroatoms, each of which is independently selected from O, S, S (= O) _p and N;

wherein said 4-7 membered monocyclic saturated heterocyclic radical or said 6-11 membered bicyclic saturated heterocyclic radical may optionally be substituted, where possible, on one or two ring atoms with N substituents, each of which is independently selected from the group consisting of from C _1-4 alkyl, C _3-6 cycloalkyl and C _1-4 alkyl substituted with one substituent selected from the group consisting of —OH and —O — C _1-4 alkyl; and wherein said 4-7 membered monocyclic saturated heterocyclic radical or said 6-11 membered bicyclic saturated heterocyclic radical may optionally be substituted on one, two or three C ring atoms with one or two substituents, each of which is independently selected from the group consisting of from —OH, halogen, C _1-4 alkyl, cyano, —C (= O) —C _1-4 alkyl, —O — C _1-4 alkyl, —NH2, —NH (C _1-4 alkyl) and - N ( _C1-4 alkyl) ₂ .

In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and their solvates, or any subgroup specified in any of the other embodiments, wherein Y is CR ⁴ .

In one embodiment, the present invention relates to those compounds of formula (I-x) and their pharmaceutically acceptable addition salts and their solvates

where all variables have the value specified in any of the other options.

In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and their solvates, or any subgroup specified in any of the other embodiments, wherein Y is N.

In one embodiment, the present invention relates to a subgroup of compounds of formula (I), referred to herein as compounds of formula (I-y), and pharmaceutically acceptable addition salts and solvates thereof

where all variables have the value specified in any of the other options. In one embodiment, the present invention relates to a subgroup of compounds of formula (I) shown in the general reaction schemes.

In one embodiment, the compound of formula (I) is selected from the group consisting of compounds 1, 4, 45, 66, 68, 73, 74, 110, 125, 138, 155, 156 and 232, their tautomers, stereoisomeric forms and free bases, any pharmaceutically acceptable addition salts and solvates.

In one embodiment, the compound of formula (I) is selected from the group consisting of compounds 1, 4, 45, 66, 68, 73, 74, 110, 125, 138, 155, 156 and 232.

In one embodiment, the compound of formula (I) is selected from the group consisting of compounds 1, 138, 155, 156 and 232, their tautomers, stereoisomeric forms and free bases, any pharmaceutically acceptable addition salts and their solvates.

In one embodiment, the compound of formula (I) is selected from the group consisting of compounds 1, 138, 155, 156 and 232.

In one embodiment, the compound of formula (I) is selected from the group consisting of compounds 1, 4, 45, 66, 68, 73, 74, 110 and 125, their tautomers, stereoisomeric forms and free bases, any pharmaceutically acceptable addition salts and solvates.

In one embodiment, the compound of formula (I) is selected from the group consisting of compounds 1, 4, 45, 66, 68, 73, 74, 110 and 125.

In one embodiment, the compound of formula (I) is selected from the group consisting of the compounds described in the examples, their tautomers, stereoisomeric forms and free bases, any pharmaceutically acceptable addition salts and solvates.

- 36 037358

In one embodiment, the compound of formula (I) is selected from the group consisting of

- 37 037358

their tautomers, stereoisomeric forms and free bases, any pharmaceutically acceptable addition salts and solvates.

In one embodiment, the compound of formula (I) is selected from the group consisting of

their tautomers, stereoisomeric forms and free bases, any pharmaceutically acceptable addition salts and solvates.

All possible combinations of the above options are considered to be within the scope of the present invention.

Methods for preparing compounds of formula (I).

In this section, as in all other sections, unless the context otherwise requires, the compounds of formula (I) also include all other subgroups and examples of all compounds described in this application.

General methods for the preparation of certain typical compounds of formula (I) are described below and in specific examples, and in general, compounds are usually prepared from starting materials that are either commercially available or are prepared by standard synthetic methods commonly used by those skilled in the art. The following diagrams are intended only to represent examples of the invention and do not limit the present invention in any way.

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

It will be apparent to those skilled in the art that the functionalization reactions shown in the Schemes below for compounds of formula (I) where Y is CR4 can also be carried out for compounds where Y is N. One skilled in the art realizes such approaches, for example, and without limitation in stages 3 and 4 of scheme 2 and scheme 18.

It will be apparent to those skilled in the art that when carrying out the reactions described in the Schemes, although not always clearly shown, it may be necessary to protect reactive functional groups (e.g., hydroxyl, amino and carboxyl groups) when desired in the final product to avoid them. unwanted participation in such reactions. For example, in Scheme 6

38 037358 the NH group in the pyrimidinyl radical can be protected by a tert-butoxycarbonyl protecting group. In general, conventional protecting groups can be used in accordance with standard practice. The protecting groups can be removed at a convenient subsequent step using methods known in the art. This is illustrated with specific examples.

It will be apparent to those skilled in the art that when carrying out the reactions described in the Schemes, it may be desirable or necessary to carry out the reactions under an inert atmosphere, such as nitrogen gas.

One skilled in the art will appreciate that it may be necessary to cool the reaction mixture before isolating the reaction product (this refers to the series of manipulations required to isolate and purify the product (s) of a chemical reaction, for example, stopping the reaction, column chromatography, extraction).

One skilled in the art will appreciate that heating the reaction mixture with stirring can provide an increase in product yield. In some reactions, microwave heating may be used instead of conventional heating to shorten the overall reaction time.

One skilled in the art will appreciate that another sequence of chemical reactions shown in the Schemes below can also lead to the desired compound of formula (I).

It will be apparent to those skilled in the art that the intermediates and final compounds shown in the Schemes below can then be functionalized by methods well known to those skilled in the art.

Scheme 1.

In general, compounds of formula (I) wherein R ² is R ^2a , which is C _1-6 alkyl, Y is CR ⁴ and all other variables are meaningful within the scope of this invention, referred to as compounds of formula (Ia), may be obtained according to the following scheme 1. In scheme 1, halogen ^{1 is} denoted as Cl, Br or I; and PG ¹ is a suitable protecting group such as, for example, tert (butoxycarbonyl). All other variables in Scheme 1 have the meaning encompassed by this invention.

In Scheme 1, the following reactions occur:

(1a)

1: at a suitable temperature, such as, for example, 80 ° C, in the presence of a suitable ligand such as, for example, 4,4'-di-tert-butyl-2,2'-dipyridyl, a suitable catalyst such as, for example , bis- (1,5-cyclooctadiene) di-μ-methoxydiiridium (I) ([Ir (OCH ₃ ) (C ₈ H ₁₂ )] ₂ ), and a suitable solvent such as, for example, heptane;

2: at a suitable temperature, such as, for example, 85 ° C, in the presence of a suitable catalyst, such as, for example, [1,1'-bis (diphenylphosphine) ferrocene] dichloropalladium (II), optionally in the form of a complex with dichloromethane, a suitable base such as, for example, potassium acetate, and a suitable solvent, such as, for example, 1,4-dioxane;

3: at a suitable temperature, such as, for example, 85 ° C, in the presence of a suitable catalyst such as, for example, based on palladium tetrakis- (Pd (PPh ₃ ) ₄ ), a suitable base such as, for example, sodium carbonate, and a suitable solvent such as, for example, 1,4-dioxane;

- 39 037358

4: at a suitable temperature, such as, for example, room temperature, in the presence of a suitable base, such as, for example, sodium hydride, and a suitable solvent, such as, for example, dimethylformamide;

5: at a suitable temperature, such as, for example, 100 ° C, in the presence of a suitable catalyst such as, for example, palladium acetate (Pd (OAc) 2), a suitable ligand such as, for example, 2,2'bis- ( diphenylphosphine) -1,1'-binaphthyl (BINAP), a suitable base such as, for example, cesium carbonate, and a suitable solvent such as, for example, 1,4-dioxane, optionally with microwave activation; or, alternatively, at a suitable temperature, such as, for example, 95 ° C, in the presence of a suitable acid, such as, for example, p-toluenesulfonic acid, and a suitable solvent, such as, for example, 1,4-dioxane;

6: at a suitable temperature, such as, for example, 0 ° C or at room temperature, or at reflux, in the presence of a suitable acid, such as, for example, trifluoroacetic acid or an aqueous solution of hydrochloric acid, with a suitable solvent, such as, for example, dichloromethane, methanol, ethyl acetate or 1,4-dioxane, or alternatively in the presence of silica in a suitable solvent, such as, for example, toluene, at a suitable temperature, such as, for example, 125 ° C, and for a suitable time, for example within 3 hours.

Scheme 2.

In general, compounds of formula (I) wherein R ² is R ^2a which is C _1-6 alkyl, R ³ is phenyl substituted with —C (= O) —R ¹⁰ and optionally substituted with other substituents within the scope of this invention, Y is CR ⁴ and all other variables have meaning in accordance with the scope of this invention, referred to in this application as compounds of formula (Ib), can be obtained according to the following scheme 2. In scheme 2, halogen ^{1 is} denoted as Cl, Br or I; and PG ¹ is a suitable protecting group such as, for example, tert- (butoxycarbonyl). All other variables in Scheme 2 have the meaning encompassed by this invention.

In Scheme 2, the following reaction conditions apply:

(lb)

1: at a suitable temperature, such as, for example, 100 ° C, in the presence of a suitable catalyst such as, for example, palladium acetate (Pd (OAc) ₂ ), a suitable ligand such as, for example, 2,2'bis- ( diphenylphosphine) -1,1'-binaphthyl (BINAP), a suitable base such as, for example, a suitable base such as, for example, cesium carbonate, and a suitable solvent such as, for example, 1,4-dioxane, optionally upon activation microwave radiation;

2: at a suitable temperature, such as, for example, 70 ° C, in the presence of a suitable base, such as, for example, lithium hydroxide, and a suitable solvent, such as, for example, a mixture of tetrahydrofuran and water;

3: at a suitable temperature, such as, for example, room temperature, in the presence of a suitable reagent for coupling reactions, such as, for example, hexafluorophosphate 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4, 5-b] pyridinium-3-oxide (HATU), a suitable base such as, for example, N, N-diisopropylethylamine, and a suitable solvent such as, for example, dimethylformamide;

4: at a suitable temperature, such as, for example, 0 ° C or at room temperature, or at reflux, in the presence of a suitable acid, such as, for example, trifluoroacetic acid or an aqueous solution of hydrochloric acid with a suitable solvent such as, for example, dichloromethane , methanol, ethyl acetate or 1,4-dioxane, and for a suitable time, for example 3 hours.

Scheme 3.

In general, compounds of formula (I) wherein R ² is R ^2b , which is C _1-6 alkyl substituted with one OH group, Y is CR ⁴ , and all other variables have meaning within the scope of this invention, referred to herein compounds of formula (Ic) can be prepared according to the following scheme 3. In scheme 3, halogen ¹ means Cl, Br or I; and PG ¹ is a suitable protecting group such as, for example, tert- (butoxycarbonyl) and PG ² is a suitable protecting group, such as, for example, tert-butyldimethylsilyl. All other variables in Scheme 3 have the meaning encompassed by this invention.

In Scheme 3, the following reaction conditions apply:

1: at a suitable temperature, such as, for example, 80 ° C, in the presence of a suitable ligand, such as, for example, 4,4'-di-tert-butyl-2,2'-dipyridyl, a suitable catalyst, such as, for example, bis - (1,5-cyclooctadiene) di-p-methoxydiiridium (I) ([Ir (OCH ₃ ) (C ₈ H ₁₂ )] ₂ ), and a suitable solvent such as, for example, heptane;

2: at a suitable temperature, such as, for example, 85 ° C, in the presence of a suitable catalyst, such as, for example, [1,1'-bis (diphenylphosphine) ferrocene] dichloropalladium (II), optionally in the form of a complex with dichloromethane, a suitable base such as, for example, potassium acetate and a suitable solvent, such as, for example, 1,4-dioxane;

3: at a suitable temperature, such as, for example, 85 ° C, in the presence of a suitable catalyst such as, for example, based on palladium tetrakis (Pd (PPh ₃ ) ₄ ), a suitable base such as, for example, sodium carbonate, and a suitable solvent such as, for example, 1,4-dioxane;

4: at a suitable temperature, such as, for example, room temperature, in the presence of a suitable base, such as, for example, sodium hydride, and a suitable solvent, such as, for example, dimethylformamide;

5: at a suitable temperature, such as, for example, 100 ° C, in the presence of a suitable catalyst such as, for example, palladium acetate (Pd (OAc) ₂ ), a suitable ligand such as, for example, 2,2'bis- ( diphenylphosphine) -1,1'-binaphthyl (BINAP), a suitable base such as, for example, cesium carbonate, and a suitable solvent, such as, for example, 1,4-dioxane, optionally by microwave irradiation;

6: at a suitable temperature, such as, for example, 0 ° C or room temperature, or at reflux, in the presence of a suitable acid, such as, for example, trifluoroacetic acid or aqueous hydrochloric acid, together with a suitable solvent, such as, for example, dichloromethane, methanol, ethyl acetate or 1,4-dioxane, or, alternatively, in the presence of silica in a suitable solvent such as, for example, toluene, at a suitable temperature, such as, for example, 125 ° C, and for a suitable time, for example 3 hours;

7: at a suitable temperature, such as, for example, room temperature, in the presence of a suitable desilylating agent, such as, for example, tetra-n-butylammonium fluoride, and a suitable solvent, such as, for example, 2-methyltetrahydrofuran or tetrahydrofuran;

8: at a suitable temperature, such as, for example, reflux temperature, in the presence of a suitable acid, such as, for example, an aqueous solution of hydrochloric acid, and a suitable solvent, such as, for example, dichloromethane, methanol, ethyl acetate or 1,4-dioxane , and for a suitable time, for example within 6 hours;

9: at a suitable temperature, such as, for example, 95 ° C, in the presence of a suitable acid, such as, for example, p-toluenesulfonic acid, and a suitable solvent, such as, for example, 1,4-dioxane.

- 41 037358

Scheme 4.

In general, compounds of formula (I) wherein R ² is R ^2b , which is C1-6 alkyl substituted with one OH group, R ³ is phenyl substituted with —C (= O) —R ¹⁰ and optionally other substituents according to the scope of this of the invention, Y is CR ⁴ , and where all other variables are meaningful within the scope of this invention, the compounds of formula (Id) referred to herein can be prepared according to the following Scheme 4. In Scheme 4, halogen ¹ is Cl, Br or I and PG ¹ is a suitable protecting group such as, for example, tert- (butoxycarbonyl) and PG ² is a suitable protecting group, such as, for example, tert-butyldimethylsilyl. All other variables in Scheme 4 are within the meaning of this invention.

In Scheme 4, the following reaction conditions apply:

(Id)

1: at a suitable temperature, such as, for example, 100 ° C, in the presence of a suitable catalyst such as, for example, palladium acetate (Pd (OAc) ₂ ), a suitable ligand such as, for example, 2,2'bis- ( diphenylphosphine) -1,1'-binaphthyl (BINAP), a suitable base such as, for example, cesium carbonate, and a suitable solvent, such as, for example, 1,4-dioxane, optionally by microwave irradiation;

2: at a suitable temperature, such as, for example, 70 ° C, in the presence of a suitable base, such as, for example, lithium hydroxide, and a suitable solvent, such as, for example, a mixture of tetrahydrofuran and water;

3: at a suitable temperature, such as, for example, room temperature, in the presence of a suitable reagent for coupling reactions, such as, for example, hexafluorophosphate 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4, 5-b] pyridinium-3-oxide (HATU), a suitable base such as, for example,, Ν-diisopropylethylamine, and a suitable solvent, such as, for example, dimethylformamide;

4: at a suitable temperature, such as, for example, room temperature, in the presence of a suitable desilylating agent, such as, for example, tetra-n-butylammonium fluoride, and a suitable solvent, such as, for example, 2-methyltetrahydrofuran or tetrahydrofuran;

5: at a suitable temperature, such as, for example, 0 ° C or room temperature, or under reflux, in the presence of a suitable acid, such as, for example, trifluoroacetic acid or aqueous hydrochloric acid, together with a suitable solvent such as dichloromethane, methanol , ethyl acetate or 1,4-dioxane, or alternatively in the presence of silica in a suitable solvent such as, for example, toluene, at a suitable temperature, such as, for example, 125 ° C, and for a suitable time, for example within 3 hours;

6: at a suitable temperature, such as, for example, reflux temperature, in the presence of a suitable acid, such as, for example, an aqueous solution of hydrochloric acid, together with a suitable solvent such as, for example, dichloromethane, methanol, ethyl acetate or 1,4- dioxane, and for a suitable time, for example within 6 hours.

Scheme 5.

In general, compounds of formula (I) wherein R ² is R ^2c which is C1-6 alkyl substituted with one Het ^3a or —NR ^6a R ^6b group where R ^6b is R ^6ba which is H, _{C1-6 alkyl and C 3- 6} cycloalkyl, Y is CR ⁴ , and where all other variables have a meaning in accordance with the scope of this invention, referred to in this application as compounds of formula (Ie) and formula (If), can be obtained according to the reaction scheme 5. In scheme 5 PG ¹ denotes a suitable protecting group such as, for example, tert- (butoxycarbonyl). All other variables in Scheme 4 have the meaning encompassed by this invention.

In Scheme 5, the following reaction conditions apply:

1: at a suitable temperature such as, for example, -78 ° C, in the presence of oxalyl chloride and dimethyl sulfoxide as reactants, a suitable base such as N, N-diisopropylethylamine, and a suitable solvent such as, for example, dichloromethane;

2: at a suitable temperature, such as, for example, room temperature, in the presence of a suitable acid, such as, for example, acetic acid, a suitable reducing agent, such as, for example, triacetoxyborohydride, and a suitable solvent, such as, for example, dichloroethane;

3: at a suitable temperature, such as, for example, 0 ° C or room temperature, or at reflux, in the presence of a suitable acid, such as, for example, trifluoroacetic acid or aqueous hydrochloric acid, together with a suitable solvent such as dichloromethane, methanol , ethyl acetate or 1,4-dioxane, or alternatively in the presence of silica in a suitable solvent such as, for example, toluene, at a suitable temperature, such as, for example, 125 ° C, and for a suitable time, for example within 3 hours

Scheme 6

In general, compounds of formula (I) wherein R ^{1 2 *} is C1-6αalkyl substituted with one OR ^7a , R ^7a is —C (= O) —R ⁹ or - (C = O) —CH (NH2) —C _1-4 αalkyl-Ar ¹ ), Y is CR ^{4 * * * *} , and where all other variables have a meaning in accordance with the scope of this invention, referred to in this application as compounds of formula (Ig), can be obtained in accordance with the reaction scheme 6. In Scheme 6, PG ¹ is a suitable protecting group such as, for example, tert- (butoxycarbonyl), tert-butyl or benzyl. All other variables in Scheme 6 have the meaning encompassed by this invention.

In Scheme 6, the following reaction conditions apply:

(XXXIII) (ig)

1: at a suitable temperature, such as, for example, room temperature, in the presence of a suitable reagent for coupling reactions, such as, for example, hexafluorophosphate 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4, 5-b] pyridinium-3-oxide (HATU), a suitable base such as, for example, N, N-diisopropylethylamine, and a suitable solvent such as, for example, a mixture of tetrahydrofuran and dimethylformamide, optionally with the following deprotection step using a suitable an acid such as, for example, hydrochloric acid, in a suitable solvent such as, for example, 1,4-dioxane;

2: at a suitable temperature, such as, for example, 0 ° C or room temperature, in the presence of a suitable acid, such as, for example, trifluoroacetic acid or an aqueous solution of hydrochloric acid, together with a suitable solvent, such as, for example, dichloromethane, methanol, ethyl acetate or 1,4-dioxane, or alternatively in the presence of silica in a suitable solvent, such as, for example, toluene, at a suitable temperature, such as, for example, 125 ° C, and for a suitable time, for example 3 hours.

Scheme 7.

In general, compounds of formula (I) wherein R ² is C _1-6 αalkyl substituted with one OR ^7b , R ^{7b is} about- 43 037358 is C 1-4 alkyl, Y is CR4, and where all other variables are by volume of the present invention, referred to herein as compounds of formula (Ih), can be prepared according to Reaction Scheme 7. In Scheme 7, halogen ¹ is Cl, Br or I; PG ¹ represents a suitable protecting group such as, for example, tert-butyldimethylsilyl; W is a leaving group such as, for example, methanesulfonate or toluenesulfonate, or halogen (Cl, Br or I). All other variables in Scheme 7 have the meaning encompassed by this invention.

In Scheme 7, the following reaction conditions apply:

(XXXVI)

1: at a suitable temperature, such as, for example, room temperature, in the presence of a suitable desilylating agent, such as, for example, tetra-n-butylammonium fluoride, and a suitable solvent, such as, for example, 2-methyltetrahydrofuran or tetrahydrofuran;

2: at a suitable temperature, such as, for example, room temperature, in the presence of a suitable base such as, for example, sodium hydride, and a suitable solvent, such as, for example, dimethylformamide;

3: at a suitable temperature, such as, for example, 85 ° C, in the presence of a suitable catalyst such as, for example, [1,1'-bis- (diphenylphosphine) ferrocene] dichloropalladium (B), optionally as a complex with dichloromethane, a suitable base such as, for example, potassium acetate, and a suitable solvent, such as, for example, 1,4-dioxane;

4: at a suitable temperature, such as, for example, 80 ° C, in the presence of a suitable catalyst such as, for example, palladium tetrakis- (Pd (PPh ₃ ) ₄ ), a suitable base such as, for example, sodium carbonate, and a suitable a solvent such as, for example, 1,4-dioxane;

5: at a suitable temperature, such as, for example, 80 ° C, in the presence of a suitable catalyst such as, for example, palladium acetate (Pd (OAc) ₂ ), a suitable ligand such as, for example, 2,2'bis- ( diphenylphosphine) -1,1'-binaphthyl (BINAP), a suitable base such as, for example, cesium carbonate, and a suitable solvent, such as, for example, 1,4-dioxane, optionally by microwave irradiation;

6: at a suitable temperature, such as, for example, 0 ° C or at room temperature, or under reflux, such as, for example, trifluoroacetic acid or an aqueous solution of hydrochloric acid, together with a suitable solvent, such as, for example, dichloromethane, methanol, ethyl acetate or 1,4-dioxane, or alternatively in the presence of silica in a suitable solvent such as, for example, toluene, at a suitable temperature, such as, for example, 125 ° C, and for a suitable time, for example for 3 h

Scheme 8.

In general, compounds of formula (I) wherein R ² is C 1-6 alkyl substituted with one OR ^7c , R ^7c is C 1-4 alkyl-NR ^8a R ^8b or C _1-4 alkyl-Het ^3b , Y is CR ⁴ , and where all other variables have meaning in accordance with the scope of this invention, referred to in this application as compounds of formula (Ij), can be obtained in accordance with the reaction scheme 8. In scheme 8 halogen ¹ is Cl, Br or I; PG ¹ represents a suitable protecting group such as, for example, tert-butoxycarbonyl; W ¹ represents a leaving group such as, for example, methanesulfonate or toluenesulfonate, or halogen (Cl, Br or I). W ² is a leaving group such as mesyl or tolyl, for example. All other variables in Scheme 7 have the meaning encompassed by this invention.

- 44 037358

In Scheme 8, the following reaction conditions apply:

1: at a suitable temperature, such as, for example, room temperature, in the presence of a suitable base, such as, for example, sodium hydride, and a suitable solvent, such as, for example, dimethylformamide,

2: at a suitable temperature, such as, for example, 55 ° C, in the presence of a reducing agent, such as, for example, sodium borohydride, and a suitable solvent, such as, for example, a mixture of tetrahydrofuran with methanol,

3: at a suitable temperature, such as, for example, 100 ° C, in the presence of a suitable catalyst, such as, for example, [1,1'-bis- (diphenylphosphine) ferrocene] dichloropalladium (II), optionally as a complex with dichloromethane, a suitable base such as, for example, potassium acetate, and a suitable solvent, such as, for example, 1,4-dioxane,

4: at a suitable temperature, such as, for example, 85 ° C, in the presence of a suitable catalyst such as, for example, palladium tetrakis (Pd (PPh ₃ ) ₄ ), a suitable base such as, for example, sodium carbonate, and a suitable solvent such as, for example, 1,4-dioxane;

5: at a suitable temperature, such as, for example, 120 ° C, in the presence of a suitable catalyst such as, for example, palladium acetate (Pd (OAc) ₂ ), a suitable ligand such as, for example, 2,2'bis- ( diphenylphosphine) -1,1'-binaphthyl (BINAP), a suitable base such as, for example, cesium carbonate, and a suitable solvent, such as, for example, 1,4-dioxane, optionally by microwave irradiation;

6: at a suitable temperature, such as, for example, 5 ° C, in the presence of a suitable base, such as, for example, triethylamine, and a suitable solvent, such as, for example, dichloromethane.

7: at a suitable temperature, such as, for example, 80 ° C, in the presence of a suitable solvent, such as, for example, acetonitrile;

8: at a suitable temperature, such as, for example, 0 ° C or at room temperature, or at reflux, in the presence of a suitable acid, such as, for example, such as, for example, trifluoroacetic acid or an aqueous solution of hydrochloric acid together with a suitable solvent, such as, for example, dichloromethane, methanol, ethyl acetate or 1,4-dioxane, or alternatively in the presence of silica in a suitable solvent such as, for example, toluene, at a suitable temperature, such as, for example, 125 ° C, and for a suitable time, for example 3 hours.

Scheme 9.

In general, compounds of formula (II) and (III), wherein R ² is R ^2a , which is C _i-6 alkyl, and where all other variables are meaningful within the scope of this invention, are referred to herein as compounds of formulas (II) and (III) can be prepared according to the following scheme 9. In scheme 9, halogen ¹ is Cl, Br or I; PG ¹ represents a suitable protecting group such as, for example, tert-butoxycarbonyl; W ¹ represents a leaving group such as, for example, methanesulfonate or toluenesulfonate, or halogen (Cl, Br or I). All other variables in Scheme 9 have the meaning encompassed by this invention.

- 45 037358

In Scheme 9, the following reaction conditions apply:

1: at a suitable temperature, such as, for example, 45 ° C, in the presence of a suitable reagent, such as, for example, di-tert-butyl dicarbonate, in the presence of a suitable catalyst, such as, for example, 4-dimethylaminopyridine (DMAP), and a suitable a solvent such as, for example, dichloromethane;

2: at a suitable temperature such as, for example, 65 ° C in the presence of a suitable solvent such as, for example, methanol;

3: in the case of (XLIXa) at a suitable temperature such as, for example, room temperature, in the presence of tri-n-butylphosphine and 1,1 '- (azodicarbonyl) piperidine and a suitable solvent such as, for example, 2-methyltetrahydrofuran;

In the case of (XLIXb), at a suitable temperature such as, for example, 80 ° C, in the presence of a suitable base such as, for example, potassium carbonate, a suitable additive such as, for example, sodium iodide, in a suitable solvent such as for example acetonitrile;

4: at a suitable temperature, such as, for example, 85 ° C, in the presence of sodium acetate, sodium formate and tetraethylammonium chloride, in the presence of a suitable catalyst such as, for example, palladium acetate (Pd (OAc) ₂ ), and a suitable solvent such such as dimethylformamide;

5: at a suitable temperature, such as, for example, 60 ° C, in the presence of sodium acetate, dehydrated sodium formate and tetraethylammonium chloride, in the presence of a suitable catalyst such as, for example, [1,1'-bis- (diphenylphosphine) ferrocene] dichloropalladium (H), optionally as a complex with dichloromethane, and a suitable solvent such as, for example, dimethylformamide,

6: at a suitable temperature, such as, for example, 40 ° C, in the presence of N-halosuccinimide and a suitable solvent, such as, for example, acetonitrile Alternatively, in the presence of a suitable reagent, such as, for example, 1,3-dibromo-5, 5-dimethylhydantoin, in a suitable solvent such as, for example, acetonitrile

Scheme 10

In general, compounds of formulas (XII) and (XIII), wherein R ² is R ^2b , which is C _1-6 alkyl substituted with one OH, and where all other variables are meaningful within the scope of this invention, referred to herein as compounds of formulas (XII) and (XIII) can be obtained according to the following reaction scheme 10. In scheme 10, halogen ¹ means Cl, Br or I, halogen ² means Cl, Br, I, PG1 means a suitable protecting group, such as, for example, tert-butoxycarbonyl, and PG ² is a suitable protecting group such as, for example, tert-butyldimethylsilyl. All other variables in Scheme 10 have the meaning encompassed by this invention.

In Scheme 10, the following reaction conditions apply:

in the case of (XLIXc) at a suitable temperature, such as, for example, room temperature, in the presence of tri-n-butylphosphine and 1,1 '- (azodicarbonyl) piperidine and a suitable solvent, such as, for example, 2-methyltetrahydrofuran, in the case of ( XLIXd) at a suitable temperature, such as, for example, 80 ° C, in the presence of a suitable base such as, for example, potassium carbonate, a suitable additive such as, for example, sodium iodide, in a suitable solvent, such as, for example,

- 46 037358 acetonitrile;

2: at a suitable temperature, such as, for example, 85 ° C, in the presence of sodium acetate, sodium formate and tetraethylammonium chloride, a suitable catalyst such as, for example, palladium acetate (Pd (OAc) ₂ ), and a suitable solvent such as, for example dimethylformamide;

3: at a suitable temperature, such as, for example, 60 ° C, in the presence of sodium acetate, dehydrated sodium formate and tetraethylammonium chloride, a suitable catalyst such as, for example, [1,1'-bis- (diphenylphosphinferrocene] palladium (P) chloride , optionally as a complex with dichloromethane, and a suitable solvent such as, for example, dimethylformamide;

4: at a suitable temperature, such as, for example, 40 ° C, in the presence of N-halogenosuccinamide and a suitable solvent, such as, for example, acetonitrile. Alternatively, in the presence of a suitable reagent such as, for example, 1,3-dibromo-5,5-dimethylhydantoin, in a suitable solvent, such as, for example, acetonitrile.

Scheme 11.

In general, compounds of formula (I) wherein R ^{1 2 is} shown in Scheme 11, Y is CR ⁴ , and where all other variables are meaningful within the scope of this invention, referred to herein as compounds of formula (Ik), can be prepared according to the following Reaction Scheme 11. In Scheme 11, PG ¹ is a suitable protecting group such as, for example, tert-butoxycarbonyl. All other variables in diagram 11 have the meaning encompassed by this invention.

In Scheme 1, the following reaction conditions apply:

1: at a suitable temperature, such as, for example, room temperature, and in the presence of a suitable solvent, such as, for example, tetrahydrofuran;

2: at a suitable temperature, such as, for example, 0 ° C or room temperature, or at reflux in the presence of a suitable acid, such as, for example, trifluoroacetic acid or an aqueous solution of hydrochloric acid, in a suitable solvent, such as, for example, dichloromethane, methanol, ethyl acetate or 1,4-dioxane, or alternatively in the presence of silica in a suitable solvent such as, for example, toluene, at a suitable temperature, such as, for example, 125 ° C, and for a suitable time, for example in for 3 hours.

Scheme 12.

In general, compounds of formula (I) wherein R ^{2 is} shown in Scheme 12, Y is CR ⁴ , and where all other variables are meaningful within the scope of this invention, referred to herein as compounds of formula (II), can be prepared by the following Reaction Scheme 12. In Scheme 12, PG ¹ is a suitable protecting group such as, for example, tert-butoxycarbonyl. All other variables in Scheme 11 have the meaning covered by this invention.

In Scheme 12, the following reaction conditions apply:

1: at a suitable temperature, such as, for example, room temperature, and in the presence of tert-butyl alcohol, 2-methyl-2-butene, sodium dihydrogen phosphate and distilled water;

2: at a suitable temperature, such as room temperature, and in the presence of 1- 47 037358

[bis- (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate (HATU) and dimethylaminopyridine (DMAP), a suitable base such as, for example, DIPEA, and a suitable a solvent such as, for example, dimethylformamide;

3: at a suitable temperature, such as, for example, room temperature, and in the presence of a suitable solvent, such as, for example, tetrahydrofuran;

4: at a suitable temperature, such as, for example, 0 ° C or room temperature, or at reflux in the presence of a suitable acid, such as, for example, trifluoroacetic acid or an aqueous solution of hydrochloric acid, in a suitable solvent, such as, for example, dichloromethane, methanol, ethyl acetate or 1,4-dioxane, or alternatively in the presence of silica in a suitable solvent such as, for example, toluene, at a suitable temperature, such as, for example, 125 ° C, and for a suitable time, for example in for 3 hours.

Scheme 13.

In general, compounds of formula (I) wherein R ^{1 2 3 is} shown in Scheme 13, Y is CR ⁴ , and where all other variables are meaningful within the scope of this invention, referred to herein as compounds of formula (Im), may be prepared according to the following Reaction Scheme 13. In Scheme 13, PG ¹ is a suitable protecting group such as, for example, tert-butoxycarbonyl. All other variables in Scheme 13 have the meaning encompassed by this invention.

In Scheme 13, the following reaction conditions apply:

1: at a suitable temperature, such as, for example, room temperature, and in the presence of tert-butyl alcohol, 2-methyl-2-butene, sodium dihydrogen phosphate and distilled water,

2: at a suitable temperature, such as room temperature, and in the presence of 1 [bis- (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate (HATU) and dimethylaminopyridine (DMAP), a suitable base such as, for example, DIPEA, and a suitable solvent, such as, for example, dimethylformamide,

3: at a suitable temperature, such as, for example, 0 ° C, and in the presence of a suitable solvent, such as, for example, terahydrofuran (AlD ₄ Li means lithium aluminum deuteride),

4: at a suitable temperature, such as, for example, 0 ° C or room temperature, or at reflux in the presence of a suitable acid, such as, for example, trifluoroacetic acid or an aqueous solution of hydrochloric acid, in a suitable solvent, such as, for example, dichloromethane, methanol, ethyl acetate or 1,4-dioxane, or alternatively in the presence of silica in a suitable solvent such as, for example, toluene, at a suitable temperature, such as, for example, 125 ° C, and for a suitable time, for example in for 3 hours.

Scheme 14.

In general, compounds of formula (I) wherein R ² is C1-6 alkyl substituted with one Het ^3a or —NR ^6a R ^6b , where R ^6a is H, R ^6b is —C (= O) —C1-4 alkyl; -C (= O) -Het ⁴ ; -S (= O) ₂ -C _1-4 alkyl, Y is CR ⁴ , and where all other variables have a meaning in accordance with the scope of this invention, referred to in this application as compounds of formula (In), formula (Io) and formula ( Ip) can be prepared according to the following Reaction Scheme 14. In Scheme 14, PG ¹ is a suitable protecting group such as, for example, tert-butoxycarbonyl. All other variables in diagram 14 have the meaning encompassed by this invention.

- 48 037358

In Scheme 14, the following reaction conditions apply:

(YU)

1: at a suitable temperature, such as, for example, room temperature, in the presence of a suitable acid, such as, for example, acetic acid, in the presence of a suitable reducing agent, such as, for example, sodium triacetoxyborohydride, in a suitable solvent, such as, for example, dichloroethane ;

2: at a suitable temperature, such as, for example, room temperature, in the presence of a suitable base, such as, for example, triethylamine, in a suitable solvent, such as, for example, tetrahydrofuran;

3: at a suitable temperature, such as, for example, room temperature, in the presence of a suitable acid, such as, for example, trifluoroacetic acid, in a suitable solvent, such as, for example, dichloromethane.

Scheme 15.

In general, compounds of formula (I) wherein R ^{1 2 *} is C _1-6 alkyl substituted with one Het ^3a or

NR ^6a R ^6b , where R ^6a is C1-4 alkyl, R ^6b is —C (= O) —C1-4 alkyl; -C (= O) -Het ⁴ ; -S (= O) ₂ -C _1-4 alkyl, Y is CR ⁴ , and where all other variables have a meaning in accordance with the scope of this invention, referred to in this application as compounds of formula (Iq), formula (Ir) and formula ( Is) can be prepared according to the following Reaction Scheme 15. In Scheme 15, PG ¹ is a suitable protecting group such as, for example, tert-butoxycarbonyl. All other variables in Scheme 15 have the meaning encompassed by this invention.

In Scheme 15, the following reaction conditions apply:

1: at a suitable temperature, such as, for example, room temperature, in the presence of a suitable acid, such as, for example, acetic acid, in the presence of a suitable reducing agent, such as, for example, sodium triacetoxyborohydride, in a suitable solvent, such as, for example, dichloroethane ;

2: at a suitable temperature, such as, for example, room temperature, in the presence of a suitable base, such as, for example, triethylamine, in a suitable solvent, such as, for example, tetrahydrofuran;

- 49 037358

3: at a suitable temperature, such as, for example, room temperature, in a suitable solvent, such as, for example, dichloromethane.

Scheme 16.

In general, compounds of formula (I) wherein R ^{1 2 3} is C1.6 alkyl substituted with one OR ^7d , R ^7d is —S (= O) 2-OH or —P (= O) - (OH) ₂ , Y denotes CR4, and where all other variables have a meaning in accordance with the scope of this invention, referred to in this application as compounds of formula (It) and formula (Iu), can be obtained according to the following reaction scheme 16. All other variables in scheme 16 have the meaning, covered by this invention.

In Scheme 16, the following reaction conditions apply:

1: at a suitable temperature, such as, for example, room temperature, in a suitable solvent, such as, for example, tetrahydrofuran, in the presence of a suitable base, such as, for example, sodium hydroxide;

2: in the presence of a suitable reagent, such as, for example, tetrazole, in the presence of a suitable oxidizing agent, such as, for example, meta-chloroperbenzoic acid, in a suitable solvent, such as, for example, acetonitrile;

3: at a suitable temperature, such as, for example, room temperature, in a suitable acid, such as, for example, hydrochloric acid, in a suitable solvent, such as, for example, acetonitrile;

Scheme 17.

In general, intermediates of formula (XII), where all variables are meaningful within the scope of this invention, can be prepared by the following Reaction Scheme 17.

In Scheme 17, the following reaction conditions apply:

1: at a suitable temperature between -5 and 5 ° C in the presence of a suitable base such as, for example, sodium tert-butoxide, in a suitable solvent, such as, for example, tetrahydrofuran;

2: at a suitable temperature between 65 and 70 ° C, in the presence of a suitable reagent such as, for example, di-tert-butyl dicarbonate, in the presence of a suitable catalyst such as, for example, 4-dimethylaminopyridine (DMAP), and a suitable solvent such as, for example, tetrahydrofuran;

3: at a suitable temperature between 45 and 50 ° C, in the presence of sodium acetate, dehydrated sodium formate and tetraethylammonichloride, a suitable catalyst such as, for example, palladium acetate or [1,1'-bis- (diphenylphosphino) ferrocene] palladium (B) chloride, optionally as a complex with dichloromethane, and a suitable solvent such as, for example, dimethylform-50 037358 mid.

Scheme 18.

In general, compounds of formula (I) wherein R ^{1 2} is C ₁ . ₆ α-alkyl substituted with one R ^{5 * * * *} , R ⁵ is fluorine, Y is CR4, and where all other variables are meaningful within the scope of this invention, referred to herein as compounds of formula (Iv), can be prepared by the following Reaction Scheme 18. All other variables in Scheme 18 are of the present invention.

In Scheme 18, the following reaction conditions apply:

matter covered

1: in the presence of a suitable fluorinating agent, such as, for example, diethylaminosulfur fluoride, a suitable solvent, such as, for example, dichloromethane, at a suitable temperature, such as, for example, room temperature.

Scheme 19.

In general, compounds of formula (I) wherein R ² is C ₁ . ₆ alkyl substituted with one OH group, Y is N, and where all other variables are meaningful within the scope of this invention, referred to herein as compounds of formula (Iw) can be prepared by the following Reaction Scheme 19. In Scheme 19, halogen ¹ denotes Cl, Br or I; PG ¹ is a suitable protecting group such as, for example, t- (butoxycarbonyl) and PG ² is a suitable protecting group, such as, for example, tert-butyldimethylsilyl. All other variables in Scheme 19 have the meaning encompassed by this invention.

In Scheme 19, the following reaction conditions apply:

1: in the presence of a suitable base such as, for example, diisopropylethylamine, in a suitable solvent, such as, for example, acetonitrile;

2: in the presence of a suitable catalyst such as, for example, [1,1'-bis- (diphenylphosphine) ferrocene] dichloropalladium (P), optionally as a complex with dichloromethane, a suitable base such as, for example, a base in the form of an aqueous solution hydrogen carbonate at a suitable temperature such as, for example, 80 ° C;

3: at a suitable temperature, such as, for example, 0 ° C or room temperature, or at reflux, in the presence of a suitable acid, such as, for example, trifluoroacetic acid or aqueous hydrochloric acid, together with a suitable solvent such as dichloromethane, methanol , ethyl acetate or 1,4-dioxane, or alternatively in the presence of silica in a suitable solvent such as, for example, toluene, at a suitable temperature, such as, for example, 125 ° C, and for a suitable time, for example within 3 hours;

4: at a suitable temperature, such as, for example, room temperature, in the presence of a suitable disilylating agent, such as, for example, tetra-n-butylammonium fluoride, and a suitable solvent, such as, for example, 2-methyltetrahydrofuran or tetrahydrofuran.

Scheme 20.

In general, compounds of formula (I) wherein R ² is C _1-6 alkyl substituted with one OH group, R ³ is phenyl substituted with —C (= O) —R ¹⁰ and optionally substituted with other substituents within the scope of this invention, Y is CR ⁴ , referred to herein as compounds of formulas (Ida), (Idb) and (Idc), can be prepared according to the following Reaction Scheme 20. In Scheme 20, halogen ¹ is Cl, Br or I; PG ¹ is a suitable protecting group such as, for example, tert-51037358 (butoxycarbonyl) and PG ² is a suitable protecting group such as, for example, tert-butyldimethylsilyl. All other variables in Scheme 20 have the meaning encompassed by this invention.

In Scheme 20, the following reaction conditions apply:

1: at a suitable temperature, such as, for example, 120 ° C, in the presence of a suitable catalyst such as, for example, palladium acetate (Pd (OAc) ₂ ), a suitable ligand such as, for example, 2,2'bis- ( diphenylphosphine) -1,1'-binaphthyl (BINAP), a suitable base such as, for example, cesium carbonate, and a suitable solvent, such as, for example, 1,4-dioxane, optionally by microwave irradiation;

2: at a suitable temperature, such as, for example, 60 ° C, in the presence of a suitable base, such as, for example, lithium hydroxide, and a suitable solvent, such as, for example, a mixture of tetrahydrofuran and water;

3: at a suitable temperature, such as, for example, room temperature, in the presence of a suitable reagent for the coupling reaction, such as, for example, hexafluorophosphate 1- [bis (dimethylamino) methylene] -1 H-1,2,3-triazolo [4 , 5-b] pyridinium-3-oxide (HATU), a suitable base such as, for example,, Ν-diisopropylethylamine, and a suitable solvent such as, for example, dimethylformamide or dichloromethane.

Scheme 21.

In general, compounds of formula (I), wherein R ^{1 2 *} is C _1-6 alkyl substituted with one OH group, Y is CR ⁴ , and where all other variables have meanings within the scope of this invention, referred to herein as compounds of formula ( Ic) can be obtained by the following Reaction Scheme 21. All other variables in Scheme 21 have the meaning encompassed by this invention.

In Scheme 21, the following reaction conditions apply:

1: at a suitable temperature, such as, for example, 90 ° C, in the presence of a suitable acid, such as, for example, p-toluenesulfonic acid, a suitable solvent, such as, for example, 1,4-dioxane.

It should be borne in mind that, where appropriate functional groups are contained, compounds of different formulas or any intermediates used to prepare them can then be derivatized according to one or more standard synthetic methods using condensation, substitution, oxidation, reduction or cleavage reactions. ... Specific substitution approaches include conventional alkylation, arylation, heteroarylation, acylation, sulfonylation, halogenation, nitration, formylation, and combinations of these modifications.

The compounds of formula (I) can be synthesized as racemic mixtures of enantiomers, which can be separated from one another by the following known resolution methods. Racemic compounds of formula (I) containing a base nitrogen atom can be converted to the corresponding diastereomeric salt mixtures by reaction with a suitable chiral acid. These diastereomeric salt forms are then separated, for example by selective or fractional crystallization, and from them the enantiomers are liberated with alkali. An alternative method for separating enantiomeric forms of 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 proceeds stereospecifically.

In the preparation of compounds of the present invention, it may be necessary to protect hard-to-reach functional groups (eg, primary and secondary amino groups) of intermediates. The necessity of such protection strongly depends on the nature of the removed functional groups and the conditions of the methods of preparation. Suitable amino protecting groups (NH-Pg) include acetyl, trifluoroacetyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection is easily determined by the person skilled in the art. For a general description of protecting groups and their uses, see F.W. Greene and P.G.M. Wuts, Protective Groups 1 N Organic Synthesis, 4th ed., Wiley, Hoboken, New Jersey, 2007.

Pharmacology.

The compounds of the present invention have been found to inhibit NF-kB inducible kinase (NIK - also known as MAP3K14). Some of the compounds of this invention can be metabolized to give the more active form 1 N vivo (prodrug). Therefore, the compounds of the invention and pharmaceutical compositions containing such compounds may be useful for the treatment or prevention of diseases such as cancer, inflammatory diseases, metabolic disorders, including obesity and diabetes, and autoimmune diseases. In particular, the compounds of the invention and pharmaceutical compositions based on them may be useful in the treatment of hematological malignant neoplasms or solid tumors. In a specific embodiment, said hematologic malignancies are selected from the group consisting of multiple myeloma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, T cell leukemia, mucosal lymphoid lymphoma, diffuse large B cell lymphoma, and mantle cell lymphoma. In another specific embodiment of the present invention, the solid cancer is selected from the group consisting of pancreatic cancer, breast cancer, melanoma, and non-small cell lung cancer.

Examples of cancers that can be treated (or that are inhibited) include, but are not limited to, carcinomas such as bladder, breast, colon carcinomas (eg, colorectal carcinomas such as colon adenocarcinoma, colon adenoma), kidney, urothelial carcinoma, carcinoma of the uterus, epidermis, liver, lung (eg, adenocarcinoma, small cell lung cancer and non-small cell lung cancer, squamous lung cancer), esophagus, head and neck, gallbladder, ovary, thyroid gland (eg, exocrine pancreatic carcinoma), stomach cancer, gastrointestinal cancer (also known as stomach cancer) (eg gastrointestinal stromal tumor), cervical, endometrial, thyroid, prostate, or skin cancer (eg squamous cell carcinoma or bulging dermatofibrosarcoma; pituitary cancer, tumor hematopoietic tissue of the lymphatic system, for example, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, B-cell lymphoma (eg, diffuse large B-cell lymphoma, mantle cell lymphoma), T-cell leukemia / lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, or Burkitt's lymphoma; a tumor of hematopoietic myeloid tissue, for example, leukemia, acute and chronic myelogenous leukemia, chronic myelomonocytic leukemia (CMML), myeloproliferative disorder, myeloproliferative syndrome, myelodysplastic syndrome, or promyelocytic leukemia; multiple myeloma; follicular thyroid cancer; hepatocellular carcinoma, tumor of mesenchymal origin (eg, Ewing's sarcoma), eg fibrosarcoma or rhabdomyosarcoma, tumor of the central or peripheral nervous system, eg astrocytoma, neuroblastoma, glioma (such as glioblastoma multiforme) or schwannoma; melanoma; seminal; teratocarcinoma; osteosarcoma; xeroderma pigmented; keratoacanthoma; follicular thyroid cancer; or Kaposi's sarcoma.

Specific examples of cancers that can be treated (or are inhibited) include B cell cancers such as multiple myeloma, Hodgkin's lymphoma, mantle cell lymphoma, diffuse large B cell lymphoma, or chronic lymphocytic leukemia, with mutations in the noncanonical signaling pathway. NFkB (for example, in the NIK (MAP3K14), TRAF3, TRAF2, BIRC2, or BIRC3 genes).

Therefore, the present invention relates to compounds of formula (I), their tautomers and stereoisomeric forms, pharmaceutically acceptable addition salts and solvates for use as a medicine.

The present invention also relates to the use of a compound of formula (I), its tautomer and stereoisomeric form, a pharmaceutically acceptable addition salt and a solvate, or a pharmaceutical composition according to the invention for the preparation of a medicament.

The present invention also relates to a compound of formula (I), its tautomer and stereoisomeric form, a pharmaceutically acceptable addition salt and a solvate, or to a pharmaceutical composition according to the invention for use in the treatment, prevention, amelioration, regulation or reduction of the risk of diseases associated with dysfunction induced by NF β-kB kinases in a mammal, including a human, and their treatment or prevention is influenced or facilitated by inhibition of the inducible NF-kB kinase.

The present invention also relates to the use of a compound of formula (I), its tautomer and

- 53 037358 a stereoisomeric form, a pharmaceutically acceptable addition salt and a solvate, or a pharmaceutical composition according to the invention for use in the preparation of a medicament for the treatment, prevention, amelioration, regulation or reduction of the risk of diseases associated with dysfunction of NF-κB-induced kinase in a mammal, including a human , while their treatment or prevention is influenced or facilitated by inhibition of inducible NF-κB kinase.

The present invention also relates to the use of a compound of formula (I), its tautomer and stereoisomeric form, pharmaceutically acceptable addition salt and solvate for use in the treatment or prevention of any of the diseases previously mentioned in this application.

The present invention also relates to the use of a compound of formula (I), its tautomer and stereoisomeric form, pharmaceutically acceptable addition salt and solvate for the preparation of a medicament for the treatment or prophylaxis of any of the diseases mentioned earlier in this application.

The compounds of this invention can be administered to mammals, preferably humans, for the treatment or prevention of any of the diseases previously mentioned in this application.

In view of the usefulness of the compound of formula (I), its tautomer and stereoisomeric form, pharmaceutically acceptable addition salt and solvate, this application provides a method of treating warm-blooded animals, including humans, suffering from any of the diseases previously mentioned in this application.

The specified method includes the introduction, namely, systemic or topical administration, preferably oral administration of a therapeutically effective amount of a compound of formula (I), its tautomer and stereoisomeric form, pharmaceutically acceptable addition salt and solvate, warm-blooded animals, including humans.

Therefore, the present invention also relates to a method of treating any of the diseases previously mentioned in this application, comprising administering a therapeutically effective amount of a compound of the invention to a patient in need thereof.

It will be apparent to those skilled in the art that a therapeutically effective amount of a compound of this invention means an amount sufficient to have therapeutic activity and that this amount varies, inter alia, depending on the type of disease, the concentration of this compound in the therapeutic formulation, and the condition of the patient. In general, the amount of a compound of this invention to be administered as a therapeutic agent for the treatment of the diseases described herein will be determined on a case by case basis by the attending physician.

One of ordinary skill in the treatment of such diseases can determine the effective therapeutic daily amount from the results of the tests described later in this application. An effective therapeutic daily amount is from about 0.005 to 50 mg / kg, in particular from 0.01 to 50 mg / kg of body weight, more particularly from 0.01 to 25 mg / kg of body weight, preferably from about 0.01 to about 15 mg / kg mg / kg, more preferably from about 0.01 to about 10 mg / kg, even more preferably from about 0.01 to about 1 mg / kg, most preferably about 0.05 to about 1 mg / kg of patient weight. A specific effective therapeutic daily amount may be from about 10 weight to 40 mg / kg of patient weight. A specific effective therapeutic daily amount can be 1, 2, 4, or 8 mg / kg body weight. The amount of a compound of the present invention, referred to herein as an active ingredient, which is required to achieve a therapeutic effect may vary from case to case, depending, for example, on the particular compound, the route of administration, the age and condition of the recipient, and the particular disease or disorder undergoing treatment. The method of treatment may also include administering the active ingredient in a regimen of one to four doses per day. In these methods of treatment, the compounds of this invention are preferably formulated prior to administration. As described below, suitable pharmaceutical formulations are prepared in a known manner using well known and readily available ingredients.

The present invention also provides compositions for the prevention or treatment of the diseases described in this application. These compositions contain a therapeutically effective amount of a compound of formula (I), its tautomer and stereoisomeric form, a pharmaceutically acceptable salt or solvate, and a pharmaceutically acceptable carrier or diluent.

Although it is possible to enter one active ingredient, it is preferable to use it in the form of a pharmaceutical composition. Accordingly, the present invention provides a pharmaceutical composition comprising a compound of the 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.

The pharmaceutical compositions of this invention can be prepared by any method known in the pharmaceutical industry using methods such as those described in Gennaro et al. Remington's Pharmaceutical Sciences (. 18 ^th ed, Mack Publishing Company, 1990, see especially Part 8:. Pharmaceutical preparations and their Manufacture). Therapeutically effective amount

- 54 037358 of a specific compound, in the form of a base or in the form of an addition salt, as an active ingredient is combined in an intimate mixture with a pharmaceutically acceptable carrier, which can be in a wide variety of forms depending on the type of preparation that is desired to be administered. Desirably, these pharmaceutical compositions are in unitary dosage form, preferably for systemic administration such as oral, percutaneous or parenteral administration; or topical administration, such as administration by inhalation, as a nasal spray, eye drops, or with a cream, gel, shampoo or the like. For example, when preparing the composition in the form of an oral dosage form, any of the usual pharmaceutical media can be used, 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 preferred oral dosage form when solid pharmaceutical carriers are used. For parenteral compositions, the carrier will typically comprise at least a large portion of sterile water, although other ingredients, for example, to aid solubility, may be included. For example, injectable solutions can be prepared in which the carrier comprises saline, glucose solution, or a mixture of saline and glucose solution when appropriate liquid carriers, suspending agents, and the like can be used. In compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and / or a suitable wetting agent, optionally combined with suitable additives of any nature in small amounts, these additives do not have any significant adverse effect on the skin. These additives may facilitate administration to the skin and / or may be useful in preparing the desired compositions. These compositions can be administered in various ways, for example, as a transdermal patch, drip or as an ointment.

It is particularly preferred to formulate the aforementioned pharmaceutical compositions in unit dosage form for easy administration and uniformity of dosage. The term unit dosage form as used in the description and claims of this application refers to physically discrete forms suitable for single dosage, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect in conjunction with the required pharmaceutical carrier. Examples of such unit dosage forms include tablets (including scored and coated tablets), capsules, pills, powder sachets, cachets, injection solutions or suspensions, teaspoon, tablespoon, and the like. and their multiple parts.

The present invention can be used for systemic administration, such as oral, transdermal, or parenteral administration, or topical administration, such as administration by inhalation, as a nasal spray, eye drops, or with a cream, gel, shampoo, or the like. It is preferred to administer the compounds orally. The accuracy of the doses and the frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, age, weight, sex, the degree of development of the disease and the general physical condition of the particular patient, as well as other type of treatment. to which a patient may be exposed, as is well known to those skilled in the art. In addition, it is obvious that the specified effective daily amount can be reduced or increased depending on the response of the subject being treated and / or depending on the judgment of the physician, prescribing the compounds according to this invention.

The compounds of this invention can be administered alone or in combination with one or more additional therapeutic agents. Combination therapy includes the administration of a single pharmaceutical dosage form that contains a compound of this invention and one or more additional therapeutic agents, as well as the administration of a compound of this invention and each additional therapeutic agent in the form of their separate pharmaceutical dosage forms. For example, a compound of this invention and a therapeutic agent can be administered to a patient together in a single oral dosage form, such as a tablet or capsule, or each agent can be administered in separate oral pharmaceutical dosage forms.

Therefore, one of the variants of the present invention relates to a product containing, as a first active agent, a compound of the invention and as another active ingredient, one or more medical preparations, more particularly one or more anticancer agents or adjuvants in the form of a combined preparation for simultaneous, separate or sequential use for the treatment of patients suffering from cancer.

Accordingly, for the treatment of the conditions described above in this application, the compounds of the invention can advantageously be used in combination with one or more other drug agents (also referred to as therapeutic agents), more particularly with other anti-cancer agents or adjuvants used in the treatment of cancer. Examples of anti-cancer agents or

- 55 037358 adjuvants (additional agents in therapy) include, but are not limited to:

coordination compounds of platinum, for example cisplatin, optionally combined with amifostine, carboplatin or oxaplatin;

taxanes such as paclitaxel, protein-coupled paclitaxel particles (AbraxaneTM), or docetaxel;

topoisomerase I inhibitors such as camptothecin compounds, eg irinotecan, SN-38, topotecan, topotecan hydrochloride;

topoisomerase II inhibitors such as antineoplastic epipodophyllotoxins or podophyllotoxin derivatives such as etoposide, etoposide phosphate or tenoposide;

antineoplastic vinca alkaloids such as vinblastine, vincristine or vinorelbine;

antitumor derivatives of nucleosides, for example, 5-fluoracil, leucovorin, gemcitabine, gemcitabine hydrochloride, capecitabine, cladribine, fludarabine, nelarabine;

alkylating agents such as chlormethine or nitrosourea, for example cyclophosphamide, chlorambucil, carmustine, thiotepa, mephalan (melphalan), lomustine, altretamine, busulfan, dacarbazine, estramustine, ifosfamide, optionally in combination with mesnomaznom, photominozamide, photominozamide ;

antitumor anthracycline derivatives, for example daunorubicin, doxorubicin, optionally in combination with dexrazoxan, doxil, idarubicin, mitoxantrone, epirubicin, epirubicin hydrochloride, valrubicin;

molecules that target the IGF-1 receptor, such as picropodophilin;

derivatives of tetracarcin, for example tetracarcin A;

glucocorticoids such as prednisone;

antibodies, such as trastuzumab (anti-HER2 antibody), rituximab (anti-CD20 antibody), gemtuzumab, gemtuzumab ozogamicin, cetuximab, pertuzumab, bevacizumab, alemtuzumab, eculizumab, CNT, tiuksetan, tiuksetan 328, tiabositumetumabTO;

estrogen receptor antagonists or selective estrogen receptor modulators or estrogen synthesis inhibitors such as tamoxifen, fulvestrant, toremifene, droloxifene, fazlodex, raloxifene, or letrozole;

aromatase inhibitors such as exemestane, anastrozole, letrazole, testolactone, and vorozol;

differentiating agents such as retinoids, vitamin D or retinoic acid and retinoic acid metabolism blockers (RAMBA), for example accutane;

DNA methyltransferase inhibitors such as azacytidine or decitabine;

antifolates such as pemetrexed disodium;

antibiotics such as actinomycin D, bleomycin, mitomycin C, dactinomycin, carminomycin, daunomycin, levamisole, plikamycin, mithramycin;

antimetabolites such as clofarabine, aminopterin, cytosine arabinoside or methotrexate, azacytidine, cytarabine, floxuridine, pentostatin, thioguanine;

agents for inducing apoptosis and anti-angiogenic agents such as Bcl-2 inhibitors, for example YC 137, BH 312, ABT 737, gossypol, HA 14-1, TW 37 or decanoic acid;

tubulin binding agents such as combrestatin, colchicines, or nocodazole;

kinase inhibitors such as EGFR inhibitors (epithelial (growth factor receptor, MTKI (multipurpose kinase inhibitors), mTOR inhibitors), such as flavoperidol, imatinib mesylate, erlotinib, gefitinib, dasatinib, lapatinib, lapatinib soodenibusilate, sapatinib, ditosylate)

farnesyltransferase inhibitors such as tipifarnib;

histone deacetylase (HDAC) inhibitors, eg sodium butyrate, hydroxamic acid suberoylanilide (SAHA), depsipeptide (FR 901228), NVP-LAQ824, R306465, quizinostat, trichostatin A, vorinostat;

inhibitors of the ubiquitin proteasome signaling pathway, for example PS-341, Velcade (MLN-341), or bortezomib;

yondelis;

telomerase inhibitors such as telomestatin;

matrix metalloproteinase inhibitors such as batimastat, marimastat, prinostat, or metastat;

recombinant interleukins such as aldesleukin, denileukin diftitox, interferon alfa 2a, interferon alfa 2b, peginterferon alfa 2b;

MAPK inhibitors;

retinoids such as alitretinoin, bexarotene, tretinoin;

arsenic trioxide;

asparaginase;

steroids such as dromostanolone pripionate, megestrol acetate, nandrolone (decanoate, fenpropionate), dexamethasone;

- 56 037358 agonists or antagonists of gonadotropin-releasing hormone, for example abarelix, goserelin acetate, histrelin acetate, leuprolide acetate;

thalidomide, lenalidomide;

mercaptopurine, mitotane, pamidronate, pegademase, pegaspargase, rasburicase;

BH3 mimetics, for example AVT-199;

MEK inhibitors such as PD98059, AZD6244, CI-1040;

colony-stimulating factor analogs, eg filgrastim, pegfilgrastim, sargramostim, erythropoietin or analogs thereof (eg darbepoetin alfa); interleukin 11; oprelvekin; zoledronate, zoledronic acid; fentanyl; bisphosphonate; palefermin;

a steroid inhibitor of cytochrome P450-dependent 17-alpha-hydroxylase-17,20-lyase (CYP17), for example, abiraterone, abiraterone acetate.

One or more drug agents and a compound of this invention can be administered simultaneously (eg, as separate or single compositions) or sequentially in any order. In the latter case, two or more compounds will be administered over a period and in an amount and in a manner that is sufficient to provide an advantageous or synergistic effect. It should be borne in mind that the preferred mode or order of administration and the corresponding dosage and treatment regimens for each component of the combination will depend on the particular medicinal agent and compound of this invention being administered, the route of administration, the particular tumor being treated, and the particular host. undergoing treatment. The optimal route and route of administration and dosage and dosage regimen can be readily determined by those skilled in the art using conventional techniques and information provided herein.

The weight ratio of a compound of this invention and one or more other anti-cancer agent (s), when used in combination, can be determined by one of ordinary skill in the art. The specified ratio and the exact dosage and frequency of administration depend on the type of the particular compound of the invention and other anticancer agent (s) used, the particular condition being treated, the severity of the condition being treated, age, weight, sex, diet, time of administration and general physical the condition of a particular patient, the route of administration, and the kind of other drugs that the patient can take, as is well known to those skilled in the art. In addition, it will be appreciated that the effective daily amount can be decreased or increased depending on the response of the subject being treated and / or depending on the judgment of the physician prescribing the compounds of this invention. The specific weight ratio of the compound of formula (I) and the other anti-cancer agent may be in the range of 1/10 to 10/1, more particularly 1/5 to 5/1, even more particularly 1/3 to 3/1.

Platinum coordination compound is advantageously administered in a dosage of 1 to 500 mg / m ² body surface area, for example 50 to 400 mg / m ^2, particularly for cisplatin in a dosage of about 75 mg / m ² and for carboplatin in a dose of about 300 mg / m ² during the course of treatment.

The taxane is advantageously administered at a dose of 50 to 400 mg / m ² body surface area, for example 75 to 250 mg / m ² , specifically for paclitaxel at a dose of about 175 to 250 mg / m ² and for docetaxel about 75 to 150 mg / m ² during the course of treatment.

Camptothecins are advantageously administered at a dose of 0.1 to 400 mg / m ² body surface area, for example 1 to 300 mg / m ² , specifically for irinotecan at a dose of about 100 to 350 mg / m ² and for topotecan about 1 to 2 mg / m ² during the course of treatment.

Antitumor podophyllotoxin derivative is advantageously administered in a dosage of 30 to 300 mg / m ² body surface area, for example 50 to 250 mg / m ^2, particularly for etoposide in a dosage of about 35 to 100 mg / m ² and for teniposide from about 50 to 250 mg / m ² during the course of treatment.

The antineoplastic vinca alkaloid is advantageously administered in a dosage of 2 to 30 mg / m ² body surface area, for example for vinblastine in a dosage of about 3 to 12 mg / m ^2, for vincristine in a dosage of about 1 to 2 mg / m ² and vinorelbine at a dose of about 10 to 30 mg / m ² during the course of treatment.

The antitumor nucleoside derivative is advantageously administered in a dosage of 200 to 2500 mg / m ² body surface area, for example 700 to 1500 mg / m ^2, particularly for 5-FU in a dosage of 200 to 500mg / m ^2, for gemcitabine in a dosage of about 800 to 1200 mg / m ² and for capecitabine about 1000 to 2500 mg / m ² during the course of treatment.

Alkylating agents such as chlormethine or nitrosourea, during the course during treatment is advantageously administered in a dosage of 100 to 500 mg / m ² body surface area, for example in a dose of 120 to 200 mg / m ^2, particularly in the case of cyclophosphamide in a dosage of about 100 to 500 mg / m ² , in the case of chlorambucil at a dose of about 0.1 to 0.2 mg / kg, in the case of carmustine at a dose of about 150 to 200 mg / m ² and in the case of lomustine at a dose of about 100 to 150 mg / m ² .

The antitumor anthracycline derivative during treatment is advantageously administered in a dosage of 10 to 75 mg / m ² body surface area, for example 15 to 60 mg / m ^2, particularly in the case of doxorubicin in a dosage of about 40 to 75 mg / m ^2, in the case of daunorubicin at a dose of about 25 to 45 mg / m ² and in the case of idarubicin at a dose of about 10 to 15 mg / m ² .

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

Antibodies are advantageously administered at a dose of about 1 to 5 mg / m ² body surface area or, as is known in the art, if there are differences. Trastuzumab is preferably administered at a dose of 1 to 5 mg / m ² body surface area, in particular 2 to 4 mg / m ² during the course of treatment.

These doses can be administered, for example, once, twice or more during the course of treatment, which can be repeated, for example, every 7, 14, 21 or 28 days.

The present invention is further illustrated by the following examples.

Examples of

Several methods for the preparation of compounds of the invention are illustrated by the following examples. Unless otherwise noted, all starting materials were obtained from commercial suppliers and were used without further purification.

Hereinafter in this application, the terms: ACN means acetonitrile, AcOH means acetic acid, AcCl means acetyl chloride, Ar means argon, BINAP means 2,2'-bis- (diphenylphosphine) -1,1'binaphthyl, BOC or Boc means tert-butoxycarbonyl, Boc ₂ O means di-tert-butyl dicarbonate, celite® means diatomaceous earth, DCM means dichloromethane, DIEA or DIPEA means diisopropylethylamine, DiPE means diisopropyl ether, h means hour (hours), min means minute (minutes), DMAP means dimethylaminopyridine, DMF stands for dimethylformamide, Et ₂ O stands for diethyl ether, EtOAc or AcOEt stands for ethyl acetate, HPLC stands for high performance liquid chromatography, IPrNH ₂ stands for isopropylamine, iPrOH stands for isopropyl alcohol, KHMDS stands for potassium bis- (trimethylsilyl) amide gamide [bis- (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium 3-oxide, LC / MS means liquid chromatography with mass spectrometry; LiHMDS stands for lithium bis- (trimethylsilyl) amide, Me stands for methyl, Me-THF stands for 2-methyltetrahydrofuran, MeOH stands for methanol, NBS stands for N-bromosuccinimide, NCS stands for N-chlorosuccinimide, NMR stands for nuclear magnetic resonance, Pd / C 10% stands for palladium on carbon with a concentration of 10%, Pd (OAc) ₂ means palladium (P) acetate, Pd (PPh ₃ ) ₂ Cl ₂ means bis- (triphenylphosphine) palladium (P) chloride Pd (PPh ₃ ) ₄ means tetrakis (triphenyl) palladium) (0), Pd (dppf) Cl ₂ or PdCl ₂ dppf means [1,1'-bis- (diphenylphosphine) ferrocene] dichloropalladium (P), Pd (t-Bu ₃ P) ₂ means bis- (tri- tert-butylphosphine) palladium (0), rt means room temperature, SFC means chromatography with supercritical mobile phase, it means enantiomeric excess, TBAF means tetrabutylammonium fluoride, tBDMS, TBDMS or SMDBT means tert-butyldimethylsilyl, TEA or r Et ₃ N means triethylamine, TFA stands for trifluoroacetic acid, THF stands for tetrahydrofuran, CV stands for column volume, Quant. means quantitative, o / n means during the night, @ means in, eq. or equiv. stands for equivalent (s), Psi stands for pounds per square inch (pressure), MR, MP, or mp stands for melting point, OR stands for optical rotation, DSC stands for differential scanning calorimetry. When the stereocenter is listed as RS, it means that a racemic mixture has been obtained. Compounds such as compound 39 and compound 124, which have two stereocenters indicated as RS, were prepared as a mixture of diastereoisomers.

It is well known to those skilled in the art that protecting groups such as TBDMS can be easily removed using TBAF in a variety of solvents such as, for example, THF. Likewise, the conditions for removing the protecting groups of BOC are well known to the person skilled in the art, typically using, for example, TFA in a solvent such as DCM, or HCl in a solvent such as dioxane.

It will be obvious to the person skilled in the art that in some cases, when an organic layer is obtained at the end of the experimental protocol, this organic layer must be dried with a typical drying agent such as MgSO ₄ , or by azeotropic distillation, and the solvent must be evaporated before use. the obtained product as a starting material in the next reaction step.

- 58 037358

A. Obtaining intermediates.

Example A1.

Getting intermediate 1

To a solution of 2,4-dibromo-6-cyananiline (200.00 g, 724.82 mmol) and DMAP (17.71 g, 144.96 mmol) in DCM (3 L), Boc ₂ О (474.58 g, 2.17 mol) was added and the reaction mixture was stirred at 45 ° C for 4 h. The crude mixture was washed sequentially with saturated NaHCO ₃ solution (2 x 1 L) and brine (2 x 1 L), dried over MgSO ₄ , filtered and concentrated in vacuo to give 323 g of intermediate 1 (56% yield, yellow solid, 86% purity by LC / MS). This product was used in the next step without further purification.

Getting intermediate 2

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

Getting intermediate 3.

Intermediate 2 (100.00 g, 265.93 mmol), 2 - ((tert-butyldimethylsilanyl) oxy) -methyl) prop-2-en-1ol (80.72 g, 398.90 mmol) and tributylphosphamide (107.61 g, 531.86 mmol) were dissolved in THF (2 L) and cooled to 0 ° C. A solution of 1,1 '- (azodicarbonyl) dipiperidine (147.61 g, 585.05 mmol) in THF (50 ml) was added dropwise in an atmosphere of N _{2 and stirred at 0 ° С for 1 h, then at 25 ° С for 12 h} The resulting mixture was triturated with petroleum ether (3 L), filtered and concentrated in vacuo. The residue was then dissolved in EtOAc (6 L), washed sequentially with water (2x2 L) and brine (2x2 L), dried over MgSO ₄ , filtered and concentrated in vacuo. Three reactions were carried out in parallel (100 g each). The resulting residues were purified by column chromatography on silica gel (SiO ₂ , mobile phase: petroleum ether / EtOAc, 10: 1). The desired fractions were collected and the solvent was concentrated to dryness in vacuo to give 350 g of intermediate 3 (78% yield, yellow oil).

Obtaining intermediate 3 a

Triethylamine (196.3 ml; 1.408 mol) was added to a solution of 2 - (((tert-butyldimethylsilanyl) oxy) methyl) prop-2-en-1-ol (114 g, 563.3 mmol) in DCM (1 L) at 0 ° С ... Methanesulfonyl chloride (56.0 ml; 704.2 mmol) was slowly added to the mixture and the mixture was stirred for 2 h at 0 ° C. The reaction was terminated by the addition of saturated aqueous NaHCO ₃ solution (100 ml) and extracted with DCM (500 ml x 2). The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc, gradient 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 equiv.) In dry THF (600 ml). After 30 min, a solution of tert-butyldimethylsilyl chloride (0.95 equiv.) In dry THF (200 ml) was added dropwise to the mixture. After about 18 hours at 05 ° C after the reaction was complete by GC, water (500 ml) was slowly added while maintaining the temperature between 0 and 5 ° C. After separation of the phases, the aqueous layer was extracted with ethyl acetate (500

- 59 037358 ml) and the combined organic layers were washed with water (500 ml). The organic phase was concentrated to a residue which was dried by azeotropic drying by coevaporation with THF to give 252.7 g of crude TBDMS protected diol alone. A portion of the diol protected with one TBDMS group (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 at a temperature between -5 and 5 ° C. An additional aliquot of methanesulfonic anhydride (0.1 eq.) And triethylamine (0.2 eq.) Were added and water (500 ml) was added after another 1 h. 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 3а (311.1 g, 57 wt% intermediate 3а in solution).

Alternative preparation of intermediate 3.

Intermediate 2 (140 g; 372.3 mmol) was dissolved in acetonitrile (1.3 L). Intermediate 3а (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 hours, cooled and concentrated under reduced pressure. The residue was dissolved in water (1 L) and extracted with ethyl acetate (1 L x 2). The combined organic phases were washed with brine (1 L), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo to give the crude product. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc, gradient 100/0 to 40/1) to give 180 g (86%; clear oil) of intermediate 3.

Obtaining intermediate 4 and intermediate 4 '

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 in vacuo, washed with Ar three times, and stirred at 85 ° С for 2 h. The resulting mixture was filtered through celite (celite®) and the solid was washed with DCM (2 L). The filtrate was concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (4 L), washed sequentially with water (2x2 L) and brine (2x2 L), dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was then purified by column chromatography on silica gel (SiO ₂ , mobile phase: petroleum ether / EtOAc, 15: 1). Collect the desired fractions and concentrate the solvent to dryness in vacuo to give a mixture of intermediates 5 and 5 '. Three reactions were carried out in parallel (each using 100-120 of intermediate 3), which gave a total of 160 g of a mixture of intermediates 4 and 4 'containing 38% of intermediate 4 (as measured by LC / MS).

Alternative preparation of intermediate 4

To a mixture of intermediates 4 and 4 'in CH ₃ CN (1.60 L), 1-bromopyrrolidine-2,5-dione (212.20 g, 1.19 mol) was added and stirred at 40 ° С for 16 h. The solvent was removed by evaporation under reduced pressure. ... The residue was dissolved in ethyl acetate (2 L), washed sequentially with NaHCO ₃ (2x1 L) and brine (2x1 L), dried over MgSO ₄ and filtered. The filtrate was evaporated in vacuo and purified by column chromatography on silica gel (SiO ₂ , mobile phase: petroleum ether / EtOAc, 50: 1). The desired fractions were collected and the solvent was concentrated to dryness in vacuo to afford 110.00 g of intermediate 4 (56% yield, yellow oil, 97% purity by LC / MS).

Alternative preparation of intermediate 4 '

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- (diphenylphosphine) ferrocene] palladium complex (II ) chloride with dichloromethane (19.34 g, 23.70 mmol) in DMF (2 L), tetra-Nbutylammonium chloride (164.60 g, 592.20 mmol) was added in an N2 atmosphere at rt. The reaction mixture was stirred overnight at

- 60 037358

60 ° C, then filtered through celite and the solid washed with DCM (400 ml). The filtrate was concentrated in vacuo. The resulting residue was dissolved in EtOAc (4 L) and the organic layer was washed sequentially with water (2 L) and brine (2 L), dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product as a black oil. This residue was purified by column chromatography on silica gel (SiO ₂ , mobile phase: petroleum ether / EtOAc, gradient 100: 0 to 10: 1). Collect the desired fractions and concentrate the solvent to dryness in vacuo to give 155 g of intermediate 4 '(70% yield, yellow oil).

Alternative preparation of intermediate 4 '

Intermediate 550 (50.0 g) was dissolved in DMF (250 ml). Dehydrated sodium formate (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 then heated at 45-50 ° C until complete conversion (usually 24 h with HPLC monitoring). Then added water (350 ml) followed by the addition of 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 through diatomaceous earth (25 g; diatomaceous earth). The filtrate was concentrated to a volume of 100-150 ml, cooled to a temperature of -10 - -5 ° C for 2 h, and filtered to obtain 37.6 g of intermediate 4 '. Additional intermediate 4 'could be isolated by filtering the mother liquor through silica gel to remove impurities, followed by cooling the filtrate to -10 ° C to crystallize additional intermediate 4'.

Getting intermediate 4'R

Intermediate 4'R

Intermediate 4'R was prepared by chiral separation of intermediate 4 '(CHIRALPAK IC column 5 cm x 25 cm; mobile phase: hexane / EtOH: 80/20; flow rate: 60.0 ml / min; wavelength: UV 254 nm; temperature : 35 ° C).

Obtaining intermediate 4R and intermediate 4S

Intermediate 4 (500 g) was purified by separation by normal phase chiral chromatography (stationary phase: Daicel Chiralpak IC 2000 g, 10 μm, mobile phase: heptane / EtOH, isocratic conditions: 80% heptane, 20% EtOH). The fractions containing the obtained products were mixed and concentrated, yielding 266 g of intermediate 4R (yield 53%, ee> 98%) and 225 g of intermediate 4S (yield 45%, ee> 98%).

Alternatively, intermediate 4 (10 g) was purified by chiral SFC (stationary phase: CHIRALPAK IC 5 μm, 250x30 mm, mobile phase: 85% CO ₂ , 15% iPrOH). Pure fractions were collected and evaporated to dryness, yielding 4.3 g of intermediate 4R (yield 43%, ee = 100%) and 4.5 g of intermediate 4S (yield 45%, ee = 100%).

Alternative preparation of intermediate 4R.

To a solution of intermediate 4'R (10.0 g) in ACN (100 ml) was added 1,3-dibromo-5,5-dimethylhydantoin (0.75 eq.) And the mixture was stirred at 20 ° С for 24-28 h, continuously observing the course of the reaction by HPLC. After complete conversion, an aqueous 5% NaHCO ₃ solution (250 ml) was added and the mixture was stirred for 30 min. Then toluene (250 ml) was 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 (99.6% conversion).

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Example A2.

Getting intermediate 5

To a solution of intermediate 4 (127.00 g, 234.70 mmol) in 1,4-dioxane (1.2 L), bis (pinacolato) dibor (74.50 g, 293.40 mmol) and potassium acetate (69.11 g, 704.24 mmol) were added. Then [1,1'bis- (diphenylphosphine) ferrocene] palladium (II) chloride (8.59 g, 11.74 mmol) was added and stirred for 4 h at 85 ° C under nitrogen atmosphere. The mixture was cooled, partitioned between EtOAc (2 L) and water (500 ml) and filtered through celite. The organic and aqueous layers were separated. The organic layer was washed sequentially with water (300 ml), brine (300 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was dissolved in DCM / EtOAc (90:10, 600 ml), filtered through 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 used directly in the next step.

Getting intermediate 5R

To a solution of intermediate 4R (20.00 g, 41.50 mmol) in 1,4-dioxane (200 ml), bis (pinacolato) dibor (13.20 g, 51.90 mmol) and potassium acetate (12.20 g, 124.60 mmol) were added. Then the complex of [1,1'-bis- (diphenylphosphine) ferrocene] palladium (II) chloride with dichloromethane (1.70 g, 2.08 mmol) was added and stirred for 4 h at 85 ° C under N ₂ . The resulting mixture was cooled, partitioned between EtOAc (200 ml) and water (100 ml) and filtered through celite. The organic and aqueous layers were separated. The organic layer was washed sequentially with water (100 ml), brine (100 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was dissolved in DCM / EtOAc (90:10, 200 ml), filtered through flash silica gel and washed with DCM / EtOAc (90:10, 1 L). The filtrate was evaporated to give 25 g of crude intermediate 5R (brown oil), which was used directly in the next step.

Getting intermediate 6

VOS _h \\

I

T | ] RS ⁴ TBDMS

A solution of intermediate 5 (160.00 g, 302.70 mmol) in 1,4-dioxane (1.2 L was treated with a solution of NaHCO ₃ (76.30 g, 908.10 mmol) in water (400 ml). Then, in an atmosphere of N ₂ was added 2,4-dichloropyrimidine (67.64 g, 545.06 mmol) and Pd (PPh ₃ ) ₄ (17.50 g, 15.13 mmol). The reaction mixture was stirred at 80 ° C under N _2. The mixture was cooled, partitioned between EtOAc (2 L) and water (800 ml) and filtered. through celite The organic and aqueous layers were separated The organic layer was sequentially washed with water (800 ml), brine (500 ml), dried over Na ₂ SO ₄ and concentrated in vacuo The residue was purified by flash chromatography on (SiO ₂ , mobile phase: petroleum ether / EtOAc gradient 100: 0 to 10: 1) Collect the desired fractions and concentrate the solvent to dryness in vacuo to give 100 g of intermediate 6 (71% yield after 2 steps, yellow solid).

Preparation of intermediate 6R and intermediate 6S

Intermediate 6 (52.00 g) was purified by chiral SFC (stationary phase: CHIRALPAK IC 5 μm, 250 x 30 mm, mobile phase: 60% CO ₂ , 40% MeOH). The desired fractions were collected and the solvent was concentrated to dryness in vacuo to obtain 25 g of intermediate 6R containing minor impurities (48% yield) and 25.1 g of intermediate 6S (48% yield).

Several combined batches of intermediate 6R (50.10 g total) were then purified by the chiral method.

SFC (stationary phase: CHIRALPAK IA 5 μm, 250 x 20 mm, mobile phase: 87.5% CO ₂ , 12.5% MeOH).

The pure fractions were mixed and the solvent was evaporated to obtain 49.10 g of intermediate 6R.

Alternative preparation of intermediate 6R

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 (PPh ₃ ) ₄ (2.42 g, 2.09 mmol) were added in an N2 atmosphere. The reaction mixture was stirred at 80 ° C under N ₂ . The mixture was cooled, partitioned between EtOAc (300 ml) and water (100 ml) and filtered through celite. The organic layer was washed with water (100 ml), brine (100 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. The resulting residue was combined with three other batches obtained from reactions with 25 g of intermediate 5R. The residue was purified by flash chromatography on silica gel (SiO ₂ , mobile phase: petroleum ether / EtOAc, gradient 100: 0 to 10: 1). The desired fractions were collected and the solvent was concentrated to dryness in vacuo to give 63 g of intermediate 6R (70% yield over two steps, yellow solid).

Alternative preparation of intermediate 6R.

To a solution of intermediate 4R (50.0 g) in toluene (400 ml) was added bis- (pinocalato) dibor (1.3 eq.), Potassium acetate (3.0 eq.), And Pd (dppf) Cl ₂ (0.05 eq.). The mixture was degassed 3 times with nitrogen and heated to 90 ° C for 12-14 hours. The mixture was then cooled to room temperature and filtered through celite, which was washed with toluene (150 ml). The filtrate was washed with water (250 Lm) and then filtered through silica gel (10 g) to obtain a toluene solution containing 49 g of intermediate 5R. To this solution, 2,4-dichloropyrimidine (1.5 eq.), NaHCO ₃ (3.0 eq.), Water (25 ml), and Pd (PPh ₃ ) ₄ (0.05 eq.) Were added. After three times degassing with nitrogen, the mixture was stirred at 90 ° C, constantly monitoring the degree of conversion by HPLC. After reaching complete conversion (24-48 h), the mixture was cooled to room temperature, filtered through celite and washed with water (250 ml). Silica gel containing thiol groups (10 g) was added to the organic layer and the mixture was stirred at 90 ° C for 3 h, then cooled to room temperature and filtered. The solvent was replaced completely with isopropanol by repeated distillation until about 100 ml of isopropanol remained. The solution was heated to 50 ° C and 250 ml of methanol was added. After stirring at 50 ° C for 4 h, the mixture was cooled to 0 ° C over 4 h, held at this temperature for 16 h, and finally filtered to obtain 26 g of intermediate 6R.

Obtaining intermediate 6a

BOS N ---- k i) ⁴ TBDMS ^f J.

kL ₄ G 'S

To a solution of intermediate 5 (3.89 g, 4.92 mmol), 5-fluoro-2,4-dichloropyrimidine (1.07 g, 6.40 mmol), and Cs ₂ CO ₃ (4.81 g, 14.80 mmol) in 1,4-dioxane (25 ml) and distilled water (2.5 ml), Pd (PPh ₃ ) ₄ (0.28 g, 0.25 mmol) was added, and the reaction mixture was heated overnight at 95 ° C. This mixture was poured onto ice and extracted with EtOAc. The organic layer was washed with brine, dried with MgSO ₄ , 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 evaporated to give 1.92 g of intermediate 6a (73% yield).

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The intermediate in the table below was prepared similarly from the corresponding starting materials.

Example A3.

Getting intermediate 7R

In a three-necked round-bottom flask, SiO2 (35-70 μm) (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 boiled (bath temperature 125 ° C) for 6 h with mechanical stirring. Then SiO ₂ (35-70 μm) was filtered off, washed sequentially with THF and EtOAc and the filtrate was evaporated to dryness to obtain 37.2 g of crude intermediate 7R, which was used directly in the next step.

Getting intermediate 392

Intermediate 392 was prepared using a similar reaction protocol described above for the preparation of intermediate 7R, but starting from intermediate 391 (310 mg; 98%).

Getting intermediate 7R

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 at a temperature below 0 ° C for another 15 min, then poured into a mixture of crushed ice and saturated aqueous K ₂ CO ₃ solution. After extraction with DCM (twice), the organic layers were combined, washed with an aqueous solution of K ₂ CO ₃ , dried over MgSO ₄ and evaporated to dryness. The residue (17.40 g) was purified by chromatography on silica gel (SiOH, irregular grains, 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 in vacuo to obtain 12.1 g of intermediate 7R (75% yield).

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Getting intermediate 7

TFA (7 ml, 91.50 mmol) was added to a solution of intermediate 6 (1.50 g, 2.91 mmol) in DCM (30 ml) at 0-5 ° С and stirred at 0-5 ° С for 1 h, then at rt for 1 hour. The crude product was poured into a mixture of crushed ice and saturated aqueous NaHCO ₃ solution. After extraction with DCM (twice), the organic layers were combined, washed with aqueous NaHCO ₃ , dried over MgSO 4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (SiOH, irregular grains, 40 μm, 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 in vacuo to give 524 mg of intermediate 7 (65% yield).

Example A4.

Getting intermediate 150

A solution of intermediate 6 (500.00 mg, 0.97 mmol) in THF (5.71 ml, 70.21 mmol) was treated with TBAF (1MB THF) (1.16 ml, 1.16 mmol) and stirred at rt for 12 h. The reaction mixture was poured into EtOAc. The organic layers were washed with water and then with brine, dried over MgSO ₄ and evaporated in vacuo. The residue (483 mg) was purified by column chromatography on silica gel (SiOH, irregular grains, 40 μm, 40 g, mobile phase: DCM / MeOH / NH4OH, gradient from 100% DCM to 98% DCM, 2% MeOH, 0.2% NH4OH). The desired fractions were collected and the solvent was evaporated to give 358 mg of intermediate 150 (92% yield).

Example A5.

Getting intermediate 271

A solution of intermediate 2 (10.00 g, 26.59 mmol) and 2-methyl-2-propen-1-ol (4.50 ml, 53.69 mmol) in Me-THF (200 ml) was cooled in an EtOH / ice bath under N ₂ until reaching internal temperature equal to -5 ° С. Added tri-n-butylphosphine (13.30 ml, 53.19 mmol). Then a solution of 1,1 '- (azodicarbonyl) piperidine (14.80 g, 58.62 mmol) in Me-THF (120 ml) was added dropwise over 25 min. The solution was stirred at this temperature for an additional 5 min, then the cooling bath was removed and the solution was stirred at rt for 18 h. The reaction mixture was poured into a 10% aqueous K ₂ CO ₃ solution and extracted with DCM. The organic layer was decanted, dried over MgSO ₄ , filtered and evaporated to dryness. The residue (20 g) was taken with heptane and the insoluble matter was removed by filtration. The filtrate was concentrated to a volume of 20 ml and purified by column chromatography on silica gel (SiOH, irregular grains, 80 g, mobile phase: heptane / EtOAc, gradient from 100: 0 to 88:12). The desired fractions were collected and the solvent was evaporated to dryness to give 10.80 g of intermediate 271 (94% yield).

Obtaining intermediate 272 and intermediate 272 '

A mixture of intermediate 271 (10.80 g, 25.11 mmol), sodium acetate (5.35 g, 65.28 mmol), formate on

- 65 037358 sodium (4.44 g, 65.28 mmol) and tetraethylammonium chloride (5.20 g, 31.38 mmol) in DMF (100 ml) was degassed by ultrasound for 10 min in an Ar flow. Pd (OAc) ₂ (563.00 mg, 2.51 mmol) was added and the resulting orange suspension was then stirred at 85 ° C (sensor temperature) for 4 h. The residue was diluted with EtOAc and water, then filtered through a celite pad. The organic layer was decanted, washed sequentially with saturated aqueous NaHCO ₃ and brine, dried over MgSO ₄ , filtered and evaporated to dryness. The residue (8.3 g, a mixture of intermediates 272 and 272 ') was dissolved in CH3CN (230 ml) and NBS (4.47 g, 25.11 mmol) was added. The reaction mixture was heated at 55 ° C (sensor temperature) for 18 hours. The reaction mixture was evaporated to dryness and the residue was taken up with a heptane / DCM mixture. The precipitate was filtered off (1 g of the derivative) and the filtrate (10 g) was purified by column chromatography on silica gel (SiOH, irregular grains, 120 g, injected into DCM, mobile phase: heptane / EtOAc, gradient from 100: 0 to 80:20 ). The desired fractions were collected and the solvent was evaporated to dryness to give 4 g of intermediate 272 (45% yield).

Getting intermediate 273

The complex of [1,1'-bis- (diphenylphosphine) ferrocene] dichloropalladium (II) with dichloromethane (243.00 mg, 0.30 mmol) was added to a solution of intermediate 272 (2.09 g, 5.95 mmol), bis- (pinacolato) dibor (1.90 g, 7.44 mmol) and potassium acetate (1.75 g, 17.85 mmol) in 1,4-dioxane (45 ml) and the reaction mixture was heated for 18 h at 85 ° С. The reaction mixture was diluted with EtOAc and filtered through a celite pad. The filtrate was washed with water, the organic layer was decanted, dried over MgSO4, filtered and evaporated to dryness. The residue was crystallized from DiPE, the residue was filtered off and dried, yielding 1.85 g of intermediate 273 (78% yield).

Getting intermediate 274

Degassed suspension of intermediate 273 (1.12 g, 2.81 mmol), 2,4-dichloropyridine (502.00 mg, 3.37 mmol), Pd (PPh ₃ ) ₄ (162.00 mg, 0.14 mmol) and Na ₂ CO ₃ solution, 2 M (4.20 ml , 8.14 mmol) in 1,4-dioxane (24 ml) was heated to 85 ° С for 18 h. The reaction mixture was partitioned between DCM and saturated aqueous NaHCO3 solution. The organic layer was decanted, dried over MgSO4, filtered and evaporated to dryness. The residue (2 g) was purified by column chromatography on silica gel (SiOH, irregular grains, 40 g, mobile phase: heptane / EtOAc, gradient 70:30 to 50:50). The desired fractions were collected and the solvent was evaporated to dryness to give 933 mg of intermediate 274 (86% yield, 85% purity by LC / MS).

Getting intermediate 361

TFA (6 ml) was added dropwise at 5 ° С to a solution of intermediate 274 (3.00 g, 7.79 mmol) in DCM (60 ml) and the reaction mixture was stirred at 5 ° С for 1 h. The reaction mixture was diluted with DCM and poured into the mixture ice and 10% aqueous solution of K ₂ CO ₃ . The insoluble matter was filtered off, washed with water, then Et ₂ O and dried to give 1.93 g of intermediate 361 (87% yield). M.p. = 207 ° C (K).

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Example A6.

Getting intermediate 8R

n

Method A.

In a sealed vessel, a solution of intermediate 7R (14.75 g, 35.54 mmol) in 1.4-dioxane (285 ml) was purged with N2. 3-amino-4-methylbenzonitrile (7 g, 53.312 mmol) and Cs ₂ CO ₃ (23.16 g, 71.083 mmol) were sequentially added, and after adding each component, the suspension was degassed. Then Pd (OAc) ₂ (798.00 mg, 3.55 mmol) and BINAP (2.21 g, 3.55 mmol) were added. The reaction mixture was degassed with nitrogen and stirred at 120 ° C (preheated bath) for 3 h. The reaction mixture was cooled to rt, poured into ice water and extracted with EtOAc. The organic layer was decanted, washed with brine, dried over MgSO ₄ , filtered through a pad of Celite® and concentrated in vacuo. The residue (30 g) was purified by column chromatography on silica gel (SiOH, irregular grains, 400 g, mobile phase: DCM / EtOAc, gradient from 100: 0 to 85:15 (12 x 200 ml)). The desired fractions were collected and the solvent was evaporated to dryness in vacuo to obtain 14.3 g of intermediate 8R (79% yield, contaminated with 7% 3-amino-4-methylbenzonitrile according to ¹ HNMR data). This solid was suspended in Et2O / CH3CN and sonicated at rt for 15 min. The residue was filtered off, washed with CH ₃ CN and dried, yielding 8.6 g of intermediate 8R (47% yield). The filtrate was evaporated and the residue was purified by column chromatography on silica gel (SiOH, irregular grains, 80 g, mobile phase: DCM / EtOAc, gradient from 100: 0 to 90:10). The fractions containing the desired product were collected and evaporated to dryness. The resulting solid was suspended in Et ₂ O / CH ₃ CN and sonicated at rt for 15 min. The precipitate was filtered off, washed with CH3CN, and dried to obtain an additional 2.6 g of intermediate 8R (yield 14%). The overall reaction yield was 62% (11.2 g).

Method B.

SiO _2, 35-70 microns (25 g) at rt was added to a solution of intermediate 9R (6.10 g, 10.00 mmol) in toluene (75 mL). The reaction mixture was boiled (bath temperature 125 ° C) for 6 h with vigorous stirring. Then SiO ₂ , 35-70 μm was filtered off, successively washed with THF and EtOAc and evaporated to dryness. The residue was taken with Et ₂ O, and the precipitate was filtered off and dried, yielding 4.34 g of intermediate 8R (85% yield).

The intermediates shown in the table below were prepared in a similar manner as described in Method A above from the appropriate starting materials. The most relevant small deviations from the original method are shown in the Method column.

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Intermediate 42 n N -— \ / \ ___ 'ΐΑ T X ^ TBDMS 4 ^{r4 N} Μ Wr o__ from intermediate 7R and intermediate 41 618 orange butter 32 BUT Intermediate 49 n n --- \ Ν '. 1 \ __ _h / X Xq- ^ TBDMS Г II ^RN ϊ Λ 0 ^ ^Χ ΟΗ from intermediate 7R and intermediate 48 292 (purity 96% by LC / MS data) 365 mg (power cleanliness 79 % by LC / MS data) thirty 37 BUT Intermediate 52 Η Ν --- \ I \ ___ Xq ^ -TBDMS ΓΙ R ' ^Ν Χζ ^Η 1 ... intermediate 7R and intermediate 51 843 (degree of purity 80 % by data LC / MS) orange butter 93 BUT

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Intermediate 55 n N --- \ / \ __ _{_} Г \ / X ^X ₀ ^ TBDMS r T ^{R n} Χλ> from intermediate 7R and intermediate 54 1293 (degree of purity 94% by data LC / MS) yellow powder To olich .. BUT Intermediate 57 n Ν --- \ Ν>. / \ AA A / X \ TTBDMS 0 ^Ν g intermediate 7R and intermediate 56 344 (purity 98% data LC / MS) 63 BUT Intermediate 60 n Ν --- \ / \ __ _h ~ AA \ q_TBDMS ii R Ν ___ from intermediate 7 R and intermediate 59 1010 (degree of purity 73% by LC / MS data) solid orange product BUT

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Intermediate 104 n N --- i ^N ^. / \ --- \ TBDMS ClXk ⁿ ^ from intermediate 7 and 3-amino-4methylbenzonitrile 261 solid yellow product colors 47 And at T = 95 ° C Intermediate 195 n N -— \ / \ ___ HH TBDMS Yr ci ςχ ό one from intermediate 7 and 2-amino-4- chlorine-A.A-dimethylbenzamide 275 (degree of purity 94% by data LC / MS) 66 And at T = 90 ° C Intermediate 199 n Ν— \ Νχ / \ ___> \ N _q ^ -TBDMS Il ^RS ^ Χγθ ' ⁰ from intermediate 7 and intermediate 198 270 (degree of purity 80% by data LC / MS) 74 And at T = 90 ° C Intermediate 246 _un _-TBDMS n U Ν ---- i I ^N ks 1 nr n ΐ intermediate 7R and intermediate 245 423 65 BUT Intermediate 256 n ₀ ^ tbdms Ν— \ 1 ^N ks / \ Y ΓιΡ ⁴ n c Wy intermediate 7R and intermediate 255 1190 (degree of purity 94% by data LC / MS) 87 BUT Intermediate 394 n N- ~ \ R / / 1 \ * / Г- ksA ^D \ / ^{0H D} '^> | UUy ^H FROM intermediate 7R and intermediate 393 3100 55 BUT

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Intermediate 398 n ^N --- \ R / / / 1 ijX "from intermediate 7R and intermediate 397 220 52 BUT at T = 80 ° C Intermediate 404 Η L · J ^d \ / ° ^h άί FROM intermediate 7R and intermediate 403 167 31 BUT at T = 80 ° C Intermediate 407 Η Ν --- \ R ^{1/1 \% χ / Sl} \\ kJ 2γ 0Η ex Λ from intermediate 7R and intermediate 406 190 26 % BUT at T = 80 ° C Intermediate 412 n N --- \ R / / 1 / ^s '<\ T ιί ^ν to 1 Η from intermediate 7R and 3-amino-4 (hydroxymethyl) benzonitrile 185 36 BUT Intermediate 433 ₂ Όκ yr ⁰ 'From intermediate 432 and intermediate 7R 81 13 BUT Intermediate 435 J? ⁿ \ m ~ ^ ° yr CaDX "^^ from intermediate 434 and intermediate 7R 192 75 BUT

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Intermediate 437 - Y OSS. from intermediate 436 and intermediate 7R 362 57 BUT Intermediate 439 - ήν Ca3Q Cf from intermediate 438 and intermediate 7R 467 (degree of purity 70% over data LC / MS) 67 BUT Intermediate 440 X / Ol JU from 3-amino-4-isopropoxy-I- methylbenzamide and intermediate 7R 597 89 BUT Intermediate 442 one from intermediate 441 and 366 (purity 81 % by data LC / MS) 52 BUT

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intermediate7K Intermediate 444 0 - ^^ ^N \ 1 ^- ¼ ^{7 14} XmC 1 ° γ ^ΝΗ άυφ F from intermediate 443 and intermediate 7R 423 (degree of purity 100% over data LC / MS) 80 BUT Intermediate 448 n rvj ^z 1 II n R or S to JJ O. N ί ^ ΧΧ from intermediate 447 and intermediate 7R 180 thirty BUT Intermediate 449 h 0 ^^ ^ζ 1 II H S or R w 'from intermediate 447 and intermediate 7R 377 (power purity 100% over data LC / MS) 54 BUT

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Intermediate 453 n o -'-pk ν-K / / ^X / Yu ⁿ Ab / R or S СlхТ H from intermediate 452 and intermediate 7R 124 nineteen BUT Intermediate 454 n Ν— \ \ / \ r7 '^ τϊ ⁴ n / O iid Η from intermediate 452 and intermediate 7R. 315 47 BUT Intermediate 482 n 0 ^, 4 Ν— \ Ι \ ^Ν 0 / S ό NHBoc from intermediate 481 and intermediate 7R. 690 (degree of purity 66% by data LC / MS) 86 BUT

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Intermediate 483 n ° / ^S \ ^N - \ R / / ^x / ¹ K D ° \ / ⁰ СлХУ Η from intermediate 7R and methyl-5-amino-2-fluoro-4-methylbenzoate 570 (degree of purity 79% by data LC / MS) 84 BUT Intermediate 486 n \ AaV ^Si <\ I if ^ν cxi A Ύ from intermediate 7R and intermediate 485 572 (purity 83 % by data LC / MS) 74 BUT Intermediate 491 / n o-- ^Sl A \ N - \ ^{X 1} ° γ ^ΝΗ AL? 0 ^^ from intermediate 490 147 26 BUT

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Intermediate 496 / Ar H O- ^S C \ N - \ ^X y \ R / from intermediate 7R and intermediate 495 165 nineteen BUT Intermediate 502 H OtBDMS ^N - \ p / CN 1 1 11 g L / L H from intermediate 7R and intermediate 499 568 80 % BUT (3 h 30 @ 120 ° C) Intermediate 503 H OtBDMS GU- ⁷ from intermediate 7R and intermediate 500 88 29% (C heat of purity 82% according to L CMS) BUT (3 h 30 @ 120 ° C)

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Intermediate 504 H OtBDMS ΤΙ City from intermediate 7R and intermediate 500V 442 65 % BUT (3 h 30 @ 120 ° C) Intermediate 511 H OtBDMS ^N --- \ P / N ~. \ R / YT CN ^ Ν (<| 1 clL1. ° H from intermediate 7R and intermediate 510 233 49 % BUT (3 h @ 120 ° C) Intermediate 514 H OtBDMS EV Ύτ CN। 1 i I cis fA ^ N ζ i LAAL H from intermediate 7R and intermediate 513 591 77% C heat 54% (according to LCMS) BUT (5 h @ 120 ° C) Intermediate 518 H OtBDMS N ^ / 'W T 1 ^cis K ^ N AAl clLLal ^X N ^Z ^ N ^ H From intermediate 7R and re / -3- [cis- 142 86% With warmth of purity 70% BUT (4 h @ 120 ° C)

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2,6-dimethyl-4-morpholinyl] methyl] - 2-methylbenzeneamine (P 0 data LCMS) Intermediate 520 H OtBDMS X / ^N -V Ύτ 1 1 ^cis ιϊ 'Ϊ X' - \ H | ^ D from intermediate 7R and intermediate 519 221 61 % BUT (4 h @ 120 ° C) Intermediate 521 H OtBDMS kg eat from intermediate 7R and intermediate 521b 282 54 % BUT (4 h @ 120 ° C) Intermediate 522 H OtBDMS N— \ r / Μ From intermediate 7R and methyl 3amino-2-methylbenzoate 1050 53 % A (3 h @ 120 ° C)

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Intermediate 528 H OtBDMS ^N - \ r / I OtBDMS from intermediate 7R and intermediate 527 306 43 % A (4 h @ 120 ° C) Intermediate 531 H OtBDMS HA Tj _CN άγ 0 ^^ from intermediate 7R and intermediate 530 527 77 % A (4 h @ 120 ° C) Intermediate 581 _n q ^ TBDMS N — ν | rk j cn Сg j0 1 ^ 0 from intermediate 7R and intermediate 580 215 pale brown butter 65 BUT

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Intermediate 600 _{n o} _tbdms N - _k ] N ^. 1 t / g cn SLA A? from intermediate 7R and intermediate 599 500 TO About lich. BUT Intermediate 619 _{n 0} ^ tbdms N— \ I Ν. 1 cn άΑ Ν _ _ —--- X Trans Β (SS or RR) from intermediate 7R and intermediate 617 226 88 BUT Intermediate 622 _n q ^ TBDMS N - x I Νς. y \> from intermediate 7R and intermediate 621 70 yellow solid 23 BUT Intemediat 637 Н ^Ν --- k R Ν '. \ _TBDMS tu uljQ ^H 1 ^RS Z ^ N- ^B0C from intermediate 7R and intermediate 636 571 64 BUT

Getting intermediate 423

A mixture of intermediate 422 (8.68 g, 47.6 mmol), intermediate 7R (13.18 g, 31.8 mmol) and Cs ₂ CO ₃ (20.7 g, 63.5 mmol) in 1,4-dioxane (260 ml) was purged with N2. Then Pd (OAc) ₂ (713 mg, 3.18 mmol) and BINAP (1.98 g, 3.18 mmol) were added. The round bottom flask was sealed, the reaction mixture was purged with nitrogen and stirred at 120 ° C for 3 hours. The resulting mixture was poured into water and DCM. Then it was filtered through celite (Celite®), decanted and the organic layer was separated, dried over

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MgSO ₄ , filtered off and evaporated. The residue (22.5 g) was purified by column chromatography on silica gel (SiOH, irregular grains, 40 μm, 120 g, mobile phase: heptane / EtOAc / MeOH: 60/35/5). The pure fractions were collected and the solvent was evaporated to give 10.66 g (60%) of intermediate 423 as a poor orange foam.

Preparation of intermediate 430 and intermediate 431

A mixture of intermediate 7R (936 mg; 2.25 mmol) in 1,4-dioxane (25 ml) was purged with nitrogen in a sealed tube. A mixture of intermediates 428 and 429 (758 mg; 3.38 mmol) and cesium carbonate (1.47 g; 4.51 mmol) were sequentially added; after each addition, the suspension was degassed. Then Pd (OAc) ₂ (51 mg, 0.226 mmol) and BINAP (140 mg, 0.226 mmol) were added. The vessel was sealed, and the reaction mixture was degassed with N2 and stirred at 120 ° С (in a preheated bath) for 4 h.

The reaction mixture was cooled to room temperature, poured into water and extracted with DCM. The organic layer was decanted, dried over MgSO ₄ , filtered through celite and evaporated to dryness. The residue was purified by column chromatography on silica gel (SiOH, irregular grains, 80 g; mobile phase: gradient from 20% EtOAc, 80% heptane to 40% EtOAc, 60% heptane. The pure fractions were collected and evaporated to dryness to give 451 mg of the intermediate 430 (33%) and 530 mg (39%) of intermediate 431.

Getting intermediate 618

¹ 'Trans A (RR or SS)

A mixture of intermediate 7R (184 mg; 0.443 mmol) in dioxane (11 ml) was purged with N2 in a sealed vessel. Intermediate 616 (156 mg; 0.663 mmol) and cesium carbonate (289 mg; 0.886 mmol) were sequentially added; after each addition, the suspension was degassed. Then Pd (OAc) ₂ (10 mg; 0.044 mmol) and BINAP (27 mg; 0.044 mmol) were added. The reaction mixture was degassed with N2 and stirred at 120 ° C (in a preheated bath) for 4 h. The reaction mixture was cooled to room temperature, poured into water and extracted with DCM. The organic layer was decanted, washed with water and brine, dried over MgSO4, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (SiOH, irregular grains, 50 g; mobile phase: gradient from 0% MeOH, 100% DCM to 5% MeOH, 95% DCM). Fractions containing the resulting product were collected and evaporated to dryness to give 234 mg (86% yield, 87% purity by LCMS) of intermediate 618.

The intermediates in the table below were prepared in a manner similar to that described in method B from the appropriate starting materials. The most relevant deviations from the reference method are indicated in the Method column.

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Intermediate number Structure Weight (mg) Output (%) Method Intermediate 552 _n q ^ TBDMS N-v I lUr U CX JU from intermediate 551 197 yellow butter 78 IN Intermediate 556 _{n 0} ^ tbdms N— \] ^ν ά ι \ r IT ⁴ o CX JU from a mixture of intermediate 555 and intermediate 556 fifty orange butter 60 IN Intermediate 558 _{n 0} ^ tbdms N — v I y luu ⁿ / (d JU from a mixture of intermediate 557 and intermediate 558 390 yellow butter 94 IN

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Intermediate 561 _n o ^ TBDMS N - to I Χχ F φτ X Cl Ju FROM a mixture of intermediate 560 and intermediate 561 419 yellow butter Quantity IN Intermediate 563 _n q ^ TBDMS N— \ | 1 \ U μ from a mixture of intermediate 562 and intermediate 563 117 yellow butter 48 IN Intermediate 577 _n q ^ TBDMS N - \ I y \> CN cx x5 from intermediate 576 363 gray solid 69 IN

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Intermediate 593 _n ^ TBDMS n 9 ν ^ 1 CN to ί5 from intermediate 592 240 93 IN Intermediate 597 n ^ TBDMS n 9 N - to l \ K j (Ate CN (a j0 from intermediate 596 170 100 in Intermediate 606 _n q ^ TBDMS N ^. ] (JP ⁴ CN CX j0 -A / ^N \ from intermediate 605 260 (purity 75 % by data LCMS) 97 in Intermediate 612 _H o ^ TBDMS N - k 1 N ^ I \% (Er CN CX j0 trans T] from intermediate 611 90 87 in Intermediate 641 Η ^N - \ RN \ ^K 1 El. TBDMS r T। H / ^ ^NH Ca JU from intermediate 640 106 63 in

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Example A7.

Getting intermediate 9R

BOC q ^ TBDMS

Method C.

In a sealed vessel, a mixture of 6R (5.15 g, 10.00 mmol) in 1,4-dioxane (80 ml) was purged with nitrogen. 3-amino-4-methylbenzonitrile (2.00 g, 15.00 mmol) and Cs ₂ CO ₃ (6.51 g, 20.00 mmol) were sequentially added; after each addition, the resulting suspension was degassed. Then Pd (OAc) ₂ (224.45 mg, 1.00 mmol) and BINAP (622.53 mg, 1.00 mmol) were added. The reaction mixture was degassed with N2 and stirred at 120 ° C (in a preheated bath) for 3 h. The reaction mixture was cooled to rt, poured into ice water and extracted with EtOAc. The organic layer was decanted, washed with brine, dried over MgSO ₄ , filtered through a pad of celite and evaporated to dryness. The residue was purified by column chromatography on silica gel (SiOH, irregular grains, 120 g, mobile phase: heptane / EtOAc, gradient 85:15 to 70:30). Collected pure fractions and evaporated to dryness to obtain 4.17 g of intermediate 9R (yield 68%).

Method D.

NaH (60% dispersion in mineral oil) (0.90 g, 22.49 mmol) was added in portions to a stirred solution of N- (5-cyano-2-methylphenyl) formamide (2.40 g, 15.00 mmol) in DMF (100 ml) at rt in the atmosphere nitrogen and stirred for 30 minutes. Then intermediate 6R (5.15 g, 1.00 mmol) was added and the reaction mixture was stirred at rt for 18 h. The resulting crude product was poured into water and extracted with EtOAc. The organic layer was decanted, washed sequentially with water and brine, dried over MgSO ₄ , filtered and concentrated to dryness to give 7.8 g of crude intermediate 9R, which was used in the next step without further purification.

The intermediates in the table below were prepared in a manner similar to that described in Method C from the appropriate starting materials. The most relevant deviations from the reference method are indicated in the Method column.

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.TBDMS VOS 'ν — at I 1 TO 1 Υ about GC ίΎ θ Η from intermediate 6R and a mixture of intermediates 16 and 17 Intermediate eighteen TBDMS BOC ΗΊΓ 1 Α ¹ ° γ ^ΝΗ from intermediate 6R and 3-amino-A, 4-dimethylbenzamide 477 almost white foam 76 FROM Intermediate 29 BOC ^ ₀ ^ -TBDMS ⁴ Ν - \ / / \ __ / Г1Г ^Ν c from intermediate 6R and intermediate 28 337 (purity 92% according to LC / MS) 41 FROM

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Intermediate 33 and intermediate 34 BOS \ <1 \ ___ „.-Tbdms ii ^R ' ^Ν 0 ^^ TBDMS Η Ν --- \ Νλ. I \ __ _χ X. Ζχ / Χ O ^ ^TBDMS ο TBDMS from intermediate 6R and intermediate 32 387 (intermediate 33) (89% purity according to LC / MS) orange oil 474 (intermediate 34) (93% purity according to LC / MS) orange oil 32 39 FROM Intermediate 38 BOC _O ^, TBDMS ⁴ N --- \ / n ^. / I CLX) n A from intermediate 6R and intermediate 37 778 60 FROM

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Intermediate 45 BOC M TBDMS ΎΎ ^rX ν αΫ from intermediate 6R and intermediate 44 1090 (purity 93% according to LC / MS) solid beige product colors 89 FROM Intermediate 61 BOC ⁴ ν— <1 \ ___ <$ ^> 1 _/ X0X _O ^, TBDMS ii R ^N from intermediate 6R and intermediate 59 525 (purity 93% according to LC / MS) light yellow powder 83 from Intermediate 63 BOC \ </ \ __ „ ^X o- ^{IBDMS Xr} 1 ⁰ D ClXY ^ GG n from intermediate 6R and methyl-4 (methyl sulfonyl) aniline 536 36 (degree ny purity 46% according to m LC / MS) from

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Mixture intermediate 68 / intermediate 69 BOS m / ⁴ \ TBDMS AA L SV ' ⁰ 0 nn ^{1 nm / N} \ TBDMS AA L SV' ⁰ ιΛρ 0 sizA O _h ___ / from intermediate 6R and intermediate 67 1210 (mixture intermediates 68/69: 98.7 / 1.3) foam pale yellow colors 93 C at T = 80 ° C Intermediate 74 BOS y— \ IA / \ ___ Ά <A / XX ^ TBDMS ubyA ^{0 N} άΑ ° l ° s. from intermediate 6R and intermediate 73 2420 (purity 73% according to LC / MS) brown foam C at T = 90 ° C Intermediate 77 VOS Y— <GA 1 \ ___ Άί Y \ / X ^X ₀ __- TBDMS From _C | 0 άΛ ' ⁷ 2500 (power purity 81% according to LC / MS) FROM

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from intermediate 6R and intermediate 76 brown solid Intermediate 79 BOS \ - V 4BDMS T II ^R N X .; 1 from intermediate 6R and intermediate 51 919 (power purity 96% according to LC / MS) Orange powder 86 FROM Intermediate 85 VOS \ —X / \ ___. q-'TBDMS Y j ^RS о αΥ = from intermediate 6 and intermediate 84 292 orange butter C at T = 85 ° C

Intermediate 89 voe \\ Y X - \ -TBDMS Yr ^s 1 to Y N. XY ^j from intermediate 6 and intermediate 88 247 deep black foam С at Т = 95 ° С Intermediate 93 BOS \ -X Ν <χ 1 \ __ _x Υ. / k / \ \ q_tbdms YY ^RS Υ. γ Y ^H from intermediate 6 and intermediate 92 698 68 (70% purity according to LC / MS) С at Т = 95 ° С Intermediate 96 your \\ 1 \ ₀ ^ TBDMS || ^R s ^X yY Cl rYY γΥγ ^ ΟΗ Сл О н 1 0 from intermediate 6 and intermediate 95 387 orange viscous oil FROM

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Intermediate 100 BOC ₀ ___TBDMS A - \ / N ^. / AAA ^ _R y AA ci ςχ ό L n from intermediate 6 and intermediate 99 360 С at Т = 85 ° С Intermediate 102 BOS A— \ A \ / x ^X _O - ^TBDMS AA || RS OlXk n A _N From intermediate 6 and 3-amino-4methylbenzonitrile 356 brown solid С at Т = 95 ° С Intermediate 105 BOS A— <Νχ. / \ __ _x A \ / \ ό—- ^TBDMS AA || RS ^X АА _С | όυό ¹ From intermediate 6 and 5-chloro-2methylaniline 540 brown solid С at Т = 95 ° С Intermediate 110 BOS _h \ - \ 1 \ __ _{_} AA / XX ^ TBDMS || ^RS ^ AA 0 From intermediate 6 and intermediate 109 249 (power purity 62% according to LC / MS) deep black foam 98 С at Т = 95 ° С Intermediate 112 VOS A— \ Ν '. / \ ___ A <A \ / \ ^X _O _-TBDMS AA || rs АА _С | Af CI From intermediate 6 and 2,5 dichloroaniline 530 (power purity 80% according to LC / MS) Quantity С at Т = 95 ° С Intermediate 114 VOS BUT- N ^. I \ ___ A Z \ V - TBDMS XJA r Fa o From intermediate 6 and 2-methoxy5 - (trifluoromethyl) aniline 390 (power purity 55% according to LC / MS) brown solid С at Т = 95 ° С

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Intermediate 116 VOS _H ν --- \ N ^. I \ ___ AA n— · TBDMS yr RS ^x r 0 From intermediate 6 and 3-amino-4chlorobenzonitrile 365 brown butter С at Т = 95 ° С Intermediate 118 BOC Y— \ N ^. / \ __ _x / \ ^X „^ TBDMS Г T ^RS N Cl From intermediate 6 and 3-amino-4chlorobenzonitrile 504 (purity 70% according to NMR) white solid 82 С at Т = 95 ° С Intermediate 120 BOC N --- \ N ^. / Г-х 'r./k/XY^TBDMS Yy if RS ⁴ Cl Oy ό 0 From intermediate 6 and 5-chloro-2methoxyaniline 960 (purity 64% according to LC / MS) brown solid Quantity С at Т = 95 ° С Intermediate 124 BOC „^ .TBDMS N --- </ I \ J Xy O / ⁰ From intermediate 6 and intermediate 123 308 (purity 86% according to LC / MS) 47 С at Т = 95 ° С

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Intermediate 128 TBDMS BOC 0 ^ \\ I CI Cl / ό From intermediate 6 from intermediate 127 530 (purity 68% according to LC / MS) 85 С at Т = 95 ° C Intermediate 131 BOC \ —X Ν— 1 \ ___ A. Xq ^ -TBDMS Yp ^rs ^ klXXi and 1 F From intermediate 6 and intermediate 130 530 M.R. (K) = 136 ° C 75 С at Т = 95 ° C Intermediate 135 BOS \\ Νς. / \ ___ Xq ^ TBDMS TJ ^S γ X JL l r <^ N kA IJ U H From intermediate 6 and intermediate 134 268 M.R. (K) = 133 ° C 37 С at Т = 95 ° С

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Intermediate BOC ⁴ N --- < 308 45 C at T = 139 j \ ___ TBDMS 00 0J RSΛ BUT? LAN From intermediate 6 and intermediate 138 95 ° C Intermediate 143 (mixture of 4 undivided diastereomers) VOS ₀ __TBDMS \\ / 1 \ J 0 ^ || RS X ^с 0 1 ^rs J 1 From intermediate 6 and intermediate 142 197 (purity 87% according to LC / MS) 200 (purity 95% according to LC / MS) 25 27 С at Т = 95 ° С Intermediate 146 BOC ' _N ___ TBDMS Νς. / V ⁰ w 0% ό From intermediate 6 and intermediate 145 370 64 С at Т = 95 ° С

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Intermediate 151 VOS i he L Y J sysD N From intermediate 150 and intermediate 149 139 38 (exodus from steppes and purity 74% dyna m LC / MS) С at Т = 95 ° С Intermediate 157 VOS \ -l, Xr ~ Q D g d UUS> n fH F From intermediate 150 and intermediate 156 119 (power purity 98% according to LC / MS) 25 С at Т = 95 ° С Intermediate 161 BOC ⁴ _N __ ^ TBDMS YYg m Dx From intermediate 6 and intermediate 160 205 (purity 95% according to LC / MS) White powder 80 (purity 59% according to LC / MS) Yellow oil 34 13 FROM

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Intermediate 164 BOC ₀ __TBDMS ° ^^ o ^ From intermediate 6R and intermediate 123 269 (purity 71% according to LC / MS) 41 С at Т = 95 ° С Intermediate 169 VOS \\ N-. / V ^х > k / \ ^RS Ύ YJ ^ TBDMS F. Jx XX From intermediate 6a and 5-chloro-2methoxyaniline 411 (purity 97% according to LC / MS) 96 FROM Intermediate 171 VOS \ —V i \ x / \ X X X 0 \ bdms F Jx L £ L 1 From intermediate 6aR and 5-chloro2-methoxyaniline 418 (purity 91% according to LC / MS) 97 FROM Intermediate 196 BOC q ^ TBDMS ° χ / Χ ο ^χ From intermediate 6S and 269 41 С at Т = 95 ° С

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intermediate 123 Intermediate 203 BOS / \ __ _{_} AL L AAV ^ TBDMS ci sipl Η 1 0 From intermediate 6R and intermediate 202 582 (purity 59% according to LC / MS) yellow solid Quantity С at Т = 95 ° С Intermediate 205 BOC q ^ TBDMS ⁴ N --- \ / 1 \ __ I LJF А / ci όυό Η 1 0 ο. ΙΙ ^, ο 1 From intermediate 6R and 5-chloro-2 [2-methyl sulfonyl] ethoxy] benzamine 190 27 FROM Intermediate 210 BOC \ - \ / \ __ _{_} 0- ^ TBDMS t t Ca Al Η 1 0. ^χ From intermediate 6R and intermediate 209 620 black foam Quantity С at Т = 95 ° С Intermediate 212 BOC Y— </ \ ___ J. AC Xq ^ TBDMS 0 X From intermediate 6R and 2- (aminophenyl) dimethylphosphine oxide 740 (purity 59% according to LC / MS) brown foam 99 С at Т = 95 ° C

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Intermediate 222 BOC ⁴ N --- <N ^. j \ ___ / 0 Υχ ^x ₀ ^ -tbdms XY "T ^ O I / SUUDU n 1 0 ^ From intermediate 6R and intermediate 221 760 (purity 66% at the rate method LC / MS) black foam Quantity С at Т = 95 ° С Intermediate 228 BOC ₀ _TBDMS ⁴ N --- \ / LN j \ J TlY Ν AD From intermediate 6R and intermediate 227 400 (purity 97% at the rate method LC / MS) 61 FROM Intermediate 232 BOS ⁴ Ν --- k / \ ___ \ ^ tbdms TT o T N / Sl DU Η 1 eg / From intermediate 6R and intermediate 231 630 (purity 85% at the rate method LC / MS) black foam Quantity C at T = 90 ° C Intermediate 240 BOC q ^ TBDMS ⁴ N— \ / ^N x 1 αγ From intermediate 6R and intermediate 239 494 (purity 93% by definition division NMR method) 77 FROM

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Intermediate 242 BOC ^ q ^ TBDMS ⁴ N --- ν / I \ __ I Tg Ν G F From intermediate 6R and 3-amino4- (trifluoromethyl) benzonitrile 613 95 FROM Mixture intermediate 247 / intermediate t247 ' SMDBT BOC ' ₀ N ^. _R / ХА тТг CI όυό А А | ₊ SMDBT boe ' ₀ N ^ _R / / Гг CW ^ 0 1 From intermediate 6R and intermediate 377/378 381 intermediate 247 (purity 87% according to LC / MS) Intermediate 247 '(purity 11% according to LC / MS) 48 FROM Intermediate 252 SMDBT boe X N --- \ / / \ -L cr ιΆ'Ά kA A ^ An /BUT 001A o From intermediate 6R and intermediate 251 397 60 FROM

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Intermediate 261 VOS U — i GA I \ __ _{_} Α, / Χ / Χ ^X _O ZhVSM5 From intermediate 6R and intermediate 260 553 (purity 84% at the rate LC / MS) Orange powder 82 FROM Intermediate 265 BOC \ N --- \ ha / V ^х / \ ^RS CX I TBDMS ζχ TJH Гк О ^F F From intermediate 6 and 2isopropoxy-5 (trifluoromethyl) aniline 502 (purity 57% according to LC / MS) 44 FROM Intermediate 269 SMDBT ^X O BOS 1 / --- N ^Z A / \ 'RS ^ p || Ca Α ^Χ AN O ^F From intermediate 6 and intermediate 268 372 (purity 78% according to LC / MS) 55 C at T = 90 ° C

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Intermediate 391 OTBDMS BOC ί / - \ / _R \ Xg cl Ν Λ Η ko From intermediate 6aR and 3-amino4-methylbenzonitrile 375 90 FROM Intermediate 417 BOS \\ χ / A AARlvomz | MG ⁴ with j A ⁿ Ουφ θ'Τ ^ From intermediate 6R and intermediate 416 340 45 C at T = 80 ° C Intermediate 505 ^В0С \ OtBDMS У J ^Ν Λ / ^ΝΗ UL jO From intermediate 6R and intermediate 501 360 57% Steppes purity 84% (LCMS) FROM (during the night at 95 ° C) Intermediate 508 ^В0С \ OtBDMS Software 1 ui Q E NT I 100 17% FROM (during the night at 80 ° C)

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From intermediate 6R and 2-methyl5 - (1-methyl-4-piperidinyl) aniline Intermediate 537 ^В0С \ OtBDMS ^N - \ r I χχ ν OOQ H From intermediate 6R and intermediate 536 488 sixteen% Steppes of purity 49% (LCMS) FROM (Зч at 95 ° С) Intermediate 551 \ / 0 Il _n > TBDMS I hK y \> ifr ⁴ ex / OH Μ From intermediate 6R and 3-amino4-methylbenzyl alcohol 4690 yellow foam 78 FROM Intermediate 568 \ / 0 —II _n _TBDMS G-d J | \ k y Cr cx Δ ⁿ From intermediate 6R and intermediate 567 540 80 FROM

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Intermediate 572 \ / ⁰ -A J] _n __TBDMS ° A-, j Dd A'D D, o From intermediate 6R and intermediate 571 850 98 FROM Intermediate 576 \ / ⁰ —II „, -TBDMS dd DBP YES _CN όυό ^ A ^ AdA From intermediate 6R and intermediate 575 633 pale brown oil 82 FROM Intermediate 584 \ / ° JJ _n ^ TBDMS ° A-d j YES _CN d ^ NH A From intermediate 6R and intermediate 583 180 56 FROM

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Intermediate 588 \ / 0 JI _n ^ .TBDMS ° Λ-, j I YY ⁴ CN cxxS Y, X From intermediate 6R and intermediate 587 315 (Purity 85% according to LCMS) 77 FROM Intermediate 592 k / 0 Ύ JJ n ^ TBDMS γγ-Υ ΥΥγ cn Ca j0 \ \ ^ F From intermediate 6R and intermediate 591 300 74 FROM At 100 ° C for 1 hour Intermediate 596 \ / о JJ _n ^ TBDMS I ^{N <} k / \ Y γγγ Υη CN ex χ5 ^ ν ^ νΥΥ ^Η ^ Ν ^ \ ^V ^ ^X 'F From intermediate 6R and intermediate 595 240 53 FROM At 100 ° C in within 1 hour

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Intermediate 605 \ / o -T L n-TBDMS 1 ^N 4 1 lUr cn ° \ / \ ^CIS Y From intermediate 6R and intermediate 604 310 (Purity 85% according to LCMS) 73 FROM Intermediate 611 \ / o J! _n _TBDMS V, j XYr cn trans 1 K From intermediate 6R and intermediate 610 121 (Purity 55% according to LCMS) 70 FROM At 100 ° C for 1 hour Intermediate 627 \/ about II p. ^ TBDMS θΑ-, j N. y St FROM) VoA Λ From intermediate 6R and intermediate 626 505 59 FROM

Example A8.

Getting intermediate 154

A mixture of intermediate 150 (300.00 mg, 0.75 mmol), intermediate 153 (198.67 mg, 0.82 mmol), and Cs ₂ CO ₃ (609.59 mg, 1.87 mmol) in 1,4-dioxane (12.77 ml) was purged with N2. Then, a catalytic amount of Pd (OAc) ₂ (13.44 mg, 59.87 μmol) and BINAP (37.28 mg, 59.87 μmol) were added to a sealed tube. The reaction mixture was purged with N2 and stirred at 120 ° C in a microwave single-mode reactor (Biotage Initiator EXP 60) with an output power ranging from 0 to 400 W for 30 min. The resulting mixture was poured into water and DCM. Then it was filtered through a celite pad, decanted and the organic layer was separated, dried with MgSO ₄ , filtered and evaporated. The residue (948 mg) was purified by column chromatography on silica gel (SiOH, irregular grains, 40 μm, 40 g, mobile

- 106 037358 phase: heptane / EYOAc / MeOHMHDOH, gradient from 50% heptane, 50% EtOAc to 40% heptane, 10% MeOH,

50% EtOAc, 1% NH4OH). Fractions with pure substance were combined and the solvent was evaporated to obtain

300 mg of intermediate 154 (66% yield).

The intermediates in the table below were prepared by methods analogous to the preparation of intermediate 154 from the corresponding starting materials.

Intermediate number Structure Weight (mg) Output (%) Intermediate 173 BOC \ —y rx / \ ___% X XJ ^ q ^ TBDMS || ^R s ^X Cl А fAf From intermediate 6 and 2-amino-4-chloro benzotrifluoride 418 64 Intermediate 179 BOC \ —y FX / \ ___ x <xX ^BDMS Pl RS ^{4 and} V ^F Y ^F L JI II JIN CIS H ¹ Cis From intermediate 6 and intermediate 178 499 66 Intermediate 181 VOS \\ rx / \ ___ X / X% ^ TBDMS || A From intermediate 6 and 4-bromo-5-chloro-2methylaniline 180 27 Intermediate 183 BOC \ - \ Ν, χ / \ ^X o ^ ^TBDMS YT ^RS А ° γ ^ρ From intermediate 6 and 5-chloro-2 (trifluoromethoxy) aniline 600 76

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Intermediate 187 BOS Y - \ rs / \ ___ A. A A7x ₀ ^ tbdms Xr XT ^RS ^ From intermediate 6 and intermediate 186 600 (Degree of purity 69% by data LC / MS) 89 Intermediate 190 BOC \ 1 \ ___ ^X ₀ ^ TBDMS || RS ^X Cl О From intermediate 6 and intermediate 189 600 89 Intermediate 193 VOS U — u Ν '. 1 \ ___ A. U L; a ^ tbdms (г CI όυό ζχλ ⁿ 0 From intermediate 6 and intermediate 192 300 40 Intermediate 218 VOS N / ¹ \ TBDMS UL A; yy Cl CX fS χ Η Η From intermediate 6R and intermediate 217 387 59

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Intermediate 224 BOC \\ 1 \ ___ II ^{s N} From intermediate 6S and 3-amino-4methylbenzonitrile 329 (Purity 82% by LC / MS data) yellow powder 55 Intermediate 236 BOC N \ / ^N _X TBDMS 00 CI G00 O From intermediate 6R and intermediate 235 207 (Purity 92% by data LC / MS) 35 Intermediate 411 n _m U \ ___ TBDMS ΎΎ ^ρ kA and ³¹⁴ G? From intermediate 7R and intermediate 410 610 95 Intermediate 458 -L -4- / __. Si * ^ 0 == 4 ^h o N - ν / / \ rJ 00k - ^^ NHBoc kA JU H From intermediate 6R and intermediate 457 604 97

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Intermediate 629 78 463 __Si- n ⁴ o N --- \ / Νς. / \ rJ / l M III 1 1 ChNVos islt I From intermediate 7R and intermediate 462 Intermediate 468 ^ Si- N- \ ^N AA A ..... From intermediate 7R and intermediate 467 396 100 Intermediate 471 ^ Si- н ^s o Ν -— </ n-. i \ rJ ⁿ Ay From intermediate 7R and intermediate 470 261 (Purity 68% by data LC / MS) 68

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Example A9.

Getting intermediate 277

To a solution of intermediate 274 (0.10 g, 0.24 mmol), intermediate 276 (56.70 mg, 0.24 mmol), BINAP (14.90 mg, 0.024 mmol), Cs ₂ CO ₃ (237.00 mg, 0.73 mmol) in 1,4-dioxane (3 ml) was added Pd (OAc) 2 (5.39 mg, 0.024 mmol) and the reaction mixture was heated for 30 min at 95 ° С. EtOAc was added to the reaction mixture, washed with water and brine. The organic layer was dried with Na ₂ SO ₄ and evaporated in vacuo to give 227 mg of intermediate 277 (65% purity by LC / MS, yellow oil) and used as it is in the next step.

The intermediates in the table below were prepared using a method similar to that for intermediate 277 from the appropriate starting materials.

Intermediate number Structure Weight (mg) Output (%) Intermediate 280 VOS \\ Cl ά, ΖΑ From intermediate 274 and intermediate 279 124 (69% by data LC / MS)

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Intermediate 281 VOS X— < Yr ci όυό Ιχ ___ Y From intermediate 274 and intermediate 99 153 (90% according to LC / MS) brown butter Intermediate 282 how X— < one - Tr Cl □ G about From intermediate 274 and intermediate 109 124 (purity 95 % by data LC / MS) brown butter Quantity Intermediate 286 VOS X— \ Ι \ __ Tg CI 0 aha o From intermediate 274 and intermediate 285 157 (90% LC / MS) brown oil Quantity Intermediate 287 how X— < 1 V— Tr g. Χ ABOUT From intermediate 274 and intermediate 88 126 (90% LC / MS) brown oil Quantity

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Intermediate 288 VOS \\ \ ___ YES ^ α Dd ddd ^ he kA DH n 1 O From intermediate 274 and intermediate 95 107 (89% according to LC / MS) brown oil Quantity Intermediate 292 VOS \ < Νχ / \ __. dd YES ci o o 0 From intermediate 274 and intermediate 291 152 (87% over data LC / MS) brown butter Quantity Intermediate 298 BOC \\ / \ ___ Yes ci Q. a ^ ^ YY ln ^N XT Ί Α ° From intermediate 274 and intermediate 297 101 (87% LC / MS data) brown oil Quantity Intermediate 301 wow \ 1 \ f Dt YES ci OU η 1 0 From intermediate 274 and intermediate 300 199 (36% according to LC / MS) brown solid substance

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Intermediate 304 BOS X — V Ν '. 1 \ __ du, ___ _C | / Y Υ γ- 0 From intermediate 274 and intermediate 303 84 (93% LC / MS) brown oil Quantity Intermediate 306 BOS X —- l Ν '. 1 \ y XT Yy Cl q6 ^H / S ^ ° From intermediate 274 and intermediate 305 143 (20% by LC / MS) brown solid Intermediate 309 VOS X— < Ν '. one XT ci aJX From intermediate 274 and intermediate 308 152 (47% according to LC / MS) Intermediate 312 VOS X— < Νς. / \ __. XT UL χΧ 0 From intermediate 274 and intermediate 311 111 (85% according to LC / MS) Quantity

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Intermediate 315 VOS \-to one \___ ifj 1 Ργ Cl / p / X k / k 0 From intermediate 274 and intermediate 314 114 brown butter (87% according to LC / MS) Quantity Intermediate 320 VOS \ < X 1 V-— m ,, ___. a / g ° 0 From intermediate 274 and intermediate 319 OF brown butter (51% by data LC / MS) Quantity Intermediate 323 VOS \ —Y χ / \ l kt P ^ CI Q Ap A ^ A ^ A ^ l 0 From intermediate 274 and intermediate 322 159 brown solid (45% according to LC / MS) Intermediate 327 BOC \ Ν --- \ ιχ / \ A to kX / y ο _χ From intermediate 274 and intermediate 326 153 brown solid (63% by data LC / MS)

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Intermediate 330 VOS N <s. / \ __ YY ci γ \ 1 1 ν Y- ° ⁿ Υν 0 From intermediate 274 and intermediate 329 106 brown solid (84% by data LC / MS) Quantity Intermediate 333 BOS \ Ν '. / Yp ^С1 YY 0 From intermediate 274 and intermediate 332 81 brown butter (90% according to LC / MS) Quantity Intermediate 337 VOS \ < Vc YY Cl άΥ ° \ / \ From intermediate 274 and intermediate 127 210 (80% according to LC / MS) 75

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Intermediate 338 VOS A — y Ν '. / \ __ Yr АА _С | Y Л 0 '/ ---' From intermediate 274 and intermediate 123 194 78 Intermediate 339 BOS A— \ ⁿ a <A Az ci Υ Λ RS 1 1 1 From intermediate 274 and intermediate 142 182 (90% according to LC / MS) 70 Intermediate 342 BOS A— \ Ν ^. 1 \ __ Yr AjA _С | FH Y From intermediate 274 and intermediate 341 61 (66% according to LC / MS) 25

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Intermediate 345 BOC ^X N - \ Ν '. one \__. Tg L / CI Q L U ___ A From intermediate 274 and intermediate 344 505 (80% according to LC / MS) 59 Intermediate 346 VOS \ <Νς. one \__ Vc y / A From intermediate 274 and 2-fluoro-3,5-dimethoxyaniline 273 (91% according to LC / MS) 81 Intermediate 347 VOS Υ— \ n <. 1 V / V D ^ln ci <y Vx On From intermediate 274 and intermediate 92 559 (61% according to LC / MS) 62

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Intermediate 352 VOS \ - to Cl O c, o '' ABOUT From intermediate 274 and intermediate 351 1306 84 Intermediate 353 BOC Ji ^{Xy 4} ηΑ CI Ca j0 ^H। 1 p. A Y X ~ x Xq ^x xx From intermediate 274 and intermediate 145 81 yellow powder (86% by data LC / MS) 22 Intermediate 356 BOC \\ ^N <x £ / А у ² Cl όυό ο. / XX ^ Α ^ Ο From intermediate 274 and intermediate 160 151 yellow butter (89% according to LC / MS) 112 yellow butter (58% according to LC / MS) 27 13

Example A10.

Getting intermediate 362

\ / ^RS

In a sealed tube, Pd (OAc) ₂ (16.00 mg, 70.20 mmol) and BINAP (44.00 mg, 70.20 mmol) were added to a preliminary degassed solution of intermediate 361 (200.00 mg, 0.70 mmol), intermediate 360 (250.00 mg, 0.78 mmol) and Cs ₂ CO ₃ (686.00 mg, 2.11 mmol) in 1,4-dioxane (10 ml) and the reaction mixture was heated at 120 ° С in a microwave single-mode reactor (Biotage Initiator EXP 60) with an output power in the range from 0 to 400 W for 20 minutes. The reaction mixture was combined with another batch (50.00 mg of intermediate 361) for work-up, EtOAc was added and poured into water. The organic layer was decanted, washed with brine, dried with MgSO ₄ , filtered and evaporated to dryness. The residue was purified by silica gel column chromatography (SiOH, irregular grains, 24 g, mobile phase: heptane / EtOAc, gradient 80:20 to 60:40). Fractions with pure substance were collected and evaporated to dryness, yielding 168 mg of intermediate 362 (34% yield)

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Example A11.

Getting intermediate 10R

Method E.

A mixture of intermediate 9R (5.30 g, 8.68 mmol) and TBAF (1 M in THF, 17.3 ml, 17.35 mmol) in Me-THF (90 ml) was stirred at rt for 3 h. The reaction mixture was poured into a 10% aqueous solution of K2CO3, EtOAc was added followed by saturated NaCl solution (to aid decantation). The organic layer was decanted, washed again with 10% aqueous K2CO3 (+ 100 ml saturated NaCl solution), then with saturated NaCl solution. The organic layer was dried with MgSO4, filtered and evaporated in vacuo. The residue was taken up in CH ₃ C N, and the precipitate was filtered off and dried to obtain 2.72 g of intermediate 10R (yield 63%).

The intermediates shown in the table below were prepared analogously to method E from the appropriate starting materials. The most important minor deviations from the reference method are indicated in the Method column.

Intermediate number Structure Weight (mg) Output (%) Method Intermediate 30 ⁱⁿ % he N --- \ / kk / \ __ 1 Ύκ 1 oiz ^ kg ^ kg n From intermediate 29 270 (95% purity according to LC / MS) 98 E Intermediate 35 VOS \ —X he Ν about DAN From intermediate 33 560 (degree of purity 97% LC / MS) Yellow powder 84 E

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Intermediate 62 VOS GA / \ s — X ^{he Ν} qX From intermediate 61 373 (degree of purity 90% LC / MS) Yellow powder 93 E Intermediate 64 VOS Y-y GA j \ __ aUh / x he From intermediate 63 267 Quantity E with 1.4 equiv. TBAF Intermediate 70 VOS Y- \ ζ '° ⁿ ιγύ ^λ o t i oisu ^ n 1 From intermediate 68 893 Almost white foam 97 E with 1 equiv. TBAF Intermediate 75 BOS Y — y HA / V— \ ΑζΑΖΧ on T ^Ν aX 0. Y— Iz intermediate 74 887 60 E with 1.7 equiv. TBAF Intermediate 78 VOS U— < ⁿ A / Vx GG ™ ci о Ργ From intermediate 77 952 (degree of purity 90% LC / MS) White foam 56 E with 1 equiv. TBAF Intermediate 80 VOS U— <GA / AX OH T N ^R N I s 1 From intermediate 79 653 Yellow powder 86 E Intermediate 90 VOS U — y ha / V \ on L T 1 Ay CI o # ⁷ 0 From intermediate 89 182 Brown oil EcTHF as solvent and 1 equiv. TBAF

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Intermediate 97 BOC X— < ⁿ .x / Vx T 11 ^RS Cl rXX -Υγ ^ ΟΗ kA XI rr rr Η 1 0 From intermediate 96 272 Orange solid EcTHF as solvent and 1 equiv. TWAB Intermediate 101 ^B0 X he / Y-- 'jp || R® ⁴ AjX Cl r L / N From intermediate 100 302 Yellow oil EcTHF as solvent and 1 equiv. TBAF Intermediate 103 BOS X— \ / V — x ΧγΧ / \ ОН T II ^RS CaJOl h A _n From intermediate 102 289 EcTHF as solvent and 1.1 equiv. TBAF Intermediate 106 VOS X— \ n. / ΧχΧ / Λ ОН Dy | Г rs ^x DG ci UD From intermediate 105 390 Yellow solid EcTHF as solvent and 1.1 equiv. TBAF

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Intermediate 111 VOS X ⁿ A 1 \ _-- x he and s intermediate 110 246 (68% purity according to LC / MS) Dark oil Quantity EcTHF as solvent and 1 equiv. TBAF Intermediate FROM VOS \\ Νχ / \ __ IS HE y || Rs CI Sl / 0 Cl From intermediate 112 424 Yellow solid EcTHF as solvent and 1.1 equiv. TBAF Intermediate 115 VOS \\ one \__ is he oi? 0 From intermediate 114 323 (77% purity according to LC / MS) Quantity EcTHF as solvent and 1.1 equiv. TBAF Intermediate 117 BOS \\ HaA ^on 1 ^Ν Г * 0 From intermediate 116 298 Yellow solid Quantity EC THF as solvent and 1.2 equiv. TBAF

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Intermediate 132 BOS \\ Νς. 1 \ __ UaUx he \ II ^RS Yes / A kA AAl n 1 F From intermediate 131 289 M.R. (K) = 203 ° C 59 EcTHF as solvent and 1.2 equiv. TBAF Intermediate 229 ^IN A he N --- \ / Νς. / \ __ / ^Ν Ai 0. / From intermediate 228 3350 E and 1.2 equiv. TBAF Intermediate 241 ^IN A he Ν --- \ / \ __ 1 YES Sk DU n 1 o. / From intermediate 240 406 99 E Intermediate 243 ^IN A he N --- \ / G T ^R N t From intermediate 242 313 73 E

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Intermediate 248 ⁱⁿ \ he N --- \ / A 1 TAA η / ci όυό A about 1 From intermediate 247 227 82 E with 1.2 equiv. TBAF Intermediate 262 VOS BUT- is he BUT From intermediate 261 373 Yellow powder 81 E Intermediate 266 BOS A — y n ^. 1 \ A YA A z \ rs Ya A ^ ⁿ ζχ Ar A Η YYy fa F From intermediate 265 234 56 E Intermediate 270 it is 1 / --- N ^Z </ \ ^ .N As | || Ca Ajh zA0a 0 ^FF 230 46 EcTHF and 1.9 equiv. TBAF

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From intermediate 269 Intermediate 461 n he / \ R 7 Yi Υν ΥΠ Η From intermediate 459 84 48 Ε with 1.1 equiv. TBAF Intermediate 464 Η he Ν — X / Ill 1 1 ^ NHBoc Sd Du Η From intermediate 463 263 49 E with 1.1 equiv. TBAF Intermediate 482bis n he Ν --- \ / N <4. 1 \ R__1 VYA YA 0 ^^ NHBoc From intermediate 482 63 17 with 0.5 equiv. TBAF Intermediate 487 Η Ν --- \ | \ Ы / \ R_ ΎτΥχ he Τ ιΓ ^ν q λ ^ην Χ From intermediate 486 460 100

Example A12.

Getting intermediate 225

TBAF (on silica gel 1.5 mmol / g) (1.08 g, 1.62 mmol) was added to a solution of intermediate 224 (329.00 mg, 0.54 mmol) in Me-THF (13.5 ml) and the reaction mixture was stirred at rt for 18 h. The next day the check showed that the reaction was completed. EtOAc was added to the reaction mixture, water and also NaCl were added twice. The layers were separated and the organic layer was dried with MgSO ₄ , filtered and the solvent was removed under reduced pressure. The residue (300 mg) was combined with another batch (400 mg) for purification. Both crude products were purified by silica gel column chromatography (SiOH, irregular grains, 40 g, DCM / MeOH mobile phase, gradient 100: 0 to 96: 4). Fractions with pure product were combined and evaporated to dryness to give 632 mg of intermediate 225 (light pink powder).

The intermediates shown in the table below were prepared by a method similar to that described for the preparation of intermediate 225 from the corresponding starting materials. The most important minor deviations from the reference method are indicated as supplementary information in the Mass (mg) column.

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Intermediate number Structure Weight (mg) Output (%) Intermediate 39 ⁱⁿ % he NY I \ J A A n L From intermediate 38 310 (purity 94 % by data LC / MS) Methodology with 4 equiv. 48 TBAF Intermediate 206 ⁱⁿ⁰ % he Ν --- ν / LJY η / ci όυό Η 1 ο ο. ^ \ ΙΙ / Ο 1 From intermediate 205 91 Methodology with 6 equiv. TBAF 58 Intermediate 229 ^vos _h he Ν --- \ / / ⁿ υυϊ Ο ^ From intermediate 228 227 68

Example A13.

Preparation of intermediate 13 and intermediate 14. Method F

To a solution of intermediate 11 and intermediate 12 (85/15) (1.11 g, 1.55 mmol) in DCM (35 ml), TFA (3.50 ml, 45.70 mmol) was added and stirred at rt for 30 min. DCM was added to the mixture and poured into an aqueous NaHCO ₃ solution. The organic and aqueous layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were dried with MgSO ₄ , filtered and evaporated in vacuo. The residue (960 mg) was purified by column chromatography on silica gel (SiOH in irregular grains, 15-40 μm, 50 g, dry application on celite, mobile phase: heptane / EtOAc / MeOH, gradient from 85% heptane, 15% EtOAc / MeOH (9: 1) to 60% heptane, 40% EtOAc / MeOH (9: 1)). The desired fractions were combined and the solvent was evaporated to dryness in vacuo to give 695 mg of a mixture of intermediate 13 and intermediate 14 (85/15) (73% yield).

The intermediates shown in the table below were prepared analogously to method F from the appropriate starting materials. The most important minor deviations from the reference method are indicated in the Method column.

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Intermediate number Structure Weight (mg) Output (%) Method Intermediate 19 tbdms n N— \ ^ν λ / Др ° l Сд JU From intermediate 18 403 Orange foam F Intermediate 46 n m U \ 4BDMS ΗΊ ^{rX n} αϋ ΡΑγ From intermediate 45 500 (degree of purity 67% by LC / MS data) pale yellow solid 67 F with DCM / TFA (6: 1, rev / rev) Intermediate 107 n Ν— \ / \ __ Rr L A \ ™ mz RA | E RS ⁴ Ργ ci όυό From intermediate 105 363 White solid 51 F with DCM / TFA (5: 1, rev / rev)

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Intermediate 119 n n --- to Ν '. / \ ___ Xq ^ TBDMS Г Y ^RS N? l Cl From intermediate 118 251 (purity 83% by data LC / MS) Yellow solid 63 F with DCM / TFA (7: 1, rev / rev) Intermediate 121 n n - x Ν '. 1 \ __,% -TBDMS 11 11 ^RS ^ ci XX 0 From intermediate 120 176 (Purity 34% by LC / MS data) White foam 34 F with DCM / TFA (4: 1, rev / rev) Intermediate 136 Η Ν --- χ Ν '. / \ ___ Xq ^ TBDMS Χγ I A Jk A. ΑΤΙ Π 1 ^ 1 kAJU U> Η From intermediate 135 97 M.R. (K) = 224 ° C 66 F with DCM / TFA (4: 1, rev / rev) Intermediate 140 Η Ν -— \ Ν '. 1 \ __ Α. ^Χ ₀ —-TBDMS XX Xj rs ^x / ..... 'X'T'TA Τα ^ οη From intermediate 139 195 74 F with DCM / TFA (4: 1, rev / rev)

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Intermediate 170 n n --- \ Ν '. 1 V ^x Л RS Αχ ^ TBDMS ^F \ An XzXjh xS XZ ⁴ ;; From intermediate 169 145 (purity 96% by data LC / MS) 42 F at Т = 5 ° C with DCM / TFA (9: 1, rev / rev) Intermediate 172 n Ν --- \ Νς. 1 \ S AJ 0 ηΖ Ybdms Xn A _n zA ^ _h Ύ 1 Υ / Ά _α From intermediate 171 133 38 F at T = 5 ° C with DCM / TFA (9: 1, rev / rev) Intermediate 174 Η Ν --- <Ν. 1 \ ___ Yk> 0 AT Xq ^ tbdms jp || ^R s ^x ηΛ ci άΤ fAf From intermediate 173 207 58 F at T = 5 ° C with DCM / TFA (4: 1, rev / rev) Intermediate 180 X N-. Г \ X. A XX _n XBDMS [Л] F ul MA _cns ασα I Cis Iz intermediate 179 231 F at T = 0-5 ° C with DCM / TFA (4: 1, rev / rev)

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Intermediate 182 n N --- \ Νςχ. one \__. L. Α, -TBDMS AfA | f RS ⁴ YES ci dX ySr From intermediate 181 104 (70% purity according to LC / MS) 67 F at T = 0- 5 ° C with DCM / TFA (4: 1, rev / rev) Intermediate 184 n N --- \ j \ __ A, / k / \ \ -tbdms jp || ^R X YES _C | όυό of T ^f From intermediate 183 337 77 F at T = 0- 5 ° C with DCM / TFA (4: 1, rev / rev) Intermediate 188 Η Ν— \ j \ __ _to ζ \ A —- tbdms AgA Α < _rs \ ^υ YES Cl d From intermediate 187 213 60 F at T = 0- 5 ° C with DCM / TFA (4: 1, rev / rev) Intermediate 191 n N --- \ Yh / \ __ „/ \% -TBDMS D RS ^X YES '^ CI o From intermediate 190 384 (purity 65 % by data LC / MS) 49 F at T = 0- 5 ° C with DCM / TFA (4: 1, rev / rev)

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Intermediate 194 n n --- \ Ν '. / \ __ „A. \ _n _-TBDMS || ^RS ^ A / ci ά Λ / Г 9 0 From intermediate 193 252 (degree of purity 97% by data LC / MS) 96 F at T = 0- 5 ° C with DCM / TFA (4: 1, rev / rev) Intermediate 204 Η Ν --- u Ν '. Ι \ __. Υχ Λ / X \, -TBDMS Ύτ ηΑ _C | Α ^ ο γγγ Η 1 0 From intermediate 203 168 White solid 57 F with DCM / TFA (6: 1, rev / rev) Intermediate 211 Η Ν ---- <Ν '. 1 \ ___ / Α / \ ^ _O - ^ ^TBDMS Tr ΥχΥ Η 1 ° '/' --- 'ο ^ From intermediate 210 207 White foam 48 F with DCM / TFA (7: 1, rev / rev) Intermediate 213 Η Ν --- u Ν '. / \ __ Α \ Α \ XT \ ZTBDMS αα Υ Α Α _Ν Α \ ^ ΑγΑ ο · ^ From intermediate 212 240 Orange solid 65 F with DCM / TFA (4: 1, rev / rev)

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Intermediate 219 n κι 7 ¹ '\ TBDMS X / \ ° Dg Ay CI XX XX ⁰ AkhdDkhk n n From intermediate 218 179 54 F at T = o ° c with DCM / TFA (6: 1, rev / rev) Intermediate 223 n N --- \ N ^. 1 \ ___ xk \ (X ™ ⁵ XY "χΧ 0 V CaDH n 1 0 From intermediate 222 324 76 F with DCM / TFA (4: 1, rev / rev) Intermediate 233 Η Ν --- \ Νςχ / \ ^ Χ χ <XX ^X o- ^TBDMS XJ ^R хД / χ / From intermediate 232 349 Orange solid 76 F with DCM / TFA (7: 1, rev / rev) Intermediate 237 n m / ¹ \ TBDMS X D / \ ° ΎΎ ^Λ Ap οι όυόχ Λ / x ΧΑι / χ / χ / Χζχ H H 1 Ln. From intermediate 236 132 (purity 81 % by data LC / MS) 73 F at T = 0 ° C with DCM / TFA (6: 1, rev / rev)

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Intermediate 253 SMDBT n ^x o N --- / / \ __ / XA kA ^ NH ί ο <= Ί | \ o From intermediate 252 221 65 F with DCM / TFA (17: 1, rev / rev) Intermediate 459 n ^ch o Ν --- \ / Ν1 \ RJ A An ZAAxAhBoc kAJU H From intermediate 458 213 44 F At T = 5 ° C with DCM / TFA (7: 1, rev / rev) Intermediate 460 ^ Si ^ H ⁴ o N ---- </ Nx / \ ^R J A γΑν / AAXA h, kA AJ N ^X Xf / X ^ H From intermediate 458 91 22 F At T = 5 ° C with DCM / TFA (7: 1, rev / rev)

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Intermediate 506 Н OtBDMS А ⁿ A / ^NH Ol / Ο From intermediate 505 370 Quantity Purity 69% (LCMS) F with DCM / TFA (4: 1, rev / rev) Intermediate 509 H OtBDMS / W 1 A / X GaO ουό Ar A ^ n From intermediate 508 85 83% Purity 81% (LCMS) F with DCM / TFA (4: 1, rev / rev) Intermediate 538 H OtBDMS N — A / GA VjJ. aAa / X N Ίχ From intermediate 537 355 89% F with DCM / TFA (5: 1, rev / rev) Intermediate 545 H OtBDMS ^N - \ r / ha / \ 3- / Xr Ά CN nA _N 00 chkhr From intermediate 544 1100 94% Purity 43% (LC / MS) F with DCM / TFA (9: 1, rev / rev)

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Intermediate 548 H OtBDMS ν XX ⁷ Ύι। AG ΟγΝΗ Μχψ From intermediate 547 473 77% Purity 77% (LCMS) F with DCM / TFA (8: 1, rev / rev) Intermediate 569 _н q ^ TBDMS N— \ I 1 yr Μ From intermediate 658 260 56 F at Т = 0 ° С and DCM / TFA (4: 1, v / v) Intermediate 573 _{n 0} „tbdms ГК 1 OL Δ ⁿ Ιχ ^ Ο From intermediate 572 210 58 F at T = 0 ° C and DCM / TFA (4: 1, v / v) Intermediate 585 О ~ Сhy ΞΕΖ \ '- О / \ \ / ---- (\ /) --- О -1 ² S ω 98 89 F at Т = 0 ° С and DCM / TFA (5: 1, v / v)

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Intermediate number Structure Weight (mg) Output (%) Method From intermediate 584 Intermediate 589 _n q ^ TBDMS N- \ I y HA lAr CN άχ From intermediate 588 270 100 F at Т = 0 ° С and DCM / TFA (4: 1, v / v)

Intermediate 634 n m / ⁴ \ / s -TBDMS Ά А ХГ ° 166 - F with DCM / Power TFA Slhd ^ 0 purity 61 % by data (18: 1, rev / rev) n | a ⁿ a LC / MS in flow From intermediate 633 15 hours

Example A14.

Getting intermediate 354

In a round bottom flask, intermediate 352 (0.10 g, 0.18 mmol) was suspended in a mixture of THF (1 ml) and water (1 ml). Then LiOH (37.90 mg, 0.89 mmol) was added and the reaction mixture was stirred at 70 ° С for 5 h 30 min. DCM was added to the reaction mixture and the mixture was acidified with aq. HCl 1 M. The organic layer was quickly separated (to avoid the slightest cleavage of the BOC group), dried with MgSO ₄ and evaporated to give 98 mg of intermediate 354 (quantitative yield). Intermediate 354 was immediately used without further purification in the next step.

Getting intermediate 355

In a round bottom flask, intermediate 354 (98.00 mg, 0.18 mmol) and 4-aminotetrahydropyran (18.60 mg, 0.18 mmol) were diluted in DMF (2.5 mL) at rt. Then HATU (135.00 mg, 0.36 mmol) and DIEA (92.10 μl, 0.53 mmol) were added and the reaction mixture was stirred at rt for 12 h. Then the reaction mixture was partitioned between water and EtOAc and the organic layer was washed with water, brine, dried with MgSO ₄ , filtered and evaporated. The residue was purified by column chromatography on silica gel (SiO ₂ , irregular grains, 24 g, mobile phase: DCM / MeOH, gradient 100: 0 to 95: 5). The product containing fractions were mixed and evaporated to give 80 mg of intermediate 355 (71% yield).

The intermediates shown in the table below were prepared by a method similar to the preparation of intermediate 355 from the corresponding starting materials.

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Intermediate number Structure Weight (mg) Output (%) Intermediate 357 VOS \\ m UNIT Sd Ig ΝΗ o A TD g-ma HQp From intermediate 354 and 3-hydroxyazetidine hydrochloride 160 (70% purity according to LC / MS) 68 Intermediate 364 BOS \ <χ 1 \ L Xt YES ci o Mt 0 From intermediate 354 and 6-Boc-2,6 diazaspiro [3.5] nonane oxalate 126 65 Intermediate 365 BOC \ <χ 1 \ A Xt YES ci o EdYa ^ ⁿ Aoc o From intermediate 354 and mpem-butyl 2,7-diazaspiro [3.5] nonane-7-carboxylate hydrochloride 90 46 Intermediate 366 BOC \ N --- \ 1 ν-- ^on HELL ^{AT CI 1} μα pi Cd jlT ^{0 n} 1 0 Trans From intermediate 354 and (lS, 3S) -3aminocyclopentanol 120 (degree of purity 90% LC / MS) White solid 62

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Intermediate 367 BOC X- \ ^N Y / Y ^it the A 1 1 1 αχγ of cis, cis From intermediate 354 and cis-3aminotsiklopentanola 140 (89% purity according to LC / MS) Yellow oil 86 Intermediate 368 BOC den Cl OL ⁿ 1 O Cis From intermediate 354 and 3-azabicyclo [3.1.0] hexane-6-methanol 150 86% purity according to LC / MS) Yellow solid 86 Intermediate 369 BOS Ν --- ν Ν '. / \ ___ / \ / \ F ^Cl hist '' Λ jXX ⁿ 1 0 From intermediate 354 and 3,3-difluorocyclobutanamine hydrochloride 110 (97% purity according to LC / MS) 61

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Intermediate 370 VOS he Ά about L YY n 1 • From intermediate 354 and 4 hydroxyhexamethyleneimine 160 (94% purity according to LC / MS) 92 Intermediate 371 eos 'and he X ά T CI Ν TRANS άΧ Trance From intermediate 354 and 3-azabicyclo [3.1.1] heptane-6-ol hydrochloride 150 (86% purity according to LC / MS) 79 Intermediate 372 VOS X— X / \ n Xp οι Cl YA 0 ^ From intermediate 354 and 2-cyanopiperazine 170 (degree of purity 43% according to LC / MS) 39

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Intermediate 373 BOC \ < ⁿ A / n M ^is He 'Pp ^vos ci A-A αιΑ Cis From intermediate 354 and cis-pyrrolo [3,4 - />] pyrrole-5 (1H) -carboxylic acid, hexahydro-, 1,1 -dimethylethyl ether 130 (86% purity according to LC / MS) 68 Intermediate 374 BOS he \\ Ϊ ij ⁴ <> ci iS ΛΑ η 1 From intermediate 354 and 2-azaspiro [3.3] heptane-6-ol 200 (38% purity according to LC / MS) 46 Intermediate 375 (mixture of 4 undivided diastereomers) VOS Y - y N <. / \ __ VOS ££ / P J R s /) Cl HN ^ Yrs £. JL he £ j j £ j ° Η 1 From intermediate 354 and trans-3-amino-1-boc4-hydroxypyrrolidine 120 (degree of purity 96% LC / MS) Yellow oil 58

Example A15.

Getting intermediate 363

In a round bottom flask, intermediate 354 (0.10 g, 0.17 mmol) and amino-2-propanol (14.60 μL, 0.19 mmol) were mixed in DMF (2.33 mL). Then EDC-HCl (53.1 mg, 0.34 mmol) and DIEA (147.00 μL, 0.85 mmol) were added and the reaction mixture was stirred for 3 h. Since a very low conversion was observed, HATU (0.13 g, 0.34 mmol) and DIEA (2 eq.) and the reaction mixture was stirred for 48 h. The reaction mixture was distributed between water and EtOAc. The organic layer was washed once with water, then with brine, dried with MgSO ₄ , filtered and evaporated. The residue was purified by silica gel column chromatography (SiOH, irregular grains, 40 g, DCM / MeOH mobile phase, gradient 100: 0 to 96: 4). The fractions containing the product were mixed and evaporated to give 81 mg of intermediate 363 (78% yield).

Example A16.

Getting intermediate 15

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In a Schlenk reactor, a mixture of 2-bromo-4- (methylsulfonyl) aniline (2.00 g, 8.00 mmol), ethynylcyclopropane (1.06 g, 16.00 mmol) and TEA (5.56 ml, 40.00 mmol) in dry DMF (40 ml) was purged with N ₂ gas ... Then Pd (PPh ₃ ) ₂ Cl ₂ (281.00 mg, 0.40 mmol) and CuI (152.00 mg, 0.80 mmol) were added. The mixture was purged with N2 and stirred at 100 ° С for 2 h. Then a new portion of ethynylcyclopropane (1.06 g, 16.00 mmol), Pd (PPh ₃ ) ₂ Cl ₂ (281 mg, 0.4 mmol) and CuI (152.00 mg, 0.80 mmol ). The mixture was purged with N2 and stirred at 100 ° С for 1 h. Then ethynylcyclopropane (1.06 g, 16.00 mmol), Pd (PPh ₃ ) ₂ Cl ₂ (281 mg, 0.4 mmol) and CuI (152.00 mg, 0.80 mmol) were added again ... The mixture was purged with N2 and stirred at 100 ° C for 1 h. The resulting mixture was cooled to rt and evaporated in vacuo. The residue (7 g) was purified by column chromatography on silica gel (SiOH, irregular grains, 15-40 μm, 220 g, dry application on celite, mobile phase: DCM / EtOAc, gradient from 100: 0 to 98: 2) ... The desired fractions were combined and the solvent was evaporated to dryness in vacuo to give 1.59 g of intermediate 15 (84% yield, according to ¹ H NMR contains 21% 2-bromo-4- (methylsulfonyl) aniline, orange solid).

Getting intermediate 16 and intermediate 17

Ϋ -........

A solution of intermediate 15 (930.00 mg, 3.95 mmol), ammonium formate (15.00 g, 237.14 mmol) and Pd / C (10 wt%) (2.50 g, 2.37 mmol) in a mixture of iPrOH (32 ml) and Me -THF (16 ml) and stirred at 70 ° C for 30 min. The crude product was filtered through a pad of celite and the celite was washed with EtOAc and iPrOH. The filtrate was evaporated in vacuo and the remaining oil was taken up in DCM and washed with water. The organic layer was dried with MgSO ₄ , filtered and evaporated in vacuo. The residue (880 mg) was purified by column chromatography on silica gel (SiOH, irregular grains, 15-40 μm, 50 g, dry application on celite, mobile phase: heptane / EtOAc / MeOH, gradient from 85% heptane, 13.5% EtOAc and 1.5% MeOH to 30% heptane, 63% EtOAc and 7% MeOH). The desired fractions were combined and the solvent was evaporated to dryness in vacuo to give 552 mg of a mixture of intermediate 16 and intermediate 17 (58% yield, pale yellow oil, 85/15 ratio by 1H NMR).

Example A17.

Getting intermediate 22

LiHMDS (1.5 M in toluene, 6.06 ml, 9.09 mmol) was added dropwise to a solution of 2-methoxyethanol (721.00 μl, 9.09 mmol) in THF (24 ml) at 5 ° С. After 30 min, 4-fluoro-3-nitroromobenzene (1.11 ml, 9.09 mmol) was quickly added and the reaction mixture was allowed to warm to rt and stirred overnight. Water was added (quenched) to the reaction mixture and EtOAc was added. The organic layer was decanted, washed with brine, dried with MgSO ₄ , filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel (SiO ₂ , 120 g, 15-40 μm, mobile phase: heptane / EtOAc, gradient from 100: 0 to 0: 100). The required fractions were combined and the solvent was evaporated to dryness in a vacuum to give 1.923 g of intermediate 22 (77% yield).

The intermediates shown in the Table below were prepared by methods analogous to the preparation of intermediate 22 from the corresponding starting materials. The most important minor deviations from the reference method are given as additional information in the Mass (g) column.

Intermediate number Structure Weight (g) Output (%) Intermediate 25 Bg one From 4-fluoro-3-nitroromobenzene 2.02 82

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Intermediate 50 N From 4-fluoro-3-nitrobenzonitrile 3.90 99 Intermediate 71 N X From 2-chloro-4-fluoro-5-nitrobenzonitrile 2.35 Brown solid Method with Me-THF 93 Intermediate 226 Ν II ABOUT ^ 0 one From 4-fluoro-3-nitrobenzonitrile 1.28 Method with Me-THF 96 Intermediate 480 Ν from About 1 From 3- (t /? Et-butoxycarbonylamino) -1-propanol and 4-chloro-3-nitro benzonitrile 10.67 Methodology with LiHMDS IN to THF 40

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Intermediate 574 CN ο ₂ ν Χ ^ Ο, / χ From 4-fluoro-3-nitrobenzonitrile and 4-hydroxy-1-methylpiperidine 0.425 Method with Me-THF 54 And 601 CN 0 0, ν- αΑ ^cis 1 X F- '' ВСС From 4-fluoro-3-nitrobenzonitrile and cis-1-LOC-3-fluoro-4-hydroxypiperidine 0.420 Method with LiHMDS (IMbTHF) in Me-THF. 92 Intermediate 607 CN 7 transT 1 From 4-fluoro-3-nitrobenzonitrile and trans-1-loc-3-fluoro-4-hydroxypy peridine 0.200 Method with LiHMDS (IMbTHF) in Me-THF 73 Intermediate 620 From 4-fluoro-3-nitrotoluene and 4-hydroxy-1-methylpiperidine 0.273 Method in Me-THF 34

Preparation of intermediate 614 and intermediate 615

CN

intermediate 614: Trans A (RR or SS) intermediate 615: Trans B (SS or RR)

A solution of LiHMDS 1.5M in THF (5.6 ml; 8.42 mmol) at 5 ° С was added dropwise to a solution of intermediate 614а (590 mg; 4.95 mmol) in Me-THF (18.4 ml). After 30 min. 4-fluoro-3-nitrobenzonitrile (823 mg; 4.95 mmol) was quickly added and the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into ice water-cooled 10% aqueous K ₂ CO ₃ and extracted with EtOAc. The organic layer was decanted, washed with brine, dried with MgSO ₄ , filtered and evaporated to dryness. The residue (1.16 g; yellow solid) was purified by chromatography on silica gel (SiO ₂ , 40 g, eluent: 98% DCM, 2% MeOH, 0.2% NH4OH to 95% DCM, 5% MeOH, 0.5% NH4OH). The product fractions were combined and the solvent was evaporated to give 486 mg of a yellow solid racemic trans product (37%). The racemic trans product was purified by chiral SFC (Chiralpak AD-H 5 μm 250 × 30 mm column, mobile phase: 95.7% CO ₂ , 4.3% MeOH (0.3% iPrNH ₂ )). Fractions with pure product were collected and the solvent was evaporated, yielding 177 mg (13%) intermediate 614 (trans A; RR or SS; eluted first) and 174 mg (13%) intermediate 615 (trans B; SS or RR; eluted second).

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Obtaining intermediate 614a

F Trans Blend (RR and SS)

Formaldehyde (10.6 ml; 141.3 mmol) was added to a mixture of trans-4-fluoro-3-hydroxypyrrolidine hydrochloride (1 g; 7.06 mmol) and acetic acid (809 μL; 14.13 mmol) in methanol (55 ml) at rt. The reaction mixture was stirred at rt for 30 min, then sodium triacetoxyborohydride (3.74 g; 17.66 mmol) was added and stirred at rt for 3 h. The mixture was basified with saturated aqueous NaHCO ₃ solution at 5 ° С.

To the mixture was added diethyl ether and washed with saturated aqueous NaHCO ₃ solution. The aqueous layer was then extracted with diethyl ether (3 times), but intermediate 614a was still in the aqueous layer. The aqueous layer was then extracted with EtOAc (3 times), but intermediate 614a was still in the aqueous layer. Then the aqueous layer was extracted with DCM (3 times). The organic layers were combined, dried over MgSO ₄ , filtered, and the solvent was evaporated at room temperature to obtain 1.09 g of intermediate 614а as a colorless volatile oil, which was used in the next step without any further purification.

Example A18.

Getting intermediate 23

In a sealed test tube, a solution of intermediate 22 (500.00 mg, 1.81 mmol), dimethylphosphine oxide (167.00 mg, 1.99 mmol), and K ₃ PO ₄ (423.00 mg, 1.99 mmol) in dry DMF (7.5 mL) was purged with N ₂ . Then Pd (OAc) ₂ (40.70 mg, 0.18 mmol) and 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (105 mg, 0.18 mmol) were added. The mixture was purged with N ₂ and stirred at 130 ° C for 3 hours. The reaction was performed twice with the same amount of intermediate 22. 2 batches were pooled. The resulting mixture was filtered through a pad of celite and this pad of celite was washed with EtOAc. The filtrate was evaporated in vacuo to give a brown oil. The residue was purified by silica gel column chromatography (SiOH, irregular grains, 15-40 μm, 80 g, dry load on celite, mobile phase: DCM / MeOH, gradient 99.5: 0.5 to 95: 5). The desired fractions were combined and the solvent was evaporated to dryness in a vacuum to obtain 0.895 g of intermediate 23 (yield 90%, orange oil).

The intermediates shown in the table below were prepared by a method analogous to the preparation of intermediate 23 from the corresponding starting materials.

The most important minor deviations from the reference method are indicated as additional information in the Mass column.

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Intermediate number Structure Weight Output (%) Intermediate 26 γ 4 = 0 o) From intermediate 25 569 mg 58 Intermediate 66 about Υ From intermediate 65 765 mg Orange resin 74 Intermediate 76 CI o From 4-bromo-5-chloro-2- methylaniline 1 g White solid Method with reaction temperature = 150 ° С 51 Intermediate 220 О o ₂ N ^ yY From 4-bromo-2-methoxy-1-nitrobenzene 334 mg Brown solid Method with reaction temperature = 150 ° C 68 Intermediate 230 about k / A / K / '' ST From intermediate 207 552 mg Red solid Method with reaction temperature = 150 ° C 83

Getting intermediate 24

I

To a solution of intermediate 23 (877.00 mg, 3.21 mmol) in MeOH (23 mL) under N ₂ was added Raney Nickel (19.00 mg, 0.32 mmol). The mixture was stirred at rt under a pressure of H ₂ 1.5 bar (150 kPa) for 3 h. The mixture was filtered through a pad of celite and the celite was washed with EtOH. The filtrate was evaporated in vacuo to give 726 mg of intermediate 24 (93% yield).

The intermediates shown in the table below were prepared by a method similar to the preparation of intermediate 24 from the corresponding starting materials. The most important minor deviations from the reference method are indicated as additional information in the Mass column.

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Intermediate number Structure Weight Output (%) Intermediate 27 X Y = O „.Φ / one From intermediate 26 490 mg 97 Intermediate 134 o — C y — νη ₂ ^F \ / From intermediate 133 1.37 g The reaction was carried out at a H2 pressure _of 3 bar (450 kPa) 94 Intermediate 156 o — C y — nh ₂ ^F x / Y From intermediate 155 2.1 g The reaction was carried out at a H2 pressure _of 3 bar 97 Intermediate 268 but ^ .0 jQa H ₂ 1G XLZ F From intermediate 267 16.7 g The reaction was carried out at a H2 pressure _of 3 bar 100

Example A19.

Getting intermediate 28

To a solution of 3-amino-4-iodobenzonitrile (0.50 g, 2.05 mmol) in THF (10 ml) was added a previously prepared solution of Pd (t-Bu ₃ P) ₂ (105 mg, 0.20 mmol) in a solution of n-propylzinc bromide in THF ( 0.5 M, 8.20 ml, 0.41 mmol) and stirred at rt for 2 h. The reaction mixture was poured into a 10% aqueous solution of K ₂ CO ₃ and EtOAc was added. The crude product was filtered through a pad of celite and the organic layer was decanted, washed with water, dried with MgSO ₄ , filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (SiOH, irregular grains, 24 g, mobile phase: heptane / EtOAc: gradient from 90% heptane, 10% EtOAc to 70% heptane, 30% EtOAc). Fractions with pure product were combined and evaporated to dryness to give 250 mg of intermediate 28 (76% yield).

The intermediate shown in the table below was prepared by a method similar to the preparation of intermediate 28 from the corresponding starting materials.

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Intermediate number Structure Weight Output (%) Intermediate 56 N II Heh From 3-amino-4-iodobenzonitrile 212 mg 59

Example A20.

Getting intermediate 31

4-Fluoro-3-nitrobenzonitrile (1.00 g, 6.02 mmol) and 2- (tert-butyldimethylsiloxy) ethanol (1.32 ml, 6.62 mmol) were dissolved in distilled THF (7 ml) (a 0.1-0.2 M solution was obtained) in an Ar atmosphere and cooled to 0 ° C. KHMDS (6.62 ml, 6.62 mmol) dissolved in distilled THF (5.3 ml) was added dropwise (a 0.5 M solution was obtained), and the color changed from colorless to dark. This solution was stirred at 0 ° C to rt for 3 h, then DCM was added to the reaction mixture and washed with saturated aqueous NH4Cl. The aqueous layer was subjected to a one-time back extraction (stripping) using DCM. The organic extracts were combined, dried over MgSO ₄ , and evaporated. The residue (1.5 g, black oil) was purified by column chromatography on silica gel (SiOH, irregular grains, 80 g, mobile phase: heptane / EtOAc, gradient from 100% heptane, 0% EtOAc to 70% heptane, 30% EtOAc). The required fractions were combined and evaporated to dryness to obtain 0.30 g of intermediate 31 (yield 15%, orange powder). However, it was purified again by silica gel column chromatography (SiOH, irregular grains, 80 g, solid loading, mobile phase: heptane / EtOAc, gradient 100: 0 to 70:30).

The desired fractions were combined and evaporated to dryness to obtain 0.659 g of intermediate 31 (yield 34%, orange powder) with a total yield of 49%.

The intermediates shown in the table below were prepared by a method similar to the preparation of intermediate 31 from the corresponding starting materials.

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Intermediate number Structure Weight (g) Output (%) Intermediate 40 1 \ 1 X O ₂ lX А С one 1.354 Yellow powder 44 From 4-fluoro-3-nitrobenzonitrile Intermediate 47 h 1 A o ₂ n ^ X c one 1.636 Yellow powder 76 /And he From 4-fluoro-3-nitrobenzonitrile Intermediate 53 1 f 0 ₂ N ^Z A one 0.922 orange powder 62 <> From 4-fluoro-3-nitrobenzonitrile

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Intermediate 58 N II .χ / Y From 4-fluoro-3-nitrobenzonitrile 0.305 Orange powder 34 Intermediate 122 CI o ₂ n- ^ 2 From 5-chloro-2-fluoro-nitrobenzonitrile 0.514 orange powder 78 Intermediate 126 CI 0 ₂ νΧ ^ From 5-chloro-2-fluoro-nitrobenzo nitrile 0.515 Orange butter 61% Intermediate 141 CI c> 1 From 5-chloro-2-fluoro-nitrobenzo nitrile 0.578 Light yellow oil 75

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Intermediate 144 CI C> X A A / A From 5-chloro-2-fluoro-nitrobenzonitrile 1.159 Light ^ yellow oil 64 Intermediate 159 CI „At A / οΎ ^ Ο X From 5-chloro-2-fluoro-nitrobenzonitrile 0.999 (degree of purity 95% over data LC / MS) Light yellow oil 51 Intermediate 340 CI JM ° a ^ t From 5-chloro-2-fluoronitrobenzene 0.545 Orange butter 89 Intermediate 343 CI Xj L ° From 5-chloro-2-fluoronitrobenzene 0.653 Colorless butter 89

Getting intermediate 32

Iron powder (0.83 g, 14.87 mmol) was added to a solution of intermediate 31 (0.96 g, 2.97 mmol), NH ₄ Cl (0.64 g; 11.90 mmol) in EtOH (8.34 mL) and distilled water (4.19 ml). The reaction mixture was stirred at 75 ° C for 3 hours. The reaction mixture was filtered through a celite pad and washed with DCM. _{Saturated NaHCO 3} solution was added and the mixture was extracted with DCM. The organic layer was dried with MgSO ₄ , filtered and evaporated to dryness to obtain 701 mg of intermediate 32 (81% yield, brown oil).

Getting intermediate 422

A mixture of intermediate 421 (10.47 g; 49.35 mmol), iron powder (13.78 g; 246.72 mmol), and ammonium chloride (10.56 g; 197.38 mmol) in EtOH (350 ml) and water (118 ml) was heated at 80 ° С for 1 The reaction mixture was cooled to room temperature, DCM was added, filtered through celite and made alkaline with a 10% aqueous solution of K2CO3. The organic layer was decanted, dried over MgSO4, filtered, and the solvent was evaporated to give 8.68 g (97%) of intermediate 422 as an orange solid, which was used in the next step without any further purification.

The intermediates shown in the table below were prepared by a method similar to the preparation of intermediate 32 from the corresponding starting materials.

The most important minor deviations from the reference method are indicated as supplementary information in the Mass (mg) column.

Intermediate number Structure Weight (mg) Output (%) Intermediate 41 N 981 (purity 90 % by data NMR) white powder 84 one one 0 ^^ From intermediate 40 Intermediate 48 l · 1 χ Η ₂ Ν ^ η c From inter] one one ) / X) H mediata 47 938 yellow powder 66 Intermediate 51 1 χ Η ₂ χ s From inter] one one one mediata 50 2440 (purity 95 % by data LC / MS) 65 Intermediate 54 r 1 ( From inter] one mediata 53 738 orange powder 91

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Intermediate 59 N _γ From intermediate 58 650 brown oil Carried out at reaction temperature = 85 ° C 95 Intermediate 88 / X ^{С |} 1 I ^x I: '- 0 From intermediate 87 414 dark red solid 86 Intermediate 92 ^C1 । I ^х ..... ό ..... From intermediate 91 997 68 Intermediate 95 CI Ap ° ⁿ H ₂ Gu 0 From intermediate 94 351 pale yellow solid 89 Intermediate 99 CI h ₂ nX ^ From intermediate 98 1280 solid almost white colors 85

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Intermediate 109 ci "U ....... about From intermediate 108 436 solid dark of red color 95 Intermediate 123 CI η ₂ ν0 ^ C) / From intermediate 122 580 yellow butter Intermediate 127 CI H ₂ From intermediate 126 512 Method: reaction at temperature = 85 ° С yellow oil Intermediate 142 CI T RS 1 P | < one From intermediate 141 429 Methodology: reaction at temperature = 85 ° С orange powder 85 Intermediate 145 CI D c> X Y SG X 650 Method: reaction at temperature = 85 ° С yellow oil 62

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From intermediate 144 Intermediate 160 CI about. / X / BUT/ From intermediate 159 771 Methodology: reaction at temperature = 85 ° С yellow butter 85 Intermediate 186 CI ^η 2 ^ν jj a 1 0 From intermediate 185 315 (purity 92 % by data LC / MS) Intermediate 198 CI A DG ^η 2 ^ν a / 1 0 From intermediate 197 380 (degree of purity 96% by data LC / MS) 95 Intermediate 227 N II yXn ₂ 0 ^ 0 1 1.08 Method: reaction at temperature = 100 ° C 97

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From intermediate 226 Intermediate 239 nh ₂ F From intermediate 23 8 255 85 Intermediate 245 N χ From intermediate 244 264 57 Intermediate 251 oJ ΧΎ ° From intermediate 250 1360 96 Intermediate 279 CI ίΎ From intermediate 278 625 (83% according to LC / MS) Intermediate 285 CI 0 JL А ίΎ। Ο _χ From intermediate 284 158 light brown solid 28

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Intermediate 291 CI 0 1 \ ^χ γ л fj '° HjN'TX From intermediate 290 492 solid light Brown color 64 Intermediate 297 Cl PT η ₂ ν ^ υ ^ γθ From intermediate 296 313 pale yellow foam 82 Intermediate 300 Cl From intermediate 299 221 orange-brown syrup 96 Intermediate 303 Cl f \ From intermediate 302 257 (purity 58 % by data LC / MS) brown butter 97 Intermediate 305 CI Η ₂ Ν ^ φ o = s ^ ° \ From 4-chloro-1-methanesulfonyl-2-nitrobenzene 450 (purity 83 % by data LC / MS)

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brown syrup Intermediate 308 ci AY h ₂ n ^z y From intermediate 307 371 (degree of purity 40% LC / MS data) brown solid 84 Intermediate 311 ci g 7 ^x Υ g 0 From intermediate 310 246 brown butter 94 Intermediate 314 ci ..ph ...... ^ 0 From intermediate 313 255 brown butter 98 Intermediate 322 CI Yri r 0 From intermediate 321 143 (degree of purity 17% by LC / MS data) brown oil 92

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Intermediate 329 0 From intermediate 328 217 brown butter 93 Intermediate 332 ci .g 0 From intermediate 331 221 (degree of purity 90% LC / MS data) brown oil 80 Intermediate 341 CI Η _2Ν φψ From intermediate 340 370 yellow butter 79 Intermediate 344 CI η ₂ νΧ ^ 1 ° From intermediate 343 679 Intermediate 351 CI 0 0 From intermediate 350 750 Quantity

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Intermediate 360 ° хЛ Abs sA у А ^Η2Ν ΑΑ \ From intermediate 359 720 87 Intermediate 410 ОН Л JH ₂ N ^ Aj0 ^ From intermediate 409 980 100 Intermediate 447 /, —N Q. ° \ a ^nh f ГТ Η ₂ Ν ^ γ From intermediate 446 481 84 Intermediate 452 O ^^ NH JL _F rm H ₂ N ^ A | A From intermediate 451 447 100 Intermediate 462 Η _? νΑΆΑΑ_ an From Intermediate 456 522 87

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Intermediate 467 N I from..... From intermediate 466 260 99 Intermediate 470 F N Г / II Z-7 Η ₂ Ν ^ ΧΧ From intermediate 469 202 (purity 74 % by data LC / MS) 92 Intermediate 490 1 ^{0 ΝΗ} Η ₂ Ν- / γ X From intermediate 489 298 96 Intermediate 567 Hun From intermediate 566 320 73 Intermediate 571 From intermediate 570 390 89

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Intermediate 575 CN A 376 100 From intermediate 574 Intermediate 580 CN BH From intermediate 579 180 yellow oil 93 Intermediate 587 CN From intermediate 586 200 90 Intermediate 591 CN h ₂ nXJ SAf From intermediate 590 150 43 Intermediate 595 CN η ₂ νΧ ^ From intermediate 594 140 94

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Intermediate 599 CN Ν F From intermediate 598 375 99 Intermediate 604 CN cis Υ] 1 Ν Γ '' Υ From intermediate 603 160 72 Intermediate 610 CN Λ ABOUT,. , · ,. trans 1 L From intermediate 609 64 72 Intermediate 617 CN Ё η ₄ 'Γ' Α p Trans (SS or RR) ° h-L \ From intermediate 615 148 96 Intermediate 621 to χ / k From intermediate 620 173 73 Intermediate 521b cis kkk Ary - ABOUT 836 quantitative From intermediate 521a

Getting intermediate 397

Intermediate 396 (2.1 g; 10 mmol) was dissolved in a mixture of THF (40 ml), methanol (20 ml), and water (20 ml). Iron (2.8 g; 50.18 mmol) and NH ₄ Cl (2.68 g; 50.18 mmol) were added. The mixture was refluxed for 2 hours. The mixture was extracted with ethyl acetate (50 ml x 2). The organic phase was washed with water (20 ml), brine (20 ml), dried with Na ₂ SO ₄ , filtered and evaporated in vacuo to give 1.75 g (97%) of intermediate 397 as a brown oil.

Getting intermediate 481

Intermediate 481 was obtained by a method similar to that for the preparation of intermediate 397, based on

- 163 037358 intermediate 480 (5.5 g; 99%).

Getting intermediate 616

A mixture of intermediate 614 (177 mg; 0.667 mmol), iron powder (186 mg; 3.337 mmol) and ammonium chloride (143 mg; 2.67 mmol) in ethanol (6 ml) and water (1 ml) was heated at 70 ° С for 1 h. The reaction mixture was cooled to room temperature, added DCM, filtered through celite and podslushivaet 10% aqueous solution of K ₂ CO ₃ . The organic layer was decanted, dried with MgSO ₄ , filtered, and evaporated to dryness to obtain 156 mg (99%) of intermediate 616.

Example A21.

Getting intermediate 36

In a sealed tube, a solution of 3-amino-4-iodobenzonitrile (1.70 g, 6.97 mmol), cyclopropylacetylene (1.50 ml, 17.42 mmol), and TEA (3.00 ml, 20.90 mmol) in DMF (50 ml) was degassed (blowing with N ₂ ). Pd (PPh ₃ ) ₂ Cl ₂ (244.00 mg; 0.35 mmol) and CuI (267.00 mg; 1.39 mmol) were added and the reaction mixture was stirred at rt for 2 h. The reaction mixture was poured into water and extracted with Et ₂ O / EtOAc. The organic layer was decanted, washed with brine, dried with MgSO ₄ , filtered and evaporated to dryness. The residue was purified by silica gel column chromatography (SiOH, irregular grains, 40 g, mobile phase: heptane / EtOAc, gradient from 80% heptane, 20% EtOAc to 60% heptane, 40% EtOAc). Fractions with pure product were combined and evaporated to dryness to obtain 1.13 g of intermediate 36 (89% yield).

The intermediates shown in the table below were prepared by a method similar to the preparation of intermediate 36 from the corresponding starting materials.

Intermediate number Structure Weight (mg) Output (%) Intermediate 254 N 745 99 one one n 2 '' one one ABOUT- From 3-amino-4-iodobenzonitrile Intermediate 484 N ..... / one From Z-amv la and tre ilkarb? \ 1 1 ⁿ γχ / О 1 [but-4-iodobenzonitrite-butyl butyl-3-in-1lata 7600 81

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Getting intermediate 37

A suspension of activated carbon (one scoop) and intermediate 36 (1.10 g, 6.04 mmol) in MeOH (30 ml) was stirred at room temperature over Saturday and Sunday. The solids were removed by filtration through celite and the filtrate was evaporated to dryness. The residue was dissolved in MeOH (30 ml) and Pd / C (10 wt%, 220 mg) was added. The suspension was hydrogenated at atm. pressure of H ₂ at rt for 3 hours. The catalyst was removed by filtration and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography (SiOH, irregular grains, 40 g, mobile phase: heptane / EtOAc, gradient from 90% heptane, 10% EtOAc to 70% heptane, 30% EtOAc). Fractions with pure product were combined and evaporated to dryness to give 509 mg of intermediate 37 (45% yield).

The intermediates shown in the table below were prepared by a method similar to the preparation of intermediate 37 from the corresponding starting materials.

Intermediate number Structure Weight (mg) Output (%) Intermediate 255 N II P From intermediate 254 577 91 Intermediate 485 Ν II ό ^Η ₂ Ν ^ ΥΥ O। From intermediate 484 6300 81

Example A22.

Getting intermediate 43

A solution of 2-fluoro-4-methylbenzonitrile (5.50 g, 40.70 mmol) in H ₂ SO ₄ (45 ml) was cooled to 0 ° C. _{Then KNO 3} (8.23 g, 81.40 mmol) was added in portions. After stirring at 0 ° С for 2 h, the reaction mixture was poured with stirring into a solution of NaHCO ₃ (103.00 g, 1.22 mol) in 1 L of ice water. The heterogeneous mixture was filtered through a glass filter. The precipitate was washed twice with water and combined. The solid was dried in vacuo at 50 ° C for 12 h to give 6.68 g of intermediate 43 (91% yield, white solid).

Getting intermediate 44

A solution of intermediate 43 (2.00 g, 11.10 mmol) in Me-THF (20 ml) and EtOH (20 ml) was hydrogenated at rt and an H ₂ pressure of 1 bar (100 kPa) in the presence of a catalytic amount of Pd / C (10 wt%, 591.00 mg, 0.55 mmol) for 2 h. The reaction mixture was filtered through a celite pad and the filtrate was evaporated in vacuo. The residue was solubilized in Me-THF (20 ml) and EtOH (20 ml), hydrogenated at rt at a H2 pressure of 1 bar (100 kPa) in the presence of a catalytic amount of Pd / C (10 wt%, 591.00 mg, 0.55 mmol) in a stream - 165 037358 2 h. The reaction mixture was filtered through a pad of celite and the filtrate was evaporated in vacuo to give a black solid. The residue was purified by column chromatography on silica gel (SiOH, irregularly shaped, 15-40 μm, 80 g, liquid loading, mobile phase: heptane / EtOAc, gradient: 80% heptane, 20% EtOAc to 60% heptane, 40% EtOAc). The desired fraction was collected and evaporated to dryness to give 610 mg of intermediate 44 (37% yield, pale yellow solid).

Example A23.

Getting intermediate 65

A mixture of 4-bromo-2-fluoro-1-nitrobenzene (3.00 g, 13.60 mmol) and Cs ₂ CO ₃ (13.50 g, 41.40 mmol) in iPrOH (30 ml) was stirred and refluxed for 2 h. The mixture was cooled to rt and filtered through a pad of celite. The celite pad was washed with iPrOH and the filtrate was evaporated in vacuo. The residue was taken up in EtOAc and water. The layers were separated and the aqueous organic layer was washed with water, dried with MgSO ₄ , filtered and evaporated in vacuo to give an orange liquid. The residue (3.6 g) was purified by column chromatography on silica gel (SiOH, irregular grains, 15-40 μm, 120 g, dry application on celite, mobile phase: heptane / DCM, gradient: from 80% heptane, 20% DCM up to 50% heptane, 50% DCM). The desired fraction was collected and evaporated to dryness to obtain 3.12 g of intermediate 65 (yield 88%, yellow liquid (which crystallized upon standing)).

Getting intermediate 67

Pd / C (10 wt%, 310.00 mg, 0.29 mmol) was added to a solution of intermediate 66 (750.00 mg, 2.92 mmol) in EtOH (30 mL) under N2. The mixture was stirred at rt in an atmosphere of H ₂ (P atm) for 3 hours. The mixture was filtered through a pad of Celite and this layer was washed with EtOH. The filtrate was evaporated in vacuo to give 630 mg of intermediate 67 (89% yield, dark green oil).

The intermediate shown in the table below was prepared by a method similar to the preparation of intermediate 67 from the corresponding starting materials.

Intermediate number Structure Weight (mg) Output (%) Intermediate 326 F O o o From intermediate 325 533 (purity 94% according to LC / MS) 96

Example A24.

Getting intermediate 72

A mixture of intermediate 71 (2.35 g, 9.30 mmol), 3,6-dihydro-2H-pyran-4boronic acid pinacol ester (3.00 g, 14.30 mmol) and K ₂ CO ₃ (1.64 g, 11.80 mmol) in a mixture of 1,4- dioxane (80 ml) and distilled water (15 ml) were purged with N2. 1,1'-Bis- (di-tert-butylphosphino) ferrocene palladium dichloride (630.00 mg, 0.97 mmol) was added and the mixture was purged with N2 and stirred at 90 ° C for 18 h. The mixture was partitioned in EtOAc / water. The organic layer was washed with brine, dried with MgSO ₄ , evaporated and purified by column chromatography on silica gel (SiOH, irregular grains, 15-40 μm, 120 g, liquid injection (DCM), mobile phase: DCM / MeOH, gradient from 100 : 0 to

95:05 at 10 CV (column volumes)) gave 1.86 g of intermediate 72 (66% yield, brown solid).

The intermediates shown in the table below were prepared by methods analogous to the preparation of intermediate 72 from the corresponding starting materials. The most important minor deviations from the reference method are given as additional information in the Mass (mg) column.

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Intermediate number Structure Mass (mg) Yield (%) Intermediate 200 from From 4-chloro-3-iodanisole 660 (70% purity according to LC / MS) lightly brown oil reaction temperature = 60 ° C 86 Intermediate 208 Cj XX ^ <s A A From intermediate 207 ISO pale brown solid reaction temperature = 60 ° C 99

Getting intermediate 73

A mixture of intermediate 72 (0.80 g, 2.66 mmol) and Pd / C (10 wt%, 140.00 mg, 0.13 mmol) in MeOH (25 ml) was stirred at rt (room temperature) in an H ₂ atmosphere for 2 h 15 min. The mixture was filtered through a pad of celite and washed with MeOH to give 525 mg of intermediate 73 (72% yield, white solid). The celite was then washed again with DCM / MeOH (80:20) to give 200 mg of a mixture of intermediates 72 and 73.

The intermediate shown in the table below was prepared by a method similar to the preparation of intermediate 73 from the corresponding starting materials.

Intermediate number Structure Weight Output (%) Intermediate 209 Xjj ^ H ₂ Gu From intermediate 208 1 g pale brown butter 98

Example A25.

Getting intermediate 83

To a solution of 3-methoxy-4-nitrobenzoic acid (0.50 g, 2.54 mmol), HATU (1.25 g, 3.30 mmol) and DIEA (1.32 ml, 7.61 mmol) in DCM (10 ml) was added 4-aminotetrahydropyran (0.26 g, 2.54 mmol) and the reaction mixture was stirred at rt for 2 h. DCM was added to the reaction mixture, washed with water, dried with Na ₂ SO ₄ and evaporated in vacuo. The residue was triturated with a minimum amount of DCM, the solid was filtered and dried in vacuo to give intermediate 83 (72% yield, pale yellow solid).

The intermediate shown in the table below was prepared by a method similar to the preparation of intermediate 83 from the corresponding starting materials.

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Intermediate number Structure Weight Output (%) Intermediate 275 Oh ho "BUT From 3-methyl-4-nitrobenzoic acid 2.12 g yellow solid 81

Getting intermediate 84

A suspension of intermediate 83 (0.51 g, 1.84 mmol), Pd / C (10 wt%, 0.26 g), and ammonium formate (1.16 g, 18.37 mmol) in EtOH (50 mL) was stirred for 2 h at 80 ° С. The reaction mixture was filtered through a pad of celite and the solution was evaporated in vacuo. The residue was applied to an Isolute® SCX-2 cartridge (cation exchange chromatography) which was washed with MeOH and then the product was eluted with 2M ammonia in MeOH. A 2 M solution of ammonia in MeOH was evaporated in vacuo to give intermediate 84 (yield 96%, white solid).

The intermediate shown in the table below was prepared by a method similar to the preparation of intermediate 84 from the corresponding starting materials.

Intermediate number Structure Weight Output (%) Intermediate 276 O ... u ^l From intermediate 275 1.97 g solid matter in nearly white colors

Example A26.

Getting intermediate 86

To a solution of 4-chloro-5-fluoro-2-nitrophenol (10.00 g, 52.21 mmol) in dry DMF (50 ml) was added K ₂ CO ₃ (11.00 g, 79.60 mmol), followed by iodomethane (4.00 ml, 64.25 mmol) and the resulting suspension was stirred at rt for 2.5 days. The resulting dark orange suspension was evaporated in vacuo to remove the DMF solvent and the residue was partitioned between EtOAc (300 ml) and 1 N HCl (100 ml). The resulting layers were separated, and the organic layer was sequentially washed with 1 M NaOH (100 ml), water (100 ml), and brine (100 ml), dried with Na ₂ SO ₄ , filtered and evaporated to give 10.34 g of intermediate 86 (yield 96%, solid dark orange).

Getting intermediate 87

A suspension of intermediate 86 (0.35 g, 1.70 mmol), 4- (dimethylamino) piperidine (0.41 g, 1.87 mmol) and CsCO ₃ (1.10 g, 3.41 mmol) in DMF (4 mL) was heated at 80 ° C for 15 min. The reaction mixture was partitioned between EtOAc and saturated NaHCO ₃ solution. The organic layer was washed with brine, dried with Na ₂ SO ₄ and evaporated in vacuo to give 553 mg of intermediate 87 (quantitative yield,

- 168 037358 yellow oil).

The intermediates shown in the table below were prepared by a method similar to the preparation of intermediate 87 from the corresponding starting materials.

Intermediate number Structure Weight (mg) Output (%) Intermediate 91 DEN ^C1 [I ^x Ar 0 ^ From intermediate 86 1630 78 Intermediate 108 ci | AA _n aa Г 0 ₂ mHA From intermediate 86 510 yellow butter Quantity Intermediate 302 about. Ci y \ AG ABOUT From intermediate 86 294 yellow butter 92 Intermediate 307 ci _с ......... ¹ From 4-chloro-5-fluoro-2-nitrotoluene 507 (degree of purity 46% LC / MS data) orange-brown solid 97 Intermediate 310 s G I ^x lX 0 From intermediate 86 292 (degree of purity 46% on LC / MS data) yellow Quantity

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butter Intermediate 313 Cl ABOUT From intermediate 86 290 (degree of purity 52% on LC / MS data) yellow butter 95 Intermediate 328 ^{C |} Γ \ X Jy / ^he ^ 0 From intermediate 86 262 (degree of purity 47% LC / MS data) orange solid 99 Intermediate 331 ci ο ₂ ν ^^ о From intermediate 86 302 yellow butter Quantity

Example A27.

Getting intermediate 94

A suspension of 3-methoxy-4-nitrobenzoic acid (0.50 g, 2.73 mmol) and NCS (0.41 g, 3.00 mmol) in CH ₃ CN (5 ml) was heated at 80 ° С for 2 h. The reaction mixture was evaporated in vacuum and the residue purified by silica gel column chromatography (Si-PPC, 40 g, cyclohexane / EtOAc mobile phase, gradient 100: 0 to 20:80). The desired fraction was collected and evaporated to dryness to give 460 mg of intermediate 94 (77% yield, yellow solid).

Example A28.

Getting intermediate 98

NaH (60% dispersion in mineral oil) (0.41 g, 10.19 mmol) was added to a solution of N-methyl-4piperidinol (1.08 g, 9.34 mmol) in DMF (9 ml) at 0 ° С and the mixture was heated to rt (room temperature) within 15 minutes. 5-Chloro-2-fluoronitrobenzene (1.49 g, 8.49 mmol) was added and the mixture was stirred at rt for an additional 2 h. The reaction mixture was partitioned between EtOAc and saturated NaHCO ₃ solution. The organic layer was washed with brine and dried with Na ₂ SO ₄ and evaporated in vacuo. The residue was purified by silica gel column chromatography (Si-PPC, 40 g, mobile phase: DCM / 2 M ammonia in MeOH, gradient 100: 0 to 90:10). The desired fraction was collected and evaporated to dryness to give 1.69 g of intermediate 94 (74% yield, yellow oil).

The intermediates shown in the table below were prepared by a method similar to the preparation of intermediate 98 from the corresponding starting materials. The most important minor deviations from the reference method are given as additional information in the Structure column.

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Intermediate number Structure Weight Output (%) Intermediate 133 Chuu o — C y — no ₂ ^f a / f < ^f From 2-fluoro-5-nitrobenzotrifluoride 1.63 g 57 Intermediate 137 he О А у - no ₂ ^F \ / F ^F From 4-fluoro-3-nitrobenzotrifluoride 451 mg 47 Intermediate 155 Ογγ о – с у – νο ₂ F. / X ^f From 2-fluoro-5-nitrobenzotrifluoride. The reaction mixture was stirred at 100 ° C overnight after the addition of all reagents 2.4 g 81

Example A29.

Getting intermediate 125

Sodium borohydride (0.54 g, 14.36 mmol) was added in portions to a solution of N-cyclopropyl-4piperidinone (1.00 g, 7.18 mmol) in a mixture of DCM (33 ml) and MeOH (3.3 ml) at 0 ° С in an Ar atmosphere. The mixture was stirred for 1 h and allowed to warm to rt. The pale yellow mixture was poured into 1M NaOH (20 ml). The layers were separated and the aqueous layer was extracted with DCM (2 x 20 ml). The combined organic extracts were passed through a phase separator and the solvent was evaporated under reduced pressure to obtain 1.25 g of intermediate 125 (yellow oil). The residue was used in the next step without further purification.

Example A30.

Getting intermediate 129

A solution of 2-bromo-5-nitrobenzotrifluoride (1.00 g, 3.704 mmol) and 3,6-dihydro2H-pyran-4-boronic acid pinacol ester (1.01 g, 4.82 mmol) in a mixture of 1,4-dioxane (15.28 ml) and distilled water (2.59 ml) was treated with K ₂ CO ₃ (2.36 g, 11.11 mmol) and purged with N2. Then the adduct dichloro [1,1'-bis- (diphenylphosphino) ferrocene] palladium (P), DCM (303.20 mg, 370.36 μmol) was added and the reaction mixture was again purged with N ₂ and stirred at 120 ° C in a single-mode microwave reactor (Biotage Initiator EXP 60) with an output power ranging from 0 to 400 W for 10 minutes [fixed 171 037358 dwell time]. Then water was added. The aqueous layer was extracted twice with DCM, dried

MgSO4, filtered and evaporated. The residue was purified by silica gel column chromatography (SiOH, irregular grains, 40 μm, DCM mobile phase, 100% DCM). Fractions with pure product were combined and the solvent was evaporated to obtain 900 mg of intermediate 129.

Getting intermediate 130

A solution of intermediate 129 (690.00 mg, 2.53 mmol) in MeOH (10.23 ml) was hydrogenated at 60 ° С in the presence of Pd / C (10 wt%, 71.64 mg, 67.30 mmol) as a catalyst at a pressure of 8 bar (800 kPa) in for 24 hours. The catalyst was filtered off through a pad of celite and the filtrate was evaporated to give 609 mg of intermediate 130.

Example A31.

Getting intermediate 138 he's about

F. /

A mixture of intermediate 137 (0.67 g, 2.65 mmol) was hydrogenated at rt in EtOAc (15.50 ml) and MeOH (15.60 ml) in the presence of Pd / C (10 wt%, 0.12 g, 0.11 mmol) as a catalyst in a Parr® apparatus for hydrogenation under pressure at a pressure of H2 4 bar (400 kPa). After 4 hours, the catalyst was filtered off through a pad of celite. The solvent was evaporated to dryness to obtain 535 mg of intermediate 138 (91% yield). This product was used in the next step without further purification.

Example A32.

Obtaining intermediate 147 CI

To a solution of 1-bromo-2-chloro-4-nitrobenzene (1.00 g, 4.42 mmol) and pyridine-4boronic acid pinacol ester (1.10 g, 5.36 mmol), K3PO4 (2.70 g, 12.72 mmol), dichloro [1,1 ' -bis- (diphenylphosphino) ferrocene] palladium II, DCM adduct (0.350 g, 0.43 mmol) in a mixture of 1,4-dioxane (15.00 ml) and distilled water (2.50 ml) was added and N2 was purged again. The reaction mixture was stirred at 110 ° C in a microwave single-mode reactor (Biotage Initiator EXP 60) with an output power ranging from 0 to 400 W for 10 min [fixed holding time]. This procedure was carried out with three 1 g batches of 1-bromo-2-chloro-4-nitrobenzene. Reaction mixtures from the three reactions were combined and water was added. The aqueous layer was extracted twice with DCM, dried with MgSO ₄ , filtered and evaporated. The residue (4.40 g) was purified by silica gel column chromatography (SiOH, irregular grains, 40 μm, mobile phase: heptane / EtOAc, gradient 60:40 to 50:50). Fractions with pure product were combined and the solvent was evaporated to obtain 1.97 g of intermediate 147 (yield 66%), which was used in the next step without purification.

Getting intermediate 148

Iodoethane (2.80 ml, 35.01 mmol) was added to a mixture of intermediate 147 (1.95 g, 8.31 mmol) in toluene (20 ml). This reaction mixture was stirred in a sealed tube at reflux (115 ° C) for 7 h. The reaction mixture was cooled to rt. Iodoethane (1.50 mL, 18.75 mmol) was added again and the mixture was stirred for another 5 h while refluxing (120 ° С). The solvent was evaporated to dryness, and 2.89 g of intermediate 148 (89% yield) was obtained, which was used as such (without purification, directly) in the next step.

Getting intermediate 149

A mixture of intermediate 148 (1.00 g, 2.56 mmol) was hydrogenated at rt in EtOH (35 ml) with platinum (IV) oxide (300 mg, 1.30 mmol) as a catalyst at a pressure of 3 bar. The next day, the catalyst was filtered off through a pad of celite and the solvent was evaporated to dryness. The residue was purified by a column

- 172 037358 chromatography on silica gel (SiOH, irregular grains, 40 μm, 40 g, mobile phase:

NH ₄ OH / DCM / MeOH, gradient from 0.5% NH4OH, 95% DCM, 5% MeOH to 1% NH4OH, 90% DCM, 10%

MeOH). Fractions with pure product were combined and the solvent was evaporated to dryness, yielding 0.690 g of intermediate 149 (yield 98%, purity = 84% as determined by LC / MS), which was used directly in the next step.

Example A33.

Getting intermediate 152

A mixture of 4-isopropylbenzyl bromide (4.18 g, 19.61 mmol), 3-nitrophenol (3.00 g, 21.57 mmol), K ₂ CO ₃ (4.06 g, 29.41 mmol) in DMF was heated at 100 ° С. Upon completion, water and EtOAc were added. The organic layer was washed with water, decanted, dried with MgSO ₄ , filtered and evaporated to dryness. The residue was recrystallized from DiPE to give 2.87 g of intermediate 152 (54% yield). M.p. = 88 ° C (K).

Getting intermediate 153

To a solution of intermediate 152 (2.80 g, 10.32 mmol) in a mixture of 1,4-dioxane (20 ml) and water (5 ml), iron powder (5.80 g, 103.20 mmol) and iron (II) sulfate heptahydrate (6.30 g, 41.28 mmol). The resulting solution was heated to reflux overnight. The reaction mixture was filtered through a pad of celite and washed with DCM. The organic layer was washed with water and K ₂ CO ₃ , dried with MgSO ₄ , filtered and evaporated to give 2.35 g of intermediate 153 (94% yield).

Example A34.

Getting intermediate 158

TEA (3.52 mL, 25.00 mmol) was added to a solution of Boc ₂ O (3.00 g, 13.77 mmol) and 2 (methylamino) ethanol (1.00 mL, 12.52 mmol) in DCM (80 ml) and stirred at rt overnight. The mixture was washed with brine, dried with MgSO ₄ , filtered and evaporated to give 2.40 g of intermediate 158 (colorless oil).

Example A36.

Getting intermediate 175

NBS (12.75 g, 71.66 mmol) and benzoyl peroxide (1.65 g, 6.83 mmol) were added to a suspension of 2-methyl-5-nitrobenzotrifluoride (14.00 g, 68.25 mmol) in AcOH (58.60 mL, 1.02 mol). The reaction mixture was heated at reflux overnight (120 ° C). Upon cooling, the solvent was removed in vacuo, EtOAc and aqueous NaHCO ₃ were added and the layers were separated. The organic layer was dried with MgSO ₄ , filtered and evaporated to give 18 g of intermediate 175 (93% yield). It was used in the next step without further purification.

Getting intermediate 176 (cis)

cis-2,6-Dimethylpiperazine (1.00 g, 8.49 mmol) was added to a stirred solution of intermediate 175 (3.62 g, 12.74 mmol) and TEA (4.72 ml, 33.98 mmol) in DCM (10.88 ml) at rt (room temperature) for 48 h. The reaction mixture was washed with 10% K ₂ CO ₃ solution. The organic layer was dried with MgSO ₄ , filtered and evaporated. The residue was purified by column chromatography on silica gel (SiOH, irregular grains, 15-40 μm, 80 g, mobile phase: DCM / MeOH / NH4OH, gradient from DCM: 100% to DCM: 98%, MeOH: 2%, NH4OH: 0.1%), 1.82 g of intermediate 176 was obtained (yield 68%).

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Obtaining intermediate 177 (cis)

Sodium cyanoborohydride (403.89 mg, 6.43 mmol) was added with stirring to a solution of intermediate 176 (1.70 g, 5.36 mmol) and formaldehyde (37 wt% in water) (481.96 μL, 6.43 mmol) in a mixture of MeOH (6.39 mL, 157.64 mmol) and AcOH (756.69 μL, 13.22 mmol) at rt under N ₂ atmosphere and stirred at rt for 2 h. Then the reaction mixture was poured into water, basified with K ₂ CO ₃ powder, extracted with DCM, dried with MgSO ₄ , filtered and evaporated to give intermediate 177 (yield 96%). It was used in the next step without purification.

Obtaining intermediate 178 (cis)

Intermediate 177 (500.00 mg, 1.51 mmol) in MeOH (12.41 ml) was hydrogenated with Raney nickel (RaNi) (329.95 mg, 5.62 mmol) as a catalyst at rt and at a pressure of 3 bar (300 kPa) for 12 h. The catalyst was filtered off through a celite pad and the filtrate was evaporated to give 489 mg of intermediate 178.

Example A37.

Getting intermediate 185

In an atmosphere of N ₂ at rt, a solution of dimethylamine in THF (2.0 M, 1.18 mL, 2.37 mmol) was added to a solution of 5-chloro-2-methyl-3-nitrobenzoic acid (340.00 mg, 1.58 mmol), HBTU (598.09 mg, 1.58 mmol ) and DIPEA (679.42 μl, 3.94 mmol) in DMF (9.77 ml, 126.16 mmol). The solution was stirred at rt for 6 hours. The solution was poured into chilled water and extracted with EtOAc. The organic layer was dried with MgSO ₄ , filtered and evaporated to dryness. The residue (2.07 g) was purified by column chromatography on silica gel (SiO2, 40 g, mobile phase: DCM / MeOH / N ^ OH, gradient from 100% DCM to 97% DCM, 3% MeOH, 0.3% NH4OH). Fractions with pure product were combined and the solvent was evaporated to dryness to obtain 315 mg of intermediate 185 (82% yield).

The intermediates shown in the table below were prepared by a method similar to the preparation of intermediate 185 from the corresponding starting materials.

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Intermediate number Structure Weight Output (%) Intermediate 189 CI Chl η ₂ νΎ <। О From (2-amino-4-chlorophenyl) acetic acid 530 mg 66 Intermediate 192 CI Λ 1 Η ₂ Ν ' ^Χ Χγ γ x ο From (2-amino-4-chlorophenyl) acetic acid 950 mg 85 Intermediate 197 Cl 5-chloro-2-methyl-3-nitrobenzoic acid 444 mg 80

Example A38.

Getting intermediate 201

A mixture of intermediate 200 (68.00 mg, 0.21 mmol) and sodium nitrate (18.00 mg; 0.21 mmol) in TFA (0.70 ml) was stirred at rt for 6 h. The mixture was poured into a mixture of ice and aqueous NaHCO ₃ solution, extracted with EtOAc, washed with brine , dried over MgSO4 and evaporated. The residue (60 g, dark oil) was purified by column chromatography on silica gel (SiOH, irregular grains, 15-40 μm, 12 g, liquid injection (DCM), mobile phase: DCM / MeOH, gradient from: 100: 0 to 95:05 at 10 CV (column volumes)), 40 mg of a residue was obtained in the form of a light yellow oil 2 containing intermediate 201 (66% purity). Subsequent purification by achiral SFC (stationary phase: CYANO μm 150 x 21.2 mm, mobile phase: 95% CO2, 5% MeOH) gave 17 mg of intermediate 201 (yield 30%, white solid).

Getting intermediate 202

A mixture of intermediate 201 (650.00 mg, 2.41 mmol) and platinum (IV) oxide (130.00 mg, 0.57 mmol) in a mixture of MeOH (20 ml) and THF (5 ml) was stirred at rt in an atmosphere of H2 for 20 min. (purged with H2, 3 times (total reaction time: 1 h)). The mixture was filtered through a pad of celite. The organic layer was evaporated and purified by column chromatography on silica gel (SiOH, irregular grains, 15-40 μm, 80 g, liquid injection (DCM), mobile phase: heptane / EtOAc, gradient from 100: 0 to 0: 100 in 10 CV). The pure fractions were combined and the solvent evaporated to dryness to give 174 mg of intermediate 202 (30% yield, white solid).

Example A39.

Getting intermediate 207

- 175 037358

NaH (60% dispersion in mineral oil) (182.00 mg, 4.55 mmol) was slowly added at 0 ° С to 2-methoxyethanol (0.36 ml, 4.55 mmol) in THF (20 ml). The mixture was stirred under N ₂ at 0 ° C for 30 minutes. 4-bromo-2-fluoronitrobenzene (1.00 g, 4.55 mmol) was added and the mixture was stirred and slowly warmed to rt for 5 h. The mixture was neutralized with HCl 1 N (pH 7), then extracted with EtOAc / NaHCO ₃ . The organic layer was washed with brine, dried with MgSO ₄ , evaporated and purified by column chromatography on silica gel (SiOH, irregular grains, 15-40 μm, 80 g, liquid injection (DCM), mobile phase; heptane / EtOAc, gradient from 100 : 0 to 50:50 at 10 CV), 1.13 g of intermediate 207 (yield 90%, white solid) was obtained.

Example A40.

Getting intermediate 214

5-Chloro-2-methyl-3-nitrobenzoic acid (3.00 g, 13.91 mmol), diphenylphosphoryl azide (4.49 ml, 20.87 mmol) and TEA (2.71 ml, 19.48 mmol) in Me-THF mixture (3.75 ml, 37.44 mmol) and 2-methyl-2propanol (3.91 ml, 41.74 mmol) was refluxed for 3 h. The mixture was poured into NH ₄ Cl and the organic layer was extracted twice with EtOAc, dried with MgSO ₄ and the solvent was evaporated to dryness. The residue (5.08 g) was taken up in EtOAc, the resulting precipitate was filtered off (impurities). The filtrate was evaporated to dryness. The residue (4.77 g) was taken up in CH3CN and the resulting precipitate was filtered off. The filtrate was evaporated to dryness and purified by column chromatography on silica gel (SiOH, irregular grains and Si 60 15-40 μm, 40 μm, 80 g, solid support, mobile phase: heptane / EtOAc, 80:20). Fractions with pure product were combined and the solvent was evaporated, yielding 3.42 g of intermediate 214 (86% yield).

Getting intermediate 215

Iron (389.56 mg, 6.98 mmol) was added with stirring to a solution of intermediate 214 (200.00 mg, 0.70 mmol) in AcOH (8 ml) and stirred at 70 ° С for 2 h. EtOAc was added to the crude mixture, filtered through celite and a layer celite was washed with EtOAc. Water was added to the filtrate, followed by K ₂ CO ₃ powder until basic pH was obtained. The organic layer was washed with brine, dried with MgSO4, filtered and evaporated. The residue (180 mg) was purified by silica gel column chromatography (SiOH, irregular grains, 40 μm, 24 g, mobile phase: heptane / EtOAc, 60:40). Fractions with pure product were combined and the solvent was evaporated to obtain 95 mg of intermediate 215 (53% yield).

Getting intermediate 216

Intermediate 215 (1.00 g, 3.89 mmol), acetyl chloride (0.35 ml, 4.87 mmol) and TEA (3.25 ml, 23.37 mmol) were added with stirring at 0 ° С to DCM (50 ml) and stirred at rt overnight. The mixture was poured into NH4Cl and the organic layer was extracted with DCM, washed with NaCl and dried. The precipitate was filtered off to obtain 483 mg of intermediate 216 (42% yield). The filtrate was evaporated to dryness and the residue (750 mg) was purified by column chromatography on silica gel (SiOH, irregular grains, 40 g, mobile phase: DCM / MeOH, gradient from 100: 0 to 98: 2). Fractions with pure product were combined and the solvent was evaporated, yielding 236 mg of intermediate 216 (yield 20%). The two batches were combined to give 719 mg of intermediate 216 (62% yield).

Getting intermediate 217

- 176 037358

At 0 ° С, a solution of HCl 4 M in dioxane (2.76 ml, 11.04 mmol) was added with stirring to a solution of intermediate 216 (660.00 mg, 2.21 mmol) in CH3CN (49.5 ml). The mixture was stirred at 0 ° C for 30 min and at rt for 1 h. The mixture was poured into chilled water and made basic by adding NH4OH. The organic layer was extracted twice with EtOAc, washed with brine, dried with MgSO ₄ , filtered and evaporated to dryness. The residue was taken up in DCM, washed with brine, evaporated and purified by column chromatography on silica gel (SiOH, irregular grains, 24 g, solid application, mobile phase: heptane / MeOH / EtOAc / NH ₄ OH, 60: 38: 2: 0.1). Fractions with pure product were combined and the solvent was evaporated to give 210 mg of intermediate 217 (48% yield).

The intermediate shown in the table below was prepared by a method similar to the preparation of intermediate 217 from the corresponding starting materials.

Intermediate number Structure Weight Output (%) Intermediate 23 5 about GU From intermediate 234 251 mg Quantity

Example A41.

Getting intermediate 221

A mixture of intermediate 220 (334.00 mg, 1.46 mmol), zinc (953.00 mg, 14.60 mmol) and AcOH (0.83 ml, 14.60 mmol) in MeOH (8 ml) was stirred at rt for 2 h. The mixture was filtered through a celite pad, and then extracted with EtOAc and 1 N HCl solution. The aqueous layer was podslushivaet 1 N NaOH solution and was extracted with EtOAc (10 times). The organic extracts were washed with brine, dried with MgSO ₄ and evaporated to give 226 mg of intermediate 221 (78% yield, brown oil).

The intermediate shown in the table below was prepared in a similar manner from the appropriate starting materials .____________________________________________

Intermediate number Structure Weight Yield (%) Intermediate 231 О \\ / ГТ Η ₂ Ν ^/ γ ^ From intermediate 230 496 mg pale brown butter 97

Example A42.

Getting intermediate 234

A solution of HATU (2.02 g, 5.32 mmol), DIPEA (1.85 ml, 10.63 mmol) and ethyl 1-methyl-4-piperidine carboxylate, HCl salt (827.80 mg, 4.61 mmol) in Me-THF (9.10 ml, 90.86 mmol) was stirred at 70 ° C for 2 h. Then intermediate 215 (910.00 mg, 3.54 mmol) was added and the mixture was stirred at 70 ° C overnight. The mixture was poured into water and the organic layer was extracted twice with DCM, dried with MgSO ₄ , filtered and evaporated to dryness. The residue (776 mg) was recovered with MeOH and DCM, triturated and filtered. The precipitate was dried to dryness to obtain 315 mg of intermediate 234 (23% yield).

- 177 037358

Example A43.

Getting intermediate 238

DIAD (3.00 ml, 15.28 mmol) was added dropwise at 5 ° С to a mixture of 5-fluoro-2-nitrophenol (1.60 g, 10.18 mmol), 2-methoxyethanol (807.00 μL, 10.18 mmol) and PPh ₃ (1.4 mmol / g on polystyrene) (10.90 g, 15.28 mmol) in THF (30 ml). The mixture was stirred at rt for 2 h. Water was added and the reaction mixture was extracted with DCM. The organic layer was decanted, dried with MgSO ₄ , filtered and evaporated to dryness. The residue was purified by silica gel column chromatography (SiOH, irregular grains, 40 g, mobile phase: heptane / EtOAc, gradient 80:20 to 60:40). The fractions were combined and evaporated to dryness to give 954 mg of intermediate 238 (43% yield).

Example A44.

Getting intermediate 244

......

Di (1-adamantyl) -N-butylphosphine (157.00 mg, 0.44 mmol) and Pd (OAc) 2 (98.00 mg, 0.44 mmol) were added to a solution of 4-chloro-3-nitrobenzonitrile (800.00 mg, 4.38 mmol) degassed by passing through N2 ), potassium cyclopropyl trifluoroborate (972.00 mg, 6.57 mmol) and CsCO ₃ (2.85 g, 8.76 mmol) in a mixture of 1,4-dioxane (18 ml) and distilled water (4 ml). The reaction mixture was stirred and heated at 100 ° C for 18 h. Then it was cooled to rt, DCM was added and poured into water. The organic layer was decanted, dried with MgSO ₄ , filtered through celite and evaporated to dryness. The residue was purified by silica gel column chromatography (SiOH, irregular grains, 24 g, mobile phase: DCM / MeOH, gradient 100: 0 to 98: 2). Fractions with pure product were combined and evaporated to dryness to obtain 546 mg of intermediate 244 (66% yield).

Example A45.

Getting intermediate 249

To a solution of 4-fluoro-2-methoxy-1-nitrobenzene (2.00 g, 11.70 mmol) in MeOH (38 ml), a solution of sodium thiomethoxide (1.50 g, 21.00 mmol) in distilled water (6.5 ml) and MeOH (38 ml) and the resulting mixture was stirred while refluxing under N2 overnight. The mixture was cooled to rt and evaporated in vacuo. The residue was triturated in a mixture of DCM and MeOH (1: 1) and the solid was filtered off. The filtrate was purified by silica gel column chromatography (15-40 μm, 240 g, mobile phase: heptane / EtOAc, gradient 100: 0 to 50:50). The fractions with the pure product were mixed and the solvent was evaporated, yielding 2.11 g of intermediate 249 (91% yield).

The intermediates shown in the table below were prepared by a method similar to the preparation of intermediate 249 from the corresponding starting materials. The most important minor deviations from the reference method are given as additional information in the Mass (mg) column.

- 178 037358

Intermediate number Structure Weight (mg) Output (%) Intermediate 289 CI ABOUT From intermediate 86 1194 (The reaction was carried out in EtOH and distilled water) yellow solid Quantity Intermediate 324 X O From 3,4-difluoro-6-nitroanisole 195 (The reaction was carried out in EtOH and distilled water) eight

Getting intermediate 250

To a solution of intermediate 249 (2.11 g, 10.60 mmol) in DCM (106 ml) under Ar atmosphere, mCPBA (5.49 g, 31.80 mmol) was added and stirred at rt for 24 h. The mixture was filtered. The filtrate was evaporated and purified by column chromatography on silica gel (SiO ₂ , dry loading, mobile phase: heptane / EtOAc, gradient from 1: 0 to 0: 1). Fractions with pure product were combined and evaporated to dryness to obtain 1.65 g of intermediate 250 (yield 67%, pale yellow crystalline substance).

The intermediates shown in the table below were prepared by a method similar to the preparation of intermediate 250 from the corresponding starting materials.

Intermediate number Structure Weight (mg) Output (%) Intermediate 290 CI o 0 ^ From intermediate 289 864 pale yellow crystalline substance 65 Intermediate 325 F O o dg o From intermediate 324 629 white solid 62

Example A46.

Getting intermediate 257

To a solution of 2-bromo-4-methylbenzonitrile (2.00 g, 10.20 mmol) in H2SO4 (7 mL) at 0 ° C was added KNO ₃ solution in H2SO4 (5 mL) (1.03 g, 10.20 mmol). The mixture was stirred at 0 ° С for 1.5 h, then the reaction mixture was poured into 500 ml of ice water. The precipitate was filtered off and washed with copious amounts of water. The precipitate was dried to obtain 2.01 g of intermediate 257 (yield 82%, white powder).

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Getting intermediate 258

In a sealed tube, a solution of intermediate 257 (1.00 g, 4.15 mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (1.05 g, 4.98 mmol) and K ₃ PO ₄ (1.76 g, 8.30 mmol) in mixtures of 1,4-dioxane (29 ml) and distilled water (3.86 ml) were degassed by passing a stream of N ₂ . A complex of [1,1'-bis- (diphenylphosphino) ferrocene] dichloropalladium (II) with dichloromethane (340.00 mg, 0.41 mmol) was added and the reaction mixture was degassed by passing a stream of N ₂ and heated at 80 ° С for 5 h. the mixture was cooled to rt, poured into water and extracted with DCM. The organic layer was decanted, dried with MgSO ₄ , filtered and evaporated to dryness. The residue (2 g, dark (black) oil) was purified by column chromatography on silica gel (SiOH, irregular grains, 80 g, mobile phase: heptane / EtOAc, gradient 100: 0 to 75:25). Fractions with pure product were combined and evaporated to dryness to give 0.787 g of intermediate 258 (78% yield, white powder).

Getting intermediate 259

A mixture of intermediate 258 (0.79 g, 3.22 mmol) and Pd / C (10 wt%, 72.00 mg, 0.067 mmol) in EtOAc (10 mL) was stirred at rt under H2 atmosphere overnight. The mixture was filtered through a pad of celite and evaporated to dryness to give intermediate 259 (white solid). This residue was used as such in the next reaction step.

Getting intermediate 260

A mixture of intermediate 259 (0.70 g, 3.27 mmol) and Pd / C (10 wt%, 174.00 mg, 0.16 mmol) in EtOH (11.5 mL) was stirred at rt under H2 atmosphere overnight. The mixture was filtered through a pad of celite. The organic layer was evaporated to give 512 mg of intermediate 260 (72% yield, 90% purity by LC / MS, white solid).

The intermediates shown in the table below were prepared by a method similar to the preparation of intermediate 259 from the corresponding starting materials. The most important minor deviations from the reference method are given as additional information in the Mass column.

Intermediate number Structure Weight (mg) Output (%) Intermediate 583 CN Tn A From intermediate 582 225 93 Intermediate 626 Η ₂ Ν ^ φ c> xul A From intermediate 625 500 The reaction was carried out in EtOAc as a solvent 78

- 180 037358

Example A47.

Getting intermediate 267

AcCl (19.5 ml) was added dropwise to a solution of 3-nitro-5- (trifluoromethyl) benzoic acid (19.50 g, 83.00 mmol) in MeOH (195 ml) at rt and stirred for 18 h. The resulting mixture was evaporated in vacuum, washed 10% K ₂ CO ₃ solution, extracted twice with DCM, dried with MgSO ₄ , filtered and evaporated in vacuo to obtain 19 g of intermediate 267 (92% yield).

Example A48.

Getting intermediate 278

A mixture of 1-bromo-2-chloro-5-methoxy-4-nitrobenzene (1.00 g, 3.75 mmol), morpholine (395.00 μl, 4.12 mmol), K ₂ CO ₃ (1.04 g, 7.51 mmol) in DMF (10 ml) stirred and heated at 80 ° C for 18 h. Another portion of morpholine (35.00 μL, 0.40 mmol) was added and the reaction mixture was stirred and heated at 80 ° C for another 23 h. The reaction mixture was added to an ice / water mixture and stirred, while a yellow precipitate fell out. This precipitate was filtered off, washed with water and EtO2, dried over MgSO4 and evaporated in vacuo to give a yellow solid. The filtrate was further extracted with EtOAc (twice) and the combined organic extracts were washed sequentially with water and saturated brine, dried with anhydrous Na ₂ SO ₄ . The solvent was removed in vacuo to give a brown solid (100 mg), which was combined with the residue and purified by silica gel column chromatography (80 g silica cartridge, mobile phase: cyclohexane / EtOAc containing 0-40% EtOAc) to give 703 mg intermediate 278 (69% yield, yellow solid).

Example A49.

Getting intermediate 283

Ethyl glycolate (0.91 ml, 9.61 mmol) was dissolved in dimethylamine (40% in water) (10 ml) and the resulting mixture was stirred at rt for 18 h. The reaction mixture was evaporated under reduced pressure. The residue was taken up in EtOH and evaporated under reduced pressure (twice) to give a colorless oil. The residue (950 mg) was purified by column chromatography on silica gel (SiO ₂ , 25 g, DCM / MeOH mobile phase, gradient 100: 0 to 95: 5). Product containing fractions were combined and evaporated under reduced pressure to give 576 mg of intermediate 283 (58% yield, colorless oil).

Getting intermediate 284

NaH (60% dispersed in mineral oil) (145.92 mg, 3.65 mmol) was added portionwise to a solution of intermediate 283 (376.00 mg, 3.65 mmol) in THF (20 ml), and the resulting mixture was stirred at rt in an atmosphere of N ₂ for 30 min. ... Intermediate 86 (0.50 g, 2.43 mmol) was added and the resulting mixture was stirred for 1 h. The reaction was quenched by adding 1 M aqueous NH ₄ Cl solution and extracted three times with EtOAc. The organic layer was separated, combined, dried with Na ₂ SO ₄ and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (SiO2, 40 g, mobile phase: DCM / MeOH, gradient 100: 0 to 95: 5). Product containing fractions were combined and evaporated under reduced pressure to give 619 mg of intermediate 284 (88% yield, off-white solid).

The intermediate shown in the table below was prepared by a method similar to the preparation of intermediate 284 from the corresponding starting materials.

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Intermediate number Structure Weight (mg) Output (%) Intermediate 321 CI Mru ^ .0 From intermediate 86 and 1 - (2hy dr oke iethyl) -4 - methyl piperazine 344 (43% purity according to LC / MS) yellow solid 72

Example A50.

Getting intermediate 294

A suspension of (3-methoxy-4-nitrophenyl) methanol (1.00 g, 5.46 mmol) and NCS (1.14 g, 8.54 mmol) in CH ₃ CN (10 ml) was heated at 80 ° С for 2 h. The reaction mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (SiO ₂ , mobile phase: cyclohexane / EtOAc, gradient from 1: 0 to 1: 1). The desired fractions were combined to give 1.093 g of intermediate 294 (89% yield, yellow solid).

Getting intermediate 295

A mixture of intermediate 294 (0.60 g, 2.76 mmol), CBr ₄ (1.19 g, 3.59 mmol), PPh ₃ (0.94 g, 3.59 mmol), and THF (5.5 mL) was heated to rt with stirring in an N2 atmosphere at 0 ° С and stirred within 30 minutes. Water was added to the mixture and extracted with DCM. The organic phase was dried with MgSO ₄ , filtered and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel (SiO ₂ , mobile phase: cyclohexane / EtOAc, gradient from 1: 0 to 0: 1). The desired fractions were combined to give 714 mg of intermediate 295 (95% yield, off-white solid).

Getting intermediate 296

A mixture of intermediate 295 (0.41 g, 1.45 mmol), 1-ethylpiperazine (0.41 ml, 3.20 mmol), K ₂ CO ₃ (0.44 g, 3.20 mmol) and DMF (6 ml) was heated with stirring at 80 ° С for 30 min. ... The mixture was cooled to rt and partitioned between water and EtOAc. The organic phase was dried with Na ₂ SO ₄ , filtered and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography (SiO ₂ , mobile phase: pentane and EtOAc (1: 1 to 0: 1), followed by DCM and MeOH (1: 0 to 9: 1)). The desired fractions were combined to give 421 mg of intermediate 296 (92% yield, yellow oil).

Example A51.

Getting intermediate 299

Iodomethane (286 μL, 4.60 mmol) was added to a suspension of intermediate 294 (100.00 mg, 0.46 mmol) and Cs ₂ CO ₃ (0.450 g, 1.38 mmol) in a mixture of THF (0.5 mL) and DMF (0.5 mL) in an Ar atmosphere with stirring. ... The reaction mixture was stirred at rt for 18 h. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic extracts were washed with saturated brine, dried with Na ₂ SO ₄ and evaporated in vacuo. The residue was purified by column chromatography on silica gel (SiO ₂ , 12 g silica cartridge, mobile phase: cyclohexane / EtOAc, gradient 100: 0 to 70:30). The desired fractions were combined to give 39 mg of intermediate 299 (36% yield, very pale yellow solid).

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Example A52.

Getting intermediate 316

Solution of 5-bromo-4-methyl-2-nitroanisole (60.00 mg, 0.24 mmol) and N-Boc pinacol ester of 1,2,5,6tetrahydropyridine-4-boronic acid (202.00 mg, 0.65 mmol) in 1,4-dioxane (5 ml) was degassed by blowing Ar through the solution for 10 min with stirring in a 10 ml screw cap reaction tube. A freshly prepared 2 M aqueous solution of sodium carbonate (0.50 ml, 1.0 mmol), degassed by blowing N2 through the solution with stirring for 15 min, was added, and then the catalyst [1,1'-bis- (diphenylphosphino) ferrocene] dichloromethane (II), complex with dichloromethane (20.00 mg, 0.027 mmol). The reaction tube was sealed under a stream of Ar and the mixture was heated at 100 ° C (block temperature) for 16 h. The mixture was cooled to rt and EtOAc (50 ml) and water (25 ml) were added. The aqueous layer was separated and further extracted with EtOAc (25 ml). The combined organic extracts were washed with water (25 ml), brine (10 ml), dried with Na ₂ SO ₄ , filtered through a celite pad and evaporated to give a red gum. This residue was purified by silica gel column chromatography (SiO ₂ cartridge, 4 g, 50 μm, mobile phase: cyclohexane / EtOAc, 1CV 100% cyclohexane, then linear gradient from 1: 0 to 0: 1). The desired fractions were combined and evaporated to give 94 mg of intermediate 316 (quantitative yield, red glass).

Getting intermediate 317

A solution of intermediate 316 (850.00 mg, 2.40 mmol) and TFA (1.90 ml, 24.80 mmol) in DCM (20 ml) was stirred at rt for 6 h. The reaction mixture was immediately purified by cation exchange chromatography (Isolute SCX-2 cartridge 50 g, mobile phase: DCM / MeOH, gradient from 1: 0 (200 ml), 1: 1 (100 ml) to 0: 1 (50 ml) The receiving flask (receiver) was replaced and the product was isolated from the cartridge with 2 M ammonia solution in MeOH ( The resulting red solution of the product was evaporated to dryness to give 566 mg of intermediate 317 (yield 93%, red glass).

Getting intermediate 318

A solution of intermediate 317 (566.00 mg, 2.28 mmol), 2-bromo-1-methoxyethane (520.00 μl, 2.77 mmol), and DIEA (1.20 ml, 7.01 mmol) in DMF (20 ml) was stirred at rt for 18 h. The reaction was complete not completely, therefore 260 μl (2.77 mmol) of 2-bromo-1-methoxyethane was added in portions and stirring was continued for another 7 hours. The mixture was then left at rt on Saturday and Sunday. DCM (20 ml) was added to the reaction mixture and immediately purified by cation exchange chromatography (50 g Isolute SCX-2 cartridge, mobile phase: DCM / MeOH, gradient from 1: 0 (100 ml), 1: 1 (100 ml) to 0 : 1 (50 ml) The receiving flask (receiver) was replaced and the cartridge was eluted with 2 M ammonia in MeOH, giving the product as a red solution.The solvents were evaporated and the crude product was purified by column chromatography on silica gel (SiO ₂ , cartridge 12 g, 15 μm SiO ₂ mobile phase: DCM / MeOH, gradient 100: 0 to 95: 5) The appropriate fractions were combined and evaporated to give 461 mg of intermediate 318 (66% yield, pale yellow gum).

Getting intermediate 319

A suspension of intermediate 318 (461.00 mg, 1.51 mmol) and Pd / C (10 wt%, 100 mg) in DCM (15 ml) and MeOH (5 ml) was stirred at rt in an atmosphere of H ₂ for 1 h. The reaction mixture was filtered through a layer of celite and evaporated in vacuo. The residue was resuspended in DCM (15 ml) and MeOH (5 ml) with Pd / C (10 wt%, (100 mg)) and stirred under H _{2 for an} additional 72 h. The reaction mixture was filtered.

- 183 037358 through a pad of celite and evaporated in vacuo to obtain 420 mg of intermediate 319 (quantitative yield, yellow oil.

Example A53.

Getting intermediate 334

NaBH ₄ (0.54 g, 14.36 mmol) was added in portions to a solution of N-cyclopropyl-4-piperidine (1.00 g, 7.18 mmol) in a mixture of DCM (33 ml) and MeOH (3.3 ml) at 0 ° С in an Ar atmosphere. The mixture was stirred for 1 h and allowed to warm to rt. The pale yellow mixture was poured into 1 M NaOH solution (20 ml) and the phases were separated. The aqueous phase was extracted with dichloromethane (2 x 20 ml). The combined organic extracts were passed through a phase separator and the solvent was evaporated under reduced pressure to obtain 1.25 g of intermediate 334 (yellow oil). The residue was used directly in the next step.

Example A54.

Getting intermediate 348

NaH (60% dispersion in mineral oil) (1.28 g, 31.99 mmol) was added in portions to a solution of 4chloro-3-methyl-6-nitrophenol (5.00 g, 26.66 mmol) in DMF (60 ml) at 0 ° С, and the mixture was stirred in for 15 minutes at this temperature. Iodomethane (1.83 mL, 29.33 mmol) was added and the mixture was warmed to rt and stirred for 24 h. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried with Na ₂ SO ₄ and evaporated in vacuo. The residue was purified by silica gel column chromatography (Si-PPC, 80 g, mobile phase: cyclohexane / EtOAc, gradient 1: 0 to 4: 1). The desired fraction was combined and evaporated in vacuo to give 4.09 g of intermediate 348 (76% yield, pale yellow solid).

Getting intermediate 349

A suspension of intermediate 348 (4.00 g, 19.80 mmol) and KMnO ₄ (6.27 g, 39.70 mmol) in distilled water (400 ml) was heated at reflux for 24 h. A second portion of KMnO ₄ (6.27 g, 39.70 mmol) was added and heating was continued for another 24 hours. Then the reaction mixture was cooled to 0 ° C and acidified to pH 2 with concentrated HCl. The aqueous layer was extracted several times with EtOAc. The organic layer was dried with MgSO ₄ and evaporated in vacuo. The residue was recovered with DCM and the precipitate was filtered off to obtain 1.81 g of intermediate 349 (23% yield based on 60% purity according to 1H NMR data). Intermediate 349 was used directly in the next step without any further purification.

Getting intermediate 350

Intermediate 349 (1.81 g, 4.69 mmol) was dissolved in MeOH (90 ml). Then added conc. H2SO4 (1.81 ml) and the resulting mixture was heated to reflux for 18 h. Then the reaction mixture was cooled to rt, mixed with another batch (from 498 mg of intermediate 349) and partitioned between water and EtOAc. The organic layer was separated, dried over MgSO4, filtered and evaporated. The residue was purified by column chromatography on silica gel (irregular grain SiO2, 80 g, mobile phase: heptane / EtOAc, 80:20). The fractions containing the products were mixed and the solvent was evaporated to give 830 mg of intermediate 350 (77% yield).

Example A55.

Getting intermediate 358

A mixture of 2-nitrobenzoic acid (1.00 g, 5.98 mmol), 3-pyrrolidinol (727.00 μl, 8.97 mmol), HATU (3.40 g, 8.97 mmol) and TEA (2.50 ml, 17.95 mmol) in DCM / THF mixture (40 ml, 1: 1, v / v) stir

- 184 037358 was carried at rt for 2 hours. DCM was added to the reaction mixture and it was poured into a 10% aqueous solution of K ₂ CO ₃ . The organic layer was decanted, dried with MgSO4, filtered and evaporated to dryness. The residue (2.6 g) was purified by column chromatography on silica gel (SiOH, irregular grains, 24 g, mobile phase: NH ₄ OH / MeOH / DCM, gradient from 0% NH4OH, 0% MeOH, 100% DCM to 1% NH4OH, 10% MeOH, 90% DCM). Fractions with pure product were combined and evaporated to dryness to give 2 g of intermediate 358, which was used directly in the next step.

Obtaining intermediate 359 from A \

O ₂ N JL [Q

A solution of TBDMS-Cl (1.08 g, 7.18 mmol) in DCM (5 ml) was added to a mixture of intermediate 358 (1.41 g, 5.98 mmol) and imidazole (1.22 g, 17.95 mmol) in Me-THF (25 ml) and the reaction mixture was stirred during the night at rt. DCM was added to the reaction mixture and poured into water. The organic layer was decanted, dried with MgSO ₄ , filtered and evaporated to dryness. The residue was purified by silica gel column chromatography (SiOH, irregular grains, 40 g, mobile phase: DCM / MeOH, gradient 100: 0 to 97: 3). Fractions with pure product were combined and evaporated to dryness to give 921 mg of intermediate 359 (44% yield). Intermediate 359 was used directly in the next step.

Example A56.

Getting intermediate 376

CI

II

I

In a round bottom flask, 5-chloro-2-iodaniline (2.00 g, 7.89 mmol), methyl propargyl ether (1.00 ml, 11.84 mmol) and TEA (1.92 ml, 13.41 mmol) were dissolved in DMF. The mixture was degassed (blowing with N ₂ ), and Pd (PPh ₃ ) ₂ Cl ₂ (0.28 g, 0.39 mmol) and CuI (0.30 g, 1.58 mmol) were added. The reaction mixture was stirred at rt for 4 h. The reaction mixture was partitioned between water and EtOAc. The organic layer was washed with brine, dried with MgSO ₄ , filtered and evaporated. The crude product was purified by silica gel column chromatography ( _{irregularly shaped SiO 2} , 40 g, mobile phase: heptane / EtOAc, 90:10 to 80:20 gradient). The product containing fractions were evaporated to give 1.013 g of intermediate 376 (yield 70%, orange liquid, which solidified on standing).

Obtaining intermediate 377 and intermediate 378

In a round bottom flask, intermediate 376 (1.01 g, 5.58 mmol) was dissolved in MeOH (50.8 mL). Then the solution was degassed by passing N ₂ , and Pd / C (10 wt%, 0.50 g, 4.74 mmol) was added. Thereafter, the reaction mixture was hydrogenated at 1 bar (100 kPa) for 4 hours. The reaction mixture was filtered through a celite pad and the filtrate was evaporated. Then the residue was dissolved in MeOH (50 ml) and degassed with a stream of N ₂ . Pd / C (10 wt%, 0.50 g, 4.74 mmol) was added and then the reaction mixture was hydrogenated at a pressure of 1 bar (100 kPa) for 4 h. The reaction mixture was filtered through a celite pad and the filtrate was evaporated. The residue was purified by silica gel column chromatography (SiOH, irregular grains, 80 g, mobile phase: heptane / EtOAc, gradient 95: 5 to 80:20). The product containing fractions were mixed and evaporated to give 336 mg of a mixture of intermediates 377 and 378 (21% yield, 70:30 NMR purity).

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Example A57.

Getting intermediate 380

DCM (30 ml) was cooled to -78 ° C and oxalyl chloride (4.53 ml, 9.06 mmol) was added followed by dodecyl methyl sulfoxide (2.11 g, 9.06 mmol). After 30 min, a suspension of intermediate 10R (3.00 g, 6.04 mmol) in DCM (30 ml) was added dropwise. The reaction mixture was stirred for 30 min at -78 ° C, then DIPEA (5.21 ml, 30.21 mmol) was added. Stirring was continued for 3 h at -78 ° C and the reaction mixture was allowed to warm to rt and was stirred overnight. Dilute NH4Cl solution was added and the aqueous layer was extracted with DCM twice. The combined extracts were dried with MgSO4, filtered and evaporated to dryness. The residue was recrystallized from Et2O, and the precipitate was filtered off, washed with DiPE, and dried to give 2.62 g of intermediate 380 (87% yield).

Getting intermediate 381

Intermediate 380 (600.00 mg, 1.21 mmol) was dissolved in a mixture of tert-butyl alcohol (44 ml) and 2-methyl-2-butene (22 ml). Then added with distilled water (44 ml) and then sodium dihydrogen phosphate (2.18 g, 18.20 mmol) and NaO ₂ Cl (2.19 g, 24.26 mmol). The suspension was vigorously stirred at rt overnight. The mixture was poured into NH4Cl and extracted with EtOAc. The organic layer was dried with MgSO ₄ , filtered, and the solvent was evaporated to give 619 mg of intermediate 381 (100% yield).

Getting intermediate 382

A mixture of EtOH (0.28 mL, 4.85 mmol), intermediate 381 (0.62 g, 1.21 mmol), HATU (0.51 mg, 1.33 mmol), DIPEA (0.52 mL, 3.03 mmol) and DMAP (14.80 mg, 0.12 mmol) in DMF (14.4 ml) was stirred at rt for 24 h. The solution was poured into water and extracted with EtOAc. The organic layer was washed sequentially with water and brine, dried with MgSO ₄ , filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (15-40 μm, 40 g, mobile phase: DCM / MeOH, gradient 100: 0 to 98: 2). Pure fractions were combined and evaporated to dryness to give 239 mg of intermediate 382 (37% yield, 98% purity by LC / MS).

Getting intermediate 383

In a round bottom flask, intermediate 382 (0.18 g, 0.34 mmol) was dissolved in THF (33 mL). Then the solution was cooled to 0 ° С and methylmagnesium bromide (0.42 ml, 1.36 mmol) was added dropwise. The solution was left under stirring, bringing to rt. Additional methyl magnesium bromide (0.42 mL, 1.36 mmol) was added at rt and the reaction mixture was stirred for an additional 2 h. The mixture was poured into saturated aqueous NH ₄ Cl and extracted with EtOAc. The organic layer was washed with brine, dried with MgSO ₄ , filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (15-40 μm, 24 g, mobile phase: DCM / MeOH, gradient 100: 0 to 95: 5). Fractions with pure product were combined and the solvent was evaporated to obtain 178 mg of intermediate 383 (100% yield, 90% purity by LC / MS).

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Example A58.

Getting intermediate 383

In a round bottom flask, intermediate 382 (164.00 mg, 0.30 mmol) was dissolved in THF (5.2 mL). Then the reaction mixture was cooled to 0 ° С and lithium aluminum deuteride (34.72 mg, 0.61 mmol) was added. The mixture was stirred for 1 h at 0 ° C, washed with 10% aqueous NaHCO ₃ and mixed with another batch (from 87 mg of intermediate 382). Then EtOAc was added to the mixture. The organic layer was washed with brine, dried with MgSO ₄ , filtered and the solvent was evaporated. The residue was purified by silica gel column chromatography (SiOH, irregular grains, 24 g, mobile phase: DCM / MeOH, gradient 99: 1 to 95: 5). The fractions containing the product were mixed and evaporated to give intermediate 384 (168 mg; 72% based on these two batches).

Example A59.

Getting intermediate 385

A mixture of compound 1 (4 g; 10.1 mmol), Boc-glycine (4.4 g; 25.22 mmol), HATU (9.6 g; 25.22 mmol), DIPEA (8.7 ml; 50.45 mmol) and DMAP (67 mg; 0.546 mmol) in DMF (120 ml) was stirred at room temperature for 18 hours. The solution was poured into ice water. Then the precipitate was filtered and washed with water. The solid was dissolved in EtOAc. The organic layer was washed with H2O, then with brine, dried with MgSO ₄ , filtered and evaporated to dryness. The residue was purified by silica gel chromatography (SiOH, irregular grains, 120 g; mobile phase: 65% heptane, 5% MeOH (+ 10% NH4OH), 35% AcOEt). Fractions with pure product were combined and evaporated to dryness, yielding 3.57 g (64%) of intermediate 385.

Getting intermediate 386

A mixture of compound 1 (2.1 g; 5.30 mmol), Boc-L-alanine (2.5 g; 13.24 mmol), HATU (5 g; 13.24 mmol), DIPEA (4.5 ml; 26.48 mmol) and DMAP (35 mg; 0.29 mmol) in DMF (63 ml) was stirred at room temperature for 18 h. The solution was poured into water and was extracted with EtOAc. The organic layer was washed with H2O, then with brine, dried with MgSO ₄ , filtered and evaporated to dryness. The residue was purified by silica gel chromatography (SiOH, irregular grains, 150 g; mobile phase: 65% heptane, 5% MeOH (+ 10% NH4OH), 35% AcOEt). Fractions with pure product were combined and evaporated to dryness to obtain 2.73 g (91%) of intermediate 386.

The intermediates shown in the table below were prepared by a method similar to the preparation of intermediates 385 and 386 from the corresponding starting materials.

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Intermediate number Structure Weight (mg) Output (%) Intermediate 387 o '''P' / Ύ ⁰ N / ^ H Η oA m / O YX χψ From compound 1 and Boc-L-valine 438 58 Intermediate 388 MG ^! Η οΎ Ν --- \ / О bk / \ rJ ХА Υγ From compound 1 and Boc-Dphenylalanine 800 98 Intermediate 389 o, X XjL-N 1 ⁿ Η Ο-Ύ Ν --- \ / Ο Ν '/ \ RJ yy _ν dA From compound 1 and Boc-D 288 Quantitative Intermediate 390 / 4 Η 0-¼ ^N --k R / О ⁿ у λ NA / γ ¹ From compound 1 and b-tert-butoxypropanoic acid 364 54

Example A60.

Getting intermediate 393

Lithium aluminum deuteride (263 mg; 6.27 mmol) was added in portions at 5 ° С to a solution of methyl 5amino-2-fluoro-4-methylbenzoate (383 mg; 2.09 mmol) in THF (20 ml) and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was carefully quenched by the addition of EtOAc and poured into ice water. Then more EtOAc was added and the organic layer was decanted, washed with brine, dried with MgSO ₄ , filtered and the solvent was evaporated to give 337 mg (quant.) Of a brown solid which was used without purification in the next step.

Example A61.

Getting intermediate 395

A mixture of 4-methyl-3-nitrobenzyl alcohol (2.5 g; 14.95 mmol) and thionyl chloride (10 ml) in DCM (40 ml) was stirred at 80 ° С overnight. The mixture was evaporated in vacuo. The crude compound (3 g) was purified by column chromatography over silica gel (eluent: petroleum ether / ethyl acetate: 10/1). The product containing fractions were evaporated in vacuo to give 2.7 g (97%) of intermediate 395 as a yellow solid.

Getting intermediate 396

A mixture of intermediate 395 (2.7 g; 14.55 mmol) and sodium isopropoxide (8.63 g; 105.14 mmol) in isopropanol was stirred at 100 ° С overnight. Water (100 ml) was added and the aqueous layer was extracted with ethyl acetate (150 ml x 2). The organic layer was washed with brine (100 ml), dried with Na ₂ SO ₄ , filtered and evaporated in vacuo.

The crude compound (3 g) was purified by column chromatography over silica gel (eluent: petroleum ether / ethyl acetate: 10/1). The fractions containing the product were evaporated in vacuo to give 2.1 g (69%) of intermediate 396 as a clear oil.

Example A62.

Getting intermediate 399

Acetyl chloride (3.09 g; 39.35 mmol) was added dropwise to a solution of methyl 3-amino-4-methylbenzoate (5 g; 30.27 mmol) and triethylamine (4.59 g; 45.4 mmol) in DCM (50 ml) at 0 ° С. the reaction mixture was stirred at room temperature overnight. Saturated aqueous NaHCO ₃ solution (100 ml) was added. The mixture was filtered and the filter cake was washed with water (30 ml x 2) and petroleum ether (30 ml x 2). The precipitate was dried in vacuo to give 5.6 g (88%) of intermediate 399 as a white solid.

Getting intermediate 400

To a solution of intermediate 399 (3.4 g; 16.24 mmol) in 1/2 THF / water mixture (30 ml) was added sodium hydroxide (3.25 g; 81.2 mmol) at room temperature. The mixture was stirred at room temperature for 24 hours and poured into a mixture of water (30 ml) and ethyl acetate (30 ml). The aqueous layer was separated and acidified with HCl (12 M) to pH 2. The precipitate that formed was filtered off and dried, yielding 2.7 g (86%) of intermediate 400 as a white solid.

Getting intermediate 401

Isobutyl chloroformate (2.3 g; 16.8 mmol) was added dropwise to a solution of intermediate 400 (2.7 g; 13.97 mmol) in THF (20 ml) at 0 ° С. Then DIPEA (5.42 g; 41.93 mmol) was added at 0 ° С and the mixture

- 189 037358 was stirred at 0 ° C for 2 hours.

Ethyl acetate (30 ml) was added to the mixture, and the organic layer was washed with water (15 ml x 3). The organic layer was dried (MgSO ₄ ), filtered and evaporated to give 3.87 g (94%) of intermediate 401 as a light yellow solid.

Getting intermediate 402

To a solution of intermediate 401 (2 g; 6.82 mmol) in deuterated methanol (50 ml), sodium bordeuteride (1.43 g; 34.1 mmol) was added slowly at 0 ° С. The mixture was stirred at room temperature for 30 minutes. The mixture was evaporated and the residue was purified by column chromatography on silica gel (eluent: petrol / ethyl acetate: 100: 0 to 0: 100. The fractions containing the product were combined and the solvent was evaporated to give 988 mg (80%) of intermediate 402 as a white solid. ...

Getting intermediate 403

A mixture of intermediate 402 (980 mg; 5.41 mmol) and sodium hydroxide (18.2 g; 324.45 mmol) in a 4/1 methanol / water mixture (20 ml) was stirred at 90 ° С for 48 h. The mixture was evaporated, water (20 ml ) and extracted with ethyl acetate (15 ml x 3). The organic layer was dried (MgSO ₄ ), filtered and evaporated to give 650 mg (86%) of intermediate 403 as a light yellow solid.

Example A63.

Getting intermediate 405

To a solution of intermediate 399 (1 g; 4.82 mmol) in THF (30 ml) dropwise at -78 ° C in a N2 atmosphere was added methylmagnesium bromide (3 M in Et ₂ O; 8.04 ml; 24.13 mmol). The reaction mixture was stirred at room temperature overnight. Saturated NH ₄ Cl solution (60 ml) was added and the reaction mixture was extracted with ethyl acetate (50 ml x 3). The organic layer was washed with brine (50 ml), dried with Na ₂ SO ₄ , filtered and evaporated in vacuo to give the crude compound.

This crude compound (0.9 g) was purified by column chromatography over silica gel (eluent: petroleum ether / ethyl acetate: 1/3). The product containing fractions were evaporated in vacuo to give 700 mg (70%) of intermediate 405 as a white solid.

Getting intermediate 406

Intermediate 406 was prepared in a manner similar to that for the preparation of intermediate 403, starting with intermediate 405 (490 mg; 89%; yellow solid).

Example A64.

Getting intermediate 408

To a solution of 2-fluoro-4-methylbenzoic acid (1 g; 6.5 mmol) in sulfuric acid (15 ml), freshly prepared С (0.415 ml) and В (0.44 ml: 10.5 mmol). The mixture was stirred at 0 ° C for 3 hours and carefully added to 66 ml of ice / ice water. The resulting mixture was stirred for 1 h. The precipitate that formed was filtered off and dried in vacuum at 50 ° С to obtain 1.26 g (98%) of intermediate 408 as a white solid.

Getting intermediate 409

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Intermediate 408 (1.26 g; 6.32 mmol) was dissolved in THF (15.7 ml). Borane-THF complex (1 M; 19 ml; 19 mmol) was added dropwise at 0 ° С. The mixture was stirred at 50 ° C. The mixture was quenched by the addition of ml saturated aqueous NaHCO ₃ solution and extracted with ethyl acetate (80 ml x 3). The organic layer was washed with brine (100 ml), dried with MgSO ₄ and filtered. The solvent was removed in vacuo to give 1.17 g (100%) of intermediate 409 as a yellow solid.

Example A65.

Obtaining intermediate 413 and intermediate 414

sodium bis- (trimethylsilyl) amide (28.15 ml; 28.15 mmol) was added dropwise at 0 ° С to a solution of isopropanol (2.15 ml; 28.15 mmol) and THF (150 ml) and the reaction mixture was stirred for 10 min. The resulting solution was added to a solution of ethyl 4-fluoro-3-nitrobenzoate (4 g; 18.76 mmol) in THF (50 ml) at 0 ° C and the reaction mixture was stirred overnight. Water (80 ml) was added and the mixture was extracted with ethyl acetate (100 ml x 3), dried with sodium sulfate, filtered and evaporated to give a yellow solid.

The residue was purified by flash chromatography on silica gel (eluent: petroleum ether / ethyl acetate 100/0 to 60/40). The fractions containing the product were combined and the solvent was evaporated to dryness in vacuo to give 3.2 g of an undefined mixture of intermediates 413 and 414 as a yellow solid.

Getting intermediate 415

Lithium aluminum hydride (0.7 g; 18.44 mmol) was added to a solution of intermediates 413 and 414 (3.2 g) in THF (60 ml) at 0 ° С. The mixture was stirred overnight at rt. At 0 ° С, water (0.49 ml) was added, followed by a 10% aqueous solution of NaOH (0.49 ml) and again water (1.47 ml). The mixture was dried with MgSO ₄ , filtered and the filtrate was evaporated in vacuo. The residue was purified by flash chromatography on a silica gel column (eluent: petroleum ether / ethyl acetate 100/0 to 60/40). The fractions containing the product were combined and the solvent was evaporated to dryness in vacuo to give 420 mg (32%) of intermediate 415 as a yellow oil.

Getting intermediate 416

A mixture of intermediate 415 (500 mg; 2.37 mmol) in methanol (10 ml) was hydrogenated at rt (15 Psi, 103.4 kPa) in the presence of platinum on activated carbon as a catalyst. After uptake of H ₂ (3 equiv.), The mixture was stirred overnight at rt. The catalyst was filtered off and the filtrate was evaporated to give 400 mg (93%) of intermediate 416 as a brown oil.

Getting intermediate 418

Trifluoroacetic acid (0.8 mL; 10.45 mmol) was added to a solution of intermediate 417 (340 mg; 0.41 mmol) in DCM. The mixture was stirred for 2 h at rt, then poured into water (15 ml) and the pH was adjusted to 10 with saturated aqueous Na ₂ CO ₃ solution. The mixture was extracted with DCM (30 ml x 3), dried with MgSO ₄ , filtered and evaporated to give 420 mg (59%) of intermediate 418 as a yellow solid.

Getting intermediate 419

- 191 037358

A mixture of intermediate 418 (400 mg; 0.36 mmol) and potassium carbonate (178.5 mg; 1.29 mmol) in methanol (5 ml) was stirred for 30 min at 80 ° С. The suspension was filtered through a pad of celite, which was washed with ethyl acetate (EtOAc) (10 ml x 3). The combined filtrates were evaporated to dryness to give 320 mg (95%) of intermediate 419 as a yellow oil.

Example A66.

Getting intermediate 420

In this reaction, which was carried out twice, 5 g of 2-fluoro-4-methylbenzoic acid were introduced each time. A mixture of 2-fluoro-4-methylbenzoic acid (5 g; 32.4 mmol), HATU (13.6 g; 35.7 mmol) and DIPEA (12.3 ml; 71.4 mmol) was stirred in DCM (129 ml) for 30 min and methylamine (17.8 ml g; 35.7 mmol). The mixture was stirred at rt for 5 hours. The mixture was evaporated. The residue was purified by chromatography on silica gel (15-40 μm, 120 g, eluent: heptane / EtOAc: 80/20 to 10/90). Fractions with pure product were mixed and the solvent was evaporated, yielding 9.07 g (84%) of intermediate 420.

The intermediates shown in the table below were prepared by a method similar to that described for the preparation of intermediate 420 from the corresponding starting materials.

The most important minor deviations from the reference method are given as additional information in the Mass column.

Intermediate number Structure Weight (mg) Output (%) Intermediate 432 MU Υ LN From 3-amino-4-methylbenzoic acid and 1- (2-aminoethyl) pyrrolidine 288 36

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Intermediate 434 NH NH ₂ - [Г n Y 0 From 3-amino-4-methylbenzoic acid and 2- (4-morpholino) ethylamine 126 12 Intermediate 436 Hu. From 3-amino-4-methylbenzoic acid and dimethylamine 700 100 Intermediate 438 "DAU 0 From 3-amino-4-methylbenzoic acid and 2- (4-morpholino) ethylamine 1530 100

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Intermediate 441 From 3-Amino-4-methylbenzoic acid and 1-methylpyrrolidine-Zamine 441 The reaction was carried out with 2.5 equiv. somi instead of 1.1 equiv. HATU 53 Intermediate 443 1 ° \ D ⁿ JI l DT Η ₂ νΑΑΑ F From 2-fluoro-4-methylbenzoic acid and methylamine 356 66 Intermediate 445 ⁰ II ^Ν - II Irs / Λ A ⁿ / Yes From 2-fluoro-4-methylbenzoic acid and 1-methylpyrrolidine-Zamine 773 100 Intermediate 450 o L II RS / ° U 1 / G ^^ Yes ^ mA ^ / X JL ⁿ From 2-fluoro-4-methylbenzoic acid and 3-aminotetrahydrofuran hydrochloride 554 77 Intermediate 495 ZI UUCH Midrange X 900 76 From oxetan-3-ylmethanamine and intermediate 494 Intermediate 521a Cis id From 2-methyl-3-nitrobenzoic acid and cis-2,6-dimethyl morpholine 1500 98

Getting intermediate 421

A mixture of fuming nitric acid (3.3 ml; 79.28 mmol) in sulfuric acid (4 ml) was added dropwise at 5 ° С over 3 minutes (ice bath) to a solution of intermediate 420 (9 g; 53.83 mmol) in sulfuric acid (120 ml ) [no exotherm observed]. The reaction mixture was stirred at 5 ° C for 3 h and quenched, taking precautions, using an ice / ice-water system (500 ml) at 0-5 ° C.

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The mixture was vigorously stirred for 1 h. The precipitate was filtered off, washed with ice and water (3 x

300 ml) and dried. The resulting solid was solubilized in DCM and the organic layer was dried

MgSO ₄ , filtered, and the solvent was evaporated to give 10.47 g (92%) of intermediate 421 as a white solid.

Example A67.

Getting intermediate 424

A mixture of 2,4-difluorobenzoic acid (2 g; 12.65 mmol), HATU (5.3 g; 13.915 mmol) and DIPEA (4.8 ml; 27.83 mmol) in DCM (50 ml) was stirred for 30 min and a 2 N solution of methylamine was added THF (7 ml; 13.915 mmol). The reaction mixture was stirred at room temperature for 18 h, poured into water and extracted with DCM. The organic layer was decanted, filtered through a chromabond® column and evaporated to dryness. The residue was purified by silica gel chromatography (SiOH, irregular grains, 40 g; gradient: 20% EtOAc, 80% heptane to 40% EtOAc, 60% heptane). Fractions with pure substance were combined and evaporated to dryness to obtain 1.68 g (77%) of intermediate 424.

Getting intermediate 425

A mixture of fuming nitric acid (0.6 ml; 14.456 mmol) in concentrated sulfuric acid (1 ml) at 5 ° С was added dropwise to a solution of intermediate 424 (1.68 g; 9.816 mmol) in concentrated sulfuric acid (21 ml). The reaction mixture was stirred at 5 ° C for 4 h and poured into ice water. The suspension was stirred at room temperature for 30 minutes. The precipitate was filtered off, washed with water, and dried, yielding 1.38 g (65%) of intermediate 425.

The intermediates shown in the table below were prepared by a method similar to that described for the preparation of intermediate 425 from the corresponding starting materials.

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Intermediate number Structure Weight (mg) Output (%) Intermediate 446 /, —N 9 ° \ X ^H o. О X у 1 О ¹ From intermediate 445 638 70 Intermediate 451 1 - ⁰ y O. ΝΗ ^χ ν 'γ 1 о 1 From intermediate 450 426 65 Intermediate 489 1 O _s ___ _X NH jy) From intermediate 488 354 53

Obtaining intermediate 426 and intermediate 427

I

Intermediate 426

Intermediate 427

A mixture of intermediate 425 (1.15 g; 5.32 mmol), cyclopropanol (337 μL; 5.32 mmol), and cesium carbonate (3.5 g; 10.64 mmol) in 1,4-dioxane (15 mL) was heated at 80 ° С for 1 h. the mixture was cooled to room temperature and DCM was added. The organic layer was washed with water, filtered through a chromabond® column and evaporated to dryness. The residue was purified by silica gel chromatography (SiOH, irregular grains, 50 g; mobile phase: gradient from 20% EtOAc, 80% heptane to 40% EtOAc, 60% heptane). The product fractions were combined and evaporated to dryness to give 860 mg (63%) of a mixture of intermediates 426 and 427, which was used directly in the next step without any further purification.

Getting inteomedia 428 and inteomedia 429

A mixture of intermediates 426 and 427 (860 mg; 3.38 mmol), iron powder (945 mg; 16.91 mmol) and ammonium chloride (724 mg; 13.53 mmol) in a mixture of ethanol (22 ml) and water (5.6 ml) was heated at 70 ° С for 1 h. The reaction mixture was cooled to room temperature, added DCM, filtered through a pad of celite and basified with 10% aqueous K ₂ CO ₃ solution. The organic layer was decanted, dried over MgSO ₄ , filtered, and evaporated to dryness to obtain 791 mg of a mixture of intermediates 428 and 429, which

- 196 037358 which were used immediately in the next step.

Example A68.

Getting intermediate 455

To a solution of 2-bromo-4-methylbenzonitrile (4.0 g; 20.40 mmol) in sulfuric acid (6 ml) at 0 ° С was added potassium nitrate (2.063 g; 20.40 mmol) in sulfuric acid (18 ml). After stirring at 0 ° C for 1.5 h, the reaction mixture was poured into 500 ml of ice water. The precipitate was collected by filtration and washed with copious amounts of water. The precipitate was dried to obtain 4.5 g (91%) of intermediate 455.

Getting intermediate 456:

A mixture of intermediate 455 (500 mg; 2.07 mmol), N-boc-propargylamine (483 mg; 3.11 mmol), tritret-butylphosphine (0.0287 ml; 0.122 mmol), diisopropylamine (0.33 ml; 2.41 mmol), copper (I) iodide ( 4.7 mg; 0.024 mmol) and dichlorobis- (triphenylphosphine) palladium (57 mg; 0.081 mmol) in 1,4-dioxane (8.8 ml) was purged three times with N2 and heated at 45 ° С for 1 h. The mixture was poured onto ice and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO ₄ , filtered and the solvent was evaporated. The residue was purified by chromatography on silica gel (80 g; 15-40 μm, eluent: heptane / EtOAc: 100/0 to 0/100). The pure fractions were mixed and the solvent was evaporated, yielding 0.594 g (91%) of intermediate 456.

Getting intermediate 457

A mixture of intermediate 456 (555 mg; 1.76 mmol) and Pd (10%) on activated carbon (187 mg) in EtOAc (11 ml) was hydrogenated at room temperature under 1 bar H2 pressure overnight. The mixture was filtered through celite and the filtrate was evaporated to dryness to give 0.352 g (69%) of intermediate 457. Example A69

Getting intermediate 465

A mixture of intermediate 455 (0.5 g; 2.074 mmol), 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.528 ml; 3.11 mmol) and tetrakis (triphenylphosphine) palladium (0) (120 mg; 0.104 mmol) in 2 N Na ₂ CO ₃ (1.82 ml; 3.63 mmol) and 1,4-dioxane (5.2 ml) was degassed and then heated at 100 ° С overnight. The mixture was poured onto ice and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO ₄ , filtered and the solvent was evaporated. The residue was purified by chromatography on silica gel (80 g, 15-40 μm, eluent: heptane / EtOAc: 100/0 to 0/100). The pure fractions were mixed and the solvent was evaporated, yielding 0.181 g (46%) of intermediate 465.

Getting intermediate 466

A mixture of intermediate 465 (250 mg; 1.33 mmol) and morpholine (821 mg; 6.64 mmol) in MeOH (4.7 ml) was stirred at 60 ° С for 1 h in a sealed tube. The mixture was poured onto ice and extracted with DCM. The organic layer was washed with brine, dried over MgSO ₄ , filtered and the solvent was evaporated. The residue was purified by chromatography on silica gel (15-40 μm, 24 g, eluent: DCM / MeOH: 100/0 to 95/5). The pure fractions were mixed and the solvent was evaporated, yielding 0.329 g (90%) of intermediate 466.

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Getting intermediate 469

Intermediate 469 was prepared in a manner similar to that used to prepare intermediate 466, starting with intermediate 465 and 3-fluoroazetidine hydrochloride (247 mg; 67%).

Example A70.

Getting intermediate 472

A mixture of intermediate 455 (500 mg; 2.07 mmol), 1-methyl-1,2,3,6tetrahydropyridine-4-boronic acid pinacol ester (509 mg; 2.28 mmol) and potassium phosphate (881 mg; 41.5 mmol) in 1, 4-dioxane (7 ml) and water (4 ml) were degassed with N ₂ . 1,1'-Bis- (diphenylphosphino) ferrocene-palladium (P) dichloride was added as a complex with dichloromethane (17 mg; 0.0207 mmol) and the reaction mixture was heated at 120 ° С for 15 min using one single-mode microwave reactor (Biotage Initiator EXP 60) with an output power ranging from 0 to 400 W. The mixture was poured into water and extracted with DCM. The organic layer was washed with brine, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by silica gel chromatography (irregular grain SiOH, 80 g; mobile phase: DCM / MeOH: 100/0 to 95/5). The fractions containing the product were collected and evaporated to dryness to give 0.515 g (96%) of intermediate 472.

Getting intermediate 475

Intermediate 475 was synthesized using the same method as used to prepare intermediate 472, starting with intermediate 455 and tert-butyl 3- (4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate (1.45 g; 93%).

Getting intermediate 473

A solution of intermediate 472 (0.478 mg; 1.86 mmol) in MeOH (21.9 ml) was hydrogenated at a H2 pressure _of 2 bar at room temperature in the presence of 10% palladium on activated carbon (54.8 mg) overnight. The mixture was filtered through celite and the filtrate was evaporated. The residue was purified by chromatography on silica gel (40 g, 15-40 μm, eluent: DCM / MeOH: 100/0 to 90/10). The fractions containing the product were mixed and the solvent was evaporated, yielding 0.155 g (36%) of intermediate 473.

Example A71.

Getting intermediate 476

TFA (4.4 ml; 58 mmol) was added to a solution of intermediate 475 (1.45 g; 4.22 mmol) in DCM (22 ml) and the mixture was stirred for 30 min, then poured onto ice, basified with K ₂ CO ₃ and extracted with DCM. The organic layer was washed with brine, dried over MgSO ₄ , filtered and the solvent was evaporated to give 0.89 g (87%) of intermediate 476.

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Getting intermediate 477

Formaldehyde (0.54 ml; 7.24 mmol) was added to a solution of intermediate 476 (0.873 g; 3.59 mmol) and sodium acetate (0.295 g; 3.6 mmol) in MeOH (30 ml) and DCM (15 ml), and the mixture was stirred at room temperature in within 5 minutes. Then sodium triacetoxyborohydride (1.53 g; 7.19 mmol) was added and the mixture was stirred for 1 h. The mixture was poured onto ice, basified with K ₂ CO ₃ and extracted with DCM. The organic layer was washed with brine, dried over MgSO ₄ , filtered and the solvent was evaporated. The residue was purified by chromatography on silica gel (15-40 μm, 80 g, eluent: DCM / MeOH: 100/0 to 90/10). The pure fractions were mixed and the solvent was evaporated, yielding 1.15 g (99%) of intermediate 477.

Getting intermediate 478

Intermediate 478 was synthesized in a manner similar to that used to prepare intermediate 473, starting with intermediate 477 (1.04 g; 84% purity by LC / MS).

Example A72.

Getting intermediate 488

A mixture of intermediate 40 (575 mg; 2.816 mmol) in concentrated HCl (11 ml) was heated at 100 ° С for 5 h. The reaction mixture was cooled to room temperature, poured into ice water and extracted with Et ₂ O. The organic layer was decanted, dried over MgSO ₄ , filtered and evaporated to dryness to give 632 mg of intermediate 488.

Example A73.

Getting intermediate 492

A solution of potassium nitrate (2.46 g; 0.024 mol) in concentrated sulfuric acid (36 ml) was added dropwise at a temperature below 5 ° С to a solution of 3-bromo-4-fluorotoluene (2.52 ml; 0.02 mol) in concentrated sulfuric acid (4 ml ). The mixture was stirred at 5 ° C for 2 h, then poured into ice water. The resulting precipitate was filtered and dried, yielding 3.94 g (84%) of intermediate 492.

Getting intermediate 492

An autoclave (300 ml) purged with N2 was charged with intermediate 492 (2.93 g; 12.5 mmol) in MeOH (117 ml). Triethylamine (3.58 ml; 25 mmol) was added followed by 1,1'-bis (diphenylphosphino) ferrocene] palladium (P) dichloride (0.615 g; 0.751 mmol). The autoclave was purged and the mixture was stirred overnight under a carbon monoxide pressure of 30 bar at 90 ° C. The mixture was evaporated. The residue was purified by chromatography on silica gel (15-40 μm, 90 g, eluent: heptane / EtOAc: 100/0 to 0/100). The pure fractions were mixed and the solvent was evaporated, yielding 1.22 g (28%) of intermediate 493.

Obtaining intermediate 494 o ύΥ ° ^η H ₂ N ^ A / A _F

A solution of lithium hydroxide (0.9 g; 21.4 mmol) in water (4.4 ml) was added to a solution of intermediate 494 (0.982 g; 5.36 mmol) in THF (47 ml). The reaction mixture was heated under reflux overnight. The mixture was poured onto ice, acidified with 3N aqueous HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO ₄ , filtered and the solvent was evaporated to give 907 mg of intermediate 494, which was used directly in the next step.

Example A74.

Getting intermediate 497

In a sealed test tube, a solution of 2-bromo-4-methyl-5-nitrobenzonitrile (1.0 g; 4.15 mmol), 1-methyl4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (1.29 g, 6.22 mmol) and K3PO4 (2.64 g, 12.44 mmol) in 1,4-dioxane (30.8 ml) in distilled water (9.7 ml) was purged with N _{2. PdCl 2} dppf (340 mg; 415 μmol) was added _{, the reaction mixture was purged with N 2} again and heated at 80 ° C for 18 h. The reaction mixture was poured into an aqueous solution of K ₂ CO ₃ and extracted with EtAOc. The organic layer was dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by silica gel chromatography (SiOH, irregular grains, 40 g; mobile phase: gradient from 0% EtOAc, 100% heptane to 40% EtOAc, 60% heptane). Fractions were collected and evaporated to dryness to give 800 mg (80%) of intermediate 497.

The compound in the table below was prepared in a similar manner to that described for the preparation of intermediate 497, starting with the appropriate starting materials.

Intermediate number Structure number Output Intermediate 498 / = ^N \ 2 from 5-bromo-1-methyl-1H-imidazole and 4,4,5,5tetramethyl-2- (4-methyl-3-nitrophenyl) -1,3,2dioxaborolane 170 mg 52%

Intermediate 499

A mixture of intermediate 497 (800 mg; 3.30 mmol) and Pd / C (10 wt%, 176 mg) in MeOH (8.3 ml) was stirred at room temperature under a H ₂ pressure of 1 atm overnight. The reaction mixture was filtered through celite and the filtrate was evaporated to dryness to give 700 mg of intermediate 499.

The compounds in the table below were prepared in a similar manner to that described for the preparation of intermediate 499, starting with the appropriate starting materials.

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Intermediate number Structure number Output Intermediate 500 Xj from intermediate 498 147 mg 100% Intermediate 500V Ν—, Xp jCI from intermediate 5 00A 700 mg 93% Intermediate 501 hn (£ n Η, -Χγ from 2- (4-methyl-3-nitrophenyl) -1 H-imidazole 1.4 g 87%

Example A75.

Intermediate 500A

A mixture of 2-nitro-4-bromotoluene (1 g; 4.629 mmol), 1-methyl-7H-pyrazole-5-boronic acid (874 mg; 6.94 mmol), K ₂ CO ₃ (1.024 g; 7.406 mmol), PdCl ₂ dppf (339 mg; 0.463 mmol) in DMF (19 ml) was stirred at 85 ° C for 18 h. The reaction mixture was evaporated. The residue was taken up in EtOAc. The organic layer was washed with water, then brine, dried over MgSO4, filtered and evaporated to dryness.

The residue was purified by silica gel chromatography (mobile phase: gradient from 0% EtOAc, 100% heptane to 30% EtOAc, 70% heptane). Fractions were collected and evaporated to dryness to give 870 mg (87%) of intermediate 500A.

Example A76.

Intermediate 510

An M solution of lithium aluminum hydride in THF (1.5 ml; 1.56 mmol) was added dropwise at 0 ° С to a solution of 3-amino-5-cyano-2-methylbenzoic acid methyl ester (297 mg; 1.56 mmol) in THF (10 ml) and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice water and extracted with EtOAc. The organic layer was decanted, washed with brine, dried over MgSO ₄ , filtered and evaporated to dryness to give 216 mg (85%) of intermediate 510.

Intermediate 512

A mixture of intermediate 510 (341 mg; 2.10 mmol) and manganese dioxide (913 mg; 10.51 mmol) in 1,4 dioxane (20 ml) was heated at 100 ° С for 6 h. The reaction mixture was cooled to room temperature, diluted with DCM, filtered through celite pad and evaporated to dryness to give 300 mg (89%) of intermediate 512 which was used directly in the next step.

The compound in the table below was prepared in a similar manner to that described for the preparation of intermediate 512, starting from the appropriate starting materials. The most significant minor deviations from the original method are indicated in the Quantity column.

Intermediate number Structure number Output Intermediate 515 H OtBDMS CN Fufu from intermediate 511 120 mg Procedure change: 18h, 100 ° C 42%

Preparation of intermediate 513.

A mixture of intermediate 512 (551 mg; 3.44 mmol), cis-2,6-dimethylmorpholine (847 μl; 6.88 mmol) and AcOH (387 μl; 6.76 mmol) in DCM (20 ml) was stirred at room temperature for 1 h. Then sodium triacetoxyborohydride (1.45 g; 6.88 mmol) was added. The reaction mixture was stirred at room temperature over the weekend. The reaction mixture was poured into a 10% aqueous K ₂ CO ₃ solution and extracted with DCM. The organic layer was decanted, filtered through Chromabond® and evaporated to dryness. The residue was purified by chromatography (SiOH with irregular grains, 24 g; mobile phase: gradient from 20% EtOAc, 80% heptane to 40% EtOAc, 60% heptane). The pure fractions were collected and evaporated to dryness to give 632 mg (52%, 73% purity by LC / MS) of intermediate 513, which was used directly in the next step.

The compounds in the table below were prepared in a similar manner to that described for the preparation of intermediate 513, starting from the appropriate starting materials.

Intermediate number Structure number Output Intermediate 516 H OtBDMS _N PO Y CN from intermediate 515 and 3-fluoroazetidine hydrochloride 100 mg 55% Intermediate 517 H OtBDMS ^N --- \ R / VA Yr y CN φιφιΑ from intermediate 515 and 3,3-difluoroazetidine 106 mg Power purity 81 % (LCMS) 31%

Example A77.

Getting intermediate 519

Lithium aluminum deuteride (203 mg; 4.832 mmol) was added in portions at 5 ° С to a solution of intermediate 521b (400 mg; 1.61 mmol) in THF (16 ml) and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was carefully quenched by the addition of EtOAc, poured out into ice water and additional EtOAc added. The organic layer was decanted, washed with brine, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by silica gel chromatography (SiOH irregular grains, 12 g; mobile phase: gradient from 0% MeOH, 100% DCM to 5% MeOH, 95% DCM). Pure fractions were collected and evaporated to dryness to give 286 mg (75%) of intermediate 519.

Example A78.

Getting intermediate 523

A mixture of 1-Boc-piperazine (5 g; 26.845 mmol), iodomethane-D3 (1.7 ml; 26.845 mmol), and potassium carbonate (11 g; 80.54 mmol) in ACN (200 ml) was heated to 85 ° С for 18 h. The suspension was filtered and the non-soluble was washed with EtOAc. The combined filtrates were evaporated to dryness.

The residue was taken up in DCM and the insoluble matter was filtered off. The filtrate was concentrated and purified by chromatography on silica gel (SiOH with irregular grains, 40 g; mobile phase:

gradient from 5% MeOH, 95% DCM to 10% MeOH, 90% DCM). Pure fractions were collected and evaporated to dryness to obtain 3.25 g (59%) of intermediate 523.

Getting intermediate 524

AD ₃

HN. J to / 2 HCI

A solution of HCl 4 N in 1,4-dioxane (11 ml; 44.27 mmol) was added to a solution of intermediate 523 (3 g; 14.757 mmol) in ACN (70 ml) and the reaction mixture was stirred for 18 h. The precipitate was filtered, washed with ACN, then Et ₂ O and dried to obtain 2.54 g (98%) of intermediate 524.

Example A79.

Getting intermediate 525

OtBDMS A O ₂ N ^^ jC

A solution of tert-butyldimethylsilane chlorine (391 mg; 2.59 mmol) in DCM (1.7 ml) was added dropwise at 5 ° С to a solution of 2,4-difluoro-5-nitrobenzenemethanol (490 mg; 2.59 mmol) and Et ₃ N (720 μl ; 5.18 mmol) in DCM (3 ml) and the reaction mixture was stirred at room temperature overnight.

Alternatively, the same reaction was performed using the same conditions starting with 2,4 difluoro-5-nitrobenzenemethanol (500 mg; 2.644 mmol) and trifluoromethanesulfonic acid tert-butyldimethylsilyl ester (0.607 ml; 2.64 mmol). The two reaction mixtures were combined for work-up: DCM was added and the suspension was poured into saturated aqueous NH ₄ Cl solution. The organic layer was decanted, washed with water, then with a 10% aqueous solution of K ₂ CO ₃ , dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by silica gel chromatography (irregular grain SiOH, 40 g; mobile phase: gradient from 10% EtOAc, 90% heptane to 30% EtOAc, 70% heptane). Pure fractions were collected and evaporated to dryness to give 858 mg of intermediate 525 (quantitative yield).

Getting intermediate 526

OtBDMS X about.

A mixture of intermediate 525 (858 mg; 2.83 mmol), cyclopropanol (717 μL; 11.3 mmol) and cesium carbonate (1.84 g; 5.66 mmol) in 1,4-dioxane (9.5 mL) was heated at 100 ° С for 2 h. the mixture was heated at 100 ° C overnight, cooled to room temperature and diluted with DCM. Water was added and the reaction mixture was extracted with DCM (three times). The combined organic layers were washed with water, dried over MgSO4, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (SiOH, irregular grains, 40 g; mobile phase: gradient from 10% EtOAc, 90% heptane to 20% EtOAc, 80% heptane). Pure fractions were collected and evaporated to dryness to give 581 mg (60%) of intermediate 526.

The intermediate in the table below was prepared in a similar manner to that described for the preparation of intermediate 526, starting with the appropriate starting materials. The most significant minor deviation from the original procedure is indicated in the yield column.

Intermediate number Structure number Output Intermediate 529 CN with From 2,4-difluoro-5-nitrobenzonitrile 790 mg 65% Measurement during the procedure: 1 h, 80 ° C

Getting intermediate 527

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A mixture of intermediate 526 (527 mg; 1.543 mmol), iron powder (431 mg; 7.717 mmol) and NH4Cl (330 mg; 6.174 mmol) in EtOH (10 ml) and distilled water (2.5 ml) was heated at 70 ° С for 1 h. The reaction mixture was cooled to room temperature, diluted with DCM, filtered through celite and podslushivaet 10% aqueous solution of K ₂ CO ₃ . The organic layer was decanted, dried over MgSO ₄ , filtered and evaporated to dryness to give 485 mg (quantitative yield) of intermediate 527, which was used directly in the next step without further purification.

The intermediate in the table below was prepared in a similar manner to that described for the preparation of intermediate 527, starting with the appropriate starting material.

Intermediate number Structure number Output Intermediate 530 CN „Г from intermediate 529 670 mg 98%

Example A80.

Getting intermediate 532.

In a dried flask, zinc (4.05 g; 62 mmol) was suspended in dried dimethylacetamide (200 ml) under N ₂ . The suspension was heated to 65 ° С, and then dibromoethane (0.45 g; 2.39 mmol) and chlorotrimethylsilane (0.207 g; 1.91 mmol) were added and then heated at 65 ° С for 0.5 h. 1-tert-butoxycarbonyl-3 was added dropwise β-iodazetidine (13.5 g; 47.68 mmol) in dimethylacetamide (100 ml) at 65 ° C and the reaction mixture was stirred at room temperature for 1 h. The crude product was used directly without treatment and purification in the next step.

Getting intermediate 533

A mixture of 4-bromo-1-methyl-2-nitrobenzene (6.06 g; 28.08 mmol), intermediate 532 (16.62 g; 47.68 mmol), Pd (dppf) Cl ₂ DCM (703 mg; 0.86 mmol) and copper iodide (I ) (323.7 mg; 1.7 mmol) in dimethylacetamide (300 ml) was stirred at 90 ° С overnight under N2. Water (900 ml) was added and the reaction mixture was extracted with ethyl acetate (600 ml x 2). The organic layers were combined, washed with water, brine, dried over Na ₂ SO ₄ , filtered and evaporated in vacuo. The crude intermediate (8 g) was purified by column chromatography over silica gel (eluent: petroleum ether / ethyl acetate = 3/1). The fractions containing the product were mixed and evaporated in vacuo to give 5 g of intermediate 533 (61%) as a yellow oil.

Getting intermediate 534

A solution of intermediate 533 (5 g; 17.1 mmol) and a 4 M solution of HCl in dioxane (50 ml; 200 mmol) in dioxane (20 ml) were stirred at room temperature overnight. The mixture was evaporated in vacuo to give 3.91 g of crude intermediate 534, which was used directly in the next reaction step without further purification.

Getting intermediate 535

A mixture of intermediate 534 (3.9 g; 17.10 mmol), paraformaldehyde (3 g; 102.62 mmol) and sodium acetate (1.4 g; 17.10 mmol) in MeOH (150 ml) was stirred at room temperature for 2 h.

- 204 037358 sodium triacetoxyborohydride (21.7 g; 102.62 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was slowly podslushivaet saturated aqueous NaHCO ₃ solution (400 ml) and was extracted with DCM (2 x 300 ml). The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated to dryness. The residue was purified by silica gel chromatography (mobile phase: petroleum ether / EtOAc (1/2)). The desired fractions were evaporated to dryness to obtain 1.58 g (45%) of intermediate 535.

Getting intermediate 536

Intermediate 535 (1.58 g; 7.66 mmol) was dissolved in THF (20 ml), MeOH (10 ml), and distilled water (10 ml). Iron powder (2.1 g; 38.35 mmol) and NH4O (2 g; 38.30 mmol) were added. The reaction mixture was heated under reflux overnight, filtered through celite and the filter cake washed with 80 ml of EtOAc / MeOH (8/1). The filtrate was evaporated to dryness. The residue was purified by silica gel chromatography (mobile phase: EtOAc / MeOH (5/1)). The desired fractions were evaporated to dryness to give 880 mg (65%) of intermediate 536.

Example A81.

Alternative preparation of intermediate 380

DCM (5 ml) was cooled to -78 ° C and oxalyl chloride (3 ml; 6.04 mmol) was added followed by the addition of DMSO (865 μl; 12.1 mmol). After 30 min, a suspension of intermediate 10R (2 g; 4.03 mmol) in DCM (15 ml) was added dropwise. The reaction mixture was stirred for 30 min at -78 ° C, then DIPEA (4.1 ml; 24.17 mmol) was added. Stirring was continued for 3 h at -78 ° C and the reaction mixture was allowed to warm to room temperature and stirred for 30 min. Diluted aqueous NH ₄ Cl solution was added and the aqueous layer was extracted with DCM (twice). The combined layers were dried over MgSO4, filtered and evaporated to dryness. The residue was crystallized from Et ₂ O and the precipitate was filtered, washed with DiPE and dried to give 2 g of intermediate 380.

Getting intermediate 540

A solution of intermediate 380 (2 g; 4.044 mmol), 2,4-dimethoxybenzylamine (3.6 ml; 24.26 mmol), and AcOH (1.4 ml; 24.26 mmol) in DCE (100 ml) was stirred for 3 h and NaBH (OAc) ₃ (8.5 g; 40.44 mmol). The reaction mixture was stirred at room temperature overnight. Saturated aqueous NaHCO ₃ solution was added and the aqueous layer was extracted with DCM. The organic layer was dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by silica gel chromatography (irregularly shaped SiOH, 80 g; mobile phase: gradient from 40% EtOAc, 60% heptane to 2% MeOH, 60% EtOAc, 40% heptane). The fractions containing the product were collected and evaporated to dryness to give 1 g (38%) of intermediate 540 and 855 mg of intermediate 380.

Getting intermediate 541

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A mixture of intermediate 540 (500 mg; 0.77 mmol), acetyl chloride (66 μl; 0.93 mmol), and Et ₃ N (215 μl; 1.55 mmol) in THF (10 ml) was stirred at room temperature for 18 h. The reaction mixture was poured into 10 % aqueous solution of K ₂ CO ₃ and extracted with DCM. The organic layer was decanted, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by silica gel chromatography (SiOH, irregular grains, 24 g; mobile phase: gradient from 0% MeOH, 100% DCM to 6% MeOH, 94% DCM). The fractions containing the product were collected and evaporated to dryness to give 540 mg (quantitative yield) of intermediate 541.

Getting intermediate 542

A mixture of intermediate 540 (415 mg; 0.64 mmol), methanesulfonyl chloride (74 μl; 0.96 mmol) and Et ₃ N (223 μl; 1.61 mmol) in THF (8 ml) was stirred at room temperature for 18 h. The reaction mixture was poured into 10 % aqueous solution of K ₂ CO ₃ and extracted with DCM. The organic layer was decanted, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by chromatography on silica gel (SiOH with irregular grains, 40 g; mobile phase: 0.1% NH4OH, 99.5% DCM, 0.5% MeOH). The fractions containing the product were collected and evaporated to dryness to give 318 mg (68%) of intermediate 542.

Example A82.

Getting intermediate 543

DIPEA (1 ml; 5.8 mmol) was added to a solution of 3-amino-4-methylbenzonitrile (661 mg; 5 mmol) and 2,4-dichloro-1,3,5-triazine (750 mg; 5 mmol) in ACN (30 ml). The reaction mixture was stirred overnight at room temperature. The solvent was removed by evaporation and the residue was partitioned between water and EtOAc. The organic layer was decanted, washed with water, then brine, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by silica gel chromatography (SiOH; irregular grains; mobile phase: gradient from 0% EtOAc, 100% petroleum ether to 50% EtOAc, 50% petroleum ether). The fractions containing the product were collected and evaporated to dryness to give 700 mg (57%) of intermediate 543.

The intermediate in the table below was prepared in a similar manner to that described for the preparation of intermediate 243, starting with the appropriate starting materials. The most significant minor deviation from the original method is indicated in the Amount column.

Intermediate number Structure number Output Intermediate 546 one SC NH CI Ap M Bs 3-amino-K, 4-dimethylbenzamide and 2,4-d ichloro-1,3,5-triazine 740 mg Treatment with acetone as solvent instead of ACN 40%

Getting intermediate 544

A solution of intermediate 5R (1.58 g; 3 mmol), intermediate 243 (663 mg; 2.7 mmol) and aqueous 2 M NaHCO ₃ (6 ml; 12 mmol) in 1,4-dioxane (24 ml) was purged with N2. _{PdCl 2} dppf (219 mg; 0.3 mmol) was added, the reaction mixture was purged with N2 again and heated at 80 ° C for 10 h. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was dried over MgSO ₄ , filtered and evaporated

- 206 037358 until dry. The residue was purified by silica gel chromatography (SiOH, irregular grains; mobile phase: gradient from 0% EtOAc, 100% petroleum ether to 50% EtOAc, 50% petroleum ether). Fractions were collected and evaporated to dryness to give 600 mg (32%) of intermediate 544.

The intermediate in the table below was prepared in a similar manner to that described for the preparation of intermediate 544, starting with the appropriate starting materials.

Intermediate number Structure number Output Intermediate 547 ^В0С \ OtBDMS Α GLG IIW 1 W ° γΝΗ uyy From intermediate 5R and intermediate 546 560 mg 46%

Example A83.

Getting intermediate 549

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 a temperature from -5 to 5 ° С for 1 h. Then, a solution of intermediate 3 a in THF (85.0 g) and the mixture was stirred for 2-4 h, monitoring the conversion by high performance liquid chromatography (HPLC). Then water (210 ml) was added dropwise and the mixture was concentrated to remove most of the THF. Then heptane (300 ml) was added and the mixture was stirred for 30 minutes. 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 layer with heptane (300 ml), to give 63.3 g of intermediate 549.

Getting intermediate 550

Dimethylaminopyridine (0.5 equiv.) Was added to a solution of intermediate 549 (50.0 g) in dry THF (500 ml), and the temperature was set at 65-70 ° С. Then di-tert-butyl dicarbonate (2.2 eq.) Was added and the mixture was stirred for 2 h, monitoring the conversion 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 to 4-6 by adding 20% aqueous AcOH solution. The layers were separated and water (350 ml) was added. After adjusting the pH to 7-8 with 8% aqueous NaHCO _{3, the} layers were separated and the organic layer was washed with water (350 ml) and concentrated to give 64 g (quantitative) of intermediate 550.

Example A84.

Getting intermediate 553

and intermediate 554

Methanesulfonyl chloride (377 μL; 4.87 mmol) was added dropwise to a solution of intermediate 8 (1.5

- 207 037358 g; 2.44 mmol) and Et ₃ N (848 μl; 6.09 mmol) in DCM (24 ml) at 5 ° С in a stream of N ₂ . The reaction mixture was stirred at 5 ° C for 1 hour and then for 2 hours at room temperature. The reaction mixture was poured into ice water and DCM was added. The organic layer was filtered through CHROMABOND® and the solvent evaporated (30 ° C) to give 1.86 g of intermediate 553 and intermediate 554 as orange foam. The crude product was used without further purification in the next reaction step.

Getting intermediate 555

and intermediate 556

In a sealed test tube, a mixture of intermediate 553 and intermediate 554 (269 mg; 0.39 mmol), pyrrolidine (0.32 ml; 3.88 mmol) in ACN (2 ml) was heated at 140 ° С using a single-mode microwave system (Anton Parr®) with an output power of range 0-400 W for 1 h. The mixture was poured into water and EtOAc. The organic layer was washed with water, brine, dried over MgSO ₄ , filtered and evaporated to dryness. The residue (160 mg, yellow oil) was purified by silica gel chromatography (irregularly shaped silica gel, 40 g, mobile phase: 0.4% NH4OH, 96% DCM, 4% MeOH). The fractions containing the product were collected and the solvent was evaporated to give 59 mg of intermediate 555 (23%) and 39 mg of a mixture of intermediate 555 and intermediate 556. The two fractions were combined for the next reaction step.

Getting intermediate 560

and intermediate 561

In a sealed tube, a mixture of intermediate 553 and intermediate 554 (850 mg; 1.23 mmol), 3.3 difluoroazetidine hydrochloride (476 mg; 3.68 mmol) and DIPEA (844 μL; 4.9 mmol) in ACN (10 ml) was heated at 140 ° С using single-mode microwave system (Anton Parr) with an output power in the range of 0-400 W for 1 h of fixed holding time. The mixture was poured into water and EtOAc. The organic layer was washed with brine, dried over MgSO ₄ , filtered and evaporated to dryness. The residue (1.05 g; orange oil) was purified by silica gel chromatography (irregularly shaped silica gel 40 g; mobile phase: 99% DCM, 1% MeOH). The product fractions were collected and the solvent was evaporated to give 555 mg of a mixture of intermediate 560 and intermediate 561.

Getting intermediate 562

- 208 037358 and intermediate 563

Intermediate 562 and intermediate 563 were prepared according to a similar procedure described for the synthesis of a mixture of intermediate 560 and intermediate 561, using a mixture of intermediate 553 and intermediate 554, and 3-fluorozetidine hydrochloride as starting materials (289 mg; mixture of intermediate 562 and intermediate 563 as a yellow oil).

Getting intermediate 557

and intermediate 558

Intermediate 557 and intermediate 558 were prepared following a similar procedure as described for the synthesis of a mixture of intermediate 555 and intermediate 556 using a mixture of intermediate 553 and intermediate 554 and 2-methoxyethylamine as starting materials (485 mg).

Getting intermediate 559

and intermediate 559bis

Intermediate 559 (145 mg; 10%) and intermediate 559bis (168 mg; 10%) were prepared according to a similar procedure described for the synthesis of a mixture of intermediate 555 and intermediate 556, using a mixture of intermediate 553 and intermediate 554, and cyclopropylamine as starting materials. substances. The time for the three reactions was reduced to 5 minutes due to overpressure.

Example A85.

Getting intermediate 564

Borane-dimethyl sulfide complex (9.9 ml; 19.87 mmol) was added dropwise to a solution of 4methyl-2-nitrobenzoic acid (3 g; 16.56 mmol) in THF (18 ml) and the mixture was stirred at 80 ° С overnight. The mixture was cooled to room temperature and a 3 M aqueous HCl solution was added dropwise to the reaction system until bubbling ceased. The mixture was extracted with EtOAc. The organic layer was washed with saturated aqueous Na ₂ CO ₃ and brine, dried over MgSO ₄ , filtered, and the solvent was removed under reduced pressure to give 2.46 g (89%) of intermediate 24.

Getting intermediate 565

Phosphorus tribromide was added to a solution of intermediate 564 (2.46 g; 14.70 mmol) in diethyl ether (150 ml). The reaction mixture was stirred at room temperature overnight. Then, a saturated aqueous solution of NaHCO _{3 was} added dropwise to the reaction mixture until a neutral pH value was reached. The mixture was extracted with diethyl ether and the organic layer was washed with brine. The resulting organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo to give 2.39 g (71%) of intermediate 656.

Getting intermediate 567

A mixture of intermediate 566 (1.17 g; 5.09 mmol), 4-hydroxypiperidine (1.03 g; 10.17 mmol) and Et ₃ N (2.13 ml; 15.26 mmol) in ACN (25 ml) was stirred under reflux for 1 h, and then stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was removed under reduced pressure to give 1 g (78%) of intermediate 567, which was used in the next reaction step without further purification.

Getting intermediate 570

Tetrahydro-1,4-oxazine (574 μl; 6.52 mmol) was added to intermediate 565 (500 mg; 2.17 mmol) in ACN (10 ml) and the solution was heated at 80 ° С for 1 h.The mixture was diluted with EtOAc and washed with aqueous solution NaHCO3 and brine. The organic layer was dried over MgSO4, filtered, and removed under reduced pressure to give 500 mg (97%) of intermediate 570.

Example A86.

Getting intermediate 578

A mixture of 3-nitro-p-tolunitrile (1.2 g; 7.40 mmol), N-bromosuccinimide (2.6 g; 14.80 mmol) and benzoyl peroxide (182 mg; 0.75 mmol) in acetic acid (15 ml) was heated in a sealed tube at 140 ° C using a single-mode microwave system (Biotage Initiator EXP 60®) with an output power in the range of 0-400 W for 40 min. The mixture was poured into ice water and solid K2CO3 and EtOAc were added. The mixture was extracted with EtOAc (3x). The organic layer was dried over MgSO ₄ , filtered and the solvent was evaporated. The residue was taken up in toluene and the solvent was evaporated to give 1.47 g of a mixture of intermediate 578 and 3-nitro-p-tolunitrile as a brown oil, which was used in the next reaction step without any further purification.

Getting intermediate 579

Et ₃ N (1.71 ml; 12.20 mmol) was added to a solution of a mixture of intermediate 578 and 3-nitro-p-tolunitrile (1.47 g; 6.10 mmol) and morpholine (0.8 ml; 9.15 mmol) in DCM (20 ml). The reaction mixture was stirred at room temperature overnight. Added water and DCM. The mixture was extracted with DCM (3X). The organic layer was dried over MgSO ₄ , filtered and the solvent was evaporated to dryness. The residue (3.07 g) was taken up in DCM and the mixture was filtered off. The filter cake was washed (twice) with DCM and the filtrate was evaporated to dryness. The residue (1.33 g; brown oil) was purified by chromatography on silica gel (SiO ₂ ; 40 g, eluent: 90% heptane, 10% EtOAc to 80% heptane, 20% EtOAc).

The product fractions were collected and the solvent was evaporated to give 226 mg (15%) of intermediate 579 as a yellow oil.

Getting intermediate 582

Cyclopropylamine (367 μl; 5.29 mmol) was added to a mixture of intermediate 578 (500 mg; 1.76 mmol) in ACN (6 ml). The reaction mixture was stirred at room temperature for 1 hour. The crude product was diluted with EtOAc and washed with NaHCO ₃ and brine. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure to give a crude product which was purified by flash chromatography eluting with DCM-MeOH to give 350 mg (91%) of intermediate 582.

Getting intermediate 586

Intermediate 578 (400 mg; 1.66 mmol) was added to a mixture of N-methylpiperazine (502 μl; 3.32 mmol) and Et ₃ N (694 μl; 4.98 mmol) in ACN (5 ml). The reaction mixture was stirred at room temperature overnight. The solvent was removed and the crude product was dissolved in EtOAc and quenched with water. The organic layer was dried, filtered and concentrated. The crude product was purified by flash chromatography using heptane and DCM. The pure fractions were collected and the solvent was evaporated to give 250 mg (58%) of intermediate 586.

The compounds in the table below were prepared in a similar manner to that used for the preparation, starting from the appropriate starting materials.

Intermediate number Structure Weight (mg) Output (%) Intermediate 590 CN 0 ₂ νΑ0 \ Y - F '^ Υρ from intermediate 578 and 3,3 difluoroazetidine hydrochloride 320 61 Intermediate 594 CN 0 ₂ νΑ0 ^ YF from intermediate 578 and 3fluoroazetidine hydrochloride 125 (92% purity according to LCMS) 64

Example A87.

Getting intermediate 598

In a sealed tube, a mixture of 4-ethenyl-3-nitrobenzonitrile (353 mg; 2.03 mmol), 3fluoroazetidine hydrochloride (678 mg; 6.08 mmol) and Et ₃ N (1.1 ml; 8.11 mmol) in MeOH (9 ml) was heated under reflux for 1 hour. The reaction mixture was poured into water and was extracted with DCM. The organic layer was decanted, dried over MgSO4, filtered and evaporated to dryness. The residue (519 mg) was purified by silica gel chromatography (SiOH, irregular grains, 24 g; mobile phase: gradient from 0.2% NH4OH, 2% MeOH, 98% DCM to 0.5% NH4OH, 5% MeOH, 95% DCM). The fractions containing the product were collected and evaporated to give 431 mg (85%) of intermediate 598.

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Example A88.

Getting intermediate 602

Into a round bottom flask containing intermediate 601 (440 mg; 1.20 mmol) and 1,4-dioxane (7 ml) was added 4 M HCl solution in dioxane (7.5 ml; 30.11 mmol), and the reaction mixture was stirred at room temperature overnight ... The crude product was concentrated and quenched with saturated NaHCO ₃ solution and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give 300 mg of intermediate 602 (94%).

The compound in the table below was prepared in a similar manner to that used to prepare intermediate 602, starting from the appropriate starting materials.

Intermediate number Structure Weight (mg) Output (%) Intermediate 608 CN trans] NH from intermediate 607 130 90

Getting intermediate 603.

To a solution of intermediate 602 (300 mg; 1.13 mmol) in MeOH (ml), formaldehyde (184 μL; 2.26 mmol) was added, followed by formic acid (427 μL; 0.01 mmol). The reaction mixture was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (300 mg; 1.41 mmol) was then added and stirring continued for 1 h. The reaction mixture was then carefully quenched by the addition of saturated NaHCO ₃ solution and extracted with EtOAc. The organic layer was evaporated to dryness and applied to a silica gel column (ethyl acetate 100%). The pure fractions were collected and the solvent was evaporated to give 250 mg (79%) of intermediate 603.

The compound in the table below was prepared in a similar manner to that used to prepare intermediate 603, starting from the appropriate starting materials.

Intermediate number Structure Weight (mg) Output (%) Intermediate 609 CN trance from intermediate 608 99 72

Example A89.

Getting intermediate 623

4-Methyl-2-nitrophenol (1 g; 6.53 mmol) was dissolved in ACN (50 ml) to give a clear, bright yellow solution. _{K 2} CO ₃ (4.5 g; 32.65 mmol) was added and the reaction mixture was stirred until the solution darkened to dark red. Added 1,2-dibromoethane (2.8 ml; 32.65 mmol) and the reaction mixture was heated under reflux at 80 ° C overnight. The reaction mixture was filtered and the filtrate was evaporated. The crude product (yellow oil) was purified on a silica gel column eluting with 5% EtOAc / heptane to give 1.37 g (80%) of intermediate 623.

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Getting intermediate 624

Intermediate 624 was prepared following a similar protocol that was used to prepare intermediate 570, starting with intermediate 623 and cyclopropylamine (600 mg; 48%).

Getting intermediate 625

To a solution of intermediate 624 (550 mg; 2.33 mmol) in DCM (10 mL) at 0 ° C was added Boc ₂ O (559 mg; 2.56 mmol). The mixture was stirred at room temperature for 2 hours. The crude product was diluted with DCM and washed with water, dried over MgSO ₄ and the solvent was removed under reduced pressure to give a crude product which was purified by flash chromatography eluting with DCM-MeOH. The product fractions were collected and the solvent was evaporated to give 704 mg (90%) of intermediate 625.

Example A90.

Obtaining intermediate 628 ^X C Br Aj no ₂

In a round-bottom flask containing MeOH (600 ml), 2-bromo-5-nitrobenzene carbaldehyde (29.17 g, 0.127 mol), trimethyl orthoformate (21 ml, 0.192 mol), and p-toluenesulfonic acid monohydrate (2.4 g, 12.6 mmol) were mixed. Then the reaction mixture was heated under reflux for 8 hours. The reaction mixture was cooled and the solvent was removed. The residue was taken up with water, K ₂ CO ₃ and DCM. The organic layer was separated, dried over MgSO4, filtered and evaporated to dryness to give 34 g (97%) of intermediate 628.

Getting intermediate 629

LA ^x o M νο ₂

A mixture of intermediate 628 (15 g; 54.33 mmol), 1,2,3,6tetrahydropyran-4-boronic acid pinacol ester (13.8 g; 65.7 mmol), potassium phosphate (34.8 g; 0.164 mol), PdCl ₂ dppf DCM ( 4.5 g; 5.5 mmol) in dioxane (210 ml) and water (60 ml) was degassed with N2 in a sealed tube and heated at 80 ° С for 16 h. The mixture was poured into a mixture of water and K ₂ CO ₃ and extracted with EtOAc. The organic layer was dried over MgSO ₄ , filtered and evaporated to dryness. The residue (25.5 g) was purified by chromatography on silica gel (330 g, SiOH, 35-40 μm, gradient from 90% heptane, 10% EtOAc to 60% heptane, 40% EtOAc). Fractions were collected and evaporated to dryness to obtain 12.21 g (80%) of intermediate 629.

Getting intermediate 630

HCl (3 M in water; 58.28 ml; 0.175 mol) was added to a solution of intermediate 630 (12.21 g; 43.72 mmol) in 1,4-dioxane (233 ml) at room temperature. The mixture was stirred for 2 hours. Water was added followed by EtOAc. The organic layer was separated, dried over MgSO ₄ , filtered and evaporated to dryness to obtain 8.97 g (88%) of intermediate 630.

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Getting intermediate 631

A solution of intermediate 630 (8.97 g; 38.5 mmol), dimethylamine (9.7 ml; 76.6 mmol) in ACN (240 ml) was stirred for 30 min. Then sodium triacetoxyborohydride (16.3 g; 76.9 mmol) was added and stirred at room temperature for 15 h. Water was added and the reaction mixture was basified with K ₂ CO ₃ and extracted with EtOAc. The organic layer was dried over MgSO ₄ , filtered and evaporated to dryness. The residue (8.24 g) was purified by chromatography on silica gel (stationary phase: SiOH, irregular grains, 15-40 μm 120 g, mobile phase: gradient from DCM 100% to DCM 95%, MeOH 5%, 0.1% NH4OH). The desired fractions were collected and the solvent was evaporated to dryness to obtain 2.15 g of intermediate 631 and 4.22 g of an impurity fraction, which was purified by chromatography on silica gel (stationary phase: SiOH, irregular grains, 1540 μm 80 g, mobile phase: gradient from DCM 100% to DCM 95%, MeOH 5%, 0.1% NH4OH). The desired fractions were collected and the solvent was evaporated to dryness to obtain an additional 2.65 g of intermediate 631. overall yield: 47%.

Getting intermediate 632

A mixture of intermediate 632 (2.15 g; 8.2 mmol), Pd / C 10% (0.43 g) in MeOH (50 ml) was hydrogenated at a H ₂ pressure of 3 bar at room temperature for 15 h. The mixture was filtered through a celite pad, and the filtrate was evaporated to dryness to obtain 1.76 g (92%) of intermediate 632.

Example A91.

Getting intermediate 635

In a hermetically sealed glass vessel, a mixture of 1-bromo-2-nitrobenzene (800 mg; 3.96 mmol), NBoc-2,3-dihydro-1H-pyrrole (938 mg; 5.54 mmol) and potassium carbonate (1.6 g; 11.88 mmol) in dry DMF (30 ml) was purged with nitrogen (10 min). Then triphenylphosphine (207 mg; 0.792 mmol) and Pd (OAc) ₂ (89 mg; 0.396 mmol) were added. The reaction mixture was heated to 100 ° C overnight, cooled to room temperature, poured into water and extracted with EtOAc. The mixture was filtered through a pad of celite and the organic layer was decanted, washed with brine, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by silica gel chromatography (SiOH, irregular grains, 40 g; mobile phase: gradient from 20% EtOAc, 80% heptane to 40% EtOAc, 60% heptane). The fractions containing the product were collected and evaporated to dryness to give 482 mg (42%) of intermediate 635.

Getting intermediate 636

A mixture of intermediate 635 (482 mg; 1.66 mmol) and Adams catalyst (platinum (IV) oxide) (75 mg; 0.332 mmol) in EtOH (40 ml) was hydrogenated at a H2 pressure _of 2 bar. The catalyst was removed by filtration through celite and the filtrate was evaporated to dryness to give 437 mg of intermediate 636.

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Example A92.

Getting intermediate 638

and intermediate 639

Intermediates 638 and 639 were prepared by chiral supercritical liquid chromatography (SFC) separation performed on intermediate 637 (CHIRALPAK AD-H, 5 μm, 250x20 mm; mobile phase: 80% CO ₂ , 20% iPrOH). Pure fractions were collected and evaporated to dryness to give 169 mg of intermediate 638 and 177 mg of intermediate 639.

Example A93.

Getting intermediate 640

Sodium triacetoxyborohydride (133 mg; 0.63 mmol) was added to a mixture of intermediate 559bis (164 mg; 0.25 mmol), formaldehyde (375 μL; 5.01 mmol), acetic acid (28.7 μL; 0.50 mmol) in MeOH (2 mL) at room temperature. The reaction mixture was stirred at room temperature under N2 overnight. The mixture was podslushivaet saturated aqueous NaHCO ₃ solution and the solvent was evaporated. The mixture was diluted with EtOAc and washed with saturated aqueous NaHCO ₃ solution. The aqueous layer was extracted with EtOAc (2x). The organic layers were combined and washed with water, brine, dried over MgSO ₄ , filtered and the solvent was evaporated.

The residue (209 mg) was purified by silica gel chromatography (SiO ₂ , 4 g; eluent: 99% DCM, 1% MeOH, 0.1% NH4OH to 99% DCM, 1% MeOH, 0.1% NH4OH). The product fractions were collected and the solvent was evaporated to give 106 mg (63%) of intermediate 640 as a yellow oil.

Example A94.

Getting intermediate 642

Ethanesulfonyl chloride (1.28 ml; 13.5 mmol) was added to a solution of tert-butyl- (3 (methylamino) phenyl) carbamate (2 g, 9 mmol), triethylamine (3.79 ml, 26.99 mmol) in ACN (100 ml) at room temperature. The solution was stirred at room temperature for 4 hours. Water was added and the reaction mixture was extracted with DCM. The organic layer was separated and dried over MgSO ₄ , filtered and the solvent was evaporated.

The residue (3.2 g) was purified by chromatography on silica gel (SiOH with irregular grains, 40 μm, 80 g, mobile phase: gradient from 90%: DCM, 10% heptane to 97% DCM, 3% MeOH, 0.3% NH4OH. Fractions were combined , and the solvent was evaporated to obtain 2.55 g of an impurity fraction, which was purified by chromatography on silica gel (SiOH, irregular grains, 40 μm, 80 g, mobile phase: gradient from 70%: DCM, 30% heptane to 97% DCM, 3 % MeOH, 0.3% NH4OH The fractions were pooled and the solvent evaporated to give 1.24 g (39%, 88% purity by LC / MS) intermediate 642 (39% purity at 88%).

- 215 037358

Getting intermediate 643

A solution of intermediate 642 (1.24 g, 3.47 mmol) in TFA (2.66 ml, 34.71 mmol) and DCM (22.1 ml) was stirred at room temperature for 12 hours. The solvent was evaporated. The residue was purified by silica gel chromatography (SiOH, irregular grains, 15-40 μm, 40 g, mobile phase: DCM: 100% to DCM: 97%, MeOH: 3%, NH4OH: 0.3%) to give 1.17 g of intermediate 643.

B. Preparation of Final Compounds.

Example B1.

Getting connection 1

A mixture of intermediate 8R (36.00 g, 71.08 mmol) and TBAF (1 M in THF, 142.15 mL, 142.15 mmol) in MeTHF (0.7 L) was stirred at room temperature for 3 h 30 min. The reaction mixture was poured into a 10% aqueous K ₂ CO ₃ solution (700 ml), diluted with EtOAc (700 ml). Then 100 ml of saturated NaCl solution was added (to aid decantation). The organic layer was decanted, washed again with 300 ml of 10% aqueous K ₂ CO ₃ solution (+ 100 ml saturated NaCl solution), then with saturated NaCl solution (200 ml). The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was taken 3 times with 300 ml of EtOH and evaporated to dryness. The residue was taken up in CH3CN and stirred at 50 ° C. Then the precipitate was filtered and dried (50 ° C under vacuum for 5 h) to obtain 27 g of compound 1 (yield 96%). Then, different batches of Compound 1 obtained from different reactions (batch 1: 36.8 g, batch 2: 27 g, batch 3: 5.7 g, batch 4: 7.45 g and batch 5: 6.7 g) were mixed together in CH ₃ N ( 250 ml) and the suspension was stirred for 15 minutes. The precipitate was filtered and dried at 50 ° C overnight to obtain 81.1 g of compound 1 (yield 97.1%). Mp: 222 ° C (DSC).

Getting compound 4

A solution of intermediate 19 (403.00 mg, 0.74 mmol) in Me-THF (8.9 ml) was treated with TBAF (1 M in THF) (0.82 ml, 0.82 mmol) and stirred at room temperature for 17 h. Celite® and the crude product mixture were added evaporated in vacuo to obtain a dry residue, which was purified by column chromatography on silica gel (SiOH, irregular grains 15-40 μm, 40 g, mobile phase: DCM / (MeOH containing 5% aq. NH ₃ ), gradient from 98: 2 to 85:15). The fractions containing the product were combined and evaporated to dryness to give a solid. This solid was recrystallized from EtOH. After cooling to room temperature, the mixture was filtered through a glass frit. The solid was washed with Et ₂ O, collected and dried in vacuo to give 191 mg of Compound 4 (60% yield over 2 steps, pale yellow solid). M.p. = 193 ° C (DSC).

Getting connection 68

A mixture of intermediate 237 (132.00 mg, 0.20 mmol) and TBAF (1 M in THF) (0.30 ml, 1 M, 0.30 mmol) in Me-THF (1.60 ml) was stirred at room temperature for 24 h. The mixture was poured into water and the organic layer was extracted with EtOAc, dried over MgSO ₄ , filtered and evaporated to dryness (batch 1, 52 mg). The aqueous phase was again extracted with DCM and MeOH. The organic layer was dried over MgSO ₄ , filtered and evaporated to dryness (batch 2, 770 mg). Insoluble in aqueous

- 216 037358 layer, the product was filtered through celite. Celite was washed with excess DCM and MeOH. This organic layer was dried over MgSO4, filtered and evaporated to dryness (batch 3, 300 mg). The batches were pooled and purified by silica gel column chromatography (SiOH, irregular grains, solid, mobile phase: DCM / MeOH, gradient 100: 0 to 90:10). The pure fractions were collected and the solvent was evaporated. The residue (84 mg) was taken with EtOH, triturated, filtered and dried to give 31 mg of compound 68 (28% yield).

Compounds in the table. 1 below was prepared in a similar manner to that described for the preparation of compound 1, starting from the appropriate starting materials. The most significant minor deviations from the reference method are indicated as additional information in the column Weight, mg).

Connection Number Structure Weight (mg) Output (%) Compound 2 n on a Gu ₀ CL XT '' ⁰ G from a mixture of intermediate 13 and intermediate 14 310 Foam is pale yellow color Procedure with 1 eq. TBAF 55 Compound 3 n on GS ₀ Λ from a mixture of intermediate 13 and intermediate 14 52 Yellow, light fine crystalline solid substance Procedure with 1 eq. TBAF nine

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Compound 5 n he N— \ Ν '/ \ 9 Ύ' ¹ g O 1 from intermediate 20 79 Procedure with 1 eq. TBAF 39 Compound 6 n he Ν '1 TA _x1 γ ^ ^ P = O ά A “λ from intermediate 21 173 Procedure with 1 eq. TBAF 65 Compound 10 n Ν --- \ Ν '/ \ __ AAD ^{he n} Y from intermediate 42 37 White powder eight Compound 11 D a. XL ^gA '0n ΎΎ ^Λ Ν Fif' from intermediate 46 228 Almost white solid colors Procedure with 1 eq. TBAF 87

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Compound 12 n N — l Ι \ __ Huul he Pp X. from intermediate 49 120 Powder yellow color 41 Compound 13 n N -— \ GY 1 \ __ aDyl, he T I ⁿ oP 1 from intermediate 52 319 White powder 47 Compound 14 n N --- < 1 \ -Ά xA / l ° n from from intermediate 55 538 Powder yellow color 51 Compound 16 Ν χρ from intermediate 60 426 Powder yellow color 53

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Compound 26 n ^<5 a _x UagA on SHHK A / A n An from intermediate 104 121 Yellow solid Procedure with 1 eq. TBAF 60 Compound 27 n N— \ HA / \ __ 'aWA ^he aA CI άΑ from intermediate 107 276 White solid Procedure with 1 eq. TBAF 97 Compound 32 n Ν --- 1 HA / \ __ OH YY ^RS N Cl from intermediate 119 68 White solid Procedure with 1 eq. TBAF 35 Compound 33 n GA 1 U— \ a2 \ / \ he It il ^RS ηΑ ci Сlх5 0 from intermediate 121 49 Yellow solid Procedure with 1 eq. TBAF 35

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Compound 37 n N --- t 1 \ __ c- Гг JL to ^F ΛΑ Ί J. λ JU TJ ^ N ^x A ^ H from intermediate 136 44 Procedure with 1 eq. TBAF 59 Compound 38 Η Ν - \ \ __ 'Aalh he Ίτ ΙΪ ^rs OU? ^χ οη from intermediate 140 102 Procedure with 1 eq. TBAF 65 Compound 47 Η Ν --- \ Ν-. / V ^x ld U \ / \ ^RS UJ but T if AgAn A from intermediate 170 70 Procedure with 1 eq. TBAF 61 Compound 48 n Ν --- \ ^Ν Λ / V ^x A / s> Z \ UJ but Mn T ίϊ laan uJl A / Pdi from intermediate 173 62 Procedure with 1 eq. TBAF 59

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Compound 49 n N --- to I \ __ he ιί ^RS y F from intermediate 174 69 Procedure with 1 eq. TBAF 42 Compound 50 n n -— \ hc / \ _. U / ud ^it kJ ^F X ^F o. w α n cis CIS from intermediate 180 94 Procedure with 1 eq. TBAF 49 Compound 51 n N --- \ GK 1 \ __ ^he X / α A from intermediate 182 47 Procedure with 1 eq. TBAF 80 Compound 52 n Ν - \ Ν '/ \ __ \ he \ II ^RS Yy Cl UL Δ V from intermediate 184 209 Procedure with 1 eq. TBAF 78

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Compound 53 n N --- \ \ __ dadHa he aDl from intermediate 188 63 Procedure with 1 eq. TBAF 37 Compound 54 n N --- <1 \ __ Άζ4 / \ he T ιϊ ^RS YES CI HELL 0 from intermediate 191 81 Procedure with 1 eq. TBAF 40 Compound 55 n N --- y is he YES α χο ABOUT from intermediate 194 103 Procedure with 1 eq. TBAF 49 Compound 56 n Ν --- i ^ хуДДу he YES _S | όυό chm Ahmad 1 from intermediate 195 68 Procedure with 1 eq. TBAF 31

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Compound 58 n N - <1 \ __ ^he Yes _S | DD dArdCH from intermediate 199 121 Procedure with 1 eq. TBAF 54 Compound 59 n Ν — λ Ν-. 1 \ __ he Yes _C | Do _o from intermediate 204 115 Procedure from 1.3 eq. TBAF 84 Compound 61 Ν --- \ DCHDON Yes DD Okhd AA yA n 1 from intermediate 211 164 Almost white solid Procedure with 1.5 eq. TBAF 97 Compound 62 n Ν - \ \ __ d od from intermediate 213 175 Yellow solid Procedure with 1.6 equiv. TBAF 92

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Compound 63 n N --- \ ΎΎ ^λ _{yL C} | Sl Tlx n n from intermediate 219 70 Procedure from 1.5 eq. TBAF 49 Compound 64 n Ν --- \ 1 \ __ ζ A '™ ABOUT V A Al SlHG n 1 O from intermediate 223 105 White solid Procedure with 1.8 equiv. TBAF 40 Compound 67 Η NY / \ e - X уЛХон ο V Α. Λ. xXY ^ Ν ^χ Ν ^χ η 1 γγ from intermediate 233 184 White solid Procedure with 1.8 equiv. TBAF 65 Compound 147 | ^Η n 1 / —Ν X ^r 1 X TT Ua ^ Ν ^χ ΝΗ χΤ from intermediate 392 310 White amorphous solid Procedure with 4 eq. TBAF and THF as solvent 98

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Compound 148 n N --- \ r ^Ν γ / he χχ D./OH ^D ^ [OOO Y> ^ H from intermediate 394 1987 81 Compound 149 Η R I V__. from intermediate 398 45 Procedure with 12 equiv of TBAF and THF as solvent 25 Compound 150 Η Ν -— \ R Ν '1 \% θ ^Η XX \ / ^οη ά A from intermediate 404 108 Procedure with 12 equiv of TBAF and THF as solvent 80 Compound 151 Η Ν '1 Χ \ ОН kJ Υ ^0Η 0k JU from intermediate 407 24 Procedure with 12 equiv of TBAF and THF as solvent 32

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Compound 152 n N --- \ 111 ^rX a / / ^he Cl DN N from intermediate 411 234 Procedure with 1 1 equiv TBAF 49 Compound 153 n N --- \ || J ^R N ucj ACT А _О Н from intermediate 412 74 51 Compound 154 n N --- \ ^ν α 1 V \ ^ A ^ / A / r \ on G II A / G ⁿ Od A _Ογ from intermediate 419 45 Procedure with 12 equiv of TBAF and THF as solvent 26 Compound 157 n N— \ R ^X he | |] n D / ° A / ^N A D D Γ1λΑ A / n | from intermediate 431 371 86

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Compound 158 he XT XAA A X ____ ^ N ^X NH Ax ^ _N - ^ \ o Ay from intermediate 433 fourteen Procedure with 1 1 eq TBAF 27 Compound 159 NH ^ _R T ^ A. ^ OV ay. ^ O from intermediate 435 75 Procedure with 1 1 eq TBAF fifty Compound 160 he NH- \ _D / x / AA χΎ Πί ΊΑ ι А TE ΑζΑ ж ТГ NH Α from intermediate 437 205 Procedure with 1 1 equiv TBAF 73 Compound 161 nh ^ _r / ° ^H χΥ Ca JCAO HT NH A ^ AG A ^ 0 from intermediate 439 236 Procedure with 1 1 equiv TBAF 66

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Compound 162 it ^ΝΗ λ D / h / A Til ⁴ i ° γ ^{ΝΗ Сl} JU from intermediate 440 302 63 Compound 163 chucAST Γιΐ ⁴ d Y “γ ^ΝΗ ά JU from intermediate 442 148 fifty Compound 165 nh- \ _r Г ° γ ^Ν ' ^Η Ca JU F from intermediate 444 233 69 Compound 166 n he Τ '11 n R or S U U 0. N. Ay γ Ky Ok JlX h | from intermediate 448 100 68

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Compound 167 n he GA 1 III Н S or R y γ A / - Y Y AA γ n 1 from intermediate 449 103 72 Compound 168 n he Ν --- \ / / A 'ril ⁴ n> 0 ° γζ% Z ^N R or s from intermediate 453 72 71 Compound 169 n he Ν --- \ / YY ⁴ Π ГД ° \ г ΑΖ Αχ S or R ΥλΤ ^χ ν ^ζ γ Η from intermediate 454 215 84 Compound 170 n he j \ r / || Υ Ν τ ΐ TaJU TG Αχ Η 41 Procedure from 1.1 eq. TBAF 56

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Compound 173 n he N — d / GA 1 \ R / 710 ν О ..... and ..... from intermediate 468 143 Procedure with 1 1 eq TBAF 44 Compound 174 n on ha / \ ^R U XrSw ⁿ гГ Χν from intermediate 471 90 Procedure with 1 1 eq TBAF 42 Compound 175 n he Ν --- \ / w from intermediate 474 51 Procedure with 1 1 equiv TBAF 46 Compound 177 W / ^0H _N 2 ui ⁿ I Y / G from intermediate 479 180 Procedure with 1 1 eq TBAF 61

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Compound 186 n he N - \ / ¹ Μ ΟγΝΗ DO from intermediate 491 87 74 Compound 187 n he ^Ν --- \ o / 1 Xd from intermediate 496 89 66 Compound 188 n on -d GD ⁷ W from intermediate 502 177 39 Compound 189 n he DDD Ϋ сч όυό from intermediate 503 29 41

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Compound 190 n he Ν — Л R / Units from intermediate 504 300 85 Compound 191 n he um kuu O '(j not. from intermediate 506 152 Procedure with 1 equiv of TBAF and THF as solvent 68 Compound 192 n he ^N - \ R / 1 \ 5-J 1 kko Sec n from intermediate 509 25 Procedure with 1 equiv of TBAF and THF as solvent 37 Compound 193 n on to Ay CN CI "A ^x lg R n from intermediate 511 52 28

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Compound 194 n he ^N - \ p / / VL- 'ut YjA ^CN 1 Jy rY' ⁵ from intermediate 514 163 33 Compound 195 n he ^N —K p / ^Ν κ 1 \ 2-7 Ut Fp CN tdUt Α Υ ', ΥνΑ / Ά from intermediate 516 62 76 Compound 196 Η he ^Ν - \ r I ^Ν κ / \ S-7 yr KjA CN ULjA Y Υν-Ύν ^ ΥΥκ / from intermediate 517 45 52 Compound 197 n he t 1 CIS G ^ O TLHLL H from intermediate 518 51 43

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Compound 198 n he ^N -Vp I / \ 2 - / X 1 CIS YES i ^ Tl T ^ ⁰ Ts111A h A 1 DD from intermediate 520 127 71 Compound 199 n on ^Ν --- P / / \ 2-7 Ac A% A from intermediate 521 65 28 Compound 208 n he ⁿ Ar / ν. A - '/ ° ⁿ O1 A ^ XyxDx 0 ^^ from intermediate 528 168 Procedure with 5 eq. TBAF 86 Compound 209 n he N— \ r / / ML XX γχ CN AA 'ο _χ ^ from intermediate 531 267 63

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Compound 210 n on ^N A> / XI XT ^{2 HCI} Ul jO from intermediate 538 57 Procedure with 3 equiv of TBAF and THF as solvent 38 Compound 213 n he ^Ν - \ r / N ^ \ R / CN Ν ^ _Ν from intermediate 545 170 Procedure with 4 equiv of TBAF and THF as solvent 45 Compound 214 n he γ rx 111 I CA ° <γ ^ΝΗ H j0 from intermediate 548 150 Treatment with THF as a solvent 51 Compound 215 n he N— \ 11Г AA _x ° ⁿ OL j0 from intermediate 552 129 Almost white solid substance 48

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Compound 216 he is N— <ν. 1 Us tu u (l JU from intermediate 556 34 Foam yellow colors 85 Compound 217 n he N ^{--- \ Ν} γ / ιΓί ^ ⁿ / kum from intermediate 558 236 White solid substance 76 Compound 218 he is Ν — Ά Ν. 1 ιΓίυ ^н q / X From intermediate 559 25 Yellow solid 22 Compound 219 n he ν p Hu from intermediate 561 262 Pale yellow solid 78 Compound 220 n he N— \ / \ A t from intermediate 563 38 Almost white solid 44

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Compound 223 n he NA at CN Q L from intermediate 577 243 Pale yellow solid Procedure with 3 equiv. TBAF 82 Compound 224 n on Ν — ν 1 \ K 1 Ι0Υ A / CN CX ό X / ⁰ from intermediate 581 129 Orange solid 74 Compound 229 he Ν — ν one 100 Ay CN όχό Ν Ϋ F from intermediate 600 270 67 Compound 233 n he g g 'T-d Trans B (SS or RR) from intermediate 619 123 78

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Obtaining compound 155 n

A solution of intermediate 423 (10.66 g, 19 mmol) in Me-THF (210 ml) was treated with TBAF (1 M in THF) (38 ml, 38 mmol) and stirred at room temperature for 3 h. The reaction mixture was poured into 10% aqueous K ₂ CO ₃ solution and concentrated. DCM / MeOH (9/1) was added and the mixture was washed with 10% aqueous K ₂ CO ₃ (3 x 400 ml), water (2 x 200 ml) and brine (2 x 400 ml). The organic layer was dried over MgSO ₄ , filtered and the solvent was evaporated. The residue was dissolved under reflux in CH3CN (800 ml + 200 ml). The solution was left to cool to room temperature overnight. The precipitate was then filtered and dried to give 6.37 g of compound 155 (75%) as an off-white solid. Mp: 218 ° C (DSC).

Obtaining compound 156 n

TBAF (1 M in THF) (1.5 ml; 1.5 mmol) was added dropwise to a solution of intermediate 430 (451 mg; 0.748 mmol) in Me-THF (15 ml) and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture poured into a 10% aqueous solution of K ₂ CO ₃ and extracted with EtOAc. The organic layer was washed with 10% aqueous K ₂ CO ₃ (2 x 30 ml), water (30 ml) and brine (30 ml), dried over MgSO ₄ , filtered and evaporated to dryness. The residue was crystallized from ACN. The precipitate was filtered, washed with Et ₂ O and dried to give 295 mg (81%) of compound 156. mp: 206 ° C (DSC).

Getting connection 232

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TBAF (1 M in THF; 0.65 ml; 0.65 mmol) was added dropwise to a solution of intermediate 618 (234 mg; 0.328 mmol) in Me-THF (10 ml) and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was poured in a 10% aqueous solution of K ₂ CO ₃ and extracted with EtOAc. The organic layer was washed with 10% aqueous K ₂ CO ₃ (2 x 30 ml), water (30 ml) and brine (30 ml), dried over MgSO ₄ , filtered and evaporated to dryness. The residue was crystallized from ACN and the precipitate was filtered, washed with Et ₂ O and dried to give 133 mg of the intermediate compound, which was suspended in MeOH at 50 ° C and stirred for 30 min. The precipitate was filtered and dried to give 77 mg (47%) of compound 232. mp: 167 ° C (DSC).

Getting compound 221

Tetrabutylammonium fluoride trihydrate (164.4 mg; 0.52 mmol) was added to a mixture of intermediate 569 (260 mg; 0.43 mmol) in Me-THF (2 ml) and stirred overnight. The reaction mixture was quenched by the addition of saturated aqueous NaHCO ₃ solution and extracted with DCM. The organic layer was dried, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel using heptane and ethyl acetate as eluent, starting with heptane and increasing the EtOAc fraction. The fractions containing the product were mixed and concentrated to give 170 mg (81%) of compound 221. So pl. = 181 ° C (MP50).

The compounds in the table below were prepared in a similar manner to that described for the preparation of compound 221, starting from the appropriate starting materials. The most significant minor deviations from the reference method are indicated as supplementary information in the Mass (mg) column.

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Connection Number Structure Weight (mg) Output (%) Compound 222 but he is N— <ν <. 1 ex te ⁿ A ^ A from intermediate 573 110 65 Compound 225 n he N— \ ⁿ A 1 \ г Αγ _CN (л Λ ^ NH A from intermediate 585 42 55 Compound 226 he Ν— \ ⁿ a L \ Χ ifjA _CN Ca χό Α ^ | te / te from intermediate 589 120 31 Compound 227 n he Ν— \ ^ν α / lAr cn (a / 0 '^^ F 140 72

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Example B2.

Alternative preparation of A compound 1

To a solution of intermediate 7R (231 g, 0.556 mol) in 1,4-dioxane (2.3 L), ptoluenesulfonic acid monohydrate (179 g, 0.95 mol) and 3-amino-4-methylbenzonitrile (110 g, 0.83 mol) were added, three times N2 and stirred at 95 ° C for 12 hours. Then the reaction mixture was cooled to 20 ° C and a solution of NaHCO _{3 was} added to neutralize the mixture. The formed precipitate was filtered and combined with another precipitate formed in the course of the reaction carried out with 179 g of the intermediate

7R. The resulting solid was dissolved in Me-THF (5 L), washed with water three times (3x5 L). Silanethiol resin [from Shanghai Meryer CO., LTD] (60 g) was added to the mixture and heated under reflux for 1.5 hours. The resulting mixture was then filtered through a pad of celite and concentrated in vacuo. The residue was suspended in EtOH (5 L) overnight, filtered and dissolved in THF (3 L). Methyl tert-butyl ether (6 L) was added to THF and the solid precipitated, filtered and dried to give 243 g of compound 1.

Alternative Method B of Preparation of Compound 1.

A solution of intermediate 6R (10.0 g) and p-toluenesulfonic acid (3.0 eq) in dioxane (100 ml) was subjected to azeotropic drying until the water content was <0.1% (determined by titration with potassium fluoride (KF) solution). Then 3-amino-4-methylbenzonitrile (1.3 eq.) Was added and the mixture was subjected to azeotropic drying until the water content was <0.3% (determined by titration with potassium fluoride (KF) solution) and the volume was approximately 50 ml. The mixture was then heated to 90 ° C for 24 h, monitoring the conversion by HPLC. After completion of the conversion, the mixture was cooled to room temperature and water (50 ml) was added. After stirring for 1 hour, the layers were separated. The organic layer was concentrated to approximately 50 ml and methyl tert-butyl ether (100 ml) was added over 2 h at 50 ° C. The mixture was cooled to 10 ° C for

- 242,037358 h and then filtered to obtain, after drying, 5 g (98% purity by HPLC) of compound 1.

Recrystallization of compound 1.

To a solution of compound 1 (270 g) in THF (1350 ml) at room temperature was slowly added methyl tert-butyl ether (2160 ml). The mixture was filtered and the product was dried under vacuum at 50 ° C to give 210 g (99.4% purity by HPLC) of Compound 1 as a yellow solid.

Alternative preparation of compound 148

Compound 148 was also prepared following a procedure similar to that for alternative preparation A of compound 1, starting with intermediate 7R and intermediate 393 (151 mg; 24%)

Alternative preparation of compound 152

Compound 152 was also prepared following a procedure similar to the procedure for alternative preparation A of compound 1, starting with intermediate 7R and intermediate 410.

Getting connection 200

A mixture of intermediate 7R (415 mg; 1 mmol), 3-amino-5-cyano-2-methylbenzoic acid methyl ester (285 mg; 1.5 mmol) and p-toluenesulfonic acid monohydrate (323 mg; 1.7 mmol) in 1,4-dioxane (5 ml) was heated at 95 ° C overnight.

The reaction mixture was poured into a 10% aqueous K ₂ CO ₃ solution and extracted with DCM / MeOH. The organic layer was decanted, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was taken up with ACN and the precipitate was filtered and dried to give 216 mg (47%) of compound 200. mp: 260 ° C (Kofler).

Example B3.

Getting compound 15

TBAF (1.5 mmol / g on silica gel) (1.60 g, 2.46 mmol) was added at room temperature to a solution of intermediate 57 (340.00 mg, 0.61 mmol) in Me-THF (15 mL) and the reaction mixture was stirred at room temperature for 18 h The reaction did not end. A solution of TBAF (1 M in THF) (1.00 ml, 1.00 mmol) was also added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc, filtered through paper and poured into 10% aqueous K ₂ CO ₃ solution. The organic layer was decanted, washed with water, then brine, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (SiOH with irregular grains, 40 g, mobile phase NH ₄ OH / MeOH / EtO Ac / heptane, 0.5% NH4OH, 10% MeOH, 50% EtOAc, 40% heptane). Pure fractions were collected and evaporated to dryness. The residue was taken up in Et ₂ O and the precipitate was filtered and dried to give 134 mg of compound 15 (50% yield). M.p. (resin) = 110 ° C (K).

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Getting connection 73

In a round bottom flask, intermediate 253 (221.00 mg, 0.38 mmol) was diluted in Me-THF (10.3 mL). Then the solution was cooled to 0 ° С and TBAF (1.5 mmol / g on silica gel, 1.52 ml, 2.29 mmol) was added. The reaction mixture was stirred for 3 h, allowing the temperature to come to room temperature and then partitioned between saturated NaHCO ₃ and DCM. The layers were separated. The aqueous layer was again extracted with DCM. The organic layers were mixed, dried over MgSO4, filtered and concentrated. The residue (225 mg) was purified by column chromatography on silica gel (SiOH, irregular grains, 40 g, mobile phase: NH4OH / DCM / MeOH, gradient from 0.2% NH4OH, 2% MeOH, 98% DCM to 1% NH4OH, 10% MeOH, 90% DCM). Pure fractions were collected and evaporated to dryness. The residue (79 mg, 44%) was crystallized from Et ₂ O. The precipitate was filtered and dried to give 54 mg of compound 73 (yield 30%). M.p. = 201 ° C (DSC).

Getting connection 74

TBAF (1.5 mmol / g on silica gel) (3.70 g, 5.57 mmol) was added to a solution of intermediate 256 (1.20 g, 1.39 mmol) in Me-THF (35 ml) and the reaction mixture was stirred at room temperature for 18 h. TBAF was added. (1 M in THF) (2.80 ml, 2.78 mmol) and the reaction mixture was stirred at room temperature for an additional 2 h. The reaction mixture was diluted with DCM, filtered through paper and poured into 10% aqueous K ₂ CO ₃ solution. The organic layer was decanted, washed with water, dried over MgSO4, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (SiOH with irregular grains, 40 g, mobile phase DCM / MeOH / NH4OH, gradient from 0.3% NH4OH, 3% MeOH, 97% DCM to 1% NH4OH, 10% MeOH, 90% DCM) ... The fractions containing the product were collected and evaporated to dryness, and the residue was purified a second time by column chromatography on silica gel (SiOH, irregular grains, 40 g, mobile phase DCM / MeOH / NH4OH with 0.5% NH4OH, 5% MeOH, 95% DCM). Pure fractions were collected and evaporated to dryness. The residue (520 mg, 54%) was crystallized from CH ₃ CN / Et ₂ O and the precipitate was filtered and dried to give 443 mg of compound 74 (yield 46%). M.p. = 124 ° C (K).

The compound in the table below was prepared in a similar manner, starting from the appropriate starting materials. The most significant minor deviations from the reference method are indicated as supplementary information in the Mass (mg) column.

Connection Number Structure Weight (mg) Output (%) Compound 71 n he N -— \ / ha / HA from intermediate 246 160 Procedure with 3 equiv. TBAF (1.5 mmol / g on silica gel 48

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Example B4.

Getting compound 7

TFA (1.50 ml, 19.60 mmol) was added dropwise to a solution of intermediate 30 (270.00 mg, 0.51 mmol) in DCM (stabilized with amylene, 10 ml) at 5 ° C and the reaction mixture was stirred for 1 h at this temperature. The reaction mixture was quenched with 10% aqueous K ₂ CO ₃ and extracted with DCM. The organic layer was decanted, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was crystallized from CH3CN and the precipitate was filtered and dried to give 165 mg of compound 7 (75% yield). Mp: 215 ° C (DSC).

Alternative preparation of compound 1 n he N— \ J food

TFA (3.93 ml, 51.35 mmol) was added at 5 ° C to a solution of intermediate 10R (1.16 g, 2.33 mmol) in DCM (25.4 ml). The reaction mixture was stirred for 30 minutes. The reaction mixture was diluted with DCM and poured into a 10% aqueous K ₂ CO ₃ solution, dried over MgSO ₄ , filtered and evaporated to dryness. The residue (1200 mg, yellow solid) was purified by column chromatography on silica gel (SiOH, irregular grains, solid, 30 g, mobile phase: NH4OH / DCM / MeOH, gradient from 100% DCM to 95% DCM, 5% MeOH , 0.5% NH4OH). The fractions containing the product were collected and evaporated to dryness to give three batches (batch 1: 167 mg, batch 2: 568 mg and batch 3: 253 mg as a yellow powder). Lots 2 and 3 were collected and purified with chiral SFC (stationary phase: CHIRALPAK IC 5 μm, 250 x 30 mm, mobile phase: 60% CO ₂ , 36% EtOH, 4% DCM). The fractions containing the product were combined and evaporated to dryness. The residue (388 mg) was combined with two other lots of compound 1 (517 mg and 200 mg) and taken up in CH3CN to give 1.165 g of compound 1 (light yellow powder).

Getting compound 66

TFA (0.47 ml, 6.12 mmol) was added at 5 ° С to a solution of intermediate 229 (227.00 mg, 0.41 mmol) in DCM (10 ml, stabilized with amylene). The reaction mixture was stirred at 0 ° C for 1 h, diluted with DCM and poured into a 10% aqueous K ₂ CO ₃ solution. The organic layer was decanted, washed with water, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was suspended in EtOH and the mixture was heated at 50 ° C for 2 h. The precipitate was filtered and dried to give 114 mg of compound 66 (61% yield). M.R. = 165 ° C (K).

The compounds in the table below were prepared in a similar manner to that described for the preparation of compounds 7, 1 or 66, starting from the appropriate starting materials. The most significant minor deviations from the reference method are indicated as supplementary information in the Mass (mg) column.

Connection Number Structure Weight (mg) Output (%) Compound 8 n N --- < ΆΟΑν he q λ ^ he from intermediate 3 5 32 Yellow powder Procedure with DCM / TFA (10: 1, v / v) 7

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Compound 9 n he N - </ \ __ 'yy ⁴ N Y from intermediate 39 160 63 Compound 13 n N— \ Νς. / \ __ GA / l ^he 1 || Ν uY 1 from intermediate 80 188 Yellow powder 35 Compound 16 n IS HE N Oky CHAHt from intermediate 62 79 Light yellow powder 24 Compound 17 n N - \ ^Ν Ά 1 A-x on Ha T o L g Sl dX n from intermediate 64 57 Procedure with DCM / TFA (5: 1, v / v) 27

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Compound 18 n N --- \ D ~ D 'JV ^ O ^N AA γΜ o 1 n Ok YES n 1 ° uh from intermediate 70 583 Almost white solid Procedure with DCM / TFA (10: 1, v / v) 79 Compound 19 n n --- \ Νς ;. j \ ___ he ^Ν o ^> Sl from intermediate 75 339 White solid Procedure with DCM / TFA (10: 1, v / v) 45 Compound 20 n Ν --- \ ^ν Ά / Α-χ mA ™ DM _S | about A.M from intermediate 78 440 White solid Procedure with DCM / TFA (10: 1, v / v) 58 Compound 22 n Ν --- \ ⁿ A / Vx xMAA on g T। Ax α А γ х ut jdy ^N 0 from intermediate 90 thirty (98% purity according to LC / MS) Solid almost white substance with DCM / TFA (1: 1, v / v) twenty

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Compound 24 n N --- \ ГК / \ __ ^ Y ^ Xx / \ he Т 11 ^RS Υγ CI СдХТ х / Η 1 О from intermediate 97 17 Off-white solid Procedure with DCM / TFA (1: 1, v / v) nine Compound 25 n he Ν --- </ ГК / \ __ / krii YjA Cl dx Δ ___ d from intermediate 101 139 Pale yellow solid Procedure with DCM / TFA (1: 1, v / v) 55 Compound 26 H 1 \ K 1 A-x ^on CaXX ^ GG tg Α Υκ n Υν from intermediate 103 52 solid white colors Procedure with DCM / TFA (5: 2, v / v) 23 Compound 27 n Ν - \ ГК 1 \ __ _{_} ΥγΑκ / Χ ОН 1 ^^ ii rs ⁴ YA ci ΥνΑ ^ ναΥ | Α from intermediate 106 38 solid white colors Procedure with DCM / TFA (5: 2, v / v) sixteen

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Compound 28 n N --- \ ⁿ a 1 DBP on HELL with | YES 0 from intermediate 111 32 Almost white solid Procedure with DCM / TFA (1: 1, v / v) 23 Compound 29 n N— \ 'ChdDx (EN p || RS Yes _S | CHA CI from intermediate 113 60 white solid Procedure with DCM / TFA (5: 2, v / v) 24 Compound 30 n N --- \ ^ν ά 1 ^he oD 0 from intermediate 115 116 Beige solid Procedure with DCM / TFA (5: 2, v / v) 44 Compound 31 n N— <TsaDla ^{on N} q 0 ^ from intermediate 117 40 Orange solid Procedure with DCM / TFA (5: 2, v / v) 17

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Compound 36 n N— \ I \ __ ^ A ^ DL / x he \ II ^RS MLD A ^ N ^x L / ⁿ F from intermediate 132 71 Procedure with DCM / TFA (4: 1, v / v) 29 Compound 41 n Ν— ^Ν Ρ / V — x DiE / l ontu J Ay Al uUCe A ^x n ^x Αι Η from intermediate 151 thirty Procedure with DCM / TFA (4: 1, v / v) 36 Compound 42 Η Ν --- \ I \ __ Λζ \ / \ he? Y || ^RS αΑζνκ X ^x ΛΛ X ^x X ^x A ^H w from intermediate 154 55 Procedure with DCM / TFA (4: 1, v / v) 22 Compound 43 Η Ν ---- \ 1 ai Vx 1 vu JL л An c χ А к JjJ / ^F X ^ X ^x X ^x HF ^X | F from intermediate 157 35 Procedure with DCM / TFA (4: 1, v / v) 35 Compound 60 n he Ν --- </ ^Ν Λ / χτ ηΡ ci cuj n 1 0 ο ^ \ ΙΙ / Ο - Λ ^χ 1 from intermediate 206 fifteen Procedure with DCM / TFA (12: 1, v / v) twenty Compound 65 Η Ν --- \ ^Ν Χ / λΆ ΧΜ / \ ^οη Τ Γ ^ν 7 - from intermediate 225 142 Yellow powder Procedure with DCM / TFA (6: 1, v / v) 28 Compound 69 Η he Ν --- \ / ^Ν Λ ί ψτ υυφτ Η 1 ο ^ from intermediate 241 75 Procedure with DCM / TFA (6: 1, v / v) 24 Compound 70 he Ν -— </ ^ν α 1 Ίγη ^{R ν} X; F from intermediate 243 117 Procedure with DCM / TFA (8: 1, v / v) 46

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Compound 72 ν ^he ci υυό A ^χ ο 1 from intermediate 248 95 Procedure with DCM / TFA (15: 1, v / v) 51 Compound 75 Η Ν -— \ ΙΑ I \ __ WMx he ^N from intermediate 262 118 White powder Procedure with DCM / TFA (6: 1, v / v) 38 Compound 76 n N - \ ⁿ a 1 V ^x A / \ RS xx? Al. ^ 0 F from intermediate 266 65 Procedure with DCM / TFA (4: 1, v / v) 34 Compound 77 ? n n G — N </ \ 'rs | I] 00 О ^F 65 Procedure with DCM / TFA (5: 1, v / v) 34

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from intermediate 270 Compound 211 o n I n ν-Ύ ^N - \ R / ⁴ N. / УТ Yy CN Μ from intermediate 541 113 Procedure with DCM / TFA (7.5: 1, v / v) at room temperature 33% Compound 212 n N n Ν— N. 1 vU ⁰ Tr Υγ CN Μ from intermediate 542 88 Procedure with DCM / TFA (7.5: 1, v / v) at room temperature 43% Compound 236 Η Ν— \ ^ν Υ / Ο <υ> ^η Ύ Ύ όιΤτ Η 1 α ^ν υ from intermediate 633 198 with DCM / TFA (18: 1, v / v) within 15 hours) 51 Compound 240 Η rj 0 Η Λ rj Г Jr Jk Гк G. ^ ГГ ^ ГГ YA I ^H 1 <from intermediate 644 85 with DCM / TFA (4: 1, v / v) 40

Example B5.

Getting connection 21

TFA (3 ml) was added to a solution of intermediate 85 (0.28 g, 0.29 mmol) in DCM (3 ml) and the reaction mixture was stirred at room temperature for 2 h. The solution was concentrated in vacuo and pure TFA (3 ml) was added, the reaction mixture stirred for an additional 4 hours. The reaction mixture was stirred for an additional 1 hour and the solution was concentrated in vacuo. The residue was treated with K ₂ CO ₃ (0.24 g, 1.75 mmol) in DMF (2 ml) for 2 h at 50 ° С. The reaction mixture was partitioned between EtOAc and water, and the organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified using an automatic purification system by weight.

Example B6.

Getting connection 23

HCl (3 M in H2O) (2.18 ml, 6.55 mmol) was added to a solution of intermediate 93 (698.00 mg, 0.65 mmol) in MeOH (10 ml), and the reaction mixture was stirred for 6 h while heating under reflux. The reaction mixture was cooled to room temperature, diluted with DCM and carefully neutralized with saturated NaHCO ₃ solution. Then a few milliliters of Me were added

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OH to solubilize the precipitate. The reaction mixture was separated and the aqueous layer was extracted with DCM / MeOH (9/1). The organic layers were combined, dried over MgSO4, filtered and concentrated. The residue (620 mg) was taken up in DCM / MeOH (9/1). The precipitate was filtered and taken up again with 15 ml DCM / MeOH (9/1). The resulting suspension was stirred for 30 min at room temperature. The precipitate was filtered, washed with Et ₂ O and dried. The resulting residue (226 mg) was purified by silica gel column chromatography (SiOH, irregular grains, solid, 40 g, mobile phase: DCM / MeOH, gradient 98: 2 to 94: 6). The fractions containing the product were concentrated to give two batches of compound 23: batch A (131 mg, 38% yield) and batch B (23 mg, 6% yield). Batch A containing several solvents was solubilized in DCM / MeOH, concentrated and taken up in CH3CN. The precipitate was filtered to obtain, after drying, batch C of compound 23 (112 mg) still containing some solvent. Finally, Batch C was dissolved in DCM / EtOH, concentrated and taken up in CH3CN. The precipitate was filtered and dried to give an additional 93 mg of compound 23 (27% yield). Mp:> 260 ° C (K). The overall yield was 33%.

Getting compound 45

about. /

HCl (3 M in H2O) (1.32 ml, 3.95 mmol) was added to a solution of intermediate 164 (269.00 mg, 0.40 mmol) in MeOH (6.0 ml), and the reaction mixture was stirred for 10 h while heating under reflux. The reaction mixture was cooled to room temperature, poured into a 10% aqueous K ₂ CO ₃ solution and extracted with DCM. The organic layer was decanted, dried over MgSO ₄ , filtered and evaporated to dryness to give an orange powder. The residue (220 mg) was purified by column chromatography on silica gel (SiOH with irregular grains, 25 g, solid residue, mobile phase NH4OH / DCM / MeOH, gradient from 0% NH4OH, 0% MeOH, 100% DCM to 1% NH4OH, 10 % MeOH, 90% DCM). The fractions containing the product were collected and evaporated to dryness to give 69 mg of a yellow solid. This solid was taken up in Et ₂ O to give 62 mg of compound 45 (34% yield, white powder). M.R. = 169 ° C (K).

The compounds in the table below were prepared in a similar manner to those described for the preparation of compound 23 or 45, starting from the appropriate starting materials.

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Connection Number Structure Weight (mg) Output (%) Compound 23 n n --- \ α / ν - χ YYY \ he y | r rs A A <EN A / ci F A / XX Lg 0 ^ from intermediate 93 93 27 Compound 34 he Ν --- \ / Ν. 1 \ Γ Ar / A / RS ^ yr _C | ° A ^ A ₀ ^ from intermediate 124 96 White powder 47 Compound 35 n ° ⁿ N --- < ⁿ A 1 \ / Yr A ^ CI Y l X / Xy from intermediate 128 105 White powder 28

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N HCl in 1,4-dioxane (0.19 ml; 0.759 mmol) was added at room temperature to a solution of intermediate 461 (84 mg; 0.152 mmol) in acetonitrile (2.4 ml) and the reaction mixture was stirred for 3 h. The precipitate was filtered, washed with acetonitrile and dried at 50 ° C in vacuo to obtain 0.068 g (82%) of compound 170. So pl. = 207 ° C (Kofler block).

Getting compound 171

Compound 171 was synthesized in a manner similar to that used to prepare compound 170, starting with intermediate 464 (235 mg; 99%; MP = 249 ° C, Kofler block).

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Getting connection 180

Compound 180 was synthesized in a manner similar to that used to prepare compound 170, starting with intermediate 482bis (162 mg; 81%; mp = resin at 194 ° C., Kofler block).

Getting compound 184

Compound 184 was prepared in a similar manner to that (using HCl, 3 N in cyclopentyl methyl ether) used to prepare compound 170, starting with intermediate 487 (223 mg; 60%; mp = resin at 134 ° C, Kofler block) ...

Getting compound 235

In a round-bottom flask containing intermediate 627 (500 mg; 0.64 mmol) and 1.4-dioxane (20 ml), a mixture of HCl 4 M / dioxane (3.5 ml; 14.01 mmol) was added and the reaction mixture was stirred at room temperature overnight. The crude product was concentrated and quenched with saturated NaHCO ₃ solution and extracted with DCM (2x50 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give a crude product that was purified by flash chromatography eluting with DCM (75%): MeOH (25%). The product fractions were collected and the solvent was evaporated to give 95 mg (32%) of compound 235.

Getting compound 237

Compound 237 was synthesized in a manner similar to that used to prepare compound 235 starting with intermediate 639 (123 mg; 86%).

Getting compound 238

Compound 238 was synthesized in a manner similar to that used to prepare compound 235 starting with intermediate 638 (116 mg; 88%).

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Example B7.

Getting connection 78

To a solution of intermediate 277 (227.00 mg, 0.242 mmol) in DCM (3 ml) was added TFA (3 ml) and stirred at room temperature for 2 h. The solution was concentrated in vacuo to give an orange oil. The residue was purified by semi-preparative reverse phase HPLC (C18 column, mobile phase: H2O + 0.1% HCO2H / CH3CN, gradient 30-80% in CH3CN). The desired fractions were combined and freeze dried to give 32 mg of compound 78 (26%, yellow solid).

Obtaining compound 110 n

Intermediate 357 (500 mg, 0.83 mmol) was stirred in DCM (37.5 ml). To this solution was added TFA (12.5 ml) at 0 ° C and stirred at room temperature for 1 h. NaHCO _{3 was} added to the resulting reaction mixture until a pH of 8 was reached. Some solids precipitated and were filtered off to give the crude product. The residue was purified by preparative high performance liquid chromatography (Waters Xbridge Prep OBD C18 100 χ 19 mm χ 5 μm, mobile phase: CH3CN / H2O (10 mM NH ₄ CO ₃ ) from 30 to 60% CH3CN for 12 min, then 100% CH3CN in for 2 min, flow rate = 25 ml / min). The pure fractions were collected and the solvent was evaporated in vacuo. The aqueous layer was lyophilized to give 102 mg of compound 110 (24% yield, white solid).

The compounds in the table below were prepared in a manner similar to that used to synthesize compounds 78 or 110, starting from the appropriate starting materials. The most significant minor deviations from the reference method are indicated as supplementary information in the Mass (mg) column.

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Connection Number Structure Weight (mg) Output (%) Compound 79 n Ν '. / V-- Yr аА ^{С |} α TA o from intermediate 280 fifteen Procedure with DCM / TFA (5: 2, v / v) white solid fifteen Compound 80 Η Ν --- i Yr ζ / ci FG φ ___ from intermediate 281 65 Almost white solid colors Procedure with DCM / TFA (2: 1, v / v) 51 Compound 81 n n --- \ Ν '. / Yr AjY _С | | AA _n Z \ a TA ^N h Yr. HCO ₂ H o from intermediate 282 57 almost white solid colors Procedure with DCM / TFA (2: 1, v / v) fifty

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Compound 82 n N - \ Νς. one \__ Th Ooo ci o άχΥ O from intermediate 286 40 almost white solid colors thirty Compound 83 n Ν --- \ Νς. I \ __ AT X, ci Л у / л υυΤ ^Ν 0 from intermediate 287 12 Procedure with DCM / TFA (2: 1, v / v) almost white solid colors 12 Compound 84 n Ν - \ Ν '. / \ __ OH Ooo ci XXI n 1 O from intermediate 288 31 Procedure with DCM / TFA (2: 1, v / v) white solid 36 Compound 85 n Ν --- k Ν <. / \ ___ Um Y ^ ci o o Y ABOUT from intermediate 282 35 almost white solid colors 28

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Compound 87 n 33 39 j V-- Te Ay ci, γΑ _Ν C A ⁿ I о ¹ from intermediate 298 almost white solid colors Compound 88 n n --- \ Te Au _C | T / e xe ^ / xy n 1 0 from intermediate 301 eight Procedure with DCM / TFA (2: 1, v / v) 10 Compound 89 n N --- \ N-. j \ __ > T, __ o. Κγ Cl <- К her 0 from intermediate 304 38 53 Compound 90 H N— \ A \ u Ay _C | ^ NA _N Ay ^NL from intermediate 306 9.2 almost white solid colors AND

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Compound 91 n N --- k 1 Xm yA ci | A ^ _n A \ '; ..... from intermediate 310 22 Procedure with DCM / TFA (2: 1, v / v) 24 Compound 92 n N --- \ OH uC ^ Y 0 from intermediate 312 51 Pale yellow solid 54 Compound 93 n AH / D Yes _Cl / D ^ D ^ I ·: ..... 0 from intermediate 315 56 Pale yellow solid 58 Compound 94 n N -— \ N ^. j \ __- D G— ' 0 from intermediate 320 26 Pale yellow solid 27

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Compound 95 n N --- \ ^ν ά / V ^x ί / ίγ y a O from intermediate 323 five Yellow solid Procedure with DCM / TFA (2: 1, v / v) five Compound 96 H N— \ Ν ^ χ 1 ΊΓ Ϊ ° ^χ x & A cy from intermediate 327 27 Reddish solid Procedure with DCM / TFA (2: 1, v / v) 32 Compound 97 n N --- \ gee / \ __. Vr ^С1 ΓΆ 1 1 Ν / - ОН из О from intermediate 330 42 Pale yellow solid 47 Compound 98 ъ_ \ / ΖΙ ¹ УУЧ1 / 38 Pale yellow solid 55

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from intermediate 333 Compound 104 n N— gk 1 Xr ku ^ 0 A Ji / from intermediate 346 63 Procedure with DCM / TFA (10: 3, v / v) 29 Compound 105 n N --- \ ^ν ά / E А YA CI у уА хе О from intermediate 347 OF Procedure with DCM / TFA (9: 1, v / v) 24 Compound 106 H that about from intermediate 352 27 DCM / TFA (10: 1, v / v) procedure 33 Compound 108 n U ⁰ 0 from intermediate 355 10 Procedure with DCM / TFA (10: 1, v / v) fifteen

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Compound 112 n N --- \ ⁿ a / V ^x ADa o From intermediate 363 sixteen DCM / TFA (10: 1, v / v) procedure 23 Connection FROM n N --- \ 1 TO / \ / DD Hu s o aDo- 0 From intermediate 364 sixteen Procedure with DCM / TFA (5: 1, v / v) 17 Compound 114 n N - \ Ά At Cl 0 άΜ 0 From intermediate 365 10 Procedure with DCM / TFA (11: 1, v / v) fifteen Compound 115 Η Ν ---- ν ΟΗ LJ Λ DM _C | _ΗΝ ΜΜ Trans Cl A η 1 О trans; From intermediate 366 36.5 DCM / TFA procedure (5: 1, v / v) white solid 40 Compound 116 n N -— v \ OH kj r> DM α _HN M ^ / ό d ^k m from intermediate 367 6.8 Procedure with DCM / TFA (3: 1, v / v) Yellow solid 6 Compound 117 uD D DM _S | cis 01 iV o. from intermediate 368 45 white solid 53 Compound 118 n Ν— <Ν ^. / \ ^ - Ч <ДД ^f ΎΎ rA ^F _{ДМ C} | _{n n} m ^ -j OL £ A o from intermediate 369 42 white solid Procedure with DCM / TFA (3: 1, v / v) 45

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Compound 119 Ύ γ cx o From intermediate 370 60 white solid 44 Compound 120 n Ac ό 0 ^x Cl ^X N ^Z TRANS ΑχO trans From intermediate 371 fifty white solid 85 Compound 121 n Ν — d ^Ν Α / \ ^Ν Α ^H (χ Cl CL / G ° n 1 o From intermediate 372 twenty 39 Compound 122 n N --- \ N0 / \ _n cis ll ^ l / - \ ^ ^NH A0 Cl XX Cl ij ⁰ 0 CIS From intermediate 373 56 white solid 58 Compound 123 he n I Ν --- \ 1 ΓΑ / \ ^ ΖΑ ILJ ⁴ X Α0 οι ^Χ _Ν ^Ζ CL ίΤ η 1 0 from intermediate 374 sixteen white solid nineteen Compound 124 (a mixture of undivided diastereomers Η Ν -— \ / \ Α \ X η ΙΙΊ ⁴ Η 1 RS / \ Υρ Cl HN ^ A ^ rs ^οη 0 from intermediate 375 40 white solid 54

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Example B8.

Getting connection 80

HCl (3 M in H2O) (1.72 ml, 5.16 mmol) was added to a solution of intermediate 281 (304.00 mg, 0.52 mmol) in EtOAc (19.3 ml) and the reaction mixture was stirred for 2 h at room temperature. The progress of the reaction was monitored by LC / MS after 2 h, but no conversion was observed. Also the reaction mixture was heated at 45 ° C overnight. To accelerate the conversion, the temperature was raised to 65 ° C for one additional day. After completion of the reaction, the resulting mixture was cooled to room temperature, poured into a 10% aqueous K ₂ CO ₃ solution, and extracted with DCM. The organic layer was decanted, dried over MgSO ₄ , filtered and evaporated to dryness. The residue (183 mg, yellow oil) was purified by column chromatography on silica gel (SiOH, irregular grains, 24 g, mobile phase: NH ₄ OH / MeOH / DCM, gradient from 0% NH4OH, 0% MeOH, 100% DCM to 1.5 % NH4OH, 15% MeOH, 85% DCM). The fractions containing the product were evaporated. The residue (103 mg, yellow oil) was purified by semi-preparative reverse phase HPLC (stationary phase: X-Bridge-C18, 5 μm 30 x 150 mm, mobile phase: gradient from 40% NH4HCO3 0.5%, 60% MeOH to 0% NH4CO3 0.5 %, 100% MeOH). The fractions containing the product were concentrated to give a colorless oil. The residue (60 mg) was precipitated with Et ₂ O to give 54 mg of compound 78 (yield 21%, white powder). Mp = 192 ° C (K).

The compounds in the table below were prepared in a similar manner to that described for the preparation of compound 80, starting with the appropriate starting materials. The most significant minor deviations from the reference method are indicated as supplementary information in the Mass (mg) column.

Connection Number Structure Weight (mg) Output (%) Compound 99 n Yr H / _C | XX ό L YES from intermediate 337 63 White powder Procedure with MeOH as solvent 36 Compound 100 n Ν --- \ α 1 V- ' tg Ay CI Υ Υ ABOUT / BUT/ from intermediate 338 eighteen White powder Procedure with MeOH as solvent AND

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Compound 101 n N --- \ N. 1 Tg CI όυό ° Y \ one from intermediate 339 40 White powder Procedure with MeOH as solvent 26 Compound 102 Η Ν --- ν TjP YES Cl ά.Α Υ from intermediate 342 80 (100% purity according to LC / MS) Procedure with EtOAc as solvent White powder 22 Procedure with MeOH as solvent (100% purity according to LC / MS) White powder 23 44 Compound 103 Η Ν ---- <Ν. / \ ___ Ττ ηΑ _С | ζχ Λ ° αΑ \ L / ° from intermediate 345 83 Yellow powder twenty Compound 107 Η Ν --- \ Ν. / \ __ Ττ YA _С | όυό ⁰ αΑ ^ ο η From intermediate 353 fifteen White powder Procedure with MeOH as a solvent 26 Compound 109 Η Ν - \ Ν. one \__ Ττ Ha a άψ 0 'ΑΑ Η From intermediate 356 48 Yellow powder Procedure with MeOH as a solvent 63

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Example B9.

Receiving compound 110 n

A mixture of intermediate 357 (160.00 mg, 0.26 mmol) in HCl / dioxane (4 M) was stirred at room temperature for 3 h.The mixture was evaporated in vacuum and purified by high performance liquid chromatography (column: Waters Xbridge Prep OBD C18 150 χ 30, 5 μm, mobile phase: water (0.05% ammonium hydroxide v / v) / CH ₃ CN, gradient from 33 to 63% CH3CN for 10 min, then 100% CH3CN for 3 min, flow rate 25 ml / min) ... The desired fractions were collected and the solvent was concentrated in vacuo to give 38 mg of compound 110 (28% yield).

Example B10.

Getting compound 111

TBAF (1 M in THF) (0.59 ml, 0.59 mmol) was added to a solution of intermediate 362 (168.00 mg, 0.29 mmol) in Me-THF (5 ml) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with EtOAc and poured into a 10% aqueous solution of K ₂ CO ₃ . The organic layer was decanted, washed with brine, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was crystallized from CH3CN / DiPE and the precipitate was filtered and dried to give 102 mg of compound 111 (yield 76%). M.p. = 219 ° C (K).

Example B11.

Getting compound 135

TFA (0.88 ml, 11.50 mmol) was added dropwise to a solution of intermediate 383 (178.00 mg, 0.34 mmol) in DCM (stabilized with amylene) (6 ml) at 5 ° С, and the reaction mixture was stirred for 30 min at this temperature. The reaction mixture was quenched with 10% aqueous K ₂ CO ₃ and extracted with DCM. The organic layer was decanted, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by silica gel column chromatography (SiOH, irregular grains, 24 g, mobile phase: DCM / MeOH, gradient 97: 3 to 95: 5). Pure fractions were collected and evaporated to dryness. The residue (98 mg) was purified by chromatography on silica gel by chiral SFC (stationary phase: 2-ethylpyridine, 6 μm 150 χ 21.2 mm, mobile phase: 75% CO ₂ , 25% MeOH (0.3% iPrNH2)). The pure fractions were mixed and the solvent was evaporated. The residue (52 mg) was crystallized from Et ₂ O, filtered and dried to give 25 mg of compound 135 (yield 17%).

Getting connection 136

TFA (0.77 mL, 10.02 mmol) was added dropwise to a solution of intermediate 384 (147.00 mg, 0.29

- 268 037 358 mmol) in DCM (stabilized with amylene) (5 ml) at 5 ° C and the reaction mixture was stirred for 1 h at this temperature. The reaction mixture was quenched with 10% aqueous K2CO3 and extracted with DCM. The organic layer was decanted, dried over MgSO4, filtered and evaporated to dryness. The residue was purified by silica gel column chromatography (irregular grain SiOH, 24 g, mobile phase: DCM / MeOH, gradient 97: 3 to 95: 5). Pure fractions were collected and evaporated to dryness. The residue (44 mg) was purified by reverse phase chromatography (stationary phase: YMC-actus Triart-C18, 10 μm, 30 × 150 mm, mobile phase: gradient from 60% NH4CO3 0.2%, 40% MeOH to 0% NH4HCO3 0.2% , 100% MeOH). The mixture was taken up in CH3CN, filtered, and dried to give 24 mg of compound 136 (yield 20%).

Example B12.

Getting compound 137

HCl (4 M in dioxane) (8 ml; 32.24 mmol) was added at room temperature to a solution of intermediate 385 (3.57 g; 6.45 mmol) in ACN (95 ml) and the reaction mixture was stirred for 3 h. The suspension was sonicated for 15 min and then filtered, washed with ACN and dried at 50 ° C under vacuum to give 2.92 g (86%) of compound 137, mp: 290 ° C (DSC).

Getting connection 138

HCl (4 M in dioxane) (35.2 ml; 140.93 mmol) was added at room temperature to a solution of intermediate 386 (16 g; 28.19 mmol) in ACN (400 ml) and the reaction mixture was stirred for 3 h. within 30 minutes. The precipitate was filtered, washed with ACN and dried to give 14.21 g (93%) of compound 138.

The compounds in the table below were prepared in a similar manner to that described for the preparation of compounds 137 and 138, starting with the appropriate starting materials.

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Intermediate number Structure Weight (mg) Output (%) Compound 139 ^ nh ₂ no A -1 92HCI.1.17H ₂ O ν-λ p / Ά HA 1 \ & / e From intermediate 387 230 54 Compound 140 ν \ -ΝΗ ₂ / R 189NSYU78N ₂ OH O-A N— \ / ^N O HA / Am ^ν Qji From intermediate 388 563 72 Compound 141 \ ^ yn ₂ HO A 192HC10 3H ₂ O N — ν / 0 Y Γΐϊ ^Ν Ic from intermediate 389 241 88 Compound 142a OH n o-L N— \ _π / O ^Ν Α A 2h ^ν Ol A from intermediate 390 80 24 Compound 142b he .0.93HC1.0.11H ₂ 0 n 0 - ¼ ^N - \ o / ⁰ HA / ⁿ Q А from intermediate 390 200 47

Example B13.

Getting compound 182

A solution of lithium hydroxide (213 mg; 5.074 mmol) in water (5 ml) was added to a solution of intermediate 483 (570 mg; 1.015 mmol) in THF (25 ml) and the reaction mixture was stirred for 18 h. lithium hydroxide (213 mg; 5.074 mmol) in water (2 ml) and the reaction mixture was stirred at room temperature for an additional 24 h. The reaction mixture was heated at 60 ° С for 4 h. The reaction mixture was acidified with 3 N aqueous HCl solution, diluted ACN and concentrated. The residue was crystallized from water. The precipitate was filtered and dried, yielding 402 mg (84%) of compound 182.

Getting connection 202

Compound 202 was prepared in a manner similar to that described for the preparation of compound 182, starting with intermediate 522 (491 mg; 84%).

C. Conversion of final compounds.

Example C1.

Getting connection 125

DIPEA (2.16 ml, 12.51 mmol) was added dropwise at 5 ° С to a mixture of compound 1 (992.00 mg, 2.50 mmol), acetic acid (0.28 ml, 5.00 mmol) and HATU (3.80 g, 10.01 mmol) in a mixture of THF (4.07 ml) and DMF (3.88 ml). The mixture was stirred at room temperature overnight. Then added water and the reaction mixture was extracted with DCM. The organic layer was decanted, dried over MgSO ₄ , filtered and evaporated to dryness. The residue (2 g, yellow oil) was purified by column chromatography on silica gel (SiOH, irregular grains, 120 g, mobile phase: DCM / MeOH, gradient from 100: 0 to 98: 2). The fractions containing the product were collected and evaporated to dryness to give 566 mg of a first batch of compound 125 (58% purity by LC / MS, yellow oil). The other fractions were collected and evaporated to dryness to give a second batch of compound 125 (800 mg, yellow oil). This batch was purified again by silica gel column chromatography (SiOH, irregular grains, 40 g, mobile phase: DCM, 100%). The fractions containing the product were collected and evaporated. The residue (563 mg, yellow powder) was taken up in CH3CN to give 393 mg of compound 125 (yield 36%, yellow powder). M.P = 213 ° C (K).

The compounds in the table below were prepared in a similar manner to that described for the preparation of compound 125, starting with the appropriate starting materials. The most significant minor deviations from the reference method are indicated as supplementary information in the Mass (mg) column.

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Connection Number Structure Weight (mg) Output (%) Compound 126 n N - у О ^N A 1 VN // Г1Г ° N Г оР from Compound 1 thirty White powder colors 6 Compound 127 n AM ABOUT % one from Compound 66 55 White powder eighteen Compound 128 n N --- <O \ __ II SAte ° A ⁿ qP from Compound 13 40 White powder 32

Example C2.

Getting connection 129

HCl (4M in dioxane) (126.00 μL, 0.50 mmol) was added dropwise at 5 ° С to a suspension of compound 1 (200.00 mg, 0.50 mmol) in CH3CN (20 ml). The reaction mixture was left to warm to room temperature and was stirred overnight. The precipitate was filtered, washed with CH3CN and dried at 50 ° C under vacuum over the weekend to obtain 204 mg of compound 129 (93% yield). M.p. = 190 ° C (K).

Example C3.

Getting connection 130

An aqueous solution of H ₂ SO4 (3M) (168.00 μL, 0.50 mmol) was added dropwise at 5 ° С to a suspension of compound 1 (200.00 mg, 0.50 mmol) in CH3CN (20 ml). The reaction mixture was left to warm to room temperature and was stirred overnight. The precipitate was filtered, washed with CH3CN and dried at 50 ° C under vacuum over the weekend to give 214 mg of compound 130 (83% yield). M.p. = 264 ° C (K).

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Example C4.

Getting compound 131

Phosphoric acid (3M) (168.00 μL, 0.50 mmol) was added dropwise at 5 ° С to a suspension of compound 1 (200.00 mg, 0.50 mmol) in CH3CN (20 ml). The reaction mixture was left to warm to room temperature and was stirred overnight. The precipitate was filtered, washed with CH3CN and dried at 50 ° C under vacuum over the weekend to obtain 228 mg of compound 131 (75% yield). M.p. = 174 ° C (K).

Example C5.

Getting connection 132

Methanesulfonic acid (33.00 μL, 0.50 mmol) was added dropwise to a suspension of compound 1 (200.00 mg, 0.50 mmol) in CH3CN (20 mL). The reaction mixture was stirred overnight. The precipitate was filtered, washed with Et2O, and dried at 50 ° C under vacuum to give 115 mg of compound 132 (46% yield). M.p. = 234 ° C (K).

Example C6.

Getting connection 133

A solution of p-toluenesulfonic acid monohydrate (96.00 mg, 0.50 mmol) in water (0.5 ml) was added dropwise to a suspension of compound 1 (200.00 mg, 0.50 mmol) in CH3CN (20 ml). The reaction mixture was stirred overnight. The precipitate was filtered, washed with Et ₂ O and dried at 50 ° C under vacuum to give 229 mg of compound 133 (79% yield). M.p. = 262 ° C (K).

Example C7.

Getting connection 134

A solution of maleic acid (58.56 mg, 0.50 mmol) in CH3CN (0.50 ml) and water (0.50 ml) was added dropwise to a suspension of compound 1 (200.00 mg, 0.50 mmol) in CH3CN (20 ml). The reaction mixture was left to warm to room temperature and was stirred overnight. The precipitate was filtered, washed with Et ₂ O and dried at 50 ° C under vacuum to give 169 mg of compound 134 (65% yield). M.p. = 190 ° C (K).

Example C8.

Getting connection 143

Compound 1 (200 mg; 0.504 mmol) was added to a suspension of sulfur trioxide and pyridine (48-50%) (163 mg; 0.504 mmol) in THF (2 ml) and the reaction mixture was stirred at room temperature for 3 h. A hydroxide solution was added potassium (28 mg; 0.504 mmol) in water (0.5 ml) and the resulting solution was cooled to 5 ° С before adding acetone. The product precipitated on standing. Then it was filtered and washed with acetone to obtain 250 mg of fraction A (> 100%).

Fraction A was collected with toluene, then EtOH, and the solvent was evaporated to dryness. The precipitate was taken up in ACN, filtered and dried to give 233 mg of fraction B (97%).

Fraction B was suspended in water and stirred for 15 minutes, then filtered and dried to give 159 mg (59%) of compound 143, mp:> 270 ° C (Kofler block).

Getting compound 144

Compound 65 (200 mg; 0.504 mmol) was added to a suspension of sulfur trioxide and pyridine (164 mg; 0.504 mmol) in THF (2 ml) and the reaction mixture was stirred at room temperature for 3 h. Potassium hydroxide solution (28 mg; 0.504 mmol) in water (0.5 ml) and the solution was cooled to 5 ° C before adding acetone. The product precipitated on standing. Then it was filtered and washed with acetone to obtain 249 mg of fraction A (> 100%).

Fraction A was washed with water, then with acetone and dried to give 127 mg (51%) of compound 144.

Example C9.

Getting connection 145

A mixture of compound 1 (250 mg; 0.63 mmol), 4-methyl-1-piperazineacetic acid (249 mg; 1.58 mmol), HATU (599 mg; 1.58 mmol), DIPEA (543 μl; 3.15 mmol) and DMAP (4 mg; 0.034 mmol) in DMF (7.5 ml) was stirred at room temperature for 18 h. The solution was poured into water and extracted with EtOAc. The organic layer was washed with H ₂ O, then brine, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by silica gel chromatography (SiOH with irregular grains, 24 g; mobile phase: from 0.2% NH4OH, 2% MeOH, 98% DCM to 0.5% NH4OH, 5% MeOH, 95% DCM). Pure fractions were collected and evaporated to dryness to obtain 395 mg of the intermediate fraction, which was dissolved in ACN (15 ml). The solution was cooled to 5 ° C and HCl (4 M in dioxane) (473 μl; 1.89 mmol) was added. The suspension was stirred for 3 h and the precipitate was filtered and dried to give 203 mg (54%) of compound 145, mp: gum at 216 ° C (Kofler block).

Getting compound 146

Compound 146 was prepared following a procedure similar to that used to prepare compound 145 starting with compound 1 and 4-methyl-1-morpholine acetic acid. 86 mg (22%) of compound 146 was obtained, resin at 186 ° C (Kofler block).

Example C10.

Getting compound 164

Diethylaminosulfur trifluoride (0.247 ml; 2.02 mmol) was added to a solution of compound 1 (200 mg;

0.504 mmol) in THF (7 ml) at -78 ° C. After 2 h, diethylaminosulfur trifluoride (0.247 ml;

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2.02 mmol) and the mixture was stirred at room temperature for 20 hours. The mixture was poured onto ice. The resulting precipitate was filtered off. The mother layer was podslushivaet potassium carbonate and was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and the solvent was evaporated. The residue was purified by chromatography on silica gel (50 g, 15-40 μm, solid precipitate, eluent: DCM / MeOH: 100 / 0-95 / 5). The pure fractions were mixed and the solvent was evaporated. The resulting residue (0.05 g) was purified by chiral SFC (stationary phase: diethylaminopropyl, 5 μm, 150x21.2 mm, mobile phase: 85% CO ₂ , 15% MeOH). The pure fractions were mixed and the solvent was evaporated to give 0.02 g (10%) of compound 164. mp = 194 ° C (Kofler block).

Example C11.

Getting compound 172

A mixture of compound 170 (39 mg; 0.086 mmol), propanoic acid (0.095 ml; 0.0946 mmol), HATU (36 mg; 0.0946 mmol), and DIPEA (0.0445 ml; 0.258 mmol) in DCM (0.8 ml) was stirred at room temperature for 18 hours The solution was poured into water and extracted with DCM. The organic layer was washed with brine, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by silica gel chromatography (SiOH, irregular grains, 4 g; mobile phase: DCM / MeOH: 100 / 0-95 / 5). Pure fractions were collected and evaporated to dryness to give 20 mg (46%) of compound 172. Mp = 193 ° C (Kofler block).

Getting connection 176

Compound 176 was synthesized in a manner similar to that used to prepare compound 172, starting with compound 171 (21 mg; 20%).

Getting compound 181

Compound 181 was synthesized in a manner similar to that used to prepare compound 172, starting with compound 180 (4 mg; 18%).

Getting connection 183

Compound 183 was synthesized by a method (solvent: DCM / THF / DMF: 50/50/5) similar to that described for the preparation of compound 172, starting with compound 182 (280 mg; 65%; mp = 209 ° C; DSC ).

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Getting compound 185

Compound 184 was synthesized by a method (solvent: DCM / THF) similar to that used to prepare compound 172, starting with compound 184 (35 mg; 45%; mp = resin at 156 ° C; Kofler block).

Getting connection 203

A mixture of compound 201 (260 mg; 0.38 mmol), 1-methylpiperazine (63 μl; 0.57 mmol), HATU (159 mg; 0.42 mmol), and DIEA (265 μl; 1.52 mmol) in DCM (10 ml) was stirred at room temperature for over 18 h. Water was added and the reaction mixture was extracted with DCM. The organic layer was filtered through Chromabond® and evaporated to dryness. The residue was purified (180 mg) by silica gel chromatography (SiOH with irregular grains, 10 g; mobile phase: gradient from 0.3% NH4OH, 3% MeOH, 97% DCM to 1.5% NH4OH, 15% MeOH, 85% DCM). Pure fractions were collected and evaporated to dryness. The residue was taken up in ACN and the precipitate was filtered and dried to give 72 mg (36% of compound 203. Mp: 294 ° C (DSC).

The compounds in the table below were prepared in a similar manner to that described for the preparation of compound 203, starting from the appropriate starting materials.

Connection Number Structure Qty Output Compound 204 n he N— / fy ya Αχ from Compound 201 and intermediate 524 78 mg 40% Compound 205 n he Ν— \ r / n <. / χχ X HDDH from Compound 202 and morpholine-dS 331 mg 38% Compound 206 n he ^Ν --- / N. / χ χΤχ from Compound 202 and 1 - cyclopropylpiperazine 205 mg 71% Compound 207 T G χ. Xx M.R .: 268 ° C (DSC) from Compound 202 and 1- (oxetane-3yl) piperazine 200 mg 67%

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Example C12.

Getting compound 178

and compounds 179

Compound 178 and Compound 179 were obtained by chiral SFC purification (stationary phase: Chiralpak IC, 5 μm, 250x20 mm, mobile phase: 50% CO ₂ , 50% EtOH (0.3% iPrNH ₂ )). The product fractions were mixed and the solvent evaporated to give 47 mg of compound 178 and 43 mg of compound 179, respectively.

Example C13.

Getting compound 201 n he

A solution of LiOH H ₂ O (77 mg; 1.83 mmol) in distilled water (2 ml) was added to a solution of compound 8 (166 mg; 0.365 mmol) in THF (10 ml) and the reaction mixture was stirred for 18 h. The reaction mixture was acidified 6 N aqueous HCl, diluted with ACN and concentrated. The residue was crystallized from a mixture of water / ACN. The precipitate was filtered, washed with water and dried to give 118 mg (72%) of compound 201. mp: 220 ° C (resin, Kofler block).

Getting connection 202

Compound 202 was prepared in a manner similar to that used to prepare compound 501, starting with intermediate 522 (491 mg; 84%). Analytical part LCMS (liquid chromatography / mass spectrometry).

High performance liquid chromatography (HPLC) measurements were performed using an LC pump, diode array (DAD) or UV detector and column as defined in the respective methods. If necessary, additional detectors were included (see the table of methods below).

The column stream was directed to a mass spectrometer (MS), which was equipped with an atmospheric pressure ionization source. It is within the competence of the person skilled in the art to set tunable parameters (eg scan range, minimum measurement time, etc.) in order to obtain ions that enable the determination of the nominal monoisotopic molecular weight (MW) of the compounds. Data collection was performed using the appropriate software. Compounds were described by their experimental retention time (R _t ) and ions. Unless otherwise indicated, in the datasheet, the indicated molecular ion corresponds to [M + H] + (protonated molecule) and / or [M-H] ^- (deprotonated molecule). In case the compound was not directly ionizable, indicate the type of adduct (ie [M + NH4] ⁺ , [M + HCOO] ^- , etc.). For molecules with complex isotopic distributions (Br, Cl, etc.), the reported value is the value obtained for the lowest isotopic mass. All results were obtained with experimental errors that are usually associated with the method used. Further, in the present specification, SQD means single quadrupole detector, RT room temperature, VEN means mos-277 037358 teak ethylsiloxane / silica hybrid, HSS means high strength silica, DAD means diode array detector.

Method code Appliance Column Mobile phase Gradient Flow Time analysis Column T Way one Waters: Acquity UPLC®-DAD and Quattro Micro ™ Waters: VEN Cl8 (1.7 μm, 2.1 x 100 mm) A: 95% CH3COONH4 7mM / 5% CH ₃ CN, B: CH3CN 84.2% A for 0.49 min, up to 10.5% A for 0.343 6.2 within 1.94 min, back to 84.2% A in 0.73 min, holding for 0.73 min. 40 Method 2 Waters: Acquity UPLC® H- Class - DAD and SQD 2 Waters: VEN Cl8 (1.7 μm, 2.1 x 100 mm) A: 95% CH3COONH4 7mM / 5% CH3CN, B: CH3CN From 84.2% Ado 10.5% A in 2.18 min, retention for 1.94 min, retention to 84.2% A in 0.73 min, retention for 0.73 min. 0.343 6.1 40 Method 3 Agilent 1200 equipped with MSD6110 Agilent ТС-С18 (5 μm, 2.1x50 mm) A: H ₂ O (0.1% TFA), B: CH3CN (0.05% TFA) 90% A retention for 0.80 min, then from 90% A to 20% Aza for 3.7 min, retention for 3.00 min, back to 90% A in 2.00 min. 0.8 10 fifty Method 4 Waters: Acquity UPLC® H- Class - DAD and QDa VEN®-S18 (1.7 μm, 2.1 х 1000 m) A: 95% CH3COONH4 7mM / 5% CH3CN, B: CH ₃ CN From 95% A to 5% A in 1 min, hold for 1.6 min, back to 95% A in 1.2 min, hold for 0.5 min. 0.5 3.3 40 Method 5 Agilent 1200 equipped with MSD6110 XBridge Shield RP18 (5μm, 2.1x50mm) A: H ₂ O (0.05% NH ₃ .H ₂ O), B: CH ₃ CN 100% A hold for 1.00 min, then 100% A to 0.8 10

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Method code Appliance Column Mobile phase Gradient 40% A in 4.00 min, then from 40% A to 5% Aza 2.50 min, back to 100% A in 2.00 min. Flow Time analysis Column T 40 Method 6 Waters: Micromass ZQ2000 Waters Acquity UPLC system equipped with PDA detector Acquity HST -C 18 (1.8 mkM, 2.1 x 100 mm) A: 95% Water (with 0.1% CH ₃ COOH), B: CH ₃ CN (c0.1% CH 3 COOH) 95% A retention for 0.4 min, then from 95% A to 5% Aza 5.2 min, retention for 0.8 min. 0.4 6.4 40 Method 7 Agilent 1100 ACEC18 column (3 μm, 3.0 x 50 mm) A: 95% Water (with 0.05% TFA), B: CH ₃ CN From 95% A to 0% A for 5.2 minutes 2.2 6.4 fifty Method 8 Agilent 1200 equipped with MSD6110 Phenomenex Luna-C18, 50x2 mm, 5 MKM A: H ₂ O (0.1% T FA, B: CH ₃ CN (0.05% TFA) 100% A retention for 1 min, then from 100% A to 40% A in 4 min, then from 40% A to 15% A in 2.5 min, then back to 100% Aza for 2 min, retention for 0.5 min. 0.8 10 fifty Method 9 Agilent 1200 equipped with MSD6110 Phenomenex Luna-C18, 50x2 mm, 5 MKM A: H ₂ O (0.1% TFA, B: CH ₃ CN (0.05% TFA) 90% A retention for 0.8 min, then from 90% A to 20% Aza 3.7 min, retention for 2 min, back to 90% A in 2 min, retention for 0.5 min 0.8 10 fifty Method code Appliance Column Mobile phase Gradient Flow Time analysis Column T Method 10 Agilent 1290 Infinity DAD LC / MS G6110A Phenomenex Kinetex Cl8 (50 x 2.1 mm, 1.7 μm) А: 0.1% НСООН in Н ₂ О В: CH ₃ CN From 90% A to 10% A in 1.5 min, hold for 0.4 min, up to 90% Aza 0.1 min. 1.5 2.0 60 Method I Agilent 1100 series DAD LC / MS G1956A YMC ODSAQC18 (50 x 4.6 mm, 3.0 μm) А: 0.1% НСООН in Н ₂ О В: CH ₃ CN 95% A to 5% A in 4.8 min, hold for 1.0 min, to 90% A in 0.2 min. 2.6 6.0 35 Method 12 Agilent 1290 Infinity DAD TOF-LC / MS G6224A YMC-pack ODS-AQ C18 (50x4.6 MM, 3 μm) А: 0.1% НСООН in Н ₂ О В: CH ₃ CN 95% A to 5% A in 4.8 min, hold for 1.0 min, to 95% A in 0.2 min. 2.6 6.0

In the table: LCMS method codes (flow expressed in ml / min; column temperature (T) in ° C; analysis time in minutes).

Melting points.

For a number of compounds, the melting points (MF) were determined using DSC1 (MettlerToledo). Melting points were measured with a gradient of 10 ° C / min. The maximum temperature was 350 ° C. Values shown are peak values. Indicated in the table as DSC.

For a number of compounds, melting points were obtained using a Kofler block (thermostat) (indicated by (K) in the analytical table), which consists of a heated plate with a linear temperature gradient, a sliding arrow and a temperature scale in degrees Celsius.

- 279 037358

For a number of compounds, melting points were obtained using a Melting Point Apparatus.

WRS-2A (designated WRS-2A in the analytical table). Melting points were measured with a temperature gradient of 5 ° C per 1 min, ranging from room temperature to a maximum value of 320 ° C.

For a number of compounds, melting points were obtained using a Mettler Toledo MP50 instrument (designated MP50 in the analytical table). Melting points were measured with a temperature gradient of 10 ° C in 1 min, starting from 50 ° C (waiting time 10 s) to a maximum value of 300 ° C.

No. Conn. T. pl. (° C) MR method Rt [M + H] + LCMS Way one 222 DSC 2.71 397 one 2 - - 2.82 504 one 3 - - 2.95 506 one four 193 DSC 2.23 429 one five 115 (resin) TO 2.17 508 one 6 148 (resin) TO 2.49 504 one 7 215 DSC 3.01 424 one eight 184 TO 2.44 443 one nine 120 (resin) TO 3.17 541 one 10 215 TO 3.01 439 one AND 215 DSC 2.74 415 one 12 159 TO 2.64 471 one 13 194 TO 3.13 453 one fourteen 162 TO 2.76 483 one fifteen 110 (resin) TO 1.32 439 four sixteen 162 (resin) TO 3.10 441 one 17 148 TO 2.44 450 one eighteen 263 DSC 2.41 492 one nineteen 284 DSC 3.21 537 one twenty - - 2.25 482 one 21 - - 3.74 515 6 22 - - 3.16 548 6 23 > 260 TO 2.67 520 6 24 - - 3.93 452 6 25 - - 3.26 505 6 26 195 DSC 2.72 396 6 27 289 DSC 3.04 405 6 28 - - 3.15 534 6 29 210 DSC 3.35 426 one thirty 224 DSC 3.14 456 one 31 295 DSC 2.79 413 one 32 274 DSC 2.97 417 one

- 280 037358

33 239 DSC 3.13 422 one 34 184 TO 3.06 466 one 35 192 K (resin) 3.40 531 one 36 263 TO 2.99 510 one 37 221 TO 2.88 525 one 38 190 TO 2.54 486 2 39 173 K (resin) 2.73 505 2 40 236 TO 2.41 452 2 41 > 260 TO 2.40 503 one 42 183 to 3.49 506 one 43 237 to 2.43 539 one 44 168 to 2.39 465 one 45 169 to 3.06 466 one 47 > 250 to 3.28 440 one 48 > 250 to 3.28 440 one 49 172 to 3.29 460 one fifty 190 to 2.65 566 one 51 200 to 3.29 484 one 52 217 to 3.34 476 one 53 245 to 2.51 477 one 54 154 to 2.69 477 one 55 135 K (resin) 2.72 560 one 56 170 TO 2.70 463 one 57 188 to 3.06 466 one 58 183 to 2.38 532 one 59 267 DSC 3.12 507 one 60 132 K (resin) 2.38 513 one 61 - - 2.70 516 one 62 228 DSC 2.29 434 one 63 262 TO 2.37 463 one 64 160 DSC 2.18 464 one 65 218 TO 2.45 397 2 66 165 TO 2.74 457 one 67 188 DSC 2.19 508 one

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68 - - 2 19 546 one 69 157 DSC 2 87 450 one 70 237 DSC 2 97 451 one 71 210 DSC 2 97 423 one 72 189 DSC 3 20 464 one 73 201 DSC 2 55 466 one 74 124 TO 2 86 455 one 75 228 TO 2 75 481 one 76 - - 3 37 484 2 77 - - 2 85 484 2 78 - - 4 15 483 6 79 - - 5 55 491 6 80 192 TO 3 81 489 6 81 - - 3 67 518 6 82 - - 4 68 507 6 83 - - 3 69 532 6 84 - - 4 82 436 6 85 - - 5 10 484 6 87 - - 3 71 532 6 88 - - 5 83 450 6 89 - - 3 72 548 6 90 - - 5 47 454 6 91 - - 3 46 502 6 92 - - 5 91 519 6 93 - - 377 532 6 94 - - 3 62 527 6 95 - - 3 50 548 6 96 - - 4 97 468 6 97 - - 459 491 6 98 - - 377 530 6 99 120 K (resin) 4 15 515 one 100 171 TO 3 61 450 one 101 104 K (resin) 3 76 489 one 102 112 K (resin) 4 01 434 one

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103 126 K (resin) 3.66 476 one 104 176 TO 3.12 420 2 105 > 250 TO 3.20 505 one 106 208 TO 3.56 464 one 107 176 to 3.22 436 one 108 > 260 to 2.97 533 one 109 152 to 2.93 449 one 110 - - 4.95 505 five 111 219 to 2.65 455 one 112 > 260 to 2.77 507 one OF 178 to 2.62 558 one 114 206 K (resin) 2.54 558 one 115 - - 5.04 533 five 116 - - 5.10 533 five 117 - - 5.01 545 five 118 - - 5.65 539 five 119 - - 5.07 547 five 120 - - 5.19 545 five 121 193 TO 5.03 543 five 122 - - 3.22 544 3 123 287 to 3.62 545 3 124 - - 5.07 534 five 125 213 to 2.98 439 one 126 200 to 3.25 467 one 127 158 to 3.01 499 one 128 156 K (resin) 3.37 495 one 129 190 TO 2.70 397 one 130 264 TO 2.71 397 one 131 174 to 2.71 397 one 132 234 to 2.70 397 one 133 262 to 2.71 397 one 134 190 to 2.71 397 one 135 166 K (resin) 2.91 425 one 136 219 TO 2.76 397 one

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137 290 DSC 2.60 454 one 138 - - 2.67 468 one 139 202 K (resin) 2.90 496 one 140 180 K (resin) 3.01 544 one 141 212 K (resin) 2.57 468 2 142a 138 DSC 2.11 483 one 142b 214 DSC 2.18 483 one 143 > 270 TO 2.18 477 one 144 - - 2.17 477 one 145 216 (resin) TO 2.61 573 one 146 186 (resin) to 2.85 524 one 147 - - 1.32 415 7 148 231 DSC 2.43 422 one 149 - - 3.27 444 nine 150 - - 3.67 404 eight 151 122 - 2.75 430 nine 152 229 DSC 2.43 420 one 153 144 (resin) TO 2.38 413 one 154 250 WRS-2A 3.02 446 nine 155 218 DSC 2.38 447 one 156 206 DSC 2.58 489 2 157 235 DSC 2.5 489 2 158 - - 2.16 512 one 159 140 (resin) TO 2.23 528 one 160 206 TO 2.43 443 one 161 245 DSC 2.28 498 one 162 143 DSC 2.63 473 one 163 150 TO 2.04 498 one 164 194 TO 2.95 399 2 165 224 DSC 2.41 451 one 166 116 DSC 2.15 516 one 167 239 DSC 2.15 516 one 130 264 TO 2.71 397 one 131 174 TO 2.71 397 one

- 284 037358

132 234 TO 2.70 397 one 133 262 TO 2.71 397 one 134 190 to 2.71 397 one 135 166 K (resin) 2.91 425 one 136 219 TO 2.76 397 one 137 290 DSC 2.60 454 one 138 - - 2.67 468 one 139 202 K (resin) 2.90 496 one 140 180 K (resin) 3.01 544 one 141 212 K (resin) 2.57 468 2 142a 138 DSC 2.11 483 one 142b 214 DSC 2.18 483 one 143 > 270 TO 2.18 477 one 144 - - 2.17 477 one 145 216 (resin) TO 2.61 573 one 146 186 (resin) to 2.85 524 one 147 - - 1.32 415 7 148 231 DSC 2.43 422 one 149 - - 3.27 444 nine 150 - - 3.67 404 eight 151 122 - 2.75 430 nine 152 229 DSC 2.43 420 one 153 144 (resin) TO 2.38 413 one 154 250 WRS-2A 3.02 446 nine 155 218 DSC 2.38 447 one 156 206 DSC 2.58 489 2 157 235 DSC 2.5 489 2 158 - - 2.16 512 one 159 140 (resin) TO 2.23 528 one 160 206 TO 2.43 443 one 161 245 DSC 2.28 498 one 162 143 DSC 2.63 473 one 163 150 TO 2.04 498 one 164 194 TO 2.95 399 2

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165 224 DSC 2 41 451 one 166 116 DSC 2 15 516 one 167 239 DSC 2 15 516 one 168 246 DSC 2 42 503 one 169 256 DSC 2 41 503 one 170 207 TO 2 and 454 one 171 249 TO 2 19 450 2 172 193 TO 2 49 510 one 173 183 DSC 2 57 510 one 174 211 DSC 2 66 498 one 175 226 TO 2 24 494 one 176 - - 2 56 506 one 177 222 DSC 2 38 494 one 178 230 TO 2 27 494 2 179 188 (resin) TO 2 26 494 2 180 194 (resin) TO 2 16 456 one 181 - - 2 44 498 one 182 - - 0 82 434 four 183 209 DSC 2 33 503 one 184 134 (resin) TO 2 15 454 one 185 156 (resin) TO 2 41 496 one 186 172 DSC 2 44 472 2 187 240 DSC 2 37 503 one 188 190 TO 2 56 477 one 189 239 TO 2 43 452 one 190 128 TO 2 63 452 one 191 122 WRS-2A 2 42 438 nine 192 250 WRS-2A 2 47 469 nine 193 188 (resin) TO 2 32 427 one 194 193 DSC 2 88 524 2 195 210 TO 2 70 484 one 196 240 TO 2 84 502 one 197 223 DSC 2 99 499 one 198 222 DSC 2 98 501 one

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199 170 (resin) TO 2 53 513 one 200 260 TO 2 75 455 one 201 220 (resin) TO 178 441 one 203 294 DSC 2 23 523 one 204 297 DSC 2 23 526 one 205 201 TO 2 28 493 one 206 238 DSC 2 53 524 one 207 268 DSC 2 15 540 one 208 234 DSC 2 59 462 2 209 254 DSC 3 12 457 one 210 - - 2 34 441 nine 211 160 (resin) TO 2 65 438 one 212 168 to 278 474 one 213 304 WRS-2A 4 66 398 eight 214 252 TO 4 08 430 eight 215 225 DSC 2 38 402 one 216 108 (resin) TO 2 25 455 one 217 151 DSC 2 18 459 one 218 115 (resin) TO 2 49 441 one 219 181 DSC 2 86 477 one 220 140 TO 2 65 459 one 221 181 MP50 2 17 485 AND 222 - - 0 59 471 10 223 129 DSC 2 38 496 one 224 238 TO 2 98 482 one 225 181 MP50 2 17 452 AND 226 298 MP50 2 36 495 AND 227 223 MP50 3 64 488 AND 228 170 MP50 2 26 470 AND 229 207 DSC 2 83 484 one 230 - - 2 45 514 AND 231 - - 2 45 514 AND 232 167 DSC 2 61 500 2 233 162 DSC 2 76 500 one 234 192 DSC 2.41 485 2 235 133 MP50 2.36 471 12 236 249 TO 2.39 499 one 237 - - 2.12 427 one 238 - - 2.12 427 one 239 116 (resin) TO 2.05 415 one 240 259 to 2.57 479 one

In the table: No. Conn. indicates the connection number; retention time (Rt) in min; MP means melting point (° C); decomp. means decomposition; n.d. means the data is not defined.

Optical Rotation (OR).

Optical rotation was measured using a polarimeter such as, for example, 341 Perkin Elmer, Autopol IV automatic polarimeter (Rodolph research analytical) or P-2000 (Jasco).

Specific optical rotation (OR): [α] θ _λ = (100 x a) / (c χ 1), where α (measured angle of rotation) denotes the angle of rotation by which the polarization plane deflects when polarized light passes through a solution with a mass concentration with and the thickness of the liquid layer 1. The concentration is expressed in grams per 100 ml of solution; the thickness of layer 1 is expressed in decimetres and is equal to 1.000 dm.

θ is the temperature (° C) and λ is the wavelength of the light used.

Unless otherwise indicated, the temperature is 20 ° C and the sodium D-line (589 nm) is used.

OR data: solvent: DMF (unless otherwise noted); temperature: 20 ° C (unless otherwise indicated); wavelength: 589 nm (unless otherwise noted); Conc. means the concentration of the sample in grams per 100 ml; OR stands for optical rotation (specific rotation); No. Conn. means the connection number.

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No. Conn. OR (°) Conc. one + 48.33 0.3 2 + 21.17 0.227 3 + 17.21 0.215 four + 8.89 0.225 7 + 27.2 0.261 eight + 21.43 0.28 nine + 29.92 0.264 10 + 50 0.25 AND + 43.61 0.342 12 + 57.28 0.183 13 + 64.29 0.28 fourteen + 49.12 0.34 fifteen + 35.19 0.27 sixteen + 68.64 0.22 17 + 18.08 0.26 eighteen + 9.51 0.284 nineteen + 47.99 0.292 twenty + 29.2 0.25 45 + 32.5 0.2 48 + 29.63 0.27 57 -35.2 0.25 59 + 28.51 0.245 60 + 15.2 0.25 61 + 13.2 0.25 62 + 15.84 0.227 63 +5.49 0.255 64 + 20.63 0.16 65 -43.85 0.26 66 + 60.43 0.23 67 + 16.5 0.273 68 + 16.15 0.26 69 + 17.31 0.26 70 + 17.31 0.26 71 + 36.36 0.253 72 + 21.60 0.25 73 + 19.33 0.3 74 + 34.75 0.259 75 + 28.18 0.33 125 + 70.57 0.35 126 + 74.52 0.231 127 + 73 0.2 128 + 100 0.2 129 + 63.33 0.21 130 + 52.08 0.221 131 + 30.81 0.214 132 + 43.6 0.241 133 + 43.86 0.207 134 + 36.19 0.21 135 + 23.08 0.26 137 +51.55 0.258 138 +54.55 0.275 139 +58.54 0.205 140 +35.65 0.292 141 +87.5 0.28 142a +38.04 0.276 142b +69.96 0.273 143 +65.15 0.264 144 -64.35 0.264 145 +74.44 0.266 146 +17.45 0.275 148 +9.44 0.339 149 +13.21 0.106 (MeOH) 150 +11.67 0.3

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151 +8.33 0.3 (MeOH) 152 +13.01 0.269 153 +61.94 0.258 154 +8.08 0.099 (MeOH) 155 +11.07 0.262 156 +12.41 0.29 157 +9.16 0.251 158 +12 (at 436 nm) 0.25 159 +8.45 0.296 160 +10.17 0.295 161 +10.77 0.26 162 +9.23 0.26 164 +43.6 0.25 165 +13.31 0.338 166 +12 0.275 167 +9.42 0.276 168 +4.12 0.267 169 +20.56 0.248 170 +54 0.25 171 +54.8 0.25 173 +29.62 0.26 174 +31.79 0.28 175 +34.64 0.28 176 +25.94 0.266 178 +9.66 0.29 179 +57.14 0.28 180 +17.49 0.263 183 +12.5 0.256 184 +34.2 0.269 185 +31.52 0.257 186 +7.58 0.264 187 +21.43 0.266 188 + 26.18 0.275 189 + 21.14 0.175 190 + 29.42 0.258 191 + 40 0.105 (MeOH) 192 +28 0.1 (MeOH) 193 +34.58 0.24 194 +22.91 0.227 195 +21.05 0.285 196 +28.46 0.26 200 +31.37 0.271 201 +29.44 0.248 203 +27.89 0.251 204 +27.09 0.251

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205 +10.04 0.259 206 +9.73 0.298 207 +10.76 0.288 20S +18.29 0.257 209 +47.92 0.288 211 +80.43 0.281 212 +58.7 0.23 213 +31.11 0.135 T = 24 ° C 214 +14.29 0.238 215 +14.62 0.26 216 +10.07 0.278 217 +11.54 0.26 218 +12.69 0.26 219 +8.63 0.255 220 +10.94 0.256 221 +13.72 0.277 222 +18.39 0.261 223 +46.55 0.29 224 +44.17 0.24 225 +34.16 0.322 226 +34.2 0.2 (MeOH) 227 +39.3 0.23 (MeOH) 228 +44.2 0.16 (MeOH) 229 +50.33 0.302 232 +40.15 0.269 233 +46.85 0.254 234 +15.75 0.254 235 +20.27 0.301 236 + 12.4 0.258

SFC-MS method.

General procedure for the SFC-MS method.

SFC measurements were performed using a supercritical analytical fluid chromatography (SFC) system consisting of a dual pump for delivering carbon dioxide (CO2) and modifier, an autosampler, a column oven, and a diode array detector equipped with a high pressure flow cell up to 400 bar. In the case of a mass spectrometer (MS) configuration, the column stream enters (MS). It is within the competence of the person skilled in the art to set tunable parameters (eg, scan range, minimum measurement time, etc.) in order to obtain ions that make it possible to determine the nominal monoisotopic molecular weight (MW) of the compounds. Data collection was performed using the appropriate software.

Analytical Methods SFC-MS (flow rate is in ml / min, column temperature (T) is in ° C, analysis time is in minutes, back pressure (BPR) in bar

Method number Column Mobile phase Gradient Flow Analysis time BPR Column T one Column Daicel Chiralpak® AD-3 (3 μm, 100 χ 4.6 mm) A: CO ₂ B: MeOH (0.3% iPrNH ₂ ) 35% B retention for 6 min 3.5-35 6 103

Analytical data SFC-MS - Rt means retention time (in minutes), method refers to the method used for (SFC) MS analysis of enantiomerically pure compounds

No. Conn. Rt Chiral purity in the UV region,% Method number 232 2.59 100 one 233 2.20 98.79 one

NMR.

NMR experiments were performed using a 500 MHz Bruker Avance 500 III spectrometer using an internal deuterium locus and equipped with a TXI triple inverse probe head (1H, 13C, 15N), or using a Bruker Avance DRX 400 spectrometer at ambient temperature using an internal deuterium locus and equipped with a SEI (1H, 13C) dual inverse sensor head with Z-gradients, and spectra were recorded at 400 MHz

- 290 037358 for proton and 100 MHz for carbon. Chemical shifts (δ) are reported in parts per million (ppm). J values are expressed in Hz.

Compound 1: 1H NMR (500 MHz, DMSO-d ₆ ): δ 8.92 (s, 1H), 8.40 (d, J = 5.3 Hz, 1H), 8.17 (d, J = 1.2 Hz, 1H), 8.07 (d , J = 1.2 Hz, 1H), 7.92 (d, J = 1.3 Hz, 1H), 7.48-7.40 (m, 3H), 7.36 (d, J = 5.4 Hz, 1H), 4.98 (t, J = 5.4 Hz , 1H), 3.69 (d, J = 9.8 Hz, 1H), 3.44 (dd, J = 10.7 Hz, 5.3 Hz, 1H), 3.34-3.39 (m, 1H, partially overlaps with the solvent peak), 3.29 (d, J = 9.8Hz, 1H), 2.37 (s, 3H), 1.27 (s, 3H).

Compound 4: ¹ H NMR (500 MHz, DMSC ^): δ 8.80 (s, 1H), 8.33-8.37 (m, 2H), 8.20 (d, J = 0.9 Hz, 1H), 8.04 (d, J = 1.6 Hz, 1H), 7.91 (d, J = 1.6 Hz, 1H), 7.52 (dd, J = 7.9 Hz, 1.9 Hz, 1H), 7.36 (s, 1H), 7.30-7.22 (m, 2H), 4.95 ( br s, 1H), 3.70 (d, J = 9.1 Hz, 1H), 3.42 (dd, J = 9.8 Hz, 1.8 Hz, 1H), 3.34-3.39 (m, 1H, partially overlaps with the solvent peak), 3.27 ( d, J = 9.1 Hz, 1H), 2.77 (d, J = 4.4 Hz, 3H), 2.30 (s, 3H), 1.24 (s, 3H).

Compound 45: 1H NMR (500 MHz, DMSC-d6): δ 8.62 (d, J = 2.5 Hz, 1H), 8.49 (d, J = 5.4 Hz, 1H), 8.13 (d, J = 1.6 Hz, 1H), 8.12 (s, 1H), 8.00 (d, J = 1.3 Hz, 1H), 7.50 (s, 1H), 7.46 (d, J = 5.4 Hz, 1H), 7.12 (d, J = 8.5 Hz, 1H), 7.01 (dd, J = 8.7 Hz, 2.7 Hz, 1H), 5.01 (t, J = 5.4 Hz, 1H), 4.24-4.20 (m, 2H), 3.74-3.69 (m, 3H), 3.46 ( dd, J = 10.7 Hz, 5.3 Hz, 1H), 3.42-3.34 (m, 4H), 3.31-3.37 (m, 1H, partially overlaps with the solvent peak), 1.30 (s, 3H).

Compound 66: 1H NMR (500 MHz, DMSO-d ₆ ): δ 8.77 (d, J = 1.9 Hz, 1 H), 8.50 (d, J = 5.4 Hz, 1H), 8.19 (s, 1H), 8.11 ( d, J = 1.9 Hz, 1H), 7.97 (d, J = 1.6 Hz, 1H), 7.51-7.45 (m, 3H), 7.27 (d, J = 8.5 Hz, 1H), 4.97 (t, J = 5.5 Hz, 1H), 4.34-4.30 (m, 2H), 3.77-3.74 (m, 2H), 3.71 (d, J = 9.8 Hz, 1H), 3.47 (dd, J = 10.7 Hz, 5.3 Hz, 1H), 3.38 (dd, J = 10.7 Hz, 5.7 Hz, 1H), 3.35 (s, 3H), 3.31 (d, J = 10.1 Hz, 1H), 1.30 (s, 3H).

Compound 68: 1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 9.39 (s, 1H), 8.90 (s, 1H), 8.36 (d, J = 5.0 Hz, 1H), 8.07 (s, 1H), 7.93 (s, 1H), 7.62 (s, 1H), 7.39 (s, 1H), 7.32 (d, J = 5.4 Hz, 1H), 7.22 (s, 1H), 4.99 (br t, J = 5.2 Hz, 1H ), 3.69 (br d, J = 9.8 Hz, 1H), 3.50-3.35 (m, 2H, partially overlaps with the solvent peak), 3.29 (br d, J = 10.1 Hz, 1H), 2.81 (br d, J = 11.0 Hz, 2H), 2.31-2.40 (m, 1H), 2.16 (s, 3H), 2.07 (s, 3H), 1.87 (brt, J = 11.2 Hz, 2H), 1.78 (br d, J = 11.0 Hz , 2H), 1.58-1.73 (m, 2H), 1.27 (s, 3H).

Compound 73: 1H NMR (500 MHz, DMSO-d6): δ 8.67 (d, J = 8.5 Hz, 1H), 8.51 (d, J = 5.4 Hz, 1H), 8.33 (s, 1H), 8.16 (d, J = 1.6 Hz, 1H), 8.03 (d, J = 1.6 Hz, 1H), 7.54 (dd, J = 8.5 Hz, 1.9 Hz, 1H), 7.46-7.50 (m, 3H), 5.04 (t, J = 5.4 Hz, 1H), 4.01 (s, 3H), 3.68 (d, J = 9.5 Hz, 1H), 3.47 (dd, J = 10.7 Hz, 5.3 Hz, 1H), 3.40 (dd, J = 10.4 Hz, 5.3 Hz, 1H), 3.29-3.33 (m, 1H, partially overlaps with the solvent peak), 3.21 (s, 3H), 1.30 (s, 3H).

Compound 74: 1H NMR (500 MHz, DMSO-d6): δ 8.92 (s, 1H), 8.38 (d, J = 5.0 Hz, 1H), 8.16 (s, 1H), 8.05 (d, J = 1.3 Hz, 1H), 7.91 (s, 1H), 7.51 (dd, J = 7.9 Hz, 1.3 Hz, 1H), 7.38-7.45 (m, 2H), 7.35 (d, J = 5.4 Hz, 1H), 4.97 (t, J = 5.2 Hz, 1H), 3.69 (d, J = 9.8 Hz, 1H), 3.44 (dd, J = 10.4 Hz, 5.3 Hz, 1H), 3.33-3.38 (m, 1H, partially overlaps with the solvent peak), 3.27-3.31 (m, 3H), 3.21 (s, 3H), 2.79 (t, J = 7.6 Hz, 2 H), 1.78 (q, J = 6.9 Hz, 2H), 1.27 (s, 3H).

Compound 110: 1H NMR (400 MHz, DMSO-d ₆ ): δ 8.63 (s, 1H), 8.50 (d, J = 5.5 Hz, 1H), 8.19 (br. S., 1H), 8.15 (d, J = 1.5 Hz, 1H), 8.05 (d, J = 1.5 Hz, 1H), 7.49 (m, 2H), 7.06 (s, 1H), 5.80 (br. S., 1H), 4.52 (m, 1H), 4.23 (m, 1H), 4.10 (m, 1H), 3.93 (s, 3H), 3.76 (m, 2H), 3.45 (s, 2H), 1.33 (s, 6H).

Compound 125: 1H NMR (400 MHz, DMSO-d ₆ ): δ 8.90 (s, 1H), 8.42 (d, J = 5.0 Hz, 1H), 8.18 (s, 1H), 8.12 (d, J = 1.5 Hz , 1H), 8.02 (s, 1H), 7.51 (s, 1H), 7.41-7.49 (m, 2H), 7.38 (d, J = 5.6 Hz, 1H), 4.00-4.14 (m, 2H), 3.62 ( d, J = 10.1 Hz, 1H), 3.39 (d, J = 10.6 Hz, 1H), 2.36 (s, 3H), 1.94 (s, 3H), 1.35 (s, 3H).

Compound 138: 1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 9.47 (br s, 1H), 8.51 (br s, 2H), 8.47 (d, J = 5.7 Hz, 1H), 8.22 (s, 1H) , 8.20 (d, J = 1.3 Hz, 1H), 8.08 (s, 1H), 7.57-8.03 (m, 1H), 7.46-7.56 (m, 3H), 5.20-7.15 (m, 1H), 4.35 (d , J = 10.7 Hz, 1H), 4.14 (d, J = 10.7 Hz, 1H), 3.95-4.09 (m, 1H), 3.73 (d, J = 10.7 Hz, 1H), 3.47 (d, J = 10.7 Hz , 1H), 2.39 (s, 3H), 1.40 (s, 3H), 1.25 (d, J = 7.3Hz, 3H).

Compound 137: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.24 (br s, 1H), 8.45 (d, J = 5.6 Hz, 1H), 8.36 (br s, 3H), 8.20 (s, 1H), 8.17 (d, J = 1.5 Hz, 1H), 8.06 (d, J = 1.5 Hz, 1H), 7.63 (br s, 1H), 7.48-7.53 (m, 1H), 7.42-7.48 (m, 2H), 6.34 (br s, 2H), 4.22 (s, 2H), 3.76-3.89 (m, 2H), 3.70 (d, J = 10.6 Hz, 1H), 3.42 (d, J = 10.6 Hz, 1H), 2.38 ( s, 3H), 1.39 (s, 3H).

Compound 148: 1H NMR (500 MHz, DMSO-d6) δ ppm 8.72 (s, 1H), 8.30 (br d, J = 5.0 Hz, 1H), 8.03 (s, 1H), 7.91 (s, 1H), 7.57 (br d, J = 7.3 Hz, 1H), 7.35 (s, 1H), 7.23 (br d, J = 5.4 Hz, 1H), 7.02 (br d, J = 10.7 Hz, 1H), 5.15 (s, 1H ), 4.99 (br t, J = 5.0 Hz, 1H), 3.67 (br d, J = 9.8 Hz, 1H), 3.39-3.46 (m, 1H), 3.34-3.39 (m, 1H), 3.28 (br d , J = 9.8 Hz, 1H), 2.21 (s, 3H), 1.26 (s, 3H).

Compound 155: 1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.86 (s, 1H), 8.40 (d, J = 5.4 Hz, 1H), 8.12-8.20 (m, 1H), 8.10 (d, J = 1.6 Hz, 1H), 8.01 (br d, J = 7.3 Hz, 1H), 7.97 (d, J = 1.3 Hz, 1H), 7.43 (s, 1H), 7.34 (d, J = 5.4 Hz, 1H), 7.23 (d, J = 11.3 Hz, 1H), 5.01 (t, J = 5.4 Hz, 1H), 3.75 (d, J = 9.5 Hz, 1H), 3.46-3.53 (m, 1H), 3.41 (dd, J = 10.7, 5.7 Hz, 1H), 3.34 (d, J = 9.5 Hz, 1H), 2.85 (d, J = 4.4 Hz, 3H), 2.34 (s, 3H), 1.31 (s, 3H).

Compound 156: 1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.53 (br d, J = 7.9 Hz, 1H), 8.39 (d, J = 5.4 Hz, 1H), 8.06-8.13 (m, 2H), 7.93-8.06 (m, 2H), 7.40 (s, 1H), 7.36 (d, J = 5.0 Hz, 1H), 7.25 (d, J = 12.3 Hz, 1H), 4.93 (t, J = 5.4 Hz, 1H ), 3.99-4.07 (m, 1H), 3.72 (br d, J = 9.8 Hz, 1H), 3.47-3.53 (m, 1H), 3.40 (br dd, J = 10.6, 5.5 Hz, 1H), 3.29 ( br d, J = 9.8 Hz, 1H), 2.81 (d, J = 4.4 Hz, 3H), 1.29 (s, 3H), 0.67-0.91 (m, 4H).

Compound 232: 1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.72 (s, 1H), 8.45-8.56 (m, 2H), 8.12 (s, 1H), 7.97 (s, 1H), 7.52 (br d , J = 8.2 Hz, 1H), 7.43-7.48 (m, 2H), 7.22 (br d, J = 8.5 Hz, 1H), 5.23-5.42 (m, 1H), 5.05- 291 037358

5.17 (m, 1H), 4.97 (br t, J = 5.0 Hz, 1H), 3.71 (br d, J = 9.8 Hz, 1H), 3.44-3.52 (m, 1H), 3.38 (br dd, J = 10.6 , 5.5

Hz, 1H), 3.28-3.33 (m, 2H, partially overlaps with the solvent peak), 3.25 (br dd, J = 9.8, 6.6 Hz, 1H),

2.74-2.95 (m, 2H), 2.28 (s, 3H), 1.30 (s, 3H).

Pharmacological part.

Biological Assay A. Inhibition of the autophosphorylation activity of recombinant human NF-kappaB-induced kinase (NIK / MAP3K14) (AlphaScreen®).

NIK / MAP3K14 autophosphorylation activity was measured using the AlphaScreen® (α-screen) format (Perkin Elmer). All test compounds were dissolved in dimethyl sulfoxide (DMSO) and further dilutions were made in assay buffer. The final concentration of DMSO in the analyzes was 1% (v / v). The assay buffer was 50 mM Tris, pH 7.5, containing 1 mM EGTA (ethylene glycol tetraacetic acid), 1 mM DTT (dithiothreitol), 0.1 mM Na ₃ VO4, 5 mM MgCl ₂ , 0.01% Tween® 20. Analyzes were performed in 384-well Alphaplates (Perkin Elmer). The incubation mixture consisted of compound, 25 μM adenosine 5'-triphosphate (ATP) and 0.2 nM NIK / MAP3K14. Incubations were initiated by the addition of GST-labeled NIK / MAP3K14 enzyme, carried out for 1 h at 25 ° C, and terminated by the addition of stop buffer containing anti-phosphoIKK Ser176 / 180 antibody. Protein A particles as an acceptor and glutathione particles as a donor were added prior to reading using an EnVision® Multilabel Plate Reader (Perkin Elmer). The signal from the wells containing blanks was subtracted from the signals obtained from all other wells and the control against the Logi ₀ concentration of the compound.

Biological Assay B. Effect of Compounds on P-IKKa Levels in L363 Cells (Multiple Myeloma with Translocation That Increases NIK Expression).

All test compounds were dissolved in DMSO and further dilutions were made in culture medium. The final concentration of DMSO was 1% (v / v) in cell assays. Human L363 cells (ATCC) were cultured in RPMI 1640 medium supplemented with GlutaMax and 10% fetal bovine serum (PAA). Cells were generally maintained at densities of 0.2x106 cells per ml 1 x 10 ⁶ cells per ml at 37 ° C in a humidified atmosphere containing 5% CO2. Cells were subcultured twice a week, splitting to obtain a low density. Cells were plated in 96-well plates (Nunc 167008) at 2x 10 ⁶ per ml medium in a volume of 75 μl per well plus 25 μl 1 μg / ml recombinant human B cell activation factor (BAFF / BLyS / TNFSF13B). The seeded cells were incubated at 37 ° C in a humidified atmosphere containing 5% CO2 for 24 hours. Drugs and / or solvents (20 μl) were added to a final volume of 120 μl. After 2 h of treatment, the plates were removed from the incubator and cell lysis was performed by adding 30 μl of 5x lysis buffer, followed by shaking on a plate shaker at 4 ° C for 10 min. At the end of this incubation, the lysed cells were centrifuged at 800 x g for 20 min at 4 ° C and the lysate was assessed for P-IKKa levels by a sandwich immunoassay performed on anti-rabbit antibody coated Mesoscale plates. Within the experiment, the results for each treatment represent the mean of 2 replicate wells. For initial screening purposes, compounds were tested using an 8 point dilution curve (1: 3 serial dilutions). For each experiment, controls (containing MG132 and BAFF, but no test drug) and blank incubation (containing MG132 and BAFF, and 10 μM ADS125117, a test concentration known to give complete inhibition) were processed in parallel. Blank incubation value was subtracted from all control and sample values. To determine the IC _{50, the} sigmoidal curve was fitted to a plot of% inhibition of P-IKKa control levels versus Log ₁₀ compound concentration.

Note: Compounds 237 and 238 were tested at a maximum top concentration of 823 nM.

Biological analysis C. Determination of antiproliferative activity on JJN-3 multiple myeloma cells (with a translocation that increases NIK expression) and KMS12-BM (NIK WT).

All test compounds were dissolved in DMSO and further dilutions were made in culture medium. The final DMSO concentration was 0.3% (v / v) in cell proliferation assays. Viability was assessed using the CellTiter-Glo cell viability assay kit (Promega). Human JJN-3 and KMS12-BM (DSMZ) cells were cultured in JAPMI 1640 medium supplemented with 2 mM L-glutamine and 10% fetal bovine serum (PAA). The cells were generally maintained as suspension cells at 37 ° C. in a humidified atmosphere containing 5% CO2. The cells were subcultured at a seeding density of 0.2x10 ⁶ / ml twice a week. Cells were plated in black 96-well plates with cell adhesion treated (Perkin Elmer). The densities used for seeding ranged from 15,000 (JJN3) to 20,000 (KMS12BM) cells per well in a total volume of 135 μl of medium. Drugs and / or solvents (15 μl) were added to a final volume of 150 μl. After 96 hours of treatment, the plates were removed from the incubator and allowed to equilibrate at room temperature for approximately 10 minutes. 75 μl of CellTiter-Glo reagent was added to each well and then capped (Perkin Elmer Topseal) and shaken on a plate shaker for 10 min. Luminescence was measured on a Topcount HTS instrument (Perkin Elmer). Within the framework of

- Experiment 292 037358 The results for each treatment represent the mean of 2 replicate wells. For initial screening purposes, compounds were tested using a 9-point dilution curve (1: 3 serial dilutions). For each experiment, control samples (containing no drug) and blank incubation (containing cells read at the time of compound addition) were processed in parallel. Blank incubation data was subtracted from all control and sample values. For each sample, the mean value for cell growth (in relative light units) is expressed as a percentage of the mean value for cell growth of the control.

The data for the compounds according to the invention obtained in the above analyzes are given in table. A (the values in the table are averaged values for all measurements for all batches of the compound), ps means not calculated).

Table A

Compound Inhibition of NIK autophosphorylation (IC50 (nM)) Inhibition of pIKKa_L-363 (IC50 (nM)) Inhibition of proliferation KMS-12 (IC50 (nM)) JJN-3 proliferation inhibition (IC50 (nM)) one 1.8 2.2 5188 85 2 4.3 4.8 > 10000 58 3 10.2 15.1 > 10000 115 four 4.2 20.9 > 10000 759 five 2511.9 > 10000 n.d. n.d. 6 446.7 > 10000 n.d. n.d. 7 5.8 n.d. 2512 148 eight 1.3 32.4 > 10000 87 nine 10.7 8.1 10233 162 10 7.4 11.5 1227 67 AND 1.8 6.0 > 10000 617 12 4.1 25.7 4898 138 13 9.2 30.9 > 10000 146 fourteen 5.5 21.4 > 10000 170 fifteen 11.0 -269.1 > 10000 117 sixteen 15.5 15.5 550 258 17 1.1 6.8 479 56 eighteen 2.6 20.0 -8128 407 nineteen 27.5 38.9 > 10000 1950 twenty 1.7 11.5 -1585 63 21 2.5 4.5 891 51 22 2.5 11.5 631 7 23 7.1 12.0 > 10000 71 24 4.5 6.0 2818 13 25 3.6 33.9 589 12 26 3.7 n.d. > 10000 255 27 9.2 n.d. > 10000 106 28 n.d. n.d. n.d. n.d. 29 17.4 n.d. > 10000 166 thirty 51.3 n.d. > 10000 > 10000 31 5.3 n.d. > 10000 2344 32 4.0 n.d. > 10000 170 33 11.2 n.d. > 10000 85 34 20.9 n.d. > 10000 316 35 37.2 n.d. 7079 129 36 75.9 n.d. 6457 51 37 37.2 n.d. 4169 17 38 30.9 n.d. > 10000 182 39 7.4 n.d. 2344 87 40 8.7 n.d. > 10000 155 41 1.7 n.d. 110 13 42 309.0 n.d. > 10000 4266 43 2.5 n.d. 251 nine 44 8.3 n.d. > 10000 219 45 9.1 37.2 > 10000 490 47 15.1 n.d. > 10000 776 48 8.9 n.d. > 10000 447 49 24.6 n.d. > 10000 1622 fifty 3.0 n.d. 102 nine 51 49.0 n.d. > 10000 363 52 41.7 n.d. > 10000 676 53 3.6 n.d. 1259 33 54 9.8 n.d. > 10000 275 55 15.5 n.d. > 10000 282 56 125.9 n.d. > 10000 1738 57 50.1 n.d. > 10000 > 10000 58 2.6 n.d. 6761 85 59 23.4 n.d. 4074 129 60 2754.2 n.d. n.d. n.d. 61 11.0 n.d. > 10000 186 62 912.0 n.d. n.d. n.d. 63 1.7 n.d. -5012 7

- 293 037358

64 1.8 18.2 1230 -246 65 4.1 103.1 > 10000 1102 66 3.0 5.9 nineteen 251 67 4.3 n.d. > 10000 -1698 68 0.8 1.9 1479 sixteen 69 4.9 n.d. > 10000 1023 70 3.9 n.d. > 10000 2188 71 7.2 n.d. > 10000 148 72 11.0 n.d. > 10000 123 73 2.2 1.4 > 10000 68 74 4.0 16.2 -1148 182 75 3.6 n.d. -3311 105 76 186.2 n.d. > 10000 2344 77 46.8 n.d. -2455 126 78 2.7 7.9 2042 87 79 47.9 75.9 -5129 91 80 15.2 208.9 1000 124 81 n.d. n.d. n.d. n.d. 82 7.6 5.3 > 10000 22 83 n.d. n.d. n.d. n.d. 84 19.1 12.9 -7586 251 85 11.3 41.7 > 10000 57 87 7.1 93.3 1175 35 88 85.1 n.d. > 10000 178 89 20.9 n.d. > 10000 -100 90 218.8 n.d. > 10000 > 10000 91 7.2 n.d. > 10000 -107 92 138.0 n.d. > 10000 389 93 11.5 n.d. > 10000 83 94 9.8 n.d. > 10000 166 95 9.3 n.d. > 10000 129 96 9.1 n.d. > 10000 -81 97 45.7 n.d. 4365 59 98 128.8 n.d. > 10000 105 99 218.8 n.d. 8318 380 100 91.2 n.d. > 10000 1413 101 49.0 n.d. 1349 447 102 403.3 n.d. > 10000 3548 103 104.7 n.d. > 10000 3715 104 12.0 n.d. > 10000 2138 105 28.5 22.9 -6607 118 106 63.1 123.0 > 10000 1622 107 41.7 n.d. > 10000 1023 108 11.0 3.8 > 3981 39 109 53.7 n.d. n.d. 676

- 294 037358

110 4.2 n.d. > 10000 193 111 3548.1 n.d. > 10000 3467 112 4.3 n.d. > 10000 twenty OF 2.6 n.d. -407 28 114 2.2 n.d. 490 nineteen 115 4.9 n.d. > 10000 166 116 6.8 n.d. > 10000 162 117 4.7 n.d. 1549 nineteen 118 25.7 n.d. > 10000 933 119 7.1 n.d. 1380 28 120 15.5 n.d. > 10000 25 121 8.5 n.d. 120 12 122 4.7 n.d. -4467 35 123 8.5 n.d. 1047 fourteen 124 1.6 n.d. 437 525 125 13.8 3.6 -6918 182 126 112.2 -6.9 -8913 151 127 128.8 11.5 > 10000 570 128 251.2 20.9 > 10000 407 129 1.4 3.2 -7943 330 130 1.5 2.2 9772 167 131 1.3 4.7 > 10000 324 132 1.3 2.2 5012 128 133 0.7 3.0 4365 170 134 0.9 2.8 5495 91 135 58.9 4365.2 n.d. n.d. 136 1.7 <0.66 > 10000 269 137 6.0 2.7 -10000 545 138 11.2 2.1 -4786 102 139 56.2 26.9 -8913 302 140 51.3 56.2 -9120 550 141 8.7 2.2 > 10000 33 142a 12.0 2.2 > 10000 3631 142b 17.0 -58.9 > 10000 977 143 6.5 12.3 > 10000 200 144 5.8 -1174.9 > 10000 -10000 145 17.4 436.5 n.d. n.d. 146 19.9 5.2 > 10000 78 147 3.9 1.2 > 10000 302 148 4.7 8.9 > 10000 523 149 10.0 102.3 n.d. n.d. 150 0.8 2.2 > 10000 91 151 22.4 426.6 n.d. n.d. 152 2.3 7.8 > 10000 272 153 1.3 6.3 > 10000 240

- 295 037358

154 1.4 6.6 > 10000 141 155 3.5 7.7 > 10000 467 156 4.8 7.8 > 10000 251 157 4.9 12.9 -7586 178 158 5.4 91.2 > 10000 1230 159 5.5 20.4 > 10000 4786 160 11.2 64.6 > 10000 4786 161 20.4 407.4 n.d. n.d. 162 5.5 19.5 > 10000 288 163 3.5 33.1 > 10000 437 164 26.9 288.4 n.d. n.d. 165 3.6 6.0 -5248 1122 166 8.9 18.6 > 10000 955 167 7.6 19.1 6166 562 168 10.7 14.5 > 10000 -1413 169 8.7 8.3 > 10000 -1000 170 1.0 2.3 -4677 81 171 1.1 34.7 > 10000 955 172 4.8 2.4 > 10000 65 173 1.8 1.3 > 10000 29 174 3.5 2.0 > 10000 71 175 1.8 2.8 -191 27 176 3.8 5.9 > 10000 91 177 3.2 1.2 -246 fourteen 178 2.0 2.6 -891 42 179 2.2 1.4 1288 58 180 3.7 44.7 n.d. n.d. 181 5.1 7.8 > 10000 195 182 n.d. n.d. n.d. n.d. 183 9.1 7.1 > 10000 501 184 2.8 19.1 > 10000 178 185 6.5 6.6 n.d. n.d. 186 4.6 n.d. n.d. n.d. 187 3.2 n.d. 1097 39 188 2.6 5.4 > 10000 54 189 30.9 1621.8 n.d. n.d. 190 34.7 2630.3 n.d. n.d. 191 13.8 4073.8 n.d. n.d. 192 72.4 2951.2 537 1175 193 1.6 1.7 > 10000 22 194 3.6 1.4 479 17 195 6.2 1.9 -3715 thirty 196 7.8 1.0 > 10000 fourteen 197 6.0 4.8 -240 33 198 4.6 5.6 -550 63

- 296 037358

199 6.9 7.4 > 10000 76 200 1.7 -0.66 > 10000 41 201 2.8 -1202.3 n.d. n.d. 202 n.d. n.d. n.d. n.d. 203 6.6 1.8 -5888 fourteen 204 6.2 1.5 -3981 fourteen 205 6.0 11.2 > 10000 162 206 5.3 n.d. -7244 71 207 5.0 13.2 -9550 66 208 6.5 10.7 > 10000 389 209 14.5 14.8 > 10000 132 210 33.1 > 10000 n.d. n.d. 211 16.2 3162.3 n.d. n.d. 212 25.1 -4466.9 n.d. n.d. 213 4.2 5.0 > 10000 1072 214 6.9 n.d. n.d. n.d. 215 1.5 2.9 > 10000 199 216 49.0 144.5 n.d. n.d. 217 9.8 107.2 -7943 4266 218 3.6 -1230.3 n.d. n.d. 219 15.5 5495.4 n.d. n.d. 220 10.2 72.4 > 10000 4571 221 32.4 645.7 n.d. n.d. 222 31.6 302.0 n.d. n.d. 223 1.6 3.1 -851 23 224 14.1 83.2 > 10000 3236 225 20.0 19.5 > 10000 195 226 4.3 33.1 > 10000 74 227 7.9 32.4 -3162 96 228 5.4 19.5 > 10000 120 229 7.6 22.4 > 10000 251 230 6.3 7.7 > 10000 46 231 7.8 12.3 > 10000 89 232 5.5 11.5 > 10000 282 233 4.6 21.4 > 10000 741 234 3.5 5.9 -6607 twenty 235 3.9 60.3 2692 457 236 2.6 42.7 178 32 237 213.8 > 831.8 n.d. n.d. 238 955.0 > 831.8 n.d. n.d. 239 13.8 354.8 n.d. n.d. 240 2.5 11.2 302 44

Examples of possible compositions

The active ingredient (a.i.) used in all of these examples refers to a compound of formula (I) including any tautomeric or stereoisomeric form or pharmaceutically acceptable addition salt or solvate thereof; in particular to any of the exemplary compounds.

Typical examples of formulations for a preparation according to the invention are as follows.

1. Tablets.

Active ingredient 5-50 mg Dicalcium phosphate 20 mg Lactose 30 mg Talc 10 mg Magnesium stearate 5 mg Potato starch up to 200 mg

2. Suspension.

An aqueous suspension was prepared for oral administration in such a way that each milliliter contained 1-5 mg of active ingredient, 50 mg of sodium carboxymethylcellulose, 1 mg of sodium benzoate, 500 mg of sorbitol and water to 1 ml.

3. Injectable preparation.

A parenteral composition was prepared by mixing 1.5% (w / v) active ingredient in 0.9% NaCl solution or 10 vol% propylene glycol in water.

4. Ointment.

Active ingredient 5-1000 mg Stearyl alcohol 3 g Lanolin 5 g White Vaseline 15 g Water up to 100 g

In this example, the active ingredient may be replaced with the same amount of any of the compounds according to the present invention, in particular the same amount of any of the exemplary compounds.

Claims (20)

CLAIM 1. Compound of formula (I) its tautomer or stereoisomeric form, where R ¹ denotes C _1-4 alkyl; R ² is C _1-6 alkyl or C _1-6 alkyl substituted with one R ⁵ ; Y is CR ⁴ or N; R ⁴ is hydrogen or halogen; R ⁵ is halogen, Het ^3a , —NR ^6a R ^6b or —OR ⁷ ; R ^6a is hydrogen or C _1-4 alkyl; R ^6b is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, -C (= O) -C1-4alkil, -C (= O) -Het ^4, S (= O) _2-C1-4alkyl, -C ( = O) -C _1-4 alkyl substituted with one substituent selected from the group consisting of —OH and —NR ^16a R ^16b , or C _1-4 alkyl substituted with one substituent selected from the group consisting of —OH and - S (= O) ₂ -C _1-4 α-alkyl; R ⁷ denotes hydrogen, C ^ alkyl, -C1-4alkyl-NR ^8a R ^8b , -C (= O) -R ⁹ , -S (= O) 2-OH, -P (= O) 2-OH, - (C = O) CH (NH2) -C1-4αalkyl-Ar ¹ or -C1-4alkyl-Het ^3b , R ^8a is hydrogen or C _1-4 alkyl; R ^8b is hydrogen, C _1-4 alkyl or C _3-6 cycloalkyl; R ⁹ is C _1-6 alkyl or C _1-6 alkyl substituted with one substituent selected from the group consisting of —NH2, —COOH and Het ⁶ ; R ^16a and R ^16b are each independently hydrogen, C _1-4 alkyl or C _3-6 cycloalkyl; R ³ is phenyl optionally substituted with one, two or three substituents, each of which is independently selected from the group consisting of halogen, cyano, C1-6 alkyl, —O — C1-4 alkyl, —C (= O) —R ¹⁰ , - S (= O) 2-C _1-4 α-alkyl, -S (= O) (= NR ^20a ) -C1-4 alkyl, -O-C1-4 alkyl substituted with one, two, three halogen atoms, -O-C1- 4αalkyl-R ¹² , C3-6 cycloalkyl, -O-C _3-6 cycloalkyl, Het ^1a , -O-Het ^1b , R ¹⁸ , R ²¹ , -P (= O) - (C1-4 alkyl) 2, -NH- C (= O) -C1-4αalkyl, -NH-C (= O) -Het ^1g , -NR ^17a R ^17b , C1-4 alkyl substituted with one, two or three halogen atoms, C _1-4 alkyl substituted with one, two or three groups —OH, C _1-4 alkyl substituted with one R ¹³ , C 1-4 alkyl substituted with one R ¹⁸ , C _2-6 alkenyl, C 2-6 alkenyl substituted with one R ¹³ ; C _2-6 alkynyl and C _2-6 alkynyl substituted with one R ¹³ ; R ¹⁰ is —OH, —O — C _1-4 alkyl, —NR ^11a R ^11b, or Het ² ; R ¹⁸ denotes a 5-membered aromatic ring containing one, two or three N atoms; wherein said 5-membered aromatic ring may be optionally substituted with one substituent selected from the group consisting of C _1-4 alkyl and C _3-6 cycloalkyl; R ²¹ is 3,6-dihydro-2H-pyran-4-yl or 1,2,3,6-tetrahydro-4-pyridinyl, where 1,2,3,6tetrahydro-4-pyridinyl may optionally be substituted at NC _1-4 alkyl or C _3-6 cycloalkyl; Het ^1a , Het ^1c and Het ^1d each independently represent a 4-7 membered monocyclic saturated heterocyclic radical containing one or two heteroatoms independently selected from O, S, S (= O) _p and N; or a 6-11 membered bicyclic saturated heterocyclic radical including fused, spiro fused and bridged rings containing one, two or three heteroatoms independently selected from O, S, S (= O) _p and N; wherein said 4-7-membered monocyclic saturated heterocyclic radical or said 6-11-membered bicyclic saturated heterocyclic radical may optionally be substituted, where possible, on one, two or three ring atoms with N substituents, each of which is independently selected from the group consisting of C _1-4 alkyl, C _3-6 cycloalkyl and C _1-4 alkyl substituted with one substituent selected from the group consisting of —OH and —C _1-4 alkyl; and wherein said 4-7 membered monocyclic saturated heterocyclic radical or said 6-11 membered bicyclic saturated heterocyclic radical may optionally be substituted on one, two or three C ring atoms with one or two substituents, each of which is independently selected from the group consisting of from —OH, halogen, C _1-4 alkyl, cyano, —C (= O) —C _1-4 alkyl, —O — C _1-4 alkyl, —NH ₂ , —NH (C _1-4 α alkyl) and -N ( _C1-4 alkyl) ₂ ; Het ^1b , Het ^1e , Het ^1g , Het ⁴ , Het ⁷ and Het ⁸ each independently represent a 4-7 membered monocyclic saturated heterocyclic radical attached to the remainder of the molecule of a compound of formula (I) through any available ring carbon atom, wherein said Het ^1b , Het ^1e , Het ^1g , Het ⁴ , Het ⁷ and Het ⁸ contain one or two heteroatoms, each of which is independently selected from O, S, S (= O) p and - 298 037358 N; and said 4-7 membered monocyclic saturated heterocyclic radical may be optionally substituted, where possible, on one or two ring atoms with N substituents, each independently selected from the group consisting of C _1-4 alkyl, C _3-6 cycloalkyl and C _1-4 alkyl substituted with one substituent selected from the group consisting of —OH and —O — C _1-4 alkyl; and said 4-7 membered monocyclic saturated heterocyclic radical may be optionally substituted at one, two or three C ring atoms with one or two substituents, each independently selected from the group consisting of —OH, halogen, C _1-4 alkyl, cyano, —C (= O) —C _1-4 alkyl, —O — C _1-4 alkyl, —NH2, —NH (C _1-4 alkyl) and —N (C _1-4 alkyl) ₂ ; Het ² represents a heterocyclic radical of formula (b-1) ....... Ν ^Ζ λ (b-1); (b-1) is an N-linked 4-7 membered monocyclic saturated heterocyclic radical optionally containing one additional heteroatom selected from O, S, S (= O) _p and N, or an N-linked 6-11 membered bicyclic saturated heterocyclic radical, including fused, spiro-fused and bridged rings, optionally containing one or two heteroatoms, each of which is independently selected from O, S, S (= O) _p and N; where in the case where (b-1) contains one or two additional N atoms, said one or two N atoms may be optionally substituted by substituents, each of which is independently selected from the group consisting of C _1-4 alkyl, C _3-6 cycloalkyl and Het ⁷ ; and wherein (b-1) may be optionally substituted on one, two or three C ring atoms with one or two substituents, each independently selected from the group consisting of halogen, —OH, cyano, C _1-4 alkyl, —O —C _1-4 alkyl, —NH2, —NH (C _1-4 alkyl), —N (C _1-4 alkyl) ₂ and C _1-4 alkyl-OH; R ^11b is hydrogen; Het ^1e ; C1-4alkyl; -C1-4alkyl-Het ⁵ ; -C1-4alkyl-Het ⁸ ; C _1-4 alkyl substituted with one, two or three substituents each independently selected from the group consisting of halogen, —OH, and —O — C _1-4 alkyl; C _3-6 cycloalkyl or C _3-6 cycloalkyl substituted with one, two or three substituents, each independently selected from the group consisting of halogen, —OH, and —OC _1-4 alkyl; R ¹³ is —O — C1-4 alkyl, —C (= O) NR ^15a R ^15b , —NR ^19a R ^19b , C3-6 cycloalkyl, Het ^1d or —C (= O) —Het ^1f ; R ¹² denotes -OH, -O-Smalkyl, -NR ^14a R ^14b , -C (= O) NR ^14c R ^14d , ^ (= O) 2-Smalkyl, -S (= O) (= NR ^20b ) C _{1 -4} alkyl, C _3-6 cycloalkyl, Ar ² or Het ^1c ; Ar ¹ is phenyl optionally substituted with one hydroxyl group; Ar ² is phenyl optionally substituted with one C _1-4 alkyl; Het ^3a , Het ^3b , Het ⁵ , Het ⁶ and Het ^1f each independently represent a heterocyclic radical of formula (c-1) ....... Ν ^Ζ ) (s-1); (c-1) is an N-linked 4-7 membered monocyclic saturated heterocyclic radical optionally containing one additional heteroatom selected from O, S, S (= O) _p and N; moreover, when (c-1) contains one additional N atom, said additional N atom may be optionally substituted with C _1-4 alkyl or C _3-6 cycloalkyl; and (c-1) may optionally be substituted on one or two of the C ring atoms with one or two substituents each independently selected from the group consisting of halogen, C _1-4 alkyl, or C _3-6 cycloalkyl; R ^11a , R ^14a , R ^14c , R ^15a , R ^17a and R ^19a are each independently hydrogen or C _1-4 alkyl; R ^14b , R ^14d , R ^15b , R ^17b and R ^19b are each independently hydrogen, C _1-4 alkyl; C _3-6 cycloalkyl; -C (= O) -C _1-4 alkyl; C _1-4 alkyl substituted with one substituent selected from the group consisting of halogen, —OH, and —O — C _1-4 alkyl; -C (= O) -C _1-4 alkyl substituted with one substituent selected from the group consisting of halogen, -OH and -O-C _1-4 alkyl, or -S (= O) ₂ -C _1-4 alkyl ; R ^20a and R ^20b each independently represent hydrogen, C _1-4 alkyl; C _3-6 cycloalkyl or C _1-4 alkyl substituted with one substituent selected from the group consisting of —OH and —O — C _1-4 alkyl; p is 1 or 2; and a pharmaceutically acceptable addition salt or solvate thereof. 2. The compound according to claim 1, where Y denotes CR ⁴ ; R ⁵ is Het ^3a , —NR ^6a R ^6b or —OR ⁷ ; R ³ is phenyl optionally substituted with one, two or three substituents, each of which is independently selected from the group consisting of halogen; cyano; C1-6alkyl; -O-C1-4alkyl; -C (= O) -R ¹⁰ ; -S (= O) 2-C _1-4 alkyl; -S (= O) (= NR ^20a ) -C _1-4 alkyl; -O-C _1-4 alkyl substituted with one, two - 299 037358 or three halogen atoms; -O-C _1-4 alkyl-K ¹² ; C _3-6 cycloalkyl; —O — C _3-6 cycloalkyl; Het ^1a ; -O-Het ^1b ; R ¹⁸ ; R ²¹ ; -P (= O) - (C1-4alkyl) 2; -NH-C (= O) -C1-4alkyl; -NH-C (= O) -Het ^1g ; -NR ^17a R ^17b ; C1-4alkyl substituted with one, two or three halogen atoms; _C1-4 alkyl substituted with one, two or three groups -IS HE; C _1-4 alkyl substituted with one R ¹³ ; C1-4alkyl substituted with one R ¹⁸ ; C2-6 alkenyl and C _2-6 alkenyl substituted with one R ¹³ ; Het ² represents a heterocyclic radical of formula (b-1) (b-1); (b-1) is an N-linked 4-7 membered monocyclic saturated heterocyclic radical optionally containing one additional heteroatom selected from O, S, S (= O) p and N, or an N-linked 6-11 membered bicyclic saturated heterocyclic radical including fused, spiro-fused or bridged rings, optionally containing one or two additional heteroatoms, each independently selected from O, S, S (= O) p and N; where in the case where (b-1) contains one or two additional N atoms, said one or two N atoms may be optionally substituted with C _1-4 alkyl; and wherein (b-1) may be optionally substituted on one, two or three C ring atoms with one or two substituents, each independently selected from the group consisting of halogen, —OH, cyano, C _1-4 alkyl, —O —C _1-4 alkyl, —NH ₂ , —NH (C _1-4 alkyl), —N (C _1-4 alkyl) _2, and C _1-4 alkyl-OH; R ^11b is hydrogen; Het ^1e ; C1-4alkyl; C1-4alkyl-Het ⁵ ; C1-4alkyl substituted with one, two or three substituents each independently selected from the group consisting of halogen, —OH, and —O — C _1-4 alkyl; C _3-6 cycloalkyl or C _3-6 cycloalkyl substituted with one, two or three substituents, each independently selected from the group consisting of halogen, —OH, and —O — C _1-4 alkyl; and R ^14b , R ^14d , R ^15b , R ^17b and R ^19b are each independently hydrogen; C _1-4 alkyl; C _3-6 cycloalkyl or C _1-4 alkyl substituted with one substituent selected from the group consisting of halogen, —OH, and —O — C _1-4 alkyl. 3. The compound according to claim 1, where R ⁵ denotes halogen, -NR ^6a R ^6b or -OR ⁷ ; R ^6a is hydrogen; R ^6b is —C (= O) —C _1-4 alkyl or —S (= O) ₂ —C _1-4 alkyl; R ⁷ denotes hydrogen, -C1-4alkyl-NR ^8a R ^8b , -C (= O) -R ⁹ , -S (= O) 2-OH or - (C = O) -CH (NH ₂ ) -C _{1 -4} alkyl-Ar ¹ ; R ^8a is hydrogen; R ^8b is C _3-6 cycloalkyl; R ³ is phenyl optionally substituted with one, two or three substituents, each of which is independently selected from the group consisting of halogen; cyano; C1-6alkyl; -O-C1-4alkyl; -C (= O) -R ¹⁰ ; -S (= O) 2-C _1-4 alkyl; -O-C _1-4 alkyl-K ¹² ; C3-6cycloalkyl; -O-C3-6cycloalkyl; Het ^1a ; -O-Het ^1b ; R ¹⁸ ; -P (= O) - (C1-4alkyl) ₂ ; -NH-C (= O) -C _1-4 alkyl; -NH-C (= O) -Het ^1g ; -NR ^17a R ^17b ; C1-4alkyl substituted with one, two or three halogen atoms; C1-4alkyl substituted with one, two or three —OH groups; C1-4alkyl substituted with one R ¹³ ; C2-6 alkenyl substituted with one R ¹³ ; and C _2-6 alkynyl substituted with one R ¹³ ; R ¹⁸ denotes a 5-membered aromatic ring containing one, two or three N atoms; moreover, said 5-membered aromatic ring may be optionally substituted with one substituent selected from the group consisting of C _1-4 alkyl; Het ^1a , Het ^1c and Het ^1d each independently represent a 4-7 membered monocyclic saturated heterocyclic radical containing one or two heteroatoms, each independently selected from O and N; wherein said 4- to 7-membered monocyclic saturated heterocyclic radical may be optionally substituted, where possible, on one or two ring atoms with an N substituent, each independently selected from the group consisting of C _1-4 alkyl, C _3-6 cycloalkyl and C _1-4 alkyl substituted with one C _1-4 alkyl; and said 4-7 membered monocyclic saturated heterocyclic radical may be optionally substituted at one, two or three C ring atoms with one or two substituents, each independently selected from the group consisting of —OH, halogen, C _1-4 alkyl, —O — C _1-4 alkyl and —N (C _1-4 alkyl) ₂ ; Het ^1b , Het ^1e , Het ^1g , Het ⁷ and Het ⁸ each independently represent a 4-7 membered monocyclic saturated heterocyclic radical attached to the remainder of the molecule of a compound of formula (I) through any available ring carbon atom, said Het ^1b , Het ^1e , Het ^1g , Het ⁷ and Het ⁸ contain one or two heteroatoms, each of which is independently selected from O and N; wherein said 4- to 7-membered monocyclic saturated heterocyclic radical may be optionally substituted, where possible, on one or two ring atoms with an N substituent, in each case independently selected from the group consisting of C _1-4 alkyl and C _3-6 cycloalkyl; and said 4-7 membered monocyclic saturated heterocyclic radical may be - 300 037358 optionally substituted on one, two or three ring C atoms with one or two substituents, each of which is independently selected from the group consisting of —OH and halogen; Het ² represents a heterocyclic radical of formula (b-1) (b-1) is an N-linked 4-7 membered monocyclic saturated heterocyclic radical, optionally containing one additional heteroatom selected from O and N, or an N-linked 6-11 membered bicyclic saturated heterocyclic radical including fused, spiro-fused and bridging rings optionally containing one or two additional N atoms; where in the case where (b-1) contains one or two additional N atoms, said one or two additional N atoms may be optionally substituted with a substituent, in each case independently selected from the group consisting of C _1-4 alkyl, C _{3- 6} cycloalkyl and Het ⁷ ; and wherein (b-1) may be optionally substituted on one, two or three C ring atoms with one or two substituents at each occurrence independently selected from the group consisting of —OH, cyano, C _1-4 alkyl, and C _1-4 alkyl-OH; R ^11b is Het ^1e ; C1-4alkyl; -C1-4alkyl-Het ⁵ ; _{—C 1-4} alkyl-Het ⁸ , C 1-4 alkyl substituted with one, two or three OH groups; or C _3-6 cycloalkyl substituted with one, two or three substituents, each independently selected from the group consisting of halogen and —OH; R ¹² is —OH, —O — C1-4 alkyl, —NR ^14a R ^14b , —C (= O) NR ^14c R ^14d , —S (= O) 2 — C _1-4 alkyl, C _3-6 cycloalkyl, Ar ² or Het ^1c ; Ar ¹ is phenyl; Het ⁵ , Het ⁶ and Het ^1f each independently represent a heterocyclic radical of formula (c-1) (s-1); (c-1) is an N-linked 4-7 membered monocyclic saturated heterocyclic radical optionally containing one additional heteroatom selected from O and N; moreover, when (c-1) contains one additional N atom, said additional N atom may be optionally substituted with C _1-4 alkyl; and R ^14b , R1 ^4d , R1 ^5b , R17 ^b and R19 ^b are each independently hydrogen; C _1-4 alkyl; C _3-6 cycloalkyl; -C (= O) -C _1-4 alkyl; C _1-4 alkyl substituted with one substituent selected from the group consisting of —OH and —O — C _1-4 alkyl or —S (= O) ₂ —C _1-4 α alkyl. 4. The compound according to claim 1 or 2, where R ⁵ means -NR ^6a R ^6b or -OR ⁷ ; R ^6a is hydrogen; R ^6b is —C (= O) —C _1-4 alkyl or —S (= O) ₂ —C _1-4 alkyl; R ⁷ is hydrogen, —C (= O) —R ⁹ , —S (= O) ₂ —OH or - (C = O) —CH (NH ₂ ) —C _1-4 alkyl-Ar ¹ ; R ⁹ is C _1-4 alkyl or C _1-4 alkyl substituted with one substituent selected from the group consisting of —NH2, —COOH and Het ⁶ ; R ³ is phenyl optionally substituted with one, two or three substituents, each of which is independently selected from the group consisting of halogen; cyano; C1-6alkyl; -O-C1-4alkyl; -C (= O) -R ¹⁰ ; -S (= O) 2-C _1-4 alkyl; —O — C _1-4 alkyl-R ¹² ; C3-6cycloalkyl; -O-C3-6cycloalkyl; Het ^1a ; -O-Het ^1b ; R ¹⁸ ; -P (= O) - (C1-4alkyl) ₂ ; -NH-C (= O) -C _1-4 α-alkyl; -NH-C (= O) -Het ^1g ; C _1-4 alkyl substituted with one, two or three halogen atoms; C _1-4 alkyl substituted with one, two or three —OH groups, and C _1-4 alkyl substituted with one R ¹³ ; R ¹⁰ is —OH, —O — C _1-4 alkyl, —NR ^11a R ^11b, or Het ² ; R ¹⁸ denotes a 5-membered aromatic ring containing one, two or three N atoms; moreover, said 5-membered aromatic ring may be optionally substituted with one substituent selected from the group consisting of C _1-4 alkyl; Het ^1a , Het ^1c and Het ^1d each independently represent a 4-7 membered monocyclic saturated heterocyclic radical containing one or two heteroatoms, each independently selected from O and N; wherein said 4- to 7-membered monocyclic saturated heterocyclic radical may be optionally substituted, where possible, on one or two ring atoms with an N substituent, each independently selected from the group consisting of C _1-4 alkyl, C _3-6 cycloalkyl and C _1-4 alkyl substituted with one —O — C _1-4 alkyl; and wherein said 4-7 membered monocyclic saturated heterocyclic radical may be optionally substituted at one, two or three C ring atoms with one or two substituents, each independently selected from the group consisting of —OH, halogen, C _1-4 alkyl , —O — C _1-4 alkyl and —N (C _1-4 alkyl) ₂ ; Het ^1b , Het ^1e and Het ^1g each independently represent a 4-7 membered monocyclic saturated - 301 037358 heterocyclic radical attached to the rest of the molecule of the compound of formula (I) through any available ring carbon atom, wherein said Het ^1b , Het ^1e and Het ^1g contain one or two heteroatoms, each of which is independently selected from O and N; wherein said 4-7 membered monocyclic saturated heterocyclic radical is optionally substituted, where possible, on one or two ring atoms with an N substituent, each independently selected from the group consisting of C _1-4 alkyl and C _3-6 cycloalkyl; and wherein said 4-7 membered monocyclic saturated heterocyclic radical may optionally be substituted at one, two or three C ring atoms with one or two —OH groups; Het ² represents a heterocyclic radical of formula (b-1) (b-1); (b-1) is an N-linked 4-7 membered monocyclic saturated heterocyclic radical optionally containing one additional N atom, or an N-linked 6-11 membered bicyclic saturated heterocyclic radical including fused, spiro fused and bridged rings, optionally containing one or two additional N atoms; where in the case where (b-1) contains one or two additional N atoms, said one or two N atoms may optionally be substituted with C _1-4 alkyl; and where (b-1) may be optionally substituted on one, two or three C ring atoms with one or two substituents, each independently selected from the group consisting of —OH, cyano, and C _1-4 alkyl-OH; R ^11b is Het ^1e ; C1-4alkyl; C1-4alkyl-Het ⁵ ; C1-4alkyl substituted with one, two or three OH groups, or C3-6cycloalkyl substituted with one, two or three substituents, each independently selected from the group consisting of halogen and —OH; R ¹³ is —O — C1-4 alkyl, —C (= O) NR ^15a R ^15b , —NR ^19a R ^19b , C3-6 cycloalkyl, Het ^1d or —C (= O) —Het ^1f ; R ¹² is —OH, —O — C1-4 alkyl, —NR ^14a R ^14b , —C (= O) NR ^14c R ^14d , —S (= O) 2 — C _1-4 alkyl, C _3-6 cycloalkyl, Ar ² or Het ^1c ; Ar ¹ is phenyl; Ar ² is phenyl optionally substituted with one C _1-4 alkyl; Het ⁵ , Het ⁶ , Het ^1f each independently represent a heterocyclic radical of formula (c-1) (s-1); (c-1) is an N-linked 4-7 membered monocyclic saturated heterocyclic radical optionally containing one additional heteroatom selected from O and N; moreover, when (c-1) contains one additional N atom, said additional N atom may be optionally substituted with C _1-4 alkyl; R ^11a , R ^14a , R ^14c , R ^15a and R ^19a are each independently hydrogen or C _1-4 alkyl; R ^14b , R ^14d , R ^15b and R ^19b are each independently hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, or C _1-4 alkyl substituted with one —O — C _1-4 alkyl. 5. The compound according to claim 1 or 2, where Y denotes CR ⁴ ; R ⁴ is hydrogen; R ⁵ is —OR ⁷ ; R ⁷ is hydrogen or —C (= O) —R ⁹ ; R ⁹ is C _1-4 alkyl; R ³ is phenyl substituted with one, two or three substituents, each of which is independently selected from the group consisting of halogen, cyano; C1-6alkyl; -OC1-4alkyl; -C (= O) -R ¹⁰ ; -S (= O) 2-C _1-4 alkyl; -O-C _1-4 alkyl-K ¹² ; -O-C3-6cycloalkyl; -O-Het ^1b ; -NH-C (= O) -Het ^1g and C1-4 alkyl substituted with one R ¹³ ; R ¹⁰ is —NR ^11a R ^11b or Het ² ; Het ^1g denotes a 4-7 membered monocyclic saturated heterocyclic radical attached to the remainder of the molecule of compounds of formula (I) through any available ring carbon atom, said Het ^1g containing one or two N atoms; and where said 4-7 membered monocyclic saturated heterocyclic radical may be optionally substituted, where possible, at one or two ring atoms of NC with _1-4 alkyl; Het ^1b denotes a 4-7 membered monocyclic saturated heterocyclic radical attached to the remainder of the molecule of compounds of formula (I) through any available ring carbon atom, said Het ^1b containing one or two N atoms; and said 4-7 membered monocyclic saturated heterocyclic radical may be - 302 037358 optionally substituted, where possible, at one or two ring N atoms with C1-4 alkyl; and said 4-7 membered monocyclic saturated heterocyclic radical may optionally be substituted at one ring C atom by one halogen atom; Het ² represents a heterocyclic radical of formula (b-1) F-i); (b-1) is an N-linked 4-7 membered monocyclic saturated heterocyclic radical, wherein (b-1) may optionally be substituted at one C atom with one —OH group; R ^11b is C _1-4 alkyl; R ¹³ is —O — C _1-4 alkyl; R ¹² is —OC _1-4 alkyl and R ^11a is hydrogen. 6. The compound according to claim 1 or 2, where R ⁴ denotes hydrogen; R ⁵ is —OR ⁷ ; R ⁷ is hydrogen or —C (= O) —R ⁹ ; R ⁹ is C _1-4 alkyl; R ³ is phenyl substituted with one, two or three substituents, each of which is independently selected from the group consisting of halogen; cyano; C1-6alkyl; -OC1-4alkyl; -C (= O) -R ¹⁰ ; -S (= O) 2-C _1-4 alkyl; —O — C _1-4 alkyl — I ¹² ; -NH-C (= O) -Het ^1g and C _1-4 alkyl substituted with one R ¹³ ; R ¹⁰ is —NR ^11a R ^11b or Het ² ; Het ^1g denotes a 4-7 membered monocyclic saturated heterocyclic radical attached to the remainder of the molecule of a compound of formula (I) through any available ring carbon atom, said Het ^1g containing one or two N atoms; and said 4-7 membered monocyclic saturated heterocyclic radical may be optionally substituted, where possible, at one or two ring atoms of N C _{1-4 with} alkyl; Het ² represents a heterocyclic radical of formula (b-1) (b-1); (b-1) is an N-linked 4-7 membered monocyclic saturated heterocyclic radical, wherein (b-1) may optionally be substituted at one C atom with one —OH group; R ^11b is C _1-4 alkyl; R ¹³ is —O — C _1-4 alkyl, R ¹² is —O — C _1-4 alkyl and R ^11a is hydrogen. 7. The compound according to claim 1 or 2, where R ² means C _1-6 alkyl substituted with one R ⁵ ; R ⁴ is hydrogen; R ⁵ is -OR ⁷ ; R ⁷ is hydrogen and R ³ is phenyl substituted with one, two or three substituents, each of which is independently selected from the group consisting of halogen; cyano; and C _1-6 alkyl. 8. The compound according to any one of claims 1-6, where R ¹ denotes methyl; R ² is methyl or —CH ₂ —OH. 9. A compound according to any one of claims 1-4, wherein R ⁴ is hydrogen. 10. A compound according to any one of claims 1-6, wherein R ⁵ is —OR ⁷ and R ⁷ is hydrogen. 11. A compound according to claim 1 or 2, wherein Het ^1a , Het ^1c and Het ^1d are each independently a 4-7 membered monocyclic saturated heterocyclic radical containing one or two heteroatoms, each independently selected from O, S, S (= O) p and N; wherein said 4- to 7-membered monocyclic saturated heterocyclic radical may optionally be substituted, where possible, on one or two ring atoms with an N substituent, each independently selected from the group consisting of C _1-4 alkyl, C _3-6 cycloalkyl and C _1-4 alkyl substituted with one substituent selected from the group consisting of —OH and —O — C _1-4 alkyl; - 303 037358 and said 4-7 membered monocyclic saturated heterocyclic radical may optionally be substituted at one, two or three C ring atoms with one or two substituents, each independently selected from the group consisting of —OH, halogen, C1. ₄ alkyl, cyano, -C (= O) -C1. ₄ alkyl, —O — C _1-4 alkyl, —NH2, NH (C _1-4 alkyl) and —N (C _1-4 alkyl) ₂ . 12. A compound according to claim 1 or 2, wherein Het ² is a heterocyclic radical of formula (b-1) ....... Ν ^Ζ λ (b-1); (b-1) is an N-linked 4-7 membered monocyclic saturated heterocyclic radical optionally containing one additional heteroatom selected from O, S, S (= O) _p and N; moreover, when (b-1) contains one additional N atom, said N atom may be optionally substituted with C _1-4 alkyl; and wherein (b-1) may be optionally substituted on one, two or three C ring atoms with one or two substituents, each independently selected from the group consisting of halogen, —OH, cyano, C _1-4 alkyl, —O —C _1-4 alkyl, —NH2, —NH (C _1-4 alkyl), —N (C _1-4 alkyl) _2, and C _1-4 alkyl-OH. 13. A compound according to claim 1, wherein the compound is selected from - 304 037358 n he Ν --- k / ^ν ύ I oo '/ --- Υ ^χ \ ^ νη ₂ Γ ^s Η 0-¼ Ν' ρυ ⁰ ΥΥΥ \ ^R Τ ϊ ^Ν ά φ Η Ν - < ΎΎ ^rX Yy Cl Χυ Υγ ο Η n-Ar ^Ν Υ 1 Χ-Ύ ΥγΑγ / \ he Τ ιϊ ^{n χζ Ο} γ ^Ν \ У XX ^ ГГ NT ku ^ Η Η he Ν — Λ / ^Ν γ 1 Ίυγ γΥ-Ν kA ΓΓ κ _ΝΗ X? / -D Ο ^ ι | Υ 0 Η Ν - λ R ^Ν Υ / ΥΎ ^ Υγγ / χ he 1 Η η ΥΥ ° 4> / ^ν \ 0υψ η 1 Υ Η he chly Here Yy CN DD O ^ A Ο-Ν ^κ Trans A (RR or SS) - 305 037358 or a pharmaceutically acceptable salt or solvate thereof. 17. The compound is or a pharmaceutically acceptable salt or solvate thereof. 18. A pharmaceutical composition comprising a compound according to any one of claims 1-17 and a pharmaceutically acceptable carrier or diluent. 19. Use of a compound according to any one of claims 1-17 as a medicament for the treatment or prevention of diseases mediated by NF-KB-inducing kinase (NIK). 20. Use of a compound according to any one of claims 1 to 17 for the prevention or treatment of cancer. 21. Use according to claim 20, wherein the cancer is B cell neoplasia. 22. The use of claim 21, wherein the B cell neoplasia is selected from multiple myeloma, Hodgkin's lymphoma, mantle cell lymphoma, diffuse large B cell lymphoma, or chronic lymphocytic leukemia. 23. Use of a pharmaceutical composition according to claim 14 for the prevention or treatment of cancer. 24. Use of a compound according to any one of claims 14 to 17 for the treatment of a hematologic malignant neoplasm.